JP4589860B2 - Method for producing hydantosaidin derivatives - Google Patents

Description

  The present invention has the following formula having excellent herbicidal activity:

Of [2R, 3S, 4R, 5S] -2-hydroxymethyl-3,4-dihydroxy-1-oxa-6,8-diazaspiro [4,4] nonane-7,9-dione) The present invention relates to a novel production intermediate and production method.

  Hydantosaidin obtained as a metabolite of actinomycetes is known as a compound having a strong herbicidal and growth-inhibiting activity not only on monocotyledonous and dicotyledonous annual weeds but also on perennial weeds (Patent Document 1, Non-Patent Documents 1 and 2).

  Hydantosaidin is a compound that exhibits outstanding safety against animals, fish and microorganisms, and has environmentally desirable properties because it is rapidly degraded in soil and is useful as an excellent herbicide. It is.

In addition to the above, the methods of Patent Document 2 and Non-Patent Documents 3 to 8 are conventionally known as chemical methods for producing hydantosaidin.
JP 62-12789 A JP-A-2-85287 M. Nakajima et al., J. Antibiot., 44, 293 (1991) H. Haruyama et al., J. Chem. Soc. Perkin Trans. I., 1637 (1991) S. Mio et al., Tetrahedron 47, 2111 (1991) S. Mio et al., Tetrahedron 47, 2133 (1991) S. Mirza, DE 4,129,728A1 (1991) GWJ Fleet et al., Tetrahedron Lett., 34, 3327 (1993) S. Terashima et al., Tetrahedron Lett., 34, 6289 (1993) Philippe Chemla, Tetrahedron Lett., 34, 7391 (1993)

  When this hydantosaidin is produced industrially, it is difficult to carry out by fermentation from actinomycetes because the production amount is too small (Patent Document 1).

  Moreover, in order to industrially carry out the methods of Patent Document 2 and Non-Patent Documents 3 to 7, various difficult problems are involved.

  For example, in the methods of Patent Document 2 and Non-Patent Document 3, expensive tartaric acid or osmium tetroxide is used as a raw material or a reagent. In Non-Patent Document 4, an expensive reagent such as trimethylsilyl trifluoromethanesulfonic acid or trimethylsilyl azide is used. In Non-Patent Document 5, an expensive reagent such as trifluoromethanesulfonic anhydride or osmium tetroxide is used, and the yield of the target product is low. In Non-Patent Document 6, many expensive reagents including tetrapropyl pearlate, trifluoromethane sulfonic anhydride and the like are used. In addition, in the methods of Non-Patent Documents 5, 6 and 7, since the stereoisomer of the spiro part of hydantoside is preferentially obtained, the herbicidal activity is greatly inferior to that of hydantosaidin. is not.

  Many of the reactions in the method of Non-Patent Document 8 are reactions that can be used only at the laboratory level because the reagents are expensive and highly toxic. Actual production (industrial production) is impossible.

  As a result of intensive studies over many years on the industrial production method of hydantocydin, the present inventors have found that hydantosaidin is highly preferentially produced in a high yield compared to stereoisomers by a production method via a novel intermediate. The present invention was completed by finding that it can be manufactured inexpensively, easily and safely.

  The present invention relates to general formula (I)

[Wherein, R ¹ and R ² represent a hydrogen atom, or R ¹ and R ² together represent an alkylidene group which may be substituted, and R ³ and R ⁴ represent a hydrogen atom or R ³ and R ⁴ together represent an optionally substituted alkylidene group, R ⁵ and R ⁶ are the same or different and are each a hydrogen atom, a formula —COR ¹⁰ (where R ¹⁰ is a lower alkyl group, a lower alkoxy group, An aryl group, an aryloxy group, an aralkyloxy group, an amino group optionally substituted by 1 to 2 lower alkyls or a lower alkenyloxy group (provided that R ⁵ and R ⁶ are Both are excluding the case of a hydrogen atom) or the formula —SO ₂ R ¹¹ (R ¹¹ represents a lower alkyl group, an aryl group, or an amino group optionally substituted by 1 to 2 lower alkyls). Group,
Preferably, R ¹ and R ² together represent an alkylidene group, R ³ and R ⁴ together represent an alkylidene group, R ⁵ represents a hydrogen atom, and R ⁶ represents a formula- A group represented by COR ¹⁰ (R ¹⁰ represents a lower alkoxy group, an aryloxy group, an aralkyloxy group or a lower alkenyloxy group);
More preferably, R ¹ and R ² together represent an isopropylidene group, R ³ and R ⁴ together represent an isopropylidene group, R ⁵ represents a hydrogen atom, and R ⁶ Represents a group represented by the formula —COR ¹⁰ (R ¹⁰ represents a lower alkoxy group). And a salt thereof,
Formula (II)

[Wherein R ¹ and R ² represent a hydrogen atom, or R ¹ and R ² together represent an alkylidene group which may be substituted, R ⁶ represents a hydrogen atom, a formula —COR ¹⁰ (R ¹⁰ Represents a lower alkyl group, a lower alkoxy group, an aryl group, an aryloxy group, an aralkyloxy group, or an amino group or a lower alkenyloxy group which may be substituted with 1 to 2 lower alkyl groups. Or a group represented by the formula —SO ₂ R ¹¹ (R ¹¹ represents a lower alkyl group, an aryl group, or an amino group optionally substituted by 1 to 2 lower alkyls), and R ⁷ represents a formula a group represented by -CH ₂ OH, formyl group, carboxyl group, lower alkoxycarbonyl group, or the formula CONHR ¹⁴ {R ¹⁴ is a hydrogen atom, a lower alkyl group, phenyl or aralkyl group (said phenyl group and aralkyl group Halogen atom, a may also be) substituted with a lower alkoxy group or a nitro group. } Represents a group represented by
Preferably, in the formula, R ¹ and R ² together represent an alkylidene group, R ⁶ represents a hydrogen atom or a formula —COR ¹⁰ (where R ¹⁰ represents a lower alkoxy group, an aryloxy group, an aralkyloxy group or a lower alkenyl group). a group represented by an oxy group.), R ⁷ represents a group represented a group represented by the formula -CH ₂ OH, a formyl group, a carboxyl group, or the formula CONH _2,
More preferably, in the formula, R ¹ and R ² together represent an isopropylidene group, R ⁶ represents a hydrogen atom or a group represented by the formula —COR ¹⁰ (R ¹⁰ represents a lower alkoxy group). R ⁷ represents a group represented by the formula —CH ₂ OH, a formyl group, a carboxyl group or a group represented by the formula CONH ₂ ;
More preferably, in the formula, R ¹ and R ² together represent an isopropylidene group, and R ⁶ represents a group represented by the formula —COR ¹⁰ (R ¹⁰ represents a lower alkoxy group). , R ⁷ represents a group represented by the formula —CH ₂ OH, a formyl group, a carboxyl group or a group represented by the formula CONH ₂ . And a salt thereof, and
Formula (III)

[Wherein R ¹ and R ² represent a hydrogen atom, or R ¹ and R ² together represent an alkylidene group which may be substituted,
Preferably, in the formula, R ¹ and R ² together represent an isopropylidene group. And a salt thereof, and
Formula (IV)

[Wherein R ¹ and R ² represent a hydrogen atom, or R ¹ and R ² together represent an alkylidene group which may be substituted,
Preferably, in the formula, R ¹ and R ² represent a hydrogen atom, or R ¹ and R ² together represent an isopropylidene group. The compound represented by the general formula (V) is characterized by hydrogenation using a Raney catalyst, preferably in the presence of an acid, more preferably in the presence of acetic acid.

[Wherein, R ¹ and R ² are as defined above. A process for producing a compound represented by
Formula (VI)

[Wherein, X represents a leaving group, R ¹ and R ² represent a hydrogen atom, or R ¹ and R ² together represent an alkylidene group which may be substituted, and R ³ and R 2 ⁴ represents a hydrogen atom or an alkylidene group in which R ³ and R ⁴ may be substituted together;
Preferably, in the formula, X represents a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a chlorine atom, a bromine atom or an iodine atom, R ¹ and R ² together represent an alkylidene group, and R ³ And R ⁴ together represent an alkylidene group,
More preferably, in the formula, X represents a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a chlorine atom, a bromine atom or an iodine atom, R ¹ and R ² together represent an isopropylidene group, R ³ and R ⁴ together represent an isopropylidene group. A compound represented by the general formula HONR ⁵ R ⁶ , wherein R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, a formula —COR ¹⁰ (R ¹⁰ is a lower alkyl group, a lower alkoxy group, an aryl group, An aryloxy group, an aralkyloxy group, a group represented by an amino group or a lower alkenyloxy group optionally substituted by 1 to 2 lower alkyls) or a formula —SO ₂ R ¹¹ (R ¹¹ is a lower group) An alkyl group, an aryl group or an amino group which may be substituted with 1 to 2 lower alkyls.), Preferably R ⁵ represents a hydrogen atom, R ⁶ Represents a group represented by the formula —COR ¹⁰ (R ¹⁰ represents a lower alkoxy group, an aryloxy group, an aralkyloxy group or a lower alkenyloxy group);
More preferably, in the formula, R ⁵ represents a hydrogen atom, and R ⁶ represents a group represented by the formula —COR ¹⁰ (R ¹⁰ represents a lower alkoxy group). Wherein the compound represented by the general formula (I) is reacted:

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ have the same meaning as described above. A process for producing a compound represented by
Formula (I)

[Wherein, R ¹ and R ² represent a hydrogen atom, or R ¹ and R ² together represent an alkylidene group which may be substituted, and R ³ and R ⁴ represent a hydrogen atom or R ³ and R ⁴ together represent an optionally substituted alkylidene group, R ⁵ and R ⁶ are the same or different and are each a hydrogen atom, a formula —COR ¹⁰ (where R ¹⁰ is a lower alkyl group, a lower alkoxy group, An aryl group, an aryloxy group, an aralkyloxy group, an amino group or a lower alkenyloxy group optionally substituted with 1 to 2 lower alkyls) or a group represented by the formula —SO ₂ R ¹¹ (R ¹¹ represents a lower alkyl group, an aryl group, or an amino group optionally substituted by 1 to 2 lower alkyls.)
Preferably, R ¹ and R ² together represent an alkylidene group, R ³ and R ⁴ together represent an alkylidene group, R ⁵ represents a hydrogen atom, and R ⁶ represents a formula- A group represented by COR ¹⁰ (R ¹⁰ represents a lower alkoxy group, an aryloxy group, an aralkyloxy group or a lower alkenyloxy group);
More preferably, R ¹ and R ² together represent an isopropylidene group, R ³ and R ⁴ together represent an isopropylidene group, R ⁵ represents a hydrogen atom, and R ⁶ Represents a group represented by the formula —COR ¹⁰ (R ¹⁰ represents a lower alkoxy group). In the presence of an acid catalyst, preferably in the presence of a sulfonic acid or mineral acid as a catalyst, more preferably in the presence of sulfuric acid or methanesulfonic acid as a catalyst, Formula (IIa)

[Wherein R ¹ , R ² and R ⁶ are as defined above. A process for producing a compound represented by
Formula (IIc)

[Wherein R ¹ and R ² represent a hydrogen atom, or R ¹ and R ² together represent an alkylidene group which may be substituted, R ⁶ represents a formula —COR ¹⁰ (R ¹⁰ represents a lower alkoxy group) A group, an aryloxy group, an aralkyloxy group, an amino group optionally substituted by 1 to 2 lower alkyl groups or a lower alkenyloxy group), and R ¹⁴ represents a hydrogen atom. ,
Preferably, in the formula, R ¹ and R ² together represent an alkylidene group, R ⁶ represents a formula —COR ¹⁰ (R ¹⁰ represents a lower alkoxy group, an aryloxy group, an aralkyloxy group or a lower alkenyloxy group. R ¹⁴ represents a hydrogen atom,
More preferably, in the formula, R ¹ and R ² together represent an isopropylidene group, R ⁶ represents a group represented by the formula —COR ¹⁰ (R ¹⁰ represents a lower alkoxy group), R ¹⁴ represents a hydrogen atom. In the presence of a solvent, preferably an alkali metal or alkaline earth metal hydroxide or a lower alcohol alkali metal salt, more preferably sodium hydroxide or potassium hydroxide. In general formula (IV), characterized in that

[Wherein, R ¹ and R ² are as defined above. A process for producing a compound represented by
Formula (IIb)

[Wherein R ¹ and R ² represent a hydrogen atom, or R ¹ and R ² together represent an alkylidene group which may be substituted, R ⁶ represents a formula —COR ¹⁰ (R ¹⁰ represents a lower alkoxy group) A group, an aryloxy group, an aralkyloxy group, an amino group optionally substituted with 1 to 2 lower alkyls, or a lower alkenyloxy group).
Preferably, in the formula, R ¹ and R ² together represent an alkylidene group, R ⁶ represents a formula —COR ¹⁰ (R ¹⁰ represents a lower alkoxy group, an aryloxy group, an aralkyloxy group or a lower alkenyloxy group. A group represented by:
More preferably, in the formula, R ¹ and R ² together represent an isopropylidene group, and R ⁶ represents a group represented by the formula —COR ¹⁰ (R ¹⁰ represents a lower alkoxy group). The compound represented by the general formula (III) is characterized by treating with ammonia in the presence of a solvent:

[Wherein, R ¹ and R ² are as defined above. And a method for producing a compound represented by
Formula (III)

[Wherein R ¹ and R ² represent a hydrogen atom, or R ¹ and R ² together represent an alkylidene group which may be substituted,
Preferably, in the formula, R ¹ and R ² together represent an alkylidene group,
More preferably, R ¹ and R ² together represent an isopropylidene group. ], Preferably oxidized with hypochlorites, chromic acid or chromate, more preferably oxidized with chromate. IV)

[Wherein, R ¹ and R ² are as defined above. ] The manufacturing method of the compound represented by this.

In R ¹ , R ² , R ³ and R ⁴ , “optionally substituted alkylidene group” means methylidene, ethylidene, n-propylidene, isopropylidene, n-butylidene, isobutylidene, s-butylidene, t-butylidene. N-pentylidene, isopentylidene, 2-methylbutylidene, neopentylidene, 1-ethylpropylidene, n-hexylidene, 1-t-butylethylidene, 1-phenylethylidene, 2,2,2-trichloroethylidene A straight or branched alkylidene group having 1 to 6 carbon atoms, a cyclic alkylidene group such as cyclopentylidene, cyclohexylidene, cycloheptylidene, benzylidene, 4-methoxybenzylidene, 2,4-dimethoxybenzylidene 3,4-dimethoxybenzylidene, 2-nitrobenzylidene And aromatic substituted alkylidene groups such as α-methoxybenzylidene and alkoxy-substituted alkylidene groups such as methoxymethylene, ethoxymethylene, 1-methoxyethylidene and 1-ethoxyethylidene, preferably having 1 to 4 carbon atoms A linear or branched alkylidene group, a cyclic alkylidene group, or an aromatic substituted alkylidene group, more preferably methylidene, ethylidene, isopropylidene, n-butylidene, cyclopentylidene, cyclohexylidene, benzylidene, most An isopropylidene group is preferred.

In R ¹⁰ , R ¹¹ and R ¹⁴ , the “lower alkyl group” means, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1 , 1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl and the like are straight or branched alkyl groups having 1 to 6 carbon atoms , Preferably a methyl or ethyl group, and most preferably a methyl group.

In R ¹⁰ and R ¹⁴ , “lower alkoxy group” means, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, s-butoxy, t-butoxy, n-pentoxy, isopentoxy, 2- Methylbutoxy, neopentoxy, n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1 , 2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy and the like, wherein the “lower alkyl group” is bonded to an oxygen atom, that is, straight or branched having 1 to 6 carbon atoms A straight chain or branched chain alkoxy group having 1 to 4 carbon atoms, and more preferably a methacrylic group. A sheet or ethoxy, most preferably ethoxy.

In R ¹⁰ and R ¹¹ , the “aryl group” is an aromatic hydrocarbon group having 5 to 14 carbon atoms such as phenyl, indenyl, naphthyl, phenanthrenyl, anthracenyl, and preferably a phenyl group. .

  The aryl group may have 1 to 3 substituents on the aryl ring. Examples of the substituent include the “lower alkyl group”, the “lower alkoxy group”, “Halogen atom” can be mentioned, preferably a lower alkyl group, and most preferably an aryl group having such a substituent is a p-toluyl group.

In R ¹⁰ , the “aryloxy group” refers to a group in which an oxygen atom is bonded to the “aryl group” such as phenyloxy, indenyloxy, naphthyloxy, phenanthrenyloxy, anthracenyloxy, and the like. That is, it is an aromatic hydrocarbon oxy group having 5 to 14 carbon atoms, preferably a phenyloxy group.

  The aryloxy group may have the same substituent as the above “aryl group”.

In R ¹⁴ , the “aralkyl group” is a group in which the “aryl group” is substituted on the “lower alkyl group” such as benzyl group, phenethyl group, α, α-dimethylbenzyl group, and the like. Is a benzyl group.

In R ¹⁰ , the “aralkyloxy group” is a group in which an oxygen atom is bonded to the “aralkyl group”, such as benzyloxy group, phenethyloxy group, α, α-dimethylbenzyloxy, and the like. Is a benzyloxy group.

In R ¹⁰ and R ¹¹ , the “amino group optionally substituted by 1 to 2 lower alkyls” means an unsubstituted amino group or an amino group substituted by 1 to 2 of the above “lower alkyl groups” And preferably an unsubstituted amino group or a dimethylamino group.

In R ¹⁰ , the “lower alkenyloxy group” means a straight chain having 2 to 6 carbon atoms such as vinyloxy, allyloxy, 2-butenyloxy, 3-methyl-2-butenyloxy, 2-methyl-2-butenyloxy, etc. Or a branched alkenyloxy group, and preferably an allyloxy group.

In R ⁷ , the “lower alkoxycarbonyl group” is a group in which the “lower alkoxy group” is bonded to a carbonyl group, such as a methoxycarbonyl group, an ethoxycarbonyl group, or a t-butoxycarbonyl group. Is a methoxycarbonyl group.

In the definition of R ¹⁴ , the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a chlorine atom.

In R ¹⁴ , the “phenyl group optionally substituted with a halogen atom, lower alkoxy group or nitro group” means an unsubstituted phenyl group or, for example, 4-methoxyphenyl, 2,4-dimethoxyphenyl, 3,4 -A phenyl group in which 1 to 3 of the “halogen atom”, the “lower alkoxy group” or the nitro group are substituted, such as dimethoxyphenyl, 4-chlorophenyl, 4-nitrophenyl, and preferably an unsubstituted phenyl group It is.

In R ¹⁴ , the “aralkyl group optionally substituted with a halogen atom, lower alkoxy group or nitro group” means the above-mentioned “aralkyl group” which is unsubstituted or, for example, 4-methoxybenzyl, 2,4-dimethoxybenzyl , 3,4-dimethoxybenzyl, 4-chlorobenzyl, 4-nitrobenzyl and the like, the “halogen atom”, the “lower alkoxy group” or an aralkyl group substituted with 1 to 3 nitro groups, Is a p-methoxybenzyl group.

  Compounds (I), (II) and (III) of the present invention can be converted to salts. Such salts include alkali metal salts such as sodium salts and potassium salts, metal salts such as alkaline earth metal salts such as calcium salts and magnesium salts, and guanidine salts, triethylamine salts and dicyclohexylamine salts. An organic base, preferably an alkali metal salt, and most preferably a sodium salt.

  Compounds (I), (II) and (III) of the present invention have asymmetric carbons in the molecule, and there are stereoisomers each having S-coordination and R-coordination. Any of those mixtures can be included in the present invention.

In the above, R ¹ and R ² are preferably alkylidene groups that may be substituted together with R ¹ and R ² , and more preferably alkylidene groups together with R ¹ and R ^2. Most preferably, R ¹ and R ² together are an isopropylidene group.

R ³ and R ⁴ are preferably alkylidene groups that may be substituted together with R ³ and R ⁴ , and more preferably R ³ and R ⁴ together are an alkylidene group; Most preferably, R ³ and R ⁴ together are an isopropylidene group.

R ⁵ is preferably a hydrogen atom.

R ⁶ is preferably a hydrogen atom or a group represented by the formula —COR ¹⁰ , and more preferably a group represented by the formula —COR ¹⁰ .

R ¹⁰ is preferably a lower alkoxy group, an aryloxy group, an aralkyloxy group or a lower alkenyloxy group, more preferably a lower alkoxy group, still more preferably a methoxy group or an ethoxy group. .

R ⁷ is preferably a group represented by the formula —CH ₂ OH, a formyl group, a carboxyl group, or a group represented by the formula —CONH ₂ .

  Below, the manufacturing method of hydantosaidin is shown.

[In the above formula, X represents a leaving group, and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹⁴ have the same meaning as described above. ]
In the above, the leaving group in the definition of X is not particularly limited as long as it is usually a group leaving as a nucleophilic residue, but preferably a halogen atom such as a chlorine atom, a bromine atom or an iodine atom. A lower alkanesulfonyloxy group such as methanesulfonyloxy and ethanesulfonyloxy; a halogeno lower alkanesulfonyloxy group such as trifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy; an ant such as benzenesulfonyloxy and p-toluenesulfonyloxy; -Lusulfonyloxy group, more preferably methanesulfonyloxy group, p-toluenesulfonyloxy group, chlorine atom, bromine atom and iodine atom.

  Next, each step will be described in more detail.

In the following steps and reactions, a hydroxyl protecting group (including R ¹ , R ² , R ³ and R ⁴ ) and a nitrogen atom protecting group (including R ⁵ , R ⁶ and R ¹⁴ ) As long as the reaction is not hindered, protection and deprotection can be performed as appropriate. That is, the protecting group can be converted, and can be used for each reaction in a protected state or in an unprotected state.

  Such hydroxyl and nitrogen protecting groups and methods of protection and deprotection can be selected and performed according to the description of TW Green, “Protective groups in Organic Synthesis” A Wiley-Interscience Publication, New York, 1981. it can.

(Process A)
This step is a step of producing a compound represented by the general formula (VI) using fructose as a starting material. Below, this process is shown in more detail.

[Wherein R ²⁰ and R ²¹ represent an alkylidene group which may be substituted, and X, R ¹ , R ² , R ³ and R ⁴ have the same meaning as described above. Steps A-1, A-2, A-3 and A-4 are carried out by known methods, for example, the method described in JG Moffatt et. Al., J. Org. Chem., 41 , 1836 (1976). It can be done according to this.

  Step A-5 is a step of producing a compound represented by the general formula (VI) from the compound represented by the general formula (X) obtained in the steps A-1 to A-4.

In this step, a leaving group is produced according to the method described in JG Moffatt et. Al., J. Org. Chem., 41 , 1836 (1976) or from a hydroxyl group known so far. It can be produced according to the usual methods.

(Process B)
This step is a step of producing a compound represented by the general formula (I) having an N—O bond from a compound represented by the general formula (VI).

By reacting with a compound represented by the general formula HONR ⁵ R ⁶ (where R ⁵ and R ⁶ are as defined above) using a base in the presence of a solvent, X is substituted, and the compound (I ) Is manufactured.

The compound represented by the general formula HONR ⁵ R ⁶ is preferably a compound in which R ⁵ is a hydrogen atom and R ⁶ is a lower alkoxycarbonyl group.

  Bases used are alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, lower alcohols such as sodium methoxide, sodium ethoxide, potassium t-butoxide. Alkali metal salts of, alkali metal hydrides such as sodium hydride and potassium hydride, alkali metals such as sodium and potassium, alkali metal amides such as sodium (bistrimethylsilyl) amide, lithium diisopropylamide, potassium carbonate, Alkali metal carbonates such as sodium carbonate, preferably alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium methoxide, sodium ethoxide, Potassium-t- Lower alkali metal salts, sodium hydride alcohols such as Tokishido, alkali metal hydride, sodium such as potassium hydride, an alkali metal such as potassium. The base is used in an amount of 1 to 10 equivalents based on the raw material.

  The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Preferably, lower alcohols such as methanol, ethanol, isopropanol, t-butyl alcohol, Aromatic hydrocarbons such as benzene, toluene and xylene, ketones such as acetone and methyl ethyl ketone, nitriles such as acetonitrile, ethers such as tetrahydrofuran, 1,4-dioxane, ether and dimethoxyethane, ethyl acetate , Esters such as butyl acetate, polar solvents such as dimethyl sulfoxide and dimethylformamide, and halogenated hydrocarbons such as methylene chloride and dichloroethane, and more preferably methanol, ethanol, isopropanol, t-butyl alcohol Like low Alcohols, tetrahydrofuran, 1,4-dioxane, ethers such as ether and dimethoxyethane, dimethyl sulfoxide, a polar solvent such as dimethylformamide.

  The reaction temperature is generally -50 ° C to 200 ° C, preferably 0 ° C to 150 ° C.

  The reaction time varies depending mainly on the reaction temperature, the raw material compound, the reaction reagent or the type of solvent used, but is usually 1 hour to 120 hours.

In the general formula (I), R ⁵ is a hydrogen atom, and R ⁶ is a formula —COR ¹⁰ (R ¹⁰ is as defined above) or a formula —SO ₂ R ¹¹ (R ¹¹ is as defined above). The compound represented by formula (1) is a compound in which R ⁵ and R ⁶ are both hydrogen atoms in compound (I) (a known compound described in Philippe Chemla, Tetrahedron Lett., 34 , 7391 (1993)) and acylation It can also be produced by reacting an agent or a sulfonylating agent in a suitable solvent in the presence of a base.

  The acylating agents used are acid halides such as acetyl chloride, propionyl chloride and benzoyl chloride, acid anhydrides such as acetic anhydride, propionic anhydride and benzoic anhydride, methyl chlorocarbonate, ethyl chlorocarbonate, chloro Carbonic acid esters such as phenyl carbonate, benzyl chlorocarbonate, isobutyl chlorocarbonate, dimethyl carbonate, carbamic acid halides such as dimethylcarbamic acid chloride and diethylcarbamic acid chloride, and isocyanates such as methyl isocyanate and trimethylsilyl isocyanate.

  The sulfonylating agents used are sulfonyl chlorides such as methanesulfonyl chloride and paratoluenesulfonyl chloride, anhydrous methanesulfonic acid, sulfonic anhydrides such as benzenesulfonyl anhydride, amino acids such as dimethylaminosulfonyl chloride, diethylaminosulfonyl chloride. Sulfonyl chlorides.

  Bases used are alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, lower alcohols such as sodium methoxide, sodium ethoxide, potassium t-butoxide. Alkali metal salts of, alkali metal hydrides such as sodium hydride and potassium hydride, alkali metals such as sodium and potassium, alkali metal amides such as sodium (bistrimethylsilyl) amide, lithium diisopropylamide, potassium carbonate, Alkali metal carbonates such as sodium carbonate, tri-lower alkyl amines such as triethylamine and diisopropylamine, heteroaromatic tertiary amines such as pyridine, N, N-dimethylaminopyridine, DBU, DBN, DABCO Cycloaliphatic amines, aromatic amines such as N, N-dimethylaniline and N, N-diethylaniline, preferably tri-lower alkylamines such as triethylamine and diisopropylamine, pyridine, N , N-dimethylaminopyridine and other heteroaromatic tertiary amines.

  The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably an aromatic hydrocarbon such as benzene, toluene, xylene, acetone, methyl ethyl ketone. Ketones such as acetonitrile, nitriles such as acetonitrile, ethers such as tetrahydrofuran, 1,4-dioxane, ether, dimethoxyethane, esters such as ethyl acetate and butyl acetate, dimethyl sulfoxide, dimethylformamide, etc. Polar solvents, halogenated hydrocarbons such as methylene chloride and dichloroethane, more preferably halogenated hydrocarbons such as methylene chloride and dichloroethane, and esters such as ethyl acetate and butyl acetate.

  The reaction temperature is generally -60 ° C to 160 ° C, preferably 0 ° C to 100 ° C.

  The reaction time varies depending mainly on the reaction temperature, the raw material compound, the reaction reagent, or the type of solvent used, but is usually 0.6 to 24 hours.

(Process C)
This step is a step of producing a bicyclic compound (IIa) by reacting in a solvent in the presence of an acid catalyst using the compound represented by the general formula (I) produced in Step B as a raw material.

In compound (I) as a raw material, R ⁵ is preferably a hydrogen atom.

  Acid catalysts used include sulfonic acids such as methanesulfonic acid, paratoluenesulfonic acid and camphorsulfonic acid, carboxylic acids such as formic acid, acetic acid, propionic acid, benzoic acid and trifluoroacetic acid, hydrochloric acid, sulfuric acid, peroxysulfonic acid. Mineral acids such as chloric acid, Lewis acids such as aluminum chloride and zinc chloride, phosphoric acids, etc., preferably sulfonic acids such as methanesulfonic acid, paratoluenesulfonic acid, camphorsulfonic acid, hydrochloric acid, sulfuric acid Mineral acids such as perchloric acid, and more preferably sulfuric acid and methanesulfonic acid. The acid catalyst is used in an amount of 0.001 to 100 equivalents, preferably 0.1 to 50 equivalents, relative to the raw material.

  The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably, aliphatic hydrocarbons such as hexane and pentane, benzene, toluene, xylene Aromatic hydrocarbons such as acetone, ketones such as methyl ethyl ketone, nitriles such as acetonitrile, ethers such as tetrahydrofuran, 1,4-dioxane, ether, dimethoxyethane, ethyl acetate, butyl acetate, etc. Esters, polar solvents such as dimethyl sulfoxide and dimethylformamide, halogenated hydrocarbons such as methylene chloride and dichloroethane, more preferably halogenated hydrocarbons such as methylene chloride and dichloroethane, ethyl acetate Esters of butyl acetate, acetonitrile A UNA nitrites.

  The reaction temperature is usually −50 ° C. to 150 ° C., preferably 0 ° C. to 50 ° C.

  The reaction time varies depending mainly on the reaction temperature, the raw material compound, the reaction reagent or the type of solvent used, but is usually 0.5 to 24 hours.

This reaction is convenient because when R ³ and R ⁴ in the starting compound (I) represent an alkylidene group which may be substituted, deprotection and cyclization can be carried out simultaneously. is there.

  Furthermore, compound (IIa) can also be produced via a tricyclic compound having an oxazolidinone ring.

  Step C-2 can be performed according to Step C using the above acid catalyst.

  Step C-3 is a step of opening the oxazolidinone ring using an alkali in the presence of a solvent.

  The alkali used is an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide or calcium hydroxide, a lower alcohol such as sodium methoxide, sodium ethoxide or potassium tert-butoxide. Alkali metal salts, preferably sodium hydroxide and potassium hydroxide.

  The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but water and a mixed solvent thereof can be used. Include alcohols such as methanol, ethanol and propanol, ketones such as acetone and methyl ethyl ketone, nitriles such as acetonitrile, ethers such as tetrahydrofuran, 1,4-dioxane, ether and dimethoxyethane, ethyl acetate , Esters such as butyl acetate, polar solvents such as dimethyl sulfoxide, dimethylformamide, and more preferably alcohols such as methanol, ethanol, propanol, tetrahydrofuran, 1,4-dioxane, ether, dimethoxyethane Like ethers , More preferably more, methanol, tetrahydrofuran.

  The reaction temperature is generally -50 ° C to 150 ° C, preferably 0 ° C to 100 ° C.

  The reaction time varies depending mainly on the reaction temperature, the raw material compound, the reaction reagent or the type of solvent used, but is usually 0.5 to 24 hours.

In the general formula (IIa), when R ⁶ is a hydrogen atom, by reacting it with an acylating agent or sulfonylating agent in a suitable solvent in the presence or absence of a base, R ⁶ is further reduced. A compound which is —COR ¹⁰ or —SO ₂ R ¹¹ (R ¹⁰ and R ¹¹ are as defined above) can be produced.

  The acylating agent used is preferably an acid halide such as acetyl chloride, propionyl chloride or benzoyl chloride, an acid anhydride such as acetic anhydride, propionic anhydride or benzoic anhydride, methyl chlorocarbonate, Carbonates such as ethyl chlorocarbonate, phenyl chlorocarbonate, benzyl chlorocarbonate, isobutyl chlorocarbonate, dimethyl carbonate, carbamic acid halides such as dimethylcarbamic acid chloride, diethylcarbamic acid chloride, methyl isocyanate, trimethylsilyl isocyanate, etc. Isocyanates.

  Preferred examples of the sulfonylating agent used include sulfonyl chlorides such as methanesulfonyl chloride and p-toluenesulfonyl chloride, anhydrous sulfonic acids such as methanesulfonic anhydride and benzenesulfonyl anhydride, dimethylaminosulfonyl chloride, diethylaminosulfonyl Aminosulfonyl chlorides such as chloride.

  Bases used include alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide, lower methoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide. Alkali metal salts of alcohol, alkali metal hydrides such as sodium hydride and potassium hydride, alkali metals such as sodium and potassium, alkali metal amides such as sodium (bistrimethylsilyl) amide and lithium diisopropylamide, potassium carbonate Alkali metal carbonates such as sodium carbonate, tri-lower alkylamines such as triethylamine and diisopropylamine, heteroaromatic tertiary amines such as pyridine and N, N-dimethylaminopyridine, DBU, DBN, DABCO Alicyclic amines such as N, N-dimethylaniline and aromatic amines such as N, N-diethylaniline, preferably tri-lower alkylamines such as triethylamine and diisopropylamine, pyridine , Heteroaromatic tertiary amines such as N, N-dimethylaminopyridine.

  The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably, aliphatic hydrocarbons such as hexane and pentane, benzene, toluene, xylene Aromatic hydrocarbons such as acetone, ketones such as methyl ethyl ketone, nitriles such as acetonitrile, ethers such as tetrahydrofuran, 1,4-dioxane, ether, dimethoxyethane, ethyl acetate, butyl acetate, etc. Esters, polar solvents such as dimethyl sulfoxide and dimethylformamide, halogenated hydrocarbons such as methylene chloride and dichloroethane, more preferably nitriles such as acetonitrile, tetrahydrofuran, 1,4-dioxane, Ether, ether like dimethoxyethane It is.

  The reaction temperature is usually −50 ° C. to 150 ° C., preferably 0 ° C. to 50 ° C.

  The reaction time varies depending mainly on the reaction temperature, the raw material compound, the reaction reagent or the type of solvent used, but is usually 0.5 to 24 hours.

(Process D)
This step is a step of producing a compound represented by the general formula (IIb) by oxidizing the primary hydroxyl group of the compound represented by the general formula (IIa) produced in the step C to an aldehyde.

  The oxidizing agent used is not particularly limited as long as it is a relatively mild oxidizing agent capable of oxidizing a primary hydroxyl group to an aldehyde, but preferably a reagent (dimethyldimethylsulfoxide oxidation (DMSO oxidation)) used for dimethylsulfoxide oxidation. For sulfoxide, dicyclohexylamide, oxalyl chloride, phosgene, chloroformate, acetic anhydride, phosphorus pentoxide, pyridine-sulfuric anhydride complex, methyl sulfide and N-chlorosuccinimide, chlorine and other chlorinating agents Of the resulting sulfonium salt), chromate such as chromic acid, oxygen in the presence of a metal catalyst such as platinum, permanganates such as potassium permanganate, sodium hypochlorite, t-butyl hypochlorite Hypochlorous acid compounds such as peroxysulfates such as oxone, ruthenium tetroxide and Ruthenium salts capable of generating it in situ, oxo ammonium salts consisting of sodium hypochlorite and TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy free radical). The equivalent of the oxidizing agent varies greatly depending on the conditions used. For example, in the case of DMSO oxidation, 1 to 5 equivalents of oxalyl chloride and 1 to 10 equivalents of DMSO are used.

  The reaction is carried out in the presence of a solvent. The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably an aromatic hydrocarbon such as benzene, toluene, xylene, methylene chloride, Halogenated hydrocarbons such as chloroform and dichloroethane, esters such as ethyl acetate and butyl acetate, ethers, tetrahydrofuran, 1,4-dioxane, ethers such as dimethoxyethane, nitriles such as acetonitrile, acetone, Ketones such as methyl ethyl ketone.

  The reaction temperature is usually −70 ° C. to 150 ° C., preferably −60 ° C. to 50 ° C.

  The reaction time varies depending mainly on the reaction temperature, the raw material compound, the reaction reagent or the type of solvent used, but is usually 0.5 to 24 hours.

(Process E)
This step is a step of producing the compound represented by the general formula (IIc) by oxidizing the aldehyde group of the compound represented by the general formula (IIb) to a carboxylic acid or ester and then amidating it.

The raw material for this step is preferably a compound in which R ⁶ is —COR ¹⁰ or —SO ₂ R ¹¹ (R ¹⁰ and R ¹¹ are as defined above), and more preferably R ⁶ is —COR ^10. It is a compound which is.

  The oxidizing agent used in the oxidation reaction is not particularly limited as long as it is an oxidizing agent capable of oxidizing aldehyde to carboxylic acid, but preferably oxygen in the presence of silver oxide, copper oxide, copper acetate or nickel acetate. Oxygen in the presence of a metal catalyst such as platinum, chromate such as chromic acid, silver salts such as silver nitrate, silver oxide, chlorite such as sodium chlorite, and peroxygen such as potassium permanganate. Manganates, ruthenium tetroxide and ruthenium salts capable of generating them in the reaction system, a combination of sodium hypochlorite and TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy free radical) An oxoammonium salt comprising nickel oxide, more preferably oxygen in the presence of silver oxide, copper oxide, copper acetate or nickel acetate, metal contacts such as platinum. Oxygen in the presence, chlorites such as sodium chlorite, ruthenium tetroxide and ruthenium salts capable of generating it in the reaction system, sodium hypochlorite and TEMPO (2,2,6,6-tetramethyl -1 -piperidinyloxy free radical), and more preferably sodium chlorite. The oxidizing agent is used in an amount of 1 to 10 equivalents with respect to the raw material.

  The reaction is carried out in the presence or absence of a solvent. The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably a tertiary alcohol such as t-butyl alcohol, benzene, toluene, xylene. Aromatic hydrocarbons such as acetone, ketones such as methyl ethyl ketone, nitriles such as acetonitrile, ethers such as tetrahydrofuran, 1,4-dioxane, ether, dimethoxyethane, ethyl acetate, butyl acetate, etc. Esters, polar solvents such as dimethyl sulfoxide and dimethylformamide, halogenated hydrocarbons such as methylene chloride and dichloroethane, water, more preferably tertiary alcohols such as t-butyl alcohol, acetonitrile Nitriles such as tetrahydrofuran, 1,4-dioxy Emissions, ethers such as ether and dimethoxyethane, and water, more preferably a 1,4-dioxane, t- butyl alcohol and water.

  The reaction temperature is usually −20 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C.

  The reaction time varies depending mainly on the reaction temperature, the raw material compound, the reaction reagent or the type of solvent used, but is usually 0.5 to 24 hours.

  Esters can be obtained by treating the carboxylic acid produced by oxidizing the aldehyde by the above method with the corresponding alcohol and acid.

  The carboxylic acid or ester obtained as described above is converted to amide (IIc) by reacting with ammonia.

  Ammonia used in this reaction is ammonia or ammonia gas dissolved in a solvent such as ethers, nitriles, alcohols, and water, and is preferably ammonia gas.

  In this reaction, it is desirable to react ammonia directly with an ester or activate a carboxylic acid before reacting ammonia.

  Such activation methods include treatment with chlorocarbonates such as methyl chlorocarbonate and ethyl chlorocarbonate in the presence of a base such as triethylamine to form an acid anhydride, thionyl chloride, phosphorus oxychloride. And the like, a method of treating with 1-methyl-2-chloropyridinium iodide, a method of treating with phosphate esters such as diethyl phosphate cyanide, etc., preferably thionyl chloride This is a method of treating with phosphorus oxychloride or the like to obtain an acid halide.

  The reaction is carried out in the presence or absence of a solvent. The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably, aliphatic hydrocarbons such as hexane and pentane, benzene, toluene, xylene Aromatic hydrocarbons such as, halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane, esters such as ethyl acetate, butyl acetate, ethers, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, etc. Ethers, nitriles such as acetonitrile, ketones such as acetone and methyl ethyl ketone, more preferably halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane, esters such as ethyl acetate and butyl acetate More preferably, it is a halogenated hydrocarbon

  The reaction temperature is usually −50 ° C. to 150 ° C., preferably 0 ° C. to 50 ° C.

  The reaction time varies depending mainly on the reaction temperature, the raw material compound, the reaction reagent or the type of solvent used, but is usually 0.5 to 24 hours.

(Process F)
In this step, among the compounds represented by the general formula (IIc) produced in Step E, R ⁶ is —COR ¹⁰ (R ¹⁰ is as defined above) in the presence of a solvent. , Cyclization to form a hydantoin ring by treating with a base to produce a tricyclic compound represented by the general formula (IV).

In compound (IIc) which is a raw material of this step, R ¹ and R ² may be a hydrogen atom or an alkylidene group which may be substituted.

  Bases used are alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, lower alcohols such as sodium methoxide, sodium ethoxide, potassium t-butoxide. Alkali metal salts of, alkali metal hydrides such as sodium hydride and potassium hydride, alkali metals such as sodium and potassium, alkali metal amides such as sodium (bistrimethylsilyl) amide, lithium diisopropylamide, potassium carbonate, Alkali metal carbonates such as sodium carbonate, tri-lower alkylamines such as triethylamine and diisopropylamine, heteroaromatic tertiary amines such as pyridine and N, N-dimethylaminopyridine, 1,8-diazabicyclo [5 .4. Such as undecan-7-ene (DBU), 1,5-diazabicyclo [4.3.0] nonane-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO) Aromatic cyclic amines, aromatic amines such as N, N-dimethylaniline and N, N-diethylaniline, preferably alkali metals such as sodium hydroxide, potassium hydroxide and calcium hydroxide Alternatively, it is an alkali metal salt of a lower alcohol such as an alkaline earth metal hydroxide, sodium methoxide, sodium ethoxide, or potassium t-butoxide. The base is used in an amount of 1 to 10 equivalents based on the raw material.

  The reaction is carried out in the presence or absence of a solvent. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably a lower alcohol such as methanol, ethanol, n-propanol, or t-butyl alcohol. , Aromatic hydrocarbons such as benzene, toluene, xylene, ketones such as acetone, methyl ethyl ketone, nitriles such as acetonitrile, ethers such as tetrahydrofuran, 1,4-dioxane, ether, dimethoxyethane, Esters such as ethyl acetate and butyl acetate, polar solvents such as dimethyl sulfoxide and dimethylformamide, halogenated hydrocarbons such as methylene chloride and dichloroethane, and water, and more preferably methanol, ethanol, n- Like propanol, t-butyl alcohol Lower alcohols, is water.

  The reaction temperature is generally -50 ° C to 100 ° C, preferably 0 ° C to 70 ° C.

  The reaction time varies depending mainly on the reaction temperature, the raw material compound, the reaction reagent, or the type of solvent used, but is usually 0.1 to 24 hours.

(Process G)
In this step, among the compounds represented by the general formula (IIb) produced in Step D, R ⁶ is —COR ¹⁰ (R ¹⁰ is as defined above) in the presence of a solvent. This is a process for producing a compound represented by the general formula (III) by treating with ammonia to add an amine to an aldehyde group to convert it to an amino alcohol and cyclize it.

The starting compound (IIb) of the present invention is preferably a compound wherein R ⁶ is a lower alkoxycarbonyl group.

  Ammonia used in this reaction is ammonia or ammonia gas dissolved in a solvent such as ethers, nitriles, alcohols and water, and is preferably ammonia water. Ammonia is used in an amount of 1 equivalent to a large excess relative to compound (IIb).

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably a lower alcohol such as methanol, ethanol, n-propanol, or t-butyl alcohol. , Aromatic hydrocarbons such as benzene, toluene and xylene, nitriles such as acetonitrile, ethers such as tetrahydrofuran, 1,4-dioxane, ether and dimethoxyethane, esters such as ethyl acetate and butyl acetate , Polar solvents such as dimethyl sulfoxide and dimethylformamide, halogenated hydrocarbons such as methylene chloride and dichloroethane, water, and more preferably methanol, ethanol, n-propanol, t-butyl alcohol, and the like. Lower alcohols, tetrahydrofuran, 1, 4 Dioxane, ether, ethers such as dimethoxyethane, water.

  The reaction temperature is generally -50 ° C to 100 ° C, preferably 0 ° C to 50 ° C.

  The reaction time varies depending mainly on the reaction temperature, the raw material compound or the type of solvent used, but is usually 0.1 hour to 24 hours.

(Process H)
This step is a step for producing the compound represented by the general formula (IV) by oxidizing the secondary hydroxyl group of the dihydrohydantoin ring of the compound represented by the general formula (III) produced by the step G. .

  The oxidizing agent used is not particularly limited as long as it oxidizes a secondary hydroxyl group and converts it to a carbonyl group. Preferably, the reagent used for DMSO oxidation (dicyclohexylamide, dimethyl sulfoxide, Oxalyl chloride, phosgene, chloroformate, acetic anhydride, phosphorus pentoxide, pyridine-sulfuric acid complex, sulfonium salt formed from methyl sulfide and N-chlorosuccinimide, chlorinating agents such as chlorine), dioxide Manganese such as manganese, permanganates such as potassium permanganate, oxygen in the presence of silver oxide, copper oxide, copper acetate or nickel acetate, oxygen in the presence of a metal catalyst such as platinum, chromic acid, etc. Silver salts such as chromate, silver nitrate, silver oxide, ruthenium tetroxide and ruthenium capable of generating it in the reaction system , Hypochlorites such as sodium hypochlorite and calcium hypochlorite, molecular halogens such as chlorine and bromine, more preferably sodium hypochlorite and hypochlorous acid Hypochlorites such as calcium and chromic acid, and more preferably chromic acid. The oxidizing agent is used in the amount of 1 to 10 equivalents based on compound (III).

  The reaction is carried out in the presence or absence of a solvent. The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably an aromatic hydrocarbon such as benzene, toluene, xylene, acetone, methyl ethyl ketone. Ketones such as acetonitrile, nitriles such as acetonitrile, ethers such as tetrahydrofuran, 1,4-dioxane, ether, dimethoxyethane, esters such as ethyl acetate and butyl acetate, dimethyl sulfoxide, dimethylformamide, etc. Polar solvents, halogenated hydrocarbons such as methylene chloride and dichloroethane, and water, and ketones such as acetone and methyl ethyl ketone, and water are more preferable.

  The reaction temperature is generally -50 ° C to 100 ° C, preferably 0 ° C to 70 ° C.

  The reaction time varies depending mainly on the reaction temperature, the raw material compound, the reaction reagent, or the type of solvent used, but is usually 0.1 to 24 hours.

(Process I)
In this step, the N—O bond of the tricyclic compound represented by the general formula (IV) produced by Step F and Step H is cleaved, and R ¹ and R ² which are protecting groups for hydroxyl groups are optionally removed. This is a process for producing hydantosaidin.

When both R ¹ and R ² are hydrogen atoms, the reaction for removing the protecting group is unnecessary.

  The order of cleavage of the N—O bond and removal of the protecting group can be appropriately changed.

  Cleavage of the N—O bond is carried out by a reaction of hydrogenation using a Raney catalyst (Na—Ni) in the presence of a solvent.

  The Raney catalyst is used in an amount 0.01 to 10 times the weight of the compound (IV).

  The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Preferably, lower alcohols such as methanol, ethanol, n-butanol, acetone, methyl ethyl ketone are used. Ketones such as acetonitrile, nitriles such as acetonitrile, ethers such as tetrahydrofuran, 1,4-dioxane, ether, dimethoxyethane, esters such as ethyl acetate and butyl acetate, dimethyl sulfoxide, dimethylformamide, etc. Polar solvents, water, and mixed solvents thereof, more preferably ethers such as tetrahydrofuran, 1,4-dioxane, ether, dimethoxyethane, lower alcohols such as methanol, ethanol, n-butanol, Water, and a mixed solvent thereof, More preferably Ri is methanol, ethanol, lower alcohols such as n- butanol, water, and mixed solvents thereof.

This reaction is preferably performed under pressure rather than normal pressure. When pressurizing, it is preferably 1 to 100 kg / cm ² , more preferably 3 to 6 kg / cm ² .

  Heating is desirable because the reaction does not proceed at room temperature. The reaction temperature is usually 30 ° C. to 150 ° C., preferably 40 ° C. to 100 ° C., more preferably 45 ° C. to 70 ° C.

  The reaction time varies depending mainly on the reaction temperature, the raw material compound, the reaction reagent or the type of solvent used, but is usually 0.5 hours to 72 hours.

When R ¹ and R ² are both hydrogen atoms, it is desirable to add an additive in order to lower the pH in the reaction system. If the additive is not added, the product hydantoside is decomposed in the reaction system and the yield is lowered, so that extreme alkalinity in the reaction system, which is considered to be the cause, is prevented. On the other hand, the Raney catalyst has a catalytic activity only in a slightly alkaline state, so it is necessary to add an additive within a range not losing the catalytic activity. By this additive, the yield is dramatically improved and the isomerization of the spiro part can be suppressed as much as possible.

  Such additives include sulfonic acids such as methanesulfonic acid, paratoluenesulfonic acid, camphorsulfonic acid, carboxylic acids such as formic acid, acetic acid, propionic acid, benzoic acid, hydrochloric acid, sulfuric acid, perchloric acid and the like. Mineral acids, Lewis acids such as aluminum chloride and zinc chloride, phosphoric acid, etc., preferably sulfonic acids such as methanesulfonic acid, paratoluenesulfonic acid, camphorsulfonic acid, formic acid, acetic acid, propionic acid, benzoic acid An organic acid such as a carboxylic acid such as an acid, and more preferably methanesulfonic acid or acetic acid.

  This additive is used in an amount of 0.01 equivalents to 0.2 equivalents, preferably 0.1 equivalents to 0.2 equivalents, relative to compound (IV).

  In this step, when the hydroxyl protecting group is deprotected after the N—O bond cleavage reaction, a spiro carbon stereoisomer may be mixed if the nitrogen atom at the 7-position of hydantoside is not protected. Therefore, it is preferable to protect the nitrogen atom after the N—O bond cleavage reaction and before deprotecting the hydroxyl protecting group. This protecting group for nitrogen atom is deprotected after deprotecting the protecting group for hydroxyl group.

  Examples of such protecting groups for nitrogen atoms include acyl groups such as acetyl group, propionyl group, benzoyl group, methoxycarbonyl group and dimethylaminocarbonyl group, sulfonyl groups such as methylsulfonyl group and paratoluenesulfonyl group. Preferably an acyl group such as an acetyl group, a propionyl group or a benzoyl group, an alkoxycarbonyl group such as a methoxycarbonyl group, an aryloxycarbonyl group such as a phenoxycarbonyl group, or a (substituted) group such as a dimethylaminocarbonyl group An aminocarbonyl group, more preferably an acetyl group.

  Each of the above steps and reactions can be performed stepwise, and in some cases, can be performed at a time in combination with successive steps and reactions. In this case, only the purification process can be performed all at once, or each reaction can be performed in one reaction vessel.

  After completion of each of the above reactions, the target product of the reaction is collected from the reaction mixture according to a conventional method.

  For example, the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added, and after washing with water, the organic layer containing the target compound is removed. After separating and drying over anhydrous magnesium sulfate or the like, the solvent is distilled off.

  If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

  Hereinafter, the present invention will be described in more detail with reference to examples.

Example 1
Fructose (573.96 g, 3.19 mol) was suspended in acetone (5.74 L), concentrated sulfuric acid (28.7 ml) was added, and the mixture was stirred at room temperature for 2.5 hours. 28% aqueous ammonia (60 ml) was added to the reaction mixture, and the resulting precipitate was filtered off through celite. The filtrate was concentrated and the concentrate was dissolved in methylene chloride and washed with water and half-saturated brine. The organic layer was concentrated and crystallized from a hexane-methylene chloride mixed solvent to obtain 371.70 g (yield 45%) of the desired product 1,2: 4,5-di-O-isopropylidene-D-fructopyranose. .

Example 2
1,2: 4,5-Di-O-isopropylidene-D-fructopyranose (352.14 g, 1.35 mol) obtained in Example 1, tetra-n-butylammonium chloride (12.65 g, 45.5 mol) and three Ruthenium chloride (10.00 g) was dissolved in methylene chloride (1.5 L), and an aqueous sodium hypochlorite solution [1.2 M, 1.3 L] was gradually added at room temperature. The reaction temperature rose to the reflux temperature. After completion of the reaction, the reaction solution was filtered through celite, and extracted from the filtrate with methylene chloride three times. The extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crystals were washed with ether-hexane (1: 1), dried, and then the desired product 1, 2: 4,5-di-O-isopropylidene-D-erythro-2,3-hexodiuro-2,6- 313.76 g (yield 90%) of pyranose was obtained.

Example 3
1,2: 4,5-Di-O-isopropylidene-D-erythro-2,3-hexodiuro-2,6-pyranose (313.76 g, 1.21 mol) obtained in Example 2 was added to ethanol (2.75 L). After dissolving, sodium borohydride (13.79 g, 0.364 mol) was added under ice cooling, and the mixture was stirred for 1 hour. The reaction solution was concentrated, saturated aqueous ammonium chloride solution was added, and the mixture was stirred for 30 minutes. The aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the desired product 1,2: 4,5-di-O-isopropylidene-D-psicopyranose as 312.91. g (99% yield) was obtained.

Example 4
1,2: 4,5-Di-O-isopropylidene-D-psicopyranose (312.91 g, 1.20 mol) obtained in Example 3 was dissolved in acetone (3.0 L), and concentrated sulfuric acid (16.6 ml) was dissolved at room temperature. In addition, it was stirred for 10 hours. Aqueous ammonia (40 ml) was added to the reaction mixture, and the resulting ammonium sulfate was filtered off through celite. The filtrate was concentrated under reduced pressure, and the resulting concentrate was partitioned between water and ethyl acetate. The aqueous layer was further extracted twice with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate: hexane 1: 3) to obtain the target compounds 1, 2 : 195.93 g (yield 63%) of 3,4-di-O-isopropylidene-D-psicofuranose was obtained.

Example 5
Triethylamine (20.5 ml, 147 mmol) was added to a methylene chloride solution (200 ml) of 1,2: 3,4-di-O-isopropylidene-D-psicofuranose (17.4 g, 66.9 mmol) obtained in Example 4 at 0 ° C. And methanesulfonyl chloride (5.7 ml, 74 mmol) were successively added dropwise and stirred for 20 minutes. The reaction was stopped by pouring water, followed by extraction three times with methylene chloride, and the organic layer was washed once with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3) to obtain the desired product 1,2: 3,4-di-O-isopropylidene- 20.9 g (92% yield) of 6-O-methanesulfonyl-D-psicofuranose was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 4.76 (d, 1H, J = 5.8 Hz), 4.62 (d, 1H, J = 5.8 Hz), 4.31 (d, 1H, J = 9.9 Hz), 4.39- 4.23 (m, 3H), 4.06 (d, 1H, J = 9.9Hz), 3.07 (s, 3H), 1.45 (s, 6H), 1.38 (s, 3H), 1.33 (s, 3H).
MS (m / z) 338 (M ⁺ ), 323, 279, 263, 229, 205, 149, 113.

Example 6
In the same manner as in Example 5, 1,2: 3,4-di-O-isopropylidene-D-psicofuranose (133 mg, 511 μmol), triethylamine (0.36 ml, 2.6 mmol) and tosyl chloride (244 mg, 1.28 mmol) ), 193 mg (yield 91%) of the target compound 1,2: 3,4-di-O-isopropylidene-6-Op-toluenesulfonyl-D-psicofuranose was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.80 (d, 2H, J = 8.4Hz), 7.36 (d, 2H, J = 8.4Hz), 4.68 (d, 1H, J = 5.8Hz), 4.56 ( d, 1H, J = 5.8Hz), 4.26 (d, 1H, J = 9.9Hz), 4.21 (q, 1H, J = 8.0Hz), 4.10 (dd, 1H, J = 10.0,8.0Hz), 4.05 ( dd, 1H, J = 10.0,8.0Hz), 4.01 (d, 1H, J = 9.9Hz), 2.45 (s, 3H), 1.40 (s, 3H), 1.36 (s, 3H), 1.35 (s, 3H ), 1.29 (s, 3H).
MS (m / z) 414 (M ⁺ ), 399, 356, 298, 240, 229, 205, 155.

Example 7
To 20 ml of a tetrahydrofuran (THF) solution of 1,2: 3,4-di-O-isopropylidene-D-psicofuranose (1.02 g, 3.92 mmol) obtained in Example 4 was added triphenylphosphine (1.23 g, 4.70 mmol). ) And N-chlorosuccinimide (NCS) (628 mg, 4.70 mmol) were sequentially added and stirred at room temperature for 40 minutes. The reaction was stopped by adding water, followed by extraction three times with ethyl acetate, and the organic layer was washed once with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 95: 5) to obtain the desired product 6-chloro-6-deoxy-1,2,3,4. 930 mg (yield 85.1%) of -di-O-isopropylidene-D-psicofuranose was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 4.80 (dd, 1H, J = 5.8, 1.0 Hz), 4.61 (d, 1H, J = 5.8 Hz), 4.28 (dd, 1H, J = 9.8 Hz), 4.23 (ddd, 1H, J = 9.3, 6.4, 1.0Hz), 4.04 (d, 1H, J = 9.8Hz), 3.59 (dd, 1H, J = 9.8, 6.4Hz), 3.54 (dd, 1H, J = 9.8, 9.3Hz), 1.44 (s, 6H), 1.37 (s, 3H), 1.32 (s, 3H).
MS (m / z) 279 (M + 1), 263,221,203,185,162,147.

Example 8
As in Example 7, 1,2: 3,4-di-O-isopropylidene-D-psicofuranose (1.02 g, 3.92 mmol), triphenylphosphine (1.23 g, 4.70 mmol) and N-bromosuccinic acid. The desired product 6-bromo-6-deoxy-1,2: 3,4-di-O-isopropylidene-D-psicofuranose 903 mg (yield 71%) was obtained from imide (NBS) (837 mg, 4.70 mmol). .

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 4.82 (d, 1H, J = 5.8Hz), 4.62 (d, 1H, J = 5.8Hz), 4.30 (dd, 1H, J = 9.6, 6.4Hz), 4.27 (d, 1H, J = 10.2Hz), 4.04 (d, 1H, J = 10.2Hz), 3.44 (dd, 1H, J = 10.2,6.4Hz), 3.38 (dd, 1H, J = 10.2,9.6Hz) ), 1.45 (s, 3H), 1.44 (s, 3H), 1.37 (s, 3H), 1.32 (s, 3H).
MS (m / z) 323 (M ⁺ ), 309,265,249,206,191,163.

Example 9
1,2: 3,4-Di-O-isopropylidene-D-psicofuranose (1.06 g, 4.07 mmol), chlorodiphenylphosphine (1.17 g, 5.29 mmol) and imidazole (610 mg, 8.96 mmol) obtained in Example 4 Iodine (1.34 g, 5.29 mmol) was added little by little to 10 ml of a toluene solution and stirred at room temperature for 10 minutes. The reaction was stopped by adding 10 ml of 1N aqueous sodium hydroxide (NaOH), and after stirring well, the aqueous layer was separated. The organic layer was washed twice with a saturated aqueous sodium thiosulfate solution. After confirming that the iodine color disappeared, the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 95: 5) to give the desired product 6-deoxy-1,2: 3,4-di-O. 1.14 g (yield 75%) of isopropylidene-6-iodo-D-psicofuranose was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 4.82 (dd, 1H, J = 5.8, 1.0 Hz), 4.64 (d, 1H, J = 5.8 Hz), 4.37 (ddd, 1H, J = 9.8, 6.4, 1.0Hz), 4.28 (d, 1H, J = 9.8Hz), 4.04 (d, 1H, J = 9.8Hz), 3.30 (dd, 1H, J = 10.0, 6.4Hz), 3.22 (dd, 1H, J = 10.0, 9.8Hz), 1.48 (s, 3H), 1.44 (s, 3H), 1.38 (s, 3H), 1.33 (s, 3H).
MS (m / z) 371 (M + 1), 355, 313, 295, 255, 237, 170.

Example 10
Methyl N-hydroxycarbamate (2.89 g, 31.7 mmol) was dissolved in 30 ml of dimethylformamide, and potassium tert-butoxide (3.56 g, 31.7 mmol) was added at room temperature with 1,2: 3,4-di-dioxide obtained in Example 5. A solution of -O-isopropylidene-6-O-methanesulfonyl-D-psicofuranose (3.50 g, 10.3 mmol) in dimethylformamide (6.5 ml) was added. After stirring at 80 ° C. for 7 hours, the mixture was poured into ice water and extracted three times with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried (Na ₂ SO ₄ ), concentrated, and purified by silica gel chromatography (ethyl acetate: hexane = 1: 3) to obtain the desired products 1, 2: 3, 1.4553 g (42% yield) of 4-di-O-isopropylidene-6-O-methoxycarbonylamino-D-psicofuranose was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.86 (1H, br.s), 4.81 (1H, dd, J = 1.1, 5.8Hz), 4.61 (1H, d, J = 5.8Hz), 4.31 (1H , dt, J = 1.1,5.8Hz), 4.28 (1H, d, J = 9.8Hz), 4.03 (1H, d, J = 9.8Hz), 4.05-3.88 (2H, m), 3.75 (3H, s) , 1.44 (3H, s), 1.43 (3H, s), 1.36 (3H, s), 1.31 (3H, s).
MS (m / z) 333 (M ⁺ ), 316,275,260,229,217,200,159,109,69,59,44.

Example 11
Methyl N-hydroxycarbamate (245 mg, 2.69 mmol) and sodium hydride (108 mg, 2.69 mmol) in 3 ml of dimethylformamide (DMF) solution at 0 ° C. with 1,2: 3,4- 3 ml of a DMF solution of di-O-isopropylidene-6-O-methanesulfonyl-D-psicofuranose (607 mg, 1.79 mmol) was added and stirred at 60 ° C. for 3 hours and a half. After air cooling at room temperature, 2 ml of a DMF solution of methyl N-hydroxycarbamate (817 mg, 8.95 mmol) and sodium hydride (358 mg, 8.95 mmol) were further added successively, and the mixture was stirred at 60 ° C. for 3 hours. The reaction was stopped by pouring water, followed by extraction three times with diethyl ether, and the organic layer was washed once with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 75: 25) to give the desired product 1,2: 3,4-di-O-isopropylidene- 301 mg (yield 50%) of 6-O-methoxycarbonylamino-D-psicofuranose was obtained.

  The instrument data was consistent with that of Example 10.

Example 12
1,2: 3,4-Di-O-isopropylidene-6-O-methanesulfonyl-D-psicofuranose (1.15 g, 3.40 mmol) obtained in Example 5 was dissolved in 20 ml of t-butanol, and at room temperature, Ethyl N-hydroxycarbamate (0.71 g, 6.80 mmol) and potassium hydroxide (85%) (0.67 g, 10.2 mmol) were added and refluxed for 3 hours. The reaction mixture was cooled, water was added, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried (Na ₂ SO ₄ ), concentrated, and purified by silica gel chromatography (ethyl acetate: hexane = 1: 3) to obtain the target compounds 1, 2: 865.5 mg (yield 73%) of 3,4-di-O-isopropylidene-6-O-ethoxycarbonylamino-D-psicofuranose was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.69 (1H, br.s), 4.83 (1H, d, J = 5.9Hz), 4.62 (1H, d, J = 5.9Hz), 4.33 (1H, t , J = 6.4Hz), 4.30 (1H, d, J = 10.0Hz), 4.21 (2H, ABq, J = 7.5Hz), 4.04 (1H, d, J = 10.0Hz), 4.02 (1H, dd, J = 5.8,11.4Hz), 3.95 (1H, dd, J = 7.4,11.4Hz), 1.46 (3H, s), 1.44 (3H, s), 1.37 (3H, s), 1.32 (3H, s), 1.29 (3H, t, J = 7.3Hz).
MS (m / z) 347 (M ⁺ ), 332,289,126,109,69,59,44.

Example 13
1,2: 3,4-Di-O-isopropylidene-6-O-methanesulfonyl-D-psicofuranose (1.27 g, 3.75 mmol) obtained in Example 5 was dissolved in t-butanol (25.0 ml). , Ethyl N-hydroxycarbamate (0.79 g, 7.50 mmol), and potassium t-butoxide (1.26 g, 11.25 mmol) were added, and the mixture was heated to reflux for 5 hours. The reaction mixture was cooled, water was added, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried (Na ₂ SO ₄ ), concentrated, and purified by silica gel chromatography (ethyl acetate: hexane = 1: 3) to obtain the target compounds 1, 2: As a result, 1.08 g (yield 83%) of 3,4-di-O-isopropylidene-6-O-ethoxycarbonylamino-D-psicofuranose was obtained.

  The instrument data was consistent with that of Example 12.

Example 14
1,2: 3,4-Di-O-isopropylidene-6-O-methanesulfonyl-D-psicofuranose (9.70 g, 28.7 mmol) obtained in Example 5 was dissolved in isopropanol (200 ml) and ethyl N -Hydroxycarbamate (6.00 g, 57.3 mmol) and potassium t-butoxide (9.65 g, 86.0 mmol) were added, and the mixture was heated to reflux for 4 hours. The reaction mixture was cooled, water was added, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried (Na ₂ SO ₄ ), concentrated, and purified by silica gel chromatography (ethyl acetate: hexane = 1: 3). 4-di-O-isopropylidene-6-O-ethoxycarbonylamino-D-psicofuranose (6.62 g, 67% yield) and 1,2: 3,4-di-O-isopropylidene-6-O- Isopropyloxycarbonylamino-D-psicofuranose (2.67 g, 26%) was obtained.

  The instrument data for 1,2: 3,4-di-O-isopropylidene-6-O-ethoxycarbonylamino-D-psicofuranose was consistent with that of Example 12.

1,2: 3,4-di-O-isopropylidene-6-O-isopropyloxycarbonylamino-D-psicofuranose
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.62 (1H, br.s), 4.99 (1H, qq, J = 6.3, 6.3Hz), 4.83 (1H, dd, J = 1.1, 5.8Hz), 4.62 (1H, d, J = 5.8Hz), 4.33 (1H, dt, J = 1.1,6.0Hz), 4.29 (1H, d, J = 9.7Hz), 4.04 (1H, d, J = 9.7Hz), 4.05 -3.89 (2H, m), 1.46 (3H, s), 1.44 (3H, s), 1.37 (3H, s), 1.31 (3H, s), 1.27 (3H, d, J = 6.3Hz).
MS (m / z) 361 (M ⁺ ), 346,332,303,268,260,244,229,186,159,142,126,69,59,44.

Example 15
1,2: 3,4-Di-O-isopropylidene-6-O-methanesulfonyl-D-psicofuranose (1.25 g, 3.81 mmol) and ethyl N-hydroxycarbamate (0.80 g, 7.6) obtained in Example 5 mmol) was dissolved in a mixed solvent of 16.0 ml of t-butanol and 8.0 ml of dimethyl sulfoxide, potassium t-butoxide (1.28 g, 11.4 mmol) was added, and the mixture was refluxed for 2 hours. The reaction solution was poured into ice water and extracted three times with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried (Na ₂ SO ₄ ), concentrated, and purified by silica gel chromatography (ethyl acetate: hexane = 1: 3) to give the desired product 1, 2: 3. 841.8 mg (yield 64%) of 4,4-di-O-isopropylidene-6-O-ethoxycarbonylamino-D-psicofuranose was obtained.

  The instrument data was consistent with that of Example 12.

Example 16
1,2: 3,4-Di-O-isopropylidene-6-O-methanesulfonyl-D-psicofuranose (296.2 mg, 0.8753 mmol) obtained in Example 5 was dissolved in 6 ml of isopropanol, and isobutyl was added at room temperature. 350 mg of N-hydroxycarbamate and 173 mg of potassium hydroxide (KOH) were added, and the mixture was stirred at the same temperature for 30 minutes, then heated to 70 to 80 ° C. and stirred for 2 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with brine, dried and concentrated. The obtained crude product was purified by silica gel chromatography (hexane: ethyl acetate = 6: 1 → 4: 1) to obtain the desired product 1,2: 3,4-di-O-isopropylidene-6-O-isobutyl. 167.6 mg (51% yield) of oxycarbonylamino-D-psicofuranose was obtained, and 92.7 mg (31%) of the raw material was recovered.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.74 (1H, s), 4.83 (1H, dd, J = 1.1, 5.8Hz), 4.62 (1H, d, J = 5.8Hz), 4.33 (1H, td , J = 1.1,6.8Hz), 4.30 (1H, d, J = 9.8Hz), 4.04 (1H, d, J = 9.8Hz), 4.05-3.90 (4H, m), 1.95 (1H, qq, J = 6.7, 6.7Hz), 1.46 (3H, s), 1.44 (3H, s), 1.37 (3H, s), 1.32 (3H, s), 0.93 (6H, d, J = 6.7Hz).
MS (m / z) 375 (M ⁺ ), 360, 317, 186, 126, 109, 69, 57, 44.

Example 17
To 6 ml of the t-butanol solution of 1,2: 3,4-di-O-isopropylidene-6-Op-toluenesulfonyl-D-psicofuranose (516 mg, 1.25 mmol) obtained in Example 6 was added ethyl N 4-Hydroxycarbamate (262 mg, 2.49 mmol) in 4 ml of ^t BuOH and potassium t-butoxide (419 mg, 3.74 mmol) were sequentially added and refluxed for 6 hours. The reaction was stopped by pouring water, followed by extraction three times with ethyl acetate, and the organic layer was washed once with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 2) to obtain the desired product 1,2: 3,4-di-O-isopropylidene- 326 mg (yield 75%) of 6-O-ethoxycarbonylamino-D-psicofuranose was obtained.

  The instrument data was consistent with that of Example 12.

Example 18
Ethyl N-hydroxycarbamate was added to 10 ml of an ethanol solution of 6-bromo-6-deoxy-1,2: 3,4-di-O-isopropylidene-D-psicofuranose (528 mg, 1.63 mmol) obtained in Example 8. (343 mg, 3.26 mmol) and potassium hydroxide (183 mg, 3.26 mmol) were added and refluxed for 9 hours. The reaction was stopped by pouring water, followed by extraction three times with ethyl acetate, and the organic layer was washed once with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the desired product 1,2: 3,4-di-O-isopropylidene- 61.2 mg (yield 11%) of 6-O-ethoxycarbonylamino-D-psicofuranose was obtained.

  The instrument data was consistent with that of Example 12.

Example 19
6-Deoxy-1,2: 3,4-di-O-isopropylidene-6-iodo-D-psicofuranose (557 mg, 1.50 mmol), ethyl obtained in the same manner as in Example 18 From N-hydroxycarbamate (474 mg, 4.51 mmol) and potassium hydroxide (253 mg, 4.51 mmol), the desired product 1,2: 3,4-di-O-isopropylidene-6-O-ethoxycarbonylamino-D-psico Furanose 54.1 mg (yield 10%) was obtained.

  The instrument data was consistent with that of Example 12.

Example 20
To a 5 ml DMF solution of acetoxime (163 mg, 2.22 mmol) and sodium hydride (NaH) (60%) (89.0 mg, 2.22 mmol) at 0 ° C., 1,2,3,4-di- O-isopropylidene-6-O-methanesulfonyl-D-psicofuranose (503 mg, 1.49 mmol) was added and stirred at 60 ° C. for 3 hours. Water was poured into the reaction solution at 0 ° C. to stop the reaction, extraction was performed three times with diethyl ether, and the organic layer was washed once with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain the desired product 1,2: 3,4-di-O-isopropylidene- 353 mg (75% yield) of 6-O-isopropylideneamino-D-psicofuranose and 7,7-dimethyl-3,4-isopropylidenedioxy-2-methylidene-1,6,8-trio as a by-product 30.3 mg (8.4% yield) of oxaspiro [4.4] nonane was obtained.

1,2: 3,4-Di-O-isopropylidene-6-O-isopropylideneamino-D-psicofuranose
¹ HNMR (200 MHz, CDCl ₃ ) δ: 4.80 (d, 1 H, J = 5.9 Hz), 4.63 (d, 1 H, J = 5.9 Hz), 4.35 (dd, 1 H, J = 8.6, 6.1 Hz), 4.26 ( d, 1H, J = 9.6Hz), 4.12 (dd, 1H, J = 11.2, 6.1Hz), 4.05 (dd, 1H, J = 11.2, 8.6Hz), 4.05 (d, 1H, J = 9.6Hz), 1.86 (s, 6H), 1.44 (s, 6H), 1.36 (s, 3H), 1.32 (s, 3H).
MS (m / z) 315 (M ⁺ ), 300,257,242,229,200,171,141.
7,7-Dimethyl-3,4-isopropylidenedioxy-2-methylidene-1,6,8-trioxaspiro [4.4] nonane
¹ HNMR (200 MHz, CDCl ₃ ) δ: 5.12 (d, 1 H, J = 5.6 Hz), 4.58 (d, 1 H, J = 1.9 Hz), 4.56 (d, 1 H, J = 5.6 Hz), 4.36 (d, 1H, J = 1.9Hz), 4.36 (d, 1H, J = 9.9Hz), 4.16 (d, 1H, J = 9.9Hz), 1.51 (s, 3H), 1.44 (s, 3H), 1.41 (s, 3H), 1.36 (s, 3H).
MS (m / z) 242 (M ⁺ ), 227, 203, 184, 169, 141, 113.

Example 21
1,2: 3,4-Di-O-isopropylidene-D-psicofuranose (24.0 g, 92.3 mmol), triphenylphosphine (29.1 g, 111 mmol), N-hydroxyphthalimide (18.1 g) obtained in Example 4 , 111 mmol) in THF (500 ml) was added dropwise azodicarboxylate (DEAD) (17.4 ml, 111 mmol) and stirred for 30 minutes at room temperature. After the solvent was distilled off under reduced pressure, a mixed solvent of hexane-diethyl ether (1: 1) was poured to precipitate crystals, and the crystals were filtered off using celite and concentrated. The obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3) to obtain the desired product 1,2: 3,4-di-O-isopropylidene-6-O-phthalimide-D. -Psychofuranose (35.4 g, yield 95%) was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.88-7.74 (m, 4H), 5.04 (d, 1H, J = 5.8Hz), 4.65 (d, 1H, J = 5.8Hz), 4.51-4.14 (m , 3H), 4.29 (d, 1H, J = 9.8Hz), 4.05 (d, 1H, J = 9.8Hz), 1.46 (s, 3H), 1.40 (s, 3H), 1.36 (s, 6H).
MS (m / z) 405 (M ⁺ ), 390,347,332,289,272,231,202,185,163.

Example 22
To 350 ml of an ethanol solution of 1,2: 3,4-di-O-isopropylidene-6-O-phthalimide-D-psicofuranose (35.4 g, 87.4 mmol) obtained in Example 21 was added hydrazine-hydrate ( 4.5 ml, 92 mmol) was added and the mixture was heated to reflux for 90 minutes. After the reaction solution had cooled to room temperature, white crystals generated during the reaction were filtered off using celite, and the filtrate was concentrated. Ethyl acetate and water were poured into the resulting residue, followed by extraction three times with ethyl acetate, and the organic layer was washed once with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3) to obtain the desired product 1,2: 3,4-di-O-isopropylidene- 22.1 g (yield 92%) of 6-O-amino-D-psicofuranose was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 5.50 (br.s, 2H), 4.73 (d, 1H, J = 5.8Hz), 4.53 (d, 1H, J = 5.8Hz), 4.31 (dd, 1H , J = 7.6, 5.4Hz), 4.25 (d, 1H, J = 9.6Hz), 4.02 (d, 1H, J = 9.6Hz), 3.76 (dd, 1H, J = 10.2, 5.4Hz), 3.67 (dd , 1H, J = 10.2, 7.6 Hz), 1.43 (s, 6H), 1.35 (s, 3H), 1.30 (s, 3H).
MS (m / z) 318 (M ⁺ ), 303,279,260,243,229,217,159.

Example 23
To 13 ml of a toluene solution of 1,2: 3,4-di-O-isopropylidene-6-O-amino-D-psicofuranose (1.34 g, 4.87 mmol) obtained in Example 22, 2 ml of triethyl orthoacetate was added. Heated to reflux for 2 hours. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the desired product 1,2: 3,4-di-O-isopropylidene- There was obtained 1.55 g (yield 92%) of 6- (1-ethoxyethylidene) -D-psicofuranose.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 4.80 (d, 1H, J = 5.8Hz), 4.63 (d, 1H, J = 5.8Hz), 4.39 (dd, 1H, J = 8.4, 7.2Hz), 4.28 (d, 1H, J = 9.7Hz), 4.05 (d, 1H, J = 9.7Hz), 4.06-3.88 (m, 3H), 4.00 (q, 2H, J = 7.1Hz), 1.94 (s, 3H ), 1.45 (s, 6H), 1.38 (s, 3H), 1.33 (s, 3H), 1.26 (t, 3H, J = 7.1Hz).
MS (m / z) 345 (M ⁺ ), 330,287,272,243,230,216,171.

Example 24
1,2: 3,4-Di-O-isopropylidene-6-O-amino-D-psicofuranose (5.00 g, 18.2 mmol) obtained in Example 22 was dissolved in 100 ml of dichloroethane, and pyridine ( 1.33 ml, 18.16 mmol) and methyl chlorocarbonate (1.47 ml, 19.1 mmol) were added and stirred at the same temperature for 1 hour. Water and brine were added to this reaction solution, extracted with dichloromethane, dried and concentrated, then purified by silica gel column chromatography (hexane: ethyl acetate = 5: 2 → 1: 1) to obtain the desired product 1, 2: 3. 5.75 g (yield 94%) of 4-di-O-isopropylidene-6-O-methoxycarbonylamino-D-psicofuranose was obtained.

  The instrument data was consistent with that of Example 10.

Example 25
1,2: 3,4-Di-O-isopropylidene-6-O-amino-D-psicofuranose (0.71 g, 2.6 mmol) obtained in Example 22 was dissolved in methylene chloride (14 ml) at 0 ° C. Pyridine (0.25 ml, 3.1 mmol) and phenyl chlorocarbonate (0.36 ml, 2.8 mmol) were added and stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted 3 times with methylene chloride. The combined organic layers were washed with dilute hydrochloric acid and half-saturated brine, dried (Na ₂ SO ₄ ) and concentrated, and the resulting crude product was purified by silica gel chromatography to obtain the desired products 1, 2: 3. , 4-Di-O-isopropylidene-6-O-phenoxycarbonylamino-D-psicofuranose (979.4 mg, yield 96%) was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 8.27 (1H, br.s), 7.41-7.33 (2H, m), 7.26-7.13 (3H, m), 4.87 (1H, dd, J = 1.0, 5.8 Hz), 4.65 (1H, d, J = 5.8Hz), 4.38 (1H, br.t, J = 5.6Hz), 4.32 (1H, d, J = 9.8Hz), 4.18-4.00 (3H, m), 1.49 (3H, s), 1.46 (3H, s), 1.39 (3H, s), 1.32 (3H, s).
MS (m / z) 395 (M ⁺ ), 360,337,262,244,109,94,59,44.

Example 26
1,2: 3,4-Di-O-isopropylidene-6-O-amino-D-psicofuranose (4.62 g, 16.8 mmol) obtained in Example 22 was dissolved in methylene chloride (60 ml) and dissolved at 0 ° C. Pyridine (1.5 ml, 18 mmol) and benzyl chlorocarbonate (2.6 ml, 18 mmol) were added. It was brought to room temperature and stirred for 1 hour. Water was added and extracted three times with methylene chloride. The organic layers were combined, washed with dilute hydrochloric acid and saturated brine, dried (Na ₂ SO ₄ ), and concentrated. The obtained crude product was purified by silica gel chromatography (ethyl acetate: hexane = 1: 3) to obtain the desired product 6-O-benzyloxycarbonylamino-1,2: 3,4-di-O-isopropylidene. 6.18 g (yield 90%) of -D-psicofuranose was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.81 (1H, br.s), 7.36 (5H, br.s), 5.19 (2H, s), 4.80 (1H, d, J = 5.8Hz), 4.60 (1H, d, J = 5.8Hz), 4.35-4.26 (2H, m), 4.08-3.91 (3H, m), 1.44 (6H, s), 1.36 (3H, s), 1.30 (3H, s).
MS (m / z) 409 (M ⁺ ), 394, 350, 307, 229, 149, 127, 113, 91, 69, 59, 44.

Example 27
1,2: 3,4-Di-O-isopropylidene-6-O-amino-D-psicofuranose (1.69 g, 6.14 mmol) obtained in Example 22 was added to 17 ml of dichloroethane solution at 0 ° C. with pyridine ( 0.52 ml, 6.4 mmol) and acetic anhydride (0.61 ml, 6.4 mmol) were sequentially added, followed by stirring at the same temperature for 30 minutes. The reaction was stopped by adding water, extracted three times with methylene chloride, and the organic layer was washed once with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 7) to obtain the desired product 6-O-acetamido-1,2: 3,4-di-. 1.71 g (88% yield) of O-isopropylidene-D-psicofuranose was obtained.

¹ H-NMR (200 MHz, DHSO-d ₆ ) δ: 11.08 (br.s, 1H), 4.86 (d, 1H, J = 5.8 Hz), 4.64 (d, 1H, J = 5.8 Hz), 4.19 (dd , 1H, J = 8.2,5.7Hz), 4.15 (d, 1H, J = 9.6Hz), 3.94 (d, 1H, J = 9.6Hz), 3.83 (dd, 1H, J = 9.8,5.7Hz), 3.77 (dd, 1H, J = 9.8, 8.2 Hz), 1.74 (s, 3H), 1.38 (s, 3H), 1.33 (s, 3H), 1.29 (s, 3H).
MS (m / z) 317 (M ⁺ ), 302,259,229,202,184,159,127.

Example 28
In the same manner as in Example 27, 1,2: 3,4-di-O-isopropylidene-6-O-amino-D-psicofuranose (1.12 g, 4.07 mmol) obtained in Example 22 and pyridine ( 0.35 ml, 4.3 mmol) and benzoyl chloride (0.50 ml, 4.3 mmol) from the target product 6-O-benzamido-1,2: 3,4-di-O-isopropylidene-D-psicofuranose 1.50 g (yield) 97%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 9.19 (br.s, 1H), 7.77-7.73 (m, 2H), 7.56-7.39 (m, 3H), 4.93 (d, 1H, J = 5.8Hz) , 4.70 (d, 1H, J = 5.8Hz), 4.41 (dd, 1H, J = 7.2, 5.1Hz), 4.34 (d, 1H, J = 9.7Hz), 4.25 (dd, 1H, J = 11.4, 5.1) Hz), 4.12 (dd, 1H, J = 11.4, 7.2Hz), 4.04 (d, 1H, J = 9.7Hz), 1.47 (s, 3H), 1.41 (s, 3H), 1.39 (s, 3H), 1.34 (s, 3H).
MS (m / z) 379 (M ⁺ ), 364, 321, 306, 263, 229, 205, 163.

Example 29
To 30 ml of a THF solution of 1,2: 3,4-di-O-isopropylidene-6-O-amino-D-psicofuranose (3.00 g, 10.9 mmol) obtained in Example 22 was added trimethylsilyl isocyanate (4.4 ml, 33 mmol) and 1 drop of triethylamine were added and stirred at room temperature for 30 minutes. The reaction was stopped by pouring water, followed by extraction three times with ethyl acetate, and the organic layer was washed once with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 4) to obtain the desired product 1,2: 3,4-di-O-isopropylidene- As a result, 3.02 g (yield 87%) of 6-O-ureido-D-psicofuranose was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.34 (br.s, 1H), 5.67 (br.s, 2H), 4.68 (dd, 1H, J = 5.8, 1.1 Hz), 4.62 (d, 1H, J = 5.8Hz), 4.41 (ddd, 1H, J = 7.8, 4.5, 1.1Hz), 4.32 (d, 1H, J = 9.8Hz), 4.05 (d, 1H, J = 9.8Hz), 4.00 (dd, 1H, J = 11.4, 7.8Hz), 3.89 (dd, 1H, J = 11.4, 4.5Hz), 1.47 (s, 3H), 1.46 (s, 3H), 1.38 (s, 3H), 1.32 (s, 3H ).
MS (m / z) 318 (M ⁺ ), 303, 279, 260, 217, 202, 185, 159.

Example 30
To 10 ml of a dichloroethane solution of 1,2: 3,4-di-O-isopropylidene-6-O-amino-D-psicofuranose (1.07 g, 3.89 mmol) obtained in Example 22 at 0 ° C. with pyridine (0.38 ml, 4.7 mmol) and dimethylcarbamoyl chloride (0.43 ml, 4.7 mmol) were added, and the mixture was stirred with heating at 50 ° C. for 12 hours. The reaction was stopped by pouring water, followed by extraction three times with methylene chloride, and the organic layer was washed once with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 4) to obtain the desired product 1,2: 3,4-di-O-isopropylidene- 6.18 g (yield 87%) of 6-O- (3,3-dimethylureido) -D-psicofuranose was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.31 (br.s, 1H), 4.85 (d, 1H, J = 5.8 Hz), 4.63 (d, 1H, J = 5.8 Hz), 4.37 (dd, 1H , J = 7.7,5.8Hz), 4.29 (d, 1H, J = 9.7Hz), 4.03 (d, 1H, J = 9.7Hz), 3.99 (dd, 1H, J = 11.2,5.8Hz), 3.93 (dd , 1H, J = 11.2,7.7Hz), 2.89 (s, 6H), 1.44 (s, 6H), 1.36 (s, 3H), 1.32 (s, 3H).
MS (m / z) 346 (M ⁺ ), 331,273,229,213,172,147.

Example 31
To 11 ml of a 1,2: 3,4-di-O-isopropylidene-6-O-amino-D-psicofuranose (1.14 g, 4.14 mmol) methylene chloride obtained in Example 22 was added triethylamine (0 0.61 ml, 4.3 mmol) and methanesulfonyl chloride (0.34 ml, 4.3 mmol) were added and stirred overnight at room temperature. The reaction was stopped by pouring water, followed by extraction three times with methylene chloride. The organic layer was washed once with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) to obtain 1,2: 3,4-di-O-isopropylidene-6- 1.29 g O-methanesulfonylamino-D-psicofuranose (88% yield) and 94.1 mg 1,2: 3,4-di-O-isopropylidene-6-O-dimethanesulfonylamino-D-psicofuranose (yield 88%) Yield 5.3%).

1,2: 3,4-Di-O-isopropylidene-6-O-methanesulfonylamino-D-psicofuranose
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.19 (br.s, 1H), 4.75 (d, 1H, J = 5.8 Hz), 4.62 (d, 1H, J = 5.8 Hz), 4.35 (dd, 1H , J = 7.0, 5.2Hz), 4.30 (d, 1H, J = 9.7Hz), 4.14 (dd, 1H, J = 12.0, 5.2Hz), 4.10 (dd, 1H, J = 12.0, 7.0Hz), 4.06 (d, 1H, J = 9.7Hz), 3.08 (s, 3H), 1.46 (s, 6H), 1.38 (s, 3H), 1.33 (s, 3H).
MS (m / z) 353 (M ⁺ ), 338,295,229,208,166.
1,2: 3,4-Di-O-isopropylidene-6-O-dimethanesulfonylamino-D-psicofuranose
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 4.87 (d, 1H, J = 5.8Hz), 4.62 (d, 1H, J = 5.8Hz), 4.40-4.16 (m, 3H), 4.30 (d, 1H , J = 9.4Hz), 4.04 (d, 1H, J = 9.4Hz), 3.35 (s, 6H), 1.45 (s, 6H), 1.38 (s, 3H), 1.33 (s, 3H).
MS (m / z) 432 (M + 1), 416,373,338,315,298,257,229,185.

Example 32
In the same manner as in Example 31, 1,2: 3,4-di-O-isopropylidene-6-O-amino-D-psicofuranose (1.03 g, 3.74 mmol) obtained in Example 22 and triethylamine ( 0.57 ml, 4.1 mmol), p-toluenesulfonyl chloride (785 mg, 4.11 mol), 775 mg 1,2,3,4-di-O-isopropylidene-6-O-p-toluenesulfonylamino-D-psicofuranose (Yield 48%) and 6-O- [bis (p-toluenesulfonyl) amino] -1,2: 3,4-di-O-isopropylidene-D-psicofuranose 741 mg (yield 34%) It was.

1,2: 3,4-Di-O-isopropylidene-6-Op-toluenesulfonylamino-D-psicofuranose
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.81 (d, 2H, J = 8.3 Hz), 7.35 (d, 2H, J = 8.3 Hz), 7.24 (br.s, 1H), 4.72 (dd, 1H , J = 5.8,1.1Hz), 4.56 (d, 1H, J = 5.8Hz), 4.52 (ddd, 1H, J = 7.6,5.8,1.1Hz), 4.27 (d, 1H, J = 9.8Hz), 4.12 (dd, 1H, J = 11.2,5.8Hz), 4.05 (dd, 1H, J = 11.2,7.6Hz), 4.02 (d, 1H, J = 9.8Hz), 2.45 (s, 3H), 1.43 (s, 3H), 1.42 (s, 3H), 1.36 (s, 3H), 1.30 (s, 3H).
MS (m / z) 429 (M ⁺ ), 414,371,356,313,296,242,216,198,171.
6-O- [bis (p-toluenesulfonyl) amino] -1,2: 3,4-di-O-isopropylidene-D-psicofuranose
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.66 (d, 4H, J = 8.4 Hz), 7.19 (d, 4H, J = 8.4 Hz), 4.84 (d, 1H, J = 5.8 Hz), 4.62 ( d, 1H, J = 5.8Hz), 4.29 (d, 1H, J = 9.8Hz), 4.32-4.21 (m, 3H), 4.05 (d, 1H, J = 9.8Hz), 2.42 (s, 6H), 1.46 (s, 3H), 1.42 (s, 3H), 1.38 (s, 3H), 1.34 (s, 3H).
MS (m / z) 583 (M ⁺ ), 568,525,411,370,299,270,238,185.

Example 33
To 12 ml of a dichloroethane solution of 1,2: 3,4-di-O-isopropylidene-6-O-amino-D-psicofuranose (1.22 g, 4.43 mmol) obtained in Example 22 at 0 ° C. with pyridine (0.43 ml, 5.3 mmol) and dimethylsulfamoyl chloride (0.57 ml, 5.3 mmol) were added, heated to 70 ° C. and stirred for 9 hours. The reaction was stopped by pouring water, followed by extraction three times with methylene chloride. The organic layer was washed once with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3) to obtain the desired product 1,2: 3,4-di-O-isopropylidene- 6.18 g (yield 70%) of 6-O-dimethylaminosulfonylamino-D-psicofuranose was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.45 (br.s, 1H), 4.75 (d, 1H, J = 5.8 Hz), 4.61 (d, 1H, J = 5.8 Hz), 4.30 (dd, 1H , J = 7.2, 5.9Hz), 4.30 (d, 1H, J = 9.9Hz), 4.08 (dd, 1H, J = 11.2, 5.9Hz), 4.04 (d, 1H, J = 9.9Hz), 4.02 (dd , 1H, J = 11.2, 7.2 Hz), 2.99 (s, 6H), 1.45 (s, 6H), 1.38 (s, 3H), 1.32 (s, 3H).
MS (m / z) 382 (M ⁺ ), 367,324,309,266,229,208,168.

Example 34
1,2: 3,4-Di-O-isopropylidene-6-O-amino-D-psicofuranose (121.4 mg, 0.441 mmol) obtained in Example 22 was dissolved in acetonitrile (4.0 ml) to give methanesulfone. Acid (14 μl, 0.22 mmol) was added and stirred at room temperature for 14 hours. Dilute aqueous ammonia was added to the reaction solution, and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine, dried (Na ₂ SO ₄ ), concentrated, and purified by silica gel chromatography (ethyl acetate: hexane = 1: 1) to obtain the desired product [1R, 5R, 6R, 6.5 mg (7% yield) of 7R] -2-aza-3,8-dioxa-1-hydroxymethyl-6,7-isopropylidenedioxybicyclo [3.2.1] octane was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 4.94 (d, 1 H, J = 5.8 Hz), 4.92 (d, 1 H, J = 5.8 Hz), 4.35 (s, 1 H), 3.95 (d, 1 H, J = 11.0Hz), 3.82 (d, 1H, J = 11.8Hz), 3.76 (d, 1H, J = 11.8Hz), 3.70 (d, 1H, J = 11.0Hz), 3.02 (br.s, 2H), 1.50 (s, 3H), 1.37 (s, 3H).
MS (m / z) 217 (M ⁺ ), 202, 159, 149, 126.

Example 35
[1R, 5R, 6R, 7R] -2-Aza-3,8-dioxa-1-hydroxymethyl-6,7-isopropylidenedioxybicyclo [3.2.1] octane (115 mg) obtained in Example 34 , 530 μmol) in 1 ml of acetonitrile was added 1 ml of methyl chloroformate at 0 ° C. and stirred at room temperature for 24 hours. The reaction was stopped by adding water, extracted three times with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the desired product [1R, 5R, 6R, 7R] -2-aza-3. , 8-Dioxa-1-hydroxymethyl-6,7-isopropylidenedioxy-2-N-methoxycarbonylbicyclo [3.2.1] octane (65.7 mg, yield 45%) was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 4.97 (1H, d, J = 5.6 Hz), 4.91 (1 H, d, J = 5.6 Hz), 4.39 (1 H, m), 4.26 (1 H, dd, J = 6.5,12.6Hz), 4.19 (1H, dd, J = 1.4,11.5Hz), 4.03 (1H, dd, J = 9.7,12.6Hz), 3.84 (3H, s), 3.72 (1H, dd, J = 1.2,11.5Hz), 3.32 (1H, dd, J = 6.5,9.7Hz), 1.51 (3H, s), 1.40 (3H, s).
¹ H-NMR (200 MHz, CDCl ₃ + D ₂ O) δ: 4.96 (1H, d, J = 5.6 Hz), 4.91 (1 H, d, J = 5.6 Hz), 4.39 (1 H, m), 4.25 (1 H , d, J = 12.6Hz), 4.19 (1H, dd, J = 1.4,11.5Hz), 4.02 (1H, d, J = 12.6Hz), 3.84 (3H, s), 3.72 (1H, dd, J = 1.2, 11.5Hz), 1.51 (3H, s), 1.39 (3H, s).
MS (m / z) 275 (M ⁺ ), 260, 217, 159, 126, 69, 59, 44.

Example 36
1,2: 3,4-Di-O-isopropylidene-6-O-phenoxycarbonylamino-D-psicofuranose (481.0 mg, 1.216 mmol) obtained in Example 25 was dissolved in 5 ml of acetonitrile and concentrated at room temperature. Sulfuric acid (7 μl, 10 mmol) was added and stirred at the same temperature for 2.5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with brine, dried, concentrated, and purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the desired product [4R, 5R, 6R. , 7R] -1-aza-5,6-isopropylidenedioxy-2,9,11-trioxatricyclo [5.3.0.1 ^4,7 ] undecan-10-one (243.4 mg, yield) 82.3%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 5.07 (d, 1H, J = 5.3 Hz), 4.95 (d, 1H, J = 5.3 Hz), 4.46 (d, 1H, J = 10.3 Hz), 4.33 ( t, 1H, J = 1.8Hz), 4.31 (d, 1H, J = 10.3Hz), 4.30 (dd, 1H, J = 12.2,1.8Hz), 3.81 (dd, 1H, J = 12.2,1.8Hz), 1.48 (s, 3H), 1.38 (s, 3H).
MS (m / z) 244 (M + 1), 228,205,185,175,149,126.

Example 37
To 5 ml of a dichloroethane solution of 1,2: 3,4-di-O-isopropylidene-6-O- (3,3-dimethylureido) -D-psicofuranose (188 mg, 542 μmol) obtained in Example 30 was added methane. Sulfonic acid (18 μl, 0.27 mmol) was added and stirred at 70 ° C. for 7 and a half hours. The reaction was stopped by pouring water, followed by extraction three times with methylene chloride. The organic layer was washed once with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the desired product [4R, 5R, 6R, 7R] -1-aza-5. , 6-Isopropylidenedioxy-2,9,11-trioxatricyclo [5.3.0.1 ^4,7 ] undecan-10-one 43.4 mg (33% yield) was obtained.

  The instrument data matched that of Example 36.

Example 38
[4R, 5R, 6R, 7R] -1-aza-5,6-isopropylidenedioxy-2,9,11-trioxatricyclo [5.3.0.1 ^4,7 obtained in Example 36] To a methanol (MeOH) solution (10 ml) of undecan-10-one (1.14 g, 4.70 mol), 10 ml of 1N NaOH aqueous solution was added and stirred at 50 ° C. for 1.5 hours. 1N hydrochloric acid (HCl) aqueous solution was added to neutralize the reaction solution, followed by extraction five times with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 4) to obtain the desired product [1R, 5R, 6R, 7R] -2-aza-3. , 8-dioxa-1-hydroxymethyl-6,7-isopropylidenedioxybicyclo [3.2.1] octane (873 mg, yield 86%) was obtained.

  The instrument data matched that of Example 34.

Example 39
1,2: 3,4-Di-O-isopropylidene-6-O-methoxycarbonylamino-D-psicofuranose (4.33 g, 13.0 mmol) obtained in Example 10 was dissolved in dichloroethane and methanesulfone at room temperature. Acid (0.42 ml) was added and stirred for 30 minutes. Water was added to this reaction solution, extracted with methylene chloride, washed with brine, dried, concentrated and purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 2: 3). [1R, 5R, 6R, 7R] -2-aza-3,8-dioxa-1-hydroxymethyl-6,7-isopropylidenedioxy-2-N-methoxycarbonylbicyclo [3.2.1] octane 3.215 g (yield 90%) was obtained.

  The instrument data matched that of Example 35.

Example 40
1,2: 3,4-Di-O-isopropylidene-6-O-ethoxycarbonylamino-D-psicofuranose (5.26 g, 15.1 mmol) obtained in Example 12 was dissolved in acetonitrile (50 ml) at room temperature. Then, 0.04 ml of concentrated sulfuric acid was added and stirred for 4 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with saturated brine, dried (Na ₂ SO ₄ ), concentrated, and purified by silica gel chromatography (ethyl acetate: hexane = 1: 3) to obtain the desired product [1R, 5R, 6R, 7R] -2-aza-3,8-dioxa-2-N-ethoxycarbonyl-1-hydroxymethyl-6,7-isopropylidenedioxybicyclo [3.2.1] octane (3.00 g, yield 68%) )Obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 4.97 (1H, d, J = 5.6 Hz), 4.91 (1 H, d, J = 5.6 Hz), 4.39 (1 H, m), 4.29 (2 H, q, J = 7.1Hz), 4.25 (1H, dd, J = 6.4,12.6Hz), 4.20 (1H, dd, J = 1.4,11.6Hz), 4.03 (1H, dd, J = 9.7,12.6Hz), 3.72 (1H , dd, J = 1.2,11.6Hz), 3.35 (1H, dd, J = 6.4,9.7Hz), 1.52 (3H, s), 1.40 (3H, s), 1.35 (3H, t, J = 7.1Hz) .
¹ H-NMR (200 MHz, CDCl ₃ + D ₂ O) δ: 4.96 (1H, d, J = 5.6 Hz), 4.91 (1 H, d, J = 5.6 Hz), 4.39 (1 H, m), 4.29 (2 H , q, J = 7.1Hz), 4.24 (1H, d, J = 12.6Hz), 4.20 (1H, dd, J = 1.4,11.5Hz), 4.02 (1H, d, J = 12.6Hz), 3.72 (1H , dd, J = 1.2,11.5Hz), 1.51 (3H, s), 1.40 (3H, s), 1.35 (3H, t, J = 7.1Hz).
MS (m / z) 289 (M ⁺ ), 274, 231, 173, 126, 69, 59, 44.

Example 41
1,2: 3,4-Di-O-isopropylidene-6-O-isopropyloxycarbonylamino-D-psicofuranose (1.58 g, 4.37 mmol) obtained in Example 14 was dissolved in acetonitrile (16.0 mL). At room temperature, concentrated sulfuric acid (0.02 ml, 0.9 mmol) was added and stirred for 2 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with saturated brine, dried (Na ₂ SO ₄ ) and concentrated. The crude product was purified by silica gel chromatography (ethyl acetate: hexane = 1: 3), and the desired product [1R , 5R, 6R, 7R] -2-aza-3,8-dioxa-1-hydroxymethyl-6,7-isopropylidenedioxy-2-N-isopropyloxycarbonylbicyclo [3.2.1] octane is 0.93. g (yield 70%) was obtained.

¹ H-NMR (200 MHz, CDCl ₃ + D ₂ O) δ: 5.06 (1H, qq, J = 6.3,6.3Hz), 4.95 (1H, d, J = 5.6Hz), 4.90 (1H, d, J = 5.6Hz), 4.38 (1H, brd.s), 4.23 (1H, d, J = 12.5Hz), 4.17 (1H, dd, J = 1.3,12.6Hz), 4.01 (1H, d, J = 12.6Hz) , 3.70 (1H, dd, J = 1.3,12.6Hz), 1.51 (3H, s), 1.40 (3H, s), 1.34 (3H, d, J = 6.3Hz), 1.32 (3H, d, J = 6.3 Hz).
MS (m / z) 303 (M ⁺ ), 288,244,217,159,149,126,69,59,44.

Example 42
To a solution of 1,2: 3,4-di-O-isopropylidene-6-O-isobutyloxycarbonylamino-D-psicofuranose (147.9 mg, 0.394 mmol) obtained in Example 16 in dichloroethane (5 ml). At room temperature, methanesulfonic acid (13 μl, 0.20 mmol) was added and stirred at the same temperature for 1 hour. Water was added to the reaction solution, extracted with ethyl acetate, washed with brine, dried, concentrated, and purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 3: 1) to obtain the desired product [ 1R, 5R, 6R, 7R] -2-aza-3,8-dioxa-1-hydroxymethyl-2-N-isobutyloxycarbonyl-6,7-isopropylidenedioxybicyclo [3.2.1] octane. 77.0 mg (yield 62%) was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 4.97 (1H, d, J = 5.6Hz), 4.91 (1H, d, J = 5.6Hz), 4.39 (1H, br.s), 4.29-4.16 (2H , m), 4.08-3.93 (3H, m), 3.72 (1H, br.d, J = 11.6Hz), 3.34 (1H, dd, J = 6.5,9.8Hz), 2.02 (1H, qq, J = 6.6 Hz), 1.51 (3H, s), 1.40 (3H, s), 0.97 (6H, d, J = 6.6Hz).
¹ H-NMR (200 MHz, CDCl ₃ + D ₂ O) δ: 4.97 (1H, d, J = 5.6 Hz), 4.91 (1 H, d, J = 5.6 Hz), 4.39 (1 H, br.s), 4.23 (1H, d, J = 12.5Hz), 4.19 (1H, br.d, J = 11.7Hz), 4.06-3.93 (2H, m), 4.01 (1H, d, J = 12.5Hz), 3.72 (1H, br.d, J = 11.7Hz), 2.02 (1H, qq, J = 6.6Hz), 1.51 (3H, s), 1.40 (3H, s), 0.96 (6H, d, J = 6.6Hz).
MS (m / z) 317 (M ⁺ ), 302,259,167,149,126,69,57,42.

Example 43
6-O-benzyloxycarbonylamino-1,2: 3,4-di-O-isopropylidene-D-psicofuranose (6.18 g, 15.1 mmol) obtained in Example 26 was dissolved in acetonitrile (100 ml) at room temperature. Concentrated sulfuric acid (0.20 mL) was added and stirred for 5 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with saturated brine, dried (Na ₂ SO ₄ ), concentrated, and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to obtain the desired product [1R, 5R, 6R. , 7R] -2-aza-2-N-benzyloxycarbonyl-3,8-dioxa-1-hydroxymethyl-6,7-isopropylidenedioxybicyclo [3.2.1] octane (4.59 g, yield) 80%).

¹ H-NMR (200 MHz, CDCl ₃ + D ₂ O) δ: 7.38 (5H, s), 5.32-5.17 (2H, m), 4.97 (1H, d, J = 5.5Hz), 4.90 (1H, d, J = 5.5Hz), 4.38 (1H, m), 4.26 (1H, d, J = 12.5Hz), 4.18 (1H, d, J = 11.6Hz), 4.02 (1H, d, J = 12.5Hz), 3.71 (1H, d, J = 11.6Hz), 1.51 (3H, s), 1.39 (3H, s).
MS (m / z) 349 (M ⁺ ), 334,290,260,216,113,92,69,59,44.

Example 44
In the same manner as in Example 39, from the 6-O-acetamido-1,2: 3,4-di-O-isopropylidene-D-psicofuranose (192 mg, 604 μmol) obtained in Example 27, the desired product [ 1R, 5R, 6R, 7R] -2-aza-2-N-acetyl-3,8-dioxa-1-hydroxymethyl-6,7-isopropylidenedioxybicyclo [3.2.1] octane 8.6 mg ( Yield 5.5%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 4.93 (d, 1 H, J = 5.6 Hz), 4.91 (d, 1 H, J = 5.6 Hz), 4.36 (t, 1 H, J = 0.7 Hz), 4.35 ( d, 1H, J = 8.1Hz), 4.21 (d, 1H, J = 8.1Hz), 3.96 (dd, 1H, J = 11.0, 0.7Hz), 3.69 (dd, 1H, J = 11.0, 0.7Hz), 2.11 (s, 3H), 1.88 (1H, br.s), 1.49 (s, 3H), 1.37 (s, 3H).
MS (m / z) 259 (M ⁺ ), 244,219,201,175,149,126.

Example 45
In the same manner as in Example 39, from the 6-O-benzamide-1,2: 3,4-di-O-isopropylidene-D-psicofuranose (241 mg, 635 μmol) obtained in Example 28, the desired product [ 1R, 5R, 6R, 7R] -2-aza-2-N-benzoyl-3,8-dioxa-1-hydroxymethyl-6,7-isopropylidenedioxybicyclo [3.2.1] octane 42.7 mg ( Yield 21%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 8.08-8.03 (m, 2H), 7.62-7.41 (m, 3H), 5.01 (d, 1H, J = 5.6Hz), 4.94 (d, 1H, J = 5.6Hz), 4.62 (d, 1H, J = 12.2Hz), 4.47 (d, 1H, J = 12.2Hz), 4.39 (t, 1H, J = 1.4Hz), 3.98 (dd, 1H, J = 11.6, 1.4Hz), 3.96 (br.s, 1H), 3.72 (dd, 1H, J = 11.6, 1.4Hz), 1.52 (s, 3H), 1.39 (s, 3H).
MS (m / z) 321 (M ⁺ ), 306, 279, 263, 216, 163, 149.

Example 46
To a dichloroethane solution (5 ml) of 1,2: 3,4-di-O-isopropylidene-6-O-methanesulfonylamino-D-psicofuranose (209 mg, 592 μmol) obtained in Example 31, was added methanesulfonic acid ( 19 μl, 0.30 mmol) was added dropwise and stirred at room temperature for 90 minutes. The reaction was stopped by pouring water, followed by extraction three times with methylene chloride. The organic layer was washed once with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel chromatography (hexane: ethyl acetate = 2: 3) to obtain the desired product [1R, 5R, 6R, 7R] -2-aza-3, 135 mg (yield 77%) of 8-dioxa-1-hydroxymethyl-6,7-isopropylidenedioxy-2-N-methanesulfonylbicyclo [3.2.1] octane was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 4.97 (d, 1 H, J = 5.5 Hz), 4.89 (d, 1 H, J = 5.5 Hz), 4.80 (dd, 1 H, J = 11.4, 0.9 Hz), 4.46 (t, 1H, J = 0.9Hz), 4.30 (d, 1H, J = 13.2Hz), 4.03 (d, 1H, J = 13.2Hz), 3.71 (dd, 1H, J = 11.4, 0.9Hz), 3.16 (s, 3H), 2.61 (br.s, 1H), 1.50 (s, 3H), 1.39 (s, 3H).
MS (m / z) 295 (M ⁺ ), 280,266,237,216,179,149,126.

Example 47
In the same manner as in Example 39, from 1,2: 3,4-di-O-isopropylidene-6-Op-toluenesulfonylamino-D-psicofuranose (121 mg, 281 μmol) obtained in Example 32 The desired product [1R, 5R, 6R, 7R] -2-aza-3,8-dioxa-1-hydroxymethyl-6,7-isopropylidenedioxy-2-Np-toluenesulfonylbicyclo [3.2 .1] 73.5 mg (yield 71%) of octane was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.84 (d, 2H, J = 8.4Hz), 7.35 (d, 2H, J = 8.4Hz), 4.93 (d, 1H, J = 5.6Hz), 4.79 ( d, 1H, J = 5.6Hz), 4.62 (dd, 1H, J = 11.5, 1.1Hz), 4.47 (d, 1H, J = 12.9Hz), 4.39 (t, 1H, J = 1.1Hz), 4.12 ( d, 1H, J = 12.9Hz), 4.08 (br.s, 1H), 3.52 (dd, 1H, J = 11.5,1.1Hz), 2.46 (s, 3H), 1.51 (s, 3H), 1.36 (s , 3H).
MS (m / z) 371 (M ⁺ ), 356,313,295,279,252,216,155,126.

Example 48
In the same manner as in Example 39, from 1,2: 3,4-di-O-isopropylidene-6-O-dimethylaminosulfonylamino-D-psicofuranose (407 mg, 1.06 mmol) obtained in Example 33 The desired product [1R, 5R, 6R, 7R] -2-aza-2-N-dimethylaminosulfonyl-3,8-dioxa-1-hydroxymethyl-6,7-isopropylidenedioxybicyclo [3.2. 1] 296 mg (yield 86%) of octane was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 5.00 (d, 1 H, J = 5.6 Hz), 4.86 (d, 1 H, J = 5.6 Hz), 4.79 (dd, 1 H, J = 11.4, 0.9 Hz) , 4.42 (t, 1H, J = 0.9Hz), 4.16 (d, 1H, J = 12.9Hz), 3.99 (d, 1H, J = 12.9Hz), 3.59 (dd, 1H, J = 11.4, 0.9Hz) 2.96 (s, 6H), 2.74 (br.s, 1H), 1.51 (s, 3H), 1.39 (s, 3H).
MS (m / z) 324 (M ⁺ ), 309,266,216,166,126.

Example 49
Methylene chloride (100 ml) to which oxalyl chloride (4.0 ml, 45.5 mmol) was added was cooled to −50 ° C. or lower, and a solution of dimethyl sulfoxide (6.46 ml, 91 mmol) in methylene chloride (120 ml) was added. [1R, 5R, 6R, 7R] -2-aza-3,8-dioxa-1-hydroxymethyl-6,7-isopropylidenedioxy-2-N-methoxy obtained in Example 39 125 ml of methylene chloride solution in which carbonylbicyclo [3.2.1] octane (5.01 g, 18.2 mmol) was dissolved was added. The mixture was stirred at the same temperature for 30 minutes, triethylamine (20.3 ml, 145 mmol) was added, the temperature was gradually raised, and the mixture was stirred at 0 ° C. for 30 minutes. To this reaction solution was added aqueous ammonium chloride (NH ₄ Cl aq), extracted with methylene chloride, washed with 1N-HCl and brine, dried and concentrated to obtain 5.86 g of a crude product. This was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 1: 2), and the desired product [1S, 5R, 6R, 7R] -2-aza-3,8-dioxa-1-formyl 3.928 g (yield 77%) of 2-N-methoxycarbonyl-6,7-isopropylidenedioxybicyclo [3.2.1] octane was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 9.38 (1H, s), 5.25 (1H, d, J = 5.5Hz), 4.97 (1H, d, J = 5.5Hz), 4.55 (1H, m), 4.22 (1H, dd, J = 1.5,11.9Hz), 3.85 (3H, s), 3.72 (1H, dd, J = 1.2,11.9Hz), 1.44 (3H, s), 1.34 (3H, s).
MS (m / z) 273 (M ⁺ ), 258,157,142,85,73,59,44.

Example 50
Oxalyl chloride (4.0 ml, 46.1 mmol) was dissolved in methylene chloride (110 ml), and a solution of dimethyl sulfoxide (5.4 ml, 77 mmol) in methylene chloride (5 ml) was added dropwise at -60 ° C. After stirring for 15 minutes, [1R, 5R, 6R, 7R] -2-aza-3,8-dioxa-2-N-ethoxycarbonyl-1-hydroxymethyl-6,7-isopropylid obtained in Example 40 was obtained. A solution of dendoxybicyclo [3.2.1] octane (11.12 g, 38.4 mmol) dissolved in methylene chloride (15 ml) was added dropwise at −60 ° C. and stirred for 30 minutes. Triethylamine (16.1 ml, 115 mmol) was added at −60 ° C. and stirred for 15 minutes, then the temperature was raised to 0 ° C. and stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted 3 times with methylene chloride. The combined organic layers were washed with dilute hydrochloric acid and half-saturated brine, dried (Na ₂ SO ₄ ), concentrated, and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to obtain the desired product [1S, 5R, 6R, 7R] -2-aza-2-N-ethoxycarbonyl-3,8-dioxa-1-formyl-6,7-isopropylidenedioxybicyclo [3.2.1] octane Rate 98%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 9.39 (1H, s), 5.62 (1H, d, J = 5.5Hz), 4.97 (1H, d, J = 5.5Hz), 4.55 (1H, br.s ), 4.30 (2H, q, J = 7.1Hz), 4.23 (1H, dd, J = 1.5, 11.9Hz), 3.72 (1H, dd, J = 1.1, 11.9Hz), 1.45 (3H, s), 1.35 (3H, s), 1.32 (3H, t, J = 7.1Hz).
MS (m / z) 287 (M ⁺ ), 272,171,98,85,71,59,44.

Example 51
Oxalyl chloride (1.1 ml, 13 mmol) was dissolved in methylene chloride (50 ml), and at −60 ° C., a solution of dimethyl sulfoxide (1.7 ml, 23 mmol) in methylene chloride (3.7 ml) was added. After stirring for 15 minutes, [1R, 5R, 6R, 7R] -2-aza-2-N-benzyloxycarbonyl-3,8-dioxa-1-hydroxymethyl-6,7-isopropylate obtained in Example 43 was obtained. A solution of redidenedioxybicyclo [3.2.1] octane (4.12 g, 11.7 mmol) in methylene chloride (14 ml) was added at −60 ° C. and stirred for 30 minutes. Triethylamine (5.4 ml, 39 mmol) was added at −60 ° C. and stirred for 15 minutes, then the temperature was raised to 0 ° C. and stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted 3 times with methylene chloride. The combined organic layers were washed with dilute hydrochloric acid and half-saturated brine, dried (Na ₂ SO ₄ ), concentrated, and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to obtain the desired product [1S, 5R, 6R, 7R] -2-aza-2-N-benzyloxycarbonyl-3,8-dioxa-1-formyl-6,7-isopropylidenedioxybicyclo [3.2.1] octane (3.77 g) Yield 92%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 9.38 (1H, s), 7.36 (5H, s), 5.25 (2H, ABq, J = 12.7Hz), 5.25 (1H, d, J = 5.4Hz), 4.96 (1H, d, J = 5.4Hz), 4.54 (1H, br.s), 4.17 (1H, dd, J = 1.3,11.6Hz), 3.69 (1H, br.d, J = 11.6Hz), 1.44 (3H, s), 1.34 (3H, s).

Example 52
Oxalyl chloride (0.80 ml, 9.1 mmol) was dissolved in methylene chloride (25 ml), and a solution of dimethyl sulfoxide (1.10 ml, 15.2 mmol) in methylene chloride (2.0 ml) was added at -60 ° C. After stirring for 15 minutes, [1R, 5R, 6R, 7R] -2-aza-3,8-dioxa-1-hydroxymethyl-6,7-isopropylidenedioxy-2-N- obtained in Example 46 was obtained. A solution of methanesulfonylbicyclo [3.2.1] octane (2.24 g, 7.58 mmol) in methylene chloride (5 ml) was added and stirred for 15 minutes. Further, triethylamine (3.20 ml, 22.7 mmol) was added at −60 ° C. and stirred for 15 minutes, then the temperature was raised to 0 ° C. and stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted 3 times with methylene chloride. The combined organic layers were washed with dilute hydrochloric acid and half-saturated brine, dried (Na ₂ SO ₄ ), concentrated, and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to obtain the desired product [1S, 5R, 6R, 7R] -2-aza-3,8-dioxa-1-formyl-6,7-isopropylidenedioxy-2-N-methanesulfonylbicyclo [3.2.1] octane Rate 90%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 9.39 (1 H, s), 5.18 (1 H, d, J = 5.4 Hz), 5.00 (1 H, dd, J = 1.9, 11.8 Hz), 4.94 (1 H, d , J = 5.4Hz), 4.65 (1H, dd, J = 1.0,1.9Hz), 3.70 (1H, dd, J = 1.0,11.8Hz), 3.09 (3H, s), 1.44 (3H, s), 1.34 (3H, s).
MS (m / z) 294 (M ⁺ +1), 278,214,162,149,79,59,44.

Example 53
[1R, 5R, 6R, 7R] -2-aza-3,8-dioxa-2-N-ethoxycarbonyl-1-hydroxymethyl-6,7-isopropylidenedioxybicyclo obtained in Example 40 [3. 2.1] Octane (1.0018 g, 3.463 mmol) and 2,2,6,6, -tetramethyl-1-piperidinyloxy free radical (TEMPO) (10 mg) were dissolved in 10 ml of methylene chloride, Saturated sodium bicarbonate aqueous solution in which 50.6 mg of tetra-n-butylammonium chloride was dissolved was added, and 3.5 ml of sodium hypochlorite aqueous solution [1.2M], 1.7 ml of saturated sodium bicarbonate aqueous solution and saturated saline at 0 ° C. 3.5 ml of the mixed solution was added over 9 minutes. The mixture was stirred at 0 ° C. for 40 minutes and then at room temperature for 40 minutes. Further, 1.7 ml of an aqueous sodium hypochlorite solution was added, and the mixture was stirred at the same temperature for 45 minutes. The reaction solution was adjusted to pH 2 with 1N-NCl, extracted with ethyl acetate, dried, concentrated, purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1), and the desired product [1S, 5R, 6R, 7R]- There was obtained 637.6 mg (64% yield) of 2-aza-2-N-ethoxycarbonyl-3,8-dioxa-1-formyl-6,7-isopropylidenedioxybicyclo [3.2.1] octane.

  The instrument data matched that of Example 50.

Example 54
[1R, 5R, 6R, 7R] -2-aza-3,8-dioxa-1-hydroxymethyl-6,7-isopropylidenedioxy-2-N-methoxycarbonylbicyclo obtained in Example 39 [3. 2.1] Saturated hydrogen carbonate in which octane (452.6 mg, 1.644 mmol) and TEMPO (10 mg) are dissolved in methylene chloride (4 ml) and potassium bromide (18 mg) and tetra-n-butylammonium chloride (24.2 mg) are dissolved. Sodium solution (3.3 ml) was added, and a mixed solution of sodium hypochlorite aqueous solution ([1.2M] 4.5 ml), saturated aqueous sodium bicarbonate solution 2.25 ml and saturated brine 4.5 ml was added at 0 ° C. over 15 minutes. It was. After stirring at 0 ° C. for 40 minutes, the mixture was stirred at room temperature for 20 minutes, an aqueous sodium sulfite solution was added, and the mixture was adjusted to pH 2 with 1N-NCl and extracted with ethyl acetate. The obtained ethyl acetate layer was dried, concentrated and purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the desired product [1S, 5R, 6R, 7R] -2-aza-3,8. -Dioxa-1-formyl-2-N-methoxycarbonyl-6,7-isopropylidenedioxybicyclo [3.2.1] octane (272.6 mg, yield 61%) was obtained.

  The instrument data matched that of Example 49.

Example 55
[1S, 5R, 6R, 7R] -2-Aza-3,8-dioxa-1-formyl-2-N-methoxycarbonyl-6,7-isopropylidenedioxybicyclo [3.2] obtained in Example 49 .1] Octane (1.0025 g, 3.669 mmol) was dissolved in a mixed solvent of water (5 ml) -1,4-dioxane (20 ml), and sodium dihydrogen phosphate dihydrate (NaH ₂ PO ₄ ) at 55 ° C. -15 ml of an aqueous solution of 2H ₂ O) (1.171 g) and sodium chlorite (NaClO ₂ ) (1.659 g) was added and stirred at the same temperature for 5 hours. Further, 5 ml of an aqueous solution of NaH ₂ PO ₄ .2H ₂ O (859 mg) and NaClO ₂ (829 mg) was added and stirred with heating for 1.5 hours. To this reaction solution, an aqueous solution of sodium sulfite (Na ₂ SO ₃ ) was added to adjust the pH to 3 with 1N-NCl, extracted with ethyl acetate, dried and concentrated, and the target product [1S, 5R, 6R, 7R] -2-aza-1-carboxy 1.01 g (yield 95%) of a crude product of -3,8-dioxa-6,7-isopropylidenedioxy-2-N-methoxycarbonylbicyclo [3.2.1] octane was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 5.25 (1H, d, J = 5.5 Hz), 4.96 (1 H, d, J = 5.5 Hz), 4.59 (1 H, m), 4.20 (1 H, dd, J = 1.5, 11.9Hz), 3.85 (3H, s), 3.69 (1H, dd, J = 0.9, 11.9Hz), 1.49 (3H, s), 1.38 (3H, s).
MS (m / z) 289 (M ⁺ ), 274, 214, 142, 73, 69, 59, 44.

Example 56
[1S, 5R, 6R, 7R] -2-aza-2-N-ethoxycarbonyl-3,8-dioxa-1-formyl-6,7-isopropylidenedioxybicyclo [3.2] obtained in Example 50 .1] Octane (3.41 g, 11.9 mmol) was dissolved in 1,4-dioxane (20 ml), and at room temperature, sodium chlorite (4.83 ml, 53.4 mmol) and sodium dihydrogen phosphate dihydrate ( 4.45 g, 29.7 mmol) of an aqueous solution (15 ml) was added. After stirring at 55 ° C. for 1 hour, a saturated aqueous sodium sulfite solution was added to decompose the generated chlorine. The reaction mixture was concentrated, [1N] aqueous sodium hydride solution (15 ml) was added, and the aqueous layer was washed with ether (50 ml × 2). The aqueous layer was adjusted to pH 3 with [4N] hydrochloric acid, and further stirred with 10 g of sodium chloride. The aqueous layer was extracted 6 times with ethyl acetate, and the combined organic layer was dried (Na ₂ SO ₄ ), concentrated, and the target product [1S, 5R, 6R, 7R] -2-aza-1-carboxy-3, 2.75 g (yield 76%) of 8-dioxa-2-N-ethoxycarbonyl-6,7-isopropylidenedioxybicyclo [3.2.1] octane was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.36 (1H, br.), 5.23 (1H, d, J = 4.8Hz), 4.96 (1H, dd, J = 0.9, 5.4Hz), 4.58 (1H, br.s), 4.29 (2H, q, J = 7.6Hz), 4.20 (1H, d, J = 11.9Hz), 3.68 (1H, d, J = 11.9Hz), 1.47 (3H, s), 1.37 ( 3H, s), 1.25 (3H, t, J = 7.6Hz).
MS (m / z) 303 (M ⁺ ), 268, 173, 142, 126, 83, 69, 59, 44.

Example 57
[1S, 5R, 6R, 7R] -2-aza-2-N-benzyloxycarbonyl-3,8-dioxa-1-formyl-6,7-isopropylidenedioxybicyclo [3. 2.1] Octane (3.77 g, 10.8 mmol) was dissolved in 1,4-dioxane (40 ml), sodium dihydrogen phosphate dihydrate (3.24 g, 21.6 mmol), and sodium chlorite (4.40 g , 48.6 mmol) in water (38 ml) was added. After stirring at 60 ° C. for 2 hours, a saturated aqueous sodium sulfite solution was added to decompose the generated chlorine. The reaction mixture was concentrated, [1N] aqueous sodium hydroxide solution (15 ml) was added, and the aqueous layer was washed with ether (50 ml). The aqueous layer was adjusted to pH 3 with dilute hydrochloric acid, extracted from the aqueous layer 6 times with ethyl acetate, and the combined organic layer was dried (Na ₂ SO ₄ ), concentrated and the target product [1S, 5R, 6R, 7R] -2-aza 2.65 g (92% yield) of 2-N-benzyloxycarbonyl-1-carboxy-3,8-dioxa-6,7-isopropylidenedioxybicyclo [3.2.1] octane was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.38-7.31 (5H, m), 6.40 (1H, br.s), 5.24 (2H, ABq, J = 12.0Hz), 5.24 (1H, d, J = 5.5Hz), 4.95 (1H, d, J = 5.5Hz), 4.57 (1H, m), 4.14 (1H, dd, J = 1.1, 12.0Hz), 3.66 (1H, br.d, J = 12.0Hz) , 1.47 (3H, s), 1.36 (3H, s).
MS (m / z) 365 (M ⁺ ), 350,321,234,176,91,69,59.

Example 58
[1S, 5R, 6R, 7R] -2-Aza-3,8-dioxa-1-formyl-6,7-isopropylidenedioxy-2-N-methanesulfonylbicyclo obtained in Example 52 [3.2 .1] Octane (2.14 g, 7.30 mmol) was dissolved in 1,4-dioxane (10 ml), sodium dihydrogen phosphate dihydrate (2.27 g, 15.2 mmol), and sodium chlorite (3.30 g 36.5 mmol) in water (10 ml) was added. After stirring at 55 ° C. for 2 hours, a saturated aqueous sodium sulfite solution was added to decompose the generated chlorine. The reaction mixture was concentrated, [1N] aqueous sodium hydroxide solution (10 ml) was added, and the aqueous layer was washed with ether (50 ml). The aqueous layer was pH3 with dilute hydrochloric acid, and extracted six times with with ethyl acetate the aqueous layer, the combined organic layers dried (Na ₂ SO _4), concentrated, the desired product [1S, 5R, 6R, 7R ] -2- aza 2.02 g (yield 89%) of -1-carboxy-3,8-dioxa-6,7-isopropylidenedioxy-2-N-methanesulfonylbicyclo [3.2.1] octane was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 5.15 (1H, d, J = 5.4 Hz), 4.96 (1 H, dd, J = 1.6, 13.5 Hz), 4.93 (1 H, d, J = 5.4 Hz), 5.05-4.75 (1H, br.), 4.70 (1H, br.s), 3.68 (1H, d, J = 13.5Hz), 3.11 (3H, s), 1.48 (3H, s), 1.37 (3H, s ).
MS (m / z) 309 (M ⁺ ), 294,279,250,230,145,85,79,59,44.

Example 59
[1S, 5R, 6R, 7R] -2-Aza-1-carboxy-3,8-dioxa-6,7-isopropylidenedioxy-2-N-methoxycarbonylbicyclo obtained in Example 55 [3.2 .1] Octane (1.70 g, 5.62 mmol) was dissolved in methylene chloride (35.0 ml), and pyridine (0.94 ml, 13 mmol) and thionyl chloride (0.74 ml, 10 mmol) were added at 0 ° C. for 1 hour at room temperature. Stirred. The reaction mixture was concentrated, the concentrate was dissolved in methylene chloride (30 ml), and ammonia gas was introduced at 0 ° C. for 10 minutes. After stirring at room temperature for 1 hour, water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with saturated brine, dried (Na ₂ SO ₄ ) and concentrated. The obtained crude product was purified by silica gel chromatography (ethyl acetate), and the desired product [1S, 5R, 6R, 7R] -2-aza-1-carbamoyl-3,8-dioxa-6,7-isopropyl. 1.49 g (yield 92%) of lidenedioxy-2-N-methoxycarbonylbicyclo [3.2.1] octane was obtained.

¹ H-NMR (200 MHz, DMSOd ₆ ) δ: 7.31 (1H, br.s), 7.04 (1H, br.s), 5.00 (1H, d, J = 5.5Hz), 4.95 (1H, d, J = 5.5Hz), 4.65 (1H, br.s), 3.95 (1H, dd, J = 1.4, 11.8Hz), 3.82 (1H, br.d, J = 11.8Hz), 3.72 (3H, s), 1.38 ( 3H, s), 1.30 (3H, s).
MS (m / z) 288 (M ⁺ ), 273,200,142,127,85,73,69,59,44.

Example 60
[1S, 5R, 6R, 7R] -2-Aza-1-carboxy-3,8-dioxa-2-N-ethoxycarbonyl-6,7-isopropylidenedioxybicyclo [3.2] obtained in Example 56 .1] Octane (9.35 g, 30.8 mmol) was dissolved in ethyl acetate (100 ml) and pyridine (4.5 ml, 62 mmol) and thionyl chloride (2.7 ml, 37 mmol) were added at 0 ° C. After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure. The concentrate thus obtained was suspended in methylene chloride (100 ml), and ammonia gas was introduced at 0 ° C. The reaction mixture was further stirred at room temperature for 1 hour, water was added to the reaction mixture, and the mixture was extracted 3 times with methylene chloride. The combined organic layers were washed with half-saturated brine, dried (Na ₂ SO ₄ ), concentrated, and the target product [1S, 5R, 6R, 7R] -2-aza-1-carbamoyl-3,8-dioxa- 7.79 g (84% yield) of 2-N-ethoxycarbonyl-6,7-isopropylidenedioxybicyclo [3.2.1] octane was obtained.

¹ H-NMR (200 MHz, DMSOd ₆ ) δ: 7.29 (1H, br.s), 7.04 (1H, br.s), 4.99 (1H, d, J = 5.5Hz), 4.94 (1H, d, J = 5.5Hz), 4.56 (1H, br.s), 4.17 (2H, q, J = 7.0Hz), 3.95 (1H, br.d, J = 11.5Hz), 3.82 (1H, br.d, J = 11.5) Hz), 1.38 (3H, s), 1.30 (3H, s), 1.23 (3H, t, J = 7.0 Hz).
MS (m / z) 303 (M ⁺ +1), 287, 230, 172, 99, 85, 70, 57, 44.

Example 61
[1S, 5R, 6R, 7R] -2-aza-2-N-benzyloxycarbonyl-1-carboxy-3,8-dioxa-6,7-isopropylidenedioxybicyclo obtained in Example 57 [3. 2.1] Octane (3.32 g, 9.09 mmol) was dissolved in ethyl acetate (50 ml), and at 0 ° C., pyridine (0.90 ml, 11 mmol) and thionyl chloride (1.3 ml, 11 mmol) were added and stirred for 10 minutes. After stirring at room temperature for 1.5 hours, ethyl acetate (100 ml) was added to the reaction solution to reach 0 ° C., and ammonia gas was introduced for 5 minutes. After stirring at room temperature for 5 hours, water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with dilute hydrochloric acid and saturated brine, dried (Na ₂ SO ₄ ), concentrated, and the target product [1S, 5R, 6R, 7R] -2-aza-2-N-benzoyloxycarbonyl-1 -2.52 g (76% yield) of carbamoyl-3,8-dioxa-6,7-isopropylidenedioxybicyclo [3.2.1] octane was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.39-7.32 (5H, m), 6.30 (1H, br.s), 5.52 (1H, br.s), 5.26 (1H, d, J = 5.4Hz) , 5.25 (2H, s), 4.91 (1H, d, J = 5.4Hz), 4.53 (1H, m), 4.13 (1H, dd, J = 1.4,12.0Hz), 3.67 (1H, dd, J = 1.1 , 12.0Hz), 1.47 (3H, s), 1.37 (3H, s).
MS (m / z) 365 (M ⁺ +1), 349,232,203,190,177,132,106,91,69,59.

Example 62
[1S, 5R, 6R, 7R] -2-Aza-1-carboxy-3,8-dioxa-6,7-isopropylidenedioxy-2-N-methanesulfonylbicyclo obtained in Example 58 [3.2 .1] Octane (1.87 g, 6.04 mmol) was dissolved in ethyl acetate (30 ml), and at 0 ° C., thionyl chloride (0.53 ml, 7.2 mmol) and pyridine (0.98 ml, 12.8 mmol) were added to room temperature. Stir for 1 hour. Subsequently, ammonia gas was introduced into the reaction solution for 10 minutes and further stirred for 2 hours. Water was added to the reaction mixture, and the aqueous layer was extracted 6 times with ethyl acetate. The combined organic layers were washed with saturated brine, dried (Na ₂ SO ₄ ), concentrated, and the target product [1S, 5R, 6R, 7R] -2-aza-1-carbamoyl-3,8-dioxa-6 , 7-isopropylidenedioxy-2-N-methanesulfonylbicyclo [3.2.1] octane (0.76 g, yield 41%) was obtained.

¹ H-NMR (200 MHz, DMSOd ₆ ) δ: 7.45 (1H, br.s), 7.27 (1H, br.s), 4.95 (2H, s), 4.64 (1H, br.s), 4.58 (1H, br.d, J = 11.7Hz), 3.86 (1H, br.d, J = 11.7Hz), 3.16 (3H, s), 1.38 (3H, s), 1.30 (3H, s).
MS (m / z) 308 (M ⁺ ), 293,276,250,129,123,65,69,59,44.

Example 63
[1S, 5R, 6R, 7R] -2-Aza-2-N-benzyloxycarbonyl-1-carbamoyl-3,8-dioxa-6,7-isopropylidenedioxybicyclo [3. 2.1] Octane (296.3 mg) was dissolved in 6 ml of methanol, 30 mg of Pd / C (10%) was added at room temperature, and a hydrogenation reaction was performed at 40 ° C. under normal pressure. The reaction solution was filtered through celite, concentrated, and the target product [1S, 5R, 6R, 7R] -2-aza-1-carbamoyl-3,8-dioxa-6,7-isopropylidenedioxybicyclo [3.2 .1] 180.0 mg (96% yield) of octane was obtained.

¹ H-NMR (200 MHz, DMSOd ₆ ) δ: 7.35 (1H, br.s), 7.18 (1H, br.s), 6.90 (1H, s), 4.83 (2H, br.s), 4.33 (1H, br.s), 3.80 (1H, d, J = 10.8Hz), 3.63 (1H, d, J = 10.8Hz), 1.37 (3H, s), 1.28 (3H, s).
MS (m / z) 230 (M ⁺ ), 215,172,125,85,69,59,44.

Example 64
[1S, 5R, 6R, 7S] -2-Aza-1-carbamoyl-3,8-dioxa-6,7-isopropylidenedioxybicyclo [3.2.1] octane (30.0 mg) obtained in Example 63 0.130 mmol) was dissolved in acetonitrile (1.0 ml), and at 0 ° C., methyl chlorocarbonate (0.12 ml) and pyridine (0.12 ml) were added. After stirring at 50 ° C. for 3 hours, potassium hydroxide (85%) (0.10 g) dissolved in methanol (1.0 ml) was added and stirred at the same temperature for 3 hours. The reaction solution was neutralized with dilute hydrochloric acid in water. The aqueous layer was extracted 3 times with ethyl acetate, and the combined organic layer was washed with saturated brine, dried (Na ₂ SO ₄ ), concentrated, and the resulting crude product was subjected to silica gel chromatography (ethyl acetate: hexane). = 6: 1), and the target product [4R, 5R, 6R, 7S] -1,9-diaza-2,11-dioxa-5,6-isopropylidenedioxytricyclo [5.3. .1 ^4,7] undecane-8,10-dione 15.9 mg (48% yield).

¹ H-NMR (200 MHz, CD ₃ OD) δ: 5.12 (1H, d, J = 5.4 Hz), 5.03 (1 H, d, J = 5.4 Hz), 4.44 (1 H, dd, J = 1.4, 1.6 Hz) 4.19 (1H, dd, J = 1.6,11.4Hz), 4.02 (1H, dd, J = 1.4,11.4Hz), 1.15 (3H, s), 1.39 (3H, s).
MS (m / z) 256 (M ⁺ ), 241,166,155,125,110,85,69,59,54,44.

Example 65
[1S, 5R, 6R, 7R] -2-aza-2-N-methoxycarbonyl-3,8-dioxa-1-formyl-6,7-isopropylidenedioxybicyclo [3.2] obtained in Example 49 .1] Octane (108.8 mg, 0.398 mmol) was dissolved in 1,4-dioxane (2.0 ml), aqueous ammonia (28%, 0.5 ml) was added at room temperature, and the mixture was stirred for 1 hour. The reaction solution was concentrated, purified by silica gel chromatography (ethyl acetate), and the desired product [4R, 5R, 6R, 7S] -1,9-diaza-2,11-dioxa-8-hydroxy-5,6- 59.7 mg (58%) of isopropylidenedioxytricyclo [5.3.0.1 ^4,7 ] undecan-10-one was obtained.

¹ H-NMR (200 MHz, CD ₃ OD) δ: 5.10 (1H, d, J = 5.4 Hz), 4.99 (1 H, d, J = 5.4 Hz), 4.91 (1 H, S), 4.25 (1 H, br. t), 4.06 (1H, dd, J = 1.6,11.2Hz), 3.79 (1H, dd, J = 1.6,11.2Hz), 1.47 (3H, s), 1.39 (3H, s).
MS (m / z) 258 (M ⁺ ), 243,225,200,183,129,69,59,44.

Example 66
[4R, 5R, 6R, 7S] -1,9-diaza-2,11-dioxa-8-hydroxy-5,6-isopropylidenedioxytricyclo [5.3.0.1] obtained in Example 65 ^4,7 ] Undecan-10-one (0.57 g, 2.2 mmol) was dissolved in acetone (10.0 ml), Jones reagent (1.5 ml) was added at room temperature, and the mixture was stirred at 40 ° C. for 1 hour. Ethyl acetate was added to the reaction solution, and the resulting insoluble material was filtered off. The filtrate was extracted 3 times with ethyl acetate, and the combined organic layer was washed with saturated brine, dried (Na ₂ SO ₄ ) and concentrated. The obtained crude product was purified by silica gel chromatography (ethyl acetate: hexane = 6: 1), and the desired product [4R, 5R, 6R, 7S] -1,9-diaza-2,11-dioxa-5. 297.8 mg (53% yield) of 6,6-isopropylidenedioxytricyclo [5.3.0.1 ^4,7 ] undecane-8,10-dione.

  The instrument data was consistent with that of Example 64.

Example 67
[1S, 5R, 6R, 7R] -2-Aza-1-carbamoyl-3,8-dioxa-6,7-isopropylidenedioxy-2-N-methoxycarbonylbicyclo obtained in Example 59 [3.2 .1] Octane (200.2 mg, 0.6945 mmol) was dissolved in 4 ml of MeOH, methanol solution of sodium methoxide [2M] (0.52 ml, 1.04 mmol) was added at room temperature, and the mixture was stirred at room temperature for 10 minutes and at 50 ° C. for 1 hour. Accompanied. To this reaction solution is added saturated brine, neutralized with 1N hydrochloric acid, extracted with ethyl acetate, dried and concentrated, and the desired product [4R, 5R, 6R, 7S] -1,9-diaza-2,11-dioxa. 160.0 mg (yield 90%) of -5,6-isopropylidenedioxytricyclo [5.3.0.1 ^4,7 ] undecane-8,10-dione was obtained.

  The instrument data was consistent with that of Example 64.

Example 68
[1S, 5R, 6R, 7R] -2-Aza-1-carbamoyl-3,8-dioxa-2-N-ethoxycarbonyl-6,7-isopropylidenedioxybicyclo [3.2] obtained in Example 60 .1] Octane (6.12 g, 20.2 mmol) was dissolved in methanol (65 ml), potassium hydroxide (85%) (1.47 g, 22.3 mmol) was added, and the mixture was stirred at 50 ° C. for 3 hours. The reaction mixture was concentrated, water was added, and the mixture was neutralized with dilute hydrochloric acid. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layer was washed with saturated brine, dried (Na ₂ SO ₄ ) and concentrated. The obtained crude product was purified by silica gel chromatography (ethyl acetate: hexane = 6: 1) to obtain the desired product [4R, 5R, 6R, 7S] -1,9-diaza-2,11-dioxa-5. 4.52 g (yield 87%) of 6-isopropylidenedioxytricyclo [5.3.0.1 ^4,7 ] undecane-8,10-dione was obtained.

  The instrument data was consistent with that of Example 64.

Example 69
[4R, 5R, 6R, 7S] -1,9-diaza-2,11-dioxa-5,6-isopropylidenedioxytricyclo [5.3.0.1 ^4,7 ] obtained in Example 64 Undecane-8,10-dione (1.4701 g, 5.738 mmol) was dissolved in 300 ml of ethanol, Raney nickel (5.2 g) was added, and the mixture was reacted with hydrogen gas (4.5 kg / cm ² ) at 55 ° C. for 5.5 hours. Celite After filtration and concentration, the desired product [2R, 3R, 4R, 5S] -6,8-diaza-2-hydroxymethyl-3,4-isopropylidenedioxy-1-oxaspiro [4.4] nonane-7, 1.4043 g (95% yield) of 9-dione was obtained.

¹ H-NMR (270 MHz, DMSO-d ₆ ) δ: 10.81 (1H, s), 8.34 (1H, s), 5.06 (1H, t, J = 5.5 Hz), 4.78-4.72 (2H, m), 4.32 -4.28 (1H, m), 3.51-3.46 (2H, m), 1.44 (3H, s), 1.25 (3H, s).
MS (m / z) 258 (M ⁺ ), 229, 149, 85, 68, 59, 44.

Example 70
[2R, 3R, 4R, 5S] -6,8-diaza-2-hydroxymethyl-3,4-isopropylidenedioxy-1-oxaspiro [4.4] nonane-7,9- obtained in Example 69 Dione (480.9 mg, 1.862 mmol) was dissolved in acetonitrile (16 ml), and acetic anhydride (0.60 ml, 4.7 mmol), pyridine (0.41 ml, 5.6 mmol) and dimethylaminopyridine (0.10 g) were added at room temperature. Stir at temperature for 1 hour. Further, acetic anhydride (0.36 ml, 2.8 mmol) and pyridine (0.27 ml, 3.7 mmol) were added and stirred for 40 minutes. 1N-NCl was added thereto, and the mixture was extracted with ethyl acetate, washed with brine, dried, concentrated, purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1), and the desired product [2R, 3R, 4R, 5S. 593.0 mg (yield 93) of 2-acetoxymethyl-6-N-acetyl-6,8-diaza-3,4-isopropylidenedioxy-1-oxaspiro [4.4] nonane-7,9-dione %)Obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 5.30 (1H, d, J = 7.0 Hz), 4.93 (1 H, dd, J = 4.3, 7.0 Hz), 4.68-4.61 (1 H, m), 4.49 (1 H , dd, J = 4.3,11.8Hz), 4.19 (1H, dd, J = 7.0,11.8Hz), 2.54 (3H, s), 2.10 (3H, s), 1.58 (3H, s), 1.32 (3H, s).
MS (m / z) 343 (M ⁺ +1), 327,243,183,126,86,69,44.

Example 71
[2R, 3R, 4R, 5S] -2-acetoxymethyl-6-N-acetyl-6,8-diaza-3,4-isopropylidenedioxy-1-oxaspiro [4.4] obtained in Example 70 Nonane-7,9-dione (254.0 mg, 0.742 mmol) was dissolved in methanol-water (5 ml-2.5 ml), Dowex 50W (H ⁺ ) (762 mg) was added at room temperature, and the mixture was heated to 50 ° C. for 40 minutes. And stirred at 70 ° C. for 2 hours. The reaction solution was filtered through celite, concentrated, and purified by silica gel column chromatography (hexane: ethyl acetate = 1: 5 → ethyl acetate → ethyl acetate: methanol = 10: 1), [2R, 3S, 4R. , 5S] -2-acetoxymethyl-6-N-acetyl-6,8-diaza-3,4-dihydroxy-1-oxaspiro [4.4] nonane-7,9-dione 88.7 mg (yield 40%) , [2R, 3S, 4R, 5S] -6-N-acetyl-6,8-diaza-3,4-dihydroxy-2-hydroxymethyl-1-oxaspiro [4.4] nonane-7,9-dione 72.1 mg (yield 37%) was obtained.

[2R, 3S, 4R, 5S] -2-Acetoxymethyl-6-N-acetyl-6,8-diaza-3,4-dihydroxy-1-oxaspiro [4.4] nonane-7,9-dione
¹ H-NMR (270 MHz, CD ₃ OD) δ: 5.06 (1H, d, J = 6.5 Hz), 4.42-4.36 (2H, m), 4.19-4.10 (2H, m), 2.49 (3H, s), 2.05 (3H, s).
MS (m / z) 302 (M ⁺ ), 260, 182, 157, 145, 128, 86, 57, 44.
[2R, 3S, 4R, 5S] -6-N-acetyl-6,8-diaza-3,4-dihydroxy-2-hydroxymethyl-1-oxaspiro [4.4] nonane-7,9-dione
¹ H-NMR (200 MHz, CD ₃ OD) δ: 5.03 (1H, d, J = 6.8Hz), 4.39-4.32 (1H, m), 4.19-4.14 (1H, m), 3.76 (1H, dd, J = 4.3, 12.1Hz), 3.67 (1H, dd, J = 5.2, 12.1Hz), 2.54 (3H, s).
MS (m / z) 260 (M ⁺ ), 242,218,200,129,116,86,73,57,44.

Example 72
[2R, 3S, 4R, 5S] -2-Acetoxymethyl-6-N-acetyl-6,8-diaza-3,4-dihydroxy-1-oxaspiro [4.4] nonane-7 obtained in Example 71 , 9-dione (190.0 mg, 0.69 mmol) was dissolved in water (1.9 ml) and hydrazine monohydrate (61 μl) was stirred at pressurized room temperature for 1 hour. This reaction solution was concentrated and purified with Diaion CHP-20P (water) to obtain 95 mg (yield 69.3%) of hydantosaidin.

Example 73
[1S, 5R, 6R, 7R] -2-Aza-1-carbamoyl-3,8-dioxa-6,7-isopropylidenedioxy-2-N-methoxycarbonylbicyclo obtained in Example 59 [3.2 .1] Dissolve octane (234.8 mg, 1.029 mmol) in methanol (4 ml) -purified water (2 ml), add 1.17 g of Dowex 50W (H ⁺ ), add 1.57 hours at 80 ° C., and further Dowex 50W (H ⁺ ). 0.7 g was added and stirred at 80 ° C. for 7.5 hours. The reaction solution was filtered through celite and concentrated to obtain the target product [1S, 5R, 6S, 7R] -2-aza-1-carbamoyl-6,7-dihydroxy-3,8-dioxa-2-N-methoxycarbonyl. Bicyclo [3.2.1] octane was obtained in 248 mg (97% yield).

¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 7.22 (1H, br.s), 7.21 (1H, br.s), 5.35 (1H, br.d, J = 4.8 Hz), 5.20 (1H, br.d, J = 7.0Hz), 4.50 (1H, br.t), 4.38-4.31 (2H, m), 3.86 (1H, br.d, J = 11.4Hz), 3.77 (1H, br.d, J = 11.4Hz), 3.70 (3H, s).
MS (m / z) 249 (M ⁺ +1), 218, 162, 115, 91, 59, 44.

Example 74
[1S, 5R, 6R, 7R] -2-Aza-1-carbamoyl-3,8-dioxa-2-N-ethoxycarbonyl-6,7-isopropylidenedioxybicyclo [3.2] obtained in Example 60 .1] Octane (14.75 g, 48.79 mol) was dissolved in methanol (290 ml) -purified water (145 ml), Dowex 50W (H ⁺ ) (73.75 g) was added, heated to 80 ° C., stirred for 20 hours, and further stirred. 32.8 g of Dowex 50W (H ⁺ ) was added and stirred at 100 ° C. for 8 hours. The reaction solution was filtered through Celite, concentrated, and the target product [1S, 5R, 6S, 7R] -2-aza-1-carbamoyl-6,7-dihydroxy-3,8-dioxa-2-N-ethoxy. Carbonyl bicyclo [3.2.1] octane was obtained in 12.55 g (yield 98%).

¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 7.21 (1H, br.s), 6.84 (1H, br.s), 4.49 (1H, d, J = 6.1 Hz), 4.38 (1H, br, s), 4.38-4.09 (2H, br), 4.33 (1H, d, J = 6.1Hz), 4.15 (2H, q, J = 7.0Hz), 3.85 (1H, br.d, J = 11.6Hz), 3.77 (1H, br.d, J = 11.6Hz), 1.22 (3H, t, J = 7.0Hz).
MS (m / z) 263 (M ⁺ +1), 217, 161, 115, 104, 69, 57, 44.

Example 75
[1S, 5R, 6S, 7R] -2-aza-1-carbamoyl-6,7-dihydroxy-3,8-dioxa-2-N-ethoxycarbonylbicyclo obtained in Example 74 [3.2.1] Octane (499.4 mg, 2.01 mmol) was added to a suspension of ethanol (10 ml) at 60 ° C. with a methanol solution of sodium methoxide (2 M) (1.3 ml, 2.6 mmol) and stirred at the same temperature for 3 hours. . The reaction solution was filtered through Celite, and 643.4 mg of the obtained 1.6345 g of crystals was purified with Diaion CHP20P (water) to obtain the target product [1S, 2R, 3S, 4R] -7,9-diaza- 111.3 mg of 2,3-dihydroxy-6,11-dioxatricyclo [5.3.0.1 ^1,4 ] undecane-8,10-dione was obtained.

¹ H-NMR (200 MHz, D ₂ O) δ: 4.67 (1H, d, J = 6.2 Hz), 4.55 (1 H, d, J = 6.2 Hz), 4.45 (1 H, br.s), 4.08 (1 H, br.d, J = 11.4Hz), 3.76 (1H, br.d, J = 11.4Hz).

Example 76
[1S, 5R, 6S, 7R] -2-aza-1-carbamoyl-6,7-dihydroxy-3,8-dioxa-2-N-ethoxycarbonylbicyclo obtained in Example 74 [3.2.1] Octane (3.0175 g, 11.51 mmol) was dissolved in methanol (60 ml) and 7.5 ml of a methanol solution of sodium methoxide (2M) was added at 50 ° C., followed by stirring at the same temperature for 1 hour and at 55 ° C. for 3 hours. Methanesulfonic acid (0.75 ml) was added at room temperature. Purified water (15 ml) and ethanol (250 ml) were added to the resulting reaction solution, Raney nickel (10.4 g) was added, and the mixture was stirred at 55 ° C. for 7 hours under hydrogen pressure (6 kg / cm ² ). This was filtered through celite, concentrated and purified with Diaion CHP-20P (water) to obtain 1.8847 g (yield 75%) as a mixture of hydantoside and epihydantoside (7.5: 1). Epihydantoside is the spiro carbon optical isomer of hydantosaidin.

Example 77
[1S, 5R, 6S, 7R] -2-aza-1-carbamoyl-6,7-dihydroxy-3,8-dioxa-2-N-ethoxycarbonylbicyclo obtained in Example 74 [3.2.1] Octane (996.0 mg, 3.80 mmol) was dissolved in 20 ml of methanol, 206 mg of sodium hydroxide (96%) was added at 55 ° C. and stirred at the same temperature for 2.5 hours, and then 0.22 ml of acetic acid was added at room temperature. To this was added 3 ml of purified water, 80 ml of ethanol and 2.6 g of Raney nickel, and the mixture was stirred at 55 ° C. for 8 hours under hydrogen pressure (5.3 kg / cm ² ). The resulting reaction solution was filtered through Celite, concentrated and purified with Diaion CHP-20P (water) to obtain 481.9 mg (yield 58%) as a mixture of hydantoside and epihydantoside (20: 1). .

  In general, it is not easy to introduce a nitrogen atom into a sugar anomeric position in a high yield while controlling the steric structure because a stereoisomer at the anomeric position is mixed or a dangerous reagent needs to be used.

  On the other hand, in the method via the intermediate (I) of the present invention, since the intermediate (I) has an O—N bond, the reactivity of the nitrogen atom can be appropriately increased, and the reaction is carried out in the molecule. Therefore, it can react easily and stereospecifically at the anomeric position, and stereoisomers are not mixed.

In addition, the bicyclic compound (II) and the tricyclic compounds (III) and (IV) are equivalent to protecting the hydroxyl group of the hydroxymethyl group at the 2-position of hydantoside and the nitrogen atom at the 6-position at the same time. It is. Furthermore, in the compound (II), when R ⁶ represents —COR ¹⁰ (R ¹⁰ is as defined above), it is not only convenient as a protecting group for the reaction to the anomeric position, but also in the future of hydantoside. Since it already has a structure that can be a carbonyl group at the 7-position, the yield can be improved and the process can be shortened.

Since the compound (II) has a bicyclo system that is not sterically distorted, it is considered to exist stably regardless of the type of the substituent of R ⁷ , and the yield of the subsequent reaction is increased.

  Furthermore, in the reaction of obtaining the compound (V) from the tricyclo compound (IV), the electron withdrawing carbonyl group is bonded to the nitrogen atom of the ON bond of the compound (IV), and the reactivity is lowered. Nevertheless, the O—N bond can be cleaved by heating under the condition of hydrogen pressure in the presence of a Raney catalyst. Moreover, the steric configuration of the spiro part can be maintained in a desirable configuration.

  Moreover, since the raw materials and reagents used are inexpensive and easy to handle throughout the entire process, and the molecular weight of each intermediate is relatively small, volume efficiency is excellent even on an industrial scale.

The following invention described in the above-mentioned prior art Philippe Chemla, Tetrahedron Lett., 34 , 7391 (1993) (hereinafter referred to as Document A)

And the present invention will be compared to explain that the present invention cannot be easily conceived from the invention described in Document A.

  First, when the reactions in the invention described in Document A are individually examined, many of the reactions are reactions that can be used only at the laboratory level and are industrially disadvantageous. It is impossible to produce.

Specifically, in the process of 2 → 3 (so-called Mitsunobu reaction), it is relatively expensive such as diethyl azodicarboxylic acid (DEAD) or triphenylphosphine (Ph ₃ P), and there is a problem in the purification method after the reaction. Is used. That is, since it is a by-product after the reaction derived from DEAD or Ph ₃ P, it is necessary to use column chromatography or the like when separating and purifying the target product, which is not an easy method industrially.

In the process of 5 → 6 , expensive trimethylsilyl triflate (TMSOTf) is used.

In the process of 6 → 7 , highly toxic Na ₂ CrO ₇ is used.

In the process of 7 → 8 , expensive ceric ammonium nitrate ((NH ₄ ) ₂ Ce (NO ₃ ) ₆ , CAN) is used.

In the process of 8 → 9 , expensive and highly toxic Mo (CO) ₆ is used.

  The method described in Document A has the above-described problems in industrial production of hitantosaidine, and further, reagents and reaction conditions for each step, etc., via the intermediate described in Document A. It is extremely difficult to adapt to industrial production by improving.

  Next, when the reaction in the invention described in the document A is examined as a whole, it becomes a stereospecific production method of hydantoside by passing through a bridged ring derivative such as compound 6. There is no difference.

Further, in the invention described in Document A, a nitrogen atom constituting a hydantocydin ring in the future is introduced at an initial stage (nitrogen atom protected by PMB in Compound 5 ), and at first glance (at least at the laboratory level) efficiently appear. However, in finding a method that can be industrially produced based on the method of Document A, the method of introducing a nitrogen atom at an initial stage is an obstacle. That is, the production of a compound having a hydroxyurea partial structure such as compound 5 which is a raw material of the bridged ring derivative 6 requires many steps and must use an industrially unsuitable method such as Mitsunobu reaction. Nevertheless, the method of the present invention is unthinkable because it sticks to the introduction of nitrogen atoms at an early stage. In the present invention, a nitrogen atom is not introduced at the initial stage, and the compound (I) which is a raw material for the bridged ring derivative is a short-stage, simple and inexpensive method suitable for industrial production [having a leaving group at the 6-position. The psicose derivative (VI) is reacted with hydroxylamine (eg, HO—NHCOOCH ₂ CH ₃ ) in which the nitrogen atom is protected under alkaline conditions.

Furthermore, the effect by the difference of the compound 5 of literature A and this-application compound (I) can mention the improvement of the reaction conditions which manufacture a bridge | crosslinking compound. In Document A, expensive trimethylsilyl triflate (TMSOTf) is used in the process of 5 → 6 , which is a ring-closing reaction. However, in the ring-closing reaction (Step C) of the present invention, an extremely In addition, an inexpensive acid can be used.

In the hydantoin ring formation reaction, the present invention is superior to the invention described in Document A. In Document A, highly toxic Na ₂ CrO ₇ is used in the hydantoin ring formation reaction (step 6 → 7 ), but in the hydantoin ring formation reaction (step F and step G) of the present invention, step F In the method G, an inexpensive base is used, and in the process G, ammonia water is used, which is an excellent industrial production method.

In addition, in the method for cleaving the ON bond of the important synthetic intermediate 8 of hydantocydin, Mo (CO) ₆ that is expensive and highly toxic is used in the document A. In the present invention, the Raney catalyst is used. The ON-N bond can be cleaved by the hydrogenation reaction by. Although it is described in Document A that this reaction does not proceed, in the present invention, as described above, the ON-N bond is cleaved by heating in the presence of Raney catalyst under hydrogen pressure conditions. From this point, the present invention cannot be easily conceived from Document A.

Thus, in place of the compound 5 in the document A, in the present invention, by using the compound (I) as an intermediate, all the problems of the method of the document A can be solved at once.

  As described above, the present invention provides a method capable of specifically producing hydantosaidin in high yield, in a simple, inexpensive and safe manner on an industrial scale, without the formation of stereoisomers. To do.

Claims (1)

Formula (IV)

[Wherein R ¹ and R ² represent a hydrogen atom, or R ¹ and R ² together represent an alkylidene group which may be substituted. The compound represented by the general formula (V) is characterized by hydrogenation using a Raney catalyst under hydrogen pressure.

[Wherein, R ¹ and R ² are as defined above. ] The manufacturing method of the compound represented by this.