JPH07116172B2 - 2-amino-3-homofuranosides - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Purpose] (Industrial field of application) The present invention relates to a novel amino sugar having an antibacterial action.

(Problems to be Solved by the Invention) The present inventors have conducted extensive studies for many years on the synthesis of a derivative having a sugar skeleton and its pharmacological activity, and as a result, have a completely different structure from known amino sugars. The present invention was completed by finding that the novel cis-2-amino-3-homosaccharide having the above-mentioned properties has an antibacterial action.

[Structure] The novel 2-amino-3-homofuranosides and pharmaceutically acceptable salts thereof of the present invention have the general formula [In the formula, R ¹ represents a hydrogen atom, a hydroxyl group protecting group selected from the following (hydroxyl group protecting group), a hydroxyl group substituent selected from the following (hydroxyl group group), R ² or R ³ Are the same or different and represent a hydrogen atom, an amino group protecting group selected from the following (amino group protecting group) or an amino group substituent selected from the following (amino group substituent group), and R ⁴ is Expression −
COR ⁶ (in the formula, R ⁶ is a hydrogen atom, a lower alkyl group, a hydroxyl group optionally protected by a group selected from the following (hydroxyl group protecting group), a group selected from the following (hydroxyl group) A hydroxyl group substituted with, a mercapto group which may be protected by a group selected from the following (mercapto protection group), a mercapto group substituted with a group selected from the following (mercapto substituent group) or a general formula -NR ² R ³ )) or formula -C
H ₂ OR ¹ (wherein R ¹ has the same meaning as described above), and R 2
⁵ is a hydrogen atom, lower alkyl group, aryl group, allyl group, vinyl group or formula (In the formula, R ⁸ represents a group similar to R ¹ , R ⁷ represents a diol protecting group selected from the following (diol protecting group group)), or R ⁴ and R ⁵ represent Together, (In the formula, R ⁹ represents the same group as R ^1. ) However,
The coordination of the 2-position substituent NR ² R ³ and the 3-position substituent R ⁴ has a cis coordination.

(Hydroxyl protecting group) Aliphatic acyl group; Aralkyl group (Hydroxyl substituent group) Lower alkyl group; Allyl group (Amino group protecting group) Aliphatic acyl group; Aromatic acyl group; Aralkyl group (Amino group substituent group) A) lower alkyl group; vinyl group (mercapto group protecting group) alkylcarbonyl group; aromatic acyl group (mercapto group substituent group) lower alkyl group; aryl group (diol protecting group) lower alkylidene group; aralkylidene group] 2-
The present invention relates to aminohomofuranosides and pharmacologically acceptable salts thereof.

In the above general formula (I), the (hydroxyl protecting group) in the definition of R ¹ and R ⁶ is, for example, formyl, acetyl,
Alkylcarbonyl groups such as propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, lauroyl, palmitoyl, stearoyl, halogenated aliphatic acyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, Examples thereof include lower alkoxy aliphatic acyl groups such as methoxyacetyl, and aliphatic acyl groups such as unsaturated aliphatic acyl groups such as (E) -2-methyl-2-butenoyl, preferably alkylcarbonyl groups. And more preferably an acetyl group.

Further, for example, benzyl, phenethyl, 3-phenylpropyl, p-methoxybenzyl, o-nitrobenzyl,
p-chlorobenzyl, p-nitrobenzyl, p-cyanobenzyl, diphenylmethyl, triphenylmethyl, α
Examples include aralkyl groups such as -naphthylmethyl, β-naphthylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, and preferably,
It is a benzyl group.

In the general formula (I), the (hydroxyl group) in the definition of R ¹ and R ⁶ is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl or hexyl. Such lower alkyl group or allyl group can be mentioned, preferably lower alkyl group or allyl group, and more preferably methyl group.

The (amino group-protecting group) in the definition of R ² and R ³ is not particularly limited as long as it is usually used as a protecting group for amino group, and preferably formyl, acetyl, propionyl,
Butyryl, isobutyryl, pentanoyl, pivaloyl,
Valeryl, isovaleryl, octanoyl, lauroyl,
Alkylcarbonyl group such as palmitoyl and stearoyl, halogenated aliphatic acyl group such as chloroacetyl, dichloroacetyl, trichloroacetyl and trifluoroacetyl, lower alkoxy aliphatic acyl group such as methoxyacetyl, (E) -2- Examples thereof include aliphatic acyl groups such as unsaturated aliphatic acyl groups such as methyl-2-butenoyl, preferably alkylcarbonyl groups,
More preferably, it is an acetyl group.

Also, for example, benzoyl, o- (dibromomethyl) benzoyl, o- (methoxycarbonyl) benzoyl, p
Aromatic phenyl groups such as -phenylbenzoyl, 2,4,6-trimethylbenzoyl, p-toluoyl, p-anisoyl, p-chlorobenzoyl, p-nitrobenzoyl, o-nitrobenzoyl, α-naphthoyl. And preferably a benzoyl group.

In addition, for example, benzyl, phenethyl, 3-phenylpropyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, o-nitrobenzyl, p-chlorobenzyl, p-
Examples thereof include aralkyl groups such as nitrobenzyl, p-cyanobenzyldiphenylmethyl, triphenylmethyl, α- or β-naphthylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, and preferably 2,4- It is a dimethoxybenzyl group.

(Amino group substituent group) in the definition of R ² and R ³ is, for example, methyl, ethyl, propyl, isopropyl, butyl,
A lower alkyl group such as isobutyl, s-butyl, t-butyl, pentyl and hexyl or a vinyl group, preferably a methyl group or an ethyl group.

Examples of the lower alkyl group in the definition of R ⁵ and R ⁶ include methyl, ethyl, propyl, isopropyl, butyl,
An alkyl group having 1 to 6 carbon atoms such as isobutyl, s-butyl, t-butyl, pentyl and hexyl is shown, and an alkyl group having 1 to 4 carbon atoms is preferable.

(Mercapto group-protecting group) in the definition of R ⁶ is, for example, an alkylcarbonyl group such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, lauroyl, palmitoyl, stearoyl, chloroacetyl. , Dichloroacetyl, trichloroacetyl,
Aliphatic acyl such as halogenated aliphatic acyl group such as trifluoroacetyl, lower alkoxy aliphatic acyl group such as methoxyacetyl, unsaturated aliphatic acyl group such as (E) -2-methyl-2-butenoyl Group or benzoyl, o- (dibromomethyl) benzoyl, o- (methoxycarbonyl) benzoyl, p-phenylbenzoyl,
2,4,6-Trimethylbenzoyl, p-toluoyl, p-
Examples thereof include aromatic acyl groups such as anisoyl, p-chlorobenzoyl, p-nitrobenzoyl, o-nitrobenzoyl, and α-naphthoyl, preferably aliphatic acyl groups, and more preferably acetyl. It is a base.

The (mercapto group substituent group) in the definition of R ⁶ is preferably methyl, ethyl, propyl, isopropyl, butyl,
Lower alkyl groups such as isobutyl, s-butyl, t-butyl, pentyl, hexyl; phenyl, p-tolyl,
It is an aryl group such as p-methoxyphenyl, p-chlorophenyl, α- or β-naphthyl, preferably a lower alkyl group, and more preferably methyl-noble.

The aryl group in the definition of R ⁵ is phenyl, p-
Tolyl, p-methoxyphenyl, p-chlorophenyl,
An aryl group such as α or β-naphthyl can be mentioned, and a phenyl group is preferable.

The (diol protecting group) in the definition of R ⁷ includes a lower alkylidene group such as methylidene, ethylidene and isopropylidene; and an aralkylidene group such as benzylidene, preferably a lower alkylidene group,
More preferably, it is an isopropylidene group.

The compound (I) of the present invention can be converted into a pharmacologically acceptable non-toxic salt, and such salt is preferably a sodium salt, potassium salt or calcium salt in the case of carboxylic acid. Alkali metal or alkaline earth metal salts such as; In the case of amines, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydrohalic acid such as hydroiodic acid, sulfuric acid, phosphoric acid, etc. Inorganic acids; lower alkylsulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, arylsulfonic acids such as p-toluenesulfonic acid, oxalic acid, maleic acid and other organic acids, and glutamic acid Amino acids such as aspartic acid can be mentioned.

The compound (I) of the present invention has various stereoisomers each having an asymmetric carbon atom in its molecule and each having an S-coordinate and an R-coordinate, and each of them or a mixture thereof. Also included in the present invention.

In the compound (I), preferred compounds include (1) a compound in which R ¹ is a hydrogen atom, an aliphatic acyl group, an aralkyl group, a lower alkyl group or an allyl group (2) R ² and R ³ are the same or Differently, a compound (3) R ⁴ which is a hydrogen atom, an aliphatic acyl group, an aromatic acyl group, an aralkyl group or a lower alkyl group has the formula —COR ⁶ (wherein R ⁶ is a hydrogen atom, a lower alkyl group, A compound (4) R ^{4 which} is an optionally protected hydroxyl group or a substituted hydroxyl group) has the formula —CH ₂ OR ¹ (in the formula, R ¹ represents a hydrogen atom or a hydroxyl-protecting group). (5) R ⁵ is a lower alkyl group or (Wherein R ⁸ represents a group similar to R ¹ and R ⁷ represents a protecting group for diol), or R ⁴ and R ⁵ are taken together, (Wherein R ⁹ represents the same group as R ¹ ). (6) R ¹ is a hydrogen atom, an aliphatic acyl group, an aralkyl group, a lower alkyl group or an allyl group, and R ² And R ³ are the same or different and each is a hydrogen atom, an aliphatic acyl group, an aromatic acyl group, an aralkyl group or a lower alkyl group, and R 3
⁴ is a formula —COR ⁶ (in the formula, R ⁶ represents a hydrogen atom, a lower alkyl group, an optionally protected hydroxyl group or a substituted hydroxyl group), and R ⁵ is a lower alkyl group or (Wherein R ⁸ represents a group similar to R ¹ and R ⁷ represents a protecting group for diol), or R ⁴ and R ⁵ are taken together, (Wherein, R ⁹ is the same groups as R ^1.), Compound (7) R ¹ is a hydrogen atom, an aliphatic acyl group, an aralkyl group, a lower alkyl group or an allyl group, R ² And R ³ are the same or different and each is a hydrogen atom, an aliphatic acyl group, an aromatic acyl group, an aralkyl group or a lower alkyl group, and R 3
⁴ is a formula —CH ₂ OR ¹ (in the formula, R ¹ represents a hydrogen atom or a hydroxyl-protecting group), and R ⁵ is a lower alkyl group or (Wherein R ⁸ represents a group similar to R ¹ and R ⁷ represents a protecting group for diol), or R ⁴ and R ⁵ are taken together, (In the formula, R ⁹ represents the same group as R ^1. )

Representative compounds of the present invention include, for example, the compounds shown in Table 1, but the present invention is not limited to these compounds.

Of the above-exemplified compounds, preferred compounds include 1,3,4,
5,7,9,10,12,13,15,17,18,19,20,22,24,25,26,27,28,2
9,30,31,32,33,34,35,36,37,39,40,43,45,46,48,49,51,
53,54,56,57,58,60,61,62,63,64,65,66,67,68,69,70,7
1,72,73,74,75,77,78,79,81,83,84,86,87,89,91,92,94,
96,98,99,100,101,102,103,104,105,106,107,108,109,1
10,111,112,114,115,117,119,120,122,123,125,127,12
8,130,132,133,134,135,136,137,138,140,141,145,146,
149,151,153,154,155,156,158,159,160,161,162,163,16
4,165,166,167,168,170,173,175,176,178,179,181,183,
The compounds of 184,186,188,189,190,191,192,193,194,195,196,197 can be mentioned.

Further, suitable compounds include 1,5,9,13,19,24,25,28,3
0,37,45,46,51,56,57,60,64,67,75,102,106,108,112,12
5,138,168 compounds can be mentioned.

The 2-amino-3-homofuranosides of the present invention can be produced by the method described below.

[Production method 1] [Production method 2] [Production method 3] [Production method 4] In the above formula, R ¹ , R ² , R ³ , R ⁷ and R ⁸ have the same meanings as described above.
M represents an alkali metal such as sodium or potassium. R ¹¹ represents a carboxy-protecting group, preferably a lower alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl and hexyl; -Halogeno lower alkyl groups such as trichloroethyl, 2-haloethyl, 2,2-dibromoethyl or benzyl, phenethyl, 3
-Phenylpropyl, p-methoxybenzyl, o-nitrobenzyl, p-chlorobenzyl, p-bromobenzyl, p-nitrobenzyl, p-halobenzyl, p-cyanobenzyldiphenylmethyl, diphenylmethyl, bis (o-nitrophenyl) Aralkyl groups such as methyl, 9-anthrylmethyl, 2,4,6-trimethylbenzyl, triphenylmethyl, α- or β-naphthylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, piperonyl. R ¹² is R
^{The same} groups as the amino-protecting group or the amino-substituent substituent in the definitions of ² and R ³ are shown. R ¹³ represents the same group as the hydroxyl protecting group or the hydroxyl substituent in the definition of R ¹ .
R ¹⁴ represents the same group as R ¹ . R ¹⁵ represents the same group as R ⁶ . R ¹⁶ represents a hydrogen atom, a lower alkyl group, an aryl group, an allyl group or a vinyl group in the definition of R ⁵ .

In the first step, for example, a compound having the general formula (II)
By reacting with dimethyltetic acid, the compound of the general formula (II
This is a step of producing an epoxy compound having I).

The starting compound (I) is prepared by the method of Chittenden et al. [JFChit
tenden, Carbohydrate Res., 84 , 352 (1980)] and Bar et al. [E.Baer and HOLFisher, Chem.Ber., 128 ,
463 (1939)], produced from D-mannitol.

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 ethers such as ether, tetrahydrofuran, dioxane and dimethoxyethane; dimethylformamide, dimethyl Mention may be made of amides such as acetamide, hexamethylphosphorotriamide or sulfoxides such as dimethylsulfoxide.

The base used is not particularly limited as long as it can generate an anion as a base, but preferably,
Mention may be made of bases such as sodium amide, sodium hydride, butyllithium, lithium ditrimethylsilylamide, lithium diisopropylamide.

The reaction temperature is −78 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C. The reaction time mainly depends on the reaction temperature,
The time is usually 10 minutes to 5 days, varying depending on the type of raw material compound or solvent and base used. After completion of the reaction, the target compound (III) of this reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to the reaction mixture, washing with water and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

The second step is a step of producing a compound having the general formula (IV), for example, by reacting a compound having the general formula (III) with an amino compound in the presence of a condensing agent.

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, halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; Aromatic hydrocarbons such as benzene, toluene and xylene; Esters such as ethyl acetate and propyl acetate; Ethers such as ether, tetrahydrofuran, dioxane and dimethoxyethane; Aliphatic hydrocarbons such as hexane and cyclohexane Amides such as dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide; sulfoxides such as dimethylsulfoxide or nitriles such as acetonitrile.

The condensing agent used is not particularly limited as long as it usually acts as a condensing agent, but preferably an organic condensing agent such as dicyclohexylcarbodiimide (DCC), diphenylcarbodiimide, diethyl cyanophosphate (DEPC). Is mentioned.

The reaction temperature is usually -50 ° C to 100 ° C, and the reaction time mainly depends on the reaction temperature, the raw material compound or the solvent used and the kind and amount of the condensing agent, but is usually 1 to
24 hours. After completion of the reaction, the target compound (IV) of this reaction
Is collected from the reaction mixture according to conventional methods. For example,
After adding an organic solvent immiscible with water to the reaction mixture and washing with water,
Obtained by distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

In the third step, for example, a compound having the general formula (IV)
This is a step of producing a compound having the general formula (V) by cyclocondensation in the presence of a base. The base used is not particularly limited as long as it acts as a base, but preferably triethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, 1,8-diazabicyclo [5.
4.0] Organic bases such as undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO); Organic base metals such as lithium diisopropylamide, lithium ditrimethylsilylamide, potassium diisopropylamide, potassium ditrimethylsilylamide, sodium methoxide, sodium ethoxide, potassium t-butoxide or sodium carbonate, potassium carbonate, sodium hydrogen carbonate, hydrogen carbonate. Potassium, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium diisopropylamide, lithium ditrimethylsilylamide,
Mention may be made of inorganic bases such as sodium methoxide, sodium ethoxide, potassium t-butoxide.

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, aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride, Halogenated hydrocarbons such as chloroform and carbon tetrachloride; Esters such as ethyl acetate and propyl acetate; Ethers such as ether, tetrahydrofuran, dioxane and dimethoxyethane; Aliphatic hydrocarbons such as hexane and cyclohexane Amides such as dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide; sulfoxides such as dimethylsulfoxide or nitriles such as acetonitrile.

The reaction temperature is generally 0 ° C. to 150 ° C., and the reaction time is usually 10 min to 50 ° C., though it varies mainly depending on the reaction temperature, the raw material compound, the base used or the solvent used.
24 hours.

During the reaction, the yield is improved by removing the produced alcohol by azeotropic distillation or the like.

After completion of the reaction, the target compound (V) of this reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to the reaction mixture, washing with water and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

The fourth step is a step of producing a compound having the general formula (VI) by reducing the carbonyl group of the compound having the general formula (V) by a conventional method.

The reducing agent to be used is not particularly limited as long as it can reduce carbonyl and does not reduce ester, but preferably sodium borohydride, lithium borohydride, zinc borohydride, hydride Examples of the reducing agent include diisobutylaluminum, diisobutylboron hydride, diborane, lithium trimethoxyaluminum hydride, lithium t-butoxyaluminum hydride, and bismethoxyethoxyaluminum hydride hydride.

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, aromatic hydrocarbons such as benzene, toluene and xylene; ether and tetrahydrofuran. , Ethers such as dioxane, dimethoxyethane and diglyme; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and isoamyl alcohol; aliphatic hydrocarbons such as hexane and cyclohexane. Can be mentioned.

The reaction temperature is usually -78 ° C to 150 ° C, and the reaction time varies depending mainly on the reaction temperature, the raw material compound, the reducing agent used or the type of solvent used, but it is usually 1 minute to 24 hours. Is.

After completion of the reaction, the target compound (VI) of this reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to the reaction mixture, washing with water and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

The fifth step is a step of producing a compound having the general formula (VII) by decarboxylating the carboxy group of the compound having the general formula (VI).

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 water or a water-containing organic solvent is preferable. As such an organic solvent, preferably tetrahydrofuran, dioxane,
Ethers such as dimethoxyethane and diglyme; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and isoamyl alcohol; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphorotriamide Examples thereof include sulfoxides such as dimethyl sulfoxide; nitriles such as acetonitrile or organic bases such as triethylamine, pyridine and collidine.

The base used is not particularly limited as long as it usually acts as a base, but preferably triethylamine, N-methylmorpholine, pyridine, 4- (N, N-
Dimethylamino) pyridine, N, N-dimethylaniline,
1,8-diazabicyclo [5.4.0] undec-7-ene (DB
U), 1,5-diazabicyclo [4.3.0] non-5-ene (DB
N), 1,4-diazabicyclo [2.2.2] octane (DABCO)
Organic bases such as or sodium carbonate, potassium carbonate,
Inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium diisopropylamide, lithium ditrimethylsilylamide, sodium methoxide, sodium ethoxide, potassium t-butoxide. You can

The reaction temperature is usually 30 ° C to 200 ° C, and the reaction time is mainly the reaction temperature, the starting compound or the solvent used,
Although it depends on the type of base, it is usually 10 minutes to 24 hours.

After completion of the reaction, the target compound (VII) of this reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to the reaction mixture, washing with water and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

The sixth step is a step of producing a compound having the general formula (VIII) by protecting the hydroxyl group of the compound having the general formula (VII) with an R ¹³ group. By this step, a compound in which the 1-position protected hydroxyl group coordinates α or β can be obtained and isolated respectively, so that the subsequent steps can be carried out using one isomer or a mixture. 8th, 9th
The process is the same.

The production can be performed by the following three methods.

Method a) Method of protecting a compound having the general formula R ¹³ OH [wherein R ¹³ has the same meaning as described above] by reacting with compound (VII) in the presence of an acid catalyst, with or without using a solvent. Often, 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 halogenated hydrocarbons such as methylene chloride and chloroform are preferably used. . The acid used is preferably an inorganic protic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, an organic protic acid such as trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid or boron trifluoride-ether, Inorganic Lewis acids such as aluminum trichloride, zinc dichloride, gallium trichloride, titanium tetrachloride, tin tetrachloride, boron trichloride, iron trichloride, antimony pentachloride, arsenic pentachloride are used. The reaction temperature and reaction time will differ depending on the starting compounds and the acid used, but will usually be -50 ° C to 100 ° C, and 10 minutes to 24 minutes.
Done on time.

Method b) Compound having the general formula R ¹³ X [wherein, R ¹³ has the same meaning as defined above, and X represents a nucleophilic leaving group such as a halogen atom such as chlorine, bromine or iodine. ] Is reacted with compound (VII) in the presence of a catalyst to protect it. 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 methylene. Halogenated hydrocarbons such as chloride, chloroform, carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene, xylene; ethers such as ether, tetrahydrofuran, dioxane, dimethoxyethane; dimethylformamide, dimethylacetamide, Amides such as hexamethylphosphorotriamide; Sulfoxides such as dimethyl sulfoxide; Nitroalkanes such as nitromethane Nitriles such as acetonitrile Ketones such as acetone; Esters such as ethyl acetate, propyl acetate and Pyridine can be mentioned.

The catalyst used is silver oxide, mercury oxide, silver acetate, mercury cyanide or mercury bromide. The reaction temperature and the reaction time vary depending on the raw material compound and the catalyst used,
Usually, it is carried out at 0 ° C to 100 ° C for 30 minutes to 24 hours.

Mainly carried out in alkylation.

Method c) Compound having the general formula R ¹³ X [wherein R ¹³ and X have the same meanings as described above, or R ¹³ X represents an acid anhydride or a mixed acid anhydride. ] In the presence of a base,
Method of reacting and protecting with I) 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 methylene chloride, chloroform or carbon tetrachloride. Such halogenated hydrocarbons; aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and cyclohexane; ethers such as ether, tetrahydrofuran, dioxane and dimethoxyethane; dimethylformamide , Dimethylacetamide, hexamethylphosphorotriamide, and esters such as ethyl acetate and propyl acetate.

The base used is not particularly limited as long as it acts as a base, but preferably triethylamine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline,
1,8-diazabicyclo [5.4.0] undec-7-ene (DB
U), 1,5-diazabicyclo [4.3.0] non-5-ene (DB
Mention may be made of organic bases such as N).

The reaction temperature and the reaction time will differ depending on the starting compounds and the base used, but they are usually -30 ° C to 150 ° C, and 1 minute to 24 hours.

Mainly used in acylation.

After completion of the reaction, the target compound (VIII) of this reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to the reaction mixture, washing with water and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

In the seventh step, the compound having the general formula (VIII) is treated with a reducing agent to open the lactam ring, and further,
If desired, a hydroxyl-protecting group (R ⁷ or / and R ¹³ )
And / or deprotection of the amino-protecting group (R ¹² ) and / or
Alternatively, protection / reprotection of hydroxyl group, substitution (R ¹ , R ⁸ or /
And R ¹⁴ ) or / and amino group protection and substitution (R ² or / and R ³ ) are carried out to produce the compound of the present invention having the general formula (IX).

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 ethers such as ether, tetrahydrofuran, dioxane, dimethoxyethane, and diglyme; toluene, toluene, Mention may be made of aromatic hydrocarbons such as xylene and benzene and aliphatic hydrocarbons such as hexane and cyclohexane.

The reducing agent used is not particularly limited as long as it is usually used as a reducing agent, but lithium aluminum hydride can be preferably mentioned.

The reaction temperature and reaction time vary depending on the raw material compound,
Usually, it is carried out at -78 ° C to 120 ° C for 10 minutes to 24 hours.

The removal of the protecting group in the desired step depends on its type, but is generally carried out as follows by methods well known in the art.

When a tri-lower alkylsilyl group is used as a hydroxyl-protecting group, it is usually removed by treatment with a compound that produces a fluorine anion such as tetrabutylammonium fluoride. The reaction solvent is not particularly limited as long as it does not inhibit the reaction, but ethers such as tetrahydrofuran and dioxane are preferable. Although the reaction temperature and the reaction time are not particularly limited, the reaction is usually performed at room temperature for 10 minutes to 18 hours.

When the hydroxyl-protecting group is an aralkyloxycarbonyl group or an aralkyl group, it can be usually removed by bringing it into contact with a reducing agent. For example, it is carried out by using a catalyst such as palladium carbon, platinum or Raney nickel to carry out catalytic reduction at room temperature or using an alkali metal sulfide such as sodium sulfide or potassium sulfide. The reaction is carried out in the presence of a solvent, the reaction solvent to be used is not particularly limited as long as it does not participate in the reaction, methanol, alcohols such as ethanol, tetrahydrofuran, ethers such as dioxane, A fatty acid such as acetic acid or a mixed solvent of these organic solvents and water is suitable. The reaction temperature and reaction time will differ depending on the starting materials and the reducing agent used, but are usually 0 ° C.
To room temperature, 5 minutes to 12 hours.

When the hydroxyl-protecting group is an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group, it can be removed by treating with a base in the presence of an aqueous solvent. The base is not particularly limited as long as it does not affect other parts of the compound, but it is preferably an alkali metal carbonate such as sodium carbonate or potassium carbonate, sodium hydroxide or potassium hydroxide. It is carried out with alkali metal hydroxides or concentrated ammonia-methanol. The solvent to be used is not particularly limited as long as it is used in a usual hydrolysis reaction, and water or water and alcohols such as methanol, ethanol and n-propanol or ethers such as tetrahydrofuran and dioxane can be used. A mixed solvent with such an organic solvent is preferable. The reaction temperature and reaction time differ depending on the starting materials, the base used, etc. and are not particularly limited, but in order to suppress side reactions, it is usually 0 ° C. to 150 ° C. and 1 to 10 hours.

When the hydroxyl-protecting group is an alkoxymethyl group, a tetrahydropyranyl group, a tetrahydrofuranyl group or a substituted ethyl group, it can be usually removed by treating with an acid in a solvent. As the acid used,
Preferred are hydrochloric acid, acetic acid-sulfuric acid or p-toluenesulfonic acid-acetic acid. The solvent used is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol and ethanol; tetrahydrofuran,
Ethers such as dioxane or a mixed solvent of these organic solvents and water is preferable. The reaction temperature and reaction time will differ depending on the starting materials and the type of acid used, but they are usually 0 ° C. to 50 ° C. and 10 minutes to 18 hours.

When the hydroxyl-protecting group is an alkenyloxycarbonyl group, the hydroxyl-protecting group is usually an aliphatic acyl group,
When it is an aromatic acyl group or an alkoxycarbonyl group, it can be eliminated by treating with a base in the same manner as the conditions of the removal reaction. In the case of allyloxycarbonyl, a method of removing it particularly using palladium and triphenylphosphine or nickel tetracarbonyl is simple and can be carried out with few side reactions. The removal of the protecting group depends on its type, but is generally carried out as follows by a method well known in the art.

The amino group-protecting group may be simultaneously removed by the above-mentioned operation for removing the hydroxyl-group protecting group.

When a tri-lower alkylsilyl group is used as the amino-protecting group, it is usually removed by treatment with a compound that produces a fluorine anion such as tetrabutylammonium fluoride. The reaction solvent is not particularly limited as long as it does not inhibit the reaction, but ethers such as tetrahydrofuran and dioxane are preferable. Although the reaction temperature and the reaction time are not particularly limited, the reaction is usually performed at room temperature for 10 minutes to 18 hours.

When the amino-hydroxyl-protecting group is an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group, it can be removed by treating with an acid or a base in the presence of an aqueous solvent. As the acid, hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid are used, and the base is not particularly limited as long as it does not affect other parts of the compound, but sodium carbonate, carbonic acid are preferred. It is carried out using alkali metal carbonates such as potassium, sodium hydroxide, alkali metal hydroxides such as potassium hydroxide or concentrated ammonia-methanol. Note that hydrolysis with a base may cause isomerization. The solvent used is not particularly limited as long as it is used in a usual hydrolysis reaction,
Water or a mixed solvent of water and an alcohol such as methanol, ethanol, n-propanol, or an organic solvent such as tetrahydrofuran or an ether such as dioxane is preferable. The reaction temperature and reaction time vary depending on the starting material, the base used and the like and are not particularly limited, but in order to suppress side reactions, it is usually 0 ° C. to 150 ° C. and 10 minutes to 10 hours.

When the amino-protecting group is an aralkyl group or an aralkyloxycarbonyl group, a catalyst such as platinum or palladium carbon is used to carry out catalytic reduction at room temperature to remove it, or an oxidant is used for removal. The method of doing is suitable.

The solvent used in the removal by reduction is not particularly limited as long as it does not participate in the reaction, alcohols such as methanol, ethanol and isopropanol, diethyl ether, tetrahydrofuran, ethers such as dioxane, toluene, Of aromatic hydrocarbons such as benzene and xylene, aliphatic hydrocarbons such as hexane and cyclohexane, esters such as ethyl acetate and propyl acetate, fatty acids such as acetic acid or their organic solvent and water Mixed solvents are preferred.

The catalyst used is not particularly limited, as long as it is usually used in a catalytic reduction reaction, but preferably palladium carbon, Raney nickel, platinum oxide, platinum black, rhodium-aluminum oxide, triphenylphosphine- Rhodium chloride and palladium-barium sulfate are used.

The pressure is not particularly limited, but is usually 1 to 10 atm.

The reaction temperature and reaction time will differ depending on the types of starting materials and catalysts, etc., but are usually 0 ° C. to 100 ° C., and 5 minutes to 24 hours.

The solvent used for removal by oxidation is not particularly limited as long as it does not participate in this reaction, but a water-containing organic solvent is preferable. Preferable examples of such an organic solvent include ketones such as acetone, methylene chloride, chloroform, halogenated hydrocarbons such as carbon tetrachloride, nitriles such as acetonitrile, diethyl ether, tetrahydrofuran and dioxane. Mention may be made of ethers, amides such as dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide and sulfoxides such as dimethylsulfoxide.

The oxidizing agent used is not particularly limited as long as it is a compound used for oxidation, but preferably potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN), 2,3-dichloro- 5,6-Dicyano-p-benzoquinone (DDQ) is used.

The reaction temperature and reaction time will differ depending on the types of starting materials and catalysts, etc., but are usually 0 ° C. to 150 ° C., and 10 minutes to 24 hours.

When the amino-protecting group is an alkenyloxycarbonyl group, a base is usually prepared in the same manner as in the removal reaction when the amino-protecting group is an aliphatic acyl group, an aromatic acyl group or a lower alkoxycarbonyl group. Can be desorbed by treating In the case of allyloxycarbonyl, a method of removing it particularly using palladium and triphenylphosphine or nickel tetracarbonyl is simple and can be carried out with few side reactions.

Incidentally, the protecting group for the hydroxyl group may be simultaneously removed by the above-mentioned operation for removing the protecting group for the amino group.

The above-mentioned reaction for removing the protective group for the hydroxyl group and reaction for removing the protective group for the amino group can be carried out in any order in a desired removal reaction.

Protection / reprotection of hydroxyl group, substitution and / or protection / substitution of amino group are carried out in the same manner as in the sixth step.

After completion of the reaction, the compound (IX) of the present invention is
Taken from the reaction mixture. For example, it can be obtained by adding an organic solvent immiscible with water to the reaction mixture, washing with water and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

In the eighth step, the compound having the general formula (VIII) is reacted with a lithium compound or a base according to a conventional method to open the lactam ring, and if desired, the desired step of the seventh step is carried out similarly or / and This is a step of producing the compound (X) of the present invention by amidating or thioesterifying the carboxy group according to the method [after converting to an acid halide and then reacting with a corresponding nucleophile]. 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 ethers such as ether, tetrahydrofuran, dioxane, dimethoxyethane and diglyme are preferably used. To be Although the lithium compound used is not particularly limited, preferred examples include organic lithium compounds such as methyllithium, butyllithium, and phenyllithium.

The reaction temperature and reaction time will differ depending on the raw material compounds and reaction reagents, but will usually be −78 ° C. to 50 ° C., and 1 minute to 5 hours. After completion of the reaction, the compound (X) of the present invention is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to the reaction mixture, washing with water and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

In the ninth step, the compound having the general formula (VIII) is treated with an acid to ring-open and re-close the ring, and further, if desired, the desired step of the seventh step is carried out in the same manner as described above. This is a step of producing a compound of the present invention having the formula (XI).

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 alcohols such as methanol, ethanol, isopropyl alcohol, benzyl alcohol and allyl alcohol. Is used.

The acid to be used is not particularly limited as long as it usually acts as an acid, but hydrochloric acid, sulfuric acid, hydrobromic acid and hydrofluoric acid are preferred.

The reaction temperature and the reaction time will differ depending on the starting compounds and the acid used, but they are usually 0 ° C. to 100 ° C. and 1 to 24 hours.

After completion of the reaction, the compound (XI) of the present invention is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to the reaction mixture, washing with water and distilling off the solvent. The obtained target compound is, if necessary,
It can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

In the 10th step, the carbonyl group of the compound having the general formula (XI) is treated with a reducing agent in the same manner as in the 4th step to form a hydroxy group, and further, if desired, the desired step of the 7th step. By similarly performing the general formula (XI
This is a step of producing the compound of the present invention having I).

The eleventh step and the eleventh step are the general formula (XI) or (XII).
The carbonyl group or hydroxy group of the compound having the formula (XIII) is treated with a reducing agent in the presence of a Lewis acid, and, if desired, the desired step of the seventh step is carried out in the same manner. It is a step of producing an invention compound.

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 ether, tetrahydrofuran, dimethoxyethane, ethers such as diglyme or benzene, toluene. Aromatic hydrocarbons such as

The reducing agent to be used is not particularly limited as long as it usually acts as a reducing agent, but preferably lithium aluminum hydride, sodium borohydride or diisobutylaluminum hydride can be mentioned.

The Lewis acid used may be an ordinary Lewis acid, but is preferably boron trifluoride-ether or aluminum trichloride.

The reaction temperature and reaction time will differ depending on the raw material compounds and the reducing agent used, but will usually be from −78 ° C. to 100 ° C., and from 10 minutes to 24 hours.

After completion of the reaction, the compound of the present invention (XIII) is prepared according to a conventional method.
Taken from the reaction mixture. For example, it can be obtained by adding an organic solvent immiscible with water to the reaction mixture, washing with water and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

The 12th step is a step of producing a compound having the general formula (XVI) by protecting or substituting the hydroxy group of the known compound having the general formula (XIV) in the same manner as in the 6th step.

The starting compound (XIV) is described in, for example, Shiozaki et al. [MS
hiozaki, N.Ishida, H.Maruyama and T.Hiraoka, Tetrahed
Ron, 39 , 2399-2407 (1983)].

In the thirteenth step, the compound having the general formula (XVI) is treated in the same manner as in the ninth step to open the ring, and if desired, the desired step of the seventh step is similarly performed and / or the protection of the carboxy group is performed, This is a step of producing a carboxy derivative (XV) which is the compound of the present invention by modifying or removing a protecting group.

The protection reaction is carried out according to a conventional method.

The removal of the protecting group depends on its type, but is generally carried out as follows by a method well known in the art.

When a lower alkyl group is used as a protecting group for the carboxy group, it can be removed by treating with an acid or a base. As the acid, hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid are used, and the base is not particularly limited as long as it does not affect other parts of the compound, but sodium carbonate, carbonic acid are preferred. It is carried out using alkali metal carbonates such as potassium, sodium hydroxide, alkali metal hydroxides such as potassium hydroxide or concentrated ammonia-methanol. Note that hydrolysis with a base may cause isomerization. The solvent to be used is not particularly limited as long as it is used in a usual hydrolysis reaction, and water or water and alcohols such as methanol, ethanol and n-propanol or ethers such as tetrahydrofuran and dioxane can be used. A mixed solvent with such an organic solvent is preferable. The reaction temperature and reaction time vary depending on the starting materials and the base used and are not particularly limited, but in order to suppress side reactions, it is usually 0 ° C. to 150 ° C. and 1 to 10 ° C.
It's time.

When the protecting group for the carboxy group is a diphenylmethyl group, it is usually removed under acidic conditions. The reaction solvent used is preferably an aromatic hydrocarbon such as anisole or a halogenated hydrocarbon such as methylene chloride or chloroform, and a fluorine-substituted organic acid such as trifluoroacetic acid is used as the acid. The reaction temperature and the reaction time will differ depending on the starting materials and the like, but are usually 30 minutes to 10 hours at room temperature.

When the protecting group for the carboxy group is an aralkyl group (including diphenylmethyl) or a halogeno lower alkyl group, it can usually be removed by bringing it into contact with a reducing agent. As the reducing agent, zinc-acetic acid is suitable when the protecting group of the carboxy group is a halogeno lower alkyl group, and when it is an aralkyl group, a catalyst such as palladium carbon, platinum or Raney nickel is used, It is carried out by catalytic reduction or using an alkali metal sulfide such as potassium sulfide or sodium sulfide. The reaction is carried out in the presence of a solvent, and the solvent used is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; acetic acid A fatty acid such as or a mixed solvent of these organic solvents and water is suitable. The reaction temperature and reaction time will differ depending on the starting materials and the reducing agent used, etc., but will usually be between 0 ° C. and room temperature, and between 5 minutes and 12 hours.

When the protecting group for the carboxy group is an alkoxymethyl group, it can be usually removed by treating with an acid. The acid used is preferably hydrochloric acid, acetic acid-sulfuric acid or p-toluenesulfonic acid-acetic acid. The reaction is carried out in the presence of a solvent, and the solvent used is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane or these A mixed solvent of the organic solvent and water is suitable. The reaction temperature and reaction time will differ depending on the starting materials and the type of acid used, but they are usually 0 ° C. to 50 ° C. and 10 minutes to 18 hours.

In addition, amidation can also be achieved by removing the protecting group for the carboxy group by an ammonia treatment according to a conventional method.

Furthermore, an amide compound or a thioester compound can be produced by reacting a carboxy group as an acid halide with a corresponding nucleophile. Incidentally, if desired, the above-obtained carboxylic acid compound is treated with water and acetic acid according to a conventional method. It is dissolved in a mixed solvent of water and an organic solvent immiscible with water, and an aqueous solution of an alkali metal carbonate or bicarbonate such as an aqueous solution of sodium hydrogencarbonate or an aqueous solution of potassium carbonate is added at 0 ° C to room temperature to obtain a pH of 7
An alkyl metal salt can be formed by filtering the precipitate that has been deposited in the vicinity and filtered.

Further, the salt thus prepared, or a carboxylic acid compound is treated with an ether such as tetrahydrofuran or N, N-
Soluble in polar solvents such as dimethylformamide, dimethylsulfoxide, hexamethylphosphorotriamide, triethylphosphate, 2 equivalents of triethylamine, organic base such as dicyclohexylamine, alkali metal hydrides such as sodium hydride or hydrogencarbonate. Sodium, sodium carbonate, using a salt produced by reacting an alkali metal carbonate or bicarbonate such as potassium carbonate, acetoxymethyl chloride, an aliphatic acyloxymethyl halides such as propionyloxymethyl bromide, 1-lower alkoxycarbonyloxyethyl halides such as 1-methoxycarbonyloxyethyl chloride, 1-ethoxycarbonyloxyethyl iodide, phthalidyl halides or (2-oxycarbonyl) By reacting 5-methyl-1,3-dioxolen-4-yl) methyl halides, it can produce protected ester again protecting group hydrolyzed easily carboxy group in vivo.
The reaction solvent is not particularly limited as long as it does not inhibit the reaction, but the above polar solvent is preferably used. The reaction temperature and the reaction time vary depending on the starting materials, the solvent and the type of the reaction reagent, but the reaction is usually carried out at 0 ° C to 100 ° C for 0.5 to 10 hours.

Incidentally, the hydroxyl group, the mercapto group in the R ⁶ group and / or the amino group-protecting group may be simultaneously removed by the above-mentioned operation for removing the carboxy-protecting group.

The removal reaction of the protecting group of the carboxy group, the removal reaction of the protecting group of the hydroxyl group, the removal reaction of the protecting group of the mercapto group, and the removal reaction of the protecting group of the amino group, the desired removal reactions may be performed in any order. it can.

The 14th step is a step similar to the 13th step and has the general formula (XI
In this step, the compound having V) is treated in the same manner as in Step 9 to produce a ring-opened carboxy derivative (XV) of the present invention.

The 15th step is a step of treating the compound having the general formula (XVI) in the same manner as in the 7th step to open the ring to produce the compound (XVII) of the present invention.

By the way, since the compound of the present invention has an asymmetric carbon atom, stereoisomerism exists for each carbon, but such a compound is (III-1 in Processes 5-8) shown below.
By carrying out the above steps using ~ 4) as starting material, all corresponding isomers can be prepared.

In [Production Method 8], the coordination of the epoxy is omitted, but various epoxy isomers that can be selectively produced are used, and the production method corresponds to Production Methods 1, 5, 6 and 7. The compound of the present invention can be produced.

[Production method 5] [Production method 6] [Production method 7] [Production method 8] In the above formula, R ¹ , R ² , R ³ , R ⁸ , R ¹⁴ and R ¹⁵ have the same meanings as described above.

The raw material compounds (III, III-1 to 4) of the present invention are
It can be stereoselectively produced by a method known in the literature as shown below. For example, the compound (XIX) is prepared by the method of Tanaka et al. [A. Tanaka, S. Otsuka and K. Yamasita, Agric. Biol. Che.
m., 48 (8), 2135 (1984)].

(Effect) The novel 2-amino-3-homo-sugar derivative of the present invention has an antibacterial action and has no toxicity, and thus is useful as a therapeutic agent.

Examples of the administration form of the compound (I) of the present invention include oral administration such as tablets, capsules, granules, powders or syrups, and parenteral administration such as injections or suppositories. These preparations are manufactured by a well-known method using additives such as an excipient, a binder, a disintegrant, a lubricant, a stabilizer, and a flavoring agent. The amount used is a symptom,
Although depending on the age and the like, 1-500 mg / kg body weight per day can be usually administered to an adult once or several times a day in divided doses.

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

Example 1 4,5-O-isopropylidene-2,3-epoxypentanoic acid Dimethyltethenic acid Sodium hydride (55% mineral oil dispersion, 25.8g, 0.6mol) was added to a solution of hydrobromide (40.2g, 0.2mol) in dimethylsulfoxide (500ml) while keeping the temperature below 20 ° C under ice cooling. , With stirring under nitrogen gas. Further
When the reaction was carried out at room temperature of 25 ° C. for 1.5 to 2 hours, dimethyltetin anion began to precipitate. A solution of a mixture of 2,3-O-isopropylidene-α-D-glyceraldehyde and acetic acid (2: 1, 21.4 g) in dimethyl sulfoxide (100 ml) was added dropwise thereto while stirring with ice cooling. The mixture is reacted at room temperature for 20 hours and put on 1.5 kg of ice. Wash the solution with ether,
The aqueous layer was acidified with 500 ml of 1N hydrochloric acid. It was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered, and the solvent was concentrated under reduced pressure to give 18.1 g of the desired product as an oil. This compound has a different configuration of epoxide, 2.6: 1.
Was a mixture of.

Example 2 N- (bis-carboethoxy) methyl-N-2,4-dimethoxybenzyl-4,5-O-isopropylidene-
2,3-epoxypentanoamide A solution of the compound of Example 1 (3.45 g, 18.3 mmol) and N-2,4-dimethoxybenzyl-N- (biscarbethoxy) methyl (5.96 g, 18.3 mmol) in methylene chloride (30 ml) was added with 4 g (19.3 mmol) of dicyclohexylcarbodiimide. mmol) was added. After stirring for 1 hour, the resulting dicyclohexylcarbodiimide / 1 water was removed by filtration, and the filtrate was concentrated and purified by column chromatography to obtain 3.78 g (41.6%).

Infrared absorption spectrum ν _max (film) 1750 (shoulder), 1740,1668,1610,1587cm-1 Mass spectrum m / z: 495 (M ⁺ ) Elemental analysis value (as C ₂₄ H ₃₃ O ₁₀ N) Calculated value: C: 58.17, H: 6.71, N: 2.83 Found: C: 57.89, H: 6.80, N: 2.91 Example 3 (1R, 2S, 5R) -6- (2,4-dimethoxybenzyl) -5
-Ethoxycarbonyl-2-[(R) -1,2-O-isopropylideneethyl] -4,7-dioxo-3-oxa-6-azabicyclo [3.2.0] heptane 4.96 g (10 mmol) of the compound of Example 2 was dissolved in 500 ml of benzene and azeotropically distilled to remove 100 ml of benzene.
Diazabicyclo [5.4.0] unde-7-cene (200 mg) was added, and the produced ethanol was azeotroped with benzene, and 150 ml was distilled off over 20 minutes. After cooling, dilute with ethyl acetate,
The extract was washed with dilute hydrochloric acid, water and saline and dried over magnesium sulfate. Concentrate and perform silica gel column chromatography (eluent: ethyl acetate-cyclohexane (1:
1)), 2.35 g of the desired product was obtained.

Infrared absorption spectrum ν _max (film) 1770, 1740 (shoulder), 1613, 1590 cm-1 NMR spectrum (60 MHz) (CDCl ₃ ) δ 1.25 (3H, t, J = 7.0Hz), 1.36 (3H, s), 1.43 (3H, s), 3.
80 (6H, s), 3.9-4.6 (9H, m), 6.3-6.5 (2H, m), 7.15 (1
H, d, J = 9.0 Hz) Example 4 (1R, 2S, 4RS, 5S) -6- (2,4-dimethoxybenzyl) -2-[(R) -1,2-O-isopropylideneethyl] -5-ethoxycarbonyl-4-hydroxy-7
-Oxo-3-oxa-6-azabicyclo [3.2.0] heptane 3.58 g of the compound of Example 3 was dissolved in 80 ml of methanol and -4
Cool to 0 ° C. Add 50 mg of silica gel powder for chromatography,
When 650 mg of sodium borohydride powder was added at once with stirring, sodium borohydride was dissolved while foaming. After 15 minutes, 2.5 ml of acetic acid was added at this temperature to decompose excess sodium borohydride. It was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate solution and brine, and dried over magnesium sulfate. After filtration and concentration, the residue was purified by silica gel column chromatography to obtain 3.51 g of an oily product.

Infrared absorption spectrum ν _max (film) 3380,1760 (shoulder), 1750-1730,1610,1588 cm-1 Example 5 (1R, 2S, 4S, 5S) -6- (2,4-dimethoxybenzyl) -2 -[(R) -1,2-O-isopropylideneethyl] -4-hydroxy-7-oxo-3-oxa-
6-azabicyclo [3.2.0] heptane 1.83 g of the compound of Example 4 was dissolved in 20 ml of pyridine and 1 ml of water to prepare 1,8-diazabicyclo [5.4.0] unde-7-cene 300.
mg was added and refluxed for 45 minutes. It was concentrated under reduced pressure and purified by silica gel column chromatography. Elution with ethyl acetate-cyclohexane (2: 1) gave 1.15 g of crystals of the target compound.

Melting point 172-173 ° C Infrared absorption spectrum ν _max (nujol) 3320,1715,1612,1590cm-1 [α] _D ²⁴ -10.5 ° (C 1.61, chloroform) Mass spectrum m / z: 379 (M ⁺ ), 364,321,279,250,193 ,
166,151,121,101 Elemental analysis value (as C ₁₉ H ₂₅ O ₇ N) Calculated value: C: 60.14, H: 6.64, N: 3.69 Measured value: C: 59.86, H: 6.56, N: 3.72 NMR spectrum (60MHz) (CDCl ₃ ) Δ 1.36 (3H, s), 1.42 (3H, s), 3.10 (1H, d, J = 2.0Hz), 3.
4-4.6 (14H, m), 5.17 (1H, d, J = 2.0Hz), 6.3-6.6 (2H,
m), 7.12 (1H, d, J = 9.0Hz) Example 6 (1R, 2S, 4RS, 5S) -6- (2,4-dimethoxybenzyl) -2- [1,2-O-isopropylideneethyl ]-
4-Methoxy-7-oxo-3-oxa-6-azabicyclo [3.2.0] heptane 379 mg of the compound of Example 5 was dissolved in dimethylformamide-methyl iodide (1: 1, 10 ml), 700 mg of silver oxide was added, and 4
Stir at room temperature for hours. After diluting with ethyl acetate,
The silver oxide was filtered off, and the organic layer was washed with water and brine. It was concentrated and purified by silica gel column chromatography. Elution with ethyl acetate-cyclohexane gave 340 mg of the target compound.

Infrared absorption spectrum ν _max (film) 1748,1610,1588 cm −1 Mass spectrum m / z: 393 (M ⁺ ) Example 7 Methyl 2,3-dideoxy-2- (2,4-dimethoxybenzylamino) -3 -C- (hydroxymethyl)-
5,6-O-isopropylidene-α-D-mannofuranoside methyl 2,3-dideoxy-2- (2,4-dimethoxybenzylamino) -3-C- (hydroxymethyl)-
5,6-O-isopropylidene-β-D-mannofuranoside To a solution of 200 mg of the compound of Example 6 in 4 ml of tetrahydrofuran was added 60 mg of lithium aluminum hydride under ice cooling, and the mixture was stirred for 40 minutes. Excessive lithium aluminum hydride was decomposed with acetic acid, diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, and dried over magnesium sulfate.
After filtration and concentration, the residue was purified by silica gel column chromatography. Elution with cyclohexane-ethyl acetate (1: 4) gave 136 mg of α-isomer with a high Rf value and β-isomer with a low Rf value.
34 mg of the isomer was obtained.

[Α-isomer] Infrared absorption spectrum ν _max (film) 3500-3300,1610,1588cm-1 Mass spectrum m / z: 397 (M ⁺ ) NMR spectrum (60MHz) (CDCl ₃ ) δ 1.34 (3H, s ), 1.39 (3H, s), 2.64 (1H, m), 2.78 (2H, s,
OH and NH), 3.7-4.3 (14H, m), 4.76 (1H, d, J = 2.5Hz),
6.3-6.5 (2H, m), 7.10 (1H, d, J = 8.5Hz) [β-isomer] Infrared absorption spectrum ν _max (film) 3500-3300,1612,1590cm-1 Mass spectrum m / z: 397 (M ⁺ ) Example 8 Methyl 2,3-dideoxy-2-amino-3-C-
(Hydroxymethyl) -5,6-O-isopropylidene-α-D-mannofuranoside 143 mg of the α-isomer of Example 7 was dissolved in 8 ml of ethanol,
500 ml of 10% palladium carbon was added, and hydrogenolysis was performed at room temperature and 1 atm for 5 hours. The catalyst was removed by filtration, concentrated, and purified by silica gel column chromatography. Methanol-
Elution with ethyl acetate (1: 9) gave 43 mg of the target compound.

Infrared absorption spectrum ν _max (film) 3360 (broad) cm-1 Mass spectrum m / z: 248 (M ⁺ +1) NMR spectrum (60MHz) (CDCl ₃ ) δ 1.35 (3H, s), 1.41 (3H, s ), 2.17 (3H, broad,), 2.64
(1H, quintuplet, J = 6.5Hz), 3.35 (3H, s), 3.50 (1H, b
d, J = 6.5Hz), 3.7-4.4 (6H, m), 4.65 (1H, d, J = 1.5Hz) Example 9 Methyl 2,3-dideoxy-2-benzoylamide-
3-C-hydroxymethyl-5,6-O-isopropylidene-α-D-mannofuranoside 37 mg of the compound of Example 8 was dissolved in 2 ml of tetrahydrofuran, and 50 mg of triethylamine and 25 mg of benzoyl chloride were added with stirring. After 15 minutes, the mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate solution and brine, and dried over magnesium sulfate. After filtration and concentration, purification by silica gel thin layer column chromatography gave 51 mg of the target compound.

Infrared absorption spectrum ν _max (film) 3350,1640 cm -1 Example 10 Methyl 2,3-dideoxy-2-benzoylamide-
3-C- (acetoxymethyl) -5,6-O-isopropylidene-α-D-mannofuranoside 29 mg of the compound of Example 9 was acetylated with pyridine-acetic anhydride (2: 1) to quantitatively obtain the target compound.

Melting point 120-121 ° C (ethyl acetate-n-hexane, 1: 9) Infrared absorption spectrum ν _max (nujol) 3360,1737,1640cm-1 Mass spectrum m / z: 378 (M ⁺ -15), 362,345,333,304,
292,232,173 [α] _D + 48.9 ° (C 1.125, ethanol) NMR spectrum (270MHz) (CDCl ₃ ) δ 1.37 (3H, s), 1.41 (3H, s), 2.04 (3H, s), 3.19 (1H,
m), 3.38 (3H, s), 3.86 (1H, dd, J = 6.6,8.4Hz), 4.13
(1H, dd, J = 7.1,8.6Hz), 4.28 (1H, dd, J = 5.5,8.4Hz),
4.41-4.34 (2H, m), 4.50 (1H, dd, J = 8.1,11.7Hz), 4.79
(1H, ddd, J = 1.0,6.4,8.8Hz), 4.84 (1H, d, J = 1.0Hz),
7.08 (1H, d, J = 8.8Hz), 7.54-7.40 (3H, m), 7.80-7.77
(2H, m) Elemental analysis (C ₂₀ H ₂₇ O ₇ as N) Calculated: C: 61.05, H: 6.92 , N: 3.56 Found: C: 61.22, H: 7.13 , N: 3.59 Example 11 Methyl 2,3-dideoxy-2-acetyl-3-C-
(2,4-dimethoxybenzylamino) -5,6-O-
Isopropylidene-α-D-mannofuranoside 393.4 mg of the compound of Example 6 was dissolved in 10 ml of tetrahydrofuran, and an ether solution of methyllithium (1.4M, 1.5 ml) was diluted with 2 ml of tetrahydrofuran and added dropwise at -78 ° C under a nitrogen stream. After 15 minutes, methyl lithium was decomposed with acetic acid. It was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate solution and brine, and dried over magnesium sulfate. After filtration and concentration, the residue was purified by silica gel column chromatography.
By eluting with cyclohexane-ethyl acetate (1: 1),
176 mg of the target compound was obtained. 106 mg of α, β-mixture was obtained, and 29 mg of β-isomer was obtained from the following fraction.

[Α-Isomer] mass spectrum m / z: 409 (M ⁺ ) [β-Isomer] mass spectrum m / z: 409 (M ⁺ ) Example 12 Methyl 2,3-dideoxy-2-[(N- 2,4-Dimethoxybenzyl) benzoylamide] -3-C-acetyl-5,6-O-isopropylidene-α-D-mannofuranoside 82 mg of the α-isomer of Example 11 was dissolved in 2 ml of tetrahydrofuran, 50 mg of triethylamine and 30 mg of benzoyl chloride were added.
mg was added with stirring. After 20 minutes, the mixture was directly filtered, concentrated and purified by silica gel column chromatography. Elution with cyclohexane-ethyl acetate (3: 2) gave 76 mg of the desired compound.

Melting point 143-146 ° C (ethyl acetate-cyclohexane) Infrared absorption spectrum ν _max (nujol) 1705,1625,1607,1588,1205cm-1 Mass spectrum m / z: 513 (M ⁺ ), 495,481,436,408,350,
322,270,188,151 [α] _D ²⁵ + 140.03 ° (C 1.21, chloroform) NMR spectrum (270MHz) (CDCl ₃ ) δ 1.31 (3H, s), 1.43 (3H, s), 2.37 (3H, s), 2.96 (3H) ,
s), 3.67 (3H, s), 3.81 (3H, s), 3.91-3.87 (1H, m), 4.
18-4.06 (3H, m), 4.36 (1H, bs), 4.51 (2H, s), 4.95 (1
H, dd, J = 2.9,7.4Hz), 5.05 (1H, d, J = 2.9Hz), 6.36 (1
H, d, J = 2.3Hz), 6.51 (1H, dd, J = 2.3,8.4Hz), 7.11 (1
H, d, J = 8.4Hz), 7.31-7.23 (5H, m) Elemental analysis value (as C ₂₈ H ₃₅ O ₈ N) Calculated value: C: 65.48, H: 6.87, N: 2.73 Measured value: C: 65.15, H: 6.86, N: 2.76 Example 13 (1S, 3S, 4S, 5R, 8R) -3-Methoxy-4- (2,4-dimethoxybenzylamino) -8- (hydroxymethyl)
-2,7-dioxa-5-oxobicyclo [3.3.0] octane 67 mg of the compound of Example 6 was added to 2 ml of dry methanol and hydrochloric acid.
Add 0.17 ml of a normal methanol solution (2 equivalents of hydrochloric acid) and
Refluxed for 5 hours. The oily substance remaining after concentration under reduced pressure was dissolved in 4 ml of methylene chloride, 200 mg of sodium hydrogen carbonate was added, and the mixture was vigorously stirred at room temperature for 30 minutes. Purified by silica gel thin layer chromatography. Deploy with ethyl acetate,
47 mg of the target compound was obtained.

Mass spectrum m / z: 354 (M ⁺ +1), 353 (M ⁺ ), 352
(M ⁺ -1), 322,166,151,121 Infrared absorption spectrum ν _max (Film) 3500-3200,1760 (broad), 1612,1588 cm-1 NMR spectrum (60 MHz) (CDCl ₃ ) δ 2.8 (2H, b), 3.2- 3.6 (5H, m), 3.70-3.85 (10H, m), 4.4
-4.9 (3H, m), 6.3-6.5 (2H, m), 7.11 (1H, d, J = 9.0Hz) Example 14 (1S, 3S, 4S, 5R, 8R) -3-Methoxy-4- ( 2,4-Dimethoxybenzylamino) -8-[(methoxydimethyl) methyloxymethyl] -2,7-dioxa-6-oxobicyclo [3.3.0] octane 20 mg of the compound of Example 13 was dissolved in 0.5 ml of dimethylformamide and 1 ml of 2,2-dimethoxypropane, 5 mg of pyridinium p-toluenesulfonate was added, and the mixture was refluxed for 1.5 hours. It was concentrated under reduced pressure and purified by silica gel column chromatography. Cyclohexane-ethyl acetate (1:
Elution in 1) yielded 15 mg of the desired compound as an oily substance.

Infrared absorption spectrum ν _max (film) 1763,1612,1588cm-1 Mass spectrum m / z: 426 (M ⁺ +1), 394352,323,29
3, 275, 204, 166, 151, 121, 91, 73, 43 NMR spectrum (400MHz) (CDCl ₃ ) δ 1.28 (3H, s), 1.30 (3H, s), 1.92 (1H, b), 3.16 ( 3H,
s), 3.37 (3H, s), 3.37 (1H, dd, J = 8.0-9.0,6.0-7.0H
z), 3.47 (1H, dd, J = 8.8,1.0Hz), 3.52 (1H, dd, J = 10.
7,1.9Hz), 3.73 (1H, dd, J = 10.7,2.4Hz), 3.78 (3H,
s), 3.83 (3H, s), 3.87, 3.70 (2H, AB-q, J = 13.6Hz), 4.
68 (1H, t, J = 1.9-2.4Hz), 4.72 (1H, d, J = 6.8Hz), 4.90
(1H, bs), 6.43 (1H, dd, J = 2.4,8.3Hz), 6.45 (1H, d, J
= 2.4 Hz), 7.13 (1H, d, J = 8.3 Hz) Example 15 (1R, 2S, 4R, 5S) -6- (2,4-dimethoxybenzyl) -2-methyl-4-benzyloxy-7 -Oxo-
3-oxa-6-azabicyclo [3.2.0] heptane It is a known compound in the form of powder in a solution of benzyl alcohol saturated with hydrochloric acid under ice cooling (1R, 2S, 4R, 5S) -6-
(2,4-Dimethoxybenzyl) -2-methyl-4-hydroxy-7-oxo-3-oxa-6-azabicyclo [3.2.0] heptane (500 mg) was added and the crystals were dissolved by stirring. It was left in a refrigerator at 0-5 ° C overnight. It was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate, and dried over magnesium sulfate. After filtration and concentration, the product is purified by silica gel column chromatography. Elution with ethyl acetate-cyclohexane (1: 2) gave 454 mg of the desired compound as crystals. Furthermore, 65 mg of the β-isomer of the compound of Example 17 was obtained.

Infrared absorption spectrum ν _max (film) 1750,1610,1586cm-1 NMR spectrum (60MHz) (CDCl ₃ ) δ 1.30 (3H, d, J = 6.0Hz), 3.38 (1H, dd, J = 0.5,4.0Hz) ),
3.71 (3H, s), 3.80 (3H, s), 4.02 (1H, d, J = 4.0Hz), 4.
11,4.40 (2H, AB-q, J = 14.0Hz), 4.39,4.71 (2H, AB-q, J
= 12.0Hz), 4.60 (1H, dq, J = 0.5,6.0Hz), 4.93 (1H,
s), 6.38-6.53 (2H, m), 7.12 (1H, d, J = 9.0Hz), 7.33
(5H, s) Example 16 Benzyl 2,3,5-trideoxy-2- (2,4-
Dimethoxybenzylamino) -3-C- (hydroxymethyl) -β-D-ribofuranoside To a solution of 38 mg of the compound of Example 15 in 2 ml of tetrahydrofuran was added 10 mg of lithium aluminum hydride under ice cooling, and the mixture was stirred at room temperature overnight. Excess lithium aluminum hydride was decomposed with acetic acid, diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate, and dried over magnesium sulfate. After filtration and concentration, the residue was purified by silica gel thin layer chromatography. When developed with cyclohexane-ethyl acetate (1: 1), 16 mg of the target compound was obtained.

Melting point 73-78 ° C (ethyl acetate-n-hexane) [Cotton] infrared absorption spectrum ν _max (film) 3350 (broad), 1610,1585 cm-1 mass spectrum m / z: 387 (M ⁺ ) NMR spectrum (60MHz) (CDCl ₃ ) δ 1.32 (3H, d, J = 6.0Hz), 2.16 (1H, m), 2.90 (2H, bs),
3.37 (1H, d, J = 6.0Hz), 3.5-4.0 (10H, m), 4.1-4.3 (1
H, m), 4.38, 4.75 (2H, AB-q, J = 12.0Hz), 4.79 (1H, s),
6.3-6.4 (2H, m), 7.09 (1H, d, J = 9.0Hz), 7.33 (5H, s) Example 17 Benzyl 2,3,5-trideoxy-2- (2,4-)
Dimethoxybenzylamino) -3-C- (benzyloxycarbonyl) -β-D-ribofuranoside It is a known compound in the form of powder (1R, 2S, 4R, 5S) -6.
-(2,4-dimethoxybenzyl) -2-methyl-4-
Hydroxy-7-oxo-3-oxa-6-azabicyclo [3.2.0] heptane (500 mg) or the compound of Example 15 was dissolved in a solution of benzyl alcohol saturated with hydrochloric acid under ice cooling and allowed to stand at room temperature overnight. It was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate, and dried over magnesium sulfate. After filtration and concentration, the product was purified by silica gel column chromatography. Ethyl acetate-cyclohexane (1:
Elution was performed in 2) to obtain 507 mg of the target compound. Further, 311 mg of α-isomer was obtained from the following fraction.

[Β-isomer] Infrared absorption spectrum ν _max (Film) 3330,1730,1610,1585cm-1 Mass spectrum m / z: 491 (M ⁺ ), 400,354,220,206,167,
151,121,91 Elemental analysis value (as C ₂₉ H ₃₃ O ₆ N) Calculated value: C: 70.85, H: 6.77, N: 2.85 Measured value: C: 70.75, H: 7.00, N: 2.80 NMR spectrum (60MHz) ( CDCl ₃ ) δ 1.34 (3H, d, J = 6.5Hz), 1.83 (1H, s), 3.12 (1H, dd, J =
6.0,9.0Hz), 3.52 (1H, d, J = 6.0Hz), 3.68 (3H, s), 3.7
4 (3H, s), 3.68-3.74 (2H, m), 4.35,4.72 (2H, AB-q, J =
12.0Hz), 4.4-4.8 (1H, m), 4.89 (1H, s), 5.13 (2H,
s), 6.25-6.4 (2H, m), 7.05 (1H, d, J = 9.0Hz), 7.28 (5
H, s), 7.30 (5H, s) [α-isomer] Infrared absorption spectrum ν _max (film) 3350,1730,1613,1588cm-1 Mass spectrum m / z: 491 (M ⁺ ), 400,354,220,206,167,
151,121,91 NMR spectrum (60MHz) (CDCl ₃ ) δ 1.27 (3H, d, J = 6.0Hz), 2.10 (1H, s), 2.82 (1H, dd, J =
7.0,10.0Hz), 3.58 (1H, dd, J = 7.0,4.0Hz), 3.59 (3H,
s), 3.68 (2H, s), 3.78 (3H, s), 4.30,4.73 (2H, AB-q, J
= 12.0Hz), 4.52 (1H, m), 4.88 (1H, d, J = 4.0Hz), 5.11
(2H, s), 6.2-6.5 (2H, m), 7.06 (1H, d, J = 9.0Hz), 7.3
2 (10H, s) Example 18 Benzyl 2,3,5-trideoxy-2-amino-3
-C-benzyloxycarbonyl-β-D-ribofuranoside 453 mg of the compound of Example 17 was dissolved in 12 ml of acetone, and an aqueous solution of 1.5 g of ceric ammonium nitrite in 8 ml of water was added thereto. After stirring for 5 minutes, dilute with ethyl acetate,
It was washed with aqueous sodium hydrogen carbonate and dried over magnesium sulfate. After filtering and concentrating, the remaining oily substance is washed with 5 ml of acetone.
The resulting mixture was dissolved in, and 5 ml of 1N hydrochloric acid was added, and the mixture was stirred for 3 hours. Acetone was distilled off under reduced pressure, 6 ml of water was added and washed with ether,
The remaining aqueous layer was made alkaline with sodium hydrogen carbonate.
It was extracted with ethyl acetate and dried over magnesium sulfate.
After filtration and concentration, 144 mg of the desired compound was obtained.

Infrared absorption spectrum ν _max (film) 1733 cm-1 Mass spectrum m / z: 341 (M ⁺ ), 234,218,204,186,114 NMR spectrum (60 MHz) (CDCl ₃ ) δ 1.30 (2H, bs), 1.39 (3H, d, J = 6.0Hz), 3.13 (1H, dd, J
= 5.5, 9.0Hz), 3.69 (1H, d, J = 5.5Hz), 4.43, 4.78 (2H,
AB-q, J = 12.0Hz), 4.4-4.9 (1H, m), 4.85 (1H, s), 5.18
(2H, s), 7.34 (5H, s), 7.36 (5H, s) Example 19 Benzyl 2,3,5-trideoxy-2-amino-3
-C-benzyloxycarbonyl-α-D-ribofuranoside When 600 mg of the α-isomer of Example 17 was treated in the same manner as in Example 18, 320 mg of the target compound was obtained. NMR spectrum (60MHz)
(CDCl ₃ ) δ 1.30 (3H, d, J ＝ 6.0Hz), 1.52 (2H, s), 2.75 (1H, dd, J ＝
8.0,9.5Hz), 3.84 (1H, dd, J = 4.5,9.5Hz), 4.49,4.84
(2H, AB-q, J = 11.5Hz), 4.66 (1H, dq, J = 6.0,8.0Hz),
5.05 (1H, d, J = 4.5Hz), 5.15 (2H, s), 7.35 (10H, s) Example 20 Benzyl 2,3,5-trideoxy-2-acetamido-3-C- (benzyloxycarbonyl) -Β-D-
Ribofuranoside The compound of Example 18 was acetylated with acetic anhydride-pyridine (1: 2) and purified by silica gel column chromatography according to a conventional method to quantitatively obtain the target compound.

Melting point 144-145 ° C (Ethyl acetate-cyclohexane) Infrared absorption spectrum ν _max (Nujol) 3270,1728,1652cm-1 Mass spectrum m / z: 383 (M ⁺ ), 368,324,292,277,24
6,204,188 [α] _D ²⁴ −74.4 ° (C = 1.03, ethanol) NMR spectrum (60 MHz) (CDCl ₃ ) δ 1.37 (3H, d, J = 6.0Hz), 1.83 (3H, s), 3.28 (1H, dd) , J ＝
6.0,9.0Hz), 4.45, 4.75 (2H, AB-q, J = 12.0Hz), 4.66 (1
H, d, J = 6.0Hz), 4.4-4.8 (1H, m), 4.96 (1H, s), 5.12
(2H, s), 5.91 (1H, bs), 7.34 (5H, s), 7.37 (5H, s) Example 21 Benzyl 2,3,5-trideoxy-2-amino-3
-C-carboxy-α-D-ribofuranoside To a solution of the compound of Example 19 (27 mg) in ethanol (2 ml) was added 0.1 N sodium hydroxide (1 ml), and the mixture was allowed to stand at room temperature overnight. 1
0.2 ml of normal hydrochloric acid was added, and the mixture was concentrated under reduced pressure. 1 ml of ethanol
Was added to dissolve the hydrochloride, and sodium chloride was removed by filtration.
30 mg of triethylamine was added to the filtrate, and the mixture was concentrated under reduced pressure.
2 ml of methylene chloride was added to dissolve the triethylamine hydrochloride. The remaining insoluble matter was obtained by decantation. The decantation was repeated several times to obtain 8 mg of the target compound in powder form.

NMR spectrum (60 MHz) (D ₂ O) δ 1.33 (3H, d, J = 6.0Hz), 2.73 (1H, dd, J = 7.5,9.0Hz),
4.00 (1H, dd, J = 5.0,9.0Hz), 4.2-4.7 (1H, m), 4.53,4.
79 (2H, AB-q, J = 12.0Hz), 5.37 (1H, d, J = 5.0Hz), 7.39
(5H, s)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication C07H 15/18 // A61K 31/34 ADZ 31/395 31/70

Claims (1)

[Claims] 1. A general formula [In the formula, R ¹ represents a hydrogen atom, a hydroxyl group protecting group selected from the following (hydroxyl group protecting group), a hydroxyl group substituent selected from the following (hydroxyl group group), R ² or R ³ Are the same or different and represent a hydrogen atom, an amino group protecting group selected from the following (amino group protecting group) or an amino group substituent selected from the following (amino group substituent group), and R ⁴ is Expression −
COR ⁶ (in the formula, R ⁶ is a hydrogen atom, a lower alkyl group, a hydroxyl group optionally protected by a group selected from the following (hydroxyl group protecting group), a group selected from the following (hydroxyl group) A hydroxyl group substituted with, a mercapto group which may be protected by a group selected from the following (mercapto protection group), a mercapto group substituted with a group selected from the following (mercapto substituent group) or a general formula -NR ² R ³ )) or formula -C
H ₂ OR ¹ (wherein R ¹ has the same meaning as described above), and R 2
⁵ is a hydrogen atom, a lower alkyl group, an aryl group, an allyl group, a vinyl group or (In the formula, R ⁸ represents a group similar to R ¹ , R ⁷ represents a diol protecting group selected from the following (diol protecting group group)), or R ⁴ and R ⁵ represent Together, (In the formula, R ⁹ represents the same group as R ^1. ) However,
The coordination of the 2-position substituent NR ² R ³ and the 3-position substituent R ⁴ has a cis coordination. (Hydroxyl protecting group) Aliphatic acyl group; Aralkyl group (Hydroxyl substituent group) Lower alkyl group; Allyl group (Amino group protecting group) Aliphatic acyl group; Aromatic acyl group; Aralkyl group (Amino group substituent group) A) lower alkyl group; vinyl group (mercapto group protecting group) alkylcarbonyl group; aromatic acyl group (mercapto group substituent group) lower alkyl group; aryl group (diol protecting group) lower alkylidene group; aralkylidene group] 2-
Aminohomofuranosides and pharmacologically acceptable salts thereof.