JPH0759575B2 - Cyclic ether derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Object] The present invention provides a novel cyclic ether derivative having an excellent antagonistic activity against platelet activating factor (hereinafter abbreviated as PAF), its inner salt and pharmacologically acceptable salt. Regarding

<Industrial application fields> (In the above formula, p represents 15 or 17)
Is a compound that has been analyzed and identified as a factor of the anaphylactic state, and has a strong platelet activation / aggregation action, neutrophil activation action, blood pressure lowering action and vascular permeability enhancing action, asthma, inflammation, It is considered to act as a kind of mediator in various pathological conditions such as endotoxin shock. Therefore, PAF antagonists are useful as excellent therapeutic agents for the above diseases.

<Prior Art> Known glycerin derivatives having a PAF antagonistic action include, for example, the following two compounds (VI) and (VII).

<Problems to be Solved by the Invention> The inventors of the present invention have conducted extensive research over many years on the synthesis of a derivative having a PAF antagonistic action and its pharmacological activity, and as a result, the hydroxyl groups at the 1-position and 2-position of glycerin have been investigated. , A conventional PAF antagonist having a chain substituent (for example, the compound (V
It was found that a derivative having a novel cyclic ether structure having a completely different structure from I) and (VII) has a strong PAF antagonism with excellent durability and bioavailability.
The present invention has been completed.

〔Constitution〕

 The novel cyclic ether derivatives of the present invention and pharmaceutically acceptable
Ru salt has the general formula[Wherein l represents an integer of 2 to 4, A and B are the same or
Are different from each other and each represents an oxygen atom or a sulfur atom. R¹And R²Nou
One is a linear or branched alkyl group having 10 to 22 carbon atoms.
Group, straight-chain or branched-chain aliphatic acyl group having 10 to 22 carbon atoms
Alternatively, the formula −CONH−R³A group having (II) (in the formula, R³Is charcoal
A linear or branched alkyl group having a prime number of 10 to 22 is shown. )
, The other isA group having the formula:₂)_mA group having- (formula
In the above, m represents an integer of 1 to 3. ) Or divalent 5 to 7
Member heterocyclic group, n is an integer of 0 to 10, and q is 0
Represents an integer from 1 to R^FourIs optionally protected hydroxy
Group, substituted hydroxyl group, optionally protected mercap
Group or a substituted mercapto group, and Q isA group having^Five, R⁶And R⁷Is the same or different
An elementary atom or a lower alkyl group is shown. ), Or formula-G
(Wherein G represents a 5- to 7-membered heterocyclic group,
The group may be a lower alkyl group, a hydroxy lower alkyl group, if desired.
Kill group, lower alkoxy group, carbamoyl group or halogen
It may have 1 to 3 nitrogen atoms as a substituent. )
, Z Represents an anion. ) Is shown. The Q group is
A group having the formula (IV) or a group having the formula -G (wherein G is
5- to 7-membered heterocyclic groups bound on the nitrogen atom
Represents a group. ), N is an integer from 1 to 10
Show. ]].

In the general formula (I), the “linear or branched alkyl group having 10 to 22 carbon atoms” represented by one of R ¹ and R ² and represented by R ³ is, for example, decyl, 3- Methylnonyl, 8-methylnonyl, 3-ethyloctyl, 3,7-dimethyloctyl, undecyl, dodecyl, tridecyl,
Tetradecyl, pentadecyl, hexadecyl, 1-methylpentadecyl, 14-methylpentadecyl, 13,13-dimethyltetradecyl, heptadecyl, 15-methylhexadecyloctadecyl, 1-methylheptadecyl, nonadecyl, aicosyl, henaicosyl and docosyl. However, it is preferably a linear or branched alkyl group having 13 to 20 carbon atoms.

Examples of the “linear or branched aliphatic acyl group having 10 to 22 carbon atoms” represented by one of R ¹ and R ² include, for example, nonylcarbonyl, decylcarbonyl, 3-methylnonylcarbonyl, 8-methylnonyl. Carbonyl, 3-ethyloctylcarbonyl, 3,7-dimethyloctylcarbonyl, undecylcarbonyl, dodecylcarbonyl, tridecylcarbonyl, tetradecylcarbonyl, pentadecylcarbonyl, hexadecylcarbonyl, 1-methylpentadecylcarbonyl, 14-methylpenta Decylcarbonyl, 13,13-dimethyltetradecylcarbonyl, heptadecylcarbonyl, 15-methylhexadecylcarbonyl, octadecylcarbonyl, 1-methylheptadecylcarbonyl, nonadecylcarbonyl, aicosylcarbonyl and heniicosylcarbonyl Examples thereof include straight-chain or branched-chain aliphatic acyl groups having 13 to 20 carbon atoms.

The “divalent 5- to 7-membered heterocyclic group” represented by E is a 5- to 7-membered heterocyclic group containing 1 to 3 sulfur, oxygen or / and nitrogen atoms, and examples thereof include furyl, thienyl and pyrrolyl. , Azepinyl, morpholinyl, thiomorpholinyl,
It corresponds to pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and these groups. Partially or completely reduced groups can be mentioned, and preferably a 5- to 7-membered heterocyclic group containing at least one nitrogen atom and optionally containing an oxygen atom or a sulfur atom is shown, for example, pyrrolyl, Azepinyl, morpholinyl, thiomorpholinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and their partial or complete groups. Reducible groups can be mentioned, and more preferably, imidazolyl, oxazolyl, isoxazolyl, thiazolyl and partially or completely reduced groups corresponding to these groups.

The protecting group of "optionally protected hydroxyl group" represented by R ⁴ includes a protecting group in the reaction and a protecting group for prodrug formation when administered to a living body, for example, formyl, acetyl, propionyl, butyryl. , Alkylbutanyl groups such as isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, halogenated alkylcarbonyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, lower alkoxyalkylcarbonyl groups such as methoxyacetyl, (E) Aliphatic acyl groups such as unsaturated alkylcarbonyl groups such as 2-methyl-2-butenoyl; arylcarbonyl groups such as benzoyl, α-naphthoyl, β-naphthoyl, o-bromobenzoyl, p-chloro Benzoyl-like halo Aryl carbonyl group, 2,
4,6-Trimethylbenzoyl, lower alkylated arylcarbonyl groups such as p-toluoyl, lower alkoxylated arylcarbonyl groups such as p-anisoyl, p-
Aroma such as nitrated arylcarbonyl group such as nitrobenzoyl and o-nitrobenzoyl, lower alkoxycarbonylated arylcarbonyl group such as o- (methoxycarbonyl) benzoyl, arylated arylcarbonyl group such as p-phenylbenzoyl Group acyl groups;
Tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, 4-
A tetrahydropyranyl or tetrahydrothiopyranyl group such as methoxytetrahydrothiopyran-4-yl;
Tetrahydrofuranyl or tetrahydrothiofuranyl groups such as tetrahydrofuran-2-yl, tetrahydrothiofuran-2-yl; trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-
Tri-lower alkylsilyl groups such as t-butylsilyl and triisopropylsilyl, silyl groups such as tri-lower alkylsilyl groups substituted with 1 or 2 aryl groups such as diphenylmethyl, diphenylbutyl, diphenylisopropyl, and phenyldiisopropyl. Lower alkoxymethyl groups such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, t-butoxymethyl, lower alkoxy such as 2-methoxyethoxymethyl Lower alkoxymethyl group, alkoxymethyl group such as halogenated lower alkoxymethyl such as 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl; 1-ethoxyethyl, 1-methyl-1-methoxy Ethyl, 1- (iso Propoxy) a lower alkoxylated ethyl group such as ethyl, 2,2,2-halogenated ethyl group such as trichloroethyl, 2- (Fueniruzereniru)
A substituted ethyl group such as an arylzelenylated ethyl group such as ethyl; benzyl, phenethyl, 3-phenylpropyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-an Lower alkyl group substituted with 1 to 3 aryl groups such as thrylmethyl, p-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, p-methoxybenzyl, p- Of methoxyphenyldiphenylmethyl, o-nitrobenzyl, p-nitrobenzyl, p-chlorobenzyl, p-bromobenzyl, p-cyanobenzyl, p-cyanobenzyldiphenylmethyl, bis (o-nitrophenyl) methyl, piperonyl Lower alkyl, lower alkoxy, nitro, such as
1 to 3 in which the aryl ring is substituted with a halogen or cyano group
Aralkyl groups such as lower alkyl groups substituted with 4 aryl groups; methoxycarbonyl, ethoxycarbonyl, t
Lower alkoxycarbonyl groups such as butoxycarbonyl, isobutoxycarbonyl, lower alkoxycarbonyl groups substituted with halogen or tri-lower alkylsilyl groups such as 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, etc. Alkoxycarbonyl group; Alkenyloxycarbonyl group such as vinyloxycarbonyl and allyloxycarbonyl;
Aryl ring with 1 to 2 lower alkoxy or nitro groups such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl A protecting group in a reaction such as optionally substituted aralkyloxycarbonyl group and a protecting group such as pivaloyloxymethyloxycarbonyl which is easily hydrolyzed in vivo for prodrug formation upon administration to a living body. And preferably an aliphatic acyl group, an aromatic acyl group, a tetrahydropyranyl group, an aralkyl group, an alkoxycarbonyl group, an alkenyloxycarbonyl group, an aralkyloxycarbonyl group and a protective group which is easily hydrolyzed in vivo.

As the substituent of the “substituted hydroxy group” represented by R ⁴ ,
For example, a group similar to the "lower alkyl group" which is defined later by R ⁵ , R ⁶ , R ⁷ and G; a nitrogen atom such as carbamoyl, N-methylcarbamoyl, N, N-dimethylcarbamoyl, N-ethylcarbamoyl A carbamoyl group which may be substituted with 1 to 2 lower alkyl groups; a lower alkanesulfonyloxy group such as methanesulfonyloxy, ethanesulfonyloxy, 1-propanesulfonyloxy; trifluoromethanesulfonyloxy, pentafluoroethanesulfonyl Examples thereof include fluorinated lower alkanesulfonyloxy groups such as oxy and arylsulfonyloxy groups such as benzenesulfonyloxy and p-toluenesulfonyloxy, and preferably 1 to 2 for the lower alkyl group or the nitrogen atom. Substituted by lower alkyl groups A carbamoyl group.

The protecting group of the "optionally protected mercapto group" represented by R ^4, is not limited as long as it is used to protect the normal mercapto, preferably, be "Securing R ⁴ It is the same group as the aliphatic acyl group, aromatic acyl group or aralkyl group in the definition of the protective group of "good hydroxyl group".

The substituent of the “substituted mercapto group” represented by R ⁴ is preferably the same group as the “lower alkyl group” defined by R ⁵ , R ⁶ , R ⁷ and G.

The "5- to 7-membered heterocyclic group" represented by G is a 5- to 7-membered heterocyclic group which contains at least one nitrogen atom, may contain an oxygen atom or a sulfur atom, and may be condensed. Shown, for example, pyrrolyl, azepinyl, morpholinyl, thiomorpholinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
1.2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl and partially or completely reduced groups corresponding to these groups, preferably a nitrogen atom Containing at least one, which may contain an oxygen atom or a sulfur atom, and represents a 5 to 7-membered aromatic heterocyclic group which may be condensed, for example, pyrrolyl, azepinyl, morpholinyl, thiomorpholinyl, pyrazolyl, imidazolyl, Oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-
Mention may be made of oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl and isoquinolyl, more preferably imidazolyl, oxazolyl, thiazolyl, quinolyl, isoquinolyl and pyridinyl.

The “lower alkyl group” represented by R ⁵ , R ⁶ , R ⁷ and G is, for example, methyl, ethyl, n-propyl, isopropyl, n.
-Butyl, s-butyl, t-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2
Carbon number such as -methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl It represents a linear or branched alkyl group having 1 to 6 carbon atoms, preferably an alkyl group having 1 to 4 carbon atoms.

The "hydroxy lower alkyl group" represented by G is a group in which 1 or 2 hydrogen atoms of the above "lower alkyl group" are substituted with a hydroxyl group. It is preferably a group in which one hydrogen atom of an alkyl group having 1 to 4 carbon atoms is substituted with a hydroxyl group.

The "lower alkoxy group" represented by G is a group in which the above-defined "lower alkyl group" is bonded to an oxygen atom, and examples thereof include an alkoxy group having 1 to 6 carbon atoms such as methoxy, ethoxy and propoxy. And is preferably an alkoxy group having 1 to 4 carbon atoms.

The "halogen atom" represented by G is fluorine, chlorine, bromine or iodine.

Z The "anion" represented by is not particularly limited, but HZ and
Preferably hydrofluoric acid, hydrochloric acid, hydrobromic acid, and iodide water.
Inorganic such as hydrohalic acid like sulfuric acid, sulfuric acid and phosphoric acid
Acid; methanesulfonic acid, trifluoromethanesulfone
Acids, lower alkyl sulfones such as ethanesulfonic acid
Acid, benzenesulfonic acid, p-toluenesulfonic acid
Organic acids such as arylsulfonic acid, oxalic acid, and maleic acid
And amino acids such as glutamic acid and aspartic acid
Can be mentioned.

In the formula (IV), when at least one of R ⁵ , R ⁶ and R ⁷ is a hydrogen atom (for example, when R ⁵ is a hydrogen atom), the formula (III) is (In the formula, E, q, n, R ⁴ , R ⁶ and R ⁷ have the same meanings as described above.)
It may be expressed as.

Similarly, if the G group is not a quaternary amine, formula (III) is (In the formula, E, q, n, R ⁴ and Q have the same meanings as described above).

The compound (I) of the present invention has a plurality of asymmetric carbons (for example, α-position and β-position of the ether oxygen atom of the ether ring) in the molecule, and each of them has R-coordination and S-coordination. There are many stereoisomers, each of which or a mixture thereof are included in the present invention.

In the compound (I), preferably, (1) a compound in which l is 2 or 3 (2) a compound in which B is an oxygen atom (3) E is a group having the formula — (CH ₂ ) _m — (in the formula, and m is the same meaning as described above.) (4) A compound in which E is a 5- to 7-membered heterocyclic group wrapping at least one nitrogen atom and optionally containing an oxygen atom or a sulfur atom (5) A compound in which E is imidazolyl, oxazolyl, isoxazolyl, thiazolyl or a partially or completely reduced group corresponding to these groups (6) The 5- to 7-membered heterocyclic group moiety defined by G has at least one nitrogen atom. A compound which is a 5- to 7-membered aromatic heterocyclic group which may be condensed and may contain an oxygen atom or a sulfur atom (7) The 5- to 7-membered heterocyclic group moiety defined by G is imidazolyl , Oxazolyl, thiazolyl, quinoli , Isoquinolyl or pyridinyl, Compound (8) n is an integer of 1 to 7 Compound (9) R ¹ is, the number 10 to 22 straight-chain or branched-chain alkyl group or the formula -CONH-R ³ carbons A compound having a group (in the formula, R ³ has the same meaning as described above) (10) a compound in which R ² is a group having the formula (III) (11) R ³ is a group having 13 to 20 carbon atoms Compounds which are chain or branched chain alkyl groups (12) Compounds in which R ⁴ is an optionally protected hydroxyl group or substituted hydroxyl group (13) R ⁵ , R ⁶ and R ⁷ are the same or different and have a carbon number A compound having 1 to 4 alkyl groups (14) a compound in which the desired substituent defined in G is a lower alkyl group or a hydroxy lower alkyl group (15) 1 is 2 or 3, and B is an oxygen atom Yes, E
Is a group having the formula — (CH ₂ ) _m — (wherein m has the same meaning as defined above), and the 5- to 7-membered heterocyclic group moiety defined by G contains at least one nitrogen atom. A 5- to 7-membered aromatic heterocyclic group which may contain an oxygen atom or a sulfur atom and which may be condensed, n is an integer of 1 to 7, and R
¹ is a linear or branched alkyl group having 10 to 22 carbon atoms or a group having the formula -CONH-R ³ (in the formula, R ³ has the same meaning as described above), and R ² is a group (III) is a compound having a group, R ³ is a linear or branched alkyl group having 13 to 20 carbon atoms, R ⁴ is an optionally protected hydroxyl group or a substituted hydroxyl group , R ⁵ , R ⁶ and R ⁷ are the same or different and each is an alkyl group having 1 to 4 carbon atoms, and the desired substituent defined by G is a lower alkyl group or a hydroxy lower alkyl group. ) 1 is 2 or 3, B is an oxygen atom, and E
Is a 5- to 7-membered heterocyclic group containing at least one nitrogen atom and optionally containing an oxygen atom or a sulfur atom, and the 5- to 7-membered heterocyclic group portion defined by G has at least one nitrogen atom. A 5- to 7-membered aromatic heterocyclic group which may be condensed and may contain an oxygen atom or a sulfur atom, n is an integer of 1 to 7, and R ¹ is a carbon number of 10 to 10 twenty two
Is a linear or branched alkyl group or a group having the formula -CONH-R ³ (wherein R ³ has the same meaning as described above), and R ² is a group having the formula (III) Compound, R ³ has 1 carbon
3 to 20 linear or branched alkyl groups, R ⁴ is an optionally protected hydroxyl group or a substituted hydroxyl group, R ⁵ , R ⁶ and R ⁷ are the same or different, and have a carbon number. 1 to 4
Compounds each of which is one alkyl group and the desired substituent defined by G is a lower alkyl group or a hydroxy lower alkyl group (17) 1 is 2 or 3, B is an oxygen atom, and E
Is a partially or completely reduced group corresponding to imidazolyl, oxazolyl, isoxazolyl, thiazolyl or a group thereof, and the 5- to 7-membered aromatic heterocyclic group moiety defined by G contains at least one nitrogen atom and oxygen. A 5- to 7-membered aromatic heterocyclic group which may contain an atom or a sulfur atom and which may be condensed, n is an integer of 1 to 7, and R ¹ has 10 to 22 carbon atoms. A compound which is a linear or branched alkyl group or a group having the formula -CONH-R ³ (wherein R ³ has the same meaning as described above), and R ² is a group having the formula (III). There, R ³ is straight or branched chain alkyl group having 13 to 20 carbon, R ⁴ is a hydroxyl group that is a good hydroxyl group or a substituted or optionally protected, R ^5, R ⁶ and R ⁷ They are the same or different and are an alkyl group having 1 to 4 carbon atoms, and the desired substituent defined by G is low. Alkyl or hydroxyalkyl lower alkyl group is the compound (18) l is 2 or 3, B is an oxygen atom, E
Is a group having the formula — (CH ₂ ) _m — (wherein m has the same meaning as defined above), and the 5- to 7-membered heterocyclic group moiety defined by G is imidazolyl, oxazolyl, thiazolyl, quinolyl. , Isoquinolyl or pyridinyl, and n is 1 to 7
And R ¹ is a linear or branched alkyl group having 10 to 22 carbon atoms or a group having the formula —CONH—R ³ (in the formula, R ³ has the same meaning as described above). And R ² is a compound having a group having the formula (III), R ³ is a linear or branched alkyl group having 13 to 20 carbon atoms, and R ⁴ is an optionally protected hydroxyl group or A substituted hydroxyl group, R ⁵ , R ⁶ and R ⁷ are the same or different and are an alkyl group having 1 to 4 carbon atoms, and the desired substituent defined by G is a lower alkyl group or a hydroxy lower alkyl group. A compound which is a group (19), l is 2 or 3, B is an oxygen atom, and E
Is a 5- to 7-membered heterocyclic group which contains at least one nitrogen atom and may contain an oxygen atom or a sulfur atom, and the 5- to 7-membered heterocyclic group portion defined by G is imidazolyl, oxazolyl, thiazolyl, Quinolyl, isoquinolyl or pyridinyl, n is an integer of 1 to 7, and R ¹ is
C10-C22 straight or branched chain alkyl group or formula
A compound having —CONH—R ³ (in the formula, R ³ has the same meaning as described above), R ² is a group having the formula (III), and R ³ has 13 to 20 carbon atoms. R ⁴ is a linear or branched alkyl group, R ⁴ is an optionally protected hydroxyl group or a substituted hydroxyl group, and R ⁵ , R ⁶ and R ⁷ are the same or different and have 1 to 4 carbon atoms. A compound having 20 alkyl groups and the desired substituent defined by G being a lower alkyl group or a hydroxy lower alkyl group (20) 1 is 2 or 3, B is an oxygen atom, and E is
Is imidazolyl, oxazolyl, isoxazolyl, thiazolyl or a partially or fully reduced group corresponding to these groups, and the 5- to 7-membered heterocyclic group moiety defined by G is imidazolyl, oxazolyl, thiazolyl, isoquinolyl, quinolyl Is pyridinyl, n is 1 to 7
And R ¹ is a linear or branched alkyl group having 10 to 22 carbon atoms or a group having the formula —CONH—R ³ (in the formula, R ³ has the same meaning as described above). And R ² is a compound having a group having the formula (III), R ³ is a linear or branched alkyl group having 13 to 20 carbon atoms, and R ⁴ is an optionally protected hydroxyl group or A substituted hydroxyl group, R ⁵ , R ⁶ and R ⁷ are the same or different and are alkyl groups having 1 to 4 carbon atoms, and the desired substituent defined by G is a lower alkyl group or a hydroxy lower alkyl group. The compound which is can be mentioned.

Specific examples of the compound having the general formula (I) of the present invention include the compounds shown in Table 1, but the present invention is not limited to these compounds.

Suitable compounds among the exemplified compounds include 7,9,13,3
2,34,35,36,39,40,42,43,44,45,46,47,48,49,50,51,52,
53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,6
9,70,77,78,79,80,91,103,104,105,106,111,112,113,11
4,115,116,117,118,120,121,122,123,124,125,126,127,
128,130,131,132,133,135,140,141,142,143,145,146,14
7,148,149,150,193,197,198,227,255,256,257,263,270
And 271. More preferable compounds include 42,44,47,51,52,58,62,63,66,68,70,105,106,1
14,115,116,117,120,121,122,126,128,132,135,140,14
2,143 and 147.

The cyclic ether derivative of the present invention can be produced by the method described below.

In the above formula, A, B, l, n, q, E, G, Q, Z ， R^Four， R^Five， R⁶And R⁷Is
Same meaning as above.

R ¹ ′ is a linear or branched alkyl group having 10 to 22 carbon atoms in the definition of R ¹ and R ² , a linear or branched aliphatic acyl group having 10 to 22 carbon atoms, or a formula-CONH Represents a group having —R ³ (wherein R ³ has the same meaning as defined above), and R ¹ ″ represents a straight chain or branched chain having 10 to 22 carbon atoms in the definition of R ¹ and R ^2. Represents an alkyl group, Y represents a halogen atom such as chlorine, bromine or iodine; an aliphatic acyloxy group; an aromatic acyloxy group; a trihalogenomethyloxy group such as trichloromethyloxy; a methanesulfonyloxy or ethanesulfonyloxy group. A lower alkanesulfonyloxy group;
Halogenated lower alkanesulfonyloxy groups such as trifluoromethanesulfonyloxy, pentafluoroethanesulfonyloxy; benzenesulfonyloxy, p-
A leaving group such as an arylsulfonyloxy group such as toluenesulfonyloxy is shown. Q ′ is a group having the formula —O—R ¹⁰ (wherein R ¹⁰ is the same as the protecting group for “optionally protected hydroxyl group” in the definition of R ⁴ ; An acyl group, an aromatic acyl group, a tetrahydropyranyl group, a tri-lower alkylsilyl group, an alkoxymethyl group and an aralkyl group) or a group having the formula -G (wherein G has the same meaning as described above). And Q ″ is
A group having the formula Y (in the formula, Y has the same meaning as described above) or a group having the formula -G (in the formula, G has the same meaning as described above).

R ⁹ represents a protective group for a hydroxyl group or a mercapto group, and
The same group as the protective group of "the hydroxyl group which may be protected" and the protective group of the "mercapto group which may be protected" defined by R ⁴ is shown.

R ⁴ ′ represents a protected hydroxyl group, a substituted hydroxyl group, a protected mercapto group or a substituted mercapto group in the definition of R ⁴ .

When R ⁴ ′ represents a protected hydroxyl group or a protected mercapto group, the protecting group must be a protecting group that is removable in distinction from the R ⁹ group.

Preferably, when R ⁴ ′ represents a protected hydroxyl group, the protecting group is a group that can be removed under acidic conditions such as a tetrahydropyranyl group, and a protecting group when it represents a protected mercapto group. A group that can be removed under weakly basic conditions, such as an aliphatic or aromatic acyl group, is used.

R ⁹ is preferably a group that can be removed under reducing conditions, such as aralkyl groups.

E ′ represents a divalent 5- to 7-membered heterocyclic group in the definition of E.

E ″ represents a group having the formula — (CH ₂ ) m— in the definition of E (in the formula, m has the same meaning as described above).

Method A and method B are methods for producing the compound having the general formula (I) of the present invention or a synthetic intermediate thereof.

The method C and the method D are as follows.
A process for producing a compound having the formula — (CH ₂ ) m— (wherein m has the same meaning as defined above) or a synthetic intermediate thereof.

In the general formula (I) of the present invention, R ² is the formula (II)
A method for producing a compound which is a group having I) or a synthetic intermediate thereof.

Method F is the same as formula (I) of the present invention in which R ² is the formula (II
A method for producing a compound having I), wherein E is a group having the formula —CH ₂ —.

Method G is the synthetic intermediates (XIV), (XIX),
(XXIII), (XXV), (XXVIII) or (XXXII) is reacted with the compound (XXXIII) or the compound having the formula HG (in the formula, G has the same meaning as described above) and the compound (I) of the present invention. )
Is a method of manufacturing.

The reaction reagents and reaction conditions in each of the above steps are described below.

The first step is a step of producing an ether compound (X) by reacting a compound having a hydroxyl group at the terminal (VIII) with a compound having an acidic hydroxyl group under the conditions of the Mitsunobu reaction.

The reaction is carried out in a solvent using a di-lower alkylazodicarboxylate such as dimethylazodicarboxylate, diethylazodicarboxylate and a triarylphosphine such as triphenylphosphine as reagents.

The reaction solvent is not particularly limited as long as it does not inhibit the reaction, but preferably, aromatic hydrocarbons such as benzene and toluene, or ethers such as ethyl ether and tetrahydrofuran can be mentioned. .

The reaction temperature and the reaction time mainly differ depending on the kinds of the raw material compounds and the reagents, but are preferably 0 ° C. to 100 ° C. and 15 minutes to 2 hours.

After completion of the reaction, the target compound (X) 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. The desired compound thus obtained can be further purified, if necessary, by a conventional method such as recrystallization, reprecipitation or chromatography.

The second step is a step of reacting the compound (XII) having a hydroxyl group or a mercapto group at the terminal with the alkylating agent (XI) in the presence of a base to produce an ether or thioether compound (X).

The solvent used is not particularly limited as long as it does not participate in this reaction, for example, ethers such as ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene and toluene; N, N-dimethyl. Amides such as formamide, N, N-dimethylacetamide;
Dimethyl sulfoxide or hexamethyl phosphorotriamide can be mentioned, preferably benzene, N, N-
It is dimethylformamide or hexamethylphosphorotriamide.

The base used is not particularly limited as long as it does not affect the other parts of the compound, preferably triethylamine, which is an acid binder, 1,5-diazabicyclo [5,4,0]. Organic bases such as undec-5-ene, pyridine, 2,6-lutidine, dimethylaniline, N, N-dimethylaminopyridine; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide or sodium hydride, Examples thereof include alkali metal hydrides such as potassium hydride, and alkali metal hydroxides are preferable. The reaction temperature is not particularly limited and is, for example, 0 ° C to 150 ° C, preferably 60 ° C to 90 ° C. The reaction time mainly varies depending on the reaction temperature and the kind of the raw material compound, and is, for example, 1 hour to 3 days, preferably 4 to 16 hours.

After completion of the reaction, the target compound (X) 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. The desired compound thus obtained can be further purified, if necessary, by a conventional method such as recrystallization, reprecipitation or chromatography.

In the third step, a compound (XII) having a hydroxyl group or a mercapto group at the terminal is reacted with an alkylating agent (XIII) in the same manner as in the second step to prepare an ether or thioether compound, and then the hydroxyl group or mercapto group is protected. The group is removed, and then a hydroxyl group or a mercapto group is added to the formula R ¹ ″ -Y (wherein R ¹ ″
And Y have the same meaning as described above. Alkylation according to the second step, the compound of formula R ¹ -Y (wherein
Y has the same meaning as described above, and R ¹ represents a linear or branched aliphatic acyl group having 10 to 22 carbon atoms. ), A reactive derivative of a carboxylic acid having the formula (1) is used, and a compound having the formula R ³ —N═C═O (R ³ has the same meaning as described above) is used according to a conventional method. Accordingly, it is a step of producing the compound (X) by carbamation.

The removal of protecting groups will vary with their type, but is generally carried out by methods well known in the art as follows.

When a silyl 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. The reaction temperature and reaction time are not particularly limited, but the reaction is usually performed at room temperature for 10 to 18 hours.

When the hydroxyl-protecting group or mercapto-protecting group is an aralkyloxycarbonyl group or an aralkyl group, it can usually be removed by bringing it into contact with a reducing agent. For example, it is achieved by carrying out catalytic reduction at room temperature using a catalyst such as palladium carbon, platinum or Raney-Nickel. The reaction is carried out in the presence of a solvent,
The reaction 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, fatty acids such as acetic acid or organic solvents thereof. A mixed solvent of water and water is suitable. The reaction temperature and reaction time will differ depending on the starting materials, the reducing agent used, etc., but will usually be 0 ° C. to room temperature, and 5 minutes to 12 hours.

It can also be removed by reacting metallic lithium or sodium in liquid ammonia or an alcohol such as methanol or ethanol at -78 ° C to -20 ° C.

Further, it can be removed by using aluminum chloride-sodium iodide or alkylsilyl halides such as trimethylsilyl iodide. The reaction is carried out in the presence of a solvent, and the reaction solvent used is not particularly limited as long as it does not participate in this reaction, but preferably, nitriles such as acetonitrile, methylene chloride, chloroform and the like. Halogenated hydrocarbons or mixed solvents thereof are used. The reaction temperature varies depending on the starting materials and the like, but is usually 0 ° C to 50 ° C. When the reaction substrate has a sulfur atom, aluminum chloride-sodium iodide is preferably used.

When the hydroxyl-protecting group or mercapto-protecting group is an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group, it can be removed by treating with a base. The base is not particularly limited as long as it does not affect other parts of the compound, but is preferably a metal alcoholate such as sodium methoxide, an alkali metal such as aqueous ammonia, sodium carbonate or potassium carbonate. It is carried out using carbonates, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or concentrated ammonia-methanol. The solvent used is not particularly limited as long as it is used in a usual hydrolysis reaction,
Preference is given to water, alcohols such as methanol, ethanol, n-propanol or organic solvents such as tetrahydrofuran, ethers such as dioxane or mixed solvents of water and organic solvents. The reaction temperature and the reaction time vary depending on the starting material and the base used and are not particularly limited, but in order to suppress side reactions, it is usually 0 ° C to 150 ° C.
It takes 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, p-toluenesulfonic acid, acetic acid and the like. 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 generally 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.

In the acylation reaction, when Y is a halogen atom, the reaction is carried out in a solvent in the presence of a base.

The reaction solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent,
Halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane; ethers such as diethyl ether, tetrahydrofuran and dioxane, or aromatic hydrocarbons such as benzene and toluene are preferably used.

The base used is not particularly limited as long as it is an amine, but triethylamine, diethylamine or pyridine is preferably used.

The reaction temperature and the reaction time will differ depending on the conditions of the starting material, solvent and base used, but when carried out in the range of 0 ° C to 120 ° C, 2 to 24 hours are preferable.

When Y represents a trihalogenomethyloxy group, a lower alkanesulfonyloxy group, a halogenated lower alkanesulfonyloxy group, an arylsulfonyloxy group, an aliphatic acyloxy group or an aromatic acyloxy group, a base is not always necessary in the reaction. No, it reacts immediately, but is accelerated when a base is used.

The solvent used in this case is not particularly limited as long as it does not participate in this reaction, for example, chloroform,
Halogenated hydrocarbons such as dichloromethane and dichloroethane or ethers, ethers such as tetrahydrofuran and dioxane may be mentioned, and dichloromethane or tetrahydrofuran is preferable. The reaction temperature is not particularly limited, but is usually 0 ° C. to 50 ° C., preferably 0 ° C. to 20 ° C., and the reaction time varies mainly depending on the reaction temperature or the kind of the raw material compound. , Usually 0.
5 to 24 hours.

After completion of the reaction, the target compound can be isolated from the reaction mixture by a conventional method. For example, a pure product can be obtained by purification by recrystallization, preparative thin-layer chromatography, column chromatography, or the like.

The carbamate reaction is performed by adding DPPA (diphenylphosphoryl azide) to a compound having the formula R ³ —COOH (wherein R ³ has the same meaning as described above) such as chloroform, toluene, benzene, dichloromethane or tetrahydrofuran. A compound which can be easily synthesized by reacting in an inert solvent, preferably toluene or benzene, in the presence of an organic base such as triethylamine or tributylamine at 0 ° C to 150 ° C, and which is directly reacted with this solution Is added, and the mixture is further reacted at 60 ° C. to 150 ° C. for 2 to 24 hours, whereby the target compound (X) can be produced. Suitably, at the time of synthesizing the isocyanate compound, it is washed with saturated sodium hydrogencarbonate water and water to remove the phosphorus compound, the solvent is distilled off and dried, and then a solvent selected from the above exemplified solvents (preferably Is dissolved in toluene) and the compound to be reacted is added and reacted, or a commercially available isocyanate compound is reacted in the same solvent.

After completion of the reaction, the target compound can be isolated from the reaction mixture by a conventional method. For example, a pure product can be obtained by purification by recrystallization, preparative thin-layer chromatography, column chromatography, or the like.

In the fourth step, in the compound (X), when the terminal Q ′ group is a group having the formula —O—R ¹⁰ (in the formula, R ¹⁰ has the same meaning as described above), the —O—R is the same. ^{In this step, 10} groups are converted into Y groups to produce compound (XIV).

First, the removal of the hydroxy-protecting group R ¹⁰ is performed according to the description of the third step.

Then, the deprotected hydroxyl group is acylated, for example, methanesulfonyl, toluenesulfonyl, trifluoromethanesulfonyl or trifluoroacetyl to synthesize an ester, or the hydroxyl group is substituted with a halogen atom.

The solvent used in the ester synthesis is not particularly limited as long as it does not participate in this reaction, and for example, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane; ether, tetrahydrofuran,
Mention may be made of ethers such as dioxane or aromatic hydrocarbons such as benzene and toluene, preferably dichloromethane or benzene. The base used is not particularly limited, but is preferably an organic base such as an acid binder such as triethylamine, pyridine, 2,6-lutidine and dimethylaniline. The reaction temperature is not particularly limited, but is preferably 0 ° C. to 25 ° C., and the reaction time is preferably 0.5 to 24 hours, varying mainly depending on the reaction temperature or the kind of the raw material compound.

The halogen substitution reaction is not particularly limited as long as it is a reaction that can substitute a hydroxyl group for a halogen atom, but is preferably carried out using carbon tetrahalide and triphenylphosphine or phosphorus trihalide. The solvent used is not particularly limited as long as it does not participate in this reaction, but halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, or nitriles such as acetonitrile are preferable. The reaction temperature is not particularly limited, but is preferably -25 ° C. to room temperature, and the reaction time is usually 1 to 60 minutes, varying mainly depending on the reaction temperature or the kind of the raw material compound.

The halogen-substituted compound can also be synthesized by reacting the above-synthesized ester with an alkali metal halide such as sodium iodide, sodium bromide or potassium chloride. The solvent used is a polar solvent capable of dissolving an alkali metal halide and is not particularly limited as long as it does not participate in the reaction, for example, sulfoxides such as dimethyl sulfoxide, N, N- Mention may be made of amides such as dimethylformamide or phosphoric triamides such as hexamethylphosphorotriamide, with N, N-dimethylformamide being preferred. Although the reaction temperature is not particularly limited, it is preferably carried out at 20 ° C. to 80 ° C., and the reaction time mainly depends on the reaction temperature or the kind of the raw material compound, but is usually 1 to
24 hours.

After completion of the reaction, the target compound can be isolated from the reaction mixture by a conventional method. For example, a pure product can be obtained by purification by recrystallization, preparative thin-layer chromatography, column chromatography, or the like.

The fifth step is a step of producing compound (XVI) by reacting compound (XV) with compound (IX) according to the first step.

In the sixth step, compound (XVII) is reacted with compound (XVIII) according to the second step to give compound (XVI)
Is a process of manufacturing.

In the seventh step, compound (XX) and compound (XVIII)
In this step, compound (XVI) is produced by reacting according to the steps.

The eighth step is a step for producing compound (XIX) by treating compound (XVI) according to the fourth step.

In the ninth step, the compound (XXII) having a hydroxyl group or a mercapto group at the terminal is reacted with the alkylating agent (XXI) in the same manner as in the second step to give an ether or thioether compound, and then according to the third step. In this step, the compound (XXIII) is produced by treating and further converting the terminal Q ′ group into a Q ″ group according to the fourth step.

In the 10th step, compound (XXIV) is reacted with compound (XXI) and treated according to the 9th step to give compound (XXIV).
V) is a manufacturing process.

In the 11th step, the compound (XXVI) and the compound (XII) are treated in the second step.
By reacting according to the process, compound (XXVII)
Is a process of manufacturing.

In the 12th step, compound (XXVII) is used as a starting material,
By carrying out the reaction according to the method described in JP-A-61-267592 and the third step, a compound in which R ² represents a group having the formula (III) in the general formula (I) of the present invention, or a synthesis thereof This is a step of producing an intermediate compound (XXVIII).

The thirteenth step is a step of producing a compound (XXX) by reacting the hydroxyl group or mercapto group of the compound (XXIX) with an allyl halide such as allyl chloride, allyl bromide or allyl iodide in a solvent in the presence of a base. Is.

The solvent to be used is not particularly limited as long as it does not participate in this reaction, and examples thereof include ethers such as ether and tetrahydrofuran; aromatic hydrocarbons such as toluene and benzene, or dimethylformamide and dimethylacetamide. Amides can be mentioned, and amides are preferable.

The base used is not particularly limited as long as it is usually used as a base, and examples thereof include alkali metal hydrides such as potassium hydride and sodium hydride; alkali metal water such as sodium hydroxide and potassium hydroxide. Oxides or pyridine, N, N-dimethylaminopyridine, 1,5-diazabicyclo [5.4.0] undec-5-ene, triethylamine, 2,6-lutidine, organic bases such as dimethylaniline can be mentioned, Preferred is an alkali metal hydride.

The reaction temperature and the reaction time will differ mainly depending on the kinds of the raw material compound, the solvent and the base, but are usually 0 ° C. to 100 ° C. and 1 to 24 hours.

In the 14th step, the double bond of the allyl group of compound (XXX) is
Oxidized in a solvent and converted to an epoxide, compound (XXXI)
Is a process of manufacturing.

The solvent used is not particularly limited as long as it does not participate in this reaction, and ethers such as ether and tetrahydrofuran or halogenated hydrocarbons such as methylene chloride and chloroform are preferable.

The oxidizing agent used is not particularly limited, but organic peroxides such as peracetic acid, perbenzoic acid, benzoyl peroxide and m-chloroperbenzoic acid are preferably used.

The reaction temperature and the reaction time mainly differ depending on the kinds of the raw material compound, the solvent, and the oxidant, but are usually -20 ° C to 80 ° C,
1 to 24 hours.

The 15th step is a step of reacting compound (XXIX) with an epihalohydrin such as epichlorohydrin, epibromohydrin, epiiodohydrin according to the conditions of the 13th step to produce compound (XXXI) Is.

The 16th step is a compound having the formula M- (CH ₂ ) _n-1 -Q ', which is produced by a conventional method with the compound (XXXI) (wherein M is an alkali metal such as lithium, sodium or potassium). atom,
Indicates magnesium halide or zinc halide, n
Represents an integer of 1 to 10, and Q'has the same meaning as described above. ) Is reacted with a solvent in a solvent, and further treated according to the description of the fourth step to produce the compound (XXXII).

The solvent used is not particularly limited as long as it does not participate in the reaction, and examples thereof include ethers such as ether and tetrahydrofuran, or aromatic hydrocarbons such as toluene and benzene. Are ethers.

The reaction temperature and the reaction time mainly differ depending on the raw material compound, the solvent, and the kind of the reagent, but are usually -78 ° C to 65 ° C, and
Minutes to 24 hours.

The 17th step is the compound (XIV) produced as described above,
(XIX), (XXIII), (XXV), (XXVIII) or (XXXI
In I), when Q ″ represents a group having the formula Y (in the formula, Y has the same meaning as described above), the amine compound (XXXIII) or the compound having the formula HG (in the formula, G Represents the same meaning as described above), and if desired,
This is a step of producing the compound (I) of the present invention by removing the protected hydroxyl group or mercapto group protecting group of R ⁴ ′ according to the third step.

The reaction solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent,
Preferable halogenated hydrocarbons such as methylene chloride and chloroform; lower alcohols such as methanol, ethanol and isopropyl alcohol; dimethylformamide; diethyl ether, tetrahydrofuran,
Ethers such as dioxane; acetonylol or water, or 2-3 such as chloroform-dimethylformamide-isopropyl alcohol = 3: 5: 5
A mixture of the above solvents of the species is used.

The reaction temperature and the reaction time will differ depending on the conditions of the starting materials and the solvent used, but the reaction may be carried out in the sealed reaction vessel (for example, a sealed tube) under a nitrogen atmosphere in the range of 20 to 80 ° C. for 1 to 48 hours. It is suitable.

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, after removing the insoluble matter precipitated from the reaction mixture, the organic solvent layer is washed with water and dried, the solvent is distilled off,
For example, a pure product can be obtained by purification by recrystallization, preparative thin layer chromatography, column chromatography and the like.

When Q ′ or Q ″ is a group having the formula —G (in the formula, G has the same meaning as described above), the compound (X),
(XIV), (XVI), (XIX), (XXIII), (XXV), (X
XVIII) and (XXXII) are the compound (I) of the present invention. In this case, the corresponding protecting compound (I) can be produced by optionally removing the protecting group in the same manner as in the 17th step.

Raw material compounds (XI), (XIII), (XVII), (X
X) and (XXVI) are novel compounds, and, for example, using a compound of dl form described in JP-A-61-267592 as a raw material,
Each can be produced by treating according to the fourth step.

Furthermore, the raw material compound of the present invention can specifically produce an optically active substance of d-form or l-form by using d- or 1-tartaric acid as a starting compound, as shown in the following reaction formula, for example. it can.

In the above formula, R ¹⁰ has the same meaning as described above, R ¹¹ represents a group similar to the group defined for R ¹⁰ , but R ¹⁰ and R ¹¹ are groups that can be selectively and separately removed. Show. R ¹² represents a lower alkyl group. R ¹⁵ and R ¹⁷ represent the same group as the protecting group of the “optionally protected mercapto group” in the definition of R ⁴ . R
¹³ and R ¹⁶ represent the same groups as defined for R ¹⁰ and R ¹¹ , but R
^10, of ^{R 11, R 13, R 15} , R 16 and R ^17, 2 or more, a group when used in the same compound, they capable of selectively removing separately from other protecting groups Shall be shown. R ¹⁴
Represents a group similar to the lower alkanesulfonyloxy group, halogenated lower alkanesulfonyloxy group and arylsulfonyloxy group in the definition of Y.

Suitably, R ¹⁰ is a monoarylmethyl group such as benzyl, R ¹¹ is a silyl group, R ¹³ is a di- or triarylmethyl group, R ¹⁵ is an aliphatic acyl group, R ¹⁶ is tetrahydropyranyl. R group, R ¹⁷ is an aromatic acyl group.

Ohno et al., Tetrahedron Letters, 23, 3507, 1982 [Ohno, et.al., Tetrahedron Lett., 23 , 3507, (1982)]
By a method similar to that described in (2)
It is possible to synthesize a compound (XXXV) in which the oxygen atom at the 3-position of (S, 3S) tartaric acid (XXXIV) is substituted with a protecting group R ¹⁰ .
18 steps).

The primary hydroxyl group of the compound (XXXV) is acylated in the same manner as in the fourth step, the acyloxy group is replaced with iodine, and then the compound is reacted with di-lower alkyl malonate to produce the compound (XXXVI) ( 19th process).

The compound (XXXVI) can be decarboxylated by heating with, for example, an aqueous solution of sodium chloride in DMSO to obtain a compound (XXXVII) obtained by adding 2 carbon to (XXXIV) (step 20).

By reducing the compound (XXXVII) with a reducing agent such as lithium aluminum hydride in an ether solvent,
An alcohol compound (XXXVIII) can be produced (21st step). The hydroxyl group of this compound is protected with R ¹¹ (preferably diphenyl t-butylsilyl group), the isopropylidene group is removed, and the generated primary hydroxyl group is protected with R ¹³ (preferably triphenylmethyl group) ( (22nd step) The secondary hydroxyl group is acylated in the same manner as in the 4th step to produce compound (XL) (23rd step). Protecting group for hydroxyl group of compound (XL)
R ¹¹ (preferably by a fluorine anion when R ¹¹ is a silyl group) is removed (step 24) and this is treated with a base (eg potassium t-butoxy in t-butanol). As a result, the optically active compound (XLII) in which the configuration at the 2-position is inverted and the ring is closed can be produced (No. 1).
25 steps).

Further, the compound (XLII) is treated according to the method described in JP-A-61-267592, whereby a mercapto compound (XLIII) having a stereocoordinate can be produced (step 26). ).

The compound (XXXVIII) can be converted into a protected thiol group having a reversed conformation in the same manner as in the 26th step (27th and 28th steps).

Compound (XLV) can be produced by treating compound (XLV) in the same manner as in steps 22 to 25 (step 29).

Compound (XLVI) can be treated in the same manner as in step 26 to produce optically active compound (XLVII) (step 30).

After protecting the secondary hydroxyl group of compound (XXXIX) with R ¹⁶ (step 31) and selectively removing the protecting group R ¹¹ , the generated hydroxyl group is acylated in the same manner as in step 4 to give compound (IL). It can be manufactured. (Step 32).

By selectively removing the protective group R ¹⁶ for the secondary hydroxyl group of compound (IL) (step 33) and treating in the same manner as in step 25, the ring-closed optical activity in which the 2-position configuration was retained was maintained. The body compound (LI) can be produced (step 34). Further, in the same manner as in the 26th step, the mercapto compound (LI
I) can be manufactured (step 35).

Compound (LIII) can be produced by using compound (XLV) in the same manner as in step 22, (step 36).

Compound (LIV) can be produced by treating compound (LIII) in the same manner as in step 31, (step 37).

Compound (LV) can be produced by using compound (LIV) in the same manner as in step 32 (step 38).

Compound (LVI) can be produced by treating compound (LV) in the same manner as in step 33 (step 39).

The compound (LVI) can be treated in the same manner as in Step 34 to produce the optically active compound (LVII) (Step 40).

Compound (LVII) can be treated in the same manner as in step 26 to produce optically active compound (LVIII) (step 41).

As a starting material, d-tartaric acid (LIX) having (2R, 3R)
And by carrying out in the same manner as in the 18th step,
Compound (LX) of (2S, 3S) can be produced (4th
2 steps).

By carrying out the same steps as the above-mentioned Steps 19 to 41 using this compound (LX), an optically active compound (LXI)
~ (LXVIII) can be produced (step 43).

On the other hand, in order to synthesize the starting material of the compound (I) of the present invention having a 5-membered ring (l = 2), a cyano compound is synthesized using a metal cyanide instead of a malonic ester, and an alcohol is prepared according to a conventional method. The compound of the corresponding optically active substance is obtained by performing steps 22 to 41 using an alcohol compound (LXIX) obtained by decomposing to synthesize an ester and further reducing the carbon by 1 carbon from the compound (XXXV). Can be manufactured.

Further, in order to synthesize the starting material of the compound (I) of the present invention having a 7-membered ring (l = 4), the compound (LXIX) is used as a starting material, and steps 19 to 41 are carried out. An optically active compound can be produced.

Either of the protective groups of the above-prepared optically active compound is removed according to the same method as in the third step, and further alkylated, acylated or carbamate-ized to give the starting compound of the present invention. It can be manufactured.

The starting compound containing a group having the formula (III) can be produced, for example, as follows.

In the above formula, R ⁴ , R ¹⁰ , R ¹² , A, B, Y and n have the same meanings as described above. W represents a divalent 5- to 7-membered heterocyclic group in the definition of E.

The hydroxyl group of compound (LXX) is protected according to a conventional method to isolate compound (LXXI) in which only one hydroxyl group is protected (step 45), and the other hydroxyl group is used as an oxidizing agent (preferably pyridinium). A chromium-based oxidizing agent such as chlorochromate) is used to form an aldehyde, which is then reacted with a metal cyanide compound such as sodium cyanide and potassium cyanide to produce a compound (LXXII) (step 46). If desired, after converting the hydroxyl group of this compound into a mercapto group according to the 26th step, an alcoholysis reaction is carried out using an alcohol such as methanol under acidic conditions such as hydrochloric acid, and the primary alcohol is again used. Compound (LXXIV) is produced by protecting compound (Step 48). If desired, the group having the formula HA- can be modified with the abovementioned protecting groups or substituents. The ester group of this compound is reduced to a hydroxyl group with a metal hydride compound such as lithium aluminum hydride, and if desired, according to the 26th step, the generated hydroxyl group is converted to a mercapto group to give a compound (LXXV). It can be manufactured (step 49).

By treating the compound (LXXV) according to the 19th to 21st steps or the 44th step, a compound in which the carbon number is increased by 2 or 1 can be produced.

The 51st step is a step of producing a compound (LXXIX) by removing the proton of the methyl group of the compound (LXXVIII) with a base in a solvent to form a carbanion, and reacting the carbanion with the compound (LXXX).

The solvent used is preferably an ether such as ether or tetrahydrofuran, and the base is an organic lithium metal compound such as butyllithium or lithium diisopropylamide, preferably lithium diisopropylamide. is there.

The reaction temperature and the reaction time will differ mainly depending on the kind of the raw material compound, but are usually −78 ° C. to 0 ° C., and 15 minutes to 4 hours.

〔effect〕

INDUSTRIAL APPLICABILITY The novel cyclic ether derivative of the present invention has a strong PAF antagonistic action with excellent durability and bioavailability, and is useful as a new type anti-shock agent, anti-thrombotic agent, anti-asthma agent and anti-allergic agent is there.

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. Its usage is symptom
Depending on age etc., 0.1-200 mg / kg body weight daily,
It can be administered once or in several divided doses.

Hereinafter, the present invention will be described more specifically with reference to Examples, Reference Examples and Test Examples.

Example 1. dl-3- [4- {3- (trans-3-heptadecylcarbamoyloxytetrahydropyran-2-yl) methoxy-5-isoxazolyl} butyl] thiazolium methanesulfonate The compound of Reference Example 4 (0.470 g) and triethylamine (0.24 g)
methanesulfonyl chloride (0.10 ml) was added to a benzene (10 ml) solution under ice cooling. After stirring for 15 minutes at room temperature, the reaction solution was washed with water, dried and concentrated. Dissolve the residue in toluene (3 ml), add thiazole (0.60 ml), and 85 ℃
On an oil bath for 4 days. The solvent was distilled off, and the residue was subjected to column chromatography using silica gel (30 g). Fractions eluted with methylene chloride-methanol (2: 1 to 1: 1) were collected to give the title compound (0.349 g) as a white powder. mp 82-86 ° C.

NMR spectrum (270 MHz, CD ₃ OD) ppm: 0.90 (3H, t, J = 7.0
Hz), 1.2 to 2.3 (38H, m), 2.69 (3H, s), 2.76 (2H, t, J =
7.3Hz), 3.04 (2H, t, J = 7.0Hz), 3.43 (1H, m), 3.58 (1
H, m), 3.93 (1H, d, J = 11.5Hz), 4.25 (1H, m), 4.56 (1
H, m), 4.62 (2H, t, J = 7.3Hz), 5.85 (1H, s), 8.29 (1H,
d, J = 4.0Hz), 8.49 (1H, d, J = 4.0Hz), elemental _{analysis: C 35 H 61 N 3 O} 8 S Calculated: C, 58.71; H, 8.59 ; N, 5.87 Found: C, 58.35; H, 8.81; N, 5.71 Example 2. dl-3- [7-hydroxy-8-{(trans-3-heptadecylcarbamoyloxytetrahydropyran-2
-Yl) methoxy} octyl] thiazolium = p-toluenesulfonate The compound of Reference Example 11 (150 mg) and thiazole (0.15 ml) were dissolved in toluene (1 ml), and the mixture was heated on an oil bath at 80 ° C for 42 hours. The solvent was evaporated and the residue was subjected to column chromatography using silica gel (4g). Fractions eluted with methylene chloride-methanol (9: 1) were collected to give the title compound (56 mg) as a powder. mp 81-84 ° C NMR spectrum (60MHz, CD ₃ OD) ppm: 0.7-2.5 (45H, m),
2.35 (3H, s), 3.04 (2H, t, J = 6.5Hz), 3.3 to 4.1 (8H,
m), 4.58 (2H, d, J = 7Hz), 4.3 to 4.9 (1H, m), 7.22 (2H,
d, J = 8Hz), 7.73 (2H, d, J = 8Hz), 8.27 (1H, d, J = 4H
z), 8.60 (1H, d, J = 4Hz) Example 3. dl-3- [7-acetoxy-8-{(trans-3-heptadecylcarbamoyloxytetrahydropyran-2
-Yl) methoxy} octyl] thiazolium = p-toluenesulfonate Isomer I of Reference Example 12 (163 mg) and thiazole (0.15 ml)
Was dissolved in toluene (1 ml) and heated on an oil bath at 80 ° C. for 110 hours. The solvent was evaporated and the residue was subjected to column chromatography using silica gel (4g). Fractions eluted with methylene chloride-methanol (7:93 to 1: 9) were collected to give the title compound (87 mg) as a resin.

NMR spectrum (60 MHz, CD ₃ OD) ppm: 0.7 to 2.3 (47 H, m),
2.00 (3H, s), 2.33 (3H, s), 2.80 ~ 4.20 (9H, m), 4.2 ~
4.7 (1H, m), 4.55 (2H, t, J = 7Hz), 4.75 ~ 5.2 (1H, m),
7.20 (2H, d, J = 8Hz), 7.72 (2H, d, J = 8Hz), 8.28 (1H,
d, J = 4Hz), 8.50 (1H, d, J = 4Hz) Elemental _{analysis: C 44 H 74 N 2 O} 9 S 2 .0.5H 2 O Calculated: C, 62.31; H, 8.91 ; N, 3.30 ; S, 7.56 Found: C, 62.29; H, 9.08; N, 2.92; S, 7.46 Reference Example 1. dl-trans-2-benzyloxymethyltetrahydropyran-3-yl N-heptadecylcarbamate A solution of stearic acid (6.082g), diphenylphosphoryl azide (3.84ml) and triethylamine (2.48ml) in benzene (200ml) was heated to reflux for 3 hours. After cooling, the reaction was washed with aqueous sodium bicarbonate solution and brine. After drying, the solvent was distilled off and the residue was redissolved in benzene (160 ml). dl-trans-2-benzyloxymethyltetrahydropyran-3-ol (1.980 g) was added, and the mixture was heated under reflux for 38 hours under a nitrogen atmosphere. After cooling, the reaction mixture was washed successively with aqueous sodium bicarbonate solution and water, dried and concentrated to dryness. The residue was subjected to column chromatography using silica gel (60 g), and the fractions eluted with hexane-methylene chloride-ether (6: 3: 1) were collected to give the title compound (3.904 g) as a white solid. Obtained. Melting point (hereinafter abbreviated as mp) 61 to 63 ° C. IR spectrum (CHCl ₃ , cm ⁻¹ ): 3460 (−NH−), 1720
(-O-CO-) mass spectrum (m / e): 503 ( M +), 412 (M + -C 7 H 7) Elemental analysis: Calculated _{C 31 H 53 NO 4: C} , 73.91; H, 10.60; N, 2.78 Found: C, 74.27; H, 10.70; N, 2.71 Reference Example 2. dl- (trans-2-hydroxymethyltetrahydropyran-3-yl) N-heptadecylcarbamate To a solution of the compound of Reference Example 3 (3.800 g) in methanol (120 ml) was added 10% palladium carbon (1.90 g), and the mixture was reacted with hydrogen gas in a Parr apparatus at room temperature and 4 atm for 8 hours. After removing the catalyst, the solvent was evaporated to give the title compound (2.729 g) as a white solid. mp 84-86 ℃ (ether) IR spectrum (CHCl ₃ , cm ^-1 ): 3570 (-OH), 3450 (-N
H), 1710 (-O-CO- ) mass spectrum (m / e): 413 ( M +), 382 (M + -CH 2 OH) Elemental analysis: Calculated _{C 24 H 47 NO 4: C} , 69.69 H, 11.45; N, 3.39 Found: C, 69.38; H, 11.35; N, 3.52 Reference Example 3. 3-Hydroxy-5- {4- (2-tetrahydropyranyl) oxybutyl} isoxazole A solution of diisopropylamine (3.08 ml) in tetrahydrofuran (100 ml) was added to a solution of n-butyllithium in hexane (1
5% by weight, 13.95 ml) is added dropwise at -25 ° to -15 ° C. -20
After stirring at ℃ for 15 minutes, 3-hydroxy-5-methylisoxazole (0.990g) in tetrahydrofuran (10ml)
The solution was added at -20 ° to -10 ° C over 10 minutes. At -10 ° C
After stirring for 30 minutes, the reaction solution was cooled to -50 ° C, and 1-bromo-3- (2'-tetrahydropyranyl) oxypropane (3.35 g) was added at once. After stirring at 15 to 20 ° C for 2 hours, acetic acid (1.20 ml) was added and the reaction mixture was poured into water.
After separating the organic layer, the aqueous layer was adjusted to pH 3 with 10% hydrochloric acid and extracted twice with ether. The organic layers were combined, washed with water, dried and concentrated, and the residue was subjected to column chromatography using silica gel (60 g). Fractions eluted with ethyl acetate-hexane (1: 2-1: 1) were collected to give the title compound (1.720 g) as a colorless oil.

NMR spectrum _{(90MHz, CDCl 3) ppm:} 9.91 (1H, s, -OH),
5.68 (1H, s), 4.58 (1H, s), 3.2 to 4.1 (4H, m), 1.3 to 2.
1 (10H, m) mass spectrum (m / e): 241 (M ⁺ ), 186,157,140 Reference Example 4. dl-trans-2- {5- (4-hydroxybutyl)-
3-isoxazolyloxy} methyltetrahydropyran-3-yl N-heptadecyl carbamate The compound of Reference Example 2 (0.827 g) and the compound of Reference Example 3 (0.48 g)
2g) and triphenylphosphine (0.577g) in tetrahydrofuran (14ml) was added a solution of dimethyl azodicarboxylate (0.321g) in tetrahydrofuran (2ml),
The mixture was stirred at room temperature for 4.5 hours. The solvent was distilled off, and the residue was subjected to column chromatography using silica gel (30 g). The oil (1.3 g) obtained by collecting the fractions eluted with ether-hexane (1: 1) was dissolved in methanol (10 ml), camphorsulfonic acid (0.05 g) was added, and the mixture was stirred at room temperature for 1 hour.
It was stirred for 6 hours. The solvent was distilled off, water was added to the residue, and the mixture was extracted with methylene chloride. The extract was dried and concentrated, and the solid residue (1.19 g) was subjected to column chromatography using silica gel (40 g). Hexane-ethyl acetate (1:
Collect the fractions eluted in 1) and the title compound (0.555g)
Got mp 86-87 ° C (methylene chloride-ether).

NMR spectrum _{(90MHz, CDCl 3) ppm:} 0.75~2.50 (42H,
m), 2.65 (2H, t, J = 6.5Hz), 3.12 (2H, td, J ₁ = 6.5Hz, J ₂
= 6Hz), 3.3 to 4.9 (9H, m) 5.67 (1H, s) IR spectrum (CHCl ₃ ) cm ^-1 : 3600 (-OH), 3450 (-NH
-), 1720 (-OCONH-) Mass spectrum (m / e): 552 (M ⁺ ) Elemental analysis, C ₃₁ H ₅₆ N ₂ O
Calculated as ₆ : C, 67.35; H, 10.21; N, 5.06 Found: C, 67.57; H, 10.42; N, 4.83 Reference Example 5. 2-Hydroxy-8- (tetrahydropyran-2-yloxy) octanenitrile Pyridinium chlorochromate (40.60 g), sodium acetate (3.86 g) and methylene chloride (200 ml) were added to a mixture of 7- (tetrahydropyran-2-yloxy)-
1-Heptanol (20.37g) in methylene chloride (200m
l) The solution was added under ice cooling. After stirring for 1 hour at 0 ° C. and 3 hours at room temperature, the reaction solution was diluted with ether (1.5 l) and passed through a column of silica gel (250 g). Concentrate the flow-through,
The residue was subjected to column chromatography using silica gel (400g). Hexane-ethyl acetate (40: 1 to 9: 1)
The fractions eluted with 7- (tetrahydropyran-
2-yloxy) heptanol (14.11 g) was obtained as a colorless oil.

NMR spectrum _{(60MHz, CDCl 3) ppm:} 1.1~2.1 (14H, m),
2.42 (2H, m), 3.1 ~ 4.1 (4H, m), 4.56 (1H, m), 9.83 (1
H, t, J = 2Hz) Aldehyde (14.11g) and potassium cyanide (12.86)
g) was dissolved in a dioxane-water mixture (1: 1,300 ml), and 6N hydrochloric acid (32.9 ml) was added dropwise over 10 minutes under ice cooling.
After stirring at 0 ° C. for 1 hour, the reaction solution was poured into water (600 ml) and extracted twice with ethyl acetate. Washing the extract with water, drying,
It was concentrated and the residue was subjected to column chromatography using silica gel (300 g). Hexane-ethyl acetate (1: 9
Fractions eluted at ~ 1: 4) are collected and the title compound (11.90.
g) was obtained as a colorless oil.

NMR spectrum _{(60MHz, CDCl 3) ppm:} 1.2~2.2 (16H, m),
3.1 to 4.2 (5H, m), 4.40 (1H, m), 4.58 (1H, m) IR spectrum (CHCl ₃ ) cm ⁻¹ : 3600,3360,2250 Reference example 6.Methyl 2,8-dihydroxyoctanoate The compound of Reference Example 5 (7.73 g) was dissolved in a mixture of ether (80 ml) and methanol (80 ml), and saturated with hydrochloric acid gas under ice cooling. After stirring at room temperature for 3 hours, water (160 ml) was added over 10 minutes under ice cooling. After stirring at room temperature for 1 hour, the reaction solution was diluted with water and then extracted 6 times with ethyl acetate. The extracts were combined, washed with water, dried and concentrated. The residue was subjected to column chromatography using silica gel (120 g), and the fractions eluted with hexane-ethyl acetate (4; 1-2: 1) were collected to give the title compound (3.75 g) as a colorless oil. It was

NMR spectrum _{(90MHz, CDCl 3) ppm:} 1.2~2.0 (10H, m),
1.67 (1H, m, -OH), 2.85 (1H, m, -OH), 3.63 (2H, t, J =
7Hz,), 4.70 (1H, m) IR spectrum (CHCl ₃ ) cm ^-1 : 3550,1735 Mass spectrum (m / e): 191 (M ⁺ +1), 131,113 Elemental analysis: Calculated as C ₉ H ₁₈ O _4. Value: C, 56.82; H, 9.54 Actual value: C, 56.46; H, 9.45 Reference Example 7. 2,8-bis (tetrahydropyran-2-yloxy)-
1-octanol _{THPO (CH 2) 6 CH (} OTHP) Compound of CH ₂ OH Example 6 (2.71g), 3,4- dihydro -2H- pyran (3.90 mL) and p- toluenesulfonic acid pyridine salt (0.072 g ) Was dissolved in methylene chloride (50 ml) and stirred at room temperature for 15 hours. After the solvent was distilled off, the residue was dissolved in tetrahydrofuran (30 ml) and added dropwise to a mixture of lithium aluminum hydride (1.081 g) and tetrahydrofuran (30 ml) over 10 minutes under ice cooling. After stirring at room temperature for 1 hour, 4% aqueous sodium hydroxide solution (4.3 ml) was added dropwise under ice cooling. The reaction solution was passed through a Celite layer, and the insoluble material was washed with tetrahydrofuran (100 ml). The filtrate was concentrated and the residue was subjected to column chromatography using silica gel (100 g). Hexane-ethyl acetate (1: 4
Fractions eluted at ~ 2: 3) were collected and the title compound (4.51
g) was obtained as a colorless oil.

NMR spectrum _{(90MHz, CDCl 3): 1.1~2.1} (22H, m), 2.1
8 (1H, t, J = 6Hz, -OH), 3.15 ~ 4.30 (9H, m), 4.35 ~ 4.8
5 (2H, m) mass spectrum (m / e): 331,330 ( M + +1), 329 Elemental analysis: C ₁₈ H ₃₄ O ₅ Calculated: C, 65.42; H, 10.37 Found: C, 65.04; H Reference Example 8. 6- {2,8-bis (tetrahydropyran-2-yloxy) octyloxy} methyl-3,4-dihydro-2H-pyran A solution of 6-hydroxymethyl-3,4-dihydro-2H-pyran (2.174g) and triethylamine (5.31ml) in benzene (45ml) was cooled in an ice-water bath and methanesulfonyl =
Chloride (2.21 ml) was added. After stirring at room temperature for 1 hour, the reaction solution was washed with water, dried and concentrated to give an oily residue (3.22
g) was obtained.

A solution of the compound of Reference Example 7 (1.049 g) in dimethylformamide (10 ml) was added to a mixture of sodium hydride (0.152 g) and dimethylformamide (10 ml) under ice cooling.
After stirring at room temperature for 1 hour, the above residue was dissolved in dimethylformamide (15 ml) and added. After stirring at room temperature for 19 hours, the reaction solution was poured into water (350 ml) and extracted twice with ethyl acetate. The extract was washed with water, dried and concentrated, and the residue was subjected to column chromatography using silica gel (60 g). Fractions eluted with hexane-ethyl acetate (9: 1) were collected to give the title compound (0.934 g) as a colorless oil.

NMR spectrum _{(60MHz, CDCl 3) ppm:} 1.0~2.3 (26H, m),
3.1 to 4.2 (11H, m), 4.35 to 4.95 (3H, m) The compound of Reference Example 7 (0.295g) was recovered from the fraction eluted with hexane-ethyl acetate (1: 4 to 1: 1). .

Reference Example 9. dl-trans-2- {2,8-bis (tetrahydropyran-2-yloxy) octyloxy} methyltetrahydropyran-3-ol Tetrahydrofuran (3 m of the compound of Reference Example 8 (0.934 g))
l) solution, borane 1M tetrahydrofuran solution (1.46m
l) was added dropwise under ice cooling. After stirring at room temperature for 4.5 hours, 30
30% with 10% sodium hydroxide aqueous solution (0.80 ml) at -40 ° C
Aqueous hydrogen peroxide solution (0.60 ml) was sequentially added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with water (50 ml) and extracted twice with ethyl acetate. The extract was washed with water, dried and concentrated, and the residue was subjected to column chromatography using silica gel (20 g).
Then, it was purified by being subjected to medium pressure liquid chromatography using a Rover B column. Hexane-ethyl acetate (7:
Fractions eluted in 3) were collected and the title compound (0.615
g) was obtained as a colorless oil.

NMR spectrum _{(90MHz, CDCl 3) ppm;} 1.1~2.5 (27H, m),
2.8 to 4.2 (10H, m), 4.4 to 5.0 (2H, m) Mass spectrum (m / e): 445,444 (M ⁺ ), 443 Reference Example 10. dl-trans-2-{(2.8-dihydroxyoctyloxy}} Methyltetrahydropyran-3-yl = N-heptadecyl carbamate A solution of stearic acid (0.94 g), diphenylphosphoryl azide (0.71 ml) and triethylamine (0.46 ml) in benzene (20 ml) was heated under reflux for 3 hours, and after cooling the reaction mixture was saturated aqueous sodium hydrogen carbonate solution (20 ml) and water. I washed it. The solvent was distilled off, and the residue (0.90 g) and the compound of Reference Example 9 (0.586 g)
g) was dissolved in toluene (15 ml), triethylamine (0.46 ml) was added, and the mixture was heated under reflux on an oil bath at 100 ° C. for 88 hr. The solvent was distilled off, and the residue was subjected to column chromatography using silica gel (20 g). Fractions eluted with hexane-ethyl acetate (3: 17-1: 4) were collected and the resulting oil (0.695g) was dissolved in methanol (15ml).
p-Toluenesulfonic acid (55 mg) was added and the mixture was heated under reflux for 1 hr. After cooling, sodium hydrogen carbonate (121 mg) was added and the solvent was evaporated. Ethyl acetate was added to the residue, the insoluble material was removed, and the mixture was concentrated. The residue was subjected to column chromatography using silica gel (12 g), and the fractions eluted with hexane-ethyl acetate (2: 3-1: 4) were collected to give the title compound (0.481 g). mp67~68 ℃ (ether - hexane) NMR spectra _{(90MHz, CDCl 3) ppm:} 0.7~2.3 (47H, m),
2.13 (2H, m, -OH), 2.9 ~ 4.2 (12H, m), 4.4 ~ 5.0 (2H,
m) IR spectrum (CHCl ₃ ) cm ^-1 : 3450,1710 Mass spectrum (m / e): 557 (M ⁺ ), 456 Elemental analysis: Calculated as C ₃₂ H ₆₃ NO ₆ : C, 68.90; H, 11.38 N, 2.51 Found: C, 68.45; H, 11.75; N, 2.69 Reference Example 11. dl-trans-2-[{2-hydroxy-8- (p-toluenesulfonyloxy)} octyloxy] methyltetrahydropyran -3-yl = N-heptadecyl carbamate The compound of Reference Example 10 (0.458 g), triethylamine (0.27 g)
ml) and 4-dimethylaminopyridine (5 mg) were dissolved in methylene chloride (10 ml), p-toluenesulfonyl chloride (0.188 g) was added under ice-cooling, and then at room temperature 14
Stir for hours. The reaction solution was washed with water, dried and concentrated, and the residue was purified by column chromatography using silica gel (12 g) and medium pressure liquid chromatography using a Rover B column. Hexane-ethyl acetate (3: 2-
Fractions eluted at 1: 1) were collected and the title compound (0.492)
g) was obtained as a white wax.

NMR spectrum _{(90MHz, CDCl 3) ppm:} 0.8~2.3 (47H, m),
2.45 (3H, s), 2.50 (1H, m, -OH), 3.0 to 4.9 (8H, m), 4.
03 (2H, t, J = 7Hz), 4.4 to 5.0 (2H, m), 7.37 (2H, d, J = 9
Hz), 7.81 (2H, d, J = 9Hz) Mass spectrum (m / e): 712 (M ⁺ +1), 540 Elemental analysis: Calculated as C ₃₉ H ₆₉ NO ₈ S: C, 65.79; H, 9.77 ; N, 1.97; S, 4.50 Found: C, 65.76; H, 9.87; N, 1.97; S, 4.50 Reference Example 12. dl-trans-2-[{2-acetoxy-8- (p-toluenesulfonyloxy. )} Octyloxy] methyltetrahydropyran-3-yl = N-heptadecyl carbamate The compound of Reference Example 11 (0.311 g) and triethylamine (0.09
ml) in benzene (6 ml) solution with acetyl chloride (0.0
4 ml) was added under ice cooling. After stirring at room temperature for 3 hours, the reaction solution was washed with water, dried and concentrated, and the residue was silica gel (10 g).
Column chromatography using a column and medium pressure liquid chromatography using a Rover B column. From the fraction eluted with hexane-ethyl acetate (3: 1), one isomer of the title compound (163 mg, designated as isomer I) was obtained as a wax. Thin layer chromatography (silica gel, solvent system, hexane-ethyl acetate, 1: 1): Rf0.5
9 NMR spectrum (60 MHz, CDCl ₃ ) ppm: 0.7 to 2.6 (47 H, m),
2.05 (3H, s), 2.46 (3H, s), 2.8 to 4.0 (9H, m), 4.00 (2
H, t, J = 6Hz), 4.2 to 5.2 (3H, m), 7.36 (2H, d, J = 9Hz),
7.82 (2H, d, J = 9Hz) IR spectrum (CHCl ₃ ) cm ⁻¹ : 3460,1720 Then, the fraction eluted with hexane-ethyl acetate (2: 1) was collected to collect another isomer (72 mg , Isomer II)
Was obtained as an oil. Thin layer chromatography (same conditions as above): Rf 0.45.

NMR spectrum _{(60MHz, CDCl 3) ppm:} 0.7~2.6 (47H, m),
2.27 (3H, s), 2.45 (3H, s), 2.8 to 4.0 (9H, m), 4.00 (2
H, t, J = 6Hz), 4.2 to 5.3 (3H, m), 7.37 (2H, d, J = 8Hz),
7.82 (2H, d, J = 8Hz) IR spectrum (CHCl ₃ ) cm ⁻¹ : 3460,1720,1710 Reference Example 13. 2R, 3S-3-O-benzyl-4-iodo-1,2-O-isopropyi Redenbutane-1,2,3-triol It was synthesized according to the method of Ohno et al. {Chem, Pharm. Bull., 33 , 572 (1985)}. 2R, 3R-3-O-benzyl-1,2-O-
Benzene (100 ml) of methanesulfonyl chloride (21.00 ml) was added dropwise to a benzene (1) solution of isopropylidethreitol (57.00 g) and triethylamine (44.10 ml) under ice cooling. After stirring at room temperature for 1 hour, the reaction solution was washed with water, dried and concentrated to give 2R, 3R-2-benzyloxy-3,4-isopropylidenedioxybutyl methanesulfonate (74.8
0 g) was obtained as a colorless oil.

NMR spectrum (CDCl ₃ ) ppm: 2.92 (3H, s, -O-SO ₂ -CH ₃ ) 3.4 to 4.5 (6H, m) 4.65 (2H, s, -CH ₂ Ph) 7.25 (5H, m, -Ph) Methanesulfonate (74.80g) , Sodium bicarbonate (113.92g) and sodium iodide (169.39g),
The mixture was heated under reflux in acetone (1.1) for 12 hours. After cooling, the reaction solution was filtered through Celite to remove insoluble materials. After distilling off the solvent, the residue was diluted with water and extracted three times with ethyl acetate. The extract was washed with water, dried and concentrated, and the oily residue was subjected to column chromatography using silica gel (600 g). Fractions eluted with hexane-ethyl acetate (95; 5) were collected to give the title compound (75.64g) as a colorless oil.

bp. 130-150 ℃ / 1mmHg. ▲ [α] ²⁶ _D ▼ ＋ 8.40 ° (c = 1.2.
5, CHCl ₃ ) NMR spectrum (CDCl ₃ ) ppm: IR spectrum (CHCl ₃ ) cm ^-1 : 518 (-I) Mass spectrum (m / e): 362 (M ⁺ ), 347 (M ⁺ -CH ₃ ) Elemental analysis: Calculated as C ₁₄ H ₁₉ O ₃ I : C, 46.22; H, 5.29; I, 35.04 Found: C, 46.47; H, 5.18; I, 35.11 Reference Example 14.2S, 3R-3-O-benzyl-4-iodo-1,2-O- Isopropylidene butane-1,2,3-triol 2S, 3S-3-O-benzyl-1,2-O-isopropylidene-threitol (48.45 g), triethylamine synthesized according to the method of Ohno et al. {Chem.Pharm.Bull., 33 , 572 (1985)}. (37.50 ml) and methanesulfonyl chloride (17.50 ml).
80 ml), 2S, 3S-2-benzyloxy-3,4-isopropylideneoxybutyl methanesulfonate (63.45 g) was obtained in the same manner as in Reference Example 13. Further, from the above methanesulfonate, sodium hydrogen carbonate (96.80 g) and sodium iodide (143.90 g), the title compound (66.87 g) was obtained in the same manner as in Reference Example 13. ▲ 〔α〕 ²⁶ _D ▼ −8.40 °
(C = 1.00, CHCl ₃ ) Reference Example 15. Ethyl 4R, 5R-4-benzyloxy-2-ethoxycarbonyl-5,6-isopropylidenedioxyhexanoate A solution of diethyl malonate (40.00g) in dimethylformamide (200ml) was added to sodium hydride (55% mineral oil suspension, 1
2.00 g) and dimethylformamide (600 ml) were added dropwise at 5-8 ° C. After stirring for 1 hour at room temperature, reference example
Dimethylformamide (300m) of 13 compounds (75.38g)
l) The solution was added dropwise at 5-8 ° C. The mixture was heated and stirred at 100 ° C. for 2 hours, allowed to cool, poured into 2 liters of water, and extracted 3 times with ethyl acetate. The extract was washed with water, dried and concentrated, and the oily residue was subjected to column chromatography using silica gel (1 kg). Fractions eluted with hexane-ethyl acetate (9: 1) were collected to give the title compound (68.92 g) as a colorless oil. bp.170-180 ℃ / 1mmHg. ▲ 〔α〕 ²⁵ _D ▼ ＋ 39.1 °
_{(C = 1.00, CHCl 3)} NMR spectrum (CDCl ₃₎ ppm: 2.01 (2H, t, J = 6.5Hz, C (3) −H ₂ ) 3.4 to 4.4 (5H, m) 4.15 (4H, m,-CH ₂ -CH ₃ × 2) 4.68 (2H, ABq, J = 12Hz, -CH ₂ Ph) 7.38 (5H, m, -Ph) IR spectrum (CHCl ₃ ) cm ^-1 : 1730 (-O-CO-) Mass spectrum (m / e): 378 (M ⁺ -CH ₃ ) Elemental analysis: Calculated as C ₂₁ H ₃₀ O ₇ : C, 63.94; H, 7.67 Measured value: C, 63.66; H, 7.49 Reference example 16.4S, 5S-4-benzyloxy-2-ethoxycarbonyl-5, Ethyl 6-isopropylidenedioxyhexanoate Diethyl malonate (35.48g), sodium hydride (55%
The title compound (58.40 g) was obtained in the same manner as in Reference Example 15 from the mineral oil suspension (10.63 g) and the compound of Reference Example 14. ▲
[Α] ²⁶ _D ▼ -39.5 ° (c = 1.00, CHCl ₃ ) Reference Example 17. Ethyl 4R, 5R-4-benzyloxy-5,6-isopropylidenedioxyhexanoate The compound of Reference Example 15 (68.70 g), sodium chloride (12.20 g)
g) and water (6.51 ml) were mixed in dimethyl sulfoxide (1.1) and heated to reflux on a 210 ° oil bath for 2 hours. After cooling, the reaction solution was poured into 2.5 l of water and extracted with ethyl acetate three times. The extract was washed with water, dried and concentrated, and the oily residue was subjected to column chromatography using silica gel (1 kg). Fractions eluted with hexane-ethyl acetate (95: 5) were collected to give the title compound (41.79 g) as a colorless oil. bp.150-160 ℃ / 1mmHg. ▲ [α] ²⁶ _D ▼ + 47.6 ° (c
= 1.32, MeOH) NMR spectrum (CDCl ₃ ) ppm: 1.23 (3H, t, J = 7.5Hz, -CH ₂ CH ₃ ). 1.6~2.0 (2H, m, C ( 3) -H 2) 2.43 (2H, t, J = 7.5Hz, C (2) -H 2) 3.3~3.6 (1H, m) 3.6~4.4 (3H, m ) 4.10 (2H, q, J = 7.5Hz,-CH ₂ -CH ₃ ) 4.69 (2H, ABq, J = 12Hz, -CH ₂ Ph) 7.38 (5H, s, -Ph) IR spectrum (CHCl ₃ ) cm ^-1: 1730 (-O-CO-) mass spectrum (m / e): 322 ( M +), 307 (M + -CH 3) elemental analysis: C ₁₈ H ₂₆ O ₅ calculated: C, 67.06; H, 8.13 Found: C, 67.06; H, 8.13 Reference Example 18.4S, 5S-4-benzyloxy-5,6-isopropylidenedioxyhexanoic acid ethyl ester The compound of Reference Example 16 (58.68 g), sodium chloride (10.43 g)
The title compound (41.79 g) was obtained from g) and water (5.56 ml) in the same manner as in Reference Example 17. ▲ 〔α〕 ²⁶ _D ▼ -47.4 °
(C = 1.30, CHCl ₃ ) Reference Example 19. 4R, 5R-4-benzyloxy-5,6-isopropylidenedioxyhexan-1-ol The compound of Reference Example 17 (47.65 g) in tetrahydrofuran (25
0 ml) solution was added dropwise to a suspension of lithium aluminum hydride (6.75 g) in tetrahydrofuran (750 ml) at 5-8 ° C. The reaction solution was stirred at room temperature for 2 hours, and 4% aqueous sodium hydroxide solution (27.00 ml) was added dropwise at 4 to 7 ° C. The suspension was filtered through Celite, concentrated and dried. The residue was subjected to column chromatography using silica gel (800 g), and the fractions eluted with hexane-ethyl acetate (2: 1) were collected to give the title compound (37.34 g) as a colorless oil. bp.150-160 ℃ / 1mmHg. ▲ ［α］ ²⁶ _D ▼ ＋ 41.8 °
(C = 1.06, CHCl ₃ ) NMR spectrum (CDCl ₃ ) ppm: 1.5-1.8 (4H, m, C ( 2) -H 2, C (3) -H 2) 1.71 (1H, s, -OH) 3.4~3.8 (4H, m) 4.02 (1H, dt, J = 7.5 , 6Hz, C (4) -H) 4.25 (1H, dt, J = 7.5,6Hz, C (5) -H) 4.71 (2H, ABq, J = 12Hz, -CH ₂ Ph) 7.38 (5H, m, -Ph) IR spectrum (CHCl ₃ ) cm ^-1 : 3450 (-OH) Mass spectrum (m / e): 280 (M ⁺ ), 265 (M ⁺ -CH ₃ ) Elemental analysis: as C ₁₆ H ₂₄ O ₄ Calculated value: C, 68.55; H, 8.63 Actual value: C, 68.23; H, 8.58 Reference Example 20. 4S, 5S-4-benzyloxy-5.6-isopropylidenedioxyhexan-1-ol The title compound (32.15 g) was obtained as a colorless oil from the compound of Reference Example 18 (41.00 g) and lithium aluminum hydride (5.78 g) in the same manner as in Reference Example 19. ▲ 〔α〕
²⁶ _D ▼ -42.5 ° (c = 1.10; CHCl ₃ ) Reference Example 21. (2R, 3R) -3-Benzyloxy-6- (t-butyldiphenylsilyl) oxy-1,2-isopropylidenedioxyhexane The compound of Reference Example 19 (19.27 g) and imidazole (10.2 g)
To a solution of 9 g) in dimethylformamide (300 ml) was added dropwise a solution of t-butyldiphenylsilyl chloride (20.77 g) in dimethylformamide (90 ml) at 5 to 7 ° C. After stirring at room temperature for 3 hours, the reaction solution was poured into 2 L of water and extracted with ethyl acetate three times. The extract was washed with water, dried and concentrated, and the oily residue was subjected to column chromatography using silica gel (700 g). Hexane-ethyl acetate (98: 2 to 95: 5)
The fractions eluted in (1) were collected to give the title compound (32.80 g) as a colorless oil. ▲ [α] ²⁶ _D ▼ + 21.4 ° (c =
1.11; CHCl ₃ ) NMR spectrum (CDCl ₃ ): ppm 1.04 (9H, s, (CH ₃ ) ₃ -C-Si) 1.4 to 1.8 (4H, m) 3.3 to 3.8 (4H, m) 4.00 (1H, dt, J = 7.5,6Hz, C (3) -H) 4.20 (1H, dt, J = 7.5,6Hz, C (2 ) -H) 4.66 (2H, ABq, J = 12Hz, -CH ₂ Ph) 7.2-7.8 (15H, m, -Ph × 3) IR spectrum (CHCl ₃ ) cm ^-1 : 1100 (Si-O) mass spectrum (M / e): 503 (M ⁺ -CH ₃ ) Elemental analysis: Calculated as C ₃₂ H ₄₂ O ₄ Si: C, 74.09; H, 8.16 Measured value: C, 74.20; H, 8.18 Reference example 22. 2S, 3S) -3-Benzyloxy-6- (t-butyldiphenylsilyl) oxy-1,2-isopropylidenedioxyhexane Compound of Reference Example 20 (18.00 g), imidazole (9.62 g)
And t-butyldiphenylsilyl chloride (19.41g)
In the same manner as in Reference Example 21, the title compound (30.97 g) was obtained as a colorless oil. ▲ [α] ²⁶ _D ▼ -20.8 ° (c =
1.25, CHCl ₃ ) Reference Example 23. (2R, 3R) -3-Benzyloxy-6- (t-butyldiphenylsilyl) oxyhexane-1,2-diol The compound of Reference Example 21 (32.49 g) was dissolved in acetic acid (300 ml) and water (30 ml), and the mixture was stirred at room temperature for 17 hours and further at 50 ° C. for 2 hours. After cooling, the solvent was distilled off, and the residue was subjected to column chromatography using silica gel (500 g).
Fractions eluted with ethyl acetate-hexane (1: 2) were collected to give the title compound (27.40 g) as a colorless oil.
▲ [α] ²⁶ _D ▼ -20.4 ° (c = 1.12, CHCl ₃ ) NMR spectrum (CDCl ₃ ) ppm: 1.05 (9H, s, (CH ₃ ) _3- C-Si) 1.5 to 1.9 (4H, m) 1.9 to 2.3 (1H, m, -OH) 2.3 to 2.65 (1H, m, -OH) 3.4 to 3.9 (6H, m) 4.53 (2H, ABq, J = 12Hz) 7.2 to 7.8 (15H, m, Ph x 3) IR spectrum (CHCl ₃ ) cm ^-1 : 3590,3460 (-OH), 1100
(Si-O) mass spectrum (m / e): 479 (M ⁺⁺ 1) Reference Example 24. (2S, 3S) -3-Benzyloxy-6- (t-butyldiphenylsilyl) oxyhexane-1,2 -Diol From the compound of Reference Example 22 (30.48 g), acetic acid (300 ml) and water (30 ml), the title compound (26.1
5 g) was obtained as a colorless oil. ▲ ［α］ ²⁶ _D ▼ ＋ 20.6
(C = 1.15, CHCl ₃ ) Reference Example 25. (2R, 3R) -3-Benzyloxy-6- (t-butyldiphenylsilyl) oxy-1-triphenylmethoxy-
Hexan-2-ol The compound of Reference Example 23 (26.22 g) and triethylamine (18.4 g)
Triphenylmethyl chloride (18.33 g) was added to a toluene (500 ml) solution of (0 ml), and the mixture was heated under reflux for 3 hours. After allowing to cool, the reaction solution was diluted with water and extracted 3 times with ethyl acetate. The extract was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried and the solvent was evaporated. The oily residue was dissolved in tetrahydrofuran (270 ml), saturated aqueous sodium hydrogen carbonate solution (90 ml) was added, and the mixture was stirred at room temperature for 1 hr. The oily substance (40 g) obtained by performing the post-treatment in the same manner as above was subjected to column chromatography using silica gel (500 g). Hexane-ethyl acetate (95: 5 ~
The fractions eluted at 9: 1) were collected and the indicated compound (37.01
g) was obtained as a colorless oil. ▲ 〔α〕 ²⁵ _D ▼ −3.55 °
_{(C = 1.03, CHCl 3)} NMR spectrum _{(CDCl 3) ppm: 1.05 (} 9H, s, (CH 3) 3 CSi) 1.4~1.8 (4H, m) 2.30 (1H, d, J = 6Hz, -OH) 3.22 (2H, d, J = 6Hz, C (1) −H ₂ ) 3.5 to 3.9 (4H, m) 4.45 (2H, ABq, J = 12Hz, -CH ₂ Ph) 7.1 to 7.8 (30H, m, −) Ph × 6) IR spectrum (CHCl ₃ ) cm ⁻¹ : 3580 (-OH), 1100 (O-S
i) Mass Spectrum (m / e): 477 ( M + -HC (CH 3) 3) Elemental analysis: C ₄₈ H ₅₂ O ₄ Si Calculated: C, 79.96; H, 7.27 Found: C, 79.71; H, 7.11 Reference Example 26. (2S, 3S) -3-Benzyloxy-6- (t-butyldiphenylsilyl) oxy-1-triphenylmethoxyhexan-2-ol The compound of Reference Example 24 (25.96 g), triethylamine (18.2
(0 ml) and triphenylmethyl chloride (18.11 g) were obtained in the same manner as in Reference Example 25 to give the title compound (36.50 g) as a colorless oil. ▲ [α] ²⁵ _D ▼ + 3.56 (c = 1.01
CHCl ₃ ) Reference Example 27. (2R, 3R) -3-Benzyloxy-6-hydroxy-1
-Triphenylmethoxy-2-hexyl methanesulfonate The compound of Reference Example 25 (36.89 g) and triethylamine (8.56
ml) in methylene chloride (500 ml), methanesulfonyl chloride (4.75 ml) was added dropwise under ice cooling (5 ° C.). After stirring at room temperature for 1 hour, the reaction solution was poured into water. The organic layer was washed with saturated brine, dried and concentrated (2R, 3R) -3-
Benzyloxy-6- (t-butyldiphenylsilyloxy) -1-triphenylmethoxy-2-hexyl methanesulfonate (40.91 g) was obtained as a colorless oil.

NMR spectrum _{(CDCl 3) ppm: 1.01 (} 9H, s, (CH 3) 3 Si-) 1.3~1.8 (4H, m) 2.96 (3H, s, -O-SO 2 -CH 3) 3.0~3.9 (5H , m) 4.50 (2H, s , -CH 2 -Ph) 4.6~4.9 (1H, m, -C H (OSO 2 CH 3) -) 7.1~7.8 (30H, m, -Ph × 3) above methanesulfonate To a solution of (40.91 g) in tetrahydrofuran (500 ml), 1N tetrabutylammonium fluoride (tetrahydrofuran) solution (61.4 ml) was added dropwise under ice cooling (5 ° C). After stirring at room temperature for 14 hours, the reaction solution was diluted with water and extracted 3 times with ethyl acetate. The extract was washed with water, dried and concentrated, and the residue was subjected to column chromatography using silica gel (700 g). Fractions eluted with hexane-ethyl acetate (4: 1 to 2: 1) were collected to give the title compound (26.45g) as a colorless oil.

▲ [α] ²⁵ _D ▼ + 21.7 ° (c = 1.22, CHCl ₃ ) NMR spectrum (CDCl ₃ ) ppm: 1.37 (1H, s, -OH) 1.4 to 1.8 (4H, m) 3.00 (3H, s, -OSO ₂ CH ₃ ) 3.30 (1H, dd, J = 11,6Hz, C (6) -H) 3.4 ~ 3.6 (2H, m) 3.60 (1H, dd, J = 11,3Hz, C (6)- H) 3.6 to 3.9 (1H, m) 4.56 (2H, s, -CH ₂ Ph) 4.82 (1H, ddd, J = 6,6,3Hz, C (5) -H) 7.2 to 7.6 (20H, m, −Ph × 4) IR spectrum (CDCl ₃ ) cm ⁻¹ : 3500 (−OH), 1360,1170
(-SO ₂ −) Mass spectrum (m / e): 483 (M ⁺ -C ₆ H ₅ ), 468 (M ⁺ -C ₆ H ₅ C
H ₃ ) Reference Example 28. (2S, 3S) -3-Benzyloxy-6-hydroxy-1
-Triphenylmethoxy-2-hexyl methanesulfonate Using the compound of Reference Example 26 (35.60 g) and in the same manner as in Reference Example 27, the title compound (25.18 g) was obtained as a colorless oil. ▲ [α] ²⁵ _D ▼ -21.7 ° (c = 1.23, CHCl ₃ ) Reference Example 29. (2S, 3R) -3-Benzyloxy-2-triphenylmethoxymethyltetrahydropyran The compound of Reference Example 27 (26.08 g) t-butanol (290 m
l) solution was added dropwise to a solution of potassium t-butoxide (7.01 g) in t-butanol (250 ml) at 25 ° C. The mixture was stirred at 40 ° C for 4 hours. After acetic acid (0.56 ml) was added to the reaction solution, the solvent was distilled off. The residue was diluted with water and extracted 3 times with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried and concentrated, and the residue was washed with silica gel (43
Column chromatography using 0 g). Fractions eluted with hexane-ethyl acetate (95: 5) were collected to give the title compound (21.04 g) as crystals.

mp 86.0-88.0 ° C (MeOH). ▲ [α] ²⁵ _D ▼ -32.8 ° (c
= 1.01, CHCl ₃ ) NMR spectrum (270MHz, CDCl ₃ ) ppm: 1.41 (1H, ddddd, J = 12.3Hz, 10.9Hz, 9.3Hz, 6.7Hz, C
(4) -Hax. ) 1.70 (2H, m, C (5) −H ₂ ) 2.26 (1H, ddddd, J = 12.3Hz, 4.2Hz, 3.9Hz, 3.9Hz, 〜1Hz, C
(4) -Heq.) 3.20 (1H, dd, J = 9.8Hz, 5.0Hz, -CH-OTr) 3.37 (1H, ddd, J = 9.3Hz, 5.0Hz, 2.0Hz, C (2) -H) 3.39 (1H, ddd, J = 11.4Hz, 9.3Hz, 5.3Hz, C (6) -Hax) 3.48 (1H, dd, J = 9.8Hz, 2.0Hz, -CH-OTr) 3.49 (1H, ddd, J = 10.9Hz, 9.3Hz, 4.2Hz, C (3) -H) 4.00 (1H, dddd, J = 11.4Hz, 2.9Hz, 2.9Hz, ~ 1Hz, C (6)
−Heq.) 4.38 (2H, ABq, J = 11.5Hz, -CH ₂ Ph) 7.0 to 7.5 (20H, m, Ph × 4) IR spectrum (CHCl ₃ ) cm ⁻¹ : 1595,1490,1450 (C ₆ H _5- ),
1090,1070 (C-O-C) Mass spectrum (m / e): 387 ( M + -C 6 H 5), 373 (M + -C
₇ H ₇₎ Elemental analysis: Calculated _{C 32 H 32 O 3: C} , 82.73; H, 6.94 Found: C, 82.56; H, 6.83 Reference Example 30. (2R, 3S) -3- Benzyloxy-2 -Triphenylmethoxymethyl tetrahydropyran The title compound (20.12 g) was obtained as crystals from the compound of Reference Example 28 (24.98 g) and potassium t-butoxide (6.06 g) in the same manner as in Reference Example 29. mp.86.5-88.5 ℃ ▲ 〔α〕
²⁵ _D ▼ + 33.0 (c = 1.00, CHCl ₃ ) Reference Example 31. (2S, 3R) -3-Hydroxy-2-triphenylmethoxymethyltetrahydropyran 10% Palladium on carbon (1.852 g) was added to a solution of the compound of Reference Example 29 (3.513 g) in ethanol (120 ml), and the mixture was shaken with hydrogen in a Parr apparatus at room temperature and 4 atm for 30 hours. After removing the catalyst, the solvent was evaporated and the residue was silica gel (90 g).
Was subjected to column chromatography. Fractions eluted with hexane-ethyl acetate (7: 1) were collected to give the title compound (2.557g) as a colorless oil. ▲ 〔α〕
²⁵ _D ▼ + 38.2 ° (c = 1.07, CHCl ₃ ) NMR spectrum (CDCl ₃ ) ppm: 1.2 to 1.8 (3H, m) 1.9 to 2.3 (1H, m) 3.00 (1H, s, -OH) 3.1 to 3.7 (5H, m) 3.75 to 4.05 (1H, m) 7.2 to 7.7 (15H, m, Ph × 3) IR spectrum (CHCl ₃ ) cm ⁻¹ : 3500 (OH), 1600,1490,145
0 (-Ph), 1090 (C -O-C) Mass spectrum (m / e): 374 ( M +), 297 (M + -C 6 H 5) Reference Example 32. (-) - 2R, 3S- Trans-3-hydroxy-2-trityloxymethyltetrahydropyran Using the compound of Reference Example 30 (2.835 g) and 10% palladium-carbon (1.499 g) and in the same manner as in Reference Example 31, the title compound (2.075 g) was obtained as a colorless oil. ▲ 〔α〕 ²⁵ _D ▼
-38.0 ° (c = 1.12, CHCl ₃ ) Reference Example 33. (2S, 3R) -2- (triphenylmethoxy) methyltetrahydropyran-3-yl = N-heptadecylcarbamate A solution of stearic acid (4.782g), diphenylphosphoryl azide (3.62ml) and triethylamine (2.34ml) in benzene (100ml) was heated to reflux for 3 hours. After allowing to cool, the reaction solution was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium hydrogen carbonate. After drying, the solvent was distilled off and the residue was dissolved in toluene (25 ml). A solution of triethylamine (2.34 ml) and the compound of Reference Example 31 (2.518 g) in toluene (25 ml) was added, the mixture was heated at 100 ° C. for 90 hours, allowed to cool, and the reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution. 3 with ethyl acetate
It was extracted twice, the extract was dried and concentrated, and the oily residue was subjected to column chromatography using silica gel (120 g). Fractions eluted with hexane-ethyl acetate (7: 1) were collected to give the title compound (3.131 g) as a colorless oil.

▲ [α] ²⁵ _D ▼ -28.5 ° (c = 1.04, CHCl ₃ ) NMR spectrum (CDCl ₃ ) ppm: 0.7 to 2.4 (37H, m) 2.8 to 3.6 (6H, m) 3.8 to 4.1 (1H, m) 4.2〜4.8 (2H, m) 7.1〜7.6 (15H, m) IR spectrum (CHCl ₃ ) cm ⁻¹ : 3460 (NH), Mass spectrum (m / e): 412 (M ⁺ -C ₁₉ H ₁₅ ), 396 (M ⁺ -C ₁₉
H ₁₅ O), 382 ( ⁺ -C ₂₁ H ₁₇ O) Reference Example 34.2 2R, 3S-2- (triphenylmethoxy) methyltetrahydropyran-3-yl = N-heptadecylcarbamate Stearic acid (3.553 g), diphenylphosphoryl azide (2.69 ml) and the compound of Reference Example 32 (1.871 g) were used to obtain the title compound (2.491 g) as a colorless oil in the same manner as in Reference Example 33. . ▲ [α] ²⁵ _D ▼ + 28.8 ° (c = 1.13, CHCl
₃ ) Reference Example 35. (2S, 3R) -2-Hydroxymethyltetrahydropyran-3-yl = N-heptadecylcarbamate P-Toluenesulfonic acid (240.0 mg) was added to a solution of the compound of Reference Example 33 (2.753 g) in methanol (55 ml), and the mixture was heated under reflux for 1 hour. After allowing to cool, sodium hydrogen carbonate (352.6m
g) was added. Methanol was distilled off, and ethyl acetate was added to remove insoluble matter. The liquid was concentrated, and the residue was subjected to column chromatography using silica gel (55 g).
Fractions eluted with hexane-ethyl acetate (2: 1 to 1: 1) were collected to give the title compound (1.476 g) as crystals. mp.9
2.0-93.5 ° C (Et ₂ O) ▲ [α] ²⁵ _D ▼ -7.20 ° (c = 1.00,
CHCl ₃ ) NMR spectrum (CDCl ₃ ) ppm: 0.7 to 2.3 (37H, m) 2.6 to 2.85 (1H, m, -OH) 2.9 to 3.8 (6H, m) 3.8 to 4.1 (1H, m) 4.4 to 4.9 ( 2H, m) IR spectrum (CHCl ₃ ) cm ^-1 : 3450 (-NH, -OH), 1710,1
510 (-NH-CO) Mass spectrum (m / e): 414 (M ⁺ +1), 382 (M ⁺ -CH ₂ OH) Elemental analysis: Calculated as C ₂₄ H ₄₇ NO ₄ Calculated value: C, 69.69; H , 11.45; N, 3.39 Found: C, 69.33; H, 11.40; N, 3.53 Reference Example 36. (2R, 3S) -2-Hydroxymethyltetrahydropyran-2-yl = N-heptadecylcarbamate Using the compound of Reference Example 34 (2.400 g) and in the same manner as in Reference Example 35, the title compound (1.305 g) was obtained as crystals. mp.92.
5-93.5 ° C, ▲ [α] ²⁵ _D ▼ + 7.25 ° (c = 1.02, CHCl ₃ ) Test Example 1. Inhibition of PAF hypotensive action Anesthetized with inactin (90 mg / kg ip) as a test animal. Wistar Imado rats (weighing 350-450 g) were used. Blood pressure was continuously measured from a cannula inserted into the femoral artery, and the drug was intravenously injected from a cannula inserted into the femoral vein. First, PAF (l-C _{16: 0} type) 10ng / kg 5
It was injected intravenously at minute intervals and repeated until the magnitude of the antihypertensive reaction became constant. Next, inject the test drug intravenously, and 1 minute later,
The same dose of PAF was administered. The test drug was administered cumulatively, and the 50% inhibitory dose (ID
₅₀ ) was determined and used as an index of PAF antagonistic activity. PAF and the test drug were dissolved in a physiological saline solution containing 0.25% bovine serum albumin (BSA), and only the test solution insoluble in this solvent was dissolved in a physiological saline solution containing 20% ethanol. .

Test Example 2. In Vitro Platelet PAF Aggregation Inhibitory Action Blood was collected from rabbits and immediately mixed with 1/9 volume of 3.8% sodium citrate. After centrifugation at 150 g for 15 minutes at room temperature, platelet-rich plasma (PRP) was obtained from the upper layer. The remaining blood was further centrifuged at 1000 g for 15 minutes to obtain platelet poor plasma (PPP) from the upper layer. Mix the appropriate amount of PRP and PPP to obtain the final platelet count of PRP in μl.
Adjusted to 600,000 pieces per item. Platelet aggregation was measured by increasing the transmitted light using an aglycometer by the method of Bourne et al. (GVR Born, J. physiol. 62 , 67-68 (1962)).
25 μl of test drug solution was added to 250 μl of RRP, and 1 minute later, 25 μl
l of PAF (C ₁₆ , final concentration 10 ^{−8 to} 3 × 10 ⁻⁸ M) was added, and then observed for 5 minutes to confirm the aggregation suppressing action. The inhibition rate was determined based on the aggregation by PAF when physiological saline was used instead of the test solution, and the IC ₅₀ was calculated from the dose-response curve.

The results of tests 1 and 2 are shown in the table.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display location C07D 405/12 207 213 215 217 233 239 257 405/14 213 417/12 307 309 313 417/14 213 233 263 307 // A61K 31/335 ACB 31/34 31/40 31/41 ACG 31/435 ABA 31/535 ABV 31/54 ABE ABF

Claims (1)

[Claims] 1. A general formula[Wherein l represents an integer of 2 to 4, A and B are the same or
Differently represent an oxygen atom or a sulfur atom. R¹And R²Nou
One is a linear or branched alkyl group having 10 to 22 carbon atoms.
Group, straight-chain or branched-chain aliphatic acyl group having 10 to 22 carbon atoms
Or formula-CONH-R³A group having (II) (in the formula, R³Has 10 carbons
Shows up to 22 straight or branched chain alkyl groups. ),
The other isA group having the formula:₂)_mA group having- (formula
In the above, m represents an integer of 1 to 3. ) Or divalent 5 to 7
Member heterocyclic group, n is an integer of 0 to 10, and q is 0
Represents an integer from 1 to R^FourIs selected from [protecting group A]
A hydroxyl group which may be protected by a group represented by [Substituent group A]
A hydroxyl group substituted with a group selected from [protecting group B]
A mercapto group which may be protected by a group selected from
Or a mel substituted with a group selected from [Substituent group B]
Represents a capto group, and Q isA group having^Five, R⁶And R⁷Is the same or different water
An elementary atom or a lower alkyl group is shown. ), Or formula-G
(Wherein G represents a 5- to 7-membered heterocyclic group,
The group may be a lower alkyl group, a hydroxy lower alkyl group, if desired.
Kill group, lower alkoxy group, carbamoyl group or halogen
It may have 1 to 3 nitrogen atoms as a substituent. )
, Z Represents an anion. ) Is shown. The Q group is
A group having the formula (IV) or a group having the formula -G (wherein G is
5- to 7-membered heterocyclic groups, condensed on the nitrogen atom
Represents a group. ), N is an integer from 1 to 10
Show. ] And a cyclic ether derivative having
Salt. [Protecting Group A] Aliphatic acyl group, aromatic acyl group, tetrahydropyrani
Or tetrahydrothiopyranyl group, tetrahydrofuran
Nyl or tetrahydrothiofuranyl group, silyl group, al
Coxymethyl group, substituted ethyl group, aralkyl group, alcohol
Xycarbonyl group, alkenyloxycarbonyl group,
Ralalkyloxycarbonyl group and hydrolyzed in vivo
Easy to protect [Protecting Group B] Aliphatic acyl group, aromatic acyl group, and aralkyl group. [Substituent Group A] Lower alkyl group, 1 to 2 lower alkyl groups at the nitrogen atom
Optionally substituted carbamoyl group, lower alkane
Sulfonyloxy group, fluorinated lower alkanesulfo
Nyloxy group and arylsulfonyloxy group. [Substituent Group B] A lower alkyl group.