JPS61152651A - Prostacycline compound and preparation thereof - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> is CO2R<4> (R<4> is H, 1-12C alkyl, etc.) or CONR<5>R<6> (R<5> and R<6> are H, 1-10C alkyl, etc.; one of X and Y is S and the other is methylene; R<2> is 3-10C alkyl, 4-7C cycloalkyl, etc.; R<3> is H, 1-7C acyl, etc.]. EXAMPLE:3-Thia-9(0)-methano-DELTA<6(9alpha)>-prostaglandin I1. USE:Antithrombotic agent and antiarteriosclerotic agent having platelet coagulation inhibiting activity. PREPARATION:The compound of formula I can be prepared by reducing a novel alpha,beta-unsaturated carbonyl compound of formula II with a reducing reagent (e.g. sodium borohydride) in a solvent at -100-+30 deg.C, and if necessary, subjecting the reaction product to deprotection, hydrolysis and salt-formation.

Description

DETAILED DESCRIPTION OF THE INVENTION TECHNICAL FIELD The present invention relates to novel prostacycleases and methods for producing the same. For details on length, incarbacycline 3rd or 4th place
This relates to prostacycleases in which the methylene group at position is converted to a sulfur atom.

PRIOR ART Prostacyclin is an autacoid produced in the living body mainly on the inner wall of arteries, and its strong physiological activity is a factor that regulates biological functions by inhibiting platelet aggregation, vasodilatory action, etc. An endowment is being made to provide this product directly as a medicine (RJ,
hewis & J・0・1ady” C11nical
Pharmacology of Prosta-
cylin ”H+aven Press, N, Y
-s 1981).

However, since natural prostacyclin has a vinyl ether bond in its molecule that is highly susceptible to hydrolysis, its half-life is 5 minutes in a near-neutral water bath solution (37C), and it cannot be said to be a desirable compound as a pharmaceutical. Therefore, intensive research and development is underway to find a synthetic glostacycline spindle that is chemically stable and has better action characteristics as a pharmaceutical.

For example, a derivative in which the oxygen atom at the 6.9-position of prostacyclin is substituted with a methylene group, that is, 9 (Q) -methanoprostacyclin (carbacycline), is known as a prostacyclin with a sufficiently satisfactory chemical stability. (D-R-Mortons・@Pros
tacyclins 1J, Le Vane & S-B
ergstr-6m, I! Jds, Raven
Press, N-Y11979w I) I) 31-4
(See 1) It is expected to be used as a medicine.

In addition, the 5th position of 9(0)-methamprostacyclin (carnocyclin) was transferred to the 6(9α) position.
0)-methano-, s(ea)-prostaglandin f
, (isocarbacyclyc/) is also chemically sufficiently safe59-1
37445).

Purpose and Structure The purpose of this invention is to provide a new knowledge of orally administered glostacycline, which is chemically safe and has excellent treatment action and action time, and a method for producing the same. The Ministry of the Invention and others conducted extensive research and completed the present invention by obtaining the compound of the present invention which binds to the methylene fund sulfur atom at the 3rd or 4th position of incarbacycline.

That is, the present invention is a formula CI) [wherein R1 is a -CO2R4 group (in the group, R4 is a hydrogen atom, or a linear or branched alkyl group of blocks a1 to 12, or an aralkyl group having 7 to 12 carbon atoms) group, or a cycloalkyl group of the woodblock wL4-7 which is unsubstituted or is substituted with at least one alkyl group having 1 to 4 carbon atoms, or a phenyl group with a pleasant or non-proprietary structure, or 1 The cation t=was), or -CON 11 6 groups (in the group, 5 and 6 may be the same or different, but each is a hydrogen atom or an alkyl group of 1 to 10 woodblock ridges, or Bon 5 and Rin 6
represents a 5- to 6-membered substituted or non-Ii substituted jJI which may be combined with the wax atom to which they are bonded and further contain all hetero atoms, and X and Y are either One is a sulfur atom, the other is a methylene group, and R2 is a straight or branched alkyl group having 3 to 10 carbon atoms, or is unsubstituted or directly substituted with at least one alkyl group having 1 to 4 carbon atoms. A cycloalkyl group having 4 to 7 carbon atoms, or a straight or branched alkenyl group having 3 to 120 carbon atoms, or a straight or branched alkynyl group having 3 to 8 carbon atoms, or A direct substituted alkynyl group having 1 to 3 carbon atoms, which may be a phenyl group or a phenoxy group, or an alkoxy group having 1 to 6 carbon atoms, or a cycloalkyl group having 5 to 8 carbon atoms; represents a hydrogen atom, an acyl group having 1 to 7 carbon atoms, a tri(carbon a1 to 7) hydrocarbon-silyl group, or a group that forms an acetal bond with the oxygen atom of the water@ group. ] New glostacyclines coated with the following and their production method.

几1 represents -CO, 几4 or -CONR'6, where 几4 is a hydrogen atom, a straight or branched chain alkyl group having 1 to 12 carbon atoms, or an aralkyl group having 7 to 12 carbon atoms, or unsubstituted or at least one carbon number 1
A 7-chloroalkyl group having 4 to 7 carbon atoms substituted with & substituted with ~4 alkyl groups, or & substituted or a non-essential phenyl group,
Or it is a cation of one child. Examples of straight chain or branched alkyl groups having 1 to 12 carbon atoms include methyl, ethyl, n-propyl, 1so-propyl, n-butyk,
5ec-butyl, tert-butyl, n-pentyl, i
so -amyl, n-hexyl, n-hegtyl, l-octyl, n-nonyl, n-decyl, n-lanticyl, n
-Dodecyl, etc. may be mentioned.

For example, benzyl, 1-phenethyl, 2-phenethyl, 3-phenylbutyl, 4-phenylbutyl, 1-(2-naphthyl)ethyl, 2-(1- naphthyl)ethyl-*t-. Unreplaced or at least one longitudinal cord 1
5 (4 to 7 carbon atoms substituted with 1 to 4 alkyl groups)
Examples of the 7-chloroalkyl group include 7-chlorobutyl,
1-propylcyclobutyl, 1-7'tylcyclobutyl, 2-methylcyclobutyl, 2-propylcyclobutyl, 3-ethylcyclobutyl, 3-propylcyclobutyl, 2,3.4-ethylcyclobutyl, Cyclopentyl, 3-ethylcyclopentyl, 3-propylcyclobentyl, 3-7"thyl-7clopentyl, 3-te
rt-)゛Tylcyclopentyl, 2.2-dimethylcyclopentyl, (1-methyl-3-propyl)cyclopentyl, (2-methyl-4-propyl)cyclopentyl, cyclohexyl, 3-ethylcyclohexyl, 3-i
so-propylcyclohexyl, 4-methylcyclohexyl, 4-ethylcyclohexyl, 4-propylcyclohexyl, 4-tert-7'tylcyclohexyl, 2
．． Examples include 2-dimethyl-7chlorohexyl, 2,6-methylcyclohexyl, (2,6-)methyl-4-propyl)cyclohexyl, and cycloheptyl.

[Substituted or unsubstituted direct substituents for phenyl groups include, for example, halogen atoms, hydroxy groups, acyloxy groups having 2 to 7 carbon atoms, alkyl groups having 1 to 4 carbon atoms which may be substituted with halogen atoms, ) An alkoxy group having 1 to 4 carbon atoms, a nitrile group, a carboxy group, or an alkoxycarbonyl group having 2 to 7 carbon atoms, which may be substituted with 10 carbon atoms, is preferable. Here, the halogen atoms include fluorine,
Chlorine or bromine, particularly fluorine or chlorine, are preferred. Examples of the acyloxy group having 2 to 7 carbon atoms include acetoxy, glopionyloxy, n-butyryloxy, 1so-butyryloxy, n-valeryloxy, 1so-valeryloxy, caproyloxy, enanteroxy, or benzoyloxy. .

Examples of the alkyl group having 1 to 4 carbon atoms which may be a-substituted with halogen include methyl, ethyl, n-propyl, 1so
Preferred examples include -7' lobil, n-7' thyl, chloromethyl, dichloromethyl, trifluoromethyl and the like. Examples of the alkoxy group having 1 to 4 carbon atoms which may be substituted with halogen include methoxy, ethoxy, lowpropoxy, 1so-propoxy, n-
Preferred examples include butoxy, chloromethoxy, dichloromethoxy, trifluoromethoxy and the like.

K element #7! Examples of the alkoxycarbonyl group of L2 to 7 include methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, hexyloxycarbonyl, etc.@The number of direct substituents includes t11L substituents t-1 to 3 as described above. , 'EL< can have one.

Examples of monovalent cations include alkali metal cations such as Na'', K+, 1/2Ca2+, 1/2MgM
+, 1/3A1g+, divalent or trivalent metal cations, ammonium ions, tetramethylammonium ions, and other ammonium cations.

-coa' 6 groups, 5 and 6 may be the same or different, but each is a hydrogen atom, or an alkyl group having 1 to 10 carbon atoms, or 6 and 86 are the caps to which they are bonded. May be rich in heteroatomic gold in the sentence together with the element 5
~6-membered substituted or unsubstituted t-synthesis. Examples of the alkyl group having a prime number of 1 to 10 include methyl, ethyl, n-propyl, 1so-propyl, n-butyl,
5ec-butyl, tert-butyl, n-pentyl, 1
Mention may be made of so-amyl, n-hexyl, n-hegtyl, n-octyl, n-nonyl, n-decyl, and the like.

In addition, as the direct substituent in the above-mentioned wjL-substituted or unsubstituted base, alkyl groups of block ridges 1 to 4 which may be 4ML-substituted with a halogen atom are preferred, such as methyl, ethyl, n-propyl, Mention may be made of 1so-jrovir, n-butyl, chloromethyl, 7chloromethyl, trifluoromethyl.

Above il
It's best to have three, preferably one. Examples of heteroatoms include nitrogen, sulfur, and enemy atoms. As for the above transfer? The 11 groups can include 1-pyrrolidyl, thiazolyl, 1-piperidyl, morpholyl, piperazyl or 5,6-cyhydrophenantridyl groups.

As Group 1, a -COOR4 group in which Group 4 is a linear or branched alkyl group having 1 to 12 carbon atoms, a bamboo carboxy group or a methoxycarbonyl group are preferable.

In either X or Y, 10,000 is a sulfur atom, and the other is a methylene group. R2 is a linear or branched alkyl group having 3 to 10 carbon atoms, or 4 to 7 carbon atoms which is unsubstituted or substituted with at least one alkyl group having 1 to 4 carbon atoms.
a cycloalkyl group, or a straight or branched alkenyl group having 3 to 12 carbon atoms, or a straight or branched alkynyl group having 3 to 8 carbon atoms, or an optionally substituted phenyl group, or a phenoxy group represents a directly substituted alkyl group having 1 to 3 carbon atoms, which is directly substituted with an alkoxy group having 1 to 6 carbon atoms, or a cycloalkyl group having 5 to 8 carbon atoms. Here, the linear or branched alkyl group having carbon a3 to a10 includes n-propyl, n-butyl, n-pentyl, 1-methylpentyl, 1.2-)methylpentyl,
n-hexyl, 2-methylhexyl, n-heptyl, n
-octyl, i-nonyl, n-del/del, etc., preferably n-pentyl, n-hexyl, 1-methylpentyl, 1
．． Examples include 2-dimethylpentyl and 2-methylhexyl. 4 to 4 carbon atoms, unsubstituted or substituted with at least one C 1-4 alkyl group
The cycloalkyl group of 7 is cyclobutyl, 1-propylcyclobutyl, 1-butylcyclobutyl, 1-
Pentylcyclobutyl, 1-hexylcyclobutyl, 2
-Methylcyclobutyl, 2-propylcyclobutyl, 3
-Ethylcyclobutyl, 3-propylcyclobutyl, ↓ 2.3.4-) Ethylcyclobutyl, cyclopentyl,
2-pentyl 7-clopentyl, z,z-dimethylcyclopentyl, 3-ethylcyclopentyl, 3-70 pylcyclopentyl, 3-butylcyclopentyl, 3-te
rt-phytylcyclopentyl, (1-methyl-3-propyl)7clopentyl, (2-methyl-3-furovyl)cyclopentyl, (2-methyl-4-7'lovyl)cyclopentyl, cyclohexyl, 3-ethylcyclohexyl, 3- 1SO-propylcyclohexyl, 4-methylcyclohexyl, 4-ethylcyclohexyl, 4-
7'lovylcyclohexyl, 4-tert-methylcyclohexyl, 2,6-methylcyclohexyl, 2,2-dimethylcyclopentyl, (2,6-cymethyl-4-7'lopyl)cyclohexyl, cyclopentyl, etc., preferably cyclopentyl, Examples include cyclohexyl.

Examples of linear or branched alkenyl groups include allyl, 3-butenyl, 2-phthynyl, 3-methyl-2-butenyl, 4-pentenyl, 3-pentenyl, 4-methyl-3-pentenyl, 2-pentenyl, 5-hexenyl, 4-hexenyl, 3-methyl-4
-hexenyl, 5-methyl-2-hexenyl, 2.5-
Dimethyl-3-hexenyl, 6-heftynyl, 5-heftynyl, 2-ethyl-5-heptenyl, 2,6-dimethyl-5-hexenyl, 7-octenyl, 8-nonenyl,
Examples include 9-decenyl, 10-undecenyl, 11-dodecenyl, 3-pentenyl, 2,6-dimethe-5-hebutenyl, and the like.

Straight-chain or branched alkynyl groups having a prime number of 3 to 8 include promethyl, 2-butynyl, 3-butynyl, 2-methyl-3-butynyl, 2-ethyl-3-butynyl, 4-
Pefuranil, 3-pentynyl, 1-ethyl-3-pentynyl, 2-methyl-3-pentynyl, 1-methyl-3-
Pentynyl, 3-hexynyl, 4-hebutynyl, 5-octynyl, preferably 1-methyl-3-pentynyl and the like can be mentioned.

The alkyl group of the substituted alkyl group having 1 to 3 carbon atoms may be straight chain or branched, for example, methyl, ethyl, n-propyl, 1so-
Propyl can be mentioned.

These alkyl groups include phenyl group; phenoxy; methoxy, ethoxy, n-propoxy, n-butoxy, 1
so-butoxy, t-butoxy, n-pentoxy, n
- Substituted with an alkoxy group having 1 to 6 carbon atoms such as hexoxy; a 7-chloroalkyl group having 5 to 8 carbon atoms such as cyclopentyl or cyclohexyl. These iic substituents may further be substituted by the same substituents as mentioned above for the phenyl group of B4.

Examples of the alkyl group having 1 to 3 carbon atoms which are directly attached include, for example, a fluorine atom, a chlorine atom, a methyl, ethyl or trifluoromethyl group. Preferred are alkyl groups having 1 to 2 carbon atoms, or propoxyethyl, ethoxyethyl, propoxyethyl, butoxymethyl, methoxyethoxy, cyclohexylmethyl, cyclohexylethyl and the like.

In particular, n-pentyl, 1-methylpentyl, cyclopentyl, 1-methyl-3-pentynyl, 2.
6-7methyl-5-hebutenyl is preferred.

几3 is a hydrogen atom, or an acyl group having 1 to 7 carbon atoms, or a tri(
& prime number 1 to 7) A group t-x that forms an acetal bond with the enemy atom of a hydrocarbon-silyl group or a water r1it group. Examples of the acyl group having 1 to 7 carbon atoms include acetyl, glopionyl, n-butyryl, 1so-butyryl, n-valeryl, iso-valeryl, caproyl,
Examples include enantyl, benzoyl, etc., or acetyl, benzoyl, etc. Examples of the tri(carbon number 1 to 7) hydrocarbon-silyl group include trimethylsilyl,
triethylsilyl, tert-butyldimethylsilyl, etc.4) alkylsilyl, tert-butyldimethylsilyl,
Diphenylalkylsilyl such as t-butyldiphenylsilyl, tripendylsilyl or dimethyl (2,4
, 6-) tert-butylphenoxy]silyl group and the like are preferred.

Examples of groups that form an acetal bond with the eR element of the water group include methoxymethyl, 1-ethoxyethyl, 2-methoxy-2-propyl, 2-ethoxy-2-propyl, (2-methoxyethoxy) To methyl, benzyloxymethyl, 2-tetrahydropyranyl, 2-tetrahydropyranyl, 4-(4-methoxytetrahydropyranyl) group or 6,6-dimethyl-3-oxa-2-oxinepicyclo(3,1,0) Kis-4-yl group 1 can be removed. Among these, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 1-ethoxyethyl, 2-methoxy-2-propyl, (2-methoxyethoxy)methyl, 4-(4-methoxytetrahydropyranyl) group, 6. 6-dimethyl-3-oxa-2-oxobicycloC3,1,03hex-4-yl group is preferred.

As R3, among these, tert-butyldimethylsilyl group, 2-tetrahydropyranyl group, acetyl group,
4-(4-methoxytetrahydropyranyl) jk16
．． b-7methyl-3-oxa-2-, rxobicyclo(
3,1,0)hex-4-yl group, dimethyl(2,4,
6-) tert-butylphenyloxy)silyl group is preferred.

Specific examples of the Glostacytaline chicken provided by the present invention are listed below.

(1) 3-thia-9(O)-methano-16(9″)-prostaglandin A) 16.17.1 B, 19.20-pentanol-15-cyclobenthyl-3-thia-9(0 )-Methano-Δ6(9″)-frostaglandin It(3) 1
6,17,18,19.20-pentanol-15-7chlorohexyl-3-thia-9(0)-methano-Δ6 (9g
)-glostaglandin l1(4) 16,17.1
8,19.20-pentanol-15-(4'-cis
-propylcyclohexyl)-3-thia-9(O)-methano5(sa)-glostaglandinl1 (5)16-methyl-3-thia-9(0)-methano-1
6 (“frostaglandin 11 (6)16.20-dimethyl-3-thia-9(O)-methanoS(S”)-prostaglandin 1(7)1
6-methyl-18,18,19,19-tetrahydro-
3-cheer-9(0)= )11/-1' (”)
-7'.

Stavlandin L1 (8) 16.20-dimethyl-18,18,19,19
-tetrahydro-3-thia-9(0)-methano-nolo(
9″)-brostag2injin11 (9)17-methyl-3-thea-9(0)-methano-Δ
6 (s“)-10 Stagransson It(10) 17
-Methyl-20-isopropylidene-3-thia-9(0
)-Methano-76 (9g)-Prostaglandin L1 (11) 16.16-Simethyl-3-thia-9 (0)
-Meta7-ja (1")-Crostaglandin 1-(12) 18-Oxa-3-thea-9(0)-Methano-, g(sa)-10 Staglanson It(13) 1
8-Oxa-16-methyl-3-thia-9(0)-methano-Δ6('')-glostaglandin I凰(14) 4
-thia-9(0)-methano-46('')-prostaglandin ■1 (15) 16.17.18,19.20-pentanol-15-cyclobenthyl-4-thia-9(0)-methano- , s(s+“)-grostaglandin 1 (16)
16.17.18,19.20-Pentano-15-cyclohexyl-4-thia-9(0)-methano-Δ6(9
111)-Prostaglandin 1l (17) 16.1
7.18,19.20-pentanol-15-(4'-
cis-propylcyclohexyl)-4-thia-9(0
)-methano-Δ6(ss)-prostaglandin 11 (18) 16-methyl-4-thia-9(0)-methano-Δ6(1″)-prostaglandin 11(19) 1
6.20-dimethyl-4-thia-9(0)-methano-j
a (s a)-glostaglandin 11 (20) 1
6-methyl-18,18,19,19-tetrahuman a-
4-thia-9(0)-methano-a6 (9g)-prostaglandin 11 (21) 16.20-dimethyl-18,18,19,
19-nato2hydro4-thia-9 (0 tomethano-76
(1m)-Prostaglandin II (22) 17-Methyl-4-thia-9(0)-methano-nolo(9″)-Prostaglandin 11(23) l
7-Methyl-20-isophropylidene-4-thia-
9(0)-methano-, s(sa)-prostaglandin l! (24) 16.16-dimethyl-4-thia-9(0)
-Methanono 5(S-)-frostaglandin 11(2
5) 18-oxa-4-thea-9(0)-methano-nolo(9″)-prostaglandin 11(26) 18-
Oxa-16-methyl-4-thia-9(0)-methanos(e“)-glostaglandinIt(27) (1
) to (2e methyl ester (28) (27) l
l-tert-butyldimethylsilyl ether (29) 11-(tetrahydro-2-pyranyl) ether (30) of (27) Sodium salt, a/monium salt, potassium salt of carboxylic acid of (1) to (26) The gross mecytalins of the invention are represented by formula [11] [wherein]
btor2・kL! , wind Y is the same as the foot prosthesis. ] By reducing the α, β-unsaturated carbonyl compound @ represented by using a reducing reagent and subjecting it to deprotection and separation of reaction diastereomers, hydrolysis reaction, and salt formation reaction as required. Manufactured.

The α,β-unsaturated carbonylated compound represented by the formula CI [], which is a raw material compound, is produced by the method described below.

As a salt test sample for reducing the α,β-unsaturated carbonyl compound represented by the formula (I []), it is preferable to use one that does not reduce 1%, such as sodium borohydride, zinc borohydride, diphenyltin hydride,
or a trialkylborohydride such as 5ec-butylborohydride, 2.6-
Di-1so-butylaluminum hydride modified by tert-butyl-4-methylphenol [J, 0. 44.1363 (1979)), or 1
．． Lithium alumina penta-hydride modified by lower al-r-rutoni such as 1'-bi-2-naphthol and ethanol (J-decoration, Chem, 5oc-, 10
1,5843 (1979)).

Examples of the reaction medium (74 °C) include lower alcohols such as methanol and ethanol, ethers such as diethyl ether, tetrahydrofuran (TH11°), and dioxane, and aromatic hydrogenated hydrogens such as benzene or toluene.

Shiomoto Trial's convenient iris preferably has a weight of 0.5 to 30 equivalents, particularly preferably 1 to 10 equivalents, based on the αtβ-unsaturated compound that is the raw material compound. The reaction temperature is -150C~8
0C1 is preferably -100C to 30C. The reaction solution thus obtained may be treated with iron according to a commonly used method.

For example, the reaction solution is poured into dilute hydrochloric acid, cloth #2 acid, or saturated ammonium chloride water bath solution, and extracted with a water-soluble organic solvent such as hexane, pentane, petroleum ether, ethyl ether, benzene, or toluene. The extracted solution is washed with brine and dried with a drying agent such as anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous potassium carbonate, etc. to obtain a crude material. The crude product can be loaded, if desired, by Kasim chromatography, thin pigeon chromatography, adult chromatography, or Nato no Kozueura Tejaku. The product thus obtained has a length according to JRvL, lbl, and arB1. It can be subjected to reaction, separation of diastereomers, hydrolysis DL, reaction, and salt formation reactions.

Removal of the stock group of the hydroxyl group can be performed, for example, when the protective group is a group that forms an a7'tal #11!1 bond with the oxygen atom of the hydroxyl group. Bili salt.

Using zinc or cation exchange resin as a catalyst, examples include water, tetrahydrofuran, ethyl ether, dioxane,
When using acetone, acetonitrile, etc. as a t-bath medium, the 11fA reaction is preferably carried out at a temperature of -78C to 80C.
It is performed frequently for 10 minutes to 3 days in the same range. In addition, when the anchoring group is a tri(urea&!11-7) hydrocarbon-silyl group, VC is, for example, in the presence of acetic acid, tetra-n-butyl-ammonium fluoride, cesium fluoride, etc.
-78''C-80G in a reaction medium as described above for a time similar to [WJ. Also, when the protecting group is an acyl group,
For example, hydrolysis in an aqueous solution or water-alcohol mixture of caustic soda, caustic potash, calcium hydroxide, or a methanol or ethanol solution containing potassium carbonate, sodium carbonate, sodium methoxide, potassium methoxide, or sodium ethoxide. It can be implemented in many ways. The superior product can be purified by separation of the noastereomer based on the 15-position water #1 group produced by the fish reaction, column chromatography, thin layer chromatography, dispersion chromatography, etc. The coffin can be made by other means.

The hydrolysis reaction of the carboxylic acid ester group is carried out in a single or mixed solution of water, methanol, or ethanol containing caustic soda or potassium hydroxide at a temperature range of -10C to 100C for 1 minute to 24 hours, or alternatively, For example, using a 1# base such as lipase, 1#0 in water or a water-rich bath solution.
It is carried out at a temperature range of 1 minute to 24 hours at a temperature of 60°C to 60°C. The product of the water reactor can be produced by the same purification means as described above.

The compound having a carboxyl group produced by the reaction for removing the a-retaining group as described above is then further subjected to a salt-forming reaction, if necessary, to give the corresponding carbon altt.

The salt formation reaction itself is known, and carboxylic acid is t[
This is carried out by a neutralization reaction with an equal amount of a basic additive such as caustic soda, potassium hydroxide, sodium carbonate, or ammonia, trimethylamine, monoethanolamine, or morpholine in a conventional manner.

Raw material compound α used for the compound of the present invention.

β-unsaturated compounds can be accessed, for example, by the following two routes.

Path-1 MiOf(+3 (Il[]! U几3 (V) Organic sulfone is esterified 6l3 D O3 0l1 [■]
[■] Convex 3 (IXI [and] Route-2 (ill) (X)
δR3 [X] 0 几3 CXII) (JR3 [XOI) δR3 (XIV) (0M2 K' Be6 Ru30 (II) [In the formula, Ru1, Ru2, and R3 are the same as the above definitions.
represents a tert-butyldimethylsilyl group, and 2 represents a halogen atom or a sulfonyloxy group. ]The above formula (
The compound of Ilil is a known compound, for example, [4th
5th One Machine Synthesis Symposium (Organized by the Society of Organic Synthetic Chemistry)
#l1yL praise and effect pages 51-54] in that case &ffi
He has been appointed with the same name. In route-1, the compound (
methyleneation using Guiteizhi's reagent or the like to obtain compound (M)'i-.

A sample used in methylenation is, for example, the Wittig test, which is prepared by reacting methyltriphenylphosphonium bromide with a base such as sodium hydride or potassium tert-butoxide. The reaction is usually carried out in ethers such as tetrahydrofuran, ethyl ether, or dimethyl sulfoxide.
It is carried out at 40C.

Compound (V) can be obtained by subjecting compound (ff) to selective hydroboration and then oxidizing it under alkaline conditions. As a selective hydroborosilone agent, the sterically bulky reaction is bright, and dicyamylborane is particularly bright.The reaction is usually carried out at -30C to OC in an ether such as tetrahydrofuran or ethyl ether. , 6 degrees later, the reaction solution was oxidized under alkaline conditions to produce the product (V). For oxidation under alkaline conditions, 6N-caustic soda water f6 and 30% is recommended.
If the upper limit *** is used, the I'V section will be performed in the lower L section.

Compound LM) can be obtained by t-norogenation or organic sulfone esterification of compound CV).

As the halogenating reagent, triphenylphosphine-R tetrachloride or triphenylphosphine-carbon tetrabromide is preferred. Anti-silicone is usually -78υ~ in dichloromethane.
It is done at 30C. For esterification of organic sulfones, methane sulfonic acid chloride or p-)luenesulfonic acid chloride is used (in the presence of a base such as pyridine or triethylamine). The reaction is carried out without a solvent or in a halogenated hydrocarbon such as dichloromethane or chloroform, usually at -30
It is carried out at C to 30C.

Compound [■] is compound [■] and H treated with base.
2O) 12 (in the formula, lfi is the same as above).As the base, sodium hydride or potassium tert-butoxide is particularly preferred.The reaction is usually carried out with Performed in formamide or dimethyl sulfoxide at OC to 30C.

The compound [-] can be obtained by treating the chemical compound [■] with a fluorinated @- compound such as tetra-n-butylammonium fluoride or cesium fluoride. The reaction is usually carried out in an ether chain such as tetrahydrofuran or ethyl ether at OC to 30C.

Compound CIX) can be obtained by oxidizing 1ft of hydroxymethyl group of compound [■] to form an aldehyde. For the oxidation of the hydroxymethyl group, an oxidation method using an amine-sulfur-pyrinne complex-dimethyl sulfoxide system that oxidizes a primary alcohol to an aldehyde is preferably used.

The reaction normally proceeds in the range of 10C to 40GO, and the oxidizing agent used is preferably used in excess of 2 to 100 times the mole.

Compound (It) can be obtained by reacting Compound (IX) with a Guitig reagent, which is the same as when treated with a base, and kL7 represents a carbon a, 1 to 3 alkyl group. As a base, sodium hydride,
Alternatively, potassium and tert-butoxide are preferred. The reaction is carried out at -20C to 30C in an ether chain such as tetrahydrofuran (THF) dimethoxyethane (13ME).

In route-2, compound LX) is obtained by reducing compound [111) with sodium borohydride, butylaluminum hydride.

The reaction is carried out in an alcohol such as methanol or ethanol, or in toluene at -78C to OC.

The compound [the shield is obtained by halogenating the compound CX or esterifying it with an organic sulfone.

The reaction can be carried out in the same manner as for the plateau of compounds (V) to CW) in route 1 above.

Compound CXIII can be obtained by reacting compound (M) with base-treated H2O)12CH,R1 [wherein R1 is as defined above] and '4. Bases include sodium or potassium hydride, y tert
-butoxide is particularly preferred. 6 is usually prepared in dimethylformamide (DMF) or dimethyl sulfoxide,
It will be held from OC to 30C.

Compound - Synthesis of compound [hire] from [■] and compound [river] in IEkk is compound 1)
It can be carried out in the same manner as the formation of [■], (IX) and (It).

The novel glostacyclines, represented by the formula (IJ) provided by Kaimei Hashimoto for M, are surprisingly very strong raw J!
11 Hostile t-;'N-. For example, 16.17゜1
8.19.20-pentanol-15-cyclopentyl-
3-thia-9(0)-methano-as(s“)-glostagranodin 1+ inhibits ADP-induced human platelet progression by IC,
. It was found that 20 nM inhibited the oxidation.

From this, it is expected that the compound of the present invention can be applied as an antithrombotic agent and an antiarteriosclerotic agent. In addition, the intermediates produced during this production are not only expected to have physiological activity, but also have great industrial significance as they can lead to new prostaglandin production.

The present invention will now be explained in detail with reference to Example t.

Example 1 α-β-unsaturated ketone 1 (119,6'Is O,2
6mmo 1) was dissolved in methanol (5aj), -2
Excess boron hydride at 5C) Add IJium, -2
The mixture was stirred at 51:' for 1 hour. After adding acetone to stop the reaction, a saturated ammonium chloride water bath solution was added. After removal of methanol, the remaining aqueous layer was extracted with ether, washed with saturated brine, and dried with anhydrous magnesium sulfate. #mediat''
After a whistle, the residue was cleaved using silica gel column chromatography to obtain the target allyl alcohol 2 (116,5~
, 97%) t-obtained as a colorless oil.

Mass m/z; 468e 4500 crush OH allyl ab co-h2 (116,0avt O,25
mmol) was added to 'I')iii' (0,221Rt), 65 thiacetic acid aqueous solution (2,2JIEj) was added, and the mixture was stirred at 50tll' for 2 hours. The reaction solution was cooled*
It was poured into yFux* water and extracted with ethyl acetate. M
The machine layer was washed with saturated saline and dried with anhydrous magnesium sulfate. Bath medium t-trade! The residue was purified by t-silica gel column chromatography, and 15
β-diol 4 (41,Ov, 4396)t, 15α-diol 3 (46,6jlft
49%) were obtained in each case as a colorless oil. 1iiiI
The spectral data of Tokusho Seijiru were as follows.

1R (neat); 3350cyy+-'+ 174
0 country 'iNMR (δ) CL) CI 3;
5.59 (3H1m), 4.10 (l)
Jlm)t 3.80 (3)L S), 3.28(
2H,s).

Mass (m/z) p 382 (M+) +
320p 277+ 197*131.99, 44° The spectral data of the low polarity component was the same as that of the different polarity component.

15α-diol 3 (46,0aF, 0.12mm
ol) f Solubilized in ethanol (1d). #g (11ILt) t'' of 5% trihydrium hydroxide water was added at the same temperature, and the mixture was stirred at the same temperature for 1 hour.After the reaction was completed, it was carefully neutralized with 5N hydrochloric acid to give a final pH of 4-3.This was added with ethyl acetate. After drying over anhydrous magnesium sulfate, the resulting crude product was subjected to N!R on a neutral silica gel cavity 91J-column to obtain carboxylic acid form 5 (33,0JIF,
74%) obtained.

IR(neat) j 3350cW&-1s 171
0cr11-”NMi4 (δ) (,'1)C1,;
5.50 (3Hm)Mass (m/z); 35
0 (M 18) = 322e 277 + 201.1
31,79,67゜By the same reaction procedure as in Example 1, α,β-unsaturated ketone 6 (54,5'Ft O, 12 mmol 1) was converted into allyl alcohol 7 (52, Ov, 95 mmol)t −
Obtained as a colorless oil.

IR+(neat); 3350m-”s 1740z
'Matrs m/z p 46 & 450t 3
84 Allyl alcohol 7 (50,0 #v, 0.I Lmmo 1 ) was prepared by the same reaction procedure as in Example 2.
As a low inertia component, 15β-diol 9(11,
0～.

27%) and 15α-diol s (
22,7r4.55%>t each was obtained as a colorless oil. The spectral data of the simple component was as follows.

IH+ (neat), "3350m-"+2950
cWI-'+ 2850crFl-'p 1740
crn-凰.

N1vlK(δ) C1) C1,; 5.57 (2)
L m), 5.38 (1)1゜s), 4.10
(1) L m)t 3.75 (3) L s).

3.24 (2H,s)・+Vass (m/z) p 382 (M”)*
364t 346e 32α258.214・Low polarity

Carboxylic acid compound 10 (15,7JIF, 75%) was obtained from 15α-diol 8 (20,019-0,052 mmol) by the same reaction procedure as in Example 3.
Obtained.

IR(neat); 3350cm-”*2950
crn-”t 2860m-t, 1735α-1°NMi(,(δ)CL)CI,; 5.65~5
．． 34 (3F1.m), 3.22 (2a d,
J ==4.6Hz).

Mass (m/z); 36g (M”)? 350
9332t 2991277, 231゜Example 7 The reaction procedure is exactly the same as in Example 1, α, β-unsaturated keto:y 11 (71,1q, 0.15 mmol) and allyl 7 alcohol 12 (58,0”iJ , 81
S) was obtained as a colorless oil.

IR (neat), +3525cW1-”+17
40crII-'.

Mass Cm/z); 4644461380゜Example 8 υ Using exactly the same reaction procedure as in Example 2, 15β-diol 14 (12,4~ , 28%
) 1, 15α-diol 13 (25
, 4 capes, 56%) were obtained as colorless oily vlJ negative. - The spectrum data of the polar component was obtained from the following ν9.

IR(neat); 3325cm-'+2900m
'+2825an "+1730tyH-"
.

NMR (δ) CDCl; 5.57 (2H,
m)t 5.38 (1)Ls)t 3.74 (3H
,s), 3.23 (2s)+2.75 (2H,
t, J=7.7Hz).

Mass m/z; 380 (M”), 362+
The spectrum data of the polar component at 344318°256.212,187° was considered to be a highly polar component.

Example 9 Carvone [15 (17,8jIF, 84%) was obtained as colorless crystals from 15α-diol 13 (22,0'% 0.058 mmol) by the same reaction procedure as in Example 3.

IR (neat) p 3450cm-”+ 3325
crn-'t 2900on "+17301M".

NMR (δ) CDCl; 5.68-5.43
(2)1. m, ), 5°38 (1 le S),
3.23 (2H, d, J=1.1)1z)・Mass (m/Z); 367 (M++1)+
34993311231・By the same reaction procedure as in Example 1, α,β-unsaturated ketone 16 (7511IFe O, 16 mmol
) to allyl alcohol 17 (56.0~, 74.4%
) was obtained as a colorless oil.

IR; 3425 pieces-t, 1730α-1°Mass
(m/z) ; 476* 458p 392° Allyl alcohol 17
(5611 L O, 12 mmol) 15β-diol 19 (8,9q, 1
9.3%) 15α-diol 1 as t-% highly polar component
8 (22.5 Iq, 48.8 Iq) were obtained as colorless oils. The spectral data of the highly polar components were as follows.

1 ru; 3350crn-', 1730 scratch-1°NMR
(δ) CD(,:1,; 5.60 (2H,m
), 5.40 (1)1df-s+, 3.74
(3Ht s), 1.81 (3Ht s), 0.98
(3H1m) -Mass (m/Z); 3
74 (Pv1'-18), 3301268+215
, 187, 81, and 41° The spectral data of the low polarity fractions were consistent with those of the arachnid component.

Carboxylic acid compound 20 (15.0 cape, 73.9 gI) was obtained from 15α-diol 18 (21.1 q, 0.054 mmol) by the same reaction procedure as in Example 3.

IR; 3350clR-"y 1700cm".

NMR (6) CDCl; 5.58 (2)4
m), 5.39 (IH.

S), 4.11 (315)1. m)t 3.99
(275′Lm), 3.80 (11-1,m
), 3.25 (2H.

S), 1.79 (3 S), 1.01 (915
Lud, J=6.51(z), 0.96 (615K
d.

J=6.8Hz).

Mass m/z; 379 (M'+13+ 36
L 343-(JT)IP ” ”1 By performing the same reaction procedure as in Example 1, α・β-fusouwa ketone 21 (87,1'9.0.17 mmo 1 )
From allylal: ff-ru22 (80,6IHip
92.296) was observed as a colorless curved substance.

IR; 3450cW1”+ 17403-1°NMi
(δ(CL)CI,); 5.20-5.70
t2H, m).

4.98 (1)i, m), 4.62 (IK
m), 3.78 (3H, sL 3.22 (2a
s), 1.68 (3)Ls), 1.60 (3)
1 s), 0.95 (3) Lm).

By the reaction procedure of Example 2 and total < tWIl, 15β-diol 24 (21,
3"Py32.4%) and 15α-diol 23 (28.5jlF, 43.4%) as polar components were used as oily substances.The spectral data of the polar components are as follows. there were.

IK; 3350Qr1-'+1740cm-".

WMRδ(C1)C13); 5.39 to 5.65
(3am) 93.74 (3H1s), 1.70
(3)1.5)-1,62(3h S)+0.95
(3HJd, J=9.0H2LMass (m/Z)
; 418 (M-18)t 40013121251
．． 227,131.91@69・The spectral data of the low polar component matched that of the high polar component.

By the same reaction procedure as in Example 3, 15α-diol 23 (26,51F* 0.051 mmol);
6-et al., carvone dispersion 25 (17,2111P, 6
7.2 h) was obtained.

IR; 3350I:M-', 1700α-1°NMR
(δ) CL)CI 3; 5.56 (2H, m)
, 5.38 (1)Ls), 5.10 (1am)
, 4.20 (1am).

3,'7's (lam)t 3.24 (2 le S)
.

1.68 (3s), 1.60 (3)1. s),
0.93 (3rd, J=5.5Hz).

Mass m/z; 423 (M”+IL 405
*3872λ' Reference Example 1 (JT)iP Methyltriphenylphosphonium (357aF, 1mmol) was dissolved in anhydrous tetrahedron (5, d), and potassium tert-butoxide (116"te) was added to this at room temperature. 1
mmol ) in anhydrous tetrahydrofuran (5d) a
t-Add. Next, α-sino unsaturated Q full y human 26 (
190#IP,Q, 5mmol) of anhydrous tetrahydrofuran (5#LA') was added using a mail ring and stirred at room temperature for 30 minutes. After the reaction was completed, saturated Nk44Cl aqueous solution was added and extracted with ethyl ether. The solution was dried with Japanese saline solution and anhydrous magnesium waxate, and the bath medium was distilled off under reduced pressure.
90.5%)'kNM δ(CL)Cl,); 6
．． 52 (1rudd, J==t6+10)1z)*
5.63 (labs), 5.00 (2dm),
4.62 (IH. m), 3.00 (rn.

IH), 0.90 (91-1.s), 0.05
(6) i.

S) fk4kmk Mass (m/z); 294 (M+-84L 2
77+237.

85.

Reference example 2 0T) 11' Under an argon atmosphere, diene body 27 (100j9.

0,2 6 6 mm o Todoroki) was added to tetrahtomifuran (
1.5aj) and -10t:' diamylborane-tetrahydrofuran solution (0.59MIO.9aO
was added and stirred for 3 hours.
IILt) was added and stirred for 1.5 hours. Missing 6N
-Na<JH aqueous solution (0.27ILt) ao %
M-defective hydrogen water (0.2 1117) t”, IJI
After stirring at room temperature for 1.5 hours, the reaction mixture was poured with ether and washed with an aqueous solution of sodium thioborate and saturated brine. Dry with anhydrous reduced magnesium oxide, remove solvent, and remove remaining &'? 'Purified by silica gel column chromatography, homoallyl alcohol 28
(97iay. 92.6%) Obtained as t-colorless oil.

1R(neat); 3400ays-', 2925c
1n't 1470cyt-"+1255t
M1-'.

NMR J (CL)Cl g); 5
．． 43 (1)1, bs)t 4.60(1d
m), 3.00 (1dm), 0.92 (9H,s)
* 0.05 (6FLs) World M! ” (tn/
z) j 312 (M++ 84) s 2 5 5
+ 237 + 85・ #Example 3 Call 28 to homo allele (230q, 0.58mm
ol) in pyridine (3,d), p-toluenesulfonyl chloride (1304,0,68mmol 1
) t-added.

The mixture was stirred at mold temperature for 6 hours and extracted with ethyl ether.

The extract was washed successively with a 10-thiosulfate aqueous solution, water, and saturated saline, and dried over magnesium mercenate. f! After removal, the residue was purified by silica gel column chromatography to obtain Sat. tosylate 29 (304,'lj% 95
h) was obtained.

1B (neat); 2925Iyn'+ 15
95crn-'w1470m-'y 1360cr1
t'.

NMR (δ) C1) C13; 7.28 (4)1.
s), 5.23 (1)Lm), 4.59
(IH, m)t 4.28-3.42 (6H, m),
2.44 (3 sL 2.58-1.15 (1
6H1m), 0.91 (9H,s).

0.07 (6 S) Mass (m/z); 466 (M-84), 40
9* 317°277.237° Reference Example 4 Sodium hydride A (40'P+ 60'4 r
1 mmol 1) 1r:1) dissolved in MF (2at), storm mK tef, t/+7:1-methyl acid (96pi * 95%e 1 mmol) t? Add using a syringe and stir for 30 minutes. DM of Tosylate 29 (435,2q* 0.79mmol)
Add F(2d) and stir for 5 minutes at mold temperature, then extract with saturated N)i, CI aqueous solution, and ethyl ether. The extract was washed with Japanese saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography to give 30 (3
12,0 IN? , 82%) as a colorless oil.

〇 (JT) 1F Tnp IH (neat); 2925cII-”+ 1
740crn'+1460on-"t143
5crRt.

NMR (δ) CDCl; 5.27 (IH,
m), 4.58 (IH.

m) * 3.72 (3B-4,8)-3,22(2
35) -0,95 (9 le s), 0.10 (6 le s)
)・Mass Cm/Z); 400 CM”-84
)l 34312511237.145° (JTHPU'i'Hf' 1 to 11-atmosphere, 30 (240,8W, 0.
50 mmol) tS ice water trahydrofuran (3rnl
), add 750μ of tetra-n-butylammonium fluoride-tetrahydrofuran (IM) and stir at mold temperature for 2.5 hours. Extract with After extraction with saturated brine and drying with anhydrous d14 magnesium, the solvent was removed using maple pressure. The resulting residue was subjected to silica gel column chromatography to produce #I, alcohol 31 (
131,319,7196) as a colorless oily substance 0 IR (neat); 3450crn-'+ 292
5crn-'+ 1730 low'+ 14351MK-
'.

to MW(δ) C1)C1s; 5.33 (1hr
n) -4-62 (I 89m)t 3.74 (3H
,s), 3.23 (2K B)-Mass (m/
z); 286 (M-84)+ 246* 1B0
- Alcohol 31 (158■) under argon atmosphere.

9.43 mmo 1 ), triethylamine (2,65
) d) t: Dissolved in anhydrous DM30 (1,6-'). 8 U, -bilinin complex (1,427 g) in anhydrous DMSU (3,7 aj) solution was added using a syringe,
Stirred at room temperature for 20 minutes. Then, the reaction solution was placed in ice water,
Extracted with ethyl ether. Wash the extract with water and add 1 g of anhydrous
The dry mflk1 bath medium was removed under pressure with ILrIIt magnesium to obtain the crude aldehyde 32 (155'f)t-. 31 obtained in this way was used in the second process without loading.
”.

Under an argon atmosphere, sodium hydride (60 qb.

13.2 '%' + 0.33 mmol) of dimethyl (
2-oxoheptyl)phosphonate (73,3q, 0
．． 33 mmol) of anhydrous tet-)hydroflough (1
1Lt) solution was added and stirred at mold temperature for 1 hour. In the dark, crude aldehyde 32 (62,6 Misaki + 0.17 mmo
l) in anhydrous tetrahydrofuran (1-),
The reaction mixture was stirred at room temperature for 1 hour, dissolved in a saturated NH4Cl water bath, and extracted with ether.

Extraction WLt - After drying with saturated brine and drying with anhydrous magnesium chlorate, the solvent was removed under reduced pressure. The separated residue was subjected to silica gel column chromatography to obtain α,β-unsaturated ketone 6 (54.5% to 69%) as a colorless oil.

IR(neat); 3450c1n-”+17
35 on t.

1'lJMR(δ) eDel, ; 7.05~5
．． 88 (lam), 5.35 (lhm)s
4.60 (lant), 3.74 (3FLs)
t 3.22 (2)i, s).

M as8 (In/z); 446 (M-18
)t 4331 aso*Embroidery Example 8 Sodium hydride (60%) under an argon atmosphere.

Dimethyl (2-cyclopentyl-2-oxoethyl)phosphonate (72,7''
A solution of FtO, 33 mmol) in anhydrous tetrahydrofuran (1d) was added, and the mixture was stirred at room temperature for 1 hour. Then crude aldehyde 32 (63,5'f* 0.17mm
A solution of o l ) in anhydrous tetrahydrofuran (1d) was added, and the mixture was stirred at room temperature for 1 hour. Thereafter, by the same operation as in Reference Example 7, α, β-unsaturated ketone 11 (71,1 to 8
9) was served as a colorless oily substance.

IR(neat) z 2950IMM-'+ 173
5cm'+1690crn-"+16603-"
+1620tM-'.

NMI also (δ) C1) C1; 7.02-5.86
(1 am), 5.23 (la mL 4.50 (1
)1t m)? 3.65(:Hts), 3.14
(2t4 g>.

Ma” (”/”) v 462 (M”) e 37
8 (M-84) t334.272,228° Sodium hydride (6
0**17.2'F-0,43mmo 1) O9k
Water Te) Rahi) 'ofuyy (3#Ij) IIl liquid Vko,
A solution of dimethyl (3-methyl-2-oxohept-5-ynyl) phosphonate (100.3% 0.43 mmol) in anhydrous tetrahydrofuran (1114) was added, and the mixture was stirred at N temperature for 1 hour. Then crude aldehyde 32 (75
Ilh0.20 mmol) of anhydrous tetrahydrofuran (
1a) Add the solution and stir at room temperature for 1 hour. Hereinafter, by the same operation as in Reference Example 7, α,β-fusouroketone 16 was prepared.
(64,21II, 66.5H) was obtained as a colorless oil.

Ib; 1740 pieces-”, 1690 pieces-t, 1670
Taku-1゜16205I-”.

NMR (δ) C1) C1m; 6.08-6.88
(3am), 5.38(1)L m), 3.72
(3H,s)t 3.22 (3ru8)11.16 (
3)1. m) - Reference Example 10 Under an argon atmosphere, sodium hydride (6 (1°17.
2 q, 0.43 mmo J ) of hydrothermal nato 2 hydrofuran (3d)! Dimethyl (4,8-dimethyl-2-
(118,71
F.

0.43 mmo 1 ) of anhydrous tetrahedral o7 y (1
#Ij) IIm it 7Ia and stirred at room temperature for 1 hour. Then crude aldehyde 32 (75q, 0.20m
A total of 9 sips of anhydrous tetrahydrofuran (l) aJ) solution of m01) were poured and stirred at Asahi temperature for 1 hour. Thereafter, by the same operation as in Example 7, α,β-unsaturated ketone 21 (92,9q
+88.0%) as a colorless oil v! Obtained as I′j[.

IR; 1740cIn-'+ 1690crn-'+
1670>'+1620c! n.

NMR (δ) C1)C13; 6.65 (IH, m
)t 6.26.6.00(1)i, each d+
J=15Hz*4Hz)*5.00~5.40 (
3H, m), 4.60 (1 lm), 3.74 (
3as), 1.68 <38°df-s), 1.
60 (3H, df-s)-0,88(3)L d f
-d J=7.0Hz) ・t)Tk-LP
□T)iP廿 33 Under an argon atmosphere, α,β-unsaturated aldehyde 26(2
,03g=5.3mmol)'k) Luxun (10
at) and cooled to -78C. Lacking diimbutylaluminum f”61’ idlide-toluene (1,7
6M.

3. Add 36- and stir at -78C for 30 minutes. Add methanol (lIILl), dilute with ethyl ether, raise the temperature to lukewarm temperature, and add saturated brine. The extract was extracted with ethyl ether, washed with Japanese brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was cleaved using silica gel column chromatography to obtain alcohol compound 33 (1.74 g, 85.3%)'tNM.
δ(CjJCl,); 5.66 (1 le bs), 4
．． 62 (IH, m), 4.12 (2 le S),
3.00(1)1. m)t O,90(9)L
S) I O, 05 (6HIS) #kffi Mass (m/Z) t 298 (iVl”-84
) + 24L 223y85・U'rHPOTHP 7 Alcohol 33 (383I
9゜1 mmol) was dissolved in dichloromethane (7d),
-60CVc was used. Missing triphenylphosphine (31519* 1.2 mmol) Oh! H40 &
I element (398jlF, 1.2rrunol)f was added, stirred at -60C for 6 hours, saturated NaHC (J3 water mash &) was added, and extracted with ethyl ether.The extracted 1fi was washed with saturated brine, anhydrous magnesium sulfate In the dry wave, the popular medium was traded.

The obtained oily substance was chromatographed using a silica gel column chromatograph using a silica gel column chromatograph, and the bromine body 34 (305jlf, 68.4
NM14 δ(C1)C13); 5.70 (1
)L bs), 4.60(11-1,m)*4.0
0 (21-Ls), 3. ．． 00(lmL 0.
90 (9H, s) to, os (6le S) Kaine.

IVlaSS (”/z) 1362 (Fd++2
-84) + 360 CM"-84)t 305,3
03,281,263.8F＞Reference Example 13 Sewater-based sodium A (32vt 60%I O,8
mm01)'t-1)Mk' (1,5id) and β-Mercaf) 7'cl Hio71jil at room temperature
It was added using a syringe and stirred for 30 minutes. Next, a DMF (2~) bath solution containing bromine compound 34 (245,019,0.55 mmol) was added, and after stirring at room temperature for 3.5 hours, a saturated N)14C1 water bath solution was added, and the mixture was extracted with ethyl ether. The extract was washed with saturated brine, and the solvent was removed with anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography to obtain 35(
212, 3 parts, 79.7 hours) was obtained as a colorless oily substance.

IR; 2925zM1-"+2850crrI'
t1740crn”.

NMi(I(δ) (CDCI 3); 5.37
(1) L m), 4.48 (1 to -L m),
3.58 (3)1. s), 3.10 (2tts
) to, go (9H, s) = 0.05 (6)L
S).

Mass (m/z); 484 (M”)* 400
t 343 - Under argon atmosphere, Nobu (251,2Q 0
．． 52 mmol) t-S water tetrahydrofuran (3
11t), tetra-n-butylammonium
Fluoride-tetrahydrofuran (IM, 630 μl
) and stirred at room temperature for 2.5 hours. Diluted with Asahi N) 14CI water bath and extracted with ethyl ether. The extract was washed with Japanese brine, dried over anhydrous magnesium sulfate, and dried. was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain alcohol 36 (116,4M9, 60.7%) as a colorless oil.

IR; 3450m "t 2950cr11-"+
2850z-'t1740α.

NMR (δ) (CIJCI 3); 5.55
(1) L m), 4.71 (1) L m), 3.7
5 (3)1. S), 3.23 (2#-1, S).

tviass (m/Z); 370 (M”L
286t 197゜/' Reference example 15 0T) iP (JT) LP 3!37 Alcohol body 35 (111, OWe
O, 31 mmol), triethylamine (1,86
d) was dissolved in anhydrous DM8U (1,2IRt). 5
U3-pyridine complex (1,03g) in anhydrous DMSOC
Add #2,61nt) solution using a syringe and incubate at room temperature.
Stirred for 0 minutes. Then, the reaction solution was poured into ice water and extracted with ethyl ether. Wash the extract with water and anhydrous tiitrl.
After drying over 11 magnesium, remove the solvent under reduced pressure.1. il
Aldehyde 37 (102, IP4) manufactured by I was obtained. The thus obtained 37 was used in the next step without stringing.

It(+;3400I:rn-'+2950z'
+2850oys-1+1740cm 't 17
20cM1”.

Sodium hydride (60%) under argon atmosphere.

Dimethyl (2-oxoheptyl)phosphonate (122,2% 0.55%
mmol 1) Ofi water was stirred for an hour. Then crude aldehyde 37 (102,1'9+0.28 mmol
) of anhydrous tetrahydrofurano (2at) #g was added thereto, and the mixture was stirred at room temperature for 1 hour. Reaction liquid! ! 21″HN) 14C
After pouring into an aqueous solution of I and extracting with ethyl ether, the 0 extract was washed with saturated saline and dried over anhydrous Tm7ium magnesium oxide.
The molten liquid was evaporated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain α,β-unsaturated ketone 1 (
110,1 Cape! 85.596) was obtained as a colorless oil.

IR(neat); 1740IMI-'+169
0c*-1+ 1670 strokes"+ 1630IMl-breath.

NMR (d) C1) C13; 6.45-6.75
(it-L m), 5.90-6.20 (IH, m
), 5.40 (1)1. m).

4.50 (IH, m) = 3.65 (3H, 5at
3.21 (2 le S).

MS (m/z); 464 (M”)
t 433t 380. 261°85°

Claims (1)

[Claims] 1 General formula [I] ▲ Numerical formulas, chemical formulas, tables, etc.▼ [I] [In the formula, R^1 is -CO_2R^4 group (in the group, R^4 is a hydrogen atom, or A linear or branched alkyl group having 1 to 12 carbon atoms, or an aralkyl group having 7 to 12 carbon atoms, or a carbon number that is unsubstituted or substituted with at least one alkyl group having 1 to 4 carbon atoms. 4 to 7 cycloalkyl group or substituted or unsubstituted phenyl group, or 1 equivalent of cation), or -CONR^5R^6 group (in the group, R^5 and R^6 may be the same or different) However, each hydrogen atom, or an alkyl group having 1 to 10 carbon atoms, or R^
5 and R^6 together with the nitrogen atom to which they are bonded represent a 5- to 6-membered substituted or unsubstituted ring which may further contain a heteroatom), and X and Y One of them represents a sulfur atom and the other represents a methylene group, and R
^2 is a linear or branched alkyl group having 3 to 10 carbon atoms, or an unsubstituted or at least 1 carbon alkyl group;
A cycloalkyl group having 4 to 7 carbon atoms substituted with 4 alkyl groups, a straight chain or branched alkenyl group having 3 to 12 carbon atoms, or a straight chain or branched alkynyl group having 3 to 8 carbon atoms , or an optionally substituted phenyl group,
or a substituted alkyl group having 1 to 3 carbon atoms substituted with a phenoxy group, an alkoxy group having 1 to 6 carbon atoms, or a cycloalkyl group having 5 to 8 carbon atoms;
3 represents a hydrogen atom, an acyl group having 1 to 7 carbon atoms, a tri (1 to 7 carbon atoms) hydrocarbon-silyl group, or a group that forms an acetal bond with the oxygen atom of a hydroxyl group. ]Prostacyclins represented by. 2. Prostacyclin according to claim 1, wherein in formula [I], R^1 is a carboxyl group or a methoxycarbonyl group. 3 In formula [I], R^2 is n-pentyl group, 1
-Methylpentyl group, cyclopentyl group, 1-methyl-
The prostacyclin according to claim 1 or 2, which is a 3-pentynyl group or a 2,6-dimethyl-5-heptenyl group. 4 Claim 1, wherein in formula [I], R^3 is a t-butyldimethylsilyl group, an acetyl group, a benzoyl group, a 2-tetrahydropyranyl group, or a 4-(4-methoxytetrahydropyranyl) group Prostacyclin according to any one of Items 1 to 3. 5 Formula [II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [II] [In the formula, R^1, R^2, R^3, X, and Y are the same as defined above. ] The α,β-unsaturated carbonyl compound represented by the formula [
I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼[I] [In the formula, R^1, R^2, R^3, X, and Y are the same as defined above. ] A method for producing prostacyclin expressed by