JPS63310863A - 9-(benzoyloxysilylmethyl)prostaglandin f2alpha, production thereof and production of isocarbacyclins using said compound - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I (R<1>-R<3> are 1-7C hydrocarbon group and R<4> is 1-6C alkyl or 3-6C alkenyl; R<5> and R<6> are tri(1-7C) hydrocarbon silyl or a group to be linked to O of OH to form acetal bond; R<7> is H, methyl or vinyl; R<8> is 3-9C alkyl, alkenyl or phenyl; R<9> is H; n is 0 or 1). EXAMPLE:5,6-Dihydro-9-deoxy-9-(hydroxydimethylphenylsilylmethyl)-PGF2a lpha. USE:A key intermediate for isocarbacyclins. The isocarbacyclins show strongly inhibitory action on blood platelet aggregation. PREPARATION:A compound shown by formula II is benzoylated with an acid halide of a benzoic acid or an acid anhydride shown by formula III in the presence of a base (e.g. pyridine) in a solvent such as THF at -100-100 deg.C, preferably -78-50 deg.C to give a compound shown by formula I.

Description

[Detailed description of the invention]

<Industrial Application Field> The present invention relates to a method for producing incarbacyclines and raw materials thereof. More specifically, the novel 9-(benzoyloxysilylmethyl) prostaglandin F2 (X
A method for producing incarbacyclines via a silylated carbacycline@1 substance [151]. <Technical background> Carbacycline is a prostaglandin (sometimes abbreviated as PG) R5 (PG), which is a physiologically active substance in vivo.
It is a prostaglandin It m R1 form in which the acid X* child at the 6.9-position of I,) is substituted with a methylene group, and is a natural prostaglandin that has an enol ether partial structure in the molecule! Because it is chemically stable compared to , it is a useful compound as a pharmaceutical such as an antithrombotic agent. In recent years, incarbacyclin, a kind of double bond isomer of carbacycline, i.e., 9(0)-Mechno6(9
α) -Prostaglandin Il was discovered to exhibit the strongest platelet aggregation inhibitory effect among its congeners, and its application as a pharmaceutical was expected (Ikegami et al., Tetrahedron Letters). Tetrahedro
nLatters) + 33 *3493 and 3497 (1983) and JP-A-59-1374
45 and 59-210044]. -(9α) Conventionally, several methods for producing such 9 (0)-methano-△-prosmeglandin It (isocarbacycline) have been known. When the body and the report are folded together, the Tetrahedron Letters (Tetrahedron Letters) are created.
rahedron L@tters), 24
, 3493 (1983) and Chemistry Letters 1984
*1069: Key intermediate A, Ka21 Bakai2,7 Iwa) Ikegami et al., Tetrahedron.
Letters (Tetrahedron Letters)
), 24, 3497 key intermediate OH=Of( incarbacycline (3) Ikegami et al., Journal of the Chemical
Fusaiety. Chemical Communication (J,
Ch@n, Soc, Ch@m1cal Comm
Uniea-tiona), 1984 *1
602: +41 Shibasaki et al., 'retrahedron Letters'
*25*5087 (1984): Chemistry Letters
, 579 (1984): OR' key intermediate incarbacycline (5) Shibasaki et al., Tetrahedron Letters (Tet
rahedron Letters), 25+
1067 (1984) and I# Open 11860-94
934-TI! j: Key intermediate Incarbacycline (6) Small A, Chemical and Pharmaceutical Predin (Cb@m, Pharm. Bull,), 32.2866 (1984): 0H jl intermediate ( dA Riichi Isocarbacycline (7
) Kojima et al., JP-A-60-28943: Key intermediate
(dA)-incarbacycline (8)
Itaniku et al., Abstracts of the 106th Annual Meeting of the Pharmaceutical Society of Japan, p379 (
1986): Key intermediate incarbacycline (9) Hari et al., Nippon Yukyo 106th Annual Meeting 1s Makoto Abstracts Collection p379 (1
986): Key intermediate incarbacycline Ql Mazuma et al., 106th Annual Meeting of the Mulberry Society of Japan - Collection of abstracts p.
380 (1986): There are 10 methods for the key intermediate incarbacycline. Of these 10 methods, method (1) and method (5)
The method uses PGE as a starting material, leads to a key intermediate through several steps, and obtains the target incarbacycline through several further steps, and cannot be described as an industrial production method. Also,
Method 12) and method (3) both involve a multi-step process from the corresponding starting materials and expensive Corey lactones to obtain key intermediates, have no total yield, and are not necessarily industrially viable. The problem is that it is not an advantageous method. In addition, in method (6) and method (7), the final product is dA
'1' is out of the question, as it can only be obtained in the body and is intended for pharmaceutical production. In method (4), the starting material is not only easily obtained from optically active (R)-4-hydroxy-2-cyclobentenone by the method of the present @ Akishika et al. However, in the process from the key intermediate to the final incarbacycline, the process from the starting material to the key intermediate poses no problem industrially. The major drawback is that the total yield is low due to a number of difficulties such as the use of In addition, method (8) is the most advantageous and highly practical for casting incarbacycline from a pure intermediate, but it has the disadvantage that the number of steps for producing the key intermediate from the starting material is relatively long.Method Method (9) has the disadvantage that carbacycline is produced as a residue during the production of the product incarbacycline.Also, method αQ can produce incarbacycline from the starting material in the shortest number of steps, but the collection rate is low. (This cannot be said to be an industrially satisfactory method.The method recently reported by the inventors of the present invention (Collection of Lectures at the 53rd Autumn Annual Meeting of Japan Society, p. 499 (1986)) is shown below. This method uses a (methylthio)thiocarbonyloxysilylmethyl derivative as a key intermediate, but there is a difficulty in selectively producing non-key intermediates, and incarbacyclines The development of industrially effective IJ!11 methods remains an unresolved problem. <Objective of the Invention> The object of the present invention is to develop a new key that enables the industrial production of incarbacyclines. The purpose of the present invention is to develop intermediates and provide efficient production methods using them. (In principle, the naming of compounds in this specification is based on the prostaglandin nomenclature.) <Structure and Effects of the Invention> 〉 The present inventors took into account the above-mentioned points and developed a practical framework for the above-mentioned item 6 (9α) (9 (0)-meta/-△-prostaglandin nomenclature (incarbacyclin wA). As a result of intensive research in order to find a method for producing silica, we have arrived at the present invention.That is, in the present invention, the compound represented by the following formula (I) OR@, its enantiomer, or any proportion thereof Compound: 4!J (hereinafter referred to as “representative compound”)
The expression ``is also the same as ``the represented compound, its mirror image, or any proportion thereof'')5.
6-dihydro-9-geoxy-9-(benzoyloxysilylmethyl) prostaglandin F. are provided as key intermediates to achieve the above objectives. In the above formula (I), xi, gt, and R1 are the same or different and represent a C1 to C1 carbonized to water* group,
Examples include methyl, ethyl, propyl, inpropyl, butyl, t-methyl, phenyl, benzyl, and tolyl groups, where # is methyl. T-butyl and phenyl groups are preferred. Especially R”R”
It is most preferable that the combination of kL+, al, and aj in the R''S i group is a cymenalphenylsilyl group. In addition, in the above formula (1), R4 is a C1-C8 furkyl group or a C3-C, realkenyl group. The C, -C0 furkyl group includes methyl, ethyl, propyl, isopropyl, butyl, 1-punal, pentyl, hexyl-is, etc., and the C8-C0 alkenyl group includes 2-propenyl. Examples include 2-pugnil, 2-hekymonyl, phenyl, etc., but methyl, ether, and 2-propenyl groups are preferred. In addition, in the above formula CI), as, R1 is 4- or different, and , ~Ct) represents a group that forms an acetal supergroup with the oxygen atom of a hydrocarbon silyl group or hydroxyl group. Examples of tri(C1~CV) hydrocarbon silyl groups include C, trimethylsilyl group, triethylsilyl group, triisopropylsilyl group. group, tri(Ct-C4)alkylsilyl such as t-butyldimethylsilyl group, diphenyl(Ct-C,
)furylsilyl group, dimethylphenyl group, etc.
Preferred examples include C1-C4) furkylphenyl group and tribenzylsilyl group. Among them, tri(C, to C4)furkylsilyl. Diphenyl(01-C,)furkylsilyl and 7enyldi(Ct-C3)alkylsilyl groups are preferred, and t-butyldimethylsilyl and trimethylsilyl groups are particularly preferred. Examples of the group forming a 7-cetal M base together with the oxygen atom of a hydroxyl group include methoxymethyl i, l-ethoxyethyl group, 2-methoxy-2-propyl group, and 2-ethoxy-2-propyl group. (2-methoxyethoxy)methyl group, benzyloxymethyl group, 2-detrahydropyranyl group. Mention may be made of the 2-tetrahydro7ranyl group or the 6,6-dimethyl-3-oxa-2-oxobicyclo[3°1.0]hex-4-yl group. 2-detrahydrovilanyl, 2-tetrahydro7ranyl, l-ethoxyethyl, 2-ethoxy-2-propyl, (2-methoxyethoxy)methyl, 6,6-dimethyl-3-oxa-2
-oxobicyclo(3,1,03hex-4-ilkami) is particularly preferred. Among these, 2-detrahydropyranyl is particularly preferred. These silyl groups and groups forming an acetal bond are hydroxyl group-protecting groups. It should be understood that these protecting groups can be easily removed in the final product stage under mildly acidic to neutral conditions to yield free hydroxyl groups useful as pharmaceuticals. A hydroxyl group-protecting group having the formula can be used in place of a silyl group or a group forming an acetal bond.In the above formula CI), R7 represents a hydrogen atom, a methyl group, or a vinyl group. In particular, when n (described below) is O, a hydrogen atom or a methyl group is preferable, and when n is 1, a methyl group is preferable. In addition, in the above formula CI), R1 is a linear or branched C8-Cfurkyl group, alkenyl group, or alkynyl group that may be interrupted by an oxygen atom; a substituted or unsubstituted phenyl group, phenoxy group, or C5A -C
1° cycloalkyl group: or C1-C, Frukin' group, optionally substituted phenyl group, substituted

[Optionally phenoxy group or optionally substituted C
8-C1° Represents a straight chain or branched C1-C, furkyl group substituted with a dichlorofurkyl group. II chain or branched C3-C which may be interrupted by an oxygen atom, 2-methoxyethyl as an alkyl group,
2-Ethoxyethyl, propyl. Butyl, pentyl, hexyl, heptyl, 2-methyl-
2-hexyl, 2-methylbutyl. Examples include 2-methylpentyl, 2-methylhexyl, 2,2-dimethyl and 1,000syl groups. Butyl, pentyl, hexyl, heptyl. 2-hexyl group, 2-methyl-2-hexyl. 2-methylbutyl and 2-methylpentyl groups are preferred. Examples of the linear or branched C3-C, fulkenyl group even if interrupted by an oxygen atom include 1-butylvinyl and 2-propylaryl. 2-benzonyl, 4-pentenyl, 2-methyl-3-pentenyl, 4-hexenyl, l,4-dimethyl-3-benzonyl, 5-hepdenyl, 1-methyl-5-hexenyl, 6-methyl-5-hebutenyl , 2,6-dimethyl-5-hebutenyl group, etc. are preferred. Examples of the straight chain or branched chain 03-C, alkynyl group which may be interrupted by an oxygen atom include 2-butynyl, 2-pentynyl/3-pentynyl, 1-methyl-
2-pentynyl and l-methyl-3-pentynyl groups are preferred. Substituted phenyl group, substituted phenoxy group, or C3-C
Examples of substituents for the 1°-substituted cycloalkyl group include halogen atoms, protected hydrogen groups (eg, silyloxy groups, C1-C, alkoxy groups, etc.)! 7 fluoromethyl group, C1-C, furkyl group, etc. Examples of the C8-C1° cycloalkyl group include cyclobutyl, cyclopentyl, cyclopentyl, cyclopentyl, cycloheptyl, cyclooctyl, and cyclodecyl. Cyclopentyl and cyclohexyl groups are preferred. FjL@ substituted with C1-C, alkoxy group, optionally substituted phenyl group, optionally substituted phenoxy group, or substituted C, ~C1, cycloalkyl group Or in a branched chain C1-CS alkyl group, as a C1-C alkoxy group,
For example, Metoyashi. Ethoxy. Propyloxy, isopropyloxy, butoxy, (-
Examples include butoxy and hexyl τoxy groups. An optionally substituted phenyl group. As the substituent of the optionally substituted phenoxy group or the optionally substituted C8-Gil+cycloalkyl group and the C8-C111 cycloalkyl group, the same ones as mentioned above can be mentioned. Straight-chain or branched *C, -CS alkyl groups include, for example, methyl, ethyl, propyl. Examples include isopropyl, butyl, ingtyl, 5ee-butyl, t-butyl, pentyl, and the like. Kakoroni 6 includes butyl, pentyl, hexyl, heptyl, 2-hexyl, 2-methyl-2-heyacyl, 2
-Methylbutyl 12-methylpentyl, cyclopentyl, cyclohetyral. Preferred examples include phenyl, phenoxy, cyclopentylmethyl, and cyclohexylmethyl groups. -ru. Note that the device y4 group may be bonded to any position 11 thereof. In addition, in the above formula (1), R1 represents a hydrogen atom or a substituent, and such substituents include the same f substituents as those listed for the substituted phenyl group of R1 above, and the substitution position is the ortho position. , meta position, and meta position. Among these, a trifluoromethyl group and a chlorine atom are preferred. Ro is a hydrogen atom or a p-90- group. m −) ') Fluoromethyl group is preferred, especially m
-Trifluoromethyl group is preferably mentioned. In addition, in the above formula CI), n represents O or l,
It is particularly preferable that n is O. In addition, in the compound represented by the above formula (I), stereoisomers exist due to the asymmetric environment in the carbon to which the substituent is bonded (g and 91 on the cyclopentane ring). In the present invention, any stereoisomer is included, and a mixture of these stereoisomers in any proportion is also acceptable.The compound represented by the formula includes all of these stereoisomers and their isomers. The most preferred compound is a compound having a three-dimensional structure represented by the formula (5) represented by the above formula (I) provided by the present invention.
Preferred specific examples of 6-dehyde cs -9-deoxy-9-(benzoyloxysilylmethyl) prostaglandin F, a group are 5,6-deL represented by the following formula CII)
Draw 9-deoxy-9-(human axysilylmethyl) R', R' for frostaglandin F2a
, R. is listed in the form of a derivative of a hydrogen atom: (01) 5.6-dihydro-9-deoxy-9-(hydroxydimethylphenylsilylmethyl) PGF, a (02) 5.6-dihydro-9-deoxy -9-(Shidroxydimethy/Shiphenylsilylremethy/Shiku 15
-Methyl PGF2a (03) 5*s-dehydro-9-deoxy-9-
(hydroxydimethylphenylsilylmethyl)-16,
16-dimethyl PG F2c1 (04) 5.6-dehyde o -9-deoxy-9-(hydroxydimethylphenylsilylmethyl)-17120-dimethyl PG
F, C1(05) 5rs-dehydro-9-deoxy-
9-(Hydroxydimethylphenylsilylmethyl)-1
B, 19.20-) Sonolu 1-fuethoxy PGF2a (06)5+6+17;18-detradehyde a -9-
Deoxy-9-(hydroxydimethylphenylsilylmethyl) PGF2a (07) 5.6-dihydro-9-deoxy-9-(
hydroxydimethylphenylsilylmethyl)-17-methyl-19,20-dinol-18-(1-propynyl)
PGF, a (08) 5,6-dihydro-9-deoxy-9-(
hydroxydimethylphenylsilylmethyl)-17-methyl-20-impropylidene PGF, a (Q9) 5.6-dihydro-9-deoxy-9-(hydroxydimethylphenylsilylmethyl)-17,18
,19,20-tetranol-16-phenoxy P G
F, a (10) 5.6-dihydro-9-deoxy-9-(
hydroxydimethylphenylsilylmethyl)-17,I
I, 19920-tetratrue 16-m-chlorophenoxyPG F2゜(11,) 5,6-dihydro-9-deoxy-9-
(Hydroxydimethylphenylsilylmethyl)-16s
17,18t19,20-pentanol-15-cyclohexyl PGk'2a (12) 5,6-dihydro-9-deoxy-9-(hydroxydimethylphenylsilylmethyl)-16117
,18,19,20-pentanol-15-cyclopentyl PGF2a (13) 5.6-dehyde o -9-deoxy-9-(
Hydroxydimethylphenylsilylmethyl-17.1
8,19.20-tetranol-16-cyclohexyl P
G F2a (14) 5.6-dihydro-9,15-bisdemoxy-16-hydroxy-9-(hydroxydimethylphenylsilylmethyl)-16-methylGF2a (15) 5.6-dihydro-9,15- Bisdeoxy-16-hydroxy-9-(hydroxydimethylphenylsilylmethyl) PGF2cL(16) (01
Compound (17) in which the hydroxydimethylphenylsilylmethyl group of ) to (15) is substituted with a hydroxytrimethylsilylmethyl group (Ql) The hydroxydimethylphenylsilylmethyl group of (15) to hydroxydimethylphenylsilylmethyl group is
Compound (18) substituted with butylsilylmethyl group (
Compounds (19) in which the hydroxydimethylphenylsilylmethyl group of 01) to (15) is substituted with a hydroxydi-t-7'tylphenylsilylmethyl group (01) to (
Compounds such as the compound in which the hydroxydimethylphenylsilylmethyl group of 15) is substituted with a hydroxydiphenylmethylsilylmethyl group are exemplified. Here a4, R1, R
Examples of compounds that take into consideration the definition of
1), 11.15 (or 16) of (01) to (19)
)-bis-tetrahydropyranyl ether (22) (01) to (lso) 1.1.15 (or 16)-bis-t-//tyldiphenylsilylneedle (23) (01) to (19) 1l-t-Butyldimethylsilyl-15 (or 16)-tetrahydropyranyl needle (24) (t) 1) to (19) 11-tetrahydrocubiranyl-15 (or 16.)-L-butyldimethylsilyl Ether (25) Methylnisglu (2) (01) to (24)
6) Ethyl ester of (01) to (24) (27)
(ol) ~ (24) 7lyl esal (28) (
01) to (24) t-butyl esters (29) (
Examples include hexyl esters of 01) to (24). Specific examples of the compounds represented by the above formula (I) are listed above as benzoylated compounds represented by the formula ([), such as (30) 9α- of (01) to (29) Benzoyl derivative (31) (ot) to 9a-(m-) of (29)
Examples include 9α-(p-talolopenzoyl) derivatives (32) (01) to (29). 516-dihydro- of the present invention represented by the above formula (I)
9-deoxy-9-(penzoyloxinlylmethyl)
Prostaglandin F2a is readily available5,6
-dihydro-9-buoxy-9-formyl prostaglandin F2a (formula [IV]) tt Starting W, it is produced through a long process as a family and leads to silylated carbacyclines which can be derived into incarbacyclines. It will be destroyed. That is, the production method of the present invention includes, as a first step, adding the following formula (V) ( R'R1R151)q(L)2-4CuLl...
...The silyl copper lithium compound represented by [v] is reacted (silyl addition reaction) to form the following formula (n) R'R"R'
5iVOH 5,6-dihydro-9-deoyac-9-(
Hydroxysilylmethyl) prostaglandin F2a is obtained, and as a second step, 5 represented by the above formula (II) is obtained.
, 6-dihydro-9-deoxy-9-(hydroxysilylmethyl) prostaglandin F2a in the presence of a basic substance to form the following formula (ln) R [wherein R1 is the same as the above formula]. ] Acid halides or acid anhydrides of benzoic acids represented by
(Benzoylation reaction) At least 5,6-dihydro-9-thioxy-9-(
benzoyloxysilylmethyl) prostaglandin F
This is a manufacturing method for obtaining type 2a. Furthermore, in the present invention, as a third step, 5,6-dihydro-9-
The following formula (Vl) 0R can be fermented into incarbacyclines by irradiating deoxy-9-(benzoyloxysilylmethyl) prostaglandin F, am with light (photocyclization anti-L5) in the presence of a solvent. - Silylated carbacyclines represented by are produced. Each step will be explained in detail below. (11 silyl addition reaction; 5,6-dihydro-9-deoxy-9-formyl prostaglandin F2c1, represented by the above formula (iv), used as a raw material in the first step of the present invention, is a compound of the above-mentioned Ikegami et al. Method (Ikegami et al., Chemistry Letters (C
hemistryL@tters), l 069
(1984) ), 5,6-dihydro-9-buoxy-9-methylene prostaglandin E
, etc. as a starting material, it is easily produced by combining hydroporation-oxidation reaction and oxidized limestone. Some of the 5,6-dehydro-9-deoxy-9-methylene prostaglandins 4 are known compounds, and are described by G.L., Bundy.
et al.'s method (USP4144253, USP40!j8805
, 4118584 (Unexamined Japanese Patent Publication No. 53-135957)
, 4130720° and 4166187). That is, 5,6-dihydro-9-buoxy-9-methylene prostaglandin E can be produced by methylenation of the carbonyl group at the 9-position of 5,6-dihydrobrostaglandin 4. Upper mi formula (IV) K Oite R', R', R',
R', R'', o and n are the same as defined above,
The groups exemplified in 5,6-dihydro-9-deoxy-9-(benzoyloxysilylmethyl)frostaglandin F2a represented by the above formula (I3) are similarly preferably mentioned, and the groups represented by the above formula (IV) 5,6-dihydro-
9-buoxy-9-formyl prostaglandin F2a
Specific examples of the above-mentioned 5t6-dihydro-9-deoxy-9-(benzoyloxysilylmethyl) prostaglandin F2a represented by the above-mentioned formula CI) are the four enzymes that are harmful to the chemical compound F2a. Preferred examples include: The silyl addition reaction of the method of the present invention is performed by converting 5,6-dihydro-9-deoyasi-9-formyl prostaglandin F2a represented by formula (IV) into a silyl copper lithium compound represented by formula (V) in an organic medium. This is achieved by reacting with In the formula (V), R1, R1,
and R1 are the same or different and represent a C, -C, hydrocarbon group, such as methyl, ethyl, propyl, butyl, t-7'thyl, phenyl, benzyl, tolyl group, especially methyl, 1-butyl , phenyl group is preferred. For example, the most preferred example of the silyl copper lithium compound is bis(dimethylphenyl) copper lithium. The amount of these silyl copper lithium compounds used is 5,6-dihydro-9-deoquin-9-hol of formula (IV). As an organic medium for smoothly proceeding the reaction, a medium inert to the above-mentioned silyl copper stadide, such as ethyl ether. Ethers such as tetrahydrofuran and dioxane, hydrocarbons such as pentane and hexane, or any mixture thereof are used, and tetrahydrofuran is preferably used. The reaction temperature is 100°C to 0°C, preferably 17°C.
It is carried out at a temperature of 8°C to -40°C, and the limestone time is usually 1 hour, about 5
3008 degrees is sufficient. After the reaction, the soybean paste is treated in a conventional manner. That is, after mixing the reaction solution with saturated ammonium chloride water or saturated ammonium sulfate water,
For example, extract hexane, pentane, petroleum ether, ethyl ether, ethyl acetate, etc. using an organic solvent soluble in IIJA in water, wash the resulting organic mixture with brine, etc. as necessary, and then extract the organic solvent using anhydrous magnesium sulfate, anhydrous magnesium sulfate, anhydrous After drying with a desiccant such as sodium sulfate or anhydrous calcium chloride, the organic medium is removed under reduced pressure to obtain a crude product. The crude product can be loaded, if desired, by ff production means such as column chromatography, thin layer chromatography, and a-body chromatography. (and the following formula (1
5,6-dihydro-9-deoxy-9 represented by 1)
-(k-Droxysilylmethyl)prostaglandin F
Class 2a! Jl will be built. (2) Benzoylation reaction: The second stage benzoylation reaction is performed using the formula obtained in the first stage (
5,6-dihydro-9-deoxy-9 represented by n)
-(hydroxysilylmethyl)prostaglandin F,
This can be achieved by reacting group a with an acid halide or acid anhydride of benzoic compound 6i represented by the above formula [formula] in the presence of a basic substance. In the above formula [2], R' represents a hydrogen atom or a substituent, and preferable examples of such substituent groups include the same substituents as those listed for the substituted phenyl group of Ra in Metalworking, for example, a fluorine atom. , halogen atoms such as chlorine atoms and bromine atoms, methoxy groups, ethoxy groups, and methyl groups. Examples include ethyl&, t-7' thyl group, triple olomethyl group, and chlorine atom and trifluoromethyl group are particularly preferred. The substitution positions of such substituents include the ortho position, meta position, and para position, but the most preferred combination is p-glolo group and 1m-trifluoromethyl group. The benzoic acids represented by the above formula [river] are subjected to the reaction as acid halides or acid anhydrides. Preferred examples of the acid halide include acid chlorides and acid bromides. The amount of these acid halides or acid anhydrides to be used is determined by the formula (
5,6-dihydro-9-deoxy-9 represented by n)
−(Hydroxysilylmethyl)prostaglandin′
The amount is 0.8 to 10 moles, preferably 0.9 to 5 times, and even more preferably 1.0 to 3 times by mole, relative to Class 2a2a. The reaction is carried out in the presence of a basic substance. Such basic substances or aromatic bases such as pyridine, 4-(dimethylamino)pyridine, imidazole,
Examples include aliphatic 4 groups such as triethylamine and triglythylamine, and inorganic bases such as sodium bicarbonate, sodium carbonate, and potassium carbonate. The amount of the basic substance to be used is U, S to 10 times by mole, preferably 0 times, per mole of the aqueous halide or acid anhydride used.
．． The amount is 9 to 5 times by mole, particularly preferably 1.0 to 3 times by mole. In order for the reaction to proceed smoothly, it is preferable to carry out the reaction in the +*i form. Such an organic medium includes an inert organic medium normally used in such an esterification reaction, such as ethyl needle, tetrahydroctane, and dioxane. Ethers such as diphtho-4-ethane, aliphatic hydrocarbons such as pentane and hexane, aromatic hydrocarbons such as benzene and toluene, methylene chloride, OCJ form,
Halogenated hydrocarbons such as carbon tetrachloride and dichloroethane, acetonitrile, or any mixture thereof are used, and preferred examples include detrahydrofuran, methylene chloride, acetonitrile, and the like. The reaction temperature is -100°C to 100°C, preferably -78°C to 50°C, more preferably 0°C to 30°C, and the reaction time varies depending on the reaction temperature, but for example, at 20°C, it is 1 hour Ih1 to
About one day is sufficient. After the reaction, the reaction solution is post-treated by a conventional method. That is, the reaction solution is mixed with hexane after terminating the reaction by adding a saturated aqueous solution of heptammonium chloride. Extraction is carried out using a commonly used water-soluble organic hot medium such as pentane, ethyl ether, or 6M ethyl. A crude product is obtained by washing with an aqueous sodium solution, drying with anhydrous sodium sulfate and anhydrous magnesium VL acid, and then distilling off the organic medium under reduced pressure. The crude product can be loaded by purification means such as Erycolumn chromatography, thin layer chromatography, liquid atomography, etc., if desired. Thus, 5,6-deoxy-9-deoxy-9- represented by the following formula CI)
(Benzoyloxysilylmethyl) prostaglandin F2a is produced. (3) Light source reaction; The third step of the light source reaction is the reaction of 5,6-tehyde a-9-deocy9-(benzoyloxysilylmethyl) floss represented by the formula CI) obtained in the second step. Taglandin F2
A silylated carbacycline represented by the formula (el) can be produced by irradiating the compound a with light in a solvent in the coexistence of N-methylcarbazole. Such a light source reaction is carried out according to the method reported by Matsuura et al. The N-methylcarbazole used is i 0.1 to 1 mole of 5,6-dihydro-9-thioxy-9-(benzoyloxysilylmethyl)frostaglandin F2a represented by the formula CI) 7 molar times, preferably 0.5 to 5 molar times, particularly preferably 0.5 molar times.
It is carried out using 8 to 3 molar amounts. In place of N-methylcarbazole, 1s214s5-tetramethoxybenzene, 1,5-dimethoxynaphthalene, 1-(dimethylamino)su7tane can also be used. The heating medium to be used is tetrahydro7rane or an alcohol such as inpropatol or propatool in the coexistence of water. The test is carried out using approximately 10% water. Light irradiation is performed by a normal method, for example, at 100 W and %iI.
It is carried out using an i-pressure mercury lamp as a light source and a Pyrex filter. An accelerating effect is observed when the photocyclization reaction is carried out in the presence of magnesium perchlorate. The magnesium perchlorate used is 2LI)
It is preferable to use chemical compounds represented by violet. The post-processing of the reaction wave is the second stage of benzoylation post-processing and the first stage.
A suitable VC is implemented according to the aspect of ff1, and the following formula (Vl
) are formulated with silylated carbacyclines. Specific examples of silylated carbacyclines represented by formula (IV) obtained by
-Deoxy-9-(benzoyloxysilylmethyl)frostaglandin F2a can be directly exemplified as a product corresponding to the compound specifically exemplified, or by the method of the present invention, a new key intermediate The formula (I
) 5,6-dehydro-9-deoxy-9-
The silylated carbacyclines represented by formula 1), which are industrially advantageously produced via (benzoyloxysilylmethyl) prostaglandin F2a, can be produced by the method separately proposed by the present inventors (#fg! et al. 9 Chemical Society of Japan, No. 53
According to Autumn Annual Conference Lecture Expenses and Effects, p. 499 (1986)), oT ability is to lead to incarbacyclines useful as pharmaceuticals through desilyl isomerization and deprotection reactions. The present invention, together with its preferred embodiments, are as follows. 1. 5,6-dihydro-9-, the following formula (I) In the formula 1, R' I R'' * and R1 are the same or a compound represented by 1, an enantiomer thereof, or a mixture thereof in any ratio Deoxy-9-(benzoyloxysilylmethyl) frostaglandin F2a. 2. The compound according to item 1, wherein the combination of R', R'' and R'' is dimethyl 7-enyl. 3. R' is C1 The compound according to item 1, which is a ~C4 alkyl group. 4. The compound according to item 1, wherein R7 is a hydrogen atom or a methyl group. 5.88 is a linear or branched C1-C0 alkyl group or C8 The compound according to item 1, which is a dichlorofurkyl group of ~C1°. 6. R8 is n-butyl group, n-pentyl group, en-hexyl group, 2-hexyl group, 2-methylhexyl group, cyclopentyl group, or cyclohexyl group. 7. The compound according to paragraph 1, wherein R1 is a hydrogen atom, p-chloro1L or m-trifluoromethyl group. 8. The compound according to paragraph 1, wherein R1 is a m-)trifluoromethyl group. The compound according to item 1. 9. The compound according to item 1, wherein n is 0. 10. The compound according to item 1, which has a steric structure represented by formula (I). 11. The compound represented by the following formula (It). 5,6-dihydro-9-deoxy-9-(hydroxysilylmethyl) prostaglandin F2a, which is a compound, its enantiomer, or a mixture thereof in any proportion, is reacted with the following formula in the presence of a basic substance. [In the formula, R9 is the same as defined above.] Benzoic l!! Compound represented by the following formula CI) reacted with #2 type #R/-logophide or acid anhydride, and its enantiomer , or a mixture thereof in any proportion 5
, 6-dehyde 0-9-deoxy-9-(benzoyloxysilylmethyl) prostaglandin F2. 11 The 5.6-dihydro-9-deoxy-9-(hydroxysilylmethyl) prostaglandin F, a group is a compound represented by the following formula (IV) HO, its enantiomer, or any @group thereof. The following formula (V) (R'R"R"bi)q (L) 2-q Cu L is added to the mixture of 5,6-dihydro-9-buoxy-9-formyl prostaglandin F2a.
5,6-dehydro-9-deoxy-9-, which is obtained by reacting the silyl steel lithium compound represented by i...-(V) and described in item 11, A method for producing (benzoyloxysilylmethyl) prostaglandin F2a. 13. 5,6-dihydro-9-deoxy-9-(benzoyloxysilylmethyl) prostaglandin, which is a compound represented by the following formula (I), its enantiomer, or a mixture thereof in any proportion. The following formula (Vl) is characterized in that F2a is irradiated with light in the presence of a solvent.In formula 1, R", R', R", R', R', R
A method for producing a silylated carbacycline which is a compound represented by @, R', R', #1, its enantiomer, or a mixture thereof in any proportion. 14. M where the solvent is hydrous tetrahydrofuran
13 sA 4K (') 41m method. 15. The first solvent in which the solvent is a water-containing impropatol
The manufacturing method described in Section 3. 16. The production method according to any one of the above items 13 to 15, in which light is irradiated in the coexistence of N-methylcarbazole. 17. The production method according to any one of the above paragraphs 13 JA"-416, which comprises irradiating light in the coexistence of magnesium perchlorate. The present invention will be explained in more detail with reference to Examples. The symbol is 5i(CHs)* -C, f(
, that is, represents a t-butyldimethylsilyl group. Example 1 Aldehyde 1 (159, OMg, 0.262 mm
ol ) tetrahydro7 run (15,0ml) Detrahydride g7 run bath of bis(dimethylphenylsilyl)copper lithium (0,27M, t, z o I
LI! l. 0.314 mmol) was added at -78°C and stirred for 30 minutes. Add 7 g (l) of saturated aqueous solution of 7 mmonium chloride to the reaction solution.
0117) was added to terminate the reaction, and the resulting mixture was subjected to needle extraction (1 oaj x 3). The ether layer was washed with saturated brine (25311t), and the separated ether layer was dried over anhydrous sodium sulfate.
K: A crude product was obtained by concentration under reduced pressure. This was subjected to column chromatography (silica gel 6/. Solvent used: hexane: ethyl acetate = 15: 1)
The target product, silyl alcohol 2 (165,089
, 0,222 mmol, 84.7%) as a colorless oil 5X (diastereomixture). TLC (hexane: ethyl acetate = 5: l); R
f O, 31°IR (CHCja); 3400.1740, 1250.830 cm. 'H-NMR (CDCI, 270M &) δ; -0,
02,0,01,0,03(ts each, 12°03
i(CH,)lX2 ), 0.36.0.37 (s
Each. 6,5iCH,X 2 ), o, s s, 0.87
(a each. 21, oStc(CL)s X 2, CHs)
. 1.1 1.7 (m-10, CHs xs ) -1
,73(tL 2. J=7.3.7.3fLz, C
Yama CH, C (01). 1.93 (dt, 1. J=7.1.7.:Hlz
, CM). 2.0-2.3 (m, 6.CH,X2.C)l
X2). 2.38 (t, 2. J=7.4Hz, CHlC
fOl)-3,66(s, 3.0CH3). 3.9-4.1 (m, 3. Cf(OX3). 5.29 (dd, 1. J==6.4. 15
．． 711z, vinyl). 5, l+ 0 (dd, l, J=5.4.1
5.3Hz, vinyl). 7.3 7J (m, 5. phenyl). "C-NMR (CDCJ, , 22.5 Maz
) δ: 1 3, L 18, 1. 18.3. 18.
4. 22.6. 24.5°25.0. 26.0.
32.0. 33.1. 37.5. 38,8゜4
2.0.48,7. 51.2. 57.4. 64.
6. 73.2°79.4. 79.5. 80.7.
127.9. 129,1°131.2. 134.
1. 135.2. 138.1° 173.4° MS (m/@); 743 (M+1), 135° Example 2 Silyl alcohol 2 obtained in Example 1 (62,38?
, 0.084 mmol) of 7cetonitrile (
3,Od) solution at 18 °C with 14-dimethylamine/pyridine (25,01?, 0.21 mmol) and m-)lifluoromethylbenzoic acid chloride (0,0
3wJ, 0.18mmol) was added and the resulting reaction mixture was stirred at 18°C for 15 hours. After the reaction, it was poured into a saturated ammonium chloride water bath (3at), and the resulting mixture was poured with ether (3m+jX3). The separated ether layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the remaining crude product was purified by column chromatography (silica gel 59. Solvent used: hexane: ethyl acetate =
20:1) 3
(69.3m9゜Q, 076 rnmol, 90.
1%) ftm colored oil (diastereomixture). TLC (hexane:I!Iethyl-5:l)
;Rf O,33°I R(C1(C4); 1710.16]0,1320.1250°1150.
830 cx'. 'HNMR(CI)C1x -270Mmu)δ;-0
,04,-0,03,0,00,(h %, 12゜08iC mountain x4), 0.40゜0.41 (m valley, 6. SiC horse x2), 0
．． 85°0.86 (s Taniya, 21, O3i
, C(CH,), X2. CH,). 1.1-1.6 (m, 10. CHl X5
). 1.74 (tt, 2. J==7.3. 7.
3[1z, CHtCHCIOl). 1.8-2.3 (m, 7.CH,X2.CHX3
). 2.40 (t, 2. J=7.6ELz,
OH, CtOl). 2.4-2.5 (m, 1. allyl C)l). 3.69 (s, 3. OCR,). 3.76 (dd, 1, J=7.3.15
．． 511z, CHO). 3.9-4.0 (m, 1. Allyl C) IO). 5.20 (a, 1. vinyl). 5.22 (d, 1, J=2.0&, vinyl). 5.65 (d, 1, J=2.3 days z,
C) I(81)0 ) -7,3-8,4(m, 9.
phenyl). "C-NMR (CDCJ, 22.5M1lz)a;
-4,6,-4,4,-4,1,-3,9,-3,7,
13.9°18.1. 1 8, 3. 1 8.5.
18.6. 22.6. 24.5°25.0. 26
,0. 32.0. 33.1. 36.9. 38.
7°39.5. 46,2. 5k, 2. 55.
7. 70.7. 73.1°78.2. 79.8.
80.0. 126,6 (q', J,, F=4
．． 1b, CF,), 127.9, 128.3. 1
29.0°129.5. 129,9. 130.6.
132.0°132.76, l 34.2. 1
35.8. 136.24°164.9. 1 73.
47°MS (m/@) p Example 3 Silyl benzoate 3 obtained in Example 2 (14,0 m
19. 15.3 amol) and magnesium perchlorate (3,4q, 15.3, amol), N
-Methylcarbazole (3,07 afl, l 6
．． 6 amol) of aqueous tetrahydro-7rane (tetrahydro-7rane:water = 10:1, s*z) solution
The sample was placed in a test chamber (d) and irradiated with light for 16 hours at 18° C. using a 500 W high-pressure mercury lamp. Reaction I @ Saturated carbonic acid solution) Pour into IJum water #1'; L (,,5 ml),
The reacted mixture was extracted with ether (3dX3). The collected needle layer was compressed under reduced pressure, and the residue was subjected to column chromatography (silica gel 1.5/, heating medium used: ethyl hexane diacetate = 100:1) to obtain the target product, silylated carbacycline 4 (8, 3J%l, 11.4μm
ole 74.7%) was obtained as a black oil (E, a mixture of the two). TLC (H+S7: el￥6!-'+LE==5:
1); Rf O846°I R(CHO4); 1740.1360.1250.1100°83001
1*'H-NMR (CDCJ, 500M) δ; 0.0
0.0.02.0.03. (s, each, 12°08i
CH, x4), 0.24.0,25. (1,26
,0,28゜(!1.Each*L 5iC1(JX2
). 0.7-1.0 (m, 21, 08iC (mount C),
X 2. C1(,). 1.0-1.7 (m, 12.CHIX6). 1.7-2.0 (m, 5.CHX3.OH,)
. 2.0-2.3 (m, 5*Ali/L-CH1X2.AllylC)I). 3.5-3.7 (m, 1. CHO), 3.66
゜3.67 (!1 each, 3.0C mountain). 4.02 (br, l, CdO), 4.9
2゜5.09 (br valley A, l, vinyl). 5.3-5.5 (m, 2. vinyl). 7.3-7.5 (m, 5. phenyl). ”CNMR (CDC & , 22.5 MFiz)
δ;-4.6. -4.5. -4+4. -4.1. -3+
9. -3.4゜1 4.1. 18,1. 18.3.
22.6. 25,1. 25.4°26.0. 2
9.2. 31.8. 33,6. 33.9. 38
．． 7°39.4. 39.7. 43.5. 43.7
．． 44.5. 45.0°46.0. 5 1.4.
56.1. 7 3.3. 78.2°119.2.
119.7. 127.7. 128.9°129.
0. 130.9. 133.8. 134.0°13
4.3. 134.4. 138.3. 138.4°143.1. 144.3. 174.1°MS (m
/e); 726 (M). High resolution M S ; C4tHt40aS is (M
”) Calculated value near 26, 4895° Measured value near 26.4906°

Claims (1)

[Claims] 1. The following formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[I] [In the formula, R^1, R^2, and R^3 are the same or different, and C_1~ C_7 represents a hydrocarbon group, R^4 represents a C_1 to C_6 alkyl group or C_3 to C_6 alkenyl group, R^5 and R^6 are the same or different, and a tri(C_1 to C_7) hydrocarbon silyl group or represents a group that forms an acetal bond with the oxygen atom of a hydroxyl group, R^7 represents a hydrogen atom, a methyl group, or a vinyl group, and R^8 represents a straight or branched chain that may be interrupted by an oxygen atom. C_3 to C_9 alkyl group, alkenyl group or alkynyl group; substituted or unsubstituted phenyl group, phenoxy group, or C_3 to C_1_0 cycloalkyl group; or C_1 to C_8 alkoxy group,
Represents a linear or branched C_1 to C_5 alkyl group substituted with an optionally substituted phenyl group, an optionally substituted phenoxy group, or an optionally substituted C_3 to C_1_0 cycloalkyl group,
R^9 represents a hydrogen atom or a substituent, and n represents 0 or 1. ] 5,6-dehydro-9-deoxy-9-(benzoyloxysilylmethyl) prostaglandin F_2_α which is a compound represented by the above, its enantiomer, or a mixture thereof in any proportion. 2. The following formula [II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼... [II] [In the formula, R^1, R^2, R^3, R^4, R^5, R
^6, R^7, R^8, and n are the same as defined above. ] 5,6-dehydro-9-deoxy-9-(hydroxysilylmethyl) prostaglandin F_2_α, which is a compound represented by, its enantiomer, or a mixture thereof in any proportion, in the presence of a basic substance. The following formula [III] ▲There are mathematical formulas, chemical formulas, tables, etc.▼... [III] [In the formula, R^9 is the same as the above definition. ] The following formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼……[I] [In the formula, R^1, R^2, R ^3, R^4, R^5, R
^6, R^7, R^8, R^9, and n are as defined above. ] A method for producing 5,6-dehydro-9-deoxy-9-(benzoyloxysilylmethyl) prostaglandin F_2_α, which is a compound represented by the following, its enantiomer, or a mixture thereof in any proportion. 3. The following formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼……[I] [In the formula, R^1, R^2, R^3, R^4, R^5, R
^6, R^7, R^8, R^9, and n are as defined above. ] 5,6-dehydro-9-deoxy-9-(benzoyloxysilylmethyl) prostaglandin F_2_α, which is a compound represented by the formula, its enantiomer, or a mixture thereof in any proportion, is exposed to light in the presence of a solvent. The following formula [VI] which is characterized by irradiation ▲There are mathematical formulas, chemical formulas, tables, etc.▼... [VI] [In the formula, R^1, R^2, R^3, R^4, R^5 ,R
^6, R^7, R^8, and n are the same as defined above, and ■ represents that the steric configuration of the double bond is E, Z, or a mixture of E and Z in any proportion. A method for producing a silylated carbacycline which is a compound represented by the following formula, its enantiomer, or a mixture thereof in any proportion.