JPS6212743A - Production of carbacycline compound - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a medicinal drug such as platelet-coagulation inhibitor, in high efficiency, by reacting 9-deoxy-9- methylene-5,6-dehydroprostaglandin E2 with an alkylborane, and oxidizing and then iodinating the reaction product. CONSTITUTION:The objective compound of formula II [G<1> is G or COOH; R<31> and R<41> are R<3> and R<4>, respectively or H is produced easily from an easily available raw material in short step, by reacting the compound of formula I (the symbol between 13 and 14 sites is double or triple bond; G is CO2R<5> or CONR<6>R<7>; R<5> is 1-10C alkyl, phenyl, etc.; R<6> and R<7> are 1-10C alkyl or together form a 5-6-membered ring of formula NR<6>R<7> which may contain hetero-atom; R<1> is H, CH3, vinyl, etc.; R<2> is 5-8C unsubstituted alkyl, alicyclic group, etc.; R<3> and R<4> are 2-7C acyl, tri(1-7C)-hydrocarbon-silyl, etc.] with the compound of formula R<8>BH2 (R<8> is hexyl or cyclohexyl of formula C6H13) in an inert organic solvent, oxidizing the product, treating with iodine in the presence of an alkali and, if necessary, subjecting the reaction product to deprotection or hydrolysis.

Description

[Detailed description of the invention] <Industrial application field> The present invention relates to a novel method for producing carbacyclines.

More specifically, the present invention relates to 9-deoxy-9-methylene-5
, 6-zohydroprostaglandin E, etc. as raw materials,
The present invention relates to a method for efficiently producing carbacyclines having pharmacological activity useful as pharmaceuticals by reacting with an alkylborane, followed by oxidation and iodination treatment.

<Prior art and its problems> Prostacyclin has useful physiological activities, such as platelet aggregation inhibiting activity and vasodilatory activity.

It is attracting attention as an extremely useful drug due to its anti-ulcer activity, anti-asthma activity, anti-cancer activity, etc., and is a useful substance in medicine and pharmacology as an in vivo cell function regulator.

However, it is often difficult to use prostacyclin as a drug because the enol ether bond contained in its skeleton is highly susceptible to hydrolysis under neutral or acidic conditions. For this reason, carbacyclines were invented in which the oxygen atom of enol ether was replaced with a carbon atom, and because of their high chemical stability, their use as a pharmaceutical substitute for natural boostacyclines is being considered.

[W, Bartmann]
and others.

7 Ngevante Chemie International Etation in English (Angew.

Chem, Int, Ed, Engl, ), 2
1.751 (1982), H'Vorbriiggen et al.
nal Ser, Rev, ) + 5.1~53
(1985)].

Many methods have been proposed for the production of carbacyclines [7-R, J.

K., Taylor), “New Synthesis 71
・Rout tow prostaglandin and thrompoxane (N@W 5ynthetic Rout
et.

Prostaglandin and Thrombo
xanes) 'edited byz S.M.P Parts & F. Scheinman (S, M,
Roberts and F. Schsinman
n) +pp 191-241 (1982)].

As far as the present inventors know, these methods can be broadly classified as follows. Namely, (1) A method of obtaining the product by Uitzteitsch reaction via an intermediate which is a bicyclo(3,3,0)octan-3-one derivative; -1, A method using bisic a(3,3,0)octane-3,7-dione as the starting material [K, C, N1culaou et al.

Journal of the Chemical Society, Chemical Communication (J, Cham, 8o
c, Chem, Comm,).

1067 (1978)].

I-2, Method using cyclooctane-1,3-diene monoepoxide as the starting material [Ikegami et al., Tetrahedron
Letters (Tetrahedron LeLt, ) +
433 (1979)'.

Chemistry Letters (Cham, Lett, L
1299 (1979)].

1-3. A method using anhydrous 5-norbornene-2,3-dicarboxylic acid as a starting material [Wanibe et al., Tetrahedron Lett,
2jJ, 2607 (1979)].

! -4, Method using 3,4-dimethoxycarbonylmethylcyclopentanone as a starting material [Sakai et al., Tetrahedron Letts
)+39, 3743 (1978)].

I-5, method using Corey lactones as starting materials [
Hayashi et al., Chemistry Letters (Chem, L@tt
, ) + 1437 (1979): Tetrahedron (T
etrahedron) + 37, 4391 (
1981): Vorbriiggen
)and others.

Angewante Chemie International Edition in Ingridx (Angew, Ch.
sm, Int, Ed, ingl, )s20
, 1046 (1981): Adv, in Prostaglandin Thromboxane and Leukotrie/Research (Adv, in Prostag
landin, Thromb* and Lauko
-triene Res・) + Vol 11+
editea by Hibi-Samuelson (&Samu
elsaon) et al., p. 299 (1983)].

1-6, a method using trishifj(4,2,0,-)ofukun body as a starting material [Morton also describes the method in the Journal of Organic Chemistry (J, 0r17. Chem, )]
.

2880 (1979)].

! -7. Vero method using 1,4-diketone as the starting material [Aristolaf et al.

Journal og organinque ξst! J
-(J, Org, Chem, )
, 46. 1954 (1981)].

9(01-meta)-Δ'1(1(ri-PGL), which has a stereospecific
- Obtaining method by hydrogenation reaction [Shibazaki et al., Journal of Organic Chemistry (J, Org,
Cherfl, ), 44, 4096 (1984
), reference], etc. These methods are methods for producing carbacyclines and have the following drawbacks. In other words, in the first method, the key intermediate bisic I:1'(3,3,0)octan-3-one derivative is produced through a multi-step process, and the second The method is 5.6 for carbacycline.
Although it has the special feature of being able to stereospecifically produce positional double bond isomers, it still has the disadvantage that the production process is relatively long.

Purpose of the Invention> Based on the above technical background, the present inventors have developed an efficient method for producing carbacyclines using readily available raw material compounds, that is, in short steps. Intensive research into methods for producing similar products (results of 5, 9
- and monodeoxy-9-methylene 5,6-dehyde a - Prostaglandin E, etc. are used as raw material compounds, and the compounds are subjected to a hydrovole reaction, an oxidation reaction, and an iodination reaction to produce carbacycline in one step. The present invention has been achieved by discovering scales that can be easily produced.

<Disclosure of the Invention> That is, the present invention provides 9-deoxy-9-methylene 5,6-dehyde prostaglandins represented by the following formula, in an inert organic medium, by the following formula: ...It is characterized by being reacted with monofurkylborane represented by four strokes, then oxidized, further treated with iodine in the presence of an alkali, and then subjected to a deprotection reaction or a hydrolysis reaction as necessary. In the following formula I1, the symbol z@B'+R'' is a method for producing carbacyclines represented by 1 as defined above.

9-deoxy-9-methy→cysine 5,6-zohydroprostaglandin &M. represented by the formula position) The carbons at positions # and 15 are asymmetric carbons. The present invention includes all isomers based on these asymmetric carbon atoms and mixtures thereof in arbitrary proportions. Since the chemical reaction in the production method of the present invention can be fully predicted to proceed without conformational change, the conformation of the carbacyclines shown by the obtained substitute symbol is the compound of 2〇, which is the raw material, That is, 9-deoxy-9-methylene 5,6-dehyde ρ 1-
The conformation is the same as that of staglandins.

In the above Daiin, the symbol giant between the 13th and 14th place is 1.
C indicates that there is a double bond or triple bond between the 3rd and 14th positions.

G represents -CO2R1 or -CONS'R, where R1 is a C1-C□ realkyl group, and the substitution is also 1. ri is an unsubstituted phenyl group, substituted and 1-ri is an unsubstituted alicyclic group,
Substituted or unsubstituted phenyl CC.

~C! )furkyl group or )! J (C, ~C2) hydrocarbon-silyl group.

C, -C,. a furkyl group and 1. For example, methyl, ethyl, n-7'ρvyl+igo-propyl, re-butyl, 5ec-butyl, tart-butyl, n
- Pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl groups, linear or branched.

The substituent of a substituted or unsubstituted phenyl group and 1° C. is 1, for example, a Hakugan atom, a hydroxy group, a C, to C, 7 siloxy group, a C to C which may be substituted with a halogen atom,
C9 which may be substituted with a furkyl group or a halogen atom
~C4 alkoxy group, nitrile group, carboxyl group, (C1-C1) alkoxycarbonyl group, etc. are preferred.

Halogen atoms and 1. C is preferably fluorine, chlorine or bromine, particularly preferably fluorine or chlorine. C2-C, acyloxy group and 1
．． For example, 7cetoxy, bupionyloxy, n-
Mention may be made of butyryloxy, 13o-butyryloxy, n-valeryloxy, 18o-valeryloxy, caproyloxy, enantyloxy or benzoyloxy.

Examples of the C1-C4 alkyl group optionally substituted with halogen include methyl, ethyl, n-p-2-vir, 1ao
-purpyru, n-butyl, chloromethyl, dichloride:lG
Preferred examples include +methyl and trifluoromethyl. Examples of the C1-C4 alkoxy group which may be substituted with halogen include methoxy.

Preferable examples include ethoxy, n-propoxy, llo-pudiboxy, n-gutoxy, methoxy, dicoulomethoxy, and trifluoromethoxy. Examples of the (C, to) alkoxycarbonyl group include methoxycarbonyl and ethoxycarbonyl.

Examples include butoxycarbonyl, hexyloxycarbonyl, and the like.

The substituted phenyl group can have 1 to 3, preferably 1 substituent as described above.

Substituted or unsubstituted alicyclic groups include saturated or unsaturated C1-C1, preferably C, -C@, 4I, preferably C6, substituted with the same substituents as mentioned above or unsubstituted. Examples include cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl and the like.

Examples of the substituted or unsubstituted phenyl CC1-C1)furkyl group include benzyl, α-7enethyl, and β-7enethyl, which are substituted or unsubstituted with the same substituents as above for the phenyl group.

)u(C,-C,)hydrocarbon silyl group, for example, trimethylsilyl, triethylsilyl.

t1MI (C) such as t-butyldimethylsilyl group.

~α) Diphenyl(C1-C4)furkylsilyl such as furkylsilyl, t-butyldiphenylsilyl, tribenzylsilyl or dimethyl-(2,4,6-)di-
Preferred examples include t-butylphenoxy)silyl and the like.

-CO■ 1f Ha, Ht are the same and l-(are different Q
The alkyl groups of Ct to Cll1 or W and R, together with the nitrogen atom to which they are bonded, further contain a heteroatom [1.degree. represents an unsubstituted ring. Here, the furkyl group of CI'' C16 includes the same alkyl groups as mentioned above. Also, the substituents in the substituted or unsubstituted ring include the same substituents as mentioned above, and the hetero atoms include nitrogen, Mention may be made of sulfur or oxygen atoms.

Examples of the above-mentioned rings include 1-pyridyl, thiazolyl,
1-piperidyl, morpholyl, piperazyl or 5,6-
Examples include cyhydrophenanthridyl group.

As G, Hs is a C1-C3° alkyl group, 1# is a methyl group, and R to C (methoxycarbonyl) is preferable.

R1 is a hydrogen atom, a methyl group, a vinyl group or a protected ethynyl group. Preferred examples of the protected ethynyl group include trimethylsilylethynyl and t-butyldimethylsilylethynyl. Among these, hydrogen atoms or methyl groups are preferred.1. stomach.

1m is an unsubstituted C5-C1 alkyl group; an optionally substituted phenyl group, an optionally substituted phenoxy group, an optionally substituted C1-C, alkyl group, or an optionally substituted C1 -C, a substituted C, -C, alkyl group substituted with a cycloalkyl group: or a substituted or unsubstituted alicyclic group. An unsubstituted alkyl group of C, to C, and C may be linear or branched (e.g., n-pentyl).

n-hexyl, 2-methyl-1-hexyl.

2-Methyl-2-hexyl, n-heptyl.

n-octyl etc., preferably n-pentyl.

n-hexyl, 2-dimethyl-1-hexyl.

2-methyl-2-hexyl and the like can be mentioned. Substituted C1-C, alkyl groups [, may be linear or branched, for example, methyl, ethyl un
7' lopil, is.

-furovir, n-butyl, t-butyl, t-butyl, n-pentyl and the like. These substituted alkyl groups include phenyl group: phenoxy group; methoxy, ethoxy+n-furboxy+1so-p-boxy, n-gutoxy.

1ao-butoxy, t-butoxy, n-pentoxy, n
- C9 to C such as hexoxy, a flukoxy group, q to C such as di'clopentyl, cyclohexyl, and a cycloalkyl group.

These substituents may be further substituted with the substituents listed above by 1° C. with the substituents of the substituted phenyl group in the R modification.

Examples of the substituted C, to Cs alkyl group include, for example, a C1 to Ct alkyl group substituted by a phenoxy group or a phenyl group, which may be substituted with a fluorine atom, a chlorine atom, a methyl, ethyl or trifluoromethyl group, or propoxymethyl, ethoxyethyl, propoxyethyl, gutoxymethyl, methoxybouvil, 2-ethoxy-1,1-dimethylethyl.

Preferred are propoxydimethylmethyl, cyclohexylmethyl, cyclohexylethyl, Schiff-hexyldimethylmethyl, 2-cyclohexyl-1,1-dimethylethyl, and the like.

As the substituted or unsubstituted alicyclic group, the same ones listed for R@ can be mentioned.

Examples of R include n-pentyl, 2-methyl-! -Hexyl, cyclopentyl or Schiff-hexyl groups are particularly preferred 1
．． stomach.

R1 and R4 are the same or different and are a group that forms a 7-cetal bond with the oxygen atom of a Q-C17 syl group, )'J (C1-C1) hydrocarbon-silyl group, or hydroxyl group.

Examples of the C1-C,7 sil group include acetyl, propionyl, n-butyryl + 180-butyryl, n-
Valeryl e 1so-valeryl, caproyl, enantyl, benzoyl and the like can be mentioned. Among these, C8-C6 aliphatic acyl groups such as 7 cetyl, n- or iso-butyryl, caproyl, or benzoyl are preferred.

As the tri(CI-C,) hydrocarbon-silyl group, R@
The same things as those mentioned above can be mentioned.

An example of a group that forms a 7-cetal bond with the oxygen atom of a hydroxyl group is methoxymethyl.

l-ethoxyethyl, 2-methoxy-2-propyl, 2
-ethoxy-2-furovir, (2-methoxyethoxy)
Methyl, benzyloxymethyl, 2-tetrahydropyranyl, 2-teYrahydrofuranyl, 4-(4-methoxy-tetrahydropyranyl) group or 6,6-dimethyl-3
-oxa-2-oxo-bicyclo(3,1,0)hex-4-yl group may be mentioned. Of these, 2
-tetrahydropyranyl, 2-tetrahydrofuranyl,
1-ethoxyethyl, 2-methoxy-2-propyl, (
2-methoxyethoxy)methyl, 4-(4-methoxytetrahydropyranyl) group or 6,6-dimethyl-3-oxa-2-oxo-bicyclo(3,1,0)hex-4
-yl group is particularly preferred.

These silyl groups, 7-syl groups, and 7-cetal bond-forming groups are to be understood as hydroxyl-protecting groups.

Among these σ groups, t-butyldimethylsilyl group, 2-tetrahydropyranyl group, and acetyl group are preferable as Rs or W.

9- shown by 2■ as above used as a raw material compound
Deoxy-9-methylene 5,6-zohydroprostaglandin E, etc. can be easily produced from purustabrangin &, by a method known per se (see Gorton et al., JP-A-53-135957). Alternatively, avian prostaglandin can be used as a zinc-methylene bromide-titanium tetrachloride mixed reaction agent [ρ
Lombardo et al., Tetrahedron.
Letters (TotrahedronLstt,), 2
3,4293 (1982): Nozaki et al., Tetrahet 97
-Letters (Tatrahedron Lett, )
+2417 (1978)] in high yields.

9-deoxy-9-methylene-5 shown by the above symbol,
6-zohydropstaglandin E2 was subjected to hydroporation reaction with monoalkylborane in an inert organic medium, followed by sequential oxidation and iodination reaction I2.
Then, the desired carbacyclines (2) are produced by subjecting them to a deprotection reaction or a hydrolysis reaction, if necessary. The inert organic medium used in the hydroporation reaction is preferably an aprotic organic medium, such as an ether type organic medium such as egur ether, isopyl ether, tetrahydrofuran, dioxane, or dimethoxyethane. The hydroporation reaction is carried out with a monoalkylborane represented by the above formula.

R- is a C6 alkyl group, such as C, H, (sexyl group), cyclohexyl group, etc., and the sexyl group is most preferably used. The amount of monoalkylborane used is equimolar based on the technical stoichiometry with respect to the raw material of the formula (1) above, but when the reaction is actually carried out, it is 0.5 molar.
5 to 2 times the mole, preferably 0.8 to 1.5 times the mole.

The reaction is carried out at -100°C to 50°C, and when monofurkylporane is added, the temperature is lowered to -100°C to 0°C, preferably -90°C.
It was carried out at ~-20℃, and then the reaction temperature was around room temperature (10
℃~25℃) K is recommended. An oxidizing agent is then added to the reaction solution. As the oxidizing agent, there are trimethylamine oxide and aqueous hydrogen peroxide, of which trimethylamine oxide is particularly preferred, and the amount used is preferably 0.68 to 1.2 times the mole of the monoalkylborane used.

The reaction temperature is -10°C to 10°C, and the reaction time is usually 1 to 5 hours. Subsequently, the reaction solution is treated with iodine in the presence of an alkali.

Before treatment with iodine, an alkali such as an aqueous sodium hydroxide solution is added to the reaction solution. For example, sodium hydroxide is added in a molar amount of 1.6 to 5 times, preferably 2 to 3 times, relative to the monoalkylborane used. The t of the iodine used is 0.8 to 1.2 times the mole of the monoalkylborane used, preferably 1.
It is 0 times the mole. The reaction is usually completed in 1 to 5 hours.

After the reaction, the reaction solution is post-treated by a known method [Zwaifel et al., Journal Op.
The American Chemical Society (J.

Amer, Chem, Soc, )+90.6
243 (1968)].

The crude product is optionally subjected to column chromatography,
Purification can be carried out by means of purification such as thin-layer μmography, liquid chromatography, column chromatography, preferably in a basic atmosphere using triethylamine. The product thus obtained can be further subjected to a deprotection reaction or a hydrolysis reaction, if necessary.

When the protecting group of the hydroxyl group is a group that forms a 7-cetal bond with the oxygen atom of the hydroxyl group, for example, acetic acid, a pyridinium salt of p-)luenesulfonic acid, or a cation exchange resin is used as a catalyst to remove the protecting group of the hydroxyl group. The reaction is preferably carried out using, for example, water, tetrahydrofuran, ethyl ether, dioxane, acetone, acetonitrile, or the like as a reaction solvent. The reaction is normally carried out at a temperature range of -78°C to +30°C for about 10 minutes to 3 days.

Protecting groups)! In the case of J (C, ~C,) hydrocarbon-silyl group, for example, acetic acid, tetrabutylammonium fluoride, cesium fluoride, etc., preferably the latter 2
(more preferably in the presence of a basic compound such as triethylamine) in the presence of a reaction solvent as described above (preferably a reaction solvent other than water) at the same temperature and for a similar period of time. Implemented. When the protecting group is an acyl group, for example, caustic soda.

Aqueous solutions of caustic potash and calcium hydroxide are also 1. <> can be carried out by hydrolysis in a water-alcohol mixed solution, or a methanol or ethanol solution containing sodium methoxide, potassium methoxide, or sodium ethoxide. Alternatively, it can be carried out by using a hydrolytic enzyme such as lipase.

The hydrolysis reaction of the ester group of the carboxyl group is the same as the deprotection conditions of the acyl group.

The product after the deprotection reaction or the hydrolysis reaction can be purified by the same purification means as described above.

014. □ゎ□－Aww cuff. , 4K, and Nilin can be easily and efficiently produced.

. Specific examples of carbacyclines produced according to the present invention include the following.

(17 carbacycline + 21 16.17.18.19.20-pentanol-15-cyclopentylcarbacycline + 3) 16
．． 17.18,19.20-pentanol-15-Schiff-
Hexylcarbacycline (4) 17.20-Dimethylcarbacycline (5115-Methylcarbacycline (61(1+-(5) methyl ester (7) (I
Ethyl ester of I~(δ) +8+ +61 11.
The 11th position of 15-bis-t-butyldimethylsilyl ether +91 +6) is a methoxyisopropyl group.

A compound in which the 15th position is protected with a t-butyldimethylsilyl group; the 11th position of (6) is a t-butyldiphenylsilyl group;
Compound all in which the 15th position is protected with a t-butyldimethylsilyl group (61, the 11th position is protected with a 4-(4-methoxytetra□hydropyranyl) group, and the 15th position is protected with a t-butyldimethylsilyl group υ (6 ), the 11th position is dimethyl (2,4,6-) sorted
-butylphenyloxy)silyl group.

The 15th position is held by a t-butyldimethylsilyl group.

protected compound.

[The method of the present invention is characterized in that the carbacycline skeleton can be easily introduced into the carbacycline skeleton using 9-deoxy-9-methine, which is an easily available starting material compound.

As described above, the method provided by the present invention provides a simple and efficient method for producing useful carbacycline drugs, and has great industrial significance.

aTs″″0″11″118″゛11 It is not limited to these.

Example 1 (SiR, Hoj(C mountain) t-t-QHe) Enyne body, mixture of Yama-Yu and (T)-mi (307,3Q
, 0.52 mmol) in dry THF solution (4-)
was cooled to -78°C. Here, a solution of thexylborane in tetrahydroborane (THF') (1.0 M) (0
, 68 ml, 0.68 mmol) (1,1
The temperature was raised to 5°C and stirred at that temperature for 1 hour. g) The solution was cooled again with O'CK and trimethylamine oxide (37,
8Q, 0.5 mmol) was added and stirred for 2.5 hours. 6N aqueous sodium hydroxide solution (0.4 m/.

2.4 mmol) followed by iodine (127.8 mmol)
0.5 mmol) of THF solution was added and stirred for 3 hours. A small amount of sodium thiosulfate aqueous solution and a saturated ammonium chloride aqueous solution were added to the reaction solution. Shake vigorously, separate into organic layer and aqueous layer, and extract the aqueous layer with pentane.1. (20 mj x 3). The organic layer was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (Msrck 7734102, hexane-ethyl acetate 40:1) to remove the five-membered ring cyclization product. An oily substance 77.4119 was obtained. This oily substance was fractionated by high performance liquid chromatography (ODS column, solvent methanol) and a mixture of 2° carbacyclines 3 and 4 was obtained.
10.3 .mu. of a mixture of 2Q and 5 and 6 were obtained. (3+4
Mixture yield of 11.1%, mixture yield of 5+6 3.3%
) 3+4 mixture TLCRf O,58 (3:1 hexane-ethyl acetate") 'a CNMR (CDC422
,5MH2n>a174.1(C=O)143.31
143.4 (C=CH-) 135.0 and 134
．． 3 (;C=l\/1 CM-0) 131.8 and 131.2 (CH=C-0
) Go to 120.4
To ^(20=CH)? 8.2 74.2 73.4 56.
7 56.351.4 (OCHj) 45.1
45.0 42.7 38.838.6 3B
, 5 38.2 36.2 36.0 33.
6 32.02B, 9 26, 1 25.2
25.0 22.7 18.4 18.214.
3 14.0 xane-ethyl acetate')' CNMR (CDC
．． 50Mmu-)6173.9 (C=O) 146.
9 to C=CH-)^ to 134.1 and 133.6 (CH=CH-0) 131
．． To 8 and 131.3^ (CH=CH-0) 121.3 (20=CH-)
84.484.3 73.9 73.6 55
．． 1 54.8 51.2 (OCR Hatake) 48.7
38.6 35.1 33.5 31.9
28.5 26.025.0 24JI 2
2.6 18.2 1B, 0 14.0 Example 2 Enyne body (dt -1+2'') (618,6 hits.

1.05 mmol) of dry THF solution (6-)
8: Cooled to ℃. Here, the THF solution of sexyl borane is added.
"Liquid (0.29M) (4.2td, 1.2
mmol) was added dropwise, the temperature was raised to 15°C, and the mixture was stirred at that temperature for 2 hours. Cool this □■ solution to 0℃ again and add trimethylamine solution.
Oxide (78.8 mg, 1.05 mmol) was added and stirred for 1 hour. 6N aqueous sodium hydroxide solution (0.7id, 4.2 mmol) followed by iodine
(266, IQ, 1.0 s'mmol)
A THF solution was added thereto, and the mixture was stirred for 14 hours. A small amount of sodium thiosulfate aqueous solution and a saturated ammonium chloride aqueous solution were added to the reaction solution. Shake, separate into organic layer and aqueous layer, and extract the aqueous layer with pentane (20 d
X3). Dry the organic layer over cold anhydrous sodium sulfate.
．． After that, the pressure was reduced to 1JI. The residue was chromatographed on silica gel (Marek 7734 20 f, hexane-ethyl acetate 50:1) to give an oily substance 210.81117 containing a 1.5-membered ring cyclization product. This σ oil was subjected to high performance liquid chromatography (column: ODS 10
/20, mobile phase: methanol, detection wavelength: 205
nm), fractionation 11, target object 3+4 (86, 2Q, 13.
9%> was obtained.

TLCR40,58 (3:1 hexane-ethyl acetate)' HNMR (CD0490 MHz, pPI)
δ0.1 (m, 12°S ICHs X 4)
1.6 2.8 (m, 12, CH, CO, CX2.C=C, CHX2.C) 3
．． 66 (S, 3°OCR,) 3.8-4.2 (m
, 2. CHO8iX2) 4.9-5.1 (m, 2
．． cHs) 5.4-5.5(m, 2.cH=cH
) IsCNMR (CDC MU 22.50 MIllz
%) δ173.7 (C=0) 150.2. (
c = cHt ) 136.3 and 135.7 (-
CH=CH-CHO8i) 130.4 and 130.3
(CI(=CHCHO8i) 107.1 (',
C=CH*) 79.7 and 79.4, 76.6 and 7
6.5 (C=C) 73.6+, Hif 3.0 (CHO
8i) 55.4 and 55.2 (CHOS 5-membered ring) 51.3 (QC) (,) 464 46.2
38.6 38.532.9 31.9 25.
9 25.0 24.9 24.4 22.6
21.8 18.3 18.0 14.0 Example 3 Carbacycline methyl ester 11.15-bis-t
-Butyldimethylsilyl ether (compound 3) 23
089 (0.39 mmol) in tetrahydrofuran (
4Wt) 1-, then tetrabutylammonium fluoride trihydrate (nBu, NF・3)LO) 5
00 "9 (1,6 mmol) was added. 16 at room temperature
After stirring for an hour, 20 - of saturated aqueous ammonium chloride solution was added and extracted with ethyl acetate (2 x 20d). The combined organic layers were washed with saturated brine (3x20-) and dried over magnesium sulfate to obtain 16089 crude product.

When this was purified by silica gel column coomadography, carbacycline methyl ester (compound?) 12
0111? (yield 85%).

CD”) 0.88 (3H, t, J=5Hz).

ONla (aTMS 3.3 (2H, br: disappeared at Dto).

3.4-3.8 (IH, br), 3.67 (3H
, S), 3.8-4.2 (IH.

br), 5.18 (IH,bt, J=-71
1z), 5.3-5.5 (2H,m) Example 4 Carbacycline methyl ester (compound 7) 1008
9 (0,276 mmol) was dissolved in methanol 1-, and 0.28 t of 2N aqueous sodium hydroxide solution was added thereto.
ri (0.56 mmol) was added and stirred at room temperature for 12 hours. After adding 10 - of water and making it acidic with dilute hydrochloric acid,
Extracted with ethyl acetate (2X 15 ml). The combined organic layers were washed with saturated brine (3×20−) and dried over magnesium sulfate to obtain a purified product of 98Q. When this was purified by silica gel column chromatography, n-hexane-ethyl acetate (3:2 to 2:8:
Carbacyclophosphorus (compound 5) ss+9 (yield: 93%) was obtained in the eluted portion (containing 0.251 acetic acid).

ONMR(δCDCl.

TMs) 0.88 (3H, t, J=5H2),
3.4'-3,8(IH,br), 3.8-
4.2 (I H, br), 5.0-5.2 (3H.

br 9 Disappeared with DtO) 5.19 (II (.

bt, J=7Hz) 5.3-5.5 (2H, m
) 'eat OIR(λ efn-') 3400+ 1710.1
090 °a
The rRt was placed in a 30-sized eggplant-shaped flannel, 10 g of dry methylene chloride was added, and the mixture was cooled to 0°C. Here, 7cetylene ketone bodies, a mixture (342.7my) of dry chloride ≦
The solution (5-) was added through a stainless steel tube under argon pressure.

Further, the container was washed with 5 drops of dry methyl chloride and added. The mixture was kept at 0°C and stirred for 1 hour. Dilute with hexane, add saturated aqueous sodium chloride solution, shake vigorously (-). Separate into organic and aqueous layers, wash organic layer with saturated aqueous sodium chloride solution, and then dry over anhydrous sulfuric acid.

This was concentrated under reduced pressure (silica gel chromatography (M
erck 7734101, hexane-ethyl acetate 25
: 1 190m) K-subjected enyne compound, 1+2 mixture.

330.419 was obtained as a pale yellow clear liquid. (Yield 9
6.6%)

Claims (1)

[Claims] 1. The following formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼……[I] [In the formula, the symbol ■ between the 13th and 14th positions is the same as the 13th and 14th positions. G is -CO_2R^5 or -CONR^6R^7, R^6 is an alkyl group of C_1 to C_1_0, substituted or unsubstituted phenyl group, substituted or unsubstituted alicyclic group, substituted or unsubstituted phenyl (C_1 to C_
2) Alkyl group or tri(C_1-C_7) hydrocarbon-
It is a silyl group, and R^6 and R^7 are the same or different alkyl groups of C_1 to C_1_0, or R^5 and R^7 together with the nitrogen atom to which they are bonded further contain a heteroatom. R^1 is a hydrogen atom, a methyl group, a vinyl group, or a protected ethynyl group; R^2 is an unsubstituted C_■ to C_ (2) Alkyl group, substituted or unsubstituted alicyclic group, or optionally substituted phenyl group or optionally substituted phenoxy group C_1~
C_6 alkoxy group or optionally substituted C
It is a substituted C_1 to C_■ alkyl group substituted with a _5 to C_8 cycloalkyl group; R^3 and R^4 are the same or different; C_2 to C_7 acyl group, tri(
C_1 to C_7) Hydrocarbon-A group that forms an acetal bond with the oxygen atom of a silyl group or a hydroxyl group. ] 9-deoxy-9-methylene 5,6-dehydroprostaglandin E_2 represented by the following formula [II] R^8BH_2......[II] [In the formula, R^8 is C_6H_1_5 represents the sexyl or cyclohexyl group. ] The compound of the following formula [III ] ▲There are mathematical formulas, chemical formulas, tables, etc.▼......[III] [In the formula, the symbols ■, R^1, and R^2 are the same as the above definitions. G^1 is the same as G or represents -COOH, R^
3^1 and R^4^1 are the same as R^3 and R^4, respectively, or represent a hydrogen atom. ] A method for producing carbacyclines represented by: 2. The method for producing carbacyclines according to claim 1, wherein the monoalkylborane is sexylborane. 3. The method for producing carbacyclines according to claim 1 or 2, wherein the oxidizing agent is trimethylamine oxide. 4. The method for producing carbacyclines according to any one of claims 1 to 3, wherein in the above formula [I], G is a methoxycarbonyl group. 5. In the above formula [I], R^2 is an n-pentyl group,
5. The method for producing carbacyclines according to any one of claims 1 to 4, which is a 2-methyl-1-hexyl group, a cyclohexyl group, or a cyclopentyl group. 6. In the above formula [I], R^3 and R^4 are the same or different, t-butyldimethylsilyl group, 2-tetrahydropyranyl group, acetyl group, 1-methoxy-1-methylethyl group, 4-(4 -methoxytetrahydropyranyl) group, 6,6-dimethyl-3-oxa-2-oxobicyclo[3,1,0]hex-4-yl group or dimethyl(
The method for producing carbacyclines according to any one of claims 1 to 5, wherein the carbacyclines are 2,4,6-tri-t-butylphenyloxy)silyl groups.