JPH0466239B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for preparing carbacycline intermediates. More details: 9(0)-Metano-△ ⁶ (9α)
-Regarding a new method for producing bicyclo[3.3.0]octene, which is a key synthetic intermediate of prostaglandin _I1 .

Carbacycline is a stable compound of prostaglandin I ₂ and is a very useful compound as an antithrombotic agent. In recent years, it has been discovered that 9(0)-methano-△ ⁶ (9α)-prostaglandin I ₁ , a type of carbacycline, is the compound that exhibits the strongest platelet inhibitory effect among its congeners, and it is being used as a drug. Applications are expected (S, Ikegami et al.
Tetrahedron hett., 33, 3493, 3497 (1983)).

Conventionally, two methods by Ikegami et al. have been known for producing 9(0)-methano-Δ ⁶ (9α)-prostaglandin I ₁ . The key intermediate is the following formula (7) or (8) Epoxides or enones were proposed as represented by

On the other hand, as a recently new key intermediate, the following formula (3) [Definitions of R ¹ , R ² , and R ³ are the same as above. ] A bicyclo[3.3.0]octene body was proposed.

(Ikegami et al., Abstracts of the 104th Annual Meeting of the Pharmaceutical Society of Japan 30H-3
(1984) and Shibasaki et al., Chemistry Letters, 579
(1984), Tetrahedron Lett., 25 , 1067 (1984)
reference).

Although the former key intermediate has a unique structure, its synthesis method is difficult to describe as an industrial method as it is synthesized in multiple steps from easily obtained starting materials. . In addition, the latter key intermediate allows chemical modification of the ω chain and is suitable for the synthesis of various derivatives.The method for its production is as follows: (i) introducing the α chain from Corey lactone through the Wittig reaction, followed by the intermediate (7 (ii) After introducing two methylene groups by Corey lactone Wittig reaction, a diene form is obtained via a diol form and a dialdehyde form, and this is selectively reduced. How to obtain (iii) from corylactone
Formyl-
There is a method of obtaining this as an enone by an intramolecular thermoene reaction (see the above reference). However, all of these methods require a multi-step process to obtain the key intermediate (3), and the overall yield is not high, so they are not necessarily advantageous.

The present inventors focused on this point, and advantageously produced bicyclo[3.3.0]octene, which is a useful key intermediate of 9(0)-methano- ^Δ6 (9α)-prostaglandin I class ₁ . As a result of research to find a method, the intermediate was obtained by a method completely different from conventional methods, using a diol compound that can be easily obtained in high yield from Corey lactone by reduction, mesylation, substitution, and hydrolysis as a starting material. This was particularly successful and led to the present invention.

That is, the method of the present invention is based on the following formula (6) [In the formula, R ¹ represents a group that forms an acetal bond with the oxygen atom of the hydroxyl group, and R ² represents tri(C ₁
~ _C7 ) represents a hydrocarbon silyl group. ] After methanesulfonylating the diol represented by methyl methylsulfinyl-methyl
The carbanion of sulfide (FAMSO) is reacted and subjected to a ring reaction to form the following formula (4). [In the formula, the definitions of R ¹ and R ² are the same as above] and this is the ketone body represented by the following formula (5). [In the formula, R ³ represents a C ₁ to C ₁₀ alkyl group or a tri(C ₁ to _{C 7} ) hydrocarbon silyl group. ] Condensed with an aldehyde compound represented by the following formula (1) [In the formula, the definitions of R ¹ , R ² , and R ³ are the same as above. ] Obtain the enone body represented by the following formula (2) by reducing the enone functional group of the enone body. [In the formula, the definitions of R ¹ , R ² , and R ³ are the same as above. ] The following formula (3) is characterized in that it is an alcohol represented by, and water molecules are selectively eliminated from it as a result. [In the formula, the definitions of R ¹ , R ² , and R ³ are the same as above. ] This is a method for producing bicyclo[3.3.0]octene, which is a carbacycline key intermediate represented by

The diol compound, which is a raw material represented by the above formula (6) used in the method of the present invention, is easily prepared in high yield from Corey lactone.

In other words, the following formula (9) [In the formula, the definitions of R ¹ and R ² are the same as above] Corey lactone (9) represented by the following is reduced with lithium aluminum hydride, the resulting diol is mesylated with methanesulfonyl chloride, and then treated with cesium acetate. After the treatment, the diacetate formed is hydrolyzed to prepare the diol of formula (6) at a total yield of about 80%. (This is shown as a reference example described later.) In the above formula (6), R ¹ represents a group that forms an acetal bond with the oxygen atom of a hydroxyl group, such as methoxymethyl, 1-ethoxyethyl, 2-methoxyethyl, 2-propyl, 2-ethoxy-2-propyl, (2-methoxyethoxy)methyl, benzyloxymethyl, 2-tetrahydropyranyl, 2
-tetrahydrofuranyl, 6,6-dimethyl-3
-oxa-2-oxo-bicyclo[3,1,0]
Examples include hex-4-yl group. Among these, R ¹ is preferably a 2-tetrahydropyranyl group, a 1-ethoxyethyl group, or a 2-methoxy-2-propyl group.

^R2 represents a tri( _C1 - _C7 ) hydrocarbon-silyl group, and examples of the tri( _C1 - _C7 ) hydrocarbon-silyl group include trimethylsilyl, triethylsilyl, and t-butyldimethylsilyl groups. (C ₁ -C ₄ )alkylsilyl group; Diphenyl (C ₁ -C ₄ )alkylsilyl group such as t-butyldiphenylsilyl group, tribenzylsilyl group, etc. can be mentioned. Among these, R ² is preferably a t-butyldiphenylsilyl group or a t-butyldimethylsilyl group.

The method of the present invention starts with methanesulfonylation of the hydroxyl group of the diol of formula (6) above. Methanesulfonylation is carried out by a method known per se, and the dimesylate product produced does not need to be purified.
It is reacted with the carbanion of FAMSO and subjected to the next step of reduction reaction. The reaction of FAMSO with a carbanion is carried out according to the method of Ogura et al. (see Katsuyuki Ogura et al., Journal of the Society of Organic Synthetic Chemistry, 32, 903 (1979)). That is, the amount of FAMSO used is 1 to 10 equivalents, preferably 3 to 6 equivalents, based on the raw material diol. Bases for FAMSO carbanion production include NaH, KH, KO ^t Bu,
There are CH ₃ Li, EtLi, n-BuLi, t-BnLi, etc.
Particularly preferably n-butyllithium is used,
0.5 to 5 equivalents, preferably 1 to 5 equivalents relative to FAMSO
It is used in 2 equivalents and used for carbanion production. The reaction is carried out in an ether type medium, and such ethers include diethyl ether, dioxane, tetrahydrofuran, etc., and tetrahydrofuran is preferably used. The reaction temperature for carbanion production is -10°C to 50°C, preferably 0°C to
Carbanion production is achieved at 30°C and reaction time is 30 minutes to 3 hours, and then crude dimesylate is added at -10°C to 10°C, preferably -5°C to 5°C, and reacted. The reaction is usually carried out at 5°C to 50°C.
Preferably, the reaction proceeds at a temperature of 10°C to 30°C, and the reaction time is determined by observing the disappearance of raw materials using thin layer chromatography or the like, but 1 hour to 30 hours is usually sufficient. After the reaction, when the reaction solution is treated by a conventional method, the following formula (10) is obtained. [In the formula, the definitions of R ¹ and R ² are the same as above. ] A crude cyclized product is obtained. This crude product is then dissolved without purification in a 5-25%, preferably 10-20%, solution of e.g. acetone, acetonitrile, THF, DME, dioxane, etc., at a temperature of -20°C to 35°C, preferably - After cooling to 10°C to 5°C, calcium carbonate and 1 to 20 equivalents, preferably 2 to 4 equivalents, preferably 2 to 4 equivalents, of N-
Bromosuccinimide is reacted in an amount of 1 to 20 equivalents, preferably 2 to 4 equivalents, based on the product of formula (10). The reaction time is usually 30 minutes to 3 hours. After the reaction, add 1 to 2 volumes of saturated sodium thiosulfate to the reaction solution and treat according to a conventional method to obtain the above formula.
Ketone bodies (4) are obtained.

Next, the obtained ketone body (4) is subjected to a condensation reaction with an aldehyde compound represented by the above formula (5). The above formula
In (5), R ³ is a C ₁ to C ₁₀ alkyl group or tri(C ₁
~ _C7 ) represents a hydrocarbon silyl group, and examples of the _C1 to _C10 alkyl group include methyl, ethyl, n-
Propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl,
Linear or branched ones such as n-decyl can be mentioned. Among these, methyl group and ethyl group are preferred. The tri( _C1 - _C7 ) hydrocarbon silyl group is the same as ^R2 . The condensation reaction proceeds through a reaction between the lithium enolate of the ketone body (4) and the aldehyde compound (5). Lithium enolate of ketone body (4) was prepared by a conventional method (“Modern
Synthetic Reaction”WABenjamin
Jnc.1972PP-629~733) easily produced,
The aldehyde compound (5) is added to the enolate compound in an amount of 1 to 5 equivalents, preferably 2 to 5 equivalents, relative to the ketone compound (4).
-100°C to -40°C, preferably -90°C using 3 equivalents
Allow the reaction to occur between ℃ and -70℃. The reaction time is 10 to 1 hour, and when the reaction solution is treated by a conventional method, the following formula (11) is obtained. [In the formula, the definitions of R ¹ , R ² , and R ³ are the same as above] An adduct represented by the following is obtained, and this is mesylated,
By post-treatment with a base, the enone represented by the above formula (1) is obtained.

Next, the desired intermediate (3) is derived from the enone form (1). This conversion method can be easily achieved by a method known per se.

(S. Ikegami et al., Chem. Pharm, Bull., 31,
4448 (1983)) In other words, the enone is produced by reducing the olefin double bond by catalytic hydrogenation reaction on palladium carbon, and then by reducing L-selectride (lithium tri-sec).
-butylborohydride) to selectively reduce the remaining carbonyl group to obtain the alcohol represented by the above formula (2). This alcohol form is converted into a mesylate form using a methanesulfonyl chloride-base system, and then subjected to an elimination reaction to obtain the following formula:
(3) [In the formula, the definitions of R ¹ , R ² , and R ³ are the same as above] A desired bicyclo[3,3,0]octene compound, which is a carbacycline key intermediate, is produced.

The characteristics of the method of the present invention are (i) the use of a diol compound, which is a raw material easily obtained from cory lactone;

(ii) Use of inexpensive reagents for the conversion reaction.

(iii) The production method is via the above formula (4), which is a novel intermediate expected to induce a new carbacycline derivative.

(iv) Unlike conventional Wittig reagents, an aldehyde is used to introduce the α chain, which is easy to chemically modify.

It can be said that it has the following characteristics.

The method of the present invention and examples will be explained in more detail below.

Example 1 Conversion of diol (1) to ketone (2) Diol (1) ~ (651.3 mg, 1.31 mmol) was dissolved in distilled methylene chloride (7 ml), and under argon substitution, -
Chilled to 25°C. Add Et ₃ N (0.640ml,
4.59 mmol, 3.5 eq) and methanesulfonyl chloride (0.310 ml, 3.93 mmol, 3 eq) were added and stirred for 5 minutes. This reaction solution was diluted with ether, a small amount of saturated brine was added, and the mixture was stirred until the organic layer became transparent. This liquid was extracted with ether, and the organic layer was washed with a small amount of saturated aqueous sodium bicarbonate solution and saturated brine, and dried over magnesium sulfate and potassium carbonate.
After the solvent was distilled off, the obtained crude product was subjected to the next reaction without being purified. Namely, FAMSO (manufactured by Aldrich)
0.550ml, 5.24mmol, 4eq) distilled into THF (12ml)
and cooled to 0°C. To this liquid was added n-BuLi (2.91 ml, 3.93 mmol, 3 eq., 1.35 Msol manufactured by Mitsuwa) and stirred for 1 hour, and then stirred for 5 minutes at room temperature. The reaction solution was again cooled to 0°C, and a solution of the crude product from above in THF (7 ml) was slowly added. The reaction solution was stirred at room temperature overnight, diluted with ether, and a small amount of saturated ammonium chloride aqueous solution was added. Further extraction with ether was performed, and the organic layer was washed with saturated brine, added with sodium sulfate, stirred for 30 minutes, and dried. After evaporating the solvent, a crude product (0.95 g) was obtained.

The crude product (0.95g) obtained here was mixed with 15% aq.
It was dissolved in acetone (20ml) and cooled to -5°C. Add anhydrous CaCO ₃ (262mg, 2.62mmol, 2eq.) to this solution,
NBS (933 mg, 5.24 mmol, 4 eq.B) was added and stirred for 50 minutes. This solution was diluted with ether (40 ml),
Add saturated aqueous sodium thiosulfate solution (20ml),
Stirred. This liquid was extracted with ether, washed with a small amount of water and saturated brine, and then dried over magnesium sulfate. After evaporation of the solvent, the crude product was purified by silica gel (SiO ₂ ) column chromatography (ethyl acetate:hexane = 1:4) to obtain ketones (2) to (370
mg, 0.752 mmol) was obtained from diol (1) in a yield of 57.4%.

(2) ~ IR; 2925, 2850, 1735, 1420, 1110 NMR; 8.02 ~ 7.32 (m, 10H), 4.80 ~ 4.60 (m, 1H),
4.45-4.15 (m, 1H), 4.15-3.25 (m,) Example 2 Conversion of ketone (2) to enone (3) Diisopropylamine (0.211 ml, 1.50 mmol) was added to THF (3 ml), cooled to 0°C,
This was mixed with n-BuLi (Mitsuwa, 1.35M, 1.11
ml, 1.50 mmol) and stirred at the same temperature for about 10 minutes.
Adjusted LDA. This LDA solution was cooled to -78℃, and ketone (2) ~ (370 mg, 0.752 mmol) was added thereto.
A THF (5 ml) solution was added and stirred at the same temperature for about 1 hour. Add methyl 4-formylbutyrate (0.38 ml, 3 mmol) to the generated enolate solution in THF (3 ml).
The solution was added and stirring continued for 20 minutes at -78°C. After diluting the reaction solution with ether, an aqueous Sat.NH ₄ Cl solution was added, and extraction was performed with ether (~100 ml).
After washing the ether layer with Sat.NaCl water and drying with MgSO ₄ , the ether was distilled off to obtain a crude product. Without producing this, methylene chloride (6 ml)
The mixture was dissolved in water and cooled to -25°C, and while stirring, triethylamine (0.314 ml, 2.26 mmol) and mesyl chloride (0.118 ml, 1.50 mmol) were added and reacted at the same temperature for about 30 minutes. Next, DBU (0.338ml,
2.26 mmol) and gradually raised the temperature to room temperature.
Stirring was continued overnight at room temperature. This reaction solution was diluted with ether and water and worked up in a conventional manner to obtain crude enone (3). This was purified using silica gel column chromatography (ethyl acetate: n-hexane = 1:2) to obtain pure enones (3) to (190
mg, 41.8% from 2~) was obtained as a pale yellow oil.

(3)〜IR ν ^nea+ _nax cm ^-1 ; 2925, 2850, 1730, 1710, 1420, 1305,
1070, 700 ¹ H-NMR δ (CDCl ₃ ) ppm; 7.84-7.24 (m, 10H, aromatic), 6.66-
6.36 (m, 1H, olefinic), 4.68-4.48 (m,
1H, acetal), 4.36-3.95 (m), 3.68 (s,
3H, Me ester), 1.10 (brs, 21H, Methyl) MS m/e; 451 (M ⁺ −THP−CooMe), 446 (M ⁺ −
OTHP− ^t Bu), 385(M ⁺ −THP− ^t Bu−
CooMe−H ₂ O) Example 3 Conversion of enone (3) ~ to olefin (4) ~ Enone (3) ~ (220 mg, 0.364 mmol) was dissolved in dry methanol (4 ml), the atmosphere was replaced with argon, and 10% Pd/C (Engelhardt 60mg) was added. Next, the mixture was replaced with hydrogen using a hydrogen balloon, and stirring was continued at 0° C. for about 1 hour and at room temperature for about 40 hours. After diluting the reaction solution with CH ₂ Cl ₂ (~50 ml), Pd/C
The resulting filtrate was concentrated to give an almost pure ketone (181 mg) as a pale yellow oil.
Dissolve this in THF (4 ml), cool to -78℃,
L-selectride (manufactured by Aldrich, 1MTHF solution,
0.728 mmol) and continued stirring at the same temperature for about 1 hour. The reaction solution was post-treated in a conventional manner to obtain crude alcohol. Add crude alcohol to CH ₂ Cl ₂ (2 ml)
Pyridine (1 ml) and methanesulfonyl chloride (0.142 ml, 1.82 mmol) were added to the mixture at 0°C, and stirring was continued at the same temperature for 1 hour at room temperature overnight. The reaction solution was diluted with ether/H ₂ O and worked up according to a conventional method to obtain crude mesylate. This was then dissolved in toluene (1 ml) and DBU (0.5 ml) was added at room temperature.
was added and reacted under heating at 100°C for 1 hour. After cooling the reaction solution to room temperature, it was diluted with ether/H ₂ O.
After treatment according to a conventional method, crude olefin (4) was obtained. This was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:4), and pure olefin (4) (48.2 mg, 22.5%, from
3~) was obtained as a pale yellow oil.

(4) ~; IR ν ^nea+ _nax cm ^-1 ; 2925, 2850, 1735, 1420, 1110, 1070, 700 1 ^H −NMR δ (CDCl ₃ ) ppm; 7.80 ~ 7.12 (m, 10H, aromatie), 5.32 ~
5.08 (m, 1H, olefinic), 4.68~4.42 (m,
1H, acetal), 3.60 (s, 3H, Me ester),
1.00 (brs, 21H, Methyl), MS m/e; 533 (M ⁺ − ^t Bu) 371 (M ⁺ −THP− ^t Bu−CooMe−H ₂ O) Reference example 1 Conversion of Corey lactone (A) ~ to diol (B) ~ Dissolve lactone (A) ~ (840 mg, 1.70 mmol) in distilled ether (5 ml) and cool with ice under a stream of argon.
It was added to an ether solution of LiAlH ₄ (Merck, 161 mg, 4.25 mmol, 3 eq). After stirring at room temperature for about 30 minutes, the reaction solution was diluted with ether, and saturated brine (about 5 ml) was slowly added dropwise. This liquid was extracted with ether, the organic layer was dried over magnesium sulfate, and the solvent was distilled off to obtain a crude product (940 mg). This was purified by silica gel (SiO ₂ ) column chromatography (ethyl acetate:hexane = 3:1),
Diol (B) ~ (810.8 mg, 1.63 mmol) yield 95.9%
I got it.

(B) ~ IR; 3375, 2950, 2850, 1470, 1200, 1110 NMR; 7.80 ~ 7.24 (m, 10H), 1.08 (s, 9H), 4.70
~4.54 (m, 1H), 4.46 ~ 4.12 (m, 2H), 4.06
~3.30 (m,), 2.20 ~ 1.38 (m,) Reference example 2 Conversion of diol (B) ~ to acetate (C) ~ Diol (B) (3.41 g, 6.85 mmol) was dissolved in distilled methylene chloride (30 ml) under an argon atmosphere at -25
Cooled to ℃. Add triethylamimine (3.34ml, 23.97mmol, 3.5eq.) and methanesulfonyl chloride (1.61ml, 20.55mmol, 3eq.) to this solution,
Stir for approximately 5 minutes. The reaction solution was diluted with ether, a small amount of saturated brine was added, and the mixture was stirred at room temperature until the organic layer became transparent. This liquid was extracted with ether, and the organic layer was washed with a small amount of saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over magnesium sulfate and potassium carbonate. After evaporation of the solvent, crude mesylate (4.50
g) was obtained.

This crude mesylate (4.50 g) was dissolved in distilled benzene (40 ml), and under an argon atmosphere, 18-crown-6 (904 mg, 3.43 mmol, 0.5 eq. manufactured by Aldrich) and cesium acetate (4.22 g, 21.98 mmol, 3.2 eq.) were dissolved in distilled benzene (40 ml). )
was added and heated under reflux for about 1 hour. After that, after stirring at room temperature overnight, heating under reflux for 30 minutes, 18−Croun6
(452 mg, 1.72 mmol, 0.25 eq) and about 1
After heating under reflux for an hour, the reaction solution was cooled to room temperature. The reaction solution was diluted with ether and a small amount of saturated brine was added. After extraction with ether, sodium sulfate was added to the obtained organic layer, stirred at room temperature for 30 minutes, and dried. The crude product obtained after evaporation of the solvent was purified by silica gel (SiO ₂ ) column chromatography (ethyl acetate:hexane = 1:4) to obtain acetate (3) ~
(3.69 g, 6.34 mmol) was obtained in a yield of 92.6%.

(6) ~ IR; 2930, 2850, 1735, 1240, 1110, 1030 NMR; 7.76 ~ 7.20 (m, 9H), 3.96 ~ 3.20 (m, ), 5.12
~4.82 (m, 1H), 3.14~2.86 (m, ), 4.74~
4.44 (m, 1H), 2.38~1.20 (m, ), 4.44~4.04
(m,), 1.08 (s, 9H) Reference example 3 Conversion of acetate (C) ~ to diol (D) ~ Acetate (C) (310 mg, 0.533 mmol) was dissolved in distilled methanol (3 ml) and potassium carbonate (183.9 mg,
1.33 mmol, 2.5 eq.) was added and stirred overnight. The reaction solution was diluted with ether, and a small amount of saturated ammonium chloride aqueous solution was added. This liquid was extracted with ether, and the organic layer was washed with saturated brine and dried over magnesium sulfate. After distilling off the solvent, the obtained crude product was purified by silica gel (SiO ₂ ) column chromatography (ethyl acetate:hexane = 2:1) to obtain diol (4) ~ (250 mg, 0.502 mmol) in a yield of 94.2%. I got it.

(D) ~ IR: 3275, 2900, 2850, 1420, 1100 NMR; 7.82 ~ 7.20 (m, 9H), 2.00 ~ 1.40 (m, )
4.72~4.52 (m, 1H), 1.07 (s, 9H), 4.34~
4.06 (m, 1H), 4.04~3.46 (m, 3H)

Claims (1)

[Claims] 1. The following formula (1) [In the formula, R ¹ represents a group that forms an acetal bond with the oxygen atom of the hydroxyl group, and R ² represents tri(C ₁ ~
_C7 ) represents a hydrocarbon silyl group, and ^R3 represents a _C1 to _C10 alkyl group or a tri( _C1 to _C7 ) hydrocarbon silyl group. ] The following formula (2) is obtained by reducing the enone functional group of the enone body represented by [In the formula, the definitions of R ¹ , R ² , and R ³ are the same as above. ] The following formula (3) is characterized in that it is an alcohol represented by the formula (3) from which water molecules are selectively eliminated. [In the formula, the definitions of R ¹ , R ² , and R ³ are the same as above. ] A method for producing bicyclo[3.3.0]octene. 2 Bicyclo [3.3 .0] Production of octene bodies. 3. The method for producing a bicyclo[3.3.0]octene compound according to claim 1 or 2, wherein R ₁ is a tetrahydropyranyl group. 4 R ² is dimethyl-t-butylsilyl group or t
-A method for producing a bicyclo[3.3.0]octene compound according to any one of claims 1 to 3, which is a butyldiphenylsilyl group. 5. The method for producing a bicyclo[3.3.0]octene compound according to any one of claims 1 to 4, wherein R ³ is a methyl group or an ethyl group.