JP2002505321A - New manufacturing method - Google Patents

Abstract

  (57) [Summary] The present invention relates to a novel method for producing a prostaglandin compound useful as a drug.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] The present invention relates to a novel production method for producing a prostaglandin compound useful as a drug.

[0002] Prostaglandins (PGs) are a family of 20-carbon fatty acids found in virtually all mammalian cells and are biosynthesized from C-20 polyunsaturated fatty acids through the cyclooxygenase enzyme system (S. Bergström). , Scie
nce, 157, 382, 1967). For decades, synthetic chemistry has devoted a great deal of effort to PGs. Due to its therapeutic potential, there is increasing interest in PG analogs. The lack of a suitable natural source linked to potential drug utility has led to the clinical development of some synthetic PG analogs. Of particular interest, both pharmacologically and clinically, are analogs in which a methyl group has been introduced into C-1.5 of the prostaglandin skeleton [a). E. FIG. Yankee et al. A
mer. Chem. Soc. , 96, 5865, 1974, b). E. FIG. Yank
ee et al. Amer. Chem. Soc. , 94, 3561, 1972, c).
. E. FIG. Yankee et al. Amer. Chem. Soc. , 96, 5875,
1964, and references cited in these documents]. The fastest mode of metabolism (inactivation) of native PGs in humans has been shown to be the oxidation of allylic C-15 alcohols followed by a very rapid reduction of the 13-14 double bond. The enzyme that causes oxidation, 15-hydroxyprostaglandin dehydrogenase, has been isolated from various tissue specimens (B. Samuelson et al., Advanc).
. Biosci. , 9, 7, 1973).

Of particular interest is 15-methyl PGF ₂ α (carboprost, Upjohn). Carboprost has been clinically listed as an alternative to methylergomethrin for the treatment of postpartum bleeding, or as an alternative if methylergomethrin caused an inappropriate response. Intramuscular injection of 250 mg carboprost in sterile aqueous solution is the best therapy currently available,
It has been very successful when there is a preparation for hysterectomy due to bleeding that cannot be stopped by (methergin). Registrations for this indication have been made in Sweden and India (Prostinefem in Sweden and Prosofen in India).
din).

[0004] The development of a total synthetic pathway for carboprost is highly desired due to its promising clinical potential. Numerous methods for the synthesis of PGs have been reported (EJC
orey et al. Amer. Chem. Soc. , 90, 3245 and 3247
, 1968). However, known synthetic procedures often involve a multi-step linear synthesis approach, which has led to high costs and low overall yields of the final product. N
Oyori et al. describe a convergent three-component coupling method.
In this method, the entire carbon skeleton is stereoselectively collected by tandem alkylation of the appropriate optically active enone (R. Noyori et al., Angew. Chem. Int. .Edn. (Eng
. ), 23, 847, 1984 and references cited therein). Prostaglandin PGE ₂ has also been synthesized using solid-phase chemistry (S. Chen, IBC International Conference on Combinatorial Synthesis of Natural Products).
nce on Combinatorial synthesis of natural products), December 1997).

[0005] The most recent approach frequently used for the synthesis of PGs is the organometallic, α-substituted 4-
Including conjugate addition to hydroxy 2-cyclopentenone (MPL Caton
, “New Synthetic Routes to Prostagland
ins) ", Academic Press NY, pg 105, 1982 and F. Sato et al., J. Org. Chem., 59, 6153, 1994. This two-component method is two independent but complementary. The introduction of an o-side chain into an endo-enone having an α-side chain, and the introduction of an α-chain into an exo-enone having an o-side chain.

The present invention relates to an enantiomerically pure endo-enone (II) having an α-side chain
Wherein the desired o-chain is enantiomerically pure β-chain iodide (VI
) Was introduced by conjugate addition of a higher order cuprate generated using The process illustrated shows that the stabilized carbanion is alkylated and resolved using an ultrasonically mediated enzymatic irreversible transesterification technique followed by endo-enone (II) with excellent optical purity (> 99% ee). ) Is described. Herein we describe an enantiomerically pure β-chain alcohol (> 99
% Ee) and its conversion to component B of very high optical purity. The reported procedure for the two-component coupling method involves the use of higher order cuprates.
Including conjugate additions to optically pure enones, but often encounters incomplete additions. This means that unreacted starting enone has to be recovered by severe column chromatography separation. In the production process of the present invention, we BF ₃ - enone using a Lewis acid such as etherate activated at a temperature say -78 ° C., followed by performing conjugate addition of higher order cuprate, the enone It indicates that it will be completely consumed. This procedure also avoids losses during the chromatographic purification, as chromatographic purification of the coupled product can be avoided. Further work-up after coupling and purification of the product in the final step gives the carboprost methyl ester of the USP specification.

Therefore, in a first aspect of the present invention, formula (I):

[0008]

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Wherein R is CH ＝ CH or CH ₂ CH ₂ , R ¹ and R ² are all hydrogen,
Or together form a bond]. The production method is represented by the formula (II):

[0010]

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Wherein R is a protecting group as defined in formula (I), wherein the compound of formula (III):

[0012]

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Wherein P ¹ is a protecting group, M is a cuprate, and the compound of formula (IA):

[0014]

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Wherein P and P ¹ are as defined above, followed by, in any order: optionally reducing (IA) and removing any protecting groups.

R is suitably CH ＝ CH or CH ₂ CH ₂ , preferably R is CH ＝ CH. Suitably, R ¹ and R ² are both hydrogen or together form a bond such that the OR ¹ and R ² groups form a carbonyl group. Preferably, R ¹ and R ² are both hydrogen.

The P and P ¹ groups may be the same or different, but are any suitable oxygen protecting groups such as tetrahydropyran, especially silyl protecting groups such as t-butyldiphenylsilyl, dimethylphenylsilyl, triethylsilyl, It can be t-butyldimethylsilyl (TBDMS), trimethylsilyl (TMS) and triisopropylsilyl. Preferably, P is TBDMS and P ¹ is TMS.

The reaction of the compounds of the formulas (II) and (III) is carried out in a suitable solvent, for example THF-hexane, THF-ether, preferably THF / ether. Preferably, the reaction is performed at a low temperature, for example, at about -78 ° C. Preferably, the reaction in the presence of a Lewis acid, in particular in the presence of BF ₃ -OEt _2. The use of BF ₃ -OEt ₂ not only activates the enone at low temperatures to drive the reaction to completion, but also avoids the problem of dehydration at the C-15 position. The higher cuprate of formula (III) is preferably formed using an organolithium reagent, preferably butyllithium.

The reduction of the compound of the formula (IA) can be carried out using a known reducing agent. For example, the reduction of cyclopentanone is preferably performed using a selective reducing agent such as K-selectride to obtain the desired cyclopentanol isomer. Triple bond reduction can be performed using conventional techniques such as Lindlar hydrogenation.

Removal of protecting groups can be performed using conventional methods. For example, if the protecting groups P and P ¹ are both silyl groups, deprotection of both groups can be achieved by the use of TBA in a suitable solvent such as THF.
This can be achieved using a fluoride reagent such as F. Preferably, the cyclopentanone moiety is reduced, followed by deprotection of the P and P ¹ groups, followed by reduction of the triple bond to give the desired compound of formula (I).

The compound of formula (II) has the formula (IV):

[0022]

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Wherein P is a leaving group as defined in formula (II), from a compound of formula (V):

[0024]

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Wherein Hal is a halogen in the presence of an organolithium reagent.
Preferably, L is a group such as -SePh that stabilizes the resulting carbanion, and Hal is bromo or iodo, preferably iodo.

Compounds of formula (IV) wherein L is SePh can be prepared from the corresponding enone and phenylselenyl chloride using literature methods. Enones can be prepared by protection of the corresponding alcohols, for example by treatment with the conventional conditions of TBDMS chloride.

Compounds of formula (V) can be prepared by halogenation of the corresponding alcohol. The corresponding alcohol is prepared using known procedures as exemplified herein.

The compound of formula (III) is a suitable cuprate, especially a higher-order cuprate, preferably a thienyl cuprate, especially a compound of formula (IIIA):

[0029]

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The dilithium [3-methyl, 3- (trimethylsilyl) oxyoctyl} -2-
This is a thienyl cyanocuplate. This is in equation (VI):

[0031]

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Wherein Hal is a halogen, in particular iodine, P ¹ is prepared from the corresponding halide of a protecting group, preferably a TMS group as defined in formula (III). This compound can be prepared according to the procedures exemplified herein.

The novel intermediates form a further aspect of the present invention. The present invention is illustrated by the following examples. Intermediate 1 Synthesis of methyl 7-iodohept-5-inoate a) Methyl-7-hydroxyhept-5-inoate J. K. Taylor et al., Tetrahedron, 42,
5849-56 (1986), prepared as an oil. bp13
0 to 132 ° C (0.5 mmHg)

[0034]

(Equation 1)

B) Methyl 7-iodohepta-5-inoate The title compound was prepared from the above α-alcohol by the method of Carl Johnson et al., JAC.
Prepared as an oil according to the method of S, 110, 4726-35 (1988). bp 110-113 ° C (0.9 mmHg)

[0036]

(Equation 2)

Intermediate 2 Synthesis of Racemic 4-Hydroxycyclopentenone Minai, manufactured according to the method of JP-A-57-62236.

[0038]

(Equation 3)

Intermediate 3 Synthesis of 1-iodo (S) -methyl-3- (trimethylsilyloxy) -oct-2-ene a) Racemic 3-methyl-oct-1-yn-3-ol The round bottom flask was cooled under a stream of nitrogen gas and a mechanical stirrer was attached through the center port. The side arm was connected to a socket with gas inlet and a cooling finger condenser. Another side arm was connected to the nitrogen inlet under static pressure. A dry ice-acetone mixture (-78
C) and the reaction flask was kept in an adiabatic bath. Anhydrous ammonia gas (KO
(Dried through a wash bottle containing H pellets) at a constant rate under a nitrogen atmosphere through a gas inlet. Ammonia condenses as it enters the reaction flask. It took about 2 hours to condense the ammonia gas to obtain about 1.6 liters of liquid ammonia. At this stage, the ammonia condensation was stopped and a nitrogen inlet was connected to the location of the ammonia bubbler. The other side arm was plugged. The sodium metal was cut into small pieces and washed with anhydrous hexane. Upon addition of the first piece with mechanical stirring, the metal dissolved and the reaction mixture turned blue. As the blue color persisted, ferric nitrate was added through the side arm. As a result, the reaction became exothermic, and upon stirring, the blue color disappeared to give an off-white sodium amide. The addition of sodium metal was continued. As soon as the sodium metal is added, the appearance of a blue color is observed and, with continued stirring, an off-white color is observed. After completion of the metal addition (1 hour for completion of the sodium metal addition), the reaction mixture was
. Stirring for 5 hours ensured complete formation of the sodium amide. During the entire process, the static pressure of nitrogen gas and the temperature of -78 ° C in the cooling finger condenser were maintained. A gas inlet tube was inserted through one side arm and acetylene gas venting (acetylene was bubbled through a paraffin trap and an empty trap maintained at -78 ° C) was continued at a constant rate for 1.5 hours, and sodium acetylide was added. Was completely formed. The acetylene aeration was discontinued, and a dropping funnel of equal pressure was attached to one side arm of the reaction flask and charged with 2-heptanone (287 g, 2.511 mol) in anhydrous ether (75 ml). Next, the contents were added dropwise with stirring over 1 hour (exothermic reaction!). The addition funnel was rinsed with ether (40 ml) and the wash was added to the reaction flask. The contents of the reaction flask were vigorously stirred and acetylene gas ventilation was continued for an additional 3 hours and left overnight without stirring. The temperature in the cooling finger condenser was slowly raised to ambient temperature to promote the evaporation of ammonia gas.

Work-up: The mechanical stirrer and the cooling finger condenser are removed, the three-necked flask is cooled to 0 ° C. under nitrogen using an ice bath, to which NH ₄ Cl solution in water in small portions of 50 ml each. added. The reaction mixture was stirred at 0 ° C. for another 0.5 hour, warmed to room temperature and stirred at room temperature for 2 hours. The resulting solution was filtered over a celite bed using a G-3 sinter funnel. The residue was washed with petroleum ether (2 × 150 ml). The contents were transferred to a separatory funnel and the aqueous layer was separated. The aqueous layer was extracted with petroleum ether (3 × 50
0 ml). The combined PE portions were washed with water (2 × 500 ml), brine (100 ml) and dried over anhydrous Na ₂ SO ₄ . Removal of volatiles under vacuum resulted in 352
g of crude β-chain alcohol were obtained. This was further purified by vacuum distillation (17 m
(bp 76-78 ° C. at mHg), 330 g of β-chain alcohol were obtained (2.360).
Mols, 94% yield). Unreacted 2-heptanone was contained in the first fraction of the distillation (bp 67-69 ° C at 17 mmHg). It was recycled the next time racemic octinol was manufactured.

Yield of racemic β-chain alcohol: 330 g, 2.360 mols, 94%. Purity> 99% was confirmed by GC analysis: column: OV-101, 90 ° C., octinol RT: 5 min, heptanone: 2.5 min. b) 3-Methyl-3-carboxy-oct-1-yn-3-ol hydrogen phthalate i) Recrystallization of phthalic anhydride-representative procedure In a precooled 5 liter round bottom flask with a magnetic stir bar, 570 g of anhydrous Phthalic acid and 2.3 liters of chloroform were charged. The contents were refluxed on a water bath for 0.5 hour and filtered hot through a sinter funnel. The undissolved residue is phthalic acid. The filtrate was placed in a tightly stoppered flask and allowed to stand in the refrigerator to obtain crystalline phthalic anhydride. This was filtered, washed with hexane and dried in a desiccator. mp 130-131 ° C. ii) 3-Methyl-3-carboxy-oct-1-yn-3-ol hydrogen phthalate In a precooled 5 liter round bottom flask with a magnetic stir bar, add racemic octinol (
0.92 kg, 6.57 mol), phthalic anhydride (0.979 kg, 6.606)
mol), DMAP (0.08 kg, 0.658 mol) and triethylamine (0.67 kg, 6.617 mol). The reaction mixture was refluxed at 80 ° C. for 6 hours, cooled to room temperature and stirred overnight. The progress of the reaction was determined by TLC (solvent system: 2 in PE).
(0% EtOAc) was monitored for disappearance of the starting octinol.
The reaction mixture was left at room temperature overnight.

Post-treatment: In a 20 liter round bottom flask with flange and mechanical stirring assembly
Add 7.4 liters of water and 0.731 liters of concentrated HCl and use an ice bath at 0 ° C.
And cooled. The hemiphthalate reaction mixture was added to this mixture with stirring, followed by chloroform (2.3 liters). Stirring was continued for 1 hour. The organic layer was separated and the aqueous layer was extracted with chloroform (3 × 3 liter). The combined organic layers were washed with water (2 × 500 ml) and brine (500 ml). It was dried over anhydrous Na ₂ SO ₄ , volatiles were removed using a rotary evaporator and dried under high vacuum.

In another 20 liter round bottom flask with flange and mechanical stirring assembly, petroleum ether (5.5 liter) was taken and cooled to 0 ° C. The hemiphthalate from the previous step was poured into PE with stirring and stirred for 1 hour. Then, the desired hemiphthalate ester crystallizes. This was filtered using a Buchner funnel, and the residue was cooled with cold PE.
(500 ml) and dried by suction. The residue was air dried (mp61-mp61).
62 ° C, 0.915 kg). The mother liquor from the filtration was concentrated under vacuum using a rotary evaporator and stored in the refrigerator to give additional hemiphthalate ester (second yield, 0.1%).
43 kg, mp 61-62 ° C). However, the compound (0.151 kg) obtained by repeating the procedure for the third yield showed a high melting point and was excluded and used for the recovery of racemic octinol. Yield of hemiphthalate ester: 1.348 kg, 71% c) Brusinphthalate of 3-methyl-oct-1-yn-3-ol Precooled, flanged 20 liter round bottom flask with mechanical stirring assembly The hemiphthalate ester of racemic octanol (0.94 kg, 3
. 262 mol), brucine (1.432 kg, 3.327 mol) and anhydrous acetone (3.75 liters). The reaction mixture was heated at 50 ° C. for 1 hour, allowed to cool to room temperature and stirred at room temperature overnight.

Work-up: The precipitated solid was filtered off using a Buchner funnel and washed with cold acetone (2 × 250 ml) to remove unwanted diastereomeric contamination. The resulting solid was air dried.

Yield: 0.739 kg, 1.028 mols, 31.5%. mp158-15
9 ° C., [α] _D = -12.0 ° ± 0.5 (c 0.88, EtOH). The mother liquor was separated for brucine recovery. d) Hemiphthalate ester of (S) -octinol from brucine salt: (S)
-3-Methyl-3-carboxy-oct-1-yn-3-ol hydrogen phthalate In a pre-cooled, flanged 20 liter round bottom flask equipped with a mechanical stirring assembly, brucine salt (0.827 kg, 1.27 kg) was added. .15 mol) and ether (8.
2 liters). To this was added concentrated HCl (0.83 liter) in small portions at 0 ° C. with stirring. The reaction mixture was stirred at 0 ° C. for 2 hours and allowed to warm to room temperature.

Work-up: The contents were transferred to a separatory funnel and the ether layer was separated. The aqueous layer was extracted with ether (2 × 500 ml). The combined ether layers were washed with water (2 × 250 ml),
Washed with brine (250 ml) and dried over anhydrous Na ₂ SO ₄ . Removal of the volatiles under vacuum provided the desired hemiphthalate ester of (S) -octynol as a viscous material. The aqueous layer was discarded. Yield of hemiphthalate ester of (S) -octinol: 0.332 kg (almost quantitative). This was used for the next reaction without purification. e) (S) -3-Methyl-oct-1-yn-3-ol Hemiphthalate of (S) -octynol in pre-cooled, flanged 20 liter round bottom flask equipped with mechanical stirring assembly and reflux condenser Ester (0.3
32 kg, 1.151 mol) was added thereto, and a NaOH solution (0.504 kg in 3.6 liter water) was added thereto at room temperature. The reaction mixture was refluxed on a water bath for 2 hours. The reaction mixture was cooled to room temperature. Then, the octinol layer separates. The contents were transferred to a separatory funnel and the supernatant layer was separated. The aqueous layer was extracted with petroleum ether (3 × 500 ml
), And mixed with the octinol fraction. The combined organic portion was distilled water (3 x 500 ml
) And washed until the pH was 7. The organic portion was dried over anhydrous Na ₂ SO _4, the crude to remove volatiles (S) - Okuchinoru 155 g (96%) was obtained. This was further purified by vacuum distillation. bp 73-76 ° C (14-15 mmHg). yield:
128.87 g, 0.921 mols, 80%, [α] _D = −2.3 ° ± 0.5 (c2.7, EtOH). Reported [α] _D = -2.33 ° (c 2.625, EtOH). f) (S) -3-Methyl-3- (trimethylsilyl) oxy-oct-1-yne In a pre-cooled 1 liter round bottom flask with a magnetic stir bar, (S) -octinol (29 g, 0.207 mol) and DMF Was put. The reaction mixture was cooled to 0 ° C. under a nitrogen atmosphere (ice bath). To the reaction mixture was added imidazole (39.44 g, 0
. (58 mol) was added little by little (〜5 g) at 0 ° C., and the mixture was stirred for 15 minutes. TMS chloride (33.72 g, 0.310 mol) was added dropwise to the reaction mixture via syringe over 45 minutes, and then stirred at 0 ° C. for 1 hour. The reaction mixture was allowed to warm to room temperature and stirred at room temperature overnight. The progress of the reaction was monitored by TLC (solvent system: 10% EtOAc in petroleum ether) for disappearance of the starting alcohol.

Work-up: The reaction mixture was poured into ice water (750 ml) and extracted with ether.
The ether layer of the supernatant was separated and the aqueous layer was extracted with ether (3 × 250 ml).
The combined organic portions were washed with water (2 × 100 ml) and brine (50 ml). It was dried over anhydrous Na ₂ SO ₄ , the volatiles were removed using a rotary evaporator and dried under high vacuum. This was purified by distillation under reduced pressure to obtain the title product. bp 87-90 ° C (12-15 mmHg). Yield: 35.09 g, 165.5 mmols, 80%. g) (S) -3-Methyl-3- (trimethylsilyl) oxy-1- (n-tributylstannyl) -oct-1-ene (E) In a precooled 500 ml round bottom flask with a magnetic stir bar, (S) )-Octinol TMS ether (7.50 g, 35.37 mmol), TBTH (16.31
g, 35.4 mmol) and AIBN (0.4 g, 2.47 mmol). The reaction mixture was evacuated and flushed with nitrogen gas. Next, add 1 flask
Immersion in an oil bath preheated to 30 ° C. Then, a violent initiation reaction occurred while generating hydrogen gas (appropriate ventilation is desirable). 1 reaction mixture under nitrogen atmosphere
Heated in a 50 ° C. oil bath for 3 hours and cooled to room temperature. Petroleum ether (150 ml) was added to the reaction mixture and stirring was continued at room temperature for 15 minutes. The reaction mixture was filtered over a celite bed using a G-3 sinter funnel. The residue was washed with anhydrous PE (60 ml) and volatiles of the combined PE layers were removed to give the desired stannane derivative in quantitative yield.

Note: This derivative was stored in a tightly stoppered flask, covered with aluminum foil and stored under nitrogen. This derivative is highly hygroscopic and photosensitive! Large-scale manufacturing
Once the operating temperature has been reached, the reactants will be mixed and will then include the addition of AIBN. h) 1-Iodo (S) -3-methyl-3- (trimethylsilyloxy) -oct-2-ene In a precooled 500 ml round bottom flask with a magnetic stir bar, stannane derivative (61
. 06g, 0.121mol), and freshly distilled THF (170ml) was added thereto.
) Was added. The reaction mixture was cooled to −78 ° C. using a dry ice-acetone bath, to which N-iodosuccinimide (27.31 g,
0.121 mol) was added via cannula at -78 ° C under nitrogen over 45 minutes. The reaction mixture was stirred at -78 C for 1 hour. Gradually raise the temperature of the bath to room temperature,
Stir for 5 minutes. The progress of the reaction was monitored by TLC (solvent system: petroleum ether) for disappearance of starting materials.

Work-up: The reaction mixture was poured on ice and filtered over a celite bed using a G-3 sinter funnel. The filtrate was extracted with PE (4 × 100 ml). The combined PE layer was washed with water (100
ml), 10% sodium thiosulfate solution (150 ml), and finally water (50 ml)
And washed. The PE portion was dried over anhydrous Na ₂ SO ₄ and the volatiles were removed under vacuum to give the desired iodide (0.072 kg). This was purified by high vacuum distillation. bp 79-82 ° C (0.1 mmHg), 0.040 kg, 0.118 mols,
97%. [Α] _D = −24.0 ° ± 0.5 (c, 1.61: CHCl ₃ ): Reported [α] _D = −22.5 ° (c, 1.2: CHCl ₃ ). Intermediate 4 4-[(tert-butyldimethylsilyl) oxy] -2-cyclopentene-1
-On production Noyori et al., Tetr. Lett, 28, 4719-20 (1987)
) According to the method of 4-hydroxycyclopentanone (intermediate 2, 10.1 g,
0.103 mmol), 4-DMAP (1.21 g, 0.00993 mol) and triethylamine (11.46 g, 0.113 mmol).

Yield: 24.03 g (light brown). This material contained some colored impurities which were removed by distillation under reduced pressure. bp 82 to 86 ° C (1 mmH
g). Yield of desired product: 20.02 g, 0.158 mols, 91.7%.

[0051]

(Equation 4)

The purity of the material was verified by HPLC using a chiracel-OD column and 1.5% isopropan-2-ol in n-hexane. Intermediate 5 a) Preparation of racemic 4-[(t-butyldimethylsilyl) oxy] -2- (phenylseleno) -2-cyclopenten-1-one J. Toru et al. Org. Chem. , 57, 4719-20 (1992).
), The TBS-derivative 4-[(tert-butyldimethylsilyl)
Oxy] -2-cyclopenten-1-one (23.84 g, 0.112 mol)
And phenylselenyl chloride (32.32 g, 0.169 mol) and pyridine (14.69 g, 0.186 mol).

Yield: 37.14 g, 90%

[0054]

(Equation 5)

B) Methyl 7- (3-hydroxy-5-oxo-1 by the two-component coupling method
Preparation of -cyclopenten-1-yl) -5-heptinoate J. Toru et al. Org. Chem. , 57, 3145-3152 (19
92), the selenyl derivative 4-[(tert-butyldimethylsilyl) oxy] -2- (phenylseleno) -2-cyclopenten-1-one (16
. 65 g, 45.3 mmol), bis (tributylstannane) (28.94 g,
49.91 mmol), n-BuLi (35.6 ml of 1.4 M in hexane, 4
9.91 mmol), iodine (25.35 g, 95.28 mmol) and THF
Made from medium HMPA (26 ml).

The product was purified by silica gel chromatography, eluting with ethyl acetate / petroleum ether. Yield of pure product: 11.11 g, 31.76 mmols, 70
%.

[0057]

(Equation 6)

C) Methyl 7- (3-hydroxy-5-oxo-1-cyclopenten-1-yl) -5-heptinoate J. Corey et al., JACS. , 94, 6190-91 (1972), TBS derivative (6.02 g, 17.22 mmol), AcOH: T
Methyl-7-[(3-tert-butyldimethylsilyl) oxy] -5-oxo-1-cyclopenten-1-yl] -hept- in HF: water (3: 1: 1) solution.
Manufactured from 5-inoate.

Yield: 2.44 g, 10.33 mmols, 60%. TLC: solvent system: 70% EtOAc in petroleum ether.

[0060]

(Equation 7)

D) Enzymatic irreversible transesterification in sonicator bath with lipase in vinyl acetate. A. Babiak et al. Org. Chem. , 55, 3377-81 (
1990); Lin et al., Tetr. Lett. , 36, 6067-68 (
1995), the hydroxy-enone (4.7 g, 19.91 mmol).
1), methyl-7-[(3-hydroxy) -5-oxo-1-cyclopentene-
Prepared from 1-yl] -hept-5-inoate and PP and / or HP lipase (crude, 7.5 g) in vinyl acetate using sonication.

Yield of desired acetate: 2.40 g, 43%.

[0063]

(Equation 8)

E) Deacetylation using guanidine in methanol Preparation of a stock solution of guanidine in methanol: A. Babiak et al. Org. Chem. , 55, 3377-81 (
1990), guanidine carbonate (28.4 g, 0.158 mol).
Sodium metal (3.56 g, 0.15 g) in methanol (0.308 l)
5 mol). Methyl-7-[((R) -3-hydroxy) -5-oxo-1-cyclopenten-1-yl] -hept-5-inoate A. Babiak et al. Org. Chem. , 55, 3377-81 (
1990) according to the method of (R) acetate (1.905 g, 6.85 mmol).
1) and from guanidine in methanol.

Note: Due to the sensitivity of β-hydroxyketone, it is recommended to perform a small scale deacetylation before performing a large scale deacetylation. Yield: 1.130 g, 4.788 mmols, 70% yield (90 optical purity). This was used to further increase optical purity using PP lipase and / or HP lipase as described below.

Procedure: Similar to the previous enzymatic resolution using a sonicator bath. Concentration was completed in 5 days. The desired product is obtained by flash chromatography in 40% PE in PE.
Isolated in ５０50% EtOAc eluate. (R) Acetate yield: optical purity:> 99.9%. This was further deacetylated with guanidine in methanol to give 1.553 g of optically pure alcohol (5.586 mmols).
> 99.9% optically pure by chiral HPLC analysis. f) Mitsunobu inversion to convert unwanted enantiomer to desired enantiomer A. Babiak et al. Org. Chem. , 55, 3377-81 (
1990).

In a pre-cooled 250 ml flask equipped with a septum inlet and a magnetic stir bar, (S)
- alcohol (2.58 g, 88% optical purity 10.93 mmol), was placed Ph ₃ P (5.74g, 21.86mmol) and freshly distilled THF. The reaction mixture was cooled to 10 ° C., to which formic acid and then diisopropyl azodicarboxylate (DIAD, 4.42 g, 21.86 mmol) were added via syringe and slowly warmed to room temperature. The pale yellow reaction mixture was stirred at room temperature for 12 hours under a nitrogen gas atmosphere. The progress of the reaction was monitored by TLC (solvent system: 70% EtOAc in PE).

Work-up: The solvent is removed under pressure and vacuum using a rotary evaporator, the brown residue obtained is dissolved in ether (70 ml) and triturated with n-hexane (165 ml) to precipitate the phosphate. I let it. The mixture was stirred at room temperature for 30 minutes, filtered on a G-3 sinter funnel and washed with ether (2 × 50 ml). The combined organic portions were transferred to another round bottom flask and volatiles were removed under vacuum using a rotavapor. The obtained residue was dissolved in MeOH (120 ml) and added to alumina (activated, neutral, 100 mL).
g) was added and stirred at room temperature overnight. The progress of the reaction was determined by TLC (solvent system: 70% in PE).
EtOAc). The reaction mixture was filtered on a G-3 sinter funnel, the remaining alumina was washed repeatedly with MeOH (3 × 100 ml) and the combined filtrate was flash evaporated using a rotary evaporator to give 13.805 g of crude product I got This was further purified by flash chromatography on a silica gel column (400 g, 200-400 mesh). 15-60% EtOA in petroleum ether
Initial elution with a gradient of c provided the unwanted 1,2-diisopropyldicarboxyhydrazine, and the desired alcohol was obtained in 80-95% EtOAc in PE. HPLC analysis using a Chiracel-OD column showed a clean inversion at the chiral center (no racemization was observed) and gave the (R) isomer with an optical purity of 88%.

The product was further enzymatically transesterified with HPL in a sonicator to give the desired (R) -acetate with optical purity> 99%. Yield: 1.891 g
, 6.802 mmols, 70%. This was further deacetylated using guanidine in methanol to give the desired (R) -alcohol with optical purity> 99%. Yield: 1.166 g, 4.94 mmols, 73% yield. g) Methyl-7-[(R) -3-tert-butyldimethylsilyl) oxy]-
5-oxo-l-cyclopenten-l-yl] -hept-5-inoate septum into a precooled 250 ml round bottom flask equipped with a septum inlet and a magnetic stir bar.
TBDMS chloride (1.90 g, 12.64 mmol) and dichloromethane were taken. The solution was cooled to 0 ° C. using an ice bath and imidazole (1.60 g, 2
(3.66 mmol) was added in one portion, followed by DMF. The reaction mixture was stirred at 0 ° C. for 15 minutes. In a separate pre-cooled flask (3 ml) in anhydrous CH ₂ Cl ₂ (
The R) -enone alcohol (1.99 g, 8.4 mmol) was taken and transferred to the reaction flask using a cannula under nitrogen. The washing solution (1 ml) was transferred to a reaction flask and stirred at 0 ° C. for 2 hours. The reaction mixture was allowed to warm to room temperature and continued overnight (-10
H). The progress of the reaction was determined by TLC (solvent: petroleum ether: EtOAc, 3
: Monitored in 7).

Work-up: The reaction mixture was poured into ice water and extracted with dichloromethane (3 × 100 ml). The combined organic layers were washed with water (30ml) and brine. Organic part is anhydrous N
Dry over a ₂ SO ₄ and remove volatiles under vacuum to give 3.80 g of oil.
This was further purified by flash chromatography on a silica gel column (150 g, 200-400 mesh) in a 15-25% EtOAc in petroleum ether eluent. Yield of desired product: 2.90 g, 4.66 mmols, 70%.
TLC: solvent system: 70% EtOAc in petroleum ether.

[0071]

(Equation 9)

The purity of the material was verified by HPLC on a chiracel-OD column with 7% isopropan-2-ol in n-hexane. Example 1 a) 2-Thienyllithium Procedure: In a precooled 100 ml round bottom flask equipped with a septum inlet and a magnetic stir bar, freshly distilled THF (30 ml) and thiophene (1.59 ml, 20 mmol)
s) was taken. The reaction mixture was cooled to −60 ° C. (dry ice—CHCl ₃ bath), and n-BuLi (1.67 ml, 1.2 M in hexane) was added dropwise via syringe over 15 minutes. The reaction mixture was stirred at −60 ° C. for 1 hour to ensure that the metallization reaction was completed. The color of thienyl lithium in THF was pale yellow. b) Preparation of vinyl lithium Procedure: In a pre-cooled 100 ml round bottom flask equipped with a septum inlet and a magnetic stir bar, B-chain iodide TMS ether in 30 ml THF (freshly distilled, anhydrous)
(6.8 g, 20 mmol) and the contents were cooled to -78 ° C under nitrogen (dry ice-acetone bath). To this, n-BuLi (21 mmol, 17.5 ml)
) Was added dropwise with a syringe at -78 ° C over 30 minutes. The reaction mixture became cloudy with a pale yellow vinyl lithium precipitate, indicating completion of the reaction. Add the contents further at -78 ° C for 1
Stirred for hours. c) Two-component coupling method Procedure: In a pre-cooled 500 ml round bottom flask with septum inlet, Cu (I) C
N (20 mmol, 1.79 g) and a magnetic stir bar were charged. The flask was capped with a rubber septum and heated with a heat gun under high vacuum to remove all traces of water. It was cooled and purged with nitrogen. THF (30 ml) was added and the suspension was cooled to −22 ° C. under nitrogen (dry ice-CCl ₄ bath). To this, preformed 2-thienyllithium (step a) was added dropwise via cannula over 10 minutes.
The contents were washed with THF (5 ml) and added to the flask. The solution then became homogeneous (pale yellow) and the desired lower order cuprate was obtained. The reaction mixture was further stirred at −22 ° C. for 1 hour.

A vinyl lithium solution (step b) was added to the above solution in the lower cuprate at −22 ° C.
Is added dropwise with a cannula over 10 minutes, washed with THF (5 ml) and the solution is
Stirring was further performed at 22 ° C. for 1 hour to obtain a uniform high-order cuprate (clear solution, pale yellowish orange). The obtained cuprate solution was cooled to -78 ° C (dry ice-acetone bath).

In a precooled 100 ml pear-shaped flask, (R) -enone TBDMS ether (
Optical purity> 99%, 3.5 g, 10 mmols) was taken and added to anhydrous ether (
40 ml) was added via syringe. Contents are 1 using dry ice-acetone bath.
Cooled to -78 ° C for 0 minutes. BF ₃ : OEt ₂ (1.29 ml, 10.5
mmols) was added dropwise with a syringe with stirring at -78 ° C and left at this temperature for 5 minutes. This solution was then added dropwise via cannula to the higher order cuprate solution (obtained in step c) at −78 ° C. under nitrogen over 45 minutes (very slow dropwise addition!). The Enone flask was washed with ether (5 ml) and the wash transferred to the reaction flask over 45 minutes. Stirring was continued at −78 ° C. for 1.5 h (reaction progress was monitored by TLC for disappearance of starting enone; solvent system: petroleum ether—10% EtOAc). The reaction mixture was washed with a saturated aqueous ammonium chloride solution (2
Quenched at −78 ° C. and warmed to room temperature. 150 ml of the reaction mixture
Of distilled water and 300 ml of ether mixture. The aqueous layer was extracted with ether (3 × 100 ml), and the combined organic portions were washed with brine and dried over anhydrous Na ₂ SO ₄ . Removal of volatiles under vacuum gave an oil (11.35 g). This product was used directly in the next step without chromatographic purification. TLC
: Solvent system: Petroleum ether-10% EtOAc. A portion of the sample was purified by flash chromatography (silica gel, 1:20 ratio, 200-400 mesh) to give the desired product in a 20% EtOAc in PE eluent for characterization. _Rf 0.31, solvent system: petroleum ether-10% EtOAc.

[0075]

(Equation 10)

Example 2 (5,6-didehydro-11-O- (tert-butyldimethylsilyl) -15
-O- (trimethylsilyl-13- (S) -methyl-PGE ₂ methyl ester Procedure: Flame dried, 250 ml round bottom flask with septum inlet and magnetic stir bar, crude TCC product in THF (anhydrous, 35 ml) [5,6-didehydro-
11-O-tert-butyldimethylsilyl) -15-O- (trimethylsilyl) -13- (S) - it was added methyl -PGE ₂ methyl ester] (11.35 g, from enone 10 m mol). The solution was cooled to −78 ° C. and treated with a K-selectride solution (32.85 ml, 30 mmol, 0.9M solution in THF) dropwise via syringe. The reaction mixture was allowed to stir at −78 ° C. for 1.5 h, to which was added a 30% aqueous solution of H ₂ O ₂ (4.54 ml, 40 mmol) dropwise. Stirring was continued for a further 15 minutes, the cooling bath was removed and the reaction mixture was allowed to warm to room temperature. Water (20
ml) was added and the organic phase was separated. The aqueous phase was extracted with EtOAc (3 × 50 m
l). The combined organic layers were washed with brine (2 × 20 ml) and dried over anhydrous Na ₂ SO ₄ . The solvent was removed under vacuum to give 13.516 g of the desired crude product. This was used as is for the next desilylation. TLC solvent system: 20% EtOAc in PE
, R _f 0.2.

A small amount of the reduced product of the selectlide obtained in the previous step was applied to silica gel (60 g
, 200-400 mesh). The desired product was obtained in petroleum ether-30% EtOAc eluent. R _f 0. 2 (solvent system: petroleum ether-20% EtOAc).

[0078]

[Equation 11]

Procedure: Pre-cooled 250 ml round bottom flask with septum inlet and magnetic stir bar
Then, the crude selectride reduction product (13.52 g) and THF (anhydrous, 35 ml) were added.
added. The solution was cooled to 0 ° C, and tetra-n-butylammonium fluoride was added thereto.
Solution (30 mmols, 30 ml of 1 M solution, 3 equivalents in THF) over 5 minutes
And added dropwise with a syringe. Stirring is by TLC analysis (solvent system: EtOAc)
The reaction was continued for 0.5 hours at 0 ° C. and 5 hours at room temperature until completion of the reaction. Remove THF under vacuum
Water (20 ml) was added and extracted with EtOAc (3 × 30 ml). Combined
The EtOAc layer was washed with water (2 × 10 ml), brine (2 × 10 ml) and dried over anhydrous Na _Two SO_FourDry on top. Concentration under vacuum gave 5.409 g of crude product
Was. This was filtered on a silica gel (350 g, 200-400 mesh) column.
Further purification by lash chromatography. Desired product is EtOAc
Obtained as a pale brown oil (1.94 g, 5.10 mmols) in the eluate.
51% yield based on the starting material (R) enone. Rf0.5 (EtOAc-based EtOAc
). This was dissolved in anhydrous ethyl acetate (50 ml), and 0.400 g of activated carbon was added thereto.
Was added and stirred at room temperature for 1 hour under a nitrogen atmosphere. Use a G-4 sintered funnel for this solution.
And filtered over a bed of celite and washed with EtOAc (30 ml). Volatile under vacuum
Removal of the residue gave 1.95 g of crude product. This is silica gel (150 g, 2
Purification by flash chromatography on a column of 100-400 mesh)
The desired product was obtained as a colorless viscous oil in the ethyl acetate eluate. This is -2
Solidified to a colorless solid upon storage at 2 ° C (chloroform-methanol gradient system)
Can also be used for flash chromatography purification). Yield: 1.90 g, 5 m
mols, 50%.

[0080]

(Equation 12)

Note: The desilylation reaction requires the use of anhydrous TBAF in THF. TBAF
When 3H ₂ O is used, the desired product cannot be obtained in high yield. Carboprost methyl ester, (15S) -15-methyl PGF2α methyl ester or Prosta-5,13-diene-1-oic methyl ester, 9,11,15-trihydroxy-15-methyl by IUPAC name described in USP -(5
Z, 9α, 11α, 13E, 15S) or (Z) -7- [1R, 2R, 3R, 5
S) -3,5-Dihydroxy-2-[(E)-(3S) -3-hydroxy-3-
Preparation of Methyl-1-octenyl] cyclopentyl] -5-heptanoic methyl ester Selective Lindlar hydrogenation was performed in batches of 0.500 g to a 1 g scale. The following procedure is a representative example.

To a pre-cooled 1000 ml two-necked round bottom flask, add the desilylated product (1.065
g, 2.80 mmols) into which benzene (100 ml) was preformed.
) And cyclohexane (300 ml) were cannulated under nitrogen. 0.315 g of Pd on CaCO _{3 with} lead was added to the reaction mixture under nitrogen. The reaction mixture was evacuated and flushed with hydrogen gas, and hydrogen gas was bubbled through the reaction mixture at a rate of 45 bubbles / min for 90 minutes with stirring. Aliquots were removed at regular intervals and the progress of the reaction was monitored by ¹³ C NMR analysis (about 15 h, ¹³ C NMR analysis should show a total disappearance of δ80 ppm alkynyl carbon). The reaction mixture was filtered using a G-4 sinter funnel and the residue was washed with EtOAc. (The recovered catalyst can be recycled). Concentration of the organic phase under vacuum provided the desired carboprost methyl ester as a colorless viscous oil (1 g). This was further purified by chromatography on silica gel in an EtOAc eluent (a chloroform-methanol gradient system can also be used for flash chromatography purification).

[0083]

(Equation 13)

The product was collected on a preparative ODS (C-18) SHIMPAK column (20 × 250
mm) and a mobile phase of acetonitrile-water (1: 1) was further purified by preparative reverse phase HPLC. UV detection: 210 nm. Preparative HPLC was performed in batches of 0.170 g each, and the recovery of pure carboprost methyl ester from USP was ~ 65%.

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY , CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP , KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW

Claims (9)

[Claims] (1) Formula (I): Wherein R is CH = CH or CH ₂ CH ₂ , R ¹ and R ² are all hydrogen,
Or together form a bond], wherein the method comprises the steps of:
Formula (II): [Wherein R is a protecting group as defined in formula (I)] and a compound of formula (III): Wherein P ¹ is a protecting group, M is a cuprate, and the compound of formula (IA): Wherein P and P ¹ are as defined above, followed by, in any order, optionally reducing (IA) and removing any protecting groups. 2. The method according to claim 1, wherein R is CH = CH. 3. The method according to claim ^1, wherein R ¹ and R ² are both hydrogen. 4. The method according to claim 1, wherein P is TBDMS and P ¹ is TMS. 5. The process according to claim 1, wherein the hydrogenation of the triple bond of the compound of the formula (IA) is carried out using Lindlar hydrogenation. 6. The process according to claim 1, wherein the reduction of the compound of formula (IA) with cyclopentanone is carried out using K-selectride. 7. A compound of the formula (I) produced according to the process of claim 1. 8. A compound of the formula (IA): Wherein P, P ¹ and R are as defined in claim 1. 9. The compound according to claim 8, wherein R is CHＣＨCH, P is TBDMS, and P ¹ is TMS.