KR20010041632A - Novel Process - Google Patents

Abstract

The present invention relates to a novel process for preparing prostaglandin compounds useful as medicaments.

Description

New method {Novel Process}

The present invention relates to a novel process for preparing prostaglandin compounds useful as medicaments.

Prostaglandins (PGs) are a group of 20-carbon fatty acids found in virtually all mammalian cells and are biosynthesized from C-20 polyunsaturated fatty acids via the cyclooxygenase enzyme system (S. Bergstroem., Science, 157, 382, 1967]. For decades, PG has concentrated extensive efforts in synthetic chemistry. Because of the potential therapeutic advantages, there has been an increased focus on PG analogs. Along with their potential drug availability, the incompatibility of suitable natural sources has led to the clinical development of many synthetic PG analogs. Of these, of particular interest, both pharmacologically and clinically, are analogs incorporating methyl groups into the prostaglandin backbone C-15 (E. Yankee et al., J. Amer. Chem. Soc., 96, 5865, 1974) b) (E. Yankee et al., J. Amer. Chem. Soc., 94, 3651, 1972) c). (E. Yankee et al., J. Amer. Chem. Soc., 96, 5875, 1964 and references cited therein). The quickest method of natural PG metabolism (inactivation) in humans has been found to be a very rapid reduction of 13-14 double bonds after oxidation of allyl-based C-15 alcohols. The oxidation-causing enzyme, 15-hydroxy prostaglandin dehydrogenase, has been isolated from various tissue combinations (B. Samuellson et al., Advanc. Biosci., 9, 7, 1973).

Of particular interest is 15-methyl PGF ₂ α (carboprost, Upjohn). Carboprost is listed in the clinic as a methylergomethrin replacement or in cases where methylergomerin causes an inappropriate response in treating postpartum bleeding. Intramuscular injection of 250 mg of carboprost in a sterile aqueous solution is the very successful best regimen currently available as a preliminary case for uterine incision since bleeding is not stopped by metterzin or the like. It is registered for such indications in Sweden and India (commercially available under the trade names Prostinefem in Sweden and Prosodin in India).

The development of a total synthetic route to carboprost is highly desirable because of its promising clinical potential. Numerous methods for the synthesis of PG have been reported (EJ Corey et al., J. Amer. Chem. Soc., 90, 3245 and 3247, 1968). However, known synthetic methods often include multistage linear synthesis, which is expensive and lowers the overall yield of the final product. Noyori et al. Reported a concentrated three-component coupling method wherein the entire carbon skeleton is stereosterically prepared by serial alkylation of an appropriately optically active enon (R. Noyori et al., Angew. Chem. Int. Edn. (Eng)., 23, 847, 1984 and references cited therein). Prostaglandin PGE ₂ was also synthesized using solid phase chemistry (S. Chen. IBC International Conference on Combinatorial synthesis of natural products, December 1997).

The most recent method often used for the synthesis of PG involves conjugated addition of organometals to α-substituted 4-hydroxy 2-cyclopentenone (MPL Caton in "New Synthetic Routes to Prostaglandins"., Academic Press NY, p. 105, 1982 and F. Sato et al., J. Org Chem., 59, 6153, 1994]. The two-component method, which consists of two independent but complementary pathways, includes introducing the o-side chain into the α-side chain containing endo-enone and introducing the α-side chain into the o-side chain containing exo-enone.

The present invention utilizes enantiomerically pure α-side chain containing endo-enone (II), and conjugates of the higher copper salts produced by using a preferred o-chain with enantiomerically pure β-chain iodide (VI). Introduction via addition. The process involves the synthesis of endo-enone (II) of good optical purity (greater than 99% ee), followed by the alkylation of stabilized carboions and their degradation using ultrasonically mediated and enzymatic irreversible transesterification reaction techniques. It is described. Here, we describe a process for the preparation of enantiomerically pure β-chain alcohols (greater than 99% ee) and a conversion to component B with very high optical purity. Processes reported for the two-component coupling method include the conjugated addition of higher copperates to optically pure enones, sometimes with incomplete additions. This includes the recovery of unreacted starting enones by wasteful column chromatography separation. In the present method, the inventors demonstrated that the Lewis acid, such as BF ₃ -etherate, was used to activate the enon at a temperature such as -78 ° C, and then conjugated with the higher sulphate to consume the enon completely. This method overcomes the chromatographic purification of the coupled product and prevents it from being lost during the chromatographic purification. Also in the last step, post-coupling treatment and purification of the product provide the carboprost methyl ether of the USP specification.

Accordingly, the first aspect of the present invention provides a compound of formula (IA) by coupling a compound of formula (II) to a compound of formula (III)

Optionally reducing compound IA,

There is provided a process for the preparation of a compound of formula (I) which comprises removing all protecting groups.

Where

R is CH = CH or CH ₂ CH ₂ ,

R ¹ and R ² are both hydrogen or together form a bond,

P is a protecting group,

P ¹ is a protecting group,

M is a sulphate.

Suitably R is 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 as an OR ¹ group, and R ² forms a carbonyl group. Preferably both R ¹ and R ² are hydrogen.

P and P ¹ groups, which may be the same or different, may be any suitable hydrogen protecting group such as tetrahydrpyran and especially silyl protecting groups such as t-butyldiphenylsilyl, dimethylphenylsilyl, triethylsilyl, t-butyldimethyl Silyl (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 carried out at reduced temperature, for example about -78 ° C. Preferably the reaction is carried out in the presence of Lewis acid, in particular BF ₃ OEt ₂ . The use of BF ₃ OEt ₂ has been found to overcome the problem of dehydration at the C-15 site as well as activation of the enon at low temperatures to complete the reaction. The higher copper salts of formula III are preferably produced using organolithium reagents, preferably butyl lithium.

Reduction of the compound of formula (IA) can be carried out using known reducing agents. Reduction of cyclopentanone, for example, is preferably carried out using a selective reducing agent such as K-selectride to give the desired cyclopentanol isomer. Reduction of triple bonds can be carried out using conventional techniques such as Lindlar hydrogenation.

Removal of the protecting group is carried out using conventional methods. For example, if both protecting groups P and P ¹ are silyl groups, deprotection of both groups can be achieved using a fluoride reagent such as TBAF in a suitable solvent such as THF. Preferably, after reducing the cyclopentanone moiety, the P and P ¹ groups are deprotected and the triple bond is reduced to provide the desired compound of formula (I).

The compound of formula II can be prepared from the reaction of a compound of formula IV with a compound of formula V in the presence of an organolithium reagent.

Where

P is as defined in Formula II above,

L is a leaving group,

Hal is halogen.

Preferably L is a group such as -SePh which stabilizes the resulting carboion ion, Hal is bromo or iodo, preferably iodo.

Compounds of formula IV, wherein L is SePh, can be prepared from the corresponding enones and phenylselenyl chloride using the methods of the literature. Enones can be prepared by protecting the corresponding alcohols, for example by treating TBDMS chloride under ordinary conditions.

Compounds of formula (V) may be prepared by halogenating the corresponding alcohols prepared using known methods as exemplified herein.

Compounds of formula III are suitable sulphates, in particular the higher sulphates and preferably thienyl sulphates, in particular the dilithium [3-methyl, 3- (trimethylsilyl) of formula IIIA prepared from the corresponding halides of formula VI ) Oxy octyl} -2-thienyl cyanogurate.

Where

Hal is halogen, in particular iodo,

P ¹ is a protecting group as defined in formula III above, preferably a TMS group.

Such compounds may be prepared according to the methods illustrated herein.

The novel intermediate forms another aspect of the present invention.

The invention is illustrated by the following examples.

〈Intermediate 1〉

Synthesis of Methyl-7-iodo Hepta-5-yonate

a) methyl-7-hydroxy hept-5-inoate

See R.J.K. Taylor et al., Tetrahedron, 42, 5849-56 (1986)], prepared the title compound as an oil (bp 130 ° C to 132 ° C at 0.5 mmHg).

b) methyl-7-iodo hepta-5-yonate

The title compound was prepared from the α-alcohol as oil (bp 110 ° C. to 113 ° C. at 0.9 mm Hg) according to the method of Carl Johnson et al., JACS, 110, 4726-35 (1988).

〈Intermediate 2〉

Synthesis of Racemic 4-hydroxy Cyclopentenone

The title compound was prepared according to the method of Japanese Patent Laid-Open No. 62236 (M. Minai, 1982).

〈Intermediate 3〉

Synthesis of 1-iodo (S) -methyl-3- (trimethylsilyloxy) -oct-2-ene

a) racemic 3-methyl-octa-1-yn-3-ol

The 3-liter three-neck round bottom flask was cooled under a nitrogen gas stream and a mechanical stirrer was installed through the middle neck. The side neck was connected to a socket with a gas inlet and a finger cold condenser. Another side neck was connected to the nitrogen inlet under static pressure. The finger cold condenser was charged with a dry ice-acetone mixture (-78 ° C.) and the reaction flask was kept in a thermal bath. Anhydrous ammonia gas (dried through a wash bottle containing KOH pellets) was bubbled through the gas inlet at a constant rate in a nitrogen atmosphere and ammonia was condensed into the reaction flask. Condensation of ammonia gas for about 2 hours gave about 1.6 liters of liquid ammonia. At this stage condensation of ammonia was stopped and a nitrogen inlet was connected instead of an ammonia bubbler. Stopped at the other side neck. The sodium metal was cut into small pieces and washed with anhydrous hexane. If the metal dissolved after the first piece was added with mechanical stirring, the reaction mixture turned blue. As soon as blue, ferric nitrate was added through the side neck and the reaction became exothermic, and upon stirring blue was bleached to give a grayish white sodium amide. Sodium metal continued to be added. The appearance of blue was observed upon addition of sodium metal, and greyish white was observed with continued stirring. After completion of the addition of the metal (to complete the addition of sodium metal takes 1 hour), the reaction mixture was stirred for about 0.5 hours to ensure completion of sodium amide formation. The static pressure of the nitrogen gas in the finger cold condenser and the temperature of −78 ° C. were maintained during the whole process. Through one side neck, insert a gas injection tube and continue to bubble acetylene gas at a constant rate (bubble acetylene through paraffin trap and keep empty trap at -78 ° C) over a period of 5 hours sodium acetylide Formation was assured. Acetylene bubbling was stopped and a pressure equal dropping funnel was placed on one side neck of the reaction flask to fill with 2-heptanone (287 g, 2.511 mol) in anhydrous ether (75 ml). The contents were then added dropwise over a period of 1 hour with stirring (exothermic reaction). The dropping funnel was rinsed with ether (40 ml) and the wash was added to the reaction flask. The contents in the reaction flask were vigorously stirred and the acetylene gas continued to bubble for another 3 hours, leaving overnight without stirring. The temperature of the finger cold condenser was slowly raised to ambient temperature to easily evaporate ammonia gas.

Finishing: The mechanical stirrer and finger cold condenser were disassembled and the 3-necked flask was cooled to 0 ° C. under nitrogen using an ice bath, to which a small amount of NH ₄ CI solution in water was added in 50 ml each. The reaction mixture was further stirred at 0 ° C. for 0.5 h, warmed to RT and stirred at RT for 2 h. The resulting solution was filtered over a layer of celite using a G-3 sinter funnel. The residue was washed with petroleum ether (2 x 150 ml). The contents were transferred to a separating funnel to separate the aqueous layer. The aqueous layer was extracted with petroleum ether (3 x 500 ml). The combined PE portions were washed with water (2 × 500 ml), brine (100 ml) and dried over anhydrous Na ₂ SO ₄ . The volatiles were removed in vacuo to yield 352 g of β-chain crude alcohol. This was further purified by distillation in vacuo (bp 76 ° C to 78 ° C at 17 mmHg) to give 330 g (2.360 mol, 94% yield) of β-chain alcohol. Unreacted 2-heptanone (bp 67 ° C. to 69 ° C. at 17 mmHg) was obtained in the initial performance distillation. This was reused in the next batch for the preparation of racemic octinol.

Yield of racemic β-chain alcohol: 330 g, 2.360 mol, 94%. Purity greater than 99% was confirmed by GC analysis: column: OV-101, 90 ° C., RT: octinol = 5 minutes: heptanone = 2.5 minutes

b) 3-methyl-3-carboxy-oct-1-yn-3-ol hydrogen phthalate

i) Recrystallization of phthalic anhydride-representative procedure

A pre-cooled 5 liter round bottom flask with magnetic stir bar was charged with 570 g of phthalic anhydride and 2.3 liters of chloroform. The contents were refluxed for 0.5 h in a water bath and hot filtered in a sinter funnel. Undissolved residue was phthalic acid. The filtrate was placed in a tightly capped flask and allowed to stand in a refrigerator to obtain crystalline phthalic anhydride. It was filtered, washed with hexane and dried in a drier. mp 130 ° C to 131 ° C.

ii) 3-methyl-3-carboxy-oct-1-yn-3-ol hydrogen phthalate

The pre-cooled 5 liter round bottom flask with magnetic stir bar was placed in 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, allowed to cool to RT and stirred overnight. The reaction progress was monitored by TLC (solvent system: 20% EtOAc in PE) for the disappearance of starting octinol. The reaction mixture was left at RT overnight.

Finishing: A 20 liter round bottom flask with flange and mechanical stirrer was charged with 7.4 liters of water and 0.731 liters of concentrated HCl and cooled to 0 ° C. using an ice bath. To the mixture was added the hemiphthalate reaction mixture with stirring, followed by the addition of chloroform (2.3 L). Stirring was continued for 1 hour. The organic layer was separated and the aqueous layer was extracted with chloroform (3 x 3 L). The combined organic layers were washed with water (2 x 500 ml) and brine (500 ml). It was dried over anhydrous Na ₂ SO ₄ and the volatiles were removed using a rotary distillation and dried in high vacuum.

Another 20 liter round bottom flask with flange and mechanical stirrer was charged with 5.5 liters of petroleum ether and cooled to 0 ° C. The hemiphthalate from the preceding step was poured into PE with stirring and stirred for 1 hour, and the desired hemiphthalate ester was crystallized. It was filtered using a Buchner funnel and the residue was washed with cold PE (500 ml) and suction dried. The residue was air dried (mp 61 ° C to 62 ° C, 0.915 kg). The mother liquor from the filtration was concentrated in vacuo using a rotary evaporator and left in the refrigerator to yield additional amount of hemiphthalate ester (second harvest, 0.43 kg, mp 61-62 ° C.). However, the mp of the compound (0.151 kg) obtained by repeating for the third crop was higher, so it was set aside and dissolved for racemic octinol recovery.

Yield of hemiphthalate ester: 1.348 g, 71%.

c) Brucin phthalate of 3-methyl-oct-1-yn-3-ol

A pre-cooled 20 liter round bottom flask with frangi and a mechanical stirrer was charged with hemiphthalate ester (0.94 kg, 3.262 mol) of racemic octanol, brucin (1.432 kg, 3.327 mol) and anhydrous acetone (3.75 L). The reaction mixture was heated at 50 ° C. for 1 h and allowed to cool to RT and stirred at RT overnight.

Finishing: The precipitated solid was filtered using a Buchner funnel and washed with cold acetone (2 x 250 ml) to remove contamination of the unwanted diastereomers. The solid obtained was air dried.

Yield: 0.739 kg, 1.028 mol, 31.5%. mp 158-189 ° C, [α] _D = -12.0 ° ± 0.5 (c 0.88, EtOH)

The mother liquor was set aside for brucin recovery.

d) Hemiphthalate esters of (S) -octinol from brucin salt: (S) -3-methyl-3-carboxy-oct-1-yn-3-ol hydrogen phthalate

A pre-cooled 20 liter round bottom flask with flange and mechanical stirrer was charged with brucin salt (0.827 kg, 1.15 mol) and ether (8.2 L). To this a small amount of concentrated HCl (0.83 L) was added with stirring at 0 ° C. The reaction mixture was stirred at 0 ° C for 2 h and allowed to warm to RT.

Finishing: The contents were transferred to a separatory funnel to separate the ether layer. The aqueous layer was extracted with ether (2 x 500 ml). The combined ether layers were washed with water (2 × 500 ml), brine (250 ml) and dried over anhydrous Na ₂ SO ₄ . The volatiles were removed in vacuo to give the desired hemiphthalate ester of (S) -octinol as a viscous material. The aqueous layer was discarded.

Yield of hemiphthalate ester of (S) -octinol: 0.332 kg (nearly quantitative). This was used without purification in the next reaction.

e) (S) -3-methyl-oct-1-yn-3-ol

A pre-cooled 20 liter round bottom flask with a flange, mechanical stirrer and reflux condenser was charged with hemiphthalate ester of (S) -octinol (0.332 kg, 1.151 mol), which contained NaOH solution (0.504 kg in 3.6 L of water). Was added at RT. The reaction mixture was refluxed for 2 hours in a water bath. The reaction mixture was cooled to RT and the octinol layer was separated. The contents were transferred to a separating funnel to separate the supernatant layer. The aqueous layer was extracted with petroleum ether (3 x 500 ml) and mixed with octinol fractions. The combined organic portions were washed with distilled water (3 x 500 ml) until pH was 7. The organic portion was dried over anhydrous Na ₂ SO ₄ and the volatiles were removed to yield 155 g (96%) of crude (S) -octinol, which was further purified by distillation in vacuo. Bp 73 ° C. to 76 ° C. at 14 mmHg to 15 mmHg.

Yield: 128.87 g, 0.921 mol, 80%, [α] _D = -2.3 ° ± 0.5 (c 2.7, EtOH). Theoretical value [a] D = -2.33 ° (c 2.625, EtOH).

f) (S) -3-methyl-3- (trimethylsilyl) oxy-oct-1-yne

A pre-cooled 1 liter round bottom flask with a mechanical stirrer was charged with (S) -octinol (29 g, 0.207 mol) and DMF. The reaction mixture was cooled to 0 ° C. under a nitrogen atmosphere (ice bath). A small amount (less than 5 g) of imidazole (39.44 g, 0.58 mol) was added to the reaction mixture at 0 ° C. and stirred for 15 minutes. To the reaction mixture was added dropwise TMS chloride (33.72 g, 0.310 mol) with a syringe over a period of 45 minutes and stirred at 0 ° C. for 1 hour. The reaction mixture was allowed to warm to RT and stirred at RT overnight. The reaction progress was monitored by TLC (solvent system: 10% EtOAc in petroleum ether) for the disappearance of the starting alcohol.

Finishing: The reaction mixture was poured into ice water (750 ml) and extracted with ether. The supernatant ether layer was separated and the aqueous layer was extracted with ether (3 x 250 ml). The combined organic portions were washed with water (2 x 100 ml) and brine (50 ml). It was dried over anhydrous Na ₂ SO ₄ and volatiles were removed using a rotary evaporator and dried in high vacuum. This was distilled off under reduced pressure to obtain the title compound. Bp 87 ° C. to 90 ° C. at 12 mmHg to 15 mmHg.

Yield: 35.09 g, 165.5 mmol, 80%.

g) (S) -3-methyl-3- (trimethylsilyl) oxy-1- (n-tributylstannyl) -oct-1-ene (E)

A pre-cooled 500 ml round bottom flask with mechanical stir bar was charged with TMS ether (7.50 g, 35.37 mmol), TBTH (16.31 g, 35.4 mmol) and AIBN (0.4 g, 2.47 mmol) of (S) -octinol. . The reaction mixture was evacuated and washed off with nitrogen gas. The flask was then immersed in a preheated 130 ° C. oil bath at which time an active initiation reaction occurred and hydrogen gas was released (a suitable vent was required). The reaction mixture was heated in an oil bath at 150 ° C. for 3 hours and cooled to RT under a nitrogen atmosphere. Petroleum ether (150 ml) was added to the reaction mixture and allowed to stir at RT for 15 minutes. The reaction mixture was filtered through a C-3 sinter funnel to the celite bed. The residue was washed with anhydrous PE (60 ml) and the combined PE layers and the volatiles removed to give the desired stannane derivative in quantitative yield.

Note: Derivatives were tightly capped into flasks and covered with aluminum foil and stored under nitrogen. It is very sensitive to moisture and light. Large scale preparation will involve adding the AIBN after mixing the reactants once the operating temperature is reached.

h) 1-iodo (S) -3-methyl-3- (trimethylsiloxy) -oct-2-ene

A pre-cooled 500 ml round bottom flask with a mechanical stir bar was charged with stanan derivatives (61.06 g, 0.121 mol), to which freshly distilled THF (170 ml) was added. The reaction mixture was cooled to −78 ° C. using a dry ice-acetone bath, in which N-iodo succinimide (27.31 g, 0.121 mol) in THF (100 ml) was added for 45 minutes under nitrogen at −78 ° C. The cannula was added over a period of time. The reaction mixture was stirred at -78 ° C for 1 hour. The temperature of the bath was gradually increased to RT and stirred at RT for 15 minutes. The reaction progress was monitored by TLC (solvent system: petroleum ether) for the disappearance of starting material.

Finishing: The reaction mixture was poured into ice and the reaction mixture was filtered through a C-3 sinter funnel in a celite bed. The filtrate was extracted with PE (4 × 100 ml). The combined PE layers were washed with water (100 ml), 10% sodium thiosulfate solution (150 ml) and finally water (50 ml). The PE portion was dried over anhydrous Na ₂ SO ₄ and volatiles were removed in vacuo to give the desired iodide (0.072 kg). It was purified by high vacuum distillation. Bp 79 ° C to 82 ° C, 0.040 kg, 0.118 mol, 97% at 0.1 mmHg.

〈Intermediate 4〉

Preparation of 4-[(tert-butyldimethylsilyl) oxy] -2-cyclopenten-l-one

In R. Noyori., Et al., Tetr. Lett., 28, 4719-20 (1987)], 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 had some colored impurities, which were removed by distillation under reduced pressure (bp 82 ° C to 86 ° C at 1 mmHg).

Purity of the material was determined by Chilasel-OD column HPLC using 1.5% isopropan-2-ol in n-hexane.

〈Intermediate 5〉

a) Preparation of racemic 4-[(t-butyldimethylsilyl) oxy] -2- (phenylseleno) -2-cyclopenten-l-one

T. Toru. et al., J. Org. Chem., 57, 4719-20 (1992)] according to the method of TBS-derivative 4-[(4-tert-butyldimethylsilyl) oxy] -2-cyclopenten-l-one (23.84 g, 0.112 mol), Prepared from phenyl selenyl chloride (32.32 g, 0.169 mol) and pyridine (14.69 g, 0.186 mol).

b) Preparation of methyl 7- (3-hydroxy-5-oxo-1-cyclopenten-l-yl) -5-heptinoate via a two-component coupling method

T. Toru. et al., J. Org. Chem., 57, 3145-3152 (1992)] selenyl derivative 4-[(tert-butyldimethylsilyl) oxy] -2- (phenylseleno) -2-cyclopenten-l-one in THF (16.65 g, 45.3 mmol), bis (tributylstanan (28.94 g, 49.91 mmol), n-BuLi (35.6 ml in hexane, 1.4 M, 49.91 mmol), iodine (25.35 g, 95.28 mmol) and HMPA (26 ml).

The product was purified by silica gel chromatography eluting with ethyl acetate / petroleum ether.

c) methyl 7- (3-hydroxy-5-oxo-1-cyclopenten-1-yl) -5-heptinoate

E.J. Corey et al, JACS., 94, 6190-91 (1972)] TBS derivative (6.02 g, 17.22 mmol), methyl-7- [in a solution of AcOH: THF: water (3: 1: 1) 3-tert-butyldimethylsilyl) oxy] -5-oxo-1-cyclopenten-l-yl] -hept-5-inoate.

d) irreversible transesterification reaction with enzyme using lipase in vinyl acetate in ultrasonic digestion tank

See K.A. Babiak, et al., J. Org. Chem., 55, 3377-81, (1990) and G Lin, et al., Tetr. Lett., 36, 6067-68 (1995)], hydroxy-enone (4.7 g, 19.91 mmmol), methyl-7-[(3-hydroxy) -5-oxo-1- in vinyl acetate Prepared by sonication from cyclopenten-l-yl] -hept-5-inot and PP lipase and / or HP lipase (crude product, 7.5 g).

Yield of desired acetate: 2.40 g, 43%.

e) deacetylation with guanidine in methanol

Preparation of Guanidine Stock Solution in Methanol

See K.A. Babiak, et al., J. Org. Chem., 55, 3377-81, (1990)] was prepared from guanidine carbonate (28.4 g, 0.158 mol), sodium metal (3.56 g, 0.155 mmmol) in methanol (0.308 L).

Methyl-7-[((R) -3-hydroxy) -5-oxo-1-cyclopenten-l-yl] -hept-5-innote

See K.A. Babiak, et al., J. Org. Chem., 55, 3377-81, (1990)] was prepared from (R) acetate (1.905 g, 6.85 mmol) and guanidine in methanol.

Note: Because β-hydroxy ketones are sensitive, it is recommended to perform the deacetylation reaction on a smaller scale before carrying out the deacetylation reaction on a larger scale.

Yield: 1.130 g, 4.788 mmol, 70% yield (90% optical purity). This was used to further improve optical purity using PPlipase and / or HPlipase as described below.

Procedure: Same as degradation by enzyme using the above ultrasonic digestion tank. Concentration was completed for 5 days. The desired product was isolated by flash chromatography in 40% to 50% EtOAc in PE eluate. Yield of (R) -acetate: optical purity:> 99.9%. This was further deacetylated with guanidine in methanol to give 1.553 g of optically pure alcohol (5.586 mmol, greater than 99.9% optical purity by chiral HPLC analysis).

f) Mitsunobu reversal to convert undesired enantiomers to target enantiomers

See K.A. Babiak, et al., J. Org. Chem., 55, 3377-81, (1990)].

A pre-cooled 250 ml flask with a diaphragm inlet and magnetic stir bar was charged with (S) -alcohol (2.58 g, 10.93 mmol, 88% optical purity), Ph ₃ P (5.74 g, 21.86 mmol) and freshly distilled THF. . The reaction mixture was cooled to 10 ° C., formic acid was added by syringe, then diisopropylazodicarboxylate (DIAD, 4.42 g, 21.86 mmol) was added and warmed slowly to RT. The light yellow reaction mixture was stirred for 12 h under a nitrogen gas atmosphere at RT. The reaction progress was monitored by TLC (solvent system: 70% EtOAc in PE).

Finishing: The solvent was removed using a rotary evaporator in vacuo under reduced pressure, and the resulting brown residue was dissolved in ether (70 ml) and triturated with n-hexane (165 ml) to precipitate phosphite. The mixture was stirred for 30 min at RT and filtered in a G-3 sinter funnel and washed with ether (2 × 50 ml). The combined organic portions were transferred to another round bottom flask and the volatiles were removed in vacuo using a rotary evaporator. The resulting residue was dissolved in MeOH (120 ml), to which alumina (activated, neutral 100 g) was added and stirred at RT overnight. The reaction progress was monitored by TLC (solvent system: 70% EtOAc in PE). The reaction mixture was filtered on a G-3 sinter funnel and the residual alumina was repeatedly washed with MeOH (3 × 100 ml), and the combined filtrates were flash evaporated using a rotary evaporator to give 13.805 g of crude product. This was further purified by flash chromatography on a column of silica gel (400 g, 200 to 400 mesh). Gradually eluting with 15% to 60% EtOAc in petroleum ether gave the desired 1,2-diisopropyl dicarboxyhydrazine and the desired alcohol in 80% to 95% EtOAc in PE. HPLC analysis using a Chilasel-OD column showed a clear inversion (no noticeable racemization reaction) with an optical purity of 88% of the (R) -isomer at the chiral center.

This product was also transesterified by an enzyme using HPL in an ultrasonic digester to give the desired (R) -acetate in greater than 99% optical purity. Yield: 1.891 g, 6.802 mmol, 70%. This was further deacetated with guanidine in methanol to give the desired (R) -alcohol with optical purity greater than 99%. Yield: 1.166 g, 4.94 mmol, 73% yield.

g) methyl-7-[(R) -3-tert-butylmethylsilyl) oxy] -5-oxo-1-cyclopenten-l-yl] -hept-5-inoate

A pre-cooled 250 ml round bottom flask with a diaphragm inlet and magnetic stir bar was charged with TBDMS chloride (1.90 g, 12.64 mmol) and dichloromethane. The solution was cooled to 0 ° C. using an ice bath, to which imidazole (1.60 g, 23.66 mmol) was added at once, followed by DMF. The reaction mixture was stirred at 0 ° C for 15 minutes. Another pre-cooled flask was charged with (R) -enone alcohol (1.99 g, 8.4 mmol) in anhydrous CH ₂ CI ₂ (3 ml), which was transferred to the reaction flask under nitrogen by cannula. The wash (1 ml) was transferred to the reaction flask and stirred at 0 ° C. for 2 hours. The reaction mixture was allowed to warm to RT and stirred further (less than 10 hours) overnight. The reaction progress was monitored by TLC (solvent system: petroleum ether: EtOAc, 3: 7).

Finishing: The reaction mixture was poured into ice water and extracted with dichloromethane (3 × 100 ml). The combined organic layers were washed with water (30 ml) and brine. The organic portion was dried over anhydrous Na ₂ SO ₄ and the evaporation was removed in vacuo to yield 3.80 g of oily material, which was columned with silica gel (150 g, 200-400 mesh) with 15% to 25% EtOAc eluent in petroleum ether. Further purification by flash chromatography at. Yield of desired product: 2.90 g, 4.66 mmol, 70%. TLC: solvent system: 70% EtOAc in petroleum ether.

The purity of the material was determined by HPLC using a Chilasel-OD column using 7% isopropan-2-ol in n-hexane.

<Example 1>

a) 2-thienyl lithium

Procedure: A pre-cooled 100 ml round bottom flask with diaphragm inlet and magnetic stir bar was charged with freshly distilled THF (30 ml) and thiophene (1.59 ml, 20 mmol). The reaction mixture was cooled to −60 ° C. (dry ice-CHCI ₃ crude), and n-BuLi (16.7 ml, 1.2 M in hexane) was added dropwise by syringe over a period of 15 minutes. The reaction mixture was stirred at -60 ° C for 1 hour to ensure completion of the metallization reaction. The color of thienyl lithium in THF was light yellow.

b) preparation of vinyllithium

Procedure: A pre-cooled 100 ml round bottom flask with diaphragm inlet and magnetic stir bar was charged with B-chain iodide TMS ether (6.8 g, 20 mmol) in 30 ml THF (freshly distilled, anhydrous) and the contents were nitrogen Cooled to -78 ° C under dry ice-acetone bath. N-BuLi (21 mmol, 17.5 ml) was added dropwise by syringe over a period of 30 minutes at -78 ° C. The reaction mixture became cloudy with a pale yellow precipitate of vinyllithium, indicating completion of the reaction. The contents were further stirred at -78 ° C for 1 hour.

c) two-component coupling method:

Procedure: Cu (I) CN (20 mmol, 1.79 g) was added to a pre-cooled 500 ml round bottom flask with a diaphragm inlet and magnetic stir bar. The flask was capped with a rubber septum and heated with a thermal sprayer at high vacuum to remove any traces of moisture, cool and purge with nitrogen. THF (30 ml) was added and the suspension was cooled to −22 ° C. under nitrogen (dry ice-CCI ₄ crude). To this a solution of preformed 2-thienyllithium (step a) was added dropwise into the cannula over a period of 10 minutes. The contents were washed with THF (5 ml) and added to the flask to make the solution homogeneous (light yellow) to afford the desired lower copper sulphate. The reaction mixture was further stirred at -22 ° C for 1 hour.

The solution of vinyl lithium (step b) was added dropwise with cannula over a period of 10 minutes at -22 ° C. to a solution of lower copper sulphate and washed with THF (5 ml), and the solution was further stirred at -22 ° C. for 1 hour. To obtain a uniform higher copper sulphate (transparent solution, pale yellow orange). The resulting copperate solution was cooled to -78 ° C (dry ice-acetone bath).

A pre-cooled 100 ml pear flask was charged with (R) -enone TBDMS ether (more than 99% optical purity, 3.5 g, 10 mmol), to which anhydrous ether (40 ml) was added by syringe. The contents were cooled to −78 ° C. for 10 minutes using a dry ice-acetone bath. To this was added BF ₃ : OEt ₂ (1.29 ml, 10.5 mmol) dropwise with a syringe with stirring, and left at this temperature for 5 minutes. The solution was then added dropwise (very slowly dropwise) to a solution of the higher copper sulphate (obtained in step c) over a period of 45 minutes under nitrogen at −78 ° C. The flask of Enone was washed with ether (5 ml) and the wash was transferred to the reaction flask over a period of 45 minutes. Stirring was continued at −78 ° C. for 1.5 h (the reaction progress was monitored by TLC (solvent system: petroleum ether 10% EtOAc) for the disappearance of the starting enone). The reaction mixture was quenched with saturated aqueous ammonium chloride solution (20 ml) at -78 ° C and warmed to RT. The reaction mixture was poured into a mixture of 150 ml of distilled water and 300 ml of ether. 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 . The volatiles were removed in vacuo to give an oil (11.35 g). The product was used 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 to 400 mesh) to give the desired product with an R _f of 0.31 in 20% EtOAc in PE eluate. Obtained (solvent system: petroleum ether 10% EtOAc).

<Example 2>

(5,6-Didehydro-11-O- (tert-butyldimethylsilyl) -15-O- (trimethylsilyl-13- (S) -methyl-PGE ₂ methyl ester

Procedure: Crude TCC product in THF (anhydrous, 35 ml) in a flame dried 250 ml round bottom flask with diaphragm inlet and magnetic stir bar [5,6-didehydro-11-O-tert-butyldimethylsilyl) -15- 0- (trimethylsilyl) -13- (S) -methyl-PGE ₂ methyl ester] (11.35 g, from 10 mmol enone) was added. The solution was cooled to -78 ° C and a solution of K-selectide (32.85 ml, 30 mmol, 0.9 M solution in THF) was added dropwise by syringe. The reaction mixture was allowed to stir at −78 ° C. for 1.5 hours, to which 30% aqueous H ₂ O ₂ solution (4.54 ml, 40 mmol) was added dropwise. Stirring continued for 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 x 50 ml). The combined organic layers were washed with brine (2 × 20 ml) and dried over anhydrous Na ₂ SO ₄ . The solvent was removed in vacuo to afford 13.516 g of the desired crude product. This was used in the next desilylation reaction. TLC solvent system: 20% EtOAc in PE, R _f 0.2.

A small portion of the selectride reduction product obtained in the previous step was purified by flash chromatography using silica gel (60 g, 200-400 mesh). The desired product was obtained in a petroleum ether 30% EtOAc eluent (R _f 0.2, solvent system: petroleum ether 20% EtOAc) eluent.

Procedure: To the pre-cooled 250 ml round bottom flask with diaphragm inlet and magnetic stir bar was added the crude select reducing product (13.52 g) and THF (anhydrous, 35 ml). The solution was cooled to 0 ° C. and a solution of tetra-n-butyl ammonium fluoride (30 mmol in THF, 30 ml, 1 M solution, 3 equiv) was added dropwise by syringe over a period of 5 minutes. Stirring was continued at 0 ° C. for 0.5 h and at rt for 5 h until the reaction was complete by TLC (solvent system: EtOAc) analysis. THF was removed in vacuo and extracted with EtOAc (3 × 30 ml) by addition of water (20 ml). The combined EtOAc layers were washed with water (2 × 10), brine (2 × 10 ml) and dried over anhydrous Na ₂ So ₄ . Concentration in vacuo gave 5.409 g of crude product. This was further purified by flash chromatography on a column of silica gel (350 g, 200-400 mesh). The desired product was obtained in an EtOAc eluate as a tan oil (1.94 g, 5.10 mmol, R _f 0.5 (solvent-based EtOAc)) in 51% yield based on starting (R) -enone. It was dissolved in anhydrous ethyl acetate (50 ml), and 0.400 g of activated charcoal was added thereto and stirred for 1 hour under a nitrogen atmosphere at RT. The solution was filtered through a C-4 sinter funnel to the celite layer and washed with EtOAc (30 ml). Removal of volatiles in vacuo gave 1.95 g of crude product which was purified by flash chromatography on a silica gel (150 g, 200 to 400 mesh) column and the desired product was obtained as a colorless viscous oil in ethyl acetate eluent, which was -22. Storage at &lt; RTI ID = 0.0 &gt; C &lt; / RTI &gt; solidified to a colorless solid (chloroform-methanol gradient machine can also be used in flash chromatography purification).

Note: It is essential to use anhydrous TBAF in THF in the desilylation reaction. Using TBAF.3H ₂ 0 does not provide good yield of the desired product.

Carboprost methyl ester, (15S) -15-methyl PGF 2α methyl ester or IUPAC nomenclature Prostar-5,13-diene-1-ioic methyl ester, 9,11,15-trihydroxy-15 as described in USP -Methyl- (5Z, 9α, 11α, 13E, 15S) or (Z) -7- [1R, 2R, 3R, 5S) -3-5-dihydroxy-2-[(E)-(3S)- Preparation of 3-hydroxy-3-methyl-1-octenyl] cyclopentyl] -5-heptenoic methyl ester

Selective Lindla hydrogenation was carried out in batches of 0.500 g to 1 g scale. The following procedure is representative.

A precooled 1000 ml two-neck flask was charged with desilylated product (1.065 g, 2.80 mmol), to which a mixture of preformed benzene (100 ml) and cyclohexane (300 ml) was added by cannula under nitrogen. To the reaction mixture was added 0.315 g of Pd on lead CaCO ₃ under nitrogen. The reaction mixture was evacuated in vacuo and washed off with hydrogen gas and bubbled hydrogen gas through the reaction mixture at a rate of 45 bubbles / min over a period of 90 minutes with stirring. Aliquots were taken out at regular time intervals and reaction progress was monitored by ¹³ C NMR analysis (about 1.5 hours, ¹³ C NMR analysis would show total disappearance of alkynyl carbon at δ 80 ppm). The reaction mixture was filtered using a G-4 sinter funnel and the residue was washed with EtOAc (the recovered catalyst can be reused). The organic phase was concentrated in vacuo to afford the desired carboprost methyl ester as a viscous colorless oil (1 g). This was further purified by chromatography on silica gel in EtOAc eluent (chloroform-methanol gradient machine can also be used for flash chromatography purification).

The product was further purified by purified reverse phase HPLC using a purified ODS (C-18) SIMPAK column (20 × 250 mm) and a mobile phase of acetonitritrit-water (1: 1): UV detection: 210 nm. When purified HPLC was performed in 0.170 g batch, the recovery of pure carboprost methyl ester of USP specification was 65%.

Claims (9)

Coupling a compound of formula II to a compound of formula III to provide a compound of formula IA, in any order Optionally reducing compound IA, A process for preparing a compound of formula (I), comprising removing all protecting groups. <Formula I> <Formula II> <Formula III> <Formula IA> Where R is CH = CH or CH ₂ CH ₂ , R ¹ and R ² are both hydrogen or together form a bond, P is a protecting group, P ¹ is a protecting group, M is a sulphate. The method of claim 1, wherein R is CH═CH. The method of claim 1 or 2, wherein both R ¹ and R ² are hydrogen. The method of claim 1, wherein P is TBDMS and P ¹ is TMS. The process according to any of claims 1 to 4, wherein the hydrogenation of the triple bond of the compound of formula (IA) is carried out using Lindla hydrogenation. 5. The process according to claim 1, wherein the reduction of cyclopentanone of formula IA is carried out using K-selectide. 6. A compound of formula (I) prepared according to the process of claims 1-6. A compound of formula IA <Formula IA> Wherein P, P ¹ and R are as defined in claim 1. The compound of claim 8, wherein R is CH = CH, P is TBDMS, and P ¹ is TMS.