KR20160070457A - Process for Preparing Lubiprostone and Intermediate Therefor - Google Patents

Abstract

The present invention relates to a process for producing rubyprostones and intermediates used therein. According to the present invention, it is possible to efficiently and economically produce rubyprostone by selectively introducing a protecting group into the coriolactone diol.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a process for preparing ruby prostone,

The present invention relates to a process for producing rubyprostone and intermediates therewithin, and more particularly to a process for efficiently and economically producing rubyprostone and intermediates used therein.

15-keto-prostaglandin derivatives of formula (I) to the pro ruby stones, 7 - ((1 R, 3 R, 6 R, 7 R) -3- ( 1,1-difluoro-cyclopentyl) -3-hydroxy -8 - a-oxo-2-oxa-bicyclo [4.3.0] non-active pharmaceutical ingredients (API) of the Gastrointestinal amino tee (Amitiza ^®) that is used for the treatment of chronic constipation acid adult non-7-yl) heptane.

[Chemical Formula 1]

Ruby prostone is mostly present in a bi-cyclic form including a hemiketal ring by reacting a hydroxyl group of C < ₁₁ > with a ketone of C < ₁₅ > This ratio varies with the solvent, the ratio of the bi-cyclic form to the mono-cyclic form in D ₂ O is 6: 1, and in CDCl _{3 it} is 96: 4 (see U.S. Patent No. 7,355,064 ).

[Reaction Scheme 1]

U.S. Pat. No. 5,284,858 and U.S. Patent No. 5,252,605 disclose a process for the preparation of a ω-chain by first introducing an ω-chain from a corialdehyde and then hydrogenating, reducing, oxidizing, A method for producing ruby prostone in 12 steps is disclosed.

[Reaction Scheme 2]

U.S. Patent No. 7,812,182 relates to a process for the introduction of an alpha -chain from coriolactools first, wherein hydrogenation, reduction, oxidation, protection and deprotection are repeated in at least 15 stages, A method for producing a stone is disclosed.

[Reaction Scheme 3]

The known production method of the rubyprostone has a complicated and long manufacturing process of repeating the hydrogenation reaction, the reduction reaction, the oxidation reaction, the protection and the deprotection reaction.

U.S. Patent No. 7,355,064 U.S. Patent No. 5,284,858 U.S. Patent No. 5,252,605 U.S. Patent No. 7,812,182

The inventors of the present invention have conducted intensive studies in order to solve the above problems in the production of rubyprostone. As a result, they have found that rubyprostone can be efficiently and economically produced by selectively introducing a protecting group into coriolactone diol, .

Accordingly, it is an object of the present invention to provide a method for efficiently and economically producing ruby prostone.

Another object of the present invention is to provide an intermediate used in the above-mentioned production method.

An embodiment of the present invention relates to a process for producing rubyprostone represented by the following formula (1)

(i) deprotecting a compound of formula (2) in the presence of a base to obtain a compound of formula (3);

(ii) reacting a compound of formula (3) with vinyl acetate in the presence of a lipase to selectively protect a primary hydroxyl group to obtain a compound of formula (4);

(iii) reacting a compound of formula (4) with benzyl chloromethyl ether to protect the secondary hydroxyl group to obtain a compound of formula (5);

(iv) reducing the ketone of the compound of formula (5) and simultaneously deprotecting the protecting group of the primary hydroxyl group to obtain a compound of formula (6);

(v) subjecting a compound of formula (6) to a Wittig reaction with a compound of formula (7) to obtain a compound of formula (8);

(vi) reacting a compound of formula 8 with benzyl bromide to protect the carboxylic acid group to give a compound of formula 9;

(vii) oxidizing the primary and secondary hydroxyl groups of the compound of formula (9) to obtain a compound of formula (10);

(viii) subjecting a compound of formula (10) to a Wittig reaction with a compound of formula (11) to obtain a compound of formula (12); And

(ix) hydrogenating and deprotonating a compound of formula (12) under hydrogen in Pd / C.

 [Chemical Formula 1]

(2)

(3)

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

(7)

[Chemical Formula 8]

[Chemical Formula 9]

[Chemical formula 10]

(11)

[Chemical Formula 12]

In this formula,

Bz is a benzoyl group,

Ac is an acetyl group,

R and Bn are benzyl groups.

Hereinafter, the production method of the present invention will be described in more detail with reference to Reaction Scheme 4 below. The method described in the following Reaction Scheme 4 exemplifies the representative method, but the reaction reagent, the reaction conditions, and the like may be changed as required.

[Reaction Scheme 4]

Step 1: Synthesis of Compound (3)

The compound of formula (3) can be prepared by deprotecting the compound of formula (2) in the presence of a base.

Examples of the base include general inorganic bases such as alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; Sodium methoxide, potassium methoxide, sodium t-butoxide, potassium t-butoxide and the like can be used, and sodium methoxide (NaOMe) is particularly suitable.

As the reaction solvent, any polar or non-polar solvent which does not affect the reaction can be used. Specifically, tetrahydrofuran, ether, methanol and the like can be used, and methanol is particularly preferable.

The reaction temperature is preferably room temperature, and the reaction time is preferably about 1 to 3 hours.

Step 2: Synthesis of Compound (4)

The compound of formula (4) can be prepared by reacting the compound of formula (3) with vinyl acetate in the presence of lipase to selectively protect the primary hydroxyl group.

As the lipase, alkaline phosphatase (ALPS) or the like may be used, but it is not limited thereto.

As the reaction solvent, tetrahydrofuran, ether, acetone and the like can be used, and tetrahydrofuran is particularly preferable.

The reaction temperature is preferably about 30 to 50 DEG C, and the reaction time is preferably about 20 to 28 hours.

Step 3: Synthesis of Compound (5)

The compound of formula (5) can be prepared by reacting the compound of formula (4) with benzyl chloromethyl ether to protect the secondary hydroxyl group.

The reaction may be carried out in the presence of a base. As the base, diisopropylethylamine, triethylamine and the like can be used, and diisopropylethylamine is particularly suitable.

As the reaction solvent, methylene chloride, chloroform and the like can be used, and methylene chloride is particularly preferable.

The reaction temperature is preferably room temperature, and the reaction time is preferably about 25 to 35 hours.

Step 4: Synthesis of compound of formula (6)

The compound of formula (6) can be prepared by reducing the ketone of the compound of formula (5) and simultaneously deprotecting the protecting group of the primary hydroxyl group.

The reaction may be carried out in the presence of a reducing agent such as diisobutyl aluminum hydride (DIBAL). Excess DIBAL is used to conduct reduction and deprotection simultaneously.

As the reaction solvent, tetrahydrofuran, ether, acetone and the like can be used, and tetrahydrofuran is particularly preferable.

The reaction temperature is preferably about -45 to -65 占 폚, and the reaction time is preferably about 30 minutes to 2 hours.

Step 5: Synthesis of Compound of Formula 8

The compound of formula (8) can be prepared by the Wittig reaction of the compound of formula (6) with the compound of formula (7).

The reaction may be carried out in the presence of a base. As the base, sodium methoxide, potassium methoxide, sodium t-butoxide, potassium t-butoxide and the like can be used, and potassium t-butoxide is particularly suitable.

As the reaction solvent, tetrahydrofuran, ether, acetone and the like can be used, and tetrahydrofuran is particularly preferable.

The reaction temperature is preferably room temperature, and the reaction time is preferably about 1 to 3 hours.

The compound of the formula 8 obtained through the above reaction can be used for the next reaction without further purification.

Step 6: Synthesis of Compound (9)

The compound of formula (9) can be prepared by reacting the compound of formula (8) with benzyl bromide to protect the carboxylic acid group.

The reaction may be carried out in the presence of a base. As the base, potassium carbonate, sodium carbonate and the like can be used, and potassium carbonate is particularly suitable.

As the reaction solvent, tetrahydrofuran, ether, acetone and the like can be used, and acetone is particularly preferable.

The reaction temperature is preferably room temperature, and the reaction time is preferably about 15 to 23 hours.

Step 7: Synthesis of compound of formula (10)

The compound of formula (10) can be prepared by the oxidation reaction of the primary and secondary hydroxyl groups of the compound of formula (9).

The reaction may be carried out in the presence of an oxidizing agent such as des-martin periodin (DMP).

As the reaction solvent, methylene chloride, chloroform and the like can be used, and methylene chloride is particularly preferable.

The reaction temperature is preferably room temperature, and the reaction time is preferably about 1 to 3 hours.

Step 8: Synthesis of compound of formula (12)

The compound of formula (12) can be prepared by subjecting a compound of formula (10) to a wittig reaction with a compound of formula (11).

The reaction may be carried out in the presence of a base. As the base, lithium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used, and lithium hydroxide is particularly suitable.

As the reaction solvent, tetrahydrofuran, methyl t-butyl ether, water and the like can be used, and particularly methyl t-butyl ether, water or a mixed solvent thereof is preferable.

The reaction temperature is preferably room temperature, and the reaction time is preferably about 45 to 55 hours.

The compound of formula (11) can be obtained by subjecting a ketone group of the following formula (13) to a difluorination reaction according to a known method to obtain a compound of the following formula (14) and then subjecting the ester group of the compound of the formula can do.

[Chemical Formula 13]

[Chemical Formula 14]

Step 9: Synthesis of Ruby Prostone

The rubyprostones of formula (I) can be prepared by hydrogenating and deprotecting the compound of formula (12) under hydrogen at Pd / C.

The reaction may be carried out in the presence of an acid. As the acid, acetic acid, hydrochloric acid, sulfuric acid, formic acid, phosphoric acid and the like can be used, and acetic acid is particularly suitable.

As the reaction solvent, isopropyl alcohol, methanol, tetrahydrofuran and the like can be used, and isopropyl alcohol is particularly preferable.

The reaction temperature is preferably room temperature, and the reaction time is preferably about 20 to 30 hours.

One embodiment of the present invention relates to a compound of formula (5), which is a production intermediate of rubyprostone.

[Chemical Formula 5]

In this formula,

Ac is an acetyl group,

R is a benzyl group.

One embodiment of the present invention relates to a method for producing the compound of Chemical Formula 5,

(i) deprotecting a compound of formula (2) in the presence of a base to obtain a compound of formula (3);

(ii) reacting a compound of formula (3) with vinyl acetate in the presence of a lipase to selectively protect a primary hydroxyl group to obtain a compound of formula (4); And

(iii) reacting a compound of formula (4) with benzyl chloromethyl ether to protect the secondary hydroxyl group to give a compound of formula (5).

(2)

(3)

[Chemical Formula 4]

In this formula,

Bz is a benzoyl group,

Ac is an acetyl group.

The detailed description of the method of preparing the compound of Chemical Formula 5 is the same as the first to third steps described above with respect to the production method of rubyprosthone, so a detailed description will be omitted in order to avoid duplication.

Another embodiment of the present invention relates to a process for preparing a rubyprostone represented by the general formula (1) from the compound of the general formula (5), and a production process according to another embodiment of the present invention

(iv) reducing the ketone of the compound of formula (5) and simultaneously deprotecting the protecting group of the primary hydroxyl group to obtain a compound of formula (6);

(v) subjecting a compound of formula (6) to a Wittig reaction with a compound of formula (7) to obtain a compound of formula (8);

(vi) reacting a compound of formula 8 with benzyl bromide to protect the carboxylic acid group to give a compound of formula 9;

(vii) oxidizing the primary and secondary hydroxyl groups of the compound of formula (9) to obtain a compound of formula (10);

(viii) subjecting a compound of formula (10) to a Wittig reaction with a compound of formula (11) to obtain a compound of formula (12); And

(ix) hydrogenating and deprotonating a compound of formula (12) under hydrogen in Pd / C.

 [Chemical Formula 5]

[Chemical Formula 6]

(7)

[Chemical Formula 8]

[Chemical Formula 9]

[Chemical formula 10]

(11)

[Chemical Formula 12]

In this formula,

Ac is an acetyl group,

R and Bn are benzyl groups.

According to the present invention, it is possible to efficiently and economically produce a ruby prostone by introducing a protecting group selectively into the coriolactone diol without a complicated and long manufacturing process.

Hereinafter, the present invention will be described in more detail with reference to Examples. It should be apparent to those skilled in the art that these embodiments are for illustrative purpose only and that the scope of the present invention is not limited to these embodiments.

Preparation Example 1: Preparation of the compound of formula (14)

Ethyl 2-oxohexanoate (13) (148 g) was diluted with methylene chloride (1480 mL) and stirred, and the reaction solution was cooled to 0 占 폚. Diethylaminosulfur trifluoride (148 mL) was slowly added dropwise and the reaction solution was warmed to room temperature and stirred for 4 hours. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate = 10: 1). After completion of the reaction, a saturated aqueous sodium bicarbonate solution (1000 mL) was slowly added. The aqueous layer was then extracted with methylene chloride (1000 mL), and the organic layer was separated and dried in anhydrous sodium sulfate. After filtration of anhydrous sodium sulfate, the filtrate was concentrated in vacuo to give a mixture which was purified by column chromatography using silica gel (hexane: ethyl acetate = 30: 1) to give pure ethyl 2,2-difluorohexanoate (14) (151 g, 90%).

Preparation Example 2: Preparation of the compound of formula (11)

Dimethyl methylphosphonate (215 mL) was diluted in THF (1450 mL) and stirred, and the reaction solution was cooled to -78 ° C. n-BuLi (804 mL) was added dropwise and stirred for 2 hours, and ethyl 2,2-difluorohexanoate (14) (145 g) was added dropwise. After stirring for 1 hour, the temperature was raised to 0 占 폚 and stirred for 1 hour. The progress of the reaction was monitored by thin layer chromatography (hexane: ethyl acetate = 1: 1). After completion of the reaction, pentane (1000 mL) was added and the pH was adjusted to 6 with 2M-sulfuric acid solution. The water layer was separated, re-extracted with pentane, and the organic layers were combined and dried in anhydrous sodium sulfate. After filtration of anhydrous sodium sulfate, the filtrate was concentrated in vacuo to give a mixture which was purified by column chromatography using silica gel (hexane: ethyl acetate = 1: 1) to give pure dimethyl 3,3-difluoro-2-oxoheptylphosphate Nat 11 (161 g, 78%) was obtained.

Example 1: Preparation of the compound of formula (III)

Coriolactone benzoate (2) (100 g) was suspended in methanol (500 mL). Then, sodium methoxide (2 g) was dissolved in methanol (10 mL), and the mixture was added dropwise at a temperature of 20 ° C to 25 ° C and stirred at room temperature for 2 hours. The progress of the reaction was confirmed by thin layer chromatography (hexane: ethyl acetate = 1: 5). After completion of the reaction, 4M-hydrochloric acid solution (8 mL) diluted in 1,4-dioxane was added to adjust the pH to 3 to 4. After stirring for 10 minutes and concentration, the mixture was suspended in methyl t-butyl ether (400 mL) and then concentrated. Then, after adding methyl t-butyl ether (1000 mL) and stirring at room temperature for 1 hour, the solid was filtered and washed with methyl t-butyl ether. Dry the solid in vacuo to a white solid (3a R, 4 S, 5 R, 6a S) -5- hydroxy-4- (hydroxymethyl) -2-hexahydro-H - cyclopenta [b] furan-2-circle (3) (59 g, 95%).

^{1 H NMR (300 MHz, CDCl} 3): δ 4.95 (1H, ddd, J = 6.9, 4.8, 2.4 Hz), 4.04 (1H, q, J = 5.1 Hz), 3.49 (2H, m), 2.84 (1H , q, J = 7.8 Hz), 2.72 (1H, m), 2.49 (1H, dd, J = 15.6, 2.4 Hz), 2.28 (1H, m), 1.91 (2H, m).

Example 2: Preparation of the compound of formula (IV)

The cyclopenta [b] furan-2 source (3) (59 g) - (3a R, 4 S, 5 R, 6a S) -5- hydroxy-4- (hydroxymethyl) -2-hexahydro-H And suspended in tetrahydrofuran (1719 mL). Vinyl acetate (31.7 mL) was added, and ALPS (34.4 g) was added, and the progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate = 1: 5) while stirring at 40 ° C for 24 hours. After completion of the reaction, the mixture was filtered through a pad of celite and concentrated in vacuo. The mixture was purified by column chromatography (hexane: ethyl acetate = 1: 5) to give the pure product from ((3a R, 4 S, 5 R, 6a S) -5- hydroxy-2-oxo-hexahydro--2 H - Cyclopenta [ b ] furan-4-yl) methyl acetate (4) (66.3 g, 90%).

^{1 H NMR (300 MHz, CDCl} 3): δ 4.95 (1H, ddd, J = 6.9, 4.2, 2.7 Hz), 4.08 (3H, m), 2.82 (1H, q, J = 7.8 Hz), 2.66 (1H m), 2.60 (1H, dd, J = 12.9, 7.2 Hz), 2.39 (1H, m), 2.10 (6H, m).

Example 3: Preparation of the compound of formula (5)

The - (cyclopenta [b] furan-4-one (3a R, 4 S, 5 R, 6a S) -5- hydroxy-2-oxo-hexahydro-H -2) methyl acetate (4) (66.3 g) The reaction mixture was dissolved in methylene chloride (773.7 mL) and stirred. Diisopropylethylamine (162 mL) was added thereto, and the reaction solution was cooled to 0 占 폚. Benzyl chloromethyl ether (119.56 mL) was added dropwise, the temperature was raised to room temperature, and the mixture was stirred for 30 hours. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate = 1: 3). After completion of the reaction, a saturated solution of ammonium chloride was added and stirred, and then the organic layer was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated in vacuo to give a viscous liquid. The mixture was purified by column chromatography (hexane: ethyl acetate = 1: 5) to give the pure product from ((3a R, 4 S, 5 R, 6a S) -5- ( Benzyloxy-methoxy) -2-oxo-hexahydro- -2 H - cyclopenta [b] furan-4-yl) methyl acetate (5) (96.2 g, yield 90%).

^{1 H NMR (300 MHz, CDCl} 3): δ 7.33 (5H, m), 4.97 (1H, ddd, J = 6.9, 4.5, 2.4 Hz), 4.77 (2H, d, J = 7.2 Hz), 4.59 (2H , d, J = 5.4 Hz) , 4.03 (4H, m), 2.83 (1H, q, J = 7.8 Hz), 2.67 (1H, m), 2.55 (1H, dd, J = 15, 2.7 Hz), 2.26 (3H, m), 2.05 (3H, s, H9).

Example 4: Preparation of the compound of formula (VI)

((3a R, 4 S, 5 R, 6a S) -5- ( Benzyloxy-methoxy) -2-oxo-hexahydro--2 H - cyclopenta [b] furan-4-yl) methyl acetate (5) ( 96.2 g) was diluted in tetrahydrofuran (1439 mL) and cooled to -50 < 0 > C to -65 < 0 > C. Diisobutyl aluminum hydride (863.4 mL) was slowly added dropwise, and the mixture was kept at -50 ° C to -65 ° C and stirred. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate = 1: 5). After stirring for 1 hour, the reaction was complete and quenched with methanol (75.78 mL). Then, the temperature was raised to room temperature, saturated potassium sodium tartrate (PST) solution (962 mL) and diethyl ether (1000 mL) were added and stirred for 1 hour. The organic layer was then separated, dried in anhydrous sodium sulfate, filtered and evaporated in vacuo to give a viscous liquid. Column and the mixture purified by chromatography (hexane: ethyl acetate = 1: 5) to give the pure product (3a R, 4 S, 5 R, 6a S) through 5- (Benzyloxy-methoxy) -4- (hydroxymethyl ) Hexahydro- 2H -cyclopenta [ b ] furan-2-ol (6) (67.7 g, 80%).

^{1 H NMR (300 MHz, CDCl} 3): δ 7.33 (5H, m), 5.58 (1H, m), 4.84 (2H, d, J = 3.3), 4.60 (2H, d, J = 5.7), 4.06 ( 1H, m), 3.62 (2H, m), 2.11 (7H, m).

Example 5: Preparation of compound of formula 8

(4-carboxybutyl) triphenylphosphonium bromide (7) (249.42 g) was suspended in tetrahydrofuran (1355 mL) and the reaction solution was cooled to 0 占 폚. Then, potassium t-butoxide (129.18 g) was added and the mixture was heated to room temperature and stirred. (3a R, 4 S, 5 R, 6a S) -5- ( Benzyloxy-methoxy) -4- (hydroxymethyl) -2-hexahydro-H - cyclopenta [b] furan-2-ol (6) ( 67.7 g) was diluted with tetrahydrofuran (680 mL), and the mixture was stirred at room temperature for 2 hours. The progress of the reaction was observed by thin layer chromatography (ethyl acetate: acetone: methanol = 10: 1: 1). After completion of the reaction, the reaction was cooled to 10 ° C and ice water (670 mL) was added. The water layer was washed with diethyl ether (1000 mL) to remove impurities and the water layer was separated and adjusted to pH 4 to pH 5 with 1N hydrochloric acid. Extracted with ethyl acetate (1000 mL) and the organic layer was separated and dried in anhydrous sodium sulfate. It is then filtered and concentrated in vacuo to afford ( Z ) -7 - (( 1R , 2S , 3R , 5S ) -3- (benzyloxymethoxy) -5- ) Cyclopentyl) hept-5-enone acid (8). The obtained (Z) -7 - ((1 R, 2 S, 3 R, 5 S) -3- ( benzyloxycarbonyl-methoxy) -5-hydroxy-2- (hydroxymethyl) cyclopentyl) hept -5 -Nonanoic acid (8) was used in the next reaction without further purification.

Example 6: Preparation of the compound of formula (9)

(Z) -7 - a ((1 R, 2 S, 3 R, 5 S) -3- ( benzyloxycarbonyl-methoxy) -5-hydroxy-2- (hydroxymethyl) cyclopentyl) hept-5 N-Acid 8 (87.14 g) was dissolved in acetone (2302 mL) and stirred. Potassium carbonate (63.64 g) was added, benzyl bromide (54.77 mL) was added, and the mixture was stirred at room temperature for 18 hours. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate = 1: 1). After completion of the reaction, the mixture was filtered through a celite pad and concentrated in vacuo to obtain a viscous liquid. The mixture was purified by column chromatography (hexane: ethyl acetate = 1: 1) to give the pure product ( Z ) -benzyl 7 - (( 1R , 2S , 3R , 5S ) -3- (benzyloxymethoxy ) -5-hydroxy-2- (hydroxymethyl) cyclopentyl) hept-5-enoate (9) (86.3 g, 80%).

^{1 H NMR (700 MHz, CDCl} 3): δ 7.35 (10H, m), 5.47 (1H, m), 5.39 (1H, m), 5.10 (2H, s), 4.80 (2H, dd, J = 20.8, M), 3.46 (1H, m), 2.35 (3H, m), 4.62 (2H, d, J = m), 2.21 (1H, m), 2.13 (2H, m), 2.02 (1H, m), 1.92 (2H, m), 1.72

Example 7: Preparation of the compound of formula (10)

(Z) - benzyl-7 - ((1 R, 2 S, 3 R, 5 S) -3- ( benzyloxycarbonyl-methoxy) -5-hydroxy-2- (hydroxymethyl) cyclopentyl) hept-5 Enoate (9) (86.3 g) was diluted in methylene chloride (863.10 mL) and the reaction was cooled to 0 < 0 > C. Death-Martin Puri Iodine (234.3 g) was added and the mixture was stirred for 10 minutes. Then, the reaction solution was warmed to room temperature and stirred for 2 hours. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate = 2: 1). After completion of the reaction, the reaction mixture was quenched with 10% sodium thiosulfate (2500 mL) and saturated sodium bicarbonate (2500 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The mixture was purified by column chromatography (hexane: ethyl acetate = 5: 1) to give the pure product ( Z ) -benzyl 7 - (( 1R , 2R , 3R ) -3- (benzyloxymethoxy) -Formyl-5-oxocyclopentyl) hept-5-enoate (10) (66.25 g, 80%).

_{^{1 H NMR (700MHz, CDCl 3}} ): δ 9.79 (1H, s), 7.31 (10H, m), 5.47 (1H, m), 5.27 (1H, m), 5.11 (2H, s), 4.78 (2H, dd, J = 13.4, 7.1 Hz ), 4.58 (2H, s), 4.52 (1H, dd, J = 14.9, 7.5 Hz), 2.99 (1H, m), 2.78 (1H, m), 2.56 (1H, m ), 2.45 (1H, m), 2.33 (4H, m), 2.06 (2H, m), 1.70 (2H, m).

Example 8: Preparation of the compound of formula (12)

(73.63 g) of dimethyl 3,3-difluoro-2-oxoheptylphosphonate (11) was diluted with methyl t-butyl ether (187 mL), lithium hydroxide (8.98 g) Lt; / RTI > Then, (Z) - benzyl-7 - ((1 R, 2 R, 3 R) -3- ( Benzyloxy-methoxy) -2-formyl-5-oxo-cyclopentyl) hept-5-enoic aeyi bit (10 ) (66.25 g) was diluted with methyl t-butyl ether (800 mL), added dropwise with water (59.6 mL), and stirred at room temperature for 48 hours. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate = 3: 1). After completion of the reaction, a saturated aqueous solution of ammonium chloride was added and stirred, and the organic layer was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give a mixture in vacuo, column chromatography (hexane: ethyl acetate = 5: 1) to give pure product (Z) - benzyl-7 - ((1 R, 2 R, 3 R) -3- (Benzyloxymethoxy) -2 - (( E ) -4,4-difluoro-3-oxooct-1-enyl) -5-oxocyclopentyl) hept-5-enoate g, 65%).

_{^{1 H NMR (700MHz, CDCl 3}} ): δ 7.32 (10H, m), 7.12 (1H, dd, J = 15.5, 8.6 Hz), 6.67 (1H, dd, J = 15.5, 0.7 Hz), 5.44 (1H, m), 5.26 (1H, m ), 5.10 (2H, s), 4.75 (2H, dd, J = 14.9, 7.1 Hz), 4.54 (2H, dd, J = 14.6, 11.7 Hz), 4.18 (1H, m ), 2.83 (2H, m), 2.35 (4H, m), 2.24 (2H, m), 2.01 (4H, m), 1.69 J = 7.2 Hz).

Example 9: Preparation of rubyprostone

( Z ) -benzyl 7 - (( 1R , 2R , 3R ) -3- (benzyloxymethoxy) -2 - (( E ) -4,4-difluoro- Enyl) -5-oxocyclopentyl) hept-5-enoate (12) (55.3 g) was diluted with isopropyl alcohol (300 mL) and stirred. 10% Pd / C (11.06 g) was diluted in isopropyl alcohol (806 mL) and acetic acid (0.53 mL) was added. The reaction mixture was stirred at room temperature under hydrogen for 24 hours. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate = 1: 1). After completion of the reaction, the mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to give a mixture. The mixture was purified by column chromatography (methylene chloride: methyl t-butyl ether = 2: 1) to obtain rubyprostone (1) (32 g, 90%).

The viscous liquid rubyprostone was dissolved in ethyl acetate (2 volumes) and vigorously stirred with hexane (10 volumes) added dropwise. The reaction solution in the dilute solution state was cooled to 5 캜 to 10 캜 and stirred to obtain a high-purity rubyprosthone.

_{^{1 H NMR (700MHz, CDCl 3}} ): δ 4.18 (1H, ddd, J = 11.4, 10.0, 7.2 Hz), 2.57 (1H, dd, J = 17.6, 7.2 Hz), 2.34 (2H, t, J = 7.4 Hz), 2.25 (1H, dd , J = 17.7, 11.6 Hz), 1.96 (4H, m), 1.81 (3H, m), 1.58 (7H, m), 1.36 (8H, m), 0.93 (3H, t , J = 7.3 Hz).

Claims (18)

(i) deprotecting a compound of formula (2) in the presence of a base to obtain a compound of formula (3);
(ii) reacting a compound of formula (3) with vinyl acetate in the presence of a lipase to selectively protect a primary hydroxyl group to obtain a compound of formula (4);
(iii) reacting a compound of formula (4) with benzyl chloromethyl ether to protect the secondary hydroxyl group to obtain a compound of formula (5);
(iv) reducing the ketone of the compound of formula (5) and simultaneously deprotecting the protecting group of the primary hydroxyl group to obtain a compound of formula (6);
(v) subjecting a compound of formula (6) to a Wittig reaction with a compound of formula (7) to obtain a compound of formula (8);
(vi) reacting a compound of formula 8 with benzyl bromide to protect the carboxylic acid group to give a compound of formula 9;
(vii) oxidizing the primary and secondary hydroxyl groups of the compound of formula (9) to obtain a compound of formula (10);
(viii) subjecting a compound of formula (10) to a Wittig reaction with a compound of formula (11) to obtain a compound of formula (12); And
(ix) hydrogenating and deprotecting a compound of formula (12) below under hydrogenation at Pd / C to produce a rubyprostone of formula (1)
(2)

(3)

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

(7)

[Chemical Formula 8]

[Chemical Formula 9]

[Chemical formula 10]

(11)

[Chemical Formula 12]

[Chemical Formula 1]

In this formula,
Bz is a benzoyl group,
Ac is an acetyl group,
R and Bn are benzyl groups. 2. The process of claim 1 wherein in step (i) the base is sodium methoxide. The method according to claim 1, wherein the lipase in step (ii) is an alkaline phosphatase (ALPS). 3. The process according to claim 1, wherein in step (iii) the reaction is carried out in the presence of a base. 5. The process according to claim 4, wherein the base is diisopropylethylamine. The process according to claim 1, wherein the reduction and deprotection reactions are carried out in the presence of diisobutyl aluminum hydride (DIBAL) in step (iv). 2. The process according to claim 1, wherein the Wittig reaction in step (v) is carried out in the presence of a base. 8. The process according to claim 7, wherein the base is potassium t-butoxide. 3. The process according to claim 1, wherein in step (vi) the reaction is carried out in the presence of a base. 10. The process of claim 9, wherein the base is potassium carbonate. 3. The process according to claim 1, wherein the oxidation reaction in step (vii) is carried out in the presence of Des-Martin puriodinan (DMP). 2. The process according to claim 1, wherein in step (viii) the Wittig reaction is carried out in the presence of a base. 13. The process according to claim 12, wherein the base is lithium hydroxide. 3. The process according to claim 1, wherein the hydrogenation and deprotection reactions in step (ix) are carried out in the presence of an acid. 15. The process according to claim 14, wherein the acid is acetic acid. Compounds of formula 5:
[Chemical Formula 5]

In this formula,
Ac is an acetyl group,
R is a benzyl group. (i) deprotecting a compound of formula (2) in the presence of a base to obtain a compound of formula (3);
(ii) reacting a compound of formula (3) with vinyl acetate in the presence of a lipase to selectively protect a primary hydroxyl group to obtain a compound of formula (4); And
(iii) a step of reacting a compound of the following formula (4) with benzyl chloromethyl ether to protect the secondary hydroxyl group:
(2)

(3)

[Chemical Formula 4]

[Chemical Formula 5]

In this formula,
Bz is a benzoyl group,
Ac is an acetyl group,
R is a benzyl group. (iv) reducing the ketone of the compound of formula (5) and simultaneously deprotecting the protecting group of the primary hydroxyl group to obtain a compound of formula (6);
(v) subjecting a compound of formula (6) to a Wittig reaction with a compound of formula (7) to obtain a compound of formula (8);
(vi) reacting a compound of formula 8 with benzyl bromide to protect the carboxylic acid group to give a compound of formula 9;
(vii) oxidizing the primary and secondary hydroxyl groups of the compound of formula (9) to obtain a compound of formula (10);
(viii) subjecting a compound of formula (10) to a Wittig reaction with a compound of formula (11) to obtain a compound of formula (12); And
(ix) hydrogenating and deprotecting a compound of formula (12) below under hydrogenation at Pd / C to produce a rubyprostone of formula (1)
[Chemical Formula 5]

[Chemical Formula 6]

(7)

[Chemical Formula 8]

[Chemical Formula 9]

[Chemical formula 10]

(11)

[Chemical Formula 12]

[Chemical Formula 1]

In this formula,
Ac is an acetyl group,
R and Bn are benzyl groups.