CN108084073A - A kind of method for purifying Bimatoprost - Google Patents

A kind of method for purifying Bimatoprost Download PDF

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Publication number
CN108084073A
CN108084073A CN201711264254.4A CN201711264254A CN108084073A CN 108084073 A CN108084073 A CN 108084073A CN 201711264254 A CN201711264254 A CN 201711264254A CN 108084073 A CN108084073 A CN 108084073A
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bimatoprost
column chromatography
percent
mesh
bemepiride
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CN108084073B (en
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陈英杰
刘念
冉海琳
吴佳
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CHONGQING YAOYOU PHARMACEUTICAL Co Ltd
Chongqing Carelife Pharmaceutical Co Ltd
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CHONGQING YAOYOU PHARMACEUTICAL Co Ltd
Chongqing Carelife Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
    • C07C405/0041—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing nitrogen

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention provides in a kind of removing Bimatoprost crude product 5, the method of 6 transisomer impurity, by removing 5,6 transisomer impurity to Bimatoprost crude product derivative, column chromatography, high-purity Bimatoprost is obtained by dissociation again, can further be recrystallized.

Description

Method for purifying bemeprostil
Technical Field
The invention relates to a purification method of bemepiride, which is used for preparing high-purity bemepiride.
Background
Bimatoprost (Bimatoprost) is a prostaglandin analogue used clinically to lower intraocular pressure in open-angle glaucoma patients or in ocular hypertension patients; the bimatoprost has the function of promoting the growth of eyelashes, and is used for promoting the growth of the eyelashes of a patient with thin eyelashes; the bemeprobamate also has the effect of activating a prostasin F2a receptor in hair follicles and promoting hair growth, and the action mechanism is expected to achieve the curative effect in the field of male baldness. The chemical name of the bimatoprost is (Z) -7- [ (1R, 2R, 3R, 5S) -3, 5-dihydroxy-2- [ (1E, 3S) -3-hydroxy-5-phenyl-1-pentenyl ] cyclopentyl ] -5-N-ethylheptenamide, and the chemical structural formula is as follows:
general methods for the preparation of bimatoprost are reported in WO1996010407, WO2002096898, EP1886992, US20090163596, org, lett, 2015, 17(3), pp 504-507, etc:
benzoyl Corey lactone is used as an initial material, an intermediate IV is obtained through steps of oxidation, Wittig-Horner reaction, reduction, hydrolysis and the like, and then a bemeprost crude product is directly obtained through the Wittig reaction, or the bemeprost V is obtained through the Wittig reaction, and then the bemeprost crude product is obtained through steps of esterification, ammonolysis and the like, and finally the bemeprost crude product is purified to obtain a bemeprost finished product. Since the synthesis process of bemepiride comprises a one-step Wittig reaction, the reaction inevitably generates bemepiride 5, 6-trans isomer III which is a main impurity of bemepiride. EP2135860 reports that the impurity level is generally 3-5%. The chemical structure and physicochemical properties of the impurity are very similar to those of bemeseritrin and are difficult to effectively remove by conventional means.
WO2012011128 discloses a method for removing 5, 6-trans isomer by preparative chromatography, the content of which is not higher than 0.15%; WO2009153206 discloses a method for reducing the total content of 15R-bemesedin and 5, 6-trans isomer to not more than 0.7% by preparative chromatography; CN102690219 discloses a method for reducing the total content of beameprostate and 5, 6-trans isomer to not more than 0.3% by preparative chromatography. The 5, 6-trans isomer is removed by means of preparative chromatography, so that the purification efficiency is low, the cost is high, and special equipment is required for production, which is not beneficial to production amplification.
CN104370786 provides a method for forming a macrolide from a prostaglandin compound and then removing the 5, 6-trans isomer, which can reduce the 5, 6-trans isomer to no detectable level, but involves many steps such as esterification, hydrolysis, recrystallization, amination, column chromatography, deprotection, etc., and the operation is complicated, and the total yield is only about 33.5% of the finished bemeprostane based on compound v.
Considering that the generation of 5, 6-trans isomer is inevitable in the process of preparing bemeseritin, and the prior art has limited removal capability and higher cost, a method for preparing high-purity bemeseritin by effectively and conveniently removing 5, 6-trans isomer impurities is required for safer application and reduction of production cost.
Disclosure of Invention
The invention aims to provide a method for preparing high-purity bimatoprost by specifically removing 5, 6-trans isomer impurities.
The method comprises the following steps:
a) derivatization: reacting the crude product of bemepiride with a halogenated silane reagent to obtain a compound II
；
b) Column chromatography: purifying the compound II by column chromatography;
c) dissociation: dissociating the compound II after column chromatography to obtain high-purity bimatoprost
；
Wherein,
r is selected from trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diisopropylsilyl or diphenylsilyl;
x is selected from chlorine, bromine or iodine.
Wherein, the crude bimatoprost is obtained by Wittig reaction, and usually contains 3-5% of 5, 6-trans isomer impurity III.
Reagents for derivatizing bemesectin are common halosilane reagents including trimethylchlorosilane (TMSCl), triethylchlorosilane (TESCl), triisopropylchlorosilane (tipsccl), tert-butyldimethylchlorosilane (TBDMSCl), tert-butyldiphenylchlorosilane (TBDPSCl), diisopropylchlorosilane (DIPSCl), diphenylchlorosilane (DPMSCl), and the like.
The filler used for column chromatography is selected from 100-200 mesh, 200-300 mesh, 300-400 mesh or 400-800 mesh column chromatography silica gel.
The eluent used for column chromatography is one or a mixture of more of organic solvents such as methanol, ethyl acetate, dichloromethane, n-heptane, n-hexane, cyclohexane, petroleum ether and the like. The column chromatography gave predominantly compound II with a 5, 6-trans isomer impurity residue of typically less than 0.10%.
The purity of the bimatoprost obtained after dissociation is not less than 99.9%, and the impurity III of the 5, 6-trans isomer is less than 0.10%.
The reagents used in the dissociation reaction are common silyl ether deprotection reagents such as hydrochloric acid, tetrabutylammonium fluoride, hydrofluoric acid and the like.
The dissociated bemepiride can be further recrystallized to obtain bemepiride in a better solid form, and the impurity level can be further reduced.
The solvent used in the recrystallization step is selected from one or a mixture of methanol, ethanol, isopropanol, tert-butanol, ethyl acetate, isopropyl acetate, butyl acetate, toluene, methyl tert-butyl ether, acetonitrile, dichloromethane, acetone, n-hexane, cyclohexane, petroleum ether and n-heptane.
The method solves the problem that 5, 6-trans isomer impurities are difficult to remove in the preparation process of the bemepiride, overcomes the defects of complicated impurity removal process and high impurity removal cost in the prior art, removes the 5, 6-trans isomer impurities by a conventional means to obtain the high-purity bemepiride, has simple and convenient operation and mild conditions, and provides an effective way for preparing the high-purity bemepiride.
Detailed Description
Example 1
Preparation of crude bimatoprost
Compound IV was prepared according to the method described in EP2495235 and compound VII was prepared according to the method described in org. Lett., 2015, 17(3), pp 504-507.
Adding 37.8g (3.5eq) of compound V into a reaction bottle, adding 50mL of tetrahydrofuran, uniformly stirring, cooling to-10 ℃, dissolving 18g (7 eq) of potassium tert-butoxide in 50mL of tetrahydrofuran, then dropwise adding into the reaction liquid, controlling the temperature to be not more than-10 ℃, after the addition is finished, keeping the temperature for reaction for 30min, dissolving 7g (1 eq) of compound VII in 50mL of tetrahydrofuran, dropwise adding into the reaction liquid, after the addition is finished, returning to room temperature for about 2h, monitoring the reaction completion by TLC (EA/MeOH =100: 5), adding 200mL of saturated ammonium chloride solution into the reaction liquid, stirring, dissolving, separating, extracting the aqueous phase with 200mL of ethyl acetate, combining the organic phase, washing with 400mL of saturated common salt, drying with 100g of anhydrous sodium sulfate, and concentrating to obtain 9g of crude bimatoprost, wherein the yield is: 94%, and 5, 6-trans isomer impurity content of 5.11% by HPLC detection.
Example 2
Preparation of tert-butyl dimethyl bemepiride
Dissolving 9g (1 eq) of crude bimatoprost in 90mL of dichloromethane, adding 13.0g (4 eq) of TBSCl and 6.6g (4.5 eq) of imidazole, stirring for reaction overnight, adding 90mL of saturated ammonium chloride solution into the reaction solution, separating, washing an organic phase with 90mL of saturated common salt solution, drying with 50g of anhydrous sodium sulfate, concentrating to obtain about 18g of yellow oily matter, performing chromatography with 500 g of 200-mesh silica gel column with 300 meshes, eluting with an eluent (n-heptane/ethyl acetate =12: 1) to obtain 15g of tert-butyl dimethyl bimatoprost, and performing HPLC detection with the purity of 99.92% and the yield: 91.5 percent, and the content of 5, 6-trans isomer impurities is 0.05 percent.
Example 3
Preparation of tert-butyl diphenyl bemeprostil
Dissolving 9g (1 eq) of crude bimatoprost in 90mL of dichloromethane, adding 23.8g (4 eq) of TBDPSCl and 6.6g (4.5 eq) of imidazole, stirring for reaction overnight, adding 90mL of saturated ammonium chloride solution into the reaction solution, separating, washing an organic phase with 90mL of saturated common salt solution, drying with 50g of anhydrous sodium sulfate, concentrating to obtain about 30g of yellow oily matter, performing chromatography with 600g of 200-mesh silica gel column with 300 meshes, eluting with an eluent (n-heptane/ethyl acetate =12: 1) to obtain 23g of tert-butyl diphenyl bimatoprost, and obtaining the yield: 94.3 percent, the purity is 99.91 percent by HPLC detection, and the content of 5, 6-trans isomer impurities is 0.04 percent.
Example 4
Preparation of trimethylsilyl bimatoprost
Dissolving 9g (1 eq) of crude bimatoprost in 90mL of dichloromethane, adding 9.4g (4 eq) of TMSCl and 6.6g (4.5 eq) of imidazole, stirring for reaction overnight, adding 90mL of saturated ammonium chloride solution into the reaction solution, separating, washing an organic phase with 90mL of saturated common salt solution, drying with 50g of anhydrous sodium sulfate, concentrating to obtain about 16g of yellow oily matter, performing column chromatography with 400g of 200-mesh silica gel of 300 meshes, and eluting (cyclohexane/ethyl acetate =12: 1) to obtain 12g of trimethylsilylbimeprost, wherein the yield is as follows: 87.7 percent, the purity is 99.93 percent by HPLC detection, and the content of 5, 6-trans isomer impurities is 0.03 percent.
Example 5
Preparation of diisopropylsilyl bimatoprost
Dissolving 9g (1 eq) of crude bimatoprost in 90mL of dichloromethane, adding 13.0g (4 eq) of DIPSCl and 6.6g (4.5 eq) of imidazole, stirring for reaction overnight, adding 90mL of saturated ammonium chloride solution into the reaction solution, separating, washing an organic phase with 90mL of saturated common salt, drying with 50g of anhydrous sodium sulfate, concentrating to obtain about 19g of yellow oily matter, performing column chromatography with 400g of 200-mesh silica gel column of 300 meshes, and eluting (petroleum ether/ethyl acetate =15: 1) to obtain 15g of diisopropylsilicaberaprost, wherein the yield is as follows: 92.1 percent, the purity is 99.93 percent by HPLC detection, and the content of 5, 6-trans isomer impurities is 0.04 percent.
Example 6
Preparation of bimatoprost
Dissolving 15g (1 eq) of tert-butyl dimethyl bevacizine in 150mL of tetrahydrofuran, adding 79mL (4 eq) of 1N hydrochloric acid solution, stirring for reacting overnight, adding 100mL of saturated saline solution into the reaction solution, separating, extracting the aqueous phase with 100mL of ethyl acetate, combining the organic phases, washing with 100mL of saturated saline solution, drying with 20g of anhydrous sodium sulfate, concentrating to obtain an oily substance, adding 100mL of methyl tert-butyl ether, pulping for 2 hours, and filtering to obtain 7.2g of white solid bevacizine, wherein the yield is as follows: 87.6 percent, the purity is 99.95 percent by HPLC detection, and the content of 5, 6-trans isomer impurities is 0.02 percent.
Example 7
Preparation of bimatoprost
Dissolving 23g (1 eq) of tert-butyl diphenyl bemepiride in 230mL of tetrahydrofuran, adding 81mL (4 eq) of 1N hydrochloric acid solution, stirring for reacting overnight, adding 100mL of saturated saline solution into the reaction solution, separating, extracting the water phase with 100mL of ethyl acetate, combining the organic phases, washing with 100mL of saturated saline solution, drying with 20g of anhydrous sodium sulfate, concentrating to obtain an oily substance, adding 100mL of methyl tert-butyl ether, pulping for 2 hours, filtering to obtain 7.3g of white solid bemepiride, wherein the yield is 86.4%, and the purity is 99.96% by HPLC detection, and the content of 5, 6-trans isomer impurities is 0.02%.
Example 8
Preparation of bimatoprost
Dissolving 12g (1 eq) of trimethylsilyl bimatoprost in 120mL of tetrahydrofuran, adding 63mL (4 eq) of 1N hydrochloric acid solution, stirring for reaction overnight, adding 100mL of saturated saline solution into the reaction solution, separating, extracting the aqueous phase with 100mL of ethyl acetate, combining the organic phases, washing with 100mL of saturated saline solution, drying with 20g of anhydrous sodium sulfate, concentrating to obtain an oily substance, adding 100mL of methyl tert-butyl ether, pulping for 2 hours, and filtering to obtain 7.3g of white solid bimatoprost, wherein the yield is as follows: 92.6 percent, the purity is 99.97 percent by HPLC detection, and the content of 5, 6-trans isomer impurities is 0.01 percent.
Example 9
Preparation of bimatoprost
Dissolving 15g (1 eq) of diisopropylsilylbimatoprost in 150mL of tetrahydrofuran, adding 79mL (4 eq) of 1N hydrochloric acid solution, stirring for reacting overnight, adding 100mL of saturated saline solution into the reaction solution, separating, extracting the aqueous phase with 100mL of ethyl acetate, combining the organic phases, washing with 100mL of saturated saline solution, drying with 20g of anhydrous sodium sulfate, concentrating to obtain an oily substance, adding 100mL of methyl tert-butyl ether, pulping for 2 hours, and filtering to obtain 7.5g of white solid bimatoprost, wherein the yield is as follows: 91.5 percent, and the purity is 99.96 percent and the content of 5, 6-trans isomer impurity is 0.02 percent by HPLC detection.
Example 10
Recrystallization of bimatoprost
Adding 7.2g of bemepiride obtained in example 6 into a reaction bottle, adding 29mL of ethyl acetate and 144mL of methyl tert-butyl ether, heating, dissolving, cooling, keeping the temperature at 50 ℃ for 1h, cooling in an ice water bath to 0-5 ℃, keeping the temperature for 1h, performing suction filtration, washing a filter cake with 15mL of methyl tert-butyl ether, and drying at 40 ℃ under reduced pressure to obtain 6.8g of white bemepiride crystals, wherein the yield is as follows: 94.4 percent, the purity is 99.98 percent by HPLC detection, and 5, 6-trans isomer impurities are not detected.
Example 11
Recrystallization of bimatoprost
Adding 7.3g of bemepiride obtained in example 7 into a reaction bottle, adding 29mL of ethyl acetate and 146mL of methyl tert-butyl ether, heating, dissolving, cooling, keeping the temperature at 50 ℃ for 1h, cooling in an ice water bath to 0-5 ℃, keeping the temperature for 1h, performing suction filtration, washing a filter cake with 15mL of methyl tert-butyl ether, and drying at 40 ℃ under reduced pressure to obtain 7.0g of white bemepiride crystals, wherein the yield is as follows: 95.9 percent, the purity is 99.99 percent by HPLC detection, and 5, 6-trans isomer impurities are not detected.
Example 12
Recrystallization of bimatoprost
Adding 7.3g of bemepiride obtained in example 8 into a reaction bottle, adding 36mL of acetonitrile and 73mL of methyl tert-butyl ether, heating, dissolving, cooling, performing heat preservation and crystallization at 35 ℃ for 1h, cooling in an ice water bath to 0-5 ℃, performing heat preservation for 1h, performing suction filtration, washing a filter cake with 36mL of methyl tert-butyl ether, and drying at 40 ℃ under reduced pressure to obtain 6.9g of white bemepiride crystals, wherein the yield is as follows: 94.5 percent, the purity is 99.98 percent by HPLC detection, and 5, 6-trans isomer impurities are not detected.
Example 13
Recrystallization of bimatoprost
Adding 7.5g of bemepiride obtained in example 9 into a reaction bottle, adding 75mL of acetonitrile, heating to dissolve, cooling, keeping the temperature at 25 ℃ for 1h, performing heat preservation and crystallization, cooling in an ice water bath to 0-5 ℃, keeping the temperature for 1h, performing suction filtration, washing a filter cake with 20mL of acetonitrile at 0 ℃, and drying at 40 ℃ under reduced pressure to obtain 6.7g of white bemepiride crystals, wherein the yield is as follows: 89.3 percent, the purity is 99.99 percent by HPLC detection, and 5, 6-trans isomer impurities are not detected.

Claims (5)

1. A method for purifying bimatoprost having the structure of formula I, comprising the steps of:
a) derivatization: reacting the crude product of bemepiride with a halogenated silane reagent to obtain a compound II
；
b) Column chromatography: purifying the compound II by column chromatography;
c) dissociation: dissociating the compound II after column chromatography to obtain high-purity bimatoprost
；
Wherein,
r is selected from trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diisopropylsilyl or diphenylsilyl;
x is selected from chlorine, bromine or iodine.
2. The purification method as claimed in claim 1, wherein the filler used in the column chromatography is selected from 100-200 mesh, 200-300 mesh, 300-400 mesh or 400-800 mesh column chromatography silica gel.
3. The purification process according to claim 1, wherein the eluent used for column chromatography is selected from one or a mixture of methanol, ethyl acetate, dichloromethane, n-heptane, n-hexane, cyclohexane and petroleum ether.
4. The purification process according to claim 1, wherein the agent for dissociation is selected from hydrochloric acid, tetrabutylammonium fluoride or hydrofluoric acid.
5. The purification process according to claim 1, further comprising a step of recrystallizing the obtained bimatoprost.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111018766A (en) * 2018-10-10 2020-04-17 广州楷模生物科技有限公司 Method for synthesizing bimatoprost
CN115677549A (en) * 2022-10-27 2023-02-03 神隆医药（常熟）有限公司 Preparation method of bimatoprost chiral isomer

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US6476064B1 (en) * 2001-06-13 2002-11-05 Allergan, Inc. Cyclopentane heptan(ene) acyl sulfonamide, 2-alkyl or 2-arylalkyl, or 2-heteroarylalkenyl derivatives as therapeutic agents
US20090163596A1 (en) * 2006-08-29 2009-06-25 Arie Gutman Bimatoprost crystalline form I
EP2135860A1 (en) * 2008-06-20 2009-12-23 Sandoz AG Improved process for the production of bimatoprost
WO2012011128A1 (en) * 2010-07-23 2012-01-26 Aptuit Laurus Private Limited Preparation of prostaglandin derivatives
CN102690219A (en) * 2011-03-24 2012-09-26 天津信汇制药股份有限公司 Method for purifying bimatoprost
CN104370786A (en) * 2013-08-15 2015-02-25 佳和桂科技股份有限公司 Processes for the preparation of isomer free prostaglandins

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6476064B1 (en) * 2001-06-13 2002-11-05 Allergan, Inc. Cyclopentane heptan(ene) acyl sulfonamide, 2-alkyl or 2-arylalkyl, or 2-heteroarylalkenyl derivatives as therapeutic agents
US20090163596A1 (en) * 2006-08-29 2009-06-25 Arie Gutman Bimatoprost crystalline form I
EP2135860A1 (en) * 2008-06-20 2009-12-23 Sandoz AG Improved process for the production of bimatoprost
WO2012011128A1 (en) * 2010-07-23 2012-01-26 Aptuit Laurus Private Limited Preparation of prostaglandin derivatives
CN102690219A (en) * 2011-03-24 2012-09-26 天津信汇制药股份有限公司 Method for purifying bimatoprost
CN104370786A (en) * 2013-08-15 2015-02-25 佳和桂科技股份有限公司 Processes for the preparation of isomer free prostaglandins

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111018766A (en) * 2018-10-10 2020-04-17 广州楷模生物科技有限公司 Method for synthesizing bimatoprost
CN111018766B (en) * 2018-10-10 2022-04-19 广州楷石医药有限公司 Method for synthesizing bimatoprost
CN115677549A (en) * 2022-10-27 2023-02-03 神隆医药（常熟）有限公司 Preparation method of bimatoprost chiral isomer

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