CN102241722B - A kind of purification process synthesizing progesterone receptor modulator gifted zafirlukast - Google Patents
A kind of purification process synthesizing progesterone receptor modulator gifted zafirlukast Download PDFInfo
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- CN102241722B CN102241722B CN201010169772.XA CN201010169772A CN102241722B CN 102241722 B CN102241722 B CN 102241722B CN 201010169772 A CN201010169772 A CN 201010169772A CN 102241722 B CN102241722 B CN 102241722B
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- Prior art keywords
- gifted
- zafirlukast
- receptor modulator
- progesterone receptor
- purification process
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- 238000000746 purification Methods 0.000 title claims abstract description 10
- 239000002379 progesterone receptor modulator Substances 0.000 title abstract description 5
- YEEZWCHGZNKEEK-UHFFFAOYSA-N Zafirlukast Chemical compound COC1=CC(C(=O)NS(=O)(=O)C=2C(=CC=CC=2)C)=CC=C1CC(C1=C2)=CN(C)C1=CC=C2NC(=O)OC1CCCC1 YEEZWCHGZNKEEK-UHFFFAOYSA-N 0.000 title description 11
- 229960004764 zafirlukast Drugs 0.000 title description 11
- 230000002194 synthesizing effect Effects 0.000 title description 2
- OOLLAFOLCSJHRE-ZHAKMVSLSA-N ulipristal acetate Chemical compound C1=CC(N(C)C)=CC=C1[C@@H]1C2=C3CCC(=O)C=C3CC[C@H]2[C@H](CC[C@]2(OC(C)=O)C(C)=O)[C@]2(C)C1 OOLLAFOLCSJHRE-ZHAKMVSLSA-N 0.000 claims abstract description 17
- 229960000499 ulipristal acetate Drugs 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- 239000000377 silicon dioxide Substances 0.000 claims description 4
- 239000012535 impurity Substances 0.000 abstract description 7
- 239000000741 silica gel Substances 0.000 description 12
- 229910002027 silica gel Inorganic materials 0.000 description 12
- 239000000047 product Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 9
- 239000013078 crystal Substances 0.000 description 7
- 230000006837 decompression Effects 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 239000012467 final product Substances 0.000 description 5
- 239000012043 crude product Substances 0.000 description 4
- 230000017858 demethylation Effects 0.000 description 4
- 238000010520 demethylation reaction Methods 0.000 description 4
- 206010013786 Dry skin Diseases 0.000 description 3
- 229960000935 dehydrated alcohol Drugs 0.000 description 3
- 229960004756 ethanol Drugs 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000011068 loading method Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 150000002989 phenols Chemical class 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 1
- 229960003328 benzoyl peroxide Drugs 0.000 description 1
- 239000003433 contraceptive agent Substances 0.000 description 1
- 230000002254 contraceptive effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides the purification process that a kind of progesterone receptor modulator ulipristal acetate is new.The method can be removed various impurity fast and obtain high purity ulipristal acetate, and method is easy and simple to handle, and yield is high, and suitability for industrialized is produced.
Description
Technical field
What the present invention relates to is a kind of progesterone receptor modulator ulipristal acetate (ulipristalacetate), i.e. 17 α-acetoxyl group-11 β-[4-(N, N-dimethylamino)-phenyl] purification process that-19-norpregna-4,9-diene-3,20-diketone is new.
Technical background
Ulipristal acetate (ulipristalacetate, formula I) is a kind of progesterone receptor modulator, tool PgR antagonism and PAA.This medicine is developed by HRA drugmaker, obtains EU Committee's approval in May, 2009, as the emergency contraception used in after the sexual intercourse of women's unprotect or contraceptive failure 5 days.
About ulipristal acetate medicine wherein a kind of typical synthetic method at United States Patent (USP) 5,929, open in 262.Be described to a kind of product in yellow crystals form with the final product that the method described in described United States Patent (USP) 5,929,262 embodiment 7 obtains, fusing point is between 183 and 185 DEG C.The existence of described yellow color shows to there is impurity, mainly phenolic compound.
PCT patent 2004/065405 discloses ulipristal acetate preparation method, and it is by the recrystallization to key intermediate Virahol half solvate, obtains not containing the ulipristal acetate crystal of solvation.The final product purity obtained in this way is wayward, and the intermediate gifted zafirlukast do not reacted completely and demethylation gifted zafirlukast remain larger.
Summary of the invention
The invention provides and a kind ofly simply can remove the method that impurity obtains high purity ulipristal acetate crystal.
Be specially:
Crude product gifted zafirlukast, by silica column purification, removes the impurity (intermediate gifted zafirlukast and demethylation gifted zafirlukast etc.) that Polarity comparision is large.Remove the impurity (mainly phenolic compound) of some low polarity again with ethyl acetate and sherwood oil recrystallization, the ratio of ethyl acetate and sherwood oil is 1: 1 ~ 1: 5.Use ethanol and water crystallization again, remove residual solvent.The ratio of second alcohol and water is 1: 1 ~ 1: 2.
The advantage of the method is:
1) silica column purification is adopted to remove intermediate gifted zafirlukast and demethylation gifted zafirlukast (these impurity can not be removed clean by other existing published methods, such as with ethanol/water or Virahol) fast;
2) impurity of some low polarity is removed with ethyl acetate and sherwood oil recrystallization;
3) can remove with ethanol/water crystallization and remain in ethyl acetate and sherwood oil in crystal;
4) simple, be applicable to industrialized production.
Embodiment
Embodiment 1
1) ulipristal acetate crude product 40g 60g silica gel (1.5 times) dense dry loading, cross silica gel and lean on 800g silica gel (200-300 order silica gel, 20 times of weight consumptions), with methylene dichloride: acetone=20: 1 wash-out, collect product, concentrate after doing and namely obtain desired product 35g.
2) concentrated dry rear 35g ulipristal acetate ethyl acetate 105ml dissolves, and adds 315ml sherwood oil, stirs one hour.Subsequent filtration.Solid sherwood oil: ethyl acetate=5: the mixing solutions 50 milliliters of 1 washes twice.Decompression drying.Obtain white solid powder 32 grams.
3) white solid powder 32 grams is dissolved in 300ml dehydrated alcohol, and control temperature (70 ~ 75 DEG C) under reflux conditions adds water 360ml, leaves standstill and drops to room temperature.Crystal filters, and 40 DEG C of decompression dryings obtain final product 28 grams.
Embodiment 2
1) the dense dry loading of ulipristal acetate crude product 80g 120g silica gel, cross silica gel and lean on 2400g silica gel (200-300 order silica gel, 30 times of weight consumptions), with methylene dichloride: acetone=10: 1 wash-out, collect product, concentrate after doing and namely obtain desired product 70g.
2) concentrated dry rear 70g ulipristal acetate ethyl acetate 210ml dissolves, and adds 210ml sherwood oil, stirs one hour.Subsequent filtration.Solid sherwood oil: ethyl acetate=1: the mixing solutions 100 milliliters of 1 washes twice.Decompression drying.Obtain white solid powder 58 grams.
3) white solid powder 58 grams is dissolved in 500ml dehydrated alcohol, and control temperature (70 ~ 75 DEG C) under reflux conditions adds water 500ml, leaves standstill and drops to room temperature.Crystal filters, and 40 DEG C of decompression dryings obtain final product 52 grams.
Embodiment 3
1) ulipristal acetate crude product 60g 100g silica gel (1.5 times) dense dry loading, cross silica gel and lean on 900g silica gel (200-300 order silica gel), with methylene dichloride: acetone=15: 1 wash-out, collect product, concentrated dry after namely obtain desired product 52g.
2) concentrated dry rear 52g ulipristal acetate ethyl acetate 156ml dissolves, and adds 780ml sherwood oil, stirs one and a half hours.Subsequent filtration.Solid sherwood oil: ethyl acetate=5: the mixing solutions 60 milliliters of 1 washes twice.Decompression drying.Obtain white solid powder 49 grams.
3) white solid powder 49 grams is dissolved in 300ml dehydrated alcohol, and control temperature (70 ~ 75 DEG C) under reflux conditions adds water 450ml, leaves standstill and drops to room temperature.Crystal filters, and 40 DEG C of decompression dryings obtain final product 47 grams.
Embodiment 4
Get US5,929, each foreign matter content of products measure of 262 embodiments 7, WO2004/065405 embodiment 3 and the embodiment of the present invention 1 gained.
The each foreign matter content of product (phenolic compound, intermediate gifted zafirlukast, demethylation gifted zafirlukast) of visible employing process for purification of the present invention gained is all starkly lower than US5,929,262 and WO2004/065405 in product.
Claims (3)
1. the industrialized purification method of a ulipristal acetate (I):
It is characterized in that the method first uses ethyl acetate and sherwood oil crystallization again with silica column purification, finally use ethanol and water crystallization desolventizing, described ethyl acetate and sherwood oil ratio are 1:1 ~ 1:5.
2. method according to claim 1, is characterized in that described silica column purification solution is methylene dichloride and acetone.
3., according to the method for claim 1 ~ 2, it is characterized in that the ratio of described second alcohol and water is 1:1 ~ 1:2.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201010169772.XA CN102241722B (en) | 2010-05-12 | 2010-05-12 | A kind of purification process synthesizing progesterone receptor modulator gifted zafirlukast |
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| CN201010169772.XA CN102241722B (en) | 2010-05-12 | 2010-05-12 | A kind of purification process synthesizing progesterone receptor modulator gifted zafirlukast |
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| CN102241722A CN102241722A (en) | 2011-11-16 |
| CN102241722B true CN102241722B (en) | 2015-11-25 |
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102295674B (en) * | 2011-07-14 | 2013-04-10 | 四川大学 | Method of acquiring high-purity 17 alpha-acetoxy-11 beta-(4-N, N-dimethylaminophenyl)-19-norpregna-4, 9-diene-3, 20-dione |
| CN102321141B (en) * | 2011-07-22 | 2013-05-15 | 上海希迈医药科技有限公司 | Amorphous substance of 17alpha-acetoxy-11beta-(4-N,N-dimethylaminophenyl)-19-norpregn-4,9-diene-3,20-diketone and preparation method thereof |
| CN102344478B (en) * | 2011-07-22 | 2013-08-07 | 上海希迈医药科技有限公司 | Crystal of 17 alpha-acetoxyl group-11 beta-(4-N, N-dimethylamino phenyl)-19-norpregna-4, 9- diene-3, 20- ketone and preparation method thereof |
| CN103755765B (en) * | 2012-04-17 | 2018-01-02 | 常州市第四制药厂有限公司 | Polymorphic of CDB-2914 and preparation method thereof |
| CN102887931B (en) * | 2012-07-07 | 2015-04-15 | 山东诚创医药技术开发有限公司 | Ulipristal acetate crystals and preparation method thereof |
| CN104418930B (en) * | 2013-08-23 | 2018-01-12 | 四川海思科制药有限公司 | A kind of high-purity CDB-2914 |
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|---|---|---|---|---|
| US5929262A (en) * | 1995-03-30 | 1999-07-27 | The United States Of America As Represented By The Department Of Health And Human Services | Method for preparing 17α-acetoxy-11β-(4-N, N-dimethylaminophyl)-19-Norpregna-4,9-diene-3, 20-dione, intermediates useful in the method, and methods for the preparation of such intermediates |
| CN1298409A (en) * | 1998-03-06 | 2001-06-06 | 研究三角协会 | 20-keto-11&beta, -arylsteroids and their derivatives having agonist or antagonist hormonal properties |
| WO2004078709A2 (en) * | 2003-02-28 | 2004-09-16 | The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | METHOD FOR PREPARING 17 α-ACETOXY-11β-(4-N,N-DIMETHYLAMINOPHENYL)-19-NORPREGNA-4,9-DIENE-3,20-DIONE, INTERMEDIATES THEREOF, AND METHODS FOR THE PREPARATION OF SUCH INTERMEDIATES |
| CN1753905A (en) * | 2003-01-22 | 2006-03-29 | 克利斯托制药股份有限公司 | Method of obtaining 17alpha-acetoxy-11beta-(4-n,n-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione |
| CN101466723A (en) * | 2006-06-14 | 2009-06-24 | 吉瑞工厂 | Industrial process for the synthesis of 17 alpha-acetoxy-11 beta- [ 4- (N, N-dimethyl-amino) -phenyl ] -19-norpregna-4, 9-diene-3, 20-dione and novel intermediates used in said process |
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2010
- 2010-05-12 CN CN201010169772.XA patent/CN102241722B/en active Active
Patent Citations (5)
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| US5929262A (en) * | 1995-03-30 | 1999-07-27 | The United States Of America As Represented By The Department Of Health And Human Services | Method for preparing 17α-acetoxy-11β-(4-N, N-dimethylaminophyl)-19-Norpregna-4,9-diene-3, 20-dione, intermediates useful in the method, and methods for the preparation of such intermediates |
| CN1298409A (en) * | 1998-03-06 | 2001-06-06 | 研究三角协会 | 20-keto-11&beta, -arylsteroids and their derivatives having agonist or antagonist hormonal properties |
| CN1753905A (en) * | 2003-01-22 | 2006-03-29 | 克利斯托制药股份有限公司 | Method of obtaining 17alpha-acetoxy-11beta-(4-n,n-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione |
| WO2004078709A2 (en) * | 2003-02-28 | 2004-09-16 | The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | METHOD FOR PREPARING 17 α-ACETOXY-11β-(4-N,N-DIMETHYLAMINOPHENYL)-19-NORPREGNA-4,9-DIENE-3,20-DIONE, INTERMEDIATES THEREOF, AND METHODS FOR THE PREPARATION OF SUCH INTERMEDIATES |
| CN101466723A (en) * | 2006-06-14 | 2009-06-24 | 吉瑞工厂 | Industrial process for the synthesis of 17 alpha-acetoxy-11 beta- [ 4- (N, N-dimethyl-amino) -phenyl ] -19-norpregna-4, 9-diene-3, 20-dione and novel intermediates used in said process |
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| CN102241722A (en) | 2011-11-16 |
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