CN103755763A - Preparation method of 17alpha-acetoxyl-11beta-(4-(N, N-dimethylamino)-phenyl)-19-norpregna-4, 9-diene-3, 20-diketone - Google Patents
Preparation method of 17alpha-acetoxyl-11beta-(4-(N, N-dimethylamino)-phenyl)-19-norpregna-4, 9-diene-3, 20-diketone Download PDFInfo
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- CN103755763A CN103755763A CN201310746236.5A CN201310746236A CN103755763A CN 103755763 A CN103755763 A CN 103755763A CN 201310746236 A CN201310746236 A CN 201310746236A CN 103755763 A CN103755763 A CN 103755763A
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Abstract
The invention provides a preparation method of 17alpha-acetoxyl-11beta-(4-(N, N-dimethylamino)-phenyl)-19-norpregna-4, 9-diene-3, 20-diketone. The preparation method comprises the steps of: adopting 11beta-(4-(N, N-dimethylamino)-phenyl)-17alpha-hydroxyl-19-norpregna-4, 9-diene-3, 20-diketone as the material, and carrying out acetylation reaction to obtain the 17alpha-acetoxyl-11beta-(4-(N, N-dimethylamino)-phenyl)-19-norpregna-4, 9-diene-3, 20-diketone. The preparation method also comprises the step of: using strong alkali to neutralize excessive acid in the reaction process. The preparation method provided by the invention has the advantages that the blank for using the strong alkali to neutralize excessive acid in reaction is made up, and due to adoption of strong-alkali solution, the volume of a reaction container can be reduced, the production cost is reduced, the waste-water discharge and emission of carbon dioxide are reduced and more convenience is brought for industrial production.
Description
Technical field
The invention belongs to chemical field, relate to a kind of 17 α-acetoxyl group-11 β-[4-(N, N-dimethylamino)-phenyl]-19-norpregna-4,9-diene-3, the preparation method of 20-diketone, is specifically related to a kind of sour 17 α-acetoxyl group-11 β-[4-(N, N-dimethylamino)-phenyl]-19-norpregna-4 excessive in highly basic neutralization reaction process that adopt, 9-diene-3, the preparation method of 20-diketone.
Background technology
17 α-acetoxyl group-11 β-[4-(N, N-dimethylamino)-phenyl]-19-norpregna-4,9-diene-3, CDB-2914 general by name or the ulipristal acetate of 20-diketone, its structural formula is as follows:
This compound is the medicine for emergency contraception and treatment hysteromyoma by the exploitation of French Laboratoire HRA Pharma company.This medicine goes on the market in 2009 Nian European Union, obtains U.S. food and drug administration (FDA) approval listing in August, 2010, and its commodity are called Ella.
At present by 11 β-[4-(N, N-dimethylamino)-phenyl]-17 Alpha-hydroxies-19-norpregna-4,9-diene-3,20-diketone is that raw material obtains 17 α-acetoxyl group-11 β-[4-(N through acetylize, N-dimethylamino)-phenyl]-19-norpregna-4,9-diene-3, the method for 20-diketone mainly contains two kinds: (1) is used the method for acetic acid, trifluoroacetic anhydride and tosic acid; (2) use the method for diacetyl oxide and perchloric acid.The disclosed preparation method of U5929262, WO2007144674 and WO2004078709 for example.Owing to all will using excessive acid in the building-up reactions of above-mentioned two kinds of methods, so in last handling process, need to use a large amount of alkali to neutralize.And because the synthetic product of gained is ester compound, generally believe and adopt highly basic can destroy product, therefore, be all generally to use in weak base and excessive acid.
U5929262 and CN201210383263.6 disclose and have used in wet chemical and superacid method; WO2004078709 discloses and has used in ammoniacal liquor and sodium bicarbonate aqueous solution and superacid method; CN201010552779.X discloses and has used in sodium carbonate and superacid method; WO2007144674 and CN201010253176.X disclose and have used in sodium acetate and superacid method.
In above-mentioned patent documentation, alkali major part used is weakly alkaline carbonate, because its solubleness in water is less thereby need to use a large amount of water, and then produces in process of production a large amount of waste water, and produces a large amount of carbon dioxides.And reaction process needs larger reaction vessel, has increased product cost.
Summary of the invention
The object of this invention is to provide a kind of 17 α-acetoxyl group-11 β-[4-(N, N-dimethylamino)-phenyl]-19-norpregna-4,9-diene-3, the preparation method of 20-diketone.The method has been abandoned and has all been adopted weak base neutralization by 11 β-[4-(N in the past, N-dimethylamino)-phenyl]-17 Alpha-hydroxies-19-norpregna-4, 9-diene-3, 20-diketone is that raw material obtains 17 α-acetoxyl group-11 β-[4-(N through acetylize, N-dimethylamino)-phenyl]-19-norpregna-4, 9-diene-3, excessive sour technology prejudice in the reaction of 20-diketone, use highly basic to neutralize the excess acid in this reaction process, reduced thus the volume of reaction vessel in industrial production, reduce product cost, reduce discharge of wastewater and Carbon emission, more be conducive to suitability for industrialized production, lab scale and scale-up have all been verified the stability of aforesaid method.
Above-mentioned purpose of the present invention is achieved through the following technical solutions:
A kind of 17 α-acetoxyl group-11 β-[4-(N; N-dimethylamino)-phenyl]-19-norpregna-4; 9-diene-3; the preparation method of 20-diketone; this preparation method comprises by 11 β-[4-(N; N-dimethylamino)-phenyl]-17 Alpha-hydroxies-19-norpregna-4; 9-diene-3; 20-diketone is that raw material obtains 17 α-acetoxyl group-11 β-[4-(N through acetylization reaction; N-dimethylamino)-phenyl]-19-norpregna-4,9-diene-3,20-diketone; it is characterized in that, this preparation method also comprises excessive sour step in use highly basic and in described reaction process.
Wherein, preferably, described highly basic is strong alkali aqueous solution, and for example sodium hydroxide and/or potassium hydroxide aqueous solution, be preferably aqueous sodium hydroxide solution.More preferably, described strong alkali aqueous solution is lower concentration strong alkali aqueous solution or saturated strong alkali aqueous solution.Further preferably, the concentration of described strong alkali aqueous solution is 0～20mol/L, is preferably 6mol/L.
Wherein, preferably, described acid is selected from one or more in acetic acid, trifluoroacetic acid, diacetyl oxide, trifluoroacetic anhydride, perchloric acid or tosic acid, more preferably perchloric acid and/or diacetyl oxide.
The present invention has verified above-mentioned preparation method's stability by lab scale and scale-up, use the excessive acid in highly basic neutralization reaction process, guarantees that sintetics is not hydrolyzed by a strong alkali, and product purity is reached more than 99%; In employing highly basic, with the volume that can reduce reaction vessel, reduce product cost, reduce discharge of wastewater and Carbon emission, be more conducive to suitability for industrialized production.This product of production 1kg of take is example, and the volume contrast of waste water, CO2 emissions and the reaction vessel forming by the excess acid in highly basic and weak base neutralization reaction is as shown in the table:
| ? | Highly basic (6mol/L sodium hydroxide) | Weak base (saturated sodium bicarbonate) |
| Wastewater discharge | 20L | 150L |
| CO2 emissions | 0L | 1300L |
| The volume of reaction vessel | 50L | 400L |
In addition, test shows to use other highly basic, and for example the excess acid in the aqueous solution of cesium hydroxide and in described reaction, can produce more impurity, affects the purity of product.
Embodiment
Referring to specific embodiment, the present invention is described.It will be appreciated by those skilled in the art that these embodiment are only for the present invention is described, the scope that it does not limit the present invention in any way.
embodiment 1
In the reaction flask that is 500mL at capacity, add diacetyl oxide 31.2ml, be cooled to-10 ℃, the rear 70%(g/g that slowly adds) perchloric acid 4.8ml, at-8 ℃～-10 ℃, stir 0.5 hour, be then cooled to-30 ℃, dropping contains 16.1g11 β-[4-(N, N-dimethylamino)-phenyl]-17 Alpha-hydroxies-19-norpregna-4,9-diene-3, in the dichloromethane solution 200ml(reaction process of 20-diketone, temperature is controlled at-20 ℃～-30 ℃), after dropwising, at-20 ℃～-30 ℃, react 1 hour, working concentration is the aqueous sodium hydroxide solution 120ml of 6mol/L, neutralizing excessive acid to the aqueous solution is alkalescence, continue to stir 1 hour, separatory, twice of 50ml water washing for organic phase, with anhydrous sodium sulfate drying, suction filtration, filtrate decompression is concentrated, the yellow soup compound obtaining is used the crystallization of 50ml Virahol, after crystal dissolves with 100ml dichloromethane solution, concentrating under reduced pressure obtains 17 α-acetoxyl group-11 β-[4-(N, N-dimethylamino)-phenyl]-19-norpregna-4, 9-diene-3, 20-diketone 11.3g, yield is 64.5%.Through high effective liquid chromatography for measuring, the purity of its product is greater than 99%.
embodiment 2
In the reaction flask that is 500mL at capacity, add diacetyl oxide 31.2ml, be cooled to-10 ℃, the rear 70%(g/g that slowly adds) perchloric acid 4.8ml, at-8 ℃～-10 ℃, stir 0.5 hour, be then cooled to-30 ℃, dropping contains 16.1g11 β-[4-(N, N-dimethylamino)-phenyl]-17 Alpha-hydroxies-19-norpregna-4,9-diene-3, in the dichloromethane solution 200ml(reaction process of 20-diketone, temperature is controlled at-20 ℃～-30 ℃), after dropwising, at-20 ℃～-30 ℃, react 1 hour, use saturated aqueous sodium hydroxide solution 27ml, neutralizing excessive acid to the aqueous solution is alkalescence, continue to stir 1 hour, separatory, twice of 50ml water washing for organic phase, with anhydrous sodium sulfate drying, suction filtration, filtrate decompression is concentrated, the yellow soup compound obtaining is used the crystallization of 50ml Virahol, after crystal dissolves with 100ml dichloromethane solution, concentrating under reduced pressure obtains 17 α-acetoxyl group-11 β-[4-(N, N-dimethylamino)-phenyl]-19-norpregna-4, 9-diene-3, 20-diketone 10.6g, yield is 60.6%.Through high effective liquid chromatography for measuring, the purity of its product is greater than 99%.
embodiment 3
In the reaction flask that is 500mL at capacity, add diacetyl oxide 31.2ml, be cooled to-10 ℃, the rear 70%(g/g that slowly adds) perchloric acid 4.8ml, at-8 ℃～-10 ℃, stir 0.5 hour, be then cooled to-30 ℃, dropping contains 16.0g11 β-[4-(N, N-dimethylamino)-phenyl]-17 Alpha-hydroxies-19-norpregna-4,9-diene-3, in the dichloromethane solution 200ml(reaction process of 20-diketone, temperature is controlled at-20 ℃～-30 ℃), after dropwising, at-20 ℃～-30 ℃, react 1 hour, working concentration is the potassium hydroxide aqueous solution 180ml of 4mol/L, neutralizing excessive acid to the aqueous solution is alkalescence, continue to stir 1 hour, separatory, twice of 50ml water washing for organic phase, with anhydrous sodium sulfate drying, suction filtration, filtrate decompression is concentrated, the yellow soup compound obtaining is used the crystallization of 50ml Virahol, after crystal dissolves with 100ml dichloromethane solution, concentrating under reduced pressure obtains 17 α-acetoxyl group-11 β-[4-(N, N-dimethylamino)-phenyl]-19-norpregna-4, 9-diene-3, 20-diketone 10.9g, yield is 62.2%.Through high effective liquid chromatography for measuring, the purity of its product is greater than 99%.
embodiment 4
In the reaction flask that is 500mL at capacity, add diacetyl oxide 31.2ml, be cooled to-10 ℃, the rear 70%(g/g that slowly adds) perchloric acid 4.8ml, at-8 ℃～-10 ℃, stir 0.5 hour, be then cooled to-30 ℃, dropping contains 16.0g11 β-[4-(N, N-dimethylamino)-phenyl]-17 Alpha-hydroxies-19-norpregna-4,9-diene-3, in the dichloromethane solution 200ml(reaction process of 20-diketone, temperature is controlled at-20 ℃～-30 ℃), after dropwising, at-20 ℃～-30 ℃, react 1 hour, use saturated potassium hydroxide aqueous solution 35ml, neutralizing excessive acid to the aqueous solution is alkalescence, continue to stir 1 hour, separatory, twice of 50ml water washing for organic phase, with anhydrous sodium sulfate drying, suction filtration, filtrate decompression is concentrated, the yellow soup compound obtaining is used the crystallization of 50ml Virahol, after crystal dissolves with 100ml dichloromethane solution, concentrating under reduced pressure obtains 17 α-acetoxyl group-11 β-[4-(N, N-dimethylamino)-phenyl]-19-norpregna-4, 9-diene-3, 20-diketone 11.0g, yield is 62.8%.Through high effective liquid chromatography for measuring, the purity of its product is greater than 99%.
embodiment 5
In the reaction flask that is 20L at capacity, add diacetyl oxide 1250ml, be cooled to-10 ℃, the rear 70%(g/g that slowly adds) perchloric acid 192ml, at-8 ℃～-10 ℃, stir 0.5 hour, be then cooled to-30 ℃; Dropping contains 640g11 β-[4-(N, N-dimethylamino)-phenyl]-17 Alpha-hydroxies-19-norpregna-4,9-diene-3, in the dichloromethane solution 8L(reaction process of 20-diketone, temperature is controlled at-20 ℃～-30 ℃); After dropwising, at-20 ℃～-30 ℃, react 1 hour, use saturated aqueous sodium hydroxide solution 1.2L, neutralizing excessive acid to the aqueous solution is alkalescence, continue to stir 1 hour, separatory, 2L water washing twice for organic phase, with anhydrous sodium sulfate drying, suction filtration, filtrate decompression is concentrated, the yellow soup compound obtaining is used the crystallization of 2L Virahol, after crystal dissolves with 4L dichloromethane solution, concentrating under reduced pressure obtains 17 α-acetoxyl group-11 β-[4-(N, N-dimethylamino)-phenyl]-19-norpregna-4,9-diene-3,20-diketone 461.3g, yield is 65.7%.Through high effective liquid chromatography for measuring, the purity of its product is greater than 99%.
embodiment 6
In the reaction flask that is 500mL at capacity, add diacetyl oxide 31.2ml, be cooled to-10 ℃, the rear 70%(g/g that slowly adds) perchloric acid 4.8ml, at-8 ℃～-10 ℃, stir 0.5 hour, be then cooled to-30 ℃, dropping contains 16.0g11 β-[4-(N, N-dimethylamino)-phenyl]-17 Alpha-hydroxies-19-norpregna-4,9-diene-3, in the dichloromethane solution 200ml(reaction process of 20-diketone, temperature is controlled at-20 ℃～-30 ℃), after dropwising, at-20 ℃～-30 ℃, react 1 hour, working concentration is the cesium hydroxide aqueous solution 120ml of 6mol/L, neutralizing excessive acid to the aqueous solution is alkalescence, continue to stir 1 hour, separatory, twice of 50ml water washing for organic phase, with anhydrous sodium sulfate drying, suction filtration, filtrate decompression is concentrated, the yellow soup compound obtaining is used the crystallization of 50ml Virahol, after crystal dissolves with 100ml dichloromethane solution, concentrating under reduced pressure obtains 17 α-acetoxyl group-11 β-[4-(N, N-dimethylamino)-phenyl]-19-norpregna-4, 9-diene-3, 20-diketone 10.5g, yield is 59.9%.Through high effective liquid chromatography for measuring, the purity of its product is 95%.
In a word, above specific description of embodiments of the present invention does not limit the present invention, and those skilled in the art can make according to the present invention various changes or distortion, only otherwise depart from spirit of the present invention, all should belong to the scope of claims of the present invention.
Claims (5)
1. 17 α-acetoxyl group-11 β-[4-(N; N-dimethylamino)-phenyl]-19-norpregna-4; 9-diene-3; the preparation method of 20-diketone; this preparation method comprises by 11 β-[4-(N; N-dimethylamino)-phenyl]-17 Alpha-hydroxies-19-norpregna-4; 9-diene-3; 20-diketone is that raw material obtains 17 α-acetoxyl group-11 β-[4-(N through acetylization reaction; N-dimethylamino)-phenyl]-19-norpregna-4,9-diene-3,20-diketone; it is characterized in that, this preparation method also comprises excessive sour step in use highly basic and in described reaction process.
2. preparation method according to claim 1, is characterized in that, described highly basic is strong alkali aqueous solution, and for example sodium hydroxide and/or potassium hydroxide aqueous solution, be preferably aqueous sodium hydroxide solution.
3. preparation method according to claim 1 and 2, is characterized in that, described strong alkali aqueous solution is lower concentration strong alkali aqueous solution or saturated strong alkali aqueous solution.
4. according to the preparation method described in any one in claims 1 to 3, it is characterized in that, the concentration of described strong alkali aqueous solution is 0～20mol/L, is preferably 6mol/L.
5. according to the preparation method described in any one in claim 1 to 4, it is characterized in that, described acid is one or more in acetic acid, trifluoroacetic acid, diacetyl oxide, trifluoroacetic anhydride, perchloric acid or tosic acid, is preferably perchloric acid and/or diacetyl oxide.
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| CN201310746236.5A CN103755763A (en) | 2013-12-30 | 2013-12-30 | Preparation method of 17alpha-acetoxyl-11beta-(4-(N, N-dimethylamino)-phenyl)-19-norpregna-4, 9-diene-3, 20-diketone |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110256519A (en) * | 2019-05-23 | 2019-09-20 | 江苏联环药业股份有限公司 | The method of one kettle way preparation uliprista acetate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN101466723A (en) * | 2006-06-14 | 2009-06-24 | 吉瑞工厂 | Industrial process for the synthesis of 17a-acetoxy-11ss-[4-(n,n-dimethyl-amino)- phenyl]-19-norpregna-4,9-diene-3,20-dione and new intermediates of the process |
| CN101684139A (en) * | 2008-09-27 | 2010-03-31 | 徐州师范大学 | Synthesis process of vecuronium bromide |
| CN102372760A (en) * | 2010-08-12 | 2012-03-14 | 杭州容立医药科技有限公司 | Synthesis method of progesterone receptor regulating agent ulipristal |
| CN102875629A (en) * | 2012-10-10 | 2013-01-16 | 苏州康润医药有限公司 | Synthetic method of ulipristal acetate |
-
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- 2013-12-30 CN CN201310746236.5A patent/CN103755763A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN101466723A (en) * | 2006-06-14 | 2009-06-24 | 吉瑞工厂 | Industrial process for the synthesis of 17a-acetoxy-11ss-[4-(n,n-dimethyl-amino)- phenyl]-19-norpregna-4,9-diene-3,20-dione and new intermediates of the process |
| CN101684139A (en) * | 2008-09-27 | 2010-03-31 | 徐州师范大学 | Synthesis process of vecuronium bromide |
| CN102372760A (en) * | 2010-08-12 | 2012-03-14 | 杭州容立医药科技有限公司 | Synthesis method of progesterone receptor regulating agent ulipristal |
| CN102875629A (en) * | 2012-10-10 | 2013-01-16 | 苏州康润医药有限公司 | Synthetic method of ulipristal acetate |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110256519A (en) * | 2019-05-23 | 2019-09-20 | 江苏联环药业股份有限公司 | The method of one kettle way preparation uliprista acetate |
| CN110256519B (en) * | 2019-05-23 | 2021-06-08 | 江苏联环药业股份有限公司 | Method for preparing ulipristal acetate by one-pot method |
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