CN110256519B - Method for preparing ulipristal acetate by one-pot method - Google Patents
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Abstract
The invention discloses a method for preparing ulipristal acetate by a one-pot method, and belongs to the technical field of medicine synthesis. The method takes a grignard compound CW-b as a raw material, and generates an intermediate CW-c through acidolysis by organic acid; CW-c is not treated, acid anhydride is directly used as an acetylation reagent for acetylation reaction under the catalysis of perchloric acid, and the product ulipristal acetate is obtained after the reaction is finished and through washing, drying, concentration and crystallization. The acidolysis and acetylation one-pot method has the advantages of continuous reaction, greatly simplified operation process, reduced cost and discharge of three wastes, high product yield which reaches about 90 percent; meanwhile, the generation of degradation impurities is effectively inhibited, and the method is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing ulipristal acetate by a one-pot method.
Background
Ulipristal acetate is a novel oral emergency contraceptive, and is an active chemical component of a new generation emergency contraceptive Ella currently sold in the United states. Its emergency contraceptive efficacy does not decrease with the delay of medication time, and at the same time, it is safe and well tolerated. Compared with the conventional emergency contraceptive levonorgestrel, ulipristal acetate has wider clinical practicability and the potential of preventing more accidental pregnancies.
There are several synthetic routes for ulipristal acetate, and the more common synthetic route is shown as the following formula:
at present, in the synthesis method of ulipristal acetate, grignard compounds and ulipristal acetate are generally hydrolyzed by inorganic acid, washed to obtain an intermediate, and acetylated to synthesize the ulipristal acetate. The synthetic process needs the working procedures of extraction, washing, concentration and the like, and the three wastes are increased while oxidation impurities and degradation impurities are easily generated. Patents CN102516345A, CN102875629A, etc. try to greatly simplify the synthetic route and reduce the cost by improving the process of the starting material bisketal moiety. Patent CN102516345A and the like optimize the synthesis part of ulipristal acetate, greatly improve the yield and purity and reduce the cost. But the environmental protection aspects such as three wastes discharge and the like are not obviously improved.
Disclosure of Invention
The purpose of the invention is as follows: aiming at the defects in the prior art, the invention aims to provide a method for preparing ulipristal acetate by a one-pot method, which has the characteristics of simple reaction process, mild reaction conditions and high product yield.
The technical scheme is as follows: in order to solve the problems, the technical scheme adopted by the invention is as follows:
a one-pot method for preparing ulipristal acetate is characterized in that 3, 3, 20, 20-bis (ethylenedioxy) -5 alpha, 17 alpha-dihydroxy-11 beta- [4- (N, N-dimethylamino) -phenyl ] -19-norpregna-9 (11) -ene (CW-b) is used as a raw material, organic acid is added to carry out acidolysis reaction to generate an intermediate 17 a-hydroxy-11 beta- [4- (N, N-dimethylamino) -phenyl ] -19-norpregna-4-9 (10) -diene-3, 20-dione (CW-c), the CW-c is directly subjected to acetylation reaction under catalysis of perchloric acid by using acid anhydride as an acetylation reagent without treatment, and after the reaction is finished, reaction liquid is treated to obtain ulipristal acetate (compound I). The reaction formula is as follows:
the method for preparing ulipristal acetate by the one-pot method comprises the following steps:
(1) adding organic acid and solvent into a reaction vessel, controlling the temperature at 0-10 ℃, then adding a Grignard compound CW-b, and carrying out temperature-controlled acid hydrolysis reaction for 0.5-2h to obtain an intermediate CW-c; the mass-volume ratio of CW-b to organic acid is (0.5-2) g/mL, and the mass-volume ratio of CW-b to solvent is (0.1-0.2) g/mL;
(2) controlling the temperature to-20-10 ℃, adding anhydride, stirring and reacting for 15-30min under controlled temperature, then cooling to-25-20 ℃, adding perchloric acid, and reacting for 0.5-1h under controlled temperature; the mass-to-volume ratio of CW-b to acid anhydride is (1-2) g/mL, and the mass-to-volume ratio of CW-b to perchloric acid is (3-7) g/mL;
(3) and after the reaction is finished, pouring the reaction solution into 10-15% sodium acetate aqueous solution, stirring, standing, layering, washing the organic layer, drying, concentrating, crystallizing by using isopropyl ether, drying to obtain a crude product of ulipristal acetate, and refining the crude product by using ethanol-water to obtain the ulipristal acetate.
The method for preparing ulipristal acetate by the one-pot method has the advantages that the temperature of acid hydrolysis is 5 ℃, and the time is 0.5 h.
The method for preparing ulipristal acetate by the one-pot method comprises the steps of controlling the temperature to be-15 ℃ in acetylation reaction, adding acetic anhydride, controlling the temperature, stirring and reacting for 15min, then cooling to be-23 ℃, adding perchloric acid, and controlling the temperature and reacting for 0.5 h.
According to the method for preparing ulipristal acetate by the one-pot method, the mass-to-volume ratio of CW-b to organic acid is 0.5g/mL, the mass-to-volume ratio of CW-b to solvent is 0.1g/mL, the mass-to-volume ratio of CW-b to anhydride is 1g/mL, and the mass-to-volume ratio of CW-b to perchloric acid is 5 g/mL.
In the method for preparing ulipristal acetate by the one-pot method, the solvent is a non-polar or non-water-soluble solvent.
In the method for preparing ulipristal acetate by the one-pot method, the solvent is any one of toluene, ethyl formate, ethyl acetate, dichloromethane or trichloromethane.
In the method for preparing ulipristal acetate by the one-pot method, the organic acid is any one of acetic acid, trichloroacetic acid or trifluoroacetic acid.
In the method for preparing ulipristal acetate by the one-pot method, the acid anhydride is acetic anhydride or trifluoroacetic anhydride.
The method for preparing ulipristal acetate by the one-pot method comprises the following steps:
(1) adding organic acid and a solvent into a reaction vessel, controlling the temperature at 5 ℃, then adding the Grignard compound CW-b, controlling the temperature and reacting for 0.5h to obtain an intermediate CW-c; the mass-volume ratio of CW-b to organic acid is 0.5g/mL, and the mass-volume ratio of CW-b to solvent is 0.1 g/mL;
(2) controlling the temperature to-15 ℃, adding anhydride, and stirring and reacting for 15min at controlled temperature; then cooling to-23 ℃, adding perchloric acid, and controlling the temperature to react for 0.5 h; the mass-volume ratio of CW-b to acid anhydride is 1g/mL, and the mass-volume ratio of CW-b to perchloric acid is 5 g/mL;
(3) and after the reaction is finished, pouring the reaction solution into a 10% sodium acetate aqueous solution, stirring, standing, layering, washing an organic layer, drying, concentrating, crystallizing by using isopropyl ether, drying to obtain a crude product of ulipristal acetate, and refining the crude product by using ethanol-water to obtain the ulipristal acetate.
Has the advantages that: compared with the prior art, the invention has the advantages that:
(1) the synthesis method has the advantages of easily obtained raw materials, simple operation, short route, high yield of the obtained product up to about 90 percent, and suitability for industrial production.
(2) The method has mild reaction conditions, and the CW-c directly reacts without being treated, thereby achieving the effect of saving resources and having good application prospect.
(3) The invention can obviously inhibit the generation of degradation impurities through the whole low-temperature reaction from the grignard compound to the ulipristal acetate, and the purity of the raw material medicine can be achieved through one-time refining.
Drawings
FIG. 1 is an HPLC chromatogram of a control of the acid hydrolyzate CW-c of example 1;
FIG. 2 is an HPLC chromatogram of the crude ulipristal acetate of example 1;
FIG. 3 shows ulipristal acetate of example 11H NMR spectrum;
FIG. 4 shows ulipristal acetate of example 113C NMR spectrum.
Detailed Description
In order to make the aforementioned objects, features and advantages of the present invention comprehensible, embodiments accompanied with examples are described in detail below.
Wherein M is the mass of the ulipristal acetate crude product, g; m0The content of the Grignard compound CW-b is g, and m is the mass of the ulipristal acetate finished product.
Example 1
The method for preparing ulipristal acetate by a one-pot method comprises the following steps:
1000mL of dichloromethane and 50mL of acetic acid are added into a 2L reaction bottle, the temperature is reduced to 0 ℃, 100g of Grignard compound CW-b is added, the reaction is carried out for 2 hours under the condition of temperature control and stirring, and TLC monitors until the Grignard compound CW-b disappears. 100mL of reaction solution is taken, washed by water, dried and concentrated to be dry, and then added with isopropyl ether to be stirred and crystallized to obtain a CW-c reference substance. Cooling the rest reaction liquid to-20 ℃, adding 100mL of acetic anhydride, controlling the temperature for reaction for 15min, continuously cooling to-25 ℃, slowly dripping 20mL of perchloric acid, keeping the temperature for reaction for 1 hour after the addition is finished, and monitoring by TLC until the acidolysis substance disappears. Pouring the reaction solution into 10% sodium acetate aqueous solution, stirring, standing, layering, washing the organic layer to be nearly neutral, drying, concentrating to be nearly dry, crystallizing by isopropyl ether, and drying to obtain 76.6g of ulipristal acetate crude product with the yield of about 85.1% (the Grignard compound CW-b in the rest reaction solution is calculated by 90 g.). The crude product is refined by ethanol-water to obtain 65.1g of ulipristal acetate finished product, the yield is 85.0 percent, and the purity is 99.7 percent by HPLC.
The HPLC chromatogram result of the acidolysis substance CW-c reference substance is shown in figure 1, and as can be seen from figure 1, the CW-c obtained by the organic acid-non-aqueous solvent system has high purity which reaches 98.8 percent, the subsequent reaction is not influenced, and the improvement of the reaction system is beneficial. HPLC (high Performance liquid chromatography) spectrum analysis is carried out on the ulipristal acetate crude product in example 1, and the result is shown in figure 2; as can be seen from FIG. 2, the crude product prepared by the method for preparing ulipristal acetate by the one-pot method of the present invention has high purity, and the improvement of the one-pot method is suitable for industrial production by combining with the yield. Ulipristal acetate prepared in example 1 was subjected to1H NMR spectrum and13c NMR spectrum analysis is carried out, and the results are shown in FIG. 3 and FIG. 4; as can be seen from FIGS. 3 and 4, ulipristal acetate prepared by one-pot method has a definite structureThe certificate is correct.
Example 2
1000mL of dichloromethane and 100mL of acetic acid are added into a 2L reaction bottle, the temperature is reduced to 10 ℃, 100g of Grignard compound CW-b is added, the reaction is carried out for 1 hour under the condition of temperature control and stirring, and TLC monitors until the Grignard compound CW-b disappears. Cooling the reaction system to-10 ℃, adding 100mL of acetic anhydride, controlling the temperature to react for 15min, continuously cooling to-20 ℃, slowly dripping 25mL of perchloric acid, keeping the temperature for reaction for 0.5h after the addition is finished, and monitoring by TLC until the acidolysis substance disappears. Pouring the reaction solution into 10% sodium acetate aqueous solution, stirring, standing, layering, washing the organic layer with water to near neutrality, drying, concentrating to near dryness, crystallizing with isopropyl ether, and oven drying to obtain crude ulipristal acetate 88.2g with yield of 88.2%. The crude product is refined by ethanol-water to obtain the finished product of ulipristal acetate.
Example 3
Adding 1000mL of ethyl acetate and 100mL of acetic acid into a 2L reaction bottle, cooling to 2 ℃, adding 100g of Grignard compound CW-b, stirring at controlled temperature for reaction for 2 hours, and monitoring by TLC until the Grignard compound disappears. Cooling the reaction system to-15 ℃, adding 100mL of acetic anhydride and 50mL of acetic acid, controlling the temperature to react for 15min, continuously cooling to-22 ℃, slowly dripping 20mL of perchloric acid, keeping the temperature for reaction for 1h after the addition is finished, and monitoring by TLC until the acidolysis substance disappears. Pouring the reaction solution into 10% sodium acetate aqueous solution, stirring, standing, layering, washing the organic layer with water to near neutrality, drying, concentrating to near dryness, crystallizing with isopropyl ether, and oven drying to obtain crude ulipristal acetate 85.4g with yield of 85.4%. The crude product is refined by ethanol-water to obtain the finished product of ulipristal acetate.
Example 4
Adding 1000mL of ethyl acetate and 50mL of trifluoroacetic acid into a 2L reaction bottle, cooling to 4 ℃, adding 100g of Grignard compound CW-b, stirring at controlled temperature for reaction for 1h, and monitoring by TLC until the Grignard compound disappears. Cooling the reaction system to-13 ℃, adding 50mL of trifluoroacetic anhydride, controlling the temperature to react for 15min, continuously cooling to-24 ℃, slowly dropwise adding 15mL of perchloric acid, keeping the temperature for reaction for 1h after the addition is finished, and monitoring by TLC until the acidolysis product disappears. Pouring the reaction solution into 10% sodium acetate aqueous solution, stirring, standing, layering, washing the organic layer to neutrality, drying, concentrating to near dryness, crystallizing with isopropyl ether, and oven drying to obtain crude ulipristal acetate 86.1g with yield of 86.1%. The crude product is refined by ethanol-water to obtain the finished product of ulipristal acetate.
Example 5
Adding 1000mL of ethyl acetate and 100mL of trifluoroacetic acid into a 2L reaction bottle, cooling to 6 ℃, adding 100g of Grignard compound CW-b, stirring at controlled temperature for reaction for 0.5h, and monitoring by TLC until the Grignard compound disappears. Cooling the reaction system to-18 ℃, adding 100mL of trifluoroacetic anhydride, controlling the temperature to react for 15min, continuously cooling to-25 ℃, slowly dripping 20mL of perchloric acid, keeping the temperature for reaction for 0.5h after the addition is finished, and monitoring by TLC until the acidolysis substance disappears. Pouring the reaction solution into 10% sodium acetate aqueous solution, stirring, standing, layering, washing the organic layer to neutrality, drying, concentrating to near dryness, crystallizing with isopropyl ether, and oven drying to obtain crude ulipristal acetate 85.1g with yield of 85.1%. The crude product is refined by ethanol-water to obtain the finished product of ulipristal acetate.
Example 6
Adding 1000mL of ethyl acetate and 200mL of acetic acid into a 2L reaction bottle, cooling to 10 ℃, adding 100g of Grignard compound CW-b, stirring at controlled temperature for reaction for 0.5h, and monitoring by TLC until the Grignard compound disappears. Cooling the reaction system to-19 ℃, adding 100mL of acetic anhydride, controlling the temperature to react for 15min, continuously cooling to-25 ℃, slowly dropwise adding 30mL of perchloric acid, keeping the temperature for reaction for 0.5h after the addition is finished, and monitoring by TLC until the acidolysis substance disappears. Pouring the reaction solution into 10% sodium acetate aqueous solution, stirring, standing, layering, washing the organic layer to neutrality, drying, concentrating to near dryness, crystallizing with isopropyl ether, and oven drying to obtain ulipristal acetate crude product 87.1g with yield 87.1%. The crude product is refined by ethanol-water to obtain the finished product of ulipristal acetate.
Example 7
1000mL of dichloromethane and 200mL of trifluoroacetic acid are added into a 2L reaction bottle, the temperature is reduced to 5 ℃, 100g of Grignard compound CW-b is added, the reaction is carried out for 0.5h by stirring at the controlled temperature, and TLC is used for monitoring until the Grignard compound CW-b disappears. Cooling the reaction system to-15 ℃, adding 100mL of trifluoroacetic anhydride, stirring and reacting for 15min under controlled temperature, continuously cooling to-23 ℃, slowly dropwise adding 20mL of perchloric acid, keeping the temperature for reaction for 0.5h after the addition is finished, and monitoring by TLC until the acidolysis substance disappears. Pouring the reaction solution into 10% sodium acetate aqueous solution, stirring, standing, layering, washing an organic layer with water to neutrality, drying, concentrating to near dryness, crystallizing with isopropyl ether, and oven drying to obtain crude ulipristal acetate 89.3g with a yield of 89.3%. The crude product is refined by ethanol-water to obtain the finished product of ulipristal acetate.
Example 8
1000mL of dichloromethane and 100mL of trifluoroacetic acid are added into a 2L reaction bottle, the temperature is reduced to 10 ℃, 100g of Grignard compound CW-b is added, the reaction is carried out for 2 hours under the condition of temperature control and stirring, and TLC is used for monitoring until the Grignard compound CW-b disappears. Cooling the reaction system to-17 ℃, adding 100mL of trifluoroacetic anhydride, controlling the temperature to react for 15min, continuously cooling to-23 ℃, slowly dropwise adding 20mL of perchloric acid, keeping the temperature for reaction for 1h after the addition is finished, and monitoring by TLC until the acidolysis product disappears. Pouring the reaction solution into 10% sodium acetate aqueous solution, stirring, standing, layering, washing the organic layer with water to neutrality, drying, concentrating to near dryness, crystallizing with isopropyl ether, and oven drying to obtain crude ulipristal acetate 86.9g with yield 86.9%. The crude product is refined by ethanol-water to obtain the finished product of ulipristal acetate.
Claims (7)
1. The method for preparing ulipristal acetate by a one-pot method is characterized in that grignard compound CW-b is used as a raw material, organic acid is added for carrying out acid hydrolysis reaction to generate intermediate CW-c; CW-c is not treated, acetylation reaction is directly carried out by taking acetic anhydride as an acetylation reagent under the catalysis of perchloric acid, and the reaction solution is treated after the reaction is finished to obtain ulipristal acetate; the organic acid is any one of acetic acid, trichloroacetic acid or trifluoroacetic acid; the reaction equation is as follows:
the method comprises the following steps:
(1) adding organic acid and solvent into a reaction vessel, controlling the temperature at 0-10 ℃, then adding the Grignard compound CW-b, controlling the temperature to perform acid hydrolysis reaction for 0.5-2h to obtain an intermediate CW-c; the mass-volume ratio of CW-b to organic acid is (0.5-2) g/mL, and the mass-volume ratio of CW-b to solvent is (0.1-0.2) g/mL;
(2) controlling the temperature to be minus 20 to minus 10 ℃, adding acetic anhydride, and reacting for 15-30 min; then cooling to minus 25 to minus 20 ℃, adding perchloric acid, and controlling the temperature to react for 0.5 to 1 hour; the mass-volume ratio of CW-b to acid anhydride is (1-2) g/mL, and the mass-volume ratio of CW-b to perchloric acid is (3-7) g/mL;
(3) and after the reaction is finished, pouring the reaction solution into 10-15% sodium acetate aqueous solution, stirring, standing, layering, washing the organic layer, drying, concentrating, crystallizing by using isopropyl ether, drying to obtain a crude product of ulipristal acetate, and refining the crude product by using ethanol-water to obtain the ulipristal acetate.
2. The one-pot process for preparing ulipristal acetate according to claim 1, wherein the temperature of acid hydrolysis is 5 ℃ and the time is 0.5 h.
3. The one-pot method for preparing ulipristal acetate according to claim 1, wherein the temperature in the acetylation reaction is controlled at-15 ℃, acid anhydride is added, the temperature is controlled, the stirring reaction is carried out for 15min, then the temperature is reduced to-23 ℃, perchloric acid is added, and the temperature is controlled, and the reaction is carried out for 0.5 h.
4. The one-pot process for preparing ulipristal acetate according to claim 1, wherein the mass-to-volume ratio of CW-b to organic acid is 0.5g/mL, the mass-to-volume ratio of CW-b to solvent is 0.1g/mL, the mass-to-volume ratio of CW-b to acid anhydride is 1g/mL, and the mass-to-volume ratio of CW-b to perchloric acid is 5 g/mL.
5. The one-pot process for preparing ulipristal acetate according to claim 1, wherein the solvent is a non-polar or non-water soluble solvent.
6. The one-pot process for preparing ulipristal acetate according to claim 1, wherein the solvent is any one of toluene, ethyl formate, ethyl acetate, dichloromethane or chloroform.
7. The one-pot process for preparing ulipristal acetate according to claim 1, comprising the steps of:
(1) adding organic acid and a solvent into a reaction vessel, controlling the temperature at 5 ℃, then adding the Grignard compound CW-b, controlling the temperature and reacting for 0.5h to obtain an intermediate CW-c; the mass-volume ratio of CW-b to organic acid is 0.5g/mL, and the mass-volume ratio of CW-b to solvent is 0.1 g/mL;
(2) controlling the temperature to-15 ℃, adding anhydride, and stirring for reaction for 15 min; then cooling to-23 ℃, adding perchloric acid, controlling the temperature and reacting for 0.5 h; the mass-volume ratio of CW-b to acid anhydride is 1g/mL, and the mass-volume ratio of CW-b to perchloric acid is 5 g/mL;
(3) and after the reaction is finished, pouring the reaction solution into a 10% sodium acetate aqueous solution, stirring, standing, layering, washing an organic layer, drying, concentrating, crystallizing by using isopropyl ether, drying to obtain a crude product of ulipristal acetate, and refining the crude product by using ethanol-water to obtain the ulipristal acetate.
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
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 |
CN102516345A (en) * | 2011-11-01 | 2012-06-27 | 上海优拓医药科技有限公司 | Preparation method of ulipristal acetate and key intermediate thereof |
CN103755763A (en) * | 2013-12-30 | 2014-04-30 | 烟台东诚生化股份有限公司 | Preparation method of 17alpha-acetoxyl-11beta-(4-(N, N-dimethylamino)-phenyl)-19-norpregna-4, 9-diene-3, 20-diketone |
CN104910235A (en) * | 2014-03-14 | 2015-09-16 | 郑州海缔邦林制药有限公司 | Novel industrial production method of ulipristal acetate and its intermediate |
CN107629107A (en) * | 2017-11-10 | 2018-01-26 | 广州市桐晖药业有限公司 | A kind of synthetic method of CDB-2914 |
-
2019
- 2019-05-23 CN CN201910437133.8A patent/CN110256519B/en active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
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 |
CN102516345A (en) * | 2011-11-01 | 2012-06-27 | 上海优拓医药科技有限公司 | Preparation method of ulipristal acetate and key intermediate thereof |
CN103755763A (en) * | 2013-12-30 | 2014-04-30 | 烟台东诚生化股份有限公司 | Preparation method of 17alpha-acetoxyl-11beta-(4-(N, N-dimethylamino)-phenyl)-19-norpregna-4, 9-diene-3, 20-diketone |
CN104910235A (en) * | 2014-03-14 | 2015-09-16 | 郑州海缔邦林制药有限公司 | Novel industrial production method of ulipristal acetate and its intermediate |
CN107629107A (en) * | 2017-11-10 | 2018-01-26 | 广州市桐晖药业有限公司 | A kind of synthetic method of CDB-2914 |
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