CN103059090B - The purification process of Abiraterone acetate oxalates and Abiraterone acetate - Google Patents
The purification process of Abiraterone acetate oxalates and Abiraterone acetate Download PDFInfo
- Publication number
- CN103059090B CN103059090B CN201110318824.XA CN201110318824A CN103059090B CN 103059090 B CN103059090 B CN 103059090B CN 201110318824 A CN201110318824 A CN 201110318824A CN 103059090 B CN103059090 B CN 103059090B
- Authority
- CN
- China
- Prior art keywords
- abiraterone acetate
- oxalates
- purification process
- salt
- acetate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to the purification process of a kind of Abiraterone acetate oxalates and Abiraterone acetate, obtaining Abiraterone acetate oxalates by oxalic acid and Abiraterone acetate crude product being reacted, then being undertaken Abiraterone acetate oxalates dissociating is obtained by reacting Abiraterone acetate。The present invention is by obtaining Abiraterone acetate oxalates and using it for purification Abiraterone acetate, the Abiraterone acetate purity obtained is high, avoided column purification Abiraterone acetate, reducing production cost, and safety does not have corrosivity, technological operation is simple, equipment requirements is low, good product quality, safety is high, is especially suitable for industrialized great production。
Description
Technical field
The present invention relates to a kind of new Abiraterone acetate salt and preparation method thereof and the purification process of Abiraterone acetate。
Background technology
Abiraterone acetate is that in androgen synthesis, key enzyme 17 α-hydroxylase-C17,20-lyase (was also once called steroid 17 α-monooxygenase inhibitor or human-cytochrome P45017α) effective selectivity oral inhibitor, can be used for treating carcinoma of prostate。On April 28th, 2011, FDA used the transitivity castration drug resistance carcinoma of prostate of docetaxel patients undergoing chemotherapy before ratifying Abiraterone acetate associating Prednisone Therapy。The chemical name of Abiraterone acetate is (3 β)-17-(3-pyridine radicals)-androstane-5,16-dien-3-ols acetate, and structural formula is as follows:
The existing prior art of the synthetic method of Abiraterone acetate open (WO9320097, WO9509178, J.Med.Chem, 1995, Vo38 (13), 2463-2471, Org.Prep.Proced.Int., 1997,29 (1), 123-134), but the description of purification process is all adopted column chromatography by these documents。
CN101044155 adopts into crystallization of saltouing to improve the efficiency of purification, Abiraterone acetate crude product is made to become salt with methanesulfonic acid, the salt making formation is precipitated out in a solvent, other major part impurities left are in a solvent, it is filtrated to get Abiraterone acetate mesylate, then it is obtained Abiraterone acetate with alkali is free。But although this purification process is when methanesulfonic acid becomes salt with Abiraterone acetate, can be directly separating from solvent, do not need column purification, but formed the suspension of stiff, it is difficult to filtered, the filter cake thickness being filtrated to get, easy residual impurity, the Abiraterone acetate mesylate being filtrated to get also needs to be further purified by recrystallization, then obtains Abiraterone acetate with alkali is free, add operating time and difficulty, be unfavorable for industrialized great production。And what obtain after its crude product is free is grease product, and purity is about 89%, wherein substantially containing impurity such as pigmentosa material, raw material, hydrolysate abiraterones。And hydrolysate abiraterone and pigmentosa impurity are difficult to remove, it is unfavorable for purifying further obtaining high-quality crude drug。
The fluoroform sulphonate of a kind of Abiraterone acetate disclosed in CN102030798, trifluoromethanesulfonic acid is reacted with Abiraterone acetate crude product, obtain the Abiraterone acetate fluoroform sulphonate of dry and comfortable easy filtration, then obtain Abiraterone acetate by free for Abiraterone acetate fluoroform sulphonate。The Abiraterone acetate fluoroform sulphonate that the method obtains is higher than Abiraterone acetate mesylate purity, color good, overcome the defect in CN101044155, simplify purifying process, but owing to trifluoromethanesulfonic acid is expensive, it is easily generated acid mist, therefore the reaction in CN102030798 can only control at low temperature (5 DEG C) below, it is unfavorable for operation, and trifluoromethanesulfonic acid also has severe corrosive, equipment corrosion is serious, post processing and production operation difficulty are big, and air pollution is serious, is therefore not suitable for very much industrialized great production。
Summary of the invention
The present invention relates to a kind of Abiraterone acetate oxalates, chemical name is (3 β)-17-(3-pyridine radicals)-androstane-5, and 16-dien-3-ols acetate oxalates is structured with formula:
The invention still further relates to-the preparation method of kind of Abiraterone acetate oxalates, the method includes Abiraterone acetate crude product and reacts in a solvent with oxalic acid, obtains Abiraterone acetate oxalates。
Concrete, it is possible to comprise the following steps:
(1) Abiraterone acetate crude product solvent is dissolved, add oxalic acid；
(2) stirring carries out salt-forming reaction, crystallize；
(3) filter, obtain Abiraterone acetate oxalates。
The solvent that step (1) uses can be one or more the mixture in acetone, acetonitrile, diisopropyl ether, ethyl acetate。Preferred acetonitrile, acetone, more preferably acetone。Make consumption be Abiraterone acetate crude product 4～30 times (volume (mL)/weight (g)) of described solvent, it is preferable that 5～20 times, more preferably 5～15 times。
The mol ratio that step (1) mesoxalic acid consumption is oxalic acid and Abiraterone acetate crude product is 0.7～2, it is preferable that 1～2。
In step (2), the temperature of salt-forming reaction is 0～55 DEG C, it is preferable that 20～55 DEG C, more preferably 30～50 DEG C。The crystallize time is 0.5～10h, it is preferable that 1～5h, more preferably 1～3h。
The invention still further relates to the Abiraterone acetate oxalates purposes for purification Abiraterone acetate。
The invention still further relates to the purification process of Abiraterone acetate, the method includes that oxalic acid and Abiraterone acetate crude product are carried out salt-forming reaction in a solvent and obtains Abiraterone acetate oxalates, and then being undertaken Abiraterone acetate oxalates dissociating is obtained by reacting Abiraterone acetate。
Concrete, it is possible to comprise the following steps:
(1) oxalic acid and Abiraterone acetate crude product are carried out salt-forming reaction in a solvent；
(2) crystallize, filters, obtains Abiraterone acetate oxalates；
(3) being carried out by Abiraterone acetate oxalates dissociates is obtained by reacting Abiraterone acetate。
The solvent that step (1) uses can be one or more the mixture in acetone, acetonitrile, diisopropyl ether, ethyl acetate。Preferred acetonitrile, acetone, more preferably acetone。Make consumption be Abiraterone acetate crude product 4～30 times (volume (mL)/weight (g)) of described solvent, it is preferable that 5～20 times, more preferably 5～15 times。
The mol ratio that step (1) mesoxalic acid consumption is oxalic acid and Abiraterone acetate crude product is 0.7～2, it is preferable that 1～2。
In step (1), the temperature of salt-forming reaction is 0～55 DEG C, it is preferable that 20～55 DEG C, more preferably 30～50 DEG C。
In step (2), the crystallize time is 0.5～10h, it is preferable that 1～5h, more preferably 1～3h。
Routine techniques can be adopted after filtration to carry out washing, dry and obtain Abiraterone acetate oxalates。
Free reaction described in step (3), it is possible to be that alkali neutralizes, for instance, Abiraterone acetate oxalates is joined in suitable organic solvent, add aqueous slkali, be obtained by reacting acetic acid bit dragon。Described organic solvent can be dichloromethane, and described aqueous slkali can be sodium carbonate or sodium bicarbonate aqueous solution。The Abiraterone acetate obtained can be further purified and obtain the Abiraterone acetate that purity is higher。
Passing through in the present invention with Abiraterone acetate, oxalic acid is formed Abiraterone acetate oxalates, the raw material that in being prepared by Abiraterone acetate crude product, unreacted is complete stays in the solution, from without crossing post removing raw material；And use oxalic acid, reduce production cost, and safety does not have corrosivity；And the color of the Abiraterone acetate oxalates obtained is off-white color, and color is good, then through being further purified after free, Abiraterone acetate purity can reach more than 99.5%。The technological operation of the present invention is simple, and equipment requirements is low, and cost is low, good product quality, and safety is high, is especially suitable for industrialized great production。
Detailed description of the invention
The preparation of embodiment 1 Abiraterone acetate crude product
Under stirring, Dehydroepiandrosterone Acetate 200g is dissolved in dry dichloromethane 2L, at 15～20 DEG C, drips Tf2O206g, 0.5h drip off, then are slowly added dropwise diisopropyl ethyl amine (i-Pr2NEt) 96g, 2h drip off, and continue reaction 3h。With frozen water (1.5L) cancellation, separatory, aqueous phase dichloromethane (500ml) extracts, and merges organic facies, and successively with each 1.5L washing of 2N hydrochloric acid and water, anhydrous sodium sulfate dries, concentrate atropurpureus grease is about 280g (AB-2)。
AB-2(280g)、THF(2L)、Pd(PPh3)2Cl2(3.7g), diethyl-(3-pyridine) borine (96g) and 2MNa2CO3(1L)。Heating, to outer temperature 80 DEG C, reacts 4～5h。Standing separatory, lower floor's aqueous phase ethyl acetate (1L) extracts, and upper organic phase rotation adds ethyl acetate (2L) after overwhelming majority THF is evaporated off, and merges organic layer, and successively with each 2L washing of water and saline solution, anhydrous sodium sulfate dries。260g dark oil thing (Abiraterone acetate crude product) is steamed to obtain in rotation。
The preparation of embodiment 2 Abiraterone acetate oxalates and the purification of Abiraterone acetate
(1) preparation of Abiraterone acetate oxalates
Abiraterone acetate crude product (260g), adds acetone 1.5L, stirring and dissolving, adds oxalic acid 67g at 50 DEG C, continue stirring 1h, be down to and 2h is stirred at room temperature。Sucking filtration, filter cake acetone drip washing, drying under reduced pressure obtains off-white color solid, i.e. Abiraterone acetate oxalates 144.9g (AB-3), and total recovery 49.7% (calculating in reference count for initiation material AB-1), HPLC purity detecting is 96.1%。
The differential scanning thermal analysis (DSC) of Abiraterone acetate oxalates:
INSTRUMENT MODEL: NETZSCHDSC204S1
Experiment condition: crucible type: standard aluminum crucible (acupuncture perforation)
Purge gas: N220mL/min；Protection gas: N270mL/min。
Temperature range: 100--300 DEG C
Heating rate: 10 DEG C/min
Measurement result: starting heat absorption at 173.1 DEG C, 175.1 DEG C reach peak value。
The fusing point (m.p) of Abiraterone acetate oxalates is 173.1 DEG C～175.1 DEG C。
(2) the free and recrystallization of Abiraterone acetate
Abiraterone acetate oxalates (AB-3) (144.9g), add dichloromethane and each 500ml of water, stirring and dissolving, adding sodium bicarbonate 75g, stir separatory, water layer dichloromethane 200ml extracts, merge organic facies, successively with water and brine It, anhydrous sodium sulfate dries, and rotation is steamed to doing to obtain 109.5g solid。
Add 440ml absolute methanol, 60 DEG C of heating for dissolving, naturally it is down to room temperature and is slowly stirred crystallize overnight, filter, drying under reduced pressure, obtaining 80.4g off-white color solid (Abiraterone acetate), yield 68.2% (calculating in reference count for Abiraterone acetate oxalates crude product), HPLC purity detecting is 99.6%。
Efficient liquid phase (HPLC) condition that described purity detecting uses:
Chromatographic column: kromasil100C18 post (4.6 × 150mm, 5 μm)
Mobile phase: 75% methanol
Detection wavelength: 210nm
Column temperature: 30 DEG C
Flow velocity: 1ml/min。
Described yield is molar percentage number。
The preparation of embodiment 3～8 Abiraterone acetate oxalates and the purification of Abiraterone acetate
Concrete operations are tested according to the method for embodiment 2, and reaction consumption and condition operate by table 1。
Table 1
Embodiment 9 (preparation of Abiraterone acetate oxalates and the investigation of influence factor thereof)
It is obtained by reacting Abiraterone acetate crude product by the AB-1 (100g) that feeds intake of step described in embodiment 1, adds acetone 750ml, stirring and dissolving, at 30 DEG C, 40 DEG C, 50 DEG C, add oxalic acid 34g respectively, continue stirring 1h, be down to and 2h is stirred at room temperature。Sucking filtration, filter cake acetone drip washing, drying under reduced pressure obtains solid (Abiraterone acetate oxalates)。Result is as shown in table 2。
Table 2
It is obtained by reacting Abiraterone acetate crude product by the AB-1 (100g) that feeds intake of step described in embodiment 1, investigates the solvent impact on becoming salt, be separately added into 750ml acetone, acetonitrile, ethyl acetate, stirring and dissolving, add oxalic acid 34g at 50 DEG C, continue stirring 1h, be down to and 2h is stirred at room temperature。Sucking filtration, filter cake acetone drip washing, drying under reduced pressure obtains solid (Abiraterone acetate oxalates)。Result is as shown in table 3。
Table 3
Comparative example 1 (methanesulfonic acid is salt-forming reagent)
Feed intake AB-1 (200g) by step described in CN101044155, it is obtained by reacting Abiraterone acetate crude product 195g, add 1L methyl tertiary butyl ether(MTBE) and 1L acetic acid ethyl dissolution, add methanesulfonic acid (49g, 1.05 equivalents), stirring and crystallizing, filters, with 200ml methyl tertiary butyl ether(MTBE) washing leaching cake。This filter cake air-dry, obtains sepia solid (Abiraterone acetate mesylate) 153g, and total recovery is 51.8% (calculating in reference count for initiation material AB-1), and HPLC purity is 78.8%。
Abiraterone acetate mesylate (153g), add dichloromethane and each 500ml of water, stirring and dissolving, adding sodium bicarbonate 39.6g, stir separatory, water layer dichloromethane 200ml extracts, merge organic facies, successively with water and brine It, anhydrous sodium sulfate dries, and rotation is steamed to doing to obtain 114.6g solid。Add 460ml absolute methanol, 60 DEG C of heating for dissolving, be naturally down to room temperature and be slowly stirred crystallize overnight, filtering, cold absolute methanol washs, and drying under reduced pressure obtains 66.8g brown solid (Abiraterone acetate), yield 54.4% (crude product based on salt calculates), purity 97.3%。
Comparative example 2 (trifluoromethanesulfonic acid is salt-forming reagent)
Feed intake AB-1 (200g) by step described in CN102030798, it is obtained by reacting Abiraterone acetate crude product 290g, add after 900mL ethyl acetate is completely dissolved and add to 3L there-necked flask, add 900mL methyl tertiary butyl ether(MTBE), after mixed liquor stirring is cooled to 0 DEG C, dropping 75g trifluoromethanesulfonic acid, drip and finish, stir 1 hour in 0 DEG C of constant temperature, remove ice bath, stir 2 hours after being warming up to room temperature, sucking filtration, 147.4g canescence Abiraterone acetate fluoroform sulphonate (HPLC purity is 95.5%) is obtained after filtration cakes torrefaction, total recovery 44.9% (calculating in reference count for initiation material AB-1)。
Abiraterone acetate fluoroform sulphonate (147.4g), add dichloromethane and each 500ml of water, stirring and dissolving, adding sodium bicarbonate 34g, stir separatory, water layer dichloromethane 200ml extracts, merge organic facies, successively with water and brine It, anhydrous sodium sulfate dries, and rotation is steamed to doing to obtain 90.2g solid。Add 390ml absolute methanol, 60 DEG C of heating for dissolving, be naturally down to room temperature and be slowly stirred crystallize overnight, filtering, cold absolute methanol washs, and drying under reduced pressure obtains 61.4g light gray solid (Abiraterone acetate), yield 57.6% (crude product based on salt calculates), purity 98.5%。
By as shown in table 4 below with comparative example 1, comparative example 2 experimental phenomena and Comparative result for embodiment 2:
Table 4
Claims (8)
1. the purification process of an Abiraterone acetate, the method includes that oxalic acid and Abiraterone acetate crude product are carried out salt-forming reaction in a solvent and obtains Abiraterone acetate oxalates, then being carried out by Abiraterone acetate oxalates dissociates is obtained by reacting Abiraterone acetate, and wherein the solvent used by salt-forming reaction is one or more the mixture in acetone, acetonitrile, diisopropyl ether, ethyl acetate。
2. the method described in claim 1, wherein the solvent used by salt-forming reaction is acetonitrile, acetone。
3. the method described in claim 1, wherein the solvent used by salt-forming reaction is acetone。
4. the mol ratio of the purification process described in claim 1, oxalic acid therein and Abiraterone acetate crude product is 0.7～2。
5. the purification process described in claim 1, wherein the temperature of salt-forming reaction is 0～55 DEG C。
6. the purification process described in claim 1, wherein the temperature of salt-forming reaction is 30～50 DEG C。
7. the purification process described in any one of claim 1-6, the solvent that wherein free reaction is used is dichloromethane。
8. the purification process described in any one of claim 1-6, the aqueous slkali that wherein free reaction is used is selected from aqueous sodium carbonate or sodium bicarbonate aqueous solution。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110318824.XA CN103059090B (en) | 2011-10-20 | 2011-10-20 | The purification process of Abiraterone acetate oxalates and Abiraterone acetate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110318824.XA CN103059090B (en) | 2011-10-20 | 2011-10-20 | The purification process of Abiraterone acetate oxalates and Abiraterone acetate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103059090A CN103059090A (en) | 2013-04-24 |
| CN103059090B true CN103059090B (en) | 2016-06-22 |
Family
ID=48102018
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110318824.XA Active CN103059090B (en) | 2011-10-20 | 2011-10-20 | The purification process of Abiraterone acetate oxalates and Abiraterone acetate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103059090B (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3080141A1 (en) | 2013-12-12 | 2016-10-19 | Basf Se | Solid form of abiraterone acetate |
| CA2938023C (en) | 2014-01-28 | 2022-03-08 | Olon S.P.A. | Procedure for the preparation of abiraterone acetate and intermediates thereof |
| WO2016088031A1 (en) * | 2014-12-02 | 2016-06-09 | Fresenius Kabi Oncology Limited | A process for purification of carfilzomib |
| CN104447934B (en) * | 2014-12-08 | 2017-03-15 | 深圳科兴生物工程有限公司 | A kind of purification process of Abiraterone acetate |
| US11447506B2 (en) | 2016-05-09 | 2022-09-20 | Anacor Pharmaceuticals, Inc. | Crystal forms of crisaborole in free form and preparation method and use thereof |
| ITUA20164793A1 (en) * | 2016-06-30 | 2017-12-30 | Ind Chimica Srl | Process for the preparation of 3β-hydroxy-17- (1H-benzimidazol-1-yl) androsta-5,16-diene |
| CN109922809B (en) * | 2016-10-11 | 2021-08-13 | 珠海贝海生物技术有限公司 | Abiraterone derivative and preparation thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102030798A (en) * | 2010-12-17 | 2011-04-27 | 深圳万乐药业有限公司 | Purification method of abiraterone acetate |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2742331B2 (en) * | 1992-03-31 | 1998-04-22 | ブリテイツシユ・テクノロジー・グループ・リミテツド | 17-substituted steroids useful for cancer treatment |
| ATE176481T1 (en) * | 1993-09-30 | 1999-02-15 | Btg Int Ltd | SYNTHESIS OF 17-(3-PYRIDYL) STEROIDS |
-
2011
- 2011-10-20 CN CN201110318824.XA patent/CN103059090B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102030798A (en) * | 2010-12-17 | 2011-04-27 | 深圳万乐药业有限公司 | Purification method of abiraterone acetate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103059090A (en) | 2013-04-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103059090B (en) | The purification process of Abiraterone acetate oxalates and Abiraterone acetate | |
| CN111423452B (en) | Intermediate of Rayleigh Lu Geli and preparation method and application thereof | |
| CN104211676B (en) | The method for obtaining olopatadine and intermediate | |
| CN103193849B (en) | A kind of preparation method of high-purity Abiraterone acetate | |
| CN107235958A (en) | A kind of synthetic method for preparing PARP inhibitor Niraparib | |
| TWI703163B (en) | Method for preparing sugammadex sodium and crystalline form thereof | |
| CN102395591B (en) | Method for preparing prasugrel | |
| CN104447600A (en) | Preparation method of parecoxib sodium compound as well as intermediate impurity and application of parecoxib sodium compound | |
| CN106256825A (en) | The synthetic method of his Wei of Dacca | |
| CN116640088A (en) | Preparation method of high-purity Lei Fen narasin | |
| JP5819284B2 (en) | Method for producing olopatadine | |
| CN114516875A (en) | Preparation method of nucleoside analogue VV116 | |
| WO2014056442A1 (en) | (2r)-2-deoxy-2,2-disubstitute-1,4-ribose lactone and preparation method and use thereof | |
| CN101704796B (en) | Preparation method of 3-morpholone | |
| CN106279155B (en) | Impurity reference substance of Tadalafei and preparation method thereof | |
| CN104803908A (en) | Hydrate of 2-isopropoxy-5-methyl-4-(4-piperidyl) aniline dihydrochloride as well as preparation method and application of hydrate | |
| CN108623455A (en) | A kind of intermediate of cardiotonic agents | |
| CN112812147A (en) | Synthetic method of abiraterone acetate and intermediate thereof | |
| WO2016066116A1 (en) | Preparation method of apremilast and intermediate thereof | |
| CN105566260A (en) | Furosemide preparation method | |
| CN106749098B (en) | A kind of preparation method preparing dioxopromethazine hydrochloride using oxygen as oxidant | |
| CN110128497A (en) | A kind of fulvestrant preparation method | |
| CN108727214B (en) | Synthetic method of anesthetic bupivacaine impurity | |
| CN108586450B (en) | Recrystallization purification method of choline M receptor anticaking agent | |
| CN105801482A (en) | Method for preparing 1-cyclopropyl-4-oxo-7-bromine-8-difluoromethoxy-1,4-dihydro-quinoline-3-nonanoic acid-ethyl ester |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C53 | Correction of patent for invention or patent application | ||
| CB02 | Change of applicant information |
Address after: Bridge 222069 Jiangsu city of Lianyungang province Lianyungang economic and Technological Development Zone Dapu Industrial Zone, Road No. 16 Applicant after: Lianyungang Runzhong Pharmaceutical Co.,Ltd. Applicant after: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Address before: Bridge 222069 Jiangsu city of Lianyungang province Lianyungang economic and Technological Development Zone Dapu Industrial Zone, Road No. 16 Applicant before: Lianyungang Runzhong Pharmaceutical Co.,Ltd. Applicant before: Jiangsu Chiatai Tianqing Pharmaceutical Co., Ltd. |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |