CN102558274B - Synthetic method applicable to industrial production of Abiraterone acetate - Google Patents
Synthetic method applicable to industrial production of Abiraterone acetate Download PDFInfo
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- CN102558274B CN102558274B CN201010581606.0A CN201010581606A CN102558274B CN 102558274 B CN102558274 B CN 102558274B CN 201010581606 A CN201010581606 A CN 201010581606A CN 102558274 B CN102558274 B CN 102558274B
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- abiraterone acetate
- synthetic method
- reaction
- oily matter
- abiraterone
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Abstract
The invention discloses a synthetic method applicable to industrial mass production of Abiraterone acetate. According to the method, Abiraterone acetate is prepared through the steps of acylation, condensation and purification; in the step of acylation, dehydroepiandrosterone acetate is used as a raw material, the solvent of dichloromethane is added to dissolve dehydroepiandrosterone acetate under stirring, trifluromethanesulfonic anhydride is added at low temperature, a reaction at low temperature is maintained, then an alkaline catalyst is added at low temperature, and a reaction at room temperature is carried out. The method provided in the invention enables reaction byproducts to be reduced, operation to be simplified and purity of an HPLC test product to be more than 97% and is applicable to industrial mass production.
Description
Technical field
The present invention relates to the synthetic method of medicinal chemicals, particularly a kind of synthetic method of applicable industrialized mass Abiraterone acetate.
Background technology
Abiraterone is a kind of oral Terminal oxidase P450 (CYP450) c17 inhibitor, by suppress male sex hormone in synthetic key enzyme---CYP450c17 reduces androgen levels, and the male sex hormone to testis and other positions of health has restraining effect, is used for the treatment of advanced prostate cancer.Abiraterone acetate is the prodrug of Abiraterone, is again Abiraterone-3-acetic ester, and its structural formula is:
First this compound and synthetic method thereof are disclosed in WO93/20097A, and its synthetic route, for taking Dehydroepiandrosterone Acetate as raw material, is prepared its fluoroform sulphonate, then obtain this compound with the common two-step reaction of diethyl (3-pyridyl) borine:
The alkaline catalysts 2 wherein using, 6-bis--tertiary butyl-4-picoline (DTBMP) is very expensive, and in disclosed method, two-step reaction all needed chromatographic column purifying, and complicated operation, is not suitable for industry's enlarging production.
The synthetic of following formula: compound disclosed in WO95/09178A:
Wherein R represents hydrogen atom, and R ' represents the acyl group of hydrogen atom or 2 to 4 carbon atoms.This patent discloses the method for reacting acetic acid synthesized Abiraterone with corresponding ethylene iodide intermediate replacement fluoroform sulphonate and (3-pyridyl)-replacement borine.
The method reaction scheme and time are all longer, the long industry's enlarging production that is therefore also not suitable for of production cycle.
Chinese patent CN101044155A discloses Abiraterone acetate-3-ester mesylate and preparation method thereof, wherein the synthetic route of Abiraterone acetate-3-ester is identical with WO93/20097A, the method purifying reclaiming by forming Abiraterone acetate-3-ester mesylate, has avoided column chromatography purification step.But the method for embodiment 2 disclosed " extensive acetic acid synthesized Abiraterone 1 " is only taking 10g scale as best implementation path, Abiraterone acetate more than synthetic 10g scale is by the purity not reaching and yield effect, the inventor has also confirmed that the method will obtain expecting that product can only be amplified at most 20g scale by experiment, but purity and yield are all very low, the above scale reaction of 20g can not get target product.10～20g scale can not be satisfied the demand for industrial amplification production.And the method requires to add the interval time of trifluoromethanesulfanhydride anhydride and alkali very short, require slowly to add alkali and control the time that adds alkali, be unfavorable for getting the raw materials ready and operating in industrial production.
When being the synthetic fluoroform sulphonate of the first step, the main technical problem of acetic acid synthesized Abiraterone easily produces by product 1, and then generate by product 2 by condensation reaction, by product 1 and 2 all can not be removed by recrystallization, and this reaction raw materials can not be converted into product completely, therefore need to reduce by controlling reaction process condition the generation of the first step byproduct of reaction, improve transformation efficiency, simplify purifying process, to adapt to industrial amplification production.
Summary of the invention
Technical problem to be solved by this invention has been to provide a kind of synthetic method of applicable suitability for industrialized production Abiraterone acetate; the method obtains Abiraterone acetate through acidylate, condensation, separation and purification; wherein acidylate step is by controlling temperature of reaction; byproduct of reaction is reduced; simplify operation; product purity reaches more than 97%, and applicable mass industrialized production.
Technical scheme of the present invention comprises following steps:
(1) acidylate: taking Dehydroepiandrosterone Acetate as raw material, add methylene chloride stirring and dissolving, successively add at low temperatures trifluoromethanesulfanhydride anhydride and basic catalyst, room temperature reaction, react complete processing reaction liquid and obtain oily matter, described low temperature is-20～10 DEG C;
(2) condensation: the oily matter that step (1) obtains reacts with diethyl (3-pyridyl) borine under palladium catalyst exists;
(3) separation and purification.
Further optimize, described in step (1), low temperature is-5～5 DEG C.
After adding trifluoromethanesulfanhydride anhydride in described step (1), low-temp reaction adds basic catalyst again after 0.5～1 hour.
Described basic catalyst is 2,6-lutidine, triethylamine, and pyridine, DIPEA is wherein a kind of, and preferably 2,6-lutidine.
Between room temperature reaction pair, be 1～6 hour in described step (1), preferably 3～4 hours.
According to documents CN101044155A and common practise, when in step (1), the usage quantity of trifluoromethanesulfanhydride anhydride and basic catalyst is respectively 1.1 equivalents and 1 equivalent, by product is less.The cancellation reactant that adds water after acylation reaction completes, extraction, organic layer filters with the strainer that is covered with acidic alumina, concentrated filtrate.The experiment proved that, acidic alumina specific filtration resistance diatomite filtration is better except chromatic effect, has avoided using the gac of leakiness while filtration.
The described palladium catalyst of step (2) is dual-triphenylphosphine palladium chloride mixture.Step (2) is Suzuki linked reaction well known to those skilled in the art, and the mixed solvent of the preferred tetrahydrofuran (THF) of reaction solvent and water, preferably 60～90 DEG C of back flow reaction.Concrete operations can be with reference to WO93/20097A.
The described separation purification method of step (3) is column chromatography method.The by product producing due to reaction is difficult to separate with recrystallization, and conventional method is to purify by column chromatography method.Select 300-400 object column chromatography silica gel to make weighting material, silica gel consumption is preferably 3-4 times of step (2) gained oily matter weight, the mixed solvent of the preferred sherwood oil of eluent and ethyl acetate, and preferably the volume ratio of sherwood oil and ethyl acetate is 9: 1.
Prove through many experiments, under low temperature, add trifluoromethanesulfanhydride anhydride low-temp reaction for some time, and add at low temperatures alkali, can the in the situation that of 40～200 grams of scale production, reduce the generation of by product, improve transformation efficiency, the oily matter that step (1) is obtained carries out HPLC test, and result shows, the ratio (peak area ratio) of product fluoroform sulphonate and raw material is greater than 3: 1.Low-temp reaction for some time getting the raw materials ready and the reinforced operating time do not affect yield for suitability for industrialized production provides sufficient.By the first step acylation reaction is reacted and is carried out temperature control; can only need carry out primary column chromatography purifying to the end product after two-step reaction; reduce the process of intermediate being carried out to column chromatography; simplify operation; after HPLC shows purifying, purity reaches more than 97%, is applicable to mass industrialized production.
Embodiment below in conjunction with embodiment is described in further detail the present invention.
Embodiment
Embodiment 1
Step 13 β-acetoxyl group androstane-5, the preparation of 16-diene-17-base triflate
In reactor, add dehydroepiandrosterone acetic ester (40g, 121mmol), add CH
2cl
2(800ml) stirring and dissolving, argon gas direct draught, cools to-5～5 DEG C.Add fast Tf
2o (22.4ml, 133mmol, 1.1 equivalents), in-5～5 DEG C of stirring reactions 40 minutes, then at-5～5 DEG C, add fast 2,6-lutidine (14.4ml, 121mmol, 1 equivalent), the reaction solution obtaining is reacted 3 hours in stirring at room temperature.By this reactant of (400ml) quencher that adds water, stratification, uses CH
2cl
2(200ml) aqueous layer extracted, merges organic layer.By 2N HCl (200ml) washing organic solution.After layering, with the anhydrous MgSO of 120g
4dry 7 minutes, with the strainer filtration that is covered with acidic alumina, use CH
2cl
2washing leaching cake, by concentrated to filtrate and washing lotion, obtains reddish-brown oily matter, and HPLC shows that the ratio of product and raw material is about 4.7: 1 (peak area ratio).
The preparation of step 2 Abiraterone acetate
In reactor, add diethyl (3-pyridyl) borine (16g, 96mmol, 0.8 equivalent), Pd (PPh
3)
2cl
2(0.8g, 1.1mmol) and 2M Na
2cO
3the aqueous solution (220ml, 0.44mol, 1.1 equivalents), dissolves step 1 gained oily matter with 520mlTHF, stirs dirty adding in reactor, 80 DEG C of oil bath back flow reaction 2 hours.Then be cooled to room temperature, add ethyl acetate (600ml) and water (600ml), stir after 5 minutes, layering, organic layer filters with after about 80g anhydrous magnesium sulfate drying half an hour, with the appropriate washing leaching cake of ethyl acetate, filtrate and washing lotion merge, and concentrating under reduced pressure obtains brownish black oily matter 69.8g.
Step 3 chromatographic column purifying
With the glass column of diameter 8cm, load the silica gel (300-400 order) of about 220g, use CH
2cl
2after being dissolved, mixes thoroughly with the silica gel of about 70g step 2 gained oily matter, after volatilizing solvent, pulverize evenly, recharge on silicagel column, surface repaves anhydrous magnesium sulfate, after silicagel column is moistening with sherwood oil, use sherwood oil instead: ethyl acetate (9: 1) wash-out, the elutriant containing excessive diethyl (3-pyridyl) borine and other impurity first flowing out discards, the elutriant of Abiraterone acetate is rich in collection, until tlc for elutriant (TLC) monitoring to almost stopping collecting without product or while having impurity to flow out.The elutriant of collection is concentrated into the dry faint yellow solid (17g, the weight yield based on starting raw material is 42.5%) that obtains.HPLC shows that its purity is 99.5%.
Embodiment 2
Step 13 β-acetoxyl group androstane-5, the preparation of 16-diene-17-base triflate
In reactor, add dehydroepiandrosterone acetic ester (200g, 0.606mol), argon replaces three times, adds CH
2cl
2(4000ml) stirring and dissolving, argon gas direct draught, cools to-20～-15 DEG C.Add fast Tf
2o (112ml, 0.666mol, 1.1 equivalents), in-20～-15 DEG C of stirring reactions 40 minutes, then at-20～-15 DEG C, add fast 2,6-lutidine (70ml, 0.6mol, 1 equivalent), the reaction solution obtaining is reacted 2 hours in stirring at room temperature.By this reactant of (2000ml) quencher that adds water, stratification, uses CH
2cl
2(1000ml) aqueous layer extracted, merges organic layer.By 2N HCl (1000ml) washing organic solution.After layering, use anhydrous MgSO
4(600g) dry 7 minutes, with the strainer filtration that is covered with acidic alumina, use CH
2cl
2washing leaching cake, by concentrated to filtrate and washing lotion, obtains reddish-brown oily matter.HPLC shows that the ratio of product and raw material is about 5.5: 1.
The preparation of step 2 Abiraterone acetate
In reactor, add diethyl (3-pyridyl) borine (90g, 0.54mol, 0.9 equivalent), Pd (PPh
3)
2cl
2(4.0g, 5.7mmol) and 2M Na
2cO
3the aqueous solution (1100ml, 2.2mol, 1.1 equivalents), argon replaces three times, oily matter step 1 being made with 2600mlTHF dissolves, and stirs dirty adding in reactor, 65 DEG C of back flow reaction of temperature 2 hours in oil bath heating.Then be cooled to room temperature, add ethyl acetate (3000ml) and water (3000ml), stir after 5 minutes, layering, organic layer filters with after about 400g anhydrous magnesium sulfate drying half an hour, with the appropriate washing leaching cake of ethyl acetate, filtrate and washing lotion merge, and concentrating under reduced pressure obtains brownish black oily matter.
Step 3 chromatographic column purifying
With the glass column of diameter 10cm, the silica gel (300-400 order) of the about 1kg of filling oily matter weight, uses CH
2cl
2after being dissolved, mixes thoroughly with the silica gel of about 340g step 2 gained oily matter, after volatilizing solvent, pulverize evenly, recharge on silicagel column, surface repaves anhydrous magnesium sulfate, after silicagel column is moistening with sherwood oil, use sherwood oil instead: ethyl acetate (9: 1) wash-out, the elutriant containing excessive diethyl (3-pyridyl) borine and other impurity first flowing out discards, the elutriant of Abiraterone acetate is rich in collection, until elutriant almost without product or have impurity flow out time stop collect.The elutriant of collection is concentrated into the dry yellow solid (100g, the weight yield based on starting raw material is 50%) that obtains.HPLC shows that purity is 97.4%.
Embodiment 3
Step 13 β-acetoxyl group androstane-5, the preparation of 16-diene-17-base triflate
In reactor, add dehydroepiandrosterone acetic ester (100g, 0.303mol), argon replaces three times, adds CH
2cl
2(2000ml) stirring and dissolving, argon gas direct draught, cools to-10～-5 DEG C.Add fast Tf
2o (56ml, 0.333mol, 1.1 equivalents), in-10～-5 DEG C of stirring reactions 40 minutes, then, at-10～-5 DEG C, add fast N, N-diisopropylethylamine (DIPEA) (54ml, 0.6mol, 1 equivalent), the reaction solution obtaining is reacted 5 hours in stirring at room temperature.By this reactant of (1000ml) quencher that adds water, stratification, uses CH
2cl
2(500ml) aqueous layer extracted, merges organic layer.By 2N HCl (500ml) washing organic solution.After layering, use anhydrous MgSO
4(300g) dry 7 minutes, filter with being covered with diatomaceous strainer, use CH
2cl
2cake is considered in washing, by concentrated to filtrate and washing lotion, obtains brown oily matter.HPLC shows that the ratio of product and raw material is about 3.0: 1.
The preparation of step 2 Abiraterone acetate
In reactor, add diethyl (3-pyridyl) borine (50g, 0.34mol, 1.12 equivalents), Pd (PPh
3)
2cl
2(2.0g, 2.85mmol) and 2M Na
2cO
3the aqueous solution (550ml, 1.1mol, 1.1 equivalents), dissolves step 1 gained oily matter with 1300mlTHF, stirs dirty adding in reactor, 75 DEG C of oil bath back flow reaction 2 hours.Then be cooled to room temperature, add ethyl acetate (1500ml) and water (1500ml), stir after 5 minutes, layering, organic layer filters with after about 200g anhydrous magnesium sulfate drying half an hour, wash in right amount worry cake by ethyl acetate, filtrate and washing lotion merge, and concentrating under reduced pressure obtains brownish black oily matter.
Step 3 chromatographic column purifying
With the glass column of diameter 10cm, the silica gel (300-400 order) of the about 580g of filling oily matter weight, uses CH
2cl
2after being dissolved, mixes thoroughly with the silica gel of about 185g step 2 gained oily matter, after volatilizing solvent, pulverize evenly, recharge on silicagel column, surface repaves anhydrous magnesium sulfate, after silicagel column is moistening with sherwood oil, use sherwood oil instead: ethyl acetate (9: 1) wash-out, the elutriant containing excessive diethyl (3-pyridyl) borine and other impurity first flowing out discards, the elutriant of Abiraterone acetate is rich in collection, until elutriant almost without product or have impurity flow out time stop collect.The elutriant of collection is concentrated into the dry faint yellow solid (36g, the weight yield based on starting raw material is 36%) that obtains.HPLC shows that purity is 98.8%.
Claims (5)
1. a synthetic method for Abiraterone acetate, comprises following steps:
(1) acidylate: taking 40～200g Dehydroepiandrosterone Acetate as raw material, add methylene chloride stirring and dissolving, successively add at low temperatures the trifluoromethanesulfanhydride anhydride of 1.1 equivalents and the basic catalyst of 1 equivalent, after adding trifluoromethanesulfanhydride anhydride, low-temp reaction adds basic catalyst for 0.5～1 hour more fast, described low temperature is-20～10 DEG C, described basic catalyst is 2,6-lutidine, room temperature reaction 1～6 hour, react the complete cancellation reactant that adds water, extraction, organic layer filters with the strainer that is covered with acidic alumina, concentrated filtrate, obtains oily matter;
(2) condensation: the oily matter that step (1) obtains reacts with diethyl (3-pyridyl) borine under palladium catalyst exists;
(3) separation and purification.
2. the synthetic method of a kind of Abiraterone acetate according to claim 1, is characterized in that, described in described step (1), low temperature is-5～5 DEG C.
3. the synthetic method of a kind of Abiraterone acetate according to claim 1, is characterized in that, in described step (1), the room temperature reaction time is 3～4 hours.
4. the synthetic method of a kind of Abiraterone acetate according to claim 1, is characterized in that, the described palladium catalyst of step (2) is dual-triphenylphosphine palladium chloride mixture.
5. the synthetic method of a kind of Abiraterone acetate according to claim 1, is characterized in that, the described separation purification method of step (3) is column chromatography method.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102816200B (en) * | 2012-09-05 | 2015-04-15 | 中山大学 | Method for preparing abiraterone acetate |
| CN102816201A (en) * | 2012-09-25 | 2012-12-12 | 成都伊诺达博医药科技有限公司 | Purification method of abiraterone |
| CN103804457A (en) * | 2012-11-07 | 2014-05-21 | 北大方正集团有限公司 | Preparation method of abiraterone acetate |
| CN104370991B (en) * | 2014-11-18 | 2016-04-27 | 仙居县力天化工有限公司 | A kind of synthetic method of Abiraterone acetic ester |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993020097A1 (en) * | 1992-03-31 | 1993-10-14 | British Technology Group Ltd. | 17-substituted steroids useful in cancer treatment |
| WO1995009178A1 (en) * | 1993-09-30 | 1995-04-06 | British Technology Group Limited | Synthesis of 17-(3-pyridyl) steroids |
| CN101044155A (en) * | 2004-08-24 | 2007-09-26 | 英国技术集团国际有限公司 | Methanesulfonate salts of abiraterone-3-esters and recovery of salts of abirater one-3-esters from solution in methyl tert-butyl ether |
| CN101528308A (en) * | 2006-08-25 | 2009-09-09 | 库伽尔生物科技公司 | Methods and compositions for treating cancer |
-
2010
- 2010-12-08 CN CN201010581606.0A patent/CN102558274B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993020097A1 (en) * | 1992-03-31 | 1993-10-14 | British Technology Group Ltd. | 17-substituted steroids useful in cancer treatment |
| WO1995009178A1 (en) * | 1993-09-30 | 1995-04-06 | British Technology Group Limited | Synthesis of 17-(3-pyridyl) steroids |
| CN101044155A (en) * | 2004-08-24 | 2007-09-26 | 英国技术集团国际有限公司 | Methanesulfonate salts of abiraterone-3-esters and recovery of salts of abirater one-3-esters from solution in methyl tert-butyl ether |
| CN101528308A (en) * | 2006-08-25 | 2009-09-09 | 库伽尔生物科技公司 | Methods and compositions for treating cancer |
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