CN104447934A - Method for purifying abiraterone acetate - Google Patents
Method for purifying abiraterone acetate Download PDFInfo
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- CN104447934A CN104447934A CN201410740491.3A CN201410740491A CN104447934A CN 104447934 A CN104447934 A CN 104447934A CN 201410740491 A CN201410740491 A CN 201410740491A CN 104447934 A CN104447934 A CN 104447934A
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- abiraterone acetate
- abiraterone
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- 0 CCC(*)*C1(CC2=CCC(C(C3)C(*)(CC4)C(C)=C3C(C)=C3CC3)C4C2(CC)CC1)N Chemical compound CCC(*)*C1(CC2=CCC(C(C3)C(*)(CC4)C(C)=C3C(C)=C3CC3)C4C2(CC)CC1)N 0.000 description 3
- ABRNDXIVBZLNDZ-UHFFFAOYSA-N CCC(C1C2(CC3)N(C)OC2CC1)C31N=C(CC(CC(C)=C)CC2)C12C=C Chemical compound CCC(C1C2(CC3)N(C)OC2CC1)C31N=C(CC(CC(C)=C)CC2)C12C=C ABRNDXIVBZLNDZ-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
Abstract
The invention belongs to the technical field of medicine synthesis, and provides a method for purifying abiraterone acetate. The method comprises the following steps: in the presence of acetic anhydride and organic bases, dissociating abiraterone acetate salt into free abiraterone acetate, wherein the high-performance liquid chromatography (HPLC) purity of dissociated abiraterone acetate is more than 99%; and then refining abiraterone acetate by virtue of acetonitrile recrystallization to obtain abiraterone acetate which has the HPLC purity of more than 99.7% and can meet the medical standards, and ensuring that the content of hydrolysis impurity abiraterone is less than 0.02%. By adopting the method provided by the invention, the problem that inevitable hydrolysis impurity abiraterone exists in a salt dissociation process of abiraterone acetate can be solved, a purification process can be simplified, and reagents can be saved; and moreover, the method is easy to operate, and is suitable for industrial production.
Description
Technical field
The invention belongs to technical field of medicine synthesis, be specifically related to a kind of purification process of Abiraterone acetate.
Background technology
Prostate cancer is the malignant tumour betided in human male prostate tissue, it is the result of prostatic acini cellular abnormality random growth, European countries' prostate-cancer incidence is high, mortality ratio is only second to lung cancer, the sickness rate of Asian countries's prostate cancer is in the trend risen rapidly, and the sickness rate of prostate cancer in China's male urinary, reproductive system malignant tumour has leapt to the 3rd.Abiraterone acetate is a kind of targeted cells pigment CYP17 (17 α-hydroxylase/C17,20-lyase) inhibitor, and Cytochrome P450 17A1 plays an important role in the generation of testosterone.Abiraterone acetate, just by T suppression cell pigment CYP17, reduces the generation of testosterone and works.On April 28th, 2011, food and drug administration have approved Abiraterone acetate (trade(brand)name: Zytiga) and (has another name called prednisone with prednisone, a kind of steroid medicine) combine treatment for previously accepting transitivity castration-resistant prostate cancer (CRPC) patient treated containing the chemotherapy regimen of docetaxel, in December, 2012, U.S. FDA approval Zytiga expands the treatment for patient before late period (transitivity) castration-resistant prostate cancer chemotherapy.Increase anti-breast cancer indication, be in the clinical III phase at present.The chemical name of Abiraterone acetate: (3 β)-17-(3-pyridyl)-androstane-5,16-dien-3-ols acetic ester, molecular formula: C
26h
33nO
2, molecular weight: 391.55.Be down the chemical structural formula of Abiraterone acetate, Abiraterone acetate is the prodrug of Abiraterone.
The syntheti c route of Abiraterone acetate mainly contains two.Patent WO9320097, CN102030798, WO 2006021777, WO2006021776, J.Med.Chem.38,2463-2471,1995, waits the synthetic route one of bibliographical information as follows:
Its synthetic route take Dehydroepiandrosterone Acetate as starting material, the first step adopts dichloromethane solvent, 2,6-di-t-butyl-4-picoline is attached sour agent, with trifluoroacetic acid anhydride reactant, use normal hexane recrystallization after product column chromatography purification, obtain 17-triflate Dehydroepiandrosterone Acetate, yield 58%.Second step suizik reacts, at sodium carbonate, and dual-triphenylphosphine palladium chloride ((PPh
3)
2pdCl
2) under existence, carry out Suzuki linked reaction at 80 DEG C with diethyl (3-pyridyl) borine, after column chromatography purification, normal hexane recrystallization, obtains Abiraterone acetate, yield 84%.Pass through two-step reaction total recovery in document less than 50%, and often walk all through column chromatography purification.Can be there is larger problem in this technique, be not suitable for suitability for industrialized production in industrialized production.Organic bases 2, the 6-bis--tertiary butyl-4-picoline (DTBMP) used in preparation, trifluoromethanesulfanhydride anhydride and diethyl-3-pyridyl borine are all very expensive.DTBMP participates in reaction and easily side reaction occurs, and causes the ethanoyl of dehydroepiandrosterone to be eliminated, and generates the by product being difficult to remove.
Patent GB 2282377, WO9509178, Org.Prep.Proced.Int, 1997,29 (l), 123-134, then report another synthetic method, and synthetic route two is as follows:
this route take dehydroepiandrosterone as raw material, first reacts with hydrazine hydrate under hydrazonium sulfate catalysis, forms dehydroepiandrosterone-17-hydrazone, then under the catalysis of tetramethyl guanidine, 17-iodo-androstane-5,16-diene-3beta-alcohol is obtained again, then at palladium reagent ((PPh with Iod R
3)
2pdCl
2) under catalysis, carry out Suzuki linked reaction with diethyl-3-pyridyl borine, obtain Abiraterone, finally Abiraterone acetylize is obtained Abiraterone acetate.The first step hydrazine hydrate, hydrazonium sulfate, react 3 days, reactant is poured into water precipitation product, is obtained by filtering separation.Yield 98%; Second step THF is solvent, and 1,1,3,3-tetramethyl guanidine is alkali, 0 DEG C of reaction, filters, concentrated, washing after dissolving, concentrated dry, recrystallization, yield 90%; 3rd step 80 DEG C reaction 48 hours, ether extraction, concentrates tetrahydrofuran (THF) (THF), crude product re crystallization from toluene, yield: 56%; 4th step ether, triethylamine, DMAP catalyzer, Acetyl Chloride 98Min. room temperature reaction 12 hours, filters, and filtrate concentrates, and first uses ethanol/water=1:1 recrystallization, rear normal hexane recrystallization, yield 84%.Or carry out acetylize with diacetyl oxide under pyridine condition.The time of whole reaction is long, the first step three days, three-step reaction 48 hours, is difficult to carry out suitability for industrialized production.Hydrazine hydrate toxicity is comparatively large, and experimental implementation danger is high, brings white elephant to three-protection design, and diethyl-3-pyridyl borine is very expensive, needs column chromatography for separation, is not suitable for suitability for industrialized production.
The Abiraterone acetate purity that route of these two lines obtains is all undesirable, all needs to adopt column chromatography method purifying, product purity and yield on the low side, be not suitable for suitability for industrialized production.And be applicable to becoming salt refining to be technique the most feasible in industrialized process for refining.
It is also the mode adopting said synthesis route one in document CN101044155, when mentioning the first step and trifluoromethanesulfonic acid anhydride reactant in document, there is the raw material reaction of about 25% not complete, but do not go separation and purification, directly carry out next step Suzuki linked reaction, the product obtained is more assorted, the Dehydroepiandrosterone Acetate having unreacted complete, diethyl (3-pyridyl) borine etc., also has some by products.Amplify to realize technique in document, the mode that have employed salify carries out purifying.Route as shown in the formula:
But the purification process of this technique is when methylsulfonic acid and Abiraterone acetate salify, the reaction solution obtained is the suspension of very thickness, be difficult to be separated by filtering, and easily cause the parcel of impurity, dissociating after needing further recrystallization purifying obtains Abiraterone acetate again.And methylsulfonic acid Ester is potential genotoxicity impurity, certain impact is brought on the quality of product and security.When the first step forms triflate, change 2,6-di-t-butyl-4-picolines in WO9320097, use comparatively cheap triethylamine instead, effect is suitable.
Document CN102030798, on the Research foundation of document CN101044155, have studied and carries out purifying by the mode of trifluoromethanesulfonic acid and Abiraterone salify.Although there is certain effect on purifying, the product obtained is greater than the impurity existence of 1% in addition.
WO2006021776 (CN101044155) and WO2006021777 disclose a kind of become the method for mesylate, CN101044155 embodiment 3 also openly can select hydrochloric acid and sulfuric acid, form Abiraterone acetate hydrochloride or Abiraterone acetate vitriol, fluoroform sulphonate method is disclosed in CN201010597372 (publication No.: CN102030798), CN201110318824 (publication No.: CN103059090) discloses into oxalate method, CN201210039644 (publication No.: CN103254265) discloses into trifluoroacetate method, CN201210201917 (publication No.: CN102731605) discloses into phosphatic method.These salifying methods can obtain the good Abiraterone acetate salt of purity.But according to the general inorganic alkaline hydrolysis salt worker skill of these patent reports, (Abiraterone acetate salt adds methylene dichloride; stirring and dissolving; add sodium bicarbonate and water or sodium carbonate and water or 20% sodium bicarbonate aqueous solution or 20% aqueous sodium carbonate; stir separatory; water layer dichloromethane extraction; merge organic phase; organic phases washed with water; anhydrous sodium sulphate or dried over mgso, suction filtration, concentrated free Abiraterone acetate) institute obtains in product and contains the deacetylated product Abiraterone (being shown below) of more Abiraterone acetate.
According to scale, this foreign matter content is not 1% to 10% etc.Therefore need the Abiraterone acetate after solution salt technique makes solution salt preferably and contain less Abiraterone impurity.
Summary of the invention:
The invention provides a kind of purification process of Abiraterone acetate.The method selects suitable solvent, and under acetic anhydride and organic bases exist, Abiraterone acetate salt dissociates and obtains Abiraterone acetate by reacting by heating, and free Abiraterone acetate high performance liquid chromatography (HPLC) purity obtained is greater than 99%.Then with suitable organic solvent such as acetonitrile or refining methanol Abiraterone acetate; very highly purified target product can be obtained; HPLC purity is greater than 99.7%; the deacetylated product Abiraterone of Abiraterone acetate is less than 0.02%; this process simplify purifying process; simple to operate, and cost is lower, is conducive to suitability for industrialized production.
Technical scheme of the present invention comprises the following steps:
The free reaction of step (1): Abiraterone acetate salt is added suitable solvent, reflux temperature is heated under acetylation reagent acetic anhydride or Acetyl Chloride 98Min. and organic bases existence, keep reflux temperature 2.5 hours, carry out in alkali and dissociate reacting Abiraterone acetate salt solution salt; Stir borehole cooling to stirring at room temperature crystallization 5 hours, suction filtration, filter cake water wash, 45 ~ 55 DEG C of dryings 8 hours, obtain Abiraterone acetate; Chemical equation is as follows:
HX represents unitary or polyprotonic acid;
Step (2) recrystallization: add Abiraterone acetate in reaction vessel, adds acetonitrile or methyl alcohol is heated to backflow, keeps reflux temperature 10 to 30 minutes.Stir lower nature and be down to stirring at room temperature crystallization 5h, suction filtration, filter cake a small amount of acetonitrile or methyl alcohol drip washing, filter cake was in 45 ~ 55 DEG C of dryings 8 hours, obtain white solid Abiraterone acetate, HPLC purity is greater than 99.7%, and Abiraterone impurity is less than 0.02%, and the mass volume ratio of Abiraterone acetate and methyl alcohol is 1:3 ~ 7; The mass volume ratio of Abiraterone acetate and acetonitrile is 1:3 ~ 5.
Abiraterone acetate salt wherein described in step (1) can be Abiraterone acetate mesylate, Abiraterone acetate fluoroform sulphonate, Abiraterone acetate hydrobromate, the acid of Abiraterone acetate hydrochloric acid, Abiraterone acetate oxalate, Abiraterone acetate vitriol, Abiraterone acetate phosphoric acid salt etc.
The solvent of described step (1) is the mixture of a kind of solvents such as methylene dichloride, trichloromethane, 1,2-ethylene dichloride, acetonitrile, tetrahydrofuran (THF), methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, tert.-butyl acetate, ether, methyl tertiary butyl ether, methyl-phenoxide or several solvent; Be preferably methylene dichloride, acetonitrile, tetrahydrofuran (THF), ethyl acetate etc.
The organic bases of described step (1) is amine organic bases; Be preferably triethylamine, diisopropylethylamine, 4,4-dimethylamino pyridines, 2,6-di-tert-butyl pyridines, 1,8-diazabicylo 11 carbon-7-alkene; Be more preferably triethylamine, diisopropylethylamine, 4,4-dimethylamino pyridines.
In theory, the acetylation reagent such as acetic anhydride, Acetyl Chloride 98Min. and hydrolysis impurity Abiraterone (deacetylated product of Abiraterone acetate) carry out acetylization reaction and can form Abiraterone acetate.3rd step synthesis Abiraterone of the synthetic route of such as WO9509178, the 4th step obtains Abiraterone acetate by Abiraterone acetylize:
therefore, the method for organic bases of the present invention (simultaneously playing catalyzer) and acetic anhydride solution salt minimizing Abiraterone impurity has theoretical foundation.And Abiraterone acetate salt inorganic base aqueous solution solution salt, do not add acetylation reagent, be then certain to produce hydrolysis impurity Abiraterone, the ratio of Abiraterone impurity is not from 1% to 10% etc.Adopt organic bases and acetylation reagent acetic anhydride or Acetyl Chloride 98Min. ratio mineral alkali 20% sodium carbonate solution or 20% sodium hydrogen carbonate solution not to add acetic anhydride, the HPLC purity of the Abiraterone acetate that solution salt obtains significantly improves, and single contaminant significantly reduces.Embodiment 10 and comparative example 2 are Abiraterone acetate mesylate solution salt, under organic bases adds acetic anhydride condition, HPLC high purity 99.3%, Abiraterone impurity only 0.18%, without the impurity being greater than 1%, and under mineral alkali does not add acetic anhydride condition, HPLC purity only 93.58%, the impurity being greater than 1% reaches 4, and the solution salt method tool of organic bases of the present invention and acetic anhydride has an unexpected effect.
After Abiraterone acetate salt solution salt, with suitable solvent such as acetonitrile or refining methanol Abiraterone acetate, the Abiraterone acetate that HPLC purity is greater than 99.7% can be obtained, hydrolysis impurity Abiraterone is not higher than 0.02%, single contaminant, not higher than 0.1%, meets the quality standard of Abiraterone acetate bulk drug completely.This method solve the problem that the inevitable hydrolysis impurity Abiraterone of Abiraterone acetate solution salt process produces, simplify purifying process, save reagent, save time, and easy handling, be applicable to suitability for industrialized production.The Abiraterone acetate that in the embodiment of the patent of invention that patent specification of the present invention is quoted, Abiraterone acetate salt solution salt obtains is a gram level, and utilize technology of the present invention successfully to produce the Abiraterone acetate of feather weight, after acetonitrile refining, HPLC purity reaches 99.8%, impurity Abiraterone content is lower than 0.02%, prove that the inventive method is applicable to suitability for industrialized production, there is novelty, creativeness and practicality.
Accompanying drawing explanation
Fig. 1 is embodiment 13 Abiraterone acetate (lot number 20110801) HPLC purity figure
Fig. 2 is embodiment 13 Abiraterone acetate (lot number 20110901) HPLC purity figure
Fig. 3 is embodiment 13 Abiraterone acetate (lot number 20111001) HPLC purity figure
Embodiment
Now further describe beneficial effect of the present invention by following examples, be interpreted as these embodiments only for the object of illustration, do not limit the scope of the invention, the simultaneously apparent change made according to the present invention of those of ordinary skill in the art and modification are also contained within the scope of the invention.
The preparation of Abiraterone acetate crude product please refer to patent WO9509178, CN102030798, WO 2006021777, WO 2006021777, WO2006021776, J.Med.Chem.38,2463-2471,1995, or with reference to patent GB 2282377, Org.Prep.Proced.Int, 1997,29 (l), 123-134, preparation.
Abiraterone acetate salify please refer to WO2006021777 preparation method and obtains Abiraterone acetate mesylate, Abiraterone acetate hydrochloride and Abiraterone acetate vitriol; Abiraterone acetate fluoroform sulphonate is obtained with reference to CN201010597372 preparation method; Obtain Abiraterone acetate oxalate with reference to CN201110318824 preparation method, obtain Abiraterone acetate trifluoroacetate with reference to CN201210039644, obtain Abiraterone acetate phosphoric acid salt with reference to CN201210201917.These salifying methods can obtain the good Abiraterone acetate salt of purity.
The selection of embodiment 1 Abiraterone acetate salify acid used
The mode often walking column chromatography is adopted to purify in WO9320097, produce due to industrialization cannot be realized, so there is document (WO2006021776, CN101044155 etc.) to mention, the mode that can adopt salify crystallization carries out purifying, and rear solution salt obtains product.With reference to described in CN102030798, we have selected several acid, are investigated by the yield of salify and the situation of thin-layer chromatography (TLC) plate and are selected a kind of suitable acid.
The selection of table 1 acid
| Acid | Salt | Proterties | Yield % |
| Oxalic acid | Abiraterone acetate oxalate | Off-white color solid | 49.7％ |
| Phosphoric acid | Abiraterone acetate phosphoric acid salt | Faint yellow solid | 50.9％ |
| Methylsulfonic acid | Abiraterone acetate mesylate | Yellow solid | 52.3 |
| Trifluoromethanesulfonic acid | Abiraterone acetate fluoroform sulphonate | Yellow solid | 56.5 |
| Trifluoroacetic acid | Abiraterone acetate trifluoroacetate | Khaki color solid | 67.8％ |
| Hydrogen bromide | Abiraterone acetate hydrobromate | Dark yellow solid | 70.0 |
| Hydrochloric acid | Abiraterone acetate hydrochloride | Yellow solid | 70.3 |
It is latent gene toxic impurities that methanesulfonates is reported as, and uses the possible residual meeting of methylsulfonic acid to cause producing methanesulfonates.And the yield of hydrochloride is higher, preferably salt hydrochlorate is final salifie form.
The preparation of embodiment 2 Abiraterone acetate hydrochloride
2.6kg Abiraterone acetate crude product, 11L ethyl acetate and 11L methyl tertiary butyl ether is added, stirring and dissolving in reactor.Stirring is cooled to 5 DEG C, drips 0.22kg concentrated hydrochloric acid.0 ~ 5 DEG C of stirring and crystallizing 2h.Stir 1 hour after being warming up to room temperature, suction filtration, filter cake methyl tertiary butyl ether drip washing, obtains yellow solid.Filter cake 35 ~ 40 DEG C of forced air dryings 4 hours, obtain off-white color solid 2.5kg.Yield: 86.7%, HPLC:98.3%.
High performance liquid chromatography (HPLC) condition that purity detecting uses: sample thief is appropriate, accurately weighed, adds acetonitrile and dissolves and dilute the solution made about containing 3mg in every 1ml, as need testing solution; Measure according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex V D).Be weighting agent (150 × 4.6mm, 5 μm) with octadecylsilane chemically bonded silica; Take acetonitrile as mobile phase A, water is Mobile phase B, carries out gradient elution by table 2 program; Flow velocity is per minute 1.0ml, and determined wavelength is 210nm, and column temperature is 40 DEG C.Precision measures need testing solution 10 μ l, injection liquid chromatography, record color atlas.The purity of principal constituent is calculated by area normalization method.
Table 2 gradient elution program
Embodiment 3 Abiraterone acetate hydrochloride solution salt
Add 250g Abiraterone acetate hydrochloride, 2.4L acetonitrile, 80g triethylamine and 50g acetic anhydride in reaction flask, under stirring, be warming up to backflow, keep reflux temperature 2.5h.Stir borehole cooling to stirring at room temperature crystallization 5h.Suction filtration, filter cake water wash, 45 ~ 55 DEG C of forced air dryings 8 hours, obtain off-white color solid 194.4g.Yield 85%.HPLC purity 99.4%, wherein Abiraterone 0.23%, do not have the impurity of content > 1%.Chemical equation is as follows:
HX is HCl.
Embodiment 4 Abiraterone acetate hydrochloride solution salt
Add 250g Abiraterone acetate hydrochloride, 3.6L ethyl acetate, 40g triethylamine and 25g acetic anhydride in reaction flask, under stirring, be warming up to backflow, keep reflux temperature 2.5h.Stir borehole cooling to stirring at room temperature crystallization 5h.Suction filtration, filter cake water wash, 45 ~ 55 DEG C of forced air dryings 10 hours, obtain off-white color solid 183.0g.Yield 80%.HPLC purity 99.2%, wherein Abiraterone 0.45%, do not have the impurity of content > 1%.
Embodiment 5 Abiraterone acetate hydrochloride solution salt
Add 250g Abiraterone acetate hydrochloride, 2.4L acetonitrile, 129.3g diisopropylethylamine and 50g acetic anhydride in reaction flask, under stirring, be warming up to backflow, keep reflux temperature 2.5h.Stir borehole cooling to stirring at room temperature crystallization 5h.Suction filtration, filter cake water wash, 45 ~ 55 DEG C of forced air dryings 8 hours, obtain off-white color solid 187.5g.Yield 82%.HPLC purity 99.1%, wherein Abiraterone 0.54%, do not have the impurity of content > 1%.
Embodiment 6 Abiraterone acetate hydrochloride solution salt
Add 250g Abiraterone acetate hydrochloride, 2.4L acetonitrile, 4, the 4-dimethylamino pyridines of 96.5g and 50g acetic anhydride in reaction flask, under stirring, be warming up to backflow, keep reflux temperature 2.5h.Stir borehole cooling to stirring at room temperature crystallization 5h.Suction filtration, filter cake water wash, 45 ~ 55 DEG C of forced air dryings 8 hours, obtain off-white color solid 192.1g.Yield 84%.HPLC purity 99.2%, wherein Abiraterone 0.60%, do not have the impurity of content > 1%.
Embodiment 7 Abiraterone acetate hydrochloride solution salt
Add 250g Abiraterone acetate hydrochloride, 1.2L tetrahydrofuran (THF), 4, the 4-dimethylamino pyridines of 96.5g and 50g acetic anhydride in reaction flask, under stirring, be warming up to backflow, keep reflux temperature 2.5h.Stir borehole cooling to stirring at room temperature crystallization 5h.Suction filtration, filter cake water wash, 45 ~ 55 DEG C of forced air dryings 8 hours, obtain off-white color solid 171.5g.Yield 75%.HPLC purity 99.0%, wherein Abiraterone 0.65%, do not have the impurity of content > 1%.
Embodiment 8 Abiraterone acetate hydrochloride solution salt
250g Abiraterone acetate hydrochloride, 2.4L acetonitrile, 80g triethylamine and 50g acetic anhydride is added, 50 DEG C of reaction 6h in reaction flask.Stir borehole cooling to stirring at room temperature crystallization 5h.Suction filtration, filter cake water wash, 45 ~ 55 DEG C of forced air dryings 8 hours, obtain off-white color solid 189.8g.Yield 83%.HPLC purity 98.7%, wherein Abiraterone 0.58%, do not have the impurity of content > 1%.
Embodiment 9 Abiraterone acetate phosphoric acid salt solution salt
Add 250g Abiraterone acetate phosphoric acid salt, 2.4L acetonitrile, 70g triethylamine and 45g acetic anhydride in reaction flask, under stirring, be warming up to backflow, keep reflux temperature 2.5h.Stir borehole cooling to stirring at room temperature crystallization 5h.Suction filtration, filter cake water wash, 45 ~ 55 DEG C of forced air dryings 8 hours, obtain off-white color solid 160.0g.Yield 80%.HPLC purity 98.6%, wherein Abiraterone 0.56%, do not have the impurity of content > 1%.
Embodiment 10 Abiraterone acetate mesylate solution salt
Add 250g Abiraterone acetate mesylate, 2.4L acetonitrile, 70g triethylamine and 45g acetic anhydride in reaction flask, under stirring, be warming up to backflow, keep reflux temperature 2.5h.Stir borehole cooling to stirring at room temperature crystallization 5h.Suction filtration, filter cake water wash, 45 ~ 55 DEG C of forced air dryings 8 hours, obtain off-white color solid 168.6g.Yield 84%.HPLC purity 99.3%, wherein Abiraterone 0.18%, do not have the impurity of content > 1%.
Embodiment 11 Abiraterone acetate oxalate solution salt
Add 250g Abiraterone acetate oxalate, 2.4L acetonitrile, 65g triethylamine and 42g acetic anhydride in reaction flask, under stirring, be warming up to backflow, keep reflux temperature 2.5h.Stir borehole cooling to stirring at room temperature crystallization 5h.Suction filtration, filter cake water wash, 45 ~ 55 DEG C of forced air dryings 8 hours, obtain off-white color solid 168.6g.Yield 83%.HPLC purity 99.1%, wherein Abiraterone 0.28%, do not have the impurity of content > 1%.
Refining of embodiment 12 Abiraterone acetate
Add the obtained 150g Abiraterone acetate of embodiment 5 in reaction flask, 1L methyl alcohol is heated to backflow and keeps reflux temperature 10min.Stir lower nature and be down to stirring at room temperature crystallization 5h.Suction filtration, filter cake methyl alcohol drip washing, filter cake, in 45 ~ 55 DEG C of forced air dryings 8 hours, obtains white solid 124.1g.Yield 83%.HPLC purity 99.7%, wherein Abiraterone 0.04%.
Embodiment 13 Abiraterone acetate hydrochloride solution salt and Abiraterone acetate refining (industrially scalable)
Because embodiment 3 products obtained therefrom is minimum containing Abiraterone impurity, therefore, amplify by the method for embodiment 3 and ingredient proportion the solution salt that feeds intake, separate salt 3 batches altogether, obtain 3 batches of Abiraterone acetate crude products, the results are shown in Table 3:
Result investigated by table 3 Abiraterone acetate hydrochloride solution salt
Note: yield is by Abiraterone acetate
In 50L reactor, add 5.0kg Abiraterone acetate crude product, 10kg acetonitrile, stir, then add 5kg acetonitrile.Be heated to backflow, keep reflux temperature 30 minutes.Naturally cool to room temperature.At room temperature stirring and crystallizing 5 hours.Suction filtration, a small amount of acetonitrile drip washing of filter cake.Filter cake, 50 DEG C of forced air dryings, obtains 4.267kg white solid (Abiraterone acetate).Yield 85.34%.HPLC purity 99.868%, wherein Abiraterone impurity 0.016%.Refining 3 batches altogether, obtain 3 batches of Abiraterone acetate fine work, the results are shown in Table 4:
Table 4 Abiraterone acetate is refining investigates result
Lot number 20110801HPLC purity is shown in Fig. 1, lot number 20110901HPLC purity is shown in Fig. 2, lot number 20111001HPLC purity is shown in Fig. 3.
Related substances separation method: HPLC method (Chinese Pharmacopoeia version in 2010 two annex V D)
Chromatographic condition:
Chromatographic column: octadecylsilane chemically bonded silica is weighting agent (welch
xB-C18,150 × 4.6mm, 5 μm or equivalent post are suitable for), detector: UV detector, determined wavelength: 210nm, column temperature: 40 DEG C, sampling volume: 10 μ l, flow velocity: 1.0ml/min, mobile phase A: acetonitrile, Mobile phase B: water.
Gradient elution is carried out by table 5 program:
Table 5 related substance HPLC elution program
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 60 | 40 |
| 11 | 82 | 18 |
| 25 | 82 | 18 |
| 40 | 90 | 10 |
| 50 | 100 | 0 |
| 70 | 100 | 0 |
| 70.1 | 60 | 40 |
| 80 | 60 | 40 |
[0082]assay method: get this product in right amount, accurately weighed, add acetonitrile and dissolve and dilute the solution made about containing 3mg in every 1ml, as need testing solution; Precision measures in right amount, makes the solution about containing 3 μ g in every 1m1, solution in contrast by dilution in acetonitrile.Get contrast solution 10 μ l injection liquid chromatography, conditioning instrumentation sensitivity, makes principal constituent chromatographic peak peak height be about 5% ~ 10% of full range; Precision measures need testing solution and each 10 μ l of contrast solution again, respectively injection liquid chromatography, record color atlas.
Measure the related substance of own product and commercially available product, result is as follows:
Table 6 Abiraterone acetate related substance detected result
Conclusion: self-control pilot scale three batch sample and commercially available product impurity system is basically identical, unanimously, impurity level is very little for dopant species.All do not detect known impurities in self-control pilot scale three batch sample and commercially available product, maximum single contaminant and total impurities are all less than commercially available product.
Result of study shows: the Abiraterone acetate raw material produced according to the synthesis technique pilot scale determined all does not detect the known impurities being greater than 0.1% and other the maximum single contaminant being greater than 0.1%.This product three batch sample related substance maximum contaminant and total impurities all very little, control of purity is reasonable, safe and reliable.
Comparative example 1 (for Abiraterone acetate fluoroform sulphonate solution salt)
Described in embodiment in CN102030798 2, Abiraterone acetate fluoroform sulphonate is added in 1L there-necked flask, then adds 250ml methylene dichloride and 250ml20%Na
2cO
3the aqueous solution, stir after 20 minutes, aqueous phase pH > 9, continue stirring at room temperature 1 hour, leave standstill phase-splitting, abandon aqueous phase, organic phase anhydrous magnesium sulfate drying, filter, concentrated, obtain brown oil (HPLC purity is 97.44%, the impurity of content > 1% 1), yield 76.4%.
Comparative example 2 (for Abiraterone acetate mesylate solution salt)
By in CN102030798 described in comparative example, Abiraterone acetate mesylate is added in 1L there-necked flask, then adds 250ml methylene dichloride and 250ml20%Na
2cO
3the aqueous solution, stir after 20 minutes, aqueous phase pH > 9, continue stirring at room temperature 1 hour, leave standstill phase-splitting, abandon aqueous phase, organic phase anhydrous magnesium sulfate drying, filter, concentrated, obtain brown oil (HPLC purity is 93.58%, the impurity of content > 1% 4), yield 81%.
By the HPLC comparison or purity of the comparative example of organic bases and each embodiment of acetic anhydride solution salt and inorganic alkaline hydrolysis salt as table 7:
The saline and alkaline middle reconciliation salt effectiveness comparison of Abiraterone acetate under the various condition of table 7
From table 7, embodiment 3 is solvent with acetonitrile, be organic bases with triethylamine, be acetylation reagent with acetic anhydride, take reflux temperature as temperature of reaction, gained Abiraterone foreign matter content is minimum.Compared with prior art, organic bases provided by the invention and acetylation reagent acetic anhydride ratio prior art inorganic bases sodium carbonate or sodium hydrogen carbonate solution is adopted not to add acetic anhydride, the HPLC purity of separating the free Abiraterone acetate that salt obtains significantly improves, single contaminant significantly reduces, especially embodiment 10 and comparative example 2 are Abiraterone acetate mesylates, under organic bases triethylamine adds acetic anhydride condition, HPLC high purity 99.3%, Abiraterone impurity only 0.18%, after acetonitrile refining, Abiraterone acetate HPLC purity reaches 99.8% further, hydrolysis impurity Abiraterone only 0.016%, meet Abiraterone acetate bulk drug medicinal standard completely, and under inorganic bases sodium carbonate do not add acetic anhydride condition, HPLC purity only 93.58%, the impurity being greater than 1% reaches 4.The solution salt method tool of the organic bases that the technology of the present invention provides and acetic anhydride has an unexpected effect.
Claims (7)
1. a purification process for Abiraterone acetate, is characterized in that comprising following steps:
The free reaction of step (1): Abiraterone acetate salt is added suitable solvent, reflux temperature is heated under acetylation reagent acetic anhydride and organic bases exist, keep reflux temperature 2.5 hours, carry out in alkali and dissociate reacting Abiraterone acetate salt solution salt; Stirring at room temperature crystallization 5 hours, suction filtration, filter cake water wash, 45 ~ 55 DEG C of dryings, obtain the free Abiraterone acetate that HPLC purity is greater than 99%; Chemical equation is as follows:
HX represents unitary or polyprotonic acid;
Step (2) recrystallization: add Abiraterone acetate in reaction vessel, add acetonitrile and be heated to backflow, keep reflux temperature 10 ~ 30 minutes, the weightmeasurement ratio of Abiraterone acetate and acetonitrile is 1:3 ~ 5, naturally stirring at room temperature crystallization 5h is down to, suction filtration, a small amount of acetonitrile drip washing of filter cake, filter cake, in 45 ~ 55 DEG C of dryings, obtains the Abiraterone acetate meeting medicinal standard that HPLC purity is greater than 99.7%.
2. the purification process as described in right 1, is characterized in that step (1) described Abiraterone acetate salt is the various salt that Abiraterone acetate can become: the acid of Abiraterone acetate mesylate, Abiraterone acetate fluoroform sulphonate, Abiraterone acetate hydrobromate, Abiraterone acetate hydrochloric acid, Abiraterone acetate oxalate, Abiraterone acetate vitriol and Abiraterone acetate phosphoric acid salt etc.
3. the purification process as described in right 1, it is characterized in that the described suitable solvent of step (1) is the mixture of a kind of solvents such as methylene dichloride, trichloromethane, 1,2-ethylene dichloride, acetonitrile, tetrahydrofuran (THF), methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, tert.-butyl acetate, ether, methyl tertiary butyl ether and methyl-phenoxide or several solvent.
4. the purification process as described in claim 1 or 3, is characterized in that the described suitable solvent of step (1) is preferably methylene dichloride, acetonitrile, tetrahydrofuran (THF) and ethyl acetate etc.
5. purification process as claimed in claim 1, is characterized in that step (1) described organic bases is amine organic bases.
6. the purification process as described in claim 1 or 5, is characterized in that described organic bases is preferably triethylamine, diisopropylethylamine, 4,4-dimethylamino pyridines, 2,6-di-tert-butyl pyridines, 1,8-diazabicylo 11 carbon-7-alkene.
7. the preparation method as described in claim 1 or 5 or 6, is characterized in that organic bases is more preferably triethylamine, diisopropylethylamine, 4,4-dimethylamino pyridines.
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