CN104710500A - Synthesis method of abiraterone acetate - Google Patents
Synthesis method of abiraterone acetate Download PDFInfo
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- CN104710500A CN104710500A CN201510118824.3A CN201510118824A CN104710500A CN 104710500 A CN104710500 A CN 104710500A CN 201510118824 A CN201510118824 A CN 201510118824A CN 104710500 A CN104710500 A CN 104710500A
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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 provides a synthesis method of abiraterone acetate. The synthesis method of the abiraterone acetate comprises the following steps: carrying out acetylation reaction with acetylchloride by a compound (II) to prepare a compound (III), enabling chemical exchange reaction by a compound (IV) to prepare an intermediate compound, and enabling reaction between the intermediate compound and the compound (III) to prepare a compound (I) which is abiraterone acetate. The method has the advantages of high process controllability, simple and short steps, no complicated post-treatment process, high yield, low cost and high purity of products, and is suitable for industrial production. The reaction route is as follows: the formula is as shown in the description.
Description
Technical field
The present invention relates to small-molecule chemical pharmaceutical formulating art, relate more specifically to a kind of synthetic method of Abiraterone acetate ester.
Background technology
Abiraterone acetate ester (abiraterone acetate, 1), chemistry 17-(3-pyridyl) androstane-5 by name, 16-diene-3 β-acetic ester, it is the orally active CYP17 enzyme irreversible inhibitor developed by Centocor Ortho company, April 28 in 2011, Nikkei U.S. FDA approval listing, treated castration-resistant prostate cancer with prednisone coupling.Abiraterone acetate is the prodrug of Abiraterone, and the Cytochrome P45017α that Abiraterone targeted inhibition regulates testosterone to generate is active, not only also has restraining effect to the male sex hormone that other position of health produces as suprarenal gland etc. to testis.
The synthetic method of current bibliographical information has following several:
1, with acetic acid dehydroepiandrosterone for raw material, be obtained by reacting steroid enol trifluoromethyl sulfonic acid with trifluoromethanesulfanhydride anhydride, be then obtained by reacting Abiraterone acetate ester with diethyl (3-pyridyl) borine.This synthetic route is shorter, but can generate the difficult by product be separated, and needs to use column chromatography separating purification.Diethyl (3-pyridyl) borine and trifluoromethanesulfanhydride anhydride expensive and poisonous.In addition, be difficult to amplify production (Potter, G.A.et al, J.Med.Chem., 1995,38, p2463-2471).
2, take dehydroepiandrosterone as raw material, first react to obtain dehydroepiandrosterone-17-hydrazone with hydrazine hydrate, then iodo forms 17-iodo-androstane-5,16-diene-3 β-ol, and then react obtained Abiraterone with 3-pyridinyl zinc bromide, last esterification obtains Abiraterone acetate ester.Although each step productive rate is not low, reactions steps is longer, and Pd catalyzer costly, is not suitable for scale operation (Wang Hongbo etc., Chinese Journal of Pharmaceuticals, 2012,43, p804-806).
3, take dehydroepiandrosterone as starting raw material, first react to obtain dehydroepiandrosterone-17-hydrazone with hydrazine hydrate.Then intermediate hydrazone and iodo form 17-iodo-androstane-5,16-diene-3 β-ol, and then are obtained by reacting Abiraterone with diethyl (3-pyridyl) borine, and last esterification obtains Abiraterone acetate ester.Each step productive rate is not low, but reactions steps is longer, and starting raw material diethyl (3-pyridyl) borine and Pd catalyzer are all costly, is not suitable for scale operation (Potter, G.A.et al, WO 9509178,1995).
So far, the synthetic method defect of bibliographical information is as follows: be existingly raw material with acetic acid dehydroepiandrosterone synthetic route cost is higher, the synthetic route taking dehydroepiandrosterone as raw material is longer, all need precious metals pd as catalyzer, and diethyl (3-pyridyl) borine and trifluoromethanesulfanhydride anhydride expensive; Byproduct of reaction is more in addition, complex operation, needs purification by column chromatography to be separated, is not suitable for suitability for industrialized production.
(1) diethyl (3-pyridyl) borine and trifluoromethanesulfanhydride anhydride expensive and poisonous;
(2) need precious metals pd as catalyzer, cost is higher;
(3) byproduct of reaction is more in addition, complex operation, and product needs purification by column chromatography to be separated;
(4) reaction scheme is longer, produces difficulty in a large number.
Summary of the invention
For overcoming the problems referred to above of the prior art, the invention provides a kind of synthetic method of roflumilast, the synthetic route of the method is shorter, and the cost of raw material and reagent is lower, yield and product purity higher, be suitable for suitability for industrialized production.
The technical solution used in the present invention is:
A synthetic method for Abiraterone acetate ester, comprises the following steps:
(1) in organic solvent, there is acetylization reaction, obtain compound (III) in compound (II) and Acetyl Chloride 98Min. under the effect of alkali at 0 ~ 50 DEG C;
(2) in organic solvent, compound (IV) issues biochemical permutoid reaction with Grignard reagent or zincon at 0 ~ 80 DEG C, obtain midbody compound (V), add the compound (III) obtained in step (1) again, and 10 ~ 18 hours are reacted at a reflux temperature under the effect of catalyzer, obtain compound (I), wherein, Nu is MgX, ZnX, X is Br or I, and described organic solvent is selected from one or more in ether, dioxane, methyl tertiary butyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran; Or
In organic solvent, compound (IV) issues biochemical permutoid reaction with n-Butyl Lithium and zincon at-90 ~-70 DEG C, obtain midbody compound (V), add the compound (III) that step (1) obtains again, and react at 20 ~ 100 DEG C under the effect of catalyzer, obtain compound (I), wherein X is Br or I, described organic solvent is selected from one or more in DMF, dioxane, methyl tertiary butyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran; Or
In organic solvent, compound (IV) issues biochemical permutoid reaction at 80 ~ 100 DEG C with connection pinacol borate under the effect of catalyzer and alkali, obtain midbody compound (V), add the compound (III) obtained in step (1) again, and react at 55 ~ 100 DEG C under the effect of alkali and catalyzer, obtain compound (I), wherein Nu is
x is Br or I, and described organic solvent is selected from one or more in DMF, N,N-dimethylacetamide, N-Methyl pyrrolidone, 2-methyltetrahydrofuran, tetrahydrofuran (THF), methyl-sulphoxide, acetonitrile, methyl tertiary butyl ether and toluene; Or
In organic solvent, compound (IV) issues biochemical permutoid reaction with methoxyl group pinacol borate and Grignard reagent at-10 ~ 40 DEG C, obtain midbody compound (V), add the compound (III) obtained in step (1) again, and react at 55 ~ 100 DEG C under the effect of alkali and catalyzer, obtain compound (I), wherein Nu is
x is Br or I, and described organic solvent is selected from one or more in DMF, N,N-dimethylacetamide, N-Methyl pyrrolidone, 2-methyltetrahydrofuran, tetrahydrofuran (THF), methyl-sulphoxide, acetonitrile, methyl tertiary butyl ether and toluene; Or
Reaction scheme is as follows:
Further, in step (1), organic solvent is selected from one or more in methylene dichloride, chloroform, tetrahydrofuran (THF), acetonitrile, DMF, ether, methyl tertiary butyl ether, ethyl acetate.
Preferably, in step (1), alkali is selected from one or more in DIPEA, triethylamine, salt of wormwood, sodium carbonate, 1,8-diazabicylo 11 carbon-7-alkene (DBU) and pyridine.
Preferably, in step (1), the time of acetylization reaction is 3 ~ 18 hours.
Further, in step (2), above-mentioned catalyzer is Pd catalyzer or Ni catalyzer.
Preferably, Pd catalyzer is selected from Pd (dppf) Cl
2, Pd (pph
3)
4, Pd (acac)
2, PdCl
2(DPPE), Pd/C or Pd (CH
3cN) Cl
2.
Preferably, Ni catalyzer is selected from Ni (DPPP) Cl
2or NiCl
2(DPPE).
More preferably, in step (2), used alkali all can be selected from one or more in Potassium ethanoate, sodium-acetate, ammonium acetate, Lithium Acetate and cesium acetate.
More preferably, in step (2), zincon is zinc chloride or zinc bromide.
Preferably, in step (2), Grignard reagent is isopropylmagnesium chloride, methylmagnesium-chloride or ethylmagnesium bromide.
Compared with prior art, the present invention has the following advantages: the present invention adopts Suzuki or the Kumada linked reaction for the treatment of different things alike, and shortens synthesis step, provides a kind of Abiraterone acetate Lipase absobed method of applicable suitability for industrialized production.The present invention has that process controllability is strong, the simple short victory of step, do not need that loaded down with trivial details last handling process, yield are high, cost is low, product purity advantages of higher, is applicable to suitability for industrialized production.
Technology key point of the present invention and wish protection point:
(1) use cheap 3-bromopyridine or 3-iodine pyridine to be starting raw material, synthesize corresponding Grignard reagent, organic zinc reagent and boronate reagent;
(2) use dehydroepiandrosterone to be raw material, be converted into its important intermediate iodo thing through 2 step reactions.
(3) under palladium metal or nickel catalysis, without the corresponding Grignard reagent of separation and Extraction, organic zinc reagent and boronate reagent, they carry out with iodo thing treating different things alike Suzuki and the Kumada linked reaction of (one-pot) then, and high productivity obtains Abiraterone acetate ester.
Embodiment
Below in conjunction with specific embodiment, the present invention is further elaborated.
Embodiment 1
Compound (III) (227mg, 0.57mmol) be dissolved in methylene dichloride (8.5ml), add DIPEA (0.16ml, 0.91mmol), Acetyl Chloride 98Min. (0.057ml, 0.8mmol), room temperature reaction 12 hours, adds water and ether, and organic phase concentrates, compound (IV) (226mg, yield 90%) is obtained with PE/EA=1:1 column chromatography.
1HNMR(400MHz,CDC1
3,δppm)：6.15(1H,m),4.6(1H,m),3.52-3.58(m,1H),2.11-2.42(m，3H),2.0(3H,s),1.81-2.11(m，4H),1.42-1.76(m,8H),1.16-1.31(m，1H)，1.09-1.13(m，1H)，1.0(3H,s),0.76(3H,s)。
Temperature of reaction in the present embodiment can be selected from 0 ~ 50 DEG C; Organic solvent is selected from one or more in methylene dichloride, chloroform, tetrahydrofuran (THF), acetonitrile, DMF, ether, methyl tertiary butyl ether, ethyl acetate; Alkali is selected from one or more in DIPEA, triethylamine, salt of wormwood, sodium carbonate, DBU, pyridine; The time of reaction is 3 ~ 18 hours.
Embodiment 2
Mg (1.65g, 69mmol) join in THF (40ml), 1 is added at 20 DEG C, 2-ethylene dibromide (1.25g, 6.7mmol), adds rear system lower than 35 DEG C, slowly add compound 4 (5.3g, 33.5mmol), reaction continues to add compound (IV) after causing.After dropwising, 50 DEG C are reacted 12 hours.
Above-mentioned system clear liquid is transferred in another flask, adds compound (III) (1.3g, 3mmol), Ni (DPPP) Cl
2(111.2mg, 0.2mmol), Zinc Chloride Anhydrous (25mg, 0.18mmol) and anhydrous THF (15ml), heating reflux reaction 12 hours.Add EA and water, regulate pH to 1 with HCl, then regulate pH to 8 with saturated sodium bicarbonate solution.Separatory, organic phase concentrates, and crude product column chromatography purification obtains compound (I) (1.7g, yield 79%).
1H-NMR(CDCl
3,400MHz,δppm):8.63(s,1H),8.47(d,J＝4,1H),7.74(d,J＝8,1H),7.30(m,1H),6.04(m,1H)5.39(t,1H),3.54(m,1H),2.20-2.40(m，3H),2.00-2.15(m，2H),1.80-1.90(m,1H),1.40-1.80(m,7H),1.23-1.26(m，2H)，1.09-1.18(m，1H)，1.07(s，3H)，1.05(s，3H)。
Embodiment 3
Mg (1.65g, 69mmol) join in THF (40ml), 1 is added at 0 DEG C, 2-ethylene dibromide (1.25g, 6.7mmol), adds rear system lower than 35 DEG C, slowly add compound (IV) (6.7g, 33.5mmol), reaction continues to add compound (IV) after causing.After dropwising, back flow reaction 2 hours.Be cooled to 20 DEG C, add Zinc Bromide Anhydrous (8.3g, 37mmol), equality of temperature continues reaction 1h.Add (III) (1.3g, 3mmol), NiCl
2(DPPE) (105.6mg, 0.2mmol), heating reflux reaction 12 hours.Add EA and water, regulate pH to 1 with HCl, then organic phase saturated sodium bicarbonate solution regulates pH to 8, separatory, and organic phase concentrates, and crude product column chromatography purification obtains 1 (867mg, productive rate 75%).
1H-NMR(CDCl
3,400MHz，δppm):8.62-8.63(m,1H),8.46-8.47(m,1H),7.76(d,J＝8,1H),7.31-7.33(m，1H),6.05(d，J＝0.8,1H),5.42(d,J＝4.8,1H),4.60-4.64(m，1H)，2.20-2.36(m，3H)，2.17(s，3H)，2.04(s,3H),1.85-1.88(m,2H),1.460-1.800(m.7H),1.20-1.25(m,2H),1.08(s,3H),1.051(s,3H)。
Embodiment 4
Mg (1.65g, 69mmol) join in THF (40ml), 1 is added at 20 DEG C, 2-ethylene dibromide (1.25g, 6.7mmol), adds rear system lower than 35 DEG C, slowly add compound (IV) (6.7g, 33.5mmol), reaction continues to add compound (IV) after causing.After dropwising, react 12 hours.
Above-mentioned system clear liquid is transferred in new round-bottomed flask, adds (III) (1.3g, 3mmol), Pd (dppf) Cl
2(146mg, 0.2mmol), 80 DEG C are reacted 12 hours.Add EA and water, regulate pH to 1 with HCl, then organic phase saturated sodium bicarbonate solution regulates pH to 8, separatory, and organic phase concentrates, and crude product column chromatography purification obtains 1 (867mg, yield:75%).
The Pd catalyzer of this step can be selected from Pd (dppf) Cl
2, Pd (pph
3)
4, Pd (acac)
2, PdCl
2(DPPE), Pd/C or Pd (CH
3cN) Cl
2.
1H-NMR(CDCl
3,400MHz,δppm):8.62-8.63(m,1H),8.46-8.47(m,1H),7.76(d,J＝8,1H),7.31-7.33(m，1H),6.05(d，J＝0.8,1H),5.42(d,J＝4.8,1H),4.60-4.64(m，1H)，2.20-2.36(m，3H)，2.17(s，3H)，2.04(s,3H),1.85-1.88(m,2H),1.460-1.800(m.7H),1.20-1.25(m,2H),1.08(s,3H),1.051(s,3H)。
Embodiment 5
Compound (IV) 3-bromopyridine (5.3g is added in 500ml three-necked bottle, 33.5mmol) with ether (70ml), pass into nitrogen, be cooled to-78 DEG C, hexane solution (the 16.8ml of slow instillation 2mol/L n-Butyl Lithium, 33.6mmol), stirring reaction 20 minutes, add zinc bromide (7.6g again, diethyl ether solution (100ml) 33.6mmol), slowly room temperature is risen to after-78 DEG C of reaction 0.5h, be concentrated into dry, add N, dinethylformamide (100ml), compound (III) (13.2g is added after stirring and dissolving, 30mmol) with Pd (dppf) Cl
2(1.3g, 1.8mmol), 70 DEG C of reactions are spent the night.Add 1mol/L hydrochloric acid and adjust pH to 1, pour ethyl acetate (50ml) into and water (50ml) stirs 0.5h, separatory, aqueous phase adds saturated sodium bicarbonate solution and adjusts pH to 8, extraction into ethyl acetate (50ml × 2), organic phase is dry, obtains compound (I) (9.0g, productive rate 76%) with PE/EA=1:1 column chromatography.
In the present embodiment after adding compound (III) and Pd catalyzer, temperature of reaction can be selected from 20 ~ 100 DEG C; The solvent reacted can be selected from one or more in DMF, dioxane, methyl tertiary butyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran; Pd catalyzer is selected from Pd (dppf) Cl
2, Pd (pph
3)
4, Pd (acac)
2, PdCl
2(DPPE), Pd/C or Pd (CH
3cN) Cl
2.
Embodiment 6
Added in methyl-sulphoxide (35ml) by compound (IV) (0.43g, 2.74mmol), reaction solution is cooled to-10 DEG C, slowly drips 2molL
-1the THF solution 2.1mL of i-PrMgCl (4.2mmol).Drip and finish, room temperature reaction 2h.The THF solution 2ml of slow dropping methoxyl group pinacol borate (0.48g, 3.1mmol), temperature of reaction controls below 40 DEG C.Drip and finish, room temperature reaction 12h.Add Pd (dppf) Cl
2(197mg, 0.27mmol) after degassed, by compound (the III) (1.0g through degassed process in advance, dimethyl sulfoxide solution (7ml) 2.28mmol) and sodium carbonate (0.73g, the aqueous solution (5ml) 6.84mmol) is added in above-mentioned solution, is warming up to 100 DEG C of reactions 2 hours.Naturally room temperature is down to after reacting completely, leach insolubles, use ethyl acetate washing leaching cake, in filtrate, add water (50ml), extraction into ethyl acetate three times (50ml × 3), merge organic phase and wash with water three times (50ml × 3), anhydrous sodium sulfate drying, filtering and concentrating, silica column purification obtains faint yellow solid, i.e. compound (I) (0.47g, productive rate is 59%).
The grignard reagent added in the present embodiment can be selected from isopropylmagnesium chloride, methylmagnesium-chloride or ethylmagnesium bromide.In this step after adding compound (III) and Pd catalyzer, temperature of reaction can be selected from 55 ~ 100 DEG C, the solvent reacted can be selected from one or more in DMF, dioxane, methyl tertiary butyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran; Pd catalyzer is selected from Pd (dppf) Cl
2, Pd (pph
3)
4, Pd (acac)
2, PdCl
2(DPPE), Pd/C or Pd (CH
3cN) Cl
2; Alkali is selected from one or more in Potassium ethanoate, sodium-acetate, ammonium acetate, Lithium Acetate and cesium acetate.
Embodiment 7
Under nitrogen protection, by Pd (dppf) Cl
2(205mg, 0.28mmol) be added to compound (IV) (0.43g, 2.74mmol), pinacol borate (1.04g is joined, 4.10mmol), Potassium ethanoate (1.07g, 10.94mmol) with in the mixing solutions of DMF (35ml), be warming up to 100 DEG C, react 3 hours; Reacted solution is cooled to room temperature, adds Pd (PPh
3)
4(312mg, 0.27mmol), after degassed, by compound (the III) (1.0g through degassed process in advance, DMF solution (7ml) 2.28mmol) and sodium carbonate (0.73g, the aqueous solution (5ml) 6.84mmol) is added in above-mentioned solution, is warming up to 100 DEG C of reactions 3.5 hours.Naturally room temperature is down to after reacting completely, leach insolubles, use ethyl acetate washing leaching cake, in filtrate, add water (50ml), extraction into ethyl acetate three times (50ml × 3), merge organic phase and wash with water three times (50ml × 3), anhydrous sodium sulfate drying, filtering and concentrating, silica column purification obtains faint yellow solid, i.e. formula compound (I) (0.55g, productive rate is 62%).
In the present embodiment after adding compound (III) and Pd catalyzer, temperature of reaction can be selected from 55 ~ 100 DEG C, the solvent of reaction can be selected from N, one or more in dinethylformamide, N,N-dimethylacetamide, N-Methyl pyrrolidone, 2-methyltetrahydrofuran, tetrahydrofuran (THF), methyl-sulphoxide, acetonitrile, methyl tertiary butyl ether and toluene; Pd catalyzer is selected from Pd (dppf) Cl
2, Pd (pph
3)
4, Pd (acac)
2, PdCl
2(DPPE), Pd/C or Pd (CH
3cN) Cl
2; Alkali is selected from one or more in Potassium ethanoate, sodium-acetate, ammonium acetate, Lithium Acetate and cesium acetate.
Above specific embodiment of the present invention is illustrated; but protection content of the present invention is not only limited to above embodiment; in art of the present invention, the usual knowledge of a GPRS, just can carry out diversified change within the scope of its technology main idea.
Claims (10)
1. a synthetic method for Abiraterone acetate ester, is characterized in that, comprises the following steps:
(1) in organic solvent, there is acetylization reaction, obtain compound (III) in compound (II) and Acetyl Chloride 98Min. under the effect of alkali at 0 ~ 50 DEG C;
(2) in organic solvent, compound (IV) issues biochemical permutoid reaction with Grignard reagent or zincon at 0 ~ 80 DEG C, obtain midbody compound (V), add the compound (III) obtained in step (1) again, and 10 ~ 18 hours are reacted at a reflux temperature under the effect of catalyzer, obtain compound (I), wherein, Nu is MgX, ZnX, X is Br or I, and described organic solvent is selected from one or more in ether, dioxane, methyl tertiary butyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran; Or
In organic solvent, compound (IV) issues biochemical permutoid reaction with n-Butyl Lithium and zincon at-90 ~-70 DEG C, obtain midbody compound (V), add the compound (III) that step (1) obtains again, and react at 20 ~ 100 DEG C under the effect of catalyzer, obtain compound (I), wherein X is Br or I, described organic solvent is selected from one or more in DMF, dioxane, methyl tertiary butyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran; Or
In organic solvent, compound (IV) issues biochemical permutoid reaction at 80 ~ 100 DEG C with connection pinacol borate under the effect of catalyzer and alkali, obtain midbody compound (V), add the compound (III) obtained in step (1) again, and react at 55 ~ 100 DEG C under the effect of alkali and catalyzer, obtain compound (I), wherein Nu is
x is Br or I, and described organic solvent is selected from one or more in DMF, N,N-dimethylacetamide, N-Methyl pyrrolidone, 2-methyltetrahydrofuran, tetrahydrofuran (THF), methyl-sulphoxide, acetonitrile, methyl tertiary butyl ether and toluene; Or
In organic solvent, compound (IV) issues biochemical permutoid reaction with methoxyl group pinacol borate and Grignard reagent at-10 ~ 40 DEG C, obtain midbody compound (V), add the compound (III) obtained in step (1) again, and react at 55 ~ 100 DEG C under the effect of alkali and catalyzer, obtain compound (I), wherein Nu is
x is Br or I, and described organic solvent is selected from one or more in DMF, N,N-dimethylacetamide, N-Methyl pyrrolidone, 2-methyltetrahydrofuran, tetrahydrofuran (THF), methyl-sulphoxide, acetonitrile, methyl tertiary butyl ether and toluene; Or
Reaction scheme is as follows:
2. the synthetic method of Abiraterone acetate ester according to claim 1, it is characterized in that: in step (1), described organic solvent is selected from one or more in methylene dichloride, chloroform, tetrahydrofuran (THF), acetonitrile, DMF, ether, methyl tertiary butyl ether, ethyl acetate.
3. the synthetic method of Abiraterone acetate ester according to claim 1, it is characterized in that: in step (1), described alkali is selected from one or more in DIPEA, triethylamine, salt of wormwood, sodium carbonate, 1,8-diazabicylo 11 carbon-7-alkene and pyridine.
4. the synthetic method of Abiraterone acetate ester according to claim 1, is characterized in that: in step (1), and the time of described acetylization reaction is 3 ~ 18 hours.
5. the synthetic method of Abiraterone acetate ester according to claim 1, is characterized in that: in step (2), and described catalyzer is Pd catalyzer or Ni catalyzer.
6. the synthetic method of Abiraterone acetate ester according to claim 5, is characterized in that: described Pd catalyzer is selected from Pd (dppf) Cl
2, Pd (pph
3)
4, Pd (acac)
2, PdCl
2(DPPE), Pd/C or Pd (CH
3cN) Cl
2.
7. the synthetic method of Abiraterone acetate ester according to claim 5, is characterized in that: described Ni catalyzer is selected from Ni (DPPP) Cl
2or NiCl
2(DPPE).
8. the synthetic method of Abiraterone acetate ester according to claim 1, is characterized in that: in step (2), described alkali is selected from one or more in Potassium ethanoate, sodium-acetate, ammonium acetate, Lithium Acetate and cesium acetate.
9. the synthetic method of Abiraterone acetate ester according to claim 1, is characterized in that: in step (2), and described zincon is zinc chloride or zinc bromide.
10. the synthetic method of Abiraterone acetate ester according to claim 1, is characterized in that: in step (2), and described Grignard reagent is isopropylmagnesium chloride, methylmagnesium-chloride or ethylmagnesium bromide.
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Cited By (2)
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| CN113292624A (en) * | 2021-04-26 | 2021-08-24 | 四川伊诺达博医药科技有限公司 | Synthesis method of abiraterone acetate impurity |
| CN116970020A (en) * | 2023-09-25 | 2023-10-31 | 天津凯莱英制药有限公司 | Abiraterone compound preparation method |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100298575A1 (en) * | 2009-05-19 | 2010-11-25 | Tamkang University | Method for preparing an aromatic boron reagent through barbier-type reaction |
| CN102627681A (en) * | 2012-03-23 | 2012-08-08 | 山东新时代药业有限公司 | Preparation method of abiraterone acetate |
| CN103012451A (en) * | 2011-09-22 | 2013-04-03 | 上海药明康德新药开发有限公司 | Industrialized preparation method of 3-ethoxycarbonyl-5-pyridine pinacol borate |
| CN103102381A (en) * | 2012-09-28 | 2013-05-15 | 北京赛林泰医药技术有限公司 | Synthesis method of novel abiraterone |
| CN103242410A (en) * | 2013-05-09 | 2013-08-14 | 苏州明锐医药科技有限公司 | Preparation method of abiraterone acetate |
| CN103804457A (en) * | 2012-11-07 | 2014-05-21 | 北大方正集团有限公司 | Preparation method of abiraterone acetate |
-
2015
- 2015-03-18 CN CN201510118824.3A patent/CN104710500A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100298575A1 (en) * | 2009-05-19 | 2010-11-25 | Tamkang University | Method for preparing an aromatic boron reagent through barbier-type reaction |
| CN103012451A (en) * | 2011-09-22 | 2013-04-03 | 上海药明康德新药开发有限公司 | Industrialized preparation method of 3-ethoxycarbonyl-5-pyridine pinacol borate |
| CN102627681A (en) * | 2012-03-23 | 2012-08-08 | 山东新时代药业有限公司 | Preparation method of abiraterone acetate |
| CN103102381A (en) * | 2012-09-28 | 2013-05-15 | 北京赛林泰医药技术有限公司 | Synthesis method of novel abiraterone |
| CN103804457A (en) * | 2012-11-07 | 2014-05-21 | 北大方正集团有限公司 | Preparation method of abiraterone acetate |
| CN103242410A (en) * | 2013-05-09 | 2013-08-14 | 苏州明锐医药科技有限公司 | Preparation method of abiraterone acetate |
Non-Patent Citations (2)
| Title |
|---|
| BERTOLDO AVITIA ET AL.: "Single-flask preparation of polyazatriaryl ligands by sequential borylation/Suzuki–Miyaura coupling", 《TETRAHEDRON LETTERS》 * |
| 黄耀曾等: "《金属有机化合物在有机合成中的应用》", 30 June 1990 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113292624A (en) * | 2021-04-26 | 2021-08-24 | 四川伊诺达博医药科技有限公司 | Synthesis method of abiraterone acetate impurity |
| CN113292624B (en) * | 2021-04-26 | 2023-12-08 | 四川伊诺达博医药科技有限公司 | Synthesis method of abiraterone acetate impurity |
| CN116970020A (en) * | 2023-09-25 | 2023-10-31 | 天津凯莱英制药有限公司 | Abiraterone compound preparation method |
| CN116970020B (en) * | 2023-09-25 | 2024-01-26 | 天津凯莱英制药有限公司 | Abiraterone compound preparation method |
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