CN103864878A - Preparation method for abiraterone acetate - Google Patents
Preparation method for abiraterone acetate Download PDFInfo
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- CN103864878A CN103864878A CN201210534773.9A CN201210534773A CN103864878A CN 103864878 A CN103864878 A CN 103864878A CN 201210534773 A CN201210534773 A CN 201210534773A CN 103864878 A CN103864878 A CN 103864878A
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- 0 *c1cccnc1 Chemical compound *c1cccnc1 0.000 description 2
- QLWNREYBZBCNRR-FBUXNDKQSA-N CC(CC=C1C)C(C)[C@H]1OC(C)=O Chemical compound CC(CC=C1C)C(C)[C@H]1OC(C)=O QLWNREYBZBCNRR-FBUXNDKQSA-N 0.000 description 1
- YWTIXRMCNXAOHU-YRNVUSSQSA-N CCNCC/C=C(\C)/CC(C)C Chemical compound CCNCC/C=C(\C)/CC(C)C YWTIXRMCNXAOHU-YRNVUSSQSA-N 0.000 description 1
- MFEIKQPHQINPRI-UHFFFAOYSA-N CCc1cccnc1 Chemical compound CCc1cccnc1 MFEIKQPHQINPRI-UHFFFAOYSA-N 0.000 description 1
- COSQWKKGTBVRCU-CALQQONXSA-N C[C@@]1(CC2)C(C(CC(C3)C(CCC(C4)[C@]5(C)CC[C@@H]4OC(C)=O)C5/C=C\C=C)=C3c3cccnc3)=CCC1C1C2[C@@](C)(CC[C@@H](C2)OC(C)=O)C2=CC1 Chemical compound C[C@@]1(CC2)C(C(CC(C3)C(CCC(C4)[C@]5(C)CC[C@@H]4OC(C)=O)C5/C=C\C=C)=C3c3cccnc3)=CCC1C1C2[C@@](C)(CC[C@@H](C2)OC(C)=O)C2=CC1 COSQWKKGTBVRCU-CALQQONXSA-N 0.000 description 1
- DHZJEYGWSNDRGN-INNQQZFDSA-N C[C@@]1(CC2)C(I)=CCC1C1C2[C@@](C)(CC[C@@H](C2)O)C2=CC1 Chemical compound C[C@@]1(CC2)C(I)=CCC1C1C2[C@@](C)(CC[C@@H](C2)O)C2=CC1 DHZJEYGWSNDRGN-INNQQZFDSA-N 0.000 description 1
- WTKFUDDFHUANII-HAHPKQJUSA-N C[C@](CC1)(C(CC2)C3C1[C@@](C)(CC[C@@H](C1)O)C1=CC3)/C2=N\N Chemical compound C[C@](CC1)(C(CC2)C3C1[C@@](C)(CC[C@@H](C1)O)C1=CC3)/C2=N\N WTKFUDDFHUANII-HAHPKQJUSA-N 0.000 description 1
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Abstract
A disclosed preparation method for abiraterone acetate comprises the following steps: under the catalysis of a palladium, nickel, copper or iron based catalyst, in an ester organic solvent, performing a coupling reaction on 3beta-acetoxyandrosta-5,16-dien-17- trifluoromethanesulfonate (III) and a compound (VIII) to obtain abiraterone acetate (I). The synthetic route is shown in the specification, and M in the synthetic route is zinc, magnesium or indium. The method provided by the invention is simple, easy for operation, low in cost, relatively high in yield and suitable for industrialized production.
Description
Technical field
The present invention relates to organic chemical synthesis field, relate in particular to a kind of preparation method of Abiraterone acetic ester.
Background technology
Abiraterone acetic ester (Abiraterone acetate), chemical name is (3 β)-17-(3-pyridyl)-androstane-5,16-dien-3-ols acetic ester, its structural formula is as follows:
Abiraterone acetic ester (Abiraterone acetate) I
Abiraterone acetic ester is used for the treatment of castration resistivity prostate cancer clinically.It is oral Cytochrome P450 c17(CYP17) enzyme inhibitors, in key enzyme CYP17 in synthetic by inhibition male sex hormone, the activity of C17, C20-lyase and 17 α-hydroxylase effectively reduces prostate specific antigen in patients with prostate cancer body (PSA) level, clinically with prednisone (prednisone) coupling.
Abiraterone acetic ester is at first by Britain's ICR (Institute of Cancer Research, ICR) research and development, and technology group of Britain (The British Technology Group, BTG) provides and subsidizes and responsible clinical study.Its first phase is clinical to be completed by German Boehringer Ingelheim (Boehringer Ingelheim), and Cougar biotech company of the U.S. bears second phase and the clinical work of three phases.Purchased Cougar biotechnology in July, 2009 Johson & Johnson (Johnson & Johnson), the Centocor Ortho Biotech(merging under Johnson & Johnson is now Janssen Biotech Inc) three phases of carrying out are clinical and declare listing.U.S. FDA is in approval Abiraterone acetic ester on April 28th, 2011 (Abiraterone acetate) listing, and commodity are called Zytiga.Europe drug administration in July in the same year (EMA) approval is gone on the market in European Union.English Patent 2265624A discloses the synthetic method of Abiraterone acetic ester the earliest, and the method synthetic route is as follows:
This route committed step has adopted Suzuki coupling, take trans-Dehydrorosterone acetate (II) as starting raw material, generate 3 β-acetoxyl group androstane-5 with trifluoromethanesulfonic acid anhydride reactant, 16-diene-17-triflate (III), there is Suzuki coupling with diethyl (3-pyridyl)-borine again and make Abiraterone acetic ester (I), two-step reaction total recovery 48.7%.In this route the first step reaction, acetoxyl group is easily eliminated generation androstane-3,5,16-triolefin-17-triflate by product, and its structural formula is as follows:
Androstane-3,5,16-triolefin-17-triflate
This by product is difficult to remove by recrystallization, can only carry out purifying by column chromatography, is a serious defect for production technique.
English Patent 2282377A subsequently discloses the another kind of synthetic method of Abiraterone acetic ester, and the method synthetic route is as follows:
This route replaces triflate with ethylene iodide intermediate, and its committed step has still adopted Suzuki coupling.React with hydrazine hydrate take dehydroepiandros-sterone (IV) as starting raw material and generate hydrazone (V); then be oxidized to ethylene iodide intermediate (VI) through iodine; carry out Suzuki coupling with diethyl (3-pyridyl)-borine again and obtain Abiraterone (VII); last acetylize obtains Abiraterone acetic ester (I), total recovery 41.5%.This route weak point is that the Suzuki linked reaction required time of committed step grows (2 days), Heck coupling easily occurs in this process and produce by product, and its structural formula is as follows:
Above-mentioned two synthetic route committed steps have all adopted Suzuki coupling, use diethyl (3-pyridyl)-borine.In Suzuki coupling, nucleophilic reagent is generally boronic acid compounds, boric acid ester compound and organoborane compounds, preparation more complicated, and cost is also higher.For example: diethyl (3-pyridyl)-borine is that isopropyl chloride and magnesium are first made Grignard reagent, carry out halogen-magnesium permutoid reaction by 3-bromopyridine and isopropylmagnesium chloride and form pyridine chlorination magnesium, and then react and obtain with diethyl methoxyl group borine.
Summary of the invention
The object of the invention is to overcome deficiency of the prior art, the preparation method of the Abiraterone acetic ester that a kind of technique is simple, easy to operate, cost is low and yield is higher is provided.
Second object of the present invention has been to provide the preparation method of two kinds of Abiraterone acetic esters.
Technical scheme of the present invention is summarized as follows:
A preparation method for Abiraterone acetic ester, comprises the following steps:
Under the catalysis of palladium, nickel, copper or iron class catalyzer, in ether organic solvent, 3 β-acetoxyl group androstane-5,16-diene-17-triflate (III) obtains Abiraterone acetic ester (I) with compound (VIII) through linked reaction, and synthetic route is:
Wherein: M is zinc, magnesium or indium.
The preparation method of the second Abiraterone acetic ester, comprises the following steps:
Under the catalysis of palladium, nickel, copper or iron class catalyzer; in ether organic solvent, 17-iodo-androstane-5,16-diene-3 β-ol (VI) obtain Abiraterone (VII) with compound (VIII) through linked reaction; acylation reaction obtains Abiraterone acetic ester (I) again, and synthetic route is:
Wherein: M is zinc, magnesium or indium.
Above-mentioned two kinds of methods, palladium class catalyzer is preferred: palladium chloride, palladium, four-(triphenyl phosphorus)-palladium, two-(triphenyl phosphorus)-palladium chloride, two-(triphenyl phosphorus)-Palladium Diacetate or 1,1 '-bis-Diphenyl phosphino ferrocene palladium chlorides;
Nickel class catalyzer is preferred: two-(triphenyl phosphorus)-nickelous chloride, acetylacetonate nickel, 1,1 '-bis-Diphenyl phosphino ferrocene Nickel Chlorides or four (triphenylphosphine) nickel;
Copper class catalyzer is preferred: cuprous iodide, cuprous bromide or trifluoromethanesulfonic acid are cuprous;
Iron class catalyzer is preferred: ferric oxide, iron trichloride or ferric acetyl acetonade.
Above-mentioned two kinds of methods,
Described compound (VIII) is preferred: 3-pyridine zinc bromide lithium chloride reagent or 3-pyridine indium dibromide lithium chloride reagent.
Above-mentioned two kinds of methods in the time that compound (VIII) is 3-pyridine magnesium bromide lithium chloride reagent, add mineral alkali simultaneously.
Mineral alkali is preferred: Anhydrous potassium carbonate, sodium carbonate, sodium hydroxide, potassiumphosphate, potassium hydroxide, hydrated barta, cesium carbonate or calcium hydroxide.
Above-mentioned two kinds of methods, ether organic solvent is preferably dry diisopropyl ether, dry ethyl-butyl ether, dry tetrahydrofuran (THF), dry methyl tertiary butyl ether, dry Isosorbide-5-Nitrae-dioxane or dry 2-methyl furan.
First method, the temperature of linked reaction is preferably; 60～100 ℃, the time of linked reaction is 20 minutes～10 hours.
Second method, the temperature of linked reaction is preferably; 60～100 ℃, the time of linked reaction is 5～30 hours.
Method technique of the present invention is simple, and easy handling, and cost is low, and yield is higher, is applicable to suitability for industrialized production.
Embodiment
3 β used in the present invention-acetoxyl group androstane-5,16-diene-17-triflate (III) and 17-iodo-androstane-5,16-diene-3 β-ol (VI) are respectively take trans-Dehydrorosterone acetate (II) and dehydroepiandros-sterone (IV) as starting raw material, prepared by referenced patent GB 2265624A, GB 2282377A and US 7700766B2.
Below in conjunction with specific embodiment, the present invention is further illustrated.
Embodiment 1
(VIII) be prepared with bibliographical information.In order to enable those skilled in the art to understand better the present invention, the present invention not to be imposed any restrictions.
Synthesizing of 1.3-pyridine zinc bromide lithium chloride reagent (VIII-1)
100mL round-bottomed flask, adds Lithium chloride (anhydrous) (1.65g, 38.9mmol) and activated zinc powder (3.4g, 51.9mmol), and oil pump vacuumizes heat gun under condition and activates 15 minutes.Vacuumize under condition and be cooled to room temperature; change argon shield; add dry tetrahydrofuran (5ml) and several 1; 2-ethylene dibromide; then add dry tetrahydrofuran (40ml) solution of 3-bromopyridine (4.1g, 17.3mmol), back flow reaction 5 hours; be cooled to hold over night after room temperature, obtain compound (VIII-1).
Synthesizing of 2.3-pyridine magnesium bromide lithium chloride reagent (VIII-2)
100mL round-bottomed flask, adds Lithium chloride (anhydrous) (1.6g, 38.9mmol), and oil pump vacuumizes heat gun under condition and activates 7 minutes; vacuumize under condition and be cooled to room temperature, add magnesium chips (1.2g, 48.6mmol); argon shield, heat gun activation 10 minutes, is cooled to room temperature.Add dry ethyl-butyl ether (5ml) and several glycol dibromides, then add dry ethyl-butyl ether (50ml) solution of 3-bromopyridine (5.1g, 32.4mmol), room temperature reaction is hold over night after 5 hours, obtains compound (VIII-2).
Synthesizing of 3.3-pyridine indium dibromide lithium chloride reagent (VIII-3)
100mL round-bottomed flask, adds Lithium chloride (anhydrous) (1.9g, 45.4mmol), and oil pump vacuumizes heat gun under condition and activates 7 minutes; vacuumize under condition and be cooled to room temperature, add indium powder (9.1g, 78.9mmol); argon shield, heat gun activation 10 minutes, is cooled to room temperature.Add dry diisopropyl ether (5ml) and several glycol dibromides, then add dry diisopropyl ether (50ml) solution of 3-bromopyridine (5.9g, 37.6mmol), room temperature reaction is hold over night after 6 hours, obtains compound (VIII-3).
Embodiment 2
(3 β)-17-(3-pyridyl)-androstane-5,16-dien-3-ols acetic ester (I): Abiraterone acetic ester (I) synthetic:
In 100ml round-bottomed flask; add 3 β-acetoxyl group androstane-5; 16-diene-17-triflate (III) (4g; 8.65mmol), two-(triphenyl phosphorus)-palladium chloride (0.06g, 0.087mmol); argon shield; add dry tetrahydrofuran (8ml), then add 3-pyridine zinc bromide lithium chloride reagent (VIII-1) (17.30mmol), 100 ℃ are reacted 20 minutes.Add the cancellation of 20ml distilled water, suction filtration falls insolubles, and with the extraction of (3 × 20ml) ethyl acetate, combining extraction liquid, anhydrous sodium sulfate drying, filters, and filtrate decompression evaporate to dryness obtains yellow oily crude product.Take sherwood oil: ethyl acetate=4:1 as moving phase, purification by silica gel column chromatography, normal hexane recrystallization, obtains Abiraterone acetic ester (I) 2.9g(yield 85%), fusing point: 143 ~ 145 ° of C.
1HNMR(400MHz,CDCl
3)δ:1.05(s,3H,19-CH
3),1.08(s,3H,18-CH
3),2.04(s,3H,CH
3CO
2),4.58~4.66(m,1H,3α-H),5.42(d,J＝4.7Hz,1H,6-H),5.99(s,1H,16-H)，7.22(dd,J
1=4.8Hz,J
2=7.8Hz,1H,Py?5-H),7.64(d,J＝7.9Hz,1H,Py?4-H),8.46(d,J＝4.6Hz,1H,Py?6-H),8.63(s,1H,Py2-H)。Anal.Calcd:C,79.75;H,8.50;N,3.58.Found:C,79.80;H,8.52;N,3.63%.
Experiment shows, adopt palladium chloride, palladium, four-(triphenyl phosphorus)-palladium, two-(triphenyl phosphorus)-Palladium Diacetate or 1,1 '-bis-Diphenyl phosphino ferrocene palladium chlorides substitute two-(triphenyl phosphorus)-palladium chloride in the present embodiment, also can catalyzed reaction, generate Abiraterone acetic ester (I).
Embodiment 3
(3 β)-17-(3-pyridyl)-androstane-5,16-dien-3-ols acetic ester (I): Abiraterone acetic ester (I) synthetic:
In 100ml round-bottomed flask; add 3 β-acetoxyl group androstane-5,16-diene-17-triflate (III) (5g, 10.8mmol); two-(triphenyl phosphorus)-nickelous chloride (0.01g; 0.15mmol), Anhydrous potassium carbonate (1.5g, 10.8mmol); argon shield; add dry ethyl-butyl ether (8ml), then add 3-pyridine magnesium bromide lithium chloride reagent (VIII-2) (32.4mmol), 100 ℃ are reacted 1 hour.Add the cancellation of 30ml distilled water, suction filtration falls insolubles, and with the extraction of (3 × 25mL) ethyl acetate, combining extraction liquid, anhydrous sodium sulfate drying, filters, and filtrate decompression evaporate to dryness obtains yellow oily crude product.Take sherwood oil: ethyl acetate=4:1 as moving phase, purification by silica gel column chromatography, normal hexane recrystallization, obtains Abiraterone acetic ester (I) 3.2g(yield 75%).
Experiment shows, adopt acetylacetonate nickel, 1,1 '-bis-Diphenyl phosphino ferrocene Nickel Chlorides or four (triphenylphosphine) nickel substitute two-(triphenyl phosphorus)-nickelous chloride in the present embodiment, also can catalyzed reaction, generate Abiraterone acetic ester (I).
Embodiment 4
(3 β)-17-(3-pyridyl)-androstane-5,16-dien-3-ols acetic ester (I) synthetic
In 100ml round-bottomed flask, add 3 β-acetoxyl group androstane-5,16-diene-17-triflate (III) (4g, 8.6mmol), cuprous iodide (0.02g, 0.09mmol), argon shield, add dry methyl tertiary butyl ether (8ml), then add 3-pyridine indium dibromide lithium chloride reagent (VIII-3) (25.8mmol), 70 ℃ are reacted 2 hours; Add the cancellation of 25ml distilled water, suction filtration falls insolubles, and with the extraction of (3 × 25mL) ethyl acetate, combining extraction liquid, anhydrous sodium sulfate drying, filters, and filtrate decompression evaporate to dryness obtains yellow oily crude product.Take sherwood oil: ethyl acetate=4:1 as moving phase, purification by silica gel column chromatography, normal hexane recrystallization, obtains Abiraterone acetic ester (I) 2.5g(yield 75%).
Experiment shows, adopts the cuprous iodide in cuprous bromide or the cuprous alternative the present embodiment of trifluoromethanesulfonic acid also can catalyzed reaction, generates Abiraterone acetic ester (I).
Embodiment 5
(3 β)-17-(3-pyridyl)-androstane-5,16-dien-3-ols acetic ester (I) synthetic
In 250ml round-bottomed flask, add 3 β-acetoxyl group androstane-5,16-diene-17-triflate (III) (4.62g; 10mmol); ferric acetyl acetonade (0.07g, 0.2mmol), potassium hydroxide (5.6g; 100mmol); argon shield, adds dry Isosorbide-5-Nitrae-dioxane (20ml); then add 3-pyridine magnesium bromide lithium chloride reagent (VIII-2) (20mmol), 60 ℃ are reacted 10 hours.Add the cancellation of 100ml distilled water, suction filtration falls insolubles, and with the extraction of (3 × 100mL) ethyl acetate, combining extraction liquid, anhydrous sodium sulfate drying, filters, and filtrate decompression evaporate to dryness obtains yellow oily crude product.Take sherwood oil: ethyl acetate=4:1 as moving phase, purification by silica gel column chromatography, normal hexane recrystallization, obtains Abiraterone acetic ester (I) 2.2g(yield 55%).
Experiment shows, adopts the ferric acetyl acetonade that ferric oxide or iron trichloride substitute the present embodiment also can catalyzed reaction, generates Abiraterone acetic ester (I).
Experiment shows, adopts sodium carbonate, sodium hydroxide, potassiumphosphate, hydrated barta, cesium carbonate or calcium hydroxide to substitute the potassium hydroxide of the present embodiment, also can generate Abiraterone acetic ester (I).
Embodiment 6
(1) 17-(3-pyridyl) androstane-5,16-diene-3 β-ol (VII) synthetic
In 100ml round-bottomed flask, add 17-iodo-androstane-5,16-diene-3 β-ol (VI) (4g, 10mmol), two-(triphenyl phosphorus)-nickelous chloride (0.07g, 0.1mmol), argon shield, add dry 2-methyl furan (10ml), add 3-pyridine zinc bromide lithium chloride reagent (VIII-1) (40mmol), 60 ℃ are reacted 30 hours; Add the cancellation of 30ml distilled water, suction filtration falls insolubles, and with ethyl acetate (25ml × 3) extraction, combining extraction liquid, anhydrous sodium sulfate drying, filters, and filtrate decompression evaporate to dryness obtains brown solid crude product.With ethyl acetate: methyl alcohol=4:3 recrystallization, obtains 17-(3-pyridyl) androstane-5,16-diene-3 β-ol (VII) 2.8g(yield 80%), fusing point: 212 ~ 215 ° of C.
1H?NMR(400MHz,CDCl
3)δ:1.05(s,3H,19-CH
3),1.07(s,3H,18-CH
3),3.51~3.58(m,1H,3α-H),5.39(d,J＝4.8Hz,1H,6-H),6.00(s,1H,16-H)，7.21~7.25(m,1H,Py?5-H),7.66(d,J＝8.0Hz,1H,Py?4-H),8.45(d,J＝4.4Hz,1H,Py?6-H),8.62(s,1H,Py?2-H)。
(2) (3 β)-17-(3-pyridyl)-androstane-5,16-dien-3-ols acetic ester (I) synthetic
In 100ml round-bottomed flask, add 17-(3-pyridyl) androstane-5,16-diene-3 β-ol (VII) (2.4g, 6.87mmol), dry ether (60ml), triethylamine (1.5ml, 11mmol), DMAP (8.4mg, 0.07mmol) and Acetyl Chloride 98Min. (0.7ml, 9.62mmol), stirring reaction 4.5 hours under room temperature, suction filtration, filtrate decompression is steamed and is desolventized, with ethanol: water=4:1 recrystallization obtains light yellow crystal product Abiraterone acetic ester (I) 2.2g(yield 82%).
Experiment shows, adopt acetylacetonate nickel, 1,1 '-bis-Diphenyl phosphino ferrocene Nickel Chlorides or four (triphenylphosphine) nickel substitute two-(triphenyl phosphorus)-nickelous chloride in the present embodiment, can catalyzed reaction, generate Abiraterone acetic ester (I).
Embodiment 7
(1) 17-(3-pyridyl) androstane-5,16-diene-3 β-ol (VII) synthetic
In 100ml round-bottomed flask; add 17-iodo-androstane-5; 16-diene-3 β-ol (VI) (5g; 12.6mmol), cuprous iodide (0.5g, 0.2mmol); argon shield; add dry diisopropyl ether (8ml), add 3-pyridine indium dibromide lithium chloride reagent (VIII-3), 70 ℃ are reacted 20 hours.Add the cancellation of 30ml distilled water, suction filtration falls insolubles, and with ethyl acetate (25ml × 3) extraction, combining extraction liquid, anhydrous sodium sulfate drying, filters, and filtrate decompression evaporate to dryness obtains brown solid crude product.With ethyl acetate: methyl alcohol=4:3 recrystallization, obtains 17-(3-pyridyl) androstane-5,16-diene-3 β-ol (VII) 2.7g(yield 62%).
(2) (3 β)-17-(3-pyridyl)-androstane-5,16-dien-3-ols acetic ester (I) synthetic, step, with embodiment 6 steps (2), obtains product Abiraterone acetic ester (I) 2.6g(yield 85%).
Experiment shows, adopts the cuprous iodide in cuprous bromide or the cuprous alternative the present embodiment of trifluoromethanesulfonic acid, can catalyzed reaction, generate Abiraterone acetic ester (I).
Embodiment 8
(1) 17-(3-pyridyl) androstane-5,16-diene-3 β-ol (VII) synthetic
In 100ml round-bottomed flask; add 17-iodo-androstane-5,16-diene-3 β-ol (VI) (2g, 5mmol); two-(triphenyl phosphorus)-Palladium Diacetate (0.04g; 0.05mmol), potassiumphosphate (1.1g, 5mmol); argon shield; add dry ethyl-butyl ether (8ml), add 3-pyridine magnesium bromide lithium chloride reagent (VIII-2) (15mmol), 100 ℃ are reacted 5 hours.Add the cancellation of 30ml distilled water, suction filtration falls insolubles, and with ethyl acetate (25ml × 3) extraction, combining extraction liquid, anhydrous sodium sulfate drying, filters, and filtrate decompression evaporate to dryness obtains brown solid crude product.With ethyl acetate: methyl alcohol=4:3 recrystallization, obtains 17-(3-pyridyl) androstane-5,16-diene-3 β-ol (VII) 1.24g(yield 71%).
(2) (3 β)-17-(3-pyridyl)-androstane-5,16-dien-3-ols acetic ester (I) synthetic, step, with embodiment 6 steps (2), obtains product Abiraterone acetic ester (I) 1.03g(yield 74%).
Experiment shows, adopt palladium chloride, palladium, four-(triphenyl phosphorus)-palladium, two-(triphenyl phosphorus)-palladium chloride or 1,1 '-bis-Diphenyl phosphino ferrocene palladium chlorides substitute two-(triphenyl phosphorus)-Palladium Diacetate in the present embodiment, can catalyzed reaction, generate Abiraterone acetic ester (I).
Embodiment 9
(1) 17-(3-pyridyl) androstane-5,16-diene-3 β-ol (VII) synthetic
In 100ml round-bottomed flask; add 17-iodo-androstane-5; 16-diene-3 β-ol (VI) (2g, 5mmol), ferric acetyl acetonade (0.02g; 0.05mmol); hydrated barta (0.86g, 5mmol), argon shield; add dry tetrahydrofuran (THF) (5ml); add 3-pyridine magnesium bromide lithium chloride reagent (VIII-2), 80 ℃ are reacted 10 hours, add the cancellation of 30ml distilled water; suction filtration falls insolubles; with ethyl acetate (25ml × 3) extraction, combining extraction liquid, anhydrous sodium sulfate drying; filter, filtrate decompression evaporate to dryness obtains brown solid crude product.With ethyl acetate: methyl alcohol=4:3 recrystallization, obtains 17-(3-pyridyl) androstane-5,16-diene-3 β-ol (VII) 1.1g(yield 65%).
(2) (3 β)-17-(3-pyridyl)-androstane-5,16-dien-3-ols acetic ester (I) synthetic, step, with embodiment 6 steps (2), obtains product Abiraterone acetic ester (I) 0.97g(yield 79%).
Experiment shows, adopts ferric oxide, iron trichloride to substitute the ferric acetyl acetonade in the present embodiment, can catalyzed reaction, generate Abiraterone acetic ester (I).
Experiment shows, adopts Anhydrous potassium carbonate, sodium carbonate, sodium hydroxide, potassiumphosphate, potassium hydroxide, cesium carbonate or calcium hydroxide to substitute the hydrated barta in the present embodiment, also can generate Abiraterone acetic ester (I).
Claims (9)
1. a preparation method for Abiraterone acetic ester, is characterized in that comprising the following steps:
Under the catalysis of palladium, nickel, copper or iron class catalyzer, in ether organic solvent, 3 β-acetoxyl group androstane-5,16-diene-17-triflate (III) obtains Abiraterone acetic ester (I) with compound (VIII) through linked reaction, and synthetic route is:
Wherein: M is zinc, magnesium or indium.
2. a preparation method for Abiraterone acetic ester, is characterized in that comprising the following steps:
Under the catalysis of palladium, nickel, copper or iron class catalyzer; in ether organic solvent, 17-iodo-androstane-5,16-diene-3 β-ol (VI) obtain Abiraterone (VII) with compound (VIII) through linked reaction; acylation reaction obtains Abiraterone acetic ester (I) again, and synthetic route is:
Wherein: M is zinc, magnesium or indium.
3. method according to claim 1 and 2, it is characterized in that described palladium class catalyzer is palladium chloride, palladium, four-(triphenyl phosphorus)-palladium, two-(triphenyl phosphorus)-palladium chloride, two-(triphenyl phosphorus)-Palladium Diacetate or 1,1 '-bis-Diphenyl phosphino ferrocene palladium chlorides; Described nickel class catalyzer is two-(triphenyl phosphorus)-nickelous chloride, acetylacetonate nickel, 1,1 '-bis-Diphenyl phosphino ferrocene Nickel Chlorides or four (triphenylphosphine) nickel; Described copper class catalyzer is that cuprous iodide, cuprous bromide or trifluoromethanesulfonic acid are cuprous; Described iron class catalyzer is ferric oxide, iron trichloride or ferric acetyl acetonade.
4. method according to claim 1 and 2, is characterized in that described compound (VIII) is 3-pyridine zinc bromide lithium chloride reagent or 3-pyridine indium dibromide lithium chloride reagent.
5. method according to claim 1 and 2 while it is characterized in that compound (VIII) for 3-pyridine magnesium bromide lithium chloride reagent, adds mineral alkali simultaneously.
6. method according to claim 5, is characterized in that described mineral alkali is Anhydrous potassium carbonate, sodium carbonate, sodium hydroxide, potassiumphosphate, potassium hydroxide, hydrated barta, cesium carbonate or calcium hydroxide.
7. method according to claim 1 and 2, it is characterized in that described ether organic solvent is dry diisopropyl ether, dry ethyl-butyl ether, dry tetrahydrofuran (THF), dry methyl tertiary butyl ether, dry Isosorbide-5-Nitrae-dioxane or dry 2-methyl furan.
8. method according to claim 1, the temperature that it is characterized in that linked reaction is 60～100 ℃, the time of linked reaction is 20 minutes～10 hours.
9. method according to claim 2, the temperature that it is characterized in that linked reaction is 60～100 ℃, the time of linked reaction is 5～30 hours.
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| CN (1) | CN103864878A (en) |
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| WO2016004910A1 (en) * | 2014-07-09 | 2016-01-14 | Zentiva, K.S. | Method of preparing abiraterone acetate of high purity applicable on industrial scale |
| CN107629103A (en) * | 2017-10-24 | 2018-01-26 | 泰州职业技术学院 | The synthetic method of the diene of 3 β acetoxyl groups, 17 aryl androstane 5,16 |
| CN112812147A (en) * | 2019-11-15 | 2021-05-18 | 江苏佳尔科药业集团股份有限公司 | Synthetic method of abiraterone acetate and intermediate thereof |
| CN112940065A (en) * | 2021-02-03 | 2021-06-11 | 山东大学 | Application of triflate in preparation of abiraterone acetate and synthetic method |
| WO2023213151A1 (en) * | 2022-05-06 | 2023-11-09 | 奥锐特药业股份有限公司 | Method for preparing abiraterone acetate and intermediate thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016004910A1 (en) * | 2014-07-09 | 2016-01-14 | Zentiva, K.S. | Method of preparing abiraterone acetate of high purity applicable on industrial scale |
| CN107629103A (en) * | 2017-10-24 | 2018-01-26 | 泰州职业技术学院 | The synthetic method of the diene of 3 β acetoxyl groups, 17 aryl androstane 5,16 |
| CN112812147A (en) * | 2019-11-15 | 2021-05-18 | 江苏佳尔科药业集团股份有限公司 | Synthetic method of abiraterone acetate and intermediate thereof |
| CN112940065A (en) * | 2021-02-03 | 2021-06-11 | 山东大学 | Application of triflate in preparation of abiraterone acetate and synthetic method |
| WO2023213151A1 (en) * | 2022-05-06 | 2023-11-09 | 奥锐特药业股份有限公司 | Method for preparing abiraterone acetate and intermediate thereof |
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