CN104558091A - Synthesis method of abiraterone acetate - Google Patents
Synthesis method of abiraterone acetate Download PDFInfo
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- CN104558091A CN104558091A CN201310484373.6A CN201310484373A CN104558091A CN 104558091 A CN104558091 A CN 104558091A CN 201310484373 A CN201310484373 A CN 201310484373A CN 104558091 A CN104558091 A CN 104558091A
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- SEDLWLHXHSHBEJ-CJLVFECKSA-N CC(C/C(/C1)=C/C2=CCC=CC=C2)(CC2)C1C1C2C(C)(CCC(OC(C)=O)=C2)C2=CC1 Chemical compound CC(C/C(/C1)=C/C2=CCC=CC=C2)(CC2)C1C1C2C(C)(CCC(OC(C)=O)=C2)C2=CC1 SEDLWLHXHSHBEJ-CJLVFECKSA-N 0.000 description 1
- LNOXMXSDHLEYFC-UHFFFAOYSA-N CC(CC1)(C(CC2)C(CC3)C1C(C)(CC1)C3=CC1=O)C2(c1ccccc1)O Chemical compound CC(CC1)(C(CC2)C(CC3)C1C(C)(CC1)C3=CC1=O)C2(c1ccccc1)O LNOXMXSDHLEYFC-UHFFFAOYSA-N 0.000 description 1
- MUMGGOZAMZWBJJ-UHFFFAOYSA-N CC(CC1)(C(CC2)C(CC3)C1C(C)(CC1)C3=CC1=O)C2O Chemical compound CC(CC1)(C(CC2)C(CC3)C1C(C)(CC1)C3=CC1=O)C2O MUMGGOZAMZWBJJ-UHFFFAOYSA-N 0.000 description 1
- YFIHGJUWDCZYSU-UHFFFAOYSA-N CC1C(CC2)(C(C)(CC3)C2C(CC2)C3C(C)(CC3)C2=CC3=O)[O]=CCNC1 Chemical compound CC1C(CC2)(C(C)(CC3)C2C(CC2)C3C(C)(CC3)C2=CC3=O)[O]=CCNC1 YFIHGJUWDCZYSU-UHFFFAOYSA-N 0.000 description 1
- CSDWBAGVORULEO-HJWRWDBZSA-N CCC(/C=C\C=C=C)C1=CCC2C1(C)CCC1C(C)(CCC(C3)O)C3=CCC21 Chemical compound CCC(/C=C\C=C=C)C1=CCC2C1(C)CCC1C(C)(CCC(C3)O)C3=CCC21 CSDWBAGVORULEO-HJWRWDBZSA-N 0.000 description 1
- PAOWPNQOTVTCAF-UHFFFAOYSA-N CCOC1=CC2=CCC(C(CC3)C(C)(CC4)C3=O)C4C2(C)CC1 Chemical compound CCOC1=CC2=CCC(C(CC3)C(C)(CC4)C3=O)C4C2(C)CC1 PAOWPNQOTVTCAF-UHFFFAOYSA-N 0.000 description 1
Classifications
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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 relates to a synthesis method of abiraterone acetate. According to the synthesis method of the abiraterone acetate, a compound 1 is taken as a revelator, and the abiraterone acetate is prepared through steps such as esterification, Grignard reagent reaction, dehydration, acylation, reduction, acetylation and the like.
Description
Technical field
The present invention relates to chemosynthesis technical field, be specifically related to a kind of synthetic method of steroid drugs Abiraterone acetate.
Background technology
Abiraterone acetate (abiraterone acetate, 1), chemistry by name 3
2-acetoxyl group-17-(3-pyridyl)-androstane-5,16-diene, it is the one orally active CYP17 enzyme irreversible inhibitor developed by Centocor Ortho company of the U.S., in April, 2011 is through U.S. FDA approval listing, clinically treat castration-resistant prostate cancer (castration resistant prostatecancer, CRPC) with prednisone (prednisone) coupling.This product is key enzyme 17 ±-hydroxylase-C17 in testosterone synthesis, the selectivity oral inhibitor of 20-lyase (human-cytochrome P45017 enzyme), the level of tumor markers prostate specific antigen (PSA) can be reduced, can be used for those and adopted pharmacological agent or underwent operative to excise and the patients with prostate cancer of tumour continuation growth.
The synthetic route of Abiraterone acetate mainly contains two:
Route 1 take dehydroepiandrosterone as raw material, and by acidylate, be obtained by reacting steroid enol trifluoromethyl sulfonic acid with trifluoromethanesulfanhydride anhydride, be then obtained by reacting with diethyl (3-pyridyl) borine, total recovery is 48.7%.
There is following shortcoming: diethyl (3-pyridyl) borine and trifluoromethanesulfanhydride anhydride price all very expensive, production cost is higher; When preparing compound 3 in this synthetic route, this step reaction of bibliographical information easily occurs to eliminate to generate androstane-3,5,16-triolefin-17-triflate by product, affect product purity and yield and be difficult to purifying, product must carry out pillar layer separation, complicated operation, is not suitable for industry's enlarging production; Trifluoromethanesulfanhydride anhydride is poisonous.
Route 2 take dehydroepiandrosterone as raw material, first reacts to obtain dehydroepiandrosterone-17-hydrazone with hydrazine hydrate, and then iodo forms 17-iodo-androstane-5,16-diene-3
2-ol, and then react obtained Abiraterone with diethyl (3-pyridyl) borine, last esterification obtains, and total recovery is 41.5%.
Route 2 has following shortcoming: diethyl (3-pyridyl) borine used in this reaction and triphenylphosphine palladium chloride expensive, industrially in a large number produce time cost higher; Need pillar layer separation in reaction process, be not suitable for scale operation; When preparing compound 6 in synthetic route, document hydrazonium sulfate is as catalyzer, and reaction needs 3d to complete, and the reaction times is longer, and higher to the requirement of reaction vessel, energy consumption is higher, affects the industrialization effect of this technique.
Domestic patent application (CN101044155, CN102816200, CN102816201 and CN102731605) is under the prerequisite not changing reaction raw materials and operational path, be optimized and improve in the method etc. of the use of the proportioning fed intake, catalyzer, the selection of solvent, the control of condition and purifying, make this technique more practical and perfect.
In addition; patent application CN102627681 and CN102838649 utilizes 17-iodo dehydroepiandrosterone acetic ester for initiator and 3-pyridine zinc halide or 3-halogen pyridine are under catalyst action and the condensation of 17-iodo dehydroepiandrosterone, then obtains the method for Abiraterone acetate through acetylize.
It is raw material with dehydroepiandros-sterone that patent application CN102898495 and CN103059091 reports a kind of; first 3 hydroxyls are protected; then Grignard reagent and 3 dehydroepiandrosterone generation grignard reactions protected are adopted, then through dehydration and 3 deprotections, then the method for target product is generated through acylation reaction.
Aforementioned disclosed document, be mainly raw material with dehydroepiandros-sterone, utilize the derivative of the triflate of dehydroepiandros-sterone 17-position (OTf) or iodo derivative and 3-bromopyridine (3 the ethyl borines replaced, zincon and grignard things) to be obtained by reacting Abiraterone acetate.But the preparation method that current dehydroepiandros-sterone is conventional is mainly that raw material is prepared with diosgenin.The first, this production process needs a large amount of sulfuric acid, easily produces a large amount of pollution to environment; Second, along with improving constantly of Environmental Protection in China consciousness, in recent years, country increases the environmental protection supervision to production of saponin enterprise, eliminate the medium and small production of saponin enterprise of part, saponin supply is becoming tight, and has caused saponin price continuous rise since 2007, to go up to 2012 more than 90 ten thousand yuan per ton by 130,000 yuan per ton at the beginning of 2007.Along with the raising of saponin price, the price of dehydroepiandros-sterone also increases very fast; 3rd, the plantation of diosgenin needs a large amount of land occupation for a long time.Therefore, develop new natural resource, find a kind of raw material of alternative dehydroepiandros-sterone, Abiraterone acetate can be prepared with the method for lower cost and environmental protection more significant.
In addition, the preparation method of disclosed Abiraterone acetate involved by bibliographical information at present, although be optimized and improve on reaction sequencing, coupling reaction catalyst, the selection of 3-pyridyl side chain and activation method, these synthetic routes still Shortcomings in production cost, reaction yield and three waste discharge etc.
Summary of the invention
Technical problem to be solved by this invention is to provide the preparation method of the Abiraterone acetate that a kind of productive rate is high, reaction conditions is gentle.
For solving the problems of the technologies described above, the technical solution used in the present invention is as follows:
A synthetic method for Abiraterone acetate, is characterized in that described synthetic method comprises the steps:
Step one: compound 1 and triethyl orthoformate generate compound 2 under the effect of catalyzer, described catalyzer be selected from mineral acid, organic acid and pyridinium salt thereof one or more;
Step 2: compound 2 and grignard reagent grignard reaction occur under the effect of catalyzer and generate compound 3; Described grignard reagent is 3-pyridyl magnesium bromide;
Step 3: compound 3 and dewatering agent reacting generating compound 4 in basic solvent; Described basic solvent be selected from pyridine or triethylamine one or both;
Step 4: compound 4 and acetylation reagent reacting generating compound 5, described acetylation reagent be selected from aceticanhydride, Acetyl Chloride 98Min. or methylvinyl acetate one or more;
Step 5: compound 5 and reductive agent are obtained by reacting compound 6;
Step 6: compound 6 and acetylation reagent react and generate Abiraterone acetate, described acetylation reagent be selected from aceticanhydride, Acetyl Chloride 98Min. one or more.
The synthetic method of described a kind of Abiraterone acetate, is characterized in that:
Step one: compound 1 and triethyl orthoformate generate compound 2 under the effect of catalyzer, described catalyzer be selected from mineral acid or organic acid and pyridinium salt thereof one or more;
Step 2: compound 2 and grignard reagent grignard reaction occur under the effect of catalyzer and generate compound 3, and described grignard reagent is 3-pyridyl magnesium bromide, and described catalyzer is selected from cupprous inorganic salt;
Step 3: compound 3 and dewatering agent reacting generating compound 4 in basic solvent; Described basic solvent be selected from pyridine or triethylamine one or both; Described dewatering agent is selected from phosphorus oxychloride, methylsulfonyl chloride or to one or more in tosylate chloride;
Step 4: compound 4 and acetylation reagent reacting generating compound 5, described acetylation reagent be selected from aceticanhydride, Acetyl Chloride 98Min. or methylvinyl acetate one or more;
Step 5: compound 5 and reductive agent are obtained by reacting compound 6, and described reductive agent is selected from sodium borohydride, POTASSIUM BOROHYDRIDE or lithium aluminum hydride;
Step 6: compound 6 reacts with acetylation reagent and generates Abiraterone acetate under the effect of acid binding agent; described acetylation reagent be selected from aceticanhydride, Acetyl Chloride 98Min. one or more, described acid binding agent be selected from pyridine, triethylamine or DMAP one or more.
The synthetic method of described a kind of Abiraterone acetate, is characterized in that:
Step one: temperature of reaction is 0 ~ 60 DEG C; Solvent for use be selected from dioxane, tetrahydrofuran (THF) or dehydrated alcohol one or more;
Step 2: compound 2 and grignard reagent are under the effect of catalyzer, and first stir 30 minutes ~ 2 hours at-20 DEG C ~ 0 DEG C, then rise 15 ~ 30 DEG C to reacting end, described catalyzer is selected from cuprous chloride or cuprous iodide;
Step 3: temperature of reaction is 25 ~ 120 DEG C;
Step 4: temperature of reaction is 20 ~ 100 DEG C;
Step 5: temperature of reaction is-20 ~ 100 DEG C; Solvent for use be selected from tetrahydrofuran (THF), methyl alcohol, ethanol, dioxane, DMF one or more or be selected from the aqueous solution of above-mentioned solvent;
Step 6: temperature of reaction is 20 ~ 60 DEG C.
The synthetic method of described a kind of Abiraterone acetate, is characterized in that:
Step one: temperature of reaction is 20 ~ 40 DEG C;
Step 2: compound 2 and grignard reagent are under the effect of catalyzer, and first stir 30 minutes ~ 2 hours at-10 DEG C ~ 0 DEG C, then rise 20 ~ 25 DEG C to reacting end, described catalyzer is selected from cuprous chloride or cuprous iodide;
Step 3: temperature of reaction is 70 ~ 90 DEG C;
Step 4: temperature of reaction is 20 ~ 100 DEG C;
Step 5: temperature of reaction is 0 ~ 25 DEG C;
Step 6: temperature of reaction is 20 ~ 30 DEG C.
Formula 1 compound
Advantage of the present invention:
1. the present invention is raw material with 4AD, and cost is low.4-alkene-androstane-3,17-diketone (being called for short 4AD), utilizing the tankage after soybean extract oil---plant sterol obtains through biological process fermentation, compared with now widely used dehydroepiandros-sterone, 4AD and ADD raw material is based on industrial waste, and more horn of plenty of originating is firm, and price is more cheap, polluting very little in production process, is a kind of advantageous raw material.Meanwhile, 4AD and the ADD purity prepared with biological fermentation process and yield are all very high, are conducive to the quality improving steroid drugs finished product.The price of current 4AD is about 700 yuan/kg, and the price of dehydroepiandros-sterone is probably 2400 ~ 2600 yuan/kg.
2. yield is high, and raw material is easy to get, and without expensive reaction reagent, cost is low.
3. high, the strong operability of feasibility, just can prepare highly purified Abiraterone acetate by simple recrystallization, be easy to industrialization.
Embodiment:
Below will the invention will be further described by embodiment, these descriptions are not be further limited content of the present invention.Person skilled should be understood that the equivalent replacement done technical characteristic of the present invention, or improves accordingly, still belongs within protection scope of the present invention.
TLC: thin-layer chromatography
The synthesis of embodiment one compound 2
Embodiment 1-1
In there-necked flask, pass into nitrogen successively, drop into 20g compound 1,40ml tetrahydrofuran (THF), 20ml triethyl orthoformate, 0.2g tosic acid, in 20 DEG C of reactions 3 hours under stirring, TLC detection reaction basic completely after, to add in 0.2ml triethylamine and after be diluted in 1000ml frozen water.After filtering discharging, under 30 DEG C of vacuum, drain to obtain 22g compound 2(content 99%).
Embodiment 1-2
In there-necked flask, pass into nitrogen successively, drop into 100g compound 1,100ml dehydrated alcohol, 100ml triethyl orthoformate pass into 1g hydrogen chloride gas, in 40 DEG C of reactions 3 hours under stirring, TLC detection reaction basic completely after, to add in 2ml triethylamine and after be diluted in 5000ml frozen water.After filtering discharging, under 30 DEG C of vacuum, drain to obtain 108g compound 2(content 98%).
Embodiment 1-3
In there-necked flask, pass into nitrogen successively, drop into 20g compound 1,40ml dioxane, 20ml triethyl orthoformate, 0.2g pyridine hydrochloride, in 0 DEG C of reaction 24 hours under stirring, TLC detection reaction basic completely after, to add in 0.2ml triethylamine and after be diluted in 1000ml frozen water.After filtering discharging, under 30 DEG C of vacuum, drain to obtain 21.3g compound 2(content 97%).
Embodiment 1-4
In there-necked flask, pass into nitrogen successively, drop into 20g compound 1,20ml dehydrated alcohol, 20ml tetrahydrofuran (THF), 20ml triethyl orthoformate, 0.2ml Glacial acetic acid, 0.2ml formic acid, in 60 DEG C of reactions 2 hours under stirring, TLC detection reaction basic completely after, to add in 0.4ml triethylamine and after be diluted in 1000ml frozen water.After filtering discharging, under 30 DEG C of vacuum, drain to obtain 20.9g compound 2(content 95%).
The synthesis of embodiment two compound 3
Embodiment 2-1
The configuration of Grignard reagent: add magnesium chips 27g in 1000ml anhydrous tetrahydro furan, 3-bromopyridine 92ml, back flow reaction, after 4 hours, is cooled to-10 DEG C.
0.1g cuprous chloride added in the above-mentioned Grignard reagent prepared, lead to nitrogen, then the 40ml tetrahydrofuran solution of 20g compound 2 is slowly added drop-wise in above-mentioned Grignard reagent, after dropwising, insulation reaction 1h at-10 DEG C.Then 20 DEG C are slowly risen to, stirring reaction 10 hours at 20 DEG C.Be diluted in after TLC has reacted in water, concentrated hydrochloric acid regulates PH to be about 3.The each 200ml extraction into ethyl acetate twice of aqueous phase, combined ethyl acetate layer, each 150ml water washing ethyl acetate layer twice, after concentrated dry ethyl acetate, recrystallizing methanol obtains 10g compound 3(content 95%).Again obtain 8.8g by recrystallizing methanol, the compound 3 of content 99.5%.
Compound 3:m/e:365.21 (100.0%); Ultimate analysis: C, 78.84; H, 8.57; N, 3.82; C
13nMR:
Embodiment 2-2
The configuration of Grignard reagent: add magnesium chips 27g in 1000ml anhydrous tetrahydro furan, 3-bromopyridine 92ml, back flow reaction, after 4 hours, is cooled to-20 DEG C.
0.1g cuprous iodide added in the above-mentioned Grignard reagent prepared, lead to nitrogen, then the 40ml toluene solution of 20g compound 2 is slowly added drop-wise in above-mentioned Grignard reagent, after dropwising, insulation reaction 0.5h at-20 DEG C.Then 25 ~ 30 DEG C are slowly risen to, stirring reaction 10 hours at 25 ~ 30 DEG C.Be diluted in water after TLC detection reaction is complete, concentrated hydrochloric acid regulates PH to be about 3.The each 200ml extraction into ethyl acetate twice of aqueous phase, combined ethyl acetate layer, each 150ml water washing ethyl acetate layer twice, after concentrated dry ethyl acetate, recrystallizing methanol obtains 10.2g compound 3(content 96%).
Embodiment 2-3
The configuration of Grignard reagent: add magnesium chips 27g in 1000ml anhydrous tetrahydro furan, 3-bromopyridine 92ml, back flow reaction, after 4 hours, is cooled to 0 DEG C.
0.1g cuprous chloride added in the above-mentioned Grignard reagent prepared, lead to nitrogen, then the 40ml benzole soln of 20g compound 2 is slowly added drop-wise in above-mentioned Grignard reagent, after dropwising, insulation reaction 2h at 0 DEG C.Then 15 DEG C are slowly risen to, stirring reaction 10 hours at 15 DEG C.Be diluted in water after TLC detection reaction is complete, concentrated hydrochloric acid regulates PH to be about 3.The each 200ml extraction into ethyl acetate twice of aqueous phase, combined ethyl acetate layer, each 150ml water washing ethyl acetate layer twice, after concentrated dry ethyl acetate, recrystallizing methanol obtains 10.8g compound 3(content 95%).
The synthesis of embodiment three compound 4
Embodiment 3-1
Be dissolved in by 10g compound 3 in the mixed solvent of 60ml pyridine and 20ml triethylamine, be added dropwise to 9ml Tosyl chloride, reaction solution is heated to 70 DEG C of clock reactions 10 hours, after be diluted in 800ml frozen water.Place and filter discharging after two hours, obtain 7.4g compound 4(content 85%).
Embodiment 3-2
Be dissolved in 80ml pyridine by 10g compound 3, be added dropwise to 4ml Tosyl chloride and 5ml phosphorus oxychloride, reaction solution is heated to 120 DEG C of clock reactions 7 hours, after be diluted in 800ml frozen water.Place and filter discharging after two hours, obtain 7.0g compound 4(content 83%).
Embodiment 3-3
Be dissolved in by 10g compound 3 in the mixed solvent of 20ml pyridine and 60ml triethylamine, be added dropwise to 9ml methylsulfonyl chloride, reaction solution is heated to 25 DEG C of clock reactions 24 hours, after be diluted in 800ml frozen water.Place and filter discharging after two hours, obtain 7.5g compound 4(content 85%).
Embodiment 3-4
By 10g compound 3, be dissolved in 80ml pyridine, be added dropwise to 9ml phosphorus oxychloride, reaction solution is heated to 80 DEG C of clock reactions 10 hours, after be diluted in 800ml frozen water.Place and filter discharging after two hours, obtain 7.4g compound 4(content 86%).
Embodiment 3-5
By 10g compound 3, be dissolved in 80ml triethylamine, be added dropwise to 4ml phosphorus oxychloride and 5ml methylsulfonyl chloride, reaction solution is heated to 90 DEG C of clock reactions 10 hours, after be diluted in 800ml frozen water.Place and filter discharging after two hours, obtain 7.3g compound 4(content 84%).
The synthesis of embodiment four compound 5
Embodiment 4-1
10g compound 4,300ml aceticanhydride, 6g tosic acid are added in reaction flask, logical nitrogen, in 20 ~ 25 DEG C of reactions 6 hours, after TLC detection reaction is complete, be cooled to 0 DEG C, filter, filter cake is diluted in 500ml frozen water, extract by ethyl acetate, after ethyl acetate washed with water is washed till neutrality, after concentrating under reduced pressure crystallization, be cooled to 0 DEG C, filter discharging, dry 11g compound 5(content 89%).
Embodiment 4-2
By in 10g compound 4,20ml aceticanhydride, 25ml Acetyl Chloride 98Min. added in reaction flask, logical nitrogen, in 70 ~ 75 DEG C of reactions 6 hours, after TLC detection reaction is complete, be cooled to 0 DEG C, filter, filter cake is diluted in 500ml frozen water, extract by ethyl acetate, after ethyl acetate washed with water is washed till neutrality, after concentrating under reduced pressure crystallization, be cooled to 0 DEG C, filter discharging, dry 11g compound 5(content 93%).
Embodiment 4-3
By in 10g compound 4,50ml methylvinyl acetate, 6g tosic acid added in reaction flask, logical nitrogen, in 95 ~ 100 DEG C of reactions 2 hours, after TLC detection reaction is complete, be cooled to 0 DEG C, filter, filter cake is diluted in 500ml frozen water, extract by ethyl acetate, after ethyl acetate washed with water is washed till neutrality, after concentrating under reduced pressure crystallization, be cooled to 0 DEG C, filter discharging, dry 11g compound 5(content 85%).
The synthesis of embodiment five compound 6
Embodiment 5-1
In reaction flask, add the aqueous ethanolic solution of 10g compound 5,100ml90%, stir, divide and add sodium borohydride 4g 3 times, every 10 minutes once.20 ~ 25 DEG C are reacted 12 hours, after TLC detection reaction is complete, be cooled to 0 DEG C, regulate PH to be 7 with 50% acetic acid.Be diluted in 1000ml frozen water, leave standstill after 2 hours and filter, massive laundering, oven dried, obtains 8g compound 6(content 80%).
Embodiment 5-2
In reaction flask, add the DMF of 10g compound 5,100ml, stir, divide and add lithium aluminium hydride 4g 3 times, every 10 minutes once.95 ~ 100 DEG C are reacted 2 hours, after TLC detection reaction is complete, be cooled to 0 DEG C, regulate PH to be 7 with 50% acetic acid.Be diluted in 1000ml frozen water, leave standstill after 2 hours and filter, massive laundering, oven dried obtains 8g compound 6(content 79%).
Embodiment 5-3
In reaction flask, add 10g compound 5,100ml dioxane, 50ml methyl alcohol, stir, divide and add POTASSIUM BOROHYDRIDE 4g 3 times, every 10 minutes once.0 ~ 5 DEG C is reacted 24 hours, after TLC detection reaction is complete, be cooled to 0 DEG C, regulates PH to be 7 with 50% acetic acid.Be diluted in 1000ml frozen water, leave standstill after 2 hours and filter, massive laundering, oven dried obtains 8.1g compound 6(content 80%).
Embodiment 5-4
In reaction flask, add 10g compound 5,100mlTHF, stir, divide and add POTASSIUM BOROHYDRIDE 4g 3 times, every 10 minutes once.-20 ~-15 DEG C are reacted 36 hours, after TLC detection reaction is complete, be cooled to 0 DEG C, regulate PH to be 7 with 50% acetic acid.Be diluted in 1000ml frozen water, leave standstill after 2 hours and filter, massive laundering, oven dried obtains 7.9g compound 6(content 80%).
The synthesis of embodiment six compound Abiraterone acetate
Embodiment 6-1
In reaction flask, add 9g compound 6,9ml aceticanhydride, 45ml pyridine, DMAP 1.8g, 20 DEG C are stirred after 5 hours, are diluted in 700ml frozen water after TLC detection reaction is complete.Place after 2 hours, filter discharging, dry, obtain 9.9g Abiraterone acetate (content 82%).
Embodiment 6-2
In reaction flask, add 9g compound 6,5ml aceticanhydride, 5ml Acetyl Chloride 98Min., 45ml pyridine, 55 ~ 60 DEG C of stirrings after 2 hours, be diluted in 700ml frozen water after TLC detection reaction is complete.Place after 2 hours, filter discharging, dry, obtain 9.9g Abiraterone acetate (content 81%).
Embodiment 6-3
In reaction flask, add 9g compound 6,9ml Acetyl Chloride 98Min., 45ml triethylamine, 30 DEG C are stirred after 5 hours, are diluted in 700ml frozen water after TLC detection reaction is complete.Place after 2 hours, filter discharging, dry, obtain 9.8g Abiraterone acetate (content 80%).
Refining of embodiment seven Abiraterone acetate
Embodiment 7-1
The Abiraterone acetate crude product re-crystallizing in ethyl acetate of 10g content 80% is obtained 7.5g content 99.6% Abiraterone acetate fine work.
Embodiment 7-2
The Abiraterone acetate crude product recrystallized from acetonitrile of 10g content 80% is obtained 7.6g content 99.5% Abiraterone acetate fine work.
Embodiment 7-3
The Abiraterone acetate crude product recrystallizing methanol of 10g content 80% is obtained 7.5g content 99.5% Abiraterone acetate fine work.
Claims (5)
1. a synthetic method for Abiraterone acetate, is characterized in that described synthetic method comprises the steps:
Step one: compound 1 and triethyl orthoformate generate compound 2 under the effect of catalyzer, described catalyzer be selected from mineral acid, organic acid and pyridinium salt thereof one or more;
Step 2: compound 2 and grignard reagent grignard reaction occur under the effect of catalyzer and generate compound 3; Described grignard reagent is 3-pyridyl magnesium bromide;
Step 3: compound 3 and dewatering agent reacting generating compound 4 in basic solvent; Described basic solvent be selected from pyridine or triethylamine one or both;
Step 4: compound 4 and acetylation reagent reacting generating compound 5, described acetylation reagent be selected from aceticanhydride, Acetyl Chloride 98Min. or methylvinyl acetate one or more;
Step 5: compound 5 and reductive agent are obtained by reacting compound 6;
Step 6: compound 6 and acetylation reagent react and generate Abiraterone acetate, described acetylation reagent be selected from aceticanhydride, Acetyl Chloride 98Min. one or more.
2. the synthetic method of a kind of Abiraterone acetate as claimed in claim 1, is characterized in that
Step one: compound 1 and triethyl orthoformate generate compound 2 under the effect of catalyzer, described catalyzer be selected from mineral acid or organic acid and pyridinium salt thereof one or more;
Step 2: compound 2 and grignard reagent grignard reaction occur under the effect of catalyzer and generate compound 3, and described grignard reagent is 3-pyridyl magnesium bromide, and described catalyzer is selected from cupprous inorganic salt;
Step 3: compound 3 and dewatering agent reacting generating compound 4 in basic solvent; Described basic solvent be selected from pyridine or triethylamine one or both; Described dewatering agent is selected from phosphorus oxychloride, methylsulfonyl chloride or to one or more in tosylate chloride;
Step 4: compound 4 and acetylation reagent reacting generating compound 5, described acetylation reagent be selected from aceticanhydride, Acetyl Chloride 98Min. or methylvinyl acetate one or more;
Step 5: compound 5 and reductive agent are obtained by reacting compound 6, and described reductive agent is selected from sodium borohydride, POTASSIUM BOROHYDRIDE or lithium aluminum hydride;
Step 6: compound 6 reacts with acetylation reagent and generates Abiraterone acetate under the effect of acid binding agent; described acetylation reagent be selected from aceticanhydride, Acetyl Chloride 98Min. one or more, described acid binding agent be selected from pyridine, triethylamine or DMAP one or more.
3. the synthetic method of a kind of Abiraterone acetate as claimed in claim 2, is characterized in that
Step one: temperature of reaction is 0 ~ 60 DEG C; Solvent for use be selected from dioxane, tetrahydrofuran (THF) or dehydrated alcohol one or more;
Step 2: compound 2 and grignard reagent under the effect of catalyzer, first-20
lower stirring 30 minutes ~ 2 hours, then rise 15 ~ 30 DEG C to reacting end, described catalyzer is selected from cuprous chloride or cuprous iodide;
Step 3: temperature of reaction is 25 ~ 120 DEG C;
Step 4: temperature of reaction is 20 ~ 100 DEG C;
Step 5: temperature of reaction is-20 ~ 100 DEG C; Solvent for use be selected from tetrahydrofuran (THF), methyl alcohol, ethanol, dioxane, DMF one or more or be selected from the aqueous solution of above-mentioned solvent;
Step 6: temperature of reaction is 20 ~ 60 DEG C.
4. the synthetic method of a kind of Abiraterone acetate as claimed in claim 3, is characterized in that
Step one: temperature of reaction is 20 ~ 40 DEG C;
Step 2: compound 2 and grignard reagent are under the effect of catalyzer, and first stir 30 minutes ~ 2 hours at-10 DEG C ~ 0 DEG C, then rise 20 ~ 25 DEG C to reacting end, described catalyzer is selected from cuprous chloride or cuprous iodide;
Step 3: temperature of reaction is 70 ~ 90 DEG C;
Step 4: temperature of reaction is 20 ~ 100 DEG C;
Step 5: temperature of reaction is 0 ~ 25 DEG C;
Step 6: temperature of reaction is 20 ~ 30 DEG C.
5. formula 1 compound
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| CN107176965A (en) * | 2016-03-09 | 2017-09-19 | 兰州大学 | One kind synthesis Abiraterone acetate new method |
| CN112940065A (en) * | 2021-02-03 | 2021-06-11 | 山东大学 | Application of triflate in preparation of abiraterone acetate and synthetic method |
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