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【结 构 式】 
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【分子编号】20086 【品名】3-(diethylboryl)pyridine 【CA登记号】 |
【 分 子 式 】C9H14BN 【 分 子 量 】147.0279 【元素组成】C 73.52% H 9.6% B 7.35% N 9.53% |
合成路线1
该中间体在本合成路线中的序号：(IV)Treatment of dehydroepiandrosterone 3-acetate (I) with triflic anhydride and 2,6-di-tert-butyl-4-methylpyridine provided the desired enol triflate (III) along with some 3,5-diene (II), which were separated by column chromatography. Subsequent coupling of triflate (III) with pyridylborane (IV) using bis(triphenylphosphine)- palladium(II) chloride as the catalyst afforded the (3-pyridyl)androstadiene (V), which after hydrolysis of the acetate ester with NaOH provided the target compound.
| 【1】 Potter, G.A.; et al.; Novel steroidal inhibitors of human cytochrome P450(17alpha) (17alpha-hydroxylase-C17,20-lyase): Potential agents for the treatment of prostatic cancer. J Med Chem 1995, 38, 13, 2463. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 20083 | Prasterone acetate;3b-Hydroxy-5-androstene-17-one acetate；Dehydroisoandrosterone acetate;Dehydroepiandrosterone 3-acetate;Dehydroepiandrosterone acetate;(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-oxo-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | 853-23-6 | C21H30O3 | 详情 | 详情 |
| (II) | 20084 | (8R,9S,10R,13S,14S)-10,13-dimethyl-2,7,8,9,10,11,12,13,14,15-decahydro-1H-cyclopenta[a]phenanthren-17-yl trifluoromethanesulfonate | C20H25F3O3S | 详情 | 详情 | |
| (III) | 20085 | (3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-[[(trifluoromethyl)sulfonyl]oxy]-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | C22H29F3O5S | 详情 | 详情 | |
| (IV) | 20086 | 3-(diethylboryl)pyridine | C9H14BN | 详情 | 详情 | |
| (V) | 20087 | (3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridinyl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | C26H33NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The condensation of 3-(methylsulfonyl)bromobenzene (I) with diethyl(3-pyridyl)borane (II) by means of Pd(PPh3)4, KOH and tetrabutylammonium iodide (TBAI) gives 3-[3-(methylsulfonyl)phenyl]pyridine (III), which is hydrogenated with H2 over PtO2 in methanol, yielding the racemic piperidine (IV). The optical resolution of (IV) with (+)-tartaric acid affords the (S)-enantiomer (V), which is alkylated by reductocondensation with propionic aldehyde and NaBH(O-tBu)3 in dichloroethane and HOAc.
| 【1】 Sonesson, C.; Lindborg, J.; An efficient synthesis of the novel dopamine autoreceptor antagonist S-(-)-OSU6162, via Palladium catalyzed cross-coupling reaction. Tetrahedron Lett 1994, 35, 48, 9063. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 43388 | (3-bromophenyl)(methyl)dioxo-lambda(6)-sulfane; 3-bromophenyl methyl sulfone | C7H7BrO2S | 详情 | 详情 | |
| (II) | 20086 | 3-(diethylboryl)pyridine | C9H14BN | 详情 | 详情 | |
| (III) | 43389 | methyl 3-(3-pyridinyl)phenyl sulfone; 3-[3-(methylsulfonyl)phenyl]pyridine | C12H11NO2S | 详情 | 详情 | |
| (IV) | 43390 | methyl 3-(3-piperidinyl)phenyl sulfone; 3-[3-(methylsulfonyl)phenyl]piperidine | C12H17NO2S | 详情 | 详情 | |
| (V) | 43391 | methyl 3-[(3S)piperidinyl]phenyl sulfone; (3S)-3-[3-(methylsulfonyl)phenyl]piperidine | C12H17NO2S | 详情 | 详情 | |
| (VI) | 15966 | propionaldehyde | 123-38-6 | C3H6O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)The condensation between 3-(bromoacetyl)pyridine (I) and either formamide or formamidine acetate produced the intermediate 4-(3-pyridyl)imidazole (II). Alternatively, intermediate (II) was prepared by palladium-catalyzed coupling between 1-trityl-4-iodoimidazole (III) and diethyl(3-pyridyl)borane (IV), followed by acidic deprotection of the resultant 1-trityl-4-(3-pyridyl)imidazole (V). In a further procedure, iodoimidazole (III) was converted to the corresponding Grignard reagent (VI), which was then coupled with 3-bromopyridine (VII) in the presence of ZnCl2 and palladium catalyst, yielding adduct (V). Subsequent acid-catalyzed deprotection gave intermediate (II). Michael addition of crotonaldehyde (VIII) to imidazole (II) furnished the (pyridylimidazolyl)butyraldehyde (IX). Condensation of aldehyde (IX) with the macrocyclic N-amino carbamate (X) produced the intermediate imine (XI), which was reduced to the corresponding amino derivative using sodium cyanoborohydride. The resultant epimeric mixture was separated by chromatography to provide the title (3R)-diastereoisomer. Alternatively, the reductive alkylation of (X) with aldehyde (IX) was carried out in the presence of sodium triacetoxyborohydride.
| 【1】 Su, W.; et al.; The in vitro and in vivo activity of CP-642,959 and its related diastereomers. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1168. |
| 【2】 Kaneko, T.; Su, W.-G.; Wu, Y.-J. (Pfizer Inc.); Carbamate and carbazate ketolide antibiotics. EP 1115732; WO 0017218 . |
| 【3】 Kaneko, T.; McMillen, W.T.; McLaughlin, R.W.; Ripin, D.H.B.; Vanerplas, B.C. (Pfizer Inc.); Synthesis of carbamate ketolide antibiotics. EP 1088828; JP 2001151792 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 53085 | 2-bromo-1-(3-pyridinyl)-1-ethanone | n/a | C7H6BrNO | 详情 | 详情 |
| (II) | 17164 | 3-(1H-imidazol-4-yl)pyridine | C8H7N3 | 详情 | 详情 | |
| (III) | 32016 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy]-9-[[(benzyloxy)carbonyl]oxy]-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoa | C55H57NO16 | 详情 | 详情 | |
| (IV) | 20086 | 3-(diethylboryl)pyridine | C9H14BN | 详情 | 详情 | |
| (V) | 53086 | 3-(1-trityl-1H-imidazol-4-yl)pyridine | n/a | C27H21N3 | 详情 | 详情 |
| (VI) | 32017 | (2S)-5-amino-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxopentanoic acid | C13H12N2O5 | 详情 | 详情 | |
| (VII) | 13265 | 3-Bromopyridine | 626-55-1 | C5H4BrN | 详情 | 详情 |
| (VIII) | 22517 | (E)-2-butenal | 4170-30-3 | C4H6O | 详情 | 详情 |
| (IX) | 53087 | 3-[4-(3-pyridinyl)-1H-imidazol-1-yl]butanal | n/a | C12H13N3O | 详情 | 详情 |
| (X) | 45787 | (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-1-amino-10-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-4-ethyl-11-methoxy-3a,7,9,11,13,15-hexamethyloctahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,8,14(1H,7H,9H)-tetrone 14-(O-methyloxime) | C32H56N4O10 | 详情 | 详情 | |
| (XI) | 53088 | (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-10-{[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-4-ethyl-11-methoxy-3a,7,9,11,13,15-hexamethyl-1-({(Z)-3-[4-(3-pyridinyl)-1H-imidazol-1-yl]butylidene}amino)octahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,8,14(1H,7H,9H)-tetrone 14-(O-methyloxime) | n/a | C44H67N7O10 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)Abiraterone acetate has been synthesized by two related routes.
a) Reaction of dehydroepiandrosterone acetate (Ia) with trifluoromethanesulfonic anhydride and triethylamine in dichloromethane gives the enol triflate (II), which is finally coupled with diethyl(3-pyridyl)borane (III) by means of PdCl2(PPh3)4 in tetrahydrofuran .
b) In an improved procedure, dehydroepiandrosterone (Ib) is converted to the corresponding hydrazone (IV) by treatment with hydrazine hydrate and a catalytic amount of hydrazine sulfate in EtOH. Subsequent reaction of hydrazone (IV) with iodine and 1,1,3,3-tetramethylguanidine (TMG) in THF/Et2O gives the vinyl iodide (V), which undergoes palladium–catalyzed cross coupling with diethyl(3-pyridyl)borane (III) to yield abiraterone (VI). Finally, alcohol (VI) is acetylated using acetic anhydride in pyridine .
| 【1】 Potter, G.A., Barrie, S.E., Jarman, M., Rowlands, M.G. Novel steroidal inhibitors of human cytochrome P45017α (17α-hydroxylase-C17,20-lyase): potential agents for the treatment of prostatic cancer. J Med Chem 1995, 38(13): 2463-71. |
| 【2】 Barrie, S.E., Jarman, M., Potter, G.A. (BTG plc.). 17-Substituted steroids useful in cancer treatment. EP 0633893, GB 2265624, US 5604213, WO 1993020097. |
| 【3】 Hunt, N.J. (BTG International Ltd). Methanesulfonate salts of abiraterone-3-esters and recovery of salts of abiraterone-3-esters from solution in methyl tert-butyl ether. CA 2576922, EP 1789432, JP 2008510780, US 2007249837, WO 2006021776. |
| 【4】 Bury, P.S. (BTG International Ltd.). Process for the preparation of 17-Ovinyl-triflates as intermediates. EP 1781683, JP 2008510781, US 2007282109, WO 2006021777. |
| 【5】 Potter, G.A. and Hardcastle, I.R. (BTG International Ltd). Synthesis of 17-(3-pyridyl) steroids. CA 2170286, EP 0721461, GB 2282377, JP 1997502994, WO 1995009178. |
| 【6】 Potter, G.A., Hardcastle, I.R., Jarman, M. A convenient, large-scale synthesis of abiraterone acetate [3β-acetoxy-17-(3-pyridyl)androsta-5,16-diene], a potential new drug for the treatment of prostate cancer. Org Prep Proced Int 1997, 29: 123. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Ia) | 20083 | Prasterone acetate;3b-Hydroxy-5-androstene-17-one acetate；Dehydroisoandrosterone acetate;Dehydroepiandrosterone 3-acetate;Dehydroepiandrosterone acetate;(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-oxo-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | 853-23-6 | C21H30O3 | 详情 | 详情 |
| (Ib) | 11713 | Dehydroepiandrosterone;prasterone；(3S,8R,9S,10R,13S,14S)-3-Hydroxy-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one | 53-43-0 | C19H28O2 | 详情 | 详情 |
| (II) | 20085 | (3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-[[(trifluoromethyl)sulfonyl]oxy]-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | C22H29F3O5S | 详情 | 详情 | |
| (III) | 20086 | 3-(diethylboryl)pyridine | C9H14BN | 详情 | 详情 | |
| (IV) | 69461 | (3S,8S,9R,10S,13R,E)-17-hydrazono-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-ol | C19H30N2O | 详情 | 详情 | |
| (V) | 69460 | (3R,8S,9R,10S,13R)-17-iodo-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol | 32138-69-5 | C19H27IO | 详情 | 详情 |
| (VI) | 69462 | (3R,8S,9R,10S,13R)-10,13-dimethyl-17-(pyridin-3-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol | C24H31NO | 详情 | 详情 |