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【结 构 式】

【分子编号】51604

【品名】(4bS,7R,8aR)-4b-benzyl-7-hydroxy-7-(1-propynyl)-4b,5,6,7,8,8a,9,10-octahydro-2-phenanthrenyl trifluoromethanesulfonate

【CA登记号】

【 分 子 式 】C25H25F3O4S

【 分 子 量 】478.5323096

【元素组成】C 62.75% H 5.27% F 11.91% O 13.37% S 6.7%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(XIV)

6-Methoxy-2-tetralone (I) was condensed with pyrrolidine (II) to produce enamine (III). Alkylation of (III) with benzyl bromide, followed by hydrolysis of the enamine function, furnished the 1-benzylnaphthalenone (IV). After formation of the chiral enamine (VI) with (S)-alpha-methylbenzylamine (V), enantioselective Michael addition of methyl vinyl ketone (VII) provided the (R)-diketone (VIII), which underwent ring closure to the phenanthrene derivative (IX) upon treatment with NaOMe. Methyl ether cleavage by using boron trichloride in the presence of tetrabutylammonium iodide afforded phenol (X). The conjugated ketone system of (X) was diastereoselectively reduced to the trans-phenanthrenone (XI) by means of lithium in liquid ammonia. Addition of the lithium acetylide of propyne (XII) to the ketone (XI) produced a diastereomeric mixture of carbinols from which the desired isomer (XIII) was isolated by flash chromatography. The phenol group of (XIII) was then converted to the aryl triflate (XIV) by reaction with trifluoromethanesulfonic anhydride and 2,6-lutidine.

1 Liu, K.K.-C.; Morgan, B.P.; Dow, R.L.; Swick, A.G. (Pfizer Inc.); Glucocorticoid receptor modulators. EP 1175383; WO 0066522 .
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) 47506 6-Methoxy-2-tetralone; 6-methoxy-3,4-dihydro-2(1H)-naphthalenone 2472-22-2 C11H12O2 详情 详情
(II) 11376 Pyrrolidine 123-75-1 C4H9N 详情 详情
(III) 47507 methyl 6-(1-pyrrolidinyl)-7,8-dihydro-2-naphthalenyl ether; 1-(6-methoxy-3,4-dihydro-2-naphthalenyl)pyrrolidine C15H19NO 详情 详情
(IV) 51596 1-benzyl-6-methoxy-3,4-dihydro-2(1H)-naphthalenone C18H18O2 详情 详情
(V) 20042 (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine C8H11N 详情 详情
(VI) 51597 1-benzyl-6-methoxy-N-[(1S)-1-phenylethyl]-3,4-dihydro-2-naphthalenamine; N-(1-benzyl-6-methoxy-3,4-dihydro-2-naphthalenyl)-N-[(1S)-1-phenylethyl]amine C26H27NO 详情 详情
(VII) 30324 3-buten-2-one; methyl vinyl ketone 78-94-4 C4H6O 详情 详情
(VIII) 51598 (1R)-1-benzyl-6-methoxy-1-(3-oxobutyl)-3,4-dihydro-2(1H)-naphthalenone C22H24O3 详情 详情
(IX) 51599 (4aS)-4a-benzyl-7-methoxy-4,4a,9,10-tetrahydro-2(3H)-phenanthrenone C22H22O2 详情 详情
(X) 51600 (4aS)-4a-benzyl-7-hydroxy-4,4a,9,10-tetrahydro-2(3H)-phenanthrenone C21H20O2 详情 详情
(XI) 51601 (4aS,10aR)-4a-benzyl-7-hydroxy-3,4,4a,9,10,10a-hexahydro-2(1H)-phenanthrenone C21H22O2 详情 详情
(XII) 51602 1-Propyne C3H4 详情 详情
(XIII) 51603 (2R,4aS,10aR)-4a-benzyl-2-(1-propynyl)-1,2,3,4,4a,9,10,10a-octahydro-2,7-phenanthrenediol C24H26O2 详情 详情
(XIV) 51604 (4bS,7R,8aR)-4b-benzyl-7-hydroxy-7-(1-propynyl)-4b,5,6,7,8,8a,9,10-octahydro-2-phenanthrenyl trifluoromethanesulfonate C25H25F3O4S 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XIV)

Palladium-catalyzed carbonylation of aryl triflate (XIV) under carbon monoxide atmosphere in the presence of methanol gave rise to the phenanthrenecarboxylate ester (XV). The ester group of (XV) was finally displaced with 4-(aminomethyl)pyridine (XVI) using trimethylaluminum catalyst to generate the target amide.

1 Liu, K.K.-C.; Morgan, B.P.; Dow, R.L.; Swick, A.G. (Pfizer Inc.); Glucocorticoid receptor modulators. EP 1175383; WO 0066522 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIV) 51604 (4bS,7R,8aR)-4b-benzyl-7-hydroxy-7-(1-propynyl)-4b,5,6,7,8,8a,9,10-octahydro-2-phenanthrenyl trifluoromethanesulfonate C25H25F3O4S 详情 详情
(XV) 51605 methyl (4bS,7R,8aR)-4b-benzyl-7-hydroxy-7-(1-propynyl)-4b,5,6,7,8,8a,9,10-octahydro-2-phenanthrenecarboxylate C26H28O3 详情 详情
(XVI) 29396 4-pyridinylmethanamine 3731-53-1 C6H8N2 详情 详情
Extended Information