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【结 构 式】

【分子编号】24989

【品名】tert-butyl (3S)-3-[4-(2-ethoxy-2-oxoethyl)phenoxy]-1-pyrrolidinecarboxylate

【CA登记号】

【 分 子 式 】C19H27NO5

【 分 子 量 】349.42712

【元素组成】C 65.31% H 7.79% N 4.01% O 22.89%

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:(VI)

The bromination of 2,7-dimethylnaphthalene (I) with N-bromosuccinimide (NBS) and UV light in CCl4 gives the monobromo derivative (II), which is treated with 2-nitropropane/NaOMe to yield 7-methylnaphthalene-2-carbaldehyde (III). The reaction of (III) with hydroxylamine-O-sulfonic acid affords the nitrile (IV), which is brominated with NBS as before to give 7-(bromomethyl)naphthalene-2-carbonitrile (V). The condensation of (V) with 2-[4-[1-(tert-butoxycarbonyl)pyrrolidin-3(S)-yloxy]phenyl]acetic acid ethyl ester (VI) by means of lithium bis(trimethylsilyl)amide yields 2-[4-[1-(tert-butoxycarbonyl)pyrrolidin-3(S)-yloxy]phenyl]-3-(7-cyano-2-naphthyl)propionic acid ethyl ester (VII) as a diastereomeric mixture. This mixture was worked up as already described to obtain the target compound DX-9065a.

1 Engh, R.A.; Neidlein, R.; Bradstetter, H.; Strein, K.; Koczmierz, R.; Marzenell, K.; Leibert, H.; von der Saal, W.; Kehr, R.; A short synthesis of the factor-Xa inhibitor DX-9065 a using palladium-catalyzed key steps. Helv Chim Acta 1997, 80, 892.
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) 24984 2,7-dimethylnaphthalene 582-16-1 C12H12 详情 详情
(II) 24985 2-(bromomethyl)-7-methylnaphthalene C12H11Br 详情 详情
(III) 24986 7-methyl-2-naphthaldehyde 52988-18-8 C12H10O 详情 详情
(IV) 24987 7-methyl-2-naphthonitrile C12H9N 详情 详情
(V) 24988 7-(bromomethyl)-2-naphthonitrile C12H8BrN 详情 详情
(VI) 24989 tert-butyl (3S)-3-[4-(2-ethoxy-2-oxoethyl)phenoxy]-1-pyrrolidinecarboxylate C19H27NO5 详情 详情
(VII) 16291 tert-butyl (3S)-3-(4-[1-[(7-cyano-2-naphthyl)methyl]-2-ethoxy-2-oxoethyl]phenoxy)-1-pyrrolidinecarboxylate C31H32N2O5 详情 详情
(VIII) 24991 tert-butyl (3S)-3-(4-[(1S)-1-[(7-cyano-2-naphthyl)methyl]-2-ethoxy-2-oxoethyl]phenoxy)-1-pyrrolidinecarboxylate C31H34N2O5 详情 详情

合成路线2

该中间体在本合成路线中的序号:(III)

A new synthesis of 2-[4-[1-(tert-butoxycarbonyl)pyrrolidin-3(S)-yloxy)phenyl]-3-(7-cyano-2-naphthyl)-2-propenoic acid ethyl ester (VI), a key intermediate in the synthesis of DX-9065a has been described: The condensation of 3(R)-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (I) with 4-hydroxyphenylacetic acid ethyl ester (II) by means of triphenylphosphine and diethyl azodicarboxylate (DEAD) in THF gives 4-[1-(tert-butoxycarbonyl)pyrrolidin-3(R)-yloxy]phenylacetic acid ethyl ester (III), which is treated with formaldehyde, K2CO3 and tetrabutylammonium iodide in hot toluene yielding 2-[4-[1-(tert-butoxycarbonyl)pyrrolidin-3(R)-yloxy]phenyl]-2-propenoic acid ethyl ester (IV). Finally, this compound is condensed with 7-(trifluoromethylsulfonyloxy)naphthalene-2-carbonitrile (V) by means a Pd catalyst in hot DMF to afford the target compound (VI).

1 Yokoyama, Y.; Synthesis of specific factor Xa inhibitor, DX-9065a. Symp Med Chem 1998, Abst L-15.
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) 16286 tert-butyl (3S)-3-hydroxytetrahydro-1H-pyrrole-1-carboxylate C9H17NO3 详情 详情
(II) 24994 Ethyl 2-(4-hydroxyphenyl)acetate 17138-28-2 C10H12O3 详情 详情
(III) 24989 tert-butyl (3S)-3-[4-(2-ethoxy-2-oxoethyl)phenoxy]-1-pyrrolidinecarboxylate C19H27NO5 详情 详情
(IV) 24996 tert-butyl (3S)-3-[4-[1-(ethoxycarbonyl)vinyl]phenoxy]-1-pyrrolidinecarboxylate C20H27NO5 详情 详情
(V) 24997 7-cyano-2-naphthyl trifluoromethanesulfonate C12H6F3NO3S 详情 详情
(VI) 16290 tert-butyl (3S)-3-[4-[(Z)-2-(7-cyano-2-naphthyl)-1-(ethoxycarbonyl)ethenyl]phenoxy]-1-pyrrolidinecarboxylate C31H32N2O5 详情 详情
(VII) 24999 7-methoxy-3,4-dihydro-2(1H)-naphthalenone 4133-34-0 C11H12O2 详情 详情
(VIII) 25000 7-methoxy-3,4-dihydro-2-naphthalenecarbonitrile C12H11NO 详情 详情
(IX) 25001 7-methoxy-2-naphthonitrile C12H9NO 详情 详情
(X) 25002 7-hydroxy-2-naphthonitrile C11H7NO 详情 详情
(XI) 25003 7-methoxy-2-naphthol 5060-82-2 C11H10O2 详情 详情
(XII) 25004 7-methoxy-2-naphthyl trifluoromethanesulfonate C12H9F3O4S 详情 详情
Extended Information