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【结 构 式】

【分子编号】16291

【品名】tert-butyl (3S)-3-(4-[1-[(7-cyano-2-naphthyl)methyl]-2-ethoxy-2-oxoethyl]phenoxy)-1-pyrrolidinecarboxylate

【CA登记号】

【 分 子 式 】C31H32N2O5

【 分 子 量 】512.60556

【元素组成】C 72.64% H 6.29% N 5.46% O 15.61%

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)

Condensation of the (3R)-3-pyrrolidinol (I) and the phenylglyoxylate (II) using a procedure described by Bittner gave the (3S)-alpha-keto-ester (III). Wittig reaction of the (3S)-alpha-keto-ester (III) and the phosphonium salts (IV) using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a base, followed by catalytic hydrogenation gave the ethyl propanoate derivatives (VI) as an equivalent mixture of two diastereoisomers. The mixture (VI) gave the pure (2S,3'S)-isomer (VII) by means of crystallization in ethanol. Pinner synthesis was applied for the single isomer (VII) to give the amidine (VIII). Treatment of the amidine (VIII) with ethyl acetimidate hydrochloride yielded the N-acetimidoyl derivative (IX). Conversion of (IX) to the final product, DX-9065a, was accomplished by acidic hydrolysis followed by crystallization. The absolute configuration of DX-9065a was assigned as (2S,3'S) based on X-ray crystallographic analysis and the (3'S) configuration of the 3 position on the pyrrolidine ring.

1 Hara, T.; Yamazaki, K.; Nagahara, T.; Kunitada, S.; Katakura, S.; Inamura, K.; Iwamoto, M.; Komoriya, S.; Yokoyama, Y.; DX-9065a. Drugs Fut 1995, 20, 6, 564.
2 Iwamoto, M.; Inamura, K.; Nagahara, T.; Komoriya, S.; Hara, T.; Katakura, S.; Yamaguchi, H.; Yokoyama, Y.; Dibasic (amidinoaryl)propanoic acid derivatives as novel blood coagulation factor Xa inhibitors. J Med Chem 1994, 37, 8, 1200-7.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12831 ethyl ethanimidoate 1000-84-6 C4H9NO 详情 详情
(I) 16286 tert-butyl (3S)-3-hydroxytetrahydro-1H-pyrrole-1-carboxylate C9H17NO3 详情 详情
(II) 16287 ethyl 2-(4-hydroxyphenyl)-2-oxoacetate C10H10O4 详情 详情
(III) 16288 tert-butyl (3S)-3-[4-(2-ethoxy-2-oxoacetyl)phenoxy]tetrahydro-1H-pyrrole-1-carboxylate C19H25NO6 详情 详情
(IV) 16289 7-[chloro(triphenyl)phosphoranyl]-2-naphthonitrile C29H21ClNP 详情 详情
(V) 16290 tert-butyl (3S)-3-[4-[(Z)-2-(7-cyano-2-naphthyl)-1-(ethoxycarbonyl)ethenyl]phenoxy]-1-pyrrolidinecarboxylate C31H32N2O5 详情 详情
(VI) 16291 tert-butyl (3S)-3-(4-[1-[(7-cyano-2-naphthyl)methyl]-2-ethoxy-2-oxoethyl]phenoxy)-1-pyrrolidinecarboxylate C31H32N2O5 详情 详情
(VII) 16292 tert-butyl (3S)-3-(4-[(1S)-1-[(7-cyano-2-naphthyl)methyl]-2-ethoxy-2-oxoethyl]phenoxy)-1-pyrrolidinecarboxylate C31H34N2O5 详情 详情
(VIII) 16293 ethyl (2S)-3-[7-[amino(imino)methyl]-2-naphthyl]-2-[4-[(3S)tetrahydro-1H-pyrrol-3-yloxy]phenyl]propanoate C26H29N3O3 详情 详情
(IX) 16294 ethyl (2S)-3-[7-[amino(imino)methyl]-2-naphthyl]-2-(4-[[(3S)-1-ethanimidoyltetrahydro-1H-pyrrol-3-yl]oxy]phenyl)propanoate C28H32N4O3 详情 详情

合成路线2

该中间体在本合成路线中的序号:(VII)

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
Extended Information