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【结 构 式】 
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【分子编号】16290 【品名】tert-butyl (3S)-3-[4-[(Z)-2-(7-cyano-2-naphthyl)-1-(ethoxycarbonyl)ethenyl]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% |
合成路线1
该中间体在本合成路线中的序号：(V)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：(VI)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 |