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【结 构 式】 
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【分子编号】10169 【品名】methyl 4-cyanobenzoate；4-Cyanobenzoic acid methyl ester 【CA登记号】1129-35-7 |
【 分 子 式 】C9H7NO2 【 分 子 量 】161.16012 【元素组成】C 67.08% H 4.38% N 8.69% O 19.86% |
合成路线1
该中间体在本合成路线中的序号：(V)The synthesis of [14C]-labeled BRL-26830A has been described: The reaction of copper sulfate (I) with sodium methabisulfite, followed by treatment with [14C]-labeled potassium cyanide (II) yields cuprous cyanide (III), which is condensed with methyl 4-bromobenzoate (IV) to afford methyl 4-cyanobenzoate (V). The reduction of (V) with Al/Ni and formic acid gives methyl 4-formylbenzoate (VI), which is condensed with nitroethane by means of butylamine and acetic acid in benzene to give methyl 4-(2-nitro-1-propenyl)benzoate (VII). The treatment of (VII) with Fe and HCl in refluxing methanol yields methyl 4-(acetonyl)benzoate (VIII), which is reductocondensed with (R*)-2-amino-1-phenylethanol (IX) by means of NaBH4 in refluxing benzene and crystallized in methanol to fractionate the optical diastereomers. Finally, the (R*,R*)-isomer (X) is treated with fumaric acid.
| 【1】 Freer, R.; Morecombe, D.J.; The synthesis of [14C]BRL 26830A, a novel beta-adrenoceptor agonist. J Label Compd Radiopharm 1992, 31, 9, 697. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 23808 | Fumaric acid; (E)-2-butenedioic acid | 110-17-8 | C4H4O4 | 详情 | 详情 | |
| (IV) | 10168 | 4-Bromobenzoic acid methyl ester; methyl 4-bromobenzoate | 619-42-1 | C8H7BrO2 | 详情 | 详情 |
| (V) | 10169 | methyl 4-cyanobenzoate；4-Cyanobenzoic acid methyl ester | 1129-35-7 | C9H7NO2 | 详情 | 详情 |
| (V) | 44596 | methyl 4-cyanobenzoate | C9H7NO2 | 详情 | 详情 | |
| (VI) | 10170 | methyl 4-formylbenzoate | 1571-08-0 | C9H8O3 | 详情 | 详情 |
| (VI) | 44597 | methyl 4-formylbenzoate | C9H8O3 | 详情 | 详情 | |
| (VII) | 10171 | methyl 4-[(Z)-2-nitro-1-propenyl]benzoate | C11H11NO4 | 详情 | 详情 | |
| (VII) | 44598 | methyl 4-[(Z)-2-nitro-1-propenyl]benzoate | C11H11NO4 | 详情 | 详情 | |
| (VIII) | 10172 | methyl 4-(2-oxopropyl)benzoate | C11H12O3 | 详情 | 详情 | |
| (VIII) | 44599 | methyl 4-(2-oxopropyl)benzoate | C11H12O3 | 详情 | 详情 | |
| (IX) | 10173 | (1R)-2-Amino-1-phenyl-1-ethanol | 2549-14-6 | C8H11NO | 详情 | 详情 |
| (X) | 44595 | methyl 4-((2R)-2-[[(2R)-2-hydroxy-2-phenylethyl]amino]propyl)benzoate | C19H23NO3 | 详情 | 详情 | |
| (X) | 44600 | methyl 4-((2R)-2-[[(2R)-2-hydroxy-2-phenylethyl]amino]propyl)benzoate | C19H23NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)2) Intermediate (IX) can also be obtained as follows: The cyclization of 4-cyanobenzoic acid methyl ester (XII) with acetylene at 15 Atm by means of cobaltocene in toluene at 180 C gives 4-(2-pyridyl)benzoic acid methyl ester (XIII), which is saponified with NaOH in methanol to the corresponding acid (XIV). The activation of (XIV) with isobutyl chloroformate yields the mixed anhydride (XV), which is condensed with N-(tert-butoxycarbonyl)-L-phenylalaninal (XVI) and KCN in dichloromethane, affording (XVII). The reaction of (XVII) with tert-butyl carbazate (V) by means of acetic acid in methanol gives hydrazone (XVIII), which is reduced to hydrazine (XIX) by means of sodium cyanoborohydride in THF. The isomerization of (XIX) by means of 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTDE) in hot diglyme yields hydrazide (XX), which is finally reduced to intermediate (IX) with diisobutylaluminum hydride in dichloromethane/THF.
| 【1】 Fassler, A.; Steiner, H.; Bold, G.; Capraro, H.-G. (Novartis AG); Process for the preparation of hydrazine derivs. useful as intermediates for the preparation of peptide analogues. WO 9746514 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 23634 | acetylene | 74-86-2 | C2H2 | 详情 | 详情 |
| (V) | 10893 | tert-butyl 1-hydrazinecarboxylate; tert-butyl carbazate | 870-46-2 | C5H12N2O2 | 详情 | 详情 |
| (IX) | 23445 | tert-butyl 2-[(2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl]-2-[4-(2-pyridinyl)benzyl]-1-hydrazinecarboxylate | C32H42N4O5 | 详情 | 详情 | |
| (XII) | 10169 | methyl 4-cyanobenzoate；4-Cyanobenzoic acid methyl ester | 1129-35-7 | C9H7NO2 | 详情 | 详情 |
| (XIII) | 23449 | methyl 4-(2-pyridinyl)benzoate | C13H11NO2 | 详情 | 详情 | |
| (XIV) | 23450 | 4-(2-pyridinyl)benzoic acid | C12H9NO2 | 详情 | 详情 | |
| (XV) | 23451 | 4-(2-Pyridyl)benzoic acid isobutoxycarbonyl anhydride | C17H17NO4 | 详情 | 详情 | |
| (XVI) | 14540 | tert-butyl N-[(1S)-1-benzyl-2-oxoethyl]carbamate | C14H19NO3 | 详情 | 详情 | |
| (XVII) | 23453 | (1R,2S)-2-[(tert-butoxycarbonyl)amino]-1-cyano-3-phenylpropyl 4-(2-pyridinyl)benzoate | C27H27N3O4 | 详情 | 详情 | |
| (XVIII) | 23454 | tert-butyl 2-((E,2R,3S)-3-[(tert-butoxycarbonyl)amino]-4-phenyl-2-[[4-(2-pyridinyl)benzoyl]oxy]butylidene)-1-hydrazinecarboxylate | C32H38N4O6 | 详情 | 详情 | |
| (XIX) | 23455 | tert-butyl 2-((2S,3S)-3-[(tert-butoxycarbonyl)amino]-4-phenyl-2-[[4-(2-pyridinyl)benzoyl]oxy]butyl)-1-hydrazinecarboxylate | C32H40N4O6 | 详情 | 详情 | |
| (XX) | 23457 | tert-butyl 2-[(2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl]-2-[4-(2-pyridinyl)benzoyl]-1-hydrazinecarboxylate | C32H40N4O6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IXa)The 4-amidinobenzoic acid intermediate (VII) is prepared by esterification of 4-cyanobenzoic acid (VIII) with MeOH in the presence of H2SO4 at reflux to give methyl 4-cyanobenzoate (IXa), which is then subjected to Pinner reaction with EtOH in the presence of HCl to yield methyl 4-[ethoxy(imino)methyl]benzoate (X). Without isolation, imidate (X) reacts with dimethylamine hydrochloride in refluxing EtOH to provide methyl 4-[(dimethylamino)(imino)methyl]benzoate (XIa). The analogous ethyl ester (XIb) can be alternatively prepared by reaction of ethyl 4-cyanobenzoate (IXb) with Me2NLi (generated from Me2NH and HexLi) in THF. Finally, either methyl (XIa) or ethyl (XIb) esters are hydrolyzed with LiOH in H2O/THF, and then acidified with HCl .
| 【1】 Pandey, A., Leitao, E.P.T., Rato, J., Song, Z.J. (Millennium Pharmaceuticals, Inc.; Merck & Co., Inc.). Methods of synthesizing factor Xa inhibitors. EP 2513058, US 201131927, WO 201108419. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IXa) | 10169 | methyl 4-cyanobenzoate；4-Cyanobenzoic acid methyl ester | 1129-35-7 | C9H7NO2 | 详情 | 详情 |
| (IXb) | 68326 | ethyl 4-cyanobenzoate | C10H9NO2 | 详情 | 详情 | |
| (XIa) | 68328 | methyl 4-[(dimethylamino)(imino)methyl]benzoate;methyl 4-(N,N-dimethylcarbamimidoyl)benzoate | C11H14N2O2 | 详情 | 详情 | |
| (XIb) | 68329 | ethyl 4-(N,N-dimethylcarbamimidoyl)benzoate | C12H16N2O2 | 详情 | 详情 | |
| (VII) | 68325 | 4-(N,N-dimethylcarbamimidoyl)benzoic acid hydrochloride | C10H12N2O2.HCl | 详情 | 详情 | |
| (VIII) | 36897 | 4-cyanobenzoic acid；4-Carboxybenzonitrile;p-Carboxybenzonitrile | 619-65-8 | C8H5NO2 | 详情 | 详情 |
| (X) | 68327 | methyl 4-[ethoxy(imino)methyl]benzoate | C11H13NO3 | 详情 | 详情 |