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【结 构 式】 
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【分子编号】36897 【品名】4-cyanobenzoic acid；4-Carboxybenzonitrile;p-Carboxybenzonitrile 【CA登记号】619-65-8 |
【 分 子 式 】C8H5NO2 【 分 子 量 】147.13324 【元素组成】C 65.31% H 3.43% N 9.52% O 21.75% |
合成路线1
该中间体在本合成路线中的序号：(III)In an alternative procedure, amine (II) was condensed with 4-cyanobenzoic acid (III) to give amide (IV). Subsequent addition of hydroxylamine to the cyano group of (IV) afforded N-hydroxy amidine (V), which was acetylated with Ac2O to produce (VI). This compound was finally reduced to the target amidine by hydrogenation over Lindlar catalyst.
| 【1】 Dodey, P.; Bondoux, M.; Ou, K.; Barth, M.; Houziaux, P. (Fournier Industrie et Santé); Novel N-benzenesulphonyl-L-proline derivs., method for preparing and therapeutic use. EP 0944618; US 6063791; WO 9824783 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 37922 | (2S)-N-(3-aminopropyl)-1-[(2,4-dichloro-3-[[(2,4-dimethyl-8-quinolinyl)oxy]methyl]phenyl)sulfonyl]-2-pyrrolidinecarboxamide | C26H30Cl2N4O4S | 详情 | 详情 | |
| (III) | 36897 | 4-cyanobenzoic acid；4-Carboxybenzonitrile;p-Carboxybenzonitrile | 619-65-8 | C8H5NO2 | 详情 | 详情 |
| (IV) | 37923 | (2S)-N-[3-[(4-cyanobenzoyl)amino]propyl]-1-[(2,4-dichloro-3-[[(2,4-dimethyl-8-quinolinyl)oxy]methyl]phenyl)sulfonyl]-2-pyrrolidinecarboxamide | C34H33Cl2N5O5S | 详情 | 详情 | |
| (V) | 37924 | (2S)-N-[3-([4-[amino(hydroxyimino)methyl]benzoyl]amino)propyl]-1-[(2,4-dichloro-3-[[(2,4-dimethyl-8-quinolinyl)oxy]methyl]phenyl)sulfonyl]-2-pyrrolidinecarboxamide | C34H36Cl2N6O6S | 详情 | 详情 | |
| (VI) | 37925 | (2S)-N-[3-([4-[[(acetoxy)imino](amino)methyl]benzoyl]amino)propyl]-1-[(2,4-dichloro-3-[[(2,4-dimethyl-8-quinolinyl)oxy]methyl]phenyl)sulfonyl]-2-pyrrolidinecarboxamide | C36H38Cl2N6O7S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：Claisen condensation of ethyl formate with N-trityl-4-piperidone (I) in the presence of NaOEt afforded the intermediate dicarbonyl enolate (II), which was subsequently condensed with ethyl hydrazinoacetate (III) to furnish the desired pyrazolopyridine (IV) accompanied by minor amounts of its regioisomer (V). After acid cleavage of the trityl protecting group of (IV), the desired isomer (VI) was isolated by recrystallization from isopropanol. Coupling of (VI) with N-Boc-L-4-nitrophenylalanine (VII) employing BOP yielded amide (VIII). Subsequent Boc group cleavage in (VIII) with trifluoroacetic acid provided amine (IX), which was coupled with 4-cyanobenzoic acid (X) using 6-chloro-2,4-dimethoxy-1,3,5-triazine (CDMT) to yield (XI). Finally, addition of hydroxylamine to the cyano group of (XI) gave the title N-hydroxyamidine.
| 【1】 Baba, K.; Tanaka, M.; Kuroki, Y.; Takata, K.; Motoyama, T.; Ueno, H. (Ube Industries, Ltd.); N-Acylamino acid amide cpds. and intermediates for preparation thereof. EP 1020467; US 6265418; WO 9906402 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 36897 | 4-cyanobenzoic acid；4-Carboxybenzonitrile;p-Carboxybenzonitrile | 619-65-8 | C8H5NO2 | 详情 | 详情 | |
| 49757 | ethyl 2-[5-[(2S)-2-amino-3-(4-nitrophenyl)propanoyl]-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl]acetate | C19H23N5O5 | 详情 | 详情 | ||
| 49758 | ethyl 2-[5-[(2S)-2-[(4-cyanobenzoyl)amino]-3-(4-nitrophenyl)propanoyl]-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl]acetate | C27H26N6O6 | 详情 | 详情 | ||
| (I) | 28590 | 2-[([[(isopropylamino)carbothioyl]disulfanyl]carbothioyl)amino]propane | C8H16N2S4 | 详情 | 详情 | |
| (II) | 49751 | sodium (4-oxo-1-trityl-3-piperidinylidene)methanolate | C25H22NNaO2 | 详情 | 详情 | |
| (III) | 49752 | ethyl 2-hydrazinoacetate | C4H10N2O2 | 详情 | 详情 | |
| (IV) | 49753 | ethyl 2-(5-trityl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)acetate | C29H29N3O2 | 详情 | 详情 | |
| (V) | 49754 | ethyl 2-(5-trityl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)acetate | C29H29N3O2 | 详情 | 详情 | |
| (VI) | 49755 | ethyl 2-(4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)acetate | C10H15N3O2 | 详情 | 详情 | |
| (VII) | 28516 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-nitrophenyl)propionic acid | C14H18N2O6 | 详情 | 详情 | |
| (VIII) | 49756 | ethyl 2-[5-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-nitrophenyl)propanoyl]-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl]acetate | C24H31N5O7 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)Tetralone (I) was reduced with NaBH4 and the resulting alcohol (II) was dehydrated with p-TsOH in refluxing toluene to yield the dihydronaphthalene (III). Oxidation of (III) with N-methylmorpholine N-oxide and OsO4 produced diol (IV), which was converted to the 2-tetralone (V) by acid-catalyzed rearrangement. The unstable tetralone (V) was condensed with the sodium salt of tert-butyl diethyl phosphonoacetate (VI) providing a mixture of olefin isomers (VII). Catalytic hydrogenation of the olefin (VIIa-c) with simultaneous removal of the carbobenzoxy group furnished the aminotetralin (VIII). This was coupled with 4-cyanobenzoic acid (IX) using EDC to give amide (X). Addition of H2S to the nitrile group of (X), followed by S-methylation provided (XI). Then, displacement of the methylthio group of (XI) by ammonium acetate and further treatment with di-tert-butyl dicarbonate yielded the Boc-protected benzamidine (XII). Deprotection with trifluoroacetic acid produced the amidino acid (XIII), which was finally esterified with EtOH and HCl.
| 【1】 Fisher, M.J.; Arfstan, A.E.; Giese, U.; et al.; Fused bicyclic Gly-Asp beta-turn mimics with specific affinity for GPIIb-IIIa. J Med Chem 1999, 42, 23, 4875. |
| 【2】 Fisher, M.J.; Happ, A.M.; Jakubowski, J.A.; Kinnick, M.D.; Kline, A.D.; Morin, J.M. Jr.; Sall, D.J.; Skelton, M.A.; Vasileff, R.T. (Eli Lilly and Company); Glycoprotein IIb/IIIa antagonists. CA 2128348; EP 0635492; JP 1996188564; US 5618843 . |
| 【3】 Fisher, M.J.; Jakubowski, J.A.; Martinelli, M.J.; Morin, J.M. Jr.; Paal, M.; Ruhter, G.; Ruterbories, K.J.; Schotten, T.; Stenzel, W.; Vasileff, R.T. (Eli Lilly and Company); Glycoprotein IIb/IIIa antagonists. EP 0804431; JP 1999502194; WO 9622288 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIa) | 36985 | tert-butyl 2-(6-[[(benzyloxy)carbonyl]amino]-1,2,3,4-tetrahydro-2-naphthalenyl)acetate | C24H29NO4 | 详情 | 详情 | |
| (VIIb) | 36986 | (E)-tert-butyl 2-[6-[[(benzyloxy)carbonyl]amino]-3,4-dihydro-2(1H)-naphthalenylidene]acetate | C24H27NO4 | 详情 | 详情 | |
| (VIIc) | 36987 | (Z)-tert-butyl 2-[6-[[(benzyloxy)carbonyl]amino]-3,4-dihydro-2(1H)-naphthalenylidene]acetate | C24H27NO4 | 详情 | 详情 | |
| (I) | 36980 | benzyl 5-oxo-5,6,7,8-tetrahydro-2-naphthalenylcarbamate | C18H17NO3 | 详情 | 详情 | |
| (II) | 36981 | benzyl 5-hydroxy-5,6,7,8-tetrahydro-2-naphthalenylcarbamate | C18H19NO3 | 详情 | 详情 | |
| (III) | 36982 | benzyl 7,8-dihydro-2-naphthalenylcarbamate | C18H17NO2 | 详情 | 详情 | |
| (IV) | 36983 | benzyl 5,6-dihydroxy-5,6,7,8-tetrahydro-2-naphthalenylcarbamate | C18H19NO4 | 详情 | 详情 | |
| (V) | 36984 | benzyl 6-oxo-5,6,7,8-tetrahydro-2-naphthalenylcarbamate | C18H17NO3 | 详情 | 详情 | |
| (VI) | 25637 | tert-butyl 2-(diethoxyphosphoryl)acetate | 6273-47-8 | C10H21O5P | 详情 | 详情 |
| (VIII) | 36988 | tert-butyl 2-(6-amino-1,2,3,4-tetrahydro-2-naphthalenyl)acetate | C16H23NO2 | 详情 | 详情 | |
| (IX) | 36897 | 4-cyanobenzoic acid；4-Carboxybenzonitrile;p-Carboxybenzonitrile | 619-65-8 | C8H5NO2 | 详情 | 详情 |
| (X) | 36989 | tert-butyl 2-[6-[(4-cyanobenzoyl)amino]-1,2,3,4-tetrahydro-2-naphthalenyl]acetate | C24H26N2O3 | 详情 | 详情 | |
| (XI) | 36990 | tert-butyl 2-[6-([4-[imino(methylsulfanyl)methyl]benzoyl]amino)-1,2,3,4-tetrahydro-2-naphthalenyl]acetate | C25H30N2O3S | 详情 | 详情 | |
| (XII) | 36991 | tert-butyl 2-[6-([4-[[(tert-butoxycarbonyl)amino](imino)methyl]benzoyl]amino)-1,2,3,4-tetrahydro-2-naphthalenyl]acetate | C29H37N3O5 | 详情 | 详情 | |
| (XIII) | 36992 | 2-[6-([4-[amino(imino)methyl]benzoyl]amino)-1,2,3,4-tetrahydro-2-naphthalenyl]acetic acid | C20H21N3O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VII)Hydrogenation of 6-nitrocoumarin (I) in the presence of Pd/C and di-tert-butyl dicarbonate provided (II). Partial reduction of the lactone function of (II) with DIBAL at low temperature gave rise to lactol (III), which was submitted to a Wittig condensation with (ethoxycarbonyl)triphenylphosphorane (IV) yielding chromaneacetic acid ethyl ester (V). The Boc protecting group of (V) was then removed with trifluoroacetic acid to afford aniline (VI), which was acylated with 4-cyanobenzoic acid (VII) in the presence of EDC to give amide (VIII). Addition of H2S to the nitrile group of (VIII), followed by S-methylation provided (IX). Then, displacement of the methylthio group of (IX) by ammonium acetate and further treatment with di-tert-butyl dicarbonate yielded the Boc-protected benzamidine (X). Finally, Boc-deprotection with trifluoroacetic acid furnished the title amidino ester.
| 【1】 Fisher, M.J.; Arfstan, A.E.; Giese, U.; et al.; Fused bicyclic Gly-Asp beta-turn mimics with specific affinity for GPIIb-IIIa. J Med Chem 1999, 42, 23, 4875. |
| 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) | 36892 | 6-nitro-2H-chromen-2-one | 2725-81-7 | C9H5NO4 | 详情 | 详情 |
| (II) | 36893 | tert-butyl 2-oxo-3,4-dihydro-2H-chromen-6-ylcarbamate | C14H17NO4 | 详情 | 详情 | |
| (III) | 36894 | tert-butyl 2-hydroxy-3,4-dihydro-2H-chromen-6-ylcarbamate | C14H19NO4 | 详情 | 详情 | |
| (IV) | 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 |
| (V) | 36895 | ethyl 2-[6-[(tert-butoxycarbonyl)amino]-3,4-dihydro-2H-chromen-2-yl]acetate | C18H25NO5 | 详情 | 详情 | |
| (VI) | 36896 | ethyl 2-(6-amino-3,4-dihydro-2H-chromen-2-yl)acetate | C13H17NO3 | 详情 | 详情 | |
| (VII) | 36897 | 4-cyanobenzoic acid；4-Carboxybenzonitrile;p-Carboxybenzonitrile | 619-65-8 | C8H5NO2 | 详情 | 详情 |
| (VIII) | 36898 | ethyl 2-[6-[(4-cyanobenzoyl)amino]-3,4-dihydro-2H-chromen-2-yl]acetate | C21H20N2O4 | 详情 | 详情 | |
| (IX) | 36899 | ethyl 2-[6-([4-[imino(methylsulfanyl)methyl]benzoyl]amino)-3,4-dihydro-2H-chromen-2-yl]acetate | C22H24N2O4S | 详情 | 详情 | |
| (X) | 36900 | ethyl 2-[6-([4-[[(tert-butoxycarbonyl)amino](imino)methyl]benzoyl]amino)-3,4-dihydro-2H-chromen-2-yl]acetate | C26H31N3O6 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)Amine (III) was synthesized from 2,2-dimethylcyclopentanone (I) by treatment with tosylmethyl isocyanide, followed by reduction of the resultant nitrile (II) with LiAlH4. Condensation of 4-cyanobenzoic acid (IV) with amine (III) produced the corresponding amide (V). Subsequent addition of hydroxylamine to the cyano group of (V) gave rise to the hydroxyamidine (VI). The target oxadiazole derivative was then obtained by condensation of (VI) with 4,4,4-trifluorobutyric acid (VII), followed by cyclization under basic conditions. Separation of the enantiomers was carried out by chiral preparative HPLC.
| 【1】 LLoyd, J.; et al.; Design and synthesis of 4-substituted benzamides as potent, selective, and orally bioavailable IKS blockers. J Med Chem 2001, 44, 23, 3764. |
| 【2】 Poss, M.A.; Lloyd, J.; Rovnyak, G.C.; Caulfield, T.J.; Atwal, K.S.; Stein, P.D.; Ahmad, S. (Bristol-Myers Squibb Co.); Benzoic acid derivs. and related cpds. as antiarrhythmic agents. WO 9837068 . |
| 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) | 43358 | 2,2-dimethylcyclopentanone | C7H12O | 详情 | 详情 | |
| (II) | 43359 | 2,2-dimethylcyclopentanecarbonitrile | C8H13N | 详情 | 详情 | |
| (III) | 43360 | (2,2-dimethylcyclopentyl)methylamine; (2,2-dimethylcyclopentyl)methanamine | C8H17N | 详情 | 详情 | |
| (IV) | 36897 | 4-cyanobenzoic acid；4-Carboxybenzonitrile;p-Carboxybenzonitrile | 619-65-8 | C8H5NO2 | 详情 | 详情 |
| (V) | 52509 | 4-cyano-N-[(2,2-dimethylcyclopentyl)methyl]benzamide | C16H20N2O | 详情 | 详情 | |
| (VI) | 52510 | 4-[amino(hydroxyimino)methyl]-N-[(2,2-dimethylcyclopentyl)methyl]benzamide | C16H23N3O2 | 详情 | 详情 | |
| (VII) | 14781 | 4,4,4-Trifluorobutyric acid | 406-93-9 | C4H5F3O2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VIII)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 |