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【结 构 式】 
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【分子编号】12372 【品名】2-Chloroacrylonitrile 【CA登记号】920-37-6 |
【 分 子 式 】C3H2ClN 【 分 子 量 】87.50832 【元素组成】C 41.18% H 2.3% Cl 40.51% N 16.01% |
合成路线1
该中间体在本合成路线中的序号：(II)The cyclization of catechol (I) with 2-chloroacrylonitrile (II) by means of K2CO3 in acetone gives 2-cyanobenzo-1,4-dioxane (III), which is hydrolyzed with ethanol and HCl to the corresponding iminoether (IV) Finally, this compound is cyclized with ethylenediamine (V) in cool ethanol.
| 【1】 Myers, P.L.; Chapleo, C.B.; 2-[2-(1,4-Benzodioxanyl)]-2-imidazoline hydrochloride. Tetrahedron Lett 1981, 22, 48, 4839-42. |
| 【2】 Chapleo, C.B.; Myers, P.L. (Reckitt & Colman Pharmaceuticals); Imidazoline deriv.. GB 2068376 . |
| 【3】 Hillier, K.; Idazoxan hydrochloride. Drugs Fut 1983, 8, 9, 778. |
| 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) | 11599 | o-Dihydroxybenzene; Catechol; Pyrocatechol | 120-80-9 | C6H6O2 | 详情 | 详情 |
| (II) | 12372 | 2-Chloroacrylonitrile | 920-37-6 | C3H2ClN | 详情 | 详情 |
| (III) | 36171 | 2,3-dihydro-1,4-benzodioxine-2-carbonitrile | C9H7NO2 | 详情 | 详情 | |
| (IV) | 36172 | ethyl 2,3-dihydro-1,4-benzodioxine-2-carboximidoate | C11H13NO3 | 详情 | 详情 | |
| (V) | 14754 | ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine | 107-15-3 | C2H8N2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)The cyclization of pyridine-3-carbaldehyde (II) with L-cysteine (I) in ethanol gives the thiazolidine derivative (III), which is treated with formic acid yielding the 3-formylthiazolidine derivative (IV). The cyclization of (IV) with 2-chloropropenenitrile (V) by means of acetic anhydride affords 3-(3-pyridil)-1H,3H-pyrrolo[1,2-c]thiazole-7-carbonitrile (VI), which is finally hydrolyzed to the target carboxamide by means of KOH in tert-butanol.
| 【1】 Fabre, J.-L.; Farge, D.; James, C.; Lavé, D. (Aventis SA); Novel 1H,3H-pyrrolo[1,2-c]thiazole derivs., their preparation and medicaments containing them. EP 0115979; US 4529728 . |
| 【2】 Lavé, D.; James, C.; Rajoharison, H.; Bost, P.E.; Cavero, I.; PYRROLO[1,2-c]THIAZOLE DERIVATIVES: POTENT PAF RECEPTOR ANTAGONISTS. Drugs Fut 1989, 14, 9, 891. |
| 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) | 14643 | L-cysteine; (R)-2-Amino-3-mercaptopropionic acid | 52-90-4 | C3H7NO2S | 详情 | 详情 |
| (II) | 12849 | Nicotinaldehyde; 3-Pyridinecarboxaldehyde | 500-22-1 | C6H5NO | 详情 | 详情 |
| (III) | 38634 | (4R)-2-(3-pyridinyl)-1,3-thiazolidine-4-carboxylic acid | C9H10N2O2S | 详情 | 详情 | |
| (IV) | 43711 | (4R)-3-formyl-2-(3-pyridinyl)-1,3-thiazolidine-4-carboxylic acid | C10H10N2O3S | 详情 | 详情 | |
| (V) | 12372 | 2-Chloroacrylonitrile | 920-37-6 | C3H2ClN | 详情 | 详情 |
| (VI) | 43712 | 3-(3-pyridinyl)-1H-pyrrolo[1,2-c][1,3]thiazole-7-carbonitrile | C12H9N3S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)Rufinamide has been obtained by several related ways: 1) Cyclization of 2,6-difluorobenzyl azide (I) with 2-propynoic acid (II) in hot toluene gives 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid (III), which is treated with refluxing SOCl2 to yield the corresponding acyl chloride (IV). Finally, this compound is treated with aqueous concentrated NH4OH. 2) Cyclization of 2,6-difluorobenyzl azide (I) with 2-chloroacrylonitrile (V) in hot water or n-heptane gives 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carbonitrile (VI), which is treated with NaOH in hot toluene/water. 3) Esterification of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid (III) with methanol/H2SO4 gives the corresponding methyl ester (VII), which is treated with NH3 in hot methanol.
| 【1】 Leeson, P.A.; Sorbera, L.A.; Rabasseda, X.; Castaner, J.; Rufinamide. Drugs Fut 2000, 25, 11, 1145. |
| 【2】 Meier, R. (Novartis AG); Fluorinated benzyltriazole derivs.. AU 8656319; EP 0199262; ES 8800176; ES 8802501; JP 1986243068 . |
| 【3】 Portmann, R. (Novartis AG); Process for preparing 1-substd. 4-cyano-1,2,3-triazoles. WO 9802423 . |
| 【4】 Burkhard, A.; Szelagiewicz, M.; Hofmeier, U.C.; Portmann, R.; Scherrer, W. (Novartis AG); Crystal modification of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide and its use as antiepileptic. WO 9856772; WO 9856773 . |
| 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) | 41769 | 2,6-difluorobenzyl azide; 2-(azidomethyl)-1,3-difluorobenzene | C7H5F2N3 | 详情 | 详情 | |
| (II) | 41770 | propiolic acid | 471-25-0 | C3H2O2 | 详情 | 详情 |
| (III) | 41771 | 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid | C10H7F2N3O2 | 详情 | 详情 | |
| (IV) | 41772 | 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carbonyl chloride | C10H6ClF2N3O | 详情 | 详情 | |
| (V) | 12372 | 2-Chloroacrylonitrile | 920-37-6 | C3H2ClN | 详情 | 详情 |
| (VI) | 41773 | 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carbonitrile | C10H6F2N4 | 详情 | 详情 | |
| (VII) | 41774 | methyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate | C11H9F2N3O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The synthesis of deuterated mosapride citrate has been reported: The cyclization of N-(4-fluorobenzyl)ethanolamine (I) with 2-chloroacrylonitrile (II) in ethyl ether gives 4-(4-fluorobenzyl)morpholine-2-carbonitrile (III), which is submitted to alcoholysis with ethanol and H2SO4, yielding the corresponding ethyl ester (IV). The reduction of (IV) with deuterated sodium borohydride (NaBD4) in THF affords the deuterated hydroxymethyl derivative (V), which is condensed with phthalimide (VI) by means of triphenylphosphine and dimethyl azodicarboxylate (AZDC) in THF to give the N-substituted phthalimide (VII). The cleavage of (VII) with hydrazine hydrate in refluxing ethanol yields the deuterated methylamine derivative (VIII), which is finally condensed with 4-amino-5-chloro-2-ethoxybenzoic acid (IX) by means of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDCD) in dichloromethane, and treated with citric acid in the usual way.
| 【1】 Kato, S.; Hirokawa, Y.; Synthesis of deuterated mosapride citrate. J Label Compd Radiopharm 1995, 36, 10, 927. |
| 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) | 12334 | 2-[(4-Fluorobenzyl)amino]-1-ethanol | C9H12FNO | 详情 | 详情 | |
| (II) | 12372 | 2-Chloroacrylonitrile | 920-37-6 | C3H2ClN | 详情 | 详情 |
| (III) | 12373 | 4-(4-Fluorobenzyl)-2-morpholinecarbonitrile | C12H13FN2O | 详情 | 详情 | |
| (IV) | 12374 | ethyl 4-(4-fluorobenzyl)-2-morpholinecarboxylate | C14H18FNO3 | 详情 | 详情 | |
| (V) | 12375 | [4-(4-Fluorobenzyl)-2-morpholinyl]methanol | C12H16FNO2 | 详情 | 详情 | |
| (VI) | 12376 | Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione | 85-41-6 | C8H5NO2 | 详情 | 详情 |
| (VII) | 12377 | 2-[[4-(4-Fluorobenzyl)-2-morpholinyl]methyl]-1H-isoindole-1,3(2H)-dione | C20H19FN2O3 | 详情 | 详情 | |
| (VIII) | 12378 | [4-(4-Fluorobenzyl)-2-morpholinyl]methylamine; [4-(4-Fluorobenzyl)-2-morpholinyl]methanamine | C12H17FN2O | 详情 | 详情 | |
| (IX) | 12333 | 4-Amino-5-chloro-2-ethoxybenzoic acid | C9H10ClNO3 | 详情 | 详情 |