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【结 构 式】 
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【分子编号】41770 【品名】propiolic acid 【CA登记号】471-25-0 |
【 分 子 式 】C3H2O2 【 分 子 量 】70.04768 【元素组成】C 51.44% H 2.88% O 45.68% |
合成路线1
该中间体在本合成路线中的序号：(II)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2
该中间体在本合成路线中的序号：(II)Diels-Alder reaction between (E,E)-1,4-diphenylbutadiene (I) and propiolic acid (II) in xylene in the presence of hydroxyquinone (A) yields cyclohexadiene carboxylic acid (III), which is then converted into its methyl ester derivative (IV) by treatment with MeOH in the presence of H2SO4. Condensation of methyl ester (IV) with N-trimethylsilylmethyl-N-butoxymethyl-benzylamine (V) in CH2Cl2 in the presence of TFA provides hexahydro isoindole derivative (VI), which is first treated with trifluoromethane sulfonic acid in CH2Cl2, followed by treatment with NaOH, to furnish benzo[f]isoindole derivative (VII). Debenzylation of (VII) by reaction with ammonium formate and Pd/C gives compound (VIII), which is then converted into derivative (X) by coupling with 2-(2-methoxyphenyl)acrylic acid (IX). The target product is finally obtained by hydrolysis of methyl ester (X) with NaOH in EtOH. Intermediate (IX) can be obtained as follows: Treatment of 2-methoxyphenylacetic acid (XI) with thionyl chloride in refluxing EtOH provides ethyl ester (XII), which then reacts with paraformaldehyde and tetrabutylammonium iodide (TBAI) and K2CO3 in refluxing toluene to afford acrylate (XIII). Finally, ethyl ester (XIII) is hydrolyzed by treatment with refluxing NaOH.
| 【1】 Truchon, A.; Sounigo, F.; Peyronel, J.-F.; Zucco, M.; Mailliet, P.; Commercon, A.; Lebrun, A. (Aventis Pharma SA); 4,9-Ethano-benzo(f)isoindole derivs. as farnesyl transferase inhibitors. WO 9703050 . |
| 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) | 13163 | p-Dihydrobenzene; Hydroquinone | 123-31-9 | C6H6O2 | 详情 | 详情 |
| (I) | 46199 | 1-[(1E,3E)-4-phenyl-1,3-butadienyl]benzene | C16H14 | 详情 | 详情 | |
| (II) | 41770 | propiolic acid | 471-25-0 | C3H2O2 | 详情 | 详情 |
| (III) | 46200 | 3,6-diphenyl-1,4-cyclohexadiene-1-carboxylic acid | C19H16O2 | 详情 | 详情 | |
| (IV) | 46201 | methyl 3,6-diphenyl-1,4-cyclohexadiene-1-carboxylate | C20H18O2 | 详情 | 详情 | |
| (V) | 19702 | N-benzyl-N-(butoxymethyl)-N-[(trimethylsilyl)methyl]amine; N-(butoxymethyl)(phenyl)-N-[(trimethylsilyl)methyl]methanamine | C16H29NOSi | 详情 | 详情 | |
| (VI) | 46202 | methyl (7aS)-2-benzyl-4,7-diphenyloctahydro-3aH-isoindole-3a-carboxylate | C29H31NO2 | 详情 | 详情 | |
| (VII) | 46203 | methyl (1R,8R,9S,13S)-11-benzyl-1-phenyl-11-azatetracyclo[6.5.2.0(2,7).0(9,13)]pentadeca-2,4,6-triene-9-carboxylate | C29H29NO2 | 详情 | 详情 | |
| (VIII) | 46204 | methyl (1R,8R,9S,13S)-1-phenyl-11-azatetracyclo[6.5.2.0(2,7).0(9,13)]pentadeca-2,4,6-triene-9-carboxylate | C22H23NO2 | 详情 | 详情 | |
| (IX) | 37790 | 2-(2-methoxyphenyl)acrylic acid | C10H10O3 | 详情 | 详情 | |
| (X) | 46205 | methyl (1R,8R,9S,13S)-11-[2-(2-methoxyphenyl)acryloyl]-1-phenyl-11-azatetracyclo[6.5.2.0(2,7).0(9,13)]pentadeca-2,4,6-triene-9-carboxylate | C32H31NO4 | 详情 | 详情 | |
| (XI) | 19706 | 2-(2-methoxyphenyl)acetic acid | 93-25-4 | C9H10O3 | 详情 | 详情 |
| (XII) | 46206 | ethyl 2-(2-methoxyphenyl)acetate | C11H14O3 | 详情 | 详情 | |
| (XIII) | 46207 | ethyl 2-(2-methoxyphenyl)acrylate | C12H14O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)Reaction of 3,4-bis(trifluoromethyl)benzonitrile (I) with NaSH by means of MgCl2 in DMF gives 3,5-bis(trifluoromethyl)benzothioamide (II), which by cyclization with hydrazine hydrate (III) and HCOOH in DMF provides 3-[3,5-bis(trifluoromethyl)phenyl]-1,2,4-triazole (IV). Esterification of propiolic acid (V) with i-PrOH in the presence of BF3·Et2O at 90 °C affords isopropyl propiolate (VI), which is iodinated with NaI in AcOH at 110 °C to obtain isopropyl (Z)-3-iodoacrylate (VII). Condensation of triazole derivative (IV) with isopropyl (Z)-3-iodoacrylate (VII) in the presence of DABCO in DMF yields intermediate (VIII), which is subjected to ester hydrolysis with LiOH in H2O/THF to provide the corresponding carboxylic acid (IX). Finally, acid (IX) is coupled with 2-hydrazinopyrazine (X) in the presence of T3P and DIEA in CH2Cl2/EtOAc .
| 【1】 McCauley, D., Shacham, S., Sandanayaka, V.P., Shechter, S. (Karyopharma Therapeutics, Inc.). Hydrazide containing nuclear transporter modulators and uses thereof. EP 2736887, JP 2014521652, KR 2014066179, US 2014235653, WO 2013019548. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 66713 | 2-Hydrazinopyrazine | 54608-52-5 | C4H6N4 | 详情 | 详情 |
| (I) | 67851 | 3,5-bis(trifluoromethyl)benzonitrile | 27126-93-8 | C9H3F6N | 详情 | 详情 |
| (II) | 67852 | 3,5-bis(trifluoromethyl)benzothioamide | 317319-15-6 | C9H5F6NS | 详情 | 详情 |
| (III) | 67853 | hydrazine hydrate | 7803-57-8 | H4N2.H2O | 详情 | 详情 |
| (IV) | 67854 | 3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazole | C10H5F6N3 | 详情 | 详情 | |
| (V) | 41770 | propiolic acid | 471-25-0 | C3H2O2 | 详情 | 详情 |
| (VI) | 67855 | isopropyl propiolate | C6H8O2 | 详情 | 详情 | |
| (VII) | 67857 | isopropyl (Z)-3-iodoacrylate | C6H9IO2 | 详情 | 详情 | |
| (VIII) | 67856 | (Z)-isopropyl 3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylate | C16H13F6N3O2 | 详情 | 详情 | |
| (IX) | 67858 | (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid | C13H7F6N3O2 | 详情 | 详情 |