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【结 构 式】 
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【分子编号】15484 【品名】(E)-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-propenoic acid 【CA登记号】 |
【 分 子 式 】C12H10F4O3 【 分 子 量 】278.2032128 【元素组成】C 51.81% H 3.62% F 27.32% O 17.25% |
合成路线1
该中间体在本合成路线中的序号：(II)The condensation of 4-(2,2,3,3-tetrafluoropropoxy)benzaldehyde (I) with refluxing acetic anhydride gives 3-[4-(2,2,3,3-tetrafluoropropoxy) phenyl]acrylic acid (II), which is treated with refluxing SOCl2 to yield the corresponding acid chloride (III). The reaction of (III) with thiosemicarbazide in toluene affords 3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]acryloylthiosemicarbazide (IV), which is cyclized by means of NaNO2 and HNO3 in water to give 3-[4-(2,2,3,3-tetrafluoropropoxy) styryl]-1,2,4-triazole (V). Finally, this compound is condensed with 2-(2,4-difluorophenyl)-3-(1,2,4-triazol-1-yl)-1,2-epoxypropane (VI) by means of NaH in hot DMF.
| 【1】 Bayles, F.T.; Boyle, F.T.; Gravestock, M.B.; Wardleworth, J.M. (AstraZeneca plc); Antifungal azole cpds.. EP 0174769; US 4925863 . |
| 【2】 Prous, J.; Castaner, J.; ICI-195739 . Drugs Fut 1988, 13, 5, 408. |
| 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) | 15481 | 4-(2,2,3,3-tetrafluoropropoxy)benzaldehyde | C10H8F4O2 | 详情 | 详情 | |
| (II) | 15484 | (E)-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-propenoic acid | C12H10F4O3 | 详情 | 详情 | |
| (III) | 22561 | (E)-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-propenoyl chloride | C12H9ClF4O2 | 详情 | 详情 | |
| (IV) | 22562 | 2-[(E)-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-propenoyl]-1-hydrazinecarbothioamide | C13H13F4N3O2S | 详情 | 详情 | |
| (V) | 15476 | 2,2,3,3-tetrafluoropropyl 4-[(E)-2-(1H-1,2,4-triazol-3-yl)ethenyl]phenyl ether; 3-[(E)-2-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]ethenyl]-1H-1,2,4-triazole | C13H11F4N3O | 详情 | 详情 | |
| (VI) | 15477 | 1-[[(2R)-2-(2,4-difluorophenyl)oxiranyl]methyl]-1H-1,2,4-triazole | C11H9F2N3O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)By condensation of 3-[2(E)-(4-(2,2,3,3-tetrafluoropropoxy)phenyl)vinyl]-1H-1,2,4-triazole (I) with (+)-(R)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1,2-epoxypropane (II) by means of anhydrous K2CO3 in hot DMF. The starting products (I) and (II) are obtained as follows: a) The condensation of 4-chlorobenzonitrile (III) with 2,2,3,3-tetrafluoropanol (IV) by means of NaH in DMF gives 4-(2,2,3,3-tetrafluoropropoxy)benzonitrile (V), which is reduced to the corresponding benzaldehyde (VI) with diisobutylaluminum hydride in toluene. The condensation of diethoxyphosphorylacetic acid ethyl ester (VII) with aldehyde (VI) by means of KOH in THF yields (E)-4-(2,2,3,3-tetrafluoropropoxy)cinnamic acid ethyl ester (VIII), which is saponified to the corresponding acid (IX) with NaOH in ethanol-water. The reaction of (IX) first with refluxing SOCl2 and then with aqueous ammonia in toluene affords the corresponding amide (X), which is finally condensed with formyl hydrazide (XI) by means of trimethyloxonium tetrafluoroborate in CH2Cl2 to give (I). b) The reaction of 1,3-dichloroacetone (XII) with 2,4-difluorobromobenzene (XIII) by means of butyllithium in ether gives 1,3-dichloro-2-(2,4-difluorophenyl)-2-propanol (XIV), which is converted into 3-chloro-2-(2,4-difluorophenyl)-1,2-epoxypropane (XV) by treatment with NaH in DMF. The reaction of (XV) with tellurium and sodium hydroxymethylsulfinate in water yields 2-(2,4-difluorophenyl)allyl alcohol (XVI), which by stereoselective epoxidation with titanium tetraisopropoxide and diethyl (+)-tartrate in methylene chloride is converted into (R)-(-)-2-(2,4-difluorophenyl)-2,3-epoxypropanol (XVII). The reaction of (XVII) with 1,2,4-triazole (XVIII) by means of K2CO3 in THF affords (S)-(-)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazole-1-yl)-propane-1,2-diol (XIX), which is finally treated with methanesulfonyl chloride and triethylamine in ether to give (II).
| 【1】 Murakami, K.; Mochizuki, H. (AstraZeneca plc; Mochida Pharmaceutical Co., Ltd.); Optically active triazole derivs. and compsns. EP 0472392; JP 1993009183 . |
| 【2】 Fromtling, R.A.; Castaner, J.; ICI-D0870. Drugs Fut 1993, 18, 5, 424. |
| 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) | 15476 | 2,2,3,3-tetrafluoropropyl 4-[(E)-2-(1H-1,2,4-triazol-3-yl)ethenyl]phenyl ether; 3-[(E)-2-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]ethenyl]-1H-1,2,4-triazole | C13H11F4N3O | 详情 | 详情 | |
| (II) | 15477 | 1-[[(2R)-2-(2,4-difluorophenyl)oxiranyl]methyl]-1H-1,2,4-triazole | C11H9F2N3O | 详情 | 详情 | |
| (III) | 15478 | 4-methylcyclohexanecarbonitrile | C8H13N | 详情 | 详情 | |
| (IV) | 15479 | 2,2,3,3-tetrafluoro-1-propanol | 76-37-9 | C3H4F4O | 详情 | 详情 |
| (V) | 15480 | 4-(2,2,3,3-tetrafluoropropoxy)benzonitrile | C10H7F4NO | 详情 | 详情 | |
| (VI) | 15481 | 4-(2,2,3,3-tetrafluoropropoxy)benzaldehyde | C10H8F4O2 | 详情 | 详情 | |
| (VII) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (VIII) | 15483 | ethyl (E)-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-propenoate | C14H14F4O3 | 详情 | 详情 | |
| (IX) | 15484 | (E)-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-propenoic acid | C12H10F4O3 | 详情 | 详情 | |
| (X) | 15485 | (E)-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-propenamide | C12H11F4NO2 | 详情 | 详情 | |
| (XI) | 15486 | formic hydrazide; Formylhydrazine | 624-84-0 | CH4N2O | 详情 | 详情 |
| (XII) | 63907 | 1,3-dichloroacetone | C3H4Cl2O | 详情 | 详情 | |
| (XIII) | 15488 | 1-bromo-2,4-difluorobenzene | 348-57-2 | C6H3BrF2 | 详情 | 详情 |
| (XIV) | 15489 | 1,3-dichloro-2-(2,4-difluorophenyl)-2-propanol | C9H8Cl2F2O | 详情 | 详情 | |
| (XV) | 15490 | 2-(chloromethyl)-2-(2,4-difluorophenyl)oxirane | C9H7ClF2O | 详情 | 详情 | |
| (XVI) | 15491 | 2-(2,4-difluorophenyl)-2-propen-1-ol | C9H8F2O | 详情 | 详情 | |
| (XVII) | 64587 | [(2R)-2-(2,4-difluorophenyl)oxiranyl]methanol | C9H8F2O2 | 详情 | 详情 | |
| (XVIII) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
| (XIX) | 15494 | (2S)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1,2-propanediol | C11H11F2N3O2 | 详情 | 详情 |