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【结 构 式】

【分子编号】15481

【品名】4-(2,2,3,3-tetrafluoropropoxy)benzaldehyde

【CA登记号】

【 分 子 式 】C10H8F4O2

【 分 子 量 】236.1659328

【元素组成】C 50.86% H 3.41% F 32.18% O 13.55%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(I)

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:(VI)

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

合成路线3

该中间体在本合成路线中的序号:(II)

4-Hydroxybenzaldehyde (I) was alkylated with 2,2,3,3-tetrafluoropropyl tosylate (A) to give ether (II). Subsequent Horner-Emmons condensation of (II) with triethyl phosphonocrotonate (III) provided dienoate (IV), that was further reduced to alcohol (V) by means of DIBAL. Oxidation of (V) with activated MnO2 then gave aldehyde (VI).

1 Tajima, Y.; Oida, S.; Konosu, T.; et al.; Synthesis and antifungal activities of R-102557 and related dioxane-triazole derivatives. Chem Pharm Bull 2000, 48, 5, 694.
2 Oida, S.; Tanaka, T.; Tajima, Y.; Konosu, T.; Somada, A.; Miyaoka, T.; Yasuda, H. (Sankyo Co., Ltd.); Triazole antifungal agent. EP 0841327; JP 1996333350; US 5977152; WO 9631491 .
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) 41331 2,2,3,3-tetrafluoropropyl 4-methylbenzenesulfonate C10H10F4O3S 详情 详情
(I) 13433 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde 123-08-0 C7H6O2 详情 详情
(II) 15481 4-(2,2,3,3-tetrafluoropropoxy)benzaldehyde C10H8F4O2 详情 详情
(III) 27705 methyl 4-amino-2-(1-naphthyl)benzoate C18H15NO2 详情 详情
(IV) 41332 ethyl (2E,4E)-5-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-pentadienoate C16H16F4O3 详情 详情
(V) 41333 (2E,4E)-5-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-pentadien-1-ol C14H14F4O2 详情 详情
(VI) 41334 (2E,4E)-5-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-pentadienal C14H12F4O2 详情 详情
Extended Information