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【结 构 式】 
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【分子编号】43394 【品名】2-iodothiophene 【CA登记号】3437-95-4 |
【 分 子 式 】C4H3IS 【 分 子 量 】210.03829 【元素组成】C 22.87% H 1.44% I 60.42% S 15.27% |
合成路线1
该中间体在本合成路线中的序号：(I)The copper-promoted coupling between 2-iodothiophene (I) and ethyl bromodifluoroacetate (II) produced ethyl 2,2-difluoro-2-(2-thienyl)acetate (III). Addition of the organolithium reagent derived from 2,4-difluorobromobenzene (IV) to ester (III) yielded ketone (V). This was converted into the oxirane (VI) by reaction with dimethyloxosulfonium methylide in DMSO. Finally, oxirane ring opening with 1,2,4-triazole (VII) provided the title compound.
| 【1】 Sakamoto, T.; Eto, H.; Kaneko, Y.; New antifungal 1,2,4-triazoles with difluro(heteroaryl)methyl moiety. Chem Pharm Bull 2000, 48, 7, 982. |
| 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) | 43394 | 2-iodothiophene | 3437-95-4 | C4H3IS | 详情 | 详情 |
| (II) | 43395 | ethyl 2,2-difluoro-2-(2-thienyl)acetate | C8H8F2O2S | 详情 | 详情 | |
| (III) | 43396 | 1-(2,4-difluorophenyl)-2,2-difluoro-2-(2-thienyl)-1-ethanone | C12H6F4OS | 详情 | 详情 | |
| (IV) | 15488 | 1-bromo-2,4-difluorobenzene | 348-57-2 | C6H3BrF2 | 详情 | 详情 |
| (V) | 43397 | 2-(2,4-difluorophenyl)-2-[difluoro(2-thienyl)methyl]oxirane | C13H8F4OS | 详情 | 详情 | |
| (VI) | 43398 | 2-(2,4-difluorophenyl)-1,1-difluoro-1-(2-thienyl)-3-(1H-1,2,4-triazol-1-yl)-2-propanol | C15H11F4N3OS | 详情 | 详情 | |
| (VII) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXI)In one method, metalation of 1-bromo-4-fluorobenzene (XI) with Mg in 2-MeTHF at 90 °C gives 4-fluorophenyl magnesium bromide (XII), which then couples with 2-bromothiophene (XIII) in the presence of NiCl2·dppe and AcOH in 2-MeTHF at 22 °C or in the presence of Pd(OAc)2 and DPPP in THF to yield 2-(4-fluorophenyl)thiophene (XIV). Finally, this compound undergoes Friedel–Crafts acylation with 5-iodo-2-methylbenzoic acid (XV) (initially chlorinated with SOCl2 in CH2Cl2) using AlCl3 in CH2Cl2, and subsequent reduction with (Me2SiH)2O in refluxing acetonitrile .
In another method, hydrolysis of methyl 5-bromo-2-methylbenzoate (XVI) with NaOH in MeOH at 50 °C gives rise to the benzoic acid (XVII) , which is then chlorinated with (COCl)2 in the presence of DMF in CH2Cl2 to yield 5-bromo-2-methylbenzoyl chloride (XVIII). Friedel–Crafts reaction of acyl chloride (XVIII) with 2-(4-fluorophenyl) thiophene (XIV) in the presence of AlCl3 in CH2Cl2 affords ketone (XIX), which is then reduced by means of Et3SiH and BF3·Et2O in CH2Cl2/acetonitrile to afford 2-(5-bromo-2-methylbenzoyl)-5-(4-fluorophenyl)thiophene (III) . Finally, compound (III) is iodinated with NaI and CuI in the presence of (MeNHCH2)2 in refluxing toluene/diglyme (IV) .
Alternatively, coupling of 4-fluorophenylboronic acid (XX) with either 2-bromothiophene (XIII) in the presence of PdCl2(PPh3)2 and Na2CO3 in dimethoxyethane at 75-80 °C or with 2-iodothiophene (XXI) in the presence of PdCl2(PPh3)2 at 50 °C affords 2-(4-fluorophenyl) thiophene (XIV) .
| 【1】 Abdel-Magid, A.F., Chisholm, M., Mehrman, S. et al. (Janssen Pharmaceutica NV; Mitsubishi Tanabe Pharma Corp.). Process for the preparation of compounds useful as inhibitors of SGLT. CN 101801371, EP 2200606, JP 2010539092, WO 2009035969. |
| 【2】 Nomura, S., Ueta, K., Kawanishi, E. (Mitsubishi Tanabe Pharma Corp.). Novel compounds having inhibitory activity against sodium-dependant transporter. EP 1651658, JP 2007518683, JP 2008266328, WO 2005012326. |
| 【3】 Nomura, S., Sakamaki, S., Hongu, M. et al. Discovery of canagliflozin, a novel C-glucoside with thiophene ring, as sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus. J Med Chem 2010, 53(17): 6355-60. |
| 【4】 Filliers, W.F.M., Broeckx, R.L.M., Nieste, P.H.J., Hatsuda, M., Yoshinaga, M., Yada, M. (Janssen Pharmaceutica NV; Mitsubishi Tanabe Pharma Corp.). Process for the preparation of compounds useful as inhibitors of SGLT. US 2010099883, WO 2010043682. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 68782 | 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene | 1030825-20-7 | C18H14BrFS | 详情 | 详情 |
| (IV) | 68783 | 2-(4-fluorophenyl)-5-(5-iodo-2-methylbenzyl)thiophene | 898566-17-1 | C18H14FIS | 详情 | 详情 |
| (XI) | 29012 | 1-bromo-4-fluorobenzene | 460-00-4 | C6H4BrF | 详情 | 详情 |
| (XII) | 13643 | 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide | 352-13-6 | C6H4BrFMg | 详情 | 详情 |
| (XIII) | 13681 | 2-Bromothiophene | 1003-09-4 | C4H3BrS | 详情 | 详情 |
| (XIV) | 68790 | 2-(4-fluorophenyl)thiophene | 58861-49-7 | C10H7FS | 详情 | 详情 |
| (XV) | 68791 | 5-iodo-2-methylbenzoic acid;2-Methyl-5-iodobenzoicacid | 54811-38-0 | C8H7IO2 | 详情 | 详情 |
| (XVI) | 68792 | methyl 5-bromo-2-methylbenzoate;methyl 5-bromo-o-toluate | 79669-50-4 | C9H9BrO2 | 详情 | 详情 |
| (XVII) | 68793 | 5-bromo-2-methylbenzoic acid;2-Methyl-5-bromobenzoic acid | 79669-49-1 | C8H7BrO2 | 详情 | 详情 |
| (XVIII) | 68794 | 5-bromo-2-methylbenzoyl chloride | C8H6BrClO | 详情 | 详情 | |
| (XIX) | 68795 | (5-bromo-2-methylphenyl)(5-(4-fluorophenyl)thiophen-2-yl)methanone | C18H12BrFOS | 详情 | 详情 | |
| (XX) | 38403 | 4-fluorophenylboronic acid | 1765-93-1 | C6H6BFO2 | 详情 | 详情 |
| (XXI) | 43394 | 2-iodothiophene | 3437-95-4 | C4H3IS | 详情 | 详情 |