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【结 构 式】 
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【分子编号】16149 【品名】2-Chloroethyl methyl sulfide; 1-Chloro-2-(methylsulfanyl)ethane 【CA登记号】542-81-4 |
【 分 子 式 】C3H7ClS 【 分 子 量 】110.60728 【元素组成】C 32.58% H 6.38% Cl 32.05% S 28.99% |
合成路线1
该中间体在本合成路线中的序号：(III)Treatment of 4-(trifluoromethoxy)aniline (I) with thiocyanogen, generated from KSCN and Br2 in cold AcOH, afforded riluzole (II). Regioselective alkylation of (II) with 2-(methylthio)ethyl chloride (III) in refluxing methyl ethyl ketone then gave the title compound.
| 【1】 Barreau, M.; Audiau, F.; Jimonet, P.; et al.; Riluzole series. Synthesis and in vivo "antiglutamate" activity of 6-substituted-2-benzothiazolamines and 3-substituted-2-imino-benzothiazolines. J Med Chem 1999, 42, 15, 2828. |
| 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) | 11131 | 4-(Trifluoromethoxy)aniline; 4-(Trifluoromethoxy)phenylamine | 461-82-5 | C7H6F3NO | 详情 | 详情 |
| (II) | 34884 | 6-(trifluoromethoxy)-1,3-benzothiazol-2-ylamine; 6-(trifluoromethoxy)-1,3-benzothiazol-2-amine | 1744-22-5 | C8H5F3N2OS | 详情 | 详情 |
| (III) | 16149 | 2-Chloroethyl methyl sulfide; 1-Chloro-2-(methylsulfanyl)ethane | 542-81-4 | C3H7ClS | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)Treatment of 4-(trifluoromethoxy)aniline (I) with thiocyanogen, generated from KSCN and Br2 in cold AcOH, afforded riluzole (II). Regioselective alkylation of (II) with 2-(methylthio)ethyl chloride (III) in refluxing methyl ethyl ketone then gave compound (IV), which was finally oxidized to the title sulfoxide by means of m-chloroperbenzoic acid.
| 【1】 Barreau, M.; Audiau, F.; Jimonet, P.; et al.; Riluzole series. Synthesis and in vivo "antiglutamate" activity of 6-substituted-2-benzothiazolamines and 3-substituted-2-imino-benzothiazolines. J Med Chem 1999, 42, 15, 2828. |
| 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) | 11131 | 4-(Trifluoromethoxy)aniline; 4-(Trifluoromethoxy)phenylamine | 461-82-5 | C7H6F3NO | 详情 | 详情 |
| (II) | 34884 | 6-(trifluoromethoxy)-1,3-benzothiazol-2-ylamine; 6-(trifluoromethoxy)-1,3-benzothiazol-2-amine | 1744-22-5 | C8H5F3N2OS | 详情 | 详情 |
| (III) | 16149 | 2-Chloroethyl methyl sulfide; 1-Chloro-2-(methylsulfanyl)ethane | 542-81-4 | C3H7ClS | 详情 | 详情 |
| (IV) | 34885 | 3-[2-(methylsulfanyl)ethyl]-6-(trifluoromethoxy)-1,3-benzothiazol-2(3H)-imine | C11H11F3N2OS2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The alkylation of 2-phenylacetic acid (I) with 2-chloroethyl(methyl)sulfide (II) by means of lithium diisopropylamide (LDA) in THF gives 4-(methylsulfanyl)-2-phenylbutyric acid (III), which is esterified with methanol/H2SO4 yielding the methyl ester (IV). The transesterification of (IV) with quinuclidin-3(R)-ol (V) by means of NaH in refluxing toluene affords the 3(R)-quinuclidinyl ester (VI), which is hydroxymethylated with paraformaldehyde and NaH in DMF giving 2(RS)-(hydroxymethyl)-4-(methylsulfanyl)-2-phenylbutyric acid 3(R)-quinuclidinyl ester (VII) as a diastereomeric mixture. Chromatographic separation of (VII) over SiO2 using CHCl3/methanol/NH4OH as a gradient elution yields the 2(S)-hydroxymethyl isomer (VIII), which is oxidized with trifluoroperacetic acid in trifluoroacetic acid affording the corresponding sulfinyl derivative (IX) as a new diastereomeric mixture. Finally, this mixture is resolved by HPLC over Kromasil C-8 SiO2 using as eluant water/acetonitrile containing 1% trifluoroacetic acid.
| 【1】 Martel, A.M.; Rabasseda, X.; Castaner, J.; Revatropate. Drugs Fut 1997, 22, 2, 135. |
| 【2】 Cross, P.E.; Stobie, A. (Pfizer Inc.); Quinuclidine esters process and intermediate for their preparation and pharmaceutical compsns. containing them. EP 0603229; JP 1994510991; JP 1997315970; WO 9306098 . |
| 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) | 16148 | Benzeneacetic acid; 2-Phenylacetic acid; Phenyl Acetic Acid | 103-82-2 | C8H8O2 | 详情 | 详情 |
| (II) | 16149 | 2-Chloroethyl methyl sulfide; 1-Chloro-2-(methylsulfanyl)ethane | 542-81-4 | C3H7ClS | 详情 | 详情 |
| (III) | 16150 | 4-(methylsulfanyl)-2-phenylbutyric acid | C11H14O2S | 详情 | 详情 | |
| (IV) | 16151 | methyl 4-(methylsulfanyl)-2-phenylbutanoate | C12H16O2S | 详情 | 详情 | |
| (V) | 16152 | (3R)-1-azabicyclo[2.2.2]octan-3-ol; (R)-(-)-Quinuclidinol | 42437-96-7 | C7H13NO | 详情 | 详情 |
| (VI) | 16153 | (3R)-1-azabicyclo[2.2.2]oct-3-yl 4-(methylsulfanyl)-2-phenylbutanoate | C18H25NO2S | 详情 | 详情 | |
| (VII) | 16154 | (3R)-1-azabicyclo[2.2.2]oct-3-yl 2-(hydroxymethyl)-4-(methylsulfanyl)-2-phenylbutanoate | C19H27NO3S | 详情 | 详情 | |
| (VIII) | 16155 | (3R)-1-azabicyclo[2.2.2]oct-3-yl (2S)-2-(hydroxymethyl)-4-(methylsulfanyl)-2-phenylbutanoate | C19H27NO3S | 详情 | 详情 | |
| (IX) | 16156 | (3R)-1-azabicyclo[2.2.2]oct-3-yl (2S)-2-(hydroxymethyl)-4-(methylsulfinyl)-2-phenylbutanoate | C19H27NO4S | 详情 | 详情 |