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【结 构 式】 
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【分子编号】12092 【品名】Methyl isothiocyanate; MITC; (Methylimino)(thioxo)methane 【CA登记号】556-61-6 |
【 分 子 式 】C2H3NS 【 分 子 量 】73.11856 【元素组成】C 32.85% H 4.14% N 19.16% S 43.85% |
合成路线1
该中间体在本合成路线中的序号：(B)Compound can be prepared in three different ways all starting from 4-methoxybenzylamine (I) [prepared by methylation of 4-hydroxybenzonitrile (V) with dimethyl sulfate in aqueous NaOH to afford 4-methoxybenzonitrile (VI), which is then hydrogenated with H2 over Raney-Ni in ethanol]: 1) By condensation of 4-methoxybenzylamine (I) with N,N',S-trimethylisothiourea hydroiodide (C) in refluxing ethanol, followed by treatment with H2SO4. 2) By reaction of 4-methoxybenzylamine (I) with diethyl iminocarbonate (A) in water to give diethyl N-(4-methoxybenzyl)iminocarbonate (II), followed by treatment with methylamine in water - ethanol - H2SO4. 3) By reaction of 4-methoxybenzylamine (I) with methyl isothiocyanate (B) in ether to yield N-(4-methoxybenzyl)-N'-methylthiourea (III), which is then methylated with MeI in refluxing methanol affording N-(4-methoxybenzyl)-N',S-dimethylisothiourea (IV). Finally, this compound is treated first with methylamine in refluxing methanol and then with H2SO4.
| 【1】 Maxwell, R.A.; Walton, E. (Glaxo Wellcome Inc.); Substituted guanidine compounds as antifibrillatory agents. US 3949089 . |
| 【2】 Castaner, J.; Blancafort, P.; Meobentine. Drugs Fut 1978, 3, 3, 204. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 12092 | Methyl isothiocyanate; MITC; (Methylimino)(thioxo)methane | 556-61-6 | C2H3NS | 详情 | 详情 |
| (A) | 39785 | 1-[ethoxy(imino)methoxy]ethane | C5H11NO2 | 详情 | 详情 | |
| (I) | 15098 | 4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine | 2393-23-9 | C8H11NO | 详情 | 详情 |
| (II) | 39786 | 1-[[(diethoxymethylene)amino]methyl]-4-methoxybenzene | C13H19NO3 | 详情 | 详情 | |
| (III) | 39788 | N-(4-methoxybenzyl)-N'-methylthiourea | C10H14N2OS | 详情 | 详情 | |
| (IV) | 39789 | 1-methoxy-4-([[(methylimino)(methylsulfanyl)methyl]amino]methyl)benzene | C11H16N2OS | 详情 | 详情 | |
| (V) | 25109 | 4-hydroxybenzonitrile | 767-00-0 | C7H5NO | 详情 | 详情 |
| (VI) | 39790 | 4-methoxybenzonitrile | 874-90-8 | C8H7NO | 详情 | 详情 |
| (C) | 39787 | [[(methylamino)(methylimino)methyl]sulfanyl]methane | C4H10N2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(D)1) By refluxing N-cyano-N',S-dimethylisoithiourea (B) and 5-methyl-4-[(2-aminoethyl)thiomethyl imidazol (III) in acetonitrile. The latter is prepared by reacting cysteamine (A) and 5-methyl-4-(hydroxymethyl)imidazol (II) (from 5-methylimidazol (I) and formalin) in acetic acid, in hydrochloric acid or in hydrobromic acid. 2) By reaction of 5-methyl-4-[(2-aminoethyl)thiomethyl]imidazol (III) with cyanodithioimido carbonic (C) acid dimethyl ester to give the isothiourea (IV), followed by reaction with methylamine. 3) By refluxing 1-methyl-3-[2-[[(5-methylimidazol-4-yl)-methyl]thio]ethyl]-2-thiourea (metiamide) (V) and lead cyanamide. The first is prepared by reaction of 5-methyl-4-[(2-aminoethyl)thiomethyl]imidazol (III) with methyl isocyanate (D).
| 【1】 Durant, G.J.; et al.; Pharmacologically active guanidine compounds. DE 2211454; DE 2265369; FR 2128505; GB 1338169; US 3950333 . |
| 【2】 Erlenmeyer, H.; et al.; Helv Chim Acta 1948, 31, 32. |
| 【3】 Durant, G.J.; et al.; Certain N-cyanoguanidines. DE 2344779; FR 2199467; GB 1397436; JP 49075574; US 3876647 . |
| 【4】 Castaner, J.; Cimetidine. Drugs Fut 1976, 1, 1, 13. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (D) | 12092 | Methyl isothiocyanate; MITC; (Methylimino)(thioxo)methane | 556-61-6 | C2H3NS | 详情 | 详情 |
| (A) | 13186 | 2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine | 60-23-1 | C2H7NS | 详情 | 详情 |
| (B) | 34072 | [[(E)-(methylamino)(methylsulfanyl)methylidene]amino](nitrilo)methane | C4H7N3S | 详情 | 详情 | |
| (I) | 34070 | 5-methyl-1H-imidazole | 822-36-6 | C4H6N2 | 详情 | 详情 |
| (II) | 14216 | (5-Methyl-1H-imidazol-4-yl)methanol | 29636-87-1 | C5H8N2O | 详情 | 详情 |
| (III) | 34071 | 2-[[(5-methyl-1H-imidazol-4-yl)methyl]sulfanyl]-1-ethanamine; 2-[[(5-methyl-1H-imidazol-4-yl)methyl]sulfanyl]ethylamine | C7H13N3S | 详情 | 详情 | |
| (IV) | 34073 | 4-[[(2-[[(cyanoimino)(methylsulfanyl)methyl]amino]ethyl)sulfanyl]methyl]-5-methyl-1H-imidazole | C10H15N5S2 | 详情 | 详情 | |
| (V) | 34074 | N-methyl-N'-(2-[[(5-methyl-1H-imidazol-4-yl)methyl]sulfanyl]ethyl)thiourea | C9H16N4S2 | 详情 | 详情 | |
| (C) | 18174 | [[bis(methylsulfanyl)methylene]amino](nitrilo)methane | 10191-60-3 | C4H6N2S2 | 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 reaction of methyl hydrazine (I) and methyl isothiocyanate (II) in either ethanol or THF afforded 2,4-dimethylthiosemicarbazide (III). Acylation of (III) with 3-fluorobenzoyl chloride in either pyridine or THF/N(Et)3 yielded 1-(3-fluorobenzoyl)-2,4-dimethylthiosemicarbazide (IV), which was easily cyclized to MDL 26,479 by warming in 1 M aqueous NaOH.
| 【1】 Miller, J.A.; Dudley, M.W.; Kehne, J.H.; Sorensen, S.M.; Wenstrup, D.L.; Kane J.M.; MDL 26,479. Drugs Fut 1992, 17, 1, 21. |
| 【2】 Dudley, M.W.; Baron, B.M.; Sorensen, S.M.; Miller, F.P.; MDL 26,479: A potential antidepressant whose mechanism of action involves interaction at the GABAA receptor complex. 29th Annu Meet Amer Coll Neuropsychopharmacol (Dec 10-14, San Juan) 1990, Abst. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 63420 | 3-fluorobenzoyl chloride | C7H4ClFO | 详情 | 详情 | ||
| (I) | 12091 | 1-Methylhydrazine; Monomethyl hydrazine | 60-34-4 | CH6N2 | 详情 | 详情 |
| (II) | 12092 | Methyl isothiocyanate; MITC; (Methylimino)(thioxo)methane | 556-61-6 | C2H3NS | 详情 | 详情 |
| (III) | 12093 | 2,4-Dimethylthiosemicarbazide; N,1-Dimethyl-1-hydrazinecarbothioamide | 6621-75-6 | C3H9N3S | 详情 | 详情 |
| (IV) | 12094 | 2-(3-Fluorobenzoyl)-N,1-dimethyl-1-hydrazinecarbothioamide | C10H12FN3OS | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VII)Condensation of 2-(4-methoxyphenyl)ethylamine (I) with either 5-chloro-2-methoxybenzoic acid (II) by means of CDI and TEA or 5-chloro-2-methoxybenzoyl chloride (III) by means of pyridine and DMAP gives the corresponding benzamide (IV), which by treatment with chlorosulfonic acid yields the sulfonyl chloride (V). Reaction of compound (V) with aqueous ammonia in acetone affords the expected sulfonamide (VI), which is finally treated with methyl isothiocyanate (VII) by means of either KOtBu or NaH in DMF.
| 【3】 Englert, H.; Mania, D.; Hartung, J.; Gögelein, H.; Kaiser, J.; Linz, W.; Wettlaufer, D. (Aventis Pharma Deutschland GmbH); Substd. benzenesulfonylureas and -thioureas, process for their preparation and their use as pharmaceuticals. CA 2116165; EP 0612724; JP 1995304728; US 5574069; US 5698596; US 5776980 . |
| 【1】 Martin, L.; Mealy, N.M.; Castaner, J.; Clamikalant sodium. Drugs Fut 2001, 26, 10, 951. |
| 【2】 Gerlach, U.; Scheidler, S.; Mania, D.; Heitsch, H.; Goegelein, H.; Hartung, J.; Englert, H.C.; Cardioselective KATP channel blockers derived from a new series of m-anisamidoethylbenzenesulfonylthioureas. J Med Chem 2001, 44, 7, 1085. |
| 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) | 48701 | 1-(p-Methoxyphenyl)ethylamine; 1-Amino-2-(4-methoxyphenyl)ethane; 2-(4-Methoxyphenyl)ethylamine; 4-(2-Aminoethyl)anisole; 4-Methoxybenzeneethanamine; 4-Methoxyphenethylamine; 4-Methoxyphenylethylamine; p-Methoxy phenethylamine; p-Methoxy phenylethylamine | 55-81-2 | C9H13NO | 详情 | 详情 |
| (II) | 48702 | 5-Chloro-2-methoxybenzoic acid; 5-Chloro-o-anisic acid | 3438-16-2 | C8H7ClO3 | 详情 | 详情 |
| (III) | 44240 | 5-chloro-2-methoxybenzoyl chloride | C8H6Cl2O2 | 详情 | 详情 | |
| (IV) | 48703 | 5-chloro-2-methoxy-N-(4-methoxyphenethyl)benzamide | C17H18ClNO3 | 详情 | 详情 | |
| (V) | 48704 | 5-[2-[(5-chloro-2-methoxybenzoyl)amino]ethyl]-2-methoxybenzenesulfonyl chloride | C17H17Cl2NO5S | 详情 | 详情 | |
| (VI) | 48705 | N-[3-(aminosulfonyl)-4-methoxyphenethyl]-5-chloro-2-methoxybenzamide | C17H19ClN2O5S | 详情 | 详情 | |
| (VII) | 12092 | Methyl isothiocyanate; MITC; (Methylimino)(thioxo)methane | 556-61-6 | C2H3NS | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VIII)trans-4-Hydroxy-L-proline (I) was esterified with methanolic HCl, generated from acetyl chloride in MeOH, and the resulting 4-hydroxyproline methyl ester (II) was protected with allyl chloroformate to afford the allyl carbamate (III). Mesylation of the hydroxyl group of (III) with methanesulfonyl chloride, followed by reduction of the methyl ester with LiBH4, provided the alcohol (V). The mesylate group of (V) was then displaced by potassium thioacetate yielding thioacetate ester (VI). Iodo compound (VII) was obtained by mesylation of alcohol (VI) followed by substitution with NaI in acetone. 1-Methyl-5-mercaptotetrazole (IX), prepared by reaction of methyl isothiocyanate (VIII) with NaN3, was then condensed with iodide (VII) to give adduct (X). After deacetylation of thioacetate (X) with methanolic NaOH, the resulting pyrrolidinethiol (XI) was coupled with enol phosphate (XII) to give the protected carbapenem (XIII). The allyl ester and carbamate protecting groups of (XIII) were finally removed by treatment with Bu3SnH in the presence of palladium catalyst.
| 【1】 Kim, D.J.; Koo, K.D.; Shin, K.J.; Kim, C.; Park, S.W.; Yoo, K.H.; Synthesis and biological properties of new 1beta-methylcarbapenems having tetrazolothioether moiety. Bioorg Med Chem Lett 2000, 10, 13, 1421. |
| 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) | 14489 | (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline | 51-35-4 | C5H9NO3 | 详情 | 详情 |
| (II) | 15796 | methyl (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylate | C6H11NO3 | 详情 | 详情 | |
| (III) | 42200 | 1-allyl 2-methyl (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate | C10H15NO5 | 详情 | 详情 | |
| (IV) | 42201 | 1-allyl 2-methyl (2S,4R)-4-[(methylsulfonyl)oxy]-1,2-pyrrolidinedicarboxylate | C11H17NO7S | 详情 | 详情 | |
| (V) | 42202 | allyl (2S,4R)-2-(hydroxymethyl)-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C10H17NO6S | 详情 | 详情 | |
| (VI) | 42203 | allyl (2S,4S)-4-(acetylsulfanyl)-2-(hydroxymethyl)-1-pyrrolidinecarboxylate | C11H17NO4S | 详情 | 详情 | |
| (VII) | 42204 | allyl (2S,4S)-4-(acetylsulfanyl)-2-(iodomethyl)-1-pyrrolidinecarboxylate | C11H16INO3S | 详情 | 详情 | |
| (VIII) | 12092 | Methyl isothiocyanate; MITC; (Methylimino)(thioxo)methane | 556-61-6 | C2H3NS | 详情 | 详情 |
| (IX) | 28420 | 5-Mercapto-1-methyl-1H-tetrazole; 1-Methyl-1H-1,2,3,4-tetraazol-5-ylhydrosulfide | 13183-79-4 | C2H4N4S | 详情 | 详情 |
| (X) | 42205 | allyl (2S,4S)-4-(acetylsulfanyl)-2-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-1-pyrrolidinecarboxylate | C13H19N5O3S2 | 详情 | 详情 | |
| (XI) | 42206 | allyl (2S,4S)-2-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-4-sulfanyl-1-pyrrolidinecarboxylate | C11H17N5O2S2 | 详情 | 详情 | |
| (XII) | 32617 | allyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C25H26NO8P | 详情 | 详情 | |
| (XIII) | 42207 | allyl (4R,5S,6S)-3-[((3S,5S)-1-[(allyloxy)carbonyl]-5-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]pyrrolidinyl)sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C24H32N6O6S2 | 详情 | 详情 |