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【结 构 式】 
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【分子编号】29984 【品名】2-chloropropane 【CA登记号】75-29-6 |
【 分 子 式 】C3H7Cl 【 分 子 量 】78.54128 【元素组成】C 45.88% H 8.98% Cl 45.14% |
合成路线1
该中间体在本合成路线中的序号：(IV)Gallopamil is obtained by condensing 2-(3,4,5-trimethoxypheny)-3-methylbutyronitrile (I) with N-(3-chloropropyl)-N-(2-(3,4-dimethoxyphenyl)ethyl]-N-methylamine (II) in the presence of bases. Compound (I) can be prepared by reaction of 3,4,5-trimethoxyphenylacetonitrile (III) with isopropyl chloride (IV) by means of NaNH2. Compound (II) is formed from 1-bromo-3-chloropropane (V) and N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylamine (VI).
| 【1】 Dengel, F. (Knoll AG); Verfahren zur herstellung basisch substituerter phenylacetonitrile. DE 1154810; DE 1158083 . |
| 【2】 Mannhold, R.; Gallopamil Hydrochloride. Drugs Fut 1984, 9, 2, 108. |
| 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) | 29985 | 3-methyl-2-(3,4,5-trimethoxyphenyl)butanenitrile | C14H19NO3 | 详情 | 详情 | |
| (II) | 29986 | 3-chloro-N-(3,4-dimethoxyphenethyl)-N-methyl-1-propanamine; N-(3-chloropropyl)-N-(3,4-dimethoxyphenethyl)-N-methylamine | C14H22ClNO2 | 详情 | 详情 | |
| (III) | 29983 | 2-(3,4,5-trimethoxyphenyl)acetonitrile | 13338-63-1 | C11H13NO3 | 详情 | 详情 |
| (IV) | 29984 | 2-chloropropane | 75-29-6 | C3H7Cl | 详情 | 详情 |
| (V) | 10358 | 1-Bromo-3-chloropropane | 109-70-6 | C3H6BrCl | 详情 | 详情 |
| (VI) | 18938 | 2-(3,4-dimethoxyphenyl)-N-methyl-1-ethanamine; N-(3,4-dimethoxyphenethyl)-N-methylamine | 3490-06-0 | C11H17NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)The reaction of 2,3-dihydro-1H-benzimidazol-2-one (I) with trichloromethyl chloroformate (II) in THF gives 2-oxo-2,3-dihydro-1H-benzimidazol-2-ylcarbonyl chloride (III), which is condensed with endo-8-methyl-8-azabicyclo[3,2,1]octan-3-amine (IV) in THF, yielding the corresponding amide (V). Finally, this compound is alkylated with isopropyl bromide (VI) and NaH in DMF.
| 【1】 Turconi, M.; et al.; Azabicycloalkyl benzimidazolone derivatives: A novel class of 5-HT3 receptor antagonists. 199th ACS Natl Meet (April 22 1990, Boston) 1990, Abst MEDI 103. |
| 【2】 Turconi, M.; Schiantarelli, P.; Borsini, F.; Rizzi, C.A.; Ladinsky, H.; Donetti, A.; Azabicycloalkyl benzimidazolones: Interaction with serotonergic 5-HT3 and 5-HT4 receptors and potential therapeutic implications. Drugs Fut 1991, 16, 11, 1011. |
| 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) | 42923 | 1,3-dihydro-2H-benzimidazol-2-one | 615-16-7 | C7H6N2O | 详情 | 详情 |
| (II) | 42918 | Chloroformic acid trichloromethyl ester; di-Phosgene; Chloroformic Acid, Trichloromethyl Ester; Trichloromethyl chloroformate; Diphosgene | 503-38-8 | C2Cl4O2 | 详情 | 详情 |
| (III) | 42924 | 2-oxo-2,3-dihydro-1H-benzimidazole-1-carbonyl chloride | C8H5ClN2O2 | 详情 | 详情 | |
| (IV) | 19105 | (1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-ylamine; (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-amine | C8H16N2 | 详情 | 详情 | |
| (V) | 42925 | N-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide | C16H20N4O2 | 详情 | 详情 | |
| (VI) | 29984 | 2-chloropropane | 75-29-6 | C3H7Cl | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)The condensation of 2-nitrophenyl isocyanate (VII) with endo-8-methyl-8-azabicyclo[3,2,1]octan-3-amine (IV) in THF/cyclohexane gives the corresponding 2-nitrophenylurea (VIII), which is reduced with H2 over Pd/C in ethanol to yield the 2-aminophenylurea (IX). The acylation of (IX) with phenyl chloroformate (X) in toluene affords the carbamate (XI), which is cyclized by means of NaOH in ethanol to afford the amide (V). Finally, this compound is alkylated with isopropyl bromide (VI) and NaH in DMF.
| 【1】 Turconi, M.; et al.; Synthesis of a new class of 2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid derivatives as highly potent 5-HT3 receptor antagonists. J Med Chem 1990, 33, 8, 2101. |
| 【2】 Turconi, M.; Schiantarelli, P.; Borsini, F.; Rizzi, C.A.; Ladinsky, H.; Donetti, A.; Azabicycloalkyl benzimidazolones: Interaction with serotonergic 5-HT3 and 5-HT4 receptors and potential therapeutic implications. Drugs Fut 1991, 16, 11, 1011. |
| 【3】 Turconi, M.; et al.; Azabicycloalkyl benzimidazolone derivatives: A novel class of 5-HT3 receptor antagonists. 199th ACS Natl Meet (April 22 1990, Boston) 1990, Abst MEDI 103. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 19105 | (1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-ylamine; (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-amine | C8H16N2 | 详情 | 详情 | |
| (V) | 42925 | N-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide | C16H20N4O2 | 详情 | 详情 | |
| (VI) | 29984 | 2-chloropropane | 75-29-6 | C3H7Cl | 详情 | 详情 |
| (VII) | 32771 | 1-isocyanato-2-nitrobenzene; 2-nitrophenyl isocyanate | 3320-86-3 | C7H4N2O3 | 详情 | 详情 |
| (VIII) | 42927 | N-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]-N'-(2-nitrophenyl)urea | C15H20N4O3 | 详情 | 详情 | |
| (IX) | 42928 | N-(2-aminophenyl)-N'-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]urea | C15H22N4O | 详情 | 详情 | |
| (X) | 13580 | 1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate | 1885-14-9 | C7H5ClO2 | 详情 | 详情 |
| (XI) | 42929 | phenyl 2-[([[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amino]carbonyl)amino]phenylcarbamate | C22H26N4O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)When 4-phenyl-3-oxobutanoic acid methyl ester (I) were reacted with thiourea (II), in the presence of sodium methoxide, condensation occurred with formation of 3,4-dihydro-6-benzyl-4-oxo-2-thioxopyrimidine (III). Reaction of the compound (III) with isopropyl chloride (IV) in alkaline medium afforded the required 2-(isopropylthio)-6-benzyl-3,4-dihydro-4-oxopyrimidine
| 【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159. |
合成路线5
该中间体在本合成路线中的序号：(IV)When 4-(3-methylphenyl-3-oxobutanoic acid methyl ester (I) were reacted with thiourea (II), in the presence of sodium methoxide, condensation occurred with formation of 3,4-dihydro-6-(3-methylbenzyl)-4-oxo-2-thioxopyrimidine (III). Reaction of the compound (III) with isopropyl chloride (IV) in alkaline medium afforded the required 2-(isopropylthio)-6-(3-methylbenzyl)-3,4-dihydro-4-oxopyrimidine
| 【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159. |
合成路线6
该中间体在本合成路线中的序号：(IV)When 2-methyl-4-phenyl-3-oxobutanoic acid methyl ester (I) were reacted with thiourea (II), in the presence of sodium methoxide, condensation occurred with formation of 5-methyl-3,4-dihydro-6-benzyl-4-oxo-2-thioxopyrimidine (III). Reaction of compound (III) with isopropyl chloride (IV) in alkaline medium afforded the required 2-(isopropylthio)-5-methyl-6-benzyl-3,4-dihydro-4-oxopyrimidine
| 【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159. |
合成路线7
该中间体在本合成路线中的序号：(IV)When 2-methyl-4-(3-methylphenyl)-3-oxobutanoic acid methyl ester (I) were reacted with thiourea (II), in the presence of sodium methoxide, condensation occurred with formation of 5-methyl-3,4-dihydro-6-(3-methylbenzyl)-4-oxo-2-thioxopyrimidine (III). Reaction of compound (III) with isopropyl chloride (IV) in alkaline medium afforded the required 2-(isopropylthio)-5-methyl-6-(3-methylbenzyl)-3,4-dihydro-4-oxopyrimidine
| 【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159. |
| 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) | 51785 | methyl (Z)-3-hydroxy-2-methyl-4-(3-methylphenyl)-2-butenoate | C13H16O3 | 详情 | 详情 | |
| (II) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (III) | 51799 | 5-methyl-6-(3-methylbenzyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone | C13H14N2OS | 详情 | 详情 | |
| (IV) | 29984 | 2-chloropropane | 75-29-6 | C3H7Cl | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(VI)The condensation of 2-(2,6-difluorophenyl)acetic acid (I) with malonic acid monoethyl ester sodium salt (II) gives 4-(2,6-difluorophenyl)-3-oxobutyric acid ethyl ester (III), which is cyclized with thiourea (IV) to yield 6-(2,6-difluorobenzyl)-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (V). Finally this compound is reacted with isopropyl chloride (VI) by means of K2CO3 to afford the target pyrimidinone.
| 【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159. |
| 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) | 51809 | 2,6-Difluorophenylacetic acid | 85068-28-6 | C8H6F2O2 | 详情 | 详情 |
| (II) | 14338 | potassium 3-ethoxy-3-oxopropanoate | 6148-64-7 | C5H7KO4 | 详情 | 详情 |
| (III) | 51810 | ethyl 4-(2,6-difluorophenyl)-3-oxobutanoate | C12H12F2O3 | 详情 | 详情 | |
| (IV) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (V) | 51811 | 6-(2,6-difluorobenzyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone | C11H8F2N2OS | 详情 | 详情 | |
| (VI) | 29984 | 2-chloropropane | 75-29-6 | C3H7Cl | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(VI)The condensation of 2-(2,6-difluorophenyl)acetic acid (I) with 2-methylmalonic acid monoethyl ester sodium salt (II) gives 4-(2,6-difluorophenyl)-2-methyl-3-oxobutyric acid ethyl ester (III), which is cyclized with thiourea (IV) to yield 6-(2,6-difluorobenzyl)-5-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (V). Finally this compound is reacted with isopropyl chloride (VI) by means of K2CO3 to afford the target pyrimidinone.
| 【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159. |
| 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) | 51809 | 2,6-Difluorophenylacetic acid | 85068-28-6 | C8H6F2O2 | 详情 | 详情 |
| (II) | 51813 | potassium 3-ethoxy-2-methyl-3-oxopropanoate | C6H9KO4 | 详情 | 详情 | |
| (III) | 51814 | ethyl 4-(2,6-difluorophenyl)-2-methyl-3-oxobutanoate | C13H14F2O3 | 详情 | 详情 | |
| (IV) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (V) | 51815 | 6-(2,6-difluorobenzyl)-5-methyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone | C12H10F2N2OS | 详情 | 详情 | |
| (VI) | 29984 | 2-chloropropane | 75-29-6 | C3H7Cl | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(II)The alkylation of 6-(2,6-difluorobenzyl)-5-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (I) with isopropyl chloride (II) by means of K2CO3 gives 6-(2,6-difluorobenzyl)-2-(isopropylsulfanyl)-5-methylpyridmidin-4(3H)-one (III), which is then methylated with Me-Cl and LDA in THF/HMPA to yield the target alpha-methylbenzyl pyrimidinone.
| 【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159. |
合成路线11
该中间体在本合成路线中的序号：(VII)The methylation of 2-(2,6-difluorophenyl)acetic acid (I) with Me-Cl and LDA in THF/HMPA gives 2-(2,6-difluorophenyl)propionic acid (II), which is condensed with 2-methylmalonic acid monoethyl ester potassium salt (III) to yield 4-(2,6-difluorophenyl)-2-methyl-3-oxopentanoic acid (IV). The cyclization of (IV) with thiourea (V) affords 6-[1-(2,6-difluorophenyl)ethyl]-5-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (VI), which is finally alkylated with isopropyl chloride (VII) to provide the target pyrimidinone derivative.
| 【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159. |
| 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) | 51809 | 2,6-Difluorophenylacetic acid | 85068-28-6 | C8H6F2O2 | 详情 | 详情 |
| (II) | 51820 | 2-(2,6-difluorophenyl)propionic acid | C9H8F2O2 | 详情 | 详情 | |
| (III) | 51813 | potassium 3-ethoxy-2-methyl-3-oxopropanoate | C6H9KO4 | 详情 | 详情 | |
| (IV) | 51821 | ethyl 4-(2,6-difluorophenyl)-2-methyl-3-oxopentanoate | C14H16F2O3 | 详情 | 详情 | |
| (V) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (VI) | 51822 | 6-[1-(2,6-difluorophenyl)ethyl]-5-methyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone | C13H12F2N2OS | 详情 | 详情 | |
| (VII) | 29984 | 2-chloropropane | 75-29-6 | C3H7Cl | 详情 | 详情 |