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【结 构 式】 
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【分子编号】21017 【品名】2-(4-methylphenyl)acetyl chloride 【CA登记号】35675-44-6 |
【 分 子 式 】C9H9ClO 【 分 子 量 】168.62256 【元素组成】C 64.11% H 5.38% Cl 21.02% O 9.49% |
合成路线1
该中间体在本合成路线中的序号：(VI)3-Indolylcarboxylic acid (I) was converted to acid chloride (II) with oxalyl chloride in refluxing CH2Cl2, and subsequently condensed with cis 1,2-cyclohexanediamine (III) to provide racemic amide (IV). Coupling of (4-methylphenyl)acetyl chloride (VI) with D-3-(2-naphthyl)alanine (V) was carried out via previous silylation of the amino acid with bis(trimethylsilyl)acetamide in THF. The resulting amide (VII) was N-alkylated with ICH3 in the presence of NaH to provide (VIII). Then, the chiral acyl amino acid (VIII) was coupled to racemic amine (IV) using 1-ethyl-3-(3-dimethylaminopropyl)- carbodiimide-HCl (EDC) and 7-aza-1-hydroxybenzotriazole (HOAt) to furnish the corresponding amide as a diastereomeric mixture, from which the desired isomer was isolated by reverse phase chromatography.
| 【1】 Potier, E.; Fincham, C.; Sisto, A.; Terracciano, R. (Menarini Industrie Farma Riunite srl); Pseudo-peptide cpds. as antagonists of neurokinines. WO 9845262 . |
| 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) | 17152 | 1H-Indole-3-carboxylic acid; Indole-3-Carboxylic acid; 3-Indolecarboxylic acid | 771-50-6 | C9H7NO2 | 详情 | 详情 |
| (II) | 17153 | 1H-indole-3-carbonyl chloride | C9H6ClNO | 详情 | 详情 | |
| (III) | 21014 | cis-1,2-Diaminocyclohexane; (1R,2S)-1,2-cyclohexanediamine; (1R,2S)-2-aminocyclohexylamine | 1436-59-5 | C6H14N2 | 详情 | 详情 |
| (IV) | 21015 | N-[(1S,2R)-2-aminocyclohexyl]-1H-indole-3-carboxamide | C15H19N3O | 详情 | 详情 | |
| (V) | 21016 | (2R)-2-amino-3-(2-naphthyl)propionic acid; D-3-(2-Naphthyl)alanine | 76985-09-6 | C13H13NO2 | 详情 | 详情 |
| (VI) | 21017 | 2-(4-methylphenyl)acetyl chloride | 35675-44-6 | C9H9ClO | 详情 | 详情 |
| (VII) | 21018 | (2R)-2-[[2-(4-methylphenyl)acetyl]amino]-3-(2-naphthyl)propionic acid | C22H21NO3 | 详情 | 详情 | |
| (VIII) | 21019 | (2R)-2-[methyl[2-(4-methylphenyl)acetyl]amino]-3-(2-naphthyl)propionic acid | C23H23NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The reaction of 2-(4-methylphenyl)acetic acid (I) with SOCl2 gives the corresponding acyl chloride (II), which is condensed with thiophene (III) by means SnCl4 yielding 2-(4-methylphenyl)-1-(2-thienyl)ethanone (IV). The reduction of (IV) with hydrazine and KOH in hot triethylene glycol affords 2-[2-(4-methylphenyl)ethyl]thiophene (V), which is condensed with 3,3-dimethylglutaric anhydride (VI), by means of AlCl3 in hot nitrobenzene giving the 5-oxopentanoic acid derivative (VII). The reduction of (VII) with hydrazine and KOH as before yields the pentanoic acid derivative (VIII), which is condensed with 4-(2,3,4-trimethoxybenzyl)piperazine (IX) by means of oxalyl chloride to afford the acyl piperazine (X). Finally, the amide group of (X) is reduced with LiAlH4 in ethyl ether.
| 【1】 Wierzbicki, M.; et al.; Amino derivatives of phenyl alkyl thiophene as inhibitors of bone resorption. Structure-activity relationship. Arzneim-Forsch Drug Res 1998, 48, 8, 840. |
| 【2】 Wierzbicki, M.; Sauveur, F.; Bonnet, J.; Brisset, M.; Tordjman, C. (ADIR et Cie.); Thiophene derivs., process for their preparation and pharmaceutical compsns. containing them. AU 9166901; EP 0429370; FR 2655043; JP 1991190872; US 5061704 . |
| 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) | 28316 | 2-(4-methylphenyl)acetic acid | 622-47-9 | C9H10O2 | 详情 | 详情 |
| (II) | 21017 | 2-(4-methylphenyl)acetyl chloride | 35675-44-6 | C9H9ClO | 详情 | 详情 |
| (III) | 13297 | Thiophene | 110-02-1 | C4H4S | 详情 | 详情 |
| (IV) | 28317 | 2-(4-methylphenyl)-1-(2-thienyl)-1-ethanone | C13H12OS | 详情 | 详情 | |
| (V) | 28318 | 2-(4-methylphenethyl)thiophene | C13H14S | 详情 | 详情 | |
| (VI) | 25549 | 4,4-dimethyldihydro-2H-pyran-2,6(3H)-dione | 4160-82-1 | C7H10O3 | 详情 | 详情 |
| (VII) | 28319 | 3,3-dimethyl-5-[5-(4-methylphenethyl)-2-thienyl]-5-oxopentanoic acid | C20H24O3S | 详情 | 详情 | |
| (VIII) | 28320 | 3,3-dimethyl-5-[5-(4-methylphenethyl)-2-thienyl]pentanoic acid | C20H26O2S | 详情 | 详情 | |
| (IX) | 24354 | 2,3-dimethoxy-4-(1-piperazinylmethyl)phenyl methyl ether | C14H22N2O3 | 详情 | 详情 | |
| (X) | 28321 | 3,3-dimethyl-5-[5-(4-methylphenethyl)-2-thienyl]-1-[4-(2,3,4-trimethoxybenzyl)-1-piperazinyl]-1-pentanone | C34H46N2O4S | 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 3,3-dimethylglutaric acid monomethyl ester (XI) with SOCl2 in dichloromethane gives the monoacyl chloride (XII), which is condensed with thiophene (III), by means of SnCl4 in dichloromethane yielding the 5-oxopentanoic ester (XIII). The reduction and simultaneous hydrolysis of (XIII) with hydrazine and KOH affords the pentanoic acid (XIV), which is reesterified with ethanol and sulfuric acid to the ester (XV). The condensation of (XV) with the previously described 2-phenylacetyl chloride (II) by means of SnCl4 in dichloromethane gives the ethanone derivative (XVI), which is reduced with hydrazine and KOH to the previously described pentanoic acid (VIII). Its condensation with piperazine (IX) to afford (X) and the final reduction to the target compound have already been described.
| 【1】 Wierzbicki, M.; et al.; Amino derivatives of phenyl alkyl thiophene as inhibitors of bone resorption. Structure-activity relationship. Arzneim-Forsch Drug Res 1998, 48, 8, 840. |
| 【2】 Wierzbicki, M.; Sauveur, F.; Bonnet, J.; Brisset, M.; Tordjman, C. (ADIR et Cie.); Thiophene derivs., process for their preparation and pharmaceutical compsns. containing them. AU 9166901; EP 0429370; FR 2655043; JP 1991190872; US 5061704 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 21017 | 2-(4-methylphenyl)acetyl chloride | 35675-44-6 | C9H9ClO | 详情 | 详情 |
| (III) | 13297 | Thiophene | 110-02-1 | C4H4S | 详情 | 详情 |
| (VIII) | 28320 | 3,3-dimethyl-5-[5-(4-methylphenethyl)-2-thienyl]pentanoic acid | C20H26O2S | 详情 | 详情 | |
| (IX) | 24354 | 2,3-dimethoxy-4-(1-piperazinylmethyl)phenyl methyl ether | C14H22N2O3 | 详情 | 详情 | |
| (X) | 28321 | 3,3-dimethyl-5-[5-(4-methylphenethyl)-2-thienyl]-1-[4-(2,3,4-trimethoxybenzyl)-1-piperazinyl]-1-pentanone | C34H46N2O4S | 详情 | 详情 | |
| (XI) | 28322 | 5-methoxy-3,3-dimethyl-5-oxopentanoic acid | C8H14O4 | 详情 | 详情 | |
| (XII) | 28323 | methyl 5-chloro-3,3-dimethyl-5-oxopentanoate | C8H13ClO3 | 详情 | 详情 | |
| (XIII) | 28324 | methyl 3,3-dimethyl-5-oxo-5-(2-thienyl)pentanoate | C12H16O3S | 详情 | 详情 | |
| (XIV) | 28325 | 3,3-dimethyl-5-(2-thienyl)pentanoic acid | C11H16O2S | 详情 | 详情 | |
| (XV) | 28326 | ethyl 3,3-dimethyl-5-(2-thienyl)pentanoate | C13H20O2S | 详情 | 详情 | |
| (XVI) | 28327 | ethyl 3,3-dimethyl-5-[5-[2-(4-methylphenyl)acetyl]-2-thienyl]pentanoate | C22H28O3S | 详情 | 详情 |