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【结 构 式】 
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【药物名称】 【化学名称】1-[3,3-Dimethyl-5-[5-[3-(4-methylphenyl)propyl]thien-2-yl]pentyl]-4-(2,3,4-trimethoxybenzyl)piperazine dihydrochloride 【CA登记号】136572-76-4, 136573-13-2 (free base) 【 分 子 式 】C35H52Cl2N2O3S 【 分 子 量 】651.78629 |
【开发单位】Servier (Originator) 【药理作用】Bone Diseases, Treatment of, Bone Resorption Inhibitors, METABOLIC DRUGS, Treatment of Osteoporosis |
合成路线1
The reaction of 3-(4-methylphenyl)propionic acid (I) with SOCl2 gives the corresponding acyl chloride (II), which is condensed with thiophene (III) by means SnCl4 yielding 3-(4-methylphenyl)-1-(2-thienyl)propan-1-one (IV). The reduction of (IV) with hydrazine and KOH in hot triethylene glycol affords 2-[3-(4-methylphenyl)propyl]thiophene (V), which is condensed with 3,3-dimethyl glutaric 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) | 28328 | 3-(4-methylphenyl)propionic acid | 1505-50-6 | C10H12O2 | 详情 | 详情 |
| (II) | 28329 | 3-(4-methylphenyl)propanoyl chloride | C10H11ClO | 详情 | 详情 | |
| (III) | 13297 | Thiophene | 110-02-1 | C4H4S | 详情 | 详情 |
| (IV) | 28330 | 3-(4-methylphenyl)-1-(2-thienyl)-1-propanone | C14H14OS | 详情 | 详情 | |
| (V) | 28331 | 2-[3-(4-methylphenyl)propyl]thiophene | C14H16S | 详情 | 详情 | |
| (VI) | 25549 | 4,4-dimethyldihydro-2H-pyran-2,6(3H)-dione | 4160-82-1 | C7H10O3 | 详情 | 详情 |
| (VII) | 28332 | 3,3-dimethyl-5-[5-[3-(4-methylphenyl)propyl]-2-thienyl]-5-oxopentanoic acid | C21H26O3S | 详情 | 详情 | |
| (VIII) | 28333 | 3,3-dimethyl-5-[5-[3-(4-methylphenyl)propyl]-2-thienyl]pentanoic acid | C21H28O2S | 详情 | 详情 | |
| (IX) | 24354 | 2,3-dimethoxy-4-(1-piperazinylmethyl)phenyl methyl ether | C14H22N2O3 | 详情 | 详情 | |
| (X) | 28334 | 3,3-dimethyl-5-[5-[3-(4-methylphenyl)propyl]-2-thienyl]-1-[4-(2,3,4-trimethoxybenzyl)-1-piperazinyl]-1-pentanone | C35H48N2O4S | 详情 | 详情 |
合成路线2
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 3-phenylpropionyl chloride (II) by means of SnCl4 in dichloromethane gives the propanone 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) | 28329 | 3-(4-methylphenyl)propanoyl chloride | C10H11ClO | 详情 | 详情 | |
| (III) | 13297 | Thiophene | 110-02-1 | C4H4S | 详情 | 详情 |
| (VIII) | 28333 | 3,3-dimethyl-5-[5-[3-(4-methylphenyl)propyl]-2-thienyl]pentanoic acid | C21H28O2S | 详情 | 详情 | |
| (IX) | 24354 | 2,3-dimethoxy-4-(1-piperazinylmethyl)phenyl methyl ether | C14H22N2O3 | 详情 | 详情 | |
| (X) | 28334 | 3,3-dimethyl-5-[5-[3-(4-methylphenyl)propyl]-2-thienyl]-1-[4-(2,3,4-trimethoxybenzyl)-1-piperazinyl]-1-pentanone | C35H48N2O4S | 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) | 28336 | tert-butyl (1R)-2-amino-1-benzyl-2-oxoethylcarbamate | C14H20N2O3 | 详情 | 详情 |