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【结 构 式】 
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【分子编号】24354 【品名】2,3-dimethoxy-4-(1-piperazinylmethyl)phenyl methyl ether 【CA登记号】 |
【 分 子 式 】C14H22N2O3 【 分 子 量 】266.34036 【元素组成】C 63.14% H 8.33% N 10.52% O 18.02% |
合成路线1
该中间体在本合成路线中的序号：(II)The condensation of N-(tert-butoxycarbonyl)-L-leucine (I) with 1-2,3,4-trimethoxybenzyl)piperazine (II) by means of N-hydroxysuccinimide (HSI) and dicyclohexylcarbodiimide (DCC) in dichloromethane gives the corresponding acylated piperazine (III), which is deprotected with dry HCl in ethyl acetate yielding the leucine derivative (IV). Finally, this compound is condensed with trans-epoxysuccinic acid monoethyl ester (V) by means of DCC and HSI as before and treated with H2SO4.
| 【1】 Hoefke, W.; et al. (Boehringer Ingelheim GmbH); 1-Aryloxy-2-hydroxy-3-[(benzimidazolin-one-substituted alkyl)-amino]-propanes and salts thereof. DE 2644833 . |
| 【2】 Prous, J.; Castaner, J.; NCO-700. Drugs Fut 1986, 11, 11, 941. |
| 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) | 24353 | (2S)-2-[[(2,2-dimethylpropanoyl)oxy]amino]-4-methylpentanoic acid | C11H21NO4 | 详情 | 详情 | |
| (II) | 24354 | 2,3-dimethoxy-4-(1-piperazinylmethyl)phenyl methyl ether | C14H22N2O3 | 详情 | 详情 | |
| (III) | 24355 | (2S)-2-[[(2,2-dimethylpropanoyl)oxy]amino]-4-methyl-1-[4-(2,3,4-trimethoxybenzyl)-1-piperazinyl]-1-pentanone | C25H41N3O6 | 详情 | 详情 | |
| (IV) | 24356 | (2S)-2-amino-4-methyl-1-[4-(2,3,4-trimethoxybenzyl)-1-piperazinyl]-1-pentanone | C20H33N3O4 | 详情 | 详情 | |
| (V) | 24344 | (2S,3S)-3-(ethoxycarbonyl)-2-oxiranecarboxylic acid | C6H8O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)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：(IX)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 |
合成路线4
该中间体在本合成路线中的序号：(IX)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5
该中间体在本合成路线中的序号：(IX)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 |
合成路线6
该中间体在本合成路线中的序号：(IV)The reductocondensation of 2,3,4-trimethoxybenzaldehyde (I) with ethyl piperazine-1-carboxylate (II) by means of NaBH3CN in AcOH gives the corresponding benzyl derivative (III), which is decarboxylated with aqueous KOH at 130 C yielding 1-(2,3,4-trimethoxybenzyl)piperazine (IV). The acylation of (IV) with chloroacetyl chloride in dichloromethane affords 1-(2-chloroacetyl)-4-(2,3,4-trimethoxybenzyl)piperazine (V)., which is finally condensed with diosmetin (VI) by means of KHCO3 in DMF.
| 【1】 Ferté, J.; Kühnel, J.-M.; Chapuis, G.; Rolland, Y.; Lewin, G.; Schwaller, M.A.; Flavonoid-related modulators of multidrug resistance: Synthesis, pharmacological activity, and structure-activity relationships. J Med Chem 1999, 42, 3, 478. |
| 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) | 22119 | 2,3,4-trimethoxybenzaldehyde | 2103-57-3 | C10H12O4 | 详情 | 详情 |
| (II) | 24694 | N-ethoxycarbonylpiperidine; Ethyl 1-piperazinecarboxylate; N-Ethoxycarbonyl piperazine; N-Carbethoxy piperazine | 120-43-4 | C7H14N2O2 | 详情 | 详情 |
| (III) | 30010 | ethyl 4-(2,3,4-trimethoxybenzyl)-1-piperazinecarboxylate | C17H26N2O5 | 详情 | 详情 | |
| (IV) | 24354 | 2,3-dimethoxy-4-(1-piperazinylmethyl)phenyl methyl ether | C14H22N2O3 | 详情 | 详情 | |
| (V) | 30011 | 2-chloro-1-[4-(2,3,4-trimethoxybenzyl)-1-piperazinyl]-1-ethanone | C16H23ClN2O4 | 详情 | 详情 | |
| (VI) | 30012 | 5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)-4H-chromen-4-one | 520-34-3 | C16H12O6 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)The condensation between bromide (I) and piperazine (II) in refluxing acetonitrile provided the disubstituted piperazine (III). The acetate ester was then hydrolyzed by means of NaOH to yield the title compound.
| 【1】 Regnier, G.; Vilaine, J.-P.; Villeneuve, N.; Bidouard, J.-P.; Iliou, J.-P.; Lenaers, A. (ADIR et Cie.); Trimetazidine derivs., process for their preparation and pharmaceutical compsns. containing them. EP 0533579; FR 2681324; JP 1993194451; US 5283246 . |
| 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) | 46025 | 4-[(3-bromopropyl)sulfanyl]-2,6-di(tert-butyl)phenyl acetate | C19H29BrO2S | 详情 | 详情 | |
| (II) | 24354 | 2,3-dimethoxy-4-(1-piperazinylmethyl)phenyl methyl ether | C14H22N2O3 | 详情 | 详情 | |
| (III) | 46026 | 2,6-di(tert-butyl)-4-([3-[4-(2,3,4-trimethoxybenzyl)-1-piperazinyl]propyl]sulfanyl)phenyl acetate | C33H50N2O5S | 详情 | 详情 |