ABT-224, AU-224, -Drug Synthesis Database

【结构式】

【药物名称】ABT-224, AU-224

【化学名称】4-(4-Amino-5-chloro-2-methoxybenzamido)piperidine-1-acetic acid butyl ester

【CA登记号】

【分子式】C₁₉H₂₈ClN₃O₄

【分子量】397.90571

【开发单位】Abbott (Originator)

【药理作用】Constipation, Agents for, Gastric Emptying Disorders,Treatment of of, GASTROINTESTINAL DRUGS, Prokinetic Agents, 5-HT4 Agonists

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

4-Amino-5-chloro-2-methoxybenzoic acid (I) was converted to the mixed anhydride (II) upon treatment with ethyl chloroformate and Et3N. Subsequent coupling of (II) with 4-amino-1-tritylpiperidine (III) afforded amide (IV). The trityl group of (IV) was then removed by acidic treatment to give piperidine (V). Finally, alkylation of (V) with butyl bromoacetate (VI) furnished the title compound.

参考文献中间体

【1】 Ito, Y.; Kato, H.; Yasuda, S.; Iwasaki, N.; Nishino, H.; Takeshita, M. (Hokuriku Seiyaku Co., Ltd.); Benzamide deriv.. EP 0640601; US 5395832; US 5500422; WO 9214705 .

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)	12419	4-Amino-5-chloro-2-methoxybenzoic acid	7206-70-4	C₈H₈ClNO₃	详情	详情
(II)	29299	4-Amino-5-chloro-2-methoxybenzoic acid methoxycarbonyl anhydride		C₁₀H₁₀ClNO₅	详情	详情
(III)	19955	1-trityl-4-piperidinylamine; 1-trityl-4-piperidinamine		C₂₄H₂₆N₂	详情	详情
(IV)	19956	4-amino-5-chloro-2-methoxy-N-(1-trityl-4-piperidinyl)benzamide		C₃₂H₃₂ClN₃O₂	详情	详情
(V)	19957	4-amino-5-chloro-2-methoxy-N-(4-piperidinyl)benzamide		C₁₃H₁₈ClN₃O₂	详情	详情
(VI)	29300	butyl 2-bromoacetate		C₃₂H₃₂ClN₃O₂	详情	详情

合成路线2

The condensation of 4-(tert-butoxycarbonylamino)piperidine (I) with butyl chloroacetate (II) by means of TEA in hot DMF gives butyl 2-[4-(tert-butoxycarbonylamino)piperdin-1-yl]acetate (III), which is deprotected with HCl in isopropanol to yield butyl 2-(4-aminopiperidin-1-yl)acetate (IV). Finally, this compound is condensed with 4-amino-5-chloro-2-methoxybenzoic acid (V) by means of ethyl chloroacetate, TEA and K2CO3 in THF to afford the target benzamide.

参考文献中间体

【1】 Sakaguchi, J.; Kato, H.; Kado, N. (Hokuriku Seiyaku Co., Ltd.); Benzamide derivs. and drugs containing the same. EP 1149832; JP 2000290254; WO 0046201 .

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)	41601	tert-butyl 4-piperidinylcarbamate; 4-tert-Boc-aminopiperidine	73874-95-0	C₁₀H₂₀N₂O₂	详情	详情
(II)	14595	n-Butyl Chloroacetate; butyl 2-chloroacetate	590-02-3	C₆H₁₁ClO₂	详情	详情
(III)	51930	butyl 2-[4-[(tert-butoxycarbonyl)amino]-1-piperidinyl]acetate		C₁₆H₃₀N₂O₄	详情	详情
(IV)	51931	butyl 2-(4-amino-1-piperidinyl)acetate		C₁₁H₂₂N₂O₂	详情	详情
(V)	12419	4-Amino-5-chloro-2-methoxybenzoic acid	7206-70-4	C₈H₈ClNO₃	详情	详情

合成路线3

A new synthetic route has been reported. 4-Amino-1-benzylpiperidine (I) was protected as the t-butyl carbamate (II) using Boc2O, and the N-benzyl group was subsequently removed by transfer hydrogenolysis, yielding 4-(t-butoxycarbonylamino)piperidine (III). Butyl chloroacetate (V), prepared by treatment of chloroacetyl chloride (IV) with n-butanol, was then condensed with piperidine (III) to afford (VI). After acidic cleavage of the Boc protecting group of (VI), the resultant amino piperidine (VII) was acylated with the mixed anhydride (VIII) to provide the target amide.

参考文献中间体

【1】 Sakaguchi, J.; et al.; An improved synthesis of butyl 4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-piperidineacetate (AU-224). Chem Pharm Bull 2001, 49, 6, 788.

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)	34808	1-Benzyl-4-piperidinylamine; 1-Benzyl-4-piperidinamine; 4-Amino-1-benzylpiperidine	50541-93-0	C₁₂H₁₈N₂	详情	详情
(II)	56563	tert-butyl 1-benzyl-4-piperidinylcarbamate		C₁₇H₂₆N₂O₂	详情	详情
(III)	41601	tert-butyl 4-piperidinylcarbamate; 4-tert-Boc-aminopiperidine	73874-95-0	C₁₀H₂₀N₂O₂	详情	详情
(IV)	11296	2-Chloroacetyl chloride; Chloroacetic chloride	79-04-9	C₂H₂Cl₂O	详情	详情
(V)	14595	n-Butyl Chloroacetate; butyl 2-chloroacetate	590-02-3	C₆H₁₁ClO₂	详情	详情
(VI)	51930	butyl 2-[4-[(tert-butoxycarbonyl)amino]-1-piperidinyl]acetate		C₁₆H₃₀N₂O₄	详情	详情
(VII)	51931	butyl 2-(4-amino-1-piperidinyl)acetate		C₁₁H₂₂N₂O₂	详情	详情
(VIII)	29299	4-Amino-5-chloro-2-methoxybenzoic acid methoxycarbonyl anhydride		C₁₀H₁₀ClNO₅	详情	详情

合成路线4

Alkylation of the benzamido piperidine (I) with ethyl chloroacetate (II) provided the piperidine acetate ethyl ester (III), which was further hydrolyzed with NaOH to the corresponding carboxylic acid (IV). The title butyl ester was prepared by reaction of acid (IV) with n-butyl bromide in the presence of K2CO3.

参考文献中间体

【1】 Sakaguchi, J.; et al.; Synthesis and gastrointestinal prokinetic activity of novel benzamide derivatives with amphoteric side chains. Chem Pharm Bull 2001, 49, 4, 424.

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)	19957	4-amino-5-chloro-2-methoxy-N-(4-piperidinyl)benzamide		C₁₃H₁₈ClN₃O₂	详情	详情
(II)	16640	Ethyl 2-bromoacetate; Ethyl bromoacetate	105-36-2	C₄H₇BrO₂	详情	详情
(III)	19959	ethyl 2-[4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-piperidinyl]acetate		C₁₇H₂₄ClN₃O₄	详情	详情
(IV)	56564	2-{4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-piperidinyl}acetic acid		C₁₅H₂₀ClN₃O₄	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)