4-(acetamido)-2-methoxybenzoic acid -Drug Synthesis Database

【结构式】

【分子编号】17956

【品名】4-(acetamido)-2-methoxybenzoic acid

【CA登记号】4093-29-2

【分子式】C₁₀H₁₁NO₄

【分子量】209.20168

【元素组成】C 57.41% H 5.3% N 6.7% O 30.59%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(II)

Saponification of 4-acetylamino-2-methoxybenzoate methyl ester (I) with NaOH in MeOH provides carboxylic acid (II), which is then coupled to cis-4-amino-1-[3-(fluorophenoxy)propyl]-3-methoxypiperidine (III) by means of ethyl chloroformate and Et3N in chloroform, affording benzamide (IV). Removal of the acetyl group either by means of HCl at reflux or with NaOH in refluxing MeOH furnishes derivative (V), which is finally converted into the desired product by chlorination with N-chlorosuccinimide (NCS) in acetic acid. Alternatively, compound (IV) can be converted into the target compound by first chlorination with NCS in HOAc, providing chloro derivative (VI), followed by acetyl removal either with HCl at 90 C or with NaOH in refluxing MeOH.

参考文献中间体

合成目标

【1】 Serra i Masia, J.; Montserrat Vidal, C.; Process for obtaining cis-4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide. ES 2019011 .

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)	12417	methyl 4-(acetamido)-2-methoxybenzoate; Methyl 4-acetamido-2-methoxybenzoate	4093-28-1	C₁₁H₁₃NO₄	详情	详情
(II)	17956	4-(acetamido)-2-methoxybenzoic acid	4093-29-2	C₁₀H₁₁NO₄	详情	详情
(III)	49554	(3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinamine; (3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidinylamine		C₁₅H₂₃FN₂O₂	详情	详情
(IV)	50814	4-(acetamido)-N-[(3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidinyl]-2-methoxybenzamide		C₂₅H₃₂FN₃O₅	详情	详情
(V)	50815	4-amino-N-[(3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidinyl]-2-methoxybenzamide		C₂₃H₃₀FN₃O₄	详情	详情
(VI)	50816	4-(acetamido)-5-chloro-N-[(3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidinyl]-2-methoxybenzamide		C₂₅H₃₁ClFN₃O₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

4-Acetylamino-2-methoxybenzoic acid (I) was treated with ethyl chloroformate and triethylamine in cold THF, and the intermediate mixed anhydride (II) was then condensed with endo-9-benzyl-9-azabicyclo [3.3.1]nonan-3-amine (III) to yield amide (IV). Hydrogenolysis of the benzyl group in the presence of Pearlman's catalyst provided secondary amine (V), which was alkylated with ethyl 4-bromobutyrate (VI) to give (VII). Aromatic chlorination with sulfuryl chloride at position 5 afforded (VIII) and, then, selective acetamide hydrolysis with 20% HCl in refluxing ethanol gave the target compound.

参考文献中间体

合成目标

【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)	17956	4-(acetamido)-2-methoxybenzoic acid	4093-29-2	C₁₀H₁₁NO₄	详情	详情
(II)	17957	4-(Acetamido)-2-methoxybenzoic acid ethoxycarbonyl anhydride		C₁₃H₁₅NO₆	详情	详情
(III)	17958	(1S,2S,5R)-9-benzyl-9-azabicyclo[3.3.1]non-2-ylamine; (1S,2S,5R)-9-benzyl-9-azabicyclo[3.3.1]nonan-2-amine		C₁₅H₂₂N₂	详情	详情
(IV)	17959	4-(acetamido)-N-[(1S,2S,5R)-9-benzyl-9-azabicyclo[3.3.1]non-2-yl]-2-methoxybenzamide		C₂₅H₃₁N₃O₃	详情	详情
(V)	17960	4-(acetamido)-N-[(1S,2S,5R)-9-azabicyclo[3.3.1]non-2-yl]-2-methoxybenzamide		C₁₈H₂₅N₃O₃	详情	详情
(VII)	17962	ethyl 4-((1S,2S,5R)-2-[[4-(acetamido)-2-methoxybenzoyl]amino]-9-azabicyclo[3.3.1]non-9-yl)butanoate		C₂₄H₃₅N₃O₅	详情	详情
(VIII)	17963	ethyl 4-((1S,2S,5R)-2-[[4-(acetamido)-5-chloro-2-methoxybenzoyl]amino]-9-azabicyclo[3.3.1]non-9-yl)butanoate		C₂₄H₃₄ClN₃O₅	详情	详情

Extended Information