6-(Aminomethyl)-3-morpholinone -Drug Synthesis Database

【结构式】

【分子编号】12367

【品名】6-(Aminomethyl)-3-morpholinone

【CA登记号】

【分子式】C₅H₁₀N₂O₂

【分子量】130.14668

【元素组成】C 46.14% H 7.74% N 21.52% O 24.59%

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：(VIII)

2) The reaction of N-(2,3-epoxypropyl)phthalimide (I) with dibenzylamine (II) at 80 C gives 1-(dibenzylamino)-3-(phthalimido)-2-propanol (III), which is hydrolyzed with refluxing concentrated HCl to afford 1-amino-3-(dibenzylamino)-2-propanol (IV). The acylation of (IV) with chloroacetyl chloride (V) in CHCl3 yields the corresponding chloroacetamide (VI), which is cyclized by means of potassium tert-butoxide in refluxing ethanol to give 6-(dibenzylaminomethyl)morpholin-3-one (VII). The debenzylation of (VII) with H2 over Pd(OH)2/C in ethanol yields 6-(aminomethyl)morpholin-3-one (VIII), which is condensed with 4-(acetamido)-5-chloro-2-ethoxybenzoyl chloride (IX) by means of triethylamine in CHCl3 to afford the monoacetylated derivative of metabolite M-2 (X). Finally, this compound is hydrolyzed with HCl in refluxing ethanol/water to give metabolite M-2. The two final steps of this sequence can also be performed in a single step by condensation of morpholinone (VIII) with 4-amino-5-chloro-2-ethoxybenzoic acid (XI) by means of carbonyldiimidazole (CDI) in THF to afford directly the metabolite M-2 after neutralization with aqueous NH4OH.

参考文献中间体

合成目标

【1】 Kato, S.; Yoshida, N.; Morie, T.; Synthesis and biological activities of metabolites of mosapride, a new gastroprokinetic agent. Chem Pharm Bull 1995, 43, 4, 699.

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)	12335	2-(2-Oxiranylmethyl)-1H-isoindole-1,3(2H)-dione; N-(2,3-Epoxypropyl)phtalimide	5455-98-1	C₁₁H₉NO₃	详情	详情
(II)	12361	N,N-Dibenzylamine; Dibenzylamine; N-Benzyl(phenyl)methanamine	103-49-1	C₁₄H₁₅N	详情	详情
(III)	12362	2-[3-(Dibenzylamino)-2-hydroxypropyl]-1H-isoindole-1,3(2H)-dione		C₂₅H₂₄N₂O₃	详情	详情
(IV)	12363	1-Amino-3-(dibenzylamino)-2-propanol		C₁₇H₂₂N₂O	详情	详情
(V)	11296	2-Chloroacetyl chloride; Chloroacetic chloride	79-04-9	C₂H₂Cl₂O	详情	详情
(VI)	12365	2-Chloro-N-[3-(dibenzylamino)-2-hydroxypropyl]acetamide		C₁₉H₂₃ClN₂O₂	详情	详情
(VII)	12366	6-[(Dibenzylamino)methyl]-3-morpholinone		C₁₉H₂₂N₂O₂	详情	详情
(VIII)	12367	6-(Aminomethyl)-3-morpholinone		C₅H₁₀N₂O₂	详情	详情
(IX)	12368	4-(Acetamido)-5-chloro-2-ethoxybenzoyl chloride		C₁₁H₁₁Cl₂NO₃	详情	详情
(X)	12369	4-(Acetamido)-5-chloro-2-ethoxy-N-[(5-oxo-1,4-oxazinan-2-yl)methyl]benzamide		C₁₆H₂₀ClN₃O₅	详情	详情
(XI)	12333	4-Amino-5-chloro-2-ethoxybenzoic acid		C₉H₁₀ClNO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

Two minor metabolites of mosapride 4-amino-5-chloro-2-ethoxy-3-hydroxy-N-(5-oxo-2-morpholinylmethyl)benzamide (A) and 4-amino-5-chloro-2-ethoxy-3-hydroxy-N-(2-morpholinylmethyl)benzamide (B) have been synthesized as follows: 1) The alkylation of 2,3-dihydroxybenzaldehyde (I) with NaH and ethyl iodide in DMSO gives 2-ethoxy-3-hydroxybenzaldehyde (II), which is nitrated with HNO3 in acetic acid yielding 2-ethoxy-3-hydroxy-4-nitrobenzaldehyde (III). The oxidation of (III) with AgNO3 in methanol/water affords the expected benzoic acid (IV), which is condensed with 2-(aminomethyl)morpholin-5-one (V) by means of carbonyldiimidazole (CDI) in THF giving the corresponding benzamide (VI). The hydrogenation of the nitro group of (VI) with H2 over Pd/C in aqueous ethanol yields 4-amino-2-ethoxy-3-hydroxy-N-(5-oxo-2-morpholinylmethyl)benzamide (VII), which is finally chlorinated to the metabolite (A) with N-chlorosuccinimide in hot DMF. 2) The reaction of the benzoic acid (IV) with SOCl2 in refluxing dichloromethane gives the corresponding acyl chloride (VIII), which is condensed with 2-(aminomethyl)-4-(4-fluorobenzyl)morpholine (IX) by means of triethylamine in dichloromethane to yield the expected amide (X). The debenzylation of (X) with 1-chloroethyl chloroformate (ACE-Cl) and reprotection with di-tert-butyl carbonate affords N-[4-(tert-butoxycarbonyl)morpholin-2-ylmethyl]-2-ethoxy-3-hydroxy-4-nitrobenzamide (XI), which is submitted to a reductive acetylation (H2 over Pd/C in acetic anhydride) giving 4-acetamido-N-[4-(tert-butoxycarbonyl)morpholin-2-ylmethyl]-2-ethoxy-3-hydroxybenzamide (XII). The chlorination of (XII) with N-chlorosuccinimide (NCS) in chloroform/DMS yields the corresponding 5-chlorobenzamide (XIII), which is finally deprotected with refluxing aqueous HCl to afford metabolite (B).

参考文献中间体

合成目标

【1】 Kato, S.; Morie, T.; Yoshida, N.; Synthesis and biological activity of 4-amino-5-chloro-2-ethoxy-3-hydroxybenzamides, metabolites of a new gastroprokinetic agent, mosapride. Chem Pharm Bull 1996, 44, 8, 1484.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	12393	4-Amino-5-chloro-2-ethoxy-3-hydroxy-N-[(5-oxo-1,4-oxazinan-2-yl)methyl]benzamide		C₁₄H₁₈ClN₃O₅	详情	详情
(B)	12394	4-Amino-5-chloro-2-ethoxy-3-hydroxy-N-(1,4-oxazinan-2-ylmethyl)benzamide		C₁₄H₂₀ClN₃O₄	详情	详情
(I)	12380	2,3-Dihydroxybenzaldehyde	24677-78-9	C₇H₆O₃	详情	详情
(II)	12381	2-Ethoxy-3-hydroxybenzaldehyde		C₉H₁₀O₃	详情	详情
(III)	12382	2-Ethoxy-3-hydroxy-4-nitrobenzaldehyde		C₉H₉NO₅	详情	详情
(IV)	12383	2-Ethoxy-3-hydroxy-4-nitrobenzoic acid		C₉H₉NO₆	详情	详情
(V)	12367	6-(Aminomethyl)-3-morpholinone		C₅H₁₀N₂O₂	详情	详情
(VI)	12385	2-Ethoxy-3-hydroxy-4-nitro-N-[(5-oxo-1,4-oxazinan-2-yl)methyl]benzamide		C₁₄H₁₇N₃O₇	详情	详情
(VII)	12386	4-Amino-2-ethoxy-3-hydroxy-N-[(5-oxo-1,4-oxazinan-2-yl)methyl]benzamide		C₁₄H₁₉N₃O₅	详情	详情
(VIII)	12387	2-Ethoxy-3-hydroxy-4-nitrobenzoyl chloride		C₉H₈ClNO₅	详情	详情
(IX)	12336	[4-(4-Fluorobenzyl)-1,4-oxazinan-2-yl]methylamine; [4-(4-Fluorobenzyl)-1,4-oxazinan-2-yl]methanamine; 2-Aminomethyl-4-(4-fluorobenzyl)morpholine	112914-13-3	C₁₂H₁₇FN₂O	详情	详情
(X)	12389	2-Ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]-3-hydroxy-4-nitrobenzamide		C₂₁H₂₄FN₃O₆	详情	详情
(XI)	12390	tert-butyl 2-[[(2-ethoxy-3-hydroxy-4-nitrobenzoyl)amino]methyl]-4-morpholinecarboxylate		C₁₉H₂₇N₃O₈	详情	详情
(XII)	12391	tert-butyl 2-([[4-(acetamido)-2-ethoxy-3-hydroxybenzoyl]amino]methyl)-4-morpholinecarboxylate		C₂₁H₃₁N₃O₇	详情	详情
(XIII)	12392	tert-butyl 2-([[4-(acetamido)-5-chloro-2-ethoxy-3-hydroxybenzoyl]amino]methyl)-4-morpholinecarboxylate		C₂₁H₃₀ClN₃O₇	详情	详情

Extended Information