2-(4-amino-3-[[(1R)-1-methyl-2-(4-morpholinyl)-2-oxoethyl]oxy]benzyl)-1H-isoindole-1,3(2H)-dione -Drug Synthesis Database

【结构式】

【分子编号】41506

【品名】2-(4-amino-3-[[(1R)-1-methyl-2-(4-morpholinyl)-2-oxoethyl]oxy]benzyl)-1H-isoindole-1,3(2H)-dione

【CA登记号】

【分子式】C₂₂H₂₃N₃O₅

【分子量】409.44184

【元素组成】C 64.54% H 5.66% N 10.26% O 19.54%

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：(XX)

Synthesis of intermediates (XX) and (XXIII): Coupling of methyl L-lactate (XII) with morpholine in presence of NaH yields amide (XIII) which is tosylated by means of NaH and p-TsCl in THF to afford (XIV). Reduction of carboxylic acid (XV) in DCE with B(OCH3)3, boron trifluoride diethyl etherate and BH3·pyr complex provides alcohol (XVI) which is then condensed with (XIV) in presence of K2CO3 in DMF to yield (XVII). Mesylation of (XVII) with MsCl in presence of Et3N in CH2Cl2 affords (XVIII), which reacts with potassium phthalimide (C) in DMF to give (XIX). Hydrogenation of phthalimide (XIX) with H2 over Pd/C in DMF provides derivative (XX). The treatment of (XIX) with NH2NH2 and p-TsOH gives amine (XXI), which is protected with di-t-butyl-dicarbonate to yield (XXII). Finally (XXIII) is obtained by reduction of the nitro moiety of (XXII) with H2 over Pd/C in EtOAc.

参考文献中间体

合成目标

【1】 Katayama, S.; Kishimoto, H.; Ae, N.; Nagata, R. (Sumitomo Pharmaceuticals Co., Ltd.); Tricyclic indole-2-carboxylic acid cpd. used as NMDA receptor antagonist. WO 0056711 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XII)	17075	propionic acid, 2-hydroxy-, methyl ester, (S)-; methyl (2S)-2-hydroxypropanoate	27871-49-4	C₄H₈O₃	详情	详情
(XIII)	41498	(2S)-2-hydroxy-1-(4-morpholinyl)-1-propanone		C₇H₁₃NO₃	详情	详情
(XIV)	41499	(1S)-1-methyl-2-(4-morpholinyl)-2-oxoethyl 4-methylbenzenesulfonate		C₁₄H₁₉NO₅S	详情	详情
(XV)	41500	3-hydroxy-4-nitrobenzoic acid	619-14-7	C₇H₅NO₅	详情	详情
(XVI)	21465	5-(hydroxymethyl)-2-nitrophenol		C₇H₇NO₄	详情	详情
(XVII)	41501	(2R)-2-[5-(hydroxymethyl)-2-nitrophenoxy]-1-(4-morpholinyl)-1-propanone		C₁₄H₁₈N₂O₆	详情	详情
(XVIII)	41502	(2R)-2-[5-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)-2-nitrophenoxy]-1-(4-morpholinyl)-1-propanone		C₁₇H₂₄N₂O₆S	详情	详情
(XIX)	41503	2-(3-[[(1R)-1-methyl-2-(4-morpholinyl)-2-oxoethyl]oxy]-4-nitrobenzyl)-1H-isoindole-1,3(2H)-dione		C₂₂H₂₁N₃O₇	详情	详情
(XX)	41506	2-(4-amino-3-[[(1R)-1-methyl-2-(4-morpholinyl)-2-oxoethyl]oxy]benzyl)-1H-isoindole-1,3(2H)-dione		C₂₂H₂₃N₃O₅	详情	详情
(XXI)	41504	(2R)-2-[5-(aminomethyl)-2-nitrophenoxy]-1-(4-morpholinyl)-1-propanone		C₁₄H₁₉N₃O₅	详情	详情
(XXII)	41505	tert-butyl 3-[[(1R)-1-methyl-2-(4-morpholinyl)-2-oxoethyl]oxy]-4-nitrobenzylcarbamate		C₁₉H₂₇N₃O₇	详情	详情
(XXIII)	41507	tert-butyl 4-amino-3-[[(1R)-1-methyl-2-(4-morpholinyl)-2-oxoethyl]oxy]benzylcarbamate		C₁₉H₂₉N₃O₅	详情	详情
(C)	27890	Potassium phthalimide	1074-82-4	C₈H₄KNO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XX)

Derivative (S)-(XI) is first treated with oxalyl chloride in EtOAc/DMF and coupled with amine (XXIII) in EtOAc in presence of Et3N providing (XXIV). Alternatively (XXIV) can be obtained as follows: reaction of (S)-(XI) with ethyl chloroformate in THF in presence of Et3N. followed by condensation with (XX) in DMF yields phthalimide (XXV). Derivative (XXIV) is then obtained by removal of the phthalate moiety with NH2NH2 and protection with di-t-butyl-dicarbonate. Hydrolysis of (XXIV) with LiOH in THF/MeOH affords carboxylic acid (XXVI) and finally the amine group of (XXVI) is deprotected with HCl in HOAc.

参考文献中间体

合成目标

【1】 Katayama, S.; Kishimoto, H.; Ae, N.; Nagata, R. (Sumitomo Pharmaceuticals Co., Ltd.); Tricyclic indole-2-carboxylic acid cpd. used as NMDA receptor antagonist. WO 0056711 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(3S)-(XI)	41497	2-[(3S)-7-chloro-2-(methoxycarbonyl)-1,3,4,5-tetrahydrobenzo[cd]indol-3-yl]acetic acid	C₁₅H₁₄ClNO₄	详情	详情
(XX)	41506	2-(4-amino-3-[[(1R)-1-methyl-2-(4-morpholinyl)-2-oxoethyl]oxy]benzyl)-1H-isoindole-1,3(2H)-dione	C₂₂H₂₃N₃O₅	详情	详情
(XXIII)	41507	tert-butyl 4-amino-3-[[(1R)-1-methyl-2-(4-morpholinyl)-2-oxoethyl]oxy]benzylcarbamate	C₁₉H₂₉N₃O₅	详情	详情
(XXIV)	41508	tert-butyl (3S)-3-[2-(4-[[(tert-butoxycarbonyl)amino]methyl]-2-[[(1R)-1-methyl-2-(4-morpholinyl)-2-oxoethyl]oxy]anilino)-2-oxoethyl]-7-chloro-1,3,4,5-tetrahydrobenzo[cd]indole-2-carboxylate	C₃₇H₄₇ClN₄O₈	详情	详情
(XXV)	41509	methyl (3S)-7-chloro-3-[2-(4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-[[(1R)-1-methyl-2-(4-morpholinyl)-2-oxoethyl]oxy]anilino)-2-oxoethyl]-1,3,4,5-tetrahydrobenzo[cd]indole-2-carboxylate	C₃₇H₃₅ClN₄O₈	详情	详情
(XXVI)	41510	(2R)-2-[5-[[(tert-butoxycarbonyl)amino]methyl]-2-([2-[(3S)-7-chloro-2-(methoxycarbonyl)-1,3,4,5-tetrahydrobenzo[cd]indol-3-yl]acetyl]amino)phenoxy]propionic acid	C₃₀H₃₄ClN₃O₈	详情	详情

Extended Information