【结 构 式】 |
【分子编号】41507 【品名】tert-butyl 4-amino-3-[[(1R)-1-methyl-2-(4-morpholinyl)-2-oxoethyl]oxy]benzylcarbamate 【CA登记号】 |
【 分 子 式 】C19H29N3O5 【 分 子 量 】379.45648 【元素组成】C 60.14% H 7.7% N 11.07% O 21.08% |
合成路线1
该中间体在本合成路线中的序号:(XXIII)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.
【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:(XXIII)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.
【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 |
---|---|---|---|---|---|---|
(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 |