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【结 构 式】

【分子编号】12346

【品名】[(2R)-4-(4-fluorobenzyl)-1,4-oxazinan-2-yl]methyl phenylmethanesulfonate

【CA登记号】

【 分 子 式 】C19H22FNO4S

【 分 子 量 】379.4524232

【元素组成】C 60.14% H 5.84% F 5.01% N 3.69% O 16.87% S 8.45%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:((R)-IX)

The synthesis of the optical enantiomers of mosapride has been described: The reductocondensation of 4-fluorobenzaldehyde (I) with ethanolamine (II) by means of NaBH4 and NaHCO3 in refluxing methanol gives 2-(4-fluorobenzylamino)ethanol (III), which is condensed with epichlorohydrin (IV) to yield the diol (V). Compound (V), without isolation, is cyclized with conc. H2SO4 to afford 2-(chloromethyl)-4-(4-fluorobenzyl)morpholine (VI), which is treated with refluxing water-formamide to afford the corresponding methanol derivative (VII). Tosylation of (VII) with tosyl chloride and triethylamine/4-(dimethylamino)pyridine in dichloromethane gives the tosylate (VIII) as a racemic mixture. The optical resolution of (VIII) with N-(p-toluenesulfonyl)-L-glutamic acid in methanol affords the (S)-tosylate [(S)-IX] and the (R)-tosylate [(R)-IX]. The reaction of both [(S)-IX] and [(R)-IX] with sodium azide followed by reduction with bis(2-methoxyethoxy)aluminum hydride (vitride) gives the chiral amines [(S)-X] and [(R)-X], which are finally condensed with 4-amino-5-chloro-2-ethoxybenzoic acid (XI) by means of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (WSC) in dichloromethane, yielding the (S)- and (R)-enantiomers of mosapride.

1 Morie, T.; Kato, S.; Harada, H.; Yoshida, N.; Matsumoto, J.; Synthesis and biological activities of the optical isomers of (±)-4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]benzamide (mosapride). Chem Pharm Bull 1994, 42, 4, 877.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
((S)-IX) 12345 [(2S)-4-(4-fluorobenzyl)-1,4-oxazinan-2-yl]methyl phenylmethanesulfonate C19H22FNO4S 详情 详情
((R)-IX) 12346 [(2R)-4-(4-fluorobenzyl)-1,4-oxazinan-2-yl]methyl phenylmethanesulfonate C19H22FNO4S 详情 详情
((R)-X) 12347 [(2R)-4-(4-Fluorobenzyl)morpholinyl]methanamine; [(2R)-4-(4-Fluorobenzyl)morpholinyl]methylamine C12H17FN2O 详情 详情
((S)-X) 12348 [(2S)-4-(4-Fluorobenzyl)-1,4-oxazinan-2-yl]methylamine; [(2S)-4-(4-Fluorobenzyl)-1,4-oxazinan-2-yl]methanamine C12H17FN2O 详情 详情
(I) 12337 4-fluorobenzaldehyde 459-57-4 C7H5FO 详情 详情
(II) 10259 Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol;2-Aminoethyl alcohol 141-43-5 C2H7NO 详情 详情
(III) 12334 2-[(4-Fluorobenzyl)amino]-1-ethanol C9H12FNO 详情 详情
(IV) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(V) 12341 1-Chloro-3-[(4-fluorobenzyl)(2-hydroxyethyl)amino]-2-propanol C12H17ClFNO2 详情 详情
(VI) 12342 2-(Chloromethyl)-4-(4-fluorobenzyl)morpholine C12H15ClFNO 详情 详情
(VII) 12343 [4-(4-Fluorobenzyl)-2-morpholinyl]methanol C12H16FNO2 详情 详情
(VIII) 12344 [4-(4-fluorobenzyl)-2-morpholinyl]methyl 4-methylbenzenesulfonate C19H22FNO4S 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:(IX)

The chiral sulfonate [(R)-IX] has been obtained in a different way: The cyclization of 2(S)-(benzyloxymethyl)oxirane (XII) with 2-aminoethyl hydrogen sulfate sodium salt (XIII) by means of NaOH in methanol gives 2(R)-(benzyloxymethyl)morpholine (XIV), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol to the chiral alcohol (XV). The condensation of (XV) with 4-fluorobenzyl chloride (XVI) by means of K2CO3 and NaI in refluxing butanone affords 4-(4-fluorobenzyl)-2(R)-(hydroxymethyl)morpholine (XVII), which is finally tosylated with tosyl chloride as before to afford [(R)-IX], already obtained.

1 Morie, T.; Kato, S.; Harada, H.; Yoshida, N.; Matsumoto, J.; Synthesis and biological activities of the optical isomers of (±)-4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]benzamide (mosapride). Chem Pharm Bull 1994, 42, 4, 877.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IX) 12346 [(2R)-4-(4-fluorobenzyl)-1,4-oxazinan-2-yl]methyl phenylmethanesulfonate C19H22FNO4S 详情 详情
(XII) 12350 Benzyl (2R)oxiranylmethyl ether; (2R)-2-[(Benzyloxy)methyl]oxirane 14618-80-5 C10H12O2 详情 详情
(XIII) 12351 Sodium 1-amino-2-(sulfonatooxy)ethane C2H6NNaO4S 详情 详情
(XIV) 12352 Benzyl (2R)-1,4-oxazinan-2-ylmethyl ether; (2R)-2-[(Benzyloxy)methyl]-1,4-oxazinane C12H17NO2 详情 详情
(XV) 12353 (2R)-1,4-Oxazinan-2-ylmethanol C5H11NO2 详情 详情
(XVI) 12354 4-Fluorobenzyl chloride; 1-(Chloromethyl)-4-fluorobenzene 352-11-4 C7H6ClF 详情 详情
(XVII) 12344 [4-(4-fluorobenzyl)-2-morpholinyl]methyl 4-methylbenzenesulfonate C19H22FNO4S 详情 详情
Extended Information