[(2R)-4-(4-fluorobenzyl)-1,4-oxazinan-2-yl]methyl phenylmethanesulfonate -Drug Synthesis Database

【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 合成路线2

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.

参考文献中间体

合成目标

【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.

参考文献中间体

合成目标

【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