(2S)-2-hydroxy-1-(4-morpholinyl)-1-propanone -Drug Synthesis Database

【结构式】

【分子编号】41498

【品名】(2S)-2-hydroxy-1-(4-morpholinyl)-1-propanone

【CA登记号】

【分子式】C₇H₁₃NO₃

【分子量】159.18516

【元素组成】C 52.82% H 8.23% N 8.8% O 30.15%

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：(XVI)

Alternatively, intermediate (XIII) can be obtained as follows: Heating of ethyl (S)-lactate (XIV) with morpholine affords amide (XVI), which then reacts with 3,4-dihydro-2H-pyran (A) in the presence of p-TsOH to give protected derivative (XVII). Grignard reaction between (XVII), bromo derivative (XVIII) and Mg turnings in THF yields protected ketone (XIX), which is treated with pyridinium p-toluenesulfonate (PPTS) (THP group removal) and reprotected by means of Tf2O and DIEA to give triflate derivative (XX). Conversion of (XX) into intermediate (XIII) is achieved by reaction with triazolone (VII) and NaH in THF.

参考文献中间体

合成目标

【1】 Tasaka, A.; Tamura, N.; Matsushita, Y.; Teranishi, K.; Hayashi, R.; Okonogi, K.; Itoh, K.; Optically active antifungal azoles. I. Synthesis and antifungal activity of (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-butanol and stereoisomers. Chem Pharm Bull 1993, 41, 6, 1035-42.
【2】 Kitazaki, T.; et al.; Optically active antifungal azoles. IX. An alternative synthetic route for 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone and its analogs. Chem Pharm Bull 1999, 47, 3, 360.

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)	13684	3,4-Dihydro-2H-pyran;2,3-Dihydro-4H-pyran; 5,6-Dihydro-4H-pyran;Dihydropyran	110-87-2	C₅H₈O	详情	详情
(VII)	43502	4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one		C₁₁H₉F₄N₃O₂	详情	详情
(XIII)	43507	2-[(1R)-2-(2,4-difluorophenyl)-1-methyl-2-oxoethyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one		C₂₀H₁₅F₆N₃O₃	详情	详情
(XIV)	43508	propyl (2S)-2-hydroxypropanoate	616-09-1	C₆H₁₂O₃	详情	详情
(XV)	10388	Morpholine	110-91-8	C₄H₉NO	详情	详情
(XVI)	41498	(2S)-2-hydroxy-1-(4-morpholinyl)-1-propanone		C₇H₁₃NO₃	详情	详情
(XVII)	43509	(2S)-1-(4-morpholinyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone		C₁₂H₂₁NO₄	详情	详情
(XVIII)	15488	1-bromo-2,4-difluorobenzene	348-57-2	C₆H₃BrF₂	详情	详情
(XIX)	43511	(2S)-1-(2,4-difluorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone		C₁₄H₁₆F₂O₃	详情	详情
(XX)	43510	(1S)-2-(2,4-difluorophenyl)-1-methyl-2-oxoethyl trifluoromethanesulfonate		C₁₀H₇F₅O₄S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XIII)

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

Extended Information