(2R,3S)-4-benzyl-3-(4-fluorophenyl)morpholinyl 3,5-bis(trifluoromethyl)benzoate -Drug Synthesis Database

【结构式】

【分子编号】18291

【品名】(2R,3S)-4-benzyl-3-(4-fluorophenyl)morpholinyl 3,5-bis(trifluoromethyl)benzoate

【CA登记号】

【分子式】C₂₆H₂₀F₇NO₃

【分子量】527.4385624

【元素组成】C 59.21% H 3.82% F 25.21% N 2.66% O 9.1%

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：(IV)

Reduction of morpholinone (I) with L-Selectride in THF at -78 C produced the intermediate lactol (II), which was condensed at low temperature with 3,5-bis(trifluoromethyl)benzoyl chloride (III) to afford acyl acetal (IV). Further reaction with dimethyl titanocene in THF-toluene at 80 C provided enol ether (V). Catalytic hydrogenation of the double bond, with concomitant N-benzyl group hydrogenolysis, yielded a 8:1 mixture of diastereomers, from which the major isomer (VI) was isolated by column chromatography. Alkylation of morpholine (VI) with N-methoxycarbonyl-2-chloroacetamidrazone (VII) (obtained by reaction of chloroacetonitrile (IX) with NaOMe and methyl carbazate in MeOH) in the presence of N-ethyl diisopropylamine (DIEA) in acetonitrile gave the intermediate (VIII), which was finally cyclized to the desired triazolone in refluxing xylene.

参考文献中间体

合成目标

【1】 Castaner, J.; Silvestre, J.S.; Bayes, M.; Sorbera, L.A.; Aprepitant and L-758298. Drugs Fut 2002, 27, 3, 211.
【2】 Cowden, C.J.; et al.; A new synthesis of 1,2,4-triazolin-5-ones: Application to the convergent synthesis of an NK1 antagonist. Tetrahedron Lett 2000, 41, 44, 8661.
【4】 Dorn, C.P.; Hale, J.J.; Maccoss, M.; Mills, S.G.; Ladduwahetty, T.; Shah, S.K. (Merck & Co., Inc.); Morpholine and thiomorpholine tachykinin receptor antagonists. EP 0577394; JP 1994172178; US 5719147; WO 9400440; WO 9516679 .
【5】 Dorn, C.P.; Hale, J.J.; Maccoss, M.; Mills, S.G. (Merck & Co., Inc.); Prodrugs of morpholine tachykinin receptor antagonists. EP 0748320; JP 1997509935; US 5691336; WO 9523798 .
【6】 MacCoss, M.; Hale, J.J.; Mills, S.G.; et al.; Phosphorylated morpholine acetal human neurokinin-1 receptor antagonists as water-soluble prodrugs. J Med Chem 2000, 43, 6, 1234.
【7】 Dolling, U.H.; Wilson, R.D.; Hands, D.; Cottrell, I.F. (Merck Sharp & Dohme Ltd.); Chemical synthesis of morpholine derivs.. WO 9965900 .
【8】 Cowden, C.J. (Merck Sharp & Dohme Ltd.); Process for the preparation of 1,2,4-triazolin-5-one derivs.. WO 0196315 .
【3】 Hale, J.J.; Mills, S.G.; MacCoss, M.; Finke, P.E.; Cascieri, M.A.; Sadowski, S.; Ber, E.; Chicchi, G.G.; Kurtz, M.; Metzger, J.; Eiermann, G.; Tsou, N.N.; Tattersall, F.D.; Rupniak, N.M.; Williams, A.R.; Rycroft, W.; Hargreaves, R.; MacIntyre, D.E.; Structural optimization affording 2-(R)-(1-(R)-3,5-bis(trifluoromethyl)phenylethoxy)-3(S)-(4-fluoro)phenyl-4-(3-oxo-1,2,4-triazol-5-yl)methylmorpholine, a potent, orally active, long-acting morpholine acetal human NK-1 receptor antagonist. J Med Chem 1998, 41, 23, 4607.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	18288	(3S)-4-benzyl-3-(4-fluorophenyl)-2-morpholinone		C₁₇H₁₆FNO₂	详情	详情
(II)	18289	(2S,3S)-4-benzyl-3-(4-fluorophenyl)-2-morpholinol		C₁₇H₁₈FNO₂	详情	详情
(III)	18290	3,5-Bis(trifluoromethyl)benzoyl chloride	785-56-8	C₉H₃ClF₆O	详情	详情
(IV)	18291	(2R,3S)-4-benzyl-3-(4-fluorophenyl)morpholinyl 3,5-bis(trifluoromethyl)benzoate		C₂₆H₂₀F₇NO₃	详情	详情
(V)	18292	(2R,3S)-4-benzyl-2-([1-[3,5-bis(trifluoromethyl)phenyl]vinyl]oxy)-3-(4-fluorophenyl)morpholine; (2R,3S)-4-benzyl-3-(4-fluorophenyl)morpholinyl 1-[3,5-bis(trifluoromethyl)phenyl]vinyl ether		C₂₇H₂₂F₇NO₂	详情	详情
(VI)	18293	(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl (2R,3S)-3-(4-fluorophenyl)morpholinyl ether; (2R,3S)-2-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-3-(4-fluorophenyl)morpholine	171482-05-6	C₂₀H₁₈F₇NO₂	详情	详情
(VII)	18294	methyl (Z)-2-chloro-1-hydrazinoethylidenecarbamate		C₄H₈ClN₃O₂	详情	详情
(VIII)	18295	methyl (Z)-2-[(2R,3S)-2-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-3-(4-fluorophenyl)morpholinyl]-1-hydrazinoethylidenecarbamate		C₂₄H₂₅F₇N₄O₄	详情	详情
(IX)	14443	2-chloroacetonitrile; chloroacetonitrile	107-14-2	C₂H₂ClN	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XVI)

Reductive alkylation of (S)-(4-fluorophenyl)glycine (VI) with benzaldehyde and NaBH4 generated the N-benzyl amino acid (XI). This was cyclized with 1,2-dibromoethane (XII) to yield the morpholinone (XIII). Reduction of the lactone function of (XIII) with L-Selectride at -70 C, followed by acylation of the intermediate lactol (XIV) with 3,5-bis(trifluoromethyl)benzoyl chloride (XV), furnished the aroyloxy morpholine (XVI) as the main isomer. Ester (XVI) was converted to the enol ether (XVII) upon treatment with dimethyltitanocene, generated from titanocene dichloride and methyllithium. Catalytic hydrogenation of the enol ether double bond of (XVII) with simultaneous benzyl group hydrogenolysis generated the desired morpholine (XVIII) along with its diastereoisomer (XIX); these were separated by flash chromatography.

参考文献中间体

合成目标

【1】 Baker, R.; Harrison, T.; Mcleod, A.M.; Owens, A.P.; Seward, E.M.; Swain, C.J.; Teall, M.R. (Merck Sharp & Dohme Ltd.); Substd. morpholine derivs. and their use as therapeutic agents. EP 0737192; EP 1099702; JP 1997507484; JP 2000219629; US 5612337; WO 9518124 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VI)	43098	(2R)-2-amino-2-(4-fluorophenyl)ethanoic acid	7292-73-1	C₈H₈FNO₂	详情	详情
(XI)	44190	(2S)-2-(benzylamino)-2-(4-fluorophenyl)ethanoic acid		C₁₅H₁₄FNO₂	详情	详情
(XII)	10252	1,2-Dibromoethane; Ethylene dibromide	106-93-4	C₂H₄Br₂	详情	详情
(XIII)	18288	(3S)-4-benzyl-3-(4-fluorophenyl)-2-morpholinone		C₁₇H₁₆FNO₂	详情	详情
(XIV)	18289	(2S,3S)-4-benzyl-3-(4-fluorophenyl)-2-morpholinol		C₁₇H₁₈FNO₂	详情	详情
(XV)	18290	3,5-Bis(trifluoromethyl)benzoyl chloride	785-56-8	C₉H₃ClF₆O	详情	详情
(XVI)	18291	(2R,3S)-4-benzyl-3-(4-fluorophenyl)morpholinyl 3,5-bis(trifluoromethyl)benzoate		C₂₆H₂₀F₇NO₃	详情	详情
(XVII)	18292	(2R,3S)-4-benzyl-2-([1-[3,5-bis(trifluoromethyl)phenyl]vinyl]oxy)-3-(4-fluorophenyl)morpholine; (2R,3S)-4-benzyl-3-(4-fluorophenyl)morpholinyl 1-[3,5-bis(trifluoromethyl)phenyl]vinyl ether		C₂₇H₂₂F₇NO₂	详情	详情
(XVIII)	18293	(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl (2R,3S)-3-(4-fluorophenyl)morpholinyl ether; (2R,3S)-2-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-3-(4-fluorophenyl)morpholine	171482-05-6	C₂₀H₁₈F₇NO₂	详情	详情
(XIX)	53292	(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl (2R,3S)-3-(4-fluorophenyl)morpholinyl ether; (2R,3S)-2-({(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-3-(4-fluorophenyl)morpholine	n/a	C₂₀H₁₈F₇NO₂	详情	详情

Extended Information