(2S)-2-(benzylamino)-2-(4-fluorophenyl)ethanoic acid -Drug Synthesis Database

【结构式】

【分子编号】44190

【品名】(2S)-2-(benzylamino)-2-(4-fluorophenyl)ethanoic acid

【CA登记号】

【分子式】C₁₅H₁₄FNO₂

【分子量】259.2801032

【元素组成】C 69.49% H 5.44% F 7.33% N 5.4% O 12.34%

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：(XIX)

Synthesis of morpholine intermediate (I): Treatment of 4-fluorophenyl acetic acid (X) with trimethylacetyl chloride (XI) and Et3N in Et2O followed by reaction with 4-(S)-benzyl-2-oxazolidinone (XII) in THF and n-BuLi in hexane affords oxazolidinone derivative (XIII). Conversion of (XIII) into azido derivative (XV) is achieved by first treatment of (XIII) in THF with a potassium bis(trimethylsilyl)amide solution in toluene followed by treatment with 2,4,6-triisopropylphenylsulfonyl azide (XIV) in THF. Hydrolysis of azido-oxazolidinone derivative (XV) by means of LiOH in THF/H2O yields azido acetic acid derivative (XVI), which is then hydrogenated over Pd/C in H2O/HOAc to afford (S)-(4-fluorophenyl)glycine (XVII). Treatment of (S)-(4-fluorophenyl)glycine (XVII) with benzaldehyde (XVIII), NaOH and NaBH4 in MeOH yields N-benzyl (S)-(4-fluorophenyl)glycine (XIX), which is then cyclized with 1,2-dibromoethane (XX) in the presence of DIEA in DMF to furnish morpholine intermediate (I).

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】 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 .
【3】 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 .

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
(X)	18999	4-Fluorophenylacetic acid; 2-(4-Fluorophenyl)acetic acid	405-50-5	C₈H₇FO₂	详情	详情
(XI)	13597	2,2-Dimethylpropanoyl chloride; Pivaloyl chloride	3282-30-2	C₅H₉ClO	详情	详情
(XII)	14694	(S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone	90719-32-7	C₁₀H₁₁NO₂	详情	详情
(XIII)	44186	(4S)-4-benzyl-3-[2-(4-fluorophenyl)acetyl]-1,3-oxazolidin-2-one		C₁₈H₁₆FNO₃	详情	详情
(XIV)	44187	2,4,6-triisopropylbenzenesulfonyl azide		C₁₅H₂₃N₃O₂S	详情	详情
(XV)	44188	(4S)-3-[(2S)-2-azido-2-(4-fluorophenyl)ethanoyl]-4-benzyl-1,3-oxazolidin-2-one		C₁₈H₁₅FN₄O₃	详情	详情
(XVI)	44189	(2S)-2-azido-2-(4-fluorophenyl)ethanoic acid		C₈H₆FN₃O₂	详情	详情
(XVII)	43098	(2R)-2-amino-2-(4-fluorophenyl)ethanoic acid	7292-73-1	C₈H₈FNO₂	详情	详情
(XVIII)	10498	Benzaldehyde;Benzoic aldehyde;Phenylmethanal	100-52-7	C₇H₆O	详情	详情
(XIX)	44190	(2S)-2-(benzylamino)-2-(4-fluorophenyl)ethanoic acid		C₁₅H₁₄FNO₂	详情	详情
(XX)	10252	1,2-Dibromoethane; Ethylene dibromide	106-93-4	C₂H₄Br₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XI)

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