• English
  • 简体中文
Login Register
Current Location: Home > Feedback Help Print

【结 构 式】

【分子编号】44189

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

【CA登记号】

【 分 子 式 】C8H6FN3O2

【 分 子 量 】195.1530632

【元素组成】C 49.24% H 3.1% F 9.74% N 21.53% O 16.4%

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:(XVI)

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).

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:(V)

The first method required the chiral building block (S)-(4-fluorophenyl)glycine (VI), which was prepared from 4-fluorophenyl acetic acid (I) by two routes. Condensation of (I) with (S)-4-benzyl-2-oxazolidinone (II), via activation as the corresponding mixed anhydride with pivaloyl chloride, furnished the N-acyl oxazolidinone (III). The potassium enolate of (III) was then reacted with 2,4,6-triisopropylphenylsulfonyl azide, producing stereoselectively azide (IV). Hydrolytic removal of the chiral auxiliary of (IV) gave (S)-azido-(4-fluorophenyl)acetic acid (V), which was then reduced to the desired amino acid (VI) by catalytic hydrogenation over Pd/C. Alternatively, 4-fluorophenyl acetic acid (I) was converted to the corresponding acid chloride (VII) with SOCl2. Bromination of (VII) under Hell-Volhard-Zelinskii conditions, followed by quenching with MeOH, afforded the racemic alpha-bromo ester (VIII). Displacement of the bromide of (VIII) with NaN3 using a phase-transfer catalyst produced the azido ester (IX). Catalytic hydrogenation of the azido group of (IX) gave the racemic amino ester, which was resolved via formation of the diastereomeric salts with (+)-dibenzoyltartaric acid. The desired (S)-amino ester (X) was then hydrolyzed to (VI) under acidic conditions.

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
(I) 18999 4-Fluorophenylacetic acid; 2-(4-Fluorophenyl)acetic acid 405-50-5 C8H7FO2 详情 详情
(II) 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
(III) 44186 (4S)-4-benzyl-3-[2-(4-fluorophenyl)acetyl]-1,3-oxazolidin-2-one C18H16FNO3 详情 详情
(IV) 44188 (4S)-3-[(2S)-2-azido-2-(4-fluorophenyl)ethanoyl]-4-benzyl-1,3-oxazolidin-2-one C18H15FN4O3 详情 详情
(V) 44189 (2S)-2-azido-2-(4-fluorophenyl)ethanoic acid C8H6FN3O2 详情 详情
(VI) 37104 (8R,9S,10R,13S,14S,17S)-17-hydroxy-2-[(Z)-hydroxymethylidene]-4,10,13,17-tetramethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-one C22H32O3 详情 详情
(VII) 44191 methyl 2-bromo-2-(4-fluorophenyl)acetate C9H8BrFO2 详情 详情
(VIII) 53260 (1R,3S,5R)-3-{[tert-butyl(dimethyl)silyl]oxy}tricyclo[3.2.0.0~2,7~]heptan-6-one n/a C13H22O2Si 详情 详情
(IX) 53261 bicyclo[3.2.0]hept-2-en-6-one 13173-09-6 C7H8O 详情 详情
(X) 43098 (2R)-2-amino-2-(4-fluorophenyl)ethanoic acid 7292-73-1 C8H8FNO2 详情 详情
Extended Information