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【结 构 式】 
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【分子编号】43098 【品名】(2R)-2-amino-2-(4-fluorophenyl)ethanoic acid 【CA登记号】7292-73-1 |
【 分 子 式 】C8H8FNO2 【 分 子 量 】169.1554632 【元素组成】C 56.8% H 4.77% F 11.23% N 8.28% O 18.92% |
合成路线1
该中间体在本合成路线中的序号：(XVII)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：(XVII)Alternatively (XVII) can be obtained as follows: Reaction of 4-fluorophenyl acetic (X) with thionyl chloride in toluene in the presence of DMF provides 4-fluorophenyl acetyl chloride (XXII), which is treated with bromine and light irradiation followed by reaction with methanol to furnish methyl bromoacetate derivative (XXIII). Treatment of (XXIII) with benzyl triethylammonium chloride (XXIV) and NaN3 in MeOH followed by hydrogenation over Pd/C in MeOH gives methyl glycine derivative (XXV) in a racemic mixture, from which (XVII) is obtained by crystallization of the corresponding dibenzoyl tartaric (DBT) salts followed by salt hydrolysis by means of refluxing HCl.
| 【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 |
|---|---|---|---|---|---|---|
| (X) | 18999 | 4-Fluorophenylacetic acid; 2-(4-Fluorophenyl)acetic acid | 405-50-5 | C8H7FO2 | 详情 | 详情 |
| (XVII) | 43098 | (2R)-2-amino-2-(4-fluorophenyl)ethanoic acid | 7292-73-1 | C8H8FNO2 | 详情 | 详情 |
| (XXII) | 37014 | 2-(4-fluorophenyl)acetyl chloride | 459-04-1 | C8H6ClFO | 详情 | 详情 |
| (XXIII) | 44191 | methyl 2-bromo-2-(4-fluorophenyl)acetate | C9H8BrFO2 | 详情 | 详情 | |
| (XXIV) | 31937 | Triethylbenzylammonium chloride; N-benzyl-N,N-diethyl-1-ethanaminium chloride; Benzyltriethylammonium chloride | 56-37-1 | C13H22ClN | 详情 | 详情 |
| (XXV) | 44192 | methyl 2-amino-2-(4-fluorophenyl)acetate | C9H10FNO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIII)The chiral amino alcohol (XIV) was obtained by reduction of (R)-(4-fluorophenyl)glycine (XIII) with LiAlH4. Finally, reductive condensation of amino alcohol (XIII) with piperidinone (XII) provided the title compound.
| 【1】 Matassa, V.G.; Pengilley, R.R.; Russell, M.G.N.; et al.; 3-[3-(Piperidin-1-yl)propyl]indoles as highly selective h5-HT1D receptor agonists. J Med Chem 1999, 42, 24, 4981. |
| 【2】 Baker, R.; Bourrain, S.; Castro Pineiro, J.L.; Chambers, M.S.; Guiblin, A.R.; Hobbs, S.C.; Jelley, R.A.; Madin, A.; Matassa, V.G.; Reeve, A.J.; Russell, M.G.N.; Showell, G.A.; Sternfeld, F.; Street, L.J.; Van Niel, M.B. (Merck Sharp & Dohme Ltd.); Azetidine, pyrrolidine and piperidine derivs.. EP 0804434; JP 1998503768; US 5854268; WO 9604274 . |
合成路线4
该中间体在本合成路线中的序号：(X)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 |
合成路线5
该中间体在本合成路线中的序号：(VI)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.
| 【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 |