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【结 构 式】 
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【分子编号】20654 【品名】3-[(2S,3R)-2-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxoazetidinyl]propanoyl chloride 【CA登记号】 |
【 分 子 式 】C25H21ClFNO3 【 分 子 量 】437.8977832 【元素组成】C 68.57% H 4.83% Cl 8.1% F 4.34% N 3.2% O 10.96% |
合成路线1
该中间体在本合成路线中的序号：(V)Treatment of acid chloride (I) with tributylamine generated the corresponding ketene, which was cyclocondensed to imine (II) to produce the racemic trans b-lactam (III). Resolution of (III) into enantiomers was then achieved by preparative HPLC on a Chiralcel OD column. Subsequent saponification of the desired enantiomer with methanolic LiOH afforded acid (IV), which was converted to acid chloride (V) upon treatment with oxalyl chloride. Further Pd-mediated coupling of (V) with the arylzinc reagent (VI) provided ketone (VII). Then, carbonyl reduction with BH3-Me2S, followed by chromatographic separation of the isomers furnished alcohol (VIII), which was finally deprotected by hydrogenolysis over Pd/C to afford the target phenol.
| 【1】 Afonso, A.; Davis, H.R. Jr.; Huynh, T.; Yumibe, N.; Clader, J.W.; Burnett, D.A.; Rosenblum, S.B.; Discovery of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone (SCH 58235): A designed, potent, orally active inhibitor of cholesterol absorption. J Med Chem 1998, 41, 6, 973. |
| 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) | 20650 | methyl 5-chloro-5-oxopentanoate; methyl-4-chloroformylbutyrate | 1501-26-4 | C6H9ClO3 | 详情 | 详情 |
| (II) | 20651 | N-[(E)-[4-(benzyloxy)phenyl]methylidene]-4-fluoroaniline; N-[(E)-[4-(benzyloxy)phenyl]methylidene]-N-(4-fluorophenyl)amine | C20H16FNO | 详情 | 详情 | |
| (III) | 20652 | (rac)-methyl 3-[(2S*,3R*)-2-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxoazetidinyl]propanoate | C26H24FNO4 | 详情 | 详情 | |
| (IV) | 20653 | 3-[(2S,3R)-2-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxoazetidinyl]propionic acid | C25H22FNO4 | 详情 | 详情 | |
| (V) | 20654 | 3-[(2S,3R)-2-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxoazetidinyl]propanoyl chloride | C25H21ClFNO3 | 详情 | 详情 | |
| (VI) | 20655 | bromo(4-fluorophenyl)zinc | C6H4BrFZn | 详情 | 详情 | |
| (VII) | 20656 | (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]-2-azetidinone | C31H25F2NO3 | 详情 | 详情 | |
| (VIII) | 20657 | (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-2-azetidinone | C31H27F2NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：trans-(XVIII)3) The reaction of 4-hydroxybenzaldehyde (XII) with benzyl bromide and K2CO3 in acetone gives 4-(benzyloxy)benzaldehyde (XIII), which is condensed with 4-fluoroaniline (XIV) in isopropanol, yielding the imine (II). Cyclization of (II) with methyl 4-(chloroformyl)butyrate (XV) by means of tributylamine in toluene affords the trans-azetidinone (XVI), which is hydrolyzed with LiOH in THF/water to provide the propionic acid derivative (XVII). The reaction of (XVII) with oxalyl chloride in dichloromethane gives the corresponding acyl chloride (XVIII), which is condensed with 4-fluorophenylmagnesium bromide (XIX) by means of ZnCl2 and Pd(PPh3)4 in THF to yield a racemic mixture of saturated trans-azetidinones that was resolved by chiral HPLC to the trans-(3R,4S)-enantiomer (XX). The enantioselective reduction of (XX) with BH3 and the chiral oxaborole catalyst CBS gives the benzylated alcohol (XI), which is finally debenzylated as before with H2 over Pd/C in ethanol.
| 【1】 Vaccaro, W.D.; Sher, R.; Davis, H.R. Jr.; 2-Azetidinone cholesterol absorption inhibitors: Increased potency by substitution of the C-4 phenyl ring. Bioorg Med Chem 1998, 6, 9, 1429. |
| 【2】 Rosenblum, S.B.; Dugar, S.; Burnett, D.A.; Clader, J.W.; McKittrick, B.A. (Schering Corp.); Hydroxy-substd. azetidinone cpds. useful as hypocholesterolemic agents. EP 0720599; JP 1996509989; US 5631365; WO 9508532 . |
| 【3】 Castañer, R.M.; Sorbera, L.A.; Castañer, J.; Ezetimibe. Drugs Fut 2000, 25, 7, 679. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| trans-(XVI) | 20652 | (rac)-methyl 3-[(2S*,3R*)-2-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxoazetidinyl]propanoate | C26H24FNO4 | 详情 | 详情 | |
| trans-(XVII) | 20653 | 3-[(2S,3R)-2-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxoazetidinyl]propionic acid | C25H22FNO4 | 详情 | 详情 | |
| trans-(XVIII) | 20654 | 3-[(2S,3R)-2-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxoazetidinyl]propanoyl chloride | C25H21ClFNO3 | 详情 | 详情 | |
| (II) | 37689 | N-[(Z)-[4-(benzyloxy)phenyl]methylidene]-4-fluoroaniline; N-[(Z)-[4-(benzyloxy)phenyl]methylidene]-N-(4-fluorophenyl)amine | C20H16FNO | 详情 | 详情 | |
| (XI) | 20657 | (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-2-azetidinone | C31H27F2NO3 | 详情 | 详情 | |
| (XII) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (XIII) | 29179 | 4-(Benzyloxy)benzaldehyde | 4397-53-9 | C14H12O2 | 详情 | 详情 |
| (XIV) | 37690 | 4-fluorophenylamine; 4-fluoroaniline | 371-40-4 | C6H6FN | 详情 | 详情 |
| (XV) | 20650 | methyl 5-chloro-5-oxopentanoate; methyl-4-chloroformylbutyrate | 1501-26-4 | C6H9ClO3 | 详情 | 详情 |
| (XIX) | 13643 | 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide | 352-13-6 | C6H4BrFMg | 详情 | 详情 |
| (XX) | 20656 | (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]-2-azetidinone | C31H25F2NO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXV)4) The reaction of methyl 4-(chloroformyl)butyrate (XV) with the chiral oxazolidinone (XXI) by means of DMAP and TEA in dichloromethane gives the acylated oxazolidinone (XXII), which is cyclized with the benzylideneimine (II) by means of TiCl4, titanium isopropoxide and TBAF in dichloromethane, yielding trans-(3R,4S)-azetidinone (XXIII). This chiral compound (XXIII) is worked up to give ezetimibe by the same reaction sequence used for its racemic analogue (XVI) but without optical resolution. 5) Racemic trans-azetidinone (XVI) can be submitted to chiral chromatography (Chiracel OD column), microbial or enzymatic subtractive resolution to provide the trans-(3R,4S)-azetidinone (XXIII) or direct microbial or enzymatic hydrolytic resolution to directly provide the trans-(3R,4S)-azetidinone-propionic acid (XXIV), the compound also obtained by hydrolysis of (XXIII) with LiOH. This (3R,4S)-free acid (XXIV) is treated with oxalyl chloride giving the (3R,4S)-acyl chloride (XXV), which by condensation with 4-fluorophenylmagnesium bromide (XIX) yields the (3R,4S)-azetidinone (XX). Reduction of (XX) with borane-dimethylsulfide complex in THF affords an equal mixture of diasteromeric alcohols that was submitted to chiral chromatography on a Chiracel OD column providing the benzylated (3'S)-alcohol (XI).
| 【1】 Afonso, A.; Davis, H.R. Jr.; Huynh, T.; Yumibe, N.; Clader, J.W.; Burnett, D.A.; Rosenblum, S.B.; Discovery of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone (SCH 58235): A designed, potent, orally active inhibitor of cholesterol absorption. J Med Chem 1998, 41, 6, 973. |
| 【2】 Castañer, R.M.; Sorbera, L.A.; Castañer, J.; Ezetimibe. Drugs Fut 2000, 25, 7, 679. |
| 【3】 Homann, M.J.; Morgan, W.B. (Schering Corp.); Resolution of trans-2-(alkoxycarbonylethyl)-lactams useful in the synthesis of 1-(4-fluoro-phenyl)-3(R)-[(S)-hydroxy-3-(4-fluorophenyl)-propyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone. US 5919672 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| trans-(XVI),(XX | 20652 | (rac)-methyl 3-[(2S*,3R*)-2-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxoazetidinyl]propanoate | C26H24FNO4 | 详情 | 详情 | |
| (II) | 37689 | N-[(Z)-[4-(benzyloxy)phenyl]methylidene]-4-fluoroaniline; N-[(Z)-[4-(benzyloxy)phenyl]methylidene]-N-(4-fluorophenyl)amine | C20H16FNO | 详情 | 详情 | |
| (XI) | 20657 | (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-2-azetidinone | C31H27F2NO3 | 详情 | 详情 | |
| (XV) | 20650 | methyl 5-chloro-5-oxopentanoate; methyl-4-chloroformylbutyrate | 1501-26-4 | C6H9ClO3 | 详情 | 详情 |
| (XIX) | 13643 | 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide | 352-13-6 | C6H4BrFMg | 详情 | 详情 |
| (XX) | 20656 | (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]-2-azetidinone | C31H25F2NO3 | 详情 | 详情 | |
| (XXI) | 12173 | (4S)-4-Phenyl-1,3-oxazolan-2-one; (4S)-4-Phenyl-2-oxazolidinone; (S)-(+)-4-Phenyl-2-oxazolidinone | 99395-88-7 | C9H9NO2 | 详情 | 详情 |
| (XXII) | 37691 | methyl 5-oxo-5-[(4S)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]pentanoate | C15H17NO5 | 详情 | 详情 | |
| (XXIII) | 65066 | methyl 3-[(2S,3R)-2-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxoazetidinyl]propanoate | C26H24FNO4 | 详情 | 详情 | |
| (XXIV) | 20653 | 3-[(2S,3R)-2-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxoazetidinyl]propionic acid | C25H22FNO4 | 详情 | 详情 | |
| (XXV) | 20654 | 3-[(2S,3R)-2-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxoazetidinyl]propanoyl chloride | C25H21ClFNO3 | 详情 | 详情 |