|
【结 构 式】 
|
【分子编号】20650 【品名】methyl 5-chloro-5-oxopentanoate; methyl-4-chloroformylbutyrate 【CA登记号】1501-26-4 |
【 分 子 式 】C6H9ClO3 【 分 子 量 】164.58836 【元素组成】C 43.79% H 5.51% Cl 21.54% O 29.16% |
合成路线1
该中间体在本合成路线中的序号：(II)The condensation of ethyl bicyclo[4.3.0]nona-3-ene-8-carboxylate (I) with methyl 4-chloroformylbutanoate (II) by means of lithium diisopropylamide in THF yields the ketodiester (III), which is reduced with NaBH4 in methanol to the hydroxydiester (IV). Acetylation of (IV) in the usual way affords the acetate (V), which is submitted to ozonolysis with O3 to give the dialdehyde (VI). The intramolecular aldol condensation of (VI) by means of Zn++ yields the desired hydroxyaldehyde (VII), which is submitted to a Horner-Wittig condensation with 2-oxoheptylidenetributylphosphorane (VIII) affording the enone (IX). The protection of the enone (X) with dihydropyran as usual yields the tetrahydropyranylether (X), which is reduced with NaSH4 in methanol to the unsaturated alcohol (Xl).
| 【1】 Sakai, K.; Amemiya, S.; Kojima, K.; A novel synthesis (±)-carbacyclin. Chem Pharm Bull 1984, 32, 4, 1349-54. |
| 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) | 34336 | ethyl (3aR,7aS)-2,3,3a,4,7,7a-hexahydro-1H-indene-2-carboxylate | C12H18O2 | 详情 | 详情 | |
| (II) | 20650 | methyl 5-chloro-5-oxopentanoate; methyl-4-chloroformylbutyrate | 1501-26-4 | C6H9ClO3 | 详情 | 详情 |
| (III) | 34337 | ethyl (3aR,7aS)-2-(5-methoxy-5-oxopentanoyl)-2,3,3a,4,7,7a-hexahydro-1H-indene-2-carboxylate | C18H26O5 | 详情 | 详情 | |
| (IV) | 34338 | ethyl (3aR,7aS)-2-(1-hydroxy-5-methoxy-5-oxopentyl)-2,3,3a,4,7,7a-hexahydro-1H-indene-2-carboxylate | C18H28O5 | 详情 | 详情 | |
| (V) | 34339 | ethyl (3aR,7aS)-2-[1-(acetoxy)-5-methoxy-5-oxopentyl]-2,3,3a,4,7,7a-hexahydro-1H-indene-2-carboxylate | C20H30O6 | 详情 | 详情 | |
| (VI) | 34340 | ethyl (3R,4S)-1-[1-(acetoxy)-5-methoxy-5-oxopentyl]-3,4-bis(2-oxoethyl)cyclopentanecarboxylate | C20H30O8 | 详情 | 详情 | |
| (VII) | 34341 | ethyl (3aS,4R,5R,6aS)-2-[1-(acetoxy)-5-methoxy-5-oxopentyl]-4-formyl-5-hydroxyoctahydro-2-pentalenecarboxylate | C20H30O8 | 详情 | 详情 | |
| (VIII) | 34342 | 1-(tributylphosphoranylidene)-2-heptanone | C19H39OP | 详情 | 详情 | |
| (IX) | 34343 | ethyl (3aS,4S,5R,6aS)-2-[1-(acetoxy)-5-methoxy-5-oxopentyl]-5-hydroxy-4-[(E)-3-oxo-1-octenyl]octahydro-2-pentalenecarboxylate | C27H42O8 | 详情 | 详情 | |
| (X) | 34344 | ethyl (3aS,4S,5R,6aR)-2-[1-(acetoxy)-5-methoxy-5-oxopentyl]-4-[(E)-3-oxo-1-octenyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]octahydro-2-pentalenecarboxylate | C33H52O9 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Keto ester (III) was prepared by Friedel-Crafts acylation of 2-fluorobiphenyl (I) with methyl glutaryl chloride (II). Subsequent Pfitzinger condensation of (III) with 5-fluoroisatin (IV) furnished the quinoline derivative (V). Chlorination of diacid (V) with SOCl2, followed by treatment with methanol produced selectively the mono-ester (VI). The remaining carboxyl group of (VI) was activated with SOCl2 in the presence of DMF, and subsequently coupled with n-octyl amine to generate amide (VII). The methyl ester group of (VII) was then hydrolyzed to acid (VIII), which was further subjected to intramolecular ring closure upon heating with triflic acid to afford the tetracyclic system (IX). Keto group reduction in (IX) to give (X) was accomplished by a two-step procedure with NaBH4 and then with HI and Ac2O.
| 【1】 Chujo, I.; et al.; Synthetic study on novel immunosuppressant KF20444. Bioorg Med Chem 2001, 9, 12, 3273. |
| 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) | 31388 | 2-fluoro-1,1'-biphenyl | 321-60-8 | C12H9F | 详情 | 详情 |
| (II) | 20650 | methyl 5-chloro-5-oxopentanoate; methyl-4-chloroformylbutyrate | 1501-26-4 | C6H9ClO3 | 详情 | 详情 |
| (III) | 56572 | methyl 5-(2'-fluoro[1,1'-biphenyl]-4-yl)-5-oxopentanoate | C18H17FO3 | 详情 | 详情 | |
| (IV) | 21552 | 5-fluoro-1H-indole-2,3-dione | 443-69-6 | C8H4FNO2 | 详情 | 详情 |
| (V) | 56573 | 3-(2-carboxyethyl)-6-fluoro-2-(2'-fluoro[1,1'-biphenyl]-4-yl)-4-quinolinecarboxylic acid | C25H17F2NO4 | 详情 | 详情 | |
| (VI) | 56574 | 6-fluoro-2-(2'-fluoro[1,1'-biphenyl]-4-yl)-3-(3-methoxy-3-oxopropyl)-4-quinolinecarboxylic acid | C26H19F2NO4 | 详情 | 详情 | |
| (VII) | 56575 | methyl 3-{6-fluoro-2-(2'-fluoro[1,1'-biphenyl]-4-yl)-4-[(octylamino)carbonyl]-3-quinolinyl}propanoate | C34H36F2N2O3 | 详情 | 详情 | |
| (VIII) | 56576 | 3-{6-fluoro-2-(2'-fluoro[1,1'-biphenyl]-4-yl)-4-[(octylamino)carbonyl]-3-quinolinyl}propanoic acid | C33H34F2N2O3 | 详情 | 详情 | |
| (IX) | 56577 | 10-fluoro-3-(2-fluorophenyl)-N-octyl-5-oxo-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]quinoline-8-carboxamide | C33H32F2N2O2 | 详情 | 详情 | |
| (X) | 56578 | 10-fluoro-3-(2-fluorophenyl)-N-octyl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]quinoline-8-carboxamide | C33H34F2N2O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)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4
该中间体在本合成路线中的序号：(XV)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5
该中间体在本合成路线中的序号：(XV)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 |
合成路线6
该中间体在本合成路线中的序号：(V)Condensation of 4-nitrophthalic anhydride (I) with O-benzyl hydroxylamine in refluxing toluene produced phthalimide (II). Catalytic transfer hydrogenation employing cyclohexene in the presence of Pd/C yielded 4-amino-N-hydroxyphthalimide (III), which was condensed with ethanesulfonyl chloride to give sulfonate (IV). Finally, acylation with acid chloride (V) furnished the title compound.
| 【1】 Kerrigan, J.E.; et al.; 6-Acylamino-2-[(alkylsulfonyl)oxy]-1H-isoindole-1,3-dione mechanism-based inhibitors of human leukocyte elastase. Bioorg Med Chem Lett 2000, 10, 1, 27. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 | |
| (I) | 31028 | 5-nitro-2-benzofuran-1,3-dione | 5466-84-2 | C8H3NO5 | 详情 | 详情 |
| (II) | 38147 | 2-(benzyloxy)-5-nitro-1H-isoindole-1,3(2H)-dione | C15H10N2O5 | 详情 | 详情 | |
| (III) | 38148 | 5-amino-2-hydroxy-1H-isoindole-1,3(2H)-dione | C8H6N2O3 | 详情 | 详情 | |
| (IV) | 38149 | 5-amino-2-[(ethylsulfonyl)oxy]-1H-isoindole-1,3(2H)-dione | C10H10N2O5S | 详情 | 详情 | |
| (V) | 20650 | methyl 5-chloro-5-oxopentanoate; methyl-4-chloroformylbutyrate | 1501-26-4 | C6H9ClO3 | 详情 | 详情 |