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【结 构 式】 
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【药物名称】Atrasentan, A-147627, (+)-A-127722, ABT-627 【化学名称】1-(N,N-Dibutylcarbamoylmethyl)-2(R)-(4-methoxyphenyl)-4(S)-(3,4-methylenedioxyphenyl)pyrrolidine-3(R)-carboxylic acid 【CA登记号】173937-91-2, 195733-43-8 (monohydrochloride) 【 分 子 式 】C29H38N2O6 【 分 子 量 】510.63601 |
【开发单位】Abbott (Originator) 【药理作用】Brain Cancer Therapy, Breast Cancer Therapy, CARDIOVASCULAR DRUGS, Diabetic Nephropathy, Agents for, ENDOCRINE DRUGS, Heart Failure Therapy, Lung Cancer Therapy, Oncolytic Drugs, Ovarian Cancer Therapy, Prostate Cancer Therapy, Renal Cancer Therapy, Treatment of Diabetic Complications, Angiogenesis Inhibitors, Endothelin ETA Receptor Antagonists |
合成路线1
The Michael reaction between 3,4-(methylenedioxy)-beta-nitrostyrene (I) and ethyl (4-methoxybenzoyl)acetate (II) in the presence of DBU gave adduct (III) as a mixture of isomers. Hydrogenation of this nitro ketone over Raney-Ni afforded, after spontaneous cyclization of the resulting amino ketone, the pyrroline (IV). Further reduction of the imine with NaBH3CN yielded a mixture of three pyrrolidine isomers. The desired trans-trans isomer (VI) could not be separated from the cis-trans isomer by column chromatography. However, the pure cis-cis compound (V) was isomerized to (VI) with NaOEt in refluxing EtOH. The protection of the amine as the tert-butyl carbamate with Boc2O, and saponification of the ester function provided the racemic acid (VII). Resolution of (VII) was achieved by conversion to the mixed anhydride (VIII) with pivaloyl chloride, followed by condensation with the lithium salt of (S)-4-benzyl-2-oxazolidinone (IX), and chromatographic separation of the resulting diastereomeric imides. Alternatively, racemic (VII) could be resolved by crystallization of its salt with (R)-a-methylbenzylamine. Removal of the Boc group from the appropriate isomer (X) with HCl in dioxan, followed by alkylation with N,N-dibutylbromoacetamide (XI) in the presence of i-Pr2NEt furnished the pyrrolidinylacetamide (XII). Finally, hydrolysis of the imide with lithium hydroperoxide provided the target acid.
| 【1】 Winn, M.; et al.; 2,4-Diarylpyrrolidine-3-carboxylic acids-potent ETA selective endothelin receptor antagonists. 1. Discovery of A-127722. J Med Chem 1996, 39, 5, 1039. |
| 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) | 20675 | 5-[(E)-2-nitroethenyl]-1,3-benzodioxole | 1485-00-3 | C9H7NO4 | 详情 | 详情 |
| (II) | 20676 | ethyl 3-(4-methoxyphenyl)-3-oxopropanoate | C12H14O4 | 详情 | 详情 | |
| (III) | 20677 | ethyl 3-(1,3-benzodioxol-5-yl)-2-(4-methoxybenzoyl)-4-nitrobutanoate | C21H21NO8 | 详情 | 详情 | |
| (IV) | 20678 | ethyl 3-(1,3-benzodioxol-5-yl)-5-(4-methoxyphenyl)-3,4-dihydro-2H-pyrrole-4-carboxylate | C21H21NO5 | 详情 | 详情 | |
| (V) | 20679 | ethyl (2S,3R,4R)-4-(1,3-benzodioxol-5-yl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylate | C21H23NO5 | 详情 | 详情 | |
| (VI) | 20680 | ethyl (2S,3S,4R)-4-(1,3-benzodioxol-5-yl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylate | C21H23NO5 | 详情 | 详情 | |
| (VII) | 20681 | (2S,3S,4R)-4-(1,3-benzodioxol-5-yl)-1-(tert-butoxycarbonyl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylic acid | C24H27NO7 | 详情 | 详情 | |
| (VIII) | 20682 | (2S,3S,4R)-4-(1,3-benzodioxol-5-yl)-1-(tert-butoxycarbonyl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylic 1,1-dimethylpropionic anhydride | C29H35NO8 | 详情 | 详情 | |
| (IX) | 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 |
| (X) | 20684 | tert-butyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-3-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-2-(4-methoxyphenyl)-1-pyrrolidinecarboxylate | C34H36N2O8 | 详情 | 详情 | |
| (XI) | 20685 | 2-Bromo-N,N-dibutylacetamide; N,N-Dibutylbromoacetamide | C10H20BrNO | 详情 | 详情 | |
| (XII) | 20686 | 2-[(2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-3-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-2-(4-methoxyphenyl)pyrrolidinyl]-N,N-dibutylacetamide | C39H47N3O7 | 详情 | 详情 |
合成路线2
Cyclization of 5-(2-nitrovinyl)-1,3-benzodioxole (I) with ethyl 2-(4-methoxybenzoyl)acetate (II) by means of DBU in THF gives the 4-nitrobutyrate (III), which is reduced with H2 over Ni in ethanol to the corresponding amine, which undergoes immediate cyclization to give the pyrroline carboxylate (IV). Reduction of pyrroline (IV) with NaCNBH3 in THF affords the expected pyrrolidine as a mixture of the (trans,trans)-(V), (cis,cis)-(VI) and (cis,trans)-(VII) isomers. Using chromatography on silica gel, only the (cis,cis)-isomer (VI) is separated and completely isomerized to the (trans,trans)-isomer (V) by treatment with NaOEt in refluxing ethanol. Pure (trans,trans)-isomer (V) or the remaining mixture of (trans,trans)-(V) and (cis,trans)-(VII) is N-protected with Boc2O in dichloromethane to provide a mixture of carbamates. Then hydrolysis of the esters is performed with NaOH in ethanol/water at room temperature, and under these conditions only the (trans,trans)-isomer hydrolyzes, giving the racemic (trans,trans)-acid (VIII). Unreacted (cis,trans)-ester (VII) is easily removed by conventional methods. Condensation of the racemic acid (VIII) with the lithium salt of the chiral oxazolidinone (IX) by means of pivaloyl chloride yields the corresponding amide as a diastereomeric mixture of (X) and (XI) that are separated by chromatography. The desired isomer (XI) is deprotected with HCl in dioxane to afford the chiral pyrrolidine (XII), which is condensed with 2-bromo-N,N-dibutylacetamide (XIII) by means of diisopropylamine in acetonitrile to give the adduct (XIV). Finally, the chiral auxiliary of (XIV) is eliminated by means of LiOOH (LiOH + H2O2) in water.
| 【1】 Leeson, P.; Castañer, R.M.; Sorbera, L.A.; Castañer, J.; Atrasentan. Drugs Fut 2001, 26, 10, 939. |
| 【2】 Winn, M.; et al.; 2,4-Diarylpyrrolidine-3-carboxylic acids-potent ETA selective endothelin receptor antagonists. 1. Discovery of A-127722. J Med Chem 1996, 39, 5, 1039. |
| 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) | 20675 | 5-[(E)-2-nitroethenyl]-1,3-benzodioxole | 1485-00-3 | C9H7NO4 | 详情 | 详情 |
| (II) | 20676 | ethyl 3-(4-methoxyphenyl)-3-oxopropanoate | C12H14O4 | 详情 | 详情 | |
| (III) | 20677 | ethyl 3-(1,3-benzodioxol-5-yl)-2-(4-methoxybenzoyl)-4-nitrobutanoate | C21H21NO8 | 详情 | 详情 | |
| (IV) | 20678 | ethyl 3-(1,3-benzodioxol-5-yl)-5-(4-methoxyphenyl)-3,4-dihydro-2H-pyrrole-4-carboxylate | C21H21NO5 | 详情 | 详情 | |
| (V) | 20680 | ethyl (2S,3S,4R)-4-(1,3-benzodioxol-5-yl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylate | C21H23NO5 | 详情 | 详情 | |
| (VI) | 20679 | ethyl (2S,3R,4R)-4-(1,3-benzodioxol-5-yl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylate | C21H23NO5 | 详情 | 详情 | |
| (VII) | 48684 | ethyl (2S,4S)-4-(1,3-benzodioxol-5-yl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylate | C21H23NO5 | 详情 | 详情 | |
| (VIII) | 20681 | (2S,3S,4R)-4-(1,3-benzodioxol-5-yl)-1-(tert-butoxycarbonyl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylic acid | C24H27NO7 | 详情 | 详情 | |
| (IX) | 10793 | [(4S)-4-Benzyl-2-oxo-1,3-oxazolidin-3-yl]lithium | C10H10LiNO2 | 详情 | 详情 | |
| (X) | 48685 | tert-butyl (2S,3S,4R)-4-(1,3-benzodioxol-5-yl)-3-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-2-(4-methoxyphenyl)-1-pyrrolidinecarboxylate | C34H36N2O8 | 详情 | 详情 | |
| (XI) | 20684 | tert-butyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-3-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-2-(4-methoxyphenyl)-1-pyrrolidinecarboxylate | C34H36N2O8 | 详情 | 详情 | |
| (XII) | 48686 | (4S)-3-[[(2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-(4-methoxyphenyl)pyrrolidinyl]carbonyl]-4-benzyl-1,3-oxazolidin-2-one | C29H28N2O6 | 详情 | 详情 | |
| (XIII) | 20685 | 2-Bromo-N,N-dibutylacetamide; N,N-Dibutylbromoacetamide | C10H20BrNO | 详情 | 详情 | |
| (XIV) | 20686 | 2-[(2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-3-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-2-(4-methoxyphenyl)pyrrolidinyl]-N,N-dibutylacetamide | C39H47N3O7 | 详情 | 详情 |
合成路线3
Condensation of 1,3-benzodioxole-5-carbaldehyde (XV) with nitromethane by means of ammonium acetate in HOAc gives the nitrostyrene (I), which is condensed with ethyl 2-(4-methoxybenzoyl)acetate (II) [obtained by reaction of acetophenone (XVI), diethyl carbonate and potassium tert-amyloxide] by means of NaOEt in THF to yield the 4-nitrobutyrate (III). Reductive cyclization of (III) with H2 over Raney-Ni in THF affords the (cis, cis)-pyrrolidine (VI), which is isomerized to the (trans,trans)-isomer (V) by means of NaOEt in refluxing ethanol. This racemic ester (V) is submitted to optical resolution with (S)-(+)-mandelic acid to provide the pure chiral ester (XVII). This compound is condensed with 2-bromo-N,N-dibutylacetamide (XIII) [obtained by reaction of 2-bromoacetyl bromide (XVIII) with dibutylamine (XIX) in toluene] by means of DIEA in acetonitrile to give the ethyl ester (XX), which is finally hydrolyzed with NaOH in hot ethanol.
| 【1】 Leeson, P.; Castañer, R.M.; Sorbera, L.A.; Castañer, J.; Atrasentan. Drugs Fut 2001, 26, 10, 939. |
| 【2】 Winn, M.; Boyd, S.A.; Hutchins, C.W.; Tasker, A.S.; Von Geldern, T.W.; Kester, J.A.; Sorensen, B.K.; Szczepankiewicz, B.G.; Henry, K.J. Jr.; Liu, G.; Wittenberger, S.J.; King, S.A. (Abbott Laboratories Inc.); Novel benzo-1,3-dioxolyl- and benzofuranyl substd. pyrrolidine derivs. as endothelin antagonists. EP 0885215; WO 9730045 . |
| 【3】 Jae, H.-S.; Hutchins, C.W.; Szczepankiewicz, B.G.; King, S.A.; Winn, M.; Boyd, S.A.; Henry, K.J.; Geldern, T.W.; Wittenberger, S.J.; Tasker, A.S.; Sorensen, B.K.; Kester, J.A. (Abbott Laboratories Inc.); Endothelin antagonists. WO 9906397 . |
| 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) | 20675 | 5-[(E)-2-nitroethenyl]-1,3-benzodioxole | 1485-00-3 | C9H7NO4 | 详情 | 详情 |
| (II) | 20676 | ethyl 3-(4-methoxyphenyl)-3-oxopropanoate | C12H14O4 | 详情 | 详情 | |
| (III) | 20677 | ethyl 3-(1,3-benzodioxol-5-yl)-2-(4-methoxybenzoyl)-4-nitrobutanoate | C21H21NO8 | 详情 | 详情 | |
| (VI) | 20679 | ethyl (2S,3R,4R)-4-(1,3-benzodioxol-5-yl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylate | C21H23NO5 | 详情 | 详情 | |
| (XIII) | 20685 | 2-Bromo-N,N-dibutylacetamide; N,N-Dibutylbromoacetamide | C10H20BrNO | 详情 | 详情 | |
| (XV) | 10127 | 1,3-Benzodioxole-5-carbaldehyde; Heliotropine | 120-57-0 | C8H6O3 | 详情 | 详情 |
| (XVI) | 11041 | 4-Methoxyacetophenone; 1-(4-Methoxyphenyl)-1-ethanone | 100-06-1 | C9H10O2 | 详情 | 详情 |
| (XVII) | 20680 | ethyl (2S,3S,4R)-4-(1,3-benzodioxol-5-yl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylate | C21H23NO5 | 详情 | 详情 | |
| (XVIII) | 14005 | 2-Bromoacetyl bromide; Bromoacetyl bromide | 598-21-0 | C2H2Br2O | 详情 | 详情 |
| (XIX) | 33492 | N,N-dibutylamine; N-butyl-1-butanamine | 111-92-2 | C8H19N | 详情 | 详情 |
| (XX) | 48687 | ethyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylate | C31H42N2O6 | 详情 | 详情 |
合成路线4
Reaction of 2-(1,3-dioxol-5-yl)acetic acid (XXI) with pivaloyl chloride and TEA gives the corresponding anhydride (XXII), which is condensed with the chiral oxazolidinone (XXIII) by means of n-BuLi in THF to yield the amide (XXIV). Condensation of (XXIV) with 2-bromoacetic acid tert-butyl ester (XXV) by means of NaHMDS in THF affords the adduct (XXVI). Elimination of the chiral auxiliary of (XXVI) by means of LiOOH in THF/water provides the chiral succinic acid hemiester (XXVII) (93% ee), which is selectively reduced with BH3THF complex to give the 4-hydroxysuccinate (XXVIII). Reaction of succinate (XXVIII) with 4-chlorophenylsulfonyl chloride, TEA and DMAP in dichloromethane yields the sulfonate (XXIX), which is condensed with 4-methoxybenzaldoxime (XXX) by means of Cs2CO3 in hot acetonitrile to afford the oxime ether (XXXI). Transesterification of the tert-butyl ester of (XXXI) with trimethyl orthoformate and p-toluenesulfonic acid in hot methanol provides the methyl ester (XXXII), which is cyclized by means of trimethylsilyl triflate and tributylamine in dichloroethane to afford a 9:1 diastereomeric mixture of perhydro-1,2-oxazines (XXXIII) and (XXXIV) which is easily separated. The reductive N-O-bond cleavage of the major oxazine diastereomer (XXXIII) by means of Zn/HOAc or H2 over Pd/C gives the trisubstituted 4-aminobutanol (XXXV), which is cyclized by means of CBr4, PPh3 and TEA to yield chiral pyrrolidine (XXXVI) (4). Finally, pyrrolidine (XXXVI) is alkylated with N,N-dibutyl-2-bromoacetamide (XIII) followed by ester hydrolysis as before.
| 【1】 Leeson, P.; Castañer, R.M.; Sorbera, L.A.; Castañer, J.; Atrasentan. Drugs Fut 2001, 26, 10, 939. |
| 【2】 McLaughlin, M.A.; Wittenberger, S.J.; Preparation of endothelin antagonist ABT-627. Tetrahedron Lett 1999, 40, 7175. |
| 【3】 Winn, M.; et al.; 2,4-Diarylpyrrolidine-3-carboxylic acids-potent ETA selective endothelin receptor antagonists. 1. Discovery of A-127722. J Med Chem 1996, 39, 5, 1039. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15787 | 4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride | 98-60-2 | C6H4Cl2O2S | 详情 | 详情 | |
| (XIII) | 20685 | 2-Bromo-N,N-dibutylacetamide; N,N-Dibutylbromoacetamide | C10H20BrNO | 详情 | 详情 | |
| (XXI) | 18117 | 2-(1,3-benzodioxol-5-yl)acetic acid; 3,4-(Methylenedioxy)phenylacetic acid | 2861-28-1 | C9H8O4 | 详情 | 详情 |
| (XXII) | 48688 | 1,3-benzodioxol-5-ylacetic 1,1-dimethylpropionic anhydride | C14H16O5 | 详情 | 详情 | |
| (XXIII) | 12867 | (4S)-4-Isopropyl-1,3-oxazolidin-2-one; (R)-4-Isopropyl-2-oxazolidinone | 17016-83-0 | C6H11NO2 | 详情 | 详情 |
| (XXIV) | 48689 | (4S)-3-[2-(1,3-benzodioxol-5-yl)acetyl]-4-isopropyl-1,3-oxazolidin-2-one | C15H17NO5 | 详情 | 详情 | |
| (XXV) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (XXVI) | 48690 | tert-butyl (3S)-3-(1,3-benzodioxol-5-yl)-4-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-4-oxobutanoate | C21H27NO7 | 详情 | 详情 | |
| (XXVII) | 48691 | (2S)-2-(1,3-benzodioxol-5-yl)-4-(tert-butoxy)-4-oxobutyric acid | C15H18O6 | 详情 | 详情 | |
| (XXVIII) | 48692 | tert-butyl (3S)-3-(1,3-benzodioxol-5-yl)-4-hydroxybutanoate | C15H20O5 | 详情 | 详情 | |
| (XXIX) | 48693 | tert-butyl (3S)-3-(1,3-benzodioxol-5-yl)-4-[[(4-chlorophenyl)sulfonyl]oxy]butanoate | C21H23ClO7S | 详情 | 详情 | |
| (XXX) | 48694 | 4-methoxybenzaldehyde oxime | C8H9NO2 | 详情 | 详情 | |
| (XXXI) | 48695 | tert-butyl (3S)-3-(1,3-benzodioxol-5-yl)-4-([[(E)-(4-methoxyphenyl)methylidene]amino]oxy)butanoate | C23H27NO6 | 详情 | 详情 | |
| (XXXII) | 48696 | methyl (3S)-3-(1,3-benzodioxol-5-yl)-4-([[(E)-(4-methoxyphenyl)methylidene]amino]oxy)butanoate | C20H21NO6 | 详情 | 详情 | |
| (XXXIII) | 48697 | methyl (3R,4R,5S)-5-(1,3-benzodioxol-5-yl)-3-(4-methoxyphenyl)-1,2-oxazinane-4-carboxylate | C20H21NO6 | 详情 | 详情 | |
| (XXXIV) | 48698 | methyl (3S,5S)-5-(1,3-benzodioxol-5-yl)-3-(4-methoxyphenyl)-1,2-oxazinane-4-carboxylate | C20H21NO6 | 详情 | 详情 | |
| (XXXV) | 48699 | methyl (2R,3S)-2-[(R)-amino(4-methoxyphenyl)methyl]-3-(1,3-benzodioxol-5-yl)-4-hydroxybutanoate | C20H23NO6 | 详情 | 详情 | |
| (XXXVI) | 48700 | methyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylate | C20H21NO5 | 详情 | 详情 |