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【结 构 式】 
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【分子编号】65586 【品名】3-[(1RS,2RS)-2-Amino-1-[(4-Chlorophenyl)Methyl]Propyl]Benzonitrile 【CA登记号】 |
【 分 子 式 】C17H17ClN2 【 分 子 量 】284.78816 【元素组成】C 71.7% H 6.02% Cl 12.45% N 9.84% |
合成路线1
该中间体在本合成路线中的序号：(Iia)Taranabant can be prepared by two different synthetic strategies. 2-Methyl-2-[5-(trifluoromethyl)pyridin-2-yloxy]propionic acid (I) is chlorinated with oxalyl chloride and DMF in CH2Cl2, and the resulting acid chloride is then coupled with 3-(4-chlorophenyl)-2(R,S)-(3-cyanophenyl)-1(R,S)-methylpropylamine (IIa) by means of NMM in CH2Cl2 to produce racemic taranabant, which is finally resolved employing chiral HPLC (1-3). Similarly, the target enantiomer is obtained by condensation of acid (I) with the (S,S)-amine (IIb) using cyanuric chloride and NMM as the coupling reagents (4). In an alternative method, acid (I) is converted to the carboxamide (III) by chlorination with SOCl2 followed by treatment with ammonium hydroxide. Subsequent coupling of amide (III) with the enol tosylate (IV) in the presence of Pd2(dba)3 and 1,4-bis(diphenylphosphino)butane (dppb) gives the N-acyl enamine (V). After hydrolysis of the cyano group to the corresponding carboxamide with K2CO3 and H2O2, asymmetric hydrogenation of the enamine double bond over chiral rhodium catalysts (generated from a dienerhodium complex salt and chiral diphosphine ligands) provides the desired isomer (VI). Reconversion of carboxamide (VI) to the target nitrile is finally accomplished by treatment with cyanuric chloride in DMF/MTBE (5, 6). Scheme 1.
| 【1】 Hagmann, W.K., Lin, L.S., Shah, S.K. et al. (Merck & Co., Inc.). Substituted amides. CA 2478183, EP 1496838, JP 2005519958, JP 2006257090, US 2004058820, US 6972295, WO 03077847. |
| 【2】 Hagmann, W.K., Lin, L.S., Shah, S.K. et al. (Merck & Co., Inc.). Substituted amides active at the cannabinoid-1 receptor. WO 2004048317. |
| 【3】 Lin, L.S., Lanza, T.J. Jr., Jewell, J.P. et al. Discovery of N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-[[5-(trifluoromethyl)pyridin-2-yl]oxy]propanamide (MK-0364), a novel, acyclic cannabinoid-1 receptor inverse agonist for the treatment of obesity. J Med Chem 2006, 49(26): 7584-7. |
| 【4】 Chen, C., Frey, L.F., Shultz, S. et al. Catalytic, enantioselective synthesis of taranabant, a novel, acyclic cannabinoid-1 receptor inverse agonist for the treatment of obesity. Org Proc Res Devel 2007, 11(3): 616-23. |
| 【5】 Campos, K.R., Klapars, A., McWilliams, J.C. et al. (Merck & Co., Inc.). Formation of tetra-substituted enamides and stereoselective reduction thereof. WO 2006017045. |
| 【6】 Weissman, S.A. (Merck & Co., Inc.). Cyanation of aromatic halides. US 2006106223. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Iia) | 65586 | 3-[(1RS,2RS)-2-Amino-1-[(4-Chlorophenyl)Methyl]Propyl]Benzonitrile | C17H17ClN2 | 详情 | 详情 | |
| (Iib) | 65587 | 3-[(1S,2S)-2-Amino-1-[(4-Chlorophenyl)Methyl]Propyl]Benzonitrile | 732982-66-0 | C17H17ClN2 | 详情 | 详情 |
| (I) | 65585 | 2-Methyl-2-[[5-(Trifluoromethyl)-2-Pyridinyl]Oxy]Propanoic Acid | 605680-62-4 | C10H10F3NO3 | 详情 | 详情 |
| (III) | 65588 | C10H11F3N2O2 | 详情 | 详情 | ||
| (IV) | 65589 | C24H20ClNO3S | 详情 | 详情 | ||
| (V) | 65590 | C26H21ClF3N3O2 | 详情 | 详情 | ||
| (VI) | 65591 | C27H27ClF3N3O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(Iia)Intermediates (II) and (IV) are prepared as follows. Alkylation of the sodium enolate of methyl 3-bromophenylacetate (VII) with 4-chlorobenzyl bromide (VIII) in cold THF followed by methyl ester hydrolysis with LiOH in aqueous acetonitrile affords 2-(m-bromophenyl)-3-(p-chlorophenyl)propionic acid (IX), which is converted to the corresponding Weinreb amide (X) by chlorination with oxalyl chloride and subsequent treatment with N,O-dimethylhydroxylamine. Addition of methylmagnesium bromide to the methoxyamide (X) gives the 3,4-diaryl-2-butanone (XI), which is then reduced using NaBH4 or LiBH(s-Bu)3 (L-selectride) to provide alcohol (XIIa) as the major diastereoisomer. After conversion of alcohol (XIIa) to the corresponding mesylate, displacement with NaN3 in hot DMF leads to azide (XIII), which is reduced by catalytic hydrogenation in the presence of PtO2 and Boc2O to afford the Boc-protected amine (XIV). Then, palladium-catalyzed substitution of the aryl bromide (XIV) with zinc cyanide yields the nitrile (XV), which is deprotected to (IIa) using HCl in EtOAc (2, 3). Similarly, coupling between 3-bromobenzonitrile (XVI) and isopropenyl acetate (XVII) in the presence of Pd2(dba)3 and 2-(dicyclohexylphosphino)-2’-(dimethylamino)biphenyl (DCPDMAB) gives 1-(m-cyanophenyl)acetone (XVIII), which is alkylated with 3-chlorobenzyl chloride (XIX) in the presence of cesium hydroxide and tetrabutylammonium iodide to yield the diarylbutanone (XX). Reduction of ketone (XX) with lithium tri(sec-butyl)borohydride produces alcohol (XXI), which is converted to the Boc-protected amine (XV) by mesylation followed by displacement with NaN3, and then reduction of the resulting azide (XXII) by catalytic hydrogenation in the presence of PtO2 and Boc2O (1). The ketonitrile (XX) is alternatively produced by palladium-catalyzed cyanuration of aryl bromide (XI) with either zinc cyanide or potassium ferrocyanide. The intermediate enol tosylate (IV) can be obtained by treatment of (XX) with sodium tert-butoxide and p-toluenesulfonic anhydride (5, 6). Preparation of the enantiomerically pure amine (IIb) can be accomplished by resolution at the stage of the diarylpropionic acid (IX) or, in a more efficient method, by dynamic kinetic resolution of (XI) via stereoselective hydrogenation to (XIIb) in the presence of the chiral Ru catalyst [(S)-xyl-BINAP]-[(S)-DAIPEN]RuCl2 and excess potassium tert-butoxide (4). Scheme 2.
| 【1】 Hagmann, W.K., Lin, L.S., Shah, S.K. et al. (Merck & Co., Inc.). Substituted amides. CA 2478183, EP 1496838, JP 2005519958, JP 2006257090, US 2004058820, US 6972295, WO 03077847. |
| 【2】 Hagmann, W.K., Lin, L.S., Shah, S.K. et al. (Merck & Co., Inc.). Substituted amides active at the cannabinoid-1 receptor. WO 2004048317. |
| 【3】 Lin, L.S., Lanza, T.J. Jr., Jewell, J.P. et al. Discovery of N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-[[5-(trifluoromethyl)pyridin-2-yl]oxy]propanamide (MK-0364), a novel, acyclic cannabinoid-1 receptor inverse agonist for the treatment of obesity. J Med Chem 2006, 49(26): 7584-7. |
| 【4】 Chen, C., Frey, L.F., Shultz, S. et al. Catalytic, enantioselective synthesis of taranabant, a novel, acyclic cannabinoid-1 receptor inverse agonist for the treatment of obesity. Org Proc Res Devel 2007, 11(3): 616-23. |
| 【5】 Campos, K.R., Klapars, A., McWilliams, J.C. et al. (Merck & Co., Inc.). Formation of tetra-substituted enamides and stereoselective reduction thereof. WO 2006017045. |
| 【6】 Weissman, S.A. (Merck & Co., Inc.). Cyanation of aromatic halides. US 2006106223. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIIa) | 65595 | C16H16BrClO | 详情 | 详情 | ||
| (XIIb) | 65596 | C16H16BrClO | 详情 | 详情 | ||
| (Iia) | 65586 | 3-[(1RS,2RS)-2-Amino-1-[(4-Chlorophenyl)Methyl]Propyl]Benzonitrile | C17H17ClN2 | 详情 | 详情 | |
| (Iib) | 65587 | 3-[(1S,2S)-2-Amino-1-[(4-Chlorophenyl)Methyl]Propyl]Benzonitrile | 732982-66-0 | C17H17ClN2 | 详情 | 详情 |
| (IV) | 65582 | (R )-(-)-4-Penten-2-ol | 64584-92-5 | C5H10O | 详情 | 详情 |
| (VII) | 50901 | methyl 2-(3-bromophenyl)acetate | 150529-73-0 | C9H9BrO2 | 详情 | 详情 |
| (VIII) | 16481 | 1-(bromomethyl)-4-chlorobenzene | 622-95-7 | C7H6BrCl | 详情 | 详情 |
| (IX) | 65592 | C15H12BrClO2 | 详情 | 详情 | ||
| (X) | 65593 | C17H17BrClNO2 | 详情 | 详情 | ||
| (XI) | 65594 | 3-(3-Bromophenyl)-4-(4-Chlorophenyl)Butan-2-One | 848310-98-5 | C16H14BrClO | 详情 | 详情 |
| (XIII) | 65597 | C16H15BrClN3 | 详情 | 详情 | ||
| (XIV) | 65598 | C21H25BrClNO2 | 详情 | 详情 | ||
| (XV) | 65599 | C22H25ClN2O2 | 详情 | 详情 | ||
| (XVI) | 26573 | 3-bromobenzonitrile | 6952-59-6 | C7H4BrN | 详情 | 详情 |
| (XVII) | 21178 | isopropenyl acetate | 108-22-5 | C5H8O2 | 详情 | 详情 |
| (XVIII) | 65600 | (3-Cyanophenyl)Acetone | C10H9NO | 详情 | 详情 | |
| (XIX) | 10356 | 1-Chloro-4-(chloromethyl)benzene; 4-Chlorobenzyl chloride | 104-83-6 | C7H6Cl2 | 详情 | 详情 |
| (XX) | 65601 | C17H14ClNO | 详情 | 详情 | ||
| (XXI) | 65602 | C17H16ClNO | 详情 | 详情 | ||
| (XXII) | 65603 | C17H15ClN4 | 详情 | 详情 |