2-Methyl-2-[[5-(Trifluoromethyl)-2-Pyridinyl]Oxy]Propanoic Acid -Drug Synthesis Database

【结构式】

【分子编号】65585

【品名】2-Methyl-2-[[5-(Trifluoromethyl)-2-Pyridinyl]Oxy]Propanoic Acid

【CA登记号】605680-62-4

【分子式】C₁₀H₁₀F₃NO₃

【分子量】249.1895496

【元素组成】C 48.2% H 4.04% F 22.87% N 5.62% O 19.26%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(I)

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.

参考文献中间体

合成目标

【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：(I)

Two procedures have been reported for the synthesis of the intermediate 2-methyl-2-[5-(trifluoromethyl)pyridin-2-yloxy]propionic acid (I). 2-Chloro-5-(trifluoromethyl)pyridine (XXIII) is coupled with lithium lactate (XXIV) employing NaH in hot DMF to produce the 2-(pyridyloxy)propionic acid (XXV). After esterification of acid (XXV) with trimethylsilyldiazomethane in MeOH/CH2Cl2, the resulting methyl ester is alkylated with iodomethane and sodium hexamethyldisilazide to furnish the (pyridyloxy)isobutyrate (XXVI). Subsequent hydrolysis of methyl ester (XXVI) with NaOH in H2O/MeOH/THF provides the target carboxylic acid intermediate (I) (1). Alternatively, the condensation of 2-hydroxy-5-(trifluoromethyl)pyridine (XXVII) with ethyl 2-bromoisobutyrate (XXVIII) in the presence of cesium carbonate provides the 2-(pyridyloxy)isobutyrate ester (XXIX), which is hydrolyzed to the corresponding carboxylic acid (I) by means of NaOH in acetonitrile/water (2, 3). Scheme 3.

参考文献中间体

合成目标

【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.

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)	65585	2-Methyl-2-[[5-(Trifluoromethyl)-2-Pyridinyl]Oxy]Propanoic Acid	605680-62-4	C₁₀H₁₀F₃NO₃	详情	详情
(XXIII)	59113	2-Chloro-5-(trifluoromethyl)pyridine; 5-Trifluoromethyl-2-chloropyridine	52334-81-3	C₆H₃ClF₃N	详情	详情
(XXIV)	65604	Lithium Lactate	16891-53-5	C₃H₅LiO₃	详情	详情
(XXV)	65605			C₉H₈F₃NO₃	详情	详情
(XXVI)	65606			C₁₁H₁₂F₃NO₃	详情	详情
(XXVII)	65607	2-Hydroxy-5-trifluoromethylpyridine; 5-(Trifluoromethyl)pyridin-2-ol	33252-63-0	C₆H₄F₃NO	详情	详情
(XXVIII)	39799	ethyl 2-bromo-2-methylpropanoate	600-00-0	C₆H₁₁BrO₂	详情	详情
(XXIX)	65608	2-Methyl-2-[[5-(Trifluoromethyl)-2-Pyridinyl]Oxy]-Propanoic Acid Ethyl Ester	913849-17-9	C₁₂H₁₄F₃NO₃	详情	详情

Extended Information