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【结 构 式】

【药物名称】telcagepant, MK-0974

【化学名称】N-[6(S)-(2,3-Difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)perhydroazepin-(3R)-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide

【CA登记号】781649-09-0, 781649-31-8 (racemate), 784157-00-2 (hydrochloride), 915312-27-5 (potassium salt)

【 分 子 式 】C26H27F5N6O3

【 分 子 量 】566.5232

【开发单位】Merck & Co., Inc. (US).

【药理作用】Calcitonin gene-related peptide (CGRP) antagonist, Antimigraine agent

合成路线1

MK-0974 (I) can be prepared by condensation of 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine (II) with aminoazepinone (III) using either p-nitrophenyl chloroformate (1) or carbonyl diimidazole (CDI) (2-5) in the presence of Et3N. Treatment of (I) with potassium tert-butoxide in ethanol gives the corresponding potassium salt ethanolate (2-5). The intermediate imidazopyridine (II) can be prepared by two related methods. Reductive alkylation of 2,3-diaminopyridine (IV) with 1-Boc-4-piperidone (V) in the presence of NaBH(OAc)3 in CH2Cl2 gives the piperidinylamino pyridine (VI), which on treatment with CDI in CH3CN yields the pyridoimidazolone derivative (VII). Acidic Boc group cleavage in (VII) then provides the target intermediate (II) (1). In a related method, 3-amino-2-chloropyridine (VIII) is reductively alkylated with 1-(ethoxycarbonyl)-4-piperidone (IX) using either NaBH(OAc)3 or NaBH4 in the presence of trifluoroacetic acid to provide (X), which is converted to the N-carbamoyl derivative (XI) upon treatment with chlorosulfonyl isocyanate. Then, cyclization of (XI) by means of palladium diacetate and bis(diphenylphosphino)butane leads to the protected imidazopyridinone (XII), from which the N-carbethoxy group is removed by hydrolysis under alkaline conditions to furnish intermediate (II) (2-5). Scheme 1.

1 Burgey, C.S., Deng, Z.J., Williams, T.M., Paone, D.V., Shaw, A.W., Nguyen, D.N. (Merck & Co., Inc.). CGRP receptor antagonists. EP 1638969, JP 2006523697, US 2004229861, US 6953790, WO 2004092166, WO 2004092168.
2 Palucki, M., Davies, I., Steinhuebel, D., Rosen, J. (Merck & Co., Inc.). Process for the preparation of caprolactam CGRP antagonist intermediate. WO 2007120589.
3 McLaughlin, M., Palucki, M., Marcantonio, K. (Merck & Co., Inc.). Process for the preparation of pyridine heterocycle CGRP antagonist intermediate. WO 2007120590.
4 Belyk, K., Rivera, N. (Merck & Co., Inc.). Process for the preparation of CGRP antagonist. WO 2007120591.
5 Belyk, K. (Merck & Co., Inc.). CGRP antagonist salt. WO 2007120592.
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) 65554 Telcagepant; MK-0974; N-[(3R,6S)-6-(2,3-Difluorophenyl)hexahydro-2-oxo-1-(2,2,2-trifluoroethyl)-1H-azepin-3-yl]-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-1-yl)-1-piperidinecarboxamide 781649-09-0 C26H27F5N6O3 详情 详情
(II) 65555 1-(Piperidin-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; 1-Piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one 185961-99-3 C11H14N4O 详情 详情
(III) 65556 (3R,6S)-3-Amino-6-(2,3-difluorophenyl)hexahydro-2-oxo-1-(2,2,2-trifluoroethyl)-1H-azepine   C14H15F5N2O 详情 详情
(IV) 54816 2,3-Diaminopyridine 452-58-4 C5H7N3 详情 详情
(V) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(VI) 65557     C15H24N4O2 详情 详情
(VII) 65558 tert-Butyl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate; 4-(2,3-Dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-1-yl)-1-piperidinecarboxylic acid 1,1-dimethylethyl ester 781649-87-4 C16H22N4O3 详情 详情
(VIII) 11160 2-Chloro-3-pyridinamine; 2-Chloro-3-pyridinylamine; 3-Amino-2-chloropyridine; 2-Chloro-3-aminopyridine 6298-19-7 C5H5ClN2 详情 详情
(IX) 13486 Ethyl 4-oxo-1-piperidinecarboxylate; N-Carbethoxy-4-piperidone 29976-53-2 C8H13NO3 详情 详情
(X) 65559     C13H18ClN3O2 详情 详情
(XI) 65560     C14H19ClN3O3 详情 详情
(XII) 65561     C14H18N4O3 详情 详情

合成路线2

In an alternative route to intermediate (III), ortho-metalation of 1,2-difluorobenzene (XXIV) with n-hexyllithium in THF followed by sequential addition of ZnCl2, CuCl and then chloroacetyl chloride (XXV) gives 2-chloro-2’,3’-difluoroacetophenone (XXVI). Subsequent condensation of chloroketone (XXVI) with vinylmagnesium bromide followed by cyclization of the resulting chlorohydrin (XXVII) under alkaline conditions yields epoxide (XXVIII). This is then coupled with diethyl acetamidomalonate (XXIX) in the presence of Pd(OAc)2 and 1,2-bis(diphenylphosphino)ethane (dppe) to generate the allyl alcohol adduct (XXX), which after conversion to the corresponding mesylate (XXXI) is reacted with 2,2,2-trifluoroethylamine (XXXII) in dimethylacetamide to furnish the allylic amine (XXXIII). Decarbethoxylation of malonate (XXXIII) by heating with LiCl in moist dimethylacetamide provides the N-acetyl aminoester (XXXIV). Then, cyclization of (XXXIV) by means of trifluoroacetic acid in hot toluene gives the azepinone derivative (XXXV). After acidic hydrolysis of acetamide (XXXV), the resulting racemic amine is resolved utilizing (-)-O,O’-di-p-toluoyl-L-tartaric acid (DTTA) in the presence of a trace amount of 5-nitrosalicylaldehyde to provide the (S)-amine ditoluoyltartrate salt (XXXVI). Finally, liberation of the tartrate salt (XXXVI) with HCl in isopropanol and simultaneous hydrogenation of the azepine double bond in the presence of Pd/BaSO4 provides the trans-perhydroazepinone (III) (2-5). Scheme 3.

2 Palucki, M., Davies, I., Steinhuebel, D., Rosen, J. (Merck & Co., Inc.). Process for the preparation of caprolactam CGRP antagonist intermediate. WO 2007120589.
3 McLaughlin, M., Palucki, M., Marcantonio, K. (Merck & Co., Inc.). Process for the preparation of pyridine heterocycle CGRP antagonist intermediate. WO 2007120590.
4 Belyk, K., Rivera, N. (Merck & Co., Inc.). Process for the preparation of CGRP antagonist. WO 2007120591.
5 Belyk, K. (Merck & Co., Inc.). CGRP antagonist salt. WO 2007120592.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(III) 65556 (3R,6S)-3-Amino-6-(2,3-difluorophenyl)hexahydro-2-oxo-1-(2,2,2-trifluoroethyl)-1H-azepine   C14H15F5N2O 详情 详情
(XXIV) 65570 1,2-Difluorobenzene 367-11-3 C6H4F2 详情 详情
(XXV) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(XXVI) 65571 2-Chloro-2',3'-difluoroacetophenone   C8H5ClF2O 详情 详情
(XXVII) 65572     C10H9ClF2O 详情 详情
(XXVIII) 65573     C10H8F2O 详情 详情
(XXIX) 16710 Diethyl 2-(acetamido)malonate; Diethyl acetamidomalonate 1068-90-2 C9H15NO5 详情 详情
(XXX) 65574     C19H23F2NO6 详情 详情
(XXXI) 65575     C20H25F2NO8S 详情 详情
(XXXII) 42542 2,2,2-trifluoroethylamine; 2,2,2-trifluoro-1-ethanamine 753-90-2 C2H4F3N 详情 详情
(XXXIII) 65576     C21H25F5N2O5 详情 详情
(XXXIV) 65577     C18H21F5N2O3 详情 详情
(XXXV) 65578     C16H15F5N2O2 详情 详情
(XXXVI) 65579     C14H13F5N2O.C20H18O8 详情 详情

合成路线3

The aminoazepinone building block (III) can be prepared as follows. 2,4-Dimethoxybenzylamine (XIII) is alkylated with 2,3-dibromopropene (XIV) in the presence of Et3N to yield amine (XV), which is condensed with 2(R)-(benzyloxycarbonylamino)-4-pentenoic acid (XVI) by means of EDC in CH2Cl2 giving amide (XVII). Subsequent coupling of vinyl bromide (XVII) with 2,3-difluorophenylboronic acid (XVIII) in the presence of 1,1’-bis(diphenylphosphino)ferrocenedichloropalladium(II)· CH2Cl2 and Na2CO3 in DMF gives (XIX). Ring-closing olefin metathesis in diene (XIX) utilizing a second-generation Grubbs catalyst generates the azepinone derivative (XX), from which the dimethoxybenzyl group is removed by means of trifluoroacetic acid in CH2Cl2 to provide compound (XXI). Hydrogenation of olefin (XXI) and simultaneous Cbz group cleavage in the presence of Pd/C and Boc2O leads to the Boc-protected aminoperhydroazepinone (XXII). After alkylation of lactam (XXII) with the 2,2,2-trifluoroethyl sulfonate (XXIII) and NaH in DMF, the N-Boc group is removed using trifluoroacetic acid to furnish the target amine (III) (1). Scheme 2.

1 Burgey, C.S., Deng, Z.J., Williams, T.M., Paone, D.V., Shaw, A.W., Nguyen, D.N. (Merck & Co., Inc.). CGRP receptor antagonists. EP 1638969, JP 2006523697, US 2004229861, US 6953790, WO 2004092166, WO 2004092168.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(III) 65556 (3R,6S)-3-Amino-6-(2,3-difluorophenyl)hexahydro-2-oxo-1-(2,2,2-trifluoroethyl)-1H-azepine   C14H15F5N2O 详情 详情
(XIII) 32115 (2,4-dimethoxyphenyl)methanamine; 2,4-dimethoxybenzylamine 20781-21-9 C9H13NO2 详情 详情
(XIV) 21748 2,3-dibromo-1-propene 513-31-5 C3H4Br2 详情 详情
(XV) 65562     C12H16BrNO2 详情 详情
(XVI) 65563 Cbz-alpha-Allyl-L-Gly; N-ALPHA-CARBOBENZOXY-L-ALPHA-ALLYL-GLYCINE; CBZ-(S)-2-AMINO-4-PENTENOIC ACID; (S)-2-CBZ-AMINO-4-PENTENOIC ACID 78553-51-2 C13H15NO4 详情 详情
(XVII) 65564     C25H29BrN2O5 详情 详情
(XVIII) 65565 2,3-Difluorophenylboronic acid; 2,3-Difluorobenzeneboronic acid 121219-16-7 C6H5BF2O2 详情 详情
(XIX) 65566     C31H33F2N2O5 详情 详情
(XX) 65567     C29H28F2N2O5 详情 详情
(XXI) 65568     C20H18F2N2O3 详情 详情
(XXII) 65569     C17H21F2N2O3 详情 详情
(XXIII) 33474 2,2,2-Trifluoroethyl trichloromethanesulfonate; 2,2,2-Trifluoroethyl trichloromethylsulfonate 23199-56-6 C3H2Cl3F3O3S 详情 详情
Extended Information