【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 |