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【结 构 式】 
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【药物名称】Apixaban, BMS-562247, BMS-562247-01 【化学名称】1-(4-Methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide 【CA登记号】503612-47-3 【 分 子 式 】C25H25N5O4 【 分 子 量 】459.4973 |
【开发单位】Bristol-Myers Squibb Company (US); developed under a worldwide collaboration with Pfizer, Inc. 【药理作用】Factor Xa Inhibitor, Anticoagulant |
合成路线1
Condensation of the chloro hydrazone (I) with dihydropyridones (IIa) and (IIb) by means of triethylamine in boiling toluene affords the pyrazolopyridines (IIIa) and (IIIb), respectively (1, 2). Reduction of the nitro derivative (IIIa) by catalytic hydrogenation over Pd/C provides aniline (IV), which is acylated with 5-bromovaleryl chloride (V) in the presence of K2CO3 in THF to furnish the bromoamide (VI). Subsequent cyclization of (VI) by means of potassium ethoxide in EtOH/THF gives the piperidone (VII) (1). Alternatively, the intermediate (VII) is obtained by condensation of the iodo compound (IIIb) with valerolactam (VIII) by means of K2CO3 and CuI in hot DMSO (2). Finally, conversion of ethyl ester (VII) to the title carboxamide is effected by heating with anhydrous ammonia in ethylene or propylene glycol in a sealed vessel, or with formamide in DMF in the presence of trifluoroacetic acid and trimethyl orthoformate (1, 2). In a further method, the pyrazolopyridinone derivative (IX) is condensed with 1-(4-iodophenyl)-2-piperidinone (X) employing K2CO3 and CuI in DMSO at 125 °C to give the adduct (XI), which is converted to the title amide via activation with tert-butyl chloroformate and triethylamine in ethyl acetate, followed by reaction with ammonium hydroxide (3). Scheme 1.
| 【1】 Shapiro, R., Rossano, L.T., Mudryk, B.M. et al. (Bristol-Myers Squibb Co.). Process for preparing 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones. WO 2007001385. |
| 【2】 Pinto, D., Quan, M., Orwat, M. et al. (Bristol-Myers Squibb Co.). Lactam-containing compounds and derivatives thereof as factor Xa inhibitors. EP 1427415, JP 2005507889, WO 03026652. |
| 【3】 Zhou, J., Li, H.-Y., Ma, P., Oh, L.M. (Bristol-Myers Squibb Co.). Synthesis of 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones. EP 1467984, JP 2005511712, US 2003181466, US 6919451, WO 03049681. |
| 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) | 65610 | 3-Chloro-5,6-dihydro-1-(4-nitrophenyl)-2(1H)-pyridinone | 536760-29-9 | C11H9ClN2O3 | 详情 | 详情 |
| (IIB) | 65611 | 1-(4-Iodophenyl)-3-morpholino-5,6-dihydropyridin-2(1H)-one; N-(4-Iodophenyl)-3-morpholino-5,6-dihydro-2H-pyridin-2-one | 473927-69-4 | C15H17IN2O2 | 详情 | 详情 |
| (IIIA) | 65612 | 4,5,6,7-Tetrahydro-1-(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester | 536759-91-8 | C22H20N4O6 | 详情 | 详情 |
| (IIIB) | 65613 | 1-(4-Methoxyphenyl)-6-(4-iodophenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester | 473927-64-9 | C22H20IN3O4 | 详情 | 详情 |
| (I) | 65609 | Ethyl chloro[(4-methoxyphenyl)hydrazono]acetate; Chloro[(4-methoxyphenyl)hydrazono]acetic acid ethyl ester | 27143-07-3 | C11H13ClN2O3 | 详情 | 详情 |
| (IV) | 65614 | 6-(4-Aminophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester | 503615-07-4 | C22H22N4O4 | 详情 | 详情 |
| (V) | 39700 | 5-bromopentanoyl chloride | 4509-90-4 | C5H8BrClO | 详情 | 详情 |
| (VI) | 65615 | C27H29BrN4O5 | 详情 | 详情 | ||
| (VII) | 65616 | 1-(4-Methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester | 503614-91-3 | C27H28N4O5 | 详情 | 详情 |
| (VIII) | 43366 | 2-piperidinone | 675-20-7 | C5H9NO | 详情 | 详情 |
| (IX) | 65617 | C14H13N3O4 | 详情 | 详情 | ||
| (X) | 65618 | 1-(4-Iodophenyl)-2-piperidinone | 385425-15-0 | C11H12INO | 详情 | 详情 |
| (XI) | 65619 | 1-(4-Methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid | 503614-92-4 | C25H24N4O5 | 详情 | 详情 |
合成路线2
The intermediate chloro hydrazone (I) is prepared by he following method. Diazotization of p-anisidine (XII) employing sodium nitrite in cold aqueous HCl yields the ntermediate diazonium salt (XIII), which undergoes Japp-Klingemann reaction with ethyl 2-chloroacetoacetate (XIV) in the presence of NaOAc to produce the target hydrazone (I) (1, 2). Scheme 2.
| 【1】 Shapiro, R., Rossano, L.T., Mudryk, B.M. et al. (Bristol-Myers Squibb Co.). Process for preparing 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones. WO 2007001385. |
| 【2】 Pinto, D., Quan, M., Orwat, M. et al. (Bristol-Myers Squibb Co.). Lactam-containing compounds and derivatives thereof as factor Xa inhibitors. EP 1427415, JP 2005507889, WO 03026652. |
| 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) | 65609 | Ethyl chloro[(4-methoxyphenyl)hydrazono]acetate; Chloro[(4-methoxyphenyl)hydrazono]acetic acid ethyl ester | 27143-07-3 | C11H13ClN2O3 | 详情 | 详情 |
| (XII) | 10478 | p-Anisidine; 4-Methoxyaniline; 4-Methoxyphenylamine | 104-94-9 | C7H9NO | 详情 | 详情 |
| (XIII) | 12149 | 1-(4-Methoxyphenyl)diazonium chloride | C7H7ClN2O | 详情 | 详情 | |
| (XIV) | 21337 | ethyl 2-chloro-3-oxobutanoate | 609-15-4 | C6H9ClO3 | 详情 | 详情 |
合成路线3
The precursor dihydropyridones (IIa) and (IIb) can be synthesized as follows. Acylation of either 4-nitroaniline (XVa) (1) or 4-iodoaniline (XVb) (2) with 5-bromovaleryl chloride (V) affords the corresponding bromoamides (XVIa) and (XVIb), which are cyclized to piperidones (XVIIa) and (XVIIb) upon treatment with potassium tert-butoxide or with potassium hydroxide under phase-transfer conditions. Piperidones (XVIIa/b) are then chlorinated by means of phosphorus pentachloride in chlorobenzene or chloroform to form the geminal dichlorides (XVIIIa) and (XVIIIb) (1, 2). Dehydrohalogenation of (XVIIIa) by means of lithium carbonate and lithium chloride in DMF at 105-110 °C then provides the chloro dihydropyridone (IIa) (1). Alternatively, the dichloro derivative (XVIIIb) is refluxed with neat morpholine (XIX) to furnish intermediate (IIb) (2). Scheme 3.
| 【1】 Shapiro, R., Rossano, L.T., Mudryk, B.M. et al. (Bristol-Myers Squibb Co.). Process for preparing 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones. WO 2007001385. |
| 【2】 Pinto, D., Quan, M., Orwat, M. et al. (Bristol-Myers Squibb Co.). Lactam-containing compounds and derivatives thereof as factor Xa inhibitors. EP 1427415, JP 2005507889, WO 03026652. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVA) | 15547 | 4-nitrophenylamine; p-Nitroaniline; 4-nitroaniline | 100-01-6 | C6H6N2O2 | 详情 | 详情 |
| (XVB) | 26393 | 4-iodoaniline; 4-iodophenylamine | 540-37-4 | C6H6IN | 详情 | 详情 |
| (XVIa) | 65620 | C11H13BrN2O3 | 详情 | 详情 | ||
| (XVIb) | 65621 | C11H13BrINO | 详情 | 详情 | ||
| (XVIIa) | 65622 | 1-(4-Nitrophenyl)-2-piperidinone | 38560-30-4 | C11H12N2O3 | 详情 | 详情 |
| (XVIIb) | 65618 | 1-(4-Iodophenyl)-2-piperidinone | 385425-15-0 | C11H12INO | 详情 | 详情 |
| (XVIIIa) | 65623 | 3,3-Dichloro-1-(4-nitrophenyl)-2-piperidinone | 881386-01-2 | C11H10Cl2N2O3 | 详情 | 详情 |
| (XVIIIb) | 65624 | 3,3-Dichloro-1-(4-iodophenyl)piperidin-2-one | 545445-10-1 | C11H10Cl2INO | 详情 | 详情 |
| (IIA) | 65610 | 3-Chloro-5,6-dihydro-1-(4-nitrophenyl)-2(1H)-pyridinone | 536760-29-9 | C11H9ClN2O3 | 详情 | 详情 |
| (IIB) | 65611 | 1-(4-Iodophenyl)-3-morpholino-5,6-dihydropyridin-2(1H)-one; N-(4-Iodophenyl)-3-morpholino-5,6-dihydro-2H-pyridin-2-one | 473927-69-4 | C15H17IN2O2 | 详情 | 详情 |
| (V) | 39700 | 5-bromopentanoyl chloride | 4509-90-4 | C5H8BrClO | 详情 | 详情 |
| (XIX) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |