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【结 构 式】

【分子编号】65611

【品名】1-(4-Iodophenyl)-3-morpholino-5,6-dihydropyridin-2(1H)-one; N-(4-Iodophenyl)-3-morpholino-5,6-dihydro-2H-pyridin-2-one

【CA登记号】473927-69-4

【 分 子 式 】C15H17IN2O2

【 分 子 量 】384.21673

【元素组成】C 46.89% H 4.46% I 33.03% N 7.29% O 8.33%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(IIB)

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

该中间体在本合成路线中的序号:(IIB)

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
Extended Information