1-(4-Iodophenyl)-2-piperidinone -Drug Synthesis Database

【结构式】

【分子编号】65618

【品名】1-(4-Iodophenyl)-2-piperidinone

【CA登记号】385425-15-0

【分子式】C₁₁H₁₂INO

【分子量】301.12689

【元素组成】C 43.88% H 4.02% I 42.14% N 4.65% O 5.31%

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：(X)

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.

参考文献中间体

合成目标

【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：(XVIIb)

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.

参考文献中间体

合成目标

【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