2-piperidinone -Drug Synthesis Database

【结构式】

【分子编号】43366

【品名】2-piperidinone

【CA登记号】675-20-7

【分子式】C₅H₉NO

【分子量】99.1326

【元素组成】C 60.58% H 9.15% N 14.13% O 16.14%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(VIII)

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：(V)

Alkylation of delta-valerolactam (V) with tert-butyl bromoacetate in the presence of NaH provided (VI). Subsequent tert-butyl ester cleavage by means of trifluoroacetic acid furnished 2-(2-oxopiperidin-1-yl)acetic acid (VII), which was finally coupled with amine (IV) to afford the title amide.

参考文献中间体

合成目标

【1】 Murray, W.V.; Jolliffe, L.; Pulito, V.; Li, X.; Novel arylpiperazines as selective alpha1-adrenergic receptor antagonists. Bioorg Med Chem Lett 2000, 10, 10, 1093.
【2】 Mulcahy, L.; Pulito, V.; Villani, F.; Li, X.; Murray, W.; Maryanoff, C.; Jolliffe, L.; Reitz, A. (Ortho-McNeil Pharmaceutical, Inc.); Arylsubstd. piperazines useful in the treatment of benign prostatic hyperplasia. EP 0984777; US 6071915; WO 9851298 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	43365	2-[4-(2-isopropoxyphenyl)-1-piperazinyl]ethylamine; 2-[4-(2-isopropoxyphenyl)-1-piperazinyl]-1-ethanamine		C₁₅H₂₅N₃O	详情	详情
(V)	43366	2-piperidinone	675-20-7	C₅H₉NO	详情	详情
(VI)	43367	tert-butyl 2-(2-oxo-1-piperidinyl)acetate		C₁₁H₁₉NO₃	详情	详情
(VII)	43368	2-(2-oxo-1-piperidinyl)acetic acid		C₇H₁₁NO₃	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XI)

Asymmetric epoxidation of benzopyran (IV) using NaOCl in the presence of the chiral catalyst (S,S)-(+)-N,N'-bis(3,5-di-t-butylsalicylidene)-1,2-cyclohexanediaminomanganese (III) chloride produced the desired (S,S)-epoxide (X). The title compound was then obtained by oxirane ring opening in (X) with the lithium derivative of 2-piperidinone (XI) in hot THF.

参考文献中间体

合成目标

【1】 Manley, P.W. (Novartis AG; Novartis Deutschland GmbH); Benzopyrans and pharmaceutical compsns. containing them. EP 0828733; JP 1999505820; US 5905156; WO 9637490 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	54658	2,2-dimethyl-N-phenyl-2H-chromene-6-sulfonamide		C₁₇H₁₇NO₃S	详情	详情
(X)	54663	(1aS,7bS)-2,2-dimethyl-N-phenyl-1a,7b-dihydro-2H-oxireno[2,3-c]chromene-6-sulfonamide		C₁₇H₁₇NO₄S	详情	详情
(XI)	43366	2-piperidinone	675-20-7	C₅H₉NO	详情	详情

合成路线4

该中间体在本合成路线中的序号：(VIII)

Synthesis of intermediate (I):
N-Protection of 2-piperidone (VIII) with PMB-Cl using KOH and TBAB in toluene gives N-PMB-2-piperidone (IX), which is then hydrolyzed with NaOH to afford 5-(4-methoxybenzylamino)pentanoic acid (X). Condensation of amine (X) with 5-bromo-2-fluorobenzaldehyde (XI) by means of Na2CO3 in DMSO/H2O then provides the tertiary amine (XII). Methylation of carboxylic acid (XII) with MeI in the presence of K2CO3 leads to the corresponding methyl ester (XIII), which then undergoes intramolecular cyclization by means of NaOMe and CO(OMe)2 to yield the N-PMB-1-benzazocine derivative (XIV). Debenzylation of compound (XIV) by means of TFA in toluene affords N-unsubstituted benzazocine (XV), which is then reductocondensed with isobutyraldehyde (XVI) by means of NaBH(OAc)3 in CH2Cl2, affording the 1-isobutyl derivative (XVII). Suzuki coupling of the 8-bromo-1-benzazocine derivative (XVII) with 4-(2-butoxyethoxy)phenylboronic acid (XVIII) by means of Pd(PPh3)4 provides adduct (XIX). Finally, hydrolysis of methyl ester (XIX) with NaOH in THF/MeOH gives the target carboxylic acid (I) (3). Scheme 2.

参考文献中间体

合成目标

【3】 Seto, M., Aikawa, K., Miyamoto, N. et al. Highly potent and orally active CCR5 antagonists as Anti-HIV-1 agents: Synthesis and biological activities of 1-benzazocine derivatives containing a sulfoxide moiety. J Med Chem 2006, 49(6): 2037-48.

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)	66037			C₂₈H₃₇NO₄	详情	详情
(VIII)	43366	2-piperidinone	675-20-7	C₅H₉NO	详情	详情
(IX)	66044	1-(p-Methoxybenzyl)-2-piperidinone	128773-73-9	C₁₃H₁₇NO₂	详情	详情
(X)	66045	5-[N-(4-methoxybenzyl)amino]pentanoic acid		C₁₃H₁₉NO₃	详情	详情
(XI)	66046	5-bromo-2-fluorobenzaldehyde	93777-26-5	C₇H₄BrFO	详情	详情
(XII)	66047			C₂₀H₂₂BrNO₄	详情	详情
(XIII)	66048			C₂₁H₂₄BrNO₄	详情	详情
(XIV)	66049			C₂₁H₂₂BrNO₃	详情	详情
(XV)	66050			C₁₃H₁₄BrNO₂	详情	详情
(XVI)	13226	2-Methylpropanal; Isobutyraldehyde	78-84-2	C₄H₈O	详情	详情
(XVII)	66051			C₁₇H₂₂BrNO₂	详情	详情
(XVIII)	66052			C₁₂H₁₉BO₄	详情	详情
(XIX)	66053			C₂₉H₃₉NO₄	详情	详情

Extended Information