1-(tert-butyl) 4-ethyl-1,4-piperidinedicarboxylate; N-Boc-4-Carbethoxypiperidine -Drug Synthesis Database

【结构式】

【分子编号】49847

【品名】1-(tert-butyl) 4-ethyl-1,4-piperidinedicarboxylate; N-Boc-4-Carbethoxypiperidine

【CA登记号】142851-03-4

【分子式】C₁₃H₂₃NO₄

【分子量】257.32996

【元素组成】C 60.68% H 9.01% N 5.44% O 24.87%

与该中间体有关的原料药合成路线共 5 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5

合成路线1

该中间体在本合成路线中的序号：(II)

Ethyl isonipecotate (I) was protected as the N-Boc derivative (II) employing di-tert-butyl dicarbonate. Sulfenylation of the lithium enolate of ester (II) with the disulfide (IV), generated from the oxidation of 4-fluorothiophenol (III), furnished the phenylsulfanyl derivative (V). Thioether (V) was then oxidized to the corresponding sulfone (VI) by means of meta-chloroperbenzoic acid. After acidic Boc group cleavage in (VI), the resultant piperidine (VII) was alkylated with propargyl bromide (VIII) to produce the N-propargyl piperidine (IX).

参考文献中间体

合成目标

【1】 Becker, D.P.; Hockerman, S.L.; Barta, T.E.; et al.; Design and synthesis of beta-sulfone and alpha-sulfone hydroxamates as potent and orally active MMP inhibitors. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 259.

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)	17410	Ethyl isonipecotate; ethyl 4-piperidinecarboxylate	1126-09-6	C₈H₁₅NO₂	详情	详情
(II)	49847	1-(tert-butyl) 4-ethyl-1,4-piperidinedicarboxylate; N-Boc-4-Carbethoxypiperidine	142851-03-4	C₁₃H₂₃NO₄	详情	详情
(III)	22971	4-fluorobenzenethiol; 4-fluorophenylhydrosulfide; 4-Fluorothiophenol	371-42-6	C₆H₅FS	详情	详情
(IV)	52287	bis(4-fluorophenyl) disulfide; 1-fluoro-4-[(4-fluorophenyl)disulfanyl]benzene		C₁₂H₈F₂S₂	详情	详情
(V)	52288	1-(1,1-dimethylethyl) 4-ethyl 4-[(4-fluorophenyl)sulfanyl]-1,4-piperidinedicarboxylate		C₁₉H₂₆FNO₄S	详情	详情
(VI)	52289	1-(1,1-dimethylethyl) 4-ethyl 4-[(4-fluorophenyl)sulfonyl]-1,4-piperidinedicarboxylate		C₁₉H₂₆FNO₆S	详情	详情
(VII)	52290	ethyl 4-[(4-fluorophenyl)sulfonyl]-4-piperidinecarboxylate		C₁₄H₁₈FNO₄S	详情	详情
(VIII)	11176	3-Bromopropyne; 3-Bromo-1-propyne	106-96-7	C₃H₃Br	详情	详情
(IX)	56377	ethyl 4-[(4-fluorophenyl)sulfonyl]-1-(2-propynyl)-4-piperidinecarboxylate		C₁₇H₂₀FNO₄S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

Ethyl nipecotate (I) was protected as the tert-butyl carbamate (II) upon treatment with Boc2O in THF. The lithium enolate of ester (II) was then sulfenylated with the disulfide (IV), prepared by oxidation of 4-fluorothiophenol (III), yielding thioether (V). This was further oxidized to the corresponding sulfone (VI) using meta-chloroperbenzoic acid. Acid cleavage of the Boc protecting group of (VI) gave piperidine (VII), which was converted to the N-cyclopropyl amine (IX) by reductive alkylation with [(1-ethoxycyclopropyl)oxy]trimethylsilane (VIII) in the presence of NaBH3CN. Displacement of the aryl fluoride of (IX) with 4-(trifluoromethoxy)phenol (X) under basic conditions afforded the diaryl ether (XI). After saponification of the ester group of (XI), the resultant carboxylic acid (XII) was coupled to O-(tetrahydropyranyl)hydroxylamine by means of EDC to produce the protected hydroxamate (XIII). Finally, removal of the tetrahydropyranyl protecting group of (XIII) with HCl in dioxan afforded the title compound.

参考文献中间体

合成目标

【1】 Villamil, C.I.; et al.; Design and synthesis of 4,4-disubstituted piperidine alpha-sulphone hydroxamates as potent and selective MMP inhibitors: The discovery of SC-77964. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 258.
【2】 Aromatic sulfone hydroxamic acid metalloprotease inhibitor. WO 0050396 .

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)	17410	Ethyl isonipecotate; ethyl 4-piperidinecarboxylate	1126-09-6	C₈H₁₅NO₂	详情	详情
(II)	49847	1-(tert-butyl) 4-ethyl-1,4-piperidinedicarboxylate; N-Boc-4-Carbethoxypiperidine	142851-03-4	C₁₃H₂₃NO₄	详情	详情
(III)	22971	4-fluorobenzenethiol; 4-fluorophenylhydrosulfide; 4-Fluorothiophenol	371-42-6	C₆H₅FS	详情	详情
(IV)	52287	bis(4-fluorophenyl) disulfide; 1-fluoro-4-[(4-fluorophenyl)disulfanyl]benzene		C₁₂H₈F₂S₂	详情	详情
(V)	52288	1-(1,1-dimethylethyl) 4-ethyl 4-[(4-fluorophenyl)sulfanyl]-1,4-piperidinedicarboxylate		C₁₉H₂₆FNO₄S	详情	详情
(VI)	52289	1-(1,1-dimethylethyl) 4-ethyl 4-[(4-fluorophenyl)sulfonyl]-1,4-piperidinedicarboxylate		C₁₉H₂₆FNO₆S	详情	详情
(VII)	52290	ethyl 4-[(4-fluorophenyl)sulfonyl]-4-piperidinecarboxylate		C₁₄H₁₈FNO₄S	详情	详情
(VIII)	52291	Cyclopropanone ethyl trimethylsilyl acetal; (1-Ethoxycyclopropoxy)trimethylsilane		C₈H₁₈O₂Si	详情	详情
(IX)	52292	ethyl 1-cyclopropyl-4-[(4-fluorophenyl)sulfonyl]-4-piperidinecarboxylate		C₁₇H₂₂FNO₄S	详情	详情
(X)	18780	4-(trifluoromethoxy)phenol	828-27-3	C₇H₅F₃O₂	详情	详情
(XI)	52293	ethyl 1-cyclopropyl-4-{[4-({4-[(trifluoromethyl)oxy]phenyl}oxy)phenyl]sulfonyl}-4-piperidinecarboxylate		C₂₄H₂₆F₃NO₆S	详情	详情
(XII)	52294	1-cyclopropyl-4-{[4-({4-[(trifluoromethyl)oxy]phenyl}oxy)phenyl]sulfonyl}-4-piperidinecarboxylic acid		C₂₂H₂₂F₃NO₆S	详情	详情
(XIII)	52295	1-cyclopropyl-N-(tetrahydro-2H-pyran-2-yloxy)-4-{[4-({4-[(trifluoromethyl)oxy]phenyl}oxy)phenyl]sulfonyl}-4-piperidinecarboxamide		C₂₇H₃₁F₃N₂O₇S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

Ethyl isonipecotate (I) was protected as the N-Boc derivative (II) and then reduced to alcohol (III) using LiAlH4. Treatment of alcohol (III) with p-toluenesulfonyl chloride in the presence of DBU afforded the intermediate tosylate (IV).

参考文献中间体

合成目标

【1】 Hennequin, L.F.A.; Stokes, E.S.E.; Thomas, A.P. (AstraZeneca AB; AstraZeneca plc); Quinazoline derivs. as VEGF inhibitors. WO 0132651 .

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)	17410	Ethyl isonipecotate; ethyl 4-piperidinecarboxylate	1126-09-6	C₈H₁₅NO₂	详情	详情
(II)	49847	1-(tert-butyl) 4-ethyl-1,4-piperidinedicarboxylate; N-Boc-4-Carbethoxypiperidine	142851-03-4	C₁₃H₂₃NO₄	详情	详情
(III)	40399	tert-butyl 4-(hydroxymethyl)-1-piperidinecarboxylate		C₁₁H₂₁NO₃	详情	详情
(IV)	49848	tert-butyl 4-([[(4-methylphenyl)sulfonyl]oxy]methyl)-1-piperidinecarboxylate		C₁₈H₂₇NO₅S	详情	详情

合成路线4

该中间体在本合成路线中的序号：(XIV)

Alkylation of the enolate derived from N-Boc ethyl isonipecotate (XIV) with allyl bromide (XV) gives the alpha-allyl ester (XVI). Double bond ozonolysis in (XIV) with reductive work-up in the presence of NaBH4 leads to lactone (XVII). Reductive ring-opening of lactone (XVII) by means of DIBAL affords diol (XVIII). This is then cyclized under Mitsunobu conditions to the spirocyclic amine (XIX). Acidic Boc group cleavage in (XIX) provides 2-oxa-8-azaspiro[4.5]decane (XX). Finally, reductive amination of cyclohexanone (XIII) with the bicyclic amine (XX) gives rise to a cis/trans mixture of diamino cyclohexanes, from which the desired trans isomer is isolated by chromatography.

参考文献中间体

合成目标

【1】 Cooper, L.C.; et al.; 4,4-Disubstituted cyclohexylamine NK1 receptor antagonists II. Bioorg Med Chem Lett 2002, 12, 13, 1759.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIII)	57089	2-[3,5-bis(trifluoromethyl)phenyl]-N-(4-oxo-1-phenylcyclohexyl)propanamide		C₂₃H₂₁F₆NO₂	详情	详情
(XIV)	49847	1-(tert-butyl) 4-ethyl-1,4-piperidinedicarboxylate; N-Boc-4-Carbethoxypiperidine	142851-03-4	C₁₃H₂₃NO₄	详情	详情
(XV)	11463	3-Bromo-1-propene; 3-Bromopropene；allyl bromide	106-95-6	C₃H₅Br	详情	详情
(XVI)	57090	1-(tert-butyl) 4-ethyl 4-allyl-1,4-piperidinedicarboxylate		C₁₆H₂₇NO₄	详情	详情
(XVII)	57091	tert-butyl 1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate		C₁₃H₂₁NO₄	详情	详情
(XVIII)	57092	tert-butyl 4-(2-hydroxyethyl)-4-(hydroxymethyl)-1-piperidinecarboxylate		C₁₃H₂₅NO₄	详情	详情
(XIX)	57093	tert-butyl 2-oxa-8-azaspiro[4.5]decane-8-carboxylate		C₁₃H₂₃NO₃	详情	详情
(XX)	57094	2-oxa-8-azaspiro[4.5]decane		C₈H₁₅NO	详情	详情

合成路线5

该中间体在本合成路线中的序号：(V)

Alkylation of ethyl isonipecotate (I) with 1-bromo-2-chloroethane (II) in the presence of K2CO3 in acetone yields ethyl 1-(2-chloro-ethyl)piperidine-4-carboxylate (III), which by treatment with LDA in THF cyclizes to the quinuclidine derivative (IV) . Alternatively, quinuclidine (IV) can be prepared by alkylation of Boc-protected ethyl nipecotate (V) with 1-bromo-2-chloroethane (II) using LiHMDS in toluene to yield the 4-(2-chloroethyl)piperidine derivative (VI), which is then N-deprotected with HCl in water/dioxane, followed by cyclization of the resulting chloro amine (VII) by means of K2CO3 in refluxing toluene . Addition of phenyl lithium (VIII) to ester (IV) in THF affords 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (IX), which finally undergoes quaternization with benzyl 2-bromoethyl ether (X) in acetonitrile/chloroform .

参考文献中间体

合成目标

【1】 Lainé, D.I., McCleland, B., Thomas, S. et al. Discovery of novel 1-azoniabicyclo[2.2.2]octane muscarinic acetylcholine receptor antagonists. J Med Chem 2009, 52(8): 2493-505.
【2】 Lainé, D.I., Palovich, M.R., McCleland, B.W., Neipp, C.E., Thomas, S.M.(GlaxoSmithKline plc). Muscarinic acetylcholine receptor antagonists. CA 2564742, CN 102040602, EP 1740177, JP 2007534769, KR 2011010841, US 200785155, US 7498440, US 8183257, US 2012157491, US 8309572, US 2013030015, WO 2005104745.
【3】 Carangio, A., Cheung, I., D’Souza, E.C.F., Leahy, J.H., Strachan, J.B. (GlaxoSmithKline plc). Methods of preparation of muscarinic acetylcholine receptor antagonists. WO 2011029896.

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)	17410	Ethyl isonipecotate; ethyl 4-piperidinecarboxylate	1126-09-6	C₈H₁₅NO₂	详情	详情
(II)	24271	1-bromo-2-chloroethane	107-04-0	C₂H₄BrCl	详情	详情
(III)	67994	ethyl 1-(2-chloroethyl)piperidine-4-carboxylate		C₁₀H₁₈ClNO₂	详情	详情
(IV)	67995	ethyl quinuclidine-4-carboxylate		C₁₀H₁₇NO₂	详情	详情
(V)	49847	1-(tert-butyl) 4-ethyl-1,4-piperidinedicarboxylate; N-Boc-4-Carbethoxypiperidine	142851-03-4	C₁₃H₂₃NO₄	详情	详情
(VI)	67996	1-tert-butyl 4-ethyl 4-(2-chloroethyl)piperidine-1,4-dicarboxylate		C₁₅H₂₆ClNO₄	详情	详情
(VII)	67997	ethyl 4-(2-chloroethyl)piperidine-4-carboxylate hydrochloride		C₁₀H₁₈ClNO₂.HCl	详情	详情
(VIII)	24014	Phenyllithium	591-51-5	C₆H₅Li	详情	详情
(IX)	67998	diphenyl(quinuclidin-4-yl)methanol;1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol		C₂₀H₂₃NO	详情	详情
(X)	35528	1-[(2-bromoethoxy)methyl]benzene; benzyl 2-bromoethyl ether	1462-37-9	C₉H₁₁BrO	详情	详情

Extended Information