4-Piperidineacetic acid ethyl ester; ethyl 2-(4-piperidinyl)acetate -Drug Synthesis Database

【结构式】

【分子编号】28087

【品名】4-Piperidineacetic acid ethyl ester; ethyl 2-(4-piperidinyl)acetate

【CA登记号】

【分子式】C₉H₁₇NO₂

【分子量】171.23952

【元素组成】C 63.13% H 10.01% N 8.18% O 18.69%

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)

Horner-Emmons condensation of 1-benzyl-4-piperidone (VI) with phosphonate (IV) furnished the unsaturated ester (VII). Hydrogenation of (VII) over Pd/C produced double bond reduction and simultaneous N-benzyl group cleavage to afford piperidine (VIII). This was finally alkylated with chloride (I) in the presence of K2CO3 and NaI.

参考文献中间体

合成目标

【1】 Buzas, A.; Merour, J.-Y.; Ollivier, R. (Laboratoires Meram SA); Benzhydryloxyethylpiperidine derivs., process for their preparation and pharmaceutical compsns., in which they are present. EP 0259227; US 4983614 .

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)	34744	1-[(2-chloroethoxy)(phenyl)methyl]benzene; benzhydryl 2-chloroethyl ether	32669-06-0	C₁₅H₁₅ClO	详情	详情
(IV)	10019	Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate	867-13-0	C₈H₁₇O₅P	详情	详情
(VI)	15720	1-benzyltetrahydro-4(1H)-pyridinone; 1-Benzyl-4-piperidone; N-Benzyl-4-piperidone; 1-(benzyl)-4-piperidinone; 1-benzylpiperidin-4-one; 1-(benzyl)piperidin-4-one	3612-20-2	C₁₂H₁₅NO	详情	详情
(VII)	34747	ethyl 2-(1-benzyl-4-piperidinylidene)acetate		C₁₆H₂₁NO₂	详情	详情
(VIII)	28087	4-Piperidineacetic acid ethyl ester; ethyl 2-(4-piperidinyl)acetate		C₉H₁₇NO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IX)

Horner-Emmons condensation of 1-benzyl-4-piperidone (VII) with phosphonate (IV) furnished the unsaturated ester (VIII). Hydrogenation of (VIII) over Pd/C produced double bond reduction and simultaneous N-benzyl group cleavage to afford piperidine (IX). This was finally alkylated with chloride (I) in the presence of K2CO3 and NaI and hydrolyzed to target compound.

参考文献中间体

合成目标

【1】 Buzas, A.; Merour, J.-Y.; Ollivier, R. (Laboratoires Meram SA); Benzhydryloxyethylpiperidine derivs., process for their preparation and pharmaceutical compsns., in which they are present. EP 0259227; US 4983614 .

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)	34744	1-[(2-chloroethoxy)(phenyl)methyl]benzene; benzhydryl 2-chloroethyl ether	32669-06-0	C₁₅H₁₅ClO	详情	详情
(IV)	10019	Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate	867-13-0	C₈H₁₇O₅P	详情	详情
(VI)	34748	ethyl 2-[1-[2-(benzhydryloxy)ethyl]-4-piperidinyl]acetate		C₂₄H₃₁NO₃	详情	详情
(VII)	15720	1-benzyltetrahydro-4(1H)-pyridinone; 1-Benzyl-4-piperidone; N-Benzyl-4-piperidone; 1-(benzyl)-4-piperidinone; 1-benzylpiperidin-4-one; 1-(benzyl)piperidin-4-one	3612-20-2	C₁₂H₁₅NO	详情	详情
(VIII)	34747	ethyl 2-(1-benzyl-4-piperidinylidene)acetate		C₁₆H₂₁NO₂	详情	详情
(IX)	28087	4-Piperidineacetic acid ethyl ester; ethyl 2-(4-piperidinyl)acetate		C₉H₁₇NO₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(III)

Protection of beta-alanine derivative (I) with di-tert-butyl dicarbonate afforded the tert-butyl carbamate (II). This was condensed with ethyl piperidine-4-acetate (III) using O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyuronium hexafluorophosphate (HATU) and diisopropyl ethylamine to give amide (IV). Subsequent Boc deprotection of (IV) with trifluoroacetic acid provided amine (V), which was coupled with 2-fluoro-4-cyanobenzoic acid (VI) in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 1-hydroxybenzotriazole yielding (VII). Treatment of the resulting cyanobenzamide (VII) with SH2 and Et3N produced the corresponding thioamide, which was S-alkylated with MeI to give (VIII). Finally, displacement of the methylthio group of (VIII) with thiazolidine (IX) furnished the corresponding amidine.

参考文献中间体

合成目标

【1】 Hayashi, Y.; Harada, T.; Katada, J.; et al.; GPIIb/IIIa integrin antagonists with the new conformational restriction unit, trisubstituted beta-amino acid derivatives, and substituted benzamidine structure. J Med Chem 1998, 41, 12, 2345.
【2】 Hayashi, Y.; Harada, T.; Tachiki, A.; Katada, J. (Nippon Steel Corp.); Fibrinogen receptor antagonists and medicinal preparations containing the same as the active ingredient. EP 0852225; JP 1998017550; WO 9749682 .

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)	28085	3-amino-2,2-dimethylpentanoic acid		C₇H₁₅NO₂	详情	详情
(II)	28086	3-[(tert-butoxycarbonyl)amino]-2,2-dimethylpentanoic acid		C₁₂H₂₃NO₄	详情	详情
(III)	28087	4-Piperidineacetic acid ethyl ester; ethyl 2-(4-piperidinyl)acetate		C₉H₁₇NO₂	详情	详情
(IV)	28088	ethyl 2-(1-[3-[(tert-butoxycarbonyl)amino]-2,2-dimethylpentanoyl]-4-piperidinyl)acetate		C₂₁H₃₈N₂O₅	详情	详情
(V)	28089	ethyl 2-[1-(3-amino-2,2-dimethylpentanoyl)-4-piperidinyl]acetate		C₁₆H₃₀N₂O₃	详情	详情
(VI)	28090	4-cyano-2-fluorobenzoic acid		C₈H₄FNO₂	详情	详情
(VII)	28091	ethyl 2-(1-[3-[(4-cyano-2-fluorobenzoyl)amino]-2,2-dimethylpentanoyl]-4-piperidinyl)acetate		C₂₄H₃₂FN₃O₄	详情	详情
(VIII)	28092	ethyl 2-[1-[3-([2-fluoro-4-[imino(methylsulfanyl)methyl]benzoyl]amino)-2,2-dimethylpentanoyl]-4-piperidinyl]acetate		C₂₅H₃₆FN₃O₄S	详情	详情
(IX)	28093	1,3-thiazolidine	504-78-9	C₃H₇NS	详情	详情

合成路线4

该中间体在本合成路线中的序号：(X)

Acid (IX) is coupled to ethyl 4-piperidineacetate (X) by means of diethylphosphoryl cyanide to give amide (XI). The ethyl ester group of (XI) is then hydrolyzed to the corresponding carboxylic acid (XII) employing NaOH in ethanol. Finally, esterification of the alcohol function of (XII) with acetic anhydride in pyridine gives rise to the target acetate ester.

参考文献中间体

合成目标

【1】 Miki, T.; Kori, M.; Mabuchi, H.; Tozawa, R.; Nishimoto, T.; Sugiyama, Y.; Teshima, K.; Yukimasa, H.; Synthesis of novel 4,1-benzoxazepine derivatives as squalene synthase inhibitors and their inhibition of cholesterol synthesis. J Med Chem 2002, 45, 20, 4571.
【2】 Yukimasa, H.; Sugiyama, Y.; Tozawa, R. (Takeda Chemical Industries, Ltd.); Benzoxazepine cpds., their production and use as lipid lowering agents. EP 0862562; EP 1097928; JP 1997136880; JP 2001097963; US 6110909; US 6613761; WO 9710224 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(IX)	63265	2-[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetic acid	C₂₄H₂₈ClNO₇	详情	详情
(X)	28087	4-Piperidineacetic acid ethyl ester; ethyl 2-(4-piperidinyl)acetate	C₉H₁₇NO₂	详情	详情
(XI)	63267	ethyl 2-(1-{2-[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}-4-piperidinyl)acetate	C₃₃H₄₃ClN₂O₈	详情	详情
(XII)	63268	2-(1-{2-[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}-4-piperidinyl)acetic acid	C₃₁H₃₉ClN₂O₈	详情	详情

Extended Information