tert-butyl 4-(2-hydroxyethyl)-1-piperidinecarboxylate -Drug Synthesis Database

【结构式】

【分子编号】43453

【品名】tert-butyl 4-(2-hydroxyethyl)-1-piperidinecarboxylate

【CA登记号】

【分子式】C₁₂H₂₃NO₃

【分子量】229.31956

【元素组成】C 62.85% H 10.11% N 6.11% O 20.93%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(IV)

4-Pyridineacetic acid (I) was hydrogenated to the corresponding piperidine (II) in the presence of PtO2. After protection of (II) as the N-Boc derivative (III), reduction of its carboxylate group with borane in THF provided alcohol (IV). Subsequent Swern oxidation of alcohol (IV) furnished aldehyde (V). This was then subjected to a Wittig condensation with carbomethoxytriphenylphosphorane to yield the unsaturated ester (VI), which was further hydrogenated to (VII) in the presence of Pd/C. After saponification of the methyl ester function of (VII), the resultant carboxylic acid was reduced to alcohol (VIII) by means of borane in THF. Conversion of alcohol (VIII) into the alkyl bromide (IX) was accomplished by treatment with carbon tetrabromide and triphenylphosphine. Then, alkylation of the phenolic hydroxyl of N-Cbz-L-tyrosine (X) with bromide (IX) in the presence of NaH in DMF afforded adduct (XI).

参考文献中间体

合成目标

【1】 Egbertson, M.S.; Laswell, W.L.; Hartman, G.D.; Duggan, M.E.; Halczenko, W. (Merck & Co., Inc.); Novel sulfonamide fibrinogen receptor antagonists. EP 0478363; EP 0743302; JP 1992288051; US 5292756 .
【2】 Egbertson, M.S.; Hartman, G.D.; Halczenko, W.; Laswell, W.L.; Duggan, M.E. (Merck & Co., Inc.); Novel sulfonamide fibrinogen receptor antagonists. WO 9319046 .
【3】 Egbertson, M.S.; Chang, C.T.C.; Duggan, M.E.; et al.; Non-peptide fibrinogen receptor antagonists. 2. Optimization of a tyrosine template as a mimic for Arg-Gly-Asp. J Med Chem 1994, 37, 16, 2537.

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)	17883	2-(4-pyridinyl)acetic acid	28356-58-3	C₇H₇NO₂	详情	详情
(II)	45854	2-(4-piperidinyl)acetic acid; 4-piperidinylacetic acid	51052-78-9	C₇H₁₃NO₂	详情	详情
(III)	19346	1-Boc-piperidin-4-ylacetic acid; 2-[1-(tert-butoxycarbonyl)-4-piperidinyl]acetic acid	157688-46-5	C₁₂H₂₁NO₄	详情	详情
(IV)	43453	tert-butyl 4-(2-hydroxyethyl)-1-piperidinecarboxylate		C₁₂H₂₃NO₃	详情	详情
(V)	59541	tert-butyl 4-(2-oxoethyl)-1-piperidinecarboxylate		C₁₂H₂₁NO₃	详情	详情
(VI)	45855	tert-butyl 4-[(E)-4-methoxy-4-oxo-2-butenyl]-1-piperidinecarboxylate		C₁₅H₂₅NO₄	详情	详情
(VII)	45856	tert-butyl 4-(4-methoxy-4-oxobutyl)-1-piperidinecarboxylate		C₁₅H₂₇NO₄	详情	详情
(VIII)	59542	tert-butyl 4-(4-hydroxybutyl)-1-piperidinecarboxylate		C₁₄H₂₇NO₃	详情	详情
(IX)	59543	tert-butyl 4-(4-bromobutyl)-1-piperidinecarboxylate		C₁₄H₂₆BrNO₂	详情	详情
(X)	39328	(2S)-2-[[(benzyloxy)carbonyl]amino]-3-(4-hydroxyphenyl)propionic acid		C₁₇H₁₇NO₅	详情	详情
(XI)	59544	(2S)-2-{[(benzyloxy)carbonyl]amino}-3-(4-{4-[1-(tert-butoxycarbonyl)-4-piperidinyl]butoxy}phenyl)propanoic acid		C₃₁H₄₂N₂O₇	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XII)

Intermediate (VII) can be obtained by following two different pathways: 1. Hydrogenation of 4-pyridine acetic acid (IX) over PtO2 in AcOH affords piperidinyl derivative (X), which is then protected with Boc2O and NaOH in THF to yield (XI). Reduction of the CO2H group of (XI) with BH3.THF in THF gives alcohol (XII), which is then subjected to Swern oxidation with oxalyl chloride and DMSO in CH2Cl2, followed by reaction with Wittig reagent (XIII) and N-methyl morpholine (NMM), to provide crotonate (XIV). Hydrogenation of (XIV) over Pd/C in MeOH furnishes methyl butyrate (XV), which is finally hydrolyzed with NaOH in MeOH. 2. Alternatively, intermediate (VII) can be obtained by reaction of diethyl malonate (XVI) with 4-vinylpyridine and NaH in EtOH to afford derivative (XVIII), which is hydrolyzed and decarboxylated with HCl/H2O and then hydrogenated over PtO2 to provide piperidine derivative (XIX). Finally, (XIX) is protected by reaction with Boc2O and NaOH in THF.

参考文献中间体

合成目标

【1】 Molino, B.F.; Klein, S.I.; Czekaj, M.; et al.; Design of a new class of orally active fibrinogen receptor antagonists. J Med Chem 1998, 41, 14, 2492.
【2】 Klein, S.I.; Molino, B.F. (Aventis Pharma SA); Antithrombotic azacycloalkylalkanoyl peptides and pseudopeptides. EP 0812205; JP 1997507213; US 5866685; WO 9510295 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	45852	4-[1-(tert-butoxycarbonyl)-4-piperidinyl]butyric acid		C₁₄H₂₅NO₄	详情	详情
(IX)	17883	2-(4-pyridinyl)acetic acid	28356-58-3	C₇H₇NO₂	详情	详情
(X)	45854	2-(4-piperidinyl)acetic acid; 4-piperidinylacetic acid	51052-78-9	C₇H₁₃NO₂	详情	详情
(XI)	19346	1-Boc-piperidin-4-ylacetic acid; 2-[1-(tert-butoxycarbonyl)-4-piperidinyl]acetic acid	157688-46-5	C₁₂H₂₁NO₄	详情	详情
(XII)	43453	tert-butyl 4-(2-hydroxyethyl)-1-piperidinecarboxylate		C₁₂H₂₃NO₃	详情	详情
(XIII)	14689	Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate	2605-67-6	C₂₁H₁₉O₂P	详情	详情
(XIV)	45855	tert-butyl 4-[(E)-4-methoxy-4-oxo-2-butenyl]-1-piperidinecarboxylate		C₁₅H₂₅NO₄	详情	详情
(XV)	45856	tert-butyl 4-(4-methoxy-4-oxobutyl)-1-piperidinecarboxylate		C₁₅H₂₇NO₄	详情	详情
(XVI)	16829	Diethyl malonate	105-53-3	C₇H₁₂O₄	详情	详情
(XVII)	45857	4-vinylpyridine		C₇H₇N	详情	详情
(XVIII)	45858	diethyl 2-[2-(4-pyridinyl)ethyl]malonate		C₁₄H₁₉NO₄	详情	详情
(XIX)	45859	4-(4-piperidinyl)butyric acid		C₉H₁₇NO₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

Alcohol (I) was converted to fluoride (II) by treatment with either diethylaminosulfur trifluoride or the Ishikawa reagent. Subsequent acid cleavage of the Boc protecting group of (III) provided piperidine (VI). Alternatively, alcohol (III) was converted to mesylate (IV), which was displaced with tetrabutylammonium fluoride to afford fluoride (V). The benzamido group of (V) was then hydrolyzed with HCl in aqueous MeOH.

参考文献中间体

合成目标

【1】 Smith, G.P.; Brundish, D.E.; Menear, K.A.; Walker, C.V.; Herold, P.; Fullerton, J.D.; Allen, M.C.; Le Grand, D.M.; Kane, P.D.; Cockcroft, X.-L.; Wathey, W.B.; Butler, P.I.; Hatto, J.D.I.; Hayler, J.D. (Novartis AG); Tetrahydroquinoline inhibitors of trypsin and thrombin. GB 2312674 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	43453	tert-butyl 4-(2-hydroxyethyl)-1-piperidinecarboxylate	C₁₂H₂₃NO₃	详情	详情
(II)	43454	tert-butyl 4-(2-fluoroethyl)-1-piperidinecarboxylate	C₁₂H₂₂FNO₂	详情	详情
(III)	43455	[4-(2-hydroxyethyl)-1-piperidinyl](phenyl)methanone	C₁₄H₁₉NO₂	详情	详情
(IV)	43456	2-(1-benzoyl-4-piperidinyl)ethyl methanesulfonate	C₁₅H₂₁NO₄S	详情	详情
(V)	43457	[4-(2-fluoroethyl)-1-piperidinyl](phenyl)methanone	C₁₄H₁₈FNO	详情	详情
(VI)	28517	4-(2-fluoroethyl)piperidine	C₇H₁₄FN	详情	详情

Extended Information