(2S)-2-{[(benzyloxy)carbonyl]amino}-3-(4-{4-[1-(tert-butoxycarbonyl)-4-piperidinyl]butoxy}phenyl)propanoic acid -Drug Synthesis Database

【结构式】

【分子编号】59544

【品名】(2S)-2-{[(benzyloxy)carbonyl]amino}-3-(4-{4-[1-(tert-butoxycarbonyl)-4-piperidinyl]butoxy}phenyl)propanoic acid

【CA登记号】

【分子式】C₃₁H₄₂N₂O₇

【分子量】554.68376

【元素组成】C 67.13% H 7.63% N 5.05% O 20.19%

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：(XI)

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：(XI)

Acid (XI) was converted to the methyl ester (XII) by alkylation with iodomethane in the presence of Cs2CO3. After removal of the N-Cbz group of (XII) by catalytic hydrogenolysis, the resultant amine (XIII) was acylated by butanesulfonyl chloride (XIV) producing sulfonamide (XV). Saponification of the ester group of (XV) with LiOH gave acid (XVI). The N-Boc group of (XVI) was finally cleaved by treatment with HCl in EtOAc.

参考文献中间体

合成目标

【1】 Egbertson, M.S.; Hartman, G.D.; Halczenko, W.; Laswell, W.L.; Duggan, M.E. (Merck & Co., Inc.); Novel sulfonamide fibrinogen receptor antagonists. WO 9319046 .
【2】 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 .
【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
(XI)	59544	(2S)-2-{[(benzyloxy)carbonyl]amino}-3-(4-{4-[1-(tert-butoxycarbonyl)-4-piperidinyl]butoxy}phenyl)propanoic acid		C₃₁H₄₂N₂O₇	详情	详情
(XII)	59545	tert-butyl 4-{4-[4-((2S)-2-{[(benzyloxy)carbonyl]amino}-3-methoxy-3-oxopropyl)phenoxy]butyl}-1-piperidinecarboxylate		C₃₂H₄₄N₂O₇	详情	详情
(XIII)	59546	tert-butyl 4-(4-{4-[(2S)-2-amino-3-methoxy-3-oxopropyl]phenoxy}butyl)-1-piperidinecarboxylate		C₂₄H₃₈N₂O₅	详情	详情
(XIV)	26779	1-butanesulfonyl chloride	2386-60-9	C₄H₉ClO₂S	详情	详情
(XV)	59547	tert-butyl 4-[4-(4-{(2S)-2-[(butylsulfonyl)amino]-3-methoxy-3-oxopropyl}phenoxy)butyl]-1-piperidinecarboxylate		C₂₈H₄₆N₂O₇S	详情	详情
(XVI)	59548	(2S)-3-(4-{4-[1-(tert-butoxycarbonyl)-4-piperidinyl]butoxy}phenyl)-2-[(butylsulfonyl)amino]propanoic acid		C₂₇H₄₄N₂O₇S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XI)

Intermediate (XI) was converted to the title compound by an alternative method, reported to provide a higher enantiomeric excess. Hydrogenolysis of the N-Cbz group of (XI) in the presence of Pd/C gave the aminoacid (XV). Subsequent acylation of (XV) with butanesulfonyl chloride (XIV) under Schotten-Baumann conditions furnished sulfonamide (XVI), which was then treated with HCl in EtOAc to remove the N-Boc protecting group.

参考文献中间体

合成目标

【1】 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
(XI)	59544	(2S)-2-{[(benzyloxy)carbonyl]amino}-3-(4-{4-[1-(tert-butoxycarbonyl)-4-piperidinyl]butoxy}phenyl)propanoic acid		C₃₁H₄₂N₂O₇	详情	详情
(XIV)	26779	1-butanesulfonyl chloride	2386-60-9	C₄H₉ClO₂S	详情	详情
(XV)	59547	tert-butyl 4-[4-(4-{(2S)-2-[(butylsulfonyl)amino]-3-methoxy-3-oxopropyl}phenoxy)butyl]-1-piperidinecarboxylate		C₂₈H₄₆N₂O₇S	详情	详情
(XVI)	59548	(2S)-3-(4-{4-[1-(tert-butoxycarbonyl)-4-piperidinyl]butoxy}phenyl)-2-[(butylsulfonyl)amino]propanoic acid		C₂₇H₄₄N₂O₇S	详情	详情

Extended Information