tert-butyl 2-aminoacetate;tert-butyl glycinate;Glycine tert-butyl ester -Drug Synthesis Database

【结构式】

【分子编号】27841

【品名】tert-butyl 2-aminoacetate;tert-butyl glycinate;Glycine tert-butyl ester

【CA登记号】6456-74-2

【分子式】C₆H₁₃NO₂

【分子量】131.17476

【元素组成】C 54.94% H 9.99% N 10.68% O 24.39%

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：(IX)

The reductocondensation of (II) with tert-butyl glycinate (IX) by means of sodium cyanoborohydride in ethanol gives tert-butyl-N-(2-indanyl)glycinate (X), which is condensed with (IV) by means of isobutyl chlorocarbonate as before yielding tert-butyl-N-[N-(tert-butoxycarbonyl)-L-alanyl]-N-(2-indanyl)glycinate (XI). Deprotection of (XI) by hydrogenolysis with H2 over Pd/C in methanol affords tert-butyl N-(L-alanyl)-N-(2-indanyl)glycinate (XII), which is reductocondensed with (VIII) using H2 and Raney-Ni in ethanol to afford tert-butyl N-[N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl]-N-(2-indanyl)glycinate (XIII). Finally, this compound is saponified with HBr in acetic acid.

参考文献中间体

合成目标

【1】 Oka, Y.; Nishikawa, K.; Miyake, A. (Takeda Chemical Industries, Ltd.); Bicyclic compounds, their production and use. EP 0051391; GB 2086393; JP 82179141; JP 8277651; US 4385051 .
【2】 Serradell, M.N.; Castaner, J.; CV-3317. Drugs Fut 1984, 9, 5, 324.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(II)	30550	1,3-dihydro-2H-inden-2-one	615-13-4	C₉H₈O	详情	详情
(IV)	61209	CBZ-L-Alanine; (2S)-2-[[(Benzyloxy)carbonyl]amino]propionic acid; N-((Phenylmethoxy)carbonyl)-alanine; Carbobenzyloxy-L-alanine		C₁₁H₁₃NO₄	详情	详情
(VIII)	20896	Ethyl 2-oxo-4-phenylbutanoate; 2-Oxo-4-phenylbutyric acid ethyl ester	64920-29-2	C₁₂H₁₄O₃	详情	详情
(IX)	27841	tert-butyl 2-aminoacetate;tert-butyl glycinate;Glycine tert-butyl ester	6456-74-2	C₆H₁₃NO₂	详情	详情
(X)	30555	tert-butyl 2-(2,3-dihydro-1H-inden-2-ylamino)acetate		C₁₅H₂₁NO₂	详情	详情
(XI)	30556	tert-butyl 2-[((2S)-2-[[(benzyloxy)carbonyl]amino]propanoyl)(2,3-dihydro-1H-inden-2-yl)amino]acetate		C₂₆H₃₂N₂O₅	详情	详情
(XII)	30557	tert-butyl 2-[[(2S)-2-aminopropanoyl](2,3-dihydro-1H-inden-2-yl)amino]acetate		C₁₈H₂₆N₂O₃	详情	详情
(XIII)	30558	ethyl (2S)-2-([(1S)-2-[[2-(tert-butoxy)-2-oxoethyl](2,3-dihydro-1H-inden-2-yl)amino]-1-methyl-2-oxoethyl]amino)-4-phenylbutanoate		C₃₀H₄₀N₂O₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

The reaction of N-(tert-butoxycarbonyl)-L-phenylalanine-N-carboxyanhydride (I) with N-methylethylenediamine (II) gives the phenyalaninamide (III), which is condensed with the N-protected chiral azetidinone (IV) by means of Cs2CO3 to yield the diaminopropionic acid derivative (V). The condensation of (V) with glycine tert-butyl ester (VI) by means of BOP and DIEA affords the peptide (VII), which, after deprotection with H2 over Pd/C, is condensed with 4-O-benzyl-L-tyrosine (VIII) by means of BOP and DIEA giving the acyclic precursor (IX). The deprotection of (IX) with TFA, followed by cyclization by means of EDC, HOAt, DIEA and DCM in DMF provides the protected cyclic precursor (X), which is finally deprotected by hydrogenation with H2 over Pd black in ethanol.

参考文献中间体

合成目标

【1】 DeHaven, R.; Dang, T.; Daubert, J.; Yaksh, T.L.; Zhang, L.; Goodman, M.; Shreder, K.; Umeno, H.; Synthesis and biological activity of a novel methylamine-bridged enkephalin analogue (MABE): A new route to cyclic peptides and peptidomimetics. J Med Chem 1998, 41, 14, 2631.

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)	27837	tert-butyl (4S)-4-benzyl-2,5-dioxo-1,3-oxazolidine-3-carboxylate	142955-51-9	C₁₅H₁₇NO₅	详情	详情
(II)	27777	N-(2-aminoethyl)-N-methylamine	109-81-9	C₃H₁₀N₂	详情	详情
(III)	27838	tert-butyl (1S)-1-benzyl-2-[[2-(methylamino)ethyl]amino]-2-oxoethylcarbamate		C₁₇H₂₇N₃O₃	详情	详情
(IV)	27845	benzyl (3R)-2-oxooxetanylcarbamate		C₁₁H₁₁NO₄	详情	详情
(V)	27839	(6S,13R)-6-benzyl-13-[[(benzyloxy)carbonyl]amino]-2,2,11-trimethyl-4,7-dioxo-3-oxa-5,8,11-triazatetradecan-14-oic acid		C₂₈H₃₈N₄O₇	详情	详情
(VI)	27841	tert-butyl 2-aminoacetate;tert-butyl glycinate;Glycine tert-butyl ester	6456-74-2	C₆H₁₃NO₂	详情	详情
(VII)	27840	tert-butyl (6S,13R)-6-benzyl-13-[[(benzyloxy)carbonyl]amino]-2,2,11-trimethyl-4,7,14-trioxo-3-oxa-5,8,11,15-tetraazaheptadecan-17-oate		C₃₄H₄₉N₅O₈	详情	详情
(VIII)	27842	(2S)-2-[[(benzyloxy)carbonyl]amino]-3-[4-(benzyloxy)phenyl]propionic acid		C₂₄H₂₃NO₅	详情	详情
(IX)	27843	tert-butyl (6S,13R)-6-benzyl-13-([(2S)-2-[[(benzyloxy)carbonyl]amino]-3-[4-(benzyloxy)phenyl]propanoyl]amino)-2,2,11-trimethyl-4,7,14-trioxo-3-oxa-5,8,11,15-tetraazaheptadecan-17-oate		C₅₀H₆₄N₆O₁₀	详情	详情
(X)	27844	benzyl (1S)-2-[[(6S,12R)-6-benzyl-1-methyl-5,8,11-trioxo-1,4,7,10-tetraazacyclotridecan-12-yl]amino]-1-[4-(benzyloxy)benzyl]-2-oxoethylcarbamate		C₄₁H₄₆N₆O₇	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VIII)

Condensation of the 1,5-benzothiazepin-8-ol derivative (I) with ethyl bromoacetate (II) in the presence of Bu4NBr and Na2CO3 in refluxing acetonitrile yields ethyl ester (III), which is then hydrolyzed with NaOH in EtOH to give the corresponding acid (IV). Subsequent coupling of carboxylic acid (IV) with (R)-2-phenylglycine methyl ester hydrochloride (V) using TBTU and DIEA in CH2Cl2 followed by hydrolysis of the resultant methyl ester (VI) with NaOH in MeOH produces the N-acyl amino acid (VII). After coupling of acid (VII) with tert-butyl glycinate (VIII), using the same procedure as above, the resulting tert-butyl ester (IX) is finally cleaved using TFA in CH2Cl2 .

参考文献中间体

合成目标

【1】 Starke, I., Blomberg, D., Dahlstrom, M. (AstraZeneca AB; AstraZeneca plc). Chemical compounds. EP 1345918, JP 2004196815, JP 2004516285, US 2004067933, US 7192945, WO 2002050051.

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)	68515	3,3-dibutyl-8-hydroxy-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide		C₂₄H₃₃NO₃S₂	详情	详情
(II)	16640	Ethyl 2-bromoacetate; Ethyl bromoacetate	105-36-2	C₄H₇BrO₂	详情	详情
(III)	68516	ethyl 2-((3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acetate		C₂₈H₃₉NO₅S₂	详情	详情
(IV)	68517	2-((3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acetic acid		C₂₆H₃₅NO₅S₂	详情	详情
(V)	68518	(R)-2-phenylglycine methyl ester hydrochloride		C₉H₁₁NO₂.HCl	详情	详情
(VI)	68519	(R)-methyl 2-(2-((3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acetamido)-2-phenylacetate		C₃₅H₄₄N₂O₆S₂	详情	详情
(VII)	68520	(R)-2-(2-((3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acetamido)-2-phenylacetic acid		C₃₄H₄₂N₂O₆S₂	详情	详情
(VIII)	27841	tert-butyl 2-aminoacetate;tert-butyl glycinate;Glycine tert-butyl ester	6456-74-2	C₆H₁₃NO₂	详情	详情
(IX)	68521	(R)-tert-butyl 2-(2-(2-((3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acetamido)-2-phenylacetamido)acetate		C₄₀H₅₃N₃O₇S₂	详情	详情

Extended Information