methyl (2S)-2-amino-3-methylbutanoate -Drug Synthesis Database

【结构式】

【分子编号】16613

【品名】methyl (2S)-2-amino-3-methylbutanoate

【CA登记号】

【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 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：(I)

(i) The formation of a 16-membered depsipeptide: For the first step, L-valine methyl ester (I) was coupled to N-Fmoc-L-threonine using the BOP reagent [(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate], removing the N-Fmoc group with Et2NH and coupling to N-Fmoc-(S-triphenylmethyl)-D-cysteine to yield the tripeptide (II). The tetrapeptide (III) was prepared by deprotection of the tripeptide (II) and BOP-mediated peptide coupling of the resulting amine with N-Fmoc-D-valine. The secondary hydroxyl group was activated as the tosylate and eliminated by treatment with DABCO to produce the internal alkene. After removal of the Fmoc protecting group by addition of Et2NH to the reaction mixture, the 16-membered depsipeptide (IV) was formed.

参考文献中间体

合成目标

【1】 Li, K.W.; Simon, J.A.; Xing, W.; Wu, J.; Total synthesis of the antitumor depsipeptide FR901228. J Am Chem Soc 1996, 118, 30, 7237.
【2】 Wang, H.-C. R.; FR901228. Drugs Fut 1999, 24, 11, 1184.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	16613	methyl (2S)-2-amino-3-methylbutanoate	C₆H₁₃NO₂	详情	详情
(II)	29877	methyl (5S,8S,11S)-1-(9H-fluoren-9-yl)-8-[(1R)-1-hydroxyethyl]-11-isopropyl-3,6,9-trioxo-5-[(tritylsulfanyl)methyl]-2-oxa-4,7,10-triazadodecan-12-oate	C₄₇H₄₉N₃O₇S	详情	详情
(III)	29878	methyl (5R,8S,11S,14S)-1-(9H-fluoren-9-yl)-5,14-diisopropyl-11-((1R)-1-[[(4-methylphenyl)sulfonyl]oxy]ethyl)-3,6,9,12-tetraoxo-8-[(tritylsulfanyl)methyl]-2-oxa-4,7,10,13-tetraazapentadecan-15-oate	C₅₉H₆₄N₄O₁₀S₂	详情	详情
(IV)	29879	methyl (2S)-2-[((Z)-2-[[(2S)-2-[[(2R)-2-amino-3-methylbutanoyl]amino]-3-(tritylsulfanyl)propanoyl]amino]-2-butenoyl)amino]-3-methylbutanoate	C₃₇H₄₆N₄O₅S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

This compound has been obtained by two related ways: 1) The hydrolysis of 4'-(bromomethyl)biphenyl-2-carbonitrile (I) with NaOAc in refluxing acetic acid gives the corresponding carbinol (II), which is oxidized with oxalyl chloride in DMSO/dichloromethane yielding the aldehyde (III). The reductocondensation of (III) with L-valine methyl ester (IV) by means of NaBH4CN in THF affords the N-alkylated valine (V), which is acylated with pentanoyl chloride (VI) and TEA in dichloromethane providing the pentanamide (VII). The reaction of the CN group of (VII) with tributyltin azide in refluxing xylene gives the tetrazol derivative (VIII). Finally, the ester group of (VIII) is hydrolyzed with NaOH to furnish the target compound. 2) L-valine methyl ester (IV) can be condensed directly with the bromo-methyl derivative (I) by means of DIEA in dichloromethane giving the N-alkylated valine (V) already reported.

参考文献中间体

合成目标

【1】 Buhlmayer, P.; Ostermayer, F.; Schmidlin, T. (Novartis AG); Acyl cpds.. EP 0443983; JP 1992235149; US 5399578; US 5965592 .
【2】 Buhlmayer, P.; et al.; Valsartan, a potent, orally active angiotensin II antagonist developed from the structurally new amino acid series. Bioorg Med Chem Lett 1994, 4, 1, 29.

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)	15332	4'-(bromomethyl)[1,1'-biphenyl]-2-carbonitrile; 4'-bromomethyl-2-cyanobiphenyl	114772-54-2	C₁₄H₁₀BrN	详情	详情
(II)	37265	4'-(hydroxymethyl)[1,1'-biphenyl]-2-carbonitrile		C₁₄H₁₁NO	详情	详情
(III)	37266	4'-formyl[1,1'-biphenyl]-2-carbonitrile		C₁₄H₉NO	详情	详情
(IV)	16613	methyl (2S)-2-amino-3-methylbutanoate		C₆H₁₃NO₂	详情	详情
(V)	37267	methyl (2S)-2-[[(2'-cyano[1,1'-biphenyl]-4-yl)methyl]amino]-3-methylbutanoate		C₂₀H₂₂N₂O₂	详情	详情
(VI)	15116	pentanoyl chloride; valeryl chloride	638-29-9	C₅H₉ClO	详情	详情
(VII)	37268	methyl (2S)-2-[[(2'-cyano[1,1'-biphenyl]-4-yl)methyl](pentanoyl)amino]-3-methylbutanoate		C₂₅H₃₀N₂O₃	详情	详情
(VIII)	37269	methyl (2S)-3-methyl-2-(pentanoyl[[2'-(1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]amino)butanoate		C₂₅H₃₁N₅O₃	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XXIX)

The N-substituted valine (XIII) has been synthesized as follows: The reaction of isobutyramide (XXII) with phosphorus pentasulfide (P4S10) in ethyl ether gives the corresponding thioamide (XXIII), which is cyclized with 1,3-dichloroacetone (XXIV) by means of MgSO4 in refluxing acetone yielding 4-(chloromethyl)-2-isopropylthiazole (XXV). The reaction of (XXV) with methylamine in water affords N-(2-isopropylthiazol-4-ylmethyl)-N-methylamine (XXVI), which is condensed with N-(4-nitrophenoxycarbonyl)-L-valine methyl ester (XXVII) by means of 4-(dimethylamino)pyridine (DMAP) and triethylamine in refluxing THF to give the thiazol-substituted L-valine ester (XXVIII). Finally, this compound is converted into the corresponding free acid with LiOH in dioxane/water. The N-(4-nitrophenoxycarbonyl)-L-valine methyl ester (XXVII) has been synthesized by reaction of chloroformate (XXI) with L-valine methyl ester (XXIX) by means of 4-methylmorpholine (MPH) in dichloromethane.

参考文献中间体

合成目标

【1】 Graul, A.; Castañer, J.; Ritonavir. Drugs Fut 1996, 21, 7, 700.
【2】 Kempf, D.J.; Norbeck, D.W.; Sham, H.L.; Zhao, C.; Sowin, T.J.; Reno, D.S.; Haight, A.R.; Cooper, A.J. (Abbott Laboratories Inc.); Retroviral protease inhibiting cpds. EP 0674513; EP 0727419; JP 1996505844; JP 1997118679; JP 1998087639; WO 9414436 .
【3】 Al-Razzak, L.; Marsh, K.C.; Manning, L.P.; Kaul, D. (Abbott Laboratories Inc.); Pharmaceutical compsns. containing HIV protease inhibitors. EP 0732923; US 5484801; WO 9520384 .
【4】 Flentge, C.; Kempf, D.; Marsh, K.; et al.; Symmetry-based inhibitors of HIV protease with high oral bioavailability. 207th ACS Natl Meet (March 13-17, San Diego) 1994, Abst MEDI 35.

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)	16597	(2S)-2-([[[(2-isopropyl-1,3-thiazol-4-yl)methyl](methyl)amino]carbonyl]amino)-3-methylbutyric acid		C₁₄H₂₃N₃O₃S	详情	详情
(XXI)	16605	4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene	7693-46-1	C₇H₄ClNO₄	详情	详情
(XXII)	16606	Isobutyramide; 2-methylpropanamide	563-83-7	C₄H₉NO	详情	详情
(XXIII)	16607	2-methylpropanethioamide	13515-65-6	C₄H₉NS	详情	详情
(XXIV)	63907	1,3-dichloroacetone		C₃H₄Cl₂O	详情	详情
(XXV)	16609	4-(chloromethyl)-2-isopropyl-1,3-thiazole		C₇H₁₀ClNS	详情	详情
(XXVI)	16610	(2-isopropyl-1,3-thiazol-4-yl)-N-methylmethanamine; N-[(2-isopropyl-1,3-thiazol-4-yl)methyl]-N-methylamine	154212-60-9	C₈H₁₄N₂S	详情	详情
(XXVII)	16611	methyl (2S)-3-methyl-2-[[(4-nitrophenoxy)carbonyl]amino]butanoate		C₁₃H₁₆N₂O₆	详情	详情
(XXVIII)	16612	methyl (2S)-2-([[[(2-isopropyl-1,3-thiazol-4-yl)methyl](methyl)amino]carbonyl]amino)-3-methylbutanoate		C₁₅H₂₅N₃O₃S	详情	详情
(XXIX)	16613	methyl (2S)-2-amino-3-methylbutanoate		C₆H₁₃NO₂	详情	详情

合成路线4

该中间体在本合成路线中的序号：(XIX)

The intermediate 3-methyl 2(S)-(2-oxoperhydropyrimidin1-yl)butyric acid (XIII) has been obtained as follows: The oxidation of 3-(benzyloxycarbonylamino)-1-propanol (XVII) with oxalyl chloride in dichloromethane gives the corresponding aldehyde (XVIII), which is reductocondensed with L-valine methyl ester (XIX) by means NaBH3CN in methanol yielding the N-substituted valine (XX). The cyclization of (XX) by elimination of the benzyloxycarbonyl group by hydrogenation with H2 over Pd/C in dichloromethane, followed by reaction with carbonyldiimidazole (CDI) affords the 3-methyl 2(S)-(2-oxoperhydropyrimidin-1-yl)butyric acid methyl ester (XXI). Finally, this compound is hydrolyzed with LiOH in dioxane/water to afford the target intermediate (XIII).

参考文献中间体

合成目标

【1】 Retroviral protease inhibiting cpds.. EP 0882024; JP 2000502085; US 5914332; WO 9721685 .
【2】 Sham, H.L.; Stewart, K.D.; Kempf, D.J. (Abbott Laboratories Inc.); Retroviral protease inhibiting cpds.. EP 0876353; JP 2000502997; WO 9721683 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XIII)	38264	(2S)-3-methyl-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]butyric acid	C₉H₁₆N₂O₃	详情	详情
(XVII)	38547	benzyl 3-hydroxypropylcarbamate	C₁₁H₁₅NO₃	详情	详情
(XVIII)	38548	benzyl 3-oxopropylcarbamate	C₁₁H₁₃NO₃	详情	详情
(XIX)	16613	methyl (2S)-2-amino-3-methylbutanoate	C₆H₁₃NO₂	详情	详情
(XX)	38549	methyl (2S)-2-[(3-[[(benzyloxy)carbonyl]amino]propyl)amino]-3-methylbutanoate	C₁₇H₂₆N₂O₄	详情	详情
(XXI)	38550	methyl (2S)-3-methyl-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]butanoate	C₁₀H₁₈N₂O₃	详情	详情

合成路线5

该中间体在本合成路线中的序号：(I)

Treatment of D-valine methyl ester (I) with chlorosulfonic acid and then with phosphorus pentachloride produced valinesulfamoyl cloride (II). This was condensed with N-(5-chloro-2-pyridinyl)piperazine (III) to afford sulfamide (IV). Basic hydrolysis of the methyl ester of (IV) gave carboxylic acid (V), which was further converted to acid chloride (VI) using oxalyl chloride in the presence of DMF. Finally, the title hydroxamic acid was obtained by condensation with N,O-bis(trimethylsilyl)hydroxylamine, followed by desilylation with MeOH.

参考文献中间体

合成目标

【1】 Castelhano, A.L.; Hendricks, R.T.; Melnick, M.J.; Campbell, J.A.; Walker, K.A.M.; Broka, C.A.; Chen, J.J. (Agouron Pharmaceuticals, Inc.; F. Hoffmann-La Roche AG); Sulfamide-metalloprotease inhibitors. DE 19802350; EP 0958287; US 5998412; WO 9832748 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	16613	methyl (2S)-2-amino-3-methylbutanoate	C₆H₁₃NO₂	详情	详情
(II)	25289	methyl (2R)-2-[(chlorosulfonyl)amino]-3-methylbutanoate	C₆H₁₂ClNO₄S	详情	详情
(III)	25290	1-(5-chloro-2-pyridinyl)piperazine	C₉H₁₂ClN₃	详情	详情
(IV)	25291	methyl (2R)-2-([[4-(5-chloro-2-pyridinyl)-1-piperazinyl]sulfonyl]amino)-3-methylbutanoate	C₁₅H₂₃ClN₄O₄S	详情	详情
(V)	25292	(2R)-2-([[4-(5-chloro-2-pyridinyl)-1-piperazinyl]sulfonyl]amino)-3-methylbutyric acid	C₁₄H₂₁ClN₄O₄S	详情	详情
(VI)	25293	(2R)-2-([[4-(5-chloro-2-pyridinyl)-1-piperazinyl]sulfonyl]amino)-3-methylbutanoyl chloride	C₁₄H₂₀Cl₂N₄O₃S	详情	详情

Extended Information