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【结 构 式】 
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【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% |
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.
| 【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 | CAS号 | 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.
| 【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.
| 【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).
| 【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 | CAS号 | 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.
| 【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 | CAS号 | 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 |