【结 构 式】 ![]() |
【分子编号】26057 【品名】L-Leucine 【CA登记号】61-90-5 |
【 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:(XXIV)4) The deamination of L-leucine (XXIV) with NaNO2, NaBr and H2SO4 gives 2(S)-bromo-4-methylpentanoic acid (XXV), which is esterified with tert-butyl acetate and BF3.AcOH to yield the tert-butyl ester (XXVI). The condensation of (XXVI) with the sodium salt of diethyl malonate affords the substituted malonic ester (XXVII), which is selectively hydrolyzed at the tert-butyl ester group with formic acid, giving the monoacid (XXVIII). The decarboxylative reduction of (XXVIII) with BH3 and SMe2 provides 3(S)-isobutylbutano-4-lactone (XXIX). Lactone (XXIX) is submitted to ring opening by treatment with trimethylsilyl iodide in ethanol, yielding 3(S)-(iodomethyl)-5-methylhexanoic acid ethyl ester (XXX). The reaction of (XXX) with sodium azide yields azide (XXXI), which is hydrolyzed with KOH in ethanol/water to afford the free acid (XVII). Finally, this compound is reduced to pregabalin by treatment with H2 over Pd/C.
【1】 Newhouse, B.J.; Ibrahim, P.; Burgess, L.E.; et al.; Potent selective nonpeptidic inhibitors of human lung tryptase. Proc Natl Acad Sci USA 1999, 96, 15, 8348. |
【2】 Sobieray, D.M.; Hoekstra, M.S.; Schwindt, M.A.; et al.; Chemical development of CI-1008, an enantiomerically pure anticonvulsant. Org Process Res Dev 1997, 1, 1, 26. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XVII) | 26051 | (3S)-3-(azidomethyl)-5-methylhexanoic acid | C8H15N3O2 | 详情 | 详情 | |
(XXIV) | 26057 | L-Leucine | 61-90-5 | C6H13NO2 | 详情 | 详情 |
(XXV) | 26058 | (2S)-2-bromo-4-methylpentanoic acid | C6H11BrO2 | 详情 | 详情 | |
(XXVI) | 26059 | tert-butyl (2S)-2-bromo-4-methylpentanoate | C10H19BrO2 | 详情 | 详情 | |
(XXVII) | 26060 | 2-(tert-butyl) 1,1-diethyl (2S)-4-methyl-1,1,2-pentanetricarboxylate | C17H30O6 | 详情 | 详情 | |
(XXVIII) | 26061 | (2S)-2-[2-ethoxy-1-(ethoxycarbonyl)-2-oxoethyl]-4-methylpentanoic acid | C13H22O6 | 详情 | 详情 | |
(XXIX) | 26062 | (4S)-4-isobutyldihydro-2(3H)-furanone | C8H14O2 | 详情 | 详情 | |
(XXX) | 26063 | ethyl (3S)-3-(iodomethyl)-5-methylhexanoate | C10H19IO2 | 详情 | 详情 | |
(XXXI) | 26064 | ethyl (3S)-3-(azidomethyl)-5-methylhexanoate | C10H19N3O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(VIII)Solid-phase peptide synthesis started with N-Boc-L-leucine linked to a PAM resin (VII). Deprotection of the Boc group was effected by treatment with trifluoroacetic acid in CH2Cl2 to give leucine-resin (VIII). Sequential couplings with the respective protected amino acids were mediated by DCC and HOBt, and trifluoroacetic acid in CH2Cl2 was used for deprotection of the Boc groups. The following protected amino acids were sequentially coupled: N-Boc-L-proline (IX), N-Boc-L-isoleucine (XI), N-Boc-L-proline (IX), N-Boc-L-glutamic acid omega-benzyl ester (XIV), N-Boc-L-phenylalanine (XVI) and N-Boc-L-aspartic acid omega-cyclohexyl ester (XVIII) to afford the peptide resins (X), (XII), (XIII), (XV), (XVII) and (XIX), respectively.
【1】 DiMaio, J. (National Research Council of Canada); Thrombin inhibitors based on the amino acid sequence of hirudin. JP 1999502203; WO 9629347 . |
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) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid;N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
(VIII) | 26057 | L-Leucine | 61-90-5 | C6H13NO2 | 详情 | 详情 |
(IX) | 16374 | (1R,4S)-7-[(2,2-dimethylpropanoyl)oxy]-7-azabicyclo[2.2.1]heptan-2-one | C11H17NO3 | 详情 | 详情 | |
(IX) | 16734 | (2S)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-L-proline; (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid | C10H17NO4 | 详情 | 详情 | |
(X) | 37334 | (2S)-4-methyl-2-[[(2S)pyrrolidinylcarbonyl]amino]pentanoic acid | 52899-07-7 | C11H20N2O3 | 详情 | 详情 |
(XI) | 30009 | (2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentanoic acid | 13139-16-7 | C11H21NO4 | 详情 | 详情 |
(XII) | 37335 | (2S)-2-[([(2S)-1-[(2S,3S)-2-amino-3-methylpentanoyl]pyrrolidinyl]carbonyl)amino]-4-methylpentanoic acid | C17H31N3O4 | 详情 | 详情 | |
(XIII) | 37336 | (2S)-4-methyl-2-([[(2S)-1-((2S,3S)-3-methyl-2-[[(2S)pyrrolidinylcarbonyl]amino]pentanoyl)pyrrolidinyl]carbonyl]amino)pentanoic acid | C22H38N4O5 | 详情 | 详情 | |
(XIV) | 25141 | (2S)-5-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid | 13574-13-5 | C17H23NO6 | 详情 | 详情 |
(XV) | 37337 | (2S)-2-[[((2S)-1-[(2S,3S)-2-[([(2S)-1-[(2S)-2-amino-5-(benzyloxy)-5-oxopentanoyl]pyrrolidinyl]carbonyl)amino]-3-methylpentanoyl]pyrrolidinyl)carbonyl]amino]-4-methylpentanoic acid | C34H51N5O8 | 详情 | 详情 | |
(XVI) | 12874 | (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine | 13734-34-4 | C14H19NO4 | 详情 | 详情 |
(XVII) | 37338 | (2S)-2-[[((2S)-1-[(2S,3S)-2-[([(2S)-1-[(2S)-2-[[(2S)-2-amino-3-phenylpropanoyl]amino]-5-(benzyloxy)-5-oxopentanoyl]pyrrolidinyl]carbonyl)amino]-3-methylpentanoyl]pyrrolidinyl)carbonyl]amino]-4-methylpentanoic acid | C43H60N6O9 | 详情 | 详情 | |
(XVIII) | 37339 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-(cyclohexyloxy)-4-oxobutyric acid | 73821-95-1 | C15H25NO6 | 详情 | 详情 |
(XIX) | 37340 | (2S)-2-[[((2S)-1-[(2S,3S)-2-[([(2S)-1-[(2S)-2-[((2S)-2-[[(2S)-2-amino-4-(cyclohexyloxy)-4-oxobutanoyl]amino]-3-phenylpropanoyl)amino]-5-(benzyloxy)-5-oxopentanoyl]pyrrolidinyl]carbonyl)amino]-3-methylpentanoyl]pyrrolidinyl)carbonyl]amino]-4-methylpentanoic acid | C53H75N7O12 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(VI)The monocyclic peptide precursor (XVIII) was prepared by solid-phase peptide synthesis by two different sequences. In the first one, N-Fmoc-L-leucine (IV) was linked to chlorotrityl resin, and the resultant resin-bound Fmoc-leucine (V) was subsequently deprotected by treatment with piperidine in DMF. To the deprotected leucine-resin (VI) was attached the diaminopropionic acid derivative (III), using either dicyclohexylcarbodiimide or diisopropylcarbodiimide as the coupling reagents, to yield the dipeptide resin (VII), which was further deprotected to (VIII) by means of piperidine in DMF.
【1】 Aimoto, S.; Akaji, K.; Synthesis of MEN11420, a glycosylated bicyclic peptide, by intramolecular double cyclization using a chloroimidazolinium coupling reagent. Tetrahedron 2001, 57, 9, 1749. |
【2】 Arcamone, F.; Maggi, C.A.; Quartara, L.; Giannotti, D. (Menarini Industrie Farma Riunite Srl); Bicyclic tachykinins antagonists, preparation thereof and their use in pharmaceutical compsn.. JP 1999501643; WO 9628467 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(IV),(V) | 19934 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-methylpentanoic acid | C21H23NO4 | 详情 | 详情 | |
(III) | 56121 | (2S)-3-[(tert-butoxycarbonyl)amino]-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}propanoic acid | C23H26N2O6 | 详情 | 详情 | |
(VI) | 26057 | L-Leucine | 61-90-5 | C6H13NO2 | 详情 | 详情 |
(VII) | 56122 | (2S)-2-[((2S)-3-[(tert-butoxycarbonyl)amino]-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}propanoyl)amino]-4-methylpentanoic acid | C29H37N3O7 | 详情 | 详情 | |
(VIII) | 56123 | (2S)-2-({(2S)-2-amino-3-[(tert-butoxycarbonyl)amino]propanoyl}amino)-4-methylpentanoic acid | C14H27N3O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号:(I)The solid phase method for the synthesis of peptides is here used starting with a phenylacetamidomethyl resin coupled with boc-protected-L-leucine (I), which was coupled successively with protected L-2,3-diaminopropionic acid (II) yielding dipeptide (III), with protected L-phenylalanine (IV), yielding tripeptide (V), with protected L-tryptophan (VI) yielding tetrapeptide (VII), and with protected L-aspartic acid (VIII), yielding pentapeptide (IX). The cyclization of (IX) by selective deprotection of the side chains of diaminopropionic acid and aspartic acid with piperidine in DMF, followed by cyclization by means of PyBop and DIEA in DMF affords the cyclic pentapeptide (X).
【1】 Lombardi, A.; D'Agostino, B.; Filippelli, A.; Pedone, C.; Matera, M.G.; Falciani, M.; De Rosa, M.; Rossi, F.; Pavone, V.; Neuronorm is a potent and water soluble neurokinin A receptor antagonist. Bioorg Med Chem Lett 1998, 8, 13, 1735. |
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) | 26057 | L-Leucine | 61-90-5 | C6H13NO2 | 详情 | 详情 |
(II) | 27439 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid | C23H26N2O6 | 详情 | 详情 | |
(III) | 27440 | (2S)-2-[((2S)-2-[(tert-butoxycarbonyl)amino]-3-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propanoyl)amino]-4-methylpentanoic acid | C29H37N3O7 | 详情 | 详情 | |
(IV) | 12874 | (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine | 13734-34-4 | C14H19NO4 | 详情 | 详情 |
(V) | 27441 | (6S,9S,12S)-6-benzyl-9-([[(9H-fluoren-9-ylmethoxy)carbonyl]amino]methyl)-12-isobutyl-2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-oic acid | C38H46N4O8 | 详情 | 详情 | |
(VI) | 25478 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(1-formyl-1H-indol-3-yl)propionic acid | C17H20N2O5 | 详情 | 详情 | |
(VII) | 27442 | (6S,9S,12S,15S)-9-benzyl-12-([[(9H-fluoren-9-ylmethoxy)carbonyl]amino]methyl)-6-[(1-formyl-1H-indol-3-yl)methyl]-15-isobutyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadecan-16-oic acid | C50H56N6O10 | 详情 | 详情 | |
(VIII) | 27443 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-(9H-fluoren-9-ylmethoxy)-4-oxobutyric acid | C23H25NO6 | 详情 | 详情 | |
(IX) | 27444 | (6S,9S,12S,15S,18S)-12-benzyl-15-([[(9H-fluoren-9-ylmethoxy)carbonyl]amino]methyl)-6-[2-(9H-fluoren-9-ylmethoxy)-2-oxoethyl]-9-[(1-formyl-1H-indol-3-yl)methyl]-18-isobutyl-2,2-dimethyl-4,7,10,13,16-pentaoxo-3-oxa-5,8,11,14,17-pentaazanonadecan-19-oic acid | C68H71N7O13 | 详情 | 详情 | |
(X) | 27445 | (2S)-2-([[(3S,6S,9S,12S)-6-benzyl-12-[(tert-butoxycarbonyl)amino]-9-(1H-indol-3-ylmethyl)-5,8,11,14-tetraoxo-1,4,7,10-tetraazacyclotetradecan-3-yl]carbonyl]amino)-4-methylpentanoic acid | C38H49N7O9 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号:(II)The peptide moiety (XVII) was prepared by solid-phase synthesis in a peptide synthesizer starting from Boc-Leu-PAM resin (I). Removal of the Boc protecting group of (I) was effected by treatment with trifluoroacetic acid in CH2Cl2. To the deprotected Leu-resin (II) were sequentially incorporated the following amino acids: N-Fmoc-L-serine(O-t-Bu) (III), N-Fmoc-L-glutamine(Trt) (V), N-Fmoc-L-cyclohexylglycine (VII), again Fmoc-L-serine(O-t-Bu) (III), and N-Fmoc-L-alanine (X) using DCC and HOBt activation in N-methyl-2-pyrrolidinone, each followed by an Fmoc deprotection cycle with piperidine in DMF. The peptide resins (IV), (VI), (VIII), (IX) and (XI) were in turn obtained.
【2】 Garsky, V.M.; Feng, D.-M.; DeFeo-Jones, D. (Merck & Co., Inc.); Conjugates useful in the treatment of prostate cancer. JP 2000509407; WO 9818493 . |
【3】 Oliff, A.I.; Jones, R.E.; Defeo-Jones, D. (Merck & Co., Inc.); A method of treating cancer. WO 0059930 . |
【1】 Feng, D.-M.; Wai, J.; Ramjit, H.G.; Sardana, M.K.; Lumma, P.K.; DeFeo-Jones, D.; Jones, R.E.; Freidinger, R.M.; Oliff, A.; Garsky, V.M.; The synthesis of a prodrug of doxorubicin designed to provide reduced systemic toxicity and greater target efficacy. J Med Chem 2001, 44, 24, 4216. |
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) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid;N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
(II) | 26057 | L-Leucine | 61-90-5 | C6H13NO2 | 详情 | 详情 |
(III) | 33118 | (2S)-3-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid | 71989-33-8 | C22H25NO5 | 详情 | 详情 |
(IV) | 53663 | (2S)-2-{[(2S)-2-amino-3-(tert-butoxy)propanoyl]amino}-4-methylpentanoic acid | n/a | C13H26N2O4 | 详情 | 详情 |
(V) | 53664 | (2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-5-oxo-5-(tritylamino)pentanoic acid | n/a | C39H34N2O5 | 详情 | 详情 |
(VI) | 53665 | (2S)-2-{[(2S)-2-{[(2S)-2-amino-5-oxo-5-(tritylamino)pentanoyl]amino}-3-(tert-butoxy)propanoyl]amino}-4-methylpentanoic acid | n/a | C37H48N4O6 | 详情 | 详情 |
(VII) | 53666 | (2S)-2-cyclohexyl-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}ethanoic acid | n/a | C23H25NO4 | 详情 | 详情 |
(VIII) | 53667 | (2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-amino-2-cyclohexylethanoyl]amino}-5-oxo-5-(tritylamino)pentanoyl]amino}-3-(tert-butoxy)propanoyl]amino}-4-methylpentanoic acid | n/a | C45H61N5O7 | 详情 | 详情 |
(IX) | 53668 | (2S,5S,8S,11S,14S)-14-amino-5-(tert-butoxymethyl)-11-cyclohexyl-2-isobutyl-17,17-dimethyl-4,7,10,13-tetraoxo-8-[3-oxo-3-(tritylamino)propyl]-16-oxa-3,6,9,12-tetraazaoctadecan-1-oic acid | n/a | C52H74N6O9 | 详情 | 详情 |
(X) | 19926 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid | C18H17NO4 | 详情 | 详情 | |
(XI) | 53669 | (2S,5S,8S,11S,14S)-14-{[(2S)-2-aminopropanoyl]amino}-5-(tert-butoxymethyl)-11-cyclohexyl-2-isobutyl-17,17-dimethyl-4,7,10,13-tetraoxo-8-[3-oxo-3-(tritylamino)propyl]-16-oxa-3,6,9,12-tetraazaoctadecan-1-oic acid | n/a | C55H79N7O10 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号:(VI)Diazotization of D-asparagine (I) in the presence of KCl afforded (R)-2-chlorosuccinamic acid (II) with retention of the configuration. Subsequent displacement of the chlorine atom of (II) with tert-butyl mercaptan provided thioether (III). Reduction of the carboxyl group of (III) by means of borane in THF gave alcohol (IV), which was converted to thioester (V) by esterification with thioacetic acid under Mitsunobu conditions. The chiral bromo acid (VII) (prepared by diazotization of L-leucine (VIII) in the presence of KBr) was then condensed with the thiol liberated from thioacetate (V) in the presence of NaOEt, yielding the corresponding thioether (VIII). Coupling of N-methyl-L-phenylalaninamide (IX) with carboxylic acid (VIII) using DCC and HOBt gave rise to amide (X). The S-tert-butyl group of (X) was then removed by means of 2-nitrobenzenesulfenyl chloride (XI) in HOAc, generating the disulfide (XII). Finally, the disulfide bond of (XII) was reductively cleaved with 2-mercaptoethanol to furnish the title thiol.
【1】 Schwartz, M.A.; Wart, H.V. (Florida State University); Mercaptosulfide metalloproteinase inhibitors. WO 9509833 . |
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) | 28237 | R-(-)-Asparagine; S-(-)-2-Aminosuccinamic acid; D-asparagine | 5794-13-8 | C4H8N2O3 | 详情 | 详情 |
(II) | 45637 | (2R)-4-amino-2-chloro-4-oxobutyric acid | C4H6ClNO3 | 详情 | 详情 | |
(III) | 45638 | (2S)-4-amino-2-(tert-butylsulfanyl)-4-oxobutyric acid | C8H15NO3S | 详情 | 详情 | |
(IV) | 45639 | (3S)-3-(tert-butylsulfanyl)-4-hydroxybutanamide | C8H17NO2S | 详情 | 详情 | |
(V) | 45640 | S-[(2S)-4-amino-2-(tert-butylsulfanyl)-4-oxobutyl] ethanethioate | C10H19NO2S2 | 详情 | 详情 | |
(VI) | 26057 | L-Leucine | 61-90-5 | C6H13NO2 | 详情 | 详情 |
(VII) | 16011 | (2R)-2-bromo-4-methylpentanoic acid | C6H11BrO2 | 详情 | 详情 | |
(VIII) | 45641 | (2R)-2-[[(2S)-4-amino-2-(tert-butylsulfanyl)-4-oxobutyl]sulfanyl]-4-methylpentanoic acid | C14H27NO3S2 | 详情 | 详情 | |
(IX) | 16015 | (2S)-2-amino-N-methyl-3-phenylpropanamide | C10H14N2O | 详情 | 详情 | |
(X) | 45642 | (2R)-2-[[(2S)-4-amino-2-(tert-butylsulfanyl)-4-oxobutyl]sulfanyl]-N-[(1S)-1-benzyl-2-(methylamino)-2-oxoethyl]-4-methylpentanamide | C24H39N3O3S2 | 详情 | 详情 | |
(XI) | 45643 | O-Nitrobenzenesulfenyl chloride; 2-nitrobenzenesulfenyl chloride; 2-nitrophenylsulfenyl chloride | 7669-54-7 | C6H4ClNO2S | 详情 | 详情 |
(XII) | 45644 | (2R)-2-([(2S)-4-amino-2-[(2-nitrophenyl)disulfanyl]-4-oxobutyl]sulfanyl)-N-[(1S)-1-benzyl-2-(methylamino)-2-oxoethyl]-4-methylpentanamide | C26H34N4O5S3 | 详情 | 详情 |