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【结 构 式】 
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【分子编号】16886 【品名】(2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propionic acid; N-alpha-t-BOC-o-benzyl-L-serine 【CA登记号】23680-31-1 |
【 分 子 式 】C15H21NO5 【 分 子 量 】295.33548 【元素组成】C 61% H 7.17% N 4.74% O 27.09% |
合成路线1
该中间体在本合成路线中的序号：(XIV)The synthesis of ganirelix was performed using usual solid-state peptide synthesis with a The following amino acids were added successively to intermediate (XIII): N-Boc-O-benzyl-L-serine (XIV), Boc-(3-pyridyl)-D-alanine (XVI) and Boc-4-chloro-D-phenylalanine (XVIII), yielding successively the peptide resins (XV), (XVII) and (XIX).
| 【1】 Robinson, J.3rd; Morgans, D.J.; Bingenheimer, W.; Arzeno, H.B.; Temporary serine protection in solid phase synthesis of LH-RH analogs. Int J Pept Protein Res 1993, 41, 4, 342. |
| 【2】 Castaner, J.; Leeson, P.; Rabasseda, X.; Ganirelix Acetate. Drugs Fut 1999, 24, 4, 393. |
| 【3】 Nestor, J.J. Jr.; Vickery, B.H. (Syntex (USA), Inc.); Nonapeptide and decapeptide analogs of LHRH as LHRH antagonists. EP 0277829; JP 1988201199; US 4801577 . |
| 【4】 Vickery, B.H. (Syntex (USA), Inc.); LHRH antagonist analogs and 19-nor-progestational steroids for therapy. EP 0301850 . |
| 【5】 Nestor, J.J. Jr.; McClure, N.L. (Syntex (USA), Inc.); Temporary minimal protection synthesis of LH-RH analogs. EP 0443532; JP 1992211096; US 5212288 . |
| 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) | 23491 | (2R)-2-[([(2S)-1-[(2S,5S,8R,11S)-2,8-bis(4-[[(ethylamino)(ethylimino)methyl]amino]butyl)-11-(4-hydroxybenzyl)-5-isobutyl-15,15-dimethyl-4,7,10,13-tetraoxo-14-oxa-3,6,9,12-tetraazahexadec-1-anoyl]pyrrolidinyl]carbonyl)amino]propionic acid | C50H86N12O10 | 详情 | 详情 | |
| (XIV) | 16886 | (2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propionic acid; N-alpha-t-BOC-o-benzyl-L-serine | 23680-31-1 | C15H21NO5 | 详情 | 详情 |
| (XV) | 23493 | (2R)-2-[([(2S)-1-[(2S,5S,8R,11S,14S)-14-[(benzyloxy)methyl]-2,8-bis(4-[[(ethylamino)(ethylimino)methyl]amino]butyl)-11-(4-hydroxybenzyl)-5-isobutyl-18,18-dimethyl-4,7,10,13,16-pentaoxo-17-oxa-3,6,9,12,15-pentaazanonadec-1-anoyl]pyrrolidinyl]carbonyl | C60H97N13O12 | 详情 | 详情 | |
| (XVI) | 23494 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-(3-pyridinyl)propionic acid | C13H18N2O4 | 详情 | 详情 | |
| (XVII) | 23495 | (2R)-2-[([(2S)-1-[(2S,5S,8R,11S,14S,17R)-2,8-bis(4-[[(ethylamino)(ethylimino)methyl]amino]butyl)-11-(4-hydroxybenzyl)-14-(hydroxymethyl)-5-isobutyl-21,21-dimethyl-4,7,10,13,16,19-hexaoxo-17-(3-pyridinylmethyl)-20-oxa-3,6,9,12,15,18-hexaazadocos-1-an | C61H99N15O13 | 详情 | 详情 | |
| (XVIII) | 23496 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-(4-chlorophenyl)propionic acid | C14H18ClNO4 | 详情 | 详情 | |
| (XIX) | 23497 | (2R)-2-[([(2S)-1-[(2S,5S,8R,11S,14S,17R,20R)-20-(4-chlorobenzyl)-2,8-bis(4-[[(ethylamino)(ethylimino)methyl]amino]butyl)-11-(4-hydroxybenzyl)-14-(hydroxymethyl)-5-isobutyl-24,24-dimethyl-4,7,10,13,16,19,22-heptaoxo-17-(3-pyridinylmethyl)-23-oxa-3,6, | C70H107ClN16O14 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)The reaction of N-(tert-butoxycarbonyl [Boc])-4-O-methyl-L-tyrosine (I) with N,O-dimethylhydroxylamine (II) by means of dicyclohexylcarbodiimide (DCC) in THF gives the corresponding amide (III), which is reduced with LiAlH4 in ethyl ether yielding N-(tert-butoxycarbonyl)-4-O-methyl-L-tyrosinal (IV). The reductocondensation of (IV) with Nomega-tosyl-L-arginine (V) in methanol/acetic acid affords Nalpha-[2(S)-(tert-butoxycarbonylamino)-3-(4-methoxyphenyl)propyl]-Nomega-tosyl-L-arginine (VI), which is then attached to a polyestyrene resin (Merrifield resin) by means of DCC and dimethylaminopyridine (DMAP) to give the starting peptide-resin complex (IX). This resin (IX) is introduced into a Beckman 990 peptide synthesizer and submitted to successive amino acid coupling cycles (deprotection with TFA and coupling with (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate [BOP]) in order to introduce successively Boc-L-proline (X), Boc-L-serine (XII), Boc-L-(2-thienyl)alanine (XIV), Boc-glycine (XVI), Boc-L-(4-benzyloxy)proline (XVIII), Boc-L-proline (X), and Boc-L-(Nomega-tosyl)arginine (XXI) yielding resins (XI), (XIII), (XV), (XVII), (XIX), (XX), and the final resin (XXII), successively. The final peptide (RMP-7) is liberated from the resin (XXII) and simultaneously deprotected by a treatment with anhydrous HF with a 10% anisole and purified by HPLC over a C18 reverse phase column using trifluoroacetic acid/acetonitrile with a 0-25% gradient. Tritiated RMP-7 is obtained by bromination of RMP-7 with Br2 in acetic acid giving a monobrominated compound (XXIII) (basically the 5-position of the thiophene ring of thienylalanine is brominated), which is then tritiated with 3H2 and Pd/C in water.
| 【1】 Graul, A.; Leeson, P.; Castañer, J.; RMP-7. Drugs Fut 1998, 23, 1, 32. |
| 【2】 Straub, J.A.; Musso, G.F.; Smart, J.L.; Lang, C.; Akiyama, A.; Bromination and subsequent catalytic tritiation of thienylalanine and 4-methyltyrosine residues in the bradykinin analog RMP-7. J Label Compd Radiopharm 1994, 34, 12, 1217-26. |
| 【3】 Malfroy-Camine, B.; Smart, J.L. (Alkermes, Inc.); Method for increasing blood-brain barrier permeability. WO 9116355 . |
| 【4】 Kozarich, J.W.; Musso, G.F.; Malfroy-Camine, B. (Alkermes, Inc.); Increasing blood-brain barrier permeability with permeabilizer peptides. WO 9218529 . |
| 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) | 16875 | (2S)-2-[(tert-Butoxycarbonyl)amino]-3-(4-methoxyphenyl)propionic acid; N-t-BOC-O-Methyl-L-tyrosine | 53267-93-9 | C15H21NO5 | 详情 | 详情 |
| (II) | 13361 | (Methoxyamino)methane; N,O-Dimethylhydroxylamine | 1117-97-1 | C2H7NO | 详情 | 详情 |
| (III) | 16877 | tert-butyl N-[(1S)-1-(4-methoxybenzyl)-2-[methoxy(methyl)amino]-2-oxoethyl]carbamate | C17H26N2O5 | 详情 | 详情 | |
| (IV) | 16878 | tert-butyl N-[(1S)-1-formyl-2-(4-methoxyphenyl)ethyl]carbamate | C15H21NO4 | 详情 | 详情 | |
| (V) | 16879 | (2S)-2-amino-5-[[imino(methylamino)methyl]amino]pentanoic acid | C7H16N4O2 | 详情 | 详情 | |
| (VI) | 16880 | (2S)-2-[[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-methoxyphenyl)propyl]amino]-5-[[imino(methylamino)methyl]amino]pentanoic acid | C22H37N5O5 | 详情 | 详情 | |
| (VII) | 16881 | (2S)-2-[benzyl[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-methoxyphenyl)propyl]amino]-5-[[imino(methylamino)methyl]amino]pentanoic acid | C29H43N5O5 | 详情 | 详情 | |
| (IX) | 16883 | methyl (2S)-2-[benzyl[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-methoxyphenyl)propyl]amino]-5-[[imino(methylamino)methyl]amino]pentanoate | C30H45N5O5 | 详情 | 详情 | |
| (X) | 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 | |
| (XI) | 16885 | tert-butyl (2S)-2-[(3S,6S)-5-benzyl-11-imino-3-(4-methoxybenzyl)-6-(methoxycarbonyl)-2,5,10,12-tetraazatridec-1-anoyl]-1-pyrrolidinecarboxylate | C35H52N6O6 | 详情 | 详情 | |
| (XII) | 16886 | (2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propionic acid; N-alpha-t-BOC-o-benzyl-L-serine | 23680-31-1 | C15H21NO5 | 详情 | 详情 |
| (XIII) | 16887 | methyl (2S)-2-[benzyl[(2S)-2-[[((2S)-1-[(2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propanoyl]pyrrolidinyl)carbonyl]amino]-3-(4-methoxyphenyl)propyl]amino]-5-[[imino(methylamino)methyl]amino]pentanoate | C45H63N7O8 | 详情 | 详情 | |
| (XIV) | 16888 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-thienyl)propionic acid；Boc-D-2-Thienylalanine | 78452-55-8 | C12H17NO4S | 详情 | 详情 |
| (XV) | 16889 | methyl (2S)-2-[benzyl[(2S)-2-([[(2S)-1-((2S)-3-(benzyloxy)-2-[[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-thienyl)propanoyl]amino]propanoyl)pyrrolidinyl]carbonyl]amino)-3-(4-methoxyphenyl)propyl]amino]-5-[[imino(methylamino)methyl]amino]pentanoate | C52H70N8O9S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIa)In a solid phase synthesizer, an a-Boc-omega-Ts-Arg-phenylacetamidomethyl resin (V) was treated with trifluoroacetic acid (TFA) in anisole and dichloromethane in order to remove the Boc protecting group, and the resulting (VI) was coupled with Boc-octahydroindolecarboxylic acid (VII) in the presence of diisopropyl carbodiimide (DIPCDI) to give the dipeptide resin (VIII). This was submitted to successive coupling cycles (deprotection with TFA, and coupling with DIPCDI) to introduce sequentially the following amino acids: Boc-D-4-propoxyproline (IV), Boc-Ser(Bzl) (XIa) to yield the following resins: (IXa),(IXb) and (X), respectively.
| 【1】 Kyle, D.J.; Hiner, R.N. (Scios Inc.); Bradykinin antagonist peptides. JP 1995504155; US 5385889 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIa) | 16886 | (2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propionic acid; N-alpha-t-BOC-o-benzyl-L-serine | 23680-31-1 | C15H21NO5 | 详情 | 详情 |
| (IXa) | 19051 | methyl (2S)-2-[[(2S,3aS,7aS)octahydro-1H-indol-2-ylcarbonyl]amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoate | C23H35N5O5S | 详情 | 详情 | |
| (IXb) | 19052 | methyl (2S)-2-[[((2S,3aS,7aS)-1-[[(2R,4S)-4-propoxypyrrolidinyl]carbonyl]octahydro-1H-indol-2-yl)carbonyl]amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoate | C31H48N6O7S | 详情 | 详情 | |
| (IV) | 19046 | (2R,4S)-1-(tert-butoxycarbonyl)-4-propoxy-2-pyrrolidinecarboxylic acid | C13H23NO5 | 详情 | 详情 | |
| (V) | 19047 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoate | C19H30N4O6S | 详情 | 详情 | |
| (VI) | 19048 | methyl (2S)-2-amino-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoate | C14H22N4O4S | 详情 | 详情 | |
| (VII) | 19049 | (2S,3aS,7aS)-1-(tert-butoxycarbonyl)octahydro-1H-indole-2-carboxylic acid | C14H23NO4 | 详情 | 详情 | |
| (VIII) | 19050 | tert-butyl (2S,3aS,7aS)-2-([[(1S)-4-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]-1-(methoxycarbonyl)butyl]amino]carbonyl)octahydro-1H-indole-1-carboxylate | C28H43N5O7S | 详情 | 详情 | |
| (X) | 19053 | methyl (2S)-2-([[(2S,3aS,7aS)-1-([(2R,4S)-1-[(2S)-2-amino-3-(benzyloxy)propanoyl]-4-propoxypyrrolidinyl]carbonyl)octahydro-1H-indol-2-yl]carbonyl]amino)-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoate | C41H59N7O9S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XII)Alkylation of N-acetyl-D-cysteine (I) with 1-fluoro-5-methyl-2-nitrobenzene (II) gave adduct (III). After hydrolysis of the acetamido group of (III) with aqueous sulfuric acid, the resulting amine (IV) was protected as the benzyl carbamate (V). Reduction of the nitro group of (V) provided amino acid (VI), which was cyclized to the benzothiazepinone (VII) using EDC. Subsequent alkylation of (VII) with ethyl bromoacetate under phase-transfer conditions yielded (VIII) (1). Cleavage of both N-Cbz group and ethyl ester by HBr in AcOH, followed by introduction of the N-Boc group afforded intermediate (X) (2). Optionally, hydrogenolysis of the N-Cbz group of (VIII) provided amino lactam (XI). This was coupled with N-Boc-O-benzylserine (XII) to give amide (XIII). Then, basic hydrolysis of the ethyl ester produced carboxylic acid (XIV).
| 【1】 Dodey, P.; Luccarini, J.-M.; Martinez, J.; Amblard, M.; Daffix, I. (Fournier Industrie et Santé); Peptides agonists of bradykinine B2 receptor. FR 2756566; WO 9824809 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 | |
| 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 | |
| (I) | 39365 | (2S)-2-(acetamido)-3-sulfanylpropionic acid | 616-91-1 | C5H9NO3S | 详情 | 详情 |
| (II) | 39366 | 2-fluoro-4-methyl-1-nitrobenzene | 446-34-4 | C7H6FNO2 | 详情 | 详情 |
| (III) | 39367 | (2S)-2-(acetamido)-3-[(5-methyl-2-nitrophenyl)sulfanyl]propionic acid | C12H14N2O5S | 详情 | 详情 | |
| (IV) | 39368 | (2S)-2-amino-3-[(5-methyl-2-nitrophenyl)sulfanyl]propionic acid | C10H12N2O4S | 详情 | 详情 | |
| (V) | 39369 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[(5-methyl-2-nitrophenyl)sulfanyl]propionic acid | C18H18N2O6S | 详情 | 详情 | |
| (VI) | 39370 | (2S)-3-[(2-amino-5-methylphenyl)sulfanyl]-2-[[(benzyloxy)carbonyl]amino]propionic acid | C18H20N2O4S | 详情 | 详情 | |
| (VII) | 39371 | benzyl (3S)-8-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-ylcarbamate | C18H18N2O3S | 详情 | 详情 | |
| (VIII) | 39372 | ethyl 2-[(3S)-3-[[(benzyloxy)carbonyl]amino]-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetate | C22H24N2O5S | 详情 | 详情 | |
| (IX) | 39376 | 2-[(3S)-3-amino-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid | C12H14N2O3S | 详情 | 详情 | |
| (X) | 39377 | 2-[(3S)-3-[(tert-butoxycarbonyl)amino]-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid | C17H22N2O5S | 详情 | 详情 | |
| (XI) | 39373 | ethyl 2-[(3S)-3-amino-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetate | C14H18N2O3S | 详情 | 详情 | |
| (XII) | 16886 | (2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propionic acid; N-alpha-t-BOC-o-benzyl-L-serine | 23680-31-1 | C15H21NO5 | 详情 | 详情 |
| (XIII) | 39374 | ethyl 2-[(3S)-3-([(2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetate | C29H37N3O7S | 详情 | 详情 | |
| (XIV) | 39375 | 2-[(3S)-3-([(2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid | C27H33N3O7S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XII)Construction of the peptide chain was carried out by solid phase synthesis on a Merrifield resin. The protected arginine bound to the resin (XV) was treated with trifluoroacetic to cleave the N-Boc group. The resulting NG-arginine-resin (XVI) was coupled with benzothiazepineacetic acid (X) by means of BOP reagent to produce (XVII). After deprotection of the Boc group of (XVII) with trifluoroacetic acid, further coupling with protected serine (XII) gave peptide resin (XIX). The Boc group of (XIX) was then deprotected with trifluoroacetic acid as above to furnish intermediate (XX).
| 【1】 Daffix, I.; Bergé, G.; Amblard, M.; et al.; Synthesis and characterization of bradykinin B2 receptor agonists containing constrained dipeptide mimics. J Med Chem 1999, 42, 20, 4193. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 39377 | 2-[(3S)-3-[(tert-butoxycarbonyl)amino]-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid | C17H22N2O5S | 详情 | 详情 | |
| (XII) | 16886 | (2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propionic acid; N-alpha-t-BOC-o-benzyl-L-serine | 23680-31-1 | C15H21NO5 | 详情 | 详情 |
| (XV) | 39378 | (2S)-5-[(amino[[(4-methylphenyl)sulfonyl]imino]methyl)amino]-2-[(tert-butoxycarbonyl)amino]pentanoic acid | C18H28N4O6S | 详情 | 详情 | |
| (XVI) | 39379 | (2S)-2-amino-5-[(amino[[(4-methylphenyl)sulfonyl]imino]methyl)amino]pentanoic acid | C13H20N4O4S | 详情 | 详情 | |
| (XVII) | 39380 | (2S)-5-[(amino[[(4-methylphenyl)sulfonyl]imino]methyl)amino]-2-([2-[(3S)-3-[(tert-butoxycarbonyl)amino]-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetyl]amino)pentanoic acid | C30H40N6O8S2 | 详情 | 详情 | |
| (XVIII) | 39381 | (2S)-2-([2-[(3S)-3-amino-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetyl]amino)-5-[(amino[[(4-methylphenyl)sulfonyl]imino]methyl)amino]pentanoic acid | C25H32N6O6S2 | 详情 | 详情 | |
| (XIX) | 39382 | (2S)-5-[(amino[[(4-methylphenyl)sulfonyl]imino]methyl)amino]-2-([2-[(3S)-3-([(2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetyl]amino)pentanoic acid | C40H51N7O10S2 | 详情 | 详情 | |
| (XX) | 39383 | (2S)-2-([2-[(3S)-3-[[(2S)-2-amino-3-(benzyloxy)propanoyl]amino]-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetyl]amino)-5-[(amino[[(4-methylphenyl)sulfonyl]imino]methyl)amino]pentanoic acid | C35H43N7O8S2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XVIIII)Further coupling with N-alpha-Boc-L-4-(Fmoc-amino)phenylalanine (XIV), followed by Fmoc deprotection with piperidine, furnished (XV). The aniline derivative (XV) was acylated with L-hydroorotic acid (XVI) to yield, after Boc group cleavage, resin (XVII). Coupling of (XVII) with N-Boc-L-serine(O-benzyl) (XVIII) and subsequent deprotection gave (XIX).
| 【1】 Stalewski, J.; Galyean, R.; Jiang, G.; et al.; GnRH antagonists: A new generation of long acting analogues incorporating p-ureido-phenylalanines at positions 5 and 6. J Med Chem 2001, 44, 3, 453. |
| 【2】 Jiang, G.; Semple, G. (Ferring BV Group Holding); GnRH antagonists being modified in positions 5 and 6. WO 9846634 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVIIII) | 16886 | (2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propionic acid; N-alpha-t-BOC-o-benzyl-L-serine | 23680-31-1 | C15H21NO5 | 详情 | 详情 |
| (XIII) | 46749 | benzyl (5S)-5-[((2S)-2-[[(2R)-2-amino-3-(4-[[(tert-butylamino)carbonyl]amino]phenyl)propanoyl]amino]-4-methylpentanoyl)amino]-6-[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]-6-oxohexyl(isopropyl)carbamate | C45H69N9O8 | 详情 | 详情 | |
| (XIV) | 46753 | (2S)-3-(4-aminophenyl)-2-[(tert-butoxycarbonyl)amino]propionic acid | 55533-24-9 | C14H20N2O4 | 详情 | 详情 |
| (XV) | 46754 | benzyl (5S,8S,11R,14S)-14-(4-aminobenzyl)-5-[[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]carbonyl]-11-(4-[[(tert-butylamino)carbonyl]amino]benzyl)-8-isobutyl-18,18-dimethyl-7,10,13,16-tetraoxo-17-oxa-6,9,12,15-tetraazanonadec-1-yl(isopropyl)carbamate | C59H87N11O11 | 详情 | 详情 | |
| (XVI) | 46755 | (4R)-2,6-dioxohexahydro-4-pyrimidinecarboxylic acid | C5H6N2O4 | 详情 | 详情 | |
| (XVII) | 46756 | benzyl (5S)-5-[((2S)-2-[[(2R)-2-([(2S)-2-amino-3-[4-([[(4R)-2,6-dioxohexahydro-4-pyrimidinyl]carbonyl]amino)phenyl]propanoyl]amino)-3-(4-[[(tert-butylamino)carbonyl]amino]phenyl)propanoyl]amino]-4-methylpentanoyl)amino]-6-[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]-6-oxohexyl(isopropyl)carbamate | C59H83N13O12 | 详情 | 详情 | |
| (XIX) | 46757 | benzyl (5S,8S,11R,14S,17S)-17-amino-5-[[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]carbonyl]-11-(4-[[(tert-butylamino)carbonyl]amino]benzyl)-14-[4-([[(4R)-2,6-dioxohexahydro-4-pyrimidinyl]carbonyl]amino)benzyl]-8-isobutyl-7,10,13,16-tetraoxo-20-phenyl-19-oxa-6,9,12,15-tetraazaicos-1-yl(isopropyl)carbamate | C69H94N14O14 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)Serine derivative (I) is converted into butyric acid derivative (II) by first treatment with isobutyl chloroformate and Et3N in THF, followed by reaction with ethereal diazomethane, Wolf rearrangement with Et3N in THF/H2O catalyzed by AgOBz and benzylation with benzyl bromide and DBU in acetonitrile. Conversion of (II) into azetidinone derivative (III) is achieved by Boc group removal by means of HCl in dioxane followed by cyclization by treatment with TMSCl, Et3N in Et2O and then t-BuMgCl. Protection of (III) using TIPSOTf and 2,5-lutidine in CH2Cl2 followed by removal of benzyl ether by hydrogenolysis over Pd(OH)2 in THF gives beta-lactam alcohol (IV), which is then oxidized by means of Dess-Martin periodinane in CH2Cl2 to yield aldehyde (V). Reaction of (V) with benzothiazole (VI) and n-BuLi in THF yields alcohol (VII), which is then deoxygenated by treatment with 1,1-(thiocarbonyl)diimidazole and DMAP in CH2Cl2 followed by reduction with Ph3SnH and AIBN in benzene to afford (VIII). Removal of the TIPS group from (VIII) by means of CsF in MeOH followed by condensation with chloride (IX) by means of KHMDS in THF finally furnishes the target product.
| 【1】 Ogilvie, W.W.; Naud, J.; Hache, B.; Yoakim, C.; O'Meara, J.A.; Do, F.; Deziel, R.; Lagace, L.; Synthesis and antiviral activity of monobactams inhibiting the human cytomegalovirus protease. Bioorg Med Chem 1999, 7, 8, 1521. |
| 【2】 Ogilvie, W.W.; O'Meara, J.; Deziel, R.; Yoakim, C. (Boehringer Ingelheim (Canada) Ltd.); Azetidinone derivs. for the treatment of HCMV infections. EP 1021405; WO 9918072 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIa) | 43532 | (4R)-4-[(R)-1,3-benzothiazol-2-yl(hydroxy)methyl]-1-(triisopropylsilyl)-2-azetidinone | C20H30N2O2SSi | 详情 | 详情 | |
| (VIIb) | 43533 | (4R)-4-[(S)-1,3-benzothiazol-2-yl(hydroxy)methyl]-1-(triisopropylsilyl)-2-azetidinone | C20H30N2O2SSi | 详情 | 详情 | |
| (I) | 16886 | (2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propionic acid; N-alpha-t-BOC-o-benzyl-L-serine | 23680-31-1 | C15H21NO5 | 详情 | 详情 |
| (II) | 43528 | benzyl (3R)-4-(benzyloxy)-3-[(tert-butoxycarbonyl)amino]butanoate | C23H29NO5 | 详情 | 详情 | |
| (III) | 43529 | (4R)-4-[(benzyloxy)methyl]-2-azetidinone | C11H13NO2 | 详情 | 详情 | |
| (IV) | 43530 | (4R)-4-(hydroxymethyl)-1-(triisopropylsilyl)-2-azetidinone | C13H27NO2Si | 详情 | 详情 | |
| (V) | 43531 | (2R)-4-oxo-1-(triisopropylsilyl)-2-azetidinecarbaldehyde | C13H25NO2Si | 详情 | 详情 | |
| (VI) | 36784 | 1,3-benzothiazole | 95-16-9 | C7H5NS | 详情 | 详情 |
| (VIII) | 43534 | (4R)-4-(1,3-benzothiazol-2-ylmethyl)-1-(triisopropylsilyl)-2-azetidinone | C20H30N2OSSi | 详情 | 详情 | |
| (IX) | 28425 | 1-[[(chlorocarbonyl)(methyl)amino]methyl]-4-(trifluoromethyl)benzene | C10H9ClF3NO | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XIII)The title compound was obtained by solid-phase peptide synthesis using a methylbenzhydrylamine resin. After attachment of N-Boc-D-alanine (I) to the resin by means of diisopropylcarbodiimide (DIC), the N-Boc protecting group was cleaved by treatment with a solution of trifluoroacetic in CH2Cl2 in the presence of 1,2-ethanedithiol, yielding the alanine-bound resin (II). To this were sequentially coupled the appropriate protected amino acids using DIC, each followed by the Boc group cleavage with trifluoroacetic acid. Coupling/deprotection cycles with N-Boc-L-proline (III), N-alpha-Boc-N-epsilon-benzyloxycarbonyl-N-epsilon-isopropyl-L-lysine (V), N-Boc-L-leucine (VII), N-alpha-Boc-N-4-Fmoc-L-4-aminophenylalanine (IX), N-alpha-Boc-N-4-Fmoc-D-4-aminophenylalanine (XI) and N-Boc-O-benzyl-L-serine (XIII), furnished the peptide resins (IV), (VI), (VIII), (X), (XII) and (XIV).
| 【1】 Rivier, J.E.; et al.; Gonadotropin-releasing hormone antagonists: Novel members of the azaline B family. J Med Chem 1995, 38, 14, 2649. |
| 【2】 Rivier, J.E.F.; Porter, J.S.; Hoeger, C.A.; Jiang, G.; Rivier, C.L. (The Salk Institute for Biological Studies); GnRH antagonists. EP 0804471; JP 1998500397; US 5506207; WO 9525741 . |
| 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) | 15889 | Ethyl 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate;(Z)-ethyl 2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetate； ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetate | 60845-81-0 | C7H9N3O3S | 详情 | 详情 |
| (II) | 46571 | (1R,2R,3aS,9aS)-1-[(3S)-3-hydroxyoctyl]-5-methoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ol | C22H34O3 | 详情 | 详情 | |
| (III) | 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 | |
| (IV) | 46743 | (2S)-N-[(1R)-2-amino-1-methyl-2-oxoethyl]-2-pyrrolidinecarboxamide | C8H15N3O2 | 详情 | 详情 | |
| (V) | 46752 | (2S)-6-[[(benzyloxy)carbonyl](isopropyl)amino]-2-[(tert-butoxycarbonyl)amino]hexanoic acid | 125323-99-1 | C22H34N2O6 | 详情 | 详情 |
| (VI) | 46744 | benzyl (5S)-5-amino-6-[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]-6-oxohexyl(isopropyl)carbamate | C25H39N5O5 | 详情 | 详情 | |
| (VII) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (VIII) | 46745 | benzyl (5S)-6-[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]-5-[[(2S)-2-amino-4-methylpentanoyl]amino]-6-oxohexyl(isopropyl)carbamate | C31H50N6O6 | 详情 | 详情 | |
| (IX) | 46746 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-(4-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]phenyl)propionic acid | 173054-11-0 | C29H30N2O6 | 详情 | 详情 |
| (X) | 51379 | 9H-fluoren-9-ylmethyl 4-((2R,5S,8S)-2-amino-8-[[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]carbonyl]-5-isobutyl-13-isopropyl-3,6,14-trioxo-16-phenyl-15-oxa-4,7,13-triazahexadec-1-yl)phenylcarbamate | C55H70N8O9 | 详情 | 详情 | |
| (XI) | 51387 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]phenyl)propionic acid | C29H30N2O6 | 详情 | 详情 | |
| (XII) | 51380 | 9H-fluoren-9-ylmethyl 4-[(2S,5R,8S,11S)-2-amino-11-[[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]carbonyl]-5-(4-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]benzyl)-8-isobutyl-16-isopropyl-3,6,9,17-tetraoxo-19-phenyl-18-oxa-4,7,10,16-tetraazanonadec-1-yl]phenylcarbamate | C79H90N10O12 | 详情 | 详情 | |
| (XIII) | 16886 | (2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propionic acid; N-alpha-t-BOC-o-benzyl-L-serine | 23680-31-1 | C15H21NO5 | 详情 | 详情 |
| (XIV) | 51381 | benzyl (5S,8S,11R,14S,17S)-17-amino-5-[[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]carbonyl]-11,14-bis(4-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]benzyl)-8-isobutyl-7,10,13,16-tetraoxo-20-phenyl-19-oxa-6,9,12,15-tetraazaicos-1-yl(isopropyl)carbamate | C89H101N11O14 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(I)N-Boc-O-Benzyl-L-serine (V) is treated with ammonium hydroxide and EDC/HOBt to afford the corresponding amide (VI). Subsequent acidic cleavage of the N-Boc group of (VI) provides O-benzyl-L-serinamide (VII). Then, coupling between cyclohexylalanine derivative (IV) and serinamide (VII) in the presence of EDC/HOBt furnishes the dipeptide derivative (VIII). Finally, dehydration of the terminal amide function of (VIII) by means of cyanuric chloride leads to the target nitrile.
| 【1】 Frye, L.L.; Cywin, C.L.; Morwick, T.; Spero, D.M.; Thomson, D.; Ward, Y. (Boehringer Ingelheim Pharmaceuticals Inc.); Cpds. useful as reversible inhibitors of cathepsin S. JP 2002538151; US 6395897; WO 0051998 . |
| 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) | 16886 | (2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propionic acid; N-alpha-t-BOC-o-benzyl-L-serine | 23680-31-1 | C15H21NO5 | 详情 | 详情 |
| (IV) | 63391 | 3-cyclohexyl-N-(4-morpholinylcarbonyl)alanine | C14H24N2O4 | 详情 | 详情 | |
| (VI) | 63392 | 1,1-dimethylethyl 2-amino-2-oxo-1-{[(phenylmethyl)oxy]methyl}ethylcarbamate | C15H22N2O4 | 详情 | 详情 | |
| (VII) | 63393 | 2-amino-3-[(phenylmethyl)oxy]propanamide | C10H14N2O2 | 详情 | 详情 | |
| (VIII) | 63394 | N-[2-[(2-amino-2-oxo-1-{[(phenylmethyl)oxy]methyl}ethyl)amino]-1-(cyclohexylmethyl)-2-oxoethyl]-4-morpholinecarboxamide | C24H36N4O5 | 详情 | 详情 |