|
【结 构 式】 
|
【分子编号】20398 【品名】(2S)-2-[(tert-butoxycarbonyl)amino]hexanoic acid 【CA登记号】 |
【 分 子 式 】C11H21NO4 【 分 子 量 】231.29208 【元素组成】C 57.12% H 9.15% N 6.06% O 27.67% |
合成路线1
该中间体在本合成路线中的序号：(I)The reaction of N-(tert-butoxycarbonyl)-L-norleucine (I) with N,O-dimethylhydroxylamine (II) by means of EDC, HOBT and TEA in DMF gives the methoxyamide (III), which is reduced with LiAlH4 to the corresponding aldehyde (IV). The reductocondensation of (IV) with 3-(trifluoromethoxy)aniline (V) by means of NaBH(OAc)3 affords the secondary amine (VI), which is acylated with chloroacetyl chloride (VII) and NaHCO3 to the chloroacetamide (VIII). The cyclization of (VIII) by means of Cs2CO3 in DMF gives the piperazinone (IX), which is finally reductocondensed with 1-(4-cyanobenzyl)imidazole-5-carbaldehyde (X) by means of NaBH(OAc)3. The intermediate 1-(4-cyanobenzyl)imidazole-5-carbaldehyde (X) has been obtained as follows: The tritylation of 1H-imidazole-4-methanol (XI) with trityl chloride and TEA in DMF gives the corresponding 1-trityl derivative (XII), which is acetylated with Ac2O and pyridine yielding the acetate (XIII). The condensation of (XIII) with 4-(bromomethyl)benzonitrile (XIV) in hot ethyl acetate affords 4-(5-acetoxyimidazol-1-ylmethyl)benzonitrile (XV), which is hydrolyzed with LiOH in THF/water providing the carbinol (XVI). Finally, this alcohol is oxidized to the target aldehyde (X) by means of SO3 and pyridine in DMSO.
| 【1】 Bergman, J.M.; Brashear, K.; Williams, T.M.; et al.; N-Arylpiperazinone inhibitors of farnesyltransferase: Discovery and biological activity. J Med Chem 1999, 42, 19, 3779. |
| 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) | 20398 | (2S)-2-[(tert-butoxycarbonyl)amino]hexanoic acid | C11H21NO4 | 详情 | 详情 | |
| (II) | 13361 | (Methoxyamino)methane; N,O-Dimethylhydroxylamine | 1117-97-1 | C2H7NO | 详情 | 详情 |
| (III) | 38382 | tert-butyl (1S)-1-[[methoxy(methyl)amino]carbonyl]pentylcarbamate | C13H26N2O4 | 详情 | 详情 | |
| (IV) | 38383 | tert-butyl (1S)-1-formylpentylcarbamate | C11H21NO3 | 详情 | 详情 | |
| (V) | 38384 | 3-(trifluoromethoxy)phenylamine; 3-(trifluoromethoxy)aniline | 1535-73-5 | C7H6F3NO | 详情 | 详情 |
| (VI) | 38385 | tert-butyl (1S)-1-[[3-(trifluoromethoxy)anilino]methyl]pentylcarbamate | C18H27F3N2O3 | 详情 | 详情 | |
| (VII) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (VIII) | 38386 | tert-butyl (1S)-1-[[(2-chloroacetyl)-3-(trifluoromethoxy)anilino]methyl]pentylcarbamate | C20H28ClF3N2O4 | 详情 | 详情 | |
| (IX) | 38387 | tert-butyl (2S)-2-butyl-5-oxo-4-[3-(trifluoromethoxy)phenyl]-1-piperazinecarboxylate | C20H27F3N2O4 | 详情 | 详情 | |
| (X) | 38388 | 4-[(5-formyl-1H-imidazol-1-yl)methyl]benzonitrile | C12H9N3O | 详情 | 详情 | |
| (XI) | 38393 | 1H-imidazol-4-ylmethanol | C4H6N2O | 详情 | 详情 | |
| (XII) | 38392 | (1-trityl-1H-imidazol-4-yl)methanol | C23H20N2O | 详情 | 详情 | |
| (XIII) | 38391 | (1-trityl-1H-imidazol-4-yl)methyl acetate | C25H22N2O2 | 详情 | 详情 | |
| (XIV) | 14200 | 4-(Bromomethyl)benzonitrile; alpha-Bromo-p-tolunitrile | 17201-43-3 | C8H6BrN | 详情 | 详情 |
| (XV) | 38390 | [1-(4-cyanobenzyl)-1H-imidazol-5-yl]methyl acetate | C14H13N3O2 | 详情 | 详情 | |
| (XVI) | 38389 | 4-[[5-(hydroxymethyl)-1H-imidazol-1-yl]methyl]benzonitrile | C12H11N3O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIII)The coupling sequences were continued with Nalpha-Boc-L-norleucine (XIII) to afford resin (XIV). Elimination of the Fmoc and OFm protecting groups of (XIV) was performed with piperidine in NMP allowing the formation of the lactam ring by cyclization with BOP and DIEA in NMP providing the macrocyclic lactam (XV).
| 【1】 Al-Obeidi, F.A.; Sharma, S.D.; de L. Castrucci, A.; Kesterson, R.A.; Lu, D.; Hadley, M.E.; Cone, R.D.; Hruby, V.J.; Cyclic lactam alpha-melanotropin analogues of Ac-Nle4-cyclo[Asp5, D-Phe7,Lys10] alpha-melanocyte-stimulating hormone-(4-10)-NH2 with bulky aromatic amino acids at position 7 show high antagonist potency and selectivity at specific melanocortin receptors. J Med Chem 1995, 38, 18, 3454. |
| 【2】 Hadley, M.E.; Hruby, V.J.; Sharma, S.D. (University of Arizona); Peptides having potent antagonist and agonist bioactivities at melanocortin receptors. US 5731408 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 25485 | N-(Tert-butoxycarbonyl)-[4-O-(9-fluorenylmethoxycarbonyl)]-L-aspartyl-[N-tau-(benzyloxymethyl)]-D-histidyl-D-2-naphthylalanyl-(N-omega-tosyl)-L-arginyl-(N-1-formyl)-D-tryptophyl-[N-6-(9-fluorenylmethoxycarbonyl)]-L-leucinamide; N-(Tert-butoxycarbonyl)-[4-O-(9-fluorenylmethoxycarbonyl)]-L-aspartyl-[N-tau-(benzyloxymethyl)]-D-histidyl-D-2-naphthylalanyl-(N-omega-tosyl)-L-arginyl-(N-1-formyl)-D-tryptophyl-[N-6-(9-fluorenylmethoxycarbonyl)]-L-leucinamide | C97H102N14O18S | 详情 | 详情 | |
| (XIII) | 20398 | (2S)-2-[(tert-butoxycarbonyl)amino]hexanoic acid | C11H21NO4 | 详情 | 详情 | |
| (XIV) | 25486 | N-(Tert-butoxycarbonyl)-D-norleucyl-[4-O-(9-fluorenylmethoxycarbonyl)]-L-aspartyl-[N-tau-(benzyloxymethyl)]-D-histidyl-D-2-naphthylalanyl-(N-omega-tosyl)-L-arginyl-(N-1-formyl)-D-tryptophyl-[N-6-(9-fluorenylmethoxycarbonyl)]-L-leucinamide; N-(Tert-butoxycarbonyl)-D-norleucyl-[4-O-(9-fluorenylmethoxycarbonyl)]-L-aspartyl-[N-tau-(benzyloxymethyl)]-D-histidyl-D-2-naphthylalanyl-(N-omega-tosyl)-L-arginyl-(N-1-formyl)-D-tryptophyl-[N-6-(9-fluorenylmethoxycarbonyl)]-L-leucinamide | C103H113N15O19S | 详情 | 详情 | |
| (XV) | 25487 | tert-butyl (1S)-1-([[(3S,6S,9R,12S,15S,23S)-23-(aminocarbonyl)-12-([1-[(benzyloxy)methyl]-1H-imidazol-5-yl]methyl)-3-[(1-formyl-1H-indol-3-yl)methyl]-6-[3-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]propyl]-9-(2-naphthylmethyl)-2,5,8,11,14,17-hexaoxo-1,4,7,10,13,18-hexaazacyclotricosan-15-yl]amino]carbonyl)pentylcarbamate | C73H91N15O14S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Mixed anhydride (II), prepared from N-Boc-L-norleucine (I) and isobutyl chloroformate in the presence of Et3N, was reacted with ethereal diazomethane to afford diazoketone (III). Then, homologation of (III) into b-amino ester (IV) was accomplished by treatment with silver benzoate and Et3N in MeOH. Subsequent hydrolysis of (IV) of the ester function with K2CO3 in aqueous MeOH, followed by Boc deprotection with HCl in dioxan furnished the b-amino acid (VI). After conversion to the trimethylsilyl amine with N-methyl-N-(trimethylsilyl)acetamide, amino acid (VI) was coupled with 2,2'-dithiobisbenzoyl cloride (VIII), prepared from acid (VII) and thionyl chloride, to yield the target bisamide.
| 【1】 Vara Prasad, J.V.N.; Loo, J.A.; Boyer, F.E.; Stier, M.A.; Gogliotti, R.D.; Turner, W.J.; Harvey, P.J.; Kramer, M.R.; Mack, D.P.; Scholten, J.D.; Gracheck, S.J.; Domagala, J.M.; 2,2'-Dithiobisbenzamides derived from alpha-, beta- and gamma-amino acids possessing anti-HIV activities: Synthesis and structure-activity relationship. Bioorg Med Chem 1998, 6, 10, 1707. |
| 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) | 20398 | (2S)-2-[(tert-butoxycarbonyl)amino]hexanoic acid | C11H21NO4 | 详情 | 详情 | |
| (II) | 20399 | N-(Tert-butoxycarbonyl)-L-norleucine isobutoxycarbonyl anhydride | C16H29NO6 | 详情 | 详情 | |
| (III) | 20400 | tert-butyl (1S)-1-[2-(1lambda(5)-diazynyl)acetyl]pentylcarbamate | C12H23N3O3 | 详情 | 详情 | |
| (IV) | 20401 | methyl (3S)-3-[(tert-butoxycarbonyl)amino]heptanoate | C13H25NO4 | 详情 | 详情 | |
| (V) | 20402 | (3S)-3-[(tert-butoxycarbonyl)amino]heptanoic acid | C12H23NO4 | 详情 | 详情 | |
| (VI) | 20403 | (3S)-3-aminoheptanoic acid | C7H15NO2 | 详情 | 详情 | |
| (VII) | 20404 | 2-[(2-carboxyphenyl)disulfanyl]benzoic acid; 2,2'-Dithiodibenzoic acid | 119-80-2 | C14H10O4S2 | 详情 | 详情 |
| (VIII) | 20405 | 2-[[2-(chlorocarbonyl)phenyl]disulfanyl]benzoyl chloride | C14H8Cl2O2S2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)Reductive condensation of 2-thienylmethylamine (I) with 2-thiophenecarboxaldehyde (II) in the presence of NaBH(OAc)3 provided bis(2-thienylmethyl)amine (III), which was coupled with N-Boc-2-aminohexanoic acid (IV) by means of EDC and HOBt, yielding amide (V). Acid deprotection of the Boc group of (V) then gave amine (VI).
| 【1】 Scott, I.L.; et al.; Novel N,N-disubstituted amides that are highly potent VLA-4 antagonists. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 284. |
| 【2】 Raju, B.G.; Scott, I.L.; Biediger, R.J.; Market, R.V.; Grabbe, V.O.; Kassir, J.M.; Kogan, T.P.; Lin, S. (Texas Biotechnology Corp.); N,N-Disubstd. amides that inhibit the binding of integrins to their receptors. US 6096773; WO 9952493; WO 9952898 . |
| 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) | 33238 | 2-thienylmethylamine; 2-thienylmethanamine | 27757-85-3 | C5H7NS | 详情 | 详情 |
| (II) | 30732 | 2-thiophenecarbaldehyde; Thiophene-2-carboxaldehyde | 98-03-3 | C5H4OS | 详情 | 详情 |
| (III) | 38466 | 2-thienyl-N-(2-thienylmethyl)methanamine; N,N-bis(2-thienylmethyl)amine | C10H11NS2 | 详情 | 详情 | |
| (IV) | 20398 | (2S)-2-[(tert-butoxycarbonyl)amino]hexanoic acid | C11H21NO4 | 详情 | 详情 | |
| (V) | 38467 | tert-butyl (1S)-1-[[bis(2-thienylmethyl)amino]carbonyl]pentylcarbamate | C21H30N2O3S2 | 详情 | 详情 | |
| (VI) | 38468 | (2S)-2-amino-N,N-bis(2-thienylmethyl)hexanamide | C16H22N2OS2 | 详情 | 详情 |