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【结 构 式】 
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【分子编号】18008 【品名】(2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propionic acid; N(alpha)-Z-L-2,3-diaminopropionic acid 【CA登记号】35761-26-3 |
【 分 子 式 】C11H14N2O4 【 分 子 量 】238.24324 【元素组成】C 55.46% H 5.92% N 11.76% O 26.86% |
合成路线1
该中间体在本合成路线中的序号：(I)Treatment of amino acid (I) with isobutylene (II) and H2SO4 in dioxane afforded tert-butyl ester (III), which was coupled with carboxylic acid (IV) in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and 1-hydroxybenzotriazole (HOBT) to give (V). Removal of the benzyloxycarbonyl protecting group by hydrogenolysis provided amine (VI) which, on reaction with 2-bromotoluenesulfonyl chloride (VII) and pyridine in refluxing ethyl acetate was converted into sulfonamide (VIII). Deprotection of both tert-butyl groups was effected by treatment with trifluoroacetic acid in dichloromethane, to give (IX) as the trifluoroacetate salt. Tritium labeled compound was then obtained by reductive debromination with tritium gas, using Pearlman's catalyst in the presence of triethylamine.
| 【1】 Thorell, J.O.; et al.; Synthesis of a C-11-labelled nitrated 1,4-dihydroquinoxaline-2,3-dione, the NMDA glycine receptor antagonist ACEA 1021 (Licostinel). J Label Compd Radiopharm 1998, 41, 4, 345-353. |
| 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) | 18008 | (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propionic acid; N(alpha)-Z-L-2,3-diaminopropionic acid | 35761-26-3 | C11H14N2O4 | 详情 | 详情 |
| (II) | 15926 | 2-methyl-1-propene; isobutylene | 115-11-7 | C4H8 | 详情 | 详情 |
| (III) | 18009 | tert-butyl (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propanoate | C15H22N2O4 | 详情 | 详情 | |
| (IV) | 18010 | 5-[2-[1-(tert-butoxycarbonyl)-4-piperidinyl]ethyl]-4-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid | C20H30N4O5 | 详情 | 详情 | |
| (V) | 18011 | tert-butyl 4-[2-[2-([[(2S)-2-[[(benzyloxy)carbonyl]amino]-3-(tert-butoxy)-3-oxopropyl]amino]carbonyl)-4-oxo-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl]ethyl]-1-piperidinecarboxylate | C35H50N6O8 | 详情 | 详情 | |
| (VI) | 18012 | tert-butyl 4-[2-[2-([[(2S)-2-amino-3-(tert-butoxy)-3-oxopropyl]amino]carbonyl)-4-oxo-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl]ethyl]-1-piperidinecarboxylate | C27H44N6O6 | 详情 | 详情 | |
| (VII) | 18013 | 2-bromo-4-methylbenzenesulfonyl chloride | C7H6BrClO2S | 详情 | 详情 | |
| (VIII) | 18014 | tert-butyl 4-[2-[2-([[(2S)-2-[[(2-bromo-4-methylphenyl)sulfonyl]amino]-3-(tert-butoxy)-3-oxopropyl]amino]carbonyl)-4-oxo-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl]ethyl]-1-piperidinecarboxylate | C34H49BrN6O8S | 详情 | 详情 | |
| (IX) | 18015 | (2S)-2-[[(2-bromo-4-methylphenyl)sulfonyl]amino]-3-[([4-oxo-5-[2-(4-piperidinyl)ethyl]-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl]carbonyl)amino]propionic acid | C25H33BrN6O6S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Esterification of N2-benzyloxycarbonyl-(S)-2,3-diaminopropionic acid (I) by means of methanolic HCl, followed by protection of the resulting aminoester (II) with Boc2O provided methyl N2-Cbz-N3-Boc-L-2,3-diaminopropionate (III). Removal of the benzyloxycarbonyl group of (III) was effected by catalytic transfer hydrogenolysis with formic acid and Pd/C. The deprotected aminoester (IV) was then condensed with n-butyl chloroformate to give carbamate (V). Subsequent cleavage of the Boc protecting group of (V) using trifluoroacetic acid furnished the target intermediate (VI).
| 【1】 Wityak, J.; Xue, C.-B.; Sielecki-Dzurdz, T.M.; Olson, R.E.; Degrado, W.F.; Cain, G.A. (DuPont Pharmaceuticals Co.); Novel isoxazoline and isoxazole fibrinogen receptor antagonists. EP 0730590; EP 0832076; JP 1997505590; JP 1999504651; US 5849736; WO 9514683; WO 9638426 . |
| 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) | 18008 | (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propionic acid; N(alpha)-Z-L-2,3-diaminopropionic acid | 35761-26-3 | C11H14N2O4 | 详情 | 详情 |
| (II) | 25093 | methyl (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propanoate | C12H16N2O4 | 详情 | 详情 | |
| (III) | 25094 | methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[(tert-butoxycarbonyl)amino]propanoate | C17H24N2O6 | 详情 | 详情 | |
| (IV) | 25095 | methyl (2S)-2-amino-3-[(tert-butoxycarbonyl)amino]propanoate | C9H18N2O4 | 详情 | 详情 | |
| (V) | 25096 | methyl (2S)-3-[(tert-butoxycarbonyl)amino]-2-[(butoxycarbonyl)amino]propanoate | C14H26N2O6 | 详情 | 详情 | |
| (VI) | 25097 | methyl (2S)-3-amino-2-[(butoxycarbonyl)amino]propanoate | C9H18N2O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)Conversion of amino acid (I) into its methyl ester derivative (II) by means of SOCl2 in MeOH, followed by coupling with ethyl isocyanatoacetate (III) and Et3N in CH2Cl2/THF yields derivative (IV). Cyclization of (IV) by means of H2O/HCl affords hydantoin (V), which reacts with 2-methylthio-2-imidazoline (VI) in an aqueous NaOH solution to provide cyclic guanidine derivative (VII). Treatment of amino acid (VIII) with isobutylene (IX) and H2SO4 in dioxane affords t-Bu ester (X), which then couples with (VII) by means of HOBt and DCC in DMF to furnish derivative (XI). Finally, tert-butyl ester is hydrolyzed by treatment with TFA in the presence of 1,2-dimercaptoethane.
| 【1】 Knolle, J.; Peyman, A.; Wehner, V.; et al.; RGD mimetics containing a central hydantoin scaffold: alphavbeta3 vs alphaIIbbeta3 selective requirements. Bioorg Med Chem Lett 2000, 10, 2, 179. |
| 【2】 Wehner, V.; Knolle, J.; Stilz, H.U.; Carniato, D.; Gourvest, J.-F.; Gadek, T.; McDowell, R. (Aventis SA); Inhibitors of bone resorption and vitronectin receptor antagonists. DE 19626701; DE 19635522; EP 0796855 . |
| 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) | 30898 | (2S)-2-amino-5-[[(benzyloxy)carbonyl]amino]pentanoic acid | C13H18N2O4 | 详情 | 详情 | |
| (II) | 42993 | methyl (2S)-2-amino-5-[[(benzyloxy)carbonyl]amino]pentanoate | C14H20N2O4 | 详情 | 详情 | |
| (III) | 18312 | ETHYL ISOCYANATOACETATE; ethyl 2-isocyanatoacetate | 2949-22-6 | C5H7NO3 | 详情 | 详情 |
| (IV) | 42994 | 12-ethyl 8-methyl (8S)-3,10-dioxo-1-phenyl-2-oxa-4,9,11-triazadodecane-8,12-dicarboxylate | C19H27N3O7 | 详情 | 详情 | |
| (V) | 42295 | (2R)-N-methyl-2-(methylamino)-3-(2-naphthyl)-N-[(1R)-2-oxo-1-(2-thienylmethyl)-2-(1,2,2-trimethylhydrazino)ethyl]propanamide | C25H32N4O2S | 详情 | 详情 | |
| (VI) | 42996 | 4,5-dihydro-1H-imidazol-2-yl methyl sulfide; 2-(methylsulfanyl)-4,5-dihydro-1H-imidazole | 5464-11-9 | C4H8N2S | 详情 | 详情 |
| (VII) | 42997 | 2-[(4S)-4-[3-(4,5-dihydro-1H-imidazol-2-ylamino)propyl]-2,5-dioxoimidazolidinyl]acetic acid | C11H17N5O4 | 详情 | 详情 | |
| (VIII) | 18008 | (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propionic acid; N(alpha)-Z-L-2,3-diaminopropionic acid | 35761-26-3 | C11H14N2O4 | 详情 | 详情 |
| (IX) | 15926 | 2-methyl-1-propene; isobutylene | 115-11-7 | C4H8 | 详情 | 详情 |
| (X) | 18009 | tert-butyl (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propanoate | C15H22N2O4 | 详情 | 详情 | |
| (XI) | 42998 | tert-butyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[(2-[(4S)-4-[3-(4,5-dihydro-1H-imidazol-2-ylamino)propyl]-2,5-dioxoimidazolidinyl]acetyl)amino]propanoate | C26H37N7O7 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The reaction of N-(benzyloxycarbonyl)-L-asparagine (I) with bis(trifluoroacetyl)iodobenzene (BTI) in DMF/water gives 3-amino-2(S)-(benzyloxycarbonylamino)propionic acid (II), wehich is protected at the amino group with tert-butoxycarbonyl anhydride yielding carbamate (III). The esterification of (III) with ethanol WSC and DMAP affords the expected ethyl ester (IV), which is selectively deprotected with methanesulfonic acid in acetonitrile providing 3-amino-2-(benzyloxycarbonylamino)propionic acid ethyl ester (V). The condensation of (V) with N-(tert-butoxycarbonyl)-beta-alanine (VI) by means of HOBT, WSC and triethylamine in DMF gives the protected propionamidopropionic ester (VII), which is selectively deprotected by hydrogenation with H2 over Pd/C in ethanol/ethyl acetate giving the 2-aminopropionic ester (VIII). The condensation of (VIII) with 4-ethylbenzenesulfonyl chloride (IX) by means of triethylamine in dichloromethane yields the sulfonamide (X), which is deprotected with methanesulfonic acid as before afording intermediate (XI) with a free amino group, which is condensed with 4-(tert-butoxycarbonylamino)benzoic acid (XII) by means of HOBT and WSC in DMF providing the fully protected target compound (XIII).
| 【1】 Ikeda, Y.; Ueki, Y.; Kishimoto, H.; Nishihara, T.; Kamikawa, Y. (Sumitomo Pharmaceuticals Co., Ltd.); 2,3-Diaminopropionic acid deriv.. US 5707994; US 6048854; WO 9511228 . |
| 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) | 14529 | (2S)-4-amino-2-[[(benzyloxy)carbonyl]amino]-4-oxobutyric acid | 2304-96-3 | C12H14N2O5 | 详情 | 详情 |
| (II) | 18008 | (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propionic acid; N(alpha)-Z-L-2,3-diaminopropionic acid | 35761-26-3 | C11H14N2O4 | 详情 | 详情 |
| (III) | 26613 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[(tert-butoxycarbonyl)amino]propionic acid | C16H22N2O6 | 详情 | 详情 | |
| (IV) | 26614 | ethyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[(tert-butoxycarbonyl)amino]propanoate | C18H26N2O6 | 详情 | 详情 | |
| (V) | 26615 | ethyl (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propanoate | C13H18N2O4 | 详情 | 详情 | |
| (VI) | 26616 | N-(tert-butoxycarbonyl)-beta-alanine | 3303-84-2 | C8H15NO4 | 详情 | 详情 |
| (VII) | 26617 | ethyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-([3-[(tert-butoxycarbonyl)amino]propanoyl]amino)propanoate | C21H31N3O7 | 详情 | 详情 | |
| (VIII) | 26618 | ethyl (2S)-2-amino-3-([3-[(tert-butoxycarbonyl)amino]propanoyl]amino)propanoate | C13H25N3O5 | 详情 | 详情 | |
| (IX) | 26619 | 4-ethylbenzenesulfonyl chloride | 16712-69-9 | C8H9ClO2S | 详情 | 详情 |
| (X) | 26620 | ethyl (2S)-3-([3-[(tert-butoxycarbonyl)amino]propanoyl]amino)-2-[[(4-ethylphenyl)sulfonyl]amino]propanoate | C21H33N3O7S | 详情 | 详情 | |
| (XI) | 26621 | ethyl (2S)-3-[(3-aminopropanoyl)amino]-2-[[(4-ethylphenyl)sulfonyl]amino]propanoate | C16H25N3O5S | 详情 | 详情 | |
| (XII) | 26622 | 4-[[(tert-butoxycarbonyl)amino](imino)methyl]benzoic acid | C13H16N2O4 | 详情 | 详情 | |
| (XIII) | 26623 | ethyl (2S)-3-[[3-([4-[[(tert-butoxycarbonyl)amino](imino)methyl]benzoyl]amino)propanoyl]amino]-2-[[(4-ethylphenyl)sulfonyl]amino]propanoate | C29H39N5O8S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)The esterification of (S)-3-amino-2-(benzyloxycarbonylamino)propionic acid (I) with methanol/HCl gives the expected methyl ester (II), which is protected with di-tert-butyl dicarbonate and triethylamine in chloroform to the fully protected compound (III). The debenzylation of (III) by treatment with formic acid over Pd/C in methanol yields the 2-amino compound (IV), which is acylated with butyl chloroformate and NaHCO3 in THF affording 2(S)-(n-butoxycarbonylamino)-3-(tert-butoxycarbonylamino)propionic acid methyl ester (V).The selctive deacylation of (V) with trifluoroacetic acid in dichloromethane affords the 3-amino-2(S)-(n-butoxycarbonylamino)propionic ester (VI), which is acylated with 3-(4-cyanobenzyloxy)isoxazole-5-carboxylic acid (VII) by means of BOP or TBTU and triethylamine or DIEA in DMF giving the cyanobenzyl derivative (VIII). Finally, this compound treated first with HCl in methanol, and then with NH3 in the same solvent to provide the target compound.
| 【1】 Xue, C.-B.; Roderick, J.; Mousa, S.; Olson, R.E.; DeGrado, W.F.; Synthesis and antiplatelet effects of an isoxazole series of glycoprotein IIb/IIIa antagonists. Bioorg Med Chem Lett 1998, 8, 24, 3499. |
| 【2】 Degrado, W.F.; Xue, C.-B. (DuPont Pharmaceuticals Co.); Cpds. containing basic and acidic termini useful as fibrinogen receptor antagonists. US 5563158; WO 9518111 . |
| 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) | 18008 | (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propionic acid; N(alpha)-Z-L-2,3-diaminopropionic acid | 35761-26-3 | C11H14N2O4 | 详情 | 详情 |
| (II) | 25093 | methyl (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propanoate | C12H16N2O4 | 详情 | 详情 | |
| (III) | 25094 | methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[(tert-butoxycarbonyl)amino]propanoate | C17H24N2O6 | 详情 | 详情 | |
| (IV) | 25095 | methyl (2S)-2-amino-3-[(tert-butoxycarbonyl)amino]propanoate | C9H18N2O4 | 详情 | 详情 | |
| (V) | 25096 | methyl (2S)-3-[(tert-butoxycarbonyl)amino]-2-[(butoxycarbonyl)amino]propanoate | C14H26N2O6 | 详情 | 详情 | |
| (VI) | 25097 | methyl (2S)-3-amino-2-[(butoxycarbonyl)amino]propanoate | C9H18N2O4 | 详情 | 详情 | |
| (VII) | 25098 | 3-[(4-cyanobenzyl)oxy]-5-isoxazolecarboxylic acid | C12H8N2O4 | 详情 | 详情 | |
| (VIII) | 25099 | methyl (2S)-2-[(butoxycarbonyl)amino]-3-[([3-[(4-cyanobenzyl)oxy]-5-isoxazolyl]carbonyl)amino]propanoate | C21H24N4O7 | 详情 | 详情 | |
| (X) | 25100 | methyl (2S)-3-([[3-([4-[amino(imino)methyl]benzyl]oxy)-5-isoxazolyl]carbonyl]amino)-2-[(butoxycarbonyl)amino]propanoate | C21H27N5O7 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)The esterification of (S)-3-amino-2-(benzyloxycarbonylamino)propionic acid (I) with methanol/HCl gives the expected methyl ester (II), which is protected with di-tert-butyl dicarbonate and triethylamine in chloroform to the fully protected compound (III). The debenzylation of (III) by treatment with formic acid over Pd/C in methanol yields the 2-amino compound (IV), which is acylated with butyl chloroformate and NaHCO3 in THF affording 2(S)-(n-butoxycarbonylamino)-3-(tert-butoxycarbonylamino)propionic acid methyl ester (V).The selctive deacylation of (V) with trifluoroacetic acid in dichloromethane affords the 3-amino-2(S)-(n-butoxycarbonylamino)propionic ester (VI), which is acylated with 3-(chloromethyl)benzoyl chloride (VII) and triethylamine in dichloromethane giving the benzamido ester (VIII). The condensation of (VIII) with 4-hydroxybenzonitrile (IX) by means of NaH or K2CO3 yields the precursor (X), which is finally treated first with HCl in methanol, and then with NH3 in the same solvent to providde the target compound.
| 【1】 Degrado, W.F.; Xue, C.-B. (DuPont Pharmaceuticals Co.); Cpds. containing basic and acidic termini useful as fibrinogen receptor antagonists. US 5563158; WO 9518111 . |
| 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) | 18008 | (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propionic acid; N(alpha)-Z-L-2,3-diaminopropionic acid | 35761-26-3 | C11H14N2O4 | 详情 | 详情 |
| (II) | 25093 | methyl (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propanoate | C12H16N2O4 | 详情 | 详情 | |
| (III) | 25094 | methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[(tert-butoxycarbonyl)amino]propanoate | C17H24N2O6 | 详情 | 详情 | |
| (IV) | 25095 | methyl (2S)-2-amino-3-[(tert-butoxycarbonyl)amino]propanoate | C9H18N2O4 | 详情 | 详情 | |
| (V) | 25096 | methyl (2S)-3-[(tert-butoxycarbonyl)amino]-2-[(butoxycarbonyl)amino]propanoate | C14H26N2O6 | 详情 | 详情 | |
| (VI) | 25097 | methyl (2S)-3-amino-2-[(butoxycarbonyl)amino]propanoate | C9H18N2O4 | 详情 | 详情 | |
| (VII) | 25107 | 3-(chloromethyl)benzoyl chloride | 63024-77-1 | C8H6Cl2O | 详情 | 详情 |
| (VIII) | 25108 | methyl (2S)-2-[(butoxycarbonyl)amino]-3-[[3-(chloromethyl)benzoyl]amino]propanoate | C17H23ClN2O5 | 详情 | 详情 | |
| (IX) | 25109 | 4-hydroxybenzonitrile | 767-00-0 | C7H5NO | 详情 | 详情 |
| (X) | 25110 | methyl (2S)-2-[(butoxycarbonyl)amino]-3-([3-[(4-cyanophenoxy)methyl]benzoyl]amino)propanoate | C24H27N3O6 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I),(III)The title compound was prepared by solid-phase synthesis using a 2-chlorotrityl resin, chloride form. N2-(Benzyloxycarbonyl)-L-2,3-diaminopropionic acid (I) was protected as the Fmoc derivative (II) upon treatment with N-(Fmoc-oxy)succinimide. After attachment of the protected diaminoacid (II) to the chloride resin, the Fmoc group was selectively removed by means of piperidine in DMF to give the resin-bound Cbz-2,3-diaminopropionic acid (III). Acylation of the free amino function of (III) with 4-(chloromethyl)benzoyl chloride (IV) provided amide (V). The chloride group of (V) was then displaced with 2-(aminomethyl)benzimidazole (VI), yielding resin (VII). The required urea functionality (IX) was obtained by coupling (VII) with cyclohexyl isocyanate (VIII). Finally, cleavage of the carboxylic acid from the resin (IX) was achieved by treatment with trifluoroacetic acid in moist dichloromethane.
| 【1】 Neustadt, B.R.; Smith, E.M. (Schering Corp.); Benzimidazole cpds. that are vitronectin receptor antagonists. EP 1135374; WO 0032578 . |
| 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),(III) | 18008 | (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propionic acid; N(alpha)-Z-L-2,3-diaminopropionic acid | 35761-26-3 | C11H14N2O4 | 详情 | 详情 |
| (II) | 49111 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid | C26H24N2O6 | 详情 | 详情 | |
| (IV) | 49112 | 4-(Chloromethyl)benzoyl chloride; p-(Chloromethyl)benzoyl chloride | 876-08-4 | C8H6Cl2O | 详情 | 详情 |
| (V) | 49113 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[[4-(chloromethyl)benzoyl]amino]propionic acid | C19H19ClN2O5 | 详情 | 详情 | |
| (VI) | 49114 | 1H-benzimidazol-2-ylmethylamine; 1H-benzimidazol-2-ylmethanamine | C8H9N3 | 详情 | 详情 | |
| (VII) | 49115 | (2S)-3-[(4-[[(1H-benzimidazol-2-ylmethyl)amino]methyl]benzoyl)amino]-2-[[(benzyloxy)carbonyl]amino]propionic acid | C27H27N5O5 | 详情 | 详情 | |
| (VIII) | 10108 | N-Methyl(1-naphthyl)methanamine; N-Methyl-N-(1-naphthylmethyl)amine; 1-Methyl-1-naphthalenemethylamine | 65473-13-4 | C12H13N | 详情 | 详情 |
| (IX) | 49116 | (2S)-3-[[4-([(1H-benzimidazol-2-ylmethyl)[(cyclohexylamino)carbonyl]amino]methyl)benzoyl]amino]-2-[[(benzyloxy)carbonyl]amino]propionic acid | C34H38N6O6 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(III)The title compound has been prepared by solid-phase combinatorial synthesis. The protected diaminopropionic acid (I) is attached to 2-chlorotrityl resin, producing the resin-bound amino acid (II). The N-Fmoc group of (II) is then selectively removed by treatment with piperidine in DMF producing (III). Condensation of amine (III) with N-ethoxycarbonyl-2-methyl-3-piperidinothioacrylamide (IV) results in the thiouracil derivative (V). This is converted into the thiocyanate (VI) upon treatment with cyanogen bromide in the presence of diisopropylethylamine. Further displacement of the thiocyanate group of (VI) with N-(2-benzimidazolyl)-1,3-propanediamine (VII) leads to the aminopyrimidone resin (VIII). Finally, acidic cleavage from the solid support (VIII) gives rise to the desired compound.
| 【1】 Zechel, C.; Backfisch, G.; Delzer, J.; Geneste, H.; Graef, C.; Hornberger, W.; Kling, A.; Lange, U.E.W.; Lauterbach, A.; Seitz, W.; Subkowski, T.; Highly potent and selective alphaVbeta3-receptor antagonists: Solid-phase synthesis and SAR of 1-substituted 4-amino-1H-pyrimidin-2-ones. Bioorg Med Chem Lett 2003, 13, 2, 165. |
| 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), (II) | 49911 | potassium 4-aminobenzenolate | C6H6KNO | 详情 | 详情 | |
| (III) | 18008 | (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propionic acid; N(alpha)-Z-L-2,3-diaminopropionic acid | 35761-26-3 | C11H14N2O4 | 详情 | 详情 |
| (IV) | 63377 | ethyl 2-methyl-3-(1-piperidinyl)-2-propenethioylcarbamate | C12H20N2O2S | 详情 | 详情 | |
| (V) | 63378 | 3-[5-methyl-2-oxo-4-thioxo-3,4-dihydro-1(2H)-pyrimidinyl]-N-{[(phenylmethyl)oxy]carbonyl}alanine | C16H17N3O5S | 详情 | 详情 | |
| (VI) | 63379 | 3-[4-(cyanosulfanyl)-5-methyl-2-oxo-1(2H)-pyrimidinyl]-N-{[(phenylmethyl)oxy]carbonyl}alanine | C17H16N4O5S | 详情 | 详情 | |
| (VII) | 63380 | N~1~-(1H-benzimidazol-2-yl)-1,3-propanediamine | C10H14N4 | 详情 | 详情 | |
| (VIII) | 63381 | 3-[4-{[3-(1H-benzimidazol-2-ylamino)propyl]amino}-5-methyl-2-oxo-1(2H)-pyrimidinyl]-N-{[(phenylmethyl)oxy]carbonyl}alanine | C26H29N7O5 | 详情 | 详情 |