【结 构 式】 |
【分子编号】28752 【品名】DL-2-Amino propane dicarboxylic acid; DL-2-Aminopentanoic acid; glutamic acid; DL-glutamic acid; (+/-)-2-Aminoglutaric acid 【CA登记号】617-65-2 |
【 分 子 式 】C5H9NO4 【 分 子 量 】147.1308 【元素组成】C 40.82% H 6.17% N 9.52% O 43.5% |
合成路线1
该中间体在本合成路线中的序号:(I)A new procedure for the synthesis of acivicin has been reported: The photochlorination of L-glutamic acid (I) gives 3-chloroglutamic acid (II); the corresponding diastereomers were separed by ion-exchange chromatography over Dowex-50 (H+). The reaction of (II) with benzyl chloroformate (III) affords N-carbobenzoxy-3-chloroglutamic acid (IV), which is anhydrized with dicyclohexylcarbodiimide to the corresponding protected anhydride (V). The reaction of (V) with lithium N-hydroxyphthalimide (VI) yields the phthalimidoxy derivative (VII), which is converted to the protected hydroxamic acid (VIII) by a treatment with hydroxylamine. The cyclization of (VIII) with triethylamine affords N-carbobenzoxytricholomic acid (IX), which is esterified with diphenyldiazomethane (X) giving the corresponding protected benzhydryl ester (Xl). The reaction of (XI) with dichloro-trisdimethylaminophosphorane (XII) yields the deprotected final compound (XIII), which is finally treated with trifluoroacetic acid and thioanisole (A).
【1】 Holladay, M.W.; Silverman, R.B.; Stereospecific total synthesis of the natural antitumor agent, (alphaS,5S)-alpha-maino-3-chloro-4,5-dihydro-5-isooxazoleacetic acid and its unnatural C-5 epimer. J Am Chem Soc 1981, 103, 24, 7357-58. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(A) | 19272 | methyl phenyl sulfide; 1-(methylsulfanyl)benzene | 100-68-5 | C7H8S | 详情 | 详情 |
(I) | 28752 | DL-2-Amino propane dicarboxylic acid; DL-2-Aminopentanoic acid; glutamic acid; DL-glutamic acid; (+/-)-2-Aminoglutaric acid | 617-65-2 | C5H9NO4 | 详情 | 详情 |
(II) | 35997 | 3-chloroglutamic acid | C5H8ClNO4 | 详情 | 详情 | |
(III) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
(IV) | 35998 | N-[(benzyloxy)carbonyl]-3-chloroglutamic acid | C13H14ClNO6 | 详情 | 详情 | |
(V) | 35999 | benzyl 4-chloro-2,6-dioxotetrahydro-2H-pyran-3-ylcarbamate | C13H12ClNO5 | 详情 | 详情 | |
(VI) | 36000 | lithium 1,3-dioxo-1,3-dihydro-2H-isoindol-2-olate | C8H4LiNO3 | 详情 | 详情 | |
(VII) | 36001 | lithium 2-[[(benzyloxy)carbonyl]amino]-3-chloro-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]-5-oxopentanoate | C21H16ClLiN2O8 | 详情 | 详情 | |
(VIII) | 36002 | N(2)-[(benzyloxy)carbonyl]-3-chloro-N(5)-hydroxyglutamine | C13H15ClN2O6 | 详情 | 详情 | |
(IX) | 36003 | 2-[[(benzyloxy)carbonyl]amino]-2-(3-oxo-5-isoxazolidinyl)acetic acid | C13H14N2O6 | 详情 | 详情 | |
(XI) | 36004 | benzhydryl 2-[[(benzyloxy)carbonyl]amino]-2-(3-oxo-5-isoxazolidinyl)acetate | C26H24N2O6 | 详情 | 详情 | |
(XII) | 36005 | N-[dichloro[bis(dimethylamino)]phosphoranyl]-N,N-dimethylamine; N-[dichloro[bis(dimethylamino)]phosphoranyl]-N-methylmethanamine | C6H18Cl2N3P | 详情 | 详情 | |
(XIII) | 36006 | benzhydryl 2-[[(benzyloxy)carbonyl]amino]-2-(3-chloro-4,5-dihydro-5-isoxazolyl)acetate | C26H23ClN2O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(VII)The reduction of N-benzyloxycarbonylprolinamide (I) with H2 over Pd/c in methanol gives prolinamide (II), which is condensed with N-benzyloxycarbonylhistidyl hydrazide (III) by means of NaNO2 - HCl in ethyl acetate yielding N-benzyloxycarbonylhistidylprolinamide (IV), The hydrolysis of (IV) with HBr in acetic acid affords histidylprolinamide (V), which is finally condensed with gamma-carboxy-gamma-butyrolactone (VI) by means of pentachlorophenol and dicyclohexylcarbodiimide in DMF. Compound (VI) is prepared by reaction of alpha-aminoglutaric acid (VII) with NaNO2 and 2N H2SO4 in water.
【1】 Fujino, M.; Nishimura, P.; Nagawa, Y.; Fukuda, N.; US 4100152 . |
【2】 Bauce, L.G.; Goren, H.J.; Synthesis of a series of residue 1-(pyroglutamic acid) analogs of thyrotropin releasing hormone. Intl J Pept Protein Res 1979, 14, 3, 216-226. |
【3】 Larsen, S.D.; Stephenson, G.A.; Bunnell, C.A.; Reutzel, S.M.; Nichols, J.R. (Eli Lilly and Company); Intermediates and process for preparing olanzapine. US 6020487 . |
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) | 37076 | benzyl (2R)-2-(aminocarbonyl)-1-pyrrolidinecarboxylate | C13H16N2O3 | 详情 | 详情 | |
(II) | 37077 | (2R)-2-pyrrolidinecarboxamide | C5H10N2O | 详情 | 详情 | |
(III) | 36138 | benzyl (1S)-2-hydrazino-1-(1H-imidazol-5-ylmethyl)-2-oxoethylcarbamate | 49706-31-2 | C14H17N5O3 | 详情 | 详情 |
(IV) | 36139 | benzyl (1S)-2-[(2S)-2-(aminocarbonyl)pyrrolidinyl]-1-(1H-imidazol-5-ylmethyl)-2-oxoethylcarbamate | C19H23N5O4 | 详情 | 详情 | |
(V) | 31253 | (2S)-1-[(2S)-2-amino-3-(1H-imidazol-5-yl)propanoyl]-2-pyrrolidinecarboxamide | C11H17N5O2 | 详情 | 详情 | |
(VI) | 37075 | 5-oxotetrahydro-2-furancarboxylic acid | C5H6O4 | 详情 | 详情 | |
(VII) | 28752 | DL-2-Amino propane dicarboxylic acid; DL-2-Aminopentanoic acid; glutamic acid; DL-glutamic acid; (+/-)-2-Aminoglutaric acid | 617-65-2 | C5H9NO4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(I)The condensation of glutamic acid (I) with 3,4-dichlorobenzoyl chloride (II) by means of Na2CO3 in water gives N-(3,4-dichlorobenzoyl)glutamic acid (III), which is treated with acetic anhydride in refluxing isopropyl ether to afford N-(3,4-dichlorobenzoyl)glutamic anhydride (IV). Finally, this compound is treated with dipentylamine (V) in water.
【1】 Zrenner, E.; Laties, A.M.; Eur J Med Chem - Chim Ther 1986, 21, 1, 9-20. |
【2】 Chiste, R.; Makovec, F.; Rovati, L.A.; Pacini, M.A.; Bani, M.; Setnikar, I.; New glutaramic acid derivatives with potent competitive and specific cholecystokinin-antagonistic activity. Arzneim-Forsch Drug Res 1985, 35, 7, 1048-1051. |
【3】 Rovati, L.C.; Chiste, R.; Bani, M.; Revel, L.; Makovec, F.; Rovati, L.A.; Differentiation of central and peripheral cholecystokinin receptors by new glutaramic acid derivatives with cholecystokinin-antagonistic activity. Arzneim-Forsch Drug Res 1986, 36, 1, 98-102. |
【4】 Rovati, L.; Makovec, F.; Senin, P.; Chiste', R. (Rotta Research Laboratorium SpA); Derivatives of glutamic acid and aspartic acid. AU 8544109; BE 0902726; CH 674203; DE 3522506; ES 8604859; FR 2566397; GB 2160869; JP 1986044855; US 4791215 . |
【5】 Castaner, J.; Serradell, M.N.; Castaner, R.M.; Lorglumide. Drugs Fut 1987, 12, 9, 851. |
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) | 28752 | DL-2-Amino propane dicarboxylic acid; DL-2-Aminopentanoic acid; glutamic acid; DL-glutamic acid; (+/-)-2-Aminoglutaric acid | 617-65-2 | C5H9NO4 | 详情 | 详情 |
(II) | 26356 | 3,4-dichlorobenzoyl chloride | 3024-72-4 | C7H3Cl3O | 详情 | 详情 |
(III) | 28750 | N-(3,4-dichlorobenzoyl)glutamic acid | C12H11Cl2NO5 | 详情 | 详情 | |
(IV) | 12129 | 3,4-Dichloro-N-(2,6-dioxotetrahydro-2H-pyran-3-yl)benzamide | C12H9Cl2NO4 | 详情 | 详情 | |
(V) | 28751 | N-pentyl-1-pentanamine | 2050-92-2 | C10H23N | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号:(I)D,L-Glutamic acid (I) was sequentially protected as the gamma-allyl ester (III), upon treatment with allyl alcohol (II) and chlorotrimethylsilane, followed by conversion to the trichloroethyl carbamate (V) by means of chloroformate (IV), and then reaction of (V) with benzyl bromide to afford the alpha-benzyl ester (VI). Deprotection of the trichloroethyl carbamate of (VI) by treatment with zinc dust and HOAc and subsequent condensation of the resulting amine with decanoyl chloride (VII) furnished amide (VIII). The allyl ester of (VIII) was then selectively cleaved by using tetrakistriphenylphosphine palladium(0) and morpholine to give carboxylic acid (IX). trans-1,2-Diaminocyclohexane (X) was protected as the mono tert-butyl carbamate (XI) and then coupled with acid (IX) in the presence of diethylphosphoryl cyanide to yield amide (XII). After acidic Boc cleavage of (XII), coupling of the resulting amine with 2,5-diphenyloxazole-4-carboxylic acid (XIII) by means of bromo-tris(pyrrolidino)phosphonium hexafluorophosphate (PyBroP) afforded (XIV). Finally, hydrolysis of the benzyl ester of (XIV) with LiOH provided the corresponding carboxylic acid.
【1】 Ducruet, A.P.; Yokokawa, F.; Rice, R.L.; tamura, K.; Lazo, J.S.; Wipf, P.; Yokokama, S.; Identification of new Cdc25 dual specificity phosphatase inhibitors in a targeted small molecule array. Bioorg Med Chem 2000, 8, 6, 1451. |
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) | 28752 | DL-2-Amino propane dicarboxylic acid; DL-2-Aminopentanoic acid; glutamic acid; DL-glutamic acid; (+/-)-2-Aminoglutaric acid | 617-65-2 | C5H9NO4 | 详情 | 详情 |
(II) | 12234 | 2-Propen-1-ol; Allyl alcohol | 107-18-6 | C3H6O | 详情 | 详情 |
(III) | 43406 | 5-(allyloxy)-5-oxonorvaline | C8H13NO4 | 详情 | 详情 | |
(IV) | 13664 | 1,1,1-Trichloro-2-[(chlorocarbonyl)oxy]ethane; 2,2,2-Trichloroethyl chloroformate | 17341-93-4 | C3H2Cl4O2 | 详情 | 详情 |
(V) | 43399 | 5-(allyloxy)-5-oxo-N-[(2,2,2-trichloroethoxy)carbonyl]norvaline | C11H14Cl3NO6 | 详情 | 详情 | |
(VI) | 43400 | 5-allyl 1-benzyl 2-[[(2,2,2-trichloroethoxy)carbonyl]amino]pentanedioate | C18H20Cl3NO6 | 详情 | 详情 | |
(VII) | 28271 | decanoyl chloride | 112-13-0 | C10H19ClO | 详情 | 详情 |
(VIII) | 43401 | 5-allyl 1-benzyl 2-(decanoylamino)pentanedioate | C25H37NO5 | 详情 | 详情 | |
(IX) | 43402 | 5-(benzyloxy)-4-(decanoylamino)-5-oxopentanoic acid | C22H33NO5 | 详情 | 详情 | |
(X) | 11300 | 2-hydroxyethyl 4-hydroxy-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate | C11H11NO6S | 详情 | 详情 | |
(XI) | 43403 | tert-butyl (1R,2R)-2-aminocyclohexylcarbamate | C11H22N2O2 | 详情 | 详情 | |
(XII) | 43404 | benzyl 5-([(1R,2R)-2-[(tert-butoxycarbonyl)amino]cyclohexyl]amino)-2-(decanoylamino)-5-oxopentanoate | C33H53N3O6 | 详情 | 详情 | |
(XIII) | 28277 | 2,5-diphenyl-1,3-oxazole-4-carboxylic acid | C16H11NO3 | 详情 | 详情 | |
(XIV) | 43405 | benzyl 2-(decanoylamino)-5-[((1R,2R)-2-[[(2,5-diphenyl-1,3-oxazol-4-yl)carbonyl]amino]cyclohexyl)amino]-5-oxopentanoate | C44H54N4O6 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号:(I)D,L-Glutamic acid (I) was sequentially protected as the gamma-allyl ester (III), upon treatment with allyl alcohol (II) and chlorotrimethylsilane, followed by conversion to the trichloroethyl carbamate (V) by means of chloroformate (IV), and then reaction of (V) with benzyl bromide to afford the alpha-benzyl ester (VI). Deprotection of the trichloroethyl carbamate of (VI) by treatment with zinc dust and HOAc and subsequent condensation of the resulting amine with decanoyl chloride (VII) furnished amide (VIII). The allyl ester of (VIII) was then selectively cleaved by using tetrakistriphenylphosphine palladium(0) and morpholine to give carboxylic acid (IX). trans-1,4-Diaminocyclohexane (X) was protected as the mono tert-butyl carbamate (XI) and then coupled with acid (IX) in the presence of diethylphosphoryl cyanide to yield amide (XII). After acidic Boc cleavage of (XII), coupling of the resulting amine with 2,5-diphenyloxazole-4-carboxylic acid (XIII) by means of bromo-tris(pyrrolidino)phosphonium hexafluorophosphate (PyBroP) afforded (XIV). Finally, hydrolysis of the benzyl ester of (XIV) with LiOH provided the corresponding carboxylic acid.
【1】 Ducruet, A.P.; Yokokawa, F.; Rice, R.L.; tamura, K.; Lazo, J.S.; Wipf, P.; Yokokama, S.; Identification of new Cdc25 dual specificity phosphatase inhibitors in a targeted small molecule array. Bioorg Med Chem 2000, 8, 6, 1451. |
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) | 28752 | DL-2-Amino propane dicarboxylic acid; DL-2-Aminopentanoic acid; glutamic acid; DL-glutamic acid; (+/-)-2-Aminoglutaric acid | 617-65-2 | C5H9NO4 | 详情 | 详情 |
(II) | 12234 | 2-Propen-1-ol; Allyl alcohol | 107-18-6 | C3H6O | 详情 | 详情 |
(III) | 43406 | 5-(allyloxy)-5-oxonorvaline | C8H13NO4 | 详情 | 详情 | |
(IV) | 13664 | 1,1,1-Trichloro-2-[(chlorocarbonyl)oxy]ethane; 2,2,2-Trichloroethyl chloroformate | 17341-93-4 | C3H2Cl4O2 | 详情 | 详情 |
(V) | 43399 | 5-(allyloxy)-5-oxo-N-[(2,2,2-trichloroethoxy)carbonyl]norvaline | C11H14Cl3NO6 | 详情 | 详情 | |
(VI) | 43400 | 5-allyl 1-benzyl 2-[[(2,2,2-trichloroethoxy)carbonyl]amino]pentanedioate | C18H20Cl3NO6 | 详情 | 详情 | |
(VII) | 28271 | decanoyl chloride | 112-13-0 | C10H19ClO | 详情 | 详情 |
(VIII) | 43401 | 5-allyl 1-benzyl 2-(decanoylamino)pentanedioate | C25H37NO5 | 详情 | 详情 | |
(IX) | 43402 | 5-(benzyloxy)-4-(decanoylamino)-5-oxopentanoic acid | C22H33NO5 | 详情 | 详情 | |
(X) | 43407 | 4-aminocyclohexylamine; 1,4-cyclohexanediamine | 3114-70-3 | C6H14N2 | 详情 | 详情 |
(XI) | 43408 | tert-butyl 4-aminocyclohexylcarbamate | C11H22N2O2 | 详情 | 详情 | |
(XII) | 43409 | benzyl 5-([4-[(tert-butoxycarbonyl)amino]cyclohexyl]amino)-2-(decanoylamino)-5-oxopentanoate | C33H53N3O6 | 详情 | 详情 | |
(XIII) | 28277 | 2,5-diphenyl-1,3-oxazole-4-carboxylic acid | C16H11NO3 | 详情 | 详情 | |
(XIV) | 43410 | benzyl 2-(decanoylamino)-5-[(4-[[(2,5-diphenyl-1,3-oxazol-4-yl)carbonyl]amino]cyclohexyl)amino]-5-oxopentanoate | C44H54N4O6 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号:(II)
【1】 Qian SS, Wu XY, Li JY, et al.2006. Preparation of D-glutamine from glutanuc acid. 有机化学.26(4):514~517 |
【2】 King EE, Kidd DAA. 1949. New synthesis of glutamine and of -dipeptides of glutamic acid from phthalylated intermediates. J Chem Soc, (1949): 3315 - 3319 |
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) | 11900 | 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride | 85-44-9 | C8H4O3 | 详情 | 详情 |
(II) | 28752 | DL-2-Amino propane dicarboxylic acid; DL-2-Aminopentanoic acid; glutamic acid; DL-glutamic acid; (+/-)-2-Aminoglutaric acid | 617-65-2 | C5H9NO4 | 详情 | 详情 |
(III) | 54082 | 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanedioic acid | 2301-52-2 | C13H11NO6 | 详情 | 详情 |
(IV) | 57860 | N-Phthalyl-DL-glutamic anhydride; Phthalyl-Dl-Glutamic anhydride | 3085-92-5 | C13H9NO5 | 详情 | 详情 |
(V) | 66455 | 5-amino-2-(1,3-dioxoisoindolin-2-yl)-5-oxopentanoic acid | C13H12N2O5 | 详情 | 详情 |