|
【结 构 式】 
|
【分子编号】25183 【品名】ethyl 3-bromo-2-oxopropanoate;ethyl 3-bromopyruvate;Bromopyruvic acid ethyl ester;ethyl 3-bromopyruvate;ethyl bromopyruvate 【CA登记号】70-23-5 |
【 分 子 式 】C5H7BrO3 【 分 子 量 】195.01278 【元素组成】C 30.8% H 3.62% Br 40.97% O 24.61% |
合成路线1
该中间体在本合成路线中的序号：(II)The cyclization of dimethylaminothioacetamide (I) with ethyl bromopyruvate (II) in refluxing ethanol gives ethyl 2-(dimethylaminomethyl)-4-thiazolecarboxylate (III), which is reduced with lithium triethyl borohydride in THF yielding 2-(dimethylaminomethyl)-4-thiazolemethanol (IV). The condensation of (IV) with 2-aminoethanethiol (V) by means of 48% HBr affords 2-(dimethylaminomethyl)-4-(2-aminoethylthiomethyl)thiazole (VI), which is finally condensed with 1-(methylthio)-2-nitro-N-methylethyleneamine (VII) in water.
| 【1】 Pioch, R.P. (Eli Lilly and Company); N-Methyl-N'-2-[[(2-dimethylaminomethyl)-4-thiazolyl]methylthio]ethyl-2-nitro-1,1-ethenediamine. EP 0049618; GB 2084581; JP 57091980; US 4375547 . |
| 【2】 Serradell, M.N.; Castaner, J.; Nizatidine. Drugs Fut 1984, 9, 9, 655. |
| 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) | 30602 | 2-(dimethylamino)ethanethioamide | C4H10N2S | 详情 | 详情 | |
| (II) | 25183 | ethyl 3-bromo-2-oxopropanoate;ethyl 3-bromopyruvate;Bromopyruvic acid ethyl ester;ethyl 3-bromopyruvate;ethyl bromopyruvate | 70-23-5 | C5H7BrO3 | 详情 | 详情 |
| (III) | 30603 | ethyl 2-[(dimethylamino)methyl]-1,3-thiazole-4-carboxylate | C9H14N2O2S | 详情 | 详情 | |
| (IV) | 30604 | [2-[(dimethylamino)methyl]-1,3-thiazol-4-yl]methanol | C7H12N2OS | 详情 | 详情 | |
| (V) | 13186 | 2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine | 60-23-1 | C2H7NS | 详情 | 详情 |
| (VI) | 30605 | N-[(4-[[(2-aminoethyl)sulfanyl]methyl]-1,3-thiazol-2-yl)methyl]-N,N-dimethylamine; 2-[([2-[(dimethylamino)methyl]-1,3-thiazol-4-yl]methyl)sulfanyl]-1-ethanamine | C9H17N3S2 | 详情 | 详情 | |
| (VII) | 13852 | N-Methyl-N-[(E)-1-(methylsulfanyl)-2-nitroethenyl]amine; (E)-N-Methyl-1-(methylsulfanyl)-2-nitro-1-ethenamine; (E)-1-Methylthio-1-methylamino-2-nitroethylene | 61832-41-5 | C4H8N2O2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)A new synthesis of thiazofurin has been described: The reaction of 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-D-ribofuranose (I) with trimethylsilyl cyanide and SnCl4 in dichloromethane gives 2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl cyanide (II), which is treated with H2S gas and dimethylaminopyridine (DMAP) in ethanol yielding the corresponding thioamide (III). The carefully controlled cyclization of (III) with 3-bromopyruvic acid ethyl ester (IV) by means of NaHCO3 in dimethoxyethane, followed by treatment with trifluoroacetic anhydride and 2,6-lutidine in the same solvent affords 2-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)thiazole-4-carboxylic acid ethyl ester (V). Elimination of the benzoyl protecting groups of (V) with NaOEt in ethanol gives 2-(beta-D-ribofuranosyl)thiazole-4-carboxylic acid ethyl ester (VI). Which is finally treated with dry ammonia in methanol to afford the target amide.
| 【1】 Garcia-Munoz, G.; Stud, M.; Fuertes, M.; Synthesis of C-glycocyl thiazoles. J Org Chem 1976, 41, 4074. |
| 【2】 Ramasamy, K.S.; Averett, D.; A modified synthesis of tiazofurin. Nucleosides Nucleotides 1999, 18, 11-12, 2425. |
| 【3】 Eastland, G.; Tiazofurine. Drugs Fut 1985, 10, 4, 304. |
| 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) | 26984 | (2R,3R,4R,5S)-5-(acetoxy)-4-(benzoyloxy)-2-[(benzoyloxy)methyl]tetrahydro-3-furanyl benzoate | C28H24O9 | 详情 | 详情 | |
| (II) | 29143 | (2S,3S,4R,5R)-4-(benzoyloxy)-5-[(benzoyloxy)methyl]-2-cyanotetrahydro-3-furanyl benzoate | C27H21NO7 | 详情 | 详情 | |
| (III) | 29144 | (2R,3S,4R,5R)-2-(aminocarbothioyl)-4-(benzoyloxy)-5-[(benzoyloxy)methyl]tetrahydro-3-furanyl benzoate | C27H23NO7S | 详情 | 详情 | |
| (IV) | 25183 | ethyl 3-bromo-2-oxopropanoate;ethyl 3-bromopyruvate;Bromopyruvic acid ethyl ester;ethyl 3-bromopyruvate;ethyl bromopyruvate | 70-23-5 | C5H7BrO3 | 详情 | 详情 |
| (V) | 29145 | ethyl 2-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-1,3-thiazole-4-carboxylate | C11H15NO6S | 详情 | 详情 | |
| (VI) | 34062 | ethyl 2-[(2R,3S,4R,5R)-3,4-bis(benzoyloxy)-5-[(benzoyloxy)methyl]tetrahydro-2-furanyl]-1,3-thiazole-4-carboxylate | C32H27NO9S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)The synthesis of selenazole is as follows: 2,3,5-Tri-O-benzoyl-beta-D-ribofuranosyl-1-carbonitrile (I) is treated with liquid hydrogen selenide, using 4-(dimethylamino)pyridine as a catalyst, under nitrogen at room temperature to give 2,5-anhydro-3,4,6-tri-O-benzoyl-D-allonselenenoamide (II). (II) is treated, in acetonitrile, with ethyl bromopyruvate. After an hour the solvent is removed in vacuo and the residue triturated with sodium bicarbonate and extracted with ethyl ether. After workup to remove the ether, chromatographic separation of the alpha- and beta-anomers on silica gel gives ethyl 2-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)selenazole-4-carboxylate (III). Compound (III) is dissolved in methanol and treated with ammonia at 0 C. After 48 h the solvent is removed, the residue extracted with chloroform, the chloroform layer discarded and the residue chromatographed on silica gel. Recrystallization of the major product from 2-propanol yields crystalline 2-beta-D-ribofuranosylselenazole-4-carboxamide. The preparation of the 5'-phosphate derivative is also described.
| 【1】 Srivastava, P.; Robins, R.K.; Synthesis and antitumor activity of 2-beta-D-ribofuranosylselenazole-4-carboxamide and related derivatives. J Med Chem 1983, 26, 3, 445-448. |
| 【2】 Eastland, G.W.; Selenazole. Drugs Fut 1985, 10, 5, 409. |
| 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) | 29143 | (2S,3S,4R,5R)-4-(benzoyloxy)-5-[(benzoyloxy)methyl]-2-cyanotetrahydro-3-furanyl benzoate | C27H21NO7 | 详情 | 详情 | |
| (II) | 29370 | (2R,3R,4S,5R)-5-(aminocarboselenoyl)-4-(benzoyloxy)-2-[(benzoyloxy)methyl]tetrahydro-3-furanyl benzoate | C27H23NO7Se | 详情 | 详情 | |
| (III) | 25183 | ethyl 3-bromo-2-oxopropanoate;ethyl 3-bromopyruvate;Bromopyruvic acid ethyl ester;ethyl 3-bromopyruvate;ethyl bromopyruvate | 70-23-5 | C5H7BrO3 | 详情 | 详情 |
| (IV) | 29731 | N-(5-amino-6-chloro-4-pyrimidinyl)-N-[6-(benzyloxy)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]amine; N(4)-[6-(benzyloxy)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-6-chloro-4,5-pyrimidinediamine | C19H21ClN4O3 | 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 precursor imidazopyrazine (III) was prepared by condensation of 2-amino-3,5-dibromopyrazine (I) with ethyl 3-bromopyruvate (II). Subsequent treatment of ester (III) with aqueous ammonia produced the corresponding amide (IV). This was then dehydrated with phosphoryl chloride, with concomitant displacement of the 8-bromine for a chloro group, to yield nitrile (V). Finally, substitution of the chloride by methyl amine in (V) furnished the target compound.
| 【1】 Sablayrolles, C.; et al.; Synthesis of imidazo[1,2-a]pyrazine derivatives with uterine-relaxing, antibronchospastic, and cardiac-stimulating properties. J Med Chem 1984, 27, 2, 206. |
| 【2】 Vitse, O.; Laurent, F.; Pocock, T.M.; et al.; New imidazol[1,2-a]pyrazine derivatives withbronchodilatory and cyclic nucleotide phosphodiesterase inhibitory activities. Bioorg Med Chem 1999, 7, 6, 1059. |
| 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) | 26178 | 3,5-dibromo-2-pyrazinamine | 24241-18-7 | C4H3Br2N3 | 详情 | 详情 |
| (II) | 25183 | ethyl 3-bromo-2-oxopropanoate;ethyl 3-bromopyruvate;Bromopyruvic acid ethyl ester;ethyl 3-bromopyruvate;ethyl bromopyruvate | 70-23-5 | C5H7BrO3 | 详情 | 详情 |
| (III) | 26179 | ethyl 6,8-dibromoimidazo[1,2-a]pyrazine-2-carboxylate | C9H7Br2N3O2 | 详情 | 详情 | |
| (IV) | 26180 | 6,8-dibromoimidazo[1,2-a]pyrazine-2-carboxamide | C7H4Br2N4O | 详情 | 详情 | |
| (V) | 26181 | 6-bromo-8-chloroimidazo[1,2-a]pyrazine-2-carbonitrile | C7H2BrClN4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XIV)N-Boc-D-Alanine (XI) is converted to the corresponding amide (XII) by reaction with ammonia in the presence of EDC and HOBt. Subsequent treatment of (XII) with Belleau's reagent (2,4-bis(4-phenoxyphenyl)-1,3,2,4-dithiaphosphetane-2,4-disulfide) furnishes thioamide (XIII). S-Alkylation of thioamide (XIII) with ethyl bromopyruvate (XIV) gives intermediate (XV), which is cyclized to thiazole (XVI) upon treatment with trifluoroacetic anhydride and 2,6-lutidine. After saponification of the ester group of (XVI) with LiOH, the resultant acid (XVII) is coupled with tripeptide (X) to provide precursor (XVIII).
| 【1】 Ley, S.V.; et al.; Total synthesis of the cyclic heptapeptide argyrin B: A new potent inhibitor of T-cell independent antibody formation. Org Lett 2002, 4, 5, 711. |
| 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) | 58834 | methyl 2-{[(2S)-2-{[(2S)-2-amino-3-(1H-indol-3-yl)propanoyl]amino}-3-(4-methoxy-1H-indol-3-yl)propanoyl]amino}acetate | C26H29N5O5 | 详情 | 详情 | |
| (XI) | 15859 | Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid | 7764-95-6 | C8H15NO4 | 详情 | 详情 |
| (XII) | 46750 | tert-butyl (1R)-2-amino-1-methyl-2-oxoethylcarbamate | C8H16N2O3 | 详情 | 详情 | |
| (XIII) | 48364 | tert-butyl (1R)-2-amino-1-methyl-2-thioxoethylcarbamate | C8H16N2O2S | 详情 | 详情 | |
| (XIV) | 25183 | ethyl 3-bromo-2-oxopropanoate;ethyl 3-bromopyruvate;Bromopyruvic acid ethyl ester;ethyl 3-bromopyruvate;ethyl bromopyruvate | 70-23-5 | C5H7BrO3 | 详情 | 详情 |
| (XV) | 58835 | ethyl 3-({(2R)-2-[(tert-butoxycarbonyl)amino]propanimidoyl}sulfanyl)-2-oxopropanoate | C13H22N2O5S | 详情 | 详情 | |
| (XVI) | 48366 | ethyl 2-[(1R)-1-[(tert-butoxycarbonyl)amino]ethyl]-1,3-thiazole-4-carboxylate | C13H20N2O4S | 详情 | 详情 | |
| (XVII) | 58836 | 2-{(1R)-1-[(tert-butoxycarbonyl)amino]ethyl}-1,3-thiazole-4-carboxylic acid | C11H16N2O4S | 详情 | 详情 | |
| (XVIII) | 58837 | methyl 2-{[(2S)-2-{[(2S)-2-{[(2-{(1R)-1-[(tert-butoxycarbonyl)amino]ethyl}-1,3-thiazol-4-yl)carbonyl]amino}-3-(1H-indol-3-yl)propanoyl]amino}-3-(4-methoxy-1H-indol-3-yl)propanoyl]amino}acetate | C37H43N7O8S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IV)Condensation of 4,5-dichloro-1,2-phenylenediamine (I) with 1-phenyl-1,2-propanedione (II) in boiling AcOH provided quinoxaline (III). Subsequent reaction of (III) with ethyl bromopyruvate (IV) led to the pyrroloquinoxaline (V). After reduction of the ester group of (V) to alcohol (VI) with LiAlH4, further oxidation with MnO2 produced aldehyde (VII). This was condensed with boiling 3-(dimethylamino)propylamine (VIII), and the resulting imine (IX) was finally reduced to the target amine with NaBH4 in MeOH. The title compound was finally converted to the dioxalate salt upon treatment with oxalic acid in isopropanol.
| 【1】 Guillon, J.; Rault, S.; Kervran, A.; Renard, P.; Manechez, D.; Pfeiffer, B.; Dallemagne, P.; Synthesis of new pyrrolo[1,2-a]quinoxalines: Potential non-peptide glucagon receptor antagonists. Eur J Med Chem 1998, 33, 4, 293. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15713 | Oxalic acid | 144-62-7 | C2H2O4 | 详情 | 详情 | |
| (I) | 18003 | 4,5-dichloro-1,2-benzenediamine; 4,5-Dichloro-o-phenylenediamine; 2-amino-4,5-dichlorophenylamine | 5348-42-5 | C6H6Cl2N2 | 详情 | 详情 |
| (II) | 31481 | 1-phenyl-1,2-propanedione | 579-07-7 | C9H8O2 | 详情 | 详情 |
| (III) | 31482 | 6,7-dichloro-2-methyl-3-phenylquinoxaline | C15H10Cl2N2 | 详情 | 详情 | |
| (IV) | 25183 | ethyl 3-bromo-2-oxopropanoate;ethyl 3-bromopyruvate;Bromopyruvic acid ethyl ester;ethyl 3-bromopyruvate;ethyl bromopyruvate | 70-23-5 | C5H7BrO3 | 详情 | 详情 |
| (V) | 31483 | ethyl 7,8-dichloro-4-phenylpyrrolo[1,2-a]quinoxaline-2-carboxylate | C20H14Cl2N2O2 | 详情 | 详情 | |
| (VI) | 31484 | (7,8-dichloro-4-phenylpyrrolo[1,2-a]quinoxalin-2-yl)methanol | C18H12Cl2N2O | 详情 | 详情 | |
| (VII) | 31486 | 7,8-dichloro-4-phenylpyrrolo[1,2-a]quinoxaline-2-carbaldehyde | C18H10Cl2N2O | 详情 | 详情 | |
| (VIII) | 25248 | N-(3-aminopropyl)-N,N-dimethylamine; N(1),N(1)-dimethyl-1,3-propanediamine | 109-55-7 | C5H14N2 | 详情 | 详情 |
| (IX) | 31485 | N(1)-[(E)-(7,8-dichloro-4-phenylpyrrolo[1,2-a]quinoxalin-2-yl)methylidene]-N(3),N(3)-dimethyl-1,3-propanediamine; N-[(E)-(7,8-dichloro-4-phenylpyrrolo[1,2-a]quinoxalin-2-yl)methylidene]-N-[3-(dimethylamino)propyl]amine | C23H22Cl2N4 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(III)Benzothiazin (III) was prepared by condensation of 2-aminothiophenol (I) with ethyl 4-bromoacetoacetate (II). Subsequent reduction of (III) with NaBH3CN provided (IV), which was brominated using N-bromosuccinimide to afford (V). This was coupled with ethyl oxalyl chloride to give amide (VI). Nitration of (VI) was then performed with HNO3 in H2SO4 at -10 C. Further reduction of the nitro group of (VII) with concomitant cyclization produced the tricyclic compound (VIII). After resolution by chiral preparative HPLC, the required (R)-enantiomer was hydrolyzed with NaOH to afford carboxylic acid (IX). This compound was finally isolated as the sodium salt upon treatment with aqueous NaHCO3, followed by lyophilization.
| 【1】 Moretti, R.; Zimmermann, K. (Novartis AG); Quinoxaline-2,3-diones with an oxa or thiaheterocyclic fused ring. CA 2157231; EP 0705835; JP 1996109185 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11043 | Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride | 4755-77-5 | C4H5ClO3 | 详情 | 详情 | |
| (I) | 25182 | 2-aminobenzenethiol | 137-07-5 | C6H7NS | 详情 | 详情 |
| (III) | 25183 | ethyl 3-bromo-2-oxopropanoate;ethyl 3-bromopyruvate;Bromopyruvic acid ethyl ester;ethyl 3-bromopyruvate;ethyl bromopyruvate | 70-23-5 | C5H7BrO3 | 详情 | 详情 |
| (IV) | 25184 | ethyl 2-[2H-1,4-benzothiazin-3(4H)-ylidene]acetate | C12H13NO2S | 详情 | 详情 | |
| (IV) | 25185 | ethyl 2-(3,4-dihydro-2H-1,4-benzothiazin-3-yl)acetate | C12H15NO2S | 详情 | 详情 | |
| (V) | 25186 | ethyl 2-(7-bromo-3,4-dihydro-2H-1,4-benzothiazin-3-yl)acetate | C12H14BrNO2S | 详情 | 详情 | |
| (VI) | 25187 | ethyl 2-[7-bromo-3-(2-ethoxy-2-oxoethyl)-2,3-dihydro-4H-1,4-benzothiazin-4-yl]-2-oxoacetate | C16H18BrNO5S | 详情 | 详情 | |
| (VII) | 25188 | ethyl 2-[7-bromo-3-(2-ethoxy-2-oxoethyl)-5-nitro-2,3-dihydro-4H-1,4-benzothiazin-4-yl]-2-oxoacetate | C16H17BrN2O7S | 详情 | 详情 | |
| (VIII) | 25189 | ethyl 2-(9-bromo-5,6-dioxo-2,3,6,7-tetrahydro-5H-[1,4]thiazino[4,3,2-de]quinoxalin-3-yl)acetate | C14H13BrN2O4S | 详情 | 详情 | |
| (IX) | 25190 | 2-[(3R)-9-bromo-5,6-dioxo-2,3,6,7-tetrahydro-5H-[1,4]thiazino[4,3,2-de]quinoxalin-3-yl]acetic acid | C12H9BrN2O4S | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XI)The reaction of imidazole (I) with tert-butoxycarbonyl anhydride in ethyl acetate, followed by acetylation with acetic anhydride gives the cis-ethylenediamine derivative (II), which is isomerized to its trans isomer (III) with I2 in THF. The cyclization of (III) with hydrazone (IV) by means of Na2CO3 in hot acetonitrile yields the tetrahydropyridazine (V), which s deprotected at the amino group with HCl in ethyl acetate affording the amine (VI). The condensation of (VI) with the protected thiourea (VII) by means of HgCl2 and Et3N in DMF gives the protected guanidine (VIII), which is hydrolyzed at the ester group with KOH in methanol/water providing the carboxylic acid (IX). Finally, this compound is deprotected with TFA in dichloromethane. The intermediate, the hydrazone derivative (IV) has been obtained by condensation of 2-ethylbutyryl hydrazide (X) with 3-bromo-2-oxobutyric acid ethyl ester in ethyl ether catalyzed by acetic acid.
| 【1】 Graves, B.J.; Zhang, L.; Escarpe, P.A.; Mendel, D.B.; Wang, K.-Y.; Chen, X.; Kim, C.U.; Williams, M.A.; Lawton, G.; Synthesis and evaluation of 1,4,5,6-tetrahydropyridazine derivatives as influenza neuraminidase inhibitors. Bioorg Med Chem Lett 1999, 9, 13, 1751. |
| 【2】 Zhang, L.; et al.; Synthesis and evaluation odf tetrahydropyridazine derivatives as influenza neuraminidase inhibitors. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 183. |
| 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) | 10255 | Imidazole; 1H-Imidazole | 288-32-4 | C3H4N2 | 详情 | 详情 |
| (II) | 31874 | tert-butyl (Z)-2-(acetamido)ethenylcarbamate | C9H16N2O3 | 详情 | 详情 | |
| (III) | 31881 | tert-butyl (E)-2-(acetamido)ethenylcarbamate | C9H16N2O3 | 详情 | 详情 | |
| (IV) | 31875 | ethyl 3-bromo-2-[(Z)-2-(2-ethylbutanoyl)hydrazono]propanoate | C11H19BrN2O3 | 详情 | 详情 | |
| (V) | 31877 | ethyl (5S,6S)-6-(acetamido)-5-[(tert-butoxycarbonyl)amino]-1-(2-ethylbutanoyl)-1,4,5,6-tetrahydro-3-pyridazinecarboxylate | C20H34N4O6 | 详情 | 详情 | |
| (VI) | 31878 | ethyl (5S,6S)-6-(acetamido)-5-amino-1-(2-ethylbutanoyl)-1,4,5,6-tetrahydro-3-pyridazinecarboxylate | C15H26N4O4 | 详情 | 详情 | |
| (VII) | 21843 | tert-butyl [(tert-butoxycarbonyl)amino]carbothioylcarbamate | 145013-05-4 | C11H20N2O4S | 详情 | 详情 |
| (VIII) | 31879 | ethyl (5S,6S)-6-(acetamido)-5-([[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl]amino)-1-(2-ethylbutanoyl)-1,4,5,6-tetrahydro-3-pyridazinecarboxylate | C26H44N6O8 | 详情 | 详情 | |
| (IX) | 31880 | (5S,6S)-6-(acetamido)-5-([[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl]amino)-1-(2-ethylbutanoyl)-1,4,5,6-tetrahydro-3-pyridazinecarboxylic acid | C24H40N6O8 | 详情 | 详情 | |
| (X) | 31876 | 2-ethylbutanohydrazide | C6H14N2O | 详情 | 详情 | |
| (XI) | 25183 | ethyl 3-bromo-2-oxopropanoate;ethyl 3-bromopyruvate;Bromopyruvic acid ethyl ester;ethyl 3-bromopyruvate;ethyl bromopyruvate | 70-23-5 | C5H7BrO3 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(X)N-Boc-D-alanine (VII) was converted into amide (VIII) via activation as the corresponding mixed anhydride with isobutyl chloroformate. Treatment of amide (VIII) with Lawesson’s reagent gave thioamide (IX). Coupling of (IX) with ethyl bromopyruvate (X) produced the intermediate hydroxythiazoline (XI), which was further dehydrated using trifluoroacetic anhydride to afford the fully protected thiazole amino acid (XII). Removal of the Boc protecting group of (XII) to give (XIII) was achieved by treatment with either trifluoroacetic acid or acetyl chloride in EtOH.
| 【1】 Xia, Z.; Smith, C.D.; Total synthesis of dendroamide A, a novel cyclic peptide that reverses multiple drug resistance. J Org Chem 2001, 66, 10, 3459. |
| 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) | 15859 | Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid | 7764-95-6 | C8H15NO4 | 详情 | 详情 |
| (VIII) | 46750 | tert-butyl (1R)-2-amino-1-methyl-2-oxoethylcarbamate | C8H16N2O3 | 详情 | 详情 | |
| (IX) | 48364 | tert-butyl (1R)-2-amino-1-methyl-2-thioxoethylcarbamate | C8H16N2O2S | 详情 | 详情 | |
| (X) | 25183 | ethyl 3-bromo-2-oxopropanoate;ethyl 3-bromopyruvate;Bromopyruvic acid ethyl ester;ethyl 3-bromopyruvate;ethyl bromopyruvate | 70-23-5 | C5H7BrO3 | 详情 | 详情 |
| (XI) | 48365 | ethyl 2-[(1R)-1-[(tert-butoxycarbonyl)amino]ethyl]-4-hydroxy-4,5-dihydro-1,3-thiazole-4-carboxylate | C13H22N2O5S | 详情 | 详情 | |
| (XII) | 48366 | ethyl 2-[(1R)-1-[(tert-butoxycarbonyl)amino]ethyl]-1,3-thiazole-4-carboxylate | C13H20N2O4S | 详情 | 详情 | |
| (XIII) | 48367 | ethyl 2-[(1R)-1-aminoethyl]-1,3-thiazole-4-carboxylate | C8H12N2O2S | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(X)The thiazole amino acid (XIX) was prepared by a similar method as above, consisting of conversion of N-Boc-D-valine (XIV) to the corresponding amide (XV) followed by thionation to (XVI). Condensation of thioamide (XVI) with ethyl bromopyruvate (X) and subsequent acid dehydration gave thiazole (XVIII). Basic hydrolysis of the ethyl ester group of (XVIII) then gave acid (XIX). Coupling of the N-Boc-amino acid (XIX) with aminoester (XIII) produced the corresponding amide (XX). Further acid cleavage of the Boc protecting group gave (XXI).
| 【1】 Xia, Z.; Smith, C.D.; Total synthesis of dendroamide A, a novel cyclic peptide that reverses multiple drug resistance. J Org Chem 2001, 66, 10, 3459. |
| 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) | 25183 | ethyl 3-bromo-2-oxopropanoate;ethyl 3-bromopyruvate;Bromopyruvic acid ethyl ester;ethyl 3-bromopyruvate;ethyl bromopyruvate | 70-23-5 | C5H7BrO3 | 详情 | 详情 |
| (XIII) | 48367 | ethyl 2-[(1R)-1-aminoethyl]-1,3-thiazole-4-carboxylate | C8H12N2O2S | 详情 | 详情 | |
| (XIV) | 48375 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid | C10H19NO4 | 详情 | 详情 | |
| (XV) | 48368 | tert-butyl (1R)-1-(aminocarbonyl)-2-methylpropylcarbamate | C10H20N2O3 | 详情 | 详情 | |
| (XVI) | 48369 | tert-butyl (1R)-1-(aminocarbothioyl)-2-methylpropylcarbamate | C10H20N2O2S | 详情 | 详情 | |
| (XVII) | 48370 | ethyl 2-[(1R)-1-[(tert-butoxycarbonyl)amino]-2-methylpropyl]-4-hydroxy-4,5-dihydro-1,3-thiazole-4-carboxylate | C15H26N2O5S | 详情 | 详情 | |
| (XVIII) | 48371 | ethyl 2-[(1R)-1-[(tert-butoxycarbonyl)amino]-2-methylpropyl]-1,3-thiazole-4-carboxylate | C15H24N2O4S | 详情 | 详情 | |
| (XIX) | 48372 | 2-[(1R)-1-[(tert-butoxycarbonyl)amino]-2-methylpropyl]-1,3-thiazole-4-carboxylic acid | C13H20N2O4S | 详情 | 详情 | |
| (XX) | 48373 | ethyl 2-((1R)-1-[[(2-[(1R)-1-[(tert-butoxycarbonyl)amino]-2-methylpropyl]-1,3-thiazol-4-yl)carbonyl]amino]ethyl)-1,3-thiazole-4-carboxylate | C21H30N4O5S2 | 详情 | 详情 | |
| (XXI) | 48374 | ethyl 2-[(1R)-1-[([2-[(1R)-1-amino-2-methylpropyl]-1,3-thiazol-4-yl]carbonyl)amino]ethyl]-1,3-thiazole-4-carboxylate | C16H22N4O3S2 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(XX)The 2,3-disubstituted maleimide intermediate (X) is prepared by N-alkylation of 1,2,3,4-tetrahydroquinoline (XIX) with ethyl 3-bromopyruvate (XX) in THF to give ethyl 3-(3,4-dihydro-2H-quinolin-1-yl)-2-oxopropionate (XXI), which by intramolecular cyclocondensation by means of MgCl2 in 2-methoxyethanol at 125 °C affords ethyl 5,6-dihydropyrrolo[3,2,1-ij]quinoline-1-carboxylate (XXII). Hydrolysis of ethyl ester (XXII) with NaOH in EtOH/H2O provides the corresponding carboxylic acid (XXIII), which is then decarboxylated to 5,6-dihydropyrrolo[3,2,1-ij]quinoline (lilolidine) (XVII) by heating to 185 °C in quinoline in the presence of CuO·Cr2O3 . Acylation of lilolidine (XVII) with (COCl)2 in Et2O, and subsequent quenching of the resulting glyoxylyl chloride with MeOH or NaOMe/MeOH affords the oxoester (XXIV), which is finally cyclocondensed with indole-3-acetamide (XXV) in the presence of t-BuOK in THF .
| 【1】 Li, C.J., Ashwell, M.A., Hill, J., Moussa, M.M., Munshi, N. (ArQule, Inc.). Maleimide derivatives, pharmaceutical compositions and methods for treatment of cancer. CN 10194970, EP 1846406, EP 2289892, JP 2008530026, US 2006223760, US 7713969, WO 2006086484. |
| 【2】 Chan, T.C.K., France, D.S., Ishii, K. (ArQule, Inc.; Kyowa Hakko Kirin Co., Ltd.). Combinational compositions and methods for treatment of cancer. KR 2011118817, US 2010297075, WO 2010093789. |
| 【3】 Reed, D.P., Barnes, N.R., Kane, J.C., Lee, C.A., Chen, J.-X., Redmon, M.P.(ArQule, Inc.). Purified pyrroloquinolinyl-pyrrolidine-2,5-dione compositions and methods for preparing and using same. US 201116022, WO 2011079142. |
| 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) | 68960 | 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione | C23H17N3O2 | 详情 | 详情 | |
| (XVII) | 68966 | 5,6-dihydropyrrolo[3,2,1-ij]quinoline;5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline;1,7-Trimethyleneindol;1,8-Trimethyleneindole | 5840-01-7 | C11H11N | 详情 | 详情 |
| (XIX) | 23859 | 1,2,3,4-tetrahydroquinoline | 635-46-1 | C9H11N | 详情 | 详情 |
| (XX) | 25183 | ethyl 3-bromo-2-oxopropanoate;ethyl 3-bromopyruvate;Bromopyruvic acid ethyl ester;ethyl 3-bromopyruvate;ethyl bromopyruvate | 70-23-5 | C5H7BrO3 | 详情 | 详情 |
| (XXI) | 68968 | ethyl 3-(3,4-dihydro-2H-quinolin-1-yl)-2-oxopropionate | C14H17NO3 | 详情 | 详情 | |
| (XXII) | 68969 | ethyl 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylate | C14H15NO2 | 详情 | 详情 | |
| (XXIII) | 68970 | 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylic acid | C12H11NO2 | 详情 | 详情 | |
| (XXIV) | 68971 | methyl 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-2-oxoacetate | C14H13NO3 | 详情 | 详情 | |
| (XXV) | 48682 | Indole-3-acetamide;3-Indoleacetamide;2-(1H-indol-3-yl) | 879-37-8 | C10H10N2O | 详情 | 详情 |