|
【结 构 式】 
|
【分子编号】19795 【品名】2-Thiazolamine; 1,3-thiazol-2-amine; 1,3-thiazol-2-ylamine 【CA登记号】96-50-4 |
【 分 子 式 】C3H4N2S 【 分 子 量 】100.14424 【元素组成】C 35.98% H 4.03% N 27.97% S 32.02% |
合成路线1
该中间体在本合成路线中的序号：(III)The dehydration of N-cyclohexyl-N'-(2-methyl-4-quinolyl)urea (I) with triphenylphosphine, CCl4 and triethylamine in refluxing methylene chloride gives N-cyclohexyl-N'-(2-methyl-4-quinolyl)carbodiimide (II), which is then condensed with 2-aminothiazole (III) in refluxing toluene.
| 【1】 DE 2847792 . |
| 【2】 Rachlin, S.; et al.; Basic antiinflammatory compounds, N,N1,N2-trisubstituted guanidines. J Med Chem 1980, 23, 1, 13-20. |
| 【3】 Blancafort, P.; Castaner, J.; Arrigoni-Martelli, E.; Serradell, M.N.; Timegadine. Drugs Fut 1981, 6, 6, 369. |
合成路线2
该中间体在本合成路线中的序号：(V)The reaction of 2,6-dichloropyridine (I) with BuLi and CO2 in THF gives 2,6-dichloropyridine-3-carboxylic acid (II) (1), which by reaction with refluxing SOCl2 yields the acyl chloride (III). The reaction of (III) with malonic ester by means of magnesium ethoxide in ethyl ether affords the nicotinoylacetic ester (IV), which is condensed with thiazol-2-amine (V) and triethylorthoformate by means of acetic anhydride providing the nicotinoyl acrylate (VI). The cyclization of (VI) by means of K2CO3 in hot dioxane gives the 7-chloro-4-oxo-1-(2-thiazolyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid ethyl ester (VII), which is condensed with the chiral pyrrolidine (VIII) by means of triethylamine yielding the proteted intermediate (IX). Finally, this compound is deprotected and hydrolyzed with hot aqueous HCl.
| 【1】 Tomita, K.; et al.; Synthesis and antitumor activity of novel 7-substituted 1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acids. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 249. |
| 【2】 Tomita, K.; Chiba, K.; Kashimoto, S.; Shibamori, K.; Tsuzuki, Y. (Dainippon Pharmaceutical Co., Ltd.); Novel cpd., process for producing the same, and antitumor agent. EP 0787726; US 5817669; WO 9534559 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 | |
| (I) | 13573 | 2,6-Dichloropyridine | 2402-78-0 | C5H3Cl2N | 详情 | 详情 |
| (II) | 26644 | 2,6-dichloronicotinic acid | 38496-18-3 | C6H3Cl2NO2 | 详情 | 详情 |
| (III) | 26645 | 2,6-dichloronicotinoyl chloride | C6H2Cl3NO | 详情 | 详情 | |
| (IV) | 26646 | ethyl 3-(2,6-dichloro-3-pyridinyl)-3-oxopropanoate | C10H9Cl2NO3 | 详情 | 详情 | |
| (V) | 19795 | 2-Thiazolamine; 1,3-thiazol-2-amine; 1,3-thiazol-2-ylamine | 96-50-4 | C3H4N2S | 详情 | 详情 |
| (VI) | 26647 | ethyl (Z)-2-[(2,6-dichloro-3-pyridinyl)carbonyl]-3-(1,3-thiazol-2-ylamino)-2-propenoate | C14H11Cl2N3O3S | 详情 | 详情 | |
| (VII) | 26648 | ethyl 7-chloro-4-oxo-1-(1,3-thiazol-2-yl)-1,4-dihydro[1,8]naphthyridine-3-carboxylate | C14H10ClN3O3S | 详情 | 详情 | |
| (VIII) | 26649 | tert-butyl (3S,4S)-4-methoxypyrrolidinyl(methyl)carbamate | C11H22N2O3 | 详情 | 详情 | |
| (IX) | 26650 | ethyl 7-[(3S,4S)-3-[(tert-butoxycarbonyl)(methyl)amino]-4-methoxypyrrolidinyl]-4-oxo-1-(1,3-thiazol-2-yl)-1,4-dihydro[1,8]naphthyridine-3-carboxylate | C25H31N5O6S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)The Grignard condensation of N-methoxy-N-methylbenzamide (I) with 4-(methylsulfanyl)benzylmagnesium bromide (II) in THF gives the expected ketone (III), which is brominated with Br2 in CCl4 yielding the alpha-bromoketone (IV). The oxidation of the thioether group of (IV) with oxone (potassium peroxymonosulfate) in dichloromethane/methanol/tert-butanol/water affords the corresponding sulfone (V) (1), which is finally cyclocondesed with thiazol-2-amine (VI) in refluxing ethanol or isopentanol.
| 【1】 Gauthier, J.Y.; Lau, C.K.; Leblanc, Y.; Li, C.-S.; Roy, P.; Therien, M.; Wang, Z. (Merck Frosst Canada Inc.); Aryl substd. 5,5 fused aromatic nitrogen cpds. as anti-inflammatory agents. EP 0802917; JP 1999501902; US 5552422; WO 9621667 . |
| 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) | 19789 | bromo[4-(methylsulfanyl)benzyl]magnesium | C8H9BrMgS | 详情 | 详情 | |
| (II) | 19788 | N-methoxy-N-methylbenzamide | C9H11NO2 | 详情 | 详情 | |
| (III) | 19790 | 2-[4-(methylsulfanyl)phenyl]-1-phenyl-1-ethanone | C15H14OS | 详情 | 详情 | |
| (IV) | 19791 | 2-bromo-2-[4-(methylsulfanyl)phenyl]-1-phenyl-1-ethanone | C15H13BrOS | 详情 | 详情 | |
| (V) | 19792 | 2-bromo-2-[4-(methylsulfonyl)phenyl]-1-phenyl-1-ethanone | C15H13BrO3S | 详情 | 详情 | |
| (VI) | 19795 | 2-Thiazolamine; 1,3-thiazol-2-amine; 1,3-thiazol-2-ylamine | 96-50-4 | C3H4N2S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XIII)Coupling of N(alpha)-Boc-N(G)-nitro-L-arginine (XII) with 2-aminothiazole (XIII) gave amide (XIV). After cleavage of the Boc group of (XIV) with HCl, the resulting amine (XV) was coupled with the intermediate carboxylic acid (XI) using diethyl cyanophosphonate to afford adduct (XVI). The terahydropyranyl group of (XVI) was finally deprotected by treatment with aqueous acetic acid.
| 【1】 Wiethe, R.W.; Andrews, R.C.; Rabinowitz, M.H.; Musso, D.L.; Chan, J.H.; McDougald, D.L.; Gaul, M.D.; Cowan, D.J.; Stanford, J.B.; Babacz, D.G.; Andersen, M.W. (Glaxo Group Ltd.); Formamide cpds. as therapeutic agents. US 6191150; WO 0012466 . |
| 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) | 29372 | N-alpha-(tert-butoxycarbonyl)-N-omega'-nitro-L-arginine | C11H21N5O6 | 详情 | 详情 | |
| (XIII) | 19795 | 2-Thiazolamine; 1,3-thiazol-2-amine; 1,3-thiazol-2-ylamine | 96-50-4 | C3H4N2S | 详情 | 详情 |
| (XIV) | 44125 | C14H23N7O5S | 详情 | 详情 | ||
| (XV) | 44126 | C9H15N7O3S | 详情 | 详情 | ||
| (XVI) | 44124 | (2R,3S)-3-[formyl(tetrahydro-2H-pyran-2-yloxy)amino]-2-isobutylhexanoic acid | C16H29NO5 | 详情 | 详情 | |
| (XVII) | 44127 | C25H42N8O7S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XII)The alkylation of 3(R)-hydroxyhexanoic acid methyl ester (I) with isobutyl bromide (II) and LDA in THF gives 3(R)-hydroxy-2(R)-isobutylhexanoic acid methyl ester (III), which is hydrolyzed with LiOH in THF/MeOH/water to yield the corresponding lithium salt (IV). The condensation of (IV) with O-tetrahydropyranyl-hydroxylamine (V) by means of DCC in ethyl acetate affords the protected hydroxamic acid (VI), which is treated with Ms-Cl and pyridine to provide the mesylate (VII). The cyclization of (VII) by means of K2CO3 in refluxing acetone gives the chiral azetidinone (VIII), which is opened by means of NaOH in dioxane/water, yielding the carboxylic acid (IX). The formylation of the NH group of (IX) with acetic formic anhydride and pyridine in dichloromethane affords the intermediate (X). The condensation of the N-protected nitro arginine (XI) with 2-aminothiazole (XII) by means of EDC in DMF gives the argininamide (XIII), which is deprotected by means of HCl in dioxane to yield the intermediate (XIV). Condensation of (XIV) with (X) by means of diethyl phosphorylcyanide (DEPC) and NMM in DMF gives the protected dipeptide (XV), which is treated with AcOH in warm water to yield the target dipeptide.
| 【1】 Rabinowitz, M.H.; Andrews, R.C.; Becherer, J.D.; et al.; Design of selective and soluble inhibitors of tumor necrosis factor-alpha converting enzyme (TACE). J Med Chem 2001, 44, 24, 4252. |
| 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) | 44116 | methyl (3R)-3-hydroxyhexanoate | C7H14O3 | 详情 | 详情 | |
| (II) | 24599 | 1-bromo-2-methylpropane | 78-77-3 | C4H9Br | 详情 | 详情 |
| (III) | 44118 | methyl (2R,3R)-3-hydroxy-2-isobutylhexanoate | C11H22O3 | 详情 | 详情 | |
| (IV) | 62871 | C10H19LiO3 | 详情 | 详情 | ||
| (V) | 52106 | 2-(aminooxy)tetrahydro-2H-pyran; O-tetrahydro-2H-pyran-2-ylhydroxylamine | C5H11NO2 | 详情 | 详情 | |
| (VI) | 44120 | (2R,3R)-3-hydroxy-2-isobutyl-N-(tetrahydro-2H-pyran-2-yloxy)hexanamide | C15H29NO4 | 详情 | 详情 | |
| (VII) | 44121 | (1R,2R)-4-methyl-1-propyl-2-[[(tetrahydro-2H-pyran-2-yloxy)amino]carbonyl]pentyl methanesulfonate | C16H31NO6S | 详情 | 详情 | |
| (VIII) | 44122 | (3R,4S)-3-isobutyl-4-propyl-1-(tetrahydro-2H-pyran-2-yloxy)-2-azetidinone | C15H27NO3 | 详情 | 详情 | |
| (IX) | 44123 | (2R,3S)-2-isobutyl-3-[(tetrahydro-2H-pyran-2-yloxy)amino]hexanoic acid | C15H29NO4 | 详情 | 详情 | |
| (X) | 44124 | (2R,3S)-3-[formyl(tetrahydro-2H-pyran-2-yloxy)amino]-2-isobutylhexanoic acid | C16H29NO5 | 详情 | 详情 | |
| (XI) | 29372 | N-alpha-(tert-butoxycarbonyl)-N-omega'-nitro-L-arginine | C11H21N5O6 | 详情 | 详情 | |
| (XII) | 19795 | 2-Thiazolamine; 1,3-thiazol-2-amine; 1,3-thiazol-2-ylamine | 96-50-4 | C3H4N2S | 详情 | 详情 |
| (XIII) | 44125 | C14H23N7O5S | 详情 | 详情 | ||
| (XIV) | 44126 | C9H15N7O3S | 详情 | 详情 | ||
| (XV) | 44127 | C25H42N8O7S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)Reaction of 2-aminothiazole (I) with thiocarbonyldiimidazole (II) in acetonitrile gave the intermediate thioimidazolide (III). This was then condensed with 2-furylmethylamine (IV) in hot DMF to yield the title thiourea derivative.
| 【1】 Venkatachalam, T.K.; Sudbeck, E.A.; Mao, C.; Uckun, F.M.; Anti-HIV activity of aromatic and heterocyclic thiazolyl thiourea compounds. Bioorg Med Chem Lett 2001, 11, 4, 523. |
| 【2】 Uckun, F.M.; Venkatachalam, T.K. (Parker Hughes Institute); Aromatic and heterocyclic thiazolyl thiourea cpds. and use. WO 0232889 . |
| 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) | 19795 | 2-Thiazolamine; 1,3-thiazol-2-amine; 1,3-thiazol-2-ylamine | 96-50-4 | C3H4N2S | 详情 | 详情 |
| (II) | 11990 | Di(1H-imidazol-1-yl)methanethione; 1,1'-Thiocarbonyldiimidazole | 6160-65-2 | C7H6N4S | 详情 | 详情 |
| (III) | 51395 | N-(1,3-thiazol-2-yl)-1H-imidazole-1-carbothioamide | C7H6N4S2 | 详情 | 详情 | |
| (IV) | 51396 | 1-(2-Furyl)methylamine; 2-Aminomethylfuran; 2-Furfurylamine; Furfurylamine | 617-89-0 | C5H7NO | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)2-Aminothiazole (I) is coupled to 3-fluorosulfonylphenyl isocyanate (II) producing the diaryl urea (III). Subsequent reaction of sulfonyl fluoride (III) with tryptamine (IV) in hot acetonitrile furnishes the target sulfonamide.
| 【1】 Beyer, D.; Kroll, H.; Bauser, M.; Siegel, S.; Brotz, H.; Endermann, R.; Schiffer, G.; Ziegelbauer, K.; Habich, D.; Pohlmann, J.; Phenyl-thiazolylurea-sulfonamides as novel inhibitors of phenylalanine-tRNA synthetase. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-756. |
| 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) | 19795 | 2-Thiazolamine; 1,3-thiazol-2-amine; 1,3-thiazol-2-ylamine | 96-50-4 | C3H4N2S | 详情 | 详情 |
| (II) | 64472 | 3-isocyanatobenzenesulfonyl fluoride | C7H4FNO3S | 详情 | 详情 | |
| (III) | 64473 | 3-{[(1,3-thiazol-2-ylamino)carbonyl]amino}benzenesulfonyl fluoride | C10H8FN3O3S2 | 详情 | 详情 | |
| (IV) | 40537 | Tryptamine; 2-(1H-Indol-3-yl)-1-ethanamine; 2-(1H-Indol-3-yl)ethylamine | 61-54-1 | C10H12N2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XIV)Alternatively, oxazole (VI) can be condensed with 2-amino-5-sulfanylthiazole (XIII) in refluxing ethanol to give thioether (IX). The intermediate 2-amino-5-sulfanylthiazole (XIII) can be obtained by reaction of 2-aminothiazole (XIV) with Br2 and KSCN to give the thiocyanato derivative (XV), which is finally reduced with NaBH4 in ethanol (4). Scheme 2.
| 【4】 Misra, N.R., Xiao, H., Kim, K.S. et al. N-(Cycloalkylamino)acyl-2-aminothiazole inhibitors of cyclin-dependent kinase 2. N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide (BMS-387032), a highly efficacious and selective antitumor agent. J Med Chem 2004, 47(7): 1719-28. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 58417 | 5-(tert-butyl)-2-(chloromethyl)-1,3-oxazole | 224441-73-0 | C8H12ClNO | 详情 | 详情 |
| (IX) | 58420 | 5-({[5-(tert-butyl)-1,3-oxazol-2-yl]methyl}sulfanyl)-1,3-thiazol-2-amine; 5-({[5-(tert-butyl)-1,3-oxazol-2-yl]methyl}sulfanyl)-1,3-thiazol-2-ylamine | 224436-97-9 | C11H15N3OS2 | 详情 | 详情 |
| (XIII) | 65783 | 2-Amino-5-thiazolethiol | 69950-00-1 | C3H4N2S2 | 详情 | 详情 |
| (XIV) | 19795 | 2-Thiazolamine; 1,3-thiazol-2-amine; 1,3-thiazol-2-ylamine | 96-50-4 | C3H4N2S | 详情 | 详情 |
| (XV) | 64136 | 2-amino-1,3-thiazole-5-sulfenyl cyanide | 23056-10-2 | C4H3N3S2 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(V)Treatment of 2,6-dichloropyridine (I) with butyllithium in THF followed by quenching with CO2 affords 2,6-dichloronicotinic acid (II) . After chlorination with boiling SOCl2, the resulting acid chloride (IIIa) is condensed with diethyl malonate by means of magnesium ethoxide in Et2O to give the nicotinoyl acetate (IV) . Alternatively, activation of 2,6-dichloronicotinic acid (II) with CDI provides imidazolide (IIIb) which, without isolation, is condensed with the potassium salt of diethyl malonate in the presence of MgCl2 and Et3N to yield the keto ester (IV) . Treatment of compound (IV) with triethylorthoformate and acetic anhydride followed by reaction with 2-aminothiazole (V) gives the enamino ester (VI), which is cyclized to the 1,8-naphthyridine derivative (VII) upon heating with K2CO3 in dioxane . Condensation of chloronaphthyridine (VII) with the chiral pyrrolidine (VIII) by means of triethylamine in acetonitrile yields the protected voreloxin (IX), which is finally hydrolyzed with hot aqueous HCl . In a related method, chloronaphthyridine (VII) is coupled with the unprotected pyrrolidine (X) to afford voreloxin ethyl ester (XI), which is finally hydrolyzed with NaOH in H2O/EtOH .
| 【1】 Tomita, K. et al. Synthesis and antitumor activity of novel 7-substituted 1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acids. 217th ACS Natl Meet (March 21-25, Anaheim) 1999, Abst MEDI 249. |
| 【2】 Tomita, K., Chiba, K., Kashimoto, S., Shibamori, K., Tsuzuki, Y. (Dainippon Sumitomo Pharma Co., Ltd.). Novel compound, process for producing the same, and antitumor agent. EP 0787726, US 5817669, WO 1995034559. |
| 【3】 Tsuzuki, Y., Tomita, K., Shibamori, K.-I., Sato, Y., Kashimoto, S., Chiba, K. Synthesis and structure-activity relationships of novel 7-substituted 1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acids as antitumor agents. Part 2. J Med Chem 2004, 47(8): 2097-109. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIIa) | 26645 | 2,6-dichloronicotinoyl chloride | C6H2Cl3NO | 详情 | 详情 | |
| (I) | 13573 | 2,6-Dichloropyridine | 2402-78-0 | C5H3Cl2N | 详情 | 详情 |
| (II) | 26644 | 2,6-dichloronicotinic acid | 38496-18-3 | C6H3Cl2NO2 | 详情 | 详情 |
| (IV) | 26646 | ethyl 3-(2,6-dichloro-3-pyridinyl)-3-oxopropanoate | C10H9Cl2NO3 | 详情 | 详情 | |
| (V) | 19795 | 2-Thiazolamine; 1,3-thiazol-2-amine; 1,3-thiazol-2-ylamine | 96-50-4 | C3H4N2S | 详情 | 详情 |
| (VI) | 26647 | ethyl (Z)-2-[(2,6-dichloro-3-pyridinyl)carbonyl]-3-(1,3-thiazol-2-ylamino)-2-propenoate | C14H11Cl2N3O3S | 详情 | 详情 | |
| (VII) | 26648 | ethyl 7-chloro-4-oxo-1-(1,3-thiazol-2-yl)-1,4-dihydro[1,8]naphthyridine-3-carboxylate | C14H10ClN3O3S | 详情 | 详情 | |
| (VIII) | 26649 | tert-butyl (3S,4S)-4-methoxypyrrolidinyl(methyl)carbamate | C11H22N2O3 | 详情 | 详情 | |
| (IX) | 26650 | ethyl 7-[(3S,4S)-3-[(tert-butoxycarbonyl)(methyl)amino]-4-methoxypyrrolidinyl]-4-oxo-1-(1,3-thiazol-2-yl)-1,4-dihydro[1,8]naphthyridine-3-carboxylate | C25H31N5O6S | 详情 | 详情 | |
| (X) | 69211 | (3S,4S)-4-methoxy-N-methylpyrrolidin-3-amine compound with 1-methyl-4-(methylsulfonyl)benzene (1:2) | C6H14N2O.2C8H10O2S | 详情 | 详情 | |
| (XI) | 69210 | ethyl 7-((3S,4S)-3-methoxy-4-(methylamino)pyrrolidin-1-yl)-4-oxo-1-(thiazol-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylate | C20H23N5O4S | 详情 | 详情 |