|
【结 构 式】 
|
【分子编号】19648 【品名】Cyanamide 【CA登记号】420-04-2 |
【 分 子 式 】CH2N2 【 分 子 量 】42.04036 【元素组成】C 28.57% H 4.8% N 66.63% |
合成路线1
该中间体在本合成路线中的序号：(II)This compound can be obtained in two related ways: 1) By reaction of N-(4-pyridyl)-N'-(1,2,2-trimethylpropyl)thiourea (I) with cyanamide (II) by means of dicyclohexylcarbodiimide (DCC) and ethyldiisopropylamine in ether. 2) The reaction of (I) with phosgene in toluene - THF by means of ethyldiisopropylamine in THF gives N-(4-pyridyl)-N'-(1,2,2-trimethylpropyl)carbodiimide (III), which is condensed with (II) by means of ethyldiisopropylamine.
| 【1】 Petersen, H.J. (Leo Pharmaceutical Products Ltd. A/S); Antihypertensive pyridylguanidine compounds. DE 2557438; FR 2294703; GB 1489879; JP 51086474; US 4057636 . |
| 【2】 Blancafort, P.; Castaner, J.; Serradell, M.N.; Hopkins, S.J.; P-1134. Drugs Fut 1981, 6, 3, 149. |
| 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) | 32176 | N-(4-pyridyl)-N'-(1,2,2-trimethylpropyl)thiourea; N-(4-pyridinyl)-N'-(1,2,2-trimethylpropyl)thiourea | C12H19N3S | 详情 | 详情 | |
| (II) | 19648 | Cyanamide | 420-04-2 | CH2N2 | 详情 | 详情 |
| (III) | 32177 | N-(4-pyridinyl)-N'-(1,2,2-trimethylpropyl)carbodiimide; N-(4-pyridyl)-N'-(1,2,2-trimethylpropyl)carbodiimide | C12H17N3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)By reaction of N,N-dimethylcarbamoylmethyl-p-(p-aminobenzoyloxy)phenylacetate (VI) with cyanamide (VII).
| 【1】 Fujii, S.; et al. (Ono Pharmaceutical Co., Ltd.); Preparation of guanidinobenzoic acid derivatives. JP 54052052 . |
| 【2】 Castaner, J.; Serradell, M.N.; Hashimoto, K.; Camostat Mesylate. Drugs Fut 1985, 10, 11, 897. |
合成路线3
该中间体在本合成路线中的序号：(IV)Tirapazamine can be obtained by several related ways: 1) By condensation of benzofurazan (I) with cyanamide disodium salt (II) in hot methanol/water. 2) The condensation of 2-nitroaniline (III) with cyanamide (IV) by heating at 100 C gives 3-amino-1,2,4-bezotriazine 1-oxide (V), which is then oxidized with 30% aqueous H2O2 in hot acetic acid. 3) The reaction of 3-hydroxy-1,2,4-benzotriazine 1-oxide (VI) with refluxing POCl3 and dimethylaniline gives 3-chloro-1,2,4-benzotriazine 1-oxide (VII), which by reaction with dry ammonia in ethanol is converted into the corresponding amino derivative (V), already obtained.
| 【1】 Schofield, K.; Robbins, R.F.; Polyazabicyclic compounds. Part II. Further derivatives of benzo-1:2:4-triazine. J Chem Soc 1957, 3186. |
| 【2】 Tennant, G.; Mason, J.C.; Heterocyclic N-oxides. Part VI. Synthesis and nuclear magnetic resonance spectra of 3-aminobenzo-1,2,4-triazines and their mono- and di-N-oxides. J Chem Soc B 1970, 911. |
| 【3】 Robinson, C.; Castaner, J.; Tirapazamine. Drugs Fut 1995, 20, 3, 256. |
| 【4】 Ley, K.; Seng, F.; Metzer, K.G. (Bayer AG); 3-Amino-1,2,4-benzotriazine-1,4-di-N-oxides and processes for their preparation. US 3868371; US 3980779; US 4001410 . |
| 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) | 11607 | 2,1,3-benzoxadiazole 1-oxide; 2,1,3-benzoxadiazol-1-ium-1-olate | 480-96-6 | C6H4N2O2 | 详情 | 详情 |
| (II) | 63311 | 2-chloro-1-ethoxyethyl ethyl ether; 2-chloro-1,1-diethoxyethane | C6H13ClO2 | 详情 | 详情 | |
| (III) | 11608 | o-Nitroaniline; 2-Nitroaniline; 2-Nitrophenylamine | 88-74-4 | C6H6N2O2 | 详情 | 详情 |
| (IV) | 19648 | Cyanamide | 420-04-2 | CH2N2 | 详情 | 详情 |
| (V) | 11609 | 3-amino-1,2,4-benzotriazin-1-ium-1-olate; 3-Amino-1,2,4-benzotriazine-1-oxide | 5424-06-6 | C7H6N4O | 详情 | 详情 |
| (VI) | 11610 | 3-hydroxy-1,2,4-benzotriazin-1-ium-1-olate | C7H5N3O2 | 详情 | 详情 | |
| (VII) | 11611 | 3-chloro-1,2,4-benzotriazin-1-ium-1-olate | C7H4ClN3O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)The condensation of 1-(3-pyridyl)ethanone (I) with dimethylformamide dimethylacetal (II) gives 3-(dimethylamino)-1-(3-pyridyl)-2-propen-1-one (III), which is cyclized with 1-(2-methyl-5-nitrophenyl)guanidine (IV) [obtained by reaction of 2-methyl-5-nitroaniline (V) with cyanamide (VI)] in refluxing isopropanol to yield the pyrimidine derivative (VII). Reduction of the nitro group of (VII) with H2 over Pd/C in THF affords the corresponding amino compound (VIII), which is finally condensed with 4-(4-methylpiperazin-1-ylmethyl)benzoyl chloride (IV) in pyridine.
| 【1】 Castaner, J.; Fernandez, R.; de Bree, F.; Sorbera, L.A.; Imatinib Mesilate. Drugs Fut 2001, 26, 6, 545. |
| 【2】 Buchdunger, E.; Mett, H.; Meyer, T.; Lydon, N.B.; Zimmermann, J.; Potent and selective inhibitors of the Abl-kinase: Phenylaminopyrimidine (PAP) derivatives. Bioorg Med Chem Lett 1997, 7, 2, 187. |
| 【3】 Zimmermann, J. (Novartis AG); Pyrimidine derivs. and process for their preparation. EP 0564409; JP 1994087834; US 5521184 . |
| 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) | 12027 | 1-(3-Pyridinyl)-1-ethanone; 1-(3-Pyridinyl)ethanone | 350-03-8 | C7H7NO | 详情 | 详情 |
| (II) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
| (III) | 47516 | (E)-3-(dimethylamino)-1-(3-pyridinyl)-2-propen-1-one | 123367-26-0 | C10H12N2O | 详情 | 详情 |
| (IV) | 47517 | N-(2-methyl-5-nitrophenyl)guanidine | 152460-07-6 | C8H10N4O2 | 详情 | 详情 |
| (V) | 47518 | 2-Amino-4-nitrotoluene; 5-Nitro-o-toluidine; 4-Nitro-2-aminotoluene; 2-methyl-5-nitrophenylamine; 2-methyl-5-nitroaniline | 99-55-8 | C7H8N2O2 | 详情 | 详情 |
| (VI) | 19648 | Cyanamide | 420-04-2 | CH2N2 | 详情 | 详情 |
| (VII) | 47519 | N-(2-methyl-5-nitrophenyl)-N-[4-(3-pyridinyl)-2-pyrimidinyl]amine; N-(2-methyl-5-nitrophenyl)-4-(3-pyridinyl)-2-pyrimidinamine | 152460-09-8 | C16H13N5O2 | 详情 | 详情 |
| (VIII) | 47520 | 4-methyl-N(3)-[4-(3-pyridinyl)-2-pyrimidinyl]-1,3-benzenediamine; N-(5-amino-2-methylphenyl)-N-[4-(3-pyridinyl)-2-pyrimidinyl]amine | 152460-10-1 | C16H15N5 | 详情 | 详情 |
| (IX) | 47521 | 4-[(4-methyl-1-piperazinyl)methyl]benzoyl chloride | 148077-69-4 | C13H17ClN2O | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XIV)Reaction of L-arabinose (XIII) with cyanamide (XIV) in aqueous methanolic ammonia gives the oxazolidine derivative (XV), which is cyclized with methyl propynoate (XVI) in refluxing ethanol to yield the anhydro uridine (XVII). Acylation of both OH groups of (XVII) by means of benzoyl cyanide (XVIII) in DMF affords the dibenzoate (XIX), which is treated with anhydrous HCl in DMF to provide the chloro uridine derivative (XX) or with HI in DMF or LiI and BH3/Et2O in DMF to provide the iodo uridine (XXI). Dehalogenation of (XX) or (XXI) by means of tri-butyltin hydride in refluxing benzene furnishes 3',5'-di-O-benzoyl-2'-deoxy-b-L-uridine (XXII). The trans-glycosylation of (XXII) with bis(trimethylsilyl)-5-fluorouracil (XXIII) by means of TMS-OTf in acetonitrile gives the corresponding 5-fluoro-L-uridine derivative (XXIV) as a mixture of the a- and b-anomers that is separated by chromatography. Debenzoylation of (XXIV) with ammonia in methanol yields 2'-deoxy-b-L-uridine (XXV), which is treated with MsCl and pyridine to afford the dimesylate (XXVI). Reaction of compound (XXVI) with NaOH in methanol/water provides the unstable intermediate (XXVII) that rearranges to the cyclic ether (XXVIII). Treatment of (XXVIII) with 1,2,4-triazole (XXIX) and p-chlorophenyl dichlorophosphate in pyridine provides the adduct (XXX), which by cleavage of the triazole ring by means of NH4OH in dioxane gives the corresponding cytidine derivative (XXXI). Finally, this compound is treated with potassium tert-butoxide in DMSO.
| 【3】 Gullen, E.; Zhu, Y.-L.; Liu, M.-C.; Dutschman, G.E.; Cheng, Y.-C.; Luo, M.-Z.; Lin, T.-S.; Design and synthesis of 2',3'-dideoxy-2',3'-didehydro-beta-L-cytidine (beta-L-d4C) and 2',3'-dideoxy-2',3'-didehydro-beta-L-5-fluorocytidine (beta-L-Fd4C), two exceptionally potent inhibitors of human hepatitis B virus (HBV) and potent inhibitors of human. J Med Chem 1996, 39, 9, 1757. |
| 【1】 Holy, A.; Nucleic acid components and their analogues. CLIII. Preparation of 2'-deoxy-L-ribonucleosides of the pyrimidine series. Coll Czech Chem Commun 1972, 37, 12, 4072. |
| 【2】 Bayes, M.; Sorbera, L.A.; Castaner, J.; ACH-126443. Drugs Fut 2002, 27, 12, 1131. |
| 【4】 Lin, T.-S.; Cheng, Y.-C. (Yale University); L-2',3'-Dideoxy nucleoside analogs as anti-hepatitis B (HBV) and anti-HIV agents. EP 0707481; JP 1996510747; US 5627160; WO 9427616 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 56917 | alpha-L-arabinofuranose | C5H10O5 | 详情 | 详情 | |
| (XIV) | 19648 | Cyanamide | 420-04-2 | CH2N2 | 详情 | 详情 |
| (XV) | 56918 | (3aS,5S,6S,6aR)-5-(hydroxymethyl)-2-iminohexahydrofuro[2,3-d][1,3]oxazol-6-ol | C6H10N2O4 | 详情 | 详情 | |
| (XVI) | 19588 | methyl propiolate | 922-67-8 | C4H4O2 | 详情 | 详情 |
| (XVII) | 39999 | (2S,3S,3aR,9aS)-3-hydroxy-2-(hydroxymethyl)-2,3,3a,9a-tetrahydro-6H-furo[2',3':4,5][1,3]oxazolo[3,2-a]pyrimidin-6-one | 3736-77-4 | C9H10N2O5 | 详情 | 详情 |
| (XVIII) | 56919 | 2-oxo-2-phenylacetonitrile | C8H5NO | 详情 | 详情 | |
| (XIX) | 40000 | [(2S,3S,3aR,9aS)-3-(benzoyloxy)-6-oxo-2,3,3a,9a-tetrahydro-6H-furo[2',3':4,5][1,3]oxazolo[3,2-a]pyrimidin-2-yl]methyl benzoate | C23H18N2O7 | 详情 | 详情 | |
| (XX) | 40001 | [(2S,3S,4S,5S)-3-(benzoyloxy)-4-chloro-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate | C23H19ClN2O7 | 详情 | 详情 | |
| (XXI) | 56920 | {(2S,3S,4S,5S)-3-(benzoyloxy)-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-4-iodotetrahydro-2-furanyl}methyl benzoate | C23H19IN2O7 | 详情 | 详情 | |
| (XXII) | 39996 | [(2S,3R,5S)-3-(benzoyloxy)-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate | C23H20N2O7 | 详情 | 详情 | |
| (XXIII) | 47859 | 5-fluoro-2-[(trimethylsilyl)oxy]-4-pyrimidinyl trimethylsilyl ether; 5-fluoro-2,4-bis[(trimethylsilyl)oxy]pyrimidine | 17242-85-2 | C10H19FN2O2Si2 | 详情 | 详情 |
| (XXIV) | 56921 | {(2S,3R,5S)-3-(benzoyloxy)-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl}methyl benzoate | C23H19FN2O7 | 详情 | 详情 | |
| (XXV) | 54714 | 5-fluoro-1-[(2S,4R,5S)-4-hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione | C9H11FN2O5 | 详情 | 详情 | |
| (XXVI) | 54709 | {(2S,3R,5S)-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-3-[(methylsulfonyl)oxy]tetrahydro-2-furanyl}methyl methanesulfonate | C11H15FN2O9S2 | 详情 | 详情 | |
| (XXVII) | 54710 | [(1S,9S,10S)-4-fluoro-5-oxo-8,11-dioxa-2,6-diazatricyclo[7.2.1.0~2,7~]dodeca-3,6-dien-10-yl]methyl methanesulfonate | C10H11FN2O6S | 详情 | 详情 | |
| (XXVIII) | 54711 | 1-[(1S,3S,5S)-2,6-dioxabicyclo[3.2.0]hept-3-yl]-5-fluoro-2,4(1H,3H)-pyrimidinedione | C9H9FN2O4 | 详情 | 详情 | |
| (XXIX) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
| (XXX) | 54712 | 1-[(1S,3S,5S)-2,6-dioxabicyclo[3.2.0]hept-3-yl]-5-fluoro-4-(1H-1,2,4-triazol-1-yl)-2(1H)-pyrimidinone | C11H10FN5O3 | 详情 | 详情 | |
| (XXXI) | 54713 | 4-amino-1-[(1S,3S,5S)-2,6-dioxabicyclo[3.2.0]hept-3-yl]-5-fluoro-2(1H)-pyrimidinone | C9H10FN3O3 | 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 bromination of styrene (II) with N-bromosuccinimide in the presence of cyanamide (I) provided 2-bromo-1-phenylethylcyanamide (III). Further addition of MeOH to (III) in the presence of HCl, followed by Na2CO3-promoted cyclization, produced the methoxyimidazoline (IV). Acylation of indoline (V) with trifluoroacetic anhydride and pyridine gave amide (VI) and subsequent chlorosulfonation yielded sulfonyl cloride (VII). This acid chloride was coupled to imidazoline (IV) in the presence of NaHCO3 in aqueous acetone to furnish a mixture of sulfonyl imidazolines (VIII) and (IX). The major isomer (IX) was isolated by column chromatography, and then, hydrolysis with HCl in MeOH at r.t. provided imidazolidinone (X). The trifluoroacetamide group of (X) was further hydrolyzed by treatment with NaOH in aqueous MeOH to give (XI). Subsequent condensation of (XI) with 4-nitrobenzoyl chloride (XII) in the presence of pyridine yielded 4-nitrobenzamide (XIII), which was finally reduced to the aminobenzamide by hydrogenation using Raney-nickel as the catalyst.
| 【1】 Jung, S.-H.; Lee, H.S.; Song, J.S.; Kim, H.M.; Han, S.B.; Lee, C.W.; Lee, M.; Choi, D.R.; Lee, J.A.; Chung, Y.H.; Yoon, S.J.; Moon, E.Y.; Hwang, H.S.; Seong, S.K.; Lee, D.K.; Synthesis and antitumor activity of 4-phenyl-1-arylsulfonyl imidazolidinones. Bioorg Med Chem Lett 1998, 8, 12, 1547. |
| 【2】 Yoon, S.J.; Chung, Y.H.; Lee, M.S.; Choi, D.R.; Lee, J.A.; Lee, H.S.; Yun, H.R.; Lee, D.K.; Moon, E.Y.; Hwang, H.S.; Choi, C.H.; Jung, S.H. (Dong-Wha Pharmaceuticals Industry Co. Ltd); Arylsulfonylimidazolone derivs. as an antitumor agent. EP 1021437; JP 2000505096; US 5929103; WO 9807719 . |
| 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) | 19648 | Cyanamide | 420-04-2 | CH2N2 | 详情 | 详情 |
| (II) | 19649 | 1-vinylbenzene | 100-42-5 | C8H8 | 详情 | 详情 |
| (III) | 19650 | 2-bromo-1-phenylethylcyanamide | C9H9BrN2 | 详情 | 详情 | |
| (IV) | 19651 | methyl 5-phenyl-4,5-dihydro-1H-imidazol-2-yl ether; 2-methoxy-5-phenyl-4,5-dihydro-1H-imidazole | C10H12N2O | 详情 | 详情 | |
| (V) | 19652 | indoline | 496-15-1 | C8H9N | 详情 | 详情 |
| (VI) | 19653 | 1-(2,3-dihydro-1H-indol-1-yl)-2,2,2-trifluoro-1-ethanone | C10H8F3NO | 详情 | 详情 | |
| (VII) | 19654 | 1-(2,2,2-trifluoroacetyl)-5-indolinesulfonyl chloride | C10H7ClF3NO3S | 详情 | 详情 | |
| (VIII) | 19655 | 2,2,2-trifluoro-1-[5-[(2-methoxy-5-phenyl-4,5-dihydro-1H-imidazol-1-yl)sulfonyl]-2,3-dihydro-1H-indol-1-yl]-1-ethanone | C20H18F3N3O4S | 详情 | 详情 | |
| (IX) | 19656 | 2,2,2-trifluoro-1-[5-[(2-methoxy-4-phenyl-4,5-dihydro-1H-imidazol-1-yl)sulfonyl]-2,3-dihydro-1H-indol-1-yl]-1-ethanone | C20H18F3N3O4S | 详情 | 详情 | |
| (X) | 19657 | 4-phenyl-1-[[1-(2,2,2-trifluoroacetyl)-2,3-dihydro-1H-indol-5-yl]sulfonyl]-2-imidazolidinone | C19H16F3N3O4S | 详情 | 详情 | |
| (XI) | 19658 | 1-(2,3-dihydro-1H-indol-5-ylsulfonyl)-4-phenyl-2-imidazolidinone | C17H17N3O3S | 详情 | 详情 | |
| (XII) | 18941 | p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride | 122-04-3 | C7H4ClNO3 | 详情 | 详情 |
| (XIII) | 19660 | 1-[[1-(4-nitrobenzoyl)-2,3-dihydro-1H-indol-5-yl]sulfonyl]-4-phenyl-2-imidazolidinone | C24H20N4O6S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：Treatment of 3-chloro-5-cyanoaniline (I) with thiophosgene afforded the corresponding aryl isothiocyanate (II). Ritter reaction of 3-ethyl-3-pentanol (III) using NaCN and H2SO4 produced formamide (IV), which was hydrolyzed to amine (V) with NaOH. Then, condensation of isothiocyanate (II) with amine (V) yielded thiourea (VI). Subsequent removal of H2S in (VI) by treatment with PPh3, CCl4 and Et3N gave carbodiimide (VII). Finally, addition of cyanamide to (VII) in the presence of i-Pr2NEt furnished the required cyanoguanidine.
| 【1】 Yoshiizumi, K.; Seko, N.; Nishimura, N.; Ikeda, S.; Yoshino, K.; Kondo, H.; Tanizawa, K.; Biologically selective potassium channel openers having 1,1-diethylpropyl group. Bioorg Med Chem Lett 1998, 8, 23, 3397. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 19648 | Cyanamide | 420-04-2 | CH2N2 | 详情 | 详情 | |
| (I) | 26535 | 3-amino-5-chlorobenzonitrile | C7H5ClN2 | 详情 | 详情 | |
| (II) | 26536 | 3-chloro-5-isothiocyanatobenzonitrile | C8H3ClN2S | 详情 | 详情 | |
| (III) | 26537 | 3-ethyl-3-pentanol | 597-49-9 | C7H16O | 详情 | 详情 |
| (IV) | 26538 | 1,1-diethylpropylformamide | C8H17NO | 详情 | 详情 | |
| (V) | 26539 | 1,1-diethylpropylamine | C7H17N | 详情 | 详情 | |
| (VI) | 26540 | N-(3-chloro-5-cyanophenyl)-N'-(1,1-diethylpropyl)thiourea | C15H20ClN3S | 详情 | 详情 | |
| (VII) | 26541 | N-(3-chloro-5-cyanophenyl)-N'-(1,1-diethylpropyl)carbodiimide | C15H18ClN3 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：Treatment of 3,5-dichloroaniline (I) with thiophosgene afforded the corresponding aryl isothiocyanate (II). Ritter reaction of 3-ethyl-3-pentanol (III) using NaCN and H2SO4 produced formamide (IV), which was hydrolyzed to amine (V) with NaOH. Then, condensation of isothiocyanate (II) with amine (V) yielded thiourea (VI). Subsequent removal of H2S in (VI) by treatment with PPh3, CCl4 and Et3N gave carbodiimide (VII). Finally, addition of cyanamide to (VII) in the presence of i-Pr2NEt furnished the required cyanoguanidine.
| 【1】 Yoshiizumi, K.; Seko, N.; Nishimura, N.; Ikeda, S.; Yoshino, K.; Kondo, H.; Tanizawa, K.; Biologically selective potassium channel openers having 1,1-diethylpropyl group. Bioorg Med Chem Lett 1998, 8, 23, 3397. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 19648 | Cyanamide | 420-04-2 | CH2N2 | 详情 | 详情 | |
| (I) | 26542 | 3,5-dichloroaniline | 626-43-7 | C6H5Cl2N | 详情 | 详情 |
| (II) | 26543 | 1,3-dichloro-5-isothiocyanatobenzene | 6590-93-8 | C7H3Cl2NS | 详情 | 详情 |
| (III) | 26537 | 3-ethyl-3-pentanol | 597-49-9 | C7H16O | 详情 | 详情 |
| (IV) | 26538 | 1,1-diethylpropylformamide | C8H17NO | 详情 | 详情 | |
| (V) | 26539 | 1,1-diethylpropylamine | C7H17N | 详情 | 详情 | |
| (VI) | 26544 | N-(3,5-dichlorophenyl)-N'-(1,1-diethylpropyl)thiourea | C14H20Cl2N2S | 详情 | 详情 | |
| (VII) | 26545 | N-(3,5-dichlorophenyl)-N'-(1,1-diethylpropyl)carbodiimide | C14H18Cl2N2 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(III)Treatment of 1-(4-aminophenyl)-4-methylpiperazine (I) with thiophosgene and Na2CO3 afforded isothiocyanate (II). Subsequent condensation of (II) with cyanamide in the presence of potassium tert-butoxide, followed by reaction of the resulting intermediate (IV) with 2-chloro-2',6'-difluoroacetophenone (V) produced the title aminothiazole.
| 【1】 Yang, Y.; Xiao, W.; Chu, S.S.; Li, L.; Chong, W.K.M.; Duvadie, R.R. (Agouron Pharmaceuticals, Inc.); 4-Aminothiazole derivs., their preparation and their use as inhibitors of cyclin-dependent kinases. WO 9921845 . |
| 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) | 31836 | 4-(4-methyl-1-piperazinyl)phenylamine; 4-(4-methyl-1-piperazinyl)aniline | C11H17N3 | 详情 | 详情 | |
| (II) | 32558 | 4-(4-methyl-1-piperazinyl)phenyl isothiocyanate; 1-(4-isothiocyanatophenyl)-4-methylpiperazine | C12H15N3S | 详情 | 详情 | |
| (III) | 19648 | Cyanamide | 420-04-2 | CH2N2 | 详情 | 详情 |
| (IV) | 32559 | N-cyano-N'-[4-(4-methyl-1-piperazinyl)phenyl]thiourea | C13H17N5S | 详情 | 详情 | |
| (V) | 32560 | 2-chloro-1-(2,6-difluorophenyl)-1-ethanone | C8H5ClF2O | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(III)The reaction of aniline (I) with di(2-pyridyl)thione (DPT) gives the corresponding isothiocyanate (II), which is condensed with cyanamide (III) and 2-bromo-1-cyclopropylethanone (IV) (obtained by bromination of acetylcyclopropane (V)) by means of NaOMe to yield the adduct (VI). This compound, without isolation, cyclizes to the target thiazole.
| 【1】 Sorensen, A.R.; Engelhardt, S.; Kurtzhals, P.; Urso, B.; Bowler, A.N.; 2,4-Diaminothiazoles: A novel class of glycogen synthase kinase-3 (GSK-3) inhibitors. 11th RSC-SCI Med Chem Symp (Sept 9 2001, Cambridge) 2001, Abst P20. |
| 【2】 Olesen, P.H.; Kurtzhals, P.; Bowler, A.N.; Soerensen, A.R.; Worsaae, H.; Hansen, B.F. (Novo Nordisk A/S); 2,4-Diaminothiazole derivs.. WO 0156567 . |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (II) | 22146 | 1-isothiocyanatobenzene; phenyl isothiocyanate | 103-72-0 | C7H5NS | 详情 | 详情 |
| (III) | 19648 | Cyanamide | 420-04-2 | CH2N2 | 详情 | 详情 |
| (IV) | 12436 | 2-Bromo-1-cyclopropyl-1-ethanone | 69267-75-0 | C5H7BrO | 详情 | 详情 |
| (V) | 12435 | Acetylcyclopropane; 1-Cyclopropyl-1-ethanone; Cyclopropylmethylketone | 765-43-5 | C5H8O | 详情 | 详情 |
| (VI) | 53529 | (Z)-3-anilino-3-[(2-cyclopropyl-2-oxoethyl)sulfanyl]-2-propenenitrile | n/a | C14H14N2OS | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(III)The reaction of propylamine (I) with di(2-pyridyl)thione (DPT) gives the corresponding isothiocyanate (II), which is condensed with cyanamide (III) and 2-bromo-1-(3-pyridyl)ethanone (IV) by means of NaOMe to yield the adduct (V). This compound, without isolation, cyclizes to the target thiazole.
| 【1】 Sorensen, A.R.; Engelhardt, S.; Kurtzhals, P.; Urso, B.; Bowler, A.N.; 2,4-Diaminothiazoles: A novel class of glycogen synthase kinase-3 (GSK-3) inhibitors. 11th RSC-SCI Med Chem Symp (Sept 9 2001, Cambridge) 2001, Abst P20. |
| 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) | 23923 | 1-propanamine | 107-10-8 | C3H9N | 详情 | 详情 |
| (II) | 53536 | Isothiocyanic acid n-propyl ester; n-Propyl isothiocyanate; Propyl isothiocyanate | 628-30-8 | C4H7NS | 详情 | 详情 |
| (III) | 19648 | Cyanamide | 420-04-2 | CH2N2 | 详情 | 详情 |
| (IV) | 53085 | 2-bromo-1-(3-pyridinyl)-1-ethanone | n/a | C7H6BrNO | 详情 | 详情 |
| (V) | 53537 | (Z)-3-{[2-oxo-2-(3-pyridinyl)ethyl]sulfanyl}-3-(propylamino)-2-propenenitrile | n/a | C13H15N3OS | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(III)The reaction of aniline (I) with di(2-pyridyl)thione (DPT) gives the corresponding isothiocyanate (II), which is condensed with cyanamide (III) and 2-bromo-1-(3-pyridyl)ethanone (IV) by means of NaOMe to yield the adduct (V). This compound, without isolation, cyclizes to the target thiazole.
| 【1】 Sorensen, A.R.; Engelhardt, S.; Kurtzhals, P.; Urso, B.; Bowler, A.N.; 2,4-Diaminothiazoles: A novel class of glycogen synthase kinase-3 (GSK-3) inhibitors. 11th RSC-SCI Med Chem Symp (Sept 9 2001, Cambridge) 2001, Abst P20. |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (II) | 22146 | 1-isothiocyanatobenzene; phenyl isothiocyanate | 103-72-0 | C7H5NS | 详情 | 详情 |
| (III) | 19648 | Cyanamide | 420-04-2 | CH2N2 | 详情 | 详情 |
| (IV) | 53085 | 2-bromo-1-(3-pyridinyl)-1-ethanone | n/a | C7H6BrNO | 详情 | 详情 |
| (V) | 53539 | (Z)-3-anilino-3-{[2-oxo-2-(3-pyridinyl)ethyl]sulfanyl}-2-propenenitrile | n/a | C16H13N3OS | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(IV)The reaction of aniline (I) with di(2-pyridyl)thione (DPT) gives the corresponding isothiocyanate (II), which is condensed with cyanamide (III) and 2-bromo-1-(3-benzyloxyphenyl)ethanone (IV) by means of NaOMe to yield the adduct (V). This compound, without isolation, cyclizes to the target thiazole.
| 【1】 Sorensen, A.R.; Engelhardt, S.; Kurtzhals, P.; Urso, B.; Bowler, A.N.; 2,4-Diaminothiazoles: A novel class of glycogen synthase kinase-3 (GSK-3) inhibitors. 11th RSC-SCI Med Chem Symp (Sept 9 2001, Cambridge) 2001, Abst P20. |
| 【2】 Olesen, P.H.; Kurtzhals, P.; Bowler, A.N.; Soerensen, A.R.; Worsaae, H.; Hansen, B.F. (Novo Nordisk A/S); 2,4-Diaminothiazole derivs.. WO 0156567 . |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (II) | 22146 | 1-isothiocyanatobenzene; phenyl isothiocyanate | 103-72-0 | C7H5NS | 详情 | 详情 |
| (III) | 53541 | 1-[3-(benzyloxy)phenyl]-2-bromo-1-ethanone | n/a | C15H13BrO2 | 详情 | 详情 |
| (IV) | 19648 | Cyanamide | 420-04-2 | CH2N2 | 详情 | 详情 |
| (V) | 53545 | (Z)-3-({2-[3-(benzyloxy)phenyl]-2-oxoethyl}sulfanyl)-3-(4-chloroanilino)-2-propenenitrile | n/a | C24H19ClN2O2S | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(III)The reaction of 4-chloroaniline (I) with di(2-pyridyl)thione (DPT) gives the corresponding isothiocyanate (II), which is condensed with cyanamide (III) and 2-bromo-1-(3-benzyloxyphenyl)ethanone (IV) by means of NaOMe to yield the adduct (V). This compound, without isolation, cyclizes to the target thiazole.
| 【1】 Sorensen, A.R.; Engelhardt, S.; Kurtzhals, P.; Urso, B.; Bowler, A.N.; 2,4-Diaminothiazoles: A novel class of glycogen synthase kinase-3 (GSK-3) inhibitors. 11th RSC-SCI Med Chem Symp (Sept 9 2001, Cambridge) 2001, Abst P20. |
| 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) | 12034 | 4-Chlorophenylamine; 4-Chloroaniline; p-Chloroaniline | 106-47-8 | C6H6ClN | 详情 | 详情 |
| (II) | 22146 | 1-isothiocyanatobenzene; phenyl isothiocyanate | 103-72-0 | C7H5NS | 详情 | 详情 |
| (III) | 19648 | Cyanamide | 420-04-2 | CH2N2 | 详情 | 详情 |
| (IV) | 53541 | 1-[3-(benzyloxy)phenyl]-2-bromo-1-ethanone | n/a | C15H13BrO2 | 详情 | 详情 |
| (V) | 53545 | (Z)-3-({2-[3-(benzyloxy)phenyl]-2-oxoethyl}sulfanyl)-3-(4-chloroanilino)-2-propenenitrile | n/a | C24H19ClN2O2S | 详情 | 详情 |