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【结 构 式】 
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【分子编号】13186 【品名】2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine 【CA登记号】60-23-1 |
【 分 子 式 】C2H7NS 【 分 子 量 】77.15032 【元素组成】C 31.14% H 9.15% N 18.16% S 41.56% |
合成路线1
该中间体在本合成路线中的序号：(V)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：(A)1) By refluxing N-cyano-N',S-dimethylisoithiourea (B) and 5-methyl-4-[(2-aminoethyl)thiomethyl imidazol (III) in acetonitrile. The latter is prepared by reacting cysteamine (A) and 5-methyl-4-(hydroxymethyl)imidazol (II) (from 5-methylimidazol (I) and formalin) in acetic acid, in hydrochloric acid or in hydrobromic acid. 2) By reaction of 5-methyl-4-[(2-aminoethyl)thiomethyl]imidazol (III) with cyanodithioimido carbonic (C) acid dimethyl ester to give the isothiourea (IV), followed by reaction with methylamine. 3) By refluxing 1-methyl-3-[2-[[(5-methylimidazol-4-yl)-methyl]thio]ethyl]-2-thiourea (metiamide) (V) and lead cyanamide. The first is prepared by reaction of 5-methyl-4-[(2-aminoethyl)thiomethyl]imidazol (III) with methyl isocyanate (D).
| 【1】 Durant, G.J.; et al.; Pharmacologically active guanidine compounds. DE 2211454; DE 2265369; FR 2128505; GB 1338169; US 3950333 . |
| 【2】 Erlenmeyer, H.; et al.; Helv Chim Acta 1948, 31, 32. |
| 【3】 Durant, G.J.; et al.; Certain N-cyanoguanidines. DE 2344779; FR 2199467; GB 1397436; JP 49075574; US 3876647 . |
| 【4】 Castaner, J.; Cimetidine. Drugs Fut 1976, 1, 1, 13. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (D) | 12092 | Methyl isothiocyanate; MITC; (Methylimino)(thioxo)methane | 556-61-6 | C2H3NS | 详情 | 详情 |
| (A) | 13186 | 2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine | 60-23-1 | C2H7NS | 详情 | 详情 |
| (B) | 34072 | [[(E)-(methylamino)(methylsulfanyl)methylidene]amino](nitrilo)methane | C4H7N3S | 详情 | 详情 | |
| (I) | 34070 | 5-methyl-1H-imidazole | 822-36-6 | C4H6N2 | 详情 | 详情 |
| (II) | 14216 | (5-Methyl-1H-imidazol-4-yl)methanol | 29636-87-1 | C5H8N2O | 详情 | 详情 |
| (III) | 34071 | 2-[[(5-methyl-1H-imidazol-4-yl)methyl]sulfanyl]-1-ethanamine; 2-[[(5-methyl-1H-imidazol-4-yl)methyl]sulfanyl]ethylamine | C7H13N3S | 详情 | 详情 | |
| (IV) | 34073 | 4-[[(2-[[(cyanoimino)(methylsulfanyl)methyl]amino]ethyl)sulfanyl]methyl]-5-methyl-1H-imidazole | C10H15N5S2 | 详情 | 详情 | |
| (V) | 34074 | N-methyl-N'-(2-[[(5-methyl-1H-imidazol-4-yl)methyl]sulfanyl]ethyl)thiourea | C9H16N4S2 | 详情 | 详情 | |
| (C) | 18174 | [[bis(methylsulfanyl)methylene]amino](nitrilo)methane | 10191-60-3 | C4H6N2S2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The reaction of 5-dimethylaminomethyl-2-furanylmethanol (I) with 2-mercaptoethylamine (II) by means of aqueous HCl gives 2-[[(5-dimethylamino-methyl-2-furanyl)methylthio]ethaneamine (III), which is then condensed with N-methyl-1-methylthio-2-nitrotheneamine (IV) by heating at 120 C. Compound (IV) is obtained by reaction of 1,1-bis(methylthio)-2-nitroethene (V) with methylamine in refluxing ethanol.
| 【1】 Price, B.J.; Bradshaw, J.; Clitherow, J.W. (Allen & Hansburys Ltd.); Aminoalkyl furan derivatives.. DE 2734070; FR 2360587; US 4128658 . |
| 【2】 Serradell, M.N.; Blancafort, P.; Castaner, J.; Hillier, K.; Ranitidine. Drugs Fut 1979, 4, 9, 663. |
| 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) | 13849 | [5-[(dimethylamino)methyl]-2-furyl]methanol | C8H13NO2 | 详情 | 详情 | |
| (II) | 13186 | 2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine | 60-23-1 | C2H7NS | 详情 | 详情 |
| (III) | 13851 | 2-[([5-[(Dimethylamino)methyl]-2-furyl]methyl)sulfanyl]-1-ethanamine; N-[(5-[[(2-Aminoethyl)sulfanyl]methyl]-2-furyl)methyl]-N,N-dimethylamine | C10H18N2OS | 详情 | 详情 | |
| (IV) | 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 |
| (V) | 13853 | Methyl 1-(methylsulfanyl)-2-nitrovinyl sulfide; 1,1-Bis(methylthio)-2-nitroethylene; 1,1-Bis(methylsulfanyl)-2-nitroethylene | 13623-94-4 | C4H7NO2S2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)The Mannich reaction of tricyclo[2.2. 1.0(2,6)]hept-3-ylamine hydrochloride (I) with 2-furanylmethanol (II) and paraformaldehyde (III) in ethanol gives 5-(tricyclo[2.2. 1.0(2,6)]hept-3-ylamino)methyl-2-furanyl methanol (IV). The reaction of compound (IV) with 2 mercaptoethylamine (V) by means of concentrated HCl affords 2 [[[5-[(tricyclo[2.2.1.0(2,6)]hept-3-yl-amino(methyl]-2-furanyl]methyl]thio]etheneamine (VI), which is converted with 1 1-bis(methylthio)-2-nitroethene (VII) in isopropyl alcohol by heating at 70 C to N-[2-[[[5 [(tricyclo[2.2.1.O(2,6)]hept-3-ylamino)methyl]-2-furanyl]methyl]thio]ethyl]-1-(methylthio)-2-nitroetheneamine (VIII). Compound (VIII) is then treated with excess methylamine in ethanol at 0 C, followed by treatment with ethereal HCl to give the desired-N-[2-[[[5 [(tricyclo[2.2. 1.0(2,6)]hept-3-ylamino)methyl]-2 furanyl]methyl]thio]ethyl] N'- methyl-2-nitro-1,1-ethenediaminehydrochloride.
| 【1】 Emig, P.; et al. (Degussa-Huls AG); Novel ethenediamine and guanidine derivatives. DE 3343884 . |
| 【2】 Castaner, J.; Prous, J.; D-16637. Drugs Fut 1986, 11, 1, 14. |
| 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) | 24124 | tricyclo[2.2.1.0(2,6)]hept-3-ylamine | C7H11N | 详情 | 详情 | |
| (II) | 13848 | 2-Furylmethanol; Furfuryl Alcohol | 98-00-0 | C5H6O2 | 详情 | 详情 |
| (IV) | 24126 | [5-[(tricyclo[2.2.1.0(2,6)]hept-3-ylamino)methyl]-2-furyl]methanol | C13H17NO2 | 详情 | 详情 | |
| (V) | 13186 | 2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine | 60-23-1 | C2H7NS | 详情 | 详情 |
| (VI) | 24128 | N-[(5-[[(2-aminoethyl)sulfanyl]methyl]-2-furyl)methyl]-N-tricyclo[2.2.1.0(2,6)]hept-3-ylamine | C15H22N2OS | 详情 | 详情 | |
| (VII) | 13853 | Methyl 1-(methylsulfanyl)-2-nitrovinyl sulfide; 1,1-Bis(methylthio)-2-nitroethylene; 1,1-Bis(methylsulfanyl)-2-nitroethylene | 13623-94-4 | C4H7NO2S2 | 详情 | 详情 |
| (VIII) | 24130 | N-[(Z)-1-(methylsulfanyl)-2-nitroethenyl]-N-[2-[([5-[(tricyclo[2.2.1.0(2,6)]hept-3-ylamino)methyl]-2-furyl]methyl)sulfanyl]ethyl]amine | C18H25N3O3S2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)The reaction of (3R,5R,6S)-6-(1(R)-hydroxyethyl)-2-oxo-1-carbapenem-3-carboxylic acid p-nitrobenzyl ester (I) with diphenyl chlorophosphate by (II) means of DMAP and DIEA in DMA/dichloromethane gives the enol phosphate (III), which is condensed with 2-aminoethanethiol (IV) in DMA to yield the 2-aminoethylsulfanyl derivative (V). The reaction of (V) with benzyl formimidate (VI) by means of DIEA in DMA affords the intermediate p-nitrobenzyl ester (VII), which is finally hydrogenated with H2 over Pd/C in water/isopropanol/N-methylmorpholine to provide the target Imipemide.
| 【1】 Kumar, Y.; Tewari, N.; Rai, B.P. (Ranbaxy Laboratories Ltd.); Process for the preparation of imipenem. WO 0294828 . |
| 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) | 22686 | 4-nitrobenzyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate | C16H16N2O7 | 详情 | 详情 | |
| (II) | 16074 | Diphenyl phosphoryl chloride; 1,1'-Diphenylphosphoryl chloride; Chlorodiphenyl Phosphate; Diphenyl chlorophosphate; Diphenylchlorophosphate | 2524-64-3 | C12H10ClO3P | 详情 | 详情 |
| (III) | 57095 | 4-nitrobenzyl (5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C28H25N2O10P | 详情 | 详情 | |
| (IV) | 13186 | 2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine | 60-23-1 | C2H7NS | 详情 | 详情 |
| (V) | 57096 | 4-nitrobenzyl (5R,6S)-3-[(2-aminoethyl)sulfanyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C18H21N3O6S | 详情 | 详情 | |
| (VI) | 57097 | benzyl iminoformate | C8H9NO | 详情 | 详情 | |
| (VII) | 57098 | 4-nitrobenzyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-({2-[(iminomethyl)amino]ethyl}sulfanyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C19H22N4O6S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(V)The condensation of 2-methoxyphenol (I) with 2-bromoethanal dimethylacetal (II) by means of K2CO3 in hot DMF gives 2-(2-methoxyphenoxy)ethanal dimethylacetal (III), which is hydrolyzed to the corresponding free aldehyde (IV) with 2N H2SO4 in methanol. The cyclization of (IV) with cysteamine (V) by means of potassium acetate in water affords 2-(2-methoxyphenoxymethyl)thiazolidine (VI), which is finally condensed with ethoxymalonyl chloride (VII) by means of KHCO3 in ethyl acetate.
| 【1】 Gandolfi, C.A.; Spinelli, S.; Tofanetti, O.; Russo, R.; Tognella, S. (Boehringer Ingelheim Italia SpA); Antitussive and mucus regulating 2-substituted thiazolidines. AU 8545242; EP 0169581; ES 8605249; GB 2164333; GB 2177690; JP 1986063669; US 4857643 . |
| 【2】 Gandolfi, C.A.; Di Domenico, R.; Spinelli, S.; Lumachi, B.; Gallico, L.; Tognella, S. (Boehringer Ingelheim Italia SpA); Beta-carbonyl-carboxyamides of 1,3-thiazolidines. EP 0333080; JP 1991504123; US 5206254 . |
| 【3】 De Angelis, L.; Moguisteine. Drugs Fut 1991, 16, 7, 618. |
| 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) | 13182 | Guaiacol; 2-Methoxyphenol | 90-05-1 | C7H8O2 | 详情 | 详情 |
| (II) | 13183 | 2-Bromo-1,1-dimethoxyethane; 2-Bromo-1-methoxyethyl methyl ether; Bromoacetaldehyde dimethyl acetal | 7252-83-7 | C4H9BrO2 | 详情 | 详情 |
| (III) | 13184 | 1-(2,2-Dimethoxyethoxy)-2-methoxybenzene; 2-(2,2-Dimethoxyethoxy)phenyl methyl ether | C11H16O4 | 详情 | 详情 | |
| (IV) | 13185 | 2-(2-Methoxyphenoxy)acetaldehyde | C9H10O3 | 详情 | 详情 | |
| (V) | 13186 | 2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine | 60-23-1 | C2H7NS | 详情 | 详情 |
| (VI) | 13187 | 2-[(2-Methoxyphenoxy)methyl]-1,3-thiazolidine; 2-Methoxyphenyl 1,3-thiazolidin-2-ylmethyl ether | C11H15NO2S | 详情 | 详情 | |
| (VII) | 13188 | ethyl 3-chloro-3-oxopropanoate; 2-Ethoxycarbonylacetyl chloride; Ethyl malonyl chloride | 36239-09-5 | C5H7ClO3 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XVIII)The reduction of N-(benzyloxycarbonyl)-L-phenylalanine (XVI) gives the corresponding aldehyde (XVII), which is cyclized with 2-sulfanylethylamine (XVIII) to yield the thiazolidine (XIX). The dehydrogenation of (XIX) by means of MnO2 affords the thiazole derivative (XX). Finally, the amino group of (XX) is deprotected with HBr to afford the desired intermediate, 2-phenyl-1(S)-(2-thiazolyl)ethylamine (XXI). Alternatively, N-(benzyloxycarbonyl)-L-phenylalanine (XVI) can be converted into the corresponding amide (XXII), which is treated with the Lawesson's reagent to yield the thioamide (XXIII). Finally, the cyclization of (XXIII) with 2-bromoacetaldehyde (XXIV) gives already reported thiazole derivative (XX) (partial racemization occurs during the synthetic process). Enantiomeric separation takes place in a later stage.
| 【1】 Roux, F.; et al.; Synthesis of dolastatin-10 and [R-Doe]-dolastatin-10. Tetrahedron 1994, 50, 18, 5345. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 54607 | (1S)-2-phenyl-1-(1,3-thiazol-2-yl)-1-ethanamine; (1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethylamine | C11H12N2S | 详情 | 详情 | ||
| (XVI) | 14505 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropionic acid; N-Carbobenzyloxy-L-phenylalanine; N-Cbz-L-Phenylalanine | 1161-13-3 | C17H17NO4 | 详情 | 详情 |
| (XVII) | 16586 | benzyl N-[(1S)-1-benzyl-2-oxoethyl]carbamate | C17H17NO3 | 详情 | 详情 | |
| (XVIII) | 13186 | 2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine | 60-23-1 | C2H7NS | 详情 | 详情 |
| (XX) | 54604 | benzyl (1S)-2-phenyl-1-(1,3-thiazolidin-2-yl)ethylcarbamate | C19H22N2O2S | 详情 | 详情 | |
| (XXI) | 24802 | 2-bromoacetaldehyde | C2H3BrO | 详情 | 详情 | |
| (XXII) | 54603 | benzyl (1S)-2-amino-1-benzyl-2-oxoethylcarbamate | 4801-80-3 | C17H18N2O3 | 详情 | 详情 |
| (XXIII) | 54605 | benzyl (1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethylcarbamate | C19H18N2O2S | 详情 | 详情 | |
| (XXIV) | 54606 | benzyl (1S)-2-amino-1-benzyl-2-thioxoethylcarbamate | C17H18N2O2S | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XVI)The reduction of N-Boc-L-phenylalanine (XIII) with B2H6 in THF gives the expected alcohol (XIV), which is oxidized with SO3/pyridine to yield the corresponding aldehyde (XV). The cyclization of (XV) with 2-sulfanylethylamine (XVI) affords the thiazolidine (XVII), which is dehydrogenated by means of MnO2 to afford the thiazole derivative (XVIII). Finally, the amino group of (XVIII) is deprotected with HCl to afford the desired intermediate, 2-phenyl-1(S)-(2-thiazolyl)ethylamine (XIX).
| 【1】 Tomioka, K.; et al.; An expeditious synthesis of dolastatin 10. Tetrahedron 1991, 32, 21, 2395. |
| 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) | 12874 | (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine | 13734-34-4 | C14H19NO4 | 详情 | 详情 |
| (XIV) | 54624 | tert-butyl (1S)-1-benzyl-2-hydroxyethylcarbamate | C14H21NO3 | 详情 | 详情 | |
| (XV) | 23452 | tert-butyl (1S)-1-benzyl-2-oxoethylcarbamate | C14H19NO3 | 详情 | 详情 | |
| (XVI) | 13186 | 2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine | 60-23-1 | C2H7NS | 详情 | 详情 |
| (XVII) | 54625 | tert-butyl (1S)-2-phenyl-1-(1,3-thiazolidin-2-yl)ethylcarbamate | C16H24N2O2S | 详情 | 详情 | |
| (XVIII) | 54626 | tert-butyl (1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethylcarbamate | C16H20N2O2S | 详情 | 详情 | |
| (XIX) | 54607 | (1S)-2-phenyl-1-(1,3-thiazol-2-yl)-1-ethanamine; (1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethylamine | C11H12N2S | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(XIX)The reduction of N-Boc-L-phenylalanine (XVI) with diborane in THF gives N-Boc-L-phenylalaninol (XVII), which is oxidized with SO3/pyridine in DMSO to yield N-Boc-L-phenylalaninal (XVIII). The cyclization of (XVIII) with 2-sulfanylethylamine (XIX) affords the thiazolidine (XX), which is dehydrogenated by means of MnO2 to provide the thiazole derivative (XXI). Finally, compound (XXI) is N-deprotected by a treatment with TFA to provide the 2-phenyl-1(S)-(2-thiazolyl)ethylamine intermediate (XXII).
| 【1】 Pettit, G.R.; Srirangam, J.K.; Singh, S.B.; Williams, M.D.; Herald, D.L.; Barkóczy, J.; Kantoci, D.; Hogan, F.; Dolastatins 24. Synthesis of (-)-dolastatin 10. X-Ray molecular structure of N,N-dimethylvalyl-valyl-dolaisoleucine tert-butyl ester. J Chem Soc Perkins Trans I 1996, 8, Suppl. 3, 859-63. |
| 【2】 Pettit, G.R.; Singh, S.B.; Williams, M.D.; Herald, D.L.; Hogan, F.; Burkett, D.D.; Clewlow, P.J.; The absolute configuration and synthesis of natural (-)-Dolastatin 10. J Am Chem Soc 1989, 111, Suppl. 3, 5463. |
| 【3】 Pettit, G.R.; Singh, S.B. (Arizona State University); Synthesis of dolastatin 10. US 4978744 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVI) | 12874 | (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine | 13734-34-4 | C14H19NO4 | 详情 | 详情 |
| (XVII) | 54624 | tert-butyl (1S)-1-benzyl-2-hydroxyethylcarbamate | C14H21NO3 | 详情 | 详情 | |
| (XVIII) | 23452 | tert-butyl (1S)-1-benzyl-2-oxoethylcarbamate | C14H19NO3 | 详情 | 详情 | |
| (XIX) | 13186 | 2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine | 60-23-1 | C2H7NS | 详情 | 详情 |
| (XX) | 54625 | tert-butyl (1S)-2-phenyl-1-(1,3-thiazolidin-2-yl)ethylcarbamate | C16H24N2O2S | 详情 | 详情 | |
| (XXI) | 54626 | tert-butyl (1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethylcarbamate | C16H20N2O2S | 详情 | 详情 | |
| (XXII) | 54607 | (1S)-2-phenyl-1-(1,3-thiazol-2-yl)-1-ethanamine; (1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethylamine | C11H12N2S | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(IV)The acylation of 5-(methylaminomethyl)furan-2-methanol (I) with 2,2,2-trichloroethyl chloroformate (II) and pyridine in dichloromethane gives the corresponding N-acyl derivative (III), which is condensed with 2-mercaptoethylamine (IV) by means of sodium methoxide in methanol to yield the thioether (V). The condensation of (V) with diphenyl methanesulfonimidocarbonate (VI) and 2-hydroxy-2-(4-hydroxyphenyl)ethylamine (VII) by means of potassium acetate and triethylamine in acetonitrile - propanol affords the protected final product (VIII), which is finally deprotected by treatment with activated Zn and potassium dihydrogen phosphate.
| 【1】 Hirai, S.; Hirano, H.; Arai, H.; Shibata, H.; Kusayanagi, Y.; Hashiba, K. (Toyama Chemical Co., Ltd.); Amine deriv. and its salts and antiulcer agent containing the same. CH 675244; DE 3828869; US 4871765 . |
| 【2】 Castaner, J.; Prous, J.; Mealy, N.; T-593. Drugs Fut 1993, 18, 9, 809. |
| 【3】 Shibata, H.; Hirai, N.; Kusayanagi, K.; Arai, H.; Hirano, H.; Synthesis of beta-hydroxyphenethyl-based compounds and their physico-chemical properties and structural features. 113th Annu Meet Pharmaceut Soc Jpn (March 29-31, Osaka) 1993, Abst 29PB 10-28. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 13663 | [5-[(Methylamino)methyl]-2-furyl]methanol | C7H11NO2 | 详情 | 详情 | |
| (II) | 13664 | 1,1,1-Trichloro-2-[(chlorocarbonyl)oxy]ethane; 2,2,2-Trichloroethyl chloroformate | 17341-93-4 | C3H2Cl4O2 | 详情 | 详情 |
| (III) | 13665 | 2,2,2-trichloroethyl [5-(hydroxymethyl)-2-furyl]methyl(methyl)carbamate | C10H12Cl3NO4 | 详情 | 详情 | |
| (IV) | 13186 | 2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine | 60-23-1 | C2H7NS | 详情 | 详情 |
| (V) | 13667 | 2,2,2-trichloroethyl (5-[[(2-aminoethyl)sulfanyl]methyl]-2-furyl)methyl(methyl)carbamate | C12H17Cl3N2O3S | 详情 | 详情 | |
| (VI) | 13668 | N-(Diphenoxymethylene)methanesulfonamide | C14H13NO4S | 详情 | 详情 | |
| (VII) | 13669 | 4-(2-Amino-1-hydroxyethyl)phenol | 104-14-3 | C8H11NO2 | 详情 | 详情 |
| (VIII) | 13670 | 2,2,2-trichloroethyl [5-((E)-6-[[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino]-8,8-dioxo-2,8lambda(6)-dithia-5,7-diaza-6-nonen-1-yl)-2-furyl]methyl(methyl)carbamate | C22H29Cl3N4O7S2 | 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 2-furan-methanol (I) with dimethylamine and formaldehyde gives 5-(dimethylaminomethyl)furan-2-methanol (II), which is condensed with 2-sulfanylethylamine (III) yielding 2-[5-(dimethylaminomethyl)furan-2-ylsulfanyl]ethylamine (IV). The condensation of (IV) with 1-(methylamino)-1-(methylsulfanyl)-2-nitroethylene (V), obtained from 1,1,-bis(methylsulfanyl)-2-nitroethylene (VI) and methylamine, in hot acetone, or by heating at 100-120 C affords N-[2-[5-(dimethylaminomethyl)furan-2-ylmethylsulfanyl]ethyl]- N'-methyl-2-nitroethylene-1,1-diamine (VII) , which is finally complexed with bismuth (+3) citrate (VIII), obtained by reaction of NO3BiO with citric acid (IX) in hot water.
| 【1】 Castaner, J.; Rabasseda, X.; Mealy, N.; Ranitidine Bismuth Citrate. Drugs Fut 1995, 20, 5, 480. |
| 【2】 Clitherow, J.W. (Glaxo Wellcome plc); Ranitidine derivs. BE 1003254; CH 679582; GB 2220937; JP 1990117684; US 5008256 . |
| 【3】 Bradshaw, J.; Price, B.J.; Clitherow, J.W.; Aminoalkyl furan derivs. GB 1565966 . |
| 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) | 13848 | 2-Furylmethanol; Furfuryl Alcohol | 98-00-0 | C5H6O2 | 详情 | 详情 |
| (II) | 13849 | [5-[(dimethylamino)methyl]-2-furyl]methanol | C8H13NO2 | 详情 | 详情 | |
| (III) | 13186 | 2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine | 60-23-1 | C2H7NS | 详情 | 详情 |
| (IV) | 13851 | 2-[([5-[(Dimethylamino)methyl]-2-furyl]methyl)sulfanyl]-1-ethanamine; N-[(5-[[(2-Aminoethyl)sulfanyl]methyl]-2-furyl)methyl]-N,N-dimethylamine | C10H18N2OS | 详情 | 详情 | |
| (V) | 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 |
| (VI) | 13853 | Methyl 1-(methylsulfanyl)-2-nitrovinyl sulfide; 1,1-Bis(methylthio)-2-nitroethylene; 1,1-Bis(methylsulfanyl)-2-nitroethylene | 13623-94-4 | C4H7NO2S2 | 详情 | 详情 |
| (VII) | 13854 | N-[2-[([5-[(Dimethylamino)methyl]-2-furyl]methyl)sulfanyl]ethyl]-N-[(E)-1-(methylamino)-2-nitroethenyl]amine; (E)-N(1)-[2-[([5-[(Dimethylamino)methyl]-2-furyl]methyl)sulfanyl]ethyl]-N(1)-methyl-2-nitro-1,1-ethenediamine; Ranitidine | 66357-35-5 | C13H22N4O3S | 详情 | 详情 |
| (VIII) | 13855 | bismuth(3+) 2-hydroxy-1,2,3-propanetricarboxylate; Bismuth Citrate | 813-93-4 | C6H5BiO7 | 详情 | 详情 |
| (IX) | 13856 | 2-Hydroxy-1,2,3-propanetricarboxylic acid; Citric acid | 77-92-9 | C6H8O7 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(III)Methyl 3-chloro-5-methoxybenzo[b]thiophene-2-carboxylate (II) was prepared from the known acid chloride (I) by treatment with methanol. Cyclization of the chloro ester (II) with cysteamine hydrochloride (III) in the presence of DBU afforded the target benzothienothiazepinone.
| 【2】 Boschelli, D.H.; Connor, D.T.; Kramer, J.B.; Unangst, P.C. (Pfizer Inc.); Benzothiophene, benzofuran and indolethiazepinones, oxazepinones and diazepinones as inhibitors of cell adhesion and as inhibitors of HIV. EP 0749434; JP 1997509961; US 5489586; WO 9524408 . |
| 【1】 Khatana, S.S.; et al.; Preparation of benzothieno[2,3-f]-1,4-oxazepin- and -thiazepin-5(2H)-ones and of benzothieno[3,2-e]-1,4-diazepin-5-ones. J Org Chem 1996, 61, 17, 6060. |
| 【3】 Gracheck, S.J. (Pfizer Inc.); Use of thiazepine, oxazepine and diazepine cpds. for inhibiting HIV, herpesvirus and suppressing the immune system. EP 0817635; JP 1999502814; WO 9629077 . |
| 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) | 13892 | 3-Chloro-5-methoxy-1-benzothiophene-2-carbonyl chloride | C10H6Cl2O2S | 详情 | 详情 | |
| (II) | 51552 | methyl 3-chloro-5-methoxy-1-benzothiophene-2-carboxylate | C11H9ClO3S | 详情 | 详情 | |
| (III) | 13186 | 2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine | 60-23-1 | C2H7NS | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(VI)The reaction of cyclopeptide (V) with 2-sulfanylethylamine (VI) by means of camphorsulfonic acid (CSA) in DMF gives the epi-2-aminoethylsulfanyl compound (VII), which is oxidized with oxone in acetonitrile/water, affording the sulfone (VIII). Finally, this compound is treated with ethylenediamine in DMF to afford the target compound.
| 【1】 Balkovec, J.M.; Bouffard, F.A.; Black, R.M. (Merck & Co., Inc.); Aza cyclohexapeptide cpds.. CA 2118757; EP 0620232; JP 1994321986; US 5378804; WO 9421677 . |
| 【2】 Balkovec, J.M.; Black, R.M.; Bouffard, F.A. (Merck & Co., Inc.); Aza cyclohexapeptide cpds.. US 5792746 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 47005 | N-[(2R,6S,9S,11R,12R,14aS,15S,20S,23S,25aS)-20-[(1R)-3-amino-1-hydroxypropyl]-23-[(1S)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-2,11,12,15-tetrahydroxy-6-[(1R)-1-hydroxyethyl]-5,8,14,19,22,25-hexaoxotetracosahydro-1H-dipyrrolo[2,1-c:2,1-l][1,4,7,10,13,16]hexaazacyclohenicosin-9-yl]-10,12-dimethyltetradecanamide | C50H82N8O16 | 详情 | 详情 | |
| (VI) | 13186 | 2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine | 60-23-1 | C2H7NS | 详情 | 详情 |
| (VII) | 47007 | N-[(2R,6S,9S,11R,12S,14aS,15S,20S,23S,25aS)-12-[(2-aminoethyl)sulfanyl]-20-[(1R)-3-amino-1-hydroxypropyl]-23-[(1S,2S)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-2,11,15-trihydroxy-6-[(1R)-1-hydroxyethyl]-5,8,14,19,22,25-hexaoxotetracosahydro-1H-dipyrrolo[2,1-c:2,1-l][1,4,7,10,13,16]hexaazacyclohenicosin-9-yl]-10,12-dimethyltetradecanamide | C52H87N9O15S | 详情 | 详情 | |
| (VIII) | 47008 | N-[(2R,6S,9S,11R,12S,14aS,15S,20S,23S,25aS)-12-[(2-aminoethyl)sulfonyl]-20-[(1R)-3-amino-1-hydroxypropyl]-23-[(1S,2S)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-2,11,15-trihydroxy-6-[(1R)-1-hydroxyethyl]-5,8,14,19,22,25-hexaoxotetracosahydro-1H-dipyrrolo[2,1-c:2,1-l][1,4,7,10,13,16]hexaazacyclohenicosin-9-yl]-10,12-dimethyltetradecanamide | C52H87N9O17S | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(A)The condensation of 1,3-dichloroacetone (I) with ethyl 3-sulfanylpropionate (II) by means of triethylamine in THF gives ethyl 3-(3-chloro-2-oxopropylsulfanyl)propionate (III), which is condensed with ethyl carbazate (IV) by means of Ts-OH in acetonitrile yielding the corresponding hydrazone (V). The cyclization of (V) with SOCl2 in DMF gives the 1,2,3-thiadiazole (VI), which is condensed with 2-aminoethanethiol (A) by means of NaI in dioxane/water afffording the bis thioether (VII). The protection of the amino group of (VII) with Boc2O yields the carbamate (VIII), which is treated with sodium methoxide in methanol to provide sodium thiolate (IX). The condensation of (IX) with the cephem derivative (X) in ethyl acetate/aqueous NaHCO3 gives the expected addition product (XI), which is further condensed with 2-(tert-butoxycarbonylamino)-2-(trityloxyimino)acetic acid (XII) by means of POCl3 in THF yielding the fully protected target compound (XIII). Finally, this compound is deprotected by treatment with TFA and triethylsilane.
| 【1】 Hecker, S.J.; Fan, A.T.; Ludwikow, M.; Wang, M.; Cho A.; Glinka, T.W.; New anti-MRSA cephalosporins with a basic aminopyridine at the C-7 position. Bioorg Med Chem Lett 2001, 11, 2, 137. |
| 【2】 Lee, V.J.; Price, M.; Zhang, Z.J.; Fan, A.; Glinka, T.; Chamberland, S.; Cho, A.; Ludwikow, M.; Hecker, S.J.; Liu, N.; Design, synthesis, and SAR of water-soluble dibasic cephalosporins active against resistant Gram-positive bacteria. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F392. |
| 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) | 13186 | 2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine | 60-23-1 | C2H7NS | 详情 | 详情 |
| (I) | 63907 | 1,3-dichloroacetone | C3H4Cl2O | 详情 | 详情 | |
| (II) | 31837 | ethyl 3-sulfanylpropanoate | 5466-06-8 | C5H10O2S | 详情 | 详情 |
| (III) | 31838 | ethyl 3-[(3-chloro-2-oxopropyl)sulfanyl]propanoate | C8H13ClO3S | 详情 | 详情 | |
| (IV) | 12556 | methyl 1-hydrazinecarboxylate; methyl carbazate | 6294-89-9 | C2H6N2O2 | 详情 | 详情 |
| (V) | 31839 | methyl 2-((E)-2-chloro-1-[[(3-ethoxy-3-oxopropyl)sulfanyl]methyl]ethylidene)-1-hydrazinecarboxylate | C10H17ClN2O4S | 详情 | 详情 | |
| (VI) | 31840 | ethyl 3-[[4-(chloromethyl)-1,2,3-thiadiazol-5-yl]sulfanyl]propanoate | C8H11ClN2O2S2 | 详情 | 详情 | |
| (VII) | 31841 | ethyl 3-[(4-[[(2-aminoethyl)sulfanyl]methyl]-1,2,3-thiadiazol-5-yl)sulfanyl]propanoate | C10H17N3O2S3 | 详情 | 详情 | |
| (VIII) | 31842 | ethyl 3-([4-[([2-[(tert-butoxycarbonyl)amino]ethyl]sulfanyl)methyl]-1,2,3-thiadiazol-5-yl]sulfanyl)propanoate | C15H25N3O4S3 | 详情 | 详情 | |
| (IX) | 31843 | sodium 4-[([2-[(tert-butoxycarbonyl)amino]ethyl]sulfanyl)methyl]-1,2,3-thiadiazole-5-thiolate | C10H16N3NaO2S3 | 详情 | 详情 | |
| (X) | 15892 | benzhydryl (6R,7R)-7-amino-3-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C23H24N2O4S2 | 详情 | 详情 | |
| (XI) | 31844 | benzhydryl (6R,7R)-7-amino-3-([4-[([2-[(tert-butoxycarbonyl)amino]ethyl]sulfanyl)methyl]-1,2,3-thiadiazol-5-yl]sulfanyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C30H33N5O5S4 | 详情 | 详情 | |
| (XII) | 31845 | 2-[3-[(tert-butoxycarbonyl)amino]phenyl]-2-[(trityloxy)imino]acetic acid | C32H30N2O5 | 详情 | 详情 | |
| (XIII) | 31846 | benzhydryl (6R,7R)-3-([4-[([2-[(tert-butoxycarbonyl)amino]ethyl]sulfanyl)methyl]-1,2,3-thiadiazol-5-yl]sulfanyl)-7-([2-[3-[(tert-butoxycarbonyl)amino]phenyl]-2-[(trityloxy)imino]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C62H61N7O9S4 | 详情 | 详情 |
合成路线15
该中间体在本合成路线中的序号：(A)The cyclization of ethyl cyanoacetate (I) with carbon disulfide gives 5-sulfanylthiazole-4-carboxylic acid ethyl ester (II), which is reduced with LiAlH4 in THF to the corresponding carbinol (III). The condensation of (III) with 2-iodoethyl phenyl sulfone (IV) affords the thioether (V), which is treated with SOCl2 in DMF to afford the chloromethyl derivative (VI). The condensation of (VI) with 2-aminoethanethiol (A) by means of NaI in dioxane/water gives the bis thioether (VII), which is protected at the amino group with Boc2 to afford the carbamate (VIII), and treated with NaOMe in methanol to provide the sodium thiolate (IX). The condensation of (IX) with the cephem derivative (X) in ethyl acetate/aqueous NaHCO3 gives the expected addition product (XI), which is further condensed with 2-(tert-butoxycarbonylamino)-2-(trityloxyimino)acetic acid (XII) by means of POCl3 in THF yielding the fully protected target compound (XIII). Finally, this compound is deprotected by treatment with TFA and triethylsilane.
| 【1】 Lee, V.J.; Price, M.; Zhang, Z.J.; Fan, A.; Glinka, T.; Chamberland, S.; Cho, A.; Ludwikow, M.; Hecker, S.J.; Liu, N.; Design, synthesis, and SAR of water-soluble dibasic cephalosporins active against resistant Gram-positive bacteria. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F392. |
| 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) | 13186 | 2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine | 60-23-1 | C2H7NS | 详情 | 详情 |
| (I) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (II) | 31848 | ethyl 5-sulfanyl-1,3-thiazole-4-carboxylate | C6H7NO2S2 | 详情 | 详情 | |
| (III) | 31849 | (5-sulfanyl-1,3-thiazol-4-yl)methanol | C4H5NOS2 | 详情 | 详情 | |
| (IV) | 31850 | 2-iodoethyl phenyl sulfone; (2-iodoethyl)(dioxo)phenyl-lambda(6)-sulfane | C8H9IO2S | 详情 | 详情 | |
| (V) | 31851 | (5-[[2-(phenylsulfonyl)ethyl]sulfanyl]-1,3-thiazol-4-yl)methanol | C12H13NO3S3 | 详情 | 详情 | |
| (VI) | 31852 | 2-[[4-(chloromethyl)-1,3-thiazol-5-yl]sulfanyl]ethyl phenyl sulfone; 4-(chloromethyl)-5-[[2-(phenylsulfonyl)ethyl]sulfanyl]-1,3-thiazole | C12H12ClNO2S3 | 详情 | 详情 | |
| (VII) | 31853 | 2-[[(5-[[2-(phenylsulfonyl)ethyl]sulfanyl]-1,3-thiazol-4-yl)methyl]sulfanyl]ethylamine; 2-[[(5-[[2-(phenylsulfonyl)ethyl]sulfanyl]-1,3-thiazol-4-yl)methyl]sulfanyl]-1-ethanamine | C14H18N2O2S4 | 详情 | 详情 | |
| (VIII) | 31854 | tert-butyl 2-[[(5-[[2-(phenylsulfonyl)ethyl]sulfanyl]-1,3-thiazol-4-yl)methyl]sulfanyl]ethylcarbamate | C19H26N2O4S4 | 详情 | 详情 | |
| (IX) | 31855 | sodium 4-[([2-[(tert-butoxycarbonyl)amino]ethyl]sulfanyl)methyl]-1,3-thiazole-5-thiolate | C11H17N2NaO2S3 | 详情 | 详情 | |
| (X) | 15892 | benzhydryl (6R,7R)-7-amino-3-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C23H24N2O4S2 | 详情 | 详情 | |
| (XI) | 31856 | benzhydryl (6R,7R)-7-amino-3-([4-[([2-[(tert-butoxycarbonyl)amino]ethyl]sulfanyl)methyl]-1,3-thiazol-5-yl]sulfanyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C31H34N4O5S4 | 详情 | 详情 | |
| (XII) | 31845 | 2-[3-[(tert-butoxycarbonyl)amino]phenyl]-2-[(trityloxy)imino]acetic acid | C32H30N2O5 | 详情 | 详情 | |
| (XIII) | 31857 | benzhydryl (6R,7R)-3-([4-[([2-[(tert-butoxycarbonyl)amino]ethyl]sulfanyl)methyl]-1,3-thiazol-5-yl]sulfanyl)-7-([2-[3-[(tert-butoxycarbonyl)amino]phenyl]-2-[(trityloxy)imino]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C63H62N6O9S4 | 详情 | 详情 |
合成路线16
该中间体在本合成路线中的序号：(IV)Neomycin B (I) was protected with Boc2O to afford (II), which was then converted to sulfonate (III) upon treatment with 2,4,6-triisopropylbenzenesulfonyl chloride and pyridine. Displacement of the sulfonate group with 2-mercaptoethylamine (IV) produced the (aminoethyl)thioether (V). This was then condensed with 9-phenoxyacrydine (VI) to furnish, after acid deprotection of the Boc groups, the title neomycin-acridine conjugate.
| 【1】 Kirk, S.R.; et al.; Neomycin - Acridine conjugate: A potent inhibitor of Rev-RRE binding. J Am Chem Soc 2000, 122, 5, 980. |
| 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) | 46454 | (2R,3S,4R,5R,6R)-5-amino-2-(aminomethyl)-6-[((1R,2R,3S,4R,6S)-4,6-diamino-2-[[(3R,4S,5R)-4-[[(2R,3R,4R,5S,6S)-3-amino-6-(aminomethyl)-4,5-dihydroxytetrahydro-2H-pyran-2-yl]oxy]-3-hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]oxy]-3-hydroxycyclohexyl | C23H46N6O13 | 详情 | 详情 | |
| (II) | 46455 | tert-butyl [(2R,3S,4R,5R,6R)-6-[((1R,2R,3S,4R,6S)-4,6-bis[(tert-butoxycarbonyl)amino]-2-[[(3R,4S,5R)-4-[((2R,3R,4R,5S,6S)-3-[(tert-butoxycarbonyl)amino]-6-[[(tert-butoxycarbonyl)amino]methyl]-4,5-dihydroxytetrahydro-2H-pyran-2-yl)oxy]-3-hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]oxy]-3-hydroxycyclohexyl)oxy]-5-[(tert-butoxycarbonyl)amino]-3,4-dihydroxytetrahydro-2H-pyran-2-yl]methylcarbamate | C53H94N6O25 | 详情 | 详情 | |
| (III) | 46456 | [(2R,3S,4R)-5-([(1R,2R,3S,5R,6S)-3,5-bis[(tert-butoxycarbonyl)amino]-2-[((2R,3R,4R,5S,6R)-3-[(tert-butoxycarbonyl)amino]-6-[[(tert-butoxycarbonyl)amino]methyl]-4,5-dihydroxytetrahydro-2H-pyran-2-yl)oxy]-6-hydroxycyclohexyl]oxy)-3-[((2R,3R,4R,5S,6S)-3-[(tert-butoxycarbonyl)amino]-6-[[(tert-butoxycarbonyl)amino]methyl]-4,5-dihydroxytetrahydro-2H-pyran-2-yl)oxy]-4-hydroxytetrahydro-2-furanyl]methyl 2,4,6-triisopropylbenzenesulfonate | C68H116N6O27S | 详情 | 详情 | |
| (IV) | 13186 | 2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine | 60-23-1 | C2H7NS | 详情 | 详情 |
| (V) | 46457 | tert-butyl [(2S,3S,4R,5R,6R)-6-[[(2S,3S,4R)-2-[[(2-aminoethyl)sulfanyl]methyl]-5-([(1R,2R,3S,5R,6S)-3,5-bis[(tert-butoxycarbonyl)amino]-2-[((2R,3R,4R,5S,6R)-3-[(tert-butoxycarbonyl)amino]-6-[[(tert-butoxycarbonyl)amino]methyl]-4,5-dihydroxytetrahydro-2H-pyran-2-yl)oxy]-6-hydroxycyclohexyl]oxy)-4-hydroxytetrahydro-3-furanyl]oxy]-5-[(tert-butoxycarbonyl)amino]-3,4-dihydroxytetrahydro-2H-pyran-2-yl]methylcarbamate | C55H99N7O24S | 详情 | 详情 | |
| (VI) | 46458 | 9-acridinyl phenyl ether; 9-phenoxyacridine | C19H13NO | 详情 | 详情 |
合成路线17
该中间体在本合成路线中的序号：(IV)The condensation of 3-acetyl-4-hydroxy-6-methyl-2H-pyran-2-one (I) with 2,4-dimethoxybenzaldehyde (II) by means of piperidine in refluxing ethanol gives the acryloyl derivative (III), which is finally cyclized with 2-aminoethanethiol (IV) in refluxing ethanol to afford the target thiazepine derivative.
| 【1】 Cai, S.X.; Spencer, J.R.; Litvak, J.; Drewe, J.A.; Shelton, E.J.; Sperandio, D. (Cytovia, Inc.); Substd. 1,4-thiazepine and analogs as activators of caspases and inducers of apoptosis and the use thereof. WO 0179187 . |
| 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) | 55829 | 3-Acetyl-4-hydroxy-6-methyl-2H-pyran-2-one | C8H8O4 | 详情 | 详情 | |
| (II) | 55830 | 2,4-Dimethoxybenzaldehyde | 613-45-6 | C9H10O3 | 详情 | 详情 |
| (III) | 55831 | 3-[(E)-3-(2,4-dimethoxyphenyl)-2-propenoyl]-4-hydroxy-6-methyl-2H-pyran-2-one | C17H16O6 | 详情 | 详情 | |
| (IV) | 13186 | 2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine | 60-23-1 | C2H7NS | 详情 | 详情 |
合成路线18
该中间体在本合成路线中的序号：(VI)Preparation of the 15-methylerythromycin A precursor (XI) is accomplished by a chemobiosynthetic approach, utilizing the diketide surrogate (IX). Synthesis of (IX) is carried out as follows. Acylation of (S)-4-benzyl-2-oxazolidinone (I) with propionyl chloride (II) affords the N-propionyl oxazolidinone (III). Diastereoselective aldol condensation of (III) with butyraldehyde (IV) employing dibutylboron triflate leads to adduct (V). Deacetylation of cysteamine hydrochloride (VI) with Ac2O provides (VII). Then, selective hydrolysis of the thioester function of (VII) under alkaline conditions provides thiol (VIII). Condensation of the acyl oxazolidinone (V) with thiol (VIII) in the presence of AlMe3 gives rise to the thioester substrate (IX) (1). Incubation of a recombinant Streptomyces coelicolor strain with the diketide surrogate (IX) leads to the production of 6-deoxy-15-methylerythronolide B (X). Subsequent bioconversion of the aglycone (X) in a Saccharopolyspora erythraea strain affords the desired 15-methylerythromycin A (XI).
| 【1】 Macielag, M.; Abbanat, D.; Ashley, G.; Foleno, B.; Fu, H.; Li, Y.; Wira, E.; Bush, K.; Structure-activity studies of 15-methyl ketolides: Optimization of the heterocyclic substituent. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-1662. |
| 【2】 Hlasta, D.; Khosla, C.; Chu, D.T.W.; Ashley, G.; Henninger, T.C.; Grant, E.B. (Ortho-McNeil Pharmaceutical, Inc.); Ketolide antibacterials. WO 0232918 . |
| 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) | 14694 | (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone | 90719-32-7 | C10H11NO2 | 详情 | 详情 |
| (II) | 15967 | propanoyl chloride; propionyl chloride | 79-03-8 | C3H5ClO | 详情 | 详情 |
| (III) | 25713 | (4S)-4-benzyl-3-propionyl-1,3-oxazolidin-2-one | C13H15NO3 | 详情 | 详情 | |
| (IV) | 23694 | butyraldehyde | 123-72-8 | C4H8O | 详情 | 详情 |
| (V) | 62287 | (4S)-4-benzyl-3-[(2S,3R)-3-hydroxy-2-methylhexanoyl]-1,3-oxazolidin-2-one | C17H23NO4 | 详情 | 详情 | |
| (VI) | 13186 | 2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine | 60-23-1 | C2H7NS | 详情 | 详情 |
| (VII) | 62288 | Ethanethioic acid, S-[2-(acetylamino)ethyl] ester; N,S-DIACETYLCYSTEAMINE; (TM)S-(2-(ACETYLAMINO)ETHYL) ETHANETHIOATE}; N,S-DIACETYL-BETA-MERCAPTOETHYLAMINE; N,s-Diacetylcysteamine; N-2-Mercaptoethylacetamide-acetate; {S-[2-(ACETYLAMINO)ETHYL] ETHANETHIOATE}; N,S-DIACETYLCYSTEAMINE*; N,S-Diacetyl-.beta.-mercaptoethylamine | 1420-88-8 | C6H11NO2S | 详情 | 详情 |
| (VIII) | 20034 | N-(2-sulfanylethyl)acetamide | 1190-73-4 | C4H9NOS | 详情 | 详情 |
| (IX) | 62289 | S-[2-(acetylamino)ethyl] (2S,3R)-3-hydroxy-2-methylhexanethioate | C11H21NO3S | 详情 | 详情 | |
| (X) | 62290 | (3R,4S,5R,6S,7S,9R,11R,12S,13R,14R)-4,6,12-trihydroxy-3,5,7,9,11,13-hexamethyl-14-propyl-2,10-oxacyclotetradecanedione | C22H40O6 | 详情 | 详情 | |
| (XI) | 62291 | (3R,4S,5R,6R,7S,9R,11R,12R,13S,14R)-6-{[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-7,12,13-trihydroxy-4-{[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-14-pr | C38H69NO13 | 详情 | 详情 |