|
【结 构 式】 
|
【分子编号】11300 【品名】2-hydroxyethyl 4-hydroxy-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate 【CA登记号】 |
【 分 子 式 】C11H11NO6S 【 分 子 量 】285.27748 【元素组成】C 46.31% H 3.89% N 4.91% O 33.65% S 11.24% |
合成路线1
该中间体在本合成路线中的序号：(VI)This compound can be prepared by two similar ways: 1) The monoacylation of ethylene glycol (I) with chloroacetyl chloride (II) and triethylamine gives 2-hydroxyethyl chloroacetate (III), which is condensed with saccharine (IV) by means of NaOH in ethylene glycol yielding 2-hydroxyethyl 3-oxo-1,2-benzisothiazoline-2-acetate 1,1-dioxide (V). Isomerization of (V) by means of potassium tert-butoxide in DMSO affords2-hydroxyethyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (VI), which is methylated with NaOH and methyl iodide in aqueous ethanol giving the corresponding N-methyl derivative (VII). Hydrolysis of (VII) with NaOH in ethanol - water yields the corresponding free acid (VIII), which is acylated with cinnamoyl chloride (IX) by means of triethylamine in dichloromethane to afford the biscinnamoyl derivative (X). Finally, this compound is treated with 2-aminopyridine (XI) in dichloromethane. 2) The preceding sequence can also be carried out with cyclohexanol (XII) instead of ethylene glycol (I), then producing compounds (XIII), (XIV), (XV) and (XVI), which by hydrolysis affords the free acid (VIII).
| 【1】 Bruzzese, T.; Dell'Acqua, E.; Ottonni, F.; Van den Heuvel, H.H. (SPA (Societa Prodotti Antibiotici)); Process for preparing benzothiazine compds. EP 0146102 . |
| 【2】 Prous, J.; Castaner, J.; CINNOXICAM. Drugs Fut 1990, 15, 2, 119. |
| 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) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (II) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (III) | 11297 | 2-hydroxyethyl 2-chloroacetate | C4H7ClO3 | 详情 | 详情 | |
| (IV) | 11298 | 1H-1,2-Benzisothiazole-1,1,3(2H)-trione; Saccharin | 81-07-2 | C7H5NO3S | 详情 | 详情 |
| (V) | 11299 | 2-hydroxyethyl 2-(1,1,3-trioxo-1,3-dihydro-2H-1,2-benzisothiazol-2-yl)acetate | C11H11NO6S | 详情 | 详情 | |
| (VI) | 11300 | 2-hydroxyethyl 4-hydroxy-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate | C11H11NO6S | 详情 | 详情 | |
| (VII) | 11301 | 2-hydroxyethyl 4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate | C12H13NO6S | 详情 | 详情 | |
| (VIII) | 11302 | 4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylic acid | C10H9NO5S | 详情 | 详情 | |
| (IX) | 11303 | (E)-3-Phenyl-2-propenoyl chloride; 3-Phenyl-2-propenoyl chloride | 102-92-1 | C9H7ClO | 详情 | 详情 |
| (X) | 11304 | 2-Methyl-1,1-dioxo-4-[[(E)-3-phenyl-2-propenoyl]oxy]-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylic (E)-2-phenyl-2-propenoic anhydride | C28H21NO7S | 详情 | 详情 | |
| (XI) | 11305 | 2-Pyridinamine; 2-Pyridinylamine; 2-Aminopyridine | 504-29-0 | C5H6N2 | 详情 | 详情 |
| (XII) | 11306 | Cyclohexanol | 108-93-0 | C6H12O | 详情 | 详情 |
| (XIII) | 11307 | cyclohexyl 2-chloroacetate | C8H13ClO2 | 详情 | 详情 | |
| (XIV) | 11308 | cyclohexyl 2-(1,1,3-trioxo-1,3-dihydro-2H-1,2-benzisothiazol-2-yl)acetate | C15H17NO5S | 详情 | 详情 | |
| (XV) | 11309 | cyclohexyl 4-hydroxy-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate | C15H17NO5S | 详情 | 详情 | |
| (XVI) | 11310 | cyclohexyl 4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate | C16H19NO5S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)D,L-Glutamic acid (I) was sequentially protected as the gamma-allyl ester (III), upon treatment with allyl alcohol (II) and chlorotrimethylsilane, followed by conversion to the trichloroethyl carbamate (V) by means of chloroformate (IV), and then reaction of (V) with benzyl bromide to afford the alpha-benzyl ester (VI). Deprotection of the trichloroethyl carbamate of (VI) by treatment with zinc dust and HOAc and subsequent condensation of the resulting amine with decanoyl chloride (VII) furnished amide (VIII). The allyl ester of (VIII) was then selectively cleaved by using tetrakistriphenylphosphine palladium(0) and morpholine to give carboxylic acid (IX). trans-1,2-Diaminocyclohexane (X) was protected as the mono tert-butyl carbamate (XI) and then coupled with acid (IX) in the presence of diethylphosphoryl cyanide to yield amide (XII). After acidic Boc cleavage of (XII), coupling of the resulting amine with 2,5-diphenyloxazole-4-carboxylic acid (XIII) by means of bromo-tris(pyrrolidino)phosphonium hexafluorophosphate (PyBroP) afforded (XIV). Finally, hydrolysis of the benzyl ester of (XIV) with LiOH provided the corresponding carboxylic acid.
| 【1】 Ducruet, A.P.; Yokokawa, F.; Rice, R.L.; tamura, K.; Lazo, J.S.; Wipf, P.; Yokokama, S.; Identification of new Cdc25 dual specificity phosphatase inhibitors in a targeted small molecule array. Bioorg Med Chem 2000, 8, 6, 1451. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 28752 | DL-2-Amino propane dicarboxylic acid; DL-2-Aminopentanoic acid; glutamic acid; DL-glutamic acid; (+/-)-2-Aminoglutaric acid | 617-65-2 | C5H9NO4 | 详情 | 详情 |
| (II) | 12234 | 2-Propen-1-ol; Allyl alcohol | 107-18-6 | C3H6O | 详情 | 详情 |
| (III) | 43406 | 5-(allyloxy)-5-oxonorvaline | C8H13NO4 | 详情 | 详情 | |
| (IV) | 13664 | 1,1,1-Trichloro-2-[(chlorocarbonyl)oxy]ethane; 2,2,2-Trichloroethyl chloroformate | 17341-93-4 | C3H2Cl4O2 | 详情 | 详情 |
| (V) | 43399 | 5-(allyloxy)-5-oxo-N-[(2,2,2-trichloroethoxy)carbonyl]norvaline | C11H14Cl3NO6 | 详情 | 详情 | |
| (VI) | 43400 | 5-allyl 1-benzyl 2-[[(2,2,2-trichloroethoxy)carbonyl]amino]pentanedioate | C18H20Cl3NO6 | 详情 | 详情 | |
| (VII) | 28271 | decanoyl chloride | 112-13-0 | C10H19ClO | 详情 | 详情 |
| (VIII) | 43401 | 5-allyl 1-benzyl 2-(decanoylamino)pentanedioate | C25H37NO5 | 详情 | 详情 | |
| (IX) | 43402 | 5-(benzyloxy)-4-(decanoylamino)-5-oxopentanoic acid | C22H33NO5 | 详情 | 详情 | |
| (X) | 11300 | 2-hydroxyethyl 4-hydroxy-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate | C11H11NO6S | 详情 | 详情 | |
| (XI) | 43403 | tert-butyl (1R,2R)-2-aminocyclohexylcarbamate | C11H22N2O2 | 详情 | 详情 | |
| (XII) | 43404 | benzyl 5-([(1R,2R)-2-[(tert-butoxycarbonyl)amino]cyclohexyl]amino)-2-(decanoylamino)-5-oxopentanoate | C33H53N3O6 | 详情 | 详情 | |
| (XIII) | 28277 | 2,5-diphenyl-1,3-oxazole-4-carboxylic acid | C16H11NO3 | 详情 | 详情 | |
| (XIV) | 43405 | benzyl 2-(decanoylamino)-5-[((1R,2R)-2-[[(2,5-diphenyl-1,3-oxazol-4-yl)carbonyl]amino]cyclohexyl)amino]-5-oxopentanoate | C44H54N4O6 | 详情 | 详情 |