1. The impurity of diuretic hydrochlorothiazide 04, also be a medical intermediate.
2. It’s mainly used for the detection of drug impurities, the synthesis of hydrochlorothiazide and the screening of medical structural fragments.
3. Presents a weak alkaline,refrigeration.
. Recommended Products is: 5250-72-6 and 22503-72-6.
A series of 3-substituted 3,4-dihydro-1,2,4-benzothiadiazine 1,1-dioxides was synthesized by condensation of substituted orthanilamides with aldehydes and the compounds tested for their efficacy as diuretic agents. Some side products and unusual reactions which occurred in the application of the general synthetic method were examined The following acetals were prepared by known methods: the diethyl acetals of bromochloroacetaldehyde, iodoacetaldehyde, dibromoacetaldehyde, ¦Á-bromoisovaleraldehyde, ¦Á-bromopropionaldehyde, ¦Á-bromomethylbutyraldehyde, phenylglyoxal, methylthioacetaldehyde, benzylthioacetaldehyde, phenylthioacetaldehyde, phenoxyacetaldehyde, p – chloro-, p-methyl-, and p-methoxyphenylacetaldehydes, and carbethoxyacetaldehyde; the dimethylacetals of ¦Á-bromophenylacetaldehyde and ¦Á-chlorophenylacetaldehyde; and the dipropyl acetal of ¦Á,¦Á-dichloropropionaldehyde. With the exception of p-isopropylphenyl- and 2,4,6-trimethylphenylacetaldehydes, the requisite aldehydes were com. available. The following general methods were used in the condensation of the substituted orthanilamide with various aldehydes. The yields varied from 30 to 90% and optimum conditions were not determined Method A. The substituted orthanilamide (0.01 mole) and 0.2 mole aldehyde component was refluxed 12 hrs. in 25-50 ml. MeCN, the solvent and excess aldehyde evaporated, and the residue crystallized Method B. The orthanilamide and 2 molar equivalents aldehyde (or its acetal) in alc.-HCl were refluxed 1-2 hrs., concentrated, diluted with CHCl3, concentrated, the mixture cooled, the product collected, washed, and recrystallized Method C. The orthanilamide (5 g.), 15-30 ml. acetal, and enough 18% alc.-HCl was heated 30-60 min. at 110-150¡ã, the alc. distilled, the mixture cooled, the solid filtered off, and washed with Et2O. In cases where the product did not crystallize, the excess solvent was removed and the residue triturated with Et2O. Method D. A mixture of the substituted orthanilamide and 1.1 equivalents aldehyde was heated 1 hr. at 200¡ã, cooled, and the crude product recrystallized The following 7-sulfamoyl-dihydrobenzothiadiazine 1,1-dioxides were thus obtained (6-, 5-, 3-substituents, method of preparation, m.p., and recrystallization solvent given): Cl, H, Me, A, 256¡ã, EtOAc-hexane; Cl, Cl, Me, A, 268-9¡ã, EtOAc-hexane; Cl, H, Et, A, 269-70¡ã, tetrahydrofuran-CHCl3; Cl, H, Pr, B, 247¡ã, MeOH-CHCl3; Cl, H, iso-Pr, A, 308-9¡ã, MeCN; Cl, H, Bu, B, 213¡ã, MeOH-CHCl3; CF3, H, Bu, B, 174-5¡ã, EtOAc-CHCl3; Cl, H, iso-Bu, B, 228¡ã, MeOH-CHCl3; Cl, H, tert-Bu, B, 326-7¡ã MeOH; Cl, H, C5H11, B, 207-8¡ã, MeOH-CHCl3; Cl, H, CH2Cl, C, 239-40¡ã, EtOAc-hexane; Cl, H, CH2Br, C, 216-17¡ã EtOAc-hexane; Cl, H, CH2I, C, 214¡ã, EtOAc-hexane; Cl, H, CHBrMe, C, 252-3¡ã, EtOAc-hexane; Cl, H, CHBrPr-iso, C, 180¡ã, EtOAc-hexane; Cl, H, CBrMeEt, C, 188-9¡ã, EtOAc-hexane; Cl, H, CHCl2, B, 280-1¡ã, MeOH-CHCl3; Br, H, CHCl2, B, 264-6¡ã, MeOH-CHCl3; F, H, CHCl2, B, 266¡ã, MeOH-CHCl3; CF3, H, CHCl2, B, 259-60¡ã, MeOH-CHCl3; Cl, H, CHClBr, C, 256¡ã, EtOAc-hexane; Cl, H, CHBr2, C, 247¡ã, EtOAc; Cl, H, CHF2, B, 296-7¡ã, MeOH-CHCl3; Cl, H, CCl2Me, B, 285¡ã, Me2COCHCl3; Cl, H, CMe2CH2OH, B, 250-1¡ã, MeOH; Cl, H, CH2OEt, B, 223¡ã, alc.-CHCl3; Cl, H, CH2COMe, C, 210¡ã, alc.-hexane; Cl, H, glycidyl, A, 246¡ã, MeCN; Cl, H, CH2SMe, B, 216-17¡ã, EtOAc-CHCl3; Cl, H, CH2CO2Et, B, 216-17¡ã, MeOH-CHCl3; Cl, H, CH2NH2, B, 178-80¡ã, Me2CO-pentane; Cl, H, piperidinomethyl, B, 173-5¡ã, EtOAc-hexane; Cl, H, Ph, B, 241-2¡ã, Me2CO-pentane; Cl, H, p-ClC6H4, D, 258-9¡ã, MeOH-CHCl3; Cl, H, o-ClC6H4, D, 272-4¡ã, MeOH-CHCl3; Cl, H, 2,4-(MeO)2C6H3, D, 211-12¡ã, MeOH; Cl, H, 3,4,5-(MeO)3C6H2, B, 244-6¡ã, Me2CO-CHCl3; Cl, H, p-EtO2CC6H4, B, 255-6¡ã, MeOH; Cl, H, p-HO2CC6H4, D, 289-90¡ã, tetrahydrofuran-CHCl3; Cl, H, 2-furyl, B, 190-5¡ã, MeOH-CHCl3; Cl, H, 2-thienyl, D, 211-13¡ã, MeOH-CHCl3; Cl, H, 2-(5-nitrofuryl), B, 239¡ã, MeOH-CHCl3; Cl, H, CH2Ph, C, 267-8¡ã, MeOH; Br, H, CH2Ph, B, 266¡ã, Me2CO-CHCl3; CF3, H, CH2Ph, B, 228¡ã, MeOH-CHCl3; Cl, H, p-MeC6H4CH2, B, 242-4¡ã, MeOH; Cl, H, p-iso-PrC6H4CH2, B, 232-3¡ã, EtOAc-hexane; Cl, H, 2,4,6-Me3C6H2CH2, B, 276-8¡ã, tetrahydrofuran-CHCl3; Cl, H, p-ClC6H4CH2, B, 245-6¡ã, MeOH-Et2O; Cl, H, p-MeOC6H4CH2, B, 239-41¡ã, MeOH; Cl, H, 3,4-(MeO)2C6H3CH2, B, 250-1¡ã, alc.; Cl, H, CHMePh, B, 231-2¡ã, EtOAc-hexane; Cl, H, CH2CH2Ph, B, 230¡ã, MeOH-CHCl3; CF3, H, CH2CH2Ph, B, 234-6¡ã, EtOAc-hexane; Cl, H, (CH2)3Ph, B, 214-15¡ã, MeOH-CHCl3; Cl, H, CH2OPh, B, 257¡ã, Me2CO-CHCl3; Cl, H, CH2SPh, B, 211-13¡ã, MeOH-CHCl3; Cl, H, CH2SCH2Ph, B, 218-19¡ã, MeOH-CHCl3; Cl, H, 3-cyclohexenyl, A, 248-9¡ã, MeOH-CHCl3; Cl, H, Cú·CPh, C, 238-9¡ã, alc.-hexane; Cl, H, 1-(2,5-endo-methylene-3-ethoxycarbonylcyclohexyl), B, 245-7¡ã, MeOH-hexane. HCHO (1.2 g., 36-8%) added to 2.94 g. 5-chloro-2,4-disulfamoylaniline in 5 ml. MeOH, the mixture refluxed 1 hr., evaporated, the residue dissolved in H2O, and cooled gave 2.05 g. 6-chloro-3,4-dihydro-7-sulfamoyl-1,2,4-benzothiadiazine, 1,1-dioxide, m. 266.5-7.5¡ã. Essentially the same procedure was used in the preparation of 5,6-dichloro-3,4-dihydro-7-sulfamoyl-1,2,4-benzothiadiazine 1,1-dioxide, m. 307-9¡ã (H2O), and the 5-methyl-6-chloro analog, m. 302-3¡ã (alc.-H2O). 5-Chloro-2,4-disulfamoylaniline (2.5 g.), 3 g. dichloroacetal, 25 ml. 18% alc.-HCl, and 0.25 ml. H2O refluxed 5 hrs., evaporated, cooled, treated with CHCl3, and refrigerated overnight gave 2 g. 6-chloro-3-dichloromethyl-3,4-dihydro-7-sulfamoyl-1,2,4-benzothiadiazine 1,1-dioxide. Difluoroacetic acid (17.9 g.) and 31 g. benzotrichloride containing a little ZnCl2 heated to reflux until HCl evolution ceased and distilled gave 15.6 g. difluoro-N,N-dimethylacetamide (I), b12 101-2¡ã. I (3.1 g.) in 150 ml. Et2O treated in 15 min. with Li diethoxyaluminum hydride in 30 ml. Et2O, the mixture stirred overnight at room temperature, a saturated aqueous solution of 5 ml. Na2SO4 then 70 g. anhydrous Na2SO4 added, the mixture filtered, the ether filtrate added to 25 ml. 4% HCl-alc., and treated with 1 g. 5-chloro-2,4-disulfamoylaniline gave 0.83 g. 6-chloro-3-difluoromethyl-3,4-dihydro-7-sulfamoyl-1,2,4-benzothiadiazine 1,1-dioxide. The crude HCl salt (prepared by method C) in 100 ml. hot dilute AcOH filtered, brought to pH 8, and cooled gave 1.1 g. 6-chloro-3,4-dihydro-3-piperidinomethyl-7-sulfamoyl-1,2,4-benzothiadiazine 1,1-dioxide, m. 173-5¡ã (decomposition). When recrystallized from Me2CO-pentane, a solvate was obtained containing one mole Me2CO. The crude HCl salt of 3-amino-methyl-3,4-dihydro-6-chloro-7-sulfamoyl-1,2,4-benzothiadiazine 1,1-dioxide in hot H2O cooled, treated with one equivalent aqueous KOH, and cooled gave the free base. 5-Chloro-2,4-disulfamoylaniline (5 g.), 25 ml. chloral, and 5 drops concentrated H2SO4 refluxed 2 hrs., the mixture diluted with CHCl3, and the crude product crystallized gave 2.8 g. 6-chloro-3,4-dihydro-7-sulfamoyl-3-trichloromethyl-1,2,4-benzothiadiazine 1,1-dioxide, m. 301-2¡ã (decomposition) (MeOH-CHCl3). 5-Chloro-2,4-disulfamoylaniline (5 g.), 25 ml. ethoxyacetal, 100 ml. tetrahydrofuran, and 1 ml. 18% alc.-HCl kept 12 hrs. at room temperature gave 0.77 g. 5-chloro-3,4-disulfamoyl-1-(2-ethoxyethylideneamino)benzene, m. 350¡ã (tetrahydrofuran). 5-Chloro-2,4-disulfamoylaniline (2 g.) and 1.98 g. p-CIC6H4CHO heated 0.5 hr. at 230-40¡ã gave 2 products, m. 257-8¡ã and m. 360¡ã, the 1st assigned the structure 6-chloro-3-(p-chlorophenyl)-3,4-dihydro-7-sulfamoyl-1,2,4-benzothiadiazine 1,1-dioxide and the 2nd the structure 5-chloro-1-(p-chlorobenzylideneamino)-2,4 -disulfamoylbenzene. 5-Chloro-2,4-disulfamoylaniline (5 g.) and 5.15 g. 3,4,5-trimethoxybenzaldehyde heated 0.5 hr. at 220-5¡ã gave 1.75 g. 5-chloro-2,4-disulfamoyl-1-(3,4,5-trimethoxybenzylideneamino)benzene, m. 300¡ã (MeOH). The same starting material heated 1 hr. with 40 ml. 2% alc.-HCl gave 4.8 g. 6-chloro-3,4-dihydro-7-sulfamoyl-3-(3,4,5-trimethoxyphenyl)-1,2,4-benzothiadiazine 1,1-dioxide, m. 244-6¡ã. Attempted crystallization from MeOH-CHCl3 gave a high yield of starting material. 5-Chloro-2,4-disulfamoylaniline (1 g.) and 0.68 g. o-carboxybenzaldehyde fused 1 hr. at 200-5¡ã gave 0.6 g 5-chloro-1-(2-carboxybenzylideneamino)-2,4-disulfamoylbenzene (II), m. 354¡ã (tetrahydrofuran-CHCl3). The same starting material warmed 1 hr. with 10 ml. 2% alc.-HCl gave 1.35 g. II. 5-Chloro-2,4-disulfamoylaniline (5 g.) heated with 15 ml. BzH gave 7.6 g. crude 7-benzylidenesulfamoyl-6-chloro-3,4-dihydro-3-phenyl-1,2,4-benzothiadiazine 1,1-dioxide, m. 241-2¡ã (Me2CO-pentane). 5-Chloro-2,4-disulfamoylaniline (5 g.), 3.78 g. glycidaldehyde, and 50 ml. 20% alc.-HCl heated 5-10 min., then refluxed 20 min. gave 3.17 g. 6-chloro-3-¦Â-hydroxyethyl-7-sulfamoyl-1,2,4-benzothiadiazine 1,1-dioxide (III), m. 320-1¡ã (decomposition) (alc.). 6-Chloro-3-epoxyethyl-3,4-dihydro-7-sulfamoyl-1,2,4-benzothiadiazine 1,1 – dioxide (0.5 g.) heated 15 min. with 20% alc.-HCl gave 0.42 g. III. 5-Chloro-2,4-disulfamoylaniline (10 g.) and 15 g. dihydroxyacetone in 50 ml. 18% alc.-HCl refluxed 6 hrs., cooled, triturated with Et2O, filtered, and recrystallized gave 12 g. III. 5-Chloro-2,4-disulfamoylaniline (2.8 g.), 1 g. glyceraldehyde, 18 ml. alc., and 12 ml. 30% alc.-HCl refluxed 15 min. gave 1.6 g. III. 5-Chloro-2,4-disulfamoylaniline (4.5 g.), 9 g. phenylglyoxal diethyl acetal, and 70 ml. 8% alc.-HCl heated 2 hrs. gave 2.42 g. 6-chloro-3-(¦Á-hydroxybenzyl) – 7-sulfamoyl-1,2,4-benzothiadiazine 1,1-dioxide, m. 282-3¡ã (decomposition). 2,3-Dichloro-4,6-disulfamoylaniline (10 g.) in 800 ml. 95% alc. refluxed overnight with 23 g. 30% aqueous glyoxal gave 2.95 g. 5,6-dichloro-3-hydroxymethyl-7-sulfamoyl-1,2,4-benzothiadiazine 1,1-dioxide, m. 278-80¡ã (decomposition) (Me2CO). III (5.9 g.) in 250 ml. tetrahydrofuran refluxed 21 hrs. with 5.9 g. NaBH4 gave 1.72 g. 6-chloro-3,4-dihydro-3-¦Â-hydroxyethyl-7-sulfamoyl-1,2,4-benzothiadiazine 1,1-dioxide, m. 234¡ã (decomposition). An analogous procedure was used for the preparation of 5,6-dichloro-3,4-dihydro-3-hydroxymethyl-7-sulfamoyl-1,2,4-benzothiadiazine 1,1-dioxide. 5-Chloro-2,4-disulfamoylaniline (2 g.), 2.8 g. ¦Á-chlorophenylacetaldehyde dimethyl acetal, 100 ml. alc., 40 ml. 23% alc.-HCl, and 3 drops H2O refluxed 1 hr. gave 6-chloro-3-¦Á-chlorobenzyl-3,4-dihydro-7-sulfamoyl-1,2,4-benzothiadiazine 1,1-dioxide (IV), m. 182-4¡ã (decomposition), after drying in vacuo m. 198-205¡ã (decomposition). 5-Chloro-2,4-disulfamoylaniline (2 g.), 3.4 g. ¦Á-bromophenylacetaldehyde dimethyl acetal, 100 ml. alc., 40 ml. 23% alc.-HCl, and 3 drops H2O treated as above gave 1.4 g. IV. The ultraviolet absorption spectra were given for a number of the above compounds
3-Substituted dihydrobenzothiadiazine 1,1-dioxides as diuretic agents. Recommended basis is hydrochlorothiazide 20. Products is: https://www.ambeed.com/products/742-20-1.html, 432499-63-3
Referemce:
Benzoxazole – Wikipedia,
Benzoxazole | C7H5NO – PubChem