Category: 5233-42-1

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 stability-indicating RP-HPLC method has been developed and validated for simultaneous determination of Valsartan & Hydrochlorothiazide and their impurities in FDC (Fixed Dose Combination) tablet dosage form. The method was developed using L1 column (250 ¡Á 4.6 mm; 5 ¦Ìm) with gradient elution using the mobile phase consisting of solvent-A (0.1% Ortho phosphoric acid) and solvent-B (100% Acetonitrile); the gradient program (Tmin/%B) was set as 0/10, 5/10, 20/60, 40/60, 41/10 and 50/10. The eluted compounds were monitored at 265 nm. The developed method was validated as per ICH guidelines with respect to specificity, linearity, limit of detection, limit of quantitation, accuracy, precision and robustness. The influence of Acid, Alk., Oxidative, Photolytic, Thermal and Humidity stress conditions, on drug product was studied. The limit of quantification results of Valsartan, Hydrochlorothiazide and their impurities are, VAL: 0.303 ¦Ìg/mL, HCTZ: 0.019 ¦Ìg/mL, VAL RC-B: 0.085 ¦Ìg/mL, VAL RC-C: 0.327 ¦Ìg/mL, HCT RC-A: 0.017 ¦Ìg/mL, CTZ: 0.080 ¦Ìg/mL and 5-Chloro HCT: 0.047 ¦Ìg/mL. The proposed method is suitable for the estimation of Valsartan & Hydrochlorothiazide impurities in tablets dosage form.

Stability indicating RP-HPLC method for quantification of impurities in valsartan and hydrochlorothiazide FDC tablet dosage form. 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

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.

The mechanism of chlorination and bromination of dihydrochlorothiazides (I) and related compounds in a mixture of H2O and CCl4, as well as bromination in dry HCONMe2, was discussed. Dropwise addition of equimolar Br in CCl4 to 3-chloro-4,6-disulfamoylaniline (II) suspended in H2O gave 97% the 2-bromo derivative (III), m. 284-9¡ã (decomposition). Recrystallization from 1:1 aqueous ethanol gave a product, m. 304¡ã (decomposition). Addition of II to a Br solution in aqueous KBr gave, after 4 hrs., quant. III, m. 287¡ã. III was also prepared in 72% yield with 100% excess Br. Treating I in a similar manner with 1 or 2 moles Br gave 94% the 5-bromo derivative (IV), m. 300¡ã. Neither 6-chloro-7-sulfamoyl-1,2,4-benzothiadiazine 1,1-dioxide, nor 3-oxo-6-chloro-7-sulfamoyl-1,2,4-dihydrobenzothiadiazine 1,1-dioxide could be brominated by this method. Chlorination of II under similar conditions resulted in a pink powder, m. 226¡ã (black foaming melt). This was extracted with Na2SO3 solutions in 1:1 aqueous MeOH to remove 15-20% N-chloro compounds and to give 33% V, m. 285-7¡ã. Similar chlorination of I with 1 mole Cl gave a 1:1 mixture of the 5-Cl derivative (VI) and the 2,5-Cl2 derivative (VII) of I, sintered at 155¡ã and became a red foam at 210-13¡ã, while chlorination with 2 moles Cl gave 98% VII. 154-6¡ã. With equimolar Br and H2O-CCl4 mixtures I (R = Me) gave 87% the 5-bromo derivative, m. 250¡ã. In a similar manner was prepared the 5-bromo deriv, of I (R = Et), m. 255¡ã (decomposition). Bromination under similar conditions of I (R = MeCH:CH), obtained by the action of crotonaldehyde on II, gave a 2: 1 mixture of the mono-brominated product and the starting product. The 3,3-dimethyl-derivative of I gave 80% the 5-bromo derivative, 216-20¡ã (decomposition), but neither the 3,3-pentamethylene derivative (VIIa) nor its p-methyl derivative could be brominated. Since 4-methyldihydrochlorothiazide readily gave 87% the 5-bromo derivative, m. 200¡ã (decomposition), the supposition that the presence of H on N-4 was necessary for the bromination of the benzene ring was ruled out. VIII (R = H) was brominated to a 1:1 mixture of VIII (R = H and R = Br), m. 259-60¡ã (decomposition), whereas IX was easily brominated to 96% 5-bromo-6-amino-7-sulfamoyl-3,3-pentamethylene1,2,4-dihydrobenzothiadiazine 1,1-dioxide, m. 198-200¡ã. Brominations in homogeneous media was effected in dry HCONMe2, with N, N’-dibromo-4,4-dimethylhydantoine (X) as the brominating agent, in order to avoid HBr formation. VIIa was successfully brominated by 0.5 mole at 5¡ã to give 98% the 5-bromo derivative (XI), m. 250-1¡ã (decomposition). The position of the Br atom was established by cleaving XI with boiling N HCl to III in 94% yield and to cyclohexanone, identified as its 2,4-dinitrophenylhydrazone. When VIIa was brominated with equimol. amounts of X, 95% 5,7-dibromo-6-chloro-3,3-pentamethylene-1,2,4-dihydrobenzothiadiazine 1,1-dioxide (XII), m. 173-7¡ã, was isolated. Cleavage of XII with boiling N HCl gave 2,4-dibromo-3-chloro-6-sulfamoylaniline (XIII) in theoretical yield and cyclohexanone. XII was also obtained by similar bromination of VIIa with 1.5 moles X in 10% yield and of XI with 0.5 mole X in 95% yield. Formation of XII was consistently accompanied by formation of strongly acidic compounds III with X gave a mixture of compounds from which XIII and 2,4,6-tribromo-3-chloroaniline were isolated. IV gave excellent yields of 5,7-dibromo-6-chloro-1,2,4- dihydrobenzothiadiazine 1,1-dioxide, m. 242-4¡ã.

Halogenation of dihydrochlorothiazides and related compounds. 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

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 new selective, sensitive and Rapid Reverse phase-UPLC method was developed and validated to determine the known potential impurities present in Telmisartan (TL) and Hydrochlorothiazide (HC) in fixed dose combination drug product. The quantification was carried out by using Acquity UPLC, HSS T3 (100 ¡Á 2.1) mm, 1.8¦Ì column, with a flow rate of 0.5mL/min at 225 nm. The mobile phase consists of 0.1% ortho phosphoric acid pH adjusted to 2.6 with diluted sodium hydroxide as Mobile phase A and acetonitrile as Mobile phase B. Separation of the impurities was achieved within 10.0 min of run time. Typical retention times of TL and HC were found to be about 5.4 and 2.0 min resp. The product was subjected to various degradation conditions and validated in terms of linearity, precision, accuracy, LOD, LOQ and robustness in accordance with ICH guidelines. The known impurities quantified in this study were HC imp-1 to 4 for Hydrochlorothiazide and TL imp-1 to 6 for Telmisartan. Recovery was established for all the impurities with resp. to LOQ to 150%. The data supports that the newly developed method is capable to determine all the potential impurities of TL and HC.

Method development and validation for the determination of potential impurities present in telmisartan and hydrochlorothiazide in fixed dose combination drug product by using reverse phase – ultra performance liquid chromatography coupled with diode-array detector. 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

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.

The following compounds were studied in adult rats: chlorothiazide (K30), 6-chloro-7-sulfamoyl-3,4-dihydro-1,2,4-benzothiadiazine 1,1-dioxide (K32), 6-chloro-7-sulfamoyl-3,4-dihydro-3-trichloromethyl-1,2,4-benzothiadiazine 1,1-dioxide (K33), 6-chloro-7-sulfamoyl-3,4-dihydro-3- methyl-1,2,4-benzothiadiazine 1,1-dioxide (K34), 6-amino-7-sulfamoyl-3,4-dihydro-1,2,4-benzothiadiazine 1,1-dioxide (K35), benzo-1,2,4,9,8,6-dithiadiazine 1,1,9,9-tetroxide (K36), 7-sulfamoyl-3,4-dihydro-1,2,4-benzothiadiazine 1,1-dioxide (K37), 5,6-dichloro-7-sulfamoyl-3,4-dihydro-1,2,4-benzothiadiazine 1,1-dioxide (K38), and 7-sulfamoyl-3-trichloromethyl-3,4-dihydro-1,2,4-benzothiadiazine 1,1-dioxide (K39). K37 and K38 with only a H at C-6 had a weak diuretic action at a dose of 4 mg./kg. A dose of 2 mg. of K30/kg. produced a larger output of Cl than 4 mg./kg. K36 was ineffective over the dose range of 0.54 mg./kg. Cl excretion showed a marked decline with K36. The dihydrochlorothiazide compounds proved to be more potent than K30. With respect to their effect on water diuresis, the order of potency was as follows: K38 > K32 > K34 > K33 > K30; for Cl excretion it was K32 > K34 > K38 > K33 > K30. K38 was most effective for water diuresis while K32 and K34 would be the compounds of choice for increasing the Cl output. The activity of some of these compounds was compared with that of urea. Albuminuria, feebleness, and anorexia were observed in animals given 2-3 g. of K30/kg. All of the test animals survived.

The diuretic action of dihydrochlorothiazide derivatives. 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

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 recent study shows that propranolol hydrochloride (PRO) related substances may also reduce the stability of tablets in storage. Therefore, it is necessary to control the level of PRO related substances in tablets. However, the anal. in U.S. pharmacopoeia could not detect PRO related substances. To overcome this, we developed a new method which can detect PRO, hydrochlorothiazide (HCT) and all of their impurities. In this study, validation studies were also performed, linear relationship with a good correlation coefficient (r2)>0.990 was found of both PRO impurities and HCT impurities in the range of 0.12-0.60, and 0.15-0.75 ¦Ìg/mL resp. Acceptable intra- and inter-assay precisions were achieved. Accuracy and robustness were reported as percent recovery, and all the recoveries were at the range of 70-130%. After validation, the methods were successfully used in the routine quality control of the tablets.

Development and validation of HPLC methods for the determination of propranolol hydrochloride and hydrochlorothiazide related substances in combination tablets. 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

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.

Ring closure of aniline-2,4-disulfonamides with acylating agents, aldehydes, or CO(NH2)2 to give sulfamoylbenzothiadiazine 1,1-dioxide derivatives was described. Sulfamoylbenzothiadiazine 1,1-dioxides promoted excretion of NaCl in animals and man and constituted a novel class of orally effective diuretic agents. Several aspects of the chemistry of this class of compounds were reported in detail. The following procedure was illustrative of the HCO2H ring closure of aniline-2,4-disulfonamides to benzothiadiazine 1,1-dioxides. The yield was typical. 5-Chloro-2,4-disulfamoylaniline (5.7 g.) in 75 ml. 98-100% HCO2H refluxed 24 hrs., the mixture cooled, 100 ml. H2O added, the product collected, washed, and recrystallized gave 6-chloro-7-sulfamoyl-l,2,4-benzothiadiazine 1,1-dioxide (Ia) in 90% yield. 5-Amino-2,4-disulfamoylaniline (1.3 g.) in 20 ml. 98-100% HCO2H refluxed 2.5 hrs. and cooled gave 1.14 g. benzo[1,2-e,5,4-e’]bis-l,2,4-thiadiazine 1,1-dioxide, m. above 500¡ã (HCONMe2). 2-Methylsulfamoylaniline (2 g.) and 5 ml. Et orthoformate heated 0.5 hr. at 125-35¡ã in an open flask, concentrated to dryness in vacuo, and the residue recrystallized gave 1.6 g. 2-methyl-l,2,4-benzothiadiazine 1,1-dioxide (I), needles. Recrystallization of I from 50% hot aqueous alc. gave 2-(N-formyl-N-methylsulfamoyl)aniline, m. 116-18¡ã. Ring closure of 5-chloro-2,4-bis(methylsulfamoyl)aniline was similarly carried out to give 6-chloro-2-methyl-7-methylsulfamoyl-1,2,4-benzothiadiazine 1,1-dioxide; recrystallization from hot aqueous alc. gave 5-chloro-2,4-bis(methylsulfamoyl)-N-formylaniline, plates, m. 192-5¡ã. Ia (15 g.) in 100 ml. Et orthoformate (II) refluxed 24 hrs. and cooled gave 15.4 g. 6-chloro-7-ethoxymethylenesulfamoyl-1,2,4-benzothiadiazine 1,1-dioxide (III), m. 195-6¡ã, resolidified and m. 210-11¡ã (MeCN-Et2O). 6-Chloro-2-methyl-7-sulfamoyl-1,2,4-benzothiadiazine 1,1-dioxide (IV) and II gave 6-chloro-7-ethoxymethylenesulfamoyl-2-methyl-l,2,4-benzothiadiazine 1,1-dioxide, m. 155-7¡ã. Similarly, 6-chloro-7-sulfamoyl-3,4-dihydro-1,2,4-benzothiadiazine 1,1-dioxide and II gave 6-chloro-7-ethoxymethylenesulfamoyl-3,4-dihydro-1,2,4-benzothiadiazine 1,1-dioxide, m. 22-30¡ã (effervescence). NH3 passed into 6.5 g. III in 50 ml. anhydrous alc. 0.5 hr. gave 3.6 g. 7-aminomethylenesulfamoyl-6-chloro-1,2,4-benzothiadiazine 1,1-dioxide, m. 309-11¡ã (alc.). IV similarly treated with NH3 gave 7-aminomethylenesulfamoyl-6-chloro-2-methyl-l,2,4-benzothiadiazine 1,1-dioxide, m. 233-4¡ã. 5-Chloroacetanilide-2,4-disulfonyl chloride (4.4 g.) added por-tionwise to 50 ml. 10% alc.-NH3, the solution evaporated to dryness, and the residue recrystallized from aqueous alc. gave 6-chloro-3-methyl-7-sulfamoyl-1,2,4-benzothiadiazine 1,1-dioxide. Similarly, with concentrated NH4OH 6-chloro-3-propyl-7-sulfamoyl-1,2,4-benzothiadiazine 1,1-dioxide and 3-amyl-6-chloro-7-sulfamoyl-1,2,4-benzothiadiazine 1,1-dioxide were prepared from the corresponding N-acylanilinedisulfonyl chlorides. 5-Chloro-2,4-disulfamoyl-N-(chloroacetyl)aniline (7.2 g.) in 30 ml. HCONMe2 heated 1.5 hrs. with 2.3 g. anhydrous KF, cooled, and diluted with H2O gave 5.5 g. 3-chloromethyl-6-chloro-7-sulfamoyl-1,2,4-benzothiadiazine 1,1-dioxide. Method (A). 5-Chloroaniline-2,4-disulfonyl chloride (7.2 g.) in 13 ml. BzCl left overnight at room temperature gave 10.9 g. 5-chloro-N-benzoylaniline-2,4-disulfonyl chloride, which washed and heated 2 hrs. on the steam bath with C6H6 and 50 ml. concentrated NH4OH gave 2.7 g. 6-chloro-3-phenyl-7-sulfamoyl-1,2,4-benzothiadiazine 1,1-dioxide (V), needles. Acidification of the ammoniacal filtrate gave 5-chloro-2,4-disulfamoyl-N-benzoylaniline (VI). Method (B). VI (1 g.) in 25 ml. concentrated NH4OH left 48 hrs. at room temperature gave 84% V. In like manner, ring closure of 5-chloro-2,4-disulfamoyl-N-(p-chlorobenzoyl)aniline gave 85% 3-(p-chlorophenyl)-6-chloro-7-sulfamoyl-l,2,4-benzothiadiazine 1,1-dioxide. 5-Chloro-2,4-disulfamoyl-N-(o-chlorobenzoyl)aniline similarly afforded 56% 3-(o-chlorophenyl)-6-chloro-7-sulfamoyl-1,2,4-benzothiadiazine 1,1-dioxide. The following substituted 1,2,4-benzothiadiazine 1,1-dioxides were obtained (substituents at 2, 3, 5, 6, and 7, recrystallization solvent, and m.p. given): H, H, H, H, SO2NH2, alc.-H2O, 319-20¡ã; H, H, H, F, SO2NH2, alc.-H2O, 304-5¡ã; H, H, H, Cl, SO2NH2, alc.-H2O, 342.5-3.0¡ã; H, H, H, Br, SO2NH2, HCONMe2-H2O, 347-9¡ã; H, H, H, CF3, SO2NH2, alc.-hexane, 294-5¡ã; H, H, H, Me, SO2NH2, AcOH-H2O, 344-5¡ã; H, H, H, OMe, SO2NH2, alc.-H2O, 305-7¡ã; H, H, H, NO2, SO2NH2, alc.-H2O, 338-9¡ã; H, H, H, NH2, SO2NH2, alc.-H2O, 323-4¡ã; Me, H, H, Cl, SO2NH2, HCONMe2-Et2O, 217-20¡ã; H, Me, H, Cl, SO2NH2, alc., 332¡ã; H, Pr, H, Cl, SO2NH2, alc.-H2O, 305-7¡ã; H, C5H11, H, Cl, SO2NH2, alc.-H2O, 269-70¡ã; H, ClCH2, H, Cl, SO2NH2, alc.-H2O, 323-6¡ã; H, Ph, H, Cl, SO2NH2, HCONMe2-H2O, above 350¡ã; H, o-ClC6H4, H, Cl, SO2NH2, alc.-H2O, above 350¡ã, H, p-ClC6H4, H, Cl, SO2NH2, alc.-H2O, above 350¡ã; H, H, Cl, H, SO2NH2, alc.-H2O, 276.5-7.5¡ã; H, H, Cl, Cl, SO2NH2, alc.-H2O, 355-6¡ã; H, H, I, Cl, SO2NH2, HCONMe2H2O, 276-7¡ã; Me, H, H, Cl, SO2NHMe, alc., 219-21¡ã; p-ClC6H4, H, H, Cl, SO2NHC6H4Cl-p, MeCN, 247-9¡ã; H, H, H, Cl, SO2NMe2, alc.-H2O, 265-7¡ã; H, H, SO2NH2, H, H, Me2CO-C6H6, 249-50¡ã; H, H, SO2NH2, H, Br, Me2CO, 291-2¡ã; H, H, SO2NH2, H, SO2NH2, alc.-H2O, 316-18¡ã; H, H, H, SO2NH2, H, alc.-H2O, 309-12¡ã; H, H, H, SO2NH2, Cl, Me2CO-ligroine, 327-30¡ã; H, H, H, Cl, H, butanone, 253-4¡ã; H, H, H, Cl, Cl, Me2CO-ligroine, 293-4¡ã; H, H, H, Cl, Me, alc.-H2O, 287-8¡ã; H, H, H, Me, Cl, MeCN, 260-1¡ã; H, H, H, Cl, MeSO2, alc.-H2O, 329-31¡ã; Me, H, H, H, H, alc., 95-7¡ã. The general procedure for the preparation of 3,4-dihydro-1,2,4-benzothiadiazine 1,1-dioxides. Method (A). The orthanilamide compound (0.02 mole) and 0.025 mole of 37% HCHO in 50 ml. 90% alc.-H2O containing 300 mg. NaOH heated 2 hrs. on the steam bath, acidified, and the mixture cooled gave 80% yield. Method (B): acid catalyzed ring closure. The orthanilamide compound (0.02 mole) and 0.04 mole paraformaldehyde in 60 ml. alc. and 60 ml. 6N HCl heated and after 1 hr. the product isolated gave an average yield of 85-90%. The following substituted 3,4-dihydro-7-sulfamoyl-1,2,4-benzothiadiazine 1,1-dioxides were thus obtained (substituents at 5 and 6 and m.p. given): H, H, 216-17¡ã; H, Cl, 262-3¡ã; H, Br, 287-8¡ã; H, CF3, 263-4¡ã; H, Me, 253-4¡ã; H, NO2, 263.5-4.5¡ã; Cl, Cl, 288-9¡ã. Likewise the following 6-chloro-substituted 3,4-dihydro-1,2,4-benzothiadiazine 1,1-dioxides were obtained (substituents at 2, 4, and 7, m.p., and recrystallization solvent given): H, H, H, 164-6¡ã, PhMe; H, Me, SO2NH2, 249-50¡ã, alc.-H2O; Me, H, SO2NH2, 239-41¡ã, alc.-H2O; Me, H, SO2NHMe, 195-7¡ã, alc.; H, H, SO2NMe2, 202-4¡ã, alc.-H2O; H, H, MeSO2, 248-9¡ã, alc.-H2O. The following 6-chloro-7-sulfamoyl-3,4-dihydro-2-substituted-1,2,4-benzothiadiazine 1,1-dioxides were obtained by ring closure of 5-chloro-2,4-disulfamoylaniline with the appropriate aldehyde. Acid cyclization was used for compounds number 1, 2, and 9, and base cyclization for the remainder (compound number, 2-substituent, m.p., and recrystallization solvent given): 1, Me, 252-3¡ã, AcOH-H2O; 2, Et, 265¡ã, AcOH-H2O; 3, CCl3, 287¡ã, ethylene glycol monomethyl ether-H2O; 4, CH2OH, 225-6¡ã, Me2CO-H2O; 5, oxiranyl, 233-5¡ã, Me2CO-H2O; 6, (CH2)5, 259-60¡ã, HCONMe2-H2O; 7, PhCH2, 260-2¡ã, AcOH-H2O; 8, p-ClC6H4, 250-1¡ã, AcOH-H2O; 9, p-O2NC6H4, 268-9¡ã, Me2CO-Et2O; 10, 2-pyridyl, 260¡ã, MeCN; 11, 5-nitro-2-furyl, 239-40¡ã, Me2CO-Et2O. 5-Chloro-2,4-disulfamoylaniline (11.4 g.) in 20 ml. HCONMe2 and 17.6 g. CCl3CHO heated 24 hrs. on the steam bath, 100 ml. H2O added, and the solid reprecipitated from dilute NH4OH gave 14.5 g. 6-chloro-7-sulfamoyl-3-trichloromethyl-3,4-dihydro-1,2,4-benzothiadiazine 1,1-dioxide. When the reaction was carried out in 60 ml. HCONMe2 in the presence of 4.6 g. anhydrous KF 3 hrs. on the steam bath, 76% 6-chloro-7-sulfamoyl-1,2,4-benzothiadiazine 1,1-dioxide, m. 330¡ã, was isolated, ¦Ë 225 and 279-80 m¦Ì, ¦Å 29,592 and 11,465. 5-Chloro-2,4-disulfamoylaniline (5.7 g.) and 5.9 g. cyclohexanone in 30 ml. HCONMe2 heated 2 hrs. with 2.3 g. anhydrous KF gave 7 g. 6-chloro-7-sulfamoyl-3,3-pentamethylene-3,4-dihydro-1,2,4-benzothiadiazine 1,1-dioxide. The following was illustrative of the method used for preparation of 3,4-dihydro-1,2,4-benzothiadiazine 1,1-dioxides. Compounds were recrystallized from aqueous alc. in yields of 35-73%. 5-Chloro-2,4-disulfamoylaniline (8.4 g.) and 3.5 g. CO(NH2)2 was heated 45-60 min. at 200¡ã (NH3 evolved), the solid cooled, dissolved in H2O, filtered, acidified, and recrystallized from aqueous alc. The following compounds were thus obtained (substituents at 4, 5, 6, 7, and m.p. given): H, H, Cl, SO2NH2, 313¡ã; H, Cl, H, SO2NH2, 314-15¡ã; H, H, SO2NH2, Cl, 323-4¡ã; H, H, Br, SO2NH2, 323-4¡ã; H, H, Me, SO2NH2, 307-8¡ã; H, H, MeO, SO2NH2, 291-3¡ã; H, H, NO2, SO2NH2, above 350¡ã; Me, H, Cl, SO2NH2, 315¡ã. Ia (5.9 g.) in 25 ml. H2O containing 0.88 g. NaOH shaken 10 min. with 3 g. Me2SO4 at room temperature, the precipitate collected, washed, dried, and crystallized gave 2.8 g. 6-chloro-4-methyl-7-sulfamoyl-1,2,4-benzothiadiazine 1,1-dioxide (VII), m. 325-6¡ã (Me2CO-alc.). VII heated 2.5 hrs. with 10% NaOH gave 5-chloro-2,4-disulfamoyl-N-methylaniline (VIII). Method (B). VIII (5 g.) in 70 ml. 98-100% HCO2H refluxed 24 hrs. and cooled to room temperature gave 4.7 g. VII. Ia (32.2 g.) added portionwise to 2.5 g. Na in 200 ml. alc., 16.3 g. CH2:CHCH2Br added, the solution warmed 24 hrs. with intermittent addition of 4 g. CH2:CHCH2Br after 6 hrs., and cooled gave 27.2 g. solids. Repeated extraction of this solid with Me2CO at room temperature gave 11.9 g. unchanged Ia and 12.5 g. 4-allyl-6-chloro-7-sulfamoyl-1,2,4-benzothiadiazine 1,1-dioxide (IX), m. 243-5¡ã (aqueous alc.). IX (1 g.) in 20 ml. 10% NaOH heated 2 hrs. gave 0.5 g. 5-chloro-2,4-disulfamoyl-N-allylaniline (IXa), m. 181-3¡ã (H2O). IX (1 g.) in 70 ml. H2O and 9 ml. N NaOH left 0.5 hr. at room temperature, cooled, acidified, and the precipitate collected gave 0.4 g. 5-chloro-2-formylsulfamoyl-4-sulfamoyl-N-allylaniline (X), needles, m. 142.5-3.5¡ã (CHCl3-Me2CO). Recrystallization of X from H2O gave IXa. 3,4-Dimethyl-1,2,4-benzothiadiazine 1,1-dioxide (11.4 g.) in 35 ml. ClSO3H heated 2.5 hrs. at 150-60¡ã, poured onto ice, the solid added to 50 ml. concentrated NH4OH, after 30-60 min. the product collected, and recrystallized gave 3,4-dimethyl-7-sulfamoyl-1,2,4-benzothiadiazine 1,1-dioxide, m. 258-60¡ã (HCONMe2-alc.). Reprecipitation of a sample from dilute NaOH gave 2-acetylsulfamoyl-4-sulfamoyl-N-methylaniline, m. 208-10¡ã (Me2CO-ligroine). Ac2O (25 ml.) left overnight at room temperature with 8.9 g. Ia in 75 ml. C5H5N, the product collected, and dried gave 7.7 g. 7-acetylsulfamoyl-6-chloro-1,2,4-benzothiadiazine 1,1-dioxide (XI), m. 299¡ã (rapid heating), pK’a 3.7, 7.2. XI (2 g.) in 10 ml. 10% NaOH heated 15 min., cooled, and acidified gave 4-acetylsulfamoyl-5-chloro-2-sulfamoylaniline (XII), plates, m. 221¡ã (Me2CO-alc.). Cyclization of XII with HCO2H gave 7-acetylsulfamoyl-6-chloro-1,2,4-benzothiadiazine 1,1-dioxide. Butyric anhydride (25 ml.) left at room temperature overnight with 8.9 g. Ia in 75 ml. C5H5N, poured into ice H2O, and acidified gave 8.1 g. 7-butyrylsulfamoyl-6-chloro-1,2,4-benzothiadiazine 1,1-dioxide, m. 286¡ã (alc.-H2O). Ia (10 g.) left 2 hrs. at room temperature with 50 ml. NHMe2, dissolved in 50 ml. 50% aqueous alc., and acidified gave 5.8 g. 5-chloro-2-dimethylaminomethylenesulfamoyl-4-sulfamoylaniline, m. 208-10¡ã (alc.-H2O). Ia (10 g.) and 13.6 g. piperidine heated 1 hr. on the steam bath, diluted with H2O, and acidified gave 3.8 g. 5-chloro-2-piperidinomethylenesulfamoyl-4-sulfamoylaniline, m. 210-12¡ã (aqueous alc.). Ia (29.6 g.) added portionwise to 150 ml. ClSO3H, the mixture heated 2 hrs. on the steam bath, cooled, poured onto crushed ice, and the solid collected gave 30.3 g. 6-chloro-1,2,4-benzothiadiazine-7-sulfonyl chloride 1,1-dioxide (XIIa), m. 259-61¡ã (Me2CO-hexane). 6-Chloro-2-methyl-7-methylsulfamoyl-1,2,4-benzothiadiazine 1,1-dioxide (68.3 g.) added portionwise to 200 ml. ClSO3H, the mixture heated 5 hrs., cooled, poured onto ice, and collected gave 60 g. 5-chloro-2-methylsulfamoylaniline-4-sulfonyl chloride (XIII), m. 158¡ã (effervescence) (Me2CO-C6H6). XIII (43.2 g.) added portionwise to 250 ml. concentrated NH4OH, the mixture heated 1 hr., concentrated, and the solid recrystallized gave 17.9 g. 5-chloro-2-methylsulfamoyl-4-sulfamoylaniline as 2 crystal modifications, m. 168-70¡ã and 188-90¡ã. XIIa (10 g.) added to 30 ml. MeNH2 and left at room temperature gave a residue, which dissolved in 200 ml. 5% NaOH, heated 2 hrs., and acidified gave 6.4 g. 5-chloro-4-methylsulfamoyl-2-sulfamoylaniline, m. 182-3¡ã (H2O). XIIa (30 g.) left at room temperature with 150 ml. anhydrous NHMe2 gave 22.8 g. 5-chloro-2-dimethylaminomethylenesulfamoyl-4-dimethylsulfamoylaniline (XIV), m. 195-7¡ã (alc.). XIV (6.7 g.) in 20 ml. 10% NaOH heated 1 hr. and acidified gave 4.0 g. 5-chloro-4-dimethylsulfamoyl-2-sulfamoylaniline, m. 158-60¡ã (aqueous alc.). Ia (3 g.) in 100 ml. MeOH reduced at room temperature and 39 lb./sq. in. initial H pressure over 1 g. 5% ruthenium-C, after 10 hrs. the mixture heated, filtered, and concentrated gave 83% 6-chloro-7-sulfamoyl-3,4-dihydro-1,2,4-benzothiadiazine 1,1-dioxide (XV). KMnO4 (3.75 g.) added portionwise to 8.9 g. XV in 150 ml. H2O and 10 ml. 20% NaOH, the solution stirred 15 min. at room temperature, warmed 5 min. on the steam bath, excess KMnO4 destroyed with 2-3 ml. alc., and the solution acidified gave 7.4 g. 6-chloro-7-sulfamoyl-1,2,4-benzothiadiazine. Similar oxidation of 6-methyl-7-sulfamoyl-3,4-dihydro-1,2,4-benzothiadiazine 1,1-dioxide gave a comparable yield of 6-methyl-7-sulfamoyl-1,2,4-benzothiadiazine 1,1-dioxide, m. 345¡ã. 5-Chloro-2,4-bis(dimethylsulfamoyl)aniline (XVI) (3.4 g.) and 10 g. 50% PhCH2CHO in alc. heated 0.5 hr. at 150¡ã, the mixture cooled, and the solid triturated with MeCN gave 2.4 g. 5-chloro-2,4-bis(dimethylsulfamoyl)-N-(2-phenylethylidene)aniline, m. 203-5¡ã (MeCN), ¦Ë 226-8 and 337-40 m¦Ì, ¦Å 27,351 and 36,106. XVI (3.4 g.), 3 g. p-O2NC6H4CHO, and 60 ml. PhMe refluxed 20 hrs., cooled, and the solid triturated with 200 ml. refluxing alc. gave 3.6 g. 5-chloro-2,4-bis(dimethylsulfamoyl)-N-(p-nitrobenzylidene)aniline, m. 221-3¡ã (MeCN), ¦Ë 276-281 m¦Ì, ¦Å 25,270. The ultraviolet absorption spectra were given for a number of 1,2,4-benzothiadiazine 1,1-dioxides and 5-chloro-2,4-disulfamoylanilines.

Diuretics: 1,2,4-benzothiadiazine 1,1-dioxides. 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

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.

2,3-Cl2C6H3NH2 (20 g.) added dropwise to 120 cc. ClSO3H, the mixture heated 48 hrs. at 110¡ã, cooled, poured onto ice, filtered, the residue added in small portions to liquid NH3, the NH3 evaporated, the residue dissolved twice in hot dilute NH4OH, and reprecipitated with AcOH gave 10.8 g. 6,5,4,1,3-Cl2(H2N)C6H(SO2NH2)2, m. 293-4¡ã. 2,5-Cl2C6H3NH2 (I) (10 g.) in 60 cc. ClSO3H heated 4 hrs. at 125¡ã, hydrolyzed, and treated in the usual manner with NH3 yielded 7.8 g. 5,2,4,1,3-Cl2(H2N)C6H(SO2NH2)2, needles, m. 258-9¡ã (EtOH). A similar run at 170¡ã during 0.5 hr. gave the monosulfonamide (II) of I, which refluxed 2 hrs. in ClSO3H, hydrolyzed, and treated with NH3 did not give a pure product. II (5.8 g.), 1.0 g. 5% Pd-C, 20 cc. 5N NaOH, and 100 cc. H2O hydrogenated 15 min. at 2 atm., filtered, and acidified gave 12.5 g. 4,6,2-Cl2(H2N)C6H2SO2NH2 (III), needles, m. 162-2¡ã (H2O). III refluxed 4 hrs. in ClSO3H and treated with NH3 gave a small amount of a mixture of III and the desired disulfonamide. III (5.7 g.) dehalogenated catalytically in the usual manner yielded 2.35 g. o-H2NC6H4SO2NH2, m. 153-4.5¡ã. 3,4-Cl2C6H3NH2 (10 g.) in 60 cc. ClSO3H heated 4 hrs. at 125¡ã, hydrolyzed, and treated with NH3 in the usual manner gave 5.5 g. 4,5,2-Cl2(H2N)C6H2SO2NH2, m. 175.5-6.5¡ã (aqueous Me2CO). 4,2-Cl(O2N)C6H3SO2NH2 (19 g.) in EtOH hydrogenated at low pressure over Pd-C gave 12.2 g. 4,2-Cl(H2N)C6H3SO2NH2, m. 144-6¡ã. The appropriate sulfonamide in 98% HCO2H refluxed 2 hrs., poured into H2O, and filtered gave 73-94% of the corresponding 1,2,4-benzothiadiazine 1,1-dioxide (IV); in this manner were prepared the following compounds (m.p. given): IV, 221-2¡ã (iso-PrOH); 5,6-dichloro-7-sulfamoyl derivative (V) of I, 314-15¡ã; 6,8-di-Cl derivative (VI) of I, 309-10¡ã; 6,7,-di-Cl derivative (VII) of I, 310-11¡ã (iso-PrOH); 6-Cl derivative (VIII) of I, 255-6¡ã. The appropriate sulfonamide in H2O, Me2CO, or aqueous Me2CO containing formalin refluxed 2 hrs., cooled (when Me2CO was used, diluted with H2O), and filtered gave 83-97% of the corresponding 3,4-dihydro-1,2,4-benzothiadiazine 1,1-dioxide; in this manner were prepared the 3,4-dihydro derivatives of the following compounds (m.p. given): V, 302-3¡ã; VI, 249-50¡ã; VII, 207-9¡ã; IV, 171-2¡ã (H2O or iso-PrOH); VIII, 172-3¡ã. V was slightly more potent than chlorothiazide (IX). Dihydro derivative of V was more active as a diuretic than IX, but not as active as dihydro derivative of IX.

Synthesis of potential diuretic agents. II. Dichloro derivatives of 1,2,4-benzothiadiazine 1,1-dioxide. 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

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.

cf. ibid. 25,229(1962). On the basis of testing 15 sulfonamide derivatives for diuretic action in rats, 6 compounds [4 highly active: hydrochlorothiazide(HCT), 5-chlorohydrochlorothiazide(HCT-55), benzthiazide(CT-S), and 3-diethylaminomethylhydrochlorothiazide(HCT-16); one moderately active: chlorothiazide(CT); and one inactive: 3-(3,4-dimethoxy-2-ethoxycarbonylphenyl)hydrochlorothiazide(HCT-18)] were chosen for comparative study on physiol. disposition in rats. A modification of the method of Baer, et al. (CA 53, 11639f) was used for the determination of these compounds in biol. materials. After an oral dose of 20 mg./kg., the rate of disappearance of the various compounds from the gastrointestinal tract was found to follow the decreasing order of HCT-55, CT-S, HCT-16, HCT, CT, and HCT-18. This order roughly parallels their oil-water partition coefficients with the exception of HCT-18, which was found to have the highest partition coefficient, although absorbed rather slowly. CT was demonstrated to have the lowest partition coefficient, which may explain its relatively slow rate of absorption from gastrointestinal epithelium. In addition, its low pKa value (the pKa1 of CT was found to be 6.7, while those of all other compounds investigated were between 9.0-9.2) may also affect its rate of absorption. For all compounds given orally, the highest concentrations were found in the kidneys, though three patterns of tissue distribution were observed. CT, HCT, and HCT-55 were all characterized by a specific affinity for the kidney tissue and very low levels in other organs; DSA was distributed rather nonspecifically in various tissues; while for CT-S and HCT-16, equally high levels were found both in the kidneys and in the liver. When given orally, the rate of excretion of the compounds in the urine was found to be essentially parallel to the rapidity of disappearance from the gastrointestinal tract, i.e., HCT-55 > CT-S > HCT > HCT-16 > CT. After intravenous injection, nearly all of the administered dose of CT-S and HCT was found in the first five-hr. urine. The percentages of urinary excretion of HCT-55, HCT-16, CT, DSA, and HCT-18 were 92, 84, 79, 58, and 29%, resp. The possible relation between the characteristics of the renal transport of these compounds and their diuretic potencies are discussed in some detail.

Oral diuretics. III. Characteristics of the dispositions of some sulfonamide diuretics and their relations to diuretic actions. 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

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.

The present work describes a simple, sensitive, and highly specific reverse phase high performance liquid chromatog. method for the simultaneous determination of impurities of lisinopril and hydrochlorothiazide from their combined dosage form. Symmetry C18 column and a mobile phase comprising of 1-hexanesulfonic acid sodium salt, triethylamine, H3PO4, acetonitrile, and methanol was used for this method. The validation showed that the method has acceptable specificity, recovery, linearity, solution stability, and precision. This method remains unaffected by small but deliberate variations, which are described in ICH guidelines.

Simultaneous determination of lisinopril and hydrochlorothiazide related impurities in lisinopril and hydrochlorothiazide combined tablet dosage forms using HPLC. 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

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.

Abstract: A novel, simple, robust and rapid reversed-phased high performance liquid chromatog. method has been developed for the separation and quant. determination of the 15 organic impurities of olmesartan medoxomil, amlodipine and hydrochlorothiazide in combined dosage forms. Successful separation of five impurities of olmesartan medoxomil, six impurities of amlodipine and four impurities of hydrochlorothiazide, and degradation products formed under stress conditions, was achieved on Inertsil ODS-3 (100 ¡Á 4.6 mm, 3.0¦Ìm) column, using gradient elution. The mobile phase A contains 0.0 2 M phosphate buffer (pH 3.3) and acetonitrile in a ratio of (95:05, volume/volume%) and mobile phase B contains 0.02 M phosphate buffer (pH 3.3), acetonitrile and methanol in a ratio of (20:60:20, volume/volume/v%). Flow rate monitored at 1.8 mL min-1, and UV detection carried out at 237 nm. During forced degradation studies, the effect of acid, base, oxidation, UV light and temperature was investigated, showing good resolution between the peaks corresponding to process and degradation-related impurities. The performance of the method was validated according to the present ICH guidelines for specificity, linearity, accuracy, precision, ruggedness and robustness. To the best of our knowledge, this is the first research paper which presents a simple and rapid HPLC method, which separates all impurities of olmesartan medoxomil, amlodipine and hydrochlorothiazide in combined dosage forms.

Stability indicating RP-HPLC method development and validation for simultaneous quantification of 15 organic impurities of olmesartan medoxomil, amlodipine and hydrochlorothiazide in combined dosage form. 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