Method for synthesizing 3, 4-dihydrobenzothiadiazine medicine through rare earth catalysis

Abstract

The invention provides a method for catalytically synthesizing a 3, 4-dihydrobenzothiadiazine medicine by using rare earth. According to the method, trifluoromethanesulfonic acid rare earth salt is taken as a catalyst, 4-amino-6-chlorobenzene-1, 3-disulfonamide, 4-amino-6-trifluoromethylbenzene-1, 3-disulfonamide and corresponding aldehyde are taken as raw materials, and seven 3, 4-difluorobenzene-1, 3-disulfonamide compounds are simply and conveniently prepared through one-step reaction. The compound is prepared from 2, 4-dihydrobenzothiadiazine medicines: cyclothiazide, buthiazide, cyclopenthiazide, hydrochlorothiazide, bendrofluthiazide, penfluthiazide and ethyl thiazide. The medicine has the effects of inducing diuresis, reducing blood pressure, resisting anxiety, resisting depression, treating edema and the like clinically. The synthesis method provided by the invention has the advantages of mild reaction conditions, simple operation, simple steps and high synthesis efficiency, has industrial application prospects, and plays a positive role in the fields of medicines, fine chemical engineering and the like.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing seven 3,4-dihydrobenzothiadiazine drugs in one step by using 4-amino-6-chlorobenzene-1,3-disulfonamide, 4-amino-6-trifluoromethylbenzene-1,3-disulfonamide and aldehyde as raw materials through a rare earth metal catalysis strategy. Background Art

[0002] 3,4-Dihydrobenzothiadiazine drugs play an important role in clinical treatment. Common drugs include: Cyclothiazide (English name Cyclothiazide, CAS registration number 2259-96-3, with diuretic, antihypertensive, anxiolytic, antidepressant and other effects), Thiabutazide (English name Thiabutazide, CAS registration number 2043-38-1, with diuretic, antihypertensive and other effects), Cyclopenthiazide (English name Cyclopenthiazide, CAS registration number 742-20-1, with diuretic, antihypertensive, treatment of edema and other effects), Hydrochlorothiazide (CAS registration number 58-93-5, with diuretic, antihypertensive and other effects), Bendroflumethiazide (CAS registration number 73-48-3, with diuretic, antihypertensive and other effects), Penflutizide (English name Penflutizide, CAS registration number 1766-91-2, used for the treatment of edema), Ethiazide (English name Ethiazide, CAS registration number 1824-58-4, with diuretic, antihypertensive and other effects).

[0003] As shown in Reaction Scheme 1, Jiang Dongfang et al. synthesized Cyclothiazide, Thiabutazide and Cyclopenthiazide by a palladium-catalyzed method, and the yields were 61%, 72% and 74% respectively. However, the reaction used precious metal palladium as a catalyst, resulting in a high cost (Qi, Z.; Wen, S.; Hao, L.; Liu, S.; Jiang, D., Org. Lett. 2023, 25, 7322-7326).

[0004]

[0005] As shown in Reaction 2, Whitehead et al. used 4-amino-6-chlorobenzene-1,3-disulfonamide and aldehyde as raw materials, and ethanol and 6 mol / L hydrochloric acid as solvents (volume ratio 1:1) to prepare cyclothiazide (46%) and cyclopenthiazide (71%). A large amount of hydrochloric acid was used in the reaction, which was prone to corrode equipment in industrial production, and the product purification process was complex and cumbersome (Whitehead, C.W.; Traverso, J.J.; Sullivan, H.R.; Marshall, F.J., Diuretics.V., J. Org. Chem. 1961, 26, 2814-2818).

[0006]

[0007] As shown in Reaction 3, Kobayashi et al. used ytterbium 3+ exchanged montmorillonite as a catalyst to achieve the synthesis of hydrochlorothiazide and ethiazide, and the reported yields were both greater than 99%. However, the catalyst used was not commercially available, and the preparation process was complex (Kitanosono, T.; Cho, S.M.; Kobayashi, S., Tetrahedron 2018, 74, 7237-7241).

[0008]

[0009] As shown in Reaction 4, List et al. used chiral phosphoric acid as a catalyst to asymmetrically synthesize (R)-bunazosin, (R)-cyclopenthiazide, (R)-bendroflumethiazide, and (R)-penflutizide, with yields of 72-81%. However, the drugs of this type used clinically are racemates, not optical isomers. Moreover, this method uses a chiral phosphoric acid (BINOL-PA) catalyst with extremely high prices, and the reaction time is as long as one week, greatly reducing the application value of this method (Cheng, X.; Vellalath, S.; Goddard, R.; List, B., J. Am. Chem. Soc. 2008, 130, 15786-15787).

[0010]

[0011] As shown in Reaction 5, Chinnusamy reported the synthesis of bendroflumethiazide catalyzed by the TEMPO (2,2,6,6-tetramethylpiperidin-1-oxyl) / NaOCl system with a yield of 98%. In this method, a variety of additives need to be added to the reaction, which results in high costs, cumbersome operations, long reaction times, and is not conducive to industrial production (Chandrasekaran, R.; Carlose, E.; Muthu, A. E.; Suresh, A.; Chinnusamy, T., ChemistrySelect. 2020, 5, 6285 - 6293).

[0012]

[0013] The present invention aims to provide a simple, efficient, mild, and environmentally friendly method for synthesizing 3,4-dihydrobenzothiadiazine antihypertensive and diuretic drugs. Summary of the Invention

[0014] As shown in Reaction 6, the present invention uses 4-amino-6-chlorobenzene-1,3-disulfonamide shown in Formula 1a, 4-amino-6-trifluoromethylbenzene-1,3-disulfonamide shown in Formula 1b, and the aldehyde shown in Formula 2 as starting materials, and uses rare earth trifluoromethanesulfonates (RE(OTf)3) as catalysts to synthesize seven 3,4-dihydrobenzothiadiazine drugs: cyclothiazide, bendroflumethiazide, cyclopenthiazide, hydrochlorothiazide, benzylhydrochlorothiazide, penflutizide, and ethiazide. The raw materials and rare earth catalysts used in the present invention can be directly purchased and are inexpensive.

[0015]

[0016] The technical solution of the present invention is as follows:

[0017] Mix commercially available 4-amino-6-chlorobenzene-1,3-disulfonamide, 4-amino-6-trifluoromethylbenzene-1,3-disulfonamide, and the corresponding aldehyde with a rare earth catalyst, add a solvent, and react at a certain temperature for a certain time to prepare the corresponding 3,4-dihydrobenzothiadiazine drugs.

[0018] The prepared 3,4-dihydrobenzothiadiazine drug molecules are the following seven compounds:

[0019] Cyclothiazide 3a: R 1 = Cl, R 2 = norbornene-5-yl;

[0020] Bendroflumethiazide 3b: R 1 = Cl, R 2 = isobutyl;

[0021] Cyclopenthiazide 3c: R 1 = Cl, R2 = cyclopentylmethyl;

[0022] Hydrochlorothiazide 3d: R 1 = Cl, R 2 = H;

[0023] Benzylhydrochlorothiazide 3e: R 1 = CF3, R 2 = benzyl;

[0024] Penflutizide 3f: R 1 = CF3, R 2 = n-pentyl;

[0025] Ethiazide 3g: R 1 = Cl, R 2 = ethyl.

[0026] In the above preparation method, 4-amino-6-chlorobenzene-1,3-disulfonamide, 4-amino-6-trifluoromethylbenzene-1,3-disulfonamide, aldehyde and rare earth trifluoromethanesulfonate (RE(OTf)3) can be directly purchased.

[0027] In the above preparation method, relative to 4-amino-6-chlorobenzene-1,3-disulfonamide or 4-amino-6-trifluoromethylbenzene-1,3-disulfonamide, the amount of aldehyde used is 1 to 10 molar equivalents, preferably 2 molar equivalents.

[0028] In the above preparation method, using 4-amino-6-chlorobenzene-1,3-disulfonamide as the raw material, reacting with 5-norbornene-2-carboxaldehyde, isovaleraldehyde, 2-cyclopentylacetaldehyde, formaldehyde, and propionaldehyde respectively to synthesize cyclothiazide, bendroflumethiazide, cyclopentiazide, hydrochlorothiazide, and ethiazide.

[0029] In the above preparation method, using 4-amino-6-trifluoromethylbenzene-1,3-disulfonamide as the raw material, reacting with phenylacetaldehyde and n-hexanal respectively to synthesize benzylhydrochlorothiazide and penflutizide.

[0030] In the above preparation method, the rare earth trifluoromethanesulfonate (RE(OTf)3) is La(OTf)3, Pr(OTf)3, Ce(OTf)3, Sm(OTf)3, Sc(OTf)3, Yb(OTf)3, Y(OTf)3, Lu(OTf)3, Tb(OTf)3, Ho(OTf)3, Er(OTf)3, Tm(OTf)3, Eu(OTf)3, Gd(OTf)3 or a mixture thereof.

[0031] In the above preparation method, relative to 4-amino-6-chlorobenzene-1,3-disulfonamide or 4-amino-6-trifluoromethylbenzene-1,3-disulfonamide, the amount of rare earth trifluoromethanesulfonate used is 0.1% to 100% molar equivalent, preferably 10% molar equivalent.

[0032] For the above preparation method, molecular sieves can be added as dehydrating agents.

[0033] For the above preparation method, the solvents commonly used are ethanol, ethyl acetate, acetonitrile, chloroform, dichloromethane, 1,2-dichloroethane, ether, tetrahydrofuran, 1,4-dioxane, toluene, chlorobenzene or mixtures thereof. The preferred solvent is dichloromethane.

[0034] For the above preparation method, the reaction temperature used is 0 - 200 °C, and the preferred temperature is 40 °C.

[0035] Advantages and positive effects of the present invention:

[0036] The 3,4-dihydrobenzothiadiazine drug molecules prepared by the present invention have effects such as reducing blood pressure and diuresis in clinical practice. The synthesis method provided by the present invention uses rare earth trifluoromethanesulfonates as catalysts, has simple operation, is suitable for large-scale preparation, and has high industrial production value. Specific embodiments

[0037] The present invention will be further illustrated below by way of examples, and the present invention is not limited to the scope of the examples.

[0038] Example 1

[0039] Synthesis of cyclothiazide (3a)

[0040] To a 25 mL round-bottom flask equipped with a magnetic stir bar, 4-amino-6-chloro-1,3-benzenedisulfonamide (285 mg, 1 mmol, 1 equiv.), 5-norbornene-2-carbaldehyde (244 mg, 1.2 mmol, 2 equiv.), dichloromethane (3 mL), ytterbium trifluoromethanesulfonate (53.6 mg, 0.1 mmol, 0.1 equiv.), and 9 - 10 activated molecular sieves (granular) were added in sequence. The mixture was stirred overnight at 40 °C. After the reaction was completed, the product was obtained by column chromatography purification (PE / EtOAc = 2:1).

[0041] White powdery solid, melting point: 234 - 235 °C; 346 mg, yield 89%, R f = 0.3 (PE / EtOAc = 1:1, v / v).

[0042] 11H NMR (400 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.92 (d, J = 11.2 Hz, 0.59H), 7.85 (d, J = 11.2 Hz, 0.42H), 7.75 (s, 0.58H), 7.71 (s, 0.43H), 7.51 (s, 0.8H), 7.50 (s, 1.21H), 7.21 (s, 0.42H), 7.09 (s, 0.56H), 6.30–6.28 (m, 0.42H), 6.26–6.23 (m, 0.57H), 6.00–6.02 (m, 0.43H), 5.95–5.93 (m, 0.56H), 3.97 (q, J = 11.3, 9.6 Hz, 1H), 3.27 (s, 0.43H), 3.02 (s, 0.57H), 2.91 (s, 0.57H), 2.85 (s, 0.44H), 2.49–2.38 (m, 1H), 2.04–1.98 (m, 0.57H), 1.84–1.90 (m, 0.43H), 1.46 (d, J = 7.4 Hz, 0.46H), 1.36 (d, J = 7.4 Hz, 0.58H), 1.32 (d, J = 8.1 Hz, 0.46H) 1.28 (d, J = 8.1 Hz, 0.58H), 0.84 (d, J = 11.6 Hz, 0.58H). 0.78 (d, J = 11.6 Hz, 0.42H). 13 13C NMR (101 MHz, DMSO-d6) δ 147.2, 146.9, 139.3, 138.5, 134.6, 134.5, 132.5, 131.8, 128.9, 128.6, 125.9, 125.8, 119.1, 118.9, 118.1, 117.8, 70.4, 49.6, 48.7, 44.2, 43.1, 42.9, 42.7, 42.7, 42.2, 30.0, 29.4. (Containing diastereoisomers)

[0043] Using the same operating procedure, the same product can also be obtained when using other rare earth metal catalysts. The specific yields and catalytic conditions are shown in the following table.

[0044]

[0045]

[0046]

[0047] Example 2

[0048] Synthesis of Bendroflumethiazide (3b)

[0049] To a 25 mL round-bottom flask equipped with a magnetic stir bar, 4-amino-6-chloro-1,3-benzenedisulfonamide (285 mg, 1 mmol, 1 equiv.), isovaleraldehyde (173 mg, 1.2 mmol, 2 equiv.), dichloromethane (3 mL), and yttrium trifluoromethanesulfonate (53.6 mg, 0.1 mmol, 0.1 equiv.) were added successively, followed by 9-10 activated molecular sieves (granular). The mixture was stirred overnight at 40 °C. After the reaction was completed, the product was purified by column chromatography (PE / EtOAc = 2:1).

[0050] White powdery solid, melting point: 214-215 °C; 324 mg, yield 92%, R f = 0.45 (PE / EtOAc = 1:1, v / v).

[0051] 1 1H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.88–7.73 (m, 2H), 7.49 (s, 2H), 7.01 (s, 1H), 4.81 (m, 1H), 1.88 (m, 1H), 1.74 (m, 1H), 1.62 (m, 1H), 0.95 (t, J = 6.4 Hz, 6H). 13 13C NMR (101 MHz, DMSO-d6) δ 147.0, 134.7, 128.6, 126.0, 118.8, 117.6, 64.9, 42.1, 24.0, 23.1, 22.1.

[0052] Using the same procedure, the same product can also be obtained when other rare earth metal catalysts are used. The specific yields and catalytic conditions are shown in the following table.

[0053]

[0054]

[0055] Example 3

[0056] Synthesis of cyclopenthiazide (3c)

[0057] To a 25 mL round-bottom flask equipped with a magnetic stir bar, 4-amino-6-chloro-1,3-benzenedisulfonamide (285 mg, 1 mmol, 1 equiv.), cyclopentylacetaldehyde (224 mg, 1.2 mmol, 2 equiv.), dichloromethane (3 mL), and yttrium trifluoromethanesulfonate (53.6 mg, 0.1 mmol, 0.1 equiv.) were added successively, followed by 9-10 activated Molecular sieve (granular). The mixture was stirred overnight at 40 °C. After the reaction was completed, the product was obtained by purification through column chromatography (PE / EtOAc = 2:1).

[0058] White powdery solid, melting point: 235 - 236 °C; 325 mg, yield 86%, R f = 0.45 (PE / EtOAc = 1:1, v / v).

[0059] 1 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.07 (s, 1H), 7.53 (s, 3H), 6.92 (s, 1H), 4.63 (dd, J = 10.1, 2.2 Hz, 1H), 1.79–0.88 (m, 11H) 13 13C NMR (101 MHz, DMSO-d6) δ 147.0, 137.6, 128.5, 126.9, 124.5, 120.5, 67.0, 44.3, 34.9, 29.9, 20.9

[0060] Using the same procedure, the same product can also be obtained when using other rare earth metal catalysts. The specific yields and catalytic conditions are shown in the following table.

[0061]

[0062]

[0063] Example 4

[0064] Synthesis of Hydrochlorothiazide (3d)

[0065] To a 25 mL round-bottom flask equipped with a magnetic stir bar were successively added 4-amino-6-chloro-1,3-benzenedisulfonamide (285 mg, 1 mmol, 1 equiv.), paraformaldehyde (60 mg, 1.2 mmol, 2 equiv. calculated as HCHO), dichloromethane (3 mL), yttrium trifluoromethanesulfonate (53.6 mg, 0.1 mmol, 0.1 equiv.), and 9 - 10 activated molecular sieve (granular). The mixture was stirred overnight at 40 °C. After the reaction was completed, the product was obtained by purification through column chromatography (PE / EtOAc = 2:1).

[0066] White powdery solid, melting point: 272 - 274 °C; 228 mg, yield 77%, R f = 0.4 (PE / EtOAc = 1:1, v / v).

[0067] 11H NMR (400 MHz, DMSO-d6) δ 8.02–8.04 (m, 2H), 7.53 (m, 2H), 7.00 (s, 1H) 4.75 (s, 2H) 13 13C NMR (101 MHz, DMSO-d6) δ 146.6, 134.3, 127.9, 125.5, 118.5, 117.0, 54.3

[0068] Using the same operation steps, the same products can also be obtained when using other rare earth metal catalysts. The specific yields and catalytic conditions are shown in the following table.

[0069]

[0070]

[0071] Example 5

[0072] Synthesis of Bendroflumethiazide (3e)

[0073] To a 25 mL round-bottom flask equipped with a magnetic stir bar, 4-amino-6-trifluoromethylbenzene-1,3-disulfonamide (319 mg, 1 mmol, 1 equiv.), phenylacetaldehyde (240 mg, 1.2 mmol, 2 equiv.), dichloromethane (3 mL), yttrium trifluoromethanesulfonate (53.6 mg, 0.1 mmol, 0.1 equiv.), and 9-10 activated molecular sieves (granular) were added in sequence. The mixture was stirred overnight at 40 °C. After the reaction was completed, the product was obtained by purification by column chromatography (PE / EtOAc = 2:1).

[0074] White powdery solid, melting point: 275-277 °C, 345 mg, yield 82%, R f = 0.3 (PE / EtOAc = 1:1, v / v).

[0075] 1 1H NMR (400 MHz, CD3OD) δ 8.25 (s, 1H), 7.64–7.70 (m, 2H), 7.16–7.27 (m, 6H), 5.02 (dd, J = 8.8 Hz, 5.0 Hz, 1H), 2.98–3.10 (m, 2H) 13 13C NMR (101 MHz, DMSO-d6) δ 40.9, 68.7, 117.0, 117.1, 123.4, 128.2, 128.7, 129.6, 130.0, 130.6, 132.0, 132.3, 136.5, 147.4.

[0076] Using the same operating steps, the same products can also be obtained when other rare earth metal catalysts are used. The specific yields and catalytic conditions are shown in the following table.

[0077]

[0078]

[0079] Example Six

[0080] Synthesis of Penflutizide (3f)

[0081] To a 25 mL round-bottom flask equipped with a magnetic stir bar, 4-amino-6-trifluoromethylbenzene-1,3-disulfonamide (319 mg, 1 mmol, 1 equiv.), hexanal (201 mg, 1.2 mmol, 2 equiv.), dichloromethane (3 mL), and yttrium trifluoromethanesulfonate (53.6 mg, 0.1 mmol, 0.1 equiv.) were successively added, and 9-10 activated molecular sieves (granular). The mixture was stirred overnight at 40 °C. After the reaction was completed, the product was obtained by purification by column chromatography (PE / EtOAc = 2:1).

[0082] White powdery solid, melting point: 257 - 258 °C; 245 mg, yield 67%, R f = 0.35 (PE / EtOAc = 1:1, v / v).

[0083] 1 1H NMR (400 MHz, CD3OD) δ 8.18 (s, 1H), 6.97 (s, 1H), 4.87 (m, 1H), 2.06–2.18 (m, 1H), 1.90–1.96 (m, 3H), 1.77–1.83 (m, 1H), 1.68–1.75 (m, 2H), 1.61–1.67 (m, 2H), 1.15–1.27 (m, 2H) 13 13C NMR (101 MHz, CD3OD) δ 148.4, 136.6, 129.6, 127.7, 120.3, 118.5, 67.1, 41.0, 37.0, 33.3, 25.9, 25.8.

[0084] Using the same operating steps, the same products can also be obtained when other rare earth metal catalysts are used. The specific yields and catalytic conditions are shown in the following table.

[0085]

[0086]

[0087] Example Seven

[0088] Synthesis of Ethiazide (3 g)

[0089] To a 25 mL round-bottom flask equipped with a magnetic stir bar, add 4-amino-6-chloro-1,3-benzenedisulfonamide (285 mg, 1 mmol, 1 equiv.), propionaldehyde (117 mg, 1.2 mmol, 2 equiv.), dichloromethane (3 mL), ytterbium(III) trifluoromethanesulfonate (53.6 mg, 0.1 mmol, 0.1 equiv.), and 9-10 activated molecular sieves (granular). Stir the mixture at 40 °C overnight. After the reaction is complete, purify by column chromatography (PE / EtOAc = 2:1) to obtain pure ethiazide.

[0090] White powdery solid, melting point: 273 - 274 °C; 232 mg, yield 76%, R f = 0.4 (PE / EtOAc = 1:1, v / v).

[0091] 1 1H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.91 (s, 1H), 7.75 (d, J = 11.2 Hz, 1H), 7.50 (s, 2H), 7.00 (s, 1H), 4.69 (m, 1H), 1.89–1.71 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 147.0, 134.7, 128.5, 126.0, 118.7, 117.4, 67.7, 26.9, 9.5.

[0092] Using the same procedure, the same product can also be obtained when using other rare earth metal catalysts. The specific yields and catalytic conditions are shown in the following table.

[0093]

[0094]

[0095]

Claims

1. A method for catalytic synthesis of 3,4-dihydrobenzothiadiazine drugs with rare earth, characterized in that, Using 4-amino-6-chlorobenzene-1,3-disulfonamide shown in Formula 1a, 4-amino-6-trifluoromethylbenzene-1,3-disulfonamide shown in Formula 1b, and aldehyde shown in Formula 2 as raw materials, seven drug molecules shown in Formulas 3a - 3g are simply prepared under the catalysis of rare earth trifluoromethanesulfonate catalyst, namely: cyclothiazide, bendroflumethiazide, cyclopenthiazide, hydrochlorothiazide, benzylhydrochlorothiazide, penflutizide, ethiazide 2. The method according to claim 1, wherein Using 4-amino-6-chlorobenzene-1,3-disulfonamide as the raw material, reacting with 5-norbornene-2-carboxaldehyde, isovaleraldehyde, 2-cyclopentylacetaldehyde, formaldehyde, and propionaldehyde respectively to synthesize cyclothiazide, bendroflumethiazide, cyclopenthiazide, hydrochlorothiazide, and ethiazide 3. The method according to claim 1, characterized in that, Using 4-amino-6-trifluoromethylbenzene-1,3-disulfonamide as the raw material, reacting with phenylacetaldehyde and hexanal respectively to synthesize benzylhydrochlorothiazide and penflutizide 4. The method according to claim 1, wherein The rare earth trifluoromethanesulfonate RE(OTf)3 is La(OTf)3, Pr(OTf)3, Ce(OTf)3, Sm(OTf)3, Sc(OTf)3, Yb(OTf)3, Y(OTf)3, Lu(OTf)3, Tb(OTf)3, Ho(OTf)3, Er(OTf)3, Tm(OTf)3, Eu(OTf)3, Gd(OTf)3 or their mixture, preferably Y(OTf)3 5. The method according to claim 1, wherein The solvents used are ethanol, ethyl acetate, acetonitrile, chloroform, dichloromethane, 1,2-dichloroethane, ether, tetrahydrofuran, 1,4-dioxane, toluene, chlorobenzene or their mixture, and the preferred solvents are ethyl acetate and dichloromethane

Images