CN116836130B - Synthesis method of 3, 4-dihydrobenzothiadiazine compound - Google Patents

Synthesis method of 3, 4-dihydrobenzothiadiazine compound Download PDF

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CN116836130B
CN116836130B CN202311109351.1A CN202311109351A CN116836130B CN 116836130 B CN116836130 B CN 116836130B CN 202311109351 A CN202311109351 A CN 202311109351A CN 116836130 B CN116836130 B CN 116836130B
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CN116836130A (en
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姜东方
喻芳芳
刘翔
黄兵兵
文思妙妙
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Harvest Pharmaceutical Co ltd
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    • C07D285/16—Thiadiazines; Hydrogenated thiadiazines
    • C07D285/18—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines
    • C07D285/20—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems
    • C07D285/22—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D285/24—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom
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    • C07D285/16—Thiadiazines; Hydrogenated thiadiazines
    • C07D285/18—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines
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    • C07D285/20—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems
    • C07D285/22—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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    • C07D285/28—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom substituted in position 6 or 7 by sulfamoyl or substituted sulfamoyl radicals with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached in position 3
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Abstract

The invention provides a synthesis method of 3, 4-dihydrobenzothiadiazine compounds, which takes compounds shown in a formula I and a formula II and DABSO as raw materials, and the raw materials are heated under the conditions of a catalyst, alkali, a solvent and oxygen to react to generate the 3, 4-dihydrobenzothiadiazine compounds shown in a formula III. The reaction substrate has the advantages of wide application range, simple and mild conditions and the like, and has wide application prospect in the aspects of synthesizing the medical intermediates and fine chemical raw materials.

Description

Synthesis method of 3, 4-dihydrobenzothiadiazine compound
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of 3, 4-dihydrobenzothiadiazine compounds.
Background
The 3, 4-dihydrobenzothiadiazine compound has nitrogen-sulfur heterocycle in the structure and has wide application in the aspects of natural products, advanced materials, medicaments, bioactive agents and the like. In pharmaceutical applications, 3, 4-dihydrobenzothiadiazines exist in many compounds having various pharmacological activities, such as antibacterial, antihypertensive, antiviral and antitumor compounds, etc., and some have been used as moderately potent diuretics, alkaline phosphatase inhibitors, phosphodiesterase inhibitors, 5-HT1A receptor agonists, HIV-1 infection antagonists, KATP channel modulators, etc.
P.A. Sathe, K.S. Vadagaonkar, M.V. Vhatkar, L.Melone, A.C. Chaskar, chemistry select 2018, 3, 277-283 discloses a method for synthesizing 3, 4-dihydrobenzothiadiazine compounds by oxidizing aryl alkynes or alkenes in the presence of iodine and DMSO to form aryl glyoxal intermediates, and then condensing with 2-aminobenzenesulfonamide in situ to obtain 3, 4-dihydrobenzothiadiazine compounds. Yu X, ma Z, zhu W, liu H, zhang Z, liu Y, zhang M, zhao J, zhang P, xia C.J. Org chem.2022 Nov 4;87 (21): 14738-14752. A synthesis of SnCl of benzothiadiazine/1- (phenylsulfonyl) -1H-benzimidazole derivatives using nitrile and 2-nitro-N-phenylbenzenesulfonamide/N- (2-nitrophenyl) benzenesulfonamide is disclosed 2 Novel ways of promoting tandem reduction, ammonolysis, condensation and deamination reactions employing insensitive and inexpensive SnCl 2 The reaction reagent of the i-PrOH is convenient to operate and has good functional group tolerance. Shi P, tu Y, wang C, kong D, ma D, bolm C.org Lett 2020 Nov 20;22 (22): 8842-8845. A process for synthesizing benzothiadiazine-1-oxide using rhodium catalyzed direct C-H bond amidation/cyclization with 1,2, 4-dioxazol-5-one as the amidating agent is disclosed. Y, xing, F, dong, X, yin, L, wang, S.—S. Li, asian J. Org. Chem. 2020, 9, 1787-1792. A method of BF is disclosed 3 ·Et 2 O-promoted redox neutral cascade condensation/[ 1,7 ]]A process for the efficient synthesis of benzothiadiazine 1, 1-dioxide by a hydride transfer/cyclisation reaction. P, du, H, zhou, Y, sui, Q, liu, K, zou, tetrahedron 2016, 72, 1573-1578A process for the asymmetric synthesis of benzothiadiazine 1, 1-dioxide using scandium catalysts is disclosed. Most of the methods have the defects of complex raw materials, harsh reaction conditions, harmful byproducts and the like.
Disclosure of Invention
The invention aims to provide a preparation method of 3, 4-dihydrobenzothiadiazine compounds, which takes compounds shown in formula I and formula II and DABSO as raw materials, and heats the raw materials under the conditions of catalyst, alkali, solvent and oxygen to react to generate the 3, 4-dihydrobenzothiadiazine compounds shown in formula III:
said R is 1 Selected from halogen, alkyl, alkenyl, alkoxy, amido, sulfonyl, aryl, fused ring, heterocyclic;
said R is 2 Selected from alkyl, amino, alkenyl, aryl, heterocyclyl, and fused ring groups;
the catalyst is a copper catalyst or a palladium catalyst.
Preferably, the copper catalyst is selected from Cu (OAc) 2 、Cu(OTf) 2 、CuCl 2 。
Preferably, the palladium catalyst is selected from Pd (OTf) 2 、Pd(OAc) 2 。
Preferably, the catalyst is Pd (OAc) 2 。
The base may be an inorganic or organic base, such as Cs 2 CO 3 、CsF、Na 2 CO 3 、Et 3 N, etc.
The solvent may be a protic solvent or an aprotic solvent, such as DCE, dioxane, THF, DMSO, meCN, DMF and the like.
Preferably, the heating temperature is 80-140 ℃.
Preferably, the preparation method specifically comprises the following steps: the compound of formula I, the compound of formula II, DABSO and the catalyst Pd (OAc) 2 Alkali Cs 2 CO 3 Placing the mixture in a reaction bottle containing solvent DMSO, heating to 80-140 ℃ in an oxygen atmosphere, monitoring the reaction by TLC, quenching after the reaction is finished, and purifying the reaction solution to obtain the compound shown in the formula III.
The invention provides a high-efficiency and green synthesis method of 3, 4-dihydrobenzothiadiazine compounds, which takes o-iodoaniline, primary amine and DABSO as raw materials to obtain the 3, 4-dihydrobenzothiadiazine compounds through heterogeneous palladium-catalyzed cyclization and amination reactions. The direct C-S, S-N and C-N functionalization is efficient, and experiments prove that the method has wide functional group tolerance and has wide application prospect in the aspects of synthesizing the medical intermediates and fine chemical raw materials.
Drawings
FIG. 1 is a structural diagram of compounds of formulas III-1 to III-15;
FIG. 2 is a structural diagram of compounds of formulas III-16 to III-25;
FIG. 3 is a structural diagram of compounds of formulas III-26 to III-34;
FIG. 4 is a structural diagram of compounds of formulas III-35 to III-41;
FIG. 5 is a structural diagram of compounds of formulas III-42 to III-47;
FIG. 6 is a compound of formula III-1 1 H NMR spectrum;
FIG. 7 is a compound of formula III-1 13 C NMR spectrum;
FIG. 8 is a compound of formula III-2 1 H NMR spectrum;
FIG. 9 is a compound of formula III-2 13 C NMR spectrum;
FIG. 10 is a diagram of a compound of formula III-3 1 H NMR spectrum;
FIG. 11 is a compound of formula III-3 13 C NMR spectrum;
FIG. 12 is a compound of formula III-4 1 H NMR spectrum;
FIG. 13 is a compound of formula III-4 13 C NMR spectrum;
FIG. 14 is a compound of formula III-5 13 C NMR spectrum;
FIG. 15 is a compound of formula III-6 1 H NMR spectrum;
FIG. 16 is a compound of formula III-6 13 C NMR spectrum;
FIG. 17 is a compound of formula III-7 13 C NMR spectrum;
FIG. 18 is a compound of formula III-8 1 H NMR spectrum;
FIG. 19 is a compound of formula III-8 13 C NMR spectrum;
FIG. 20 is a compound of formula III-9 1 H NMR spectrum;
FIG. 21 is a compound of formula III-9 13 C NMR spectrum;
FIG. 22 is a diagram of a compound of formula III-10 1 H NMR spectrum;
FIG. 23 is a compound of formula III-10 13 C NMR spectrum;
FIG. 24 is a reaction mechanism diagram of the present invention.
Detailed Description
In order to better understand the technical scheme and advantages of the present invention, the present invention will be further described below through the specific embodiments.
Example 1: synthesis of 7-methyl-3-phenyl-3, 4-dihydro-2H-benzo [ e ] [1,2,4] thiadiazine-1, 1-dioxide (III-1)
2-iodo-4-methylaniline (0.2 mmol), benzylamine (0.24 mmol), DABSO (0.24 mmol), catalyst (10 mol%) and base (0.4 mmol) were placed in a reaction flask containing a solvent, heated in an oxygen atmosphere, and the reaction was monitored by TLC. After the reaction is completed, saturated NH is added 4 The reaction was quenched with aqueous Cl and the resulting mixture was diluted with EA. The organic layer was separated and extracted with EtOAc, and the combined extracts were washed with brine, anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated in vacuo and purified by column chromatography to give 7-methyl-3-phenyl-3, 4-dihydro-2H-benzo [ e ]][1,2,4]Thiadiazine 1, 1-dioxide (III-1). The corresponding III-1 yields under the conditions of different temperatures, catalysts, alkali and solvents are as follows:
(1) The reaction temperature was 80℃and the catalyst Cu (OAc) 2 The alkali is Cs 2 CO 3 The solvent is DCE, and the yield is 31%;
(2) The reaction temperature is 80 ℃, and the catalyst is Cu (OTf) 2 The alkali is Cs 2 CO 3 The solvent is DCE, and the yield is 38%;
(3) The reaction temperature is 80 ℃, and the catalyst is CuCl 2 The alkali is Cs 2 CO 3 The solvent is DCE, and the yield is 23%;
(4) ReactionThe temperature was 80℃and the catalyst Pd (OTf) 2 The alkali is Cs 2 CO 3 The solvent was DCE with 41% yield;
(5) The reaction temperature was 80℃and the catalyst Pd (OAc) 2 The alkali is Cs 2 CO 3 The solvent was DCE with a yield of 49%;
(6) The reaction temperature was 80℃and the catalyst Pd (OAc) 2 The alkali is CsF, the solvent is DCE, and the yield is 44%;
(7) The reaction temperature was 80℃and the catalyst Pd (OAc) 2 The alkali is Na 2 CO 3 The solvent is DCE, and the yield is 23%;
(8) The reaction temperature was 80℃and the catalyst Pd (OAc) 2 The base is Et 3 N, solvent DCE, yield 19%;
(9) The reaction temperature was 80℃and the catalyst Pd (OAc) 2 The alkali is Cs 2 CO 3 The solvent is dioxane, and the yield is 11%;
(10) The reaction temperature was 80℃and the catalyst Pd (OAc) 2 The alkali is Cs 2 CO 3 The solvent is THF, and the yield is 15%;
(11) The reaction temperature was 80℃and the catalyst Pd (OAc) 2 The alkali is Cs 2 CO 3 The solvent is DMSO, and the yield is 66%;
(12) The reaction temperature was 80℃and the catalyst Pd (OAc) 2 The alkali is Cs 2 CO 3 Solvent MeCN with 17% yield;
(13) The reaction temperature was 80℃and the catalyst Pd (OAc) 2 The alkali is Cs 2 CO 3 DMF as solvent gave 27% yield;
(14) The reaction temperature was 100deg.C and the catalyst Pd (OAc) 2 The alkali is Cs 2 CO 3 The solvent is DMSO, and the yield is 73%;
(15) The reaction temperature was 120℃and the catalyst Pd (OAc) 2 The alkali is Cs 2 CO 3 The solvent is DMSO, and the yield is 85%;
(16) The reaction temperature was 140℃and the catalyst Pd (OAc) 2 The alkali is Cs 2 CO 3 The solvent was DMSO, yield 85%.
The possible reaction mechanisms leading to the present invention in connection with FIG. 24 are: transfer of Pd (II) occurs first, forming Pd (II) class compound A with the I-1 compound, and then A reacts with DABSO to provide coordination and intercalation of sulfur dioxide, forming intermediate B and DABCO radical cations. On the other hand, II-1 compound and O 2 The oxidation reaction between them generates primary aldimine C in situ, followed by nucleophilic attack of primary aldimine C to produce the coupled products E and Pd (0). Pd (0) is at O 2 Oxidized in the presence of Pd (II) which will re-enter the catalytic cycle, and intermediate E undergoes intramolecular cyclization to give the product III-1 compound.
Example 2: synthesizing 3, 4-dihydrobenzothiadiazine compound shown in formula III-a by using benzyl amine as raw material
The catalyst of formula I (0.2 mmol), benzyl amine (0.24 mmol), DABSO (0.24 mmol), pd (OAc) 2 (10 mol%) and base Cs 2 CO 3 (0.4 mmol) was placed in a reaction flask containing solvent DMSO, heated at 120℃in an oxygen atmosphere and the reaction monitored by TLC. After the reaction is completed, saturated NH is added 4 The reaction was quenched with aqueous Cl and the resulting mixture was diluted with EA. The organic layer was separated and extracted with EtOAc, and the combined extracts were washed with brine, anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated in vacuo and purified by column chromatography to give 3, 4-dihydrobenzothiadiazines of formula III-a. The structures of the formula I and the formula III-a and the yield are as follows:
(1) Formula I is 2-iodo-4, 5-dimethylaniline, formula III-a is 6, 7-dimethyl-3-phenyl-3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine-1, 1-dioxide, i.e., III-2, in 84% yield;
(2) Formula I is 2-iodo-4, 6-dimethylaniline, formula III-a is 5, 7-dimethyl-3-phenyl-3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine-1, 1-dioxide, i.e., III-3, in 80% yield;
(3) Formula I is 4-cyclopropyl-2-iodoaniline, formula III-a is 7-cyclopropyl-3-phenyl-3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine-1, 1-dioxide, i.e. III-4, in 76% yield;
(4) Formula I is 4-decyl-2-iodoaniline, formula III-a is 7-decyl-3-phenyl-3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine-1, 1-dioxide, i.e., III-5, in 71% yield;
(5) Formula I is 2-iodo-4-methoxyaniline, formula III-a is 7-methoxy-3-phenyl-3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine-1, 1-dioxide, i.e., III-6, in 88% yield;
(6) Formula I is 4-benzyl-2-iodoaniline, formula III-a is 7-benzyl-3-phenyl-3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine-1, 1-dioxide, i.e., III-7, in 80% yield;
(7) Formula I is 4-chloro-2-iodoaniline, formula III-a is 7-chloro-3-phenyl-3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine-1, 1-dioxide, i.e., III-8, in 82% yield;
(8) Formula I is 4-bromo-2-iodoaniline, formula III-a is 7-bromo-3-phenyl-3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine-1, 1-dioxide, i.e., III-9, in 85% yield;
(9) Formula I is 2, 4-diiodoaniline, formula III-a is 7-iodo-3-phenyl-3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine-1, 1-dioxide, i.e., III-10, in 78% yield;
(10) Formula I is 2-iodo-4- (4-methylbenzyl) aniline, formula III-a is 7- (4-methylbenzyl) -3-phenyl-3, 4-dihydro-2 h-benzo [ e ] [1,2,4] -thiadiazine 1, 1-dioxide, i.e., III-11, in 81% yield;
(11) Formula I is 2-iodo-4- (piperidin-1-yl) aniline, formula III-a is 3-phenyl-7- (piperidin-1-yl) -3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine 1, 1-dioxide, i.e., III-12, in 66% yield;
(12) Formula I is N- (4-amino-3-iodophenyl) acetamide, formula III-a is N- (1, 1-dioxo-3-phenyl-3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazin-7-yl) acetamide, namely III-13, and the yield is 73%;
(13) Formula I is 4- (3-iodo-4-aminophenyl) morpholine, formula III-a is 7-morpholino-3-phenyl-3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine-1, 1-dioxide, i.e., III-14, in 62% yield;
(14) Formula I is 4-amino-3-iodobenzenesulfonamide, formula III-a is 3-phenyl-3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine-7-sulfonamide-1, 1-dioxide, i.e., III-15, in 77% yield;
(15) 3-iodonaphthalen-2-amine of formula I, 3-phenyl-3, 4-dihydro-2 h-naphtho [2,3-e ] [1,2,4] thiadiazine-1, 1-dioxide of formula III-a, i.e., III-16, in 69% yield;
(16) Formula I is 6-iodobenzo [ d ] oxazol-7-amine, formula III-a is 2-phenyl-2, 3-dihydro-1 h-oxazolo [4',5':5,6] benzo [1,2-e ] [1,2,4] thiadiazine-4, 4-dioxide, i.e. III-17, in 54% yield;
(17) Formula I is 5-iodobenzo [ b ] thiophen-6-amine, formula III-a is 3-phenyl-3, 4-dihydro-2 h-thieno [3',2':4,5] benzo [1,2-e ] [1,2,4] thiadiazine-1, 1-dioxide, i.e., III-18, in 58% yield;
(18) Formula I is 6-iodobenzo [ d ] thiazol-7-amine, formula III-a is 2-phenyl-2, 3-dihydro-1 h-thiazolo [4',5':5,6] benzo [1,2-e ] [1,2,4] thiadiazine-4, 4-dioxide, i.e., III-19, in 53% yield;
(19) Formula I is 3-iododibenzothiophene-4-amine, formula III-a is 2-phenyl-2, 3-dihydro-1 h-benzo [4',5' ] thieno [3',2':5,6] benzo [1,2-e ] [1,2,4] thiadiazine-4, 4-dioxide, i.e., III-20, in a yield of 47%.
Example 3: synthesizing 3, 4-dihydrobenzothiadiazine compound shown in formula III-b by using benzyl amine as raw material
2-iodo-4-methylaniline (0.2 mmol), formula II (0.24 mmol), DABSO (0.24 mmol), catalyst Pd (OAc) 2 (10 mol%) and base Cs 2 CO 3 (0.4 mmol) was placed in a reaction flask containing solvent DMSO, heated at 120℃in an oxygen atmosphere and the reaction monitored by TLC. After the reaction is completed, saturated NH is added 4 The reaction was quenched with aqueous Cl and the resulting mixture was diluted with EA. The organic layer was separated and extracted with EtOAc and the combined extracts were extracted with brineWashing, anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated in vacuo and purified by column chromatography to give 3, 4-dihydrobenzothiadiazines of formula III-b. The structures and yields of formulas II, III-b are as follows:
(1) Formula II is p-toluenemethylamine, formula III-b is 7-methyl-3- (p-tolyl) -3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine-1, 1-dioxide, i.e., III-21, in 80% yield;
(2) Formula II is (4-methoxyphenyl) methylamine, formula III-b is 3- (4-methoxyphenyl) -7-methyl-3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine-1, 1-dioxide, i.e. III-22, in 84% yield;
(3) Formula II is 4- (aminomethyl) benzonitrile, formula III-b is 4- (7-methyl-1, 1-dioxo-3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazin-3-yl) benzonitrile, i.e. III-23, in 78% yield;
(4) Formula II is (4-chlorophenyl) methylamine, formula III-b is 3- (4-chlorophenyl) -7-methyl-3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine-1, 1-dioxide, i.e., III-24, in 72% yield;
(5) Formula II is (4-bromophenyl) methylamine, formula III-b is 3- (4-bromophenyl) -7-methyl-3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine-1, 1-dioxide, i.e., III-25, in 79% yield;
(6) Formula II is naphthalen-2-ylmethylamine, formula III-b is 7-methyl-3- (naphthalen-2-yl) -3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine-1, 1-dioxide, i.e., III-26, in 69% yield;
(7) Formula II is (3 h-indol-3-yl) methylamine, formula III-b is 3- ((1 h-indol-3-yl) methyl) -7-methyl-3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine-1, 1-dioxide, i.e., III-27, in 62% yield;
(8) Formula II is (tetrahydrofuran-2-yl) methylamine, formula III-b is 7-methyl-3- (tetrahydrofuran-2-yl) -3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine-1, 1-dioxide, i.e., III-28, in 74% yield;
(9) 3-methylbutan-1-amine of formula II, 3-isobutyl-7-methyl-3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine-1, 1-dioxide of formula III-29 in 77% yield;
(10) Formula II is (tetrahydrothiophen-2-yl) methylamine, formula III-b is 7-methyl-3- (tetrahydrothiophen-2-yl) -3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine-1, 1-dioxide, i.e. III-30, in a yield of 72%;
(11) Formula II is cyclopentylmethylamine, formula III-b is 3-cyclopentyl-7-methyl-3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine-1, 1-dioxide, i.e., III-31, in 80% yield;
(12) Formula II is cyclohexylmethylamine, formula III-b is 3-cyclohexyl-7-methyl-3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine-1, 1-dioxide, i.e., III-32, in 83% yield;
(13) Formula II is (tetrahydro-2 h-pyran-4-yl) methylamine, formula III-b is 7-methyl-3- (tetrahydro-2 h-pyran-4-yl) -3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine-1, 1-dioxide, i.e. III-33, in 72% yield;
(14) Formula II is 1, 3-xylylenediamine, formula III-b is 3,3' - (1, 3-phenylene) bis (7-methyl-3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine-1, 1-dioxide), i.e., III-34, in 64% yield;
(15) Formula II is hept-1-amine, formula III-b is 3-hexyl-7-methyl-3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine-1, 1-dioxide, i.e., III-35, in 81% yield;
(16) Formula II is 1,3, 5-benzenetrimethylamine, formula III-b is 3,3' - (benzene-1, 3, 5-triyl) tris (7-methyl-3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine 1, 1-dioxide), i.e. III-36, in 50% yield;
(17) The formula II is octadecen-1-amine and the formula III-b is 3-heptadecyl-7-methyl-3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine-1, 1-dioxide, i.e. III-37, in 67% yield.
Example 4: synthesizing 3, 4-dihydrobenzothiadiazine compound shown in formula III-c by taking 4-amino-2-chloro-5-iodobenzenesulfonamide as raw material
4-amino-2-chloro-5-iodobenzenesulfonamide (0.2 mmol), formula II (0.24 mmol), DABSO (0.24 mmol), catalyst Pd (OAc) 2 （10 mol %）And alkali Cs 2 CO 3 (0.4 mmol) was placed in a reaction flask containing solvent DMSO, heated at 120℃in an oxygen atmosphere and the reaction monitored by TLC. After the reaction is completed, saturated NH is added 4 The reaction was quenched with aqueous Cl and the resulting mixture was diluted with EA. The organic layer was separated and extracted with EtOAc, and the combined extracts were washed with brine, anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated in vacuo and purified by column chromatography to give 3, 4-dihydrobenzothiadiazines of formula III-c. The structures and yields of the formula II and the formula III-c are as follows:
(1) Formula II is bicyclo [2.2.1] hept-5-en-2-ylamine, formula III-c is 3- (bicyclo [2.2.1] hept-5-en-2-yl) -6-chloro-3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine-7-sulfonamide-1, 1-dioxide, i.e. III-38, in 61% yield;
(2) Formula II is ethylamine, formula III-c is 6-chloro-3-methyl-3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine-7-sulfonamide-1, 1-dioxide, i.e., III-39, in 65% yield;
(3) Formula II is propylamine, formula III-c is 6-chloro-3-ethyl-3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine-7-sulfonamide-1, 1-dioxide, i.e., III-40, in 69% yield;
(4) Formula II is 2-cyclopentylethylamine, formula III-c is 6-chloro-3- (cyclopentylmethyl) -3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine-7-sulfonamide-1, 1-dioxide, i.e., III-41, in 74% yield;
(5) Formula II is 2, 3-dimethylpentan-1-amine, formula III-c is 6-chloro-3- (3-methylpentan-2-yl) -3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine-7-sulfonamide-1, 1-dioxide, i.e. III-42, in 70% yield;
(6) Formula II is benzylamine, formula III-c is 6-chloro-3-phenyl-3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine-7-sulfonamide-1, 1-dioxide, i.e., III-43, in 76% yield;
(7) 2-cycloheptylethylamine of formula II, 6-chloro-3- (cycloheptylmethyl) -3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine-7-sulfonamide-1, 1-dioxide of formula III-44 in 75% yield;
(8) Formula II is phenethylamine, formula III-c is 3-benzyl-6-chloro-3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine-7-sulfonamide-1, 1-dioxide, i.e., III-45, in 72% yield;
(9) 2-phenylpropan-1-amine of formula II, 6-chloro-3- (1-phenylethyl) -3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine-7-sulfonamide-1, 1-dioxide of formula III-c, i.e. III-46 in 70% yield;
(10) Formula II is 2-methylpropan-1-amine, formula III-c is 6-chloro-3-isopropyl-3, 4-dihydro-2 h-benzo [ e ] [1,2,4] thiadiazine-7-sulfonamide-1, 1-dioxide, i.e., III-47, in a yield of 72%.
Characterization data of the compounds represented by the formulas III-1 to III-10 are as follows:
formula III-1: melting point 82-84 ℃; 1 H NMR (400 MHz, DMSO-d 6 , ppm):δ7.85 (s, 1H), 7.76-7.67 (m, 1H), 7.57-7.27 (m, 6H), 7.15-7.06 (m, 1H), 6.69 (d,J= 7.5 Hz, 1H), 5.62 (s, 1H), 2.26 (s, 3H)； 13 C NMR (100 MHz, DMSO-d 6 , ppm):δ 138.0, 133.7, 132.2, 132.1, 129.4, 129.1, 127.3, 126.7, 126.3, 117.6, 65.3, 19.3；MS：[M+H] + 275.0851；
formula III-2: melting point 77-79 ℃; 1 H NMR (400 MHz, DMSO-d 6 , ppm):δ8.15-8.04 (m, 1H), 7.86 (s, 1H), 7.63-7.24 (m, 6H), 6.63-6.45 (m, 1H), 5.65 (s, 1H), 2.34 (s, 3H), 2.21 (s, 3H)； 13 C NMR (100 MHz, DMSO-d 6 , ppm):δ 147.7, 138.4, 136.8, 132.0, 131.1, 129.4, 129.1, 127.1, 126.1, 119.3, 66.8, 19.9, 18.3；MS：[M+H] + 289.1001；
formula III-3: melting point 89-91 ℃; 1 H NMR (400 MHz, DMSO-d 6 , ppm):δ8.10-7.94 (m, 2H), 7.68 (s, 1H), 7.51-7.24 (m, 5H), 6.88 (dt,J= 2.4, 1.2 Hz, 1H), 5.53 (s, 1H), 2.28 (s, 3H), 1.97 (s, 3H)； 13 C NMR (100 MHz, DMSO-d 6 , ppm):δ145.9, 138.4, 133.1, 132.3, 129.4, 129.1, 127.1, 125.9, 124.5, 122.4, 66.5, 21.5, 18.2；MS：[M+H] + 289.1002；
formula III-4: melting point 111-113 ℃; 1 H NMR (400 MHz, DMSO-d 6 , ppm):δ 8.04 (dd,J= 2.0, 1.0 Hz, 1H), 7.86 (s, 1H), 7.71-7.16 (m, 6H), 6.96 (dt,J= 7.4, 1.5 Hz, 1H), 6.73 (d,J= 7.6 Hz, 1H), 5.61 (s, 1H), 2.26 (p,J= 7.0 Hz, 1H), 1.19-1.01 (m, 1H), 0.87 (m, 3H)； 13 C NMR (100 MHz, DMSO-d 6 , ppm):δ 146.0, 138.4, 134.7, 129.9, 129.4, 129.3, 129.1, 127.4, 127.1, 117.1, 63.8, 18.7, 5.1；MS：[M+H] + 301.1006；
formula III-5: melting point 168-170 ℃; 1 H NMR (400 MHz, DMSO-d 6 , ppm):δ7.96 (d,J= 1.9 Hz, 1H), 7.79 (s, 1H), 7.64-7.25 (m, 6H), 7.09 (dd,J= 7.5, 1.9 Hz, 1H), 6.72 (d,J= 7.5 Hz, 1H), 5.62 (s, 1H), 2.65-2.52 (m, 2H), 1.64-1.45 (m, 2H), 1.40-1.05 (m, 14H), 0.96-0.81 (m, 3H)； 13 C NMR (100 MHz, DMSO-d 6 , ppm):δ 144.3, 134.6, 131.9, 131.2, 129.4, 129.1, 128.6, 127.1, 126.3, 118.2, 65.8, 35.7, 32.7, 31.6, 30.6, 29.8, 29.7, 29.5, 26.6, 22.8, 14.1；MS：[M+H] + 401.2252；
formula III-6: melting point 189-191 ℃; 1 H NMR (400 MHz, DMSO-d 6 , ppm):δ 7.79 (s, 1H), 7.68-7.19 (m, 7H), 6.82-6.61 (m, 2H), 5.53 (s, 1H), 3.79 (s, 3H)； 13 C NMR (100 MHz, DMSO-d 6 , ppm):δ154.2, 145.9, 130.7, 129.4, 129.1, 127.1, 126.9, 122.9, 118.2, 116.9, 66.8, 55.6；MS：[M+H] + 291.0794；
formula III-7: melting point 153-155 ℃; 1 H NMR (400 MHz, DMSO-d 6 , ppm):δ 8.10-7.85 (m, 2H), 7.72-7.12 (m, 12H), 6.77 (d,J= 7.5 Hz, 1H), 5.63 (s, 1H), 3.94 (d,J= 1.6 Hz, 2H)； 13 C NMR (100 MHz, DMSO-d 6 , ppm):δ 145.7, 141.6, 133.6, 131.1, 130.9, 130.4, 129.5, 129.4, 129.0, 128.7, 127.1, 125.1, 118.0, 64.0, 39.7；MS：[M+H] + 351.1168；
formula III-8:melting point 147-149 ℃; 1 H NMR (400 MHz, DMSO-d 6 , ppm):δ 8.16 (d,J= 2.1 Hz, 1H), 7.95 (s, 1H), 7.68-7.27 (m, 6H), 7.23 (dd,J= 7.6, 2.0 Hz, 1H), 6.69 (d,J= 7.5 Hz, 1H), 5.62 (s, 1H)； 13 C NMR (100 MHz, DMSO-d 6 , ppm):δ143.8, 137.7, 130.8, 130.8, 129.4, 129.1, 127.1, 126.6, 125.0, 118.8, 66.5；MS：[M+H] + 295.0308；
formula III-9: melting point 82-84 ℃; 1 H NMR (400 MHz, DMSO-d 6 , ppm):δ 8.24-8.09 (m, 2H), 7.74-7.26 (m, 7H), 6.65 (d,J= 7.5 Hz, 1H), 5.65 (s, 1H)； 13 C NMR (100 MHz, DMSO-d 6 , ppm):δ 146.2, 135.4, 134.1, 129.4, 129.3, 129.1, 128.8, 127.1, 120.1, 116.7, 65.7；MS：[M+H] + 338.9794；
formula III-10: melting point 156-158 ℃; 1 H NMR (400 MHz, DMSO-d 6 , ppm):δ8.36-8.20 (m, 2H), 7.57 (dd,J= 7.5, 2.0 Hz, 2H), 7.48-7.29 (m, 5H), 6.51 (d,J= 7.5 Hz, 1H), 5.73 (s, 1H)； 13 C NMR (100 MHz, DMSO-d 6 , ppm):δ148.2, 139.1, 135.0, 131.9, 129.4, 129.1, 127.4, 127.1, 119.0, 100.9, 65.8；MS：[M+H] + 386.9655。
it should be noted that the above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.

Claims (5)

1. The synthesis method of the 3, 4-dihydrobenzothiadiazine compound is characterized in that the 3, 4-dihydrobenzothiadiazine compound shown in the formula III is produced by taking the compound shown in the formula I and the formula II and DABSO as raw materials and heating the raw materials under the conditions of a catalyst, alkali, a solvent and oxygen, and reacting the raw materials:
;
the formula III is selected from compounds with structures shown in formulas III-1 to III-15 and III-21 to III-47:
；
the catalyst is selected from Cu (OAc) 2 、Cu(OTf) 2 、CuCl 2 、Pd(OTf) 2 、Pd(OAc) 2 One of them.
2. The method for synthesizing 3, 4-dihydrobenzothiadiazine compounds according to claim 1, wherein the base is Cs 2 CO 3 。
3. The method for synthesizing 3, 4-dihydrobenzothiadiazine compounds according to claim 1, wherein said solvent is DMSO.
4. The method for synthesizing 3, 4-dihydrobenzothiadiazine compounds according to claim 1, wherein the heating temperature is 80-140 ℃.
5. The method for synthesizing the 3, 4-dihydrobenzothiadiazine compound according to claim 1, which is characterized by comprising the following steps: the compound of formula I, the compound of formula II, DABSO and the catalyst Pd (OAc) 2 Alkali Cs 2 CO 3 Placing the mixture in a reaction bottle containing solvent DMSO, heating to 80-140 ℃ in an oxygen atmosphere, monitoring the reaction by TLC, quenching after the reaction is finished, and purifying the reaction solution to obtain the compound shown in the formula III.
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