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Synthesis method of 4H-1, 2, 4-benzothiadiazine-1, 1-dioxide derivative

A technology of benzothiadiazine and 4H-1, applied in the field of synthesis of 4H-1,2,4-benzothiadiazine-1,1-dioxide derivatives, can solve the toxicity of ethyl orthoformate Large, difficult separation and purification, low yield of aldehyde ring closure, etc., to achieve the effect of reducing synthesis cost, high synthesis efficiency, and good functional group tolerance

Pending Publication Date: 2021-12-10
LANZHOU UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] However, no effective synthesis method for this type of compound has been reported. Among them, ethyl orthoformate is more toxic, the yield of aldehyde ring closure is low, side reactions are easy to occur during high temperature ring closure, and separation and purification are difficult.

Method used

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  • Synthesis method of 4H-1, 2, 4-benzothiadiazine-1, 1-dioxide derivative
  • Synthesis method of 4H-1, 2, 4-benzothiadiazine-1, 1-dioxide derivative
  • Synthesis method of 4H-1, 2, 4-benzothiadiazine-1, 1-dioxide derivative

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062]

[0063] Add N,N-diphenylmethacrylamide 1a (47 mg, 0.2 mmol), 1 mL of anhydrous dichloroethane, and then add chlorosulfonyl isocyanate (70 mg, 0.5 mmol) into a 10 mL dry reaction tube ), and the mixture was stirred at 80 °C for 5 h. After the reaction mixture was concentrated under reduced pressure, it was separated by silica gel column chromatography (eluent was petroleum ether / ethyl acetate (v / v = 5 / 1-1 / 2)) to obtain 54 mg of product 4-phenyl-3 -Isopropenyl-4H-1,2,4-benzothiadiazine-1,1-dioxide 2a, 90% yield.

[0064] This reaction also can be carried out in isonitrile, methylene dichloride, chloroform, toluene, and its corresponding reaction time and productive rate are as shown in table 1:

[0065] Table 1

[0066]

[0067] X-ray single crystal diffraction test is carried out to product 2a, can find that this product has the structural unit of benzothiadiazine (such as figure 1 shown).

[0068] The NMR data of product 2a as Figure 2~3 As shown, the deta...

Embodiment 2

[0073]

[0074] Add N-methyl-N-phenylbenzamide 1b (42 mg, 0.2 mmol) to a 10 mL dry reaction tube, 1 mL of anhydrous dichloroethane, and then add chlorosulfonyl isocyanate (70 mg, 0.5 mmol), and the mixture was stirred at 80 °C for 6 h. After the reaction mixture was concentrated under reduced pressure, it was separated by silica gel column chromatography (eluent was petroleum ether / ethyl acetate (v / v = 5 / 1-1 / 2)) to obtain 49 mg of product 4-methyl-3 -Phenyl-4 H -1,2,4-Benzothiadiazine-1,1-dioxide 2b in 91% yield.

[0075] NMR data on product 2b as Figure 4~5 As shown, the details are as follows:

[0076] 1 H NMR (400 MHz, CDCl 3 ): δ 8.03 (dd, J = 1.2 Hz, 8.0 Hz, 1H), 7.71 (t, J = 7.2 Hz, 1H), 7.63 (d, J = 6.8 Hz, 2H), 7.47–7.58 (m, 4H), 7.42 (d, J =8.4Hz, 1H), 3.59(s, 3H).

[0077] 13 C NMR (100 MHz, CDCl 3 ): δ 160.8, 138.7, 133.4, 133.3, 131.9, 129.3, 128.9, 126.9, 124.8, 123.9, 116.4, 39.7.

[0078] HRMS (ESI) for C 14 h 12 N 2 o 2 SNa [M+Na] + calc...

Embodiment 3

[0080]

[0081] Add 1-(3,4-dihydroquinolin-1-yl)-2,2-dimethylacetone 1c (43 mg, 0.2 mmol) to a 10 mL dry reaction tube, 1 mL of anhydrous dichloroethane , then added chlorosulfonyl isocyanate (70 mg, 0.5 mmol), and the mixture was stirred at 80 °C for 6 h. After the reaction mixture was concentrated under reduced pressure, it was separated by silica gel column chromatography (eluent was petroleum ether / ethyl acetate (v / v = 5 / 1-1 / 2)) to obtain 42 mg of the product 3-tert-butyl- 6,7-dihydro-5 H -1,2,4-Benzothiadiazine-1,1-dioxide 2c, 75% yield.

[0082] NMR data on product 2c as Figure 6~7 As shown, the details are as follows:

[0083] 1 H NMR (400 MHz, CDCl 3 ): δ 7.80 (d, J = 6.8 Hz, 1H), 7.40 (d, J = 6.8Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 4.17–4.19 (m, 2H), 3.05 (t, J =6.4 Hz,2H), 2.16 (m, 2H), 1.50 (s, 9H).

[0084] 13 C NMR (100 MHz, CDCl 3 ): δ 167.3, 136.2, 133.4, 127.4, 126.1, 123.7, 122.3, 47.9, 40.6, 29.4, 27.1, 21.5.

[0085] HRMS (ESI) for C 14 h ...

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Abstract

The invention relates to a synthesis method of a 4H-1, 2, 4-benzothiadiazine-1, 1-dioxide derivative. The method comprises the following steps: under a heating condition, taking an aprotic solvent as a reaction medium, mixing N-aryl amide with a structure represented by a general formula I with chlorosulfonyl isocyanate, and carrying out a continuous reaction process of [2+2]-cyclization / carbon dioxide removal / sulfonylation so as to generate the 4H-1, 2, 4-benzothiadiazine-1, 1-dioxide derivative with a structure represented by a general formula II in one step, wherein the structure of the general formula I is shown in the specification, the structure of the general formula II is shown in the specification, Ar represents a substituted or unsubstituted monocyclic or polycyclic aromatic ring, and R1 and R2 represent a hydrogen atom and a substituted or unsubstituted hydrocarbon group. The method is low in cost, non-toxic and high in synthesis efficiency.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing 4H-1,2,4-benzothiadiazine-1,1-dioxide derivatives. Background technique [0002] 1,2,4-benzothiadiazine-1,1-dioxide has important uses in drug development and research. For example, hydrochlorothiazide has a mild antihypertensive effect and is the basic drug for the treatment of hypertension. It can also be used to treat various types of edema and is the first choice for the treatment of moderate edema. Diazoxide is the earliest non-selective potassium ion channel opener used clinically. It is mainly used in the first aid of hypertensive crisis, idiopathic hypoglycemia in children and the treatment of severe hypoglycemia caused by islet cell tumors. In addition, compounds containing this type of skeleton also have anti-inflammatory, antibacterial, and hair growth stimulating effects, such as the following activity containing 1,2,4-benzothiadia...

Claims

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Application Information

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IPC IPC(8): C07D285/24C07D513/06C07D513/04C07D285/20
CPCC07D285/24C07D513/06C07D513/04C07D285/20
Inventor 罗永春张欢欢
Owner LANZHOU UNIVERSITY
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