JPS6025984A - Preparation of benzothiazine derivative - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a hypotensor, antibacterial agent, etc. by one process, by reacting a 2-aminobenzenesulfonamide derivative with a carboxylic acid derivative in the presence of a polyphosphoric acid trimethylsilyl ester. CONSTITUTION:A 2-aminobenzenesulfonamide derivative shown by the formula I (R<1>-R<4> are H, or halogen) is reacted with a carboxylic acid derivative shown by the formula R<5>CO2H(R<5> is H, alkyl, alkenyl, cycloalkyl, arylalkyl, aryl, or heterocylic ring) by the use of a polyphosphoric acid trimethylsilyl ester as a condensation agent at 30-200 deg.C to give the desired 2H-1,2,4-benzothiazin-1,1- dioxide derivative shown by the formula II. An amount of the polyphosphoric acid trimethylsilyl ester is 0.5-100 equivalent, preferably 2-30 equivalent based on 1 equivalent compound shown by the formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention represents a compound represented by the general formula 4 (wherein R1, R'', R8 and R are hydrogen atoms or), and R5 is a hydrogen atom, an alkyl group, an alkenyl group, or a cycloalkyl group. , arylalkyl group, aryl group or heterocyclic group), 4-benzothiadiazine 1.1-
The present invention relates to a method for producing a dioxide derivative.

The 2H-1,2,4-benzothiadiazine 1,1-dioxide derivative represented by the general formula (I) obtained by the method of the present invention has physiological activities such as antihypertensive agents and antibacterial agents. (e.g. J, G, TOpl
iSS et al., J. Mea., chem, 15, 894
(1972)).

Conventionally, 2H-1,2,4- represented by the general formula α)
Benzothiadiazine 1,1-dioxide derivatives.

A 2-aminobenzenesulfonamide derivative represented by the corresponding general formula (where R, R, R and R represent a hydrogen atom or )/logen atom) and a 2-aminobenzenesulfonamide derivative represented by the general formula is a hydrogen atom, an alkyl group, an alkenyl group, a cycloalkyl group, an arylalkyl group, an aryl group, or a heterocyclic group). , Journal of the Chemical Society of Japan, 19713.1810).

As a result of numerous studies to shorten this manufacturing process, the present inventors have developed a 2-aminobenzenesulfonamide derivative represented by the general formula (n) and a carboxylic acid derivative represented by the general formula (Ill). It was discovered that the 5J-1,2,4-benzothiadiazine 1,1-dioxide derivative represented by the above formula (I) can be produced in step 1 by reacting the 5J-1,2,4-benzothiadiazine 1,1-dioxide derivative with the formula (I) in the presence of polyphosphoric acid trimethylsilyl ester. . Note that this polyphosphoric acid trimethylsilyl ester can be easily produced by the reaction of phosphorus pentoxide and hexamethyldisiloxane (for example, K, y
ama-moto,)i,Watanabel,(3
ham, Lett, 19E12, 12.25).

2-aminebenzene represented by the general formula (n) or a hydrogen atom and a halogen atom such as fluorine, chlorine, bromine, and fluorine can be used in combination.

Examples of the stronger 2-aminebenzenesulfonamide derivatives include 2-aminebenzenesulfonamide, 2-amino-8-chlorobenzenesulfonamide, and 2-amino-4-chlorobenzenesulfonamide.
-chlorobenzenesulfonamide, 2-amino-5-chlorobenzenesulfonamide, 2-amino-6-chlorobenzenesulfonamide, 2-amino-4-fluorobenzenesulfonamide% 2-amino-5-fluorobenzenesulfonamide, 2-amino -8-bromobenzenesulfonamide, 2-amino-4-bromobenzenesulfonamide, 2-amino-5-bromobenzenesulfonamide, 2-amino-6-bromobenzenesulfonamide, 2-amino-t-iodobenzenesulfone Amide,
2-amino-5-iodobenzenesulfonamide, 2-
Amino-8,4-dichlorobenzenesulfonamide, 2
-amino-4,5-dichlorobenzenesulfonamide,
2-amino-4,6-dichlorobenzenesulfonamide, 2-amino-4,5-difluorobenzenesulfonamide, 2-amino-4,5-dibromobenzenesulfonamide, 2-amino-8,4,5,6 -detrachlorobenzenesulfonamide can be exemplified.

As the carboxylic acid derivative represented by the general formula (III), a benzoic acid derivative represented by the general formula can be used. The substituents Rn, R10, R11, R12 and R18 in formula (V) can be used in combination with the substituents shown below. i.e. hydrogen atoms, halogen atoms such as fluorine, chlorine, bromine and iodine, alkoxy groups such as nitro, cyan, hydroxy, methoxy and ethoxy groups, methyl, ethyl, propyl and hexyl groups. An alkyl group having 1 to 10 carbon atoms.

Such benzokuma derivatives include benzoic acid, 2-chlorobenzoic acid, 8-chlorobenzoic acid, 4-chlorobenzoic acid, 8-fluorobenzoic acid, 4-fluorobenzoic acid, 8-chlorobenzoic acid,
-bromobenzoic acid, 4-bromobenzoic acid, 8-cyanobenzoic acid, 4-cyanobenzoic acid, 8-hydroxybenzoic acid, 4-hydroxybenzoic acid, 8-methoxybenzoic acid,
4-methoxybenzoic acid, 8-ethoxybenzoic acid, 4-ethoxybenzoic acid, 2-toluic acid, 8-toluic acid.

Examples include 4-toluic acid, 3-ethylbenzoic acid, and Φ-ethylbenzoic acid. In addition, other usable general formulas ([Carboxylic acid derivatives represented by 0 include acetic acid, formic acid, propionic acid, and butanoic acid.

Straight-chain and branched alkylcarboxylic acids having 1 to 15 carbon atoms, such as pentanoic acid, hexanoic acid, decanoic acid and pivalic acid, cycloalkanecarboxylic acids, cyclobutanecarboxylic acids, cyclopentanecarboxylic acids, cycloalkanecarboxylic acids 4 to 15 carbon atoms, such as acids and cyclodecanecarboxylic enzymes. ), cycloalkanecarboxylic acids, arylalkylcarboxylic acids of carbon number 8 to 16', such as phenylacetic acid, phenylpropionic acid, phenylphthanecarboxylic acid, acrylic acid, crotonic acid, hexenoic acid, nonenoic acid and cinnamic acid. Examples include unsaturated carboxylic acids having 8 to 15 carbon atoms such as acids, and heterocyclic carboxylic acids such as nicotinic acid and furocarboxylic acid.

The amount of trimethylsilyl polyphosphate used in the method of the present invention is determined by the amount of 2 expressed by the general formula ((1)).
-0.5 equivalent of amine benzenesulfonamide derivative ~
Although ioo equivalents can be used.

In order to carry out the reaction with good yield and economically, it is preferable to use 2 to 80 equivalents.

Carbon rr'i represented by the above general formula (I[I)
The amount used is 1 equivalent of the 4 2-amine benzenesulfonamide derivatives represented by the above general formula (II).
: It is possible to use 1 to 10 equivalents, but in order to achieve a good yield and to carry out the reaction economically, it is preferable to use 1 to 5 equivalents.

When carrying out the method of the present invention, the reaction can proceed quickly without using a reaction solvent. ; Aromatic solvents such as benzene, toluene, chlorobenzene, and nitrobenzene; Sulfur solvents such as sulfolane and diphenylsulfone; Ether solvents such as ethyl ether, propyl ether, tetrahydrofuran dioxane, phenyl ether, and anisole; Oyohinitromethane acetonitrile, vinegar Solvents such as ethyl chloride can be used.

-Also, in the present invention, the reaction temperature can be selected from 0°C to 800°C, but the reaction proceeds slowly at low temperatures, and the reaction at extremely high temperatures is not economical. A target? In order to obtain a good yield and economically, it is preferable to select a reaction temperature of 80°C to 200°C.

Next, the present invention will be explained in more detail with reference to Examples.

Distilled pentoxide 7 (2,84 f 2 o mmoJ) was suspended in dehydrated 1,2-dichloroethane 5d, and hexamethyldisiloxane (4,26 ml, 20 n1 mo/
? ) f Added at room temperature under a nitrogen stream. 15 minutes at room temperature
After stirring for 15 minutes while heating under reflux, add benzoin (805 ml,
2.5 mmoz) followed by 2-aminebenzenesulfonamide (4B1~.2.5 mmoz)
added. The reaction solution was heated under reflux for 5 hours, and the resulting solution f was poured into 180 tJ me of ice water. The formed crystals were filtered, washed with water, and dried to give 8-phenyl-
4.80 mg (yield: 74) of 214-1,2,4-benzothiadiazine 1,1-dioxide was obtained. A more pure compound was obtained by recrystallization from ethanol, m, J), 811°C (literature value 817°C).

■, R, (infrared absorption spectrum): 12"10
1150a% Example 2 3-Phenyl-2H-1,2,4-benzothiapentoxide (2,s4y, zonnmoz) was suspended in 5 ml of dehydrated methylene chloride, and hexamethyldisiloxane (4,257d) was suspended in 5 ml of dehydrated methylene chloride. , 20mm07)
was added at room temperature under a nitrogen stream. After stirring for 80 minutes at room temperature, the methylene chloride was distilled off under a stream of nitrogen. 5 m, l'; c of dehydrated sulfolane was added to the obtained distillation residue, and further benzoic acid (805 ml) was added.

2.5 mmol) and 2-aminobenzenesulfonamide (41311 ng, 2.5 mm0J) were added. Example 1 was prepared by heating the reaction solution to 120° C. for 2 hours and pouring the resulting solution into 800 rnl of ice water.
8-phenyl-2H-1,2,4-benzothiadiazine 1,1-dioxide was obtained in the same manner as above. Yield: 545■ (8
Section 4) Pentoxide 7 (2,84,f, 20 mmoJ
) was added to 5 ml of dehydrated methylene chloride, and hexamethyldisiloxane (4,26 mm, 20 mm) was added at room temperature under a nitrogen stream. After stirring at room temperature for 80 minutes, methylene chloride was added under an inhibitor stream. The distillation residue obtained was heated to 160°C, and benzoic acid (305 nog, 2.5
mmot'), 2-aminebenzenesulfonamide (
481 mg, 2.511111101) was added. 8-phenyl-2H-1,2,4-benzothiadiazine 1,1-dioxide was prepared in the same manner as in Example 1 by reacting at the same temperature for 2 hours and pouring the resulting solution into 300711 ice water. Obtained.

Yield 54BTq (1114%) 4-Toluyl 840 was obtained by the same operation as in Example 8.
mW, 2.5 mmoz) and 2-aminobenzenesulfonamide (481Mi7, zt5 mtuoz) to 8-(+tolyl)-72H-1.2.4-benzothiadiazine 1.1-dioxide 680 yv ( A yield of 889/) was obtained. m. p. 355℃ (literature value 855
℃) 1, R. : 1280, 1155 o and 880an
4-Methoxybenzoin □ by the same operation as in Example 8
(880++y, 2.5 mm07) and 2-aminobenzenesulfonamide (4811+v, L
5 mmol) to 8-(4-methoxyphenyl)
-2H-1. 2. 4-Benzothiadiazine 1,1-dioxide 120m? (yield 89%).

m, p. 824°C (literature value 824°C) 1, R. : 1
i11B0, 1160. 1250 and 880cm
4-chlorobenzoic acid (39
1yy, z. b mmol 2-aminobenzease/l/honamide (4311n9, L5 mmoz)
From 8-(4-ri).

Lophenyl]ZH 1,Z,4-benzothiadiazine 1
．． 672 .mu. of 1-dioxide (yield: 92 qb) was obtained.

Tfl. p. 848℃ (literature value 840 ~ 842.5℃
)1, R. :1260, 1150 and 825crn
'8-Nitrobenzoic acid (
4ZOmg, 2.5mmOj? ) and 2-aminobenzenesulfonamide (431q, 2.511mO
f) to 8-(3-nitrophenyl)-ZI(-1,
Z,4-Benzothiadiazine 1,1-dioxide 758
~(Yield: 96 cm) was obtained.

■B, p, 845℃ (literature value 888-884.5℃)
1.R. : 1290, 1160. 1580 and 1850m-1 Li-nitrobenzoin G (420'ing, 2.5 mmoz) was prepared by the same procedure as in Example 8.
) and 2-aminebenzenesulfonamide (431 m
g, 2.5 mmoz) to 3-(4-nitrophenyl)-2H- 1. 2. 705 mg (yield 98%) of 4-hen'sothiacyazine 1.1-dioxide was obtained.

m, p, 889°C (literature value 376-17.5°C) engineering. R
．． : 1280, 1160, 1580 and 18
50 cmNicotine liquor (
810 mg, 2.5 mmol) and 2-aminebenzenesulfonamide (481 mg, 2.5 mmol)
8-(3-bilicinori'-2)(-1,2,4
-Benzothiadiazine 1,1-dioxide 264m'j
(yield: 41 cm). m, p, 818℃, R3:
1280 and 1150cm' elemental analysis two calculated values (a)
C55,60H8,47N 16.22 actual value (9))
O55,68H8,84N 16°17side Cinnamic acid (8707 ng) was obtained by the same procedure as in Example 3.

2.5 mmol) (!l: 2-aminebenzenesulfonamide (481”i7, 2.5 mmol
) to 8-(2-7x 2/l/ x 7nyl) -2
H-1,2,4,-Benzothiadiazine 1. l-dioxide 710 m'! (yield 91%). mp,
840°C (literature value 822-824..5°C) 1, R,: 1260.1155 and 970crn-
2-phenylpropion f by the same operation as 1 oxide Example 8
l'f((375+++s+, 2.5u+mo/)
and 2-aminobenzenesulfonamide (4131m'J
, 2.5 mmol) to 1.1 8-(2-phenylethyl)-2H-1,2,4-benzothiadiazine
-dioxide 634π7 (yield 89%) was obtained. m, p
, 286°C 1, R,: 1280 and 1150>-1 Elemental analysis:
Pitch 1. Value (related) 062.94 H4,90N 9.7
9 Actual measurement value (A) 068.14 ) 141.65 NL?
? Dicyclohexane carbon Hq (s'tomq, Z, 5 mmoz) and 2-
7 Minohensensulfonamide (481mg, 2.
5 + nmoJ ) to 3-zochlorohexyl-2H-1
,L 4-benzothiadiazine 1,1-dioxide 5q
6rrq (yield 87ti) was obtained.

m, p, 285°C 1, R,: 1280 and '160 on'-" Elemental analysis two calculated values (%) G 50.1D H6,06N
10.61 Actual value (%) Q 59.14. 1 work 6
．． 11 N 11j, 52 Caproic acid (290■, 2.5111m0I and 2-
Amine benzenesulfonamide (481!, 2.5
470 my (yield: 75%) of 3-pentyl-2H-1,2,4-benzothiadiazine 1,1-dioxide was obtained from 1 mmol. m, p, 167-16 (1℃ (literature value 142-144℃) ■, R1: 2925, 1285 and 1160 cm
-' Pivalic acid (255r
q, 2.5 mmo7? ) and 2-aminebenzenesulfonamide (491'?, 2.5 m1m0J)
310 m9 of 8-(t-butyl)-1H-1,2,4-penzothiadiane 1,1-dioxide (yield 5z%)
) was obtained. m, p, 258°C 1, R,: 2975.
1280 and 1185c+++” elemental analysis two calculated values (
H) 055.46 H5,88N], 1.76 Actual value (%) C55,50H5,90N 11.78 Butanoic acid (220 2.5 m
moz) and 2-amino-4-chlorobenzenesulfonamide (519 ~, 2.5 mmol to 6-chloro-8-propyl 2'H-1,2,4-benzothiadiadiyl,1-dioxide 474 my (78% )
', I K'l l'v.

m, p, 265℃ (literature value 266-267℃) ■, R
,: 2980.1280 and 1160crnAs described above, the present invention comprises a 2-amine benzenesulfonamide derivative represented by the general formula (n), a carboxylic acid derivative represented by the general formula (III), and a total phosphoric acid. By reacting in the presence of trimethylsilyl ester, 2H-1,2,4 represented by the above formula (I) is obtained in step 1.
・It is recognized as a new and useful invention in that it enables the production of benzothiasia 1,1-oxide rust conductor in one step, making it possible to mass-produce useful compounds with physiological activity such as antihypertensive agents and antibacterial agents at low cost. .

Claims (1)

[Claims] 1 General formula (wherein R, R, R and R represent a hydrogen atom or a halogen atom, and R is a hydrogen atom, an alkyl group, an alkenyl group, a cycloalkyl group, an arylalkyl group, an aryl group) or a heterocyclic group) represented by I(-1,21
, 4-benzothiadiazine 1,1-dioxide derivative, in which polyphosphoric acid trimethylsilyl ester is present as a condensing agent to produce the general formula (wherein R1, R2, R8 and R4 are the same as the above-mentioned substituents) It is characterized by reacting a 2-aminobenzenesulfonamide derivative represented by the formula % with a carboxylic acid derivative represented by the general formula % (1) (wherein R is the same as the above-mentioned substituent). 21(-
A method for producing a 1,2,4-benzothiadiazine 1,1-dioxide derivative.