JPH10130273A - New imidazobenzothiazine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound expected to have utility as medicine and agrochemical. SOLUTION: This compound is shown by formula I (R1 is a 1-6C alkyl; R2 is a 1-2C alkyl; R2 and R3 are each a 1-2C alkyl, a halogen or nitro) such as 4H-imidazo[2,1-c][1,4]benzothiazine-2-carboxylate, etc. The compound is obtained, for example, by reacting a 1,4-benzothiazine derivative of formula II as a starting raw material with a halopyruvic acid ester such as ethyl bromopyruvate to give a quaternary ammonium salt of formula III as an intermediate and heating the intermediate under reflux.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel imidazobenzothiazine derivative which is expected to be useful as pharmaceuticals and agricultural chemicals.

[0002]

BACKGROUND OF THE INVENTION Many compounds having a 1,4-benzothiazine skeleton have been reported to date, and many of them have important biological activities.

[0003] On the other hand, very few research reports have been made on imidazobenzothiazine derivatives, and there is a case in which a compound (II) represented by the following structural formula was synthesized by Shridhar et al. No remarkable results have been obtained for these anthelmintic activities (Indian JC
hem., 21B, 130 (1982)).

[0004]

Embedded image

However, since many compounds having a 1,4-benzothiazine skeleton have an important physiological activity, it is presumed that some imidazobenzothiazine derivatives also have an important physiological activity. .

Accordingly, an object of the present invention is to obtain a novel imidazobenzothiazine derivative.

On the other hand, the inventors of the present application have previously attempted a Pinner-type cyclization reaction using an acid-alcohol solution on a sulfoxide compound (5) obtained by allowing an oxidizing agent to act on a sulfide compound (4). As shown in the following formula, at the same time as the cyclization, the Pummerer reaction with the alcohol proceeds, and the 3-mer of the structural formula (2)
It has been proposed that amino-2-substituted-2H-1,4-benzothiazine can be obtained (Japanese Patent Application No. 7-303865).

[0008]

(Equation 1)

The 1,4-benzothiazine derivative obtained here is a novel substance which is expected to be useful as a pharmaceutical or agrochemical, but the present inventors further studied the 1,4-benzothiazine derivative of 1,4-benzothiazine. Using a ring and an amino group,
A method for forming an imidazole ring as shown in the following formula was studied.

[0010]

(Equation 2)

As a result, the 1,4-benzothiazine derivative was reacted with ethyl bromopyruvate in DMF at 100 ° C., but no satisfactory result was obtained. However, the 1,4-benzothiazine ring was not reacted with ethyl bromopyruvate. It has been found that, once a quaternary ammonium salt is formed between the two, and then heated and refluxed, an imidazole ring is formed with a high yield and the desired product is obtained.

[0012]

Accordingly, the present invention proposes a novel imidazobenzothiazine derivative represented by the following structural formula (1).

[0013]

Embedded image

In the formula, R ₁ is a chain or cyclic alkyl group having 1 to 6 carbon atoms, R ₂ is an alkyl group having 1 or 2 carbon atoms,
₃ and R ₄ are hydrogen, an alkyl group having 1 or 2 carbon atoms, a halogen group, a nitro group

As the imidazobenzothiazine derivative, for example, as shown in the following reaction formula, a 1,4-benzothiazine derivative is used as a starting material, and a halopyruvate such as ethyl bromopyruvate is allowed to act on the derivative to give a quaternary ammonium salt. It is obtained by forming a salt and then heating to reflux.

[0016]

(Equation 3)

The 1,4-benzothiazine derivative as a starting material can be obtained by cyclizing a sulfoxide compound using an acid-alcohol solution as described above.

[0018]

Embodiments of the present invention will be described below. Example 1 (A) Synthesis of quaternary ammonium salt of 3-amino-2-substituted-2H-1,4-benzothiazine <Operation> 3-Amino-2-substituted-2H-1,4-benzothiazine
In contrast, 1.5 equivalents of ethyl bromopyruvate were stirred in the solvent tetrahydrofuran (THF) for 24 hours at room temperature. As a result, a crude 3-amino-2-substituted-2H-1,4-benzothiazine quaternary ammonium salt was obtained. Here, the obtained quaternary ammonium salt was used for the next reaction without purification.

(B) Synthesis of 4H-imidazo [2,1-c] [1,4] benzothiazine-2-carboxylate <Operation> The obtained quaternary ammonium salt was heated to reflux in methanol for 6 hours. The reaction solution was neutralized with an aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, and the solvent was distilled off to obtain a crude purified product.

<Purification> The crude product was subjected to silica gel column chromatography (n-hexane: ethyl acetate =
2: 3) to give the desired product. Rf value 0.17 (Eluent, CHCl ₃ : MeOH = 50: 1)

<Identification> From the 1H-NMR (CDCl ₃ ) spectrum of this compound, δ (ppm) 2.18 (3H, s) was CH ₃ CO- group, 3.97 (2H, s)
-SCH ₂ -group, 7.13 to 7.45 (4H, m) aromatic ring hydrogen, 7.77
(1H, s) showed imidazole hydrogen and 8.62 (1H, br) showed amino hydrogen.

Also, from the 1H-NMR (DMSO-d6) spectrum, δ
(ppm) 2.05 (3H, s ) in CH ₃ CO group, from 7.17 to 7.58 (4H, m) in the aromatic ring hydrogen, 7.72 (IH, s) imidazole hydrogen, 10.37 (1
H, br) showed a signal of an amino group.

Further, the compound obtained from the fact that absorption of a carboxyl group was observed at 1650 cm ^-1 from the IR spectrum was 4H-imidazo [2,1-c] [1,4] benzothiazine-2-carboxylate. It was confirmed.

In the synthesis of 4H-imidazo [2,1-c] [1,4] benzothiazine-2-carboxylate, a similar experiment was conducted by changing the amount of ethyl bromopyruvate, the solvent, the reaction conditions and the like. went. As a result, it was clarified that similar reactivity was exhibited. The yield and the like are shown in Table 1 below.

[0025]

[Table 1]

The ethyl bromopyruvate used in the step of synthesizing the imidazobenzothiazine derivative has no activity toward halogen, nitro and alkyl groups on the aromatic ring. Synthesis of compounds containing functional groups such as nitro and alkyl groups is of course also possible.

[0027]

In summary, according to the present invention, a novel imidazobenzothiazine derivative can be obtained by forming an imidazole ring using a 1,4-benzothiazine ring and an amino group of a 1,4-benzothiazine derivative. did it.

Claims (2)

[Claims] 1. A novel imidazobenzothiazine derivative represented by the following structural formula (1). Embedded image In the formula, R ₁ is a chain or cyclic alkyl group having 1 to 6 carbon atoms,
R ₂ is an alkyl group having 1 or 2 carbon atoms; R ₃ and R ₄ are hydrogen; an alkyl group having 1 or 2 carbon atoms; a halogen group; 2. The method according to claim 1, wherein a 1,4-benzothiazine derivative represented by the following structural formula (2) is used as a starting material, and a quaternary ammonium salt represented by the following structural formula (3) is obtained as an intermediate. New imidazobenzothiazine derivative. Embedded image Embedded image In the formula, R ₁ is a chain or cyclic alkyl group having 1 to 6 carbon atoms,
R ₂ is an alkyl group having 1 or 2 carbon atoms; R ₃ and R ₄ are hydrogen; an alkyl group having 1 or 2 carbon atoms; a halogen group;