JPS58177984A - Production of benzothiazinecarboxylic acid - Google Patents

Abstract

PURPOSE:The reaction of a corresponding ester is effected in a nonaqueous solvent containing an alcohol in the presence an alkali metal hydroxide, then the reaction mixture is acidified to give the titled compound used as an important synthetic intermediate of nonsteroidal anti-inflammatory in high yield. CONSTITUTION:An ester of formula I (R is lower alkyl) is heated in an alcohol- containing nonaqueous solvent such as aromatic hydrocarbon or ether in the presence of an alkali metal hydroxide, preferably sodium or potassium hydroxide at the boiling point of the solvent used for 2-5hr to effect reaction. Then, the resultant product is acidified under cooling to give 4-hydroxy-2-methyl-2H-1,2- benzothiazine-3-carboxylic acid 1,1-dioxide of formula II. It is necessary to make the alkali metal hydroxide participate in the reaction in the state of solution or suspension, thus a solvent dissolving an alkali metal hydroxide is used as the nonaqueous solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to 4-hydroxy-2-methyl-2, which is an important intermediate in the synthesis of non-steroidal anti-inflammatory drugs.
H-1,2-benzothiazine-3-carboxylic acid 1,1-
The present invention relates to an industrially advantageous method for producing dioxide.

Conventionally, esters represented by the general formula (1) (wherein R represents a lower alkyl group) (this substance exists as keto and enol tautomers, but in the general formula (1), it is expressed in the enol form) ), 4-hydroxy-2-methyl-2H-1,2-benzothiazine-6- represented by formula (2)
A method for producing carboxylic acid 1,1-dioxide (which also exists as keto and enol tautomers)
- Keto w was considered difficult to implement because it is easily decarboxylated. That is, the product that can be isolated by this method has the formula (
2) The decarboxylated product shown by 2, that is, 2-methyl-2H-1,2
-benzothiazin-4(3u)-one 1,1-dioxide is the main one (e.g. J, Het, erocycle
cchem, 1ro66ro (1976))
.

Subsequently, a method for producing the carboxylic acid represented by the formula (2) was disclosed in Shikai 52-151180, and the ester represented by the general formula (1) was prepared in the presence of a hydroxide ion source such as an alkali metal hydroxide. The formula (
It was shown that the carboxylic acid represented by 2) can be isolated, and a reaction method in a non-aqueous solvent in the presence of a crown ether was shown as a preferred method.

However, even in the case of this method, the yield is only 619% when using expensive raw ether and reacting for a long time of 50 hours in a non-aqueous solvent such as benzene, so it is more advantageous. Development of a manufacturing method is desired.

The present inventors converted the carboxyl group of the carbo/acid represented by formula (2) into a reactive functional group, such as an acid halide or an active ester with N-hydroxysuccinimide, or a mixed acid anhydride with a halognoxic acid ester. By conducting an arylation reaction on various amines, it is possible to produce a group of excellent anti-inflammatory agents, such as piroxicam, when the amine component is 2-aminopyridine. As a result of focusing on the method for producing the carboxylic acid represented by formula (2), the present invention was completed.

In the method of the present invention, an alkali metal hydroxide represented by the general formula MOH (where M represents an alkali metal) is used, and an ester represented by the general formula (1) is heated in a nonaqueous solvent containing alcohol. The carboxylic acid salt produced by the reaction described below is once separated and oxidized in cold water to isolate the carboxylic acid represented by formula (2) as an insoluble crystal, or
When the non-aqueous solvent used is not water-soluble, it is also possible to extract the carboxylic acid salt from the reaction solution with water and acidify the resulting aqueous solution under cooling to obtain the desired product.

Usable alkali metal hydroxides include sodium hydroxide, potassium hydroxide, and lithium hydroxide, but from a practical standpoint, it is preferable to use sodium hydroxide and potassium hydroxide. In addition, as the non-aqueous solvent, aromatic hydrocarbons such as benzene, toluene, and xylene, ketones such as methyl butyl ketone and diglopyl ketone, and ethers such as dioxane and dibutyl ether can be used. Alcohols themselves can also be used. Furthermore, as alcohols contained in the non-aqueous solvent, so-called lower alcohols such as methanol, ethanol, propatool, and butanol, and middle and higher alcohols such as amyl alcohol and hexylalconopeoctanol can also be used. Since the reaction is generally carried out under heating, the non-aqueous solvent used must have a suitably high boiling point and the property of not taking part in the reaction itself.

Furthermore, as a characteristic implementation method of the present invention, MOH is involved in the reaction in a dissolved state or a finely suspended state in the nonaqueous solvent selected in this way, and in order to achieve this purpose, It is necessary to use a non-aqueous solvent that dissolves the MOH. That is, one method is to add -HMO to a solvent with a relatively low boiling point such as methanol or ethanol.
H is dissolved and distilled off as necessary during the reaction process.
~It is also possible to carry out the reaction while maintaining MOH in a suspended state in the reaction solution.

The amount of MOH used in the present invention is in the range of 2 to 10 times, preferably 4 to 8 times, by mole per mole of the ester represented by the general formula (1).

Therefore, when MOH is dissolved in alcohol in advance and used together with other non-aqueous solvents, the amount of alcohol is generally M
It is in the range of about 5 to 40 times, usually 10 to 20 times, relative to OH.

In addition, the amount of the nonaqueous solvent used in the present invention is determined by the general formula (
It is sufficient as long as the amount can dissolve the ester shown in 1).
It is used in an amount of 5 to 60 times, usually 10 to 40 times, relative to the ester. In the present invention, the non-aqueous solvent refers to a solvent whose upper limit is the amount of water that does not adversely affect the reaction in the target reaction of the present invention. The amount is usually 20 mol or less per 1 mol of the ester represented by general formula 1, and when this amount is 20 mol or more, the yield of the target product decreases rapidly.

The reaction temperature in the present invention is preferably carried out at the boiling point of the solvent used, and the temperature range is selected from 50 to 200 °C. The reaction time can be 1 to 10 hours, usually 2 to 5 hours.

The reaction reagents selected in this way and the reaction products obtained under the reaction conditions are usually precipitated as alkali metal salts, so they are separated and, if necessary, alcohol, acetone, etc. , washed with solvents such as benzene, petroleum ether, methylene chloride, etc., and then dissolved in water. It is advisable to cool the temperature of the water used to below 10° C. in order to prevent the decomposition of the metal compound. Next, an acid is added to this aqueous solution to adjust the pH to 6 or less, preferably in the range of 1 to 3. The acids used are preferably so-called inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, and dilute hydrochloric acid is usually easy to use.

The target product can be isolated from this acidic liquid by a method such as filtration. The yield according to the method of the present invention is 70 or more, and 9
It is also easy to make it 0% or more.

The obtained carboxylic acid represented by formula (2) can be further purified as required by, for example, being treated with activated carbon with alcohol or recrystallized. In this case as well, it is preferable to operate at a low temperature of 40°C or lower to avoid decarboxylation reactions, etc., and to increase the recovery rate, water etc.
It is also a good idea to add a solvent that does not dissolve the carboxylic acid shown in 2).

By the method of the present invention, β-ketoester, which is generally said to have a poor hydrolysis yield, can be obtained by the simple operation described above.
It is surprising that it can be converted to β-ketocarbo/acid in a short time and in high yield. As described above, the implementation of the present invention is extremely practical both in terms of the reagents used and in terms of reaction operations, and has great economic and technical value.

Next, the present invention will be further explained by examples.

Example 1 Sodium hydroxide 32. Of (0.8 mol) wo3
Dissolved in 0Cl m/methanol, and the solution was diluted with 50-6
The mixture was added to 1 t of xylene kept at 0°C and stirred. Then methyl 4-hydroxy-2-methyl-2H-1.

26.9 f (0.1 mol) of 2-benzothiazine-6-carboxylate 1,1-dioxide were added.

Next, the temperature was finally raised to about 120°C while methanol was distilled out of the thread. Approximately 2 during this time
It took time. The resulting cloudy reaction solution was cooled to about 15°C, and the product was separated. Wash the waste with acetone,
Thereafter, it was dissolved in 500 m of ice water, and a small amount of insoluble matter was removed by filtration. Concentrated hydrochloric acid with a concentration of 36% was added little by little to the aqueous solution under water cooling to bring the pH to an acidic state around 1, and the precipitated crystals were separated and washed with 500ml of cold water. Furthermore, this crystal was dissolved in 120 ml of methanol at 35°C, activated carbon 157 was added, and after stirring, the activated carbon was removed by Sawabetsu, and while the methanol solution of Solution F was cooled in ice water, cold water was added to it for 2 hours.
00m/poured. After cooling sufficiently, add 1 piece of scale-like crystal.
It was isolated by filtration and washed with cold water. The obtained crystals were air-dried to give 20.72% of 4-hydroxy-2-methyl-2H-1.2-benzothiazine-6-carboxylic acid (yield: 811%).
) was obtained.

Melting point: 141°C (decomposition) IR (cotton':;, cm-1): 3'450. 3
100-2500.

1 650, 1 580, 1 550.

1 460, 1 350, 1 295.

1 270, 1 1 Bo, 1 1 60.

1130, 1070, 1050.

920, 845,775 NMR (δDM80-d6, ppm): 2.9
0 (3H, S), 7.7-8.2 (4H.

MS m), 9.0-10.4 (2H, br) Examples 2-8 Experiments were conducted under various conditions according to the method of Example 1, and the experimental results are shown. However, the raw material Gostil used was 13
．． 5S and sodium hydroxide were 8.07, and the yield of carboxylic acid was calculated based on the weight before purification. The results are shown in the table.

Reference example 1 Thorium hydroxide 8. Of/ (0.2 mol) in water 1
87 (1 mol) in 150 iJ of methanol containing
2H-1,2-benzothiazine-3-=calhokyflate 200 ml of xylene at 70°C in which 135 g (0.05 mol) of 1,1-dioxide was dissolved! and stirred. Next, the temperature was gradually raised, and the reaction was continued for 15 hours while methanol was distilled out of the thread.

The reaction temperature during this period was finally 117°C. The reaction mixture was cooled in ice water and the product was separated before dipping into ice water for 4 hours.
Dissolved in ooml. Concentrated hydrochloric acid (filtered 6 ml) was added little by little to this solution to make it acidic, and the precipitated crystals were separated and washed with cold water at 200 mA'. The obtained crystals were air-dried to give 4-hydroxy 2-methyl-2H-1,2-benzothiazine-
6-carboxylic acid J2.3f (yield 18 .0%) was obtained.

Comparative Example 1 Methyl 4-hydroxy-2-methyl-2H-1゜2-benzothiazine-6-carboxylate 1,1-dioxide 1o y (o, o37 mol) and sodium hydroxide 321 (0,8 mol) The solution was added to 100 me of water and heated at 90-95°C for 15 hours, then the reaction mixture was cooled in ice water. Add concentrated hydrochloric acid little by little to this mixture.
H was adjusted to 1. The precipitate was separated by i4 and washed with water. It was then dissolved in warm methanol and filtered through phlegm. The r solution was cooled in ice water and water was added. The resulting precipitated crystals were separated and air-dried to obtain 14 g of 4-hydroxy-2-methyl-2H-1,2-pentthiazine-6-carboxylic acid (yield: 142%).

Claims (1)

[Claims] (1) A product obtained by heating an ester represented by the general formula (1) (wherein R represents a lower alkyl group) in an alcohol-containing nonaqueous solvent in the presence of an alkali metal hydroxide. By acidification, 4-hydroxy-2-methyl-2H-1,
A method for producing benzothiazinecarboxylic acid, which comprises producing 2-benzothiazine-6-carboxylic acid 1,1-dioxide.