JPS589105B2 - 2-(4'-Chlorphenyl)-3-thikane-4-metathiazanone-1.1-Dioxide Ruino Seizouhouhou - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula [R is CnH2n+1:n=1-4 or CnH2n
-1: represents n=3 to 4.

The present invention relates to a novel method for producing 2-(4'-chlorophenyl)-3-substituted-4-methathiazanone-1,1-dioxides represented by the following.

These compounds are extremely useful substances as tranquilizing muscle relaxants, and the substance of the present invention has the general formula (R is the same as above).

) can be easily obtained by oxidizing metathiazanones shown in

Several methods have been known for the synthesis of metathiazanones, but some require expensive raw materials and others have low yields, so they are not advantageous as industrial production methods. .

For example, according to Japanese Patent Publication No. 35-632, metathiazanone is synthesized by adding methylamine to parachlorobenzaldehyde to form a Schiff base and condensing it with β-mercaptopropionic acid, but this method has a low yield.

According to Japanese Patent Publication No. 45-26495, parachlorobenzaldehyde is reacted with N-methyl-β-mercaptopropionamide to form N-methyl-β-(α-hytrooxy-p-chlorobenzyl)-thiopropionamide. Metathiazanone is obtained by dehydration and ring closure, but this method requires a long and expensive manufacturing process for the raw material N-methyl-β-mercaptopropionamide.

Furthermore, according to Japanese Patent Publication No. 48-33752, metathiazanone is obtained by reacting p-chlorpenzal chloride and N-methyl-β-mercaptopropionamide in the presence of pyridine, but even with this method, the raw material, Both solvents are expensive and the yield is only 51%.

A particular disadvantage of the above method is that metathiazanone cannot be obtained in a pure form.

As a result of careful consideration of economically advantageous production methods for metathiazanone, the present inventors have already proposed several methods that are advantageous for industrial production.

(Patent Application No. 47-78755 (Japanese Patent Application No. 49-35389)
), Japanese Patent Application No. 1973-29375 (Japanese Patent Application No. 116-1973)
No. 079), Japanese Patent Application No. 1424-15) (Japanese Unexamined Patent Publication No. 50-93982) However, these production processes still lacked the purity of the metathiazanone produced.

As a result of intensive research to obtain industrially advantageous high-purity, high-yield metathiazanone, the present inventors amidated the thioacetal of general formula (■I) as shown in the reaction formula below.
It was discovered that metathiazanone can be obtained in quantitative yield and in good purity by reacting chlorobenzaldehyde thioacetal amide (■) with an equimolar amount of p-chlorobenzaldehyde in the presence of an acid catalyst, and has developed an advantageous industrial production method. The present invention has been achieved.

[R is CnH2n+1: n=1 to 4, or CnH2
n-1: n = 3, 4, R' is a hydrogen atom or Cn
H2n+1: n=1 to 8 or represents an aryl group.

] In order to obtain metathiazanone-1,1-dioxides, which are the compounds of the present invention, by oxidizing the metathiazanones, an oxidizing agent that is generally used for converting organic sulfides into sulfone compounds, such as potassium permanganate and permanganate, is used. Although oxidation may be carried out using hydrogen oxide, etc., it is preferable to use the oxidation method described in Japanese Patent Application No. 142415/1987 filed by the present inventors, that is, hydrogen peroxide and tungstic acid or its salts, or peroxide. Oxidation is preferably carried out using hydrogen and molybdic acid or its salts.

Further, the present invention will be explained in detail.

The thioacetal ester (■) used as a raw material can also be synthesized by a known method (Bull. Chem.
．． Soc. Japan, 45 913 (1972)),
The inventors have alternatively used p-chlorobenzaldehyde and β
- Quantitative production of thioacetal esters by simply adding a small amount of acid to an equimolar alcoholic solution of mercaptopropionic acid (
It was confirmed that it could be obtained with a yield of 95 to 98%.

The thioacetal ester (■) easily obtained in this way can be prepared as it is or after dissolving it in an organic solvent, preferably methanol, ethanol, benzene, etc., by adding a primary amine to the thioacetal ester. Add ~2 times the mole, preferably 15 to 2.0 times the mole,
Thioacetalamide (■) can be produced by reacting at a temperature of 5 to 60°C.

In this amidation reaction, the reaction time can be shortened by adding a small amount of alkali, such as caustic soda, caustic potash, sodium carbonate, or metal alcoholate, and the reaction can be carried out industrially advantageously.

The alkali is usually used in an amount of 0.5 to 10%, but it can be freely selected depending on the reaction time and reaction temperature.

In the reaction step between thioacetalamide (■) and p-chlorobenzaldehyde, (■) is dissolved in an organic solvent such as benzene, toluene, xylene, chloroform, dichloroethane, etc., preferably benzene or toluene, and then treated with an acid catalyst, e.g. p-Toluenesulfonic acid, benzenesulfonic acid, sulfuric acid, hydrochloric acid, potassium sulfite, preferably p-
-Add toluenesulfonic acid for 1-24 hours, 80-13
The reaction mixture is heated at 0°C, washed with water after the reaction, and the solvent is distilled off to quantitatively obtain metathiazanones (■).

The metathiazanones obtained in this manner are generally of high purity with no impurities observed in nuclear magnetic resonance spectroscopy.

For example, there is no record of crystals of 2-(4'-chlorophenyl)-3-methyl-4-metathiazanone in which R is a methyl group, but metathiazanone (■) obtained by the above method (
R=CH3) crystallizes without the need for a purification step and has a melting point of 4.
Give a temperature of 9-51°C.

In this way, extremely pure metathiazanone can be obtained in high yield through a simple reaction.

The 2-(4'-chlorophenyl)-3-substituted-4-metathiazanones obtained as described above were oxidized with 2-
(4'-Chlorphenyl)-3-substituted-4-methathiazanone-1,1-dioxides (V) are obtained.

A preferred oxidation method is to dissolve metathiazanones (■) in benzenes, alcohols, or lower alkyl halides, and add 2 to 10 times the mole of 30 to 35% hydrogen peroxide (to metathiazanone), tungstic acid or molybdic acid, or the like. It was added dropwise to a solution of 1 to 50% salts (based on metathiazanone) with stirring, and reacted at 20 to 80°C for 0.5 to 5 hours. After the reaction, if a water-insoluble solvent was used, the aqueous layer was separated, and the alcohol When using such a product, it can be easily obtained by concentrating, extracting the water-insoluble solvent, washing with water, concentrating the solvent, cooling, and collecting the precipitated crystals by filtration.

In addition, in the present invention, since metathiazanone (■) is obtained with high purity, there is no need to isolate it from the reaction solution of metathiazanone (■) after the ring-closing reaction, and the oxidation process can be carried out continuously, making it suitable for industrial use. This is extremely advantageous.

Examples are shown below.

Example 1 (a) Ester thioacetal (■, R'=CH3) 1
Dissolve 9 g (0.052 mol) in 50 ml of methanol, and add a solution of 0.5 g of caustic soda and 10 ml of methanol.

Furthermore, 20 ml of 40% methylamine aqueous solution was added and stirred at room temperature for 3 days.

This reaction solution was added to 250 ml of water with stirring to precipitate crystals.

The crystals are filtered and dried to obtain 18.9 g (100%) of N-methyl-thioacetalamide (■).

A pure product can be obtained by recrystallizing it with benzene.

Melting point 115.5-116.5°C (b) N-methyl-teoacetalamide (■, R=CH3) 6.0 g (16.
6 mmol) and p-chlorobenzaldehyde 2.35 g
(16.6 mmol) was dissolved in 30 ml of toluene, and p
- Add 0.2 g of toluenesulfonic acid and heat under reflux for 8 hours.

After cooling the reaction solution, it is washed with saturated sodium bicarbonate water and then with water.

Toluene was distilled off under reduced pressure to obtain a viscous oil.

If this is left at room temperature for a day, all the crystals are 2-(4'-
Chlorphenyl)-3-methyl-4=metathiazanone (
(2), R=CH3) is obtained.

Yield 7.7g (96%) Further recrystallized with ether-n-hexane, melting point 49-5
Obtain 1°C.

(c) Add 62 mg of sodium tungstate dihydrate to 8.5 ml of 30% hydrogen peroxide solution, and while stirring at 60°C, 2-(4'-chlorophenyl)-3-methyl-4
- Metathiazanone (■, R=CH3) 6.0g in 20m
1 of a solution dissolved in benzene was added dropwise over 30 minutes.

After the dropwise addition was completed, the mixture was stirred at 60°C for 1 hour, separated, and washed with 60°C warm water.

The organic layer was cooled to room temperature or lower to precipitate crystals, and filtered to obtain 6.9 g of white crystals.

This crystal contains 1/2 molecule of benzene as a crystal solution.

Yield 90%.

While melting this at about 60°C, expel benzene and recrystallize it from isopropanol to produce 2-(4'-chlorophenyl)-3-methyl=4-metathiazanone-1,1-dioxide (V,R=CH3)5 .6g was obtained.

Melting point: 115.5°C.

Yield 82%. Example 2 (a) Ester thioacetanol (■, R'=CH3)
3.6 g was dissolved in 10 ml of methanol, 0.5 ml of a 28% methanol solution of sodium methylate and 2 ml of a 70% aqueous ethylamine solution were added, and N-ethylthioacetal (■, R =C2H5)
get.

Yield 3.1g after recrystallization with benzene or isopropanol
(Yield 81%).

Melting point 117-119°C.

(b) N-ethyl-thioacetalamide (■, R=C
2H5) 1.00 g (2.56 mmol) and p-chlorobenzaldehyde 0.36 g (2.56 mmol) in the same manner as in Example 1(b) to prepare 2-(4'-chlorophenyl)-3-ethyl-4-metathiazanone. 1.30g (■
, R=C2H5).

Yield 99%.

Melting point: 110°C. (c) 2-(4'-chlorophenyl)-
3-ethyl-4-metathiazanone (■, R=C2H5)
Example 1 (c
), 2-(4'-chlorophenyl)-3-
Ethyl-4-metathiazanone-1,1-dioxide (
1.14 g of V,R=C2H5) was obtained.

Melting point: 157°C.

Yield 79%. Example 3 (a) Ester thioacetal (■, R'=CH3)3
．． 6 g of N-
Allyl-thioacetal (■, R=-CH2CH=CH
2) is obtained.

Yield after benzene recrystallization: 2.8 g (yield: 70%), melting point: 9
8-100℃.

(b) N-allyl-thioacetalamide (■, R=C
2-(4
'-chlorophenyl)-3-allyl-4-metathiazanone (■, R=CH2CH=CH2) is obtained.

Yield 0.5 g (78%) after recrystallization from benzene.

Claims (1)

[Claims] 1 General formula (R is CnH2n+1:n=1, 2, 3, 4 or C
nH2n-1: n=3, 4. ) is reacted with valachlorbenzaldehyde to form 2-(4'-chlorophenyl)-3-4-substituted-4-metathiazanones represented by the general formula (R is the same as above), and then this is A method for producing 2-(4'-chlorophenyl)-3-substituted-4-methathiazanone-1,1-dioxides represented by the general formula (R is the same as above), which is characterized by oxidation. 2 A compound represented by the general formula (R' represents a hydrogen atom, CnH2n+1:n=1 to 8, or an aryl group) has a general formula (R represents CnH2n+1:n=1 to 4, or CnH2
n-1: represents n=3, 4. ) to produce a compound represented by the general formula (R is the same as above), and then reacted with valachlorbenzaldehyde to the compound to form a compound represented by the general formula (R is the same as above). 2-(4'-chlorophenyl)-3-substituted-4-metathiazanone represented by the general formula (R is the same as above), and then oxidized. A method for producing (chlorophenyl)-3-substituted-4-metathiazanone-1,1-dioxide.