JPH0586795B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial application field] The present invention is based on the formula ():

[Chemical formula] S-(-)-3-(β-hydroxyphenethyl)-2-iminothiazolidine or its salt is reacted with a chlorinating reagent in an organic solvent, and then treated with an alkali. Expression():

[Problems to be solved by conventional technology and invention]

S-(-)-6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole (hereinafter referred to as levamisole) represented by the formula () is useful as an animal anthelmintic or immune enhancer. It is. Conventionally, levamisole has been produced as racemic tetramisole, which is a mixture of equal amounts with its optical isomer dextramisole (U.S. Pat. Nos. 4107170, 3855234 and 3274209).
It is known that it can be produced by a method of optically splitting it (see the specifications of U.S. Pat. No. 3,565,907, U.S. Pat. No. 3,579,530, and British Patent No. 8,329,869). These methods either use racemic styrene oxide as a starting material or use phenacyl halide as a starting material ():

Racemic (±)-3-(β-hydroxyphenethyl)-2-iminothiazolidine represented by
This production method involves substituting this hydroxyl salt with chlorine and then ring-closing the resulting racemic tetramisole, which is optically resolved as a salt with various optically active acids.
However, since this production method requires a special optically active acid to be provided during optical resolution, there is a problem in that the steps including the recovery step are complicated. On the other hand, a method for directly producing levamisole without optical resolution is also known, and the following production method has been disclosed. (1) Production method using optically active l-(-)-phenylethylenediamine as a starting material (Tetrahedron Letters, 1467
(1967)). (2) Production method using optically active l-(-)-1-phenylaziridine as a starting material (French Patent No. 2224
-See specification No. 475). (3) A production method using phenacyl halide and 2-ethanolamine as starting materials and undergoing asymmetric reduction during the process (see the specifications of US Pat. No. 4,314,066 and US Pat. No. 4,166,824). In method (1), during production, the by-product is produced by the formula ():

There is a problem in that the yield of the desired levamisole is low because isolebamisole represented by the following formula is produced. Method (2) cannot be said to be an industrial production method because it is not easy to synthesize l-(-)-phenylaziridine as a raw material. Method (3) has the problem of poor asymmetry during asymmetric reduction. As described above, there is no known method for obtaining levamisole at a relatively low cost and with good optical yield by using an optically active substance as a starting material. The present inventors have discovered an optically active S-
We have already established a method for obtaining (-)-3-(β-hydroxyphenethyl)-2-iminothiazolidine with high optical purity and high yield (Patent application 1983-
No. 27084). Therefore, we have continued to conduct intensive research on a method for easily synthesizing levamisole with high optical purity in high yield using this optically active compound (2). Generally, when replacing a hydroxyl group bonded to an asymmetric carbon atom with an amino group, there are two methods: (1) directly replacing the hydroxyl group with an amino group, (2) indirectly replacing the hydroxyl group with a halogen atom, sulfonyloxy group, or sulfuric acid ester group. Alternatively, a method of replacing with a phosphate group or the like and then further substituting with an amino group is used. Method (1) is often carried out industrially in the presence of a catalyst, and it is generally said that a dehydrogenation reaction occurs during the process, and amination proceeds via an aldehyde or ketone, thus causing racemization. Since this method is easy to use, it cannot be said to be an effective method from the viewpoint of maintaining optical purity. Therefore, method (2) is used, but the compound () used as the starting material of the present invention is a special type of alcohol that has an amino group and an imino group in the same molecule, and its optical purity is There are no known examples of halogen substitution with almost no damage. Particularly when considered on an industrial level, chlorine substitution is effective, but such an example is of course unknown. The only known reaction is a chlorination reaction of a salt of racemic compound (2) (see US Pat. No. 4,107,170 and US Pat. No. 3,679,696). Also formula ():

There is also no known example in which levamisole represented by the formula () was obtained by simultaneously ring-closing the compound represented by the formula (I) and its salt without racemization by replacing chlorine with an imino group in the molecule. In compound (), the hydroxyl group to be replaced with chlorine is located at the highly reactive benzyl position, and a normally stable benzyl cation is likely to be formed, so torasemization is likely to occur. Therefore, how to suppress racemization was an important point. In addition, since the reaction center is at the benzyl position, it is stabilized by conjugation with the phenyl group, so it is easy to form the formula ():

[Method for solving problems]

The present inventors first focused on the use of thionyl chloride as a chlorination reagent with the aim of imparting stereoselectivity to the chlorination process and producing levamisole at low cost. We pursued stereoselective chlorination reactions of hydroxyl groups in salts. As a result, we discovered the following remarkable fact and completed the present invention. That is, the reaction between S-(-)-3-(β-hydroxyphenethyl)-2-iminothiazolidine of compound () and thionyl chloride is a chlorine substitution reaction in which stereoinversion occurs preferentially. This tendency is remarkable for the hydrochloride of ). Furthermore, by carrying out this reaction in a low polarity organic solvent, it became possible to more preferentially carry out stereoinversion, that is, to improve the optical yield of the final target product, levamisole. Furthermore, if organic chlorine is used in this reaction, the reaction time can be considerably shortened, and depending on the selection of the organic solvent, it is possible to improve the optical purity. In the second step, cyclization dehydrochlorination step, although it is said that the target compound levamisole is likely to racemize under alkaline conditions, racemization hardly occurs even when heated under strongly alkaline conditions. It was discovered that cyclization can be performed without The present invention will be explained in more detail below. [Example] The present invention provides an optically active S-
(-)-3-(β-hydroxyphenylethyl)-
Using 2-iminothiazolidine or a salt thereof as a starting material, levamisole represented by the formula () consists of two steps: (1) chlorination of the hydroxyl group and (2) cyclodehydrochlorination of the chlorine-substituted product. Relating to a method of manufacturing. The compound () with the (S) configuration represented by the formula () is
It can be prepared with high optical purity by a method using styrene chlorohydrin obtained by microbial reduction reaction of phenacyl halide (Japanese Patent Application No. 27084/1984). Compound () or a salt thereof is used as a starting material in the present invention. Salts include hydrochloride, p-
Toluenesulfonate, sulfate, perchlorate, etc. are used, but hydrochloride is preferred. Compound()
The salt of the compound () in an organic solvent containing the above acid
can be easily obtained without racemization by processing. Examples of the chlorination reagent in the chlorination step of the hydroxyl group of compound () include thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, and sulfuryl chloride, with thionyl chloride being preferred. In the chlorination step, the selection of the organic solvent used is an important factor in maintaining high optical purity (see Comparative Example 1). As the organic solvent, a low polarity solvent or a halogenated hydrocarbon having 2 or less carbon atoms is preferable because levamisole can be obtained with good optical purity. Hydrocarbons having 5 to 12 carbon atoms can be used as the low polar solvent, preferably decane, octane,
Saturated hydrocarbons such as isooctane, hexane, and pentane can be selected. Preferred halogenated hydrocarbons include carbon tetrachloride and methylene chloride. Furthermore, the coexistence of an organic base in the chlorination step increases the reaction rate and improves the yield of the desired product. When methylene chloride is used as a solvent, optical purity is improved by coexisting an organic base. Examples of the organic base to coexist include nitrogen-containing organic compounds such as pyridine or substituted pyridines such as picoline, lutidine, and choline, quinolines,
Examples include imidazole or substituted imidazoles, indoles, aniline or substituted products thereof. Preference is given to pyridine or substituted pyridines, imidazole or aniline. The reaction temperature in the chlorination step is -40 to 70°C, preferably -20 to 55°C. The amount of chlorinating reagent used is 1 to 10% of the starting compound () or its salt.
It may be about twice the molar equivalent, preferably 1 to 7 times the molar equivalent.
It is twice the molar equivalent, more preferably 1 to 5 times the molar equivalent. The amount of the organic base used is 0.01 to 1.0 times the molar equivalent of the starting compound () or its salt,
Preferably it is 0.05 to 0.2 times the molar equivalent. The chlorinated hydrochloride (compound ()) obtained in the chlorination step can be further treated with an alkali to perform cyclodechlorination to produce the target product, levamisole. The alkalis used include ammonia water, alkali metal or alkaline earth metal hydroxides,
An aqueous solution or a methanol solution of carbonate or acetate is used, and as a reaction solvent, methanol, isopropanol, etc. are preferable as an organic solvent. In the case of a reaction in an aqueous solution, the target product can be extracted and separated using an organic solvent that is difficult to mix with water. It is also possible to carry out the cyclization and dechlorination step in a two-layer system of water and an organic solvent, and a so-called phase transfer catalytic reaction can be employed. It is possible to use a solution with an alkali concentration of 0.1N to 10N, and the amount used is, for example, 1 to 20 molar equivalents, preferably 1 to 10 molar equivalents, relative to the hydrochloride of the chloride (compound ()). More preferably, it is 2 to 5 molar equivalents. This reaction can be carried out for 10 to 20 hours at room temperature, but by heating to 50 to 90°C, the reaction time can be shortened without deteriorating the optical purity. Levamisole with high optical purity obtained in this way is
If necessary, pure levamisole can be isolated by recrystallization. Next, the present invention will be explained in more detail using production examples, examples, and comparative examples, but the present invention is not limited to these. In addition, in the following examples, the salt of compound () is
Identification was confirmed by IR, ¹ H-NMR, and neutralization titration. The total yield was determined by gravimetric analysis. Optical purity was determined by comparison with the specific optical rotation of the pure product. In addition, the identity of the salt of the chlorinated product was confirmed by IR and ¹ H-NMR. On the other hand, levamisole was isolated by column chromatography and its identity was confirmed by ¹ H-NMR. Furthermore, the specific rotation of the product thus isolated was determined, and the optical purity was determined by comparing it with the specific rotation of the pure product. The yield is calculated using high-performance liquid chromatography (column: FINEPAK manufactured by JASCO Corporation).
SIL C18, mobile phase: 0.1M triethylamine acetate aqueous solution: acetonitrile = 25:1, detection: UV
(λ=254nm)). Production example 1 S-(-)-3-(β-hydroxyphenethyl)-
Production method of 2-iminothiazolidine Optically active (S)-styrene oxide ([α] ²⁵ _D = +
18.9 g of 22.3° (C=1, chloroform), 20.4 g of ethyleneimine, 0.22 g of KOH and 158 μm of water were mixed and reacted at 65° C. for 6 hours with stirring. After the reaction, ethyleneimine is recovered by distillation and β-(S)
-1-(β-hydroxyphenethyl)aziridine
A crude reaction product containing 17.5 g was obtained. The specific optical rotation of this crude reaction product was [α] ²⁵ _D =+28.3° (C=0.42, ethanol). 13.7 g of thiourea was dissolved in 150 ml of water, 9.9 ml of concentrated sulfuric acid was added under ice-cooling, and then the above crude reaction product was added dropwise, stirred for 30 minutes, and then reacted at 100°C for 3 hours. After the reaction was completed, the pH was adjusted to 9.0 with concentrated aqueous ammonia, and the mixture was extracted with chloroform. The solvent was distilled off, and the obtained crude reaction product was crystallized from isopropanol to give 15.5 g of S-(-)-3-
(β-hydroxyphenethyl)-2-iminothiazolidine was obtained. This compound had a melting point of 127-129°C and a specific optical rotation [α] ²⁵ _D =+123° (C = 0.64, chloroform). Example 1 S-(-)-3-(β-hydroxyphenethyl)-
Production of 2-iminothiazolidine hydrochloride 4.71 g of S-(-)-3-(β-hydroxyphenethyl)-2-iminothiazolidine obtained in Production Example 1
(21.2 mmol, [α] ²⁵ _D = +123° (C = 1.0,
15 ml of a 6.34N hydrochloric acid-isopropanol solution prepared by blowing hydrogen chloride gas into isopropanol into 20 ml of an isopropanol solution of CHCl ₃ ))
was added and reacted at room temperature for 6 hours. After filtering the reaction mixture and washing with ether, the resulting solid was
Dry under reduced pressure at 40°C to obtain 5.02 g of white solid (total yield: 92
%, [α] ²⁵ _D = +70.3° (C = 1.0, MeOH), optical purity: 93%ee). Recrystallization was carried out from isopropanol. Example 2 S-(-)-3-(β-hydroxyphenethyl)-
Production of perchlorate of 2-iminothiazolidine S- obtained in Production Example 1 in the same manner as in Example 1
Equimolar amounts of (-)-3-(β-hydroxyphenethyl)-2-iminothiazolidine and perchlorate were reacted in methanol, and recrystallization was performed from isopropanol. The total yield was 75%, the specific optical rotation was [α] ²⁵ _D = +59.7° (C = 1.20, MeOH), and the optical purity was
It was 96%ee. Examples 3 to 18 and Comparative Examples In Examples 3 to 5 and Comparative Examples, 1 mmol of S-(-)-3-(β-hydroxyphenethyl)-2-iminothiazolidine hydrochloride obtained in Example 1 was added to 2 ml of solvent. was added, and 2 mmol of thionyl chloride was added with stirring, followed by reaction at room temperature. In Examples 6 to 13, 0.1 mmol of an organic base was added to 2 ml of solvent, and then thionyl chloride was added, and then the (S)-(-)-3-(β-hydroxyphenethyl)-2-imino compound obtained in Example 1 was prepared. Thiazolidine hydrochloride was added and reacted. In Examples 14 to 18, the (S) obtained in Example 1 was added to 2 ml of the solvent.
-(-)-3-(β-hydroxyphenethyl)-2-
Iminothiazolidine hydrochloride was added, then thionyl chloride was added, and an organic base was immediately added to react. In all Examples, after the completion of the reaction, filtration,
After drying under reduced pressure, 3 times molar equivalent of
Levamisole was obtained by treatment with NaOH. The results are shown in Table 1.

〔Effect of the invention〕

According to the present invention, levamisole () with high optical purity can be easily produced in high yield.

Claims (1)

[Claims] 1 Formula (): S-(-)-3-(β-hydroxyphenethyl)-2-iminothiazolidine or a salt thereof is treated with a chlorinating reagent in an organic solvent. Formula () characterized by reaction and then alkali treatment: S-(-)-6-phenyl-2,
3,5,6-tetrahydroimidazo[2,1-
b] Method for producing thiazole. 2. The manufacturing method according to claim 1, wherein the reaction between the compound represented by formula () and the chlorinating agent in an organic solvent is carried out in the presence of an organic base. 3. The manufacturing method according to claim 1 or 2, wherein the organic solvent is a halide. 4. The production method according to claim 3, wherein the halide is carbon tetrachloride or methylene chloride. 5. The method according to claim 1 or 2, wherein the organic solvent is a hydrocarbon having 5 to 12 carbon atoms. 6. The production method according to claim 5, wherein the hydrocarbons are saturated hydrocarbons. 7. The method according to claim 6, wherein the saturated hydrocarbon is n-pentane, n-hexane, n-octane, isooctane or n-decane. 8. The production method according to claim 2, wherein the organic base is an amine. 9. The production method according to claim 2 or 8, wherein the organic base is a nitrogen-containing heterocyclic compound. 10. The production method according to claim 9, wherein the nitrogen-containing heterocyclic compound is pyridine or a derivative thereof, or imidazole or a derivative thereof. 11 Claims 1, 2, 3, 4, and 5 in which the chlorination agent is thionyl chloride
Section 6, Section 7, Section 8, Section 9 or Section 1
The manufacturing method described in item 0. 12 Claims 1, 2, 3, and 4, wherein the salt of S-(-)-3-(β-hydroxyphenethyl)-2-iminothiazolidine is a hydrochloride.
Section, Section 5, Section 6, Section 7, Section 8, Section 9,
The manufacturing method according to item 10 or 11. 13 S-(-)-3-(β-hydroxyphenethyl)-2-iminothiazolidine salt is perchlorate,
Claims 1, 2, 3, 4, which are sulfates or p-toluenesulfonates;
Section 5, Section 6, Section 7, Section 8, Section 9, Section 1
The manufacturing method according to item 0 or item 11.