A novel levamisole intermediate compound and its preparation method and use

Abstract

The present invention belongs to the field of organic synthesis, and specifically relates to a novel levamisole intermediate compound and a preparation method thereof, wherein the novel levamisole intermediate compound has a structure shown in formula (III), and the present invention also relates to a method for preparing levamisole using the novel levamisole intermediate compound, and the use of the obtained levamisole in preparing a pharmaceutically acceptable salt thereof, and the present invention also discloses a method for racemization of S-configuration 3-(β-chlorophenethyl)-2-iminothiazolidine, and realizes the recycling of S isomers. The present invention has mild reaction conditions, simple operation, low raw material cost, and is more suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and specifically relates to a novel levamisole intermediate compound and a preparation method thereof, a method for preparing levamisole using the novel levamisole intermediate compound, and use of the prepared levamisole in preparing a pharmaceutically acceptable salt thereof. Background Art

[0002] Levamisole, chemical name: (S)-6-phenyl-2,3,5,6-tetrahydro-imidazole [2,1-B] thiazole, is a broad-spectrum and highly effective anthelmintic that can be used to treat infections of roundworms, hookworms, pinworms and Strongyloides stercoralis. The mechanism of action of levamisole is to selectively inhibit succinate dehydrogenase in the muscles of the worm, which blocks the synthesis of succinate, thereby affecting the anaerobic metabolism of the muscles of the worm, causing neuromuscular depolarization, and continuous muscle contraction and paralysis. Levamisole is the levorotatory form of tetramisole, and its activity is 1-2 times that of tetramisole (racemic form), and its toxic side effects are lower. In addition, levamisole also has immunomodulatory and immune-stimulating functions. In order to improve the solubility of levamisole, levamisole is further salified and marketed in the form of levamisole hydrochloride and levamisole phosphate.

[0003] Patent publication number US4107170A reports a method for synthesizing tetramisole hydrochloride. 3-(β-hydroxyphenethyl)-2-iminothiazolidine hydrochloride is chlorinated to obtain 3-(β-chlorophenethyl)-2-iminothiazolidine hydrochloride, which is then alkalized, cyclized, and salified to obtain a racemic compound tetramisole hydrochloride.

[0004]

[0005] Patent publication number GB1152544A and the literature Journal of Medicinal Chemistry, 1968, 11(1):169-171. report a method for preparing levamisole by resolving tetraimidazole, wherein tetraimidazole is resolved by L-(+)-camphorsulfonic acid and L-(+)-camphorsulfonic acid is removed to obtain levamisole. The remaining dexamisole can be racemized with potassium tert-butoxide in dimethyl sulfoxide (DMSO) solvent to obtain tetraimidazole due to the acidity of the hydrogen atom connected to the chiral center at the benzyl position, and enter the next resolution cycle.

[0006]

[0007] The racemization method of dextran is carried out under the conditions of strong base, anhydrous DMSO and high temperature of 100°C. After the racemization is completed, water is added to supplement the protons to obtain tetramisole. The racemization method has the following problems:

[0008] 1) The price of the solvent anhydrous DMSO used is relatively high, which increases the solvent cost.

[0009] 2) DMSO has a high boiling point and is miscible with water. Recovering anhydrous DMSO from a mixture of DMSO, tert-butyl alcohol, and water is a cumbersome, time-consuming, and energy-consuming task, which increases production and operating costs.

[0010] 3) Tetramisole is not stable under high temperature and strong alkaline conditions. It will degrade in the presence of a small amount of water to produce impurities A, C and E. The limit of these impurities in the European Pharmacopoeia EP11.0 is ≤ 0.2%. Due to the existence of these degradation reactions, the racemization yield reported in Journal of Medicinal Chemistry, 1968, 11(1): 169-171 is only 62%.

[0011] Summary of the invention

[0012] The present invention aims at the deficiencies of the above-mentioned prior art and provides a novel levamisole intermediate compound and a preparation method thereof. The novel levamisole intermediate compound can be further used to synthesize levamisole and pharmaceutically acceptable salts thereof.

[0013] The specific technical solutions are as follows:

[0014] The first object of the present invention is to provide a novel levamisole intermediate compound having a structure shown in formula (III):

[0015]

[0016] Wherein, R is selected from the following functional groups:

[0017]

[0018] R1 is selected from a hydrogen atom, a C1-C4 straight chain or branched chain alkyl group, and R2 is selected from a C1-C3 straight chain or branched chain alkyl group.

[0019] The second object of the present invention is to provide a method for preparing the novel levamisole intermediate compound as described above, comprising the following steps: reacting a salt of a racemic compound (I) 3-(β-chlorophenethyl)-2-iminothiazolidine with a chiral acidic compound (II), wherein the R isomer is precipitated from the system in the form of a compound (III), and simultaneously displacing a molecule of acid H + Y - After filtration, compound (III) can be obtained. The S isomer is still in the form of H + Y -The salt compound (ⅠV) exists in the mother liquor, thereby achieving the separation of the two isomers of the racemic compound (Ⅰ). The above step is the kinetic resolution step of the racemic compound (Ⅰ).

[0020]

[0021] Among them, H + Y - It means hydrochloric acid, hydrobromic acid, benzenesulfonic acid or p-toluenesulfonic acid, etc.

[0022] Further, H + Y - It means hydrochloric acid or p-toluenesulfonic acid.

[0023] Furthermore, in the process of reacting the racemic compound (I) with the chiral acidic compound (II), the solvent used is selected from C1-C5 alcohol solvents and mixed solvents thereof with water, C3-C6 ketone solvents and mixed solvents thereof with water, acetonitrile and mixed solvents thereof with water, tetrahydrofuran and mixed solvents thereof with water.

[0024] Furthermore, the C1-C5 alcohol solvents include methanol, ethanol, isopropanol, butanol, pentanol, etc., and the C3-C6 ketone solvents include acetone, butanone, methyl isobutyl ketone, etc.

[0025] Furthermore, the solvent used is selected from C1-C5 alcohol solvents and mixed solvents thereof with water.

[0026] Furthermore, the solvent used is selected from a mixed solvent of a C1-C5 alcohol solvent and water.

[0027] Furthermore, the solvent used is selected from a mixed solvent of methanol and water, a mixed solvent of ethanol and water, and a mixed solvent of isopropanol and water.

[0028] Furthermore, during the reaction of the racemic compound (I) with the chiral acidic compound (II), an auxiliary strong base or weak acid salt such as ammonium acetate or potassium acetate can be optionally added to promote the equilibrium to move to the right, thereby increasing the yield, but at the same time also reducing the chiral purity of the compound (III).

[0029] Furthermore, the amount of the chiral acidic compound (II) is 0.3 to 1.0 molar equivalent.

[0030] Furthermore, the amount of the chiral acidic compound (II) is 0.4 to 0.6 molar equivalents.

[0031] By adopting the above technical scheme, the free base 3-(β-chlorophenethyl)-2-iminothiazolidine contained in the split compound (III) has an R isomer content of usually ≥90%, and an S isomer content of usually ≤10%. After being slurried and purified with a C1-C3 alcohol solvent or a mixed solvent of a C1-C3 alcohol solvent and water, the R isomer content is usually ≥98%, and the S isomer content is usually ≤2%.

[0032] In the resolution step of the racemic compound (I), the racemic compound (I) can only exist stably in the form of a salt. All attempts to remove the acid from the racemic compound (I) and separate its free base have resulted in a significant reduction in the purity of the free base, and the main impurity produced is tetramisole. The free base of the racemic compound (I) cannot exist stably. The possible reasons are as follows: the free base after the acid radical is removed will undergo an intramolecular nucleophilic substitution reaction, and cyclization will produce tetramisole and hydrochloric acid. The driving force of the reaction is that tetramisole itself can act as an acid-binding agent to combine with hydrochloric acid to form tetramisole hydrochloride. Since the free base of the racemic compound (I) cannot be separated, the conventional method of using a chiral acid to resolve the free base of the racemic compound (I) is not feasible.

[0033]

[0034] If the racemic compound (I) is directly resolved with a chiral acid, that is, the chiral acid replaces H + Y - Theoretically, it is not feasible to obtain the chiral acid salt of racemic compound (I) because the acidity of chiral acid is significantly weaker than that of H + Y - (hydrochloric acid, hydrobromic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.), weak acid cannot convert strong acid H + Y - If it is replaced, there will be no driving force for the reaction to proceed.

[0035] The present invention uses a specific chiral acid to achieve the purpose of replacing a strong acid with a weak acid in a specific organic solvent. This utilizes the difference in solubility between a pair of enantiomers of the free base of the racemic compound (I) and the salt products of different acids. In the present invention, when the R isomer of the racemic compound (I) is salified with a specific chiral acid to generate a compound (III) with a lower solubility and precipitates from the reaction system, the reaction equilibrium is broken, and the acid radical H of the R isomer of the racemic compound (I) is + Y - That is, it is replaced, thus achieving the kinetic resolution of the racemic compound (I). The S isomer compound (IV) of the racemic compound (I) cannot generate a chiral acid salt with lower solubility, so it still retains the acid radical H + Y - dissolved in the reaction system.

[0036] The third object of the present invention is to provide a method for preparing levamisole, using the novel levamisole intermediate compound as described above, comprising the following steps: cyclizing compound (III) in the presence of a base to obtain levamisole (V), and simultaneously obtaining a carboxylic acid anion compound (VI), wherein compound (VI) is acidified to recover a chiral acidic compound (II) as a resolving agent,

[0037]

[0038] The alkali is selected from ammonia water, alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates and the like.

[0039] Furthermore, the base is selected from alkali metal carbonates and alkali metal bicarbonates, such as sodium carbonate, sodium bicarbonate and the like.

[0040] Furthermore, the acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid and the like.

[0041] Furthermore, the acid is selected from hydrochloric acid.

[0042] The fourth object of the present invention is to provide use of levamisole in preparing a pharmaceutically acceptable salt thereof, wherein the levamisole is prepared using the preparation method of levamisole as described above.

[0043] Furthermore, pharmaceutically acceptable salts of levamisole include levamisole hydrochloride, levamisole phosphate and the like.

[0044] The fifth object of the present invention is to provide a method for racemization of compound (IV), which can racemize the S isomer by-product compound (IV) produced in the process of preparing compound (III) under the action of a racemization agent, regenerate the racemic compound (I), and enter the next splitting cycle, thereby realizing the recycling of compound (IV).

[0045]

[0046] Furthermore, the racemic reagent is selected from hydrochloric acid or a reagent that can generate hydrochloric acid.

[0047] Furthermore, the reagents capable of generating hydrochloric acid include sodium chloride and sulfuric acid, as well as thionyl chloride and water.

[0048] Furthermore, the racemic reagent is selected from hydrochloric acid.

[0049] In the present invention, in order to racemize the S isomer compound (IV) produced by the splitting step of the racemic compound (I) to obtain the racemic compound (I), it is necessary to use the property of the chiral carbon atom at the benzyl position to form a planar carbon cation under acidic conditions. In the present invention, hydrochloric acid is used as a reaction reagent, and part of the compound (IV) undergoes an SN2 reaction to flip the configuration to generate an R isomer, and part undergoes an SN1 reaction to generate a carbon cation intermediate and then generate a racemic compound (I). The generated R isomer also undergoes an SN2 reaction and an SN1 reaction at the same time. As the reaction time increases, the final equilibrium state is reached to obtain a racemic compound (I) with an R / S ratio of about 50 / 50. The reaction is shown below.

[0050]

[0051] Compared with the prior art, the present invention has the following beneficial effects:

[0052] (1) The present invention creatively resolves the racemic compound (I), and the resolved compound (III) can be used as an intermediate for preparing levamisole (V) and its pharmaceutically acceptable salts. At the same time, the chiral acidic compound (II) as a resolving agent can be recovered. The remaining compound (IV) can be racemized under acidic conditions to efficiently obtain the racemic compound (I) and enter the next resolution cycle;

[0053] (2) The present invention avoids the use of anhydrous DMSO, thus avoiding the cumbersome, time-consuming and energy-consuming work of recovering anhydrous DMSO, which can significantly reduce the cost of raw materials and workshop operating expenses;

[0054] (3) The present invention avoids the degradation of tetraimidazole under the high temperature and strong base racemization conditions of the prior art, and significantly improves the racemization yield. For example, when the present invention racemizes compound (IV), the yield is usually greater than 90%;

[0055] (4) The present invention is simple to operate, has mild reaction conditions, can maximize the yield, and reduce the production cost of levamisole, thus having high economic and social benefits. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Figure 1 The hydrogen spectrum of levamisole prepared in Example 4 of the present invention 1 H NMR;

[0057] Figure 2 This is the chiral HPLC spectrum of levamisole prepared in Example 4 of the present invention. DETAILED DESCRIPTION

[0058] The technical solution of the present invention will be described below in conjunction with specific embodiments, which are only representative embodiments of the present invention, rather than all embodiments. Based on the embodiments of the present invention, other embodiments obtained by ordinary technicians in the field without creative work are all within the scope of protection of the present invention.

[0059] Example 1 Preparation of racemic compound (I)

[0060] Preparation of the hydrochloride of racemic compound (I): Add 125.0g of concentrated hydrochloric acid to a pressure bottle, cool to 0±5°C, and drop 59.8g of concentrated sulfuric acid. After the dropwise addition is complete, add 75.0g of 3-(β-hydroxyphenylethyl)-2-iminothiazolidine hydrochloride and 33.9g of sodium chloride. Seal the pressure bottle, heat to 50±5°C and react for 10h. The reaction solution is cooled to 20-30°C, 225.0g of water is added, stirred to precipitate solids, cooled to 0-5°C, filtered, and the filter cake is rinsed with 60.0g of ice water. The filter cake is dried to obtain 76.7g of light yellow powder with a yield of 95.5%. Melting point 167.5-169.7°C. 1 H NMR(400MHz,DMSO-d6)δ10.14(s,1H),9.84(s,1H),7.71-7.60(m,2H),7.49-7.34(m,3H),5.59(dd ,J=9.8,5.1Hz,1H),4.46(dd,J=14.8,9.8Hz,1H),4.13-3.94(m,3H),3.46(td,J=7.5,1.3Hz,2H).

[0061] Preparation of p-toluenesulfonate of racemic compound (I): 5.0 g of racemic compound (I) hydrochloride was added with 100.0 g of water, stirred and dissolved, and 3.7 g of p-toluenesulfonic acid monohydrate was added, solid precipitated, filtered, rinsed with water, and 6.4 g of light yellow solid was obtained, with a yield of 86.0%. 1 H NMR (400MHz, DMSO-d6) δ9.88(s,1H),9.47(s,1H),7.63-7.56(m,2H),7.51-7.38(m,5H),7.14-7.08(m,2H),5.58(dd,J=9.7,5.1Hz,1 H), 4.33 (dd, J=14.8, 9.7Hz, 1H), 4.06 (tt, J=7.6, 4.0Hz, 2H), 3.96 (dd, J=14.8, 5.1Hz, 1H), 3.47 (td, J=7.5, 1.4Hz, 2H), 2.29 (s, 3H).

[0062] Example 2 Preparation of Compound (III) (R is )

[0063] 15.0g of racemic compound (I) was added with an appropriate amount of solvent, heated to 50-60°C to dissolve, and an appropriate amount of chiral acidic compound (II) L-(-)-di-p-methylbenzoyltartaric acid was added, and the temperature was lowered for crystallization. Filtering, rinsing, and drying gave 14.9g of compound (III) as a light yellow solid with a yield of 43.8% and an isomer ratio of R / S = 92.69 / 7.31. According to this operation, the results of preparing compound (III) under different resolution conditions are shown in Table 1. The mother liquor was filtered and decompressed to remove the solvent to obtain an oily substance, 2g / g of ethyl acetate was added, stirred and slurried, filtered, and dried to obtain 8.1g of a light yellow solid, namely compound (IV), with an isomer ratio of R / S = 16.57 / 83.43.

[0064] R is The results of preparing compound (III) under different resolution conditions are shown in Table 1.

[0065] Table 1 Results of preparing compound (III) under different resolution conditions

[0066]

[0067] Remark: a When a mixed solvent of organic solvent and water is used, the percentage is the mass fraction; b R / S is the configuration of 3-(β-chlorophenethyl)-2-iminothiazolidine in compound (III).

[0068] Purification of compound (III) (R is : 14.8g of the prepared compound (III) with an isomer ratio of R / S = 92.69 / 7.31 was added with 88.8g of methanol, stirred and slurried at room temperature for 12h. Filtered, washed with methanol, and dried to obtain 13.6g of a light yellow solid with an isomer ratio of R / S = 98.87 / 1.13 and a yield of 91.9%. 1 H NMR (400MHz, DMSO-d6) δ7.83(d,J=8.1Hz,4H),7.64-7.36(m,5H),7.32(d,J=7.9Hz,4H),5.67(d,J=1.5Hz,2H),5.5 7(dd,J=9.7,5.2Hz,1H),4.36(dd,J=14.8,9.7Hz,1H),4.09-3.87(m,3H),3.44(td,J=7.5,1.5Hz,2H),2.36(s,6H).

[0069] Example 3 Preparation of Compound (III) (R is other functional groups)

[0070] When R is selected from other functional groups, the results of separation and preparation of compound (III) are shown in Table 2.

[0071] Separation conditions: 500 mg of compound (I) hydrochloride, 1.0 molar equivalent of chiral acidic compound (II), 3.0 g of 65% ethanol, stirring and dissolving at 20°C, cooling to -20°C for crystallization, filtering, eluting, and drying to obtain compound (III).

[0072] Table 2 Results of separation and preparation of compound (III) when R is selected from other functional groups

[0073]

[0074]

[0075] Remark: a R / S is the configuration of 3-(β-chlorophenethyl)-2-iminothiazolidine in compound (III).

[0076] Example 4 Preparation of Levamisole (V)

[0077] 9.40 g of compound (III) (R Add 37.6g of water and 4.77g of sodium carbonate, raise the temperature to 40±5℃, and react for 2h. Add 20.0g of toluene, separate the liquids, and extract the aqueous phase once with 10.0g of toluene. Combine the toluene phases, remove the solvent under reduced pressure, and obtain 2.92g of light yellow oil, namely levamisole (V), with a chiral purity of 99.24%, containing 0.76% dexamisole, and turn into a light yellow solid after standing overnight, with a yield of 95.4%. 1 H NMR (400MHz, DMSO-d6) δ7.41-7.17(m,5H),5.32(t,J=8.9Hz,1H),3.70-3.55(m,3H),3.3 3(ddd,J=8.9,6.4,4.3Hz,1H), 3.06(td,J=8.7,6.6Hz,1H), 2.85(dd,J=9.4,8.5Hz,1H).

[0078] The aqueous phase of the previous separation was diluted with 100.0 g of water, and hydrochloric acid was added dropwise to adjust the pH to 2.0. Solid precipitated, which was filtered, rinsed with water, and dried to obtain 5.46 g of white solid, i.e., the recovered chiral acidic compound (II) L-(-)-di-p-methylbenzoyltartaric acid, with a yield of 94.3%. 1 H NMR (400MHz, DMSO-d6) δ7.97-7.84(m,4H),7.46-7.35(m,4H),5.83(s,2H),2.41(s,6H).

[0079] Example 5 Preparation of racemic compound (I)

[0080] 8.00 g of the hydrochloride of compound (IV) recovered in Example 2, with an isomer ratio of R / S of 16.57 / 83.43, was added to a pressure bottle, and 17.6 g of 36% concentrated hydrochloric acid was added. The pressure bottle was closed, the temperature was raised to 50±5°C, and the reaction was performed for 6 hours. The mixture was cooled to room temperature, 24.00 g of water was added dropwise, and the mixture was stirred for crystallization. The temperature was further lowered to 0-5°C, filtered, rinsed with water, and dried to obtain 7.60 g of a light yellow solid with a yield of 95.0%, i.e., racemic compound (I), with an isomer ratio of R / S of 49.36 / 50.64.

[0081] Example 6 Preparation of Levamisole Hydrochloride

[0082] 1.40 g of levamisole was dissolved in 9.0 g of toluene, and 2.5 ml of 4 mol / L hydrochloric acid ethyl acetate solution was added, and stirred at room temperature for 1 hour. Filtered, washed with toluene, and dried to obtain 1.57 g of nearly white solid, with a yield of 95.2%. 1 H NMR (400MHz, DMSO-d6) δ11.64 (s, 1H), 7.51-7.34 (m, 5H), 5.77 (dd, J = 10.4, 8.3Hz, 1H), 4. 24(t,J=10.3Hz,1H),4.05-3.93(m,2H),3.85-3.71(m,2H),3.66(dd,J=10.2,8.3Hz,1H).

[0083] Example 7 Preparation of Levamisole Phosphate

[0084] 1.40g of levamisole was dissolved in 9.0g of toluene, and 950mg of 85% phosphoric acid was added, and stirred at room temperature for 1h. The solvent was removed under reduced pressure, and 9.0g of toluene was added, and the mixture was slurried at room temperature for 1h. Filtered, washed with toluene, and dried to obtain 1.95g of light yellow solid, with a yield of 94.2%. 1 H NMR (400MHz, DMSO-d6) δ8.28-7.63(m,4H),7.43-7.18(m,5H),5.44(t,J=9.1Hz,1H),3.83(t,J=9.1Hz,1H),3. 79-3.66(m,2H),3.46(ddd,J=9.3,6.9,5.1Hz,1H),3.28(ddd,J=9.3,8.2,7.1Hz,1H),3.10(d,J=18.1Hz,1H).

[0085] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A levamisole intermediate compound, characterized in that: It has the structure shown in formula (III): Wherein, R is selected from the following functional groups: R1 is selected from a hydrogen atom, a C1-C4 straight chain or branched chain alkyl group, and R2 is selected from a C1-C3 straight chain or branched chain alkyl group.

2. A method for preparing the compound according to claim 1, characterized in that: The method comprises the following steps: a racemic compound (I) reacts with a chiral acidic compound (II), and the R isomer is precipitated from the system in the form of a compound (III), and the compound (III) can be obtained by filtration, and the S isomer is still precipitated in the form of a H + Y - The salt compound (I V) exists in the mother liquor. Among them, H + Y - means hydrochloric acid, hydrobromic acid, benzenesulfonic acid or p-toluenesulfonic acid; In the reaction of the racemic compound (I) with the chiral acidic compound (II), the solvent used is selected from a mixed solvent of a C1-C5 alcohol solvent and water, a mixed solvent of a C3-C6 ketone solvent and water, a mixed solvent of acetonitrile and water, and a mixed solvent of tetrahydrofuran and water.

3. The method for preparing the compound according to claim 2, characterized in that: The amount of the chiral acidic compound (II) is 0.3-1.0 molar equivalent.

4. The method for preparing the compound according to claim 2 or 3, characterized in that: The racemization method of the compound (IV) comprises the following steps: under the action of a racemization agent, the compound (IV) is racemized to prepare a racemic compound (I), The racemic reagent is selected from hydrochloric acid or a reagent that can generate hydrochloric acid, The reagent capable of generating hydrochloric acid is selected from sodium chloride and sulfuric acid, or thionyl chloride and water.

5. A method for preparing levamisole, characterized in that: Using the compound as claimed in claim 1, comprising the following steps: Compound (III) is subjected to cyclization in the presence of a base to obtain levamisole (V) and compound (VI) at the same time, compound (VI) is subjected to acidification to recover chiral acidic compound (II), The base is selected from ammonia water, alkali metal hydroxides, alkali metal carbonates, and alkali metal bicarbonates; the acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, and acetic acid.

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