Preparation method for efficiently synthesizing CB1 antagonist pyrazole derivative

Abstract

The invention relates to a preparation method for efficiently synthesizing 5-(4-chlorphenyl)-1-(2, 4-dichlorophenyl)-N-(piperidine-1-yl)-4, 5-dihydro-1H-pyrazole-3-formamide, which comprises the following steps: (a) condensing a compound II and a compound III in an ether solvent under the catalysis of an alkaline reagent, and recrystallizing by using a mixed solvent to obtain a compound IV; (b) carrying out electrochemical (3 + 2) cyclization addition reaction on the compound IV and a compound V in a mixed solvent to obtain a compound VI; (c) hydrolyzing the compound VI under an alkaline condition to generate a compound VII; and (d) condensing the compound VII with a compound VIII under the action of a catalyst, and recrystallizing to obtain a compound I. According to the preparation method, an electrochemical organic synthesis technology is introduced, a synthetic route is optimized by using a green and environment-friendly electrochemical reaction method, the safety is high, the yield is high, and reagents such as iodized salt used in the electrochemical synthesis process can be recycled.

Description

Technical Field

[0001] The present invention belongs to the field of chemical synthesis, and particularly relates to a preparation method for efficiently synthesizing a CB1 antagonist pyrazole derivative. Background Art

[0002] The structural formula of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-4,5-dihydro-1H-pyrazole-3-carboxamide is shown as (I): It is a CB1 antagonist and is applicable to the treatment of disorders involving cannabinoid receptor disorders or disorders that can be treated by controlling the CB1 receptor. It is a drug for obesity in clinical phase I.

[0003] The original research company of this drug is Esteve Pharmaceuticals LLC. Currently, there have been many patents reporting the preparation methods of compound I, such as European patents EP1946779, EP1950203 and patent applications with international publication numbers WO2005 / 074920, WO2007 / 017125. These patents all synthesize the pyrazoline ring through organocatalytic (3+2) cyclization.

[0004] For example, in the method of WO2007017125 for the organic synthesis of compound I, p-chlorobenzaldehyde (compound IX) and ethyl 2-oxopropionate (compound X) are dissolved in absolute ethanol. Under low-temperature conditions, an aqueous NaOH solution is added to form a yellow-orange precipitate. The insoluble sodium 4-(4-chlorophenyl)-2-oxo-3-butanoate is separated by filtration. The sodium salt is treated with a 2M HCl solution, filtered and dried to obtain 4-(4-chlorophenyl)-2-oxobut-3-enoic acid (compound XI). Under an argon atmosphere, compound IV, 2,4-dichlorophenylhydrazine hydrochloride (compound II), and glacial acetic acid are mixed, heated under reflux, and then placed in ice water to obtain a viscous substance. After extraction with dichloromethane and drying over anhydrous sodium sulfate, the solvent is removed to obtain a pale yellow viscous substance, 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid (compound VII). An excess of thionyl chloride is added to compound VII, and the mixture is stirred vigorously at room temperature. The solvent is removed by distillation under reduced pressure to obtain a viscous brown product, 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carbonyl chloride (compound XII). Under an argon atmosphere, 1-aminopiperidine (compound VIII) and triethylamine are dissolved in dichloromethane. The resulting mixture is cooled to 0 °C in ice, and the compound XII obtained in the previous step is added dropwise to the mixture. The resulting reaction mixture is stirred overnight at room temperature (25 °C). Then, it is washed with a saturated aqueous sodium bicarbonate solution, then with water, dried over sodium sulfate, filtered, and evaporated to dryness in a rotary evaporator. The resulting crude solid is recrystallized from ethanol to obtain compound I with an overall yield of 22.7%.

[0005] In the above organic synthesis process, toxic and pungent reagents such as thionyl chloride are used; an inert gas is used multiple times during the operation to ensure an oxygen-free environment, which has high requirements for the reaction apparatus; in the operation method, a low-temperature stirring method is adopted multiple times, with repeated operations, increasing the time cost. In order to improve the yield and quality of compound I and reduce costs, it is very necessary to design a new synthesis route and reduce the use of harmful reagents.

[0006] In the above organic synthesis method, the yield of each synthesis step is lower than 75%, resulting in an overall yield lower than 30%. Moreover, an inert gas is repeatedly used during the synthesis to ensure an oxygen-free environment, which has strict requirements for the operation technology and reaction vessel. The organic synthesis method has great limitations. Summary of the Invention

[0007] To solve the above technical problems in the prior art, the object of the present invention is to synthesize the key intermediate of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-4,5-dihydro-1H-pyrazole-3-carboxamide by an electro-chemical reaction method and optimize the synthesis route, effectively improving the yield, reducing the cost and reducing the use of harmful reagents.

[0008] The technical solution of the present invention is as follows:

[0009] A preparation method for efficiently synthesizing 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-4,5-dihydro-1H-pyrazole-3-carboxamide, the preparation method comprising the following steps:

[0010] (a) Condensing compound II and compound III in a solvent under the catalysis of a basic reagent, and recrystallizing with a mixed solvent to obtain compound IV;

[0011] Compound II is 2,4-dichlorophenylhydrazine hydrochloride, and the structural formula is:

[0012] Compound III is ethyl glyoxylate, and the structural formula is:

[0013] Compound IV is ethyl 2-(2-(2,4-dichlorophenyl)hydrazono)acetate, and the structural formula is:

[0014]

[0015] (b) Subjecting compound IV and compound V to an electrochemical (3+2) cycloaddition reaction in a mixed solvent to obtain compound VI;

[0016] Compound V is p-chlorostyrene, and the structural formula is:

[0017] Compound VI is ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylate, and the structural formula is:

[0018] (c) Hydrolyzing compound VI under basic conditions to form compound VII;

[0019] Compound VII is 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid, and the structural formula is:

[0020] (d) Condensing compound VII with compound VIII under the action of a catalyst and recrystallizing to obtain compound I,

[0021] The compound VIII is 1-aminopiperidine, and its structural formula is:

[0022] The compound I is 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-4,5-dihydro-1H-pyrazole-3-carboxamide, and its structural formula is:

[0023] Further, (a) the solvent is tetrahydrofuran, toluene, methanol, ethyl acetate.

[0024] Further, (a) the basic reagent is triethylamine, DIPEA (the DIPEA is N,N-diisopropylethylamine), DMAP (the DMAP is 4-dimethylaminopyridine).

[0025] Further, (a) the mixed solvent is a mixture of dichloromethane and ethyl acetate; preferably, the volume ratio of dichloromethane to ethyl acetate is 2:1.

[0026] Further, (b) the mixed solvent is a mixture of ethyl acetate and 1.0 M aqueous potassium iodide solution in a volume ratio of 1:3 to 1:4.

[0027] Further, (b) the electrochemical (3+2) cycloaddition reaction uses a graphite rod as both the reaction anode and the reaction cathode, and the electrochemical reaction is carried out at a constant current density of 20-40 mA / cm -2 under the condition that the total reaction charge is 4-6 F.

[0028] Further, after the electrochemical (3+2) cycloaddition reaction in (b) is completed, the reaction solution is extracted with ethyl acetate, washed with 20% sodium metabisulfite and water respectively, dehydrated with anhydrous sodium sulfate, and the solvent is concentrated by distillation under reduced pressure, and the compound VI is obtained by recrystallization.

[0029] Further, (c) the hydrolysis under basic conditions is carried out by heating under reflux in a basic solution, adding hydrochloric acid, and adjusting the pH to 2-3 to end the reaction;

[0030] Preferably, the basic solution is an aqueous sodium hydroxide solution; further preferably, the concentration of the aqueous sodium hydroxide solution is 500 mg / ml;

[0031] Preferably, the heating reflux temperature is 65 °C and the heating reflux time is 0.5 h.

[0032] Further, (d) the catalyst is an amide condensation catalyst, namely TFH (TFH is N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate) and NMI (NMI is N-methylimidazole), DCC (DCC is dicyclohexylcarbodiimide), HATU (HATU is 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate).

[0033] Further, (d) the condensation is carried out by stirring for 6 h. After the condensation is completed, the solvent is removed by distillation under reduced pressure, and the product is extracted with ethyl acetate and water. The organic layer is dried and then evaporated to dryness, and recrystallized with ethanol to obtain Compound I.

[0034] The key technical points of the present invention are as follows:

[0035] The preparation method of the present invention introduces electrochemical organic synthesis technology, uses a green and environmentally friendly electrochemical reaction method to synthesize the key intermediate of compound 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-4,5-dihydro-1H-pyrazole-3-carboxamide, and optimizes the synthesis route. Moreover, reagents such as iodide salts used in the electrochemical synthesis process can be recycled and reused.

[0036] The synthesis route of the present invention has high safety and high yield. Compared with the yield of less than 23% in the existing patents, the synthesis route of the present invention can reach 51%, providing a basis and guarantee for the large-scale and safe synthesis of Compound I and reducing the synthesis cost. Description of the Drawings

[0037] Figure 1 Reaction route diagram for synthesizing Compound I of the present invention;

[0038] Figure 2 Spectrum of Compound I, wherein, Figure 2 A is the liquid chromatography spectrum, Figure 2 B is the liquid chromatography-mass spectrometry spectrum;

[0039] Figure 3 1H NMR spectrum of Compound I;

[0040] Figure 4 1H NMR spectrum of Compound IV;

[0041] Figure 5 1H NMR spectrum of Compound VI;

[0042] Figure 6 13C NMR spectrum of Compound I. Detailed Embodiments

[0043] The following examples are used to further explain the present invention, but the examples do not limit the present invention in any form.

[0044] Example 1

[0045] A preparation method for efficiently synthesizing Compound I, comprising the following steps:

[0046] (a) Synthesis of ethyl 2-(2-(2,4-dichlorophenyl)hydrazono)acetate (Compound IV): Dissolve 2,4-dichlorophenylhydrazine hydrochloride (2.135 g, 10 mmol), ethyl glyoxylate (1.23 g, 12 mmol) and triethylamine (1.21 g, 12 mmol) in tetrahydrofuran (80 ml). After stirring for 12 hours, filter the mixture by suction filtration, and evaporate the filtrate to dryness. After drying, add ethyl acetate and water to separate layers, and extract the aqueous layer with ethyl acetate. Wash the remaining organic fraction twice with water, once with sodium chloride solution, add sodium sulfate for drying, evaporate to dryness, and recrystallize from CH / EA (2:1 v / v) to obtain orange-yellow crystals. Recrystallize three times to obtain the product ethyl 2-(2-(2,4-dichlorophenyl)hydrazono)acetate (2.129 g, yield 81.6%).

[0047] (b) Synthesis of ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylate (Compound VI): Dissolve IV (2.129 g, 8.16 mmol) and 4-chlorostyrene (3.39 g, 24.47 mmol) in ethyl acetate to prepare a 0.5 M solution. Add a 1.0 M potassium iodide solution according to ethyl acetate / aqueous potassium iodide solution = 1:4. Use a graphite rod as the reaction anode and reaction cathode, and carry out an electrochemical reaction at a constant current density of 35 mA / cm-2. The total reaction charge is 5 F (3936 C). After the reaction is completed, extract the reaction solution with ethyl acetate, wash it once with 20% sodium metabisulfite, once with water, dehydrate with anhydrous sodium sulfate, concentrate the solvent by distillation under reduced pressure, and place it in the refrigerator for recrystallization to obtain the product ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylate (2.239 g, yield 69%).

[0048] (c) Synthesis of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid (Compound VII): Dissolve VI (2.239 g, 5.63 mmol) in methanol (10 ml), add an aqueous sodium hydroxide solution (600 mg / 1.2 ml), heat under reflux at 65 °C for 0.5 h, add hydrochloric acid, adjust the pH to 2 - 3, remove the solvent by centrifugation, and dry to obtain a white precipitate, thus obtaining the product 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid.

[0049] (d) Synthesis of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-4,5-dihydro-1H-pyrazole-3-carboxamide (Compound I): Dissolve VII (474.3 mg, 1.28 mmol) and 1-aminopiperidine (154.2 mg, 1.54 mmol) in acetonitrile, add TFH (393 mg, 1.4 mmol) and NMI (221.7 mg, 2.7 mmol), stir at room temperature for 6 h, distill off the solvent under reduced pressure, extract with ethyl acetate and water, dry the organic layer over anhydrous sodium sulfate and then evaporate to dryness, recrystallize from ethanol to obtain the product as a greyish-brown solid, 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-4,5-dihydro-1H-pyrazole-3-carboxamide (363.9 mg, yield 76.2%), with an overall yield of 43.4%.

[0050] The liquid mass spectrometry spectrum, 1H NMR spectrum, and 13C NMR spectrum of Compound I are as Figure 2 、 3 shown in Figure 6.

[0051] Example 2

[0052] A preparation method for the efficient synthesis of Compound I, comprising the following steps:

[0053] (a) Synthesis of ethyl 2-(2-(2,4-dichlorophenyl)hydrazono)acetate (Compound IV): Dissolve 2,4-dichlorophenylhydrazine hydrochloride (2.135 g, 10 mmol), ethyl glyoxylate (1.23 g, 12 mmol) and triethylamine (1.21 g, 12 mmol) in tetrahydrofuran (80 ml), stir for 12 hours, filter the mixture by suction filtration, and evaporate the filtrate to dryness. After drying, add ethyl acetate and water to separate layers, and extract the aqueous layer with ethyl acetate. Wash the remaining organic fraction twice with water, once with sodium chloride solution, add sodium sulfate for drying, evaporate to dryness, and recrystallize from CH / EA (2:1 v / v) to obtain orange-yellow crystals. Recrystallize three times to obtain the product ethyl 2-(2-(2,4-dichlorophenyl)hydrazono)acetate (2.297 g, yield 84.5%).

[0054] (b) Synthesis of ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylate (Compound VI): Dissolve IV (2.297 g, 8.45 mmol) and p-chlorostyrene (2.93 g, 21.13 mmol) in ethyl acetate to prepare a solution with a concentration of 0.5 M. Add a 1.0 M potassium iodide solution according to ethyl acetate / aqueous potassium iodide solution = 1:3. Use a graphite rod as the reaction anode and the reaction cathode, and carry out an electrochemical reaction at a constant current density of 30 mA / cm-2. The total reaction charge is 5 F (4077 C). After the reaction, extract the reaction solution with ethyl acetate, wash it once with 20% sodium metabisulfite, wash it once with water, dehydrate it with anhydrous sodium sulfate, concentrate the solvent by distillation under reduced pressure, and recrystallize it in the refrigerator to obtain the product ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylate (2.661 g, yield 76%).

[0055] (c) Synthesis of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid (Compound VII): Dissolve VI (2.239 g, 6.69 mmol) in methanol (10 ml), add an aqueous sodium hydroxide solution (600 mg / 1.2 ml), heat and reflux at 65 °C for 0.5 h, add hydrochloric acid, adjust the pH to 2 - 3, remove the solvent by centrifugation, dry it, and obtain a white precipitate to obtain the product 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid.

[0056] (d) Synthesis of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-4,5-dihydro-1H-pyrazole-3-carboxamide (Compound I): Dissolve VII (518.3 mg, 1.39 mmol) and 1-aminopiperidine (166.1 mg, 1.65 mmol) in acetonitrile, add TFH (400 mg, 1.4 mmol) and NMI (221.7 mg, 2.7 mmol), stir at room temperature for 6 h, distill off the solvent under reduced pressure, extract with ethyl acetate and water, dry the organic layer with anhydrous sodium sulfate and then spin-dry it, and recrystallize it with ethanol to obtain the product 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-4,5-dihydro-1H-pyrazole-3-carboxamide as a grayish-brown solid (411.3 mg, yield 79.3%), and the total yield is 51%.

[0057] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A method for efficiently synthesizing 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-4,5-dihydro-1H-pyrazole-3-carboxamide, characterized in that: The preparation method comprises the following steps: (a) condensing compound II and compound III in a solvent under the catalysis of an alkaline reagent, and recrystallizing with a mixed solvent to obtain compound IV; the compound II is 2,4-dichlorophenylhydrazine hydrochloride, the compound III is ethyl glyoxylate, and the compound IV is ethyl 2-(2-(2,4-dichlorophenyl)hydrazine hydrazine)acetate; (b) Compound IV is reacted with Compound V in a mixed solvent by an electrochemical (3+2) cycloaddition reaction to obtain Compound VI; Compound V is p-chlorostyrene, and Compound VI is ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylate; (c) Compound VI is hydrolyzed under alkaline conditions to generate Compound VII; Compound VII is 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid; (d) Compound VII is condensed with compound VIII in the presence of a catalyst and recrystallized to obtain compound I, wherein compound VIII is 1-aminopiperidine and compound I is 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-4,5-dihydro-1H-pyrazole-3-carboxamide.

2. The preparation method according to claim 1, characterized in that: (a) The solvent is tetrahydrofuran, toluene, methanol or ethyl acetate.

3. The preparation method according to claim 1, characterized in that: (a) The alkaline reagent is triethylamine, DIPEA or DMAP.

4. The preparation method according to claim 1, characterized in that: (a) The mixed solvent is a mixture of dichloromethane and ethyl acetate; preferably, the volume ratio of dichloromethane to ethyl acetate is 2:

1.

5. The preparation method according to claim 1, characterized in that: (b) The mixed solvent is ethyl acetate and 1.0 M potassium iodide aqueous solution mixed in a volume ratio of 1:3 to 1:

4.

6. The preparation method according to claim 1, characterized in that: (b) The electrochemical (3+2) cycloaddition reaction is carried out using a graphite rod as a reaction anode and a reaction cathode at a constant current density of 20 to 40 mA / cm -2 The electrochemical reaction is carried out under the condition that the total reaction charge is 4 to 6F.

7. The preparation method according to claim 1, characterized in that: (b) After the electrochemical (3+2) cycloaddition reaction is completed, the reaction solution is extracted with ethyl acetate, washed with 20% sodium pyrosulfite and water, respectively, and dehydrated with anhydrous sodium sulfate. The solvent is concentrated by vacuum distillation and recrystallization to obtain compound VI.

8. The preparation method according to claim 1, characterized in that: (c) The hydrolysis under alkaline conditions is heating under reflux in an alkaline solution, adding hydrochloric acid, and adjusting the pH to 2-3 to terminate the reaction; Preferably, the alkaline solution is a sodium hydroxide aqueous solution; further preferably, the concentration of the sodium hydroxide aqueous solution is 500 mg / ml; Preferably, the heating reflux temperature is 65° C. and the heating reflux time is 0.5 h.

9. The preparation method according to claim 1, characterized in that: (d) The catalyst is an amide condensation catalyst such as TFH and / or NMI, DCC, or HATU.

10. The preparation method according to claim 1, characterized in that: (d) The condensation was stirred for 6 hours. After the condensation was completed, the solvent was distilled off under reduced pressure, extracted with ethyl acetate and water, and the organic layer was dried and spin-dried, and recrystallized with ethanol to obtain compound I.

Images