Synthesis and purification method of lebroxan intermediate

Abstract

The invention discloses a method for synthesizing and purifying a lebrexan intermediate, and belongs to the technical field of organic synthesis. In order to solve the problems of cumbersome operation, low yield and purity in the prior art, the invention provides a method for synthesizing and purifying a lebrexan intermediate, comprising: using compound II as a raw material, an oxidation reaction occurs in a toluene aqueous solution under the action of a catalyst and an oxidant to generate compound I, after quenching the reaction, adjusting the pH, collecting the aqueous phase, and crystallizing to obtain compound I under the action of acetonitrile and acetone. The present invention optimizes and screens the crystallization solvent, controls the solvent addition order and proportion, and the crystallization temperature, and obtains a high-purity lebrexan intermediate compound I with high yield, does not require the preparation of seed crystals, gradient cooling, reduced pressure distillation, etc., and greatly simplifies the operation.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing and purifying a lebrexan intermediate. Background Art

[0002] Orexin receptor is a G protein-coupled receptor that contains two subtypes: OX1 and OX2. Orexin signaling can control feeding behavior and wakefulness and sleep states. Lebrexan is a potent orexin receptor antagonist that has important applications in the treatment of sleep disorders such as insomnia.

[0003] ((1R, 2S)-2-(((2, 4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)cyclopropyl)carboxylic acid, the chemical formula of which is shown in the following formula I:

[0004] .

[0005] The compound of formula I is an important intermediate for the synthesis of leborax. In CN113727962B, the synthesis method of compound I is as follows: ((1R, 2S)-2-(((2, 4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)cyclopropyl)methanol (compound II) is oxidized by sodium hypochlorite and catalyzed by 2, 2, 6, 6-tetramethylpiperidine-1-oxyl radical (TEMPO) to generate the corresponding aldehyde (compound III), which is further oxidized by sodium chlorite to generate ((1R, 2S)-2-(((2, 4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)cyclopropyl)carboxylic acid (compound I), and the reaction formula is as follows:

[0006] .

[0007] The above preparation method requires the preparation of seed crystals during separation and purification, and the conditions required for the preparation of seed crystals are relatively harsh, so the yield and purity of the obtained product are low. Therefore, an efficient purification method for ((1R, 2S)-2-(((2, 4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)cyclopropyl)carboxylic acid is needed. Summary of the invention

[0008] In view of the problems of cumbersome operation, low product yield and purity in the prior art, the present invention provides a method for synthesizing and purifying a leprosy intermediate, which comprises the following steps:

[0009] Synthesis reaction: Compound II is used as a raw material, sodium dihydrogen phosphate is used as a base, and toluene and water are used as reaction solvents. Under the action of a catalyst, a reaction system containing compound III is first obtained under the oxidation action of sodium hypochlorite, and then a reaction system containing compound I is obtained under the oxidation action of sodium chlorite. The reaction formula is as follows:

[0010] ;

[0011] Post-treatment: after quenching the reaction, adding a caustic alkali aqueous solution, separating the aqueous layer and the organic layer, collecting the aqueous layer, extracting the organic layer with water, collecting and combining the aqueous layers, adjusting the pH of the aqueous layer to 2-3, adding water, and obtaining an aqueous phase containing compound I; then adding acetonitrile to the aqueous phase, dripping acetone at -15°C-25°C, stirring and crystallizing, and after the crystallization is completed, performing solid-liquid separation, washing and drying to obtain compound I;

[0012] Wherein, when quenching the reaction, a sodium sulfite aqueous solution is used for quenching, and the ratio of compound II, sodium sulfite in the sodium sulfite aqueous solution, and water in the sodium sulfite aqueous solution is controlled to be 0.2324 kg: 0.02-0.03 kg: 0.2-0.3 L;

[0013] The caustic soda aqueous solution is a 20-30 wt % sodium hydroxide aqueous solution, and the ratio of compound II to the sodium hydroxide aqueous solution is controlled to be 0.2324 kg: 0.10-0.15 L;

[0014] When the organic layer is extracted with water, the ratio of compound II to the water used to extract the organic layer is controlled to be 0.2324 kg: 4-5 L;

[0015] The ratio of compound II, aqueous phase, acetonitrile and acetone was controlled to be 0.02324 kg: 0.5~1 L: 1~1.5 L: 3~4 L.

[0016] Preferably, in the above-mentioned synthesis and purification method of the lebroxan intermediate, acetone is added dropwise at 15°C to 25°C.

[0017] Preferably, in the above-mentioned synthesis and purification method of the lebroxan intermediate, the ratio of compound II, aqueous phase, acetonitrile and acetone is controlled to be 0.02324 kg: 0.8~1 L: 1~1.2 L: 3~3.4 L.

[0018] In the present invention, if acetone is added directly at one time, crystallization will fail. Therefore, in the above-mentioned synthesis and purification method of the intermediate of Lebrexan, acetone is added dropwise, and when acetone is added dropwise, the temperature change of the system is controlled within ±3°C.

[0019] Wherein, in the above-mentioned synthesis and purification method of the intermediate of Lebroxan, the stirring and crystallization time is 1 to 2 hours.

[0020] Wherein, in the above-mentioned synthesis and purification method of the leprosy intermediate, the drying is vacuum drying at 45-55°C.

[0021] Among them, in the above-mentioned synthesis and purification method of the levofloxacin intermediate, after adding the caustic alkali aqueous solution, the system is stirred at 50-70°C for 1-2 hours, and then cooled to 50°C or below and allowed to stand to separate the aqueous layer and the organic layer.

[0022] Among them, in the above-mentioned synthesis and purification method of the lebroxan intermediate, a 4-6N hydrochloric acid aqueous solution is used to adjust the pH of the water layer to 2-3.

[0023] Among them, in the above-mentioned synthesis and purification method of the lebroxan intermediate, when oxidized by sodium hypochlorite, the reaction temperature is 5~35°C; when oxidized by sodium chlorite, the reaction temperature is 5~35°C.

[0024] Among them, in the above-mentioned synthesis and purification method of the lebroxan intermediate, the specific operation of the synthesis reaction is: mixing compound II, a catalyst, toluene and an aqueous sodium dihydrogen phosphate solution, adding an aqueous sodium hypochlorite solution at 5~35°C, and obtaining a reaction system containing compound III under the oxidation action of sodium hypochlorite, and then adding an aqueous sodium chlorite solution at 5~35°C, and obtaining a reaction system containing compound I under the oxidation action of sodium chlorite.

[0025] Among them, in the above-mentioned synthesis and purification method of the lebroxan intermediate, the catalyst is 2, 2, 6, 6-tetramethylpiperidine-1-oxyl free radical.

[0026] Among them, in the above-mentioned synthesis and purification method of the lebroxan intermediate, the dosage ratio of the compound II, the catalyst, toluene, sodium dihydrogen phosphate in the sodium dihydrogen phosphate aqueous solution, sodium hypochlorite in the sodium hypochlorite aqueous solution and sodium chlorite in the sodium chlorite aqueous solution is 0.76~0.78 mol: 0.015~0.018 mol: 4~6L: 0.25~0.28 mol: 0.23~0.27 mol: 0.85~1.00 mol.

[0027] Among them, in the above-mentioned synthesis and purification method of the lebroxan intermediate, the mass concentration of the sodium dihydrogen phosphate aqueous solution is 10~12%.

[0028] Among them, in the above-mentioned synthesis and purification method of Lebroxan intermediate, the mass concentration of the sodium hypochlorite aqueous solution is 10~12%.

[0029] Among them, in the above-mentioned synthesis and purification method of the lebroxan intermediate, the mass concentration of the sodium chlorite aqueous solution is 25~30%.

[0030] Beneficial effects of the present invention:

[0031] The present invention optimizes the synthesis process of the lebroxan intermediate compound I and its post-processing steps, screens the crystallization solvent, controls the solvent addition order and ratio, first adds acetonitrile, then drops acetone, performs crystallization, and controls the crystallization temperature, so that the high-purity compound I can be obtained with high yield; the method of the present invention does not require the preparation of seed crystals, gradient cooling, reduced pressure distillation, etc., greatly simplifies the operation, overcomes the defects of the prior art, and is more conducive to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 The HPLC chromatogram of compound I obtained in Example 1.

[0033] Figure 2 This is the HPLC chromatogram of compound I obtained in Test Example 1.

[0034] Figure 3 This is the HPLC chromatogram of compound I obtained in Test Example 7. DETAILED DESCRIPTION

[0035] Hereinafter, the constitution and effects of the present invention will be described in more detail through embodiments and test examples. However, the following embodiments and test examples are provided only for the purpose of illustrating the present invention, and therefore the present invention is not limited thereto.

[0036] Example 1

[0037]

[0038] A mixture of 232.4 g (768.65 mmol, 1.00 equiv.) of [(1R, 2S)-2-{[(2, 4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)cyclopropyl]methanol (Compound II), 2, 2, 6, 6-tetramethylpiperidin-1-oxyl free base (2.4 g, 15.37 mmol, 0.02 equiv.), toluene (4.6 L) and an aqueous sodium dihydrogen phosphate solution (sodium dihydrogen phosphate 30.43 g, 253.65 mmol, 0.33 equiv. and water 0.23 kg) was cooled at an external temperature of 5°C, and a 12% aqueous sodium hypochlorite solution (143.04 g, 230.59 mmol, 0.30 equiv.) was added at 35°C or below, followed by stirring. 25% aqueous sodium chlorite solution (333.67 g, 922.38 mmol, 1.20 equiv.) was added at 35° C. or below. Completion of the reaction was confirmed by HPLC analysis.

[0039] Add a quenching reagent, sodium sulfite aqueous solution (27.24 g of sodium sulfite and 0.26 L of water) and stir. Add 30% sodium hydroxide aqueous solution (0.11 L) thereto, stir at an external temperature of 50°C for 1 hour, cool to 30°C or below and let stand. Store the aqueous layer, add water (4.6 L) to the organic layer and stir, then let stand. Drain the organic layer, mix the aqueous layer, adjust the pH to 2-3 with 5N hydrochloric acid aqueous solution, add water to make the total volume of the aqueous phase 10L, add acetonitrile (10 L), and slowly drop acetone (30 L) at 15°C, with a temperature change of no more than ±3°C. After the addition is complete, stir at 15°C, and solids slowly precipitate. After crystallization for 1 h, filter with suction, wash the filter cake with acetone (3 L), and the resulting solid is vacuum dried (50°C). The product 232.54 g is weighed, with a yield of 95.64%. The HPLC chromatogram is as follows Figure 1 As shown, the purity is 99.56%.

[0040] Test Example 1 (refer to the crystallization conditions of CN113727962B)

[0041] The reaction process is consistent with Example 1. During the post-treatment process, the organic layer is discharged, and after the water layer is mixed, the pH is adjusted to 2.5-4.0 with 5N hydrochloric acid, and toluene (30 L) is added for extraction. After the organic phase is concentrated, acetonitrile (50 L×2) is added for vacuum distillation to remove toluene as much as possible, and then acetonitrile is added to make the total volume 46.4 L. Stir and dissolve at an external temperature of 65°C, and confirm crystallization after cooling. Heat again to an internal temperature of more than 40°C, cool to an internal temperature of less than -15°C at -20°C / H to precipitate solids, filter to obtain the solids, and wash with acetonitrile. The obtained solid is vacuum dried at 50°C to obtain 217.5 g of the product with a yield of 89.45%. The HPLC chromatogram is as follows Figure 2 As shown, the purity is 96.59%.

[0042] Test Example 2

[0043] The reaction process was consistent with Example 1 (scale reduction 10 times, compound II amount 23.24 g). During the post-treatment, the pH was adjusted to 2-3 with 5N hydrochloric acid aqueous solution, water was added to make the total volume of the aqueous phase 1 L, acetonitrile (1 L) was added, and stirred at 15 ° C. After 1 h, the solution was clear and no solid precipitated.

[0044] Test Example 3

[0045] The reaction process was consistent with Example 1 (scale reduction 10 times, compound II amount 23.24 g). During the post-treatment, the pH was adjusted to 2-3 with 5N hydrochloric acid aqueous solution, water was added to make the total volume of the aqueous phase 1 L, acetone (1 L) was added, and stirred at 15 ° C. After 1 h, the solution was clear and no solid precipitated.

[0046] Test Example 4

[0047] The reaction process was consistent with Example 1 (scale reduction 10 times, compound II amount 23.24 g). During the post-treatment, the pH was adjusted to 2-3 with 5N hydrochloric acid aqueous solution, water was added to make the total volume of the aqueous phase 1 L, methanol (1 L) was added, and water was slowly added dropwise at 15°C, maintaining the temperature. After 1 hour, the solution was clear and no solid was precipitated.

[0048] Test Example 5

[0049] The reaction process was consistent with Example 1 (scale reduction 10 times, compound II amount 23.24 g). During the post-treatment, the pH was adjusted to 2-3 with 5N hydrochloric acid aqueous solution, water was added to make the total volume of the aqueous phase 1 L, acetonitrile (1 L) was added, and n-heptane was slowly added at 15 ° C. When n-heptane was added to 5 L, the solution was clear and no solid precipitated.

[0050] Test Example 6

[0051] The reaction process was consistent with Example 1 (scale reduction 10 times, compound II amount 23.24 g). During the post-treatment, the pH was adjusted to 2-3 with 5N hydrochloric acid aqueous solution, water was added to make the total volume of the aqueous phase 1 L, acetone (3 L) was added, and acetonitrile (1 L) solution was slowly added dropwise at 15 ° C. The temperature was maintained and stirred. The solution was clear and no solid was precipitated.

[0052] Test Example 7

[0053] The reaction process was consistent with Example 1 (scale reduction 10 times, compound II dosage 23.24g). During the post-treatment, 5N hydrochloric acid aqueous solution was used to adjust the pH to 2-3, water was added to make the total volume of the aqueous phase 1L, acetonitrile (1L) was added, acetone (3L) was slowly added dropwise at -15°C, the temperature was maintained and stirred, and solids slowly precipitated. After crystallization for 1 hour, suction filtration was performed, the filter cake was washed with acetone (0.3L), and the obtained solid was vacuum dried (50°C), and the product was weighed to obtain 23.88g, with a yield of 98.23%. The HPLC chromatogram was as follows: Figure 3 As shown, the purity is 97.91%.

[0054] Example 1 Compound I obtained 1 H NMR (400 MHz, DMSO) δ 12.56 (s, 1H), 8.19 (s,1H), 7.47 - 7.37 (m, 1H), 7.33 - 7.23 (m, 2H), 7.15 - 7.05 (m, 1H), 4.66 (d, J = 10.2 Hz, 1H), 4.31 (d, J= 10.2 Hz, 1H), 2.47 (s, 3H), 2.28 (s, 3H), 2.15(t, J = 6.7 Hz, 1H), 1.68 - 1.43 (m, 2H).

[0055] Example 1 Compound I obtained 13 C NMR (101 MHz, DMSO) δ 170.63 (s), 160.40 (d, J = 243.5 Hz), 156.99 (s), 154.15 (s), 147.35 (s), 143.07 (d, J = 7.6 Hz),137.42 (s), 128.63 (d, J = 8.5 Hz), 122.71 (d, J = 2.6 Hz), 113.51 (d, J =21.8 Hz), 112.24 (d, J = 20.8 Hz), 69.01 (s), 31.82 (d, J = 2.0 Hz), 24.37(s), 22.84(s), 17.65(s), 16.60(s).

[0056] Comparing Example 1 with Experimental Example 1, the post-treatment process in Experimental Example 1 requires gradient cooling and crystallization, which is complex, and the product yield and purity are also lower than those of the product obtained in Example 1.

[0057] It can be seen from Experimental Examples 2-5 that if acetone or acetonitrile is used alone as a crystallization solvent, solids cannot be precipitated in the end. Therefore, the present invention continues to try to use a combination of multiple solvents as a crystallization solvent, such as adding methanol first and then water, or adding acetonitrile first and then n-heptane, but no crystals are precipitated. This indicates that the crystallization solvent to be used in the crystallization process of the preparation method of the intermediate of Lebrexan is an important parameter.

[0058] The difference between Test Example 6 and Example 1 is that the order of adding acetonitrile and acetone is different, but the results of the two methods are completely different.

[0059] The difference between Test Example 7 and Example 1 is that the temperature during the crystallization process is different. When the temperature is set to -15°C, although the yield of the final product is slightly increased, the purity is reduced and the product quality is reduced.

[0060] In summary, in the process of preparing the intermediate of Lebrexan, the present invention adds acetonitrile and then slowly drips acetone during the post-treatment process, and stirs only at -15°C to 15°C, or even at room temperature without using gradient cooling, and finally obtains a high-purity and high-yield Lebrexan intermediate. Compared with the crystallization conditions of the prior art, which are more harsh, the solvent volume, stirring speed and cooling speed will greatly affect the crystal precipitation, and it is very easy for crystallization to fail and obtain a viscous solid. The crystallization conditions of the present invention only need to control the order and proportion of solvent addition to successfully crystallize and obtain the product, and the process operation is simple.

Claims

1. A method for synthesizing and purifying a leprosy intermediate, characterized in that: The following steps are involved: Synthesis reaction: Compound II, catalyst, toluene and sodium dihydrogen phosphate aqueous solution are mixed, and sodium hypochlorite aqueous solution is added at 5-35°C. Under the oxidation action of sodium hypochlorite, a solution containing compound A reaction system is prepared, and then a sodium chlorite aqueous solution is added at 5-35°C, and under the oxidation of sodium chlorite, a reaction system containing compound I is obtained; when the sodium hypochlorite is oxidized, the reaction temperature is 5-35°C; when the sodium chlorite is oxidized, the reaction temperature is 5-35°C; the catalyst is 2, 2, 6, 6-tetramethylpiperidine-1-hydrocarbyloxy free radical; the amount ratio of compound II, catalyst, toluene, sodium dihydrogen phosphate in sodium dihydrogen phosphate aqueous solution, sodium hypochlorite in sodium hypochlorite aqueous solution and sodium chlorite in sodium chlorite aqueous solution is 0.76-0.78 mol: 0.015-0.018 mol: 4-6 L: 0.25-0.28 mol: 0.23-0.27 mol: 0.85-1.00 mol; the reaction formula is as follows: ； Post-treatment: After quenching the reaction, a caustic soda solution is added, the aqueous layer and the organic layer are separated, the aqueous layer is collected, the organic layer is extracted with water, the aqueous layers are collected and combined, the pH of the aqueous layer is adjusted to 2-3, and water is added to obtain an aqueous phase containing compound I; Then, acetonitrile is added to the aqueous phase, and acetone is added dropwise at -15°C to 25°C, and the mixture is stirred for crystallization. After the crystallization is completed, the mixture is subjected to solid-liquid separation, washing, and drying to obtain compound I; Wherein, when quenching the reaction, a sodium sulfite aqueous solution is used for quenching, and the ratio of compound II, sodium sulfite in the sodium sulfite aqueous solution, and water in the sodium sulfite aqueous solution is controlled to be 0.2324 kg: 0.02-0.03 kg: 0.2-0.3 L; The caustic soda aqueous solution is a 20-30 wt % sodium hydroxide aqueous solution, and the ratio of compound II to the sodium hydroxide aqueous solution is controlled to be 0.2324 kg: 0.10-0.15 L; When the organic layer is extracted with water, the ratio of compound II to the water used to extract the organic layer is controlled to be 0.2324 kg: 4-5 L; The ratio of compound II, aqueous phase, acetonitrile and acetone was controlled to be 0.02324 kg: 0.5~1 L: 1~1.5 L: 3~4 L.

2. The method for synthesizing and purifying a leprosy intermediate according to claim 1, characterized in that: Add acetone dropwise at 15℃~25℃.

3. The method for synthesizing and purifying a leprosy intermediate according to claim 1, characterized in that: The ratio of compound II, aqueous phase, acetonitrile and acetone was controlled to be 0.02324 kg: 0.8~1 L: 1~1.2 L: 3~3.4 L.

4. The method for synthesizing and purifying a leprosy intermediate according to claim 1, characterized in that: When acetone was added dropwise, the temperature change of the system was controlled within ±3°C.

5. The method for synthesizing and purifying a leprosy intermediate according to claim 1, characterized in that: The stirring crystallization time is 1 to 2 hours.

6. The method for synthesizing and purifying a leprosy intermediate according to claim 1, characterized in that: The drying is vacuum drying at 45-55°C.

7. The method for synthesizing and purifying a leprosy intermediate according to any one of claims 1 to 6, characterized in that: At least one of the following is met: After adding the caustic alkali aqueous solution, the system is stirred at 50-70°C for 1-2 hours, then cooled to 50°C or below and allowed to stand to separate the aqueous layer and the organic layer; The pH of the aqueous layer was adjusted to 2-3 using 4-6N hydrochloric acid aqueous solution.

8. The method for synthesizing and purifying a leprosy intermediate according to claim 1, characterized in that: The mass concentration of the sodium dihydrogen phosphate aqueous solution is 10-12%.

9. The method for synthesizing and purifying a leprosy intermediate according to claim 1, characterized in that: The mass concentration of the sodium hypochlorite aqueous solution is 10-12%.

10. The method for synthesizing and purifying a leprosy intermediate according to claim 1, characterized in that: The mass concentration of the sodium chlorite aqueous solution is 25-30%.

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