Preparation and refining method of evocamide intermediate

Abstract

The invention belongs to the field of medicinal chemistry, and particularly relates to a preparation and refining method of an evocamide intermediate, which can be used for preparing a compound as shown in a formula III in a high-purity, high-yield and high-efficiency manner by constructing a homogeneous reaction system, so that high-purity evocamide is prepared, and the method is more suitable for industrial large-scale production.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a method for preparing and purifying an evokorhexetine intermediate. Background Technology

[0002] Evocalcet is an allosteric agonist of the calcium-sensitive receptor (CaSR) used to treat secondary hyperparathyroidism. Its chemical structure is as follows:

[0003]

[0004] CN105517992A discloses a method for synthesizing evokcarbate, which uses (R)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester as a raw material and obtains evokcarbate (Formula I) through substitution reactions, nucleophilic substitution reactions, etc. The deprotection reaction and crystallization process used in this method is time-consuming and cumbersome. The purity of the relevant substances is not up to standard, making it impossible to directly proceed to the next step of industrial production; further purification is required after salt formation. Summary of the Invention

[0005] The purpose of this invention is to provide a method for synthesizing evokorbutane intermediate formula III that is simple to operate, has a high yield, excellent purity, and high production efficiency.

[0006] This invention provides a method for preparing evokalx intermediate III, comprising the following steps:

[0007]

[0008] Acetyl chloride was added to an alcohol solvent to react, followed by the addition of an alcohol solution of compound IV. The temperature was controlled, purified water was added, the reaction was carried out, and post-treatment was performed to obtain compound III.

[0009] Furthermore, the alcohol solvent is methanol, ethanol, isopropanol or n-butanol, and isopropanol is more preferably used.

[0010] Furthermore, the mass molar ratio of the compound of formula IV to acetyl chloride is 1:2.5 to 4.0, preferably 1:3.5 to 4.0.

[0011] Further, the volume-to-mass ratio of the purified water to the compound of formula IV is 0.3 to 1.2:1, preferably 0.6 to 1.2:1, and more preferably 0.6:1.

[0012] Furthermore, the temperature control temperature is 50℃~65℃.

[0013] Further, the post-processing steps are as follows: adding seed crystals of compound III, cooling to allow crystallization, washing, and drying to obtain compound III.

[0014] Furthermore, in the post-processing step, the temperature for cooling and crystallization is 0℃~20℃, more preferably 0℃~10℃.

[0015] Furthermore, the present invention provides a method for preparing an evokorheic acetate intermediate, comprising the following steps:

[0016]

[0017] Acetyl chloride was added dropwise to an isopropanol solution, and the mixture was stirred to react. Then, an isopropanol solution of compound IV was added dropwise. The temperature was controlled at 50-65°C. Purified water was added, and the mixture was stirred to react. The reaction was monitored until the endpoint was reached. Seed crystals of compound III were added, and the mixture was cooled to crystallize. The crystals were then filtered and washed to obtain compound III.

[0018] Further, the volume-to-mass ratio of the purified water to the compound of formula IV is 0.3 to 1.2:1, preferably 0.6 to 1.2:1, and more preferably 0.6:1.

[0019] Furthermore, the molar ratio of the compound of formula IV to acetyl chloride is 1:2.5 to 4.0, preferably 1:3.5 to 4.0.

[0020] Furthermore, in the post-processing step, the temperature for cooling and crystallization is 0℃~20℃, more preferably 0℃~10℃.

[0021] Furthermore, the present invention also provides a method for preparing evokalex, comprising the following steps:

[0022]

[0023] Step 1: Add acetyl chloride to an alcohol solvent to react, then add an alcohol solution of compound IV dropwise, control the temperature, add purified water, react, and then post-process to obtain compound III;

[0024] Step 2: Compound III reacts with SM3 in an organic solvent in the presence of a palladium catalyst, a base, and a ligand to prepare compound II;

[0025] Step 3: The compound of formula III is hydrolyzed under alkaline conditions to obtain the compound of formula I.

[0026] Further, the alcohol solvent in step 1 is methanol, ethanol, isopropanol or n-butanol, and isopropanol is more preferably used.

[0027] Further, the volume-to-mass ratio of purified water to compound IV in step 1 is 0.3 to 1.2:1, preferably 0.6 to 1.2:1, and more preferably 0.6:1.

[0028] Further, the molar ratio of the compound of formula IV described in step 1 to acetyl chloride is 1:2.5 to 4.0, preferably 1:3.5 to 4.0.

[0029] Furthermore, the temperature control in step 1 is 50℃~65℃.

[0030] Further, the post-processing step described in step 1 involves adding seed crystals of compound III, cooling to allow crystallization, washing, and drying to obtain compound III.

[0031] Furthermore, in the post-processing step described in step 1, the temperature for cooling and crystallization is 0℃~20℃, more preferably 0℃~10℃.

[0032] Further, step 1 is as follows: acetyl chloride is added dropwise to an isopropanol solution, the mixture is stirred and reacted, then an isopropanol solution of compound IV is added dropwise, the temperature is controlled at 50-65°C, purified water is added, the mixture is stirred and reacted, the reaction is monitored until the endpoint is reached, seed crystals of compound III are added, the mixture is cooled to crystallize, filtered, and washed to obtain compound III.

[0033] Further, the organic solvent in step 2 is benzene, toluene, or xylene, and more preferably toluene.

[0034] Further, the palladium catalyst described in step 2 is palladium acetate, palladium acetate or palladium chloride, preferably palladium acetate.

[0035] Further, the ligand described in step 2 is 1,1'-bis(diphenylphosphino)ferrocene, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (S-PHOS) or 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-PHOS), and more preferably 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

[0036] Further, the alkali mentioned in step 2 is sodium tert-butoxide, cesium carbonate, potassium carbonate, or sodium carbonate, preferably cesium carbonate.

[0037] Furthermore, the alkali used in step 3 is sodium hydroxide.

[0038] The preparation method described in this invention can shorten the reaction time of compound III, and by adding water, a homogeneous reaction system can be constructed, thereby improving the purity and yield of compound III, and thus preparing high-purity ixoraxetine (i.e. compound I).

[0039] V / m: In the field of chemistry, it usually refers to the ratio of volume to mass. For example, 1V / m means that when reacting with 1g of compound of formula IV, 1ml of water needs to be added to the system. Attached Figure Description

[0040] Figure 1 HPLC chromatogram of Example 1;

[0041] Figure 2 HPLC chromatogram of Example 2;

[0042] Figure 3 HPLC chromatogram of Example 3-1;

[0043] Figure 4 HPLC chromatogram of Example 3-2. Detailed Implementation

[0044] The present invention will be further illustrated by the following embodiments and in conjunction with the accompanying drawings, but these embodiments do not constitute any limitation on the present invention.

[0045] HPLC analysis method:

[0046] Preparation of test solution: Take the test sample, dissolve it in water, and prepare a 0.3 mg / mL solution as the test solution;

[0047] Preparation of the reaction solution test solution: Take an appropriate amount of the reaction solution, dilute it with 10% acetonitrile aqueous solution to prepare a 0.3 mg / mL solution, which is used as the reaction solution test solution;

[0048] Column: Agilent Zorbax SB-phenyl (250m × 4.6mm, 5um);

[0049] Mobile phase A: triethylamine phosphoric acid aqueous solution (take 5 ml of triethylamine and 7 ml of phosphoric acid, 1000 ml of water), mobile phase B: acetonitrile, perform gradient elution according to the table below;

[0050]

[0051] Flow rate: 1.0 mL / min; Detection wavelength: 225 nm; Column temperature: 40 ℃; Injection volume: 20 μL;

[0052] The specific structures of the impurities mentioned in the embodiments are as follows:

[0053]

[0054] All of the above impurities are commercially available products.

[0055] Example 1

[0056] Preparation of isopropanol solution for Formula IV: Mix 3.48 g of Formula IV compound and 4.97 g of isopropanol, and dissolve thoroughly. Add 11.61 g of isopropanol to the reaction flask, add 3.10 g of acetyl chloride dropwise at 0–10 °C, wash thoroughly with 0.84 g of isopropanol, and stir at 0–10 °C for 0.5 h. Maintain the temperature of the reaction system at 0–30 °C, add the isopropanol solution of Formula IV dropwise, wash thoroughly with 2.49 g of isopropanol, and raise the temperature to 50–60 °C. Maintain the temperature of the reaction system at 50–65 °C, add purified water (0.6 V / m), and continue stirring at 55–56 °C for 2 h. Monitor the reaction with HPLC until the endpoint (Formula IV content ≤ 1.0%). After the reaction was complete, seed crystals of compound III (2.11 mg, purchased from Shengyang Runze (Beijing) Technology Co., Ltd.) were added to the system. The mixture was stirred at 55–65 °C for 1 hour. The reaction system was then cooled to 0–10 °C and stirred to induce crystallization for 1 hour. The mixture was filtered, and the filter cake was washed with isopropanol (4.98 g) and dried under vacuum at 50–60 °C to obtain 2.25 g of a white solid, with a yield of 73.9% and a purity of 99.77% (see appendix for details). Figure 1 ).

[0057] Example 2

[0058] Preparation of isopropanol solution for Formula IV: Mix Formula IV (3.48 g) and isopropanol (4.97 g) thoroughly and set aside. Add isopropanol (11.61 g) to the reaction flask, add acetyl chloride (3.01 g) dropwise at 0–10 °C, wash thoroughly with isopropanol (0.84 g), and stir at 0–10 °C for 0.5 h. Maintain the reaction temperature at 0–30 °C, add the isopropanol solution of Formula IV dropwise, wash thoroughly with isopropanol (2.49 g), and heat to 50–65 °C for 2 h. Take a sample and monitor the reaction to the endpoint (Formula IV content ≤ 1.0%) using HPLC. After the reaction is complete, add Formula V seed crystals (2.11 mg, purchased from Shengyang Runze (Beijing) Technology Co., Ltd.), and stir at 55–65 °C for 1 h. Cool the reaction system to 0–10 °C and stir to allow crystals to precipitate for 3 h. The filter cake was washed with isopropanol (4.98 g) and filtered again. It was then dried under vacuum at 50–60 °C to give 2.42 g of a white solid, yield 79.5%, purity 92.60% (see appendix for details). Figure 2 ).

[0059] The intermediate formula III prepared in Examples 1 and 2 was analyzed using the above-described HPLC detection conditions. The specific purity data are as follows:

[0060] Table 1. HPLC purity data for Examples 1 and 2

[0061]

[0062] The data in the table shows that, compared with the heterogeneous system Example 2, the homogeneous system Example 1 has a lower impurity content (especially impurity C) and a significantly higher product purity; and Example 1 has a shorter crystallization time, is easier to operate, and saves process time compared with Example 2.

[0063] Example 3 explores the effect of adding different volumes of water on the reaction.

[0064] Referring to the method in Example 1, only the amount of water added during the reaction was adjusted. The specific results are shown in the table below:

[0065] Table 2. Effects of different water addition amounts on product purity and yield.

[0066]

[0067] Example 4: Comparative Study on the Effects of Different Acid Proportions on Purity and Yield in the Deprotection Step

[0068] The same purification method as in Example 1 was used, except that the ratio of acetyl chloride was adjusted. Detailed data are shown in the table below:

[0069] Table 2. Effects of different acid ratios on product purity and yield.

[0070]

[0071]

[0072] The data in the table shows that the yield is low when the acid equivalent is small, such as 2.5 equivalents. The yield is high and stable when the acid equivalent is 3.5 or 3.6 equivalents.

[0073] Example 5: Comparative Study of the Effects of Crystallization Temperature and Crystallization Time on Purity and Yield

[0074] The same purification method as in Example 1 was used, except that the crystallization temperature was adjusted. Detailed data are shown in the table below:

[0075] Table 3. Effects of different crystallization temperatures on product purity and yield.

[0076]

[0077] The data in the table shows that the crystallization temperature has a significant impact on the product yield. When the crystallization temperature is 20–30℃, the yield is significantly lower compared to the crystallization temperature of 0–10℃.

[0078] Example 6 Scale-up Experiment

[0079] Preparation of Formula IV isopropanol solution: Mix Formula IV compound (3.3 kg) and isopropanol (4.72 kg) thoroughly and dissolve for later use. Add isopropanol (11.00 kg) to the reaction vessel, add acetyl chloride (2.94 kg) dropwise at 0–10 °C, wash thoroughly with isopropanol (0.80 kg), and stir at 0–10 °C for 0.5 h. Maintain the temperature of the reaction system at 0–30 °C, add Formula IV isopropanol solution dropwise, wash thoroughly with isopropanol (2.36 kg), and raise the temperature to 50–60 °C. Maintain the temperature of the reaction system at 50–65 °C, add purified water (2.00 kg) dropwise, and continue stirring at 55–65 °C for 2 h. Take a sample (0.5 ml of reaction solution), monitor the reaction with HPLC until the endpoint (Formula IV content ≤ 1.0%). After the reaction is complete, add Formula V seed crystals (2.00 g) to the system, and stir at 55–65 °C for 1 h. The reaction system was cooled to 0–10 °C and stirred to induce crystallization for 1 hour. The mixture was filtered, and the filter cake was washed with isopropanol (4.72 kg) and filtered again. The mixture was dried under vacuum at 50–60 °C to obtain 2.16 kg of a white solid, with a yield of 74.1% and a purity of 99.81%.

[0080] Example 7 Preparation of Compound II

[0081] Preparation of ethyl 4-bromophenylacetate toluene solution: Mix 1.3 kg of ethyl 4-bromophenylacetate and 0.88 kg of toluene, and dissolve thoroughly for later use.

[0082] Preparation of sodium chloride aqueous solution: Mix purified water (9.3 kg) and sodium chloride (0.7 kg) thoroughly and set aside.

[0083] Add purified water (4.6 kg) and sodium hydroxide (0.74 kg) to the reaction vessel, stir until dissolved, then add compound III (2.0 kg) and toluene (8.72 kg). Stir at 20–30 °C for 0.5 h, then separate the liquids. Concentrate the organic phase under reduced pressure at 45–50 °C until no droplets remain. Add toluene (10.46 kg) to the residue, dissolve until dissolved, then transfer to the reaction vessel. Add cesium carbonate I (3.5 kg), X-phos (0.056 kg), palladium acetate (0.024 kg), purified water (0.078 kg), and ethyl 4-bromophenylacetate toluene solution, then rinse thoroughly with toluene (0.88 kg). After purging with nitrogen three times, stir at 95–105 °C for 6 h, monitoring the reaction to the endpoint with HPLC. Once the reaction is complete, cool the reaction system to 20–30 °C, filter, wash the filter cake with toluene (1.24 kg), and collect the filtrate. The filtrate was washed successively with purified water (16.0 kg) and sodium chloride aqueous solution, and the organic phase was collected. Ethylenediamine (0.032 kg) and activated carbon (0.4 kg) were added to the organic phase, and the mixture was stirred for 2 h before collecting the filtrate. The filtrate was kept at a temperature of 20–30 °C, and 4 M hydrochloric acid aqueous solution (1.16 kg) and methyl tert-butyl ether (14.8 kg) were added dropwise, followed by stirring to induce crystallization for 1 h. The mixture was filtered, and the filter cake was vacuum dried to obtain 1.78 kg of an off-white solid, with a yield of 75.7% and a purity of 98.77%.

[0084] Example 8: Preparation of Compound I

[0085] Preparation of sodium hydroxide ethanol aqueous solution: Sodium hydroxide (0.02 kg), purified water (1.05 kg) and anhydrous ethanol (0.9 kg), mix well and dissolve for later use.

[0086] Preparation of citric acid aqueous solution: Mix 0.39 kg of citric acid monohydrate and 3.62 kg of purified water, and dissolve thoroughly for later use.

[0087] Add purified water (4.32 kg), sodium hydroxide (0.35 kg), and anhydrous ethanol (5.93 kg) to the reaction vessel, stir and heat to 50–55 °C, then add compound II (1.5 kg). Maintain the temperature at 55–65 °C and stir for 0.5 h, monitoring the reaction to the endpoint using HPLC. After the reaction is complete, filter, wash the filter cake with a sodium hydroxide-ethanol aqueous solution, and collect the filtrate. Add citric acid aqueous solution dropwise to the filtrate at 55–65 °C until solid precipitates, then stir and crystallize at 55–65 °C for 0.5 h. Continue adding the remaining citric acid aqueous solution until the system pH reaches 7–9, then stir and crystallize for 1 h. Cool the system to 20–30 °C and maintain the temperature while stirring for 1 h. Filter, and wash the filter cake sequentially with anhydrous ethanol (1.8 kg), purified water (4.5 kg), and anhydrous ethanol (1.8 kg), collecting the filter cake. After vacuum drying, 1.15 kg of white solid was obtained, with a yield of 89.9% and a purity of 99.74%.

Claims

1. A method for preparing evokalx intermediate III, characterized in that, Includes the following steps: Acetyl chloride was added to an alcohol solvent to react, and then an alcohol solution of compound IV was added dropwise. Water was added while the temperature was controlled, and the reaction was carried out. After post-treatment, compound III was obtained.

2. The method for preparing evokalex intermediate III according to claim 1, characterized in that, The alcohol solvent is methanol, ethanol, isopropanol or n-butanol, and isopropanol is more preferably used.

3. The method for preparing evokalex intermediate III according to claim 1, characterized in that, The mass molar ratio of the compound of formula IV to acetyl chloride is 1:2.5 to 4.0, preferably 1:3.5 to 4.

0.

4. The method for preparing evokalex intermediate III according to claim 1, characterized in that, The volume-to-mass ratio of water to compound IV is 0.3 to 1.2:1, preferably 0.6 to 1.2:1, and more preferably 0.6:

1.

5. The method for preparing evokalex intermediate III according to claim 1, characterized in that, The post-processing steps are as follows: adding seed crystals of compound III, cooling to crystallize, washing, and drying to obtain compound III. The cooling to crystallize temperature is 0℃~20℃, and more preferably 0℃~10℃.

6. The method for preparing evokalex intermediate III according to claim 1, characterized in that, Acetyl chloride is added dropwise to an isopropanol solution, and the mixture is stirred to react. Then, an isopropanol solution of compound IV is added dropwise, and the temperature is controlled at 50-65°C. Water is added, and the mixture is stirred to react. The reaction is monitored until the endpoint is reached. Seed crystals of compound III are added, and the mixture is cooled to crystallize. The crystals are then filtered and washed to obtain compound III.

7. The method for preparing evokalex intermediate III according to claim 6, characterized in that, The volume-to-mass ratio of water to compound IV is 0.3–1.2:1, preferably 0.6–1.2:1, and more preferably 0.6:

1. The molar ratio of compound IV to acetyl chloride is 1:2.5–4.0, preferably 1:3.5–4.

0. In the post-treatment step, the cooling temperature for crystallization is 0°C–20°C, and more preferably 0°C–10°C.

8. A method for preparing evokalose, characterized in that, Includes the following steps: Step 1: Add acetyl chloride to an alcohol solvent to react, then add an alcohol solution of compound IV dropwise, control the temperature, add water, react, and then post-process to obtain compound III; Step 2: Compound III reacts with SM3 in an organic solvent in the presence of a palladium catalyst, a base, and a ligand to prepare compound II; Step 3: The compound of formula III is hydrolyzed under alkaline conditions to obtain the compound of formula I.

9. The method for preparing evokine according to claim 8, characterized in that, Step 1 is as follows: acetyl chloride is added dropwise to an isopropanol solution, the mixture is stirred and reacted, then an isopropanol solution of compound IV is added dropwise, the temperature is controlled at 50-65℃, water is added, the mixture is stirred and reacted, the reaction is monitored until the endpoint is reached, seed crystals of compound III are added, the mixture is cooled to crystallize, filtered, and washed to obtain compound III.

10. The method for preparing evokine according to claim 8, characterized in that, The organic solvent in step 2 is benzene, toluene, or xylene, more preferably toluene; the palladium catalyst in step 2 is palladium acetate, palladium acetate, or palladium chloride, preferably palladium acetate; the ligand in step 2 is 1,1'-bis(diphenylphosphino)ferrocene, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, or 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, more preferably 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; and the base in step 2 is sodium tert-butoxide, cesium carbonate, potassium carbonate, or sodium carbonate, preferably cesium carbonate.

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