CN112028754A - A kind of preparation method of safinamide mesylate intermediate - Google Patents

Abstract

The invention relates to a preparation method of a safinamide mesylate intermediate. The method comprises adding a concentrated organic phase into an organic solvent under nitrogen protection, heating up to 40-45°C, and then cooling it down to a temperature of 40-45°C by a uniform cooling method. 28-35 ℃, add the mixture of crystal seed and organic solvent; the above-mentioned solution system is cooled to 3-8 ℃ by gradient cooling mode, after filtration and drying, the target product safinamide mesylate intermediate is obtained, that is, compound 4 of formula 4 -(3-Fluorobenzyloxy)-benzaldehyde. In the invention, the organic phase obtained after the reflux reaction is purified and crystallized by means of gradient cooling, and the product is directly obtained through one-step purification, which not only has simple operation steps, greatly improves the efficiency and purity, but also reduces the amount of solvent used, and the reaction conditions are mild and green. It is environmentally friendly, increases the safety and reliability of the preparation, and is more conducive to embodying the principle of safe and controllable drug use, and has a high industrialization development prospect.

Description

A kind of preparation method of safinamide mesylate intermediate

technical field

The invention relates to the technical field of preparation of pharmaceutical intermediates, in particular to a preparation method of a safinamide mesylate intermediate 4-(3-fluorobenzyloxy)-benzaldehyde.

Background technique

Safinamide mesylate (compound of formula 1 below), Chinese name (2S)-[4-(3-fluorobenzyloxy)benzylamino]propionamide methanesulfonate, listed in the United States in 2017, as A selective monoamine oxidase B inhibitor approved for the adjunctive treatment of Parkinson's disease patients with "off phase". Safinamide was first disclosed in European patent EP0400495B, the application date was May 25, 1990, and it was jointly developed by Italian Zambon Group and Newlang Biopharmaceutical, and its trade name was Xadago.

The Chinese patent CN200880120328.X (authorized publication number: CN101896456B) filed by Newlang Pharmaceutical Company on December 1, 2008 discloses the method for preparing safinamide mesylate, and mentions that in the preparation process of safinamide, it is easy to produce the following Impurity of the compound of formula 2, the chemical name of the impurity is: (S)-2-[3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)-benzylamino]propionamide. This impurity is highly toxic to the enzymes of the cytochrome P450 system. Once it enters the human body, it will cause extremely serious side reactions. Therefore, strict control is required in the preparation process of the API or its intermediates and the obtained products. Must be below 0.03%.

According to the research, the original source of impurities (compound of formula 2) in the API is the compound of formula 3 (chemical name: 3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)benzaldehyde), The synthesis process is shown in Figure 1. The compound of formula 3 is subjected to subsequent reaction together with the compound of formula 4 (chemical name: 4-(3-fluorobenzyloxy)-benzaldehyde), the main product of this step reaction, thereby producing the compound of formula 2. The synthesis process of the compound of formula 2 is shown in Figure 2. However, this di-alkylated impurity has similar chemical-physical properties to the alkylated derivatives, and it is difficult to purify by traditional methods. The intermediate in the mesylate preparation process is purified to control the impurity content, which is an extremely effective method for controlling the subsequent impurity content.

The above-mentioned patent CN200880120328.X also discloses the purification method of the compound of formula 4. The crude product of 4-(2-fluorobenzyloxy)benzaldehyde prepared by phase transfer catalysis is stirred at 30-35°C for 30min, and then at 30-35°C. To this mixture was added n-hexane (11 kg) over 30 min at °C with stirring, cooled to 0-5 °C and stirred for an additional 1 h at this temperature after which the solid was collected by filtration and dried under reduced pressure to give: 8.0 kg (89% yield) 4-(2-fluorobenzyloxy)benzaldehyde; 1 kg of the product prepared above was dissolved in 2 kg of diisopropyl ether under reflux and stirring, and the solution was allowed to dissolve within 10-15 min Cooled to 50-55°C and inoculated with 5 g of high-purity 4-(2-fluorobenzyloxy)benzaldehyde (GC purity 99.9 area % and (VIb) content below 0.005%), the suspension was heated for 45-60 min Internally cooled to 10-15°C and stirred for an additional hour, the precipitate was finally collected by filtration, washed with cold diisopropyl ether (0.2Kg) and dried under reduced pressure to give 0.93kg of 3-( 2-Fluorobenzyl)-4-(2-fluorobenzyloxy)benzaldehyde content of 4-(2-fluorobenzyloxy)benzaldehyde.

When the above method prepares 4-(2-fluorobenzyloxy)benzaldehyde, it needs to be purified in two steps, the impurity content can be controlled at 50ppm, the methods and steps are cumbersome, the operation is complicated, and the solvent consumption is large; the impurity content of one-step purification is 100ppm, The impurity content is relatively high, which is liable to adversely affect the safety, effectiveness and quality controllability of the subsequent compounds (bulk drug safinamide or its mesylate) and preparations containing the bulk drug.

Therefore, how to efficiently prepare high-purity 4-(3-fluorobenzyloxy)-benzaldehyde needs to be improved.

SUMMARY OF THE INVENTION

The technical problem to be solved by the present invention is aimed at the current situation of the prior art, and provides a preparation method of a safinamide mesylate intermediate whose product purity is improved by gradient cooling. In the preparation method, the purification process of the product is completed in one step, and the operation is simple. , The amount of solvent is small.

The technical solution adopted by the present invention to solve the above-mentioned technical problems is: a preparation method of an intermediate of safinamide mesylate, comprising the following steps:

Under stirring conditions, 2-fluorobenzyl chloride, 4-hydroxy-benzaldehyde, potassium carbonate, and phase transfer catalyst are refluxed in an organic solvent in a nitrogen atmosphere, and after the reaction is completed, a concentrated organic phase is obtained through pretreatment; It also includes the following steps:

Under nitrogen protection, the above-mentioned concentrated organic phase is added to an organic solvent, the temperature is raised to 40-45°C, and then cooled to 28-35°C by a uniform cooling method, and the mixture of crystal seed and organic solvent is added;

The above-mentioned solution system is cooled to 3-8 ℃ in a gradient cooling mode, filtered and dried to obtain the target product safinamide mesylate intermediate, that is, the compound 4-(3-fluorobenzyloxy)-benzaldehyde of the following formula 4,

Preferably, the gradient cooling method includes at least three gradient temperatures, and each gradient temperature is obtained by uniform cooling under stirring conditions, and at each gradient temperature, the temperature is kept warm for 1-4 hours.

Preferably, the stirring rate is 250-300 rpm, and the cooling rate is 5-15°C/h, preferably 5-10°C/h.

Preferably, the gradient cooling method is to cool down to 25°C at a rate of 5-10°C/h, keep stirring for 3 hours; then continue to cool down to 20°C at a rate of 5-10°C/h, keep stirring for 3 hours; Continue to cool down to 15°C at a rate of 5-10°C/h, keep stirring for 2 hours; then cool down to 5°C at a rate of 5-10°C/h, keep stirring for 3 hours. In this way, a high-yield and high-purity product can be obtained through one-step purification.

In the above scheme, after adding the mixture of the seed crystal and the organic solvent, the stirring speed is controlled to be 250-300 rpm, the stirring is carried out for 20-30 minutes, and then the gradient cooling is carried out.

Preferably, the concentrated organic phase is added to a mixed solvent of toluene and cyclohexane, wherein the volume ratio of toluene and cyclohexane is 1/(6-10). More preferably, it is 1/8.

In the present invention, the pretreatment process is to cool the solution system after the reflux reaction to 20-40° C., filter, and wash the obtained organic phase with water, then replace with nitrogen, and concentrate the organic phase.

Preferably, the phase transfer catalyst is tetradecyltrimethylammonium bromide or tetrabutylammonium bromide.

In each of the above schemes, the mixture of the seed crystal and the organic solvent is a mixture of 4-(3-fluorobenzyloxy)-benzaldehyde and cyclohexane after crystallization, and the ratio of the two is 1:4.

Compared with the prior art, the advantages of the present invention are: the organic phase obtained after the reflux reaction is purified and crystallized by a gradient cooling method, and the product is directly obtained by one-step purification, which not only has simple operation steps, but also greatly improves the efficiency and purity. , and reduces the amount of solvent used, the reaction conditions are mild, green and environmentally friendly, and the safety and reliability of the preparation are increased, which is more conducive to reflecting the principle of safe and controllable medication, and has a high industrialization development prospect.

Description of drawings

Fig. 1 is the synthetic steps diagram of the compound of formula 3 in the background of the present invention;

Fig. 2 is the synthetic steps diagram of the compound of formula 2 in the background of the present invention;

Fig. 3 is the LC-MS detection figure of impurity in the product of Example 1 of the present invention;

Fig. 4 is the LC-MS detection figure of impurity in the product of Comparative Example 1 of the present invention;

Fig. 5 is the LC-MS detection pattern of 4-(2-fluorobenzyloxy)benzaldehyde standard substance in the prior art.

Detailed ways

The present invention will be further described in detail below with reference to the embodiments of the accompanying drawings.

Example 1:

The preparation method of the intermediate (4-(3-fluorobenzyloxy)-benzaldehyde) of safinamide mesylate in the present embodiment is:

2-Fluorobenzyl chloride (6.0 kg, 41.50 moL), 4-hydroxy-benzaldehyde (4.7 kg, 38.33 moL), potassium carbonate (5.2 kg, 37.33 moL) and decabromide were mixed under stirring conditions under nitrogen atmosphere. A mixture of tetraalkyltrimethylammonium (0.49kg, 1.46moL) in toluene (11.4kg) slowly reached the reflux level and refluxed for 6h;

After the reaction, cool down to 20-40°C, filter, wash the organic phase with purified water, replace with nitrogen, concentrate the organic phase, add toluene/cyclohexane (1/8, 9V), protect with nitrogen, and heat up to 40-45°C ;

Heating to make the solution clear, stirring for 10-20 minutes, and then cooling at a rate of 5°C/h, the stirring rate is 100-120rpm; when the temperature drops to 30°C, the mixture of seed crystals and cyclohexane is added, and the stirring rate is controlled to be Stir at 250-300rpm for 20-30 minutes, then continue to cool down to 25°C at a rate of 5°C/h, keep stirring for 3 hours; continue to cool down to 20°C at a rate of 5°C/h, keep stirring for 3 hours; Cool down to 15°C at a rate of 5°C/h, keep stirring for 2 hours; then cool down to 5°C at a rate of 5°C/h, keep stirring for 3 hours;

After filtration, the filter cake was rinsed with cyclohexane and dried to obtain the target product. The yield was 93%. The obtained product was detected by LC-MS, and the content of impurities in the product was calculated by the external standard method.

Example 2:

The preparation method of the intermediate (4-(3-fluorobenzyloxy)-benzaldehyde) of safinamide mesylate in the present embodiment is:

2-Fluorobenzyl chloride (6.0 kg, 41.50 moL), 4-hydroxy-benzaldehyde (4.7 kg, 38.33 moL), potassium carbonate (5.2 kg, 37.33 moL) and tetrabutyl were mixed under stirring under nitrogen atmosphere The mixture of ammonium bromide (0.49kg, 1.46moL) in toluene (11.4kg) slowly reached the reflux level and refluxed for 6h;

After the reaction, cool down to 20-40°C, filter, wash the organic phase with purified water, replace with nitrogen, concentrate the organic phase, add toluene/cyclohexane (1/8, 9V), protect with nitrogen, and heat up to 40-45°C ;

Heating to make the solution clear, stirring for 10-20 minutes, and then cooling at a rate of 10°C/h, the stirring rate is 100-120rpm, and when the temperature drops to 30°C, add the mixed solution of seed crystals and cyclohexane, and control the stirring rate to be Stir at 250-300rpm for 20-30 minutes, then continue to cool down to 25°C at a rate of 10°C/h, keep stirring for 2 hours; then continue to cool down to 20°C at a rate of 10°C/h, keep stirring for 2 hours; Cool down to 15°C at a rate of 10°C/h, keep stirring for 3 hours; then cool down to 5°C at a rate of 10°C/h, keep stirring for 3 hours;

After filtration, the filter cake was rinsed with cyclohexane and dried. Yield 90%.

Comparative Example 1:

Prepare 4-(3-fluorobenzyloxy)-benzaldehyde according to the method in patent CN200880120328.X, the method is as follows:

In the first step, 2-fluorobenzyl chloride (6.0kg, 41.50moL), 4-hydroxy-benzaldehyde (4.7kg, 38.33moL), potassium carbonate (5.2kg, 37.33moL) were prepared under stirring conditions in a nitrogen atmosphere. The mixture of tetradecyltrimethylammonium bromide (0.49kg, 1.46moL) in toluene (11.4kg) slowly reached the reflux level and refluxed for 6h;

In the second step, the solution was concentrated at atmospheric pressure, 3.6 kg of toluene were added and distilled off and the operation was repeated again;

In the third step, the heterogeneous mixture was cooled to room temperature and the solids were removed by filtration, then residual solvent was removed under reduced pressure and 1.4 kg of toluene was added to the oily residue; the mixture was heated to 30-35 °C and seeded with 3% pure 4 -(2-Fluorobenzyloxy)benzaldehyde;

In the fourth step, the heterogeneous mixture was stirred at 30-35° C. for 30 minutes, and then n-hexane (11 kg) was added to the mixture at 30-35° C. within 30 minutes while maintaining stirring;

The fifth step, after cooling to 0-5° C. and stirring at this temperature for another hour, the solid was collected by filtration and dried under reduced pressure to obtain: 8.0 kg, 89% yield. The obtained product was detected by LC-MS, and the content of impurities in the product was calculated by external standard method.

Table 1 shows the method for determining the content of the intermediate impurity 3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)benzaldehyde in Example 1 and Comparative Example 1. The content of impurities in the sample was calculated by the external standard method, and the standard 3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)benzaldehyde was made into a solution of 250 ng/mL and injected. At the same time, the sample was accurately weighed to make a 250ng/mL solution and injected. Calculate the content of impurities in the sample based on the peak area ratio.

Table 1 3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)benzaldehyde LC-MS detection method

Table 2 is the sample detection data of Example 1 and Comparative Example 1 and the corresponding impurity content results. The impurity peak time is about 10.972min; Figures 3 and 4 are the impurities in the samples of Example 1 and Comparative Example 1. LC-MS Detection chart, Figure 5 is the LC-MS detection chart of the 4-(2-fluorobenzyloxy)benzaldehyde standard substance in the prior art. It can be seen that the impurity content of Example 1 is much lower than that of Comparative Example 1.

Table 2 Test results

sample Peak area Impurity content Intermediate particle size Comparative Example 1 2352 158.1ppm 1410μm Example 1 205 12.0ppm 49.5μm

Claims (9)

1. a preparation method of safinamide mesylate intermediate, comprises the following steps: Under stirring conditions, 2-fluorobenzyl chloride, 4-hydroxy-benzaldehyde, potassium carbonate, and phase transfer catalyst are refluxed in an organic solvent in a nitrogen atmosphere, and after the reaction is completed, a concentrated organic phase is obtained through pretreatment; It also includes the following steps: Under nitrogen protection, the above-mentioned concentrated organic phase is added to an organic solvent, the temperature is raised to 40-45°C, and then cooled to 28-35°C by a uniform cooling method, and the mixture of crystal seed and organic solvent is added; The above-mentioned solution system is cooled to 3-8 ℃ in a gradient cooling mode, filtered and dried to obtain the target product safinamide mesylate intermediate, that is, the compound 4-(3-fluorobenzyloxy)-benzaldehyde of the following formula 4,

2. the preparation method of safinamide mesylate intermediate according to claim 1, is characterized in that: described gradient cooling mode comprises at least three gradient temperatures, and each gradient temperature is all obtained by uniform cooling under stirring condition , at each gradient temperature, keep stirring for 1-4h. 3. The preparation method of safinamide mesylate intermediate according to claim 2, is characterized in that: stirring rate is 250-300rpm, and cooling rate is 5-15 ℃/h. 4. the preparation method of the safinamide mesylate intermediate according to claim 3, is characterized in that: described gradient cooling mode is to be cooled to 25 ℃ with the speed of 5-10 ℃/h, heat preservation and stirring 3 hours; Continue to cool down to 20°C at a rate of 5-10°C/h, keep stirring for 3 hours; then continue to cool down to 15°C at a rate of 5-10°C/h, keep stirring for 2 hours; then keep stirring at 5-10°C/h The temperature was lowered to 5 °C at a rate of 100 °C, and the mixture was kept stirring for 3 hours. 5. the preparation method of safinamide mesylate intermediate according to claim 1, is characterized in that: after adding the mixture of crystal seed and organic solvent, control stirring speed is 250-300rpm, stir 20-30 minutes and carry out again Gradient cooling. 6. according to the preparation method of the safinamide mesylate intermediate described in any one of claim 1～5, it is characterized in that: concentrated organic phase adds in the mixed solvent of toluene and cyclohexane, wherein, toluene The volume ratio to cyclohexane is 1/(6-10). 7. according to the preparation method of the safinamide mesylate intermediate described in any one of claim 1～5, it is characterized in that: described pretreatment process is to cool down the solution system after backflow reaction to 20-40 °C, filtered, the resulting organic phase was washed with water, then replaced with nitrogen, and the organic phase was concentrated. 8. according to the preparation method of the safinamide mesylate intermediate described in any one of claim 1～5, it is characterized in that: described phase transfer catalyst is tetradecyl trimethyl ammonium bromide or Tetrabutylammonium bromide. 9. according to the preparation method of the safinamide mesylate intermediate described in any one of claim 1～5, it is characterized in that: the mixture of described crystal seed and organic solvent is 4-(3- after crystallization A mixture of fluorobenzyloxy)-benzaldehyde and cyclohexane, the ratio of the two is 1:4.

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