Process for the preparation of a key intermediate of the sodium montelukast side chain acid

Abstract

The application discloses a preparation method of a key intermediate of a montelukast sodium side chain acid, belongs to the technical field of pharmaceutical intermediates, and relates to a key intermediate of a montelukast sodium side chain acid, i.e. 1-bromomethylcyclopropylacetonitrile, which is characterized by the preparation method of the 1-bromomethylcyclopropylacetonitrile. The preparation method is as follows: taking tribromoneopentyl alcohol as a starting material, and obtaining 1-bromomethylcyclopropylacetonitrile through a cyclization reaction, an iodination reaction and a cyano substitution reaction. The 1-bromomethylcyclopropylacetonitrile is prepared by using a brand-new synthesis process, starting from tribromoneopentyl alcohol, through a cyclization reaction, an iodination reaction and a cyano substitution reaction. The method solves the blank of the preparation method of 1-bromomethylcyclopropylacetonitrile in the prior art, and also solves the defects of a long reaction theoretical cycle and a low actual yield and a large amount of impurities in the reaction of preparing 1-bromomethylcyclopropylacetonitrile by first preparing 1-hydroxymethylcyclopropylacetonitrile and then reacting phosphorus tribromide with the 1-hydroxymethylcyclopropylacetonitrile.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical intermediates, and more particularly relates to a preparation method of a key intermediate of a side chain acid of montelukast sodium. BACKGROUND

[0002] Montelukast sodium [trade name is singular (singular)] is a powerful leukotriene receptor antagonist developed by Merck Company, which can selectively bind with leukotriene receptors in the respiratory tract, block the action of allergic mediators, improve respiratory inflammation, and make the airway unobstructed. It was first marketed in Finland and Mexico in February 1998, in the United Kingdom and the United States in April and October of the same year, and landed in the Chinese market in 2002. According to the 2008 edition of the Guidelines for the Prevention and Treatment of Bronchial Asthma in China, leukotriene modulators are the only long-term control drugs that can be used alone in addition to inhaled hormones, and can be used as a replacement therapy for mild asthma and a combination therapy for moderate to severe asthma.

[0003] 1-bromomethylcyclopropylacetonitrile is a key intermediate of 1-mercaptomethylcyclopropylacetic acid, which is a starting material for synthesizing montelukast sodium, and the chemical formula of 1-bromomethylcyclopropylacetonitrile is as follows:

[0004] ;

[0005] At present, there is no report on the preparation method of 1-bromomethylcyclopropylacetonitrile. As a supplement, there are many patents on 1-hydroxymethylcyclopropylacetonitrile:

[0006] For example, the national invention patent with the patent number 202210282384.5 discloses the preparation of 1-hydroxymethylcyclopropylacetonitrile from 1,1-cyclopropanedimethanol.

[0007] For example, the national invention patent with the patent number 201210541983.0 discloses a synthesis method of 1-hydroxymethylcyclopropylacetonitrile. Triisopropyl alcohol is refluxed in an organic solvent in the presence of Zn powder and an alkaline catalyst. After the reaction is complete, the temperature is lowered, ammonia gas is introduced for zinc removal, then filtration is performed, and the solvent of the filtrate is recovered to obtain compound I 1-bromomethylcyclopropylmethanol. 1-bromomethylcyclopropylmethanol is added with cyanide under alkaline conditions in an organic solvent to perform a substitution reaction. After the reaction is complete, post-treatment is performed to obtain compound II 1-hydroxymethylcyclopropylacetonitrile.

[0008] Therefore, it is of great significance to develop an environmentally friendly and economically feasible synthesis method of 1-bromomethylcyclopropylacetonitrile. SUMMARY

[0009] In order to solve the above problems, overcome the shortcomings of the prior art, the application provides a 1-bromomethylcyclopropylacetonitrile, which can effectively solve the problems of long process cycle, the need to use strong acid reagent phosphorus tribromide, low yield of 1-bromomethylcyclopropylacetonitrile and many impurities by preparing 1-hydroxymethylcyclopropylacetonitrile first and then reacting with phosphorus tribromide and 1-hydroxymethylcyclopropylacetonitrile to generate 1-bromomethylcyclopropylacetonitrile.

[0010] The specific technical scheme for solving the above technical problems is a preparation method of a key intermediate of a side chain acid of montelukast sodium, the key intermediate of the side chain acid of the montelukast sodium being 1-bromomethylcyclopropylacetonitrile, characterized by the fact that the preparation method of the 1-bromomethylcyclopropylacetonitrile is to use tribromoneopentyl alcohol as a starting material, to perform a cyclization reaction, an iodination reaction and a cyano substitution reaction to obtain the 1-bromomethylcyclopropylacetonitrile.

[0011] Specifically,

[0012] (1) cyclization reaction;

[0013] Methanol is used as a reaction solvent, tribromoneopentyl alcohol is added, then sodium borohydride and a metal chloride are added, and the reaction is carried out at a first reaction temperature of 20-25 DEG C for 10-15 h; after the reaction is completed, filtration is performed, methanol is used for top washing, and the mother liquor is subjected to vacuum distillation and filtration until no liquid drops appear in the condenser tube, so that a solution containing intermediate 1 is obtained;

[0014] (2) iodination reaction;

[0015] In the solution containing intermediate 1, dichloromethane, triphenylphosphine and pyridine are added, the temperature is lowered to a second reaction temperature of-15 DEG C to 0 DEG C, elemental iodine is added, the second reaction temperature is maintained, and stirring is performed until the reaction is completed; then, 10% sodium thiosulfate solution is added, and stirring is performed for about 0.5 h; the layers are separated, the dichloromethane phase is taken, anhydrous sodium sulfate is added for drying for about 0.5 h, filtration is performed, dichloromethane is used for top washing, and the mother liquor is subjected to vacuum distillation and filtration until no liquid drops appear in the condenser tube, so that intermediate 2 is obtained;

[0016] (3) cyano substitution reaction;

[0017] Under room temperature conditions, the solvent, TBAB and cyanide are added to step (2), the temperature is raised to 70 DEG C to 90 DEG C until the reaction is completed, the temperature is lowered to 0 DEG C to 5 DEG C, and stirring is performed for about 1 h, so that a solution containing 1-bromomethylcyclopropylacetonitrile is obtained.

[0018] In step (1), the metal chloride includes nickel chloride or tin chloride;

[0019] The mass ratio of the amounts of the tribromoneopentyl alcohol, methanol, sodium borohydride and metal chloride is 1:(10-15):(0.15-0.30):(0.40-0.80).

[0020] In step (2), the mass ratio of intermediate 1: dichloromethane: triphenylphosphine: pyridine: elemental iodine is 1: (8-15): (1.80-2.80): (0.50-0.70): (1.60-2.0).

[0021] In step (3), the solvent is DMF, DMAC, sulfolane or dimethyl sulfoxide, or a mixture of two or more thereof, and the cyanide is zinc cyanide or barium cyanide.

[0022] In step (3), the mass ratio of intermediate 2: solvent: TBAB: cyanide is 1: (5.5-7.5): (0.20-0.30): (0.35-0.55).

[0023] The solution containing 1-bromomethylcyclopropylacetonitrile can also be post-treated, specifically including

[0024] The solution containing 1-bromomethylcyclopropylacetonitrile is suction filtered, and washed with purified water; purified water and ethyl acetate are added to the suction filtered mother liquor, which is stirred at 20-30°C for about 0.5 h; the layers are separated, and the ethyl acetate phase is taken, which is extracted with purified water, and the ethyl acetate is recovered by distillation under reduced pressure to obtain a brownish red liquid; the brownish red liquid is distilled under high temperature and reduced pressure, and a fraction of 161-163°C / 20 mmHg is collected to obtain 1-bromomethylcyclopropylacetonitrile.

[0025] In the process, the mass ratio of intermediate 2: purified water: ethyl acetate is 1: (10.0-15.0): (10.0-20.0).

[0026] The present application has the following beneficial effects:

[0027] The present application creatively uses tribromoneopentyl alcohol as a starting material, and 1-bromomethylcyclopropylacetonitrile is prepared by a completely new synthesis process through cyclization reaction, iodination reaction and cyano substitution reaction, which solves the blank of the preparation method of 1-bromomethylcyclopropylacetonitrile in the prior art, and also solves the defects of a long theoretical reaction period and a low actual yield and a large amount of impurities in the reaction of first preparing 1-hydroxymethylcyclopropylacetonitrile, and then reacting phosphorus tribromide and 1-hydroxymethylcyclopropylacetonitrile to obtain 1-bromomethylcyclopropylacetonitrile.

[0028] The present application uses tribromoneopentyl alcohol as a starting material to obtain intermediate 1 through cyclization reaction, and creatively uses a specific iodination reaction to obtain intermediate 2 with a double halogenated site, and uses a specific cyano substitution reaction to directly obtain 1-bromomethylcyclopropylacetonitrile, which has a short reaction period, does not need to use phosphorus tribromide, and has a purity of more than 96.0% and a small amount of impurities. BRIEF DESCRIPTION OF DRAWINGS

[0029] ATTACHMENTFigure 1 is a gas chromatogram of Example 1 of the present application;

[0030] attached Figure 2 is a gas chromatogram of Example 5 of the present application;

[0031] attached Figure 3 is a gas chromatogram of Prior Art 1 of the present application;

[0032] attached Figure 4 is a gas chromatogram of Comparative Example 1 of the present application;

[0033] attached Figure 5 is a gas chromatogram of Comparative Example 2 of the present application;

[0034] attached Figure 6 is a gas chromatogram of Comparative Example 3 of the present application;

[0035] attached Figure 7 is a gas chromatogram of Comparative Example 4 of the present application;

[0036] attached Figure 8 is a gas chromatogram of Comparative Example 6 of the present application;

[0037] attached Figure 9 is a gas chromatogram of Comparative Example 7 of the present application; DETAILED DESCRIPTION

[0038] In the description of the present application, specific details are set forth in order to provide a thorough understanding of embodiments of the application. However, it will be understood by those skilled in the art that the application can be practiced without the specific details. In other instances, well-known structures and functions have not been described in detail in order to avoid obscuring the subject matter of the present application. It will be appreciated that the same

[0039] DETAILED DESCRIPTION

[0040] In order to better understand the present application, specific examples are described, it is worth emphasizing that the effect of the examples and various embodiments within the scope of the present application, including the respective agents and the content of the agent ratio, there is no substantial difference, can achieve the effects described in the present application and solve the above problems, other combinations are not listed here;

[0041] Example 1

[0042] (1) cyclization reaction;

[0043] Into a 1 L three-necked flask, 500 ml of methanol was added, 32.5 g of tribromoneopentyl alcohol (100 mmol) was added at 20-25 °C, then 4.91 g of sodium borohydride (130 mmol) and 19.44 g of nickel chloride (150 mmol) were added, and the reaction was maintained at 20-25 °C for 10-15 h; TLC detection showed that the reaction was complete. After the reaction was completed, filtration was performed, and 50 ml of methanol was used for washing. The mother liquor was subjected to vacuum distillation until no liquid drops appeared in the condenser tube, and 15.5 g of intermediate 1 was obtained, with a molar yield of 94.1%.

[0044] (2) Iodination reaction;

[0045] Into a 1 L three-necked flask, 500 ml of methanol was added, 32.5 g of tribromoneopentyl alcohol (100 mmol) was added at 20-25 °C, then 4.91 g of sodium borohydride (130 mmol) and 19.44 g of nickel chloride (150 mmol) were added, and the reaction was maintained at 20-25 °C for 10-15 h; TLC detection showed that the reaction was complete. After the reaction was completed, filtration was performed, and 50 ml of methanol was used for washing. The mother liquor was subjected to vacuum distillation until no liquid drops appeared in the condenser tube, and 15.5 g of intermediate 1 was obtained, with a molar yield of 94.1%.

[0046] (3) Cyanosubstitution reaction;

[0047] Into a 1 L three-necked flask, 500 ml of methanol was added, 32.5 g of tribromoneopentyl alcohol (100 mmol) was added at 20-25 °C, then 4.91 g of sodium borohydride (130 mmol) and 19.44 g of nickel chloride (150 mmol) were added, and the reaction was maintained at 20-25 °C for 10-15 h; TLC detection showed that the reaction was complete. After the reaction was completed, filtration was performed, and 50 ml of methanol was used for washing. The mother liquor was subjected to vacuum distillation until no liquid drops appeared in the condenser tube, and 15.5 g of intermediate 1 was obtained, with a molar yield of 94.1%.

[0048] Example 2

[0049] (1) Cyclization reaction;

[0050] Into a 1 L three-necked flask, 350 ml of methanol was added, 19.5 g of tribromoneopentyl alcohol (60 mmol) was added at 20-25 °C, then 3.19 g of sodium borohydride (84.5 mmol) and 17.07 g of tin chloride (90 mmol) were added, and the reaction was maintained at 20-25 °C for 10-15 h; TLC detection showed that the reaction was complete. After the reaction was completed, filtration was performed, and 30 ml of methanol was used for washing. The mother liquor was subjected to vacuum distillation until no liquid drops appeared in the condenser, and 9.22 g of intermediate 1 was obtained, with a molar yield of 93.1%.

[0051] (2) Iodination reaction;

[0052] Into a 1 L three-necked flask, 350 ml of methanol was added, 19.5 g of tribromoneopentyl alcohol (60 mmol) was added at 20-25 °C, then 3.19 g of sodium borohydride (84.5 mmol) and 17.07 g of tin chloride (90 mmol) were added, and the reaction was maintained at 20-25 °C for 10-15 h; TLC detection showed that the reaction was complete. After the reaction was completed, filtration was performed, and 30 ml of methanol was used for washing. The mother liquor was subjected to vacuum distillation until no liquid drops appeared in the condenser, and 9.22 g of intermediate 1 was obtained, with a molar yield of 93.1%.

[0053] (3) Cyanosubstitution reaction;

[0054] Into a 1 L three-necked flask, 350 ml of methanol was added, 19.5 g of tribromoneopentyl alcohol (60 mmol) was added at 20-25 °C, then 3.19 g of sodium borohydride (84.5 mmol) and 17.07 g of tin chloride (90 mmol) were added, and the reaction was maintained at 20-25 °C for 10-15 h; TLC detection showed that the reaction was complete. After the reaction was completed, filtration was performed, and 30 ml of methanol was used for washing. The mother liquor was subjected to vacuum distillation until no liquid drops appeared in the condenser, and 9.22 g of intermediate 1 was obtained, with a molar yield of 93.1%.

[0055] Example 3

[0056] (1) Cyclization reaction;

[0057] Into a 1 L three-necked flask, 600 ml of methanol was added, 460.63 g of tribromoneopentyl alcohol (125 mmol) was added at 20-25 °C, then 6.14 g of sodium borohydride (162.5 mmol) and 24.30 g of nickel chloride (187.5 mmol) were added, and the reaction was maintained at 20-25 °C for 10-15 h; TLC detection showed that the reaction was complete. After the reaction was completed, filtration was performed, and 40 ml of methanol was used for washing. The mother liquor was subjected to vacuum distillation until no liquid drops appeared in the condenser, and 18.95 g of intermediate 1 was obtained, with a molar yield of 91.9%.

[0058] (2) Iodination reaction;

[0059] Into a 1 L three-necked flask, 460.63 g of tribromoneopentyl alcohol (125 mmol) was added at 20-25 °C, then 6.14 g of sodium borohydride (162.5 mmol) and 24.30 g of nickel chloride (187.5 mmol) were added, and the reaction was maintained at 20-25 °C for 10-15 h; TLC detection showed that the reaction was complete. After the reaction was completed, filtration was performed, and 40 ml of methanol was used for washing. The mother liquor was subjected to vacuum distillation until no liquid drops appeared in the condenser, and 18.95 g of intermediate 1 was obtained, with a molar yield of 91.9%.

[0060] (3) Cyanosubstitution reaction;

[0061] Into a 1 L three-necked flask, 460.63 g of tribromoneopentyl alcohol (125 mmol) was added at 20-25 °C, then 6.14 g of sodium borohydride (162.5 mmol) and 24.30 g of nickel chloride (187.5 mmol) were added, and the reaction was maintained at 20-25 °C for 10-15 h; TLC detection showed that the reaction was complete. After the reaction was completed, filtration was performed, and 40 ml of methanol was used for washing. The mother liquor was subjected to vacuum distillation until no liquid drops appeared in the condenser, and 18.95 g of intermediate 1 was obtained, with a molar yield of 91.9%.

[0062] Example 4

[0063] (1) Cyclization reaction;

[0064] Into a 1L three-necked flask, 400ml methanol was added, 26.0g tribromoneopentyl alcohol (80mmol) was added at 20-25℃, then 3.93g sodium borohydride (104mmol) and 15.55g nickel chloride (120mmol) were added, and the reaction was maintained at 20-25℃ for 10-15h; TLC detection showed that the reaction was complete. After the reaction was completed, filtration was performed, and the filtrate was washed with 30ml of methanol. The filtrate was distilled under reduced pressure until no liquid drops appeared in the condenser tube, to obtain 12.17g of intermediate 1, with a molar yield of 92.2%.

[0065] (2) Iodination reaction;

[0066] Into a 1L three-necked flask, 400ml methanol was added, 26.0g tribromoneopentyl alcohol (80mmol) was added at 20-25℃, then 3.93g sodium borohydride (104mmol) and 15.55g nickel chloride (120mmol) were added, and the reaction was maintained at 20-25℃ for 10-15h; TLC detection showed that the reaction was complete. After the reaction was completed, filtration was performed, and the filtrate was washed with 30ml of methanol. The filtrate was distilled under reduced pressure until no liquid drops appeared in the condenser tube, to obtain 12.17g of intermediate 1, with a molar yield of 92.2%.

[0067] (3) Cyanosubstitution reaction;

[0068] Into a 1L three-necked flask, 400ml methanol was added, 26.0g tribromoneopentyl alcohol (80mmol) was added at 20-25℃, then 3.93g sodium borohydride (104mmol) and 15.55g nickel chloride (120mmol) were added, and the reaction was maintained at 20-25℃ for 10-15h; TLC detection showed that the reaction was complete. After the reaction was completed, filtration was performed, and the filtrate was washed with 30ml of methanol. The filtrate was distilled under reduced pressure until no liquid drops appeared in the condenser tube, to obtain 12.17g of intermediate 1, with a molar yield of 92.2%.

[0069] In order to more intuitively show the product advantages of the present application, the preparation method of a key intermediate of the side chain acid of montelukast sodium in the present application is compared with the preparation method of the key intermediate of the side chain acid of montelukast sodium in the prior art.

[0070] Existing technology I (based on the national invention patent 201210541983.0, which discloses a method for synthesizing 1-hydroxymethylcyclopropylacetonitrile, involves reacting tribromopentyl alcohol in an organic solvent under reflux with zinc powder and an alkaline catalyst. After the reaction is complete, the mixture is cooled, ammonia is introduced for zinc removal, and then the mixture is filtered. The solvent is recovered from the filtrate to obtain compound I, 1-bromomethylcyclopropylmethanol.)

[0071] Table 1: Product Comparison for 1-Bromomethylcyclopropylacetonitrile Prepared by Different Reaction Mechanisms

[0072]

[0073] Analysis of the data in Table 1 shows that:

[0074] In Examples 1-4, tribromo-neopentol was used as the starting material, and 1-bromomethylcyclopropylacetonitrile was obtained through cyclization, iodination and cyano substitution reactions without the need for strong acid reagents.

[0075] Theoretically, 1-bromomethylcyclopropylacetonitrile can be prepared by first preparing 1-hydroxymethylcyclopropylacetonitrile, and then reacted with a strong acid reagent to generate 1-bromomethylcyclopropylacetonitrile. Although it is theoretically feasible, actual experiments have verified that although 1-bromomethylcyclopropylacetonitrile can be obtained, the impurity content is high, the product data is not stable and has large fluctuations, and the reproducibility is poor.

[0076] This may be due to the poor stability of phosphorus tribromide, which is easily decomposed in water. In addition, the bromination reaction conditions are relatively harsh, resulting in poor process stability. Furthermore, tetrabutylammonium bromide (TBAB) is a phase transfer catalyst, and sodium cyanide has poor solubility in organic solvents. If TBAB is not added, the effect of the solid-liquid two-phase reaction will be significantly worse, ultimately causing significant fluctuations in product quality.

[0077] This invention eliminates the need to dry the intermediate of 1-bromomethylcyclopropylacetonitrile, allowing it to be directly incorporated into the next reaction step. It also avoids the use of strong acid reagents and highly toxic sodium cyanide, reducing pollution to humans and the environment. Furthermore, this process eliminates the need for column purification, effectively shortening the preparation cycle and improving work efficiency. The purity of 1-bromomethylcyclopropylacetonitrile is above 96.0%.

[0078] To more intuitively demonstrate the advantages of the "iodination reaction process" in the preparation method of the key intermediate of sodium montelukast side chain acid of the present invention, an equivalent substitution method is used for comparison.

[0079] Comparative Example 1:

[0080] The preparation method is the same as in Example 1, except that dichloromethane was not added during the preparation of this comparative example.

[0081] Comparative Example 2:

[0082] The preparation method is the same as that of Example 1, except that triphenylphosphine is not added in the preparation process of the present comparative example;

[0083] Comparative Example 3:

[0084] The preparation method is the same as that of Example 1, except that pyridine is not added in the preparation process of the present comparative example;

[0085] Table 2: Comparison table of experimental data of different iodination processes

[0086]

[0087]

[0088] From the data analysis in Table 2, it can be seen that:

[0089] During the iodination reaction, the intermediate can well undergo iodination reaction in the dichloromethane, triphenylphosphine and pyridine system, and the intermediate 2 is obtained,

[0090] According to Comparative Examples 1-3, it can be seen that replacing dichloromethane or triphenylphosphine or pyridine system leads to a decrease in the content of 1-bromomethylcyclopropylacetonitrile and an increase in the content of impurities during the synthesis of 1-bromomethylcyclopropylacetonitrile.

[0091] In order to more intuitively show the advantages of the preparation method of the key intermediate of the sodium montelukast side chain acid "cyan substitution reaction process" of the present application, an equivalent replacement method is used for comparison,

[0092] Comparative Example 4:

[0093] The preparation method is the same as that of Example 1, except that cyanide is replaced by sodium cyanide in the preparation process of the present comparative example;

[0094] Table 3: Comparison table of experimental data of different cyan substitution reaction processes

[0095] Starting material Cyanide 1 -bromomethylcyclopropylacetonitrile content Maximum impurity content Example 1 Tribromoneopentanol Zinc cyanide 96.7 1.45 Example 2 Tribromoneopentanol Barium cyanide 97.4 0.8 Comparative Example 4 Tribromoneopentanol Sodium cyanide 80.3 11.1

[0096] From the data analysis in Table 3, it can be seen that:

[0097] Replacing zinc cyanide in Example 1 or barium cyanide in Example 2 with sodium cyanide in Comparative Example 4 leads to a decrease in the content of 1-bromomethylcyclopropylacetonitrile from about 97% to 80.3%, and especially the content of impurities increases to 11.1%, which may be due to the high activity of sodium cyanide during the cyan substitution reaction, and the polymerization of the intermediate 2 with the dihalogenated site, thereby causing the increase of by-products.

[0098] Comparative Example 5:

[0099] The preparation method is the same as that in Example 1, except that TBAB is replaced by being omitted in the preparation process of the present comparative example;

[0100] Table 4: Comparison table of experimental data of cyano substitution reaction process with different cyanides

[0101] Starting material Catalyst 1 -bromomethylcyclopropylacetonitrile content / % Maximum impurity content / % Example 1 Tribromoneopentanol TBAB 96.7 1.45 Comparative Example 5 Tribromoneopentanol - - -

[0102] From the data analysis in Table 4, it can be seen that:

[0103] From the comparison between Example 1 and Example 5, it can be seen that tetrabutylammonium bromide (TBAB) is a phase transfer catalyst, and sodium cyanide has poor solubility in organic solvents. If TBAB is not added, the effect of the solid-liquid two-phase reaction will be significantly reduced, which will eventually cause significant fluctuations in product quality, and there is no practical test significance.

[0104] As a preferred embodiment of the present application, the present application further studies the creation of the dihalogenated site for the cyano substitution reaction,

[0105] Among them, the reactors of Examples 1-4 are tank reactors, except that the reactors of Examples 5-8 are creatively introduced into micro-channel reactors; to solve the problem of harsh reaction conditions in Examples 1-4, the dihalogenated site produces cyano substitution reaction, resulting in the production of 1-bromomethylcyclopropylacetonitrile impurities;

[0106] Among them, the technical scheme of the present application further includes:

[0107] The reactor is a micro-channel reactor, the micro-channel reactor is provided with an SMⅠ inlet and an SMⅡ inlet, the SMⅠ solution and the SMⅡ solution are respectively connected to the SMⅠ inlet and the SMⅡ inlet through a feeding pump, the micro-channel reactor is heated, the feeding pump is started, the flow rates of the SMⅠ and SMⅡ pipelines are set, the feeding pump is contacted and reacted in the mixer, and the temperature is kept constant;

[0108] The solution containing intermediate 2 is added to the SMⅠ inlet, and the solvent, TBAB and cyanide in the defined proportions are added to the SMⅡ inlet, the temperature is raised to 70-120℃, and the reaction is carried out until completion, then the temperature is lowered to 0-5℃, and stirring is carried out for about 1h, to obtain a solution containing 1-bromomethylcyclopropylacetonitrile

[0109] Specifically:

[0110] (1) cyclization reaction;

[0111] Methanol was used as the reaction solvent, and then tribromoneopentanol, sodium borohydride and metal chloride were added, and the reaction was carried out at a first reaction temperature of 20-25°C for 10-15h; after the reaction was completed, filtration was performed, methanol was used for top washing, and the mother liquor was distilled under reduced pressure until no liquid drops appeared in the condenser tube to obtain a solution containing intermediate 1;

[0112] (2) Iodination reaction;

[0113] Dichloromethane, triphenylphosphine and pyridine were added to the solution containing intermediate 1, the temperature was lowered to a second reaction temperature of -15°C to 0°C, and then elemental iodine was added, the second reaction temperature was maintained, and stirring was performed until the reaction was completed; then 10% sodium thiosulfate solution was added, and stirring was performed for about 0.5h; after separation, the dichloromethane phase was taken, anhydrous sodium sulfate was added for drying for about 0.5h, filtration was performed, dichloromethane was used for top washing, and the mother liquor was distilled under reduced pressure until no liquid drops appeared in the condenser tube to obtain intermediate 2;

[0114] (3) Cyanosubstitution reaction;

[0115] The solution containing intermediate 2 was added to the SM I inlet of the microchannel reactor,

[0116] The solvent, TBAB and the reaction molar amount of cyanide were added to the SM II inlet of the microchannel reactor, the temperature was raised to 70°C-120°C, the reaction was carried out until completion, the temperature was lowered to 0-5°C, and stirring was performed for about 1h to obtain a solution containing 1-bromomethylcyclopropylacetonitrile;

[0117] The solution containing 1-bromomethylcyclopropylacetonitrile was filtered, and purified water was used for top washing; purified water and ethyl acetate were added to the filtered mother liquor, stirring was performed at 20-30°C for about 0.5h; after separation, the ethyl acetate phase was taken, purified water was used for extraction of the ethyl acetate phase, and ethyl acetate was recovered by distillation under reduced pressure to obtain a brownish red liquid; the brownish red liquid was distilled under high temperature and reduced pressure, and the fraction at 161-163°C / 20mmHg was collected to obtain 1-bromomethylcyclopropylacetonitrile.

[0118] Table 5: Comparison table of experimental data of different cyanosubstitution reaction processes

[0119]

[0120] From the data analysis in Table 5, it can be seen that:

[0121] Compared with Example 5, the performance indicators of 1-bromomethylcyclopropylacetonitrile in Examples 1-4 have little difference, and there is no significant difference in impurity content, but the reaction time is greatly shortened from 6h to 4h due to the increase of the temperature in Example 5, and the product quality is not affected, which has a positive production significance.

[0122] To more intuitively demonstrate the advantages of the "cyano substitution reaction process" used in the preparation method of the key intermediate of sodium montelukast side chain acid of the present invention, an equivalent substitution method is used for comparison.

[0123] Comparative Example 6:

[0124] The preparation method is the same as in Example 5, except that the reactor in this comparative example is replaced with a tank reactor.

[0125] Comparative Example 7:

[0126] The preparation method is the same as in Example 5, except that in the preparation process of this comparative example, cyanide is replaced with sodium cyanide;

[0127] Table 6: Comparison of Experimental Data for Different Cyano Substitution Reaction Processes

[0128]

[0129] Analysis of the data in Table 6 shows that:

[0130] (1) Comparison Example 6 with Examples 1-2 and Example 5:

[0131] The difference between Comparative Example 6 and Examples 1-2 lies in the reaction temperature. In Comparative Example 6, the content of 1-bromomethylcyclopropylacetonitrile is reduced to only 24.3%, while the content of the maximum impurity increases sharply from 0.8-1.3% to 62.1%.

[0132] Therefore, while increasing the temperature can shorten the reaction cycle, it also leads to a significant decrease in the content of 1-bromomethylcyclopropylacetonitrile and a significant increase in the content of the maximum impurity.

[0133] The difference between Comparative Example 6 and Example 5 lies in the reactor. In Comparative Example 6, the content of 1-bromomethylcyclopropylacetonitrile is reduced to only 24.3%, and the maximum impurity content increases sharply from 0.8% to 62.1%.

[0134] This may be because the iodination reaction yielded intermediate 2 with dihalogenated sites, and a specific cyano substitution reaction was used to directly obtain 1-bromomethylcyclopropylacetonitrile. However, this cyano substitution reaction is different from other cyano substitution reactions. It has extremely stringent requirements on reaction temperature and catalyst. If the reaction temperature is too high, the dihalogenated sites of intermediate 2 will undergo cyano substitution, resulting in the generation of a large number of impurities.

[0135] This invention creatively employs a microchannel reactor as the reaction device to prepare the 1-bromomethylcyclopropylacetonitrile of this invention. This not only shortens the reaction cycle by increasing the temperature, but also avoids the problems of reduced 1-bromomethylcyclopropylacetonitrile content and increased impurity content caused by high temperature.

[0136] The principle can be that the micro-channel reactor belongs to a dynamic reaction, which can effectively separate the generated 1-bromomethylcyclopropylacetonitrile from the raw material zinc cyanide or barium cyanide, avoiding the problem that the content of 1-bromomethylcyclopropylacetonitrile is reduced and the content of impurities is increased due to the side reaction of 1-bromomethylcyclopropylacetonitrile and raw materials;

[0137] (2) Compared with Example 5, the comparative example 7 is different in catalyst.

[0138] Compared with Example 5, the comparative example 7 is different in catalyst. Although the comparative example 7 also uses high temperature and introduces the micro-channel reactor of the application as a reaction device to prepare 1-bromomethylcyclopropylacetonitrile of the application, the final reaction period can be shortened to 4h, the content of 1-bromomethylcyclopropylacetonitrile is reduced from 97.6% in Example 5 to 81.6%, and the maximum impurity content is increased from 0.8% to 6.2%, and the micro-channel reactor does not well solve the problem that the content of 1-bromomethylcyclopropylacetonitrile is reduced and the content of impurities is increased due to the side reaction of 1-bromomethylcyclopropylacetonitrile and raw materials;

[0139] According to the impurity chromatogram of Comparative Example 4, Comparative Example 6 and Comparative Example 7, it can be seen that the peak time of the maximum impurity peak of Comparative Example 4 and Comparative Example 7 is consistent, and different from that of Comparative Example 6,

[0140] This shows that the impurities of Comparative Example 4 and Comparative Example 7 are not the same as those of Comparative Example 6, which also verifies the above principle that the impurities of Comparative Example 6 can be due to the fact that the reaction temperature is too high, which will cause the cyano substitution reaction of the double halogenated site of intermediate 2, resulting in the generation of a large amount of impurities;

[0141] And the impurities of Comparative Example 4 and Comparative Example 7 are due to the fact that sodium cyanide has high activity during the cyano substitution reaction, and the intermediate 2 with double halogenated site appears polymerization and other phenomena, thereby causing the generation of by-products.

[0142] Therefore, by using tribromoneopentyl alcohol as a starting material to obtain intermediate 1 through cyclization reaction, and creatively using a specific iodination reaction to obtain intermediate 2 with double halogenated site, and using a specific cyano substitution reaction to directly obtain 1-bromomethylcyclopropylacetonitrile, the process has a short reaction period, does not need to use phosphorus tribromide, and the purity of the obtained product is above 96.0%, and the by-product has low impurities.

[0143] In summary: the application creatively takes tribromoneopentyl alcohol as a starting material, and through cyclization reaction, iodination reaction and cyano substitution reaction, 1-bromomethylcyclopropylacetonitrile is prepared by using a brand-new synthesis process, the blank of the preparation method of 1-bromomethylcyclopropylacetonitrile in the prior art is solved, and the defects of long reaction theoretical cycle, low actual yield and more impurities in the reaction of first preparing 1-hydroxymethylcyclopropylacetonitrile and then reacting phosphorus tribromide and 1-hydroxymethylcyclopropylacetonitrile to generate 1-bromomethylcyclopropylacetonitrile are also well solved,

[0144] The application takes tribromoneopentyl alcohol as a starting material to obtain an intermediate 1 through cyclization reaction, and creatively adopts a specific iodination reaction to obtain an intermediate 2 with a double halogenated site, and a specific cyano substitution reaction is used to directly obtain 1-bromomethylcyclopropylacetonitrile, the process has a short reaction cycle, does not need to use phosphorus tribromide, the purity of the obtained product is above 96.0%, and the by-product has low impurities.

Claims

1. Process for the preparation of a key intermediate of the side chain acid of montelukast sodium, said key intermediate of the side chain acid of montelukast sodium being 1-bromomethylcyclopropylacetonitrile, characterized in that The method for preparing 1-bromomethylcyclopropylacetonitrile is to use tribromoneopentol as the starting material and obtain 1-bromomethylcyclopropylacetonitrile through cyclization reaction, iodination reaction and cyano substitution reaction. (1) Cyclization reaction; Using methanol as the reaction solvent, tribromo-neopentol was added, followed by sodium borohydride and metal chloride. The reaction was carried out at the first reaction temperature for 10-15 hours. After the reaction was complete, the mixture was filtered, washed with methanol, and the mother liquor was filtered under reduced pressure until no droplets appeared in the condenser, yielding a solution containing intermediate 1. (2) Iodination reaction; Dichloromethane, triphenylphosphine, and pyridine were added to a solution containing intermediate 1. The mixture was cooled to the second reaction temperature, and elemental iodine was added. The second reaction temperature was maintained, and the mixture was stirred until the reaction was complete. Then, a 10% sodium thiosulfate solution was added, and the mixture was stirred for about 0.5 hours. The mixture separated into layers, and the dichloromethane phase was collected. Anhydrous sodium sulfate was added and the mixture was dried for about 0.5 hours. The mixture was filtered, washed with dichloromethane, and the mother liquor was filtered under reduced pressure until no droplets appeared in the condenser to obtain intermediate 2. (3) Cyano substitution reaction; At room temperature, solvent, TBAB and cyanide are added to step (2), the temperature is raised to 70℃~90℃ and the reaction is completed, then the temperature is lowered to 0~5℃ and stirred for about 1h to obtain a solution containing 1-bromomethylcyclopropylacetonitrile; In step (1), the metal chloride includes nickel chloride or tin chloride; The mass ratio of tribromopentyl alcohol:methanol:sodium borohydride:metal chloride is 1:(10~15):(0.15~0.30):(0.40~0.80). In step (3), the solvent is DMF, DMAC, sulfolane or dimethyl sulfoxide or a mixture of two or more of them, and the cyanide is zinc cyanide or barium cyanide.

2. A process for the preparation of a key intermediate of sodium montelukast side chain acid according to claim 1, characterized by: In step (2), the mass ratio of intermediate 1: dichloromethane: triphenylphosphine: pyridine: elemental iodine is 1: (8~15): (1.80~2.80): (0.50~0.70): (1.60~2.0).

3. The method for preparing the key intermediate of montelukast sodium side chain acid according to claim 1, characterized in that: In step (1), the temperature of the first reaction is 20~25℃; In step (2), the second reaction temperature is -15~0℃.

4. A process for the preparation of a key intermediate of sodium montelukast side chain acid as claimed in claim 1, wherein the process comprises of: In step (3), the mass ratio of intermediate 2: solvent: TBAB: cyanide is 1: (5.5~7.5): (0.20~0.30): (0.35~0.55).

5. A process for the preparation of a key intermediate of sodium montelukast side chain acid as claimed in claim 1, wherein the process comprises of: Post-treatment of solutions containing 1-bromomethylcyclopropylacetonitrile includes: The solution containing 1-bromomethylcyclopropylacetonitrile was filtered and washed with purified water. Purified water and ethyl acetate were added to the mother liquor and stirred at 20-30°C for about 0.5 h. The layers were separated, and the ethyl acetate phase was collected. The ethyl acetate phase was extracted with purified water, and the ethyl acetate was recovered by vacuum distillation to obtain a brownish-red liquid. The brownish-red liquid was distilled at high temperature and vacuum, and the fraction collected at 161-163°C / 20 mmHg was obtained to give 1-bromomethylcyclopropylacetonitrile.

6. A process for the preparation of a key intermediate of sodium montelukast side chain acid as claimed in claim 5, wherein the process comprises of: The mass ratio of intermediate 2, purified water, and ethyl acetate is 1:(10.0~15.0):(10.0~20.0).

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