Process for the preparation of an azelastine intermediate

Abstract

The application discloses a preparation method of an azelastine intermediate, relates to the technical field of medicines, and aims to solve the problems of a complex synthesis process and a low conversion rate of the azelastine intermediate. The application comprises the following steps: S1, reaction: mixing BBMZ, PD and an organic base according to a molar ratio of 1:1.0-2.0:0.8-1.2, and reacting at a temperature of 80-100 DEG C for 3-5 h; S2, dissolution: adding 1-3 times weight of an organic solvent into the reaction mixture to promote dissolution of a reaction product; S3, filtration: removing a by-product hydrochloride of the organic base by filtration; S4, crystallization: adding 0.5-2 times weight of water into the filtrate to stir and crystallize, and controlling a temperature range of 20-45 DEG C; S5, crystal growing: cooling the solution to 0-10 DEG C, and continuing to stir for not less than 1 h; S6, filtration and washing: sequentially washing the filter cake with an organic solvent and water; and S7, drying: drying the washed filter cake at a temperature of 20-30 DEG C by air blowing for 5-6 h to obtain a PDA product. The application not only improves production efficiency and product quality, but also remarkably reduces environmental influence, and has important industrial application value.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medicine, and particularly relates to a preparation method of an imazodastine intermediate. BACKGROUND

[0002] PDA is an important intermediate of the antiallergic drug imazodastine, and its structural formula is as follows:

[0003]

[0004] The traditional synthesis process is as follows: PD, BBMZ, anhydrous potassium carbonate, DMF, a catalyst and water are added into a reaction bottle, temperature control is performed to 90-95 DEG C for reaction, the residual amount of BBMZ is monitored during the reaction, the reaction is stopped after reaching the conversion balance, and after cooling, the filter cake is filtered and washed with DMF, and the filtrates are combined; the DMF in the filtrates is evaporated under reduced pressure, water and concentrated hydrochloric acid are added after evaporation, and the unreacted BBMZ is dissolved and removed by filtration, the filtrate is washed with dichloromethane for several times, and the organic phase is discarded, sodium hydroxide solution is added dropwise to the water phase to adjust the pH value, and the solid crystal is precipitated, filtered, washed, and vacuum dried to obtain a light yellow solid PDA crude product; the light yellow solid is dissolved in dichloromethane, dried with anhydrous sodium sulfate, the sodium sulfate is removed by filtration, the filtrates are combined, the filtrates are evaporated under reduced pressure, petroleum ether is added for refining, and the filtrate is filtered and vacuum dried to obtain a light yellow powder solid.

[0005] However, the traditional process has the following obvious defects: the reaction time is long and the yield is low, only 58.9%, which affects the production efficiency and economic benefits; the operation process is complicated, a large number of reagents are involved, which increases the operation difficulty and cost; a large amount of impurities are generated in the reaction process, and one extraction purification and twice crystallization purification operations are required in the post-treatment stage, which generates a large amount of three wastes and causes great pressure on the environment; when petroleum ether is used for crystallization at last, the product is easy to be agglomerated and adhered to the wall, which is difficult to handle, and the final product is easy to be adhered to the packaging bag, which brings great inconvenience to the subsequent feeding operation.

[0006] Therefore, the existing traditional synthesis process has problems in production efficiency, operation difficulty, environmental protection and product handling, and it is necessary to develop a more efficient, environmentally friendly and easy-to-operate preparation method. SUMMARY

[0007] To solve the above problems, that is, to solve the problems raised in the above background art, the present application proposes a preparation method of an azelastine intermediate, which comprises the following steps: S1, reaction: mixing BBMZ, PD and an organic base in a proportion of 1:1.0-2.0:0.8-1.2 by mole ratio, and reacting at a temperature of 80-100℃ for 3-5h; S2, dissolution: adding 1-3 times weight of an organic solvent to the reaction mixture to promote the dissolution of the reaction product; S3, filtration: removing the hydrochloride salt of the by-product organic base by filtration; S4, crystallization: adding 0.5-2 times weight of water to the filtrate to stir and crystallize, and controlling the temperature range to be 20-45℃; S5, crystal growing: cooling the solution to 0-10℃, and continuing to stir for not less than 1h; S6, filtration and washing: washing the filter cake with organic solvent and water in sequence; S7, drying: drying the washed filter cake at a temperature of 20-30℃ by air blowing for 5-6h to obtain the PDA product.

[0008] Further provided in the present application is that in the S1, the organic base includes but is not limited to one or more of 4-methylaminopiperidine, DBU, DBN or MTBD, preferably DBU.

[0009] Further provided in the present application is that the structure of the organic base is as follows:

[0010]

[0011] Further provided in the present application is that in the S2, the organic solvent includes but is not limited to one or more of toluene, o-xylene, m-xylene, p-xylene or xylene, preferably toluene.

[0012] The present application has the beneficial technical effects that the present application has significant environmental protection and economic benefits. Firstly, by using organic base instead of traditional inorganic base and canceling the addition of reaction solvent, the reaction time is greatly shortened, and a high reaction conversion rate of more than 95% can be achieved in only 3 hours, and the organic base can be recycled after being converted into hydrochloride, reducing resource waste. Secondly, the present application has excellent impurity removal effect, and high-quality PDA products better than traditional process can be obtained by one crystallization, and crystalline PDA can be obtained, and the X-ray powder diffraction pattern thereof has characteristic peaks at specific diffraction angles 2θ=3.5°, 7.0°, 14.0°, 17.1°, 18.5°, 19.3° and 28.2°, indicating its unique crystal structure. The obtained crystal product has good physical properties, no adhesion of packaging material problem, and little product loss in the post-processing process, and the final yield can reach more than 90%. In addition, the present process simplifies the use of materials and solvents, only uses 4 kinds of materials and one kind of solvent, simplifies the recovery process, reduces the amount of waste liquid, and reduces environmental pollution. The operation process is simplified from the original 16 steps to 7 steps, significantly shortening the production time, improving the production efficiency, and reducing the energy consumption. Finally, the by-product of the present process is hydrochloride of organic base, which has a single component and is easy to recycle. Compared with the existing process, the by-product components are complex and can only be treated as hazardous waste, which forms a sharp contrast. BRIEF DESCRIPTION OF DRAWINGS

[0013] Figure 1 The process flow chart of the present application is shown.

[0014] Figure 2 The X-ray powder diffraction pattern of PDA obtained by the process of the embodiment of the present application is shown.

[0015] Figure 3 The HPLC spectrum of PDA obtained by the process of the embodiment of the present application is shown.

[0016] Figure 4 The process flow chart of the comparative example is shown.

[0017] Figure 5 The X-ray powder diffraction pattern of PDA obtained by the comparative example is shown.

[0018] Figure 6 The HPLC spectrum 1 of PDA obtained by the comparative example is shown.

[0019] Figure 7 The HPLC spectrum 2 of PDA obtained by the comparative example is shown. DETAILED DESCRIPTION

[0020] The following refers to the accompanying Figures 1-7Preferred embodiments of the present application will now be described. Those skilled in the art will appreciate that the application is not limited to these embodiments, which are presented for purposes of illustration only.

[0021] The present application provides a preparation method of an azelastine intermediate, and particularly relates to a preparation method of 1-{1-[ (4-fluorophenyl) methyl]-1H-benzimidazol-2-yl)-N-methyl-4-piperidinamine (abbreviation: PDA) by using 1-(4-fluorobenzyl)-2-chlorobenzimidazole (abbreviation: BBMZ) and 4-methylaminopiperidine (abbreviation: PD) as raw materials. Example 1

[0022] As shown in Figure 1

[0023] S1, reaction: BBMZ 10.0 kg (1.0 eq), PD 4.6 kg (1.05 eq) and DBU 5.8 kg (1.0 eq) are mixed in a reaction bottle, and the temperature is raised to 90-100 DEG C for 3 h, and the residual BBMZ is controlled to 2.6%, and the reaction is stopped;

[0024] S2, dissolution: 30 kg of toluene is added to the reaction mixture to promote the dissolution of the reaction product;

[0025] S3, filtration: the hydrochloride salt of the by-product organic base is removed by filtration;

[0026] S4, crystallization: 10 kg of water is added to the filtrate for crystallization under stirring, and the temperature is controlled in the range of 20-45 DEG C;

[0027] S5, crystal growth: the solution is cooled to 0-10 DEG C, and the stirring is continued for not less than 1 h;

[0028] S6, filtration and washing: the filter cake is washed with 10 kg of toluene and 20 kg of water in sequence;

[0029] S7, drying: the washed filter cake is dried by blowing air at a temperature of 20-30 DEG C for 5-6 h to obtain 12.2 kg of white flaky crystals, the molar yield is 94.0%, and the product purity is 99.5%.

[0030] Recovery of organic solvent: the filtrate is collected, and is left to stand at room temperature to separate the lower aqueous phase, the upper organic phase is subjected to reflux water separation, and the toluene is collected after the water content is qualified, the amount of collected toluene is 34.6 kg, the recovery rate is 86.5%, and the purity is 99.7%, which meets the requirement of the purity of not less than 99.0% for repeated use.

[0031] ​Recovery of organic base: The byproduct was slowly added to a 30% sodium methoxide solution, the pH value was controlled not to be less than 12, after stirring at room temperature for 30 min, filtration was performed, and after recovering methanol by concentrating the filtrate under reduced pressure, PD was recovered under high vacuum, to obtain 42.32 g of PD, the recovery rate was 47%, and the purity was 99.4%, which met the requirement that the purity for repeated use was not less than 98.0%. Example two:

[0032] As shown in Figure 1

[0033] S1, reaction: BBMZ 100 g (1.0 eq) and PD 89.8 g (2.05 eq) were mixed in a reaction bottle, and the temperature was increased to 90-100°C for reaction for 3 h, the residual BBMZ was controlled to be 1.4%, and the reaction was stopped;

[0034] S2, dissolution: 300 g of dimethylbenzene was added to the reaction mixture to promote the dissolution of the reaction product;

[0035] S3, filtration: the hydrochloride salt of the byproduct organic base was removed by filtration, and the byproduct was used for recovering PD;

[0036] S4, crystallization: 100 g of water was added to the filtrate for crystallization under stirring, and the temperature was controlled to be in the range of 20-45°C;

[0037] S5, crystallization: the solution was cooled to 0-10°C, and the stirring was continued for not less than 1 h;

[0038] S6, filtration and washing: the filter cake was washed with 100 g of dimethylbenzene and 200 g of water in sequence;

[0039] S7, drying: the washed filter cake was dried at a temperature of 20-30°C by blowing air for 5-6 h to obtain white flaky crystals 124.5 g, the molar yield was 95.90%, and the product purity was 99.7%.

[0040] Recovery of organic solvent: the filtrate was collected, and was allowed to stand at room temperature to separate into a lower aqueous phase and an upper organic phase, the upper organic phase was subjected to reflux water separation, and after the water content was qualified, dimethylbenzene was collected, the amount of dimethylbenzene collected was 336.2 g, the recovery rate was 84%, and the purity was 98.7%, which met the requirement that the purity for repeated use was not less than 98.0%.

[0041] Recovery of organic base: The byproduct was slowly added to a 30% sodium methoxide solution, the pH value was controlled not to be less than 12, after stirring at room temperature for 30 min, filtration was performed, and after recovering methanol by concentrating the filtrate under reduced pressure, PD was recovered under high vacuum, to obtain 42.32 g of PD, the recovery rate was 47%, and the purity was 99.4%, which met the requirement that the purity for repeated use was not less than 98.0%. Example three:

[0042] ​As shown in Figure 1

[0043] S1, reaction: add BBMZ 100 g (1.0 eq), PD 46.0 g (1.05 eq) and DBN 57.2 g (1.2 eq) into the reaction bottle, heat to 90~100℃ for 4h, control the residual of BBMZ 3.4%, stop the reaction;

[0044] S2, dissolution: add 150 g of o-xylene to the reaction mixture to promote the dissolution of the reaction product;

[0045] S3, filtration: remove the hydrochloride salt of the byproduct organic base by filtration, which is used for recycling DBN;

[0046] S4, crystallization: add 50 g of water to the filtrate and stir to crystallize, and control the temperature range to be 20~45℃;

[0047] S5, crystal growth: cool the solution to 0~10℃, continue to stir for not less than 1h;

[0048] S6, filtration and washing: wash the filter cake with 100 g of o-xylene and 200 g of water in turn;

[0049] S7, drying: dry the washed filter cake at a temperature of 20~30℃ for 5~6h to obtain white flaky crystals 121.0 g, molar yield 93.2%, product purity 99.4%.

[0050] Recovery of organic solvent: collect the filtrate, stand at room temperature, discard the lower aqueous phase, and perform reflux water separation on the upper organic phase. After the water content is qualified, it is collected. The amount of o-xylene collected is 215.0 g, the recovery rate is 86%, and the purity is 98.7%, which meets the requirement of purity not less than 98.0% for repeated use.

[0051] Recovery of organic base: slowly add the byproduct to a 30% sodium methoxide solution, control the pH value not less than 12, stir at room temperature for 30 min, filter, and then recover methanol by reducing pressure concentration and DBN by high vacuum vacuumization. DBN 52.6 g is obtained, the recovery rate is 92%, and the purity is 98.7%, which meets the requirement of purity not less than 98.0% for repeated use. Example four

[0052] As shown in Figure 1

[0053] S1, reaction: add BBMZ 100 g (1.0 eq), PD 46.0 g (1.05 eq) and MTBD 64.6 g (1.1 eq) into the reaction bottle, heat to 90~100℃ for 5h, control the residual of BBMZ 4.1%, stop the reaction;​​

[0054] S2, dissolving: 150 g of m-xylene was added to the reaction mixture to promote the dissolution of the reaction product;

[0055] S3, filtering: the hydrochloride salt of the by-product organic base was removed by filtration, which was used for the recovery of MTBD;

[0056] S4, crystallization: 50 g of water was added to the filtrate to stir and crystallize, and the temperature range was controlled at 20-45°C;

[0057] S5, crystallization: the solution was cooled to 0-10°C, and the stirring was continued for not less than 1 h;

[0058] S6, filtering and washing: the filter cake was washed with 100 g of m-xylene and 200 g of water in turn;

[0059] S7, drying: the washed filter cake was dried by blowing air at a temperature of 20-30°C for 5-6 h to obtain white flaky crystals 121.4 g, with a molar yield of 93.5%, and a product purity of 99.5%.

[0060] Recovery of organic solvent: the filtrate was collected and allowed to stand at room temperature to separate the lower aqueous phase, and the upper organic phase was subjected to reflux water separation. After the water content was qualified, the m-xylene was collected, with a recovery rate of 87% and a purity of 99.0%, which met the requirement of a purity of not less than 98.0% for repeated use.

[0061] Recovery of organic base: the by-product was slowly added to a 30% sodium methoxide solution, the pH value was controlled to be not less than 12, and after stirring at room temperature for 30 min, the filtrate was concentrated under reduced pressure to recover methanol, and then MTBD was recovered under high vacuum, to obtain 52.3 g of MTBD, with a recovery rate of 81% and a purity of 98.2%, which met the requirement of a purity of not less than 98.0% for repeated use. Example Five:

[0062] As shown in the following scheme: Figure 1

[0063] S1, reaction: BMBZ 100 g (1.0 eq), PD 46.0 g (1.05 eq) and DBU 70.1 g (1.2 eq) were mixed in a reaction bottle, and the temperature was raised to 80-90°C for reaction for 3 h, with a residual BMBZ of 2.1%, and the reaction was stopped;

[0064] S2, dissolving: 150 g of p-xylene was added to the reaction mixture to promote the dissolution of the reaction product;

[0065] S3, filtering: the hydrochloride salt of the by-product organic base was removed by filtration, which was used for the recovery of DBU;

[0066] ​S4, Crystallization: 50 g of water was added to the filtrate to stir and crystallize, and the temperature range was controlled at 20-45 °C;

[0067] S5, Crystal growth: the solution was cooled to 0-10 °C, and stirring was continued for not less than 1 h;

[0068] S6, Filtration and washing: the filter cake was washed with 100 g of p-xylene and 200 g of water in turn;

[0069] S7, Drying: the washed filter cake was air-dried at a temperature of 20-30 °C for 5-6 h to obtain white flaky crystals 123.1 g, with a molar yield of 94.8%, and a product purity of 99.6%.

[0070] Recovery of organic solvent: the filtrate was collected and allowed to stand at room temperature to separate the lower aqueous phase, and the upper organic phase was subjected to reflux water separation. After the water content was qualified, the p-xylene was collected, with a recovery rate of 88% and a purity of 99.2%, which met the requirement of a purity of not less than 98.0% for repeated use.

[0071] Recovery of organic base: the byproduct was slowly added to a 30% sodium methoxide solution, and the pH value was controlled to be not less than 12. After stirring at room temperature for 30 min, the filtrate was concentrated under reduced pressure to recover methanol, and then DBU was recovered under high vacuum, to obtain DBU 63.1 g, with a recovery rate of 90% and a purity of 99.4%, which met the requirement of a purity of not less than 98.0% for repeated use.

[0072] Comparative Example:

[0073] As shown in Figure 4 :

[0074] S1, Reaction: under laboratory conditions, the following raw materials were added to a reaction bottle: BBMZ 100.0 g (1 eq), PD 45.0 g (1.03 eq), potassium carbonate 106.7 g (2.0 eq), potassium iodide 4.5 g, DMF 450 g, and water 22.5 g. The mixture was controlled to a temperature of 90-95 °C, and maintained at this temperature for 12 h. The residual BBMZ was 42.3%, and the reaction was continued to 24 h, after which the residual BBMZ was reduced to 26.2%. Further reaction was continued to 35 h, and the residual BBMZ was reduced to 25.7%. When the conversion reached equilibrium, the reaction was stopped and the temperature was lowered to 20-25 °C;

[0075] S2, Filtration: the filter cake after reaction was washed with 45 g of DMF, and the filtrate was combined;

[0076] S3, Concentration under reduced pressure: the DMF was evaporated under reduced pressure until completely evaporated;

[0077] S4, Dissolution: 1124 g of water and 135 g of concentrated hydrochloric acid were added to the residue after evaporation in sequence for dissolution;

[0078] S5, Filtration: Filtration was performed to remove the incompletely reacted BBMZ;

[0079] S6, Washing of the aqueous phase: The filtrate was washed with 900 g of dichloromethane for 3 times each time, and the organic phase was discarded;

[0080] S7, Crystallization: A 20% sodium hydroxide solution was added dropwise to the aqueous phase, and the pH value was adjusted to 13 to precipitate a light yellow solid;

[0081] S8, Filtration and washing: The precipitated light yellow solid filter cake was filtered and washed with water;

[0082] S9, Drying: Air-drying was performed at a temperature of 20-30°C for 5-6 h to obtain 96.2 g of light yellow solid;

[0083] S10, Dissolution: 560 g of dichloromethane was added to dissolve the light yellow solid;

[0084] S11, Drying: Anhydrous sodium sulfate was added for drying under stirring at room temperature for 4-5 h;

[0085] S12, Filtration and washing: The sodium sulfate was removed by filtration, and the filter cake was washed with dichloromethane, and the filtrate was combined;

[0086] S13, Concentration: The filtrate was evaporated under reduced pressure until completely evaporated;

[0087] S14, Crystallization: 169 g of petroleum ether was added for purification;

[0088] S15, Filtration and washing: The filter cake was filtered and washed with petroleum ether;

[0089] S16, Drying: Air-drying was performed at a temperature of 20-30°C for 5-6 h to obtain 76.4 g of light yellow powder solid.

[0090] It can be seen from the detection spectrum Figure 6 and Figure 7 that the molar yield of PDA is 58.9%, and the purity of PDA is 98.0%.

[0091] It can be seen that the present application has significant environmental and economic benefits. First, by using organic base instead of traditional inorganic base and eliminating the addition of reaction solvent, the reaction time is greatly shortened, and a high reaction conversion rate of more than 95% can be achieved in only 3 hours. At the same time, the organic base can be recycled after being converted into hydrochloride, reducing resource waste. Second, the present application performs excellently in impurity removal effect, and can obtain high-quality PDA products superior to traditional processes through one crystallization, and can obtain crystalline PDA, which has characteristic peaks at specific diffraction angles 2theta = 3.5°, 7.0°, 14.0°, 17.1°, 18.5°, 19.3° and 28.2° in the X-ray powder diffraction pattern, indicating its unique crystal structure. The obtained crystalline product has good physical properties, no adhesion to packaging material problem, and little product loss in the post-processing process, and the final yield can reach more than 90%. In addition, the present process simplifies the use of materials and solvents, only uses 4 materials and one solvent, simplifies the recovery process, reduces the amount of waste liquid, and reduces environmental pollution. The operation process is simplified from the original 16 steps to 7 steps, significantly shortening the production time, improving the production efficiency, and reducing the energy consumption. Finally, the by-product of the present process is hydrochloride of organic base, which is single in composition and easy to recycle. Compared with the existing process, the by-product composition is complex and can only be treated as hazardous waste, which forms a sharp contrast.

[0092] Although the present application has been described with reference to the preferred embodiments, various modifications can be made to it without departing from the scope of the present application, and equivalent substitutions can be made to the components thereof, and in particular, the technical features mentioned in each embodiment can be combined in any manner as long as there is no structural conflict. The present application is not limited to the specific embodiments disclosed herein, but includes all technical solutions falling within the scope of the claims.

[0093] In the description of the present application, the terms "center", "upper", "lower", "left", "right", "vertical", "horizontal", "inner", "outer" and the like indicating the direction or positional relationship are based on the direction or positional relationship shown in the drawings, which is merely for the convenience of description, and does not indicate or imply that the device or element must have a particular orientation, be constructed and operated in a particular orientation, and therefore cannot be understood as a limitation on the present application. In addition, the terms "first", "second", "third" are only for descriptive purposes and cannot be understood as indicating or implying relative importance.

[0094] In addition, it needs to be explained that in the description of the present application, unless otherwise explicitly specified and limited, the terms "mounting", "connection", "connecting" should be understood in a broad sense, for example, can be fixed connection, can also be detachable connection, or integrally connected; can be mechanical connection, can also be electrical connection; can be directly connected, can also be indirectly connected through an intermediate medium, can be the communication inside two elements. For those skilled in the art, the specific meaning of the above terms in the present application can be understood according to the specific circumstances.

[0095] The term "comprising" or any other similar word is intended to encompass a non-exclusive inclusion, so that a process, article, or apparatus / device including a series of elements includes not only those elements, but also other elements not explicitly listed, or inherent to such process, article, or apparatus / device.

[0096] So far, the technical solutions of the present application have been described in combination with the preferred embodiments shown in the drawings, but those skilled in the art can easily understand that the protection scope of the present application is obviously not limited to these specific embodiments. Those skilled in the art can make equivalent changes or replacements to the related technical features without departing from the principles of the present application, and the technical solutions after the changes or replacements will fall within the protection scope of the present application.

Claims

1. A process for the preparation of an intermediate of azelastine characterized by: The method comprises the following steps: S1, reaction: mixing 1-(4-fluorobenzyl)-2-chlorobenzimidazole, 4-methylaminopiperidine and an organic base in a molar ratio of 1:1.0-2.0:0.8-1.2, and reacting at a temperature of 80-100°C for 3-5h; S2, dissolution: adding 1-3 times the weight of an organic solvent to the reaction mixture to promote dissolution of the reaction product; S3, filtration: removing the hydrochloride salt of the byproduct organic base by filtration; S4, crystallization: adding 0.5-2 times the weight of water to the filtrate, stirring to crystallize, and controlling the temperature range to be 20-45°C; S5, crystal growth: cooling the solution to 0-10°C, continuing to stir for not less than 1h; S6, filtration and washing: sequentially washing the filter cake with an organic solvent and water; S7, drying: drying the washed filter cake at a temperature of 20-30°C by blowing air for 5-6h to obtain the 1-{1-[ (4-fluorophenyl) methyl]-1H-benzimidazol-2-yl}-N-methyl-4-piperidinamine product; In the S1, the organic base is selected from one or more of 4-methylaminopiperidine, DBU, DBN or MTBD; The structure of the organic base is as follows: ； In the S2, the organic solvent is selected from one or more of toluene, o-xylene, m-xylene, p-xylene or xylene.

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