Preparation method of letemovir key intermediate

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a preparation method of a letemovir key intermediate. According to the method, 2, 6-difluorobenzonitrile is taken as an initial raw material, and the 2-bromine-6-fluoroaniline is synthesized through four steps of reaction including ammonolysis, diazotization bromination, amidation and Hofmann degradation. The method is simple to operate, mild in condition, excellent in yield and quality and suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and particularly relates to a method for preparing a key intermediate of Letermovir. Background Art

[0002] Letermovir is a potent anti-cytomegalovirus drug. Its clinical studies have shown that Letermovir has good safety and efficacy. Letermovir was launched in the United States in November 2017. It is mainly used to treat adult patients who are seropositive for cytomegalovirus after allogeneic hematopoietic stem cell transplantation and can prevent CMV infection. Compared with other approved drugs, Letermovir has no cross-tolerance and has good market prospects.

[0003] Patent CN115784896A discloses a method for preparing 2-bromo-6-fluoroaniline, which uses 2-fluoroaniline as a starting material and obtains the target product through acetylation, sulfonylation, aminolysis, deacetylation, bromination, desulfonamide and other steps. The reaction process is lengthy, the operation is cumbersome, the yield is low, and chlorosulfonic acid is used in the reaction, which is dangerous to operate and causes great environmental pollution; the reaction formula is as follows:

[0004]

[0005] Patent CN116063184A discloses another method for preparing 2-bromo-6-fluoroaniline: 2-fluoroaniline is used as the starting material, and sulfuric acid is reacted at 180-200°C to form a sulfonic acid group; in the second step, bromination is performed using hydrogen peroxide and hydrobromic acid; in the third step, the sulfonic acid group is removed to obtain the target product. The reaction formula is as follows:

[0006]

[0007] The first step of this route is harsh, using high temperature conditions and highly corrosive materials, making it difficult to select equipment for production. The second step uses hydrogen peroxide, which poses an explosion risk.

[0008] The above two routes also have the disadvantages of low selectivity, multiple isomers, low product purity, etc. Therefore, it is an urgent technical problem to be solved in the art to find a method with mild conditions, simple operation and low cost that can be successfully used for the industrial production of 2-bromo-6-fluoroaniline, a key intermediate of Letermovir. Summary of the invention

[0009] In order to make up for the deficiencies of the prior art, the present invention provides a method for preparing a key intermediate of Letermovir.

[0010] The present invention is achieved through the following technical solutions:

[0011] A method for preparing a key intermediate of Letermovir, the synthesis route is shown in the following reaction formula:

[0012]

[0013] Further, the synthesis steps are as follows:

[0014] (1) 2,6-difluorobenzonitrile reacts with ammonia to form 2-amino-6-fluorobenzonitrile;

[0015] (2) 2-amino-6-fluorobenzonitrile is diazotized and brominated to obtain 2-bromo-6-fluorobenzonitrile;

[0016] (3) 2-bromo-6-fluorobenzonitrile is hydrolyzed to form 2-bromo-6-fluorobenzamide;

[0017] (4) 2-Bromo-6-fluorobenzamide undergoes Hofmann degradation to generate the target product 2-bromo-6-fluoroaniline.

[0018] Furthermore, step (1) is to add 1 part of 2,6-difluorobenzonitrile and 2 to 20 parts of solvent ethanol by mass into a reaction container, add 2 to 20 parts of ammonia water at a temperature of 20-50°C, then increase the temperature, control the temperature at 120-140°C, and keep the temperature for reaction for 12 hours; then cool down, reduce the pressure and concentrate to recover ethanol (vacuum 20-30 mmHg, temperature 50-60°C) until no liquid flows out, add water to the residue, filter, and dry in an oven at 60°C to obtain a yellow solid 2-amino-6-fluorobenzonitrile;

[0019] Furthermore, in step (2), the diazonium salt is first prepared and then decomposed.

[0020] Furthermore, the hydrolysis conditions used are acidic reagents or alkaline reagents, the acidic reagent is sulfuric acid; the alkaline reagent is sodium hydroxide.

[0021] Further, step (2) is to add 1 part of 2-amino-6-fluorobenzonitrile to the reaction container, then add 2 to 20 parts of hydrobromic acid, stir, control the temperature at 10 degrees, and drop 1 to 2 parts of a solution prepared by sodium nitrite and water. After the addition, stir for a period of time (15 minutes to 1 hour) to prepare the diazonium salt for use; add 0.1 to 5 parts of cuprous bromide and 2 to 20 parts of hydrobromic acid to another reaction bottle, control the temperature at 0-80°C, and drop the diazonium salt solution in the step; after the addition, continue stirring, keep warm and react for 2 hours; then cool to 0-5°C, filter with suction to obtain 2-bromo-6-fluorobenzonitrile;

[0022] Further, step (3) is to add 1 part of 2-bromo-6-fluorobenzonitrile to the reaction container, add 2 to 20 parts of sulfuric acid, raise the temperature to 30-80°C, and keep warm for 12 hours. Then, pour the reaction solution into 6000g of crushed ice in batches, stir well, and filter to obtain 2-bromo-6-fluorobenzamide.

[0023] Further, step (4) is: add 0.5 to 5 parts of sodium hydroxide and 2 to 20 parts of water to the reaction container; then cool to 0-5 degrees, add 0.5 to 5 parts of sodium hypochlorite dropwise with stirring, and then control the temperature to 0-10°C and add 1 part of 2-bromo-6-fluorobenzamide in batches after the addition, keep the temperature at 0-10°C for 2 hours, then gradually increase the temperature, and finally reflux at 100-110°C for 2 hours; then cool to 20-30°C, Ethyl acetate was added for extraction and separation. The organic phase was dried and filtered over anhydrous magnesium sulfate. The filtrate was first concentrated under reduced pressure by a water pump (vacuum 20-30 mmHg, temperature 50-60°C) to recover ethyl acetate until no liquid flowed out to obtain an oily substance. The oil pump was then used to add a distillation column (distillation column 20 cm long, glass spring packing 10 cm long) for reduced pressure distillation, vacuum 0.4-5 mmHg, and the 80-90°C fraction was collected to obtain a colorless transparent liquid 2-bromo-6-fluoroaniline.

[0024] Furthermore, the reaction conditions used in step (4) are: using an aqueous solution of at least one base of sodium hydroxide and potassium hydroxide as a solvent, and using at least one halogenating agent of NCS (N-chlorosuccinimide), NBS (N-bromosuccinimide), chlorine, bromine, and sodium hypochlorite.

[0025] The above parts are all calculated by mass.

[0026] Compared with the prior art, the present invention has the following advantages:

[0027] The invention adopts the economical and readily available raw material 2,6-difluorobenzonitrile, and obtains 2-bromo-6-fluoroaniline through amination, diazotization bromination, hydrolysis to amide, and Hofmann degradation, thereby overcoming the shortcomings of the existing method of harsh conditions, complicated operation, and low product purity. The method is simple to operate, has mild conditions, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] The present invention will be further described below in conjunction with the accompanying drawings.

[0029] Figure 1 It is the gas chromatogram of 2-bromo-6-fluoroaniline in Example 2. DETAILED DESCRIPTION

[0030] The present invention is described below with reference to examples, but the present invention is not limited thereto. In the art, simple replacement or improvement made by technicians in the field to the present invention belongs to the technical solution protected by the present invention.

[0031] Example 1

[0032] (1) 2,6-difluorobenzonitrile reacts with ammonia to form 2-amino-6-fluorobenzonitrile;

[0033] The step (1) is to add 2,6-difluorobenzonitrile and 2-20 parts of solvent ethanol into a reaction container, control the temperature at 20-50°C, add 2-20 parts of ammonia water, then increase the temperature, control the temperature at 120-140°C, and keep the temperature for reaction for 12 hours; then cool down, reduce pressure and concentrate to recover ethanol until no liquid flows out, add water to the residue, filter, and dry in an oven at 60°C to obtain a yellow solid 2-amino-6-fluorobenzonitrile; the reduced pressure and concentration conditions are vacuum 20-30 mmHg and temperature 50-60°C.

[0034] (2) 2-amino-6-fluorobenzonitrile is diazotized and brominated to obtain 2-bromo-6-fluorobenzonitrile;

[0035] Specifically, step (2) is to add 2-amino-6-fluorobenzonitrile to a reaction container, then add 2 to 20 parts of hydrobromic acid, stir, control the temperature at 10 degrees, and drop 1 to 2 parts of a solution prepared by sodium nitrite and water. After the addition is completed, stir for 15 minutes to 1 hour to prepare a diazonium salt for use; add 0.1 to 5 parts of cuprous bromide and 2 to 20 parts of hydrobromic acid to another reaction bottle, control the temperature at 0-80°C, drop the diazonium salt solution in the step; after the addition is completed, continue to stir, keep warm and react for 2 hours; then cool to 0-5°C, filter with suction to obtain 2-bromo-6-fluorobenzonitrile.

[0036] (3) 2-bromo-6-fluorobenzonitrile is hydrolyzed to form 2-bromo-6-fluorobenzamide;

[0037] Step (3) is to add 2-bromo-6-fluorobenzonitrile to the reaction container, add 2 to 20 parts of sulfuric acid, and after the addition, heat to 30-80°C and keep warm for 12 hours. Then pour the reaction solution into 6000g of crushed ice in batches, stir well and filter to obtain 2-bromo-6-fluorobenzamide. The hydrolysis conditions used are acidic reagents or alkaline reagents, the acidic reagent is sulfuric acid; the alkaline reagent is sodium hydroxide.

[0038] (4) 2-Bromo-6-fluorobenzamide undergoes Hofmann degradation to generate the target product 2-bromo-6-fluoroaniline.

[0039] Step (4) comprises: adding 0.5 to 5 parts of sodium hydroxide and 2 to 20 parts of water to a reaction container; then cooling the reaction container to 0-5 degrees, adding 0.5 to 5 parts of sodium hypochlorite dropwise while stirring, and then controlling the temperature to 0-10 degrees Celsius and adding 2-bromo-6-fluorobenzamide in batches after the addition is completed. After the addition is completed, the reaction is carried out at 0-10 degrees Celsius and the reaction is carried out for 2 hours. Then the temperature is gradually increased, and finally the reaction is carried out under reflux at 100-110 degrees Celsius for 2 hours. Then the reaction container is cooled to 20-30 degrees Celsius, and ethyl acetate is added for extraction, and the liquids are separated. The organic phase is dried and filtered with anhydrous magnesium sulfate. The filtrate is first concentrated under reduced pressure with a water pump to recover ethyl acetate until no liquid flows out to obtain an oily substance, and then an oil pump is used to add a distillation column (the distillation column is 20 cm long and the glass spring filler is 10 cm long) for reduced pressure distillation, and the vacuum is 0.4-5 mmHg. The fraction of 80-90 degrees Celsius is collected to obtain a colorless transparent liquid 2-bromo-6-fluoroaniline. The reaction conditions used are: an aqueous solution of at least one base, sodium hydroxide or potassium hydroxide, is used as a solvent, and at least one halogenating agent, NCS N-chlorosuccinimide, NBS N-bromosuccinimide, chlorine, bromine, or sodium hypochlorite, is used.

[0040] In this embodiment, the above parts are all calculated by mass.

[0041] Example 2

[0042] Preparation of 2-amino-6-fluorobenzonitrile

[0043] Add 19.0g of 2,6-difluorobenzonitrile and 100g of solvent ethanol to the reaction vessel, stir, control the temperature at 20-50℃, add 300g of ammonia water, then heat up, control the temperature at 120-140℃, and keep the reaction for 12 hours. Then cool down, reduce pressure and concentrate to recover ethanol (vacuum 20-30mmHg, temperature 50-60℃) until no liquid flows out, add 400ml of water to the residue, filter, and dry in an oven at 60℃ to obtain 18.1g of yellow solid 2-amino-6-fluorobenzonitrile, with a purity of 98.0% and a yield of 97%. After testing, the experimental results show that the peak position of the product is consistent with the standard sample, which is 2-amino-6-fluorobenzonitrile.

[0044] Preparation of 2-bromo-6-fluorobenzonitrile

[0045] Add 88 g of 2-amino-6-fluorobenzonitrile to the reaction vessel, then add 1105 g of hydrobromic acid, stir, control the temperature at 0-10 degrees, and dropwise add a solution made of 55 g of sodium nitrite and 120 mL of water. After adding, stir to prepare a diazonium salt solution for use.

[0046] In another reaction bottle, add 88g of cuprous bromide and 200g of hydrobromic acid, control the temperature at 40-50 degrees, and drop the above diazonium salt solution. After addition, continue stirring and keep warm for 2 hours. Then cool to 0-5°C, filter with suction, and obtain 107.9g of 2-bromo-6-fluorobenzonitrile, with a content of 97% and a yield of 85%. After testing, the experimental results show that the peak position of the product is consistent with the standard sample, which is 2-bromo-6-fluorobenzonitrile.

[0047] Preparation of 2-bromo-6-fluorobenzamide

[0048] Add 720g of 2-bromo-6-fluorobenzonitrile to the reaction vessel, add 5000g of sulfuric acid, add, heat to 45-55 degrees, and keep warm for 12 hours. Then pour the reaction solution into 6000g of crushed ice in batches, filter after sufficient stirring, and obtain 672g of 2-bromo-6-fluorobenzamide, with a content of 98% and a yield of 85%. After testing, the experimental results show that the product peak position is consistent with the standard sample, which is 2-bromo-6-fluorobenzamide.

[0049] Preparation of 2-bromo-6-fluoroaniline

[0050] Add 120 g of sodium hydroxide and 2000 g of water to the reaction container; then cool to 5 degrees, add 440 g of sodium hypochlorite dropwise with stirring, and then add 2-bromo-6-fluorobenzamide 218.0 g in batches at a temperature of 0-10 ° C. After the addition, keep the temperature at 0-10 ° C for 2 hours, then gradually increase the temperature, and finally reflux at 100-110 ° C for 2 hours. Then the temperature was lowered to 20-30°C, ethyl acetate was added for extraction, and the organic phase was dried and filtered with anhydrous magnesium sulfate. The filtrate was first concentrated under reduced pressure by a water pump (vacuum 20-30 mmHg, temperature 50-60°C) to recover ethyl acetate until no liquid flowed out to obtain an oily substance, and then an oil pump was added to a rectification column (rectification column 20 cm long, glass spring filler 10 cm long) for reduced pressure rectification, vacuum 0.4-5 mmHg, and 80-90°C fractions were collected to obtain 133.0 g of colorless transparent liquid 2-bromo-6-fluoroaniline, purity 99.9%, and yield 70%. After testing, the product peak position was consistent with the standard sample, which was 2-bromo-6-fluoroaniline.

[0051] Example 3

[0052] Preparation of 2-amino-6-fluorobenzonitrile

[0053] Add 19.0 g of 2,6-difluorobenzonitrile and 200 g of ethanol solvent to the reaction vessel, stir, control the temperature at 20-50°C, add 200 g of ammonia water, then increase the temperature, control the temperature at 120-140°C, and keep the temperature for 12 hours. Then cool down, reduce the pressure and concentrate to recover ethanol (vacuum 20-30 mmHg, temperature 50-60°C) until no liquid flows out, add 400 ml of water to the residue, filter, and dry in an oven at 60°C to obtain 18.0 g of yellow solid 2-amino-6-fluorobenzonitrile, with a purity of 98.0% and a yield of 97%;

[0054] Preparation of 2-bromo-6-fluorobenzonitrile

[0055] Add 88g of 2-amino-6-fluorobenzonitrile to the reaction vessel, then add 805g of hydrobromic acid, stir, stir, control the temperature at 0-10 degrees, and drop a solution made of 49g of sodium nitrite and 120mL of water. After adding, stir for a while to prepare a diazonium salt solution for use.

[0056] In another reaction bottle, add 50g of cuprous bromide and 144g of hydrobromic acid, control the temperature at 10-20 degrees, and add the above diazonium salt solution. After the addition, continue stirring and keep warm for 2 hours. Then cool to 0-5°C and filter with suction to obtain 103.0g of 2-bromo-6-fluorobenzonitrile, with a content of 97% and a yield of 81%.

[0057] Preparation of 2-bromo-6-fluorobenzamide

[0058] Add 720 g of 2-bromo-6-fluorobenzonitrile and 6000 g of sulfuric acid to the reaction vessel, heat to 70-80 degrees, and keep warm for 12 hours. Then pour the reaction solution into 6000 g of crushed ice in batches, stir well, and filter to obtain 720 g of 2-bromo-6-fluorobenzamide, with a content of 98% and a yield of 91%.

[0059] Preparation of 2-bromo-6-fluoroaniline

[0060] Add 150 g of sodium hydroxide and 2000 g of water to the reaction container; then cool to 5 degrees, add 540 g of sodium hypochlorite dropwise with stirring, and then add 218.0 g of 2-bromo-6-fluorobenzamide in batches at a temperature of 0-10 ° C. After the addition, keep the temperature at 0-10 ° C for 2 hours, then gradually increase the temperature, and finally reflux at 100-110 ° C for 2 hours. Then the temperature was lowered to 20-30°C, ethyl acetate was added for extraction, and the organic phase was dried and filtered with anhydrous magnesium sulfate. The filtrate was first concentrated under reduced pressure with a water pump (vacuum 20-30 mmHg, temperature 50-60°C) to recover ethyl acetate until no liquid flowed out to obtain an oily substance, and then an oil pump was added to a distillation column (distillation column 20 cm long, glass spring filler 10 cm long) for reduced pressure distillation, vacuum 0.4-5 mmHg, and 80-90°C fractions were collected to obtain 133.0 g of colorless transparent liquid 2-bromo-6-fluoroaniline, purity 99.9%, yield 70%. The product peak position is consistent with the standard sample. The product gas chromatogram is shown in Figure 1 .

[0061] Unless otherwise specified, the reagents and raw materials used in the present invention are commercially available. If there is a conflict between the Chinese name of the compound in the present invention and the structural formula, the structural formula shall prevail, unless there is an obvious error in the structural formula.

Claims

1. A method for preparing a key intermediate of Letermovir, characterized in that: The synthetic route is shown in the following reaction formula:

2. The preparation method according to claim 1, characterized in that: The synthesis steps are as follows: (1) 2,6-difluorobenzonitrile reacts with ammonia to form 2-amino-6-fluorobenzonitrile; (2) 2-amino-6-fluorobenzonitrile is diazotized and brominated to obtain 2-bromo-6-fluorobenzonitrile; (3) 2-bromo-6-fluorobenzonitrile is hydrolyzed to form 2-bromo-6-fluorobenzamide; (4) 2-Bromo-6-fluorobenzamide undergoes Hofmann degradation to generate the target product 2-bromo-6-fluoroaniline.

3. The preparation method according to claim 2, characterized in that: Step (1) is to add 1 part of 2,6-difluorobenzonitrile and 2-20 parts of solvent ethanol in parts by weight into a reaction container, control the temperature at 20-50° C., add 2-20 parts of ammonia water, then increase the temperature, control the temperature at 120-140° C., and keep the temperature for reaction for 12 hours; then cool down, reduce pressure and concentrate to recover ethanol until no liquid flows out, add water to the residue, filter, and dry in an oven at 60° C. to obtain a yellow solid 2-amino-6-fluorobenzonitrile; the reduced pressure and concentration conditions are vacuum 20-30 mmHg, temperature 50-60° C.; the above components are in parts by weight.

4. The preparation method according to claim 2, characterized in that: Step (2) first prepares the diazonium salt and then decomposes the diazonium salt.

5. The preparation method according to claim 2, characterized in that: The hydrolysis conditions used in step (3) are acidic reagents or alkaline reagents, the acidic reagent is sulfuric acid; the alkaline reagent is sodium hydroxide.

6. The preparation method according to claim 2, characterized in that: Step (2) is to add 1 part of 2-amino-6-fluorobenzonitrile to a reaction container, then add 2 to 20 parts of hydrobromic acid, stir, control the temperature at 10 degrees, and dropwise add a solution prepared by 1 to 2 parts of sodium nitrite and water. After the addition is completed, stir for 15 minutes to 1 hour to prepare a diazonium salt for standby use; add 0.1 to 5 parts of cuprous bromide and 2 to 20 parts of hydrobromic acid to another reaction bottle, control the temperature at 0-80°C, dropwise add the diazonium salt solution in the step; after the addition is completed, continue stirring, and keep the temperature for reaction for 2 hours; then cool to 0-5°C, filter with suction, and obtain 2-bromo-6-fluorobenzonitrile.

7. The preparation method according to claim 2, characterized in that: Step (3) is to add 1 part of 2-bromo-6-fluorobenzonitrile to a reaction container, add 2 to 20 parts of sulfuric acid, raise the temperature to 30-80° C., and keep warm for 12 hours. Then, pour the reaction solution into 6000 g of crushed ice in batches, stir well, and filter to obtain 2-bromo-6-fluorobenzamide.

8. The preparation method according to claim 2, characterized in that: Step (4) comprises: adding 0.5 to 5 parts of sodium hydroxide and 2 to 20 parts of water to a reaction container; then cooling the reaction container to 0-5 degrees, adding 0.5 to 5 parts of sodium hypochlorite dropwise with stirring, and then controlling the temperature to 0-10°C and adding 1 part of 2-bromo-6-fluorobenzamide in batches after the addition is completed, and then keeping the temperature at 0-10°C for reaction for 2 hours, and then gradually raising the temperature, and finally refluxing at 100-110°C for reaction for 2 hours; then cooling the reaction container to 20-30°C, adding ethyl acetate for extraction, separating the liquids, drying and filtering the organic phase with anhydrous magnesium sulfate, and first using a water pump to reduce pressure and concentrate the filtrate to recover ethyl acetate until no liquid flows out to obtain an oily substance, and then using an oil pump to add a distillation column for reduced pressure distillation, and vacuum distilling at 0.4-5 mmHg, collecting a fraction at 80-90°C to obtain a colorless transparent liquid 2-bromo-6-fluoroaniline.

9. The preparation method according to claim 8, characterized in that: In step (4), the filtrate is first concentrated by water pump under reduced pressure conditions of 20-30 mmHg vacuum, 50-60° C., 20 cm long distillation column, and 10 cm long glass spring packing.

10. The preparation method according to claim 1, characterized in that: The reaction conditions used in step (4) are: an aqueous solution of at least one base, sodium hydroxide or potassium hydroxide, as a solvent, and at least one halogenating agent, NCS N-chlorosuccinimide, NBS N-bromosuccinimide, chlorine, bromine, or sodium hypochlorite.

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