Preparation method of 5-bromo (chloro)-2-methylpyrimidine

Abstract

The invention relates to a preparation method of an organic compound 5-bromo (chloro)-2-methylpyrimidine, and belongs to the technical field of organic synthesis. Comprising the following steps: a) preparation of a malondialdehyde passivator (US3974159A): firstly preparing a Vismier reagent, and then reacting the Vismier reagent with isobutyl vinyl ether at a low temperature to synthesize the malondialdehyde passivator; b) halogenating the malonaldehyde passivating agent at low temperature by using NBS (or NCS); c) performing cyclization on acetamidine hydrochloride (or acetamidine acetate) and the bromo (chloro) malonaldehyde passivator to obtain a crude product; and rectifying the crude product to obtain the 5-bromo (chloro)-2-methylpyrimidine. The method has the advantages of easily available raw materials, low cost, simple operation and easy amplification production, and has potential industrial amplification prospects.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a preparation method of 5-bromo(chloro)-2-methylpyrimidine. Background Art

[0002] 5-bromo(chloro)-2-methylpyrimidine, CAS: 7752-78-5 (54198-89-9), English name: 5-bromo-2-methylpyrimidine (5-chloro-2-methyl-pyrimidine), is a common organic synthon that can be used as a molecular skeleton to participate in the synthesis and modification of bioactive molecules; the bromine (chlorine) unit on the pyrimidine ring can undergo Suzuki and Stille coupling reactions under appropriate conditions to attach an aromatic group at position 5. In addition, halogen atoms (bromine or chlorine) can be converted into boron units. With the help of the diverse reactivity of boron atoms (oxidation, coupling, amination, etc.), more possibilities can be provided for the further derivatization of the compound. Therefore, 5-bromo(chloro)-2-methylpyrimidine has broad development prospects in the pharmaceutical field.

[0003] The synthesis literature of 5-bromo-2-methylpyrimidine includes 1): reaction of dimethyl zinc or trimethyl aluminum with 5-bromo-2-iodopyrimidine (patent WO 2014 / 75392A1; WO2014 / 98831A1), but since dimethyl zinc or trimethyl aluminum are explosive compounds, they are extremely easy to spontaneously combust in the air, and the yield is low (about 36%), the process is not suitable for large-scale production. 2): 2-methyl-5-bromopyrimidine-4-carboxylic acid synthesizes 5-bromo-2-methylpyrimidine by decarboxylation (patent WO2011 / 130628A1), with a yield of 61%. However, the raw material 2-methyl-5-bromopyrimidine-4-carboxylic acid is relatively expensive, and the raw material is not easy to obtain, which is not conducive to industrial production. 3): 2-amino-5-bromopyrimidine is used as a raw material, after diazotization, Sandmeyer reaction or Schiemann reaction, or 2-hydroxy-5-bromopyrimidine is used as a raw material, and 2-halogen-5-bromopyrimidine is obtained by halogenation reagent reaction; then a carboxylic acid diester is used to react with 2-halogen-5-bromopyrimidine to obtain a 2-substituted product; finally, the 2-substituted product is reacted under alkaline and high temperature conditions to obtain 2-methyl-5-bromopyrimidine (patent CN113683571A). However, this route has a diazotization reaction, the reaction is highly dangerous, or the raw material 2-hydroxy-5-bromopyrimidine is expensive, and the raw material is not easy to obtain, which is not conducive to industrial production.

[0004] The above method route has the disadvantages of expensive raw materials, flammable and explosive raw materials, high reaction risk, low yield, etc. Therefore, it is necessary to solve these technical problems to reduce its production cost to meet the growing market demand. Summary of the invention

[0005] The invention aims to solve the shortcomings of the existing 5-bromo(chloro)-2-methylpyrimidine preparation process, such as high raw material cost, flammable and explosive raw materials, high reaction risk, low yield and the like. The invention uses cheap and readily available N,N-dimethylformamide as a starting raw material to prepare a Vismier reagent, which is then reacted with isobutyl vinyl ether to synthesize a malondialdehyde passivator; the malondialdehyde passivator is halogenated and then cyclized with acetamidine to obtain 5-bromo(chloro)-2-methylpyrimidine; the 5-bromo(chloro)-2-methylpyrimidine prepared by the route has high purity and high yield; the preparation method of the invention has the characteristics of cheap and readily available raw materials, short reaction route and conventional reactions, mild reaction conditions, high yield, easy industrial production and the like.

[0006] The preparation method of 5-bromo-2-methylpyrimidine provided by the present invention comprises the following steps:

[0007] a) Using a halogenated reagent as a solvent and a reaction reagent, adding N,N-dimethylformamide to prepare a Vismier reagent, and then reacting with isobutyl vinyl ether to synthesize a malondialdehyde passivating agent;

[0008] b): the malondialdehyde passivating agent and the halogenating agent react under the catalysis of the catalytic agent to generate the halogenated malondialdehyde passivating agent;

[0009] c) cyclizing the halogenated malondialdehyde passivator and acetamidine to obtain a crude 5-X(bromo, chloro)-2-methylpyrimidine product, and distilling the crude product to obtain a finished product;

[0010] The reaction equation is as follows:

[0011]

[0012] In step a) of the above technical solution, the halogenated reagent used to prepare the Vismier reagent is one of thionyl chloride, oxalyl chloride and phosphorus oxychloride, preferably thionyl chloride; the preparation temperature of the Vismier reagent is 0°C to 108°C, preferably 0°C to 60°C.

[0013] In step a) of the above technical solution, the molar ratio of the halogenating reagent and N,N-dimethylformamide used in the Vismier reagent preparation method is 5 to 3:1, preferably 3:1.

[0014] In step b) of the above technical solution, the halogenating agent of the malondialdehyde passivator is one of bromosuccinimide, liquid bromine, and chlorosuccinimide, preferably bromosuccinimide and chlorosuccinimide, and the reaction temperature is -5°C to 5°C.

[0015] In step b) of the above technical solution, the solvent used in the halogenation reaction of the malondialdehyde passivator is one of dichloromethane, dichloroethane and tetrahydrofuran, preferably dichloroethane.

[0016] In step b) of the above technical solution, the catalyst used in the halogenation reaction of the malondialdehyde passivator is azobisisobutyronitrile (AIBN).

[0017] In step b) of the above technical solution, the molar ratio of the halogenating agent used in the halogenation reaction of the malondialdehyde passivator to the malondialdehyde passivator (or N,N-dimethylformamide) is 1:1.

[0018] In step b) of the above technical solution, the catalyst used in the halogenation reaction of the malondialdehyde passivator is AIBN, and the molar ratio of AIBN to the malondialdehyde passivator (or N,N-dimethylformamide) is 0.02 to 0.2:1, preferably 0.02:1.

[0019] In step c) of the above technical solution, the solvent selected for the cyclization reaction of the halogenated malondialdehyde passivator and acetamidine is one of acetonitrile, methanol, dimethyl sulfoxide, and N,N-dimethylformamide, preferably acetonitrile.

[0020] In step c) of the above technical solution, in the cyclization reaction between the halogenated malondialdehyde passivator and acetamidine, the acetamidine is acetamidine hydrochloride or acetamidine acetate, preferably acetamidine hydrochloride.

[0021] In step c) of the above technical solution, the base used in the cyclization reaction of the halogenated malondialdehyde passivator and acetamidine is one of triethylamine, sodium methoxide, potassium carbonate, potassium bicarbonate, sodium carbonate and sodium bicarbonate, preferably triethylamine.

[0022] In step c) of the above technical solution, the molar ratio of the base used in the cyclization reaction of the halogenated malondialdehyde passivator and acetamidine to the malondialdehyde passivator (or N,N-dimethylformamide) is 2.05 to 2.3:1, preferably 2.1:1.

[0023] In step c) of the above technical solution, the molar ratio of acetamidine salt and malondialdehyde passivator (or N,N-dimethylformamide) used in the cyclization reaction of halogenated malondialdehyde passivator and acetamidine is 1.05-1.5:1, preferably 1.2:1.

[0024] In step c) of the above technical solution, the reaction temperature of the halogenated malondialdehyde passivator and acetamidine cyclization reaction is between 0°C and 87°C.

[0025] Compared with the synthesis method reported in the literature, the present invention has the following beneficial effects: the present invention uses readily available raw materials, avoids the use of flammable and explosive reagents or expensive raw materials, reduces costs, and the chemical reaction is a conventional chemical reaction without dangerous reactions, which is convenient for industrial scale-up production. DETAILED DESCRIPTION

[0026] The present invention will be further described below by specific examples. These embodiments should be understood to be only used to illustrate the present invention and not to limit the scope of protection of the present invention. After reading the content of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent changes and modifications also fall within the scope defined by the claims of the present invention.

[0027] Example 1

[0028] The preparation method of 5-bromo-2-methylpyrimidine provided in this embodiment has the following reaction equation:

[0029]

[0030] The specific steps include:

[0031] 97.66g (987.26mmol, 3.0eq) of thionyl chloride was added to a 500ml four-necked bottle, cooled to <5°C, and 20g (273.64mmol, 1.0eq) of DMF was added dropwise, and the temperature was controlled at <10°C. After the addition, the temperature was raised to 40°C and stirred for 4h to 6h, and the mixture was concentrated under reduced pressure until no distillation occurred, and 20ml of DCE was added. The mixture was further concentrated under reduced pressure until no distillation occurred, and then 20g of DCE was added and the mixture was concentrated under reduced pressure until no distillation occurred, and then the mixture was dried to a solid state using an oil pump to obtain 35.41g of Vismier reagent.

[0032] Put Vismier reagent and 100 ml DCE into a 500 ml four-necked bottle, cool to <5°C, add 27.41 g isobutyl vinyl ether (273.64 mmol, 1.0 eq) dropwise, control the temperature at <10°C, raise the temperature to 40°C and stir overnight to obtain a malondialdehyde passivator.

[0033] The reaction solution of the malondialdehyde passivator was cooled to <-5°C, 1 g (6.09 mmol, 0.02 eq) of AIBN was added, and 48.7 g (273.64 mmol, 1.0 eq) of NBS was added in batches, and the temperature was controlled at <0°C. After the addition, the mixture was kept warm and stirred at 0°C for 6 hours. After TLC detection, the malondialdehyde passivator was completely reacted, and the mixture was concentrated under reduced pressure until no distillation occurred. 200 ml of acetonitrile was added for later use.

[0034] 38.8 g (410.41 mmol, 1.5 eq) of acetamidine hydrochloride and 200 ml of acetonitrile were placed in a 1000 ml four-necked bottle, cooled to <5°C, and 69.25 g (684.35 mmol, 2.5 eq) of TEA were added dropwise, and the temperature was controlled at <10°C. After the addition, the acetonitrile solution of the previously prepared bromomalonaldehyde passivator was continued to be added dropwise, and the temperature was controlled at <10°C. After the addition, the mixture was stirred at 10°C for 20 min, and the temperature was raised to reflux and stirred for 6 h. The purity of the product was about 70% by TLC. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The solvent was evaporated, and the temperature was continued to be raised to obtain 28.41 g of 5-bromo-2-methylpyrimidine. The content was 98% by HPLC, and the molar yield was 60%.

[0035] Example 2

[0036] The preparation method of 5-bromo-2-methylpyrimidine provided in this embodiment has the following reaction equation:

[0037]

[0038] The specific steps include:

[0039] Place 104.2 g (820.92 mmol, 3.0 eq) of oxalyl chloride in a 500 ml four-necked bottle, cool to <5°C, dropwise add 20 g (273.64 mmol, 1.0 eq) of DMF, control the temperature at <10°C, raise the temperature to 40°C, keep stirring for 4 to 6 hours, concentrate under reduced pressure until no distillation occurs, add 20 ml of DCE, continue to concentrate under reduced pressure until no distillation occurs, add 20 g of DCE, concentrate under reduced pressure until no distillation occurs, and then use an oil pump to dry to a solid state to obtain 35.41 g of Vismier reagent.

[0040] Put Vismier reagent and 100 ml DCE into a 500 ml four-necked bottle, cool to <5°C, add 27.41 g isobutyl vinyl ether (273.64 mmol, 1.0 eq) dropwise, control the temperature at <10°C, raise the temperature to 40°C and stir overnight to obtain a malondialdehyde passivating agent.

[0041] The reaction solution of the malondialdehyde passivator was cooled to <-5°C, 1 g of AIBN (6.09 mmol, 0.02 eq) was added, and 43.73 g of bromine (273.64 mmol, 1.0 eq) was added dropwise. The temperature was controlled at <0°C. After the addition, the mixture was kept warm and stirred at 0°C for 6 hours. After TLC detection, the malondialdehyde passivator reacted completely. The mixture was concentrated under reduced pressure until no distillation occurred, and 200 ml of acetonitrile was added for later use.

[0042] 38.8 g (410.41 mmol, 1.5 eq) of acetamidine hydrochloride and 200 ml of acetonitrile were placed in a 1000 ml four-necked bottle, cooled to <5°C, and 69.25 g (684.35 mmol, 2.5 eq) of TEA were added dropwise, and the temperature was controlled at <10°C. After the addition, the acetonitrile solution of the previously prepared bromomalonaldehyde passivator was continued to be added dropwise, and the temperature was controlled at <10°C. After the addition, the mixture was stirred at 10°C for 20 min, and the mixture was heated to reflux and stirred for 6 h. The purity of the product was about 70% by TLC. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The solvent was evaporated, and the temperature was continued to be increased to obtain 27.46 g of 5-bromo-2-methylpyrimidine. The content was 98% by HPLC, and the molar yield was 58%.

[0043] Example 3

[0044] The preparation method of 5-chloro-2-methylpyrimidine provided in this embodiment has the following reaction equation:

[0045]

[0046] The specific steps include:

[0047] 97.66g (987.26mmol, 3.0eq) of thionyl chloride was added to a 500ml four-necked bottle, cooled to <5°C, and 20g (273.64mmol, 1.0eq) of DMF was added dropwise, and the temperature was controlled at <10°C. After the addition, the temperature was raised to 40°C and stirred for 4h to 6h, and the mixture was concentrated under reduced pressure until no distillation occurred, and 20ml of DCE was added. The mixture was further concentrated under reduced pressure until no distillation occurred, and then 20g of DCE was added and the mixture was concentrated under reduced pressure until no distillation occurred, and then the mixture was dried to a solid state using an oil pump to obtain 35.41g of Vismier reagent.

[0048] Put Vismier reagent and 100 ml DCE into a 500 ml four-necked bottle, cool to <5°C, add 27.41 g isobutyl vinyl ether (273.64 mmol, 1.0 eq) dropwise, control the temperature at <10°C, raise the temperature to 40°C and stir overnight to obtain a malondialdehyde passivating agent.

[0049] The reaction solution of the malondialdehyde passivator was cooled to <-5°C, 1 g (6.09 mmol, 0.02 eq) of AIBN was added, and 36.54 g (273.64 mmol, 1.0 eq) of NCS was added in batches, and the temperature was controlled at <0°C. After the addition, the mixture was kept warm and stirred at 0°C for 6 hours. After TLC detection, the malondialdehyde passivator reacted completely, and the mixture was concentrated under reduced pressure until no distillation occurred. 200 ml of acetonitrile was added for later use.

[0050] 38.8 g (410.41 mmol, 1.5 eq) of acetamidine hydrochloride and 200 ml of acetonitrile were placed in a 1000 ml four-necked bottle, cooled to <5°C, and 69.25 g (684.35 mmol, 2.5 eq) of TEA were added dropwise, and the temperature was controlled at <10°C. After the addition, the acetonitrile solution of the chloromalonaldehyde passivator prepared above was continued to be added dropwise, and the temperature was controlled at <10°C. After the addition, the mixture was stirred at 10°C for 20 min, and the temperature was raised to reflux and stirred for 6 h. The purity of the product was about 70% by TLC. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The solvent was evaporated, and the temperature was continued to be raised to obtain 20.76 g of 5-bromo-2-methylpyrimidine. The content was 98% by HPLC, and the molar yield was 59%.

[0051] Example 4

[0052] The preparation method of 2-methylpyrimidine provided in this embodiment has the following reaction equation:

[0053]

[0054] The specific steps include:

[0055] 97.66g (987.26mmol, 3.0eq) of thionyl chloride was added to a 500ml four-necked bottle, cooled to <5°C, and 20g (273.64mmol, 1.0eq) of DMF was added dropwise, and the temperature was controlled at <10°C. After the addition, the temperature was raised to 40°C and stirred for 4h to 6h, and the mixture was concentrated under reduced pressure until no distillation occurred, and 20ml of DCE was added. The mixture was further concentrated under reduced pressure until no distillation occurred, and then 20g of DCE was added and the mixture was concentrated under reduced pressure until no distillation occurred, and then the mixture was dried to a solid state using an oil pump to obtain 35.41g of Vismier reagent.

[0056] Put Vismier reagent and 100 ml DCE into a 500 ml four-necked bottle, cool to <5°C, add 27.41 g isobutyl vinyl ether (273.64 mmol, 1.0 eq) dropwise, control the temperature to <10°C, raise the temperature to 40°C and stir overnight to obtain malondialdehyde passivator. Concentrate under reduced pressure until no distillation occurs, add 200 ml acetonitrile for later use.

[0057] 38.8 g (410.41 mmol, 1.5 eq) of acetamidine hydrochloride and 200 ml of acetonitrile were placed in a 1000 ml four-necked bottle, cooled to <5°C, and 69.25 g (684.35 mmol, 2.5 eq) of TEA were added dropwise, and the temperature was controlled at <10°C. After the addition, the acetonitrile solution of the malondialdehyde passivator prepared above was continued to be added dropwise, and the temperature was controlled at <10°C. After the addition, the mixture was stirred at 10°C for 20 min, and the temperature was raised to reflux and stirred for 6 h. The purity of the product was about 90% by TLC. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The solvent was evaporated, and the temperature was continued to be raised to obtain 21.89 g of 2-methylpyrimidine. The content was 98% by HPLC, and the molar yield was 85%.

Claims

1. A method for preparing 5-bromo(chloro)-2-methylpyrimidine, characterized in that: The steps include: a) Using a halogenated reagent as a solvent and a reaction reagent, adding N,N-dimethylformamide to prepare a Vismier reagent, and then reacting with isobutyl vinyl ether to synthesize a malondialdehyde passivating agent; b): the malondialdehyde passivating agent and the halogenating agent react under the catalysis of the catalytic agent to generate the halogenated malondialdehyde passivating agent; c) Halogenated malondialdehyde deactivator and acetamidine cyclization to obtain 5-X (bromo, chloro) -2-methylpyrimidine.

2. The method for preparing 5-bromo(chloro)-2-methylpyrimidine according to claim 1, characterized in that: In step a), the halogenating agent is thionyl chloride, oxalyl chloride or phosphorus oxychloride, and the preparation temperature of the Vismier reagent is between 0° C. and 108° C.; the molar ratio of the halogenating agent and N,N-dimethylformamide used in the preparation of the Vismier reagent is 5 to 3:

1.

3. The method for preparing 5-bromo(chloro)-2-methylpyrimidine according to claim 1, characterized in that: In step b), the halogenating agent of the malondialdehyde passivator is one of bromosuccinimide, liquid bromine, and chlorosuccinimide, and the reaction temperature is -5°C to 5°C; the molar ratio of the halogenating agent used in the halogenation reaction of the malondialdehyde passivator to the malondialdehyde passivator (or N,N-dimethylformamide) is 1:

1.

4. The method for preparing 5-bromo(chloro)-2-methylpyrimidine according to claim 1, characterized in that: In step b), the catalyst used in the halogenation reaction of the malondialdehyde passivator is azobisisobutyronitrile (AIBN); the molar ratio of the catalyst used in the halogenation reaction of the malondialdehyde passivator to the malondialdehyde passivator (or N,N-dimethylformamide) is 0.02 to 0.2:

1.

5. The method for preparing 5-bromo(chloro)-2-methylpyrimidine according to claim 1, characterized in that: In step b), the solvent used in the halogenation reaction of the malondialdehyde passivator is one of dichloromethane, dichloroethane and tetrahydrofuran.

6. The method for preparing 5-bromo(chloro)-2-methylpyrimidine according to claim 1, characterized in that: In step c), the solvent selected for the cyclization reaction of the halogenated malondialdehyde passivator and acetamidine is one of acetonitrile, methanol, dimethyl sulfoxide and N,N-dimethylformamide.

7. The method for preparing 5-bromo(chloro)-2-methylpyrimidine according to claim 1, characterized in that: In step c), in the cyclization reaction between the halogenated malondialdehyde passivator and acetamidine, the acetamidine is acetamidine hydrochloride or acetamidine acetate; and the molar ratio of the acetamidine salt and the malondialdehyde passivator (or N,N-dimethylformamide) used in the cyclization reaction between the halogenated malondialdehyde passivator and acetamidine is 1.05 to 1.5:

1.

8. The method for preparing 5-bromo(chloro)-2-methylpyrimidine according to claim 1, characterized in that: In step c), the base used in the cyclization reaction of the halogenated malondialdehyde passivator and acetamidine is one of triethylamine, sodium methoxide, potassium carbonate, potassium bicarbonate, sodium carbonate and sodium bicarbonate.

9. The method for preparing 5-bromo(chloro)-2-methylpyrimidine according to claim 1, characterized in that: In step c), the molar ratio of the base used in the cyclization reaction of the halogenated malondialdehyde passivator and acetamidine to the malondialdehyde passivator (or N,N-dimethylformamide) is 2.05-2.3:

1.

10. The method for preparing 5-bromo(chloro)-2-methylpyrimidine according to claim 1, characterized in that: In step c), the cyclization reaction temperature of the halogenated malondialdehyde passivator and acetamidine is between 0°C and 87°C.

Images