A process for the preparation of 4-chloropyrrolopyrimidines

Abstract

The application relates to a preparation method of 4-chloropyrrolopyrimidine, in particular to a four-step high-yield synthesis of 4-chloropyrrolopyrimidine by taking diethyl malonate and bromoacetaldehyde diethyl acetal as raw materials, through substitution reaction, then ring closure reaction with formamidine acetate, ring closure reaction under acidic conditions, and then chlorination reaction with phosphorus oxychloride; the preparation method of 4-chloropyrrolopyrimidine provided by the synthesis route is a preparation method with high yield, low cost, easy operation and suitability for industrialization.

Description

Technical Field

[0001] This invention relates to the field of pharmaceuticals, and more specifically to a method for preparing 4-chloropyrrolopyrimidine. Background Technology

[0002] Tofacitinib is a JAK inhibitor. JAKs are intracellular enzymes that effectively inhibit the activity of JAK1 and JAK3, blocking the signal transduction of various inflammatory cytokines. Clinical studies have demonstrated that this drug has good therapeutic effects on various inflammatory diseases such as rheumatoid arthritis, ulcerative colitis, and psoriasis.

[0003] With the increasing market demand for tofacitinib, the market demand for its key intermediate, 4-chloropyrrolopyrimidine, is also growing. Currently, Chinese patent CN104860950A reports the following synthetic route for 4-chloropyrrolopyrimidine: using ethyl cyanoacetate and bromoacetaldehyde diethanolate as starting materials, 4-chloropyrrolopyrimidine is synthesized in four steps via substitution reaction, followed by a two-step cyclization reaction and a chlorination reaction. The problems include low yield and high cost. Summary of the Invention

[0004] To address the problems of low yield and high cost in existing technologies, this invention provides a method for preparing 4-chloropyrrolopyrimidine.

[0005] The present invention adopts the following technical solution:

[0006] A method for preparing 4-chloropyrrolopyrimidine includes the following steps:

[0007] S1. Add diethyl malonate to DMF, then add potassium carbonate, and add bromoacetaldehyde diethanolate dropwise while controlling the temperature. After the addition is complete, raise the temperature to 100°C. ℃ After the reaction is complete, the mixture is filtered, the filtrate is distilled off to remove DMF, and the residue is distilled to obtain intermediate 1.

[0008] S2, intermediate 1, is added to anhydrous ethanol, followed by formamidine acetate, and then a 20% sodium ethoxide solution is added dropwise. After the addition is complete, the temperature is raised to 70°C. ℃ Stir and react for 5 hours, then keep warm at 70°C. ℃ Add ammonia water dropwise, and after the addition is complete, keep the temperature at 70°C. ℃ The reaction was carried out for 6 hours. After the reaction was completed, the filtrate was concentrated to dryness, water was added, the mixture was stirred for 1 hour, filtered, and the filter cake was dried to obtain the intermediate.

[0009] S3. Add intermediate 2 to hydrochloric acid and maintain the temperature at 50°C. ℃ After the reaction is complete, the temperature is lowered, the mixture is filtered, the filter cake is washed with water, filtered again, and the filter cake is dried to obtain intermediate 3.

[0010] S4. Add intermediate 3 to phosphorus oxychloride and heat to 100°C. ℃ The reaction was carried out for 3 hours, and then phosphorus oxychloride was distilled off under reduced pressure. The residue in the reactor was slowly added to a 10% sodium bicarbonate solution, filtered, and the filter cake was recrystallized with ethyl acetate to obtain the product 4-chloropyrrolopyrimidine.

[0011] Preferably, the diethyl malonate equivalent in step S1 is 2.2.

[0012] Preferably, the temperature controlled in step S1 is 15°C. ℃ .

[0013] Preferably, the potassium carbonate equivalent in step S1 is 2.

[0014] Preferably, the formamidine acetate equivalent in step S2 is 1.2.

[0015] Preferably, the sodium ethoxide equivalent in step S2 is 1.5.

[0016] Preferably, the ammonia equivalent in step S3 is 1.2.

[0017] Preferably, the hydrochloric acid equivalent in step S3 is 3.

[0018] Preferably, the phosphorus oxychloride equivalent in step S4 is 5.

[0019] The beneficial effects of this invention are as follows:

[0020] Using diethyl malonate and bromoacetaldehyde diethanol condensate as raw materials, 4-chloropyrrolopyrimidine was synthesized in high yield in four steps via substitution reaction, followed by cyclization reaction with formamidine acetate, cyclization reaction under acidic conditions, and chlorination reaction with phosphorus oxychloride.

[0021] The method for preparing 4-chloropyrrolopyrimidine provided by this invention is a high-yield, low-cost, easy-to-operate, and industrially suitable preparation method. Attached Figure Description

[0022] Figure 1 This is the reaction route diagram for Example 4 of the present invention - chloropyrrolopyrimidine. Detailed Implementation

[0023] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.

[0024] This embodiment provides a method for preparing 4-chloropyrrolopyrimidine, such as... Figure 1 As shown, the specific steps include:

[0025] Example 1:

[0026] Add 179g of diethyl malonate to 300ml of DMF, then add 110g of potassium carbonate. While controlling the temperature, add 100g of bromoacetaldehyde diethanolate dropwise. After the addition is complete, raise the temperature by 100°C. ℃ The reaction proceeded. After the reaction was complete, the mixture was filtered, DMF was distilled off from the filtrate, and the residue was distilled to give 120g of intermediate 1, with a yield of 86%.

[0027] 120g of intermediate 1 was added to 300ml of anhydrous ethanol, followed by 50g of formamidine acetate, and then 220g of 20% sodium ethoxide solution was added dropwise. After the addition was complete, the temperature was raised to 70°C. ℃ Stir and react for 5 hours. Then keep warm at 70°C. ℃ Add 18g of ammonia solution dropwise. After the addition is complete, keep the temperature at 70°C. ℃ The reaction was carried out for 6 hours. After the reaction was complete, the filtrate was concentrated to dryness, water was added, and the mixture was stirred for 1 hour. The mixture was then filtered, and the filter cake was dried to obtain 81 g of intermediate 2, with a yield of 82%.

[0028] Add 81g of intermediate 2 to 300ml of 5N hydrochloric acid and maintain the temperature at 50°C. ℃ The reaction was carried out. After the reaction was complete, the mixture was cooled, filtered, the filter cake was washed with water, filtered again, and the filter cake was dried to obtain 46g of intermediate 3, with a yield of 96%.

[0029] Add 46g of intermediate 3 to 300g of phosphorus oxychloride, and heat to 100°C. ℃ The reaction was carried out for 3 hours, and then phosphorus oxychloride was distilled off under reduced pressure. The residue was slowly added to a 10% sodium bicarbonate solution, filtered, and the filter cake was recrystallized with ethyl acetate to obtain 45g of 4-chloropyrrolopyrimidine, with a yield of 88%.

[0030] Example 2:

[0031] Add 190g of diethyl malonate to 300ml of DMF, then add 110g of potassium carbonate. While controlling the temperature, add 100g of bromoacetaldehyde diethanolate dropwise. After the addition is complete, raise the temperature by 100°C. ℃ The reaction proceeded. After the reaction was complete, the mixture was filtered, DMF was distilled off from the filtrate, and the residue was distilled to give 117 g of intermediate 1, with a yield of 84%.

[0032] 117g of intermediate 1 was added to 280ml of anhydrous ethanol, followed by 56g of formamidine acetate, and then 218g of 20% sodium ethoxide solution was added dropwise. After the addition was complete, the temperature was raised to 70°C. ℃ Stir and react for 5 hours. Then keep warm at 70°C. ℃ Add 20g of ammonia solution dropwise. After the addition is complete, keep the temperature at 70°C. ℃The reaction was carried out for 6 hours. After the reaction was complete, the filtrate was concentrated to dryness, water was added, and the mixture was stirred for 1 hour. The mixture was then filtered, and the filter cake was dried to obtain 79 g of intermediate 2, with a yield of 81%.

[0033] Add 79g of intermediate 2 to 300ml of 5N hydrochloric acid and maintain the temperature at 50°C. ℃ The reaction was carried out. After the reaction was complete, the mixture was cooled, filtered, the filter cake was washed with water, filtered again, and the filter cake was dried to obtain 44g of intermediate 3, with a yield of 95%.

[0034] Add 44g of intermediate 3 to 300g of phosphorus oxychloride, and heat to 100°C. ℃ The reaction was carried out for 3 hours, and then phosphorus oxychloride was distilled off under reduced pressure. The residue was slowly added to a 10% sodium bicarbonate solution, filtered, and the filter cake was recrystallized with ethyl acetate to obtain 42g of 4-chloropyrrolopyrimidine, with a yield of 86%.

[0035] The above description is merely a preferred embodiment of the present invention and does not constitute any limitation on the technical scope of the present invention. Therefore, all technical solutions formed by equivalent substitution or equivalent transformation fall within the protection scope claimed by the present invention.

Claims

1. A method for preparing 4-chloropyrrolopyrimidine, characterized in that, Includes the following steps: S1. Diethyl malonate was added to DMF, followed by potassium carbonate. Bromoacetaldehyde diethanol was added dropwise under controlled temperature. After the addition was complete, the temperature was raised to 100℃ for reaction. After the reaction was complete, the mixture was filtered, DMF was distilled off from the filtrate, and the residue was distilled to obtain 2-(2,2-diethoxyethyl)diethyl malonate. S2, diethyl 2-(2,2-diethoxyethyl)malonate was added to anhydrous ethanol, formamidine acetate was added, and then 20% sodium ethoxide solution was added dropwise. After the addition was complete, the temperature was raised to 70°C and the reaction was stirred for 5 hours. Then, ammonia water was added dropwise while maintaining the temperature at 70°C. After the addition was complete, the reaction was maintained at 70°C for 6 hours. After the reaction was complete, the filtrate was concentrated to dryness, water was added, the mixture was stirred for 1 hour, filtered, and the filter cake was dried to obtain 4-amino-6-hydroxy-5-(2,2-diethoxyethyl)pyrimidine. S3. Add 4-amino-6-hydroxy-5-(2,2-diethoxyethyl)pyrimidine to hydrochloric acid and react at 50°C. After the reaction is complete, cool down, filter, wash the filter cake with water, filter again, and dry the filter cake to obtain 4-hydroxypyrrolo[2,3-d]pyrimidine. S4. Add 4-hydroxypyrrolo[2,3-d]pyrimidine to phosphorus oxychloride, heat to 100℃ and react for 3 hours, then distill off phosphorus oxychloride under reduced pressure, slowly add the residue to a 10% sodium bicarbonate solution, filter, and recrystallize the filter cake with ethyl acetate to obtain the product 4-chloropyrrolopyrimidine.

2. The method for preparing 4-chloropyrrolopyrimidine according to claim 1, characterized in that: The diethyl malonate equivalent in step S1 is 1-3.

3. The method for preparing 4-chloropyrrolopyrimidine according to claim 1, characterized in that: The temperature control temperature mentioned in step S1 is 10℃-30℃.

4. The method for preparing 4-chloropyrrolopyrimidine according to claim 1, characterized in that: The potassium carbonate equivalent in step S1 is 1-2.

5. The method for preparing 4-chloropyrrolopyrimidine according to claim 1, characterized in that: The amount of formamidine acetate equivalent in step S2 is 1-2.

6. The method for preparing 4-chloropyrrolopyrimidine according to claim 1, characterized in that: The sodium ethoxide equivalent in step S2 is 1-2.

7. The method for preparing 4-chloropyrrolopyrimidine according to claim 1, characterized in that: The ammonia equivalent in step S2 is 1-1.

2.

8. The method for preparing 4-chloropyrrolopyrimidine according to claim 1, characterized in that: The hydrochloric acid equivalent in step S3 is 2-5.

9. The method for preparing 4-chloropyrrolopyrimidine according to claim 1, characterized in that: The phosphorus oxychloride equivalent in step S4 is 3-10.

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