A process for the preparation of 4-chloropyrrolopyrimidines
Using 7H-pyrrolo[2,3-D]pyrimidine as a starting material, and employing boron trihalide to protect the ortho-nitrogen atom of pyrrolopyrimidine, combined with oxidation and chlorination reactions, the problems of difficult-to-obtain starting materials and long routes were solved, and a high-yield synthesis of 4-chloropyrrolopyrimidine was achieved.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- SHANGDONG KANGNUO BIOENGINEERING CO LTD
- Filing Date
- 2026-02-13
- Publication Date
- 2026-05-29
AI Technical Summary
Existing methods for synthesizing 4-chloropyrrolopyrimidine involve difficult-to-obtain raw materials and lengthy routes, resulting in high synthesis costs and hindering the expansion of product applications.
Using 7H-pyrrolo[2,3-D]pyrimidine as a raw material, it is oxidized by reacting with a deprotonated base and boron trihalide to generate 7H-pyrrolo[2,3-D]pyrimidine-3-oxide, which is then reacted with lithium chloride and phosphorus oxychloride to prepare 4-chloropyrrolopyrimidine.
It improves the oxidation yield of the target nitrogen atom, reduces the formation of byproducts, is easy to operate, and has a high overall yield, providing an economical and efficient synthetic route.
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Abstract
Description
Technical Field
[0001] This invention relates to a method for preparing 4-chloropyrrolopyrimidine, belonging to the field of pharmaceutical intermediate synthesis technology. Background Technology
[0002] 4-Chloropyrrolopyrimidine (CAS No. 3680-69-1) is an important pharmaceutical intermediate, primarily used in the synthesis of tofacitinib. Tofacitinib, developed by Pfizer, is a JAK inhibitor that blocks inflammatory cytokine signaling by inhibiting JAK1 and JAK3 activity, and is indicated for inflammatory diseases such as rheumatoid arthritis, ulcerative colitis, and psoriasis. 4-Chloropyrrolopyrimidine also serves as a raw material for antibacterial and antitumor drugs, holding crucial application value in the field of pharmaceutical chemistry.
[0003] Regarding the synthetic route of 4-chloropyrrolopyrimidine, a search of existing literature, including patents and literature [CN110790768A; CN110724145A; CN107827893A; CN107033206A; WO201554572A1; WO201644772A1; Chemistry Letters, 2015, 44, 64; Bioorganic and medicinal chemistry letters, 2002, 12, 2153; Bioorganic and Medicinal Chemistry Letters, 2010, 20, 7297], reports the use of 4-hydroxypyrrolopyrimidine as a raw material, which is chlorinated with chlorine gas (solid phosgene or phosphorus oxychloride) to produce 4-chloropyrrolopyrimidine.
[0004] Patents and literature [CN107011347A; CN110343112A; Chemistry of Heterocyclic Compounds, 2018, 54, 638] report the use of 4-amino-6-chloro-5-acetaldehyde pyrimidine as a raw material, which undergoes a cyclization reaction under the action of hydrochloric acid or acetic acid to generate 4-chloropyrrolopyrimidine.
[0005] There are many reported synthetic methods, but most of them use raw materials that are not readily available or are too long. Therefore, researching and exploring synthetic methods for 4-chloropyrrolopyrimidine, providing readily available and inexpensive raw materials, and adopting more reasonable routes can better expand the applications of this product. Summary of the Invention
[0006] This invention was made to solve the above-mentioned problems, and its purpose is to provide a preparation method with high yield and economical route.
[0007] To solve the above-mentioned technical problems, the present invention adopts the following technical solution: 7H-pyrrolo[2,3-D]pyrimidine is used as a raw material and first reacted with a deprotonated base and boron trihalide, followed by selective oxidation in the presence of hydrogen peroxide without purification. Then, it reacts with a base to generate 7H-pyrrolo[2,3-D]pyrimidine-3-oxide, and finally reacts with phosphorus oxychloride in the presence of lithium chloride to obtain 4-chloropyrrolopyrimidine. In this invention, 7H-pyrrolo[2,3-D]pyrimidine is used as a raw material, and boron trihalide is used to protect pyrrole and its adjacent nitrogen atoms, which can greatly improve the oxidation yield of the target nitrogen atom, reduce the formation of by-products, simplify the operation, and achieve a high overall yield. This invention provides a route reference for the synthesis of such compounds.
[0008] This invention provides a method for preparing 4-chloropyrrolopyrimidine, comprising the following steps: A. 7H-pyrrolo[2,3-D]pyrimidine is mixed in an organic solvent, a deprotonated base is added under low temperature, then boron trihalide is added, and the reaction is carried out under low temperature. After heating, the mixture is filtered, the solvent is concentrated, acetic acid and hydrogen peroxide are added to react, and the reaction is quenched by adding sodium hydroxide aqueous solution to obtain 7H-pyrrolo[2,3-D]pyrimidine-3-oxide. B. Mix 7H-pyrrolo[2,3-D]pyrimidine-3-oxide and lithium chloride in a chlorine-containing solvent, and add phosphorus oxychloride under reflux to react and obtain 4-chloropyrrolopyrimidine.
[0009] The synthetic route of this invention is represented by the following reaction equation:
[0010] Furthermore, under preferred conditions, in step A, the low-temperature condition is -30 to 0°C.
[0011] Further, under preferred conditions, in step A, the organic solvent is selected from tetrahydrofuran or 2-methyltetrahydrofuran.
[0012] Further, under preferred conditions, in step A, the deprotonated base is selected from sodium hydride, methyllithium, or n-butyllithium.
[0013] Further, under preferred conditions, in step A, the boron trihalide is selected from boron trichloride or boron tribromide. (Note: Boron trichloride is introduced into the reaction equipment in a gaseous state, and its weight is measured using a boron trichloride cylinder after deducting the weight.) Furthermore, under preferred conditions, in step A, the concentration of hydrogen peroxide is selected from 20-30%.
[0014] Further, under preferred conditions, in step A, the molar ratio of 7H-pyrrolo[2,3-D]pyrimidine, base, boron trihalide and hydrogen peroxide is 1:1-1.2:1-1.8:1.4-2.
[0015] Further, under preferred conditions, in step B, the chlorine-containing solvent is selected from dichloromethane or 1,2-dichloroethane.
[0016] Further, under preferred conditions, in step B, the molar ratio of 7H-pyrrolo[2,3-D]pyrimidine-3-oxide, lithium chloride, and phosphorus oxychloride is 1:0.1-0.2:1-1.5. Beneficial effects of the invention
[0017] 1. This invention uses inexpensive and readily available 7H-pyrrolo[2,3-D]pyrimidine as raw material to prepare 4-chloropyrrolopyrimidine through a three-step reaction. The route is short, easy to operate, and has a high overall yield.
[0018] 2. This invention uses boron trihalide to protect pyrrole and its adjacent nitrogen atom, which can greatly improve the oxidation yield of the target nitrogen atom, reduce the generation of by-products, and is easy to operate.
[0019] 3. The present invention uses lithium chloride to catalyze phosphorus oxychloride chlorination (without adding lithium chloride, under the same conditions, the molar ratio of 2-position / 4-position chlorinated products is 2.3 / 5.5), which greatly improves selectivity. Attached Figure Description
[0020] Figure 1 The HNMR spectrum of 4-chloropyrrolopyrimidine was obtained in Example 5. Specific Implementation
[0021] The present invention will be further illustrated below with specific examples. These embodiments should be understood as illustrative only and not as limiting the scope of protection of the present invention. After reading the description of the present invention, those skilled in the art can make various alterations 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. Example 1
[0022] Under nitrogen protection, 11.9 g (0.1 mol) of 7H-pyrrolo[2,3-D]pyrimidine was mixed in 120 mL of THF. 2.5 M n-butyllithium (44 mL, 0.11 mol) was added at -20 °C, and the mixture was stirred for 2 hours. Then, boron trichloride (16.4 g, 0.14 mol) was slowly introduced, and the reaction was continued at low temperature for 4 hours. After the reaction was complete, the mixture was brought to room temperature, filtered, and the solvent was concentrated. At room temperature, 120 mL of acetic acid and 21.5 g of hydrogen peroxide (30%) were added, and the reaction was continued for 1 hour. After the reaction was complete, most of the acetic acid was concentrated under reduced pressure. NaOH (2N) solution was added to adjust the pH to 9-10, and the mixture was stirred at room temperature for 2 hours. 80 mL of dichloromethane was added for extraction twice, the organic layers were combined, concentrated, and the crude product was slurried with cold ethanol, filtered, and dried to obtain 12.6 g of intermediate 2, with a yield of 93% and an HPLC purity of 99.1%. 1 HNMR(400MHz, CDCl3): 12.1(s, 1H), 8.86(s, 1H), 8.31(s, 1H), 6.90(s,1H), 6.28(s, 1H)ppm. Example 2
[0023] Under nitrogen protection, 11.9 g (0.1 mol) of 7H-pyrrolo[2,3-D]pyrimidine was mixed in 120 mL of THF. 60% NaH (4.4 g, 0.11 mol) was added at -10 °C, and the mixture was stirred for 1 hour. Then, 14.1 g (0.12 mol) of boron trichloride was slowly introduced, and the reaction was continued at low temperature for 6 hours. After the reaction was complete, the mixture was heated to room temperature, filtered, and the solvent was concentrated. At room temperature, 120 mL of acetic acid and 21.5 g of hydrogen peroxide (30%) were added. After the addition was complete, the reaction was continued for 1 hour. After the reaction was complete, most of the acetic acid was concentrated under reduced pressure. NaOH (2N) solution was added to adjust the pH to 9-10, and the mixture was stirred at room temperature for 2 hours. 80 mL of dichloromethane was added for extraction twice, the organic layers were combined, concentrated, and the crude product was slurried with cold ethanol, filtered, and dried to obtain 11.9 g of intermediate 2, with a yield of 88% and an HPLC purity of 98.9%. Example 3
[0024] Under nitrogen protection, 11.9 g (0.1 mol) of 7H-pyrrolo[2,3-D]pyrimidine was mixed in 120 mL of THF. 60% NaH (4.4 g, 0.11 mol) was added at -10 °C, and the mixture was stirred for 1 hour. Then, 14.1 g (0.12 mol) of boron tribromide was slowly added, and the reaction was continued at low temperature for 3 hours. After the reaction was complete, the mixture was heated to room temperature, filtered, and the solvent was concentrated. At room temperature, 120 mL of acetic acid and 25.8 g of hydrogen peroxide (25%) were added, and the reaction was continued for 1 hour. After the reaction was complete, most of the acetic acid was concentrated under reduced pressure. NaOH (2N) solution was added to adjust the pH to 9-10, and the mixture was stirred at room temperature for 2 hours. 80 mL of dichloromethane was added for extraction twice, the organic layers were combined, concentrated, and the crude product was slurried with cold ethanol, filtered, and dried to obtain 11.2 g of intermediate 2, with a yield of 83% and an HPLC purity of 98.5%. Example 4
[0025] Under nitrogen protection, intermediate 2 (13.5 g, 0.1 mol) and lithium chloride (0.64 g, 0.015 mol) were mixed in 100 mL of dichloromethane. Under reflux, a solution of phosphorus oxychloride (18.4 g, 0.12 mol) dissolved in 30 mL of dichloroethane was slowly added. After the addition was complete, the reaction continued for 2 hours. Then, 50 mL of ice water was slowly added, and the mixture was allowed to separate into layers. The organic layer was washed twice with 50 mL of saturated sodium bicarbonate aqueous solution. The organic layer was concentrated, and the crude product was recrystallized from petroleum ether and ethyl acetate to give 14.1 g of 4-chloropyrrolopyrimidine, with a yield of 92% and an HPLC purity of 99.4%. ¹H NMR (400 MHz, DMSO-d6): 12.57 (s, 1H), 8.57 (s, 1H), 7.70 (d, 1H), 6.61 (d, 1H) ppm. Example 5
[0026] Under nitrogen protection, intermediate 2 (13.5 g, 0.1 mol) was mixed in 100 mL of dichloromethane. Under reflux, a solution of phosphorus oxychloride (23 g, 0.15 mol) dissolved in 50 mL of dichloroethane was slowly added. After the addition was complete, the reaction continued for 5 hours. Then, 80 mL of ice water was slowly added, and the mixture was allowed to separate into layers. The organic layer was washed twice with 80 mL of saturated sodium bicarbonate aqueous solution. The organic layer was concentrated, and the crude product was recrystallized from petroleum ether and ethyl acetate to give 12.7 g of 4-chloropyrrolopyrimidine, with a yield of 83% and an HPLC purity of 99%.
[0027] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.
Claims
1. A method for preparing 4-chloropyrrolopyrimidine, characterized in that, Includes the following steps: A. 7H-pyrrolo[2,3-D]pyrimidine is mixed in an organic solvent, a deprotonated base is added under low temperature, then boron trihalide is added, and the reaction is carried out under low temperature. After heating, the mixture is filtered, the solvent is concentrated, acetic acid and hydrogen peroxide are added to react, and the reaction is quenched by adding sodium hydroxide aqueous solution to obtain 7H-pyrrolo[2,3-D]pyrimidine-3-oxide. B. Mix 7H-pyrrolo[2,3-D]pyrimidine-3-oxide and lithium chloride in a chlorine-containing solvent, and add phosphorus oxychloride under reflux to react and obtain 4-chloropyrrolopyrimidine.
2. The method for preparing 4-chloropyrrolopyrimidine according to claim 1, characterized in that: In step A, the low temperature condition is -30 to 0°C; the organic solvent is selected from tetrahydrofuran or 2-methyltetrahydrofuran.
3. The method for preparing 4-chloropyrrolopyrimidine according to claim 1, characterized in that: In step A, the deprotonated base is selected from sodium hydride, methyllithium, or n-butyllithium.
4. The method for preparing 4-chloropyrrolopyrimidine according to claim 1, characterized in that: In step A, the boron trihalide is selected from boron trichloride or boron tribromide.
5. The method for preparing 4-chloropyrrolopyrimidine according to claim 1, characterized in that: In step A, the concentration of hydrogen peroxide is selected from 20-30%.
6. The method for preparing 4-chloropyrrolopyrimidine according to claim 1, characterized in that: In step A, the molar ratio of 7H-pyrrolo[2,3-D]pyrimidine, base, boron trihalide and hydrogen peroxide is 1:1-1.2:1-1.8:1.4-2.
7. The method for preparing 4-chloropyrrolopyrimidine according to claim 1, characterized in that: In step B, the chlorine-containing solvent is selected from dichloromethane or 1,2-dichloroethane.
8. The method for preparing 4-chloropyrrolopyrimidine according to claim 1, characterized in that: In step B, the molar ratio of 7H-pyrrolo[2,3-D]pyrimidine-3-oxide, lithium chloride and phosphorus oxychloride is 1:0.1-0.2:1-1.5.