Preparation method of 4-chloro-5H-pyrrolo [3, 2-D] pyrimidine-2-amine

Abstract

The invention relates to a preparation method of 4-chloro-5H-pyrrolo [3, 2-D] pyrimidine-2-amine, which comprises the following steps: step 1, synthesizing a compound B from a compound A; 2, synthesizing a compound C from the compound B; 3, synthesizing a compound D from the compound C; wherein the structures of the compound A, the compound B, the compound C and the compound D are respectively as follows: # imgabs0 #. Compared with the prior art, the preparation method disclosed by the invention has the advantages that the process is simple, only three-step reaction is needed, and complicated post-treatment is not needed; the cost is controllable, raw materials are easy to obtain, reagents are cheap, and the prepared compound is a key intermediate of kinase inhibitor drugs, has important application value in research and development of anti-cancer and anti-inflammatory drugs and has high potential economic benefits; the method has no harsh reaction conditions, is simple to operate and is suitable for large-scale production.

Description

Technical Field

[0001] The present invention belongs to the technical fields of medicinal chemistry and organic synthesis, and particularly relates to a preparation method of 4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine. Background Art

[0002] Pyrrolopyrimidine amine compounds exhibit significant biological activities due to their unique nitrogen-containing heterocyclic structures, and have attracted much attention particularly in the fields of anti-cancer, anti-viral and kinase inhibitors. In recent years, 4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine has become a core intermediate in drug research and development due to the high-efficiency regulation ability of its derivatives on target proteins. For example:

[0003] Patent WO2015192119A1 discloses heat shock protein 90 inhibitors based on 2-amino-4-aryl pyrimidines for the treatment of neurodegenerative diseases. The intermediate structure of one of its examples is:

[0004]

[0005] Patent WO2015168279A1 developed pyrrolopyrimidine amine compounds for the treatment of TLR7 activity-related diseases (such as asthma, ulcerative colitis). The intermediate structure of one of its examples is:

[0006]

[0007] Patent WO2020252043A1 discloses the application of pyrrolopyrimidine diamino compounds in cancer diagnosis and treatment. The intermediate structure of one of its examples is:

[0008]

[0009] In the preparation process of the above compounds, 4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine is required. The structural formula of 4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine is:

[0010]

[0011] However, although 4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine has been commercialized, there are not many literatures and patents reporting its synthesis route. And although using 2-amino-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one to prepare 4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine is a feasible method, the existing synthesis methods of 2-amino-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one (Compound C) as an intermediate have defects such as complex routes, low yields or high costs, which severely restrict its industrial application.

[0012] There are several different synthetic routes for the synthesis of 2-amino-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one. Among them, the synthetic route with practical application value is to obtain 2-amino-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one through multiple steps using 2-amino-6-methyl-5-nitro-4-pyrimidinone as the raw material. Other synthetic routes have problems such as long routes, low yields, and difficult availability of raw materials, and have no practical application value. Starting from 2-amino-6-methyl-5-nitro-4-pyrimidinone, Teaahcdron Lett 1993, 34, 4595 and J Org Chem 1995, 60, 7947 reported the following synthetic route:

[0013] Route 1:

[0014]

[0015] Regarding the last step in Synthetic Route 1, the reported yield is only 48%, and the reaction time requires 4 days. The main reason for the low yield of this reaction is that 2-amino-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one has poor stability under alkaline conditions.

[0016] Synth Commun 1998, 32, 3797 reported an improved method, as shown in Synthetic Route 2; this synthetic route uses a benzyloxymethyl protecting group instead of the pivaloyloxymethyl protecting group in Route 1 to avoid the use of strong alkaline reagents during the deprotection process.

[0017] Route 2:

[0018]

[0019] Although Route 2 avoids strong alkaline conditions in the final deprotection group compared to Route 1, it requires the use of a noble metal palladium catalyst for pressurized hydrogenation. WO2006122003 describes an improved method for Route 2, using benzyl bromide instead of BnOCH2Cl to protect the nitrogen atom at the 3-position of pyrimidinone, but there is also the need to use a large equivalent of noble metal palladium catalyst in the step of removing the protecting group.

[0020] J.Org.Chem.1999, 64, 8411 and US6693193 describe an improved method for Route 1, which does not require the use of a pivaloyloxymethyl protecting group to protect the nitrogen atom at the 3-position of pyrimidinone, and the route steps are shorter. However, HelChem Acta 2004, 87, 2507 reported that this improved method could not be achieved, and the reported experimental results were not reproducible. Summary of the Invention

[0021] In view of the problem in the above-mentioned existing technologies that there is a lack of an industrially applicable preparation route for 4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine, the present invention provides a preparation method for 4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine.

[0022] The preparation method for 4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine provided by the present invention is simple in operation, low in cost and suitable for industrial production.

[0023] The object of the present invention can be achieved by the following technical solutions:

[0024] The present invention provides a preparation method for 4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine, comprising the following steps:

[0025] Step 1: Synthesize compound B from compound A;

[0026] Step 2: Synthesize compound C from compound B;

[0027] Step 3: Synthesize compound D from compound C;

[0028] Among them, the structures of compound A, B, C, and D are as follows:

[0029]

[0030] The synthesis route of the preparation method for 4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine provided by the present invention is as follows:

[0031]

[0032] In an embodiment of the present invention, in Step 1, the method for synthesizing compound B from compound A is:

[0033] Add compound A to water, add a strong base reagent, carry out a reaction, after the reaction is completed, adjust the pH of the system, precipitate a solid product, and obtain compound B through suction filtration, washing with water and vacuum drying.

[0034] In an embodiment of the present invention, in Step 1, the reaction conditions are heating at 100 - 130 °C for 15 - 20 hours. Preferably, the reaction temperature is 120 °C.

[0035] In an embodiment of the present invention, in Step 1, adjusting the pH of the system means adjusting the pH of the system to 4 - 5 with dilute hydrochloric acid.

[0036] In an embodiment of the present invention, in Step 1, the strong base is selected from one of lithium hydroxide, sodium hydroxide or potassium hydroxide.

[0037] In one embodiment of the present invention, in step 1, the amount of the strong base is 2.0 - 3.0 times the amount of compound A (2,4-dichloropyrrolo[3,2-D]pyrimidine).

[0038] In one embodiment of the present invention, in step 2, the method for synthesizing compound C from compound B is as follows:

[0039] Dissolve compound B in an alcoholic solution of ammonia, carry out the reaction. After the reaction is completed, remove the solvent by vacuum distillation, precipitate the solid product, wash it with water, filter it by suction, and dry it under vacuum to obtain compound C.

[0040] In one embodiment of the present invention, in step 2, the reaction conditions are: heat and stir at 100 - 130 °C for 36 - 48 hours; in step 2, the preferred reaction temperature is 120 °C.

[0041] In one embodiment of the present invention, in step 2, the ammonia source is selected from ammonia methanol solution or ammonia ethanol solution.

[0042] In one embodiment of the present invention, in step 2, in the ammonia solution, the amount-of-substance concentration of NH 3 is 4 - 7.5 M.

[0043] In one embodiment of the present invention, in step 3, the method for synthesizing compound D from compound C is as follows:

[0044] Mix compound C with phosphorus oxychloride and carry out the reaction. After the reaction is completed, remove phosphorus oxychloride by vacuum distillation, quench the remaining concentrated solution with ice water, adjust the pH of the system, then extract with ethyl acetate, collect the organic phase, spin dry, wash the solid product with saturated sodium bicarbonate, filter it by suction, and dry it under vacuum to obtain compound D.

[0045] In one embodiment of the present invention, in step 3, the reaction conditions are: heat and stir at 90 - 120 °C for 12 hours; preferably, the reaction temperature is 100 °C.

[0046] In one embodiment of the present invention, in step 3, adjusting the pH of the system means: adjusting the pH to 9.0 - 10 with sodium hydroxide solution.

[0047] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0048] 1. The process of the present invention is simple and straightforward, only requiring three-step reactions without complex post-treatment;

[0049] 2. The cost of the present invention is controllable, the raw materials are easily available, and the reagents are inexpensive. The compound prepared by the present invention is a key intermediate of kinase inhibitor drugs and has important application value in the research and development of anti-cancer and anti-inflammatory drugs, with relatively high potential economic benefits;

[0050] 3. The present invention has no harsh reaction conditions, is easy to operate, and is suitable for large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1 1H NMR spectrum of 4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine prepared in Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0052] The present invention will be described in detail below with reference to specific examples. The following examples will help those skilled in the art to further understand the present invention, but do not limit the present invention in any form. Without departing from the concept of the present invention, those skilled in the art can also make several adjustments and improvements. These all fall within the protection scope of the present invention. The raw materials and reagents used in the present invention are all commercially available AR or CP grades.

[0053] Example 1

[0054] This example provides a method for preparing 4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine, and the steps are as follows:

[0055] Step (1): Synthesis of 2-chloro-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one

[0056] Dissolve 2,4-dichloropyrrolo[3,2-d]pyrimidine (91 g, 480 mmol) in 1400 mL of water, add lithium hydroxide monohydrate (40 g, 960 mmol), and stir the reaction at 110 °C for 20 hours. After the reaction system is cooled to room temperature, adjust the pH to 5.0 with dilute hydrochloric acid, and a white solid precipitates. After filtration, washing with water, and vacuum drying, 2-chloro-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (63 g, yield 77%) is obtained.

[0057] Step (2): Synthesis of 2-amino-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one

[0058] Dissolve 2-chloro-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (50 g, 300 mmol) in 750 mL of 6 mol / L ammonia methanol solution, and stir at 110 °C for 48 hours. After the reaction system is cooled to room temperature, the solvent is removed by distillation under reduced pressure, and a yellow solid precipitates. After washing with water, filtration, and drying, 2-amino-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one (28 g, yield 62%) is obtained.

[0059] Step (3): Synthesis of 4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine

[0060] 2-Amino-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one (30 g, 200 mmol) was mixed with 300 mL of phosphorus oxychloride and stirred at 110 °C for 12 hours. After the reaction system was cooled to room temperature, most of the phosphorus oxychloride was removed by distillation under reduced pressure. The concentrated solution was quenched with ice water, and the pH was adjusted to 9.0 - 10 with 1 mol / L sodium hydroxide solution. After extraction with ethyl acetate, the organic phase was collected and dried by rotary evaporation. The obtained solid product was washed with saturated sodium bicarbonate for 3 hours, then filtered by suction and dried in vacuo to obtain the target product 4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine (22.4 g, yield 66%). Its hydrogen spectrum is as shown in Figure 1 shown below. The 1H NMR (proton nuclear magnetic resonance) spectrum data are as follows: 1H NMR (400 MHz, DMSO-d 6 ) δ 11.76 (s, 1H), 7.65 (t, J = 3.0 Hz, 1H), 6.34 (s, 2H), 6.22 (dd, J = 3.0, 1.4 Hz, 1H).

[0061] Example 2

[0062] This example provides a method for preparing 4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine.

[0063] This example is basically the same as Example 1, with the special feature that:

[0064] In this example, compared with Example 1, the reaction temperature was changed. In the preparation of the first-step compound 2-chloro-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, the reaction was carried out at 90 °C. Monitored by thin-layer chromatography (TLC). After the reaction was completed, the product was obtained after treatment, with a yield of 52%. The second and third steps were the same as those in Example 1.

[0065] Example 3

[0066] This example provides a method for preparing 4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine.

[0067] This example is basically the same as Example 1, with the special feature that:

[0068] In this example, compared with Example 1, the reaction temperature was changed. In the preparation of the first-step compound 2-chloro-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, the reaction was carried out at 120 °C. Monitored by thin-layer chromatography (TLC). After the reaction was completed, the product was obtained after treatment, with a yield of 71%. The second and third steps were the same as those in Example 1.

[0069] Example 4

[0070] This example provides a method for preparing 4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine,

[0071] This example is basically the same as Example 1, with the special feature that:

[0072] In this example, compared with Example 1, the type of basic reagent is changed. In the preparation of the first-step compound 2-chloro-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, sodium hydroxide is used as the basic reagent. By TLC tracking, after the reaction is completed, the product is obtained through treatment, and the yield is 63%. The second and third steps are the same as those in Example 1.

[0073] Example 5

[0074] This example provides a method for preparing 4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine,

[0075] This example is basically the same as Example 1, with the special feature that:

[0076] In this example, compared with Example 1, the type of basic reagent is changed. In the preparation of the first-step compound 2-chloro-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, potassium hydroxide is used as the basic reagent. By TLC tracking, after the reaction is completed, the product is obtained through treatment, and the yield is 60%. The second and third steps are the same as those in Example 1.

[0077] Example 6

[0078] This example provides a method for preparing 4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine,

[0079] This example is basically the same as Example 1, with the special feature that:

[0080] In this example, compared with Example 1, the reaction temperature is changed. In the preparation of the second-step compound 2-amino-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one, the reaction is carried out at 120 °C. After the reaction is completed, the product is obtained through treatment, and the yield is 50%. The first and third steps are the same as those in Example 1.

[0081] Example 7

[0082] This example provides a method for preparing 4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine,

[0083] This example is basically the same as Example 1, with the special feature that:

[0084] In this embodiment, compared with Embodiment 1, the type of solvent for dissolving ammonia is changed. In the preparation of the second-step compound 2-amino-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one, an ammonia ethanol solution is used as the ammonia source. After the reaction is completed, the product is obtained through treatment, and the yield is 53%. The first step and the third step are the same as those in Embodiment 1.

[0085] The method of the above embodiments of the present invention uses 2,4-dichloropyrrolo[3,2-d]pyrimidine as the starting material, and realizes the synthesis of the target product through three-step reactions: first, it reacts with an alkaline solution to generate the intermediate 2-chloro-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one; then it is ammoniated to introduce an amino group to obtain 2-amino-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one; finally, 4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine is prepared through a chlorination reaction.

[0086] This method has the characteristics of a short synthesis route, a simple operation process, easily available raw materials, etc., can effectively improve the synthesis efficiency, is convenient for scale-up production, and is conducive to industrial promotion.

[0087] As a key pharmaceutical intermediate, 4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine plays an important role in the design and development of kinase inhibitors, and particularly shows significant potential in the fields of anti-cancer and anti-inflammatory drugs.

[0088] The above description of the embodiments is for the convenience of those of ordinary skill in the art to understand and use the invention. Obviously, those who are familiar with the technology in this field can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative labor. Therefore, the present invention is not limited to the above embodiments, and the improvements and modifications made by those skilled in the art without departing from the scope of the present invention according to the disclosure of the present invention should be within the protection scope of the present invention.

Claims

1. A method for preparing 4-chloro-5H-pyrrolo[3,2-D]pyrimidin-2-amine, characterized in that: The steps include: Step 1, synthesizing compound B from compound A; Step 2, synthesizing compound C from compound B; Step 3, synthesizing compound D from compound C; Among them, the structures of compounds A, B, C, and D are as follows:

2. The method for preparing 4-chloro-5H-pyrrolo[3,2-D]pyrimidin-2-amine according to claim 1, characterized in that: Step 1, the method for synthesizing compound B from compound A is: Compound A is added to water, and a strong base reagent is added to react. After the reaction is completed, the pH of the system is adjusted to precipitate a solid product, which is filtered, washed with water and dried in vacuo to obtain compound B.

3. The method for preparing 4-chloro-5H-pyrrolo[3,2-D]pyrimidin-2-amine according to claim 2, characterized in that: In step 1, the reaction conditions are heating at 100-130° C. for 15-20 hours; In step 1, adjusting the pH of the system means adjusting the pH of the system to 4-5 with dilute hydrochloric acid; In step 1, the strong base is selected from one of lithium hydroxide, sodium hydroxide or potassium hydroxide.

4. The method for preparing 4-chloro-5H-pyrrolo[3,2-D]pyrimidin-2-amine according to claim 2, characterized in that: In step 1, the amount of the strong base is 2.0-3.0 times the amount of compound A.

5. The method for preparing 4-chloro-5H-pyrrolo[3,2-D]pyrimidin-2-amine according to claim 1, characterized in that: Step 2, the method for synthesizing compound C from compound B is: Compound B is dissolved in an alcohol solution of ammonia to carry out a reaction. After the reaction is completed, the solvent is removed by distillation under reduced pressure to precipitate a solid product, which is then washed with water, filtered and dried in vacuo to obtain compound C.

6. The method for preparing 4-chloro-5H-pyrrolo[3,2-D]pyrimidin-2-amine according to claim 5, characterized in that: In step 2, the reaction conditions are: heating and stirring at 100-130° C. for 36-48 hours; In step 2, the ammonia source is selected from ammonia methanol solution or ammonia ethanol solution.

7. The method for preparing 4-chloro-5H-pyrrolo[3,2-D]pyrimidin-2-amine according to claim 5, characterized in that: In step 2, the molar concentration of NH3 in the ammonia solution is 4-7.5M.

8. The method for preparing 4-chloro-5H-pyrrolo[3,2-D]pyrimidin-2-amine according to claim 1, characterized in that: Step 3, the method for synthesizing compound D from compound C is: Compound C was mixed with phosphorus oxychloride to react. After the reaction was completed, the phosphorus oxychloride was removed by reduced pressure distillation. The remaining concentrated solution was quenched with ice water, the pH of the system was adjusted, and then extracted with ethyl acetate. The organic phase was collected and dried by rotation. The solid product was washed with saturated sodium bicarbonate, filtered and vacuum dried to obtain compound D.

9. The method for preparing 4-chloro-5H-pyrrolo[3,2-D]pyrimidin-2-amine according to claim 8, characterized in that: In step 3, the reaction conditions are: heating and stirring at 90-120° C. for 12 hours.

10. The method for preparing 4-chloro-5H-pyrrolo[3,2-D]pyrimidin-2-amine according to claim 8, characterized in that: In step 3, adjusting the pH of the system refers to: adjusting the pH to 9.0-10 with sodium hydroxide solution.

Images