A method for preparing 2-chloro-4-(methoxymethyl)pyrimidine

Abstract

The invention discloses a method for preparing 2-chloro-4-(methoxymethyl)pyrimidine, and belongs to the field of medical technology. Starting from 4-chloroacetoacetate methyl ester (1), an intermediate (2) is obtained by ring-closing with urea; then the intermediate (2) reacts with a chlorination reagent to obtain an intermediate (3), and finally the intermediate (3) is dechlorinated to obtain 2-chloro-4-(methoxymethyl)pyrimidine. The invention avoids the generation of impurities and improves the quality of the product by designing a new reaction route; in the reaction process, by-products are removed before the final step, the post-processing process is simple to operate, the process has good reproducibility, and can be smoothly scaled up to a kilogram-level reaction scale.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and specifically relates to a method for preparing 2-chloro-4-(methoxymethyl)pyrimidine. Background Art

[0002] 2-Chloro-4-methoxy methyl-pyrimidine, English name: 2-Chloro-4-methoxy methyl-pyrimidine, CAS: 1289387-30-9, has a wide range of applications in medicinal chemistry and organic synthesis, especially for the construction of biologically active compounds with pyrimidine ring skeletons.

[0003] At present, the synthesis of 2-chloro-4-(methoxymethyl)pyrimidine is relatively difficult, and the literature is not sufficient. Therefore, it is necessary to develop a synthesis method with easy-to-obtain raw materials, convenient operation, easy-to-control reaction, and suitable overall yield. Summary of the invention

[0004] In view of the above-mentioned deficiencies in the prior art, the present invention provides a method for preparing 2-chloro-4-(methoxymethyl)pyrimidine, which is simple and stable to operate, easy to separate the products in each step, has a high yield, is environmentally friendly, and is suitable for industrial-scale production.

[0005] The present invention provides a method for preparing 2-chloro-4-(methoxymethyl)pyrimidine, and the synthetic route is as follows:

[0006]

[0007] The method comprises the following steps: starting from 4-chloroacetoacetate methyl ester (1), ring-closing with urea to obtain an intermediate (2); then reacting the intermediate (2) with a chlorination agent to obtain an intermediate (3); and finally dechlorinating the intermediate (3) to obtain 2-chloro-4-(methoxymethyl)pyrimidine.

[0008] Furthermore, the technical method of the present invention adopts the following specific steps:

[0009] Step 1: Synthesis of intermediate (2)

[0010] Methyl 4-chloroacetoacetate (1), Lewis acid and urea are heated in a solution to obtain 6-(chloromethyl)uracil, which is then reacted with sodium methoxide in an organic solvent to obtain an intermediate (2).

[0011] Furthermore, the Lewis acid is selected from triphenylboron, boron trifluoride or tris(2,6-difluorophenyl)boron.

[0012] Furthermore, the heating reaction temperature is 70-90°C.

[0013] Furthermore, the organic solvent is methanol, DMF or dioxane, which mainly plays a dissolving role and has no obvious effect on the reaction yield; the preferred solvent is methanol.

[0014] Furthermore, the molar ratio of the methyl 4-chloroacetoacetate (1), Lewis acid, urea and sodium methoxide is 1:1-1.2:1-3:1.2-3.

[0015] Step 2: Synthesis of intermediate (3)

[0016] The intermediate (2), phosphorus pentachloride and polyphosphoric acid are heated in an organic solvent to react to obtain the intermediate (3).

[0017] Furthermore, the organic solvent is selected from toluene, xylene, dichloroethane, acetonitrile or any combination of the above solvents, and the preferred solvent is toluene.

[0018] Furthermore, the heating reaction temperature is 70-90°C.

[0019] Furthermore, in the intermediate (2), the molar ratio of phosphorus pentachloride to polyphosphoric acid is 1:2-3:0.2-0.5.

[0020] Step 3: Synthesis of 2-chloro-4-(methoxymethyl)pyrimidine (Ⅰ)

[0021] The intermediate (3), zinc powder, trimethylsilyl chloride and acid are heated in an organic solvent to react to obtain 2-chloro-4-(methoxymethyl)pyrimidine (I).

[0022] Furthermore, the organic solvent is selected from tetrahydrofuran, acetonitrile, methanol or any combination of the above solvents, and the preferred solvent is methanol.

[0023] Furthermore, the acid is hydrochloric acid or glacial acetic acid.

[0024] Furthermore, the reducing agent is zinc powder.

[0025] Furthermore, the molar ratio of the intermediate (3) to the reducing agent is 1:2-4.

[0026] Beneficial effects of the present invention

[0027] 1) The present invention avoids the generation of impurities and improves the quality of the product by designing a new reaction route;

[0028] 2) The present invention optimizes the preparation process. In the reaction process, by-products are removed before the final step. The post-treatment process is simple to operate and has good process reproducibility, and can be smoothly expanded to a kilogram-level reaction scale. DETAILED DESCRIPTION

[0029] The present invention will be further described below in conjunction with specific embodiments. 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.

[0030] Example 1

[0031] first step:

[0032] Methyl 4-chloroacetoacetate (1 eq), triphenylboron (1.2 eq) and urea (3 eq) were added to toluene (4 v), and the solution was stirred and heated to 70-90 ° C for reaction for 3 hours. Ice water was added to the reaction solution, and the solid was filtered after stirring and added to a methanol (5 V) solution of sodium methoxide (1.2 eq). The reaction was refluxed and heated for 3 hours, then dried by rotation. Dilute hydrochloric acid was added to adjust the pH to 7, and ethyl acetate was added for extraction. After drying by rotation, a white intermediate 2 (yield 81%) was obtained.

[0033] Step 2:

[0034] Intermediate 2 (1 eq), phosphorus pentachloride (3 eq) and polyphosphoric acid (0.3 eq) were added to toluene (5 V), and the reaction solution was stirred at 80° C. for 9 hours. After cooling, the reaction solution was poured into ice water, and the pH value was adjusted to 7 with sodium bicarbonate aqueous solution, and extracted with dichloromethane. The organic layer was spin-dried to obtain a light yellow intermediate 3 (yield 95%).

[0035] Step 3:

[0036] Intermediate 3 (1 eq), zinc powder (3 eq), trimethylsilyl chloride (1 eq) and glacial acetic acid (6 eq) were added to methanol (10 V), stirred at 70-75 ° C for 16 hours, filtered after cooling, and methanol / water slurry was used to obtain 2-chloro-4-(methoxymethyl)pyrimidine (yield 76%). 1 H NMR (CDCl3, 400MHz) δ 8.60-8.59 (d, J = 5.6 Hz, 1H), 7.43-7.41 (d, J = 6 Hz, 1H), 4.51 (s, 2H), 3.47 (s, 3H).

[0037] Example 2

[0038] first step:

[0039] Methyl 4-chloroacetoacetate (1 eq), boron trifluoride (1.2 eq) and urea (2 eq) were added to dioxane (5 v), the solution was stirred and heated to 70-90 ° C for reaction for 3 hours, ice water was added to the reaction solution, the solid was filtered after stirring, and added to a methanol (5 V) solution of sodium methoxide (3 eq). The reaction was refluxed and heated for 3 hours, then dried by rotation, dilute hydrochloric acid was added to adjust the pH to 7, ethyl acetate was added for extraction, and white intermediate 2 was obtained after drying (yield 82%).

[0040] Step 2:

[0041] Intermediate 2 (1 eq), phosphorus pentachloride (2 eq) and polyphosphoric acid (0.4 eqv) were added to xylene (5 V), and the reaction solution was stirred at 70-90 ° C for 9 hours. After cooling, the reaction solution was poured into ice water, and the pH value was adjusted to 7 with sodium bicarbonate aqueous solution, and extracted with dichloromethane. The organic layer was spin-dried to obtain a light yellow intermediate 3 (yield 94%).

[0042] Step 3:

[0043] Intermediate 3 (1 eq), zinc powder (4 eq), trimethylsilyl chloride (1 eq) and hydrochloric acid (2 eq) were added to methanol (10 V), stirred at 70-75 ° C for 16 hours, filtered after cooling, and methanol / water slurry was used to obtain 2-chloro-4-(methoxymethyl)pyrimidine (yield 78%).

[0044] The above embodiments describe the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above embodiments, and the above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the scope of the principles of the present invention, the present invention may have various changes and improvements, and these changes and improvements all fall within the scope of protection of the present invention.

Claims

1. A method for preparing 2-chloro-4-(methoxymethyl)pyrimidine, characterized in that: The following steps are involved: The first step is to heat methyl 4-chloroacetoacetate (1), Lewis acid and urea in a solution to obtain 6-(chloromethyl)uracil, and then react with sodium methoxide in an organic solvent A to obtain an intermediate (2); the Lewis acid is selected from triphenylboron or boron trifluoride; the organic solvent A is methanol, DMF or dioxane; the heating reaction temperature is 70-90°C; Step 2: heating the intermediate (2), phosphorus pentachloride and polyphosphoric acid in an organic solvent B to obtain an intermediate (3); Step 3: The intermediate (3), zinc powder, trimethylsilyl chloride and acid are heated in an organic solvent C to react to obtain 2-chloro-4-(methoxymethyl)pyrimidine (4).

2. The method for preparing 2-chloro-4-(methoxymethyl)pyrimidine according to claim 1, characterized in that: In the first step, the molar ratio of methyl 4-chloroacetoacetate (1), Lewis acid, urea and sodium methoxide is 1:1-1.2:1-3:1.2-3.

3. The method for preparing 2-chloro-4-(methoxymethyl)pyrimidine according to claim 1, characterized in that: In the second step, the organic solvent B is selected from toluene, xylene, dichloroethane, acetonitrile or any combination of the above solvents; the heating reaction temperature is 70-90°C.

4. The method for preparing 2-chloro-4-(methoxymethyl)pyrimidine according to claim 1, characterized in that: In the second step, the molar ratio of the intermediate (2), phosphorus pentachloride and polyphosphoric acid is 1:2-3:0.2-0.

5.

5. The method for preparing 2-chloro-4-(methoxymethyl)pyrimidine according to claim 1, characterized in that: In the third step, the organic solvent C is selected from tetrahydrofuran, acetonitrile, methanol or any combination of the above solvents; and the acid is hydrochloric acid or glacial acetic acid.

6. The method for preparing 2-chloro-4-(methoxymethyl)pyrimidine according to claim 1, characterized in that: In the third step, the molar ratio of the intermediate (3) to the zinc powder is 1:2-4.

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