A preparation method of 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one

Abstract

The present invention discloses a preparation method of 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one. This method uses 2-amino-3-methoxypyridine and 2-acetylbutyrolactone as raw materials, and successively undergoes cyclization reaction, chlorination reaction, and boron trichloride demethylation reaction to obtain the compound 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one. Compared with the prior art, the present invention adopts a different method from the previous process, develops a more concise and efficient synthetic route, the process flow has low requirements for equipment, the overall three-step molar yield can reach more than 80%, and it is suitable for industrialization. This method has stable process and high reproducibility between batches.

Description

Technical Field

[0001] The present invention relates to a preparation method of 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one, belonging to the technical field of pharmaceutical synthesis. Background Art

[0002] 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one is an important intermediate of paliperidone and also its main existing impurity. Paliperidone is a drug for treating schizophrenia developed by Johnson & Johnson in the United States, which has long-acting properties. The structural formulas of 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one (1) and paliperidone (2) are as follows:

[0003]

[0004] So far, many methods for synthesizing 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one have been reported. Among them, the methods reported in patents US2009 / 48272, 2009, A1 and US2010 / 4447, 2010, A1 are to mix 2-amino-3-hydroxypyridine with excessive 2-acetylbutyrolactone and toluene, add 5eq phosphorus oxychloride, and the yield is about 74%. The reaction formula is as follows:

[0005]

[0006] Repeating the prior art, it is found that the addition of phosphorus oxychloride will enhance the activity of 2-acetylbutyrolactone, and then enhance the reaction of the lactone with 2-amino-3-hydroxypyridine. A large amount of phosphorus oxychloride also destroys the lactone bond, thereby reducing the reaction of the acetyl group with the amino group. The quenching of a large excess of phosphorus oxychloride has a lag, the post-treatment is cumbersome, the yield is low, and the expected result is not achieved.

[0007] The method reported in patent WO2011 / 73997, 2011, A2 is to react 9-hydroxy-3-(2-hydroxyethyl)-2-methyl 4H-pyrido[1,2-a]pyrimidin-4-one with thionyl chloride for chlorination. Repeating the prior art, it is found that the 9-position hydroxyl group will also be chlorinated, accounting for 27-33% of the total, and the difficulty of post-treatment purification increases. The reaction formula is as follows:

[0008]

[0009] The method reported in Patent US2021 / 230212, 2021, A1 uses a palladium catalyst for catalytic hydrogenation at a temperature of 45 - 60 °C to obtain the target product. The selected catalyst is palladium on carbon. Orthogonal experiments were carried out on the catalyst dosage and reaction pressure, and it was found that there are by-products of dechlorination and by-products of pyridine ring reduction. The post-treatment is cumbersome and not conducive to industrial production. The reaction formula is as follows:

[0010]

[0011] In the above synthetic routes, there are problems of increasing by-products and difficult post-treatment. Therefore, it is necessary to conduct in-depth research on the synthesis process of 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one, provide a better, safer and more stable reaction route that meets industrial production to meet the growing market demand. Summary of the Invention

[0012] In order to overcome the above technical defects, the present invention provides a method for preparing 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one. This method uses 2-amino-3-methoxypyridine and 2-acetylbutyrolactone as raw materials, and successively undergoes cyclization reaction, chlorination reaction, and boron trichloride demethylation reaction to obtain 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one. Compared with the prior art, the present invention adopts a different method from the previous process, develops a more concise and efficient synthetic route, the process flow has low requirements for equipment, the overall three-step molar yield can reach more than 80%, which is suitable for industrialization, and this method is stable and easy to implement.

[0013] The method for preparing 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one according to the present invention includes the following operating steps:

[0014] A. Cyclization reaction: Mix compound 1, compound 2 with an organic solvent, and reflux and separate water in the presence of a Lewis acid catalyst to obtain compound 3;

[0015] B. Chlorination reaction: Dissolve compound 3 in toluene, and heat up and react in thionyl chloride or phosphorus trichloride to obtain compound 4;

[0016] C. Demethylation reaction: Mix compound 4 with an organic solvent, and react in the presence of boron trichloride and a catalyst to obtain 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one.

[0017] The reaction route is shown as follows:

[0018]

[0019] Further, in the above technical solution, the organic solvent in step A is selected from toluene or xylene.

[0020] Further, in the above technical solution, the molar ratio of compound 1 to compound 2 in step A is 1:1.1 - 1.2.

[0021] Further, in the above technical solution, the molar ratio of compound 3 to thionyl chloride or phosphorus trichloride in step C is 1:1.15 - 1.20.

[0022] Further, in the above technical solution, the catalyst in step C is selected from sodium iodide or potassium iodide. The presence of the catalyst is very important for demethylation. Without the catalyst, the demethylation conversion rate of the reaction does not exceed 6%.

[0023] Further, in the above technical solution, the organic solvent in step C is selected from one or more of dichloromethane, 1,2 - dichloroethane, dioxane or tetrahydrofuran.

[0024] Further, in the above technical solution, the molar ratio of compound 4, the catalyst to boron trichloride in step C is 1:0.05 - 0.15:3.0 - 3.5.

[0025] Further, in the above technical solution, the 3-(2 - chloroethyl)-2 - methyl - 9 - hydroxy - 4H - pyrido[1,2 - a]pyrimidin - 4 - one obtained in step C, English name 3-(2 - Chloroethyl)-2 - methyl - 9 - hydroxy - 4H - pyrido[1,2 - a]pyrimidin - 4 - one, CAS: 260273 - 82 - 3.

[0026] Advantages of the invention

[0027] Compared with the prior art, the present application uses 2 - amino - 3 - methoxypyridine as a raw material, and is synthesized by a three - step method of specific Lewis acid ring - closing reaction, followed by hydroxyl chlorination and finally de - protection. The process has low requirements for equipment, and the overall three - step molar yield can reach more than 80%. It effectively avoids the relevant impurities of chlorine - containing by - products and is suitable for industrial scale - up production. Specific examples

[0028] The present invention will be further described below through specific examples. These examples should be understood as only for illustrating the present invention and not for limiting the protection scope of the present invention. After reading the content recorded in the present invention, those skilled in the art can 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.

[0029] Synthesis of 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one

[0030] Example 1

[0031]

[0032] 24.8 g (0.2 mol) of 2-amino-3-methoxypyridine, 29.5 g (0.23 mol) of 2-acetylbutyrolactone and 300 mL of xylene were put into a dry and clean 500 mL four-necked round-bottom flask and mixed. 3.9 g of yttrium chloride was added, 2.8 g of boron trifluoride-ether complex was added, and the mixture was heated to reflux for water separation for 5 hours. It was filtered while hot. After the filtrate was cooled, xylene was distilled off under reduced pressure (-0.0098 MPa / 60 - 70 °C) until 3 volumes remained. n-Hexane was added for pulping, and then filtered. The filter cake was washed with a mixed solution of cold n-hexane and xylene, and dried to obtain 43.9 g of 9-(methoxy)-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, with a yield of 93.6% and HPLC of 99.3%. 1 1H-NMR (400 MHz, CDCl3): 8.98 - 8.93 (m, 1H), 7.89 (t, 1H), 7.45 - 7.41 (m, 1H), 4.20 (s, 1H), 3.84 (s, 3H), 3.56 - 3.50 (m, 2H), 3.22 (s, 3H), 2.21 - 2.15 (m, 2H).

[0033] Example 2

[0034]

[0035] 24.8 g (0.2 mol) of 2-amino-3-methoxypyridine, 29.5 g (0.23 mol) of 2-acetylbutyrolactone and 300 mL of toluene were put into a dry and clean 500 mL four-necked round-bottom flask and mixed. 5.1 g of tris(pentafluorophenyl)borane was added, 4.3 g of boron trifluoride-ether complex was added dropwise, and the mixture was heated to reflux for water separation for 6 hours. Toluene was distilled off under reduced pressure (-0.0098 MPa / 45 - 55 °C) until 2 volumes remained. n-Hexane was added for pulping, and then filtered. The filter cake was washed with a mixed solution of cold n-hexane and toluene, and dried to obtain 44.4 g of 9-(methoxy)-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, with a yield of 94.8% and HPLC of 99.1%.

[0036] Example 3

[0037]

[0038] 35.1 g (0.15 mol) of 9-(methoxy)-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one and 280 mL of toluene were charged into a dry and clean 500 mL four-necked round-bottom flask and mixed. 1 - 2 drops of DMF were added. At room temperature, 20.5 g (0.1725 mol) of thionyl chloride was added. The temperature was raised to 75 - 80 °C and the reaction was carried out for 4 hours. After cooling, the mixture was concentrated under reduced pressure (-0.0098 MPa / 45 - 55 °C) until no more liquid flowed. Toluene was added again and the mixture was further concentrated to remove the remaining thionyl chloride. Then 100 mL of toluene was added. The temperature was raised to 50 °C, 50 mL of n-hexane was added and the mixture was allowed to stand. A small amount of oily substance separated out. The mixture was further concentrated under reduced pressure, n-hexane was added for pulping, filtered, and the filter cake was washed with cold n-hexane and dried to obtain 34.4 g of 9-(methoxy)-3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, with a yield of 90.7% and HPLC purity of 99.6%. 1 1H-NMR(400MHz,CDCl3):8.95 - 8.91(m,1H),8.06(t,1H),7.43 - 7.38(m,1H),3.84(s,3H),3.52 - 3.47(m,2H),3.10(s,3H),2.46 - 2.40(m,2H).

[0039] Example 4

[0040]

[0041] 25.3 g (0.1 mol) of 9-(methoxy)-3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one and 40 mL of dichloromethane / 40 mL of dioxane were charged into a dry and clean 500 mL four-necked round-bottom flask and mixed. 2.9 g of sodium iodide was added. The temperature was cooled to -30 °C, and 320 mL (0.32 mol) of 1.0 mol / L boron trichloride / dichloromethane solution was added dropwise. The temperature was controlled at -20~-30 °C and the reaction was carried out for 3 hours. The temperature was raised to -10 °C, and 20% aqueous sodium carbonate solution was added dropwise to quench the reaction. The mixture was allowed to stand and separate layers at room temperature. The organic phase was washed with water and saturated sodium chloride solution, and the organic phase was concentrated under reduced pressure. n-Hexane was added for crystallization to obtain 21.3 g of 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one, with a yield of 89.3% and HPLC purity of 99.8%. 1 1H-NMR(400MHz,CDCl3):8.45(s,1H),7.12(t,1H),7.08 - 7.02(m,1H),4.3(s,1H),3.84 - 3.79(m,2H),3.19 - 3.10(m,2H),2.53(s,3H).

[0042] Example 5

[0043]

[0044] 25.3 g (0.1 mol) of 9-(methoxy)-3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one and 40 mL of dichloromethane / 40 mL of dioxane were added to a dry and clean 500 mL four-necked round-bottom flask and mixed. 2.8 g of potassium iodide was added. The temperature was lowered to -30 °C, and 300 mL (0.30 mol) of 1.0 mol / L boron trichloride / dichloromethane solution was added dropwise. The temperature was controlled at -20 to -30 °C and the reaction was carried out for 3 hours. The temperature was raised to -10 °C, and 20% aqueous sodium carbonate solution was added dropwise to quench. It was allowed to stand and layer at room temperature. The organic phase was washed with water and saturated sodium chloride solution, and the organic phase was concentrated under reduced pressure. n-Hexane was added for crystallization to obtain 21.7 g of 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one, with a yield of 91.1% and HPLC of 99.7%.

[0045] As mentioned above, the above are only the preferred specific embodiments of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention, according to the technical solution and inventive concept of the present invention, making equivalent substitutions or changes should be covered within the protection scope of the present invention.

Claims

1. A preparation method of 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one, characterized in that, The reaction route is as follows: ； It includes the following steps: A. Cyclization reaction: Mix compound 1, compound 2 with an organic solvent, reflux and separate water in the presence of a Lewis acid catalyst to obtain compound 3; the Lewis acid catalyst is selected from YCl3 / BF3-Et2O or BF3-Et2O / B(C6F5)3; the molar ratio of compound 1 to compound 2 is 1:1.1-1.2; B. Chlorination reaction: Dissolve compound 3 in toluene, heat and react in thionyl chloride or phosphorus trichloride to obtain compound 4; C. Demethylation reaction: Mix compound 4 and an organic solvent, react in the presence of boron trichloride and a catalyst to obtain 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one; the catalyst is selected from sodium iodide or potassium iodide; the molar ratio of compound 4, the catalyst to boron trichloride is 1:0.05-0.15:3.0-3.

5.

2. The preparation method of 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one according to claim 1, characterized in that: In step A, the organic solvent is selected from toluene or xylene.

3. The preparation method of 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one according to claim 1, characterized in that: In step B, the molar ratio of compound 3 to thionyl chloride or phosphorus trichloride is 1:1.15-1.

20.

4. The preparation method of 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one according to claim 1, characterized in that: In step C, the organic solvent is selected from one or more of dichloromethane, 1,2-dichloroethane, dioxane or tetrahydrofuran.

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