A method for synthesizing a key intermediate of paliperidone

Abstract

The invention discloses a method for synthesizing a key intermediate of paliperidone, and belongs to the field of pharmaceutical intermediates. The method comprises the following steps: 2-amino-3-hydroxypyridine and α-acetyl-γ-butyrolactone, and cyclization under the action of a catalyst to obtain 3-(2-hydroxyethyl)-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidine-4-one; then catalytic hydrogenation to obtain 2-methyl-3-(2-hydroxy)ethyl-9-hydroxy-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one; and finally chlorination to obtain the key intermediate of paliperidone 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidine-4-one. The process of the present invention is relatively concise and efficient, which not only improves the quality of the key intermediate of paliperidone, but also reduces the generation of known impurities, effectively reduces the three wastes, and reduces the cost.

Description

Technical Field

[0001] The invention relates to a preparation method of a key intermediate of paliperidone, 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, and belongs to the technical field of pharmaceutical intermediate synthesis. Background Art

[0002] 3-(2-Chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one is a key intermediate of paliperidone, which is an atypical antipsychotic developed by Johnson & Johnson in the United States and a 5-HT antagonist belonging to the class of benzisoxazole derivatives. At the same time, the intermediate can also be used to synthesize paliperidone palmitate, a new antipsychotic drug approved by the FDA on December 19, 2006. Paliperidone palmitate is an ester formed by the reaction of the 9-hydroxyl group with palmitic acid. The dosage form is changed and injected for acute short-term and long-term maintenance treatment of schizophrenia.

[0003] In existing public patents or documents, the mainstream synthesis method is to prepare 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one by cyclization of 2-amino-3-hydroxypyridine (hydroxybenzyl protected or unprotected) with α-acetyl-γ-butyrolactone, chlorination with phosphorus oxychloride, and catalytic hydrogenation. The reaction equation is as follows:

[0004]

[0005] To summarize the above-mentioned process methods, the yield of the synthesis process is relatively low, and multiple recrystallization purifications are required. The catalytic hydrogenation will produce the chlorine impurity 3-ethyl-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, and the requirements for solvent selection, hydrogenation pressure and equipment are relatively high.

[0006] Therefore, it is necessary to further improve the synthesis process of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, and provide a better process route with easy-to-obtain raw materials, safety and stability, less three wastes, and high yield to meet the growing market demand. Summary of the invention

[0007] In order to overcome the above technical defects, the present invention proposes a new synthesis method of a key intermediate of paliperidone. 2-amino-3-hydroxypyridine and α-acetyl-γ-butyrolactone are used as raw materials, and 3-(2-hydroxyethyl)-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one is obtained by ring closure under the action of a catalyst; then 2-methyl-3-(2-hydroxy)ethyl-9-hydroxy-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one is obtained by catalytic hydrogenation; finally, the key intermediate of paliperidone 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one is obtained by chlorination. The process flow of the present invention is relatively simple and efficient, which not only improves the quality of the key intermediate of paliperidone, reduces the generation of known impurities, effectively reduces the three wastes, and reduces the cost.

[0008] The present invention discloses a method for preparing a key intermediate of paliperidone, 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, wherein the reaction equation is as follows:

[0009]

[0010] The steps include:

[0011] In the first step, 2-amino-3-hydroxypyridine 1 and α-acetyl-γ-butyrolactone 2 are used as raw materials and reacted in a dehydrating solvent under the action of boron trifluoride and tris(pentafluorophenyl)boron catalyst to obtain the ring-closed product 3;

[0012] In the second step, the ring-closure product 3 is subjected to a palladium-carbon catalytic hydrogenation reaction in an alcohol solvent to obtain the hydrogenated product 4;

[0013] In the third step, the hydrogenation product 4 reacts with boron trifluoride ether complex to form a cyclic complex, followed by chlorination with thionyl chloride and finally quenching with an organic amine to obtain the key intermediate 5 of paliperidone.

[0014] Furthermore, in the above technical solution, in the first step, the dehydration solvent is selected from heptane, cyclohexane, 1,4-dioxane, toluene or xylene.

[0015] Furthermore, in the first step of the above technical scheme, the molar ratio of 2-amino-3-hydroxypyridine, α-acetyl-γ-butyrolactone, tri(pentafluorophenyl)borane and boron trifluoride ether is 1:1.1-1.2:0.03-0.05:0.06-0.10.

[0016] Furthermore, in the second step of the above technical solution, the alcohol solvent is selected from methanol, ethanol or isopropanol.

[0017] Furthermore, in the second step of the above technical solution, palladium carbon is selected from 5% or 10% wet palladium carbon with common market specifications, and the process is carried out under a hydrogen pressure of 0.15-0.45 MPa.

[0018] Furthermore, in the third step of the above technical solution, the organic amine is selected from triethylamine or diisopropylethylamine.

[0019] Furthermore, in the third step of the above technical solution, the molar ratio of the hydrogenation product 4 to the boron trifluoride ether complex, thionyl chloride and the organic amine is 1:1.1-1.2:1.05-1.10:2.5-2.8.

[0020] Furthermore, in the above technical scheme, the 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, CAS: 130049-82-0, English name: 3-(2-Chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one.

[0021] The present invention has the following beneficial effects:

[0022] 1) The process of the present invention is green and environmentally friendly. The mixed catalyst in the first step greatly reduces the generation of three wastes and can be reused (the mother liquor concentration can be applied 4-5 times), which is conducive to industrialized production and cost saving.

[0023] 2) In the present invention, in the third step, boron trifluoride ether complex is used to generate a cyclic complex with the hydrogenation product 4, thereby protecting the 9-position hydroxyl group from being affected during the chlorination process and avoiding the generation of impurities that are difficult to remove.

[0024] 3) The product preparation process is smooth by first catalytic hydrogenation and then chlorination, and the yield of each step is high, and the purity is as high as more than 99.7%. Specific embodiments

[0025] The present invention will be further described below by specific examples. 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.

[0026] Example 1

[0027]

[0028] 55.1 g (0.5 mol) of 2-amino-3-hydroxypyridine and 70.5 g (0.55 mol) of α-acetyl-γ-butyrolactone were mixed with 500 mL of toluene, and the mixture was heated to 35-40°C, 7.7 g of tri(pentafluorophenyl)borane was added, 4.3 g of boron trifluoride ether complex was added dropwise, the mixture was heated to reflux and water was separated for 15 hours, most of the toluene was evaporated by atmospheric distillation, the mixture was cooled to 30-35°C, n-heptane was added for pulping, the mixture was filtered, the filter cake was rinsed with n-heptane, and the mixture was dried to obtain 103.1 g of 3-(2-hydroxyethyl)-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, with a yield of 93.6% and an HPLC yield of 99.3%. 1 HNMR(400MHz, DMSO-d6):10.46(s,1H),8.71-8.63(m,2H),7.36-7.20(m,1H),4.72(s,1H),3.52-3.48(m,2H),2.89(s,3H),2.19-2.13(m,2H).

[0029] Example 2

[0030]

[0031] 55.1 g (0.5 mol) of 2-amino-3-hydroxypyridine and 70.5 g (0.55 mol) of α-acetyl-γ-butyrolactone were mixed with 600 mL of xylene, the mixture was heated to 35-40°C, 7.7 g of tri(pentafluorophenyl)borane was added, 4.3 g of boron trifluoride ether complex was added dropwise, the mixture was heated to reflux and water was separated for 10 hours, the mixture was cooled and then distilled under reduced pressure (absolute pressure was not greater than 0.01 MPa, and temperature was controlled to be less than 70°C) until about 180 mL of xylene remained, n-heptane was added for pulping, the mixture was filtered, the filter cake was rinsed with n-heptane, and the mixture was dried to obtain 106.6 g of 3-(2-hydroxyethyl)-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, with a yield of 96.8% and an HPLC index of 99.5%.

[0032] Example 3

[0033]

[0034] Dissolve 50g of 3-(2-hydroxyethyl)-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one in 500mL of methanol, add 5.5g of 5% Pd / C, replace hydrogen three times under vacuum, pressurize to 25-30psi at 20-25℃ and react for 6 hours. The remaining raw material is detected to be less than 0.05%, filter under nitrogen protection, and the filtrate is concentrated under reduced pressure until no liquid is obtained to obtain 49.8g of 2-methyl-3-(2-hydroxy)ethyl-9-hydroxy-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one, with a yield of 97.8%. LC-MS[M+H]225.1.

[0035] Example 4

[0036]

[0037] Dissolve 50g of 3-(2-hydroxyethyl)-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one in 500mL of methanol, add 3.3g of 10% Pd / C, replace hydrogen three times under vacuum, pressurize to 30-35psi at 20-25°C and react for 5 hours. The remaining raw material is detected to be less than 0.05%, and the filtrate is sealed and concentrated under nitrogen protection. The filtrate is reduced in pressure and concentrated until no liquid flows to obtain 49.3g of 2-methyl-3-(2-hydroxy)ethyl-9-hydroxy-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one, with a yield of 96.9%.

[0038] Example 5

[0039]

[0040] 44.9 g (0.2 mol) of 2-methyl-3-(2-hydroxy)ethyl-9-hydroxy-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one was mixed with 500 mL of dichloromethane, 34.1 g (0.24 mol) of boron trifluoride ether complex was added dropwise at room temperature, stirred at room temperature for 1 hour, and DMF was added. 0.1g, 25.2g (0.212mol) of thionyl chloride was added dropwise, the temperature was raised to 35°C for reaction for 5 hours, the temperature was lowered to -10°C, 67.2g (0.52mol) of N,N-diisopropylethylamine was added dropwise, the temperature was reacted for 2 hours, dilute hydrochloric acid was added to adjust the pH to 6-7, the organic phase was washed with 5% potassium bicarbonate and water respectively, the organic phase was concentrated to no liquid, butyl acetate was added for replacement, and n-heptane was added for recrystallization to obtain 41.6g of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, with a yield of 85.7%, HPLC: 99.8%. 1HNMR(400MHz, DMSO-d6):5.71(s,1H),4.48-4.42(m,1H),3.95-3.86(m,1H),3.78-3.63(m,3H),2.91-2.86(m,2H),2.28(s,3H),2.05-1.80(m,4H).

[0041] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A method for synthesizing a key intermediate of paliperidone, characterized in that: The reaction route is as follows: ； The steps include: In the first step, 2-amino-3-hydroxypyridine 1 and α-acetyl-γ-butyrolactone 2 are used as raw materials and reacted in a dehydrating solvent under the action of boron trifluoride etherate and tris(pentafluorophenyl)boron catalyst to obtain the ring-closed product 3; In the second step, the ring-closure product 3 is subjected to a palladium-carbon catalytic hydrogenation reaction in an alcohol solvent to obtain the hydrogenated product 4; In the third step, the hydrogenation product 4 reacts with boron trifluoride etherate to form a cyclic complex, followed by chlorination with thionyl chloride and finally quenching with an organic amine to obtain the key intermediate 5 of paliperidone.

2. The method for synthesizing the key intermediate of paliperidone according to claim 1, characterized in that: In the first step, the dehydration solvent is selected from heptane, cyclohexane, 1,4-dioxane, toluene or xylene.

3. The method for synthesizing the key intermediate of paliperidone according to claim 1, characterized in that: In the first step, the molar ratio of 2-amino-3-hydroxypyridine, α-acetyl-γ-butyrolactone, tri(pentafluorophenyl)borane, and boron trifluoride ether is 1: 1.1-1.2: 0.03-0.05: 0.06-0.

10.

4. The method for synthesizing the key intermediate of paliperidone according to claim 1, characterized in that: In the second step, the alcohol solvent is selected from methanol, ethanol or isopropanol.

5. The method for synthesizing the key intermediate of paliperidone according to claim 1, characterized in that: In the second step, palladium carbon is selected from 5% or 10% wet palladium carbon, and the process is carried out under a hydrogen pressure of 0.15-0.45 MPa.

6. The method for synthesizing the key intermediate of paliperidone according to claim 1, characterized in that: In the third step, the organic amine is selected from triethylamine or diisopropylethylamine.

7. The method for synthesizing the key intermediate of paliperidone according to claim 1, characterized in that: In the third step, the molar ratio of hydrogenation product 4, boron trifluoride etherate, thionyl chloride, and organic amine is 1: 1.1-1.2: 1.05-1.10: 2.5-2.8.

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