A method for synthesizing a pharmaceutical intermediate

Abstract

The present invention provides a method for synthesizing a pharmaceutical intermediate, which is characterized in that: using 4-bromopyridine-2-carbaldehyde as a raw material, undergoing two-step palladium-catalyzed coupling reaction to obtain the pharmaceutical intermediate compound 3; the synthesis method comprises the following steps: S1. Synthesis of compound 2: adding 4-bromopyridine-2-carbaldehyde, 5-chloro-2-methoxyphenylboronic acid, Na 2 CO 3 , Pd(PPh 3 ) 4 , dioxane into a reaction flask, reacting at a temperature of 60-120 °C, and obtaining compound 2 after the reaction is completed; S2. Synthesis of compound 3: adding compound 2, 3-trifluoromethylphenylboronic acid, XPhos Pd G 3 , K3PO4, dioxane, and water into a reaction flask, reacting at a temperature of 60-120 °C, and obtaining compound 3 after the reaction is completed. By optimizing the reaction process conditions, the total yield reaches 50%-60%, the reaction conditions are mild and controllable, and the post-treatment is simple, greatly reducing the production cost and being very suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of organic pharmaceutical synthesis, and particularly relates to a synthesis method of a pharmaceutical intermediate. Background Art

[0002] Parkinson's disease (PD) is a common neurodegenerative disease, which is more common in the elderly. The average onset age is about 60 years old, and the juvenile Parkinson's disease with onset before 40 years old is less common. The prevalence of PD in people over 65 years old in China is about 1.7%.

[0003] Research shows that LRRK2 is the genetic cause of familial and idiopathic Parkinson's disease (PD), and is related to neuronal death, vesicle trafficking, mitochondrial dysfunction and inflammation. Therefore, LRRK2 kinase inhibitors may be useful in the treatment of Parkinson's disease. PF-06456384 is a highly effective, brain penetrant and selective LRRK2 inhibitor, which has been further described in in vivo safety and pharmacodynamic studies. Therefore, the research on the synthesis of PF-06456384 is of great significance.

[0004] Compound 3 is an important intermediate for the synthesis of PF-06456384, and the structural formula of compound 3 is:

[0005]

[0006] At present, there are mainly two existing synthesis methods for compound 3. Synthesis method 1 uses palladium-catalyzed coupling twice, and then reduction reaction and oxidation reaction are carried out in sequence. The synthesis route of synthesis method 1 is as follows:

[0007]

[0008] Synthesis method 2 also uses palladium-catalyzed coupling twice, and then oxidizes to obtain the target product. The route of synthesis method 2 is as follows:

[0009]

[0010] Both of the two existing synthesis methods of compound 3 use reduction reaction and oxidation reaction, and the chemical properties are very active and the reaction is violent. The post-treatment produces a large amount of waste solvent and waste water pollution, which is difficult to control in large-scale production; and the synthesis route is long, the reaction yield is unstable, and the production cost is high. Summary of the Invention

[0011] The purpose of the present invention is to provide a synthesis method of a pharmaceutical intermediate. By optimizing the reaction process conditions, this synthesis method has short synthesis steps, high yield, can be applied to large-scale production, and greatly reduces the production cost, providing very positive support for the treatment research of Parkinson's disease.

[0012] The technical solution adopted by the present invention to solve the above technical problems is as follows:

[0013] The synthetic route adopted by the present invention is as follows:

[0014]

[0015] The present invention provides a method for synthesizing a pharmaceutical intermediate. Using 4-bromopyridine-2-carbaldehyde as a raw material, through two-step palladium-catalyzed coupling reactions, the pharmaceutical intermediate compound 3 is obtained. The synthetic method includes the following steps:

[0016] S1. Synthesis of compound 2:

[0017]

[0018] Add 4-bromopyridine-2-carbaldehyde, 5-chloro-2-methoxyphenylboronic acid, Na 2 CO 3 , Pd(PPh 3 ) 4 , and dioxane into a reaction flask. The reaction temperature is 60 - 120 °C. After the reaction is completed, compound 2 is obtained;

[0019] S2. Synthesis of compound 3:

[0020]

[0021] Add compound 2, 3-trifluoromethylphenylboronic acid, XPhos Pd G 3 , K 3 PO 4 , dioxane, and water into a reaction flask. The reaction temperature is 60 - 120 °C. After the reaction is completed, compound 3 is obtained.

[0022] As a preferred embodiment, the reaction temperature in step S1 is 80 - 100 °C, and the reaction time is 3 - 8 hours. Further preferably, the reaction temperature in step S1 is 90 °C, and the reaction time is 3 hours.

[0023] As a preferred embodiment, the reaction temperature in step S2 is 80 - 100 °C.

[0024] As a preferred embodiment, in steps S1 and S2, after the raw materials are added into the reaction flask, the air in the reaction flask is replaced with an inert gas, and then the reaction is carried out at the above temperature.

[0025] As a preferred embodiment, the volume ratio of dioxane to water in step S2 is: 8:1 to 12:1, preferably 10:1.

[0026] As a preferred embodiment, the molar volume ratio of 4-bromopyridine-2-carbaldehyde to dioxane in step S1 is 0.3 - 0.4 mol / L, preferably 0.36 mol / L; the molar concentration of 5-chloro-2-methoxyphenylboronic acid in the reaction solution is 0.3 - 0.4 mol / L, preferably 0.36 mol / L; the molar concentration of Na 2 CO 3 in the reaction solution is 1.3 - 1.5 mol / L, preferably 1.43 mol / L; the molar concentration of Pd(PPh 3 ) 4 in the reaction solution is 0.03 - 0.04 mol / L, preferably 0.036 mol / L;

[0027] In step S2, the molar concentration of compound 2 in the reaction solution is 0.3 - 0.5 mol / L, preferably 0.39 mol / L; the molar concentration of 3-trifluoromethylphenylboronic acid in the reaction solution is 0.3 - 0.5 mol / L, preferably 0.46 mol / L; the molar concentration of XPhos Pd G 3 in the reaction solution is 0.03 - 0.05 mol / L, preferably 0.039 mol / L; the molar concentration of K 3 PO 4 in the reaction solution is 1.1 - 1.3 mol / L, preferably 1.15 mol / L.

[0028] As a preferred embodiment, after the reaction in step S1 is completed, the reaction solution is directly concentrated, and compound 2 is obtained by purification on a chromatographic column.

[0029] As a preferred embodiment, after the reaction in step S2 is completed, extraction is carried out with a mixed solution of ethyl acetate and water, then the organic solution is dried, concentrated, and compound 3 is obtained by purification on a chromatographic column; wherein the ratio of ethyl acetate to water is 4:3 - 4:5, preferably 1:1.

[0030] As a preferred embodiment, the drug is PF-06456384.

[0031] The present invention also provides a method for synthesizing a drug intermediate, using 4-bromopyridine-2-carbaldehyde as a raw material to synthesize the drug intermediate compound 2; the structural formula of compound 2 is as follows:

[0032]

[0033] 4-bromopyridine-2-carbaldehyde, 5-chloro-2-methoxyphenylboronic acid, Na 2 CO 3 , Pd(PPh 3 ) 4, dioxane was added to the reaction flask, and the reaction temperature was 60 - 120 °C. After the reaction was completed, compound 2 was obtained.

[0034] The present invention also provides a method for synthesizing a pharmaceutical intermediate. Compound 3 is synthesized from compound 2, and the structural formula of compound 3 is as follows:

[0035]

[0036] Compound 2, 3 - trifluoromethylphenylboronic acid, XPhos Pd G 3 , K 3 PO 4 , dioxane, and water were added to the reaction flask, and the reaction temperature was 60 - 120 °C. After the reaction was completed, compound 3 was obtained.

[0037] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0038] The present invention uses commercially available 4 - bromopyridine - 2 - carbaldehyde as a raw material, and through two - step palladium - catalyzed coupling, a pharmaceutical intermediate can be obtained. By optimizing the reaction process conditions, the total yield reaches 50% - 60%. The reaction conditions are mild and controllable, and the post - treatment is simple, greatly reducing the production cost and being very suitable for industrial production. Specific Embodiments

[0039] The technical solutions of the present invention will be described in detail below in conjunction with examples. However, the protection scope of the present invention is not limited thereto: The reagents and materials used below are all commercial products unless otherwise specified.

[0040] Example 1: Synthesis of Compound 2

[0041] Compound 1 (4 - bromopyridine - 2 - carbaldehyde) (2.00 g, 10.8 mmol), 5 - chloro - 2 - methoxyphenylboronic acid (2.00 g, 10.8 mmol), Na 2 CO 3 (4.56 g, 43.0 mmol), Pd(PPh 3 ) 4 (1.24 g, 1.08 mmol), 30 ml of dioxane were successively added to the reaction flask. After purging with nitrogen three times, the reaction was carried out at 90 °C for 3 hours. After detecting by TLC (PE:EtOAC = 10:1) that the raw materials were completely reacted, it was cooled to room temperature, 100 ml of water was added, and it was extracted with ethyl acetate (80 ml * 3). After drying and filtering, the extraction solution was concentrated and purified by column chromatography to obtain compound 2 (2.10 g, 8.48 mmol, yield 78.86%), a yellow solid.

[0042] 11H NMR: (400 MHz, DMSO-d6): δ 10.04 (s, 1H), 8.85 (d, J = 4.8 Hz, 1H), 8.05 (d, J = 1.2 Hz, 1H), 7.86 (dd, J = 1.6, 4.8 Hz, 1H), 7.45 - 7.58 (m, 2H), 7.23 (d, J = 8.4 Hz, 1H), 3.82 (s, 3H).

[0043] Example 1-1:

[0044] To the reaction flask were successively added compound 1 (4-bromopyridine-2-carbaldehyde) (2.00 g, 10.8 mmol), 5-chloro-2-methoxyphenylboronic acid (2.00 g, 10.8 mmol), Na 2 CO 3 (4.56 g, 43.0 mmol), Pd(PPh 3 ) 4 (1.24 g, 1.08 mmol), THF (30 ml), water (15 ml). The reaction system was purged with nitrogen three times and reacted at 60 °C for 1 hour. The target product was not detected.

[0045] Example 1-2:

[0046] To the reaction flask were successively added compound 1 (4-bromopyridine-2-carbaldehyde) (2.00 g, 10.8 mmol), 5-chloro-2-methoxyphenylboronic acid (2.00 g, 10.8 mmol), Na 2 CO 3 (4.56 g, 43.0 mmol), Pd(PPh 3 ) 4 (1.24 g, 1.08 mmol), dioxane (30 ml), water (15 ml). The reaction system was purged with nitrogen three times and reacted at 60 °C for 1 hour. The target product was not detected.

[0047] Example 1-3:

[0048] To the reaction flask were successively added compound 1 (4-bromopyridine-2-carbaldehyde) (2.00 g, 10.8 mmol), 5-chloro-2-methoxyphenylboronic acid (2.00 g, 10.8 mmol), Na 2 CO 3 (4.56 g, 43.0 mmol), Pd(PPh 3 ) 4 (1.24 g, 1.08 mmol), dioxane (30 ml). The reaction system was purged with nitrogen three times and reacted at 60 °C for 1 hour. By TLC detection, it was able to track that the raw materials had reacted completely and there was a main new product spot formed.

[0049] Example 1-4:

[0050] To the reaction flask, compound 1 (4-bromopyridine-2-carbaldehyde) (2.00 g, 10.8 mmol), 5-chloro-2-methoxyphenylboronic acid (2.00 g, 10.8 mmol), and Na 2 CO 3 (4.56 g, 43.0 mmol), Pd(PPh 3 ) 4 (1.24 g, 1.08 mmol), dioxane (30 ml) were added successively. After purging with nitrogen three times, the reaction was carried out at 90 °C for 1 hour. The target product could be tracked by TLC detection, and the reaction rate was faster than that at 60 °C.

[0051] Examples 1-5:

[0052] To the reaction flask, compound 1 (4-bromopyridine-2-carbaldehyde) (2.00 g, 10.8 mmol), 5-chloro-2-methoxyphenylboronic acid (2.00 g, 10.8 mmol), and Na 2 CO 3 (4.56 g, 43.0 mmol), Pd(PPh 3 ) 4 (1.24 g, 1.08 mmol), dioxane (30 ml) were added successively. After purging with nitrogen three times, the reaction was carried out at 120 °C for 1 hour. The target product could be tracked by TLC detection, but it was found that the impurities increased in the detection results.

[0053] Examples 1-6:

[0054] To the reaction flask, compound 1 (4-bromopyridine-2-carbaldehyde) (2.00 g, 10.8 mmol), 5-chloro-2-methoxyphenylboronic acid (2.00 g, 10.8 mmol), and Na 2 CO 3 (4.56 g, 43.0 mmol), Pd(PPh 3 ) 4 (1.24 g, 1.08 mmol), dioxane (30 ml) were added successively. After purging with nitrogen three times, the reaction was carried out at 90 °C for 3 hours. The TLC detection showed that the reaction was complete. Through the reaction monitoring under different temperature conditions of 60 °C, 90 °C, and 120 °C, it was found that the reaction effect at 90 °C was the best and the yield was the highest.

[0055] Examples 1-7:

[0056] To the reaction flask, compound 1 (4-bromopyridine-2-carbaldehyde) (2.00 g, 10.8 mmol), 5-chloro-2-methoxyphenylboronic acid (2.00 g, 10.8 mmol), and Na 2 CO 3(4.56 g, 43.0 mmol), Pd(PPh 3 ) 4 (1.24 g, 1.08 mmol), dioxane (30 ml), purged with nitrogen three times, reacted at 90 °C for 5 hours, the aldehyde group was retained, and the reaction was complete.

[0057] Examples 1 - 8:

[0058] To the reaction flask were successively added compound 1 (4-bromopyridine-2-carbaldehyde) (2.00 g, 10.8 mmol), 5-chloro-2-methoxyphenylboronic acid (2.00 g, 10.8 mmol), Na 2 CO 3 (4.56 g, 43.0 mmol), Pd(PPh 3 ) 4 (1.24 g, 1.08 mmol), dioxane (30 ml), purged with nitrogen three times, reacted at 90 °C for 8 hours, the aldehyde group was retained, and the reaction was complete.

[0059] Example 2: Synthesis of compound 3

[0060] To the reaction flask were successively added compound 2 (2.10 g, 8.48 mmol) from Example 1, 3-(trifluoromethyl)phenylboronic acid (1.93 g, 10.2 mmol), XPhos Pd G 3 (717 mg, 848 μmol), K 3 PO 4 (5.40 g, 25.4 mmol), dioxane (20 mL), water (2 mL), purged with nitrogen three times, reacted at 90 °C for 3 hours. After detecting by TLC (PE:EtOAc = 10:1) that the raw materials had completely reacted, it was cooled to room temperature, 100 ml of water was added, and it was extracted with a mixed solvent of EtOAc:water = 1:1 (EtOAc is ethyl acetate). After drying and filtration, the extraction solution was concentrated, and the crude product was purified by chromatography to obtain compound 3 (2.20 g, 6.16 mmol, yield 72.61%), a yellow oily product.

[0061] 1 1H NMR: (400 MHz, DMSO-d6): δ 10.06 (s, 1H), 8.87 (d, J = 4.8 Hz, 1H), 8.16 (s, 1H), 8.05 (s, 2H), 7.96 (dd, J = 1.6, 4.8 Hz, 1H), 7.82 - 7.88 (m, 2H), 7.66 - 7.71 (m, 2H), 7.32 (d, J = 8.4 Hz, 1H), 3.88 (s, 3H).

[0062] Example 2 - 1:

[0063] Add compound 2 (2.10 g, 8.48 mmol) from Example 1, 3-trifluoromethylphenylboronic acid (1.93 g, 10.2 mmol) to the reaction flask in sequence, 3 ) 4 (980 mg, 848 μmol), Na 2 CO 3 (2.6 g, 25.4 mmol), dioxane (10 mL), water (2 mL), displace with nitrogen three times, and no reaction occurs at 90 °C.

[0064] Example 2-2:

[0065] Add compound 2 (2.10 g, 8.48 mmol) from Example 1, 3-trifluoromethylphenylboronic acid (1.93 g, 10.2 mmol) to the reaction flask in sequence, K 2 CO 3 (3.51 mg, 25.4 mmol), Pd(dppf)Cl 2 (615 mg, 848 μmol), DMF (10 mL), water (2 mL), displace with nitrogen three times, and no target product is traced at 90 °C.

[0066] Example 2-3:

[0067] Add compound 2 (2.10 g, 8.48 mmol) from Example 1, 3-trifluoromethylphenylboronic acid (1.93 g, 10.2 mmol) to the reaction flask in sequence, K 3 PO 4 (5.39 mg, 25.4 mmol), Pd(dppf)Cl 2 (615 mg, 848 μmol), DMF (10 mL), water (2 mL), displace with nitrogen three times, and no reaction occurs at 90 °C.

[0068] Example 2-4:

[0069] Add compound 2 (2.10 g, 8.48 mmol) from Example 1, 3-trifluoromethylphenylboronic acid (1.93 g, 10.2 mmol) to the reaction flask in sequence, XPhos Pd G 3 (717 mg, 848 μmol), K 3 PO 4(5.40 g, 25.4 mmol), dioxane (20 mL), water (2 mL), purged with nitrogen three times, reacted at 60 °C for 3 hours. After detecting that the raw materials were completely reacted by TLC (PE:EtOAc = 10:1), cooled to room temperature, added 100 mL of water, extracted with a mixed solvent of EtOAc:water = 1:1 (EtOAc is ethyl acetate), concentrated the organic solution, dried over anhydrous sodium sulfate, and then concentrated the organic phase. The crude product was purified by chromatography to obtain compound 3 (yield 53.5%), a yellow oily product.

[0070] Example 2 - 5:

[0071] To the reaction flask were successively added compound 2 (2.10 g, 8.48 mmol) from Example 1, 3 - (trifluoromethyl)phenylboronic acid (1.93 g, 10.2 mmol), XPhos Pd G 3 (717 mg, 848 μmol), K 3 PO 4 (5.40 g, 25.4 mmol), dioxane (20 mL), water (2 mL), purged with nitrogen three times, reacted at 120 °C for 3 hours. After detecting that the raw materials were completely reacted by TLC (PE:EtOAc = 10:1), cooled to room temperature, added 100 mL of water, extracted with a mixed solvent of EtOAc:water = 1:1 (EtOAc is ethyl acetate), concentrated the organic solution, dried over anhydrous sodium sulfate, and then concentrated the organic phase. The crude product was purified by chromatography to obtain compound 3 (yield 42.8%), a yellow oily product.

Claims

1. A method for synthesizing a pharmaceutical intermediate, characterized in that: using 4-bromopyridine-2-carbaldehyde as a raw material, undergoing two-step palladium-catalyzed coupling reaction to obtain the pharmaceutical intermediate compound 3; the synthesis method comprises the following steps: S1. Synthesis of compound 2: 4-Bromopyridine-2-carbaldehyde, 5-chloro-2-methoxyphenylboronic acid, Na 2 CO 3 ,Pd(PPh 3 ) 4 , dioxane were added to the reaction flask, the reaction temperature was 60 - 120 °C, and compound 2 was obtained after the reaction was completed; S2. Synthesis of compound 3: Add the compound 2,3-trifluoromethylphenylboronic acid, XPhos Pd G 3 , K 3 PO 4 , dioxane, and water into the reaction flask, and react at a temperature of 60 - 120 °C to obtain compound 3 after the reaction is completed; In the step S2, the volume ratio of dioxane to water is: 8:1 to 12:1; In the step S2, the molar concentration of compound 2 in the reaction solution is 0.3 - 0.5 mol / L; the molar concentration of 3-trifluoromethylphenylboronic acid in the reaction solution is 0.3 - 0.5 mol / L; the molar concentration of XPhos Pd G 3 in the reaction solution is 0.03 - 0.05 mol / L; the molar concentration of K 3 PO 4 in the reaction solution is 1.1 - 1.3 mol / L.

2. The method for synthesizing a pharmaceutical intermediate according to claim 1, characterized in that: The reaction temperature in step S1 is 80 - 100 °C, and the reaction time is 3 - 8 hours.

3. The method for synthesizing a pharmaceutical intermediate according to claim 2, characterized in that: The reaction temperature in step S1 is 90 °C, and the reaction time is 3 hours.

4. The method for synthesizing a pharmaceutical intermediate according to claim 1, characterized in that: The reaction temperature in step S2 is 80 - 100 °C.

5. The method for synthesizing a pharmaceutical intermediate according to claim 1, characterized in that: In steps S1 and S2, after the raw materials are added to the reaction flask, the air in the reaction flask is displaced with an inert gas, and then the reaction is carried out at the said temperature.

6. The method for synthesizing a pharmaceutical intermediate according to claim 1, characterized in that: In the step S1, the molar concentration of 4-bromopyridine-2-carbaldehyde in the reaction solution is 0.3 to 0.4 mol / L; the molar concentration of 5-chloro-2-methoxyphenylboronic acid in the reaction solution is 0.3 to 0.4 mol / L; the molar concentration of Na 2 CO 3 in the reaction solution is 1.3 to 1.5 mol / L; the molar concentration of Pd(PPh 3 ) 4 in the reaction solution is 0.03 to 0.04 mol / L.

7. The method for synthesizing a pharmaceutical intermediate according to claim 1, characterized in that: After the reaction in step S1 is completed, the reaction solution is directly concentrated, and purified by a chromatographic column to obtain compound 2.

8. The method for synthesizing a pharmaceutical intermediate according to claim 1, characterized in that: After the reaction in step S2 is completed, extraction is carried out with a mixed solution of ethyl acetate and water, then the organic solution is dried, concentrated, and purified by a chromatographic column to obtain compound 3; wherein the ratio of ethyl acetate to water is 4:3 to 4:

5.

9. The method for synthesizing a pharmaceutical intermediate according to claim 1, characterized in that: The said drug is PF-06456384.

10. A method for synthesizing a pharmaceutical intermediate, characterized in that: using 4-bromopyridine-2-carbaldehyde as a raw material to synthesize the pharmaceutical intermediate compound 2; the structural formula of compound 2 is as follows: 4-Bromopyridine-2-carbaldehyde, 5-chloro-2-methoxyphenylboronic acid, Na 2 CO 3 , Pd(PPh 3 ) 4 , dioxane were added to the reaction flask, the reaction temperature was 60 - 120 °C, and compound 2 was obtained after the reaction was completed.

11. A method for synthesizing a pharmaceutical intermediate, characterized in that: compound 3 is synthesized from compound 2, and the structural formula of the said compound 2 is as follows: The structural formula of compound 3 is as follows: Add the compound 2,3-trifluoromethylphenylboronic acid, XPhos Pd G 3 , K 3 PO 4 , dioxane, and water into the reaction flask. The reaction temperature is 60 - 120 °C. After the reaction is completed, compound 3 is obtained.

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