A novel process for the preparation of a drug lumacaftor intermediate

Abstract

The application discloses a new method for preparing a lumacaftor intermediate. The method uses 5-bromo-6-chloropyridin-2-amine as a starting material, methyl boronic acid, palladium acetate and a ligand L1 to obtain a methylation product. Then, the methylation product is subjected to a Suzuki coupling reaction with m-tert-butoxycarbonyl phenyl boronic acid under the catalysis of tris(dibenzylideneacetone)dipalladium and a ligand L2 to synthesize 3-(6-amino-3-methylpyridin-2-yl)benzoic acid tert-butyl ester. The method can synthesize 3-(6-amino-3-methylpyridin-2-yl)benzoic acid tert-butyl ester at a high yield, and the method uses a small amount of catalyst, has mild reaction conditions and is easy to separate, so that the method is beneficial to industrial implementation and application promotion.

Description

TECHNICAL FIELD

[0001] The present application relates to a new method for preparing a drug lumacaftor intermediate, belonging to the technical field of organic synthesis. BACKGROUND

[0002] In 2015, the first compound drug Orkambi approved by the US FDA for the treatment of cystic fibrosis is composed of lumacaftor and ivacaftor. And 6-chloro-5-methylpyridin-2-amine and 3-(6-amino-3-methylpyridin-2-yl) benzoic acid tert-butyl ester are a key drug molecule intermediate for synthesizing lumacaftor and other drugs.

[0003]

[0004] The synthesis of 6-chloro-5-methylpyridin-2-amine reported in the literature Org. Process Res. Dev. 2020, 24, 1175-1179 has a low yield, and the synthesis of 6-chloro-5-methylpyridin-2-amine from organic boron reagent and bromide is as follows:

[0005]

[0006] At present, the synthesis yield of 6-chloro-5-methylpyridin-2-amine reported in the literature is moderate, and the synthesis route is long when 5-bromo-6-chloropyridin-2-amine is used as the raw material. 6-chloro-5-methylpyridin-2-amine is prepared by three-step reaction, the amino functional group needs to be protected to carry out Suzuki coupling reaction, and the coupling yield of aryl halide and methyl boronic acid is 82%, and the total yield of 6-chloro-5-methylpyridin-2-amine is only 70.2%.

[0007] Therefore, it is an important economic value research work to design a new catalyst to catalyze the efficient coupling of 5-bromo-6-chloropyridin-2-amine and methyl boronic acid to prepare 6-chloro-5-methylpyridin-2-amine. SUMMARY

[0008] The present application is aimed at the above-mentioned problems and defects existing in the prior art, and a new method for preparing drug molecule intermediates 6-chloro-5-methylpyridin-2-amine and 3-(6-amino-3-methylpyridin-2-yl) benzoic acid tert-butyl ester by palladium catalysis is developed, and applied to the synthesis of raw drug lumacaftor.

[0009] To achieve the above-mentioned application purposes, the technical solutions adopted by the present application are as follows:

[0010]

[0011] Under the protection of nitrogen, a certain amount of Pd(OAc)2, ligand L1 and a certain volume ratio of toluene and water were added into the reaction bottle and stirred for 5 minutes. Then a certain amount of compound 1, methyl boronic acid and potassium phosphate were added into the reaction bottle in turn, the reaction bottle was closed and stirred at a certain temperature for a certain time. After the reaction was completed, a certain amount of water and dichloromethane were added, the aqueous phase was added with a certain amount of dichloromethane for extraction three times, the organic phases were combined, the organic phase was washed with a certain amount of saturated sodium chloride solution, a proper amount of anhydrous sodium sulfate was added for drying for 2 hours, filtered, the solvent was recovered by distillation under reduced pressure, and the residue was separated by silica gel column chromatography, using a mixture of petroleum ether / ethyl acetate = 4:1 as the eluent, the first band eluent was collected, the solvent was recovered by distillation under reduced pressure, and compound 2 was obtained.

[0012] Under the protection of nitrogen, a certain amount of Pd2dba3, ligand L2 and a certain volume ratio of toluene and water were added into the reaction bottle and stirred for 5 minutes. Then a certain amount of compound 2, m-tert-butoxycarbonyl phenyl boronic acid and potassium phosphate were added into the reaction bottle in turn, the reaction bottle was closed and stirred at a certain temperature for a certain time. After the reaction was completed, a certain amount of water and dichloromethane were added, the aqueous phase was added with a certain amount of dichloromethane for extraction three times, the organic phases were combined, the organic phase was washed with a certain amount of saturated sodium chloride solution, a proper amount of anhydrous sodium sulfate was added for drying for 2 hours, filtered, the solvent was recovered by distillation under reduced pressure, and the residue was separated by silica gel column chromatography, using a mixture of petroleum ether / ethyl acetate = 2:1 as the eluent, the third band eluent was collected, the solvent was recovered by distillation under reduced pressure, and compound 3 was obtained.

[0013] In the reaction bottle, a certain amount of compound 4 (commercial reagent) was dissolved in a certain amount of tetrahydrofuran with stirring, a certain amount of oxalyl chloride was added, and after stirring for a certain time, the residual oxalyl chloride was removed by distillation under reduced pressure. The residue was dissolved in a certain amount of toluene, and a certain amount of compound 3, triethylamine and 4-dimethylaminopyridine were added in turn, and stirred at room temperature for a certain time. After the reaction was completed, a certain amount of water and dichloromethane were added, extracted, and the organic phase was separated. The aqueous phase was added with a certain amount of dichloromethane for extraction, and the extraction was repeated three times. The organic phases were combined, washed with a certain amount of saturated sodium chloride solution, and the organic phase was separated. A proper amount of anhydrous sodium sulfate was added for drying for a certain time, filtered, the solvent was recovered by distillation under reduced pressure, and the residue was separated by silica gel column chromatography, using a mixture of petroleum ether / ethyl acetate = 4:1 as the eluent, the third band eluent was collected, the solvent was recovered by distillation under reduced pressure, and compound 5 was obtained.

[0014] Synthesis of lumacaftor: a certain amount of compound 5 was added to a reaction bottle, a certain amount of acetonitrile was added, compound 5 was dissolved under stirring, a certain amount of (6M) hydrochloric acid solution was added, then stirred at a certain temperature for a certain time, after the reaction was completed, a certain amount of water was added, the product was precipitated in the form of white solid, suction filtration, the crude product was washed with a certain amount of deionized water, and naturally dried for a certain time to obtain the raw drug lumacaftor.

[0015] The advantages of the present application are: the synthesis method has mild reaction conditions, high yield, and good application prospect. BRIEF DESCRIPTION OF DRAWINGS

[0016] Figure 1 is the nuclear magnetic resonance hydrogen spectrum of compound 2

[0017] Figure 2 is the nuclear magnetic resonance carbon spectrum of compound 2

[0018] Figure 3 is the nuclear magnetic resonance hydrogen spectrum of compound 3

[0019] Figure 4 is the nuclear magnetic resonance carbon spectrum of compound 3

[0020] Figure 5 is the nuclear magnetic resonance hydrogen spectrum of compound 5

[0021] Figure 6 is the nuclear magnetic resonance carbon spectrum of compound 5

[0022] Figure 7 is the nuclear magnetic resonance hydrogen spectrum of raw drug lumacaftor

[0023] Figure 8 is the nuclear magnetic resonance carbon spectrum of raw drug lumacaftor DETAILED DESCRIPTION

[0024] Example 1: Synthesis of lumacaftor

[0025]

[0026] Synthesis of compound 2: 500 mg (2.4 mmol) of compound 1, 218 mg (4.8 mmol) of methylboronic acid, 2.7 mg (0.012 mmol) of palladium acetate, 8.0 mg (0.024 mmol) of ligand L1, and 1.5 g (7.2 mmol) of anhydrous potassium phosphate were added to a reaction bottle under nitrogen protection, and 5 mL of a mixed solvent of toluene and water in a volume ratio of 4:1 was stirred for 5 min. The reaction bottle was closed, and the reaction bottle was placed in a reactor at 100°C and stirred for 10 h. After the reaction was completed, 5 mL of water and 5 mL of dichloromethane were added for extraction, and the organic phase was separated. The aqueous phase was extracted with 5 mL of dichloromethane three times, and the organic phases were combined. The organic phase was washed with 10 mL of saturated sodium chloride, and the organic phase was separated. An appropriate amount of anhydrous sodium sulfate was added to dry the organic phase for 2 h, and then filtered. The solvent was recovered by reduced pressure distillation, and the residue was separated by silica gel column chromatography. Petroleum ether / ethyl acetate = 4:1 was used as the eluent, and the first band was collected. The solvent was recovered by reduced pressure distillation to obtain 330 mg of white solid, which was compound 2, with a yield of 95%. 1 H NMR (600 MHz, Methanol-d4) δ 7.34 (d, J = 8.2 Hz, 1H), 6.44 (d, J = 8.2 Hz, 1H), 4.86 (s, 2H), 2.19 (s, 3H); 13 C NMR (151 MHz, Methanol-d4) δ 158.03, 147.45, 141.28, 118.72, 107.21, 16.81.

[0027] Synthesis of compound 3: 300 mg (2.1 mmol) of compound 2, 700 mg (3.15 mmol) of m-tert-butoxycarbonylphenylboronic acid, 9.6 mg (0.011 mmol) of Pd2dba3, 13.7 mg (0.042 mmol) of ligand L2, and 1.3 g (6.3 mmol) of anhydrous potassium phosphate were added to a reaction bottle under nitrogen protection, and 3 mL of a mixed solvent of toluene and water in a volume ratio of 4:1 was stirred for 5 min. The reaction bottle was closed, and the reaction bottle was placed in a reactor at 100°C and stirred for 10 h. After the reaction was completed, 5 mL of water and 5 mL of dichloromethane were added for extraction, and the organic phase was separated. The aqueous phase was extracted with 5 mL of dichloromethane three times, and the organic phases were combined. The organic phase was washed with 10 mL of saturated sodium chloride, and the organic phase was separated. An appropriate amount of anhydrous sodium sulfate was added to dry the organic phase for 2 h, and then filtered. The solvent was recovered by reduced pressure distillation, and the residue was separated by silica gel column chromatography. Petroleum ether / ethyl acetate = 2:1 was used as the eluent, and the first band was collected. The solvent was recovered by reduced pressure distillation to obtain 540 mg of white solid, which was compound 3, with a yield of 90%. 1H NMR (600 MHz, Methanol-d4) δ 8.09 - 7.93 (m, 2H), 7.65 (d, J = 7.6 Hz, 1H), 7.62 - 7.51 (m, 1H), 7.43 (dd, J = 8.5, 2.7 Hz, 1H), 6.58 (dd, J = 8.4, 2.7 Hz, 1H), 4.87 (s, 2H), 2.13 (s, 3H), 1.62 (s, 9H); 13 C NMR (151 MHz, Methanol-d4) δ 165.70, 157.49, 154.22, 140.94, 140.86, 132.85, 131.71, 129.39, 128.27, 127.89, 119.07, 108.29, 81.09, 27.04, 17.19.

[0028] Synthesis of compound 5: In a reaction flask, 242 mg (1.0 mmol) of compound 4 (commercial reagent) was dissolved in 3 mL of tetrahydrofuran with stirring, 0.13 mL (1.5 mmol) of oxalyl chloride was added, after stirring at room temperature for 0.5 hours, the residual oxalyl chloride was removed by distillation under reduced pressure, the residue was dissolved with 5 mL of toluene, 284.4 mg (1.0 mmol) of compound 3, 0.2 mL (1.5 mmol) of triethylamine and 1.2 mg (0.1 mmol) of 4-dimethylaminopyridine were added in turn, and stirred at room temperature for 1 hour. After the reaction was completed, 5 mL of water and 5 mL of dichloromethane were added, extracted, and the organic phase was separated, the aqueous phase was extracted with 5 mL of dichloromethane each time, and the extraction was repeated three times, and the organic phase was combined, The organic phase was washed with 10 mL of saturated sodium chloride, the organic phase was separated, an appropriate amount of anhydrous sodium sulfate was added and dried for 2 hours, filtered, and the solvent was recovered under reduced pressure, and the residue was separated by silica gel column chromatography, using a mixture of petroleum ether / ethyl acetate = 4:1 as the eluent, The third band eluent was collected, and the solvent was recovered under reduced pressure to obtain 305 mg of white solid as compound 5, with a yield of 60%. 1 H NMR (600 MHz, Chloroform-d) δ 8.15 - 8.08 (m, 1H), 8.07 - 8.04 (m, 1H), 8.02 (d, J = 7.9 Hz, 1H), 7.72 (s, 1H), 7.60 (t, J = 9.5 Hz, 2H), 7.48 (td, J = 7.7, 2.1 Hz, 1H), 7.25 (d, J = 8.1 Hz, 1H), 7.21 (d, J = 2.6 Hz, 1H), 7.09 (dd, J = 8.2, 2.3 Hz, 1H), 2.28 (s, 3H), 1.77 (q, J = 3.4 Hz, 2H), 1.60 (d, J = 2.3 Hz, 9H), 1.18 (q, J = 3.4 Hz, 2H); 13C NMR (151 MHz, Chloroform-d) δ 171.69, 165.43, 155.54, 148.91, 144.17, 143.64, 140.88, 139.85, 134.96, 132.77, 132.15, 131.70, 129.88, 129.10, 128.13, 126.89, 126.54, 112.79, 112.33, 110.14, 31.20, 28.17, 19.16, 17.10.

[0029] Synthesis of drug substance lumacaftor: 300 mg (0.59 mmol) of compound 5 was added to a reaction bottle, 4 mL of acetonitrile was added, compound 5 was dissolved under stirring, 3 mL (6M) of hydrochloric acid solution was added, then stirred at 60°C for 2 hours, after the reaction was completed, 30 mL of water was added, the product was precipitated as a white solid, suction filtration, the crude product was washed with 10 mL of deionized water, and naturally dried to obtain 222 mg of white solid as drug substance lumacaftor, the yield was 83%. 1 H NMR (600 MHz, DMSO-d6) δ 13.10 (s, 1H), 9.02 (s, 1H), 8.15 - 7.83 (m, 3H), 7.73 (dd, J = 15.9, 8.0 Hz, 2H), 7.56 (d, J = 5.8 Hz, 2H), 7.45 - 7.27 (m, 2H), 2.23 (s, 3H), 1.51 (s, 2H), 1.16 (s, 2H);13C NMR (151 MHz, DMSO-d6) δ 167.58, 155.38, 149.62, 143.30, 141.27, 140.23, 136.80, 133.61, 130.11, 129.26, 128.82, 127.00, 126.76, 113.77, 112.67, 110.57, 31.83, 19.19, 16.12.

Claims

1. A method for preparing the intermediate compound 3 of the drug lumacaftor, characterized in that, The synthesis includes the following steps: Under nitrogen protection, starting material 1 is reacted with methylboronic acid in a solvent via a Suzuki coupling reaction, followed by purification through extraction, drying, filtration, vacuum distillation, and silica gel column chromatography to obtain compound 2. Compound 2 is then reacted with m-tert-butoxycarbonylphenylboronic acid under nitrogen protection via a Suzuki coupling reaction, followed by purification through extraction, drying, filtration, vacuum distillation, and silica gel column chromatography to generate compound 3. The synthetic route is shown in Formula I. ； The structural formula of ligand L1 is Formula II; the structural formula of ligand L2 is Formula III. 。 2. The method for preparing the drug lumacaftor intermediate compound 3 according to claim 1, characterized in that, The molar ratio of raw material 1 to methylboric acid is 1:

2.

3. The method for preparing the pharmaceutical intermediate compound 3, according to claim 1, is characterized in that, The molar ratio of palladium acetate to ligand L1 is 1:2, and the molar ratio of palladium acetate to raw material 1 is 200:

1.

4. The method for preparing the drug lumacaftor intermediate compound 3 according to claim 1, characterized in that, In the process of synthesizing compound 2, the molar ratio of raw material 1 to potassium phosphate is 1:

3.

5. The method for preparing the pharmaceutical intermediate compound 3, according to claim 1, is characterized in that, In the process of synthesizing compound 2, the solvent is a mixed solvent of toluene and water with a volume ratio of 5:1, the amount used is 4 L / mol of raw material 1, the reaction temperature is 100℃, and the reaction time is 10 hours.

6. The method for preparing the pharmaceutical intermediate compound 3, according to claim 1, is characterized in that, The molar ratio of compound 2 to m-tert-butoxycarbonylphenylboronic acid is 2:

3.

7. The method for preparing the pharmaceutical intermediate compound 3, according to claim 1, is characterized in that, Tris-(dibenzylacetone)dipalladium and ligand L2 are used as catalysts in a molar ratio of 1:2, and the molar ratio of tris-(dibenzylacetone)dipalladium to compound 2 is 1:

200.

8. The method for preparing the pharmaceutical intermediate compound 3, according to claim 1, is characterized in that, In the process of synthesizing compound 3 from compound 2, the molar ratio of compound 2 to potassium phosphate is 1:

3.

9. The method for preparing the pharmaceutical intermediate compound 3, according to claim 1, is characterized in that, In the process of synthesizing compound 3 from compound 2, the solvent is a mixed solvent of toluene and water with a volume ratio of 5:1, the amount used is 4 L / mol of compound 2, the reaction temperature is 100℃, and the reaction time is 10 hours.

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