Alflutinib is under investigation in clinical trial NCT03452592 (Efficacy and Safety of Alflutinib in Locally Advanced or Metastatic Non-small Cell Lung Cancer Patients With T790M).
Firmonertinib is an orally available selective inhibitor of the epidermal growth factor receptor (EGFR) mutant form T790M, with potential antineoplastic activity. Upon administration, firmonertinib specifically binds to and inhibits the tyrosine kinase activity of EGFR T790M, a secondarily acquired resistance mutation. This prevents EGFR T790M-mediated signaling and leads to cell death in EGFR T790M-expressing tumor cells. EGFR, a receptor tyrosine kinase that is mutated in many tumor cell types, plays a key role in tumor cell proliferation and tumor vascularization. Compared to some other EGFR inhibitors, alflutinib may have therapeutic benefits in tumors with T790M-mediated drug resistance.
FIRMONERTINIB is a small molecule drug with a maximum clinical trial phase of III (across all indications) and has 4 investigational indications.
Example 3: N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethoxyl)-5-{[4-(1-methyl-H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide
Step 1: Synthesis of N2-methyl-N2-[2-(dimethylamino)ethyl]-6-(2,2,2-trifluoroethoxyl)-N5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]-3-nitropyridin-2,5-diamine
The compound was synthesized in the same manner as those in Step 1 of Example 1 with a yield of 86%. MS m/z: 545 [M+1].
Step 2: Synthesis of N2-methyl-N2-[2-(dimethylamino)ethyl]-6-(2,2,2-trifluoroethoxyl)-N5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]pyridin-2,3,5-triamine
The compound was synthesized in the same manner as those in Step 2 of Example 2 with a yield of 56%. MS m/z: 515 [M+1].
Step 3: Synthesis of N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethoxyl)-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide
Patent application CN105315259A protects the compound of formula I and discloses its preparation method as follows:
Example 1: Preparation of 6-chloro-3-nitro-2-(2,2,2-trifluoroethoxy)pyridine (XI-1)
Add toluene (24.0L) to the reactor, then add 2,6-dichloro-3-nitropyridine (3000g, 15.54mol), adjust the internal temperature between -20℃ and -10℃, and add sodium hydrogen (933g, 23.33mol) in batches. Add 2,2,2-trifluoroethanol (1586g, 16.00mol) toluene (6.0L) solution dropwise. React for 2h, and monitor the reaction end point by TLC and HPLC. After the reaction is completed, add 10% ammonium chloride solution (6.0L) dropwise. Let stand and separate. Wash the organic phase with water (6.0L) and concentrate under reduced pressure. Add ethyl acetate (0.3L), heat to 40-50℃, add n-heptane (2.7L) dropwise, cool to -15 to -5℃ after dripping, and continue crystallization for 3 hours, and filter with suction. Obtain 3017g of product solid, with a yield of 75.65%.
Example 2: Preparation of 6-chloro-3-amino-2-(2,2,2-trifluoroethoxy)pyridine (X-1)
At room temperature, add acetonitrile (21.0L) and water (21.0L) to the reactor, start stirring, add 6-chloro-3-nitro-2-(2,2,2-trifluoroethoxy)pyridine (3017.0g, 11.76mol) obtained in Example 1, and add hydrosulfite (15.1Kg, 70.54mol). Control the temperature at 27-33°C to react for 2 hours. Add 36% concentrated hydrochloric acid (11.9Kg, 117.60mol) dropwise, and continue to react for 1.5 hours. Add solid sodium bicarbonate (12.8Kg, 12.96mol). Filter, separate the mother liquor, wash the organic phase with saturated brine (21.0L), and concentrate under reduced pressure to obtain an oily substance. Theoretically calculated for the next step reaction.
Example 3: Preparation of 6-chloro-3-(2,2,2-trifluoroacetamido)-2-(2,2,2-trifluoroethoxy)pyridine (IX-1)
At room temperature, dichloromethane (10.4 L) was added to the reaction kettle, stirring was started, 6-chloro-3-amino-2-(2,2,2-trifluoroethoxy)pyridine (2664 g, 11.76 mol) obtained in Example 2 was added, diisopropylethylamine (2279 g, 17.64 mol) was added, the temperature was controlled at -15 to -10°C, a dichloromethane (5.2 L) solution of trifluoroacetic anhydride (2963 g, 14.11 mol) was added dropwise, and stirring was continued for 20 minutes after the addition was completed. Water (13.0 L) was added dropwise, the layers were separated, the organic phase was concentrated under reduced pressure, and the next step reaction was theoretically calculated.
1 H NMR(400MHz,DMSO-d6)δ11.23(s,7H),7.95(d,J8.0Hz,1H),7.34(d,J8.0Hz,1H),5.03(q,J8.9Hz,2H)
Example 4: Preparation of 6-chloro-5-nitro-3-(2,2,2-trifluoroacetamido)-2-(2,2,2-trifluoroethoxy)pyridine (VIII-1)
At room temperature, concentrated sulfuric acid (11.7 L) was added to the reaction kettle, stirring was started, 6-chloro-3-(2,2,2-trifluoroacetamido)-2-(2,2,2-trifluoroethoxy)pyridine (3.9 Kg, 11.76 mol) obtained in Example 3 was added, and potassium nitrate solid (1783.4 g, 17.64 mol) was added in batches. After the addition, stirring was continued for about 40 minutes. After monitoring the reaction, the temperature was lowered to control the internal temperature at 10-25°C, and dichloromethane (27.3 L) was added dropwise. Stirring was continued, stirring was continued for 45 minutes, and the layers were separated. The organic phase was taken and washed once with water (11.7 L). The organic phase was concentrated under reduced pressure and theoretically calculated for the next step reaction.
Example 5: Preparation of 6-chloro-5-nitro-3-amino-2-(2,2,2-trifluoroethoxy)pyridine (VII-1)
At room temperature, methanol (13.0 L) was added to the reactor, 6-chloro-5-nitro-3-(2,2,2-trifluoroacetamido)-2-(2,2,2-trifluoroethoxy)pyridine (4322 g, 11.76 mol) obtained in Example 4 was added, p-toluenesulfonic acid monohydrate (3355 g, 17.64 mol) was added, the temperature was controlled at 60-65°C for 15 hours, and the methanol was removed under reduced pressure. Methyl tert-butyl ether (13.0 L) and water (6.5 L) were added, and the pH was adjusted to 7-8 with potassium carbonate. Layering was performed, the organic phase was washed once with water (8.6 L), separated, and concentrated under reduced pressure. n-heptane (21.5 L) was added, the temperature was controlled at 60-65°C and stirred for 1 hour, cooled to room temperature, filtered, and the filter cake was dried with air at 50°C for 18 hours to obtain 1475 g of the product.
The total yield of the five-step reaction from Example 1 to Example 5 is 34.9%.
Example 6: Preparation of 2-chloro-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (V-1)
Toluene (50 mL) was added to a 100 mL reaction bottle, and the compound of formula VII-1, 6-chloro-5-nitro-3-amino-2-(2,2,2-trifluoroethoxy)pyridine (5.0 g, 18.4 mmol), the compound of formula VI, 3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole (5.8 g, 23.8 mmol), p-toluenesulfonic acid monohydrate (1.8 g, 9.2 mmol) were added in sequence, and the reaction mixture was heated to 110-115°C and reacted for 24 hours. The temperature was lowered to 22°C, filtered by suction, and the filter cake was dried at 50°C for 20 hours to obtain the compound of formula V-1, 2-chloro-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (10.4 g, 74.7 HPLC area% purity). According to the HPLC purity conversion, the next step reaction was carried out.
Example 7: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (IV)
Add N,N-dimethylformamide (30 mL) to a 250 mL reaction bottle, add the compound of formula V-1 obtained in Example 6, 2-chloro-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (10.4 g, 16.22 mmol), stir, add potassium carbonate (4.48 g, 32.44 mol), N,N,N’-trimethylethylenediamine (2.48 g, 24.33 mol) in sequence, heat the reaction mixture to 77-82°C, keep warm for 1-1.5 hours. Add water (60 mL), and cool to room temperature after addition. Filter by suction, transfer the filter cake to a 50 L reactor, add acetonitrile (40 mL), and heat to reflux for 2 hours. The mixture was cooled to room temperature and filtered with suction. The filter cake was dried at 50°C for 18 hours to give a compound of formula IV, 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (6.7 g). The total yield of the two-step reaction with Example 6 was 66.8%.
Example 8: Preparation of 2-chloro-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine p-toluenesulfonate (V-1′)
Toluene (7.43 L) was added to a 20 L reactor, and compound VII-1 6-chloro-5-nitro-3-amino-2-(2,2,2-trifluoroethoxy)pyridine (743.0 g, 2.74 mol), compound VI 3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole (866.7 g, 3.56 mol), p-toluenesulfonic acid monohydrate (780.7 g, 4.10 mol) were added in sequence, stirred, and the reaction mixture was heated to 110-115°C and reacted for 36 hours. The temperature was controlled at 15-30°C, tetrahydrofuran (3.72 L) was added and stirred for 30 minutes. Filtered by suction, the filter cake was transferred to a 50 L reactor, tetrahydrofuran (4.46 L) was added, and heated to reflux for 3 hours. The temperature was lowered to 15-25°C, filtered, and the filter cake was dried at 50°C for 17 hours to obtain 2-chloro-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine p-toluenesulfonate (1719 g, 85.96 HPLC area% purity). The purity was calculated according to HPLC and used for the next step reaction.
Example 9: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (IV)
Add N,N-dimethylformamide (5.14L) to a 50L reactor, add 2-chloro-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine p-toluenesulfonate (1714.0g, 2.261mol) obtained in Example 8, stir, add potassium carbonate (624.7g, 4.52mol), N,N,N’-trimethylethylenediamine (346.2g, 3.39mol) in sequence, heat the reaction mixture to 77-82°C, keep warm for 1-1.5 hours. Add water (10.28L), and cool to room temperature after adding. Filter by suction, transfer the filter cake to a 50L reactor, add acetonitrile (6.86L), and heat to reflux for 2 hours. The temperature was lowered to 15-25°C, filtered with suction, and the filter cake was dried at 50°C for 18 hours to obtain the compound of formula IV, 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (1142 g). The total yield of the two-step reaction with Example 8 was 76.54%.
Example 10: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (IV)
Acetonitrile (10 mL) was added to a 50 L reactor, and 2-chloro-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine p-toluenesulfonate (1.0 g, 1.5 mmol) obtained in Example 8 was added, and stirred. Potassium carbonate (577 mg, 3 mmol) and N,N,N’-trimethylethylenediamine (320 mg, 2.25 mmol) were added in sequence. The reaction mixture was heated to 77-82°C and kept for 1-2 hours. Water (10 mL) was added and the temperature was cooled to room temperature after the addition. The product was filtered to give a compound of formula IV, 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (629 mg) with a purity of 95.94%. The total yield of the two-step reaction with Example 8 was 77%.
Example 11: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (III’)
Add the compound of formula IV 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (4.0 g, 7.34 mmol) to a 100 mL reaction bottle at room temperature, add tetrahydrofuran (27 mL) and water (13 mL), and stir for 10 to 20 minutes. Add hydrosulfite (9.6 g, 44.1 mmol) to the reactor in batches. After addition, continue stirring for 10 to 20 minutes. Control the temperature of the reactor to 30 to 35 ° C for reaction. The purity of the product compound of formula III’ was 64.68% after sampling the liquid phase after 2 hours of reaction. The reaction was continued until 17 hours after the reaction. 40 mL of water was added to the reaction solution, and the layers were separated by standing. The tetrahydrofuran phase was taken, and the aqueous phase was extracted twice with 100 mL of dichloromethane. The organic phases were combined, washed with saturated brine, separated by standing, and concentrated under reduced pressure to obtain 3.2 g of solid with a purity of 62.32%.
Example 12: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (III’)
In a 100mL single-mouth bottle, there is 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (2.0g, 3.67mmol), palladium carbon (200mg), ethanol (20mL), hydrogen balloon replacement twice, hydrogen gas, magnetic stirring, room temperature overnight (17 hours). After the reaction is completed, suction filtration, the filtrate is taken, and it is concentrated to dryness under reduced pressure to obtain 2.1g of product with a purity of 56.93%.
Example 13: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (III’)
At room temperature, add the compound of formula IV 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (1317.0 g, 2.42 mol) to a 50 L reactor, add tetrahydrofuran (8.8 L) and water (4.3 L), and stir for 10 to 20 minutes. Add hydrosulfite (2970.0 g, 14.52 mol) to the reactor in batches. After adding, continue stirring for 10 to 20 minutes. Control the temperature of the reactor to 40-45 ° C and react for 2 hours. Add concentrated hydrochloric acid (5882.2 g, 58.08 mol) to the reactor. After the addition is complete, heat to 42 to 47 ° C and react for 15 hours. Add 30% sodium hydroxide (2323.2g, 58.08mol) aqueous solution dropwise, and then add solid sodium bicarbonate (1219.7g, 14.52mol) in batches to adjust the pH value to 6-8. After stirring for 20 minutes, filter with suction, let the filtrate stand and separate. The organic phase is concentrated under reduced pressure to obtain 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine, with a purity of 97.1%. Calculated based on the theoretical yield of 100%, it is directly used in the next step reaction.
Example 14: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine dihydrochloride (III-1)
To the 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine obtained in Example 13, THF (5.3 L) and ethanol (4.0 L) were added, the temperature was raised to 50-70°C, and concentrated hydrochloric acid (617.8 g, 6.1 mol) was added dropwise. After the addition was completed, the mixture was cooled to room temperature and stirred for 12 hours. Filtered by suction, the filter cake was dried by air at 50°C to obtain 1507.4 g of a crude product. Methanol (6.0 L) and ethanol (4.5 L) were added to a 20 L reaction bottle, and the above crude product was added, the temperature was raised to 55-60 ° C, hot slurry was added for 1-2 hours, the temperature was lowered to room temperature, and suction was filtered to obtain 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine dihydrochloride (1335.6 g), the liquid phase purity was 99.80%, and the total yield of the two-step reaction with Example 13 was 94.0%. Melting point: 236.6-240.8 ° C.
Example 15: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine dihydrochloride (III-1)
At room temperature, add the compound of formula IV 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (1136.0 g, 2.09 mol) to a 50 L reactor, add acetonitrile (7.95 L) and water (7.95 L), and stir for 10 to 20 minutes. Add hydrosulfite (2563.9 g, 12.50 mol) to the reactor in batches. After adding, continue stirring for 10 to 20 minutes. Control the temperature of the reactor to 35 to 40 ° C and react for 3 hours. Add concentrated hydrochloric acid (2505.3 g, 25.08 mol) to the reactor. After the addition is complete, heat to 35 to 45 ° C and react for 18 hours. 30% sodium hydroxide (1003.2 g, 25.08 mol) aqueous solution was added dropwise to adjust the pH value to 6-8. Solid sodium bicarbonate (1053.5 g, 12.54 mol) was added to adjust the pH value to 7-8. After stirring for 40 minutes, the mixture was filtered, the filtrate was allowed to stand, the layers were separated, and the organic phase was concentrated under reduced pressure. The purity of the liquid phase was detected to be 97.60%.
Add ethanol (5.68 L) to the product of the previous step, raise the temperature to 50-70°C, and drop concentrated hydrochloric acid (522 g, 5.23 mol). After the dropwise addition is completed, cool to room temperature and stir for 15 hours. Filter by suction, and air dry the filter cake at 50°C to obtain 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine dihydrochloride (780 g), with a liquid phase purity of 98.74%.
Example 16: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamido)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine hydrochloride (II-1)
2-[2-(Dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine dihydrochloride (1543.5 g, 2.63 mol) was added to a 50 L reactor, and dichloromethane (13.1 L) and triethylamine (532.2 g, 5.26 mol) were added. The mixture was stirred and cooled to -10 to -5 °C, and a solution of 3-chloropropionyl chloride (501.5 g, 3.95 mol) in dichloromethane (10.0 L) was added dropwise. After the addition is completed, keep warm and stir for 10 to 20 minutes, filter with suction, and the filter cake is formula II-12-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamide)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine hydrochloride wet product (2683.5g), which is calculated based on the theoretical yield of 100% and is directly used in the next reaction.
Example 17: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I, crude product)
The wet product (2683.5 g) of Formula II 2-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamide)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine hydrochloride obtained in Example 16 was added to a 20L reactor, and acetonitrile (16.8L) and triethylamine (1329.3g, 13.15mol) were added, stirred, and heated to reflux for 4 hours. Cooled to room temperature, purified water (4.20L) was added, stirred at room temperature for 3-4 hours, and filtered. The filter cake was transferred to a 50L reactor, dichloromethane (17L) was added, and the pH value was adjusted to 7-8 with saturated sodium bicarbonate aqueous solution (17L). Liquid separation, the organic phase was transferred to a 20L reactor, activated carbon (84.3g) was added, refluxed for 1 hour, cooled to 20-30°C, and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain the compound of formula I 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (1390g), with a total yield of 92.9% and a purity of 99.21% for the two-step reaction with Example 16.
Example 18: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (III’)
At room temperature, add the compound of formula IV 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (20.0 g, 36.73 mmol) to a 1L reaction bottle, add tetrahydrofuran (134 mL) and water (66 mL), and stir for 10 to 20 minutes. Add hydrosulfite (47.9 g, 220.38 mmol) to the reaction bottle in batches. After addition, continue stirring for 10 to 20 minutes. Control the internal temperature to 35-40°C and react for 3 hours. Add concentrated hydrochloric acid (89.3 g, 881.52 mmol) to the reaction bottle. After the addition is complete, heat to 42 to 47°C and react for 17 hours. 30% sodium hydroxide (35.26 g, 881.52 mmol) aqueous solution was added dropwise, and solid sodium bicarbonate (18.5 g, 220.38 mmol) was added in batches to adjust the pH value to 6-8. After stirring for 30 minutes, the mixture was filtered, and the filtrate was allowed to stand and separated. The organic phase was concentrated to dryness under reduced pressure to obtain 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (19.2 g) with a purity of 95.8% and a yield of 97.12%.
Example 19: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamido)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine hydrochloride (II-1)
Add 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5 g, 9.72 mmol) to a 250 mL reaction bottle, add dichloromethane (42 mL), stir, protect with argon, cool to -5 to 0°C, and add 3-chloropropionyl chloride (1.851 g) and dichloromethane (33 mL) dropwise. After the addition is complete, the mixture is stirred for 10-20 minutes at a temperature maintained at room temperature. After the reaction is complete, the mixture is concentrated under reduced pressure to obtain 2-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamido)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine hydrochloride (7.0 g) with a purity of 85.67%. Melting point: 233.5-238.9°C.
Example 20: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I, crude product)
The 2-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamido)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine hydrochloride obtained in Example 19 was added to a 250 mL reaction bottle, and acetonitrile (45 mL) and triethylamine (4.9 g) were added. The mixture was stirred magnetically and protected by argon. The temperature was raised to reflux in an oil bath. The reaction was allowed to react for 6 h. Water (23 mL) was added dropwise, and the mixture was naturally cooled to room temperature in an oil bath. The mixture was filtered with suction, and the filter cake was transferred to a 500 mL reaction bottle. Dichloromethane (100 mL) was added, and the pH value was adjusted to 7-8 with saturated aqueous sodium bicarbonate solution (100 mL). The liquids were separated and the organic phase was concentrated under reduced pressure. The solid was dried in an oven at 50°C to give 2-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamide)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (4.1 g) with a purity of 97.7%. The total yield of the two-step reaction with Example 19 was 74.17%.
Comparative Example 1: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I, crude product)
2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (1 g, 1.94 mmol) was added to a 50 mL multi-necked flask, tetrahydrofuran (10 mL) was used as the solvent, argon was replaced three times, and stirring was maintained at 0-5°C under argon protection, and 3-chloropropionyl chloride (0.37 g, 2.92 mmol), the addition was completed in 15 minutes, and the mixture was stirred at 0-5°C for 1 hour. Sodium hydroxide (0.31 g, 7.77 mmol) and water (1 mL) were added to the reaction solution, and the temperature was raised to 65°C and stirred for 15 hours. Saturated ammonium chloride solution (10 mL) was added, and the liquids were separated. The organic phase was washed with saturated sodium bicarbonate solution (10 mL). The liquids were separated and the organic phase was concentrated to dryness to obtain 1.04 g of a yellow solid with a yield of 94.9% and a purity of 87.35%.
Comparative Example 2: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I, crude product)
Add 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5.0 g) to a 250 mL reaction bottle, add acetone (50 mL) and potassium carbonate (940 mg), stir, protect with argon, cool to -50°C, and add 3-chloropropionyl chloride (1.481 g) dropwise. After the addition is completed, the temperature is raised to -20°C and stirred for 30 minutes. A solution of sodium hydroxide (350 mg) and water (60 ml) is added dropwise over 10 minutes. The mixture is stirred at room temperature for 3 to 4 hours. The mixture is filtered and the filter cake is dried in an oven at 50°C to obtain a compound of formula II-1′, 2-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamide)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (4.28 g) with a purity of 64.18%.
Add 2-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamido)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (4.28 g) to a 250 mL reaction bottle, add acetonitrile (45 ml) and triethylamine (3.606 g), stir magnetically, protect with argon, heat in an oil bath to reflux, and react for 6 h. Water (23 ml) was added dropwise, the temperature was naturally lowered in an oil bath and stirring was continued overnight (16 h), filtered with suction, and the solid was dried to obtain 2-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamido)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (3.3 g) with a purity of 95.13% and a two-step yield of 59.42%.
Example 21: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)
The crude product (1390 g) of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine was transferred to a 50L reactor, acetone (25.0L) was added, argon was replaced 3 times, the temperature was raised to 45-50°C, all the solids were dissolved, and purified water (6.95L) was added dropwise. After the addition was completed, the mixture was cooled to 20-25°C and stirred for 2 hours. The mixture was filtered and the filter cake was vacuum dried at 50°C for 24 hours to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (895g). The reaction yield is 66.7% and the purity is 99.89%.
Example 22: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)
In a 250mL three-necked flask, add 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine crude product (5.0g), add ethyl acetate 100mL, heat to 70-75°C in an oil bath to dissolve all the solids, then cool naturally to 25°C in an oil bath, filter and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (3.1g) with a purity of 99.73% and a yield of 62.0%.
Example 23: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)
In a 250mL three-necked flask, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5.0g), add ethyl acetate 100mL, heat to 70-75°C in an oil bath, dissolve all the solids, continue to stir for 30min, and drop 150mL of n-heptane. After the drop is complete, cool to 25°C in an oil bath, filter by suction, and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (4.0g), with a purity of 99.32% and a yield of 80%.
Example 24: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)
In a 250mL three-necked flask, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5.0g), add acetonitrile 75mL, heat in an oil bath to 77-82°C, dissolve all the solids, and drop 25mL of water. After dripping, naturally cool to 25°C in the oil bath, filter with suction, and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (4.3g), with a purity of 99.64% and a yield of 86%.
Example 25: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)
In a 250mL three-necked flask, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5.0g), add acetonitrile 75mL, heat in an oil bath to 77-82°C, dissolve all the solids, and continue to stir for 30min. Cool naturally to 25°C in the oil bath, filter with suction, and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (4.0g), with a purity of 99.45% and a yield of 80%.
Example 26: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)
In a 250mL three-necked flask, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5.0 g), add 20mL of tetrahydrofuran, heat in an oil bath to 45-50°C to dissolve all the solids, continue to stir and maintain the temperature for 30 minutes, and add 40mL of n-heptane dropwise. After the addition was completed, the mixture was naturally cooled to 25°C in an oil bath, filtered and dried to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (4.23 g) with a purity of 99.51% and a yield of 84.6%.
Example 27: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)
In a 250mL three-necked flask, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5.0g), add 100mL of isopropanol, heat to 50°C in an oil bath, dissolve all the solids, and continue to stir for 30 minutes. Cool naturally to 22°C in the oil bath, filter with suction, and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (4.25g), with a purity of 99.51% and a yield of 85%.
Example 28: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)
In a 250mL three-necked flask, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5.0g), add 75mL of methanol, and heat to 55-60°C in an oil bath to dissolve all the solids. Cool naturally to 17°C in the oil bath, stir overnight, filter with suction, and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (3.55g), with a purity of 99.63% and a yield of 71%.
Example 29: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)
In a 250mL three-necked flask, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5.0 g), add 50mL of dichloromethane, heat in an oil bath to 40°C to dissolve all the solids, continue to stir and maintain the temperature for 30 minutes, and add 100mL of n-heptane dropwise. The mixture was naturally cooled to 15°C in an oil bath, stirred overnight, filtered and dried to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (3.78 g) with a purity of 99.56% and a yield of 75.6%.
Example 30: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)
In a 250mL three-necked flask, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5.0g), add 100mL of toluene, heat to 65°C in an oil bath, dissolve all the solids, and continue to stir for 30 minutes. Cool naturally to 20°C in the oil bath, filter with suction, and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (3.27g), with a purity of 99.57% and a yield of 65.4%.
Example 31: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)
In a 250mL three-necked flask, add 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine crude product (5.0g), add DMF50mL, heat to 80°C in an oil bath, dissolve all the solids, continue to stir for 30min, and drop 25mL of water. Naturally cool to 20°C in the oil bath, filter with suction, and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (3.84g), with a purity of 99.77% and a yield of 76.8%.
Example 32: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)
To a 25 mL single-necked bottle, add 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine crude product (1.0 g), add tetrahydrofuran (6 mL), protect with argon, heat in an oil bath to 40-45°C until all the solution is dissolved, continue to stir and keep warm for 30 min, cool naturally to 22°C in an oil bath, filter and obtain a solid. The solid was transferred to a crystallization dish and dried to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (622 mg) with a purity of 99.83% and a yield of 62.2%.
Example 33: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)
To a 50 mL single-mouth bottle, add 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine crude product (1.0 g), add acetone (15 mL), protect with argon, heat in an oil bath to 45-50° C. until all the solution is dissolved, and then continue to stir and keep warm for 30 min, cool naturally to 22° C. in an oil bath, filter and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (537 mg) with a purity of 99.83% and a yield of 53.7%.
Example 34: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)
To a 50 mL single-mouth bottle, add 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine crude product (1.0 g), add tetrahydrofuran (8 mL), protect with argon, heat in an oil bath to 40-45° C. until all the solution is dissolved, and continue to stir and keep warm for 30 min. Add water (16 mL) dropwise, cool naturally to 21° C. in an oil bath, filter and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (880 mg) with a purity of 99.68% and a yield of 88.0%.
Example 35: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)
To a 100 mL single-mouth bottle, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (1.0 g), add ethanol (35 mL), protect with argon, heat in an oil bath to 75-80° C. until all the solution is dissolved, add water (10 mL) dropwise over 10 min, cool naturally to 20° C. in an oil bath, filter with suction, and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (915 mg), with a yield of 91.5% and a purity of 99.49%.
Example 36: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)
To a 50 mL single-mouth bottle, add 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine crude product (1.0 g), add xylene (20 mL), protect with argon, heat in an oil bath to 80° C. until all the solution is dissolved, cool naturally to 20° C. in an oil bath, filter with suction, and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (798 mg), with a yield of 79.8% and a purity of 99.48%.
Example 37: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)
In a 250mL three-necked flask, add 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine crude product (5.0g), add ethanol 125mL, heat in an oil bath to 75-80°C to dissolve all the solids, continue to stir and keep warm for 30min, then cool naturally to 25°C in an oil bath, filter and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (3.7g) with a purity of 99.66% and a yield of 74%.
Example 38: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)
To a 100 mL single-mouth bottle, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (1.0 g), add methanol (35 mL), protect with argon, heat in an oil bath to 80° C. until all the solution is dissolved, add water (10 mL) dropwise over 10 min, cool naturally to 20° C. in an oil bath, filter and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (912 mg), with a yield of 91.2% and a purity of 99.53%.
