(R)-3-[4-Amino-3-(4-phenoxy-phenyl)- pyrazolo[3,4-

Step 4A mixture of (R)-tert-butyl 3-[4-amino-3-iodo-lH-pyrazolo[3, 4-d]pyrimidin-l- yl]piperidine-l-carboxylate (1 g, 2.25 mmol, 1 .00 equiv), (4-phenoxyphenyl)boronic acid (530 mg, 2.48 mmol, 1.10 equiv), sodium carbonate (480 mg, 4.53 mmol, 2.01 equiv) and tetrakis( triphenylphosphine)palladium (78 mg, 0.07 mmol, 0.03 equiv) in , 4-dioxane (60 mL) and water (15 mL) was stirred under nitrogen at 90°C for 24 h. The reaction mixture was cooled to room temperature and then concentrated under vacuum. The residue was dissolved in 500 mL of dichloromethane. The resulting solution was washed with 200 mL of water, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with dichloromethane/methanol (100/1) to give 700 mg (64percent) of (R)-tert-butyl 3-[4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3, 4-d]pyrimidin-l- yl]piperidine-l-carboxylate as a yellow solid.A mixture of (R)-tert-butyl 3[4-amino-3-iodo-1H-pyrazolo[3, 4-d]pyrimidin-1-yl]piperidine-1-carboxylate (1 g, 2.2.5 mmol, 1.00 equiv), (4-phenoxyphenyl)boronic acid (530 mg, 2.48 mmol, 1.10 equiv), sodium carbonate (480 mg, 4.53 mmol, 2.01 equiv) and tetrakis(triphenyiphosphine)palladium (78 mg, 0.07 mmol, 0.03 equiv) in 1, 4-dioxane (60 mL) and water (15 mL) was stirred under nitrogen at 90°C for 24 h. The reaction mixture was cooled to room temperature and then concentrated under vacuum. The residue was dissolved in 500 mL of dichloromethane. The resulting solution was washed with 200 mL of water, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with dichloromethauefmethanol (100/1) to give 700 mg (64percent) of (R)ert-butyl 1H-pyrazolo[3, 4-d]pyrimidin-1-yi]piperidine-1-carboxylate as a yellow solid.Step 4. A mixture of tert-butyl 3-[4-amino-3-iodo-1H-pyrazolo[3, 4-d]pyrimidin-1-yl]piperidine-1-carboxylate (1 g, 2.25 mmol, 1.00 equiv), (4-phenoxyphenyl)boronic acid (530 mg, 2.48 mmol, 1.10 equiv), sodium carbonate (480 mg, 4.53 mmol, 2.01 equiv) and tetrakis(triphenylphosphine)palladium (78 mg, 0.07 mmol, 0.03 equiv) in 1, 4-dioxane (60 mL) and water (15 mL) was stirred under nitrogen at 90°C for 24 h. The reaction mixture was cooled to room temperature and then concentrated under vacuum. The residue was dissolved in 500 mL of dichloromethane. The resulting solution was washed with 200 mL of water, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with dichloromethane/methanol (100/1) to give 700 mg (64percent) of tert-butyl 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3, 4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a yellow solid.Step 4 (R) -1-Boc-3- (4-amino-3-iodo-1H-pyrazolo [3, 4-D] pyrimidin-1-yl) piperidine (12.8G, 29 mmol), 4-phenoxyphenylboronic acid (6.8 g, 32 mmol), PdCl2 (dppf) (0.5 g, 0.69 mmol), Sodium carbonate (6.1 g, 58 mmol), 1, 4-dioxane (160 ml) and water (40 ml) were added and the mixture was heated to 80 ° C overnight.After confirming the completion of the reaction, Filter, spin dry, Add water, extract with ethyl acetate, dry, The product was purified by column chromatography (8.5 g, yield 60percent).600g of (S) -t-butyloxycarbonyl-3-hydroxypiperidine, 780g of triphenylphosphine and 3L of ethyl acetate was added to the reaction flask and stirred to be clear, After clearing, 300 g of 4-amino-3- (4-phenoxyphenyl) -1H-pyrido (3, 4-d)Continue stirring 10 ~ 30min, Dark, temperature control at 10 ~ 15 ° C began to drop under the conditions of diisopropyl azodicarboxylate, After the addition was completed, the temperature was raised to 25 ~ 30 ° C, the reaction was stirred 3 ~ 4h; stop the reaction, cooled to 0 ° C, Start dropping lllOmL concentrated HC1, after the addition was completed, warmed to room temperature, the reaction was stirred 3 ~ 4h; stop the reaction, Add 3L of purified water and stir, then respectively add 1.8L chloroform extraction 5 times and 1.8L ethyl acetate extraction 2 times, After extraction, add 1.2L of ethyl acetate, cooled to 0 ° C, began dropping 25percent NaOH solution, Adjust the pH value to 8 ~ 9, precipitated a large amount of solid, stirring crystallization, crystallization end, centrifugal rejection rejection, The filter cake was washed with a small amount of ethyl acetate, the resulting filter cake 55 ~ 60 ° C under vacuum, Vacuum -0.080MPa ~-0 lOOMPa, Intermediate I336.3g, yield 88.1percent.Under nitrogen protection, Ph3P (29.0 g, 112 mmol, 1.25 eq), (3S)-hydroxy-1-tert-butoxycarbonylpiperidine (18.0 g, 89.3 mmol, 1.0 eq) dissolved in tetrahydrofuran 150ml, cooled to 0 °C , the control temperature does not exceed 5 °C , in 20-30 min by adding DIAD (25.1g, 125mmol, 1.4eq) in tetrahydrofuran (40ml) solution, add, the yellow solution to continue stirring 10min.And then added at 0~5 °C 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3, 4-d]pyrimidine (28.1 g, 93.9 mmol, 1.05 eq)In tetrahydrofuran (150 ml) was added and the mixture was stirred at room temperature for 5h. Add water 3.2ml, warm to 50-60 °C 30min, Then, magnesium chloride (27.0 g, 280 mmol, 2.5 eq) was added, stirred at reflux for 2.5 h, Cooled to 0 ° C, filtered, washed with tetrahydrofuran (50 ml x 2), removed by rotary evaporation to remove the solvent, The residual oily substance was beaten with ethyl acetate (300 ml), n-hexane (50 ml) was added, filtered, and the residue was washed with ethyl acetate (30 ml x 2). The filtrate was washed with water (100 ml x 2), saturated brine (150 ml) Washed with anhydrous sodium sulfate, the filtrate was removed by rotary evaporation solvent, the residue Ph3PO content: 5.6wtpercent, and then adding isopropyl alcohol (40ml) in the residue to 50-60 ° C stirring, cooling crystallization, Filtration of a small amount of cold isopropanol and drying in vacuo gave 28.1 g of product (yield 72percent by weight, pale yellow solid), Ph3PO content: 0.8 wtpercent.To a solution of 1-boc-3-(S)-hydroxypiperidine (3.98 g, 19.8 mmol) and triphenylphosphine (5.19 g, 19.8 mmol) in THF (150 ml) was added DIAD (3.9 ml, 19.8 mmol). The yellow solution was stirred 1 minute then Intermediate 2 (4.0 g, 13.2 mmol) was added and the reaction was heated with a heat gun (3-5 minutes) until the solid had dissolved. After stirring for 1 hour at room temperature, the solvent was removed and the resulting brown oil was subjected to flash chromatography (30percent then 50percent THF/hexanes) to provide 4.45 g (69percent) of Intermediate 3 (trace of triphenylphosphine oxide is present) as a light brown foam.Example 1. Synthesis of (i?)-l-(Diisopropyl diazodicarboxylate (DAID, 1.2 ml) was added to a solution of 1-tert-butyloxycarbonyl-3-(S)-hydroxypiperidine ( 1.0 g, ) and triphenylphosphine (2.59g) in tetrahydrofuran (50.0ml). To the resulting yellow solution, 3-(p-phenoxyphenyl)-1, 2, 5, 7-tetraza-1H-inden-4-ylamine (1.0g). was added and warmed till dissolution, and stirred overnight at room temperature. The reaction mixture was filtered and the solvent was distilled under vacuum to get an oily residue, which was further purified by flash chromatography (30-50 percent ethyl acetate/ hexane) on silicagel to give 0.3 g (0.3 w/w) of tert-butyloxycarbonyl-(1S)-1-[(3R)-3-piperidyl]-3-(p-phenoxyphenyl)-1, 2, 5, 7-tetraza-1H-inden-4-ylamine as a light brown solid. The resulting solid was dissolved in dichloromethane (5 ml) and trifluoroacetic acid (0.6 ml) was added to it. After completion of reaction, water was added to reaction mass, followed by addition of methyl tert-butyl ether (20.0 ml). The layers were separated and the aqueous layer was basified with potassium carbonate and extracted with dichloromethane (15.0 ml x 2). The organic layer dried over sodium sulfate, filtered and evaporated to yield 0.2 g (0.6 w/w) of title compound as light yellow oil.Intermediate 1 (5g) was dissolved in dry DMF (50 mL) and potassium carbonate (8.8 g) was added. The suspension was stirred at ambient temperature for 2 h. After dropwise addition of Intermediate 2 (9 g) dissolved in DMF (10 mL) the reaction mixture was heated at 80°C for 14 h. The organic layer was separated and the water layer extracted with EtOAc (3x20 mL). The organic layers were combined and dried over Na3-(4-phenoxyphenyl) lH-pyrazolo [3, 4-d] pyrimidin-4-amine (1.14g, 3.76mmol)was dissolved DMF (30mL) in, and then the reaction solution was added (S)-tert-butyl 3-((methylsulfonyl) oxy) piperidine-1-carboxylate (4.2g, 15.04mmol), cesium carbonate(0.64mL, 8.21 mmol), 4- dimethylaminopyridine pyridine (3.67g, 11.28mmol). Was stirredat 90 deg.] C 8h, the reaction was completed, distilled under reduced pressure of DMF, and extracted with dichloromethane (150mL × 3), brine (60mL), dried over anhydroussodium sulfate, the solvent was distilled off under reduced pressure, the crude productwas silica gel column Analysis of separation and purification (methylene chloride /methanol (V / V) = 40/1), to give the product (1.28g, 70percent).Compound 2g (6.6mmol) of Formula 8 and 1.4g (6.6mmol) t-butyl -3S- chloro - piperidine-1-AEster, 4.6g of cesium carbonate was dissolved 30mlDMF, heated to 100 , for 12 hours. The reaction mixture was pouredInto 150ml water and extracted with ethyl acetate, the organic phase was dried and concentrated to give a pale yellow solid 2.63g, Yield 82percent.A mixture of compound (III) (Pgi = Boc, Pg2 = H) (636 mg, 2.00 mmol), Pd(OAc)2 (44 mg, 0.20 mmol), 1, 10-phenanthroline (36 mg, 0.20 mmol), K2C03 (304 mg, 2.20 mmol), 1-bromo-4-phenoxybenzene (548 mg, 2.20 mmol) and N, N-dimethylacetamide (DMA) (10 ml)was heated in a sealed tube under argon atmosphere at 150°C for 16 h with intensive stirring.The product (III) was isolated and purified similarly to that described in the Example 1. Yield642 mg (66percent), viscous yellowish oil. The analytical data of the obtained compound (III)correspond to that of the product obtained in the Example 1.4-Bromodiphenyl ether (X = Br) (3.74 g, 15 mmol) was dissolved in 1, 4-dioxane (50 ml)Addition of pinacol diboronate(4.52 g, 18 mmol), Potassium acetate (1.78 g, 18 mmol).Then, the catalyst [1, 1'-bis (diphenylPhosphine) ferrocene] palladium dichloride [Pd (dppf) 2Cl2] (1.5 mmol, 1.11 g).With stirring, heated to 100 ° C, the reaction 5h (TLCDetection of raw materials disappear).Then, Intermediate (14) (4.44 g, 10 mmol) was added, and the reaction was maintained at 100 ° C for 22 hours14 disappears).Then, after distilling off the organic solvent, Intermediate (9) (yellow solid, 3.41 g, yield 70percent, chemical purity and optical purity> = 99percent) was obtained.A mixture of 3 -(4-phenoxyphenyl)- 1 H-pyra.zolo [3 , 4-d]pyrimidin-4-amine compoundof formula-9 (60 gms), NMP (480 ml), (S)-tert-butyl-3-(tosyloxy)piperidine- 1 -carboxylatecompound of formula-ha (86 gms) and cesium carbonate (161 gms) was heated to 70-75°C under nitrogen atmosphere and stirred for 12 hrs. Cooled the reaction mixture to 25-30°C. Ethyl acetate was added to the reaction mixture at 25-30°C. Filtered the reaction mixture and washed with ethyl acetate. Water was added to the filtrate at 25-30°C and stirred for 15 mins.Both the organic and aqueous layers were separated. The organic layer was washed with water. Distilled off the solvent from the organic layer completely under reduced pressure to get the title compound. Yield: 77 gms.3-(4-Phenoxyphenyl)-1H-[3, 4-d]pyrazolopyrimidine-4-amine (185 mg, 0.61 mmol), (S)-1-tert-butoxycarbonyl-3-hydroxypiperidine (246 mg, 1.22 mmol) andTriphenylphosphine (640 mg, 2.44 mmol) dissolved in dry tetrahydrofuran, Diisopropyl azodicarboxylate (0.6 mL, 3.05 mmol) was added dropwise, Heat to 40C for 12 hours.After the end of the reaction, the tetrahydrofuran was removed, After column purification3-[4-Amino-3-(4-phenoxyphenyl)-1-[3, 4-d]Tert-butyl pyrazolopyrimimidinylpiperidinecarboxylateDissolved in dichloromethane (6 mL), Add trifluoroacetic acid (6 mL), The reaction was performed at room temperature for 12 hours.HPLC monitored the progress of the reaction.After the reaction is complete, remove trifluoroacetic acid and add water and methanol.The HPLC preparative column was separated and freeze-dried to give 111 mg of trifluoroacetate salt of the target compound in a yield of 38%.HPLC purification conditions: starting acetonitrile ratio 25%, retention time t 1/2 = 10 minutes.4-Bromodiphenyl ether (X = Br) (3.74 g, 15 mmol) was dissolved in 1, 4-dioxane (50 ml)Addition of pinacol diboronate(4.52 g, 18 mmol), Potassium acetate (1.78 g, 18 mmol).Then, the catalyst [1, 1'-bis (diphenylPhosphine) ferrocene] palladium dichloride [Pd (dppf) 2Cl2] (1.5 mmol, 1.11 g).With stirring, heated to 100 C, the reaction 5h (TLCDetection of raw materials disappear).Then, Intermediate (14) (4.44 g, 10 mmol) was added, and the reaction was maintained at 100 C for 22 hours14 disappears).Then, after distilling off the organic solvent, Intermediate (9) (yellow solid, 3.41 g, yield 70%, chemical purity and optical purity> = 99%) was obtained.200g intermediate I and 800mL ethyl acetate was added to the reaction flask, stirring, Then add 216mL triethylamine stirring to dissolve, stirring 20 ~ 30min, At room temperature, 1044.3 mL of a THF solution containing 44.3 mL of acryloyl chloride was added dropwise, Control 1 ~ 1.5h, the addition is complete, the temperature was controlled at 25 ~ 30 C, After the addition is completed, the temperature control reaction between the range of 25 ~ 30 C 1.5 ~ 2h, After the reaction, add 120mL5% diluted hydrochloric acid wash, Control rhoEta = 5 ~ 6, respectively, and then sodium bicarbonate and 120mL saturated brine twice, dried over anhydrous sodium sulfate, concentrated under reduced pressure, 212.7 g of solid was obtained in a yield of 93.4% and a purity of 99.5%.

Molecular Weight:486.6
XLogP3:4.4
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:7
Rotatable Bond Count:6
Exact Mass:486.23793884
Monoisotopic Mass:486.23793884
Topological Polar Surface Area:108
Heavy Atom Count:36
Complexity:734
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes