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CAS No. : | 1276110-38-3 | MDL No. : | MFCD27987084 |
Formula : | C15H21IN6O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | YQXAEBHPCJZKKX-SECBINFHSA-N |
M.W : | 444.27 | Pubchem ID : | 58441419 |
Synonyms : |
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Signal Word: | Warning | Class: | |
Precautionary Statements: | P261-P280-P301+P312-P302+P352-P305+P351+P338 | UN#: | |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With sodium carbonate In 1,4-dioxane; water at 90℃; for 24 h; Inert atmosphere | 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. |
64% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water at 90℃; for 24 h; Inert atmosphere | 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. |
64% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water at 90℃; for 24 h; Inert atmosphere | 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. |
64% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water at 90℃; for 24 h; Inert atmosphere | 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. |
60% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In 1,4-dioxane; water at 80℃; Inert atmosphere | (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). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: With palladium dichloro <1,1'-bis(diphenylphosphino)ferrocene>; potassium acetate In 1,4-dioxane at 100℃; for 5 h; Stage #2: at 100℃; for 22 h; |
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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With caesium carbonate; In N,N-dimethyl-formamide; at 80℃;Inert atmosphere; | The 3-iodo--1H- pyrazolo [3,4-d] pyrimidin-4-ylamine (4.3g, 16.57mM, 1.0equiv) was dissolved in N, N- dimethylformamide (60mL),And cesium carbonate were sequentially added (6.753g, 35mM, 2.1equiv), (S) -3- (methanesulfonyloxy) piperidine-l-carboxylate (5.549g,19.88mM, 1.2equiv), and heated at 80 in nitrogen, after completion of the reaction by TLC, concentrated under reduced pressure most of the N, N- dimethylFormamide, was added water (60mL), and extracted with ethyl acetate (3 × 30), and the combined organic layers were washed with water, normal saline. The organic layer wasDried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (petroleum ether: ethyl acetate = 2: 1) to give a white solid after treatment Compound 4 (5.8g,79percent). |
30% | With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;Inert atmosphere; | Step 28a: (R)-tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (Intermediate 28a) To a stirred solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (500 mg, 1.9 mmol) in DMF (10 mL) was added cesium carbonate (1.56 g, 4.7 mmol) followed by (S)-tert-butyl 3-(methylsulfonyloxy)piperidine-1-carboxylate (535 mg, 1.9 mmol) at room temperature under N2 atmosphere. The reaction mixture was heated to 80° C. and stirred further for 16 h at that temperature. After the completion of reaction (monitored by TLC), solvent was removed under reduced pressure, water was added and extracted with ethyl acetate (2.x.25 mL). The organic layer was separated, dried over Na2SO4 and solvent was removed under reduced pressure. The crude compound was purified by silica gel column chromatography [Methanol/DCM: 2/98] to afford Intermediate 28a (240 mg, 30percent) as brown solid. TLC: 5percent MeOH/DCM:ethylactate (1:1) (Rf: 0.3). 1H-NMR (CDCl3, 200 MHz): delta 8.38 (s, 1H), 6.02 (bs, 2H), 4.82-4.64 (1H), 4.31-4.02 (m, 2H), 3.44-3.20 (m, 1H), 2.95-2.65 (m, 1H), 2.25-2.08 (m, 2H), 1.95-1.58 (m, 2H), 1.42 (s, 9H). MS: m/z=445 (M++1). Chiral HPLC purity (SAV-MA8002-56): 98.19percent at 9.73 RT (0.1percent TFA in hexane: ethanol/70:30, flow rate: 1 mL/min, Chiralpak, ADH, 250.x.4.6 mm, 5 um [SHCL061002]. |
10% | With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;Inert atmosphere; | To a suspension of fe/ -butyl (3S)-3-methylsulfonyloxypiperidine-1 -carboxylate (13.88 g, 49.7 mmol) and 3-iodo-1 H-pyrazolo[3,4-d]pyrimidin-4-amine (1 1 .47 g, 43.9 mmol) in DMF (240 mL) was added cesium carbonate (36.22 g, 1 1 1 .2 mmol) under a nitrogen atmosphere. The reaction was then heated to 80 °C for 16 h, cooled and concentrated to dryness. The residue was taken up in ethyl acetate (200 ml_), the mixture was sonicated before being filtered giving a dark orange filtrate. The filtrate was washed with water (2 chi 150 ml_), brine (2 chi 150 ml_), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a dark orange film. Further purification by flash column chromatography (DCM/EtOAc 1 :1) afforded the crude product as a light yellow powder. Trituration with methanol gave fe/ -butyl (3R)-3-(4-amino-3-iodo^yrazolo[3,4-c ]pyrimidin-1 -yl)piperidine-1 -carboxylate (2.12 g, 4.77 mmol, 10percent yield) as an off white solid. UPLC-MS (ES+, Short acidic): 1 .60 min, m/z 445.2 [M+H]+ H-NMR (400 MHz, DMSO-c/6): delta (ppm) 8.22 (s, 1 H, ArH), 4.66-4.53 (m, 1 H, CH), 4.15-3.65 (m, 2H), 3.55-3.36 (m, 0.5H), 3.21 -3.08 (m, 0.5H), 3.05-2.92 (m, 1 H), 2.20-2.08 (m, 1 H), 2.07-1 .99 (m, 1 H), 1 .96-1 .80 (m, 1 H), 1 .60-1 .47 (m, 1 H), 1 .45-1 .24 (m, 9H) |
26.9 g | With potassium carbonate; In N,N-dimethyl acetamide; at 100℃; for 10h; | A suspension solution of 14.6 g of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine synthesized by the method described in WO 2007/126841, 25 g of (S)-tert-butyl 3-(methylsulfonyloxy)piperidine-1-carboxylate obtained in Step 1, and 69 g of potassium carbonate in 150 ml of DMA was heated to 100°C, and was stirred for 10 hours. The suspension solution was cooled to room temperature, and then 300 ml of water was added thereto. A solid thus obtained was collected by filtration and washed with water, and the solid was dried. Thus, 26.9 g of the title compound was obtained as a yellow solid. Physical property value: m/z [M+H]+ 446.2 |
13.8 g | A mixture of 3-iodo-1H-pyrazolo[3,4-djpyrimidin-4-amine (Formula III, when X is iodo, 18 g), cesium carbonate (51.8 g), and dimethylaminopyridine (0.88 g) was addedto N-methylpyrrolidinone (400 mL) under nitrogen at room temperature. The temperature of the reaction mixture was raised to 70°C. A solution of tert-butyl (3S)-3- [(methylsulfonyl)oxyjpiperidine-1-carboxylate (Formula IV, when Pr? is Boc and Pr2 is methylsulfonyl, 29 g) in N-methylpyrrolidone (150 mL) was added drop-wise to thesolution over a period of one hour at 70°C. The reaction mixture was stirred overnight at70°C. Water (1.7 L) was added to the reaction mixture, then the mixture was stirred at5°C for 3 hours, and then stirred overnight at room temperature. The yellowish solidproduct was filtered, then washed with water (100 mL). The resulting solid was dried at45°C under vacuum for 9 hours to obtain the title compound.Yield: 13.8g | |
13.8 g | With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 70℃;Inert atmosphere; | Example 4: Preparation oftert-butyl (3R)-3-(4-amino-3-iodo-lH-pyrazolor3.4- dlpyrimidin-l-vDpiperidine-l-carboxylate (Formula V. when X is iodine and Pr1 is Boc) A mixture of 3-iodo-lH-pyrazolo[3,4-d]pyrimidin-4-amine (Formula III, when X is iodine, Example 1, 18 g), cesium carbonate (51.8 g), and dimethylaminopyridine (0.88 g) was added to N-methylpyrrolidone (400 mL) under nitrogen at room temperature. The temperature of the reaction mixture was raised to 70°C. A solution of tert-butyl (3S)-3- [(methylsulfonyl)oxy]piperidine-l-carboxylate (Formula IV, when Pr1 is Boc and Pr2 is mesyl, Example 3, 29 g) in N-methylpyrrolidone (150 mL) was added drop-wise over a period of 1 hour at 70°C. The reaction mixture was stirred overnight at 70°C. Water (1.7 L) was added to the reaction mixture, then the mixture was stirred at 5°C for 3 hours, and then stirred overnight at room temperature. The yellowish solid product was filtered, then washed with water (100 mL). The resulting solid was dried at 45 °C under vacuum for 9 hours to obtain the title compound. Yield: 13.8 g |
With di-isopropyl azodicarboxylate; triethylphosphine; In tetrahydrofuran; at 5 - 200℃; for 12.5h; | A solution of diisopropyl azodicarboxylate in tetrahydrofuran (30 mL) was added drop wise tostined solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidine-4-amine (Formula III, 5.9 g), (S)-tertbutyl-3-hydroxypiperidine-1-carboxylate (Formula IV, L=H; 10 g), triethylphosphine (11.8 g), and tetrahydrofuran (300 mL) at 5-10 °C over 30 mm. The resulting mixture was stined at room temperature for 12 h and then concentrated under vacuum. The residue was purified on silica gel column then eluted with dichloromethane and methanol (10:1) to give (R)-tert-butyl-3-(4-amino- 3 -iodo- 1 H-pyrazolo[3 ,4-d]pyrimidine- 1 -yl)piperidine- 1 -carboxylate | |
26.9 g | With potassium carbonate; In N,N-dimethyl acetamide; at 100℃; for 10h; | (Step 2) Synthesis of (R)-tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (0188) A suspension solution of 14.6 g of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine synthesized by the method described in WO 2007/126841, 25 g of (S)-tert-butyl 3-(methylsulfonyloxy)piperidine-1-carboxylate obtained in Step 1, and 69 g of potassium carbonate in 150 mL of DMA was heated to 100° C., and was stirred for 10 hours. The suspension solution was cooled to room temperature, and then 300 mL of water was added thereto. A solid thus obtained was collected by filtration and washed with water, and the solid was dried. Thus, 26.9 g of the title compound was obtained as a yellow solid. |
26.9 g | With potassium carbonate; In N,N-dimethyl acetamide; at 100℃; for 10h; | (Step 2) Synthesis of (R)-tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl) piperidine-1-carboxylate 3-Iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (14.6 g) synthesized by the method described in the pamphlet of International Publication No. WO 2007/126841, (S)-tert-butyl 3-(methylsulfonyloxy) piperidine-1-carboxylate (25 g) obtained in (Step 1), and potassium carbonate (69 g) were suspended in DMA (150 mL), and the suspension was heated to 100° C. and stirred for 10 hours. After the mixture was cooled to room temperature, water (300 mL) was added thereto, and the precipitated solid was collected by filtration, washed with water, and then dried to obtain 26.9 g of the title compound as a yellow solid. Physical property value: m/z [M+H]+ 446.2 |
26.9 g | With potassium carbonate; In N,N-dimethyl acetamide; at 100℃; for 10h; | A suspension solution of 14.6 g of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine synthesized by the method described in WO 2007/126841, 25 g of (S)-tert-butyl 3-(methylsulfonyloxy)piperidine-1-carboxylate obtained in Step 1, and 69 g of potassium carbonate in 150 mL of DMA was heated to 100° C., and was stirred for 10 hours. The suspension solution was cooled to room temperature, and then 300 mL of water was added thereto. A solid thus obtained was collected by filtration and washed with water, and the solid was dried. Thus, 26.9 g of the title compound was obtained as a yellow solid. Physical property value: m/z [M+H]+ 446.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38.7% | With water; sodium carbonate In tetrahydrofuran for 6h; Inert atmosphere; Reflux; | 28.28b Step 28b: (R)-tert-butyl 3-(4-amino-3-(5-methoxy-1H-indol-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (Intermediate 28b) To a stirred solution of Intermediate 28a (100 mg, 0.33 mmol) in THF/H2O (8 mL) was added 1-(tert-butoxycarbonyl)-5-methoxy-1H-indol-2-ylboronic acid (150 mg, 515 mmol), aqueous Na2CO3 (106 mg) (dissolved in minimum water) solution and Pd(TPP)4 (10 mg). The reaction mixture was purged with argon for 1 h and further refluxed for 6 h. Progress of the reaction was monitored by TLC. The reaction mass was filtered through a pad of celite and concentrated the filtrate under vacuum. The crude compound was purified by column chromatography using 50% EtOAc/hexane to afford compound 3 (60 mg, 38.7%) as orange solid. TLC: 5% MeOH in EtOAc/DCM (1:1) (Rf: 0.5). 1H-NMR (CDCl3, 500 MHz): δ 8.83 (s, 1H), 8.38 (s, 1H), 7.34 (d, J=8.4 Hz, 2H), 7.08 (s, 1H), 6.94 (d, J=8 Hz, 1H), 6.82 (s, 1H), 5.91 (s, 2H), 4.97-4.91 (m, 1H), 4.32 (bs, 2H), 3.82 (s, 3H), 2.95 (bs, 2H), 2.62 (s, 1H), 2.5 (bs, 1H), 2.32-2.2 (m, 3H), 2.01 (d, 2H), 1.47 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 16h; | |
80% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; | 1.a Synthesis of (R) -1-Boc-3- (4-amino-3-iodo-1H-pyrazolo [3,4-D] pyrimidin-1-yl) piperidine A solution of 4-amino-3-iodo-lH-pyrazolo [3,4-D] pyrimidine (10 g, 38 mmol)(S) -1-Boc-3-hydroxypiperidine (17 g, 85 mmol)Triphenylphosphine (20 g, 76 mmol) was added to a three-necked flask,THF (120 ml) was added,Cooling to 0 ,Diisopropyl azodicarboxylate (DIAD) (15.2 g, 76 mmol)And tetrahydrofuran (THF) (30 ml). After about 1 h, the reaction mixture was added dropwise and slowly rose to room temperature overnight.The reaction solution was spin-dried,Ethyl acetate extraction, drying,The product was purified by column chromatography after concentration(R) -1-Boc-3- (4-amino-3-iodo-1H-pyrazolo [3,4-D] pyrimidin-1-yl) piperidine (13.5 g, yield 80%). |
75% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 20h; | 2 Example 2 Synthesis of intermediate (14) Intermediate (13) (10 g, 0.038 mol), piperidinol (8) (17 g, 0.085 mol), triphenylphosphine (20 g,0.076 mol) was added to a 250 ml three-necked flask, THF (150 mL) was added, the temperature was lowered to 0 ° C, and a mixed solution of DIAD (15.2 g, 0.076 mol) and THF (50 mL) was added dropwise.After the addition was completed, the mixture was slowly warmed to room temperature and stirred for 20 h (TLC confirmed the disappearance of the starting material).After the completion of the reaction, the reaction mixture was evaporated to dryness, stirred and added with MTBE (100 mL), cooled to 0 ° C., and kept stirring for 2 h after a large amount of solid was precipitated. The mixture was filtered and dried to obtain Intermediate (14) (12.6 g, 75%). |
70% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran for 12h; Inert atmosphere; | 1 Example 1 Preparation of Intermediate la Procedure: 3-Iodo-4-amino-1H-pyrazolo[3,4-d]pyrimidine (6.45 g, 24.7 mmol), (S)-1-Boc-3-hydroxypiperidine (9.93 g, 49.4) (3)mmol, triphenylphosphine PPh3 (9.73 g, 37.1 mmol) was placed in a 250 mL round-bottomed flask, magnets were added, 130mL THF was added, and stirred under nitrogen atmosphere at room temperature; diisopropyl azodicarboxylate was taken. DIAD(7.5 g, 37.1 mmol) was dissolved in about 30 mL of THF and slowly added dropwise to the reaction system. After completion ofthe dropwise addition, the reaction was continued for about 12 hours. According to the results of TLC (thin-layerchromatography), the reaction was stopped and concentrated under reduced pressure. Silica gel column chromatography usingpetroleum ether-ethyl acetate as eluent to give a white solid 1a, yield 70%, |
70% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 10 - 20℃; for 12h; Large scale; | 1.I Part I: Preparation of Compound 1b Operation steps: Compound 1a (1.29 kg, 4.94 mol), (S) -1-Boc-3-hydroxypiperidine (1.99 kg, 9.88 mol) triphenyl phosphorus PPh3(2.59 kg, 9.88 mol) are added separately 12.9L THF glass reactor, stir and cool to 10 ° C; take diisopropyl azodicarboxylate DIAD (2.0kg, 9.88mol) and dissolve in about 500mL THF, slowly add to the reaction system, and control the reaction system The temperature does not exceed 20 degrees; the reaction is continued for about 12 hours after the dropwise addition is completed, the reaction is detected to be complete, and the reaction is stopped.The reaction solution was first filtered through celite and the filtrate was concentrated under reduced pressure to remove THF; 10.3L to the concentrate was added acetonitrile was stirred beating filtration, the filter cake was dried to give a white solid was then collected by suction filtration Ends 1b, yield 70%, |
69% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 16h; | |
58% | Stage #1: 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine; (S)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester With triphenylphosphine In tetrahydrofuran at 0℃; for 0.166667h; Stage #2: With di-isopropyl azodicarboxylate In tetrahydrofuran at 20℃; for 20h; | |
51% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 12h; | |
51.3% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0℃; | 1.B Step B: Synthesis of Compound 4 Compound 2 (15 g, 57.47 mmol),(S)-1-tert-butoxycarbonyl-3-hydroxypiperidine (23.2 g, 114.9 mmol),Triphenylphosphine (30.1 g, 114.9 mmol) and 150 ml of THF were cooled to 0 ° C in an ice salt bath.Add DIAD (23.2g, 114.9mmol),Raise to room temperature and stir overnight.Column chromatography gave a solid 13.1 g.Yield: 51.3%. |
42% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 18h; Inert atmosphere; | |
41.2% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20 - 70℃; for 72h; | 32.2 Step 2To a solution of 3-iodo-lH-pyrazolo[3,4~d]pyrimidin-4-ylamine (4.0 g, 15.32 mmol,1.0 eq), (S)-3-h ydroxypiperidine- 1 -carboxylic acid tert-butyl ester (4.313 g, 21.44 mmol, 1.4 eq), and PPh, (8.031 g, 30.64 mmol, 2.0 eq) in dry THF (200 mL), DIAD (4.658 g, 22.98 mmol, 1.5 eq) was added at room temperature. The reaction mixture was stirred at 70° C for 72 h. The reaction mixture was concentrated and purified by silica gel chromatography (eiuted with PE: EtOAc =1 : 3 ) to afford ( )-tert-butyl 3-(4-ammo-3-iodo- ] H-pyrazolo[3,4- d]pyrimidin-l -yl)piperidine- l-carboxylate (2.8 g, 41.2% in yield). |
41.2% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 70℃; for 72h; | 22.2 To a solution of 3-iodo-4H-pyrazolo[3,4.d]pyrimidin-4-ylamine (4.0 g, 15.32 mmol, 1.0 eq), (S)-3-hydroxypiperidine-1-carhoxylic acid tert-butyl ester (4.313 g, 21.44 mmol, 1 .4 eq), and PPh3 (8,031 g, 30.64 mmol, 2.0 eq) in dry THF (200 mE), DIAD (4.658 g, 22.98 mmol, 1.5 eq) was added at room temperature. The reaction mixture was stirred at 70° C for 72 h. The reaction mixture was concentrated and purified by silica gel chromatography (doted with PU: EtOAc =1:1) to afford (R)-tert-butyl 3-(4-amino-3-iodo-4H-pyrazolo[3,4-d]pyrimidin-4-ylpiperidine-1-carboxylate (2.8 g, 41.2% in yield). |
41.2% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 70℃; for 72h; | 1.3; 9.1; 32.2 Step 2. To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (4.0 g, 15.32 mmol,1.0 eq), (S)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (4.313 g, 21.44 mmol, 1.4eq), and PPh3 (8.03 1 g, 30.64 mmol, 2.0 eq) in dry THF (200 mL), DIAD (4.658 g, 22.98 mmol, 1.5 eq) was added at room temperature. The reaction mixture was stirred at 70° C for 72 h. The reaction mixture was concentrated and purified by silica gel chromatography (eluted with PE: EtOAc =1:1) to afford (R)-tert-butyl 3-(4amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (2.8 g, 41.2% in yield). |
41.2% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20 - 70℃; for 72h; | 32.2 Step 2 To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (4.0 g, 15.32 mmol, 1.0 eq), (S)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (4.313 g, 21.44 mmol, 1.4 eq), and PPh3 (8.031 g, 30.64 mmol, 2.0 eq) in dry THF (200 mL), DIAD (4.658 g, 22.98 mmol, 1.5 eq) was added at room temperature. The reaction mixture was stirred at 70° C. for 72 h. The reaction mixture was concentrated and purified by silica gel chromatography (eluted with PE: EtOAc=1:1) to afford (R)-tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (2.8 g, 41.2% in yield). |
33% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 10 - 20℃; for 12.5h; | A.3; F.1 Step 3To a stirred mixture of 3-iodo- 1 H-pyrazolo[3,4-d]pyrimidin-4-amine (5.9g, 22.6 mmol, 1.00 equiv), (S)-tert-butyl 3-hydroxypiperidine-l-carboxylate (lOg, 50 mmol, 2.2 equiv) and triphenylphosphine (1 1.8g, 45 mmol, 2.0 equiv) in tetrahydrofuran (300 mL) at 10 °C was added a solution of diisopropyl azodicarboxylate in tetrahydrofuran (30 mL) dropwise in 30 min. The resulting mixture was stirred at room temperature for 12 h and then concentrated under vacuum. The residue was purified on a silica gel column eluted with dichloromethane/methanol (100/1) to give 3g (33%) of (R)-tert-butyl 3-(4-amino-3-iodo-lH- pyrazolo[3,4-d]pyrimidin-l-yl)piperidine-l -carboxylate as a yellow solid |
33% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 10 - 20℃; for 12.5h; | 1.3 To a stirred mixture of 3~iodo-lH-pyrazolo[3,4-d]pyriniidin-4-amine (5.9g, 22.6 mmol, 1.00 equiv), (S)-tert-butyl 3-hydroxypiperidine-l-carboxylate (lOg, 50 mmol, 2.2 equiv) and triphenylphosphine (1 L8g, 45 mmol, 2.0 equiv) in tetrahydrofuran (300 mL) at 10 °C was added a solution of diisopropyl azodicarboxylate in tetrahydrofuran (30 mL) dropwise in 30 min. The resulting mixture was stirred at room temperature for 12 h and then concentrated under vacuum. The residue was purified on a silica gel column eluted with dichloromethaiie/meihanol (100/1) to give 3g (33%) of (R)-tert-buiyl 3-(4-ammo-3~iodo~lH- pyrazolo[3,4-d]pyrimidin-l-yl)piperidine- 1-earboxylaie as a yellow solid. |
33% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 10 - 20℃; for 12.5h; | 19.3 Synthesis of (R)-2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile Step 3. To a stirred mixture of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (5.9 g, 22.6 mmol, 1.00 equiv), (S)-tert-butyl 3-hydroxypiperidine-1-carboxylate (10 g, 50 mmol, 2.2 equiv) and triphenylphosphine (11.8 g, 45 mmol, 2.0 equiv) in tetrahydrofuran (300 mL) at 10° C. was added a solution of diisopropyl azodicarboxylate in tetrahydrofuran (30 mL) dropwise in 30 min. The resulting mixture was stirred at room temperature for 12 h and then concentrated under vacuum. The residue was purified on a silica gel column eluted with dichloromethane/methanol (100/1) to give 3 g (33%) of (R)-tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate as yellow solid. |
30% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 10 - 20℃; for 12.5h; | |
24% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at -10 - 0℃; for 6h; Inert atmosphere; | 34.c c. Preparation of (R)-tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-dJ pyrimidin-1- yl)piperidine-1-carboxylate (Core-A) a. Preparation of tert-butyl (1,4-trans)-4-(4-amino-3-iodo-1H-pyrazolo[3,4-dJ pyrimidin-1- yl)cyclohexylcarbam ate (53) [00501j To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (12 g, 46 mmol) and tert-butyl (ls,4s)-4-hydroxycyclohexylcarbamate (12.93 g, 60.1 mmol) was added triphenyiphosphine (7.53 g, 28.75 mmol) at room temperture followed by addition of DEAD (15.95 g, 69 mmol) dropwise at -5°C under N2 atmosphere. The reaction mixture was stirred and raised to room temperature automatically with further stirring for 6 hrs at RT. Partitioned with ethyl acetate and brine, the organic layer was extracted with EA twice. The combined organic layer was dried over MgSO4. After filtration, the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to give tert-Butyl (1 ,4-trans)- 4-(4-amino-3 -iodo- 1H-pyrazolo [3 ,4-d]pyrimidin- 1 -yl)cyclohexyl carbamate (53) (11 g, 52%) as a white solid. c. Preparation of (R)-tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-dJ pyrimidin-1- yl)piperidine-1-carboxylate (Core-A) [00546j (R)-tert-Butyl 3 -(4-amino-3-iodo- 1 H-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidine- 1- carboxylate (Core-A) (8 g, 24%) was obtained as a white solid from 3-iodo-1H-pyrazolo[3,4- d]pyrimidin-4-amine (20 g, 76.6 mmol) and (S)-tert-butyl 3-hydroxypiperidine-1-carboxylate (30.8 g, 153.3 mmol), following a similar procedure outlined in Example 19. LC-MS (ESI): m/z (M+1) 445.1. |
3 mg | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 10 - 20℃; for 12h; | 2 Reference 2 Synthesis of (R)-tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate To a stirred mixture of 3-iodo-lH-pyrazolo[3,4-d]pyrimidin-4-amine (5.9 g, 22.6 mmol, 1.00 equiv), (S)-tert-butyl 3-hydroxypiperidine-l -carboxylate (lOg, 50 mmol, 2.2 equiv) and triphenylphosphine (1 1.8g, 45 mmol, 2.0 equiv) in tetrahydrofuran (300 mL) at 10 °C was added a solution of diisopropyl azodicarboxylate in tetrahydrofuran (30 mL) dropwise in 30 min. The resulting mixture was stirred at room temperature for 12 h and then concentrated under vacuum. The residue was purified on a silica gel column eluted with dichloromethane/methanol (100/1) to give 3g of (R)-tert-butyl 3-(4-amino-3-iodo-lH- pyrazolo[3,4-d]pyrimidin-l-yl)piperidine-l-carboxylate as a yellow solid. |
With di-isopropyl azodicarboxylate In tetrahydrofuran at 0 - 60℃; for 2h; | Synthesis of intermediate 3-b Synthesis of intermediate 3-b: 3-a Scheme 3 To a solution of intermediate 1-c (2.0 g, 7.7 mmol), intermediate 3-a (3.1 g, 15.3 mmol) and triphenylphosphine polymer-bound (7.7 g, ~3 mmol/g triphenyl phosphine loading) in THF cooled to 0°C was added DIAD (4.5 ml, 23.0 mmol) dropwise. After the addition was completed, the reaction was heated for 2 hours at 60°C and then cooled to room temperature. The reaction was filtered a nd the filtrate was adsorbed on silica gel. Purification by silica gel chromatography provided intermediate 3-b as a white solid. | |
580 mg | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 40℃; for 12h; Inert atmosphere; | 9.1 Step one: Synthesis of (R)-3-(3-iodo-4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidinecarboxylic acid tert-butylEster (CDA-132) 3-Iodo-1H-[3,4-d]pyrazolopyrimidin-4-amine (B, 200 mg, 0.77 mmol)Soluble in dry tetrahydrofuran,Triphenylphosphine (603 mg, 2.30 mmol) was added,(S)-1-tert-Butoxycarbonyl-3-hydroxypiperidine (310 mg, 1.54 mmol).Diisopropyl azodicarboxylate (0.92 mL, 4.60 mmol) was added dropwise under nitrogen protection.After the addition was completed, it was stirred at 40°C for 12 hours.After the end of the reaction, the tetrahydrofuran was removed,Purification by column gave 580 mg of a mixture containing CDA-132. |
1.5 g | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; Inert atmosphere; | 1.4 Step 4: Synthesis of Compound i Compound triphenylphosphine (7g, 3.5eq) and THF (100mL) were mixed and to the mixure diisopropyl azodicarboxylate(DIAD) (5mL, 3.5eq) was added dropwise under the protection of nitrogen at 0 °C, followed by addition of(S)-1-(tert-butoxycarbonyl)-3-hydroxypiperidine (3 g, 2 eq), Compound h (1 g, 1 eq). The resultant was stirred at roomtemperature overnight, and then subjected to concentration and column chromatography, giving 1.5 g of solid. |
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 5 - 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 90℃; for 24h;Inert atmosphere; | 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 90C 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 (64%) 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. |
64% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃; for 24h;Inert atmosphere; | 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 90C 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 (64%) of (R)ert-butyl 1H-pyrazolo[3,4-d]pyrimidin-1-yi]piperidine-1-carboxylate as a yellow solid. |
64% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃; for 24h;Inert atmosphere; | 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 90C 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 (64%) of tert-butyl 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a yellow solid. |
64% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃; for 24h;Inert atmosphere; | 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 (64%) of tert-butyl 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a yellow solid. |
60% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 80℃;Inert atmosphere; | (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 60%). |
With palladium 10% on activated carbon; caesium carbonate; In water; toluene; at 95℃; for 48h;Inert atmosphere; | Example 6: Preparation of tert-butyl (3R)-3-r4-amino-3-(4-phenoxyphenyl)-lH- pyrazolor3.4-dlpyrimidin-l-vHpiperidine-l-carboxylate (Formula VII. wherein Pr1 is Boc) tert-Butyl (3R)-3 -(4-amino-3 -iodo- lH-pyrazolo [3 ,4-d]pyrimidin- 1 -yl)piperidine- 1 - carboxylate (Formula V, when X is iodine and Pr1 is Boc, Example 4, 12 g), cesium carbonate (21.9 g), and phenoxyphenylboronic acid (Formula VI, when R1 and R2 are hydrogen, 8.6 g) were added into a mixture of toluene (300 mL) and water (30 mL) under nitrogen. Palladium on carbon (2 g, 10% palladium, 50% wet) was added to the reaction mixture, and then the reaction mixture was stirred at 95 C for 24 hours. Palladium on carbon (2 g, 10% palladium, 50% wet) and phenoxyphenylboronic acid (2 g) were added to the reaction mixture, and then the reaction mixture was stirred for another 24 hours. The reaction mixture was then diluted with water (50 mL) and ethyl acetate (100 mL), and the organic layer was separated off and passed through a Hyflo. The organic layer was evaporated to obtain a dark brown viscous crude solid (22 g), which was used as such for the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With sodium carbonate In 1,2-dimethoxyethane; water at 80℃; for 12h; Inert atmosphere; | F.2 Step 2Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed (R)-tert-butyl 3-[4-amino-3-iodo- lH-pyrazolo[3,4- d]pyrimidin-l -yl]piperidine-l-carboxylate (2 g, 4,50 mmol, 1.00 equiv), 4-borono- benzenaminium chloride (0.934 g), Pd(PPh3)4 (0.312 g), ethylene glycol dimethyl ether (100 mL), sodium carbonate (1.194 g), arid water(20 mL). The resulting solution was stirred for 12 h at 80 °C in an oil bath. The resulting mixture was concentrated under vacuum and residue was loaded onto a silica gel column and eluied with dichloromethane/methanol (50:1) ο give 1.5 g (81 %) of (R)-tert-butyl 3-(4-amino-3-(4-aminophenyl)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)piperidine-l-carboxylate as a brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sodium carbonate In N,N-dimethyl-formamide at 90℃; for 15h; Inert atmosphere; | N.1 Step 1Into a 250 mL 3 -necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of tert-butyl (3R)~3-[4-amino-3-iodo- lH- pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l -carboxylate (500 mg, 1.13 mmol, 1.00 equiv) in l,4-dioxane/H20 (100/30 mL), 2-[4-(2,6-difluorophenoxy)phenyl]-4,4,5,5-tetramethyl- 1,3,2- dioxaborolane (420 mg, 1.26 mmol, 1.1 equiv), sodium carbonate (240 mg, 2.26 mmol, 2.0 equiv), and Pd(PPh3)4 (65 mg, 0.06 mmol, 0.05 equiv). The resulting solution was stirred for 15 h at 90 °C in an oil bath and then concentrated under vacuum. The residue was diluted with water and extracted with dichloromethane and the organic layers combined. The organics were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column and eiuted with dichloromethane/methanol (10/1) to give 500 mg (85%) of tert-butyl (3R)-3-[4-amino-3-[4-(2,6-difluorophenoxy)- phenyl]-lH-pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carboxylate as a white solid. |
85% | With sodium carbonate In 1,4-dioxane; water at 90℃; for 15h; Inert atmosphere; | 19.1 Step 1 Into a 250 n L 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of tert-butyi (3R)-3-[4-aHimo-3-iodo-IH~ pyrazolo[3,4-d]pyrimidin- i-yl jpiperidme- 1 -carboxylate (500 mg, 1.13 mmol, LOO equiv) in I ,4-dioxane/H20 (100/30 mL), 2-[4-(2,6-difluorophenoxy)phenyl]^4,5,5-tetraniethyl-1 ,3,2- dioxaborolane (420 mg, 1.26 mmol, 1.1 equiv), sodium carbonate (240 mg, 2.26 mmol, 2.0 equiv), and Pd(PPh3)4 (65 mg, 0.06 mmol, 0.05 equiv). The resulting solution was stirred for 15 h at 90 °C in an oil bath and then concentrated under vacuum. The residue was diluted with water and extracted with dichloromethane and the organic layers combined. The organics were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column and eluied with dichloromethane/methanol (10/1) to give 500 mg (85%) of tert-butyl (3R)-3-[4-amino-3-[4-(2,6-difluorophenoxy)~ phenyl]-lH-pyrazolo[3,4-d3pyrimidin-l-yl]piperidine-l -carboxylate as a white solid. |
85% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water at 90℃; for 15h; Inert atmosphere; | 13.1 Into a 250 mE 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of tert-butyl (3R)-3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carhoxylate (500mg, 1.13 mmol, 1.00 equiv) in I ,4-dioxane/H20 (100/30 mE), 2-[4-(2,6-difluorophenoxy)phenylj-4,4,5,5-tetramethyl-1 ,3,2- dioxaborolane (420 mg, 1.26 mmol, 1.1 equiv), sodium carbonate (240 mg, 2.26 mmol, 2.0 equiv), and Pd(PPh3)4 (65 mg, 0.06 mmol, 0.05 equiv). The resulting solution was stirred for 15 h at 90 °C in an oil bath and then concentrated under vacuum. The residue was diluted with water and extracted with dichloromethane and the organic layers combined. The organics were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (10/1) to give 500 mg (85%) of tert-butyl (3R)-3-[4-amino-3-[4-(2,6-difluorophenoxy)-phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a white solid. |
85% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water at 90℃; for 15h; Inert atmosphere; | 19.1 Step 1. Into a 250 mL 3-necked round-bottom flask purged and maintained under an inertatmosphere of nitrogen, was placed a solution of tert-butyl (3R)-3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (500 mg, 1.13 mmol, 1.00 equiv) in 1,4-dioxane/H2O (100/30 mL), 2-[4-(2,6-difluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (420 mg, 1.26 mmol, 1.1 equiv), sodium carbonate (240 mg, 2.26 mmol, 2.0 equiv), and Pd(PPh3)4 (65 mg, 0.06 mmol, 0.05 equiv). The resulting solution was stirredfor 15 h at 90 °C in an oil bath and then concentrated under vacuum. The residue was diluted with water and extracted with dichloromethane and the organic layers combined. The organics were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column and eluted with dichioromethane/methanol (10/1) to give 500 mg (85%) of tert-butyl (3R)-3-[4-amino-3-[4-(2,6-difluorophenoxy)-phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a white solid. |
85% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water at 90℃; for 15h; Inert atmosphere; | 19.1 Step 1 Into a 250 mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of tert-butyl (3R)-3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (500 mg, 1.13 mmol, 1.00 equiv) in 1,4-dioxane/H2O (100/30 mL), 2-[4-(2,6-difluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (420 mg, 1.26 mmol, 1.1 equiv), sodium carbonate (240 mg, 2.26 mmol, 2.0 equiv), and Pd(PPh3)4 (65 mg, 0.06 mmol, 0.05 equiv). The resulting solution was stirred for 15 h at 90° C. in an oil bath and then concentrated under vacuum. The residue was diluted with water and extracted with dichloromethane and the organic layers combined. The organics were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (10/1) to give 500 mg (85%) of tert-butyl (3R)-3-[4-amino-3-[4-(2,6-difluorophenoxy)-phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With sodium carbonate In 1,2-dimethoxyethane; water at 80℃; Inert atmosphere; | M.2 Step 2Into a 100 mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl (3R)-3-[4-amino-3-iodo-lH-pyrazolo[3,4- d]pyrimidin-l -yl]piperidine- l-carboxylate (300 mg, 0.68 mmol, 1.00 equiv), 2-[4-(3- fluorophenoxy)phenyl]-4,4,5,5-tetramethyl-l ,3,2-dioxaborolane (255 mg, 0.81 mmol, 1.20 equiv), sodium carbonate (143 g, 1.35 mol, 1998.01 equiv), ethylene glycol dimethyl ether (50 mL), water (15 mL), and Pd(PPh3)4 (40 mg, 0.03 mmol, 0.05 equiv). The resulting solution was stirred overnight at 80 °C and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane / methanol (100/1 ) to give 260 mg (76%) of tert-butyl (3R)-3-[4-amino-3-[4-(3-fluorophenoxy)phenyl]-lH- pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l -carboxylate as a yellow solid. |
76% | With sodium carbonate In monoethylene glycol diethyl ether; water at 80℃; Inert atmosphere; | 17.2 S†gjD_2Into a 100 mL 3 -necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl (3R)-3-[4-amino-3-iodo-l H-pyrazolo[3,4- d]pyrimidin-l -yl]piperidine-i-carboxylate (300 mg, 0.68 mmol, 1.00 equiv), 2-[4-(3- fluorophenoxy)phenyl]-4,4,5,5-tetramethyl-l ,3,2-dioxaborolane (255 mg, 0.81 mmol, 1.20 equiv), sodium carbonate (143 g, 1.35 mol, 1998.01 equiv), ethylene glycol dimethyl ether (50 mL), water (15 mL), and Pd(PPh3)4 (40 mg, 0.03 mmol, 0.05 equiv). The resulting solution was stirred overnight at 80 °C and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane / methanol (100/1 ) to give 260 mg (76%) of tert-butyl (3R)-3-[4-amino-3-[4~(3-fluorophenoxy)phenyl]-lH- pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l -carboxylate as a yellow solid. |
76% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,2-dimethoxyethane; water at 80℃; Inert atmosphere; | 17.2 Step 2. Into a 100 mL 3 necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl (3R)-3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (300 mg, 0.68 mmol, 1.00 equiv), 2-[4-(3-fluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (255 mg, 0.81 mmol, 1.20 equiv), sodium carbonate (143 g, 1.35 mol, 1998.01 equiv), ethylene glycol dimethyl ether(50 mL), water (15 mL), and Pd(PPh3)4 (40 mg, 0.03 mmol, 0.05 equiv). The resulting solution was stirred overnight at 80 °C and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane / methanol (100/1) to give 260 mg (76%) of tert-butyl (3R)-3-[4-amino-3-[4-(3-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a yellow solid. |
76% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,2-dimethoxyethane; water at 80℃; Inert atmosphere; | 17.2 Synthesis of (R)-2-(3-(4-amino-3-(4-(3-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile Step 2 Into a 100 mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl (3R)-3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (300 mg, 0.68 mmol, 1.00 equiv), 2-[4-(3-fluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (255 mg, 0.81 mmol, 1.20 equiv), sodium carbonate (143 g, 1.35 mol, 1998.01 equiv), ethylene glycol dimethyl ether (50 mL), water (15 mL), and Pd(PPh3)4 (40 mg, 0.03 mmol, 0.05 equiv). The resulting solution was stirred overnight at 80° C. and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100/1) to give 260 mg (76%) of tert-butyl (3R)-3-[4-amino-3-[4-(3-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With sodium carbonate In 1,4-dioxane; water at 90℃; for 12h; | O.5 Step 5Into a 250-mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of tert-butyl (3R)-3-[4-amino-3-iodo-lH- pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carboxylate (500 mg, 1.13 mmol, 1.00 equiv) in l,4-dioxane/H20 (100/30 mL), 2-[4-(2,5-difluorophenoxy)phenyl]-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (420 mg, 1.26 mmol, 1.1 equiv), sodium carbonate (240 mg, 2.26 mmol, 2.0 equiv), and Pd(PPh3)4 (65 mg, 0.06 mmol, 0.05 equiv). The resulting solution was stirred for 12 h at 90 °C in an oil bath and then concentrated under vacuum. The residue was diluted with water and the resulting solution was extracted with dichloromethane and the organic layers were combined. The combined organics were washed with brine, dried overanhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel and eluted with dichloromethane/methanol ( 10/1) to give 5 0 mg (87%) of tert-butyl (3R)-3-[4- amino-3-[4-(2,5-difluorophenoxy)phenyl]-lH-pyrazolo[3,4-d]pyrimidin- l-yl]pirjeridine-l- carboxyiate as a white solid. |
87% | With sodium carbonate In 1,4-dioxane; water at 90℃; for 12h; Inert atmosphere; | 21.5 Step 5 Into a 250-mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of tert-butyl (3R)-3-[4-amino-3-iodo-lH- pyrazolo[3,4-d]pyrimidin~l~yI]piperidme-l-carboxylate (500 mg, 1.13 mmol, 1.00 eq iv) in l,4-dioxane H20 ( 100/30 mL), 2-[4-(2,5-difluorophenoxy)phenyl]-4,4,5,5-tetramethyl- 1 ,3,2- dioxaborolane (420 mg, 1.26 mmol, 1.1 equiv), sodium carbonate (240 mg, 2.26 mmol, 2.0 equiv), and Pd(PPli3) (65 mg, 0.06 mmol, 0.05 equiv). The resulting solution was stirred for 12 h at 90 °C in an oil bath and then concentrated under vacuum. The residue was diluted with water and the resulting solution was extracted with dichJoromethane and the organic layers were combined. The combined organics were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel and elated with dichloromethane/methanol (10/1) to give 510 mg (87%) of tert-butyl (3R)-3-[4- amino-3-[4-(2,5-dif.uorophenoxy)phenyl]-lH-pyrazolo[3,4-dlpyrimidin- l-yl]piperidine-l- carboxylate as a white solid. |
87% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water at 90℃; for 12h; Inert atmosphere; | 14.5 Into a 250-mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of tert-butyl (3R)-3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (500 mg, 1.13 mmdl, 1.00 equiv) in 1,4-dioxane/H2O (100/30 mL), 2-[4-(2,5-difiuorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (420 mg, 1.26 mmol, 1.1. equiv), sodium carbonate (240 mg, 2.26 mmnol, 2.0 equiv), and Pd(PPh3)4 (65 mg, 0.06 mmol, 0.05 equiv). The resulting solution was stirred for 12 h at 90 °C in an oil bath and then concentrated under vacuum. The residue was diluted with water and the resulting solution was extracted with dichioromethane and the organic layers were combined, The combined organics were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel and eluted with dichloromethane/methanol (10/1) to give 510 mg (87%) of tert-butyl (3R)-3-[4- amino-3-[4-(2,5-difluorophenoxy)phenyl]- 1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a white solid. |
87% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water at 90℃; for 12h; Inert atmosphere; | 21.5 Step 5. Into a 250-mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of tert-butyl (3R)-3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (500 mg, 1.13 mmol, 1.00 equiv) in 1,4-dioxane/H2O (100/30 mL), 2-[4-(2,5-difluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (420 mg, 1.26 mmol, 1.1 equiv), sodium carbonate (240 mg, 2.26 mmol, 2.0 equiv), and Pd(PPh3)4 (65 mg, 0.06 mmol, 0.05 equiv). The resulting solution was stirred for 12 h at 90 °C in an oil bath and then concentrated under vacuum. The residue was diluted with water and the resulting solution was extracted with dichloromethane and the organic layers were combined. The combined organics were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel and eluted with dichloromethane/methanol (10/1) to give 510 mg (87%) of tert-butyl (3R)-3-[4-amino-3-[4-(2,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a white solid. |
87% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water at 90℃; for 12h; Inert atmosphere; | 21.5 Step 5 Into a 250-mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of tert-butyl (3R)-3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (500 mg, 1.13 mmol, 1.00 equiv) in 1,4-dioxane/H2O (100/30 mL), 2-[4-(2,5-difluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (420 mg, 1.26 mmol, 1.1 equiv), sodium carbonate (240 mg, 2.26 mmol, 2.0 equiv), and Pd(PPh3)4 (65 mg, 0.06 mmol, 0.05 equiv). The resulting solution was stirred for 12 h at 90° C. in an oil bath and then concentrated under vacuum. The residue was diluted with water and the resulting solution was extracted with dichloromethane and the organic layers were combined. The combined organics were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel and eluted with dichloromethane/methanol (10/1) to give 510 mg (87%) of tert-butyl (3R)-3-[4-amino-3-[4-(2,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium carbonate In 1,4-dioxane at 90℃; for 16h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 10 - 20℃; for 12.5h; | 9.1 Step.A mixture of 3~iodo- 3H-pyrazoio[3,4-d]pyrimidin-4-amme ( 5,9g. 22,6 mmol, 3.00 equiv), (S)-tert-butyB-hydroxypiperidine- l-carboxylaie (10g,50mmol, 2.2equiv), triphenyiphosphine ( 1 1.8 g, 45 mmol, 2 equiv) in tetrahydrofuran (300 mL) was stirred at 10 °C. Diisopropyl azodicarboxylate in tetrahydrofuran (30 mL) was dropped in die mixture slowly in 30 min.The resulting mixture was stirred for 12 h at room temperature was and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100/1) to give 3 g (33%) of (R)-tert-butyl 3-(4-am'mo-3-iodo- 1 H- pyrazolo[3,4~dJpyrimidin-l-yl)piperidine-l -carboxyIate as yellow solid. MS (ESI, pos. ion) m/z: 45 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.5% | With caesium carbonate In N,N-dimethyl-formamide at 60℃; for 12h; | 18.2 Step 2 Into a 1000 mL 3-necked round-bottom flask, was placed a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (6 g, 22.99 mmol, 1.00 equiv) in N,N-dimethylformamide (500 mL), tert-butyl (3S)-3-[[(4-methylbenzene)sulfonyl]oxy]piperidine-1-carboxylate (9.8 g, 27.57 mmol, 1.20 equiv), and cesium carbonate (13.3 g, 40.82 mmol, 1.78 equiv). The resulting solution was stirred for 12 h at 60° C. in an oil bath and then quenched by the addition of 1500 mL of water. The resulting solution was extracted with dichloromethane and the organic layers combined. The organics were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and elution with ethyl acetate/petroleum ether (60%) gave 2.8 g (27%) of tert-butyl (3R)-3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (96.5%, e.e.) as a off-white solid. |
27% | With caesium carbonate In N,N-dimethyl-formamide at 60℃; for 12h; | 18.2 S gg.2into a 1000 mL 3-necked round-bottom flask, was placed a solution of 3-iodo-lH- pyrazolo[3,4-d]pyrimidin-4-amine (6 g, 22,99 mmol, 1.00 equiv) in N,N-dimethylfomiamide (500 mL), tert-butyl (3S)-3-[[(4-methylbenzene)suIfonyl]oxy]piperidine-l-carboxylate (9,8 g, 27.57 mmol, 1.20 equiv), and cesium carbonate (13,3 g, 40.82 mmol, 1 .78 equiv). The resulting solution was stirred for 12 h at 60 °C in an oil bath and then quenched by the addition of 1500 mL of water. The resulting solution was extracted with dichloromethane and the organic layers combined. The organics were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and elution with ethyl acetate/petroleum ether (60%) gave 2.8 g (27%) of tert-butyl (3R)-3-[4-amino-3~iodo- 1 H-pyrazolo[3,4-d]pyrimidin- 1 -yl]piperidine-l -carboxylate(96.5%,e.e.) as a off-white solid. |
27% | With caesium carbonate In N,N-dimethyl-formamide at 60℃; for 12h; | 12.7 lnto a 1000 mL 3-necked round-bottom flask, was placed a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (6 g, 22.99 rnmol, 1.00 equiv) in N,N-dimethylformamide (500 mE), tert-butyl (3S)-3-[[(4-methylhenzene)sulfonyljoxy]piperidine- 1-carboxylate (9.8 g, 27.57 mmol, 1.20 equiv), and cesium carbonate (13.3 g, 40.82 mmol, 1.78 equiv). The resulting solution was stirred for 12 h at 60 °C in an oil bath and then quenched by the addition of 1500 mL of water. The resulting solution was extracted with diehloromethane and the organic layers combined. The organics were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and elution with ethyl acetate/petroleum ether (60%) gave 2.8 g (27%) of tert-butyl (3R)-3-[4-arnino-3-iodo- 1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (96.5%,e.e.) as a off-white solid. |
27% | With caesium carbonate In N,N-dimethyl-formamide at 60℃; for 12h; | 18.2 Step 2. Into a 1000 mL 3-necked round-bottom flask, was placed a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (6 g, 22.99 mmol, 1 .00 equiv) in N,N-dimethylformamide (500 mL), tert-butyl (3S)-3-[[(4-methylbenzene)sulfonyl]oxy]piperidine-1-carboxylate (9.8 g,27.57 mmol, 1.20 equiv), and cesium carbonate (13.3 g, 40.82 mmol, 1.78 equiv). The resulting solution was stirred for 12 h at 60 °C in an oil bath and then quenched by the addition of 1500 mL of water. The resulting solution was extracted with dichloromethane and the organic layers combined. The organics were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and elution with ethyl acetate/petroleum ether (60%) gave 2.8 g (27%) of tert-butyl (3R)-3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (96.5%,e.e.) as a off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With sodium carbonate In monoethylene glycol diethyl ether; water at 80℃; for 12h; Inert atmosphere; | 9.2 Step 2Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed (R)-tert-butyl 3-[4-amino-3-iodo-lH-pyrazolo[3,4- d]pyrimidin-l -yl]piperidine-i-carboxyIate (2 g, 4.50 mmol, 1.00 equiv), 4-borono- benzenaminium chloride (0.934 g), Pd(PPh3)4 (0.312 g), ethylene glycol dimethyl ether (100 mL), sodium carbonate (1.194 g), and water(20 mL). The resulting solution was stirred for 12 h at 80 °C in an oil bath. The resulting mixture was concentrated under vacuum and residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (50: 1) to give 1.5 g (81 %) of (R)-tert-butyl 3-(4-amino-3-(4-aminophenyl)- lH-pyrazolo[3,4- d]pyrimidin-l -yl)piperidine-l -carboxylate as a brown solid. MS (ESI, pos. ion) m/z:410(M+1) |
81% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,2-dimethoxyethane; water at 80℃; for 12h; Inert atmosphere; | 9.2 Step 2. Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed (R)-tert-butyl 3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (2 g, 4.50 mmol, 1.00 equiv), 4-boronobenzenaminium chloride (0.934 g), Pd(PPh3)4 (0.312 g), ethylene glycol dimethyl ether (100 mL), sodium carbonate (1.194 g), and water(20 mL). The resulting solution was stirred for 12 h at 80 °C in an oil bath. The resulting mixture was concentrated under vacuum and residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (50: 1) to give 1.5 g (81 %) of (R)-tert-butyl 3-(4-amino-3-(4-aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate as a brown solid. MS (ESI, pos. ion) m/z: 410(M+1). |
81% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,2-dimethoxyethane; water at 80℃; for 12h; Inert atmosphere; | 9.2 Step 2 Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed (R)-tert-butyl 3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (2 g, 4.50 mmol, 1.00 equiv), 4-borono-benzenaminium chloride (0.934 g), Pd(PPh3)4 (0.312 g), ethylene glycol dimethyl ether (100 mL), sodium carbonate (1.194 g), and water (20 mL). The resulting solution was stirred for 12 h at 80° C. in an oil bath. The resulting mixture was concentrated under vacuum and residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (50:1) to give 1.5 g (81%) of (R)-tert-butyl 3-(4-amino-3-(4-aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate as a brown solid. MS (ESI, pos. ion) m/z: 410 (M+1) |
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,2-dimethoxyethane; water at 80℃; for 12h; Inert atmosphere; | 6.2 into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed (R)-tert-butyl 3-[4-amino-3-iodo-1(0.934 g), Pd(PPh3)4 (0.312 g), ethylene glycol dimethyl ether (100 mL), sodium carbonate (1.194 g), and water(20 mL). The resulting solution was stirred for 12 h at 80 °C in an oil bath. The resulting mixture was concentrated under vacuum and residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (50:1) to give 1.5 g (81%) of (R)-tert-butyl 3-(4-amino-3-(4-aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yflpiperidine-1-carboxylate as a brown solid, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃;Inert atmosphere; | Step Into a 100 mL, 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of text- butyl (3R)-3-[4-amino-3-iodo- 1 H- pyrazolo[3,4-d]pyrimidin~l~yijpiperidine-l -carboxylate (300 mg, 0.68 mmol, S .00 equiv) in dioxane/H20(7/3=V/V) (30 mL), <strong>[1402238-32-7][4-(2-fluorophenoxy)phenyl]boronic acid</strong> (500 mg, 2, 16 mmol, 6.99 equiv), sodium carbonate (200 mg, 1.89 mmol, 0.26 equiv), and Pd(PPh j)4 (500 mg, 0.43 mmol, 3.19 equiv), The resulting solution was stirred overnight at 100 C in an oil bath an then concentrated under vacuum. The residue was loaded onto a silica gel column and elated with dichloromethane/methanol (100: 1) to give 0.2 g (59%) of tert-butyl (3R)-3-[4- amino-3-[4-(2-fluorophenoxy)phenyl]-lH-pyrazolo[3,4-d]pyrirnidin-l-yl]piperidine-l- carboxylate as a light yellow solid. |
59% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃; | Into a 100 mL, 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl (3R)-3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyriniidin-1-yl]piperidine-1-carhoxylate (300 tug, 0.68 mrnol, 1.00 equiv) in dioxane/H2O(7/3=VIV) (30 mL), <strong>[1402238-32-7][4-(2-fluorophenoxy)phenyl]boronic acid</strong> (500 mg, 2.16 inmol, 6.99 equiv), sodium carbonate (200 mg, 1.89 mmdl, 0.26 equiv), and Pd(PPh)4 (500mg, 0.43 mmol, 3.1.9 equiv). The resulting solution was stirred overnight at 100 C in an oil bath an then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100:1) to give 0.2 g (59%) of teitbutyl (3R)-3-[4-amino-3-[4-(2-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrmidin-1-yl]piperidine-1-carboxylate as a light yellow solid. |
59% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃;Inert atmosphere; | Step 1 Into a 100 mL, 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl (3R)-3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (300 mg, 0.68 mmol, 1.00 equiv) in dioxane/H2O(7/3=V/V) (30 mL), <strong>[1402238-32-7][4-(2-fluorophenoxy)phenyl]boronic acid</strong> (500 mg, 2.16 mmol, 6.99 equiv), sodium carbonate (200 mg, 1.89 mmol, 0.26 equiv), and Pd(PPh3)4 (500 mg, 0.43 mmol, 3.19 equiv). The resulting solution was stirred overnight at 100 C. in an oil bath an then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100:1) to give 0.2 g (59%) of tert-butyl (3R)-3-[4-amino-3-[4-(2-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a light yellow solid. |
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃;Inert atmosphere; | Step 1. Into a 100 mL, 3-necked round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of tert-butyl (3R)-3-[4amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (300 mg, 0.68 mmol, 1.00 equiv) in dioxane/H2O(7/3=V/V) (30 mL), <strong>[1402238-32-7][4-(2-fluorophenoxy)phenyl]boronic acid</strong> (500 mg, 2.16 mmol, 6.99 equiv), sodium carbonate (200 mg, 1.89 mmol, 0.26 equiv), and Pd(PPh3)4 (500 mg, 0.43 mmol, 3.19 equiv). The resulting solution was stirred overnight at 100 C in an oilbath an then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100:1) to give 0.2 g (59%) of tert-butyl (3R)-3-[4-amino-3-[4-(2-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a light yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; potassium carbonate In 1,4-dioxane; water monomer at 80℃; | |
70% | With anhydrous sodium carbonate In monoethylene glycol diethyl ether; water monomer at 80℃; for 12h; Inert atmosphere; | 22.1 Step...Into a 100 mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed tert-butyl (3R)-3-[4-amino-3-iodo-lH-pyrazolo[3,4- dJpyrimidin- l -yl]piperidme-l -carboxylate (400 mg, 0.90 mmol, 1.00 equiv), (2-fluoro-4- phenoxyphenyl)boronic acid (250 mg, 1.08 mmol, 1.20 equiv), sodium carbonate (190 mg, 1.79 mmol, 1.99 equiv), ethylene glycol dimethyl ether (50 mL), water (15 mL), andPd(PPh3)4 (52 mg, 0.04 mmol, 0.05 equiv). The resulting solution was stirred for 12 h at 80 °C and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100/1 ) to give 320 rag (70%) of tert-butyl (3R)-3-[4- amino-3-(2-fluoro-4-phenoxyphenyl)- 1 H-pyrazolo[3,4-d]pyrimidin- 1 -yl]piperidine- 1 - carboxylate as a yellow solid. |
70% | With anhydrous sodium carbonate; (1,1-dimethyl-2-oxo-ethyl)-carbamic acid tert-butyl ester In 1,2-dimethoxyethane; water monomer at 80℃; for 12h; Inert atmosphere; | 15.1 Into a 100 mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed tert-butyl (3R)-3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (400 mg, 0.90 mmol, 1.00 equiv), (2-fluoro-4- phenoxyphenyl)boronic acid (250 mg, 1.08 mmol, 1.20 equiv), sodium carbonate (1.90 mg, 1.79 mmol, 1.99 equiv), ethylene glycol dimethyl ether (50 mE), water (15 mL), and Pd(PPh3)4 (52 mg, 0.04 mmol, 0.05 equiv). The resulting solution was sdned for 12 h at 80°C and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100/1) to give 320 mg (70%) of tert-butyl (3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a yellow solid. |
70% | With tetrakis-(triphenylphosphine)-palladium; anhydrous sodium carbonate In 1,2-dimethoxyethane; water monomer at 80℃; for 12h; Inert atmosphere; | 22.1 Step 1. Into a 100 mL 3-necked round-bottom flask purged and maintained under an inertatmosphere of nitrogen, was placed tert-butyl (3R)-3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (400 mg, 0.90 mmol, 1.00 equiv), (2-fluoro-4-phenoxyphenyl)boronic acid (250 mg, 1.08 mmol, 1.20 equiv), sodium carbonate (190 mg, 1.79 mmol, 1.99 equiv), ethylene glycol dimethyl ether (50 mL), water (15 mL), and Pd(PPh3)4 (52 mg, 0.04 mmol, 0.05 equiv). The resulting solution was stirred for 12 h at 80 °C and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100/1) to give 320 mg (70%) of tert-butyl (3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yljpiperidine-1-carboxylate as a yellow solid. |
70% | With tetrakis-(triphenylphosphine)-palladium; anhydrous sodium carbonate In 1,2-dimethoxyethane; water monomer at 80℃; for 12h; Inert atmosphere; | 22.1 Step 1 Into a 100 mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed tert-butyl (3R)-3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (400 mg, 0.90 mmol, 1.00 equiv), (2-fluoro-4-phenoxyphenyl)boronic acid (250 mg, 1.08 mmol, 1.20 equiv), sodium carbonate (190 mg, 1.79 mmol, 1.99 equiv), ethylene glycol dimethyl ether (50 mL), water (15 mL), and Pd(PPh3)4 (52 mg, 0.04 mmol, 0.05 equiv). The resulting solution was stirred for 12 h at 80° C. and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100/1) to give 320 mg (70%) of tert-butyl (3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a yellow solid. |
2.7 g | With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; potassium carbonate In 1,4-dioxane at 80℃; | 1.1 Step 1 Into a 100-mL round-bottom flask, was placed 1,4-dioxane (40 mL), water (10 mL), tert-butyl (3R)-3-[4-amino-3-iodo-l H-pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l- carboxylate (3.108 g, 7.00 mmol, 1.00 equiv), (2-fluoro-4-phenoxyphenyl)boronic acid (1.624 g, 7.00 mmol, 1.00 equiv), potassium carbonate (2.898 g, 32.89 mmol, 4.70 equiv) and Pd(dppf)Cl2 (57.1 mg, 0.4 mmol, 0.06 equiv). The resulting solution was stirred overnight at 80° C in an oil bath. The solids were then filtered out and the resulting solution was diluted with water. The resulting mixture was extracted ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtrated, and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :3). This resulted in 2.7 g of tert-butyl (3R)-3-[4-amino-3-(2-fluoro-4- phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carboxylate as a black solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With sodium carbonate In 1,4-dioxane; water at 90℃; for 12h; Inert atmosphere; | 18.3 Step 3Into a 250 mL 3-necked round-bottom flask purged and maintained under an inert, atmosphere of nitrogen, was placed a solution of tert-butyl (3R)-3-[4-amino-3-iodo-lH" pyrazolof3,4-d]pyrimidin-l~yI]piperidine-l -carboxylate (500 mg, 1.13 mmol, 1.00 equiv) in l,4-dioxane/H20 (100/30 mL), 2-[4-(2,3-difluorophenoxy)phenyl]-4,4,5,5-tetramethyl-l ,3,2- dioxaborolane (420 mg, 1.26 mmol, 1.3 equiv), sodium carbonate (240 mg, 2.26 mmol, 2.0 equiv), and Pd(PPh3)4 (65 mg, 0.06 mmol, 0.05 equiv). The resulting solution was stirred for 12 h at 90 °C in an oil b&th. The resulting mixture was concentrated under vacuum and the resiude was diluted with water. The resulting solution was extracted with dichloromethane and the organic layers were combined, washed with brine and filtered. The filtrate was dried over anhydrous sodium sulfate and coticentraied under vacuum. The residue was loaded onto a silica gel column and elution with dichloromethane/methanol ( 10/1 ) gave 480 mg (82%) of tert-butyl (3R)-3-[4~amino-3-[4-(2,3-difluorophenoxy)phenylj-lH-pyrazolo[3,4-d]pyrimidin- l~yl]piperidine- l -carboxylate as a white solid. |
82% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water at 90℃; for 12h; Inert atmosphere; | 12.8 Into a 250 mE 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of tert-butyl (3R)-3-[4-amino-3-iodo- 1W pyrazolo[3,4-d]pyrimidin- 1-yl]piperidine-1-carboxylate (500 mg, 1.13 nimol, 1.00 equiv) in I ,4-dioxane/H20 (100/30 mL), 2-[4-(2,3-difiuorophenoxy)phenyl]-4.4,5,5-tetramethyl-1 ,3,2- dioxaborolane (420 mg, 1.26 mmol, 1.1 equiv), sodium carbonate (240 mg, 2.26 mmol, 2.0 equiv), and Pd(PPh3)4 (65 mg, 0.06 mmol, 0.05 equiv). The resulting solution was stirred for 12 h at 90 °C in an oil bath. The resulting mixture was concentrated under vacuum and the resiude was diluted with water. The resulting solution was extracted with diehloromethane and the organic layers were combined, washed with brine and filtered. The filtrate was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and elution with diehloromethane/methanol (10/1) gave 480 mg (82%) of tert-butyl (3R)-3-[4-amino-3-[4-(2,3-difluorophenoxy)phenylj- 1H-pyrazoio[3,4-d]pyrimidin- 1 -yl]piperidine- I -earboxylate as a white solid. |
82% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water at 90℃; for 12h; Inert atmosphere; | 18.3 Step 3. Into a 250 mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of tert-butyl (3R)-3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (500 mg, 1.13 mmol, 1.00 equiv) in 1,4-dioxane/H2O (100/30 mL), 2- [4-(2,3-difluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (420 mg, 1.26 mmol, 1.1 equiv), sodium carbonate (240 mg, 2.26 mmol, 2.0 equiv), and Pd(PPh3)4 (65 mg, 0.06 mmol, 0.05 equiv). The resulting solution was stirred for 12 h at 90 °C in an oil bath. The resulting mixture was concentrated under vacuum and the resiude was diluted with water. The resulting solution was extracted with dichioromethane and the organic layers were combined, washed with brine and filtered. The filtrate was driedover anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded ontoa silica gel column and elution with dichloromethane/methanol (10/1) gave 480 mg (82%) of tert-butyl (3R)-3-[4-amino-3-[4-(2,3-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a white solid. |
82% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water at 90℃; for 12h; Inert atmosphere; | 18.3 Step 3 Into a 250 mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of tert-butyl (3R)-3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (500 mg, 1.13 mmol, 1.00 equiv) in 1,4-dioxane/H2O (100/30 mL), 2-[4-(2,3-difluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (420 mg, 1.26 mmol, 1.1 equiv), sodium carbonate (240 mg, 2.26 mmol, 2.0 equiv), and Pd(PPh3)4 (65 mg, 0.06 mmol, 0.05 equiv). The resulting solution was stirred for 12 h at 90° C. in an oil bath. The resulting mixture was concentrated under vacuum and the residue was diluted with water. The resulting solution was extracted with dichloromethane and the organic layers were combined, washed with brine and filtered. The filtrate was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and elution with dichloromethane/methanol (10/1) gave 480 mg (82%) of tert-butyl (3R)-3-[4-amino-3-[4-(2,3-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With sodium carbonate In monoethylene glycol diethyl ether; water at 80℃; for 12h; Inert atmosphere; | 20.1 Into a 100 mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed tert-butyl (3R)-3-[4-amino-3-iodo-lH-pyrazolo[3,4- djpyrimidin-l -yljpiperidine-l -carboxylate (400 mg, 0.90 mmol, 1.00 equiv), 2-[4-(3,5- difluorophenoxy)phenyl]~4,4,5,5-tetramethyl- l ,3,2-dioxaborolane (360 mg, 1.08 mmol, 1 .20 equiv), sodium carbonate (190 mg, 1.79 mmol, 1.99 equiv), ethylene glycol dimethyl ether (50 mL), water (15 mL), and Pd(PPh3)4 (52 mg, 0.04 mmol, 0.05 equiv). The resulting solution was stirred for 12 h at 80 °C and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100/1) to give 340 mg (72%) of tert-buiy. (3R)-3-[4-amino-3-[4-(3,5-difluorophenoxy)phenyl]- 1 H- pyrazolo[3,4-d3pyrimidin-l-yl]piperidine-l -carboxylate as a yellow solid. |
72% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,2-dimethoxyethane; water at 80℃; for 12h; Inert atmosphere; | 20.1 Step 1. Into a 100 mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed tert-butyl (3R)-3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (400 mg, 0.90 mmol, 1.00 equiv), 2-[4-(3,5-difluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (360 mg, 1.08 mmol, 1.20 equiv), sodium carbonate (190 mg, 1.79 mmol, 1.99 equiv), ethylene glycol dimethyl ether (50 mL), water (15 mL), and Pd(PPh3)4 (52 mg, 0.04 mmol, 0.05 equiv). The resulting solution was stirred for 12 h at 80 °C and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichioromethane/methanol (100/1) to give 340 mg (72%) of tert-butyl (3R)-3-[4-amino-3-[4-(3,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a yellow solid. |
72% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,2-dimethoxyethane; water at 80℃; for 12h; Inert atmosphere; | 20.1 Step 1 Into a 100 mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed tert-butyl (3R)-3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (400 mg, 0.90 mmol, 1.00 equiv), 2-[4-(3,5-difluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (360 mg, 1.08 mmol, 1.20 equiv), sodium carbonate (190 mg, 1.79 mmol, 1.99 equiv), ethylene glycol dimethyl ether (50 mL), water (15 mL), and Pd(PPh3)4 (52 mg, 0.04 mmol, 0.05 equiv). The resulting solution was stirred for 12 h at 80° C. and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100/1) to give 340 mg (72%) of tert-butyl (3R)-3-[4-amino-3-[4-(3,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51.1% | With sodium carbonate In 1,4-dioxane; water at 90℃; | 32.3 Step 3A solution of (R)-tert-buiyl 3-(4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidin-l- yl)piperidine- l -carboxylate (2.8 g, 6.16 mmol, l .Oeq), 2-(4-(2,3-difluorophenoxy)-2- fluorophenyI)-4,4,5,5-tetramethyl-l,3,2-dioxaboro]ane (1 .7 g, 6.16 mmol, 3.0 eq), Pd(PPh3) (0.28 g, 0.08 mmol, 0.07 eq) and Na2O03 (3.7 g, 15.4 mmol, 2.5 eq) in dioxane H20(40/lOmL) was stirred at 90° C overnight. The reaction mixture was concentrated and purified by Pre-TLC to afford (R)-tert-butyl 3-(4-amino-3-(4-(2,3-difluorophenoxy)-2- fluorophenyl)- lH-pyrazoio[3,4-d]pyrimidm-3 -y3)piperidine- 1 -carboxylate ( 1.7g, 51.3 % yield). |
51.1% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water at 90℃; | 22.3 A solution of (R)-tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (2.8 g, 6.16 mmol, 1.0eq), 24-(2,3-difluorophenoxy)-2- fluorophenyl)-4,4,5,5..tetramethyl-1,3,2.dioxaborolane (1.7 g, 6.16 mrnol, 1.0 eq), Pd(PPh3)4 (0.28 g, 0.08 nunol, 0.07 eq) and Na2CO3 (1.7 g, 15.4 mmol, 2.5 eq) in dioxane/H20 (40/lOmL) was stirred at 90°C overnight. The reaction mixture was concentrated and purified by PreLC to afford (R)-tert’butyl 3-(4-amino.3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyridin-1-yl)piperidine-1-carboxylate (1.7g. 51.1 % yield). |
51.1% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water at 90℃; | 32.3 Step 3. A solution of (R)-tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (2.8 g, 6.16 mmol, 1.0 eq), 2-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.7 g, 6.16 mmol, 1.0 eq), Pd(PPh3)4 (0.28 g, 0.08 mmol, 0.07 eq) and Na2CO3 (1.7 g, 15.4 mmol, 2.5 eq) in dioxane/H2O (40/10mL) was stirred at 90°C overnight. The reaction mixture was concentrated and purified by Pre-TLC to afford (R)-tert-butyl 3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (1.7g, 51.1% yield). |
51.1% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water at 90℃; | 32.3 Step 3 A solution of (R)-tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (2.8 g, 6.16 mmol, 1.0 eq), 2-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.7 g, 6.16 mmol, 1.0 eq), Pd(PPh3)4 (0.28 g, 0.08 mmol, 0.07 eq) and Na2CO3 (1.7 g, 15.4 mmol, 2.5 eq) in dioxane/H2O (40/10 mL) was stirred at 90° C. overnight. The reaction mixture was concentrated and purified by Pre-TLC to afford (R)-tert-butyl 3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (1.7 g, 51.1% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 80 °C 2: trifluoroacetic acid / dichloromethane / 3 h / 20 °C 3: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 4 h / 20 °C 4: pyrrolidine; chloro-trimethyl-silane / dichloromethane / 1 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water at 90℃; for 24h; Inert atmosphere; | 19.4 Step 4 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 (64%) of tert-butyl 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate at 100℃; for 2h; | 35.a a. Preparation of (R)-tert-butyl 3-(4-amino-3-(4-(4-methylpyridin-2-yl carbamoyl)phenyl) -1 Hpyrazolo[3,4-dJpyrimidin-1-yl)piperidine-1-carboxylate (624-1) a. Preparation of (R)-tert-butyl 3-(4-amino-3-(4-(4-methylpyridin-2-yl carbamoyl)phenyl) -1 Hpyrazolo[3,4-dJpyrimidin-1-yl)piperidine-1-carboxylate (624-1) [005501 (R)-tert-Butyl 3 -(4-amino-3 -(4-(4-methylpyridin-2-ylcarbamoyl)phenyl)- 1H-pyrazolo [3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (624-1) (850 mg, 47%) was obtained as a white solid from (R)-tert-butyl 3 -(4-amino-3-iodo- 1H-pyrazolo[3 ,4-d]pyrimidin- l-yl) piperidine- 1- carboxylate (Core-A) (1.5 g, 3.4 mmol) and N-(4-(4-methylpyridine)- 2-yl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (623-2) (2 g, 5.9 mmol), following a similar procedure outlined in US 8,377,946 (Example 2). LC-MS (ESI): m/z (M+1) 529.3. |
47% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In N,N-dimethyl-formamide at 80℃; Inert atmosphere; | 3 To a suspension of (R)-tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl) piperidine- 1 -carboxylate (1.5 g, 3.4 mmol), N-(4-Methylpyridin-2-yl)-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzamide (2.0 g. 5.9 mmol) and Na2CO3 (1.07 g, 10.2 mmol) in DME (35 mL) and water (5 mL) were added Pd(PPh3)4 (200 mg, 0.22mmol). The resulting mixture was purged with N2 before heated to 80 °C overnight under N2 atmosphere. The solvents were evaporated and the residual was directly loaded to a silica gel column was purified by column chromatography to (R)-tert-Butyl 3-(4- amino-3-(4-(4-methylpyridin-2-ylcarbamoyl)phenyl)-1H-pyrazolo [3,4-d]pyrimidin- 1 -yl)piperidine-1 - carboxylate (850 mg, 47%) as white solid. LC-MS (ESI): m/z (M+1) 529.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate at 100℃; for 2h; | 36.a a. Preparation of (R)-tert-butyl 3-(4-amino-3-(4-(4-(trifluoromethyl)pyridin-2- ylcarbamoyl)phenyl)-1H-pyrazolo[3,4-dJpyrimidin-1-yl)piperidine-1-carboxylate (625-1) a. Preparation of (R)-tert-butyl 3-(4-amino-3-(4-(4-(trifluoromethyl)pyridin-2- ylcarbamoyl)phenyl)-1H-pyrazolo[3,4-dJpyrimidin-1-yl)piperidine-1-carboxylate (625-1) [00554j (R)-tert-Butyl 3 -(4-amino-3 -(4-(4-trifluoromethylpyridin-2-ylcarbamoyl)phenyl)- 1H- pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (625-1) (1 g, 64%) was obtained as a white solid from (R)-tert-butyl 3 -(4-amino-3 -iodo- 1H-pyrazolo [3 ,4-d] pyrimidin- l-yl) piperidine-1-carboxylate (Core-A) (1.2 g, 2.7 mmol) and N-(4-(4-trifluoromethylpyridine)-2- yl)-4-(4,4,S ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)benzamide (1 .38 g, 3.5 mmol), following a similar procedure outlined in US 8,377,946 (Example 2). LC-MS (ESI): m/z (M+1) 583.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In dichloromethane | 39.a a. Preparation of (R)-tert-butyl 3-(4-amino-3-(4-(4-isopropylpyridin-2-ylcarbamoyl)phenyl)- 1H-pyrazolo[3,4-dJpyrimidin-1-yl)piperidine-1-carboxylate (613-1) a. Preparation of (R)-tert-butyl 3-(4-amino-3-(4-(4-isopropylpyridin-2-ylcarbamoyl)phenyl)- 1H-pyrazolo[3,4-dJpyrimidin-1-yl)piperidine-1-carboxylate (613-1) [005651 (R)-tert-Butyl 3 -(4-amino-3 -(4-(4-isopropylpyridin-2-ylcarbamoyl)phenyl)- 1H- pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (613-1) (1.04 g, 69 %) was obtained as a yellow solid from (R)-tert-butyl 3 -(4-amino-3 -iodo- 1H-pyrazolo [3 ,4-d]pyrimidin- 1 -yl) piperidine-1-carboxylate (Core-A) (1.2 g, 2.7 mmol) and N-(4-isopropylpyridin-2-yl)-4- (4,4,5,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)benzamide (611-4) (1.18 g, 3.24 mmol), following a similar procedure outlined in US 8,377,946 (Example 2). LC-MS (ESI): m/z (M+1) 557.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In dichloromethane | 37.a a. Preparation of (R)-tert-butyl 3-(4-amino-3-(4-(4-propylpyridin-2-ylcarbamoyl)phenyl)-1H- pyrazolo[3,4-dJpyrimidin-1-yl)piperidine-1-carboxylate (614-1) a. Preparation of (R)-tert-butyl 3-(4-amino-3-(4-(4-propylpyridin-2-ylcarbamoyl)phenyl)-1H- pyrazolo[3,4-dJpyrimidin-1-yl)piperidine-1-carboxylate (614-1) [00557j (R)-tert-Butyl 3 -(4-amino-3 -(4-(4-propylpyridin-2-ylcarbamoyl)phenyl)- 1 Hpyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (614-1) (1.26 g, 83 %) was obtained as a yellow solid from (R)-tert-butyl 3 -(4-amino-3 -iodo- 1H-pyrazolo [3 ,4-d]pyrimidin- l-yl) piperidine-1-carboxylate (Core-A) (1.21 g, 2.73 mmol) and N-(4-propylpyridin-2-yl)-4- (4,4,5,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)benzamide (612-6) (1 .0 g, 2.73 mmol)following a similar procedure outlined in US 8,377,946 (Example 2). LC-MS (ESI): m/z (M+1) 557.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate at 100℃; for 2h; | 34.d d. Preparation of (R)-tert-butyl 3-(4-amino-3-(4-(pyridin-2-ylcarbamoyl) phenyl) -1 Hpyrazolo[3,4-dJpyrimidin-1-yl)piperidine-1-carboxylate (623-3) d. Preparation of (R)-tert-butyl 3-(4-amino-3-(4-(pyridin-2-ylcarbamoyl) phenyl) -1 Hpyrazolo[3,4-dJpyrimidin-1-yl)piperidine-1-carboxylate (623-3) [00547j (R)-tert-Butyl 3 -(4-amino-3 -(4-(pyridin-2-ylcarbamoyl)phenyl)- 1H-pyrazolo [3 ,4-d] pyrimidin-1-yl)piperidine-1-carboxylate (623-3) (1 g, 72%) was obtained as a white solid from (R)-tert-butyl 3 -(4-amino-3-iodo- 1H-pyrazolo[3 ,4-d]pyrimidin- l-yl) piperidine- 1 -carboxylate (Core-A) (1.2 g, 2.7 mmol) and N-(pyridin-2-yl)-4- (4,4,5,5 -tetramethyl- 1,3 ,2-dioxaborolan-2- yl)benzamide (623-2) (1.13 g, 3.5 mmol), following a similar procedure outlined in US 8,377,946 (Example 2). LC-MS (ESI): m/z (M+1) 515.2. |
360 mg | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate In 1,2-dimethoxyethane at 95℃; for 12h; Inert atmosphere; | 9.2 Step 2: Synthesis of (R)-3-(3-(4-(pyridin-2-ylcarbamoyl)phenyl)-4-amino-1H-pyrazole [3,4-d]-Pyridin-1-yl)piperidinecarboxylic acid tert-butyl ester (CDA-133): To the reaction flask was added a mixture (580 mg) containing CDA-132 in the previous step.N-(pyridin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(500mg, 1.54mmol),Ethylene glycol dimethyl ether (6mL, 2mol/L),Sodium carbonate solution (3 mL, 2M).After exhausting oxygen and filling with nitrogen,[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloride dichloromethane complex (63 mg, 0.08 mmol) was added,Heat to 95°C under nitrogen and stir for 12 hours.After cooling, add 50mL of water,Extract three times with ethyl acetate,The organic phases were combined and dried over anhydrous sodium sulfate.After removing the solvent and purifying the column, it contains360 mg of a mixture of CDA-133. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate at 100℃; for 2h; | 38.c c. Preparation of (R)-tert-butyl 3-(4-amino-3-(4-(4-cyanopyridin-2-yl carbamoyl)phenyl) -1 Hpyrazolo[3,4-dJpyrimidin-1-yl)piperidine-1-carboxylate (626-3) c. Preparation of (R)-tert-butyl 3-(4-amino-3-(4-(4-cyanopyridin-2-yl carbamoyl)phenyl) -1 Hpyrazolo[3,4-dJpyrimidin-1-yl)piperidine-1-carboxylate (626-3) [00562j (R)-tert-Butyl 3 -(4-amino-3 -(4-(4-cyanopyridin-2-ylcarbamoyl)phenyl)- 1 H-pyrazolo [3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (626-3) (830 mg, 46%) was obtained as a white solid from (R)-tert-butyl 3 -(4-amino-3-iodo- 1H-pyrazolo[3 ,4-d] pyrimidin- l-yl) piperidine- 1- carboxylate (Core-A) (1.5 g, 3.37 mmol) and N-(4-(4-cyanopyridine)-2-yl)-4-(4,4,5,5- tetramethyl- 1,3 ,2-dioxaborolan-2-yl)benzamide (1 .41 g, 4.05 mmol), following a similar procedure outlined in US 8,377,946 (Example 2). LC-MS (ESI): m/z (M+1) 540.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water for 14h; Inert atmosphere; Reflux; | 7 General procedure C: Suzuki cross-coupling (Thermal) General procedure: [00149] A mixture of fe/f-butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-rf]pyrimidin-1-yl)piperidine-1- carboxylate (1 .0 eq.), boronic acid or pinacol ester (1.5 eq.) and potassium carbonate (2.0 eq.) in 1 ,4-dioxane and water (3: 1 , 0.1 M) was degassed by bubbling nitrogen through it for 25 min. 1 ,1 '- Jb/'s(Diphenylphosphino)ferrocene-palladium(ll) dichloride dichloromethane complex (0.05 eq.) was added and the mixture was degassed again by bubbling nitrogen through it for 30 min. The mixture was then heated under reflux for 14 h. The reaction mixture was filtered over Celite. The residue was rinsed with DCM. Water was added to the filtrate and the layers were partitioned. The aqueous layer was extracted with DCM (2 χ) . The combined organic extracts were filtered using a phase separator and concentrated under reduced pressure to give a residue which was further purified by flash column chromatography (DCM/MeOH 1 00:0 to 90:1 0) to give the desired compound. [00244] te/f-Butyl (3 ?)-3-[4-amino-3-[4-[[(2-fluorophenyl)sulfonylaminolmethyllphenyllpyrazolo[3,4- tflpyrimidin-1 -yllpiperidine-1 -carboxylate [00245] Following general procedure C, a mixture of fe/f-butyl (3R)-3-(4-amino-3-iodo- pyrazolo[3,4-rf]pyrimidin-1 -yl)piperidine-1 -carboxylate (4.04 g, 9.09 mmol) and [4-[[(2- fluorophenyl)sulfonylamino]methyl]phenyl]boronic acid (4.35 g, 13.64 mmol) gave fe/ -butyl (3R)-3- [4-amino-3-[4-[[(2-fluorophenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1 -yl]piperidine- 1 -carboxylate (4.03 g, 6.93 mmol, 76% yield) as a thick oil. [00246] UPLC-MS (ES+, Short acidic): 2.06 min, m/z 582.4 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water for 1.5h; Inert atmosphere; Heating; Microwave irradiation; | 1 General procedure D: Suzuki cross-coupling (Microwave irradiation) General procedure: [00151] A mixture of fe/f-butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-rf]pyrimidin-1 -yl)piperidine-1 - carboxylate (1 .0 eq.), boronic acid or pinacol ester (1 .5 eq.) and potassium carbonate (2.0 eq.) in 1 ,4-dioxane and water (3: 1 , 0.1 M) was degassed by bubbling nitrogen through it for 1 5 min. 1 ,1 '- Jb/'s(diphenylphosphino)ferrocene-palladium(ll) dichloride dichloromethane complex (0.05 eq.) was added and the mixture was degassed again by bubbling nitrogen through it for 15 min. The mixture was then heated under microwave irradiation for 90 min. The reaction mixture was filtered over Celite and the residue was rinsed with DCM. Water was added to the filtrate and the layers were partitioned. The aqueous layer was extracted with DCM (2 χ) . The combined organic extracts were filtered over a phase separator and then concentrated under reduced pressure and the residue further purified by flash column chromatography (DCM/MeOH 100:0 to 90:10) to give the desired compound. [00157] fe/f-Butyl (3 ?)-3-[4-amino-3-[4-(methanesulfonamidomethyl)phenvnpyrazolo [3,4- tflpyrimidin-1 -yllpiperidine-1 -carboxylate [00158] Following general procedure D, fe/f-butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-rf]pyrimidin- 1 -yl)piperidine-1 -carboxylate (200.0 mg , 0.45 mmol) and [4- (methanesulfonamidomethyl)phenyl]boronic acid (134.1 mg , 0.59 mmol) afforded fe/f-butyl (3R)-3- [4-amino-3-[4-(methanesulfonamidomethyl)phenyl]pyrazolo[3,4-rf]pyrimidin-1 -yl]piperidine-1 - carboxylate (218.0 mg, 0.43 mmol, 97% yield) as a brown gum. UPLC-MS (ES+, Short acidic): 1 .46 min, m/z 502.4 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
257 mg | With 4-methyl-morpholine; palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In N,N-dimethyl acetamide; at 110℃; for 2h; | 300 mg of (R)-tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate obtained in Synthetic Example 1 was dissolved in 3 ml of NMP. 118 mg of <strong>[4570-41-6]benzo[d]oxazol-2-amine</strong>, 20 mg of xantphos, and 0.15 ml of N-methylmorpholine were added thereto, and a degassing operation was carried out. Thereafter, 7.6 mg of palladium acetate was added thereto, and in a carbon monoxide atmosphere, the mixture was heated to 110°C and stirred for 2 hours. After the mixture was cooled, 4.5 ml of methanol and 0.45 ml of a 5 N aqueous solution of sodium hydroxide were added thereto, and the mixture was stirred for 30 minutes at room temperature. Thereafter, the pH was adjusted to 5.3 with 2 N HCl, and a solid thus obtained was collected by filtration. The crude product was purified using a silica gel column (eluent:chloroform-methanol), and thus 257 mg of the title compound was obtained as a white solid. Physical property value: m/z [M+H]+ 479.3 |
257 mg | With palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1-methyl-pyrrolidin-2-one; at 110℃; for 2h; | (Step 1) Synthesis of (R)-tert-butyl 3-(4-amino-3-((benzo[d]oxazol-2-yl)carbamoyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (0190) 300 mg of (R)-tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate obtained in Reference Example 1 was dissolved in 3 mL of NMP. 118 mg of <strong>[4570-41-6]benzo[d]oxazol-2-amine</strong>, 20 mg of xantphos, and 0.15 mL of N-methylmorpholine were added thereto, and a degassing operation was carried out. Thereafter, 7.6 mg of palladium acetate was added thereto, and under a carbon monoxide atmosphere, the mixture was heated to 110° C. and stirred for 2 hours. After the mixture was cooled, 4.5 mL of methanol and 0.45 mL of a 5 N aqueous solution of sodium hydroxide were added thereto, and the mixture was stirred for 30 minutes at room temperature. Thereafter, the pH was adjusted to 5.3 with 2 N HCl, and a solid thus obtained was collected by filtration. The crude product was purified by a silica gel column (chloroform-methanol), and thus 257 mg of the title compound was obtained as a white solid. |
257 mg | 300 mg of (R)-tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate obtained in Synthetic Example 1 was dissolved in 3 mL of NMP. 118 mg of <strong>[4570-41-6]benzo[d]oxazol-2-amine</strong>, 20 mg of xantphos, and 0.15 mL of N-methylmorpholine were added thereto, and a degassing operation was carried out. Thereafter, 7.6 mg of palladium acetate was added thereto, and under a carbon monoxide atmosphere, the mixture was heated to 110° C. and stirred for 2 hours. After the mixture was cooled, 4.5 mL of methanol and 0.45 mL of a 5 N aqueous solution of sodium hydroxide were added thereto, and the mixture was stirred for 30 minutes at room temperature. Thereafter, the pH was adjusted to 5.3 with 2 N hydrochloric acid, and a solid thus obtained was collected by filtration. The crude product was purified by a silica gel column (chloroform-methanol), and thus 257 mg of the title compound was obtained as a white solid. (0529) Physical property value: m/z [M+H]+ 479.3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.26 g | With bis-triphenylphosphine-palladium(II) chloride; 2-(Diethylamino)ethanol In 1-methyl-pyrrolidin-2-one at 120℃; for 1h; | 2 Synthetic Example 2 Synthesis of (R)-4-amino-1-(1-(tert-butyloxycarbonyl)piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid 2 g of (R)-tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate obtained in Synthetic Example 1, 3 ml of 2-diethylaminoethanol, and 158 mg of Pd(PPh3)2Cl2 were dissolved in 20 ml of NMP. After the system was purged with carbon monoxide, and then the solution was heated to 120°C. After the solution was stirred for 1 hour, the solution was cooled to room temperature. 10 ml of methanol was added thereto, and then 6 ml of a 5 N aqueous solution of sodium hydroxide was added thereto. The mixture was stirred for 10 minutes. Water was added thereto, and then the aqueous layer was washed with ethyl acetate. The aqueous layer was adjusted to pH 4 with hydrochloric acid, and a solid thus precipitated was collected by filtration, washed with water, and then dried. Thus, 1.26 g of the title compound was obtained as a pale yellow solid. Physical property value: m/z [M+H]+ 363.1 |
1.26 g | Stage #1: carbon monoxide; (R)-3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester With bis-triphenylphosphine-palladium(II) chloride; 2-(Diethylamino)ethanol In 1-methyl-pyrrolidin-2-one at 120℃; for 1h; Stage #2: With water; sodium hydroxide In 1-methyl-pyrrolidin-2-one; methanol at 20℃; for 0.166667h; | 2 Reference Example 2 Synthesis of (R)-4-amino-1-(1-(tert-butyloxycarbonyl) piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid Reference Example 2 Synthesis of (R)-4-amino-1-(1-(tert-butyloxycarbonyl) piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid (R)-tert-Butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (2 g) obtained in Reference Example 1, 2-diethylaminoethanol (3 mL), and Pd(PPh3)2Cl2 (158 mg) were dissolved in NMP (20 mL). After purging of the system with carbon monoxide, the solution was heated to 120° C. The solution was stirred for 1 hour and then cooled to room temperature. Methanol (10 mL) was added thereto, then a 5 N aqueous sodium hydroxide solution (6 mL) was added thereto, and the mixture was stirred for 10 minutes. After water was added, the aqueous layer was washed with ethyl acetate and adjusted to pH 4 with hydrochloric acid, and the precipitated solid was collected by filtration, washed with water, and then dried to obtain 1.26 g of the title compound as a pale yellow solid. Physical property value: m/z [M+H]+ 363.1 |
1.26 g | Stage #1: carbon monoxide; (R)-3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester With bis-triphenylphosphine-palladium(II) chloride; 2-(Diethylamino)ethanol In 1-methyl-pyrrolidin-2-one at 120℃; for 1h; Stage #2: With water; sodium hydroxide In 1-methyl-pyrrolidin-2-one; methanol at 20℃; for 0.166667h; | 2 Synthetic Example 2 Synthesis of (R)-4-amino-1-(1-(tert-butyloxycarbonyl)piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid 2 g of (R)-tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate obtained in Synthetic Example 1, 3 mL of 2-diethylaminoethanol, and 158 mg of Pd(PPh3)2Cl2 were dissolved in 20 mL of NMP. After the system was purged with carbon monoxide, and then the solution was heated to 120° C. After the solution was stirred for 1 hour, the solution was cooled to room temperature. 10 mL of methanol was added thereto, and then 6 mL of a 5 N aqueous solution of sodium hydroxide was added thereto. The mixture was stirred for 10 minutes. Water was added thereto, and then the aqueous layer was washed with ethyl acetate. The aqueous layer was adjusted to pH 4 with hydrochloric acid, and a solid thus precipitated was collected by filtration, washed with water, and then dried. Thus, 1.26 g of the title compound was obtained as a pale yellow solid. Physical property value: m/z [M+H]+ 363.1 |
1.26 g | Stage #1: carbon monoxide; (R)-3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester With bis-triphenylphosphine-palladium(II) chloride; 2-(Diethylamino)ethanol In 1-methyl-pyrrolidin-2-one at 120℃; for 1h; Stage #2: With water; sodium hydroxide In 1-methyl-pyrrolidin-2-one; methanol for 0.166667h; | 2 Reference Example 2 Synthesis of (R)-4-amino-1-(1-(tert-butyloxycarbonyl)piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid (R)-tert-Butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (2 g) obtained in Reference Example 1, 2-diethylaminoethanol (3 mL), and Pd(PPh3)2Cl2 (158 mg) were dissolved in NMP (20 mL). After purging of the system with carbon monoxide, the solution was heated to 120°C. The solution was stirred for 1 hour and then cooled to room temperature. Methanol (10 mL) was added thereto, then a 5 N aqueous sodium hydroxide solution (6 mL) was added thereto, and the mixture was stirred for 10 minutes. After water was added, the aqueous layer was washed with ethyl acetate and adjusted to pH 4 with hydrochloric acid, and the precipitated solid was collected by filtration, washed with water, and then dried to obtain 1.26 g of the title compound as a pale yellow solid. Physical property value: m/z[M+H]+ 363.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With hydrogenchloride In 1,4-dioxane; water at 20℃; for 16h; | 1.4; 95.7; 112.4 Step 4: Synthesis of compound (R) -3-iodo-1- (piperidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine (R) -tert-butyl 3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1-carboxylate (1.0 g, 2.25 mmol) was dissolved in dioxane (6 mL), and then hydrochloric acid (4N, 6 mL) was added to the reaction solution.Stir at room temperature for 16 hours. After the reaction, add dilute aqueous sodium hydroxide solution.Adjusted to pH = 9, extracted with dichloromethane (150mL), washed with saturated brine (60mL),Dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and separate and purify by silica gel column chromatography(DCM / MeOH (v / v) = 12 / 1-6 / 1), 700 mg of product was obtained, yield: 90%. |
83% | With hydrogenchloride In 1,4-dioxane; methanol at 20℃; for 14h; | 94 3-Iodo-1 -[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine Example 94: N-[[4-[4-amino-1-[(3R)-1-methyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3- yl]phenyl]methyl]-2-methoxy-benzamide 3-Iodo-1 -[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine To a stirred solution of tert-butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1 -yl)piperidine-1 - carboxylate (500 mg, 1.1 3 mmol) in methanol (15 mL) was added hydrogen chloride in 1 ,4-dioxane (4 M, 0.78 mL, 22.51 mmol). The reaction was stirred at room temperature for 14 h then the solvent was removed under reduced pressure. Further purification by flash column chromatography (DCM/ 7 N NH3 in MeOH 100:0 to 90:10) gave 3-iodo-1 -[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (357 mg, 0.93 mmol, 83% yield) as a white solid. UPLC-MS (ES+, Short acidic): 0.74 min, m/z 345.0 [M+H]+ |
With trifluoroacetic acid In dichloromethane at 20℃; for 6h; | 6 Example 6: Process for the preparation of 3-(4-iodo)-1-(piperidine-3-yl)-1H-pyrazolo[3,4- d]pyrimidine-4-amine Trifluoroacetic acid (3.0 mL) was added to a solution of (R)-tert-butyl-3-(4-amino-3-iodo-1H- pyrazolo[3,4-d]pyrimidine-1-yl)piperidine-1-carboxylate (Formula V, 2.8 g) in dichloromethane (300 mL) at 0-10 °C. The reaction mass was heated to room temperature and stined for 6 h. The mass was concentrated and the residue was dissolved in dichloromethane (100 mL) and washed with saturated sodium bicarbonate solution (100 mL). The aqueous layer was saturated with sodium chloride (10 g) and extracted with dichloromethane (100 mL). Both organic layers were concentrated to get 3 -iodo- 1 -(piperidine-3 -yl)- 1 H-pyrazolo [3 ,4-d]pyrimidine-4-amine |
With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
166 mg | Stage #1: (R)-3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester; [4-[[(2,6-difluorobenzoyl)amino]methyl]-3-fluorophenyl]boronic acid With potassium carbonate In 1,4-dioxane; water for 0.416667h; Inert atmosphere; Stage #2: With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 In 1,4-dioxane; water at 120℃; for 14.5h; Inert atmosphere; | 62 General procedure C General procedure: General procedure C A mixture of tert-butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1 -yl)piperidine-1 -carboxylate (1.0 eq.), boronic acid or pinacol ester (1.5 eq.) and potassium carbonate (2.0 eq.) in 1 ,4-dioxane and water (3:1 , 0.1 M) was degassed by bubbling nitrogen through it for 25 min. 1 ,1 '- bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.05 eq.) was added and the mixture was degassed again by bubbling nitrogen through it for 30 min. The mixture was then heated at 1 20 °C for 14 h. The reaction mixture was filtered over Celite. The cake was rinsed with DCM. Water was added to the filtrate and the layers were partitioned. The aqueous layer was extracted with DCM (2 ×). The combined organic extracts were filtered over phase separator and then concentrated under reduced pressure to give a dark solid. Further purification by flash column chromatography (DCM/MeOH 100:0 to 90:10) gave the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
208.5 mg | Stage #1: (R)-3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester; [4-[[(2-fluorobenzoyl)amino]methyl]phenyl]boronic acid With potassium carbonate In 1,4-dioxane; water for 0.25h; Inert atmosphere; Stage #2: With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 In 1,4-dioxane; water at 120 - 140℃; Inert atmosphere; Microwave irradiation; | 1 General procedure D General procedure: General procedure D A mixture of tert-butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1 -yl)piperidine-1 -carboxylate (1.0 eq.), boronic acid or pinacol ester (1.5 eq.) and potassium carbonate (2.0 eq.) in 1 ,4-dioxane and water (3:1 , 0.1 M) was degassed by bubbling nitrogen through it for 15 min. 1 ,1 '- bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.05 eq.) was added and the mixture was degassed again by bubbling nitrogen through it for 15 min. The mixture was then heated under microwave irradiation at 120-140 °C for 60-90 minutes. The reaction mixture was either purified by SCX and used as such or purified using the following procedure, unless stated used crude. The mixture filtered over Celite. The cake was rinsed with DCM. Water was added to the filtrate and the layers were partitioned. The aqueous layer was extracted with DCM (2 ×). The combined organic extracts were filtered over phase separator and then concentrated under reduced pressure to give a dark solid. Further purification by flash column chromatography (DCM/MeOH 100:0 to 90:10) gave the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.2 g | With hydrogenchloride In methanol at 45℃; for 0.5h; | 7 Example 7: Preparation of 3-iodo- 1 -[(3R)-piperidin-3-ylj- 1H-pyrazolo[3,4-djpyrimidin-4- amine monohydrochloride (hydrochloride salt of Formula VI, when X is iodo) A mixture of tert-butyl (3R)-3-(4-amino-3-iodo- 1H-pyrazolo [3 ,4-d Ipyrimidin- 1- yl)piperidine-1-carboxylate (Formula V, when X is iodo and Pr’ is Boc, 1.7 g) andmethanolic hydrochloric acid (15 mL) was stirred for 30 minutes at 45°C. The reaction mixture was evaporated to complete dryness at a temperature not more than 45°C, thenwashed with ethyl acetate (30 mL), and then re-evaporated to complete dryness at a temperature not exceeding 45°C to obtain the title compound.‘HNMR(DMSO-d6, 400 MHz) 1.8-2.0 (m, 2H), 2.0-2.2 (m, 2H), 3.2-3.5 (m, 3H), 2.99-3.0 (m, 1H), 5.12 (s, 1H), 8.66 (s, 1H), 9.52-9.72 (bs, 2H)Mass mlz = 345.3 [M+Hj |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water at 100℃; for 24h; Inert atmosphere; | 1.C.1 Step 1: Preparation of (R)-3- 4-amino-3-[2-(4-methoxy-phenyl) isoindoline-1-one-5-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl)Piperidine-1-carboxylic acid tert-butyl ester The (R)-3-(4-amino-3-iodo-1H-pyrazolo[3,4-d] pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (400mg, 0.9 mM,1.0equiv), 4- (4,4,5,5- tetramethyl- - [3,2] dioxolane Borane-yl) -2- (4-methoxyphenyl) iso indol-1-one (362mg,0.99mM, 1.1equiv), tetrakis (triphenylphosphine) palladium (62mg, 0.054mM, 0.06equiv) and sodium carbonate (200mg, 1.89mM,2.1equiv) in a mixture of dioxane (4mL) and water (1mL) in at 100 was heated under nitrogen atmosphere 24h. WillThe reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure, the residue was partitioned between the two phases in saturated aqueous sodium bicarbonate and ethyl acetate, separate the organicLayer, the aqueous layer was extracted twice with ethyl acetate, the combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (petroleum ether:Ethyl acetate = 1: 2) to give a white solid (340mg, 68% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,2-dimethoxyethane; water at 85℃; for 48h; Inert atmosphere; | 2.B.1 Step 1: The (R)-3- (4- amino-3-iodo--1H- pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1-carboxylic acid tert-butyl ester(483 mg, 1 . 09 mm, 1 . 0equiv), 4-(4, 4,5,5-tetramethyl-[1,3,2]dioxapentaborane-2-yl)-2-(pyridine-2-yl)isoindoline-1-one (402 mg, 1.2 mm, 1 . 1equiv), tetrakis(triphenylphosphine) palladium (72 mg, 0 . 062 mm, 0 . 06equiv) and sodium carbonate (232 mg, 2 . 18 mm, 2 . 1equiv) in a mixture of ethylene glycol dimethyl ether (3 ml) and water (1.5 ml) in the mixture, in 85 °C heating in nitrogen atmosphere under 48h. Cooling the reaction mixture to the room temperature and reduced pressure to remove the solvent, the residue in saturated sodium bicarbonate aqueous solution and ethyl acetate two-phase distribution, separating organic layer, the aqueous layer is extracted two times with ethyl acetate, the combined organic extract is dried with anhydrous sodium sulfate, filtered and concentrated. Column chromatography (petroleum ether: ethyl acetate = 1:4) processing to obtain white solid (440 mg, yield 77%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,2-dimethoxyethane; ethanol at 90℃; for 12h; | |
82% | Stage #1: 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole; (R)-3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester With sodium carbonate In 1,2-dimethoxyethane; ethanol for 0.0833333h; Inert atmosphere; Stage #2: With tetrakis(triphenylphosphine) palladium(0) In 1,2-dimethoxyethane; ethanol at 90℃; for 12h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride In acetone at 40 - 50℃; for 6h; | 10 Example 10: process for the preparation of 3-(4-iodo)-1-(piperidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine dihydrochloride Hydrochloric acid (15% in 15 mL isopropyl alcohol) was added to a solution of (R)-tert-butyl-3-(4-amino-3-iodo- 1 H-pyrazolo[3 ,4-d]pyrimidine- 1 -yl)piperidine- 1 -carboxylate (ibrutinib, 5 g) in acetone (50 mL) and stined for 6 hours at 40-50 °C. The reaction mass was cooled to room temperature, filtered, and washed with acetone (10 mL). The wet material was dried under vacuum at 50 °C to get 3-(4-iodo)- 1 -(piperidine-3 -yl)-l H-pyrazolo [3 ,4-d]pyrimidine-4-amine dihydrochloride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,2-dimethoxyethane; water at 105℃; for 2h; | Step 1: Intermediate 10-a Step 1: Intermediate 10-a To a degassed solution of intermediate 3-b (1.1 g, 2.8 mmol), intermediate 2-f (1.3 g, 2.9 mmol) and potassium carbonate (1.1 g, 8.3 mmol) in DME (14.8 ml) and water (3.7 ml) was added PdCI2(dppf) (203 mg, 0.3 mmol) and the reaction was heated in a pressure vessel at 105 °C for 2 hours and then cooled to room temperature. Ethyl acetate was added and the reaction was filtered over celite. A saturated aqueous solution of ammonium chloride was added to the filtrate, the organic layer was separated, washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. Purification by silica gel chromatography provided intermediate 10-a as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4 g | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water at 90℃; for 12h; Inert atmosphere; | |
0.1 g | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water at 100℃; Inert atmosphere; | 1.5 Step 5: Synthesis of Compound e Compound d (0.9g, 1.2eq), Compound i (0.1g, 1eq), Pd(PPh3)4 (0.013g, 0.05eq), K2CO3 (0.062g, 2eq), 1,4- dioxane / H2O (12mL, 5/1) were mixed and stirred overnight under nitrogen at 100°C, followed by concentration anddirect column chromatography, giving 0.1g of solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 12h;Inert atmosphere; | 3-iodo-4-amino-1H-pyrazolo [3,4-d] pyrimidine (6.45g, 24.7mmol), (R) -1-Boc-3-hydroxypiperidine (9.93g, 49.4 mmol), triphenylphosphine PPh3 (9.73 g, 37.1 mmol) was placed in a 250 mL round-bottomed flask, placed in a magnet, 130 mL of THF was added, and stirred at room temperature under the protection of nitrogen; diisopropyl azodicarboxylate was taken DIAD (7.5g, 37.1mmol) was dissolved in about 30mL of THF, and slowly added to the reaction system. After the dropwise addition was completed, the reaction was continued for about 12 hours. According to the results of TLC (thin-layer chromatography), the reaction was stopped and concentrated under reduced pressure. Silica gel column chromatography was performed with petroleum ether-ethyl acetate as eluent to obtain white solid 1b with a yield of 68%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,2-dimethoxyethane; water at 80℃; Inert atmosphere; | 33.b (R) -1-Boc-3- (4-amino-3- (4-benzylphenyl) -1H-pyrazolo[3,4-D] pyrimidin-1-yl) piperidineSynthesis 500ml single mouth bottle,(4-amino-3-iodo-1H-pyrazolo [3,4-D] pyrimidin-1-yl) piperidine (2.6 g, 5.9 mmol)4-benzylphenylboronic acid pinacol ester (1.2 g, 5.9 mmol)Na2CO3 (2.31 g, 31 mmol),Dimethoxyethane (DME) (150 ml),H2O (30 ml).N2 replacement 3 times,The catalyst tetratriphenylphosphine palladium (Pd (PPh3) 4) (0.23 g, 0.3 mmol) was added,N2 replacement 3 times. Heated to 80 ° C,Reflux overnight, raw material reaction finished. The reaction system is an orange clear solution.Rotate most of the solvent, add water, extract DCM, dry the organic phase,The product was purified by column chromatography (2.1 g, yield 75%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | <strong>[101-55-3]4-Bromodiphenyl ether</strong> (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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine In N,N-dimethyl-formamide at 80℃; for 13h; Inert atmosphere; | 2 General procedure: A mixture of compound 11 (10.4mmol), 12a-12o (52mmol), Pd(PPh3)4 (0.78mmol), CuI (2.08mmol), triethylamine (20.8mmol) and DMF (40mL) was stirred under nitrogen atmosphere at 80°C for 10h-13h. Then the reaction mixture was allowed to cool to room temperature and a mixture of ethyl acetate and water was added, the organic layer was separated and extracted with saturated brines, dried over Na2SO4 and concentrated under reduced pressure. The residues were purified by silica gel column chromatography eluting at a gradient of 30-50% ethyl acetate in petroleum ether, giving the crude products 13a-13o, which were used for next step without purification (Yield of crude: 60-80%). To a stirred solution of compound 13a-13o (10.25mmol) in ethyl acetate (20mL) was added 4M HCl in dioxane (25mL), and it was stirred at room temperature for 6-8h. Then, the solid was collected by filtration and was dried on vacuum to afford 14a-14o. The solid was directly used for the next step as HCl salt (Yield: 60-80%). |
73.6% | With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine In N,N-dimethyl-formamide at 80℃; Inert atmosphere; | 2.B Step B: Synthesis of Compound 6 Compound 4 (4.45 g, 10 mmol), CuI (0.38 g, 2 mmol), Pd (PPh3) 4 (1.39 g, 1.2 mmol),Et3N (2.03g, 20mmol),Compound 5 (6.62 g, 50 mmol) and 50 ml of DMF were warmed to 80 ° C under nitrogen overnight.Down to room temperature,After concentration column chromatography, the solid was 3.31 g.Yield: 73.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine In N,N-dimethyl-formamide at 80℃; Inert atmosphere; | 3 General procedure: A mixture of compound 11 (10.4mmol), 12a-12o (52mmol), Pd(PPh3)4 (0.78mmol), CuI (2.08mmol), triethylamine (20.8mmol) and DMF (40mL) was stirred under nitrogen atmosphere at 80°C for 10h-13h. Then the reaction mixture was allowed to cool to room temperature and a mixture of ethyl acetate and water was added, the organic layer was separated and extracted with saturated brines, dried over Na2SO4 and concentrated under reduced pressure. The residues were purified by silica gel column chromatography eluting at a gradient of 30-50% ethyl acetate in petroleum ether, giving the crude products 13a-13o, which were used for next step without purification (Yield of crude: 60-80%). To a stirred solution of compound 13a-13o (10.25mmol) in ethyl acetate (20mL) was added 4M HCl in dioxane (25mL), and it was stirred at room temperature for 6-8h. Then, the solid was collected by filtration and was dried on vacuum to afford 14a-14o. The solid was directly used for the next step as HCl salt (Yield: 60-80%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine In N,N-dimethyl-formamide at 80℃; Inert atmosphere; | 4 General procedure: A mixture of compound 11 (10.4mmol), 12a-12o (52mmol), Pd(PPh3)4 (0.78mmol), CuI (2.08mmol), triethylamine (20.8mmol) and DMF (40mL) was stirred under nitrogen atmosphere at 80°C for 10h-13h. Then the reaction mixture was allowed to cool to room temperature and a mixture of ethyl acetate and water was added, the organic layer was separated and extracted with saturated brines, dried over Na2SO4 and concentrated under reduced pressure. The residues were purified by silica gel column chromatography eluting at a gradient of 30-50% ethyl acetate in petroleum ether, giving the crude products 13a-13o, which were used for next step without purification (Yield of crude: 60-80%). To a stirred solution of compound 13a-13o (10.25mmol) in ethyl acetate (20mL) was added 4M HCl in dioxane (25mL), and it was stirred at room temperature for 6-8h. Then, the solid was collected by filtration and was dried on vacuum to afford 14a-14o. The solid was directly used for the next step as HCl salt (Yield: 60-80%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine In N,N-dimethyl-formamide at 80℃; Inert atmosphere; | 5 General procedure: A mixture of compound 11 (10.4mmol), 12a-12o (52mmol), Pd(PPh3)4 (0.78mmol), CuI (2.08mmol), triethylamine (20.8mmol) and DMF (40mL) was stirred under nitrogen atmosphere at 80°C for 10h-13h. Then the reaction mixture was allowed to cool to room temperature and a mixture of ethyl acetate and water was added, the organic layer was separated and extracted with saturated brines, dried over Na2SO4 and concentrated under reduced pressure. The residues were purified by silica gel column chromatography eluting at a gradient of 30-50% ethyl acetate in petroleum ether, giving the crude products 13a-13o, which were used for next step without purification (Yield of crude: 60-80%). To a stirred solution of compound 13a-13o (10.25mmol) in ethyl acetate (20mL) was added 4M HCl in dioxane (25mL), and it was stirred at room temperature for 6-8h. Then, the solid was collected by filtration and was dried on vacuum to afford 14a-14o. The solid was directly used for the next step as HCl salt (Yield: 60-80%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine In N,N-dimethyl-formamide at 80℃; Inert atmosphere; | 6 General procedure: A mixture of compound 11 (10.4mmol), 12a-12o (52mmol), Pd(PPh3)4 (0.78mmol), CuI (2.08mmol), triethylamine (20.8mmol) and DMF (40mL) was stirred under nitrogen atmosphere at 80°C for 10h-13h. Then the reaction mixture was allowed to cool to room temperature and a mixture of ethyl acetate and water was added, the organic layer was separated and extracted with saturated brines, dried over Na2SO4 and concentrated under reduced pressure. The residues were purified by silica gel column chromatography eluting at a gradient of 30-50% ethyl acetate in petroleum ether, giving the crude products 13a-13o, which were used for next step without purification (Yield of crude: 60-80%). To a stirred solution of compound 13a-13o (10.25mmol) in ethyl acetate (20mL) was added 4M HCl in dioxane (25mL), and it was stirred at room temperature for 6-8h. Then, the solid was collected by filtration and was dried on vacuum to afford 14a-14o. The solid was directly used for the next step as HCl salt (Yield: 60-80%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In water; N,N-dimethyl-formamide at 85℃; Inert atmosphere; | 10.2 General procedure: In the second step, the boric acid product from the previous step was added to 70 mL of DMF that had been bubbled with Ar. Compound 1a and tetrakistriphenylphosphine palladium were stirred under the protection of Ar, and then 2N aq. K 2 CO 3 aqueous solution was added. The reaction system was heated to 85° C. under Ar protection, and the reaction was completed overnight. TLC followed the reaction completely. It was cooled to room temperature, filtered through celite and washed several times with ethyl acetate. The mixture was washed with water three times, washed with saturated brine, dried, filtered, and concentrated under reduced pressure. The mixture was purified with silica gel column chromatography using petroleum ether-ethyl acetate as eluent. Chemical reagents and data characterization:Intermediate 8a (R1=H), Reagents: Compound 3a (30 mmol), n-Butyllithium (33.3 mmol), triisopropyl borate(39.4 mmol), Compound 1a (17.3 mmol), tetrakistriphenylphosphine palladium (0.78 mmol), 2N aq. K2CO3 (26 mL),White solid, yield 60% (two steps), |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 2-methyltetrahydrofuran; water for 24h; Reflux; Large scale; | 1.II.C Step C: Add compound 1b (1.40 kg, 3.15 mol) and sodium carbonate (1.34 kg, 12.56 mol) to a glass reactor with 11.2 L of 2-methyltetrahydrofuran and 2.24 L of water, and then add tetratriphenylphosphine Palladium (36.4g, 31.5mmol), stir and start heating, and then add compound 2c (1.25kg, 5.35mol) in portions. The reaction is refluxed for about 24 hours and the reaction is detected to be complete. The reaction is stopped and the temperature is lowered to room temperature. Filter the soil and concentrate the filtrate under reduced pressure to remove most of the 2-methyltetrahydrofuran. Dichloromethane and water are added for extraction. The dichloromethane phase is washed three times with water. The dichloromethane phase is separated and concentrated under reduced pressure. Hexane was recrystallized to give 2d as a white solid product with a yield of 62%. |
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In water; N,N-dimethyl-formamide at 85℃; Inert atmosphere; | 12.2 In the second step, the boric acid product from the previous step was added to 70 mL of DMF that had been bubbled with Ar. Compound 1a and tetrakistriphenylphosphine palladium were stirred under the protection of Ar, and then 2N aq. K 2 CO 3 aqueous solution was added. The reaction system was heated to 85° C. under Ar protection, and the reaction was completed overnight. TLC followed the reaction completely. It was cooled to room temperature, filtered through celite and washed several times with ethyl acetate. The mixture was washed with water three times, washed with saturated brine, dried, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether-ethyl acetate as eluent to give a white solid.Intermediate 10a (R1 = H), Reagents: Compound 5a (3 mmol), n-Butyllithium (3.33 mmol), triisopropyl borate(3.94 mmol), Compound 1a (1.73 mmol), Tetratriphenylphosphine Palladium (0.078 mmol), 2N aq. K2CO3 (2.6 mL) ProductWhite solid, 30% yield (two steps), |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In water; N,N-dimethyl-formamide at 85℃; Inert atmosphere; | 14.2 In the second step, the boric acid product of the previous step (2.3 mmol), compound 1a (1.73 mmol) of tetraphenylphosphine palladium (0.078 mmol) were added to 7 mL of DMF that had just been sparged with Ar, and the mixture was stirred under Ar and then 2.6 mL of 2N aq. K2CO3 aqueous solution was added. The reaction system was heated to 85° C. under Ar protection, and the reaction was completed overnight. TLC followed the reaction completely. Cool to room temperature, filter through celite, and wash EA several times. Then it was extracted with ethyl acetate, washed with water three times, washed with saturated brine, dried, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography with petroleum ether-ethyl acetate as eluent to obtain 11 as a white solid. Yield: 25% , |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In water; N,N-dimethyl-formamide at 85℃; Inert atmosphere; | 15.2 In the second step, the boric acid product from the previous step (1.5 mmol), compound 1a (1.1 mmol) tetrakistriphenylphosphine palladium (0.06 mmol) were added to 5 mL of DMF that had just been sparged with Ar and stirred under Ar and then 1.5 mL of 2N aq. K2CO3 aqueous solution was added. The reaction system was heated to 85° C. under Ar protection, and the reaction was completed overnight. TLC followed the reaction completely. Cool to room temperature, filter through celite, and wash EA several times. Then, the mixture was extracted with ethyl acetate, washed with water three times, washed with saturated brine, dried, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography with petroleum ether-ethyl acetate as eluent to obtain 12 as a white solid. Yield 15% , |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water at 80℃; for 6h; | 1.1-5.1 As shown in Figure 1, a method for preparing ibrutinib-d5 comprises the following steps: (1) 20 g of (3R)-1-Boc-3-(4-amino-3-iodo-1H-pyrazolo[3,4-D]pyrimidin-1-yl)piperidine was suspended in 300 mL of 1 , in 4-dioxane and 40 mL of water, 12.5 g of 4-benzyloxybenzeneboronic acid was added, 10 g of potassium carbonate and 1.2 g of tetrakistriphenylphosphine palladium were sequentially added, and the mixture was reacted at 80 ° C for 6 hours. TLC showed the reaction was complete, the reaction solution was concentrated to remove 1,4-dioxane, and 50 mL of water was added to room temperature for 3 hours. After suction filtration, the filter cake was washed with water and dried to obtain 20 g of Compound C in a yield of 85%; |
73% | With chloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II); potassium carbonate In 1,4-dioxane; water at 95℃; for 1.5h; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,2-dimethoxyethane; water at 95℃; for 12h; Inert atmosphere; | 117.1 Compound (R) -tert-butyl 3- (4-amino-3- (4-bromophenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1-carboxylic acid ester (R) -tert-butyl 3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1-carboxylate (1.7g, 3.8 mmol) is dissolved in a mixed solvent of ethylene glycol dimethyl ether (50 mL) and water (12 mL),Then 4-bromobenzeneboronic acid (1 g, 4.98 mmol), potassium carbonate (1.1 g, 7.7 mmol) and tetratriphenylphosphine palladium dichloride (45 mg, 0.038 mmol) were added in sequence.Protected by nitrogen, heated to 95 ° C and stirred for 12 hours.Stop heating, cool to room temperature, filter, and concentrate.Silica gel column chromatography was separated and purified (DCM / MeOH (v / v) = 40/1) to obtain a yellow solid 1.47g, yield: 81%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.78% | With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; potassium carbonate In 1,4-dioxane; water monomer at 105℃; for 8h; Inert atmosphere; Cooling with ice; | 2.4 2.4 Synthesis of Intermediates 2-8: Weigh 436 mg (1.35 mmol) of intermediate 2-4 in turn,Intermediate 2-7 500 mg (1.13 mmol),Pd(dppf)Cl2 25mg (0.03mmol),K2CO3 468mg (3.39mmol) was added to a 10mL three-neck flask,nitrogen protection,Add a mixed solution of 1,4-dioxane:water (3:1) under ice bath conditions,Then transfer to 105°C to start the reflux reaction.After 8h, the progress of the reaction was monitored by TLC. After the reaction was completed, the reaction solution was cooled to room temperature first.The Pd(dppf)Cl2 was removed by suction filtration with celite, then the filtrate was extracted with water (100 mL×4) and 100 mL of ethyl acetate, and the organic phase was dried over anhydrous Na2SO4.The concentrated filtrate was separated by column chromatography to obtain 456 mg of light brown solid 2-8 with a yield of about 78.6%; |
Tags: 1276110-38-3 synthesis path| 1276110-38-3 SDS| 1276110-38-3 COA| 1276110-38-3 purity| 1276110-38-3 application| 1276110-38-3 NMR| 1276110-38-3 COA| 1276110-38-3 structure
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P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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