* 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.
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).
With di-isopropyl azodicarboxylate; triphenylphosphine In ethyl acetate at 10 - 30℃; Darkness; Industrial scale
600g of (S) -t-butyloxycarbonyl-3-hydroxypiperidine, 780g of triphenylphosphine and 3L of ethyl acetate was added to the reaction flask and stirred to be clear,After clearing, 300 g of 4-amino-3- (4-phenoxyphenyl) -1H-pyrido (3,4-d)Continue stirring 10 ~ 30min,Dark, temperature control at 10 ~ 15 ° C began to drop under the conditions of diisopropyl azodicarboxylate,After the addition was completed, the temperature was raised to 25 ~ 30 ° C, the reaction was stirred 3 ~ 4h; stop the reaction, cooled to 0 ° C,Start dropping lllOmL concentrated HC1, after the addition was completed, warmed to room temperature, the reaction was stirred 3 ~ 4h; stop the reaction,Add 3L of purified water and stir, then respectively add 1.8L chloroform extraction 5 times and 1.8L ethyl acetate extraction 2 times,After extraction, add 1.2L of ethyl acetate, cooled to 0 ° C, began dropping 25percent NaOH solution,Adjust the pH value to 8 ~ 9, precipitated a large amount of solid, stirring crystallization, crystallization end, centrifugal rejection rejection,The filter cake was washed with a small amount of ethyl acetate, the resulting filter cake 55 ~ 60 ° C under vacuum,Vacuum -0.080MPa ~-0 lOOMPa,Intermediate I336.3g, yield 88.1percent.
72%
Stage #1: With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 5℃; for 0.166667 h; Inert atmosphere Stage #2: at 0 - 20℃; for 5 h; Inert atmosphere
Under nitrogen protection, Ph3P (29.0 g, 112 mmol, 1.25 eq), (3S)-hydroxy-1-tert-butoxycarbonylpiperidine (18.0 g, 89.3 mmol, 1.0 eq) dissolved in tetrahydrofuran 150ml, cooled to 0 °C , the control temperature does not exceed 5 °C , in 20-30 min by adding DIAD (25.1g, 125mmol, 1.4eq) in tetrahydrofuran (40ml) solution, add, the yellow solution to continue stirring 10min.And then added at 0~5 °C 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (28.1 g, 93.9 mmol, 1.05 eq)In tetrahydrofuran (150 ml) was added and the mixture was stirred at room temperature for 5h. Add water 3.2ml, warm to 50-60 °C 30min, Then, magnesium chloride (27.0 g, 280 mmol, 2.5 eq) was added, stirred at reflux for 2.5 h, Cooled to 0 ° C, filtered, washed with tetrahydrofuran (50 ml x 2), removed by rotary evaporation to remove the solvent, The residual oily substance was beaten with ethyl acetate (300 ml), n-hexane (50 ml) was added, filtered, and the residue was washed with ethyl acetate (30 ml x 2). The filtrate was washed with water (100 ml x 2), saturated brine (150 ml) Washed with anhydrous sodium sulfate, the filtrate was removed by rotary evaporation solvent, the residue Ph3PO content: 5.6wtpercent, and then adding isopropyl alcohol (40ml) in the residue to 50-60 ° C stirring, cooling crystallization, Filtration of a small amount of cold isopropanol and drying in vacuo gave 28.1 g of product (yield 72percent by weight, pale yellow solid), Ph3PO content: 0.8 wtpercent.
69%
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 1.05 - 1.08333 h; Heating / reflux
To a solution of 1-boc-3-(S)-hydroxypiperidine (3.98 g, 19.8 mmol) and triphenylphosphine (5.19 g, 19.8 mmol) in THF (150 ml) was added DIAD (3.9 ml, 19.8 mmol). The yellow solution was stirred 1 minute then Intermediate 2 (4.0 g, 13.2 mmol) was added and the reaction was heated with a heat gun (3-5 minutes) until the solid had dissolved. After stirring for 1 hour at room temperature, the solvent was removed and the resulting brown oil was subjected to flash chromatography (30percent then 50percent THF/hexanes) to provide 4.45 g (69percent) of Intermediate 3 (trace of triphenylphosphine oxide is present) as a light brown foam.
38%
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃;
Example 1. Synthesis of (i?)-l-('3-(4-Amino-3-('4-phenoxyphenyl)-lH- pyrazolo [3 A-d] pyrimidin- 1 -yQpiperidin- 1 -yl)prop-2-en-2,3 ,3 -dy 1 -one (Compound 122). Scheme 5. Preparation of Compound 122 35 36 Compound 122 [96] Step 1. 3-Iodo-lH-pyrazolo[3,4-^pyrimidin-4-amine (31). lH-Pyrazolo[3,4- d]pyrimidin-4-amine, 30 (5.0 g, 37 mmol, 1 equiv) was suspended in DMF (100 mL) and N-iodosuccinimide ( IS) (10.7 g, 45 mmol, 1.2 equiv) was added. The reaction was heated at 80 °C for 2 hours. The reaction was cooled to room temperature and then to 0 °C and was quenched by the drop-wise addition of water (200 mL). The resulting solids were collected by filtration, washed with water and cold ethanol, and dried in a vacuum oven to yield 31 (8.1 g, 84percent yield) as a beige solid. [97] Step 2. Phenoxyphenyl -lH-pyrazolo[3,4-< ]pyrimidin-4-amine (33). Compound 31 (4.0 g, 15.3 mmol, 1 equiv), boronic acid 32 (6.56 g, 30.7 mmol, 2 equiv), and potassium phosphate tribasic monohydrate (10.56 g, 45.9 mmol, 3 equiv) were dissolved in dioxane (50 mL) and water (20 mL). The mixture was sparged with nitrogen for 20 minutes and tetrakis(triphenylphosphine)palladium (2.70 g, 2.3 mmol, 0.15 equiv) was added. The mixture was sparged with nitrogen for an additional 5 minutes and then heated at reflux for 24 hours. The reaction was cooled to room temperature and stirred overnight, giving a beige precipitate. The reaction mixture was diluted with water (50 mL) and the solids were collected by filtration. The crude product was triturated with methanol (150 mL) to yield 3.9 g of 85percent pure product. The purity was further improved by trituration with ethyl acetate (100 mL), yielding 33 (3.6 g, 77percent yield, 90percent pure) as a beige solid. [98] Step 3. (R ert-Butyl 3-(4-amino-3-(4-phenoxyphenvn-lH-pyrazoror3.4- Compound 33 (1.80 g, 5.9 mmol, 1 equiv), protected piperidine, 34 (1.43 g, 7.1 mmol, 1.2 equiv), triphenylphosphine (2.33 g, 8.9 mmol, 1.5 equiv), and diisopropyl azodicarboxylate (1.80 g, 8.9 mmol, 1.5 equiv) were dissolved in THF (200 mL) and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate (1 x 300 mL) and brine (1 x 300 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was adsorbed onto silica gel and purified using an Analogix automated chromatography system eluting with 0-8percent methanol in dichloromethane. All fractions containing product were combined and re- chromatographed using the above conditions to yield 35 (1.1 g, 38percent yield) as a white foam. [99] Step 4. (7?V3-(4-Phenoxyphenvn- 1 -(piperidin-3-νΠ- 1 //-pyrazoloH A- dlpyrimidin-4-amine hydrochloride (36). Compound 35 (700 mg, 1.48 mmol, 1 equiv) was dissolved in dioxane (8 mL). A solution of hydrogen chloride in dioxane (4 mL of a 4 N solution in dioxane, 16 mmol, 10.7 equiv) was added and the reaction was stirred at room temperature overnight. The reaction was diluted with diethyl ether (20 mL) and the resulting solids were collected by filtration under a stream of nitrogen. The product was further dried in a vacuum oven to yield 36 (550 mg, 88percent yield) as an off-white solid. [100] Step 5. (_)- l-(3-(4-Amino-3-(4-phenoxyphenyl)- lH-pyrazolor3,4- ( Ipyrimidin- 1 -yDpiperidin- 1 -yl)prop-2-en-2,3 ,3 -dy- 1 -one (Compound 122). [101] A) DMF (0.003 mL, 0.03 mmol, 0.02 equiv) was added to commercially available acrylic acid-d4 (126 mg, 1.66 mmol, 1 equiv, 99 atom percent D) followed by oxalyl chloride (0.16 mL, 1.83 mmol, 1.1 equiv). The mixture was stirred for 30 minutes, at which point all gas evolution had ceased. The resulting acryloyl-d3 chloride (37) was used as such. [102] B) In a 20 mL vial, triethylamine (0.46 mL, 3.18 mmol, 3 equiv) was added to a suspension of 36 (450 mg, 1.06 mmol, 1 equiv) in dichloromethane (10 mL). The reaction was stirred for 15 minutes, resulting in a clear solution. Acryloyl-d3 chloride (37) (0.10 mL, 1.17 mmol, 1.1 equiv, prepared above) was then added and the reaction was stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane (50 mL) and washed with 5percent citric acid (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using an Analogix automated chromatography system eluting with 0-8percent methanol in dichloromethane. All fractions containing product were pooled and concentrated to give a colorless film which was dissolved in benzene/methanol (5 mL) and lyophilized to yield Compound 122 (170 mg, 36percent yield, [M+H]+ = 444.3) as a white powder.
0.3 g
Stage #1: With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran Stage #2: at 20℃;
Diisopropyl diazodicarboxylate (DAID, 1.2 ml) was added to a solution of 1-tert-butyloxycarbonyl-3-(S)-hydroxypiperidine ( 1.0 g,) and triphenylphosphine (2.59g) in tetrahydrofuran (50.0ml). To the resulting yellow solution, 3-(p-phenoxyphenyl)-1,2,5,7-tetraza-1H-inden-4-ylamine (1.0g). was added and warmed till dissolution, and stirred overnight at room temperature. The reaction mixture was filtered and the solvent was distilled under vacuum to get an oily residue, which was further purified by flash chromatography (30-50 percent ethyl acetate/ hexane) on silicagel to give 0.3 g (0.3 w/w) of tert-butyloxycarbonyl-(1S)-1-[(3R)-3-piperidyl]-3-(p-phenoxyphenyl)-1,2,5,7-tetraza-1H-inden-4-ylamine as a light brown solid. The resulting solid was dissolved in dichloromethane (5 ml) and trifluoroacetic acid (0.6 ml) was added to it. After completion of reaction, water was added to reaction mass, followed by addition of methyl tert-butyl ether (20.0 ml). The layers were separated and the aqueous layer was basified with potassium carbonate and extracted with dichloromethane (15.0 ml x 2). The organic layer dried over sodium sulfate, filtered and evaporated to yield 0.2 g (0.6 w/w) of title compound as light yellow oil.
Reference：
[1] Patent: CN106995446, 2017, A, . Location in patent: Paragraph 0044-0046
[2] Patent: CN106967071, 2017, A, . Location in patent: Paragraph 0019
[3] Patent: US2008/214501, 2008, A1, . Location in patent: Page/Page column 12
[4] Organic and Biomolecular Chemistry, 2015, vol. 13, # 18, p. 5147 - 5157
[5] Patent: WO2014/22390, 2014, A1, . Location in patent: Paragraph 95; 98
[6] Journal of Medicinal Chemistry, 2015, vol. 58, # 24, p. 9625 - 9638
[7] Patent: CN105481862, 2016, A, . Location in patent: Paragraph 0166; 0167; 0170
[8] Patent: WO2017/163257, 2017, A1, . Location in patent: Page/Page column 19
[9] Patent: CN106008526, 2016, A, . Location in patent: Paragraph 0016; 0063; 0064; 0065
[10] Patent: CN107759602, 2018, A, . Location in patent: Paragraph 0231; 0236-0237
3
[ 940890-90-4 ]
[ 330786-24-8 ]
[ 1022150-11-3 ]
Yield
Reaction Conditions
Operation in experiment
80%
Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 21 - 22℃; for 2 h; Stage #2: at 80℃; for 14 h;
Intermediate 1 (5g) was dissolved in dry DMF (50 mL) and potassium carbonate (8.8 g) was added. The suspension was stirred at ambient temperature for 2 h. After dropwise addition of Intermediate 2 (9 g) dissolved in DMF (10 mL) the reaction mixture was heated at 80°C for 14 h. The organic layer was separated and the water layer extracted with EtOAc (3x20 mL). The organic layers were combined and dried over Na2SC>4. Solvent evaporation at reduced pressure and recrystallization result in 6.3g (80percent) tert-butyl-(3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo [3,4-d] pyrimidin- 1 -yl]piperidine - 1 -carboxylate.
70%
With dmap; caesium carbonate In N,N-dimethyl-formamide at 90℃; for 8 h;
3-(4-phenoxyphenyl) lH-pyrazolo [3,4-d] pyrimidin-4-amine (1.14g, 3.76mmol)was dissolved DMF (30mL) in, and then the reaction solution was added (S)-tert-butyl 3-((methylsulfonyl) oxy) piperidine-1-carboxylate (4.2g, 15.04mmol), cesium carbonate(0.64mL, 8.21 mmol), 4- dimethylaminopyridine pyridine (3.67g, 11.28mmol). Was stirredat 90 deg.] C 8h, the reaction was completed, distilled under reduced pressure of DMF,and extracted with dichloromethane (150mL × 3), brine (60mL), dried over anhydroussodium sulfate, the solvent was distilled off under reduced pressure, the crude productwas silica gel column Analysis of separation and purification (methylene chloride /methanol (V / V) = 40/1), to give the product (1.28g, 70percent).
Reference：
[1] Patent: WO2017/137446, 2017, A1, . Location in patent: Page/Page column 15; 18; 19
[2] Patent: CN105399756, 2016, A, . Location in patent: Paragraph 0155; 0173-0174
4
[ 330786-24-8 ]
[ 1022150-11-3 ]
Yield
Reaction Conditions
Operation in experiment
82%
With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 12 h;
Compound 2g (6.6mmol) of Formula 8 and 1.4g (6.6mmol) t-butyl -3S- chloro - piperidine-1-AEster, 4.6g of cesium carbonate was dissolved 30mlDMF, heated to 100 , for 12 hours. The reaction mixture was pouredInto 150ml water and extracted with ethyl acetate, the organic phase was dried and concentrated to give a pale yellow solid 2.63g,Yield 82percent.
Reference：
[1] Patent: CN105622613, 2016, A, . Location in patent: Paragraph 0109; 0198; 0199; 0200; 0201; 0202; 0203
5
[ 101-55-3 ]
[ 1022150-11-3 ]
Yield
Reaction Conditions
Operation in experiment
66%
With 1,10-Phenanthroline; palladium diacetate; potassium carbonate In N,N-dimethyl acetamide at 150℃; for 16 h; Sealed tube; Inert atmosphere
A mixture of compound (III) (Pgi = Boc, Pg2 = H) (636 mg, 2.00 mmol), Pd(OAc)2 (44 mg,0.20 mmol), 1,10-phenanthroline (36 mg, 0.20 mmol), K2C03 (304 mg, 2.20 mmol), 1-bromo-4-phenoxybenzene (548 mg, 2.20 mmol) and N,N-dimethylacetamide (DMA) (10 ml)was heated in a sealed tube under argon atmosphere at 150°C for 16 h with intensive stirring.The product (III) was isolated and purified similarly to that described in the Example 1. Yield642 mg (66percent), viscous yellowish oil. The analytical data of the obtained compound (III)correspond to that of the product obtained in the Example 1.
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.
With caesium carbonate In 1-methyl-pyrrolidin-2-one at 70 - 75℃; for 12 h; Inert atmosphere
A mixture of 3 -(4-phenoxyphenyl)- 1 H-pyra.zolo [3 ,4-d]pyrimidin-4-amine compoundof formula-9 (60 gms), NMP (480 ml), (S)-tert-butyl-3-(tosyloxy)piperidine- 1 -carboxylatecompound of formula-ha (86 gms) and cesium carbonate (161 gms) was heated to 70-75°C under nitrogen atmosphere and stirred for 12 hrs. Cooled the reaction mixture to 25-30°C. Ethyl acetate was added to the reaction mixture at 25-30°C. Filtered the reaction mixture and washed with ethyl acetate. Water was added to the filtrate at 25-30°C and stirred for 15 mins.Both the organic and aqueous layers were separated. The organic layer was washed with water. Distilled off the solvent from the organic layer completely under reduced pressure to get the title compound. Yield: 77 gms.
With di-isopropyl azodicarboxylate; triphenylphosphine; In ethyl acetate; at 10 - 30℃;Darkness; Industrial scale;
600g of (S) -t-butyloxycarbonyl-3-hydroxypiperidine, 780g of triphenylphosphine and 3L of ethyl acetate was added to the reaction flask and stirred to be clear,After clearing, 300 g of 4-amino-3- (4-phenoxyphenyl) -1H-pyrido (3,4-d)Continue stirring 10 ~ 30min,Dark, temperature control at 10 ~ 15 C began to drop under the conditions of diisopropyl azodicarboxylate,After the addition was completed, the temperature was raised to 25 ~ 30 C, the reaction was stirred 3 ~ 4h; stop the reaction, cooled to 0 C,Start dropping lllOmL concentrated HC1, after the addition was completed, warmed to room temperature, the reaction was stirred 3 ~ 4h; stop the reaction,Add 3L of purified water and stir, then respectively add 1.8L chloroform extraction 5 times and 1.8L ethyl acetate extraction 2 times,After extraction, add 1.2L of ethyl acetate, cooled to 0 C, began dropping 25% NaOH solution,Adjust the pH value to 8 ~ 9, precipitated a large amount of solid, stirring crystallization, crystallization end, centrifugal rejection rejection,The filter cake was washed with a small amount of ethyl acetate, the resulting filter cake 55 ~ 60 C under vacuum,Vacuum -0.080MPa ~-0 lOOMPa,Intermediate I336.3g, yield 88.1%.
80.2%
Under nitrogen protection, Ph3P (29.2g, 112mmol), (3S)-hydroxy-1-tert-butoxycarbonylpiperidine (18.0g, 89.3mmol) was dissolved in 150ml of tetrahydrofuran, cooled to 0 C, the control temperature did not exceed A solution of DIAD (25.3 g, 125 mmol) in tetrahydrofuran (40 ml) was added at 5 C over 20-30 min. Then at 0~5CA solution of 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (28.4 g, 93.8 mmol) in tetrahydrofuran (150 ml) was added, Stir at room temperature for 5 h. Add 3.2 ml of water, then add zinc chloride (18.2 g, 134 mmol), stir to warm to 30-40 C for 2.5 h, cool to 0 C ~ 5, filter, and wash with tetrahydrofuran (50 ml × 2), remove the solvent by rotary evaporation The residual oil was slurried with ethyl acetate (300 ml), hexane (50 ml) was added, filtered, and the residue was washed with ethyl acetate (30 ml × 2), and the filtrate was water (100ml × 2), saturated brine (150ml) The organic layer was washed with anhydrous sodium sulfate, and the solvent was evaporated to remove the solvent. The residue was purified by the solvent. The content of Ph3PO was 3.81% (Comparative MgCl2: 32.4% by weight), and isopropanol (40 ml) was added to the residue to warm. Stirring at 50-60 C, cooling the crystals, filtering a small amount of cold isopropanol washing, product: 31.5 g (yield 80.2%), Ph3PO content: 0.28% (compared with MgCl 2 method: yield 85.2%; Ph3PO content: 14 wt%)
72%
Under nitrogen protection, Ph3P (29.0 g, 112 mmol, 1.25 eq), (3S)-hydroxy-1-tert-butoxycarbonylpiperidine (18.0 g, 89.3 mmol, 1.0 eq) dissolved in tetrahydrofuran 150ml, cooled to 0 C , the control temperature does not exceed 5 C , in 20-30 min by adding DIAD (25.1g, 125mmol, 1.4eq) in tetrahydrofuran (40ml) solution, add, the yellow solution to continue stirring 10min.And then added at 0~5 C 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (28.1 g, 93.9 mmol, 1.05 eq)In tetrahydrofuran (150 ml) was added and the mixture was stirred at room temperature for 5h. Add water 3.2ml, warm to 50-60 C 30min, Then, magnesium chloride (27.0 g, 280 mmol, 2.5 eq) was added, stirred at reflux for 2.5 h, Cooled to 0 C, filtered, washed with tetrahydrofuran (50 ml x 2), removed by rotary evaporation to remove the solvent, The residual oily substance was beaten with ethyl acetate (300 ml), n-hexane (50 ml) was added, filtered, and the residue was washed with ethyl acetate (30 ml x 2). The filtrate was washed with water (100 ml x 2), saturated brine (150 ml) Washed with anhydrous sodium sulfate, the filtrate was removed by rotary evaporation solvent, the residue Ph3PO content: 5.6wt%, and then adding isopropyl alcohol (40ml) in the residue to 50-60 C stirring, cooling crystallization, Filtration of a small amount of cold isopropanol and drying in vacuo gave 28.1 g of product (yield 72% by weight, pale yellow solid), Ph3PO content: 0.8 wt%.
69%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 1.05 - 1.08333h;Heating / reflux;
To a solution of 1-boc-3-(S)-hydroxypiperidine (3.98 g, 19.8 mmol) and triphenylphosphine (5.19 g, 19.8 mmol) in THF (150 ml) was added DIAD (3.9 ml, 19.8 mmol). The yellow solution was stirred 1 minute then Intermediate 2 (4.0 g, 13.2 mmol) was added and the reaction was heated with a heat gun (3-5 minutes) until the solid had dissolved. After stirring for 1 hour at room temperature, the solvent was removed and the resulting brown oil was subjected to flash chromatography (30% then 50% THF/hexanes) to provide 4.45 g (69%) of Intermediate 3 (trace of triphenylphosphine oxide is present) as a light brown foam.
38%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃;
Example 1. Synthesis of (i?)-l-('3-(4-Amino-3-('4-phenoxyphenyl)-lH- pyrazolo [3 A-d] pyrimidin- 1 -yQpiperidin- 1 -yl)prop-2-en-2,3 ,3 -dy 1 -one (Compound 122). Scheme 5. Preparation of Compound 122 35 36 Compound 122 [96] Step 1. 3-Iodo-lH-pyrazolo[3,4-^pyrimidin-4-amine (31). lH-Pyrazolo[3,4- d]pyrimidin-4-amine, 30 (5.0 g, 37 mmol, 1 equiv) was suspended in DMF (100 mL) and N-iodosuccinimide ( IS) (10.7 g, 45 mmol, 1.2 equiv) was added. The reaction was heated at 80 C for 2 hours. The reaction was cooled to room temperature and then to 0 C and was quenched by the drop-wise addition of water (200 mL). The resulting solids were collected by filtration, washed with water and cold ethanol, and dried in a vacuum oven to yield 31 (8.1 g, 84% yield) as a beige solid. [97] Step 2. Phenoxyphenyl -lH-pyrazolo[3,4-< ]pyrimidin-4-amine (33). Compound 31 (4.0 g, 15.3 mmol, 1 equiv), boronic acid 32 (6.56 g, 30.7 mmol, 2 equiv), and potassium phosphate tribasic monohydrate (10.56 g, 45.9 mmol, 3 equiv) were dissolved in dioxane (50 mL) and water (20 mL). The mixture was sparged with nitrogen for 20 minutes and tetrakis(triphenylphosphine)palladium (2.70 g, 2.3 mmol, 0.15 equiv) was added. The mixture was sparged with nitrogen for an additional 5 minutes and then heated at reflux for 24 hours. The reaction was cooled to room temperature and stirred overnight, giving a beige precipitate. The reaction mixture was diluted with water (50 mL) and the solids were collected by filtration. The crude product was triturated with methanol (150 mL) to yield 3.9 g of 85% pure product. The purity was further improved by trituration with ethyl acetate (100 mL), yielding 33 (3.6 g, 77% yield, 90% pure) as a beige solid. [98] Step 3. (R ert-Butyl 3-(4-amino-3-(4-phenoxyphenvn-lH-pyrazoror3.4- Compound 33 (1.80 g, 5.9 mmol, 1 equiv), protected piperidine, 34 (1.43 g, 7.1 mmol, 1.2 equiv), triphenylphosphine (2.33 g, 8.9 mmol, 1.5 equiv), and diisopropyl azodicarboxylate (1.80 g, 8.9 mmol, 1.5 equiv) were dissolved in THF (200 mL) and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate (1 x 300 mL) and brine (1 x 300 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was adsorbed onto silica gel and purified using an Analogix automated chromatography system eluting with 0-8% methanol in dichloromethane. All fractions containing product were combined and re- chromatographed using the above conditions to yield 35 (1.1 g, 38% yield) as a white foam. [99] Step 4. (7?V3-(4-Phenoxyphenvn- 1 -(piperidin-3-nuPi- 1 //-pyrazoloH A- dlpyrimidin-4-amine hydrochloride (36). Compound 35 (700 mg, 1.48 mmol, 1 equiv) was dissolved in dioxane (8 mL). A solution of hydrogen chloride in dioxane (4 mL of a 4 N solution in dioxane, 16 mmol, 10.7 equiv) was added and the reaction was stirred at room temperature overnight. The reaction was diluted with diethyl ether (20 mL) and the resulting solids were collected by filtration under a stream of nitrogen. The product was further dried in a vacuum oven to yield 36 (550 mg, 88% yield) as an off-white solid. [100] Step 5. (_)- l-(3-(4-Amino-3-(4-phenoxyphenyl)- lH-pyrazolor3,4- ( Ipyrimidin- 1 -yDpiperidin- 1 -yl)prop-2-en-2,3 ,3 -dy- 1 -one (Compound 122). [101] A) DMF (0.003 mL, 0.03 mmol, 0.02 equiv) was added to commercially available acrylic acid-d4 (126 mg, 1.66 mmol, 1 equiv, 99 atom% D) followed by oxalyl chloride (0.16 mL, 1.83 mmol, 1.1 equiv). The mixture was stirred for 30 minutes, at which point all gas evolution had ceased. The resulting acryloyl-d3 chloride (37) was used as such. [102] B) In a 20 mL vial, triethylamine (0.46 mL, 3.18 mmol, 3 equiv) was added to a suspension of 36 (450 mg, 1.06 mmol, 1 equiv) in dichloromethane (10 mL). The reaction was stirred for 15 minutes, resulting in a clear solution. Acryloyl-d3 chloride (37) (0.10 mL, 1.17 mmol, 1.1 equiv, prepared above) was then added and the reaction was stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane (50 mL) and washed with 5% citric acid (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using an Analogix automated chromatography system eluting with 0-8% methanol in dichloromethane. All fractions containing product were pooled and concentrated to give a colorless film which was dissolved in benzene/methanol (5 mL) and lyophilized to yield Compound 122 (170 mg, 36% yield, [M+H]+ = 444.3) as a white powder.
With di-isopropyl azodicarboxylate;
As shown in scheme I, a was used to synthesize b, wherein a is commercially available or can be prepared by methods known in the art. Using a to synthesize b with (S)-N-tert-butoxycarbonyl-3-piperidinol gave an R-configuration intermediate b. Intermediate b (0.1g) (1ml) was treated with 4NHCl in dioxane and stirred for 1 hour at room temperature then concentrated to dryness to form a product 0.08g. It was dissolved in 4ml dichloromethane. Diisopropylethylamine (0.2mL), cyclopropanecarboxylic acid (0.03g), and 2-(7-azabenzotriazolyl)-N,N,N?,N?-tetramethyluronium hexafluorophosphate HATU (0.15g) were successively added and stirred at room temperature for 30 minutes. Diluted with 20ml of dichloromethane, washed successively with water, saturated brine, dried over anhydrous Na2SO4, filtered, and spin dried in vacuo. The residue was purified by column chromatography to give compound 1 (0.03g).
0.3 g
Diisopropyl diazodicarboxylate (DAID, 1.2 ml) was added to a solution of 1-tert-butyloxycarbonyl-3-(S)-hydroxypiperidine ( 1.0 g,) and triphenylphosphine (2.59g) in tetrahydrofuran (50.0ml). To the resulting yellow solution, 3-(p-phenoxyphenyl)-1,2,5,7-tetraza-1H-inden-4-ylamine (1.0g). was added and warmed till dissolution, and stirred overnight at room temperature. The reaction mixture was filtered and the solvent was distilled under vacuum to get an oily residue, which was further purified by flash chromatography (30-50 % ethyl acetate/ hexane) on silicagel to give 0.3 g (0.3 w/w) of tert-butyloxycarbonyl-(1S)-1-[(3R)-3-piperidyl]-3-(p-phenoxyphenyl)-1,2,5,7-tetraza-1H-inden-4-ylamine as a light brown solid. The resulting solid was dissolved in dichloromethane (5 ml) and trifluoroacetic acid (0.6 ml) was added to it. After completion of reaction, water was added to reaction mass, followed by addition of methyl tert-butyl ether (20.0 ml). The layers were separated and the aqueous layer was basified with potassium carbonate and extracted with dichloromethane (15.0 ml x 2). The organic layer dried over sodium sulfate, filtered and evaporated to yield 0.2 g (0.6 w/w) of title compound as light yellow oil.
With triphenylphosphine; In tetrahydrofuran; at 5 - 10℃;
1L three bottles to join4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine 20 g (66 mmol)S-1-tert-butoxycarbonyl-3-hydroxypiperidine (26.6 g, 132 mmol); triphenylphosphine (51.9 g, 198 mmol) was added to dry tetrahydrofuran (400 mL) and cooled to 5-10 C.Under nitrogen, 40 g (198 mmol) of diisopropyl azodicarboxylate was slowly added dropwise to the flask and the reaction was carried out at 30 C for 12 hours. The reaction solution was cooled to 0 to 10 C, and 20 g of 36% hydrochloric acid was added dropwise(198 mmol), and the temperature was raised to 40 C for 1 hour.Water was added, stirred, extracted three times with dichloromethane, and the aqueous phase was collected and washed with hydrogenSodium hydroxide solution to adjust the water phase into alkaline (pH> 10), precipitate solid, filter, collect solid, blast 50 baking 12 hours(4-phenoxyphenyl) -1- (piperidin-3-yl) -1H-pyrazolo (3,4-d) pyrimidin-4-amine (V) 22.4 g, molar yield 87.9%. (HPLC purity 99.6%; optical purity ?99.8%).
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 40℃; for 12h;
3-(4-Phenoxyphenyl)-1H-[3,4-d]pyrazolopyrimidine-4-amine (185 mg, 0.61 mmol),(S)-1-tert-butoxycarbonyl-3-hydroxypiperidine (246 mg, 1.22 mmol) andTriphenylphosphine (640 mg, 2.44 mmol) dissolved in dry tetrahydrofuran,Diisopropyl azodicarboxylate (0.6 mL, 3.05 mmol) was added dropwise,Heat to 40C for 12 hours.After the end of the reaction, the tetrahydrofuran was removed,After column purification3-[4-Amino-3-(4-phenoxyphenyl)-1-[3,4-d]Tert-butyl pyrazolopyrimimidinylpiperidinecarboxylateDissolved in dichloromethane (6 mL),Add trifluoroacetic acid (6 mL),The reaction was performed at room temperature for 12 hours.HPLC monitored the progress of the reaction.After the reaction is complete, remove trifluoroacetic acid and add water and methanol.The HPLC preparative column was separated and freeze-dried to give 111 mg of trifluoroacetate salt of the target compound in a yield of 38%.HPLC purification conditions: starting acetonitrile ratio 25%, retention time t 1/2 = 10 minutes.
With hydrogenchloride; In methanol; water; at 50℃;
Compound (IV) (Pgi = Pg2 = Boc) (2.93 g, 5 mmol) was dissolved in MeOH (15 ml), then 33% HC1 (3 ml) was added, and the reaction mass was heated at 50C for 4 st with intensive stirring (note: a foam is forming during the reaction due to isolation of gaseous by-products). After completion of the reaction the resulting solution was cooled to room temperature and evaporated to dryness (note: the vapor contains HC1). Saturated Na2CO3 solution (5 ml) was added to the dry residue and the mixture was extracted with EtOAc (3 x 10 ml). The extract was dried over Na2SO4 and evaporated in vacuum. Yield 1.89 g (98%), white amorphous mass.
92%
With hydrogenchloride; In methanol; at 20℃; for 2h;
Compound 2.5g (5.1mmol) of formula 10 was added to the methanol solution in 25ml of hydrochloric acid, stirred at room temperature 2hour. Concentrated under reduced pressure, the residue was added 30ml of water, extracted with ethyl acetate, the organic phase was washed with 5% aqueousSodium hydroxide solution was washed until neutral. The organic phase was concentrated under reduced pressure to give a pale yellow oil 1.82g, yield 92%
91%
With hydrogenchloride; In ethyl acetate; for 0.5h;
Tert-butyl-( 1R)-3-4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine- 1- carboxylate (3 g) was dissolved in 3 M HC1-EtOAc (15 mL). After 30 mm the solution was treated with saturated sodium bicarbonate solution. The organic layer was separated and the water layer extracted with DCM (3x10 mL). The organic layers were combined and dried over Na2504. Evaporation of the solvent gives 2.1 g (91%) 3-(4- phenoxyphenyl)- 1 -[(3R)-3 -piperidyl]pyrazolo[3 ,4-d]pyrimidin-4-ammne.
88%
With trifluoroacetic acid; at 20℃; for 12h;
Intermediate (9) (48.6 g, 0.1 mol) was added to trifluoroacetic acid (200 mL) and reacted at room temperature for 12 h (TLC confirmed the completion of the reaction).Then, it was neutralized with Na2CO3 solution and extracted with CH2Cl2. The combined organic phases were dried over anhydrous sodium sulfate and concentrated to give Intermediate (10) (3.40 g, yield 88%).
85%
With trifluoroacetic acid; In dichloromethane; at 20℃;
In the reaction flask,(R) -1-Boc-3- (4-amino-3- (4-phenoxyphenyl)Pyrazolo [3,4-D] pyrimidin-1-yl) piperidine (8 g, 16.4 mmol) was added to a solution of trifluoroacetic acid (40 ml)And methylene chloride (40 ml)Room temperature reaction overnight.Point plate (TLC) After confirming that the reaction is complete,After neutralization with saturated Na2CO3 solution to pH 7-8,Extracted with dichloromethane (DCM), the organic phases were combined, dried over anhydrous sodium sulfate,The product was purified by column chromatography (5.4 g, yield 85%).
83%
With hydrogenchloride; In 1,4-dioxane; water; at 20℃; for 16h;
The (R) - tert-butyl-3- (4-amino-3- (4-phenoxyphenyl) lH-pyrazolo [3,4-d]pyrimidin-1-yl) -1-piperidine - carboxylate (1.28g, 2.63mmol) was dissolved in1,4-dioxane (6mL), and then the reaction mixture was added to hydrochloric acid (6mL,4mol / L) was stirred for 16h at room temperature, the reaction after the addition ofdilute sodium hydroxide aqueous solution was adjusted to PH = 9, extracted withdichloromethane (150mL × 3), brine (60mL), dried over anhydrous sodium sulfate, thesolvent was distilled off under reduced pressure, the crude product was purified bysilica gel column chromatography ( dichloromethane / methanol (V / V) = 12 / 1-6 / 1),to give the product (840mg, 83%).
81.1%
With hydrogenchloride; In water; at 20℃;
In room temperature,To the above reaction solution was added concentrated hydrochloric acid (2.3 vol)The compound (7) is converted into the compound (8).Raw material conversion is complete,Rotate most of the solvent.To the crude was added DCM (6 vol) and water (6 vol)Dispensing.The organic phase was extracted once with water (6 vol).Consolidate the aqueous phase,Wash with DCM (6Vol) three times.Water phase adjusted to pH 9-10,Precipitation of a large number of solid compounds 8,Yield 81.1%
80%
To a solution of Intermediate 3 (4.4 g, 9.0 mmol) in CH2Cl2 (20 ml) was added TFA (2.8 ml, 36.2 mmol). After stirring 2 hrs at room temperature, the solvent was removed and the residue was partitioned between ethyl acetate (250 ml) and dilute aq. K2CO3. The organic layer was dried (MgSO4), filtered and concentrated to 70 ml. The resulting solution was stirred and 4.0M HCl in dioxane (4 ml) was added to provide a thick light orange precipitate. The precipitate was collected by filtration and washed with ethyl acetate (50 ml). The material was then partitioned between ethyl acetate (300 ml) and dilute aq. K2CO3. The organic layer was dried (MgSO4), filtered and concentrated to provide 2.78 g (80%) of Intermediate 4 as a light yellow foam.
64%
With trifluoroacetic acid; In dichloromethane; at 20℃; for 12h;
Step 5A mixture of (R)-tert-butyl 3-[4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidm-l-yl]piperidine~l~carboxylate (700 mg, 1.44 mmol, 1.00 equiv) indichioromethane ( 100 mL) and irifluoroacetic acid (20 mL) was stirred at room temperature for 12 h. The reaction mixture was concentrated under vacuum to yield 580 mg of crude (R)- 3-(4-phenoxyphenyl)-l -(piperidin-3-yl)-lH-pyrazolo[3,4-d]pyrimidin-4-aniine as a yellow
With trifluoroacetic acid; In dichloromethane; at 20℃; for 12h;
A mixture of (R)-tertbutyl 3[4-amino-3-(4-phenoxyphenyl) 1H-pyrazolo[3,4 d]pyrimidin.yl]piperidinet-carboxylate (700 mg, I A4 mmol, 1,00 equiv) in dichloromethane (100 mL) and trifluoroacetic acid (20 mL) was stirred at room temperature for 12 Ii. The reaction mixture was concentrated under vacuum to yield 580 mg of crude (R) 3-(4-phenoxyphenyl)-1-piperidin-3-yi)-1R-pyrazolo[3,4-d]pyrimidin-4-amine as a yellow oil.
With trifluoroacetic acid; In dichloromethane; at 20℃; for 12h;
Step 5. A mixture of tert-butyl 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (700 mg, 1.44 mmol, 1.00 equiv) in dichloromethane (100 mL) and trifluoroacetic acid (20 mL) was stirred at room temperature for 12 h. The reaction mixture was concentrated under vacuum to yield 580 mg of crude 3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a yellow oil.
With trifluoroacetic acid; In dichloromethane; at 20℃; for 12h;
Step 5 A mixture of tert-butyl 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (700 mg, 1.44 mmol, 1.00 equiv) in dichloromethane (100 mL) and trifluoroacetic acid (20 mL) was stirred at room temperature for 12 h. The reaction mixture was concentrated under vacuum to yield 580 mg of crude 3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a yellow oil.
0.2 g
With trifluoroacetic acid; In dichloromethane;
Diisopropyl diazodicarboxylate (DAID, 1.2 ml) was added to a solution of 1-tert-butyloxycarbonyl-3-(S)-hydroxypiperidine ( 1.0 g,) and triphenylphosphine (2.59g) in tetrahydrofuran (50.0ml). To the resulting yellow solution, 3-(p-phenoxyphenyl)-1,2,5,7-tetraza-1H-inden-4-ylamine (1.0g). was added and warmed till dissolution, and stirred overnight at room temperature. The reaction mixture was filtered and the solvent was distilled under vacuum to get an oily residue, which was further purified by flash chromatography (30-50 % ethyl acetate/ hexane) on silicagel to give 0.3 g (0.3 w/w) of tert-butyloxycarbonyl-(1S)-1-[(3R)-3-piperidyl]-3-(p-phenoxyphenyl)-1,2,5,7-tetraza-1H-inden-4-ylamine as a light brown solid. The resulting solid was dissolved in dichloromethane (5 ml) and trifluoroacetic acid (0.6 ml) was added to it. After completion of reaction, water was added to reaction mass, followed by addition of methyl tert-butyl ether (20.0 ml). The layers were separated and the aqueous layer was basified with potassium carbonate and extracted with dichloromethane (15.0 ml x 2). The organic layer dried over sodium sulfate, filtered and evaporated to yield 0.2 g (0.6 w/w) of title compound as light yellow oil.
22.4 g
1L three bottles to join4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine 20 g (66 mmol)S-1-tert-butoxycarbonyl-3-hydroxypiperidine (26.6 g, 132 mmol); triphenylphosphine (51.9 g, 198 mmol) was added to dry tetrahydrofuran (400 mL) and cooled to 5-10 C.Under nitrogen, 40 g (198 mmol) of diisopropyl azodicarboxylate was slowly added dropwise to the flask and the reaction was carried out at 30 C for 12 hours. The reaction solution was cooled to 0 to 10 C, and 20 g of 36% hydrochloric acid was added dropwise(198 mmol), and the temperature was raised to 40 C for 1 hour.Water was added, stirred, extracted three times with dichloromethane, and the aqueous phase was collected and washed with hydrogenSodium hydroxide solution to adjust the water phase into alkaline (pH> 10), precipitate solid, filter, collect solid, blast 50 baking 12 hours(4-phenoxyphenyl) -1- (piperidin-3-yl) -1H-pyrazolo (3,4-d) pyrimidin-4-amine (V) 22.4 g, molar yield 87.9%. (HPLC purity 99.6%; optical purity ?99.8%).
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.
Example 1. Synthesis of (i?)-l-('3-(4-Amino-3-('4-phenoxyphenyl)-lH- pyrazolo [3 A-d] pyrimidin- 1 -yQpiperidin- 1 -yl)prop-2-en-2,3 ,3 -dy 1 -one (Compound 122). Scheme 5. Preparation of Compound 122 35 36 Compound 122 [96] Step 1. 3-Iodo-lH-pyrazolo[3,4-^pyrimidin-4-amine (31). lH-Pyrazolo[3,4- d]pyrimidin-4-amine, 30 (5.0 g, 37 mmol, 1 equiv) was suspended in DMF (100 mL) and N-iodosuccinimide ( IS) (10.7 g, 45 mmol, 1.2 equiv) was added. The reaction was heated at 80 C for 2 hours. The reaction was cooled to room temperature and then to 0 C and was quenched by the drop-wise addition of water (200 mL). The resulting solids were collected by filtration, washed with water and cold ethanol, and dried in a vacuum oven to yield 31 (8.1 g, 84% yield) as a beige solid. [97] Step 2. Phenoxyphenyl -lH-pyrazolo[3,4-< ]pyrimidin-4-amine (33). Compound 31 (4.0 g, 15.3 mmol, 1 equiv), boronic acid 32 (6.56 g, 30.7 mmol, 2 equiv), and potassium phosphate tribasic monohydrate (10.56 g, 45.9 mmol, 3 equiv) were dissolved in dioxane (50 mL) and water (20 mL). The mixture was sparged with nitrogen for 20 minutes and tetrakis(triphenylphosphine)palladium (2.70 g, 2.3 mmol, 0.15 equiv) was added. The mixture was sparged with nitrogen for an additional 5 minutes and then heated at reflux for 24 hours. The reaction was cooled to room temperature and stirred overnight, giving a beige precipitate. The reaction mixture was diluted with water (50 mL) and the solids were collected by filtration. The crude product was triturated with methanol (150 mL) to yield 3.9 g of 85% pure product. The purity was further improved by trituration with ethyl acetate (100 mL), yielding 33 (3.6 g, 77% yield, 90% pure) as a beige solid. [98] Step 3. (R ert-Butyl 3-(4-amino-3-(4-phenoxyphenvn-lH-pyrazoror3.4- Compound 33 (1.80 g, 5.9 mmol, 1 equiv), protected piperidine, 34 (1.43 g, 7.1 mmol, 1.2 equiv), triphenylphosphine (2.33 g, 8.9 mmol, 1.5 equiv), and diisopropyl azodicarboxylate (1.80 g, 8.9 mmol, 1.5 equiv) were dissolved in THF (200 mL) and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate (1 x 300 mL) and brine (1 x 300 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was adsorbed onto silica gel and purified using an Analogix automated chromatography system eluting with 0-8% methanol in dichloromethane. All fractions containing product were combined and re- chromatographed using the above conditions to yield 35 (1.1 g, 38% yield) as a white foam. [99] Step 4. (7?V3-(4-Phenoxyphenvn- 1 -(piperidin-3-nuPi- 1 //-pyrazoloH A- dlpyrimidin-4-amine hydrochloride (36). Compound 35 (700 mg, 1.48 mmol, 1 equiv) was dissolved in dioxane (8 mL). A solution of hydrogen chloride in dioxane (4 mL of a 4 N solution in dioxane, 16 mmol, 10.7 equiv) was added and the reaction was stirred at room temperature overnight. The reaction was diluted with diethyl ether (20 mL) and the resulting solids were collected by filtration under a stream of nitrogen. The product was further dried in a vacuum oven to yield 36 (550 mg, 88% yield) as an off-white solid. [100] Step 5. (_)- l-(3-(4-Amino-3-(4-phenoxyphenyl)- lH-pyrazolor3,4- ( Ipyrimidin- 1 -yDpiperidin- 1 -yl)prop-2-en-2,3 ,3 -dy- 1 -one (Compound 122). [101] A) DMF (0.003 mL, 0.03 mmol, 0.02 equiv) was added to commercially available acrylic acid-d4 (126 mg, 1.66 mmol, 1 equiv, 99 atom% D) followed by oxalyl chloride (0.16 mL, 1.83 mmol, 1.1 equiv). The mixture was stirred for 30 minutes, at which point all gas evolution had ceased. The resulting acryloyl-d3 chloride (37) was used as such. [102] B) In a 20 mL vial, triethylamine (0.46 mL, 3.18 mmol, 3 equiv) was added to a suspension of 36 (450 mg, 1.06 mmol, 1 equiv) in dichloromethane (10 mL). The reaction was stirred for 15 minutes, resulting in a clear solution. Acryloyl-d3 chloride (37) (0.10 mL, 1.17 mmol, 1.1 equiv, prepared above) was then added and the reaction was stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane (50 mL) and washed with 5% citric acid (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using an Analogix automated chromatography system eluting with 0-8% methanol in dichloromethane. All fractions containing product were pooled and concentrated to give a colorless film which was dissolved in benzene/methanol (5 mL) and lyophilized to yield Compound 122 (170 mg, 36% yield, [M+H]+ = 444.3) as a white powder.
9.1 g
With hydrogenchloride; In methanol; at 45℃; for 1h;
Example 9: Preparation of 3-(4-phenoxyphenyl)-l-r(3R)-piperidin-3-yll-lH-pyrazolor3.4- dlpyrimidin-4-amine hydrochloride salt (hydrochloride salt of Formula VIII) Methanolic hydrochloric acid (50 mL) was added to the dark brown viscous crude solid as obtained from Example 6 (22 g). The reaction mixture was stirred at 45 C for 1 hour and then evaporated to complete dryness at 45 C and degassed using methanol (50 chi 3 mL). The crude material obtained was washed further with ethyl acetate (100 mL) at room temperature. The light brown solid was filtered off and dried under vacuum. The filtrate was evaporated under vacuum at 40C to 45C to complete dryness, then ethyl acetate (50 mL) was added to the mixture, and then the mixture was stirred vigorously for 1 hour at room temperature. The mixture was filtered off to obtain the title compound as light brown solid. Yield: 9.1 g
26 g
With hydrogenchloride; In ethyl acetate; at 21 - 22℃;
50g (0.1027mol) of crude intermediate 3 was suspended in 100 ml ethyl acetate at ambient temperature. 200ml 3 M HC1 in EtOAc solution were added under stirring to this suspension. After 15min the formation of a bulky mass was observed. The stirring was continued at ambient temperature overnight. The resulting precipitate was filtered, washed with 50ml ethyl acetate and dried at 80C under vacuum (180 mbar), yielding 43.35g (99.3 %) (0098) After purification from a MeOH/iPrOH mixture 26g (0.0613 mol, 83%) of the HC1 salt of intermediate 4 was obtained in the form of a milky powder (melting point 264-266C).
In 2-ethoxy-ethanol; at 20 - 120℃; for 8h;Inert atmosphere;
Charge XI-Boc (0.3g, l .Oeq.) at r.t under N2. Charge formamidine acetate (15eq) into Rl under N2. Charge C2H5OC2H4OH (13V) into Rl under N2. Heat to 120C (inter temp) and stir the mixture at 120C for 8hrs. In this reaction mixture,4.3% of Imp-B also could be observed. Cool the reaction mixture to r.t. Add dropwise H20 (40mL,13V) and EA (15V). Separate the mixture and extract the aqueous phase with EA twice.
tert-butyl (R,E)-(2-(4-(4-(3-(4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-4-oxobut-2-en-1-yl)piperazin-1-yl)ethyl)carbamate[ No CAS ]
(R,E)-N-(2-(4-(4-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo-[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-4-oxobut-2-en-1-yl)piperazin-1-yl)ethyl)-3-(5,5-difluoro-1,3,7,9-tetramethyl-5H-dipyrrolo-[1,2-c:2′,1′-f][1,3,2]diazaborinin-2-yl)propanamide[ No CAS ]
(R)-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)(cyclopropyl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.03 g
As shown in scheme I, a was used to synthesize b, wherein a is commercially available or can be prepared by methods known in the art. Using a to synthesize b with (S)-N-tert-butoxycarbonyl-3-piperidinol gave an R-configuration intermediate b. Intermediate b (0.1g) (1ml) was treated with 4N HCl in dioxane and stirred for 1 hour at room temperature then concentrated to dryness to form a product 0.08g. It was dissolved in 4ml dichloromethane. Diisopropylethylamine (0.2mL), cyclopropanecarboxylic acid (0.03g), and 2-(7-azabenzotriazolyl)-N,N,N?,N?-tetramethyluronium hexafluorophosphate HATU (0.15g) were successively added and stirred at room temperature for 30 minutes. Diluted with 20ml of dichloromethane, washed successively with water, saturated brine, dried over anhydrous Na2SO4, filtered, and spin dried in vacuo. The residue was purified by column chromatography to give compound 1 (0.03g).
t-butyl-3(S)-chloro-piperidine-1-carboxylate[ No CAS ]
[ 1022150-11-3 ]
Yield
Reaction Conditions
Operation in experiment
82%
With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 12h;
Compound 2g (6.6mmol) of Formula 8 and 1.4g (6.6mmol) t-butyl -3S- chloro - piperidine-1-AEster, 4.6g of cesium carbonate was dissolved 30mlDMF, heated to 100 , for 12 hours. The reaction mixture was pouredInto 150ml water and extracted with ethyl acetate, the organic phase was dried and concentrated to give a pale yellow solid 2.63g,Yield 82%.
With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 70 - 75℃; for 12h;Inert atmosphere;
A mixture of 3 -(4-phenoxyphenyl)- 1 H-pyra.zolo [3 ,4-d]pyrimidin-4-amine compoundof formula-9 (60 gms), NMP (480 ml), (S)-tert-butyl-3-(tosyloxy)piperidine- 1 -carboxylatecompound of formula-ha (86 gms) and cesium carbonate (161 gms) was heated to 70-75C under nitrogen atmosphere and stirred for 12 hrs. Cooled the reaction mixture to 25-30C. Ethyl acetate was added to the reaction mixture at 25-30C. Filtered the reaction mixture and washed with ethyl acetate. Water was added to the filtrate at 25-30C and stirred for 15 mins.Both the organic and aqueous layers were separated. The organic layer was washed with water. Distilled off the solvent from the organic layer completely under reduced pressure to get the title compound. Yield: 77 gms.
(R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36 g
With hydrogenchloride; In ethyl acetate; isopropyl alcohol; at 25 - 30℃; for 16h;
Ethyl acetate-HC1 (291 ml) was added to a mixture of (R)-tert-butyl-3-(4-amino-3-(4-phenoxyphenyl)- 1 H-pyrazolo [3 ,4-d]pyrimidin- 1 -yl)piperidine- 1 -carboxylate compound offormula-12 (110 gms) and isopropyl alcohol (220 ml) at 25-30C and stirred for 16 hrs.Filtered the reaction mixture, washed with ethyl acetate and dried to get the title compound.The obtained compound was dissolved in a mixture of isopropyl alcohol (360 ml) and water(52 ml) at 75-80C. Cooled the reaction mixture to 0-5C and stirred for 60 mins at the sametemperature. Filtered the precipitated solid, washed with isopropyl alcohol and dried to get the title compound. Yield: 36 gms; MR: 260-265C; Chiral purity by HPLC: 99.52%, other isomer: 0.48%; chloride content: 15.52%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 100 - 105℃; for 4h;Inert atmosphere;
Example 8: 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) A mixture of tert-butyl (3R)-3-(4-amino-3-bromo-lH-pyrazolo[3,4-d]pyrimidin-l- yl)piperidine-l -carboxylate (Formula V, when X is bromine and Pr1 is Boc, Example 5, 5 g), potassium carbonate (8.7 g), and phenoxyphenylboronic acid (Formula VI, when R1 and R2 are hydrogen, 4 g) were added to a mixture of dioxane (45 mL) and water (25 mL) under nitrogen. [l, l'-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane (0.45 g) was added to the reaction mixture, and then the reaction mixture was stirred at 100C to 105C for 4 hours. The reaction mixture was then diluted with water (150 mL) and ethyl acetate (100 mL), and was then stirred for 10 minutes to 15 minutes at room temperature. The organic layer was separated out. The aqueous layer was again extracted with ethyl acetate (100 mL) at room temperature. The organic layers were combined, and then washed with a brine solution (50 mL). The excess of ethyl acetate was recovered under vacuum at a temperature not more than 50C. Hexane (100 mL) was added to the crude material, and then the mixture was stirred overnight at room temperature to obtain a sticky mass. The excess solvent was dried completely under vacuum at a temperature not more than 50C to obtain the title compound (1.2 g), which was used as such for next step.
Intermediate 1 (5g) was dissolved in dry DMF (50 mL) and potassium carbonate (8.8 g) was added. The suspension was stirred at ambient temperature for 2 h. After dropwise addition of Intermediate 2 (9 g) dissolved in DMF (10 mL) the reaction mixture was heated at 80°C for 14 h. The organic layer was separated and the water layer extracted with EtOAc (3x20 mL). The organic layers were combined and dried over Na2SC>4. Solvent evaporation at reduced pressure and recrystallization result in 6.3g (80percent) tert-butyl-(3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo [3,4-d] pyrimidin- 1 -yl]piperidine - 1 -carboxylate.
70%
With dmap; caesium carbonate; In N,N-dimethyl-formamide; at 90℃; for 8h;
3-(4-phenoxyphenyl) lH-pyrazolo [3,4-d] pyrimidin-4-amine (1.14g, 3.76mmol)was dissolved DMF (30mL) in, and then the reaction solution was added (S)-tert-butyl 3-((methylsulfonyl) oxy) piperidine-1-carboxylate (4.2g, 15.04mmol), cesium carbonate(0.64mL, 8.21 mmol), 4- dimethylaminopyridine pyridine (3.67g, 11.28mmol). Was stirredat 90 deg.] C 8h, the reaction was completed, distilled under reduced pressure of DMF,and extracted with dichloromethane (150mL × 3), brine (60mL), dried over anhydroussodium sulfate, the solvent was distilled off under reduced pressure, the crude productwas silica gel column Analysis of separation and purification (methylene chloride /methanol (V / V) = 40/1), to give the product (1.28g, 70percent).
(E)-1-(R)-3-(4-amino-3-(4-phenoxy-phenyl)-1H-pyrazole[3,4-d]pyrimidine-1-yl)piperidine-((4aR,7aS)-tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrole-6 (3H)-yl)-2-but-en-1-one[ No CAS ]
(E)-1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-yl)-4-((1R,4R)-2-thia-5-azabicyclo[2.2.1]hept-5-yl)butan-2-en-1-one[ No CAS ]
tert-butyl-(R)-3-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylate[ No CAS ]
[ 1022150-11-3 ]
Yield
Reaction Conditions
Operation in experiment
66%
With 1,10-Phenanthroline; palladium diacetate; potassium carbonate; In N,N-dimethyl acetamide; at 150℃; for 16h;Sealed tube; Inert atmosphere;
A mixture of compound (III) (Pgi = Boc, Pg2 = H) (636 mg, 2.00 mmol), Pd(OAc)2 (44 mg,0.20 mmol), 1,10-phenanthroline (36 mg, 0.20 mmol), K2C03 (304 mg, 2.20 mmol), 1-bromo-4-phenoxybenzene (548 mg, 2.20 mmol) and N,N-dimethylacetamide (DMA) (10 ml)was heated in a sealed tube under argon atmosphere at 150C for 16 h with intensive stirring.The product (III) was isolated and purified similarly to that described in the Example 1. Yield642 mg (66%), viscous yellowish oil. The analytical data of the obtained compound (III)correspond to that of the product obtained in the Example 1.
200g intermediate I and 800mL ethyl acetate was added to the reaction flask, stirring,Then add 216mL triethylamine stirring to dissolve, stirring 20 ~ 30min,At room temperature, 1044.3 mL of a THF solution containing 44.3 mL of acryloyl chloride was added dropwise,Control 1 ~ 1.5h, the addition is complete, the temperature was controlled at 25 ~ 30 C,After the addition is completed, the temperature control reaction between the range of 25 ~ 30 C 1.5 ~ 2h,After the reaction, add 120mL5% diluted hydrochloric acid wash,Control rhoEta = 5 ~ 6, respectively, and then sodium bicarbonate and 120mL saturated brine twice, dried over anhydrous sodium sulfate, concentrated under reduced pressure,212.7 g of solid was obtained in a yield of 93.4% and a purity of 99.5%.
(R)-1-(piperidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
38%
In dichloromethane; at 20℃; for 12h;
3-(4-Phenoxyphenyl)-1H-[3,4-d]pyrazolopyrimidine-4-amine (185 mg, 0.61 mmol),(S)-1-tert-butoxycarbonyl-3-hydroxypiperidine (246 mg, 1.22 mmol) andTriphenylphosphine (640 mg, 2.44 mmol) dissolved in dry tetrahydrofuran,Diisopropyl azodicarboxylate (0.6 mL, 3.05 mmol) was added dropwise,Heat to 40C for 12 hours.After the end of the reaction, the tetrahydrofuran was removed,After column purification3-[4-Amino-3-(4-phenoxyphenyl)-1-[3,4-d]Tert-butyl pyrazolopyrimimidinylpiperidinecarboxylateDissolved in dichloromethane (6 mL),Add trifluoroacetic acid (6 mL),The reaction was performed at room temperature for 12 hours.HPLC monitored the progress of the reaction.After the reaction is complete, remove trifluoroacetic acid and add water and methanol.The HPLC preparative column was separated and freeze-dried to give 111 mg of trifluoroacetate salt of the target compound in a yield of 38%.HPLC purification conditions: starting acetonitrile ratio 25%, retention time t 1/2 = 10 minutes.
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