Name: 1422006-32-3|3-Bromo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine|97%
Brand: Ambeed
SKU: A157016
Rating: 92 (32 reviews)

1
[ 1404480-15-4 ]
1-isopropyl-3-bromo-4-amino-1H-pyrazolo[3,4-d]pyrimidine [ No CAS ]
[ 1224844-38-5 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 20 - 88℃; for 7.5h;Inert atmosphere; Large scale;	To a l 00 liter glass reactor at room temperature was charged compound 2 (2. 7 kg) and compound Sa(2.8 kg). The reaction mixture was stirred under nitrogen atmosphere and then 43.4 kg of 1,4-dioxane and 14.0kg of water were cadded. The reaction mixture was stirred under argon atmosphere followed by the addition ofl.O kg of tetrakis(triphenylphosphine)palladimn(O) and 5.7 kg of sodimn carbonate. The reaction mixture washeated at reflux (88 C) for 7.5 hours under argon atmosphere until in-process HPLC showed completion of thel 0 reaction. After cooling room temperature, the reaction mixture was distilled under vacumn to approximately l 0L. To this mixture were added 60.0 kg of water and ll.O kg of ethyl acetate. The mixture was stirred at 22 oc forl hourA and then filtered. The wet cake was transferred to a 100 liter glass reactor, mixed with 60.0 kg of waterand ll.O kg of ethyl acetate, and stirred at 22 oc for 30 minutes. The mixture was filtered. The wet cake waswashed with 8.0 kg of water and 8.5 kg of ethyl acetate. After washing, the wet cake was transfer to a l 00 liter15 glass reactor, mixed with 12.6 kg of ethyl acetate and stirred at 22 oc for 30 minutes. The mixture was againfiltered and washed with 5.7 kg of ethyl acetate. After drying the crude product at 54 oc under vacumn with aslight nitrogen bleed, it (2.36 kg) was charged to a 200 gal GLCS Still. The still was purge with nitrogen and200.0 kg of methanol was added. The mixture was heated to 60 C. To this mixture was added a suspension of1.0 kg of activated carbon in 14.5 kg of methanol. The resulting mixture was heated for l hour at 60 C. The hot20 mixture was filtered through a preheated (60 oq glass Nutsche filter. The cake was wash with 70.0 kg of hotmethanol. The combined filtrates were distilled under vacumn to approximately l 0 L. 28.4 kg of ethyl acetatewere added. The mixture was stir at 25 oc for 3 0 minutes and filtered. The wet cake was washed with 12.7 kg ofethyl acetate. The desired product of Formula I was dried at 50 oc under vacumn with a slight nitrogen bleeduntil the Loss on Drying is not more than 1.0%.

Reference： [1]Patent: WO2013/23184,2013,A1 .Location in patent: Paragraph 00239; 00240

2
[ 83255-86-1 ]
[ 75-26-3 ]
1-isopropyl-3-bromo-4-amino-1H-pyrazolo[3,4-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium carbonate; In N,N-dimethyl-formamide; at 86℃; for 15h;	A solution of <strong>[83255-86-1]3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-amine</strong> (11 g, 51.4 mmol) in DMF (103 mL) was treated with K2CO3(s) (14.2 g, 103 mmol) and 2-bromopropane (5.31 mL, 56.5 mmol). The resulting mixture was stirred for 15 h at 85 C, before introducing additional 2- bromopropane (1.45 mL, 15.4 mmol) and resuming heating for another 1 h. After cooling to RT, the mixture then was diluted with water (800 mL), and extracted with EtOAc (2 x 500 mL). The combined organic extracts were back extracted with water (3 x 500 mL), and then dried over anhydrous Na2SO4(s), filtered, and concentrated to afford the title compound (12.3 g, 93%). MS (apci) m/z = 256.0, 258.0 (M+H).
73.4%	With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 60℃; for 3h;	3-Bromo-lH-pyrazolo[3,4-d]pyrimidin-4-amine (l) (21.4 g, 0.1 mol) and potassium carbonate (27 .64 g,0.2 mol, 2 eq) were suspended in anhydrous DMF (110 mL) and stirred at 60 oc for 0.5 h. To this mixture, isopropylbromide (9.9 mL, 0.105 mol, 1.05 eq) was added at the same temperature. The resulting mixture wasstirred at 60 oc for additional2.5 hand then was allowed to cool to room temperature. The mixture was filtered,25 the cake was washed with small amount of isopropyl acetate and the filtrate was concentrated in vacuo. Theresidue was partitioned between water and isopropyl acetate (100 mL/400 mL). The aqueous layer was extractedwith isopropyl acetate (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried overMgS04, filtered and rinsed with isopropyl acetate (50 mL x 3). The filtrate was concentrated in vacuo to affordthe crude product (23.4 g, 91.4% yield) as a yellow solid. The product obtained was suspended in methanol (2530 mL) and stirred for l h. The solid was collected by filtration, rinsed with methanol (4 mL), and dried in vacuo toafford the desired product 2 (l8.8g, 73.4% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): i5 8.23 (s,lH, pyrimidine), 5.00 (m, lH, iPr), 1.44 (d, J = 6.8 Hz, 6H, iPr); 13C NMR (100 MHz, DMSO-d6): i5 157.3,156.4, 152.9, 116.6, 99.4, 48.7, 21.6.
47%		The solution of 3-bromo-lH-pyrazolo[3,4-d]pyrimidin-4-amine (10.7 g, 0.05 mol), K2CO3 (13.8 g, 0.1 mol) in dry DMF (60 mL) was stirred at 60 C for 30 min, then 2- bromopropane (5 mL, 0.0525 mol) was added and the resultant solution was stirred at 60 C for 3 h, cooled down, filtered, and concentrated. The residue was diluted with isopropyl acetate (200 mL). The organic layer was washed with water (100 mL), brine (100 mL), dried (Na2S04), filtered and concentrated. The crude was triturated with MeOH to obtain 3-bromo-l-isopropyl- lH-pyrazolo[3,4-d]pyrimidin-4-amine (6.0 g, 47%) as a light yellow solid. MR (500 MHz, CDCh) delta 8.32 (s, 1H), 6.20 (s, 2H), 5.10 (dt, J = 13.4, 6.7 Hz, 1H), 1.54 (d, J= 6.7 Hz, 6H).

Reference： [1]Patent: WO2019/143991,2019,A1 .Location in patent: Paragraph 00531-00534
[2]Patent: WO2013/23184,2013,A1 .Location in patent: Paragraph 00229; 00230
[3]Journal of Medicinal Chemistry,2016,vol. 59,p. 358 - 373
[4]Patent: WO2017/44720,2017,A1 .Location in patent: Paragraph 00159

3
[ 1224844-66-9 ]
1-isopropyl-3-bromo-4-amino-1H-pyrazolo[3,4-d]pyrimidine [ No CAS ]
[ 1224844-38-5 ]

Yield	Reaction Conditions	Operation in experiment
67.3%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 20 - 110℃; for 3h;Inert atmosphere;	3-Bromo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2) (20 g, 78.1 mmol) and 5-( 4,4,5,5-15 tetramethyl-1,3,2-dioxaborolan-2-yl)benzo [d]oxazol-2-amine (5) (26.4 g, 102 mmol,l.3 eq) were dissolved in amixture of 1,4-dioxane and water (300 mL/100 mL). To this mixture Pd(PPh3) 4 (7.21 g, 6.25 mmol, 0.08 eq) andsodium carbonate (41.4 g, 391 mmol, 5 eq) were added sequentially. The resulting mixture was degassed andback-filled with argon three times and then refluxed at 110C for 3 h with stirring. The mixture was allowed tocool to room temperature, filtered and the cake was washed with ethyl acetate (50 mL x 2). The combined20 filtrate was concentrated in vacuo. The residue was suspended in a mixture of water and ethyl acetate (500mL/100 mL) and stirred for 30 min. The solid was collected by filtration, rinsed with water (50 mL) and ethylacetate (100 mL). The crude product thus obtained was suspended in ethyl acetate (100 mL) and stirred for 30min. The solid was collected by filtration, rinsed with ethyl acetate (50 mL), and dried in vacuo to afford thecrude product of Formula I(20 g, 83% yield). The above obtained product (20 g) was dissolved in refluxing25 methanol (1600 mL), and activated charcoal (6 g, 30% W/W) was added. The mixture was refluxed for 30 min,and then the hot mixture was filtered through a Buchner funnel. The cake was washed with hot methanol (1 00mL x 3). The combined filtrates were concentrated. The solid was slurried in ethyl acetate (300 mL), and thesuspension was stirred at room temperature for 30 min. The solid was collected by filtration, washed with ethylacetate (50 mL x 2), and dried in vacuo to afford the desired product of Formula I as polymorph Form A30 (16.27g, 67.3% yield). m.p.: 273.67 oc (Onset Temperature); 1H NMR (400 MHz, DMSO-d6): i5 8.26 (s, 1H,pyrimidine), 7.56 (s, 2H, oxazol-2-amine), 7.48 (d, J = 8.1 Hz, 1H, Ph), 7.45 (d, J = 1.4 Hz, 1H, Ph), 7.27 (del, J= 8.1, 1.6 Hz, 1H, Ph), 5.08 (m, 1H, iPr) and 1.52 (d, J = 6.7 Hz, 6H, iPr); 13C NMR (100 MHz, DMSO-d6): i5163.4, 158.1, 155.4, 153.2, 148.3, 144.4, 143.7, 128.8, 120.5, 115.0, 108.8, 97.5, 48.0 and 21.8; analysis(%calcd, % found for C15H15N70): C (58.24, 58.04), H (4.87, 4.83), N (31.70, 31.49); greater than 99% purity35 based on LC-MS analysis.

Reference： [1]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 1561 - 1567
[2]Patent: WO2013/23184,2013,A1 .Location in patent: Paragraph 00237; 00238

4
[ 1422006-32-3 ]
[ 1841080-57-6 ]