[ CAS No. 83255-86-1 ] {[proInfo.proName]}

Name: 83255-86-1|3-Bromo-1H-pyrazolo[3,4-d]pyrimidin-4-amine|96%
Brand: Ambeed
SKU: A234857
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Quality Control of [ 83255-86-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 83255-86-1 ]

Product Details of [ 83255-86-1 ]

CAS No. :	83255-86-1	MDL No. :	MFCD12196922
Formula :	C₅H₄BrN₅	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	GZQVGSRUUTUJNG-UHFFFAOYSA-N
M.W :	214.02	Pubchem ID :	340230
Synonyms :

Calculated chemistry of [ 83255-86-1 ] Expand+

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	9
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	3.0
Num. H-bond donors :	2.0
Molar Refractivity :	43.79
TPSA :	80.48 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.01 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.4
Log Po/w (XLOGP3) :	0.84
Log Po/w (WLOGP) :	0.71
Log Po/w (MLOGP) :	0.0
Log Po/w (SILICOS-IT) :	1.13
Consensus Log Po/w :	0.62

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.3
Solubility :	1.07 mg/ml ; 0.00499 mol/l
Class :	Soluble
Log S (Ali) :	-2.11
Solubility :	1.65 mg/ml ; 0.00771 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.67
Solubility :	0.462 mg/ml ; 0.00216 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.13

Safety of [ 83255-86-1 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 83255-86-1 ]

* 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.

Upstream synthesis route of [ 83255-86-1 ]
Downstream synthetic route of [ 83255-86-1 ]

[ 83255-86-1 ] Synthesis Path-Upstream 1~5

1
[ 2380-63-4 ]
[ 83255-86-1 ]

Yield	Reaction Conditions	Operation in experiment
72%	With N-Bromosuccinimide In N,N-dimethyl-formamide at 80℃; for 2.5 h;	lH-pyrazolo[3,4-d]pyrimidin-4-amine (20.0 g, 148.0 mmol) and N- bromosuccinimide (27.7 g, 155.4 mmol) are suspended in DMF (400 ml) and heated to 80°C for 2.5 hrs. After cooling to room temperature, the reaction is quenched with water (dropwise, 800 ml). The precipitate is filtered and suspended in a saturated solution of Na₂S03 (100 ml). The solid was filtered and washed with water (3 x 100 ml) and cold ethanol (2 x 50 ml). After drying under vacuum, the 3-bromo-lH- pyrazolo[3,4-d]pyrimidin-4-amine is obtained as beige solid (22.7 g, 105.9 mmol, 72percent).
64.4%	With N-Bromosuccinimide In N,N-dimethyl-formamide at 80℃; for 8 h;	The mixture of S1 (10 g, 74 mmol) and N-bromosuccinimide(15.8 g, 89 mmol) in DMF (100 mL) was stirred at 80 °C for 8 h. The resulting mixture was allowed to cool to room temperature and then diluted with 300 mL of water. The precipitate was filtered and washed with 2 60 mL of saturated aqueous sodium sulfite, 2 100 mL of water, respectively, and dried under vacuum to yield S2 as a light-yellow solid (10.2 g, 64.4percent), which was used directly without further purification. 1H NMR (300 MHz, DMSO d6) d13.78 (s, 1H), 8.19 (s, 1H), 6.89 (s, 2H)
27.9 g	With N-Bromosuccinimide In N,N-dimethyl-formamide at 60℃; for 4 h;	A mixture of 1H-pyrazolo[3,4-djpyrimidin-4-amine (Formula II, 25 g), Nbromosuccinimide (36.2 g), and dimethylformamide (150 mL) was stirred at 60°C for 4 hours. The reaction mixture was gradually cooled to 25°C to 30°C, and then filtered. Deionized water (750 mL) was added to the filtrate, and the mixture was stirred at 25°C to30°C for 30 minutes. The solid obtained was filtered, then washed with deionized water (50 mL), and then dried under vacuum at 60°C for 10 hours to 12 hours to obtain the title compound.Yield: 27.9 g

27.9 g	With N-Bromosuccinimide In N,N-dimethyl-formamide at 60℃; for 4 h;	Example 2: Preparation of 3-bromo-lH-pyrazolor3.4-dlpyrimidin-4-amine (Formula III, when X is bromine) A mixture of lH-pyrazolo[3,4-d]pyrimidin-4-amine (Formula II, 25 g), N- bromosuccinimide (36.2 g), and dimethylformamide (150 mL) was stirred at 60°C for 4 hours. The reaction mixture was gradually cooled to room temperature, and then filtered. The filtrate was poured into deionized water (750 mL), and then the mixture was stirred at room temperature for 30 minutes. The solid obtained was filtered, then washed with water (50 mL). The resulting solid was dried at 60°C under vacuum for 10 hours to 12 hours to obtain the title compound. Yield: 27.9 g
2.5 g	With bromine In water at 20℃; for 2 h; Reflux	To a solution of 4-aminopyrazolo[3,4-d]pyrimidine (2g) and H2O 25 mL, bromine (2 g) was added dropwise at room temperature, and the mixture was stirred at room temperature for 1 h.Then, it was reacted under reflux for 1 h, dried under reduced pressure, and dissolved in water.The title compound (2.5 g) was obtained.

Reference： [1] Patent: WO2017/17619, 2017, A1, . Location in patent: Page/Page column 8-9
[2] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 17, p. 4774 - 4786
[3] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1982, vol. 18, # 7, p. 753 - 755[4] Khimiya Geterotsiklicheskikh Soedinenii, 1982, # 7, p. 982 - 984
[5] Patent: EP2548877, 2013, A1, . Location in patent: Paragraph 0416
[6] ChemMedChem, 2013, vol. 8, # 10, p. 1673 - 1680
[7] Patent: WO2016/79693, 2016, A1, . Location in patent: Page/Page column 25
[8] Patent: WO2016/151438, 2016, A1, . Location in patent: Page/Page column 10-11
[9] Patent: WO2017/161344, 2017, A1, . Location in patent: Paragraph 0813; 0818
[10] Patent: WO2017/134685, 2017, A2, . Location in patent: Page/Page column 31
[11] Journal of Medicinal Chemistry, 2017, vol. 60, # 24, p. 9976 - 9989
[12] Patent: WO2018/2958, 2018, A1, . Location in patent: Page/Page column 35; 36
[13] Patent: CN105198887, 2017, B, . Location in patent: Paragraph 0027-0069; 0075-0117; 0123-0141; 0147-0165
[14] Patent: CN108329321, 2018, A, . Location in patent: Paragraph 0499; 0502; 0503

2
[ 90914-41-3 ]
[ 83255-86-1 ]

Reference： [1] Patent: WO2016/187723, 2016, A1, . Location in patent: Page/Page column 51

3
[ 5399-92-8 ]
[ 83255-86-1 ]

Reference： [1] Patent: WO2016/187723, 2016, A1,

4
[ 83255-86-1 ]
[ 1022150-11-3 ]

Reference： [1] Patent: WO2016/151438, 2016, A1,

5
[ 83255-86-1 ]
[ 1224844-38-5 ]

Reference： [1] Patent: WO2013/23184, 2013, A1,
[2] Patent: WO2013/23184, 2013, A1,

[ 83255-86-1 ] Synthesis Path-Downstream 1~109

1
[ 2380-63-4 ]
[ 83255-86-1 ]

Yield	Reaction Conditions	Operation in experiment
84%	With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 90℃; for 1h;	N-bromosuccinimide (6.65 g, 37.35 mmol) was added to a stirred solution of 1H-pyrazolo[3,4-d]pyrimidin-4-amine (7) (5.04 g,37.35 mmol) in N, N-dimethylformamide (DMF) (30 mL). The reaction was heated at 90 C for 1 h. Upon completion, the reaction was quenched with water (400 mL). The suspension was filtered and the filtercake was washed completely with water to yield compound 8 as a yellow solid (6.71 g, 84%). 1H NMR (400 MHz, DMSO-d6) delta 13.77 (s,1H), 8.18 (s, 1H).
82%	With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20 - 65℃; for 4h;	The compound 4-aminopyrazolo[3,4-d]pyrimidine (50 g, 0.37 mol) was added to a three-neck flask.And N,N-dimethylformamide (200 mL),Add N-bromosuccinimide (78.1 g, 0.44 mol) dropwise at room temperatureA solution consisting of N,N-dimethylformamide (150 mL) was added dropwise to 65 C and stirred for 4 h.The reaction solution was evaporated to dryness. Water (500 mL)The yellow solid was precipitated, the pH was adjusted to 7, and the filter cake was washed with water (250 mL) and cold ethanol (250 mL). Vacuum drying to obtain a pale yellow solid 65g, the yield was 82%.
79.9%	With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 80℃; for 3h;	4-Aminopyrazolo[3,4-d]pyrimidine (5 g, 37 mmol) was dissolved in 30 ml DMFAdd NBS (7.9g, 44.4mmol), stir, and heat in 80C oil bath.The color of the solution changed from light yellow to red, and the reaction was 3h.After TLC detection, the basic reaction was complete, cooled to room temperature, and the reaction solution was poured into 300 ml of ice water and stirred.A large amount of yellow solid was precipitated, filtered, and the filter cake was washed with ice water and dried.A pale yellow solid was obtained, 6.33 g, yield 79.9%.

79.9%	With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 80℃; for 3h;	Dissolve 4-aminopyrazolo [3,4-d] pyrimidine (5g, 37mmol) in 30mL DMF, add NBS (7.9g, 44.4mmol), react at 80 C for 3h, TLC detection, The reaction was basically completed, cooled to room temperature, the reaction solution was poured into 300 mL of ice water, stirred, and a large amount of yellow solid was precipitated, filtered, and the filter cake was washed with ice water and dried to obtain 6.33 g of light yellow solid with a yield of 79.9%.
79.9%	With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 80℃;	Dissolve 4-aminopyrazolo[3,4-d]pyrimidine (5g, 37mmol) in 30ml DMF, add N-bromosuccinimide (7.9g, 44.4mmol), stir, 80C oil bath After heating, the color of the solution changed from light yellow to red. After 3 hours of reaction, the TLC test showed that the reaction was basically complete. Cool to room temperature, pour the reaction solution into 300ml of ice water, stir, and precipitate a large amount of yellow solid. Filter and wash the filter cake with ice water And dried to obtain 6.33 g of light yellow solid with a yield of 79.9%.
72%	With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 80℃; for 2.5h;	lH-pyrazolo[3,4-d]pyrimidin-4-amine (20.0 g, 148.0 mmol) and N- bromosuccinimide (27.7 g, 155.4 mmol) are suspended in DMF (400 ml) and heated to 80C for 2.5 hrs. After cooling to room temperature, the reaction is quenched with water (dropwise, 800 ml). The precipitate is filtered and suspended in a saturated solution of Na2S03 (100 ml). The solid was filtered and washed with water (3 x 100 ml) and cold ethanol (2 x 50 ml). After drying under vacuum, the 3-bromo-lH- pyrazolo[3,4-d]pyrimidin-4-amine is obtained as beige solid (22.7 g, 105.9 mmol, 72%).
64.4%	With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 80℃; for 8h;	The mixture of S1 (10 g, 74 mmol) and N-bromosuccinimide(15.8 g, 89 mmol) in DMF (100 mL) was stirred at 80 C for 8 h. The resulting mixture was allowed to cool to room temperature and then diluted with 300 mL of water. The precipitate was filtered and washed with 2 60 mL of saturated aqueous sodium sulfite, 2 100 mL of water, respectively, and dried under vacuum to yield S2 as a light-yellow solid (10.2 g, 64.4%), which was used directly without further purification. 1H NMR (300 MHz, DMSO d6) d13.78 (s, 1H), 8.19 (s, 1H), 6.89 (s, 2H)
64%	With N-Bromosuccinimide; N,N-dimethyl-formamide; at 80℃; for 8h;	General procedure: The mixture of 17 (10 g, 74 mmol) and N-iodosuccinimide (20.0 g,89 mmol) in DMF (100 mL) was stirred at 80 C for 8 h. The resulting mixture was allowed to cool to room temperature and then diluted with 300 mL of water. The precipitate was filtered and washed with2×60 mL of saturated aqueous sodium sulfite, 2×100 mL of water,respectively, and dried under vacuum to yield 18a as a yellow solid (13.1 g, 70%), which was used directly without further purification. 1HNMR (300 MHz, DMSO-d6) delta 13.75 (s, 1H), 8.15 (s, 1H), 6.92 (s, 2H).
	With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 60℃; for 4h;	N-Bromosuccinimide (37.0 mmol, 6.59 g) was added to a stirred suspension of 1H-pyrazolo[3,4-d]pyrimidin-4-amine (37.0 mmol, 5.00 g) in 50 mL DMF and heated to 60 C for 4 hr. The reactionmixture was concentrated in vacuum. The residual brown solid was stirred in di-ethylether and filtered to give 11.9 g of 3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100%). The crude product was used directly in the next step.
27.9 g	With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 60℃; for 4h;	A mixture of 1H-pyrazolo[3,4-djpyrimidin-4-amine (Formula II, 25 g), Nbromosuccinimide (36.2 g), and dimethylformamide (150 mL) was stirred at 60C for 4 hours. The reaction mixture was gradually cooled to 25C to 30C, and then filtered. Deionized water (750 mL) was added to the filtrate, and the mixture was stirred at 25C to30C for 30 minutes. The solid obtained was filtered, then washed with deionized water (50 mL), and then dried under vacuum at 60C for 10 hours to 12 hours to obtain the title compound.Yield: 27.9 g
27.9 g	With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 60℃; for 4h;	Example 2: Preparation of 3-bromo-lH-pyrazolor3.4-dlpyrimidin-4-amine (Formula III, when X is bromine) A mixture of lH-pyrazolo[3,4-d]pyrimidin-4-amine (Formula II, 25 g), N- bromosuccinimide (36.2 g), and dimethylformamide (150 mL) was stirred at 60C for 4 hours. The reaction mixture was gradually cooled to room temperature, and then filtered. The filtrate was poured into deionized water (750 mL), and then the mixture was stirred at room temperature for 30 minutes. The solid obtained was filtered, then washed with water (50 mL). The resulting solid was dried at 60C under vacuum for 10 hours to 12 hours to obtain the title compound. Yield: 27.9 g
	With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 60℃;Inert atmosphere;	[0818] Example 4: 3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (I6): (1485) 250mL argon purged, flame-dried flask, 50mL DMF was added to dissolve 5g (37mmol) of starting material I5. NBS (6.5g, 36.5mmol) was added and the reaction heated to 60C overnight. Upon cooling, and completion of reaction monitored by TLC, precipitate was filtered to yield intermediate I6. LC-MS (ES+) calcd for C5H4BrN5 (M+H)+ 213.97, found 213.76, 215.71.
	With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 70℃; for 5h;	To a stirred suspension of lH-pyrazolo-[3,4-(i]pyrimidin-4-ylamine (8-1 ; 50 g) in DMF (500 mL) N-bromosuccinimide (66 g) was added and the reaction mass was heated for 5 h at 70 C. The solvent was removed under reduced pressure. Water was added to the residue and stirred for 30 minutes. The reaction mass was filtered and the solid and washed with diethyl ether. The product was dried under reduced pressure overnight to obtain the title compound as a brown solid.
	With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 80℃; for 2h;	To a stirred solution of 1H-pyrazolo[3,4-d]pyrimidin-4-amine (IV, 100 g) in DMF(1.0 L) was charged N- bromosuccinimide (171.33 g) portion wise and stirred for 2 hours at 80 C. The reaction mass was concentrated and was poured into the water (2.0 L) and the solid was filtered. Residue was washed with water and suck dried. Wet cake was dried by azeotropic distillation with toluene to obtain compound (V).
		Step one, 50mmol compound (1), three drops of DMF and 50mL of thionyl chloride was added to a 500mL reaction flask,After stirring for 1 hour at room temperature, 65 mmol of bromine as a brominating agent was added dropwise,After dropping the system temperature was raised to 60 C, and the reaction was stirred at this temperature 3h, stop heating, the reaction flask was added 150mL of toluene, stirred and evaporated under reduced pressure toluene and unreacted thionyl chloride and bromine,After stirring, 100 mL of toluene was added, and 150 mL of distilled water was added. The organic layer was separated and washed three times with distilled water. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain Compound (2). 50 mmol of compound (2), 55 mmol of R-SnMe3, 1.5 mmol of Pd (PPh3) 4 and 30 mL of dichloroethane were added to a 250 mL three- necked flask, the system temperature was raised to 70 C,And the reaction was stirred at this temperature 24h, the solvent was evaporated under reduced pressure to the residue was added 30mL KF methanol saturated solution, stirred at room temperature for 4h, filtered, filtrate was added 30mL of distilled water,The organic layer was separated, washed with water (10 mL × 2), dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to give a crude solid. The crude solid was recrystallized from isopropanol and dried under reduced pressure to obtain compound (3),Yield 72%;
2.5 g	With bromine; In water; at 20℃; for 2h;Reflux;	To a solution of 4-aminopyrazolo[3,4-d]pyrimidine (2g) and H2O 25 mL, bromine (2 g) was added dropwise at room temperature, and the mixture was stirred at room temperature for 1 h.Then, it was reacted under reflux for 1 h, dried under reduced pressure, and dissolved in water.The title compound (2.5 g) was obtained.

Reference： [1]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 1561 - 1567
[2]Bioorganic Chemistry,2020,vol. 94
[3]Patent: CN109111446,2019,A .Location in patent: Paragraph 0134; 0135; 0136
[4]Patent: CN109369654,2019,A .Location in patent: Paragraph 0103; 0108-0109
[5]Patent: CN111018865,2020,A .Location in patent: Paragraph 0059; 0083-0084
[6]Patent: CN111171035,2020,A .Location in patent: Paragraph 0068; 0115; 0116
[7]Patent: WO2017/17619,2017,A1 .Location in patent: Page/Page column 8-9
[8]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 4774 - 4786
[9]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 1562 - 1576
[10]Chemistry of Heterocyclic Compounds,1982,vol. 18,p. 753 - 755
Khimiya Geterotsiklicheskikh Soedinenii,1982,p. 982 - 984
[11]Patent: EP2548877,2013,A1 .Location in patent: Paragraph 0416
[12]ChemMedChem,2013,vol. 8,p. 1673 - 1680
[13]Patent: WO2016/79693,2016,A1 .Location in patent: Page/Page column 25
[14]Patent: WO2016/151438,2016,A1 .Location in patent: Page/Page column 10-11
[15]Patent: WO2017/161344,2017,A1 .Location in patent: Paragraph 0813; 0818
[16]Patent: WO2017/134685,2017,A2 .Location in patent: Page/Page column 31
[17]Journal of Medicinal Chemistry,2017,vol. 60,p. 9976 - 9989
[18]Patent: WO2018/2958,2018,A1 .Location in patent: Page/Page column 35; 36
[19]Patent: CN105198887,2017,B .Location in patent: Paragraph 0027-0069; 0075-0117; 0123-0141; 0147-0165
[20]Patent: CN108329321,2018,A .Location in patent: Paragraph 0499; 0502; 0503

2
[ 83255-86-1 ]
[ 14215-97-5 ]
[ 90914-43-5 ]

Reference： [1]Journal of Medicinal Chemistry,1984,vol. 27,p. 1119 - 1127

3
[ 83255-86-1 ]
[ 90914-42-4 ]

Reference： [1]Journal of Medicinal Chemistry,1984,vol. 27,p. 1119 - 1127

4
[ 83255-86-1 ]
[ 90914-44-6 ]

Reference： [1]Journal of Medicinal Chemistry,1984,vol. 27,p. 1119 - 1127

Yield	Reaction Conditions	Operation in experiment
		, wherein each modified base is independently selected from the group consisting of ... 3-iodo-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine, 3-bromo-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine, 3-chloro-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine, 3Iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine, 3-Bromo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine and 3-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine.

6
[ 83255-86-1 ]
[ 1419223-03-2 ]

Reference： [1]Patent: EP2548877,2013,A1

7
[ 85275-45-2 ]
[ 83255-86-1 ]
C₁₅H₂₁BrN₆O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 12.5h;Inert atmosphere;	General procedure: To a mixture of triphenylphosphine (18.5 g, 70.4 mmol), tert-butyl 3-hydroxypyrrolidine-1-carboxylate (8.8 g, 46.9 mmol) and 18b (5.0 g, 23.5 mmol) in THF (300 mL) was added diisopropyl azodicarboxylate (14.2 g, 70.4 mmol) at 0 C. The reaction mixture was stirred at this temperature for 0.5 h under argon. After that, the reaction mixture was allowed to warm to room temperature with stirring for 12 h. The resulting mixture was then concentrated to afford the crude product, which was purified by silica gel column chromatography (eluting with0-10% MeOH in DCM) to provide the desired Boc-protected monoamine as a white solid (7.1 g, 79%). Then to the solid in EtOAc (20 mL) was added 4 N HCl in EtOAc (30 mL). The reaction mixture was stirred at room temperature for 1 h. After complete conversion of the starting material, excess EtOAc was removed under vacuum. The residue was diluted in EtOAc and water. The water layer was basified with 2 NNaHCO3 solution and extracted with EtOAc (2×100 mL). The organic layers were then washed with water followed by brine. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to provide 9c as a white solid (4.7 g, 90%) without further purification. 1H NMR (300 MHz, DMSO-d6) delta 8.24 (s, 1H), 5.56-5.42(m, 1H), 4.15-4.10 (m, 1H), 3.55-3.45 (m, 2H), 3.30-3.24 (m, 1H),3.12-3.09 (s, 1H), 2.11-2.06 (m, 1H); MS (ESI) m/z: 283.0 [M+H]+.

Reference： [1]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 1562 - 1576

8
[ 1426699-08-2 ]
[ 83255-86-1 ]
[ 1426699-72-0 ]

Yield	Reaction Conditions	Operation in experiment
75%	With caesium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 120℃; for 4h;	To a mixture of tert-butyl 3-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]azetidine-1-carboxylate (1.0 g, 2.7 mmol) (from Example 1, Step 5, racemic intermediate) and <strong>[83255-86-1]3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-amine</strong> (0.629 g, 2.94 mmol) in N,N-dimethylformamide (8 mL) was added potassium iodide (44 mg, 0.27 mmol) and cesium carbonate (1.30 g, 4.01 mmol). The resulting mixture was heated to 120 C. and stirred for 4 h. After cooling, water was added and stirred briefly before the solids were filtered. The resulting solids were washed with water, purified on silica gel (eluted with 0-10% MeOH in dichloromethane) to give 1.11 g (75%) of the desired product as a yellow gum. LCMS calculated for C23H29BrClN6O3 (M+H)+: m/z=551.1; Found: 551.1.

Reference： [1]Patent: US2013/59835,2013,A1 .Location in patent: Paragraph 1000

9
[ 83255-86-1 ]
[ 1419223-02-1 ]

Reference： [1]Patent: EP2548877,2013,A1

10
[ 83255-86-1 ]
[ 143900-44-1 ]
[ 1419223-01-0 ]

Yield	Reaction Conditions	Operation in experiment
16.5 g	With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; toluene; at -10 - 20℃; for 3h;	<strong>[83255-86-1]3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-amine</strong> (37.0 mmol, 7.92 g), (S)-tert-butyl 3-hydroxypiperidine-1-carboxylate (62.9 mmol, 12.7 g) and triphenylphosphine (62.9 mmol, 16.5 g) in dry THF (150 mL) was cooled to -10 C. DEAD (62.9 mmol, 28.8 mL, 40% solution in toluene) was added dropwise. The reaction mixture was allowed to warm to rt and was stirred 3 h. EtOAc was added and extraction with 10% NaCl-sol. The organic layer was dried (Na2SO4), filtered and concentrated. The product was purified using silica gel chromatography (dichloromethane/methanol = 97/3 (v/v%) + TEA to give 16.5 g of (R)-tert-butyl 3-(4-amino-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (100%).
	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 3h;Inert atmosphere;	Nitrogen protection, compound of formula 1 (60 g, 0.28 mol), compound of formula 2 (84.6 g, 0.42 mol)And triphenylphosphine (257.4 g, 0.98 mol) were added to dry THF (10 eq volume)A light brown suspension, down to 0 ,DIAD (198.4 g, 0.98 mol) was added dropwise,Dropping process to maintain the temperature below 5 , the solution gradually turned pale yellow clarification,Dropping gradually rose to 20 C the reaction was stirred 3h, concentrated hydrochloric acid (10eq) was added,Rose to 50 C and stirred for 2h,Down to room temperature, filtered,The filter cake was washed with a small amount of THF, concentrated in vacuo to a dry weight to give a white solid 74.0 g,Yield 71.0%, chemical purity of 98.5%.Take 30g, with free aqueous solution of sodium bicarbonate to obtain free base 22.9g, free rate of 95.1%Chemical Purity 98.5%
	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 3h;Inert atmosphere;	To anhydrous THF (10 eq volume) were added the compound of Formula 5-Br (60 g, 0.28 mol), the compound of Formula 6-Boc (84.6 g, 0.42 mol) and triphenylphosphine (257.4 g, 0.98 mol) under the protection of nitrogen atmosphere to obtain a pale brown suspension. A reaction temperature was reduced to 0 C., and DIAD (198.4 g, 0.98 mol) was added dropwise while keeping the temperature below 5 C. The reaction solution gradually became a pale yellow clear solution. Afier completing the addition, the temperature was gradually raised to 20 C., and meanwhile the reaction solution was stirred for 3 hours. Concentrated hydrochloric acid (10 eq) was added. The temperature was raised to 50 C., and the reaction solution was stirred for another 2 hours. Then, the temperature was reduced to room temperature, and the reaction mixture was filtered. The filter cake was washed with a small amount of THF, and concentrated in vacuo to dryness to constant weight to afford 74.0 g of an off-white solid in 71.0% yield and 98.5% chemical purity. To 30 g of the off-white solid was added an aqueous solution of sodium bicarbonate to afford 22.9 g of a free base in 95.1% yield and 98.5% chemical purity. mlz (MH+) 297, 1H NMR (400 MHz, DMSO) oe 1.94-2.11 (m, 4H), 2.92-2.98 (m, 1H), 3.01-3.36 (m, 2H), 3.45-3.47 (m, 1H), 5.12-5.19 (m, 1H), 8.50-8.51 (s, 1H), 9.61-9.87 (dd, 2H).

Reference： [1]Patent: EP2548877,2013,A1 .Location in patent: Paragraph 0417
[2]Patent: CN107353291,2017,A .Location in patent: Paragraph 0050; 0051; 0052; 0053; 0054; 0055
[3]Patent: US2018/44339,2018,A1 .Location in patent: Paragraph 0081; 0082; 0083; 0084; 0085; 0086

11
[ 24424-99-5 ]
[ 83255-86-1 ]
tert-butyl N-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-tert-butoxycarbonyl-carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With dmap; In tetrahydrofuran; at 20℃; for 24h;	A suspension of 3-bromo-1 /-/-pyrazolo[3,4-c]pyrimidin-4-amine (1.0 g, 4.7 mmol), Boc20 (4.08 g, 18.7 mmol) and DMAP (57 mg, 0.47 mmol) in THF (20 mL) was stirred at room temperature for 24 h. The solvent was concentrated in vacuo then the crude mixture was dissolved in methanol (20 mL). Aq. sat. NaHCO3(10 mL) was added and the reaction mixture stirred at room temperature for 30 mins then water (20 mL) was added and the reaction mixture was extracted with DCM (2 chi 50 mL). The combined organics were passed through a hydrophobic frit and concentrated in vacuo. The crude product was purified by fee (0-10% MeOH:DCM) to return the title compound (1.55 g, 80%) as a pale yellow solid. LCMS [M-H]- 414.1 and 412.2.

Reference： [1]ChemMedChem,2013,vol. 8,p. 1673 - 1680
[2]Patent: WO2017/178844,2017,A1 .Location in patent: Paragraph 00228

12
[ 83255-86-1 ]
C₄₃H₄₆BrN₅O₇ [ No CAS ]

Reference： [1]ChemMedChem,2013,vol. 8,p. 1673 - 1680

13
[ 83255-86-1 ]
[ 1224844-38-5 ]

Reference： [1]Patent: WO2013/23184,2013,A1
[2]Patent: WO2013/23184,2013,A1
[3]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 1561 - 1567

14
[ 83255-86-1 ]
[ 75-26-3 ]
3-bromo-2-isopropyl-2H-pyrazolo[3,4-d]pyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
3.1%	With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 80℃; for 3h;	3-Bromo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1) (21.4 g, 0.1 mol) and potassimn carbonate (27 .64 g,0.2 mol, 2 eq) were suspended in anhydrous DMF (210 mL) and stirred at 80 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 80 oc for additional 2.5 h and then was allowed to cool to room temperature. The mixture was5 concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (MeOH IDCM: 1:80 to 1:1 0) to afford the desired product 3-bromo-2-isopropyl-2H-pyrazolo[3,4-d]pyrimidin-4-amine(2a) (800 mg, 3.1%) as a solid.

Reference： [1]Patent: WO2013/23184,2013,A1 .Location in patent: Paragraph 00241; 00242

15
[ 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

16
[ 83255-86-1 ]
[ 1542034-16-1 ]

Reference： [1]Synthesis,2013,vol. 45,p. 3259 - 3262

17
[ 83255-86-1 ]
[ 1542034-19-4 ]

Reference： [1]Synthesis,2013,vol. 45,p. 3259 - 3262

18
[ 83255-86-1 ]
[ 1542034-22-9 ]

Reference： [1]Synthesis,2013,vol. 45,p. 3259 - 3262

19
[ 83255-86-1 ]
[ 1180556-68-6 ]

Reference： [1]Synthesis,2013,vol. 45,p. 3259 - 3262

20
[ 83255-86-1 ]
[ 1542034-28-5 ]

Reference： [1]Synthesis,2013,vol. 45,p. 3259 - 3262

21
[ 83255-86-1 ]
[ 1542034-29-6 ]

Reference： [1]Synthesis,2013,vol. 45,p. 3259 - 3262

22
[ 83255-86-1 ]
[ 293751-03-8 ]
[ 1542034-15-0 ]