[ CAS No. 1780378-34-8 ]

Name: 1780378-34-8|2-Bromo-5-chloropyrazolo[1,5-a]pyrimidine|97%
Brand: Ambeed
SKU: A171772
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Quality Control of [ 1780378-34-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 1780378-34-8 ]

CAS No. :	1780378-34-8	MDL No. :	MFCD20258252
Formula :	C₆H₃BrClN₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	CENCDGBTIIPQBO-UHFFFAOYSA-N
M.W :	232.47	Pubchem ID :	84696181
Synonyms :

Calculated chemistry of [ 1780378-34-8 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	9
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	45.7
TPSA :	30.19 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.08 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.0
Log Po/w (XLOGP3) :	2.31
Log Po/w (WLOGP) :	2.15
Log Po/w (MLOGP) :	1.95
Log Po/w (SILICOS-IT) :	1.8
Consensus Log Po/w :	2.04

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.34
Solubility :	0.106 mg/ml ; 0.000455 mol/l
Class :	Soluble
Log S (Ali) :	-2.58
Solubility :	0.608 mg/ml ; 0.00262 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.19
Solubility :	0.15 mg/ml ; 0.000647 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.11

Safety of [ 1780378-34-8 ]

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

Application In Synthesis of [ 1780378-34-8 ]

* 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.

Downstream synthetic route of [ 1780378-34-8 ]

[ 1780378-34-8 ] Synthesis Path-Downstream 1~23

1
[ CAS Unavailable ]
[ 1780378-34-8 ]

Yield	Reaction Conditions	Operation in experiment
68%	With trichlorophosphate at 110℃; for 3h;	2 Step 2-2-Bromo-5-chloro-pyrazolo[1,5-a]pyrimidine A mixture of (2-bromopyrazolo[1,5-a]pyrimidin-5-yl)oxysodium (1.00 g, 4.24 mmol) in POCl3 (10 mL) was stirred at 110° C. for 3 hours. On completion, the mixture was concentrated in vacuo. The residue was diluted with EA (20 mL), washed with NaHCO3 (10 ml), and concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (0.67 g, 68% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J=7.2 Hz, 1H), 6.84 (d, J=7.2 Hz, 1H), 6.69 (s, 1H).

Reference： [1]Current Patent Assignee: KYMERA THERAPEUTICS INC - US2019/192668, 2019, A1 Location in patent: Paragraph 2542; 2544

2
[ 1780378-34-8 ]
[ 2357108-34-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 3 h / 130 °C / Sealed tube; Microwave irradiation 2: potassium carbonate; (chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)) / water / 17 h / 90 °C

Reference： [1]Current Patent Assignee: KYMERA THERAPEUTICS INC - US2019/192668, 2019, A1

3
[ 1780378-34-8 ]
[ 2357108-35-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 3 h / 130 °C / Sealed tube; Microwave irradiation 2: potassium carbonate; (chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)) / water / 17 h / 90 °C 3: water; lithium hydroxide / tetrahydrofuran / 17 h / 20 °C

Reference： [1]Current Patent Assignee: KYMERA THERAPEUTICS INC - US2019/192668, 2019, A1

4
2-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine [ No CAS ]
[ 365996-30-1 ]
tert-butyl N-[(1S,2R)-2-[(2-bromopyrazolo[1,5-a]pyrimidin-5-yl)amino]cyclohexyl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 130℃; for 3h;Sealed tube; Microwave irradiation;	-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine (620 mg, 2.67 mmol), tert-butyl N-[(1S,2R)-2-amino cyclohexyl]carbamate (686 mg, 3.20 mmol, CAS184954-75-4) and DIPEA (379 mg, 2.93 mmol) were taken up into a microwave tube in NMP (6 mL). The sealed tube was heated at 130 C. for 3 hours under microwave. On completion, the mixture was concentrated in vacuo to remove the solvent. Then the residue was purified by silica gel chromatography to give the title compound (1.00 g, 91% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J=7.6 Hz, 1H), 6.10 (s, 1H), 5.98 (d, J=7.6 Hz, 1H), 5.76 (s, 1H), 4.94 (br s, 1H), 4.20-4.11 (m, 1H), 4.01-3.92 (m, 1H), 2.00-1.83 (m, 1H), 1.75-1.49 (m, 6H), 1.45 (s, 9H), 1.39-1.22 (m, 1H).

Reference： [1]Patent: US2019/192668,2019,A1 .Location in patent: Paragraph 2542; 2545

5
[ 1006-64-0 ]
2-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine [ No CAS ]
2-bromo-5-(2-phenylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.7 g	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 120℃; for 1h;	To a solution of 2-bromo-5-chloropyrazolo [1, 5-a] pyrimidine (1.8 g, 7.80 mmol) in DMF (20 mL) were added <strong>[1006-64-0]2-phenylpyrrolidine</strong> (1.26 g, 8.57 mmol) and DIPEA (3.0 g, 23.41 mmol), the reaction was stirred at 120C for about 1 h. The reaction mixture was cooled to ambient temperature, poured into H 2O (100 mL), extracted with EA (50 mL 2). The combined organic layers were concentrated and purified by chromatography on silica gel (eluent: DCM/EA = 10/1) to afford the desired compound as a yellow solid (1.7 g). MS (ESI, m/e) [M+1] + 343.0, 345.0.

Reference： [1]Patent: WO2019/210828,2019,A1 .Location in patent: Paragraph 1417; 1418

6
[ 2357108-27-9 ]
[ 1780378-34-8 ]

Yield	Reaction Conditions	Operation in experiment
1.8 g	With trichlorophosphate In acetonitrile at 95℃; for 16h;	F1.2 Step 2: 2-bromo-5-chloropyrazolo [1, 5-a] pyrimidine To a mixture of 2-bromopyrazolo [1, 5-a] pyrimidin-5-ol (2.0 g, 9.40 mmol) in CH 3CN (20 mL) was added phosphoryl trichloride (7 mL), the mixture was heated at 95 °C for about 16 h. Cooled to ambient temperature, poured into H 2O (100 mL) slowly. The precipitate was collected by filtration and dried under vacuum to give the product as yellow solid (1.8 g). MS (ESI, m/e) [M+1] + 231.9, 233.9.

Reference： [1]Current Patent Assignee: BEIGENE LTD. - WO2019/210828, 2019, A1 Location in patent: Paragraph 1415; 1416

7
[ 1780378-34-8 ]
[ 2383085-63-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 120 °C 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / 1,4-dioxane; water / 16 h / 95 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: BEIGENE LTD. - WO2019/210828, 2019, A1

8
[ 1780378-34-8 ]
[ 2383085-64-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 120 °C 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / 1,4-dioxane; water / 16 h / 95 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 4 h / 20 °C

Reference： [1]Current Patent Assignee: BEIGENE LTD. - WO2019/210828, 2019, A1

9
[ 1780378-34-8 ]
[ 2383085-61-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 120 °C 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / 1,4-dioxane; water / 16 h / 95 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 4 h / 20 °C 4: dmap; triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 96 h / 20 °C

Reference： [1]Current Patent Assignee: BEIGENE LTD. - WO2019/210828, 2019, A1

10
[ 1780378-34-8 ]
[ 2566572-53-8 ]
[ 2711726-93-9 ]

Yield	Reaction Conditions	Operation in experiment
69%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In 1,4-dioxane; water at 80℃; for 0.25h;

Reference： [1]Drew, Samuel L.; Thomas-Tran, Rhiannon; Beatty, Joel W.; Fournier, Jeremy; Lawson, Kenneth V.; Miles, Dillon H.; Mata, Guillaume; Sharif, Ehesan U.; Yan, Xuelei; Mailyan, Artur K.; Ginn, Elaine; Chen, Jie; Wong, Kent; Soni, Divyank; Dhanota, Puja; Chen, Pei-Yu; Shaqfeh, Stefan G.; Meleza, Cesar; Pham, Amber T.; Chen, Ada; Zhao, Xiaoning; Banuelos, Jesus; Jin, Lixia; Schindler, Ulrike; Walters, Matthew J.; Young, Stephen W.; Walker, Nigel P.; Leleti, Manmohan Reddy; Powers, Jay P.; Jeffrey, Jenna L. [Journal of Medicinal Chemistry, 2020, vol. 63, # 19, p. 11235 - 11257]

Yield	Reaction Conditions	Operation in experiment
	With trichlorophosphate at 100℃; for 1h;	Intermediate O: 5-chloro-2-(2-fluorophenyl)pyrazolo[1,5-a]pyrimidine General procedure: [001111] A mixture of 2-(2-fluorophenyl)pyrazolo[1,5-a]pyrimidin-5-ol (Intermediate O2) (0.66 g, 2.86 mmol) and POCl3 (14.38 mL,154.26 mmol) was heated to 100 °C for 1 h. The resulting mixture was concentrated in vacuo and the residue was dissolved in EtOAc (50 mL). The mixture was washed with water (40 mL), sat. aq. NaHCO3 (30 mL), water (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo to afford the title compound as a beige solid. [001112] LC-MS (Method 3B): Rt 1.91 mins; MS m/z 248.0 = [M+H]+ [001113] NMR (500 MHz, chloroform-d) δ 8.59 (dd, J = 7.3, 0.9 Hz,1H), 8.11 (td, J = 7.7,1.8 Hz,1H),7.40 (dddd, J = 8.3,7.1, 5.1,1.8 Hz,1H),7.29 - 7.23 (m,1H),7.20 (ddd, J = 11.3, 8.3,1.2 Hz,1H),7.08 (dd, J = 3.6, 0.9 Hz,1H), 6.81 (d, J = 7.2 Hz,1H).

12
[ 1780378-34-8 ]
[ 2738608-12-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: trichlorophosphate / N,N-dimethyl-formamide / 20 °C 2: N-ethyl-N,N-diisopropylamine / ethanol / 20 - 85 °C