[ CAS No. 669734-35-4 ]

Name: 669734-35-4|5-Bromo-2-chloro-N-cyclopropylbenzamide|98%
Brand: Ambeed
SKU: A449693
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3d Animation Molecule Structure of 669734-35-4

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Quality Control of [ 669734-35-4 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 669734-35-4 ]

SDS Specification

Alternatived Products of [ 669734-35-4 ]

Product Details of [ 669734-35-4 ]

CAS No. :	669734-35-4	MDL No. :	MFCD04226747
Formula :	C₁₀H₉BrClNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	HVXQTKXSRJBMDT-UHFFFAOYSA-N
M.W :	274.54	Pubchem ID :	4806983
Synonyms :

Calculated chemistry of [ 669734-35-4 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.3
Num. rotatable bonds :	3
Num. H-bond acceptors :	1.0
Num. H-bond donors :	1.0
Molar Refractivity :	59.65
TPSA :	29.1 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.8 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.35
Log Po/w (XLOGP3) :	3.07
Log Po/w (WLOGP) :	2.93
Log Po/w (MLOGP) :	3.0
Log Po/w (SILICOS-IT) :	3.25
Consensus Log Po/w :	2.92

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.6
Solubility :	0.0697 mg/ml ; 0.000254 mol/l
Class :	Soluble
Log S (Ali) :	-3.35
Solubility :	0.123 mg/ml ; 0.000449 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.46
Solubility :	0.00943 mg/ml ; 0.0000344 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	1.62

Safety of [ 669734-35-4 ]

Signal Word:	Warning	Class:
Precautionary Statements:	P261-P264-P270-P271-P280-P301+P312-P302+P352-P304+P340-P330-P363-P501	UN#:
Hazard Statements:	H302-H312-H332	Packing Group:
GHS Pictogram:

Application In Synthesis of [ 669734-35-4 ]

* 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 [ 669734-35-4 ]

[ 669734-35-4 ] Synthesis Path-Downstream 1~14

1
[ 21900-52-7 ]
[ 765-30-0 ]
[ 669734-35-4 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 5-bromo-2-chloro-benzoyl chloride; Cyclopropylamine In dichloromethane at 0℃; for 0.166667h; Stage #2: With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 2h;	5-Bromo-2-chloro-N-cyclopropyl-benzamide To a suspension of 5-bromo-2-chlorobenzoic acid (17.6 g, 75 mmol) in CH2Cl2 (180 mL) was added oxalyl chloride (7.0 mL, 83 mmol). DMF (8 drops) was added, and the mixture was stirred for 2 h at rt (gas evolution). The mixture was reduced under reduced pressure, and the crude residue was diluted with CH2Cl2 (530 mL). The mixture was cooled to 0° C., and a sol. of cyclopropylamine (5.8 mL, 83 mmol) in CH2Cl2 (45 mL) was added dropwise. The mixture was stirred for 10 min at 0° C., and was allowed to warm to rt. DIPEA (14.3 mL, 84 mmol) was added, and the mixture was stirred for 2 h at rt. The mixture was diluted with more CH2Cl2, and was washed with aq. 10% HCl, water, and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The residue was triturated with hexane, filtered, and dried under high vacuum to yield the title compound (19.3 g, 94%). LC-MS: tR=0.84 min; ES+: 316.89.
	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 19h;	14.1 Step 1 : S-Bromo^-chloro-N-cyclopropylbenzamideTo a toluene solution (1 M) of 5-bromo-2-chlorobenzoic acid (1 eq.) and DMF (1.2 eq.) was added at 0 0C oxalyl chloride (1.2 eq.) dropwise over 1 h. The resulting solution was stirred at 0 0C for 2 h before the volatiles were removed in vacuo. The resulting residue was taken up in dichloromethane (1 M), cooled to 0 0C and added sequentially cyclopropylamine (1.5 eq.) and Hunig"s base (2 eq.) dropwise over 1 h. The resulting suspension was stirred at RT for 18 h. The reaction was quenched with 1 Ν HCl and extracted with dichloromethane. The combined organic extracts were dried over MgSO4, filtered and the filtrate concentrated in vacuo to ~ 1/3 in volume. The resulting white suspension was added an equivalent volume of hexanes and the title compound was isolated via vacuum filtration.
	Stage #1: 5-bromo-2-chloro-benzoyl chloride; Cyclopropylamine With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 17h; Stage #2: With hydrogenchloride In dichloromethane; water	5-Bromo-2-chloro-N-cyclopropylbenzamide. Into a flame-dried 250 mL round-bottom flask equipped with a magnetic stir bar and under N2 were added 5-bromo-2-chlorobenzoic acid (10.0 g, 42.5 mmol) and DMF (3.9 mL, 51.0 mmol) in toluene (80 mL). The sol. was cooled to 0 0C, and oxalyl chloride (4.4 mL, 51.0 mmol) was added dropwise over 1 h. The resulting mixture was stirred at 0 0C for 2 h and then the volatiles were removed. The resulting crude reaction mixture was dissolved in CH2Cl2 (100 mL) and cooled to 0 0C in an ice bath. Cyclopropylamine (4.5 mL, 63.7 mmol) was added dropwise over 1 h followed by addition of DIPEA (11.8 mL, 85.0 mmol). The resulting sol. was stirred at rt for 16 h. The reaction mixture was poured into a 1 L separatory funnel containing aq. IM HCl (600 mL). The mixture was extracted with CH2Cl2 (6 x 250 mL). The combined org. layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The product was crystallized from hexane/CH2Cl2 and isolated by filtration to give the title compound (8.24 g, 71%).

With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 17h;

Into a flame-dried 250 mL round-bottom flask equipped with a magnetic stir bar and under N2 were added 5-bromo-2-chlorobenzoic acid (10.0 g, 42.5 mmol) and DMF(3.9 mL, 51.0 mmol) in toluene (80 mL). The sol. was cooled to 0 0C, and oxalyl chloride (4.4 mL, 51.0 mmol) was added dropwise over 1 h. The resulting mixture was stirred at 0 0C for 2 h and then the volatiles were removed. The resulting crude reaction mixture was dissolved in CH2Cl2 (100 mL) and cooled to 0 0C in an ice bath. Cyclopropylamine (4.5 mL, 63.7 mmol) was added dropwise over 1 h followed by addition of DIPEA (11.8 mL, 85.0 mmol). The resulting sol. was stirred at rt for 16 h. The reaction mixture was poured into a 1 L separatory funnel containing IM aq. HCl (600 niL). The mixture was extracted with CH2Cl2 (6 x 250 mL). The combined org. layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The product was crystallized from hexanes/CH2Cl2 and isolated by filtration to give the title compound (8.24 g, 71%).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - US2008/214598, 2008, A1 Location in patent: Page/Page column 9
[2]Current Patent Assignee: MERCK & CO INC - WO2007/9250, 2007, A1 Location in patent: Page/Page column 36
[3]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2007/88514, 2007, A1 Location in patent: Page/Page column 38
[4]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2007/49224, 2007, A1 Location in patent: Page/Page column 23-24

2
[ 669734-35-4 ]
[ 945999-91-7 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 5-bromo-2-chloro-N-cyclopropylbenzamide With dimethylsulfide borane complex In tetrahydrofuran at 20℃; for 2h; Heating / reflux; Stage #2: With hydrogenchloride In tetrahydrofuran; water for 1h; Heating / reflux; Stage #3: With sodium hydroxide In tetrahydrofuran; water at 20℃;	A sol. of 5-bromo-2-chloro-N-cyclopropylbenzamide (12.0 g, 43.7 mmol) in THF (100 mL) was placed into a 250 mL round-bottom flask, equipped with a magnetic stir bar and under N2. The sol. was treated with dropwise addition of BH3.Me2S (13.1 mL, 131 mmol), and the resulting suspension was stirred at rt for 1 h. The mixture was heated to reflux for 1 h, cooled to rt, and slowly quenched with dropwise addition of 1M aq. HCl (25 mL). The suspension was again refluxed for 1 h, cooled to rt, and basified to pH=10-11 with 1M aq. NaOH. The mixture was poured into a 500 mL separatory funnel containing 1M aq. NaOH (350 mL). The mixture was extracted with EtOAc (3×100 mL). The combined org. layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude amine was used directly in the next step.
	Stage #1: 5-bromo-2-chloro-N-cyclopropylbenzamide With dimethylsulfide borane complex In tetrahydrofuran at 20℃; for 2h; Heating / reflux; Stage #2: With hydrogenchloride In tetrahydrofuran; water for 1h; Heating / reflux; Stage #3: With sodium hydroxide In tetrahydrofuran; water	A sol. of 5-bromo-2-chloro-N-cyclopropylbenzamide (12.0 g, 43.7 mmol) in THF (100 mL) was placed into a 250 mL round-bottom flask, equipped with a magnetic stir bar and under N2. The sol. was treated with dropwise addition of BH3.Me2S (13.1 mL, 131 mmol), and the resulting suspension was stirred at rt for 1 h. The mixture was heated to reflux for 1 h, cooled to rt, and slowly quenched with dropwise addition of 1M aq. HCl (25 mL). The suspension was again refluxed for 1 h, cooled to rt, and basified to pH=10-11 with 1M aq. NaOH. The mixture was poured into a 500 mL separatory funnel containing 1M aq. NaOH (350 mL). The mixture was extracted with EtOAc (3×100 mL). The combined org. layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude amine was used directly in the next step.
	Stage #1: 5-bromo-2-chloro-N-cyclopropylbenzamide With dimethylsulfide borane complex In tetrahydrofuran at 20℃; for 2h; Heating / reflux; Stage #2: With hydrogenchloride; water In tetrahydrofuran at 20℃; for 1h; Heating / reflux; Stage #3: With sodium hydroxide; water In tetrahydrofuran at 20℃;	N-(5-bromo-2-chlorobenzyl)cyclopropylamine A sol. of 5-bromo-2-chloro-N-cyclopropylbenzamide (12.0 g, 43.7 mmol) in THF (100 mL) was placed into a 250 mL round-bottom flask, equipped with a magnetic stir bar and under N2. The sol. was treated with dropwise addition of BH3.Me2S (13.1 mL, 131 mmol), and the resulting suspension was stirred at rt for 1 h. The mixture was heated to reflux for 1 h, cooled to rt, and slowly quenched with dropwise addition of aq. 1M HCl (25 μL). The suspension was again refluxed for 1 h, cooled to rt, and basified to pH=10-11 with aq. 1M NaOH. The mixture was poured into a 500 mL separatory funnel containing aq. 1M NaOH (350 mL). The mixture was extracted with EtOAc (3*100 mL). The combined org. layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude amine was used directly in the next step.

	Stage #1: 5-bromo-2-chloro-N-cyclopropylbenzamide With borane In tetrahydrofuran at 0 - 20℃; for 2h; Heating / reflux; Stage #2: With hydrogenchloride; water In tetrahydrofuran	14.2 Step 2: N-(5-Bromo-2-chlorobenzyl)cyclopropanamineAt 0 0C, a suspension of 5-bromo-2-chloro-N-cyclopropylbenzamide from the previous step (1 eq.) in THF (0.4 M) was added borane (1 M THF solution, 3 eq.). The resulting suspension was warmed to RT over 1 h and then heated at reflux for 1 h. The now pale yellow solution was re-cooled to 0 0C and carefully quenched with 1 Ν aq. HCl. The resulting mixture was heated at reflux for 1 h to ensure complete breakdown of the amine-borane complex. Following careful neutralization with 1 Ν aq. NaOH, the aqueous layer was separated and back extracted with EtOAc. The combined organic extracts EPO were washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude product thus obtained was purified further by way of column chromatography (SiO2, Hex -> 80:20 (v/v) Hex : Et2O) to reveal the title compound as a colorless oil
	Stage #1: 5-bromo-2-chloro-N-cyclopropylbenzamide With dimethylsulfide borane complex In tetrahydrofuran at 20℃; for 2h; Heating / reflux; Stage #2: With hydrogenchloride In tetrahydrofuran; water for 1h; Heating / reflux; Stage #3: With sodium hydroxide In tetrahydrofuran; water at 20℃;	N-(5-bromo-2-chlorobenzyl)cyclopropylamine. A sol. of 5-bromo-2-chloro-N-cyclopropylbenzamide (12.0 g, 43.7 mmol) in THF (100 mL) was placed into a 250 mL round-bottom flask, equipped with a magnetic stir bar and under N2. The sol. was treated with dropwise addition OfBH3-Me2S (13.1 mL, 131 mmol), and the resulting suspension was stirred at rt for 1 h. The mixture was heated to reflux for 1 h, cooled to rt, and slowly quenched with dropwise addition of aq. IM HCl (25 rnL). The suspension was again refluxed for 1 h, cooled to rt, and basified to pH = 10-11 with aq. IM NaOH. The mixture was poured into a 500 mL separatory funnel containing aq. IM NaOH (350 mL). The mixture was extracted with EtOAc (3 x 100 mL). The combined org. layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude amine was used directly in the next step.
	Stage #1: 5-bromo-2-chloro-N-cyclopropylbenzamide With dimethylsulfide borane complex In tetrahydrofuran at 20℃; for 2h; Heating / reflux; Stage #2: With hydrogenchloride In water at 20℃; for 1h; Heating / reflux; Stage #3: With sodium hydroxide In water at 20℃;	A sol. of 5-bromo-2-chloro-N-cyclopropylbenzamide (12.0 g, 43.7 mmol) in THF (100 mL) was placed into a 250 mL round-bottom flask, equipped with a magnetic stir bar and under N2. The sol. was treated with dropwise addition of borane- dimethylsulfide complex (13.1 mL, 131 mmol), and the resulting suspension was stirred at rt for 1 h. The mixture was heated to reflux for 1 h, cooled to rt, and slowly quenched with dropwise addition of IM aq. HCl (25 mL). The suspension was again refluxed for 1 h, cooled to rt, and basified to pH = 10-11 with IM aq. NaOH. The mixture was poured into a 500 mL separatory funnel containing IM aq. NaOH (350 mL). The mixture was extracted with EtOAc (3 x 100 mL). The combined org. layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude amine was used directly in the next step.

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - US2009/62342, 2009, A1 Location in patent: Page/Page column 8
[2]Current Patent Assignee: JOHNSON & JOHNSON INC - US2009/88457, 2009, A1 Location in patent: Page/Page column 10
[3]Current Patent Assignee: JOHNSON & JOHNSON INC - US2009/176823, 2009, A1 Location in patent: Page/Page column 13-14
[4]Current Patent Assignee: MERCK & CO INC - WO2007/9250, 2007, A1 Location in patent: Page/Page column 36-37
[5]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2007/88514, 2007, A1 Location in patent: Page/Page column 38-39
[6]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2007/49224, 2007, A1 Location in patent: Page/Page column 24

3
[ 669734-35-4 ]
[ 165059-42-7 ]
[ 1007392-82-6 ]

Yield	Reaction Conditions	Operation in experiment
68%	With sodium carbonate In N,N-dimethyl-formamide at 80℃; for 2h;	2-Chloro-N-cyclopropyl-5-(3-methoxy-propenyl)-benzamide 5-Bromo-2-chloro-N-cyclopropyl-benzamide (19,3 g, 70.5 mmol) was dissolved in a mixture of DMF (350 mL) and 1-propanol (210 mL). Pd(OAc)2(PPh3)3 (2.64 g, 3.53 mmol) was added. (E)-2-(3-Methoxypropenyl)4,4,5,5-tetramethyl-1,3,2-dioxaborolane (15 mL, 70.5 mmol) was added through a syringe, and aq. 2M Na2CO3 (123 mL) was added. The mixture was stirred at 80° C. for 2 h, and allowed to cool to rt. Aq. 10% HCl was added carefully until a pH of 2 was reached. The solvents were partially removed under reduced pressure, and the residue was extracted with Et2O (3*). The combined org. extracts were washed with water and brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:2→1:1→EtOAc) yielded the title compound (12.7 g, 68%). LC-MS: tR=0.82 min; ES+: 266.17.

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - US2008/214598, 2008, A1 Location in patent: Page/Page column 9

4
[ 21739-92-4 ]
[ 765-30-0 ]
[ 669734-35-4 ]