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[ CAS No. 651780-27-7 ] {[proInfo.proName]}

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Chemical Structure| 651780-27-7
Chemical Structure| 651780-27-7
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Product Details of [ 651780-27-7 ]

CAS No. :651780-27-7 MDL No. :MFCD11045248
Formula : C10H8BrNO3 Boiling Point : -
Linear Structure Formula :- InChI Key :ADEQGMXEHRCMKL-UHFFFAOYSA-N
M.W : 270.08 Pubchem ID :53401270
Synonyms :

Calculated chemistry of [ 651780-27-7 ]

Physicochemical Properties

Num. heavy atoms : 15
Num. arom. heavy atoms : 9
Fraction Csp3 : 0.2
Num. rotatable bonds : 3
Num. H-bond acceptors : 4.0
Num. H-bond donors : 0.0
Molar Refractivity : 57.8
TPSA : 52.33 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.85 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.79
Log Po/w (XLOGP3) : 2.95
Log Po/w (WLOGP) : 2.77
Log Po/w (MLOGP) : 2.04
Log Po/w (SILICOS-IT) : 2.72
Consensus Log Po/w : 2.65

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.62
Solubility : 0.0649 mg/ml ; 0.00024 mol/l
Class : Soluble
Log S (Ali) : -3.71
Solubility : 0.0525 mg/ml ; 0.000194 mol/l
Class : Soluble
Log S (SILICOS-IT) : -4.25
Solubility : 0.0153 mg/ml ; 0.0000565 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 2.65

Safety of [ 651780-27-7 ]

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 [ 651780-27-7 ]

* 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 [ 651780-27-7 ]
  • Downstream synthetic route of [ 651780-27-7 ]

[ 651780-27-7 ] Synthesis Path-Upstream   1~5

  • 1
  • [ 651780-27-7 ]
  • [ 57764-49-5 ]
YieldReaction ConditionsOperation in experiment
96% With hydrogen; triethylamine In ethanol at 0℃; for 1 h; 10percent Palladium on carbon (1.5g) and triethylamine (7.5 g, 82.4 mmol) were added to a solution of ethyl 6-bromobenzisoxazole-3-carboxylate (20g, 0. 081mol) in ethanol (300ml) at 0 °C under an atmosphere of nitrogen. The nitrogen atmosphere was removed by evacuation and replaced with hydrogen gas, and the reaction mixture was maintained for 1 hour. The hydrogen atmosphere was removed by evacuation and replaced with nitrogen gas, and the palladium removed by filtration through Celite. The filter cake was washed with ethanol (3 x 50 mL) and the filtrates were concentrated. The residue was dissolved in dichloromethane (200 mL) and the solution was washed with water (4 x 50 mL), dried (sodium sulfate) and evaporated to provide 13.0 g of the product as a yellow solid (96percent). The ester was saponified using sodium hydroxide to provide the acid. The acid was coupled with the bicyclobase according to procedure A. Literature reference: Angell, R. M.; Baldwin, I. R.; Bamborough, P.; Deboeck, N. M.; Longstaff, T.; Swanson, S. W004010995A1 The following acid was prepared using this method: 1,2-Benzisoxazole-3-carboxylic acid.
96% With hydrogen; triethylamine In ethanol at 0℃; for 1 h; Diethyl malonate (12.6 g, 79 mmol) was added to a suspension of sodium hydride (3.16 g, 132 mmol) in dimethylsulfoxide (60 ml) over 30 min. The temperature of the reaction rose to 60 °C and the mixture clarified. 1,4-Dibromo-2-nitrobenzene (10 g, 36.0 mmol) was added and the solution was maintained for 2 h at 100 °C. The reaction mixture was allowed to cool to rt and was poured into ice (300g-400g). The precipitated solids were isolated by filtration and dried to provide 11.0 g of the product (89percent). The ester (11.0 g, 32.0 mmol) was diluted with a 2 N solution of sodium hydroxide (32 mL, 63 mmol) and the reaction mixture was maintained at room temperature for 16 h. The aqueous layer was extracted with dichloromethane (20 mL) and was acidified. The precipitated solids were isolated by filtration and dried to provide 7.00 g of the acid (89percent). Sulfuric acid (1 mL) was added to a solution of the acid (7.00 g, 27.0 mmol) in ethanol (60 ml). The reaction mixture was warmed to reflux, maintained for 2 h, and was concentrated under reduce pressure. The residue was partitioned between ethyl acetate (250 mL) and saturated sodium carbonate (50 mL) and the organic layer was washed with saturated sodium carbonate (50 mL) and brine (50 mL). The organic layer was dried (sodium sulfate) and concentrated to provide 8.00 g (98percent) of the ester as a liquid. Under N2 atmosphere, sodium ethylate was formed with sodium (33.5 g, 1.46 mol) in ethanol (1.0 L). Isoamylnitrite (225 mL) was added to a solution of the ester (420 g, 1.46 mol) in ethanol (3 L) in a 10 L three-necked round bottom flask and the mixture was warmed to 60 °C. A solution of sodium ethoxide, prepared from sodium metal (33.5 g, 1.46 mmol) in ethanol (1 L) was added dropwise and the reaction mixture was maintained for 2 h. The reaction mixture was allowed to cool to rt and was neutralized with 2 N hydrochloric acid. The reaction mixture was extracted with ethyl acetate (4 x 2L) and the combined organic layers were washed with water (2 x 1 L) and brine (2 x 1 L) and dried (sodium sulfate). The residue was purified by chromatography (1/1 to 0/1 hexane/ethyl acetate) to provide 110 g of the product ( 28percent). 10percent Palladium on carbon (1.5g) and triethylamine (7.5 g, 82.4 mmol) were added to a solution of ethyl 6-bromobenzisoxazole-3-carboxylate (20g, 0.081mol) in ethanol (300ml) at 0 °C under an atmosphere of nitrogen. The nitrogen atmosphere was removed by evacuation and replaced with hydrogen gas, and the reaction mixture was maintained for 1 hour. The hydrogen atmosphere was removed by evacuation and replaced with nitrogen gas, and the palladium removed'by filtration through Celite. The filter cake was washed with ethanol (3 x 50 mL) and the filtrates were concentrated. The residue was- dissolved in dichloromethane (200 mL) and the solution was washed with water (4 x 50 mL), dried (sodium sulfate) and evaporated to provide 13.0 g of the product as a yellow solid (96percent). The ester was saponified using sodium hydroxide to provide the acid. The acid was coupled with 1,4-diazabicyclo[3.2.2]nonane according to procedure A.
96% With hydrogen; triethylamine In ethanol at 0℃; for 1 h; 10percent Palladium on carbon (1.5 g) and triethylamine (7.5 g, 82.4 mmol) were added to a solution of ethyl 6-bromobenzisoxazole-3-carboxylate (20 g, 0.081 mol) in ethanol (300ml) at 0° C. under an atmosphere of nitrogen. The nitrogen atmosphere was removed by evacuation and replaced with hydrogen gas, and the reaction mixture was maintained for 1 hour. The hydrogen atmosphere was removed by evacuation and replaced with nitrogen gas, and the palladium removed by filtration through Celite. The filter cake was washed with ethanol (3.x.50 mL) and the filtrates were concentrated. The residue was dissolved in dichloromethane (200 mL) and the solution was washed with water (4.x.50 mL), dried (sodium sulfate) and evaporated to provide 13.0 g of the product as a yellow solid (96percent). The ester was saponified using sodium hydroxide to provide the acid. The acid was coupled with the bicyclobase according to procedure A.
Reference: [1] Patent: WO2005/63767, 2005, A2, . Location in patent: Page/Page column 44-45
[2] Patent: WO2005/111038, 2005, A2, . Location in patent: Page/Page column 66-67
[3] Patent: US2005/250808, 2005, A1, . Location in patent: Page/Page column 40
  • 2
  • [ 199328-35-3 ]
  • [ 651780-27-7 ]
YieldReaction ConditionsOperation in experiment
28% With sodium ethanolate; isopentyl nitrite In ethanol at 60℃; for 2 h; Under N2 atmosphere, sodium ethylate was formed with sodium (33.5 g, 1.46 mol) in ethanol (1. 0 L). Isoamylnitrite (225 mL) was added to a solution of the ester (420 g, 1.46 mol) in ethanol (3 L) in a 10 L three-necked round bottom flask and the mixture was warmed to 60 °C. A solution of sodium ethoxide, prepared from sodium metal (33.5 g, 1.46 mmol) in ethanol (1 L) was added dropwise and the reaction mixture was maintained for 2 h. The reaction mixture was allowed to cool to rt and was neutralized with 2 N hydrochloric acid. The reaction mixture was extracted with ethyl acetate (4 x 2L) and the combined organic layers were washed with water (2 x 1 L) and brine (2 x 1 L) and dried (sodium sulfate). The residue was purified by chromatography (1/1 to 0/1 hexane/ethyl acetate) to provide 110 g of the product (28percent).
28% With sodium ethanolate; isopentyl nitrite In ethanol at 60℃; for 2 h; Isoamylnitrite (225 mL) was added to a solution of the ester (420 g, 1.46 mol) in ethanol (3 L) in a 10 L three-necked round bottom flask and the mixture was warmed to 60° C. A solution of sodium ethoxide, prepared from sodium metal (33.5 g, 1.46 mmol) in ethanol (1 L) was added dropwise and the reaction mixture was maintained for 2 h. The reaction mixture was allowed to cool to rt and was neutralized with 2 N hydrochloric acid. The reaction mixture was extracted with ethyl acetate (4.x.2 L) and the combined organic layers were washed with water (2.x.1 L) and brine (2.x.1 L) and dried (sodium sulfate). The residue was purified by chromatography (1/1 to 0/1 hexane/ethyl acetate) to provide 110 g of the product (28percent).
28% With sodium ethanolate; isopentyl nitrite In ethanol at 60℃; for 2 h; Isoamylnitrite (225 mL) was added to a solution of the ester (420 g, 1.46 mol) in ethanol (3 L) in a 10 L three-necked round bottom flask and the mixture was warmed to 60° C. A solution of sodium ethoxide, prepared from sodium metal (33.5 g, 1.46 mmol) in ethanol (1 L) was added dropwise and the reaction mixture was maintained for 2 h.
The reaction mixture was allowed to cool to rt and was neutralized with 2 N hydrochloric acid.
The reaction mixture was extracted with ethyl acetate (4*2 L) and the combined organic layers were washed with water (2*1 L) and brine (2*1 L) and dried (sodium sulfate).
The residue was purified by chromatography (1/1 to 0/1 hexane/ethyl acetate) to provide 110 g of the product (28percent).
Reference: [1] Patent: WO2005/63767, 2005, A2, . Location in patent: Page/Page column 44
[2] Patent: US2005/250808, 2005, A1, . Location in patent: Page/Page column 40
[3] Patent: US2007/78147, 2007, A1, . Location in patent: Page/Page column 72
  • 3
  • [ 141-52-6 ]
  • [ 100487-82-9 ]
  • [ 651780-27-7 ]
YieldReaction ConditionsOperation in experiment
51% With isopentyl nitrite In ethanol at 60℃; for 24 h; (20). A solution of methyl 2-(4-brarao-2-mtropbenyl )acetate (3.43 g, 12.5 .ramoi, 1.0 eq.) in ethanol (62.5 mL, 0.2 M) was treated with isoa yl nitrite (2.1 mL, 16.25 mmol, 1.3 eq.) a d- sodium ethoxide (893 mg, 13.13 mmol, 1.05 eq.). The reaction mixture was stirred at 60 °C. After 24 h, the mixture was neutralized with 1M HO solution and concentrated. The residue was extracted with EiOAc (3X). The combined extracts were washed with brine, dried over Na SO,*, filtered and concentrated. Purification using Hash chromatography an silica ge (0-35percent EtOAc/hexanes) to provide the title compound as a pale yellow solid (1.73 g, 51percent yield): ES-MS ( - 1 f : 270.2
Reference: [1] Patent: WO2016/115282, 2016, A1, . Location in patent: Page/Page column 80
[2] Patent: WO2004/10995, 2004, A1, . Location in patent: Page/Page column 49-50
  • 4
  • [ 875258-18-7 ]
  • [ 110-46-3 ]
  • [ 651780-27-7 ]
YieldReaction ConditionsOperation in experiment
28% With sodium ethanolate In ethanol at 60℃; for 2 h; Diethyl malonate (12.6 g, 79 mmol) was added to a suspension of sodium hydride (3.16 g, 132 mmol) in dimethylsulfoxide (60 ml) over 30 min. The temperature of the reaction rose to 60 °C and the mixture clarified. 1,4-Dibromo-2-nitrobenzene (10 g, 36.0 mmol) was added and the solution was maintained for 2 h at 100 °C. The reaction mixture was allowed to cool to rt and was poured into ice (300g-400g). The precipitated solids were isolated by filtration and dried to provide 11.0 g of the product (89percent). The ester (11.0 g, 32.0 mmol) was diluted with a 2 N solution of sodium hydroxide (32 mL, 63 mmol) and the reaction mixture was maintained at room temperature for 16 h. The aqueous layer was extracted with dichloromethane (20 mL) and was acidified. The precipitated solids were isolated by filtration and dried to provide 7.00 g of the acid (89percent). Sulfuric acid (1 mL) was added to a solution of the acid (7.00 g, 27.0 mmol) in ethanol (60 ml). The reaction mixture was warmed to reflux, maintained for 2 h, and was concentrated under reduce pressure. The residue was partitioned between ethyl acetate (250 mL) and saturated sodium carbonate (50 mL) and the organic layer was washed with saturated sodium carbonate (50 mL) and brine (50 mL). The organic layer was dried (sodium sulfate) and concentrated to provide 8.00 g (98percent) of the ester as a liquid. Under N2 atmosphere, sodium ethylate was formed with sodium (33.5 g, 1.46 mol) in ethanol (1.0 L). Isoamylnitrite (225 mL) was added to a solution of the ester (420 g, 1.46 mol) in ethanol (3 L) in a 10 L three-necked round bottom flask and the mixture was warmed to 60 °C. A solution of sodium ethoxide, prepared from sodium metal (33.5 g, 1.46 mmol) in ethanol (1 L) was added dropwise and the reaction mixture was maintained for 2 h. The reaction mixture was allowed to cool to rt and was neutralized with 2 N hydrochloric acid. The reaction mixture was extracted with ethyl acetate (4 x 2L) and the combined organic layers were washed with water (2 x 1 L) and brine (2 x 1 L) and dried (sodium sulfate). The residue was purified by chromatography (1/1 to 0/1 hexane/ethyl acetate) to provide 110 g of the product ( 28percent). 10percent Palladium on carbon (1.5g) and triethylamine (7.5 g, 82.4 mmol) were added to a solution of ethyl 6-bromobenzisoxazole-3-carboxylate (20g, 0.081mol) in ethanol (300ml) at 0 °C under an atmosphere of nitrogen. The nitrogen atmosphere was removed by evacuation and replaced with hydrogen gas, and the reaction mixture was maintained for 1 hour. The hydrogen atmosphere was removed by evacuation and replaced with nitrogen gas, and the palladium removed'by filtration through Celite. The filter cake was washed with ethanol (3 x 50 mL) and the filtrates were concentrated. The residue was- dissolved in dichloromethane (200 mL) and the solution was washed with water (4 x 50 mL), dried (sodium sulfate) and evaporated to provide 13.0 g of the product as a yellow solid (96percent). The ester was saponified using sodium hydroxide to provide the acid. The acid was coupled with 1,4-diazabicyclo[3.2.2]nonane according to procedure A.
Reference: [1] Patent: WO2005/111038, 2005, A2, . Location in patent: Page/Page column 66-67
  • 5
  • [ 64-17-5 ]
  • [ 141-52-6 ]
  • [ 100487-82-9 ]
  • [ 651780-27-7 ]
YieldReaction ConditionsOperation in experiment
37% at 20 - 60℃; for 18 h; Step 2 6-bτoτno-beπzord1isoxazo1e-3-caτboxylic acid ethyl esterA solution of (4-bromo-2-nitro-phenyl)-acetic acid methyl ester (0.99 g, 3.61 mmol) in ethanol (8 mL) at room temperature is treated with isoamyl nitrite (0.60 mL, 4.47 mmol). A solution of NaOEt in ethanol (1.9 M, 2.0 mL) is added, and the mixture is stirred at 60 0C for 2 hours and at room temperature for 16 hours. The mixture is neutralized with HCl (1.0 M, 4.0 mL) and concentrated under reduced pressure. The residue is extracted with ethyl acetate (2OmL x 2) and the combined organic layers are dried over sodium sulfate and concentrated under reduced pressure. The residue is purified via silica gel chromatography eluting with 25percent ethyl acetate in hexanes to give the title compound (0.36 g, 37percent). ES/MS m/e 269.8; 271.8 (M+l).
Reference: [1] Patent: WO2007/92751, 2007, A2, . Location in patent: Page/Page column 26
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