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[ CAS No. 127264-14-6 ]

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2D
Chemical Structure| 127264-14-6
Chemical Structure| 127264-14-6
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Product Details of [ 127264-14-6 ]

CAS No. :127264-14-6MDL No. :MFCD06797641
Formula : C10H11BrO Boiling Point : 287.7°C at 760 mmHg
Linear Structure Formula :-InChI Key :-
M.W :227.10Pubchem ID :21831160
Synonyms :

Computed Properties of [ 127264-14-6 ]

TPSA : 9.2 H-Bond Acceptor Count : 1
XLogP3 : 2.9 H-Bond Donor Count : 0
SP3 : 0.40 Rotatable Bond Count : 2

Safety of [ 127264-14-6 ]

Signal Word:WarningClass:N/A
Precautionary Statements:P261-P305+P351+P338UN#:N/A
Hazard Statements:H302-H315-H319-H335Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 127264-14-6 ]

  • Upstream synthesis route of [ 127264-14-6 ]
  • Downstream synthetic route of [ 127264-14-6 ]

[ 127264-14-6 ] Synthesis Path-Upstream   1~3

  • 1
  • [ 127264-14-6 ]
  • [ 133099-07-7 ]
YieldReaction ConditionsOperation in experiment
93.2%
Stage #1: With potassium hydroxide In water; toluene at 100℃; for 15.25 h;
Stage #2: With hydrogen bromide In water; toluene
This Example illustrates a process for preparing a compound of formula (IV). [0045] 3-(S)-(I -carbamoyl- l,l-diphenylmethyl)pvrrolidine L-(+)-tartrate (1.0 g, 2.33 mmol), potassium hydroxide (0.45 g, 7.04 mmol), methyltriethylammonium chloride (0.05 g, 0.32 mmol), 2 mL of water and 10 mL of toluene were charged into the bottom flask; a yellowish solution was formed. A solution of 5-(2-bromoethyl)-2,3-dihydrobenzofuran (0.6 g, 2.64 mmol) in 7 mL of toluene was added dropwise in 15 minutes. The reaction mixture was heated to 100 0C and stirred for 15 hours. Then the reaction mixture was cooled down to 20 °C. After that, 15 mL of toluene and 10 mL of water were added, the mixture was stirred for 20 minutes at atmospheric pressure and the layers were separated. The aqueous layer was extracted and the organic layer was dried with Na2SO4. Then 1 mL of concentrated hydrobromic acid solution was charged and the mixture was concentrated by distillation under vacuum. Then 10 mL of acetone and 10 mL of diisopropylether were charged and then the solvent was evaporated by distillation under vacuum to give 1.1 g (93.2percent molar yield) of a yellowish solid. (HPLC purity (method A): 92.19percent). [0046] The results demonstrate the improved yield of a compound of formula (IV) prepared by reacting the L-(+)-tartrate salt of 3 -(S)-(I -carbamoyl- 1,1- diphenylmethyl)pyrrolidine of formula (V) with 5-(2-bromoethyl)-2,3-dihydrobenzofuran of <n="14"/>formula (VI), methyltriethylammonium chloride, and potassium hydroxide, in the presence of toluene and water.
90.67%
Stage #1: With potassium hydroxide In 2-methyltetrahydrofuran; water at 60 - 70℃;
Stage #2: for 16 h; Heating / reflux
Stage #3: With hydrogen bromide In 2-methyltetrahydrofuran; water at 0 - 20℃; for 2 h;
This Example illustrates a process for preparing a compound of formula (IV). This Example also illustrates the conversion of a compound of formula (IV) to the hydrobromide salt.[0048] Into a reaction vessel were charged 2,2-diphenyl-2-[(35)-pyrrolidin-3- yl]acetamide L-(+)-tartrate (90.00 g, 0.21 mol), methyltriethylammonium chloride (4.82 g, 0.03 mol) and 2-methyltetrahydrofuran (180 mL). The resulting suspension was heated to 60-70 °C. To the suspension was added a solution of potassium hydroxide (69.79 g, 1.05 mol) in water (180 mL), keeping the temperature between 60 and 70 0C. The mixture was heated to reflux and to this mixture was added dropwise a solution of 5-(2-bromoethyl)-2,3- dihydro-1-benzofuran (56.98 g, 0.25 mol) in 2-methyltetrahydrofuran (270 mL). The resulting mixture was heated at reflux for 16 h and cooled to room temperature. The phases were separated and the organic phase was washed twice with 180 mL of a 10percent aqueous solution of ammonium chloride. The remaining water was distilled azeotropically and hydrobromic acid 48percent (28.19 mL) was added dropwise at room temperature. The resulting suspension was cooled to 0-5 °C, stirred at this temperature for 2 h and filtered. An almost white solid was obtained (188.0 g, l.o.d. = 48.83percent, 90.67percent yield, HPLC purity (method B): 98.96percent). This solid can be optionally dried at 60 °C under vacuum. This solid can be optionally further purified as in Example 4.[0049] The results demonstrate a process for preparing (S)-2- { 1 -[2-(2,3- dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide hydrobromide of formula (IV) in high yield and purity.
84.92%
Stage #1: With potassium hydroxide In water; butanone at 75℃; for 6 h;
Stage #2: With hydrogen bromide In water; butanone at 0 - 5℃; for 2 h;
This Example illustrates a process for preparing a compound of formula (IV). [0054] To a 500 mL, three-neck round bottom flask, equipped with a reflux condenser and a thermometer, was added 2,2-diphenyl-2-[(3S)-pyrrolidin-3-yl]acetamide L-(+)-tartrate (54.15 g, 125.8 mmol), 5-(2-bromoethyl)-2,3-dihydrobenzofuran (34.86 g, 153.5 mmol), potassium hydroxide (20.78 g, 370.4 mmol), methyltriethylammonium chloride (2.810 g, 18.53 mmol), methylethylketone (170 mL) and water (34.0 mL). The reaction mixture was heated to reflux (about 75 °C) and stirred at this temperature for 6 hours, after which time it was cooled to 20-25 0C and methylethylketone (96 mL) and water (106 mL) were added. The mixture was stirred and the layers were separated. To the organic layer 10percent aqueous solution of ammonium chloride (106 mL) was added. The mixture was stirred and the layers were separated. The organic layer was evaporated to dryness and methylethylketone (106 , mL) was added to the residue. The mixture was stirred until complete dissolution and hydrobromic acid (13 mL) was added resulting in the formation of a precipitate. The resulting suspension was cooled to 0-5 0C and stirred at this temperature for 2 h. The suspension was filtered and the solid was washed with methylethylketone (2 x 20 mL). A slightly brown solid was obtained (90.72 g, l.o.d. = 41.51percent, 84.92 percent yield, HPLC purity (method C): 95.68percent).
76.3%
Stage #1: With potassium hydroxide In toluene at 100℃; for 16.25 h;
Stage #2: With hydrogen bromide In water; toluene
This Example illustrates a process for preparing a compound of formula (IV). [0042] 3-(5)-(l-carbamoyl-l,l-diphenyhnethyl)pyrrolidine L-(+)-tartrate (1.0 g, 2.33 mmol), potassium hydroxide (0.45 g, 7.04 mmol), methyltriethylammonium chloride (0.05 g, 0.32 mmol) and 10 mL of toluene were charged into the bottom flask; a yellowish solution is formed. A solution of 5-(2-bromoethyl)-2,3-dihydrobenzofuran (0.6 g, 2.64 mmol) in 5 mL <n="13"/>of toluene was added dropwise in 15 minutes. The reaction mixture was heated to 100 °C and stirred for 16 hours; then the reaction mixture was cooled down to 20 °C, and 15 mL of toluene and 20 mL of water were added. The mixture was stirred for 20 minutes at atmospheric pressure and the layers were separated. The aqueous layer was extracted and the organic layer was dried with Na2SO4. After that, 1 mL of concentrated hydrobromic acid solution was charged and the mixture was concentrated by distillation under vacuum. Then 10 mL of acetone and 10 mL of diisopropylether were charged and the solvent was evaporated by distillation under vacuum to give 0.9 g (76.3percent molar yield) of a yellowish solid. (HPLC purity (method A): 65.46percent).[0043] The results demonstrate that a compound of formula (IV) can be prepared by reacting the L-(+)-tartrate salt of 3-(5)-(l-carbamoyl-l,l-diphenylmethyl)pyrrolidine of formula (V) with 5-(2-bromoethyl)-2,3-dihydrobenzofuran of formula (VI) in the presence of toluene, methyltriethylammonium chloride, and potassium hydroxide.

Reference: [1] Patent: WO2008/29257, 2008, A2, . Location in patent: Page/Page column 12-13
[2] Patent: WO2008/29257, 2008, A2, . Location in patent: Page/Page column 13
[3] Patent: WO2008/29257, 2008, A2, . Location in patent: Page/Page column 14
[4] Patent: WO2008/29257, 2008, A2, . Location in patent: Page/Page column 11-12
[5] Patent: WO2011/70419, 2011, A1, . Location in patent: Page/Page column 12-15
[6] Organic Process Research and Development, 2012, vol. 16, # 10, p. 1591 - 1597
  • 2
  • [ 127264-14-6 ]
  • [ 134002-25-8 ]
  • [ 133099-07-7 ]
YieldReaction ConditionsOperation in experiment
84.92%
Stage #1: With potassium hydroxide; triethylmethylammonium chloride In water; butanone at 75℃; for 6 h; Heating / reflux
Stage #2: With hydrogen bromide In water; butanone
EXAMPLE 3; This example illustrates a process for preparing (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide or a salt thereof wherein a substantially enantiomerically pure 2,2-diphenyl-2-[(3S)-pyrrolidin-3-yl]acetamide or salt thereof, as determined by the inventive method, is used as an intermediate compound. In particular, this example illustrates that when using 2,2-diphenyl-2-[(3S)-pyrrolidin-3-yl]acetamide having less than 0.2percent of the (R)-enantiomer as determined by the HPLC method of Example 1, the obtained (S)-darifenacin hydrobromide has less than 0.06percent of the (R)-enantiomer of darifenacin hydrobromide as determined by the HPLC method of Example 2.To a flask was added: 2,2-diphenyl-2-[(3S)-pyrrolidin-3-yl]acetamide (54.15 g, 125.8 mmol, 99.63percent ee as determined by chiral HPLC method of Example 1), 5-(2-bromoethyl)-2,3-dihydrobenzofuran (34.86 g, 153.5 mmol), potassium hydroxide (20.78 g, 370.4 mmol), methyltriethylammonium chloride (2.810 g, 18.53 mmol), methylethylketone (170 mL) and water (34.0 mL). The reaction mixture was heated to reflux (approximately 75° C.) and stirred for 6 hours, after which time the reaction mixture was cooled to 20-25° C. After cooling, methylethylketone (96 mL) and water (106 mL) were added with stirring and the layers were separated. Ammonium chloride (106 mL, 10percent aqueous solution) was added to the organic layer with stirring and the layers were separated. The organic layer was evaporated to dryness and methylethylketone (106 mL) was added to the residue. The mixture was stirred until dissolution and hydrobromic acid (13 mL) was added, after which a precipitate formed. The resulting suspension was cooled to 0-5° C. and stirred at this temperature for 2 hours. The suspension was filtered and the solid was washed with methylethylketone (2.x.20 mL). A solid was obtained (90.72 g, l.o.d.=41.51percent, 84.92percent yield, 95.68percent HPLC purity, 99.88percent ee as determined by chiral HPLC method of Example 2).
Reference: [1] Patent: US2008/312455, 2008, A1, . Location in patent: Page/Page column 7
[2] Patent: US2010/204296, 2010, A1, . Location in patent: Page/Page column 7
[3] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2013, vol. 52, # 6, p. 824 - 828
  • 3
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  • [ 133099-07-7 ]
Reference: [1] Patent: WO2008/126106, 2008, A2,
[2] Patent: WO2008/126106, 2008, A2,
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