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[ CAS No. 345965-52-8 ]

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Chemical Structure| 345965-52-8
Chemical Structure| 345965-52-8
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CAS No. :345965-52-8MDL No. :MFCD07374439
Formula : C10H9BrO2 Boiling Point : -
Linear Structure Formula :-InChI Key :-
M.W :241.08Pubchem ID :16227966
Synonyms :

Computed Properties of [ 345965-52-8 ]

TPSA : 37.3 H-Bond Acceptor Count : 2
XLogP3 : 2.4 H-Bond Donor Count : 1
SP3 : 0.30 Rotatable Bond Count : 2

Safety of [ 345965-52-8 ]

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 [ 345965-52-8 ]

  • Upstream synthesis route of [ 345965-52-8 ]
  • Downstream synthetic route of [ 345965-52-8 ]

[ 345965-52-8 ] Synthesis Path-Upstream   1~17

  • 1
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Reference: [1] Tetrahedron, 2016, vol. 72, # 16, p. 1941 - 1953
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  • [ 847361-67-5 ]
Reference: [1] Patent: WO2005/56529, 2005, A1, . Location in patent: Page/Page column 47
[2] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 3, p. 887 - 892
[3] Patent: WO2006/133559, 2006, A1,
  • 3
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  • [ 847361-67-5 ]
Reference: [1] Patent: WO2005/21487, 2005, A1, . Location in patent: Page/Page column 58
  • 4
  • [ 345965-52-8 ]
  • [ 75-65-0 ]
  • [ 360773-84-8 ]
YieldReaction ConditionsOperation in experiment
23 g With diphenyl phosphoryl azide; N-ethyl-N,N-diisopropylamine In toluene for 5 h; Molecular sieve; Reflux To the solution of 1-(4-bromophenyl)cyclopropanecarboxylic acid (40 g, 165 mmol, available from Amatek Chemical AC-0350) in toluene (800 ml), in the presence of activated molecular sieves (15g), N,N-diisopropylethylamine (27.5 g, 497 mmol), Diphenylphosphoryl azide (54.7 g, 215 mmol) and tert-Butanol (380 ml) were added. The resulting mixture was refluxed 5 hours. The mixture was cooled to room temperature and the solvents evaporated in vacuo. The residue was dissolved in ethyl acetate (200 ml) and washed with 5percent citric acid (200 ml), aqueous NaHCO3 (200 ml) and brine (200 ml). Collected organics after drying over Na2SO4 and solvent evaporation afforded a crude residue which was purified by flash chromatography on silica gel eluting with a mixture petroleum ether/ethyl acetate 4:1. Collected fractions after solvent evaporation afforded the title compound (D4) (23.0 g) as a solid.
1.3 g at 20℃; Molecular sieve; Reflux General procedure: A solution of 2a (2.26g, 9.42mmol) in MeOH (19mL) was added a 6.0N solution of sodium hydroxide (9.42mL, 56.5mmol). The reaction mixture was refluxed overnight and was added a 4.0M HCl solution in dioxane (15.0mL, 60mmol) at rt. The solvent was removed under reduced pressure. A solution of the residue in anhydrous t-BuOH (0.20L) with flame dried 4 molecular sieve powder (1.0g) was added diphenyl phosphorazidate (2.45mL, 11.3mmol) and triethylamine (2.64mL, 18.8mmol). The reaction mixture was stirred at rt for 1.0h and then heated under reflux overnight. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography with pre-packed silica gel disposable column to afford the title compound 3a (1.42g, 51percent) and 4a (0.63g, 30percent).
Reference: [1] Patent: US6359135, 2002, B1, . Location in patent: Page column 113-114
[2] Patent: US6369225, 2002, B1, . Location in patent: Page column 42, 112
[3] Patent: US2008/81802, 2008, A1, . Location in patent: Page/Page column 8
[4] Patent: WO2012/76063, 2012, A1, . Location in patent: Page/Page column 36-37
[5] Patent: US2013/261100, 2013, A1, . Location in patent: Paragraph 0264-0265
[6] Tetrahedron, 2016, vol. 72, # 16, p. 1941 - 1953
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  • [ 24424-99-5 ]
  • [ 360773-84-8 ]
Reference: [1] Patent: WO2005/63239, 2005, A1, . Location in patent: Page/Page column 129
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  • [ 1014645-87-4 ]
Reference: [1] Patent: WO2012/76063, 2012, A1,
  • 7
  • [ 124276-67-1 ]
  • [ 345965-52-8 ]
YieldReaction ConditionsOperation in experiment
69%
Stage #1: With potassium hydroxide In ethylene glycol at 160℃; for 6 h;
Stage #2: With hydrogenchloride In water; ethylene glycol
A mixture of compound XV-2 (7.5 g, 33.78 mmol), KOH (7.6 g, 135 mmol) and ethylene glycol (50 mL) were heated to 160°C for 6 hrs. The mixture was cooled to room temperature, water (200 mL) was added and the mixture was acidified to pH=3~4 with aq. HCl (2 N) to precipitate the product. The product was collected by filtration to yield compound XV- 3 (5.6 g, yield 69percent). MS (ESI) m/z (M+H)+ 240.
330 mg With sodium hydroxide In ethanol; water at 100℃; Step 2:
Preparation of 1-(4-bromophenyl)cyclopropancarboxylic acid
1-(4-bromophenyl)cyclopropancarbonitrile (256 mg) prepared in Step 1 was dissolved in a mixed solution of ethanol (2.5 mL) and an aqueous solution of sodium hydroxide (1.2 mL, 25percent w/w).
The mixture was heated to 100°C, and stirred overnight.
Upon completion of the reaction, ice was added to the reaction mixture, followed by addition of dichloromethane and 1N aqueous solution of hydrochloric acid.
The organic layer thus formed was separated, dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure to obtain the target compound as oil (330 mg).
1H NMR (300 MHz, DMSO-d6): δ 12.38 (s, 1H), 7.46(d, 2H), 7.26(d, 2H), 1.42(q, 2H), 1.11 (q, 2H)
330 mg With sodium hydroxide In ethanol; water at 100℃; Step 2:
Preparation of 1-(4-bromophenyl)cyclopropancarboxylic acid
1-(4-bromophenyl)cyclopropancarbonitrile (256 mg) prepared in Step 1 was dissolved in a mixed solution of ethanol (2.5 mL) and an aqueous solution of sodium hydroxide (1.2 mL, 25percent w/w).
The mixture was heated to 100° C., and stirred overnight.
Upon completion of the reaction, ice was added to the reaction mixture, followed by addition of dichloromethane and 1N aqueous solution of hydrochloric acid.
The organic layer thus formed was separated, dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure to obtain the target compound as oil (330 mg).
1H NMR (300 MHz, DMSO-d6): δ 12.38 (s, 1H), 7.46 (d, 2H), 7.26 (d, 2H), 1.42 (q, 2H), 1.11 (q, 2H)
Reference: [1] Patent: US6359135, 2002, B1, . Location in patent: Page column 113
[2] Patent: US6369225, 2002, B1, . Location in patent: Page column 42, 112
[3] Journal of Medicinal Chemistry, 2010, vol. 53, # 16, p. 6003 - 6017
[4] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 3, p. 887 - 892
[5] Patent: WO2013/25733, 2013, A1, . Location in patent: Paragraph 0490
[6] Patent: WO2004/814, 2003, A1, . Location in patent: Page 88
[7] Patent: WO2004/48374, 2004, A1, . Location in patent: Page 51
[8] Patent: WO2005/19161, 2005, A1, . Location in patent: Page/Page column 51
[9] Patent: WO2005/21487, 2005, A1, . Location in patent: Page/Page column 57
[10] Patent: WO2005/56529, 2005, A1, . Location in patent: Page/Page column 46
[11] Patent: WO2010/141761, 2010, A2, . Location in patent: Page/Page column 47
[12] Patent: US2011/82164, 2011, A1, . Location in patent: Page/Page column 24
[13] Patent: US2011/82181, 2011, A1, . Location in patent: Page/Page column 16
[14] Patent: WO2012/78593, 2012, A2, . Location in patent: Page/Page column 123-124
[15] Patent: WO2012/78805, 2012, A1, . Location in patent: Page/Page column 91-92
[16] Patent: US2012/258987, 2012, A1, . Location in patent: Page/Page column 41
[17] Patent: WO2013/189865, 2013, A1, . Location in patent: Page/Page column 27-28
[18] Patent: EP2738174, 2014, A2, . Location in patent: Paragraph 0182; 0183
[19] Patent: US2014/163226, 2014, A1, . Location in patent: Paragraph 0330-0332
[20] Patent: WO2006/133559, 2006, A1, . Location in patent: Page/Page column 33-34
[21] Advanced Synthesis and Catalysis, 2018, vol. 360, # 22, p. 4306 - 4311
  • 8
  • [ 16532-79-9 ]
  • [ 107-04-0 ]
  • [ 345965-52-8 ]
YieldReaction ConditionsOperation in experiment
82%
Stage #1: With N-benzyl-N,N,N-triethylammonium chloride; potassium hydroxide In water at 50℃; for 3 h;
Stage #2: at 100℃; for 72 h;
A solution of 4-bromophenylacetonitrile (50.0 g, 255 mmol), 1-bromo-2-chloroethane (26.5 mL, 319 mmol), benzyltriethylammonium chloride (1.16 g, 5.10 mol), and potassium hydroxide (100 g, 1.79 mol) in water (100 mL) was stirred at 50°C for 3 h. Ethanol (400 mL) was added to the reaction mixture, and the mixture was stirred at 100°C for 3 days. The reaction mixture was neutralized by pouring it into 5 N hydrochloric acid (360 mL) with ice cooling. The reaction mixture was extracted with dichloromethane, the organic layer was dried with anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the residue, and the precipitate was collected by filtration and dried under reduced pressure to obtain the title compound (50.4 g, 82percent) as a white solid. 1H-NMR (500 MHz, CDCl3) δ: 1.23 (2H, q, J = 3.7 Hz), 1.67 (2H, q, J = 3.7 Hz), 7.22 (2H, dt, J = 8.6, 2.2 Hz), 7.43 (2H, dt, J = 8.6, 2.2 Hz)
Reference: [1] Patent: EP2700643, 2014, A1, . Location in patent: Paragraph 0200
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YieldReaction ConditionsOperation in experiment
51% With N-benzyl-N,N,N-triethylammonium chloride; sodium hydroxide In water at 70 - 150℃; for 22 h; Step 1 : Preparation of l-(4-bromophenyl)cyclopropanecarboxylic acid To a mixture of 4-bromophenylacetonitrile (5.0 g, 25.44 mmol) and benzyltriethylammonium chloride (144.9 mg, 0.63 mmol) was added 1,2-dibromoethane (7.45 mL, 86.5 mmol). The reaction mixture was heated to 70 °C followed by dropwise addition of 50percent aqueous sodium hydroxide solution (25 mL). The reaction mixture was heated at 70 °C for 7 h and then heated at 150 °C for 15 h. After the completion of reaction as confirmed by TLC, the reaction mixture was diluted with diethyl ether ( 100 mL). The aqueous layer was separated and acidified with 50percent aqueous HCl to pH 1. The crude compound was diluted with ethyl acetate (500 mL). The organic layer was separated, washed with water (2 x 10 mL), dried over Na2S04 and concentrated to afford title compound (3.1 g, 51 percent) as a solid. ESIMS (m/z): 241.5 (M-l )
51% With N-benzyl-N,N,N-triethylammonium chloride; sodium hydroxide In water at 70 - 150℃; for 22 h; Step 1:
Preparation of 1-(4-bromophenyl)cyclopropanecarboxylic acid
To a mixture of 4-bromophenylacetonitrile (5.0 g, 25.44 mmol) and benzyltriethylammonium chloride (144.9 mg, 0.63 mmol) was added 1,2-dibromoethane (7.45 mL, 86.5 mmol).
The reaction mixture was heated to 70 °C followed by dropwise addition of 50percent aqueous sodium hydroxide solution (25 mL).
The reaction mixture was heated at 70 °C for 7 h and then heated at 150 °C for 15 h.
After the completion of reaction as confirmed by TLC, the reaction mixture was diluted with diethyl ether (100 mL).
The aqueous layer was separated and acidified with 50percent aqueous HCl to pH 1.
The crude compound was diluted with ethyl acetate (500 mL).
The organic layer was separated, washed with water (2 x 10 mL), dried over Na2SO4 and concentrated to afford title compound (3.1 g, 51 percent) as a solid.
ESIMS (m/z): 241.5 (M-1)
Reference: [1] Patent: WO2013/38429, 2013, A2, . Location in patent: Page/Page column 75-76
[2] Patent: EP2755722, 2017, B1, . Location in patent: Paragraph 0180
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YieldReaction ConditionsOperation in experiment
75.14% at 15 - 55℃; for 48.25 h; Sealed tube; Inert atmosphere A sealed tube was charged with 1-phenyl cyclopropane carboxylic acid (3.0 g, 18.5mmol), sodium acetate (1.75 g, 1.1 eq) and glacial acetic acid (10 mL). To the stirredsolution at 15 00, Br2 (1 .2 mL, 1 .0 eq) was added under nitrogen atmosphere. Then, the reaction mixture was stirred at room temperature for 15 mm and gradually raised the temperature to 55 00 and maintained the same for another 48 h. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organiclayer was washed with water and brine solution and then wasdried and concentrated. The obtained product was triturated with n-hexane to yield the title compound (3.34 g, 75.14percent) as a pale yellowish solid.
Reference: [1] Patent: WO2014/202580, 2014, A1, . Location in patent: Page/Page column 128
[2] Patent: US2008/81802, 2008, A1, . Location in patent: Page/Page column 8
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Reference: [1] Patent: US6369261, 2002, B1, . Location in patent: Page column 111
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  • [ 345965-52-8 ]
Reference: [1] Patent: US2011/82164, 2011, A1,
[2] Patent: WO2012/78593, 2012, A2,
[3] Patent: US2011/82181, 2011, A1,
[4] Patent: WO2012/78805, 2012, A1,
[5] Patent: US2012/258987, 2012, A1,
[6] Patent: WO2013/25733, 2013, A1,
[7] Patent: WO2013/189865, 2013, A1,
[8] Patent: EP2738174, 2014, A2,
[9] Patent: US2014/163226, 2014, A1,
[10] Advanced Synthesis and Catalysis, 2018, vol. 360, # 22, p. 4306 - 4311
  • 13
  • [ 133017-10-4 ]
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Reference: [1] Tetrahedron, 2016, vol. 72, # 16, p. 1941 - 1953
  • 14
  • [ 13675-18-8 ]
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  • [ 1159489-46-9 ]
Reference: [1] Organic Process Research and Development, 2017, vol. 21, # 11, p. 1859 - 1863
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  • [ 1215205-50-7 ]
YieldReaction ConditionsOperation in experiment
80% With thionyl chloride In methanol at 0 - 70℃; To a 50 mL round-bottom flask was added l-(4-bromophenyl)cyclopropane-1- carboxylic acid 149a (2 g, 8.30 mmol, 1.00 equiv.) and methanol (20 mL). Thionyl chloride(2.96 g, 24.88 mmol, 3.00 equiv.) was added drop·wise with stirring at 0°C. The resultingmixture was stined at 70 °C ovemight. After cooling to room temperature, the reaction wasquenched by the addition of water/ice. The aqueous mixture was extracted with ethyl acetate5 (50 mL x 2). The combined organic extracts were vvashed with brine (50 rnL x 2, dried overanhydrous sodium sulfate, and concentrated under vacuum. The crude product was purifiedby Flash-Prep-HPLC eluting with EA/PE (from 0percent to 10percent '.vithin 20 rnin) to give methyl1-(4-bromophenyl)cyclopropa.ne-l-carboxyate 149b (l.7g, 80percent;) as colorless oil
Reference: [1] Patent: WO2018/39386, 2018, A1, . Location in patent: Page/Page column 295; 296
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  • [ 64-17-5 ]
  • [ 1215205-50-7 ]
Reference: [1] Organic Process Research and Development, 2017, vol. 21, # 11, p. 1859 - 1863
[2] Patent: WO2010/141761, 2010, A2, . Location in patent: Page/Page column 47
[3] Patent: US2011/82164, 2011, A1, . Location in patent: Page/Page column 24
[4] Patent: US2011/82181, 2011, A1, . Location in patent: Page/Page column 16
[5] Patent: WO2012/78593, 2012, A2, . Location in patent: Page/Page column 124
[6] Patent: WO2012/78805, 2012, A1, . Location in patent: Page/Page column 92
[7] Patent: US2012/258987, 2012, A1, . Location in patent: Page/Page column 42
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Reference: [1] Patent: US2011/82164, 2011, A1,
[2] Patent: US2011/82181, 2011, A1,
[3] Patent: WO2012/78593, 2012, A2,
[4] Patent: US2012/258987, 2012, A1,
[5] Organic Process Research and Development, 2017, vol. 21, # 11, p. 1859 - 1863
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