(1-Bromocyclopentyl)(2-chlorophenyl)methanone [C12H12BrClO]

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2018-05-26 16h:27m:08s (UTC)

Cl

O

1. Query Br

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2018-05-26 16:28:38

Cl

O

Br

Rx-ID: 28008062 View in Reaxys 1/7 Yield 99 %

Conditions & References With copper(ll) bromide in ethyl acetate, T= 77 °C Morris, Patrick J.; Moaddel, Ruin; Zanos, Panos; Moore, Curtis E.; Gould, Todd; Zarate, Carlos A.; Thomas, Craig J.; Organic Letters; vol. 19; nb. 17; (2017); p. 4572 - 4575 View in Reaxys

98 %

Racemic norketamine hydrochloride was prepared starting from 2-chlorobenzonitrile.Treatment with cyclopentylmagnesium bromide in the presenceof copper (I) bromide, followed by hydrolysis, gave the cyclopentyl-(2-chlorophenyl) ketone (Weiberth and Hall, 1987). This was brominated with Nbromosuccinimide,followed by treatment with liquid ammonia to form animine intermediate. Thermal rearrangement of the imine afforded (R,S)-norketamine (Fig. 1). The structures of these chemicals were confirmed by1H and 13C NMR spectra with use of a Varian Gemini (300 MHz) instrument(Agilent Technologies, Mulgrave, VIC, Australia). NMR spectra were recordedin CDCl3 solution using tetramethylsilane (0 ppm) and CDCl3 (77.0 ppm) asinternal standards for 1H and 13C, respectively. Optical resolution of theenantiomers was accomplished through formation of the diastereomeric tartratesalts (Hong and Davisson, 1982). With N-Bromosuccinimide, toluene-4-sulfonic acid in dichloromethane, Time= 6h Li, Yibai; Coller, Janet K.; Hutchinson, Mark R.; Klein, Kathrin; Zanger, Ulrich M.; Stanley, Nathan J.; Abell, Andrew D.; Somogyi, Andrew A.; Drug Metabolism and Disposition; vol. 41; nb. 6; (2013); p. 1264 - 1272 View in Reaxys

91%

2.1 :(2-Chlorophenyl)-cyclopentyl-methanone (1 g, 4.80 mmol) was treated with copper(II) bromide (2.7 g, 12.09 mmol) in ethyl acetate (10 mL). The mixture was heated at about 80° C. for about 2.5 hours. The mixture was filtered, the filtrate was evaporated, and the crude residue was washed with hexane to give the title product (1.25 g, 91percent). 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J=7.5 Hz, 1H), 7.46-7.28 (m, 3H), 2.46-2.29 (m, 4H), 2.03-1.93 (m, 2H), 1.90-1.83 (m, 2H); LC-MS: m/z=288 (MH)+. With copper(ll) bromide in ethyl acetate, Time= 2.5h, T= 80 °C Patent; AUSPEX PHARMACEUTICALS, INC.; US2008/268071; (2008); (A1) English View in Reaxys

89 %

1 : 3.1.1 3-((1-(2-Chlorophenyl)-2-oxocyclohexyl)amino)propyl acetate hydrochloride (7) (2-Chlorophenyl)(cyclopentyl)methanone (22) (10 g, 48.0 mmol) was dissolved in EtOAc (100 mL) followed by addition of Cu(II)Br2 (27 g, 120.9 mmol). The solution was refluxed for 3 h and cooled to 25 °C. The solid was filtered and the filtrate was evaporated under reduced pressure. Some solid began to form while evaporating solvent under reduced pressure. DCM (100 mL) was added to the solid formed and solution cooled to 0 °C in an ice bath. After standing for 10 min. the solution was filtered and the filtrate concentrated under reduced pressure to obtain (1-bromocyclopentyl)(2-chlorophenyl)methanone14 (23) as a yellow oil (12.3 g, 89percent). 1H NMR (CDCl3) δ 7.70 (dd, J = 7.4, 1.8 Hz, 1H), 7.43 (dd, J = 7.9, 1.3 Hz, 1H), 7.37 (td, J = 7.4, 1.8 Hz, 1H), 7.30 (td, J = 7.4, 1.3 Hz, 1H), 2.45–2.27 (m, 4H), 2.09–2.01 (m, 2H), 1.89–1.82 (m, 2H); 13C NMR (CDCl3) δ 199.47, 138.87, 130.83, 130.55, 130.16, 128.33, 126.49, 74.29, 40.42, 23.26. MS m/z 289.3 (M2H+, 24 percent) 207.4 (M−Br−, 100percent). (0015) With copper(ll) bromide in ethyl acetate, Time= 3h, Reflux, Inert atmosphere Jose, Jiney; Gamage, Swarna A.; Harvey, Martyn G.; Voss, Logan J.; Sleigh, James W.; Denny, William A.; Bioorganic and Medicinal Chemistry; vol. 21; nb. 17; (2013); p. 5098 - 5106 View in Reaxys

89 %

1 : Example 1; rac-3-((l-(2-Chlorophenyl)-2-oxocyclohexyl)amino)propyl acetate hydrochloride (rac- C30Ac). (Scheme 2) (2-chlorophenyl)(cyclopentyl)methanone [US 20080268071] (21) (10 g, 48.0 mmol) was dissolved in ethyl acetate (100 mL) followed by addition of Cu(II)Br2(27 g, 120.9 mmol). The solution was refluxed for 2.5 h and cooled to 25 °C. The solid was filtered and the filtrate was evaporated under reduced pressure. Some solid began to form while evaporating solvent under reduced pressure. DCM (100 mL) was added to the solid formed and solution cooled to 0 °C in an ice bath. After standing for 10

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min. the solution was filtered and the filtrate concentrated under reduced pressure to obtain (l-bromocyclopentyl)(2- chlorophenyl)methanone (22) as a yellow oil (12.3 g, 89 percent).XH NMR (400 MHz, CDC13) δ 7.70 (dd, J = 7.4, 1.8 Hz, 1H), 7.43 (dd, J = 7.9, 1.3 Hz), 7.37 (td, J = 7.4, 1.8 Hz, 1H), 7.30 (td, J = 7.4, 1.3 Hz, 1H), 2.45-2.27 (m, 4H), 2.09-2.01 (m, 2H), 1.89-1.82 (m, 2H);13C NMR (101 MHz, CDC13) δ 199.47, 138.87, 130.83, 130.55, 130.16, 128.33, 126.49, 74.29, 40.42, 23.26. MS m/z 289.3 (M2H+, 24 percent) 207.4 (M - Br", 100 percent) With copper(ll) bromide in ethyl acetate, Time= 2.5h, Reflux Patent; AUCKLAND UNISERVICES LIMITED; SLEIGH, James Wallace; DENNY, William Alexander; JOSE, Jiney; GAMAGE, Swarnalatha Akuratiya; HARVEY, Martyn Gregory; VOSS, Logan James; WO2014/57414; (2014); (A1) English View in Reaxys

Cl 2H

2H

O Cl

O

2

H

2H 2H

2H

2H 2H

2H

Br 2H

2H

2H 2H

2H

Rx-ID: 28008063 View in Reaxys 2/7 Yield

Conditions & References 1.2 :The procedure of Step 2 is carried out as described in U.S. Pat. No. 3,254,124. d9-(2-Chlorophenyl)-cyclopentyl-methanone (about 21 g) is treated with bromine (about 10 g) in carbon tetrachloride (about 80 mL). The title product is isolated by standard extractive workup and used immediately in the next step without any further purification. With bromine in tetrachloromethane Patent; AUSPEX PHARMACEUTICALS, INC.; US2008/268071; (2008); (A1) English View in Reaxys 8 : Example 8 Nonstereoselective Synthesis of Deuterated Norketamine Example 8 Nonstereoselective Synthesis of Deuterated Norketamine Scheme 2 The synthesis was conducted following a general reaction sequence as described by Parcell, 1981 (Scheme 2). In the first step, o-chlorobenzonitrile is reacted with cyclopentyl magnesium bromide (obtained by bromination of the commercially available cyclopentane-dio to give cyclopentane bromide -dg 6 and then by Grignard reaction) to give deuterated 1-chlorophenyl-cyclopentyl ketone 7, followed by alpha- bromination of the ketone to give 8, and then reaction with ammonia to form an alpha- hydroxy imine l-hydroxycyclopentyl-(l-chlorophenyl)-ketone-N-methylimine 9. Thermal rearrangement with ring expansion of 9 leads to racemic norketamine 10 with overall yield of 70percent. NMR and MS-spectroscopy confirmed the identity of the products. With bromine Patent; AMORSA THERAPEUTICS, INC.; NIVOROZHKIN, Alex; LANDRAU, Nelson; (144 pag.); WO2016/73653; (2016); (A1) English View in Reaxys

Cl

N

O

2H

Br 2H

2H

2H 2H

2H

Rx-ID: 42637106 View in Reaxys 3/7 Yield

Conditions & References Reaction Steps: 2 2: bromine

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With bromine, 1: |Grignard Reaction Patent; AMORSA THERAPEUTICS, INC.; NIVOROZHKIN, Alex; LANDRAU, Nelson; (144 pag.); WO2016/73653; (2016); (A1) English View in Reaxys

Cl Cl

O N

Br

Rx-ID: 36532934 View in Reaxys 4/7 Yield

Conditions & References Reaction Steps: 2 1.1: magnesium; iodine / diethyl ether / 1 h 1.2: 16 h 2.1: N-Bromosuccinimide; toluene-4-sulfonic acid / dichloromethane / 6 h With N-Bromosuccinimide, iodine, toluene-4-sulfonic acid, magnesium in diethyl ether, dichloromethane Li, Yibai; Coller, Janet K.; Hutchinson, Mark R.; Klein, Kathrin; Zanger, Ulrich M.; Stanley, Nathan J.; Abell, Andrew D.; Somogyi, Andrew A.; Drug Metabolism and Disposition; vol. 41; nb. 6; (2013); p. 1264 - 1272 View in Reaxys

Cl 2H

2H

O Cl

O

2H

Br2Cu

2H

2H 2H

2H

Br 2H

2H

2H 2H

2H

Rx-ID: 28008057 View in Reaxys 5/7 Yield 83%

Conditions & References 3.2 :Step 2 d8-(1-Bromocylopentyl)-(2-chlorophenyl)-methanone: d8-(2-Chlorophenyl)-cyclopentyl-methanone (400 mg, 1.84 mmol) was treated with copper (II) bromide (1.22 g, 5.46 mmol) in ethyl acetate (40 mL). The mixture was heated at about 80° C. for about 2.5 hours. The mixture was filtered, the filtrate was evaporated, and the crude residue was washed with hexane to give the title product (450 mg, 83percent). 1H NMR (300 MHz, CDCl ) δ 7.68 (d, 1H, J=7.8 Hz), 7.44-7.26 (m, 3H); LC-MS: m/z=297 (MH)+. 3 in ethyl acetate, Time= 2.5h, T= 80 °C Patent; AUSPEX PHARMACEUTICALS, INC.; US2008/268071; (2008); (A1) English View in Reaxys

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Cl

Br

O

Br O

Br

Cl

Rx-ID: 25811570 View in Reaxys 6/7 Yield

Conditions & References 1 : Preparation of a-bromo-(o-chlorophenyl)cyclopentylketone 2 Example-1 Preparation of a-bromo-(o-chlorophenyl)cyclopentylketone 2 To a solution of (o-chlorophenyl)cyclopentyl ketone 1 (21.0 g, 0.1 mol) in 25 ml of anhydrous carbon tetrachloride under inert atmosphere was added, dropwise at 0° C., bromine (16.17 g, 0.1 mol) in 100 ml of carbon tetrachloride, over a period of 30 minutes. After all the bromine had been added, an orange suspension formed. The suspension was stirred for 30 minutes at room temperature and then washed using a 10percent (w/v) solution of sodium bisulfite (2*100 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to dryness to give the a-bromo-(o-chlorophenyl)cyclopentyl ketone 2 (24.0 g, 83percent) as a dark yellow oil, ready for use without further purification in Example 2. Patent; Randox Laboratories Limited; US2003/224447; (2003); (A1) English View in Reaxys

Cl

O

Br

Rx-ID: 7029224 View in Reaxys 7/7 Yield

Conditions & References Keton (V), N-Bromsuccinimid Patent; Stevens; BE634208; (1962); ; vol. 61; nb. 5569c; (1964) View in Reaxys o-Cl-Ph-Cyclopentylketon IX, Br2 Patent; Parke; Davis and Co.; US3254124; (1966); ; vol. 65; nb. 5414h; (1966) View in Reaxys

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2018-05-26 16:28:38

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