2-(tert-butylamino)-1-(3-chlorophenyl)propan-1-one [Bupropion, Wellbutrin]

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Reactions (44)

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Substances (17)

Citations (23)

Conditions

References

1

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Rx-ID: 4631051 Find similar reactions

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With bromine

1.) MeOH, 2.) CH3CN; Multistep reaction;

Musso, David L.; Mehta, Nariman B.; Soroko, Francis E.

Bioorganic and Medicinal Chemistry Letters, 1997 , vol. 7, # 1 p. 1 - 6 Title/Abstract

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With bromine

T=0 - 5°C; 5 h; Heating / reflux; Hide Experimental Procedure

EOS ECZACIBASI OZGUN KIMYASAL URUNLER SANAYI VE TICARET A.S.

Patent: WO2004/24674 A1, 2004 ; Location in patent: Page 3 ; Title/Abstract

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EXAMPLE; Preparation of Bupropion Hydrochloride

0.1 mole of 3'-chloropropiophenone was dissolved in 250 ml of tert-butylamine. 0.11 mole of bromine was added dropwise to this solution at [0-5°C.] The reaction mixture was stirred for 1 hour at [0-5°C] and then refluxed for 4 hours. Excess of tert- butylamine was removed under reduced pressure. Obtained oily residue was dissolved in 250 ml of ethyl acetate and washed with 250 ml of water. 200 ml of 1 N of HCl was added to ethyl acetate phase, stirred and separated. The water phase was washed with 250 ml of ethyl acetate and separated. The water phase was concentrated at reduced pressure and the residue was crystallised from isopropyl alcohol. Thus, bupropion hydrochloride was obtained in pure form

2

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Rx-ID: 7289390 Find similar reactions

entspr. α-Bromketon, t.-Butylamin;

Wellcome

Patent: DE2064934 , 1970 ; Chem.Abstr., 1972 , vol. 76, # 33965 Full Text Show Details

entspr. α-Chlorketon, t.-Butylamin;

Wellcome

Patent: DE2064934 , 1970 ; Chem.Abstr., 1972 , vol. 76, # 33965 Full Text Show Details

entspr. α-Brompropiophenon, H2N-tBu;

Patent: DE2059618 ; Chem.Abstr., 1972 , vol. 76, # 3551k Full Text Show Details

Hide Details entspr. α-Chlorpropiophenon, H2N-tBu;

Patent: DE2059618 ; Chem.Abstr., 1972 , vol. 76, # 3551k Full Text Show Details

3

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Rx-ID: 8698285 Find similar reactions

in dichloromethane

T=-40 - 0°C; Substitution;

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Fang, Qun K.; Han, Zhengxu; Grover, Paul; Kessler, Donald; Senanayake, Chris H.; Wald, Stephen A.

Tetrahedron Asymmetry, 2000 , vol. 11, # 18 p. 3659 - 3663 Title/Abstract

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4

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Rx-ID: 8698286 Find similar reactions

in dichloromethane

T=-40 - 0°C; Substitution;

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Fang, Qun K.; Han, Zhengxu; Grover, Paul; Kessler, Donald; Senanayake, Chris H.; Wald, Stephen A.

Tetrahedron Asymmetry, 2000 , vol. 11, # 18 p. 3659 - 3663 Title/Abstract

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5

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Rx-ID: 9262194 Find similar reactions

100%

Stage #1: in acetonitrile

T=20°C; 5 h; Heating / reflux; Stage #2: With potassium hydroxide in water; ethyl acetate; acetonitrile

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SOSEI R and D LTD.

Patent: WO2007/102019 A1, 2007 ; Location in patent: Page/Page column 4-5 ; Title/Abstract

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Crude 2-bromo-1-(3-chlorophenyl)propan-1-one (2) (152 g, 0.65 mol) was dissolved in 600 ml of acetonitrile (HPLC grade) in a 3-necked 2 L round bottomed flask fitted with a condenser and a dropping funnel. Tert-butylamine (172.5 ml, 1.63 mol) was added drop wise to the resulting mixture, at room temperature and under nitrogen. The reaction mixture was then heated to reflux for approximately 5 hours. During this time the reaction progress was monitored by TLC analysis (silica, hexane: ethyl acetate, 90:10). On consumption of the starting material, the reaction mixture was cooled to room temperature, filtered through celite and the celite washed with approximately 250 ml of ethyl acetate. The filtrate was washed with a 2M solution of KOH (350 ml). The layers were separated and the organic phase was dried over sodium sulphate anhydrous, filtered and concentrated to dryness to give a pale orange oil (147 g, quantitative yield), which did not need any further purification.1H-NMR (500 MHz, CDCI3) δH 7.98 (s, 1H), 7.87 (d, 1H), 7.56 (d, 1H), 7.43 (m, 1H), 4.29 (m, 1H), 2.04 (broad singlet, 1H), 1.35 (d, 3H), 1.05 (s, 9H).

in 1-methyl-pyrrolidin-2-one

T=50 - 60°C; 0.166667 h;

Hamad, Mohamed O.; Kiptoo, Paul K.; Stinchcomb, Audra L.; Crooks, Peter A.

Bioorganic and Medicinal Chemistry, 2006 , vol. 14, # 20 p. 7051 - 7061 Title/Abstract

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in acetonitrile

T=60°C; Kinetics;

Kalendra, Diane M.; Sickles, Barry R.

Journal of Organic Chemistry, 2003 , vol. 68, # 4 p. 1594 - 1596 Title/Abstract

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BIOVAIL LABORATORIES INTERNATIONAL S.R.L.

Patent: WO2007/2597 A2, 2007 ;

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Location in patent: Page/Page column 187; 188 ; Title/Abstract

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1:

3-Chloro-propiophenone starting material was brominated in methylene chloride by dropping bromine under controlled conditions. On reaction completion the mother liquor was worked up and then the second reaction was executed by transferring the bromoderivative solution onto the tert-butylamine. The second substitution reaction (the tert-butyl amine amino- group substitutes the bromine atom) forms the final bupropion molecule. After work up of the mother liquor, a bupropion toluene solution was obtained. The solvent was evaporated and bupropion was dissolved in isopropanol. From the isopropanol solution, the hydrobromide was precipitated with hydrogen bromide gas. On precipitation completion, the product was centrifuged, washed with isopropanol and dried under vacuum. On dryer discharge approval it was discharged in Kraft drums within double polyethylene bags.

With 1-methyl-pyrrolidin-2-one in toluene

T=20 - 65°C; 3 h; Hide Experimental Procedure

ALEMBIC LIMITED

Patent: WO2008/99418 A2, 2008 ; Location in patent: Page/Page column 5; 8 ; Title/Abstract

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1.b: (b) Preparation of bupropion; N-methyl pyrrolidone (NMP) (100ml) was added to organic layer obtained in step (a) and stirred at 20°C to 35°C. Tertiary butyl amine (108.3g) was added to the above reaction mixture and heated to 60°C to 65°C for 3 hours. The progress of the reaction was monitored on TLC. After completion of reaction, water (500ml) was added and stirred for 30min at 20°C to 35°C. The organic layer was separated and washed with water (500mlx2) and brine (500ml). This organic layer was taken for next step i.e. hydrochloride salt preparation.

2.5 - 5.5 h; Heating / reflux; Product distribution / selectivity; Hide Experimental Procedure

Wu, Chaogang; Xiang, Huayou; Yu, Xianghua; He, Chun; Li, Fengying; Shi, Xianghong; Lu, Chengyue; Chen, Guoliang; Ge, Yangxiang

Patent: US2009/12328 A1, 2009 ; Location in patent: Page/Page column 1; 3-4 ; Title/Abstract

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1; 2; 4; 5:

The reactions were carried out according to a molar ratio of m-chloroprophenone:bromine:t-butylamine:HCl in 1:0.92:5:1.To 1 mole of m-chloroprophenone heated to 75+/-5° C., bromine was added dropwise under stirring, and the reaction temperature was kept at 75+/-5° C. during the addition and kept for 3 hours after the addition, m-chloro-α-bromopropiophenone (compound of formula (II)) was obtained. t-Butylamine was added to m-chloro-α-bromopropiophenone obtained above and the reaction mixture was refluxed for 5.5 hours. After excessive tbutylamine was evaporated below 100° C., the concentrated solution was cooled down to room temperature and then extracted with 1000 ml of toluene and 200 ml of water. The organic phase was dried with anhydrous magnesium sulfate (20 g) to obtain a solution of bupropion free base (compound III). HCl gas was bubbled into the solution of bupropion free base at room temperature until the PH value the reaction mixture was less than or equal to 4. After filtration, crude product of bupropion hydrochloride was obtained. The crude product of bupropion hydrochloride was dissolved in 1500 ml of ethyl acetate heated to 60° C., and decolorized with activated carbon (3 g) for 30 minutes and filtered. Then filtrate was cooled down, crystal bupropion hydrochloride crystallized. Wet product of bupropion hydrochloride was obtained after filtration and was dried in vacuum (-0.04-0.09 MPa, 60+/-5° C.) for 5 hours to obtain pure product. Total yields was 75percent based on m-chloropropiophenone; HPLC's purify was over 99.9percent.Example 2The reaction were carried out according to a mole ratio of mchloropropiophenon:bromine:t-butylamine:HCl in 1:0.97:8:1.2.To 1 mole of m-chloropropiophenone heated to 60+/-5° C., bromine was added dropwise under stirring. The reaction temperature was kept at 60+/-5° C. during the addition of bromine, and kept for 5.5 hours after the addition. m-Chloro-α-bromopropiophenone (compound of formula (II)) was obtained.tButylamine was added to m-chloro-α-bromopropiophenone obtained above and the reaction mixture was refluxed for 3 hours. Excessive t-butylamine was removed by evaporation below 80° C. The concentrated solution was cooled down to room temperature and then extracted with 800 ml of ethyl acetate and 280 ml of water. The organic phase was dried with anhydrous magnesium sulfate (15 g) to obtain a solution of bupropion free base. A solution of HCl in ethyl acetate was added at room temperature to the organic phase. Crude product of bupropion hydrochloride was obtained after filtration. The crude product of bupropion hydrochloride was dissolved in 1200 ml of methanol and 120 ml of water at 80° C., decolorized with activated carbon (5 g) for 20 minutes and filtered. The filtrate was cooled and filtered to obtain wet product of bupropion hydrochloride. The wet product was dried in vacuum (-0.04-0.09 MPa, 80° C.) for 3 hours to obtain pure product. Total yield was 70percent based on m-chloropropiophenone, and the HPLC's purify was higher than or equal to 99.9percent.Example 4The reactions were carried out in accordance with a mole ratio of m-chloropropiophenone:bromine:t-butylamine:HCl in 1:1:10:1.5.A mixture of 1 mole of m-chloropropiophenone and dichoroethane was heated to 65+/-5° C. Bromine was added dropwise to this mixture under stirring. The reaction temperature was kept at 65+/-5° C. during the addition of bromine and kept for 5 hours after the addition. Dichloroethane was then evaporated under reduce pressure at 60° C. m-Chloro-α-bromopropiophenone (compound of formula (II)) was obtained.After t-Butylamine was added to the compound obtained above, the reaction mixture was refluxed for 2.5 hours. Excessive t-butylamine was evaporated at 140° C. The concentrated solution was cooled down to room temperature and then extracted with a mixture of 1200 ml of ethyl formate and 260 ml of water. The organic phase was dried with 25 g anhydrous sodium sulfate to obtain a solution of bupropion free base. Then a solution of HCl in ethyl formate was added at room temperature. Crude product of bupropion hydrochloride was obtained after filtration. The crude product was added to a mixture of dissolved in 1400 ml of isopropanol and 700 ml of water heated to 90 ° C., decolorized with activated carbon (8 g) for 40 minutes and filtered. The filtrate was cooled down and filtered to obtain wet product of bupropion hydrochloride. The wet product was dried in vacuum (-0.04-0.09 MPa, 90° C.) for 2 hours to obtain pure product. Total yield was 80percent based by m-chloropropiophenoone; and the HPLC's purify was 99.9percent.Example 5The reactions were carried out in accordance with a mole ratio of mchloropropiophenone:bromine:t-butylamine:HCl in 1:1.08:4:1.3.To 1 mole of m-chloropropiophenone heated to 85+/-5° C., bromine was added dropwise under stirring. The reaction temperature was kept at 85+/-5° C. during and after the addition of bromine, and the reaction was carried on for 2 hours. Then m-chloro-α-bromopropiophenone (compound of formula (II)) was obtained.t-Butylamine was added to the compound above and the reaction mixture was refluxed for 5 hours. Excessive t-butylamine was evaproated at 90° C. The concentrated solution was cooled down to room temperature and then extracted with a mixture of 1400 ml of dichloromethane and 220 ml of water. The organic phase was dried with 20 g anhydrous magnesium sulfate to obtain a solution of bupropion free base. The solution of HCl in dichloromethane was added at room temperature. Crude product of bupropion hydrochloride was obtained after filtration. The crude product was dissolved in a mixture of 1800 ml of ethanol and 100 ml of water that was heated to 75° C., then decolorized with activated carbon (7 g) for 30 minutes and filtered. The filtrate was cooled down and filtered to obtain wet product of bupropion hydrochloride. The wet product was dried in vacuum (-0.04-0.09 MPa, 50° C.) for 7 hours to obtain pure product. Total yield was 78percent based on m-chloropropiophenone; and the HPLC's purify was 99.9percent. in water; acetone

2.5 h; Heating / reflux; Product distribution / selectivity; Hide Experimental Procedure

Wu, Chaogang; Xiang, Huayou; Yu, Xianghua; He, Chun; Li, Fengying; Shi, Xianghong; Lu, Chengyue; Chen, Guoliang; Ge, Yangxiang

Patent: US2009/12328 A1, 2009 ; Location in patent: Page/Page column 1; 3 ; Title/Abstract

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3:

The reactions were carried out according to a mole ratio of m-chloropropiophenone:bromine:t-butylamine:HCl in: 1:1.05:6:0.8.To 1 mole of m-chloropropiophenone was heated to 70+/-5° C., bromine was added dropwise under stirring. The reaction temperature was kept at 70+/-5° C. during the addition of bromine and kept for 5.5 hours after the addition. m-chloro-αbromopropiophenone (compound of formula (II)) was obtained.t-Butylamine was added to a solution of m-chloro-α-bromopropiophenone obtained above in acetone and water and the

reaction mixture was refluxed for 2.5 hours. Acetone, water and excessive t-butylamine was evaproated at the temperature of 120° C. The concentrated solution was cooled down to room temperature and then extracted with 1500 ml of chloroform and 250 ml of water. The organic phase was dried with anhydrous sodium sulfate (30 g) and concentrated to dryness under reduced pressure. A solution of HCl in ethanol was added to the concentrated solution at room temperature and a crude product of bupropion hydrochloride was obtained after filtration. The crude product of bupropion hydrochloride was added to 2000 ml ethanol and heated to 70° C., decolorized by activated carbon (2 g) for 30 minutes and filtered. The filtrate was cooled and filtered to obtain wet product of bupropion hydrochloride. The wet product was dried in vacuum (-0.04-0.09 MPa, 70° C.) for 4 hours to obtain pure product. Total yield was 72percent based on m-chloropropiophenone; and the HPLC's purify was 99.9percent. in dichloromethane

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BIOVAIL LABORATORIES INTERNATIONAL SRL; TURCHETTA, Stefano; ZENONI, Maurizio

Patent: WO2010/15692 A2, 2010 ; Location in patent: Page/Page column 198-199 ; Title/Abstract

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1:

EXAMPLE 1 : PREPARATION OF BUPROPION HBR SALTBupropion HBr salt was prepared according to the method shown in Scheme 1 :Scheme 1Bromination Reaction3 '-chloropropiophenone 2-bromo-3 '-chloro-propiophenone MW = 168.62 MW = 247.52Amination Reaction2-t-butylamino-3'-chloro-propiophenoneMW = 239.75Work Up / Precipitation / Drying3) dryingBupropion.HBr IntermediateFinishing StepBupropion.HBr Sieving ^ Bupropion.HBr Intermediate Packaging Final Release(a) Bromination and condensation reactions 3-Chloropropiophenone starting material was brominated in methylene chloride by dropping bromine under controlled conditions. On reaction completion the mother liquor was worked up and then the second reaction was executed by transferring the bromoderivative solution onto the tert-butylamine. The second substitution reaction (the tert-butylamine amino-group substitutes the bromine atom) forms the final bupropion molecule. After work up of the mother liquor, a bupropion toluene solution was obtained. The solvent was evaporated and bupropion was dissolved in isopropanol. From the isopropanol solution, the hydrobromide was precipitated with hydrogen bromide gas. On precipitation completion, the product was centrifuged, washed with isopropanol and dried under vacuum. On dryer discharge approval it was discharged in Kraft drums within double polyethylene bags.In the last finishing step, the above intermediate was sieved to obtain the Final Release which was packed in Kraft drums within double polyethylene bags.Elemental analysis of the bupropion HBr was carried out using a Fisons Elemental Analyser EA 1108. The results were consistent with the molecular formula of bupropion HBr.

6

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With sodium carbonate in water

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Rx-ID: 10614988 Find similar reactions

University of Kentucky Research Foundation

Patent: US2009/17102 A1, 2009 ; Location in patent: Page/Page column 7 ; Title/Abstract

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1:

1.0 g of bupropion hydrochloride salt was dissolved in the minimum amount of water in 250 ml flask. The contents of the flask were transferred to a separatory funnel, to which 20 ml of 10percent aqueous sodium carbonate was added, and the mixture was extracted with methylene chloride (3.x.50 ml). The combined methylene chloride extracts were washed with water (3.x.50 ml), then brine solution (50 ml), dried over anhydrous K2CO3, filtered and the filtrate stripped down under reduced pressure on a rotary evaporator to give the desired product as a yellow oil (7.9 g, 90percent yield). 1H NMR (CDCl3, 400 MHz): δ 7.90 (s, 1H), 7.81 (d, j=7.8 Hz, 1H), 7.48 (d, j=7.8 Hz, 1H), 7.37 (dd, j1=j2=7.8 Hz, 1H), 4.24 (qt, J=7.2 Hz, 1H), 1.19 (d, j=7.2 Hz, 3H), 0.97 (s, 9H) ppm. ppm; MS m/z 240 (M+). LC-MS m/z 240 (M+) single peak at Rt=8.40 min.

With sodium hydroxide in water

pH=12; Product distribution / selectivity; Hide Experimental Procedure

COLLEGIUM PHARMACEUTICAL, INC.

Patent: WO2007/117581 A2, 2007 ; Location in patent: Page/Page column 18 ; Title/Abstract

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1:

Bupropion base can be prepared as described in U.S. Patent Nos. 6,280,763, 6,312,716 and 6,582,737. In one embodiment, 1.2 g bupropion HCl is dissolved in 20 ml of distilled water to which 0.1 N NaOH is added until the pH is about 12. The mixture is extracted with 50 ml of diethyl ether followed by centrifugation. The ether phase containing the bupropion base is separated and the remaining aqueous phase is extracted three times with 80 ml diethyl ether. The ether phases are combined and dried (removal of residual water) over 15 g anhydrous K2CO3, filtered, and the ether is removed via evaporation. The bupropion base is stored under nitrogen gas in a tight bottle in the dark.

With ammonia in water

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COLLEGIUM PHARMACEUTICAL, INC.

Patent: WO2007/117581 A2, 2007 ; Location in patent: Page/Page column 18 ; Title/Abstract

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1:

The modified procedure of bupropion base preparation is conducted under an inert atmosphere. In this procedure, concentrated ammonium hydroxide solution is used to convert bupropion HCl into bupropion base, the base is extracted three times with diethyl ether and the combined ether phases are dried over sodium sulfate. The solvent is removed under slightly reduced pressure at a water bath temperature of 300C. The bupropion base is stored under nitrogen gas in a tight bottle in the dark.

7

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Rx-ID: 12098344 Find similar reactions

Multi-step reaction with 2 steps 1: bromine / CH2Cl2 / cooling 2: 1-methyl-pyrrolidin-2-one / 0.17 h / 50 - 60 °C View Scheme

Hamad, Mohamed O.; Kiptoo, Paul K.; Stinchcomb, Audra L.; Crooks, Peter A.

Bioorganic and Medicinal Chemistry, 2006 , vol. 14, # 20 p. 7051 - 7061 Title/Abstract

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Multi-step reaction with 2 steps 1: 48percent HBr; Br2 / CH2Cl2; H2O / 35 °C 2: acetonitrile / 60 °C View Scheme

Kalendra, Diane M.; Sickles, Barry R.

Journal of Organic Chemistry, 2003 , vol. 68, # 4 p. 1594 - 1596 Title/Abstract

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8

Synthesize Find similar Multi-step reaction with 4 steps 1.1: LDA / tetrahydrofuran / -78 °C 1.2: tetrahydrofuran / -78 °C 2.1: 82 percent / AD-mix-β; H2O / 2methyl-propan-2-ol 3.1: lutidine / CH2Cl2 / -40 °C 4.1: CH2Cl2 / -40 - 0 °C View Scheme

9

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Rx-ID: 15545623 Find similar reactions

Fang, Qun K.; Han, Zhengxu; Grover, Paul; Kessler, Donald; Senanayake, Chris H.; Wald, Stephen A.

Tetrahedron Asymmetry, 2000 , vol. 11, # 18 p. 3659 - 3663 Title/Abstract

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Synthesize Find similar Multi-step reaction with 4 steps 1.1: LDA / tetrahydrofuran / -78 °C 1.2: tetrahydrofuran / -78 °C 2.1: 82 percent / AD-mix-α; H2O / 2methyl-propan-2-ol 3.1: lutidine / CH2Cl2 / -40 °C 4.1: CH2Cl2 / -40 - 0 °C View Scheme

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Rx-ID: 15545624 Find similar reactions

Fang, Qun K.; Han, Zhengxu; Grover, Paul; Kessler, Donald; Senanayake, Chris H.; Wald, Stephen A.

Tetrahedron Asymmetry, 2000 , vol. 11, # 18 p. 3659 - 3663 Title/Abstract

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10

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Rx-ID: 15562355 Find similar reactions

Fang, Qun K.; Han, Zhengxu; Grover, Paul; Kessler, Donald; Senanayake, Chris H.; Wald, Stephen A.

Tetrahedron Asymmetry, 2000 , vol. 11, # 18 p. 3659 - 3663 Title/Abstract

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11

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Rx-ID: 15562357 Find similar reactions

Fang, Qun K.; Han, Zhengxu; Grover, Paul; Kessler, Donald; Senanayake, Chris H.; Wald, Stephen A.

Tetrahedron Asymmetry, 2000 , vol. 11, # 18 p. 3659 - 3663 Title/Abstract

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12

Synthesize Find similar Multi-step reaction with 3 steps 1: 82 percent / AD-mix-β; H2O / 2methyl-propan-2-ol 2: lutidine / CH2Cl2 / -40 °C 3: CH2Cl2 / -40 - 0 °C View Scheme

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Rx-ID: 15565350 Find similar reactions

Fang, Qun K.; Han, Zhengxu; Grover, Paul; Kessler, Donald; Senanayake, Chris H.; Wald, Stephen A.

Tetrahedron Asymmetry, 2000 , vol. 11, # 18 p. 3659 - 3663 Title/Abstract

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13

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Rx-ID: 15565351 Find similar reactions

Fang, Qun K.; Han, Zhengxu; Grover, Paul; Kessler, Donald; Senanayake, Chris H.; Wald, Stephen A.

Tetrahedron Asymmetry, 2000 , vol. 11, # 18 p. 3659 - 3663 Title/Abstract

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14

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Rx-ID: 17417253 Find similar reactions

Musso, David L.; Mehta, Nariman B.; Soroko, Francis E.

Bioorganic and Medicinal Chemistry Letters, 1997 , vol. 7, # 1 p. 1 - 6 Title/Abstract

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15

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Rx-ID: 17455518 Find similar reactions

Musso, David L.; Mehta, Nariman B.; Soroko, Francis E.

Bioorganic and Medicinal Chemistry Letters, 1997 , vol. 7, # 1 p. 1 - 6 Title/Abstract

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16

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Rx-ID: 26050083 Find similar reactions

17

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75%

Stage #1: (+/-)-1-(3-chlorophenyl)-2hydroxypropan-1-one With 2,6dimethylpyridine; trifluoromethylsulfonic anhydride in dichloromethane

T=-40°C; 0.5 h; Stage #2: tert-butylamine in dichloromethane

12 h; Further stages.;

Amarante, Giovanni W.; Rezende, Patricia; Cavallaro, Mayra; Coelho, Fernando

Tetrahedron Letters, 2008 , vol. 49, # 23 p. 3744 - 3748 Title/Abstract

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75%

Stage #1: (+/-)-1-(3-chlorophenyl)-2hydroxypropan-1-one With 2,6dimethylpyridine; trifluoromethylsulfonic anhydride in dichloromethane

T=-78 - -40°C; 0.5 h; Stage #2: tert-butylamine in dichloromethane

T=-40 - 0°C; 14 h;

Amarante, Giovanni W.; Cavallaro, Mayra; Coelho, Fernando

Journal of the Brazilian Chemical Society, 2011 , vol. 22, # 8 p. 1568 - 1584 Title/Abstract

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Synthesize Find similar Multi-step reaction with 9 steps 1.1: water; lithium hydroxide hydrate / acetonitrile / 4 h / 50 - 60 °C 2.1: triethylamine / acetone / 0.08 h / 0 °C 3.1: sodium azide / acetone / 2 h / 20 °C 4.1: toluene / 2 h / Reflux; Inert atmosphere 5.1: water / 2 h / Reflux 6.1: sodium tetrahydroborate / methanol / 0.17 h / 0 - 20 °C / Inert atmosphere 7.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 2 h / 20 °C 8.1: 1-hydroxy-3H-benz[d] [1,2]iodoxole-1,3-dione / dimethyl sulfoxide / 30 h / 20 °C 9.1: 2,6-dimethylpyridine; trifluoromethylsulfonic anhydride / dichloromethane / 0.5 h / -78 - -40 °C 9.2: 14 h / -40 - 0 °C View Scheme

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Rx-ID: 31781283 Find similar reactions

Amarante, Giovanni W.; Cavallaro, Mayra; Coelho, Fernando

Journal of the Brazilian Chemical Society, 2011 , vol. 22, # 8 p. 1568 - 1584 Title/Abstract

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18

Synthesize Find similar Multi-step reaction with 8 steps 1.1: triethylamine / acetone / 0.08 h / 0 °C 2.1: sodium azide / acetone / 2 h / 20 °C 3.1: toluene / 2 h / Reflux; Inert atmosphere 4.1: water / 2 h / Reflux 5.1: sodium tetrahydroborate / methanol / 0.17 h / 0 - 20 °C / Inert atmosphere 6.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 2 h / 20 °C 7.1: 1-hydroxy-3H-benz[d] [1,2]iodoxole-1,3-dione / dimethyl sulfoxide / 30 h / 20 °C 8.1: 2,6-dimethylpyridine; trifluoromethylsulfonic anhydride / dichloromethane / 0.5 h / -78 - -40 °C 8.2: 14 h / -40 - 0 °C

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Rx-ID: 31781314 Find similar reactions

Amarante, Giovanni W.; Cavallaro, Mayra; Coelho, Fernando

Journal of the Brazilian Chemical Society, 2011 , vol. 22, # 8 p. 1568 - 1584 Title/Abstract

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View Scheme

19

Synthesize Find similar Multi-step reaction with 4 steps 1.1: sodium tetrahydroborate / methanol / 0.17 h / 0 - 20 °C / Inert atmosphere 2.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 2 h / 20 °C 3.1: 1-hydroxy-3H-benz[d] [1,2]iodoxole-1,3-dione / dimethyl sulfoxide / 30 h / 20 °C 4.1: 2,6-dimethylpyridine; trifluoromethylsulfonic anhydride / dichloromethane / 0.5 h / -78 - -40 °C 4.2: 14 h / -40 - 0 °C View Scheme

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Rx-ID: 31781323 Find similar reactions

Amarante, Giovanni W.; Cavallaro, Mayra; Coelho, Fernando

Journal of the Brazilian Chemical Society, 2011 , vol. 22, # 8 p. 1568 - 1584 Title/Abstract

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20

Synthesize Find similar Multi-step reaction with 7 steps 1.1: sodium azide / acetone / 2 h / 20 °C 2.1: toluene / 2 h / Reflux; Inert atmosphere 3.1: water / 2 h / Reflux 4.1: sodium tetrahydroborate / methanol / 0.17 h / 0 - 20 °C / Inert atmosphere 5.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 2 h / 20 °C 6.1: 1-hydroxy-3H-benz[d] [1,2]iodoxole-1,3-dione / dimethyl sulfoxide / 30 h / 20 °C 7.1: 2,6-dimethylpyridine; trifluoromethylsulfonic anhydride / dichloromethane / 0.5 h / -78 - -40 °C 7.2: 14 h / -40 - 0 °C View Scheme

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Rx-ID: 31781348 Find similar reactions

Amarante, Giovanni W.; Cavallaro, Mayra; Coelho, Fernando

Journal of the Brazilian Chemical Society, 2011 , vol. 22, # 8 p. 1568 - 1584 Title/Abstract

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21

Synthesize Find similar Multi-step reaction with 6 steps 1.1: toluene / 2 h / Reflux; Inert atmosphere 2.1: water / 2 h / Reflux 3.1: sodium tetrahydroborate / methanol / 0.17 h / 0 - 20 °C / Inert atmosphere 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 2 h / 20 °C 5.1: 1-hydroxy-3H-benz[d] [1,2]iodoxole-1,3-dione / dimethyl sulfoxide / 30 h / 20 °C 6.1: 2,6-dimethylpyridine; trifluoromethylsulfonic anhydride / dichloromethane / 0.5 h / -78 - -40 °C 6.2: 14 h / -40 - 0 °C View Scheme

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Rx-ID: 31781369 Find similar reactions

Amarante, Giovanni W.; Cavallaro, Mayra; Coelho, Fernando

Journal of the Brazilian Chemical Society, 2011 , vol. 22, # 8 p. 1568 - 1584 Title/Abstract

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22

Synthesize Find similar Multi-step reaction with 5 steps 1.1: water / 2 h / Reflux 2.1: sodium tetrahydroborate / methanol / 0.17 h / 0 - 20 °C / Inert atmosphere 3.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 2 h / 20 °C 4.1: 1-hydroxy-3H-benz[d] [1,2]iodoxole-1,3-dione / dimethyl sulfoxide / 30 h / 20 °C 5.1: 2,6-dimethylpyridine; trifluoromethylsulfonic anhydride / dichloromethane / 0.5 h / -78 - -40 °C 5.2: 14 h / -40 - 0 °C View Scheme

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Rx-ID: 31781385 Find similar reactions

Amarante, Giovanni W.; Cavallaro, Mayra; Coelho, Fernando

Journal of the Brazilian Chemical Society, 2011 , vol. 22, # 8 p. 1568 - 1584 Title/Abstract

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23

Synthesize Find similar Multi-step reaction with 3 steps 1.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 2 h / 20 °C 2.1: 1-hydroxy-3H-benz[d] [1,2]iodoxole-1,3-dione / dimethyl sulfoxide / 30 h / 20 °C 3.1: 2,6-dimethylpyridine; trifluoromethylsulfonic anhydride / dichloromethane / 0.5 h / -78 - -40 °C 3.2: 14 h / -40 - 0 °C View Scheme

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Rx-ID: 31781389 Find similar reactions

Amarante, Giovanni W.; Cavallaro, Mayra; Coelho, Fernando

Journal of the Brazilian Chemical Society, 2011 , vol. 22, # 8 p. 1568 - 1584 Title/Abstract

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24

Synthesize Find similar Multi-step reaction with 11 steps 1.1: 1,4-diaza-bicyclo[2.2.2]octane / 30 °C / Sonication 2.1: 1H-imidazole; dimethyl sulfoxide / 20 °C / Inert atmosphere 3.1: water; lithium hydroxide hydrate / acetonitrile / 4 h / 50 - 60 °C 4.1: triethylamine / acetone / 0.08 h / 0 °C 5.1: sodium azide / acetone / 2 h / 20 °C 6.1: toluene / 2 h / Reflux; Inert atmosphere 7.1: water / 2 h / Reflux 8.1: sodium tetrahydroborate / methanol / 0.17 h / 0 - 20 °C / Inert atmosphere 9.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 2 h / 20 °C 10.1: 1-hydroxy-3H-benz[d] [1,2]iodoxole-1,3-dione / dimethyl sulfoxide / 30 h / 20 °C 11.1: 2,6-dimethylpyridine; trifluoromethylsulfonic anhydride / dichloromethane / 0.5 h / -78 - -40 °C 11.2: 14 h / -40 - 0 °C View Scheme

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Rx-ID: 31781605 Find similar reactions

Amarante, Giovanni W.; Cavallaro, Mayra; Coelho, Fernando

Journal of the Brazilian Chemical Society, 2011 , vol. 22, # 8 p. 1568 - 1584 Title/Abstract

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25

Synthesize Find similar Multi-step reaction with 2 steps 1.1: 1-hydroxy-3H-benz[d] [1,2]iodoxole-1,3-dione / dimethyl sulfoxide / 30 h / 20 °C 2.1: 2,6-dimethylpyridine; trifluoromethylsulfonic anhydride / dichloromethane / 0.5 h / -78 - -40 °C 2.2: 14 h / -40 - 0 °C View Scheme

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Rx-ID: 31781673 Find similar reactions

Amarante, Giovanni W.; Cavallaro, Mayra; Coelho, Fernando

Journal of the Brazilian Chemical Society, 2011 , vol. 22, # 8 p. 1568 - 1584 Title/Abstract

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26

Synthesize Find similar Multi-step reaction with 10 steps 1.1: 1H-imidazole; dimethyl sulfoxide / 20 °C / Inert atmosphere 2.1: water; lithium hydroxide hydrate / acetonitrile / 4 h / 50 - 60 °C 3.1: triethylamine / acetone / 0.08 h / 0 °C 4.1: sodium azide / acetone / 2 h / 20 °C 5.1: toluene / 2 h / Reflux; Inert atmosphere 6.1: water / 2 h / Reflux 7.1: sodium tetrahydroborate / methanol / 0.17 h / 0 - 20 °C / Inert atmosphere 8.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 2 h / 20 °C 9.1: 1-hydroxy-3H-benz[d] [1,2]iodoxole-1,3-dione / dimethyl sulfoxide / 30 h / 20 °C 10.1: 2,6-dimethylpyridine; trifluoromethylsulfonic anhydride / dichloromethane / 0.5 h / -78 - -40 °C 10.2: 14 h / -40 - 0 °C View Scheme

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Rx-ID: 31781683 Find similar reactions

Amarante, Giovanni W.; Cavallaro, Mayra; Coelho, Fernando

Journal of the Brazilian Chemical Society, 2011 , vol. 22, # 8 p. 1568 - 1584 Title/Abstract

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27

Synthesize Find similar 97%

With hydrogen chloride in aq. phosphate buffer; water-d2

T=20°C; pH=7; 264 h; Hide Experimental Procedure

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Rx-ID: 40361600 Find similar reactions

DEUTERX, LLC; DEWITT, Sheila; JACQUES, Vincent; VAN DER PLOEG, Leonardus, H.T.

Patent: WO2015/95713 A1, 2015 ; Location in patent: Paragraph 00140-00141 ; Title/Abstract

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1:Synthesis of rac-l-(m-chlorophenyl)-2-(tert-butylamino)-(2-2H)-propan-l-one

Preparation of 25mM deuterated pH = 7 phosphate buffer: Deuterated phosphate buffer (100 mM, pH = 7) was prepared by dissolving 259.5 mg of potassium phosphate (K3PO4) in deuterated water (D20, 12.0 mL) and adding 264 μ, 20percent deuterium chloride (DC1) in D20. The resulting 100 mM solution was diluted with 3 times the volume of D20 to give a 25 mM pH = 7 buffer. Synthesis of rac-l-(m-chlorophenyl)-2-(tert-butylamino)-(2-2H)-propan-l-one Bupropion, rac- 1 -(m-chlorophenyl)-2-(tert-butylamino)-propan- 1 -one (500 mg, 2.09 mmol) was dissolved in 20 mL of 25 mM deuterated pH = 7 phosphate buffer. The solution was shaken at room temperature while monitoring H/D exchange by LCMS. After 1 1 days, LC-MS analysis showed almost complete deuterium incorporation with percentD = 99.7percent at the chiral center. The reaction mixture was washed with a saturated solution of sodium bicarbonate (satd aHC03, 80 mL) and ethyl acetate (EtOAc, 400 mL) for just 1 min in order to minimize exposure of the deuterated material to the aqueous solution. The organic layer was quickly separated and dried over sodium sulfate ( a2S04). The reaction was repeated starting with 437 mg of bupropion (1.82 mmol) and the organic layers were combined. The solvent (750 mL total) was evaporated in vacuo to give 0.91 g (3.78 mmol) of rac- l-(m -chloropheny 1)- 2-(tert-butylamino)-(2-2H)-propan-l-one as a colorless oil. Overall yield: 0.91 g (3.78 mmol, 97percent); percentD = 99.2percent at the chiral center.

28

Synthesize Find similar With hydrogenchloride in water; ethyl acetate

Hide Experimental Procedure

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Rx-ID: 23059837 Find similar reactions

EOS ECZACIBASI OZGUN KIMYASAL URUNLER SANAYI VE TICARET A.S.

Patent: WO2004/24674 A1, 2004 ; Location in patent: Page 3 ; Title/Abstract

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EXAMPLE; Preparation of Bupropion Hydrochloride

0.1 mole of 3'-chloropropiophenone was dissolved in 250 ml of tert-butylamine. 0.11 mole of bromine was added dropwise to this solution at [0-5°C.] The reaction mixture was stirred for 1 hour at [0-5°C] and then refluxed for 4 hours. Excess of tert- butylamine was removed under reduced pressure. Obtained oily residue was dissolved in 250 ml of ethyl acetate and washed with 250 ml of water. 200 ml of 1 N of HCl was added to ethyl acetate phase, stirred and separated. The water phase was washed with 250 ml of ethyl acetate and separated. The water phase was concentrated at reduced pressure and the residue was crystallised from isopropyl alcohol. Thus, bupropion hydrochloride was obtained in pure form With hydrogenchloride in isopropyl alcohol

T=0 - 10°C; pH=2; 1 h; Hide Experimental Procedure

ALEMBIC LIMITED

Patent: WO2008/99418 A2, 2008 ; Location in patent: Page/Page column 5; 8 ; Title/Abstract

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1.c: (c) Preparation of bupropion hydrochloride; The organic layer obtained in step (b) was cooled to 0°C to 10°C. Isopropanol saturated with hydrochloric acid (IPA-HCl) was added slowly until pH 2 of the reaction is obtained. The reaction mixture was stirred for 1 hour at the same temperature. The solid was filtered .and washed with toluene (100ml). The solid was suck dried and

dried in oven at 70°C to 75°C to give bupropion hydrochloride (12Og). .bul.HPLC purity: 99.7percent With hydrogenchloride in toluene

T=20°C; pH=4; Product distribution / selectivity; Hide Experimental Procedure

Wu, Chaogang; Xiang, Huayou; Yu, Xianghua; He, Chun; Li, Fengying; Shi, Xianghong; Lu, Chengyue; Chen, Guoliang; Ge, Yangxiang

Patent: US2009/12328 A1, 2009 ; Location in patent: Page/Page column 1-3 ; Title/Abstract

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1:

The reactions were carried out according to a molar ratio of m-chloroprophenone:bromine:t-butylamine:HCl in 1:0.92:5:1.To 1 mole of m-chloroprophenone heated to 75+/-5° C., bromine was added dropwise under stirring, and the reaction temperature was kept at 75+/-5° C. during the addition and kept for 3 hours after the addition, m-chloro-α-bromopropiophenone (compound of formula (II)) was obtained. t-Butylamine was added to m-chloro-α-bromopropiophenone obtained above and the reaction mixture was refluxed for 5.5 hours. After excessive tbutylamine was evaporated below 100° C., the concentrated solution was cooled down to room temperature and then extracted with 1000 ml of toluene and 200 ml of water. The organic phase was dried with anhydrous magnesium sulfate (20 g) to obtain a solution of bupropion free base (compound III). HCl gas was bubbled into the solution of bupropion free base at room temperature until the PH value the reaction mixture was less than or equal to 4. After filtration, crude product of bupropion hydrochloride was obtained. The crude product of bupropion hydrochloride was dissolved in 1500 ml of ethyl acetate heated to 60° C., and decolorized with activated carbon (3 g) for 30 minutes and filtered. Then filtrate was cooled down, crystal bupropion hydrochloride crystallized. Wet product of bupropion hydrochloride was obtained after filtration and was dried in vacuum (-0.04-0.09 MPa, 60+/-5° C.) for 5 hours to obtain pure product. Total yields was 75percent based on m-chloropropiophenone; HPLC's purify was over 99.9percent.

Hide Details With hydrogenchloride in dichloromethane

T=20°C; Product distribution / selectivity; Hide Experimental Procedure

Wu, Chaogang; Xiang, Huayou; Yu, Xianghua; He, Chun; Li, Fengying; Shi, Xianghong; Lu, Chengyue; Chen, Guoliang; Ge, Yangxiang

Patent: US2009/12328 A1, 2009 ; Location in patent: Page/Page column 1-2; 4 ; Title/Abstract

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5:

The reactions were carried out in accordance with a mole ratio of m-chloropropiophenone:bromine:t-butylamine:HCl in 1:1.08:4:1.3.To 1 mole of m-chloropropiophenone heated to 85+/-5° C., bromine was added dropwise under stirring. The reaction temperature was kept at 85+/-5° C. during and after the addition of bromine, and the reaction was carried on for 2 hours. Then m-chloro-α-bromopropiophenone (compound of formula (II)) was obtained.t-Butylamine was added to the compound above and the reaction mixture was refluxed for 5 hours. Excessive tbutylamine was evaproated at 90° C. The concentrated solution was cooled down to room temperature and then extracted with a mixture of 1400 ml of dichloromethane and 220 ml of water.

The organic phase was dried with 20 g anhydrous magnesium sulfate to obtain a solution of bupropion free base. The solution of HCl in dichloromethane was added at room temperature.

Crude product of bupropion hydrochloride was obtained after filtration. The crude product was dissolved in a mixture of 1800 ml of ethanol and 100 ml of water that was heated to 75° C., then decolorized with activated carbon (7 g) for 30 minutes and filtered. The filtrate was cooled down and filtered to obtain wet product of bupropion hydrochloride. The wet product was dried in vacuum (-0.04-0.09 MPa, 50° C.) for 7 hours to obtain pure product. Total yield was 78percent based on m-chloropropiophenone; and the HPLC's purify was 99.9percent.

With hydrogenchloride in ethyl acetate

T=20°C; Product distribution / selectivity; Hide Experimental Procedure

Wu, Chaogang; Xiang, Huayou; Yu, Xianghua; He, Chun; Li, Fengying; Shi, Xianghong; Lu, Chengyue; Chen, Guoliang; Ge, Yangxiang

Patent: US2009/12328 A1, 2009 ; Location in patent: Page/Page column 1-3 ; Title/Abstract

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2:

The reaction were carried out according to a mole ratio of m-chloropropiophenon:bromine:t-butylamine:HCl in 1:0.97:8:1.2.To 1 mole of m-chloropropiophenone heated to 60+/-5° C., bromine was added dropwise under stirring. The reaction temperature was kept at 60+/-5° C. during the addition of bromine, and kept for 5.5 hours after the addition. m-Chloro-αbromopropiophenone (compound of formula (II)) was obtained.t-Butylamine was added to m-chloro-α-bromopropiophenone obtained above and the reaction mixture was refluxed for 3 hours. Excessive t-butylamine was removed by evaporation below 80° C. The concentrated solution was cooled down to room temperature and then extracted with 800 ml of ethyl acetate and 280 ml of water. The organic phase was dried with anhydrous magnesium sulfate (15 g) to obtain a solution of bupropion free base. A solution of HCl in ethyl acetate was added at room temperature to the organic phase. Crude product of bupropion hydrochloride was obtained after filtration. The crude product of bupropion hydrochloride was dissolved in 1200 ml of methanol and 120 ml of water at 80° C., decolorized with activated carbon (5 g) for 20 minutes and filtered. The filtrate was cooled and filtered to obtain wet product of bupropion hydrochloride. The wet product was dried in vacuum (-0.04-0.09 MPa, 80° C.) for 3 hours to obtain pure product. Total yield was 70percent based on m-chloropropiophenone, and the HPLC's purify was higher than or equal to 99.9percent.

With hydrogenchloride in ethanol

T=20°C; Product distribution / selectivity; Hide Experimental Procedure

Wu, Chaogang; Xiang, Huayou; Yu, Xianghua; He, Chun; Li, Fengying; Shi, Xianghong; Lu, Chengyue; Chen, Guoliang; Ge, Yangxiang

Patent: US2009/12328 A1, 2009 ; Location in patent: Page/Page column 1-3 ; Title/Abstract

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3:

The reactions were carried out according to a mole ratio of m-chloropropiophenone:bromine:t-butylamine:HCl in: 1:1.05:6:0.8.To 1 mole of m-chloropropiophenone was heated to 70+/-5° C., bromine was added dropwise under stirring. The reaction temperature was kept at 70+/-5° C. during the addition of bromine and kept for 5.5 hours after the addition. m-chloro-αbromopropiophenone (compound of formula (II)) was obtained.t-Butylamine was added to a solution of m-chloro-α-bromopropiophenone obtained above in acetone and water and the reaction mixture was refluxed for 2.5 hours. Acetone, water and excessive t-butylamine was evaproated at the temperature of 120° C. The concentrated solution was cooled down to room temperature and then extracted with 1500 ml of chloroform and 250 ml of water. The organic phase was dried with anhydrous sodium sulfate (30 g) and concentrated to dryness under reduced pressure. A solution of HCl in ethanol was added to the concentrated solution at room temperature and a crude product of bupropion hydrochloride was obtained after filtration. The crude product of bupropion hydrochloride was added to 2000 ml ethanol and heated to 70° C., decolorized by activated carbon (2 g) for 30 minutes and filtered. The filtrate was cooled and filtered to obtain wet product of bupropion hydrochloride. The wet product was dried in vacuum (-0.04-0.09 MPa, 70° C.) for 4 hours to obtain pure product. Total yield was 72percent based on m-chloropropiophenone; and the HPLC's purify was 99.9percent.

With hydrogenchloride in formic acid ethyl ester

T=20°C; Product distribution / selectivity; Hide Experimental Procedure

Wu, Chaogang; Xiang, Huayou; Yu, Xianghua; He, Chun; Li, Fengying; Shi, Xianghong; Lu, Chengyue; Chen, Guoliang; Ge, Yangxiang

Patent: US2009/12328 A1, 2009 ; Location in patent: Page/Page column 1-4 ; Title/Abstract

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4:

The reactions were carried out in accordance with a mole ratio of m-chloropropiophenone:bromine:t-butylamine:HCl in 1:1:10:1.5.A mixture of 1 mole of m-chloropropiophenone and dichoroethane was heated to 65+/-5° C. Bromine was added dropwise to this mixture under stirring. The reaction temperature was kept at 65+/-5° C. during the addition of bromine and kept for 5 hours after the addition. Dichloroethane was then evaporated under reduce pressure at 60° C. m-Chloro-α-bromopropiophenone (compound of formula (II)) was obtained.After tButylamine was added to the compound obtained above, the reaction mixture was refluxed for 2.5 hours. Excessive t-butylamine was evaporated at 140° C. The concentrated solution was cooled down to room temperature and then extracted with a mixture of 1200 ml of ethyl formate and 260 ml of water. The organic phase was dried with 25 g anhydrous sodium sulfate to obtain a solution of bupropion free base. Then a solution of HCl in ethyl formate was added at room temperature. Crude product of bupropion hydrochloride was obtained after filtration. The crude product was added to a mixture of dissolved in 1400 ml of isopropanol and 700 ml of water heated to 90 ° C., decolorized with activated carbon (8 g) for 40 minutes and filtered. The filtrate was cooled down and filtered to obtain wet product of bupropion hydrochloride. The wet product was dried in vacuum (-0.04-0.09 MPa, 90° C.) for 2 hours to obtain pure product.

Total yield was 80percent based by m-chloropropiophenoone; and the HPLC's purify was 99.9percent.

29

Synthesize Find similar With hydrogenchloride in methanol; water; acetone

T=0 - 67°C; Purification / work up; Hide Experimental Procedure

Rx-ID: 23076434 Find similar reactions

ERREGIERRE S.P.A.

Patent: WO2004/89873 A1, 2004 ; Location in patent: Page 7 ; Title/Abstract

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11:Example 11

Example 11; Crude Bupropion hydrochloride 40 g, Methyl alcohol 50 g , Acetone 80 g are fed into a 250 ml flask. The mixture is stirred at 60-65°C until dissolution is complete, then distilled at atmospheric pressure until precipitation is triggered and becomes abundant (maximum temperature reached is 67°C). Acetone 50 g, 37percent Hydrochloric acid 0.4 g are added while hot.

The mass is cooled to 0-3°C, then the product is filtered off and washed with Acetone 40 g The wet product is dried at 70-80°C. 36.4 g of Bupropion hydrochloride are obtained and sifted with a 36 mesh sieve.

Stage #1: in methanol

T=20 - 35°C; Stage #2: in isopropyl alcohol

T=25 - 60°C; Heating / reflux; Purification / work up; Hide Experimental Procedure

ALEMBIC LIMITED

Patent: WO2008/99418 A2, 2008 ; Location in patent: Page/Page column 8 ; Title/Abstract

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2:

Example-2; Impure bupropion hydrochloride (12Og) was stirred with methanol (360ml) at 20 to 35°C.The mixture is filtered through hyflobed. The hyflobed was washed with methanol (120ml).The combined filtrate was distilled completely to get mass. To the mass, isopropyl alcohol(60ml) was added and distilled out under vacuum at 55°C to 60°C. Again isopropyl alcohol(60ml) was added and distilled out under vacuum at 55°C to 60°C. Isopropyl alcohol (600ml) was added and heated to reflux for 30 min. The suspension was cooled to 25°C to 35°C and stirred for 1 hour. The solid was filtered and washed with isopropyl alcohol (120ml) and suck dried. The solid was dried in vacuum dryer at 70°C to 75°C till LOD is obtained below 0.5percent to get pure bupropion hydrochloride (10Og)HPLC purity: 99.9percent

30

Synthesize Find similar in DMF (N,N-dimethylformamide); ethyl acetate

T=0 - 95°C; Purification / work up; Hide Experimental Procedure

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Rx-ID: 23156837 Find similar reactions

ERREGIERRE S.P.A.

Patent: WO2004/89873 A1, 2004 ; Location in patent: Page 3 ; Title/Abstract

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2:Example 2

Example 2; Crude Bupropion hydrochloride 40 g, Dimethylformamide 160 g are fed into a 1 litre flask. The mixture is stirred at 90-95°C until dissolution is complete. Then: Ethyl acetate 200 g is added. At 75-80°C the product crystallises. The mixture is cooled slowly to a temperature between 0 and 3°C. Then the product is filtered off and washed with: Ethyl acetate 90 g The wet product is dried at 70-80°C 33 g of Bupropion hydrochloride are obtained and sifted with a 36 mesh sieve.

With hydrogenchloride in methanol; water; isopropyl alcohol

T=0 - 75°C; Purification / work up; Hide Experimental Procedure

ERREGIERRE S.P.A.

Patent: WO2004/89873 A1, 2004 ; Location in patent: Page 6-7 ; Title/Abstract

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10:Example 10

Example 10; Crude Bupropion hydrochloride 40 g Methyl alcohol 50 g Isopropyl alcohol 80 G are fed into a 250 mi flask. The mixture is stirred at 60-70°C until dissolution is complete, then distilled at atmospheric pressure until precipitation is triggered and becomes abundant (maximum temperature reached is 75°C). isopropyl alcohol 50 9 37percent Hydrochloric acid 0.4 g are added while hot. The mass is cooled to 0-3°C, then the product is filtered off and washed with Isopropyl alcohol 40 g The wet product is dried at 70-80°C. 33 g of Bupropion hydrochloride are obtained and sifted with a 36 mesh sieve.

With hydrogenchloride in methanol; water; toluene

T=0 - 79°C; Purification / work up; Hide Experimental Procedure

ERREGIERRE S.P.A.

Patent: WO2004/89873 A1, 2004 ; Location in patent: Page 8-9 ; Title/Abstract

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14:Example 14

Example 14; Crude Bupropion hydrochloride 40 g, Methyl alcohol 50 g, Toluene 80 g are fed into a 250 ml flask. The mixture is stirred at 40-45°C until dissolution is complete, then distilled at atmospheric pressure until precipitation is triggered and becomes abundant (maximum temperature reached is +79°C). Toluene 50 g, 37percent Hydrochloric acid 0.4 g are added while hot.

The mass is cooled to 0-3°C, then the product is filtered off and washed with: Toluene 40g. The wet product is dried at 70-80°C. 35.5 g of Bupropion hydrochloride are obtained and sifted with a 36 mesh sieve.

Hide Details With hydrogenchloride in methanol; DMF (N,N-dimethylformamide); water

T=0 - 95°C; Purification / work up; Hide Experimental Procedure

ERREGIERRE S.P.A.

Patent: WO2004/89873 A1, 2004 ; Location in patent: Page 9-10 ; Title/Abstract

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16:Example 16

Example 16; Crude Bupropion hydrochloride 40 g, methyl alcohol 50 g, dimethylformamide 80 g are fed into a 250 ml flask. The mixture is stirred at 35-40°C until dissolution is complete, then distilled at atmospheric pressure to 95°C. Distillation is continued under slight vacuum until crystallisation is triggered. Atmospheric pressure is restored and: Dimethylformamide 50 g 37percent Hydrochloric acid 0.4 g are added at 70°C. The mass is cooled to a temperature between 0 and 3°C, then the product is filtered off and washed with: dimethylformamide 20g Acetone 40 g The wet product is dried at 70-80°C. 27 g of Bupropion hydrochloride are obtained and sifted with a 36 mesh sieve.

With hydrogenchloride in methanol; ethanol; water

T=0 - 79°C; Purification / work up; Hide Experimental Procedure

ERREGIERRE S.P.A.

Patent: WO2004/89873 A1, 2004 ; Location in patent: Page 8 ; Title/Abstract

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13:Example 13

Example 13; Crude Bupropion hydrochloride 40 g, Methyl alcohol 50 gt, Ethanol 80 g are fed into a 250 ml flask. The mixture is stirred at 40-45°C until dissolution is complete, then distilled at atmospheric pressure until precipitation is triggered and becomes abundant (maximum temperature reached is +79°C). After cooling to 30-40°C : Ethanol 50 g, 37percent HCI 0.4 g are added. The mass is cooled to a temperature between 0 and 3°C, then the product is filtered off and washed with: Ethanol 40 g The wet product is dried at 70-80°C. 22 g of Bupropion hydrochloride are obtained and sifted with a 36 mesh sieve.

With hydrogenchloride in methanol; diethylene glycol dimethyl ether; water

T=0 - 85°C; Purification / work up; Hide Experimental Procedure

ERREGIERRE S.P.A.

Patent: WO2004/89873 A1, 2004 ; Location in patent: Page 7-8 ; Title/Abstract

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12:Example 12

Example 12; Crude Bupropion hydrochloride 40 g, methyl alcohol 50 g, Diglyme 80 g are fed into a 250 ml flask. The mixture is stirred at 50-55°C until dissolution is complete, then distilled at atmospheric pressure until precipitation is triggered and becomes abundant (maximum temperature reached is 85°C). Diglyme 50 g 37percent Hydrochloric acid 0.4percent are added while hot. The mass is cooled to 0-3°C, then the product is filtered off and washed with: Diglyme 20 g Acetone 40 g The wet product is dried at 70-80°C. 36.4 g of Bupropion hydrochloride are obtained and sifted with a 36 mesh sieve.

With hydrogenchloride in methanol; water; Sec-butyl alcohol

T=0 - 93°C; Purification / work up; Hide Experimental Procedure

ERREGIERRE S.P.A.

Patent: WO2004/89873 A1, 2004 ; Location in patent: Page 6; 10 ; Title/Abstract

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9; 17:Example 9; 17

Example 9; Crude Bupropion hydrochloride 110 g, Methanol 150 g 2-Butanol 250.7 g are fed into a 1 litre flask. The mixture is heated under reflux to 73-75°C until dissolution is complete.

The solution is then filtered at this temperature and distilled at atmospheric pressure to 92-93°C, the temperature at which the product crystallises. 2-Butanol 125. 3 g 37percent Hydrochloric acid 0.8 g are now added. The mass is cooled to 0-3°C, then the product is filtered off and washed with: 2-Butanol 141. 4 g The wet product is dried at 70-80°C. 107 g of Bupropion hydrochloride are obtained and sifted with a 36 mesh sieve.Example 17; The method described in example 9 was repeated on an industrial scale, using the following components: Crude Bupropion hydrochloride 235 Kg Methyl alcohol 300 Kg 2-Butanol (used for dissolving 501 Kg Bupropion hydrochloride) 2-Butanol (added during crystallisation) 251 Kg 37percent Hydrochloric acid 1. 73 Kg 2-Butanol (used for washing precipitate) 283 Kg About 225 Kg of dry Bupropion hydrochloride were obtained.

With hydrogenchloride in methanol; 2-methoxy-ethanol; water

T=0 - 90°C; Purification / work up; Hide Experimental Procedure

ERREGIERRE S.P.A.

Patent: WO2004/89873 A1, 2004 ; Location in patent: Page 9 ; Title/Abstract

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15:Example 15

Example 15; Crude Bupropion hydrochloride 40 g, Methyl alcohol 50 g Methyl cellosolve 80 g are fed into a 250 ml flask. The mixture is stirred at 35-40°C until dissolution is complete, then distilled at atmospheric pressure to 90°C. Distillation is continued under slight vacuum until crystallisation is triggered. Atmospheric pressure is restored and: Methyl cellosolve 50 g, 37percent Hydrochloric acid 0.4 g are added at 65°C. The mass is cooled to 0-3°C, then the product is filtered off and washed with: Methyl cellosolve 20g Acetone 40 g The wet product is dried at 7080°C. 27.8 g of Bupropion hydrochloride are obtained and sifted with a 36 mesh sieve. in DMF (N,N-dimethylformamide); Sec-butyl alcohol

T=-2 - 95°C; Purification / work up; Hide Experimental Procedure

ERREGIERRE S.P.A.

Patent: WO2004/89873 A1, 2004 ; Location in patent: Page 4 ; Title/Abstract

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4:Example 4

Example 4; Crude Bupropion hydrochloride 40 g, Dimethylformamide 160 g are fed into a 1 litre flask. The mixture is stirred at 90-95°C until dissolution is complete. Then 2-Butanol 400 g is added The mixture is cooled to a temperature between -2°C and +2°C and then stirred at this temperature until crystallisation is abundant. The product is filtered off and washed with: 2Butanol 60 g The wet product is dried at 70-80°C. 18 g of Bupropion hydrochloride are obtained and sifted with a 36 mesh sieve. in DMF (N,N-dimethylformamide); acetone

T=0 - 95°C; Purification / work up; Hide Experimental Procedure

ERREGIERRE S.P.A.

Patent: WO2004/89873 A1, 2004 ; Location in patent: Page 4-5 ; Title/Abstract

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5:Example 5

Example 5; Crude Bupropion hydrochloride 40 g, Dimethylformamide 160 g are fed into a 1 litre flask. The mixture is stirred at 90-95°C until dissolution is complete. Then Acetone 200 g is added. The mixture is slowly cooled to a temperature between 0 and 3°C and the crystallised product is filtered off and washed with: Acetone 90 g The wet product is dried at 70-80°C. 30 g of Bupropion hydrochloride are obtained and sifted with a 36 mesh sieve. in DMF (N,N-dimethyl-formamide)

T=0 - 95°C; Purification / work up; Hide Experimental Procedure

ERREGIERRE S.P.A.

Patent: WO2004/89873 A1, 2004 ; Location in patent: Page 5 ; Title/Abstract

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7:Example 7

Example 7; Crude Bupropion hydrochloride 40 g, Dimethylformamide 160 g are fed into a 250 ml flask. The mixture is stirred at 90-95°C until dissolution is complete and cooled slowly to 02°C. The crystalline mass is then stirred at this temperature for about half an hour. The product is filtered off, washing with: Ethyl acetate 60 g The wet product is dried at 70-80°C. 25.5 g of Bupropion hydrochloride are obtained and sifted with a 36 mesh sieve. in ethanol

T=0 - 75°C; Purification / work up; Hide Experimental Procedure

ERREGIERRE S.P.A.

Patent: WO2004/89873 A1, 2004 ; Location in patent: Page 5-6 ; Title/Abstract

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8:Example 8

Example 8; Crude Bupropion hydrochloride 40 g, Ethanol 100 g are fed into a 250 ml flask. The mixture is stirred at 70-75°C under reflux until dissolution is complete, cooled slowly to 0-2°C and stirred at this temperature for about half an hour. The product is filtered off, washing with: Ethanol 20 g The wet product is dried at 70-80°C. 31 g of Bupropion hydrochloride are obtained and sifted with a 36 mesh sieve. in methanol

T=0 - 65°C; Purification / work up; Hide Experimental Procedure

ERREGIERRE S.P.A.

Patent: WO2004/89873 A1, 2004 ; Location in patent: Page 3-4 ; Title/Abstract

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3:Example 3

Example 3; Crude Bupropion hydrochloride 40 g Methanol, 40g are fed into a 250 ml flask. The mixture is stirred at 60-65°C until dissolution is complete, cooled slowly to a temperature between 0 and 3°C and the precipitated mass is stirred at this temperature for about half an hour. The product is then filtered off and washed with: Methanol 20 g The wet product is dried at 70-80°C. 22 g of Bupropion hydrochloride are obtained and sifted with a 36 mesh sieve.

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Rx-ID: 28096939 Find similar reactions

Stage #1: in 1-methyl-pyrrolidin-2one

T=50 - 60°C; 0.166667 h; Stage #2: With hydrogenchloride in isopropyl alcohol

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University of Kentucky Research Foundation

Patent: US2009/17102 A1, 2009 ; Location in patent: Page/Page column 6-7 ; Title/Abstract

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1:

Bupropion was synthesized by a modification of a previously published method. (Perrine, et al., Journal of Chemical Education 2000, 77(11), 1479-1480). 12.24 g (72.6 mmole) of mchloropropiophenone, was dissolved in 25.0 ml of methylene chloride in a 50-ml round-bottom flask. A few drops of 1.0 M solution of Br2 in methylene chloride were added with stirring and the reaction was briefly warmed to initiate the reaction (as judged by the disappearance of the color of the bromine). Then, the flask was placed in an ice bath and 11.6 g (72.5 mmol) of the bromine in methylene chloride solution was added drop-wise with stirring. The methylene chloride was removed by distillation. 35 ml of t-butylamine and 25 ml of NMP were added, and the flask was heated in a 50-60° C. water bath with stirring for 10 min. Then, the contents of the flask were transferred to a separatory funnel, of 100 ml of 10percent aqueous sodium carbonate was added, and the mixture was extracted with ether (3.x.50 ml). The combined ether extracts were washed with water (3.x.50 ml), then brine solution (50 ml), dried over anhydrous K2CO3, and transferred to a beaker chilled in an ice bath. A 20:100 v/v mixture of concentrated HCl and isopropyl alcohol was added drop-wise with stirring until the contents are acidic. The desired product was filtered at the pump, washed with ether, and dried to afford BUP. HCl as a white solid (20.1 g, 95percent yield), m.p. 236-238° C. (lit. (Mehta, U.S. Pat. No. 3,819,706) m.p. 233234° C.). 1H NMR (DMSO-d6, 400 MHz): δ 9.75 (d, J=12.3 Hz, 1H), 8.63 (br, 1H), 8.27 (s, 1H), 8.17 (d, J=7.8 Hz, 1H), 7.85 (d, J=7.8 Hz, 1H), 7.69 (d, J1=7.8 Hz, J2=7.8 Hz, 1H), 5.32 (qt, J=7.2 Hz, 1H), 1.53 (m, J=7.2 Hz, 3H), 1.32 (s, 9H) ppm. 13C NMR (DMSO-d6, 300 MHz): δ 203.60, 136.56, 133.83, 132.94, 130.70, 127.87, 126.98, 52.10, 50.31, 29.39, 22.18 ppm.

Stage #1: in 1-methyl-pyrrolidin-2one

T=55°C; 0.25 h; Stage #2: With hydrogenchloride in diethyl ether

T=0°C; pH=2.0; 1 h;

AUSPEX PHARMACEUTICALS, INC.

Patent: US2010/75950 A1, 2010 ; Location in patent: Page/Page column 12 ; Title/Abstract

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1.2:

Step 2; 2-(tent-Butylamino)-1-(3-chlorophenyl)propan-1-one hydrochloride: tert-Butyl amine (1.68 mL, 16.02 mmol) was added to 2-bromo-1-(3-chloro-phenyl)-propan-1-one dissolved in Nmethyl-2-pyrrolidone (1.25 mL). The resulting mixture was heated at about 55° C. for about 15 minutes, and then cooled to ambient temperature. The mixture was poured into a saturated aqueous sodium carbonate solution, extracted with diethyl ether, washed with water and then brine, dried, and concentrated to obtain a residue. The residue was dissolved in diethyl ether (10 mL), and at about 0° C. the pH of the resulting solution was then adjusted to about 2.0 using a saturated solution of hydrochloric gas in diethyl ether (2.0 mL). After stirring for about 1 hour at about 0° C., the resulting precipitant was collected by filtration and dried in vacuo to obtain the title compound as a white solid (0.250 g, 29percent in 2 steps). mp: 225-229° C. 1H NMR (400 MHz, CDCl3) δ 1.31 (s, 9H), 1.52 (d, J=6.8 Hz, 3H), 5.30-5.33 (m, 1H), 7.67 (t, J=8.0 Hz, 1H), 7.86 (d, J=8.0 Hz, 1H), 8.17 (d, J=7.6 Hz, 1H), 8.28 (s, 1H), 8.63 (br, exchangeable with D2O, 1H), 9.58 (br, exchangeable with D2O, 1H); IR (KBr) υ 3369, 2982, 2926, 2845, 2770, 2676, 2604, 2451, 2269, 2018, 1691, 1559, 1459, 1413, 1236, 1132, 1076, 1004, 905, 787, 740 cm-1; MS 240 (M+1).

123 g

Stage #1: in 1-methyl-pyrrolidin-2one; toluene

T=20 - 60°C; Stage #2: With hydrogenchloride in isopropyl alcohol; toluene

T=0 - 10°C; 1.16667 h;

Reddy, Y. Thirupathi; Reddy, P. Narsimha; Reddy, M. Nikhil; Rajitha; Crooks, Peter A.

Synthetic Communications, 2010 , vol. 40, # 11 p. 1566 - 1573 Title/Abstract

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32

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Rx-ID: 33946714 Find similar reactions

RHINE PHARMACEUTICALS, LLC; KHAN, Arifulla; REINHARD, John, Frederick, Jr.

Patent: WO2012/118562 A1, 2012 ; Location in patent: Page/Page column 36-37 ;

80%

Title/Abstract

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33

Synthesize Find similar Stage #1: With oxalyl dichloride; dimethyl sulfoxide in dichloromethane

T=-70 - -60°C; Swern Oxidation; 3.81667 h; Stage #2: With triethylamine in dichloromethane

T=-15 - -5°C; Stage #3: With hydrogenchloride in diethyl ether; dichloromethane

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Rx-ID: 33946718 Find similar reactions

RHINE PHARMACEUTICALS, LLC; KHAN, Arifulla; REINHARD, John, Frederick, Jr.

Patent: WO2012/118562 A1, 2012 ; Location in patent: Page/Page column 27-30 ; Title/Abstract

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VI.3: Oxydation /StepS / 1971-12-1Reaction conditions.bul. 5 g, alcohol (+) (lot No.1971-9-3).bul. (COCl)2 (2.5 eq), DMSO (5 eq), Et3N (5.4 eq).bul. DCM (170 ml)Observations/Notes.bul. Slowly added DMSO at temp below -70C into (COCl)2 in DCM and stirred for 20 minutes..bul. Added alcohol solution at temp below -60C and stirred for 209 minutes..bul. Reaction mixture was heated to -15C and slowly added TEA. Stirred at -15C to -IOC fro 30 minutes..bul. Heated reaction mixture to -5C and added cold water, (extracted at temp below 5C)..bul. Separated organic phase and extracted inorganic with DCM (2x50 ml)..bul. Combined organic phases washed with brine and dried over MgS04 at temp, below 5C..bul. Mixture was filtered and immediately added HCl/diethyl ether 2M solution..bul. Reaction mixture was concentrated and coevaporated with heptanes..bul. Added heptanes, stirred for 2 hours and filtered.Isolated Material.bul.

Yield: 6.5 g, crude.bul. LotNo.: 1971-12-1.bul. HPLC: 97.7percentAdditional Comments/Notes.bul. Recrystallizations tests showed that material do not crystallize from IPA/water, EtOH/water.Product crystallized from EtOH diethyl ether (Mussso method)..bul. 6.2 g crude lot 1971 - 12- 1 dissolved in 20 ml EtOH at 50C, added Et20 (60 ml) and stirred at rt for 18 hours..bul. Product was filtered and currently is drying under high vacuum at 60C.

34

Synthesize Find similar Multi-step reaction with 3 steps 1: sodium hydrogencarbonate / ethyl acetate; water / 0.17 h / 25 °C 2: CHIRACLCEL OD-H CSP / isopropyl alcohol; trifluoroacetic acid; hexane / Resolution of racemate 3: sodium hydrogencarbonate / ethyl acetate; water View Scheme

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Rx-ID: 33946721 Find similar reactions

RHINE PHARMACEUTICALS, LLC; KHAN, Arifulla; REINHARD, John, Frederick, Jr.

Patent: WO2012/118562 A1, 2012 ; Title/Abstract

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35

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Rx-ID: 33946723 Find similar reactions

Stage #1: With sodium hydrogencarbonate in water; ethyl acetate

RHINE PHARMACEUTICALS, LLC; KHAN, Arifulla; REINHARD, John, Frederick, Jr.

Patent: WO2012/118562 A1, 2012 ; Location in patent: Page/Page column 36-37 ;

Stage #2: With hydrogenchloride in hexane; isopropyl alcohol

Title/Abstract

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Hide Experimental Procedure

Isolation of Bupropion Hydrochlorides from the Chromatographic Fractions[0077] The pooled fractions of Enantiomer 2 (ca. 8.0 L) were evaporated under reduced pressure using at an external bath temperature of 25°C. To the resultant oily residue ethyl acetate (1.0 L) was added and the mixture was mechanically stirred until a clear solution was obtained. After transferring a separation funnel, an aqueous solution of sodium hydrogen carbonate (17.0 g in 300 mL HPLC quality water; 202.5 mmol) was added in several portions. The solution was extracted and the aqueous layer was discarded. The organic layer was washed with water (0.4 L) and then dried over anhydrous magnesium sulphate (30 g). The solution was filtered and the drying agent washed with fresh ethyl acetate (2 x 100 mL). The combined filtrates were concentrated under reduced pressure at 25°C. The resulting oil was taken into a mixture of hexane:2propanol (90:10 (v/v); 300 mL). A freshly prepared anhydrous solution of hydrogen chloride in hexane:2-propanol was added in excess to convert the free base into the corresponding hydrochloride. Evaporation under reduced pressure at 25°C furnished an off-white solid. To facilitate filtration and removal of colored impurities a final washing step with an inert organic solvents was performed. Specifically, methyl-tert. butyl-ether (200 mL) was added, and the crude hydrochloride adhering to the wall of the flask was broken and homogenized with a spatula.

The resultant slurry was filtered and the solid was washed repeatedly with of hexane (3 x 200 mL). Yield after drying at 25°C in vacuum: 9.9 g (35.8 mmol mmol, 80percent) of a white solid.

The pooled fractions of Enantiomer 1 (ca. 5 L) were treated as described above to yield 9.9 g of a white solid (25.8 mmol, 80percent).[0078] The practical feasibility of the general process

outlined above was further demonstrated via a further study employing a 25g amount of racemic bupropion hydrochloride. All individual process steps detailed above were implemented successfully with excellent results, ultimately producing both (R)(-) and (S)(+) bupropion enantiomers in an 80percent or better yield, with excellent levels of optical purity, with an estimated ee greater than 98percent for both enanatiomers, and comparable chemical purity.Analytical Characterization of the Isolated Enantiomers[0079] Chiral purity: Fractions were examined by LC, with results as follows:Sample Chiral LC purityRacemate 50.0 / 50.0percent(R)(-) bupropion 99.44percent (98.9percente.e.)(S)(+) bupropion 99.72percent (99.4percente.e.)

36

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Rx-ID: 29215098 Find similar reactions

AUSPEX PHARMACEUTICALS, INC.

Patent: US2010/75950 A1, 2010 ; Location in patent: Page/Page column 13 ; Title/Abstract

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37

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Rx-ID: 28733381 Find similar reactions

Stage #1: in dichloromethane

T=-40 - 0°C; Stage #2: With DCl in MTBE (methyl tert-butyl ether); diethyl ether

T=0°C; Hide Experimental Procedure

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CONCERT PHARMACEUTICALS, INC.

Patent: WO2009/105218 A2, 2009 ; Location in patent: Page/Page column 30; 32-33 ; Title/Abstract

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1:

To a solution of 23a (187 mg, 1.01 mmol) in CH2Cl2 (3.53 mL) at -78 °C was added trifluoromethanesulfonic anhydride (0.258 mL, 1.53 mmol) followed by 2,4,6-tri- te/Y-butylpyridine (604 mg, 2.44 mmol). The reaction was stirred for 5 min and then the flask was removed from the bath and allowed to warm to 0 0C. After stirring for 1 h, the reaction was cooled to -40 0C and d9-t-butylamine (0.333 mL, 3.03 mmol) was added. The reaction was stirred for 30 min at -40 0C, warmed to 0 °C, and then stirred at 0 °C for 30 min. The reaction was quenched with 0.002 M Na2CO3 in D2O (99.9 atom percent D deuterium oxide (Cambridge Isotopes)) and diluted with CH2Cl2. The organic layer was washed twice with 0.002 M Na2CO3 in D2O, and then the combined aqueous solutions were washed once with CH2Cl2. The combined organic solutions were dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by chromatography on a silica plug (0 to 10 to 30 to 80 to 100percent EtOAc in heptane). Concentration of the desired fractions afforded a residue which was dissolved in MTBE (2.4 mL) and cooled to 0 °C. DCl (2.02 mL, 1 M in Et2O, 98 atom percent D DCl in Et2O (Sigma-Aldrich)) was added and the resulting slurry was stirred for 45 min. Stirring was stopped, and the solvent was carefully removed with a pipet. The residue was rinsed once with cold (0 °C) MTBE and then the flask was placed under high vacuum overnight. Compound 101a (87 mg, 30percent) was obtained as a white solid. 1H NMR (DMSO): δ 9.23 (br s, IH), 8.70-8.55 (m, IH), 8.28 (s, IH), 8.16 (d, J= 7.5, IH), 7.87 (d, J= 7.5, IH), 7.68 (t, J= 8.5, IH), <n="34"/>1.49 (s, 3H). MS (M+H): 250.2. Chiral HPLC (Chiralcel OD-H, hexane/IPA (99:1)): 96percent ee.

38

Synthesize Find similar With hydrogen bromide in isopropyl alcohol

T=0 - 80°C; 2.33333 h; Heating / reflux; Hide Experimental Procedure

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Rx-ID: 25598128 Find similar reactions

BIOVAIL LABORATORIES INTERNATIONAL S.R.L.

Patent: WO2007/2597 A2, 2007 ; Location in patent: Page/Page column 187; 188; 214; 299 ; Title/Abstract

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1; 085:

(a) Bromination and condensation reactions; 3-Chloro-propiophenone starting material was brominated in methylene chloride by dropping bromine under controlled conditions. On reaction completion the mother liquor was worked up and then the second reaction was executed by transferring the bromoderivative solution onto the tert-butylamine. The second substitution reaction (the tert-butyl amine amino- group substitutes the bromine atom) forms the final bupropion molecule. After work up of the mother liquor, a bupropion toluene solution was obtained.

The solvent was evaporated and bupropion was dissolved in isopropanol. From the isopropanol solution, the hydrobromide was precipitated with hydrogen bromide gas. On precipitation completion, the product was centrifuged, washed with isopropanol and dried under vacuum. On dryer discharge approval it was discharged in Kraft drums within double polyethylene bags.; Form I:; A 250 ml flask equipped with overhead stirrer and gas inlet was charged with 34 g of bupropion base and 138 ml of isopropanol. The solution was maintained under stirring while 13g of gaseous HBr was introduced through the gas inlet in a time of 20' while the internal temperature of the mixture raises from 25 to 40oC. . During the gas addition a heavy white precipitate formed. At the end of the gas addition the temperature of the mixture was raised to reflux (80oC), to get complete solution of the suspended solid. The temperature was then lowered to 25oC in 1 hour and further lowered to 0-5oC in 1 additional hour. The precipitate obtained was filtered and washed with 20 ml of cold isopropanol. The discharged wet solid was dried under vacuum (SOmmHg) in a static drier at 50oC for. 16 hours. 34 g of bupropion hydrobromide form I were obtained.

With hydrogen bromide in isopropyl alcohol

T=0 - 80°C; Product distribution / selectivity; Hide Experimental Procedure

BIOVAIL LABORATORIES INTERNATIONAL SRL; TURCHETTA, Stefano; ZENONI, Maurizio

Patent: WO2010/15692 A2, 2010 ; Location in patent: Page/Page column 209-210 ; Title/Abstract

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3:

EXAMPLE 3: Preparation and Stability Study of Bupropion HBr Polymorphs I, II and III Bupropion hydrobromide polymorphic forms I, II and III were prepared in the following manner and their stability was studied under the conditions described below:Form I:A 250 ml flask equipped with overhead stirrer and gas inlet was charged with 34 g of bupropion base and 138 ml of isopropanol. The solution was maintained under stirring while 13g of gaseous HBr was introduced through the gas inlet in a time of 20' while the internal temperature of the mixture raises from 25°C to 400C. During the gas addition a heavy white precipitate formed. At the end of the gas addition the temperature of the mixture was raised to reflux (800C), to get complete solution of the suspended solid. The temperature was then lowered to 25°C in 1 hour and further lowered to 0-50C in 1 additional hour. The precipitate obtained was filtered and washed with 20 ml of cold isopropanol. The discharged wet solid was dried under vacuum (30mmHg) in a static drier at 500C for 16 hours. 34 g of bupropion hydrobromide form I were obtained. Samples of bupropion hydrobromide form I were subjected to the conditions for the accelerated stability study and the shelf life stability study as described for example in U.S. patent number 7,241,805 (eg. see examples 10 and 11), the contents of which are incorporated herein by reference. PXRD studies carried out after 3 months and 6 months for each sample gave the same results. The PXRD profile of one of the samples of form I after 6 months in the accelerated stability condition is provided in figure 24.

39

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T=20°C;

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Rx-ID: 38467974 Find similar reactions

Vladiskovic, Chiara; Masciocchi, Norberto

Crystal Growth and Design, 2014 , vol. 14, # 7 p. 3603 - 3611 Title/Abstract

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40

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Rx-ID: 33946716 Find similar reactions

100%

Stage #1: m-chloro-α-tbutylaminopropiophenone hydrochloride With sodium hydrogencarbonate in water; ethyl acetate

T=25°C; 0.166667 h; Stage #2: trifluoroacetic acid in ethyl acetate

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RHINE PHARMACEUTICALS, LLC; KHAN, Arifulla; REINHARD, John, Frederick, Jr.

Patent: WO2012/118562 A1, 2012 ; Location in patent: Page/Page column 35 ; Title/Abstract

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R,S) Bupropion Trifluoroacetate from the Corresponding Hydrochloride[0075] Racemic bupropion hydrochloride (24.9 g, 90.2 mmol) was suspended in ethyl acetate (400 mL) with magnetically stirring. To the stirred suspension was added at 25°C an aqueous solution of sodium hydrogencarbonate (17.0 g in 300 mL HPLC quality water; 202.5 mmol, 2.25 equivalents) in several portion over 5 min. The resulting two phase system was stirred for further 5 min and then transferred into a separation funnel. The organic layer was isolated and dried over anhydrous MgS04 (30 g). The solution was filtered and the drying agent washed with several portion of fresh ethyl acetate (2 x 50 mL). To the combined organic phases was added a solution of trifluoroacetic acid (8.0 mL, 12.3 g, 0.108 mmol, 1.20 equivalents) in 100 mL ethyl acetate. The resultant colorless solution was evaporated under reduced pressure at a bath temperature of 25°C to yield an off-white solid (31.7 g, quantitative) after drying in vacuum.

A

B

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41

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Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / ethyl acetate; water / 0.17 h / 25 °C 2: CHIRACLCEL OD-H CSP / isopropyl alcohol; trifluoroacetic acid; hexane / Resolution of racemate View Scheme

RHINE PHARMACEUTICALS, LLC; KHAN, Arifulla; REINHARD, John, Frederick, Jr.

Patent: WO2012/118562 A1, 2012 ; Title/Abstract

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A

B

42

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With CHIRACLCEL OD-H CSP in hexane; isopropyl alcohol; trifluoroacetic acid

Resolution of racemate; Purification / work up; Hide Experimental Procedure

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RHINE PHARMACEUTICALS, LLC; KHAN, Arifulla; REINHARD, John, Frederick, Jr.

Patent: WO2012/118562 A1, 2012 ; Location in patent: Page/Page column 35-36 ; Title/Abstract

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Preparative Separation of (R,S)-Burpropion TFA salt on CHIRALPAK OD-H.[0076] Feed solution preparation: Bupropion trifluoroacetate (31.7 g), prepared as described above, was dissolved in 1.40 L of a mixture of hexane:2-propanol (80:20 (v/v)).Column Conditioning: A column packed with CHIRACLCEL OD-H CSP (250 x 50 mm i.d., 5 micron particles) was washed with a mixture of hexane:2-propanol:trifluoroacetic acid 90:10:0.1 (v/v) for 20 min at a flow rate of 120 mL/min. Subsequently, the column was conditioned with a mobile phase system consisting of hexane:2-propanol:2- propylamine:trifluoroacetic acid 90:10:0.025:0.03 (v/v) for 20 min at a flow rate of 120 mL/min. A typical preparative chromatogram is depicted in Figure 4. After this treatment, the chromatographic separation was carried out using the conditions summarized in Table 7 Table 7 Nonpolar Ion Paring Conditions Used for the Separation of Bupropion Trifluoroacetate Enantiomers on CHIRALCEL OD-H CSPColumn CHIRALCEL OD-H (250 x 50 mm i.d., packed with 5.0 micronCSP particlesMobile Phase Hexane:2-Propanol:Trifluoroacetic acid:2-Propylamine90:10:0.025:0.03Flow Rate 120 mL/minSystem 64 barPressureDetection UV 280 nmTemperature 25 CSample 22.6 g Bupropion Trifluoroacetate / L in mobile phaseInject.

Volume 25 mL (565 mg)Cycle Time 3.7 min/cycle

43

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T=20°C;

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Rx-ID: 38467973 Find similar reactions

Vladiskovic, Chiara; Masciocchi, Norberto

Crystal Growth and Design, 2014 , vol. 14, # 7 p. 3603 - 3611 Title/Abstract

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44

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in diethyl ether

T=20°C; Hide Experimental Procedure

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COLLEGIUM PHARMACEUTICAL, INC.

Patent: WO2007/117581 A2, 2007 ; Location in patent: Page/Page column 19 ; Title/Abstract

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3:

Bupropion base solution in diethyl ether is prepared as described in Example 1. An equimolar solution of stearic acid in diethyl ether will be added dropwise over about 3 hours to a magnetically stirred solution of bupropion base. The mixture will be stirred overnight at ambient temperature. The solvent will be removed under slightly reduced pressure at a water bath temperature of 300C. The bupropion stearate will be stored in a tight bottle in the dark. The structure of this material will be confirmed by 1H NMR (CDCI3), mass spectrometry, elemental

analysis and thin layer chromatography (TLC).