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4 reactions in Reaxys
2017-09-21 21h:34m:31s (EST)
Cl
1. Query
F
N
Search as: As drawn
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Cl N
F
I
F
N
Cl
Rx-ID: 28992959 View in Reaxys 1/4 Yield 76 %
Conditions & References 1 :Cool a solution of diisopropylamine (80.6 niL, 0.575 mol) in THF (1 L) to about -5 0C using an ice water/MeOH bath. Add /z-butyllithium (2.5 M in hexanes, 212 mL, 0.530 mol) dropwise over 1 h via a syringe pump (4 mL/min) while maintaining the reaction temperature between -5 to 0 0C during the addition. Stir the lithium diisopropylamide (LDA) solution for 1 h at 0 °C and then transfer it via canula, over 1 h, to a -78 0C solution of 2-chloro-4-fluoro-benzonitrile (68.7 g, 0.442 mol) in THF (1 L). Allow the temperature of the reaction mixture to warm to about -65 0C during the initial addition of the LDA solution; however, keep the internal temperature below -70 0C during the remainder of the LDA addition. Keep the temperature of the resulting dark red-orange reaction mixture below -70 0C for 5 h and add iodomethane (251.2 g, 1.77 mol, ~3 mL/min) at such a rate that the reaction temperature is maintained below -65 0C during the addition. Allow the reaction mixture to slowly warm overnight. After stirring for 14 h, the temperature of the reaction mixture is -5 0C. Quench the reaction with saturated aqueous ammonium chloride (500 mL) and water (750 mL) and dilute with diethyl ether (about 2 L). Separate the layers and extract the aqueous layer with diethyl ether (about 1 L). Dry the combined organic layer (about 5.5 L) over MgSO4, filter, and concentrate to afford the crude title compound as a red-brown oily solid (about 86.7 g). Subject the crude residue (dry loaded on silica gel using methylene chloride) to flash chromatography (silica gel (10 x 30 cm), gradient of 99: 1 to 93:7 hexane/EtOAc) to obtain the title compound (56.7 g, 76percent) as a white solid, m.p. 63 - 65 0C; 1H NMR (300 MHz, CDCl3): δ 7.54 (dd, J= 8.6, 5.6 Hz, IH), 7.08 (dd, J = 8.6, 8.6 Hz , IH), 2.36 (d, / = 2.4 Hz, 3H). Stage 1: With lithium diisopropyl amide in tetrahydrofuran, hexanes, Time= 6h, T= -78 - -65 °C Stage 2: in tetrahydrofuran, hexanes, Time= 14h, T= -65 - -5 °C Patent; ELI LILLY AND COMPANY; WO2006/124447; (2006); (A2) English View in Reaxys
74 %
1 : Preparation 12-Chloro-4-fluoro-3-methyl-benzonitrile Preparation 12-Chloro-4-fluoro-3-methyl-benzonitrileTo a solution of diisopropylamine (474 mL, 3.35 mol) in anhydrous THF (5.8 L) at-5 °C under a nitrogen atmosphere is added dropwise 2.5 M n-butyllithium in hexanes (1.24 L, 3.10 mol) over 3 h and the resulting mixture is stirred at -5 °C for one additional hour. The LDA solution is added dropwise to a solution of 2-chloro-4-fluoro-benzonitrile (400 g, 2.58 mol) in anhydrous THF (5.8 L) at -70 °C over 6 h and then stirred at -70 °C overnight. lodomethane (643 mL, 10.32 mol) is added dropwise over 2.5 h and the temperature is raised to -5 °C for 17 h. Saturated aqueous ammonium chloride (3 L) is added. The solution is diluted with water (3.5 L) and extracted with diethyl ether (2 x 2 L). The organic phases are separated, combined, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a black solid. The solid is purified through a silica gel pad eluting withEtOAc/hexanes (1/40) to obtain the title compound (323 g, 74percent). 1H NMR (300 MHz, CDCls) δ 7.08 (dd, J= 8.6, 8.6 Hz, 1H), 7.54 (dd, J= 8.6, 5.6 Hz, 1H), 2.36 (d, J= 2.4 Hz, 3H). Stage 1: With n-butyllithium, N-ethyl-N,N-diisopropylamine in tetrahydrofuran, hexane, T= -70 °C Stage 2: in tetrahydrofuran, hexane, Time= 19.5h, T= -70 - -5 °C Patent; ELI LILLY AND COMPANY; JADHAV, Prabhakar Kondaji; SAEED, Ashraf; GREEN, Jonathan Edward; KRISHNAN, Venkatesh; MATTHEWS, Donald Paul; STEPHENSON, Gregory Alan; WO2013/55577; (2013); (A1) English View in Reaxys
74 %
With n-butyllithium, diisopropylamine in tetrahydrofuran, hexane, Time= 17h, T= -70 - -5 °C , Inert atmosphere Saeed, Ashraf; Vaught, Grant M.; Gavardinas, Kostas; Matthews, Donald; Green, Jonathan E.; Losada, Pablo Garcia; Bullock, Heather A.; Calvert, Nathan A.; Patel, Nita J.; Sweetana, Stephanie A.; Krishnan, Venkatesh; Henck, Judith W.; Luz, John G.; Wang, Yong; Jadhav, Prabhakar; Journal of Medicinal Chemistry; vol. 59; nb. 2; (2016); p. 750 - 755 View in Reaxys 2-chloro-4-fluorobenzonitrile (1g) and TMEDA (1.13 mL) in THF (10 mL) were cooled to-78 °C, under nitrogen. Secbutyllithium (1. 3M in cyclohexane, 8.54 ML) was added over 20min, keeping the temperature BELOW-70 °C. The mixture was then stirred at -78 C FOR 2. 5H. Methyl iodode (0. 5ML) was added and the mixture allowed to warm to 15 °C, over 35MIN. The reaction was quenched with a saturated aqueous solution of ammonium chloride and the product was extracted with ethyl acetate. The ethyl acetate was washed with brine, dried (MgS04), filtered and concentrated under reduced pressure to give crude product (1.28g). Retention time 2.12 min (standard)
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Stage 1: With N,N,N,N,-tetramethylethylenediamine, sec.-butyllithium in tetrahydrofuran, cyclohexane, Time= 2.5h, T= -78 - -70 °C Stage 2: in tetrahydrofuran, cyclohexane, Time= 0.583333h, T= 15 °C Patent; ASTRAZENECA AB; WO2004/99144; (2004); (A1) English View in Reaxys Cl
Cl Br
(v3)
F
-1 N
Zn
F
N
Rx-ID: 29451526 View in Reaxys 2/4 Yield
Conditions & References
55 mg
With tetrakis(triphenylphosphine) palladium(0) in N,N-dimethyl-formamide, Time= 0.0416667h, T= 200 °C , Microwave irradiation Schlienger, Nathalie; Lund, Birgitte W.; Pawlas, Jan; Badalassi, Fabrizio; Bertozzi, Fabio; Lewinsky, Rasmus; Fejzic, Alma; Thygesen, Mikkel B.; Tabatabaei, Ali; Bradley, Stefania Risso; Gardell, Luis R.; Piu, Fabrice; Olsson, Roger; Journal of Medicinal Chemistry; vol. 52; nb. 22; (2009); p. 7186 - 7191 View in Reaxys Cl
Cl O F
F
N
NH 2
Rx-ID: 25690072 View in Reaxys 3/4 Yield
Conditions & References 1 With pyridine, oxalyl dichloride in N,N-dimethyl-formamide, Time= 1h, T= 0 - 10 °C Patent; TAKEDA PHARMACEUTICAL COMPANY LIMITED; WO2007/15567; (2007); (A1) Japanese View in Reaxys Cl
Cl Br
F
N
(v2)
Zn
N
F
N
Rx-ID: 23850993 View in Reaxys 4/4 Yield 71 %
Conditions & References 8 :Example 8 2-Chloro-4-fluoro-3-methylbenzonitrile (198RL18) 3-Bromo-2-chloro-6-fluorotoluene (7.0 g, 31 mmol), zinc cyanide (3.7 g, 31 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.81 g, 1.56 mmol) was added to a flask under argon atmosphere. Dry DMF (35 mL) was added and the reaction mixture was stirred under argon at 120° C. The reaction was monitored by GC-MS and full conversion was observed after 2 hours. The mixture was diluted with dichloromethane (300 mL), washed with water (100 mL) and 4percent magnesium sulfate solution (100 mL), dried over magnesium sulphate, filtered, and evaporated to give a clear oil. The product was further purified by column chromatography on silica gel using n-heptane/ethyl acetate (9:1) giving a white solid (3.79 g, 71percent). 1H-NMR (CDCl3) δ 7.43 (dd, 1H, J=5.6, 8.8, Ar-H), 6.87 (t, 1H, J=8.8, Ar-H), 2.36 (d, 3H, J=2.4, CH3). With tetrakis(triphenylphosphine) palladium(0) in N,N-dimethyl-formamide, Time= 2h, T= 120 °C , Product distribution / selectivity Patent; Schlienger, Nathalie; Thygesen, Mikkel Boas; Pawlas, Jan; Badalassi, Fabrizio; Lewinsky, Rasmus; Lund, Birgitte Winther; Olsson, Roger; US2006/160845; (2006); (A1) English View in Reaxys
42 %
3 :Example 3 2-Chloro-4-fluoro-3-methylbenzonitrile (165RL87a) 3-Bromo-2-chloro-6-fluorotoluene 165RL91 (173 mg, 0.78 mmol), zinc cyanide (91 mg, 0.78 mmol) and tetrakis(triphenylphosphine)palladium(0) (27 mg, 23 μmol) was charged in a vial, DMF (1 mL) added, and the mixture irradiated for 150 sec at 200° C. in a microwave oven.
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Diethyl ether (30 ml) was added and the reaction mixture washed with magnesium sulphate (4percent solution, 3*20 mL) followed by brine (20 mL). The organic layer was dried and evaporated. The product was further purified by column chromatography on silica gel using n-heptane/ethyl acetate (9:1) giving a white solid (55 mg, 42percent). GC/MS m/z 169 [M+H]+. 1H-NMR (CDCl3, 300 MHz) δ 7.43 (dd, 1H, J=5.6, 8.8, Ar-H), 6.87 (t, 1H, J=8.8, Ar-H), 2.36 (d, 3H, J=2.4, CH3). With tetrakis(triphenylphosphine) palladium(0) in N,N-dimethyl-formamide, Time= 0.0416667h, T= 200 °C , Microwave, Product distribution / selectivity Patent; Schlienger, Nathalie; Thygesen, Mikkel Boas; Pawlas, Jan; Badalassi, Fabrizio; Lewinsky, Rasmus; Lund, Birgitte Winther; Olsson, Roger; US2006/160845; (2006); (A1) English View in Reaxys
Copyright © 2017 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.
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