5-bromo-2-chloro-1,3-difluorobenzene

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Compound (250) can be prepared in the same manner as in Preparation Example 240, except for replacing compound (P102) with 4-chloro-3,5-difluorophenol. The 4-chloro-3,5-difluorophenol can be prepared by reacting a Grignard reagent prepared from 1-bromo-4-chloro-3,5-difluorobenzene with t-butyl hydroperoxide or converting the same Grignard reagent to a boric ester, and oxidizing the product with hydrogen peroxide under a basic condition. It is also prepared by nitrating 2-chloro-1,3-difluorobenzene (obtainable by decomposing a diazonium salt of 2,6-difluoroaniline in the presence of cuprous chloride or in hydrochloric acid), reducing the nitro-compound to obtain 4-chloro-3,5-difluoroaniline, and decomposing its diazonium salt in sulfuric acid.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Compound (250) can be prepared in the same manner as in Preparation Example 240, except for replacing compound (P102) with 4-chloro-3,5-difluorophenol. The 4-chloro-3,5-difluorophenol can be prepared by reacting a Grignard reagent prepared from 1-bromo-4-chloro-3,5-difluorobenzene with t-butyl hydroperoxide or converting the same Grignard reagent to a boric ester, and oxidizing the product with hydrogen peroxide under a basic condition. It is also prepared by nitrating 2-chloro-1,3-difluorobenzene (obtainable by decomposing a diazonium salt of 2,6-difluoroaniline in the presence of cuprous chloride or in hydrochloric acid), reducing the nitro-compound to obtain 4-chloro-3,5-difluoroaniline, and decomposing its diazonium salt in sulfuric acid.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Compound (250) can be prepared in the same manner as in Preparation Example 240, except for replacing compound (P102) with 4-chloro-3,5-difluorophenol. The 4-chloro-3,5-difluorophenol can be prepared by reacting a Grignard reagent prepared from 1-bromo-4-chloro-3,5-difluorobenzene with t-butyl hydroperoxide or converting the same Grignard reagent to a boric ester, and oxidizing the product with hydrogen peroxide under a basic condition. It is also prepared by nitrating 2-chloro-1,3-difluorobenzene (obtainable by decomposing a diazonium salt of 2,6-difluoroaniline in the presence of cuprous chloride or in hydrochloric acid), reducing the nitro-compound to obtain 4-chloro-3,5-difluoroaniline, and decomposing its diazonium salt in sulfuric acid.

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6-chloro-2-fluoro-3-methylphenol (9.96 g, 62.0 mmol) and 18-crown-6 (4.5 g, 17.03 mmol) were dissolved in dry DMSO (100 mL) and treated with 20% potassium t-butoxide in THF (34.8 g, 62.0 mmol) in THF for 15 minutes at room temperature. 5-bromo-2-chloro-1,3-difluorobenzene (14.11 g, 62.0 mmol) was added in one portion and the reaction mixture heated at 130° C. for 3 days. The reaction mixture was filtered through Celite™, cooled to ambient temperature and water was added to afford the crude product as a black precipitate which was filtered off, washed with water and air dried. The crude product was dissolved in DCM, dried over MgSO4, and filtered through a plug of 45 g silica gel which was eluted with 500 mL DCM. The filtrate was concentrated to an amber oil and crystallized by addition of EtOH (150 mL). The precipitate was cooled in an ice bath and filtered to afford 2-[(5-bromo-2-chloro-3-fluorophenyl)oxy]-1-chloro-3-fluoro-4-methylbenzene (8.7 g, 23.64 mmol, 38.1% yield) as a white solid. The mother liquor was concentrated to dryness and crystallized from IPA (70 mL) to give a second batch of the desired product (4.55 g, 12.36 mmol, 19.93% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.61 (dd, J=8.56, 1.97 Hz, 1H), 7.30-7.47 (m, 2H), 6.74 (s, 1H), 2.29 (d, J=1.56 Hz, 3H). The reaction mixture was filtered through Celite™ cooled to ambient temperature water was added to afford the crude product as a black precipitate which was filtered off washed with water and air dried The crude product was dissolved in DCM dried over MgSO4 filtered through a plug of 45 g silica gel which was eluted with 500 mL DCM The filtrate was concentrated to an amber oil crystallized by addition of EtOH (150 mL) The precipitate was cooled in an ice bath filtered

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Compound (250) can be prepared in the same manner as in Preparation Example 240, except for replacing compound (P102) with 4-chloro-3,5-difluorophenol. The 4-chloro-3,5-difluorophenol can be prepared by reacting a Grignard reagent prepared from 1-bromo-4-chloro-3,5-difluorobenzene with t-butyl hydroperoxide or converting the same Grignard reagent to a boric ester, and oxidizing the product with hydrogen peroxide under a basic condition. It is also prepared by nitrating 2-chloro-1,3-difluorobenzene (obtainable by decomposing a diazonium salt of 2,6-difluoroaniline in the presence of cuprous chloride or in hydrochloric acid), reducing the nitro-compound to obtain 4-chloro-3,5-difluoroaniline, and decomposing its diazonium salt in sulfuric acid.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5-bromo-2-chloro-1,3-difluorobenzene (2000 mg, 8.2 mmol) was stirred at room temperature in THF under N2 and the i-PrMgCl—LiCl (1.3M solution in THF) was added over about 1 minute—very slight exotherm noticed to ˜30° C. Reaction was stirred at room temperature for 30 minutes followed by the addition of methyl trifluoroacetate (1580 mg, 12.3 mmol, 1.24 mL) over about 1 minute—slight exotherm to ˜40° C. Solvents were evaporated under reduced pressure to provide the desired product. 1H NMR (CDCl3) δ ppm: 8.05 (s, 2H). noticed to ˜30° C Reaction Solvents were evaporated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5-bromo-2-chloro-1,3-difluorobenzene (2000 mg, 8.2 mmol) was stirred at room temperature in THF under N2 and the isopropylmagnesium chloride/LiCl reagent (1310 mg, 9.02 mmol, 6.94 mL) was added over about 1 minute—very slight exotherm noticed to ˜30° C. Reaction was stirred at room temperature for 30 minutes followed by the addition of methyl trifluoroacetate (1580 mg, 12.3 mmol, 1.24 mL) over about 1 minute—slight exotherm to ˜40° C. Solvents were evaporated under reduced pressure to provide the desired product. 1H NMR (CDCl3) δ ppm: 8.05 (s, 2H). noticed to ˜30° C Reaction Solvents were evaporated under reduced pressure