methyl 2-(2,4-dichlorophenyl)acetate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: The title compound was prepared in analogy to Example 1, steps 2 to 5, from 2,4-dichlorobenzeneacetic acid methyl ester [CAS Reg. No. 91361-41-0] and 2-benzyloxy-isonicotinic acid (which was made as described below from 2-chloro isonicotinic acid), leading to 2-(2-benzyloxy-pyridin-4-yl)-3-(2,4-dichloro-phenyl)-1,1,1-trifluoro-butan-2-ol, followed by cleavage of the benzyl protecting group by hydrogenation over Pd/C-10% (0.75 g) in ethyl actetate (150 ml). In step 4, methyl iodide was used as an alkylating agent and the improved procedure described in example 117 was used. MS (m/e)=364.0 [MH+].

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: The title compound was prepared in analogy to Example 1, steps 2 to 5, from 2,4-dichlorobenzeneacetic acid methyl ester [CAS Reg. No. 91361-41-0] and 2-benzyloxy-isonicotinic acid (which was made as described below from 2-chloro isonicotinic acid), leading to 2-(2-benzyloxy-pyridin-4-yl)-3-(2,4-dichloro-phenyl)-1,1,1-trifluoro-butan-2-ol, followed by cleavage of the benzyl protecting group by hydrogenation over Pd/C-10% (0.75 g) in ethyl actetate (150 ml). In step 4, methyl iodide was used as an alkylating agent and the improved procedure described in example 117 was used. MS (m/e)=364.0 [MH+].

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

Procedure: To a stirred mixture of 22 parts of methyl 2,4-dichlorobenzeneacetate and 135 parts of N,N-dimethylformamide are added 3.1 parts of a sodium hydride dispersion 78% while nitrogen gas is introduced. After stirring till foaming has ceased, there are added 15 parts of 2-bromopropane and the whole is stirred for 3 hours at room temperature. The reaction mixture is poured onto water and the product is extracted twice with 2,2'-oxybispropane. The combined extracts are washed with water, dried, filtered and evaporated, yielding 24.5 parts (94%) of methyl 2,4-dichloro-α-(1-methylethyl)benzeneacetate as a residue. is introduced the whole is stirred for 3 hours at room temperature The reaction mixture is poured onto water the product is extracted twice with 2,2'-oxybispropane The combined extracts are washed with water dried filtered evaporated

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

Procedure: To a stirred mixture of 22 parts of methyl 2,4-dichlorobenzeneacetate and 135 parts of N,N-dimethylformamide are added 3.1 parts of sodium hydride dispersion 78% while nitrogen gas is introduced. The whole is stirred till foaming has ceased and cooled in an ice-bath. Then there are added dropwise 16 parts of iodomethane. Upon completion, stirring is continued for 3 hours at room temperature. The reaction mixture is poured onto water and the product is extracted with 2,2'-oxybispropane. The extract is washed with water, dried, filtered and evaporated, yielding 20 parts (80%) of methyl 2,4-dichloro-α-methylbenzeneacetate as a residue. is introduced cooled in an ice-bath Upon completion, stirring The reaction mixture is poured onto water the product is extracted with 2,2'-oxybispropane The extract is washed with water dried filtered evaporated

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

Procedure: To a stirred mixture of 22 parts of methyl 2,4-dichlorobenzeneacetate and 135 parts of N,N-dimethylformamide are added 3.1 parts of sodium hydride dispersion 78% while nitrogen gas is introduced. The whole is stirred till foaming has ceased and cooled in an ice-bath. Then there are added dropwise 16 parts of iodomethane. Upon completion, stirring is continued for 3 hours at room temperature. The reaction mixture is poured onto water and the product is extracted with 2,2'-oxybispropane. The extract is washed with water, dried, filtered and evaporated, yielding 20 parts (80%) of methyl 2,4-dichloro-α-methylbenzeneacetate as a residue. is introduced cooled in an ice-bath Upon completion, stirring The reaction mixture is poured onto water the product is extracted with 2,2'-oxybispropane The extract is washed with water dried filtered evaporated

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (2,4-Dichloro-phenyl)acetic acid methyl ester (Example 41; 28.7 mg, 0.131 mmol), palladium acetate (2.0 mg, 0.009 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (7.2 mg, 0.018 mmol), potassium phosphate (56 mg, 0.263 mmol) and water (0.1 mL) were added to a solution of (E)-4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1,1,1-trifluoro-2-trifluoromethyl-3-buten-2-ol (Example 26-(5); 50 mg, 0.088 mmol) in toluene (1 mL). After replacement with nitrogen, the mixture was stirred at 100° C. overnight. Then, the reaction mixture was filtered through amino silica gel, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to give the target compound as a colorless oil (3.9 mg, 7%). Then, the reaction mixture was filtered through amino silica gel the filtrate was concentrated under reduced pressure The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=2:1)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (2,4-Dichloro-phenyl)acetic acid methyl ester (Example 41; 28.7 mg, 0.131 mmol), palladium acetate (2.0 mg, 0.009 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (7.2 mg, 0.018 mmol), potassium phosphate (56 mg, 0.263 mmol) and water (0.1 mL) were added to a solution of (E)-4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1,1,1-trifluoro-2-trifluoromethyl-3-buten-2-ol (Example 26-(5); 50 mg, 0.088 mmol) in toluene (1 mL). After replacement with nitrogen, the mixture was stirred at 100° C. overnight. Then, the reaction mixture was filtered through amino silica gel, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to give the target compound as a colorless oil (3.9 mg, 7%). Then, the reaction mixture was filtered through amino silica gel the filtrate was concentrated under reduced pressure The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=2:1)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Degassed toluene (0.13 mL) and water (0.013 mL) were added to t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)dimethylsilane (Example 23-(1); 15.7 mg, 0.0259 mmol), palladium (II) acetate (0.8 mg, 0.004 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (3 mg, 0.007 mmol) and potassium phosphate (20.0 mg, 0.0942 mmol). After replacement with nitrogen, (2,4-dichloro-phenyl)acetic acid methyl ester (Example 41; 17 mg, 0.078 mmol) was added. After replacement with nitrogen, the mixture was heated while stirring at an external temperature of 96 to 104° C. for 30 minutes. The reaction mixture was diluted with diethyl ether and filtered through cotton plug, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=50/1) to give the title compound (3 mg, 17%). Degassed toluene (0.13 mL) and water (0.013 mL) After replacement with nitrogen, the mixture was heated filtered through cotton plug the filtrate was concentrated under reduced pressure The residue was purified by silica gel chromatography (hexane/ethyl acetate=50/1)

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

Procedure: The title compound was prepared in analogy to Example 1, steps 2 to 5, from 2,4-dichlorobenzeneacetic acid methyl ester [CAS Reg. No. 91361-41-0] and 2-benzyloxy-isonicotinic acid (which was made as described below from 2-chloro isonicotinic acid), leading to 2-(2-benzyloxy-pyridin-4-yl)-3-(2,4-dichloro-phenyl)-1,1,1-trifluoro-butan-2-ol, followed by cleavage of the benzyl protecting group by hydrogenation over Pd/C-10% (0.75 g) in ethyl actetate (150 ml). In step 4, methyl iodide was used as an alkylating agent and the improved procedure described in example 117 was used. MS (m/e)=364.0 [MH+].