2-(2-methoxyethoxy)acetyl chloride

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

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: Under a nitrogen atmosphere, 2.56 ml (29.8 mmol) of oxalyl chloride and 2 drops of DMF are added to 1.69 ml (14.9 mmol) of 2-(2-methoxyethoxy)-acetic acid (Fluka; Buchs/Switzerland) in 75 ml of methylene chloride. After 17 h at RT, the reaction mixture is carefully concentrated by evaporation in a RE with the exclusion of moisture. A 1H-NMR spectrum of the residue exhibits the signals of the title compound in addition to signals of ≈40% solvent (especially methylene chloride): 1H-NMR (200 MHz, CDCl3): 3.37 (s, MeO), 3.58 and 3.77 (2d, J=5 Hz, CH2 --CH2), 4.48 (s, CH2). That mixture is used above. the reaction mixture is carefully concentrated by evaporation in a RE with the exclusion of moisture in addition to signals of ≈40% solvent (especially methylene chloride): 1H-NMR (200 MHz, CDCl3): 3.37 (s, MeO), 3.58 and 3.77 (2d, J=5 Hz, CH2 --CH2), 4.48 (s, CH2)

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

Procedure: Under a nitrogen atmosphere, 2.56 ml (29.8 mmol) of oxalyl chloride and 2 drops of DMF are added to 1.69 ml (14.9 mmol) of 2-(2-methoxyethoxy)-acetic acid (Fluka; Buchs/Switzerland) in 75 ml of methylene chloride. After 17 h at RT, the reaction mixture is carefully concentrated by evaporation in a RE with the exclusion of moisture. A 1H-NMR spectrum of the residue exhibits the signals of the title compound in addition to signals of ≈40% solvent (especially methylene chloride): 1H-NMR (200 MHz, CDCl3): 3.37 (s, MeO), 3.58 and 3.77 (2d, J=5 Hz, CH2 --CH2), 4.48 (s, CH2). That mixture is used above. the reaction mixture is carefully concentrated by evaporation in a RE with the exclusion of moisture in addition to signals of ≈40% solvent (especially methylene chloride): 1H-NMR (200 MHz, CDCl3): 3.37 (s, MeO), 3.58 and 3.77 (2d, J=5 Hz, CH2 --CH2), 4.48 (s, CH2)

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

Procedure: (2-Methoxy-ethoxy)-acetyl chloride (2.13 g, 13.99 mmol) was added to an ice-cold solution of 6-chloronicotinic acid hydrazide (2 g, 11.66 mmol) and N-methylmorpholine (1.92 mL, 17.49 mmol) in dichloromethane (60 mL) and the mixture was stirred at room temperature for 18 hours. The mixture was then treated with sodium hydrogen carbonate solution and concentrated in vacuo. The aqueous residue was extracted with dichloromethane (×2) and the combined organic solutions were washed with brine and dried over sodium sulfate and concentrated in vacuo to give a pale yellow residue. The residue was then stirred in diethyl ether for 2 hours, filtered and dried to afford the title compound as a pale yellow solid in 51% yield, 1.7 g. concentrated in vacuo The aqueous residue was extracted with dichloromethane (×2) the combined organic solutions were washed with brine dried over sodium sulfate concentrated in vacuo to give a pale yellow residue filtered dried

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

Procedure: (2-Methoxy-ethoxy)-acetyl chloride (2.13 g, 13.99 mmol) was added to an ice-cold solution of 6-chloronicotinic acid hydrazide (2 g, 11.66 mmol) and N-methylmorpholine (1.92 mL, 17.49 mmol) in dichloromethane (60 mL) and the mixture was stirred at room temperature for 18 hours. The mixture was then treated with sodium hydrogen carbonate solution and concentrated in vacuo. The aqueous residue was extracted with dichloromethane (×2) and the combined organic solutions were washed with brine and dried over sodium sulfate and concentrated in vacuo to give a pale yellow residue. The residue was then stirred in diethyl ether for 2 hours, filtered and dried to afford the title compound as a pale yellow solid in 51% yield, 1.7 g. concentrated in vacuo The aqueous residue was extracted with dichloromethane (×2) the combined organic solutions were washed with brine dried over sodium sulfate concentrated in vacuo to give a pale yellow residue filtered dried

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

Procedure: Prepared as described in Example 1 using (1R,2S)-1-[1-(4-fluorophenyl)-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine (50 mg, 0.13 mmol) and 2-(2-methoxyethoxy)acetyl chloride (0.039 mL, 0.38 mmol). Yield 52 mg (80%). Prepared

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

Procedure: To 1-(4-(2-(3-aminopyridin-4-yl)ethoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (Intermediate E) (50 mg, 0.094 mmol) and DMAP (5.71 mg, 0.047 mmol) in DCM (3.0 mL) was added 2-(2-methoxyethoxy)acetyl chloride (30 μl, 0.281 mmol) at 0° C. and the reaction mixture stirred at RT for 1.5 hr. The solvent was removed in vacuo and the residue subjected to SCX capture and release eluting with 1% NH3 in MeOH solution. The residue was purified by column chromatography (4.0 g) gradient elution with 0-8% MeOH in DCM and the product fractions concentrated in vacuo to give N-(4-(2-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)ethyl)pyridin-3-yl)-2-(2-methoxyethoxy)acetamide (Example 22) as a light purple solid (35 mg, 56%): m/z 651 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.25 (9H, s), 2.40 (3H, s), 3.26 (5H, m), 3.50 (2H, m), 3.70 (2H, m), 4.15 (2H, s), 4.40 (2H, t), 6.35 (1H, s), 6.98 (1H, d), 7.35 (2H, m), 7.42 (2H, m), 7.50 (3H, m), 7.62 (1H, d), 7.87 (1H, d), 8.07 (1H, dd), 8.36 (1H, d), 8.56 (1H. br s), 8.60 (1H, s), 8.76 (1H, br s), 9.55 (1H, br s.). The solvent was removed in vacuo eluting with 1% NH3 in MeOH solution The residue was purified by column chromatography (4.0 g) gradient elution with 0-8% MeOH in DCM the product fractions concentrated in vacuo

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

Procedure: To a solution of 1-(4-((3-aminopyridin-4-yl)methoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (Intermediate C) (50 mg, 0.10 mmol) and DIPEA (33.5 μl, 0.19 mmol) in anhydrous DCM (1.0 mL) and anhydrous DMF (0.2 mL) was added 2-(2-methoxyethoxy)acetyl chloride (15 μl, 0.11 mmol). The reaction mixture was stirred for 12 hr at RT. LC-MS indicated 50% conversion to the desired product. 2-(2-methoxyethoxy) acetyl chloride (15 μl, 0.11 mmol) was added and the reaction mixture stirred at RT. After 6 hr, LC-MS indicated the reaction had gone to completion. MeOH (2.0 mL) and AcOH (5 drops) were added and the reaction mixture was subjected to SCX capture and release, eluting with 1% NH3 in MeOH. The solvent was removed in vacuo and the crude material purified by column chromatography (4 g, 0-10% MeOH in EtOAc, gradient elution) to afford N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-3-yl)-2-(2-methoxyethoxy) acetamide (Example 17) as a white solid (27 mg, 43%): m/z 637 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 2.39 (3H, s), 3.18 (3H, s), 3.36 (2H, m), 3.61 (2H, m), 4.14 (2H, s), 5.33 (2H, s), 6.35 (1H, s), 6.97 (1H, d), 7.35 (2H, d), 7.43 (2H, d), 7.67-7.55 (4H, m), 7.92 (1H, d), 8.27 (1H, d), 8.46 (1H, d), 8.58 (1H, s), 8.74 (1H, s), 8.80 (1H, s), 9.65 (1H, s).

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

Procedure: To 15.3 g of N-(2,3-dimethylnaphtyl)-N-(2-oxo-tetrahydrofuran-3-yl)-amine in 120 ml of toluene are added dropwise 12.2 g of 2-methoxyethoxy-acetyl chloride (MAC) in 20 ml of toluene and afterwards 8.1 g of triethylamine in 20 ml of toluene. The temperature of the reaction rises to 35° and is then raised to 40° for 2 hours. There are subsequently added dropwise a further 2 g of MAC and 1.5 g of triethylamine. The temperature is held overnight at 40°, and afterwards a further 2 g of MAC are added dropwise. After 4 hours, the reaction mixture is cooled to room temperature and filtered, and the filtrate is concentrated by evaporation to yield a resinous residue, which is purified through silica gel 60 using ethyl acetate as the eluant. The solid product occurring from the residue is recrystallised from isopropanol with the addition of active charcoal. The resulting product is the colourless diastereoisomeric mixture of the compound No. 32, m.p. 142°-146°. rises to 35° is then raised to 40° for 2 hours After 4 hours filtered the filtrate is concentrated by evaporation to yield a resinous residue, which is purified through silica gel 60 using ethyl acetate as the eluant is recrystallised from isopropanol with the addition of active charcoal the colourless diastereoisomeric mixture of the compound No

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

Procedure: To 15.3 g of N-(2,3-dimethylnaphtyl)-N-(2-oxo-tetrahydrofuran-3-yl)-amine in 120 ml of toluene are added dropwise 12.2 g of 2-methoxyethoxy-acetyl chloride (MAC) in 20 ml of toluene and afterwards 8.1 g of triethylamine in 20 ml of toluene. The temperature of the reaction rises to 35° and is then raised to 40° for 2 hours. There are subsequently added dropwise a further 2 g of MAC and 1.5 g of triethylamine. The temperature is held overnight at 40°, and afterwards a further 2 g of MAC are added dropwise. After 4 hours, the reaction mixture is cooled to room temperature and filtered, and the filtrate is concentrated by evaporation to yield a resinous residue, which is purified through silica gel 60 using ethyl acetate as the eluant. The solid product occurring from the residue is recrystallised from isopropanol with the addition of active charcoal. The resulting product is the colourless diastereoisomeric mixture of the compound No. 32, m.p. 142°-146°. rises to 35° is then raised to 40° for 2 hours After 4 hours filtered the filtrate is concentrated by evaporation to yield a resinous residue, which is purified through silica gel 60 using ethyl acetate as the eluant is recrystallised from isopropanol with the addition of active charcoal the colourless diastereoisomeric mixture of the compound No