1,1,3,3-tetramethoxypropane

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

Procedure: The mixture of 3-hydrazinobenzoic acid (2.0 g), 1,1,3,3-tetramethoxypropane (2.2 ml) and conc. hydrochloric acid (2.4 ml) in methanol (10.0 ml) was heated under reflux for 2 hours, and the mixture was evaporated in vacuo. The residue was dissolved in ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution and brine. The residue was obtained by evaporating solvent, and purified by column chromatography on silica gel eluting with dichloromethane. The fractions containing the desired product were collected and evaporated in vacuo to give methyl 3-(pyrazol-1-yl)benzoate (1.33 g). was heated under reflux for 2 hours the mixture was evaporated in vacuo The residue was dissolved in ethyl acetate washed with a saturated aqueous sodium bicarbonate solution and brine The residue was obtained by evaporating solvent purified by column chromatography on silica gel eluting with dichloromethane The fractions containing the desired product were collected evaporated in vacuo

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

Procedure: A mixture of 35.2 g (0.2 mole) of 2-hydrazino-4(3H)-quinazolinone, 250 ml of water, 30 ml of methanol and 36.6 ml of concentrated hydrochloric acid is stirred with 36.08 g (0.22 mole) of 1,1,3,3-tetramethoxy-propane at 40° C. The desired product precipitates after a short time from the solution initially formed. After a reaction of one hour in total at 40° C., 29.8 g of 2-(1H-pyrazol-1-yl)-4(3H)-quinazolinone (melting point 148°-50°) are isolated. The desired product precipitates after a short time from the solution initially formed After a reaction of one hour in total at 40° C.

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

Procedure: A mixture of 7.08 g of (3-amino-1H-pyrazol-4-yl)-2-furanylmethanone (prepared as described in U.S. Pat. appliction Ser. No. 612,811, filed May 24, 1984), 8.20 g of malonaldehyde bis(dimethyl acetal) and 100 ml of glacial acetic acid was heated at reflux for 8 hours. The solvent was evaporated and the solid was worked up as described in Example 50 to give 4.92 g of 2-furanylpyrazolo[1,5-a]pyrimidin-3-yl-methanone, mp 222°-224° C. prepared was heated at reflux for 8 hours The solvent was evaporated

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

Procedure: A mixture of 1.87 g of (3-amino-1H-pyrazol-4-yl)phenylmethanone (prepared as described in U.S. Patent application Ser. No. 612,811, filed May 24, 1984), 1.64 g of malonaldehyde bis(dimethyl acetal) and 25 ml of glacial acetic acid was heated at reflux for 6 hours. The solvent was evaporated and the solid was worked up as described in Example 50 and gave 1.70 g of phenylpyrazolo[1,5-a]pyrimidin-3-yl-methanone, mp 174°-175° C. prepared was heated at reflux for 6 hours The solvent was evaporated

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

Procedure: A stirred mixture of 10.88 g of 5-amino-4-pyrazolecarboxylic acid, ethyl ester, 11.51 g of malonaldehyde bis(dimethyl acetal) and 100 ml of glacial acetic acid was heated at reflux for 16 hours, then worked up as described in Example 50 to give 7.8 g of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid, ethyl ester. was heated at reflux for 16 hours

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium nitrite (359 mg, 5.2 mmol) in water (5 ml) was added dropwise to a stirred, cooled (0° C.) suspension of 3-bromo-4-trifluoromethoxyaniline (Description 19) (1.02 g, 4 mmol) in aqueous hydrochloric acid (37%, 10 ml). The mixture was stirred at 0° C. for 30 min., then added dropwise to a stirred, cooled (-5° C.) suspension of tin (II) chloride dihydrate (4.06 g, 18 mmol) in aqueous hydrochloric acid (37%, 10 ml). The mixture was stirred at 0° C. for 30 min., then at room temperature for 30 min. The mixture was poured into cooled (0° C.) aqueous sodium hydroxide (4M, 200 ml) and extracted with ethyl acetate (3×100 ml). The combined organic fractions were washed with aqueous sodium hydroxide (4M, 2×100 ml) and brine (100 ml), dried (MgSO4) and evaporated under reduced pressure. The residue was dissolved in ethanol (10 ml), cooled in ice and ethanolic hydrogen chloride (5M, 0.76 ml, 3.8 mmol) was added. The solvent was evaporated under reduced pressure, ethanol (50 ml) and malonaldehyde bis(dimethyl acetal) (0.63 ml, 0.62 g, 3.8 mmol) were added. The mixture was heated under reflux for 30 min., cooled and the solvent was evaporated under reduced pressure. Saturated aqueous sodium hydrogen carbonate (50 ml) and water (20 ml) were added and the mixture was extracted with ethyl acetate (3×50 ml). The combined organic fractions were washed with brine (50 ml), dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (92:8) to give the title compound as a yellow oil (801 mg, 65%). 1H NMR (360 MHz, CDCl3) δ 8.04 (1H, d, J=2.6 Hz), 7.90 (1H, d, J=2.4 Hz), 7.74 (1H, d, J=1.8 Hz), 7.68 (1H, dd, J=8.9, 2.6 Hz), 7.39 (1H, d, J=8.9 Hz), and 6.50 (1H, dd, J=2-4, 1.8 Hz). m/z (ES+) 307, 309 (M+1). cooled added dropwise to a stirred cooled The mixture was stirred at 0° C. for 30 min. at room temperature for 30 min The mixture was poured extracted with ethyl acetate (3×100 ml) The combined organic fractions were washed with aqueous sodium hydroxide (4M, 2×100 ml) and brine (100 ml) dried (MgSO4) evaporated under reduced pressure The residue was dissolved in ethanol (10 ml) cooled in ice were added The mixture was heated under reflux for 30 min. cooled the solvent was evaporated under reduced pressure Saturated aqueous sodium hydrogen carbonate (50 ml) and water (20 ml) were added the mixture was extracted with ethyl acetate (3×50 ml) The combined organic fractions were washed with brine (50 ml) dried (MgSO4) evaporated under reduced pressure The residue was purified by flash column chromatography on silica gel eluting with hexane/EtOAc (92:8)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium nitrite (359 mg, 5.2 mmol) in water (5 ml) was added dropwise to a stirred, cooled (0° C.) suspension of 3-bromo-4-trifluoromethoxyaniline (Description 19) (1.02 g, 4 mmol) in aqueous hydrochloric acid (37%, 10 ml). The mixture was stirred at 0° C. for 30 min., then added dropwise to a stirred, cooled (-5° C.) suspension of tin (II) chloride dihydrate (4.06 g, 18 mmol) in aqueous hydrochloric acid (37%, 10 ml). The mixture was stirred at 0° C. for 30 min., then at room temperature for 30 min. The mixture was poured into cooled (0° C.) aqueous sodium hydroxide (4M, 200 ml) and extracted with ethyl acetate (3×100 ml). The combined organic fractions were washed with aqueous sodium hydroxide (4M, 2×100 ml) and brine (100 ml), dried (MgSO4) and evaporated under reduced pressure. The residue was dissolved in ethanol (10 ml), cooled in ice and ethanolic hydrogen chloride (5M, 0.76 ml, 3.8 mmol) was added. The solvent was evaporated under reduced pressure, ethanol (50 ml) and malonaldehyde bis(dimethyl acetal) (0.63 ml, 0.62 g, 3.8 mmol) were added. The mixture was heated under reflux for 30 min., cooled and the solvent was evaporated under reduced pressure. Saturated aqueous sodium hydrogen carbonate (50 ml) and water (20 ml) were added and the mixture was extracted with ethyl acetate (3×50 ml). The combined organic fractions were washed with brine (50 ml), dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (92:8) to give the title compound as a yellow oil (801 mg, 65%). 1H NMR (360 MHz, CDCl3) δ 8.04 (1H, d, J=2.6 Hz), 7.90 (1H, d, J=2.4 Hz), 7.74 (1H, d, J=1.8 Hz), 7.68 (1H, dd, J=8.9, 2.6 Hz), 7.39 (1H, d, J=8.9 Hz), and 6.50 (1H, dd, J=2-4, 1.8 Hz). m/z (ES+) 307, 309 (M+1). cooled added dropwise to a stirred cooled The mixture was stirred at 0° C. for 30 min. at room temperature for 30 min The mixture was poured extracted with ethyl acetate (3×100 ml) The combined organic fractions were washed with aqueous sodium hydroxide (4M, 2×100 ml) and brine (100 ml) dried (MgSO4) evaporated under reduced pressure The residue was dissolved in ethanol (10 ml) cooled in ice were added The mixture was heated under reflux for 30 min. cooled the solvent was evaporated under reduced pressure Saturated aqueous sodium hydrogen carbonate (50 ml) and water (20 ml) were added the mixture was extracted with ethyl acetate (3×50 ml) The combined organic fractions were washed with brine (50 ml) dried (MgSO4) evaporated under reduced pressure The residue was purified by flash column chromatography on silica gel eluting with hexane/EtOAc (92:8)

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

Procedure: A mixture of 1,1,3,3-tetramethoxy-propane (13.6 g, 83 mmol) and 1-cyclopentylhydrazine-2-carboxylic acid tert-butyl ester from Ex B18 (16.6 g, 83 mmol) in water (150 mL) was treated with conc HCl (21 mL, 252 mmol) and the resulting mixture was heated at reflux overnight. The reaction mixture was allowed to cool to RT and was extracted with ether. The extracts were washed with brine, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated in vacuo to give 1-cyclopentyl-1H-pyrazole (8.0 g, 71% yield). 1H NMR (400 MHz, CDCl3): δ 7.52 (s, 1 H), 7.43 (s, 1 H), 6.24 (s, 1 H), 4.68 (m, 1 H), 2.20-1.71 (m, 8 H); MS (ESI) m/z: 137.1 [M+H+] the resulting mixture was heated at reflux overnight was extracted with ether The extracts were washed with brine dried over anhydrous MgSO4 filtered The filtrate was concentrated in vacuo

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

Procedure: A mixture of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-hydrazino-4-trifluoromethylsulphonylpyrazole (1.6 g), 1,1,3,3-tetramethoxypropane (0.58 g), ethanol (10 ml) and concentrated hydrochloric acid (1 ml) was heated under reflux for 4 hours. After evaporation in vacuo the residue was dissolved in dichloromethane (200 ml) and washed in turn with sodium bicarbonate solution (2×50 ml) and with water (50 ml). Filtration (phase separating paper), followed by evaporation gave a red solid, which was purified by chromatography on silica, eluting with dichloromethane/hexane (1:1). The product was recrystallised from toluene giving 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-pyrazol-1-yl-4-trifluoromethylsulphonylpyrazole (0.6 g) as a white solid, m.p. 191°-193° C. was heated under reflux for 4 hours After evaporation in vacuo the residue was dissolved in dichloromethane (200 ml) washed in turn with sodium bicarbonate solution (2×50 ml) and with water (50 ml) Filtration (phase separating paper) followed by evaporation gave a red solid, which was purified by chromatography on silica eluting with dichloromethane/hexane (1:1) The product was recrystallised from toluene

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

Procedure: A mixture of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-hydrazino-4-trifluoromethylsulphonylpyrazole (1.6 g), 1,1,3,3-tetramethoxypropane (0.58 g), ethanol (10 ml) and concentrated hydrochloric acid (1 ml) was heated under reflux for 4 hours. After evaporation in vacuo the residue was dissolved in dichloromethane (200 ml) and washed in turn with sodium bicarbonate solution (2×50 ml) and with water (50 ml). Filtration (phase separating paper), followed by evaporation gave a red solid, which was purified by chromatography on silica, eluting with dichloromethane/hexane (1:1). The product was recrystallised from toluene giving 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-pyrazol-1-yl-4-trifluoromethylsulphonylpyrazole (0.6 g) as a white solid, m.p. 191°-193° C. was heated under reflux for 4 hours After evaporation in vacuo the residue was dissolved in dichloromethane (200 ml) washed in turn with sodium bicarbonate solution (2×50 ml) and with water (50 ml) Filtration (phase separating paper) followed by evaporation gave a red solid, which was purified by chromatography on silica eluting with dichloromethane/hexane (1:1) The product was recrystallised from toluene

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

Procedure: C45H41F6 PS2, FW=790.90 g/mol. Aniline (2.86 g, 30.0 mmol) and 1,1,3,3-tetramethoxypropane (1.99 g, 12.1) were dissolved in acetic acid (10 mL) and heated to 80 C for 15 minutes. The solution was removed from the heat and a 60% solution of hexafluorophosphoric acid (2 mL) was slowly added. The reaction mixture was then poured into water (200 mL) and the anilinium hexafluorophosphate salt of 1,1,3,3-tetramethoxypropane, a yellow solid, was collected. Sodium acetate (0.023 g, 0.24 mmol), anilinium salt (0.044 g, 0.12 mmol), and 2-(4-Isopropylphenyl)-6-(phenyl)-4-methylthiopyrylium hexafluorophosphate (0.108 g, 0.24 mmol) are combined in a flask containing acetic anhydride (0.6 mL) and acetic acid (0.6 mL). The reaction is heated to 95 C for 8 minutes. Once the reaction is complete, the reaction mixture is poured into water and the brown precipitate is filtered off. The precipitate is dissolved in acetonitrile and crystallized out with ether. The resulting red crystals are collected in 63% yield. Melting point 165-167° C.; 1H NMR (500 MHz, CD3CN, ppm) d 7.65 (t, 2H, J=19.4 Hz), 7.34 (d, 4H, J=7.33 Hz), 7.25 (s, 10H), 7.22 (d, 4H, J=6.6 Hz), 7.09 (d, 2H, J=7.7 Hz), 6.42 (t, 1H, J=12.1 Hz), 6.23 (d, 2H, J=13.6 Hz), 2.82 (m, 2H), 1.16 (d, 12H, 7.0 Hz); UV(DCM): max 893 nm (log e 312,000±17,000 M−1 cm−1). heated to 80 C for 15 minutes The solution was removed from the heat a 60% solution of hexafluorophosphoric acid (2 mL) was slowly added The reaction mixture was then poured into water (200 mL) the anilinium hexafluorophosphate salt of 1,1,3,3-tetramethoxypropane, a yellow solid, was collected The reaction is heated to 95 C for 8 minutes the brown precipitate is filtered off The precipitate is dissolved in acetonitrile crystallized out with ether The resulting red crystals are collected in 63% yield

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5-Bromo-2-nitrobenzaldehyde (6.03 g, 26.2 mmol) was dissolved in MeOH (200 mL) and treated with 5N HCl (10 mL). The mixture was heated to 70° C. and iron powder (7.32 g, 131 mmol) was added in five portions every 5 min. The reaction was monitored by TLC, and upon completion, the reaction was cooled, DCM (200 mL) added and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to about 150 mL. To this material, a solution of 1,1,3,3-tetramethoxypropane (9.52 ml, 57.7 mmol) in 5N HCl (10 mL) pre-mixed for 45 min was added. The reaction mixture was stirred at 80° C. for 60 min. Toluene (100 mL) and HOAc (40 mL) were added and the solution was heated to 110° C. for 3 h, then cooled and evaporated to dryness under reduced pressure. The crude material was purified using silica chromatography (20-60% ethyl acetate in hexane gradient) to provide 6-bromoquinoline-3-carbaldehyde. Step 2 6-Bromoquinoline-3-carbaldehyde (2.8 g, 12.0 mmol) and methyl(triphenylphosphoranylidene)acetate (4.0 g, 12.0 mmol) were dissolved in dry THF (50 mL) and heated to 50° C. After 40 min the solution was evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to 60% EtOAc in hexane gradient) gave methyl 3-(6-bromoquinolin-3-yl)acrylate as a mixture of E and Z isomers. Step 3 Methyl 3-(6-bromoquinolin-3-yl)acrylate (0.91 g, 3.1 mmol) 2-methylphenyl boronic acid (0.61 g), potassium acetate (1.0 g) and bis(4-(di-tert-butylphosphino)-N,N-dimethylbenzenamine)dichloropalladium (II) (0.19 g) were suspended in ethanol (70 mL) and water (5 mL) and heated to reflux for 90 min. LC/MS showed the bromoquinoline had been consumed the reaction was evaporated to dryness under reduced pressure. The crude was partitioned between EtOAc and water. The organic layer was dried with magnesium sulfate, evaporated to dryness under reduced pressure and purified using silica chromatography (hexane to EtOAc gradient) to give methyl 3-(6-o-tolylquinolin-3-yl)acrylate. Step 4 LiOH monohydrate (0.42 g) (solution in water, 10 mL) was added to a solution of methyl 3-(6-o-tolylquinolin-3-yl)acrylate (0.32 g, 1.05 mmol) in MeOH (50 mL) and heated to 50° C. The reaction was monitored by TLC and once the ester had been consumed, 5N HCl (2 mL) was added and the mixture was concentrated to dryness under reduced pressure. The crude acid was dried under high vacuum then dissolved in thionyl chloride (30 mL) and heated to 80° C. for 1 h. The solution was evaporated to dryness under reduced pressure and the crude acid chloride dissolved in DCM (50 mL). A solution of N-methylcyclohexylamine (660 uL) and DIEA (850 uL) in DCM (10 mL) was added slowly and the mixture stirred for 15 min. Additional DCM (50 mL) and water (80 mL) were added and the phases were separated. The organic layer was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to EtOAc gradient) gave the desired amide. This material was dissolved in MeOH (50 mL) and treated with 10 wt % palladium on carbon (0.12 g). The mixture was hydrogenated at 50 psi for 30 min until the reduction was complete by LC/MS. The mixture was filtered through a pad of celite and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to EtOAc gradient) provided N-cyclohexyl-N-methyl-3-(6-o-tolylquinolin-3-yl)propanamide. Step 5 N-Cyclohexyl-N-methyl-3-(6-o-tolylquinolin-3-yl)propanamide (0.13 g) and m-chloroperbenzoic acid (0.11 g) were dissolved in chloroform and heated to reflux for 10 min. DCM (30 mL) and 1N NaOH (70 mL) were added and the phases mixed and separated. The organic layer was dried with magnesium sulfate and evaporated to dryness under reduced pressure. The crude N-oxide was dissolved in a mixture of trifluoromethylbenzene (20 mL) and tert-butylamine (0.20 mL), then p-toluenesulfonic anhydride (0.15 g) was added. The mixture was stirred until LC/MS analysis showed the desired amine had formed. Water (100 mL), 5N NaOH (30 mL), and DCM (70 mL) were added and the phases were separated. The organic layer was dried with magnesium sulfate before evaporating to dryness. Purification using silica chromatography (hexane to EtOAc gradient) gave the 2-(tert-butylamino)-quinoline. This material was dissolved in TFA (30 mL) and heated to reflux. After the deprotection was complete by LC/MS, the solution was evaporated to dryness under reduced pressure and the crude material was basified using saturated sodium bicarbonate and DCM. Silica purification (0-10% MeOH in DCM gradient) gave 3-(2-amino-6-o-tolylquinolin-3-yl)-N-cyclohexyl-N-methylpropanamide. MS (ESI, pos. ion) m/z: 402 (M+1). upon completion, the reaction was cooled filtered through a pad of celite The filtrate was concentrated under reduced pressure to about 150 mL was added the solution was heated to 110° C. for 3 h cooled evaporated to dryness under reduced pressure The crude material was purified