benzene-1,2-dicarboxamide

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

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

Procedure: Compound 3 (2.5 g) was treated with N-(3-bromopropyl)phthalimide (2.19 g) and diisopropylethylamine (2 ml) in DMF (10 ml). The reaction mixture was heated at 100° C. for 3 hours and then diluted with chloroform (300 ml) and extracted with water (4×300 ml). The chloroform was removed on a rotary evaporator and the residue subjected to flash chromatography using chloroform and methanol/chloroform as eluants to obtain the desired phthlamide adduct (Compound 4). Hydrazine hydrate (0.75 ml) was added to a solution of the phthalimide compound 4 (1.7 g) in 100% reagent alcohol (100 ml). The reaction mix was refluxed overnight and cooled to room temperature for about 1 hr. The reaction mix was then cooled at 4° C. overnight and the precipitate obtained by filtration. The solid was washed with ethanol chilled to −20° C. (2×20 ml) and dried in vacuo. The residue was dissolved in chloroform (300 ml), filtered and extracted twice with water (200 ml). The chloroform was removed on a rotary evaporator to give 1,4-Bis[(3-(3-aminopropyl)-oleoylamino)-2-hydroxypropyl]piperazine (Compound 5) in a quantitative yield. This material was acidified with HCL in dioxane and purified on reverse phase (C-18) flash chromatography using aqueous methanol as eluant and characterized by TLC and mass spectrometry. extracted with water (4×300 ml) The chloroform was removed on a rotary evaporator

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

Procedure: To a solution of the product of example 35 (85 mg, 0.45 mmol) in DMF (1 mL), under a nitrogen atmosphere, was added potassium salt of phthalamide (96 mg, 0.52 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with a mixture of ice-water and filtered. The slightly pink solid was washed with water to give the titled compound as a white product (79 mg, 62% yield). The reaction mixture was quenched with a mixture of ice-water filtered The slightly pink solid was washed with water

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

Procedure: To a solution of the product of example 35 (85 mg, 0.45 mmol) in DMF (1 mL), under a nitrogen atmosphere, was added potassium salt of phthalamide (96 mg, 0.52 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with a mixture of ice-water and filtered. The slightly pink solid was washed with water to give the titled compound as a white product (79 mg, 62% yield). The reaction mixture was quenched with a mixture of ice-water filtered The slightly pink solid was washed with water

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

Procedure: A mixture of 2-((4-fluoro-1-(2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-ylamino)furo[3,2-d]pyrimidin-4-yl)piperidin-4-yl)methyl)isoindoline-1,3-dione (0.510 g, 0.795 mmol, prepared using W from Preparation #X.1, V, U with phthalamide, G, A with 2,4-dichlorofuro[3,2-d]pyrimidine [ArkPharm] and B with 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-amine [WO 2010/027500 Intermediate 21, Step C]) in MeOH (20 mL) was treated with hydrazine hydrate (0.190 mL, 2.50 mmol). The mixture was heated at about 70° C. for about 3 h. The mixture was cooled to rt and concentrated in vacuo. The residue was dissolved in DCM/MeOH (10:1) (30 mL) and stirred for about 30 min. The resulting suspension was filtered and the filtrate was concentrated in vacuo to give 4-(4-(aminomethyl)-4-fluoropiperidin-1-yl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)furo[3,2-d]pyrimidin-2-amine (0.41 g, 100%). LC/MS (Table 2, Method i) Rt=1.60 min; MS m/z 512 (M+H)+. prepared The mixture was cooled to rt concentrated in vacuo The residue was dissolved in DCM/MeOH (10:1) (30 mL) The resulting suspension was filtered the filtrate was concentrated in vacuo

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5-methyl-4H-3,1-benzoxazin-2,4-dione (Preparation VIIA) (19.7 g, 111 mmol) in methanesulfonic acid (150 mL) was added N-(hydroxymethyl)phthalimide (20.3 g, 111 mmol). The reaction mixture was heated to 50° C. and stirred for 3 hours. After cooling to room temperature, the reaction mixture was diluted with 2000 mL of Et2O. After stirring for an additional 1 hour, the precipitate was filtered, washed with Et2O and dried affording 30.7 g of crude phthalamide. 1H NMR showed a 3:2 mixture of the 6- and 8-substituted regioisomers respectively. The crude material was used directly in the next reaction where the two regeoisomers were separated. After cooling to room temperature After stirring for an additional 1 hour the precipitate was filtered washed with Et2O dried

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

Procedure: Compound 3 (2.5 g) was treated with N-(3-bromopropyl)phthalimide (2.19 g) and diisopropylethylamine (2 ml) in DMF (10 ml). The reaction mixture was heated at 100° C. for 3 hours and then diluted with chloroform (300 ml) and extracted with water (4×300 ml). The chloroform was removed on a rotary evaporator and the residue subjected to flash chromatography using chloroform and methanol/chloroform as eluants to obtain the desired phthlamide adduct (Compound 4). Hydrazine hydrate (0.75 ml) was added to a solution of the phthalimide compound 4 (1.7 g) in 100% reagent alcohol (100 ml). The reaction mix was refluxed overnight and cooled to room temperature for about 1 hr. The reaction mix was then cooled at 4° C. overnight and the precipitate obtained by filtration. The solid was washed with ethanol chilled to −20° C. (2×20 ml) and dried in vacuo. The residue was dissolved in chloroform (300 ml), filtered and extracted twice with water (200 ml). The chloroform was removed on a rotary evaporator to give 1,4-Bis[(3-(3-aminopropyl)-oleoylamino)-2-hydroxypropyl]piperazine (Compound 5) in a quantitative yield. This material was acidified with HCL in dioxane and purified on reverse phase (C-18) flash chromatography using aqueous methanol as eluant and characterized by TLC and mass spectrometry. extracted with water (4×300 ml) The chloroform was removed on a rotary evaporator

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

Procedure: Compound 3 (2.5 g) was treated with N-(3-bromopropyl)phthalimide (2.19 g) and diisopropylethylamine (2 ml) in DMF (10 ml). The reaction mixture was heated at 100° C. for 3 hours and then diluted with chloroform (300 ml) and extracted with water (4×300 ml). The chloroform was removed on a rotary evaporator and the residue subjected to flash chromatography using chloroform and methanol/chloroform as eluants to obtain the desired phthlamide adduct (Compound 4). Hydrazine hydrate (0.75 ml) was added to a solution of the phthalimide compound 4 (1.7 g) in 100% reagent alcohol (100 ml). The reaction mix was refluxed overnight and cooled to room temperature for about 1 hr. The reaction mix was then cooled at 4° C. overnight and the precipitate obtained by filtration. The solid was washed with ethanol chilled to −20° C. (2×20 ml) and dried in vacuo. The residue was dissolved in chloroform (300 ml), filtered and extracted twice with water (200 ml). The chloroform was removed on a rotary evaporator to give 1,4-Bis[(3-(3-aminopropyl)-oleoylamino)-2-hydroxypropyl]piperazine (Compound 5) in a quantitative yield. This material was acidified with HCL in dioxane and purified on reverse phase (C-18) flash chromatography using aqueous methanol as eluant and characterized by TLC and mass spectrometry. extracted with water (4×300 ml) The chloroform was removed on a rotary evaporator

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

Procedure: To a solution of (2-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,3-dioxan-5-yl)methanol (360 mg, 1.48 mmol, intermediate 68) in dry THF (12 mL) was added polymer supported triphenylphosphine (˜3 mmol/g, 1.5 g, 4.44 mmol) and phthalamide (326 mg, 2.22 mmol) followed by diisopropylazodicarboxylate (450 mg, 2.22 mmol). The reaction mixture was stirred at room temperature for 18 hr then heated at 35° C. for 4 hr. The reaction mixture was filtered and the filtrate diluted with DCM (50 mL) and washed with a saturated aqueous NaHCO3 (25 mL). The organic layer was washed with water (25 mL) and brine (25 mL), separated, dried over Na2SO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 2-((2-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,3-dioxan-5-yl)methyl)isoindoline-1,3-dione as a colourless solid (226 mg) contaminated with diisopropyl azodicarboxylate byproduct. To a suspension of this solid (165 mg, 0.44 mmol) in MeOH (150 mL) and THF (20 mL) was added ammonium formate (300 mg, mmol) and 10% Pd/C (300 mg). The mixture was heated at reflux for 2 hr. The mixture was quickly filtered whilst hot and the cake washed with DCM (50 mL) and EtOAC (50 mL). The filtrate was concentrated under reduced pressure and the crude residue was dissolved in IPA (5 mL) and 5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (134 mg, 0.46 mmol) and DIPEA (0.31 mL, 1.76 mmol) were then added. Propylphosphonic anhydride solution (50% wt in EtOAc, 0.33 mL, 0.48 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 16 hr. The mixture was concentrated under reduced pressure and purified via silica gel chromatography (0-5% 7 N NH3 in MeOH/DCM) to give an oil. This oil was dissolved in EtOH (1 mL), hydrazine (1 mL) was added and the mixture heated at reflux for 16 hr. The solvents were removed under reduced pressure and the residue was dissolved in MeOH and passed through an SCX column eluting with 0-5% 7 N NH3 in MeOH/DCM. Purification via preparative HPLC gave 167 as a colourless solid (4 mg, 1% over four steps). 1H NMR (400 MHz, CDCl3) δ 9.82 (s, 1H), 8.25 (s, 1H), 7.36-7.29 (m, 1H), 7.07-6.99 (m, 2H), 6.18 (s, 2H), 5.74 (s, 1H), 4.46 (dd, J=11.4, 4.5 Hz, 2H), 3.88 (s, 3H), 3.67 (t, J=11.3 Hz, 2H), 2.64 (d, J=6.7 Hz, 2H), 2.41-2.32 (m, 1H). Alkyl NH2 not observed. LCMS (ES+) m/z 451 (M+1). then heated at 35° C. for 4 hr The reaction mixture was filtered the filtrate diluted with DCM (50 mL) washed with a saturated aqueous NaHCO3 (25 mL) The organic layer was washed with water (25 mL) and brine (25 mL) separated dried over Na2SO4 concentrated under reduced pressure Purification via silica gel column chromatography (0-100% EtOAc/isohexane)

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

Procedure: Compound 3 (2.5 g) was treated with N-(3-bromopropyl)phthalimide (2.19 g) and diisopropylethylamine (2 ml) in DMF (10 ml). The reaction mixture was heated at 100° C. for 3 hours and then diluted with chloroform (300 ml) and extracted with water (4×300 ml). The chloroform was removed on a rotary evaporator and the residue subjected to flash chromatography using chloroform and methanol/chloroform as eluants to obtain the desired phthlamide adduct (Compound 4). Hydrazine hydrate (0.75 ml) was added to a solution of the phthalimide compound 4 (1.7 g) in 100% reagent alcohol (100 ml). The reaction mix was refluxed overnight and cooled to room temperature for about 1 hr. The reaction mix was then cooled at 4° C. overnight and the precipitate obtained by filtration. The solid was washed with ethanol chilled to −20° C. (2×20 ml) and dried in vacuo. The residue was dissolved in chloroform (300 ml), filtered and extracted twice with water (200 ml). The chloroform was removed on a rotary evaporator to give 1,4-Bis[(3-(3-aminopropyl)-oleoylamino)-2-hydroxypropyl]piperazine (Compound 5) in a quantitative yield. This material was acidified with HCL in dioxane and purified on reverse phase (C-18) flash chromatography using aqueous methanol as eluant and characterized by TLC and mass spectrometry. extracted with water (4×300 ml) The chloroform was removed on a rotary evaporator

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

Procedure: Compound 3 (2.5 g) was treated with N-(3-bromopropyl)phthalimide (2.19 g) and diisopropylethylamine (2 ml) in DMF (10 ml). The reaction mixture was heated at 100° C. for 3 hours and then diluted with chloroform (300 ml) and extracted with water (4×300 ml). The chloroform was removed on a rotary evaporator and the residue subjected to flash chromatography using chloroform and methanol/chloroform as eluants to obtain the desired phthlamide adduct (Compound 4). Hydrazine hydrate (0.75 ml) was added to a solution of the phthalimide compound 4 (1.7 g) in 100% reagent alcohol (100 ml). The reaction mix was refluxed overnight and cooled to room temperature for about 1 hr. The reaction mix was then cooled at 4° C. overnight and the precipitate obtained by filtration. The solid was washed with ethanol chilled to −20° C. (2×20 ml) and dried in vacuo. The residue was dissolved in chloroform (300 ml), filtered and extracted twice with water (200 ml). The chloroform was removed on a rotary evaporator to give 1,4-Bis[(3-(3-aminopropyl)-oleoylamino)-2-hydroxypropyl]piperazine (Compound 5) in a quantitative yield. This material was acidified with HCL in dioxane and purified on reverse phase (C-18) flash chromatography using aqueous methanol as eluant and characterized by TLC and mass spectrometry. extracted with water (4×300 ml) The chloroform was removed on a rotary evaporator

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

Procedure: To a stirred solution of crude 5-(3,5-dicyano-2,6-dimethyl-1,4-dihydro-pyridin-4-yl)-3-(2-hydroxy-ethylamino)-indazole-1-carboxylic acid tert-butyl ester (0.6 g), from Synthetic Example 22, in THF (14.3 mL), under Argon, was added sequentially triphenylphosphine (1.08 g, 4.13 mmol), phthalamide (0.21 g, 1.45 mmol), followed by diisopropyl azadicarboxylate (DIAD, 0.31 g, 1.52 mmol) dropwise over 30 minutes. The mixture was stirred overnight at room temperature. The mixture was quenched with saturated sodium hydrogencarbonate solution and extracted with EtOAc. The combined organic extracts were washed with brine, dried and concentrated. The residue was partially purified by chromatography on silica gel, followed by preparative reverse phase HPLC to give 5-(3,5-dicyano-2,6-dimethyl-1,4-dihydro-pyridin-4-yl)-3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethylamino]-indazole-1-carboxylic acid tert-butyl ester (131 mg) which was used directly in the next step. The mixture was quenched with saturated sodium hydrogencarbonate solution extracted with EtOAc The combined organic extracts were washed with brine dried concentrated The residue was partially purified by chromatography on silica gel