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N2-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)spiro[3.3]heptane-2,6-diamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
In 1,2-dimethoxyethane; dichloromethane; at 85℃; for 16h;Sealed tube;
N2-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)spiro[3.3]heptane-2,6-diamineA 20 mL scintillation vial was charged with 3-(2,5-dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole (170 mg, 0.42 mmol) and <strong>[1239589-52-6]tert-butyl (6-aminospiro[3.3]heptan-2-yl)carbamate</strong> (113 mg, 0.5 mmol). Reagents were suspended in a mixture of DME (3.4 mL) and DCM (0.8 mL). The vial was sealed and heated to 85 C for 16 h. Upon completion (with concomitant Boc deprotection) the reaction was cooled and concentrated. The residue was purified by Si02chromatography (MeOH/DCM gradient 0-15%) to afford the title compound (71.5 mg, 0.145 mmol, 35%) as a white solid.
2,4,6-trichlorophenyl-1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate[ No CAS ]
tert-butyl (6-(1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxamido)spiro[3.3]heptan-2-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With dmap; triethylamine; In tetrahydrofuran; at 45℃; for 3h;Inert atmosphere;
2,4,6-Trichlorophenyl 1-benzyl-5-(methylcarbamoyl)-6-oxo- 1,6-dihyd ropyrid ine-3- carboxylate (80 mg, 0.172 mmol), N,N-dimethylpyridin-4-amine (5 mg, 0.041 mmol), ter1butyl (6-aminospiro[3.3]heptan-2-yl)carbamate (78 mg, 0.344 mmol), triethylamine (0.08 mL, 0.574 mmol) and THF (1 mL) were stirred at 45 C under N2 for 3 h. The reaction mixture was concentrated to give 200 mg of an off white solid which was purified by chromatography on 5i02 (Biotage SNAP 10 g cartridge, eluting with O-6O% (2S% EtOH in EtOAc)/cyclohexane). The desired fractions were concentrated to give ter1butyl (6-( 1-benzyl-5-(methylcarbamoyl)-6-oxo- 1,6-d ihydropyridine-3-carboxamido)spiro[3.3]heptan-2-yl)carbamate (86 mg, 0.148 mmol, 86 % yield) as a colourless oil. LCMS (2 mm Formic): Rt= 1.09 mi [MH] = 495.
1-(3-methoxybenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid[ No CAS ]
N5-(6-aminospiro[3.3]heptan-2-yl)-1-(3-methoxybenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
24.8%
General procedure: To a stock solution of 1-(3-methoxybenzyl)-5-(methylcarbamoyl)-6-oxo- 1,6-dihyd ropyrid me3-carboxylic acid (316 mg, 1 mmol) and HATU (380 mg) in DMF (5 mL) was added DIPEA (520 pL).The mixture was shaken and sonicated to aid dispersion. The mixture was aliquoted (0.55 mL) to a set of preweighed amines (as shown in the table below). These were capped and shaken and left to stand at rt for 18 h. The samples were purified by MDAP (High pH). The solvent was dried under a stream of nitrogen to give the required products. Example 93 was dissolved in DCM (0.5 mL) and treated with TFA (0.5 mL) and the solution left to stand in a capped vial at rt for 2 h. The reactionmixture was evaporated and the residue dissolved in MeOH (0.5 mL). The solution was applied to a MeOH-preconditioned 100 mg SCX-2 cartridge which were then washed with MeOH (1 mL) followed by 2M ammonia in MeOH solution (1 mL). The basic washes were evaporated to dryness to give the final deprotected compound as the free base (as shown in the table below).
1-(2-fluoro-3-methylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid[ No CAS ]
1-(2-fluoro-3-methylbenzyl)-N5-(3-fluorocyclobutyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
General procedure: To a stock solution of 1-(2-fluoro-3-methylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6- dihydropyridine-3-carboxylic acid (350 mg, 1.1 mmol) dissolved in DMF (5.5 mL) was added HATU (502 mg, 2.13 mmol) and DIPEA (570 pL, 3.3 mmol). The mixture was sonicated to aid dispersion and further DMF (5.5 mL) was added. An aliquot (1.0 mL) of this mixture was added to the appropriate amine (0.12 mmol) in DMF (0.3 mL) in a vial which was subsequently sealed, sonicatedand left to stand at rt for 3 h. The samples were reduced to 1 mL, then injected as is and purified by MDAP (High pH). The solvent was removed using a plate dryer to give the required products as shown in the table.DCM (0.5 mL) and TFA (0.5 mL) were added to the product derived from the amine monomer used to prepare example 130 and the vial was capped and left to stand at rt for 2 h. Thesolvent was removed using a plate dryer. The residue was redissolved in MeOH (0.5 mL) and applied to the top of a SCX-2 SPE cartridge (1 g, preconditioned with MeOH (1 mL)). The cartridge was eluted with further MeOH (1 mL) followed by 2M NH3/MeOH (1 mL). The solvent was evaporated from the sample under a stream of nitrogen. The residue was dissolved in DCM (1 mL)and applied to a aminopropyl cartridge (100 mg), (preconditioned with CHCI3), and this was eluted with further CHCI3 (1 mL) and concentrated to provide the desired example 130
1-(3-(2-hydroxyethoxy)benzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid[ No CAS ]
N5-(6-aminospiro[3.3]heptan-2-yl)-1-(3-(2-hydroxyethoxy)benzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
13.1%
General procedure: To a stock solution of 1-(3-(2-hydroxyethoxy)benzyl)-5-(methylcarbamoyl)-6-oxo-1,6- dihydropyridine-3-carboxylic acid (337 mg, 0.97 mmol) and HATU (374 mg) in DMF (5.5 mL) was added DIPEA (550 pL). The solution was shaken and sonicated to aid dispersion and aliquoted (0.55 mL) to a set of preweighed amines (as shown in table below). Additional DIPEA (55 pL) was added to example 107 reaction mixture to compensate for HCI salt of the amine monomer. After 18 h at rt,the samples were injected as is and purified by MDAP (High pH). The solvent was dried under a stream of nitrogen to give the required products. Example 111 was dissolved in DCM (0.5 mL) and treated with TFA (0.5 mL) and the solution left to stand in a capped vial at rt for 2 h. The reaction mixture was evaporated and example 111 was dissolved in MeOH (0.5 mL). The solution wasapplied to a MeOH-preconditioned 100 mg SCX-2 cartridge which was then washed with MeOH (1 mL) followed by 2 M ammonia in MeOH solution (1 mL). The basic washes were evaporated to dryness to give the final deprotected compound as the free base (as shown in table below). Example 111 was re-purified by MDAP (High pH). The solvent was dried under a stream of nitrogen to give the required product.
1-(3-methylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid[ No CAS ]
N5-(6-aminospiro[3.3]heptan-2-yl)-N3-methyl-1-(3-methylbenzyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 1h;Sealed tube; Sonication;
General procedure: To a stock solution of 1-(3-methylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-d ihydropyrid ine-3- carboxylic acid (300 mg, 1.0 mmol) and HATU (380 mg, 1.0 mmol) dissolved in DMF (5 mL) was added DIPEA (520 pL, 3.0 mmol). The mixture was shaken and sonicated to aid dispersion. Analiquot (0.5 mL) of this mixture was added to the appropriate amine (0.12 mmol) in a vial which was subsequently sealed. NOTE: to the reaction containing the monomer amine used to prepare example 72 was added additional DIPEA (50 pL, 0.286 mmol). Each vial was shaken before being allowed to stand at rt for 18 h. NOTE: to the reaction containing monomer amine used to prepare example 71 was added further HATU (0.038 g, 0.100 mmol) and DIPEA (0.052 mL, 0.300 mmol)before this mixture was left to stand at room temp for 1 h. The samples were injected as is and purified by MDAP (High pH). The solvent was dried under a stream of nitrogen in the plate blowdown apparatus to give the required products. The product derived from the monomer amine used to prepare example 69 was determined to still have impurities present and so was repurified by being dissolved in MeOH:DMSO (1 mL, 1:1) and purified by MDAP (High pH). The solvent wasevaporated under a stream of nitrogen to give the required product. The product derived from the amine monomer used to prepare example 71 was dissolved in DCM (0.5 mL), TFA (0.5 mL) was added and the vial was capped and sonicated to aid dispersion. The mixture was left to stand at rt for 2 h and then the solvent was removed. The residue was redissolved in MeOH (0.5 mL) and applied to the top of a SCX-2 SPE cartridge (100 mg, preconditioned with MeOH (1 mL)). Thecartridge was eluted with further MeOH (1 mL) followed by 2M NH3/MeOH (1 mL). The solvent was dried under a stream of nitrogen in the plate blowdown apparatus to give the required products as shown in the table below.
With hydrogenchloride; In 1,4-dioxane; at 20℃; for 4h;
(6-Amino-spiro[3.3]hept-2-yl)-carbamic acid tert-butyl ester 12 (100 mg, 0.442 mmol) was added to 4N HCl in dioxane (4 mL) and the resulting mixture was stirred at rt for 4 hrs. The resulting suspension was carefully filtered and washed with Et2O to afford 13 (50 mg, 57%) as the dihydrochloride salt and having the appearance of a white solid. 1H NMR (400 MHz, CDC13) delta 8.27 (s, 6H), 3.50-3.54 (m, 2H), 2.33-2.39 (m, 2H), 2.14-2.22 (m, 6H).
5-bromo-4-fluoro-1-methylpyridin-2(1H)-one[ No CAS ]
[ 1239589-52-6 ]
tert-butyl (6-((5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)amino)spiro[3.3]heptan-2-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With caesium carbonate; In dimethyl sulfoxide; at 50℃;
A mixture of Example 1c (0.015 g, 0.073 mmol) and tert-butyl (6-aminospiro [3.3] heptan-2-yl) carbamate (0.02 g, 0.087 mmol) in dimethyl sulfoxide (0.4 mL) was treated with cesium carbonate (0.047 g, 0.146 mmol) and heated at 50 C overnight. The reaction mixture was partitioned between ethyl acetate and water, and washed with saturated aqueous sodium chloride. The aqueous layers were combined and extracted with ethyl acetate (2 x 10 mL) . The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0 to 70of a 3: 1 mixture of ethyl acetate/ethanol in heptanes) to provide 0.0237 g (79% yield) of the title compound.
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