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Preparation of compound 4A mixture of compound 3 (1.3 g, 4.11 mmol) and Pd(OH)2 (200 mg) in 15 mL of MeOH was stirred under 55 psi of H2 at 35 0C overnight. The mixture was filtered and the filtrate was evaporated. The residue was dissolved in DCM, dried over anhydrous Na2SO4 and concentrated. The residue was dissolved in anhydrous ether, then HCl(g)/MeOH was added dropwise until pH = 6-7. The mixture was filtered to afford compound 4 (0.95 g). 1H NMR (CD4O, HCl salt) delta: 3.72 (s, 4 H), 3.30 (t, 4 H), 1.99 (t 4 H), 1.43 (9 H).
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 60℃; for 15h;Product distribution / selectivity;
Example 78; Preparation of Compound 78B; Step A; To a vial were added 4-chloro-3-nitro pyridine (2 mmol) and spirocyclic amine (2 mmol). The starting materials were dissolved in 4 ml. of dichloromethane followed by the addition of DIPEA (6 mmol). The reaction was stirred at 60° for about 15 hours, then the reaction mixture was concentrated and using preparative liquid chromatography (0-5percent methanol in ethyl acetate) to provide compound 78A. Recovered 1.6 mmol (80percent) of 274. Mass calculated for formula C17H24N4O4 348.18, observed LCMS m/z 348.20 (M+H).; Using the methods described in Steps A and B above, and using the appropriate reactants, the following intermediate compounds were made:
To a solution of <strong>[929302-18-1]2,7-diaza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester hydrochloride</strong> (100 mg, 0.381 mmol) in DCE (10 mL) was added an aqueous solution of formaldehyde (37 percent w/w, 40 muL, 0.537 mmol). The mixture was stirred at RT for 10 min, then sodium triacetoxyborohydride (121 mg, 0.571 mmol) was added and stirring was continued for 1 h. Water was added to the reaction mixture before being loaded onto an Isolute.(R). SCX-2 cartridge. The cartridge was washed with MeOH then eluted with 2 M NH3 in MeOH to give 7-methyl-2,7-diaza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester. To a solution of 7-methyl-2,7-diaza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester in DCM (5 mL) was added TFA (1 mL) and the resulting mixture was stirred at RT for 1 h. The reaction mixture was loaded onto an Isolute.(R). SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to give the title compound as a colourless oil (45 mg, 84 percent). 1H NMR (400 MHz, CDCl3): delta 1.81 (m, 4 H), 2.22 (s, 3 H), 2.28 (m, 2 H), 3.22 (bs, 4 H) and 3.38 (bs, 2 H).
To a solution of <strong>[929302-18-1]2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester hydrochloride</strong> (100 mg, 0.381 mmol) in DCE (10 mL) was added an aqueous solution of formaldehyde (37 percent w/w, 40 muL, 0.537 mmol). The mixture was stirred at RT for 10 min, then sodium triacetoxyborohydride (121 mg, 0.571 mmol) was added and stirring was continued for 1 h. The reaction mixture was added water and loaded onto an Isolute.(R). SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to give 7-methyl-2,7- diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester. To a solution of 7-methyl-2,7- <n="49"/>^diazaspiro[3.5]nonane-2-carboxylic acid fert-butyl ester in DCM (5 mL) was added TFA (1 mL) and the resulting mixture was stirred at RT for 1 h. The reaction mixture was loaded onto an Isolute.(R). SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to give the title compound as a colourless oil (45 mg, 84 percent). 1H NMR (400 MHz, CDCl3): delta 1.81 (m, 4 H), 2.22 (s, 3 H), 2.28 (m, 2 H), 3.22 (bs, 4 H) and 3.38 (bs, 2 H).
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 110℃; for 20h;
Example 23Preparation of Compound 33Step A - Synthesis of Compound 23BCompound 23A (0.274 g, 1.04 mmol) was combined with 4,6- dichloropyrimidine (0.196 g, 1.31 mmol) and DIPEA (0.45 mL, 2.6 mmol) in dioxane (6 mL) and the resulting reaction was heated to 110 °C and allowed to stir at this temperature for 20 hours. The reaction mixture was cooled to room temperature, concentrated in vacuo, and the resulting residue was purified using preparative TLC to provide Compound 23B as an off-white solid.
tert-butyl 7-((6-chloropyridin-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With potassium carbonate; In acetonitrile; at 70℃; for 16h;
A solution of 2,7-diazaspiro [3.5] nonane-2-carboxylic acid tert-butyl ester hydrochloride (400 mg, 1.5 mmol)And 2-chloro-5- (chloromethyl) pyridine(243 mg, 1.5 mmol) was dissolved in acetonitrile (50 mL), potassium carbonate (621 mg, 4.5 mmol) was added and reacted at 70 ° C for 16 hours.After cooling to room temperature, ethyl acetate (100 mL) and water (50 mL) were added, the phases were separated and the aqueous phase was extracted with ethyl acetate (150 mL x2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give The title compound was obtained as a yellow oil (480 mg, yield 90percent).
5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole-6-yl)-N-(5-((2-methyl-2,7-diazaspiro[3,5]nonane-2-yl)methyl)pyridine-2-yl)pyridine-2-amine[ No CAS ]
tert-butyl 7-(6,7-dimethoxyquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 16h;
[0513] Procedure: To a stirred solution of 4-chloro-6,7-dimethoxyquinazoline (0.2 g, 0.89 mmol) in DMF (10 mL) was added K2CO3 (0.184 g, 1.33 mmol) followed by <strong>[929302-18-1]2-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]nonan-7-ium hydrochloride</strong> (0.221 g, 0.979 mmol). Reaction mixture was stirred for 16 h at 90 °C. Progress of the reaction was monitored by TLC. Reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (2 x 50mL). The combined organic layer was washed with brine (10mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The crude residue was purified by combiflash using ethyl acetate in hexaneto afford tert-butyl 7-(6,7- dimethoxyquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (0.3g, 81percent) as an off white solid. LC-MS (ES) m/z =415.2 [M+H]+.
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