4,7-DIAZA-SPIRO[2.5]OCTANE-7-CARBOXYLIC ACID TERT-BUTYL ESTER

In the 1L three-mouth reaction bottle, 64.9 g of 4, 7-diazaspiro[2.5]octane and 650 mL of EtOH were added in sequence.Temperature control below 30 °C, Slowly add 51g NaOH, Temperature control below 5 °C, Add 252.6g (Boc) 2O dropwise, After the addition is completed, slowly rise to room temperature. Stir the reaction at room temperature for 13 h, TLC monitors the reaction completely, filter, Desolvent, Purified by the column49.7-diazaspiro[2.5]octane-7-carboxylic acid tert-butyl ester 89.7 g, The yield was 73percent.A vial was charged with 5-amino-3, 6-dichloro-l, 2, 4-triazine (108.5 mg, 0.658 mmol), diisopropylethylamine (0.5 mL, 2.87 mmol), tert-butyl 2-(4, 7-diazaspiro[2.5]octan-7- yl)acetate (154.8 mg, 0.650 mmol) in dioxane (2.5 mL). The mixture was heated at 155 C for 9.5 h using microwave. The mixture was concentrated to remove all of solvent. The residue was dissolved in dichloromethane, washed with aqueous sodium bicarbonate solution. The organic solution was separated. The aqueous solution was mixed with brine, extracted with dichloromethane (2 x 35 mL). The combined organic solution was dried over anhydrous sulfate, concentrated to afford a residue. The residue was purified with flash column chromatography on silica using 1-10% methanol in dichloromethane to afford product (118.3 mg) in 53% yield. NMR (500 MHz, Chloroform-d) delta 5.24 (s, 2H), 3.91 (t, J = 4.5 Hz, 2H), 3.42 (m, 2H), 3.33 (s, 2H), 1.43 (s, 9H), 0.96 (m, 4H). MS for C14H21 CIN6O2: 341.2 (MH+).To a suspension of 300 mg of 3-methyl-1 -(tetrahydro-pyran-2-yl)-6-[4-(tetrahydro- pyran-2-yloxy)-phenyl]-1 H-pyrazolo[3, 4-b]pyridine-4-carboxylic acid sodium salt in 7.5 ml of DCM were added 0.12 ml of Hunig's base, 376 mg of BEP and 146 mg ofTo a solution of tert-b tyl 4, 7-diazaspiro[2.5]octane-7-carboxylate (0.16 g, 0.73 mmol) and 4-((2-fluoro-4-(methylsulfonyl)phenoxy)methyl)cyclohexanone (0.20 g, 0.67 mmol) in DCE (5 mL) at room temperature under nitrogen was added acetic acid (76.0 mu, 1.30 mmol) and sodium triacetoxyborohydride (0.35 g, 1.7 mmol). The mixture was heated at 45 °C for 3 days. The reaction formed a major side product (alcohol) from ketone starting material. The mixture was quenched with saturated NaHC03 (aq.). The organic layer was separated and the aqueous layer was extracted once with DCM. The combined organic phases were concentrated under reduced pressure and purified by preparative HPLC. The pure fractions were combined, neutralized with saturated NaHC03 (aq.), and concentrated under reduced pressure. The aqueous residue was extracted twice with DCM and the combined organic layers were dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to afford the more polar title compound as an off-white gum (7.7 mg, 2.3percent). The less polar cis analog was also obtained as an off-white gum (1.2 mg, 0.4percent). Exact mass calculated for C25H37FN2O5S: 496.2, found: LCMS m/z = 497.4 [M+H]+; lU NMR (400 MHz, CDC13) delta ppm 0.55-0.64 (m, 2H), 0.66-0.72 (m, 2H), 1.08-1.36 (m, 4H), 1.45 (s, 9H), 1.75-1.89 (m, 1H), 1.93-2.02 (m, 2H), 2.09-2.18 (m, 2H), 2.87-2.97 (m, 1H), 3.03 (s, 3H), 3.08-3.13 (m, 2H), 3.17 (s, 2H), 3.40 (bs, 2H), 3.90 (d, J = 6.32 Hz, 2H), 7.06 (t, J = 8.21 Hz, 1H), 7.62-7.66 (m, 1H), 7.66-7.70 (m, 1H).Step 2:4-(trifluoroacetyl)-4, 7-diazaspiro[2.5]octane hydrochloridePyridine (500 mul) and trifluoroacetic anhydride (786 mul, 5.64 mmol) were added to a dichloromethane (10 ml) solution of the compound (1.0 g, 4.70 mmol) obtained in Step 1 above under ice cooling and the resulting mixture was stirred for 15 minutes.After completion of the reaction, trifluoroacetic acid (6 ml) was added and the resulting mixture was stirred at room temperature for 1 hour.The reaction solvent was evaporated under reduced pressure and then the residue was subjected to azeotropic distillation with toluene.The residue was diluted with chloroform and the organic layer was washed with saturated aqueous sodium bicarbonate solution and brine and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography [chloroform:methanol = 40:1 (v/v)].The residue obtained was subjected to azeotropic distillation with 4 N hydrochloric acid/dioxane and then dried under reduced pressure to give the title compound (751 mg, 65percent) as a colorless solid.1H-NMR (400 MHz, DMSO-d6) delta: 1.15-1.21 (4H, m), 3.14-3.19 (2H, m), 3.24 (2H, t, J=5.4 Hz), 3.84-3.91 (2H, m).MS (ESI) m/z: 209 [(M+H)+].

Molecular Weight:212.29
XLogP3:0.8
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:212.152477885
Monoisotopic Mass:212.152477885
Topological Polar Surface Area:41.6
Heavy Atom Count:15
Complexity:266
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes