2,8-DIAZA-SPIRO[4.5]DECANE-2-CARBOXYLIC ACID TERT-BUTYL ESTER

Wihte powder

Preparation of compound 6Compound 5 (30 g, 0.08 mol) in MeOH (100 mL) was hydrogenated at the exist of 20percent Pd(OH)Tert-Butyl-8-benzyl-2, 8-diazaspiro[4.5]decane-2-carboxylate (10.0 g, 30.3 mmol) is dissolved in EtOH (100 ml). Palladium hydroxide (1.0 g, 20% on carbon powder, moisture ca. 60%) is added and the mixture is stirred at rt under hydrogen (50 psi) overnight. The reaction mixture is filtered through Celite and the filtrate is concentrated in vacuo to afford the title compound. LC-MS (Method 1): 241.3.To a solution of 8the product of EXAMPLE ZD (7. 95 G, 24.0 mol) and Pd (OH) 2 (2.4 g) in 200 mi of flusk, EtOH (96 ML) and acetic acid (1. 2 ml) are added at ambient temperature. The reaction mixture was stirred under H2 at room temperature for 15 h. The catalysts were removed by filtration and EtOH was evaporated down to to provide the title compound; Rf= 0.05 (ethyl acetate only).8-Benzyl-2, 8-diaza-spiro[4.5]decane-2-carboxylic acid tert-buty ester (5 r'moi) is dissolved in a mixture of 20 mL EtOH and 2 mL acetic acid. Palladium hydroxide (1 g, 20 wt. % on carbon) is added and the reaction mixture hydrogenated on a Paar apparatus at 50 0C and 50 psi for 22 h. The reaction mixture is filtered through Celite and concentrated in vacuo to afford the title compound.General procedure: To a stirred solution of 6-(2-fluoroethyl)-2, 6-diazaspiro[3.4]octane (Intermediate X11) (0.107 g, 0.640 mmol) and Et3N (0.089 mL, 0.640 mmol) in DCM (2 mL) was added 5-((1, 2, 3, 5, 6, 7-hexahydro-s-indacen-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)- methyl)-1H-1, 2, 4-triazole-3-sulfonyl chloride (Intermediate B4) (0.205 g, 0.438 mmol) in DCM (4 mL). The reaction was stirred at RT for 90 min then concentrated in vacuo. The residue was redissolved in 4 M HCl in dioxane (3 mL) and stirred for 16 h. The reaction mixture was concentrated in vacuo and the crude product was purified by acidic prep HPLC (20-50% MeOH in water) to afford the title compound (23 mg, 11%) as a white solid.LCMS m/z 461.1 (M+H)+(ES+).1H NMR (DMSO-d6) d 13.25 (s, 1H), 9.01 (s, 1H), 6.98 (s, 1H), 4.50 (dt, J = 47.4, 4.8 Hz, 2H), 3.95 - 3.82 (m, 4H), 2.87 - 2.77 (m, 5H), 2.76 - 2.72 (m, 1H), 2.71 - 2.59 (m, 8H), 1.98 (p, J = 7.4 Hz, 4H), 1.88 (t, J = 7.1 Hz, 2H).Step 1: tert-butyl 8-(2-ethyl-7-methyl-3-nitropyrazolo[1, 5-a]pyridin-5-yl)-2, 8-diazaspiro[4.5]decane-2-carboxylate (37a) Intermediate 2 (0.7 g, 2.0 mmol), Pd2(dba)3 (0.2 g, 0.2 mmol), X-PHOS (0.2 g, 0.5 mmol), and Cs2CO3 (2.0 g, 7.0 mmol) were added to a screw capped test tube. The tube was evacuated and back filled with argon. 2-((2-ethyl-5-(2-(3-hydroxyazetidine-1-carbonyl)-2, 8-diazaspiro[4.5]decan-8-yl)pyrazolo[1, 5-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile (Compound 18) Starting from Intermediate 1 (100 mg, 0.22 mmol) and proceeding in analogy to preparation Example 11, using To a 50 ml round bottom flask was added fe/ -butyl 2, 8-diazaspiro[4.5]decane-2-carboxylate (320 mg, 1 .41 mmol), 2-(1 , 3-dioxoisoindolin-2-yl)acetaldehyde (321 mg, 1 .70 mmol), MeOH (15 ml) and AcOH (20 drops) at 15C and the RM was stirred at 15C for 1 h. Solid NaBH3CN (133 mg, 2.12 mmol) was added and the RM was stirred at 15C for 6 h. The RM was concentrated, redissolved in a mixture of EtOAc and an aq. solution of NaHC03(10%) and the phases were separated. The aq. phase was extracted with EtOAc, the combined organic phases were washed with water, concentrated and directly used for the next step without further purification. The title compound was obtained as a solid (520 mg).Method F: Rt = 1 .44 min; MS m/z [M+H]+414.

Molecular Weight:240.34
XLogP3:1.4
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:240.183778013
Monoisotopic Mass:240.183778013
Topological Polar Surface Area:41.6
Heavy Atom Count:17
Complexity:290
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes