Imidazo[4,5-c]pyridine,7-bromo-(7CI,9CI)

Step 2: 7-bromo-lH-imidazo[4, 5-c]pyridine 5-oxide To a stirred solution of 7-bromo-lH-imidazo[4, 5-c]pyridine (1.0 g, 5.05 mol) and chloroform (20 mL) was added m-chloroperoxybenzoic acid (2.83 g, 12.6 mmol) and the reaction mixture stirred for 30 min at RT. The reaction mixture was filtered, washed with chloroform (10 mL), and the white solid was dried under high vacuum. The solid resulting solid was dissolved in a dichloromethane and methanol mixture, absorbed onto celite and purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% methanol in dichloromethane with 3% triethylamine) affording 7-bromo-lH- imidazo[4, 5-c]pyridine 5-oxide as a white solid (580 mg, 54%) used as is in the next step.Step 3: 7-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4, 5-c]pyridine 5-oxide To a stirred solution of 7-bromo-lH-imidazo[4, 5-c]pyridine 5-oxide (425 mg, 1.99 mmol) and N, N- dimethylformaldehyde (5.5 mL) at 0 C was added N, N-diisopropylethylamine (1.05 mL, 5.96 mmol), tetrabutylammonium iodide (74 mg, 0.199 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (0.78 mL, 3.97 mmol) and the reaction mixture stirred for 30 min at RT. The reaction mixture was washed with water (10 mL) and extracted with dichloromethane (2 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) affording an approximate 3:2 mixture of 7-bromo-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazo[4, 5-c]pyridine 5-oxide and 7-bromo-3-((2- (trimethylsilyl)ethoxy)methyl)-3H-imidazo[4, 5-c]pyridine 5-oxide N-(2- (trimethylsilyl)ethoxy)methane regioisomers as an orange foam (580 mg, 54%): H NMR (400 MHz, DMSO-d6; reported as an approximate 3:2 mixture of N-(2-(trimethylsilyl)ethoxy)methane isomers) delta 8.73 (d, = 1.5 Hz, 0.6 H), 8.60 (d, = 1.6 Hz, 1H), 8.38 (d, = 1.5 Hz, 1H), 8.36 (d, = 1.5 Hz, 0.6H), 8.10 (s, 1H), 8.09 (s, 0.6H), 5.76 (s, 1.3H), 5.48 (s, 2H), 3.63 - 3.59 (m, 1.4H), 3.56 - 3.50 (m, 2H), 0.97 - 0.91 (m, 3H), -0.01 (s, 9H), -0.02 (s, 6H). Step 4: 7-bromo-N-(tert-butyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4, 5-c]pyrid^ amine To a stirred solution of 7-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4, 5-c]pyridine 5- oxide (102 mg, 0.296 mmol) and 1 , 2-dichloroethane (1.5 niL) was added N, N-diisopropylethylamine (0.195 niL, 1.11 mmol), i-butylamine (0.039 mL, 0.37 mmol) and bromotripyrrolidinophosphonium hexafluorophosphate (180 mg, 0.385 mmol) and the reaction mixture stirred for 22 h at RT. The reaction mixture was washed with saturated sodium bicarbonate solution (10 mL) and extracted with dichlorome thane (2 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in heptane) affording an approximate 3:2 mixture of 7-bromo-N-(tert-butyl)-l-((2-(trimethy and 7-bromo-N-(tert-butyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4, 5-c]pyridin-4-amine N- SEM regioisomers (47 mg, 40%): H NMR (400 MHz, DMSO-d6; reported as an approximate 3:2 mixture of N-SEM isomers) delta 8.00 (s, 0.7H), 7.95 (s, 1H), 7.81 (s, 0.7H), 7.77 (s, 1H), 6.02 (br s, 0.8H), 5.77 (s, 2H), 5.54 (s, 1.6H), 5.43 (br s, 1H), 3.63 - 3.57 (m, 3.7H), 1.02 - 0.89 (m, 3.8H), 0.00 (s, 6H), -0.02 (s, 9H).Step 3: 7-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4, 5-c]pyridine 5-oxide To a stirred solution of 7-bromo-lH-imidazo[4, 5-c]pyridine 5-oxide (425 mg, 1.99 mmol) and N, N- dimethylformaldehyde (5.5 mL) at 0 C was added N, N-diisopropylethylamine (1.05 mL, 5.96 mmol), tetrabutylammonium iodide (74 mg, 0.199 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (0.78 mL, 3.97 mmol) and the reaction mixture stirred for 30 min at RT. The reaction mixture was washed with water (10 mL) and extracted with dichloromethane (2 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) affording an approximate 3:2 mixture of 7-bromo-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazo[4, 5-c]pyridine 5-oxide and 7-bromo-3-((2- (trimethylsilyl)ethoxy)methyl)-3H-imidazo[4, 5-c]pyridine 5-oxide N-(2- (trimethylsilyl)ethoxy)methane regioisomers as an orange foam (580 mg, 54%): H NMR (400 MHz, DMSO-d6; reported as an approximate 3:2 mixture of N-(2-(trimethylsilyl)ethoxy)methane isomers) delta 8.73 (d, = 1.5 Hz, 0.6 H), 8.60 (d, = 1.6 Hz, 1H), 8.38 (d, = 1.5 Hz, 1H), 8.36 (d, = 1.5 Hz, 0.6H), 8.10 (s, 1H), 8.09 (s, 0.6H), 5.76 (s, 1.3H), 5.48 (s, 2H), 3.63 - 3.59 (m, 1.4H), 3.56 - 3.50 (m, 2H), 0.97 - 0.91 (m, 3H), -0.01 (s, 9H), -0.02 (s, 6H).Step 3: 7-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4, 5-c]pyridine 5-oxide To a stirred solution of 7-bromo-lH-imidazo[4, 5-c]pyridine 5-oxide (425 mg, 1.99 mmol) and N, N- dimethylformaldehyde (5.5 mL) at 0 C was added N, N-diisopropylethylamine (1.05 mL, 5.96 mmol), tetrabutylammonium iodide (74 mg, 0.199 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (0.78 mL, 3.97 mmol) and the reaction mixture stirred for 30 min at RT. The reaction mixture was washed with water (10 mL) and extracted with dichloromethane (2 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) affording an approximate 3:2 mixture of 7-bromo-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazo[4, 5-c]pyridine 5-oxide and 7-bromo-3-((2- (trimethylsilyl)ethoxy)methyl)-3H-imidazo[4, 5-c]pyridine 5-oxide N-(2- (trimethylsilyl)ethoxy)methane regioisomers as an orange foam (580 mg, 54%): H NMR (400 MHz, DMSO-d6; reported as an approximate 3:2 mixture of N-(2-(trimethylsilyl)ethoxy)methane isomers) delta 8.73 (d, = 1.5 Hz, 0.6 H), 8.60 (d, = 1.6 Hz, 1H), 8.38 (d, = 1.5 Hz, 1H), 8.36 (d, = 1.5 Hz, 0.6H), 8.10 (s, 1H), 8.09 (s, 0.6H), 5.76 (s, 1.3H), 5.48 (s, 2H), 3.63 - 3.59 (m, 1.4H), 3.56 - 3.50 (m, 2H), 0.97 - 0.91 (m, 3H), -0.01 (s, 9H), -0.02 (s, 6H). Step 4: 7-bromo-N-(tert-butyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4, 5-c]pyrid^ amine To a stirred solution of 7-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4, 5-c]pyridine 5- oxide (102 mg, 0.296 mmol) and 1 , 2-dichloroethane (1.5 niL) was added N, N-diisopropylethylamine (0.195 niL, 1.11 mmol), i-butylamine (0.039 mL, 0.37 mmol) and bromotripyrrolidinophosphonium hexafluorophosphate (180 mg, 0.385 mmol) and the reaction mixture stirred for 22 h at RT. The reaction mixture was washed with saturated sodium bicarbonate solution (10 mL) and extracted with dichlorome thane (2 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in heptane) affording an approximate 3:2 mixture of 7-bromo-N-(tert-butyl)-l-((2-(trimethy and 7-bromo-N-(tert-butyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4, 5-c]pyridin-4-amine N- SEM regioisomers (47 mg, 40%): H NMR (400 MHz, DMSO-d6; reported as an approximate 3:2 mixture of N-SEM isomers) delta 8.00 (s, 0.7H), 7.95 (s, 1H), 7.81 (s, 0.7H), 7.77 (s, 1H), 6.02 (br s, 0.8H), 5.77 (s, 2H), 5.54 (s, 1.6H), 5.43 (br s, 1H), 3.63 - 3.57 (m, 3.7H), 1.02 - 0.89 (m, 3.8H), 0.00 (s, 6H), -0.02 (s, 9H). Step 5: N-(tert-butyl)-7-(4-cyclopropyl-6, 6-dimethyl-8, 9-dihydro-6H-[l, 4]oxazino[4, 3-e]purin-2- yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4, 5-c]pyridin-4-amine 4-cyclopropyl-6, 6-dimethyl-2-(tributylstannyl)-8, 9-dihydro-6H-[l, 4]oxazino[4, 3-e]purine (64.5 mg, 0.12 mmol) and 7-bromo-N-(tert-butyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4, 5- c]pyridin-4-amine (46 mg, 0.115 mmol) were dissolved in 1, 4-dioxane (2.5 mL) in a microwave vial equipped with a stir bar and the mixture was purged with nitrogen gas for 10 min. Copper(I) thiophene-2-carboxylate (22 mg, 0.115 mmol) and tetrakis(triphenylphosphine)palladium(0) (13.3 mg, 0.012 mmol) were then added and the reaction mixture was microwaved at 140 C for 35 min. The reaction mixture was filtered through a celite bed and washed with dichlorome thane (10 mL). The filtrate was concentrated to dryness in vacuo, dissolved in ethyl acetate and washed with brine (10 niL). The organic layer was separated, dried over sodium sulfate and concentrated to afford crude N-(tert-butyl)-7-(4-cyclopropyl-6, 6-dimethyl-8, 9-dihydro-6H-[l, 4]oxazino[4, 3-e]purin-2-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazo[4, 5-c]pyridin-4-amine used for the next step without any further purification.3-Bromo-3-deazapurine base (A, 426.0 mg; 2.15 mmol) wasdissolved in N, O-bis(trimethylsylil)acetamide (BSA, 0.6 ml;2.15 mmol) and the reaction mixture was refluxed at room temperaturefor 1 h and 30 min under inert atmosphere of argon.Excess BSA was evaporated under reduced pressure and yellow solid of silylated base was obtained. 6-Hydroxy-2, 3-di-O-benzyl-4, 5-didehydro-L-ascorbic acid (HdBAA, 622.7 mg; 1.43 mmol) and silylated base were dissolved in dry acetonitrile (20.0 ml) and stirred under argon atmosphere at room temperature. TMSOTf (1.80 ml, 4 0.45 ml) was then added to the reaction mixture and additionally stirred and heated at 55e70 C overnight. After evaporatingthe solvent under reduced pressure, crude yellowish-greenproduct was obtained and washed with CH2Cl2 and saturated solutionof NaHCO3. Organic layer was dried over MgSO4 andconcentrated under reduced pressure. Crude product mixture waspurified by silica gel column chromatography(dichloromethane:methanol 25:1) and product 1 (Z:E 4:1;14.7 mg; 1.32%) was obtained as yellow oil by rechromatography (petroleum ether:etylacetate 1:1). MS (ESI): m/z 518.2([MH]). Anal. Calcd. for C26H20BrN3O4 (517.06): C, 60.24; H, 3.89;N, 8.11. Found: C, 60.19; H, 3.88; N, 8.13.(Z)-1: 1H NMR (DMSO-d6): d 5.14 (s, 2H, OCH2-2), 5.30 (s, 2H, OCH2-3), 5.39 (d, 2H, 3J 6.5 Hz, H-6), 5.67 (t, 1H, 3J 6.5 Hz, H-5), 7.24e7.50 (m, 10H, C6H5), 8.44 (s, 1H, H-20), 8.49 (s, 1H, H-80), 8.93(s, 1H, H-60) ppm.(Z)-1: 13C NMR (DMSO-d6): d 40.96 (C-6), 72.97 (OCH2-3), 73.94(OCH2-2), 100.96 (C-30), 104.31 (C-5), 123.02 (C-2), 143.66 (C-20), 127.8e128.9 (C6H5), 135.33/135.64/135.72* (C-2a, C-3a), 135.33/135.64/135.72* (C-40), 141.30 (C-60), 141.98 (C-4), 142.10 (C-50), 143.66 (C-20), 147.86 (C-80), 163.57 (C-1) ppm. *Could not be unequivocally assigned.step 1 : Following the procedures as described in steps 1 - 3 of referential example 13, tert-butyl 2-acetyl- 5H-pyrrolo[3, 2-i ]pyrimidine-5-carboxylate was prepared using 2-chloro-5H-pyrrolo[3, 2-i ]pyrimidine in place of 5-chloro-lH-pyrrolo[3, 2-6]pyridine: lH NMR (400 MHz, CDC13) delta 9.50 (s, 1H), 8.07 (d, J = 3.6 Hz, 1H), 6.93 (d, J = 3.7 Hz, 1H), 2.86 (s, 3H), 1.72 (s, 9H); MS(ESI) m/z: 262.2 [M+l] +.

Molecular Weight:198.02
XLogP3:1.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Exact Mass:196.95886
Monoisotopic Mass:196.95886
Topological Polar Surface Area:41.6
Heavy Atom Count:10
Complexity:130
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes