4-broMo-1-Methyl-1H-pyrazolo[3,4-c]pyridine

The requisite (4S)-1, 4-dimethyl-4, 5, 6, 7-tetrahydro-1H-pyrazolo[3, 4-c]pyridine was prepared in the following manner. Reaction of C8 at elevated temperature with trimethylboroxin in the presence of sodium carbonate and tetrakis(triphenylphosphine)palladium(0) afforded 1, 4-dimethyl-1H-pyrazolo[3, 4-c]pyridine. This material was reduced using the method described for synthesis of C9 from C8 in the product was subjected to supercritical fluid chromatography to separate the enantiomers (Column: Chiral Technologies, Chiralpak IC, 5 mum; Eluent: 4:1 carbon dioxide/methanol). The second-eluting enantiomer was collected and used for synthesis of Example 20. The absolute stereochemistry was arbitrarily assigned.Acetic acid (5 mL) was added to a solution of C8 (226 mg, 1.07 mmol) in ethanol (30 mL), and the mixture was hydrogenated (30 psi hydrogen) over platinum(IV) oxide monohydrate (78.4 mg, 0.320 mmol) for 18 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated in vacuo to provide the product as a gum. Nuclear Overhauser Effect (NOE) studies supported the indicated regiochemistry of the methyl group. By 1H NMR, this material contained residual acetic acid. Corrected yield: 146 mg, 0.67 mmol, 63%. LCMS m/z 138.1 [M+H]+. 1H NMR (400 MHz, CDCl3) delta 7.33 (br s, 1H), 4.32 (br s, 2H), 3.79 (s, 3H), 3.31-3.39 (m, 2H), 2.87-2.94 (m, 2H).Sodium hydride (60% in mineral oil, 0.524 g, 13.1 mmol) was added to a solution of C7 (3.20 g, 10.9 mmol) in tetrahydrofuran (20 mL), and the reaction mixture was heated at reflux for 1.5 hours, then allowed to sit at room temperature for 90 hours. Additional sodium hydride (1 equivalent) was added, and the reaction mixture was heated at reflux for 3 hours. After cooling to room temperature, the mixture was quenched with water, diluted with saturated aqueous sodium chloride solution, and extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) afforded the product as a solid. Yield: 1.51 g, 7.12 mmol, 65%. 1H NMR (400 MHz, CDCl3) delta 8.87 (s, 1H), 8.38 (s, 1H), 8.03 (s, 1H), 4.19 (s, 3H).General Procedure 3c (GP 3c): Sonogashira coupling (Conditions C) To a mixture of the respective halide in THF (5 mL per mmol halide) are added the alkyne (typically 1.5 -2.0 eq), dichlorobis(triphenylphosphine)palladium (II) (PdCt2(PPh3)2) (5-10 mol-%), copper (I) iodide (20 mol-%), and a 1M solution of tetra-N-butylammonium fluoride in THF (2.0 - 3.0 eq.) under inert atmosphere at room temperature. The mixture is then allowed to react for 30 min at 80 C in a microwave oven. After cooling to room temperature, the mixture is diluted with water, and repeatedly extracted with dichloromethane. The combined organic layers are dried over magnesium sulfate and evaporated. Column chromatography or preparative HPLC yield the pure target compound.; Intermediate 3.1 Preparation of 3-(1-Methyl-1H-pyrazolo[3, 4-c]pyridin-4-ylethynyl)-phenylamine [Show Image] In an adaption of GP 3c , 639 mg of General Procedure 2 (GP 2): Hydrazone cyclization; The respective hydrazone (prepared as described in GP 1) was dissolved in dry THF (- 9 mL per mmol hydrazone), treated with 50-60% NaH (1.2 to 2.2 eq.) and subsequently refluxed for 90 min. The reaction mixture was quenched with water, extracted with ethyl acetate, the combined organic layers dried and concentrated in vacuo. The precipitate was filtered and subsequently triturated with diisopropylether to yield the desired product. Flash column chromatography of the mother liquor provided a second batch of the analytically pure product. Alternatively, in most cases concentration of the crude reaction mixture to dryness provided the cyclized product in sufficient purity for subsequent transformations.; Intermediate 1.4; Preparation of N'-[1-(3, 5-Dibromo-pyridin-4-yl)-meth-(E)-ylidene]-hydrazinecarboxylic acid tert-butyl ester; [Show Image] In analogy to GP 1, 1.37 g of 3, 5-dibromo-pyridine-4-carbaldehyde (5.17 mmol, 1 eq; commercially available or prepared as described in US6232320 or WO2005110410) were dissolved in 24 mL 1-PrOH, treated with 2.05 g tert-butyl carbazate (15.5 mmol, 3 eq.) and heated to 120 C for 30 min (employing a Biotage Initiator microwave oven in batch mode). The precipitate was filtered and washed with cold 1-PrOH to yield 1.66 g of the Boc-hydrazone (4.37 mmol, 85% yield). 1H-NMR (d6-DMSO; 400 MHz): 11.36 (br., 1 H); 8.74 (s, 2 H); 8.04 (s, 1 H); 1.44 (s, 9 H).General Procedure 2 (GP 2): Hydrazone cyclization The respective hydrazone (prepared as described in GP 1) was dissolved in dry THF (- 9 mL per mmol hydrazone), treated with 50-60% sodium hydride (1.2 to 2.2 eq.) and subsequently refluxed for 90 min. The reaction mixture was quenched with water, extracted with ethyl acetate, the combined organic layers dried and concentrated in vacuo. The precipitate was filtered and subsequently triturated with diisopropylether to yield the desired product. Flash column chromatography of the mother liquor provided a second batch of the analytically pure product. Alternatively, in most cases concentration of the crude reaction mixture to dryness provided the cyclized product in sufficient purity for subsequent transformations.; Intermediate 2.2 Preparation of 2-(4-Bromo-pyrazolo[3, 4-c]pyridin-1-yl)-ethanol [Show Image] In analogy to GP2, 520 mg of 2-{N'-[1-(3, 5-Dibromo-pyridin-4-yl)-meth-(E)-ylidene]-hydrazino}-ethanol (Intermediate 1.2, 1.61 mmol, 1 eq) were dissolved in 14 mL dry THF, treated at rt with 155 mg 50-60% sodium hydride (3.54 mmol, 2.2 eq) and subsequently refluxed for 90 min. The reaction mixture was quenched with water, extracted with ethyl acetate, the combined organic layers dried and concentrated in vacuo to yield 424 mg of a crude product, which was optionally further purified by trituration or flash column chromatography. LC-MS: [M+H]+ = 243 (Br isotope pattern)General Procedure 4 (GP 4): Suzuki coupling (Conditions B); The heteroaryl halide (1 eq), the respective aryl pinacolato boronate or aryl boronic acid (1.2 to 1.5 eq.) and FibreCat 1032 (Johnson-Matthey; 0.38 mmol/g loading; 6 mol%) were weighed into a Biotage microwave vial and capped. EtOH (-9 mL per mmol halide) and 1M aq. K2CO3 solution (1.5 eq.) were added by syringe. The resulting mixture was prestirred (10 sec) and subsequently heated to 100-130 C for 20 min in a Biotage Initiator microwave oven. After filtration and concentration in vacuo, the residue was taken up in ethyl acetate and water was added, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried and concentrated in vacuo. The residue was optionally purified by flash column chromatography and/or trituration and/or preparative HPLC.; Intermediate 3.4; Preparation of 2-Methoxy-4-(1-methyl-1H-pyrazolo[3, 4-c]pyridin-4-yl)-phenylamine; [Show Image] In analogy to GP 4, 355 mg of Intermediate 2.1 (1.67 mmol, 1 eq.), 630 mg of 2-methoxy-4-(4, 4, 5, 5-tetramethyl-[1, 3, 2]dioxaborolan-2-yl)-phenylamine (2.51 mmol, 1.5 eq.) and 268 mg of FibreCat 1032 (0.1 mmol, 6 mol%) were weighed into a Biotage microwave vial and capped. 15 mL EtOH and 2.51 mL 1M aq. K2CO3 solution (2.51 mmol, 1.5 eq.) were added by syringe. The resulting mixture was prestirred (10 sec) and subsequently heated to 130 C for 20 min in a Biotage Initiator microwave oven. After filtration and concentration in vacuo, the residue was taken up in ethyl acetate and water was added, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried and concentrated in vacuo. Flash column chromatography yielded 231 mg of the desired product (0.90 mmol, 54% yield) along with additional fractions of impure material. 1H-NMR (d6-DMSO; 400 MHz): 8.99 (s, 1 H); 8.30 - 8.32 (m, 2 H); 7.12 - 7.16 (m, 2 H); 6.76 (d, 1 H); 5.03 (br. s, 2 H); 4.16 (s, 3 H); 3.85 (s, 3 H). MS (ESI): [M+H]+ = 255.General Procedure 3 (GP 3): Suzuki coupling (Conditions A); The heteroaryl halide (1 eq), the respective aryl pinacolato boronate or aryl boronic acid (1.2 to 1.5 eq.) and Pd(PPh3)4 (6 mol%) were weighed into a Biotage microwave vial and capped. Toluene (6 mL per mmol halide), EtOH (6 mL per mmol halide) and 1M aq. Na2CO3 solution (2 eq.) were added by syringe. The resulting mixture was prestirred (10 sec) and subsequently heated to 120 C for 15 min (fixed hold time) in a Biotage Initiator microwave reactor. The reaction mixture was diluted with water and ethyl acetate, the layers were separated and the aqueous layer extracted with ethyl acetate. The combined organic layers were dried and concentrated in vacuo. The residue was optionally purified by flash column chromatography and/or trituration and/or preparative HPLC.; Intermediate 3.1; Preparation of 4-(1-Methyl-1 H-pyrazolo[3, 4-c]pyridin-4-yl)-phenylamine; [Show Image] In analogy to GP 3, 1.06 g of Intermediate 2.1 (5 mmol, 1 eq.), 1.31 g of 4-(4, 4, 5, 5-tetramethyl-[1, 3, 2]dioxaborolan-2-yl)-phenylamine (6 mmol, 1.2 eq.) and 347 mg Pd(PPh3)4 (6 mol%) were weighed into a Biotage microwave vial and capped. 30 mL toluene, 30 mL EtOH and 1M aq. Na2CO3 solution (9.65 mL, 1.9 eq.) were subsequently added by syringe. The resulting mixture was prestirred (10 sec) and subsequently heated to 120 C for 15 min (fixed hold time) in a Biotage Initiator(at) microwave reactor. The reaction mixture was diluted with water and ethyl acetate, the layers were separated and the aqueous layer extracted with ethyl acetate. The combined organic layers were dried and concentrated in vacuo to yield after trituration 701 mg of the desired product (3.13 mmol, 63% yield), which was used for subsequent transformations without further purification. 1H-NMR (d6-DMSO; 400 MHz): 8.97 (s, 1 H); 8.24 - 8.25 (m, 2 H); 7.46 (d, 2 H); 6.69 (d, 2 H); 5.40 (br. s, 2 H); 4.15 (s, 3 H).

Molecular Weight:212.05
XLogP3:1.2
Hydrogen Bond Acceptor Count:2
Exact Mass:210.97451
Monoisotopic Mass:210.97451
Topological Polar Surface Area:30.7
Heavy Atom Count:11
Complexity:153
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes