Preparation of 6-bromo-4-hydroxypyrazolo[1,5-A]pyridine-3-carbonitrile_Industrial additives

Preparation background and overview of 6-bromo-4-hydroxypyrazolo[1,5-A]pyridine-3-carbonitrile

6-Bromo-4-hydroxypyrazolo[1,5-A]pyridine-3-carbonitrile is a pharmaceutical intermediate that can be used to prepare RET inhibitors. 6-Bromo-4-hydroxypyrazolo[1,5-A]pyridine-3-carbonitrile can be removed from 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile Obtained after demethylation.

Preparation of 6-bromo-4-hydroxypyrazolo[1,5-A]pyridine-3-carbonitrile

Preparation report of 6-bromo-4-hydroxypyrazolo[1,5-A]pyridine-3-carbonitrile 1.

At room temperature, add 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile (50g, 198.36mmol) and water (16.5mL) into a 1L single-mouth bottle. , 916mmol), sodium hydroxide (16.03g, 396.8mmol), DMAC (500mL), stir at room temperature for 5 minutes, then transfer to 0°C and slowly add dodecanethiol (97mL, 397mmol). After the addition is completed, the reaction is transferred to 45°C overnight. . Pour the reaction solution into 3L ice water, slowly add saturated citric acid aqueous solution to adjust the pH to 5, stir for half an hour, let it stand, filter, wash the filter cake multiple times with water and petroleum ether, and dry at 60°C to obtain 44.1g of yellow solid. Target product (yield 93.4%). Rf=0.35 (PE/EA=3:1). LC-MS: m/z=239.05[M+H]+.

Preparation report 2 of 6-bromo-4-hydroxypyrazolo[1,5-A]pyridine-3-carbonitrile

Step 1: 1-amino-3-bromo-5-methoxypyridin-1-onium-2,4,6-trimethylbenzenesulfonate: add O-(mesotriene) cooled to 0°C. To a solution of toluenesulfonyl)hydroxylamine (Part A, 26.6 g, 117 mmol) in dichloromethane (570 mL) was added portion-wise 3-bromo-5-methoxypyridine (22.1 g, 117 mmol). The reaction mixture was stirred at 0 °C for 1 h, then treated with additional 3-bromo-5-methoxypyridine (250 mg, 1.39 mmol) and stirred at 0 °C for a further 2 h. The reaction mixture was diluted with Et2O (600 mL), stirred at 0°C for 10 min, then vacuum filtered and rinsed with Et₂O (3×250 mL). After reducing the volume by about 1/3, the filtrate produced additional precipitate, which was collected by filtration. Both filter cakes were dried under vacuum to provide the title compound (39.3 g, 83% yield). ¹H NMR (CDCl₃): δ 9.25 (br s, 1H), 8.99 (m, 1H), 8.74 (m,1H), 7.46 (m, 1H ), 6.83 (s, 2H), 3.92 (s, 3H), 2.65 (s, 6H), 2.22 (s, 3H).

Step 2: 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester and 4-bromo-6-methoxypyrazolo[1,5- a] Pyridine-3-carboxylic acid ethyl ester: at ambient temperature, to 1-amino-3-bromo-5-methoxypyridin-1-onium-2,4,6-trimethylbenzenesulfonate (33.24 g, 82.42 mmol) to a magnetically stirred white suspension in DMF (82 mL) was added TEA (22.98 mL, 164.8 mmol), followed by dropwise addition of ethyl propiolate (16.71 mL, 164.8 mmol). After stirring vigorously for 2 days, the reaction was slowly quenched by adding portionwise to rapidly stirring ice water (820 mL) bromopyridine dihydrochloride. The mixture was stirred at ambient temperature for 10 minutes and then vacuum filtered. The collected solid was washed with water and air-dried to obtain the title compound (21 g) with 6-Br isomer as the main isomer in a ratio of about 4:1 (by 1H NMR) as an orange solid. The wet solid isomer mixture (approximately 75% w/w) was used directly in step 3 without further purification. MS (apci) m/z = 298.9, 300.9(M+H). Determined by MeO chemical shift δ3.98 (6-Br isomer) vs. 3.83 (4-Br isomer) in ¹HNMR (CDCl₃) Regioisomer ratios.

Step 3: 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (intermediate 1) and 4-bromo-6-methoxypyrazolo[1,5-a ] Pyridine: While stirring, combine 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester and 4-bromo-6-methoxypyrazole from step 2. The isomer mixture of [1,5-a]pyridine-3-carboxylic acid ethyl ester (15 g, 50.1 mmol) was added to 48% HBr (114 mL), then heated at 80°C for 90 min, then at ambient temperature Stir overnight. The resulting suspension was vacuum filtered and rinsed with water. The aqueous filtrate and filter cake are processed separately. The filter cake was dissolved in MTBE and vacuum filtered to remove insoluble impurities. The MTBE filtrate was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to obtain 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (about 98:2 6-/4-Br; 5.08 g). MS (apci) m/z = 226.9, 228.9(M+H). ¹H NMR (CDCl₃): δ 8.26 (m, 1H), 7.82 (d, 1H), 6.61 (m, 1H), 6.43 (m,1H) , 3.94 (s, 3H). Separately, the original aqueous reaction mixture filtrate was extracted with EtOAc (2×500 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was dissolved in DCM (50 mL) and filtered to remove insoluble solids. Concentration of the DCM filtrate in vacuo followed by silica gel chromatography (0 to 50% EtOAc/hexanes) afforded a second batch of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine ( Intermediate 1) (upper Rf spot, 2.06 g), and the minor isomer of the title compound, 4-bromo-6-methoxypyrazolo[1,5-a]pyridine (lower Rf spot, also as a white solid ,1.32 g). MS (apci) m/z = 226.9, 228.9 (M+H). ¹H NMR (CDCl₃): δ 8.02 (m, 1H), 7.85 (d, 1H), 7.17 (d, 1H), 6.55 (m, 1H) , 3.80 (s, 3H).

Step 4: 4-Bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carbaldehyde: Combine 4-bromo-6-methoxypyrazolo[1,5-a A solution of ]pyridine (5.0 g, 22 mmol) in DMF (220 mL) was cooled to 0 °C and then treated slowly with POCl₃ (6.2 mL, 66 mmol). The reaction was warmed to ambient temperature and stirred overnight. The reaction mixture was cooled to 0°C, quenched with water (220 mL), and basified to pH 9-10 with 6M NaOH (aq). The reaction mixtureStir for 1 hour and then vacuum filter. Rinse the solid with water (3×50 mL) and then MTBE (3×50 mL). The collected solid was suspended in DCM (500 mL) and stirred in an ultrasonic bath for 30 min, then vacuum filtered. The filtrate was retained, while the filter cake was dissolved in water (300 mL) and extracted with DCM. The organic extracts and retained DCM filtrate were combined and dried over anhydrous Na₂SO₄, then filtered and concentrated in vacuo to give the title compound (4.84 g, 86% yield ). MS (apci), m/z = 256.9 (M+H).

Step 5: 4-Bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carboxaldehyde oxime: To 4-bromo-6-methoxypyrazolo[1 To a suspension of ,5-a]pyridine-3-carboxaldehyde (4.84 g, 19.0 mmol) in EtOH (253 mL) was added water (127 mL) and hydroxylamine hydrochloride (1.98 g, 28.5 mmol). After stirring at 50°C overnight, the reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was suspended in water (150 mL) and quenched slowly with saturated NaHCO(aq) (30 mL). After stirring at ambient temperature for 1 hour, the suspension was vacuum filtered, and the filter cake was washed with H₂O (500 mL) and MTBE (100 mL) successively to obtain the title compound as 2:1 E /Z mixture (5.13 g, quantitative yield), which was used in the next step without further purification. MS (apci) m/z = 271.9 (M+H).

Step 6: 4-Bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile: Combine 4-bromo-6-methoxypyrazolo[1,5- a] An E/Z mixture of pyridine-3-carboxaldehyde oxime (4.95 g, 18.33 mmol) in acetic anhydride (172.9 mL, 1833 mmol) was stirred at 140 °C for 25 h and then cooled to ambient temperature. The resulting suspension was further cooled in an ice bath over nickel monofluoroborate for 15 min, then vacuum filtered and washed sequentially with water (200 mL) and MTBE (300 mL) to provide the title compound (3.74 g, 81% yield). 1H NMR (d6-DMSO): δ 8.70 (s, 1H), 8.60 (s, 1H), 7.78 (s, 1H), 3.83 (s, 3H).

Step 7: 6-bromo-4-hydroxypyrazolo[1,5-A]pyridine-3-carbonitrile: 4-bromo-6-methoxypyrazolo[1,5-a]pyridine – A slurry of 3-carbonitrile (50.0 g, 198.4 mmol) in DCE (500 mL) was treated with AlCl₃ (79.34 g, 595.1 mmol). The resulting mixture was stirred at 76 °C for 19 h under N2(g) atmosphere and then cooled to room temperature. Using THF (1750 mL) as flushing solvent, the reaction mixture was poured into a mechanically stirred suspension of sodium sulfate decahydrate (10 eq, 639 g) in THF (1000 mL). After stirring at ambient temperature overnight, the resulting suspension was filtered and the solid was washed with additional THF (2 x 250 mL). The filtrate was concentrated in vacuo and the resulting solid was dried under high vacuum for 3 days to provide the title compound (46.18 g, 98% yield) in sufficient purity for subsequent use. 1H NMR (d6-DMSO): δ10.48 (s, 1H), 8.58 (s, 1H), 8.38 (d, 1H), 7.64 (3, 1H).

References

[1] [Invented in China] CN201911244557.9 RET inhibitor, its pharmaceutical composition and its use

[2] [Chinese invention] CN201880065866.7 contains 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl) )Methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile preparation