* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: at -20 - 0℃; for 0.5 h; Large scale Stage #2: at 10℃; Large scale Stage #3: With ferrous(II) sulfate heptahydrate; sulfuric acid In dichloromethane; water at 20℃; Large scale
At -20 ° C ~ -10 ° C (preferably -10 ° C),1700 g of ethyl pyruvate was dropped into 1400 g of 35percent hydrogen peroxide solution.The reaction was kept for 30 minutes and used.1400 g of 4-bromopyridine hydrochloride (Cpd 1) was added to ice water.At a temperature less than 10 ° C,Adjust the pH to 8-9 with potassium carbonateExtracted twice with 7L of dichloromethane (DCM).Dry; pour the above organic phase into a 50L reaction flask,Add 1.4 L of water to the reaction solution.4073g ferrous sulfate heptahydrate,448mL concentrated sulfuric acid,Stir at room temperature;At -10 ° C to 0 ° C (preferably -5 ° C),Add ethyl pyruvate / hydrogen peroxide solution,Continue the reaction for 4 hours; extract with 7L of water,Spin dry to give ethyl 4-bromopyridine-2-carboxylate (Cpd 2)1390g.The yield was 82percent.
Reference：
[1] Patent: CN108516953, 2018, A, . Location in patent: Paragraph 0067-0071; 0076-0083
[2] Patent: CN105153023, 2018, B, . Location in patent: Paragraph 0059; 0060-0061
2
[ 64-17-5 ]
[ 30766-03-1 ]
[ 62150-47-4 ]
Yield
Reaction Conditions
Operation in experiment
86%
at 20 - 70℃; for 12 h;
To a stirred solutionof 4-bromopicolinic acid 4 (20 g, 87.33 mmol) in ethanol (250 mL) cooled to 5 °C, sulfuric acid (3 mL) was added and the reaction mixture was slowly cooled down to room temperature and then heated at 70 °C for 12 h. Upon completion of the reaction (TLC), the solvent was evaporated under vacuum. The residue was dissolved in ethyl acetate (500 mL), washed with ice cold water (100 mL), saturated by sodium bicarbonate solution (100 mL) and brine solution (100 mL). The organic layer was separated and dried over anhydrous sodium sulfate. The solvent was evaporated under vacuum and purified by column chromatography (hexane–ethyl acetate = 20 : 80) to give compound 5 (86 percent).
Reference：
[1] Russian Journal of General Chemistry, 2017, vol. 87, # 3, p. 550 - 553[2] Zh. Obshch. Khim., 2017, vol. 87, # 3, p. 550 - 553,4
3
[ 62150-47-4 ]
[ 131747-45-0 ]
Yield
Reaction Conditions
Operation in experiment
62%
With sodium tetrahydroborate In ethanol at 20 - 40℃;
At a temperature of less than 40 ° C,Dissolve 1300 g of Cpd 2 in 7 L of ethanol.Add 400g of sodium borohydride in batches,Stir at room temperature overnight;2N hydrochloric acid was added dropwise at a temperature of less than 20 ° C to adjust the pH to weakly alkaline,Rotate most of the ethanol,add water,Adjusted to strong alkaline with potassium carbonate,Extracted with ethyl acetate (EA),Wash the product to the aqueous phase with 1N hydrochloric acid.Extracted with EA,The aqueous phase is added with potassium carbonate to adjust to strong alkalinity,EA extraction, sodium chloride washing,Dry over anhydrous sodium sulfate and spin dry.Through the column, 4-bromopyridine-2-methanol (Cpd 3) 650 g was obtained. The yield was 62percent.
Reference：
[1] Patent: CN108516953, 2018, A, . Location in patent: Paragraph 0067-0068; 0072-0073; 0076-0083
4
[ 75-16-1 ]
[ 62150-47-4 ]
[ 477252-20-3 ]
Yield
Reaction Conditions
Operation in experiment
84%
at 25℃; for 0.5 h; Cooling with ice
Equip a three-liter, three-neck round bottom flask with an addition funnel, a reflux condenser, a nitrogen inlet, and a temperature probe. Charge with methylmagnesium bromide (3.2M in 2-methyltetrahydrofuran, 239.07 mL, 765.01 mmol) and cool in an ice bath. To the addition funnel, add a solution of ethyl 4-bromopyridine-2-carboxylate (80.0 g, 347.73 mmol) in THF (800.0 mL). Add the solution dropwise to the methylmagnesium bromide solution while keeping the internal temperature below 25° C. Remove the cooling bath and allow stirring at 25° C. for 30 minutes. Cool the reaction mixture to 5° C. and quench carefully with the dropwise addition of aqueous hydrochloric acid solution (1M) while keeping the internal temperature below 30° C. Add additional aqueous hydrochloric acid solution (1M) until the mixture reaches a pH of around 7. Remove the cooling bath and dilute with ethyl acetate (EtOAc; 200 mL). Isolate the organic layer, dry over anhydrous sodium sulfate, filter through a CELITE® plug and rinse with EtOAc. Concentrate the filtrate to give an orange oil. Purify by using a silica gel plug eluting with hexane/EtOAc (3/1) to give the title compound (63.15 g; 84.0percent yield) as a colorless oil. MS (m/z): 216/218 (M+1/M+3).
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; methanol; at 80℃; for 15.0h;Inert atmosphere;
To a stirring solution of compound 2.3 (32.4 g,. 0.14 mol). compound 2,4 (32.2 g, 0.17 mol) and Pd(PPh2)4 (8.08 g, 7 ram of) in 1 ,4-dioxane/nrietrianoi (800 rnL 1 :1) was added Na2COs (22.3 g,u.21 mol) under an argon atmosphere and the mixture was stirred at 80C for 15 nr. The solvent was removed under reduced pressure and the resulting residue was diluted with wafer (500 rnL) and extracted with EtOAc (3 x 500 ml). The combined organic layers were dried and concentrated under reduced pressure to give a crude, which was purified by flash chromatography (silica gel/ RhoEpsilon.Alpha 2: 1) to give ethyl 4-(4-formylphenyl picolinate (2.5, 14.2 g, 40%) as a yellow solid.
With sodium hydride; In 1,2-dimethoxyethane; mineral oil; at 30℃; for 2.0h;Inert atmosphere;
A solution of <strong>[62150-47-4]ethyl 4-bromo-2-picolinate</strong> (1e) (92%, 20.6 g, 82.3 mmol) and acetone (2.43 mL, 32.9 mmol) in DME (100 mL) was added dropwise to a stirred suspension of NaH (60% suspension in oil, 6.6 g, 165 mmol) in DME (100 mL) under an atmosphere of argon at room temperature. The temperature was slowly increased until reflux was achieved, and a vigorous evolution of gas was observed after 10 min and the brown suspension turned dark red. The reaction mixture was allowed to cool to room temperature and was stirred for 2 h. The solvent was removed in vacuo and the red-orange paste slowly treated with water (200 mL). The resultant insoluble mixture was acidified as described in previously to pH 6.5 and the copious amount of yellow solid so obtained was collected by filtration and washed with water until the washing appeared colourless. The solid was oven-dried under vacuum (40C, ca. 30 mm) for 2 days to yield the crude triketone 5e as a yellow solid (15.3 g).
In tetrahydrofuran; 2-methyltetrahydrofuran; at 25℃; for 0.5h;Cooling with ice;
Equip a three-liter, three-neck round bottom flask with an addition funnel, a reflux condenser, a nitrogen inlet, and a temperature probe. Charge with methylmagnesium bromide (3.2M in 2-methyltetrahydrofuran, 239.07 mL, 765.01 mmol) and cool in an ice bath. To the addition funnel, add a solution of ethyl 4-bromopyridine-2-carboxylate (80.0 g, 347.73 mmol) in THF (800.0 mL). Add the solution dropwise to the methylmagnesium bromide solution while keeping the internal temperature below 25 C. Remove the cooling bath and allow stirring at 25 C. for 30 minutes. Cool the reaction mixture to 5 C. and quench carefully with the dropwise addition of aqueous hydrochloric acid solution (1M) while keeping the internal temperature below 30 C. Add additional aqueous hydrochloric acid solution (1M) until the mixture reaches a pH of around 7. Remove the cooling bath and dilute with ethyl acetate (EtOAc; 200 mL). Isolate the organic layer, dry over anhydrous sodium sulfate, filter through a CELITE plug and rinse with EtOAc. Concentrate the filtrate to give an orange oil. Purify by using a silica gel plug eluting with hexane/EtOAc (3/1) to give the title compound (63.15 g; 84.0% yield) as a colorless oil. MS (m/z): 216/218 (M+1/M+3).
2-{4-[(4-[1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl]oxy}pyridin-2-yl)amino]pyridin-2-yl}propan-2-ol 4-methylbenzenesulfonate[ No CAS ]
To a stirred solutionof 4-bromopicolinic acid 4 (20 g, 87.33 mmol) in ethanol (250 mL) cooled to 5 C, sulfuric acid (3 mL) was added and the reaction mixture was slowly cooled down to room temperature and then heated at 70 C for 12 h. Upon completion of the reaction (TLC), the solvent was evaporated under vacuum. The residue was dissolved in ethyl acetate (500 mL), washed with ice cold water (100 mL), saturated by sodium bicarbonate solution (100 mL) and brine solution (100 mL). The organic layer was separated and dried over anhydrous sodium sulfate. The solvent was evaporated under vacuum and purified by column chromatography (hexane-ethyl acetate = 20 : 80) to give compound 5 (86 %).
With ethanol; hydrazine hydrate; at 70℃; for 12.0h;
To a stirred solution of <strong>[62150-47-4]ethyl 4-bromopicolinate</strong> 5 (15 g, 65.51 mmol) in ethanol (150 mL) was added hydrazine hydrate (6.55 g, 6.42 mL, 131.01 mmol). The reaction mixture was heated at 70 C for 12 h. Upon completion of the reaction (TLC), the solid precipitate was filtered off and dried under vacuum to give compound 6 (85 %).
0.620 g
With hydrazine hydrate; In ethanol; at 0 - 20℃; for 0.5h;
To a stirred solution of <strong>[62150-47-4]ethyl 4-bromopicolinate</strong> (CAS Number 62150-47-4; 0.700 g, 3.04 mmol) in ethanol (7 ml) was added hydrazine hydrate (0.456 g, 9.12 mmol) drop-wise at 0C. The reaction temperature was raised from 0C to rt and stirred for an additional 30 mm. Ethanol wasremoved under reduced pressure. To the crude reaction, was added water (50 ml) and the product was extracted in EtOAc (2 x 50 ml). Combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 4-bromopicolinohydrazide (0.620 g, 2.88 mmol, Cmde). The cmde solid was directly used for next step without purification. LCMS: Method C, 1.291 mi MS: ES+ 216.13.
With sodium tetrahydroborate; In ethanol; at 20 - 40℃;
At a temperature of less than 40 C,Dissolve 1300 g of Cpd 2 in 7 L of ethanol.Add 400g of sodium borohydride in batches,Stir at room temperature overnight;2N hydrochloric acid was added dropwise at a temperature of less than 20 C to adjust the pH to weakly alkaline,Rotate most of the ethanol,add water,Adjusted to strong alkaline with potassium carbonate,Extracted with ethyl acetate (EA),Wash the product to the aqueous phase with 1N hydrochloric acid.Extracted with EA,The aqueous phase is added with potassium carbonate to adjust to strong alkalinity,EA extraction, sodium chloride washing,Dry over anhydrous sodium sulfate and spin dry.Through the column, 4-bromopyridine-2-methanol (Cpd 3) 650 g was obtained. The yield was 62%.
At -20 C ~ -10 C (preferably -10 C),1700 g of ethyl pyruvate was dropped into 1400 g of 35% hydrogen peroxide solution.The reaction was kept for 30 minutes and used.1400 g of 4-bromopyridine hydrochloride (Cpd 1) was added to ice water.At a temperature less than 10 C,Adjust the pH to 8-9 with potassium carbonateExtracted twice with 7L of dichloromethane (DCM).Dry; pour the above organic phase into a 50L reaction flask,Add 1.4 L of water to the reaction solution.4073g ferrous sulfate heptahydrate,448mL concentrated sulfuric acid,Stir at room temperature;At -10 C to 0 C (preferably -5 C),Add ethyl pyruvate / hydrogen peroxide solution,Continue the reaction for 4 hours; extract with 7L of water,Spin dry to give ethyl 4-bromopyridine-2-carboxylate (Cpd 2)1390g.The yield was 82%.
With sulfuric acid; iron(II) sulfate; In dichloromethane; water; at -10 - 0℃; for 1.0h;Autoclave; Large scale;
first step:Add ethyl pyruvate to a 20-liter three-necked flask, cool to 0 C, add hydrogen peroxide dropwise under mechanical stirring, and control the temperature below 0 C during the dropping process, and place it for use after dropping;Dichloromethane and 4-bromopyridine hydrochloride free dichloromethane solution were added to a 200 liter autoclave(eg take 5 kg of 4-bromopyridine hydrochloride, dissolve in 30 liters of water, adjust the pH to 8 with sodium bicarbonate, and extract three times with 50 liters of dichloromethane)Ferrous sulfate and a 50% by weight aqueous solution of sulfuric acid, stirred and lowered to a temperature of minus 10 degrees.The reagent prepared in the 20 liter reaction bottle is added dropwise, and the temperature of the dropping process is controlled between minus 10 degrees and 0 degrees, and the mixture is stirred and kept for one hour.TCL detection reaction is over,The reaction system was added to 100 liters of water, stirred well for 30 minutes, and liquid was separated. This operation was repeated until the aqueous phase was colorless, and the organic phase was concentrated to give 8.5 kg of crude product.It is a brown-red liquid A, which is used directly in the next step without purification.
The second step: 8.5 kg of A was added to 35 liters of ammonia water in batches, methane was stirred overnight, and centrifuged to obtain a crude product which was washed with ethyl acetate and centrifuged to obtain 4.5 kg of amide;
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