There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.
Type
HazMat fee for 500 gram (Estimated)
Excepted Quantity
USD 0.00
Limited Quantity
USD 15-60
Inaccessible (Haz class 6.1), Domestic
USD 80+
Inaccessible (Haz class 6.1), International
USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic
USD 100+
Accessible (Haz class 3, 4, 5 or 8), International
USD 200+
Structure of 89402-43-7 * Storage: {[proInfo.prStorage]}
* 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.
Reference：
[1] Chemistry - A European Journal, 2005, vol. 11, # 6, p. 1903 - 1910
5
[ 123-91-1 ]
[ 98027-80-6 ]
[ 89402-43-7 ]
[ 98-80-6 ]
[ 25297-51-2 ]
Yield
Reaction Conditions
Operation in experiment
26.7%
With sodium carbonate In hexane; water; ethyl acetate
Step 1: 4-bromo-2-chloro-6-phenylpyridine A round-bottomed flask was charged with 4-bromo-2,6-dichloropyridine (Combi-Blocks Inc., 553 mg, 2.437 mmol), phenylboronic acid (446 mg, 3.66 mmol) and trans-dichlorobis(triphenylphosphine)palladium (ii) (27.8 mg, 0.04 mmol). The vial was placed under nitrogen atmosphere using two evacuation/backfill cycles. 1,4-dioxane (12 ml) and sodium carbonate (775 mg, 7.31 mmol) in water (4.1 ml) were added. The reaction mixture was sealed under nitrogen and heated at 80° C. for 1.5 h. The reaction mixture combined with that on pp14 was partitioned between EtOAc and brine. The aqueous layer was back extracted with EtOAc (2*) and the combined EtOAc layers were dried (Na2SO4) and concentrated. The crude material was dissolved in DCM, and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0percent to 20percent EtOAc in hexane, to provide 2,6-dichloro-4-phenylpyridine (146 mg, 0.652 mmol, 26.7percent yield) as light-yellow oil. MS m/z=224.0 [M]
With potassium fluoride; 18-crown-6 ether; potassium carbonate; cesium fluoride In sulfolane; dimethyl sulfoxide at 120 - 200℃; for 3 h;
400 g of sulfolane and 400 g of dimethylsulfoxide were weighed into a 1000 mL flask and dehydrated to a temperature of less than 0.05percent at 200 ° C under a pressure of 0.07 MPa (negative pressure)96 g (1.66 mol) of cesium fluoride, 96 g (1.66 mol) of potassium fluoride, 120 g (0.67 mol) of trichloropyridine, 2 g of 18-crown ether and 3 g of potassium carbonate were weighed into a reaction flask at 120 ° C and heated to 200 ° C The product was collected in about 3 hours. 95 g (0.51 mol) of the product was obtained in 90percent yield. The purity was 96.8percent as determined by gas chromatography.
Reference：
[1] Patent: CN106008329, 2016, A, . Location in patent: Paragraph 0008; 0009
[2] Synthetic Communications, 2004, vol. 34, # 23, p. 4301 - 4311
[3] Patent: US33478, 1990, E1,
[4] Patent: US4565568, 1986, A,
[5] Patent: US4678509, 1987, A,
7
[ 103999-77-5 ]
[ 13400-13-0 ]
[ 89402-43-7 ]
Yield
Reaction Conditions
Operation in experiment
88%
With potassium-fluoride In sulfolane; tetrahydrothiophene 1,1-dioxide (sulfolane)
(c) 5-chloro-2,3-difluoropyridine A suspension of 64.6 g (1.1 mol) of potassium fluoride and 11.25 g (0.075 mol) of cesium-fluoride in 240 ml of sulfolane (1,1-dioxo-tetrahydrothiophene) is heated to 140° C. By reducing the pressure 50 ml of sulfolane are distilled off. To the suspension a solution of 61.4 g (0.37 mol) of 2,5-dichloro-3-fluoropyridine in 20 ml of sulfolane is added. The reaction-mixture is then stirred for 35 hours at a temperature of 140°, cooled and poured into ice/water. The organic material is extracted with ether. The ethereal layer is washed with water dried over magnesium sulfate, filtered and evaporated to yield 48.7 g of a colourless oil (88percent of the theory) which boils at 65-66° at 133 mbar.
88%
With potassium fluoride In sulfolane; tetrahydrothiophene 1,1-dioxide (sulfolane)
(c) 5-chloro-2,3-difluoropyridine A suspension of 64.6 g (1.1 mol) of potassium fluoride and 11.25 g (0.075 mol) of cesium-fluoride in 240 ml of sulfolane (1,1-dioxo-tetrahydrothiophene) is heated to 140° C. By reducing the pressure 50 ml of sulfolane are distilled off. To the suspension a solution of 61.4 g (0.37 mol) of 2,5-dichloro-3-fluoropyridine in 20 ml of sulfolane is added. The reaction-mixture is then stirred for 35 hours at a temperature of 140°, cooled and poured into ice/water. The organic material is extracted with ether. The ethereal layer is washed with water dried over magnesium sulfate, filtered and evaporated to yield 48.7 g of a colourless oil (88percent of the theory) which boils at 65°-66° at 133 mbar.
Reference：
[1] Patent: US4935051, 1990, A,
[2] Patent: US4713109, 1987, A,
8
[ 103999-77-5 ]
[ 89402-43-7 ]
Reference：
[1] Bulletin des Societes Chimiques Belges, 1990, vol. 99, # 9, p. 647 - 671
[2] Patent: US4831148, 1989, A,
Reference：
[1] European Journal of Organic Chemistry, 2002, # 24, p. 4174 - 4180
17
[ 89402-43-7 ]
[ 514797-99-0 ]
Reference：
[1] Chemistry - A European Journal, 2005, vol. 11, # 6, p. 1903 - 1910
[2] European Journal of Organic Chemistry, 2002, # 24, p. 4174 - 4180
18
[ 89402-43-7 ]
[ 514797-97-8 ]
Reference：
[1] European Journal of Organic Chemistry, 2002, # 24, p. 4174 - 4180
[2] Patent: EP2305672, 2011, A1,
19
[ 89402-43-7 ]
[ 246847-98-3 ]
Yield
Reaction Conditions
Operation in experiment
85.94%
at 120℃; for 24 h; Autoclave
5-chloro-2,3-difluoro-pyridine (100g, 0.669mol) and ammonia (1.125L, 8.025mol) added to the autoclave.After the reaction 120 sealed 24h, the reaction was complete, the cooling pale yellow solid precipitation, filtration, the filter cake was washed with water, and the filtrate was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate, the organic phase was distilled off under reduced pressure, with beating a small amount of petroleum ether, filtration, and precipitation cake cake obtained will be collected at the same time to give the compound 2-amino-3-fluoro-5-chloropyridine 84.22g, yield 85.94percent.
76%
With ammonia In water at 150℃; for 1 h; Microwave irradiation
Example 4Preparation of 6-chloro-1-(pentan-3-yl)-1H-imidazo[4,5-b]pyridin-2-ol; Example 4(a) 5-chloro-3-fluoropyridin-2-amine: To a 20 mL microwave vial equipped with a stir bar was added 5-chloro-2,3-difluoropyridine (2.0 g, 41 mmol). Ammonium hydroxide (ca 12 mL) was then added and the mixture was stirred until homogeneous. The solution was capped and heated in the microwave reactor at 150° C. for three 20 minute increments until a white solid precipitated out of solution. The white solid was filtered, washed with water, and dried to afford 2-amino-5-chloro-3-fluoropyridine (1.5 g, 76percent yield), characterized by 1H NMR (d6-DMSO).
73%
With ammonia In water at 165℃; for 3 h;
Example 5(a) 5-Chloro-3-fluoropyridin-2-amine.; To a stainless steel high pressure reactor was added 5-chloro-2,3-difluoropyridine (18.0 g) and ammonium hydroxide (65 mL). The reaction was heated to 165° C. for three hours. The reaction mixture was then cooled to room temperature and diluted with water (100 mL). The resultant solid was filtered, dried, re-dissolved in CH2Cl2, and passed through a silica gel plug to afford 12.8 g (73percent) of the title compound as an off-white solid.
Reference：
[1] Patent: CN105669539, 2016, A, . Location in patent: Paragraph 0058; 0059; 0060
[2] Patent: US2008/242695, 2008, A1, . Location in patent: Page/Page column 34
[3] Patent: US2008/242695, 2008, A1, . Location in patent: Page/Page column 34
20
[ 89402-43-7 ]
[ 514797-96-7 ]
Yield
Reaction Conditions
Operation in experiment
78%
Stage #1: Heating / reflux
Example 6(a) 5-Chloro-3-fluoro-2-hydroxypyridine. To a solution of NaOH (101 g, 2.5 mol) in water (500 mL) was added 5-chloro-2,3-difluoropyridine (101 g, 0.68 mol) as a liquid, and the resulting mixture was heated to reflux overnight. After cooling to room temperature, the mixture was filtered through a pad of celite and the pH was adjusted to 1 by the addition of concentrated HCl. The resulting solid was removed by filtration and dissolved in ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The title compound was obtained as a white solid (78 g, 78percent) and was used without additional purification. The product was characterized by 1H NMR.
With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2’,4’,6’-triisopropyl-1,1‘-biphenyl][2-(2-aminoethyl)phenyl]palladium(ll); tetrabutylammomium bromide In 2-methyltetrahydrofuran at 70℃; Inert atmosphere
[00316] 3-fluoro-2-hydrazinyl-5- (i-methyl-i H-pyrazol-4-yl)-pyridine was synthesized according to Scheme 14 by the following procedure. A 60 L jacketed reactor was fitted with a 5 L addition funnel and the jacket temperature was set to 20±5 °C. 36.0 L (15 Vol) of 2- methyltetrahydrofuran was added to the reactor via a 20 tm inline filter with vacuum using polypropylene transfer lines. The solution was sparged by bubbling nitrogen through a dipstick in the solution for 1±0.5 h with agitation. After 1 h the dipstick was removed but the nitrogen sweep continued. 1.55 kg of sparged 2-MeTHF was removed to be used as rinse volumes. 36.7 g of Pd2dba3, 75.6 g X-Phos, 259 g of tetrabutylammonium bromide, and 7397 g of potassium phosphate tribasic were added to the reactor. The manhole was rinsed with 0.125 kg of sparged 2-MeTHF. The reactor was agitated and the nitrogen sweep continued for 1±0.5 h. Then the nitrogen sweep was stopped and the reaction left under a positive pressure of nitrogen.[00317] 3.6 L (1.5 Vol) of sparged water was prepared in advance by bubbling nitrogen through a 4 L bottle of water for 1±0.5 h. The nitrogen sparged water was transferred to the 5 L addition funnel via a 20 tm inline filter with vacuum using polypropylene transfer lines, then slowly added to the reaction while maintaining the internal temperature at 20±5 °C. The 5 L addition funnel was replaced with a 2 L addition funnel. 2412 g of 5-chloro-2,3-difluoropyridine was added to the 2 L addition funnel. The 5-chloro-2,3-difluoropyridine was then added to the reaction through the 2 L addition funnel. The 2L addition funnel was rinsed with 0.060 kg of sparged 2-MeTHF. 83.8 g (1.15 equivalents) of 1-methylpyrazole-4-boronic acid, pinacol ester was added to reactor, the reactor was swept with nitrogen for 1±0.5 h, then left under a positive pressure of nitrogen. The internal temperature of the reactor was adjusted to 70±5 °C. The batch was agitated at 70±5 °C for at least 4 hours after the final reagent was added. A sample was taken from the reaction and the reaction progress assayed for conversion. The progress of the reaction was checked every 2 hours until the reaction was completed (e.g., greater than 99percent conversion). The batch was cooled to 20±5 °C.[00318] A 20percent w/v sodium bisulfite solution (12.0 L, 5 Vol) was prepared by charging 12.0 L of water then 2411 g sodium bisulfite to an appropriate container and agitating until homogeneous. The 20percent sodium bisulfite solution was transferred into the reactor and agitated for 30 minutes. The agitation was stopped, the phases allowed to settle, and the aqueous phase was removed. A 0.5 M potassium fluoride solution (12.0 L, 5 Vol) was prepared by charging 12.0 L of water and 348 g of potassium fluoride to an appropriate container and agitating until homogenous. The 0.5 M potassium fluoride solution was transfened into the reactor and agitated for 30 mm. The agitation was stopped, the phases were allowed to settle, and the aqueous phase was removed. A 25percent w/v sodium chloride solution (12.0 L, 5 Vol) was prepared by charging an appropriate container with 12.0 L of water and 2999 g of sodium chloride and agitating until homogeneous. The 25percent sodium chloride solution was transferred into the reactor and agitated for 30 mm. The agitation was stopped, the phases were allowed to settle, and the aqueous phase was removed from the reactor.[00319] The organic phase was distilled at constant volume (36 L, 15 Vol) while maintaining the internal temperature of the reactor at 50±5 °C by adjusting the vacuum pressure until no more than 0.3percent of water remained. 2-Methyltetrahydrofuran was added to the reactor as needed to maintain constant volume. The batch was cooled to 20 °C and transferred into drums. The batch was transfeffed using a polish filter (using a 5 tm inline filter) into a 60 L jacketed reactor withbatched concentrator attached. 1.2 L of 2-MeTHF was used to rinse the drums. The batch was concentrated to about 9 Vol while maintaining the internal temperature of the vessel at 50±5adjusting the vacuum pressure. The batch was then distilled at constant volume (22.0 L, 9Vol) while maintaining the internal temperature of the vessel at 50±5 °C by adjusting the vacuum pressure. Heptane was added with residual vacuum until a 15percent 2-MeTHF:heptane supernatant mixture was obtained. The pressure was brought to atmospheric pressure under nitrogen. The reactor was cooled to 20±5 °C over 2±2 h. The batch was agitated at 20±5 °C until an assay of the supernatant indicated that the amount of product was 7 mg/mL 2,3-difluoro-1-methyl-i H-pyrazol-4-yl)pyridine.[00320] A 10percent 2-MeTHF:heptane (7.2 L, 3 Vol) wash solution was prepared by mixing 720 mL of 2-MeTHF and 6.5 L of heptane. The batch sluffy was filtered through an Aurora filter fitted with a 25 tm polypropylene filter cloth, resulting in heavy crystals that required pumping with a diaphragm pump using polypropylene transfer lines through the top of the reactor while stirring. The mother liquor was recycled to complete the transfer. The reactor and filter cake were washed with two portions of the 10percent 2-MeTHF:heptane wash solution (3.6 L each). The product cake was dried on a frit under a nitrogen stream at ambient temperature. The 2,3- difluoro-5-(i-methyl-1H-pyrazol-4-yl)pyridine was detennined to be dry when the ‘H NMR assay was 0.05±0.05. 2.635 kg was isolated as an off white crystalline solid (85percent yield).
Reference：
[1] Patent: WO2014/210042, 2014, A2, . Location in patent: Paragraph 00316-00320
[2] Journal of Medicinal Chemistry, 2016, vol. 59, # 6, p. 2328 - 2342
23
[ 89402-43-7 ]
[ 847818-55-7 ]
[ 1151801-90-9 ]
Yield
Reaction Conditions
Operation in experiment
76%
With potassium phosphate; palladium diacetate; XPhos In 1,4-dioxane; water at 100℃; for 12 h; Inert atmosphere; Reflux
General procedure: Typical procedure 1: a mixture of 5-chloro-2-fluoropyridine 5a(6.60 g, 50.2 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid(6.30 g, 50.1 mmol), Pd(OAc)2 (0.46 g, 2.1 mmol), 2-dicyclohexylphosphino-20,40,60-triisopropylbiphenyl (1.99 g, 4.1 mmol), and K3PO4 (26.30 g, 123.7 mmol) in dioxane/water (80 mL/8 mL)was stirred at 100 C under N2 atmosphere until the reaction wascompleted by TLC. After the solution was concentrated underreduced pressure, the product was purified via column chromatographyto afford compound 6 found.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 16, p. 3483 - 3493
[2] Journal of Medicinal Chemistry, 2015, vol. 58, # 5, p. 2417 - 2430
24
[ 89402-43-7 ]
[ 1151801-90-9 ]
Yield
Reaction Conditions
Operation in experiment
87%
With chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2’,4’,6’-triisopropyl-1,1‘-biphenyl][2-(2-aminoethyl)phenyl]palladium(ll) In water; iso-butanol at 20 - 80℃; Inert atmosphere
2,3-Difluoro-5- (i-methyl-i H-pyrazol-4-yl)pyridine was synthesized according to Scheme 13 by the following procedure. A boronic-ate complex sluffy was prepared in a first 3- neck-2-L round-bottom flask (RBF 1). RBF 1 was charged with 141 g (66.4 wtpercent, 0.9 equivalents based on boronic ester) of lithium 2-hydroxy-4,4,5,5-tetramethyl-2-(i-methyl-1H- pyrazol-4-yl)- 1,3 ,2-dioxaborolan-2-uide. 120 mL (1.6 Vol relative to 5-chloro-2,3- difluoropyridine) of nitrogen-sparged (2 h) 2-BuOH and 120 mL (1.6 Vol) nitrogen-sparged (2 h) water were added to RBF 1. Agitation and N2 sweep were initiated. The reaction was aged at 20 °C for at least 30 mm (reactions aged to 24 h were also successful).[00310] A second 3-neck-2-L round-bottom flask (RBF 2) was charged with 1.48 g (0.004 equivalents) of Xphos-palladacycle and 450 mL (6 Vol relative to 5-chloro-2,3-difluoropyridine) of nitrogen-sparged (2 h) 2-BuOH. VacuumlN2 flush was cycled through RBF 2 three times to inert the RBF with N2. The batch in RBF 2 was heated to 80 °C. 75 g (1.0 equivalents) of 5- chloro-2,3-difluoropyridine was added to RBF 2.[00311] The slurry of boronic-ate complex was transferred from RBF 1 to a 500 mL dropping funnel. RBF 1 was rinsed with 30 mL (0.4 Vol) 2-BuOH. Using the dropping funnel, the sluffy of boronic-ate complex was added over 1 h to the hot solution mixture in RBF 2. After 1 h, 95percent conversion was observed. If greater than 90percent conversion was not observed, additional boronic-ate complex slurry was added (0.1 equivalents at a time with 1.6 Vol of 1:1 2- BuOH/water relative to boronic-ate complex). After the conversion was complete, the batch was cooled to 50 °C. While cooling, 600 mL (8 Vol) of toluene was added to RBF 2. 300 mL (4 Vol) of 20percent w/v NaHSO3 in water was added to RBF 2 and the batch was stirred at 50 °C for at least 1 h. The batch was polish filtered using a 5 micron Whatman filter at 50 °C, into a 2-L Atlas reactor. RBF 2 was rinsed with 30 mL (4.0 Vol) of a 1:1 2-BuOH:toluene solution. The temperature of the batch was adjusted to 50 °C in the Atlas reactor while stuffing. The stirring was stopped and the phases were allowed to settle for at least 15 mm while maintaining the batch at 50 °C. The bottom, aqueous layer was separated from the batch. The Atlas reactor was charged with 300 mL (4 Vol) of a 20percent w/v NaHSO3 solution and the batch was stirred at 50°C for 1 h. The agitation was stopped and the phases were allowed to settle for at least 15 mm at 50°C. The bottom, aqueous layer was removed. Agitation was initiated and the Atlas reactor was charged with 200 mL (4 Vol) of 0.5 M KF while keeping the batch at 50 °C for at least 30 mm. The agitation was stopped and the phases were allowed to settle for at least 15 mm at 50 °C. The bottom, aqueous layer was removed. Agitation was initiated and the reactor was charged with 300 mL (4 Vol) of water. The batch was aged at 50 °C for at least 30 mm. Agitation was stopped and the phases were allowed to settle for at least 15 mm at 50 °C. The bottom, aqueous later was removed.[00312] The organic phase was concentrated by distillation under reduced pressure (180 ton, jacket temp 70°C, internal temp about 50 °C) to a minimal stir volume (about 225 mL). 525 mL (7 Vol) of 2-BuOH was added to the Atlas reactor. The organic batch was again concentrated using reduced pressure (85-95 torr, jacket temp 75 °C, internal temp about 55 °C) to a minimal stir volume (about 125 mL). The total volume of the batch was adjusted to 250 mL with 2- BuOH.[00313] 525 mL (7 Vol) heptane was added to the slurry mixture in the Atlas reactor. The jacket temperature was adjusted to 100 °C and the batch was aged for more than 15 mm, until the batch became homogeneous. The batch was cooled to 20 °C over at least 3 h. A sample of the mixture was taken and the supernatant assayed for 2,3-difluoro-5-(1-methyl-1H-pyrazol-4- yl)pyridine. If the concentration was greater than 10 mg/mL, the aging was continued for at least 1 h until the supernatant concentration was less than 10 mg/mL. The batch was filtered using a medium frit. The filter cake was washed with 150 mL (2 Vol) 30percent 2-BuOH/heptane solution followed by 150 mL (2 Vol) heptane. The filter cake was dried under N2/vacuum. 76.64 g of 2,3-difluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridine was isolated as a white solid (87percent yield).
With caesium fluoride; potassium fluoride; In sulfolane; (2S)-N-methyl-1-phenylpropan-2-amine hydrate;
(c) 64.6 g (1.11 mol) of potassium fluoride and 11.25 g (0.074 mol) of caesium fluoride are suspended in 240 ml of sulfolane and the suspension is heated to 140 C. 50 mol of sulfolane are distilled off by decreasing the pressure and then 61.4 g (0.37 mol) of <strong>[103999-77-5]2,5-dichloro-3-fluoropyridine</strong> and 1.45 g (0.0055 mol) of 18-crown-6 in 20 ml of sulfolane are added to the suspension. This reaction mixture is stirred for 35 hours at 140 C. and then taken up in ice water. The product is isolated from the aqueous mixture either by extraction with ether or by steam distillation, affording 48.7 g (88% of theory) of 5-chloro-2,3-difluoropyridine, b.p. 65-66 C. at 133 mbar.
With potassium carbonate; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; hexane; ethyl acetate; acetonitrile;
Example P2 Methyl 2-[4-(5-chloro-3-fluoropyridin-2-yloxy)phenoxy]-propionate A solution of 14.95 g (0.10 mol) of <strong>[89402-43-7]5-chloro-2,3-difluoropyridine</strong> in 30 ml of acetonitrile is added dropwise to a mixture of 21.6 g (0.11 mol) of methyl 2-(4-hydroxyphenoxy)propionate, 15.2 g (0.11 mol) of potassium carbonate, 1.45 g (0.0055 mol) of 18-crown-6 and 100 ml of acetonitrile and the reaction mixture is then heated for 40 hours to a temperature in the range from 50° to 60° C. The mixture is taken up in ice water, the organic phase is separated, the aqueous phase is extracted three times with ethyl acetate and the combined organic phases are dried and concentrated by evaporation, affording an oily residue which for purification is dissolved in a mixture of hexane and ethyl acetate and filtered through silica gel. The solvent is evaporated off, affording from the filtrate 20.4 g (63percent of theory) of methyl 2-[4-(5-chloro-3-fluoropyridin-2-yloxy)phenoxy]propionate, m.p. 58° -59° C.
With hydrazine; In propan-1-ol; for 6h;Heating / reflux;
7.5 g of the compound obtained in Step 3 and 9.57 ml of hydrazine monohydrate were added to 50 ml of n-propanol, the resulting mixture was refluxed for 6 hours, and distilled under a reduced pressure to remove the solvent. The resulting residue was dissolved in 80 ml of chloromethane, washed with water, and dried over anhydrous magnesium sulfate. The dried organic layer was concentrated under a reduced pressure to obtain 7.26 g of the title compound.
EXAMPLE 4 For the preparation of 2,3-difluoropyridine, 179.4 g (1.2 mol) of 5-chloro-2,3-difluoropyridine, and 4.5 g of 5% Pd/C (50% water-moist) as catalyst, are placed, together with 598.5 g (1.5 mol) of tri (C8 /C10) alkylamine as base, in a reaction vessel (autoclave). The reaction solution is heated to 90 C. and reductively dechlorinated with hydrogen at this temperature. After the uptake of hydrogen has ended, the reaction solution is stirred for a short time before being cooled to room temperature and neutralized with sodium hydroxide solution, and the catalyst is filtered off with suction from the reaction mixture. The organic phase is separated off and distilled at atmospheric pressure, and the resulting distillate is dried and then fractionated. The remaining mother liquor, forerunnings, intermediate runnings and residues from distillation are recycled without further pretreatment to the subsequent batch. Conversion: 95.0% (by GC) Yield: 127.7 g (1.1 mol) of 2,3-difluoropyridine 91.7% based on the 5-chloro-2,3-difluoropyridine employed. Purity: >99 (GC area-%) 2,3 -difluoropyridine
palladium-carbon;
The amine mother liquor, together with the production residues from the initial batch, is made up with 179.4 g (1.2 mol) of 5-chloro-2,3-difluoropyridine and 4.5 g of 5% Pd/C (50% water-moist) and, analogously to the initial batch, is reductively dechlorinated and worked up correspondingly. The production residues resulting from the fractionation (forerunnings, intermediate runnings and residues from distillation) are recycled without further pretreatment to the subsequent batch. Conversion: 99.5% (by GC) Yield: 135.6 g (1.18 mol) of 2,3-difluoropyridine 98.2% based on the 5-chloro-2,3-difluoropyridine employed. Purity: >99.9 (GC area-%) 2,3-difluoropyridine
With potassium fluoride; C6H10BNO4; In dimethyl sulfoxide; at 60℃; for 5h;
36.5 g of 2,3,5-trichloropyridine (0.2 mol) was added to a dry reactor.292 g of dimethyl sulfoxide, 34.8 g of potassium fluoride (0.62 mol),0.32 g of boron-containing compound I-1 (0.019 mol), and the mixture was heated to 60 C for 5 h.After the reaction of the raw materials is completed, the residue potassium chloride is removed by centrifugation.The mother liquid was removed under reduced pressure of the solvent dimethyl sulfoxide, and 29.5 g of 2,3-difluoro-5-chloropyridine was extracted with dichloromethane to give a qualitative content of 96%, yield 95%.The molar ratio of the fluorinated halogen to the fluorinating reagent in the raw material is 1:1.55, the molar ratio of the reactant (the material to be fluorinated) to the boron-containing compound is 1:0.1, and the weight ratio of the raw materials to the solvent other than the solvent is 1: 4.
90%
With potassium fluoride; 18-crown-6 ether; potassium carbonate; cesium fluoride; In sulfolane; dimethyl sulfoxide; at 120 - 200℃; for 3h;
400 g of sulfolane and 400 g of dimethylsulfoxide were weighed into a 1000 mL flask and dehydrated to a temperature of less than 0.05% at 200 C under a pressure of 0.07 MPa (negative pressure)96 g (1.66 mol) of cesium fluoride, 96 g (1.66 mol) of potassium fluoride, 120 g (0.67 mol) of trichloropyridine, 2 g of 18-crown ether and 3 g of potassium carbonate were weighed into a reaction flask at 120 C and heated to 200 C The product was collected in about 3 hours. 95 g (0.51 mol) of the product was obtained in 90% yield. The purity was 96.8% as determined by gas chromatography.
With potassium carbonate; cesium fluoride; In dimethyl sulfoxide;
EXAMPLE 13 PREPARATION OF 5-CHLORO-2,3-DIFLUOROPYRIDINE Cesium fluoride (125 g, 0.82 mol) and DMSO (300 ml) were placed in a fluorination flask equipped with a mechanical stirrer, a thermometer, and a distilling head. About 50 ml DMSO were distilled off, under vacuum, to dry the system. 2,3,5-Trichloropyridine (50 g, 0.27 mol) and potassium carbonate (2.5 g, 0.018 mol) were added and the mixture was heated at 130-140 C. for 7 hours, with vigorous stirring. The product was distilled directly out of the reaction mixture, under vacuum. The DMSO was watered out and the product was redistilled to give a clear, colorless liquid (11.9 g, 29% of theoretical, b.p. 70-73 C. a 85 mmHg).
With potassium carbonate; In dimethyl sulfoxide;
EXAMPLE 13 PREPARATION OF 5-CHLORO-2,3-DIFLUOROPYRIDINE Cedium fluoride (125 g, 0.82 mol) and DMSO (300 ml) were placed in a fluorination flask equipped with a mechanical stirrer, a thermometer, and a distilling head. About 50 ml DMSO were distilled off, under vacuum, to dry the system. 2,3,5-Trichloropyridine (50 g, 0.27 mol) and potassium carbonate (2.5 g, 0.018 mol) were added and the mixture was heated at 130-140 C. for 7 hours, with vigorous stirring. The product was distilled directly out of the reaction mixture, under vacuum. The DMSO was watered out and the product was redistilled to give a clear, colorless liquid (11.9 g, 29% of theoretical, b.p. 70-73 C.a85 mmHg).
With potassium carbonate; cesium fluoride; In dimethyl sulfoxide;
EXAMPLE 13 Preparation of 5-Chloro-2,3-Difluoropyridine Cesium fluoride (125 g, 0.82 mol) and DMSO (300 ml) were placed in a fluorination flask equipped with a mechanical stirrer, a thermometer, and a distilling head. About 50 ml DMSO were distilled off, under vacuum, to dry the system. 2,3,5-Trichloropyridine (50 g, 0.27 mol) and potassium carbonate (2.5 g, 0.018 mol) were added and the mixture was heated at 130-140 C. for 7 hours, with vigorous stirring. The product was distilled directly out of the reaction mixture, under vacuum. The DMSO was watered out and the product was redistilled to give a clear, colorless liquid (11.9 g, 29% of theoretical, b.p. 70-73 C. a 85 mmHg).
With potassium hexamethylsilazane; In toluene; at 0℃; for 1h;
Potassium hexamethyldisilazane (1.34 ml, 0.5 M solution in toluene) was slowly added to a solution of 5-Chloro-2, 3-difluoro-pyridine (0.1 g) and N-Boc-4-Cyano-Piperidine (0.14 g) in 3 ml toluene at 0C, under nitrogen. The mixture was stirred at 0C for I hr. After cooling, the reaction mixture was quenched in IN HCI. The aqueous phase was extracted twice with ethyl acetate and the combined organic were washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by chromatography [Si02 ; hexane-ethyl acetate-hexane (4: 1) ] to give 111 mg (49%) of 5- chloro-4'-cyano-3-fluoro-3', 4', 5', 6'-tetrahydro-2'H- [2, 4'] bipyridinyl-1'-carboxylic acid tert- butyl ester; MS (ES+) 240 (M-Boc+ H+).
3-chloro-5,6-difluoro-2-hydrazinopyridine[ No CAS ]
[ 89402-43-7 ]
Yield
Reaction Conditions
Operation in experiment
With copper(II) sulfate; acetic acid; In water; at 24℃;Heating / reflux;
17.9 g of the compound obtained in Step 2 was added to a mixture of 360 ml of acetic acid and 135 ml of water, and 450 ml of 10percent aqueous copper sulfate was added dropwise thereto. The resulting mixture was refluxed for 24 hours while removing water using a Dean-Stark trap, to obtain 12.9 g of the title compound.
EXAMPLE 13 The procedure was as in Example 12, but instead of 271.9 g (4.68 mol) of potassium fluoride, 254.7 g (4.38 mol) of potassium fluoride mixed with 45.0 g (0.296 mol) of cesium fluoride and instead of 21.3 g of tetra-n-octylphosphonium bromide, 28.4 g of this compound were employed. The other quantities used remained unchanged, as well as the reaction conditions (time, vessel) and the working up and analysis. 144.5 g (0.967 mol, 53.7% of theory) of 5-chloro-2,3-difluoropyridine and 70.2 g (0.423 mol, 23.5% of theory) of 3,5-dichloro-2-fluoropyridine were obtained in the mixture of the low-boiling components (516.2 g) removed by distillation (space efficiency: 20.1 g/l*h, selectivity: 90%).
23
[ 16063-70-0 ]
[ 23906-97-0 ]
[ 823-56-3 ]
[ 89402-43-7 ]
Yield
Reaction Conditions
Operation in experiment
With potassium fluoride; potassium carbonate; cesium fluoride; In sulfolane;
EXAMPLE 8 850 g of sulfolane, 204.3 g (3.3 mol) of potassium fluoride/cesium fluoride (9:1), 7.5 g of potassium carbonate and 20.4 g of tetra-n-octylphosphonium bromide as the phase transfer catalyst were azeotropically dried by removal of about 100 g of sulfolane by distillation (170 C.). 273.5 g (1.5 mol) of 2,3,5-trichloropyridine were then added at 190 C. and the reaction mixture was heated to 215 C. After about 2 h reflux commenced. This was maintained for 20 h, and all the substance which boiled below 3 mm Hg/140 C. was then removed from the reaction mixture by distillation. A first fraction (15.8 g) which contained 14.2 g of 5-chloro-2,3-difluoropyridine and 1.3 g of 3,5-dichloro-2-fluoropyridine (determined by GC by means of internal standard) was obtained.
With potassium-fluoride; In sulfolane; tetrahydrothiophene 1,1-dioxide (sulfolane);
(c) 5-chloro-2,3-difluoropyridine A suspension of 64.6 g (1.1 mol) of potassium fluoride and 11.25 g (0.075 mol) of cesium-fluoride in 240 ml of sulfolane (1,1-dioxo-tetrahydrothiophene) is heated to 140 C. By reducing the pressure 50 ml of sulfolane are distilled off. To the suspension a solution of 61.4 g (0.37 mol) of <strong>[103999-77-5]2,5-dichloro-3-fluoropyridine</strong> in 20 ml of sulfolane is added. The reaction-mixture is then stirred for 35 hours at a temperature of 140, cooled and poured into ice/water. The organic material is extracted with ether. The ethereal layer is washed with water dried over magnesium sulfate, filtered and evaporated to yield 48.7 g of a colourless oil (88% of the theory) which boils at 65-66 at 133 mbar.
88%
With potassium fluoride; In sulfolane; tetrahydrothiophene 1,1-dioxide (sulfolane);
(c) 5-chloro-2,3-difluoropyridine A suspension of 64.6 g (1.1 mol) of potassium fluoride and 11.25 g (0.075 mol) of cesium-fluoride in 240 ml of sulfolane (1,1-dioxo-tetrahydrothiophene) is heated to 140 C. By reducing the pressure 50 ml of sulfolane are distilled off. To the suspension a solution of 61.4 g (0.37 mol) of <strong>[103999-77-5]2,5-dichloro-3-fluoropyridine</strong> in 20 ml of sulfolane is added. The reaction-mixture is then stirred for 35 hours at a temperature of 140, cooled and poured into ice/water. The organic material is extracted with ether. The ethereal layer is washed with water dried over magnesium sulfate, filtered and evaporated to yield 48.7 g of a colourless oil (88% of the theory) which boils at 65-66 at 133 mbar.
With potassium fluoride; hydrogen fluoride; tetrabutylammomium bromide; sodium nitrite; In sulfolane; dichloromethane;
Example P9 5-Chloro-2,3-difluoropyridine A 500 ml polytetrafluoroethylene reactor equipped with stirrer, thermometer and reflux condenser is charged with 120 g of hydrogen fluoride. A solution of 40.7 g (0.25 mol) of <strong>[78607-32-6]3-amino-2,5-dichloropyridine</strong> in 100 ml of sulfolane is added dropwise at a temperature in the range from 0° C. to +10° C. Then 20.7 g (0.3 mol) of sodium nitrite are introduced into this solution at +50° C. The resultant nitrogen is removed from the reactor through reflux condenser. Gas evolution ceases after 2 hours at +50° C. 150 ml of methylene chloride are added to the reaction mixture which is then poured into ice water. The two-phase mixture is neutralised with ammonia solution. The organic phase is separated and dried over sodium sulfate. The solvent is distilled off and then 200 ml of sulfolane, 166 g (2.879 mol) of potassium fluoride and 2 g of tetrabutylammonium bromide are added to the mixture of sulfolane and the product. This reacton mixture is stirred for 7 hours at 179° C. The product is subsequently distilled off directly from the sulfolane solution. The crude product is purified by distillation, affording the 5-chloro-2,3-difluoropyridine, b.p. 137°-139° C.
Comparison Example 8 Preparing 2,3-difluoro-5-chloropyridine by Reacting <strong>[823-56-3]2-fluoro-3,5-dichloropyridine</strong> Using tetraphenylphosphonium bromide as Catalyst 166 g (1 mol) of <strong>[823-56-3]2-fluoro-3,5-dichloropyridine</strong>, 68.4 g (1.2 mol) of potassium fluoride and 4.19 g (0.01 mol) of tetraphenylphosphonium bromide are employed and the procedure described in Example 11 is followed. The reaction conditions (reaction temperature, time) and conversion and yield for Example 11 and Comparison Example 8 are given in Table 4 below.
Example 11 Preparing 2,3-difluoro-5-chloropyridine by Reacting <strong>[823-56-3]2-fluoro-3,5-dichloropyridine</strong> Using tetrakis(diethylamino)phosphonium bromide A 500 ml four-necked flask which is equipped with thermometer, anchor stirrer and reflux condenser with bubble counter is charged with 166 g (1 mol) of <strong>[823-56-3]2-fluoro-3,5-dichloropyridine</strong>, 68.4 g (1.2 mol) of potassium fluoride and 3.99 g (0.01 mol) of tetrakis(diethylamino)phosphonium bromide. The reaction mixture is then heated with stirring to the predetermined reaction temperature and is allowed to react for the time indicated. After the end of the reaction the reaction mixture is cooled and poured into water which is employed in excess, the mixture is subjected to extraction with methylene chloride, and the isolated methylene chloride phase is washed with water, dried and then subjected to fractional distillation under reduced pressure.
8-(piperidin-3-ylacetyl)-8-azabicyclo[3.2.1]octan-3-ol hydrochloride[ No CAS ]
[ 89402-43-7 ]
8-[1-(5-chloro-3-fluoropyridin-2-yl)piperidin-3-yI]acetyI-8-azabicyclo[3.2.1]octan-3-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44%
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 180℃; for 0.333333h;Microwaved;
A mixture of 8-[piperidm-3-ylacety]]-8-azabicyclo[3.2.1]octan-3-ol hydrochloride (27.4 mg,0.0000950 mol), <strong>[89402-43-7]5-chloro-2,3-difluoropyridine</strong> (0.0156 g, 0.000104 mol) and N,N- diisopropylethylamine (0.0496 mL, 0.000285 mol) in N-methylpyrrolidinone (0.500 raL, 0.00518 mol) was microwaved at 180 °C for 20 min. The resultant mixture was applied on RP-HPLC to give the desired product (16 mg 44percent. LCMS (M+H) 382.2.
With caesium carbonate; In dimethyl sulfoxide; at 110℃; for 4.5h;
Reference Production Example 25 A mixture of 3.85 g of <strong>[89402-43-7]5-chloro-2,3-difluoropyridine</strong>, 8.80 g of diethyl malonate, 25 ml of dimethyl sulfoxide and 17.9 g of cesium carbonate was stirred for 4.5 hours at 110°C under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, then, to this was added ice water, and extracted with ethyl acetate. The organic layer was washed with saturated brine twice, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure, to obtain 5.83 g of diethyl (5-chloro-3-fluoro-2-pyridyl) malonate. 1H-NMR (CDCl3, TMS) delta (ppm): 1.29 (6 H, t, J=7.1 Hz), 4.28 (4 H, q, J=7.1 Hz), 5.03 (1 H, s), 7.49 (1 H, dd, J=9.0, 2.0 Hz), 8.39 (1 H, d, J=2.0 Hz)
5-chloro-2,3-difluoro-pyridine (100g, 0.669mol) and ammonia (1.125L, 8.025mol) added to the autoclave.After the reaction 120 sealed 24h, the reaction was complete, the cooling pale yellow solid precipitation, filtration, the filter cake was washed with water, and the filtrate was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate, the organic phase was distilled off under reduced pressure, with beating a small amount of petroleum ether, filtration, and precipitation cake cake obtained will be collected at the same time to give the compound 2-amino-3-fluoro-5-chloropyridine 84.22g, yield 85.94%.
76%
With ammonia; In water; at 150℃; for 1h;Microwave irradiation;Product distribution / selectivity;
Example 4Preparation of 6-chloro-1-(pentan-3-yl)-1H-imidazo[4,5-b]pyridin-2-ol; Example 4(a) 5-chloro-3-fluoropyridin-2-amine: To a 20 mL microwave vial equipped with a stir bar was added 5-chloro-2,3-difluoropyridine (2.0 g, 41 mmol). Ammonium hydroxide (ca 12 mL) was then added and the mixture was stirred until homogeneous. The solution was capped and heated in the microwave reactor at 150 C. for three 20 minute increments until a white solid precipitated out of solution. The white solid was filtered, washed with water, and dried to afford 2-amino-5-chloro-3-fluoropyridine (1.5 g, 76% yield), characterized by 1H NMR (d6-DMSO).
73%
With ammonia; In water; at 165℃; for 3h;Product distribution / selectivity;
Example 5(a) 5-Chloro-3-fluoropyridin-2-amine.; To a stainless steel high pressure reactor was added 5-chloro-2,3-difluoropyridine (18.0 g) and ammonium hydroxide (65 mL). The reaction was heated to 165 C. for three hours. The reaction mixture was then cooled to room temperature and diluted with water (100 mL). The resultant solid was filtered, dried, re-dissolved in CH2Cl2, and passed through a silica gel plug to afford 12.8 g (73%) of the title compound as an off-white solid.
Example 6(a) 5-Chloro-3-fluoro-2-hydroxypyridine. To a solution of NaOH (101 g, 2.5 mol) in water (500 mL) was added 5-chloro-2,3-difluoropyridine (101 g, 0.68 mol) as a liquid, and the resulting mixture was heated to reflux overnight. After cooling to room temperature, the mixture was filtered through a pad of celite and the pH was adjusted to 1 by the addition of concentrated HCl. The resulting solid was removed by filtration and dissolved in ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The title compound was obtained as a white solid (78 g, 78%) and was used without additional purification. The product was characterized by 1H NMR.
First step A starting material (128) (35 g) and sodium hydroxide (20.6 g) were dissolved in water (300 mL), and the mixture was heated at reflux for 2.5 hours. After cooled to 0 C, concentrated hydrochloride acid (44.7 mL) was added, water (120 mL) was added, and the precipitated solid was collected by filtration to afford the crude product (129) (25.9 g). To the filtrate was added a 4 mol/L sodium hydroxide aqueous solution to make the solution neutral, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate to afford the crude product (2) (5.29 g).
Example 196: 3-(Azetidin-3-yloxy)-2-benzyloxy-5-chloro-pyridine.; Step A: Preparation of 2-benzyloxy-5-chloro-3-fluoro-pyhdine.; To 60percent NaH in mineral oil (1.0 g, 25.0 mmol) in THF (25 ml_) was added benzyl alcohol (2.7 g, 2.6 ml_, 25.0 mmol) dropwise. After 1 h, 5-chloro-2,3-difluoro-pyhdine (3.73 g, 25.0 mmol) was added in THF (5 ml_). After an additional 18h, H2O was added and the mixture extracted with EtOAc (2X). The combined organics were washed with brine and dried. Silica gel chromatography (1 -15percent EtOAc in hexanes) gave 4.02 g (67percent yield) of the title compound as a clear oil. 1H NMR (CDCI3): 7.91 (d, J = 2.2 Hz, 1 H), 7.48-7.46 (m, 2H), 7.39-7.32 (m, 4H), 5.44 (s, 2H).
2-(4-hydroxy-2,6-dimethylphenyl)hexahydro-4,7-ethanoindene-1,3-dione[ No CAS ]
[ 89402-43-7 ]
2-[4-(5-chloro-3-fluoropyridin-2-yloxy)-2,6-dimethylphenyl]hexahydro-4,7-ethanoindene-1,3-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dmap; potassium carbonate; at 140℃; for 0.666667h;Microwave irradiation;
Step 6: Preparation of 2-[4-(5-chloro-3-fluoropyridin-2-yloxy)-2,6-dimethylphenyl]hexahydro-4,7- ethanoindene-1 ,3-dione To a mixture of 2-(4-hydroxy-2,6-dimethylphenyl)hexahydro-4,7-ethanoindene-1 ,3-dione (0.4Og, 0.0013mol), <strong>[89402-43-7]5-chloro-2,3-difluoropyridine</strong> (0.2Og, 0.0013mol) and potassium carbonate (0.40g, 0.0029mol) is added Lambda/,Lambda/-dimethylaminopyridine (10ml), and the reaction mixture is then heated at 14O0C for 40 minutes under microwave irradiation. After cooling to room temperature 2M aqueous hydrochloric acid is added, and the crude product is extracted with ethyl acetate. The organic phase is separated, washed with distilled water, then dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is then purified by preparative reverse phase HPLC to afford 2-[4-(5-chloro-3-fluoropyridin-2-yloxy)-2,6-dimethylphenyl]hexahydro-4,7- ethanoindene-1 ,3-dione as a cream solid.
With potassium acetate;tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In 1,4-dioxane; at 80℃; for 10h;
1) Preparation of 5-(2,2-diethoxyethoxy)-2,3-difluoropyridine A 1,4-dioxane solution (30 ml) of tris(dibenzylideneacetone)dipalladium(0) (115 mg, 0.20 mmol) and tricyclohexyl phosphine (135 mg, 0.48 mmol) was degassed, then stirred at room temperature for 30 minutes. To the reaction solution, added were bis(pinacolato)diboron (1.87 g, 7.36 mmol), potassium acetate (985 mg, 10.0 mmol) and <strong>[89402-43-7]5-chloro-2,3-difluoropyridine</strong> (1.0 g, 6.69 mmol), then degassed and stirred at 80°C for 10 hours. The reaction solution was cooled to room temperature, water was added, the insoluble matter was separated by filtration, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated saline water, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product (2.6 g) containing 2,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine as an orange oil.
With tris-(dibenzylideneacetone)dipalladium(0); potassium acetate; tricyclohexylphosphine; In 1,4-dioxane; at 85℃; for 16h;Inert atmosphere;
A mixture of of tris(dibenzyIideneacetone)dipalladium(0) (185 mg, 0.200 mmol) and tricyclohexyl phosphine (135 mg, 0.480 mmol), bis (pinacolato)diboron (1.95 g, 7.69mmol), potassium acetate (985 mg, 10.0 mmol) and <strong>[89402-43-7]5-chloro-2,3-difluoropyridine</strong> (1.00 g, 6.69 mmol) in 1 ,4-dioxane solution (30 mL) was bubbled with nitrogen and stirred at 85 °C for 16 h under nitrogen. The reaction mixture was diluted with water was added, filtered and extracted with ethyl acetate. Combined organic portions were washed with saturated saline water, then dried over anhydrous sodium sulfate and concentrated. The crude product (2.8 g) was obtained as orange oil. LC-MS (ESI): m/z 160 [M - H]"; 0.82 min (ret time).
With tris-(dibenzylideneacetone)dipalladium(0); potassium acetate; tricyclohexylphosphine; In 1,4-dioxane; at 85℃; for 16h;Inert atmosphere;
D42 2,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine A mixture of of tris(dibenzylideneacetone)dipalladium(0) (185 mg, 0.200 mmol) and tricyclohexyl phosphine (135 mg, 0.480 mmol), bis(pinacolato)diboron (1.95 g, 7.69 mmol), potassium acetate (985 mg, 10.0 mmol) and <strong>[89402-43-7]5-chloro-2,3-difluoropyridine</strong> (1.00 g, 6.69 mmol) in 1,4-dioxane solution (30 mL) was bubbled with nitrogen and stirred at 85° C. for 16 h under nitrogen. The reaction mixture was diluted with water was added, filtered and extracted with ethyl acetate. Combined organic portions were washed with saturated saline water, then dried over anhydrous sodium sulfate and concentrated. The crude product (2.8 g) was obtained as orange oil. LC-MS (ESI): m/z 160 [M-H]-; 0.82 min (ret time).
To a solution of ethyl cyanoacetate (Aldrich) (4 g, 35.4 mmol) in anhydrous DMSO (30 mL) at 0 C. was added slowly NaH (60%, 1.42 g, 35.6 mmol). The mixture was stirred at 0 C. for 0.5 h, then 5-chloro-2,3-difluoropyridine (Combi-Blocks) (5.3 g, 35.6 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. Water was added. The organic layer was separated, the aqueous layer was then extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4, concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:4, 1:1) to give (5-chloro-3-fluoro-pyridin-2-yl)-acetonitrile as a yellow gum (3.2 g, 37%).Step BTo the solution of (5-chloro-3-fluoro-pyridin-2-yl)-acetonitrile (2.8 g, 11.5 mmol) in DMSO (30 mL) was added NaCl (2 g, 34 mmol). The reaction mixture was heated at 170 C. for 2 h. The mixture was partitioned between ethyl acetate and water. Organic layer was separated, the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:4, 1:3) to give (5-chloro-3-fluoro-pyridin-2-yl)-acetonitrile as a brown oil (0.85 g, 43%).
A solution of <strong>[89402-43-7]5-chloro-2,3-difluoro-pyridine</strong> in EtOH was stirred at 80 °C for 16 h. The mixture was poured onto a saturated solution of sodium hydrogen carbonate and extracted with DCM. The organic layer was separated, dried (MgS04), filtered and the solvents evaporated in vacuo to yield intermediate 47 (1.64 g, 99percent) as a white solid.
99%
Example A475-Chloro-2-ethoxy-3-fluoro-pyridineA solution of <strong>[89402-43-7]5-chloro-2,3-difluoro-pyridine</strong> in EtOH was stirred at 80° C. for 16 h.The mixture was poured onto a saturated solution of sodium hydrogen carbonate and extracted with DCM.The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo to yield intermediate 47 (1.64 g, 99percent) as a white solid.
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 100℃;
Step C: <strong>[89402-43-7]5-Chloro-2,3-difluoropyridine</strong> (0.20 g, 1.3 mmol) was added to a mixture of (S)-methyl 5-(2-oxo-l-(piperidin-4-yl)pyrrolidin-3-yloxy)picolinate hydrochloride (0.17 g, 0.44 mmol) and DIEA (0.38 mL, 2.2 mmol) in DMF (1.5 mL). The mixture was stirred at 100 °C overnight and then cooled to ambient temperature. The mixture was partitioned between saturated aqueous NH4C1 (20 mL) and EtOAc (50 mL). The organic phase was washed successively with water (20 mL), water (20 mL) and then brine (20 mL). The combined organic phases were dried over MgS04, filtered and concentrated. The residue was purified on silica (eluting with EtOAc) to afford (S)-methyl 5-(l-(l-(5-chloro-3- fluoropyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)picolinate (0.17 g, 0.38 mmol, 86percent).
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃;
Step A: To a solution of (S)-methyl 3-fluoro-4-(2-oxo-l-(piperidin-4- yl)pyrrolidin-3-yloxy)benzoate hydrochloride (Example 151, Step B; 2.0 g, 5.9 mmol) in DMF (3 mL) was added N-ethyl-N-isopropylpropan-2-amine (3.8 g, 30 mmol) and 5-chloro- 2,3-difluoropyridine (2.7 g, 18 mmol) and the reaction was heated to 60 °C overnight. The reaction was next diluted with EtOAc (30 mL) and washed with water (30 mL), and brine (30 mL), and the combined organic phases were dried over MgS04, filtered and concentrated under vacuum. The crude material was purified on silica using a gradient of DCM to 1 : 19 EtOAc:DCM as eluent to yield (S)-methyl 4-(l-(l-(5-chloro-3-fluoropyridin-2-yl)piperidin- 4-yl)-2-oxopyrrolidin-3-yloxy)-3-fluorobenzoate (1.5 g, 54percent)
Adding water separately in the reaction kettle 20L, dimethyl sulfoxide 40L, sodium hydroxide to 9.5 kg (237mol), stirring, add R-2 - (P-hydroxy-phenoxy) propionic acid (optical purity 99.5%, content 99%) 18 kg (99mol), heating under stirring to the 45 C reaction 1 hour. By adding 17 kg (113.7mol) of 5-chloro -2,3-difluoro-pyridine, heating to 95 C reaction 6 hours, HPLC tracking of the reaction, when the raw material R-2 - (P-hydroxy-phenoxy) propionic acid is less than 1% of the, stop the reaction. Pressure reducing and recovering the solvent, adding residues 40L water to stir and dissolve, using 15% hydrochloric acid to adjust PH=3, separating solid under stirring, filtering, alkyne grass ester acid drying to 30 kg. Yield 97.1%, content of 99.1%, optical purity 99.2%.
91.3%
Add 15 mL of DMF to a 50 mL three-necked flask equipped with a constant pressure dropping funnel, a condenser and a thermometer.6.37g (0.035mol) R-HPPA, to be completely dissolved, add 7.26g (0.0525mol) K2CO3 particles, heat to 70-80 C stirMix for 2h, the system turns pink,4.76g (0.032mol) was then kept under constant temperature with a constant pressure dropping funnel.2,3-Difluoro-5-chloropyridine was slowly added dropwise to the reaction system, and it was dropped in about 30 minutes. Then, the temperature was raised to 90 C to keep the reaction, and the experiment was followed up by TLC, and the reaction was finished for about 8 hours. After the reaction solution is cooled to room temperature, adjust the pH of the system to 2-3 under ice bath conditions, and adjustDuring the process, a beige solid appeared and disappeared with the stirring. The ice bath was stirred for 1 hour, and there was a constant beige.The solid was precipitated, washed with water, suction filtered, dried to give 9.10 g of a beige solid, yield: 91.3%, and the purity was 97.5% by HPLC.
62%
N, N - dimethyl formamide (40 ml), (R)-2 - (4 - hydroxy-phenoxy) propionic acid (0.02 muM, 3 . 64g), potassium carbonate (0.02 muM, 2 . 76g), 75 C under stirring 0.5h after, then adding an equivalent amount of potassium carbonate, to continue stirring 0.5h. Slowly dropping 2,3-difluoro -5 - chloro pyridine (0.02 muM, 3 . 00g), after the completion of the dropping, the reaction temperature to maintain 75 C, 12h. Stop heating, cooling to room temperature, the reaction solution is poured into 100 ml ice water, dilute hydrochloric acid to adjust the pH 4 - 5, filter, a small amount of ice water washing three times, vacuum drying, be (R)-2-[4-(3-fluoro-5-chloro pyridine-2-yloxy) phenoxy] propionic acid white solid 3.86g, yield 62.0%.
62%
N, N-dimethylformamide (40 mL),(R) - (+) - 2- (4-hydroxyphenoxy) propionic acid (0.02 mol, 3.64 g)Potassium carbonate (0.02 mol, 2.76 g),After stirring at 75 C for 0.5 h,Then add the same amount of potassium carbonate,Continue stirring for 0.5 h.Slowly dropping 2,3-difluoro-5-chloropyridine (0.02 mol, 3.00 g)After dripping,The reaction temperature was maintained at 75 C,overnight.Stop heating,Cooled to room temperature,The reaction solution was poured into 200 mL of ice water,Dilute hydrochloric acid to adjust pH 4-5, filter,Washed with a small amount of ice water three times,Vacuum drying,(R) -2- [4- (3-fluoro-5-chloropyridin-2-oxy) phenoxy] propionic acid as a white solid, 3.86 g,Yield 62.0%.
62.0%
N, N-dimethylformamide (40 mL), (R) - (+) - 2- (4-hydroxyphenoxy) propionic acid (0.02 mol, 3.64 g) Potassium carbonate (0.02 mol, 2.76 g), After stirring at 75 C for 0.5 h, Then add the same amount of potassium carbonate, Continue stirring for 0.5 h. A solution of 2,3-difluoro-5-chloropyridine (0.02 mol, 3.00 g) After dripping, The reaction temperature was maintained at 75 C, overnight. Stop heating, Cooled to room temperature, The reaction solution was poured into 200 mL of ice water, Dilute hydrochloric acid to adjust pH 4-5, filter, Washed with a small amount of ice water three times, Vacuum drying, (R) -2- [4- (3-fluoro-5-chloropyridin-2-yloxy) phenoxy] propionic acid as a white solid, 3.86 g, Yield 62.0%.
62%
N, N-dimethylformamide (40 mL),(R) - (+) - 2- (4-hydroxyphenoxy) propionic acid(0.02 mol, 3.64 g),Potassium carbonate (0.02 mol, 2.76 g),Stirring at 0.5 C for 0.5 h, then add the same amount of potassium carbonate, continue stirring 0.5h.A solution of 2,3-difluoro-5-chloropyridine (0.02 mol, 3.00 g)After completion of the dropwise addition, the reaction temperature was maintained at 75 C overnight.The heating was stopped, the mixture was cooled to room temperature, and the reaction solution was poured into 200 mL of ice water,Dilute hydrochloric acid to adjust the pH 4-5, filter, washed with a small amount of ice water three times,Vacuum drying, too(R) -2- [4- (3-fluoro-5-chloropyridin-2-yloxy) phenoxy] propionic acidWhite solid 3.86 g,Yield 62.0%.
62%
N, N-dimethylformamide (40 mL),(R) - (+) - 2- (4-hydroxyphenoxy) propionic acid (0.02 mol, 3.64 g)Potassium carbonate (0.02 mol, 2.76 g),After stirring at 75 C for 0.5 h,Then add the same amount of potassium carbonate,Continue stirring for 0.5 h.A solution of 2,3-difluoro-5-chloropyridine (0.02 mol, 3.00 g)After dripping,The reaction temperature was maintained at 75 C,overnight.Stop heating,Cooled to room temperature,The reaction solution was poured into 200 mL of ice water,Dilute hydrochloric acid to adjust pH 4-5,filter,Washed with a small amount of ice water three times,Vacuum drying,(R) -2- [4- (3-fluoro-5-chloropyridin-2-yloxy) phenoxy] propionic acid as a white solid, 3.86 g,Yield 62.0%.
62%
N,N-dimethylformamide (40 mL),<strong>[94050-90-5](R)-(+)-2-(4-hydroxyphenoxy)propionic acid</strong> (0.02 mol, 3.64 g),Potassium carbonate (0.02 mol, 2.76 g),After stirring at 75 C for 0.5 h,Add the same amount of potassium carbonate,Stirring was continued for 0.5 h. Slowly add 2,3-difluoro-5-chloropyridine (0.02 mol, 3.00 g),After the completion of the dropwise addition, the reaction temperature was maintained at 75 C overnight. Stop heating and cool to room temperature. Pour the reaction solution into 200 mL of ice water.Dilute hydrochloric acid to adjust pH 4-5, filter,Wash three times with a small amount of ice water,Vacuum drying,(R)-2-[4-(3-Fluoro-5-chloropyridin-2-oxy)phenoxy]propionic acidWhite solid 3.86g,The yield was 62.0%.
62%
N, N - dimethyl formamide (40 ml), (R)-2 - (4 - hydroxy-phenoxy) propionic acid (0.02 muM, 3 . 64 g), potassium carbonate (0.02 muM, 2 . 76 g), 75 C under stirring 0.5 h after, then adding an equivalent amount of potassium carbonate, to continue stirring 0.5 h. Slowly dropping 2, 3 - difluoro -5 - chloro pyridine (0.02 muM, 3 . 00 g), after the completion of the dropping, the reaction temperature to maintain 75 C, 12 h. Stop heating, cooling to room temperature, the reaction solution is poured into 100 ml ice water, dilute hydrochloric acid to adjust the pH 4 - 5, filter, a small amount of ice water washing three times, vacuum drying, be (R)-2 - [4 - (3 - fluoro -5 - chloro pyridine -2 - yloxy) phenoxy] propionic acid white solid 3.86 g, yield 62.0%.
With tetrabutylammomium bromide; potassium carbonate; In N,N-dimethyl-formamide; at 60 - 70℃; for 2h;
500 g of DMF was added to a 1000 mL four-necked flask, 100 g of compound A was charged,113.6 g of potassium carbonate and 5 g of tetrabutylammonium bromide, the temperature was raised to 60 C, and 120.31 g of the product was added dropwise2,3-difluoro-5-chloropyridine in 50 g of DMF in a mixed solution at a controlled temperature of 65 to 70 C,After completion of the dropwise addition, the reaction was allowed to proceed for about 2 hours, the reaction was completed,The pH was adjusted to 7 to 8 with hydrochloric acid, stirred for 1 hour, filtered, and the solid was the ether compound (Compound H) and dried.
5.92 g
(R) -2- (4- (5-chloro-3-fluoropyridin-2-yloxy)Phenoxy) propanoic acid In a reactor equipped with a magnetic stirrer,Thermometer and condenser 100mL three-necked flask was added N, N- dimethylformamide (DMF) (40mL),(R) 2- (4-hydroxyphenoxy) propionic acid (0.02 mol),After stirring to dissolve,Potassium carbonate (0.04 mol) was added portionwiseHeating to 60 ~ 80 stirring 0.5 ~ 1.0hr.2,3-Difluoro-5-chloropyridine (0.02 mol) was added dropwise,Continue stirring reaction 6 ~ 8hr.The reaction was cooled to room temperature,Poured into ice water (250 mL)To the mixture was slowly added dilute hydrochloric acid,Adjusted to pH = 4 ~ 5,filter,Washed,The title compound (5.92 g) was dried to give a white solid.
With tetrabutylammomium bromide; potassium carbonate; In N,N-dimethyl-formamide; at 55 - 60℃; for 2h;
500 g of DMF was placed in a 1000 mL four-necked flask, and 100 g of Compound A, 113. 6 g of potassium carbonate and 5 g of tetrabutylammonium bromide were added, and the temperature was raised to 60 C. 90.3 g of Compound B was added dropwise, and the temperature was controlled at 60 to 55 C. At the end of the addition, the reaction was about 2 hours and the reaction was completed.Add to 1000g water,Adjust the pH to 7~8 with hydrochloric acid and stir for 1 hour.Filtered, the solid is etherified and dried.
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;
Preparation Example 134 To a mixture of <strong>[166272-81-7]methyl 4-chloro-3-hydroxybenzoate</strong> (500 mg), 5-chloro-2,3-difluoropyridine (801 mg), and DMF (10 ml) was added potassium carbonate (1.48 g), followed by stirring at 80 C. for 16 hours. The reaction mixture was returned to room temperature, and water was added thereto, followed by carrying out a separation of the layers using ethyl acetate. The organic layer was washed sequentially with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 90:10) to obtain 521 mg of methyl 4-chloro-3-[(5-chloro-3-fluoropyridin-2-yl)oxy]benzoate as a colorless solid.
Amine-I: l-(5-chloro-3-fluoropA solution of tert-butyl piperazine-l-carboxylate (745 mg, 4.00 mmol), 5-chloro-2,3- difluoropyridine (598 mg, 4 mmol), and DIEA (699 mu, 4.00 mmol) in NMP was heated at 160-165 °C for 1 h. After cooled down, the residue was treated with 50percent TFA in DCM (5ml) for 1 h. The solvent was removed, then residue was purified by silicon gel column with DCM, then 5percent MeOH in DCM to give l-(5-chloro-3-fluoropyridin-2-yl)piperazine (213mg, 0.988 mmol, 24.69 percent yield), white solid. 500MHz) 88.08 (1H, s), 7.64 (1H, s), 3.69 (4H,m), 3.34 (4H,m).
With potassium hexamethylsilazane; In toluene; at -5℃; for 1h;Inert atmosphere;
Step 1: 1-(5-chloro-3-fluoropyridin-2-yl)cyclopropanecarbonitrile Under an atmosphere of argon, <strong>[89402-43-7]5-chloro-2,3-difluoropyridine</strong> (6 g, 4.17 ml, 40.1 mmol, Eq: 1.00) was combined with toluene (60.0 ml). Then cyclopropanecarbonitrile (2.69 g, 3.02 ml, 40.1 mmol, Eq: 1.00) was added to the solution. At -5° C., potassium bis(trimethylsilyl)amide (80.3 ml, 40.1 mmol, Eq: 1.00) was added dropwise over 30 min. The dark brown reaction was stirred for 1 hour at -5° C., and then for 2 h at room temperature. The reaction mixture was poured into satd. NH4Cl solution (50 ml) and extracted with 2*100 ml ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (70 g column, from 100percent to 50percent heptane in ethyl acetate). The title compound was obtained as a orange oil (1.55 g, 13.8percent, MS (m/e)=197.2 [M+H+].
13.8%
With potassium hexamethylsilazane; In toluene; at -5 - 20℃; for 3h;Inert atmosphere;
Under an atmosphere of argon, <strong>[89402-43-7]5-chloro-2,3-difluoropyridine</strong> (6 g, 4.17 ml, 40.1 mmol, Eq: 1.00) was combined with toluene (60.0 ml). Then cyclopropanecarbonitrile (2.69 g, 3.02 ml, 40.1 mmol, Eq: 1.00) was added to the solution. At -5°C, potassium bis(trimethylsilyl)amide (80.3 ml, 40.1 mmol, Eq: 1.00) was added dropwise over 30min. The dark brown reaction was stirred for 1 hour at -5°C, and then for 2h at room temperature. The reaction mixture was poured into satd. NH4C1 solution (50 ml) and extracted with 2x100 ml ethyl acetate. The organic layer was dried over Na2S04, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (70 g column, from 100percent to 50percent heptane in ethyl acetate). The title compound was obtained as a orange oil (1.55 g, 13.8 percent, MS (m/e) = 197.2 [M+H+].
3%
[347] A solution of cyclopropanecarbonitrile (650 L, 8.826 mmol) in toluene (5.0 mL) was cooled to 0°C. Lithium bis(trimethylsilyl)amide (17 mL of 0.5 M toluene solution, 8.500 mmol) was added, and the resultant reaction mixture was warmed to room temperature and stirred for 30 minutes. The above solution was added to <strong>[89402-43-7]5-chloro-2,3-difluoro-pyridine</strong> (1.3 g, 8.694 mmol) in toluene (5 mL) at room temperature, and stirring was continued overnight. The reaction was mixture was partitioned between saturated aqueous NaHCO3 and EtOAc. The organics were collected, washed with brine and water, dried (Na2SO4), filtered, and concentrated. The crude residue was purified by silica gel chromatography (linear gradient of 0-100percent ethyl acetate/heptane to provide 1-(5-chloro-3-fluoro-2- pyridyl)cyclopropanecarbonitrile (62 mg, 3percent) ESI-MS m/z calc. 196.02, found 197.04 (M+1).
With potassium hexamethylsilazane; In toluene; at 0 - 25℃; for 3.5h;
To a solution of <strong>[89402-43-7]5-chloro-2,3-difluoropyridine</strong> (1.39 g, 9.29 mmol, Eq: 1.00) and 1-tert- butyl 2-methyl azetidine-l,2-dicarboxylate (2 g, 9.29 mmol, Eq: 1.00) in toluene (15 ml) was added dropwise at 0°C over 15 min a 0.5 M solution of KHMDS (18.6 ml, 9.29 mmol,Eq: 1.00) in toluene. The colorless solution turned into light brown. After stirring at 0°C for 45 min, the reaction mixture was allowed to warm up to 25 °C. The reaction mixture was stirred for 2.5 h. Saturated aqueous NH4C1 solution (100 ml) was added and the aqueous phase was extracted with AcOEt (2x150 ml). The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, 40g, 10percent to 60percent AcOEt in heptane) to yield a colorless viscous oil as a racemate (1.746 g; 55percent). m/z = 345.2 [M+H]+.
55%
With potassium hexamethylsilazane; In toluene; at 0 - 25℃; for 3.5h;
To a solution of <strong>[89402-43-7]5-chloro-2,3-difluoropyridine</strong> (1.39 g, 9.29 mmol, Eq: 1.00) and 1-tert-butyl 2-methyl azetidine-1,2-dicarboxylate (2 g, 9.29 mmol, Eq: 1.00) in toluene (15 ml) was added dropwise at 0° C. over 15 min a 0.5 M solution of KHMDS (18.6 ml, 9.29 mmol, Eq: 1.00) in toluene. The colorless solution turned into light brown. After stirring at 0° C. for 45 min, the reaction mixture was allowed to warm up to 25° C. The reaction mixture was stirred for 2.5 h. Saturated aqueous NH4Cl solution (100 ml) was added and the aqueous phase was extracted with AcOEt (2×150 ml). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, 40 g, 10percent to 60percent AcOEt in heptane) to yield a colorless viscous oil as a racemate (1.746 g; 55percent). m/z=345.2 [M+H]+.
tert-butyl 4-((5-chloro-3-fluoropyridin-2-yl)oxy)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
Intermediate 29: 5-Chloro-3-fluoro-2-(piperidin-4-yloxy)pyridine hydrochloride A solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (0.5 g, 2.4 mmol) in DMF (5 mL) was added to a suspension of sodium hydride (0.065 g, 2.7 mmol) in DMF (3 mL) at room temperature and stirred for 30 minutes. <strong>[89402-43-7]5-Chloro-2,3-difluoropyridine</strong> (0.4 g, 2.7 mmol) was added at 0° C. and then heated at 60° C. for 4 hours. The reaction was poured into cold water and extracted with ethyl acetate. The combined organic layer was washed with brine and then dried over sodium sulfate and concentrated. The crude compound was purified by silica column chromatography eluted with 0-20percent ethyl acetate in hexane to yield tert-butyl 4-(5-chloro-3-fluoropyridin-2-yloxy)piperidine-1-carboxylate (0.5 g, 60percent yield). 12percent HCl in dioxane (5 mL) was added to tert-butyl 4-(5-chloro-3-fluoropyridin-2-yloxy)piperidine-1-carboxylate (0.5 g, 1.5 mmol) in dioxane (2 mL) and stirred at room temperature for 2 hours. The reaction was concentrated. The crude compound was purified by trituration with diethyl ether (10×2 mL) to afford 5-chloro-3-fluoro-2-(piperidin-4-yloxy)pyridine hydrochloride (0.3 g, 34percent yield). [0661] 1H NMR (400 MHz, DMSO-d6) delta ppm 1.88-1.97 (m, 2H) 2.13-2.19 (m, 2H) 3.09-3.14 (m, 2H) 3.21-3.24 (m, 2H) 5.27-5.31 (m, 1H) 8.06-8.09 (m, 2H) 8.91-8.92 (m, 2H)
60%
Intermediate 29: 5-Chloro-3-fluoro-2-(piperidin-4-yloxy)pyridine hydrochloride A solution of tert-butyl 4-hydroxypiperidine- 1 -carboxylate (0.5 g, 2.4 mmol) in DMF (5 mL) was added to a suspension of sodium hydride (0.065 g, 2.7 mmol) in DMF (3 mL) at room temperature and stirred for 30 minutes. <strong>[89402-43-7]5-Chloro-2,3-difluoropyridine</strong> (0.4 g, 2.7 mmol) was added at 0 C and then heated at 60 C for 4 hours. The reaction was poured into cold water and extracted with ethyl acetate. The combined organic layer was washed with brine and then dried over sodium sulfate and concentrated. The crude compound was purified by silica column chromatography eluted with 0-20percent ethyl acetate in hexane to yield tert-butyl 4-(5-chloro-3-fluoropyridin-2-yloxy) piperidine-l-carboxylate (0.5 g, 60percent yield). 12percent HCI in dioxane (5 mL) was added to tert-butyl 4-(5-chloro-3-fluoropyridin-2- yloxy)piperidine- 1 -carboxylate (0.5 g, 1.5 mmol) in dioxane (2 mL) and stirred at room temperature for 2 hours. The reaction was concentrated. The crude compound was purified by trituration with diethyl ether (10 x 2 mL) to afford 5-chloro-3-fluoro-2-(piperidin-4- yloxy)pyridine hydrochloride (0.3 g, 34percent yield). 1H NMR (400 MHz, DMSO- d6) delta ppm 1.88-1.97 (m, 2H) 2.13-2.19 (m, 2H) 3.09-3.14 (m, 2H) 3.21-3.24 (m, 2H) 5.27-5.31 (m, 1H) 8.06-8.09 (m, 2H) 8.91-8.92 (m, 2H)
Preparation of tert-butyl 4-((5-chloro-3-fluoropyridin-2-yl)oxy)piperidine- 1-carboxylate. To a solution of tert-butyl-4-hydroxy-l -piped dinecarboxylate (135 mg, 0.67 mmol) in DMF (2.2 mL) was added sodium hydride (60percent w/w, 113 mg, 2.825 mmol). The mixture stirred at ambient temperature for 30 minutes and then <strong>[89402-43-7]5-chloro-2,3-difluoropyridine</strong> (100 mg, 0.67 mmol) was added. The reaction mixture was stirred for 60 h at 60°C. After cooling to ambient temperature, the reaction mixture was diluted with DCM and washed with saturated NaHCCb(aq) and then water. Then the organic extracts were washed with brine and dried over anhydrous Na2S04(s), filtered and concentrated in vacuo to afford the title compound (assume theoretical yield, 222 mg, 0.671 mmol) in sufficient purity for step 2. MS (apci) m/z = 213.1 (M-Boc).
With sodium hexamethyldisilazane; In tetrahydrofuran; toluene; at 20℃;Inert atmosphere;
A solution of sodium bis(trimethylsilyl)amide (610 mL, 40percent in tetrahydrofuran, 1.326 mole) was added to a cooled solution of <strong>[89402-43-7]5-chloro-2,3-difluoropyridine</strong> (198.2 g, 1.326 mole) and isobutyronitrile (238 mL, 2.65 mole) in toluene (2 L). The mixture was stirred under nitrogen at RT overnight before addition of saturated aqueous ammonium chloride (1 L). Phases were separated and the aqueous extracted with ethyl acetate (2 x 1 L). Combined organicswere dried (MgSO4) and concentrated in vacuo at 40 °C to give the title compound (259.8 g,95percent) 1H NMR (400 MHz, DMSO-d6): 8.57 (1H, dd), 8.24 (1H, dd), 1.74 (6H, bd).
95%
With sodium hexamethyldisilazane; In tetrahydrofuran; toluene; at 20℃;Inert atmosphere;
Preparation 52: 2-(S-Chloro-3-fluoro-pyridin-2-yl)-2-methyl-propionitrileA solution of sodium bis(trimethylsilyl)amide (610 mL, 40percent in tetrahydrofuran, 1.326 mole) wasadded to a cooled solution of <strong>[89402-43-7]5-chloro-2,3-difluoropyridine</strong> (198.2 g, 1.326 mole) andisobutyronitrile (238 mL, 2.65 mole) in toluene (2 L). The mixture was stirred under nitrogen at RT overnight before addition of saturated aqueous ammonium chloride (1 L). Phases were separated and the aqueous extracted with ethyl acetate (2 x 1 L). Combined organics were dried (MgSO4) and concentrated in vacuo at 40 °C to give the title compound (259.8 g, 95percent) 1 HNMR (400 MHz, DMSO-d6): 8.57 (1H, dd), 8.24 (1H, dd), 1.74 (6H, bd).
95%
With sodium hexamethyldisilazane;
Preparation 61: 2-(5-Chloro-3-fluoro-pyridin-2-yl)-2-methyl-propionitrileA solution of sodium bis(trimethylsilyl)amide (610 mL, 40percent in tetrahydrofuran, 1.326 mole) was added to a cooled solution of <strong>[89402-43-7]5-chloro-2,3-difluoropyridine</strong> (198.2 g, 1.326 mole) andisobutyronitrile (238 mL, 2.65 mole) in toluene (2 L). The mixture was stirred under nitrogen at RT overnight before addition of saturated aqueous ammonium chloride (1 L). Phaseswere separated and the aqueous extracted with ethyl acetate (2 x 1 L). Combined organicswere dried (Mg504) and concentrated in vacuo at 40 °C to give the title compound (259.8 g,95percent) 1H NMR (400 MHz, DMSO-d6): 8.57 (1H, dd), 8.24 (1H, dd), 1.74 (6H, bd).
95%
With sodium hexamethyldisilazane; In tetrahydrofuran; toluene; at 20℃;Inert atmosphere; Cooling with ice;
A solution of sodium bis(trimethylsilyl)amide (610 mL, 40percent in tetrahydrofuran, 1.326 mole) was added to an ice- cooled solution of <strong>[89402-43-7]5-chloro-2,3-difluoropyridine</strong> (198.2 g, 1.326 mole) and isobutyronitrile (238 mL, 2.65 mole) in toluene (2 L). The mixture was stirred under nitrogen atRT overnight before addition of saturated aqueous ammonium chloride (1 L). Phases were separated and the aqueous extracted with ethyl acetate (2 x 1 L). Combined organic extracts were dried (MgSO4) and concentrated in vacuo at 40 °C to give the title compound (259.8 g, 95percent) 1H NMR (400 MHz, DMSO-d6): 8.57 (1H, dd), 8.24 (1H, dd), 1.74 (6H, broad).
10.6 g
With sodium hexamethyldisilazane; In tetrahydrofuran; toluene; at -78℃; for 1h;
PREPARATION EXAMPLE 6 To a mixture of <strong>[89402-43-7]5-chloro-2,3-difluoropyridine</strong> (9.0 g), isobutyronitrile (4.2 g), and toluene (120 mL) was added NaHMDS (2 M in THF, 30.6 mL) at -78° C. The mixture was then stirred for 1 hour. The mixture was diluted with sat. aq. NH4Cl (50 mL) and warmed to room temperature. The mixture was then diluted with EtOAc (300 mL), washed with water (100 mL), brine (100 mL), dried over Na2SO4, concentrated, and then purified by silica gel column chromatography (EtOAc/hexanes) to give 2-(5-chloro-3-fluoropyridin-2-yl)-2-methylpropanenitrile (10.6 g) as a solid.
Step 1 Synthesis of 2-acetylamino-5-chloro-3-fluoropyridine: Under a nitrogen atmosphere, DMF (200 mL) and THF (830 mL) were added to acetamide (94.8 g, 1.61 mol), and the mixture was warmed to 50°C. A 40 wtpercent sodium hexamethyldisilazide THF solution (629 g, 1.37 mol) was added dropwise thereto, and the mixture was stirred for 2 hours at the same temperature. <strong>[89402-43-7]5-Chloro-2,3-difluoropyridine</strong> (100.0 g, 0.67 mol) was then added, THF (20 mL) was further added, and the mixture was stirred for 3 hours at the same temperature. The reaction mixture was cooled to 0°C, 2.8 M HCl (500 mL) was added, the mixture was warmed to room temperature, and the organic layer was separated. The organic layer was washed with a 20 wtpercent sodium chloride aqueous solution (500 mL), and the solvent was distilled off under reduced pressure. THF (500 mL) was added to the residue, and the mixture was heated to 70°C to dissolve the residue. After cooling to room temperature and confirming the precipitation of solids, n-heptane (1500 mL) was added, and the mixture was further cooled to 0°C and stirred for 3 hours at that temperature. The precipitated crystals were collected by filtration, washed with a mixed solvent of THF (100 mL) and n-heptane (500 mL), and dried under reduced pressure to obtain the title compound (91.2 g). Yield: 72percent 1H-NMR (CDCl3) delta (ppm): 2.36 (3H, s), 7.49 (1H, dd, J = 2.0, 9.5 Hz), 7.78 (1H, br), 8.17 (1H, d, J = 2.0 Hz) MS (ESI+): 189 [M+1]+
With sodium carbonate; In hexane; water; ethyl acetate;
Step 1: 4-bromo-2-chloro-6-phenylpyridine A round-bottomed flask was charged with <strong>[98027-80-6]4-bromo-2,6-dichloropyridine</strong> (Combi-Blocks Inc., 553 mg, 2.437 mmol), phenylboronic acid (446 mg, 3.66 mmol) and trans-dichlorobis(triphenylphosphine)palladium (ii) (27.8 mg, 0.04 mmol). The vial was placed under nitrogen atmosphere using two evacuation/backfill cycles. 1,4-dioxane (12 ml) and sodium carbonate (775 mg, 7.31 mmol) in water (4.1 ml) were added. The reaction mixture was sealed under nitrogen and heated at 80 C. for 1.5 h. The reaction mixture combined with that on pp14 was partitioned between EtOAc and brine. The aqueous layer was back extracted with EtOAc (2*) and the combined EtOAc layers were dried (Na2SO4) and concentrated. The crude material was dissolved in DCM, and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 20% EtOAc in hexane, to provide 2,6-dichloro-4-phenylpyridine (146 mg, 0.652 mmol, 26.7% yield) as light-yellow oil. MS m/z=224.0 [M]
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole lithium hydroxy-ate complex[ No CAS ]
[ 89402-43-7 ]
[ 1151801-90-9 ]
Yield
Reaction Conditions
Operation in experiment
87%
With chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2?,4?,6?-triisopropyl-1,1?-biphenyl][2-(2-aminoethyl)phenyl]palladium(ll); In water; iso-butanol; at 20 - 80℃;Inert atmosphere;
2,3-Difluoro-5- (i-methyl-i H-pyrazol-4-yl)pyridine was synthesized according to Scheme 13 by the following procedure. A boronic-ate complex sluffy was prepared in a first 3- neck-2-L round-bottom flask (RBF 1). RBF 1 was charged with 141 g (66.4 wtpercent, 0.9 equivalents based on boronic ester) of lithium 2-hydroxy-4,4,5,5-tetramethyl-2-(i-methyl-1H- pyrazol-4-yl)- 1,3 ,2-dioxaborolan-2-uide. 120 mL (1.6 Vol relative to 5-chloro-2,3- difluoropyridine) of nitrogen-sparged (2 h) 2-BuOH and 120 mL (1.6 Vol) nitrogen-sparged (2 h) water were added to RBF 1. Agitation and N2 sweep were initiated. The reaction was aged at 20 °C for at least 30 mm (reactions aged to 24 h were also successful).[00310] A second 3-neck-2-L round-bottom flask (RBF 2) was charged with 1.48 g (0.004 equivalents) of Xphos-palladacycle and 450 mL (6 Vol relative to <strong>[89402-43-7]5-chloro-2,3-difluoropyridine</strong>) of nitrogen-sparged (2 h) 2-BuOH. VacuumlN2 flush was cycled through RBF 2 three times to inert the RBF with N2. The batch in RBF 2 was heated to 80 °C. 75 g (1.0 equivalents) of 5- chloro-2,3-difluoropyridine was added to RBF 2.[00311] The slurry of boronic-ate complex was transferred from RBF 1 to a 500 mL dropping funnel. RBF 1 was rinsed with 30 mL (0.4 Vol) 2-BuOH. Using the dropping funnel, the sluffy of boronic-ate complex was added over 1 h to the hot solution mixture in RBF 2. After 1 h, 95percent conversion was observed. If greater than 90percent conversion was not observed, additional boronic-ate complex slurry was added (0.1 equivalents at a time with 1.6 Vol of 1:1 2- BuOH/water relative to boronic-ate complex). After the conversion was complete, the batch was cooled to 50 °C. While cooling, 600 mL (8 Vol) of toluene was added to RBF 2. 300 mL (4 Vol) of 20percent w/v NaHSO3 in water was added to RBF 2 and the batch was stirred at 50 °C for at least 1 h. The batch was polish filtered using a 5 micron Whatman filter at 50 °C, into a 2-L Atlas reactor. RBF 2 was rinsed with 30 mL (4.0 Vol) of a 1:1 2-BuOH:toluene solution. The temperature of the batch was adjusted to 50 °C in the Atlas reactor while stuffing. The stirring was stopped and the phases were allowed to settle for at least 15 mm while maintaining the batch at 50 °C. The bottom, aqueous layer was separated from the batch. The Atlas reactor was charged with 300 mL (4 Vol) of a 20percent w/v NaHSO3 solution and the batch was stirred at 50°C for 1 h. The agitation was stopped and the phases were allowed to settle for at least 15 mm at 50°C. The bottom, aqueous layer was removed. Agitation was initiated and the Atlas reactor was charged with 200 mL (4 Vol) of 0.5 M KF while keeping the batch at 50 °C for at least 30 mm. The agitation was stopped and the phases were allowed to settle for at least 15 mm at 50 °C. The bottom, aqueous layer was removed. Agitation was initiated and the reactor was charged with 300 mL (4 Vol) of water. The batch was aged at 50 °C for at least 30 mm. Agitation was stopped and the phases were allowed to settle for at least 15 mm at 50 °C. The bottom, aqueous later was removed.[00312] The organic phase was concentrated by distillation under reduced pressure (180 ton, jacket temp 70°C, internal temp about 50 °C) to a minimal stir volume (about 225 mL). 525 mL (7 Vol) of 2-BuOH was added to the Atlas reactor. The organic batch was again concentrated using reduced pressure (85-95 torr, jacket temp 75 °C, internal temp about 55 °C) to a minimal stir volume (about 125 mL). The total volume of the batch was adjusted to 250 mL with 2- BuOH.[00313] 525 mL (7 Vol) heptane was added to the slurry mixture in the Atlas reactor. The jacket temperature was adjusted to 100 °C and the batch was aged for more than 15 mm, until the batch became homogeneous. The batch was cooled to 20 °C over at least 3 h. A sample of the mixture was taken and the supernatant assayed for 2,3-difluoro-5-(1-methyl-1H-pyrazol-4- yl)pyridine. If the concentration was greater than 10 mg/mL, the aging was continued for at least 1 h until the supernatant concentration was less than 10 mg/mL. The batch was filtered using a medium frit. The filter cake was washed with 150 mL (2 Vol) 30percent 2-BuOH/heptane solution followed by 150 mL (2 Vol) heptane. The filter cake was dried under N2/vacuum. 76.64 g of 2,3-difluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridine was isolated as a white solid (87percent yield).
With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2?,4?,6?-triisopropyl-1,1?-biphenyl][2-(2-aminoethyl)phenyl]palladium(ll); tetrabutylammomium bromide; In 2-methyltetrahydrofuran; at 70℃;Inert atmosphere;
[00316] 3-fluoro-2-hydrazinyl-5- (i-methyl-i H-pyrazol-4-yl)-pyridine was synthesized according to Scheme 14 by the following procedure. A 60 L jacketed reactor was fitted with a 5 L addition funnel and the jacket temperature was set to 20±5 °C. 36.0 L (15 Vol) of 2- methyltetrahydrofuran was added to the reactor via a 20 tm inline filter with vacuum using polypropylene transfer lines. The solution was sparged by bubbling nitrogen through a dipstick in the solution for 1±0.5 h with agitation. After 1 h the dipstick was removed but the nitrogen sweep continued. 1.55 kg of sparged 2-MeTHF was removed to be used as rinse volumes. 36.7 g of Pd2dba3, 75.6 g X-Phos, 259 g of tetrabutylammonium bromide, and 7397 g of potassium phosphate tribasic were added to the reactor. The manhole was rinsed with 0.125 kg of sparged 2-MeTHF. The reactor was agitated and the nitrogen sweep continued for 1±0.5 h. Then the nitrogen sweep was stopped and the reaction left under a positive pressure of nitrogen.[00317] 3.6 L (1.5 Vol) of sparged water was prepared in advance by bubbling nitrogen through a 4 L bottle of water for 1±0.5 h. The nitrogen sparged water was transferred to the 5 L addition funnel via a 20 tm inline filter with vacuum using polypropylene transfer lines, then slowly added to the reaction while maintaining the internal temperature at 20±5 °C. The 5 L addition funnel was replaced with a 2 L addition funnel. 2412 g of <strong>[89402-43-7]5-chloro-2,3-difluoropyridine</strong> was added to the 2 L addition funnel. The <strong>[89402-43-7]5-chloro-2,3-difluoropyridine</strong> was then added to the reaction through the 2 L addition funnel. The 2L addition funnel was rinsed with 0.060 kg of sparged 2-MeTHF. 83.8 g (1.15 equivalents) of 1-methylpyrazole-4-boronic acid, pinacol ester was added to reactor, the reactor was swept with nitrogen for 1±0.5 h, then left under a positive pressure of nitrogen. The internal temperature of the reactor was adjusted to 70±5 °C. The batch was agitated at 70±5 °C for at least 4 hours after the final reagent was added. A sample was taken from the reaction and the reaction progress assayed for conversion. The progress of the reaction was checked every 2 hours until the reaction was completed (e.g., greater than 99percent conversion). The batch was cooled to 20±5 °C.[00318] A 20percent w/v sodium bisulfite solution (12.0 L, 5 Vol) was prepared by charging 12.0 L of water then 2411 g sodium bisulfite to an appropriate container and agitating until homogeneous. The 20percent sodium bisulfite solution was transferred into the reactor and agitated for 30 minutes. The agitation was stopped, the phases allowed to settle, and the aqueous phase was removed. A 0.5 M potassium fluoride solution (12.0 L, 5 Vol) was prepared by charging 12.0 L of water and 348 g of potassium fluoride to an appropriate container and agitating until homogenous. The 0.5 M potassium fluoride solution was transfened into the reactor and agitated for 30 mm. The agitation was stopped, the phases were allowed to settle, and the aqueous phase was removed. A 25percent w/v sodium chloride solution (12.0 L, 5 Vol) was prepared by charging an appropriate container with 12.0 L of water and 2999 g of sodium chloride and agitating until homogeneous. The 25percent sodium chloride solution was transferred into the reactor and agitated for 30 mm. The agitation was stopped, the phases were allowed to settle, and the aqueous phase was removed from the reactor.[00319] The organic phase was distilled at constant volume (36 L, 15 Vol) while maintaining the internal temperature of the reactor at 50±5 °C by adjusting the vacuum pressure until no more than 0.3percent of water remained. 2-Methyltetrahydrofuran was added to the reactor as needed to maintain constant volume. The batch was cooled to 20 °C and transferred into drums. The batch was transfeffed using a polish filter (using a 5 tm inline filter) into a 60 L jacketed reactor withbatched concentrator attached. 1.2 L of 2-MeTHF was used to rinse the drums. The batch was concentrated to about 9 Vol while maintaining the internal temperature of the vessel at 50±5adjusting the vacuum pressure. The batch was then distilled at constant volume (22.0 L, 9Vol) while maintaining the internal temperature of the vessel at 50±5 °C by adjusting the vacuum pressure. Heptane was added with residual vacuum until a 15percent 2-MeTHF:heptane supernatant mixture was obtained. The pressure was brought to atmospheric pressure under nitrogen. The reactor was cooled to 20±5 °C over 2±2 h. The batch was agitated at 20±5 °C until an assay of the supernatant indicated that the amount of product was 7 mg/mL 2,3-difluoro-1-methyl-i H-pyrazol-4-yl)pyridine.[00320] A 10percent 2-MeTHF:heptane (7.2 L, 3 Vol) wash solution was prepared by mixing 720 mL of 2-MeTHF and 6.5 L of heptane. The batch sluffy was filtered through an Aurora filter fitted with a 25 tm polypropylene filter cloth, resulting in heavy crystals that required pumping with a diaphragm pump using polypropy...
With potassium phosphate; palladium diacetate; XPhos; In 1,4-dioxane; water; at 100℃; for 12h;Inert atmosphere; Reflux;
General procedure: Typical procedure 1: a mixture of 5-chloro-2-fluoropyridine 5a(6.60 g, 50.2 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid(6.30 g, 50.1 mmol), Pd(OAc)2 (0.46 g, 2.1 mmol), 2-dicyclohexylphosphino-20,40,60-triisopropylbiphenyl (1.99 g, 4.1 mmol), and K3PO4 (26.30 g, 123.7 mmol) in dioxane/water (80 mL/8 mL)was stirred at 100 C under N2 atmosphere until the reaction wascompleted by TLC. After the solution was concentrated underreduced pressure, the product was purified via column chromatographyto afford compound 6 found.
4-((5-chloro-3-fluoropyridin-2-yl)oxy)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 18h;
A solution of 4-hydroxybenzonitrile (6.55 g, 55.0 mmol)2-chlorobenzothiazole (6.51 mL, 50.0 mmol)And K2CO3 (7.60 g, 55.0 mmol)In DMF (20 mL)The suspension is heated to120 ° CAnd keep it for 18 hours.The reaction mixture was allowed to cool to rt,With heptane:EtOAc (1: 1,300 mL)Diluted with 0.2 N NaOH (200 mL),Saturated Na2CO3 (50 mL) and brine (50 mL).Dried by Na2SO4,Filtered and concentrated to dryness,The crude product was purified, purified by crystallization (heptane: EtOAc)To give the desired beige solid ether 3a.Nitrile 3c was prepared starting from nitrile 3a from <strong>[89402-43-7]5-chloro-2,3-difluoropyridine</strong> and 4-hydroxybenzonitrile at a reaction temperature of 90 ° C.The title compound was obtained as a colorless solid containing about 7percent of the by-product, and the by-product was transferred to the next step and removed in that step.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;
To a solution of compound 5 (10.0 g, 66.9 mmol) in DMF (50 mL) was added K2CO3 (18.5 g, 133.7 mmol), compound 6 (14.7 g, 66.9 mmol). The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc 200 mL (100mL x 2). The combined organic layers were washed with H2O (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=100/1 to 30: 1 ). Compound 7 (15.0 g, 58percent yield) was obtained as a white solid. LCMS (conditions A): RT = 1 .42 min MS: (M+H+): 349.7
(R)-2-[4-(4-cyano-2-fluorophenoxy)phenoxy]propionyl chloride[ No CAS ]
[ 89402-43-7 ]
C21H14ClF2N3O3[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With sodium carbonate; triethylamine; In water; at 0 - 10℃; for 1h;
The acid chloride reaction solution was synthesized in the same manner as in Example 1.To 1000ml, 75g of water, 58g of <strong>[89402-43-7]2,3-difluoro-5-chloropyridine</strong>, 42g of sodium carbonate and 5g of triethylamine were added and the temperature was lowered to 0-5, dropping acid chloride reaction solution, the control temperature of 5 ~ 10 , the dropwise addition was completed, the reaction for 1 hour, the reaction was completed, layered, organic phase offDissolved, to give the crude product, was added 200g of methanol was heated to 50 ° C dissolved, cooled to 5 ° C, precipitated the solid, filtered to give the product, a white solidBody, yield: 81percent, content: 95percent.
2-(4-hydroxyphenoxy)propionic acid-2-propynyl ester[ No CAS ]
2-[4-(5-chloro-3-fluoropyridin-2-yloxy)-phenoxy]-propionic acid propargyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With potassium hydroxide; In toluene; at 70 - 75℃; for 10h;Inert atmosphere;
To equipped with a condenser, thermometer,Magnetic 1000ml three-necked flask was added 55g (0.25mol) intermediate,14 g (0.25 mol) of potassium hydroxide and 200 ml of toluene were added and 44.3 g (0.3 mol) of <strong>[89402-43-7]5-chloro-2,3-difluoropyridine</strong> was added dropwise under the protection of nitrogen. The dropwise addition time was 1 h, Then at 70 ~ 75 for 9h. The reaction was completed, cooled to room temperature filtration, the organic phase was added 100 mL of water was stirred for 0.5 h, the aqueous phase was separated, the organic phase was added activated carbon 5 g, heated to reflux bleaching 2 h, cooled to room temperature filtration, the filter cake was washed with a small amount of toluene, Toluene was removed from the rotary vacuum pump to give 74 g of clodinafop propargyl alcohol in 96percent yield.
To a suspension of NaH (2.94 g, 73.56 mmol) in THF (50 mL) was added 2,2,2-trifluoroethanol (7.36 g, 73.56 mmol) slowly at 20 C, and the mixture was stirred for 1 hour. <strong>[89402-43-7]5-chloro-2,3-difluoro-pyridine</strong> (10 g, 66.88 mmol) was then added, and the mixture was stirred at 20 C for another 4 hours. The mixture was quenched with sat.NH4Cl (50 mL) and extracted with EtOAc (100 mL x 2). The combined organic phase was washed with brine (50 mL ), dried over Na2S04, filtered and concentrated to afford A-92 (15000 mg, 65.34 mmol) as an oil. 1H NMR (400MHz, CDC13) _ = 7.83 (d, 1H), 7.38 (dd, 1H), 4.73 (q, 2H).
With copper(l) iodide; 1,10-Phenanthroline; caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 2h;Inert atmosphere;
General procedure: A solution of 13 (3.12g, 10.0mmol), 2-fluoro or 2-bromo substituted pyridine (11.0mmol), CuI (0.19g, 1.00mmol), 1,10-phenanthroline (0.18g, 1.00mmol) and Cs2CO3 (9.77g, 30mmol) in DMF (50mL) was stirred under N2 at 80°C for 2h. Aqueous NH4Cl solution (10percent) was added to the cooled reaction mixture, and the mixture was extracted with EtOAc several times. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After concentration under reduced pressure, the residue was purified by silica gel chromatography to obtain 14.
methyl (1s,4s)-4-hydroxy-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-indole]-5'-carboxylate[ No CAS ]
[ 89402-43-7 ]
methyl (1s,4s)-4-((5-chloro-3-fluoropyridin-2-yl)oxy)-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-indole]-5'-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
189 mg
To a suspension of sodium hydride (60percent in oil, 65.4 mg) and tetrahydrofuran (5 ml) was added methyl (Is, 4s) -4-hydroxy- 2 ' -oxo-1' , 2' -dihydrospiro [cyclohexane-1, 3' -indole] -5' - carboxylate (150 mg) at 0°C, and the mixture was stirred at the same temperature for 30 min. After stirring, 5-chloro-2, 3- difluoropyridine (98 mg) was added. After stirring at room temperature overnight, to the mixture was added saturated aqueous ammonium chloride solution at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (189 mg) . (1138) MS: [M+H]+ 405.1.
Add n-butyllithium in hexanes (110 g, 381 mmol, 2.5 mol/L) to a solution of acetonitrile (17.2 g, 419 mmol) in anhydrous THF (50 mL )at -78 C under nitrogen. The mixture is stirred at -78 C for 30 min. Then added with a solution of 5-chloro-2,3-difluoro20 pyridine ( 60.0 g, 3 81 mmol) in THF (1 00 mL) and the mixture is stirred at -78 C for 2 h. The reaction mixture is warmed to 20 C and stirred for 1 h. The reaction mixture is quenched with sat. NH4Cl (300 mL). The reaction mixture is extracted with EtOAc (200 mL x 3). The combined organic phases are washed with water (100 mL), brine (100 mL), concentrated to afford a yellow residue, which is purified by column chromatography on silica gel elutingwith PE:EtOAc (1 0:1) to afford title compound 2-(5-chloro-3-fluoro-2-pyridyl)acetonitrile (20.0 g, 30.8%) as a yellow oil. LCMS (m/z): 170.8 [M+H]
1-(tert-butyloxycarbonyl)-6'-chloro-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-b]pyridine][ No CAS ]
1-(tert-butyloxycarbonyl)-4'-chloro-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-c]pyridine][ No CAS ]
Yield
Reaction Conditions
Operation in experiment
First, 1-(tert-butyloxycarbonyl)-4-cyanopiperidine (301.9 mg) and <strong>[89402-43-7]5-chloro-2,3-difluoropyridine</strong> (0.298 mL) were dissolved in toluene (2.87 mL), and the mixture was cooled to 0C. A 0.5 M toluene solution (2.87 mL) of potassium bis (trimethylsilyl) amide was added dropwise to the above mixture, and then the resultant mixture was heated to room temperature and was stirred for 2.5 hours. The reaction solution was placed in a test tube containing 1 M hydrochloric acid (3 mL), and the organic layer was separated, followed by extraction with ethyl acetate. The organic layer thus collected all together was washed with water and saturated brine in sequence, was dried with sodium sulfate, and then was filtered. The filtrate was concentrated and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane = 5/95 to 40/60) to obtain a mixture (280.7 mg) of 1-(tert-butyloxycarbonyl)-4-(5-chloro-3-fluoropyridin-2-yl) -4-cyanopiperidine and 1-(tert-butyloxycarbonyl)-4-(5-chloro-2-fluoropyridin-3-yl) -4-cyanopiperidine. MS (ESI) m/z:340 [M+H]+._Then, lithium tri-tert-butoxyaluminum hydride and a 1.0 M tetrahydrofuran solution (3.742 mL) were added to a 1,4-dioxane solution (3.852 mL) of the mixture (280 mg) of 1-(tert-butyloxycarbonyl)-4-(5-chloro-3-fluoropyridin-2-yl) -4-cyanopiperidine and 1-(tert-butyloxycarbonyl)-4-(5-chloro-2-fluoropyridin-3-yl) -4-cyanopiperidine, and the mixture was dividedly placed in three reaction vessels, and heated by using microwaves at 130C for 20 minutes. After the reaction solution was cooled to 0C, a 0.5 M sodium hydroxide aqueous solution (12 mL) was slowly added dropwise thereto, followed by celite filtration while washing with deionized water and ethyl acetate. After the organic solvent in the filtrate was removed by evaporation under reduced pressure, the residue was subjected to extraction with ethyl acetate, washing with deionized water, drying with sodium sulfate, and then filtration. The residue obtained by concentrating the filtrate was purified by silica gel thin layer chromatography (ethyl acetate/hexane = 50/50) to obtain the title compounds (79.5 mg and 24.1 mg), respectively.1-(tert-butyloxycarbonyl)-6?-chloro-1?,2?-dihydrospiro[pipe ridine-4,3?-pyrrolo[3,2-b]pyridine][0290] 1H-NMR (400MHz, CDCl3) delta: 1.47 (s, 9H), 1.57-1.68 (m, 2H), 1.90-2.02 (m, 2H), 2.96-3.13 (m, 2H), 3.55 (s, 2H), 3.82 (br.s, 1H), 3.98-4.15 (m, 2H), 6.78 (d, J=2.0Hz, 1H) , 7.80 (d, J=2.1Hz, 1H). MS (ESI) m/z:324 [M+H]+.1-(tert-butyloxycarbonyl)-4?-chloro-1?,2?-dihydrospiro[pipe ridine-4,3?-pyrrolo[2,3-c]pyridine][0291] MS (ESI) m/z:324 [M+H]+.
1-(tert-butyloxycarbonyl)-4-(5-chloro-2-fluoropyridin-3-yl)-4-cyanopiperidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium hexamethylsilazane; In toluene; at 0 - 20℃; for 2.5h;
First, 1-(tert-butyloxycarbonyl)-4-cyanopiperidine (301.9 mg) and <strong>[89402-43-7]5-chloro-2,3-difluoropyridine</strong> (0.298 mL) were dissolved in toluene (2.87 mL), and the mixture was cooled to 0C. A 0.5 M toluene solution (2.87 mL) of potassium bis (trimethylsilyl) amide was added dropwise to the above mixture, and then the resultant mixture was heated to room temperature and was stirred for 2.5 hours. The reaction solution was placed in a test tube containing 1 M hydrochloric acid (3 mL), and the organic layer was separated, followed by extraction with ethyl acetate. The organic layer thus collected all together was washed with water and saturated brine in sequence, was dried with sodium sulfate, and then was filtered. The filtrate was concentrated and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane = 5/95 to 40/60) to obtain a mixture (280.7 mg) of 1-(tert-butyloxycarbonyl)-4-(5-chloro-3-fluoropyridin-2-yl) -4-cyanopiperidine and 1-(tert-butyloxycarbonyl)-4-(5-chloro-2-fluoropyridin-3-yl) -4-cyanopiperidine. MS (ESI) m/z:340 [M+H]+.
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 100℃; for 16h;Inert atmosphere;
To a solution of compound 1 (5g, 33.5mmol, 1 eq) in Dry DMF (37ml_) was added Morpholine (0.95ml_, 1 1 mmol, 0.33eq) followed by DiPEA (10.2ml_, 56.9mmol, 1.7eq) at RT under Argon atmosphere. The mixture was heated to 100C for 16h. Then, the reaction mixture was cooled to RT and poured on ice-water (300ml_). The reaction mixture was extracted with EtOAc (2x100ml_). The combined organic layer was dried over Na2S04 and concentrated under reduced pressure to give a crude product. The crude product was purified by combiflash column chromatography using 10% EtOAc in petroleum ether as an eluent to give compound 2 (2.5g, 34.73%) as an off- white solid.
With sodium methylate; In methanol; at 65℃; for 2h;
To a solution of compound 1 (1 g, 6.687mmol, 1 eq) in Dry Methanol (5ml_), a solution of 30% NaOMe (1 .8ml_, 10.03mmol, 1.5eq) was added dropwise and the reaction mixture was heated to 65C for 2h (Reaction was monitored by 1 HNMR and LCMS). Then, the reaction mixture was cooled to RT and concentrated under reduced pressure to give a residue. Residue was dissolved in EtOAc and washed with water. The separated organic layer was dried over Na2S04 and concentrated under reduced pressure to give compound 2 (750mg, 69.89%) as colorless liquid; which was sufficiently pure to use for next step.
With sodium hydroxide; toluene-4-sulfonic acid; In dimethyl sulfoxide;
EXAMPLE 16 PREPARATION OF 2-(4-(3-FLUORO-5-CHLORO-2-PYRIDINYLOXY)PHENOXY)PROPIONIC ACID, METHYL ESTER A solution of NaOH (2.7 g, 0.068 mol) in a few ml of water was added to 2-(4-hydroxyphenoxy)propionic acid (6.09 g, 0.033 mol) in 55 ml DMSO and the mixture was stirred for 20 minutes under nitrogen. <strong>[89402-43-7]5-Chloro-2,3-difluoropyridine</strong> (5.0 g, 0.033 mol) was added and the mixture was heated at 70 C. for 5 hours. The reaction was then poured over ice and extracted with CH2 Cl2. The organic layer was washed with water, dried over Na2 SO4 and the solvent removed by rotary evaporation. The residual oil was dissolved in 130 ml dry methanol, p-toluene sulfonic acid (0.5 g, 0.003 mmol) was added and the mixture was stirred at room temperature for 24 hours. The methanol was removed by rotary evaporation. The residue was taken up in ether, washed with dilute aqueous NaOH, and dried over Na2 SO4. The ether was removed by rotary evaporation to yield a tan oil which solidified on trituration with methylcyclohexane to give a white solid (6.4 g, 59%, m.p. 53-56 C.).
59%
With sodium hydroxide; toluene-4-sulfonic acid; In dimethyl sulfoxide;
EXAMPLE 16 PREPARATION OF 2-(4-(3-FLUORO-5-CHLORO-2-PYRIDINYLOXY)PHENOXY)PROPIONIC ACID, METHYL ESTER A solution of NaOH (2.7 g, 0.068 mol) in a few ml of water was added to 2-(4-hydroxyphenoxy)propionic acid (6.09 g, 0.033 mol in 55 ml DMSO and the mixture was stirred for 20 minutes under nitrogen. <strong>[89402-43-7]5-Chloro-2,3-difluoropyridine</strong> (5.0 g, 0.033 mol) was added and the mixture was heated at 70 C. for 5 hours. The reaction was then poured over ice and extracted with CH2 Cl2. The organic layer was washed with water, dried over Na2 SO4 and the solvent removed by rotary evaporation. The residual oil was dissolved in 130 ml dry methanol, p-toluene sulfonic acid (0.5 g, 0.003 mmol) was added and the mixture was stirred at room temperature for 24 hours. The methanol was removed by rotary evaporation. The residue was taken up in ether, washed with dilute aqueous NaOH, and dried over Na2 SO4. The ether was removed by rotary evaporation to yield a tan oil which solidified on trituration with methylcyclohexane to give a white solid (6.4 g, 59%, m.p. 53-56 C.).
59%
With sodium hydroxide; toluene-4-sulfonic acid; In dimethyl sulfoxide;
EXAMPLE 16 Preparation of 2-(4-(3-Fluoro-5-Chloro-2-Pyridinyloxy)Phenoxy)Propionic Acid, Methyl Ester A solution of NaOH (2.7 g, 0.068 mol) in a few ml of water was added to 2-(4-hydroxyphenoxy)propionic acid (6.09 g, 0.033 mol) in 55 ml DMSO and the mixture was stirred for 20 minutes under nitrogen. <strong>[89402-43-7]5-Chloro-2,3-difluoropyridine</strong> (5.0 g, 0.033 mol) was added and the mixture was heated at 70 C. for 5 hours. The reaction was then poured over ice and extracted with CH2 Cl2. The organic layer was washed with water, dried over Na2 SO4 and the solvent removed by rotary evaporation. The residual oil was dissolved in 130 ml dry methanol, p-toluene sulfonic acid (0.5 g, 0.003 mmol) was added and the mixture was stirred at room temperature for 24 hours. The methanol was removed by rotary evaporation. The residue was taken up in ether, washed with dilute aqueous NaOH, and dried over Na2 SO4. The ether was removed by rotary evaporation to yield a tan oil which solidified on trituration with methylcyclohexane to give a white solid (6.4 g, 59%, m.p. 53-56 C.).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In ethanol; water; toluene at 80℃; for 10h;
4.1. General procedures for preparation of compounds 7a-c and 13
General procedure: A mixture of corresponding arylborate esters or 3,4,5-trimethoxyphenylboronic acid (2.5 mmol), compound 6(3 mmol), K2CO3 (8 mmol) and Pd(dppf)Cl2 (0.25 mmol) in amixture of toluene (8.0 mL), ethanol (6.0 mL) and water (3.0 mL)was heated at 80 C. The reaction was monitored with TLC (PE/EA,8/1, v/v). After 10 h, the reaction mixture was extracted with ethylacetate. The organic layers were separated, dried and concentratedin vacuo. The crude products were purified with silica gel columnchromatography using PE/EA (25/1, v/v) as eluents to afford compounds7a-c and 13.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
HazMat Fee +
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
