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Excepted Quantity
USD 0.00
Limited Quantity
USD 15-60
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USD 80+
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Structure of 1513-65-1 * 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] Journal of Organic Chemistry, 1989, vol. 54, # 7, p. 1726 - 1731
3
[ 773837-37-9 ]
[ 1513-65-1 ]
[ 2893-33-6 ]
[ 3939-15-9 ]
Reference：
[1] Journal of Labelled Compounds and Radiopharmaceuticals, 2011, vol. 54, # 8, p. 411 - 417
[2] Journal of Labelled Compounds and Radiopharmaceuticals, 2011, vol. 54, # 8, p. 411 - 417
4
[ 1513-65-1 ]
[ 1597-32-6 ]
Yield
Reaction Conditions
Operation in experiment
94%
With ammonia In water at 105℃; for 15 h;
Example 13: (4S)-Λ/-Methyl-Λ/-(f5-(4-methyl-1-piperazinvnimidazoπ .2-aloyridin-2- vπmethyl)-3,4-dihvdro-2H-pyranof3,2-b1pyridin-4-arnine EPO <DP n="41"/>A) 6-Fluoro-2-pyridinamine: A solution of 2,6-difluoropyridine (50 g, 434 mmol) in ammonium hydroxide (200 mL, 28.0- 30.0percent) was heated at 1050C in a steel bomb for 15 hours. The reaction was cooled in an ice bath and the precipitate filtered, rinsed with cold water, and dried to yield 6-fluoro-2- pyridinamine (45.8 g, 94percent yield) as a white solid. 1H-NMR (CDCI3): δ 7.53 (m, 1 H)1 6.36 (dd, 1 H), 6.26 (dd, 1 H), 4.56 (s, 2H).
94%
With ammonia In water at 105℃; for 15 h;
A solution of 2,6-difluoropyridine (50 g, 434 mmol) in ammonium hydroxide (200 mL, 28.0-30.0percent) was heated at 1050C in a steel bomb for 15 hours. The reaction was cooled in an ice bath and the precipitate filtered, rinsed with cold water, and dried to yield 6-fluoro-2-pyridinamine (45.8 g, 94percent yield) as a white solid. 1H-NMR (CDCI3): δ 7.53 (m, 1H), 6.36 (dd, 1H), 6.26 (dd, 1H), 4.56 (s, 2H).
94%
With ammonia In water at 105℃; for 15 h;
A solution of 2,6-difluoropyridine (50 g, 434 mmol) in ammonium hydroxide (200 mL, 28.0-30.0percent) was heated at 1050C in a steel bomb for 15 hours. The reaction was cooled in an ice bath and the precipitate filtered, rinsed with cold water, and dried to yield 6-fluoro-2-pyridinamine (45.8 g, 94percent yield) as a white solid. 1H-NMR (CDCI3): δ 7.53 (m, 1 H), 6.36 (dd, 1 H), 6.26 (dd, 1 H), 4.56 (s, 2H).
94%
With ammonia In water at 105℃; for 15 h;
A solution of 2,6-difluoropyridine (50 g, 434 mmol) in ammonium hydroxide (200 ml_, 28.0-30.0percent) was heated at 1050C in a steel bomb for 15 hours. The reaction was cooled in an ice bath and the precipitate filtered, rinsed with cold water, and dried to yield 6-fluoro-2-pyridinamine (45.8 g, 94percent yield) as a white solid. 1H-NMR (CDCI3): δ 7.53 (m, 1 H)1 6.36 (dd, 1 H), 6.26 (dd, 1 H), 4.56 (s, 2H).
94%
With ammonia In water at 105℃; for 15 h;
A solution of 2,6-difluoropyridine (50 g, 434 mmol) in ammonium hydroxide (200 mL, 28.0-30.0percent) was heated at 1050C in a steel bomb for 15 hours. The reaction was cooled in an ice bath and the precipitate filtered, rinsed with cold water, and dried to yield 6-fluoro-2-pyridinamine (45.8 g, 94percent yield) as a white solid. 1H-NMR (CDCI3): δ 7.53 (m, 1H), 6.36 (dd, 1H), 6.26 (dd, 1H), 4.56 (S1 2H).
92%
With ammonium hydroxide In water at 110℃;
2-(chloromethyl)-5-fluoroimidazoH ,2-alpyridine: 2,6-difluoropyridine (31.5 ml_, 0.348 mol) was diluted with 30percent ammonium hydroxide(20OmL) in a steel bomb and heated to 110s C overnight. The bomb was cooled to room temperature over two hours then further cooled to 0Q C for two hours. The resulting solid was filtered and rinsed with water to obtain 26.39 g as a white solid. The filtrate was extracted with dichloromethane, dried over sodium sulfate and concentrated to afford an additional 9.3g (92percent overall yield) of 6-fluoro-2- pyridinamine. A portion of the solid (5g, 0.044 mol) was dissolved in 1 ,2- dichloroethane (20 mL) and 1 ,3-dichloro-2-propanone (34.2 mL, 4.34 mol) was added in two portions. The reaction was stirred at 409 C over two days. The resulting solid was collected by filtration, dissolved in absolute ethanol (100 mL), and refluxed at 90Q C overnight. Solvent was evaporated and dichloromethane and saturated aqueous sodium bicarbonate was added to the residue. The aqueous layer was extracted two times with dichloromethane and once with a 3:1 chloroform: isopropanol mixture. Combined organics were dried over sodium sulfate and concentrated to a 3.61 g (62percent) of 2-(chloromethyl)-5-fluoroimidazo[1 ,2-a]pyridine as a black oil which solidified upon standing. 1H NMR (400 MHz, DMSO-D6) δ 5.02 (s,2H), 7.29 (d, 1 H), 7.74 (d, 1 H), 7.88 (m, 1 H), 8.41 (s, 1 H); MS m/z 185 (M+1). EPO <DP n="47"/>B) 1 -[(5-fluoroimidazo[1 ,2-a]pyridin-2-yl)methyl]-1 ,2,3 ,4,4a,5,6,1 Ob-octahydro-1 ,10- phenanthroline:
Reference：
[1] Patent: WO2006/76131, 2006, A2, . Location in patent: Page/Page column 39-40
[2] Patent: WO2007/27999, 2007, A2, . Location in patent: Page/Page column 35
[3] Patent: WO2006/36816, 2006, A2, . Location in patent: Page/Page column 59-60
[4] Patent: WO2006/26703, 2006, A2, . Location in patent: Page/Page column 64-65
[5] Patent: WO2007/87549, 2007, A2, . Location in patent: Page/Page column 44; 59
[6] Tetrahedron, 2002, vol. 58, # 3, p. 489 - 493
[7] Patent: WO2006/96444, 2006, A2, . Location in patent: Page/Page column 14.B.A
[8] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 7, p. 2186 - 2190
[9] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 1, p. 188 - 193
[10] Patent: US6235731, 2001, B1,
[11] Organic Process Research and Development, 2009, vol. 13, # 4, p. 781 - 785
5
[ 773837-37-9 ]
[ 1513-65-1 ]
[ 2893-33-6 ]
[ 3939-15-9 ]
Reference：
[1] Journal of Labelled Compounds and Radiopharmaceuticals, 2011, vol. 54, # 8, p. 411 - 417
[2] Journal of Labelled Compounds and Radiopharmaceuticals, 2011, vol. 54, # 8, p. 411 - 417
6
[ 2402-78-0 ]
[ 1513-65-1 ]
Yield
Reaction Conditions
Operation in experiment
95 %Spectr.
With tetramethylammonium fluoride In N,N-dimethyl-formamide at 20℃; for 24 h;
General procedure: General Procedure E: General Experimental Details for NMR Yields Reported in Figure 3. In a drybox, anhydrous NMe4F (18.6 mg, 0.2 jumol, 2 equiv) and the appropriate aryi chloride or nitroarene substrate (0.1 nimol, 1 equiv) were weighed into a 4 mL vial equipped with a micro stirbar. DMF (0.5 mL) was added, and the viai was removed from the drybox and stirred at room temperature unless otherwise noted for 24 hours. The reaction was cooled to room temperature and an internal standard (1, 3, 5-trifluorobenzene, 100 iL of a 0.5 M solution in toluene) was added. An aliquot was removed for analysis by 59F NMR spectroscopy and GCMS.
Reference：
[1] Patent: US4071521, 1978, A,
[2] Angewandte Chemie - International Edition, 2006, vol. 45, # 17, p. 2720 - 2725
[3] Organic Letters, 2015, vol. 17, # 8, p. 1866 - 1869
[4] Journal of Organic Chemistry, 2015, vol. 80, # 24, p. 12137 - 12145
[5] Patent: WO2017/24167, 2017, A1, . Location in patent: Page/Page column 29; 33; 35
7
[ 110-86-1 ]
[ 1513-65-1 ]
[ 372-48-5 ]
Yield
Reaction Conditions
Operation in experiment
32%
at 500℃; Gas phase; Inert atmosphere
Example 7; Fluorination of PyridineIn this example fluorination of pyridine was carried out using CuF2, CuF2+AlF3 mixture and CuAl01. The experimental conditions as mentioned in Example 1 were followed. The percentage conversions of pyridine to fluoropyridine derivatives are given in Table 6.
Reference：
[1] Patent: US2010/16607, 2010, A1, . Location in patent: Page/Page column 5
[2] Organic Process Research and Development, 2008, vol. 12, # 2, p. 349 - 354
[3] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 7, p. 803 - 810
[4] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 7, p. 803 - 810
8
[ 2402-78-0 ]
[ 2402-77-9 ]
[ 1513-65-1 ]
Reference：
[1] Patent: US4071521, 1978, A,
9
[ 141-86-6 ]
[ 1513-65-1 ]
Reference：
[1] Journal of Fluorine Chemistry, 1981, vol. 18, p. 497 - 506
[2] Patent: US4075252, 1978, A,
10
[ 685517-67-3 ]
[ 685517-71-9 ]
[ 1513-65-1 ]
Reference：
[1] European Journal of Organic Chemistry, 2004, # 5, p. 1018 - 1024
11
[ 110-86-1 ]
[ 2344-10-7 ]
[ 1513-65-1 ]
[ 700-16-3 ]
[ 371-77-7 ]
Reference：
[1] Journal of Fluorine Chemistry, 1982, vol. 21, p. 159 - 170
12
[ 109-09-1 ]
[ 1513-65-1 ]
Reference：
[1] Journal of Organic Chemistry, 1989, vol. 54, # 7, p. 1726 - 1731
13
[ 110-86-1 ]
[ 1513-65-1 ]
[ 54471-09-9 ]
[ 54471-08-8 ]
[ 54471-05-5 ]
Reference：
[1] Journal of Fluorine Chemistry, 1982, vol. 21, p. 171 - 190
Reference：
[1] Patent: CN106905229, 2017, A, . Location in patent: Paragraph 0018; 0019; 0020; 0021
[2] Organometallics, 2017, vol. 36, # 6, p. 1091 - 1106
25
[ 1513-65-1 ]
[ 80392-79-6 ]
Reference：
[1] European Journal of Organic Chemistry, 2004, # 5, p. 1018 - 1024
26
[ 2591-86-8 ]
[ 1513-65-1 ]
[ 155601-65-3 ]
Yield
Reaction Conditions
Operation in experiment
60%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -78℃; for 0.5 h; Stage #2: at -78℃; for 0.333333 h;
Under N2, to a solution of 2,6-difluoropyridine (4.95 g, 43.0 mmol) in anhydrous THF (100 mL) cooled at- -78°C was added LDA (2.0 M in heptane/THF/ethylbenzene, 23.0 mL, 46.0 mmol). After the mixture was stirred at -780C for 30 min 1-formylpiperidine (4.98 g, 44.0 mmol) was added. The mixture was stirred at -78°C for 20 min, and at -78°C aqueous HCl (3 N, 60 mL) and Et2O (50 mL) were added. The ether layer was collected and the aqueous layer was extracted with Et2O (3 X 100 mL). The combined extracts were dried over anhydrous Na2SO4. After filtration the solvent was removed, and the residue was purified by flash chromatography on silica gel (CH2Cl2/hexanes, 1:1 v/v) to afford 2,6-difluoro-pyridme-3- carbaldehyde as a pale yellow liquid (1.41 g, 60percent).
Reference：
[1] European Journal of Organic Chemistry, 2004, # 5, p. 1018 - 1024
28
[ 1513-65-1 ]
[ 67242-59-5 ]
[ 155601-65-3 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1997, vol. 34, # 3, p. 789 - 795
29
[ 1513-65-1 ]
[ 685517-67-3 ]
Yield
Reaction Conditions
Operation in experiment
70%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -75℃; for 1 h; Stage #2: With iodine In tetrahydrofuran; hexane
DiisopropyIamine (141.3 mL, 101.19 g, 1 mol) and 2,6-difluoropyridine (115.08 g, 1 mol) were added consecutively to a solution of butyllithium (l.δM in hexane, 625 mL, 1 mol) in0 tetrahydrofuran (2000 mL) kept in a dry ice/methanol bath. After 1 h at -75 °C, the mixture was treated with a solution of iodine (253.8 g, 1 mol) in tetrahydrofuran (1000 mL). The mixture was washed with a 10percent aqueous solution (500 mL) of sodium sulfite, the organic phase was dried (MgSO4) and the volatiles were evaporated under reduced pressure. The residue was purified by vacuum distillation to give 169g of colorless oily product, which was crystallized to afford5 colorless platelets. Yield: 70percent.[00237] 1H NMR (400MHz, CDC13): δ 8.20 (dd, J = 8.1 and 15.6Hz, 1H), 6.70 (dd, J = 2.9 and8.2Hz, 1H).
66%
Stage #1: With 2,2,6,6-tetramethyl-piperidine; n-butyllithium; zinc dichloro(N,N,N′,N′-tetramethylethylenediamine) In tetrahydrofuran; hexane at 20℃; for 2 h; Inert atmosphere Stage #2: With iodine In tetrahydrofuran; hexane at 20℃; Inert atmosphere
General procedure: To a stirred, cooled (0 C) solution of 2,2,6,6-tetramethylpiperidine (0.25 mL, 1.5 mmol) in THF (2-3 mL) were successively added BuLi (about 1.6 M hexanes solution, 1.5 mmol) and, 5 min later, ZnCl2TMEDA[51] (0.13 g, 0.50 mmol). The mixture was stirred for 15 min at 0 C before introduction of the substrate (1.0 mmol) at 0-10 C. After 2 h at room temperature, a solution of I2 (0.38 g, 1.5 mmol) in THF (4 mL) was added. The mixture was stirred overnight before addition of an aqueous saturated solutionof Na2S2O3 (4 mL) and extraction with AcOEt (320 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. Purification by chromatographyon silica gel (the eluent is given in the product description) led to the compounds described below.
66%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane; pentane at -78℃; for 1 h; Stage #2: With iodine In tetrahydrofuran; hexane; pentane
Diisopropylamine (7.0mL, 50mmol) and 2,6-difluoropyridine (4.5mL, 50mmol) were added consecutively to a solution of n-butyllithium (20mL, 50mmol, 2.5mol/L in hexane) in THF (100mL) and pentane (30mL) at −78°C. After 1h at −78°C, the mixture was treated with a solution of iodine (13g, 5.0mmol) in THF (50mL) before being washed with 10percent aqueous Na2SO3 (25mL). The organic phase was dried and the volatiles evaporated. Crystallization of the residue from pentane afforded the product as colorless crystals (8.0g, 66percent). 1H NMR (400MHz, CDCl3): δ 8.20 (td, 1H, J=8.1, 7.3), 6.70 (dd, 1H, J=8.3, 3.0). 13C NMR (100MHz, CDCl3): 161.9 (dd, J=248, 13), 160.1 (dd, J=242, 14), 153.5 (dd, J=7, 2), 108.2 (dd, J=35, 6), 69.1 (dd, J=41, 6). 19F NMR (376MHz, CDCl3): δ −69.1, −81.5. GC–MS m/z calcd. for C5H2F2IN [M+]: 241, found: 241. MP: 40–42°C.
61%
Stage #1: With n-butyllithium In toluene at -78℃; for 4 h; Inert atmosphere Stage #2: With iodine In toluene at -70 - 20℃; Inert atmosphere Stage #3: With water In toluene at 20℃; Inert atmosphere
To a mixture of 2,6-difluoropyridine (1.15 g, 10 mmol, 10. eqv) in toluene (300 ml) was added n-BuLi (4.8 ml, 12 mmol, 1.2 eqv) at -78 °C under nitrogen and the mixture was stirred at the same temperature for 4 hrs. Iodine (2.53 g,10 mmol) was added with the temperature still below -70 °C. The mixture was allowed to warm up to RT and quenched with 10 ml water. The organic solvent was removed under vacuum and the product was collected by filtration. Chromatography by silica gel (petroleum ether: EtOAc =50: 1 to 5: 1) to give 2,6- difluoro-3-iodopyridine as solid (1.49 g, 6.1 mmol, 61percentyield) ESI-MS (M+l): 242 calc. for C5H2F2I 241.
Reference：
[1] European Journal of Organic Chemistry, 2004, # 5, p. 1018 - 1024
[2] Organic Letters, 2007, vol. 9, # 25, p. 5175 - 5178
[3] Tetrahedron Letters, 2004, vol. 45, # 36, p. 6697 - 6701
[4] Patent: WO2009/89263, 2009, A2, . Location in patent: Page/Page column 77
[5] Tetrahedron, 2016, vol. 72, # 17, p. 2196 - 2205
[6] Chinese Chemical Letters, 2017, vol. 28, # 3, p. 525 - 530
[7] Patent: WO2011/143366, 2011, A1, . Location in patent: Page/Page column 68
30
[ 1513-65-1 ]
[ 4111-54-0 ]
[ 685517-67-3 ]
Reference：
[1] Patent: US5204477, 1993, A,
31
[ 685517-67-3 ]
[ 685517-71-9 ]
[ 1513-65-1 ]
Reference：
[1] European Journal of Organic Chemistry, 2004, # 5, p. 1018 - 1024
32
[ 1513-65-1 ]
[ 685517-71-9 ]
Reference：
[1] European Journal of Organic Chemistry, 2004, # 5, p. 1018 - 1024
[2] Chinese Chemical Letters, 2017, vol. 28, # 3, p. 525 - 530
33
[ 1513-65-1 ]
[ 121-43-7 ]
[ 136466-94-9 ]
Yield
Reaction Conditions
Operation in experiment
94%
Stage #1: With n-butyllithium; lithium diisopropyl amide In tetrahydrofuran; hexane at -78℃; for 0.5 h; Stage #2: at 20℃; for 1 h;
L2 was synthesized according to literature procedures [S1,S2] with some modifications. In around-bottomed flask, lithium diisopropylamide (LDA) solution was prepared as follows: THF (20mL) solution of diisopropylamine (3.4 mL) was slowly added n-butyl lithium (1.67 M in n-hexane,24 mmol, 14 mL) at 0 C, then was stirred at the same temperature for 20 min. In anotherround-bottomed flask, THF (20 mL) solution of 2,6-difluoropyridine (20 mmol, 1.8 mL) was stirredat −78 C and was added LDA solution prepared above via a cannula. After stirring at −78 C for 30min, the reaction mixture was added THF (10 mL) solution of trimethyl borate (24 mmol, 2.5 g, 2.7mL), then warmed to ambient temperature over 1 h. The reaction was quenched by adding 2Maqueous sodium hydroxide (40 mL). Separated aqueous layer was neutralized (pH 8) by adding 4Mhydrochloric acid and extracted with ethyl acetate (organic layer A). Re-adding 4M hydrochloricacid to the aqueous layer to pH 6.5 afforded insoluble organic materials. Repeated extraction withethyl acetate for three times gave organic layer B. Re-adding 4M hydrochloric acid to the aqueouslayer to pH 4 followed by repeated extraction with ethyl acetate for three times gave organic layer C.The combined organic layer (B and C) was dried over anhydrous sodium sulfate, and concentrated invacuo. 2,6-difluoropyridine-3-boronic acid was obtained in 94percent yield (3.0 g, 19 mmol) as theresidue. This compound was used for the next step without further purification.
90%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1 h; Inert atmosphere Stage #2: at 20℃; for 1 h; Inert atmosphere Stage #3: With water; sodium hydroxide In tetrahydrofuranInert atmosphere
Under a nitrogen atmosphere, 7.5 mL (12 mmol) of 1.6 M lithium diisopropylamine and 0.91 mL (10 mmol) of 2,6-difluoropyridine were added to 40 mL of tetrahydrofuran, and kept reacting at -78°C for 1 h. After the addition of 1.40 mL (12.5 mmol) of trimethyl borate, the temperature was naturally warmed to room temperature and the mixture was kept mixing to react for 1 h. The reaction mixture was quenched by slowly adding 20 mL of an aqueous solution of 5wtpercent NaOH, after stirring for 10min, an aqueous solution of 3N HCl was added dropwisely to adjust the pH to neutral. The mixture was extracted several times with ethyl acetate and the organic phases were combined, solvent was removed by rotary evaporation to give 1.43 g of white solid in 90percent yield. 1H NMR (400 MHz, CDCl3, ppm): δ 8.45 (d, 1H), 6.94 (d, 1H), 5.33 (s, 2H).
90%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1 h; Inert atmosphere Stage #2: at -78 - 20℃; for 1 h;
(1) Synthesis of 2,6-difluoro-pyridyl-3-boronic acid Under a nitrogen atmosphere, 7.5 mL (12 mmol) of 1.6 M lithium diisopropylamine and 0.91 mL (10 mmol) of 2,6-difluoropyridine were added to 40 mL of tetrahydrofuran, and kept reacting at -78° C. for 1 h. After the addition of 1.40 mL (12.5 mmol) of trimethyl borate, the temperature was naturally warmed to room temperature and the mixture was kept mixing to react for 1 h. The reaction mixture was quenched by slowly adding 20 mL of an aqueous solution of 5 wt percent NaOH, after stirring for 10 min, an aqueous solution of 3N HCl was added dropwisely to adjust the pH to neutral. The mixture was extracted several times with ethyl acetate and the organic phases were combined, solvent was removed by rotary evaporation to give 1.43 g of white solid in 90percent yield. 1H NMR (400 MHz, CDCl3, ppm): δ 8.45 (d, 1H), 6.94 (d, 1H), 5.33 (s, 2H).
Reference：
[1] Journal of Fluorine Chemistry, 2016, vol. 181, p. 56 - 60
[2] Inorganic Chemistry, 2009, vol. 48, # 3, p. 1030 - 1037
[3] Patent: EP2727928, 2014, A1, . Location in patent: Paragraph 0027
[4] Patent: US8859771, 2014, B2, . Location in patent: Page/Page column 11
[5] Journal of Nanoscience and Nanotechnology, 2018, vol. 18, # 10, p. 7047 - 7052
34
[ 1513-65-1 ]
[ 121-43-7 ]
[ 7732-18-5 ]
[ 136466-94-9 ]
Yield
Reaction Conditions
Operation in experiment
90%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran; diethyl ether at -78℃; for 1 h; Stage #2: With sodium hydroxide In tetrahydrofuran; diethyl ether at 20℃; for 0.166667 h; Inert atmosphere Stage #3: With hydrogenchloride In tetrahydrofuran; diethyl ether
Under the protection of nitrogen, 7.5 ml (12mmol) 1.6M lithium diisopropylamine of slow instillment to -78 ° C THF solution containing 0.91 ml (10mmol) 2, 6-difluoropyridine and 40 ml ethyl ether of the mixed solution, keep -78 ° C temperature stirring reaction 1h. To be the reaction system by adding 1.40 ml (12.5mmol) after three methyl ester borate, natural temperature raising to room temperature, to continue stirring reaction 1h. Reaction mixed solution is slowly added 20 ml of the mass fraction of 5percent aqueous solution of NaOH of termination reaction, stirring 10 min later, by adding proper dropwise 3N adjusting the pH value of the aqueous solution of HCl to neutral. Ethyl acetate extraction many times, combined with the phase, rotary evaporate the solvent, get white solid 1.43g, the yield is 90percent.
Reference：
[1] Patent: CN103173209, 2016, B, . Location in patent: Paragraph 0056-0059
[2] Patent: US5204477, 1993, A,
35
[ 1513-65-1 ]
[ 136466-94-9 ]
Reference：
[1] Organic Letters, 2007, vol. 9, # 25, p. 5175 - 5178
[2] European Journal of Organic Chemistry, 2008, # 8, p. 1458 - 1463
STEP A: 2,6-difluoro-3-nitropyridine To a stirred solution of 20 g. of 2,6-difluoropyridine in 100 ml. of concentrated sulfuric acid at about 20 C., was added 75 ml. of 90% fuming nitric acid over 20 minutes. The mixture was kept at room temperature overnight, warmed to 35 C. over 15 minutes and held at this temperature for 10 minutes. The solution was cooled and poured into ice. The oil was extracted with 400 ml. of ether and the ether extract was washed with bicarbonate solution until all of the acid was neutralized. The ether was dried, evaporated and the residue was distilled at 0.1 mm. The only fraction came over at 50 C.
With dihydrogen peroxide; nitric acid; at 0 - 60℃; for 3h;
To a solution of 2,6-difluoropyridine (5.00 g, 43.4 mmol) in Conc.HN03 (36.3 mL, 869 mmol) was added concentrated H2S04 (34.7 mL, 652 mmol) slowly at 0 C and the reaction mixture was heated at 60 C for 3h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled at room temperature, poured into crushed ice (120 mL) and extracted with DCM (2 c 100 mL). The organic layer was separated, washed with an aqueous saturated NaHC03 solution (120 mL), dried over anhydrous Na2S04 and concentrated under vacuum to afford 2,6-difluoro-3-nitropyridine X-12a (3.20 g crude) as a yellow oil. (0877) This compound was used as such for the next reaction without further purification. 1 H NMR (400 MHz, DMSO-cfe) d 7.47 (dd, J=8.80, 2.45 Hz, 1 H) 8.91 -9.00 (m, 1 H).
To a solution of 2,6-difluoropyridine (25.0 g, 217 mmol) in tetrahydrofuran (300 ml) was added dropwise 1.6 N n-butyllithium-hexane solution (163 ml) at -70 C., and the mixture was stirred at -70 C. for 1 hr. Dry ice (14.5 g, 330 mmol) was added at -70 C., and the mixture was stirred at -70 C. for 30 min, and then under ice-cooling for 1 hr. The reaction mixture was poured into ice water, and washed with ethyl acetate. The aqueous layer was adjusted to pH=3 with 3N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of diethyl ether and hexane to give the object product (21.7 g, 62.9%) as a solid. 1H-NMR (CDCl3) δ; 6.89-6.94 (1H, m), 8.48-8.57 (1H, m).
Synthesis of 2,6-difluoronicotinic acid A 2.62 M solution of n-butyllithium in THF (29.1 mL) was added dropwise to a solution of diisopropylamine (11.7 mL) in tetrahydrofuran (310 mL) under ice-cooling in a nitrogen atmosphere, and the reaction solution was stirred under ice-cooling for one hour. After cooling the reaction solution to -78C, a solution of 2,6-difluoropyridine [CAS# 1513-65-1] (8 g) in tetrahydrofuran (10 mL) was added dropwise to the reaction solution, and the reaction solution was stirred at -78C for three hours. Then, an excessive amount of crushed dry ice was added to the reaction solution in a nitrogen stream, and the reaction solution was stirred at -78C for 20 minutes and at room temperature for three hours. Water and diethyl ether were added to the reaction solution, and the aqueous layer was separated. The aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid. Then, ethyl acetate was added and the organic layer was separated. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 10.4 g of a crude product of the title compound. The property values of the compound are as follows. 1H-NMR (CD3OD) δ (ppm): 7.08 (dd, J = 8.4, 2.8 Hz, 1H) 8.58 (dd, J = 17.2, 8.4 Hz, 1H).
To a stirring -78 0C solution of LDA (91.34 ml of 1.8 M in heptane/THF/ethylbenzene, 164.41 mmol) and TBDF (201 ml) was added slowly over 20 min. a solution of 2,6- difluoropyridine (18.92 g, 164.41 mmol) in THF (20 ml) so that the internal temperature stayed below -70 0C. After the addition, the reaction was stirred for 3 h at -78 0C. Dry ice (about 22 g) was treated with a stream of N2 gas before being added to the mixture over a 5 min. period. The internal temperature rose to -50 0C as a result of an exothermic reaction. Once the internal temperature stabilized back to -78 0C, it was stirred for 30 min before being gradually warmed to RT arid then stirred for 18 h. The solution was acidified to pH 2.5 with HCl (10% aqueous solution). The organic solvents were removed under vacuum, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, decanted, and concentrated under vacuum. The crude was treated with cold Et2O. The beige solid was isolated by filtration and washed twice with small amounts of cold diethyl ether to yield title compound.
12.3 ml of N,N-diisopropylamine was mixed with 100 ml of THF. Thereafter, 50 ml of a hexane solution containing 1.6 mol/liter n-butyllithium was mixed therewith at -78C. The obtained mixture was stirred at -78C for 20 minutes. Thereafter, 10.1 g of 2,6-difluoropyridine dissolved in 50 ml of THF was added to the reaction mixture at -78C over 10 minutes. The obtained mixture was stirred for 30 minutes. Thereafter, dry ice was added to the reaction mixture, and the obtained mixture was stirred for 4 hours, while the temperature thereof was gradually raised to a room temperature. Thereafter, water was added to the reaction mixture, followed by partition with MTBE. Subsequently, concentrated hydrochloric acid was added to the water layer, so that the pH thereof was adjusted to pH 1, followed by extraction with ethyl acetate. The organic layer was washed with a saturated saline solution, and it was then dried over sodium sulfate, followed by concentration under reduced pressure. The obtained residue was washed with a mixed solvent of hexane and MTBE, so as to obtain 8.69 g of 2,6-difluoronicotinic acid.2,6-difluoronicotinic acid [Show Image] 1H-NMR (DMSO-D6) δ: 7.30 (1H, dd, J = 8.2, 2.4 Hz), 8.59 (1H, dd, J = 8.2, 4.1 Hz).
Example 8; Synthesis of Aldehyde ReagentsAldehyde reagents that are used in making compounds are prepared according to the following protocols. In these reactions, the unprotected aldehyde isolated after step 5, or the subsequently Boc-protected aldehyde may be used in preparation of compounds.(6-ethoxy-pyridin-3-yl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester 57 is prepared in six steps from 2,6-difluoro-pyridine 39 as shown in Scheme 8. Step 1-Preparation of 2,6-difluoro-nicotinic acid (51)In a round bottom flask, to 2,6-difluoro-pyridine (39, 7.10 g, 61.7 mmol) in 150.0 mL of tetrahydrofuran under an atmosphere of nitrogen at -78 C., n-butyllithium (26.0 mL, 2.50 M in hexane, 65.0 mmol) is slowly added. After 30 minutes, 3.0 g of dry ice is added and an hour later the reaction is allowed to warm to room temperature. The reaction is poured into water, extracted with ethyl acetate and the aqueous layer is adjusted to pH 4-5 with 1 N hydrochloric acid. This is extracted with ethyl acetate and the organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound (51, 5.6 g).
Stage #1: acetonitrile With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.75h;
Stage #2: 2,6-difluoro pyridine In tetrahydrofuran; hexane at -78 - 20℃; for 2.5h;
Example 13: (4S)-Λ/-Methyl-Λ/-(f5-(4-methyl-1-piperazinvnimidazoϖ .2-aloyridin-2- vϖmethyl)-3,4-dihvdro-2H-pyranof3,2-b1pyridin-4-arnine EPO <DP n="41"/>A) 6-Fluoro-2-pyridinamine: A solution of 2,6-difluoropyridine (50 g, 434 mmol) in ammonium hydroxide (200 mL, 28.0- 30.0%) was heated at 1050C in a steel bomb for 15 hours. The reaction was cooled in an ice bath and the precipitate filtered, rinsed with cold water, and dried to yield 6-fluoro-2- pyridinamine (45.8 g, 94% yield) as a white solid. 1H-NMR (CDCI3): δ 7.53 (m, 1 H)1 6.36 (dd, 1 H), 6.26 (dd, 1 H), 4.56 (s, 2H).
94%
With ammonia; In water; at 105℃; for 15h;
A solution of 2,6-difluoropyridine (50 g, 434 mmol) in ammonium hydroxide (200 mL, 28.0-30.0%) was heated at 1050C in a steel bomb for 15 hours. The reaction was cooled in an ice bath and the precipitate filtered, rinsed with cold water, and dried to yield 6-fluoro-2-pyridinamine (45.8 g, 94% yield) as a white solid. 1H-NMR (CDCI3): δ 7.53 (m, 1H), 6.36 (dd, 1H), 6.26 (dd, 1H), 4.56 (s, 2H).
94%
With ammonia; In water; at 105℃; for 15h;
A solution of 2,6-difluoropyridine (50 g, 434 mmol) in ammonium hydroxide (200 mL, 28.0-30.0%) was heated at 1050C in a steel bomb for 15 hours. The reaction was cooled in an ice bath and the precipitate filtered, rinsed with cold water, and dried to yield 6-fluoro-2-pyridinamine (45.8 g, 94% yield) as a white solid. 1H-NMR (CDCI3): δ 7.53 (m, 1 H), 6.36 (dd, 1 H), 6.26 (dd, 1 H), 4.56 (s, 2H).
94%
With ammonia; In water; at 105℃; for 15h;
A solution of 2,6-difluoropyridine (50 g, 434 mmol) in ammonium hydroxide (200 ml_, 28.0-30.0%) was heated at 1050C in a steel bomb for 15 hours. The reaction was cooled in an ice bath and the precipitate filtered, rinsed with cold water, and dried to yield 6-fluoro-2-pyridinamine (45.8 g, 94% yield) as a white solid. 1H-NMR (CDCI3): δ 7.53 (m, 1 H)1 6.36 (dd, 1 H), 6.26 (dd, 1 H), 4.56 (s, 2H).
94%
With ammonia; In water; at 105℃; for 15h;
A solution of 2,6-difluoropyridine (50 g, 434 mmol) in ammonium hydroxide (200 mL, 28.0-30.0%) was heated at 1050C in a steel bomb for 15 hours. The reaction was cooled in an ice bath and the precipitate filtered, rinsed with cold water, and dried to yield 6-fluoro-2-pyridinamine (45.8 g, 94% yield) as a white solid. 1H-NMR (CDCI3): δ 7.53 (m, 1H), 6.36 (dd, 1H), 6.26 (dd, 1H), 4.56 (S1 2H).
92%
With ammonium hydroxide; In water; at 110℃;
2-(chloromethyl)-5-fluoroimidazoH ,2-alpyridine: 2,6-difluoropyridine (31.5 ml_, 0.348 mol) was diluted with 30% ammonium hydroxide(20OmL) in a steel bomb and heated to 110s C overnight. The bomb was cooled to room temperature over two hours then further cooled to 0Q C for two hours. The resulting solid was filtered and rinsed with water to obtain 26.39 g as a white solid. The filtrate was extracted with dichloromethane, dried over sodium sulfate and concentrated to afford an additional 9.3g (92% overall yield) of 6-fluoro-2- pyridinamine. A portion of the solid (5g, 0.044 mol) was dissolved in 1 ,2- dichloroethane (20 mL) and 1 ,3-dichloro-2-propanone (34.2 mL, 4.34 mol) was added in two portions. The reaction was stirred at 409 C over two days. The resulting solid was collected by filtration, dissolved in absolute ethanol (100 mL), and refluxed at 90Q C overnight. Solvent was evaporated and dichloromethane and saturated aqueous sodium bicarbonate was added to the residue. The aqueous layer was extracted two times with dichloromethane and once with a 3:1 chloroform: isopropanol mixture. Combined organics were dried over sodium sulfate and concentrated to a 3.61 g (62%) of 2-(chloromethyl)-5-fluoroimidazo[1 ,2-a]pyridine as a black oil which solidified upon standing. 1H NMR (400 MHz, DMSO-D6) δ 5.02 (s,2H), 7.29 (d, 1 H), 7.74 (d, 1 H), 7.88 (m, 1 H), 8.41 (s, 1 H); MS m/z 185 (M+1). EPO <DP n="47"/>B) 1 -[(5-fluoroimidazo[1 ,2-a]pyridin-2-yl)methyl]-1 ,2,3 ,4,4a,5,6,1 Ob-octahydro-1 ,10- phenanthroline:
82.6%
Reference Example 58 Synthesis of 2-amino-6-fluoropyridine A solution of 30.0 g of 2,6-difluoropyridine in 150 mL (4.6 equivalents) was stirred in a sealed tube (inner pressure 12.1 kgcm-2) for 5 hours at 130 C. The reaction mixture was cooled to 0 C., which was left standing for two hours. Resulting crude crystals (plates) were collected by filtration with a glass filter, which were dried at 40 C. for 2 hours under reduced pressure (24.2 g, yield 82.6%). 1H-NMR (CDCl3, 300 MHz) δ: 4.33-4.74 (2H, br s), 6.20 (1H, m), 6.30 (1H, m), 7.48 (1H, m). Elemental analysis for C5H5H2F Calcd.: C, 53.57; H, 4.50; N, 24.97; F, 16.95 Found: C, 53.44; H, 4.45; N, 24.97; F, 17.25
DiisopropyIamine (141.3 mL, 101.19 g, 1 mol) and 2,6-difluoropyridine (115.08 g, 1 mol) were added consecutively to a solution of butyllithium (l.deltaM in hexane, 625 mL, 1 mol) in0 tetrahydrofuran (2000 mL) kept in a dry ice/methanol bath. After 1 h at -75 C, the mixture was treated with a solution of iodine (253.8 g, 1 mol) in tetrahydrofuran (1000 mL). The mixture was washed with a 10% aqueous solution (500 mL) of sodium sulfite, the organic phase was dried (MgSO4) and the volatiles were evaporated under reduced pressure. The residue was purified by vacuum distillation to give 169g of colorless oily product, which was crystallized to afford5 colorless platelets. Yield: 70%.[00237] 1H NMR (400MHz, CDC13): delta 8.20 (dd, J = 8.1 and 15.6Hz, 1H), 6.70 (dd, J = 2.9 and8.2Hz, 1H).
66%
General procedure: To a stirred, cooled (0 C) solution of 2,2,6,6-tetramethylpiperidine (0.25 mL, 1.5 mmol) in THF (2-3 mL) were successively added BuLi (about 1.6 M hexanes solution, 1.5 mmol) and, 5 min later, ZnCl2TMEDA[51] (0.13 g, 0.50 mmol). The mixture was stirred for 15 min at 0 C before introduction of the substrate (1.0 mmol) at 0-10 C. After 2 h at room temperature, a solution of I2 (0.38 g, 1.5 mmol) in THF (4 mL) was added. The mixture was stirred overnight before addition of an aqueous saturated solutionof Na2S2O3 (4 mL) and extraction with AcOEt (320 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. Purification by chromatographyon silica gel (the eluent is given in the product description) led to the compounds described below.
66%
Diisopropylamine (7.0mL, 50mmol) and 2,6-difluoropyridine (4.5mL, 50mmol) were added consecutively to a solution of n-butyllithium (20mL, 50mmol, 2.5mol/L in hexane) in THF (100mL) and pentane (30mL) at -78C. After 1h at -78C, the mixture was treated with a solution of iodine (13g, 5.0mmol) in THF (50mL) before being washed with 10% aqueous Na2SO3 (25mL). The organic phase was dried and the volatiles evaporated. Crystallization of the residue from pentane afforded the product as colorless crystals (8.0g, 66%). 1H NMR (400MHz, CDCl3): delta 8.20 (td, 1H, J=8.1, 7.3), 6.70 (dd, 1H, J=8.3, 3.0). 13C NMR (100MHz, CDCl3): 161.9 (dd, J=248, 13), 160.1 (dd, J=242, 14), 153.5 (dd, J=7, 2), 108.2 (dd, J=35, 6), 69.1 (dd, J=41, 6). 19F NMR (376MHz, CDCl3): delta -69.1, -81.5. GC-MS m/z calcd. for C5H2F2IN [M+]: 241, found: 241. MP: 40-42C.
61%
To a mixture of 2,6-difluoropyridine (1.15 g, 10 mmol, 10. eqv) in toluene (300 ml) was added n-BuLi (4.8 ml, 12 mmol, 1.2 eqv) at -78 C under nitrogen and the mixture was stirred at the same temperature for 4 hrs. Iodine (2.53 g,10 mmol) was added with the temperature still below -70 C. The mixture was allowed to warm up to RT and quenched with 10 ml water. The organic solvent was removed under vacuum and the product was collected by filtration. Chromatography by silica gel (petroleum ether: EtOAc =50: 1 to 5: 1) to give 2,6- difluoro-3-iodopyridine as solid (1.49 g, 6.1 mmol, 61%yield) ESI-MS (M+l): 242 calc. for C5H2F2I 241.
With CO2; lithium diisopropyl amide; In tetrahydrofuran; cyclohexane;
EXAMPLE 64 4-(3-Bromoanilino)-7-fluoropyrido[2,3-d]pyrimidine 2,6-Difluoronicotinic acid. 2,6-Difluoropyridine (7.89 mL, 0.087 mmol) is added dropwise under N2 at 78 C. to a stirred solution of lithium diisopropylamide (59.0 mL of a 1.5N solution in cyclohexane, 0.089 mmol) in THF (250 mL). After 2 h at 78 C., a stream of dry CO2 is passed through the solution and the mixture is diluted with water and washed with EtOAc. The aqueous portion is neutralized with 3N HCl, extracted with EtOAc and worked up to give 2,6-difluoronicotinic acid (13.4 g, 97%). 1 H NMR (DMSO) δ 8.59 (1H, dd, J=9.2, 8.2 Hz), 7.30 (1H, dd, J=8.2, 2.1 Hz), 4.03 (1H, brs).
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 90℃;
9.1; 12.1
To 2,6-difluoro-pyridine (20, 100 g, 869 mmol) in 500 mL of N-methylpyrrolidone, 4-methoxy-benzylamine (60, 136 mL, 1.043 mol) and N,N-diisopropylethylamine (304 mL, 1.738 mol) were added. The reaction was stirred at 90° C. overnight, then poured into 8 L of water. The precipitate was collected by filtration and washed with water, then taken up in ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was triturated with heptane and collected by filtration to provide the desired compound (61, 151 g, 650 mmol, 74.8% yield).
74.8%
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 90℃;
7.1
Example 7; Synthesis of 6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine 496-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine 49 is prepared in seven steps from 2,6-difluoro-pyridine 39 and 4-methoxy-benzylamine 40 as shown in Scheme 7. Step 1-Preparation of (6-fluoro-pyridin-2-yl)-(4-methoxy-benzyl)-amine (41)To 2,6-difluoro-pyridine (39, 100 g, 869 mmol) in 500 mL of N-methylpyrrolidinone, 4-methoxy-benzylamine (40, 136 mL, 1.043 mol) and N,N-diisopropylethylamine (304 mL, 1.738 mol) are added. The reaction is stirred at 90° C. overnight, then poured into 8 L of water. The resulting precipitate is collected by filtration and washed with water, then taken up in ethyl acetate and washed with water. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is triturated with heptane and collected by filtration to provide the desired compound (41, 151 g, 650 mmol, 74.8% yield).
74.8%
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 90℃;
10.1 Step 1-Preparation of (6-fluoro-pyridin-2-yl)-(4-methoxy-benzyl)-amine (78)
To 2,6-difluoro-pyridine (49, 100 g, 869 mmol) in 500 mL of N-methylpyrrolidinone, 4-methoxy-benzylamine (77, 136 mL, 1.043 mol) and N,N-diisopropylethylamine (304 mL, 1.738 mol) were added. The reaction was stirred at 90° C. overnight, then poured into 8 L of water. The precipitate collected by filtration and washed with water, then taken up in ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was triturated with heptane and collected by filtration to provide the desired compound (78, 151 g, 650 mmol, 74.8% yield).
69%
With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 90℃; for 18h;
12.1 Step 1.
Step 1. Preparation of 6-fluoro-N-(4-methoxybenzyl)pyridin-2-amine To a solution of 2,6-difluoropyridine (50 g, 434 mmol) in anhydrous dimethyl sulfoxide (140 mL) was added N,N-diisopropylethylamine (112 g, 866 mmol), and para-methoxybenzyl amine (65.5 g, 477 mmol). The reaction mixture was heated to 90° C. for 18 hours. After cooling to ambient temperature, the reaction mixture was quenched with water (300 mL) and the aqueous layer was extracted with ethyl acetate (4*100 mL). The combined organic fractions were washed with water (3*75 mL), brine (100 mL), dried over anhydrous magnesium sulfate, and filtered. Concentration of the filtrate in vacuo gave an orange residue which was triturated with methanol (100 mL) to give the title compound as a colorless solid (78.8 g, 69% yield): 1H NMR (300 MHz, CDCl3) δ 7.47 (q, J=8.2 Hz, 1H), 7.28 (dt, J=6.5, 2.6 Hz, 2H), 6.92-6.87 (m, 2H), 6.21-6.15 (m, 2H), 5.07 (d, J=4.2 Hz, 1H), 4.42 (d, J=5.7 Hz, 2H), 3.81 (s, 3H).
With potassium carbonate In ethyl acetate; N,N-dimethyl-formamide
9 (6-fluoro-pyridin-2-yl)-(4-methoxy-benzyl)-amine
(6-fluoro-pyridin-2-yl)-(4-methoxy-benzyl)-amine To a solution of 2,6-di-fluoro-pyridine (2.2 g, 1 equiv.) in DMF (20 mL) is added 4-methoxy-benzylamine (5.6 g, 2.2 equiv.) and potassium carbonate (12 g, 4.4 equiv.). After heating at 50° C. for 16 hours, the solution is cooled to rt and filtered through Celite. The filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography using a gradient of hexane:EtOAc (19:1→4:1) to give the title compound. 1H NMR (CDCl3): δ 7.49-7.41 (dd, J=7&8 Hz, 1H), 7.24-7.28 (m, 2H), 6.90-6.85 (m, 2H), 6.19-6.13 (m, 2H), 4.40 (d, J=6 Hz, 2H), 3.80 (s, 3H). ES-MS: calcd. for C13H13FN2O (232.25); found: 233.4 [M+H].
a 2,6-Difluoro-3-nitropyridine To a mixture of concentrated sulphuric acid (600 mL) and fuming nitric acid (90%, 400 mL) in a ice-bath (internal temperature maintained at 5-10 C.) was added drop-wise 2,6-difluoropyridine (200 g, 1.74 mol). The resulting mixture was stirred overnight at room temperature. The mixture was poured slowly into 3 kg of ice and extracted with Et2O (2*2 L). The combined organic layers were washed with aqueous 1.5 N NaOH (2*1 L), then with aqueous saturated NaHCO3 (400 mL) or until pH is around 8-9. The organic layers were dried over MgSO4, filtrated and concentrated under reduced pressure until constant weight (to remove unreacted 2,6-difluoropyridine: 10-12%). The title compound was obtained as a yellow liquid (207.3 g, 74% yield).
With potassium <i>tert</i>-butylate In tetrahydrofuran
5 2-Fluoro-6-(2-propoxyethoxy)pyridine
Example 5 2-Fluoro-6-(2-propoxyethoxy)pyridine 2-Propoxyethanol (1.89 g, 18.1 mmol) was dissolved in 50 mL THF, treated with potassium tert-butoxide (3.05 g, 27.2 mmol), stirred to uniform solution, placed in an addition funnel, and added dropwise to a solution of 2,6-difluoropyridine in 50 mL THF. After stirring overnight at room temperature, the solution was diluted with brine and extracted with ether. The ether extracts were combined and dried over Na2SO4, then concentrated in vacuo to yield 2-fluoro-6-(2-propoxyethoxy)-pyridine (3.33 g, 93%) as a yellow oil.
In tetrahydrofuran at 150℃; for 0.333333h; microwave irradiation;
90
In a microwave tube was placed 2,6-difluoropyridine (0.500 mL, 5.47 mmol), dimethylamine, (2.0 M solution in THF, 4.11 mL, 8.21 mmol). The mixture was heated at 150° C. for 20 min. Water was added and the mixture was extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 536 mg of a crude yellow oil, which was purified by column chromatography (3/1 Hex/ethyl acetate) to give 500 mg of 6-fluoro-N,N-dimethylpyridin-2-amine as a light yellow oil. To a solution of diisopropylamine (0.15 mL, 1.1 mmol) in 2 mL of THF at 0° C. was added butyllithium (1.6 M in hexane, 0.69 mL, 1.1 mmol). The reaction stirred for 30 minutes and was then cooled to 60° C. at which time 6-fluoro-N,N-dimethylpyridin-2-amine (0.124 g, 0.88 mmol) was added in 1 mL of THF. The reaction stirred at -60° C. for 45 min. Then triisopropyl borate (0.25 mL, 1.1 mmol) was added and the reaction was allowed to stir for 1 h at 23° C. Ammonium chloride (sat.) was added and the mixture was extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 136 mg of a brown oil, which was purified by column chromatography (3/1 hexanes/ethyl acetate to 1/1 EtOAc/hexanes) to give 46 mg of a white solid. ES+=185.1 (M+H)
In tetrahydrofuran; (2S)-N-methyl-1-phenylpropan-2-amine hydrate;
(1) Fifty (50) g of 2,6-difluoropyridine was dissolved in 200 ml of tetrahydrofuran, and into the solution 326 ml of 1.6M n-butyl lithium-tetrahydrofuran solution was added dropwise at -70 C., followed by an hour's stirring at the same temperature. To the reaction mixture 29 g of dry ice blocks were added little by little, followed by 30 minutes' stirring at the same temperature. Raising the temperature to about 5 C., 500 ml of ice water was added. The reaction mixture was washed twice with ethyl acetate, and the aqueous layer was adjusted to pH 3 with conc. hydrochloric acid. The aqueous layer was then extracted with chloroform. The extract was washed with saturated saline water, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The crystalline precipitate was collected by filtration, and recrystallized from diethyl ether-n-hexane to provide 63 g of 2,6-difluoro-3-pyridinecarboxylic acid (m.p. 170-171 C.).
a) Analogously to example 6 a) 2,6-difluoropyridine is reacted with lithiumdiisopropylamide. Then J2 is added to the mixture at -60 to -70 and customary work-up yields 2,6-difluoro-3-iodopyridine.
a) 0,6 M of n-butyllithium are added at -10 to 0,6 M of diisopropylamin in 600 ml THF. The mixture is cooled to -70, 0,6 M of 2,6-difluoropyridin are added and after stirring for 15 minutes 0,6 M of trimethylborate are added at the same temperature. The mixture is allowed to warm up to -30. Then the borate ester is hydrolyzed with dilute HCl, the product extracted with ether, washed, dried and the solvent removed. Thus, 2,6-difluoro-pyridine-3-boronic acid is obtained.
Under the protection of nitrogen, 7.5 ml (12mmol) 1.6M lithium diisopropylamine of slow instillment to -78 C THF solution containing 0.91 ml (10mmol) 2, 6-difluoropyridine and 40 ml ethyl ether of the mixed solution, keep -78 C temperature stirring reaction 1h. To be the reaction system by adding 1.40 ml (12.5mmol) after three methyl ester borate, natural temperature raising to room temperature, to continue stirring reaction 1h. Reaction mixed solution is slowly added 20 ml of the mass fraction of 5% aqueous solution of NaOH of termination reaction, stirring 10 min later, by adding proper dropwise 3N adjusting the pH value of the aqueous solution of HCl to neutral. Ethyl acetate extraction many times, combined with the phase, rotary evaporate the solvent, get white solid 1.43g, the yield is 90%.
With hydrogenchloride; n-butyllithium; diisopropylamine; In tetrahydrofuran;
a) 0.6 m of n-butyllithium are added to 0.6 m of diisopropylamine in 600 ml of THF at -10. Then the mixture is cooled to -60 to -70 and 0.6 m of 2,6-difluoropyridine are added. The mixture is stirred for further 15 minutes and 0.6 m of trimethylborate is added at -60. The mixture is allowed to warm to -30 and is hydrolyzed by addition of 170 ml of HCl (25%) and 100 ml of H2 O. Ether is added and after customary work-up 2,6-difluoropyridine-3-boronic acid is obtained.
12 Preparation of 2,6-Difluoro-3-pyridinecarboxylic acid, methyl ester
EXAMPLE 12 Preparation of 2,6-Difluoro-3-pyridinecarboxylic acid, methyl ester To a stirred solution of 91 ml (0.182 mol) of 2.0 molar lithium diisopropylamide (in hexanes) in 200 mL dry tetrahydrofuran cooled to -70° under nitrogen was added dropwise a solution of 20.0 g of 2,6-difluoropyridine (0.174 mol) in 75 mL dry tetrahydrofuran such that the temperature was maintained below -60°. The solution was stirred at -70° for 3 hours and was then added via a cannula to a solution 21.7 g (0.230 mol) of methyl chloroformate in 100 mL dry tetrahydrofuran cooled to -70° under nitrogen. After stirring another hour at -70°, the mixture was poured into water and extracted with ether. The combined organic layers were washed with brine, dried over magnesium sulfate, and evaporated to a semisolid which was purified by flash chromatography to afford 13.0 g (43%) orange oil: NMR (CDCl3, 200 MHz) 3.95 (3H, s), 6.9 (1H, m), 8.5 (1H, m); IR (neat) 1745, 1730, 1610, 1415, 1290 cm-1.
13.0 g (43%)
With lithium diisopropyl amide In tetrahydrofuran
1 Preparation of 2,6-Difluoro-3-pyridinecarboxylic acid, methyl ester
EXAMPLE 1 Preparation of 2,6-Difluoro-3-pyridinecarboxylic acid, methyl ester To a stirred solution of 91 ml (0.182 mol) of 2.0 molar lithium diisopropylamide (in hexanes) in 200 mL dry tetrahydrofuran cooled to -70° under nitrogen was added dropwise a solution of 20.0 g of 2,6-difluoropyridine (0.174 mol) in 75 mL dry tetrahydrofuran such that the temperature was maintained below -60°. The solution was stirred at -70° fo 3 hours and was then added via a cannula to a solution 21.7 g (0.230 mol) of methyl chloroformate in 100 mL dry tetrahydrofuran cooled to -70° under nitrogen. After stirring another hour at -70°, the mixture was poured into water and extracted with ether. The combined organic layers were washed with brine, dried over magnesium sulfate, and evaporated to a semisolid which was purified by flash chromatography to afford 13.0 g (43%) orange oil: NMR (CDCl3, 200 MHz) 3.95 (3H, s), 6.9 (1H, m), 8.5 (1H, m); IR (neat) 1745, 1730, 1610, 1415, 1290 cm-1.
With sodium hydride; In N,N-dimethyl-formamide; at 20 - 70℃; for 4h;
Manufacturing Example 55-1-1 4-(6-Fluoro-pyridin-2-yloxymethyl)-benzonitrile; To an N,N-dimethylformamide (50 mL) solution of 2,6-difluoropyridine (5 g, 43.4 mmol) and 4-(hydroxymethyl)benzonitrile (8.67 g, 65.1 mmol) was added sodium hydride (2.56 g, 65.1 mmol, 60% in oil) at room temperature. This mixture was stirred for 4 hours at 70 C. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH-silica gel column chromatography (heptane:ethyl acetate=10:1-4:1) to obtain the title compound (5.99 g, 61%).1H-NMR Spectrum (CDCl3) delta (ppm): 5.41 (2H, s), 6.74-6.77 (1H, m), 6.87-6.89 (1H, m), 7.63-7.66 (2H, m), 7.85-7.88 (2H, m), 7.90-7.96 (1H, m).
61%
With sodium hydride; In N,N-dimethyl-formamide; at 20 - 70℃; for 4h;
To an N,N-dimethylformamide (50 mL) solution of 2,6-difluoropyridine (5 g, 43.4 mmol) and 4-(hydroxymethyl)benzonitrile (8.67 g, 65.1 mmol) was added sodium hydride (2.56 g, 65.1 mmol, 60% in oil) at room temperature. This mixture was stirred for 4 hours at 70 C. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH-silica gel column chromatography (heptane:ethyl acetate=10:1-4:1) to obtain the title compound (5.99 g, 61%). 1H-NMR Spectrum (CDCl3) delta (ppm): 5.41 (2H, s), 6.74-6.77 (1H, m), 6.87-6.89 (1H, m), 7.63-7.66 (2H, m), 7.85-7.88 (2H, m), 7.90-7.96 (1H, m).
2-fluoro-6-(4-{2-[(6-fluoropyridin-2-yl)oxy]ethyl}-2-methoxyphenoxy)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
28%
With potassium hydroxide In N,N-dimethyl-formamide at 110℃; for 20h;
4.a
a) 2-fluoro-6-(4-{2-[(6-fluoropyridin-2-yl)oxy]ethyl}-2-methoxyphenoxy)pyridine. [Show Image] To a suspension of KOH (2 mmol ; 112 mg) in anhydrous DMF (1 mL) under argon, was added 4-(2-hydroxyethyl)-2-methoxyphenol (1 mmol ;168 mg) followed by 2,6-Difluoropyridine (1 mmol ; 0. 1 ml). The reaction mixture was stirred at 110°C for 20h. After quenching with NaOH (0,1N ; 3 mL), the mixture was extracted with ethyl acetate (3*5 mL). Combined organic phases were dried over Na2SO4, concentrated in vacuo, to give a clear oil (50 mg ; 0.14 mmol ; 28 %), after purification by flash chromatography on silica gel (gradient cylohexane/dichloromethane). MS(ES): m/e 359 (M+H)+
With sodium hydride; In dimethyl sulfoxide; at 120℃;
a) 2-(4-ethyl-2-methoxyphenoxy)-6-fluoropyridine. [Show Image] To a suspension of NaH (1.2 mmol ; 50 mg) in anhydrous DMSO (1 mL) under argon, was added 4-ethyl-2-methoxyphenol (1 mmol;152.2 mg) followed by 2,6-difluoropyridine (1 mmol ; 0.1 ml). The reaction mixture was stirred at 120C overnight. After quenching with NaOH (0.1N; 3 mL), the mixture was extracted with dichloromethane (3*5 mL). Combined organic phases were dried over Na2SO4, concentrated in vacuo, to give light yellow oil (250 mg ; 1 mmol ; 100%), used without further purification. MS(ES): m/e 248 (M+H)+.
2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With potassium hydroxide In N,N-dimethyl-formamide at 110℃; for 24h;
5.a
a) 2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine [Show Image] To a suspension of KOH (2.8 mmol; 157 mg) under argon, in DMF (2 mL), were added 2-methoxy-4-propylphenol (2.1 mmol; 0,34 mL), and 2,6-difluoropyridine (2,0 mmol ; 0.18 mL). The reaction was heated to 110°C for 24hr. After quenching with NaOH (0,1N ; 3 mL), extractions with ethyl acetate (2*3 mL), drying over MgSO4, and concentration, the crude was purified by chromatography (gradient cylohexane/dichloromethane) to give the desired product as a white solid (449 mg ; 1.72 mmol ; 86%). MS (ES) m/e 262 (M+H)+
86%
With potassium hydroxide In N,N-dimethyl-formamide at 110℃; for 20h;
Stage #1: 2,6-difluoro pyridine With n-butyllithium In tetrahydrofuran at 0℃; for 0.333333h;
Stage #2: pyrrolidine In tetrahydrofuran at 0℃; for 0.5h; Further stages.;
62.5%
With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 16h;
1.1 Step 1:
To a stirred solution of 2,6-difluoropyridine (10 g, 86.9 mmol, 1 eq) in DMF (100 ml_) was added K2CO3 (24 g, 173.9 mmol, 2 eq) followed by pyrrolidine (10.7 ml_, 130.4 mmol, 1.5 eq) at RT and the resultant reaction mixture was heated at 90°C for 16 h. The reaction was monitored by TLC, and TLC analysis indicated formation of a polar spot. The reaction mixture was quenched with ice water and extracted with ethyl acetate (2x200 ml_). The combined organic layer was dried over Na2S04 and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 100-200 mesh) using 0-4% ethyl acetate in petroleum ether as an eluent to afford 2-fluoro-6- (pyrrolidin-1 -yl)pyridine (9 g, 62.5% yield) as a pale yellow liquid. LCMS: m/z 167.36 (M+H).
Stage #1: 2,6-difluoro pyridine With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.5h;
Stage #2: di-tert-butyl oxalate In tetrahydrofuran at -78 - -20℃; for 0.833333h;
Stage #3: With water; ammonium chloride In tetrahydrofuran
6.33
6.33. Preparation of l-tert-Butyl-6-fluoro-lH-pyrazolo [3,4-bl pyridine-3- carboxylic acid(2,6-Difluoro-pyridin-3-yl)-oxo-acetic acid tert-butyi ester (23): To a solution of 2,6-difluoropyridine (22) (2.7 ml, 30 mmol) in 30 ml of THF at -78°C was added dropwise a freshly prepared solution of lithium diisopropylamine (32 mmol). The resulting solution was maintained at -78°C for 30 min. To the stirring solution was added dropwise a preloaded solution of di-tert-buty oxylate (7.7 g, 38 mmol) in 30 ml of THF at -78°C. The reaction mixture was stirred at -78°C for 30 min and then at -200C for 20 min. The solution was quenched with a saturated solution of NH4C l(aq) and then diluted with Et2O. The layers were separated and the organic layer was dried over Na2SO4 and then concentrated in vacuo to yield the product 23 (6.93 g, 95%) as a yellow oil: 1H NMR (300 MHz, (CDCl3) δ 8.49 (dd, IH), 7.04 (dd, JHH= 8.2 Hz , JHF= 2.9 Hz, IH), 1.61 (s, 9H).
Stage #1: 3,5-dimethyl-1H-pyrazole With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 0.5h; Inert atmosphere; Schlenk technique;
Stage #2: 2,6-difluoro pyridine In N,N-dimethyl-formamide at 25℃; for 10h; Inert atmosphere; Schlenk technique;
73%
Stage #1: 3,5-dimethyl-1H-pyrazole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Inert atmosphere;
Stage #2: 2,6-difluoro pyridine In N,N-dimethyl-formamide; mineral oil at 20℃; for 4h;
1.1; 2.1 Preparation of Ligand A
Step 1: Nitrogen protection, 3,5-dimethyl-1H-pyrazole (16.7 g, 1.74 mol) dissolved in dry DMF(60 mL) 60% NaH (9.0 g, 2.26 mol) was added in four portions at 0 °C. After stirring for 30 minutes,2,6-Difluoropyridine was added dropwise, and the mixture was warmed to room temperature and stirred for 4 h. Quench the reaction by adding an appropriate amount of water, extracting three times with dichloromethane, and combining the organic phases.Dry with MgSO4. The MgSO4 was filtered off and the solvent was removed.The crude product is subjected to column chromatography,A white solid (24 g, yield 73%) was obtained.
73%
With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 5h; Inert atmosphere; Schlenk technique;
50%
Stage #1: 3,5-dimethyl-1H-pyrazole With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5h;
Stage #2: 2,6-difluoro pyridine In N,N-dimethyl-formamide at 20℃; for 0.5h;
1.B
3,5-Dimethylpyrazole (944 mg, 9.82 mmol) was dissolved in dry N, N- dimethylformamide (10 mL). Sodium hydride (60% in mineral oil, 470 mg, 1 1 .79 mmol) was added. After stirring for 30 min at room temperature 2,6-difluoropyridine (1 .13 g, 9.82 mmol) was added and stirring was continued for 30 min at room temperature. The reaction mixture was poured into water and stirred over night. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered and evaporated. The crude product was purified by flash chromatography using ethyl acetate/heptane as eluent to give 2-(3,5-dimethyl-pyrazol- 1 -yl)-6-fluoro-pyridine (1 .3 g, 50%) as a colourless oil.
Stage #1: N-(4-chlorophenyl)formamide With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.25h;
Stage #2: 2,6-difluoro pyridine In N,N-dimethyl-formamide at 60℃;
1.A
4-Chloroaniline (2.0 g, 15.68 mmol) and formic acid (10 ml_, 265 mmol) were heated to reflux for 1 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. Water was added. The resulting mixture was basified with aqueous sodium carbonate and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered and evaporated to give λ/-(4- chloro-phenyl)-formamide (2.4 g) as the crude product.λ/-(4-Chloro-phenyl)-formamide (2.4 g, 15.43 mmol) was dissolved in dry λ/,λ/-dimethylformamide (20 ml_) and sodium hydride (60% in mineral oil, 0.74 g, 18.51 mmol) was added. After stirring for 15 min at room temperature, 2,6-difluoropyridine (1.4 ml_, 15.43 mmol) was added and the reaction mixture was stirred at 600C over night. The cooled mixture was poured into water (200 ml_) and the resulting solid was filtered off, washed with water and dried in vacuo to give (4-chloro-phenyl)-(6-fluoro- pyridin-2-yl)-amine (3.22 g) as the crude product.3,5-Dimethylpyrazole (430 mg, 4.49 mmol) was dissolved in N, /V-di methyl - formamide (10 ml_) and sodium hydride (60% in mineral oil, 216 mg, 5.39 mmol) was added. After stirring for 30 min at room temperature (4-chloro-phenyl)-(6-fluoro-pyridin- 2-yl)-amine (1.0 g, 4.5 mmol) was added. The reaction mixture was stirred at 600C over night. Water was added and extracted with ethyl acetate. The combined organic phases were dried with magnesium sulphate, filtered and evapotated. The crude product was purified by flash chromatography using dichloromethane/methanol as eluent to give (4-chloro-phenyl)-[6-(3,5-dimethyl-pyrazol-1 -yl)-pyridin-2-yl]-amine (800 mg, 60%) as a yellow oil. LC-ESI-HRMS of [M+H]+ shows 299.1078 Da. CaIc. 299.106349 Da, dev. 4.9 ppm.
Stage #1: N-(4-chlorophenyl)formamide With sodium hydride In N,N-dimethyl-formamide for 0.25h;
Stage #2: 2,6-difluoro pyridine In N,N-dimethyl-formamide at 70℃;
1.C
4-Chloro-phenylH6-fluoro-pyridin-2-yl)-amine (Intermediate compound)Sodium hydride (1 .2 g, 30.9 mmol) was added to a solution of Λ/-(4-chloro- phenyl)-formamide (4 g, 25.7 mmol) in Λ/,Λ/-dimethylformamide (40 ml_) and stirred for 15 minutes. 2,6-Difluoropyhdine (2.96 g, 25.7 mmol) was added, the reaction mixture was stirred at 70°C overnight and poured into a stirred ice-water solution. The resulting participate was filtrated off and dried to give (4-chloro-phenyl)-(6-fluoro-pyhdin-2-yl)- amine (5.95 g) as the crude product. The crude product was used without further purification.
L2 was synthesized according to literature procedures [S1,S2] with some modifications. In around-bottomed flask, lithium diisopropylamide (LDA) solution was prepared as follows: THF (20mL) solution of diisopropylamine (3.4 mL) was slowly added n-butyl lithium (1.67 M in n-hexane,24 mmol, 14 mL) at 0 C, then was stirred at the same temperature for 20 min. In anotherround-bottomed flask, THF (20 mL) solution of 2,6-difluoropyridine (20 mmol, 1.8 mL) was stirredat -78 C and was added LDA solution prepared above via a cannula. After stirring at -78 C for 30min, the reaction mixture was added THF (10 mL) solution of trimethyl borate (24 mmol, 2.5 g, 2.7mL), then warmed to ambient temperature over 1 h. The reaction was quenched by adding 2Maqueous sodium hydroxide (40 mL). Separated aqueous layer was neutralized (pH 8) by adding 4Mhydrochloric acid and extracted with ethyl acetate (organic layer A). Re-adding 4M hydrochloricacid to the aqueous layer to pH 6.5 afforded insoluble organic materials. Repeated extraction withethyl acetate for three times gave organic layer B. Re-adding 4M hydrochloric acid to the aqueouslayer to pH 4 followed by repeated extraction with ethyl acetate for three times gave organic layer C.The combined organic layer (B and C) was dried over anhydrous sodium sulfate, and concentrated invacuo. 2,6-difluoropyridine-3-boronic acid was obtained in 94% yield (3.0 g, 19 mmol) as theresidue. This compound was used for the next step without further purification.
90%
Under a nitrogen atmosphere, 7.5 mL (12 mmol) of 1.6 M lithium diisopropylamine and 0.91 mL (10 mmol) of 2,6-difluoropyridine were added to 40 mL of tetrahydrofuran, and kept reacting at -78C for 1 h. After the addition of 1.40 mL (12.5 mmol) of trimethyl borate, the temperature was naturally warmed to room temperature and the mixture was kept mixing to react for 1 h. The reaction mixture was quenched by slowly adding 20 mL of an aqueous solution of 5wt% NaOH, after stirring for 10min, an aqueous solution of 3N HCl was added dropwisely to adjust the pH to neutral. The mixture was extracted several times with ethyl acetate and the organic phases were combined, solvent was removed by rotary evaporation to give 1.43 g of white solid in 90% yield. 1H NMR (400 MHz, CDCl3, ppm): delta 8.45 (d, 1H), 6.94 (d, 1H), 5.33 (s, 2H).
90%
(1) Synthesis of 2,6-difluoro-pyridyl-3-boronic acid Under a nitrogen atmosphere, 7.5 mL (12 mmol) of 1.6 M lithium diisopropylamine and 0.91 mL (10 mmol) of 2,6-difluoropyridine were added to 40 mL of tetrahydrofuran, and kept reacting at -78 C. for 1 h. After the addition of 1.40 mL (12.5 mmol) of trimethyl borate, the temperature was naturally warmed to room temperature and the mixture was kept mixing to react for 1 h. The reaction mixture was quenched by slowly adding 20 mL of an aqueous solution of 5 wt % NaOH, after stirring for 10 min, an aqueous solution of 3N HCl was added dropwisely to adjust the pH to neutral. The mixture was extracted several times with ethyl acetate and the organic phases were combined, solvent was removed by rotary evaporation to give 1.43 g of white solid in 90% yield. 1H NMR (400 MHz, CDCl3, ppm): delta 8.45 (d, 1H), 6.94 (d, 1H), 5.33 (s, 2H).
Reference Example 30; (2,6-Difluoropyridin-3-yl)(phenyl)methanoneTo a solution of 2,6-difluoropyridine (1.0 g, manufactured by Tokyo Chemical Industry Co., Ltd.) in tetrahydrofuran (40 mL, manufactured by Kanto Chemical Co., Inc.), lithium diisopropylamide (23% solution in tetrahydrofuran/ethylbenzene/heptane, 5.79 mL, manufactured by Sigma-Aldrich Corp.) was added dropwise at -78 C., and the mixture was stirred for 30 minutes. Subsequently, <strong>[6919-61-5]N-methoxy-N-methylbenzamide</strong> (1.46 mL, manufactured by Sigma-Aldrich Corp.) was further added at the same temperature, and while the temperature was gradually raised to room temperature, the mixture was stirred overnight. A saturated aqueous solution of ammonium chloride (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3×30 mL), washed with brine (30 mL), and dried (MgSO4). The solvent was then evaporated, to give 1.90 g of the title compound. LC-MS: HPLC retention time 1.63 minutes, m/z (M-F+OMe) 232, condition C-1.
EXAMPLE 37; 3-{5-[(6-amino-1H-pyrazolo[3,4-b]pyridin-3-yl)methoxy]-2-chlorophenoxy}-5-chlorobenzonitrile (37-9); Step 1: 1-(2,6-difluoropyridin-3-yl)ethanone (37-2); A solution of freshly distilled diisopropylamine (14.7 mL, 104.3 mmol) in 10 mL of anhydrous THF was cooled to -78 and treated with 1.6 M solution of n-BuLi in hexanes (64.0 mL, 102.5 mmol). The resulting solution naturally warmed to -200 and was maintained at -20 for 1.5 hours. The solution was cooled to -78 and 2,6 difluoro pyridine (37-1) was added dropwise. The reaction was continued with stirring for 2 hours at -78 C. before a solution of 9.7 mL (86.9 mmol) of the Weinryb amide was added in 20 mL of THF. The resulting solution was warmed to ambient temperature overnight before quenching with a brine solution. The mixture was extracted with EtOAc (3×), and the combined organic layers were washed with H2O (1×), brine (2×), dried over MgSO4, and concentrated in vacuo. The crude product was purified via flash silica gel chromatography (0-40% EtOAc/Hexane) to yield the desired product 37-2. 1H NMR (CDCl3): 2.68(s,3H), 6.95(d,1H), 8.50(q,1H).
With trifluoromethanesulfonic acid anhydride; In dichloromethane;
Synthesis of 2,6-difluoro-3-nitropyridine Tetramethylammonium nitride (4.5 g) was suspended in dichloromethane (10 ml), and a solution of trifluoromethanesulfonic anhydride (5.56 ml) in dichloromethane (5 ml) was added dropwise at room temperature. After stirring at room temperature for 1.5 hours, a solution of 2,6-difluoropyridine (2 ml) in dichloromethane (5 ml) was added at room temperature, and the reaction solution was heated under reflux overnight. After leaving to cool, the reaction solution was poured into an ice-cooled saturated sodium bicarbonate solution. Dichloromethane was added and the organic layer was separated. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and the organic layer was concentrated under reduced pressure to obtain the title compound (3.84 g). The property values of the compound are as follows. 1H-NMR (CDCl3) delta (ppm): 7.03-7.07 (m, 1H), 8.66-8.73 (m, 1H).
Under N2, to a solution of 2,6-difluoropyridine (4.95 g, 43.0 mmol) in anhydrous THF (100 mL) cooled at- -78C was added LDA (2.0 M in heptane/THF/ethylbenzene, 23.0 mL, 46.0 mmol). After the mixture was stirred at -780C for 30 min 1-formylpiperidine (4.98 g, 44.0 mmol) was added. The mixture was stirred at -78C for 20 min, and at -78C aqueous HCl (3 N, 60 mL) and Et2O (50 mL) were added. The ether layer was collected and the aqueous layer was extracted with Et2O (3 X 100 mL). The combined extracts were dried over anhydrous Na2SO4. After filtration the solvent was removed, and the residue was purified by flash chromatography on silica gel (CH2Cl2/hexanes, 1:1 v/v) to afford 2,6-difluoro-pyridme-3- carbaldehyde as a pale yellow liquid (1.41 g, 60%).
In 1,2-dichloro-ethane at 100℃; for 1h; Inert atmosphere;
Intermediate 27: 2 -difluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridineUnder an atmosphere of nitrogen, a mixture of 2,6-difluoropyridine (7.89ml_, 87mmol), 4,4,4,,4,,5,5,5,,5,-octamethyl-2,2'-bi-1 ,3,2-dioxaborolane (25.4g, 100mmol), 1 ,10- phenanthroline (0.626g, 3.48mmol) and chlorobis(1 ,5-cyclooctadiene)iridium(l) dimer (0.574g, 0.634mmol) was treated with 1 ,2-dichloroethane (80mL). Nitrogen was passed through the mixture for 5 minutes after which time the mixture was heated at 100°C for 1 hour. The cooled reaction mixture was added to a mixture of diethyl ether (600ml_) and aqueous sodium hydroxide solution (4M, 800ml_) and the phases were separated. The aqueous phase was ice-cooled and acidified with aqueous hydrochloric acid (5M) and the resulting precipitate was filtered, washed with water and dried to afford the title compound (15g, 62.2mmol, 72% yield). LCMS (Method A): Rt 0.63 minutes; m/z 160 (ionises as the boronic acid) (MH+)
38.3%
With 1,10-Phenanthroline; bis(η4-1,5-cyclooctadiene)-di-μ-methoxy-diiridium(I) In tert-butyl methyl ether at 70℃; for 4h; Inert atmosphere;
1.1 step l
To the mixture of 2,6-difluoropyridine (100 g, 0.869 mol) in MTBE (1.0 L) was added bis(pinacolato)diboron (250 g, 0.984 mol), bis(l,5- cyclooctadiene)di^-methoxydiiridium(I) (5.00 g) and 1 , 10-phenanthroline (5.00 g). The mixture was stirred at 70 °C for 4 h under nitrogen gas. The mixture was evaporated to give a brown solid which was dissolved in pet ether, filtered and the solvent evaporated. The crude product which was purified by Si02 chromatography eluting with pet ether to afford 2,6-difluoro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridine (80.0 g, 38.3%) as white solid. 1H NMR: CDC13 400MHz: 5 7.09 (s, 2H), 1.28 (s, 12H).
32.7 g
With bis(η4-1,5-cyclooctadiene)-di-μ-methoxy-diiridium(I); 4,4'-di-tert-butyl-2,2'-bipyridine In tert-butyl methyl ether at 45℃; for 5h; Inert atmosphere;
Synthesis of 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine (VIII)
Bis(pinacolato)diboron (68.8 g, 0.27 mol); 4,4‘-di-tert-butyl bipyridine (2.10 g, 7.82 mmol) and (1 ,5-cyclooctadiene) (methoxy) iridium (I) dimer (2.59 g, 3.91 mmol) were suspended in methyl-te/f-butylether (10 ml_) under inert atmosphere and 2,6-difluoropyridine(VII) (23.8 ml_, 0.26 mol) was added. The temperature was slowly raised to 45 °C and the reaction mixture was stirred at this temperature for 5 h. The reaction mixture was then allowed to cool down to room temperature and was concentrated under reduced pressure. The isolated residue was purified by filtration over a short silica gel column using pentane as eluent to deliver the desired product (VIII) as colorless solid (32.7 g, 0.14 mol). HPLC Method A: Ret. Time: 0.68 min; m/z 581 NMR (300 MHz, CDCI3) d (ppm): 7.08 (2H, m); 1.28 (12H, s)
36 %Spectr.
With C29H35CoN4Si at 23℃; for 18h; Inert atmosphere; Glovebox; regioselective reaction;
Intermediate 36-ethyl-W-(6-fluoro-2-pyridinyl)-1 ,3-benzothiazol-2-Under an atmosphere of nitrogen, an ice-cooled solution of 6-ethyl-1 ,3-benzothiazol-2- amine (387mg, 2.17mmol) in Nu,Nu-dimethylformamide (15ml_) was treated portionwise with sodium hydride (60percent in oil) (130mg, 3.26mmol) and the mixture was stirred for 15 minutes. A solution of 2,6-difluorpyridine (250mg, 2.17mmol) in N,N-dimethylformamide (5mL) was added and the mixture was slowly allowed to warm to ambient temperature overnight. The mixture was treated cautiously with saturated aqueous ammonium chloride (20ml_) and ethyl acetate (20ml_). The organic phase was dried over magnesium sulfate, filtered and evaporated to dryness. The product was purified by chromatography on silica using a gradient elution from 0 to 50percent ethyl acetate in cyclohexane to afford the title compound (58mg, 0.21 mmol, 10percent yield). LCMS (Method A): Rt 1 .33 minutes; m/z 274 (MH+)
Stage #1: 5-chlorothiazolo[5,4-b]pyridin-2-amine; 2,6-difluoro pyridine With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; Inert atmosphere; Cooling with ice;
Stage #2: With ammonium chloride In water; N,N-dimethyl-formamide; mineral oil
Intermediate 17: 5-chloro-N-(6-fluoro-2-pyridinyl)[1 ,3]thiazolo[5,4-b]pyridin-2 -amineUnder an atmosphere of nitrogen, a solution of 5-chloro[1 ,3]thiazolo[5,4-b]pyridin-2-amine (4.75g, 25.6mmol) in dry Ν,Ν-dimethylformamide (50ml_) was treated with 2,6- difluoropyridine (3g, 26.1 mmol) and the mixture was cooled with an ice/water bath. Sodium hydride (60% in oil) (2.09g, 52.1 mmol) was added portionwise and the mixture was stirred whilst being allowed to slowly warm to ambient temperature overnight. The mixture was treated cautiously with aqueous ammonium chloride solution (5%, 20ml_) and water (100ml_). The mixture was then extracted with chloroform (2 x 150ml_) and the combined organic fraction was evaporated to dryness. The product was purified by flash chromatography on silica using a gradient elution from 0 to 100% ethyl acetate in cyclohexane to afford the title compound (4.9g, 17.5mmol, 67% yield). LCMS (Method A): Rt 1 .10 minutes; m/z 281 (MH+).
With caesium carbonate In acetonitrile at 70℃; for 12h; Sealed vessel;
58.1
Step 1 : A suspension of cesium carbonate (41.1 g, 126 mmol), 2,6-difluoropyridine (1 1.01 mL, 121 mmol) and morpholine (10.00 mL, 1 15 mmol) in ACN (100 mL) was heated to 70 °C for 12 hours in a sealed vessel. The reaction mixture was cooled to RT and filtered. The obtained filtrate was concentrated under reduced pressure. The crude material was purified by silica gel chromatography (5-25 % EtOAc/hexanes) to provide 13.7 g, of 4-(6-fluoropyridin-2-yl)morpholine.
2.1. Typical Procedure A solution of ethylpyridine (1.6 mL, 14 mmol) in THF (50 mL) was cooled to -78 C. A solution of n-butyllithium in hexane (4.8 mL, 12 mmol) was added within 15 min, keeping the temperature below - 60 C during the addition. The resulting deep red solution was stirred at -78 C for 30 min. The temperature was then raised to -20 C, at which point 2-fluoropyridine (0.5 mL, 12 mmol) was added dropwise, keeping the temperature below -10 C. After raising the temperature to r. t. within 20 min, the mixture was refluxed for 1 h. After cooling to r. t., the electrophile (6 mmol) was added and the solution refluxed for 1 h (4), 2 h (5), 16 h (7), 36 h (6), or 48 h (8 and 1), respectively. After cooling to r. t., the reaction mixture was quenched with water and extracted three times with MTBE. Volatiles were then removed in vacuo and hexane was added to the oily residue. After stirring overnight, the precipitated solid was filtered off, washed with hexane and dried in vacuo. The products were obtained as slightly off-white solids.
2.1. Typical Procedure A solution of ethylpyridine (1.6 mL, 14 mmol) in THF (50 mL) was cooled to -78 C. A solution of n-butyllithium in hexane (4.8 mL, 12 mmol) was added within 15 min, keeping the temperature below - 60 C during the addition. The resulting deep red solution was stirred at -78 C for 30 min. The temperature was then raised to -20 C, at which point 2-fluoropyridine (0.5 mL, 12 mmol) was added dropwise, keeping the temperature below -10 C. After raising the temperature to r. t. within 20 min, the mixture was refluxed for 1 h. After cooling to r. t., the electrophile (6 mmol) was added and the solution refluxed for 1 h (4), 2 h (5), 16 h (7), 36 h (6), or 48 h (8 and 1), respectively. After cooling to r. t., the reaction mixture was quenched with water and extracted three times with MTBE. Volatiles were then removed in vacuo and hexane was added to the oily residue. After stirring overnight, the precipitated solid was filtered off, washed with hexane and dried in vacuo. The products were obtained as slightly off-white solids.
13.8 g (129 mmol) of 2-ethylpyridine were dissolved in 220 ml of water-free tetrahydrofurane and cooled to -80C. 100 ml (270 mmol) of butyllithium (2.7 M solution in heptane) were added via a double needle over a period of 30 min. Meanwhile the solution coloured to dark red. After warming the mixture to -50C a solution of 13.6 ml (2 5 7 mmol) 2, 6-difluoropyridine in 190 ml THF was added. The mixture was heated under reflux for 4 hours. After cooling down to room temperature the mixture was quenched with 280 ml of saturated ammonium chloride solution and the organic solvent was removed under reduced pressure. 500 ml of diethylether and 300 ml water were added to the residue and the aqueous layer was washed five times with 200 ml of ethylacetate. The combined organic layers were washed three times with 100 ml of saturated sodium chloride solution, dried with sodium sulphate, filtrated and concentrated. The residue was washed twice with 50.0 ml of isopropanol and then filtrated. The mother liquor was concentrated, stored at -0C overnight and filtrated. The residue was washed with small amounts of isopropanol. The combined solids were dried at 30C in vacuum over night. 19.26 g (51%) product were obtained as a slightly yellow coloured solid that was used in the next synthesis without further purification.
Example 102 2-Chloro-5-(6-fluoro-pyridin-2-yloxy)-N-(1 -hydroxy-cyclohexylmethyl)- benzamide102.1 2-chloro-5-( ( 6-fluorop yridin-2-yl)oxy)benzoic acidTo a solution of <strong>[56961-30-9]2-chloro-5-hydroxybenzoic acid</strong> (282 mg) in anh. DMSO (3.3 mL) was added Cs2C03 (1600 mg) and the suspension was stirred for 20 min at RT. 2,6- difluoropyridine (0.150 mL) was added and the reaction mixture was stirred for 18h at 80°C. It was quenched with H20 and extracted with EtOAc. The aqueous phase was acidified with a 25percent aqueous solution of hydrochloric acid and extracted with EtOAc. The organic phase was dried over MgS04 and concentrated in vacuo to give 438 mg of the titled crude compound as a beige solid.LC-MS (B): tR = 0.70 min; [M+ H]+: 267.94
102.1 2-chloro-5-((6-fluoropyridin-2-yl)oxy)benzoic acid To a solution of <strong>[56961-30-9]2-chloro-5-hydroxybenzoic acid</strong> (282 mg) in anh. DMSO (3.3 mL) was added Cs2CO3 (1600 mg) and the suspension was stirred for 20 min at RT. 2,6-difluoropyridine (0.150 mL) was added and the reaction mixture was stirred for 18 h at 80° C. It was quenched with H2O and extracted with EtOAc. The aqueous phase was acidified with a 25percent aqueous solution of hydrochloric acid and extracted with EtOAc. The organic phase was dried over MgSO4 and concentrated in vacuo to give 438 mg of the titled crude compound as a beige solid. LC-MS (B): tR=0.70 min; [M+H]+: 267.94
1-(6-fluoropyridin-2-yl)cyclobutanecarbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
4.9 g
With sodium hexamethyldisilazane; In tetrahydrofuran; toluene; at 0 - 20℃; for 2h;
1-(6-Fluoropyridin-2-yl)<strong>[4426-11-3]cyclobutanecarbonitrile</strong> To a 0 C. solution of 2,6-difluoropyridine (5.0 g, 43 mmol), <strong>[4426-11-3]cyclobutanecarbonitrile</strong> (3.5 g, 43 mmol), and toluene (100 mL) was added sodium hexamethyldisilazide (NaHMDS, 2.0 M in THF, 24 mL, 47 mmol). The resulting mixture was warmed to rt and stirred for 2 h. The mixture was then diluted with EtOAc (200 mL) and water (100 mL). The aqueous layer was extracted with EtOAc and the combined organic phases were washed with brine, dried over Na2SO4, concentrated, and purified using silica gel chromatography to provide the desired product (4.9 g) as a colorless oil.
Stage #1: cuminol With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 1h;
Stage #2: 2,6-difluoro pyridine In N,N-dimethyl-formamide; mineral oil at 20℃;
A76.a a- Synthesis of Int. 138
a- Synthesis of Int. 138: A sol. of 6 (3.1 g, 20 mmol) in dry DMF (60 mL) was treated at 0°C with NaH 60% (0.99 g, 25 mmol). After stirring for lh at r.t., 2,6-difluoro-pyridine (2.4 g, 21 mmol) was added and the r.m. was stirred at r.t. overnight. The r.m. was quenched with water 200 mL and the mixture was extracted with DCM 3x. The organic layer was dried and concentrated to give 5.7 g of Int. 138, colorless oil (100%, purity 89%) which was used like this in the next step.
2,6-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50.8%
With (1,5-cyclooctadiene)(methoxy)iridium(I) dimer; 4,4'-di-tert-butyl-2,2'-bipyridine In tetrahydrofuran at 100℃; for 0.0833333h; Microwave irradiation;
With n-butyllithium; C28H41ClNPPtSi In hexane; 1,3,5-trimethyl-benzene at 20 - 150℃; for 4h; Inert atmosphere; Overall yield = 72 %; Overall yield = 69 mg; regioselective reaction;
In tetrahydrofuran; for 12.0h;Inert atmosphere; Schlenk technique;
A Schlenk flask with a stir bar was charged with NaOMe (4.7 g, 87 mmol) and sealed with a rubber septum, and THF (200 mL) was added via cannula. Under N2(g) atmosphere, 2,6-difluoropyridine (5.0 g, 43 mmol) was added dropwise to the stirring solution via syringe to form 2-(methoxy)-6-fluoropyridine. This reaction was stirred overnight (approximately 12 h) then THF was removed under reduced pressure.
N,N-dimethyl-3-phenyl-1H-pyrazolo[3,4-b]pyridin-6-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
24%
LDA (304 muL in 1.8 M solution in heptane, THF and ethyl benzene, 0.547 mmol, 1.2 eq.) was added dropwise to a stirred solution of 2,6-difluoropyridine 27 (52 mg, 0.456 mmol, 1.0 eq.) in THF (2 mL) at -78 C. After stirring at -78 C for 0.5 h, N-methoxy-N-metylbenzamide (150 muL, 0.912 mmol, 2.0 eq.) was added to the reaction mixture and stirred for 2 h. The reaction mixture was quenched with water and extracted with EtOAc, dried over MgSO4 and evaporated in reduced pressure, to give the crude product of ketone for use of next reaction directly. (NH2)2·H2O was added to a stirred solution of the crude product of ketone and dimethyl amine (103 muL, 2.28 mmol, 5.0 eq.) in N-methylpyrrolidone (4.5 mL) and stirred at rt for 1 h. the reaction mixture was quenched with water and extracted with CHCl3, dried over MgSO4, and evaporated in reduced pressure, to give the crude product. Purification with Yamazen automated chromatography with Hex:EtOAc = 1:1 as eluent to give the ethyl ester product 28 (30 mg, 24%) as a colourless solid, 1H NMR (300 MHz, CDCl3) delta 8.06 (1H, d, J = 9 Hz), 7.94 (1H, dd, J = 9.0, 3.0 Hz), 7.52-7.36 (5H, m), 6.55 (1H, d, J = 9.0 Hz), 3.23 (6H, s); MS (ESI) m/z 239 [(M + H)+], RT 1.29 min (Condition A).
LDA (304 muL in 1.8 M solution in heptane, THF and ethyl benzene, 0.547 mmol, 1.2 eq.) was added dropwise to a stirred solution of 2,6-difluoropyridine 27 (52 mg, 0.456 mmol, 1.0 eq.) in THF (2 mL) at -78 C. After stirring at -78 C for 0.5 h, N-methoxy-N-metylbenzamide (150 muL, 0.912 mmol, 2.0 eq.) was added to the reaction mixture and stirred for 2 h. The reaction mixture was quenched with water and extracted with EtOAc, dried over MgSO4 and evaporated in reduced pressure, to give the crude product of ketone for use of next reaction directly. (NH2)2·H2O was added to a stirred solution of the crude product of ketone and azetidine (130 muL, 2.28 mmol, 5.0 eq.) in N-methylpyrrolidone (4.5 mL) and stirred at rt for 1 h. the reaction mixture was quenched with water and extracted with CHCl3, dried over MgSO4, and evaporated in reduced pressure, to give the crude product. Purification with Yamazen automated chlomatography with Hex:EtOAc = 1:1 as eluent to give the ethyl ester product 29 (90 mg, 79%) as a colourless solid, 1H NMR (300 MHz, CDCl3) delta 8.06 (1H, d, J = 9.0 Hz), 7.96-7.92 (2H, m), 7.55-7.49 (2H, m), 7.44-7.39 (1H, m), 6.24 (1H, d, J = 9.0 Hz), 4.23 (2H, q, J = 7.5 H), 2.54-2.45 (2H, m); MS (ESI) m/z 251 [(M + H)+], RT 1.22 min (Condition A).
3-phenyl-6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
6%
LDA (304 muL in 1.8 M solution in heptane, THF and ethyl benzene, 0.547 mmol, 1.2 eq.) was added dropwise to a stirred solution of 2,6-difluoropyridine 27 (52 mg, 0.456 mmol, 1.0 eq.) in THF (2 mL) at -78 C. After stirring at -78 C for 0.5 h, N-methoxy-N-metylbenzamide (150 muL, 0.912 mmol, 2.0 eq.) was added to the reaction mixture and stirred for 2 h. The reaction mixture was quenched with water and extracted with EtOAc, dried over MgSO4 and evaporated in reduced pressure, to give the crude product of ketone for use of next reaction directly. (NH2)2·H2O was added to a stirred solution of the crude product of ketone and pyrrolidine (162 muL, 2.28 mmol, 5.0 eq.) in N-methylpyrrolidone (4.5 mL) and stirred at rt for 1 h. the reaction mixture was quenched with water and extracted with CHCl3, dried over MgSO4, and evaporated in reduced pressure, to give the crude product. Purification with Yamazen automated chromatography with Hex:EtOAc = 1:1 as eluent to give the ethyl ester product 30 (6.7 mg, 6%) as a colourless solid, 1H NMR (300 MHz, CDCl3) delta 8.06 (1H, d, J = 8.0 Hz), 7.96-7.94 (2H, m), 7.53-7.40 (3H, m), 6.34 (1H, d, J = 8.0 Hz), 4.48 (2H, q, J = 8.0 Hz), 3.60 (4H, br s), 2.08 (4H, br m), 1.45 (3H, t, J = 8.0 Hz); MS (ESI) m/z 265 [(M + H)+], RT 1.29 min (Condition A).
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 100℃; for 5h;
Step 1. Preparation of N-(2,4-dimethoxybenzyl)-6-fluoropyridin-2-amine To a mixture of (2,4-dimethoxyphenyl)methanamine (117.5 mL, 782.0 mmol) and N,N-diisopropylethylamine (147.6 mL, 847.2 mmol) in anhydrous dimethyl sulfoxide (500 mL) was added 2,6-difluoropyridine (75.0 g, 651.7 mmol). The resulting mixture was heated to 100 C. for 5 hours and then allowed to cool to ambient temperature. The mixture was diluted with ethyl acetate (600 mL), washed with water (1000 mL), saturated ammonium chloride (2*200 mL), brine (100 mL), and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo provided a residue, which was triturated in methanol (250 mL) to afford the title compound as a colorless solid (140.0 g, 82% yield): 1H NMR (300 MHz, CDCl3) delta 7.44 (q, J=8.2 Hz, 1H), 7.22 (d, J=8.2 Hz, 1H), 6.49 (d, J=2.3 Hz, 1H), 6.44 (dd, J=8.2, 2.4 Hz, 1H), 6.21 (dd, J=8.0, 2.4 Hz, 1H), 6.12 (dd, J=7.7, 2.3 Hz, 1H), 5.17-5.07 (m, 1H), 4.40 (d, J=6.0 Hz, 2H), 3.84 (s, 3H), 3.81 (s, 3H); MS (ES+) m/z 263.2 (M+1).
82%
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 100℃; for 5h;
To a mixture of (2,4-dimethoxyphenyl)methanamine (117.5 ml_, 782.0 mmol) and A/./V-diisopropylethylamine (147.6 mL, 847.2 mmol) in anhydrous dimethyl sulfoxide (500 mL) was added 2,6-difluoropyridine (75.0 g, 651.7 mmol). The resulting mixture was heated to 100 C for 5 hours and then cooled to ambient temperature. T he mixture was diluted with ethyl acetate (600 mL), washed with water (1000 mL), saturated ammonium chloride (2 c 200 mL), brine (100 mL), and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo provided a residue, which was triturated in methanol (250 mL) to afford the title compound as a colorless solid (140.0 g, 82% yield): 1H-NMR (300 MHz, CDCI3) d 7.44 (q, J = 8.2 Hz, 1 H), 7.22 (d, J = 8.2 Hz, 1 H), 6.49 (d, = 2.3 Hz, 1 H), 6.44 (dd, J = 8.2, 2.4 Hz, 1 H), 6.21 (dd, J (0749) = 8.0, 2.4 Hz, 1 H), 6.12 (dd, J = 7.7, 2.3 Hz, 1 H), 5.17-5.07 (m, 1 H), 4.40 (d, J = 6.0 Hz, 2H), 3.84 (s, 3H), 3.81 (s, 3H); MS (ES+) m/z 263.2 (M + 1).
Under nitrogen protection,2,6-difluoropyridine (11.5 g, 0.1 mol),Boc2O (26.0 g, 0.12 mol) and tetrahydrofuran 130 mL,After stirring until completely dissolved,The ice salt bath drops to -15 C,Start the dropwise addition of a previously prepared 1M LDA tetrahydrofuran solution (0.13 mol).The temperature control during the whole dropping process does not exceed -10 C.After the addition is completed,Stir for 2-3 hours with heat.Then naturally rise to room temperature and stir the reaction overnight.There is almost no residue in the TLC test. The reaction solution was again lowered to 0 C.Add 15% hydrochloric acid aqueous solution to pH=1-2 (note that the acidity adjustment is not too strong,When not controlling the hydrolysis of acid,A small amount of 2-hydroxy-6-fluoro-pyridine-3-carboxylic acid was detected.Significantly exothermic during the addition process,Control temperature does not exceed 30 C,After the addition is completed, the temperature is raised to 35-40 C.Continue to stir the reaction for 1-2 hours.Detect if there is still a small amount remaining,It can be supplemented with 15% hydrochloric acid and then kept warm and stirred until the reaction is completed.After falling to room temperature,Then add saturated aqueous sodium carbonate solution,Adjust pH=4-5,Add ethyl acetate 70mL and extract twice.Washed with saturated saline,Dry over anhydrous sodium sulfate,After steaming the solvent,After beating with 88 mL of methyl tert-butyl ether and n-heptane (1:8 by volume),Obtained 13.5 g of 2,6-difluoropyridine-3-carboxylic acid as a pale yellow solid.Yield 85%,HPLC: 98.1%,The product is consistent with the standard sample in HPLC.
1,8-diazabicyclo[5.4.0]undec-7-ene carbon dioxide complex[ No CAS ]
[ 171178-50-0 ]
Yield
Reaction Conditions
Operation in experiment
81%
Under nitrogen protection,2,6-difluoropyridine (11.5 g, 0.1 mol) and tetrahydrofuran 120 mL,After stirring until completely dissolved,Dry ice/acetone system to -75 C,Start adding and pre-configuring1M LDA tetrahydrofuran solution (0.12 mol),The temperature control during the entire dropping process does not exceed -60 C.After the addition was completed, the mixture was stirred for 1.5 hours.Subsequently DBU-CO2 complex (0.11 mol)Dissolved in 65mL tetrahydrofuran solution,The temperature control does not exceed -60 C and drops into the reaction solution.Stir for 2 hours with heat.Naturally warm to room temperature and stir the reaction overnight.There is almost no residue in the TLC test.The reaction solution was again lowered to 0 C.A 15% aqueous hydrochloric acid solution was added dropwise to pH = 3-5.Significantly exothermic during the addition process,The control temperature does not exceed 20 C,After the addition is completed, the reaction is stirred for 1-2 hours.Add ethyl acetate 70mL and extract twice.Washed with saturated saline,Dry over anhydrous sodium sulfate,After steaming the solvent,After beating with 80 mL of methyl tert-butyl ether and n-heptane (1:8 by volume),A pale yellow solid of 12.9 g of 2,6-difluoropyridine-3-carboxylic acid was obtained in a yield of 81%. HPLC: 97.2%.
methyl (3S)-1-(6-fluoropyridin-2-yl)pyrrolidine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 80℃; for 18.0h;
A mixture of 2,6-difluoropyridine [1513-65-1] (1.00 g, 8.69 mmol), (5)-3-methyl pyrrolidine-3 -carboxylate hydrochloride [1099646-61-3] (1.58 g, 9.56 mmol) and potassium carbonate (3.60 g, 26.1 mmol) in NMP (65 mL) was stirred at 80C for 18 h. The reaction mixture was diluted with EtOAc and H20. The layers were separated and the aqueous phase was extracted with EtOAc (5 times). The organic extracts were combined and the solvent was removed under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 120 g GraceResolv, liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 100:0 to 50:50) to afford intermediate 186 (1.6 g, 82%) as a colorless oil.
(3R,5S)-tert-butyl 4-(6-fluoropyridin-2-yl)-3,5-dimethylpiperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37.73%
With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; lithium hexamethyldisilazane; at 0 - 80℃;
A stirred solution of (3S,5R)-tert-butyl 3,5- dimethylpiperazine-1 -carboxylate (20 g, 93.0 mmol, 1 eq) in LiHMDS (200 mL) was cooled to 0C and 2,6-difluoropyridine (26.8 mL, 280.3 mmol, 3 eq), and xanthophos (3.24 g, 5 mmol, 0.06 eq) were added followed by Pd2(dba)3 (2.5 g, 2.7 mmol, 0.03 eq). Then, the resultant reaction mixture was stirred overnight at 80C. The reaction was monitored with TLC, and TLC indicated formation of a non-polar spot. The reaction mixture was quenched with ice water (100 mL), filtered through celite and washed with ethyl acetate. The layers were separated, and the aqueous layer extracted with ethyl acetate (2x150 mL) and washed with brine solution (1x100 mL). The combined organic layer was dried over Na2S04, and concentrated under reduced pressure to give crude product. The crude product was purified by column chromatography (silica gel, 100-200 mesh) using 0-5% ethyl acetate in petroleum ether as an eluent to afford (3R,5S)-tert-butyl 4-(6-fluoropyridin-2-yl)-3,5-dimethylpiperazine-1 -carboxylate (20 g, 37.73% yield) as a brown liquid. LCMS: m/z 310.54 (M+H).
With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 16h;
1.1 Step 1:
To a stirred solution of compound 1 (10.5g, 84mmol, 1 eq) in DMF (200ml_) was added K2CO3 (40.6g, 294mmol, 2.5eq) followed by compound 2 (27g, 126mmol, 1.5eq) at RT. The resulting reaction mixture was heated at 90 °C for 16h. The reaction was monitored by TLC. TLC analysis indicated formation of a non-polar spot. Reaction mixture was quenched with ice water and extracted with ethyl acetate (2x300mL). The combined organic layer was dried over Na2S04 and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 100-200) using 0-15% ethyl acetate in petroleum ether as an eluent to give Compound 3 (14.5g, 86.3% yield) as colour less liquid. LCMS: 98.24% with m/z 185.09 (M+H
4-((6-fluoropyridin-2-yl)oxy)-2-methylpentan-2-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
Stage #1: 2-methyl-2,4-pentanediol With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 0.333333h; Inert atmosphere;
Stage #2: 2,6-difluoro pyridine In tetrahydrofuran; mineral oil at 20℃; for 0.5h; Inert atmosphere;
2-[1-(6-fluoropyridin-2-yl)azetidin-3-yl]ethan-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
12%
With pyridine In 1,4-dioxane at 100℃;
2-(Azetidin-3-yl)ethanol HCl (1.0 g, 7.26 mmol) was slurried in dioxane (10 ml), and 2,6- difluoropyridine (1.0 ml, 1.5 eq) was added followed by pyridine (3 ml, 5 eq). The reaction was heated to 100 °C overnight. The reaction mixture was diluted with ethyl acetate, washed with water, treated with brine, dried with MgSO4, and filtered, and then the solvent was removed in vacuo to give the crude product. The crude product was purified on the ISCO (25 g silica, applied with DCM, eluted with 30- 60% ethyl acetate/hexane over 6 min) to give 2-[1-(6-fluoropyridin-2-yl)azetidin-3-yl]ethan- 1-ol (0.17 g oil, 12% yield, HPLC Rf 2.22 min, MS m/z (M+1) 197.2, TLC 50% ethyl acetate/ hexane Rf 0.18).
1-[(6-fluoropyridin-2-yl)azetidin-3-yl]methanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 100℃;
Azetidin-3-ylmethanol HCl (1.0 g, 8.1 mmol) was slurried in dioxane (10 ml), and 2,6- difluoropyridine (0.75 ml, 1 eq) was added followed by Hunig’s base (3.5 ml, 2.5 eq). The reaction was heated to 100 °C overnight. The reaction mixture was diluted with ethyl acetate, washed with water, treated with brine, dried with MgSO4, filtered and the solvent was removed in vacuo to give the crude product. The crude product was purified on the ISCO (25 g silica, applied with DCM, eluted with 30- 60% ethyl acetate/hexane over 5 min) to give 1-(6-fluoropyridin-2-yl)azetidin-3-yl]methanol (0.75 g oil, 51% yield, HPLC Rf 1.83 min, MS m/z (M+1) 183.1, TLC 50% ethyl acetate/hexane Rf 0.17).
With [(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1, 1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)] palladium(II) methanesulfonate; sodium t-butanolate In tetrahydrofuran at 50℃; for 18.0833h; Inert atmosphere;
1 Preparation of compound 8
T-BuXPhosPdG3 (t-BuXPhosPdG3) in a THF (8 mL) suspension of 2,6-difluoropyridine (62 mg, 0.54 mmol), imidazole [1,2-a] pyridine-7-amine (108 mg, 0.81 mmol). 43.7 mg (0.055 m mmol) and t-BuONa (0.48 mL, 0.96 mmol) were added, nitrogen was bubbled for 5 minutes, and the mixture was stirred at 50 ° C. for 18 hours. The reaction mixture was allowed to cool to room temperature, filtered through Celite, saturated brine was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered, and the filtrate was distilled off under reduced pressure. The obtained residue was purified by flash chromatography (silica gel, elution solvent: chloroform / methanol 9/1), and the solvent was distilled off under reduced pressure to obtain compound 8 (18.4 mg, 0.08 mmol) as a white solid. 15%) was obtained.
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