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[ CAS No. 1895-39-2 ] {[proInfo.proName]}

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Chemical Structure| 1895-39-2
Chemical Structure| 1895-39-2
Structure of 1895-39-2 * Storage: {[proInfo.prStorage]}
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Product Details of [ 1895-39-2 ]

CAS No. :1895-39-2 MDL No. :MFCD00064771
Formula : C2ClF2NaO2 Boiling Point : -
Linear Structure Formula :- InChI Key :MRTAVLDNYYEJHK-UHFFFAOYSA-M
M.W : 152.46 Pubchem ID :2734985
Synonyms :
Chemical Name :Sodium 2-chloro-2,2-difluoroacetate

Calculated chemistry of [ 1895-39-2 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.5
Num. rotatable bonds : 1
Num. H-bond acceptors : 4.0
Num. H-bond donors : 0.0
Molar Refractivity : 16.49
TPSA : 40.13 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.41 cm/s

Lipophilicity

Log Po/w (iLOGP) : -5.01
Log Po/w (XLOGP3) : 1.15
Log Po/w (WLOGP) : 0.41
Log Po/w (MLOGP) : 0.49
Log Po/w (SILICOS-IT) : 1.15
Consensus Log Po/w : -0.36

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.44
Solubility : 5.49 mg/ml ; 0.036 mol/l
Class : Very soluble
Log S (Ali) : -1.59
Solubility : 3.94 mg/ml ; 0.0259 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.44
Solubility : 55.4 mg/ml ; 0.363 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.23

Safety of [ 1895-39-2 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 1895-39-2 ]

* 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.

  • Upstream synthesis route of [ 1895-39-2 ]
  • Downstream synthetic route of [ 1895-39-2 ]

[ 1895-39-2 ] Synthesis Path-Upstream   1~32

  • 1
  • [ 67-56-1 ]
  • [ 1895-39-2 ]
  • [ 1514-87-0 ]
Reference: [1] Journal of Fluorine Chemistry, 2002, vol. 113, # 1, p. 47 - 50
  • 2
  • [ 64-17-5 ]
  • [ 1895-39-2 ]
  • [ 383-62-0 ]
Reference: [1] Journal of Fluorine Chemistry, 2002, vol. 113, # 1, p. 47 - 50
  • 3
  • [ 1895-39-2 ]
  • [ 100-83-4 ]
  • [ 85684-61-3 ]
YieldReaction ConditionsOperation in experiment
36% With potassium carbonate In N,N-dimethyl-formamide at 95℃; for 5 h; [0471j A solution of sodium chlorodifluoroacetate (12.48 g, 82 mmol) and 3-hydroxybenzaldehyde (5.00 g, 40.9 mmol) in DMF (75 ml) was added over 3 hours to a solution of DMF (25 ml) containing potassium carbonate (8.49 g, 61.4 mmol) at 95 °C. The reaction was allowed to age for an additional 2 hours and then cooled. The reaction mixyure was diluted with water (100 ml) and extracted with ethyl acetate (4 x50 ml). The organic extract was washed with 10percent (mlv) aqueous LiC1 solution (3 x 25 ml), dried over sodium sulfate, filtered and evaporated to give a residue that was flash chromatographed (15percent EtOAc/hexane) to give 3-(difluoromethoxy)benzaldehyde (2.50 g, 14.52 mmol, 36percent) as a yellow oil. The NMR was consistent with the proposed structre.
Reference: [1] Patent: WO2014/127042, 2014, A1, . Location in patent: Paragraph 0471
  • 4
  • [ 1895-39-2 ]
  • [ 188554-13-4 ]
  • [ 85684-61-3 ]
Reference: [1] Patent: WO2011/159553, 2011, A1, . Location in patent: Page/Page column 30-31
  • 5
  • [ 1895-39-2 ]
  • [ 123-08-0 ]
  • [ 73960-07-3 ]
YieldReaction ConditionsOperation in experiment
75% With potassium carbonate In water; N,N-dimethyl-formamide at 100℃; for 15 h; Take 2g hydroxybenzaldehyde with DMF / H2O (9: 1) to which was added 1.2eq.K2CO3,2.0eq. NaCO2CF2Cl, the reaction temperature to 100 15h or until the reaction is complete.Cooled to room temperature, 20percent NaOH aq was added to adjust the pH to 11, add MTBE, the combined organic phase was washed with water, concentrated and dried to give the product as a pale yellow liquid after flash column chromatography. [2.1g, yield: 75percent].
Reference: [1] Patent: CN104059082, 2016, B, . Location in patent: Paragraph 0061; 0062
  • 6
  • [ 1895-39-2 ]
  • [ 139-85-5 ]
  • [ 127842-54-0 ]
YieldReaction ConditionsOperation in experiment
90%
Stage #1: With potassium carbonate In water; N,N-dimethyl-formamide at 100℃; for 2 h;
Stage #2: With hydrogenchloride In water; N,N-dimethyl-formamide
Stage #3: With sodium hydroxide In water; N,N-dimethyl-formamide
[00434] To a solution of 3,4-dihydroxybenzaldehyde (300 mg, 2.2mmol) in DMF (9.0 mL) and H2O (1.0 mL) was added sodium chlorodifluoroacetate (1.33 g) and K2CO3 (729 mg). The mixture was heated up to 100°C for 2 h before cooling down to rt. Concentrated HCl (1.54 mL) and H2O (2.0 mL) were added and the reaction was stirred overnight. The mixture was neutralized with IN NaOH to pH > 9, extracted with EtOAc, washed with brine, dried over MgS O4 and concentrated. The crude product was purified by silica gel chromatography to give 132 A (470 mg, 90percent yield). 1H NMR (400 MHz, CDCl3) δ ppm 6.29 - 6.89 (m, 2 H) 7.42 (d, J=8.35 Hz, 1 H) 7.66 - 7.90 (m, 2 H) 9.95 (s, 1 H).
65% With potassium carbonate In water; N,N-dimethyl-formamide at 80℃; for 16 h; Sodium chlorodifluoroacetate (88 g, 58mmol) was added to a suspension of 3,4-dihydroxybenzaldehyde (11) (20 g, 14 mmol), potassiumcarbonate (80 g, 58 mmol) and water (10 mL, 58 mmol) in DMF (200 mL). Thesuspension was heated to 80 °C for 16h and then cooled to rt and diluted with water. The aqueous phase was extractedwith EtOAc and the combined organic fractions were washed with water, brine,dried and concentrated. The residue was partially purified by columnchromatography, eluting with 5-10percent EtOAc/petrol to give 3,4-bis(difluoromethoxy)benzaldehyde(22.5 g, 65percent) as a colourless oil; δH (400 MHz, CDCl3)6.60 (t, J = 72 Hz, 1H, OCHF2), 6.64 (t, J = 72 Hz, 1H, OCHF2), 7.42 (d, J5,6= 8.0 Hz, 1H, H5), 7.76–7.78 (m,2H, H2, H6), 9.96 (s, 1H, CHO); δC(125 MHz, CDCl3) 115.2 (t, J= 259 Hz), 115.4 (t, J = 259 Hz),121.5, 122.2, 128.5, 134.2, 142.4, 147.0 189.7; nmax 794, 1038, 1381, 1509, 1698, cm–1.The 3,4-bis(difluoromethoxy)benzaldehyde coeluted with approximately 10-20percentunidentified colourless oil: δH (400 MHz, CDCl3) 7.13 (s,1H), 7.19 (d, J = 8.0 Hz, 1H), 7.30(s, 1H), 7.59 (d, J = 1.5 Hz, 1H), 7.61(dd, J = 1.5 Hz, 8.0 Hz, 1H), 9.91(s, 1H).
Reference: [1] Patent: WO2006/76246, 2006, A2, . Location in patent: Page/Page column 220
[2] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 24, p. 6868 - 6873
[3] Patent: WO2009/20642, 2009, A1, . Location in patent: Page/Page column 69
[4] Patent: US2010/35931, 2010, A1, . Location in patent: Page/Page column 17
  • 7
  • [ 1895-39-2 ]
  • [ 99-93-4 ]
  • [ 83882-67-1 ]
YieldReaction ConditionsOperation in experiment
51% With sodium hydroxide In N,N-dimethyl-formamide at 100℃; for 14 h; To a stirred solution of 4-hydroxy acetophenone (GQ, 5.0 g, 36.76 mmol) in DMF (50 mL) was added sodium 2-chloro-2,2-difluoroacetate (6.2 g, 40.44 mmol) followed by NaOH (1.76 g, 44.11 mmol) and the reaction mixture was stirred at 100C for 14 h. After completion of the reaction, the reaction mixture was diluted with cold water and the product was extracted with EtOAc. The combined organic layer was dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 20-30percent EtOAc/hexane to afford compound GR (3.5 g, 51.0percent) as a colorless liquid. 1H NMR (400 MHz, DMSO-d6): _ 8.05-8.01 (m, 2H), 7.59-7.22 (m, 3H), 2.50 (s, 3H); LC-MS: m/z 187.0 [M+H]+.
Reference: [1] Patent: WO2018/165520, 2018, A1, . Location in patent: Page/Page column 215-216
  • 8
  • [ 1895-39-2 ]
  • [ 139-85-5 ]
  • [ 151103-08-1 ]
YieldReaction ConditionsOperation in experiment
57.5% With sodium carbonate In water; N,N-dimethyl-formamide at 80℃; for 6 h; In a 100 ml round bottom flask, 3,4-dihydroxybenzaldehyde (5.1 g, 36.9 mmol, 1.0 eq), Na2CO3(11.73 g, 110.7 mmol, 3.0 eq) was suspended in 250 mL of DMF, 8.57 g of sodium chlorodifluoroacetate, (56.1 mmol, 1.5 eq) in 20 ml of water was added and the temperature was raised to 80 ° C for 6 hours. The reaction solution was adjusted to pH 5-6 with 1.0 M / L hydrochloric acid and extracted with ethyl acetate 20 mL x 3. The organic phase was collected and dried over anhydrous MgSO4. The solvent was evaporated under reduced pressure to give the crude product, which was purified by column chromatography. Stripping Ethyl Acetate: Petroleum Ether (1:20) to give A3.99 g of monosubstituted compound, 57.5percent yield, 0.26 g of disubstituted product, yield 3.75percent
46% With sodium hydroxide In water; N,N-dimethyl-formamide at 120℃; for 2 h; To a solution of 3,4-dihydroxybenzaldehyde (1.66 g, 12 mmol)and sodium chlorodifluoroacetate (1.83 g, 12 mmol) in DMF (15 mL) and water (0.3 mL) was added sodium hydroxide (0.48 g,12 mmol). Then, the mixture was heated at 120° C and stirred at this temperature for 2 h. The solvent was removed by vacuum distillation, and to the residue was added aqueous HCl (2 mL). The mixture was extracted with Et2O and washed with brine.The solvent was removed under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/EtOAc = 80:20) to afford 12 as a white solid (1.05 g,5.28 mmol, 46percent). ESI-MS (m/z): 187.4 ([MH]).
44%
Stage #1: With sodium hydroxide In water; N,N-dimethyl-formamide at 120℃; for 2 h;
Stage #2: With hydrogenchloride In water
A solution of 3,4-dihydroxybenzaldehyde (16.6 g, 120 mmol) and sodium chlorodifluoroacetate (18.3 g, 120 mmol) in dimethylformamide (150 ml) and water (3 ml) was added with sodium hydroxide (4.8 g, 120 mmol), heated to 120° C. and stirred at this temperature for 2 hrs.
The solvent was removed by vacuum distillation and the residue added with aqueous hydrochloric acid (20 ml).
The mixture was extracted with diethyl ether (2*50 ml), the combined organic layers were washed with water and brine and the solvent removed under reduced pressure.
The crude product was purified by chromatography on silica gel (hexane/ethyl acetate 8:2) to furnish 4-difluoromethoxy-3-hydroxybenzaldehyde as a colourless solid (10 g, 52.8 mmol, 44percent yield).
39% With sodium hydroxide In water; N,N-dimethyl-formamide at 120℃; for 2 h; Production Example 19-1
4-(Difluoromethoxy)-3-hydroxybenzaldehyde
Commercially available 3,4-dihydroxybenzaldehyde (5 g, 36.2 mmol) and commercially available sodium chlorodifluoroacetate (5.57 g, 36.5 mmol) were dissolved in N,N-dimethylformamide (45 mL) and water (905 μL), and then sodium hydroxide (1.48 g, 37.0 mmol) was added at room temperature, and the mixture was heated and stirred at 120° C. for 2 hours.
The solvent was evaporated under vacuum, the residue was cooled to 0° C., and 5 M hydrochloric acid and diethyl ether were added for partition.
The organic layer was washed with water and a saturated saline solution, and then the solvent was evaporated.
The residue was dissolved in dichloromethane and the resultant was purified with silica gel column chromatography (n-heptane:ethyl acetate 9:1-7:3), and then the target fraction was concentrated under vacuum to obtain the title compound (2.66 g, 39percent).
1H-NMR Spectrum (CDCl3) δ (ppm): 5.69-5.74 (1H, m), 6.65 (1H, t, J=72.5 Hz), 7.23-7.31 (1H, m), 7.46 (1H, dd, J=8.4, 1.8 Hz), 7.54 (1H, d, J=1.8 Hz), 9.92 (1H, s).
37% With sodium hydroxide In water; N,N-dimethyl-formamide at 120℃; for 2 h; To a solution of 3,4-dihydroxybenzaldehyde (41.52 g, 0.3 mol, 1.0 eq) and sodium chloro(difluoro)acetate (45.75 g, 0.3 mol, 1.0 eq) in DMF (375 ml) and water (7.5 ml) was added NaOH (12 g, 0.3 mol, 1.0 eq) and the resulting mixture was heated at 120 °C for 2 h. The solvent was removed by vacuum distillation and aqueous HCl was added to the residue. The mixture was extracted with EA (500 ml x 2) and the solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel (PE/EA from 10/1 to 8/1) to afford 4-(difluoromethoxy)-3-hydroxybenzaldehyde (20.86 g, 37percent yield, 99.8percent purity) as a white solid.
36.9% With sodium hydroxide In water; N,N-dimethyl-formamide at 120℃; for 2 h; To a solution of 3,4-dihydroxybenzaldehyde (41.52 g, 0.3 mol, 1.0 eq) and sodium chloro(difluoro)acetate (45.75 g, 0.3 mol, 1.0 eq) in DMF (375 ml) and water (7.5 ml) was added NaOH (12 g, 0.3 mol, 1.0 eq) and the resulting mixture was heated at 120 °C for 2 h. The solvent was removed by vacuum distillation and HCl and water were added to the residue. The mixture was extracted with EA (500 ml x 2) and the solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel (PE/EA from 10/1 to 8/1) to furnish Intermediate 1 (20.86 g, 36.9percent yield, 99.8percent purity) as a white solid.
24%
Stage #1: With sodium hydroxide In DMF (N,N-dimethyl-formamide) at 55℃; for 16 h;
Stage #2: With hydrogenchloride In DMF (N,N-dimethyl-formamide); water
3,4-Dihydroxybenzaldehyde (20 g, 145 mmol), chlorodifluoroacetic acid sodium salt (55.19 g, 362 mmol) and sodium hydroxide (5.50 g, 138 mmol) were stirred in DMF (1200 mL) at 55°C under nitrogen for 16 hours. The pH was adjusted to 1.0 by the addition of 10 percent aqueous HC1 followed by extraction with ethyl acetate (3x 500 mL). The combined extracts were evaporated under vacuum. The residue was purified on silica gel using a 10-20percent ethyl acetate/hexane gradient. 4-difluoromethoxy-3- hydroxybenzaldehyde was isolated in 24percent yield (6.62 G). IH NMR (CDC13,400 MHz) 8 6.1 (br s, 1H), 6.48-6. 85 (t, 1H OCHF2), 7.26 (d, 1H), 7.44 (d, 1H), 7.55 (s, 1H), 9.91 (s, 1H).
24% With sodium hydroxide In N,N-dimethyl-formamide at 55℃; for 16 h; Intermediate E Synthesis of 4-difluoromethoxy-3-hydroxybenzaldehyde 3,4-Dihydroxybenzaldehyde (20 g, 145 mmol), chlorodifluoroacetic acid sodium salt (55.19 g, 362 mmol) and sodium hydroxide (5.50 g, 138 mmol) were stirred in DMF (1200 mL) at 55° C. under nitrogen for 16 hours. The pH was adjusted to 1.0 by the addition of 10percent aqueous HCl followed by extraction with ethyl acetate (3.x.500 mL). The combined extracts were evaporated under vacuum. The residue was purified on silica gel using a 10-20percent ethyl acetate/hexane gradient. 4-difluoromethoxy-3-hydroxybenzaldehyde was isolated in 24percent yield (6.62 g). 1H NMR (CDCl3, 400 MHz) δ 6.1 (br s, 1H), 6.48-6.85 (t, 1H OCHF2), 7.26 (d, 1H), 7.44 (d, 1H), 7.55 (s, 1H), 9.91 (s, 1H).

Reference: [1] Patent: CN105732348, 2016, A, . Location in patent: Paragraph 0034; 0039; 0040
[2] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 22, p. 7332 - 7339
[3] Patent: US2008/15226, 2008, A1, . Location in patent: Page/Page column 10
[4] Journal of Medicinal Chemistry, 2014, vol. 57, # 3, p. 793 - 816
[5] Patent: US2014/235614, 2014, A1, . Location in patent: Paragraph 0470; 0471; 0472
[6] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 18, p. 4594 - 4597
[7] Patent: WO2013/21021, 2013, A1, . Location in patent: Page/Page column 39; 40
[8] Patent: WO2004/94411, 2004, A1, . Location in patent: Page 111
[9] Patent: US2007/254913, 2007, A1, . Location in patent: Page/Page column 36
[10] Patent: EP2070913, 2009, A1, . Location in patent: Page/Page column 21-22
[11] Patent: CN102964297, 2018, B, . Location in patent: Paragraph 0020-0021; 0277-0278
  • 9
  • [ 25934-52-5 ]
  • [ 1895-39-2 ]
  • [ 151103-09-2 ]
YieldReaction ConditionsOperation in experiment
84% With sodium hydroxide In N,N-dimethyl-formamide at 120℃; for 2 h; To a two-necked 100ml flask was added 3-hydroxy-cyclopentyloxy (1.65g, 8.6mmol), chlorodifluoromethane sodium fluoroacetate (2.44g, 16mmol), NaOH solution (20mmol / L, 0.8ml) and N, N- dimethylformamide (DMF, 12ml), the reaction was heated to 120 2h, thin layer chromatography (TLC ) detecting the progress of the reaction, the reaction was complete after the DMF removed at reduced pressure and the residue was purified by silica gel column chromatography as a colorless oil cyclopentyloxy-4-difluoro-3- methoxybenzaldehyde (z-61.75g, yield 84percent)
Reference: [1] Patent: CN105523954, 2016, A, . Location in patent: Paragraph 0025; 0026
  • 10
  • [ 591-20-8 ]
  • [ 1895-39-2 ]
  • [ 262587-05-3 ]
YieldReaction ConditionsOperation in experiment
61% With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 2 h; Intermediates T18A and T18BT18.1 [0412] l-Bromo-3-(difluoromethoxy)benzene (T18.1). To a solution of 3- bromophenol (commercially available from Sigma- Aldrich, St. Louis, MO, USA) (1.28 g, 7.39 mmol) in DMF (12.0 mL) was added sodium 2-chloro-2,2-difluoroacetate (commercially available from Sigma-Aldrich, St. Louis, MO, USA) (2.82 g, 18.49 mmol) and Cs2CO3 (4.82 g, 14.79 mmol). The reaction mixture was heated at 100°C. Gas was released from the reaction so care should be taken. After 2 hours, the reaction was cooled to room temperature then diluted with EtOAc, washed with water and then brine and re- extracted three times with EtOAc. The combined organic layers were dried over magnesium sulfate and then filtered, concentrated, and purified with silica gel chromatography (0-5percent EtOAc in hexanes) to yield T18.1 as an oil that was used without further purification (yield 61percent).
61% With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 2 h; l-Bromo-3-(difluoromethoxy)benzene (T7.1). To a solution of 3- bromophenol (available from Sigma Aldrich) (1.28 g, 7.39 mmol) in DMF (12.0 mL) was added sodium 2-chloro-2,2-difluoroacetate (available from Sigma Aldrich )(2.82 g, 18.49 mmol) and cesium carbonate (4.82 g, 14.79 mmol). The reaction mixture was heated at 100°C. Gas was released from the reaction so care should be taken. After 2 hours, the reaction was cooled to room temperature then diluted with EtOAc, washed with water and then brine and re-extracted three times with EtOAc. The combined organic layers were dried over magnesium sulfate and then filtered, concentrated, and purified with silica gel chromatography (0-5percent EtOAc in hexanes) to yield T7.1 as an oil that was used without further purification (yield 61percent).
Reference: [1] Patent: WO2010/45258, 2010, A2, . Location in patent: Page/Page column 179; 180
[2] Patent: WO2009/111056, 2009, A1, . Location in patent: Page/Page column 151-152
  • 11
  • [ 1895-39-2 ]
  • [ 162401-62-9 ]
YieldReaction ConditionsOperation in experiment
81.4%
Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 0.5 h;
Stage #2: With water; sodium hydroxide In methanol at 50℃; for 2 h;
A solution of 2.1 g of anhydrous potassium carbonate was added to 10 mL Anhydrous N,N-dimethylformamide, and the temperature was raised to 100 °C. Under stirring, a solution of 2.22 g of 3-cyclopropylmethoxy-4-hydroxybenzoic acid methyl ester (V) was added to a solution of 3.05 g of sodium 2-chloro-2,2-difluoroacetate in 10 mL of anhydrous N,N-dimethylformamide solution was slowly added to the above reaction system. The reaction temperature was maintained and the reaction was stirred for 0.5 hour and then allowed to cool to room temperature. Add ethyl acetate, water, 50mL, shaking layered, The aqueous layer was extracted with 2X30 mL of ethyl acetate, the organic phases were combined, washed with water, Saturated brine, dried over anhydrous sodium sulfate, concentrate. The concentrated oily solution was dissolved in 10 mL of methanol, Add 3mol/L aqueous solution of sodium hydroxide 5mL, heated to 50 °C, The reaction was stirred for 2 hours. Concentrated under reduced pressure, with 6mol/L hydrochloric acid to adjust to strong acid to form a white precipitate, which was cooled to 5 °C for 2 hours, suction, washing, Dried to give 2.1 g of a white solid, 81.4percent yield.
Reference: [1] Patent: CN104177253, 2016, B, . Location in patent: Paragraph 0044; 0045
  • 12
  • [ 1895-39-2 ]
  • [ 121-33-5 ]
  • [ 162401-70-9 ]
YieldReaction ConditionsOperation in experiment
91% With caesium carbonate In DMF (N,N-dimethyl-formamide); water at 100℃; for 3.5 h; A solution of 4-hydroxy-3-methoxybenzaldehyde (2.0 g, 0.013 mol), sodium 2-chloro- 2, 2-difluoroacetate (4.8 g, 0.031 mol) and cesium carbonate (72 mg, 0.018 mol) in DMF (14 mL) and water (14 mL) was heated at 100°C for 3.5 hours. The mixture was acidified with concentrated hydrochloric acid and extracted with ethyl acetate (2x 25 mL). The organic layer was washed with water (2x25 mL), dried (MgSO4) and the solvent removed under reduced pressure. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (1: 4) as eluent gave 4-(difluoromethoxy)-3-methoxybenzaldehyde (2.41 g, 91percent) as an oil. 8 (250 MHz, CDCI3) : 3.76 (s, 3H); 6.49 (t, JF-H=74. 0 Hz, 1H) ; 7.11 (d, J=8.0 Hz, 1H) ; 7.27 (dd, Je=1. 7 Hz, J2=8.0 Hz, 1 H) ; 7.31 (d, J=1.7 Hz, 1 H) ; 9.74 (s, 1 H).
Reference: [1] Patent: WO2005/58883, 2005, A1, . Location in patent: Page/Page column 131
  • 13
  • [ 55717-45-8 ]
  • [ 1895-39-2 ]
  • [ 845827-14-7 ]
YieldReaction ConditionsOperation in experiment
58% With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 20 h; A mixture of 2-bromo-5-hydroxypyridine (1.2 g, 6.9 mmol), sodium chlorodifluoroacetate (2.1 g, 13.8 mmol), and potassium carbonate (1.24 g, 8.97 mmol) in anhydrous DMF (10 ml) was stirred at 80° C. for 20 h.
After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water.
The aqueous layer was back extracted with EtOAc and the combined organics was dried (Na2SO4) and concentrated.
The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0percent to 10percent EtOAc in hexane, to provide 2-bromo-5-(difluoromethoxy)pyridine (0.89 g, 4.0 mmol, 58percent yield) as colorless oil. ESI (M+1) 225.8.
43% With potassium carbonate In N,N-dimethyl-formamide at 80℃; Potassium carbonate (2.4 g, 17.3 mmols) and sodium chlorodifluoroacetate (4.2 g, 27.5 mmols) were added to a DMF (20 mL) solution of 2-bromo-5-hydroxypyridine (2.4 g,13.8 mmols) and stirred overnight at 80°C. The reaction liquid was cooled to room temperature, added ether, washed with water and dried over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, the resulting residue was purified on silica gel column chromatography (C-300; hexane: ethyl acetate =100:1-100:2) to provide the title compound (1.32 g, 43percent).
35% With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 18 h; 14.1
2-Bromo-5-difluoromethoxy-pyridine
6-Bromo-pyridin-3-ol (purchased from ABCR) (0.50 g, 2.87 mmol), sodium chloro-difluoro-acetate (0.88 g, 5.75 mmol) and potassium carbonate (0.50 g, 3.59 mmol) are dissolved in 5 ml N,N-Dimethylformamide and stirred at 80° C. for 18 hours.
Water is added and the mixture is extracted with diethyl ether twice.
The organic phase is dried and concentrated under reduced pressure.
The mixture is purified by silica gel chromatography (eluent: cyclohexane/ethyl acetate 5percent->15percent).
Yield: 0.23 g (35percent of theory)
Mass spectrometry (ESI-): m/z=224, 226 [M+H]+
Reference: [1] Journal of Medicinal Chemistry, 2010, vol. 53, # 23, p. 8421 - 8439
[2] Patent: US2013/225552, 2013, A1, . Location in patent: Paragraph 0902
[3] Patent: EP1741703, 2007, A1, . Location in patent: Page/Page column 73
[4] Patent: US2018/37594, 2018, A1, . Location in patent: Paragraph 0280-0283
[5] Patent: US2014/249104, 2014, A1, . Location in patent: Page/Page column
  • 14
  • [ 2362-12-1 ]
  • [ 1895-39-2 ]
  • [ 888327-32-0 ]
YieldReaction ConditionsOperation in experiment
19% With potassium carbonate In water; N,N-dimethyl-formamide at 120℃; for 12 h; EXAMPLE 101Preparation of: 2-Amino-5-[4-(difluoromethoxy)-3-methylphenyl]-5-(3-ethoxy-4-fluorophenyl)-3- methyl-3,5-dihydro-4H-imidazol-4-oneStep 1 : 4-Bromo-1-(difluoromethoxy)-2-methylbenzene; In a 250 mL round-bottomed flask was placed 4-bromo-2-methylphenol (50 g, 267 mmol) and DMF (241 mL). Water (26.7 mL) was added to give a colorless solution. K2CO3 (148 g, 1069 mmol) was then added. Sodium 2-chloro-2,2-difluoroacetate (61.1 g, 401 mmol) was added and reaction heated to 120 0C for 12 h. The reaction was cooled to room temperature and partitioned between EtOAc (1000 mL) and water (1000 mL). The layers were separated and organic washed with water (2 x 500 mL) and brine (2x 500 mL). The organic layer was dried over Na2SO4 and filtered. The solvent was removed and crude material was passed through a plug of silica eluting with hexanes to provide 12.29 g, 19percent, of the title compound as a clear oil.
Reference: [1] Patent: WO2008/115552, 2008, A1, . Location in patent: Page/Page column 72
  • 15
  • [ 2075-46-9 ]
  • [ 1895-39-2 ]
  • [ 956477-64-8 ]
YieldReaction ConditionsOperation in experiment
97%
Stage #1: With caesium carbonate In N,N-dimethyl-formamide at 120℃; for 0.0833333 h;
Stage #2: for 0.5 h;
Cs2CO3 (14.41 g, 44.2 mmol) was suspended in a solution of 4-nitro-1H-pyrazole(5.00 g, 44.2 mmol) and DMF (40 mL). After heating to 120 °C for 5 mm, solid sodium2-chloro-2,2-difluoroacetate (13.48 g, 88 mmol) was added in 10 equal portions over 20 mm. The reaction was complete after 10 mm of additional heating. The mixture wasadded to a separatory funnel containing 100 mL water and extracted with Et20 (2 x 50 mL). The combined organic layers were concentrated. Purification by normal-phasechromatography eluting with a gradient of hexanes/EtOAc yielded 1 -(difluoromethyl)-4- nitro-1H-pyrazole (6.99 g, 42.9 mmol, 97percent yield) as a clear, colorless oil. ‘H NMR(500MHz, CDC13) ö 8.58 (s, 1H), 8.22 (s, 1H), 7.39-7.05 (t,J= 60Hz, 1H).
97%
Stage #1: With caesium carbonate In N,N-dimethyl-formamide at 120℃; for 0.0833333 h;
Stage #2: at 120℃; for 0.5 h;
CS2CO3 (14.41 g, 44.2 mmol) was suspended in a solution of 4-nitro-lH-pyrazole (5.00 g, 44.2 mmol) and DMF (40 mL). After heating to 120 °C for 5 min, solid sodium 2-chloro-2,2-difluoroacetate (13.48 g, 88 mmol) was added in 10 equal portions over 20 min. The reaction was complete after 10 min of additional heating. The mixture was added to a separatory funnel containing 100 mL water and extracted with Et20 (2 x 50 mL). The combined organic layers were concentrated. Purification by normal-phase chromatography eluting with a gradient of hexanes/EtOAc yielded 1 -(difluoromethyl)-4- nitro-lH-pyrazole (6.99 g, 42.9 mmol, 97percent yield) as a clear, colorless oil. 'H NMR (500MHz, CDCI3) δ 8.58 (s, 1H), 8.22 (s, 1H), 7.39 - 7.05 (t, J= 60 Hz, 1H).
41% With sodium hydrogencarbonate In N,N-dimethyl-formamide at 100℃; [00559] Intermediate 56a: I -(diluoromethyl)-4-nitro-pyrazole[00560] Sodium chiorodifluoroacetate (2.7g, 17.6gmmol) was added to a solution of 4- nitropyrazole (1 .OOg, 8.84mmol) and NaHCO3 (1 .49g, 1 7.6gmmol) in DMF (8mL) and the solution heated to 100°C overnight. More NaHCO3 (1.49g, 17.6gmmol) and 4-nitropyrazole (1.OOg, 8.84mmol) were added and stirring was continued overnight. More NaHCO3 (1 .49g, 1 7.6gmmol) and 4-nitropyrazole (1 .Og, 8.84mmol) were added and stirring was continued overnight. The solutionwas then cooled to room temperature and the mixture was diluted with water (5OmL) and EtOAc (5OmL). The insoluble precipitate was filtered off and the organic layer separated. The aqueous was extracted with EtOAc (3 x 5OmL) and the combined organic layers were washed with brine (5OmL), dried over Na2504 and concentrated in vacuo. The residue was purified by column chromatography using an eluent of 50percent EtOAc in heptane to give 1-(difluoromethyl)-4-nitro-pyrazole (0.58g,3.S9mmol, 41percent yield) as a pale yellow oil.1H NMR (CDCI3, 400MHz) O/ppm: 8.59 (1H, 5), 8.24 (1H, 5), 7.23 (1H, t, J= 60.0Hz). MS Method 2: RT: 1.16 mi mlz 164.0 [M+H]
Reference: [1] Patent: WO2015/116886, 2015, A1, . Location in patent: Page/Page column 200
[2] Patent: WO2015/116882, 2015, A1, . Location in patent: Page/Page column 84; 88
[3] Patent: WO2016/51193, 2016, A1, . Location in patent: Paragraph 00558; 00559; 00560
[4] Patent: WO2017/74832, 2017, A1, . Location in patent: Page/Page column 202
  • 16
  • [ 1895-39-2 ]
  • [ 4983-28-2 ]
  • [ 1192813-64-1 ]
YieldReaction ConditionsOperation in experiment
39.7% at 90℃; for 24 h; Step A: 2-Chloro-5-(Difluoromethoxy)pyrimidine 2-Chloropyrimidin-5-ol (1 g, 7.66 mmol) and sodium 2-chloro-2,2-difluoroacetate (3.50 g, 22.98 mmol) in N,N-dimethylformamide (20 mL) and water (0.2 mL) were heated to 90° C. for 24 hours and concentrated in vacuo. The residue was purified by column chromatography (5-30percent ethyl acetate/hexanes) to afford 2-chloro-5-(difluoromethoxy)pyrimidine (549 mg, 3.04 mmol, 39.7percent yield) as a pale yellow oil. MS (LC/MS) R.T.=1.32; [M+H]+=181.14.
39.7% at 90℃; for 24 h; Step A: 2-Chloro-5-(Difluoromethoxy)pyrimidine2-Chloropyrimidin-5-ol (1 g, 7.66 mmol) and sodium 2-chloro-2,2- difluoroacetate (3.50 g, 22.98 mmol) in N,N-dimethylformamide (20 mL) and water (0.2 mL) were heated to 90 °C for 24 hours and concentrated in vacuo. The residue was purified by column chromatography (5-30 percent ethyl acetate/hexanes) to afford 2- chloro-5-(difluoromethoxy)pyrimidine (549 mg, 3.04 mmol, 39.7 percent yield) as a pale yellow oil. MS (LC/MS) R.T. = 1.32; [M+H]+ = 181.14.
Reference: [1] Patent: US2009/270405, 2009, A1, . Location in patent: Page/Page column 90
[2] Patent: WO2011/53292, 2011, A1, . Location in patent: Page/Page column 149-150
  • 17
  • [ 5418-51-9 ]
  • [ 1895-39-2 ]
  • [ 1192813-41-4 ]
YieldReaction ConditionsOperation in experiment
15% for 48 h; Reflux 2-Hydroxy-5-nitro-pyridine (5 g) was treated with sodium chlorodifluoro- acetate (11.5 g) in refluxing acetonitrile (186 ml) for 2 days. The solvent was evaporated, the residue poured into ethyl acetate, washed with brine, dried over sodium sulfate and then concentrated in vacuo. Chromatography on silica gel (eluent: hexane / ethyl acetate 1 :1) afforded 2-difluoromethoxy-5-nitro-pyridine (1 g, 15percent) and l-difluoromethyl-5-nitro-lH- pyridin-2-one (90 mg, 1.5percent). 2-Difluoromethoxy-5-nitro-pyridine: MS (ES+) 191 (MΗ+); IH NMR (400 MHz, CDCl3) 7.05 (d, IH), 7.51 (t, IH), 8.53 (dd, IH), 9.09 (d, IH). 1-Difluoromethyl-5-nitro-lH-pyridin-2-one: MS (ES+) 191 (MΗ+); 6.65 (d, IH), 7.63 (t, IH), 8.14 (dd, IH), 8.73 (d, IH).
15% for 48 h; Reflux Step A: 2-Hydroxy-5-nitro-pyridine (5 g) was treated with sodium chlorodifluoro- acetate (1 1.5 g) in refluxing acetonitrile (186 ml) for 2 days. The solvent was evaporated, the residue poured into ethyl acetate, washed with brine, dried over sodium sulfate and then concentrated in vacuo. Chromatography on silica gel (eluent: hexane / ethyl acetate 1 :1) afforded 2-difluoromethoxy-5-nitro-pyridine (I g, 15percent) and l-difluoromethyl-5-nitro-lH- pyridin-2-one (90 mg, 1.5percent). 2-Difluoromethoxy-5-nitro-pyridine: MS (ES+) 191 (MH+); IH NMR (400 MHz, CDCl3) 7.05 (d, IH), 7.51 (t, IH), 8.53 (dd, IH), 9.09 (d, IH). 1-Difluoromethyl-5-nitro-l//-pyridin-2-one: MS (ES+) 191 (MH+); 6.65 (d, IH), 7.63 (t, IH), 8.14 (dd, IH), 8.73 (d, IH).
Reference: [1] Patent: WO2010/9968, 2010, A1, . Location in patent: Page/Page column 44
[2] Patent: WO2009/138219, 2009, A2, . Location in patent: Page/Page column 45
[3] Patent: WO2011/3684, 2011, A1, . Location in patent: Page/Page column 32
  • 18
  • [ 5418-51-9 ]
  • [ 1895-39-2 ]
  • [ 1192813-41-4 ]
Reference: [1] Patent: US2012/108583, 2012, A1, . Location in patent: Page/Page column 34
  • 19
  • [ 6602-32-0 ]
  • [ 1895-39-2 ]
  • [ 947249-27-6 ]
YieldReaction ConditionsOperation in experiment
43% With sodium hydroxide In N,N-dimethyl-formamide at 55℃; for 111 h; A mixture of 2-bromopyridin-3-ol (3.55 g, 20.4 mmol), sodium chlorodifluoroacetate (6.22 g, 40.8 mmol), and NaOH (0.90 g, 22.4 mmol) in DMF (20 ml) was heated at 55° C. for 111 h.
The reaction was allowed to cool to rt and concentrated, and resulting residue was partitioned between EtOAc/sat. Na2CO3 (80 ml/40 ml).
The organic phase was collected and washed with brine (40 ml), dried (Na2SO4), concentrated and the resulting residue was purified by flash chromatography (SiO2, 100:0-0:100 hexanes-EtOAc) to provide 1.95 g (43percent) of 2-bromo-3-(difluoromethoxy)pyridine: LCMS (m/z, MH+): 225.9, tR=0.74 min; 1H NMR (CDCl3, 400 MHz) δ 8.23-8.33 (m, 1H), 7.52-7.60 (m, 1H), 7.27-7.35 (m, 1H), 6.60 (t, J=72.4 Hz, 1H).
43% With sodium hydroxide In N,N-dimethyl-formamide at 55℃; for 111 h; A mixture of 2- bromopyridin-3-ol (3.55 g, 20.4 mmol), sodium chlorodifluoroacetate (6.22 g, 40.8 mmol), and NaOH (0.90 g, 22.4 mmol) in DMF (20ml) was heated at 550C for 111 h. The reaction was allowed to cool to rt and concentrated, and resulting residue was partitioned between EtOAc/sat. Na2CO3 (80ml/40ml). The organic phase was collected and washed with brine(40ml), dried (Na2SO^, concentrated and the resulting residue was purified by flash chromatography (SiO2, 100 : 0 - 0 : 100 hexanes-EtOAc) to provide 1.95 g (43percent) of 2-bromo-3-(difluoromethoxy)pyridine: LCMS (m/z, MH+): 225.9, tR = 0.74min; 1H NMR(CDCl3, 400 MHz) δ 8.23-8.33 (m, 1 H), 7.52-7.60 (m, 1 H), 7.27-7.35 (m, 1 H), 6.60 (t, J= 72.4 Hz, I H).
35% With caesium carbonate In water; N,N-dimethyl-formamide at 100℃; for 36 h; Preparation 1022-Bromo- -difluoromethoxypyridineTo a solution of 2-bromo-3-pyridinol (1 .26 g, 7.23 mmol) in DMF (35 mL) and water (5 mL) was added sodium chlorodifluoroacetate (2.93 g, 18.1 mmol) followed by cesium carbonate (4.71 g, 14.5 mmol). The reaction was heated to 100 °C for 36 hours before partitioning between EtOAc and water. The organic layer was collected, dried over magnesium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with EtOAc:heptane 1 :3 to afford the title compound as a colourless oil (570 mg, 35percent).1H NMR (400 MHz; DMSO-d6): δ 7.15-7.55 (t, 1 H), 7.55 (m, 1 H), 7.80 (m, 1 H), 8.25 (m, 1 H).LCMS Rt = 1 .91 minutes MS m/z 226 [M79BrH]+
Reference: [1] Patent: US2013/210818, 2013, A1, . Location in patent: Paragraph 0414
[2] Patent: WO2009/115572, 2009, A2, . Location in patent: Page/Page column 125
[3] Patent: WO2012/7869, 2012, A2, . Location in patent: Page/Page column 107
  • 20
  • [ 15126-06-4 ]
  • [ 1895-39-2 ]
  • [ 1131614-23-7 ]
Reference: [1] Organic Process Research and Development, 2011, vol. 15, # 3, p. 721 - 725
[2] Organic Process Research and Development, 2012, vol. 16, # 11, p. 1854 - 1860
  • 21
  • [ 15126-06-4 ]
  • [ 1895-39-2 ]
  • [ 1131614-23-7 ]
  • [ 1296014-72-6 ]
Reference: [1] Organic Process Research and Development, 2011, vol. 15, # 3, p. 721 - 725
  • 22
  • [ 15126-06-4 ]
  • [ 1895-39-2 ]
  • [ 1131614-23-7 ]
  • [ 1296014-72-6 ]
Reference: [1] Organic Process Research and Development, 2011, vol. 15, # 3, p. 721 - 725
  • 23
  • [ 269410-08-4 ]
  • [ 1895-39-2 ]
  • [ 1206640-82-5 ]
YieldReaction ConditionsOperation in experiment
84% With 18-crown-6 ether In acetonitrile for 18 h; Reflux Step 1: l-(difluoromethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole [00218] A 100 mL round bottom flask was charged with 4-pyrazoleboronic acid pinacol ester (1.0 g, 5.15 mmol), 18-crown-6 (0.27 g, 1.03 mmol) and anhydrous acetonitrile (25 mL). The reagents were stirred until a colorless solution formed then sodium chlorodifluoroacetate (0.94 g, 6.18 mmol) was added and the reaction mixture heated to reflux for 18 h. After this time the reaction mixture was cooled to r.t. and the precipitated solid removed by filtration through celite, washing with EtOAc (3 x 20 mL). Combined organics were filtered through a hydrophobic frit and condensed to give a pale yellow oil. The crude product was purified by flash silica column chromatography (gradient elution ο-hexane to 33percent EtOAc in /so-hexane) to give the title compound as a colorless solid (1.06 g, 84percent). MS (ES+) consistent with target (M+H)+.
84% With 18-crown-6 ether In acetonitrile for 18 h; Reflux Step 1 : 1 -(difluoromethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- pyrazole [00256] A 100 mL round bottom flask was charged with 4-pyrazoleboronic acid pinacol ester (1 .0 g, 5.15 mmol), 18-crown-6 (0.27 g, 1 .03 mmol) and anhydrous acetonitrile (25 mL). The reagents were stirred until a colorless solution formed then sodium chlorodifluoroacetate (0.94 g, 6.18 mmol) was added and the reaction mixture heated to reflux for 18 h. After this time the reaction mixture was cooled to r.t. and the precipitated solid removed by filtration through Celite, washing with EtOAc (3 x 20 mL). Combined organics were filtered through a hydrophobic frit and condensed to give a pale yellow oil. The crude product was purified by flash silica column chromatography (gradient elution, 0-33percent EtOAc in /so-hexane) to give the title compound as a colorless solid (1 .06 g, 84percent). MS (ES+) consistent with target (M+H)+.
80% for 24 h; Reflux; Inert atmosphere Step 1: To acetonitrile (100 ml) was added compound 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 101-1 (4.0 g, 0.21 mol), sodium chlorodifluoroacetate (3.77 g 0.25 mol, 15-crown-5 (103.8 g, 0.65 mol), and the reaction mixture was heated to reflux under nitrogen and stirred for 24 h, cooled to room temperature, the reaction mixture was poured into water (50 ml) to quench the reaction, and extracted with EA (100 ml×3), washed with saturated brine (20 ml), dried over Na2SO4, and filtered, and the filtrate was evaporated to give compound 101-2 (4.1 g, yield 80percent) as a white solid. MS m/z (ESI): 245.1 [M+H]+.
47% With 18-crown-6 ether In acetonitrile for 20 h; Reflux Reference Example 1711-(Difluoromethyl)-1H-pyrazole-4-boronic acid pinacol ester A suspension of 1H-pyrazole-4-boronic acid pinacol ester (5.16 g, 26.6 mmol), CF2ClCO2Na (4.86 g, 31.9 mmol), and 18-crown-6 (1.41 g, 5.32 mmol) in CH3CN (100 mL) was refluxed for 20 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt to give the title compound (3.03 g, 47percent yield) as a yellow oil: 1H NMR (300 MHz, CDCl3): δ ppm 1.33 (12H, s), 7.22 (1H, t, J=60.7 Hz), 7.89 (1H, s), 8.13 (1H, s).
500 mg With 18-crown-6 ether In acetonitrile for 20 h; Reflux A suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (516 mg, 2.66 mmol), CF2ClCO2Na (486 mg, 3.19 mmol), and 18-crown-6 (141 mg, 0.532 mmol) in CH3CN (150 mL) was heated to reflux for 20 hours. After cooled to room temperature, thereaction mixture was poured into water and extracted with EtOAc. The extracts were washed with brine, dried over MgSO4, and concentrated under reduced pressure to afford a crude 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (500 mg), which was used for the next step without further purification. MS (ESI) m/z: 245 [M+H]+.
1.54 g With 18-crown-6 ether In acetonitrile at 90℃; for 16 h; E)
1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
To a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.50 g), sodium chlorodifluoroacetate (1.41 g) and acetonitrile (35 mL) was added 18-crown-6 (0.409 g).
The reaction mixture was stirred at 90° C. for 16 hr, poured into water, and the mixture was extracted with ethyl acetate.
The extract was washed with saturated brine, and dried over anhydrous sodium sulfate.
The solvent was evaporated under reduced pressure to give the title compound (1.54 g).
MS (API+): [M+H]+245.1.

Reference: [1] Patent: WO2014/159218, 2014, A1, . Location in patent: Paragraph 00218
[2] Patent: WO2014/159224, 2014, A1, . Location in patent: Paragraph 00256
[3] Patent: US2017/8889, 2017, A1, . Location in patent: Paragraph 0324; 0325
[4] Patent: US2010/197651, 2010, A1, . Location in patent: Page/Page column 84
[5] Patent: WO2014/1377, 2014, A1, . Location in patent: Page/Page column 119; 120
[6] Patent: US2016/159808, 2016, A1, . Location in patent: Paragraph 1374; 1375
[7] Patent: US2017/44132, 2017, A1, . Location in patent: Paragraph 0697; 0698
[8] Patent: TW2017/14883, 2017, A, . Location in patent: Paragraph 0198
  • 24
  • [ 36953-37-4 ]
  • [ 1895-39-2 ]
  • [ 832735-56-5 ]
YieldReaction ConditionsOperation in experiment
85% Reflux Example 26i
4-Bromo-2-(difluoromethoxy)pyridine
4-Bromopyridin-2(1H)-one (200 mg, 1.15 mmol) and sodium 2-chloro-2,2-difluoroacetate (210 mg, 1.38 mmol) were slurried in dry acetonitrile (8 mL).
The mixture was refluxed overnight, allowed to cool to r.t. and directly extracted with pentane (3*5 mL).
The combined organic phases were evaporated to give 219 mg (85percent yield) of the title compound:
1H-NMR (500 MHz DMSO-d6) δ 8.18 (d, 1H), 7.70 (t, 1H), 7.56 (d, 1H), 7.50 (s, 1H); MS (CI+) m/z 226 224 [M+1]+
39% With potassium carbonate In N,N-dimethyl-formamide at 95℃; for 2 h; Sodium chloro(difluoro)acetate (5.26 g, 34.5 mmol) and potassium carbonate (0568) (3.57 g, 25.8 mmol) were added to a solution of 4-bromopyridin-2(1 /-/)-one (3.00 g, 17.2 mmol) in /V,/V-dimethylformamide (30 mL), and the reaction mixture was stirred at 95 °C for 2 hours. Water (100 mL) was added, and the resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed sequentially with water (200 mL) and with saturated aqueous sodium chloride solution (150 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Eluent: 15: 1 petroleum ether / ethyl acetate) afforded the product as a pale yellow oil. Yield: 1 .5 g, 6.7 mmol, 39percent. 1H NMR (400 MHz, CDCI3) δ 8.04 (d, J=5.5 Hz, 1 H), 7.44 (t, JHF=72.6 HZ, 1 H), 7.27 (dd, J=5.4, 1 .6 Hz, 1 H), 7.12 (br d, J=1 .5 Hz, 1 H).
Reference: [1] Patent: US2010/125087, 2010, A1, . Location in patent: Page/Page column 21
[2] Patent: WO2018/2760, 2018, A1, . Location in patent: Page/Page column 100
  • 25
  • [ 6636-78-8 ]
  • [ 1895-39-2 ]
  • [ 1206977-80-1 ]
YieldReaction ConditionsOperation in experiment
72% With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 4 h; 0097] As shown in step 3-i of Scheme 3, 2-chloro-3-hydroxypyridine (Compound 1005,2.0 g, 15.4 mmol, obtained from Aldrich Chemical Co.) was dissolved in 40 mL of DMF and5.0 mL of water along with sodium chlorodifluoroacetate (4.71 g, 30.9 mmol, obtained fromLancaster Synthesis, Inc.) and anhydrous potassium carbonate (2.56 g; 18.5 mmol). The reaction mixture was heated in an oil bath at 1000C for 2 hours. Another equivalent of sodium chlorodifluoroacetate and 1.2 equiv. of potassium carbonate were added and heating continued for an additional 2.0 hours. After this time, the reaction was cooled and the volatiles removed under reduced pressure. The residue was partitioned between brine and ethyl acetate and the organics washed once more with brine, dried over Na2SO4, filtered, and the volatiles removed under reduced pressure. The product was purified by silica gel chromatography, eluting with a hexanes/DCM to DCM gradient, to produce 2-chloro-3- (difluoromethoxy)pyridine as a white solid (Compound 1006, 2.0 g, 72percent yield): ESMS (M+H) 180; 1H NMR (CDCl3) δ 8.05 (m, IH), 7.45(m, IH), 6.90(m,lH), 6.60(t, IH; J=75Hz), 4.0 l(s, 3H).
72% With potassium carbonate In water; N,N-dimethyl-formamide at 100℃; for 4 h; As shown in step 3-i of Scheme 3,2-chloro-3-hydroxypyridine (Compound 1005,2.0 g, 15.4 mmol, obtained from Aldrich Chemical Co.) was dissolved in 40 mL of DMF and5.0 mL of water along with sodium chlorodifluoroacetate (4.71 g, 30.9 mmol, obtained fromLancaster Synthesis, Inc.) and anhydrous potassium carbonate (2.56 g; 18.5 mmol). The reaction mixture was heated in an oil bath at 1000C for 2 hours. Another equivalent of sodium chlorodifluoroacetate and 1.2 equiv. of potassium carbonate were added and heating continued for an additional 2.0 hours. After this time, the reaction was cooled and the volatiles removed under reduced pressure. The residue was partitioned between brine and ethyl acetate and the organics washed once more with brine, dried over Na2SO4, filtered, and the volatiles removed under reduced pressure. The product was purified by silica gel chromatography, eluting with a hexanes/DCM to DCM gradient, to produce 2-chloro-3-(difluoromethoxy)pyridine as a white solid (Compound 1006, 2.0 g, 72percent yield): ESMS (M+H) 180; 1H NMR (CDCl3) δ 8.05 (m, IH), 7.45(m, IH), 6.90(m,lH), 6.60(t, IH; J=75Hz), 4.0 l(s, 3H).
72% With potassium carbonate In water; N,N-dimethyl-formamide at 100℃; for 4 h; As shown in step 3(a)-i of Scheme 3(a), 2-chloro-3-hydroxypyridine (Compound 2005, 2.0 g, 15.4 mmol, obtained from Aldrich Chemical Co.) was dissolved in 40 mL of DMF and 5.0 mL of water along with sodium chlorodifluoroacetate (4.71 g, 30.9 mmol, obtained from Lancaster Synthesis, Inc.) and anhydrous potassium carbonate (2.56 g; 18.5 mmol). The reaction mixture was heated in an oil bath at 100°C for 2 hours. Another equivalent of sodium chlorodifluoroacetate and 1.2 equiv. of potassium carbonate were added and heating continued for an additional 2.0 hours. After this time, the reaction was cooled and the volatiles removed under reduced pressure. The residue was partitioned between brine and ethyl acetate and the organics washed once more with brine, dried over Na2S04, filtered, and the volatiles removed under reduced pressure. The product was purified by silica gel chromatography, eluting with a hexanes/DCM to DCM gradient, to produce 2-chloro-3- (difluoromethoxy)pyridine as a white solid (Compound 2006, 2.0 g, 72percent yield): ESMS (M+H) 180; 1H NMR (CDC13) δ 8.05 (m, 1H), 7.45(m, 1H), 6.90(m,lH), 6.60(t, 1H; J = 75Hz), 4.01(s, 3H).
69% With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 1 h; This reaction was carried out 3 times. A mixture of potassium carbonate (282 g, 2.04 mol) and N,N-dimethylformamide (750 mL) was heated to 100 °C and slowly treated, in a drop-wise manner over 1 hour, with a solution of 2-chloropyridin-3-ol (66.7 g, 515 mmol) and sodium chloro(difluoro)acetate (200 g, 1.31 mol) in N,N-dimethylformamide (750 mL). After completion of the addition, the reaction mixture was stirred at 100 °C for 1 hour, then cooled to 25 °C and partitioned between water (10 L) and tert-butyl methyl ether (5 L). The aqueous layer was extracted with ethyl acetate (4 x 2.5 L), and the combined organic layers were washed with saturated aqueous sodium chloride solution (6 x 2.5 L), dried over sodium sulfate, filtered, and concentrated in vacuo. The combined crude products from the three reactions were purified via distillation at reduced pressure (30-40 °C, 1-5 mm Hg) to provide the product as a colorless oil. Yield: 192 g, 1.07 mol, 69percent. LCMS m/z 180.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.26-8.30 (m, 1 H), 7.60 (br d, J=8.2 Hz, 1 H), 7.28 (br dd, J=8.0, 4.8 Hz, 1 H), 6.60 (t, JHF=72.5 Hz, 1 H).

Reference: [1] Patent: WO2010/96389, 2010, A1, . Location in patent: Page/Page column 39-40; 42
[2] Patent: WO2010/135014, 2010, A1, . Location in patent: Page/Page column 47-49
[3] Patent: WO2011/87776, 2011, A1, . Location in patent: Page/Page column 51; 53
[4] Patent: WO2014/207601, 2014, A1, . Location in patent: Page/Page column 88
  • 26
  • [ 695-96-5 ]
  • [ 1895-39-2 ]
  • [ 1214348-81-8 ]
YieldReaction ConditionsOperation in experiment
98% With caesium carbonate In water; N,N-dimethyl-formamide at 100℃; for 4 h; To a solution of 2-bromo-4-chlorophenol (1 g, 4.8 mmol) in DMF/water (45 mL/5 mL) was added sodium chlorodifluoroacetate (1.95 g, 12.0 mmol) and cesium carbonate (3.14 g, 9.64 mmol), and the reaction mixture was heated to 100° C. for 4 hours.
The reaction mixture was cooled and diluted with TBME (20 mL) and water (20 mL).
The organic layer was collected, washed with saturated aqueous NaHCO3 solution, brine, dried over Na2SO4 and concentrated in vacuo to afford the title compound (1.21 g, 98percent).
1HNMR (400 MHz, CDCl3): δ ppm 6.52 (m, 1H), 7.18 (t, 1H), 7.31 (m, 1H), 7.64 (d, 1H).
48% With caesium carbonate In water; N,N-dimethyl-formamide at 100℃; for 16 h; To a solution of 2-bromo-4-chlorophenol (4.98 g, 24.0 mmol) in DMF (25 mL) was added sodium chlorodifluoroacetate (8.42 g, 55.2 mmol), cesium carbonate (10.97 g, 33.67 mmol) and water (2.5 mL).
The reaction was stirred at 100° C. for 16 hours.
The reaction mixture was partitioned between ethyl acetate and water, the organic portion washed with brine, dried (MgSO4), and evaporated.
The crude product was purified by flash chromatography on silica eluting with 0-20percent EtOAc in heptanes to yield 2-bromo-4-chloro-1-(difluoromethoxy)benzene as a clear, colorless oil (2.98 g, 48percent). LCMS (ESI) no m/z signal; 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 7.90 (d, 1H), 7.54 (dd, 1H), 7.38 (d, 1H), 7.28 (t, 1H).
48% With caesium carbonate In water; N,N-dimethyl-formamide at 100℃; for 16 h; To a solution of 2-bromo-4-chlorophenol (4.98 g, 24.0 mmol) in DMF (25 mL) was added sodium chlorodifluoroacetate (8.42 g, 55.2 mmol), cesium carbonate (10.97 g, 33.67 mmol) and water (2.5 mL). The reaction was stirred at 100 °C for 16 hours. The reaction mixture was partitioned between ethyl acetate and water, the organic portion washed with brine, dried (MgS04), and evaporated. The crude product was purified by flash chromatography on silica eluting with 0-20percent EtOAc in heptanes to yield 2-bromo- 4-chloro-l-(difluoromethoxy)benzene (2.98 g, 48percent) as a clear, colorless oil. LCMS (ESI) no m/z signal; 1H NMR (400 MHz, DMSO-^): δ 7.90 (d, 1H), 7.54 (dd, 1H), 7.38 (d, 1H), 7.28 (t, 1H).
Reference: [1] Patent: US2014/315933, 2014, A1, . Location in patent: Paragraph 0556; 0557; 0558
[2] Patent: US2015/336962, 2015, A1, . Location in patent: Paragraph 0638
[3] Patent: WO2018/166993, 2018, A2, . Location in patent: Page/Page column 92
[4] Patent: WO2011/3065, 2011, A2, . Location in patent: Page/Page column 99
  • 27
  • [ 1895-39-2 ]
  • [ 147460-41-1 ]
  • [ 954235-83-7 ]
YieldReaction ConditionsOperation in experiment
58% With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 15 h; itermediteExthp1eI5. ‘sulfOnamide ‘,“a) .To a solutiOn of 2-brotho-5-fludrophenol (3g. 15.7 mmol) in DMF (5 ml) was added cesium carbonate (7.7 g, 23.56 mmol, 1.5 eq) and sodium chlorodifluoroacetate(6 g, 39.26 nimol;2:5 eq) and the reaction mixture was heated at 100°C for 15 h. Thereaction mixture was then exttacted with Water and ethyl acetate (3 x 50 mI) Thecombined Organic layer was washed with water, brine and dried over sodium sulphate. The solvent was distilled off to afford the crude residue which was purified by column chromatography (60-120 silica ge110percent ethyl acetate in hexane) in 58 percent yield (2.2 g).
Reference: [1] Patent: WO2014/162039, 2014, A1, . Location in patent: Page/Page column 41
[2] Patent: EP2394987, 2011, A1, . Location in patent: Page/Page column 9
[3] Patent: WO2012/143329, 2012, A1, . Location in patent: Page/Page column 121
  • 28
  • [ 4214-79-3 ]
  • [ 1895-39-2 ]
  • [ 1214323-40-6 ]
Reference: [1] Patent: WO2012/3283, 2012, A1, . Location in patent: Page/Page column 226
  • 29
  • [ 16879-02-0 ]
  • [ 1895-39-2 ]
  • [ 1214377-45-3 ]
YieldReaction ConditionsOperation in experiment
53% With sodium hydroxide In N,N-dimethyl-formamide at 55℃; for 18 h; solution of 6-chloropyridin-2-ol (1.0 equiv.), sodium 2-chloro-2,2-difluoroacetate (2.0 equiv.) and sodium hydroxide (1.1 equiv.) in DMF (0.77 M) was heated at 55° C. for 18 hrs, the reaction mixture was then partitioned between EtOAc and sat. NaHCO3 solution, the aqueous was extracted by EtOAc for 3 more times, combined organic was washed by water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo. The crude product was purified via silica gel to yield 2-chloro-6-(difluoromethoxy)pyridine in 53percent yield: LCMS (m/z): 180.0 (MH+), Rt=0.87 min. 1H NMR (400 M Hz, CHLOROFORM-d) δ ppm 7.69 (t, J=8.0 Hz, 1H), 7.44 (t, J=72 Hz, 1H), 7.14 (d, J=7.8 Hz, 1H), 6.83 (d, J=7.8 Hz, 1H).
Reference: [1] Patent: US2012/225061, 2012, A1, . Location in patent: Page/Page column 106
  • 30
  • [ 16879-02-0 ]
  • [ 1895-39-2 ]
  • [ 1214377-45-3 ]
Reference: [1] ChemMedChem, 2015, vol. 10, # 4, p. 715 - 726
  • 31
  • [ 1054483-78-1 ]
  • [ 1895-39-2 ]
  • [ 1333222-12-0 ]
YieldReaction ConditionsOperation in experiment
53% at 80℃; Sealed tube In a sealed tube was added 2-hydroxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (300 mg, 1.357 mmol), sodium chlorodifluoroacetate (320 mg, 2.036 mmol) in acetonitrile (5 mL). This suspension was heated to 80°C and stirred overnight. The reaction mixture was cooled down to rt, diluted with EtOAc, washed with an aqueous solution of NaHC03 and brine. The organic layer dried over MgS04, filtered and evaporated. Purification by flash chromatography on silica gel (CH2CI2/MeOH, 95/5) gave the title compound (197 mg, 53percent yield). MS: 272.8 [M+H]+, Rt (6) = 3.12 min.
53% at 80℃; Sealed tube 2-Difluoromethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine
In a sealed tube was added 2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (300 mg, 1.357 mmol), sodium chlorodifluoroacetate (320 mg, 2.036 mmol) in acetonitrile (5 mL).
This suspension was heated to 80° C. and stirred overnight.
The reaction mixture was cooled down to rt, diluted with EtOAc, washed with an aqueous solution of NaHCO3 and brine.
The organic layer dried over MgSO4, filtered and evaporated.
Purification by flash chromatography on silica gel (CH2Cl2/MeOH, 95/5) gave the title compound (197 mg, 53percent yield). MS: 272.8 [M+H]+, Rt(6)=3.12 min.
Reference: [1] Patent: WO2013/57711, 2013, A1, . Location in patent: Page/Page column 49
[2] Patent: US2015/342951, 2015, A1, . Location in patent: Paragraph 0859-0860
  • 32
  • [ 1895-39-2 ]
  • [ 269409-70-3 ]
  • [ 1333222-12-0 ]
YieldReaction ConditionsOperation in experiment
53% at 80℃; Sealed tube In a sealed tube was added 2-hydroxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (300 mg, 1.357 mmol), sodium chlorodifluoroacetate (320 mg, 2.036 mmol) in acetonitrile (5 mL). This suspension was heated to 80°C and stirred overnight. The reaction mixture was cooled down to rt, diluted with EtOAc, washed with an aqueous solution of NaHC03 and brine. The organic layer dried over MgS04, filtered and evaporated. Purification by flash chromatography on silica gel (CH2CI2/MeOH, 95/5) gave the title compound (197 mg, 53percent yield). MS: 272.8 [M+H]+, Rt (6) = 3.12 min.
Reference: [1] Patent: WO2013/88404, 2013, A1, . Location in patent: Page/Page column 96
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