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Structure of 1514-87-0
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 1514-87-0 |
Formula : | C3H3ClF2O2 |
M.W : | 144.50 |
SMILES Code : | O=C(OC)C(F)(Cl)F |
MDL No. : | MFCD00000775 |
InChI Key : | AWUPLMYXZJKHEG-UHFFFAOYSA-N |
Pubchem ID : | 73935 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H225-H314 |
Precautionary Statements: | P210-P280-P305+P351+P338-P310 |
Class: | 3(8) |
UN#: | 2924 |
Packing Group: | Ⅱ |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In ISOPROPYLAMIDE; at 110℃; for 3h; | To a solution of 4.6 g of <strong>[186590-01-2]4-fluoro-2-hydroxy-benzonitrile</strong> in 15 ml_ of anhydrous dimethylacetamide were added 6.8 g of methyl chlorodifluororacetate and 6.5 g of potassium carbonate. The resulting mixture was degassed by bubbling argon through it and heated to 1100C for 2h then an additional 6.5 g of methyl chlorodifluororacetate and 6.5 g of potassium carbonate were added. The resulting mixture was heated to 11O0C for another hour then concentrated under reduced pressure. The residue was taken into ethyl acetate, washed twice with a molar aqueous solution of sodium hydroxide, with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient from heptane 100 to heptane 80/ ehtyl acetate 20) to give 4.78 g of 2-difluoromethoxy-4-fluoro-benzonitrile as a yellowish liquid. C8H4F3NO (187.12), MS(ESI): 188.0 (M+H+). | |
With potassium carbonate; In ISOPROPYLAMIDE; at 110℃; for 3h; | To a solution of 4.6 g of <strong>[186590-01-2]4-fluoro-2-hydroxy-benzonitrile</strong> in 15 mL of anhydrous dimethylacetamide were added 6.8 g of methyl chlorodifluororacetate and 6.5 g of potassium carbonate. The resulting mixture was degassed by bubbling argon through it and heated to 110 C. for 2 h then an additional 6.5 g of methyl chlorodifluororacetate and 6.5 g of potassium carbonate were added. The resulting mixture was heated to 110 C. for another hour then concentrated under reduced pressure. The residue was taken into ethyl acetate, washed twice with a molar aqueous solution of sodium hydroxide, with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient from heptane 100 to heptane 80/ethyl acetate 20) to give 4.78 g of 2-difluoromethoxy-4-fluoro-benzonitrile as a yellowish liquid.C8H4F3NO (187.12), MS (ESI): 188.0 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13%; 21% | With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 16h; | Methyl chlorodifluoroacetate (15.3 mL, 145 mmol) was added to a suspension of 3,4- dihydroxybenzaldehyde (5.0 g, 36 mmol) and potassium carbonate (20.0 g, 145 mmol) in DMF (10 mL). The suspension was heated to 60 0C for 16 h and then diluted with water. The aqueous phase was extracted with EtOAc and the combined organic fractions were washed with saturated aqueous NaHCOs, water, brine, dried and concentrated. The residue was purified by column chromatography, eluting with 10% EtOAc/petrol to give 3,4-bis(difluoromethoxy)benzaldehyde (1.1 g, 13%) as a colourless oil; deltaH (400 MHz, CDCI3) 6.60 (t, J = 72 Hz, 1 H, OCHF2), 6.64 (t, J = 72 Hz, 1 H, OCHF2), 7.42 (d, J5,6 = 8.0 Hz, 1 H, H5), 7.76-7.78 (m, 2H, HZ, H6), 9.96 (s, 1 H, CHO); deltac (125 MHz, CDCI3) 115.2 (t, J = 259 Hz), 1 15.4 (t, J = 259 Hz), 121.5, 122.2, 128.5, 134.2, 142.4, 147.0 189.7; vmax 794, 1038, 1381 , 1509, 1698, cm"1. Further elution provided 4-difluoromethoxy-3-hydroxybenzaldehyde (1.43 g, 21 %) as a colourless crystalline solid; mp 94-95 0C (recrystallized from EtOAc); deltaH (500 MHz, CDCI3) 5.82 (s, 1 H, OH), 6.65 (t, J = 72.0 Hz, 1 H, CHF2), 7.27 (d, J5,6 = 8.0 Hz, 1 H, H5), 7.44 (dd, J5,6 = 8.0, J2,6 = 2.0 Hz, 1 H, H6), 7.54 (d, J2,6 = 2.0 Hz, 1 H, HZ), 9.92 (s, 1 H, CHO); deltac (125 MHz, CDCI3) 115.6 (t, J = 259 Hz), 117.1 , 119.2, 123.1 , 134.6, 142.9, 147.8, 190.9; vmax 1087, 1237, 1508, 1592, 1686, 2859, 3313 cm"1. |
13%; 21% | With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 16h; | Methyl chlorodifluoroacetate (15.3 mL, 145mmol) was added to a suspension of 3,4-dihydroxybenzaldehyde (11) (5.0 g, 36 mmol) and potassiumcarbonate (20.0 g, 145 mmol) in DMF (10 mL). The suspension was heated to 60 C for 16 h and then diluted with water. The aqueous phase wasextracted with EtOAc and the combined organic fractions were washed withsaturated aqueous NaHCO3, water, brine, dried and concentrated. Theresidue was purified by column chromatography, eluting with 10% EtOAc/petrol togive 3,4-bis(difluoromethoxy)benzaldehyde (1.1 g, 13%) as a colourless oil; deltaH(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); deltaC (125MHz, 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.Further elution provided 4-difluoromethoxy-3-hydroxybenzaldehyde (1.43 g, 21%)as a colourless crystalline solid; mp 94-95 C (recrystallized from EtOAc); deltaH (500 MHz, CDCl3)5.82 (s, 1H, OH), 6.65 (t, J = 72.0 Hz, 1H, CHF2), 7.27 (d, J5,6= 8.0 Hz, 1H, H5), 7.44 (dd, J5,6 = 8.0, J2,6 = 2.0 Hz, 1H, H6), 7.54 (d, J2,6 = 2.0 Hz, 1H, H2),9.92 (s, 1H, CHO); deltaC (125MHz, CDCl3) 115.6 (t, J =259 Hz), 117.1, 119.2, 123.1, 134.6, 142.9, 147.8, 190.9; nmax 1087, 1237, 1508, 1592, 1686,2859, 3313 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In a solution of 5.0 g of <strong>[3032-81-3]3,5-dichloro-1-iodobenzene</strong> in 50 ml of t-butylmethylether, 12.2 ml of n-butyl lithium (1.58M hexane solution) was added dropwise at -78°C with stirring, after the completion of the addtion dropwise, stirred at the same temperature for 30 minutes. 6.6 g of chlorodifluoroacetic acid methyl ester was added dropwise at -78°C with stirring in the reaction mixture, after the completion of the addition drropwise, continued to stir at 0°C for further 30 minutes. After the completion of the reaction, the reaction mixture was poured in 100 ml of saturated ammonium chloride aqueous solution, extracted with ethyl acetate (100 ml x 1). The organic phase was dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 4.6 g of crude aimed product as pale yellow oily substance. The resulting product was used as such without purification for the next step. 1H NMR (CDCl3, Me4Si, 300MHz) delta7.97 (s, 2H), 7.68 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium fluoride; copper(l) iodide; In 1-methyl-pyrrolidin-2-one; at 120℃;Inert atmosphere; | NMP (145 mL) is degassed 30 min with Ar and is then heated to 80 C. KF (7.62 g, 131 mmol), Cul (I) (24.99 g, 131 mmol) and <strong>[40263-57-8]2-iodopyridin-3-ol</strong> (29 g, 131 mmol) are added in one portion, followed by methyl 2-chloro-2,2-difluoroacetate (55.4 mL, 525 mmol).The resulting mixture is heated at 120 C under N2 for 3 nights. The mixture is allowed to cool to RT and is then poured gently into a slowly stirring mixture of 50% concentrated NaCI (1 L) solution and Et20 (4L). The organic layer is decanted carefully and the aqueous layer is extracted with Et20 (3x). The combined organic layers are concentrated, washed with brine (4x), dried with MgS04, filtered and concentrated. Flash chromatography on silica (DCM:MeOH 1.2%-10) then with (i- Pr20:EtOAc 9:1 ) follwed by trituration in heptane provides 12a1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 1h; | To a solution of 93 mg (0.71 mmol) of 4-hydroxy-1-methyl piperidine in 1.0 ml of N,N-dimethylformamide, 0.28 g (0.86 mmol) of cesium carbonate and 0.32 mg (2.2 mmol) of methyl chlorodifluoroacetate were added, and the reaction solution was stirred at 100° C. for 1 hour. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative thin layer chromatography [n-hexane/ethyl acetate=75/25 (V/V)] to provide 55 mg of the title compound as a colorless oil (yield: 43percent). 1H-NMR spectrum (500 MHz, CDCl3) delta ppm: 8.53 (2H, s), 6.62 (1H, t, J=71 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55%Chromat. | With copper(l) iodide; 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosan/[18F]fluoride; N,N,N,N,-tetramethylethylenediamine; In N,N-dimethyl-formamide; acetonitrile; at 100 - 150℃; for 0.333333h;Inert atmosphere; Sealed tube; | General procedure: [18F]KF/K222 inMeCN was added to a V-vial containing CuI (11 mg) and a magnetic stirrer bar. The solvent was evaporated under N2 at 100 C (2 min). The vial was removed from heat,and a solution of methyl chlorodifluoroacetate (6 ml), TMEDA (9 ml) and aryl (or heteroaryl) iodide (0.037 mmol) in DMF (300 ml) was added via syringe. The sealed vial was heated at 150 C for 20 min. The reaction was quenched by the addition ofwater (100 ml). An aliquot was removed for analysis by radioTLC and HPLC toobtain the RCY and product identity, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 90℃; for 20.0h;Inert atmosphere; | To a solution of 6-bromo-2,3-dihydro-lH-inden-5-ol (500 mg, 2.34 mmol) in N,N- dimethylformamide (30 mL) was added sodium hydride (800 mg, 60%> in mineral oil, 20.0 mmol) under nitrogen. Methyl 2-chloro-2,2-difluoroacetate (1.70 g, 11.7 mmol) was added and the resulting mixture was stirred at 90 C for 20 h. The reaction mixture was allowed to cool to RT and diluted with ethyl acetate (100 mL). Water (30 mL) was added and the phases were separated. The organic phase was washed with water (2x), brine, dried and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (1/10). The appropriate fractions were combined and concentrated under vacuum to afford 5-bromo-6-(difluoromethoxy)-2,3-dihydro-lH-indene (240 mg, 39%>) as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
623 mg | With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 19.5h; | A mixture of 1-(3-hydroxy-1H-pyrazol-1-yl)ethanone (20.0 g), m<strong>[383-62-0]ethyl 2-chloro-2,2-difluoroacetate</strong> (23.6 g), <strong>[383-62-0]ethyl 2-chloro-2,2-difluoroacetate</strong> (3.99 g) and potassium carbonate (32.6 g) in DMF (160 mL) was stirred at 50 C. for 19.5 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (623 mg). 1H NMR (300 MHz, CDCl3) delta5.98 (1H, d, J=2.7 Hz), 6.83 (1H, t, J=73.0 Hz), 7.45 (1H, d, J=2.7 Hz), 8.06 (1H, brs); MS m/z 135.1 [M+1]+. |
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