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USD 0.00
Limited Quantity
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Structure of 1570-64-5 * 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.
With 1,2-dithiolane; aluminum (III) chloride; sulfuryl dichloride In melt for 4 h;
General procedure: o-Cresol (melted) or m-cresol (5.41 g, 50.0 mmol), AlCl3 (0.25 g) and the catalyst (100 mg)were added to a dried 50 ml round-bottomed flask. Sulfuryl chloride (4.66 ml, 57.7 mmol) wasthen added slowly over 2 h via a pressure-equalizing dropping funnel. The reaction mixture wasstirred for 2 h before being quenched with water (20 ml). The reaction mixture was worked up,and the crude products were weighed until constant mass and then analyzed by quantitative GC.
93.4 %Chromat.
at 20℃; for 4 h;
Freshly distilled sulfuryl chloride (4.66 mL, 57.7 mmol) was added slowly over 2 h to a mixture of o-cresol or m-cresol (5.41 g, 50 mmol), AlCl3 (0.25 g, 1.875mmol) and an additive (100 mg) in a round bottomed flask (50mL). The mixture was stirred at room temperature for a further 2 h, then worked up and analyzed by GC as shown for m-xylenol.
Reference：
[1] Synthetic Communications, 2002, vol. 32, # 2, p. 279 - 286
[2] Synlett, 2011, # 11, p. 1537 - 1542
[3] Journal of the Chemical Society, Chemical Communications, 1980, # 1, p. 8 - 9
[4] Journal of the Chemical Society, Chemical Communications, 1980, # 1, p. 8 - 9
[5] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1928, vol. 60, p. 161[6] Chem. Zentralbl., 1928, vol. 99, # II, p. 767
[7] Tetrahedron Letters, 1988, vol. 29, # 11, p. 1319 - 1322
[8] Tetrahedron, 1982, vol. 38, # 15, p. 2339 - 2346
[9] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1928, vol. 60, p. 161[10] Chem. Zentralbl., 1928, vol. 99, # II, p. 767
[11] Journal of the Chemical Society, 1928, p. 3269
[12] Tetrahedron Letters, 1983, vol. 24, # 30, p. 3117 - 3120
[13] Tetrahedron, 1982, vol. 38, # 15, p. 2339 - 2346
[14] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1988, p. 385 - 392
[15] Synthetic Communications, 2002, vol. 32, # 5, p. 735 - 740
[16] Tetrahedron Letters, 2003, vol. 44, # 29, p. 5491 - 5494
[17] Journal of Organic Chemistry, 2012, vol. 77, # 13, p. 5823 - 5828
[18] Journal of Sulfur Chemistry, 2015, vol. 36, # 1, p. 74 - 85
[19] Journal of Sulfur Chemistry, 2018, vol. 39, # 6, p. 607 - 621
2
[ 94-74-6 ]
[ 1570-65-6 ]
[ 1570-64-5 ]
[ 95-71-6 ]
[ 608-25-3 ]
[ 108372-60-7 ]
[ 553-97-9 ]
[ 95-48-7 ]
[ 488-17-5 ]
[ 87-64-9 ]
Reference：
[1] Journal of Photochemistry and Photobiology A: Chemistry, 2012, vol. 228, # 1, p. 8 - 14
3
[ 108-41-8 ]
[ 1570-64-5 ]
[ 6640-27-3 ]
[ 873-63-2 ]
[ 87-64-9 ]
Reference：
[1] Journal of Physical Chemistry, 1994, vol. 98, # 37, p. 9158 - 9164
4
[ 95-48-7 ]
[ 1570-65-6 ]
[ 1570-64-5 ]
Reference：
[1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2004, vol. 43, # 6, p. 1335 - 1338
5
[ 94-74-6 ]
[ 1570-65-6 ]
[ 1570-64-5 ]
[ 1216257-46-3 ]
[ 95-71-6 ]
[ 553-97-9 ]
[ 95-48-7 ]
Reference：
[1] Russian Journal of Applied Chemistry, 2009, vol. 82, # 3, p. 396 - 401
6
[ 94-74-6 ]
[ 1570-65-6 ]
[ 1570-64-5 ]
[ 95-71-6 ]
[ 608-25-3 ]
[ 108372-60-7 ]
[ 553-97-9 ]
[ 95-48-7 ]
[ 488-17-5 ]
[ 87-64-9 ]
Reference：
[1] Journal of Photochemistry and Photobiology A: Chemistry, 2012, vol. 228, # 1, p. 8 - 14
7
[ 209919-30-2 ]
[ 1570-64-5 ]
Yield
Reaction Conditions
Operation in experiment
95%
With dihydrogen peroxide In acetonitrile at 30 - 35℃; for 0.166667 h; Schlenk technique
General procedure: an oven-dried Schlenk flask was allowed to cool to room temperature and charged sequentially with arylboronic acid (1 mmol), MeCN (3.0 mL) and silica chloride (0.5 mmol). The reaction was then activated by addition of 30percent H2O2 (1.0 equiv.) and stirred at 30–35 °C for the required time as given in Table 5. The progress of reaction was monitored by TLC. After complete conversion of starting material, the reaction mixture was filtered to remove silica gel. The reaction mixture was neutralized with 5percent NaHCO3 solution (5 mL). Then the product was extracted with ethyl acetate (30 mL) and subsequently washed with distilled water (10 mL). The organic extract was dried over Na2SO4 and the solvent was removed under reduced pressure. The resultant product was purified by column chromatography using silica gel with n-hexane and ethyl acetate as solvent to get the pure product. The structure of the product was confirmed by GC–MS, M.P. and 1H NMR spectroscopic techniques.
With copper(l) iodide; cesium hydroxide; butane-2,3-dione dioxime In water; dimethyl sulfoxide at 120℃; for 12 h;
General procedure: The appropriate aryl halide (1 mmol), CsOH (3 mmol), andH2O (1 mL) were added over 0.1 h, to a stirred solutionof CuI (19.0 mg, 10 molpercent) and Dimethylglyoxime (L6;23.2 mg, 20 molpercent) in DMSO (1 mL), and the reactionmixture was stirred at 120 °C (aryl iodides) or (aryl bromides).The progress of the reaction was monitored by TLC(EtOAc–hexane). The reaction mixture was then cooled toroom temperature and acidified with 0.5 M HCl (0.5 mL).The resulting mixture was extracted with EtOAc (3×10 mL)and dried (Na2SO4). Evaporation of the solvent gave a residuethat was purified by column chromatography.
Reference：
[1] Journal of Chemical Sciences, 2018, vol. 130, # 2,
9
[ 14495-51-3 ]
[ 1570-64-5 ]
Yield
Reaction Conditions
Operation in experiment
78%
With copper(l) iodide; cesium hydroxide; butane-2,3-dione dioxime In water; dimethyl sulfoxide at 120℃; for 18 h;
General procedure: The appropriate aryl halide (1 mmol), CsOH (3 mmol), andH2O (1 mL) were added over 0.1 h, to a stirred solutionof CuI (19.0 mg, 10 molpercent) and Dimethylglyoxime (L6;23.2 mg, 20 molpercent) in DMSO (1 mL), and the reactionmixture was stirred at 120 °C (aryl iodides) or (aryl bromides).The progress of the reaction was monitored by TLC(EtOAc–hexane). The reaction mixture was then cooled toroom temperature and acidified with 0.5 M HCl (0.5 mL).The resulting mixture was extracted with EtOAc (3×10 mL)and dried (Na2SO4). Evaporation of the solvent gave a residuethat was purified by column chromatography.
Reference：
[1] Journal of Chemical Sciences, 2018, vol. 130, # 2,
10
[ 95-48-7 ]
[ 1570-64-5 ]
Yield
Reaction Conditions
Operation in experiment
98%
at 25℃; for 5 h; Large scale
The opening of the tail gas absorption system, in 2000L enamel in the reactor, the vacuum suction molten 700 kg of O-cresol, in the measuring tank into the perineum 900 kg chloride spare. Opening for stirring the frozen brine cooling to room temperature (25 °C) start instillment sulfuryl chloride, about 5 hours after adding. After the completion of the dropping, the reaction liquid obtained, the reaction liquid heating 45 °C left out of hydrogen chloride and sulfur dioxide vacuum for 30 minutes, to 925 kg 4 - cresol chlorine neighbour, content of 98percent. The exhaust gas generated by the hydrogen chloride by a multi-stage falling-film absorption tower to make hydrochloric acid used for the follow-up process, sulfur dioxide after drying, with the chlorine gas through the catalyst synthesis of the tower, and then cooling to obtain sulfur chloride, recycling.
98.2%
at 65℃; for 0.5 h;
In a 1000 equipped with stirring, thermometer, reflux condenser and dropping funnelAdd 218g o-methylphenol (2 mol, 99percent by mass) into a four-ml bottle.Heated to 65 °C, began to pass chlorine, chlorine gas to 11g (0.15 mol),At the same time adding hydrogen peroxide (content 30percent),85 g (1.2 moles) of chlorine gas and 80 g (0.7 moles) of oxygen peroxide water,Stop the chlorine gas and add hydrogen peroxide dropwise, continue to hold the heat for 0.5 hours to stop the reaction, keep it standing for stratification, and cool the organic phase to obtain the product.284.3g, HPLC detection mass content 98.5percent, yield 98.2percent; water phase to waste water treatment station.
95 %Chromat.
With aluminum (III) chloride; 1,2-dithiacyclooctane; sulfuryl dichloride In melt for 4 h;
General procedure: o-Cresol (melted) or m-cresol (5.41 g, 50.0 mmol), AlCl3 (0.25 g) and the catalyst (100 mg)were added to a dried 50 ml round-bottomed flask. Sulfuryl chloride (4.66 ml, 57.7 mmol) wasthen added slowly over 2 h via a pressure-equalizing dropping funnel. The reaction mixture wasstirred for 2 h before being quenched with water (20 ml). The reaction mixture was worked up,and the crude products were weighed until constant mass and then analyzed by quantitative GC.
95 %Chromat.
at 20℃; for 4 h;
Freshly distilled sulfuryl chloride (4.66 mL, 57.7 mmol) was added slowly over 2 h to a mixture of o-cresol or m-cresol (5.41 g, 50 mmol), AlCl3 (0.25 g, 1.875mmol) and an additive (100 mg) in a round bottomed flask (50mL). The mixture was stirred at room temperature for a further 2 h, then worked up and analyzed by GC as shown for m-xylenol.
Reference：
[1] Patent: CN106365975, 2017, A, . Location in patent: Paragraph 0027; 0028; 0029
[2] Patent: CN107488108, 2017, A, . Location in patent: Paragraph 0034; 0035
[3] Journal of Organic Chemistry, 2012, vol. 77, # 13, p. 5823 - 5828
[4] Journal of Organic Chemistry, 2017, vol. 82, # 14, p. 7529 - 7537
[5] Synthesis, 1986, # 10, p. 868 - 870
[6] Asian Journal of Chemistry, 2018, vol. 30, # 1, p. 167 - 170
[7] Journal fuer Praktische Chemie - Practical Applications and Applied Chemistry (Germany), 1999, vol. 341, # 1, p. 59 - 61
[8] Gazzetta Chimica Italiana, 1898, vol. 28 I, p. 211
[9] Journal fuer Praktische Chemie (Leipzig), 1888, vol. <2> 38, p. 328
[10] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1989, p. 1529 - 1536
[11] Tetrahedron, 2002, vol. 58, # 40, p. 8059 - 8065
[12] Indian Journal of Chemistry - Section A Inorganic, Physical, Theoretical and Analytical Chemistry, 2001, vol. 40, # 11, p. 1196 - 1202
[13] Journal of the Indian Chemical Society, 2002, vol. 79, # 5, p. 420 - 425
[14] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 10, p. 1162 - 1166
[15] Journal of Sulfur Chemistry, 2015, vol. 36, # 1, p. 74 - 85
[16] Journal of Chemistry, 2016, vol. 2016,
[17] Patent: US2494993, 1945, ,
[18] Journal of Sulfur Chemistry, 2018, vol. 39, # 6, p. 607 - 621
11
[ 1228447-92-4 ]
[ 1570-64-5 ]
Reference：
[1] Chemical Communications, 2010, vol. 46, # 20, p. 3454 - 3456
12
[ 5330-38-1 ]
[ 1570-64-5 ]
Reference：
[1] Synthesis, 2005, # 15, p. 2479 - 2481
With 1,2-dithiolane; aluminum (III) chloride; sulfuryl dichloride In melt for 4 h;
General procedure: o-Cresol (melted) or m-cresol (5.41 g, 50.0 mmol), AlCl3 (0.25 g) and the catalyst (100 mg)were added to a dried 50 ml round-bottomed flask. Sulfuryl chloride (4.66 ml, 57.7 mmol) wasthen added slowly over 2 h via a pressure-equalizing dropping funnel. The reaction mixture wasstirred for 2 h before being quenched with water (20 ml). The reaction mixture was worked up,and the crude products were weighed until constant mass and then analyzed by quantitative GC.
93.4 %Chromat.
at 20℃; for 4 h;
Freshly distilled sulfuryl chloride (4.66 mL, 57.7 mmol) was added slowly over 2 h to a mixture of o-cresol or m-cresol (5.41 g, 50 mmol), AlCl3 (0.25 g, 1.875mmol) and an additive (100 mg) in a round bottomed flask (50mL). The mixture was stirred at room temperature for a further 2 h, then worked up and analyzed by GC as shown for m-xylenol.
Reference：
[1] Synthetic Communications, 2002, vol. 32, # 2, p. 279 - 286
[2] Synlett, 2011, # 11, p. 1537 - 1542
[3] Journal of the Chemical Society, Chemical Communications, 1980, # 1, p. 8 - 9
[4] Journal of the Chemical Society, Chemical Communications, 1980, # 1, p. 8 - 9
[5] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1928, vol. 60, p. 161[6] Chem. Zentralbl., 1928, vol. 99, # II, p. 767
[7] Tetrahedron Letters, 1988, vol. 29, # 11, p. 1319 - 1322
[8] Tetrahedron, 1982, vol. 38, # 15, p. 2339 - 2346
[9] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1928, vol. 60, p. 161[10] Chem. Zentralbl., 1928, vol. 99, # II, p. 767
[11] Journal of the Chemical Society, 1928, p. 3269
[12] Tetrahedron Letters, 1983, vol. 24, # 30, p. 3117 - 3120
[13] Tetrahedron, 1982, vol. 38, # 15, p. 2339 - 2346
[14] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1988, p. 385 - 392
[15] Synthetic Communications, 2002, vol. 32, # 5, p. 735 - 740
[16] Tetrahedron Letters, 2003, vol. 44, # 29, p. 5491 - 5494
[17] Journal of Organic Chemistry, 2012, vol. 77, # 13, p. 5823 - 5828
[18] Journal of Sulfur Chemistry, 2015, vol. 36, # 1, p. 74 - 85
[19] Journal of Sulfur Chemistry, 2018, vol. 39, # 6, p. 607 - 621
Reference：
[1] Gazzetta Chimica Italiana, 1898, vol. 28 I, p. 211
41
[ 108-41-8 ]
[ 1570-64-5 ]
[ 6640-27-3 ]
[ 873-63-2 ]
[ 87-64-9 ]
Reference：
[1] Journal of Physical Chemistry, 1994, vol. 98, # 37, p. 9158 - 9164
42
[ 1570-64-5 ]
[ 105-39-5 ]
[ 94-74-6 ]
Yield
Reaction Conditions
Operation in experiment
86%
Stage #1: With potassium carbonate; potassium iodide In N,N-dimethyl-formamide for 0.0666667 h; Microwave irradiation Stage #2: With sodium hydroxide In N,N-dimethyl-formamide for 0.0833333 h; Microwave irradiation
General procedure: The three ligands were prepared by microwave synthesis in the following route (Scheme 1). A mixture of 3-chlorophenol (5 mmol) for 1, 4-chloro-2-methylphenol (5 mmol) for 2 or 2,4,6-trichlorophenol (5 mmol) for 3, ethyl chloroacetate (5 mmol), K2CO3 (5 mmol), KI (1 mmol), PEG-600 (0.5 mmol), and DMF(2 mL) was irradiated in a microwave oven under 200 W for 4 min, then 5 mL of NaOH (2 M) was added and irradiated 5 min at 500 W. After cooling to room temperature, the resulting aqueous solution was acidified (pH 6) by the addition of a 1 M HCl solution under vigorous stirring. Column chromatography provided three white solids. 1H NMR (DMSO/TMS, 500 MHz, ppm): HCPA (Yield: 88percent) δ 13.17 (s, 1H), 7.40 (t, J = 8.3 Hz, 1H), 7.14–7.07 (m, 2H), 7.02–6.97 (m, 1H), 4.83 (s, 2H). HMCPA (Yield: 86percent) δ 13.04 (s, 1H), 7.22 (d, J = 2.2 Hz, 1H), 7.15 (dt, J = 10.3, 5.1 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 4.70 (d, J = 12.1 Hz, 2H), 2.18 (s, 3H). HTCPA (Yield: 83percent) δ 13.25 (s, 1H), 7.81 (s, 2H), 4.68 (s, 2H).
Reference：
[1] Journal of Coordination Chemistry, 2016, vol. 69, # 3, p. 541 - 550
[2] RSC Advances, 2016, vol. 6, # 72, p. 67610 - 67618
43
[ 1570-64-5 ]
[ 79-11-8 ]
[ 94-74-6 ]
Reference：
[1] DRP/DRBP Org.Chem.,
[2] Proceedings of the Royal Society of London, Series B: Biological Sciences, 1946, vol. 133, p. 300,306
[3] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2003, vol. 42, # 8, p. 2010 - 2014
[4] Journal of Agricultural and Food Chemistry, 2011, vol. 59, # 9, p. 4801 - 4813
[5] Journal of Agricultural and Food Chemistry, 2012, vol. 60, # 31, p. 7581 - 7587
[6] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 12, p. 3180 - 3186
[7] Letters in Drug Design and Discovery, 2013, vol. 10, # 1, p. 35 - 43
[8] Journal of Heterocyclic Chemistry, 2016, vol. 53, # 1, p. 183 - 187
44
[ 1570-64-5 ]
[ 105-36-2 ]
[ 94-74-6 ]
Reference：
[1] Journal of Agricultural and Food Chemistry, 2016, vol. 64, # 47, p. 8986 - 8993
45
[ 1570-64-5 ]
[ 94-74-6 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 2015, vol. 52, # 1, p. 173 - 179
[2] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 23, p. 5601 - 5603
46
[ 1570-64-5 ]
[ 54852-68-5 ]
Reference：
[1] Monatshefte fur Chemie, 2013, vol. 144, # 2, p. 179 - 181
[2] Journal of the Chemical Society. Perkin Transactions 2, 2000, # 6, p. 1113 - 1118
[3] Chemistry - A European Journal, 2005, vol. 11, # 18, p. 5397 - 5407
With sulfuric acid; sodium nitrite; In hexane; di-isopropyl ether; water; at 1 - 40℃; for 2h;
step 1 Production of 4-chloro-2-methyl-6-nitrophenol To a mixture of 4-chloro-2-methylphenol (6.42 g) and sodium nitrite (10.4 g) were added n-hexane (75 mL) and diisopropyl ether (35 mL) and water (50 mL), and 4.5N sulfuric acid (110 mL) was added dropwise at room temperature. After stirring at room temperature for 2 hr, solid precipitated in the reaction mixture was collected by filtration to give the title compound (5.32 g) as a yellow solid.
With sulfuryl dichloride; at 25℃; for 5h;Large scale;
The opening of the tail gas absorption system, in 2000L enamel in the reactor, the vacuum suction molten 700 kg of O-cresol, in the measuring tank into the perineum 900 kg chloride spare. Opening for stirring the frozen brine cooling to room temperature (25 C) start instillment sulfuryl chloride, about 5 hours after adding. After the completion of the dropping, the reaction liquid obtained, the reaction liquid heating 45 C left out of hydrogen chloride and sulfur dioxide vacuum for 30 minutes, to 925 kg 4 - cresol chlorine neighbour, content of 98%. The exhaust gas generated by the hydrogen chloride by a multi-stage falling-film absorption tower to make hydrochloric acid used for the follow-up process, sulfur dioxide after drying, with the chlorine gas through the catalyst synthesis of the tower, and then cooling to obtain sulfur chloride, recycling.
98.2%
With dihydrogen peroxide; chlorine; at 65℃; for 0.5h;
In a 1000 equipped with stirring, thermometer, reflux condenser and dropping funnelAdd 218g o-methylphenol (2 mol, 99% by mass) into a four-ml bottle.Heated to 65 C, began to pass chlorine, chlorine gas to 11g (0.15 mol),At the same time adding hydrogen peroxide (content 30%),85 g (1.2 moles) of chlorine gas and 80 g (0.7 moles) of oxygen peroxide water,Stop the chlorine gas and add hydrogen peroxide dropwise, continue to hold the heat for 0.5 hours to stop the reaction, keep it standing for stratification, and cool the organic phase to obtain the product.284.3g, HPLC detection mass content 98.5%, yield 98.2%; water phase to waste water treatment station.
95%Chromat.
With aluminum (III) chloride; 1,2-dithiacyclooctane; sulfuryl dichloride; In melt; for 4h;
General procedure: o-Cresol (melted) or m-cresol (5.41 g, 50.0 mmol), AlCl3 (0.25 g) and the catalyst (100 mg)were added to a dried 50 ml round-bottomed flask. Sulfuryl chloride (4.66 ml, 57.7 mmol) wasthen added slowly over 2 h via a pressure-equalizing dropping funnel. The reaction mixture wasstirred for 2 h before being quenched with water (20 ml). The reaction mixture was worked up,and the crude products were weighed until constant mass and then analyzed by quantitative GC.
With hydrogenchloride; oxygen; copper dichloride; In water; at 50℃; for 0.333333h;Microwave irradiation;
General procedure: Phenols (78mmol) and a catalytic amount of CuCl2 (7.8mmol) were dissolved in 100mL of aqueous hydrochloric acid solution (6mol/L), and the mixture was bubbled with dioxygen (22 mL/min). The reaction was performed on a microreactor at 50 C and measured by gas chromatography (GC). After GC showed the disappearance of the starting material, the reaction was extracted with dichloromethane (100mL × 2), and the organic layer was washed with water (50mL × 2) and fractionated to give the desired product.
95%Chromat.
With aluminum (III) chloride; sulfuryl dichloride; 1,3-bis(methylthio)propane; at 20℃; for 4h;
Freshly distilled sulfuryl chloride (4.66 mL, 57.7 mmol) was added slowly over 2 h to a mixture of o-cresol or m-cresol (5.41 g, 50 mmol), AlCl3 (0.25 g, 1.875mmol) and an additive (100 mg) in a round bottomed flask (50mL). The mixture was stirred at room temperature for a further 2 h, then worked up and analyzed by GC as shown for m-xylenol.
96.6%Chromat.
With tetrahydro-4-methyl-2H-thiopyran; aluminum (III) chloride; sulfuryl dichloride; at 20℃; for 4h;
General procedure: Phenol (melted), o-cresol (melted) or m-cresol (50.0 mmol), AlCl3 (25-50 mg) and the appropriate cyclic sulfide 1-4 (0.28-0.40 mmol; see Tables 1-4 for details) were placed in a dried round bottomed flask (50 ml). The mixture was stirred as sulfuryl chloride (4.44 ml,55.0 mmol) was added slowly over 2 h via a pressure equalizing dropping funnel and for 2 h further. The reaction was quenched with water (20 ml) and the organic components were then extracted with diethyl ether (3×30 ml). The combined ether layers were dried over MgSO4, whichwas removed by filtration. The solvent was removed under reduced pressure to give the crude product, which was weighed. Quantitative GC analysis was conducted on a weighed aliquot of the product with a known quantity of tetradecane.
97.1%Chromat.
With aluminum (III) chloride; sulfuryl dichloride; at 20℃; for 4h;
General procedure: To a mixture of melted o-cresol or m-cresol (10.8 g, 100.0 mmol), AlCl3 (0.5 g) and the appropriate poly(alkylene sulfide) (1-26, 0.2 g), freshly distilled SO2Cl2 (8.9 ml,110.0 mmol) was slowly added over 2 h. The reaction mixture was stirred for 2 h longer and then quenched with water (30 ml) and the products were extracted with Et2O (3×30 ml). The organic layers were dried over MgSO4, filtered, and the solvent was removed under vacuum. The crude product was weighed and analyzed quantitatively by GC. Some reactions had different amounts of polymer catalyst and/or aluminum chloride (see results section), but were otherwise conducted in the same manner.
With triethylamine; In dichloromethane; at 0 - 20℃; for 15h;
Acetyl chloride (0.45mL, 4.2 mmol) was added in a drop wise manner at 0 C in anice bath to a solution of4-chloro-o-cresol (600 mg, 4.2 mmol)in a solvent mixture of CH2Cl2/triethylamine (11 mL, 10:1). Themixture was stirred at room temperature for 15 h. After evaporating the solventto dryness, H2O was added to theresidue, which was extracted thrice with EtOAc. The combined organic layer waswashed with brine. After drying over Na2SO4, the solventwas removed and the crude product was subjected to chromatography on silica gelwith a 9:1 mixture of hexane:EtOAc to yield a colorless oil of 1 (792 mg, 97%). 1H NMR (300 MHz, CDCl3) delta 2.16 (s, 3H), 2.31(s, 3H), 6.94 (d, J=8.4 Hz, 1H), 7.19(m, 2H) MS (DART) m/z 185 [M+].
With sodium hydroxide; In 1,1-dichloroethane; water; acetone; for 3h;Heating / reflux;
Example 105 Ethenesulfonic acid 4-chloro-2-methylphenyl ester (105) To a stirred mixture of 4-chloro-2-methylphenol (24.7 g, 173 mmol) in acetone (10 ml), dichloroethane (25 ml) and water (45 ml) at 0-5 C. was added drop wise simultaneously 2-chloro-1-ethane sulfonyl chloride (28.2 g, 173 mmol) and a solution of 25% sodium hydroxide (60 g) during approximately one hour. The mixture was stirred for one hour at Sand for one hour at room temperature. Water was added and the mixture was extracted twice with DCM. The organic phase was dried with sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with hexane-ethyl acetate which gave the title compound (33.4 g, 83%).
With aluminum (III) chloride; sodium chloride; at 180℃;
General procedure: A mixture of anhydrous AlCl3 (40 g, 300 mmol) andNaCl (8 g, 137 mmol) were heated to 180 C. A mixture of appropriate4-halo-3-methyl phenol (10.7 mmol) or 4-halo-2-methyl phenol and maleicanhydride (4 g, 40.8 mmol) was added to the above melt with vigorous stirringfor 2 min, and then poured into a mixture of ice and 12 M HCl. The mixture waskept for 30 min, and the precipitate was filtered and dried at room temperature overnight. The residue obtained was powdered and extracted with n-hexane withvigorous stirring at 50 C. The extract was concentrated under reducedpressure and crystallized from chloroform to afford the correspondinghalogenated products.
Example 31; To phenol 138 (5 g, 35.06 mmol, 1 equiv.) was added CH2Cl2 (110 mL) and treated with triethylamine (7.33 mL, 52.59 mmol, 1.2 equiv.) and DMAP (856 mg, 7.02 mmol, 0.2 equiv.). TBSCl (6.34 g, 61.08 mmol, 1.2 equiv.) was slowly added and the reaction mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction mixture was diluted with CH2Cl2 (400 mL) and quenched with water (200 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (200 mL). The combined organic layer was washed with water and brine then dried (over Na2SO4), filtered and concentrated in vacuo to obtain a clear oil of 139. See below for characterization after bromination. To 139 (10.14 g, 39.51 mmol, 1 equiv.) was added CCl4 (160 mL, 0.25 M) and to it added N-Bromosuccinimide (7.0 g, 39.51 mmol, 1 equiv.) and benzoyl peroxide (955 mg, 3.95 mmol, 0.1 equiv.). The mixture was stirred under an inert atmosphere, refluxed and a ultra violet lamp shined to the reaction flask. The reaction was cooled and the solid filtered over a sintered funnel and the filtrate concentrated in vacuo. Purification was carried out by ISCO flash column chromatography was carried out with Hexanes to yield 140. 300 MHz 1H NMR (CDCl3) delta (ppm) 7.31 (d, J=2.1 Hz, 1H), 7.13 (d, J=2.7 Hz, 1H), 6.73 (d, J=9 Hz, 1H), 4.45 (s, 2H), 1.05 (s, 9H), 0.29 (s, 6H). Rf(100% Hexanes): 0.35 To lactam 115 (30 mg, 0.07 mmol, 1 equiv.) was added DMF (1 mL) and cooled in an ice bath to 0 C. before added sodium hydride (3.4 mg, 0.08 mmol, 60% mineral oil, 1.2 equiv.) and stirred for 5 minutes under a nitrogen atmosphere. Bromide 140 (70 mg, 0.21 mmol, 3 equiv.) was added and the reaction was allowed to stir for 30 minutes at 0 C. The reaction was quenched with water and diluted with Ethyl Acetate. The organic layer was washed with water and brine before being dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography eluting with 4/1 EtOAc/Hexanes to afford the desired product 141. See below for characterization after PMB deprotection. Bisphenol 141 was made in a similar fashion as described elsewhere. 300 MHz 1H NMR (CDCl3) delta (ppm) 9.05 (d, J=4.2 Hz, 1H), 8.35 (d, J=8.7 Hz, 1H), 7.74 (dd, J1=4.5 Hz, J2=4.2 Hz, 1H), 7.23-7.20 (m, 2H), 6.94-6.92 (d, J=8.1 Hz, 1H), 4.95 (d, J=17.4 Hz, 1H), 4.92 (d, J=15.0 Hz, 1H), 4.67 (d, J=17.4 Hz, 1H), 4.47 (d, J=15.0 Hz, 1H), 3.37 (s, 3H), 3.14 (s, 3H). 300 MHz 19F NMR (CDCl3) delta (ppm) -76.23 (TFA salt). MS: 448.20 (M+1).
With potassium carbonate; In cyclohexane; for 17h;Heating / reflux;
30mL of cyclohexane, 1.43g [(LOMMOL)] of 4-chloro-2-methylphenol, 2.86g (10. [5MMOL)] of (S)-ethyl O-p-toluenesulfonyl lactate, and 2.76g (20mmol) of powdery [K2C03] were put in a 50mL flask equipped with a cooling condenser-attached Dean- Stock and reacted for 17 hours while refluxing. The reaction mixture was filtered without cooling and the solid cake was washed with 20mL of warm cyclohexane. The cyclohexane layer, the filtrate, was condensed to obtain 2.26g of the target compound (yield = 93%; purity = 98%; optical purity = 99. [4%).] Rf=0.68 (EA: [HX=1] : 4); 1H NMR [(CDCL3,] [200MHZ)] [6] 1.24 (t, J=7. 2Hz, 3H), 1.62 (d, J=6. 8Hz, 3H), 2.25 (s, 3H), 4.20 (q, J=7. 2Hz, 2H), 4.69 (q, J=6. 8Hz, 1H), 6. [58 7.] 13 (m, [3H) ;] MS (70eV) m/z 244 [(M+),] 242 (M+), 169,142, 125,107, 89,77
75%
With sodium hydroxide; In N,N-dimethyl-formamide;
In a 500 mL three-neck round bottom flask equipped with a mechanical stirrer, 34.2 g (0.24 mol) of 4-chloro o-cresol was added,NaOH 9.6 g (0.24 mol) and 200 mL of DMF, stirred at room temperature (25C) for 1 h, and prepared by dissolving 50 mL of DMF in step S154.5 g (0.2 mol) of ethyl (S)-2-p-toluenesulfonylpropionate was slowly added dropwise to the above system, and the reaction was stirred at 30C.The progress of the reaction was monitored by TLC. When the sulfonation product was consumed (about 8 h or so), the reaction was stopped.Add saturated brine to the mixture for a few minutes at room temperature, extract three times with petroleum ether, and combine the organic phases.The organic phase was washed four to five times with dilute sodium hydroxide solution with a mass fraction of 2%, and the organic phase was dried over anhydrous sodium sulfate and filtered.Desolvation gave 36.4 g of ethyl (R)-2-(4-chloro-2-methylphenoxy)propionate as a light yellow oil.
With N,N,N,N,N,N-hexamethylphosphoric triamide; formaldehyd; N,N,N,N,-tetramethylethylenediamine; In tetrahydrofuran; toluene; at 4 - 20℃; for 52h;Heating / reflux;
To the solution of ETHYLMAGNESIUM bromide (400 mL, 1.0 M in THF) was added 4- CHLORO-2-METHYLPHENOL (57 g, 0.4 mol) in 75 mL toluene slowly at 4 C. To the above solution was added tetramethylethylenediamine (45g, 0.39 mol) followed by adding PARAFORMALDEHYDE (30 g) then HMPA (72.1g, 0.4 mol) at room temperature. The reaction mixture was REFLUXED 4 hours then stirred at room temperature for 48 hours. The reaction mixture was quenched with 50% HCI (450 ml). The aqueous solution was extracted with ethyl acetate (4X250ML). Combined organic solution was washed with brine, dried over MGS04 and concentrated under vacuum. Concentrated residue was chromatographed on silica gel (5% ethyl acetate in hexane) to give 40.8 g (60%) OIL. 1H NMR (400 MHz, CECI3) 8 2. 25 (s, 3H), 7.36 (m, 2H), 9.8 (s, 1 H), 11.16 (s, 1 H).
Example 139; 5-(4-Chloro-2-methylphenoxymethyl)quinazoline-2,4-diamine; [00391] Step 1; <strong>[1570-64-5]4-Chloro-2-methylphenol</strong> (0.12 g, 0.83 mmol) and potassium carbonate were added to a cooled (0 C) and stirred solution of 2-bromomethyl-6- nitrobenzonitrile [W. T. Ashton and J. B. Hynes, J. Med. Chem, 16, 1233 (1973)] (0.2 g, 0.83 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was stirred at 0 C for 1.5 hours, then diluted with pyridine (1.5 mL), water, stirred for 1 hour, filtered and dried to yield 155 mg of 2-(4-chloro-2- methylphenoxymethyl) -6-nitrobenzonitrile.
5-(4-chloro-2-methylphenoxy)-6-methyl-N,N-dipropylpyrazolo[1,5-a]pyrimidine-7-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 5h;
Example 53: 5-(4-chloro-2-methylphenoxy)-6-methyl-N,N-dipropylpyrazolo[1,5-a]pyrimidine-7-amine: To a solution of 5-chloro-6-methyl-N,N-dipropylpyrazolo[1,5-a]pyrimidine-7-amine (150 mg) in dimethylformamide (3.0 mL), 4-chloro-o-cresol (96 mg) and cesium carbonate (276 mg) were added. The mixture was stirred for 5 hours at 80C. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane : ethyl acetate = 100 : 0 ? 95 : 5) to give the title compound (190 mg) having the following physical data. TLC: Rf 0.60 (hexane : ethyl acetate = 7:1); 1H-NMR (300MHz, CDCl3): delta 7.87, 7.24-7.28, 7.18-7.24, 7.07, 6.21, 3.40-3.48, 2.33, 2.16, 1.46-1.61, 0.88.
2-(4-chloro-2-methylphenoxy)-5-nitropyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran; ethyl acetate; mineral oil;
Step A 2-(4-Chloro-2-methyl-phenoxy)-5-nitropyridine <strong>[1570-64-5]4-Chloro-2-methylphenol</strong> (101 mg, 0.71 mmol) was dissolved in tetrahydrofuran (2.1 mL) and the solution was treated with sodium hydride (60% dispersed in mineral oil, 31 mg, 0.78 mmol). After stirring for 30 minutes at 22 C., 2-chloro-5-nitropyridine (101 mg, 0.64 mmol) was added and the reaction mixture was heated to reflux for 1 hour. The solution was cooled to ambient temperature, quenched with saturated aqueous NH4 Cl and concentrated in vacuo. The residue was redissolved in ethyl acetate then washed 2* with saturated NaHCO3, saturated NaCl, dried over anhydrous Na2 SO4 and concentrated in vacuo.
70%Chromat.
With sodium hydroxide; In tetrahydrofuran; water; at 110℃; under 3000.3 Torr; for 0.333333h;Flow reactor; Green chemistry;
General procedure: Two solutions, one with the aryl halide (0.56 mmol, 1.0equivalent) in THF-H2O (2.5 mL, 3:2 v/v) and one with phenol (0.84mmol, 1.5 equivalent) and NaOH (0.84 mmol, 1.5 equivalent) in THF-H2O(2.5 mL, 3:2 v/v) were prepared and then introduced into Asia microfluidicreactor by Pump A & B.. The mixture was pumped through a preheated 1 mL glassmicrofluidic reactor at a predetermined flow rate to achieve the desiredresidence time. The crude product was collected in a flask and extracted withethyl acetate. The organic phase was combined, dried MgSO4 andconcentrated under reduced pressure. The isolated crude product was purifiedusing a prepacked silica cartridge on a Teledyne CombiFlash Rf 200instrument. Fractions corresponding to the product peak were combined andconcentrated using rotavap. For the synthesis of compound 3e and 3f correspondingsodium alkoxides were used as input for the second pump.
2-(4-chloro-2-methyl-phenoxy)-3-methyl-5-nitropyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran; ethyl acetate; mineral oil;
Step A 2-(4-Chloro-2-methyl-phenoxy)-3-methyl-5-nitropyridine Sodium hydride (60% in mineral oil, 1.08 g, 27 mmol) was washed 3* with hexanes then a solution of 4-chloro-2-methylphenol (3.50 g, 24.5 mmol) dissolved in tetrahydrofuran (40 mL) was added. The solution was stirred for 20 minutes then <strong>[22280-56-4]2-chloro-3-methyl-5-nitropyridine</strong> (4.02 g, 23.3 mmol) was added and the reaction mixture was heated to reflux for 3 hours. After cooling, the mixture was concentrated in vacuo then dissolved in ethyl acetate and washed with water, 3* with saturated NaHCO3 and saturated NaCl then dried over Na2 SO4 and concentrated in vacuo.
2,5'-dichloro-2'-hydroxy-3'-methyl-4-methylsulfonylbenzophenone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride;aluminium trichloride; In dichloromethane; 1,1,2,2-tetrachloroethane;
b) 2,5'-Dichloro-2'-hydroxy-3'-methyl-4-methylsulfonylbenzophenone (Table 1, Example No. 100) 5.06 g of 2-chloro-4-methylsulfonylbenzoyl chloride are added in portions at room temperature to a mixture of 2.85 g of 4-chloro-2-methylphenol and 5.40 g of aluminum chloride in 100 ml of 1,1,2,2-tetrachloroethane, and the mixture is subsequently refluxed for 7 hours. When cold, the reaction mixture is poured onto 200 g of ice and 500 ml of concentrated hydrochloric acid. The organic phase is separated off, and the aqueous phase is extracted twice using 50 ml of dichloromethane. The combined organic phases are washed until neutral, dried over magnesium sulfate and evaporated. Recrystallization from a mixture of ethyl acetate and diisopropyl ether gives 4.2 g (60% of theory) of 2,5'-dichloro-2'-hydroxy-3'-methyl-4-methylsulfonylbenzophenone in the form of colorless crystals with a melting point of 175-180 C.
(5-chloro-2-hydroxy-3-methylphenyl)-(4-isopropylphenyl)-methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; nitrogen; triethylamine
8.A 4-[(5-Chloro-2-hydroxy-3-methylphenyl)-(4-isopropylphenyl)-methylene]-amino}-butanamide [X1 =5-Cl, X2 =4-iC3 H7, X3 =H, n=3, R=NH2.
(A) (5-Chloro-2-hydroxy-3-methylphenyl)-(4-isopropylphenyl)-methanone. 15.61 g (0.109 mol) of 4-chloro-2-methylphenol, 15.37 ml (0.109 mol) of triethylamine and 150 ml of CH2 Cl2 are introduced into a 250 ml flat-bottomed flask. The mixture is heated to 40° C. and 20 g (0.109 mol) of 4-isopropylbenzoyl chloride are added dropwise. Boiling is continued for 8 hours. The mixture is evaporated to dryness, the residue is extracted with CH2 Cl2 and the methylene chloride solution is washed with water, dried and evaporated. The residue is recrystallized from pentane. This gives white crystals, melting at 61°-62° C. 30 g (0.103 mol) of the compound of the formula STR8 are introduced into a wide-necked Erlenmeyer flask. The reaction mixture is heated to 90° C. with stirring, 30 g (0.224 mol) of AlCl3 are added gradually and the mixture is then heated to 180° C. and kept at this temperature for 10 minutes. It is then allowed to cool to 50° C., 100 ml of liquid nitrogen are added and the mixture is stirred for 10 minutes. This gives a powder which is precipitated from a mixture of 200 g of ice and 100 ml of concentrated HCl. Extraction is carried out with CH2 Cl2 and the methylene chloride solution is washed with water, dried and evaporated. The oil is filtered on silica in order to purify it. This gives a yellow oil (nD22.5 =1.619).
(5-Chloro-2-hydroxy-3-methylphenyl)-(4-ethylphenyl)-methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; nitrogen; triethylamine;aluminium chloride; In diethyl ether; water;
A solution of 50.6 g (0.3 mol) of 4-ethylbenzoyl chloride in 200 ml of diethyl ether is added dropwise to a solution of 42.8 g (0.3 mol) of 4-chloro-2-methylphenol and 30.4 g (0.3 mol) of triethylamine in 1 liter of diethyl ether. After stirring for 4 hours at ambient temperature and standing overnight, 500 ml of water are added to the reaction mixture. After decantation, the organic phase is washed with `carbonated` water and then with water and dried over MgSO4. After evaporation, a brown oil is obtained; the ester product is of the formula STR7 82 g (0.3 mol) of the obtained ester are introduced into a 500 ml Erlenmeyer flask and heated to 100 C. with stirring. 82 (0.615 mol) of aluminium chloride are added in portions and the temperature is then raised gradually to 180-185 C. and kept there for 10 minutes. After cooling the residue, liquid nitrogen is poured onto it so that the product can be crushed. The ground residue is introduced into a stirred mixture of 200 ml of water, 200 g of ice and 20 ml of 12N hydrochloric acid. The product is extracted with methylene chloride and the methylene chloride solution is washed with water and dried over MgSO4. The evaporated extract is purified on a column of Merck silica gel 40 with an 8/2 petroleum ether/methylene chloride mixture as the eluent. The product obtained melts at 152-155 C.
With pyridine; In dichloromethane; at 0 - 20℃; for 3h;
Pyridine (4.22 ml) was added to a solution of 4-chloro-2-methylphenol (5.Og) in dichloromethane (35 ml). The mixture was cooled to 0 0C and ethyl chloroformate (3.69 ml) was added drop-wise. Reaction mixture was allowed to warm to ambient temperature and stir for 3 hours (a white ppt had formed). 2N HCI was added (25 ml) and the organic phases separated. Organic phase was washed with aq copper sulphate solution, then sat NaCI solution and dried over MgSO4. Mixture was fitered and filtrate solvens removed in vacuo to afford a clear colourless oil. (7.19 g; 96%). Rf = 0.47 (1 :9 EtOAc : Hexane).
With caesium carbonate; In acetonitrile; for 5h;Heating / reflux;
Intermediate 3: 4-chloro-2-methyl-1-r(2-methylpropyl)oxylbenzene; To a solution of 4-chloro-2-methylphenol (50 g, 0.35 mol) in acetonitrile (500 ml.) was added cesium carbonate (228 g, 0.70 mol) and 1-bromo-2-methylpropane (57 ml_, 1.5 eq.) The reaction mixture was stirred at reflux for 5 hours; After cooling, the cesium carbonate was filtered and the solvent was evaporated under reduced pressure. The title compound was obtained as a yellow oil (47 g, 68%) GC/MS: m/z 198 (M+) Rt: 1.59 min.
68%
With caesium carbonate; In acetonitrile; for 5h;Heating / reflux;
To a solution of 4-chloro-2-methylphenol (50 g, 0.35 mol) in acetonitrile (500 ml.) was added cesium carbonate (228 g, 0.70 mol) and 1-bromo-2-methylpropane (57 ml_, 1.5 eq.) The reaction mixture was stirred at reflux for 5 hours. After cooling, the salts were removed by filtration and the filtrate was evaporated under reduced pressure. The title compound was obtained as a yellow oil (47 g, 68%). GC/MS: m/z 198 (M+), Rt: 1.59 min.
methyl (R)-2-(4-chloro-2-methylphenoxy)propanoate(a) <strong>[1570-64-5]4-Chloro-2-methylphenol</strong> (8.56 g, 60 mmol) was dissolved in 3.167M aqueous KOH (18.95 mL, theoretical amount) and the solution evaporated at 80 C./25 mmHg to a viscous syrup. To this was added diethylene glycol dimethyl ether (12 mL) and the solution again evaporated at ca. 95 C./25 mmHg to a volume of ca. 11 mL. The remaining syrup was diluted with acetonitrile (5 mL), and the solution added at -20 C. with stirring to a solution of the S-fluorosulfonate prepared in Example 10 (9.3 g, 50 mmol) in acetonitrile (15 mL). After continuing to stir at room temperature overnight the solvent was removed at 25 mmHg at room temperature, water was added and the product isolated with dichloromethane. Fractionation gave 9.22 g (80.6%) of product, b.p. 77-79 C./0.02 mmHg, n.m.r. 1.60 (d, 3H), 2.23 (s, 3H), 3.72 (s, 3H), 4.68 (q, 1H), 6.56 (d, 1H) and 7.02-7.28 (m, 2H); i.r. 1761, 1496, 1250, 1149, 815; [alpha]18+26.88.
Intermediate 2: 4-chloro-2-methylphenyl cvclopropylmethyl etherTo a solution of 4-chloro-2-methylphenol (5.33 g, 37.4 mmol) in acetonitrile (125 ml.) was added Cesiumcarbonate (24.4 g, 74.8 mmol) then 15 minutes later (bromomethyl)cyclopropane (7.57 g, 56.1 mmol). The reaction mixture was stirred at reflux for 17 hours. The resulting precipitate was filtered and the filtrate was evaporated under reduced pressure. The residue was put in ethyl acetate and the organic phase was washed with 10% potassium carbonate aqueous solution then with brine to give after evaporation the title compound as a yellow oil (6.89 g, 94%). <n="17"/>1H NMR (300 MHz, CDCI3, ppm) delta: 7.0 (brs, 1 H), 6.96 (brd, 1 H), 6.58 (d, 1 H), 3.68 (d, 2H), 2.13 (s, 3H), 1.17 (m, 1 H), 0.53 (m, 2H), 0.26 (m,2H).
Example A.I; Preparation of intermediate 1; 4-chloro-2-methylphenol [1570-64-5] (0.0049 mol) was stirred in dioxane (15 ml). Sodium hydride (0.0049 mol) was added and the mixture was stirred for 30 minutes. 2- Bromo-2-methylpropanoic acid, 1,1-dimethylethyl ester [23877-12-5] (0.005 mol) was added and the reaction mixture was stirred overnight at 6O0C. Water (5 ml) was added. The mixture was washed with dichloromethane. The layers were separated. The aqueous layer was acidified with HCl, then extracted with dichloromethane. The separated organic layer was washed, filtered through Extrelut, and the filtrate was evaporated. The residue was purified over silica gel (Supelco) on a glass filter (eluent : CH2Cl2). The product fractions were collected and the solvent was evaporated, yielding 0.145 g of intermediate 1.
With di-isopropyl azodicarboxylate; triphenylphosphine; In toluene; at 100℃; for 2h;
<strong>[1570-64-5]4-Chloro-2-methylphenol</strong> (14.1 mg, 98.9 mumol) was combined with PPh3 (26.0 mg, 98.9 mumol) dissolved in toluene (87.8 muL), and the mixture heated at 100 C. DIAD (19.5 muL, 98.9 mumol) was combined with (S)-3-((S)-2-benzyloxy-1-hydroxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester (19.1 mg, 59.3 mumol) dissolved in toluene (58.0 muL), and slowly added to the heated mixture and stirred for two hours. The mixture was cooled to room temperature and concentrated. The residue was treated with 1.25M HCl in EtOH (474.6 muL) overnight at room temperature. The mixture was concentrated, the residue was redissolved in a mixture of MeCN (0.4 mL), AcOH (0.6 mL) and water (0.6 mL), filtered and purified by reverse phase preparative HPLC to yield the title compound as a mono-TFA salt (7.8 mg, 99% purity). MS m/z: [M+H]+ calcd for C20H24ClNO2, 346.15; found 346.2.
4-chloro-2-methylphenol (1.57 g; 11 mmol, 1.0 equiv) was solved in 10 mL of dry THF at -15 C under argon was added carefully in portions NaH (0.48 g, 60% in oil, 12 mmol, 1.1 equiv). After the resultant white suspension was stirred for 30 min, oxalyl chloride (0.82 g, 6.5 mmol, 0.5 equiv) in 10 mL of THF was added slowly dropwise with the reaction still cooled in an ice acetone bath. The reaction was then stirred at -15 C for 2 h. The final mix was poured onto ice, washed with saturated NH4Cl, brine and water, and then dried over Na2SO4. Evaporation under reduced pressure gave the crude product, which was recrystallized from acetone/ethyl acetate twice to give a white powder of AOE1 (1.60 g, 86%). Anal. Calcd for C16H12Cl2O4: C 56.7; H 3.6. Found: C 56.6; H 3.7.1H NMR (400 MHz, DMSO): delta = 2.24 (s, 7-H3, 7'-H3), 7.36 (d, 3J6,5 = 8.8, 6-H1, 6'-H1), 7.4 (dd, 3J5,6 = 8.8, 4J5,3 = 2.2, 5-H1, 5'-H1), 7.50 (d, 4J3,5 = 1.8, 3-H1, 3'-H1) ppm.13C NMR (400 MHz, DMSO): delta = 15.40, 123.37, 126.94, 130.59, 130.78, 132.07, 147.29, 154.22 ppm.13C NMR (400 MHz, DMSO): delta = 15.40, 123.37, 126.94, 130.59, 130.78, 132.07, 147.29, 154.22 ppm.
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃;Inert atmosphere;
General procedure: Phenol (72 mg, 0.76 mmol), PPh3 (249 mg, 0.95 mmol), and 20a were dissolved in anhydrous tetrahydrofuran (10 mL) and stirred at 0 C. 95% DIAD (275 mg, 1.29 mmol) was slowly added and stirred at room temperature. The reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated in vacuo to obtain yellowish oil. Excess phenol was neutralized into water soluble sodium salt with saturated NaHCO3 solution. The reaction mixture was extracted with CHCl3. The organic extract was dried over anhydrous sodium sulfate and evaporated in vacuo. The residue thus obtained was purified by column chromatography with n-hexane-ethyl acetate 5:1 on silica gel to afford 18aa as white solid (139 mg, 53%).
With Agaricus bisporus tyrosinase; oxygen; ascorbic acid; In water; at 20℃; for 24h;pH 7.0;Na-phosphate buffer; Enzymatic reaction;
General procedure: A panel of phenols (Fig. 7) were oxidized, including para-cresol 1, 4-ethyl phenol 2, 4-tert-butyl phenol 3, 4-sec-butyl phenol 4, 2,4-di-tert-butyl phenol 5, meta-cresol 6, 3,4-dimethyl phenol 7, 4-chloro phenol 8, 4-chloro-2-methyl phenol 9, 2-methoxy-4-methyl phenol 10, 2-methoxy phenol 11, 3-(4-hydroxyphenyl)propionic acid 12, 4-hydroxyphenylacetic acid 13, bis(4-hydroxyphenyl)methane 14 and tyrosol 15. As a general procedure phenol (0.05 mmol), tyrosinases (263-526 IU) and AA (1.5 equiv) were placed in 0.1 M Na-phosphate buffer pH 7.0 (5.0 mL) in vigorous stirring at room temperature. For insoluble aqueous phenols 3, 5, 14 substrates were dissolved in CH3CN (1.0 mL) and then added to the buffer solutions. Oxidations were performed using homogeneous and heterogeneous conditions. Reactions were monitored by thin layer chromatography (TLC). After the disappearance of the substrate, the reaction mixture was acidified with a solution of HCl 1.0 N and extracted twice with EtOAc. The organic extracts were treated with a saturated solution of NaCl and dried over anhydrous Na2SO4, then filtered and concentrated under vacuum to yield a colored crude. In the case of immobilized enzyme, biocatalyst was first recovered by filtration and the solution was subjected to the same work up described above. The obtained colored residue was treated with pyridine, HMDS and TMCS (HMDS-TMCS, 2:1 v/v) under vigorous stirring at room temperature for 30 min, then allowed to stand for 5 min.50 All products were identified by 1H NMR, 13C NMR and GC-MS. 1H NMR and 13C NMR were recorded on a Bruker 200 MHz spectrometer using CDCl3 as solvent. All chemical shift are expressed in parts per million (delta scale). GC-MS analysis were performed on a GCMS-QP5050 Shimadzu apparatus using a SPB column (25 m × 0.25 mm and 0.25 mm film thickness) and an isothermal temperature profile of 100 C for 2 min, followed by a 10 C/min temperature gradient to 280 C for 25 min. The injector temperature was 280 C. Chromatography-grade helium was used as the carrier gas with a flow of 2.7 mL/min. Mass spectra were recorded with an electron beam of 70 eV.
With sodium hypochlorite; sodium iodide; sodium hydroxide; In methanol; water; at 0 - 10℃; for 2.5h;
To a stirred solution of 5.08 g (35.63 mmol) of 4-chloro-2-methylphenol, 6.42 g (42.83 mmol) of NaI, and 1.74 g (43.50 mmol) of NaOH in 70 mL of methanol at 0-10 C. is added 71 mL (47.69 mmol) of 5% aqueous NaOCl solution (commercial bleach) dropwise over 1.5 hours. After addition of NaOCl solution is complete the reaction mixture is stirred for an additional hour at 0-10 C., then 25 mL of 10 wt. % aqueous sodium thiosulfate is added. The mixture is acidified using 5% HCl, then extracted with methylene chloride (i.e., dichloromethane, DCM). The combined organic phases are washed with an equal volume each of 10 wt. % aqueous sodium thiosulfate, then water, then brine, then dried over anhydrous magnesium sulfate, then filtered through a pad of silica gel, and then concentrated to give crude compound. This crude is recrystallized from hexanes to afford 9.37 g (98%) product as white needles. 1H NMR showed product is 4-chloro-2-iodo-6-methylphenol.
With dihydrogen peroxide; In acetonitrile; at 30 - 35℃; for 0.166667h;Schlenk technique;
General procedure: an oven-dried Schlenk flask was allowed to cool to room temperature and charged sequentially with arylboronic acid (1 mmol), MeCN (3.0 mL) and silica chloride (0.5 mmol). The reaction was then activated by addition of 30% H2O2 (1.0 equiv.) and stirred at 30-35 C for the required time as given in Table 5. The progress of reaction was monitored by TLC. After complete conversion of starting material, the reaction mixture was filtered to remove silica gel. The reaction mixture was neutralized with 5% NaHCO3 solution (5 mL). Then the product was extracted with ethyl acetate (30 mL) and subsequently washed with distilled water (10 mL). The organic extract was dried over Na2SO4 and the solvent was removed under reduced pressure. The resultant product was purified by column chromatography using silica gel with n-hexane and ethyl acetate as solvent to get the pure product. The structure of the product was confirmed by GC-MS, M.P. and 1H NMR spectroscopic techniques.
With oxygen; cobalt(II) diacetate tetrahydrate; sodium hydroxide; In ethylene glycol; at 80℃; for 8h;
General procedure: a mixture of substrate 2-cresol or 4-chloro-2-cresol (1 mmol), Co(OAc)2·4H2O (0.01 mmol, 2.5 mg) and NaOH (4.0 mmol, 160 mg) in EG (5 mL) wasstirred with O2 (1 atm) being bubbled at 80 oC for 8 h. Hydrochloric acid (10 mL, 2%) and MTBE (10 mL) were successively added to thereaction mixture. The organic layer was separated, and the aqueous phase wasfurther extracted with MTBE (10mL × 2). The combined organic phase was dried over anhydrous sodium sulfate andconcentrated to give a residue, which was purified by column chromatography onsilica gel (eluents: petroleum ether/ethyl acetate, 10/1).
With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 100℃; for 0.833333h;
General procedure: Example 1 Preparation of 5-(2-(2,4-dimethoxyphenoxy)-5-(trifluoromethyl)benzamido)picolinic acid (65) [embedded image] A solution of 2-fluoro-5-(trifluoromethyl)benzoyl chloride (2.98 mL, 19.72 mmol) in dichloromethane (22.3 mL) was added drop-wise to a mixture of methyl 5-aminopyridine-2-carboxylate (3.0 g, 19.72 mmol), pyridine (4.80 mL, 59.16 mmol) and dichloromethane (89.4 mL) at 0 C. The mixture was removed from the ice bath after 1.5 hours and was stirred at room temperature for 0.5 hours. The mixture was poured into 1N HCl (50 mL) and dichloromethane (50 mL). The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was slurried in hexanes to remove impurities. The solid was isolated by filtration rinsing with hexanes to yield methyl 5-[[2-fluoro-5-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate (5.16 g, 76%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) - 11.18 (s, 1H), 8.95 (d, J=2.5 Hz, 1H), 8.38 (dd, J=8.6, 2.5 Hz, 1H), 8.16 (dd, J=6.1, 2.4 Hz, 1H), 8.13 (d, J=8.6 Hz, 1H), 8.09-7.98 (m, 1H), 7.67 (t, J=9.2 Hz, 1H), 3.88 (s, 3H) ppm. ESI-MS m/z calc. 342.06. found 343.2 (M+1)+. Retention time: 1.54 minutes (3 minutes run).To 5-[[2-fluoro-5-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate (51.3 mg, 0.15 mmol) in N-methylpyrrolidinone (1 mL) was added 2,4-dimethoxyphenol (23.1 mg, 0.45 mmol), cesium carbonate (146.6 mg, 0.45 mmol) and the mixture was heated at 100 C. for 50 minutes to yield methyl 5-(2-(2,4-dimethoxyphenoxy)-5-(trifluoromethyl)benzamido)picolinate that was taken into the next step without further purification.Sodium hydroxide (150 -L, 3M) and methanol (150 -L) were added to the methyl 5-(2-(2,4-dimethoxyphenoxy)-5-(trifluoromethyl)benzamido)picolinate prepared in the previous step, and the reaction was stirred at 50 C. from 3 hours. The reaction mixture was filtered and purified by reverse phase preparative chromatography utilizing a gradient of 10-99% acetonitrile in water containing HCl as a modifier to yield 5-(2-(2,4-dimethoxyphenoxy)-5-(trifluoromethyl)benzamido)picolinic acid hydrochloric acid (65) (37.3 mg, 49%). 1H NMR (400 MHz, DMSO-d6) - 10.97 (s, 1H), 8.97 (d, J=2.5 Hz, 1H), 8.35 (dd, J=8.8, 2.5 Hz, 1H), 8.09 (d, J=8.6 Hz, 1H), 8.00 (d, J=2.3 Hz, 1H), 7.78 (dd, J=8.9, 2.4 Hz, 1H), 7.24 (d, J=8.8 Hz, 1H), 6.92-6.69 (m, 2H), 6.61 (dd, J=8.8, 2.8 Hz, 1H), 3.79 (s, 3H), 3.73 (s, 3H) ppm. ESI-MS m/z calc. 462.10. found 463.5 (M+1)+. Retention time: 1.81 minutes (3 minutes run). The following compounds were prepared using a procedure similar to the one described above for compound 65 from the following alcohols.
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 80℃; for 2.5h;
General procedure: Example 11 Preparation of 4-(4,5-dichloro-2-(4-chloro-2-methoxyphenoxy)benzamido)benzoic acid (18) [embedded image] A solution of 4,5-dichloro-2-fluoro-benzoyl chloride (794.5 mg, 3.49 mmol) in dichloromethane (7.3 mL) was added drop-wise to a mixture of methyl 4-aminobenzoate (528.0 mg, 3.49 mmol), pyridine (847.6 -L, 10.48 mmol) and dichloromethane (11.0 mL) at 0 C. The reaction was stirred and allowed to warm up to room temperature over 1.5 hours. To the reaction, water (10 mL) was added. The solid was isolated by filtration, washed with water (210 mL) and hexane (210 mL) to yield methyl 4-[(4,5-dichloro-2-fluoro-benzoyl)amino]benzoate (955 mg, 80%) as a light pink solid. ESI-MS m/z calc. 341.00. found 342.2 (M+1)+. Retention time: 1.75 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) - 10.90 (s, 1H), 8.03 (d, J=6.7 Hz, 1H), 8.02-7.95 (m, 2H), 7.93 (d, J=9.4 Hz, 1H), 7.88-7.76 (m, 2H), 3.84 (s, 3H) ppm.A mixture of methyl 4-[(4,5-dichloro-2-fluoro-benzoyl)amino]benzoate (34.21 mg, 0.1 mmol), 4-chloro-2-methoxyphenol (12.16 -l, 0.1 mmol), potassium carbonate 13.82 mg, 0.1 mmol) and N-methylpyrrolidinone (1 mL) were heated at 80 C. for 2.5 hours. Methanol (100 -L) and sodium hydroxide (3M, 100 -L, 0.3 mmol) were added and the reaction was stirred at 50 C. for 2 hours. An additional 100 -L of MeOH and 100 -L of 3M NaOH were added and the reactions were heated for another hour. The reaction mixture was filtered and purified by reverse phase preparative chromatography utilizing a gradient of 10-99% acetonitrile in water containing HCl as a modifier to yield 4-(4,5-dichloro-2-(4-chloro-2-methoxyphenoxy)benzamido)benzoic acid (18) (11.78 mg, 25%). ESI-MS m/z calc. 464.99. found 466.3 (M+1)+. Retention time: 2.20 minutes (3 minutes run). The following compounds were prepared using a procedure similar to the one described above for compound 18 from the following alcohols.
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 1.5h;
General procedure: Example 2 Preparation of 5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic acid (51) [embedded image] A solution of 4,5-dichloro-2-fluoro-benzoyl chloride (4.35 g, 19.13 mmol) in dichloromethane (40 mL) was added drop-wise to a mixture of methyl 5-aminopyridine-2-carboxylate (2.91 g, 19.13 mmol), pyridine (4.64 mL, 57.39 mmol) and dichloromethane (60 mL) at 0 C. The reaction was stirred and allowed to warm up to room temperature over 2 hours. The mixture was poured into 1N HCl (50 mL) and dichloromethane (50 mL). The two layers were separated. The aqueous layer was extracted with dichloromethane (3200 mL). The combined organic layer was washed with water (1150 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was slurried in hexanes to remove impurities. The solid was isolated by filtration using hexane to yield methyl 5-[(4,5-dichloro-2-fluoro-benzoyl)amino]pyridine-2-carboxylate (5.33 g, 81%) as a cream color solid. 1H NMR (400 MHz, DMSO-d6) - 11.11 (s, 1H), 8.94 (d, J=2.5 Hz, 1H), 8.36 (dd, J=8.6, 2.5 Hz, 1H), 8.12 (d, J=8.6 Hz, 1H), 8.08 (d, J=6.6 Hz, 1H), 7.95 (d, J=9.6 Hz, 1H), 3.87 (s, 3H) ppm. ESI-MS m/z calc. 342.00. found 343.1 (M+1)+. Retention time: 1.72 minutes (3 minutes run).Methyl 5-[(4,5-dichloro-2-fluoro-benzoyl)amino]pyridine-2-carboxylate (50 mg, 0.14 mmol), 4-fluoro-2-methoxy-phenol (18.27 -L, 0.16 mmol) and K2CO3 (60.41 mg, 0.44 mmol) were combined in DMF (0.5 mL) and heated at 70 C. for 1.5 hours to form methyl 5-[[4,5-dichloro-2-(4-fluoro-2-methoxy-phenoxy)benzoyl]amino]pyridine-2-carboxylate. Aqueous NaOH (145.7 -L of 3 M, 0.44 mmol) was then added and heating continued for 30 min. HPLC purification (1-99% CH3CN/5 mM HCl) provided 5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic acid (51) (35.28 mg, 54%) as a white solid. 1H NMR (400 MHz, DMSO-d6) - 13.05 (s, 1H), 10.96 (s, 1H), 8.93 (d, J=2.4 Hz, 1H), 8.30 (dd, J=8.7, 2.5 Hz, 1H), 8.08 (d, J=8.6 Hz, 1H), 7.97 (s, 1H), 7.27 (dd, J=8.9, 5.8 Hz, 1H), 7.12 (dd, J=10.7, 2.9 Hz, 1H), 6.91 (s, 1H), 6.84 (td, J=8.5, 2.9 Hz, 1H), 3.75 (s, 3H) ppm. ESI-MS m/z calc. 450.02. found 451.1 (M+1)+. Retention time: 1.61 minutes (3 minutes run). The following compounds were prepared using a procedure similar to the one described above for compound 51 from the following alcohols.
bis(3-chloro-6-hydroxy-5-methylphenyl)selenium[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
With pyridine; selenium(IV) oxide; at 55℃; for 240h;
In a 10 ml round-bottom flask, 650 mg of 4-chloro-2-methylphenol (45 mmol) were dissolved in 6.3 ml of pyridine, 506 mg of selenium dioxide (45 mmol) were added and the mixture was heated to 55 C. in an oil bath. After 10 days, the reaction solution was diluted with 50 ml of ethyl acetate and filtered. The organic phase was first washed twice with 40 ml each time of 10% hydrochloric acid and twice with 40 ml each time of water. After drying over magnesium sulphate, the solvent was removed by distillation and the crude product was purified by means of column chromatography. This was done using an automated column system from BUeCHI-Labortechnik GmbH, Essen. The column length was 16 cm and the diameter 6 cm. The eluent used was cyclohexane/ethyl acetate, working with an ethyl acetate gradient: 1-5% (over 15 min), 3-20% (over 20 min), 20-60% (20 min). The pumping rate was 50 ml/min. The product obtained was dissolved in dichloromethane with a 5% addition of methanol and blanketed with cyclohexane, in order to enable crystallization at the interface. Colourless, acicular crystals were obtained. (0195) Yield: 393 mg (1.0 mmol), 48% (0196) 1H NMR: (400 MHz, CDCl3) delta [ppm]=2.25 (s, 6H), 7.09-7.11 (m, 2H), 7.19-7.22 (m, 2H) (0197) 13C NMR: (100 MHz, CDCl3) delta [ppm]=16.67, 125.57, 126.32, 126.91, 131.99, 132.24, 152.60
General procedure: The three ligands were prepared by microwave synthesis in the following route (Scheme 1). A mixture of 3-chlorophenol (5 mmol) for 1, 4-chloro-2-methylphenol (5 mmol) for 2 or 2,4,6-trichlorophenol (5 mmol) for 3, ethyl chloroacetate (5 mmol), K2CO3 (5 mmol), KI (1 mmol), PEG-600 (0.5 mmol), and DMF(2 mL) was irradiated in a microwave oven under 200 W for 4 min, then 5 mL of NaOH (2 M) was added and irradiated 5 min at 500 W. After cooling to room temperature, the resulting aqueous solution was acidified (pH 6) by the addition of a 1 M HCl solution under vigorous stirring. Column chromatography provided three white solids. 1H NMR (DMSO/TMS, 500 MHz, ppm): HCPA (Yield: 88%) delta 13.17 (s, 1H), 7.40 (t, J = 8.3 Hz, 1H), 7.14-7.07 (m, 2H), 7.02-6.97 (m, 1H), 4.83 (s, 2H). HMCPA (Yield: 86%) delta 13.04 (s, 1H), 7.22 (d, J = 2.2 Hz, 1H), 7.15 (dt, J = 10.3, 5.1 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 4.70 (d, J = 12.1 Hz, 2H), 2.18 (s, 3H). HTCPA (Yield: 83%) delta 13.25 (s, 1H), 7.81 (s, 2H), 4.68 (s, 2H).
4-chloro-6-(4-chloro-2-methylphenoxy)-2,5-dimethylpyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With sodium hydroxide; In tetrahydrofuran; water;
Two solutions, one with the aryl halide (0.56 mmol, 1.0 equivalent) in THF- H2O (2.5 mL, 3:2 v/v) and one with phenol (0.84 mmol, 1.5 equivalent) and NaOH (0.84 mmol, 1.5 equivalent) in THF-H2O (2.5 mL, 3:2 v/v) were prepared and then introduced into Asia microfluidic reactor by Pump A & B (see, e.g., Figure 4). The mixture was pumped through a preheated 1 mL glass microfluidic reactor at a predetermined flow rate to achieve the desired residence time. The crude product was collected in a flask and extracted with ethyl acetate. The organic phase was combined, dried MgSO4 and concentrated under reduced pressure. The isolated crude product was purified using a prepacked silica cartridge on a Teledyne CombiFlash Rf 200 instrument. Fractions corresponding to the product peak were combined and concentrated using rotavap to afford 2 as white powder (131 mg, 83percent). 1H NMR (CDC13) delta2.09 (s, 3H), 2.36 (s, 3H), 2.41 (s, 3H), 6.97 (d, J= 8.8 Hz, 1H) and 7.15-7.23 (m, 2H); 13C NMR (CDC13) delta11.6, 16.4, 25.4, 113.2, 123.4, 127.0, 130.8, 131.1, 132.3, 149.9, 160.5, 165.3 and 167.5; mass spectrum (APCI), m/z calcd for C13H13C12N2O (M+H)+ 283.0399, found 283.0396.
83%Chromat.
With sodium hydroxide; In tetrahydrofuran; water; at 110℃; under 3000.3 Torr; for 0.333333h;Flow reactor; Green chemistry;
General procedure: Two solutions, one with the aryl halide (0.56 mmol, 1.0equivalent) in THF?H2O (2.5 mL, 3:2 v/v) and one with phenol (0.84mmol, 1.5 equivalent) and NaOH (0.84 mmol, 1.5 equivalent) in THF?H2O(2.5 mL, 3:2 v/v) were prepared and then introduced into Asia microfluidicreactor by Pump A & B.. The mixture was pumped through a preheated 1 mL glassmicrofluidic reactor at a predetermined flow rate to achieve the desiredresidence time. The crude product was collected in a flask and extracted withethyl acetate. The organic phase was combined, dried MgSO4 andconcentrated under reduced pressure. The isolated crude product was purifiedusing a prepacked silica cartridge on a Teledyne CombiFlash Rf 200instrument. Fractions corresponding to the product peak were combined andconcentrated using rotavap. For the synthesis of compound 3e and 3f correspondingsodium alkoxides were used as input for the second pump.
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃;
General procedure: To an oven-dried round bottomed flask with a stirring bar was added a solution of substituted phenol (0.01 mol, 1 eq.) and K2CO3 (1.2 eq.) in 50 mL of dry DMF. Excess ethyl chloroacetate dissolved in 10 mL of DMF was then slowly added through a dropping funnel to the above solution.The resulting mixture was stirred at 90 C for 5-6 h. The reaction was quenched with saturated NaCl solution, then extracted with dichloromethane(DCM), washed with brine, dried over MgSO4 and then concentrated on a rotary evaporator affording methyl 2-phenoxyacetate 1 (80%-95% yield) which was used for the next step without further purification [17].This product 1 (0.009 mol, 1 eq.) wasdissolved in 30 mL of ethanol and then placed in a round-bottomed flask equipped with a stirring bar; 80% of hydrazine hydrate (0.018 mol, 2 eq.) was slowly added to this mixture at room temperature through a dropping funnel. The resulting solution was heated up to reflux temperature and stirring was continued under this condition for another 6 h. The reaction mixture was filtered through celite,the filtrate was washed with brine, dried over MgSO4, and then concentrated in vacuo. The crudephenoxyacetohydrazide 2 was used directly without further purification in the next step.
With triethylamine; In dichloromethane; at 0℃; for 12h;
To a solution of compoond 1-1 (10.0 g, 70.1 mmol, 1.0 eg) in DCM (100 rnL) was added TEA (14.2 gs 140 mmo, 2.00 eq) and prop-2-enoyl chloride (7.00 g, 77,2 rnmoi, 1 , 10 eq), The mixture was stirred at 0 C for 12 hour. The reaction mixture was diluted with DCM (100 rnL), washed with water (30 mL*2) and brine (20 rnL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give compound 1-3 as a colorless oil (1 1.5 g, 83% yield), which was used in the next step without further purification. 'HNMR; (400 MHz, CDCb) delta 7.26 (ds J~2 Hz, 1 H), 7.260-7.198 (m, 1H), 7.020 (d, J=8 Hz, 1H), 6.654 (d, J==17.2 Hz, 1 H), 6.398-6.328 (m, 1H), 6.069 (d, J=9.6 Hz, 1H), 2.1 89 (s, 3H).
With sodium monochloroacetic acid; sodium hydroxide; at 100℃; for 1h;
Sodium chloroacetate making: in 3000L enamel in the reactor, into the chloroacetic acid 800 kg, adding water 1250L stirring to dissolve, in the 20 C the following batch adding anhydrous sodium carbonate, and adjust the pH value to 6.5 left, about the consumption of 450 kg of sodium carbonate, sodium acetate solution to obtain qualified chlorine, then the qualified chlorine sodium acetate solution is delivered to the condensation in the process of sodium chloroacetate metering tank in standby.In 5000L enamel reaction kettle adding 860 kg of 30% sodium hydroxide solution, opening the stirring of the cresol chlorine neighbour qualified chloride to 925 kg in the reaction, the temperature of the salt forming when the temperature reaches 100 C when, starting to drop a knotter good chloroethyl acid sodium solution, 1 hour after adding, kettle to maintain alkaline conditions, to pH 10. Reflux heat insulation 3 hours. To the circulating water cooling to 35 C following, separate out a large amount sodium salt, then use the separation materials are solid-liquid separation, the filter cake washing twice, shall 2 a 4 chloro sodium salt wet product.3. sodium salt preparationThe 2 a 4 chloro sodium salt wet product direct drying, to obtain the content 90.2% sodium salt of 1572 kg.Through the 2 a 4 chloro sodium salt can be preparing various content of the soluble sodium salt powder, specific example as follows:80% soluble sodium salt powder: will be 1000 kg 90.2% sodium salt by adding anhydrous sodium sulfate 120 kg, and evenly mixed to obtain white 80% soluble powder product 1115 kg.56% soluble sodium salt powder: will be 1000 kg 90.2% sodium salt by adding anhydrous sodium sulfate 600 kg, and evenly mixed to obtain white 56% soluble sodium salt powder 1600 kg.4. the acidification reactionThe 2 a 4 chloro sodium salt added to the pulp in the wet product dissolved in water, and then transported to the in the acidifies the cauldron, heating 80 C dropwise 30% salt water acidified to pH value 1.5, lowering the temperature to 40 C following into the filter in the filtering, washing 2 times, dried to obtain content is 98% of the finished product 1235 kg.
2-chloro-4,6-dimethylindeno[2,1-c]chromen-7(11bH)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
34%
With toluene-4-sulfonic acid; In chloroform; at 60℃; for 0.5h;
General procedure: To a solution of 5a (0.3mmol, 1 equiv) and 6a (0.6mmol, 2 equiv) in chloroform (3.0mL, 0.1M), p-chlorophenylsulfonic acid (0.15mmol, 0.5 equiv) was added at 60C. The resulting mixture was stirred for about 0.5h. After completion, volatiles were removed under reduced pressure and the desired product 7aa was purified by flash column chromatography (petrol ether/ethyl acetate=20/1).
(4-chloro-2-methylphenoxy)difluoroacetic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40.3%
With sodium hydride; In 1,4-dioxane; mineral oil; at 0 - 100℃; for 3h;Inert atmosphere; Cooling with ice;
General procedure: An appropriate phenol (0.002 mol) and <strong>[354-08-5]difluorobromoacetic acid</strong> 2a (0.345 g, 0.002 mol) were dissolved in the anhydrous dioxane (5-6 mL). The solution was chilled to 0 C (ice/water bath). Sodium hydride (0.1 g, 0.0042 mol, 0.170 g of 60% mineral oil suspension) was added in portions under argon. The temperature of the reaction mixture rose to 40 C. The reaction mixture was stirred at 100 C for 3h. The reaction mixture was allowed to cool to the room temperature. Then the reagents were poured to the 2 N HCl (12.5 mL). The reaction mixture was extracted with ethyl acetate. Organic layer was washed with water and then with sodium bicarbonate solution. Aqueous layers were acidified again with 2N HCl to pH 1 and extracted again with ethyl acetate. The organic layer was dried with the anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The appropriate crude difluorophenoxyacetic acids (3a, 3c, 3e, 3g) were obtained.
(4-chloro-2-methylphenoxy)fluoroacetic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65.9%
General procedure: An appropriate phenol (0.002 mol) was dissolved in the anhydrous THF (3 mL). The solution was chilled to 0 C (ice/water bath). Sodium hydride (0.116 g, 0.0048 mol, 0.19 g of 60% mineral oil suspension) was added in portions under argon. The reagents were stirred for 15 min, then bromofluoroacetic acid 2b (0.002 mol, 0.345 g) in the anhydrous THF (2 mL) at 0-5 C was added dropwise. The reagents were stirred for 10 min at 0-5 C followed by 30 min at room temperature. After completion of the reaction, water (10 mL) was added to the reagents. Then the reaction mixture was acidified to pH 1 with 2N HCl and extracted with ethyl acetate. The organic layer was dried with the anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude product (oil) was triturated with hexane (10 - 15 mL), and then stored in a refrigerator. The product (3b, 3d, 3f, 3h) was filtered off as a light-creamy solid.
With potassium carbonate; In acetone; at 20 - 60℃; for 16h;
To a solution of 4-chloro-2-methylphenol (100mg, 0.7mmol) in acetone (2.5mL) were added methyl 2-bromopropanoate (86muL, 1.1 equiv) and K2CO3 (194mg, 2 equiv) at rt. After being stirred at 60C for 16h, the reaction mixture was concentrated under reduced pressure to afford the crude residue which was purified by silica gel chromatography (hexanes:ethyl acetate:dichloromethane=50:1:2) to give ester (methyl 2-(4-chloro-2-methylphenoxy)propanoate) as a colorless oil. A mixture of ester (102mg, 0.44mmol) and hydrazine (69muL, 5 equiv) in EtOH (2mL) was stirred at 80C for 13h. After being concentrated under reduced pressure, the crude residue (acylhydrazide) was redissolved in EtOH (1mL) and 2-(trifluoromethoxy)benzaldehyde (76muL, 1.2 equiv) was added at rt. After being stirred at 80C for 16h, the resulting precipitated product was collected by filtration and dried to give 8a as a white solid.(E)-2-(4-Chloro-2-methylphenoxy)-N'-(2-(trifluoromethoxy)benzylidene)propanehydrazide (8a). White solid, mp: 147.5-149.1C; 1H NMR (400MHz, CDCl3) delta 9.55 (s, 1H, isomer a), 9.15 (s, 1H, isomer b), 8.38 (s, 1H, isomer a), 8.20 (d, J=7.6Hz, 1H, isomer a), 8.02 (s, 1H, isomer b), 7.84 (d, J=7.6Hz, 1H, isomer b), 7.49-7.41 (m, 1H, isomer a, b), 7.36-7.30 (m, 1H, isomer a, b), 7.28-7.23 (m, 1H, isomer a, b), 7.19 (s, 1H, isomer a), 7.15-7.08 (m, 1H, isomer a, b), 7.02 (dd, J=8.6Hz, 1H, isomer b), 6.78 (d, J=8.8Hz, 1H, isomer a), 6.63 (d, J=8.4Hz, 1H, isomer b), 5.55 (q, J=6.8Hz, 1H, isomer b), 4.78 (q, J=6.8Hz, 1H, isomer a), 2.31 (s, 3H, isomer a), 2.27 (s, 3H, isomer b), 1.71 (d, J=6.8Hz, 3H, isomer b), 1.67 (d, J=6.8Hz, 3H, isomer a); 13C NMR (100MHz, CDCl3) delta 173.0, 168.4, 153.7, 142.9, 132.0, 131.7, 131.3, 130.9, 129.6, 127.9, 127.4, 127.35, 127.3, 127.2, 127.1, 126.3, 126.2, 120.9, 114.8, 76.3, 71.5, 19.0, 18.1, 16.6, 16.4; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C18H17ClF3N2O3 401.0874, found 401.0873.
With copper(l) iodide; cesium hydroxide; butane-2,3-dione dioxime; In water; dimethyl sulfoxide; at 120℃; for 12h;
General procedure: The appropriate aryl halide (1 mmol), CsOH (3 mmol), andH2O (1 mL) were added over 0.1 h, to a stirred solutionof CuI (19.0 mg, 10 mol%) and Dimethylglyoxime (L6;23.2 mg, 20 mol%) in DMSO (1 mL), and the reactionmixture was stirred at 120 C (aryl iodides) or (aryl bromides).The progress of the reaction was monitored by TLC(EtOAc-hexane). The reaction mixture was then cooled toroom temperature and acidified with 0.5 M HCl (0.5 mL).The resulting mixture was extracted with EtOAc (3×10 mL)and dried (Na2SO4). Evaporation of the solvent gave a residuethat was purified by column chromatography.
With copper(l) iodide; cesium hydroxide; butane-2,3-dione dioxime; In water; dimethyl sulfoxide; at 120℃; for 18h;
General procedure: The appropriate aryl halide (1 mmol), CsOH (3 mmol), andH2O (1 mL) were added over 0.1 h, to a stirred solutionof CuI (19.0 mg, 10 mol%) and Dimethylglyoxime (L6;23.2 mg, 20 mol%) in DMSO (1 mL), and the reactionmixture was stirred at 120 C (aryl iodides) or (aryl bromides).The progress of the reaction was monitored by TLC(EtOAc-hexane). The reaction mixture was then cooled toroom temperature and acidified with 0.5 M HCl (0.5 mL).The resulting mixture was extracted with EtOAc (3×10 mL)and dried (Na2SO4). Evaporation of the solvent gave a residuethat was purified by column chromatography.
(S)-4-chloro-2-methylphenyl 5-oxopyrrolidine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
General procedure: To a round bottom flask with a stirring bar, L-pyroglutamic acid(10 mmol), phenol/aromatic amine (11 mmol) and DMAP (1 mmol) in dry CH2Cl2 (30 mL) was stirred for 10 min, followed by addition of DCC(11 mmol). The mixture was allowed to stir at room temperature overnight. The reaction was filtered through a coarse frit and the filtrate diluted with CH2Cl2 (50 mL), washed with brine (3×20 mL), dried over MgSO4, and concentrated to dryness. The crude mixture was purified using flash column chromatography (MeOH/ CH2Cl2=1/30) to give the pure products.
With potassium carbonate; In acetone; at 20 - 60℃; for 16h;
General procedure: To a solution of 4-chloro-2-methylphenol (100mg, 0.7mmol) in acetone (2.5mL) were added methyl 2-bromopropanoate (86muL, 1.1 equiv) and K2CO3 (194mg, 2 equiv) at rt. After being stirred at 60C for 16h, the reaction mixture was concentrated under reduced pressure to afford the crude residue which was purified by silica gel chromatography (hexanes:ethyl acetate:dichloromethane=50:1:2) to give ester (methyl 2-(4-chloro-2-methylphenoxy)propanoate) as a colorless oil. A mixture of ester (102mg, 0.44mmol) and hydrazine (69muL, 5 equiv) in EtOH (2mL) was stirred at 80C for 13h. After being concentrated under reduced pressure, the crude residue (acylhydrazide) was redissolved in EtOH (1mL) and 2-(trifluoromethoxy)benzaldehyde (76muL, 1.2 equiv) was added at rt. After being stirred at 80C for 16h, the resulting precipitated product was collected by filtration and dried to give 8a as a white solid
With potassium carbonate; In acetone; at 20 - 60℃; for 16h;
General procedure: To a solution of 4-chloro-2-methylphenol (100mg, 0.7mmol) in acetone (2.5mL) were added methyl 2-bromopropanoate (86muL, 1.1 equiv) and K2CO3 (194mg, 2 equiv) at rt. After being stirred at 60C for 16h, the reaction mixture was concentrated under reduced pressure to afford the crude residue which was purified by silica gel chromatography (hexanes:ethyl acetate:dichloromethane=50:1:2) to give ester (methyl 2-(4-chloro-2-methylphenoxy)propanoate) as a colorless oil. A mixture of ester (102mg, 0.44mmol) and hydrazine (69muL, 5 equiv) in EtOH (2mL) was stirred at 80C for 13h. After being concentrated under reduced pressure, the crude residue (acylhydrazide) was redissolved in EtOH (1mL) and 2-(trifluoromethoxy)benzaldehyde (76muL, 1.2 equiv) was added at rt. After being stirred at 80C for 16h, the resulting precipitated product was collected by filtration and dried to give 8a as a white solid
4-chloro-2-methyl-1-[(3E)-pent-3-en-2-yloxy]benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With tetrabutylammomium bromide; potassium carbonate; In acetone; at 56℃;
General procedure: a. 4-Chloropent-2-ene, 1.50 g (14.0 mmol), and potassium carbonate, 3.9 g (28.0 mmol), were added to a mixture of 2.0 g (14.0 mmol) of phenol 1-4 and 0.50 g (1.4 mmol) of Bu4NBr in acetone. The mixture was refluxed until the reaction was complete (TLC) and cooled, and the precipitate was filtered off. The filtrate was evaporated, and the residue was purified by column chromatography on Al2O3 using petroleum ether as eluent.
ethyl (S)-2-(p-toluenesulfonyl)propionate[ No CAS ]
[ 66513-22-2 ]
Yield
Reaction Conditions
Operation in experiment
76%
With sodium hydroxide; In N,N-dimethyl-formamide;Industrial scale;
In the 2000L reactor, add 787.2kg DMF, 173.6kg 4-chloro-o-cresol (exothermic, need to be heated and melted and then pumped into the kettle), and add 48.7kg of sodium hydroxide in a temperature-controlled manner at 25~30C. After the addition, 276.2 kg of ethyl (S)-2-p-toluenesulfonyl propionate obtained in the step S1 is added dropwise at a temperature of 25 to 30 C, and the reaction is carried out by stirring at room temperature for 4 to 5 hours. At the same time, the pH value is measured. If the content of the raw material is lowered slowly, and the pH value is <9, then 5% (2.45 kg) of sodium hydroxide is added during the feeding, and the reaction is continued for 12 hours.Raw material (S)-2-p-toluenesulfonyl propionate ethyl ester content <1%, reaction Stop the reaction. After the reaction is completed, the reaction solution is diluted by adding 720 kg of water under stirring at a temperature of 25 to 30 C (exothermic, temperature control to 25 to 30 C), and 206 L of n-heptane is added to the reaction solution to separate the liquid. The lower inorganic phase, after the upper organic phase is transferred, the lower inorganic phase is returned to the kettle and extracted once with 206 L of n-heptane, and the organic phase is separated into about 700 L. The organic phase was washed 3 times with 3% sodium hydroxide solution, 103 kg each time, and there was no 4-chloro-o-cresol in the organic phase of the gas phase detection. The organic phase was washed with 200 L of water and the pH was checked to be neutral. The obtained organic phase is distilled under reduced pressure to recover n-heptane, and the temperature of n-heptane is recovered.System <70 C. When the gas phase detection of n-heptane residual amount <1%, the distillation was stopped, the cooling was cooled to room temperature, and the product was barreled to obtain 192 kg of pale yellow product.
methyl 5-(4-chloro-2-methylphenoxy)pentanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 30h;
Potassium carbonate (8.25 mmol, 1.14 g)4-chloro-2-methylphenol (7.5 mmol, 1.07 g) andMethyl 5-bromopentanoate (5.0 mmol, 0.72 mL) was added to a DMF (37.5 mL) solution at room temperature. The mixtureStir for 30 hours. Saturated aqueous ammonium chloride solution was added to the mixture to stop the reaction, and the mixture was extracted with diethyl ether.The organic phase was washed with saturated brine and then dried over anhydrous sodium sulfate.After filtering the organic phase, the filtrate was concentrated under reduced pressure.The obtained residue was subjected to silica gel column chromatography.(Hexane / ethyl acetate)Methyl 5- (4-chloro-2-methylphenoxy) pentanoate(0.99 g) was obtained as a colorless liquid in a yield of 52%.
(S)-isopropyl 2-(5-(2-bromoethoxy)-4'-(4,4-dimethylpiperidin-1-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)-2-(tert-butoxy)acetate[ No CAS ]
(S)-isopropyl 2-(tert-butoxy)-2-(5-(2-(4-chloro-2-methylphenoxy)ethoxy)-4'-(4,4-dimethylpiperidin-1-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35.8%
With potassium carbonate; In N,N-dimethyl-formamide; at 85℃;
To a solution of (S)-isopropyl 2-(5-(2-bromoethoxy)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)-2-(tert-butoxy)acetate (30 mg, 0.052 mmol), 4-chloro-2-methylphenol (7.42 mg, 0.052 mmol) in DMF (25 mL) was added potassium carbonate (71.9 mg, 0.520 mmol). The mixture was stirred overnight at 85 C, cooled, filtered, and the filtrate was concentrated. The residue was purified by silica gel column (n-hexane:EtOAc/l : 1) to afford (S)-isopropyl 2-(tert-butoxy)-2-(5-(2-(4-chloro-2- methylphenoxy)ethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (17 mg, 0.019 mmol, 35.8 % yield) as a oil. LCMS (M + H) = 638.
tert-butyl (2-(4-chloro-2-methylphenoxy)ethyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
29%
To a stirred solution of 4-chloro-2-methylphenol (1 g, 7.01 mmoL) in DMF (15 mL) was added CS2CO3 (4.57 g, 14.02 mmoL) in one-portion . The reaction mixture was stirred at 20 C for 0.5 h. Then2-((tert-butoxycarbonyl)amino)ethyl methanesulfonate (1.677 g, 7.01 mmoL) was added and heated up to 120 C for 16 h. LCMS showed most of the starting material was consumed. The reaction mixture was diluted with water (100 ml) and ethyl acetate (200 ml), organic layer separated and washed with brine (200 ml x 3), dried over anhydrous Na2SC>4, filtered and concentrated to give a yellow oil. The crude product was purified by silical gel chromatography (5%~l0% ethyl acetate/petroleum ether) to obtain tert- butyl (2-(4-chloro-2-methylphenoxy)ethyl)carbamate (0.6 g, 2.034 mmoL, 29.0 % yield) as a white solid. LCMS: Retention time (0.1% TFA): 1.716 min, m/z: (M+Na) = 308.
To a solution of p 4-chloro-2-methylphenol (1.0 g, 7.01 mmol) in water (22 mL) was added 2-bromoethanol (1.315 g, 10.52 mmol), NaOH (0.421 g, 10.52 mmol) and the mixture was stirred at 90 C for 16 h. Then, the reaction solution was cooled to room temperature and the pH was adjusted to about 7 with acetic acid, extracted with DCM (3 x 20 mL), the organic combined layers were dried over anhydrous NaiSOr and evaporated in vacuum to give a yellow crude product. The crude product was purified by silica gel chromatography eluting with pet. etherEtOAc (6: 1-5: 1) to give 2-(4-chloro-2- methylphenoxy)ethanol (500 mg, 2.55 mmol, 36.3 % yield). LCMS (M + H) = 187.
Step 1 A 100 mL round bottom flask was charged with AcOH (18 mL) and H2SO4 (2 mL), then cooled to 0 C. C1-N-(hydroxymethyl)acetamide (4.32 g, 35 mmol) and 4-chloro-2-methylphenol (5 g, 35 mmol) were added portionwise to the stirring acidic solution, then the reaction mixture allowed to warm to ambient temperature overnight. The reaction mixture was poured into ice-cold H2O then extracted with CH2Cl2*3. Combined organic layers were washed with brine, dried over Na2SO4 and concentrated to produce a colorless oil. The intermediate was dissolved in EtOH (10 mL), treated with conc. HCl (3 mL) and refluxed for 2 h. The resulting yellow suspension was then stored at -10 C. overnight and filtered with EtOH to yield 2-(aminomethyl)-4-chloro-6-methylphenol, hydrochloride as a white fluffy solid (1.67 g, 23% yield).
With water; dihydrogen peroxide; ferric wild type dehaloperoxidase B In methanol at 25℃; for 0.0833333h; Enzymatic reaction;
HPLC Reactivity Studies
General procedure: Enzyme assays (250 μL total volume)were performed in triplicate in 100mM KPi at pH 7 (unless otherwiseindicated) containing 5% MeOH at room temperature. A typical reactionwas initiated by the addition of 500 μMH2O2 to a solution containing10 μM enzyme and 500 μM substrate, and quenched after 5 minwith an excess of catalase. Enzyme variants included ferric WT DHP B,ferric DHP B (Y28F/Y38F) [42], oxyferrous WT DHP B, HSM and HRP.Mechanistic probes were added prior to the addition of H2O2, including500 μM 4-bromophenol (MeOH), 500 μM D-mannitol (KPi), 100mM5,5-dimethyl-1-pyrroline N-oxide (DMPO; MeOH) or 10% v/v DMSO,and adjustments were made to ensure a final 5% MeOH concentrationfor all reactions except DMPO (10% MeOH final). A 200 μL aliquot ofthe reaction mixture was diluted 4-fold with 600 μL 100mM KPi at thereaction pH, and the diluted samples were analyzed using a Waterse2695 Separations Module coupled to a Waters 2998 photodiode arraydetector and equipped with a Thermo Fisher Scientific ODS Hypersil(150mm×4.6 mm) 5 μM particle size C18 column. Separation wasperformed using a linear gradient of binary solvents (solvent A,water + 0.1% TFA; solvent B, acetonitrile + 0.1% TFA). The elutionconsisted of the following conditions: (1.5 mL/min A:B) 95:5 to 5:95linearly over 12 min, 5:95 isocratic for 2 min, 5:95 to 95:5 over 1 min,then isocratic for 3 min. Data analysis was performed using the WatersEmpower software package.
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