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USD 0.00
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USD 15-60
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Structure of 372-31-6 * 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 sodium ethanolate In ethanol at 20 - 90℃; for 24 h; Inert atmosphere
To a stirred solution of ethyl 4.4,44rifluoro—3-oxobutanoate 101 (3 g. 1 &30 nim-ol) in ethin.iol (30 mL) under argon atmosphere were added urea 102- (978 mg, 16.30 mmol) and freshly prepared sodium ethoxide (750 mg of Na in 30 mL of EtOH) at Pt; the mixture was heated to 90 °C and stirred for 24 h. The reaction was monitored by TIE; after completion of the reaction, the volati Ic-s were removed in vacua, diluted with water (25 mL), acidified with 1 N SC1 UO niL) and extracted with EtOAc (2 x 40 niL). The comb med organic extracts were dried over sodium sulfate, filtered and concentrated in vacua to afford compound 103 (650 mg, 22percent) as a white solid. TL-C: 5percent CH3OR CK2CI2 (1?,: 0.3); ‘H-NMR (DMSO-percent, 500 MHz): 6 1107 (s. 114), i1.54(s. iS). 6.07 (s, 1H
Reference：
[1] Patent: WO2015/57945, 2015, A1, . Location in patent: Paragraph 00121
[2] Journal of Organic Chemistry, 1959, vol. 24, p. 113
[3] Journal of the American Chemical Society, 1958, vol. 80, p. 5744,5751
2
[ 17356-08-0 ]
[ 372-31-6 ]
[ 368-54-7 ]
Reference：
[1] Russian Chemical Bulletin, 2013, vol. 62, # 4, p. 1060 - 1065[2] Izvestiya Akademii Nauk. Seriya Khimicheskaya, 2013, # 4, p. 1059 - 1064,6
[3] RSC Advances, 2017, vol. 7, # 28, p. 17427 - 17441
[4] Journal of the American Chemical Society, 1948, vol. 70, p. 500
3
[ 372-31-6 ]
[ 108-46-3 ]
[ 575-03-1 ]
Yield
Reaction Conditions
Operation in experiment
89%
With iodine In toluene at 90℃; for 18 h;
General procedure: Iodine (25 molpercent) was added into a mixture of 3-alkoxyphenol (5 mmol) and ethyl 4,4,4-trifluoroacetoacetate (6 mmol) in toluene(1 mL). The reaction was heated at 90°C and stirred for a period of 18 hours and monitored by TLC. Upon completion, the reaction mixture was cooled to room temperature, diluted with 10 mL of ethyl acetate, and washed with 10 mL of distilled water. The combined organic layers were dried over anhydrous sodium sulfate and the solvent removed under vacuum. Purification of the product was performed via flash chromatography (silica gel, hexane/ethyl acetate = 95/5 to80/20).
88.9%
With sulfuric acid In ethanol at 80℃;
Concentrated sulfuric acid (2 mL) and trifluoroacetoacetate (3.7 g, 10 mmol) were added dropwisein turn to the solution of resorcinol (2.2 g, 10 mmol) in ethanol (4 mL) with stirring. Then the mixture was heated to maintain at 80° C until the end of the reaction was detected by TLC. The resulted thickmagenta liquid was dripped into 10 mL of cold water with rigorous stirring. The precipitate wasfiltered and dried to give compound 1. Yield 88.9percent, m.p. (melting point) 175–176° C [lit. (literature)178–179° C] [54].
87%
at -40 - 0℃; for 2.5 h;
Resorcinol (2 g, 18.2 mmol) was carefully dissolved in conc. H2SO4 (3 mL) under -40°C, and the appropriate ethyl trifluoroacetoacetate (3.0 mL, 20.5 mmol) was added. After stirring for 1 h, the mixture was gradually warmed to 0 °C and stirred for another 1.5 h. When the reaction was complete, the reaction mixture was poured into ice/water (20 mL), and the precipitate was recovered by filtration and washed with water to obtain the desired compound 12g as white needle crystal.
79.4%
at 20℃; for 25 h; Cooling with ice
Resorcinol 0.55g (5mmol) and concentrated sulfuric acid 8.0mL, stirring to dissolve,Under ice-cooling, 0.73 mL (5 mmol) of ethyl 4,4,4-trifluoroacetoacetate was slowly added dropwise under cooling in an ice water bath, and the mixture was stirred for 1 h under ice-cooling in an ice-water bath. The reaction was performed at room temperature for 24 h. Into a lot of ice water with vigorous stirring,A precipitate generated, suction filtration, cake with anhydrous ethanol recrystallization,0.91 g of 7-hydroxy-4-trifluoromethylcoumarin (A3) was obtained as a white powder in a yield of 79.4percent
73.9%
for 18 h; Cooling with ice
1) 30 ml of concentrated sulfuric acid was stirred in an ice bath, to which was added 5.5 g of resorcinol and was added 9.2 g of trifluoro ethyl acetoacetate dropwise. The solution turned yellow from yellowish. The reaction was carried out for 18 hours. The reaction liquid was poured into ice/water mixture, and a lot of solid was precipitated, which was filtrated. The cake was washed with water to neutral. Recrystallization with 75percent ethanol gave 8.5 g of white crystal. Melting point: 218-220°C, yield: 73.9percent.
73.9%
With sulfuric acid In water for 18 h;
1) 30 ml of concentrated sulfuric acid was stirred in an ice bath, to which was added 5.5 g of resorcinol and was added 9.2 g of trifluoro ethyl acetoacetate dropwise. The solution turned yellow from yellowish. The reaction was carried out for 18 hours. The reaction liquid was poured into ice/water mixture, and a lot of solid was precipitated, which was filtrated. The cake was washed with water to neutral. Recrystallization with 75percent ethanol gave 8.5 g of white crystal. Melting point: 218-220° C., yield: 73.9percent.
70%
at 10 - 20℃;
General procedure: The other 7,4-disubstituted coumarins, including compounds 8-12, were synthesised by using the Pechmann reaction [3,4], as described elsewhere [38]. In the typical procedure, it was added drop wise 3-susbtituted phenol (0.015 mol) and 2-acetyl ethyl acetate or 2-trifluoroacetyl ethyl acetate (0.013 mol) to 17mL of concentrated sulfuric acid, the mixture being kept at 10 °C in an ice bath. This mixture was stirred at room temperature for at least 18 h, and, then, poured in 70 mL of crushed ice. The obtained precipitate was filtered under vacuum, washed subsequently with cold water, and dissolved in a 20-mL 5percent sodium hydroxide solution. This solution was filtered, and it was added a 2M sulfuric acid solution to acidify it. The crude product was recuperated by filtration with a water ejector, washed with cold water, dried, and crystallized from 95percent ethanol. In all cases, the obtained coumarins were characterized by IR, 1H NMR and 13C NMR spectroscopy [38]. The chemical yields and melting points (m.p.) are presented in Table 1.
55.6%
at 0℃; for 12 h;
Thirty mL of concentrated sulfuric acid was placed in a three-necked flask and cooled to 0 ° C in an ice-salt bath.2. 11.0 g resorcinol and 12mL ethyl trifluoroacetoacetate were mixed under ultrasound hook , to give a mixed solution of both.3. The mixed solution will be dripped into concentrated sulfuric acid under r rapid stirring, drip rate was maintained at one drop per two seconds, to ensure that the system temperature does not exceed 0 ° C. After the mixed solution was dropped, stirring was continued for 12h.4. After the reaction, the reaction solution was poured into 500mL ice water in a large beaker under rapid stirring, to dilute the concentrated sulfuric acid to the weak acid, which a large number of pink flocs appeared and filtered.
54%
at 100℃; for 0.5 h; Microwave irradiation
Synthesis 7-Hydroxy-4-trifluoromethylcoumarin (1) was synthesized according to a known procedure [50] . Resorcinol (2) (440 mg, 4.00 mmol), ethyl 4,4,4-trifluoroacetoacetate (3) (736 mg, 585 μl, 4.00 mmol), and trifluoroacetic acid (2 ml) were heated in an oven-dried, 10-ml, heavy-walled microwave reaction vessel equipped with a cross-shaped, magnetic stirring bar and closed with a snap cap to 100 °C for 30 min in a Discovery microwave (CEM). After cooling to RT, the reaction mixture was slowly added to an ice/water mixture (120 ml, 1:1) under vigorous stirring. The pink precipitate was filtered off, washed with cooled distilled water and dried under reduced pressure. Chromatography on silica gel with PE/EtOAc (8:2) provided the fluorescent dye 1 (497 mg, 2.16 mmol, 54percent) as a colorless solid. The analytical data were generally consistent with those reported previously [50,51]. TLC: Rf 0.58 (PE/EtOAc, 1:1); mp: 182 °C; IR (ATR, film): 3395 (O-H), 3106, 1893, 1766, 1709 (C=O), 1630, 1607, 1575, 1519, 1494, 1441, 1405, 1362, 1337, 1284, 1214, 1190, 1158, 1120, 1008, 963, 891, 856, 821, 798, 750, 743, 721, 710, 670, 657 cm-1; 1H NMR (DMSO-d6): δ = 6.76 (s, 1 H, 3-H), 6.83 (d, J = 2.4 Hz, 1 H, 8-H), 6.91 (dd, J = 8.9, 2.4 Hz, 1 H, 6-H), 7.56 (dd, J = 8.9, 1.6 Hz, 1 H, 5-H), 10.95 (br s, 1 H, OH) ppm; 13C NMR (DMSO-d6): δ = 103.2 (C-8), 105.3 (C-8a), 112.0 (q, JC-F = 5.8 Hz, C-3), 114.1 (C-6), 121.8 (q, JC-F = 275.8 Hz, C-4), 126.2 (C-5), 139.8 (q, JC-F = 31.9 Hz, C-4a), 156.0 (CF3), 158.9 (C-2), 162.2 (C-7) ppm; 19F NMR (DMSO-d6): δ = -63.6 ppm; HRMS (ESI): calcd. for [C10H6F3O3]+ ([M+H]+): 231.02636; found: 231.02635; Anal.: calcd. for C10H5F3O3: C, 52.19; H, 2.19; found: C, 52.03 +- 0.09; H, 2.23 +- 0.03.
52%
at 0 - 20℃; for 12 h;
General procedure: A solution of 1,3-dihydroxybenzene (11.0 g, 100 mmol) in substituted ethyl acetoacetate (100 mmol)was added dropwise to stirring H2SO4 kept at 0° C. After completion of the addition, the reactionmixture was kept stirring for 12 h at room temperature and then poured onto ice-water. The crudeproducts were filtrated and recrystallized from ethanol [18].
Reference：
[1] Synthetic Communications, 2006, vol. 36, # 20, p. 2949 - 2956
[2] Monatshefte fur Chemie, 2013, vol. 144, # 3, p. 411 - 414
[3] Tetrahedron Letters, 2002, vol. 43, # 50, p. 9195 - 9197
[4] Synthetic Communications, 2004, vol. 34, # 21, p. 3997 - 4003
[5] Tetrahedron Letters, 2014, vol. 55, # 49, p. 6715 - 6717
[6] Molecules, 2018, vol. 23, # 3,
[7] Journal of Fluorine Chemistry, 1982, vol. 20, p. 187
[8] European Journal of Medicinal Chemistry, 2015, vol. 95, p. 153 - 165
[9] Journal of the American Chemical Society, 2015, vol. 137, # 2, p. 757 - 769
[10] Patent: CN106831683, 2017, A, . Location in patent: Paragraph 0037; 0038; 0039
[11] Patent: EP2698369, 2014, A1, . Location in patent: Paragraph 0025; 0052
[12] Patent: US2014/113911, 2014, A1, . Location in patent: Paragraph 0140
[13] Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2011, vol. 79, # 3, p. 428 - 436
[14] Journal of Materials Chemistry B, 2014, vol. 2, # 37, p. 6188 - 6191
[15] Journal of Medicinal Chemistry, 2013, vol. 56, # 11, p. 4671 - 4690
[16] Patent: CN107674055, 2018, A, . Location in patent: Paragraph 0055-0062
[17] Analytical Biochemistry, 2014, vol. 456, # 1, p. 70 - 81
[18] Molecules, 2016, vol. 21, # 6,
[19] Chemistry of Heterocyclic Compounds, 2007, vol. 43, # 2, p. 151 - 159
[20] Journal of Chemical & Engineering Data, 1981, vol. 26, # 3, p. 348 - 350
[21] Journal of the Chemical Society, 1951, p. 3235,3238
[22] Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 22, p. 3107 - 3110
[23] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 1, p. 272 - 275
[24] RSC Advances, 2014, vol. 4, # 28, p. 14501 - 14506
[25] Medicinal Chemistry Research, 2014, vol. 23, # 6, p. 2821 - 2833
[26] Journal of Organic Chemistry, 2015, vol. 80, # 18, p. 8951 - 8953
[27] Chinese Journal of Chemistry, 2015, vol. 33, # 12, p. 1353 - 1358
[28] Chemical Communications, 2017, vol. 53, # 28, p. 3952 - 3955
[29] European Journal of Medicinal Chemistry, 2018, vol. 151, p. 434 - 449
[30] New Journal of Chemistry, 2018, vol. 42, # 11, p. 8805 - 8814
Stage #1: With potassium hydroxide In methanolReflux Stage #2: for 24 h; Reflux
Take potassium hydroxide 29.8g (0.53mol) input with mechanical stirring with reflux condenser 250mL four-necked flask was slowly added 100mL of methanol, stirring for stand-by 43.4 g (0.52 mol) of cyanoacetamide were charged into a flask equipped with a mechanical stirrer, constant pressure dropping funnel, drying tube and reflux condenser 500mL four-necked flask, add 150mL of methanol, mechanical stirring heating reflux, the reaction solution was changed from cloudy to light yellow transparent and added 100 g (0.54 mol) of ethyl trifluoroacetoacetate, keep the reflux state, slowly dropping the configured potassium hydroxide methanol solution, Heated to reflux reaction 24h, central control raw materials cyanoacetamide reaction is complete, Change the reflux device for the distillation device, Methanol recovery 3/4, The residue was added to cold water, cooled, adjusted with dilute hydrochloric acid PH = 3-4, stirred 0.5h, the reaction mixture was filtered, the filter cake washed with water to give the white target 2,6-dihydroxy-3-cyano-4 - (trifluoromethyl) pyridine, dried at 80 to constant weight to give 84.5 g, yield 80.1percent, hplc 98percent.
Reference：
[1] Patent: CN107382848, 2017, A, . Location in patent: Paragraph 0034-0045
8
[ 383-63-1 ]
[ 141-78-6 ]
[ 372-31-6 ]
Yield
Reaction Conditions
Operation in experiment
70.7%
Stage #1: at 0 - 5℃; for 1 h; Stage #2: at 0 - 65℃; for 25 h;
Synthesis of 4,4,4-trifluoro-acetoacetic acid ethyl ester, to a dried 250ml four-necked flask was added 69.0g of acetic acid ethyl ester, cooled to 0-5°C with an ice-salt bath, 26.3 g of solid sodium ethoxide was added, stirred for 1 hour at 0-5°C, 50g of trifluoroacetic acid ethyl ester was added dropwise. After dropping was completed, stirring was continued for one hour maintaining the temperature at 0-5°C. Heat to 60-65°C. At 60-65°C, stirred for 24 hours until trifluoroacetic acid ethyl ester <1percent. Cooled, under reduced pressure excess acetic acid ethyl ester was concentrated, obtaining a brown solid, at 20°C,to which was added dropwise 155g 3N HCl until PH≤2. Extracted twice using 100ml of 1,2-dichloroethane, and concentrated to give a crude brown oil, distillation of the crude give 45.8g transparent liquid, yield 70.7percent, purity: 96.8percent (GC).
Reference：
[1] Journal of Fluorine Chemistry, 1982, vol. 20, p. 187
[2] Patent: CN103214355, 2016, B, . Location in patent: Paragraph 0076
[3] Bulletin des Societes Chimiques Belges, 1926, vol. 35, p. 414[4] Bulletin de la Classe des Sciences, Academie Royale de Belgique, 1926, vol. <5> 12, p. 680,692[5] Chem. Zentralbl., 1927, vol. 98, # I, p. 996,1286
[6] Journal of the American Chemical Society, 1947, vol. 69, p. 1819
[7] Journal of the American Chemical Society, 1946, vol. 68, p. 102
[8] Tetrahedron, 1964, vol. 20, p. 2162 - 2166
[9] Patent: WO2015/85464, 2015, A1, . Location in patent: Paragraph 65-67
[10] Patent: CN106188013, 2016, A, . Location in patent: Paragraph 0010; 0011; 0019
[11] Patent: CN106699506, 2017, A, . Location in patent: Page/Page column 0001; 0002; 0003; 0004; 0005; 0006; 0007; 0008
Reference：
[1] Journal of the Chinese Chemical Society, 2007, vol. 54, # 3, p. 749 - 757
[2] Phosphorus, Sulfur and Silicon and Related Elements, 1997, vol. 126, p. 1 - 10
Reference：
[1] Polish Journal of Chemistry, 1984, vol. 58, # 1-3, p. 85 - 95
24
[ 372-31-6 ]
[ 372-29-2 ]
Reference：
[1] ACS Chemical Neuroscience, 2017, vol. 8, # 12, p. 2746 - 2758
[2] Journal of Heterocyclic Chemistry, 1972, vol. 9, p. 513 - 522
[3] Tetrahedron, 2015, vol. 71, # 36, p. 6196 - 6203
[4] Journal of Agricultural and Food Chemistry, 2016, vol. 64, # 3, p. 552 - 562
[5] Patent: CN105272973, 2016, A, . Location in patent: Paragraph 0098; 0101; 0102
[6] Patent: CN105294671, 2016, A, . Location in patent: Paragraph 0114; 0117; 0118
25
[ 631-61-8 ]
[ 372-31-6 ]
[ 64-19-7 ]
[ 372-29-2 ]
Yield
Reaction Conditions
Operation in experiment
96.5%
at 90℃; for 3 h; Large scale
Ammonia reactor volume of 1000L, with stirring, thermometer, metering tank and condenser.368.0 kg (2.0 kmol) of ethyl 4,4,4-trifluoroacetoacetate was added to the reaction vessel through a metering tank,After the addition, the temperature was raised to 90 ° C. Then, 323.4 kg (4.2 kmol) of ammonium acetate was charged, and the mixture was incubated at 90C for 3 hours.The temperature of the reaction solution was cooled to 30 ° C, and the mixture was stirred and allowed to stand for 30 minutes. The reaction liquid is divided into two layers, the lower layer is an organic phase,Weight of 359.6kg, the content of ethyl 3-amino-4,4,4-trifluorocrotonate was 98.2percent and the yield was 96.5percent;The upper layer is aqueous phase, the weight of water phase is 330.6kg, and the content of acetic acid in water phase is 36.3percent.
Reference：
[1] Patent: CN105985253, 2016, A, . Location in patent: Paragraph 0012; 0022
Reference：
[1] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 6, p. 3395 - 3402
28
[ 372-31-6 ]
[ 88-17-5 ]
[ 35853-41-9 ]
Yield
Reaction Conditions
Operation in experiment
23%
at 120℃; for 3 h; Inert atmosphere
2-(Trifluoromethyl)aniline (0.54 mL, 4.3 mmol) and ethyl 4,4,4-trifluoro-3-oxobutanoate (0.62 mL, 4.3 mmol) was added to a round bottomed flask equipped with a large oval stirrer bar followed by polyphosphoric acid (4.0 g). The reaction mass was stirred at 120 °C for 3 h under N2. The gold brown sticky mass was then quenched with ice water (50 mL) and extracted with DCM (2 × 20 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to offer the product as beige solid that did not require purification (0.27 g, 23 percent yield).
Reference：
[1] European Journal of Medicinal Chemistry, 2010, vol. 45, # 8, p. 3374 - 3383
[2] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 2012, vol. 51, # 9, p. 1411 - 1416,6
[3] Monatshefte fur Chemie, 2008, vol. 139, # 2, p. 179 - 181
[4] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 23, p. 5466 - 5469
[5] CrystEngComm, 2018, vol. 20, # 16, p. 2316 - 2323
29
[ 122-51-0 ]
[ 372-31-6 ]
[ 571-55-1 ]
Yield
Reaction Conditions
Operation in experiment
97.1%
at 135℃; for 18 h;
Ethyl 4,4,4-trifluoro-3-oxobutanoate (30 g, 162.9 mmol) was added to a solution of triethoxymethane (72.4 g, 488.8 mmol) in acetic anhydride (50 mL). The mixture was stirred at 135° C. for 18 h. The brown mixture was concentrated to afford ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate, 1f (38 g, 97.1percent) as a brown oil, which was used in the following reaction without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 1.23-1.33 (m, 3H) 1.40 (dt, J=14.18, 7.19 Hz, 3H) 4.19-4.36 (m, 4H) 7.66-7.87 (m, 1H).
92.6%
for 6 h; Reflux
Ethyl trifluoroacetoacetate (0.036 mol), triethyl orthoformate (0.059 mol) andAcetic anhydride (0.108πο1) was added to a three-necked flask and refluxed for 6 hours,After completion of the reaction, the mixture was distilled under reduced pressure and the mixture was collected at 98 to 105 ° C to obtain 7.4 g of a pale yellow oily liquid,Yield 92.6percent.
91%
at 120℃; for 2.5 h;
[00520] To a solution of ethyl-(4,4,4,-trifluoro)-3-oxobutyrate (20 g, 0.11 mol) in acetic anhydride (33.3 g, 0.33 mol) was added triethyl orthoformate (24.1 g, 0.165 mol). The reaction mixture was heated at 120 oC for 2.5 h. The low-boiling components were removed and the residue was distilled under reduced pressure to give ethyl 2-ethoxymethyllene-4,4,4-trifluoro-3- oxobutytate (1) (23.5 g, 91percent) as an oil, which was used without further purification.
90%
at 120℃; for 6 h;
In a 500 mL four-necked flask, trifluoroacetoacetate ethyl-(4,4,4-trifluoro)-3-oxobutyrate (18400 mg, 100 mmol), triethylorthoformate (44400 mg, 300 mmol) and acetic anhydride(61200 mg, 600 mmol) were added and heated at 120 C for 6 h. Then, the solvent was removed and the product was then distilledunder vacuum over a column to give a colorless liquid, yield 90percent.
80%
at 120℃; for 6 h;
78.3 g (0.425 mol) of ethyl trifluoroacetoacetate, 103 g (0.638 mol) of triethyl orthoformate and 130 g (1.275 mol) of acetic anhydride were placed in a 500 ml three-necked flask,Heated to 120 reaction 6h.To distillation unit will be 100 low boiling point substances removed by distillation.Then the pump vacuum to remove low boilers,The oil pump was distilled under reduced pressure to give ethyl 2-ethoxymethylene-4,4,4-trifluoroacetoacetate as a colorless liquid,About 81g,Yield 80percent.
75%
at 120 - 140℃; for 1.5 h;
Stage 2Ethyl 2-[1-ethoxymethylidene]-4,4,4-trifluoro-3-oxobutyrate An amount of 101 g (548.5 mmol) of ethyl 4,4,4-trifluoro-3-oxobutyrate, 164 g (1106 mmol) of triethyl orthoformate and 114.1 g (1118 mmol) of acetic anhydride were stirred in a distillation apparatus at 120° C. for 1 hour, and then the temperature was increased to 140° C. over the course of 30 minutes. Partial cooling was followed by distillation under a membrane pump vacuum.Yield: 103.6 g (75percent of theory) 1H-NMR (CD3CN) 1.2-1.4 (m, 6H), 4.2-4.4 (m, 4H), 7.75-7.95 (1H)
64%
at 120 - 140℃; for 7 h;
A mixture of ethyl-4,4,4-trifluoroacetoacetate (19, 37.8 g, 206 mmol), triethyl orthoformiate (45.6 g, 308 mmol) and acetic anhydride (58.1 mL, 615 mmol) was heated at 120 °C for 2 h and then at 140 °C for 5 h. Low boiling solvents were removed in vacuo. The residue was distilled under vacuum (ca. 10 mm Hg). After removing low boiling fraction (bp 70 - 90 °C at 10 mm Hg) the main fraction (bp 110 - 115 °C at ca. 10 mm Hg) was collected as a light yellow, thick oil. Yield: 31.57 g (64percent) as an E/Z mixture. 1H NMR (400 MHz) δ 1.15 - 1.55 (6H, m, isomer 1, +6H, m, isomer 2), 4.09 - 4.44 (4H, m, isomer 1, +4H, m, isomer 2), 7.72 (1H, s, isomer 1), 7.81 (1H, s, isomer 2).
194.6 g
at 100 - 105℃; for 6 h;
The acetic anhydride (367.6 g, 3.6 moles) is heated to 100-105° C., to which a mixture of crude ethyl trifluoroacetoacetate (˜0.96 mole) and triethyl orthoformate (266.8 g, 1.8 moles) is added drop-wise. The reaction mixture is kept at 100-105° C. for 6 hours. The reaction mixture is cooled to 60-70° C. and then concentrated under vacuum to remove excessive acetic anhydride, triethyl orthoformate, and generated ethyl acetate. A pale brown liquid (194.6 g) is obtained. The yield of two steps is 81percent.
Reference：
[1] Journal of medicinal chemistry, 2000, vol. 43, # 21, p. 3995 - 4004
[2] Patent: US2018/170909, 2018, A1, . Location in patent: Paragraph 0824; 0825
[3] Patent: CN106432183, 2017, A, . Location in patent: Paragraph 0031; 0032
[4] Patent: WO2016/151403, 2016, A1, . Location in patent: Paragraph 00520
[5] Journal of Molecular Structure, 2018, vol. 1171, p. 631 - 638
[6] Tetrahedron Letters, 2017, vol. 58, # 8, p. 744 - 747
[7] Patent: CN107501182, 2017, A, . Location in patent: Paragraph 0032; 0033; 0040; 0047; 0054; 0061; 0068
[8] Journal of Organic Chemistry, 2012, vol. 77, # 1, p. 47 - 56
[9] Patent: US2010/305124, 2010, A1, . Location in patent: Page/Page column 16
[10] Journal of Fluorine Chemistry, 2012, vol. 136, p. 38 - 42
[11] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 10, p. 2877 - 2881
[12] Journal of the American Chemical Society, 1951, vol. 73, p. 3684
[13] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2008, vol. 63, # 4, p. 351 - 362
[14] Patent: US2010/69646, 2010, A1, . Location in patent: Page/Page column 8
[15] Molecules, 2012, vol. 17, # 12, p. 14205 - 14218
[16] Molecules, 2015, vol. 20, # 3, p. 4383 - 4394
[17] Patent: US2015/158808, 2015, A1, . Location in patent: Paragraph 0073-0074
[18] Patent: WO2015/85464, 2015, A1, . Location in patent: Paragraph 70
[19] Patent: CN105601618, 2016, A, . Location in patent: Paragraph 0029
[20] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 21, p. 5203 - 5206
[21] Chinese Chemical Letters, 2017, vol. 28, # 1, p. 121 - 125
[22] Chinese Chemical Letters, 2017, vol. 28, # 2, p. 253 - 256
[23] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 4, p. 2319 - 2325
[24] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 1, p. 325 - 330
[25] Patent: CN106317025, 2017, A, . Location in patent: Paragraph 0023; 0028; 0029
30
[ 372-31-6 ]
[ 571-55-1 ]
Yield
Reaction Conditions
Operation in experiment
92.6%
for 6 h; Reflux
A solution of ethyl trifluoroacetoacetate (0.036 mol)Triethyl orthoformate (0.059 mol) and acetic anhydride (0.108 mol) were added to a 100 ml three-necked flask,Reflux reaction for 6 hours,After the completion of the reaction with a vacuum pump distillation,A fraction of 98 to 105 ° C was collected,To give 7.4 g of a pale yellow oily liquid in a yield of 92.6percent.
Reference：
[1] Patent: CN106336379, 2017, A, . Location in patent: Paragraph 0035; 0036
31
[ 122-51-0 ]
[ 372-31-6 ]
[ 571-55-1 ]
Yield
Reaction Conditions
Operation in experiment
56%
at 120℃; for 24 h; Reflux
A mixture of 18.4 g (0.1 mol) of ethyl trifluoroacetoacetate, 60 g (0.4 mol) of ethyl orthoformate was refluxed at 120 °C for 24 hours, providing the removal of volatile products from reaction mixture. The liquid remaining in the flask was distilled in vacuum. The first fraction (13.5 g, 56 percent yield) contained ethyl ethoxymethylenetrifluoroacetoacetate as a colorless liquid collected at 130-132 °C/10 Torr. The second fraction (10 g, 30 percent) as yellow liquid of compound 3 was collected at 157-159 °C/10 Torr. NMR data of compound 3: 1H NMR (500 MHz, CDCl3): δ 1.25 (t, 3H, CH3, 3JHH = 7 Hz), 1.34 (t, 6H, 2CH3, 3JHH = 7 Hz), 3.84 and 3.93 (both m, 2H, CH2O), 4.30-4.35 (m, 4H, 2CH2), 6.17 (s, 1H, CHO), 7.61 (s, 1H, CH). 19F NMR (376 MHz, CDCl3/C6F6): δ 95.1 (s, CF3). 13C NMR (125 MHz, CDCl3): δ 13.75, 14.12, 14.88, 61.28, 61.98, 65.56, 96.13, 110.48, 119.16 (q, 1JCF = 275 Hz), 119.46, 130.59, 147.55 (q, 2JCF = 38 Hz), 163.34, 163.40. HRMS calcd for C14H18F3O6 [M+H]+ 339.1050; found 339.1050.
Reference：
[1] Patent: CN106234374, 2016, A, . Location in patent: Paragraph 0029
33
[ 372-31-6 ]
[ 400-36-2 ]
Yield
Reaction Conditions
Operation in experiment
46 %Spectr.
With sulfuric acid In n-heptane; water at 90 - 140℃; for 2.5 h;
aqueous sulfhric acid (98 wt-percent, 5.13 ml, 94.3 mmol), and n-hexane (25 ml) were mixed at ambient pressure and at ambient temperature, after the mixing the resulting mixture was heated with an oil bath to 90°C, the time from mixing until the 90°C were reached was 10 mm. Then, within 20 mm, the temperature of the oil bath was increased to 110°C, while nhexane was continuously distilled off and fresh n-hexane (83 ml) was added dropwise to thereaction mixture. Then the reaction mixture was stirred for 2 h at 110°C.1H and 19F NMR of the distillate indicated a yield of 42percent of compound of formula (1) in formof a solution in n-hexane.The amount of compound of formula (2) is lower than 5percent.No residual sulfhric acid was detected in the product. Example 1 was repeated with two differences: with n-heptane instead of n-hexane and withheating from 90°C to 140°C instead of 90°C to 110°C in the oil bath.The yield of compound of formula (1) was 46percent in form of a solution in n-heptane.The amount of compound of formula (2) is lower than 5percent.No residual sulfuric acid was detected in the product.
Reference：
[1] Bulletin de la Classe des Sciences, Academie Royale de Belgique, 1926, vol. <5> 12, p. 691,718[2] Chem. Zentralbl., 1927, vol. 98, # I, p. 1287
[3] Patent: WO2016/23929, 2016, A1, . Location in patent: Page/Page column 10; 11; 12
With sulfuric acid; sodium hydrogencarbonate In chloroform
EXAMPLE 2 STR5 5-Trifluoromethyl-3-hydroxy-1-methylpyrazole A flask was charged with 6 kg of ether and 6164.2 g (33.5 mol) of ethyl 4,4,4-trifluoroacetoacetate. With stirring 1542.4 g (33.5 mol) methylhydrazine was added. The temperature was maintained at about 24° C. during the addition. After one additional hour of stirring the reaction was complete. Solvent was stripped to remove most of the ether and the residue was then slurried in 12 1 of chloroform with vigorous stirring. To the slurry was added 50 ml of concentrated sulfuric acid and the mixture was stirred overnight. An additional 100 ml of sulfuric acid was added and the slurry was washed once with 3 1 of water and 5 times with 3 1 of 10percent sodium bicarbonate to remove the 5-hydroxy isomer and twice with 3 1 of water. The aqueous layers and undissolved crystals were twice extracted sequentially with 4 1 of chloroform. Chloroform was stripped on a rotary evaporator at 40° C. under vacuum to yield 1405.9 g (25.3percent yield) of a solid, m.p. 130°-131° C.
Reference：
[1] Patent: US4855442, 1989, A,
36
[ 372-31-6 ]
[ 60-34-4 ]
[ 122431-37-2 ]
[ 119022-51-4 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1990, vol. 27, # 2, p. 243 - 245
[2] Journal of Heterocyclic Chemistry, 1990, vol. 27, # 2, p. 243 - 245
37
[ 372-31-6 ]
[ 60-34-4 ]
[ 119022-51-4 ]
[ 128455-64-1 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1990, vol. 27, # 2, p. 243 - 245
38
[ 100-63-0 ]
[ 372-31-6 ]
[ 96145-98-1 ]
Yield
Reaction Conditions
Operation in experiment
98%
at 10 - 80℃; for 6.5 h;
(Reference Example 2) Synthesis of 5-hydroxy-1-phenyl-3-trifluoromethylpyrazole: Ethyl 4,4,4-trifluoroacetoacetate (18.4 g (0.1 mol)) was dissolved in 12.0 g (0.2 mol) of acetic acid. The resulting solution was cooled to 10°C or less with stirring, and 11.8 g (0.11 mol) of phenylhydrazine was added dropwise thereto over 0.5 hours. After the dropwise addition, the solution was stirred at room temperature for 1 hour and subsequently at 80°C for 5 hours. When the reaction was completed, the reaction solution was cooled to room temperature, and 100 mL of water was added thereto. The produced crystal was collected by filtration, washed twice with 50 mL of water and dried by a hot air drier to obtain 22.3 g (yield: 98.0percent) of the title compound as a pale yellow crystal. LC-MS(EI): m/z=228 (M+), melting point: 190-192°C.
92%
for 12 h; Reflux
Ethyl 4, 4, 4-1rifluoro3-oxobutanoate (S3, 200 p1., 1.37 mmoi, I equiv) and phenyihydrazine (148 IrL. 1.37 inmol, 1.00 equiv) were dissolved in ethanol (1.4 mL) and the resulting mixture was stirred for 12 hours at reflux. The reaction mixture was cooled to 24 c and the solvent was evaporated in vacuo. The residue was dissolved into ethyl acetate (3 mL) and washed with IN HCI (3 x 3 mL). The organic layer was dried over sodium sulfate, filtrated and concentrated in vacuo. The resulting material was washed with dichloromn ethane (5 mL) to afford the compound as orange solid (289 mg, 92percent).Rf 0.25 (30percent ethyl acetate—hexanes; UV). ‘HNMR (500 MHz, DMSOd6): d 7.71 (d, 2H, H2, J = 8.0 Hz), 7.51 (dd, 2H, J = 8.0 Hz, H3), 7.38 (t, IH, J = 8.0 Hz, H4), 5.94 (s, 1Ff, H,). ‘3C NMR (125 MHz, DMSOd6): ö 153.7 (C), 140.4 (q, 2JCF 37.4 Hz, C), 137.7 (C), 129.1 (CH), 127.2 (CH), 122.3 (CH), 121.3 (q, IJCF 266.9Hz, CF3), 85.6 (q, 3JCF =1.6 Hz, CH). ‘9F NMR (375 MHz, DMS&-do): 61.8. IR (ATR.FTIR), cm”1: 3373 (br),1599 (in), 1505 (in), 1491 (m), 1456 (m), 1407(m), 1151 (s), 1119 (s), 984 (s), 758 (s), 691(s). HRMSESI (m/z): [M+H1 calculated for C10H8F3N50, 229.0583; found, 229.0598.
87.9%
With hydrogenchloride In ethanol; water for 1 h; Heating / reflux
20 g (184.9 mmoles) of phenylhydrazine and 4 ml of concentrated hydrochloric acid were added to a solution of 34.1 g (184.9 mmoles) of ethyl trifluoroacetoacetate dissolved in 500 ml of ethanol. The mixture was refluxed for 1 hour with heating, to give rise to a reaction. After the completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove the most part of the solvent contained therein. The residue was mixed with water to precipitate crystals. The crystals were collected by filtration, washed with water until the filtrate became neutral, and dried to obtain 37.1 g (yield: 87.9percent) of 1-phenyl-3-trifluoromethyl-1H-pyrazol-5-ol as ocherous crystals. 1H-NMR [CDCl3/TMS, δ (ppm) ]:
7.68-7.41 (5H,m), 5.86 (1H,s), 3.71 (1H,s)
87.9%
With hydrogenchloride In ethanol for 1 h; Heating / reflux
REFERENCE EXAMPLE 9 Production of 1-phenyl-3-trifluoromethyl-1H-pyrazol-5-ol; 20 g (184.9 mmoles) of phenylhydrazine and 4 ml of concentrated hydrochloric acid were added to a solution of 34.1 g (184.9 mmoles) of ethyl trifluoroacetoacetate dissolved in 500 ml of ethanol. The mixture was refluxed for 1 hour with heating, to give rise to a reaction. After the completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove the most part of the solvent contained therein. The residue was mixed with water to precipitate crystals. The crystals were collected by filtration, washed with water until the filtrate became neutral, and dried to obtain 37.1 g (yield: 87.9percent) of 1-phenyl-3-trifluoromethyl-1H-pyrazol-5-ol as ocherous crystals. 1H-NMR [CDCl3/TMS, δ (ppm)]: 7.68-7.41 (5H,m), 5.86 (1H,s), 3.71 (1H,s)
72%
at 110℃;
Phenylhydrazine (433 mg, 4 mmol) and ethyl 4,4,4-trifluoroacetoacetate(736 mg, 4 mmol) were dissolved in glacial aceticacid. The reaction mixture was stirred at 110 C until TLC (hexane/EtOAc 1:1) showed complete consumption of the startingmaterial. Upon cooling a white solid precipitated from the solutionand was filtered and washed with ice-cold ethanol. Purification byflash column chromatography afforded the title compound as awhite solid (652 mg, 2.86 mmol, 72percent). 1H NMR (400 MHz, DMSOd6,ppm) d: 5.94 (s, 1H), 7.39 (t, J = 8.0 Hz, 1H), 7.52 (t, J = 8.0 Hz,2H), 7.71 (d, J = 8.0 Hz, 2H), 12.49 (s, 1H) ppm; 13C NMR (100MHz, DMSO-d6, ppm) d: 85.6, 121.3 (q, 1JCF = 267 Hz), 122.3,127.2, 129.1, 137.7, 140.4 (d, 2JCF = 37 Hz), 153.7 ppm.
71.8%
at 10 - 80℃; for 6.5 h;
(Reference Example 2) Synthesis of 5-hydroxy-1-phenyl-3-trifluoromethylpyrazole 18.4 g (0.1 mole) of ethyl 4,4,4-trifluoroacetoacetate was dissolved in 12.0 g (0.2 mole) of acetic acid. The solution was cooled to 10°C or lower with stirring. Thereto was dropwise added, in 0.5 hour, 11.8 g (0.11 mole) of phenylhydrazine. After the dropwise addition, the mixture was stirred at room temperature for 1 hour and successively at 80°C for 5 hours to give rise to a reaction. After the reaction, the mixture was cooled to room temperature. Thereto were added 100 ml of water. The resulting crystals were collected by filtration, washed with 50 ml of water twice, and dried in a hot-air drier, to obtain 22.3 g (yield: 98.0percent) of a title compound as light yellow crystals.
67%
With toluene-4-sulfonic acid In ethanol for 24 h; Reflux
Ethyl 4,4,4-trifluoro-3-oxobutanoate (5 mmol0.92 g), phenylhydrazine (5 mmol, 0.55 g) and 4-toluene sulfonic acid (TsOH,1 mmol, 0.17 g) were refluxed in 25 mL ethanol for 24 h. After cooling the reaction mixture, ethanol was evaporated and the residue was extracted with ethyl acetate (20 mL 3). The combined organic layer was then washed with sodium bicarbonate solution and dried with MgSO4. The crude product was purified through column chromatography. Compound 3 was obtained in 67percent yield. Ketoenol tautomerism of compound 3 was existed as data showed from 1H, 13C NMR spectra. 1H NMR (500 MHz, acetone-d6) δ: 11.04(s, 1H, OH), 7.82 (d, J 8.0 Hz, 2H), 7.51 (t, J 7.5 Hz, 2H), 7.37 (t,J 7.5 Hz, 1H) ppm. 13C NMR (125 MHz, acetone-d6) δ: 206.6, 153.9,142.5 (q, 2JC-F 37.5 Hz) 139.1, 129.8, 128.0, 123.2122.3 (q,1JC-F 266.5 Hz, CF3), 86.7 ppm. 19F NMR (470 MHz, acetone-d6) δ: 63.66 (s, CF3) ppm.
Reference：
[1] Patent: EP1767528, 2007, A1, . Location in patent: Page/Page column 11-12
[2] Journal of the American Chemical Society, 2018, vol. 140, # 12, p. 4259 - 4268
[3] Patent: WO2018/226828, 2018, A2, . Location in patent: Paragraph 0220; 0221; 0222
[4] Patent: EP1364946, 2003, A1, . Location in patent: Page/Page column 192
[5] Patent: US2005/256004, 2005, A1, . Location in patent: Page/Page column 28
[6] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 11, p. 2973 - 2983
[7] Patent: EP1990336, 2008, A1, . Location in patent: Page/Page column 12
[8] Dyes and Pigments, 2015, vol. 121, p. 138 - 146
[9] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 5, p. 1189 - 1192
[10] Medicinal Chemistry Research, 2014, vol. 23, # 1, p. 158 - 167
39
[ 59-88-1 ]
[ 372-31-6 ]
[ 96145-98-1 ]
Yield
Reaction Conditions
Operation in experiment
81%
With potassium carbonate In ethanolReflux
General procedure: A 3.9 g, 27 mmol of phenylhydrazine hydrochloride was added to 27 mmol of the corresponding ethyl 4-polyfluoroalkyl-3-oxo ester and 3.9 g, 30 mmol of K2CO3. The mixture was refluxed in 50 ml of ethanol for 3–4 h. The solvent was removed in vacuo. The precipitate was isolated and washed with water and hexane.
Reference：
[1] Journal of Fluorine Chemistry, 2018, vol. 206, p. 72 - 81
[2] Journal of Heterocyclic Chemistry, 2016, vol. 53, # 3, p. 754 - 761
40
[ 372-31-6 ]
[ 96145-98-1 ]
Yield
Reaction Conditions
Operation in experiment
79%
With hydrogenchloride; phenylhydrazine In methanol
(b) A mixture of 44 ml (0.3 mol) of ethyl trifluoroacetoacetate and 33 mL (335.4 mmol) of phenylhydrazine in 60 ml of methanol containing 6 ml of conc. HCl solution was refluxed with stirring for 1.5 hours. After adding activated charcoal with stirring, the hot mixture was filtered. The residue was washed with methanol (2*70 ml), diluted with water, and the resulting white solid was filtered. The solid was washed with hexane and dried to afford 54.3 g (79percent) of 1-phenyl-3-trifluoromethyl-5-hydroxypyrazole as a pale solid.
Reference：
[1] Patent: US5750550, 1998, A,
41
[ 372-31-6 ]
[ 344-72-9 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1985, vol. 22, p. 1621 - 1630
[2] Journal of Heterocyclic Chemistry, 1991, vol. 28, # 4, p. 907 - 911
[3] Journal of Heterocyclic Chemistry, 1991, vol. 28, # 4, p. 907 - 911
[4] Patent: WO2014/167444, 2014, A1,
[5] Journal of Heterocyclic Chemistry, 2016, vol. 53, # 1, p. 183 - 187
[6] Patent: CN102942565, 2016, B,
[7] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 2, p. 1625 - 1629
[8] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 6, p. 3395 - 3402
42
[ 17356-08-0 ]
[ 372-31-6 ]
[ 344-72-9 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 23, p. 6171 - 6182
43
[ 122-51-0 ]
[ 372-31-6 ]
[ 60-34-4 ]
[ 111493-74-4 ]
Reference：
[1] Patent: CN107935929, 2018, A, . Location in patent: Paragraph 0024; 0032-0034
[2] Patent: CN108719301, 2018, A, . Location in patent: Paragraph 0013; 0014; 0015
44
[ 372-31-6 ]
[ 111493-74-4 ]
Reference：
[1] Molecules, 2012, vol. 17, # 12, p. 14205 - 14218
[2] Molecules, 2015, vol. 20, # 3, p. 4383 - 4394
[3] Patent: CN106234374, 2016, A,
[4] Patent: CN106336409, 2017, A,
[5] Patent: CN106986827, 2017, A,
[6] Patent: CN107033083, 2017, A,
[7] Patent: CN106317025, 2017, A,
[8] Patent: CN106749024, 2017, A,
[9] Journal of Molecular Structure, 2018, vol. 1171, p. 631 - 638
45
[ 372-31-6 ]
[ 60-34-4 ]
[ 1481-02-3 ]
Yield
Reaction Conditions
Operation in experiment
85.8%
at 50℃; for 5 h;
0.1 ml of methyl hydrazine and 250 mL three-necked flask, add 10 mL of anhydrous ethanol, stirring heated to 50 C , dropwise 0. 1moL ethyl trifluoroacetoacetate, heating reflux 5 h, cooling crystallization , Vacuum filtration, drying, in a yellow solid; Yield: 85.8percent.
Reference：
[1] Patent: CN103951663, 2016, B, . Location in patent: Paragraph 0091; 0092; 0093
[2] Australian Journal of Chemistry, 2010, vol. 63, # 5, p. 785 - 791
46
[ 372-31-6 ]
[ 2440-60-0 ]
[ 175354-56-0 ]
Reference：
[1] Journal of Medicinal Chemistry, 1996, vol. 39, # 8, p. 1720 - 1728
47
[ 372-31-6 ]
[ 187035-79-6 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 18, p. 2573 - 2577
48
[ 62-53-3 ]
[ 372-31-6 ]
[ 25199-84-2 ]
Yield
Reaction Conditions
Operation in experiment
46.5%
Stage #1: at 110℃; for 1 h; Stage #2: With sulfuric acid In water at 90℃; for 1 h;
A mixture of aniline (9.30 g, 100 mmol) and ethyl 4,4,4-trifluoro-3-oxobutanoate (36.8 g, 200 mmol) was stirred at 110 °C for 1 hour. The reaction mixture was concentrated under reduced pressure, and then diluted with water (20 mL). Conc. H2S04 (110 g, 1.13 mol) was added carefully and the mixture stirred at 90°C forhour, then cooled to room temperature and poured into ice water (500 mL). The precipitate was collected by filtration, and then recrystallised from ethanol (50 mL) to give the title compound (9.90 g, 46.5percent yield) as a white solid. ‘H NMR (400 MHz, DMSO-d6): 12.34 (bs, 1H), 7.75 (m, 2H), 7.45 (d, 1H), 7.32 (m, 1H), 6.99 (s, 1H). MS mlz 214.20 [M+Hjt
Reference：
[1] Synthesis, 2003, # 13, p. 2005 - 2010
[2] Patent: WO2018/165385, 2018, A1, . Location in patent: Paragraph 00362
[3] European Journal of Organic Chemistry, 2003, # 11, p. 2115 - 2121
[4] Patent: US2012/214803, 2012, A1, . Location in patent: Page/Page column 172
[5] Patent: US2008/275057, 2008, A1, . Location in patent: Page/Page column 86
49
[ 372-31-6 ]
[ 208517-35-5 ]
Reference：
[1] Synthesis, 2005, # 16, p. 2751 - 2757
50
[ 122-51-0 ]
[ 372-31-6 ]
[ 57-13-6 ]
[ 154934-97-1 ]
Yield
Reaction Conditions
Operation in experiment
72%
Stage #1: at 80℃; for 4 h; Stage #2: With sodium ethanolate In ethanol at 20℃; for 2.25 h; Stage #3: With acetic acid In ethanol at 20 - 30℃;
Under nitrogen atmosphere, urea (2.9 g, 0.05 mol), ethyl 4,4,4-trifluoro-3-oxobutyrate (8.9 g, 0.05 mol) and triethyl orthoformate (7.9 g, 0.05 mol) were dissolved in ethanol (10 mL) and the EPO <DP n="7"/>solution was heated to 80 °C for 4 h. Then the reaction mixture was cooled to 20 °C and sodium ethoxide solution (21 wt.percent in ethanol, 16.9 g, 0.05 mol) was added under stirring at the same temperature over 15 min. The reaction mixture was stirred for 2 h, followed by addition of water (75 niL) and acetic acid (2 mL) at 20 to 30 °C. The resulting slurry was filtered and the filter cake was washed with water (20 mL) and dried at 45 °C. Yield: 8.2 g (72percent) white solid1H NMR (400 MHz, (CD3)2SO): δ = 8.69 (s, IH), 4.24 (q, J= 7.1 Hz, 2H), 1.28 (t, J= 7.1 Hz, 3H). 13C NMR (100 MHz, (CD3)2SO): δ = 161.4, 158.7 (q, J= 35 Hz), 155.5, 154.7, 119.2 (q, J= 278 Hz), 105.7, 61.3, 13.7.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 18, p. 2573 - 2577
52
[ 372-31-6 ]
[ 371-40-4 ]
[ 328956-08-7 ]
Reference：
[1] European Journal of Organic Chemistry, 2003, # 11, p. 2115 - 2121
53
[ 62-55-5 ]
[ 372-31-6 ]
[ 117724-63-7 ]
Yield
Reaction Conditions
Operation in experiment
90.8%
Stage #1: at 30℃; for 2.5 h; Large scale Stage #2: With tri-n-propylamine In acetonitrile at 30 - 40℃; for 4 h; Large scale
(1) into a chain130 kg of acetonitrile into the reactor,32 kg of thioacetamide was added with stirring,90 kg of ethyl trifluoroacetoacetate was added dropwise at 30 ° C,Drop finished,Continue to maintain the chain reaction for 2.5 hours. (2) to form a ringAfter the completion of the chain reaction,120 kg of tri-n-propylamine was added dropwise at 30 ° C,Dropping time for 1 hour,Drop finished,The temperature was raised to 70 ° C for 3 hours to form a ring-forming reaction. (3) hydrolysisAfter the ring-forming reaction,The acetonitrile, water and tri-n-propylamine were separated by vacuum distillation,Respectively, with water acetonitrile fraction and tri-n-propylamine fraction. After acetonitrile and tri-n-propylamine were removed,The reaction solution was cooled to 30 ° C,Add 45percent NaOH alkaline solution 93kg,The temperature was raised to 55 ° C for 1 hour to carry out hydrolysis reaction.(4) acidificationAfter the hydrolysis reaction is complete,Cooling to 40 ,30percent hydrochloric acid was added dropwise for acidification,Transferred to pH = 1-2, and then continue to cool to 0 ,Add 200kg of water,Stirring for 0.5 hours,Filter,Centrifugal,The filter cake is dried and dried2-methyl-4-trifluoromethyl-5-thiazolecarboxylic acid 82.0 kg,Content of 95.3percent,Yield 90.8percent (based on ethyl trifluoroacetoacetate).The raw materials used in the preparation are commercially available.
Reference：
[1] Patent: CN106349183, 2017, A, . Location in patent: Paragraph 0029-0047
54
[ 372-31-6 ]
[ 75-05-8 ]
[ 117724-63-7 ]
Yield
Reaction Conditions
Operation in experiment
85.05%
Stage #1: at 0 - 25℃; Stage #2: for 3 h; Reflux Stage #3: at 25 - 35℃;
Step 1: In a four-necked reaction flask equipped with a mechanical stirrer, thermometer and air duct, 92 gTrifluoroacetoacetate, 230 g of acetonitrile and 2.24 g of KOH, and the mixture was cooled in an ice bath to 0 to 25 ° C,Slowly enter the 39.4 g of chlorine and 21 g of hydrogen sulfide gas, ventilation time of about 3-5h. After the completion of access to the gas insulation reaction 1h, and then blow off the generated hydrogen chloride gas, excessive chlorine and hydrogen sulfide gas.Step 2: To the above reaction, dropwise add 112g of triethylamine. After adding dropwise, the mixture is heated to reflux and refluxed for 3 hours. The resulting triethylamine hydrochloride is filtered and the filtrate is distilled to recover the solvent.Step 3: temperature control 25-35 , dropping 30percent sodium hydroxide solution 170g, insulation reaction 2 ~ 3h.Step four: 180g 30percent hydrochloric acid solution for acidification, a large number of white precipitate precipitation. After the completion of the dropwise addition, the reaction was allowed to proceed for 1 h, followed by filtration and drying to obtain 92.55 g of the substance, content: 97.02percent, yield: 85.05percent.
Reference：
[1] Patent: CN106316978, 2017, A, . Location in patent: Paragraph 0010; 0011; 0012; 0013; 0014; 0015; 0016-0029
55
[ 122-51-0 ]
[ 372-31-6 ]
[ 155377-19-8 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 7, p. 2785 - 2795
[2] Patent: EP1845081, 2007, A1,
With 1,8-diazabicyclo[5.4.0]undec-7-ene In ethanol at 70 - 80℃;
To a three-necked flask was added ethyl trifluoroacetoacetate (0.16 mL, 1.0 eq.),DBU (0.19 mL, 1.2 eq.),Add absolute ethanol (10 mL) to dissolve.A solution of formamidine hydrochloride in ethanol (0.09 g of formamidine hydrochloride in 2 mL of ethanol,The amount of formamidine hydrochloride1.05 eq.).Dropping the temperature to 70-80 ° C for 3 to 5 hours.TLC monitoring,The reaction was complete.The solvent was distilled off under reduced pressure,Diluted with water (20 mL)With 1mol / L hydrochloric acid adjusted pH = 6 ~ 7,Extraction with ethyl acetate (3 x 8 mL)The organic phase was combined with anhydrous sulfuric acidSodium drying, filtration, vacuum distillation of the solvent was light yellow solid, add petroleum ether (5mL) shock, filter, filter cake washed with petroleum ether,The oven was dried at 55 ° C for 2 hours to give a pale yellow flake solid in 96percent yield.
Reference：
[1] Patent: CN106188013, 2016, A, . Location in patent: Paragraph 0012; 0013; 0019
With toluene-4-sulfonic acid In toluene for 38 h; Heating / reflux
A mixture of ethyl 4,4, 4-trifluoroacetoacetate (14.7 mL, 0.1 mol, 1.6 eq), acrylamide (4.5 g, 0.063 mol, 1.0 eq) and p-toluenesulphonic acid (0.156 g, 0.82 mmol, 0.013 eq) in toluene (60 mL) was refluxed for 38 h with azeotropic removal of water (Dean-Stark conditions). The reaction mixture was then concentrated to a small volume, by slow distillation of toluene at atmospheric pressure. Toluene (60 mL) was-added and again the reaction mixture was concentrated, through slow distillation of toluene. Afier repeating this operation three times, the reaction mixture was concentrated in vacuo and the solid residue was purified by flash chromatography (silica gel, eluent gradient: from hexane/ethyl acetate 9: 1 to hexane/ethyl acetate 8: 2). The title compound was obtained as a brownish solid (3.8 g, yield = 25percent). LC-MS (ESI+), MH+ : 238,210, 190.; Description 33: 6-Hydroxy-2-trifluoromethyl-4, 5-dihydro-pyridine-3-carboxylic acid ethyl ester A mixture of ethyl 4,4, 4-trifluoroacetoacetate (14.7 mL, 0.1 mol, 1.6 eq), acrylamide (4.5 g, 0.063 mol, 1.0 eq) and p-toluenesulphonic acid (0.156 g, 0.82 mmol, 0.013 eq) in toluene (60 mL) was refluxed for 38 h with azeotropic removal of water (Dean-Stark conditions). The reaction mixture was then concentrated to a small volume, by slow distillation of toluene at atmospheric pressure. Toluene (60 mL) was added and again the reaction mixture was concentrated, through slow distillation of toluene. After repeating this operation three times, the reaction mixture was concentrated in vacuo and the solid residue was purified by flash chromatography (silica gel, eluent gradient: from hexane/ethyl acetate 9: 1 to hexane/ethyl acetate 8: 2). The title compound was obtained as a brownish solid (3.8 g, yield = 25percent). LC-MS (ESI+), MH+ : 238,210, 190.
25%
With toluene-4-sulfonic acid In toluene for 38 h; Heating / reflux
A mixture of ethyl 4,4, 4-trifluoroacetoacetate (14.7 mL, 0.1 mol, 1.6 eq), acrylamide (4.5 g, 0.063 mol, 1.0 eq) and p-toluenesulphonic acid (0.156 g, 0.82 mmol, 0.013 eq) in toluene (60 mL) was refluxed for 38 h with azeotropic removal of water (Dean-Stark conditions). The reaction mixture was then concentrated to a small volume, by slow distillation of toluene at atmospheric pressure. Toluene (60 mL) was added and again the reaction mixture was concentrated, through slow distillation of toluene. After repeating this operation three times, the reaction mixture was concentrated in vacuo and the solid residue was purified by flash chromatography (silica gel, eluent gradient: from hexane/ ethyl acetate 9: 1 to [HEXANE/ETHYL] acetate 8: 2). The title compound was obtained as a brownish solid (3.8 g, yield = 25percent). LC-MS [(ESI+),] MH+: 238,210, 190.
25%
With toluene-4-sulfonic acid In toluene for 38 h; Heating / reflux
A mixture of ethyl 4,4,4-trifluoroacetoacetate (14.7 ml, 0.1 mol, 1.6 eq), acrylamide (4.5 g, 0.063 mol, 1.0 eq) and p-toluenesulphonic acid (0.156 g, 0.82 mmol, 0.013 eq) in toluene (60 ml) was refluxed for 38 h with azeotropic removal of water (Dean-Stark conditions). The reaction mixture was then concentrated to a small volume, by slow distillation of toluene at atmospheric pressure. Toluene (60 ml) was added and again the reaction mixture was concentrated, through slow distillation of toluene. After repeating this operation three times, the reaction mixture was concentrated in vacuo and the solid residue was purified by flash chromatography (silica gel, eluent gradient: from hexane/ethyl acetate 9:1 to hexane/ethyl acetate 8:2). The title compound was obtained as a brownish solid (3.8 g, yield = 25percent). LC-MS (ESI+), MH+: 238, 210, 190
With sodium ethanolate; In ethanol; at 20 - 90℃; for 24.0h;Inert atmosphere;
To a stirred solution of ethyl 4.4,44rifluoro-3-oxobutanoate 101 (3 g. 1 &30 nim-ol) in ethin.iol (30 mL) under argon atmosphere were added urea 102- (978 mg, 16.30 mmol) and freshly prepared sodium ethoxide (750 mg of Na in 30 mL of EtOH) at Pt; the mixture was heated to 90 C and stirred for 24 h. The reaction was monitored by TIE; after completion of the reaction, the volati Ic-s were removed in vacua, diluted with water (25 mL), acidified with 1 N SC1 UO niL) and extracted with EtOAc (2 x 40 niL). The comb med organic extracts were dried over sodium sulfate, filtered and concentrated in vacua to afford compound 103 (650 mg, 22%) as a white solid. TL-C: 5% CH3OR CK2CI2 (1?,: 0.3); ?H-NMR (DMSO-%, 500 MHz): 6 1107 (s. 114), i1.54(s. iS). 6.07 (s, 1H
General procedure: Iodine (25 mol%) was added into a mixture of 3-alkoxyphenol (5 mmol) and ethyl 4,4,4-trifluoroacetoacetate (6 mmol) in toluene(1 mL). The reaction was heated at 90C and stirred for a period of 18 hours and monitored by TLC. Upon completion, the reaction mixture was cooled to room temperature, diluted with 10 mL of ethyl acetate, and washed with 10 mL of distilled water. The combined organic layers were dried over anhydrous sodium sulfate and the solvent removed under vacuum. Purification of the product was performed via flash chromatography (silica gel, hexane/ethyl acetate = 95/5 to80/20).
88.9%
With sulfuric acid; In ethanol; at 80℃;
Concentrated sulfuric acid (2 mL) and trifluoroacetoacetate (3.7 g, 10 mmol) were added dropwisein turn to the solution of resorcinol (2.2 g, 10 mmol) in ethanol (4 mL) with stirring. Then the mixture was heated to maintain at 80 C until the end of the reaction was detected by TLC. The resulted thickmagenta liquid was dripped into 10 mL of cold water with rigorous stirring. The precipitate wasfiltered and dried to give compound 1. Yield 88.9%, m.p. (melting point) 175-176 C [lit. (literature)178-179 C] [54].
87%
With sulfuric acid; at -40 - 0℃; for 2.5h;
Resorcinol (2 g, 18.2 mmol) was carefully dissolved in conc. H2SO4 (3 mL) under -40C, and the appropriate ethyl trifluoroacetoacetate (3.0 mL, 20.5 mmol) was added. After stirring for 1 h, the mixture was gradually warmed to 0 C and stirred for another 1.5 h. When the reaction was complete, the reaction mixture was poured into ice/water (20 mL), and the precipitate was recovered by filtration and washed with water to obtain the desired compound 12g as white needle crystal.
79.4%
With sulfuric acid; at 20℃; for 25h;Cooling with ice;
Resorcinol 0.55g (5mmol) and concentrated sulfuric acid 8.0mL, stirring to dissolve,Under ice-cooling, 0.73 mL (5 mmol) of ethyl 4,4,4-trifluoroacetoacetate was slowly added dropwise under cooling in an ice water bath, and the mixture was stirred for 1 h under ice-cooling in an ice-water bath. The reaction was performed at room temperature for 24 h. Into a lot of ice water with vigorous stirring,A precipitate generated, suction filtration, cake with anhydrous ethanol recrystallization,0.91 g of 7-hydroxy-4-trifluoromethylcoumarin (A3) was obtained as a white powder in a yield of 79.4%
73.9%
With sulfuric acid; for 18h;Cooling with ice;
1) 30 ml of concentrated sulfuric acid was stirred in an ice bath, to which was added 5.5 g of resorcinol and was added 9.2 g of trifluoro ethyl acetoacetate dropwise. The solution turned yellow from yellowish. The reaction was carried out for 18 hours. The reaction liquid was poured into ice/water mixture, and a lot of solid was precipitated, which was filtrated. The cake was washed with water to neutral. Recrystallization with 75% ethanol gave 8.5 g of white crystal. Melting point: 218-220C, yield: 73.9%.
73.9%
With sulfuric acid; In water; for 18h;
1) 30 ml of concentrated sulfuric acid was stirred in an ice bath, to which was added 5.5 g of resorcinol and was added 9.2 g of trifluoro ethyl acetoacetate dropwise. The solution turned yellow from yellowish. The reaction was carried out for 18 hours. The reaction liquid was poured into ice/water mixture, and a lot of solid was precipitated, which was filtrated. The cake was washed with water to neutral. Recrystallization with 75% ethanol gave 8.5 g of white crystal. Melting point: 218-220 C., yield: 73.9%.
70%
With sulfuric acid; at 10 - 20℃;
General procedure: The other 7,4-disubstituted coumarins, including compounds 8-12, were synthesised by using the Pechmann reaction [3,4], as described elsewhere [38]. In the typical procedure, it was added drop wise 3-susbtituted phenol (0.015 mol) and 2-acetyl ethyl acetate or 2-trifluoroacetyl ethyl acetate (0.013 mol) to 17mL of concentrated sulfuric acid, the mixture being kept at 10 C in an ice bath. This mixture was stirred at room temperature for at least 18 h, and, then, poured in 70 mL of crushed ice. The obtained precipitate was filtered under vacuum, washed subsequently with cold water, and dissolved in a 20-mL 5% sodium hydroxide solution. This solution was filtered, and it was added a 2M sulfuric acid solution to acidify it. The crude product was recuperated by filtration with a water ejector, washed with cold water, dried, and crystallized from 95% ethanol. In all cases, the obtained coumarins were characterized by IR, 1H NMR and 13C NMR spectroscopy [38]. The chemical yields and melting points (m.p.) are presented in Table 1.
55.6%
With sulfuric acid; at 0℃; for 12h;
Thirty mL of concentrated sulfuric acid was placed in a three-necked flask and cooled to 0 C in an ice-salt bath.2. 11.0 g resorcinol and 12mL ethyl trifluoroacetoacetate were mixed under ultrasound hook , to give a mixed solution of both.3. The mixed solution will be dripped into concentrated sulfuric acid under r rapid stirring, drip rate was maintained at one drop per two seconds, to ensure that the system temperature does not exceed 0 C. After the mixed solution was dropped, stirring was continued for 12h.4. After the reaction, the reaction solution was poured into 500mL ice water in a large beaker under rapid stirring, to dilute the concentrated sulfuric acid to the weak acid, which a large number of pink flocs appeared and filtered.
54%
With trifluoroacetic acid; at 100℃; for 0.5h;Microwave irradiation;
Synthesis 7-Hydroxy-4-trifluoromethylcoumarin (1) was synthesized according to a known procedure [50] . Resorcinol (2) (440 mg, 4.00 mmol), ethyl 4,4,4-trifluoroacetoacetate (3) (736 mg, 585 mul, 4.00 mmol), and trifluoroacetic acid (2 ml) were heated in an oven-dried, 10-ml, heavy-walled microwave reaction vessel equipped with a cross-shaped, magnetic stirring bar and closed with a snap cap to 100 C for 30 min in a Discovery microwave (CEM). After cooling to RT, the reaction mixture was slowly added to an ice/water mixture (120 ml, 1:1) under vigorous stirring. The pink precipitate was filtered off, washed with cooled distilled water and dried under reduced pressure. Chromatography on silica gel with PE/EtOAc (8:2) provided the fluorescent dye 1 (497 mg, 2.16 mmol, 54%) as a colorless solid. The analytical data were generally consistent with those reported previously [50,51]. TLC: Rf 0.58 (PE/EtOAc, 1:1); mp: 182 C; IR (ATR, film): 3395 (O-H), 3106, 1893, 1766, 1709 (C=O), 1630, 1607, 1575, 1519, 1494, 1441, 1405, 1362, 1337, 1284, 1214, 1190, 1158, 1120, 1008, 963, 891, 856, 821, 798, 750, 743, 721, 710, 670, 657 cm-1; 1H NMR (DMSO-d6): delta = 6.76 (s, 1 H, 3-H), 6.83 (d, J = 2.4 Hz, 1 H, 8-H), 6.91 (dd, J = 8.9, 2.4 Hz, 1 H, 6-H), 7.56 (dd, J = 8.9, 1.6 Hz, 1 H, 5-H), 10.95 (br s, 1 H, OH) ppm; 13C NMR (DMSO-d6): delta = 103.2 (C-8), 105.3 (C-8a), 112.0 (q, JC-F = 5.8 Hz, C-3), 114.1 (C-6), 121.8 (q, JC-F = 275.8 Hz, C-4), 126.2 (C-5), 139.8 (q, JC-F = 31.9 Hz, C-4a), 156.0 (CF3), 158.9 (C-2), 162.2 (C-7) ppm; 19F NMR (DMSO-d6): delta = -63.6 ppm; HRMS (ESI): calcd. for [C10H6F3O3]+ ([M+H]+): 231.02636; found: 231.02635; Anal.: calcd. for C10H5F3O3: C, 52.19; H, 2.19; found: C, 52.03 +- 0.09; H, 2.23 +- 0.03.
52%
With sulfuric acid; at 0 - 20℃; for 12h;
General procedure: A solution of 1,3-dihydroxybenzene (11.0 g, 100 mmol) in substituted ethyl acetoacetate (100 mmol)was added dropwise to stirring H2SO4 kept at 0 C. After completion of the addition, the reactionmixture was kept stirring for 12 h at room temperature and then poured onto ice-water. The crudeproducts were filtrated and recrystallized from ethanol [18].
With sulfuric acid; In n-heptane; water; at 90 - 140℃; for 2.5h;
aqueous sulfhric acid (98 wt-%, 5.13 ml, 94.3 mmol), and n-hexane (25 ml) were mixed at ambient pressure and at ambient temperature, after the mixing the resulting mixture was heated with an oil bath to 90C, the time from mixing until the 90C were reached was 10 mm. Then, within 20 mm, the temperature of the oil bath was increased to 110C, while nhexane was continuously distilled off and fresh n-hexane (83 ml) was added dropwise to thereaction mixture. Then the reaction mixture was stirred for 2 h at 110C.1H and 19F NMR of the distillate indicated a yield of 42% of compound of formula (1) in formof a solution in n-hexane.The amount of compound of formula (2) is lower than 5%.No residual sulfhric acid was detected in the product. Example 1 was repeated with two differences: with n-heptane instead of n-hexane and withheating from 90C to 140C instead of 90C to 110C in the oil bath.The yield of compound of formula (1) was 46% in form of a solution in n-heptane.The amount of compound of formula (2) is lower than 5%.No residual sulfuric acid was detected in the product.
General procedure: The corresponding beta-ketoester (1 eq.) and NH4OAc (5 eq.) were refluxed in methanol (for 4a-c, eh,j, l) or in mixture benzene-AcOH (5:1) with Dean-Stark trap (for 4d, i, k) for 5-6 hours. Afterremoving of solvents under reduced pressure the residue was extracted with ether, washed withwater, sat. NaHCO3 and brine, dried over CaCl2. Solvent was evaporated to give enamine, whichwas used without purification.
With ammonium acetate; In ethanol; mineral oil; for 8h;Reflux;
2) Synthesis of Compound 4 In 250mLRound-bottom flask was placed50mmol of 4,4,4-trifluoro-ethyl acetoacetate,Join100mL of absolute ethanolStirring,Then added200mmol ammonium acetate.It was heated to reflux for about 8hAfter TLC to detect the disappearance of starting material.The system was introduced into 500mL of water,(100mL × 3) and extracted with dichloromethane,To take lower organic phase,Dried over anhydrous sodium sulfate,The solvent was removed,To give compound 4.
With ammonium acetate; In ethanol; for 8h;Reflux;
Placed in 250mL round bottom flask was 50mmol 4,4,4-trifluoro-ethyl acetoacetate, was added 100mL of absolute ethanol with stirring, and then add 200mmol ammonium acetate. It was heated to reflux for about 8h. after TLC to detect the disappearance of starting material. The system was introduced into 500mL of water, (100mL × 3) and extracted with dichloromethane, and the lower layer organic phase was dried over anhydrous sodium sulfate and then filtered, solvent was removed to give compound 4.
With ammonium acetate; at 65℃; for 3h;
In a 1000 mL four-necked flask, equipped with a mechanical stirrer, a bubble counter, a dosing funnel and a thermometer, was added 200.0 g (98 % purity, 1.06 mol, 1.00 eq) of ethyl 4,4,4-trifluoro-3-oxo- butanoate. After heating to 65 C internal temperature 143.6 g (1.86 mol, 1.75 eq) of ammonium acetate was added portionwise. After further stirring at 65 C for 3 h GC monitoring (GC = gas chromatography) revealed complete conversion. The reaction mixture was then cooled to 22 C and 200 mL of saturated brine were added. The phases were separated and the organic phase was washed with 1 x 200 mL of saturated brine. Consequently, 179.6 g (89% purity, 0.88 mol, 0.83 eq) of ethyl 3 -amino-4, 4, 4-trifluoro- crotonate were obtained as a clear, yellow oil. In a 1000 mL four-necked flask, equipped with a mechanical stirrer, a distillation head with reflux condenser and bubble counter, a dosing funnel and a thermometer the obtained ethyl 3-amino-4,4,4-trifluoro-crotonate was dissolved in 755 mL of sodium methoxide (30 w% in methanol, 2.89 mol, 2.72 eq) at 0 C. Afterwards 117.6 mL (98% purity, 0.96 mol, 0.91 eq) of methyl 2,3-dichloropropionate was dosed over 1.5 h at 0-10 C. The resulting yellow suspension was stirred for further 0.5 h at this temperature until a HPLC measurement indicated complete conversion of starting materials. The suspension was heated to 65-70 C internal temperature and 400 g of methanol were distilled off. Subsequently, 438.8 g of aqueous sodium hydroxide (20 w%, 2.19 mol, 2.06 eq) were dosed slowly to the reaction solution at 70 C within 1.5 h to result in a yellow suspension. From this mixture another 283 g of methanol were distilled off. Then 150 mL of deionized water were added and the suspension was cooled to 0-10 C. The suspension was then treated with 280 mL of aqueous concentrated hydrogen chloride (37 w%) until pH 2 was reached to furnish solid precipitation. The solid was filtered, washed with 6 x 250 mL ice-cold deionized water and dried at 40 C and 10 mbar vacuum to leave 167.6 g (97% purity, 0.79 mol, 74% yield) of a white solid. 1 H-NMR (400 MHz; DMSO-d6) d = 8.09 (d, J= 8.0 Hz, 1H), 6.96 (d, J= 8.0 Hz, 1H).
To 21 g of sodium methoxide (28% methanol solution) , 4 g of <strong>[22007-68-7]2-methylpropionamidine hydrochloride</strong> and 4 g of 4,4,4- trifluoro-3-oxo-butanoic acid ethyl ester were added. This mixture was heated under reflux for 17 hours. The reaction mixture was left standing to cool and then concentrated. To the residue, 10% hydrochloric acid was added. A precipitated crystal was collected by filtration. This crystal was washed with water. This crystal was dissolved in ethyl acetate. This ethyl acetate solution was dried over anhydrous magnesium sulfate and then concentrated. The residue was washed with hexane to obtain 2.8 g of 2- isopropyl-6-trifluoromethylpyrimidin-4-ol . 2-isopropyl-6-trif luoromethylpyrimidin-4-ol1H-NMR: 1.40(d,6H) , 2.98-3.05 (m, IH) , 6.71(s,lH) , 13.03(bs,lH)
A mixture of aniline (9.30 g, 100 mmol) and ethyl 4,4,4-trifluoro-3-oxobutanoate (36.8 g, 200 mmol) was stirred at 110 C for 1 hour. The reaction mixture was concentrated under reduced pressure, and then diluted with water (20 mL). Conc. H2S04 (110 g, 1.13 mol) was added carefully and the mixture stirred at 90C forhour, then cooled to room temperature and poured into ice water (500 mL). The precipitate was collected by filtration, and then recrystallised from ethanol (50 mL) to give the title compound (9.90 g, 46.5% yield) as a white solid. ?H NMR (400 MHz, DMSO-d6): 12.34 (bs, 1H), 7.75 (m, 2H), 7.45 (d, 1H), 7.32 (m, 1H), 6.99 (s, 1H). MS mlz 214.20 [M+Hjt
General Procedure 98: 4-Trifluoromethyl-1H-quinolin-2-one (Intermediate 465)Aniline (7.0 g, 75.3 mmol) and trifluoro ethylacetoacetate (15.4 ml, 105 mmol) were heated at 110 C. for 45 min. The excess ester was removed in vacuo. 75% H2SO4 was added and the mixture was heated at 90 C. for 45 min. After cooling, the mixture was poured onto ice and the resulting precipitate was collected by filtration to give title compound (7.0 g, 44%) which was used in the next step without further purification.MW: 212.15HPLCMS (Method C): [m/z]: 214
With triethylamine; In toluene;Heating / reflux;
To a solution of the ester (5.46 mmol) and triethylamine (101 g, 10.86 mmol) in toluene (5 mL) was added a solution of aniline (6.52 mmol) in toluene (2 mL) at room temperature. The reaction mixture was refluxed until the reaction was complete. After workup, compound 56 was obtained, which was pure enough to be used in the next step.
(Reference Example 2) Synthesis of 5-hydroxy-1-phenyl-3-trifluoromethylpyrazole: Ethyl 4,4,4-trifluoroacetoacetate (18.4 g (0.1 mol)) was dissolved in 12.0 g (0.2 mol) of acetic acid. The resulting solution was cooled to 10C or less with stirring, and 11.8 g (0.11 mol) of phenylhydrazine was added dropwise thereto over 0.5 hours. After the dropwise addition, the solution was stirred at room temperature for 1 hour and subsequently at 80C for 5 hours. When the reaction was completed, the reaction solution was cooled to room temperature, and 100 mL of water was added thereto. The produced crystal was collected by filtration, washed twice with 50 mL of water and dried by a hot air drier to obtain 22.3 g (yield: 98.0%) of the title compound as a pale yellow crystal. LC-MS(EI): m/z=228 (M+), melting point: 190-192C.
92%
In ethanol; for 12h;Reflux;
Ethyl 4, 4, 4-1rifluoro3-oxobutanoate (S3, 200 p1., 1.37 mmoi, I equiv) and phenyihydrazine (148 IrL. 1.37 inmol, 1.00 equiv) were dissolved in ethanol (1.4 mL) and the resulting mixture was stirred for 12 hours at reflux. The reaction mixture was cooled to 24 c and the solvent was evaporated in vacuo. The residue was dissolved into ethyl acetate (3 mL) and washed with IN HCI (3 x 3 mL). The organic layer was dried over sodium sulfate, filtrated and concentrated in vacuo. The resulting material was washed with dichloromn ethane (5 mL) to afford the compound as orange solid (289 mg, 92%).Rf 0.25 (30% ethyl acetate-hexanes; UV). ?HNMR (500 MHz, DMSOd6): d 7.71 (d, 2H, H2, J = 8.0 Hz), 7.51 (dd, 2H, J = 8.0 Hz, H3), 7.38 (t, IH, J = 8.0 Hz, H4), 5.94 (s, 1Ff, H,). ?3C NMR (125 MHz, DMSOd6): oe 153.7 (C), 140.4 (q, 2JCF 37.4 Hz, C), 137.7 (C), 129.1 (CH), 127.2 (CH), 122.3 (CH), 121.3 (q, IJCF 266.9Hz, CF3), 85.6 (q, 3JCF =1.6 Hz, CH). ?9F NMR (375 MHz, DMS&-do): 61.8. IR (ATR.FTIR), cm?1: 3373 (br),1599 (in), 1505 (in), 1491 (m), 1456 (m), 1407(m), 1151 (s), 1119 (s), 984 (s), 758 (s), 691(s). HRMSESI (m/z): [M+H1 calculated for C10H8F3N50, 229.0583; found, 229.0598.
87.9%
With hydrogenchloride; In ethanol; water; for 1h;Heating / reflux;
20 g (184.9 mmoles) of phenylhydrazine and 4 ml of concentrated hydrochloric acid were added to a solution of 34.1 g (184.9 mmoles) of ethyl trifluoroacetoacetate dissolved in 500 ml of ethanol. The mixture was refluxed for 1 hour with heating, to give rise to a reaction. After the completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove the most part of the solvent contained therein. The residue was mixed with water to precipitate crystals. The crystals were collected by filtration, washed with water until the filtrate became neutral, and dried to obtain 37.1 g (yield: 87.9%) of 1-phenyl-3-trifluoromethyl-1H-pyrazol-5-ol as ocherous crystals. 1H-NMR [CDCl3/TMS, delta (ppm) ]: 7.68-7.41 (5H,m), 5.86 (1H,s), 3.71 (1H,s)
87.9%
With hydrogenchloride; In ethanol; for 1h;Heating / reflux;
REFERENCE EXAMPLE 9 Production of 1-phenyl-3-trifluoromethyl-1H-pyrazol-5-ol; 20 g (184.9 mmoles) of phenylhydrazine and 4 ml of concentrated hydrochloric acid were added to a solution of 34.1 g (184.9 mmoles) of ethyl trifluoroacetoacetate dissolved in 500 ml of ethanol. The mixture was refluxed for 1 hour with heating, to give rise to a reaction. After the completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove the most part of the solvent contained therein. The residue was mixed with water to precipitate crystals. The crystals were collected by filtration, washed with water until the filtrate became neutral, and dried to obtain 37.1 g (yield: 87.9%) of 1-phenyl-3-trifluoromethyl-1H-pyrazol-5-ol as ocherous crystals. 1H-NMR [CDCl3/TMS, delta (ppm)]: 7.68-7.41 (5H,m), 5.86 (1H,s), 3.71 (1H,s)
72%
With acetic acid; at 110℃;
Phenylhydrazine (433 mg, 4 mmol) and ethyl 4,4,4-trifluoroacetoacetate(736 mg, 4 mmol) were dissolved in glacial aceticacid. The reaction mixture was stirred at 110 C until TLC (hexane/EtOAc 1:1) showed complete consumption of the startingmaterial. Upon cooling a white solid precipitated from the solutionand was filtered and washed with ice-cold ethanol. Purification byflash column chromatography afforded the title compound as awhite solid (652 mg, 2.86 mmol, 72%). 1H NMR (400 MHz, DMSOd6,ppm) d: 5.94 (s, 1H), 7.39 (t, J = 8.0 Hz, 1H), 7.52 (t, J = 8.0 Hz,2H), 7.71 (d, J = 8.0 Hz, 2H), 12.49 (s, 1H) ppm; 13C NMR (100MHz, DMSO-d6, ppm) d: 85.6, 121.3 (q, 1JCF = 267 Hz), 122.3,127.2, 129.1, 137.7, 140.4 (d, 2JCF = 37 Hz), 153.7 ppm.
71.8%
With acetic acid; at 10 - 80℃; for 6.5h;
(Reference Example 2) Synthesis of 5-hydroxy-1-phenyl-3-trifluoromethylpyrazole 18.4 g (0.1 mole) of ethyl 4,4,4-trifluoroacetoacetate was dissolved in 12.0 g (0.2 mole) of acetic acid. The solution was cooled to 10C or lower with stirring. Thereto was dropwise added, in 0.5 hour, 11.8 g (0.11 mole) of phenylhydrazine. After the dropwise addition, the mixture was stirred at room temperature for 1 hour and successively at 80C for 5 hours to give rise to a reaction. After the reaction, the mixture was cooled to room temperature. Thereto were added 100 ml of water. The resulting crystals were collected by filtration, washed with 50 ml of water twice, and dried in a hot-air drier, to obtain 22.3 g (yield: 98.0%) of a title compound as light yellow crystals.
67%
With toluene-4-sulfonic acid; In ethanol; for 24h;Reflux;
Ethyl 4,4,4-trifluoro-3-oxobutanoate (5 mmol0.92 g), phenylhydrazine (5 mmol, 0.55 g) and 4-toluene sulfonic acid (TsOH,1 mmol, 0.17 g) were refluxed in 25 mL ethanol for 24 h. After cooling the reaction mixture, ethanol was evaporated and the residue was extracted with ethyl acetate (20 mL 3). The combined organic layer was then washed with sodium bicarbonate solution and dried with MgSO4. The crude product was purified through column chromatography. Compound 3 was obtained in 67% yield. Ketoenol tautomerism of compound 3 was existed as data showed from 1H, 13C NMR spectra. 1H NMR (500 MHz, acetone-d6) delta: 11.04(s, 1H, OH), 7.82 (d, J 8.0 Hz, 2H), 7.51 (t, J 7.5 Hz, 2H), 7.37 (t,J 7.5 Hz, 1H) ppm. 13C NMR (125 MHz, acetone-d6) delta: 206.6, 153.9,142.5 (q, 2JC-F 37.5 Hz) 139.1, 129.8, 128.0, 123.2122.3 (q,1JC-F 266.5 Hz, CF3), 86.7 ppm. 19F NMR (470 MHz, acetone-d6) delta: 63.66 (s, CF3) ppm.
A mixture of trfluoroacetoacetic acid ethyl ester (3.68 g, 20 mmol) and 4-hydrazinobenzoic acid hydrochloride (3.77 g, 20 mmol) in ethanol (15 mL) was stirred at 100 C. in a sealed tube for 8 hours. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was triturated with ether/hexane (5:1 v/v) to provide 4-(5-hydroxy-3-trifluoromethyl-pyrazol-1-yl)-benzoic acid ethyl ester (2.67 g, 45% yield) as an off white solid.
To a solution of <strong>[33786-89-9]5-chloro-1,3-phenylenediamine</strong> (15.0 g, 0.105 mol) in 70 mL ethanol was added ethyl 4,4,4-trifluoroacetoacetate (20.4 g, 0.111 mol), then the mixture was heated at reflux for 18 h. The solvent was removed under reduced pressure until the product began to precipitate. The material was allowed to crystallize for 2 h, whereupon it was filtered and rinsed with cold ether to afford 10.9 g (37%) of 5-amino-7-chloro-3,4-dihydro-4-hydroxy-4-(trifluoromethyl)-1H-quinolin-2-one, a tan solid. The filtrate was concentrated until solid began to precipitate and afforded an additional 3.0 g (10%). 1H NMR (400 MHz, acetone-d6) delta11.0 (broad s, 1H), 9.64 (s, 1H), 7.42 (t, 1H, J=8.1), 6.99 (d, 1H, J=8.1), 6.90 (s, 1H), 6.79 (d, 1H, J=8.1).
With hydrogenchloride; phenylhydrazine; In methanol;
(b) A mixture of 44 ml (0.3 mol) of ethyl trifluoroacetoacetate and 33 mL (335.4 mmol) of phenylhydrazine in 60 ml of methanol containing 6 ml of conc. HCl solution was refluxed with stirring for 1.5 hours. After adding activated charcoal with stirring, the hot mixture was filtered. The residue was washed with methanol (2*70 ml), diluted with water, and the resulting white solid was filtered. The solid was washed with hexane and dried to afford 54.3 g (79%) of 1-phenyl-3-trifluoromethyl-5-hydroxypyrazole as a pale solid.
1-(2-pyrimidinyl)-3-trifluoromethyl-5-hydroxypyrazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In water; acetic acid;
(b) A mixture of 2 g (9 mmol) of 2-hydrazinopyrimidine and ethyl trifluoroacetoacetate (2.6 ml; 9.1 mmol) in 10 ml of acetic acid was refluxed for 60 hours with stirring under nitrogen and then cooled. The mixture was concentrated in vacuo, the residue was diluted with 100 ml of water, and the mixture was extracted with ethyl acetate (3*). The combined organic layer was dried over magnesium sulfate, and concentrated in vacuo. The resulting residue was dried in vacuo to afford 700 mg of 1-(2-pyrimidinyl)-3-trifluoromethyl-5-hydroxypyrazole as a red gum.
1-(5-chloro-pyridin-2-yl)-3-trifluoromethyl-5-hydroxy-pyrazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In hexane; acetic acid; ethyl acetate;
(b) A mixture of 1.445 g (10 mmol) of <strong>[27032-63-9]2-hydrazino-5-chloropyridine</strong> and ethyl trifluoroacetoacetate (1.5 ml; 10 mmol) in 5 ml of acetic acid was refluxed overnight with stirring under nitrogen and then cooled. The mixture was concentrated in vacuo, the residue was diluted with ethyl acetate, and the solid mixture was filtered. The filtrate was washed with saturated sodium bicarbonate solution, the aqueous layer was extracted with ethyl acetate, and the combined organic layer was dried over magnesium sulfate. The organic layer was concentrated in vacuo, the residue was purified by flash chromatography (ethyl acetate) and crystallized (from ethyl acetate/hexane followed by hexane) to afford 1.42 g of 1-(5-chloro-2-pyridyl)-3-trifluoromethyl-5-hydroxy-pyrazole as a white solid, m.p. 58-59 C.
B2 (2E/Z, 4E) N-Isobutyl 3-methyl-11-(2-trifluoromethyl-4-quinolinyloxy)undeca-2,4-dienamide Starting from 2-trifluoromethyl-4-chloroquinoline and 1,7-heptanediol. Ethyl trifluoroacetoacetate (3.7 g) and aniline (1.8 ml) were reacted together in polyphosphoric acid according to Joullie et al, J. Med. Chem., 16, 134 (1973), to give 2-trifluoromethyl-4-hydroxyquinoline (1.8 g).
With sulfuric acid; sodium hydrogencarbonate; In chloroform;
EXAMPLE 2 STR5 5-Trifluoromethyl-3-hydroxy-1-methylpyrazole A flask was charged with 6 kg of ether and 6164.2 g (33.5 mol) of ethyl 4,4,4-trifluoroacetoacetate. With stirring 1542.4 g (33.5 mol) methylhydrazine was added. The temperature was maintained at about 24 C. during the addition. After one additional hour of stirring the reaction was complete. Solvent was stripped to remove most of the ether and the residue was then slurried in 12 1 of chloroform with vigorous stirring. To the slurry was added 50 ml of concentrated sulfuric acid and the mixture was stirred overnight. An additional 100 ml of sulfuric acid was added and the slurry was washed once with 3 1 of water and 5 times with 3 1 of 10% sodium bicarbonate to remove the 5-hydroxy isomer and twice with 3 1 of water. The aqueous layers and undissolved crystals were twice extracted sequentially with 4 1 of chloroform. Chloroform was stripped on a rotary evaporator at 40 C. under vacuum to yield 1405.9 g (25.3% yield) of a solid, m.p. 130-131 C.
With sodium methylate; In methanol; ethanol; hexane;
(1) Ethyl trifluoroacetoacetate (29.2g, 0.16mol) and formamidine hydrochloride (12.9g, 0.16mol) were added to ethanol(150ml), and to this was dropwise added sodium methoxide (28% in methanol, 30.9g, 0.16mol) at room temperature, and the resulting mixture was stirred at 50ØC for 2 hours, further refluxed for 13 hours. After cooling, the reaction mixture was evaporated, and brine was added to the residue. The resulting mixture was neutralized with concentrated hydrochloric acid (pH 4), and the crystal separated was filtered, washed with cold water, and dried. Furthermore, the filtrate was extracted with ethyl acetate (3 times), and dried, and then evaporated. The mixed solution of hexane:ethyl acetate=5:1 was added to the residue, and the crystal separated was collected by filtration, then dried to give 4-hydroxy-6-trifluoromethylpyrimidine. Total yield:17.0g 1H-NMR(DMSO-d6) delta: 6.83(1H, s), 8.38(1H, s), 13.15(1H, br s). 19F-NMR(DMSO-d6)delta: -69.99 m.p.:167-169 ØC
As shown in Scheme 1, to a 250 mL round-bottomflask, trifluoroacetoacetate (0.05 mol), acetamidine hydrochloride (0.05 mol), sodium methoxide (0.075 mol),and ethanol (100 mL) were added and refluxed for 10 h. After that, the mixture was acidified with 1 mol/L HCl to pH 7. The crude products were extracted using ethylacetate to produce intermediate 1. Then, intermediate 1(0.05 mol), POCl3(0.1 mol), and CH3CN(120 mL) wereadded to a 250 mL round-bottom flask to react for 0.5 hat a reflux temperature, and then, diisopropylethylamine(0.06 mol) was added dropwise. After continuously refluxingfor 8 h, excess POCl3and CH3CNwere distilled, andthen, ice water mixture (60 mL) was added. Finally, themixture was alkalify with 5 mol/L to pH 9 and extractedusing CH2Cl2to give intermediate 2 (Xie et al. 2013).2-Methyl-6-(trifluoromethyl)pyrimidin-4-ol (1) White crystals;yield 85.7%; m.p. 140-142 C; 1H NMR (DMSO-d6,500 MHz, ppm) delta: 13.03 (s, 1H, pyrimidine-OH), 6.68 (s,1H, pyrimidine-H), 2.36 (s, 3H); 13C NMR (DMSO-d6,125 MHz, ppm) delta: 162.78, 162.16, 152.03 (q, J = 35.5 Hz),122.33, 120.15, 111.12, 21.74.
With sodium methylate; In ethanol; water;
(1) To a suspension of ethyl trifluoroacetoacetate (18.4g, 0.1mol) and acetamidine hydrochloride (9.5g, 0.1mol) in ethanol (100ml) was dropwise added 28% sodium methylate (19.3g, 0.1mol) under cooling with ice. The resulting mixture was stirred at room temperature for 1 hour, and further refluxed for 12 hours. After cooling, the reaction mixture was evaporated, water (150ml) was added to the residue, then the mixture was neutralized with concentrated hydrochloric acid. The crystal separated was collected by filtration, washed with water, and dried to give 4-hydroxy-2-methyl-6-trifluoromethylpyrimidine (9.8g). m.p.:141-143 ØC 1H-NMR(CDCl3) delta 2.57(3H, s), 6.72(1H, s), 13.4(1H, br s). 1H-NMR(DMSO-d6) delta 2.36(3H, s), 6.67(1H, s). 19F-NMR(DMSO-d6) delta -72.13.
To 12.6 g of sodium methoxide (28% methanol solution), 3.1 g of acetoamidine hydrochloride and 3 g of 4,4,4- trifluoro-3-oxo-butanoic acid ethyl ester were added. This mixture was stirred at 800C for 20 hours. The reaction mixture was left standing to cool and then concentrated. To the residue, 10% hydrochloric acid was added, followed by extraction three times with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was washed with hexane to obtain 2.4 g of 2-methyl-6-trifluoromethylpyrimidin-4-ol . 2-methyl-6-trifluoromethylpyrimidin-4-ol1H-NMR (DMSO-d6): 2.35(s,3H), 6.68(s,lH), 13.02(bs,lH)
A solution of ethyl 4,4,4-trifluoroacetoacetate (commercially available, 4 mL, 27.3 mmol, 1.05 eq.) in polyphosphoric acid (22 mL) was heated to 100 C. <strong>[452-83-5]2-chloro-5-fluoroaniline</strong> (3.78 g, 26.0 mmol, 1 eq.) was added slowly to the stirred hot solution. The resulting reaction mixture was further heated to 150 C. and then stirred at that temperature overnight (approximately 18 hours). The reaction was cooled to room temperature and water was added carefully. The resulting light brown precipitate was collected by vacuum filtration, washed with water and dissolved in ethyl acetate. The ethyl acetate solution was washed with brine, dried over anhydrous MgSO4 and concentrated on a rotary evaporator. The crude product was purified by flash chromatography on silica gel using hexane/ethyl acetate to give 3.54 g (51% yield) of the desired product as an off-white solid; MP=141-142; MS (ES) m/z (relative intensity): 266 (M+H)+ (100).
51%
With PPA; at 100 - 150℃; for 18h;
A solution of ethyl 4,4,4-trifluoroacetoacetate (commercially available, 4 mL, 27.3 mmol, 1.05 eq.) in polyphosphoric acid (22 mL) was heated to 1000C. 2-chloro-5- fluoroaniline (3.78 g, 26.0 mmol, 1 eq.) was added slowly to the stirred hot solution. The resulting reaction mixture was further heated to 1500C and then stirred at that temperature overnight (approximately 18 hours). The reaction was cooled to room temperature and water was added carefully. The resulting light brown precipitate was collected by vacuum filtration, washed with water and dissolved in ethyl acetate. The ethyl acetate solution was washed with brine, dried over anhydrous MgSO4 and concentrated on a rotary evaporator. The crude product was purified by flash chromatography on silica gel <n="81"/>using hexane/ethyl acetate to give 3.54 g (51% yield) of the desired product as an off- white solid; MP = 141-142; MS (ES) m/z (relative intensity): 266 (M+H)+ (100).
ethyl 2-oxo-4-(2-(trifluoromethoxy)phenyl)-6-(trifluoromethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With sodium hydrogen sulfate; silica gel; In acetonitrile;Heating / reflux;
EXAMPLE 22. Ethyl 2-oxo-4-(2-(trifluoromethoxy)phenyl)-6-(trifluoromethyl)-l,2,3,4 tetrahydropyrimidine-5- carboxylate. Ethyl 2-oxo-4-(2-(trifluoromethoxy)phenyl)-6-(trifluoromethyl)-l,2,3,4 tetrahydropyrimidine-5- carboxylate: Ethyl 4,4,4,trifluoro-3-oxobutanoate (200mg, 1.08 mmol) was added to a solution of (trifluoromethoxy)benzaldehyde (103 mg, 0.54mmol) in CH3CN at room temperature. To this solution was added urea (64.8 mg, 1.08 mmol) followed SiO2-NaHSO4 (20mg, 0.1 mmol). The reaction mixture was stirred overnight at reflux. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with CHC13 (250 ml) and filtrate was concentrated to afford 3.9 g (87%) as a off- white solid. [M+H]+ calcd for C14H16FN2O3, 398.25, found 398.
With acetic anhydride; hydrazine hydrate; In methanol;
(2) ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate A mixture of ethyl 4,4,4-trifluoro-3-oxobutanoate (64.8 g, 0.352 mol), triethyl orthoformate (117ml, 0.7039 mol) and acetic anhydride (100 mL, 1.06 mol) was stirred at 120C for 2 hr, and heated under reflux for 5 hr. The reaction mixture was concentrated under reduced pressure. Hydrazine monohydrate (25.6 ml, 0.528 mol) and methanol (500 mL) were added to the residue, and the mixture was heated under reflux for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The extract concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (49.66 g) as crystals. 1H-NMR (CDCl3) delta: 1.28(4H, t, J=7.1Hz) 4.25 (2H, q, J=7.0Hz) 8.59 (1H, s) 14.13 (1H, t) MASS m/z: 208.97 (MH+)
Example 10a Preparation of 1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-ol <n="165"/>Into a 250 mL flask was weighed 5.01 g of 4,4,4-trifluoro-3-oxo-butyric acid ethyl ester, 4.88 g of 2-chlorophenylhydrazine hydrochloride, and 100 mL of ethanol. The resulting solution was heated at 90-95 °C for 18 h then was concentrated in vacuo to remove ethanol. The residue was washed into a separatory funnel with ethyl acetate and 1 M HCl. The ethyl acetate was separated, washed with brine, was dried, and concentrated in vacuo. The residue was partially purified by silica gel flash chromatography (Jones Flashmaster, 70 g Silica gel, gradient elution from 100percent hexanes to 20percent ethyl acetate over 30 minutes). Appropriate fractions were combined and concentrated and product was precipitated by addition of excess hexanes. The solid precipitate was collected by filtration and was dried under high vacuum to afford the intermediate 2-(2-Chlorophenyl)-5-trifluoromethyl-2H-pyrazol-3-ol as a tan powder, yield: 3.73 g (52percent). 1H NMR (DMSO-d6): delta 12.25(br s, 1H), 7.72(d, J= 8 Hz, 1H), 7.5-7.65(m, 3H), 5.94(s, 1H).
With sodium hydrogensulfate on silicagel; In neat (no solvent); at 80℃; for 0.333333h;Green chemistry;
General procedure: A mixture of 2-aminopyridine-3-carboxaldehyde (2.0 mmol), carbonyl compound (3.0 mmol) and NaHSO4-SiO2 (0.4g) were taken in 10 ml RB Flask. The reaction mixture was homogenized with the help of glass rod. The resulting mixture was stirred in an oil-bath (80 C) for the appropriate time (Table-3). After completion of the reaction, as monitored by TLC, the reaction mixture was cooled to room temp and EtOAc (40 ml) was added to it, stirred for 5 min and filtered. The solvent was evaporated and the crude product was purified by column chromatography on silica gel by eluting with EtOAc-n-hexane (2:8) and crystallization from hot ethanol afforded the corresponding pure 1,8-naphthyridine derivatives.
With piperidine; In ethanol; for 3h;Reflux;
mixture of <strong>[206997-15-1]2-amino-5-bromopyridine-3-carboxaldehyde</strong> (15.Og) and ethyl 4,4,4- trifluoroacetoacetate (10.8ml) in ethanol (100ml) containing piperidine (7.4ml) was stirred and heated to reflux for 3 hours. The reaction mixture was cooled in an ice bath and the required product that precipitated as a yellow solid, 17.5g, was filtered from solution, washed with a little cold ethanol and sucked to dryness. 1HNMR (CDCl3) delta: 9.30(leta, d, 8.67(1H, s), 8.52(1H, d), 4.50(2H, q), 1.45(3H, t)
To 12.58 g of sodium methoxide (28% methanol solution), 2.97 g of 2, 2-dimethylpropionamidine hydrochloride and 4 g of 4, 4 , 4-trifluoro-3-oxo-butanoic acid ethyl ester were added. This mixture was stirred at 80C for 10 hours and then heated under reflux for 6 hours. The reaction mixture was left standing to cool and then concentrated. To the residue, 10% hydrochloric acid was added, followed by extraction three times with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was washed with hexane to obtain 2.4 g of 2- (1, 1-dimethylethyl) -6-trifluoromethylpyrimidin-4- ol.2- (1, 1-dimethylethyl) -6-trifluoromethylpyrimidin-4-ol 1 H-NMR ( DMSO-d6 ) : 1 . 30 ( s , 9H ) , 6 . 72 ( s , lH ) , 12 . 70 (bs , lH )
5.61 g of O-methylisouronium sulfate and 3 g of 4,4,4- trifluoro-3-oxo-butanoic acid ethyl ester were added. This mixture was stirred at 80C for 20 hours. The reaction mixture was left standing to cool and then concentrated. To the residue, 10% hydrochloric acid was added. A precipitated crystal was collected by filtration and then washed with water to obtain 1.5 g of 2-methoxy-6- trifluoromethylpyrimidin-4-ol . 2-methoxy-6-trifluoromethylpyrimidin-4-ol1H-NMR (DMSO-d6) : 3.93(s,3H) , 6.50(s,lH) , 13.00(bs,lH)
With potassium carbonate; In water; at 20℃; for 0.25h;Microwave irradiation;
General procedure: The corresponding amidine hydrochloride (2.54 mmol) and powdered K2CO3 (5.76 mmol) were dissolved in water (5.0 mL) in a 20-mL vessel. The beta-keto ester (2.31 mmol) was added and the resulting mixture was irradiated for 5?15 min (see Table 2). Upon the end of the reaction (TLC, hexanes/EtOAc, 5:1), the mixture was diluted with sat. aq NH4Cl (5.0 mL) and extracted with CH2Cl2 (3 × 15 mL). The combined organic phases were dried (anhyd Na2SO4) and filtered. The filtrate was rotary evaporated and the obtained crude product was purified by column chromatography [silica gel, hexane/EtOAc mixtures or recrystallized (EtOH)].
To 40 g of sodium methoxide (28percent methanol solution) , 5 g of <strong>[57297-29-7]cyclopropanecarboxamidine hydrochloride</strong> and 7.63 g of 4, 4, 4-trifluoro-3-oxo-butanoic acid ethyl ester were added. This mixture was stirred at 800C for 10 hours and then heated under reflux for 12 hours. The reaction mixture was left standing to cool and then concentrated. To the residue, 10percent hydrochloric acid was added and then a precipitated crystal was collected by filtration. This crystal was washed with water and then dissolved in ethyl acetate. The ethyl acetate solution was dried over anhydrous magnesium sulfate and then concentrated. The residue was washed with hexane to obtain 4.6 g of 2-cyclopropyl-6- trifluoromethylpyrimidin-4-ol . 2-cyclopropyl-6-trifluoromethylpyrimidin-4-ol1H-NMR (DMSO-d6): 1.02-1.14 (m, 4H) , 1.96-2.03 (m, IH) , 6 . 58 ( s , IH ) , 13 . 21 (bs , lH )
With L-proline/SiO2; at 80℃; for 0.233333h;Microwave irradiation; Sealed tube;
General procedure: Oven Heating ProcedureIn a typical experiment of Knoevenagel condensation reaction catalyzed by immobillized L-proline,aldehyde (7 mmol), ethyl trifluoroacetoacetate (14 mmol) and 4.5 g of L-proline/SiO2 were thoroughlyground in a mortar. The mixture was charged in a microwave tube (capacity 10 mL), then sealed withpolytetrafluoroethylene film and heated in an oven at 80 C for 6-8 h (monitored by HPLC). Themixture was allowed to cool to room temperature. Ethyl acetate was added and the resulting mixturewas filtered, and the residue was sequentially washed with ethyl acetate or dichloromethane for at leastthree times. The combined solution was evaporated under reduced pressure, and the crude product wasrecrystallized from ethanol or ethyl acetate.
With L-proline/SiO2; at 80℃; for 0.233333h;Microwave irradiation; Sealed tube;
General procedure: Oven Heating ProcedureIn a typical experiment of Knoevenagel condensation reaction catalyzed by immobillized L-proline,aldehyde (7 mmol), ethyl trifluoroacetoacetate (14 mmol) and 4.5 g of L-proline/SiO2 were thoroughlyground in a mortar. The mixture was charged in a microwave tube (capacity 10 mL), then sealed withpolytetrafluoroethylene film and heated in an oven at 80 C for 6-8 h (monitored by HPLC). Themixture was allowed to cool to room temperature. Ethyl acetate was added and the resulting mixturewas filtered, and the residue was sequentially washed with ethyl acetate or dichloromethane for at leastthree times. The combined solution was evaporated under reduced pressure, and the crude product wasrecrystallized from ethanol or ethyl acetate.
With gadolinium(III) chloride hexahydrate; at 80℃; for 4.5h;
General procedure: To a mixture of o-aromatic diamines (200 mg, 1.85 mmol) and 1,3-dicarbonyl compound (722 mg, 5.55 mmol), GdCl3*6H2O (25 mg, 0.09 mmol) was added and the mixture was stirred at 80C for 3.0 hr. After completion of the reaction (TLC), the reaction mixture was poured into ice cold water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the corresponding 2-methyl benzimidazole. The crude material was further purified by through column chromatography by using 10% ethyl acetate in hexane.
4-trifluoromethyl-7-hydroxy-8-chlorocoumarin[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With perchloric acid; at 20 - 80℃; for 2h;
Compound 2 (<strong>[6201-65-6]2-chloro-1,3-benzenediol</strong>) (0.400 g) was dispersed in 1.5 mL of 70% perchloric acid followed by the addition of compound 3 (ethyl trifluoroacetoacetate) (0.36 mL). The reaction solution was heated to 80 C with stirring, returned to room temperature after 2 hours, and partitioned with saturated sodium bicarbonate and ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate and separated by column chromatography (n-hexane: ethyl acetate = 2: 1) to give compound 1 (0.39 g) as a pale yellow solid in yield For 72%
With sulfuric acid; trifluoroacetic acid; at 90℃; for 3h;
Example 2 ofKR2Ol 10001415A was repeated: A mixture of ethyl trifluoroacetylacetate (3.65 ml, 25.0 mmol), trifluoroacetic acid (0.974 ml,12.7 mmol), and sulfuric acid (0.326 ml, 6.0 mmol) was stirred at 90 C for 3 h. The mixturewas then diluted with ethyl acetate (25 ml) and mixed with an aqueous, saturated NaHCO3 solution (15 ml). The aqueous phase was separated, and the organic phase was extracted with aqueous saturated NaHCO3 solution (15 ml). The aqueous phases weere combined and were acidified with 2M aqueous hydrochloric acid, and extracted with ethyl acetate (5 times with 5ml). The combined organic extracts were dried with Na2SO4 over night. The drying agent was filtered off, rinsed with AcOEt (2 times with 5 ml), and the combined organic phases were concentrated under reduced pressure (40 C, 140 to 17 mbar). Obtained was a colorless solid. Analysis by 1H and 19F NMR revealed this solid to be mainly the hydrated form of trifluoroacetylacetic acid, which is compound of formula (2), containing less than 10% of theenol form of the water-free trifluoroacetylacetic acid, which is compound of formula (1).
General procedure: A 3.9 g, 27 mmol of phenylhydrazine hydrochloride was added to 27 mmol of the corresponding ethyl 4-polyfluoroalkyl-3-oxo ester and 3.9 g, 30 mmol of K2CO3. The mixture was refluxed in 50 ml of ethanol for 3-4 h. The solvent was removed in vacuo. The precipitate was isolated and washed with water and hexane.
General procedure: To a suspension of compound 1 (1 eq), compound 2 (1.2 eq), CH3SO3H was added in one portion. The mixture was stirred at RT 12 h. LC-MS showed that starting material was consumed completely. The reaction mixture was poured into ice-water (100 mL) and stirred for 30 min. The formed precipitate was filtered and washed with water and EA, dried to afford the crude compound 3 and use at the next step directly.
Ammonia reactor volume of 1000L, with stirring, thermometer, metering tank and condenser.368.0 kg (2.0 kmol) of ethyl 4,4,4-trifluoroacetoacetate was added to the reaction vessel through a metering tank,After the addition, the temperature was raised to 90 C. Then, 323.4 kg (4.2 kmol) of ammonium acetate was charged, and the mixture was incubated at 90C for 3 hours.The temperature of the reaction solution was cooled to 30 C, and the mixture was stirred and allowed to stand for 30 minutes. The reaction liquid is divided into two layers, the lower layer is an organic phase,Weight of 359.6kg, the content of ethyl 3-amino-4,4,4-trifluorocrotonate was 98.2% and the yield was 96.5%;The upper layer is aqueous phase, the weight of water phase is 330.6kg, and the content of acetic acid in water phase is 36.3%.
Step 1: In a four-necked reaction flask equipped with a mechanical stirrer, thermometer and air duct, 92 gTrifluoroacetoacetate, 230 g of acetonitrile and 2.24 g of KOH, and the mixture was cooled in an ice bath to 0 to 25 C,Slowly enter the 39.4 g of chlorine and 21 g of hydrogen sulfide gas, ventilation time of about 3-5h. After the completion of access to the gas insulation reaction 1h, and then blow off the generated hydrogen chloride gas, excessive chlorine and hydrogen sulfide gas.Step 2: To the above reaction, dropwise add 112g of triethylamine. After adding dropwise, the mixture is heated to reflux and refluxed for 3 hours. The resulting triethylamine hydrochloride is filtered and the filtrate is distilled to recover the solvent.Step 3: temperature control 25-35 , dropping 30% sodium hydroxide solution 170g, insulation reaction 2 ~ 3h.Step four: 180g 30% hydrochloric acid solution for acidification, a large number of white precipitate precipitation. After the completion of the dropwise addition, the reaction was allowed to proceed for 1 h, followed by filtration and drying to obtain 92.55 g of the substance, content: 97.02%, yield: 85.05%.
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In ethanol; at 70 - 80℃;
To a three-necked flask was added ethyl trifluoroacetoacetate (0.16 mL, 1.0 eq.),DBU (0.19 mL, 1.2 eq.),Add absolute ethanol (10 mL) to dissolve.A solution of formamidine hydrochloride in ethanol (0.09 g of formamidine hydrochloride in 2 mL of ethanol,The amount of formamidine hydrochloride1.05 eq.).Dropping the temperature to 70-80 C for 3 to 5 hours.TLC monitoring,The reaction was complete.The solvent was distilled off under reduced pressure,Diluted with water (20 mL)With 1mol / L hydrochloric acid adjusted pH = 6 ~ 7,Extraction with ethyl acetate (3 x 8 mL)The organic phase was combined with anhydrous sulfuric acidSodium drying, filtration, vacuum distillation of the solvent was light yellow solid, add petroleum ether (5mL) shock, filter, filter cake washed with petroleum ether,The oven was dried at 55 C for 2 hours to give a pale yellow flake solid in 96% yield.
(1) into a chain130 kg of acetonitrile into the reactor,32 kg of thioacetamide was added with stirring,90 kg of ethyl trifluoroacetoacetate was added dropwise at 30 C,Drop finished,Continue to maintain the chain reaction for 2.5 hours. (2) to form a ringAfter the completion of the chain reaction,120 kg of tri-n-propylamine was added dropwise at 30 C,Dropping time for 1 hour,Drop finished,The temperature was raised to 70 C for 3 hours to form a ring-forming reaction. (3) hydrolysisAfter the ring-forming reaction,The acetonitrile, water and tri-n-propylamine were separated by vacuum distillation,Respectively, with water acetonitrile fraction and tri-n-propylamine fraction. After acetonitrile and tri-n-propylamine were removed,The reaction solution was cooled to 30 C,Add 45% NaOH alkaline solution 93kg,The temperature was raised to 55 C for 1 hour to carry out hydrolysis reaction.(4) acidificationAfter the hydrolysis reaction is complete,Cooling to 40 ,30% hydrochloric acid was added dropwise for acidification,Transferred to pH = 1-2, and then continue to cool to 0 ,Add 200kg of water,Stirring for 0.5 hours,Filter,Centrifugal,The filter cake is dried and dried2-methyl-4-trifluoromethyl-5-thiazolecarboxylic acid 82.0 kg,Content of 95.3%,Yield 90.8% (based on ethyl trifluoroacetoacetate).The raw materials used in the preparation are commercially available.
5-ethoxycarbonyl-1,3-bis[2-ethoxy-1-(4-hydroxybenzyl)-2-oxoethyl]-3,4,5,6-tetrahydropyrimidin-1-iumtrifluoroacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
In aq. acetate buffer; at 20℃; for 24h;pH 5.9;
General procedure: To a solution of the appropriate amino ester hydrochloride 2a?f (5.4 mmol) in acetate buffer (pH5.9) (1.5 mL) trifluoromethyl 1,3-dicarbonyl compound 1a?c (2.7 mmol) and formaldehyde 33percent aqueoussolution (11 or 40 mmol) were added. The resulting mixture was stirred for 24 h at room temperature, then itwas extracted with CH2Cl2 (3 x 10 mL) and the combined organic layers were dried over Na2SO4 andevaporated in vacuo. The product was purified by column chromatography on Kieselgel 60 (chloroform?MeOH10:0?9:1 or hexane?EtOAc 10:0?7:3).
Take potassium hydroxide 29.8g (0.53mol) input with mechanical stirring with reflux condenser 250mL four-necked flask was slowly added 100mL of methanol, stirring for stand-by 43.4 g (0.52 mol) of cyanoacetamide were charged into a flask equipped with a mechanical stirrer, constant pressure dropping funnel, drying tube and reflux condenser 500mL four-necked flask, add 150mL of methanol, mechanical stirring heating reflux, the reaction solution was changed from cloudy to light yellow transparent and added 100 g (0.54 mol) of ethyl trifluoroacetoacetate, keep the reflux state, slowly dropping the configured potassium hydroxide methanol solution, Heated to reflux reaction 24h, central control raw materials cyanoacetamide reaction is complete, Change the reflux device for the distillation device, Methanol recovery 3/4, The residue was added to cold water, cooled, adjusted with dilute hydrochloric acid PH = 3-4, stirred 0.5h, the reaction mixture was filtered, the filter cake washed with water to give the white target 2,6-dihydroxy-3-cyano-4 - (trifluoromethyl) pyridine, dried at 80 to constant weight to give 84.5 g, yield 80.1%, hplc 98%.
80.1%
With potassium hydroxide; In methanol; for 24.0h;Reflux;
Take potassium hydroxide 29.8g (0.53mol)Slowly add 100 mL of methanol into a 250 mL four-necked flask equipped with mechanical stirring and reflux condenser, stir and cool for use;43.4 g (0.52 mol) of cyanoacetamide was charged with mechanical stirring,a 500 mL four-neck bottle with a constant pressure dropping funnel, a drying tube and a reflux condenser.Add 150 mL of methanol and heat to reflux with mechanical stirring.The reaction solution was changed from turbid to pale yellow transparent, and then 100 g (0.54 mol) of ethyl trifluoroacetoacetate was added thereto, and the potassium hydroxide methanol solution was slowly added dropwise while maintaining the reflux state.Heating and refluxing for 24 hours, the control of the raw material cyanoacetamide is complete,Change the reflux device to a distillation unit, recover 3/4 of methanol, and add cold water to the residue.Under cooling conditions, adjust pH = 1 with dilute hydrochloric acid, stir for 0.5 h,The reaction solution is filtered, and the filter cake is washed with water.The white target 2,6-dihydroxy-3-cyano-4-(trifluoromethyl)pyridine was obtained.Drying to constant weight at 80 C gave 84.5 g, yield 80.1%, hplc 98%.
With potassium hydroxide; at 75℃; for 6.0h;
One,Cyanacetamide,Ethyl trifluoroacetateAfter mixing with KOH,The reaction was refluxed at 75 C for 6 h.After filtering,washing,drying,Obtaining 2,6-dihydroxy-3-cyano-4-trifluoromethylpyridine;
In ethyl trifluoroacetate was added to the three vial (0.1mol),DBU (0.12 mol) was stirred in absolute ethanol (200 mL).Stir for 1 hour, add dropwise ethanol dissolution A solution of acetamidine hydrochloride (0.12 mol),After the addition,Heating back, TLC tracks the progress of the reaction,After the disappearance of the raw material point, the reaction is stopped and heated to reflux; the solvent is dried, the ice water is slightly cooled, and the pH is adjusted to 5-6 with dilute hydrochloric acid;Extract with ethyl acetate, separate the layers, and combine the organic phases.After solvent removal, a white solid was obtained.The mass was 16.03 g (theoretical value 17.81 g), and the yield was 90.1%.
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