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Excepted Quantity
USD 0.00
Limited Quantity
USD 15-60
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USD 80+
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USD 150+
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Structure of 446-35-5 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Research on Chemical Intermediates, 2010, vol. 36, # 8, p. 975 - 983
2
[ 446-35-5 ]
[ 55687-23-5 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2007, vol. 55, # 2, p. 255 - 267
[2] Journal of Medicinal Chemistry, 1981, vol. 24, # 1, p. 93 - 101
3
[ 446-35-5 ]
[ 55687-33-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 1981, vol. 24, # 1, p. 93 - 101
4
[ 446-35-5 ]
[ 327-92-4 ]
Yield
Reaction Conditions
Operation in experiment
94%
at 20 - 50℃; for 1 h; Large scale
42.5 kg of fuming nitric acid and 280 kg of concentrated sulfuric acid were injected into the reaction kettle at a temperature of 20 to 30 ° C,Then, 100 kg of 2,4-difluoronitrobenzene was added dropwise under stirring,Dropping process to control the reaction temperature of 20 ~ 45 ,After the dropping was completed, the temperature was raised to 50 ° C,And reacted for at least 1 h,Then, 0.5 mL of the stirring solution,0.5 mL of dichloroethane was added,Take the upper organic phase,Washed,And then the mass content of 2,4-difluoronitrobenzene was detected under the condition of liquid phase analysis,When the mass content of 2,4-difluoronitrobenzene is less than 0.2percent200 kg of 1,2-dichloroethane was added to the reaction kettle to extract,The obtained upper layer is a concentrated solution containing 1,2-dichloroethane containing 1,5-difluoro-2,4-dinitrobenzene, and the lower concentrated sulfuric acid phase is returned to the reaction kettle,100 kg of 1,2-dichloroethane,Extraction stratification,A dilute solution of 1,2-dichloroethane containing 1,5-difluoro-2,4-dinitrobenzene was again obtained,The resulting 1,2-dichloroethane containing 1,5-difluoro-2,4-dinitrobenzene was twice obtainedThe solution is stirred and mixed uniformly,A total of 422.5 kg of a 1, 2-dichloroethane solution of 1,5-difluoro-2,4-dinitrobenzene was obtained.among them,The content of 1,5-difluoro-2,4-dinitrobenzene was 28.7percentYield 94percent
Reference：
[1] Patent: CN105837563, 2016, A, . Location in patent: Paragraph 0041; 0045; 0046
[2] Recueil des Travaux Chimiques des Pays-Bas, 1916, vol. 35, p. 142[3] Chem. Zentralbl., 1913, vol. 84, # II, p. 760
5
[ 148854-10-8 ]
[ 327-92-4 ]
[ 446-35-5 ]
[ 367-82-8 ]
Reference：
[1] Journal of Fluorine Chemistry, 1998, vol. 92, # 1, p. 27 - 32
6
[ 446-35-5 ]
[ 367-27-1 ]
Reference：
[1] Chemische Berichte, 1937, vol. 70, p. 2396,2400
7
[ 611-06-3 ]
[ 2106-50-5 ]
[ 446-35-5 ]
[ 700-37-8 ]
Reference：
[1] Chemical Communications, 1996, # 3, p. 297 - 298
8
[ 611-06-3 ]
[ 2106-50-5 ]
[ 446-35-5 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2008, vol. 350, # 17, p. 2677 - 2682
9
[ 133117-48-3 ]
[ 372-18-9 ]
[ 19064-24-5 ]
[ 446-35-5 ]
Reference：
[1] Journal of Fluorine Chemistry, 1998, vol. 92, # 1, p. 27 - 32
10
[ 98-95-3 ]
[ 402-67-5 ]
[ 19064-24-5 ]
[ 446-35-5 ]
[ 2265-94-3 ]
[ 350-46-9 ]
[ 1493-27-2 ]
Reference：
[1] Journal of Fluorine Chemistry, 1981, vol. 18, p. 363 - 374
11
[ 67-56-1 ]
[ 446-35-5 ]
[ 446-38-8 ]
Reference：
[1] Patent: CN106220516, 2016, A, . Location in patent: Paragraph 0044
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1985, vol. 21, # 11, p. 2173 - 2178[2] Zhurnal Organicheskoi Khimii, 1985, vol. 21, # 11, p. 2376 - 2382
14
[ 446-35-5 ]
[ 124-41-4 ]
[ 446-38-8 ]
[ 448-19-1 ]
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1985, vol. 21, # 11, p. 2173 - 2178[2] Zhurnal Organicheskoi Khimii, 1985, vol. 21, # 11, p. 2376 - 2382
[3] Journal of Organic Chemistry USSR (English Translation), 1985, vol. 21, # 11, p. 2173 - 2178[4] Zhurnal Organicheskoi Khimii, 1985, vol. 21, # 11, p. 2376 - 2382
15
[ 67-56-1 ]
[ 446-35-5 ]
[ 448-19-1 ]
Yield
Reaction Conditions
Operation in experiment
87.38%
With potassium <i>tert</i>-butylate In toluene at 0 - 20℃;
Toluene (500 ml) was added into clean and dry round bottom flask, then 2,4- difluoro-1 -nitrobenzene (500 gms) was added. The reaction mass was cooled to 0°C then methanol (100 ml) was slowly added to reaction mass at 0°C. To the reaction mass potassium tert-butoxide (PTB) (353 gms) was added in lots (10 lots) at 0°C. The reaction mass was stirred at 0°C for 15-30 minutes, then temperature raised to 20°C and the reaction mass was stirred at 20°C for 4 hrs. The reaction mass was decomposed in water (1500 ml). The contents were stirred for 10-15 minutes followed by toluene was added to the reaction mass. The layers were separated, and the aqueous layer was extracted with toluene followed by separated the organic layer. Total organic layer was washed with water (1000 ml). The organic layer was then washed with brine solution (NaCl (50 gms) + water (500 ml)) and dried over sodium sulphate. The solvent was distilled out under vacuum. Petroleum ether (1000 ml) was added to the residue and the contents were cooled to below 10°C then stirred for 30 minutes. The solid was filtered off and washed with petroleum ether (200 ml). The solid was dried at 50-60°C for 3-5 hrs (Yield - 470 gms; 87.38percent).
Reference：
[1] Patent: WO2018/207120, 2018, A1, . Location in patent: Page/Page column 11
[2] Organic Process Research and Development, 2014, vol. 18, # 7, p. 912 - 918
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1985, vol. 21, # 11, p. 2173 - 2178[2] Zhurnal Organicheskoi Khimii, 1985, vol. 21, # 11, p. 2376 - 2382
19
[ 67-56-1 ]
[ 446-35-5 ]
[ 865-47-4 ]
[ 448-19-1 ]
[ 1369809-57-3 ]
Reference：
[1] Organic Process Research and Development, 2014, vol. 18, # 7, p. 912 - 918
20
[ 446-35-5 ]
[ 124-41-4 ]
[ 448-19-1 ]
[ 4920-84-7 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1916, vol. 35, p. 142[2] Chem. Zentralbl., 1913, vol. 84, # II, p. 760
21
[ 446-35-5 ]
[ 124-41-4 ]
[ 446-38-8 ]
[ 448-19-1 ]
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1985, vol. 21, # 11, p. 2173 - 2178[2] Zhurnal Organicheskoi Khimii, 1985, vol. 21, # 11, p. 2376 - 2382
[3] Journal of Organic Chemistry USSR (English Translation), 1985, vol. 21, # 11, p. 2173 - 2178[4] Zhurnal Organicheskoi Khimii, 1985, vol. 21, # 11, p. 2376 - 2382
22
[ 446-35-5 ]
[ 446-33-3 ]
Reference：
[1] Synthesis, 2000, # 12, p. 1659 - 1661
23
[ 446-35-5 ]
[ 394-41-2 ]
Reference：
[1] Patent: CN106220516, 2016, A,
24
[ 611-06-3 ]
[ 446-35-5 ]
Yield
Reaction Conditions
Operation in experiment
100%
With trihexyl (tetradecyl) phosphonium tetrafluoroborate; potassium fluoride In dimethyl sulfoxide at 180℃; for 1.8 h;
General procedure: dry dimethylsulfoxide (10 ml) was preheated in a screw-capped Teflon reactor at 180 °C before adding the phase transfer catalyst (0.86 mmol), KF (0.5 g) and 1,2-dichloro-4-nitrobenzene (6 mmol). The reaction was carried out under nitrogen with stirring. Samples were withdrawn periodically during the reaction, filtered to remove the solid salts and analyzed by gas chromatography (HP-5). Compounds were identified by comparison with authentic samples and by gas chromatography–mass spectrometry (Shimadzu QP 5000).
90%
With potassium fluoride In sulfolane; methanol at 100 - 180℃; for 8 h;
Example 6; Into a 50 mL flask equipped with a reflux condenser, 25 g of sulfolane was charged and the inner temperature thereof was adjusted at 140° C. To this, the solution obtained by dissolving 4.5 g of potassium fluoride, which was the same as used in Example 1, in 60 g of methanol was added dropwise together with removing distilled methanol out the system. The addition of all amount of the methanol solution of potassium fluoride dropwise was finished and methanol was hardly distilled out at all, and then, the concentration was further conducted at 160° C. at 2.7 kPa to obtain a potassium fluoride dispersion essentially consisting of potassium fluoride and sulfolane. The potassium fluoride dispersion was analyzed with gas chromatography area comparison method. The amount of methanol was 0.02percent by weight or less per 1 part by weight of sulfolane.The potassium fluoride dispersion cooled at 100° C. was mixed with 5 g of 2,4-dichloronitrobenzene. The obtained mixture was kept for 8 hours at 180° C. with stirring. The obtained reaction mixture was cooled to 100° C. and then, 100 g of toluene was added thereto. The obtained mixture was cooled to room temperature. The precipitated solid was separated by filtration and the separated solid was washed with 10 g of toluene. The filtrate and wash liquid were mixed and the obtained solution was analyzed with gas chromatography internal standard method. The yield of 2,4-difluoronitrobenzene was 90percent and the yield of chlorofluoronitrobenzene was 10percent.
89%
With potassium fluoride In sulfolane at 100 - 180℃; for 10 h;
Example 5; Into a 50 mL flask equipped with a reflux condenser, 25 g of sulfolane was charged and the inner temperature thereof was adjusted at 140° C. To this, the solution obtained by dissolving 4.5 g of potassium fluoride, which was the same as used in Example 1, in 60 g of methanol was added dropwise together with removing distilled methanol out the system. The addition of all amount of the methanol solution of potassium fluoride dropwise was finished and methanol was hardly distilled out at all, and then, 10 g of toluene was added to the concentrate. The concentration was further continued to remove a mixed solution of methanol and toluene. After that, residual toluene was removed by reducing to 6 kPa at the same temperature to obtain a potassium fluoride dispersion essentially consisting of potassium fluoride and sulfolane.The potassium fluoride dispersion cooled at 100° C. was mixed with 5 g of 2,4-dichloronitrobenzene. The obtained mixture was kept for 10 hours at 180° C. with stirring. The obtained reaction mixture was cooled to 100° C. and then, 100 g of toluene was added thereto. The obtained mixture was cooled to room temperature. The precipitated solid was separated by filtration and the separated solid was washed with 10 g of toluene. The filtrate and wash liquid were mixed and the obtained solution was analyzed with gas chromatography internal standard method. The yield of 2,4-difluoronitrobenzene was 92percent and the yield of chlorofluoronitrobenzene was 8percent.; Example 10; Into a 200 mL flask, 53 g of methanol and 4.4 g of potassium hydroxide were charged. The mixture was stirred at room temperature to prepare a methanol solution of potassium hydroxide. To the prepared methanol solution of potassium hydroxide, 3.3 g of 47percent by weight hydrofluoric acid was added dropwise while cooling to keep at an inner temperature of 30° C. or less to prepare a potassium fluoride solution.Into a 50 mL flask equipped with a reflux condenser, 25 g of sulfolane was charged and the inner temperature thereof was adjusted at 140° C. To this, the above-mentioned potassium fluoride solution was added dropwise together with removing distilled mixed solution of methanol and water out the system. The addition of all amount of the potassium fluoride solution dropwise was finished and methanol and water were hardly distilled out at all, and then, the concentration was continued at 160° C. at 2.7 kPa to remove residual methanol and water to obtain a potassium fluoride dispersion essentially consisting of potassium fluoride and sulfolane.The potassium fluoride dispersion cooled at 100° C. was mixed with 5 g of 2,4-dichloronitrobenzene. The obtained mixture was kept for 10 hours at 180° C. with stirring. The obtained reaction mixture was cooled to 100° C. and then, 100 g of toluene was added thereto and the obtained mixture was cooled to room temperature. The precipitated solid was separated by filtration and the separated solid was washed with 10 g of toluene. The filtrate and wash liquid were mixed to analyze with gas chromatography internal standard method. The Yield of 2,4-difluoronitrobenzene was 89percent and the yield of chlorofluoronitrobenzene was 9percent.
Reference：
[1] Catalysis Today, 2012, vol. 198, # 1, p. 300 - 304
[2] Patent: US2009/99387, 2009, A1, . Location in patent: Page/Page column 8
[3] Patent: US2009/99387, 2009, A1, . Location in patent: Page/Page column 7-9
[4] Tetrahedron, 1995, vol. 51, # 22, p. 6363 - 6376
[5] Journal of the American Chemical Society, 1956, vol. 78, p. 6034,6037
[6] Journal of Fluorine Chemistry, 2007, vol. 128, # 6, p. 608 - 611
[7] Patent: US5354439, 1994, A,
[8] Patent: US5354439, 1994, A,
[9] Patent: US5354439, 1994, A,
[10] Patent: US5354439, 1994, A,
[11] Patent: US5354439, 1994, A,
[12] Patent: US5502260, 1996, A,
25
[ 611-06-3 ]
[ 2106-50-5 ]
[ 446-35-5 ]
[ 700-37-8 ]
Reference：
[1] Chemical Communications, 1996, # 3, p. 297 - 298
26
[ 611-06-3 ]
[ 2106-50-5 ]
[ 446-35-5 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2008, vol. 350, # 17, p. 2677 - 2682
27
[ 611-06-3 ]
[ 446-35-5 ]
Reference：
[1] Patent: US5502260, 1996, A,
[2] Patent: US5502260, 1996, A,
28
[ 367-25-9 ]
[ 446-35-5 ]
Reference：
[1] ChemSusChem, 2012, vol. 5, # 2, p. 312 - 319
[2] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 4, p. 1047 - 1051
29
[ 611-06-3 ]
[ 446-35-5 ]
Reference：
[1] Patent: US5502260, 1996, A,
30
[ 611-06-3 ]
[ 446-35-5 ]
[ 700-37-8 ]
Yield
Reaction Conditions
Operation in experiment
13 %Chromat.
With potassium fluoride; tetramethlyammonium chloride In sulfolane at 170℃; for 4 h;
EXAMPLES General Procedure for the Examples [0094] The potassium fluoride, the 2,4-dichloronitrobenzene and the solvent are charged to a Schott tube or reactor placed under a nitrogen atmosphere and then heating is carried out at the temperature indicated for 4 h. After 4 h, the reaction mixture is subsequently filtered and analyzed by gas chromatography. Example 1 [0095] In this example, the general procedure was used under the following conditions: dichloronitrobenzene (DCNB) with the amount of potassium fluoride stoichiometrically necessary for a double exchange (in fact, a slight excess equal to 1.05 SA) and an amount of tetramethylammonium chloride (TMAC) equal to 0.04 times the amount of dichloronitrobenzene, expressed in moles. The figures between brackets located before the name of the chemical product express its molar ratio, the substrate being taken as reference. (1) DCNB+(2) KF+(0.04) TMAC+(3) Solvent/170° C., 4 h, Schott tubes
32 - 50 %Chromat.
With cesium fluoride In hexanedinitrile at 180 - 220℃; for 0.166667 h; Microwave irradiation
Example 2 [0097] Test Under Microwaves in Adiponitrile [0098] The test molecule is in this instance DCNB with solely cesium fluoride. [0099] Characteristics of the equipment used for the text: [0100] the reactor is made of quartz and has a volume of 40 ml [0101] the stirrer is made of glass [0102] the maximum power of the generator is 300 W. [0103] Temperature regulation is manual and not automatic; the power of the microwave radiation is adjusted manually as a function of time to keep the temperature constant. All the compounds are introduced at ambient temperature; the microwave radiation is switched on and operates at full power (P=300 W) until the desired temperature is achieved. The power of the generator is then adjusted in order to keep the medium at the desired temperature. [0104] The molar ratios with respect to DCNB are as follows:
20 %Chromat.
With potassium fluoride; tetramethlyammonium chloride In pimelonitrile at 170℃; for 4 h;
EXAMPLES General Procedure for the Examples [0094] The potassium fluoride, the 2,4-dichloronitrobenzene and the solvent are charged to a Schott tube or reactor placed under a nitrogen atmosphere and then heating is carried out at the temperature indicated for 4 h. After 4 h, the reaction mixture is subsequently filtered and analyzed by gas chromatography. Example 1 [0095] In this example, the general procedure was used under the following conditions: dichloronitrobenzene (DCNB) with the amount of potassium fluoride stoichiometrically necessary for a double exchange (in fact, a slight excess equal to 1.05 SA) and an amount of tetramethylammonium chloride (TMAC) equal to 0.04 times the amount of dichloronitrobenzene, expressed in moles. The figures between brackets located before the name of the chemical product express its molar ratio, the substrate being taken as reference. (1) DCNB+(2) KF+(0.04) TMAC+(3) Solvent/170° C., 4 h, Schott tubes
15 %Chromat.
With potassium fluoride; tetramethlyammonium chloride In octanedinitrile at 170℃; for 4 h;
EXAMPLES General Procedure for the Examples [0094] The potassium fluoride, the 2,4-dichloronitrobenzene and the solvent are charged to a Schott tube or reactor placed under a nitrogen atmosphere and then heating is carried out at the temperature indicated for 4 h. After 4 h, the reaction mixture is subsequently filtered and analyzed by gas chromatography. Example 1 [0095] In this example, the general procedure was used under the following conditions: dichloronitrobenzene (DCNB) with the amount of potassium fluoride stoichiometrically necessary for a double exchange (in fact, a slight excess equal to 1.05 SA) and an amount of tetramethylammonium chloride (TMAC) equal to 0.04 times the amount of dichloronitrobenzene, expressed in moles. The figures between brackets located before the name of the chemical product express its molar ratio, the substrate being taken as reference. (1) DCNB+(2) KF+(0.04) TMAC+(3) Solvent/170° C., 4 h, Schott tubes
17 %Chromat.
With potassium fluoride; tetramethlyammonium chloride In Glutaronitrile at 170℃; for 4 h;
EXAMPLES General Procedure for the Examples [0094] The potassium fluoride, the 2,4-dichloronitrobenzene and the solvent are charged to a Schott tube or reactor placed under a nitrogen atmosphere and then heating is carried out at the temperature indicated for 4 h. After 4 h, the reaction mixture is subsequently filtered and analyzed by gas chromatography. Example 1 [0095] In this example, the general procedure was used under the following conditions: dichloronitrobenzene (DCNB) with the amount of potassium fluoride stoichiometrically necessary for a double exchange (in fact, a slight excess equal to 1.05 SA) and an amount of tetramethylammonium chloride (TMAC) equal to 0.04 times the amount of dichloronitrobenzene, expressed in moles. The figures between brackets located before the name of the chemical product express its molar ratio, the substrate being taken as reference. (1) DCNB+(2) KF+(0.04) TMAC+(3) Solvent/170° C., 4 h, Schott tubes
46 %Chromat.
With potassium fluoride; tetramethlyammonium chloride In benzonitrile at 170℃; for 4 h;
EXAMPLES General Procedure for the Examples [0094] The potassium fluoride, the 2,4-dichloronitrobenzene and the solvent are charged to a Schott tube or reactor placed under a nitrogen atmosphere and then heating is carried out at the temperature indicated for 4 h. After 4 h, the reaction mixture is subsequently filtered and analyzed by gas chromatography. Example 1 [0095] In this example, the general procedure was used under the following conditions: dichloronitrobenzene (DCNB) with the amount of potassium fluoride stoichiometrically necessary for a double exchange (in fact, a slight excess equal to 1.05 SA) and an amount of tetramethylammonium chloride (TMAC) equal to 0.04 times the amount of dichloronitrobenzene, expressed in moles. The figures between brackets located before the name of the chemical product express its molar ratio, the substrate being taken as reference. (1) DCNB+(2) KF+(0.04) TMAC+(3) Solvent/170° C., 4 h, Schott tubes
13 %Chromat.
With potassium fluoride; tetramethlyammonium chloride In hexanedinitrile at 170℃; for 4 h;
EXAMPLES General Procedure for the Examples [0094] The potassium fluoride, the 2,4-dichloronitrobenzene and the solvent are charged to a Schott tube or reactor placed under a nitrogen atmosphere and then heating is carried out at the temperature indicated for 4 h. After 4 h, the reaction mixture is subsequently filtered and analyzed by gas chromatography. Example 1 [0095] In this example, the general procedure was used under the following conditions: dichloronitrobenzene (DCNB) with the amount of potassium fluoride stoichiometrically necessary for a double exchange (in fact, a slight excess equal to 1.05 SA) and an amount of tetramethylammonium chloride (TMAC) equal to 0.04 times the amount of dichloronitrobenzene, expressed in moles. The figures between brackets located before the name of the chemical product express its molar ratio, the substrate being taken as reference. (1) DCNB+(2) KF+(0.04) TMAC+(3) Solvent/170° C., 4 h, Schott tubes
17 %Chromat.
With potassium fluoride; tetramethlyammonium chloride In 2-methylglutaronitrile at 170℃; for 4 h;
EXAMPLES General Procedure for the Examples [0094] The potassium fluoride, the 2,4-dichloronitrobenzene and the solvent are charged to a Schott tube or reactor placed under a nitrogen atmosphere and then heating is carried out at the temperature indicated for 4 h. After 4 h, the reaction mixture is subsequently filtered and analyzed by gas chromatography. Example 1 [0095] In this example, the general procedure was used under the following conditions: dichloronitrobenzene (DCNB) with the amount of potassium fluoride stoichiometrically necessary for a double exchange (in fact, a slight excess equal to 1.05 SA) and an amount of tetramethylammonium chloride (TMAC) equal to 0.04 times the amount of dichloronitrobenzene, expressed in moles. The figures between brackets located before the name of the chemical product express its molar ratio, the substrate being taken as reference. (1) DCNB+(2) KF+(0.04) TMAC+(3) Solvent/170° C., 4 h, Schott tubes
32 %Chromat.
With potassium fluoride; tetramethlyammonium chloride In phthalonitrile at 170℃; for 4 h;
EXAMPLES General Procedure for the Examples [0094] The potassium fluoride, the 2,4-dichloronitrobenzene and the solvent are charged to a Schott tube or reactor placed under a nitrogen atmosphere and then heating is carried out at the temperature indicated for 4 h. After 4 h, the reaction mixture is subsequently filtered and analyzed by gas chromatography. Example 1 [0095] In this example, the general procedure was used under the following conditions: dichloronitrobenzene (DCNB) with the amount of potassium fluoride stoichiometrically necessary for a double exchange (in fact, a slight excess equal to 1.05 SA) and an amount of tetramethylammonium chloride (TMAC) equal to 0.04 times the amount of dichloronitrobenzene, expressed in moles. The figures between brackets located before the name of the chemical product express its molar ratio, the substrate being taken as reference. (1) DCNB+(2) KF+(0.04) TMAC+(3) Solvent/170° C., 4 h, Schott tubes
44 %Chromat.
With potassium fluoride; tetramethlyammonium chloride In caprylnitrile at 170℃; for 4 h;
EXAMPLES General Procedure for the Examples [0094] The potassium fluoride, the 2,4-dichloronitrobenzene and the solvent are charged to a Schott tube or reactor placed under a nitrogen atmosphere and then heating is carried out at the temperature indicated for 4 h. After 4 h, the reaction mixture is subsequently filtered and analyzed by gas chromatography. Example 1 [0095] In this example, the general procedure was used under the following conditions: dichloronitrobenzene (DCNB) with the amount of potassium fluoride stoichiometrically necessary for a double exchange (in fact, a slight excess equal to 1.05 SA) and an amount of tetramethylammonium chloride (TMAC) equal to 0.04 times the amount of dichloronitrobenzene, expressed in moles. The figures between brackets located before the name of the chemical product express its molar ratio, the substrate being taken as reference. (1) DCNB+(2) KF+(0.04) TMAC+(3) Solvent/170° C., 4 h, Schott tubes
7 %Chromat.
With potassium fluoride; tetramethlyammonium chloride In butanedinitrile at 170℃; for 4 h;
EXAMPLES General Procedure for the Examples [0094] The potassium fluoride, the 2,4-dichloronitrobenzene and the solvent are charged to a Schott tube or reactor placed under a nitrogen atmosphere and then heating is carried out at the temperature indicated for 4 h. After 4 h, the reaction mixture is subsequently filtered and analyzed by gas chromatography. Example 1 [0095] In this example, the general procedure was used under the following conditions: dichloronitrobenzene (DCNB) with the amount of potassium fluoride stoichiometrically necessary for a double exchange (in fact, a slight excess equal to 1.05 SA) and an amount of tetramethylammonium chloride (TMAC) equal to 0.04 times the amount of dichloronitrobenzene, expressed in moles. The figures between brackets located before the name of the chemical product express its molar ratio, the substrate being taken as reference. (1) DCNB+(2) KF+(0.04) TMAC+(3) Solvent/170° C., 4 h, Schott tubes
30 %Chromat.
With potassium fluoride; tetramethlyammonium chloride In heptanenitrile at 170℃; for 4 h;
EXAMPLES General Procedure for the Examples [0094] The potassium fluoride, the 2,4-dichloronitrobenzene and the solvent are charged to a Schott tube or reactor placed under a nitrogen atmosphere and then heating is carried out at the temperature indicated for 4 h. After 4 h, the reaction mixture is subsequently filtered and analyzed by gas chromatography. Example 1 [0095] In this example, the general procedure was used under the following conditions: dichloronitrobenzene (DCNB) with the amount of potassium fluoride stoichiometrically necessary for a double exchange (in fact, a slight excess equal to 1.05 SA) and an amount of tetramethylammonium chloride (TMAC) equal to 0.04 times the amount of dichloronitrobenzene, expressed in moles. The figures between brackets located before the name of the chemical product express its molar ratio, the substrate being taken as reference. (1) DCNB+(2) KF+(0.04) TMAC+(3) Solvent/170° C., 4 h, Schott tubes
Reference：
[1] Journal of Medicinal Chemistry, 2005, vol. 48, # 6, p. 1729 - 1744
45
[ 446-35-5 ]
[ 367-81-7 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1916, vol. 35, p. 142[2] Chem. Zentralbl., 1913, vol. 84, # II, p. 760
46
[ 611-06-3 ]
[ 446-35-5 ]
[ 21397-07-9 ]
Reference：
[1] Patent: US5354439, 1994, A,
47
[ 611-06-3 ]
[ 2106-50-5 ]
[ 446-35-5 ]
[ 700-37-8 ]
Reference：
[1] Chemical Communications, 1996, # 3, p. 297 - 298
48
[ 611-06-3 ]
[ 446-35-5 ]
[ 700-37-8 ]
Yield
Reaction Conditions
Operation in experiment
13 %Chromat.
With potassium fluoride; tetramethlyammonium chloride In sulfolane at 170℃; for 4 h;
EXAMPLES General Procedure for the Examples [0094] The potassium fluoride, the 2,4-dichloronitrobenzene and the solvent are charged to a Schott tube or reactor placed under a nitrogen atmosphere and then heating is carried out at the temperature indicated for 4 h. After 4 h, the reaction mixture is subsequently filtered and analyzed by gas chromatography. Example 1 [0095] In this example, the general procedure was used under the following conditions: dichloronitrobenzene (DCNB) with the amount of potassium fluoride stoichiometrically necessary for a double exchange (in fact, a slight excess equal to 1.05 SA) and an amount of tetramethylammonium chloride (TMAC) equal to 0.04 times the amount of dichloronitrobenzene, expressed in moles. The figures between brackets located before the name of the chemical product express its molar ratio, the substrate being taken as reference. (1) DCNB+(2) KF+(0.04) TMAC+(3) Solvent/170° C., 4 h, Schott tubes
32 - 50 %Chromat.
With cesium fluoride In hexanedinitrile at 180 - 220℃; for 0.166667 h; Microwave irradiation
Example 2 [0097] Test Under Microwaves in Adiponitrile [0098] The test molecule is in this instance DCNB with solely cesium fluoride. [0099] Characteristics of the equipment used for the text: [0100] the reactor is made of quartz and has a volume of 40 ml [0101] the stirrer is made of glass [0102] the maximum power of the generator is 300 W. [0103] Temperature regulation is manual and not automatic; the power of the microwave radiation is adjusted manually as a function of time to keep the temperature constant. All the compounds are introduced at ambient temperature; the microwave radiation is switched on and operates at full power (P=300 W) until the desired temperature is achieved. The power of the generator is then adjusted in order to keep the medium at the desired temperature. [0104] The molar ratios with respect to DCNB are as follows:
20 %Chromat.
With potassium fluoride; tetramethlyammonium chloride In pimelonitrile at 170℃; for 4 h;
EXAMPLES General Procedure for the Examples [0094] The potassium fluoride, the 2,4-dichloronitrobenzene and the solvent are charged to a Schott tube or reactor placed under a nitrogen atmosphere and then heating is carried out at the temperature indicated for 4 h. After 4 h, the reaction mixture is subsequently filtered and analyzed by gas chromatography. Example 1 [0095] In this example, the general procedure was used under the following conditions: dichloronitrobenzene (DCNB) with the amount of potassium fluoride stoichiometrically necessary for a double exchange (in fact, a slight excess equal to 1.05 SA) and an amount of tetramethylammonium chloride (TMAC) equal to 0.04 times the amount of dichloronitrobenzene, expressed in moles. The figures between brackets located before the name of the chemical product express its molar ratio, the substrate being taken as reference. (1) DCNB+(2) KF+(0.04) TMAC+(3) Solvent/170° C., 4 h, Schott tubes
15 %Chromat.
With potassium fluoride; tetramethlyammonium chloride In octanedinitrile at 170℃; for 4 h;
EXAMPLES General Procedure for the Examples [0094] The potassium fluoride, the 2,4-dichloronitrobenzene and the solvent are charged to a Schott tube or reactor placed under a nitrogen atmosphere and then heating is carried out at the temperature indicated for 4 h. After 4 h, the reaction mixture is subsequently filtered and analyzed by gas chromatography. Example 1 [0095] In this example, the general procedure was used under the following conditions: dichloronitrobenzene (DCNB) with the amount of potassium fluoride stoichiometrically necessary for a double exchange (in fact, a slight excess equal to 1.05 SA) and an amount of tetramethylammonium chloride (TMAC) equal to 0.04 times the amount of dichloronitrobenzene, expressed in moles. The figures between brackets located before the name of the chemical product express its molar ratio, the substrate being taken as reference. (1) DCNB+(2) KF+(0.04) TMAC+(3) Solvent/170° C., 4 h, Schott tubes
17 %Chromat.
With potassium fluoride; tetramethlyammonium chloride In Glutaronitrile at 170℃; for 4 h;
EXAMPLES General Procedure for the Examples [0094] The potassium fluoride, the 2,4-dichloronitrobenzene and the solvent are charged to a Schott tube or reactor placed under a nitrogen atmosphere and then heating is carried out at the temperature indicated for 4 h. After 4 h, the reaction mixture is subsequently filtered and analyzed by gas chromatography. Example 1 [0095] In this example, the general procedure was used under the following conditions: dichloronitrobenzene (DCNB) with the amount of potassium fluoride stoichiometrically necessary for a double exchange (in fact, a slight excess equal to 1.05 SA) and an amount of tetramethylammonium chloride (TMAC) equal to 0.04 times the amount of dichloronitrobenzene, expressed in moles. The figures between brackets located before the name of the chemical product express its molar ratio, the substrate being taken as reference. (1) DCNB+(2) KF+(0.04) TMAC+(3) Solvent/170° C., 4 h, Schott tubes
46 %Chromat.
With potassium fluoride; tetramethlyammonium chloride In benzonitrile at 170℃; for 4 h;
EXAMPLES General Procedure for the Examples [0094] The potassium fluoride, the 2,4-dichloronitrobenzene and the solvent are charged to a Schott tube or reactor placed under a nitrogen atmosphere and then heating is carried out at the temperature indicated for 4 h. After 4 h, the reaction mixture is subsequently filtered and analyzed by gas chromatography. Example 1 [0095] In this example, the general procedure was used under the following conditions: dichloronitrobenzene (DCNB) with the amount of potassium fluoride stoichiometrically necessary for a double exchange (in fact, a slight excess equal to 1.05 SA) and an amount of tetramethylammonium chloride (TMAC) equal to 0.04 times the amount of dichloronitrobenzene, expressed in moles. The figures between brackets located before the name of the chemical product express its molar ratio, the substrate being taken as reference. (1) DCNB+(2) KF+(0.04) TMAC+(3) Solvent/170° C., 4 h, Schott tubes
13 %Chromat.
With potassium fluoride; tetramethlyammonium chloride In hexanedinitrile at 170℃; for 4 h;
EXAMPLES General Procedure for the Examples [0094] The potassium fluoride, the 2,4-dichloronitrobenzene and the solvent are charged to a Schott tube or reactor placed under a nitrogen atmosphere and then heating is carried out at the temperature indicated for 4 h. After 4 h, the reaction mixture is subsequently filtered and analyzed by gas chromatography. Example 1 [0095] In this example, the general procedure was used under the following conditions: dichloronitrobenzene (DCNB) with the amount of potassium fluoride stoichiometrically necessary for a double exchange (in fact, a slight excess equal to 1.05 SA) and an amount of tetramethylammonium chloride (TMAC) equal to 0.04 times the amount of dichloronitrobenzene, expressed in moles. The figures between brackets located before the name of the chemical product express its molar ratio, the substrate being taken as reference. (1) DCNB+(2) KF+(0.04) TMAC+(3) Solvent/170° C., 4 h, Schott tubes
17 %Chromat.
With potassium fluoride; tetramethlyammonium chloride In 2-methylglutaronitrile at 170℃; for 4 h;
EXAMPLES General Procedure for the Examples [0094] The potassium fluoride, the 2,4-dichloronitrobenzene and the solvent are charged to a Schott tube or reactor placed under a nitrogen atmosphere and then heating is carried out at the temperature indicated for 4 h. After 4 h, the reaction mixture is subsequently filtered and analyzed by gas chromatography. Example 1 [0095] In this example, the general procedure was used under the following conditions: dichloronitrobenzene (DCNB) with the amount of potassium fluoride stoichiometrically necessary for a double exchange (in fact, a slight excess equal to 1.05 SA) and an amount of tetramethylammonium chloride (TMAC) equal to 0.04 times the amount of dichloronitrobenzene, expressed in moles. The figures between brackets located before the name of the chemical product express its molar ratio, the substrate being taken as reference. (1) DCNB+(2) KF+(0.04) TMAC+(3) Solvent/170° C., 4 h, Schott tubes
32 %Chromat.
With potassium fluoride; tetramethlyammonium chloride In phthalonitrile at 170℃; for 4 h;
EXAMPLES General Procedure for the Examples [0094] The potassium fluoride, the 2,4-dichloronitrobenzene and the solvent are charged to a Schott tube or reactor placed under a nitrogen atmosphere and then heating is carried out at the temperature indicated for 4 h. After 4 h, the reaction mixture is subsequently filtered and analyzed by gas chromatography. Example 1 [0095] In this example, the general procedure was used under the following conditions: dichloronitrobenzene (DCNB) with the amount of potassium fluoride stoichiometrically necessary for a double exchange (in fact, a slight excess equal to 1.05 SA) and an amount of tetramethylammonium chloride (TMAC) equal to 0.04 times the amount of dichloronitrobenzene, expressed in moles. The figures between brackets located before the name of the chemical product express its molar ratio, the substrate being taken as reference. (1) DCNB+(2) KF+(0.04) TMAC+(3) Solvent/170° C., 4 h, Schott tubes
44 %Chromat.
With potassium fluoride; tetramethlyammonium chloride In caprylnitrile at 170℃; for 4 h;
EXAMPLES General Procedure for the Examples [0094] The potassium fluoride, the 2,4-dichloronitrobenzene and the solvent are charged to a Schott tube or reactor placed under a nitrogen atmosphere and then heating is carried out at the temperature indicated for 4 h. After 4 h, the reaction mixture is subsequently filtered and analyzed by gas chromatography. Example 1 [0095] In this example, the general procedure was used under the following conditions: dichloronitrobenzene (DCNB) with the amount of potassium fluoride stoichiometrically necessary for a double exchange (in fact, a slight excess equal to 1.05 SA) and an amount of tetramethylammonium chloride (TMAC) equal to 0.04 times the amount of dichloronitrobenzene, expressed in moles. The figures between brackets located before the name of the chemical product express its molar ratio, the substrate being taken as reference. (1) DCNB+(2) KF+(0.04) TMAC+(3) Solvent/170° C., 4 h, Schott tubes
7 %Chromat.
With potassium fluoride; tetramethlyammonium chloride In butanedinitrile at 170℃; for 4 h;
EXAMPLES General Procedure for the Examples [0094] The potassium fluoride, the 2,4-dichloronitrobenzene and the solvent are charged to a Schott tube or reactor placed under a nitrogen atmosphere and then heating is carried out at the temperature indicated for 4 h. After 4 h, the reaction mixture is subsequently filtered and analyzed by gas chromatography. Example 1 [0095] In this example, the general procedure was used under the following conditions: dichloronitrobenzene (DCNB) with the amount of potassium fluoride stoichiometrically necessary for a double exchange (in fact, a slight excess equal to 1.05 SA) and an amount of tetramethylammonium chloride (TMAC) equal to 0.04 times the amount of dichloronitrobenzene, expressed in moles. The figures between brackets located before the name of the chemical product express its molar ratio, the substrate being taken as reference. (1) DCNB+(2) KF+(0.04) TMAC+(3) Solvent/170° C., 4 h, Schott tubes
30 %Chromat.
With potassium fluoride; tetramethlyammonium chloride In heptanenitrile at 170℃; for 4 h;
EXAMPLES General Procedure for the Examples [0094] The potassium fluoride, the 2,4-dichloronitrobenzene and the solvent are charged to a Schott tube or reactor placed under a nitrogen atmosphere and then heating is carried out at the temperature indicated for 4 h. After 4 h, the reaction mixture is subsequently filtered and analyzed by gas chromatography. Example 1 [0095] In this example, the general procedure was used under the following conditions: dichloronitrobenzene (DCNB) with the amount of potassium fluoride stoichiometrically necessary for a double exchange (in fact, a slight excess equal to 1.05 SA) and an amount of tetramethylammonium chloride (TMAC) equal to 0.04 times the amount of dichloronitrobenzene, expressed in moles. The figures between brackets located before the name of the chemical product express its molar ratio, the substrate being taken as reference. (1) DCNB+(2) KF+(0.04) TMAC+(3) Solvent/170° C., 4 h, Schott tubes
With palladium on activated charcoal; hydrogen In methanol at 20℃;
Add in 100mL single-mouth bottles2,4-Difluoro-1-nitrobenzene (1 g), methanol (10 mL) and Pd/C (100 mg) were replaced with hydrogen three times and stirred at room temperature for 2-3 h. Filtration and concentration of the filtrate under reduced pressure afforded 810 mg.
Reference：
[1] Synthetic Communications, 2012, vol. 42, # 2, p. 213 - 222
[2] Synthesis and Reactivity in Inorganic, Metal-Organic and Nano-Metal Chemistry, 2011, vol. 41, # 1, p. 114 - 119
[3] Journal fuer Praktische Chemie (Leipzig), 1934, vol. <2> 140, p. 97,111
[4] Chemische Berichte, 1937, vol. 70, p. 2396,2400
[5] Journal fuer Praktische Chemie (Leipzig), 1934, vol. <2> 140, p. 97,111
[6] Chemische Berichte, 1937, vol. 70, p. 2396,2400
[7] Recueil des Travaux Chimiques des Pays-Bas, 1916, vol. 35, p. 142[8] Chem. Zentralbl., 1913, vol. 84, # II, p. 760
[9] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1959, p. 71,73; engl. Ausg. S. 64, 66
[10] Patent: US4375550, 1983, A,
[11] Advanced Synthesis and Catalysis, 2011, vol. 353, # 8, p. 1306 - 1316
[12] Chinese Chemical Letters, 2012, vol. 23, # 5, p. 545 - 548
[13] Chinese Chemical Letters, 2014, vol. 25, # 8, p. 1137 - 1140
[14] Patent: CN108707139, 2018, A, . Location in patent: Paragraph 1043; 1046; 1047; 1048
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With trihexyl (tetradecyl) phosphonium tetrafluoroborate; potassium fluoride; In dimethyl sulfoxide; at 180℃; for 1.8h;
General procedure: dry dimethylsulfoxide (10 ml) was preheated in a screw-capped Teflon reactor at 180 C before adding the phase transfer catalyst (0.86 mmol), KF (0.5 g) and 1,2-dichloro-4-nitrobenzene (6 mmol). The reaction was carried out under nitrogen with stirring. Samples were withdrawn periodically during the reaction, filtered to remove the solid salts and analyzed by gas chromatography (HP-5). Compounds were identified by comparison with authentic samples and by gas chromatography-mass spectrometry (Shimadzu QP 5000).
90%
With potassium fluoride; In sulfolane; methanol; at 100 - 180℃; for 8h;Product distribution / selectivity;
Example 6; Into a 50 mL flask equipped with a reflux condenser, 25 g of sulfolane was charged and the inner temperature thereof was adjusted at 140 C. To this, the solution obtained by dissolving 4.5 g of potassium fluoride, which was the same as used in Example 1, in 60 g of methanol was added dropwise together with removing distilled methanol out the system. The addition of all amount of the methanol solution of potassium fluoride dropwise was finished and methanol was hardly distilled out at all, and then, the concentration was further conducted at 160 C. at 2.7 kPa to obtain a potassium fluoride dispersion essentially consisting of potassium fluoride and sulfolane. The potassium fluoride dispersion was analyzed with gas chromatography area comparison method. The amount of methanol was 0.02% by weight or less per 1 part by weight of sulfolane.The potassium fluoride dispersion cooled at 100 C. was mixed with 5 g of <strong>[611-06-3]2,4-dichloronitrobenzene</strong>. The obtained mixture was kept for 8 hours at 180 C. with stirring. The obtained reaction mixture was cooled to 100 C. and then, 100 g of toluene was added thereto. The obtained mixture was cooled to room temperature. The precipitated solid was separated by filtration and the separated solid was washed with 10 g of toluene. The filtrate and wash liquid were mixed and the obtained solution was analyzed with gas chromatography internal standard method. The yield of 2,4-difluoronitrobenzene was 90% and the yield of chlorofluoronitrobenzene was 10%.
89 - 92%
With potassium fluoride; In sulfolane; at 100 - 180℃; for 10h;Product distribution / selectivity;
Example 5; Into a 50 mL flask equipped with a reflux condenser, 25 g of sulfolane was charged and the inner temperature thereof was adjusted at 140 C. To this, the solution obtained by dissolving 4.5 g of potassium fluoride, which was the same as used in Example 1, in 60 g of methanol was added dropwise together with removing distilled methanol out the system. The addition of all amount of the methanol solution of potassium fluoride dropwise was finished and methanol was hardly distilled out at all, and then, 10 g of toluene was added to the concentrate. The concentration was further continued to remove a mixed solution of methanol and toluene. After that, residual toluene was removed by reducing to 6 kPa at the same temperature to obtain a potassium fluoride dispersion essentially consisting of potassium fluoride and sulfolane.The potassium fluoride dispersion cooled at 100 C. was mixed with 5 g of <strong>[611-06-3]2,4-dichloronitrobenzene</strong>. The obtained mixture was kept for 10 hours at 180 C. with stirring. The obtained reaction mixture was cooled to 100 C. and then, 100 g of toluene was added thereto. The obtained mixture was cooled to room temperature. The precipitated solid was separated by filtration and the separated solid was washed with 10 g of toluene. The filtrate and wash liquid were mixed and the obtained solution was analyzed with gas chromatography internal standard method. The yield of 2,4-difluoronitrobenzene was 92% and the yield of chlorofluoronitrobenzene was 8%.; Example 10; Into a 200 mL flask, 53 g of methanol and 4.4 g of potassium hydroxide were charged. The mixture was stirred at room temperature to prepare a methanol solution of potassium hydroxide. To the prepared methanol solution of potassium hydroxide, 3.3 g of 47% by weight hydrofluoric acid was added dropwise while cooling to keep at an inner temperature of 30 C. or less to prepare a potassium fluoride solution.Into a 50 mL flask equipped with a reflux condenser, 25 g of sulfolane was charged and the inner temperature thereof was adjusted at 140 C. To this, the above-mentioned potassium fluoride solution was added dropwise together with removing distilled mixed solution of methanol and water out the system. The addition of all amount of the potassium fluoride solution dropwise was finished and methanol and water were hardly distilled out at all, and then, the concentration was continued at 160 C. at 2.7 kPa to remove residual methanol and water to obtain a potassium fluoride dispersion essentially consisting of potassium fluoride and sulfolane.The potassium fluoride dispersion cooled at 100 C. was mixed with 5 g of <strong>[611-06-3]2,4-dichloronitrobenzene</strong>. The obtained mixture was kept for 10 hours at 180 C. with stirring. The obtained reaction mixture was cooled to 100 C. and then, 100 g of toluene was added thereto and the obtained mixture was cooled to room temperature. The precipitated solid was separated by filtration and the separated solid was washed with 10 g of toluene. The filtrate and wash liquid were mixed to analyze with gas chromatography internal standard method. The Yield of 2,4-difluoronitrobenzene was 89% and the yield of chlorofluoronitrobenzene was 9%.
With potassium fluoride; tetramethlyammonium chloride; dimethyl sulfoxide;
EXAMPLE 1 The following were charged into a 70 ml reactor under a nitrogen atmosphere: 17.7 g (306 mmoles) of potassium fluoride, 1.3 g (12 mmoles) of tetramethylammonium chloride, 17.0 g of dimethyl sulfoxide, and 19.6 g (102 mmoles) of <strong>[611-06-3]2,4-dichloronitrobenzene</strong>. The reaction mixture was treated with ultrasonic sound, while the temperature was maintained at 130 C. for 30 minutes. After filtration, an analysis of the crude reaction product gave the following results: conversion of <strong>[611-06-3]2,4-dichloronitrobenzene</strong>: 67.1% yield of fluorochloronitrobenzenes: 52% yield of 2,4-difluoronitrobenzene: 13.9%
EXAMPLE 14 A procedure analogous to that described in Example 13 but using unground potassium fluoride as the starting material leads, after heating for 4 h 30 at 130 C., to the following results: Conversion of <strong>[611-06-3]2,4-dichloronitrobenzene</strong> =99.7%. Yield of 2,4-difluoronitrobenzene=90.4%. Yield of fluorochloronitrobenzenes =9.7%. After treatment and distillation, 173.9 g of product (yield of 2,4-difluoronitrobenzene 87.4%, purity 96.3%) were obtained.
EXAMPLE 2 The same method was used as in Example 1. The reaction mass was not subjected to the action of ultrasonic sound but was heated at 130 C. for 30 minutes: conversion of <strong>[611-06-3]2,4-dichloronitrobenzene</strong>: 43.8% yield of fluorochloronitrobenzenes: 34.3% yield of 2,4-difluoronitrobenzene: 4.0%
With potassium fluoride; In sulfolane;
EXAMPLE 17 2.4 g of potassium fluoride (41.4 mmoles), 3.9 g of <strong>[611-06-3]2,4-dichloronitrobenzene</strong> (20.5 mmoles) and 6 g of sulfolane were charged into a 50 ml reactor placed under a nitrogen atmosphere. The mixture was heated at 180 C. for 11 hours. The reaction mixture was then filtered and the filtrate analyzed by GPC: Conversion of <strong>[611-06-3]2,4-dichloronitrobenzene</strong> =85.5%. Yield of 2,4-difluoronitrobenzene=29.0%. Yield of fluorochloronitrobenzenes: 44.7%.
With potassium fluoride; In sulfolane;
EXAMPLE 30 The method of Example 17 was repeated by heating a mixture of potassium fluoride (61.5 mmoles, 3.6 g), <strong>[611-06-3]2,4-dichloronitrobenzene</strong> (20.5 mmoles, 3.9 g) and sulfolane (6.2 g) at 180 C. for 6 hours: Conversion of <strong>[611-06-3]2,4-dichloronitrobenzene</strong>: 81.7% Yield of 2,4-difluoronitrobenzene: 47.7%
b Subsequent batch The 220 g of intermediate products and <strong>[611-06-3]2,4-dichloronitrobenzene</strong> from Example 9a) were admixed with 548.0 g (2.85 mol) of fresh <strong>[611-06-3]2,4-dichloronitrobenzene</strong>, and the reaction was carried out as for the initial batch. The amount of 2,4-difluoronitrobenzene isolated was, after fractionation, 420.2 g (92.7% of theory), based on fresh <strong>[611-06-3]2,4-dichloronitrobenzene</strong> used, besides 160 g of intermediate products and <strong>[611-06-3]2,4-dichloronitrobenzene</strong>.
With N-Bromosuccinimide; sulfuric acid; at 60℃; for 6h;
Dissolve 2,4-difluoronitrobenzene (1.51g, 9.50mmol) in concentrated H2SO4 (12mL). After warming to 60 C, add NBS (1.86g, 10.45mmol) in three batches. Stir well and react for 6h. . By TLC, the raw materials were completely reacted. Stop the reaction and cool down, then pour into ice water. Extraction with DCM, combined organic phases and column chromatography (PE / EA = 125/1) gave 1.43 g of slightly yellow oil, yield: 63.62%, and combined portions were combined and treated.
With sodium carbonate;potassium iodide; In N,N-dimethyl-formamide; at 50℃; for 5h;
Ethyl-4-amino-i-piperidine-carboxylate (11.9 g, 69 mmol) was added to a stirred suspension of 2,4-difluoronitrobenzene (10.0 g, 63 mmol), sodium carbonate (6.7 g, 63 mmol) and potassium iodide (0.1 g, 0.6 mmol) in dimethylformamide (100 ml_). The mixture was heated to 50 0C, stirred for 5 hours and then allowed to cool. The reaction mixture was diluted with water (130 mL) and ethyl acetate (200 ml_). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2 x 200 mL). The organic extracts were combined, extracted with a 10% aqueous solution of citric acid (250 mL), dried over MgSO4 and evaporated under reduced pressure. The residue was purified by column chromatography on silica, eluting with ethyl acetate/hexane (1 :2) to give the title compound (16.9g, 86% yield) as a yellow solid. (Rf: 0.5 (ethyl acetate/hexane 7:8))
With potassium carbonate; In acetonitrile; at 120℃;
[0623] A solution of 2,4-difluoronitrobenzene (0.400 mL, 3.65 mmol, 1.00 equiv) in acetonitrile was charged with K2CO3 (0.605 g, 4.38 mmol, 1.20 equiv) followed by ethyl-2-amino-5-thiazolecarboxylate (0.628 g, 3.65 mmol, 1.00 equiv) as a solid. The heterogeneous mixture was sealed and heated to 120 C. overnight. The solution was filtered and then concentrated in vacuo. Purification by flash chromatography afforded ethyl-2-[(3-fluoro-6-nitro-1-phenyl)amino]-5-thiazolecarboxylate as a yellow solid (9%). This intermediate was coupled with 2-chloro-6-methyl aniline according to the procedure for compound 528 to afford N-(2-Chloro-6-methylphenyl)-2-[3-(fluoro-6-nitro-1-phenyl)amino]-5-thiazolecarboxamide (21%). The title compound was synthesized by reacting this intermediate with excess N-(3-aminopropyl)-imidazole at 80 C. followed by purification by reverse phase preparative HPLC.
With lithium hydroxide; In water; dimethyl sulfoxide; at 20℃; for 18h;
Add <strong>[138564-58-6]2-amino-5-methyl-thiophene-3-carbonitrile</strong> (10.0 g, 72.4 mmol) and 2,4- [DIFLUORO-1-NITRO-BENZENE] (8.00 mL, 73.0 mmol) to DMSO (130 mL) and stir under nitrogen at ambient temperature. Add lithium hydroxide monohydrate (6.10 g, 145 mmol) in one portion and stir at ambient temperature. After 18 hours, add deionized water (390 mL) dropwise at [10-20 C.] Adjust the pH to 7-8 with concentrated [HC1] (-6 mL) and stir for 4 hours. Filter the crude product and rinse with 3: 1/water : DMSO, then water. Dry at [50 C] to constant weight. Purify by flash chromatography, eluting with methylene chloride to give the title compound 10.3 g (62%) [:'H] NMR (400 MHz, [DMSO-D6)] [5] 9.83 (bs, 1H), 8. 28 (m, [1H),] 7.12 (s, 1H), 6.91 (m, [1H),] 6.73 (m, 1H), 2.53 (s, 3H). HRMS (ES) exact mass M+H calcd for [C12H8FN302S] 300.0219 ; found 300.0219.
With sodium hydride In tetrahydrofuran at 45℃; for 18h;
4
Dissolve 2-amino-5-ethyl-thiophene-3-carbonitrile (8.2g, [54MMOL)] and 2,4- difluoronitrobenzene (8. 6g, [54MMOL)] in tetrahydrofuran (20ml) and add to a stirring solution of sodium hydride (50% dispersion in mineral oil) (4. [1G, 1.] 4equiv) in tetrahydrofuran [(50ML)] under a nitrogen atmosphere. Maintain the rate of addition to keep the temperature below [45 °C] and gas evolution under control. Stir [18H.] Pour the mixture into a mixture of ice and [2NHC1,] extract into ethyl acetate, dry [(MGS04)] and concentrate under reduced pressure. Dissolve in ethanol (100ml) and collect [2- (5-FLUORO-2-NITRO-] phenylamino) -5-ethyl-thiophene-3-carbonitrile by filtration as a yellow solid (7.9g, 50%): mass spectrum (LCMS) 292 [(M+L),] 314 (M+Na). NMR [(H,] 300 MHz, CDC13) : 8 9.7 (1H broad), 8.25 [(LH,] m), 6.80 [(1H,] s), 6.75 [(LH,] dd), 6.65 [(1H,] s), 2.80 (2H, q), 1.35 (3H, t).
With lithium hydroxide; In water; dimethyl sulfoxide; at 55℃; for 16h;
Combine 2, [4-DIFLUORO-L-NITRO-BENZENE] (5.36g, 33.69 mmol), 2-amino-5- trifluoromethyl-benzonitrile (5. [701G, 30.] 63 mmol) and lithium hydroxide monohydrate (2.57g, 61.25 mmol) in methyl sulfoxide (DMSO, 70 ml). Heat the resulting mixture to [55 C] for 16 hours. Cool the reaction mixture to ambient temperature, then pour into approximately 250 ml of ice water and stir for one hour. Filter the resulting mixture, wash with a large amount of water and collect the precipitate to obtain 9. [53G] of the title compound (29.30 mmol, 96% yield) as a yellow amorphous solid: Mass Spectrum (m/e): 324 [(M-1)
With tert-butoxide; In tetrahydrofuran; at 0℃; for 0.5h;
To a solution of trifluoroethanol in 4 mL dry THF, was added tert-butoxide (378 mg, 3.37 mmol) at 0 C. The resulting mixture was added dropwise to the solution of 2, 4-difluoro-1-nitro-benzene (536 mg, 3.37 mmol) in 5 mL dry THF at 0C. The mixture was stirred at 0C for 30 minutes, then diluted with ethyl acetate and washed with brine. The organic layers were combined and concentrated in vacuo to give 4-fluoro-l-nitro-2- (2, 2,2- trifluoro-ethoxy)-benzene.
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 25 - 105℃; for 48h;
To the solution of 2,4-difluoro- I -nitrobenzene (1.80 g, 11.0 mmol) and DIEA (1.93 ml, 11.0 mmol) in THF (20 ml) was added 5-isopropoxyl-1H pyrazol-3-amine (1.30 g, 80% pure 7.4 mmol) at 25 C. After addition, the reaction mixture was stirred at 105 C for 48 hrs. The solvent was removed under reduced pressure and the resulted residue was purified by column chromatography (hexane : EtOAc = 5 : 1) to give the title compound as a yellow solid (0.22 g, 66% pure, 7%). MS: Calcd. : 280; Found: [M+H]+ 281.
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 2h;
N-(3-Chlorobenzyl)-5-fluoro-2-nitrobenzenamine:; 2,4-Difluoronitrobenzene (2.9 g, 18.1 mmol), 3-chlorobenzylarnine (2.6 g, 18.1 mmol) 0 and LambdazetaiV-diisopropylethylamine (2.4 g, 18.1 mmol) were stirred in acetonitrile (25 mL) at room temperature for 2 hours. The solvent was evaporated and the crude mixture was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated in vacuo to collect the title compound (4.8 g, 95 percent yield). 1H NMR (400 MHz, CDCl3): delta 8.55 (s, IH), 8.25 (dd, IH), 7.32-7.21 (m, 4H), 6.41 (m, 2H), 4.50 (d, 2H).
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 60℃; for 2 - 3h;
A mixture of 2,4-difluoronitrobenzene (0.35 mL) and N,N-diisopropylethylamine (1.28 mL) was added to a mixture of the compound obtained from the step a above (800 mg) in dimethyl sulphoxide (10 mL). The reaction mixture was stirred at 600C for about 2-3 h, poured into ice-cold water, and extracted with dichloromethane. The solvent was evaporated under vacuum to yield the title compound (850 mg) as a semi-solid.
With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 2h;
15
N-(3 -Bromobenzyl)-5 -fluoro-2-nitrobenzenamine :; 2,4-Difluoronitrobenzene (2.9 g, 18.1 mmol), 3-Bromobenzylamine (2.6 g, 18.1 mmol) and AζiV-diisopropylethylamine (2.4 g, 18.1 mmol) were stirred in acetonitrile (25 mL) at room temperature for 2 hours. The solvent was evaporated and the crude mixture was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated in vacuo to collect the title compound (4.8 g, 95 % yield). 1H NMR (400 MHz, CDCl3): δ 8.55 (s, IH), 8.25 (dd, IH), 7.32-7.21 (m, 4H), 6.41 (m, 2H), 4.50 (d, 2H).
With N-ethyl-N,N-diisopropylamine; In acetonitrile; for 18h;Heating / reflux;
1 -(2-(3 ,5-DichloiObenzylamino)-4-fluoro-nitrobenzene:; A mixture of 2,4-difluoronitrobenzene (5.0 mmol), <strong>[39989-43-0]3,5-dichlorobenzylamine</strong> (5.0 mmol), N, N- diisopropylethylamine (10.0 mmol) and acetonitrile (25 mL) was heated at reflux for 18 h, cooled and concentrated in vacuo. The residue was dissolved in ethyl acetate; this solution was washed with water, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using 5 % ethyl acetate in hexanes as eluent to yield the title compounds as a yellowish solid (46 %). 1H NMR (400 MHz, CDCl3): delta 9.28 (br s, 1 H)5 7.88 (m, 1 H)5 7.34 (s, 1 H)5 7.22 (s, 2 H), 6.44 (m, 1 H), 6.30 (dd, 1 H), 4.43 (d, 2 H).
With sodium hydrogencarbonate; caesium carbonate; acetic acid; In diethyl ether; N,N-dimethyl-formamide;
Example 148 This illustrates the synthesis of (2-fluoro-4-nitro-phenyl)acetic acid 148. A round-bottomed flask was charged with diethyl malonate (8.6 g, 54 mmol), cesium carbonate (29.3 g, 90 mmol), and anhydrous DMF (36 mL). The mixture was warmed to 70 C. and 2,4-difluoronitrobenzene (5.75 g, 36 mmol) was added in a dropwise fashion with vigorous stirring. The reaction medium immediately turned dark purple. After the addition was complete, the reaction was stirred at 70 C. for 30 minutes. After cooling to room temperature, the reaction was quenched with 4 mL of acetic acid and then poured into 300 mL of 0.3 N HCl(aq). The purple color discharged completely upon addition to the acid. The mixture was then neutralized by adding solid NaHCO3 until no gas evolution took place. The mixture was extracted 2*150 mL 1:1 diethyl ether:hexanes. The combined organic layers were washed 2*100 mL DI water and 1*50 mL sat. brine. The organic layer was dried over MgSO4 and concentrated to a yellow oil. This oil was suspended in 40 mL of 6N HCl(aq) and the mixture heated to reflux for 16 h. Upon cooling, crystals separated and were collected by filtration. The crystals were dried under vacuum to yield 2-fluoro-4-nitro-phenylacetic acid (148) as off-white crystals (5.42 g). 1H NMR (400 MHz) (d4-MeOH) delta 8.06 (1H, d); 8.04 (1H, d); 7.60 (1H, t); 3.81 (2H, s).
A round-bottomed flask was charged with diethyl malonate (8.6 g, 54 mmol), cesium carbonate (29.3 g, 90 mmol), and anhydrous DMF (36 mL). The mixture was warmed to 70 C. and 2,4-difluoronitrobenzene (5.75 g, 36 mmol) was added in a dropwise fashion with vigorous stirring. The reaction medium immediately turned dark purple. After the addition was complete, the reaction was stirred at 70 C. for 30 minutes. After cooling to room temperature, the reaction was quenched with 4 mL of acetic acid and then poured into 300 mL of 0.3 N HCl(aq). The purple color discharged completely upon addition to the acid. The mixture was then neutralized by adding solid NaHCO3 until no gas evolution took place. The mixture was extracted 2×150 mL 1:1 diethyl ether:hexanes. The combined organic layers were washed 2×100 mL DI water and 1×50 mL sat. brine. The organic layer was dried over MgSO4 and concentrated to a yellow oil. This oil was suspended in 40 mL of 6N HCl(aq) and the mixture heated to reflux for 16 h. Upon cooling, crystals separated and were collected by filtration. The crystals were dried under vacuum to yield 2-fluoro-4-nitro-phenylacetic acid (148) as off-white crystals (5.42 g). 1H NMR (400 MHz) (d4-MeOH) delta 8.06 (1H, d); 8.04 (1H, d); 7.60 (1H, t); 3.81 (2H, s).
With water; potassium hydroxide In tetrahydrofuran at 52 - 58℃;
1 Example 1
Add 274.4 g of water to a 1L four-necked flask, and slowly add 117.6 g (2.1 mol) of potassium hydroxide.Stir until the solution is clear, add 111.36 g of tetrahydrofuran, and raise the temperature to 52 ° C.111.36g (0.7mol) of 2,4-difluoronitrobenzene was added dropwise,During the dropwise addition, the internal temperature of the reaction was maintained at 55-58 ° C. After the 0.5 hour dropwise addition was completed, the temperature was kept under stirring for 1-1.5 hours. The liquid phase detection raw material was <0.5%, and the reaction was complete. Ensure the system temperature is higher than 30 ,36% by weight of hydrochloric acid was added dropwise to adjust the pH = 4, and the layers were left to stand.After removing the solvent under reduced pressure in the organic layer, 104 g of an oil was obtained with a yield of 95% and a liquid phase content of 95.3%.
91.3%
With potassium hydroxide In water; toluene at 55 - 60℃;
1 (1) Preparation of 4-fluoro-2-hydroxynitrobenzene
In a 5L four-necked flask, 556 g (3.50 mol) of 2,4-difluoronitrobenzene was added, and heated to 55 ° C. 2000 g (7.14 mol) of 20% aqueous KOH solution was added dropwise, the temperature was controlled between 55-60°C for 3-4 hours. After completion of the addition, reacted at 55-60°C for 5-6 hours. GC control ,2,4-difluoronitrobenzene <1.0%. Toluene 300 g was added, stirred for 30 minutes, cooled to 50°C, layer separation was carried out, 30% hydrochloric acid (800 g) was dropped to the aqueous layer, such that the temperature does not exceed 60°C. The pH was adjusted between 5-6, stirred for 30 min, recalculate pH = 5-6. heated, and steam distilled for 5 hours. After the end of distillation, layer separation was carried out, oil 500 g was separated to obtain 4-fluoro-2-hydroxy nitrobenzene. Yellow oily liquid. GC content of 99.7%, the yield of 91.3%.
With calcium hydroxide; potassium hydroxide; sulfuric acid In water
1 EXAMPLE 1
EXAMPLE 1 159.1 g (1 mol) of 2,4-difluoronitrobenzene and 550 g of water are initially introduced and are heated to 55° C. With vigorous stirring, 241.2 g (2.15 mol) of 50% strength potassium hydroxide solution are added dropwise over 4 hours and the temperature is maintained at 55° C. (exothermic reaction). Stirring is then continued for another 2 hours at this temperature. The pH is then adjusted to 4.3 (25° C.) using 88 g of sulfuric acid, and 74.1 g of calcium hydroxide are added. The pH is readjusted to 5.0 and the introduction of steam is started. During distillation the pH is decreased from 5 to 1.5 by dropwise addition of sulfuric acid. The product is isolated by cooling and filtering the distillate. After drying, 117.9 g (0.750 mol, 75% of theory) of bright yellow 2-nitro-5-fluorophenol is obtained, which is more than 99.9% pure according to GC and HPLC (solidification point 32.1° C.). If sodium hydroxide is used instead of potassium hydroxide and/or if acidification is with hydrochloric acid instead of sulfuric acid and/or if calcium chloride is used instead of calcium hydroxide as fluoride scavenger, then essentially the same result is obtained.
With potassium hydroxide In water at 70 - 90℃; for 3h;
Hydroxyl substitution
A certain amount of 2,4-difluoronitrobenzene, water, and potassium hydroxide are sequentially added to the reaction vessel, and the temperature naturally rises.After incubation at 70-90°C for about 2 hours at 70-90°C, the incubation is continued for 1 hour and sample is taken to 2,4-difluoronitrobenzene at <0.5%. After the sample is qualified, a certain amount of hydrochloric acid is added, and the product and water are azeotroped. The mixture is heated evenly after stirring, and the product is distilled out by steam distillation. About 92 °C began to produce products. Distillation is complete, the product barrel, Intermediate 1 to be the next reaction. Wherein, the intermediate 1 is C6H4FNO3, the product is C6H4FNO3 and potassium fluoride KF; the mass ratio of C6H4FNO3 and potassium fluoride KF is 157:58;
With potassium hydroxide at 50℃; for 6h; Flow reactor;
1.S1 Synthesis of S1, 2-nitro-5-fluorophenol:
Synthesis of S1, 2-nitro-5-fluorophenol: add water to the reactor, then add 2,4-difluoronitrobenzene, add potassium hydroxide solution at a temperature of 50 , after the filling, stir for 6 hours , And cooled to room temperature, the aqueous layer was neutralized with hydrochloric acid to weakly acidic, extracted with cyclohexane, stirred, stand still for layering, combined the organic phases, and desolventized to obtain the yellow solid 2-nitro-5-fluorophenol;
EXAMPLE 5 The following were charged into a 30 ml reactor closed with a septum, under a nitrogen atmosphere: 4.06 g of KF (70 mmoles), 0.3 g of Me4 NC1 (2.7 mmoles), 5.63 g of 2,4-dichloronitrobenzene (29.3 mmoles), and 8.16 of dimethyl sulfoxide. The mixture was treated with ultrasonic sound in cycles. For 75% of each 1-second cycle, the ultrasonic sound was inactive. The temperature was kept at 130 C. for 30 minutes. Conversion of 2,4-dichloronitrobenzene: 84% Yield of fluorochloronitrobenzene: 47% Yield of 2,4-difluoronitrobenzene: 34%
N-(5-fluoro-2-nitrophenyl)-S-methyl-L-cysteine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sulfuric acid; triethylamine; In water; acetone;
EXAMPLE 1 N-(5-Fluoro-2-nitrophenyl)-<strong>[1187-84-4]S-methyl-L-cysteine</strong> 16.2 g of (-)-S-Methyl-L-cysteine (0.1 mol) are suspended in a mixture of 120 ml of water and 120 ml of acetone in a four-necked flask under N2. 30.4 ml (22.2 g) of triethylamine (0.22 mol) are added rapidly while stirring. 15.9 g of 2,4-difluoronitrobenzene (0.1 mol) are added, with further stirring, to the resulting yellow solution. The mixture is heated to reflux for 7.5 hours while stirring (orange-colored solution) and the acetone is then stripped off under reduced pressure on a rotary evaporator; the aqueous residue is transferred to a separating funnel and extracted 2* with approximately 50 ml of methyl tert-butyl ether (MTB ether). This extract is composed, in the main, of 2,4-difluoronitrobenzene and is discarded. The aqueous phase is transferred to a four-necked flask and 150 ml of MTB ether are added to it, after which the mixture is adjusted, while being cooled (<25 C.), to pH 1 with approximately 25 ml of 38% sulfuric acid. The mixture is then stirred thoroughly until clear phases are formed. The ether phase is separated off and the aqueous phase is extracted once again with 50 ml of MTB ether.
4-ethoxycarbonyl-5-methyl-1-(2-nitro-5-fluorophenyl)-1H-imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30.5 g (65%)
With potassium carbonate; In acetonitrile;
Step a. 4-Ethoxycarbonyl-5-methyl-1-(2-nitro-5-fluorophenyl)-1H-imidazole A mixture of 2,4-difluoronitrobenzene (36.6 g, 230 mmol), ethyl 4-methyl-5-imidazolecarboxylate (35.6 g, 231 mmol), potassium carbonate (36.5 g, 264.4 mmol) and acetonitrile (250 ml) was stirred at 25° C. for 96 h. The reaction mixture was filtered and the solvent removed under reduced pressure. The residue was submitted to flash chromatography on silica gel 60 eluding with toluene graduated to toluene/ethyl acetate (1:1) to give 30.5 g (65percent) of 4-ethoxycarbonyl-5-methyl-1-(2-nitro-5-fluorophenyl)-1H-imidazole. 1 H-NMR (CDCl3): delta1.40 (t, 3H), 2.35 (s, 3H), 4.40 (q, 2H), 7.70 (dd, 1H), 7.40-7.50 (m, 1H), 7.50 (s, 1H), 8.25 (dd, 1H).
30.5 g (65%)
With potassium carbonate; In acetonitrile;
Step a. 4-Ethoxycarbonyl-5-methyl-1-(2-nitro-5-fluorophenyl)-1H-imidazole A mixture of 2,4-difluoronitrobenzene (36.6 g, 230 mmol), ethyl 4-methyl-5-imidazolecarboxylate (35.6 g, 231 mmol), potassium carbonate (36.5 g, 264.4 mmol) and acetonitrile (250 ml) was stirred at 25°C for 96 h. The reaction mixture was filtered and the solvent removed under reduced pressure. The residue was submitted to flash chromatography on silica gel 60 eluding with toluene graduated to toluenelethyl acetate (1:1) to give 30.5 g (65percent) of 4-ethoxycarbonyl-5-methyl-1-(2-nitro-5-fluorophenyl)-1H-imidazole. 1H-NMR (CDCl3): delta 1.40 (t, 3H), 2.35 (s, 3H), 4.40 (q, 2H), 7.70 (dd, 1H), 7.40-7.50 (m, 1H), 7.50 (s, 1H), 8.25 (dd, 1H).
Preparation 2 2-Ethyl-1-(2-nitro-5-fluorophenyl)-4-methyl-1H-imidazole Combine 100 g of 2,4-difluoronitrobenzene, 69 g of <strong>[931-36-2]2-ethyl-4-methylimidazole</strong> and 100 g of K2 CO3 in 700 mL of acetonitrile, and stir at room temperature for 4 days. Remove the solvent under vacuum. Slurry the residue in 300 mL of CH2 Cl2 and chromatograph over 1 kg of silica gel using CH2 Cl2. Combine the appropriate fractions and remove the solvent under vacuum. Crystallize the residue from pet ether to provide the title compound. NMR (CDCl3):delta1.20(t,3), 2.25(s,3), 2.44(q,2), 6.59(s,1), 7.3(d,1), 7.30(m,1), and 8.09(m,1) ppm.
With potassium carbonate; In N-methyl-acetamide; ethylene glycol; dimethyl sulfoxide;
EXAMPLE 3 N,N,N-Trimethyl-2-(5-beta-hydroxyethoxy-2-nitroanilino)ethanaminium Iodide STR18 Compound (3) was prepared as follows: To a stirred solution of 2,4-difluoronitrobenzene (3.2 g, 20 mmol), N,N-dimethylethylenediamine (1.76 g, 20 mmol), and potassium carbonate (2.8 g, 20 mmol) was heated at 80° for 2 hours in dimethyl sulfoxide with catalytic amount of TDA-1. Another equivalent of potassium carbonate and 5 eq of ethylene glycol was added and heating was continue for another hour. After aqueous workup, an orange oil was obtained which was quaternized in dimethylformamide to give the desired product in 70percent yield (5.8 g, 14 mmol). Its melting point was 238°-40° C.
EXAMPLE 26A 2-Ethoxy-4-fluoronitrobenzene To a solution of anhydrous sodium ethoxide (0.55 mole) [prepared by dissolving sodium metal (12.6 g, 0.55 mole) in anhydrous ethanol (300 ml)] at 0 C. is added 2,4-difluoronitrobenzene (79.5 g, 0.50 mole) dropwise over an 8 hour period. Upon completion of addition the reaction mixture is allowed to warm to room temperature and stirred overnight. The solid is removed by filtration, and triturated with toluene and water. The toluene extract is combined with the original filtrate, dried with anhydrous sodium sulfate and the solvent is removed under vacuum to afford 218 g of a yellow oil which was distilled at 0.3 mm, b.p. 95-98 C. to afford substantially pure 2-ethoxy-4-fluoronitrobenzene. STR20
1.A Step A
Step A Preparation of 1-(3-amino-4-nitrophenyl)piperazine hydrofluoride A mixture of 31.8 g. (0.200 mol) of 2,4-difluoronitrobenzene, 13 g. of liquid ammonia and 100 ml. of dry ethanol is heated at 100° C. in a rocking bomb for 24 hours. The mixture is cooled, vented and diluted to 300 ml. with water and filtered to give 22.5 g. of 2-amino-4-fluoronitrobenzene, m.p. 91°-94° C. The crude aminofluoronitrobenzene (15.9 g., 0.102 mol) is treated with 24 g. of piperazine in 80 ml. of acetonitrile for one hour at reflux. The mixture is cooled and filtered and the cake is dried to give 19 g. of 1-(3-amino-4-nitrophenyl)piperazine hydrofluoride, m.p. 228°-230° C. dec.
Tetrakis(dimethylamino)phosphonium chloride[ No CAS ]
[ 611-06-3 ]
[ 81175-49-7 ]
[ 446-35-5 ]
Yield
Reaction Conditions
Operation in experiment
With potassium fluoride;
Preparing 2,4-difluoronitrobenzene by Reacting 2,4-dichloronitrobenzene A 1.5 l four-necked flask which is equipped with thermometer, anchor stirrer and reflux condenser with bubble counter is charged with 192 g (1 mol) of 2,4-dichloronitrobenzene, 550 ml of tetramethylene sulfone (TMS), 136.8 g (2.4 mol) of potassium fluoride and 5.99 g (0.015 mol) of tetrakis(diethylamino)phosphonium bromide (Example 7) or, respectively, 3.63 g (0.015 mol) of tetrakis(dimethylamino)phosphonium chloride (Example 8).
Comparison Example 6 Preparing 2,4-difluoronitrobenzene by Reacting 2,4-dichloronitrobenzene Using tetraphenylphosphonium bromide as Catalyst 192 g (1 mol) of 2,4-dichloronitrobenzene, 550 ml of tetramethylene sulfone, 136.8 g (2.4 mol) of potassium fluoride and 6.29 g (0.015 mol) of tetraphenylphosphonium bromide are employed and the procedure described in Example 7 and 8 is followed.
ethyl 2-(5-fluoro-2-nitroanilino)benzo[b]thiophene-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In dimethyl sulfoxide;
STARTING MATERIAL SYNTHESIS EXAMPLE 5 Ethyl 2-aminobenzo[b]thiophene-3-carboxylate (69.3 g) and 2,4-difluoronitrobenzene (50 g) were dissolved in dimethyl sulfoxide (550 ml) and heated to 50 C. Thereto was added potassium carbonate (63 g) and the mixture was stirred at 100 C. for 70 min. After cooling, the reaction mixture was allowed to cool to 70 C. and poured into water (2.5 L). The reaction mixture was allowed to stand still, and filtered. The filtrated orange crystals were washed with ethyl acetate to give ethyl 2-(5-fluoro-2-nitroanilino)benzo[b]thiophene-3-carboxylate (50.7 g). melting point 137-140 C. 1H-NMR (400 MHz, CDCl3) δ: 12.40(br.s, 1H), 8.33-8.29(m, 2H), 7.79(dd, J=7.8, 2.9 Hz, 1H), 7.65(d, J=8.3 Hz, 1H), 7.42(dd, J=8.3, 8.2 Hz, 1H), 7.29(dd, J=6.9, 8.3 Hz, 1H), 6.80-6.77(m, 1H), 4.54(q, J=6.8 Hz, 2H), 1.49(t, J=6.8 Hz, 3H). IR (KBr): 3085, 2993, 1624, 1582, 1553, 1510, 1274, 1206, 1035 cm-1. MS: m/e 360.
Synthesis of 1,3-difluoro-2-iodo-4-nitrobenzene (17c): 2,4-Difluoro-1-nitrobenzene 15 (159 mg, 1.0 mmol) in THF (2 mL) was added to a solution of TMPZnCl.LiCl (2) (1.3 M in THF, 0.85 mL, 1.1 mmol) at 25 C. and the reaction mixture was then stirred at this temperature for 45 min according to TP 2. 12 (381 mg, 1.5 mmol) dissolved in dry THF (2 mL) was then dropwise added and the resulting mixture was stirred for 0.5 h. The reaction mixture was quenched with a sat. aq. Na2S2O3 solution (10 mL) and with a sat. aq. NH4CI solution (20 mL), extracted with diethyl ether (3×50 mL) and driedanhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo. Purification by flash-chromatography (CH2Cl2/n-pentane, 1:1) furnished compound 17c (256 mg, 90%) as a colourless solid. m.p.: 46.1-47.5 C.1H NMR (300 MHz, CDCl3) δ: 8.12-8.17 (m, 1 H), 7.04-7.08 (m, 1 H).13C NMR (75 MHz, CDCl3) δ: 165.6 (dd, J=5.0 Hz, J=252.6 Hz), 156.4 (dd, J=6.9 Hz, J=264.1 Hz), 127.7 (dd, J=2.3 Hz, J=10.3 Hz), 111.6 (dd, J=4.2 Hz, J=26.1 Hz), 74.3 (dd, J=29.2 Hz, J=1.9 Hz).MS (70 eV, El) m/z (%): 285 (100) [M+], 258 (17), 239 (19), 227 (17), 167 (25), 149 (66), 112 (58), 71 (11), 57 (12), 44 (12).IR (ATR) v (cm-1): 3098, 2926, 2855, 2359, 1916, 1739, 1602, 1584, 1529, 1463, 1425, 1336, 1301, 1277, 1218, 1147, 1105, 1011, 860, 827, 751, 698, 669, 621, 616.HRMS (El) for C6H2F2INO2 (284.9098): 284.9094.
74%
With (TMP)2Zn.MgCl2; iodine; In tetrahydrofuran; at 25℃;Inert atmosphere;
A dry, argon-filled Schlenk tube with a magnetic stirrer bar and septum is initially charged with 2,4- difluoro-1 -nitrobenzene (159 mg, 1 mmol) in anhydrous THF (2 ml). After adding (TMP^Zn.MgCh (3.00 ml, 1.2 mmol) at 25 C, the mixture is stirred for 30 min, then a solution of iodine (381 mg, 1.5 mmol) in anhydrous THF (2 ml) is added dropwise and the mixture is stirred at 25 C overnight. For workup, the mixture is diluted with aqueous sat. NH4CI solution (30 ml) and aqueous sat. Na2S203 solution (30 ml) and extracted with ethyl acetate (3 x 30 ml). After the combined organic phases have been dried over Na2S04, the solvent has been distilled off and purification has been effected by column chromatography on silica gel (heptane : ethyl acetate), the desired compound (210 mg, 74% of theory) was obtained as a colourless crystalline product. ¾ NMR (400 MHz, CDC13): δ in ppm = 8.15 (m, 1 H), 7.06 (m, 1 H)
Example 2959: 2-(4-benzo[l ^^Joxadiazol-S-yl-S-chloro-S-cyclopropylmethoxy- phenyl)-4-methyl-pentanoic acidStep l2-(3-Fluoro-4-nitro-phenyl)-2-isobutyl-malonic acid diethyl esterTo a solution of 2-isobutylmalonic acid diethyl ester (75.0 g, 0.35 mol) in DMF (200 mL) was added sodium hydride (60% in mineral oil, 13.0 g, 0.57 mol) over 20 min. at O0C. The reaction mixture was stirred at O0C for 0.5 h, then warmed to 250C. The reaction mixture was cooled down to O0C again and a solution of 2,4-difluoronitro-benzene (50.0 g, 0.31 mol) in DMF (150 mL) was added dropwise at O0C. The reaction mixture was stirred at 25 0C for 16 h. After cooling, the reaction mixture was poured into ice water (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organic phases washed with water (3 x 100 mL), brine (100 mL), and dried (MgSC^). Evaporation of the solvent <n="160"/>under reduced pressure gave a brown oil. The crude product (92.0 g, 82%) was used for the next step without purification. 1H NMR (300 MHz, CDC13/TMS): delta 8.03 (t, J = 8.4 Hz, IH), 7.70 (dd, J = 12.9, 1.7 Hz, IH), 7.47 (d, J = 8.5 Hz, IH), 4.25^1.18 (m, 4H), 2.28 (d, J= 6.3 Hz, 2H), 1.54-1.45 (m, IH), 1.25 (t, J= 7.0 Hz, 6H), 0.82 (d, J= 7.0 Hz, 6H); 13C NMR (75 MHz, CDCI3/TMS): delta 169.2, 154.5 (d, 1JcF = 263.1 Hz), 146.9 (d, unresolved), 125.3, 124.1 (d, 3JCF = 3.6 Hz), 118.6 (d, 2JCF = 23.3 Hz), 62.0, 60.3, 44.1, 24.7, 23.6, 13.9.
To a solution of 2-isobutylmalonic acid diethyl ester (75.0 g, 0.35 mol) in DMF (200 mL) was added sodium hydride (60% in mineral oil, 13.0 g, 0.57 mol) over 20 mm. at 0C. The reaction mixture was stirred at 0C for 0.5 h, then warmed to 25C. The reaction mixture was cooled down to 0 C again and a solution of 2,4-difluoronitro-benzene (50.0 g, 0.31 mol) in DMF (150 mL) was added dropwise at 0C. The reaction mixture was stirred at 25 C for 16 h. After cooling, the reaction mixture was poured into ice water (200 mL) and extracted with EtOAc (3x100 mL). The combined organic phases washed with water (3 * 100 mL), brine (100 mL), and dried (MgSCH). Evaporation of the sol vent under reduced pressure gave a. brown oil. The crude product (92.0 g, 82%) was used for the next step without purification. 1H NMR (300 MHz, CDCk/TMS): delta 8.03 (t, J= 8.4 Hz, 1 H), 7.70 (dd, ./ 12.9, 1.7 Hz, 1 H), 7.47 i d. ./ 8.5 Hz, 1 H), 4.25-4.18 (in, 4H), 2.28 (d, J- 6.3 Hz, 2H), 1.54- 1.45 (m, 1 H), 1.25 (t, J = 7.0 Hz, 6H), 0.82 (d, J = 7.0 Hz, 6H);3C NMR (75 MHz, CDCfy'TMS): delta 169.2, 154.5 (d,CF= 263.1 Hz), 146.9 (d, unresolved), 125.3, 124.1 (d,3JCF;;;3.6 Hz), 1 18.6 (d, VCF= 23.3 Hz), 62.0, 60.3, 44.1 , 24.7, 23.6, 1 3.9.
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 85℃; for 18h;
1.2 2,4-Difluoro-1-nitrobenzene (?3?, 1 eq) is dissolved in DMF, and a solution of ?2? (1 eq) in DMF is added. After addition of N-ethyldiisopropylamine (1 eq), the reaction is heated at 85 C. for 18 hours. After cooling, the solvent is removed in vacuo, the residue is taken up in diethyl ether and washed three times with water. The organic phase is dried over sodium sulfate, and the solvent is removed in vacuo, giving the crude product ?4? in a yield of 64%, which is employed in the next step without further purification; LC-MS: 2.496 min; m/e 275.15 (M+H+); 297.15 (M+Na+).
At 0 C., 1.94 g (17.2 mmol) of potassium tert-butoxide are added to a solution of 2.5 g (14.4 mmol) of <strong>[13466-43-8]3-bromo-2-hydroxypyridine</strong> in 30 ml of anhydrous DMF, and the mixture is stirred at room temperature for 45 minutes. After this period, a solution of 2.51 g (15.8 mmol) of 2,4-difluoronitrobenzene in 10 ml of anhydrous DMF is added dropwise to the reaction mixture. Stirring at room temperature is continued for 15 hours. 120 ml of water are then added, and the mixture is extracted with ethyl acetate. The organic extract is washed with water and saturated sodium chloride solution. After drying over anhydrous sodium sulphate, the mixture is filtered and the filtrate is freed from the solvent on a rotary evaporator. The crude product is initially freed from coarse impurities by filtration with suction through silica gel using cyclohexane/ethyl acetate 5:1?1:1 as mobile phase. The product is then isolated by preparative HPLC. To this end, 2.1 g of the crude product obtained are dissolved in 5 ml of acetonitrile and chromatographed in 10 portions. Chromatography: column: Kromasil 100C18, 5 mum, 250*20 mm; flow rate: 25 ml/min; temperature: 40 C.; UV detection: 210 nm; mobile phase: water/acetonitrile 68:32. This gives 367 mg (8% of theory) of the title compound. 1H-NMR (400 MHz, DMSO-d6, delta/ppm): 8.31 (dd, 1H), 8.07 (dd, 1H), 7.93 (dd, 1H), 7.80 (dd, 1H), 7.61 (dd, 1H), 6.34 (dd, 1H). LC/MS (method 4): Rt=1.93 min. MS (ES+, m/z): 313/315 (79Br/81Br) (M+H)+.
trans-N-[4-(2-Amino-5-fluoro-phenoxy)-cyclohexyl]-methanesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydride; In N,N-dimethyl-formamide;
Trans-N-[4-(2-Amino-5-fluoro-phenoxy)-cyclohexyl]-methanesulfonamide 1.2 g sodium hydride were added to an ice cooled solution of 2.15 g trans-<strong>[224309-64-2](4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester</strong> in 50 ml DMF. After 1 hour 1.64 ml 2,4-difluoronitrobenzene were added and the mixture was stirred at this temperature for 1 hour. The coolant was removed and the reaction mixture was stirred for 4 hours. The mixture was diluted with EtOAc and washed with water and brine two times. The mixture was dried over magnesium sulfate, filtered and the filtrate was evaporated. Purification is achieved by silica gel column chromatography with iso-hexane/EtOAc (gradient: 100% iso-hexane->5:1 iso-hexane: EtOAc->3:1 iso-hexane: EtOAc). The residue was triturated with diethylether. Yield: 1.19 g
IV.1 (R)-3-(5-Fluoro-2-nitro-phenoxy)-piperidine-1 -carboxylic acid fe/f-butyl ester (R)-3-Hydroxy-piperidine-1 -carboxylic acid te/t-butyl ester (4.7 g) in THF (60 ml) was cooled to 0C. At this temperature LiHMDS (1 M; 28.0 ml in THF) was added drop wise and the reaction m ixture was stirred for 45 minutes. Then 2,4-difluoronitro- benzene (4.1 g) in THF (1 0 ml) was added and stirring was continued for 1 6 hours. The reaction mixture was quenched with sat. aq . NH CI and concentrated in vacuo. The aqueous layer was adjusted to pH 3 with 1 0% aq . KHSO4 and extracted with DCM . The organic layer was passed through a hydrophobic frit, concentrated and purified by chromatography (silica gel, hexan/EtOAc 4/1 ).Yield: 6.7 g
1 .2 g sodium hydride were added to an ice cooled solution of 2.15 g trans-(4- hydroxy-cyclohexyl)-carbamic acid terf-butyl ester in 50 ml DMF. After 1 hour 1 .64 ml 2,4-difluoronitrobenzene were added and the mixture was stirred at this temperature for 1 hour. The coolant was removed and the reaction mixture was stirred for 4 hours. The mixture was diluted with EtOAc and washed with water and brine two times. The mixture was dried over magnesium sulfate, filtered and the filtrate was evaporated. Purification is achieved by silica gel column chromatography with iso-hexane/ EtOAc (gradient: 100% iso-hexane -> 5:1 iso-hexane : EtOAc -> 3:1 iso-hexane : EtOAc ). The residue was triturated with diethylether.Yield: 1 .19 g
Step D1. Synthesis of D-2. A mixture of D-1 (16.02 mmol) and substituted aniline (16.02 mmol) was stirred at 130 C. After 92 h, the mixture was cooled to rt and a black solid was formed. The mixture containing the black solid was dissolved in DCM (50 mL) and washed with satd. aq. NaHCO3 solution (30 mL×1). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on a 120 g of Redi-Sep column using 0 to 50% gradient of EtOAc in hexane over 27 min and then 50% isocratic of EtOAc in hexane for 27 min as eluent to give D-2.; Prepared according to Step D1 in General Procedure D using 2,4-difluoronitro-benzene (0.571 mL, 5.20 mmol) and <strong>[35216-39-8]3-(methylsulfonyl)aniline</strong> (0.891 g, 5.20 mmol) to give 5-fluoro-N-(3-(methylsulfonyl)phenyl)-2-nitroaniline as a bright yellow solid: 1H NMR (400 MHz, DMSO-d6) delta ppm 9.65 (1H, s), 8.25 (1H, dd, J=9.6, 6.1 Hz), 7.85-7.89 (1H, m), 7.64-7.75 (3H, m), 6.98 (1H, dd, J=11.4, 2.6 Hz), 6.79-6.87 (1H, m), 3.24 (3H, s); LC-MS (ESI) m/z 311.0 [M+H] 5-Fluoro-N1-(3-(methylsulfonyl)phenyl)benzene-1,2-diamine
With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 1h;
a) To a solution of 2,4-difluoro-nitrobenzene (2.0 g, 12.6 mmol) and (lR)-l-(2,4- dichlorophenyl)ethanamine (prepared from Example 1, 2.4 g, 12.6 mmol) in anhydrous DMSO (20 mL) was added K2CO3 (3.5 g, 25.2 mmol). The reaction mixture was heated at 120 C for 1 h. After cooling to room temperature, the mixture was diluted with deionized water (100 mL), and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried (Na2S04), filtered, and concentrated in vacuo. The crude product was used without further purification (0.65 g, 2.0 mmol, 16%).
5-fluoro-2-nitro-N-(2,2,2-trifluoroethyl)aniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
17 g
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran;Reflux;
To a stirred solution of 2,4- difluoronitrobenzene (10.3 ml, 94.286 mmol) in THF (100 ml), <strong>[373-88-6]2,2,2-trifluoroethanamine hydrochloride</strong> (12.75 g, 94.286 mmol) was added followed by DIPEA (46.8 ml, 282.85 mmol) and the reaction mixture was stirred at reflux temperature for overnight. The reaction mixture was cooled to room temperature and quenched with water (250 ml). The mixture was extracted with ethyl acetate (3 x 300) and washed with brine (300 ml). The mixture was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography to yield 17 g of product as yellow solid. APCI-MS (m/z) 239.21 (M+H)+.
With lithium hexamethyldisilazane; In tetrahydrofuran; at -5 - 20℃;
(3R,3aR,6R,6aR)-6-(5-fluoro-2-nitro-phenoxy)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol 2.2 ml (20.0 mmol) 2,4-difluoro-1-nitro-benzene and 2.9 g (20.0 mmol) <strong>[641-74-7]1,4:3,6-dianhydro-D-mannitol</strong> in 70 ml THF are cooled to -5 C. 20 ml (20.0 mml) 1M LiHMDS in THF are added dropwise and the reaction mixture is allowed to warm to RT and stirred over night. 1M HCl is added and the mixture is extracted with EtOAc. The organic phases are pooled and washed with water, dried and evaporated. The residue is purified by FC. Yield: 2.7 g (47%), ESI-MS: m/z=286 (M+H)+, Rt(HPLC): 0.80 min (HPLC-H)
47%
With lithium hexamethyldisilazane; In tetrahydrofuran; at -5 - 20℃;
Intermediate I I I.1 : (3R,3aR,6R,6aR)-6-(5-fluoro-2-nitro-phenoxy)-2.3,3a,5,6,6a- hexahvdrofuro[3,2-b]furan-3-ol 2.2 ml (20.0 mmol) 2,4-difluoro-1 -nitro-benzene and 2.9 g (20.0 mmol) 1 ,4:3,6- dianhydro-D-mannitol in 70 ml THF are cooled to -5C. 20 ml (20.0 mml) 1 M LiHMDS in THF are added dropwise and the reaction mixture is allowed to warm to RT and stirred over night. 1 M HCI is added and the mixture is extracted with EtOAc. The organic phases are pooled and washed with water, dried and evaporated. The residue is purified by FC. Yield: 2.7 g (47%), ESI-MS: m/z = 286 (M+H)+, R,(HPLC): 0.80 min (HPLC-H)
47%
With lithium hexamethyldisilazane; In tetrahydrofuran; at -5 - 20℃;
Intermediate II.5: (3R,3aR,6R,6aR)-6-(2-amino-5-fluoro-phenoxy)-2,3,3a,5,6,6ahexahydrofuro[3,2-blfuran-3-olStep 1:2.2 ml (20.0 mmol) 2,4-difluoro-1-nitro-benzene and 2.9 g (20.0 mmol) 1,4:3,6- dianhydro-D-mannitol in 70 ml THF are cooled to -5C. 20 ml (20.0 mml) 1M LiHMDS in THF are added dropwise and the reaction mixture is allowed to warm to RT and stirred over night. 1M aq. HCI is added and the mixture is extracted with EtOAc. The organic phases are pooled and washed with water, dried and evaporated. The residue is purified by FC.Yield: 2.7 g (47%), ESI-MS: m/z = 286 (M+H)+, Rt (HPLC): 0.80 min (HPLC-H)
47%
With lithium hexamethyldisilazane; In tetrahydrofuran; at -5 - 20℃;
Intermediate III.1 : 2.2 ml (20.0 mmol) 2,4-difluoro-1 -nitro-benzene and 2.9 g (20.0 mmol) 1 ,4:3,6- dianhydro-D-mannitol in 70 ml THF are cooled to -5C. 20 ml (20.0 mml) 1 M LiHMDS in THF are added dropwise and the reaction mixture is allowed to warm to RT and stirred over night. 1 M HCI is added and the mixture is extracted with EtOAc. The organic phases are pooled and washed with water, dried and evaporated. The residue is purified by FC. (0565) Yield: 2.7 g (47%), ESI-MS: m/z = 286 (M+H)+, R,(HPLC): 0.80 min (HPLC-H)
To ethanol (70 mL) was added compound 68 2,4-difluoro-1-nitrobenzene (5.0 g, 31.44 mmol), and cesium carbonate (30.66 g, 94.34 mmol). The mixture was heated and stirred overnight. After TLC indicated the reaction was completed, the mixture was evaporated to dryness, diluted with water, and extracted with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to remove solvent, thus obtaining a crude product. The crude product was further isolated and purified by column chromatography to obtain a white solid (5.5g, yield 95%).
92%
(aox-4-fluoro-1-nitro-benzeneTo a cold (0 C) mixture of ethanol (0.735 mL, 12.6 mmol) in THE (15 mL)was added sodium hydride (60% dispersion in mineral oil, 553 mg, 13.83 mmol). The reaction mixture wasstirred at 0C for 15 mm, after which a solution of 2,4-difluoro-1-nitrobenzene (1.38 mL, 12.6 mmol) in THE (25 mL) was added dropwise. After stirring for an additional 90 mm at room temperature the reaction was quenched with water the mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated in vacua. The residue was purified by column chromatography (heptane/ethylacetate = 100/0 to 85/15 v/v%) to afford 2-ethoxy-4-fluoro-1-nitro-benzene (2.15 g, 92 %).
Ethanol (83mg, 1.82mmol) Soluble in toluene (8ml), Cool to 0 - 5 C in an ice bath, Slowly add potassium tert-butoxide (205mg, 1.82mmol), Keep the temperature at 0 - 5 C, Stir for 15 minutes, Slowly add 2,4-difluoronitrobenzene (290mg, 1.82mmol), React in ice bath for 2 hours, Diluted with water and extracted with ethyl acetate, Dry over anhydrous sodium sulfate and filter, Concentrate under reduced pressure to give a light yellow solid.
rac-cis-4-(5-fluoro-2-nitro-phenoxy)-tetrahydro-furan-3-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃;
A mixture of 2,4-difluoronitrobenzene (2.81 ml; 25.7 mmol), (3S,4S)-4-(tert-butyl-dimethyl-silanyloxy)-tetrahydro-furan-3-ol (Intermediate Vll.3, 7.00 g; 25.6 mmol THF(100 ml), and sodium hydride (60% dispersion in mineral oil; 1 .03 g; 25.7 mmol) isstirred at RT over night. DCM is added and the mixture is extracted with water. Theorganic layer is separated, dried with magnesium sulphate, filtered and evaporated. The residue is purified by FC (DCM).Yield: 6.07 g (66%), ESI-MS: m/z = 358 (M+H)Synthesis from 2,4-difluoronitrobenzene and 1 ,4-<strong>[4358-64-9]anhydroerythritol</strong> (2 eq.) applying DMF as solvent.ESl-MS: m/z = 244 (M+H)
5-fluoro-N-(2-fluoroethyl)-2-nitro-aniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84.9%
With N-ethyl-N,N-diisopropylamine; In ethanol; at 0 - 20℃;Inert atmosphere;
To a magnetically stirred solution of 2,4-difluoronitrobenzene (2.17 ml_, 19.810 mmol) and <strong>[460-08-2]2-fluoroethylamine hydrochloride</strong> (1.97 g, 19.8 mmol) in ethanol (40 ml.) at 0 Cunder nitrogen was added A/,A/-diisopropylethylamine (6.54 ml_, 39.6 mmol) and the resultingmixture was agitated at ambient temperature overnight. The mixture was poured into water(200 ml.) to give a suspension, which was stirred for 30 min and filtered. The solid was washedwith water (2 x 20 ml.) and dried under vacuum at 40 C for 3 h to give the desired product 5-15 fluoro-A/-(2-fluoroethyl)-2-nitro-aniline as a yellow solid (3.4 g, 16.82 mmol, 84.9%).[00517] 1HNMR (300MHz, DMSO-d6) Shift = 8.39 (br. s., 1H), 8.23 - 8.13 (m, 1H),6.98(dd, J=2.6, 12.3 Hz, 1H), 6.57 (ddd, J=2.6, 7.4, 9.7 Hz, 1H), 4.73 (t, J=4.9 Hz, 1H), 4.57 (t,J=4.9 Hz, 1H), 3.81 - 3.72 (m, 1H), 3.71 - 3.63 (m, 1 H).
2-chloro-1-(2-nitro-5-fluorophenoxy)-4-trifluoromethylbenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
10 g
With potassium carbonate; In N,N-dimethyl-formamide; at 10℃; for 3h;
15.9 g (0.1 mol) of 2,4-difluoronitrobenzene was added to a 150 ml single-necked flask,150 ml of N, N-dimethylformamide was added,1.5 times the molar amount of potassium carbonate was added,The system was cooled to 10 ,And then slowly adding 19.6 g (0.1 mol) of <strong>[35852-58-5]2-chloro-4-trifluoromethylphenol</strong> for about 1 h,Keep the temperature reaction 2h, The system was then poured into 500 water and extracted with ethyl acetate,Dried over anhydrous magnesium sulfate,The solvent was distilled off,The product was purified by column chromatography to give 10 g of product.The product is 2-chloro-1-(2-nitro-5-fluorophenoxy)-4-trifluoromethylbenzene,
4-(3-fluoro4-nitrophenoxy)-N-methylpyridine-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 80 - 90℃; for 6h;
In the 250 mL three-necked flask,16 g of 2,4-difluoronitrobenzene was added,15g4-hydroxypyridylformamide,15 g of potassium carbonate, 100 mL of N, N-dimethylformamide,Temperature control 80-90 C for 6 hours. The reaction solution was lowered to room temperature,The reaction solution was poured into 300 mL of water and extracted with ethyl acetate 70 mL x 3 to combine the organic phases,Water 50 mL x 2 The organic phase was washed, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure,To give 26.3 g of a yellow solid,Yield 91.0%, purity 92.6%.
4-fluoro-1-(5-fluoro-2-nitrophenyl)-1H-pyrazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
155 mg
To a mixture of 60% sodium hydride (56 mg) and THF (15 mL) was added <strong>[35277-02-2]4-fluoro-1H-pyrazole</strong> (103 mg) at 0C. The mixture was stirred at 0C for 1 hr, and to the mixture was added 2,4-difluoro-1l-nitrobenzene (0.110 mL). The mixture was stirred overnight at room temperature, to the mixture was added saturated aqueous ammonium chloride solution at 0C, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (155 mg). MS: [M+H]+226.1.
With potassium carbonate; In dimethyl sulfoxide; at 90℃; for 12.0h;
Potassium carbonate (246.39 mg, 1.78 mmol) was added into the compound 32-B (100 mg, 594.25 mumol) and 2,4-difluoro-nitrobenzene (435 mg, 2.73 mmol) in 3mL dimethyl sulfoxide solution, and stirred at 90C for 12 hours, then diluted with 10 mL 10% hydrochloric acid solution, and washed by EtOAc 60 mL (20 mL×3), the aqueous phase was adjusted by 10% sodium hydroxide to pH around 10, then extracted with EtOAc 120 mL (40 mL×3). The organic phase was washed by saturated brine 60 mL, dried over anhydrous sodium sulfate, then filtered and concentrated to give the crude product compound 33-A. MS m/z: 308.1 [M+H]+
4-[6-(4-chlorophenoxy)-1H-benzimidazol-1-yl]-2-methylbutan-2-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Multi-step reaction with 2 steps
1.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 0.5 h / 110 °C
1.2: 3 h / 150 °C
2.1: formic acid; zinc / methanol / 3 h / 60 °C
Stage #1: 4-amino-2-methyl-2-butanol; 2,4-Difluoronitrobenzene With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 110℃; for 0.5h;
Stage #2: 4-chloro-phenol With caesium carbonate In 1-methyl-pyrrolidin-2-one at 150℃; for 3h;
3.i Step (i):
A mixture of 2,4-difluoro-1-nitrobenzene (Compound 30, 200 mg), 4-amino-2-methylbutan-2-ol (136 mg), diisopropylethylamine (263 μL), and NMP (2.0 mL) was stirred at 110° C. for 30 minutes. To the reaction mixture were added cesium carbonate (819 mg) and 4-chlorophenol (186 mg), and the mixture was stirred at 150° C. for 3 hours. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added thereto to separate layers. The organic layer was washed with water, dried over sodium sulfate, and then concentrated in vavuo. The obtained residue was purified by silica gel column chromatography (eluting solution: hexane/ethyl acetate=1/1) to give Compound 36 (350 mg).
5-fluoro-N-(3-morpholinopropyl)-2-nitroaniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
With potassium carbonate; In N,N-dimethyl-formamide; at 50℃;
The synthetic pathways for the preparation of compounds 6e-g are depicted in Scheme S2. In a 25 mL round bottom flask, compound 3 (159 mg, 1 mmol) and 3-morpholinopropan-1-amine (4a, 144mg, 1mmol) were dissolved in DMF (10 mL) and heated to 50 C for overnight. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed three times with saturated aqueous NaCl, and dried over anhydrous Na2SO4. And then, product by column chromatography purification. 5-fluoro-N-(3-morpholinopropyl)-2-nitroaniline (5a), yield 56%. 1H NMR (400 MHz, DMSO-d6) delta 8.53 (s, 1H), 8.16 (dd, J = 9.6, 6.0 Hz, 1H), 6.89 (dt, J = 12.5, 3.5 Hz, 1H), 6.51 (ddd, J = 10.1, 7.5, 2.8 Hz, 1H), 3.61 (t, J = 4.7 Hz, 4H), 3.38 (q, J = 6.3 Hz, 2H), 2.37 (t, J = 6.2 Hz, 6H), 1.77 (p, J = 6.4 Hz, 2H).
2-fluoro-5-(3-fluoro-4-nitrophenoxy)aniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With potassium carbonate; In dimethyl sulfoxide; at 90℃; for 2h;
To <strong>[62257-16-3]3-amino-4-fluorophenol</strong> (363mg, 2.930mmol) and 2,4-difluoro-1-nitrobenzene (500mg,3.223mmol) in DMSO (10ml) was added K23 (118g, 8.537mmol).Stir the solution at 90C for 2 hoursAt this time, the solution was extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 6:1-5:1), and the resulting solution was concentrated under reduced pressureAfter shrinking, 620 mg of yellow solid was obtained with a yield of 80%.
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