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Structure of 95-74-9 * 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.
Stage #1: With hydrogenchloride; 1,1,1,3',3',3'-hexafluoro-propanol; iron In water at 20℃; for 0.5 h; Stage #2: With sodium hydrogencarbonate In water
General procedure: The nitro compound (1 equiv), HFIP (10 equiv), Fe powder (5 equiv) were mixed in a tube. Then 2 N HCl aqueous solutions was added to the reaction mixture. After stirring at room temperature for 30 min, the reaction mixture was neutralized with sat. NaHCO3 (aq.) and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was then purified by column chromatography on silica gel to furnish the desired amine product.
Reference：
[1] Journal of the American Chemical Society, 2017, vol. 139, # 47, p. 17089 - 17097
[2] Tetrahedron Letters, 2017, vol. 58, # 37, p. 3646 - 3649
[3] Chemische Berichte, 1884, vol. 17, p. 534
[4] Recueil des Travaux Chimiques des Pays-Bas, 1932, vol. 51, p. 98,109
[5] Chem. Zentralbl., 1910, vol. 81, # I, p. 260
[6] Recueil des Travaux Chimiques des Pays-Bas, 1913, vol. 32, p. 247
[7] Journal of the American Chemical Society, 1959, vol. 81, p. 5641,5644
[8] Journal of the American Chemical Society, 1959, vol. 81, p. 5641,5644
[9] Journal of the Chemical Society, 1927, p. 2903
[10] Journal of the American Chemical Society, 1944, vol. 66, p. 1781
[11] Collection of Czechoslovak Chemical Communications, 1964, vol. 29, p. 776 - 794
[12] Journal of Organic Chemistry, 1998, vol. 63, # 2, p. 393 - 395
[13] Patent: CN104163764, 2016, B, . Location in patent: Paragraph 0044-0047
Reference：
[1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2007, vol. 46, # 4, p. 713 - 715
4
[ 99-99-0 ]
[ 95-74-9 ]
Reference：
[1] Chemische Berichte, 1884, vol. 17, p. 534
[2] Journal of the Chemical Society, 1927, p. 2903
[3] Collection of Czechoslovak Chemical Communications, 1964, vol. 29, p. 776 - 794
5
[ 42533-63-1 ]
[ 95-74-9 ]
Reference：
[1] Chemische Berichte, 1892, vol. 25, p. 83
6
[ 95-49-8 ]
[ 95-74-9 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1913, vol. 32, p. 247
7
[ 88-51-7 ]
[ 95-74-9 ]
Reference：
[1] Journal of Chemical Crystallography, 2013, vol. 43, # 12, p. 655 - 663
8
[ 121-86-8 ]
[ 42460-61-7 ]
[ 95-74-9 ]
Reference：
[1] Chem. Zentralbl., 1910, vol. 81, # I, p. 260
9
[ 15545-48-9 ]
[ 124-40-3 ]
[ 95-74-9 ]
Reference：
[1] Journal of the Chemical Society. Perkin Transactions 2, 2001, # 11, p. 2230 - 2232
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2, 2001, # 11, p. 2226 - 2229
12
[ 7664-93-9 ]
[ 106-49-0 ]
[ 95-74-9 ]
[ 615-65-6 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1873, vol. 168, p. 199
[2] Chemische Berichte, 1889, vol. 22, p. 2535,2536
13
[ 7647-01-0 ]
[ 7664-93-9 ]
[ 106-49-0 ]
[ 56461-98-4 ]
[ 95-74-9 ]
[ 615-65-6 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1873, vol. 168, p. 199
[2] Chemische Berichte, 1889, vol. 22, p. 2535,2536
14
[ 7647-01-0 ]
[ 110-89-4 ]
[ 7149-79-3 ]
[ 64-19-7 ]
[ 95-74-9 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1886, vol. 235, p. 242
15
[ 95-74-9 ]
[ 452-73-3 ]
Yield
Reaction Conditions
Operation in experiment
81.8%
Stage #1: at 5 - 15℃; for 5 h; Stage #2: at -5 - 80℃;
1L reactor (equipped with a condenser, the gas phase outlet diameter is1/6 to 1/5 of thediameter of the kettle), and the temperature is lowered to 20 °C or lower. Under stirring, 424 g (21.2 mol, 20 eq) of anhydrous hydrogen fluoride is added, and the temperature is lowered after the feed is completed. To 5 °C or less,150 g (1.059 mol, 1 eq) of 3-chloro-4-methylaniline wasadded dropwise, and the temperature was controlled in the range of 5 to 15 °C, and the addition was completed in about 3 hours, and the temperature was kept for 2 hours.After thecompletion of theheat preservation, thetemperature was lowered to 5 °C or less, and 73.1 g of sodium nitrite (1.06 mol, 1 eq) was added in portions, and the reaction temperature was controlled within the rangeof-5 to 15 °C, and the mixture was added forabout 4 hours, and the heat was kept for 1 hour.After the heat preservation, the temperature of the reaction kettle is programmed (strictly controlling the heating rate:when thetemperature is in the range of 0 to 20 °C, the temperature is raised by 0.5 to 1 °C per hour,when the temperature is in the range of 20 to 80 °C, the temperature is raised by 1 to 2 °C per hour), and the temperature is raised to 80 °C and keep warm for2h.After the heat preservation is completed, the temperature is lowered to 30 to 35 °C, and the layers are separated. The organic layer is neutralized to a pH of 7 to 8 by a dilute alkali, and steam distillation is carried out. The organic layer is 141 g at room temperature, and the purity of the gas chromatographic detection is 93.4percent. The distillation obtained 125.1 g of qualified product, the yield was 81.8percent, and the purity of 2-chloro-4-fluorotoluene obtained by gas chromatography was 99.9percent.
Reference：
[1] Patent: CN108569948, 2018, A, . Location in patent: Paragraph 0035-0059
16
[ 95-74-9 ]
[ 5162-82-3 ]
Reference：
[1] Journal fuer Praktische Chemie (Leipzig), 1889, vol. <2> 39, p. 496[2] Justus Liebigs Annalen der Chemie, 1891, vol. 265, p. 349
17
[ 95-74-9 ]
[ 21423-81-4 ]
Reference：
[1] Patent: US4562199, 1985, A,
18
[ 143-33-9 ]
[ 95-74-9 ]
[ 21423-81-4 ]
Reference：
[1] Journal of the Chemical Society, 1947, p. 637,640
[2] Zhurnal Obshchei Khimii, 1936, vol. 6, p. 909,912[3] Chem. Zentralbl., 1937, vol. 108, # I, p. 1942
19
[ 95-74-9 ]
[ 21423-81-4 ]
Reference：
[1] Journal fuer Praktische Chemie (Leipzig), 1889, vol. <2> 39, p. 496[2] Justus Liebigs Annalen der Chemie, 1891, vol. 265, p. 349
20
[ 95-74-9 ]
[ 615-62-3 ]
Reference：
[1] Patent: DE156333, , ,
[2] Justus Liebigs Annalen der Chemie, 1907, vol. 355, p. 366[3] Justus Liebigs Annalen der Chemie, 1909, vol. 371, p. 388
[4] Patent: US4577011, 1986, A,
[5] Patent: US4558040, 1985, A,
[6] Patent: DE156333, , ,
21
[ 7647-01-0 ]
[ 7664-93-9 ]
[ 106-49-0 ]
[ 56461-98-4 ]
[ 95-74-9 ]
[ 615-65-6 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1873, vol. 168, p. 199
[2] Chemische Berichte, 1889, vol. 22, p. 2535,2536
22
[ 95-74-9 ]
[ 21971-21-1 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1907, vol. 355, p. 366[2] Justus Liebigs Annalen der Chemie, 1909, vol. 371, p. 388
23
[ 95-74-9 ]
[ 88-51-7 ]
Yield
Reaction Conditions
Operation in experiment
99.1%
With sulfuric acid In 1,2-dichloro-benzene at 240℃; for 8 h; Autoclave
To 141.6 g (1.00 ) of 2-chloro-4-amino-toluene with 1,2-dichlorobenzene in 2,000 [0163] Dosage for 4 In the L stainless steel reactor Flask, 101.0 g of sulfuric acid (1.03 ) for 30 minutes. [0165] the reactor and raising the temperature of the external temperature and the reaction was performed at reflux for 240 8 hours. The reaction can be generated during the reflux reaction Dean-separated and the organic components were using Stark trap. [0167] into a discrete compound of the stainless steel of 4 L dryer, maintaining the temperature more than 200 Hg vacuum at 150 While, and dried for 8 hours, to give a final 2-chloro-4-amino toluene-5-sulfonic acid in 219.7 g. 2-chloro-4-amino-2-chloro-4-amino toluene-5-sulfonic acid in toluene yields according to the standard of was 99.1percent.
99.2%
With sulfuric acid In 1,2-dichloro-benzene at 240℃; for 8.5 h; Dean-Stark
141.6 g (1.00 mol) of 2-chloro-4-aminotoluene and 2,000 ml of 1,2-dichlorobenzene were placed in a glass material reactor having a capacity of 4 L,After stirring, 100.1 g (1.00 mol) of sulfuric acid was added over 30 minutes.Then, the temperature outside the reactor was raised, and the reflux reaction was carried out at 240 DEG C for 8 hours. The reaction water generated at this time was separated from organic components using a Dean-Stark trap.The reaction was filtered through a 2 L fluid filter and the filtrate was washed with 100 mL of 1,2-dichlorobenzene. The washed filtrate is collected in a 4 L glass reactor for reuse after distillation in a subsequent reaction, and 2-chloro-4-aminotoluene-5-sulfonic acid in a wet cake state is put into a 4 L stainless steel material drier or a glass vacuum drier, And dried at 130 to 160 DEG C for 7 hours while maintaining a vacuum of 200 mmHg or more to obtain 219.7 g of 2-chloro-4-aminotoluene-5-sulfonic acid. The yield of 2-chloro-4-aminotoluene-5-sulfonic acid according to the criteria of 2-chloro-4-aminotoluene was 99.2percent. As a result of HPLC analysis, the content of residual 2-chloro-4-aminotoluene was 0.10percent by weight, no other organic impurities were detected, and the purity according to the diazotization titration was 97.8percent. The appearance of the resulting 2-chloro-4-aminotoluene-5-sulfonic acid was in the form of a white powder, and an aqueous ammonia solution having a concentration of 2-chloro-4-aminotoluene-5-sulfonic acid of 1.3percent was prepared and analyzed by ultraviolet spectroscopy The absorbance was measured at a wavelength of 400 nm and the result was 0.041. To confirm the residue (insoluble matter and tar) when the product was dissolved, 2-chloro-4-aminotoluene prepared in an aqueous alkali solution (pH 9, aqueous ammonia solution) -5-sulfonic acid was dissolved and filtered. As a result,The weight percentage of insoluble matter was found to be 0.051 (insoluble,percent).
Reference：
[1] Patent: KR2015/104064, 2015, A, . Location in patent: Paragraph 0161-0165
[2] Patent: KR2016/92961, 2016, A, . Location in patent: Paragraph 0151-0159
[3] Patent: DE175378, , ,
[4] Patent: DE175378, , ,
24
[ 110-01-0 ]
[ 7664-93-9 ]
[ 95-74-9 ]
[ 88-51-7 ]
Reference：
[1] Patent: US4447368, 1984, A,
25
[ 95-74-9 ]
[ 2835-95-2 ]
Yield
Reaction Conditions
Operation in experiment
85.36%
With copper; copper(l) chloride; sodium hydroxide In ethanol at 175℃; for 4 h; Autoclave; Inert atmosphere; Industrial scale
In a 4800L autoclave, 1700 kg of 50percent sodium hydroxide solution was added, 1850 kg of an ethanol solution containing 1000 kg of 3-chloro-4-methylaniline was added, 50 kg of cuprous chloride and 15 kg of copper powder were added, and the reaction vessel was sealed and replaced with nitrogen 5 times. Warm up to 175°C, incubate for 4 hours, sample and analyze. After passing the test, cool down. Ethanol is recovered under reduced pressure, filtered into an 8000L tank, neutralized by adding 1450 kg of industrial hydrochloric acid to weak acidity, extracted with 2000 L of ethyl acetate and extracted three times, and ethyl acetate is recovered under reduced pressure. , get crude. The crude product was added with 1000 kg of ethanol, heated to 60° C., and 50 kg of activated carbon was added. After stirring for 1 hour, the mixture was filtered and cooled to 5° C. to obtain 707 kg of a product with a yield of 85.36percent and a purity of 99.8percent.
Reference：
[1] Patent: CN107963974, 2018, A, . Location in patent: Paragraph 0030-0032; 0036; 0037
26
[ 95-74-9 ]
[ 7149-80-6 ]
Reference：
[1] Patent: WO2010/19208, 2010, A1,
27
[ 95-74-9 ]
[ 54788-38-4 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1907, vol. 355, p. 366[2] Justus Liebigs Annalen der Chemie, 1909, vol. 371, p. 388
28
[ 95-74-9 ]
[ 102170-52-5 ]
Yield
Reaction Conditions
Operation in experiment
64%
With N-Bromosuccinimide In dichloromethane at 20℃; for 0.166667 h;
Example 41: (5-Chloro-2-((E)-3-13-(4-fl uorobenzvl)-3,8-diazabicvdo13 .2. I loct-8-vll-3- oxopropenyl} -4-methylphenyl)-urea; a) 2-Bromo-5-chloro-4-methylphenylamine; 3-Chloro-4-methylphenylamine (20.0 g; 0.141 mmol) is dissolved in CH2CI2 (200 ml) and combined within 5 min. with a solution of NBS (25.1 g; 0.141 mmol) in CH2CI2 (800 ml). The reaction mixture is stirred for 5 min at room temp. , evaporated to a volume of -200 ml and diluted with hexanes (1000 ml). The resulting precipitate is filtered off, the filtrate evaporated to dryness and purified via chromatography (Si02, hexanes / TBME 10: 1) to render the title compound as yellowish crystals (12.3 g; 40 percent). A second batch of title compound is obtained by re-chromatography of mixed fractions (7.5 g; 24 percent). 1H-NMR (400MHz; DMSO-d6), No. (ppm) : 2.13 (s, 3H) ; 5.32 (s, 2H, NH2) ; 6.81 (s, 1 H); 7.31 (s, 1 H). MS (m/z) ES+: 221 (100, M+) ; 219 (80) ; 184 (35 ); 140 (100) ; 104 (50) ; 77 (65) ; 52 (58) ; 51 (60).
Reference：
[1] Patent: WO2005/103054, 2005, A2, . Location in patent: Page/Page column 71
[2] Journal of Medicinal Chemistry, 2002, vol. 45, # 17, p. 3692 - 3702
29
[ 95-74-9 ]
[ 102170-52-5 ]
Yield
Reaction Conditions
Operation in experiment
34%
With bromine In diethyl ether; acetic acid at 0 - 5℃; for 0.75 h; Under argon
[00148] To a solution of 3-chloro-4-methylaniline (10.0 g, 70.6 mmol) in diethyl ether/acetic acid (v/v 1/1, 350 ml) cooled in an ice-bath was dropwise added bromine (4 ml) over a 35 min period under an argon atmosphere while the temperature of the reaction mixture was kept below 5 C. Stirring was continued for 10 min after the addition of bromine; then the yellow reaction mixture was partitioned between dichloromethane (250 ml) and dilute brine (200 ml). The organic layer was washed with more dilute brine (200 ml), dried (Na2SO4), and concentrated in vacuo to an oily residue. This was redissolved in dichloromethane (200 ml) and the solution was washed with saturated aqueous sodium bicarbonate (3200 ml; caution: gas is evolved), dried (Na2SO4) and concentrated in vacuo to leave a brown wet solid. Purification by column chromatography on gradient elution with dichloromethane in hexanes (25 to 30percent) gave in order of elution: [00149] a. 5-chloro-2,6-dibromo-4-methylaniline as a white solid (4.63 g) mp 77-78 C. [00150] b. the desired product, 2-bromo-5-chloro-4-methylaniline (5.32 g, 34percent), mp 90 C., 1H-NMR (CDCl3) 2.23 (s, 3H, 4-CH3), 3.99 (br s, 2H, NH2), 6.78 (s, 1H, 6-H), 7.26 (s, 1H, 3-H). MS (FAB, m/z) 219, 221, 223 [(M+H)+, BrCl isotopic pattern]. Elemental Analysis: Found: C, 38.04; H, 3.20; N, 6.35; Cl, 16.04; Br, 36.28. C7H7BrClN requires: C, 38.13; H, 3.20; N, 6.35; Cl, 16.08; Br, 36.24 [00151] c. 2-bromo-3-chloro-4-methylaniline as a white solid (1.22 g) mp 48-56 C.
Reference：
[1] Journal of Medicinal Chemistry, 2002, vol. 45, # 17, p. 3692 - 3702
[2] Patent: US6699861, 2004, B1, . Location in patent: Page column 13-14
30
[ 95-74-9 ]
[ 117738-77-9 ]
Reference：
[1] Zhurnal Obshchei Khimii, 1936, vol. 6, p. 909,912[2] Chem. Zentralbl., 1937, vol. 108, # I, p. 1942
[3] Zhurnal Obshchei Khimii, 1936, vol. 6, p. 909,912[4] Chem. Zentralbl., 1937, vol. 108, # I, p. 1942
[5] Zhurnal Obshchei Khimii, 1936, vol. 6, p. 909,912[6] Chem. Zentralbl., 1937, vol. 108, # I, p. 1942
General procedure: The nitro compound (1 equiv), HFIP (10 equiv), Fe powder (5 equiv) were mixed in a tube. Then 2 N HCl aqueous solutions was added to the reaction mixture. After stirring at room temperature for 30 min, the reaction mixture was neutralized with sat. NaHCO3 (aq.) and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was then purified by column chromatography on silica gel to furnish the desired amine product.
With palladium on carbon; hydrogen; at 120℃; under 11251.1 Torr;
Examples 17 to 26 investigated the effects of different carbon-loaded large-scale noble metal catalysts in solvent-free liquid phase hydrogenation Synthesis of Halogenated Aromatic Amines. Weighing the activated carbon with the particle size of 1000 mesh and the specific surface area of 1000m2 / g for the preparation of the catalyst. The slurry was prepared by adding H2PdCl4 or H2PtCl6 solution slowly according to different noble metal loading, 5h, add ammonia to adjust the pH to 8.5, and the temperature dropped to room temperature, filtration, filter cake washed with deionized water to neutral; then filter cake at 60 configured into a slurry, dropping excess formic acid solution, stirring , And the filter cake was washed with deionized water to neutral and vacuum dried at 110 C to prepare the noble metal catalyst. The catalyst was treated with different calcination conditions to obtain different carbon-supported large-scale noble metal catalysts. To a 500 ml reaction vessel 200 g of <strong>[121-86-8]3-chloro-4-methylnitrobenzene</strong> was added, 2.5g by different carbon carrying large particle size of precious metal catalyst, close the reactor; first with nitrogen replacement reactor inside the air three times, and then replaced with hydrogen three times, and then heated to 120 C, and the hydrogen pressure rose to 1.5MPa, To 1000r/min; to maintain the reaction temperature and pressure until the end of the reaction; cooling cooling, remove the reactor liquid, filter separation of the catalyst, and the use of phase separation of the water in the filtrate, The target product, 3-chloro-4-methylaniline, was analyzed by gas chromatography. The results are shown in Table 3.
With sulfuric acid; sodium nitrite; In hexane; water;
EXAMPLE 2 2-(4-Chloro-2,3-dihydro-2,5-dimethylbenzofuran-7-yl)-N-methoxy-N-methyldiazenecarboxamide (2) 283 g of 3-chloro-4-methylaniline was added to a solution of 1000 ml of water and 500 ml of concentrated sulfuric acid, causing the temperature of the mixture to rise from ambient to 95° C. The mixture was cooled and stirred at room temperature for 30 minutes, then cooled to 5° C. and a solution of 145 g of sodium nitrite in 500 ml of water was slowly added (1.5 hours) to the stirred mixture at 5°-10° C. The mixture was stirred at about 5° C. for one hour, then added over two hours to a stirred solution of 1.2 liters of concentrated sulfuric acid in 2 liters of water, at 105°-110° C. The resulting mixture was stirred at 110° C. for one hour, then held at room temperature for 18 hours. Then 3.5 liters of hexane was added, the mixture was stirred for 30 minutes, allowed to stand, and the two liquid phases were separated. The hexane phase was filtered, washed with water, dried (MgSO4) and concentrated to dryness to give crude 3-chloro-4-methylphenol (2A).
With hydrogenchloride; sodium hydroxide; sulfuric acid; sodium nitrite; In water;
EXAMPLE 4 (5-chloro-3,4-dihydro-2,6-dimethyl-2H-1-benzopyran-8-yl)diazenecarboxylic acid methyl ester (4) 1.3 liters of concentrated sulfuric acid was added to a stirred mixture of 566 g of 3-chloro-4-methylaniline and 3 liters of water. The mixture warmed to 104° C. The mixture was cooled to 10°-15° C. and stirred while a solution of 290 g sodium nitrite in 1 liter of water was added drop-by-drop (over 2 hours). The mixture was stirred for 1 hour at about 10° C., then was added drop-by-drop (over 2 hours) to a stirred solution of 1 liter of concentrated sulfuric acid in 1.5 liters of water, at 110°-115° C. The resulting mixture was stirred at reflux temperature for one hour, cooled to room temperature and extracted with ether. The extract (4 liters) was mixed with 4 liters of water. The resulting mixture was stirred at 15° C. while 700 ml of a 50percent aqueous solution of sodium hydroxide was slowly added (over 1 hour). The aqueous phase was separated, cooled to 15°-20° C. and stirred while 1.3 liters of concentrated hydrochloric acid was added. The resulting mixture was extracted with ether, the extract was dried (MgSO4) and the solvent was evaporated to give 3-chloro-4-methylphenol (4A), as an amber oil.
With sulfuric acid; In 1,2-dichloro-benzene; at 240℃; for 8h;Autoclave;
To 141.6 g (1.00 ) of 2-chloro-4-amino-toluene with 1,2-dichlorobenzene in 2,000 [0163] Dosage for 4 In the L stainless steel reactor Flask, 101.0 g of sulfuric acid (1.03 ) for 30 minutes. [0165] the reactor and raising the temperature of the external temperature and the reaction was performed at reflux for 240 8 hours. The reaction can be generated during the reflux reaction Dean-separated and the organic components were using Stark trap. [0167] into a discrete compound of the stainless steel of 4 L dryer, maintaining the temperature more than 200 Hg vacuum at 150 While, and dried for 8 hours, to give a final 2-chloro-4-amino toluene-5-sulfonic acid in 219.7 g. 2-chloro-4-amino-2-chloro-4-amino toluene-5-sulfonic acid in toluene yields according to the standard of was 99.1%.
99.2%
With sulfuric acid; In 1,2-dichloro-benzene; at 240℃; for 8.5h;Dean-Stark;
141.6 g (1.00 mol) of 2-chloro-4-aminotoluene and 2,000 ml of 1,2-dichlorobenzene were placed in a glass material reactor having a capacity of 4 L,After stirring, 100.1 g (1.00 mol) of sulfuric acid was added over 30 minutes.Then, the temperature outside the reactor was raised, and the reflux reaction was carried out at 240 DEG C for 8 hours. The reaction water generated at this time was separated from organic components using a Dean-Stark trap.The reaction was filtered through a 2 L fluid filter and the filtrate was washed with 100 mL of 1,2-dichlorobenzene. The washed filtrate is collected in a 4 L glass reactor for reuse after distillation in a subsequent reaction, and 2-chloro-4-aminotoluene-5-sulfonic acid in a wet cake state is put into a 4 L stainless steel material drier or a glass vacuum drier, And dried at 130 to 160 DEG C for 7 hours while maintaining a vacuum of 200 mmHg or more to obtain 219.7 g of 2-chloro-4-aminotoluene-5-sulfonic acid. The yield of 2-chloro-4-aminotoluene-5-sulfonic acid according to the criteria of 2-chloro-4-aminotoluene was 99.2%. As a result of HPLC analysis, the content of residual 2-chloro-4-aminotoluene was 0.10% by weight, no other organic impurities were detected, and the purity according to the diazotization titration was 97.8%. The appearance of the resulting 2-chloro-4-aminotoluene-5-sulfonic acid was in the form of a white powder, and an aqueous ammonia solution having a concentration of 2-chloro-4-aminotoluene-5-sulfonic acid of 1.3% was prepared and analyzed by ultraviolet spectroscopy The absorbance was measured at a wavelength of 400 nm and the result was 0.041. To confirm the residue (insoluble matter and tar) when the product was dissolved, 2-chloro-4-aminotoluene prepared in an aqueous alkali solution (pH 9, aqueous ammonia solution) -5-sulfonic acid was dissolved and filtered. As a result,The weight percentage of insoluble matter was found to be 0.051 (insoluble,%).
With bromine; In diethyl ether; acetic acid; at 0 - 5℃; for 0.75h;Under argon;
[00148] To a solution of 3-chloro-4-methylaniline (10.0 g, 70.6 mmol) in diethyl ether/acetic acid (v/v 1/1, 350 ml) cooled in an ice-bath was dropwise added bromine (4 ml) over a 35 min period under an argon atmosphere while the temperature of the reaction mixture was kept below 5 C. Stirring was continued for 10 min after the addition of bromine; then the yellow reaction mixture was partitioned between dichloromethane (250 ml) and dilute brine (200 ml). The organic layer was washed with more dilute brine (200 ml), dried (Na2SO4), and concentrated in vacuo to an oily residue. This was redissolved in dichloromethane (200 ml) and the solution was washed with saturated aqueous sodium bicarbonate (3200 ml; caution: gas is evolved), dried (Na2SO4) and concentrated in vacuo to leave a brown wet solid. Purification by column chromatography on gradient elution with dichloromethane in hexanes (25 to 30%) gave in order of elution: [00149] a. 5-chloro-2,6-dibromo-4-methylaniline as a white solid (4.63 g) mp 77-78 C. [00150] b. the desired product, 2-bromo-5-chloro-4-methylaniline (5.32 g, 34%), mp 90 C., 1H-NMR (CDCl3) 2.23 (s, 3H, 4-CH3), 3.99 (br s, 2H, NH2), 6.78 (s, 1H, 6-H), 7.26 (s, 1H, 3-H). MS (FAB, m/z) 219, 221, 223 [(M+H)+, BrCl isotopic pattern]. Elemental Analysis: Found: C, 38.04; H, 3.20; N, 6.35; Cl, 16.04; Br, 36.28. C7H7BrClN requires: C, 38.13; H, 3.20; N, 6.35; Cl, 16.08; Br, 36.24 [00151] c. 2-bromo-3-chloro-4-methylaniline as a white solid (1.22 g) mp 48-56 C.
3'-chloro-4-cyclopropyl-4'-methyl-1,2,3-thiadiazole-5-carboxanilide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
With 2-chloro-1-methyl-pyridinium iodide; triethylamine; In tetrahydrofuran; at 20℃; for 10h;
Example 2 Production of 3'-chloro-4-cyclopropyl-4'-methyl-1,2,3-thiadiazole-5-carboxanilide (Compound No. 1-95) 4-Cyclopropyl-1,2,3-thiadiazolecarboxylic acid (4 g; 24 mmols), 2-chloro-1-methylpyridinium iodide (7.2 g; 28 mmols), triethylamine (5.9 g; 58 mmols) and 2-chloro-4-methylaniline (3.7 g; 26 mmols) were dissolved or suspended in THF (50 ml), followed by stirring at room temperature for 10 hours. Water was added thereto to stop the reaction, the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 3:1) to thereby obtain 6.9 g of 3'-chloro-4-cyclopropyl-4'-methyl-1,2,3-thiadiazole-5-carboxanilide. Yield: 99% Physical properties: mp. 150 - 153C
With N-Bromosuccinimide; In dichloromethane; at 20℃; for 0.166667h;
Example 41: (5-Chloro-2-((E)-3-13-(4-fl uorobenzvl)-3,8-diazabicvdo13 .2. I loct-8-vll-3- oxopropenyl} -4-methylphenyl)-urea; a) 2-Bromo-5-chloro-4-methylphenylamine; 3-Chloro-4-methylphenylamine (20.0 g; 0.141 mmol) is dissolved in CH2CI2 (200 ml) and combined within 5 min. with a solution of NBS (25.1 g; 0.141 mmol) in CH2CI2 (800 ml). The reaction mixture is stirred for 5 min at room temp. , evaporated to a volume of -200 ml and diluted with hexanes (1000 ml). The resulting precipitate is filtered off, the filtrate evaporated to dryness and purified via chromatography (Si02, hexanes / TBME 10: 1) to render the title compound as yellowish crystals (12.3 g; 40 %). A second batch of title compound is obtained by re-chromatography of mixed fractions (7.5 g; 24 %). 1H-NMR (400MHz; DMSO-d6), No. (ppm) : 2.13 (s, 3H) ; 5.32 (s, 2H, NH2) ; 6.81 (s, 1 H); 7.31 (s, 1 H). MS (m/z) ES+: 221 (100, M+) ; 219 (80) ; 184 (35 ); 140 (100) ; 104 (50) ; 77 (65) ; 52 (58) ; 51 (60).
With hydrogenchloride; boron trichloride;diethylaluminium chloride; In n-heptane; water; ethyl acetate; 1,2-dichloro-ethane; Petroleum ether;
82.a. 1-(2-amino-4-chloro-5-methylphenyl)-2-chloro-ethanone 3-chloro-4-methylaniline (44.4 ml; 0.366 mol) in 1,2-dichloroethane (440 ml), under an argon atmosphere, is cooled down in an ice bath. The following are added dropwise and in the order of this mixture: boron trichloride (1M in heptane; 400 ml; 0.4 mol), chloroacetonitrile (28 ml; 0.44 mol) and diethylaluminium chloride (1M in heptane; 400 ml; 0.4 mol). For the addition, the temperature is maintained below 20 C. The resultant mixture is then heated at reflux for 3 hours, then cooled down to 10 C. The hydrolysis of the reaction medium is then carried out cautiously using 2N hydrochloric acid (240 ml) and it is heated at reflux for 1 hour. Water (1 l) and ethyl acetate (1 l) are added, the mixture obtained is agitated for 15 minutes before separating the phases. The aqueous phase is again extracted with ethyl acetate (200 ml), and the combined organic phases are washed with water (500 ml). After drying over magnesium sulphate the organic phase is concentrated. The residue is taken up in petroleum ether (fraction having a boiling point of 45 to 60 C.; 150 ml) and the mixture thus obtained is left for 16 hours at 4 C. The resultant precipitate is collected by filtration, washed with petroleum ether and dried under reduced pressure in order to produce the product in the title (25 g; 31% yield). M.p. 129-130 C. NMR 1H (DMSO): 2.20 (s, 3H); 4.98 (s, 2H); 6.90 (s, 1H); 7.15 (wide peak, 2H); 7.70 (s, 1H). IR (KBr): 871, 1018, 1183, 1225, 1270, 1533, 1577, 1619, 1662 cm-1.
With hydrogenchloride; boron trichloride;diethylaluminium chloride; In n-heptane; water; ethyl acetate; 1,2-dichloro-ethane; Petroleum ether;
82.a. 1-(2-amino-4-chloro-5-methylphenyl)-2-chloro-ethanone 3-chloro-4-methylaniline (44.4 ml; 0.366 mol) in 1,2-dichloroethane (440 ml), under an argon atmosphere, is cooled down in an ice bath. The following are added dropwise and in the order of this mixture: boron trichloride (1M in heptane; 400 ml; 0.4 mol), chloroacetonitrile (28 ml; 0.44 mol) and diethylaluminium chloride (1M in heptane; 400 ml; 0.4 mol). For the addition, the temperature is maintained below 20 C. The resultant mixture is then heated at reflux for 3 hours, then cooled down to 10 C. The hydrolysis of the reaction medium is then carried out cautiously using 2N hydrochloric acid (240 ml) and it is heated at reflux for 1 hour. Water (1 l) and ethyl acetate (1 l) are added, the mixture obtained is agitated for 15 minutes before separating the phases. The aqueous phase is again extracted with ethyl acetate (200 ml), and the combined organic phases are washed with water (500 ml). After drying over magnesium sulphate the organic phase is concentrated. The residue is taken up in petroleum ether (fraction having a boiling point of 45 to 60 C.; 150 ml) and the mixture thus obtained is left for 16 hours at 4 C. The resultant precipitate is collected by filtration, washed with petroleum ether and dried under reduced pressure in order to produce the product in the title (25 g; 31% yield). M.p. 129-130 C. NMR 1H (DMSO): 2.20 (s, 3H); 4.98 (s, 2H); 6.90 (s, 1H); 7.15 (wide peak, 2H); 7.70 (s, 1H). IR (KBr): 871, 1018, 1183, 1225, 1270, 1533, 1577, 1619, 1662 cm-1.
N-(3-chloro-4-methylphenyl)-DL-2-chloro-mandelamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In dichlorobenzene, 1,2-; for 6.0h;Heating / reflux; Dean-Stark apparatus;
A mixture of 52.72 g of DL-<strong>[10421-85-9]2-chloromandelic acid</strong> and 40 g of 3-chloro-4-methylaniline in 400 ml of 1,2-dichlorobenzene is refluxed for 6 hours, while removing the water formed using Dean-Stark apparatus. After cooling to RT, the mixture is left to crystallize and the precipitate formed is filtered off by suction. The expected product is obtained after recrystallization from a DCM/iso ether mixture, m.p.=164 C.
With calcium carbonate; In methanol; dichloromethane; at 20℃;
Example 310A 5-chloro-2-iodo-4-methylaniline 3-CHLORO-4-METHYLANILINE (1. 50G, 10.6 mmol) and benzyltrimethylammonium dichloroiodate (4.60g, 13.2 mmol) were dissolved in CH2C12 (50 mL) and MEOH (20 mL), then CACO3 (3.10g, 31. 0 mmol) was added and the reaction stirred at room temperature overnight. The reaction was diluted with Et20 (200 mL), filtered through CELITE and concentrated. The crude material was purified by column chromatography using 97. 5/2. 5 HEXANE/ETOAC, giving the product (1. 80g, 63%) as light tan solids. MS (DCI) m/e 268 and 270 (M+H) + ; IH NMR (300 MHz, CDC13) 8 7.48 (s, 1H), 6.76 (s, 1H), 4.00 (v br s, 2H), 2.22 (s, 3H).
With triethylamine; In dichloromethane; at 0 - 20℃;
1.023 mmol amine 20a-h in 5 mi dichlormethane are cooled to 0 C. Consecutively, 0.121 ML (1.125 mmol) malonic acid methylester chloride and 0.156 ml (1.125 MMOL) triethyl amine are added slowly and the reaction mixture is stirred at room temperature overnight. The reaction mixture is treated with brine and extracted with dichlormethane (3x). The combined organic phases are dried over NA2SO4, filtered and evaporated. The residue is put on silica gel and purified by column chromatography (35g silica gel, Eluent : ethyl acetate/n-heptane). Yield : 261 mg (98 %) 21 A, PALE beige crystals; 282 mg (96 %) 21 B, YELLOW crystals ; 284 mg (97 %) 21c, yellow crystals ; 226 mg (90 %) 21d, yellow crystals ; 269 mg (71 %) 21e, yellow crystals ; 307 mg (88 %) 21f, yellow crystals ; 293 mg (100 %) 21G, YELLOW CRYSTALS ; 253 mg (96 %) 21H, YELLOW crystals.
With bis(trifluoromethanesulfonyl)amide; In acetonitrile; at 20℃; for 1h;
EXAMPLE 22; 1-Acetyl-piperidine-4-carboxylic Acid (3-chloro-4-methyl-phenyl)-{3-[5-(2,4-dimethyl-6-oxo-1,6-dihydro-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-butyl}-amide (102); step 1-; To a mixture of 3-chloro-4-methyl-phenylamine (2.5 g, 17.65 mmol) and trifluoromethanesulfonimide (0.33 g, 1.20 mmol) in MeCN (20 mL) was added methyl vinyl ketone (1 mL, 12.05 mmol) at RT. After 1 h silica gel and Na2CO3 (200 mg) were added to the mixture and it was concentrated in vacuo. The crude product was purified by SiO2 column chromatography eluting with n-hexane:EtOAc (4:1) to afford 1.3 g (51%) of 100: NMR (CDCl3) delta 2.15 (s, 3H), 2.25 (s, 3H), 2.73 (t, 2H), 3.35 (t, 2H), 3.93 (br, 1H), 6.4 (dd, 1H), 6.6 (d, 1H), 6.98 (d, 1H).
51%
EXAMPLE 22; 3-(3-(3-Chloro-4-methyl-phenyl)-3-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-butyl}-ureido)-propionic acid methyl ester; Step 1-; To a mixture of 3-chloro-4-methyl-phenylamine (2.5 g, 17.65 mmol) and trifluoromethanesulfonimide (0.33 g, 1.20 mmol) in MeCN (20 mL) was added methyl vinyl ketone (1 mL, 12.05 mmol) at RT. After 1 h silica gel and Na2CO3 (200 mg) were added to the mixture and it was concentrated in vacuo. The crude product was purified by SiO2 column chromatography eluting with n-hexane:EtOAc (4:1) to afford 1.3 g (51%) of 100: NMR (CDCl3) delta 2.15 (s, 3H), 2.25 (s, 3H), 2.73 (t, 2H), 3.35 (t, 2H), 3.93 (br, 1H), 6.4 (dd, 1H), 6.6 (d, 1H), 6.98 (d, 1H).
51%
With bis(trifluoromethanesulfonyl)amide; In acetonitrile; at 20℃; for 1h;
To a mixture of 3-chloro-4-methyl-phenylamine (2.5 g, 17.65 minol) and trifluoromethanesulfonimide (0.33 g, 1.20 mmol) in MeCN (20 mL) was added methyl vinyl ketone (1 mL, 12.05 mmol) at RT. After 1 h silica gel and Na2C03 (200 mg) were added to the mixture and it was concentrated in vacuo. The crude product was purified by SiOz column chromatography eluting with n-hexane:EtOAc (4:1) to afford 1.3 g (51 %) of 107: NMR (CDC13) No. 2.15 (s, 3H), 2.25 (s, 3H), 2.73 (t, 2H), 3.35 (t, 2H), 3.93 (br, 1H), 6.4 (dd, 1H), 6.6 (d, 1H), 6.98 (d, 1H);
With N-ethyl-N,N-diisopropylamine; potassium iodide; In DMF (N,N-dimethyl-formamide); at 80℃; for 4h;
To a solution of 82 (224 mg, 0.67 mmol) dissolved in DMF (3 mL) was added KI (120 mg, 0.72 mmol), 3-chloro-4-methyl-phenylamine (105 mg, 0.74 mmol) and DIPEA (0.12 mL, 0.69 mmol) and the reaction mixture was stirred at 80 C for 4 h. The mixture was allowed to cool to RT, diluted with water and extracted with DCM. The combined DCM extracts were dried (Na2S04) and concentrated. The crude product was purified by Si02 column chromatography eluting with a CH2Cl2: MeOH: NH40H (99: 0.7:0.07) to afford 83 (146 mg, 49%) as an off-white solid: ms (LCMS) m/z 440 (M + H).
3-chloro-N-(3-chloropropyl)-4-methylaniline hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78.5%
<strong>[95-74-9]3-Chloro-4-methylaniline</strong> (10.0 g, 70.6 mmol), 1-bromo-3-chloropropane (34.7 mL, 55.6 g, 353 mmol) and triethylamine (21.4 g, 212 mmol) were charged. The mixture was stirred at 25-28C for 24 hrs. Water (50 mL) and methyl ethyl ketone (25 mL) were added for partitioning. The organic layer was washed twice with water (50 mL). Conc. hydrochloric acid (35 mL, 5.7 eq) was dropwise added to the organic layer under ice-cooling. The mixture was stirred at room temperature for 1 hr. The crystals were collected by filtration, washed with diisopropyl ether (10 mL) and dried in vacuo at 50C to give the title compound (14.12 g, yield 78.5%) as pale-yellow crystals. 1H-NMR (300 MHz, DMSO)delta: 2.11 (2H,quint,J=6.9Hz), 2.28 (3H,s), 3.29 (2H,t,J=7.3Hz), 3.76 (2H,t,J=6.5Hz), 7.16-7.37 (3H,m).
4-(3-Chloro-4-methyl-phenylamino)-6,7-dimethoxy-quinoline-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
350.9 mg (99.4%)
In 2-ethoxy-ethanol; pyridine hydrochloride;
4-(3-Chloro-4-methyl-phenylamino)-6,7-dimethoxy-quinoline-3 carbonitrile Using an analogous procedure to that described in Example 367, 248.7 mg (1 mmol) of <strong>[214470-55-0]4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile</strong> in 10 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 170.0 mg (1.2 mmol) of 2-chloro-4-amino-toluene to give 350.9 mg (99.4%) of the product as a yellow solid, m.p.>250 C., mass (electrospray, m/e): M+H 353.9,355.8.
With aqueous nitric acid; sulfuric acid; sodium nitrite; In hexane; water; acetic acid;
EXAMPLE 3 2-(4-Chloro-2,3-dihydro-2,5-dimethylbenzofuran-7-yl)hydrazinecarboxylic Acid Methyl Ester (3) 283.0 g of 3-chloro-4-methylaniline, 1000 ml of water and 500 ml of concentrated sulfuric acid were mixed, initially at room temperature. The temperature of the mixture rose to 95° C. The mixture was stirred at room temperature for 30 minutes, cooled to 5° C. and a solution of 145 g of sodium nitrite in 500 ml of water was slowly added (1.5 hours) to the stirred mixture at 5°-10° C., then the mixture was stirred at about 5° C. for one hour. The resulting solution was added over two hours to a stirred solution of 1.2 liters of concentrated sulfuric acid in 2 liters of water, at 105°-110° C., and the resulting mixture was stirred at 110° C. for one hour, then held at room temperature for 18 hours. Then 3.5 liters of hexane was added, the mixture was stirred for 30 minutes, allowed to stand, and the two liquid phases were separated. The hexane phase was filtered, washed with water, dried (MgSO4) and concentrated to dryness to give crude (91percent) <strong>[615-62-3]3-chloro-4-methylphenol</strong> (3A). 245.0 g of 3A was mixed with 1.6 liters of glacial acetic acid, and the resulting solution was stirred at 8°-10° C. while 109.6 g of 90percent aqueous nitric acid was added (two hours). The mixture was stirred at 10°-15° C. for five hours, poured over ice water and extracted with ether/hexane. The extract was washed with water, dried and stripped to dryness. The residue was stirred with 3 liters of hexane and the hexane solution was filtered through silica gel. The filtrate was held at -20° C. for 16 hours, filtered, and the filtrate was concentrated to one liter, charcoaled, then held at -30° to -35° C. for two hours and filtered. The solid products were combined to give 3-chloro-4-methyl-6-nitrophenol (3B).
With aqueous nitric acid; sulfuric acid; sodium nitrite; In hexane; water; acetic acid;
Example 1 1(4-Chloro-2,3-dihydro-2,5-dimethylbenzofuran-7-yl)-4-methoxy-4-methylsemicarbazide (1) 283 g of 3-chloro-4-methylaniline, 1000 ml of water and 500 ml of concentrated sulfuric acid were mixed, initially at room temperature. The temperature of the mixture rose to 95° C. The mixture was stirred at room temperature for 30 minutes, cooled to 5° C. and a solution of 145 g of sodium nitrite in 500 ml of water was slowly added (1.5 hours) to the stirred mixture at 5°-10° C., then the mixture was stirred at about 5° C. for one hour. The resulting solution was added over two hours to a stirred solution of 1.2 liters of concentrated sulfuric acid in 2 liters of water, at 105°-110° C., and the resulting mixture was stirred at 110° C. for one hour, then held at room temperature for 18 hours. Then 3.5 liters of hexane was added, the mixture was stirred for 30 minutes, allowed to stand, and the two liquid phases were separated. The hexane phase was filtered, washed with water, dried (MgSO4) and concentrated to dryness to give crude (91percent) <strong>[615-62-3]3-chloro-4-methylphenol</strong> (1A). 245.0 g of 1A was mixed with 1.6 liters of glacial acetic acid, and the resulting solution was stirred at 8°-10° C. while 109.6 g of 90percent aqueous nitric acid was added (two hours). The mixture was stirred at 10°-15° C. for five hours, poured over ice water and extracted with ether/hexane. The extract was washed with water, dried and stripped to dryness. The residue was stirred with 3 liters of hexane and the hexane solution was filtered through silica gel. The filtrate was held at -20° C. for 16 hours, filtered, and the filtrate was concentrated to one liter, charcoaled, then held at -30° to -35° C. for two hours and filtered, to give 3-chloro-4-methyl-6-nitrophenol (1B).
With aqueous nitric acid; sulfuric acid; sodium nitrite; In hexane; water; acetic acid;
EXAMPLE 4 4-chloro-2,3-dihydro-2,5-dimethylbenzofuran-7-yl)diazenecarboxylic acid methyl ester (4) 238 g of 3-chloro-4-methylaniline, 1000 ml of water and 500 ml of concentrated sulfuric acid were mixed, initially at room temperature. The temperature of the mixture rose to 95° C. The mixture was stirred at room temperature for 30 minutes, cooled to 5° C. and a solution of 145 g of sodium nitrite in 500 ml of water was slowly added (1.5 hours) to the stirred mixture at 5°-10° C., then the mixture was stirred at about 5° C. for one hour. The resulting solution was added over two hours to a stirred solution of 1.2 liters of concentrated sulfuric acid in 2 liters of water, at 105°-110° C., and the resulting mixture was stirred at 110° C. for one hour, then held at room temperature for 18 hours. Then 3.5 liters of hexane was added, the mixture was stirred for 30 minutes, allowed to stand, and the two liquid phases were separated. The hexane phase was filtered, washed with water, dried (MgSO4) and concentrated to dryness to give crude (91percent) <strong>[615-62-3]3-chloro-4-methylphenol</strong> (4A). 245.0 g of 4A was mixed with 1.6 liters of glacial acetic acid, and the resulting solution was stirred at 8°-10° C. while 109.6 g of 90percent aqueous nitric acid was added (two hours). The mixture was stirred at 10°-15° C. for five hours, poured over ice water and extracted with ether/hexane. The extract was washed with water, dried and stripped to dryness. The residue was stirred with 3 liters of hexane and the hexane solution was filtered through silica gel. The filtrate was held at -20° C. for 16 hours, filtered, and the filtrate was concentrated to one liter, charcoaled, then held at -30° C. to -35° C. for two hours and filtered, to give 3-chloro-4-methyl-6-nitrophenol (4B).
EXAMPLE 18 141.5 g (1.0 mol) of 4-amino-2-chlorotoluene are initially introduced into 500 ml of sulpholane, and 99.1 g (1.01 mols) of 100% strength H2 SO4 are added dropwise in the course of 15 minutes, during which period the temperature increases to 80 C. The mixture is heated to 207 C., and the reaction water is distilled off in the course of 1.5 hours, during which period the temperature increases to 218 C. The suspension is cooled to room temperature. The yield of 2-amino-4-chloro-5-methylbenzenesulphonic acid is 91.0%.
(b) 3-Chloro-4-methylbenzonitrile A mixture of 3-chloro-4-methylaniline (515.01 g, 3.64 mol), concentrated hydrochloric acid (930 ml) and water (930 ml) was stirred and cooled to 0, when a solution of sodium nitrite (259.77 g, 3.765 mol) in water (540 ml) was added dropwise at 0-5. The cuprous cyanide prepared in (a) was then dissolved in sodium cyanide solution [sodium cyanide (421.98 g, 8.6 mol) in water 1350 ml], and this solution was heated to 70 when the cold diazonium salt solution was added dropwise to the rapidly stirred cuprous cyanide solution at 60-70. Following the addition, the reaction mixture was stirred at 70 for 0.5 h. Ether (3000 ml) was then added to the reaction mixture, and this mixture was then filtered. The ether layer was separated, and was then washed with hydrochloric acid (1500 ml, 2M), and then with water (1500 ml). The ether solution was then dried (MgSO4) and concentrated under reduced pressure to afford a dark brown solid. Distillation of the solid in vacuo afforded 3-chloro-4-methylbenzonitrile as a yellow solid, b.p. 120-126/16 mmHg.
5-methyl-4-imidazolecarbonyl chloride hydrochloride[ No CAS ]
[ 95-74-9 ]
N-(3-chloro-4-methylphenyl)-5-methyl-4-imidazolecarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With triethylamine; In water; acetone;
EXAMPLE 2 To a solution of 740 g (5.22 moles) of 3-chloro-4-methylaniline and 1054.6 g (10.44 moles) of triethylamine in 10 liters of acetone at room temperature and vigorous stirring, there were added slowly 945 g (5.22 moles) of 5-methyl-4-imidazolecarbonyl chloride hydrochloride. After the addition was ended, the mixture was refluxed for 1 hour and then allowed to cool to room temperature and filtered. The liquid filtrate was evaporated until a slight precipitation appeared, it was then poured over 20 liters of cold water with stirring, filtered and the precipitate was dried to give N-(3-chloro-4-methylphenyl)-5-methyl-4-imidazolecarboxamide, a crude yellowish product. Crystallisation from isopropyl alcohol gave 1108 g (85% yield) of the desired pure product having the same characteristics as the one obtained in Example 1.
General procedure: The target ligands IV (Matht (a), Chmatht (b) and Tfmatht (c)) were synthesized from 4-methyl (I a), 3-chloro-4-methyl- (I b) and 2-(trifluoromethyl)aniline (I c) by several procedures(scheme 1) [23-25]. The commercially available aniline I (0.01 mole) was dissolved inthe minimum amount of benzene and treated with carbon disulphide (0.01 mole, 0.70mL)and triethylamine (0.01 mole, 1.40mL). The solution was cooled to 0 C and left for 5 days.After complete precipitation of the triethylammonium dithiocarbamate salt, the solutionwas filtered. The solid was washed with anhydrous ether and air dried for about 10 min.The salt was then dissolved in about 7.5mL of chloroform, treated with 1.4mL of triethylamineand cooled to 0 C. To the solution was added ethyl chloroformate (0.01 mole,1.02mL) dropwise over a 15-min period under intense stirring. The resulting solution wasstirred at 0 C for 10 min and allowed to warm to room temperature for 1 h. The chloroformsolution was washed with 3M HCI and twice with water and was dried over Na2SO4.The chloroform was evaporated and the aryl isothiocyanate II was distilled in vacuo.The obtained isothiocyanate II (0.005 mole) was mixed with water (10 ml) and NaN3(0.011 mole, 0.715 g) and refluxed with intense stirring until the suspension disappeared.The solution was cooled to room temperature and washed with TBME. Waterwas separated and acidified with 3M HCI (Caution The HN3 elevation). The sediment of 1H-tetrazole-5-thiol III was separated by the filtration and used for alkylation withoutfurther purification. The 1H-tetrazole-5-thiol III (0.004 mole) was dissolved in solution of KOH(0.004 mole, 0.224 g) in ethanol (10 mL). To the solution allyl bromide (0.005 mole,0.43 mL) was added and the mixture was heated at 50 C for 1 h. Solvent removed invacuo and to the residue was added water 5mL and dichloromethane 10 mL.Dichloromethane was separated and removed to give target ligand IV.
5.30 N"-(3-Chloro-4-methyl-phenvn-N'-[2- (2.6-dioxo-piperidin-3-vn-l-oxo-2. 3-dihvdro-lH-isoindol-5-ylmethyll-N-cvano-guanidine; Step 1: Preparation of (3-chloro-4-methyl-phenyl)-carbamic acid phenyl ester.; 2-chloro-4-amino toluene (282 mg, 2 mmol) was dissolved in THF (10 mL). The mixture was added sodium hydride (128 mg, 3.2 mmol) and stirred at room temperature for 15 minutes. Dipehnyl N- cyano-carbonimidate (715 mg, 3.0 mmol) was added and the mixture was heated to reflux for 4 hours. The reaction mixture was cooled to room temperature, quenched by saturated NH4Cl (10 mL), filtered and the solid was dried in oven to give (3-chloro-4-methyl-phenyl)-carbamic acid phenyl ester as solid (0.5 g, 87percent).
g) Me3Al (290 muL, 0.57 mmol, 2M in toluene) was added to a solution of the 3-Chloro-4-methylphenylamine (65 mg, 0.46 mmol) in dry dichloroethane (1 mL) at ambient temperature. Stirred for 20 minutes, then (2R,3S)-2-(4-Cyclopentylaminophenyl)-1-(2-methylbenzoyl)piperidine-3-carboxylic acid ethyl ester (100 mg, 0.23 mmol) dissolved in dry dichloroethane (1 mL) was added to it. The reaction mixture was then heated to 85 C. for 3 h, cooled to r.t, diluted with CH2Cl2 (20 mL), washed with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with CH2Cl2 (20 mL) and the combined organic layer was dried (MgSO4) and concentrated. The residue was purified by reverse phase preparative HPLC (20-95% gradient of CH3CN-H2O with 0.1% TFA as additive), the product containing fractions were pooled together and concentrated. The residue was diluted with CH2Cl2 (30 mL), washed with saturated aqueous NaHCO3 solution. The CH2Cl2 layer was dried (MgSO4) and concentrated to get the pure (2R,3S)-2-(4-Cyclopentylaminophenyl)-1-(2-methylbenzoyl)piperidine-3-carboxylic acid (3-chloro-4-methylphenyl)amide in 50% yield.1H NMR (400 MHz, CDCl3) 8.4 (bs, 1H), 7.55 (s, 1H), 7.37-7.05 (m, 9H), 6.55-6.52 (m, 2H), 3.77-3.70 (m, 1H), 3.30-3.16 (m, 1H), 3.04-2.91 (m, 2H), 2.43-1.94 (m, 8H), 1.71-1.46 (m, 11H).
With iodine; sodium hydrogencarbonate; potassium iodide; In water; at 20℃; for 72h;
INTERMEDIATE 15 - PREPARATION of 5-chloro-2-iodo-4-methylaniline. A solution of iodine (9.86 g; 38.84 mmol) and potassium iodide (6.45 g; 38.84 mmol) in water was added dropwise to a suspension of 3-chloro-4-methylaniline (5.00 g; 35.31 g) in a solution of sodium bicarbonate (4.75 g; 56.50 mmol). The resulting mixture was stirred 72 hours at room temperature filtrated and the solid dissolved in dichloromethane, washed with a saturated solution of sodium thiosulphate, dried over magnesium sulphate and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in heptane) to yield 2.30 g (24%) of 5-chloro-2-iodo-4-methylaniline as a brown solid.ESI/APCI(+): 268 (M+H).
24%
With iodine; sodium hydrogencarbonate; potassium iodide; In water; at 20℃; for 72h;
INTERMEDIATE 45 - PREPARATION of 5-chloro-2-iodo-4-methylaniline. A solution of iodine (9.86 g; 38.84 mmol) and potassium iodide (6.45 g; 38.84 mmol) in water was added dropwise to a suspension of 3-chloro-4-methylaniline (5.00 g; 35.31 g) in a solution of sodium bicarbonate (4.75 g; 56.50 mmol). The resulting mixture was stirred for 72 hours at room temperature and filtered. The solid was dissolved in dichloromethane, washed with a saturated solution of sodium thiosulfate, and the organic layer was dried and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in heptane) to yield 2.30 g (24%) of the title compound as a brown solid.ESI/APCI(+): 268 (M+H).
24%
With iodine; sodium hydrogencarbonate; potassium iodide; In water; at 20℃; for 72h;
A solution of iodine (9.86 g; 38.84 mmol) and potassium iodide (6.45 g; 38.84 mmol) in water was added dropwise to a suspension of 3-chloro-4-methylaniline (5.00 g; 35.31 g) in a solution of sodium bicarbonate (4.75 g; 56.50 mmol). The resulting mixture was stirred for 72 hours at room temperature and filtered. The solid was dissolved in dichloromethane, washed with a saturated solution of sodium thiosulfate, and the organic layer was dried and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in heptane) to yield 2.30 g (24%) of the title compound as a brown solid. [0636] ESI/APCI(+): 268 (M+H).
24%
With iodine; sodium hydrogencarbonate; potassium iodide; In water; at 20℃; for 72h;
A solution of iodine (9.86 g; 38.84 mmol) and potassium iodide (6.45 g; 38.84 mmol) in water was added dropwise to a suspension of 3-chloro-4-methylaniline (5.00 g; 35.31 g) in a solution of sodium bicarbonate (4.75 g; 56.50 mmol). The resulting mixture was stirred 72 hours at room temperature filtrated and the solid dissolved in dichloromethane, washed with a saturated solution of sodium thiosulphate, dried over magnesium sulphate and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in heptane) to yield 2.30 g (24%) of 5-chloro-2-iodo-4-methylaniline as a brown solid. [0541] ESI/APCI(+): 268 (M+H).
24%
With iodine; sodium hydrogencarbonate; potassium iodide; In water; at 20℃; for 72h;
INTERMEDIATE 137 - PREPARATION of 5-chloro-2-iodo-4-methylaniline; A solution of iodine (9.86 g; 38.84 mmol) and potassium iodide (6.45 g; 38.84 mmol) in water was added dropwise to a mixture of 3-chloro-4-methylaniline (5.00 g; 35.31 g), sodium bicarbonate (4.75 g; 56.50 mmol) in water. The resulting mixture was stirred 72 hours at room temperature filtrated and the solid dissolved in dichloromethane, washed with a saturated solution of sodium thiosulphate dried and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in heptane) to yield 2.30 g (24%) of the title compound as a brown solid. ESI/APCI(+): 268 (M+H).
With Iodine monochloride; In methanol; dichloromethane; at 5 - 20℃; for 1h;Industrial scale;
A solution of iodine monochloride (87.6 g, 540 mmol) in dichloromethane (800 ml) was added dropwise to a solution of compound A (51 g, 360 mmol) in methanolControl the dropping rate, keep the reaction temperature stable below 5 .After the addition was completed, the reaction was carried out at room temperature for 1 hour. The TLC (PE / EA = 20/1) test material almost disappeared and a new main point was formed.The reaction solution with a mass percentage concentration of 40% NaOH solution to adjust PH to 8-9, and then washed to a yellow sodium sulfite solution.The methylene chloride phases were separated and the aqueous phase was extracted once more with DCM (600 ml). The organic phases were combined, washed once more with water, once with saturated brine and dried to dryness.40 g of compound B was beaten with petroleum ether, and the yield was 41%, which was directly used for the next reaction.
General Procedure: 4-Aminoquinazolines were prepared according to literature methods with a slight procedural modification. A typical procedure utilized is demonstrated for compound 10 as a representative example. In a 25 mL seal-tube reaction vessel equipped with a magnetic stirrer, 100.0 mg (0.445 mmol) of 4-chloro-6,7-dimethoxy-quinazoline was added followed by 2.0 mL of acetonitrile and 62.5 mg (0.490 mmol) of 4-chloroaniline. The vessel was sealed and heated to 100 C. After stirring at said temperature for a period of one day, the reaction was cooled,solvent evaporated via speed-vac, and tritiated three times with cold acetonitrile. Any remaining solvent was evaporated in vacuo to afford 140 mg (quantitative yield) of 10 as a white crystalline solid.
With triethylamine;potassium iodide; In N,N-dimethyl-formamide; at 20℃; for 72h;
Step 1: 3-chloro-N-(3-chloropropyl)-4-methylaniline To a solution of 3-chloro-4-methylaniline (14.16 g, 100 mmol) in DMF (N,N-dimethyl formamide) (10 mL), were added 1-bromo-3-chloropropane (30.5 mL, 300 mmol), potassium iodide (1.66 g, 10 mmol) and triethylamine (60 mL). The mixture was stirred for 3 days at room temperature, then distilled off the solvents with a low boiling point, diluted with ethyl ether, and washed by a saturated saline. The separated organic phase was dried with sodium sulfate and concentrated under reduced pressure. The concentrate was separated through column chromatography (petroleum ether/ethyl acetate=25/1, v/v) to obtain compound 1 as light brown oil (18.64 g, yield: 86%). 1HNMR (CDCl3, 300 MHz) delta: 7.01-6.98 (d, 1H, J=8.1 Hz), 6.64-6.63 (d, 1H, J=2.4 Hz), 6.46-6.42 (dd, 1H, J=2.4 Hz, 5.7 Hz), 3.66-3.62 (t, 2H, J=6.3 Hz), 3.31-3.27 (t, 2H, J=6.6 Hz), 2.45 (s, 3H), 2.09-2.01 (m, 2H).
86%
With triethylamine; potassium iodide; In N,N-dimethyl-formamide; at 20℃; for 72h;
In the 3 - chloro -4 - methylaniline (14.16 g, 100 mmol) in DMF (N, N - dimethyl formamide) (10 ml) are added in the solution 1 - bromo -3 - chloro propane (30.5 ml, 300 mmol), potassium iodide (1.66 g, 10 mmol) and triethylamine (60 ml). This mixture to stir at room temperature 3 days. Then the evaporation of the low boiling point solvent, ether dilution, and saturated salt water washing, separation of the organic phase with sodium sulfate drying and concentrating under reduced pressure. Concentrate the chromatographic separation column chromatography (petroleum ether/ethyl acetate=25/1, v/v), the obtained product 1 is light brown oil (18.64 g, yield 86%).
75%
With potassium carbonate; potassium iodide; In acetonitrile; at 110℃;Microwave irradiation;
General procedure: A mixture of anilines 10a-c (9.00 mmol), 1-bromo-3-chloropropane (0.49 g, 3.00 mmol), and KI (0.05 g, 0.30 mmol) in MeCN(5.00 mL) was reacted in microwave reactor at 110 C for 15 min.The solvent was evaporated in vacuo, diluted with water (30 mL),and extracted with EtOAc (30 mL 3). The combined organic layerwas dried (MgSO4) and filtered, then the solvent was evaporated invacuo. The residue was purified by column chromatography on silica gel to yield corresponding compounds 11a-c. 4.1.9.1. 3-Chloro- N-(3-chloropropyl)-4-methylaniline (11a). Yellow oil (0.49 g, 75%). 1H NMR (CDCl3, 500 MHz) d: 7.52 (d,J = 2.3 Hz, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.38 (m, 1H), 3.73 (m, 2H),3.53 (2H, m), 2.40 (s, 3H, CH3), 2.23 (m, 2H,). ESI-MS m/z: 219[M+H] +
With naphthalene-1,3,6-trisulfonic acid; In water; isopropyl alcohol; for 0.983333h;Reflux;
To a 50 ml single-necked flask with a condenser tube and a magnetic stirrer containing 9 ml of a 52% isopropanol aqueous solution by volume was added 1.0 mmol of 4-methyl-3-chloroaniline, 1.0 mmol of dehydroacetic acid, and 0.05 mmol of 1,3,6-naphthalenetrisulfonic acid catalyst, magnetically stir and mix at room temperature. Heating until reflux occurs, keeping the reaction time at reflux for 59min, TLC (thin plate chromatography) detection, the raw material point disappears, and the reaction is cooled to room temperature to precipitate a large amount of solids, standing, suction filtration,The filter residue was washed with anhydrous ethanol (3ml × 3) and dried under vacuum at 80 C to obtain 3- [1- (3-chloro4-methylphenylimino) ethyl] -4-hydroxy-6-methyl- 2H-pyran-2-one,The purity was 98.4% as determined by high performance liquid chromatography, and the calculated yield was 84%.To the filtrate, 4-methyl-3-chloroaniline and dehydroacetic acid were directly added, and then reused.
General procedure: To a mixture of aniline (2 mmol), trimethyl orthoformate (1 mmol), in a test tube with magnetic stirring, tin (II) chloride-choline chloride (2:1) (30 mol %) ionic liquid was added. The test tube was heated in an oil bath at 90 C for 20 minutes and then was cooled to room temperature and ethyl acetate (20 mL) was added slowly and filtered off to extract the product from the deep eutectic solvent. Then the solvent and other volatile compounds were removed under reduced pressure to give solid crude products. Further purification was carried out by simple silica gel with the mixture of ethyl acetate and hexane (4:1) or recrystallization in hexane or the mixture of acetone and tert-butylmethylether providing a colorless or yellow powder.
With sodium carbonate; In water; at 20℃; for 0.5h;Green chemistry;
General procedure: Amine 1 (1 mmol) and enone 2 (1.2 mmol) were added to aqueous sodium carbonate solution (0.1 M, 1 ml) at corresponding temperature. Then the mixture was stirred until amine was completely consumed (monitored by TLC) or an appropriate time and extracted with ethyl acetate (3×10 ml). The combined organic layers washed with brine (10 ml), dried over Na2SO4, filtered, and concentrated in vacuo. Flash column chromatography afforded beta-amino carbonyl compound.
With ionic liquid immobilized on gamma-Fe2O3(at)SiO2 nanoparticles; In water; at 100℃; for 0.833333h;
General procedure: To a solution of amine (1 mmol) in water (2 ml) was added tetrahydro-2,5-dimethoxyfuran (1.1 mmol) and gamma-Fe2O3(at)SiO2-Sb-IL (0.08 g). The reaction mixture was stirred at 100 C for a certain period of time as required to complete the reaction. During that time, the reaction was monitored constantly by TLC. After completion of the reaction, the catalyst was removed by using a magnet and washed with ethyl acetate. The aqueous solution was extracted by ethyl acetate (3 × 5 ml). The combined organic phase was dehydrated with anhydrous sodium sulfate. After the evaporation of the solvent, the residue was purified by silica gel flash chromatography using petroleum ether/ethyl acetate as the eluent to afford the pure product. 1-(3-Chloro-4-methylphenyl)-1H-pyrrole (3s). IR (KBr): 1610, 1510, 1473, 1380, 1334, 1251, 1076, 1047, 1028, 937, 858, 819 cm-1; 1H NMR (CDCl3, 500 MHz) delta: 2.38 (s, 3H), 6.34 (t, J = 2.0 Hz, 2H), 7.04 (t, J = 2.0 Hz, 2 H), 7.19 (dd, J = 8.5, 2.5 Hz, 1H), 7.26 (d, J = 8.5 Hz,1H), 7.40 (d, J = 2.5 Hz, 1H) ppm; 13C NMR (CDCl3, 125 MHz) delta: 19.5, 110.8, 118.6, 119.3, 121.1, 131.7, 132.2, 135.1, 139.7 ppm; ESI-MS: m/z = 192 (M + 1)+; Anal. Calcd. for C11H10ClN: C, 68.93; H, 5.26; N, 7.31. Found: C, 69.10; H, 5.08; N, 7.49.
With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 6h;
General procedure: To a stirred solution of 3,4-dichloroaniline 4b (1.94 g, 12.0 mmol) in THF (20.0 mL) were added ethyl chloroglyoxylate (1.11 mL, 10.0 mmol) and Et3N (15.2 mL, 11.0 mmol) at 0 C. The mixture was stirred at room temperature for 6 h. After the precipitate was filtrated off, the filtrate solution was concentrated under reduced pressure. The residue was dissolved in EtOAc, and washed with 1.0 M HCl, saturated NaHCO3 and brine, then dried over MgSO4. Concentration under reduced pressure to provide the title compound 6b (1.58 g, 95% yield) as white powder, which was used without further purification.
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h;
To asolution of 3-chloro-4-methylaniline 10a (0.85 g, 6.00 mmol) in DCM (15.00 mL), EDC HCl (1.72 g, 9.00 mmol) and acetic acid(0.34 mL, 6.00 mmol) were added successively at room temperature, and the resulting reaction mixture was stirred for 12 h atthe same temperature. Then the reaction mixture was concentrated under reduced pressure. The residue was purified by silicagel column chromatography (EtOAc/PE 1:4) to furnish the titlecompound 23a (0.84 g, yield 76%). 1H NMR (CDCl3, 500 MHz) d:7.92 (s, 1H, NH), 7.57 (br s, 1H, Ar-H), 7.26-7.23 (m, 1H, Ar-H),7.11-7.09 (m, 1H, Ar-H), 2.29 (s, 3H, CH3), 2.14 (s, 3H, CH3). ESIMS m/z: 184 [M+H]+.
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h;
General procedure: To asolution of 3-chloro-4-methylaniline 10a (0.85 g, 6.00 mmol) in DCM (15.00 mL), EDC HCl (1.72 g, 9.00 mmol) and acetic acid(0.34 mL, 6.00 mmol) were added successively at room temperature, and the resulting reaction mixture was stirred for 12 h atthe same temperature. Then the reaction mixture was concentrated under reduced pressure. The residue was purified by silicagel column chromatography (EtOAc/PE 1:4) to furnish the titlecompound 23a (0.84 g, yield 76%).
1-acetyl-N-(3-chloro-4-methylphenyl)piperidine-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h;
General procedure: To asolution of 3-chloro-4-methylaniline 10a (0.85 g, 6.00 mmol) in DCM (15.00 mL), EDC HCl (1.72 g, 9.00 mmol) and acetic acid(0.34 mL, 6.00 mmol) were added successively at room temperature, and the resulting reaction mixture was stirred for 12 h atthe same temperature. Then the reaction mixture was concentrated under reduced pressure. The residue was purified by silicagel column chromatography (EtOAc/PE 1:4) to furnish the titlecompound 23a (0.84 g, yield 76%).
1-methylsulfonyl-N-(3-chloro-4-methylphenyl)piperidine-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h;
General procedure: To asolution of 3-chloro-4-methylaniline 10a (0.85 g, 6.00 mmol) in DCM (15.00 mL), EDC HCl (1.72 g, 9.00 mmol) and acetic acid(0.34 mL, 6.00 mmol) were added successively at room temperature, and the resulting reaction mixture was stirred for 12 h atthe same temperature. Then the reaction mixture was concentrated under reduced pressure. The residue was purified by silicagel column chromatography (EtOAc/PE 1:4) to furnish the titlecompound 23a (0.84 g, yield 76%).
N-(3-chloro-4-methylphenyl)-2,2,2-trifluoroacetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92.8%
With pyridine; In dichloromethane; at 0 - 20℃; for 1h;
To a solution of 3-chloro-4-methylaniline (14.2 g, lOOmmol) dissolved in DCM (250 ml), was added pyridine (75 ml, 0.8Omol) and added dropwise trifluoroacetic anhydride (16.5m1, 1 12.Smmol) at OC .The mixture was stuffed at room temperature for 1 hour. The reaction mixture was washed with 10% aqueous HC1, then with water. The organic phase was dried over Na2SO4 and concentrated to give the title compound, which was used without further purification (22g ,92.8%).
4-(3'-chloro-4'-methylphenylamino)-8-methoxyquinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76.48%
With pyridine hydrochloride; In isopropyl alcohol; for 0.75h;Reflux;
General procedure: A mixture of compound 1VI (0.040 g, 0.22 mmol), m-chloroaniline (0.036 g, 0.31 mmol) and pyridine hydrochloride was heated at reflux for 45 min in isopropanol (6 mL), after the reaction is over by TLC, it was cooled to room temperature and the petroleum ether (4 mL) and NaHCO3 (10 mL) were added into the reaction mixture. The product was filtered and recrystallised from ethanol to give the title compound 1. Compound 2 was prepared in the same manner as 1.
With N-chloro-succinimide; In N,N-dimethyl-formamide; at 20℃;
2,3-Dichloro-4-methylaniline To a solution of 3-chloro-4-methylaniline (1 equiv.) in DMF (0.7 M) at 0 C. was added NCS (1 equiv.) in DMF dropwise. The reaction was stirred at room temperature overnight. Water and ethyl acetate was added to the solution and the layers were separated. The organic layer was washed with H2O, dried over Na2SO4 and concentrated. The resulting residue was purified by column chromatography on silica gel to give 2,3-dichloro-4-methylaniline (26%). 1H NMR (400 MHz, DMSO-d6) delta ppm: 6.98 (d, J=8.4 Hz, 1H), 6.69 (d, J=8.4 Hz, 1H), 5.41 (brs. 2H), 2.20 (s, 3H).
diethyl 1-(1-((4-chloro-3-methylphenyl)amino)-2-ethoxy-2-oxoethyl)hydrazine-1,2-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With tris(p-bromophenylammoniumyl) hexachloroantimonate; In nitromethane; at 20℃;Inert atmosphere;
General procedure: To a stirred mixture of anilines (1, 1.0mmol), diazoacetates (2, 1.0mmol) and azodicarboxylates (3, 1.0mmol) in MeNO2 (2.0mL) under argon atmosphere, TBPA+SbCl6- (5mol%) were added. The reactions were performed at room temperature and completed within 12-26h as monitored by TLC. The products 5 were isolated by column chromatographic separation.
(2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)piperidine-3-carboxylic acid[ No CAS ]
[ 95-74-9 ]
[ 1346623-20-8 ]
Yield
Reaction Conditions
Operation in experiment
84%
With 4-methyl-morpholine; HATU; In dichloromethane; at 20℃; for 24h;
To a 100 mL flask containing (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)piperidine-3-carboxylic acid (2.71 g, 6.38 mmol) in 20 mL of dichloromethane was added 3-chloro-4-methylaniline (0.85 mL, 7.01 mmol, 1.1 equiv.) followed by N-methylmorpholine (1.05 mL, 968 mg, 9.57 mmol, 1.5 equiv.) and HATU (2.91 g, 7.66 mol, 1.2 equiv.). After stirring for 24 hours at ambient temperature the reaction mixture was concentrated in vacuo, diluted with 50 mL of isopropyl acetate and 20 mL of water and stirred for 15 minutes. The undissolved solids were filtered off and the aqueous layer was discarded. The organic phase was washed twice with 20 mL of water and then concentrated in vacuo to dryness. The solids were evaporated twice with 30 mL of ethanol. The resulting residue was then dissolved in 22 mL of refluxing ethanol and 4 mL of water was added. The resulting solution was then refluxed for 15 minutes (until initial seed bed was formed) and then slowly cooled to r.t. The slurry was subsequently stirred for 3 hours and the solids were filtered off. The solids were then washed with 10 mL of 7:3 ethanol/water and dried in a vacuum oven for 24 hours at 50 OC to afford 2.95 g of (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-methyl-3-chlorophenyl]piperidine-3-carboxamide as colorless crystals (84% yield).
N-(3-chloro-4-methylphenyl)ethanesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
With pyridine; In dichloromethane; at 20℃; for 18h;
A solution of 3-chloro-4-methylaniline (0.500 g, 3.53 1 mmol), ethanesulfonyl chloride (0.501 mL, 5.297 mmol) and pyridine (0.341 mL, 4.237 mmol) in dichloromethane (15 mL) was stirred at the room temperature for 18 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous 1M-hydrochloric acid solution, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 80 %) to give N(3-chloro-4-methylphenyl)ethanesulfonamide as red solid (0.528 g, 64.0 %).
methyl 4-(((3-chloro-4-methylphenyl)amino)methyl)-3-fluorobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47.9%
With potassium carbonate; In acetonitrile; at 20℃; for 15h;
[3559] A solution of 3-chloro-4-methylaniline ( 1.000 g, 7.062 mmol), methyl 4-(bromomethyl)-3-fluorobenzoate ( 1.919 g, 7.768 mmol) and potassium carbonate ( 1.952 g, 14.124 mmol) in acetonitrile ( 10 mL) was stirred at the room temperature for 15 hr, filtered to remove solids, and concentrated under the reduced pressure to remove the solvents. The residue was chromatographed (Si02, 40 g cartridge; ethyl acetate / hexane = 0 % to 10 %) to give methyl 4-(((3-chloro-4-methylphenyl)amino)methyl)-3-fluorobenzoate as pale yellow oil ( 1 .041 g, 47.9 %).
General procedure: To a solution of aniline (0.93 g,10 mmol) in 10% HCl (50 mL) cooled in an ice-bath was added NaNO2 (0.74 g,10.7 mmol). The mixture was stirred at 0 C for 0.5 h and followed by the addition of NaN3 (0.72 g,11 mmol). The mixture was stirred at 0 C for 0.5 h and the aqueous layer was extracted by EtOAc (3×50 mL). The organic layer was dried over MgSO4 overnight. After filtration, EtOAc was evaporated to give 20a as yellow oil (1.09 g, yield 92%), which was used directly in the next reaction without further purification. Compounds 20b-20z and 20aa were prepared from compounds19b-19z and 19aa in a similar manner as described for compound 20a, respectively.
General procedure: Compound 4(10 mmol) was dissolved in HCl (6 mol/mL, 10 mL) at 0 C. To theabove reaction mixture, the solution of sodium nitrite (0.6 g,8.5 mmol) in H2O (25 mL) was added dropwise at 5 to 0 C within30 min. The solution was vigorously stirred at 0-5 C for 30 min. Sodium azide (40 mmol) in H2O (50 mL) was added dropwise intothe reaction mixture at 0-5 C. The resulting solution was stirred at room temperature for 2-4 h followed by diluting with ice water(200 mL) and extracting with EtOAc (3 x 100 mL). The combined organic layer was washed with water (2 x 60 mL), saturated aqueous NaHCO3 (2 x 60 mL) and brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford compound 5. The residual crude product was used directly without purification.
(3β)-3-hydroxyandrosta-5,7-diene-17-(O-carboxymethyl)oxime[ No CAS ]
[ 95-74-9 ]
C28H35ClN2O3[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 8h;
General procedure: For the synthesis of intermediates 8a-o, a mixture of 7 (150 mg, 0.417 mmol), phenylamine derivatives (0.5 mmol) dissolved in DMF (15 mL), then HATU (160 mg, 0.42 mmol) and DIPEA (0.72 mL, 0.417 mmol) were added. The whole mixture was stirred in room temperature for 8 h. The mixture was then poured into cold water and extracted with ethylacetate. The organic extracts were dried over anhydrous MgSO4 and the solvent was removed under reduced pressure. The product was purified by chromatographic column to give solid as intermediates 8a-o.
With tert.-butylnitrite; iron; In dimethyl sulfoxide; at 30℃; for 8h;Inert atmosphere;
General procedure: A mixture of p-anisidine (1.0 mmol, 123 mg), t BuONO (1.1 mmol, 113.3 mg), diphenyl diselenide (0.5 mmol, 156 mg), freshly prepared Fe(0) catalyst (1 mmol) and DMSO (3 mL) was stirred under room temperature (30 C) for 8 hours (TLC) under argon atmosphere and the product was extracted by ethyl acetate. The extract was washed with water (20 mL) and brine (20 mL). Then the organic phase was dried over Na2SO4 and evaporated to leave the crude product which was purified by column chromatography over silica gel (hexane/ethyl acetate 98:2) to provide the pure (4-methoxyphenyl)(phenyl)selane 3 as a gummy liquid (215 mg, 82%).
(3-chloro-4-methylphenyl)-(phenyl)telluride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With tert.-butylnitrite; iron; In dimethyl sulfoxide; at 80℃; for 12h;Inert atmosphere;
General procedure: A mixture of p-anisidine(1.0 mmol, 123 mg), tBuONO (1.1 mmol, 113.3 mg), diphenyl ditelluride (0.5 mmol, 204 mg), freshly prepared Fe(0) catalyst (1 mmol) and DMSO (3 mL) was stirred at 80 C (silicon oil bath) for 12 hours (TLC) under argon atmosphere and the product was extracted by ethyl acetate. The extract was washed with water (20 mL) and brine (20 mL). Then the organic phase was dried over Na2SO4 and evaporated to leave the crude product which was purified by column chromatography over silica gel (hexane/ethyl acetate 98:2) to provide the pure (4-methoxyphenyl)(phenyl)tellane 3 as a gummy liquid (230 mg, 74%).
(3-chloro-4-methylphenyl)(4-methoxyphenyl)tellane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With tert.-butylnitrite; iron; In dimethyl sulfoxide; at 80℃; for 12h;Inert atmosphere;
General procedure: A mixture of p-anisidine(1.0 mmol, 123 mg), tBuONO (1.1 mmol, 113.3 mg), diphenyl ditelluride (0.5 mmol, 204 mg), freshly prepared Fe(0) catalyst (1 mmol) and DMSO (3 mL) was stirred at 80 C (silicon oil bath) for 12 hours (TLC) under argon atmosphere and the product was extracted by ethyl acetate. The extract was washed with water (20 mL) and brine (20 mL). Then the organic phase was dried over Na2SO4 and evaporated to leave the crude product which was purified by column chromatography over silica gel (hexane/ethyl acetate 98:2) to provide the pure (4-methoxyphenyl)(phenyl)tellane 3 as a gummy liquid (230 mg, 74%).
With tert.-butylnitrite; iron; In dimethyl sulfoxide; at 80℃; for 8h;Inert atmosphere;
General procedure: A mixture of p-anisidine (1.0 mmol, 123 mg), tBuONO (1.1 mmol, 113.3 mg), diphenyl disulfide (0.5 mmol, 109 mg), freshly prepared Fe(0) catalyst (1 mmol) and DMSO (3 mL) was stirred under 80 C in silicon oil bath for 8 hours (TLC) under argon atmosphere and the product was extracted by ethyl acetate. The extract was washed with water (20 mL) and brine (20 mL). Then the organic phase was dried over Na2SO4 and evaporated to leave the crude product which was purified by column chromatography over silica gel (hexane/ethyl acetate 98:2) to provide the pure (4-methoxyphenyl)(phenyl)sulfane 4 as a gummy liquid (175 mg, 81%).
Taking 3 - chloro -4 - methylaniline 1.41g, triphosgene 1.10g for 100 ml in the reaction tube, the toluene is added to 45 ml, under ice bath reaction, TLC tracking detection, 1h reaction is complete. Then adding 0.25g ETS - 10, raising the temperature to 100 C reaction, TLC detection, about 2h reaction is complete. The solution in toluene obtained solid product to two 1, 3 - (3 - chloro 4 - methyl phenyl) urea 1.50g, m.p.271 . 1 - 271.3 C, yield 97%, purity 98.15% (HPLC). Centrifugal solid catalyst and distillation of toluene are used for the repeated reaction, reaction conditions, raw material on the same, repeated 5 times and, yield is 95% or more, to be repeated 6 times and, yield is 89%, purity 97% or more.
1L reactor (equipped with a condenser, the gas phase outlet diameter is1/6 to 1/5 of thediameter of the kettle), and the temperature is lowered to 20 C or lower. Under stirring, 424 g (21.2 mol, 20 eq) of anhydrous hydrogen fluoride is added, and the temperature is lowered after the feed is completed. To 5 C or less,150 g (1.059 mol, 1 eq) of 3-chloro-4-methylaniline wasadded dropwise, and the temperature was controlled in the range of 5 to 15 C, and the addition was completed in about 3 hours, and the temperature was kept for 2 hours.After thecompletion of theheat preservation, thetemperature was lowered to 5 C or less, and 73.1 g of sodium nitrite (1.06 mol, 1 eq) was added in portions, and the reaction temperature was controlled within the rangeof-5 to 15 C, and the mixture was added forabout 4 hours, and the heat was kept for 1 hour.After the heat preservation, the temperature of the reaction kettle is programmed (strictly controlling the heating rate:when thetemperature is in the range of 0 to 20 C, the temperature is raised by 0.5 to 1 C per hour,when the temperature is in the range of 20 to 80 C, the temperature is raised by 1 to 2 C per hour), and the temperature is raised to 80 C and keep warm for2h.After the heat preservation is completed, the temperature is lowered to 30 to 35 C, and the layers are separated. The organic layer is neutralized to a pH of 7 to 8 by a dilute alkali, and steam distillation is carried out. The organic layer is 141 g at room temperature, and the purity of the gas chromatographic detection is 93.4%. The distillation obtained 125.1 g of qualified product, the yield was 81.8%, and the purity of 2-chloro-4-fluorotoluene obtained by gas chromatography was 99.9%.
tert-butyl 2-((3-chloro-4-methylphenyl)amino)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
19%
With potassium carbonate; potassium iodide; In acetone; at 60℃;Inert atmosphere;
[0151] To a solution of 3-chloro-4-methylaniline (400 mg, 2.83 mmol) in acetone (35 mL) was added tert-butyl 2-bromopropanoate (890 mg, 4.26 mmol), KI (940 mg, 5.66 mmol), and K2CO3 (781 mg, 5.66 mmol). The mixture was heated at 60C under N2 then filtrated and concentrated. The residue was purified using silica gel eluting with PE/EA (2: 1) to give tert-butyl 2-((3-chloro-4-methylphenyl)amino)propanoate (151 mg, 19% yield).
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