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Structure of 933-88-0 * Storage: {[proInfo.prStorage]}
With hydrogen bromide In hexane; water; ethyl acetate; acetonitrile
Example 6 Preparation of 2-bromo-1-o-tolylethanone (I15) To a solution of 2-methylbenzoyl chloride (169 μl, 1.29 mmol) in dry acetonitrile (5 ml) and cooled at 0° C., under nitrogen atmosphere, was added (diazomethyl)-trimethylsilane (1.94 ml, 3.88 mmol, 2M in hexane). The reaction was stirred at room temperature for 15 hours, then it was cooled at 0° C. and 48percent HBr (512 μl, 4.53 mmol) was slowly added. The reaction was stirred at room temperature for 3 hours. EtOAc and water were added, the organic layer was separated and the aqueous phase was neutralized with 1M NaOH and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness to obtain 2-bromo-1-o-tolylethanone (250 mg, 91percent yield). This intermediate was used in the next step without any further purification. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.82-7.91 (m, 1H), 7.45-7.52 (m, 1H), 7.25-7.40 (m, 2H), 4.86 (s, 2H), 2.41 (s, 3H).
91%
Stage #1: at 0 - 20℃; for 15 h; Inert atmosphere Stage #2: With hydrogen bromide In hexane; water; acetonitrile at 0 - 20℃; for 3 h;
To a solution of 2-methylbenzoyl chloride (169 μ, 1.29 mmol) in dry acetonitrile (5 ml) and cooled at 0°C, under nitrogen atmosphere, (diazomethyl)trimethylsilane (1.94 ml, 3.88 mmol, 2M in hexane) was added. The reaction was stirred at room temperature for 15h, then it was cooled at 0°C and 48percent HBr (512 μ, 4.53 mmol) was slowly added. The reaction was stirred at room temperature for 3h. EtOAc and water were added, the organic layer was separated and the aqueous phase was neutralized with 1M NaOH and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness to obtain 2-bromo-l-o- tolylethanone (250 mg, 91percent yield). This intermediate was used in the next step without any further purification.1H NMR (300 MHz, DMSO- 6) δ ppm 7.82 - 7.91 (m, 1 H), 7.45 - 7.52 (m, 1 H), 7.25 - 7.40 (m, 2 H), 4.86 (s, 2 H), 2.41 (s, 3 H).
Reference：
[1] Journal of Agricultural and Food Chemistry, 2005, vol. 53, # 24, p. 9566 - 9570
[2] Chemische Berichte, 1935, vol. 68, p. 227,230
[3] Diss. <T. H. Berlin 1932> S. 60,
8
[ 141-78-6 ]
[ 933-88-0 ]
[ 51725-82-7 ]
Reference：
[1] Journal of Organic Chemistry, 1988, vol. 53, # 24, p. 5597 - 5601
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1988, vol. 53, # 4, p. 839 - 850
11
[ 933-88-0 ]
[ 95-53-4 ]
[ 22978-49-0 ]
Reference：
[1] Chemical Communications, 2015, vol. 51, # 7, p. 1371 - 1374
[2] Journal of Organic Chemistry, 1981, vol. 46, # 22, p. 4511 - 4515
[3] Justus Liebigs Annalen der Chemie, 1971, vol. 752, p. 115 - 135
12
[ 933-88-0 ]
[ 165309-37-5 ]
[ 137975-06-5 ]
Reference：
[1] Journal of Medicinal Chemistry, 1996, vol. 39, # 18, p. 3547 - 3555
13
[ 933-88-0 ]
[ 137977-97-0 ]
[ 137973-76-3 ]
Yield
Reaction Conditions
Operation in experiment
96%
Stage #1: With magnesium hydroxide In dichloromethane; water at 10℃; for 0.5 h; Stage #2: for 3 h;
To a 3 L reactor was added 1- (4-amino-2-methylbenzoyl) -7-chloro-5-oxo-2,3,4,5-tetrahydro- 1 H- 1 -benzazepine (70. 0 g, 212.90 mmol), dichloromethane (560 ml) and distilled water (140 ml), and the mixture was stirred for 1 hour. Magnesium hydroxide (14.90 g, 14.90 mmol) was added to the reaction mixture at 10 ° C. or lower, and the mixture was stirred for 30 minutes. 2-Methylbenzoyl chloride (30.42 ml) was gradually added to the reaction mixture, followed by stirring for 3 hours. The reaction mixture was filtered to remove magnesium hydroxide and the pH of the reaction mixture was adjusted to pH 8 to 9 using aqueous sodium hydroxide solution and then the organic layer was separated. The obtained organic layer was dried with sodium sulfate (Na 2 SO 4), filtered and concentrated under reduced pressure to give 7-chloro-1- [2-methyl-4 - [(2-methylbenzoyl) amino] benzoyl] -5 - oxo-2,3,4,5-tetrahydro-1 H-1-benzazepine 91.35 g was obtained (yield: 96percent).
90.6%
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 2 h;
Compound (IX) (14.0g, 42.58mmol) was dissolved in dichloromethane (350 mL of) was added diisopropylethylamine (11.0g, 85.16mmol), stirred for 15min, then was added portionwise o-methylbenzoic chloride (7.90g, 51.10mmol), at RT for 2h, TLC detection, the reaction was complete. The reaction mixture was poured into water (200 mL), the organic phase washed with water twice (200mlx2), dried over anhydrous sodium sulfate, and methylene chloride to give a spin product 2-methyl-4- (2-methyl-benzoylamino) benzene acid (17.24g, 90.6percent).
88%
With triethylamine In dichloromethane at 20℃; for 2.25 h;
The compound (IX) (18.0 g, 54.75 mmol) was dissolved in dichloromethane (150 mL)Triethylamine (15.22 mL, 109.49 mmol) was added, stirred for 15 min,Then, 2-methylbenzoyl chloride (10.16 g, 65.70 mmol) was slowly added dropwise and reacted for 2 h at room temperature. The reaction was complete by TLC. The reaction solution was poured into water (100 mL), and the organic phase water was washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, removal of the dichloromethane gave the product compound (X) (21.53 g, 88percent).
88.2%
With pyridine In dichloromethane at 0 - 10℃; for 2 h;
The intermediate 10.0g,Pyridine 3.5g, 150ml dichloromethane into 500ml reaction flask,Stirring, dropping 4.9 g of 2-methylbenzoyl chloride in dichloromethane under the condition of 0 DEG C,The reaction was heated to 10 ° C for 2h, followed by TLC sampling, showing no starting material and the reaction was completed.The pH was adjusted to 2 with 6N aqueous hydrochloric acid, the layers were separated and the organic layer was concentrated under reduced pressure to give a light yellow solid,Recrystallization by addition of methanol and cyclohexane afforded 12g as an off-white solid in 88.2percent yield with an HPLC purity of 99.5percent.
86.1%
With pyridine In dichloromethane at 20 - 30℃;
To a 250 ml reaction flask was added 50 ml of dichloromethane, 5.6 ml of pyridine, and the compound of the formula III was added with stirring, then 3.5 g of o-methylbenzoyl chloride was added, and the reaction was completed at 20 to 30 ° C with stirring. Filtered 6.95g crude tolvaptan, purity95.39percent, impurity M 0.56percent.The solid obtained in the above step was added to a solvent of 32 g of ethyl acetate/dichloromethane/isopropyl ether (volume ratio 1:4:1), heated to 50 ° C to 60 ° C, stirred and dissolved, cooled and crystallized, and filtered to obtain a white solid 6.1 g. , yield: 86.1percent, purity: 99.51percent, impurity M content 0.04percent.
185 g
With sodium hydrogencarbonate In dichloromethane; water at 0 - 5℃;
Example 4 Preparation of 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine 1-(4-Amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (185 gm) as obtained in example 3 was dissolved in methylene chloride (4000 ml) and then added sodium bicarbonate solution (10percent, 47.3 gm). The reaction mass was cooled to 0 to 5° C. and then added 2-methyl benzoyl chloride (95.7 gm) slowly. The pH of the reaction mass was adjusted to 7.0 to 8.0 with aqueous sodium bicarbonate solution (120 ml). The separated aqueous layer was extracted with methylene chloride and then concentrated to obtain a residual solid of 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (185 gm).
Reference：
[1] Patent: JP2018/12690, 2018, A, . Location in patent: Paragraph 0029; 0030
[2] Patent: CN105315169, 2016, A, . Location in patent: Paragraph 0170; 0224; 0225
[3] Patent: CN105753735, 2016, A, . Location in patent: Paragraph 0181; 0217; 0218
[4] Patent: CN106883175, 2017, A, . Location in patent: Paragraph 0017; 0018
[5] Patent: CN108503586, 2018, A, . Location in patent: Paragraph 0044; 0045; 0054; 0055; 0056
[6] Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 8, p. 1743 - 1754
[7] Tetrahedron Asymmetry, 2010, vol. 21, # 19, p. 2390 - 2393
[8] Patent: WO2012/46244, 2012, A1, . Location in patent: Page/Page column 9
[9] Patent: US2013/190490, 2013, A1, . Location in patent: Paragraph 0064; 0065
With sodium hydroxide; In dichloromethane; at 20℃; for 1h;
A mixture of (R)-2-phenylpropyl amine (1.24 g; 9.17 mmol), 1N NaOH (20 mL), and dichloromethane (20 mL) is treated with o-toluoyl chloride (1.42 g; 9.17 mmol) added dropwise; the mixture is then stirred at room temperature for 1 hour. The phases are separated and the aqueous layer extracted with dichloromethane (2×70 ml). The combined extracts are washed with water (1×30 mL) and brine (1×30 mL), dried over magnesium sulfate, and evaporated to give the product as a white solid.
EXAMPLE 11 To a suspension of 636 mg of 4-carbamoylimidazolium-5-olate in 15 ml of dry pyridine was dropwisely added 1.0 g of o-methylbenzoyl chloride at less than 5 C. in N2 atmosphere. After being stirred for 2 hours at 41-43 C., the reaction mixture was cooled to room temperature and 658 mg of triethylamine was added. Then the reaction mixture was concentrated under reduced pressure. To the residue was added chloroform (about 20 ml) and then separated crystals were filtered off, washed with chloroform, toluene and ether, and dried to give 600 mg of 5-carbamoyl-1H-imidazol-4-yl o-methyl benzoate, m.p. 181.5-182.5 C. Recrystallized was 447 mg of crude material from N,N-dimethylformamide and water. Amount: 416 mg. m.p.: 185-185.5 C. (dec.)
General procedure: The general protocol followed for preparing beta-oxo-ylides was described here taking alpha-(6-chloronicotinoyl)-alpha-(cyano)methylenetriphenylphosphorane (5a) as an example. The remaining beta-oxo-ylides (5b-p) were prepared in a similar manner. Triethylamine (1.06 g, 0.01 mol) was added drop wise to a stirred suspension of cyanomethyltriphenylphosphonium chloride (3a, 1.68 g, 0.005 mol) in 10 mL dry CH2Cl2 at 10-15 C under N2 atmosphere. The reaction mixture was stirred at room temperature for 30 min and a solution of 6-chloronicotinoyl chloride (4a, 0.88 g, 0.005 mol) in 5 mL CH2Cl2 was added drop wise in about 15 min. After vigorous stirring for 12 h at room temperature, the reaction mixture was diluted with 10 mL CH2Cl2 and washed with 3 × 10 mL water. The organic layer was separated, dried over anhydrous sodium sulfate and the solvent was removed on rotavapor. The crude product was recrystallized from a 1:4 mixture of CH2Cl2 and hexane to obtain alpha-(6-chloronicotinoyl)-alpha-(cyano)methylenetriphenylphosphorane (5a). Yield: 2.09 g (95%).
(2-methylphenyl)(5-(4-fluorophenyl)thiophen-2-yl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
Next, a solution of 2-methylbenzoic acid chloride (0.86 g, 5.6 mmol) in methylene chloride (6 mL) was cooled to 2 C. Aluminum chloride (0.9 g, 6.6 mmol) was added to the resulting reaction solution such that the temperature of the reaction solution was 10 C. or less. Aluminum chlorideAnd after stirring for 15 minutes, methylene chloride of 2- (4-fluorophenyl) thiophene (1 g, 5.6 mmol) obtained in the first step such that the temperature of the reaction solution becomes 10 C. or less The solution (3 mL) was added dropwise to the reaction solution, and the mixture was stirred for 1 hour at the same temperature, heated to 23 C., and stirred for 3 hours.Ice (30 g) is added to the obtained reaction liquid to dilute, and then separated. The aqueous layer is extracted with methylene chloride, combined with the previously obtained methylene chloride layer, washed with water, and concentrated under reduced pressure.Crude crystals of 2- (4-fluorophenyl) -5- (2-methylbenzoyl) thiopheneObtained (1.61 g, 97%). The crude crystals were recrystallized from ethyl acetate / hexane (0.65 g, yield 40 mol%) to obtain the desired product as yellow crystals. The purity of the yellow crystals was determined by high performance liquid chromatography (HPLC) to be 99.89%.
N-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)thiocarbamoyl)-2-methylbenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
Add ammonium thiocyanate (45 mmol) and 50 mL of acetone to a two-necked round bottom flask, add o-methylbenzoyl chloride (45 mmol),Stir at room temperature for 10 min, raise the temperature to reflux for 1 hour, and then add 5-amino-3- (trifluoromethyl) -2-cyanopyridine (30 mmol) in acetone.After refluxing for 6 hours, it was cooled to room temperature, poured into 100 mL of water, adjusted to pH 8.0 with sodium bicarbonate, and filtered with suction to obtain a pale yellow solid product A3 (8.19 g, yield 75%).
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