* 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] European Journal of Organic Chemistry, 2002, # 13, p. 2094 - 2108
2
[ 18595-13-6 ]
[ 99548-56-8 ]
Reference：
[1] Chemical Communications, 2005, # 44, p. 5583 - 5585
[2] Chemistry - A European Journal, 2009, vol. 15, # 24, p. 5956 - 5968
3
[ 61940-22-5 ]
[ 18595-13-6 ]
Yield
Reaction Conditions
Operation in experiment
97%
With hydrogen In methanol; water at 0 - 25℃; for 1.5 h;
A mixture of methyl 2-methyl-6-nitrobenzoate (3.80g, 19.5 mmol) and 10percent palladium-carbon (containing 50percent water) (1.03g) was stirred under a hydrogen atmosphere in methanol (20mL) at 20-25°C for 1.5 hours. After filtering off palladium-carbon, the solvent was distilled off under reduced pressure to give methyl 2-amino-6-methylbenzoate (3.13g, 97percent). 1H-NMR (CDCl3) δ:2.43(3H,s), 3.88(3H,s), 2.37(3H,s), 6.52(1H,s), 6.54(1H,s), 7.08(1H,t,J=7.9Hz)
Reference：
[1] Chemical Communications, 2005, # 44, p. 5583 - 5585
[2] Chemistry - A European Journal, 2009, vol. 15, # 24, p. 5956 - 5968
[3] Patent: EP1844768, 2007, A1, . Location in patent: Page/Page column 27
[4] Bulletin de la Societe Scientifique de Bretagne, 1956, vol. 31, p. Sonderheft S.9,41
[5] Patent: US2002/19414, 2002, A1,
[6] Journal of the American Chemical Society, 2014, vol. 136, # 10, p. 3744 - 3747
4
[ 4389-50-8 ]
[ 18107-18-1 ]
[ 18595-13-6 ]
Yield
Reaction Conditions
Operation in experiment
100%
at 20℃; for 1.5 h;
Example 130 Synthesis of (+/-)-Isopropyl 5- [acetyl- (3, 5-bistrifluoromethylbenzyl) amino] -6-methyl- tetrahydrobenzo [b] azepine-1-carboxylate Step 1. Preparation of 2-Amino-6-methyl-benzoic acid methyl ester. Dissolve 2-Amino-6-methyl-benzoic acid (3.00 g, 19.8 mmol) in ethylacetate (100 mL) and ethanol (100 mL) and add (trimethylsilyl) diazomethane (19.8 mL, 39.7 mmol, 2M in hexane) at room temperature and stir the solution for 1 h 30 min. Remove the solvent under reduced pressure to afford the title compound (3.30 g, quantitative). lH NMR (CDC13, 300 MHz) S 2.43 (s, 3H), 3.89 (s, 3H), 5.11 (brs, 2H), 6.52 (m, 2H), 7.08 (t, J = 7.7 Hz, 1H). MS (ES+): 166 (M+H).
16.5 g
at 20℃; for 4 h;
2.0 M diethyl ether solution of trimethylsilyldiazomethane was added under ice cooling to a mixture of 15.1 g of 2-amino-6-methylbenzoic acid, 150 mL of ethyl acetate, 150 mL of ethanol. After the mixture was stirred at ambient temperature for 4 hr, the reaction mixture was concentrated under reduced pressure to obtain 16.5 g of methyl 2-amino-6-methyl benzoate. Methyl 2-amino-6-methylbenzoate 1H-NMR (CDCl3) δ: 6.94 (1H, t, J = 8.0 Hz), 6.40-6.38 (2H, m), 4.96 (2H, s), 3.75 (3H, s), 2.29 (3H, s).
In ethanol; hexane; ethyl acetate; at 20℃; for 1.5h;
Example 130 Synthesis of (+/-)-Isopropyl 5- [acetyl- (3, 5-bistrifluoromethylbenzyl) amino] -6-methyl- tetrahydrobenzo [b] azepine-1-carboxylate Step 1. Preparation of 2-Amino-6-methyl-benzoic acid methyl ester. Dissolve 2-Amino-6-methyl-benzoic acid (3.00 g, 19.8 mmol) in ethylacetate (100 mL) and ethanol (100 mL) and add (trimethylsilyl) diazomethane (19.8 mL, 39.7 mmol, 2M in hexane) at room temperature and stir the solution for 1 h 30 min. Remove the solvent under reduced pressure to afford the title compound (3.30 g, quantitative). lH NMR (CDC13, 300 MHz) S 2.43 (s, 3H), 3.89 (s, 3H), 5.11 (brs, 2H), 6.52 (m, 2H), 7.08 (t, J = 7.7 Hz, 1H). MS (ES+): 166 (M+H).
In diethyl ether; ethanol; ethyl acetate; at 20℃; for 4h;
Reference Production Example 12 Step (1) To a mixture of 15.1 g of 2-amino-6-methylbenzoic acid, 150 mL of ethyl acetate, and 150 mL of ethanol, a 2.0M diethyl ether solution of trimethylsilyldiazomethane was added under ice cooling. After stirring at room temperature for 4 hours, the mixture was concentrated under reduced pressure to obtain 16.5 of 2-amino-6-methylbenzoic acid methyl ester. 1H-NMR (CDCl3) delta(ppm): 6.94 (1H, t, J = 8.0Hz), 6.40-6.38 (2H, m), 4.96 (2H, s), 3.75 (3H, s), 2.29 (3H, s).
16.5 g
In diethyl ether; ethanol; ethyl acetate; at 20℃; for 4h;
2.0 M diethyl ether solution of trimethylsilyldiazomethane was added under ice cooling to a mixture of 15.1 g of 2-amino-6-methylbenzoic acid, 150 mL of ethyl acetate, 150 mL of ethanol. After the mixture was stirred at ambient temperature for 4 hr, the reaction mixture was concentrated under reduced pressure to obtain 16.5 g of methyl 2-amino-6-methyl benzoate. Methyl 2-amino-6-methylbenzoate 1H-NMR (CDCl3) delta: 6.94 (1H, t, J = 8.0 Hz), 6.40-6.38 (2H, m), 4.96 (2H, s), 3.75 (3H, s), 2.29 (3H, s).
With pyridine; In dichloromethane; toluene; at 0 - 20℃; for 14h;
Step 2. Preparation of 2-Isopropoxycarbonylamino-6-methyl-benzoic acid methyl ester. Add isopropyl chloroformate (19.8 mL, 19.8 mmol, 1.0 M in toluene) dropwise to a solution of 2-Amino-6-methyl-benzoic acid methyl ester (3.27 g, 19.8 mmol) and pyridine (4.0 mL, 50 mmol) in dichloromethane (39 mL) at 0C under an atmosphere of nitrogen and stir at room temperature for 14 h. Add 1M HCl and separate the layers. Extract the aqueous layer with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (3.80 g, 76%) :'H NMR (CDCl3) 8 1.29 (d, J = 6.5 Hz, 6H), 2.43 (s, 3H), 3.94 (s, 3H), 5.00 (septuplet, J = 6.5 Hz, 1H), 6.90 (d, J = 8.1 Hz, 1H), 7.32 (t, J = 8.1 Hz, 1H), 8.07 (d, J = 8.1 Hz, 1H), 8.86 (brs, 1H). MS (ES+): 252 (M+H).
Once a homogeneous solution was achieved, formalin (37% in methanol; 1.76 ml excess) was added dropwise. The solution was allowed to cool to room temperature and then chilled to 0 C. for 4 days. The resulting solid was collected and air-dried to afford 476 mg (82%) of 2-hydroxymethyl-4-methylsaccharin, mp 196-198 C. 1 H nmr (300 MHz, CDCl3) 7.767 (1H, t, J=6.75 Hz); 7.732 (1H, d, J=7.72 Hz); 7.600 (1H, d, J=6.64 Hz); 5.361 (2H, d, J-8.00 Hz); 3.296 (1H, t, J=8.16 Hz); 2.793 (3H, s). IR (KBr, cm1): 3505 (s); 3070 (w); 1735 (s); 1580 (m).
52
[ 4389-50-8 ]
[ 67-68-5 ]
[ 74-88-4 ]
[ 18595-13-6 ]
Yield
Reaction Conditions
Operation in experiment
4.23 g (39%)
With potassium hydroxide;
EXAMPLE 1 Powdered potassium hydroxide (7.4 g; 132 mmol; 2 equiv.) was admixed with dimethyl sulfoxide (DMSO) (100 ml), and the mixture was stirred for 5 minutes. 6-Methylanthranilic acid (10.0 g; 66 mmol) was then added to the mixture and iodomethane (4.52 ml; 73 mmol; 1.1 equiv.) added dropwise. The reaction mixture was stirred for 30 minutes at room temperature, then diluted with ether (250 ml), washed with water (3*100 ml), dried (MgSO4) and concentrated. The crude product was filtered through a pad of flash grade (32-63) silica gel and eluted with 1:9 ether:hexane to afford 4.23 g (39%) of methyl 6-methylanthranilate as an oil. 1 H nmr (300 MHz, CDCl3) 7.078 (1H, t, J=7.67 Hz); 6.529 (2H, d, J=7.79 Hz); 5.111 (2H, br s); 3.887 (3H, s); 2.424 (3H, s). IR (neat film, cm-1): 3480 (m), 3380 (m), 2950 (w), 1690 (s); 1605 (s).
4.23 g (39%)
With potassium hydroxide;
PREPARATION 1 Powdered potassium hydroxide (7.4 g, 0.132 mol) was admixed with dimethyl sulfoxide (DMSO) (100 ml), and the mixture was stirred for 5 minutes. 6-Methylanthranilic acid (10.0 g, 0.066 mol) was then added to the mixture and iodomethane (4.52 ml, 0.073 mol) added dropwise. The reaction mixture was stirred for 30 minutes at room temperature, then diluted with 250 ml of ether, washed with water (3*100 ml), dried over magnesium sulfate and concentrated. The crude product was filtered through a pad of flash grade (32-63) silica gel and eluted with 1:9 ether:hexane to afford 4.23 g (39%) of methyl 6-methylanthranilate as an oil.
4.23 g (39%)
With potassium hydroxide;
Preparation 1 Powdered potassium hydroxide (7.4 g, 0.132 mol) was admixed with dimethyl sulfoxide (DMSO) (100 ml), and the mixture was stirred for 5 minutes. 6-Methylanthranilic acid (10.0 g, 0.066 mol) was then added to the mixture and iodomethane (4.52 ml, 0.073 mol) added dropwise. The reaction mixture was stirred for 30 minutes at room temperature, then diluted with 250 ml of ether, washed with water (3*100 ml), dried over magnesium sulfate and concentrated. The crude product was filtered through a pad of flash grade (32-63) silica gel and eluted with 1:9 ether:hexane to afford 4.23 g (39%) of methyl 6-methylanthranilate as an oil.
In hexane; water; ethyl acetate; tert-butyl alcohol;
a. Dimethyl 4-hydroxy-5-methylquinoline-2,3-dicarboxylate A stirred mixture of <strong>[18595-13-6]methyl 2-amino-6-methylbenzoate</strong> (1.50 g, 9.08 mM) and dimethyl acetylenedicarboxylate (1.40 g, 9.82 mM) in t-butanol (20 mL) was refluxed fpr 18 hr under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and potassium t-butoxide (1.10 g, 9.82 mM) was added in one portion whereupon a precipitate formed. After refluxing this mixture for 1.5 hr, it was cooled to room temperature and filtered to separate the solids. The solids were dissolved in water and the resulting solution acidified with 1N H2 SO4 to form a precipitate. The mixture was filtered and the collected solids were washed with water and dried to give the title compound (1.66 g, 66.4%) as a tan solid. An analytical sample of this material was obtained by recrystallization of a portion from ethyl acetate/hexane to give off white crystals, mp 167-168 C.; MS(CI): 276 (M+H). Analysis for C14 H13 NO5. 0.15 H2 O: Calculated: C, 60.50; H, 4.83; N, 5.04 Found: C, 60.45; H, 4.82; N, 4.95
With potassium hexamethylsilazane; In tetrahydrofuran; at 20℃; for 1h;Inert atmosphere;
General procedure: To a solution of methyl 2-amino-4-chlorobenzoate (300 mg, 1.6 mmol) and ethyl 2-phenoxyacetate (320 mg, 1.8 mmol) in anhydrous THF (9 mL) was added KHMDS (4.8 mL, 1.0 M in THF, 4.8 mmol) in one portion with vigorous stirring under a nitrogen atmosphere. The reaction mixture was stirred at rt until completion of the reaction (10 min) then MeOH was added. The reaction mixture was concentrated under reduced pressure and the resulting residue was taken up in water and acidified with 1 N HCl until precipitation occurred. The precipitate was filtered, washed with EtOH then dried to give 7-chloro-4-hydroxy-3-phenoxyquinolin-2(1H)-one (Table 2, entry 1) as a pale pink powder (449 mg, 92%).
<Step (2)> To a mixture of 16.5 g of <strong>[18595-13-6]2-amino-6-methylbenzoic acid methyl ester</strong> and 300 mL of toluene, 44.5 g of triphosgene was added at room temperature, followed by stirring while heating under reflux for 2.5 hours. After concentration under reduced pressure, 2-isocyanate-6-methylbenzoic acid methyl ester was obtained. 1H-NMR (CDCl3) delta(ppm): 7.28-7.24 (1H, m), 7.07-7.04 (1H, m), 6.98-6.95 (1H, m), 3.97 (3H, s), 2.36 (3H, s).
In toluene; for 2.5h;Reflux;
44.5 g of triphosgene was added in the mixture of 16.5 g of the obtained <strong>[18595-13-6]methyl 2-amino-6-methylbenzoate</strong> and 300 mL of toluene and the mixture was refluxed under heating with stirring for 2.5 hr. The reaction mixture was concentrated under reduced pressure to obtain methyl 2-isocyanate-6-methylbenzoate. Methyl 2-isocyanate-6-methylbenzoate 1H-NMR (CDCl3) delta: 7.28-7.24 (1H, m), 7.07-7.04 (1H, m), 6.98-6.95 (1H, m), 3.97 (3H, s), 2.36 (3H, s).
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