* 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] Organic Process Research and Development, 2012, vol. 16, # 5, p. 1082 - 1089
2
[ 83-41-0 ]
[ 1975-50-4 ]
[ 23876-13-3 ]
[ 23876-12-2 ]
Reference：
[1] Patent: CN105237317, 2016, A, . Location in patent: Paragraph 0077; 0078
3
[ 1975-50-4 ]
[ 23876-13-3 ]
Yield
Reaction Conditions
Operation in experiment
84%
Stage #1: With sodium tetrahydroborate In tetrahydrofuran at 20℃; for 0.5 h; Stage #2: With methanesulfonic acid In tetrahydrofuran
500ml of THF and 76.5 gm NaBH4 was stirred for 30 min. at ambient temperature. Solution of 2-Methyl-3-nitro benzoic acid in THF (25Og in 750 ml) was added and stirred for 0.5 hour at ambient temperature. Further, methanesulphonic acid (90 ml) was added to the reaction mixture and stirred until the completion of reaction. The reaction mixture is extracted with ethyl acetate by addition of Hydrochloric acid and product organic layer is separated out.[0120] Ethyl acetate is evaporated to give 2-Methyl-3-nitrobenzyl alcohol as yellow oil, which is further treated with cyclohexane and crystallized to give 2-Methyl-3-nitrobenzyl alcohol[0121] (Yield: -210 g., 84percent)
27 g
Stage #1: With sodium tetrahydroborate In tetrahydrofuran at 25℃; for 0.5 h; Stage #2: With methanesulfonic acid In tetrahydrofuran at 25℃; for 72.75 h;
Reference Production Example 15 Step (1) A mixture of 9.4 g of sodium borohydride and 150 mL of tetrahydrofuran was stirred at 25°C for 30 minutes. 2-methyl-3-nitrobenzoic acid (30.8 g) was added, followed by stirring at 25°C for 30 minutes. After ice cooling of this mixed solution, 11.0 mL of methanesulfonic acid was slowly added over 45 minutes. The reaction mixture was stirred at 25°C for 3 days. Water was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed in turn with 10percent hydrochloric acid and a saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 27.0 g of 3-hydroxymethyl-2-methyl-1-nitrobenzene. 1H-NMR (CDCl3) δ(ppm):1.81 (1H, s), 2.44 (3H, s), 4.79 (2H, s), 7.34 (1H, t, J = 7.8 Hz), 7.65 (1H, d, 7.6 Hz), 7.72 (1H, d, J = 8.1 Hz).
27.0 g
Stage #1: With sodium tetrahydroborate In tetrahydrofuran at 25℃; for 0.5 h; Stage #2: With methanesulfonic acid In tetrahydrofuran at 25℃; for 72 h;
A mixture of 9.4 g of sodium borohydride and 150 mL of tetrahydrofuran was stirred at 25°C for 30 min. 30.8 g of 2-methyl-3-nitrobenzoic acid was added to the mixture, which was further stirred at 25°C for 30 min. This mixture solution was ice-cooled and 11.0 mL of methanesulfonic acid was gradually added to the mixture over 45 min. The reaction mixture was stirred at 25°C for 3 days. Water was poured into the reaction mixture to extract the mixture with ethyl acetate. The organic phase was washed with an aqueous 10percent hydrochloric acid solution and saturated saline, dried by magnesium sulfate anhydride, and then, concentrated under reduced pressure to obtain 27.0 g of 3-hydroxymethyl-2-methyl-1-nitrobenzene. (0809) 3-hydroxymethyl-2-methyl-1-nitrobenzene 1H-NMR (CDCl3) δ:1.81 (1H, s), 2.44 (3H, s), 4.79 (2H, s), 7.34 (1H, t, J = 7.8 Hz), 7.65 (1H, d, 7.6 Hz), 7.72 (1H, d, J = 8.1 Hz).
Reference：
[1] Journal of Medicinal Chemistry, 1985, vol. 28, # 10, p. 1533 - 1536
[2] Patent: WO2006/123356, 2006, A1, . Location in patent: Page/Page column 21
[3] European Journal of Medicinal Chemistry, 1995, vol. 30, # 12, p. 973 - 982
[4] Helvetica Chimica Acta, 1948, vol. 31, p. 65,74
[5] Patent: WO2013/162072, 2013, A1, . Location in patent: Page/Page column 938
[6] European Journal of Medicinal Chemistry, 2015, vol. 101, p. 651 - 667
[7] Patent: EP2927218, 2015, A1, . Location in patent: Paragraph 0826
[8] Patent: EP2940012, 2015, A1, . Location in patent: Paragraph 0808; 0809
4
[ 89929-95-3 ]
[ 23876-13-3 ]
Reference：
[1] Angewandte Chemie - International Edition, 2005, vol. 44, # 9, p. 1378 - 1382
5
[ 83-41-0 ]
[ 1975-50-4 ]
[ 23876-13-3 ]
[ 23876-12-2 ]
Reference：
[1] Patent: CN105237317, 2016, A, . Location in patent: Paragraph 0077; 0078
6
[ 59382-59-1 ]
[ 23876-13-3 ]
Reference：
[1] Patent: US4942246, 1990, A,
7
[ 39053-41-3 ]
[ 23876-13-3 ]
Reference：
[1] European Journal of Medicinal Chemistry, 1995, vol. 30, # 12, p. 973 - 982
[2] Helvetica Chimica Acta, 1948, vol. 31, p. 65,74
8
[ 83647-42-1 ]
[ 23876-13-3 ]
Reference：
[1] Helvetica Chimica Acta, 1948, vol. 31, p. 65,74
9
[ 59383-08-3 ]
[ 23876-13-3 ]
Reference：
[1] Helvetica Chimica Acta, 1948, vol. 31, p. 65,74
10
[ 71516-35-3 ]
[ 23876-13-3 ]
Reference：
[1] Helvetica Chimica Acta, 1948, vol. 31, p. 65,74
11
[ 23876-12-2 ]
[ 23876-13-3 ]
Reference：
[1] Journal of the Chemical Society. Perkin transactions 1, 1969, vol. 14, p. 1935 - 1939
12
[ 83-41-0 ]
[ 23876-13-3 ]
Reference：
[1] Journal of the Chemical Society. Perkin transactions 1, 1969, vol. 14, p. 1935 - 1939
13
[ 23876-11-1 ]
[ 23876-13-3 ]
Reference：
[1] Journal of the Chemical Society. Perkin transactions 1, 1969, vol. 14, p. 1935 - 1939
14
[ 23876-13-3 ]
[ 23876-15-5 ]
Reference：
[1] Journal of Medicinal Chemistry, 1985, vol. 28, # 10, p. 1533 - 1536
[2] Journal of the Chemical Society. Perkin transactions 1, 1969, vol. 14, p. 1935 - 1939
[3] Journal of the Chemical Society. Perkin transactions 1, 1969, vol. 14, p. 1935 - 1939
500ml of THF and 76.5 gm NaBH4 was stirred for 30 min. at ambient temperature. Solution of 2-Methyl-3-nitro benzoic acid in THF (25Og in 750 ml) was added and stirred for 0.5 hour at ambient temperature. Further, methanesulphonic acid (90 ml) was added to the reaction mixture and stirred until the completion of reaction. The reaction mixture is extracted with ethyl acetate by addition of Hydrochloric acid and product organic layer is separated out.[0120] Ethyl acetate is evaporated to give 2-Methyl-3-nitrobenzyl alcohol as yellow oil, which is further treated with cyclohexane and crystallized to give 2-Methyl-3-nitrobenzyl alcohol[0121] (Yield: -210 g., 84%)
27 g
Reference Production Example 15 Step (1) A mixture of 9.4 g of sodium borohydride and 150 mL of tetrahydrofuran was stirred at 25C for 30 minutes. 2-methyl-3-nitrobenzoic acid (30.8 g) was added, followed by stirring at 25C for 30 minutes. After ice cooling of this mixed solution, 11.0 mL of methanesulfonic acid was slowly added over 45 minutes. The reaction mixture was stirred at 25C for 3 days. Water was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed in turn with 10% hydrochloric acid and a saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 27.0 g of 3-hydroxymethyl-2-methyl-1-nitrobenzene. 1H-NMR (CDCl3) delta(ppm):1.81 (1H, s), 2.44 (3H, s), 4.79 (2H, s), 7.34 (1H, t, J = 7.8 Hz), 7.65 (1H, d, 7.6 Hz), 7.72 (1H, d, J = 8.1 Hz).
27.0 g
A mixture of 9.4 g of sodium borohydride and 150 mL of tetrahydrofuran was stirred at 25C for 30 min. 30.8 g of 2-methyl-3-nitrobenzoic acid was added to the mixture, which was further stirred at 25C for 30 min. This mixture solution was ice-cooled and 11.0 mL of methanesulfonic acid was gradually added to the mixture over 45 min. The reaction mixture was stirred at 25C for 3 days. Water was poured into the reaction mixture to extract the mixture with ethyl acetate. The organic phase was washed with an aqueous 10% hydrochloric acid solution and saturated saline, dried by magnesium sulfate anhydride, and then, concentrated under reduced pressure to obtain 27.0 g of 3-hydroxymethyl-2-methyl-1-nitrobenzene. (0809) 3-hydroxymethyl-2-methyl-1-nitrobenzene 1H-NMR (CDCl3) delta:1.81 (1H, s), 2.44 (3H, s), 4.79 (2H, s), 7.34 (1H, t, J = 7.8 Hz), 7.65 (1H, d, 7.6 Hz), 7.72 (1H, d, J = 8.1 Hz).
With iron; ammonium chloride; In ethanol; water; for 2h;Reflux;
To a stirred solution of (2-Methyl-3-nitro-phenyl)-methanol (13) (100 mg, 0.598 mmol) in EtOH (5 mL) and water (1 mL) were added added iron powder (183 mg, 3.29 mmol) and ammonium chloride (22 mg, 0.419 mmol) and the resultant mixture was refluxed for 2 hours. Reaction mixture was then brought to room temperature and filtered through a bed of celite. Filtrate was diluted with EtOAc, washed with water, dried over sodium sulfate and concentrated under reduced pressure to afford Intermediate 14 (70 mg, 85%) as yellow gum.
In ethanol; pyrographite;
1. 3-Amino-2-methylbenzyl alcohol A solution of 203 g of <strong>[23876-13-3]2-methyl-3-nitrobenzyl alcohol</strong> in 1000 ml of ethanol is hydrogenated in the presence of 5 g of 10% strength Pd/carbon at from 30 to 35 C. The catalyst is filtered off, the solution is evaporated down and the resulting solid is dried. 145 g of 3-amino-2-methylbenzyl alcohol (mp. 104-108 C.) are obtained.
In ethanol; pyrographite;
1. 3-Amino-2-methylbenzyl alcohol A solution of 203 g of <strong>[23876-13-3]2-methyl-3-nitrobenzyl alcohol</strong> in 1,000 ml of ethanol is hydrogenated in the presence of 5 g of 10% strength Pd/carbon at from 30 to 35 C. The catalyst is filtered off, the solution is evaporated down and the resulting solid is dried. 145 g of 3-amino-2-methylbenzyl alcohol of melting point 104 -108 C. are obtained.
palladium/charcoal; In ethanol;
Preparation of 3-amino-2-methylbenzyl alcohol A solution of <strong>[23876-13-3]2-methyl-3-nitrobenzyl alcohol</strong> (2.0 g, 12 mmol) in ethanol (100 ml) was hydrogenated over 10% palladium/charcoal (0.1 g) for 2 hours, at an initial pressure of 3.5 bar. The solution was filtered through celite and evaporated to give 3-amino-2-methylbenzyl alcohol (1.67 g, quantitative), m.p. 104-106
EXAMPLE 10 3-Amino-2-methylbenzenemethanol A solution of <strong>[23876-13-3]2-methyl-3-nitrobenzenemethanol</strong> (10.0 g, 59.8 mmol) in methanol is treated with Raney Nickel and shaken under hydrogen gas (50 psi) in a Parr Shaker. The solution is filtered through Celite and evaporated. Recrystallization of the residue from isopropyl ether gives pure 3-amino-2-methylbenzenemethanol (7.4 g, 90%), mp=106-108 C. The following compounds are prepared according to the procedure of Example 10.
With sodium borohydrid; In methanol; chloroform; water; tert-butyl alcohol;
(1) 2-Methyl-3-nitrobenzyl alcohol 39.0 g (0.2 mol) of methyl 2-methyl-3-nitrobenzoate was dissolved in 600 ml of tert-butanol. Then, 19.0 g of sodium borohydride was added thereto, and 150 ml of methanol was further dropwise added over a period of one hour at the refluxing temperature. Further, refluxing was continued for one hour to complete the reaction. The reaction mixture was left to cool, and water was added thereto. The solvent was distilled off under reduced pressure. To the residue, water and chloroform were added. The organic layer was separated and dried over anhydrous sodium sulfate. Further, the solvent was distilled off to obtain 30.7 g of 2-methyl-3-nitrobenzyl alcohol.
With sodium hydroxide; tetrabutylammomium bromide; dimethyl sulfate; In water; benzene;
(2) 2-methyl-3-nitrobenzyl methyl ether 30.1 g (0.18 mol) of <strong>[23876-13-3]2-methyl-3-nitrobenzyl alcohol</strong> obtained above, was dissolved in 200 ml of benzene. Then, 0.2 g of tetra-n-butylammonium bromide and a 50% aqueous solution containing 20.1 g of sodium hydroxide were sequentially added thereto. Then, 27.2 g of dimethyl sulfate was dropwise added thereto at room temperature, and the mixture was further stirred for 3 hours for reaction. To the reaction solution, water was added. The organic layer were separated and washed sequentially with water, a 2% hydrochloric acid aqueous solution, water and a saturated sodium chloride aqueous solution. Then, the solvent was distilled off to obtain 30.9 g of 2-methyl-3-nitrobenzyl methyl ether. Oily substance.
a) 2-(2-Chlorobenzyl)-6-nitrotoluene and 2-(4-chlorobenzyl)-6-nitrotoluene A mixture of 25 g (0.15 mol) of <strong>[23876-13-3]2-methyl-3-nitrobenzyl alcohol</strong> and 25 ml (0.22 mol) of tintetrachloride in 250 ml of chlorobenzene is refluxed for 3 hours with stirring. After cooling 50 ml of N-methylpiperazine is slowly instilled. The precipitate is suctioned off and washed several times with ethyl acetate. The combined filtrates are dried on sodium sulfate and concentrated by evaporation and the temperature must not rise above 160 C. The residue (39 g) with a mixture of 33 parts of cyclohexane and 1 part of ethyl acetate is subjected twice to a pressure column chromatography. Thus 9.3 g (24%) of 2-(2-chlorobenzyl)-6-nitrotoluene, melting point 54-56 C., and 16 g (41%) of 2-(4-chlorobenzyl)-6-nitrotoluene, melting point 62-63 C. are obtained.
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