* 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.
With selenious acid In 1,4-dioxane; water at 100℃; for 6 h;
A solu-tion of 10.47 g (0.081 mol) of selenous acid in 30 mL of water was added with stirring to a solution of 20 g (0.162 mol) of (6-methylpyridin-2-yl)methanol (3a) in 150 mL of 1,4-dioxane, and the mixture was stirred for 6 h at 100°C. Metallic selenium was filtered off, the solvent was distilled off from the filtrate under reduced pressure, and the residue was treated with hot hexane (3 × 150 mL). The solvent was distilled off from the combined extracts under reduced pressure, and the product was not purified additionally. Yield 14.76 g (0.121 mol, 75percent), mp 3133°C. 1 H NMR spectrum (DMSO-d 6 ), δ, ppm: 2.61 s (3H, Me), 7.49 d (1H, 5-H, J = 7.5 Hz), 7.71 d (1H, 3-H, J = 7.5 Hz), 7.86 d.d (1H, 4-H, J = 7.5, 7.5 Hz), 9.93 s (1H, CHO). Mass spectrum: m/z 122.06 (I rel 100percent) [M + H] + . Calculated: M 122.06.
Reference：
[1] Tetrahedron Letters, 1999, vol. 40, # 9, p. 1635 - 1636
[2] Organometallics, 2016, vol. 35, # 10, p. 1505 - 1513
[3] Russian Journal of Organic Chemistry, 2017, vol. 53, # 7, p. 963 - 970[4] Zh. Org. Khim., 2017, vol. 53, # 7, p. 951 - 958,8
[5] Dalton Transactions, 2012, vol. 41, # 22, p. 6661 - 6670
[6] Polish Journal of Chemistry, 2006, vol. 80, # 8, p. 1377 - 1383
[7] Pharmaceutical Bulletin, 1955, vol. 3, p. 232
[8] European Journal of Inorganic Chemistry, 2000, # 3, p. 463 - 475
[9] Yakugaku Zasshi, 1958, vol. 78, p. 957,959[10] Chem.Abstr., 1959, p. 3219
[11] Dalton Transactions, 2012, vol. 41, # 37, p. 11476 - 11481
[12] Yakugaku Zasshi, 1958, vol. 78, p. 661,665[13] Chem.Abstr., 1958, p. 18399
[14] ACS Catalysis, 2018, vol. 8, # 2, p. 1417 - 1426
2
[ 1122-71-0 ]
[ 1122-72-1 ]
[ 934-60-1 ]
Yield
Reaction Conditions
Operation in experiment
94.9%
With sodium hypochlorite; C8H18NPol; sodium hydrogencarbonate In water; toluene at 15 - 20℃; for 4.5 h;
EXAMPLE 5 3.00 g (0.0244 mol) of 6-methyl-2-pyridinemethanol, 0.076. g of PIPO obtained in Reference Example 1 (2,2,6,6-tetramethylpiperidine-1-oxyl-4-yl group: 0.000244 mol), 6.0 g of toluene and 3.0 g of a 5percent by weight aqueous solution of sodium hydrogen carbonate (sodium hydrogen carbonate: 0.0018 mol) were placed in a 100 ml reaction vessel. Then, with maintaining the temperature at 15 to 20° C., reaction was conducted while 13.5 g of a 13.4percent by weight aqueous solution of sodium hypochlorite (sodium hypochlorite: 0.0244 mol) was dropped over 4 hours by a microsyringe pump under stirring. Stirring was conducted for another 0.5 hour to complete the reaction. The reaction mixture after the reaction was completed was separated into the organic phase and the water phase and each phase was analyzed by liquid chromatography. By the reaction, 6-methyl-2-pyridinecarbaldehyde was produced with yield of 94.9percent (based on 6-methyl-2-pyridinemethanol). As a by-product, 3.1percent (based on 6-methyl-2-pyridinemethanol) of 6-methylpicolinic acid was produced.
93%
With sodium hypochlorite; C13H26N2OPol; sodium hydrogencarbonate In water; toluene at 15 - 20℃; for 4.5 h;
EXAMPLE 6 The experiment was conducted in the same manner as in Example 5, except that 0.072 g of 2020NO obtained in Reference Example 8 (2,2,6,6-tetramethylpiperidine-1-oxyl-4-yl group: 0.000244 mol) was used instead of PIPO. As a result, by the reaction, 6-methyl-2-pyridinecarbaldehyde was produced with yield of 93.0percent (based on 6-methyl-2-pyridinemethanol). As a by-product, 2.6percent (based on 6-methyl-2-pyridinemethanol) of 6-methylpicolinic acid was produced.
80.8%
With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate In water; toluene at 15 - 20℃; for 4.5 h;
COMPARATIVE EXAMPLE 2 The experiment was conducted in the same manner as in Example 5, except that 0.038 g (0.000244 mol) of 2,2,6,6-tetramethylpiperidine-1-oxyl was used instead of PIPO. As a result, by the reaction, 6-methyl-2-pyridinecarbaldehyde was produced with yield of 80.8percent (based on 6-methyl-2-pyridinemethanol). As a by-product, 9.0percent (based on 6-methyl-2-pyridinemethanol) of 6-methylpicolinic acid was produced.
With thionyl chloride In dichloromethane for 0.666667 h; Heating / reflux
Manufacturing Example 10-1-1 2-Chloromethyl-6-methyl-pyridine; A solution of (6-methyl-pyridin-2-yl)-methanol (1.44 g, 11.7 mmol), thionyl chloride (1.45 mL, 19.9 mmol) and methylene chloride (20 mL) was stirred under reflux for 40 minutes. The reaction solution was cooled to room temperature and then concentrated under a reduced pressure. The residue was partitioned into sodium bicarbonate solution and diethyl ether. The organic layer was concentrated under a reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate) to obtain the title compound (1.42 g, 85.8percent).1H-NMR Spectrum (DMSO-d6) δ (ppm): 2.47 (3H, s), 4.72 (2H, s), 7.22 (1 H, d, J=7.6 Hz), 7.33 (1H, d, J=7.6 Hz), 7.72 (1H, dd, J=7.6, 7.6 Hz).
85.8%
Stage #1: With thionyl chloride In dichloromethane for 0.666667 h; Heating / reflux Stage #2: With sodium hydrogencarbonate In diethyl ether; water
A solution of (6-methyl-pyridin-2-yl)-methanol (1.44 g, 11.7 mmol), thionyl chloride (1.45 mL, 19.9 mmol) and methylene chloride (20 mL) was stirred under reflux for 40 minutes. The reaction solution was cooled to room temperature and then concentrated under a reduced pressure. The residue was partitioned into sodium bicarbonate solution and diethyl ether. The organic layer was concentrated under a reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate) to obtain the title compound (1.42 g, 85.8percent). 1H-NMR Spectrum (DMSO-d6) δ (ppm): 2.47 (3H, s), 4.72 (2H, s), 7.22 (1H, d, J=7.6 Hz), 7.33 (1H, d, J=7.6 Hz), 7.72 (1H, dd, J=7.6, 7.6 Hz).
Reference：
[1] Journal of the American Chemical Society, 2005, vol. 127, # 29, p. 10197 - 10204
[2] Patent: US2009/82403, 2009, A1, . Location in patent: Page/Page column 64
[3] Patent: US2007/105904, 2007, A1, . Location in patent: Page/Page column 61
[4] Chinese Chemical Letters, 2018, vol. 29, # 11, p. 1637 - 1640
[5] Chemistry Letters, 1998, # 9, p. 915 - 916
[6] Yakugaku Zasshi, 1954, vol. 74, p. 790[7] Chem.Abstr., 1955, p. 11646
[8] Journal of the Chemical Society, 1958, p. 3594,3601
[9] Yakugaku Zasshi, 1955, vol. 75, p. 1233[10] Chem.Abstr., 1956, p. 8664
[11] Journal of Medicinal Chemistry, 1992, vol. 35, # 3, p. 438 - 450
4
[ 1122-71-0 ]
[ 68470-59-7 ]
Yield
Reaction Conditions
Operation in experiment
70%
With carbon tetrabromide; triphenylphosphine In dichloromethane at 0℃; for 0.5 h;
A. To a stirred solution of (6-methylpyridin-2-yl)methanol (640 mg, 5.2 mmol) and carbon tetrabromide (2.77 g, 8.35 mmol) in dichloromethane (12 mL) at 00C was added PPh3 (0.4 g x 4, 6.1 mmol) at 2 min intervals. The reaction was continued for total of 30 min. and then the mixture was directly purified with Flashmaster using 10percent EtOAc in hexanes to give 2-(bromomethyl)-6- methylpyridine as a crystalline solid (675 mg, 70percent).
52%
With carbon tetrabromide; triphenylphosphine In dichloromethane at 20℃; for 3 h;
Reference Example 33 2-Bromomethyl-6-methyl-pyridine; To a solution of (6-methyl-pyridin-2-yl)-methanol (0.6 g, 4.872 mmol) in DCM (18 mL) were added triphenylphosphine (1.68 g, 6.405 mmol) and carbon tetrabromide (1.97 g, 5.940 mmol) before the resulting mixture was stirred at RT for 3 h. The crude reaction mixture was then concentrated in vacuo and the resultant residue purified by column chromatography to give the title compound as a pale pink oil (0.47 g, 52 percent). [M + H]+ 185.8 (79Br) 187.8 (81Br)
33.5%
Stage #1: With phosphorus tribromide In tetrahydrofuran at 20℃; Stage #2: With ammonia In water; ethyl acetate
Intermediate 11 : 2-(bromomethyl)-6-methylpyridi; (6-methyl-2-pyridinyl)methanol (ALDRICH, 300 mg, 2.436 mmol) were dissolved in 10 mL of anhydrous THF. Phosphorous tribromide (ALDRICH, 0.252 mL, 2.68 mmol) was added. Reaction mixture was stirred at room temperature overnight. Solvent was evaporated andresidue was purified by silica column chromatography using hexane:EtOAc as eluents to give a white solid. This solid was partitioned between EtOAc and distilled water (basified with NH3 (32percent, aqueous). Organic layer was dried with MgS04 (anh). Solvent was evaporated to obtain the title compound (152 mg, 0.817 mmol, 33.5percent yield). 1 H NMR (300 MHz, DMSO-cfe) δ ppm: 7.68 (t, 1 H), 7.33 (d, 1 H), 7.17 (d, 1 H), 4.62 (s, 2H), 2.44 (s, 3H). [ES+MS] m/z 186 (M).
33.5%
With phosphorus tribromide In tetrahydrofuran at 20℃;
Intermediate 11: 2-(bromomethyl)-6-methylpyridine (6-methyl-2-pyridinyl)methanol (ALDRICH, 300 mg, 2.436 mmol) were dissolved in 10 mL of anhydrous THF. Phosphorous tribromide (ALDRICH, 0.252 mL, 2.68 mmol) was added. Reaction mixture was stirred at room temperature overnight. Solvent was evaporated and residue was purified by silica column chromatography using hexane:EtOAc as eluents to give a white solid. This solid was partitioned between EtOAc and distilled water (basified with NH3 (32percent, aqueous). Organic layer was dried with MgSO4 (anh). Solvent was evaporated to obtain the title compound (152 mg, 0.817 mmol, 33.5percent yield). 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.68 (t, 1H), 7.33 (d, 1H), 7.17 (d, 1H), 4.62 (s, 2H), 2.44 (s, 3H). [ES+MS] m/z 186 (M).
Reference：
[1] Journal of the American Chemical Society, 1994, vol. 116, # 18, p. 8410 - 8411
[2] Patent: WO2008/110793, 2008, A1, . Location in patent: Page/Page column 112
[3] Patent: WO2008/125839, 2008, A2, . Location in patent: Page/Page column 44
[4] Tetrahedron Letters, 2001, vol. 42, # 32, p. 5393 - 5395
[5] Canadian Journal of Chemistry, 2002, vol. 80, # 8, p. 973 - 982
[6] Patent: WO2012/49161, 2012, A1, . Location in patent: Page/Page column 29-30
[7] Patent: US2013/203802, 2013, A1, . Location in patent: Paragraph 0246; 0247
[8] Journal of the Chemical Society, 1958, p. 3594,3601
[9] Tetrahedron Asymmetry, 2009, vol. 20, # 14, p. 1672 - 1682
[10] Patent: WO2011/79076, 2011, A1, . Location in patent: Page/Page column 81; 119
[11] Chemistry - A European Journal, 2015, vol. 21, # 19, p. 7053 - 7056
[12] Patent: WO2006/117754, 2006, A1, . Location in patent: Page/Page column 44
5
[ 1122-72-1 ]
[ 1122-71-0 ]
Reference：
[1] Journal of the American Chemical Society, 1994, vol. 116, # 18, p. 8410 - 8411
[2] J. Appl. Chem. USSR (Engl. Transl.), 1980, vol. 53, # 4, p. 724 - 727[3] Zhurnal Prikladnoi Khimii (Sankt-Peterburg, Russian Federation), 1980, vol. 53, # 4, p. 917 - 920
[4] Chemical Communications (Cambridge, United Kingdom), 2018, vol. 54, # 83, p. 11805 - 11808
[5] Patent: EP150984, 1991, B1,
[6] Patent: US4826833, 1989, A,
6
[ 13287-64-4 ]
[ 1122-71-0 ]
Yield
Reaction Conditions
Operation in experiment
94%
Reflux
(a) adding glacial acetic acid into the reaction bottle, adding 2,6-lutidine, heating and mixing uniformly, wherein the mass ratio of glacial acetic acid to 2,6-lutidine is 2.5: 1;(b) hydrogen peroxide (volume fraction of 28percent) and the catalyst sequentially added to the reaction flask of step (a), the reaction 3 hours,Wherein the catalyst is tungsten oxide, which is added in an amount of 5percent of the mass of 2,6-lutidine and the amount of the hydrogen peroxide is 1.5 times of the mass of 2,6-lutidine;(c) adding an equal amount of hydrogen peroxide (volume fraction of 28percent) in step (b) to a reaction flask for 7 hours;(d) After the reaction in step (c) is completed, the reaction mixture is distilled under reduced pressure to collect a fraction of 130-150 ° C / 12 mmHg;(e) refluxing the fraction obtained in the step (d) with acetic anhydride (the volume fraction of the fraction and the acetic anhydride is 0.7), ending the reaction to recover the glacial acetic acid to dry, the mother liquor and the alkali solution (10percent Potassium solution) was refluxed for 8 hours, the volume fraction of the fraction and potassium hydroxide solution was 1: 3, and then cooled to room temperature; (f) countercurrently extracting the refluxing reaction solution in step (e) with twice the volume of methylene chloride six times, combining the extracts,Dichloromethane was recovered by distillation to give 6-methyl-2-pyridylmethanol.In this embodiment, the yield of the reaction product 6-methyl-2-pyridylmethanol is 94percent and the selectivity of the reaction is as high as 95.2percent. The purity of the final product obtained after analysis is 99.1percent, which fully satisfies the requirements of the pharmaceutical manufacturing enterprises Synthesis needs.
Reference：
[1] Patent: CN104610134, 2017, B, . Location in patent: Paragraph 0029-0036; 0038-0045; 0047-0054; 0056-0063;
[2] Yakugaku Zasshi, 1954, vol. 74, p. 790[3] Chem.Abstr., 1955, p. 11646
[4] Helvetica Chimica Acta, 1955, vol. 38, p. 1114,1116
[5] Journal of Medicinal Chemistry, 1992, vol. 35, # 3, p. 438 - 450
[6] Yakugaku Zasshi, 1958, vol. 78, p. 661,665[7] Chem.Abstr., 1958, p. 18399
7
[ 1195-59-1 ]
[ 1122-71-0 ]
Yield
Reaction Conditions
Operation in experiment
55%
at 25℃; for 6 h; Inert atmosphere; Sealed tube; UV-irradiation
A glass reaction vessel was charged with 47.3 mg of Catalyst D, 123.4 mg (1.0 mmol) of benzyl methyl ether, 15.5 mg (0.08 mmol) of TsOH.H2O, 30 mL of dehydrated methanol and , And a magnetic stirrer. Then, argon gas was introduced into the sealed reaction system and irradiated with ultraviolet light for 7.5 hours while stirring the reaction system (rotational speed of the magnetic stirrer: about 600 rpm) at 25 ° C. Then, by GC-MS analysis, a yield of toluene of 95percent was obtained (see Table 10). Table 10 also shows the conversion of benzyl methyl ether.
Reference：
[1] Patent: JP2015/59098, 2015, A, . Location in patent: Paragraph 0084-0087; 0097; 0129; 0133; 0138
8
[ 1073-23-0 ]
[ 1122-71-0 ]
Reference：
[1] Heterocycles, 1986, vol. 24, # 8, p. 2169 - 2172
[2] Journal of Medicinal Chemistry, 1992, vol. 35, # 3, p. 438 - 450
[3] Yakugaku Zasshi, 1954, vol. 74, p. 790[4] Chem.Abstr., 1955, p. 11646
[5] Yakugaku Zasshi, 1958, vol. 78, p. 661,665[6] Chem.Abstr., 1958, p. 18399
9
[ 78539-91-0 ]
[ 1122-71-0 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1985, p. 2719 - 2724
10
[ 13287-64-4 ]
[ 75-36-5 ]
[ 1122-71-0 ]
Reference：
[1] Patent: US6255305, 2001, B1,
11
[ 1195-59-1 ]
[ 108-48-5 ]
[ 1122-71-0 ]
Reference：
[1] European Journal of Organic Chemistry, 2013, # 29, p. 6496 - 6500
12
[ 108-48-5 ]
[ 1122-71-0 ]
Reference：
[1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1980, vol. 16, # 1, p. 89 - 93[2] Khimiya Geterotsiklicheskikh Soedinenii, 1980, vol. 16, # 1, p. 105 - 110
[3] Patent: CN104610134, 2017, B,
With sodium hypochlorite; C8H18NPol; sodium hydrogencarbonate In water; toluene at 15 - 20℃; for 4.5 h;
EXAMPLE 5 3.00 g (0.0244 mol) of 6-methyl-2-pyridinemethanol, 0.076. g of PIPO obtained in Reference Example 1 (2,2,6,6-tetramethylpiperidine-1-oxyl-4-yl group: 0.000244 mol), 6.0 g of toluene and 3.0 g of a 5percent by weight aqueous solution of sodium hydrogen carbonate (sodium hydrogen carbonate: 0.0018 mol) were placed in a 100 ml reaction vessel. Then, with maintaining the temperature at 15 to 20° C., reaction was conducted while 13.5 g of a 13.4percent by weight aqueous solution of sodium hypochlorite (sodium hypochlorite: 0.0244 mol) was dropped over 4 hours by a microsyringe pump under stirring. Stirring was conducted for another 0.5 hour to complete the reaction. The reaction mixture after the reaction was completed was separated into the organic phase and the water phase and each phase was analyzed by liquid chromatography. By the reaction, 6-methyl-2-pyridinecarbaldehyde was produced with yield of 94.9percent (based on 6-methyl-2-pyridinemethanol). As a by-product, 3.1percent (based on 6-methyl-2-pyridinemethanol) of 6-methylpicolinic acid was produced.
93%
With sodium hypochlorite; C13H26N2OPol; sodium hydrogencarbonate In water; toluene at 15 - 20℃; for 4.5 h;
EXAMPLE 6 The experiment was conducted in the same manner as in Example 5, except that 0.072 g of 2020NO obtained in Reference Example 8 (2,2,6,6-tetramethylpiperidine-1-oxyl-4-yl group: 0.000244 mol) was used instead of PIPO. As a result, by the reaction, 6-methyl-2-pyridinecarbaldehyde was produced with yield of 93.0percent (based on 6-methyl-2-pyridinemethanol). As a by-product, 2.6percent (based on 6-methyl-2-pyridinemethanol) of 6-methylpicolinic acid was produced.
80.8%
With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate In water; toluene at 15 - 20℃; for 4.5 h;
COMPARATIVE EXAMPLE 2 The experiment was conducted in the same manner as in Example 5, except that 0.038 g (0.000244 mol) of 2,2,6,6-tetramethylpiperidine-1-oxyl was used instead of PIPO. As a result, by the reaction, 6-methyl-2-pyridinecarbaldehyde was produced with yield of 80.8percent (based on 6-methyl-2-pyridinemethanol). As a by-product, 9.0percent (based on 6-methyl-2-pyridinemethanol) of 6-methylpicolinic acid was produced.
With thionyl chloride; In dichloromethane; for 0.666667h;Heating / reflux;
Manufacturing Example 10-1-1 2-Chloromethyl-6-methyl-pyridine; A solution of (6-methyl-pyridin-2-yl)-methanol (1.44 g, 11.7 mmol), thionyl chloride (1.45 mL, 19.9 mmol) and methylene chloride (20 mL) was stirred under reflux for 40 minutes. The reaction solution was cooled to room temperature and then concentrated under a reduced pressure. The residue was partitioned into sodium bicarbonate solution and diethyl ether. The organic layer was concentrated under a reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate) to obtain the title compound (1.42 g, 85.8%).1H-NMR Spectrum (DMSO-d6) delta (ppm): 2.47 (3H, s), 4.72 (2H, s), 7.22 (1 H, d, J=7.6 Hz), 7.33 (1H, d, J=7.6 Hz), 7.72 (1H, dd, J=7.6, 7.6 Hz).
85.8%
A solution of (6-methyl-pyridin-2-yl)-methanol (1.44 g, 11.7 mmol), thionyl chloride (1.45 mL, 19.9 mmol) and methylene chloride (20 mL) was stirred under reflux for 40 minutes. The reaction solution was cooled to room temperature and then concentrated under a reduced pressure. The residue was partitioned into sodium bicarbonate solution and diethyl ether. The organic layer was concentrated under a reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate) to obtain the title compound (1.42 g, 85.8%). 1H-NMR Spectrum (DMSO-d6) delta (ppm): 2.47 (3H, s), 4.72 (2H, s), 7.22 (1H, d, J=7.6 Hz), 7.33 (1H, d, J=7.6 Hz), 7.72 (1H, dd, J=7.6, 7.6 Hz).
With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 0℃; for 0.5h;
A. To a stirred solution of (6-methylpyridin-2-yl)methanol (640 mg, 5.2 mmol) and carbon tetrabromide (2.77 g, 8.35 mmol) in dichloromethane (12 mL) at 00C was added PPh3 (0.4 g x 4, 6.1 mmol) at 2 min intervals. The reaction was continued for total of 30 min. and then the mixture was directly purified with Flashmaster using 10% EtOAc in hexanes to give 2-(bromomethyl)-6- methylpyridine as a crystalline solid (675 mg, 70%).
52%
With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 20℃; for 3h;
Reference Example 33 2-Bromomethyl-6-methyl-pyridine; To a solution of (6-methyl-pyridin-2-yl)-methanol (0.6 g, 4.872 mmol) in DCM (18 mL) were added triphenylphosphine (1.68 g, 6.405 mmol) and carbon tetrabromide (1.97 g, 5.940 mmol) before the resulting mixture was stirred at RT for 3 h. The crude reaction mixture was then concentrated in vacuo and the resultant residue purified by column chromatography to give the title compound as a pale pink oil (0.47 g, 52 %). [M + H]+ 185.8 (79Br) 187.8 (81Br)
33.5%
Intermediate 11 : 2-(bromomethyl)-6-methylpyridi; (6-methyl-2-pyridinyl)methanol (ALDRICH, 300 mg, 2.436 mmol) were dissolved in 10 mL of anhydrous THF. Phosphorous tribromide (ALDRICH, 0.252 mL, 2.68 mmol) was added. Reaction mixture was stirred at room temperature overnight. Solvent was evaporated andresidue was purified by silica column chromatography using hexane:EtOAc as eluents to give a white solid. This solid was partitioned between EtOAc and distilled water (basified with NH3 (32%, aqueous). Organic layer was dried with MgS04 (anh). Solvent was evaporated to obtain the title compound (152 mg, 0.817 mmol, 33.5% yield). 1 H NMR (300 MHz, DMSO-cfe) delta ppm: 7.68 (t, 1 H), 7.33 (d, 1 H), 7.17 (d, 1 H), 4.62 (s, 2H), 2.44 (s, 3H). [ES+MS] m/z 186 (M).
33.5%
With phosphorus tribromide; In tetrahydrofuran; at 20℃;
Intermediate 11: 2-(bromomethyl)-6-methylpyridine (6-methyl-2-pyridinyl)methanol (ALDRICH, 300 mg, 2.436 mmol) were dissolved in 10 mL of anhydrous THF. Phosphorous tribromide (ALDRICH, 0.252 mL, 2.68 mmol) was added. Reaction mixture was stirred at room temperature overnight. Solvent was evaporated and residue was purified by silica column chromatography using hexane:EtOAc as eluents to give a white solid. This solid was partitioned between EtOAc and distilled water (basified with NH3 (32%, aqueous). Organic layer was dried with MgSO4 (anh). Solvent was evaporated to obtain the title compound (152 mg, 0.817 mmol, 33.5% yield). 1H NMR (300 MHz, DMSO-d6) delta ppm: 7.68 (t, 1H), 7.33 (d, 1H), 7.17 (d, 1H), 4.62 (s, 2H), 2.44 (s, 3H). [ES+MS] m/z 186 (M).
With carbon tetrabromide; triphenylphosphine; In dichloromethane; for 1h;Cooling with ice; Inert atmosphere;
To an ice cooled a solution of (6-methylpyridin-2-yl)methanol (400 mg, 3.25 mmol) in dichloromethane (16 mL) under an atmosphere of dry nitrogen was added triphenylphosphine (1278 mg, 4.87 mmol) and carbon tetrabromide (1616 mg, 4.87 mmol). The mixture was stirred for 1 hour. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica, eluting with 2-4% methanol in dichloromethane to give 2- (bromomethyl)-6-methylpyridine as an oil (402 mg).
To a solution of the compound (6-methylpyridine-2-yl)methanol (2 g) (commercially available) in carbon tetrachloride (40 ml), was added phosphorous bromide (2.2 g) dropwise and stirred the reaction mixture at 800C for 3 hours and then at room temperature for overnight. It was quenched with water and 10% sodium hydroxide solution. The solvent was evaporated under reduced pressure and the aqueous layer was extracted with dichloromethane. The organic layer was collected and washed with 10% sodium hydroxide solution, water and brine, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue thus obtained was purified by column chromatography using 10% ethyl acetate in hexane to furnish the title compound.Yield = 1.7 g.
With phosphorus tribromide; In tetrahydrofuran; at 20℃;Inert atmosphere;
12 g of 6-methyl-2-pyridinemethanol (manufactured by Tokyo Chemical Industry Co., Ltd.) and 100 mL of tetrahydrofuran were added into a 300 mL three-necked flask under a nitrogen atmosphere and stirred at room temperature. After adding 25 g of phosphorus tribromide (manufactured by Tokyo Chemical Industry Co., Ltd.) dropwise while cooling the mixture with ice, and then, the mixture was stirred at room temperature overnight. An aqueous solution of saturated ammonium chloride and ethyl acetate were added thereto to perform liquid separating and extraction, an organic phase obtained was concentrated, a product was purified by a silica gel column chromatography (Developing solvent: Hexane/Ethyl Acetate), and thus, 6-methyl-2-(bromomethyl) pyridine was obtained as light red oil.
E 2-Chloromethyl-6-methyl-pyridine hydrochloride
EXAMPLE E 2-Chloromethyl-6-methyl-pyridine hydrochloride 2-(Hydroxymethyl)-6-methylpyridine (3.7 g, 29.4 mmol) was added portion wise at 0° C. to thionylchloride (35 mL, 477 mmol). The reaction mixture was then stirred at room temperature for 18 h. Excess thionylchloride was removed under vacuum and the crude 2-chloromethyl-6-methyl-pyridine hydrochloride (5.1 g, light brown solid) was used without any further purification.
With thionyl chloride for 0.5h; Inert atmosphere; Reflux;
18.0 g
With thionyl chloride at 0℃; for 1.5h;
8 2-(Chloromethyl)-6-methylpyridine
At 0°C, thionyl chloride (30.0 mL) was added to (6-methylpyridin-2-yl)methanol (13.0 g) over 30 min, followed by stirring for 1 hr. Vacuum distillation of the solution afforded the desired compound. 18.0 g [refer to WO 2011/079076 Al].
2.04 g
With thionyl chloride In dichloromethane at 0 - 60℃; for 3h; Inert atmosphere; Schlenk technique;
With sulfuryl dichloride In Carbon tetrachloride
With thionyl chloride In Carbon tetrachloride
With thionyl chloride In toluene at 40℃; for 17h; Inert atmosphere;
4.2.13. 2-(tert-Butoxy)-N,N-dimethyl-N-((6-methylpyridin-2-yl)methyl)-2-oxoethanaminium bromide (2m)
6-Methylpyridine-2-carboxylic acid (409 mg, 2.98 mmol) was treated with SOCl2 (1.7 mL) at 0 °C and the mixture was stirred for 4 h at 40 °C under an Ar atmosphere. The resulting mixture was concentrated by evaporation. The residue was dissolved in MeOH (9.0 mL) and stirred for 14 h at room temperature. The resulting mixture was concentrated by evaporation and the residue was treated with saturated aqueous K2CO3. The mixture was extracted with EtOAc and the combined extracts were washed with brine. The solution was dried over Na2SO4 and concentrated by evaporation to afford methyl 6-methylpyridine-2-carboxylate (400 mg, 89% yield) as a pale brown oil. Subsequent steps were the same with the preparation of 2i. The overall yield from methyl 6-methylpyridine-2-carboxylate was 46%. Colorless crystals, mp 143-146 °C; IR (ATR) νmax/cm-1 3009, 2985, 2970, 1737, 1624, 1598, 1577, 1479, 1460, 1416, 1394, 1369, 1320, 1245, 1202, 1158, 1141, 1097, 1041, 1013, 989, 948, 932, 892, 854, 815, 790, 756, 715; 1H NMR (400 MHz, CDCl3) δ 7.75 (1H, d, J = 7.4 Hz, ArH), 7.69 (1H, dd, J = 7.6, 7.4 Hz, ArH), 7.24 (1H, dd, J = 7.6, 0.8 Hz, ArH), 5.21 (2H, s, CH2), 4.54 (2H, s, CH2), 3.72 (6H, s, N(CH3)2), 2.56 (3H, s, ArCH3), 1.53 (9H, s, tBu); 13C{1H} NMR (101 MHz, CDCl3) δ 163.7, 159.0, 148.1, 137.6, 125.2, 124.4, 84.7, 66.0, 61.3, 52.1, 27.9, 24.3; HRMS (ESI): calcd. for C15H25N2O2 [M - Br]+ 265.1911, found 265.1908.
3-chloro-4-((6-methylpyridin-2-yl)methoxy)aniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 20h;
15A. Preparation of 3-Chloro-4-(6-methyl-pyridin-2-ylmethoxy)-phenylamine To a mixture of (6-methyl-pyridin-2-yl)-methanol (280 mg, 2.29 mmol), 4-amino-2-chloro-phenol (359 mg, 2.5 mmol) and triphenylphosphine (0.655 mg, 2.5 mmol) in THF (8 ml) was added DIAD (0.49 ml, 2.5 mmol) and the mixture was stirred at rt for 20 h. The mixture was concentrated in vacuo, diluted with 1N HCl (30 ml), washed with EtOAc (3*20ml) and basified to pH 12 by 1N NaOH. The mixture was extracted with EtOAc (4*40 ml); the combined EtOAc extracts were washed with brine (1*20 ml), dried (MgSO4), filtered and concentrated in vacuo to give 15A (?? mg,??% pure)
Step A: Preparation of 2-(6-methylpyridin-2-yl)furo[2,3-c]pyridin-3-amine: To a 0 C. solution of NaH (70.86 mg, 1.772 mmol) in DMF was added (6-methylpyridin-2-yl)methanol (200 mg, 1.624 mmol). After 10 minutes, <strong>[13958-98-0]3-bromoisonicotinonitrile</strong> (270.2 mg, 1.476 mmol) in 5 mL DMF was added and the solution was warmed to 60 C. overnight. The reaction mixture was cooled to room temperature, diluted with H2O and EtOAc, and the layers were separated. The organic layer was dried (MgSO4), filtered, and concentrated to afford crude. 3-((6-methylpyridin-2-yl)methoxy)isonicotinonitrile as the intermediate. This material was dissolved in DMF and combined with NaH (59.66 mg, 1.492 mmol). The mixture was heated at 60 C. overnight, then cooled to room temperature, diluted with H2O and EtOAc, and the layers were separated. The organic layer was concentrated and purified by silica gel chromatography (8% MeOH/CH2Cl2) provided 89 mg (32%) of the desired product. MS (APCI-pos) M+1=226.3.
With sodium hydride; In tetrahydrofuran; mineral oil; at 70℃; for 16h;Inert atmosphere;
5-Fluoro-2-((6-methylpyridin-2-yl)methoxy)nicotinic acid (21k)To a solution of <strong>[38186-88-8]2-chloro-5-fluoronicotinic acid</strong> (2.0g, 11.4mmol) in THF (30ml) under a N2 atmosphere was added (6-methylpyridin-2-yl)methanol (1.75g, 16.0mmol) followed by a portion-wise addition of NaH (60percent dispersion in mineral oil, 1.37g, 34mmol). The resulting suspension was stirred at 70°C for 16h and then cooled to room temperature and quenched with 1M NaOH (20ml). After washing with DCM (x2), the aqueous layer was acidified with concentrated HC1 until the product precipitated out of solution (~ pH 4). The solids were filtered, washed with 3/40 and then dried under high vacuum to afford the title compound(1.92g, 64percent) as a white solid.NMR delta 8.40-8.29 (2H, m), 8.11 (1H, dd, J 8.2, 3.1), 7.82 (1H, d, J7.9), 7.73 (1H, d, J 7.9), 5.73 (2H, s), 2.73 (3H, s);MS (m/e) 263 [M+H]+, Rt 0.48min (QC Method 1)
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