* 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 sodium tetrahydroborate In tetrahydrofuran; ethanol for 0.75 h;
To a solution of 5-bromopyridine-2-carbaldehyde (5.00 g, 26.9 mmol) dissolved in a mixture of ethanol (75 mL) and THF (25 mL) was added sodium borohydride (0.407 g, 10.8 mmol) in small portions. After 45 minutes 0.5 mL water was added and the mixture and evaporated to dryness. The oily residue was subjected to flash chromatography (silica, EtOAc/EtOH/Et3N 90:5:5) to give (5-bromo-pyridin-2-yl)-methanol (4.81 g, 86percent) as pale-yellow oil.
84%
Stage #1: With sodium tetrahydroborate In ethanol at 0 - 20℃; for 4 h; Stage #2: With water; sodium hydrogencarbonate In ethanol
Example 14.1: (5-Bromo-pyridin-2-vl)-methanolA mixture of 5-bromo-pyridine-2-carbaldehyde (0.5 g, 2.68 mmol) in ethanol (30 ml_) was cooled in an ice bath. Sodium borohydride (0.41 g, 10.75 mmol) was added and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated, dried, the residue dissolved in dichloromethane (30 ml.) and quenched with a saturated aqueous sodium bicarbonate solution. The organic phase was separated and the aqueous phase was extracted further with dichloromethane (2 x 10 ml_). The combined organic phase was dried over sodium sulfate and concentrated to give the product as an off- white solid (426 mg, 84 percent). 1H NMR (300 MHz, CDCI3): δ (ppm) 8.61 (d, 1 H), 7.82 (dd, 1 H), 7.23 (d, 1 H), 4.73 (s, 2H), 3.92 (bs, 1 H).
50%
at 23℃; for 4 h;
To a stirred solution of 5-bromopicolinaldehyde (0.5 g, 2.68 mmol, 1.0 eq) in methanol (10 mL) was added NaBH4 (0.18 g, 5.37 mmol, 2 eq) and stirred at room temperature for 4h. methanol was evaporated and diluted with with ethyl acetate (10mL), washed with water (15 mL), dried over sodium sulphate and evaporated under reduced pressure to get crude compound. This crude was purified by column chromatography using 100-200 silica gel 20 percent ethyl acetate-petrol ether as eluent system to get (5-bromopyridin-2- yl)methanol (0.2 g, 50 percent).
0.2 g
With sodium tetrahydroborate In methanol at 20℃; for 4 h;
Step 2 To a stirred solution of 5-bromopicolinaldehyde (0.5 g, 2.68 mmol, 1.0 eq) in methanol (10 mL) was added NaBH4 (0.18 g, 5.37 mmol, 2 eq) and stirred at room temperature for 4 h. methanol was evaporated and diluted with ethyl acetate (10 mL), washed with water (15 mL), dried over sodium sulfate and evaporated under reduced pressure to get crude compound. This crude was purified by column chromatography using 100-200 silica gel 20percent ethyl acetate-petrol ether as eluent system to get (5-bromopyridin-2-yl)methanol (0.2 g, 50percent).
1.94 g
at 0 - 20℃; for 2 h;
In the 0 °C ice bath, add NaBH4 (1.220 g) to a solution of 5-bromopyridinecarboxaldehyde (2.010 g) in methanol (30 mL). After adding NaBH4, remove the water bath and naturally warm to room temperature. After stirring at room temperature for 2 hours, the reaction mixture was quenched with EtOAc. Extracted with EA (50 mL × 2), the combined organic phases were washed with a saturated NaCl solution. Drying over anhydrous Na2SO4 and concentrated to afford 1.940 g (5-bromopyridin-2-yl)methanol.
Reference：
[1] Journal of Inorganic Biochemistry, 2012, vol. 111, p. 1 - 9
[2] Journal of Porphyrins and Phthalocyanines, 2010, vol. 14, # 6, p. 469 - 480
[3] Patent: US2013/12530, 2013, A1, . Location in patent: Paragraph 0178
[4] Patent: WO2008/32191, 2008, A2, . Location in patent: Page/Page column 58
[5] Patent: WO2013/13815, 2013, A1, . Location in patent: Page/Page column 228
[6] Chemistry - A European Journal, 2006, vol. 12, # 13, p. 3472 - 3483
[7] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 4, p. 1407 - 1412
[8] Patent: WO2004/814, 2003, A1, . Location in patent: Page 70
[9] Journal of the American Chemical Society, 2009, vol. 131, # 40, p. 14508 - 14520
[10] Patent: WO2006/60461, 2006, A1, . Location in patent: Page/Page column 165
[11] Patent: US2007/105904, 2007, A1, . Location in patent: Page/Page column 100
[12] Patent: US2013/29962, 2013, A1, . Location in patent: Paragraph 1102
[13] Angewandte Chemie - International Edition, 2013, vol. 52, # 25, p. 6464 - 6467[14] Angew. Chem., 2013, vol. 125, # 25, p. 6592 - 6595,4
[15] Journal of the American Chemical Society, 2013, vol. 135, # 38, p. 14052 - 14055
[16] Patent: WO2016/82930, 2016, A1, . Location in patent: Page/Page column 37-38
[17] Patent: EP1873153, 2008, A1, . Location in patent: Page/Page column 89
[18] Patent: TW2018/29406, 2018, A, . Location in patent: Page/Page column 29
3
[ 31181-64-3 ]
[ 88139-91-7 ]
Yield
Reaction Conditions
Operation in experiment
77%
Stage #1: at 20 - 53℃; for 1 h; Stage #2: With sodium hydrogencarbonate In water at 20℃;
To a flask containing 5-Bromo-2-methyl-pyridine 1-oxide (1.14g, 6.20mmol) purged with argon was slowly added trifluoroacetic acid (lOmL). The mixture stirred for 0.5hrs at room temperature and 0.5hrs at 53°C. The mixture was cooled and diluted with saturated sodium bicarbonate. The aqueous solution stirred overnight at room temperature and was extracted with ethyl acetate, and concentrated to afford the title compound (895mg, 77percent) as a brown solid. *H NMR (300 MHz, CDCI3): 8 8.64 (s, 1H), 7.83 (d, 1H), 7.22 (d, 1H), 4.75 (s, 2H).
Reference：
[1] Patent: WO2006/20879, 2006, A1, . Location in patent: Page/Page column 114
[2] Journal of Medicinal Chemistry, 1987, vol. 30, # 5, p. 871 - 880
[3] Tetrahedron, 1997, vol. 53, # 24, p. 8257 - 8268
[4] Journal of Medicinal Chemistry, 2011, vol. 54, # 13, p. 4721 - 4734
4
[ 30766-11-1 ]
[ 88139-91-7 ]
Yield
Reaction Conditions
Operation in experiment
64%
Stage #1: With dimethylsulfide borane complex In tetrahydrofuran at 0 - 20℃; for 24 h; Stage #2: With methanol In tetrahydrofuran at 0℃; for 1 h; Reflux
A-3: 6-Methoxymethyl-3-(pyrimidin-5-ylamino)-pyridine-2-carboxylic acid methyl esterStep 1: 5-Bromo-pyridin-2-yl-methanolTo a solution of 5-bromopyridin-2-carboxylic acid (8 g, 42.1 mmol) in THF (100 ml) was added borane-dimethylsulphide (16 ml, 168.30 mmol) dropwise at 0° C. After warming-up to ambient temperature stirring was continued for 24 hours. The solution was cooled again to 0° C., quenched with MeOH and refluxed for 1 h. Solvents were removed and the residue was treated with water. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried, filtered and concentrated under reduced pressure to afford 4.76 g (64percent) of the title compound.MS: M=188.0 190.0 (M+H)+
64%
Stage #1: With dimethylsulfide borane complex In tetrahydrofuran at 0 - 20℃; for 24 h; Stage #2: With methanol In tetrahydrofuran for 1 h; Reflux
A-3: 6-Methoxymethyl-3-fpyrimidin-5-ylamino)-pyridine-2-carboxylic acid methyl esterStep 1: 5-Bromo-pyridin-2-yl-methanolTo a solution of 5-bromopyridin-2-carboxylic acid (8 g, 42.1 mmol) in THF (100 ml) was added borane-dimethylsulphide (16 ml, 168.30 mmol) dropwise at 0°C. After warming-up to ambient temperature stirring was continued for 24 hours. The solution was cooled again to 0°C, quenched with MeOH and refluxed for lh. Solvents were removed and the residue was treated with water. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried, filtered and concentrated under reduced pressure to afford 4.76 g (64 percent) of the title compound.+MS: M = 188.0 190.0 (M+H)
64%
Stage #1: With dimethylsulfide borane complex In tetrahydrofuran at 0 - 20℃; for 24 h; Stage #2: With methanol In tetrahydrofuran at 0℃; for 1 h; Reflux
To a solution of 5-bromopyridin-2-carboxylic acid (8 g, 42.1 mmol) in THF (100 ml) was added borane-dimethylsulphide (16 ml, 168.30 mmol) dropwise at 0° C. After warming-up to ambient temperature stirring was continued for 24 hours. The solution was cooled again to 0° C., quenched with MeOH and refluxed for 1 h. Solvents were removed and the residue was treated with water. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried, filtered and concentrated under reduced pressure to afford 4.76 g (64percent) of the title compound. MS: M=188.0 190.0 (M+H)+
64%
Stage #1: With dimethylsulfide borane complex In tetrahydrofuran at 0 - 20℃; for 24 h; Inert atmosphere Stage #2: With methanol In tetrahydrofuran at 0℃; Reflux
To a solution of 5-bromopyridin-2-carboxylic acid (8 g, 42.1 mmol) in THF (100 ml) was added borane-dimethylsulphide (16 ml, 168.30 mmol) dropwise at 0°C. After warming-up to ambient temperature stirring was continued for 24 hours. The solution was cooled again to 0°C, quenched with MeOH and refluxed for lh. Solvents were removed and the residue was treated with water. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried, filtered and concentrated under reduced pressure to afford 4.76 g (64 percent) of the title compound. MS: M = 188.0 190.0 (M+H)+
With sodium tetrahydroborate In methanol at 20℃; for 12 h; Cooling with ice
5-bromo-2-pyridinecarboxylic acid, methyl ester (648mg, 3mmol) was dissolved in a solution of methanol (10ml) was slowly added sodium borohydride (340mg, 9mmol) in an ice bath after complete addition the ice bath was removed, warmed to at room temperature, the reaction was stirred for 12 hours; then 1N HCl was added to adjust PH 1, again was added saturated sodium bicarbonate solution to adjust PH 8, and then extracted with ethyl acetate, the organic phase was dried over anhydrous magnesium sulfate and filtered , concentrated under reduced pressure to give 5-bromo-2-pyridinemethanol (535 mg of the, white solid), yield: 94.8percent.
90%
Stage #1: at 0 - 20℃; Stage #2: With hydrogenchloride In water Stage #3: With potassium carbonate In water
Intermediate 5,4 (5 -Bromopyridin-2-y] (methanol Methyl 5-bromopyridine-2-carboxylate (2.00 g, 9.27 mmol) was dissolved in ethanol (20.0 mL). Sodium borohydride (1 .05 g, 27.8 mmol) was added at 0°C, and the mixture was stirred at room temperature for 18 h. The mixture was then concentrated under reduced pressure, quenched with 1 N hydrochloric acid, neutralized with solid potassium carbonate and extracted with dichloro- methane. The organic layer was dried over magnesium sulfate and evaporated to give 1.57 g (90percent of th.) of the title compound. LC-MS (method 6): Rt = 0.56 min; MS (ESIpos): m/z (percent) = 188.0 (100) [M+H]+.
Reference：
[1] Patent: CN103360407, 2016, B, . Location in patent: Paragraph 0135; 0138; 0139
[2] Patent: WO2013/4551, 2013, A1, . Location in patent: Page/Page column 35
[3] Chemistry - A European Journal, 2011, vol. 17, # 38, p. 10670 - 10681
6
[ 624-28-2 ]
[ 68-12-2 ]
[ 88139-91-7 ]
Yield
Reaction Conditions
Operation in experiment
59.2%
Stage #1: With n-butyllithium In hexane; toluene at -78℃; for 2 h; Stage #2: at -78℃; for 0.166667 h;
Manufacturing Example 54-1-1 (5-Bromo-pyridin-2-yl)-methanol; To a toluene (300 mL) solution of 2,5-dibromopyridine (10.0 g, 42.2 mmol) was added dropwise n-butyl lithium (2.55 M n-hexane solution, 18.2 mL, 46.4 mmol) on a dry ice-ethanol bath (-78° C.) under nitrogen atmosphere, which was stirred for 2 hours at -78° C. N,N-dimethylformamide (3.7 g, 50.6 mmol) was then added dropwise thereto and stirred for 10 minutes at -78° C. Sodium borohydride (3.20 g, 84.4 mmol) and methanol (20.0 mL) were then added and stirred for 30 minutes at room temperature. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:1-->2:1) to obtain the title compound (4.70 g, 59.2percent).1H-NMR Spectrum (DMSO-d6) δ (ppm): 4.54 (2H, d, J=5.6 Hz), 5.28 (1H, t, J=5.6 Hz), 7.44-7.47 (1H, m), 8.03-8.05 (1H, m), 8.59-8.60 (1H, m).
Reference：
[1] Tetrahedron Letters, 2000, vol. 41, # 22, p. 4335 - 4338
[2] Patent: US2009/82403, 2009, A1, . Location in patent: Page/Page column 101
[3] Journal of Medicinal Chemistry, 2007, vol. 50, # 21, p. 5147 - 5160
[4] Patent: EP2301930, 2016, B1, . Location in patent: Paragraph 0063
7
[ 900186-89-2 ]
[ 88139-91-7 ]
Yield
Reaction Conditions
Operation in experiment
80%
With potassium carbonate In tert-butyl methyl ether; water at 20℃; for 1 h;
Step II; A slurry of compound 36 (10.0 g, 33.1 mmol) in TBME (100 ml) was treated with 20percent potassium carbonate (20 ml) solution and stirred at room temperature for 1 h. The layers were separated and the organic layer was washed with water. The solution thus obtained was concentrated to 10 mL volume and 20 mL heptanes was added at 45-50 C. Solution was cooled to 20-25 C and additional 20 mL heptanes was charged. Reaction was agitated at 20-25 C for 2 hours and filtered. Product was dried overnight under vacuum at 15-25 C to give 5.0 g (80percent) of product. 1H NMR (CDCl3) δ 3.36 (bs, Hz, 1 -OH), 4.75 (d, J=9.07 Hz, 2H), 7.21 (d, J=8.31 Hz, 1H), 7.83 (d, J=8.28 Hz, 1H), 8.64 (d, J=1.89 Hz, 1H).
Stage #1: With 3-chloro-benzenecarboperoxoic acid In dichloromethane for 2 h;
Part A: Compound 413 (3.5 g, 20.7 mmol) was dissolved in methylene chloride (100 ml) and m-CPBA (4.95 g, 28.9 mmol) was added. The reaction mixture was stirred for two hours and then quenched with saturated sodium carbonate and stirred overnight. The organic layer was dried over sodium sulfate and the concentrated to provide a yellow solid (3.8 g). The solid was placed under argon and trifluoroacetic anhydride (15 mL) was added slowly. The reaction was stirred for 30 minutes at room temperature and then refluxed for 30 minutes. The reaction was cooled to room temperature and quenched slowly with saturated sodium bicarbonate. Methylene chloride was added and the organic layer was washed dried over sodium sulfate and concentrated. Column chromatography (2 to 1 ethyl acetate/hexanes) provided the desired product (3.O g, 78percent).1H NMR (400 MHz, CDCI3) δ 8.65 (d, 1H), 7.8 (m, 1H), 7.2 (d, 1H), 4.7 (s, 2H).
Reference：
[1] Patent: WO2007/84451, 2007, A1, . Location in patent: Page/Page column 146
[2] Journal of Medicinal Chemistry, 1987, vol. 30, # 5, p. 871 - 880
[3] Polyhedron, 2010, vol. 29, # 7, p. 1854 - 1862
[4] Journal of Medicinal Chemistry, 2011, vol. 54, # 13, p. 4721 - 4734
9
[ 77199-09-8 ]
[ 88139-91-7 ]
Yield
Reaction Conditions
Operation in experiment
80%
Stage #1: With sodium tetrahydroborate In methanol at 20 - 70℃; for 0.833333 h; Stage #2: With hydrogenchloride In water
Example 593-(((5-(l-(4-(2,3-Dimethylphenoxy)butanoyl)-l,2,3,4-tetrahydroquinolin-5-yl)pyridin-2- yl)methoxy)carbonylamino)propanoic acid[00204] To a solution of NaBH4 (0.822 g, 21.73 mmol) in MeOH (25 mL) was added ethyl 5-bromopicolinate (1.0 g, 4.35 mmol) portion-wise over a period of 10 min at room temperature. The mixture was stirred at room temperature for 10 min and then heated to 70 °C for 30 min. The solvent was removed in vacuo, and the resulting residue was diluted with EtOAc and water. The aqueous phase was adjusted to pH 7 with 1 N aq. HCl, and extracted with EtOAc. The combined organic layer was dried over MgS04, filtered, and concentrated in vacuo to afford the title compound (0.65 g, 80percent yield) as a white solid. LCMS, [M+H]+ = 187.9.
Stage #1: With acetic acid In dichloromethane for 0.5 h; Stage #2: With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; for 4 h;
To a solution of 5-bromo-pyridine-2-carbaldehyde (0.30 g, 1.62 mmol) in DCM (15 ml.) was added morpholine (0.1O g, 1.13 mmol) and glacial acetic acid (2 mL) and stirred the resulting reaction mixture for 30 min. followed by addition of sodium triacetoxyborohydride (0.86 g, 4.05 mmol). The resulting reaction mixture was stirred for 4 h at room temperature. After completion of reaction (TLC monitoring), the reaction mixture was diluted with DCM, added water and extracted the organic layer. The organic layer was dried over Na2SO4 and concentrated. The crude residue was purified over silica- gel [100-200 M, compound H-A (0.21 g, 69percent) eluted in 1.50percent EtOAc-hexane and compound H-B (0.12 g, 28percent) eluted in 5 percent EtOAc-hexane.
With copper(l) iodide In propiononitrile at 110℃; for 4 h;
Step 2:; (5-Bromo-pyridin-2-yl)-methanol (1.0 g), NaCN (521 mg), Pd(PPh3)4 (612 mg), and CuI (200 mg) were taken up in degassed EtCN and heated at 110°C (4 h). The solution was partitioned between EtOAc and 10 percent NH4OH (aq.). The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave a yellow solid. Purification via flash chromatography (1/2 hexanes/EtOAc, Siψ2) gave 341 mg (48 percent) of (5-cyano-pyridin-2-yl)-methanol as a white solid.
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0) In N,N-dimethyl-formamide at 80℃; for 7.5 h; Inert atmosphere
Preparation of 6-(hydroxymethyl)nicotinonitrile (17A). A mixture of 5-bromo-2-hydroxymethylpyridine (4.90 g, 26.1 mmol), S-phos dicyclohexyl(2',6'-dimethoxy-[l,r-biphenyl]-2-yl)phosphine (250 mg, 0.609 mmol), zinc cyanide (1.90 g, 16.2 mmol), and tris(dibenzylideneacetone) dipalladium (250 mg, 0.273 mmol) in DMF (5.5 mL) was degassed with a stream of Ar passing through the mixture for 1 minute. The mixture was heated at 80 °C under N2. After 4.5 hours, a second batch of the catalysts were prepared by mixing S-phos dicyclohexyl(2',6'-dimethoxy-[l, l'-biphenyl]-2- yl)phosphine (250 mg, 0.609 mmol) and tris (dibenzylideneacetone) dipalladium (250 mg, 0.273 mmol) in DMF (2 mL) under N2. The mixture was stirred at 35 °C for 2 minutes before it was added to the reaction mixture. After an additional 3 hours, water (0.5 mL) was added. The mixture was stirred for 1.5 hours and was allowed to cool to room temperature and was mixed with silica gel. The solvents were removed at 50 °C. The solids were purified by chromatography on silica using EtOAc in heptane (20-50percent) as eluent to give 6- (hydroxymethyl)nicotinonitrile (17A) as a white powder (1.38 g). MS m/z = 135 [M+H]+. 'HNMR (400 MHz, CDC13) δ 8.85 (s, IH), 7.97 (dd, J=1.96, 8.02 Hz, IH), 7.47 (d, J=8.22 Hz, IH), 4.86 (s, 2H), 2.61-3.26 (m, IH).
With thionyl chloride In dichloromethane at 0 - 20℃; for 3 h;
Part B: Compound 413A (500 mg, 2.7 mmol) was dissolved in methylene chloride (5 mL) and cooled in an ice bath. Thionyl chloride (480 mg, 4.05 mmol) was added dropwise and stirred at room temperature for 3 hours. The reaction was quenched with saturated sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated to provide the desired product (510 mg, 92percent).
0.8 g
With thionyl chloride In dichloromethane at 0℃; for 4 h;
Step 1 Preparation of 5-Bromo-2-chloromethyl-pyridine To a stirred solution of (5-Bromo-pyridin-2-yl)-methanol (1 g, 5.319 mmol) in CH2Cl2 (20 mL) is added drop wise thionyl chloride (0.57 mL, 7.979 mmol) at 0° C. then stirred for another 4 hours. Reaction mixture is diluted with saturated sodium bicarbonate solution and extracted with CH2Cl2. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by column chromatography using 7percent ethyl acetate in hexane as an eluent to afford the title compound (0.8 g). 1HNMR (400 MHz, DMSO-d6) δ: 4.7 (s, 2H), 7.53 (d, 8.36 Hz, 1H), 8.09-8.11 (dd, J1=2.44 Hz, J2=8.23 Hz, 1H), 8.69 (d, J=2.4 Hz, 1H), LC-MS (m/z): [M+H]=206.0.
4 g
With thionyl chloride In dichloromethane at 0 - 20℃; for 4 h;
To the stirred solution of (5-Bromo-pyridin-2-yl)-Methanol (5gm, 26.59mmol, 1 eq) in DCM (50mL) at 0°C is added Thionyl chloride (3ml_) drop wise at RT then stirred at RT for 4h. After completion, the reaction mixture quenched with saturated sodium bicarbonate solution and extracted with DCM (3X100ml_). The combined organic layer dried over sodium sulphate and evaporated under reduced pressure. The crude is purified by column chromatography using silica 100-200 mesh using 10percent EtOAc: Hexane as eluent to afford title compound (4g) as brown colored liquid. 1 NMR (400 MHz, DMSO) δ: 4.77 (s, 2H), 7.54 (d, J = 8.64Hz, 1 H), 8.09-8.12 (dd, J1 = 2.4Hz, J2 = 8.32Hz, 1 H), 8.70 (d, J = 5.96Hz, 1 H).
Reference：
[1] Journal of Porphyrins and Phthalocyanines, 2010, vol. 14, # 6, p. 469 - 480
[2] Patent: WO2007/84451, 2007, A1, . Location in patent: Page/Page column 147
[3] Chemistry - A European Journal, 2011, vol. 17, # 38, p. 10670 - 10681
[4] Journal of Organic Chemistry, 2004, vol. 69, # 2, p. 250 - 262
[5] Patent: WO2006/76415, 2006, A2, . Location in patent: Page/Page column 46
[6] Patent: US2008/4449, 2008, A1, . Location in patent: Page/Page column 13-14
[7] Patent: WO2011/14774, 2011, A1, . Location in patent: Page/Page column 29
[8] Journal of Medicinal Chemistry, 2011, vol. 54, # 13, p. 4721 - 4734
[9] Patent: US2013/237502, 2013, A1, . Location in patent: Paragraph 0323
[10] Patent: WO2014/172443, 2014, A1, . Location in patent: Page/Page column 21
19
[ 88139-91-7 ]
[ 380894-77-9 ]
Reference：
[1] Patent: CN105330689, 2016, A,
20
[ 88139-91-7 ]
[ 936342-91-5 ]
Yield
Reaction Conditions
Operation in experiment
98%
at 20℃; for 12 h;
5-bromo-2-pyridinemethanol (500 mg, 2.66 mmol) was dissolved in thionyl chloride (5 ml) at room temperature, The mixture was stirred for 12 hours and concentrated under reduced pressure to 5-bromo-2-chloromethylpyridine monohydrochloride(635 mg, white solid) in 98percent yield.
69.2%
With thionyl chloride In toluene at 0 - 20℃; for 0.0833333 h;
Manufacturing Example 54-1-2 5-Bromo-2-chloromethyl-pyridine hydrochloride; To a toluene (20.0 mL) solution of (5-bromo-pyridin-2-yl)-methanol (4.70 g, 25.0 mmol) described in Manufacturing Example 54-1-1 was added dropwise thionyl chloride (3.65 mL, 50.1 mmol) on an ice bath (0° C.) under nitrogen atmosphere, which was stirred for 5 minutes at room temperature. The solvent was evaporated under a reduced pressure to obtain the title compound (4.2 g, 69.2percent) as a hydrochloride.1H-NMR Spectrum (DMSO-d6) δ (ppm): 4.78 (2H, s), 7.55-7.57 (1H, m), 8.11-8.14 (1H, m), 8.70-8.72 (1H, m).
69.2%
With thionyl chloride In toluene at 0 - 20℃; for 0.0833333 h;
To a toluene (20.0 mL) solution of (5-bromo-pyridin-2-yl)-methanol (4.70 g, 25.0 mmol) described in Manufacturing Example 54-1-1 was added dropwise thionyl chloride (3.65 mL, 50.1 mmol) on an ice bath (0° C.) under nitrogen atmosphere, which was stirred for 5 minutes at room temperature. The solvent was evaporated under a reduced pressure to obtain the title compound (4.2 g, 69.2percent) as a hydrochloride. 1H-NMR Spectrum (DMSO-d6) δ (ppm): 4.78 (2H, s), 7.55-7.57 (1H, m), 8.11-8.14 (1H, m), 8.70-8.72 (1H, m).
To a flask containing 5-Bromo-2-methyl-pyridine 1-oxide (1.14g, 6.20mmol) purged with argon was slowly added trifluoroacetic acid (lOmL). The mixture stirred for 0.5hrs at room temperature and 0.5hrs at 53C. The mixture was cooled and diluted with saturated sodium bicarbonate. The aqueous solution stirred overnight at room temperature and was extracted with ethyl acetate, and concentrated to afford the title compound (895mg, 77%) as a brown solid. *H NMR (300 MHz, CDCI3): 8 8.64 (s, 1H), 7.83 (d, 1H), 7.22 (d, 1H), 4.75 (s, 2H).
With 1H-imidazole; In dichloromethane; at 21℃; for 16h;Inert atmosphere;
To a solution of <strong>[88139-91-7](5-bromopyridin-2-yl)methanol</strong>25 (3.65 g, 19.4 mmol) in anhydrous dichloromethane (DCM) (50 mL), tert-butyldimethylsilyl chloride (3.22 g, 21.3 mmol) and imidazole (2.90 g, 42.6 mmol) were added and stirred overnight at room temperature (RT). The reaction mixture was quenched with saturated ammonium chloride and extracted with dichloromethane (3 times). The combined organic layer was dried with anhydrous sodium sulfate and concentrated. The resultant crude was subjected to flash chromatography with silica column and 10% ethyl acetate in hexanes as eluent to give 5 (5.29 g, 90%) as colorless oil. Rf 0.51 (10% ethyl acetate in hexanes). 1H NMR (400 MHz, CDCl3) delta 8.54 (d, J=2.4 Hz, 1H), 7.80 (dd, J=8.4 Hz, J=2.3 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 4.76 (s, 2H), 0.94 (s, 9H), 0.10 (s, 6H). 13C NMR (101 MHz, CDCl3) delta 160.1, 149.7, 139.3, 121.6, 118.6, 65.7, 26.0, 18.4, -5.3. HRMS (ESI+) calcd for C12H21BrNOSi+ [M+H]+ 302.0570, found: 302.0577.
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃;
Intermediate 18.1.1 5-Bromo-2-(tert-butyl-dimethyl-silanyloxymethyl)-pyridineTo a stirred solution of <strong>[88139-91-7](5-bromo-pyridin-2-yl)-methanol</strong> (500 mg) in DMF (2 ml) at room temperature, was added tert-butyl-chloro-dimethyl-silane (0.48 g) and imidazole (0.36 g). After overnight stirring, ethyl acetate was added followed by water and mixture extracted 3 times with ethyl acetate. The organic layer was separated; washed with water and brine solution, then dried and concentrated to afford 800 mg of the title compound. ESI mass spectrum: [M]+ = 302.
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃;
Synthesis Example 18.1Intermediate 18.1.15-Bromo-2-(tert-butyl-dimethyl-silanyloxymethyl)-pyridineTo a stirred solution of <strong>[88139-91-7](5-bromo-pyridin-2-yl)-methanol</strong> (500 mg) in DMF (2 ml) at room temperature, was added tert-butyl-chloro-dimethyl-silane (0.48 g) and imidazole (0.36 g). After overnight stirring, ethyl acetate was added followed by water and mixture extracted 3 times with ethyl acetate. The organic layer was separated; washed with water and brine solution, then dried and concentrated to afford 800 mg of the title compound. ESI mass spectrum: [M]+=302.
3.75 g
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 0.833333h;
The 5-bromo-2-([teit-butyl(dimethyl)silyl]oxy}methyl)pyridine used in the above process was prepared from <strong>[88139-91-7]5-bromo-2-hydroxymethylpyridine</strong> (2.5 g, 13 mmol) which was dissolved in DMF (25 mL) and imidazole (1.81 g, 27 mmol) and tertbutyldimethylsilyl chloride (2.20 g, 15 mmol) were added. The reaction mixture was stirred at room temperature for 50 mm and then poured into water (50 mL). This was extracted with diethyl ether (3 x 50 mL) and the combined organic layers were washed with brine (1 x 50 mL), dried (MgSO4) and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel; 5% EtOAc in heptanes) to give the desired material (3.75 g) as a colourless oil. LCMS: m/z 302/304 [M+H].
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 1h;
To a solution of 5-bromo-2-formylpyridine (4.6 g, 25 mmol) in methanol (30 ml) was added sodium borohydride (0.93 g, 25 mmol) at 0C with stirring, and the resulting mixture was stirred for 1 hour. After evaporating the solvent in vacuo, the residue obtained was diluted with ether, poured into water (20 ml) and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo. Subsequently, to a solution of the residue obtained and imidazole (3.4 g, 49 mmol) in N,N-dimethylformamide (30 ml) was added t-butyldimethylsilyl chloride (4.1 g, 27 mmol) with stirring, and the resulting mixture was stirred at room temperature for 1 hour. After stirring, the reaction mixture was poured into water (50 ml) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:49 to 1:9) as the eluent to afford the title compound (6.8 g) in a yield of 90 % as a white crystalline solid. 1H-NMR Spectrum (400 MHz, CDCl3) delta ppm: 0.12 (s, 6H), 0.95 (s, 9H), 4.78 (s, 2H), 7.42 (d, 1H, J=8.6 Hz), 7.82 (dd, 1H, J=2.3 Hz, 8.6 Hz), 8.56 (d, 1H, J=2.3 Hz). IR Spectrum (KBr): 1008, 1104, 1258, 1377, 1471, 1578 cm-1. Mass Spectrum (FAB+) m/z: 302 ((M+H)+).
Manufacturing Example 54-1-1 (5-Bromo-pyridin-2-yl)-methanol; To a toluene (300 mL) solution of 2,5-dibromopyridine (10.0 g, 42.2 mmol) was added dropwise n-butyl lithium (2.55 M n-hexane solution, 18.2 mL, 46.4 mmol) on a dry ice-ethanol bath (-78 C.) under nitrogen atmosphere, which was stirred for 2 hours at -78 C. N,N-dimethylformamide (3.7 g, 50.6 mmol) was then added dropwise thereto and stirred for 10 minutes at -78 C. Sodium borohydride (3.20 g, 84.4 mmol) and methanol (20.0 mL) were then added and stirred for 30 minutes at room temperature. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:1?2:1) to obtain the title compound (4.70 g, 59.2%).1H-NMR Spectrum (DMSO-d6) delta (ppm): 4.54 (2H, d, J=5.6 Hz), 5.28 (1H, t, J=5.6 Hz), 7.44-7.47 (1H, m), 8.03-8.05 (1H, m), 8.59-8.60 (1H, m).
With thionyl chloride; In dichloromethane; at 0 - 20℃; for 3h;
Part B: Compound 413A (500 mg, 2.7 mmol) was dissolved in methylene chloride (5 mL) and cooled in an ice bath. Thionyl chloride (480 mg, 4.05 mmol) was added dropwise and stirred at room temperature for 3 hours. The reaction was quenched with saturated sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated to provide the desired product (510 mg, 92%).
A slurry of 36 (10.0 g, 33.1mmol) in TBME (100 ml) was treated with 20% potassium, carbonate (20 ml) solution and stirred at room temperature for 1 h. The layers were separated and the organic layer was washed with water. The TBME and water were removed by atmospheric distillation and azeotropic distillation with acetonitrile (100 ml) and further concentrated under vacuum to a volume of 40 ml. A Karl Fischer was performed to confirm the removal of water (KF ? 0.2). To the acetonitrile concentrate was added dropwise thionyl chloride (3.2 ml, 43.7 mmol) while keeping the temperature below 45 0C. The reaction mixture was then heated at 45 C for 2 h at which time an HPLC assay indicated complete reaction. The reaction mixture was cooled to 25 0C and quenched with water (20 ml) while keeping the temperature below 40 0C. The reaction mixture was slowly poured into a mixture of 20% sodium carbonate (40 ml) and toluene (100 ml), stirred for 10 min and the layers were partitioned. The toluene extract was concentrated under reduced pressure to a volume of about 20 ml. A KF was performed to confirm the removal of water (KF ? 0.2).
Example 1A; Preparation of [(5-Bromo-Pyridin-2-ylMethyl)-Phosphonic Acid Diethyl Ester] Hydrochloride; Into a solution of 5-bromo-2-hydroxymethyl-pyridine (BHMP, 50.0 g, 266 mmol) in toluene (100 mL) and MeCN (150 mL) was added thionyl chloride (35.0 mL, 57.1 g, 479 mmol). This reaction mixture was stirred at 45 C. for 4 hours. Toluene (250 mL) was added to the reaction mixture and the reaction mixture was cooled to 0 C. The reaction was quenched with 20% potassium carbonate solution (450 ml), keeping the temperature below 30 C. The reaction mixture was stirred for 10 min and the layers were partitioned. The organic layer was washed once with water (100 mL) and the organic layer was concentrated under reduced pressure to a volume of about 200 mL. The concentrated crude solution was transferred to a distillation apparatus. At room temperature, triethyl phosphite (200 mL, 1144 mmol) was added to the crude concentrated solution and the reaction mixture was heated to 145 C. until reaction was completed. Distillate driven off of the reaction mixture during the heating period was collected (200 mL). After 12 hours of heating the reaction mixture was cooled to 0 C. A solution of 5-6N HCl in isopropanol (150 mL) was slowly added to the cooled reaction mixture over a period of 1 hour, keeping the internal temperature below 5 C. Heptanes (350 mL) were then added to the mixture over 1 hours and the resultant slurry was stirred for another hour. The solid product was collected by vacuum filtration, washed with 10% IPA/heptanes and dried under vacuum at room temperature to provide 81 g of product (89%). Mp. 118-120 C. 1H NMR (400 MHz, CDCl3) delta 1.29 (t, J=7.05 Hz, 6H), 3.88 (d, J=22.3 Hz, 2H), 4.19 (m, 4H), 7.88 (dd, J=8.57 Hz, 1H), 8.34 (dd, J=8.55, 2.18 Hz, 1H), 8.71 (s, 1H).
NaH (0.525 g, 13.1 mmol, 60% in mineral oil) was added to a solution of alcohol 41 (1.872, 10.1 mmol) and 5-bromo-2-(chloromethyl)pyridine (58) (prepared by chlorination of (5-bromo-2-pyridinyl)methanol, as reported by van den Heuvel et al., 2004) (2.5 g, 12.1 mmol) in anhydrous DMF (40 rnL) at 5 0C. The resulting mixture was stirred at room temperature for 2 h and then quenched with water (300 mL). The precipitate was filtered off, washed with water and dried to give (6S)-6-[(5-bromo-2-pyridinyl)methoxy]-2-nitro-6,7- dihydro-5H-imidazo[2,l-6][l,3]oxazine (59) (3.087 g, 86%) as a light brown solid: mp 171-173 0C; 1H NMR [(CD3)2SO] delta 8.65 (dd, J= 2.3, 0.4 Hz, 1 H), 8.04 (dd, J = 8.4, 2.4 Hz, 1 H), 8.02 (s, 1 H), 7.35 (dd, J = 8.4, 0.4 Hz, 1 H), 4.72-4.66 (m, 3 H), 4.49 (br d, J= 12.0 Hz, 1 H), 4.35- 4.21 (m, 3 H). Anal. (Ci2HnBrN4O4) C, H, N. HPLC purity: 99.4%.
0.8 g
With thionyl chloride; In dichloromethane; at 0℃; for 4h;
Step 1 Preparation of 5-Bromo-2-chloromethyl-pyridine To a stirred solution of (5-Bromo-pyridin-2-yl)-methanol (1 g, 5.319 mmol) in CH2Cl2 (20 mL) is added drop wise thionyl chloride (0.57 mL, 7.979 mmol) at 0 C. then stirred for another 4 hours. Reaction mixture is diluted with saturated sodium bicarbonate solution and extracted with CH2Cl2. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by column chromatography using 7% ethyl acetate in hexane as an eluent to afford the title compound (0.8 g). 1HNMR (400 MHz, DMSO-d6) delta: 4.7 (s, 2H), 7.53 (d, 8.36 Hz, 1H), 8.09-8.11 (dd, J1=2.44 Hz, J2=8.23 Hz, 1H), 8.69 (d, J=2.4 Hz, 1H), LC-MS (m/z): [M+H]=206.0.
4 g
With thionyl chloride; In dichloromethane; at 0 - 20℃; for 4h;
To the stirred solution of (5-Bromo-pyridin-2-yl)-Methanol (5gm, 26.59mmol, 1 eq) in DCM (50mL) at 0C is added Thionyl chloride (3ml_) drop wise at RT then stirred at RT for 4h. After completion, the reaction mixture quenched with saturated sodium bicarbonate solution and extracted with DCM (3X100ml_). The combined organic layer dried over sodium sulphate and evaporated under reduced pressure. The crude is purified by column chromatography using silica 100-200 mesh using 10% EtOAc: Hexane as eluent to afford title compound (4g) as brown colored liquid. 1 NMR (400 MHz, DMSO) delta: 4.77 (s, 2H), 7.54 (d, J = 8.64Hz, 1 H), 8.09-8.12 (dd, J1 = 2.4Hz, J2 = 8.32Hz, 1 H), 8.70 (d, J = 5.96Hz, 1 H).
With sodium tetrahydroborate; In tetrahydrofuran; ethanol; for 0.75h;
To a solution of 5-bromopyridine-2-carbaldehyde (5.00 g, 26.9 mmol) dissolved in a mixture of ethanol (75 mL) and THF (25 mL) was added sodium borohydride (0.407 g, 10.8 mmol) in small portions. After 45 minutes 0.5 mL water was added and the mixture and evaporated to dryness. The oily residue was subjected to flash chromatography (silica, EtOAc/EtOH/Et3N 90:5:5) to give (5-bromo-pyridin-2-yl)-methanol (4.81 g, 86%) as pale-yellow oil.
84%
Example 14.1: (5-Bromo-pyridin-2-vl)-methanolA mixture of 5-bromo-pyridine-2-carbaldehyde (0.5 g, 2.68 mmol) in ethanol (30 ml_) was cooled in an ice bath. Sodium borohydride (0.41 g, 10.75 mmol) was added and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated, dried, the residue dissolved in dichloromethane (30 ml.) and quenched with a saturated aqueous sodium bicarbonate solution. The organic phase was separated and the aqueous phase was extracted further with dichloromethane (2 x 10 ml_). The combined organic phase was dried over sodium sulfate and concentrated to give the product as an off- white solid (426 mg, 84 %). 1H NMR (300 MHz, CDCI3): delta (ppm) 8.61 (d, 1 H), 7.82 (dd, 1 H), 7.23 (d, 1 H), 4.73 (s, 2H), 3.92 (bs, 1 H).
50%
With methanol; sodium tetrahydroborate; at 23℃; for 4h;
To a stirred solution of 5-bromopicolinaldehyde (0.5 g, 2.68 mmol, 1.0 eq) in methanol (10 mL) was added NaBH4 (0.18 g, 5.37 mmol, 2 eq) and stirred at room temperature for 4h. methanol was evaporated and diluted with with ethyl acetate (10mL), washed with water (15 mL), dried over sodium sulphate and evaporated under reduced pressure to get crude compound. This crude was purified by column chromatography using 100-200 silica gel 20 % ethyl acetate-petrol ether as eluent system to get (5-bromopyridin-2- yl)methanol (0.2 g, 50 %).
With sodium tetrahydroborate; In tetrahydrofuran; ethanol; at -78℃; for 2h;
To a solution of 5-bromo-pyridine-2-carbaldehyde [(L.] Oeq. ) in THF : EtOH (1: 1; 0.2M) [AT-78C] was added NaBH4 (4. [0EQ.).] The mixture was stirred for 2h [AT-78C,] quenched with excess [ACOH,] poured in aqueous HCl [(1M),] stirred for [15MIN,] neutralized to pH = 7 with NaOH [(1M)] and extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried over [NA2S04,] filtered and concentrated to afford the title compound as an oil.
Preparation of Example 316; Step 1 :; The 5-bromo-pyridine-2-carbaldehyde (2.0 g) was taken up in MeOH and cooled to OC. Sodium borohydride (450 mg) was added in portions at 0C. The solution was warmed to 25C and stirred at that temperature for 1.5 h. The solution was concentrated, and the residue was quenched with 1 M HCI (aq.)- The solution was stirred at 25C for 0.5 h. The solution was rendered basic via addition of solid K2CO3. The mixture was extracted with CH2CI2. The combined organic layers were dried (MgSO4), filtered, and concentrated to give (5-bromo- pyridin-2-yl)-methanol as a white solid.
With sodium tetrahydroborate; In methanol; hexane; toluene; at 20℃; for 0.5h;
To a toluene (300 mL) solution of 2,5-dibromopyridine (10.0 g, 42.2 mmol) was added dropwise n-butyl lithium (2.55 M n-hexane solution, 18.2 mL, 46.4 mmol) on a dry ice-ethanol bath (-78 C.) under nitrogen atmosphere, which was stirred for 2 hours at -78 C. N,N-dimethylformamide (3.7 g, 50.6 mmol) was then added dropwise thereto and stirred for 10 minutes at -78 C. Sodium borohydride (3.20 g, 84.4 mmol) and methanol (20.0 mL) were then added and stirred for 30 minutes at room temperature. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:1?2:1) to obtain the title compound (4.70 g, 59.2%). 1H-NMR Spectrum (DMSO-d6) delta (ppm): 4.54 (2H, d, J=5.6 Hz), 5.28 (1H, t, J=5.6 Hz), 7.44-7.47 (1H, m), 8.03-8.05 (1H, m), 8.59-8.60 (1H, m).
0.2 g
With sodium tetrahydroborate; In methanol; at 20℃; for 4h;
Step 2 To a stirred solution of 5-bromopicolinaldehyde (0.5 g, 2.68 mmol, 1.0 eq) in methanol (10 mL) was added NaBH4 (0.18 g, 5.37 mmol, 2 eq) and stirred at room temperature for 4 h. methanol was evaporated and diluted with ethyl acetate (10 mL), washed with water (15 mL), dried over sodium sulfate and evaporated under reduced pressure to get crude compound. This crude was purified by column chromatography using 100-200 silica gel 20% ethyl acetate-petrol ether as eluent system to get (5-bromopyridin-2-yl)methanol (0.2 g, 50%).
With methanol; sodium tetrahydroborate; at 0℃; for 1h;
(23a) 5-Bromo-2-([t-butyl(dimethyl)silyl]oxy}methyl)pyridine To a solution of 5-bromo-2-formylpyridine (4.6 g, 25 mmol) in methanol (30 ml) was added sodium borohydride (0.93 g, 25 mmol) at 0C with stirring, and the resulting mixture was stirred for 1 hour. After evaporating the solvent in vacuo, the residue obtained was diluted with ether, poured into water (20 ml) and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo. Subsequently, to a solution of the residue obtained and imidazole (3.4 g, 49 mmol) in N,N-dimethylformamide (30 ml) was added t-butyldimethylsilyl chloride (4.1 g, 27 mmol) with stirring, and the resulting mixture was stirred at room temperature for 1 hour. After stirring, the reaction mixture was poured into water (50 ml) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:49 to 1:9) as the eluent to afford the title compound (6.8 g) in a yield of 90 % as a white crystalline solid. 1H-NMR Spectrum (400 MHz, CDCl3) delta ppm: 0.12 (s, 6H), 0.95 (s, 9H), 4.78 (s, 2H), 7.42 (d, 1H, J=8.6 Hz), 7.82 (dd, 1H, J=2.3 Hz, 8.6 Hz), 8.56 (d, 1H, J=2.3 Hz). IR Spectrum (KBr): 1008, 1104, 1258, 1377, 1471, 1578 cm-1. Mass Spectrum (FAB+) m/z: 302 ((M+H)+).
1.94 g
With methanol; sodium tetrahydroborate; at 0 - 20℃; for 2h;
In the 0 C ice bath, add NaBH4 (1.220 g) to a solution of 5-bromopyridinecarboxaldehyde (2.010 g) in methanol (30 mL). After adding NaBH4, remove the water bath and naturally warm to room temperature. After stirring at room temperature for 2 hours, the reaction mixture was quenched with EtOAc. Extracted with EA (50 mL × 2), the combined organic phases were washed with a saturated NaCl solution. Drying over anhydrous Na2SO4 and concentrated to afford 1.940 g (5-bromopyridin-2-yl)methanol.
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 20℃; for 1h;
Step 2: 5-Bromo-2-hydroxymethyl-pyridine-1-oxide5-Bromo-pyridin-2-yl-methanol (6.0 g, 31.9 mmol) was dissolved in methylenechloride (80 ml) and cooled to 0 C. A solution of 3-chloroperbenzoic acid (8.26 g, 47.9 mmol) in methylenechloride (20 ml) was slowly added, the ice bath was removed after completion of the addition, and the reaction mixture was stirred at ambient temperature for 1 h. The solvent was removed and the crude product was purified by silica gel chromatography using ethyl acetate to yield 3.68 g (56%) of the title compound.MS: M=204.0 & 206.2 (M+H)+
56%
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 20℃; for 1h;
Step 2: 5-Bromo-2-hydroxymethyl-pyridine-l -oxide5-Bromo-pyridin-2-yl-methanol (6.0 g, 31.9 mmol) was dissolved in methylenechloride (80 ml) and cooled to 0C. A solution of 3-chloroperbenzoic acid (8.26 g, 47.9 mmol) inmethylenechloride (20 ml) was slowly added, the ice bath was removed after completion of the addition, and the reaction mixture was stirred at ambient temperature for lh. The solvent was removed and the crude product was purified by silica gel chromatography using ethyl acetate to yield 3.68 g (56 %) of the title compound.MS: M = 204.0 & 206.2 (M+H)+
56%
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 20℃; for 1h;
5-Bromo-pyridin-2-yl-methanol (6.0 g, 31.9 mmol) was dissolved in dichloromethane (80 ml) and cooled to 0 C. A solution of 3-chloroperbenzoic acid (8.26 g, 47.9 mmol) in dichloromethane (20 ml) was slowly added, the ice bath was removed after completion of the addition, and the reaction mixture was stirred at ambient temperature for 1 h. The solvent was removed and the crude product was purified by silica gel chromatography using ethyl acetate to yield 3.68 g (56%) of the title compound. MS: M=204.0 & 206.2 (M+H)+
56%
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 20℃; for 1h;Inert atmosphere;
5-Bromo-pyridin-2-yl-methanol (6.0 g, 31.9 mmol) was dissolved in dichloromethane (80 ml) and cooled to 0C. A solution of 3-chloroperbenzoic acid (8.26 g, 47.9 mmol) in dichloromethane (20 ml) was slowly added, the ice bath was removed after completion of the addition, and the reaction mixture was stirred at ambient temperature for lh. The solvent was removed and the crude product was purified by silica gel chromatography using ethyl acetate to yield 3.68 g (56 %) of the title compound.MS: M = 204.0 & 206.2 (M+H)+
With peracetic acid; In dichloromethane; at 18 - 25℃; for 12h;
To a solution of <strong>[88139-91-7](5-bromo-pyridin-2-yl)-methanol</strong> [(L.] Oeq. ) in [CH2CL2] (0.2M) was added peracetic acid (3. [0EQ.).] The mixture was stirred for 12h, diluted with [CHZCLZ] and neutralized with aqueous [NAOH] (1M) to pH = 7. The organic phase was decanted, dried over [NA2SO4] and upon concentration the title compound crystallized as a white solid and was isolated by filtration.
With triethylamine; at -10 - 20℃; for 1h;Inert atmosphere;
To a solution of (5-bromo-2-pyridyl)methanol (1 .46 g, 7.75 mmol) , cooled to -10 C under a nitrogen atmosphere, were added successively triethylamine (1 .4 mL, 10.07mmol) and methanesulfonyl chloride (0.66 mL, 8.52 mmol). The reaction mixture was allowed to warm to room temperature whilst stirring for 1 h. The mixture was quenched with water (15 mL) and then extracted with DCM (3 chi 15 mL). The organic phase was separated, dried using a phase separator and then concentrated under reduced pressure to provide (5-bromo-2-pyridyl)methyl methanesulfonate (2.06 g, 7.73 mmol, 100% yield) as a red oil, which was used as such immediately for the next step. This mixture was used in the next reaction without further purification, assumed quantitative.
71%
With triethylamine; In dichloromethane; at 0 - 20℃;
(5-bromopyridin-2-yl)methyl methanesulfonate In a 50-mL round bottom flask, <strong>[88139-91-7](5-bromopyridin-2-yl)methanol</strong> (500 mg, 2.66 mmol, 1.00 equiv) and TEA (210 mg, 2.08 mmol, 1.00 equiv) were dissolved in dichloromethane (10 mL), to which was added methanesulfonyl chloride (300 mg, 2.62 mmol, 1.00 equiv) slowly at 0 C. The resulting solution was then stirred overnight at room temperature. When the reaction was done, it was quenched by 20 mL water and the resulting mixture was extracted with dichloromethane (3*20 mL). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to afford (5-bromopyridin-2-yl)methyl methanesulfonate (500 mg, 71%) as yellow oil.
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;
Example 15.1 : Methanesulfonic acid 5-bromo-pyridin-2-ylmethyl esterA mixture of (5-Bromo-pyridin-2-yl)-methanol (60 mg, 0.32 mmol) in dichloromethane (2 ml) was cooled in as ice bath. To the mixture was then added triethylamine (0.13 ml_, 0.96 mmol) followed by methanesulfonyl chloride (0.05 mL, 0.64 mmol). The reaction mixture was stirred at room temperature for 2 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate (5 mL). The organic phase was separated and the aqueous phase extracted further with dichloromethane (2 x 5 mL). The combined organic phase was washed with brine, dried over sodium sulfate and concentrated to give the product as a pale brown oil.
With triethylamine; at -30 - 0℃; for 1h;
To a solution of the product of Step 1 (20 g, 106 mmol) and Et3N (17,8 ml, 128 mmol, 1.2 eq.) in CH3Cl2 (300 ml) kept ~-30C was slowly added CH3SO2Cl (9.1 ml, 118 mmol, 1.1 eq.). The slurry was stirred for 1 h while it warmed up to 0 C. The reaction mixture was diluted with aq. NaHCO3 (500 ml) and the organic layer was separated. The aqueous layer was extracted with Et2O (2x200 ml) and the combined organic layers was washed with aq. NaHCO3 (2x300 ml) and brine (300 ml). The solution was dried over MgSO4, filtered and evaporated to give the crude mesylate, which was used as such for the next step. 1H NMR: 8.67 (d, J = 2.0 Hz, 1 H), 7.89 (dd, J = 8.4, 2.4 Hz, 1 H), 7.33 (d, J = 8.4 Hz, 1 H), 5.28 (s, 2H), 3.10 (s, 3H).
With triethylamine; In dichloromethane; at 0℃; for 0.25h;
To a sol. of <strong>[88139-91-7]5-bromo-2-(hydroxymethyl)pyridine</strong> (2.50 g, 13.3 mmol) and Et3N (2.78 mL, 19.9 mmol) in CH2CI2 (67 mL) is added at 0C methansulfonyl chloride (1.14 mL, 14.6 mmol). The mixture is stirred at 0 C for 15 min. Aq. sat. NaHC03 is added, and the phases are separated. The org. layer is washed with brine, dried over Na2S04, filtered, and the solvents are evaporated under reduced pressure. Purification of the crude was purified by automated FC (Biotage, 100g KP column, EtOAc / heptane 0? 30%) yields the title product. LC-MS: tR = 0.57 min, MH+ = 268.15 (conditions 4).
With triethylamine; In tetrahydrofuran; for 1h;Cooling with ice;
Preparation of 2-(((3,5-bis(trifluoromethyl)phenyl)thio)methyl)-5-bromopyridine (8A). Methanesulfonyl chloride (5.35 mL, 69.1 mmol) was added dropwise to an ice cold solution of <strong>[88139-91-7]5-bromo-2-hydroxymethylpyridine</strong> ( 10.0 g, 53.2 mmol) and TEA (1 1.1 mL, 80.0 mmol) in THF ( 150 mL). The mixture was stirred for 1 hour. Water was then added and the product was extracted into EtOAc (2x). The combined organic layers were dried over anhydrous MgSO/i, filtered, and concentrated in vacuo to give the mesylate as an oil. 3,5-bis-Trifluoromethyl benzenethiol (8.91 mL, 53.2 mmol) was dissolved in MeOH (150 mL). Aqueous sodium hydroxide (2N, 31.9 mL, 63.8 mmol) was added and then the mixture was stirred for 5 minutes. The mesylate was added as a suspension in MeOH (40 mL) and the mixture was stirred for 1 hour at room temperature before the MeOH was removed in vacuo. The resulting residue was partitioned between water and EtOAc, the layers were separated, and the aqueous layer was extracted with EtOAc (lx). The combined extracts were dried over anhydrous MgS04, filtered, and concentrated in vacuo to give 2- (((3,5-bis(trifluoromethyl)phenyl)thio)methyl)-5-bromopyridine (8A) (22.3g, 101% yield) as an oil. MS m/z = 416 [M+H]+. lH NMR (400 MHz, CDC13) delta ppm 8.59 (s, 1 H) 7.73 - 7.79 (m, 3 H) 7.63 (s, 1 H) 7.26 (d, J=8.02 Hz, 1 H) 4.29 (s, 2 H).
With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 1h;
A solution of <strong>[88139-91-7](5-bromopyridin-2-yl)methanol</strong> (500 mg, 2.66 mmol) in THF (10 mL) was cooled to 0 C and treated with TEA (0.482 mL, 3.46 mmol) and methanesulfonyl chloride (0.252 mL, 3.19 mmol). The mixture was slowly warmed to RT and stirred for lhour. The reaction was diluted with DCM, quenched with a saturated aqueous solution of NH4CI and the mixture was extracted with DCM. The combined organic layer was washed with brine, dried over MgS04, and concentrated to (5-bromopyridin-2-yl)methyl methanesulfonate (Intermediate 177a, 700 mg, 2.63 mmol, 99 % yield) which was used for next step without purification. LC-MS (Method A5): 1.72 min, [M + H]+=265.9 and 267.9; H NMR (500 MHz, CDCl3) delta 8.68 (d, 7=2.2 Hz, 1H), 7.90 (dd, 7=8.3, 2.2 Hz, 1H), 7.39 (d, 7=8.3 Hz, 1H), 5.29 (s, 2H), 3.10 (s, 3H).
With triethylamine; In dichloromethane; at 0℃; for 2.5h;Inert atmosphere;
A solution of <strong>[88139-91-7](5-bromo-pyridin-2-yl)-methanol</strong> (20.0 g, 106 mmol) in 150 mL of dichloromethane was cooled to 00C under nitrogen. Triethylamine (19.3 mL, 138 mmol) was added, followed by methanesulfonyl chloride (9.95 ml, 128 mmol). After 2.5 hours, the mixture was quenched with 50 mL of water and diluted with 100 mL of dichloromethane. The organic layer was washed with an additional 50 mL of water and then the aqueous layer was extracted <n="33"/>with 100 mL of methylene chloride. The organic extracts were dried over sodium sulfate, filtered and concentrated to provide (5-bromopyridin-2-yl)methyl methanesulfonate as a red solid that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 268.1 for MH-H+(81Br).
In tetrahydrofuran; at 0 - 20℃; for 2h;
A solution of <strong>[88139-91-7](5-bromopyridin-2-yl)methanol</strong> (1.940 g) in THF (20 mL). Then methylsulfonyl chloride (1.780 g) was added dropwise Into the solution. After the addition of methylsulfonium chloride, the ice bath was removed and allowed to warm to room temperature. After stirring at room temperature for 2 hours, the reaction mixture was washed with water (50mL) and quenched. Extracted with EA (50 mL × 2), The combined organic phases were washed with aq. sat. NaCl (50 mL). Dry anhydrous Na2SO4, Concentration gave 2.75 g of crude product (5-bromopyridin-2-yl)methyl methanesulfonate.
With copper(l) iodide;tetrakis(triphenylphosphine) palladium(0); In propiononitrile; at 110℃; for 4h;
Step 2:; (5-Bromo-pyridin-2-yl)-methanol (1.0 g), NaCN (521 mg), Pd(PPh3)4 (612 mg), and CuI (200 mg) were taken up in degassed EtCN and heated at 110C (4 h). The solution was partitioned between EtOAc and 10 % NH4OH (aq.). The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave a yellow solid. Purification via flash chromatography (1/2 hexanes/EtOAc, Sitheta2) gave 341 mg (48 %) of (5-cyano-pyridin-2-yl)-methanol as a white solid.
5-bromo-2-pyridinemethanol (500 mg, 2.66 mmol) was dissolved in thionyl chloride (5 ml) at room temperature, The mixture was stirred for 12 hours and concentrated under reduced pressure to 5-bromo-2-chloromethylpyridine monohydrochloride(635 mg, white solid) in 98percent yield.
69.2%
With thionyl chloride; In toluene; at 0 - 20℃; for 0.0833333h;
Manufacturing Example 54-1-2 5-Bromo-2-chloromethyl-pyridine hydrochloride; To a toluene (20.0 mL) solution of (5-bromo-pyridin-2-yl)-methanol (4.70 g, 25.0 mmol) described in Manufacturing Example 54-1-1 was added dropwise thionyl chloride (3.65 mL, 50.1 mmol) on an ice bath (0° C.) under nitrogen atmosphere, which was stirred for 5 minutes at room temperature. The solvent was evaporated under a reduced pressure to obtain the title compound (4.2 g, 69.2percent) as a hydrochloride.1H-NMR Spectrum (DMSO-d6) delta (ppm): 4.78 (2H, s), 7.55-7.57 (1H, m), 8.11-8.14 (1H, m), 8.70-8.72 (1H, m).
69.2%
With thionyl chloride; In toluene; at 0 - 20℃; for 0.0833333h;
To a toluene (20.0 mL) solution of (5-bromo-pyridin-2-yl)-methanol (4.70 g, 25.0 mmol) described in Manufacturing Example 54-1-1 was added dropwise thionyl chloride (3.65 mL, 50.1 mmol) on an ice bath (0° C.) under nitrogen atmosphere, which was stirred for 5 minutes at room temperature. The solvent was evaporated under a reduced pressure to obtain the title compound (4.2 g, 69.2percent) as a hydrochloride. 1H-NMR Spectrum (DMSO-d6) delta (ppm): 4.78 (2H, s), 7.55-7.57 (1H, m), 8.11-8.14 (1H, m), 8.70-8.72 (1H, m).
With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; isopropyl alcohol; at 140℃; for 0.333333h;Microwave;
A mixture of <strong>[88139-91-7](5-bromopyridin-2-yl)methanol</strong> (0.205 g, 1.09 mmol), (35)-N,7V-dibenzyl-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)chroman-3-amine (0.13 M in isopropanol, 8.4 mL, 1.09 mmol), l,r-bis(diphenylphosphino)ferrocene-palladium(ii)dichloride dichloromethane complex (0.045 g, 0.05 mmol), and 2 M potassium carbonate (1.64 mL, 3.28 mmol) was irradiated in a microwave synthesizer at 140 0C for 20 min. The solution was filtered through a pad of celite and concentrated in vacuo. The residue was purified by column chromatography using a gradient of ethyl acetate in heptane. The crude was dissolved in chloroform and insoluble material was removed. The solvent was evaporated in vacuo yielding an oil, 0.360 g (76 %); 1U NMR (400 MHz, DMSO-J6) delta ppm 8.46 (d, 1 H), 7.79 (dd, 1 H), 7.54 (d, 1 H), 7.24 - 7.34 (m, 8 H), 7.06 - 7.22 (m, 3 H), 6.69 - 6.83 (m, 2 H), 5.51 (t, 1 H), 4.64 (d, 2 H), 4.28 - 4.39 (m, 1 H), 3.99 - 4.10 (m, 1 H), 3.59 - 3.74 (m, 4 H), 2.86 - 3.11 (m, 1 H), 2.39 - 2.49 (m, 1 H); MS (APPI/APCI) m/z 437 [M+H+].
With N-Bromosuccinimide; triphenylphosphine; In dichloromethane; at 0 - 23℃; for 1h;
To a stirred solution of <strong>[88139-91-7](5-bromopyridin-2-yl)methanol</strong> (0.2 g, 1.06 mmol, 1.0 eq) in dichloromethane (5 mL) was added triphenyl phosphine (0.4 g, 1.59 mmol, 1.5 eq), and N- bromosuccinimide (0:3 g, 1.59 mmol, 1.5 eq) at 0 C and allowed to stir at room temperature for 1 h. The reaction mixture was quenched with water, and extracted with dichloromethane (2 x 10ml_). The organic layer was washed with brine (30 ml_), dried over sodium sulphate, concentrated and crude was purified by silica gel (100-200 mesh) column chromatography using ethyl acetate/petrol ether (1 :9) as eluent to get 5-bromo-2-(bromomethyl)pyridine (0.2 g. ~ 77 %).
Ca. 77%
With N-Bromosuccinimide; triphenylphosphine; In dichloromethane; at 0 - 20℃; for 1h;
Step 3 To a stirred solution of <strong>[88139-91-7](5-bromopyridin-2-yl)methanol</strong> (0.2 g, 1.06 mmol, 1.0 eq) in dichloromethane (5 mL) was added triphenyl phosphine (0.4 g, 1.59 mmol, 1.5 eq), and N-bromosuccinimide (0.3 g, 1.59 mmol, 1.5 eq) at 0 C. and allowed to stir at room temperature for 1 h. The reaction mixture was quenched with water, and extracted with dichloromethane (2*10 mL). The organic layer was washed with brine (30 mL), dried over sodium sulfate, concentrated and crude was purified by silica gel (100-200 mesh) column chromatography using ethyl acetate/petrol ether (1:9) as eluent to get 5-bromo-2-(bromomethyl)pyridine (0.2 g, ?77%).
With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 0℃; for 48h;
Step A: 5-bromo-2-(bromomethyl)pyridine5-Bromo-2-hydroxymethylpyridine (1 g, 5.32 mmol) was dissolved in dichloromethane (26.6 ml and cooled to 0 C. Triphenylphosphine (1.604 g, 6.12 mmol) was added followed by carbon tetrabromide (2.028 g, 6.12 mmol) which caused the reaction to become yellow andheterogeneous. After 48 h, the mixture was concentrated by half and directly purified by silica gel column chromatography (0-37%, EtOAc-hexanes) to yield the title compound. 1H NMR(500 MHz, CDC13) delta 8.64 (t, J2.7 Hz, IH), 7.82 (m, IH), 7.35 (dd, J7.8 & 3.1 Hz, IH), 4.51 (s,2H).
With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 0℃; for 48h;
5-Bromo-2-hydroxymethylpyridine (1 g, 5.32 mmol) was dissolved in dichloromethane(26.6 ml) and cooled to 0 C. Triphenylphosphine (1.604 g, 6.12 mmol) was added followed by5 carbon tetrabromide (2.028 g, 6.12 mmol) which caused the reaction to become yellow andheterogeneous. After 48 h, the mixture was concentrated by half and directly purified by silicagel column chromatography (0-37%, EtOAc-hexanes) to yield the title compound. 1H NMR(500 MHz, CDCh) 8 8.64 (t, J2.7 Hz, IH), 7.82 (m, IH), 7.35 (dd, J7.8 & 3.1 Hz, IH), 4.51 (s,2H).
With carbon tetrabromide; triphenylphosphine; In tetrahydrofuran; dichloromethane; for 0.0833333h;
To a solution of <strong>[88139-91-7](5-bromopyridin-2-yl)methanol</strong> (1.5 g, 8.0 mmol) in DCM (10ml) was added triphenylphosphine (1.9 g, 7.2 mmol), then was added a solution of carbontetrabromide (2.1 g, 6.4 mmol) in 5 mL THF. The resulting mixture was stirred for 5 mm, then evaporated to dryness, and purified using 0 to 10% ethyl acetate in hexanes. LC-MS [M+H]:251.74
With phosphorus tribromide; In acetonitrile; at 20℃; for 48h;
5-Bromo-2-(hydroxymethyl)pyridine (14.0 g, 74.5 mmol, 1.0 eq) was dissolved in acetonitrile (200 mL) and phosphorous tribromide (9.0 mL, 97.0 mmol, 1.30 eq) was added dropwise over 10 minutes to give a white suspension. The resulting mixture was stirred at room temperature over 48 h. Water was added (15 mL) before neutralising the reaction mixture with 50 % NaOH (aq) until pH 7 was achieved. Water (100 mL) and DCM (200 mL) were added and the mixture separated. The aqueous layer was washed with DCM (200 mL). The combined organic layers were dried over MgS04, filtered and the solvent removed in vacuo to yield a purple oil (18.5 g, 99.5 %); LC-MS Rt = 2.71 min (Method B), m/z 250, 252 (MH+). Intermediate 6 was used without further purification in future reactions.
With phosphorus tribromide; In dichloromethane; at 0 - 20℃; for 2h;
To <strong>[88139-91-7](5-bromopyridin-2-yl)methanol</strong> (100 mg, 0.53 mmol) in DCM (10 ml) at 0C was added the Phosphorus tribromide (720 mg, 2.65 mmol). The reaction was stirred at room temperature for 2 hours. The reaction was quenched with NaHCOs at 0C and extracted with DCM. The organic solvent was dried over anhydrous MgS04 then removed under reduced pressure. The crude product was directly used in the next step without any further purification. LC/MS: m/z 252 (M+H)+
[3-fluoro-4-(trifluoromethoxy)phenyl]boronic acid[ No CAS ]
[ 88139-91-7 ]
[ 1263417-37-3 ]
Yield
Reaction Conditions
Operation in experiment
60%
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In ethanol; water; toluene; at 89℃; for 2h;Inert atmosphere;
A stirred mixture of <strong>[88139-91-7](5-bromo-2-pyridinyl)methanol</strong> (105) (753 mg, 4.00 mmol), 3-fluoro-4-(trifluoromethoxy)phenylboronic acid (56) (see Example 2G) (1.165 g, 5.20 mmol) and Pd(dppf)Cl2 (366 mg, 0.50 mmol) in toluene (40 mL) and EtOH (20 mL) was degassed for 15 min (vacuum pump) and then N2 was added. An aqueous solution of 2M Na2CO3 (10 mL, 20.0 mmol) was added by syringe and the stirred mixture was again degassed for 15 min, and then N2 was added. The resulting mixture was stirred at 89 0C for 2 h, and then cooled, diluted with aqueous NaHCO3 (120 mL) and extracted with CH2Cl2 (6x 100 mL). The extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with 50-75% CH2Cl2/petroleum ether firstly gave foreruns, and then further elution with 75% CH2Cl2/petroleum ether and 0-0.5% MeOH/CH2Cl2 gave {5-[3-fluoro-4- (trifluoromethoxy)phenyl]-2-pyridinyI}methanol (106) (687 mg, 60%) as a light yellow-brown solid: mp 51-53 0C; 1H NMR (CDCl3) delta 8.76 (d, J = 1.9 Hz, 1 H), 7.84 (dd, J = 8.1, 2.3 Hz, 1 H), 7.46-7.34 (m, 4 H), 4.83 (d, J = 5.1 Hz, 2 H), 3.47 (t, J = 5.2 Hz, 1 H); HRESlMS calcd for CI3HI0F4NO2 mlz [M + H]+ 288.0642, found 288.0641.
60%
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In ethanol; water; toluene; at 89℃; for 2h;Inert atmosphere;
Y. Synthesis of (6S)-6-({5-[3-fluoro-4-(trifluoromethoxy)phenyl]-2-pyridinyl}methoxy)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (22) by the method of Scheme 17 A stirred mixture of <strong>[88139-91-7](5-bromo-2-pyridinyl)methanol</strong> (105) (753 mg, 4.00 mmol), 3-fluoro-4-(trifluoromethoxy)phenylboronic acid (56) (see Example 2G) (1.165 g, 5.20 mmol) and Pd(dppf)Cl2 (366 mg, 0.50 mmol) in toluene (40 mL) and EtOH (20 mL) was degassed for 15 min (vacuum pump) and then N2 was added. An aqueous solution of 2M Na2CO3 (10 mL, 20.0 mmol) was added by syringe and the stirred mixture was again degassed for 15 min, and then N2 was added. The resulting mixture was stirred at 89 C. for 2 h, and then cooled, diluted with aqueous NaHCO3 (120 mL) and extracted with CH2Cl2 (6*100 mL). The extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with 50-75% CH2Cl2/petroleum ether firstly gave foreruns, and then further elution with 75% CH2Cl2/petroleum ether and 0-0.5% MeOH/CH2Cl2 gave {5-[3-fluoro-4-(trifluoromethoxy)phenyl]-2-pyridinyl}methanol (106) (687 mg, 60%) as a light yellow-brown solid: mp 51-53 C.; 1H NMR (CDCl3) delta 8.76 (d, J=1.9 Hz, 1H), 7.84 (dd, J=8.1, 2.3 Hz, 1H), 7.46-7.34 (m, 4H), 4.83 (d, J=5.1 Hz, 2H), 3.47 (t, J=5.2 Hz, 1H); HRESIMS calcd for C13H10F4NO2m/z [M+H]+ 288.0642, found 288.0641.
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; N,N-dimethyl-formamide; at 90℃; for 2.5h;Inert atmosphere;
[Example 1]tert-Butyl 4-[2-(4-methanesufonylphenoxymethyl)pyridin-5-yl]piperidine-1-carboxylate (1) Benzyl 4-[(2-hydroxymethyl)pyridin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate To a solution of 5-bromopyridin-2-methanol (100 mg, 0.532 mmol) and <strong>[286961-15-7]benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate</strong> (200 mg, 0.585 mmol) in dry N,N-dimethylformamide (1.3 mL) - dry tetrahydrofuran (1.3 mL) was added [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (complex with dichloromethane) (22 mg, 0.027 mmol) and cesium carbonate (347 mg, 1.06 mmol). The mixture was stirred at 90C under N2 for 2.5 hours, allowed to cool to room temperature, diluted with water (5 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetaste=1/2) to give the title compound as an orange oil (120 mg, yield 70%).1H NMR(CDCl3,400 MHz) : delta= 2.5-2.6(2H, m), 3.58(1H, brs), 3.7-3.8(2H, m), 4.1-4.2(2H, m), 4.76(2H, s), 5.18(2H, s), 6.0-6.2(1H, m), 7.22(1H, d, J=8 Hz), 7.3-7.4(5H, m), 7.65(1H, dd, J=2 Hz, 8 Hz), 8.57(1H, d, J=2 Hz).
70%
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; N,N-dimethyl-formamide; at 90℃; for 2.5h;Inert atmosphere;
[Example 1] tert-Butyl 4-[2-(5-methanesulfonylindol-1-ylmethyl)pyridin-5-yl]piperidine-1-carboxylate (1) Benzyl 4- [2- (hydroxymethyl) pyridin-5-yl]-3, 6-dihydro-2H-pyridine-1-carboxylate To a solution of 5-bromopyridine-2-methanol (100 mg, 0.532 mmol) and <strong>[286961-15-7]benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate</strong> (200 mg, 0.585 mmol) in dry N,N-dimethylformamide (1.3 mL) - dry tetrahydrofuran (1.3 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (22 mg, 0.027 mmol) and cesium carbonate (347 mg, 1.06 mmol) under N2. After stirring at 90C for 2.5 hours, cooled to room temperature, the reaction mixture was poured into water (5 mL), and was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate = 1/2), to give the title compound as an orange oil (120 mg, yield 70%) . 1H NMR (CDCl3 400 MHz): delta= 2.5-2.6 6 (2H, m), 3.58 (1H, br s), 3.7-3.8 (2H, m), 4.1-4.2 (2H, m), 4.76 (2H, s), 5.18 (2H, s), 6.0-6.2 (1H, m), 7.22 (1H, d, J = 8 Hz), 7.3-7.4 (5H, m), 7.65 (1H, dd, J = 2 Hz, 8 Hz), 8.57 (1H, d, J = 2 Hz).
Example A60Preparation of intermediate 60: 5-Bromo-2-ethoxymethyl-pyridineA 60% suspension of sodium hydride in mineral oils (0.073 g, 3.19 mmol) was added to a stirred solution of <strong>[88139-91-7]5-bromo-2-(hydroxymethyl)pyridine</strong> (0.5 g, 2.66 mmol) in tetrahydrofuran (10 ml). The mixture was stirred at 0 C for 30 min. and then iodoethane (0.498 g, 3.19 mmol) was added. The mixture was stirred at 60 C for 18 h., then diluted with diethyl ether and washed with a saturated solution of ammonium chloride in water. The organic layer was separated, dried (Na2S04), filtered and the solvents evaporated in vacuo to yield intermediate 60 (0.520 g, 90%) as a colourless oil.
90%
A 60% suspension of sodium hydride in mineral oils (0.073 g, 3.19 mmol) was added to a stirred solution of <strong>[88139-91-7]5-bromo-2-(hydroxymethyl)pyridine</strong> (0.5 g, 2.66 mmol) in THF (10 ml). The mixture was stirred at 0 C for 30 min. and then iodoethane (0.498 g, 3.19 mmol) was added. The mixture was stirred at 60 C for 18 h. and then diluted with Et20 and washed with a saturated solution of ammonium chloride in water. The organic layer was separated, dried (Na2S04), filtered and the solvents evaporated in vacuo to yield intermediate 56 (0.520 g, 90%) as a colourless oil.
90%
Example A60 Preparation of intermediate 60: 5-Bromo-2-ethoxymethyl-pyridine A 60% suspension of sodium hydride in mineral oils (0.073 g, 3.19 mmol) was added to a stirred solution of <strong>[88139-91-7]5-bromo-2-(hydroxymethyl)pyridine</strong> (0.5 g, 2.66 mmol) in tetrahydrofuran (10 ml). The mixture was stirred at 0 C. for 30 min. and then iodoethane (0.498 g, 3.19 mmol) was added. The mixture was stirred at 60 C. for 18 h., then diluted with diethyl ether and washed with a saturated solution of ammonium chloride in water. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo to yield intermediate 60 (0.520 g, 90%) as a colourless oil.
90%
Example A56 5-Bromo-2-ethoxymethyl-pyridine A 60% suspension of sodium hydride in mineral oils (0.073 g, 3.19 mmol) was added to a stirred solution of <strong>[88139-91-7]5-bromo-2-(hydroxymethyl)pyridine</strong> (0.5 g, 2.66 mmol) in THF (10 ml). The mixture was stirred at 0 C. for 30 min. and then iodoethane (0.498 g, 3.19 mmol) was added. The mixture was stirred at 60 C. for 18 h. and then diluted with Et2O and washed with a saturated solution of ammonium chloride in water. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo to yield intermediate 56 (0.520 g, 90%) as a colourless oil.
A-3: 6-Methoxymethyl-3-(pyrimidin-5-ylamino)-pyridine-2-carboxylic acid methyl esterStep 1: 5-Bromo-pyridin-2-yl-methanolTo a solution of 5-bromopyridin-2-carboxylic acid (8 g, 42.1 mmol) in THF (100 ml) was added borane-dimethylsulphide (16 ml, 168.30 mmol) dropwise at 0 C. After warming-up to ambient temperature stirring was continued for 24 hours. The solution was cooled again to 0 C., quenched with MeOH and refluxed for 1 h. Solvents were removed and the residue was treated with water. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried, filtered and concentrated under reduced pressure to afford 4.76 g (64%) of the title compound.MS: M=188.0 & 190.0 (M+H)+
64%
A-3: 6-Methoxymethyl-3-fpyrimidin-5-ylamino)-pyridine-2-carboxylic acid methyl esterStep 1: 5-Bromo-pyridin-2-yl-methanolTo a solution of 5-bromopyridin-2-carboxylic acid (8 g, 42.1 mmol) in THF (100 ml) was added borane-dimethylsulphide (16 ml, 168.30 mmol) dropwise at 0C. After warming-up to ambient temperature stirring was continued for 24 hours. The solution was cooled again to 0C, quenched with MeOH and refluxed for lh. Solvents were removed and the residue was treated with water. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried, filtered and concentrated under reduced pressure to afford 4.76 g (64 %) of the title compound.+MS: M = 188.0 & 190.0 (M+H)
64%
To a solution of 5-bromopyridin-2-carboxylic acid (8 g, 42.1 mmol) in THF (100 ml) was added borane-dimethylsulphide (16 ml, 168.30 mmol) dropwise at 0 C. After warming-up to ambient temperature stirring was continued for 24 hours. The solution was cooled again to 0 C., quenched with MeOH and refluxed for 1 h. Solvents were removed and the residue was treated with water. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried, filtered and concentrated under reduced pressure to afford 4.76 g (64%) of the title compound. MS: M=188.0 & 190.0 (M+H)+
64%
To a solution of 5-bromopyridin-2-carboxylic acid (8 g, 42.1 mmol) in THF (100 ml) was added borane-dimethylsulphide (16 ml, 168.30 mmol) dropwise at 0C. After warming-up to ambient temperature stirring was continued for 24 hours. The solution was cooled again to 0C, quenched with MeOH and refluxed for lh. Solvents were removed and the residue was treated with water. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried, filtered and concentrated under reduced pressure to afford 4.76 g (64 %) of the title compound. MS: M = 188.0 & 190.0 (M+H)+
With sodium tetrahydroborate; In methanol; at 20℃; for 12h;Cooling with ice;
5-bromo-2-pyridinecarboxylic acid, methyl ester (648mg, 3mmol) was dissolved in a solution of methanol (10ml) was slowly added sodium borohydride (340mg, 9mmol) in an ice bath after complete addition the ice bath was removed, warmed to at room temperature, the reaction was stirred for 12 hours; then 1N HCl was added to adjust PH 1, again was added saturated sodium bicarbonate solution to adjust PH 8, and then extracted with ethyl acetate, the organic phase was dried over anhydrous magnesium sulfate and filtered , concentrated under reduced pressure to give 5-bromo-2-pyridinemethanol (535 mg of the, white solid), yield: 94.8%.
90%
Intermediate 5,4 (5 -Bromopyridin-2-y] (methanol Methyl 5-bromopyridine-2-carboxylate (2.00 g, 9.27 mmol) was dissolved in ethanol (20.0 mL). Sodium borohydride (1 .05 g, 27.8 mmol) was added at 0C, and the mixture was stirred at room temperature for 18 h. The mixture was then concentrated under reduced pressure, quenched with 1 N hydrochloric acid, neutralized with solid potassium carbonate and extracted with dichloro- methane. The organic layer was dried over magnesium sulfate and evaporated to give 1.57 g (90% of th.) of the title compound. LC-MS (method 6): Rt = 0.56 min; MS (ESIpos): m/z (%) = 188.0 (100) [M+H]+.
Example 593-(((5-(l-(4-(2,3-Dimethylphenoxy)butanoyl)-l,2,3,4-tetrahydroquinolin-5-yl)pyridin-2- yl)methoxy)carbonylamino)propanoic acid[00204] To a solution of NaBH4 (0.822 g, 21.73 mmol) in MeOH (25 mL) was added <strong>[77199-09-8]ethyl 5-bromopicolinate</strong> (1.0 g, 4.35 mmol) portion-wise over a period of 10 min at room temperature. The mixture was stirred at room temperature for 10 min and then heated to 70 C for 30 min. The solvent was removed in vacuo, and the resulting residue was diluted with EtOAc and water. The aqueous phase was adjusted to pH 7 with 1 N aq. HCl, and extracted with EtOAc. The combined organic layer was dried over MgS04, filtered, and concentrated in vacuo to afford the title compound (0.65 g, 80% yield) as a white solid. LCMS, [M+H]+ = 187.9.
General procedure: A solution of this <strong>[88139-91-7](5-bromo-pyridin-2-yl)-methanol</strong> (4.80 g, 23.0 mmol) in DMF (25 mL) was added drop wise over 5 minutes to a slurry of sodium hydride (1.10 g, 27.6 mmol) in DMF (50 mL) at 0 C. under N2. The mixture was stirred for 15 minutes before the drop wise addition of a solution of methyl iodide (1.57 mL, 25.3 mmol) in DMF (25 mL). The mixture was allowed to reach room temperature and was then stirred overnight. The mixture was poured into brine and extracted with EtOAc. The combined organic layers were thoroughly washed with brine, dried over MgSO4 and evaporated to dryness to give the title compound as a yellow oil (4.77 g, 98%) sufficiently pure for the next step.
93%
Sodium hydride (4.98 g, 207 mmol) was added portionwise to (5-bromopyridin-2- yl)methanol (30 g, 160mmol) in THF (450 mL) at 0C over a period of 10 minutes under nitrogen. The resulting solution was stirred at 25C for 0.5 h. Methyl iodide (12.97mL, 207mmol) was added dropwise to the solution at 0C. The resulting mixture was stirred at 25 C for 16 h. The reaction mixture was diluted with MeOH (20 mL). The crude product was purified by FCC, eluting with a gradient of 10% to 60% EtOAc in heptane. Pure fractions were evaporated to dryness to afford 5- bromo-2-(methoxymethyl)pyridine (30.0 g, 93%>) as a yellow liquid. NMR Spectrum (300 MHz, CDC13): delta 3.48 (3H, s), 4.54 (2H, s), 7.34 (1H, dd), 7.83 (1H, dd), 8.61 (1H, d).
47.2%
To a stirred solution of <strong>[88139-91-7](5-bromopyridin-2-yl)methanol</strong> (2 g, 10.63 mmol) in dry THF (10 mL) at O C, was added NaH (60%, 0.85 1 g, 21.2?7 mmol) and the resulting solution was stirred at O c for 15 min. Methyliodide (1.52 g, 10.63 mmol) was added at Oc and the resulting reaction mixture was stirred at rt for 1 h. The progress of the reaction was monitored by TLc. After complete consumption of starting material, the reactionmixture was quenched with ice and extracted with ethyl acetate. The combined organie layers were dried oyer Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography to afford the title compound (1 g, 47.2%).
425 mg
Under ice-cooling, sodium hydride (117 mg, 60%, dispersed in liquid paraffin) was added to a solution of 5-bromo-2-pyridine methanol (500 mg) in N,N-dimethyl formamide (5.0 mL), followed by stirring for 15 minutes, and methyl iodide (202 muL) was added thereto, followed by stirring for 1 hour. Ethyl acetate was added to the reaction mixture, then, the resultant product was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residues were purified by silica gel column chromatography (hexane:ethyl acetate=1:0?2:1), whereby 5-bromo-2-(methoxy methyl)pyridine (425 mg) was obtained
tert-butyl 5-(6-(hydroxymethyl)pyridin-3-yl)isoindoline-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium phosphate; dichloro[1,1?-bis[bis(1,1-dimethylethyl)phosphino]ferrocene-P,P?]palladium; In ethanol; water; at 100℃; for 0.5h;Sealed tube; Inert atmosphere;
To a 25 mL microwave vial with a stir bar was added tert-butyl 5-(4,4,5,5- tetramethyl- 1,3 ,2-dioxaborolan-2-yl)isoindoline-2-carboxylate (260 mg, 0.75 mmol), (5- bromopyridin-2-yl)methanol (212 mg, 1.13 mmol), 1,1 ?-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (49 mg, 0.075 mmol), and K3P04 (480 mg, 2.3 mmol). The vial was sealed, and then EtOH (4 ml) and water (2 ml) were added. The mixture was flushed with nitrogen, and then heated to 100C for 30 minutes. LC showed very good reaction. The reaction was diluted with 1 mL of water, and the organic layer was diluted with EtOAc (5 mL). The crude solution was sucked out with a syringe. The solution was evaporated on a rotavapor, andthe residue was dissolved in DCM and injected onto a 24G ISCO column. The desired productwas isolated by MPLC with hexane and EtOAc gradient. The product was eluted at about 100%EtOAc. It was a yellow solid. LC-MS [M+1]: 327.2
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); In N,N-dimethyl-formamide; at 80℃; for 7.5h;Inert atmosphere;
Preparation of 6-(hydroxymethyl)nicotinonitrile (17A). A mixture of 5-bromo-2-hydroxymethylpyridine (4.90 g, 26.1 mmol), S-phos dicyclohexyl(2',6'-dimethoxy-[l,r-biphenyl]-2-yl)phosphine (250 mg, 0.609 mmol), zinc cyanide (1.90 g, 16.2 mmol), and tris(dibenzylideneacetone) dipalladium (250 mg, 0.273 mmol) in DMF (5.5 mL) was degassed with a stream of Ar passing through the mixture for 1 minute. The mixture was heated at 80 C under N2. After 4.5 hours, a second batch of the catalysts were prepared by mixing S-phos dicyclohexyl(2',6'-dimethoxy-[l, l'-biphenyl]-2- yl)phosphine (250 mg, 0.609 mmol) and tris (dibenzylideneacetone) dipalladium (250 mg, 0.273 mmol) in DMF (2 mL) under N2. The mixture was stirred at 35 C for 2 minutes before it was added to the reaction mixture. After an additional 3 hours, water (0.5 mL) was added. The mixture was stirred for 1.5 hours and was allowed to cool to room temperature and was mixed with silica gel. The solvents were removed at 50 C. The solids were purified by chromatography on silica using EtOAc in heptane (20-50%) as eluent to give 6- (hydroxymethyl)nicotinonitrile (17A) as a white powder (1.38 g). MS m/z = 135 [M+H]+. 'HNMR (400 MHz, CDC13) delta 8.85 (s, IH), 7.97 (dd, J=1.96, 8.02 Hz, IH), 7.47 (d, J=8.22 Hz, IH), 4.86 (s, 2H), 2.61-3.26 (m, IH).
With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 110℃; for 2h;Inert atmosphere;
(5-bromopyridin-2-yl)methanol (75.0 g, 399.0 mmol, 1.0 equiv), zinc cyanide (141.0 g, 1.197 mol, 3.0 equiv) and tetrakis(triphenylphosphine)palladium(0) (46.1 g, 39.9 mmol, 0.1 equiv) were dissolved in N,N-dimethylformamide (750.0 mL, 1 ,0 mL/g) and degassed with nitrogen for 30 minutes. The reaction mixture was heated at 110 C for 2 h. LCMS indicated formation of the product. After completion of the reaction, the mixture was allowed to cool to room temperature, diluted with water (700 mL) and extracted with ethyl acetate (3 x 700 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was adsorbed onto a plug of silica gel (230-400 mesh) and purified through a Biotage lsolera-one pre-packed silica gel column, eluting with a gradient of 40% ethyl acetate in hexane to provide 6-(hydroxymethyl)nicotinoniirile as white solid. H NMR (400 MHz, DMSO-) delta 8.93 (dt, J = 1.8, 0.8 Hz, IH), 8,32 - 8.28 (m, IH), 7.66 (dt, J = 8.3, 0.9 Hz, IH), 5.68 (td, J = 5.9, 0.8 Hz, IH), 4,64 (d, J = 5.8 Hz, 2H). MS (ESI, pos. ion) m/z: 135.0 [M+l]
2-(((3,5-bis(trifluoromethyl)phenyl)thio)methyl)-5-bromopyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Methanesulfonyl chloride (5.3 mL, 69.1 mmol) was added dropwise to a solution of 5-bromo-2-hydroxymethylpyridine (Sigma-Aldrich Chemical Company, Inc., St. Louis, MO, USA) (10.0 g, 53.2 mmol) and TEA (11.1 mL, 80.0 mmol) in THF (150 mL) at 0 oC. The mixture was stirred for 1 h. Water was then added and the mixture was extracted with EtOAc (2 x). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give the mesylate as an oil. <strong>[130783-02-7]3,5-bis-trifluoromethyl benzenethiol</strong> (8.9 mL, 53.2 mmol) was dissolved in MeOH (150 mL). Aqueous sodium hydroxide (2 N, 31.9 mL, 63.8 mmol) was added and then the mixture was stirred for 5 min. The mesylate was added as a suspension in MeOH (40 mL) and the mixture was stirred for 1 h at RT before the MeOH was removed in vacuo. The resulting residue was partitioned between water and EtOAc, the layers were separated, and the aqueous layer was extracted with EtOAc (1 x). The combined extracts were dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give 2-(((3,5-bis(trifluoromethyl)phenyl)thio)methyl)-5-bromopyridine (34a) (22.3 g, 101% yield) as an oil. MS m/z = 416/418 [M+H]+. 1H NMR (400 MHz, CDCl3) ^ ppm 8.59 (s, 1 H) 7.73 - 7.79 (m, 3 H) 7.63 (s, 1 H) 7.26 (d, J = 8.02 Hz, 1 H) 4.29 (s, 2 H).
(5-(cyclohex-1-en-1-yl)pyridin-2-yl)methanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; palladium diacetate; In tetrahydrofuran; water; at 40℃; for 24h;Inert atmosphere;
To a dry flask was added (5-bromopyridin-2-yl)methanol (1.128 g, 6 mmol), Pd(0Ac)2 (67.36 mg, 0.30 mmol), Sphos (246.4 mg, 0.6 mmol), 1- cyclohexene-l-yl-boronic acid (1.134 g, 9 mmol), K3PO4 (2.547 g, 12 mmol) . The mixture was backflushed with argon (3X), and 55 ml THF and 0.22 ml water were added. The mixture was stirred at 40 °C for 24 h. The reaction mixture was poured onto water and extracted with EtOAc (3X). The combined organic layer was washed with brine, dried with Na2S04, concentrated under vacuum and purified by chromatography providing (5-(cyclohex-l-en-l-yl)pyridin-2-yl)methanol (1.08 g, 95percent yield) as a yellowish solid. NMR (300 MHz, cdch) delta 8.54 (s, 1H), 7.65 (dd, J= 8.1, 2.2 Hz, 1H), 7.22 (d, J= 8.1 Hz, 1H), 6.20 - 6.10 (m, 1H), 4.74 (s, 2H), 2.44 - 2.33 (m, 2H), 2.27 - 2.17 (m, 2H), 1.85 - 1.74 (m, 2H), 1.73 - 1.62 (m, 2H).
(5-(6-(trifluoromethyl)pyrazin-2-yl)pyridin-2-yl)methanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
Stage #1: (5-bromopyridin-2-yl)methanol; bis(pinacol)diborane With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 90℃; for 2h; Inert atmosphere;
Stage #2: 2-chloro-6-(trifluoromethyl)pyrazine With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate In 1,4-dioxane; water at 90℃; for 18h; Inert atmosphere;
(5-(6-(Trifluoromethyl)pyrazin-2-yl)pyridiri-2-yl)methanol INTF45
A suspension of (5-bromopyridin-2-yl)methanol (1 g, 5.32 mmol), Bispin (1 .5 g, 5.91 mmol) and KOAc (1 .6 g, 16.0 mmol) in dioxane (20 ml.) was heated to 30 °C then degassed (N2). PdCl2(dppf)-CH2Cl2 (0.217 g, 0.266 mmol) was added and the reaction mixture heated to 90 °C for 2 hrs. The reaction mixture was cooled to 40 °C whereupon 2-chloro-6- (trifluoromethyl)pyrazine (0.97 g, 5.32 mmol), CS2CO3 (3.47 g, 10.6 mmol) and water (5 ml.) were added. The mixture was degassed (N2), then PdCl2(dppf)-CH2Cl2 (0.217 g, 0.266 mmol) was added and the mixture was again degassed (N2). The reaction mixture was then heated to 90 °C for 18 hrs. The reaction mixture was part concentrated (to approx. 5 ml.) then taken up with water (20 ml.) and EtOAc (50 ml.) and passed through celite, eluting with EtOAc (20 ml_). The phases were then diluted with water (20 ml.) and partitioned. The organic phase was washed with brine (30 ml_), dried (Na2S04), filtered and concentrated onto silica (5 g). The crude product was purified by chromatography on silica (40 g cartridge, 0-100% EtOAc /iso- hexanes) to afford (5-(6-(trifluoromethyl)pyrazin-2-yl)pyridin-2-yl)methanol (980 mg, 3.76 mmol, 71 % yield) as an off-white solid. Rt 1 .38 min (H PLC, acidic); m/z 256 (M+H)+(ES+);1H N MR (500 MHz, DMSO-de) d 9.69 (s, 1 H), 9.28 (d, J = 2.3 Hz, 1 H), 9.20 (s, 1 H), 8.56 (dd, J = 8.2, 2.3 Hz, 1 H), 7.70 (d, J = 8.2 Hz, 1 H), 5.59 (t, J = 5.8 Hz, 1 H), 4.67 (d, J = 5.8 Hz, 2H).
(5-(4-(methylsulfonyl)phenyl)pyridin-2-yl)methanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36%
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate In 1,4-dioxane; water at 100℃; Inert atmosphere;
1 Step 1: (5-(4-(methylsulfonyl)phenyl)pyridin-2-yl)methanol
To a stirred solution of (5-bromopyridin-2-yl)methanol (420 mg, 2.6 mmol) and 4,4,5,5-tetramethyl- 2-(4-(methylsulfonyl)phenyl)-1 ,3,2-dioxaborolane (0.66 g, 2.7 mmol) in dry dioxane (4 ml_), a solution of cesium carbonate (1 .39 g, 4.3 mmol) in water (1 mL) was added at RT. The resulting mixture was flushed with nitrogen for 10 min. Then Tetrakis(triphenylphosphine)pailadium(0) (49 mg, 0.04 mmol) was added and the mixture was flushed again with nitrogen. The reaction mixture was stirred overnight at 100 °C. After completion of the reaction, the reaction mixture was filtered through celite pad and the filtrate was concentrated under vacuum. The resulting crude product was purified by flash chromatography (Eluent: 7%MeOH in DCM) to afford the title compound. Yield: 36.0% (250 mg, white solid). 1H NMR (400 MHz, DMSO-de): d 8.89 (s, 1 H), 8.19 (t, J = 10.4 Hz, 1 H), 8.01 (d, J = 9.6 Hz, 4H), 7.61 (d, J = 10.4 Hz, 1 H), 5.51 (t, J = 7.6 Hz, 1 H), 4.66 (d, J = 9.6 Hz, 2H), 3.27 (s, 3H). LCMS: (Method A) 264.2 (M+H), Rt.0.91 min, 90.2% (Max).
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