* 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; calcium chloride In tetrahydrofuran; methanol at 0℃;
To a cooled (0 °C) solution of 24 (4.0 g, 23.3 mmol) and CaCl2 (10.3 g, 93.2 mmol) in dry MeOH-THF (2 : 1, 30 mL) was added portionwise NaBH4 (1.8 g, 46.6 mmol). After cooling to 0 °C, water was added to quench the reaction. The solvent were removed by evaporation and the residue was dissolved in water and extracted with CHCl3. The extracts was dried over MgSO4 and concentrated by evaporation to give 25 (3.3 g, 98 percent) as a white solid.
87%
With sodium tetrahydroborate; calcium chloride In tetrahydrofuran; methanol at 0 - 20℃; for 48 h;
Compound 6 was prepared according to a modified procedure (Comba, P., et al. inorg. Chem. 52, 6481-6501 (2013)). To a mixture of methanol (24 ml) and tetrahydrofurane (14 ml) were added 5 (4.1 g, 23.87 mmol) and calcium chloride (10.5 g, 95.48 mmol). The reaction mixture was cooled to 0 °C. Then, sodium borohydride (1.8 g, 47.74 mmol) was added portionwise. The resulting mixture was stirred at room temperature for 24 h. Then, the same amounts of methanol, tetrahydrofurane, calcium chloride, and sodium borohydride were added following the same procedure, and the reaction mixture was stirred for 24 h. After this time, water (80 ml) was added to the reaction mixture, which was stirred for 2 h. The product was extracted with EtOAc (3 χ 180 ml). The combined organic layer was washed with brine (100 ml), dried over MgS04 and concentrated to dryness under reduced pressure to afford 6 (3.0 g, 87percent) as a pale white solid. XH N MR (300 MHz, CDCI3): δ 8.38 (d, J = 5.5 Hz, 1H), 7.34 (s, 1H), 7.18 (dd, J = 5.5, 2.0 Hz, 1H), 4.71 (s, 2H), 4.19 (br s, 1H).13C N MR (75 M Hz, CDCIs): δ 161.6, 149.5, 145.0, 122.8, 121.1, 64.2. H RMS (ESI-TOF) calcd. for C6H6CIN NaO+ [M+Na]+ 166.0036, found: 166.0028.
Reference：
[1] Chemical Communications, 2009, # 20, p. 2848 - 2850
[2] Bulletin of the Chemical Society of Japan, 2015, vol. 88, # 6, p. 784 - 791
[3] Synthetic Communications, 2005, vol. 35, # 24, p. 3187 - 3190
[4] Inorganic Chemistry, 2013, vol. 52, # 11, p. 6481 - 6501
[5] Angewandte Chemie - International Edition, 2017, vol. 56, # 23, p. 6483 - 6487[6] Angew. Chem., 2017, vol. 129, # 23, p. 6583 - 6587,5
[7] Patent: WO2017/102934, 2017, A1, . Location in patent: Page/Page column 23
[8] Heterocycles, 2000, vol. 53, # 4, p. 797 - 804
[9] Patent: US2004/186114, 2004, A1, . Location in patent: Page/Page column 61; 62; 64
[10] Patent: US5891889, 1999, A,
2
[ 1121-76-2 ]
[ 420-37-1 ]
[ 63071-10-3 ]
Yield
Reaction Conditions
Operation in experiment
43%
Stage #1: at 20℃; for 2 h; Stage #2: With ammonium peroxodisulfate In methanol; water for 1 h; Heating / reflux
4-Chloro-2-(hydroxymethyl)pyridine : A solution of 4-CHLOROPYRIDINE ASOXIDE (5 G, 38.6 MMOL) and TRIMETHYLOXONIUM TETRAFLUOROBORATE (5.94 G, 40.1 MMOI) in CH2CL2 (115 mL) was stirred for two hours at ambient temperature. The solvent was evaporated and the residue taken up in MeOH (115 mL) and heated to near boiling. Ammonium persulfate (1.76 G, 7.72 MMOL) dissolved in H2O (7.7 mL) was added and the mixture was heated to reflux for 30 min. A second portion of ammonium persulfate (0.88 G) in H2O (3.9 mL) was added and the mixture was refluxed for another 30 min. The solvent was evaporated and the residue was partitioned between CHZCTZ and aqueous Na2CO3 (10percent w/v). The organic layer was washed with H2O, dried over MgSO4 and evaporated leaving 2.4 G (43percent) of the title compound. 1H NMR (CDC13) 8 8.20 (d, 1H, J=5. 0 Hz, H-6); 7.31 (s, 1H, H-3); 7.04 (d, 1H, J=5. 0 Hz, H-5); 5.46 (s, LH, OH); 4.61 (s, 2H, CH2).
Reference：
[1] Patent: WO2005/12323, 2005, A2, . Location in patent: Page/Page column 46
[2] Journal of Medicinal Chemistry, 1998, vol. 41, # 11, p. 1777 - 1788
[3] Patent: EP1422228, 2004, A1, . Location in patent: Page 199
3
[ 3678-63-5 ]
[ 63071-10-3 ]
Yield
Reaction Conditions
Operation in experiment
18%
Stage #1: With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; for 1.5 h; Stage #2: at 100℃; for 1 h; Stage #3: With sodium hydroxide; water In methanol at 0 - 20℃; for 1.5 h;
Manufacturing Example 51-1-1 (4-Chloro-pyridin-2-yl)-methanol; To a mixture of 4-chloro-2-picoline (1.0 g, 7.84 mmol) and dichloromethane (20 mL), was added m-chloroperbenzoic acid (3.5 g, 13.2 mmol) on an ice bath, which was stirred for 1.5 hours at room temperature. Water and sodium hydrogencarbonate were added to the reaction, followed by extraction with dichloromethane. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. Acetic anhydride (20 mL) was added to the residue obtained by concentrating the filtrate under a reduced pressure, and this was stirred for 1 hour at 100° C. The reaction mixture was cooled to room temperature and concentrated under a reduced pressure. A 5 N aqueous sodium hydroxide solution (1.57 mL, 7.87 mmol) was added to a mixture of the resulting residue and methanol (20 mL) on an ice bath, which was stirred for 1.5 hours at room temperature. Water was added to the mixture, which was then extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=6:1) to obtain the title compound (200 mg, 18percent).1H-NMR Spectrum (CDCl3) δ (ppm): 4.76 (2H, s), 7.23-7.25 (1H, m), 7.32-7.33 (1H, m), 8.46 (1H, d, J=5.6 Hz).
Reference：
[1] Patent: US2009/82403, 2009, A1, . Location in patent: Page/Page column 99
[2] Journal of Medicinal Chemistry, 1983, vol. 26, # 2, p. 218 - 222
[3] Pharmaceutical Bulletin, 1953, vol. 1, p. 293,296
[4] Pharmaceutical Bulletin, 1953, vol. 1, p. 293,296
4
[ 63071-06-7 ]
[ 63071-10-3 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2000, vol. 48, # 10, p. 1514 - 1518
[2] Patent: US2007/105904, 2007, A1, . Location in patent: Page/Page column 98
Stage #1: for 0.5 h; Reflux Stage #2: for 2.5 h; Reflux
Concentrated sulfuric acid (0.25 mL) was added to a solution of 4-chloropyridine hydrochloride (3.00 g) in methanol (25 mL), followed by refluxing for 0.5 hours. An aqueous solution (25 mL) of ammonium persulfate (12.2 g) was added to the reaction mixture, followed by refluxing for 2.5 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. A sodium carbonate aqueous solution was added to the obtained residues, and the resultant product was extracted with ethyl acetate. The organic layer was 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=1:1→0:1), whereby (4-chloro pyridin-2-yl)methanol (1.90 g) was obtained
Reference：
[1] Organic and Biomolecular Chemistry, 2014, vol. 12, # 30, p. 5781 - 5788
12
[ 98-98-6 ]
[ 63071-10-3 ]
Reference：
[1] Inorganic Chemistry, 2013, vol. 52, # 11, p. 6481 - 6501
[2] Bulletin of the Chemical Society of Japan, 2015, vol. 88, # 6, p. 784 - 791
13
[ 931-19-1 ]
[ 63071-10-3 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2000, vol. 48, # 10, p. 1514 - 1518
14
[ 5470-66-6 ]
[ 63071-10-3 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2000, vol. 48, # 10, p. 1514 - 1518
Reference：
[1] Yakugaku Zasshi, 1957, vol. 77, p. 11,13[2] Chem.Abstr., 1957, p. 8745
20
[ 63071-10-3 ]
[ 22282-65-1 ]
Reference：
[1] Patent: WO2005/12323, 2005, A2,
21
[ 63071-10-3 ]
[ 63071-13-6 ]
Yield
Reaction Conditions
Operation in experiment
59%
With manganese(IV) oxide In chloroform for 2.5 h; Reflux
A suspension of 25 (2.0 g, 13.9 mmol) and MnO2 (15 g) in dry CHCl3 (24 mL) was refluxed for 2.5 hr. After removal of MnO2 by filtration, the filtrate was concentrated by evaporation to give 26 (1.2 g, 59 percent) as a pale yellow solid.
425 mg
With manganese(IV) oxide In ethyl acetate for 3.5 h; Reflux
Manganese dioxide (3.03 g) was added to a solution of (4-chloropyridin-2-yl)methanol (1.00 g) obtained in Reference Example 21-7 (1) in ethyl acetate (20 mL), followed by refluxing for 3.5 hours. The reaction mixture was cooled to room temperature, the insoluble materials were filtered off, and the solvent was distilled off under reduced pressure. The obtained residues were purified by silica gel column chromatography (hexane:ethyl acetate=9:1→1:1), whereby 4-chloropicolinic aldehyde (425 mg) was obtained
Reference：
[1] Chemical Communications, 2009, # 20, p. 2848 - 2850
[2] Inorganic Chemistry, 2013, vol. 52, # 11, p. 6481 - 6501
[3] Synthesis, 1996, # 8, p. 991 - 996
[4] Tetrahedron, 1997, vol. 53, # 24, p. 8257 - 8268
[5] Bulletin of the Chemical Society of Japan, 2015, vol. 88, # 6, p. 784 - 791
[6] Yakugaku Zasshi, 1957, vol. 77, p. 11,13[7] Chem.Abstr., 1957, p. 8745
[8] Patent: WO2007/25307, 2007, A2, . Location in patent: Page/Page column 306
[9] Patent: US2016/168139, 2016, A1, . Location in patent: Paragraph 0983; 0986; 0987
[10] Patent: WO2008/106139, 2008, A1, . Location in patent: Page/Page column 475
Reference：
[1] Inorganic Chemistry, 2013, vol. 52, # 14, p. 8131 - 8143
[2] Bulletin of the Chemical Society of Japan, 2015, vol. 88, # 6, p. 784 - 791
With manganese(IV) oxide; In chloroform; for 2.5h;Reflux;
A suspension of 25 (2.0 g, 13.9 mmol) and MnO2 (15 g) in dry CHCl3 (24 mL) was refluxed for 2.5 hr. After removal of MnO2 by filtration, the filtrate was concentrated by evaporation to give 26 (1.2 g, 59 %) as a pale yellow solid.
With manganese(IV) oxide; In chloroform; for 1.5h;Heating / reflux;
[00324] A suspension OfMnO2 (7.3 g, 84 mmol) and (4-chloro-pyrmdin-2-yl)methanol(1 g, 7 mmol) in CHCl3 was heated to refulx for 90 minutes. The mixture was filtered though a layer of Celite and concentrated in vacuo to afford 520 mg of 4-chloropicolinaldehyde as a white solid. HPLC 1.8 minutes and MS 142 as M=I peak.
425 mg
With manganese(IV) oxide; In ethyl acetate; for 3.5h;Reflux;
Manganese dioxide (3.03 g) was added to a solution of <strong>[63071-10-3](4-chloropyridin-2-yl)methanol</strong> (1.00 g) obtained in Reference Example 21-7 (1) in ethyl acetate (20 mL), followed by refluxing for 3.5 hours. The reaction mixture was cooled to room temperature, the insoluble materials were filtered off, and the solvent was distilled off under reduced pressure. The obtained residues were purified by silica gel column chromatography (hexane:ethyl acetate=9:1?1:1), whereby 4-chloropicolinic aldehyde (425 mg) was obtained
With manganese(IV) oxide; In chloroform; for 1.5h;Heating / reflux;
[0360] A suspension OfMnO2 (7.3 g, 84 mmol) and (4-chloro-pyrindin-2-yl)methanol(1 g, 7 mmol) in CHCl3 was heated to refulx for 90 minutes. The mixture was filtered though a layer of Celite and concentrated in vacuo to afford 520 mg of 4-chloropicolinaldehyde as a white solid. HPLC 1.8 minutes and MS 142 as M=I peak.
Example 4 (4-chloro-pyridin-2-yl)-methanol To a solution of ethyl 4-chloropicolinate (11.14 g, 60 mmol) in abs. ethanol (450 ml) was added, with stirring at 0 C., sodium borohydride (3.63 g, 96 mmol). The mixture was stirred at for one hour, and another 30 minutes at room temperature. After heating to 70 C. for one hour, water was added cautiously at room temperature. The pH-value was adjusted to 5.5 with aqueous HCl (4M). After stirring for 14 hours, the volatiles were removed in vacuo. Water was added, and the mixture was extracted with dichloromethane (2*200 ml each). The organic phase was dried over sodium sulfate, filtered, and evaporated to yield (4-chloro-pyridin-2-yl)-methanol as a clear yellow oil. C6H6ClNO, Fw 143.57. 1H NMR (360 MHz, CDCl3): delta=8.33 (d, J=5.4 Hz, 1H); 7.28 (d, J=1.6 Hz, 1H); 7.12 (dd, J=5.4, 1.6 Hz, 1H); 4.66 (s, 2H); 3.98 (br s, 1H).
With 1H-imidazole; In DMF (N,N-dimethyl-formamide); at 20℃; for 0.25h;
2-(((TERT-BUTYIDIMETHYLSILYL) OXY) METHYL)-4-CHLOROPYRIDINE : To a mixture of 4-chloro-2- (hydroxymethyl) pyridine (360 mg, 2.51 mmol) and imidazole (684 mg, 10.04 MMOL) in DMF (2 mL) was added'BuMezSiCl (452 mg, 3.0 MMOL) in several portions at room temperature. The mixture was stirred for 15 min and extracted with ether (50 mL). The extract was washed with water (5 mL x 3), dried over MGSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with CHZCL2 to give the title compound (600 mg, 93%) as a colourless OIL. 1H NMR (CDCl3) 8 8.30 (d, 1H,---5. 3 Hz, H-6); 7.44 (d, 1H, J=1.1 Hz, H-3); 7.07 (dd, 1H, J1=5. 3, J2=2.0 Hz, H-5); 4.73 (s, 2H, CH2) ; 0.88 (s, 9H); 0.05 (s, 6H); 13C NMR (CDCL3) 8 163.7 (C-2), 150.0 (C-6), 145.3 (C-4), 122.6 (C-3), 120.8 (C-5), 65.9 (CH2), 26.3 ((CH3)3C), 18.7 ((CH3)3C),-4. 6 ( (ME) 2SI).
Manufacturing Example 51-1-1 (4-Chloro-pyridin-2-yl)-methanol; To a mixture of 4-chloro-2-picoline (1.0 g, 7.84 mmol) and dichloromethane (20 mL), was added m-chloroperbenzoic acid (3.5 g, 13.2 mmol) on an ice bath, which was stirred for 1.5 hours at room temperature. Water and sodium hydrogencarbonate were added to the reaction, followed by extraction with dichloromethane. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. Acetic anhydride (20 mL) was added to the residue obtained by concentrating the filtrate under a reduced pressure, and this was stirred for 1 hour at 100 C. The reaction mixture was cooled to room temperature and concentrated under a reduced pressure. A 5 N aqueous sodium hydroxide solution (1.57 mL, 7.87 mmol) was added to a mixture of the resulting residue and methanol (20 mL) on an ice bath, which was stirred for 1.5 hours at room temperature. Water was added to the mixture, which was then extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=6:1) to obtain the title compound (200 mg, 18%).1H-NMR Spectrum (CDCl3) delta (ppm): 4.76 (2H, s), 7.23-7.25 (1H, m), 7.32-7.33 (1H, m), 8.46 (1H, d, J=5.6 Hz).
a 2-[(2-Hydroxymethyl-pyridin-4-yl)-methyl-amino]-ethanol A mixture of (4-chloro-pyridin-2-yl)-methanol (20.0 g, 139 mmol) and 2-methylaminoethanol (11.7 ml, 146 mmol) is stirred for 1 h at 140 C. After cooling to room temperature the viscous oil is employed without additional purification for the synthesis described in step b).
With sodium hydroxide; In aqueous dimethylamine; water;
Example 7 (4-dimethylamino-pyridin-2-yl)-methanol A solution of (4-chloro-pyridin-2-yl)-methanol (6.68 g, 47 mmol) in aqueous dimethylamine (30 ml, 7.9 M, 5 equiv.) was heated to 155 C. for 14 hours in a pressure reactor. After evaporation of the volatiles, the residue was taken up in water and the pH adjusted to a value of 8.5 with sodium hydroxide (4M in water). The mixture was concentrated on a rotary evaporator, and the beige solid was extracted with chloroform in a Soxhlet apparatus for 16 hours. The extract was evaporated, and the crude product was recrystallized from methanol/diethyl ether. C8H12N2O, Fw 152.20. 1H NMR (360 MHz, CDCl3): delta=7.88 (d, J=6.8 Hz, 1H); 6.76-6.60 (m, 2H); 4.67 (s, 2H); 3.12 (s, 6H).
Example 9a (4-pyrrol-1-yl-pyridin-2-yl)-methanol (4-Chloro-pyridin-2-yl)-methanol (1.71 g, 11.9 mmol) was suspended in 20 ml 1,3-Dimethyl-2-imidazolidinone (DMEU) under an inert atmosphere at 0 C. Pyrrol (1.97 ml, 28.4 mmol) and potassium tert.-butylate (3.2 g, 28.5 mmol) were added, and the mixture was stirred for 6 hours at 105 C. After cooling to room temperature, the reaction mixture was stirred for additional 12 hours at room temperature. After evaporation of the volatiles, the residue was partitioned between water and diethyl ether at pH 9. The combined organic extracts were dried over sodium sulfate, filtered, and evaporated to yield the crude product. After column chromatography (silica gel, hexane/ethyl acetate 1:2), (4-pyrrol-1-yl-pyridin-2-yl)-methanol was obtained as brownish powder. C10H10N2O, Fw 174.20. 1H NMR (360 MHz, CDCl3): delta=8.43 (d, J=5.5 Hz, 1H); 7.22 (s, 1H); 7.03-7.15 (m, 3H); 6.25-6.38 (m, 2H); 4.73 (s, 2H); 2.95 (s, br, 1H, OH).
With triethylamine;dmap; In dichloromethane; at 18 - 25℃; for 0.5h;
In a 50-mL round-bottomed flask was dissolved <strong>[63071-10-3](4-chloropyridin-2-yl)methanol</strong> (4.6 g, 32.04 mmol) and tosyl chloride (6.72 g, 35.24 mmol) in DCM (10 mL) to give a colorless solution. To the mixture was added TEA (8.93 mL, 64.08 mmol) and DMAP (0.05 g). The reaction was stirred at RT for 0.5h, and washed with sat NH4CI (20 mL). The organic layer was dried (Na2SO4), filtered, and concentrated to give crude (4-chloropyridin-2-yl)methyl 4- methylbenzenesulfonate. To this product was added methyl 4-hydroxybenzoate (3.07 g, 20.15 mmol), K2CO3 (11.14 g, 80.60 mmol), and MeCN (100 mL). The reaction was stirred at 80 0C for 4h. The solvent was removed under reduced pressure, and to the residue was added water (50 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (2 X 50 mL), and the combined organic layers were dried (Na2SO4), and concentrated to give crude methyl 4-((4-chloropyridin-2-yl)methoxy)benzoate. To this material was added LiOH (0.828 g, 34.57 mmol) and MeOH (100 mL). The reaction mixture was heated to 70 0C overnight and the solvent was removed under reduced pressure. The residue was diluted with water (50 mL) and concentrated HCl (12N) was added dropwise to adjust the pH to 1. The precipitate was collected by filtration to yield the title compound. 1H NMR (DMSO-ddelta) 65.28 (s, 2 H), 7.14 (d, 2 H), 7.54 (dd, 1 H), 7.66 (d, 1 H), 7.91 (d, 2 H), 8.58 (d, 1 H), 12.69 ( br s, 1 H).
Example 307 Synthesis of (4-chloropyridin-2-yl)methyl 4-methylbenzenesulfonate. Sodium hydride (44 g, 60%, 1.096 mol) was added to a cooled (0 C.) solution of <strong>[63071-10-3](4-chloropyridin-2-yl)methanol</strong> (80 g, 548 mmol) in THF (1500 mL) at 0 C. The mixture was stirred at 0 C. for 1 h, and tosyl chloride (104 g, 548 mmol) was added. After stirring at 0 C. for another 3 h, the mixture was quenched with H2O (50 mL), and extracted with ethyl acetate (120 mL*3), the combined organic layers were washed with brine, dried over with anhydrous magnesium sulphate, filtered, and concentrated to afford (4-chloropyridin-2-yl)methyl 4-methylbenzenesulfonate (162 g, crude) as a brown oil which was used in the next step without purification. ESI-MS [M+H]+: 296.1.
A mixture of intermediate 6a (0.0007 mol) and 4-chloro-2-pyridinemethanol (0.0007 mol) in HCI/dioxane 4N (0.0001 mol), CH3CN (2.5 ml) and EtOH (1 ml) was stirred at 65C for 18 hours. The mixture was cooled at room temperature, diluted with CH2CI2 and washed with K2CO3 10% aqueous solution. The organic layer was decanted, dried (MgSO4), filtered and the solvent was evaporated till 15ml. The residue was filtered off and dried, yielding 0.168 g (64%) of compound 24 ( M. P.: 1 15C).
A mixture of intermediate 6b (0.0007 mol) and 4-chloro-2-pyridinemethanol (0.0007 mol) in HCI/dioxane 4N (0.0001 mol), CH3CN (2 ml) and EtOH (0.8 ml) was stirred at 65C for 18 hours. The mixture was cooled at room temperature, poured into K2CO3 10% aqueous solution and extracted with CH2CI2. The precipitate was filtered, washed with CH3CN and dried, yielding 0.155 g (53%) of compound 25 ( M. P.: 186C).
A mixture of intermediate 16 (0.0005 mol), 4-chloro-2-pyridinemethanol (0.0005 mol) and HCI/dioxane 4N (0.0001 mol) in CH3CN (1.5ml) and EtOH (0.5ml) was stirred at 65C for 18 hours. HCI (0.2eq) and dioxane 4N (29mul) were added. The mixture was stirred at 65C for 18 hours, then cooled to room temperature, poured out into K2CO3 10% aqueous solution and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (0.18g) was purified by column chromatography over silica gel (eluent: CH2CI2/CH3OH/NH4OH 93/7/0.5; 10mum). The pure fractions were collected and the solvent was evaporated. The residue (0.03g, 14%) was crystallized from CH3CN/DIPE. The precipitate was filtered off and dried, yielding 0.03g (9%) of compound 2 (M. P.: 163C).
With hydrogenchloride; In 1,4-dioxane; acetonitrile; at 65℃; for 18h;
A mixture of intermediate 2 (0.0012 mol), 4-chloro-2-pyridinemethanol (0.0012 mol) and HCI/dioxane 4N (0.0002 mol) in CH3CN (1 OmI) was stirred at 65C for 18 hours, then cooled to room temperature, poured out into K2CO3 10% aqueous solution and extracted with CH2CI2/CH3OH (few). The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (0.52g) was purified by column chromatography over kromasil (eluent: CH2CI2/CH3OH/NH4OH 97/3/0.3 to 91/9/0.9; 3- 5mum). The pure fractions were collected and the solvent was evaporated. The residue <n="87"/>(0.3g, 60%) was crystallized from CH3CN. The precipitate was filtered off and dried, yielding 0.292g (51 %) of compound 14 as a hydrochloric acid salt (.1.52HCI, M. P.: 1100C).
A mixture of intermediate 30 (0.236 mmol), 4-chloro- 2-pyridinemethanol (0.283 mmol) and HCI/dioxane 4M (0.0471 mmol) in acetonitrile (1 ml) and EtOH (0.8 ml) was heated at 65C for 18 hours. The reaction mixture was cooled to room temperature and HCI 3N (0.5ml) was added to complete the reaction at 65C for 18 hours. The reaction mixture was cooled to room temperature, diluted with DCM and quenched with a 10% solution of potassium carbonate. The organic layer was decanted, dried over MgSO4, filtered and evaporated to dryness. The residue was purified by HPLC (H679 - XTerra MSC18 - eluent: CH3CN/NH4CO3 0.5% 20/80 to CH3CN 100). The pure fractions were collected and evaporated to dryness, yielding 41 mg of (37%) of compound 16.
A mixture of intermediate 35 (1.029 mmol), 4-chloro-2-pyridinemethanol (1.235 mmol) and HCI/dioxane 4N (1.235 mmol) in acetonitrile (3 ml) and EtOH (2.4 ml) was heated at 65C for 18 hours. The reaction mixture was cooled to room tempertaure and HCI 3N (2 ml) was added. The reaction mixture was heated at 65C for 4 hours more. The reaction mixture was diluted with EtOAc and quenched with a 10% solution of potassium carbonate. The organic layer was decanted, dried over MgSO4, filtered and evaporated to dryness. The residue was purified by HPLC (3Og SiO2 15/40mum - eluent: DCM/MeOH/NH4OH 90/10/1 ). The pure fractions were collected and evaporated to dryness, yielding 185mg (66%) of intermediate 36.
4-[[(4-chloro-2-pyridinyl)methyl]sulfanyl]aniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
<strong>[63071-10-3](4-chloro-2-pyridinyl)methanol</strong> (3.0 g) was dissolved in methylene chloride (30 ml), DMF (3 droplets) was added to the mixture, thionyl chloride (3.8 ml) was added to the mixture at 0C, and the mixture was stirred for 16 hours at room temperature. The solvent was removed under reduced pressure, and a solution (10.5 ml) of the obtained residue in water was added dropwise to an aqueous solution (76 ml) of 4-aminothiophenol (2.18 g) and sodium hydroxide (2.09 g) in methanol. The mixture was stirred for 1 hour at room temperature, the solvent was removed under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 4-[[(4-chloro-2-pyridinyl)methyl]sulfanyl]aniline (0.60 g). 1H-NMR (200 MHz, CDCl3) delta 3.75 (2H, br), 4.24 (2H, s), 6.52 to 6.60 (3H, m), 7.09 to 7.17 (2H, m), 7.22 to 7.27 (1H, m), 8.27 to 8.41 (1H, m)
[0181] To a solution of the above alcohol (430 mg, 3.0 mmol) in DMF (10 mL) was added NaH (144 mg of a 60% dispersion in mineral oil, 3.60 mmol) and the mixture was then cooled in an ice bath. Benzyl bromide (437 uL, 3.60 mmol) was then added and the mixture was stirred at room temperature for 3 h. After normal aqueous work-up and short column chromatographic purification, 600 mg of desired benzyl ether was obtained.
4-Chloro- 2-pyridinemethanol (400 mg, 0.0028 mol) was dissolved in chloroform (24 ml). Thionyl chloride (0.40 ml, 0.0056 mol) and DMF (2 drops) were added. The mixture was stirred 4 hours at 8O0C. The solvent was evaporated. The residue was taken back in MeOH (18 ml) and ethanolamine (1.38 ml, 0.014 mol) was added. The mixture was stirred 4 hours at 800C. The solvent was evaporated. The residue was poured out onto water and extracted with EtOAc. The organic layer was separated, washed with a saturated solution of sodium hydrogen carbonate, dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (40-63mum) (eluent: DCM/MeOH 85/15). The pure fractions were collected and the solvent was evaporated, yielding 310 mg (60%) of intermediate 64 as an orange oil.
With triethylamine; In dichloromethane; at 0 - 20℃; for 0.5h;
Method XXVI(4-chloropyridin-2-yl)methyl methanesulfonateTo a solution of <strong>[63071-10-3](4-chloropyridin-2-yl)methanol</strong> (3 g, 20.90 mmol) in dichloromethane (60 ml) was added triethylamine (2.90 mL, 20.90 mmol) and methanesulfonyl chloride (1.617 mL, 20.90 mmol) at 0 C. The reactionmixture was stirred at 20 C for 30 min. The reaction was quenched with addition of water. The reaction mixture was extracted with dichloromethane and the organic layer dried (magnesiumsulphate) and evaporated.Purification with flash silica chromatography with elution gradient ethylacetate in petroleumeter 20 to 40%. Fractions containing product was evaporated to give the title compound (4.13 g, 89%). m/z (APCI) (M+H)+ 222.
280 mg
With triethylamine; In dichloromethane; at 0 - 25℃; for 12h;
To a solution of (4-chloro-2-pyridyl)methanol (240.0 mg, 1.67 mmol, CAS RN 63071-10-3) in DCM (5 mL) was added TEA (0.48 mL, 3.34 mmol) , the reaction was cooled to 0C and methanesulfonyl chloride (0.27 mL, 3.49 mmol) was added dropwise. The reaction was stirred at 25 C for 12 h. The reaction was quenched with 0, extracted three times with DCM (10 mL) and the combined organic layers were dried over Na2S04 and concentrated to yield 280 mg of a red oil which was used in the next step without further purification.
Intermediate 34 1 -(3-bromo-4-{ r(4-chloro-2- pyridinyl)methyl1oxy)phenyl)ethanoneTo a stirred solution of <strong>[63071-10-3](4-chloro-2-pyridinyl)methanol</strong> (Commercial eg Aldrich) (0.2g) in THF (5ml) were added 1 -(3-bromo-4-hydroxyphenyl)ethanone (0.3g) and triphenylphosphine (0.547g). This was stirred for 10 min before cooling and adding slowly DEAD (0.363g). This was stirred for 16h. The reaction mixture was partitioned between water and ethyl acetate. The aqueous was reextracted with ethyl acetate and the combined organics were washed with brine, dried over sodium sulfate and concentrated in vacuo. This was purified through silica eluting with 0-35% ethyl acetate in hexane to give the title compound, 0.30gMass Spec: [MH]+= 340, 342
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; for 16h;
Intermediate 34, 1-(3-bromo-4-[(4-chloro-2-pyridinyl)methyl]oxy}phenyl)ethanone To a stirred solution of <strong>[63071-10-3](4-chloro-2-pyridinyl)methanol</strong> (Commercial eg Aldrich) (0.2 g) in THF (5 ml) were added 1-(3-bromo-4-hydroxyphenyl)ethanone (0.3 g) and triphenylphosphine (0.547 g). This was stirred for 10 min before cooling and adding slowly DEAD (0.363 g). This was stirred for 16 h. The reaction mixture was partitioned between water and ethyl acetate. The aqueous was reextracted with ethyl acetate and the combined organics were washed with brine, dried over sodium sulfate and concentrated in vacuo. This was purified through silica eluting with 0-35% ethyl acetate in hexane to give the title compound, 0.30 g Mass Spec: [MH]+=340, 342
With N-ethyl-N,N-diisopropylamine; In toluene; at 125 - 140℃; for 2.5h;Inert atmosphere;
Synthesis of fe -butyl 2-(2-(hvdroxymethyl)pyridin-4 ylamino)ethylcarbamate.[0314] To a 40 mL pressure tube equipped with a stir bar was added 4-chloro-2- pyridylmethanol (0.25 g, 1.74 mmol), N,N-diisopropylethylamine (1.52 mL, 8.71 mmol), and toluene (0.925 mL; 8.71 mmol) was added teri-butyl (2- aminoethyl)carbamate (0.55g, 3.50 mmol). The vessel was purged with argon and then placed in an oil bath pre-heated to 125 C. The temperature of the oil bath was increased to 140 C over 30 minutes. After 2 hours, TLC (conditions below) indicated near complete consumption of the starting material. The reaction was cooled to ambient temperature and the toluene layer was decanted. Methanol (15 mL) was added and the mixture was heated to ca. 40 C for 5 minutes to break up the solid residual. After concentrating the mixture down to 1/5 of its original volume, CHCI3 (5 rriL) was added and the residue was loaded onto a 5 cm x 15 cm silica gel column equilibrated with dichoromethane (DCM) + 0.5% triethylamine. Flashchromatography with DCM to DCM/10% Methanol with 0.5% triethylamine provided an inseparable mixture of the compound and starting /eri-butyl (2- aminoethyl)carbamate (1 : 1.4 molar ratio). Rf= 0.38 (15% MeOH/DCM + 0.1% TEA, 254 nm UV). This mixture was used in the next step without further purification. NMR (400 MHz, CD3OD): (9) 7.93 (d, J= 5.6 Hz, 1 H), 6.75 (d, J= 2.4 z, 1 H), 6.48 (dd, J= 6.0, 2.4 Hz, 1 H), 4.54 (s, 2H), 3.66 (s, 1 H), 3.26 (m, 4H), 1.46 (s, 9H); (tert- butyl 2-aminoethylcarbamate) 3.33 (m, 2H), 3.12 (t, J= 6.4 Hz, 2H), 2.71 (t, J= 6.4 Hz, 2H), 1.44 (s, 9H).
With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; for 4h;Reflux;
Preparation of Intermediate 1-17; (4-Amino-2-pyridyl)methanolReagents: (a) acetamide, Pd(OAc)2, Xanthphos, Cs2C03, /?-dioxane, reflux, 4 h (b) KOH,EtOH, reflux.[0244] Step 1. N-[2-(Hydroxymethyl)-4-pyridyl]acetamide. A solution of (4-chloro-2- pyridyl)methanol (1.0 g, 6.89 mmol), acetamide (0.61 g, 10.3 mmol), Pd(OAc)2 (0.075 g, 0.345 mmol), and Xanthphos (0.40 g, 0.689 mmol) in /?-dioxane (20 mL) was stirred at reflux for 4 h. After cooling, the mixture was filtered through Celite with the aid of additional DCM, then concentrated under vacuum. The residue was purified by column chromatography (Si02, MeOH 20% in CH2C12 with 0.1% NH4OH), to give the title compound; 1H NMR (DMSO- 6) delta 10.0 (s, 1H), 8.29 (d, 1H), 7.63 (d, 1H), 7.46 (dd, 1H), 5.41 (t, 1H), 4.49 (d, 1H), 2.08 (s, 3H).
With mu-diiodo-di((eta5-pentamethylcyclopentadienyl)(iodo)iridium); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 20 - 110℃; for 20h;
General procedure: [Cp*IrI2]2 (1 mol %, 0.01 mmol), xantphos (2 mol %,0.02 mmol) and dioxane (2 mL) were stirred shortly in a Schlenk tube at room temperature. Subsequently, 3-pyridinemethanol (2.0 mmol), benzamidine hydrochloride(1.0 mmol), and cesium carbonate (1.0 mmol)were added. The mixture was heated under 110C for 20 h and then cooled down to room temperature. The resulting solution was purified by column chromatography with petroleum ether-ethyl acetate(10 : 1) as an eluent to give 2,4-diphenyl-6-(pyridin-3-yl)-1,3,5-triazine (3a) as a white solid.
With mu-diiodo-di((eta5-pentamethylcyclopentadienyl)(iodo)iridium); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 20 - 110℃; for 20h;
General procedure: [Cp*IrI2]2 (1 mol %, 0.01 mmol), xantphos (2 mol %,0.02 mmol) and dioxane (2 mL) were stirred shortly in a Schlenk tube at room temperature. Subsequently, 3-pyridinemethanol (2.0 mmol), benzamidine hydrochloride(1.0 mmol), and cesium carbonate (1.0 mmol)were added. The mixture was heated under 110C for 20 h and then cooled down to room temperature. The resulting solution was purified by column chromatography with petroleum ether-ethyl acetate(10 : 1) as an eluent to give 2,4-diphenyl-6-(pyridin-3-yl)-1,3,5-triazine (3a) as a white solid.
With silver(l) oxide; In 1,4-dioxane; at 20℃; for 24h;
General procedure: Freshly prepared Ag2O (2.20 mmol) was added at room temperature to a solution of pyridin-2-ylmethanol (1.00 mmol) and 2-iodopropane (2.20 mmol) in 1,4-dioxane (10 mL) and stirred for 24 h. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate. Filtrate was concentrated under vacuum.The resulting material was purified by flash chromatography on a Biotage instrumentusing 4-g flash cartridge and eluted with 12-15% ethyl acetate in hexane to give isopropyl picolinate (2) (65% yield).
Concentrated sulfuric acid (0.25 mL) was added to a solution of 4-chloropyridine hydrochloride (3.00 g) in methanol (25 mL), followed by refluxing for 0.5 hours. An aqueous solution (25 mL) of ammonium persulfate (12.2 g) was added to the reaction mixture, followed by refluxing for 2.5 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. A sodium carbonate aqueous solution was added to the obtained residues, and the resultant product was extracted with ethyl acetate. The organic layer was 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=1:1?0:1), whereby (4-chloro pyridin-2-yl)methanol (1.90 g) was obtained
6-(trifluoromethyl)-3-pyridinylboronic acid[ No CAS ]
[ 63071-10-3 ]
[4-[6-(trifluoromethyl)-3-pyridyl]-2-pyridyl]methanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
With [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(ll) [Pd-118]; sodium carbonate; In 1,4-dioxane; water; at 100℃; for 3h;
To 279 (4-chloro-2-pyridyl)methanol (1.51 g, 10.5 mmol), 280 [6-(trifluoromethyl)-3-pyridyl]boronicacid (1.99 g, 10.5 mmol), 267 sodium carbonate (3.40 g, 32.1 mmol) and 258 1,1?-bis(di-tertbutylphosphino)ferrocenedichloropalladium (Pd-118, 0.70 g, 1.07 mmol) were added 115 1,4-dioxane (50mL) and 52 water (5 mL) and the mixture was stirred at 100 C. for 3 hr. The reaction mixture wasconcentrated under reduced pressure and the obtained residue was purified by silica gel columnchromatography (petroleum ether/ethyl acetate) to give the 281 title compound ( 1.36 g , 5.35 mmol,51%). MS (ESI) m/z 255 (M+H)+
With toluene-4-sulfonic acid; at 150℃; for 0.75h;Microwave irradiation;
A stirred mixture of (4-chloropyridine-2-yl)methanol (200 mg, 1.4 mmol) and p25 toluenesulfonic acid monohydrate (27 mg, 0.14 mmol) in morpholine (0.6 mL, 7.0 mmol) wasirradiated in the microwave at 150C for 45 mm then diluted with EtOAc (10 mL) and washed with water (3 x 10 mL) and brine. The aqueous layers were extracted further with EtOAc (10 mL) and the combined organic extracts were discarded (impure product, 35 mg). The aq. layers were combined and basifiedto pH 14 with 1M aq. NaOH and extracted furtherwithEtOAc (2 x 40 mL). These organic extracts were washed with water at pH 14 and brine then dried (MgSO4) and concentrated in vacuo to give (4-morpholinopyridin-2-yl)methanol V (76 mg, 28%) as a near-colourless solid. 1H NMR (500 MHz, ODd3) O 8.21 (d, J= 6.0 Hz, 1H), 6.66 (d, J= 2.4 Hz, 1H), 6.57 (dd, J=6.0, 2.5 Hz, 1 H), 4.64 (s, 2H), 3.92 - 3.75 (m, 5H), 3.34- 3.23 (m, 4H); LCMS (method B):1.21 mm (195.1, MH).
With diethylamino-sulfur trifluoride; In dichloromethane; at -78℃; for 0.166667h;
To a solution of <strong>[63071-10-3](4-chloropyridin-2-yl)methanol</strong> (1 g, 6.97 mmol) in DCM (40 niL) at -78 C was slowly added diethylaminosulfur trifluoride (2.245 g, 13.93 mmol). The reaction mixture was stirred at -78 C for 10 min. The reaction mixture was quenched with aqueous 10% NaHCC solution and diluted with dichloromethane (50 mL). The organic layer was separated, diluted with dichloromethane, filtered through the celite, dried over Na2S04, filtered, and concentrated under pressure to afford 4-chloro-2-(fluoromethyl)pyridine (0.5 g) as a violet oil. LCMS (ESI) m/e 146.4 [(M+H)+, calcd for CeHeClFN, 146.0]; LC/MS retention time (method B): = 0.68 min.
With sodium azide; In water; N,N-dimethyl-formamide; at 85℃; for 336h;
Sodium azide (1.3 g, 20.89 mmol) was added to a mixture of 6 (1.0 g, 6.96 mmol) in dimethylformamide (10.5 ml) and water (0.52 ml). The resulting mixture was stirred at 85 C for 14 d. After this time, water (5 ml) was added and the product was extracted with EtOAc (3 x 7 ml). The combined organic layer was washed with brine (7 ml), dried over anhydrous MgS04, filtered and concentrated to dryness under reduced pressure to afford 7 (634 mg, 60%) as a pale yellow solid. XH NM (300 MHz, CDCI3): delta 8.42 (d, J = 5.5 Hz, 1H), 6.97 (dd, J = 2.0, 0.5 Hz, 1H), 6.83 (dd, J = 5.5, 2.0 Hz, 1H), 4.72 (s, 2H), 3.93 (s, 1H). 13C NMR (75 MHz, CDCI3): delta 161.8, 149.9, 149.7, 113.0, 110.7, 64.3. HRMS (APPI) calcd. for C6H7N40+ [M+H]+ 151.0614, found: 151.0601
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