* 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 hydroxide In tetrahydrofuran at 0 - 20℃; for 15 h;
General procedure: Ester (FAE, 4a-m, 2a or 2b) (500 mg scale, 1 equiv.) was dissolvedin 6 ml THF at 0 °C in a 25 ml round-bottom flask. ThenNaOH(aq) (5 equiv.) was added dropwise and stirred for 15 h atroom temperature. After starting materials were consumed (byTLC), water (20 ml) was added. The reaction mixture was washedwith ethyl acetate (2 x 20 ml). The aqueous solution was acidified(pH 2-3) with 1 M HCl(aq) causing precipitation of a solid, whichwas filtered and dried under vacuum. Recrystallization in ethanolafford clean compound.
Reference：
[1] European Journal of Medicinal Chemistry, 2017, vol. 126, p. 1011 - 1020
2
[ 29682-15-3 ]
[ 75754-04-0 ]
Reference：
[1] Patent: JP2017/171619, 2017, A,
3
[ 29682-15-3 ]
[ 98-80-6 ]
[ 75754-04-0 ]
Reference：
[1] Journal of Medicinal Chemistry, 2011, vol. 54, # 13, p. 4721 - 4734
To a solution of 5-bromopicolinic acid (12.6, 6.0 g, 29.9 mmol) in methanol (60 mL), sulfuric acid (3.0 mL) was added at 0 °C and the reaction mixture was heated at 70 °C for 6 h. After completion, cooled the mixture to room temperature and methanol was removed under reduced pressure. To the mixture, water (50 mL) was added and pH was adjusted to 6 by a solution of sodium bicarbonate .The product was extracted with ethyl acetate (200 mL), the organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified by washings with diethyl ether and pentane to afford methyl 5-bromopicolinate (12.5) as white solid. Yield: 6.0 g, 92.0percent.
86.9%
Stage #1: at 20℃; for 3 h; Reflux
(a) Preparation of methyl 5-bromopicolinate 2:To a 100 mL round bottle flask with 5-bromopicolinic acid (7.0 g, 35 mmol) in methanol (80 mL) was added dropwise thionyl chloride (3.0 mL) at ambient temperature. After addition the reaction mixture was heated to reflux for 3 h. Methanol was removed and ethyl acetate (100 mL) was added to the residue and was adjusted pH to 7.0 by addition of sodium bicarbonate solution. The organic phase was separated and dried over sodium sulfate. The organic solvent was removed and methyl 5-bromopicolinate 2 was obtained as white solid which was used for the next step of the reaction without further purification. Yield: 6.57 g, 86.9percent
80%
With thionyl chloride In dichloromethane at 0 - 50℃; for 12 h;
Example 89 - Preparation of Intermediate 25 [ 00379 ] The synthesis of Intermediate 25 followed General Procedure 1 following. Intermediate 25 [ 00380 ] To a cooled solution (0°C) of 5-bromopyridine-2-carboxylic acid (50.0 g, 0.247 mol, 1.0 eq) in anhydrous methanol (400 mL) was added thionyl chloride (107.0 mL, 2.47 mol, 10.0 eq) dropwise. The reaction mixture was slowly brought to ambient temperature and then heated at 50°C for 12 hours. The reaction was monitored by TLC and LC-MS. After completion, the reaction mixture was concentrated under reduced pressure to obtain a white solid residue, which was slowly quenched with saturated sodium bicarbonate. The white solid was filtered to give desired product methyl-5-bromopyridine-2-carboxylate (43.0 g, yield-80percent) m/z 216.14; 1H NMR (400 MHz, DMSO) δ 8.86 (d, J = 1.9 Hz, 1H), 8.28 (dd, J = 8.4, 2.4 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 3.89 (s, 3H) ppm.
79%
at 20℃; for 12 h; Reflux
5-bromo-2-pyridinecarboxylic acid (1.65 g, 8.19 mmol) was dissolved in a methanol solution (30 ml) at room temperature, concentrated sulfuric acid (2.5 ml) was added dropwise, heated, condensed and refluxed for 12 hours, The reaction solution was slowly added dropwise to a saturated sodium bicarbonate solution (200 ml), extracted with ethyl acetate (100 ml * 3) and washed with a saturated sodium chloride solution (100 ml * 2). The organic phase was dried over anhydrous magnesium sulfate Filtered and concentrated under reduced pressure to give methyl 5-bromo-2-pyridinecarboxylate (white solid, 1.39 g), yield: 79percent
76%
at 60℃; for 18 h;
Example 53; 3-(3,4-Dichloro-phenoxy)-6-(4-isopropyl-piperazine-1-carbonyl)-pyridine-2-carbonitrile trifluoroacetic acid salt Step A; 5-Bromo-pyridine-2-carboxylic acid methyl ester. A mixture of 5-bromo-2-pyridine carboxylic acid (26.2 g, 0.124 mol) and conc. H2SO4 (12.5 mL) in MeOH (250 mL) was heated to 60° C. and diluted with additional MeOH (250 mL). After 18 h at 60° C., the mixture was cooled to rt, diluted with DCM, and washed with a solution consisting of 21 g KOH in 200 mL water, sat. K2CO3, and water. The organic layer was dried and concentrated to give the title compound (21.4 g, 76percent) as a white solid. This material was used in the next step without further purification.
Reference：
[1] Patent: WO2018/126072, 2018, A1, . Location in patent: Paragraph 0246; 0247
[2] Patent: WO2012/76898, 2012, A1, . Location in patent: Page/Page column 64-65
[3] European Journal of Organic Chemistry, 2014, vol. 2014, # 22, p. 4780 - 4784
[4] Patent: WO2016/44662, 2016, A1, . Location in patent: Paragraph 00379-00380
[5] Patent: CN103360407, 2016, B, . Location in patent: Paragraph 0135-0137
[6] Patent: US2007/281923, 2007, A1, . Location in patent: Page/Page column 23
[7] ChemMedChem, 2017, vol. 12, # 24, p. 2044 - 2053
[8] Patent: WO2009/55828, 2009, A1, . Location in patent: Page/Page column 282
[9] Patent: WO2009/156966, 2009, A1, . Location in patent: Page/Page column 38
[10] Journal of Medicinal Chemistry, 2013, vol. 56, # 7, p. 3012 - 3023
[11] Patent: WO2015/48503, 2015, A2, . Location in patent: Paragraph 0129
[12] Patent: US2015/252057, 2015, A1, . Location in patent: Paragraph 0937; 0938; 0939
9
[ 30766-11-1 ]
[ 18107-18-1 ]
[ 29682-15-3 ]
Yield
Reaction Conditions
Operation in experiment
87%
at 20℃; for 1 h; Inert atmosphere
Example 29(i) (TMS)CHN2, MeOH, benzene, 0°C to room temperature, 1 h, 87percent. (ii) (trimethylsily)acetylene, PdCI2(PPh3)2, Cul, DIEA, THF, 70°C, 14h, 95percent. (iii) K2CO3, MeOH, room temperature, 40 min, 84percent. (iv) 4-ethylnylaniline, Cu(OAc)2, pyridine, MeOH, room temperature, 20 h. (v) 3N NaOH, MeOH, reflux, 40 min, 31 percent (from 142). (vi) EDC. HCI, HOBt, DIEA, DMF, 13, 0°C, 1 h, then room temperature, 36h, 74percent. (vii) hydroxylamine hydrochloride, 25percent NaOMe/MeOH, THF, 0°C, 2h, then room temperature, 16h, 40percent.5-Bromopyridine-2-carboxylic acid (140): To an ice-cold solution of 139 (3.00 g, 15.0 mmol) dissolved in anhydrous MeOH (20 mL) and benzene (20 mL) is added dropwise (TMS)CHN2 (2.5 ml, 5.0 mmol, 2.0 equiv), then is allowed to warm to ambient temperature with stirring is continued under argon for 1 h. The reaction is monitored byLC/MS and TLC. The resulting solution is condensed to dryness with a rotavapor, and the residue is purified by CombiFlash (eluting with 0-10percent EtOAc in hexane) to give 140 as with solid (2.79 g, 87 percent yield). 1 H NMR (300 MHz, CDCI3) 53.93 (s, 3H), 7.56 (d, J=9.3 Hz, 1 H), 8.10 (d, J=10.5 Hz, 1 H), 8.93 (s, 1 H); 13C NMR (300 MHz, CDCIs) 552.88, 125.52, 128.28, 139.40, 147.03, 151 .62, 165.23; MS (ESI, positive): m/z 490 [M+H+].
Reference：
[1] Patent: WO2012/31298, 2012, A2, . Location in patent: Page/Page column 123-124
[2] Patent: WO2014/138484, 2014, A1, . Location in patent: Page/Page column 187; 188
[3] Patent: WO2016/22724, 2016, A1, . Location in patent: Page/Page column 330
[4] Green Chemistry, 2018, vol. 20, # 17, p. 3931 - 3943
10
[ 624-28-2 ]
[ 107-31-3 ]
[ 29682-15-3 ]
Yield
Reaction Conditions
Operation in experiment
55%
Stage #1: With trimethylsilylmethyllithium In toluene at -78 - 0℃; for 0.5 h; Stage #2: for 3 h; Stage #3: With iodine; potassium carbonate In toluene at 20℃; for 18 h;
General procedure: N,N-Dimethylaminoethanol (0.85 ml, 8.5 mmol, 1 equiv.) and(trimethylsilyl)methyllithium 1 M (25.3 ml, 25.3 mmol, 3 equiv.)was added dropwise to 25 ml of dry toluene at 0 °C and the solutionwas stirred for 30 min to form TMSCH2Li-LiDMAE (in situ). Then, Asolution of 2,5-dibromopyridine 1 (2 g, 8.5 mmol, 1 equiv.) in 9 mlof dry toluene was added dropwise. The reaction mixture wasstirred for 30 min, cooled to 78 °C and added methyl formate(5.2 ml, 85 mmol, 10 equiv.) or ethyl formate (6.9 ml, 85 mmol,10 equiv.) in 10 ml of toluene. The reaction mixture stirred for 3 h,and I2 (6.4 g, 25.5 mmol, 3 equiv.), K2CO3 (5.8 g, 42.5 mmol, 5 equiv.)and 20 ml methanol or ethanol were added. The mixture wasstirred at room temperature for 18 h and added 10 ml of a sat.aqueous Na2SO3 solution.Water (10 ml)was added and the mixtureextracted with dichloromethane (3x40 ml), washed with water(1 x 25 ml) and brine (1 x 25 ml). The residue was purified bysilica-gel flash column chromatography (eluent: heptane/diethylether 2: 1) to obtain 2a-b.4.2.2.1. Methyl 5-bromopicolinate (2a). From 1 (2 g) gave 2a(997 mg, 55percent); white solid; >99percent purity; mp 103-104 °C (reported98.0-102.0 °C [30a]); 1H NMR (600 MHz, CDCl3)δ 8.77 (dd, J = 2.2,0.71 Hz, 1H, H2), 8.01 (dd, J = 8.3, 0.8 Hz, 1H, H5), 7.98 (dd, J = 2.3,2.2 Hz, 1H, H6), 3.99 (s, 1H, CH3);13C NMR (100 MHz, CDCl3):δ 165.0(C]O, C-7), 151.0(C-2), 146.3(C-4), 139.7(C-6), 126.3(C-5),125.1(C-1); HRMS (ESI) m/z [M+H]+ calcd for C7H7BrNO2 +215.9660,found 215.9659. Data was in accordance with those reported [30a].
Reference：
[1] European Journal of Medicinal Chemistry, 2017, vol. 126, p. 1011 - 1020
11
[ 67-56-1 ]
[ 201230-82-2 ]
[ 223463-13-6 ]
[ 29682-15-3 ]
Reference：
[1] Journal of Organic Chemistry, 2001, vol. 66, # 2, p. 605 - 608
12
[ 30766-11-1 ]
[ 75-77-4 ]
[ 29682-15-3 ]
Yield
Reaction Conditions
Operation in experiment
0.21 g
at 20℃;
To a solution of 5-bromo picolinic acid (0.20 g, 0.99 mmol) in MeOH (5 mL) was added TMSCl (0.50 mL, 3.96 mmol). The reaction mixture was left to stir at room temperature overnight. Water (20 mL) was added to quench the reaction and extracted three times with DCM (50 mL). Organic layer was combined, dried over Na2SO4 and concentrated in vacuo to give compound 4 as a white solid (0.21 g, 94percent) 1H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H), 8.03 – 7.97 (m, 2H), 3.96 (s, 3H).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 4, p. 744 - 749
13
[ 624-28-2 ]
[ 29682-15-3 ]
Reference：
[1] Tetrahedron, 2005, vol. 61, # 45, p. 10748 - 10756
[2] Journal of Organic Chemistry, 2001, vol. 66, # 2, p. 605 - 608
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 4, p. 1407 - 1412
18
[ 29682-15-3 ]
[ 88139-91-7 ]
Yield
Reaction Conditions
Operation in experiment
94.8%
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
General procedure: To a solution of methyl 5-bromopicolinate (2.16 g, 10 mmol) in THF (50 mL) at 0 °C was added a solution of 10 mL of 3.0 M methyl magnesium bromide in diethyl ether (30 mmol) dropwise over 0.5 h. The reaction mixture was stirred at rt for 1 h, quenched with saturated NH4C1 (1 mL) and partitioned between saturated NaHC03 (10 mL) and EtOAc (2* 15 mL). The combined organic layers were dried over Na2S04 and concentrated. The residue was purified by gradient elution on silica gel (0 to 20percent EtOAc in petroleum) to afford the title compound as a yellow oil (1.75 g, 81percent). LRMS m/z (M+H) 218.1 found, 218.1 required.
68%
at 0 - 20℃; Inert atmosphere
[00494] Intermediate 45a: 2-(5-bromo-2-pyridyl)propan-2-oI[00495] To a solution of methyl 5-bromopyridine-2-carboxylate (2.lg, 9.72mmol) in dry THF(48mL) at 0 °C, under nitrogen, was slowly added bromo(methyl)magnesium 2.7M in Et20 (10.8mL,29.l6mmol). The resulting solution was allowed to warm to room temperature and stirred overnight. The reaction was then quenched by the dropwise addition of sat. aq. NH4CI (2mL) then diluted with sat. aq. NaHCO3 (3OmL). The aqueous layer was extracted with EtOAc (2 x 3OmL). The combined organic extracts were washed with brine (3OmL), dried over Na2504 and concentrated in vacuo.The crude material was purified by flash column chromatography using an eluent of 0-100percent EtOAcin heptane to give 2-(5-bromo-2-pyridyl)propan-2-ol (1 .43g, 6.64mmol, 68percent yield) as a yellow oil.1H NMR (CDCI3, 400MHz) O/ppm: 7.89 (1H, m), 7.83 (1H, dd, J= 8.4Hz, 2.4Hz), 7.33 (1H, dd, J=8.4Hz, 0.8Hz), 4.41 (1 H, br 5), 1 .55 (6H, 5).MS Method 2: RT: 1.31 mi m/z 217.8 [M+H]
With tetrabutyl ammonium fluoride; N,N-dimethyl-formamide; silver(l) oxide In tetrahydrofuran at 90℃; for 18 h;
This compound is synthesized as described by adaptation of the following reference: Tye et al., Tet. Lett., 2008, 49, 3939. To a stirred suspension of methyl-5-bromo-2- pyridine carboxylate (0.25 g, 1.16 mmol) and 2-(trimethylsilyl)pyridine (0.48 mL), 3.48 mmol) in anhydrous N,N-dimethyl formamide (7.5 mL) is added silver (I) oxide (0.27 g, 1.16 mmol), allyl palladium chloride dimer (21 mg, 5 molpercent) and tetrabutyl ammonium fluoride (IM in THF, 0.116 mL). The reaction is heated at 90 0C for 18 h. The reaction mixture is filtered and washed with EtOAc. The filtrate is concentrated under reduced pressure. Purification by column chromatography (silica, eluent DCM, 0- 2percent MeOH) gives 0.12g (48percent) of methyl 2,3'-bipyridine-6'-carboxylate. m/z = 215 [M++H].
Reference：
[1] Patent: WO2009/156966, 2009, A1, . Location in patent: Page/Page column 38-39
[2] European Journal of Medicinal Chemistry, 2017, vol. 126, p. 1011 - 1020
28
[ 29682-15-3 ]
[ 1158763-55-3 ]
Reference：
[1] Patent: WO2012/3189, 2012, A1,
29
[ 29682-15-3 ]
[ 1201326-81-9 ]
Reference：
[1] Patent: WO2012/76898, 2012, A1,
[2] Journal of Medicinal Chemistry, 2013, vol. 56, # 7, p. 3012 - 3023
30
[ 29682-15-3 ]
[ 1380672-71-8 ]
Reference：
[1] Patent: WO2012/76898, 2012, A1,
[2] Journal of Medicinal Chemistry, 2013, vol. 56, # 7, p. 3012 - 3023
31
[ 29682-15-3 ]
[ 1380672-07-0 ]
Reference：
[1] Patent: WO2012/76898, 2012, A1,
[2] Journal of Medicinal Chemistry, 2013, vol. 56, # 7, p. 3012 - 3023
32
[ 29682-15-3 ]
[ 1214353-79-3 ]
Yield
Reaction Conditions
Operation in experiment
59%
Stage #1: With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 60℃; for 20 h; Stage #2: at 0 - 95℃; for 2 h;
A mixture of 5-bromo-pyridine-2-carboxylic acid methyl ester (CAN 29682-15-3, 50 g, 0.23 mol) and m-CPBA (CAN 937-14-4, 80 g, 0.46 mol) in 400 mL dry methylene chloride was heated to 60° C. for 20 h. After that, the mixture was quenched with saturated sodium sulfite solution and extracted with ethyl acetate (2.x.200 mL). The organic layer was washed with brine (2.x.200 mL) and evaporated to dryness. The residue was purified by column chromatography (silica gel, 300 g, eluting with 15percent ethyl acetate in petroleum ether) to obtain a brown oil. The brown oil, 5-bromo-2-(methoxycarbonyl)pyridine 1-oxide (30 g, 0.13 mol) was added into phosphoryl trichloride (CAN 10025-87-3, 80 mL) at 0° C. over 1 h, then the mixture was heated to 95° C. for 1 h. After that the mixture was evaporated to dryness, the residue was dissolved in water (50 mL), extracted with ethyl acetate (3.x.50 mL) and the organic layer was evaporated to dryness to obtain the product as a white solid (19 g, 59percent); MS (EI): m/e=249.9 [M+H]+.
With triethylamine;bis-triphenylphosphine-palladium(II) chloride; In acetonitrile; at 60℃; under 3878.71 Torr; for 16h;
2,5-Dibromopyridine (9.5 g, 40. 10MMOL), PDCL2 (PPH3) 2 (844 mg), triethylamine (8. 36 mL), methanol (38 mL), and acetonitrile (114 mL) were combined, heated under carbon monoxide atmosphere (75 psi) at 60oC for 16 hours and concentrated. The residue was purified by flash chromatography eluting with 25% ethyl acetate in hexane. The title compound (5.02 g) was obtained at 58% yield. MS (DCI/MH3) M/Z : 215.95 (M+H) +. LH NMR (500 MHz, DMSO- D6) 8 ppm 3.91 (s, 3 H) 8.00 (d, J=8.11 Hz, 1 H) 8. 27 (dd, J=8.42, 2.49 Hz, 1 H) 8.86 (d, J=1.56 Hz, 1 H)
With triethylamine;1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; In DMF (N,N-dimethyl-formamide); at 50℃; under 1551.49 Torr; for 6h;Parr apparatus;
The synthesis of the 5-bromopyridine-2-carboxylic acid methyl ester was achieved following the procedure of Chambers and Marfat (Synth. Commun. 1997, 27, 515). A solution of 2,5-dibromopyridine (10.0 g, 42.2 mmol), 1,1'-bis(diphenylphosphino)ferrocene (dppf, 1.4 g, 2.5 mmol), Pd(OAc)2 (0.3 g, 1.3 mmol), Et3N (12 mL, 84 mmol) in dry MeOH (40 mL) and dry DMF (40 mL) was deairated under a stream of CO for 10 min, then shaken in a Parr apparatus under 30 psi CO at 50 C. for 6 h. The mixture was diluted with EtOAc (600 mL) and washed with H2O (2×100 mL), brine (100 mL), dried over anhydrous MgSO4 and concentrated to give a solid. Flash column chromatography, using 20% EtOAc in hexane as the eluent, gave the 5-bromopyridine-2-carboxylic acid methyl ester as a white solid (5.77 g).
To a solution of 5-bromopicolinic acid (12.6, 6.0 g, 29.9 mmol) in methanol (60 mL), sulfuric acid (3.0 mL) was added at 0 C and the reaction mixture was heated at 70 C for 6 h. After completion, cooled the mixture to room temperature and methanol was removed under reduced pressure. To the mixture, water (50 mL) was added and pH was adjusted to 6 by a solution of sodium bicarbonate .The product was extracted with ethyl acetate (200 mL), the organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified by washings with diethyl ether and pentane to afford methyl 5-bromopicolinate (12.5) as white solid. Yield: 6.0 g, 92.0%.
86.9%
(a) Preparation of methyl 5-bromopicolinate 2:To a 100 mL round bottle flask with 5-bromopicolinic acid (7.0 g, 35 mmol) in methanol (80 mL) was added dropwise thionyl chloride (3.0 mL) at ambient temperature. After addition the reaction mixture was heated to reflux for 3 h. Methanol was removed and ethyl acetate (100 mL) was added to the residue and was adjusted pH to 7.0 by addition of sodium bicarbonate solution. The organic phase was separated and dried over sodium sulfate. The organic solvent was removed and methyl 5-bromopicolinate 2 was obtained as white solid which was used for the next step of the reaction without further purification. Yield: 6.57 g, 86.9%
80%
With thionyl chloride; In dichloromethane; at 0 - 50℃; for 12h;
Example 89 - Preparation of Intermediate 25 [ 00379 ] The synthesis of Intermediate 25 followed General Procedure 1 following. Intermediate 25 [ 00380 ] To a cooled solution (0C) of 5-bromopyridine-2-carboxylic acid (50.0 g, 0.247 mol, 1.0 eq) in anhydrous methanol (400 mL) was added thionyl chloride (107.0 mL, 2.47 mol, 10.0 eq) dropwise. The reaction mixture was slowly brought to ambient temperature and then heated at 50C for 12 hours. The reaction was monitored by TLC and LC-MS. After completion, the reaction mixture was concentrated under reduced pressure to obtain a white solid residue, which was slowly quenched with saturated sodium bicarbonate. The white solid was filtered to give desired product methyl-5-bromopyridine-2-carboxylate (43.0 g, yield-80%) m/z 216.14; 1H NMR (400 MHz, DMSO) delta 8.86 (d, J = 1.9 Hz, 1H), 8.28 (dd, J = 8.4, 2.4 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 3.89 (s, 3H) ppm.
79%
With sulfuric acid; at 20℃; for 12h;Reflux;
5-bromo-2-pyridinecarboxylic acid (1.65 g, 8.19 mmol) was dissolved in a methanol solution (30 ml) at room temperature, concentrated sulfuric acid (2.5 ml) was added dropwise, heated, condensed and refluxed for 12 hours, The reaction solution was slowly added dropwise to a saturated sodium bicarbonate solution (200 ml), extracted with ethyl acetate (100 ml * 3) and washed with a saturated sodium chloride solution (100 ml * 2). The organic phase was dried over anhydrous magnesium sulfate Filtered and concentrated under reduced pressure to give methyl 5-bromo-2-pyridinecarboxylate (white solid, 1.39 g), yield: 79%
76%
With sulfuric acid; at 60℃; for 18h;
Example 53; 3-(3,4-Dichloro-phenoxy)-6-(4-isopropyl-piperazine-1-carbonyl)-pyridine-2-carbonitrile trifluoroacetic acid salt Step A; 5-Bromo-pyridine-2-carboxylic acid methyl ester. A mixture of 5-bromo-2-pyridine carboxylic acid (26.2 g, 0.124 mol) and conc. H2SO4 (12.5 mL) in MeOH (250 mL) was heated to 60 C. and diluted with additional MeOH (250 mL). After 18 h at 60 C., the mixture was cooled to rt, diluted with DCM, and washed with a solution consisting of 21 g KOH in 200 mL water, sat. K2CO3, and water. The organic layer was dried and concentrated to give the title compound (21.4 g, 76%) as a white solid. This material was used in the next step without further purification.
With thionyl chloride; at 65℃; for 2h;
5-Bromopyridine-2-carboxylic acid (10 g) was dissolved in 260 mL MeOH. SOCl2 (26 mL) was added dropwise to this solution over a period of 10 min (Caution: Exothermic reaction). The reaction mixture was heated to 65 0C for 2 h at which point the reaction was found complete by TLC (an aliquot was evaporated to dryness, the residue taken up in satd. aq. NaHCO3 and extracted with ethyl acetate). The reaction mixture was evaporated to dryness. The residue was basified with satd. aq. NaHCO3 and extracted with ethyl acetate. The combined ethyl acetate layer was dried (Na2SO4) and evaporated under reduced pressure to obtain 9.2 g of the solid product. TLC Rf 0.5 (40% Ethyl acetate-hexane).
Step 3: Synthesis of 5-bromo-pyridine-2-carboxylic acid methyl ester:; To a solution of 5-bromo-pyridine-2-carboxylic acid (1.2 g, 5.0 mmol) in methanol (20 mL) was added catalytic amount of cone, sulfuric acid (0.5mL) while keeping the temperature of reaction mixture between 100C to 150C. The reaction mixture was then refluxed for about 5 hours and then the solvent was evaporated. The oily residue was then poured into cold water (25 mL) and pH was adjusted to pH 7-8 by adding 2N NaOH aqueous solution. The aqueous layer was then extracted with 2 x 25OmL of dichloromethane. The combined organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford title compound (1.2 g).
With sulfuric acid; at 0 - 60℃; for 4h;
[0129j To a solution of 5-bromopicolinic acid (5 g, 24.7 mmol) in methanol (50 mL) was added concentrated sulfuric acid (1 mL) at 0 C and the resulting solution was stirred at 60 C for 4 h. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was dissolved in ethyl acetate (300 mL) and washed with saturated sodium bicarbonate solution (200 mL x 2), brine (300 mL), dried over sodium sulfate and concentrated under vacuum to afford the title compound methyl 5-bromopicolinate (5.1 g, crude) as an off-white solid which was used for the next step without further purification. Calculated M+H: 216.03; Found M+H: 216.01.
With thionyl chloride; at 0 - 60℃; for 12h;
Step 1: (0939) A solution of 5-bromopyridine-2-carboxylic acid (5.0 g, 24.75 mmol) in MeOH (30 mL) was added thionyl chloride (10 mL) dropwise at 0 C. Then the mixture was stirred for 12 hours at 60 C. After removal of solvent and the residual thionyl chloride, the crude product methyl 5-bromopyridine-2-carboxylate was obtained and used in the next step without further purification.
5-bromo-2-(methoxycarbonyl)-1A[5]-pyridin-1-olate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With urea hydrogen peroxide adduct; trifluoroacetic anhydride; In acetonitrile; at 0℃; for 2h;
Step B; 5-Bromo-1-oxo-pyridine-2-carboxylic acid methyl ester. To a 0 C. mixture of <strong>[29682-15-3]5-bromo-pyridine-2-carboxylic acid methyl ester</strong> (10.1 g, 46.8 mmol) and urea hydrogen peroxide complex (9.33 g, 99.2 mmol) in acetonitrile (150 mL) was added trifluoroacetic anhydride (13.0 mL, 93.7 mmol). After 2 h, the mixture was poured into 0.5 M HCl and extracted with DCM. The organic layer was washed with satd. aq. NaHCO3, dried, and concentrated. The residue was purified by FCC (ethyl acetate (EtOAc)/hexanes) to give the title compound (9.70 g, 89%) as a colorless viscous oil. MS (ESI): mass calcd. for C7H6BrNO3, 230.95; m/z found, 232.2 [M+H]+. 1H NMR (d6-acetone): 8.49-8.48 (m, 1H), 7.63-7.62 (m, 2H), 3.89 (s, 3H).
83%
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 45℃;
Into a 1 -L round-bottom flask, was placed methyl 5-bromopyridine-2-carboxylate (13-1, 45 g, 208.30 mmol, 1.00 equiv) and dichloromethane (450 mL). This was followed by the addition of m-CPBA (108.125 g, 626.56 mmol, 3.01 equiv) in portions at 0C. The resulting solution was stirred overnight at 45C. The resulting mixture was concentrated under vacuum. The residue was dissolved in 500 mL of EA and the pH value of the solution was adjusted to 8 with sodium carbonate. The resulting solution was extracted with 3x300 mL of ethyl acetate. The organic layer was collected and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 40 g (83%) of 5-bromo-2-(methoxycarbonyl)- lA[5]-pyridin-l-olate (13-2) as a light yellow solid.
58.4%
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 20℃; for 12h;
Example 90 - Preparation of Intermediate 26 [ 00381] The synthesis of Intermediate 26 followed General Procedure 18 following. General Procedure 18 Intermediate 25 Intermediate 26 [ 00382 ] To a cooled solution (0C) of methyl-5-bromopyridine-2- carboxylate (Intermediate 25, 20.0 g, 92.6 mmol, 1.0 eq) in dichloromethane (200 mL), was added m-CPBA (24.0 g, 139 mmol, 1.5 eq) portionwise. The reaction mixture was slowly brought to ambient temperature and stirred for 12 hours. After completion (monitored by TLC and LC-MS), the reaction mixture was concentrated under reduced pressure to obtain a white solid residue, which was slowly quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The crude compound was purified by column chromatography using silica gel (silica 60-120 mesh size), eluting with dichloromethane : methanol (5% - 8% gradient) to give the desire product 5-bromo-2-(methoxycarbonyl)pyridine-l-oxide (12.52 g, yield-58.4%) m/z 234.11 [M+2]+; 1H NMR (400 MHz, CDC13) delta 8.42 (d, J = 1.6 Hz, 1H), 7.61 - 7.51 (m, 1H), 7.47 - 7.39 (m, 1H), 3.98 (s, 3H) ppm.
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 60℃; for 20h;
A mixture of <strong>[29682-15-3]5-bromo-pyridine-2-carboxylic acid methyl ester</strong> (CAN 29682-15-3, 50 g, 0.23 mol) and m-CPBA (CAN 937-14-4, 80 g, 0.46 mol) in 400 mL dry methylene chloride was heated to 60C for 20 h. After that, the mixture was quenched with saturated sodium sulfite solution and extracted with ethyl acetate (2 x 200 mL). The organic layer was washed with brine (2 x 200 mL) and evaporated to dryness. The residue was purified by column chromatography (silica gel, 300 g, eluting with 15% ethyl acetate in petroleum ether) to obtain a brown oil. The brown oil, 5-bromo-2-(methoxycarbonyl)pyridine 1 -oxide (30 g, 0.13 mol) was added into phosphoryl trichloride (CAN 10025-87-3, 80 mL) at 0C over 1 h, then the mixture was heated to 95 C for 1 h. After that the mixture was evaporated to dryness, the residue was dissolved in water (50 mL), extracted with ethyl acetate (3 x 50 mL) and the organic layer was evaporated to dryness to obtain the product as a white solid (19 g, 59%); MS (EI): m/e = 249.9 [M+H]+.
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 60℃; for 20h;
a) 5-Bromo-6-chloro-pyridine-2-carboxylic acid methyl ester A mixture of <strong>[29682-15-3]5-bromo-pyridine-2-carboxylic acid methyl ester</strong> (CAN 29682-15-3, 50 g, 0.23 mol) and m-CPBA (CAN 937-14-4, 80 g, 0.46 mol) in 400 mL dry methylene chloride was heated to 60 C for 20 h. After that, the mixture was quenched with saturated sodium sulfite solution and extracted with ethyl acetate (2 x 200 mL). The organic layer was washed with brine (2 x 200 mL) and evaporated to dryness. The residue was purified with by column chromatography (silica gel, 300 g, eluting with 15% ethyl acetate in petroleum ether) to obtain a brown oil. The brown oil, 5-bromo-2- (methoxycarbonyl)pyridine 1-oxide (30 g, 0.13 mol) was added into phosphoryl trichloride (CAN 10025-87-3, 80 mL) at 0 C over 1 h, then the mixture was heated to 95 C for 1 h. After that the mixture was evaporated to dryness, the residue was dissolved in water (50 mL), extracted with ethyl acetate (3 x 50 mL) and the organic layer was evaporated to dryness to obtain the product as a white solid (19 g, 59%); MS (EI): m/e = 249.9 [MH+].
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 60℃; for 20h;
a) 5-Bromo-6-chloro-pyridine-2-carboxylic acid methyl ester A mixture of <strong>[29682-15-3]5-bromo-pyridine-2-carboxylic acid methyl ester</strong> (CAN 29682-15-3, 50 g,0.23 mol) and m-CPBA (CAN 937-14-4, 80 g, 0.46 mol) in 400 mL dry methylene chloride was heated to 60 00 for 20 h. After that, the mixture was quenched with saturated sodium sulfite solution and extracted with ethyl acetate (2 x 200 mL). The organic layer was washed with brine (2 x 200 mL) and evaporated to dryness. The residue was purifiedwith by column chromatography (silica gel, 300 g, eluting with 15% ethyl acetate inpetroleum ether) to obtain a brown oil. The brown oil, 5-bromo-2-(methoxycarbonyl)pyridine 1-oxide (30 g, 0.13 mol) was added into phosphoryl trichloride(CAN 10025-87-3, 80 mL) at 0 C over 1 h, then the mixture was heated to 95 C for 1After that the mixture was evaporated to dryness, the residue was dissolved in water (50mL), extracted with ethyl acetate (3 x 50 mL) and the organic layer was evaporated todryness to obtain the product as a white solid (19 g, 59%); MS (El): mle = 249.9 [MH?i.
To a solution of 5-bromo-pyridine-2-carboxylic acid methyl ester [(L.] [OEQ.)] (see Synth. Commun., [1997,] [27,] 515) in THF : MeOH (2: 1; 0.2M) was added aqueous LiOH (1M ; 3. [0EQ.).] The mixture was stirred for 12h, concentrated and dried under vacuum. The residue was diluted in CH2CI2 (0.2M), oxalyl chloride [(8.] [OEQ.)] was added and the mixture was stirred for 3h, concentrated, dried under vacuum and diluted in [CH2C12] (0.2M). Cyclopropylamine [(LOEQ.)] was added and the mixture was stirred for 2h, poured in saturated aqueous [NAHC03] and extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried over [NA2S04,] filtered and concentrated. Flash chromatography (CH2Cl2 : EtOAc; 9: 1) afforded the title compound as a yellow solid.
With hydrazine; In methanol; for 1h;Heating / reflux;
Hydrazine hydrate (5.3mL, 108.3mmol) was added to an ice-cooled solution of the product of preparation methyl 5-bromopyridine-2-carboxylate [(7.80g, 36.1 mmol) J. Org. Chem, 66,605-608] dissolved in methanol (100mL) and the mixture was heated under reflux for 1 hour. The solvent was concentrated to low volume under reduced pressure and was then cooled. The precipitate that formed was filtered off, washed with methanol and dried in vacuo to give the title product in 89% yield, 6.94g. ¹H NMR(DMSO-D6, 400MHz) No.: 4.40-4.65 (brs, 7.90-7.95(d, 1H), 8.21(d, 1H), 8.70(s, 1H), 9.90- 10.0 (brs, 1 H). MS APCI+ m/z 216, 218 [MH]+
86%
With hydrazine; In ethanol; at 25℃; for 3h;Heating / reflux;
Example 2000 Step 1 To a solution of 2000A (1 g, 4.6 mmol) in EtOH (12 mL) was added hydrazine (0.22 mL, 6.9 mmol) at 250C and the mixture was heated to reflux for 3 h. The reaction mixture was cooled to 00C and the resulting precipitate was filtered and washed with cold EtOH to afford 2000B (0.86 g, 86% yield).
86%
With hydrazine; In methanol; water; for 48h;Heating / reflux;
Preparation 1; 5-Bromopyridine-2-carbohvdrazide; 5-Bromo-pyridine-2-carboxylic acid methyl ester [(18.1 Og, 83mmol) J. Org. Chem., 2001 , 66, 605] and hydrazine monohydrate (12.5ml_, 250mmol) were dissolved in methanol (40OmL) and the mixture was heated under reflux for 48 hours. The reaction mixture was then filtered and the residue was dried in vacuo to afford the title compound as a solid in 86% yield, 15.4Og. 1HNMR(DMSO-D6, 400MHz) delta: 4.57(d, 2H), 7.91(m, 1 H), 8.22(m, 1 H), 8.72(m, 1 H), 9.98(m, 1 H); LRMS ES+ m/z 217 [M+H]+
With hydrazine; In methanol; for 48h;Heating / reflux;
Preparation 6 5-Bromo-pyridine-2-carboxylic acid hydrazide 5-Bromo-pyridine-2-carboxylic acid methyl ester (J. Org. Chem., 2001, 66(2), 605-608, compound 4) (18.10g, 83mmol) and hydrazine monohydrate (12.5mL, 250mmol) were dissolved in methanol (400mL) and the reaction mixture heated to reflux for 48 hours. The reaction mixture was then filtered-and the precipitate COLLECTED DRIED IN VACUO to yield the title product, 15. 40G. 1HNMR (DMSO-D6, 400MHZ) No.: 4. 57 (d, 2H), 7 91(m, 1H), 8.22(m, 1H), 8.72 (m, . H), 9.98(m, 1H). MS ES+ m/z 217 [MH]+
With hydrazine hydrate; In ethanol; at 25 - 26℃; for 48h;Inert atmosphere;
5-Bromo-pyridine-2-carboxylic acid methyl ester (107 g, 495 mmol) was taken in EtOH (2 L) at 25-26 C under nitrogen atmosphere. Hydrazine hydrate (123 mL, 2475 mmol) was added to the reaction mixture and stirred for 48 h at 25 C (reaction completion was confirmed by TLC). The reaction mixture was concentrated to get a crude product that was precipitated as a white solid (74.6 g, 70% yield). The crude product was taken as such for the next step without further purification. 1HNMR (300 MHz, DMSO-d6) 8 9.99 (t, J= 4.3 Hz, 1H), 8.74 (dd, J= 2.4, 0.7 Hz, 1H), 8.23 (dd, J= 8.4, 2.4 Hz, 1H), 7.92 (dd, J = 8.4, 0.7 Hz, 1H), 4.59 (d, J= 4.4 Hz, 2H). LC/MS (Method A): 218.0 (M+H)+.
With copper(l) iodide; triethylamine;bis-triphenylphosphine-palladium(II) chloride; at 20 - 60℃;
Intermediate 17; Preparation of 5-(3,3-dimethylbut-1-ynyl)picolinic acid; Methyl 5-(3,3-dimethylbut-1-ynyl)picolinate To a 250 mL sealed reaction vessel was added methyl 5-bromopyridine-2-carboxylate (5 g, 23 mmol), copper(I) iodide (0.43 g, 2.3 mmol), bis(triphenylphosphine) palladium(II) chloride (3.23 g, 4.6 mmol), and triethylamine (80 mL). The mixture was allowed to stir for approximately 10 minutes upon which 3,3-dimethylbut-1-yne ( 2.83 g, 34.5 mmol) was added. The tube was sealed, stirred at room temperature overnight, and heated at 60 C. for one hour. The mixture was allowed to cool, and then concentrated under vacuum to a residue. The residue was purified by column chromatography on silica gel using EtOAc/hexanes (1:10) as eluent to give the product (4.62 g, 92%) as a tan solid which was used directly in the next step.
With potassium fluoride;palladium diacetate; CyJohnPhos; In 1,4-dioxane; at 130℃; for 4h;
Example 2 5-[2-Fluoro-4-('2-trifluoromethyl-biphenyl-4-yloxymethyl)-phenyl]-pyridine-2-carboxylic acid [00121] Step 1: To a round-bottom flask containing methyl 5-bromopicolinate(0.50 g, 2.3 mmol), <strong>[170981-26-7](2-fluoro-4-methylphenyl)boronic acid</strong> (0.53 g, 3.5 mmol), palladium acetate (52 mg, 0.23 mmol), 2-(dicyclohexylphosphino)biphenyl (0.16g, 0.46 mmol) and potassium fluoride (0.40 g, 6.9 mmol) is added anhydrous 1,4-dioxane (10 ml). The flask is purged with argon and sealed. The mixture is stirred at 13O0C for 4 hours and then cooled to EPO <DP n="26"/>ambient temperature before water (20 ml) is added. The mixture is extracted with EtOAc (20 ml x 2), dried over MgSO4, and concentrated. The residue is purified by silica gel column chromatography (EtOAc/Hexane, gradient) to give 5-(2-fluoro-4-methyl-phenyl)-pyridine-2- carboxylic acid methyl ester 5 (0.36 g, 63% yield): 1H NMR (400 MHz, DMSO-d6) delta 8.88 (s, 1 H), 8.15 (m, 2 H), 7.57 (t, 1 H, J = 8.0 Hz), 7.24 (d, 1 H, J = 11.6 Hz), 7.20 (d, 1 H, J = 8.0 Hz), 3.91 (s, 3 H), 2.39 (s, 3 H); LC-MS m/z: 246.0 (M+l).
Sodium carbonate (0.636 g, 6.0 mmol) in water (2.0 mL) was added to a mixture of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (0.442 g, 2.0 mmol), 5- bromopyridine-2-carboxylic acid methyl ester (0.518 g, 2.4 mmol) and tetrakis(triphenylphosphine)palladium (69 mg, 0.06 mmol) in ethanol (3.0 mL) and toluene (3.0 mL).The resulting mixture was heated at 120 0C for 3 h. The organic solvents were removed under reduced pressure. The residue was diluted with water, and adjusted with IN HCl to pH = 4. The precipitates were collected by filtration, washed with water and EtOAc, and dried to give the desired product (0.25 g, 58%). LCMS: (M+H) = 217.0.
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; ruphos; In toluene; at 100℃; for 18h;Inert atmosphere;
Under N2, a mixture 1 -methylpiperazine (232 mg,2.31 mmol) and <strong>[29682-15-3]methyl 5-bromopicolinate</strong> (500 mg, 2.31mmol), tris(dibenzylideneacetone)dipalladium (53 mg,0.058 mmol), Ru-Phos (108 mg, 0.23 mmol) and cesiumcarbonate (2.26 g, 6.94 mmol) in toluene (20 mE) washeated at 1000 C. for 18 hours. Then it was cooled to roomtemperature and filtrated. The filtrate was concentrated invacuo. And the residue was washed with PE-EA to givecompound 3 as a white solid (528 mg, 100%).
72%
With potassium phosphate;dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 20 - 100℃; for 96h;
Methyl 5-bromo 2-carboxylate (250 mg, 1.16 mmol, 1 eq), potassium phosphate (334 mg, 1.62 mmol, 1.4 eq), S-Phos (96 mg, 0.231 mmol, 0.2 eq) and Pd2dba3 (13 mg, 0.058 mmol, 0.05 eq) were stirred in toluene (5 ml) under nitrogen. N-Methylpiperazine (155 mul, 1.39 mmol, 1.2 eq) was added and the mixture was stirred at 100 C. for 48 h, then allowed to cool to room temperature and stirred for a further 48 h. The reaction mixture was poured onto a SCX column and washed through with MeOH, then with 2M NH3 in MeOH to elute the product. Product fractions were evaporated to afford 5-(4-methylpiperazin-1-yl)pyridine-2-carboxylate as an orange oil which crystallized on standing (194 mg, 72% yield). 1H NMR (399.902 MHz, DMSO) delta 2.24 (s, 3H), 2.43-2.48 (m, 4H), 3.35-3.40 (m, 4H), 3.81 (s, 3H), 7.32-7.37 (m, 1H), 7.88 (d, 1H), 8.38 (d, 1H). MS: m/z 236 (MH+)
33%
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 110℃; for 16h;
A 50-mL round-bottom flask fitted with a nitrogen inlet, a magnetic stir bar, a thermometer, and a condenser was charged with methyl 5-bromopyridine-2-carboxylate (300 mg, 1.39 mmol), 1-methylpiperazine (167 mg, 1.67 mmol), potassium phosphate (416 mg, 1.96 mmol), toluene (10 mL), Sphos (11.5 mg, 0.03 mmol), and Pd2(dba)3 (7.2 mg, 0.01 mmol). The resulting solution was stirred for 16 h at 110 C. in an oil bath and then cooled to 23 C. The resulting mixture was diluted with water (30 mL) and the product was extracted with ethyl acetate (6*30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/petroleum ether (3:7 v/v) to afford methyl 5-(4-methylpiperazin-1-yl)pyridine-2-carboxylate (130 mg, 33%). LCMS: (ESI) m/z 236 [M+H].
23%
With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); 2-dicyclohexylphosphino-2?,6?-dimethoxybiphenyl; In toluene; at 100℃; for 72h;Inert atmosphere;
Under N2, a mixture 1-methylpiperazine (440 mg, 4.44 mmol) and <strong>[29682-15-3]methyl 5-bromopicolinate</strong> (800 mg, 3.70 mmol), tris(dibenzylideneacetone)dipalladium (170 mg, 0.19 mmol), S-Phos (304 mg, 0.74 mmol) and potassium phosphate (1.10 g, 5.18 mmol) in toluene (20 ml) was heated at 100 C. for 3 days. Then it was cooled to room temperature and filtrated. The filtrate was concentrated in vacuo, and the residue was purified by silica gel chromatography (PET/EtOAc=1:1, EtOAc) to give desired product as a white solid (200 mg, 23%).
With potassium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In 1,4-dioxane; at 90℃; for 18h;
5-(6-Methyl-pyridin-3-ylamino)-pyridine-2-carboxylic Acid Methyl Ester A mixture of <strong>[29682-15-3]5-bromo-pyridine-2-carboxylic acid methyl ester</strong> (2.5 g, 11.3 mmol), 6-methyl-pyridin-3-ylamine (1.84 g, 17.0 mmol), Pd(OAc)2 (76 mg, 0.34 mmol), rac-BINAP (212 mg, 0.34 mmol), and K2CO3 (7.84 g, 56.7 mmol) in dioxane (75 ml) was heated to 90 C. for 18 h. The mixture was allowed to cool to RT and then concentrated in vacuo. Purification by flash chromatography (DCM/MeOH 100:0 to 95:5) afforded 5-(6-methyl-pyridin-3-ylamino)-pyridine-2-carboxylic acid methyl ester (2.38 g, 86%). HPLC (System 1, 0-100% CH3CN): tR=2.397 min, MS (ES+): 244 [M+1].
86%
With potassium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 90℃; for 18h;
5-(6-Methyl-pyridin-3-ylamino)-pyridine-2-carboxylic acid methyl esterA mixture of <strong>[29682-15-3]5-bromo-pyridine-2-carboxylic acid methyl ester</strong> (2.5 g, 1 1.3 mmol), 6-methyl- pyridin-3-ylamine (1.84 g, 17.0 mmol), Pd(OAc)2 (76 mg, 0.34 mmol), rac-BINAP (212 mg, 0.34 mmol), and K2CO3 (7.84 g, 56.7 mmol) in dioxane (75 ml) was heated to 90 0C for 18 h. The mixture was allowed to cool to RT and then concentrated in vacuo. Purification by flash chromatography (DCM/MeOH 100:0 to 95:5) afforded 5-(6-methyl-pyridin-3-ylamino)- pyridine-2-carboxylic acid methyl ester (2.38 g, 86%). HPLC (System 1 , 0-100% CH3CN): tR = 2.397 min, MS (ES+): 244 [M+1].
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; at 80℃; for 1h;
To a slurry of methyl 5-bromo-2-pyridinecarboxylate (1 g, 4.6 mmol), tetrakis(triphenylphosphine)palladium(0) (0.21 g, 0.185 mmol), ethylene glycol dimethyl ether (25 mL) and 2 N sodium carbonate (22 mL, 44 mmol) was added [6- (methyloxy)-2-naphthalenyl]boronic acid (1.12 g, 5.55 mmol) and the reaction mixture was heated at 80 0C for 1 h. The reaction mixture was cooled to room <n="142"/>temperature, then diluted with water, followed by ethyl acetate. The layers were separated and the ethyl acetate layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude material was partially dissolved in dichloromethane and filtered. The filtrate was purified by flash chromatography over silica using a hexanes: ethyl acetate gradient of 0 to 30% ethyl acetate to afford 0.127 g of methyl 5-[6-(methyloxy)-2-naphthalenyl]-2-pyridinecarboxylate. The aqueous layer was acidified with IN hydrochloric acid to pH 6 (litmus paper) and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with brine, dried over magnesium sulfate, filtered, and concentrated. This crude material was triturated with hot dichloromethane to afford 0.22 g of 5-[6-(methyloxy)-2-naphthalenyl]-2- pyridinecarboxylic acid. To a solution of 5-[6-(methyloxy)-2-naphthalenyl]-2- pyridinecarboxylic acid (0.219 g, 0.784 mmol) in methanol (7 mL) was slowly added thionyl chloride (0.114 mL, 1.57 mmol). The reaction mixture was heated at 75 0C for 2 days. The reaction mixture was cooled to room temperature, then concentrated. The crude material was diluted with saturated sodium bicarbonate, followed by ethyl acetate. The layers were separated and the ethyl acetate layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to afford 0.16 g of methyl 5- [6-(methyloxy)-2-naphthalenyl]-2-pyridinecarboxylate. This afforded the combined total of 0.287 g (21%) of methyl 5-[6-(methyloxy)-2-naphthalenyl]-2- pyridinecarboxylate. 1H NMR (400 MHz, DMSO-J6): delta 9.16 (d, J = 2 Hz, IH), 8.38 (dd, J = 8, 2 Hz, IH), 8.35 (s, IH), 8.14 (d, J = 8 Hz, IH), 7.94 (m, 3H), 7.38 (d, J = 2 Hz, IH), 7.22 (dd, J = 9, 3 Hz, IH), 3.89 (s, 3H), 3.89 (s, 3H).
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 20 - 90℃;Inert atmosphere;
Step 4: Synthesis of methyl 5-(4,4,5,5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)pyridine-2- carboxylate:; To a solution of <strong>[29682-15-3]5-bromo-pyridine-2-carboxylic acid methyl ester</strong> (0.5 g, 2.3 mmol) in 1,4 dioxane (25 mL) were added bispinacolatodiborane (1.05 g, 4.1 mmol), potassium acetate <n="40"/>(1.13 g, 11.5 mmol) and Pd (dppf)Cl2 (0.28 g, 0.34 mmol) under argon at room temperature. The mixture was heated at 80-900C for about 6 hours. It was cooled to room temperature, concentrated under reduced pressure and then purified through filtering column using sintered funnel full of 230-400 mesh size silica gel. It was eluted with 50% ethylacetate in hexane and concentrated to afford title compound (0.23 g). MS m/e .264.27. (MH+)
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; water; at 110℃; for 0.25h;Sealed tube; Microwave irradiation;
General procedure: A mixture of 2a or 2b (1 g, 1 equiv.), bis(-pinacolato)diboron (1.2 equiv.), [1,10-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane(10 mol %), potassium acetate (2 equiv.), 1,4-dioxane (15 ml) andwater (7.5 ml) was sealed in a 20 ml microwave reaction vial(Biotage). The vial was irradiated in a microwave apparatus at110 C, high absorption for 15 min. The reaction mixturewas cooledto room temperature (afforded crude 3a or 3b) and used to the nextstep without purification. An appropriate alkyl halide (0.95 equiv.),cesium carbonate (2.0 equiv) and water (4 ml) were added directlyto the reaction mixture. The vial was sealed and irradiated in amicrowave apparatus at 110 C, normal absorption for 30-90 min.After cooling to room temperature, water (100 ml) was added andthe mixture was extracted with ethyl acetate (4 x 100 ml). Theorganic layer was washed with brine (200 ml), dried with anhydrousNa2SO4(s) and concentrated. The residue was purified bysilica-gel flash column chromatography (eluent: ethyl acetate/heptane = 1:1) to obtain the esters 4a and 4j-m.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 90℃; for 3h;Inert atmosphere;
The compound 156a (500 mg, 2.31 mmol) was dissolved in 1,4-dioxane (20 mL), and the compound 156b (705.3 mg, 2.78 mmol), KOAc (453.6 mg, 4.63 mmol) and PdCl2 ( dppf) (169.4 mg, 0.23 mmol), replaced with nitrogen three times, and then the reaction solution was stirred at 90 C for 3 hours. Cooled to room temperature, filtered and concentrated, the concentrate was used directly in the next reaction feed.
With tetrabutyl ammonium fluoride; N,N-dimethyl-formamide; silver(l) oxide;bis(eta3-allyl-mu-chloropalladium(II)); In tetrahydrofuran; at 90℃; for 18h;
This compound is synthesized as described by adaptation of the following reference: Tye et al., Tet. Lett., 2008, 49, 3939. To a stirred suspension of methyl-5-bromo-2- pyridine carboxylate (0.25 g, 1.16 mmol) and 2-(trimethylsilyl)pyridine (0.48 mL), 3.48 mmol) in anhydrous N,N-dimethyl formamide (7.5 mL) is added silver (I) oxide (0.27 g, 1.16 mmol), allyl palladium chloride dimer (21 mg, 5 mol%) and tetrabutyl ammonium fluoride (IM in THF, 0.116 mL). The reaction is heated at 90 0C for 18 h. The reaction mixture is filtered and washed with EtOAc. The filtrate is concentrated under reduced pressure. Purification by column chromatography (silica, eluent DCM, 0- 2% MeOH) gives 0.12g (48%) of methyl 2,3'-bipyridine-6'-carboxylate. m/z = 215 [M++H].
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 100℃; for 2h;Inert atmosphere;
To a solution of <strong>[29682-15-3]methyl 5-bromopicolinate</strong> (9.5 g, 44.2 mmol) in 1,4-dioxane (100 mL) and water (20 mL) was added K2C03 (16.8 g, 132.6 mmol), phenylboronic acid (5.7 g, 46.4 mmol) and PdC12(dppf) (0.5 g), and the resulting mixture was stirred for 3 hours at 100C under nitrogen atmosphere. The mixture was cooled to room temperature and filtered, the filtrate was poured into water (200 mL), and extracted with ethyl acetate (100 mL x 2). The combined organic phase was dried over sodium sulfate, concentrated and re-crystallized from petroleum ether: ethyl acetate= 10/1 to give compound 2-2a (8.7 g, 92% yield) as a brown solid; LCMS (ESI): m/z 214 [M+Hf?.
49%
With palladium diacetate; caesium carbonate; tris-(o-tolyl)phosphine; at 90℃; for 16h;
Methyl 5-bromopicolinate (250 mg),Phenylboronic acid (250 mg)In DMF (10 mL) was added palladium (II) acetate (30 mg),Cesium carbonate (1 g) and tri-o-tolylphosphine (40 mg) were added,And the mixture was stirred at 90 C. for 16 hours. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain methyl 5-phenylpicolinate120 mg (yield 49%) was obtained.
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]+.
methyl 5-((trimethylsilyl)ethynyl)picolinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
With copper(l) iodide; trans-bis(triphenylphosphine)palladium dichloride; triethylamine; In tetrahydrofuran; at 60℃; for 18h;Inert atmosphere;
A 100-mL round bottom flask was loaded with <strong>[29682-15-3]methyl 5-bromopicolinate</strong> (1.00 g, 4.63 mmol), PdCl2(PPh3)2 (66 mg, 0.093 mmol), and CuI (27 mg, 0.14 mmol) under nitrogen atmosphere. A mixture of NEt3/THF (30 mL, 1:1, v/v) was added under nitrogen, followed by ethynyltrimethylsilane (2.0 mL, 14 mmol). The solution was stirred at 60 C for 18 h under nitrogen. The crude reaction mixture was filtered through a pack of Celite, and the filtrate concentrated under reduced pressure. The residual brown oil was purified by flash column chromatography on SiO2 (hexanes:EtOAc = 9:1, v/v) to afford 2 as a brown solid (1.07 g, 99%). 1H NMR (400 MHz, CDCl3, 298 K): delta 8.76 (dd, J = 2.0, 0.7 Hz, 1H), 8.07 (dd, J = 8.1, 0.7 Hz, 1H), 7.87 (dd, J = 8.1, 2.0 Hz, 1H), 4.00 (s, 3H), 0.27 (s, 9H); 13C NMR (100 MHz, CDCl3, 298 K): delta 165.3, 152.5, 146.3, 139.9, 124.5, 123.9, 102.1, 100.7, 53.2, -0.2. FT-IR (thin film on NaCl, cm-1): 2957, 1716, 1444, 1368, 1313, 1246, 1225, 1194, 1134, 1018, 868, 843, 794, 760, 701. HRMS (CI) calcd for C12H16NO2Si [M + H]+ 234.0945, found 234.0949.
97%
With copper(l) iodide; trans-bis(triphenylphosphine)palladium dichloride; triethylamine; In tetrahydrofuran; at 60℃; for 5h;Inert atmosphere;
To a solution of methyl 5-bromopyridine-2-carboxylate, 49 (1 g,4.63 mmol) in THF (15 mL) (degassed under argon) were added dichlorobis(triphenylphosphine)palladium (0.163 mg, 0.23 mmol),CuI (88 mg, 0.46 mmol), Et3N (15 mL) and ethynyltrimethylsilane(1.98 mL, 13.89 mmol). The stirred mixture was heated at 60 C for5 h. The mixture was then filtered on Celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography 90/10 (petroleum ether/EtOAc) to afford 51 (1.05 g) as a brown oil in 97% yield. 1H NMR (300 MHz,CDCl3) delta 9.10 (d, J 2.0 Hz, 1H), 8.81 (d, J 2.1 Hz, 1H), 8.32 (t,J 2.1 Hz, 1H), 3.95 (s, 3H), 0.26 (s, 9H). 13C NMR (75 MHz, CDCl3)delta 165.2, 155.9, 149.6, 139.8, 125.5, 120.4, 100.4, 99.8, 52.6, 0.2. MS(ESI): m/z (%): 234 (100) [MH].
95%
With N-ethyl-N,N-diisopropylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In tetrahydrofuran; at 70℃; for 14h;Sealed vessel; Inert atmosphere;
Methyl 5-[2-(trimethylsilyl)ethynyl]pyridine-2-carboxylate (141 ): To an oven- dried round bottom flask equipped with a condenser and magnetic stir bar is added 140 (2.00 g, 9.30 mmol), bis (triphenylphosphine) palladium (II) dichloride (0.197 g, 0.28 mmol, 0.03 equiv) and copper (I) iodide (0.053 g, 0.28 mmol, 0.03 equiv). The vessel is then sealed with a rubber septum under argon, and then anhydrous THF (20 mL) and diisopropylethylamine (20 mL) is added. Finally, (trimethylsily)acetylene (1 .80 mL, 13.0 mmol, 1 .40 equiv) is added and the reaction mixture is heated to 70C in an oil bath for 14 h. The resulting yellow suspension is filtered through a celite pad, and the filtrate is condensed to dryness with a rotavapor, and the residue is treated with water (100 mL), extracted with EtOAc (3x100 mL). The combined extracts are washed with water (100 mL), brine (100 mL) and dried over anhydrous Na2SO . The crude product is purified by flash chromatography (eluting with 0-10% EtOAc in hexane) to afford 141 (2.06 g, 95% yield) as white solid. It changed to brown solid in 10 min. (Caution: prevent from exposure to light.). 1 H NMR (300 MHz, CDCI3) 50.25 (s, 9H), 3.92 (s, 3H), 7.49 (d, J=8.7 Hz, 1 H), 8.21 (d, J=10.5 Hz, 1 H), 9.12 (s, 1 H); 13C NMR (75 MHz, CDCI3) 50.20, 52.72, 98.65, 103.22, 125.00, 126.96, 137.36, 146.77, 151 .19, 165.44; MS (ESI, positive): m/z 224 [M+H+].
85%
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In acetonitrile; at 90℃;
A suspension of <strong>[29682-15-3]methyl 5-bromopicolinate</strong> 4 (2.65 g, 13.10 mmol), TMS-acetylene (3.70 mL, 26.20 mmol), Pd(PPh3)2Cl2 (0.46 g, 0.66 mmol) and CuI (0.25 g, 1.31 mmol) in acetonitrile (25 mL) in a reaction tube was heated while stirring at 90 C overnight. The reaction was filtered through celite and solid residue was washed three times with ether. Filtrate was concentrated and the crude residue purified by column using Hexane:EtOAc (5:2) to give compound 6 as a brown solid (2.60 g, 85 %). 1H NMR (400 MHz, CDCl3) delta 8.73 (s, 1H), 8.03 - 7.97 (m, 1H), 7.82 (ddd, J = 8.1, 2.0, 0.9 Hz, 1H), 3.94 (s, 3H), 0.27 (s, 9H). 13C NMR (101 MHz, CDCl3) delta 165.1, 152.3, 146.0, 139.7, 124.3, 123.7, 101.8, 100.5, 52.9, -0.5.
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In tetrahydrofuran; at 60℃; for 5h;
General procedure: A mixture of V-01 (922 mg, 4.292 mmol), ethynyltrimethylsilane (506 mg, 5.153 mmol), Pd(PPh3)2Cl2 (150 mg, 0.214 mmol), CuI (25 mg, 0.131 mmol), TEA (1.73 g, 17.16 mmol) was dissolved in anhydrous THF (20 mL). The mixture was stirred at 60 for 5 h. The solvent was removed under reduced pressure. The residue was partitioned between ethyl ether and water. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and then the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography with PE/EA (50/1-20/1) to give 0.9 g (90.4%) of V-13 as a brown oil.
Rieke Zinc (slightly excess by estimation) was stirred in 10 mL of THF under argon. tert- utyl 4-(bromomethyl)piperidine-l-carboxylate (1.0 g, 3.6 mmol) in 5 mL of THF was added. The resulting mixture was stirred at rt for 3 h. The solution was then allowed to settle and the supernatant was stransferred via a syringe to a stirred 5 mL of DMA solution. Methyl 5-bromopicolinate (0.78 g, 3.6 mmol) and Cl2Ni(Ph2PCH2CH2PPh2) were added sequentially, and the resulting mixture was stirred at rt for 60 h. LC-MS indicated a partial conversion. The reaction mixture was quenched with 15 mL of sat. NH4C1, and extracted with 50 mL of EtOAc. The organic layer was washed with brine (20 mL), dried over MgS04, filtered, and concentrated under reduced pressure to give an oil which was purified by silica gel flash chromatography, eluting with 10-80 % EtOAc in hexanes, to give methyl 5- - tert- butoxycarbonyl)piperidin-4-yl)methyl)picolinate as a white solid (200 mg, 17%).
With potassium carbonate;palladium bis[bis(diphenylphosphino)ferrocene] dichloride; In N,N-dimethyl-formamide; at 140℃; for 0.166667h;Inert atmosphere; microwave vial;
To a microwave vial was charged with methyl 5- bromopicolinate (250 mg, 1.22 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-l,3-dioxolan- 2-yl)-5,6-dihydropyridine-l(2H)-carboxylate (393 mg, 1.34 mmol), K2CO3 (400 mg, 3.03 mmol), and 3 mL of DMF. The vial was then flushed with argon whilePdCl2(dppf)2 (42 mg, 0.060 mmol) was added. The resulting mixture was then capped and heated at 140 C for 10 min in a microwave reactor. LC-MS indicated that the reaction was complete. The reaction mixture was then partitioned between EtOAc (25 mL) and water (10 mL). The organic layer was washed with brine (10 mL), dried over MgS04, filtered, and concentrated under reduced pressure to give an oil which was purified by silica gel column chromatography, eluting with 0-60% EtOAc in hexanes, to give methyl 5-(l-(tert-butoxycarbonyl)-l,2,3,6-tetrahydropyridin-4-yl)picolinate (250 mg, 68%). LC-MS (ESI) m/z 319 (M + H)+.
68%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In water; N,N-dimethyl-formamide; at 60 - 70℃; for 1.33333h;Inert atmosphere; Microwave irradiation;
a) step 1: methyl 5-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)picolinate To a solution of <strong>[29682-15-3]methyl 5-bromopicolinate</strong> (205 mg, 930 flmol) in DMF (2 ml) under nitrogen atroom temperature, was added tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-l(2H)-carboxylate (300 mg, 970 flmol), followed by sodium carbonate 2M aq.(650 f..Ll, 1.3 mmol). The reaction mixture was degased with argon for 10 minutes. Finally,dichloro[ 1,1 '-bis( diphenylphosphino )ferrocene ]palladium(II) dichloromethane adduct (30.5 mg, 41.7 flmol) was added and the mixture was then stirred at 60C in microwave for 10 minutes,and then 70C for 70 minutes. Ethyl acetate and water were added to the reaction mixture. Bothlayers were separated and the aqueous layer was extracted two times with ethyl acetate. Thecombined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo.The crude brown oil was purified with flash column chromatography on silica (Eluent: Heptane/ethyl acetate 0 to 20) to provide 202 mg (68 %) of the title compound as a white solid.MS (m/e): 319.5 (M+H-56)
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; ruphos; In toluene; at 100℃;Inert atmosphere;
Under N2, a mixture of tert-butyl piperazine-1 - carboxylate (448 mg, 2.41 mmol), methyl 5-bromopicoli- nate (520 mg, 2.41 mmol), Ruphos (109 mg, 0.24 mmol), Pd2(dba)3 (55 mg, 0.06 mmol) and Cs2CO3 (2.35 g, 7.23 mmol) in toluene (20 ml) was heated at 1000 C. for overnight. Then it was cooled to room temperature and filtered. The residue was concentrated in vacuum to afford a yellow solid (750 mg, 96%).
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 100℃; for 10h;Inert atmosphere;
Example 21Methyl 4-(6-((3-fluoro-2'-(trifluoromethyl)-2^'-bipyridin-5-yl)methylcarbamoyl)pyridin-3- yl)piperazine-l-carboxylate (49)[0206] Step 1 : To a flask containing <strong>[29682-15-3]methyl 5-bromopicolinate</strong> 49-1 (1.48 g, 6.85 mmol), tert-butyl piperazine- l-carboxylate 49-2 (1.53 g, 8.22 mmol), Pd2(dba)3 (315 mg, 0.34 mmol), BINAP (462 mg, 0.69 mmol) and Cs2C03 (5.50 g, 17.20 mmol) under argon was added anhydrous toluene (30 mL). The mixture was stirred at 100 C for 10 hours. After cooling to room temperature, the solvent was removed by rotary evaporation. The residue was redissolved in ethyl acetate (100 mL), washed with H20 and brine, dried over Na2S04, and concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flashchromatography, eluted with 5% methanol in dichloromethane to give tert-butyl 4-(6- (methoxycarbonyl)pyridin-3-yl)piperazine- l-carboxylate 49-3 as a yellow solid. MS m/z 322.1 (M + 1)
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 100℃;Inert atmosphere;
To a solution of <strong>[29682-15-3]methyl 5-bromopicolinate</strong> (14.8 g, 68.5 mmol) and tert-butyl piperazine-1-carboxylate (15.3 g,82.2 mmol) in toluene (150 mE) was added cesium carbonate (55.8 g, 171.3 mmol), tris(dibenzylideneacetone)dipalladium(O) (3.15 g, 3.44 mmol) and (+/-)-2,2?-l3is(diphenyl- phosphino)-1,1?-binaphthyl (4.62 g, 7.42 mmol), then it was stirred at 100 C. under nitrogen overnight. After cooling, it was quenched by water (100 mE) and extracted with ethyl acetate (100 mEx3). The combined organic layers were washed by brine (200 mE), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=5/1) to give tert-butyl 4-(6-(methoxycar- bonyl)pyridin-3-yl)piperazine-1 -carboxylate (12.0 g, 55% yield) as a brown solid. EC-MS: (Agilent ECMS 1200-6120, Column:Waters X-l3ridge C18 (30 mmx4.6 mmx3.5 jim); Column Temperature: 40 C.; Flow Rate: 2.0 mE/mm; Mobile Phase:from 90% [water+10 mM NH4HCO3] and 10% [CH3CN] to 5% [water+10 mM NH4HCO3] and 95% [CH3CN] in 1.0 mm, then under this condition for 1.0 mm). Purity is 82.48%, Rt=0.991 mm; MS Calcd.: 321.17; MS Found:322.2 [M+H]. Chemical Formula: C1 6H23N304, Molecular Weight: 321.37.
In methanol; benzene; at 20℃; for 1h;Inert atmosphere;
Example 29(i) (TMS)CHN2, MeOH, benzene, 0C to room temperature, 1 h, 87%. (ii) (trimethylsily)acetylene, PdCI2(PPh3)2, Cul, DIEA, THF, 70C, 14h, 95%. (iii) K2CO3, MeOH, room temperature, 40 min, 84%. (iv) 4-ethylnylaniline, Cu(OAc)2, pyridine, MeOH, room temperature, 20 h. (v) 3N NaOH, MeOH, reflux, 40 min, 31 % (from 142). (vi) EDC. HCI, HOBt, DIEA, DMF, 13, 0C, 1 h, then room temperature, 36h, 74%. (vii) hydroxylamine hydrochloride, 25% NaOMe/MeOH, THF, 0C, 2h, then room temperature, 16h, 40%.5-Bromopyridine-2-carboxylic acid (140): To an ice-cold solution of 139 (3.00 g, 15.0 mmol) dissolved in anhydrous MeOH (20 mL) and benzene (20 mL) is added dropwise (TMS)CHN2 (2.5 ml, 5.0 mmol, 2.0 equiv), then is allowed to warm to ambient temperature with stirring is continued under argon for 1 h. The reaction is monitored byLC/MS and TLC. The resulting solution is condensed to dryness with a rotavapor, and the residue is purified by CombiFlash (eluting with 0-10% EtOAc in hexane) to give 140 as with solid (2.79 g, 87 % yield). 1 H NMR (300 MHz, CDCI3) 53.93 (s, 3H), 7.56 (d, J=9.3 Hz, 1 H), 8.10 (d, J=10.5 Hz, 1 H), 8.93 (s, 1 H); 13C NMR (300 MHz, CDCIs) 552.88, 125.52, 128.28, 139.40, 147.03, 151 .62, 165.23; MS (ESI, positive): m/z 490 [M+H+].
In diethyl ether; toluene; at 20℃; for 4.5h;
To a suspension of 5-bromopicolinic acid (2.0 g, 9.94 mmol) in MeOH (2 mi toluene (20 ml) was added TMS-diazomethane (20M in diethyl ether; 5.47 ml, 10.94 mmol, Matrix Scientific) dropwise. The reaction was stirred at room temperature for 3 hours. An additional 0.2 eq (0.99 mL) of TMS-diazomethane was added and the reaction stirred for 1.5 hours. The reaction was concentrated and the brown solid was carried to next step without further work up. MS m/z [M+H]+ = 217.9. Calculated from C7H6BrN02: 216.032
In methanol; diethyl ether; toluene; at 20℃; for 4.5h;
To a suspension of 5-bromopicolinic acid (2.0 g, 9.94 mmol) in MeOH (2 ml)/toluene (20 ml) was added TMS-diazomethane (20M in Et2O; 5.47 ml, 10.94 mmol, Matrix Scientific) dropwise. The reaction was stirred at room temperature for 3 hours. An additional 0.2 eq (0.99 mL) of TMS-diazomethane was added and the reaction stirred for 1.5 hours. The reaction was concentrated and the brown solid was carried to next step without further work up. MS m/z [M+H]+ = 217.9.
Intermediate XVI5-(4-{(S)-1-[(S)-6-(2-Hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridine-2-carboxylic acid 2 M aqueous Na2CO3 solution (1.3 mL) was added to a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one (0.60 g) and <strong>[29682-15-3]5-bromo-pyridine-2-carboxylic acid methyl ester</strong> (0.41 g) in N,N-dimethylformamide (4 mL). The resulting mixture was sparged with argon for 10 min, before [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane complex (61 mg) was added. The mixture was heated to 100 C. and stirred at this temperature overnight. After cooling to ambient temperature, the mixture was diluted with ethyl acetate and extracted with water and brine. The aqueous extracts were combined, acidified (pH ca. 5-6) using citric acid, and extracted with CH2Cl2/MeOH (ca. 10:1). The combined organic extracts were washed with brine and dried (MgSO4). The solvent was removed and the residue was purified by chromatography on silica gel (CH2Cl2/MeOH 98:2->50:50) to afford the title compound as a resin-like solid.Yield: 0.44 g (73% of theory); Mass spectrum (ESI+): m/z=475 [M+H]+.
With potassium carbonate;[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); In 1,4-dioxane; water; at 80℃; for 16h;
Methyl 5-bromopicolinate (5.0 g, 23.1 mmol), <strong>[148839-33-2](5-chloro-2-methylphenyl)boronic acid</strong> (4.5 g, 26.6 mmol), Pd(dppf)Cl2 (1.9 g, 2.3 mmol), and K2CO3 (6.4 g, 46.3 mmol) were dissolved in 1,4-dioxane (100 mL) and water (25 mL) and the resulting mixture was heated to 80 C. After 16 h the resulting mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 110℃; for 12h;Inert atmosphere;
5-Bromo-pyridine-2-carboxylic acid methyl ester (CAN 29682-15-3, 2.16 g, 0.01 mol), cyclopropylboronic acid (CAN 411235-57-9, 0.9 g, 0.01 mol), tris(dibenzylideneacetone)dipalladium (CAN 52409-22-0, 0.2 g), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (CAN 161265-03-8, 0.3 g) and cesium carbonate (CAN 534-17-8, 3.3 g, 0.01 mol) was added into 1.4-dioxane (40 mL). The mixture was stirred for 12 h at 110 C. under nitrogen atmosphere. Subsequently, the mixture was filtered and concentrated. The residue was poured into water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give crude product. The crude product was purified by a flash column chromatography (silica gel, 50 g, eluting with 20% ethyl acetate in petroleum ether) to give product (0.8 g, 45%); MS (EI): m/e 178.1 [M+H]+.
45%
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 110℃; for 12h;Inert atmosphere;
5-Bromo-pyridine-2-carboxylic acid methyl ester (CAN 29682-15-3, 2.16 g, 0.01 mol), cyclopropylboronic acid (CAN 411235-57-9, 0.9 g, 0.01 mol),tris(dibenzylideneacetone)dipalladium (CAN 52409-22-0, 0.2 g), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (CAN 161265-03-8, 0.3 g) and cesium carbonate (CAN 534-17-8, 3.3 g, 0.01 mol) was added into 1.4-dioxane (40 mL). The mixture was stirred for 12 h at 110C under nitrogen atmosphere. Subsequently, the mixture was filtered and concentrated. The residue was poured into water (20 mL) and extracted with ethyl acetate - I l l -(3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give crude product. The crude product was purified by a flash column chromatography (silica gel, 50 g, eluting with 20% ethyl acetate in petroleum ether) to give product (0.8 g, 45%); MS (EI): m/e 178.1 [M+H]+.
A mixture of 5-bromo-pyridine-2-carboxylic acid methyl ester (CAN 29682-15-3, 50 g, 0.23 mol) and m-CPBA (CAN 937-14-4, 80 g, 0.46 mol) in 400 mL dry methylene chloride was heated to 60 C. for 20 h. After that, the mixture was quenched with saturated sodium sulfite solution and extracted with ethyl acetate (2×200 mL). The organic layer was washed with brine (2×200 mL) and evaporated to dryness. The residue was purified by column chromatography (silica gel, 300 g, eluting with 15% ethyl acetate in petroleum ether) to obtain a brown oil. The brown oil, 5-bromo-2-(methoxycarbonyl)pyridine 1-oxide (30 g, 0.13 mol) was added into phosphoryl trichloride (CAN 10025-87-3, 80 mL) at 0 C. over 1 h, then the mixture was heated to 95 C. for 1 h. After that the mixture was evaporated to dryness, the residue was dissolved in water (50 mL), extracted with ethyl acetate (3×50 mL) and the organic layer was evaporated to dryness to obtain the product as a white solid (19 g, 59%); MS (EI): m/e=249.9 [M+H]+.
{3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile hydrochloride[ No CAS ]
[ 29682-15-3 ]
[ 1416784-87-6 ]
Yield
Reaction Conditions
Operation in experiment
63.6%
With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In toluene; at 100℃;Inert atmosphere;
Step 1: methyl 5-{3-(cyanomethyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl}-7H- pyrrolo[2,3-d]pyrimidin-4-yl)- -pyrazol-l-yl]azetidin-l-yl}pyridine-2-carboxylateA mixture of 2,2'-bis(diphenylphosphino)-l, r-binaphthyl (660 mg, 1.1 mmol), {3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH- pyrazol-l-yl]azetidin-3-yl}acetonitrile hydrochloride (4.76 g, 10.7 mmol), methyl 5- bromopicolinate (3.00 g, 13.9 mmol), palladium acetate (240 mg, 1.1 mmol) and cesium carbonate (10 g, 32 mmol) in toluene (120 mL) was de-gassed and recharged with nitrogen for three times. The reaction mixture was stirred at 100Covernight. After cooling the reaction mixture was quenched with water, and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with MeOH indichloromethylene (0 - 5%) to afford the desired product (3.70 g, 63.6%). LCMS (M+H)+ : m/z = 545.3.
With tetrakis(triphenylphosphine) palladium(0); cesium fluoride; In 1,2-dimethoxyethane; at 100℃; for 0.25h;Inert atmosphere; Microwave irradiation;
Step 1 To a solution of 5-bromo-pyridine-2-carboxylic acid methyl ester (500 mg, 2.3 mmol, 1 eq) in dimethoxyethane (6 mL) was added <strong>[216019-28-2]3-isopropylphenylboronic acid</strong> (495 mg, 3 mmol, 1.3 eq) and cesium fluoride (1.05 g, 6.9 mmol, 3 eq). The mixture was degassed for 15 min and tetrakis(triphenylphosphine)palladium (133 mg, 0.12 mmol, 0.05 eq) was added. The mixture was heated at 100 C. for 15 min under microwave irradiation. After cooling, the mixture was poured on water (10 mL) and extracted with ethyl acetate (3*20 mL). The organic layers were dried over magnesium sulphate, filtered and evaporated to dryness. The crude residue was purified by flash chromatography using cyclohexane and ethyl acetate (100/0 to 0/100) to afford 5-(3-isopropyl-phenyl)-pyridine-2-carboxylic acid methyl ester as a colorless oil (380 mg, 64% yield).
64%
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,2-dimethoxyethane; at 100℃; for 0.25h;Microwave irradiation;
Step 1 To a solution of 5-bromo-pyridine-2-carboxylic acid methyl ester (500 mg, 2.3 mmol, 1 eq) in dimethoxyethane (6 mL) was added <strong>[216019-28-2]3-isopropylphenylboronic acid</strong> (495 mg, 3 mmol, 1.3 eq) and cesium fluoride (1.05 g, 6.9 mmol, 3 eq). The mixture was degassed for 15 min and tetrakis(triphenylphosphine)palladium (133 mg, 0.12 mmol, 0.05 eq) was added. The mixture was heated at 100 C. for 15 min under microwave irradiation. After cooling, the mixture was poured on water (10 mL) and extracted with ethyl acetate (3*20 mL). The organic layers were dried over magnesium sulphate, filtered and evaporated to dryness. The crude residue was purified by flash chromatography using cyclohexane and ethyl acetate (100/0 to 0/100) to afford 5-(3-isopropyl-phenyl)-pyridine-2-carboxylic acid methyl ester as a colorless oil (380 mg, 64% yield).
In tetrahydrofuran; diethyl ether; at 0 - 20℃; for 1h;
General procedure: To a solution of methyl 5-bromopicolinate (2.16 g, 10 mmol) in THF (50 mL) at 0 C was added a solution of 10 mL of 3.0 M methyl magnesium bromide in diethyl ether (30 mmol) dropwise over 0.5 h. The reaction mixture was stirred at rt for 1 h, quenched with saturated NH4C1 (1 mL) and partitioned between saturated NaHC03 (10 mL) and EtOAc (2* 15 mL). The combined organic layers were dried over Na2S04 and concentrated. The residue was purified by gradient elution on silica gel (0 to 20% EtOAc in petroleum) to afford the title compound as a yellow oil (1.75 g, 81%). LRMS m/z (M+H) 218.1 found, 218.1 required.
68%
In tetrahydrofuran; diethyl ether; at 0 - 20℃;Inert atmosphere;
[00494] Intermediate 45a: 2-(5-bromo-2-pyridyl)propan-2-oI[00495] To a solution of methyl 5-bromopyridine-2-carboxylate (2.lg, 9.72mmol) in dry THF(48mL) at 0 C, under nitrogen, was slowly added bromo(methyl)magnesium 2.7M in Et20 (10.8mL,29.l6mmol). The resulting solution was allowed to warm to room temperature and stirred overnight. The reaction was then quenched by the dropwise addition of sat. aq. NH4CI (2mL) then diluted with sat. aq. NaHCO3 (3OmL). The aqueous layer was extracted with EtOAc (2 x 3OmL). The combined organic extracts were washed with brine (3OmL), dried over Na2504 and concentrated in vacuo.The crude material was purified by flash column chromatography using an eluent of 0-100% EtOAcin heptane to give 2-(5-bromo-2-pyridyl)propan-2-ol (1 .43g, 6.64mmol, 68% yield) as a yellow oil.1H NMR (CDCI3, 400MHz) O/ppm: 7.89 (1H, m), 7.83 (1H, dd, J= 8.4Hz, 2.4Hz), 7.33 (1H, dd, J=8.4Hz, 0.8Hz), 4.41 (1 H, br 5), 1 .55 (6H, 5).MS Method 2: RT: 1.31 mi m/z 217.8 [M+H]
In tetrahydrofuran; at 0℃; for 1h;Inert atmosphere; Sealed tube;
Intermediate No.62-(5-Bromopyridin-2-yl)propan-2-olMethyl 5-bromopicolinate (500 mg, 2.31 mmol) was dissolved in THF (7.0 mL) and the flask was sealed with a septum and flushed with argon. The mixture was cooled to 0 C and methylmagnesium bromide (3.1 mL, 9.3 mmol, 3M in THF) was added. The resulting mixture was allowed to stir at 0 C for 1 hour before the reaction was quenched with saturated N2012/00129190 aqueous ammonium chloride and extracted with EtOAc. The organic layer was then washed with brine, dried over anhydrous MgSC , filtered, and concentrated in vacuo to afford the title compound, which was used without further purification. LRMS (ESI) calc'd for C8H10BrNO [M+H]+: 216, Found: 216.
5-Bromo-N-methylpicoIinaniide O N MeHN x 7 To a 50 mL flask is added methyl 5-bromopicolinate (2.0 g, 9.3 mmol) and methylamine (2 M, 18.5 mL, 37.0 mmol). The reaction mixture is stirred at room temperature overnight. After concentration, a white solid is obtained, which is used in next step without further purification (2.0 g, 100%). ( MS: [M+1] 216)
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; triphenylphosphine; In N,N-dimethyl-formamide; at 20 - 80℃; for 20h;
Step 1: 5-(3-Fluoro-phenylethynyl)-pyridine-2-carboxylic acid methyl ester Bis-(triphenylphosphine)-palladium(II)dichloride (406 mg, 580 muiotaetaomicron, 0.05 equiv.) was dissolved in 25 ml DMF. (2.5 g, 11.6 mmol) 5-Bromo-pyridine-2-carboxylic acid methyl ester and 3- fluorophenylacetylene (2.22 g, 18.5 mmol, 1.6 equiv.) were added at room temperature. Triethylamine (3.5 g, 4.84 ml, 34.7 mmol, 3 equiv.), triphenylphosphine (91 mg, 347 muiotaetaomicron, 0.03 equiv.) and copper(I)iodide (66 mg, 347 muiotaetaomicron, 0.03 equiv.) were added and the mixture was stirred for 20 hours at 80C. The reaction mixture was cooled and evaporated to dryness with Isolute sorbent. The crude product was purified by flash chromatography on silica gel (70 g) eluting with an ethyl acetate:heptane gradient 0: 100 to 80:20. The desired 5-(3-fluoro- phenylethynyl)-pyridine-2-carboxylic acid methyl ester (1.95 g, 66 % yield) was obtained as a light yellow solid, MS: m/e = 256.3 (M+H+).
66%
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; triphenylphosphine; In N,N-dimethyl-formamide; at 20 - 80℃; for 20h;
-(3-Fluoro-phenylethynyl)-pyridine-2-carboxylic acid methyl ester Bis-(triphenylphosphine)-palladium(II)dichloride (406 mg, 580 muiotaetaomicron, 0.05 equiv.) was dissolved in 25 ml DMF. (2.5 g, 11.6 mmol) 5-Bromo-pyridine-2-carboxylic acid methyl ester and 3- fluorophenylacetylene (2.22 g, 18.5 mmol, 1.6 equiv.) were added at room temperature. Triethylamine (3.5 g, 4.84 ml, 34.7 mmol, 3 equiv.), triphenylphosphine (91 mg, 347 muiotaetaomicron, 0.03 equiv.) and copper(I)iodide (66 mg, 347 muiotaetaomicron, 0.03 equiv.) were added and the mixture was stirred for 20 hours at 80C. The reaction mixture was cooled and evaporated to dryness with Isolute sorbent. The crude product was purified by flash chromatography on silica gel (70 g) eluting with an ethyl acetate: heptane gradient 0: 100 to 80:20. The desired 5-(3-fluoro- phenylethynyl)-pyridine-2-carboxylic acid methyl ester (1.95 g, 66 % yield) was obtained as a light yellow solid, MS: m/e = 256.3 (M+H+).
With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine; In tetrahydrofuran; at 40℃;Sealed tube; Inert atmosphere;
To a sealed tube were added methyl 5-bromopyridine-2-carboxylate (450 mg, 2.083 mmol) in THF (4 ml) followed by tetrakis(triphenylphosphine)palladium (193 mg, 0.167 mmol), copper(i) iodide (20 mg, 0.104 mmol), triethylamine (2.3 ml, 16.66 mmol) under N2. Finally cyclopropylacetylene (275 mg, 4.17 mmol) was added. The yellow mixture was stirred at 40 C. for overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4. The solution was filtered and concentrated to give the crude material as an orange oil. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 15% to 30% to 45% EtOAc in Heptane, to provide methyl 5-(cyclopropylethynyl)picolinate (390 mg, 1.938 mmol, 93% yield) as an orange solid. MS m/z=202.2 (M+H).
93%
With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine; In tetrahydrofuran; at 40℃;Inert atmosphere;
To a microwave vial were added methyl 5-bromopyridine-2-carboxylate (0.285 mL, 2.083 mmol), THF (4 mL), tetrakis(triphenylphosphine)palladium (193 mg, 0.167 mmol), copper(i) iodide (3.53 mul, 0.104 mmol), and triethylamine (2.318 mL, 16.66 mmol) under nitrogen. Cyclopropylacetylene (0.353 mL, 4.17 mmol) was added and the resulting yellow mixture was stirred at 40 C. overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with saturated NaCl and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude material as an orange oil. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column, eluting with a gradient of 15% to 30% to 45% EtOAc in Heptane, to provide methyl 5-(cyclopropylethynyl)picolinate (390 mg, 1.938 mmol, 93% yield) as an orange solid. m/z (ESI+) 202.2 (M+H)+.
methyl 5-(prop-1-yn-1-yl)pyridinecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
38%
With tetrakis(triphenylphosphine) palladium(0) In toluene at 100℃;
2 Step 2: Methyl 5-(prop-1 -yn-1 -yl)picolinate
To a solution of methyl 5-bromopicolinate (0.60g, 2.77 mmol) in toluene (50 mL) was added tributyl(prop-1 -yn-1 -yl)stannane (1.01 mL, 3.32 mmol, Sigma Aldrich) and tetrakis(triphenylphosphine)palladium (0.04 g, 0.036 mmol, Strem Chemicals, Inc.). The reaction was stirred overnight at 100 °C. The reaction was allowed to cool to RT and concentrated. The residue was adsorbed onto a plug of 10% w/w KF Silica and chromatographed with a silica gel column eluting with a gradient of 10% to 100% EtOAc in hexane, to provide methyl 5-(prop-1 -yn-1 -yl)picolinate (0.18, 1.05 mmol, 38% yield). MS m/z [M+H]+ = 176.0
37.8%
With tetrakis(triphenylphosphine) palladium(0) In toluene at 100℃;
85.2 Methyl 5-(prop-l-yn-l-yl)picolinate
To a solution of methyl 5-bromopicolinate (0.60g, 2.77 mmol) in toluene (50 mL) was added tributyl(prop-l -yn-l-yl)stannane (1.01 mL, 3.32 mmol, Sigma Aldrich) and tetrakis(triphenylphosphine)palladium (0.04 g, 0.036 mmol, Strem Chemicals, Inc.). The reaction was stirred overnight at 100 °C. The reaction was allowed to cool to rt and concentrated. The residue was adsorbed onto a plug of 10% w/w KF Silica and chromatographed with a silica gel column eluting with a gradient of 10% to 100% EtOAc in hexane, to provide methyl 5-(prop-l-yn-l -yl)picolinate (0.18, 1.05 mmol, 37.8 % yield). MS m/z [M+H]+ = 176.0. Calculated from Ci0H9NO2: 175.184
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In N,N-dimethyl acetamide; at 80℃; for 12h;Inert atmosphere;
To a mixture of 2,2'-(9,9-dihexyl-9H-fluorene-2,7-diyl)-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (60 mg,0.093 mmol), picMe-Br (106 mg, 0.47 mmol), and tetrakis(triphenylphosphine) palladium [Pd(PPh3)4] (6 mg) was added a degassed mixture of DMA (8 mL) and potassium carbonate (129 mg, 0.93 mmol). The mixture was stirredat 80 C for 12 h under the protection of nitrogen. After cooled to RT, the mixture was poured into 60 mL distilled water. It was extracted with DCM (3 20 mL) and the combined organic layer was dried over anhydrous magnesium sulfate. The solvent was removed off by rotary evaporation and the residue was passed through a flash silica gel column with EA-DCM (V/V, 1/10) as the eluent to give colorless solid (40 mg, yield 66%). 1H NMR (CDCl3,400 MHz, TMS), delta (ppm): 9.04 (s, 2H), 8.25 (d, J = 8.0 Hz,2H), 8.10 (d, J = 8.0 Hz, 2H), 7.88 (d, J = 7.8 Hz, 2H), 7.65 (d, J = 7.8 Hz, 2H), 7.60 (s, 2H), 4.06 (s, 6H), 2.10-2.00 (m,4H), 1.38-0.94 (m, 24H), 0.78 (t, J = 6.8 Hz, 6H), MALDI-TOFMS (m/z) for C43H52N2O4, Calcd: 660.40, Found,660.43 [M], 683.41 [M+ + Na].
66%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In N,N-dimethyl acetamide; at 80℃; for 12h;Inert atmosphere;
To a mixture of 2,2?-(9,9-dihexyl-9H-fluorene-2,7-diyl)bis(4,4,5,5-tetramethyl-1,3,2-di-oxaborolane) (60mg, 0.093mmol), picMe-Br (106mg, 0.47mmol), and tetrakis (triphenylphosphine) palladium [Pd(PPh3)4] (6mg) was added a degassed mixture of DMA (8mL) and potassium carbonate (129mg, 0.93mmol). The mixture was stirred at 80C for 12h under the protection of nitrogen. After cooled to RT, the mixture was poured into 60mL distilled water. It was extracted with DCM (3×20mL) and the combined organic layer was dried over anhydrous magnesium sulfate. The solvent was removed off by rotary evaporation and the residue was passed through a flash silica gel column with EA-DCM (V/V, 1/10) as the eluent to give colorless solid (40mg, yield 66%). 1H NMR (CDCl3, 400MHz, TMS), delta (ppm): 9.04 (s, 2H), 8.25 (d, J=8.0Hz, 2H), 8.10 (d, J=8.0Hz, 2H), 7.88 (d, J=7.8Hz, 2H), 7.65 (d, J=7.8Hz, 2H), 7.60 (s, 2H), 4.06 (s, 6H), 2.10-2.00 (m, 4H), 1.38-0.94 (m, 24H), 0.78 (t, J=6.8Hz, 6H), MALDI-TOF MS (m/z) for C43H52N2O4, Calcd: 660.40, Found, 660.43 [M], 683.41 [M++Na].
With caesium carbonate; (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl; bis(dibenzylideneacetone)-palladium(0); In 1,4-dioxane; at 130℃; for 3h;Microwave irradiation;
Step 2: (0941) A mixture of methyl 5-bromopyridine-2-carboxylate (compound 95-A-1, 0.72 g, 3.28 mmol), <strong>[1246551-25-6]tert-butyl 3-oxo-1,2,5,6,8,8a-hexahydroimidazo[1,5-a]pyrazine-7-carboxylate</strong> (racemic compound M, 0.40 g, 1.64 mmol), bis(dibenzylideneacetone) palladium (94.4 mg, 0.164 mmol), (+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (196.8 mg, 0.33 mmol), cesium carbonate (160.4 mg, 4.92 mmol) in dioxane (3 mL) was stirred for 3 hours at 130 C. in microwave. After removal of solvent, the residue was purified by column to afford product 95-A-2 as white solid. MS: calc'd 377 (MH+), measured 377 (MH+).
To a mixture of <strong>[29682-15-3]methyl 5-bromopicolinate</strong> (0.5 g, 2.31 mmol), Cul (0.18 g, 0.69 mmol), Pd(PPh3)4 (0.27 g, 0.23 mmol) and trimethylamine (10 ml) was added trimethyl(prop-1-yn-1-yl)silane (0.4 ml, 3.47 mmol) at room temperature. To the resultant mixture was added a solution of tetrabutylammonium fluoride (TBAF) (1 M in THE, 4.29 ml) over 20 minutes. The mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with 0H2012. The organic layer was collected, dried over anhydrous MgSO4 and concentrated in vacuo to yieldproduct as black oil. The product obtained was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 2, Rf = 0.4) to give the title compound (Example 4-1) (0.31g, 75.61%)
With sodium hydroxide; In tetrahydrofuran; at 0 - 20℃; for 15h;
General procedure: Ester (FAE, 4a-m, 2a or 2b) (500 mg scale, 1 equiv.) was dissolvedin 6 ml THF at 0 C in a 25 ml round-bottom flask. ThenNaOH(aq) (5 equiv.) was added dropwise and stirred for 15 h atroom temperature. After starting materials were consumed (byTLC), water (20 ml) was added. The reaction mixture was washedwith ethyl acetate (2 x 20 ml). The aqueous solution was acidified(pH 2-3) with 1 M HCl(aq) causing precipitation of a solid, whichwas filtered and dried under vacuum. Recrystallization in ethanolafford clean compound.
With lithium hydroxide monohydrate; In tetrahydrofuran; water; at 20℃;
General procedure: Step 1: To the stirred solution of compounds 5 and 7 (1.0 eq) in themixture of THF and water (2:1) was added lithium hydroxide monohydrate(2.2 eq), and the reaction mixture was stirred at room temperaturefor 4 h. The reaction mixture was concentrated under vacuo and diluted with water, acidified with an aqueous solution of citric acidup to pH-4 ~ 5. The compound was extracted with ethyl acetate, andthe combined organic layers were washed with brine, dried over anhyd.Na2SO4, filtered and concentrated under vacuo to afford acids 6 and 8. To the stirred solution of carboxylic acid (3 and 4) (1.0 eq) in DCM(10 mL/ mmol) was added carbonyldiimidazole (CDI) (1.1 eq) and thereaction mixture was stirred for 30 min. N-hydroxybenzamidine, 2(1.0 eq) was added to this mixture and was stirred at room temperaturefor 6 h. After completion, the reaction mixture was diluted with DCM,washed with water and brine, dried over anhyd. Na2SO4, filtered andconcentrated under vacuo. The crude product was dissolved in tolueneand refluxed for 16 h. After completion of the reaction (monitored byTLC), the reaction mixture was cooled, and the solvent was removedunder vacuo. The product was purified by column chromatographyeluted with ethyl acetate:hexane (2:8) to yield the pure product.
methyl 6-methoxy-[2,3'-bipyridine]-6'-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With caesium carbonate; In 1,4-dioxane; water; at 110.0℃; for 1.5h;Sealed tube; Microwave irradiation;
General procedure: A mixture 2a or 2b (1 g, 1 equiv.), anappropriate pinacol boronate ester (1.2 equiv.), [1,10-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (10 mol %), cesium carbonate (2.0 equiv.), 1,4-dioxane (8 ml) and water (4 ml) was sealed in a 20 ml microwavereaction vial (Biotage). The vial was irradiated in a microwaveapparatus at 110 C, normal absorption for 30-90 min. The reactionmixture was cooled to room temperature and work up was performedas described in method 1 to obtain the esters 4b-i.
With caesium carbonate; In 1,4-dioxane; water; at 110℃; for 1.5h;Sealed tube; Microwave irradiation;
General procedure: A mixture 2a or 2b (1 g, 1 equiv.), anappropriate pinacol boronate ester (1.2 equiv.), [1,10-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (10 mol %), cesium carbonate (2.0 equiv.), 1,4-dioxane (8 ml) and water (4 ml) was sealed in a 20 ml microwavereaction vial (Biotage). The vial was irradiated in a microwaveapparatus at 110 C, normal absorption for 30-90 min. The reactionmixture was cooled to room temperature and work up was performedas described in method 1 to obtain the esters 4b-i.
methyl 5-(5-methylthiophen-2-yl)picolinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With caesium carbonate; In 1,4-dioxane; water; at 110℃; for 1.5h;Sealed tube; Microwave irradiation;
General procedure: A mixture 2a or 2b (1 g, 1 equiv.), anappropriate pinacol boronate ester (1.2 equiv.), [1,10-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (10 mol %), cesium carbonate (2.0 equiv.), 1,4-dioxane (8 ml) and water (4 ml) was sealed in a 20 ml microwavereaction vial (Biotage). The vial was irradiated in a microwaveapparatus at 110 C, normal absorption for 30-90 min. The reactionmixture was cooled to room temperature and work up was performedas described in method 1 to obtain the esters 4b-i.
With caesium carbonate In 1,4-dioxane; water at 110℃; for 1.5h; Sealed tube; Microwave irradiation;
4.2.3.1.2. Method 2.
General procedure: A mixture 2a or 2b (1 g, 1 equiv.), anappropriate pinacol boronate ester (1.2 equiv.), [1,10-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (10 mol %), cesium carbonate (2.0 equiv.), 1,4-dioxane (8 ml) and water (4 ml) was sealed in a 20 ml microwavereaction vial (Biotage). The vial was irradiated in a microwaveapparatus at 110 °C, normal absorption for 30-90 min. The reactionmixture was cooled to room temperature and work up was performedas described in method 1 to obtain the esters 4b-i.
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; ruphos; In toluene; at 100℃; for 18h;Inert atmosphere;
Under N2, a mixture <strong>[5978-75-6]9H-<strong>[5978-75-6]fluoren-9-amine hydrochloride</strong></strong> (100 mg, 0.46 mmol) and methyl 5-bromopicolinate (105 mg, 0.49 mmol), tris(dibenzylideneacetone)dipalladium (21 mg, 0.023 mmol), RuPhos (43 mg, 0.092 mmol) and cesium carbonate (450 mg, 1.38 mmol) in toluene (4 ml) was heated at 100 C. for 18 hrs. Then it was cooled to room temperature and filtrated. The filtrate was dissolved in methanol (1 ml) and acetic acid (1 ml). Sodium cyanoborohydride (58 mg, 0.92 mmol) was added at 0 C. It was stirred at 0 C. to room temperature for 6 hrs. Then it was concentrated in vacuo. The residue was mixed with saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The combined organic layers were concentrated in vacuo and the residue was purified by pre-TLC to give compound methyl 5-(9H-fluoren-9-ylamino)picolinate as an oil. (130 mg, 90%).
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; for 3h;Reflux;
10500] A mixture of the Compound 1 (830 mg), the Compound 2 (1.0 g), tetrakis(triphenylphosphine)palladium (802 mg), an aqueous solution of sodium carbonate (2 mol/L, 4.63 mE), toluene (15 mE), ethanol (5 mE), and water (2 mE) was heated under reflux for 3 hours. The reaction mixture was allowed to cool to room temperature, and then ethyl acetate was added thereto, and the resulting mixture was stirred, and then the resulting organic layers were separated, washed with water, dried, and concentrated under reduced pressure. The resulting residues were purified by silica gel column chromatography (hexane:ethyl acetate=90:10 to 55:45) to give the Compound 3 (706 mg) as a colorless powdet MS (APCI): mlz 256 [M+H]
706 mg
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; for 3h;Reflux;
Compound 1 (830 mg),Compound 2 (1.0 g),Tetrakis (triphenylphosphine) palladium(802 mg),Aqueous sodium carbonate solution(2 mol / L, 4.63 mL),Toluene (15 mL),Ethanol (5 mL),Water (2 mL)Was heated to reflux for 3 hours.The reaction mixture was allowed to cool to room temperature,After adding ethyl acetate and stirring,The organic layer was separated,Wash with water,Dried and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90: 10 to 55: 45) to obtain compound 3 (706 mg) as a colorless powder.
methyl 5-(4-n-octyloxyphenyl)pyridine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49%
With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In 1,2-dimethoxyethane; water; at 85℃; for 3h;Inert atmosphere;
General procedure: δIn a 100 mL two-necked round-bottomed flask, commercially available Methyl 5-bromopyridine-2-carboxylate (0.75 mmol) and 4-alkoxyboronic acids 2a-e (0.75 mmol) were dissolved in 1,2-dimetoxyethane (15 mL) and then catalytic amount of Pd(PPh3)4 (0.0325 mmol) under Argon atmosphere. To this solution, saturated aqueous solution of NaHCO3 was added and the reaction mixture was heated to reflux for 3 h at 85 C. The end of the reaction was monitored by TLC (hexane: ethyl acetate/3:1). After removing the volatile components in vacuo, the resulting mixture was extracted into CHCl3 (x 3) and the combined organic phases were washed with saturated aqueous NaCl solution and dried over Na2SO4. The solvent was removed under reduced pressure. The residue was dissolved in chloroform and filtered on silica gel in order to remove the catalyst. After evaporation of the solvent, the crude product was purified by column chromatography on silicagel eluting with hexane:ethyl acetate/3:1.The optical rotation of compounds 3d and 3e was measured for the proof of the optical purity.The characterization of the final compounds is based on 1H, 13C NMR (Bruker Avance III 500 spectrometer, in CDCl3 solution, with tetramethylsilane as internal standard). The detection of molecular ions was performed by full MS electrospray ionization [MS ESI (+)].The proposed structures are in full agreement with the spectroscopic data.2.2.2. Methyl 5-(4-n-octyloxyphenyl)pyridine-2-carboxylate (3a)Yield: 49%, 0.125 g; colorless crystals. 1H-NMR (500 MHz,CDCl3): δ(ppm) 8.95 (dd, Jz2.4 Hz and 0.6 Hz, Pyridine Ar-H),8.19 (dd, Jz8.2 Hz and 0.6 Hz, Pyridine Ar-H), 7.99 (dd, Jz8.2 Hzand 2.4 Hz, Pyridine Ar-H), 7.58 (d, Jz8.8 Hz, 2 Ar-H), 7.03 (d,Jz8.8 Hz, 2 Ar-H), 4.04-4.01 (m, 5H, OCH2 and OCH3), 1.85-1.80(m, 2H, CH2), 1.52-1.46 (m, 2H, CH2), 1.41-1.26 (m, 8H, 4 CH2), 0.90(t, Jz7.0 Hz, 3H, CH3). 13C-NMR (125 MHz, CDCl3):δ (ppm) 165.74 (CO), 160.07, 145.68, 139.48, 128.64 (Ar-C), 147.81,134.33, 128.47, 125.22, 115.31 (Ar-CH), 68.22 (OCH2), 52.87 (OCH3),31.80, 29.34, 29.23, 29.19, 26.02, 22.65 (CH2), 14.09 (CH3).C21H27NO3 MW: 341.44 g/mol. Full MS ESI (electrospray ionization)(+) [50.00-1000.00]: 341 (58) [M], 282 (59) [M-C2H3O2], 170(100) [C11H8NO].
methyl 5-(4-n-decyloxyphenyl)pyridine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37%
With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In 1,2-dimethoxyethane; water; at 85℃; for 3h;Inert atmosphere;
General procedure: deltaIn a 100 mL two-necked round-bottomed flask, commercially available Methyl 5-bromopyridine-2-carboxylate (0.75 mmol) and 4-alkoxyboronic acids 2a-e (0.75 mmol) were dissolved in 1,2-dimetoxyethane (15 mL) and then catalytic amount of Pd(PPh3)4 (0.0325 mmol) under Argon atmosphere. To this solution, saturated aqueous solution of NaHCO3 was added and the reaction mixture was heated to reflux for 3 h at 85 C. The end of the reaction was monitored by TLC (hexane: ethyl acetate/3:1). After removing the volatile components in vacuo, the resulting mixture was extracted into CHCl3 (x 3) and the combined organic phases were washed with saturated aqueous NaCl solution and dried over Na2SO4. The solvent was removed under reduced pressure. The residue was dissolved in chloroform and filtered on silica gel in order to remove the catalyst. After evaporation of the solvent, the crude product was purified by column chromatography on silicagel eluting with hexane:ethyl acetate/3:1.The optical rotation of compounds 3d and 3e was measured for the proof of the optical purity.The characterization of the final compounds is based on 1H, 13C NMR (Bruker Avance III 500 spectrometer, in CDCl3 solution, with tetramethylsilane as internal standard). The detection of molecular ions was performed by full MS electrospray ionization [MS ESI (+)].The proposed structures are in full agreement with the spectroscopic data.
methyl 5-(4-(S)-3,7-dimethyloctyloxyphenyl)pyridine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In 1,2-dimethoxyethane; water; at 85℃; for 3h;Inert atmosphere;
General procedure: deltaIn a 100 mL two-necked round-bottomed flask, commercially available Methyl 5-bromopyridine-2-carboxylate (0.75 mmol) and 4-alkoxyboronic acids 2a-e (0.75 mmol) were dissolved in 1,2-dimetoxyethane (15 mL) and then catalytic amount of Pd(PPh3)4 (0.0325 mmol) under Argon atmosphere. To this solution, saturated aqueous solution of NaHCO3 was added and the reaction mixture was heated to reflux for 3 h at 85 C. The end of the reaction was monitored by TLC (hexane: ethyl acetate/3:1). After removing the volatile components in vacuo, the resulting mixture was extracted into CHCl3 (x 3) and the combined organic phases were washed with saturated aqueous NaCl solution and dried over Na2SO4. The solvent was removed under reduced pressure. The residue was dissolved in chloroform and filtered on silica gel in order to remove the catalyst. After evaporation of the solvent, the crude product was purified by column chromatography on silicagel eluting with hexane:ethyl acetate/3:1.The optical rotation of compounds 3d and 3e was measured for the proof of the optical purity.The characterization of the final compounds is based on 1H, 13C NMR (Bruker Avance III 500 spectrometer, in CDCl3 solution, with tetramethylsilane as internal standard). The detection of molecular ions was performed by full MS electrospray ionization [MS ESI (+)].The proposed structures are in full agreement with the spectroscopic data.
methyl 5-(4-(3,7-dimethyloctyloxy)phenyl)pyridine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In 1,2-dimethoxyethane; water; at 85℃; for 3h;Inert atmosphere;
General procedure: deltaIn a 100 mL two-necked round-bottomed flask, commercially available Methyl 5-bromopyridine-2-carboxylate (0.75 mmol) and 4-alkoxyboronic acids 2a-e (0.75 mmol) were dissolved in 1,2-dimetoxyethane (15 mL) and then catalytic amount of Pd(PPh3)4 (0.0325 mmol) under Argon atmosphere. To this solution, saturated aqueous solution of NaHCO3 was added and the reaction mixture was heated to reflux for 3 h at 85 C. The end of the reaction was monitored by TLC (hexane: ethyl acetate/3:1). After removing the volatile components in vacuo, the resulting mixture was extracted into CHCl3 (x 3) and the combined organic phases were washed with saturated aqueous NaCl solution and dried over Na2SO4. The solvent was removed under reduced pressure. The residue was dissolved in chloroform and filtered on silica gel in order to remove the catalyst. After evaporation of the solvent, the crude product was purified by column chromatography on silicagel eluting with hexane:ethyl acetate/3:1.The optical rotation of compounds 3d and 3e was measured for the proof of the optical purity.The characterization of the final compounds is based on 1H, 13C NMR (Bruker Avance III 500 spectrometer, in CDCl3 solution, with tetramethylsilane as internal standard). The detection of molecular ions was performed by full MS electrospray ionization [MS ESI (+)].The proposed structures are in full agreement with the spectroscopic data.
methyl 5-[8-(benzyloxy)-2-methylimidazo[1,2-a]pyridin-3-yl]pyridine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
With palladium diacetate; caesium carbonate; triphenylphosphine In 1,4-dioxane for 48h; Reflux;
5.1.22. Methyl 5-[8-(benzyloxy)-2-methylimidazo[1,2-a]pyridin-3-yl]pyridine-2-carboxylate (5)
A mixture of 3 (1.50 g, 6.29 mmol), methyl 5-bromopyridine-2-carboxylate (1.50 g, 6.94 mmol), Pd(OAc)2 (150 mg, 0.67 mmol), PPh3(350 mg, 1.33 mmol), and Cs2CO3 (3.10 g, 9.51 mmol) in 1,4-dioxane(30 mL) was refluxed for 2 days with stirring and allowed to cool toroom temperature. The mixture was filtered through a Celite pad andevaporated in vacuo. The residue was purified using silica-gel columnchromatography (hexane/EtOAc=1:0 to 1:4) to give the product(1.47 g, 62% yield). 1H NMR (CDCl3) δ ppm 2.54 (3H, s), 4.06 (3H, s),5.38 (2H, s), 6.52 (1H, d, J=7.6 Hz), 6.64 (1H, t, J=7.0 Hz),7.29-7.41 (3H, m), 7.47-7.53 (2H, m), 7.69-7.74 (1H, m), 7.96 (1H,dd, J=8.0, 2.2 Hz), 8.29 (1H, dd, J=8.1, 0.7 Hz), 8.87-8.89 (1H, m);MS (ESI) m/z [M+H]+ 374.
Stage #1: 1H-imidazole; methyl 5-bromopicolinate With copper(l) iodide; 1,10-Phenanthroline; potassium carbonate In N,N-dimethyl-formamide at 75℃; for 72h; Inert atmosphere;
Stage #2: With water
Preparation of Acid BG
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed methyl 5-bromopyridine-2-carboxylate (1.00 g, 4.629 mmol, 1.00 equiv), imidazole (630.26 mg, 9.258 mmol, 2.00 equiv), CuI (88.16 mg, 0.463 mmol, 0.1 equiv), 1,10- phenanthroline (166.83 mg, 0.926 mmol, 0.20 equiv), K2CO3(1919.22 mg, 13.887 mmol, 3.00 equiv), DMF (20.00 mL). The resulting solution was stirred for 3 days at 75 °C. The solids were collected by filtration. The resulting solid was diluted with 20 mL of water. The pH value of the solution was adjusted to 5 with HCl (1M). The resulting mixture was concentrated. The crude product was purified by re-crystallization from MeOH. This resulted in 400 mg (crude) of 5- (imidazol-1-yl)pyridine-2-carboxylic acid as a off-white solid. LCMS: [M+1]+=204.
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