* 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 potassium permanganate; Aliquat 336 In water at 110℃; for 2.5 h;
After dissolving 2-bromo-5-picoline (100 g, 0.291 mol) in 1000 ml of water, Aliquat336 (2 ml) was added, and then potassium permanganate (251 g, 0.797 mol) was gradually added over a period of 1 hour and 30 minutes while stirring at 110°C. This mixture was further stirred for an hour, the reaction mixture was filtered through celite without cooling and washed with water, and the filtrate was concentrated to approximately half volume under reduced pressure. After adding 48percent hydrobromic acid (.similar.300 ml), the precipitated crystals were filtered, washed with water and dried to yield the title compound (white crystals 52 g, 44percent).1H-NMR(CDCl3)δ(ppm) 7.64(1H,d,J=8.0Hz), 8.08(1H,d,J=8.0Hz), 9.03(1H,s).
Reference：
[1] Synthesis, 1994, # 1, p. 87 - 92
[2] Journal of Materials Chemistry, 2005, vol. 15, # 48, p. 5164 - 5173
[3] Patent: EP1391451, 2004, A1, . Location in patent: Page 143
[4] Journal of Organic Chemistry, 1949, vol. 14, p. 509,513
[5] Synthesis, 2003, # 4, p. 551 - 554
[6] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 21, p. 4681 - 4684
2
[ 5006-66-6 ]
[ 6311-35-9 ]
Reference：
[1] Patent: US4112102, 1978, A,
[2] Chemistry - A European Journal, 2010, vol. 16, # 7, p. 2170 - 2180
3
[ 1603-41-4 ]
[ 6311-35-9 ]
Reference：
[1] Synthesis, 1994, # 1, p. 87 - 92
[2] Journal of Organic Chemistry, 1949, vol. 14, p. 509,513
4
[ 149806-06-4 ]
[ 6311-35-9 ]
Reference：
[1] Green Chemistry, 2018, vol. 20, # 17, p. 3931 - 3943
5
[ 6311-35-9 ]
[ 79-37-8 ]
[ 6271-78-9 ]
Reference：
[1] Patent: US2018/65983, 2018, A1,
6
[ 6311-35-9 ]
[ 6271-78-9 ]
Reference：
[1] Journal of Organic Chemistry, 1949, vol. 14, p. 509,513
7
[ 67-56-1 ]
[ 6311-35-9 ]
[ 26218-78-0 ]
Yield
Reaction Conditions
Operation in experiment
55%
Stage #1: With oxalyl dichloride In dichloromethane for 1 h;
Methyl 6-bromonicotinate. In a 100 ml round-bottomed flask were placed 6-bromonicotinic acid (540 mg, 2.7 mmol), DCM (20 ml), and DMF (1 drop). Oxalyl chloride (1 ml) was added, resulting in vigorous gas evolution. The reaction was stirred for 1 hr after which the solvent was removed in vacuo. The residue was treated with MeOH and the solvent removed in vacuo. The residue was partitioned between DCM and saturated NaHCψ3 and the organic layer was dried over Na2SO4. The solvent was removed to afford 369 mg (55percent yield) of the methyl 6-bromonicotinate. 1H NMR (500 MHz) δ (ppm) 9.00 (dd, J = 2.0, 0.5 Hz, IH), 8.25 (dd, J= 8.5, 2.5 Hz, IH), 7.42 (dd, J= 8.5, 0.5 Hz, IH), 3.96 (s, 3H).
52%
at 0 - 70℃; for 3 h;
To a solution of 6-bromonicotinic acid (14.3, 2.0 g, 9.90 mmol) in methanol (20 mL), sulfuric acid (2.0 mL) was added at 0 °C and the reaction mixture was heated at 70 °C for 3 h. After completion, the reaction mixture was cooled to room temperature and solvent was removed under reduced pressure. The crude was diluted with water (50 mL) and pH was adjusted to 6 by saturated solution of sodium bicarbonate .The reaction mixture was extracted with ethyl acetate (100 mL), organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to get crude. The crude was purified by washings with diethyl ether and pentane to afford methyl 6- bromonicotinate (14.2) as yellow solid. Yield: 1.10 g, 52.0percent.
40%
Stage #1: With oxalyl dichloride; N,N-dimethyl-formamide In tetrahydrofuran; dichloromethane at 20℃; for 1 h; Stage #2: for 0.166667 h;
Step 2a. Methyl 6-bromonicotinate (compound 1001-5) To a solution of 6-bromonicotinic acid (500 mg, 2.5 mmol) in dichloromethane (10 mL) and THF (5 mL) was added oxalyl chloride (1.4 mL, 0.016 mol) followed by addition of one drop of DMF. The mixture was stirred at room temperature for 1 h. After removal of solvent, the residue was dissolved in anhydrous methanol (5 mL) and continued to stir for 10 min. The reaction mixture was quenched with ice water and filtered to afford 1001-5 as a pale yellow solid (212 mg, 40percent). LCMS: m/z 213.1 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 3.96 (s, 3H), 7.42 (d, J=8.4 Hz, 1H), 8.25 (dd, J=8.0 Hz, 2.0 Hz, 1H), 9.00 (d, J=2.0 Hz, 1H).
Reference：
[1] Journal of the American Chemical Society, 2011, vol. 133, # 34, p. 13445 - 13454
[2] Heterocycles, 1994, vol. 38, # 7, p. 1551 - 1572
[3] Patent: WO2008/21388, 2008, A1, . Location in patent: Page/Page column 191-192
[4] Patent: WO2018/126072, 2018, A1, . Location in patent: Paragraph 0255; 0256
[5] Patent: US2014/18368, 2014, A1, . Location in patent: Paragraph 0162; 0174
[6] Chemistry - A European Journal, 2010, vol. 16, # 7, p. 2170 - 2180
8
[ 6311-35-9 ]
[ 74-88-4 ]
[ 26218-78-0 ]
Yield
Reaction Conditions
Operation in experiment
94%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 12 h;
6-bromonicotinic acid (1.00g, 4.95mmol) was dissolved in N, N-dimethylformamide (30 mL) was added methyl iodide (0.703g, 4.95mmol) and potassium carbonate (1.03g, 7.43mmol). The reaction was stirred at 20 deg.] C for 12 hours. The reaction solution was added water (100 mL) was diluted, extracted with ethyl acetate (30mLx3),The organic phase was dried over anhydrous sodium sulfate, filtered,The filtrate was concentrated under reduced pressure, purified by silica gel column chromatography separation gel (2: 1 petroleum ether / ethyl acetate, Rf = 0.5) to give 6-bromo-nicotinic acid methyl ester (1.00 g of, white solid), yield: 94percent.
0.909 g
With potassium carbonate In N,N-dimethyl-formamide at 0 - 55℃; for 4 h;
Methyl iodide (1.06 g, 0.007 mole) was added at 0 - 5 °C to a stirred suspension of 6-bromonicotinic acid (1.0 g, 0.004 mol) and K2C03 ( 2.06 g, 0.014 mole) in DMF (15 inL) at 25 - 30 °C and then reaction mass was warmed to 55 °C for 4 hours. The reaction mixture was poured on to cold water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine solution (50 mL) and dried over anhydrous Na2S04 and concentrated under vacuum to obtain methyl 6-bromonicotinate. Yield: 0.909 g; - NMR (DMSO- , 400 MHz) δ ppm: 3.89 (s, 3H), 7.83 - 7.85 (d, J = 8.3 Hz, 1H), 8.18 - 8.21 (dd, J = 2.3, 8.2 Hz, 1H), 8.87 - 8.88 (d, J = 2.3 Hz, 1H); Mass (m/z): 216.1 (M+H) +.
Reference：
[1] Patent: CN105566324, 2016, A, . Location in patent: Paragraph 0517; 0518; 0519; 0520
[2] Patent: WO2018/42362, 2018, A1, . Location in patent: Page/Page column 44
9
[ 6311-35-9 ]
[ 18107-18-1 ]
[ 26218-78-0 ]
Reference：
[1] Chemical Communications, 2010, vol. 46, # 36, p. 6726 - 6728
[2] Green Chemistry, 2018, vol. 20, # 17, p. 3931 - 3943
10
[ 186581-53-3 ]
[ 6311-35-9 ]
[ 26218-78-0 ]
Reference：
[1] Journal of Organic Chemistry, 1949, vol. 14, p. 509,513
11
[ 6311-35-9 ]
[ 98-80-6 ]
[ 29051-44-3 ]
Yield
Reaction Conditions
Operation in experiment
67.1%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water for 6 h; Inert atmosphere
General procedure: Under an argon atmosphere, compound (16, 17, 18) (1 equiv.), boronic acid (1.2 equiv.) and Pd[P(C6H5)3]4(1molpercent) were dissolved in a mixed solution of dioxane/H2O (10:1). K2CO3 (2 equiv.) was added and the mixture was heated under reflux for 6h. The reaction mixture was cooled to room temperature and the dioxane was removed by rotary evaporation. H2O was added and the solution was adjusted to pH=1–3 with 2N HCl. The white solid precipitate was collected by filtration and dried to give the desired compound.
Reference：
[1] Inorganic Chemistry, 2012, vol. 51, # 4, p. 2105 - 2114
[2] European Journal of Inorganic Chemistry, 2012, # 7, p. 1025 - 1037
[3] Organic Letters, 2016, vol. 18, # 23, p. 6094 - 6097
[4] European Journal of Medicinal Chemistry, 2017, vol. 137, p. 96 - 107
12
[ 6311-35-9 ]
[ 23100-12-1 ]
Reference：
[1] Synthesis, 1994, # 1, p. 87 - 92
13
[ 6311-35-9 ]
[ 21543-49-7 ]
Reference：
[1] Synthesis, 1994, # 1, p. 87 - 92
14
[ 6311-35-9 ]
[ 149806-06-4 ]
Reference：
[1] Synthesis, 1994, # 1, p. 87 - 92
15
[ 6311-35-9 ]
[ 122306-01-8 ]
Yield
Reaction Conditions
Operation in experiment
74.5%
Stage #1: With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at 0℃; for 0.333333 h; Stage #2: With sodium tetrahydroborate In tetrahydrofuran; water at 0℃; for 1.83333 h;
After dissolving 6-bromonicotinic acid (65.7 g, 0.325 mol) in tetrahydrofuran (1600 ml), triethylamine (54 ml, 0.39 mol) and ethyl chloroformate (32.6 ml, 0.341 mol) were added while stirring on ice. The mixture was stirred for 20 minutes while cooling on ice, and the white crystals which precipitated upon filtration were removed and washed with tetrahydrofuran. The filtrate was stirred while cooling on ice, and an aqueous solution (211 ml) of sodium borohydride (18.4 g, 0.488 mol) was gradually added dropwise over a period of 30 minutes. After continued stirring for 1 hour and 20 minutes while cooling on ice, 800 ml of water was added and extraction was performed with ethyl acetate (600 ml x 2), and then after washing the combined organic layers with brine (300 ml) and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to yield the title compound (45.5 g, 74.5percent). This was used without further purification for the following reaction.1H-NMR(CDCl3)δ(ppm) 4.70(2H,s), 7.46(1H,d,J=8.0Hz), 7.59(1H,d,J=8.0Hz), 8.34(1H,brs).
Reference：
[1] Patent: EP1391451, 2004, A1, . Location in patent: Page 143-144
[2] Journal of Medicinal Chemistry, 1994, vol. 37, # 4, p. 542 - 550
[3] Journal of Medicinal Chemistry, 2012, vol. 55, # 7, p. 3201 - 3215
[4] Patent: CN105566324, 2016, A,
16
[ 6311-35-9 ]
[ 122306-01-8 ]
Yield
Reaction Conditions
Operation in experiment
59%
With BH3 In tetrahydrofuran; water
Step 2) 2-Bromo-5-hydroxymethylpyridine To a cooled (0° C.), stirred suspension of 6-bromonicotinic acid (13.8 g, 0.068 mol), prepared according to Campbell, et al. Aust. J. Chem. 1971, 24, 277, in THF (20 mL) was added 1.0M BH3 in THF (204 mL, 0.204 mol). The mixture was stirred at room temperature for 3 h, recooled to 0° C., and saturated aqueous K2 CO3 and water were added. The mixture was extracted with EtOAc, and the combined extracts were washed with water, dried (MgSO4), and concentrated to give a yellow oil. Purification by flash chromatography (2percent MeOH/CH2 Cl2) gave 7.5 g (59percent) of a yellow solid, mp 49°-51° C. 1 H NMR (DMSO-d6): d 4.50 (d, J=5.7 Hz, 2H), 5.40 (t, J=5.7 Hz, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.70 (dd, J=8.3 Hz, 1.5 Hz, 1H), 8.35 (d, J=1.5 Hz, 1H).
59%
With BH3 In tetrahydrofuran; water
Step 1) 2-Bromo-5-hydroxymethylpyridine To a cooled (0° C.), stirred suspension of 6-bromonicotinic acid (13.8 g, 0.068 mol), prepared according to Campbell, et al. Aust. J. Chem. 1971, 24, 277, in THF (20 mL) was added 1.0M BH3 in THF (204 mL, 0.204 mol). The mixture was stirred at room temperature for 3 h, recooled to 0° C., and saturated aqueous K2 CO3 and water were added. The mixture was extracted with EtOAc, and the combined extracts were washed with water, dried, and concentrated to give a yellow oil. Purification by flash chromatography (2percent MeOH/CH2 Cl2) gave 7.5 g (59percent) of a yellow solid, mp 49°-51° C. 1 H NMR (DMSO-d6) δ 4.50 (d, J=5.7 Hz, 2H), 5.40 (t, J=5.7 Hz, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.70 (dd, J=8.3, 1.5 Hz, 1H), 8.35 (d, J=1.5 Hz, 1H).
59%
With BH3 In tetrahydrofuran; water
Step 2 2-Bromo-5-hydroxymethylpyridine To a cooled (0° C.), stirred suspension of 6-bromonicotinic acid (13.8 g, 0.068 mol), prepared according to Campbell, et al. Aust. J. Chem. 1971, 24, 277, in THF (20 mL) was added 1.0M BH3 in THF (204 mL, 0.204). The mixture was stirred at room temperature for 3 h, recolled to 0° C., and saturated aqueous K2 CO3 and water were added. The mixture was extracted with EtOAc, and the combined extracts were washed with water, dried (MgSO4), and concentrated to give a yellow oil. Purification by flash chromatography (2percent MeOH/CH2 Cl2) gave 7.5 g (59percent) of a yellow solid, mp 49°-51° C. 1 H NMR (DMSO-d6): δ 4.50 (d, J=5.7 Hz, 2H), 5.40 (t, J=5.7 Hz, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.70 (dd, J=8.3 Hz, 1.5 Hz, 1H), 8.35 (d, J=1.5 Hz, 1H).
Reference：
[1] Patent: US5256654, 1993, A,
[2] Patent: US5283242, 1994, A,
[3] Patent: US5149699, 1992, A,
17
[ 6311-35-9 ]
[ 168173-56-6 ]
Reference：
[1] Journal of Medicinal Chemistry, 2012, vol. 55, # 7, p. 3201 - 3215
18
[ 6311-35-9 ]
[ 216444-00-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 9, p. 2074 - 2078
19
[ 6311-35-9 ]
[ 889676-37-3 ]
Yield
Reaction Conditions
Operation in experiment
81%
Stage #1: With 1,1'-carbonyldiimidazole In dimethyl sulfoxide at 20℃; for 16 h; Stage #2: With ammonia In water; dimethyl sulfoxide at 0℃; for 1 h;
Preparation 66-Brom o-nicotinam ideTo a solution of 6-bromo-nicotinic acid (4.8g, 23.8 mmol) in dimethylsulfoxide (20ml) was added at room temperature carbonyldiimidazole (4.8g, 29.6 mmol), and the mixture stirred for 16 hours. To the mixture was added dropwise, with cooling in ice bath, 0.880 ammonia solution (40ml), then the mixture stirred for 1 hour, then poured into water (20ml). The precipitate was filtered, washed with water and dried in vacuo to give the title product as a white solid in 81percent yield, 3.9g.1 HNMR(DMSO-D6, 300MHz) δ: 7.66(br.s, 1H), 7.73(d, 1H), 8.09(m, 1H), 8.15(br.s, 1H), 8.78(d, 1 H). <n="20"/>micro analysis found (percent); C(36.00), 1-1(2.60), N(13.67); C6H5N2Br requires (percent); C(35.84), H(2.51), N(13.93)
79%
Stage #1: With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 3 h; Stage #2: With ammonium hydroxide In tetrahydrofuran at 20℃;
A suspension of 6-Bromonicotinic acid (2 g) and CDI (1.8 g) in THF was stirred at room temperature. After 3 h the NH4OH (8 mL) were added dropwise to the mixture and stirred at room temperature overnight. Then, the solution was concentrated under reduced pressure. Light yellow solid. HPLC purity: 97.1percent. Yield: 79percent.
Reference：
[1] Journal of Medicinal Chemistry, 2018, vol. 61, # 11, p. 4860 - 4882
[2] Patent: WO2007/52124, 2007, A1, . Location in patent: Page/Page column 18-19
[3] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 17, p. 4150 - 4155
With potassium permanganate; Aliquat 336; In water; at 110℃; for 2.5h;
After dissolving 2-bromo-5-picoline (100 g, 0.291 mol) in 1000 ml of water, Aliquat336 (2 ml) was added, and then potassium permanganate (251 g, 0.797 mol) was gradually added over a period of 1 hour and 30 minutes while stirring at 110C. This mixture was further stirred for an hour, the reaction mixture was filtered through celite without cooling and washed with water, and the filtrate was concentrated to approximately half volume under reduced pressure. After adding 48% hydrobromic acid (?300 ml), the precipitated crystals were filtered, washed with water and dried to yield the title compound (white crystals 52 g, 44%).1H-NMR(CDCl3)delta(ppm) 7.64(1H,d,J=8.0Hz), 8.08(1H,d,J=8.0Hz), 9.03(1H,s).
After dissolving 6-bromonicotinic acid (65.7 g, 0.325 mol) in tetrahydrofuran (1600 ml), triethylamine (54 ml, 0.39 mol) and ethyl chloroformate (32.6 ml, 0.341 mol) were added while stirring on ice. The mixture was stirred for 20 minutes while cooling on ice, and the white crystals which precipitated upon filtration were removed and washed with tetrahydrofuran. The filtrate was stirred while cooling on ice, and an aqueous solution (211 ml) of sodium borohydride (18.4 g, 0.488 mol) was gradually added dropwise over a period of 30 minutes. After continued stirring for 1 hour and 20 minutes while cooling on ice, 800 ml of water was added and extraction was performed with ethyl acetate (600 ml x 2), and then after washing the combined organic layers with brine (300 ml) and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to yield the title compound (45.5 g, 74.5%). This was used without further purification for the following reaction.1H-NMR(CDCl3)delta(ppm) 4.70(2H,s), 7.46(1H,d,J=8.0Hz), 7.59(1H,d,J=8.0Hz), 8.34(1H,brs).
Methyl 6-bromonicotinate. In a 100 ml round-bottomed flask were placed <strong>[6311-35-9]6-bromonicotinic acid</strong> (540 mg, 2.7 mmol), DCM (20 ml), and DMF (1 drop). Oxalyl chloride (1 ml) was added, resulting in vigorous gas evolution. The reaction was stirred for 1 hr after which the solvent was removed in vacuo. The residue was treated with MeOH and the solvent removed in vacuo. The residue was partitioned between DCM and saturated NaHCtheta3 and the organic layer was dried over Na2SO4. The solvent was removed to afford 369 mg (55% yield) of the methyl 6-bromonicotinate. 1H NMR (500 MHz) delta (ppm) 9.00 (dd, J = 2.0, 0.5 Hz, IH), 8.25 (dd, J= 8.5, 2.5 Hz, IH), 7.42 (dd, J= 8.5, 0.5 Hz, IH), 3.96 (s, 3H).
52%
With sulfuric acid; at 0 - 70℃; for 3h;
To a solution of <strong>[6311-35-9]6-bromonicotinic acid</strong> (14.3, 2.0 g, 9.90 mmol) in methanol (20 mL), sulfuric acid (2.0 mL) was added at 0 C and the reaction mixture was heated at 70 C for 3 h. After completion, the reaction mixture was cooled to room temperature and solvent was removed under reduced pressure. The crude was diluted with water (50 mL) and pH was adjusted to 6 by saturated solution of sodium bicarbonate .The reaction mixture was extracted with ethyl acetate (100 mL), organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to get crude. The crude was purified by washings with diethyl ether and pentane to afford methyl 6- bromonicotinate (14.2) as yellow solid. Yield: 1.10 g, 52.0%.
40%
Step 2a. Methyl 6-bromonicotinate (compound 1001-5) To a solution of <strong>[6311-35-9]6-bromonicotinic acid</strong> (500 mg, 2.5 mmol) in dichloromethane (10 mL) and THF (5 mL) was added oxalyl chloride (1.4 mL, 0.016 mol) followed by addition of one drop of DMF. The mixture was stirred at room temperature for 1 h. After removal of solvent, the residue was dissolved in anhydrous methanol (5 mL) and continued to stir for 10 min. The reaction mixture was quenched with ice water and filtered to afford 1001-5 as a pale yellow solid (212 mg, 40%). LCMS: m/z 213.1 [M+1]+. 1H NMR (400 MHz, CDCl3): delta 3.96 (s, 3H), 7.42 (d, J=8.4 Hz, 1H), 8.25 (dd, J=8.0 Hz, 2.0 Hz, 1H), 9.00 (d, J=2.0 Hz, 1H).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 2h;
Synthesis of (6-bromopyridin-3-yl)(4-methylpiperazin-l-yl)methanone (152): 6- Bromonicotinic acid (151) (500 mg, 2.5 mmol) was dissolved in CH2C12 (15 mL) and 1- methylpiperazine (274 mg, 2.7 mmol) was added at 0 C. EDC1 (573 mg, 3 mmol) and HOBt (402 mg, 3 mmol) were added to this reaction mixture at 0 C followed by DIPEA (642 mg, 5 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was transferred into water (20 mL) and extracted with CH2C12 (30 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated under reduced pressure to give (6- bromopyridin-3-yl)(4-methylpiperazin-l-yl)methanone (152). Yield (400 mg, 52%). LCMS: m/z 285.1 M+H]+; = 1. 35 min.
With trifluoroacetic acid; In water; acetonitrile;
EXAMPLE 31 2-bromo-5-[(2-methylpyrrolidin-1-yl)carbonyl]pyridine The desired product was prepared by substituting <strong>[6311-35-9]6-bromonicotinic acid</strong> for 2-methylnicotinic acid in Example 1. After workup the crude compound was purified by HPLC on C-18 column using a solvent system increasing over 50 minutes in a gradient of 5% to 100% acetonitrile/water containing 0.01% TFA to provide the desired product as the trifluoroacetate salt. MS m/e 268.9 (M+H)+; 1H NMR (DMSO-d6) delta0.86 (d, 0.75H), 1.25 (d, 2.25H), 1.48-1.63 (m, 1H), 1.66-1.80 (m, 1H), 1.81-1.97 (m, 1H), 2.00-2.13 (m, 1H), 3.27-3.37 (m, 0.5H), 3.45-3.54 (m, 1.5H), 3.88-4.00 (m, 0.25H), 4.09-4.21 (m, 0.75H), 7.72 (d, 1H), 7.87 (dd, 1H), 8.52 (d, 1H).
With trifluoroacetic acid; In water; acetonitrile;
EXAMPLE 31 2-bromo-5-[(2-methylpyrrolidin-1-yl)carbonyl]pyridine The desired product was prepared by substituting <strong>[6311-35-9]6-bromonicotinic acid</strong> for 2-methylnicotinic acid in Example 1. After workup the crude compound was purified by HPLC on a C-18 column using a solvent system increasing over 50 minutes in a gradient of 5% to 100% acetonitrile/water containing 0.01% TFA to provide the desired product as the trifluoroacetate salt. MS m/e 268.9 (M+H)+; 1H NMR (DMSO-d6) delta 0.86 (d, 0.75H), 1.25 (d, 2.25H), 1.48-1.63 (m, 1H), 1.66-1.80 (m, 1H), 1.81-1.97 (m, 1H), 2.00-2.13 (m, 1H), 3.27-3.37 (m, 0.5H), 3.45-3.54 (m, 1.5H), 3.88-4.00 (m, 0.25H), 4.09-4.21 (m, 0.75H), 7.72 (d, 1H), 7.87 (dd, 1H), 8.52 (d, 1H).
With trifluoroacetic acid; In water; acetonitrile;
EXAMPLE 31 2-bromo-5-[(2-methylpyrrolidin-1-yl)carbonyl]pyridine The desired product was prepared by substituting <strong>[6311-35-9]6-bromonicotinic acid</strong> for 6-methylnicotinic acid in Example 1. After workup the crude compound was purified by HPLC on a C-18 column using a solvent system increasing over 50 minutes in a gradient of 5% to 100% acetonitrile/water containing 0.01% TFA to provide the desired product as the trifluoroacetate salt. MS m/e 268.9 (M+H)+; 1H1NMR (DMSO-d6) delta 0.86 (d, 0.75H), 1.25 (d, 2.25H), 1.48-1.63 (m, 1H), 1.66-1.80 (m, 1H), 1.81-1.97 (m, 1H), 2.00-2.13 (m, 1H), 3.27-3.37 (m, 0.5H), 3.45-3.54 (m, 1.5H), 3.88-4.00 (m, 0.25H), 4.09-4.21 (m, 0.75H), 7.72 (d, 1H), 7.87 (dd, 1H), 8.52 (d, 1H).
Step 2) 2-Bromo-5-hydroxymethylpyridine To a cooled (0 C.), stirred suspension of 6-bromonicotinic acid (13.8 g, 0.068 mol), prepared according to Campbell, et al. Aust. J. Chem. 1971, 24, 277, in THF (20 mL) was added 1.0M BH3 in THF (204 mL, 0.204 mol). The mixture was stirred at room temperature for 3 h, recooled to 0 C., and saturated aqueous K2 CO3 and water were added. The mixture was extracted with EtOAc, and the combined extracts were washed with water, dried (MgSO4), and concentrated to give a yellow oil. Purification by flash chromatography (2% MeOH/CH2 Cl2) gave 7.5 g (59%) of a yellow solid, mp 49-51 C. 1 H NMR (DMSO-d6): d 4.50 (d, J=5.7 Hz, 2H), 5.40 (t, J=5.7 Hz, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.70 (dd, J=8.3 Hz, 1.5 Hz, 1H), 8.35 (d, J=1.5 Hz, 1H).
7.5 g (59%)
With BH3; In tetrahydrofuran; water;
Step 1) 2-Bromo-5-hydroxymethylpyridine To a cooled (0 C.), stirred suspension of 6-bromonicotinic acid (13.8 g, 0.068 mol), prepared according to Campbell, et al. Aust. J. Chem. 1971, 24, 277, in THF (20 mL) was added 1.0M BH3 in THF (204 mL, 0.204 mol). The mixture was stirred at room temperature for 3 h, recooled to 0 C., and saturated aqueous K2 CO3 and water were added. The mixture was extracted with EtOAc, and the combined extracts were washed with water, dried, and concentrated to give a yellow oil. Purification by flash chromatography (2% MeOH/CH2 Cl2) gave 7.5 g (59%) of a yellow solid, mp 49-51 C. 1 H NMR (DMSO-d6) delta 4.50 (d, J=5.7 Hz, 2H), 5.40 (t, J=5.7 Hz, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.70 (dd, J=8.3, 1.5 Hz, 1H), 8.35 (d, J=1.5 Hz, 1H).
7.5 g (59%)
With BH3; In tetrahydrofuran; water;
Step 2 2-Bromo-5-hydroxymethylpyridine To a cooled (0 C.), stirred suspension of 6-bromonicotinic acid (13.8 g, 0.068 mol), prepared according to Campbell, et al. Aust. J. Chem. 1971, 24, 277, in THF (20 mL) was added 1.0M BH3 in THF (204 mL, 0.204). The mixture was stirred at room temperature for 3 h, recolled to 0 C., and saturated aqueous K2 CO3 and water were added. The mixture was extracted with EtOAc, and the combined extracts were washed with water, dried (MgSO4), and concentrated to give a yellow oil. Purification by flash chromatography (2% MeOH/CH2 Cl2) gave 7.5 g (59%) of a yellow solid, mp 49-51 C. 1 H NMR (DMSO-d6): delta 4.50 (d, J=5.7 Hz, 2H), 5.40 (t, J=5.7 Hz, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.70 (dd, J=8.3 Hz, 1.5 Hz, 1H), 8.35 (d, J=1.5 Hz, 1H).
6.A A.
A. 6-Bromonicotinic Acid Phosphorus pentabromide (18 g.) was added carefully to 6-hydroxynicotinic acid (4.17 g) and the resulting mixture was heated with stirring for about 1/4 hour at 70°-80° and then 1 hour at 120°. During the heating, the resulting dark red liquid solidified to a yellow mass. After cooling, the mass was added to iced water, and the resulting white precipitate of 6-bromonicotinic acid was filtered off, washed with water, and recrystallized from aqueous ethanol (yield 4g, m.p. 190°-195°). The compound was used directly in the next stage.
With phosphorus(V) oxybromide at 170℃; for 0.166667h; Neat (no solvent);
Preparation 66-Brom o-nicotinam ideTo a solution of <strong>[6311-35-9]6-bromo-nicotinic acid</strong> (4.8g, 23.8 mmol) in dimethylsulfoxide (20ml) was added at room temperature carbonyldiimidazole (4.8g, 29.6 mmol), and the mixture stirred for 16 hours. To the mixture was added dropwise, with cooling in ice bath, 0.880 ammonia solution (40ml), then the mixture stirred for 1 hour, then poured into water (20ml). The precipitate was filtered, washed with water and dried in vacuo to give the title product as a white solid in 81% yield, 3.9g.1 HNMR(DMSO-D6, 300MHz) delta: 7.66(br.s, 1H), 7.73(d, 1H), 8.09(m, 1H), 8.15(br.s, 1H), 8.78(d, 1 H). <n="20"/>micro analysis found (%); C(36.00), 1-1(2.60), N(13.67); C6H5N2Br requires (%); C(35.84), H(2.51), N(13.93)
79%
A suspension of 6-Bromonicotinic acid (2 g) and CDI (1.8 g) in THF was stirred at room temperature. After 3 h the NH4OH (8 mL) were added dropwise to the mixture and stirred at room temperature overnight. Then, the solution was concentrated under reduced pressure. Light yellow solid. HPLC purity: 97.1%. Yield: 79%.
With 2-chloro-1-methyl-pyridinium iodide; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 96h;
DIPEA (5.5 ml, 29 mmol) and 2-chloro-l-methylpyridinium iodide (8 g, 26 mmol) were added to a solution of 5-bromopyridin-2-amine 1 (2.56 g, 14.8 mmol) and <strong>[6311-35-9]6-bromonicotinic acid</strong> (3 g, 14.8 mmol) 2 in THF (150 ml). The reaction mixture was stirred at RT for 4 days. Then the precipitate was filtered off. The filtrate was concentrated and dissolved in chloroform (250 ml), washed with water and brine and dried over Na2SO4. The solvent was evaporated to give a crude product, which was recrystallized from ethyl acetate to give 6-bromo-N-(5- bromopyridin-2-yl)nicotinamide 3 (4.3 g, 81 %) as a white solid. Mp. 204 -205 0C. 1H-NMR (400 MHz, CDCl3): delta = 11.33 (s, IH), 8.93 (s, IH), 8.54 (s, IH), 8.25 (d, J= 8.8 Hz IH), 8.17(d, J= 8.8 Hz IH), 8.11 (d, J = 6.4Hz, IH), 7.82 (d, J= 8.4Hz IH). MS (ESI): m/z = 357 (M+)
With 2-chloro-1-methyl-pyridinium iodide; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 48h;
2-Chloro-l-methylpyridinium iodide (2.2 g, 9.8 mmol) and DIPEA (1 ml) were added to a mixture of 5-fluoropyridin-2-amine 1 (554 mg, 4.9 mmol) and <strong>[6311-35-9]6-bromonicotinic acid</strong> 2 (1 g, 4.9 mmol) in THF. The reaction mixture was stirred at rt for 2 days. At the conclusion of the reaction, the reaction mixture was concentrated to 1/3 of its volume and the precipitated product was filtered off. The filtrate was concentrated, diluted with chloroform (100 ml), washed with water and brine and then dried over Na2SO4. Evaporation of the solvent gave a crude yellow product, which crystallized in EtOAc to give 6-bromo-N-(5-fluoropyridin-2- yl)nicotinamide 3 (1.05g, 71 %) as a white solid. Mp. 173-174 0C.1H-NMR (400 MHz, CDCl3): delta = 11.27 (s, IH), 8.94 (s, IH), 8.43 (s, IH), 8.27 (d, J = 8.0 Hz, IH), 8.2 (d, J = 12 Hz, IH), 7.83 (m, 2H). <n="65"/>MS (ESI): m/z = (297, M+H).
With 2-chloro-1-methyl-pyridinium iodide; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 96h;
2-Chloro-l-methylpyridinium iodide (2.99 g, 10 mmol) and DIPEA (3mL) were added to a mixture of methyl 6-aminonicotinate 1 (760 mg, 5 mmol) and <strong>[6311-35-9]6-bromonicotinic acid</strong> 2 (1 g, 5 mmol) in THF (15OmL). The reaction mixture was stirred at rt (=room temperature) for 4 days. At the conclusion of the reaction, the reaction mixture was concentrated to 1/3 of its volume and the precipitated product was filtered off. The filtrate was concentrated, diluted with chloroform (100 ml), washed with water and brine and dried over Na2SO4. Evaporation of the solvent gave a crude yellow product, which crystallized in EtOAc to give methyl 6-(6- bromonicotinamido)nicotinate 3 as a white solid (1 g, 65.4 %). Mp. 234 - 235 0C. <n="54"/>1H-NMR (400 MHz, CDCl3): delta = 11.5 (s, IH), 8.96 (d, J = 2.0 Hz, IH), 8.93 (s, IH), 8.36 (dd, J = 2.0Hz, J = 8.0 Hz, IH), 8.33 (d, J = 12Hz, IH), 8.28 (dd, J = 2.4 Hz5 J = 8.0 Hz, IH), 7.83 (d, J = 8.4 Hz, IH), 3.88 (s, 3H). MS (ESI): m/z = 338 (M+2H)
With 2-chloro-1-methyl-pyridinium iodide; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 48h;
2-Chloro-l-methylpyridinium iodide (2.18 g, 9.8 mmol) and DIPEA (2.1 ml 11.5 mmol) were added to a mixture of 6-bromo pyridin-2-amine 1 (1 g, 5.7 mmol) and <strong>[6311-35-9]6-bromonicotinic acid</strong> 2 (1.16 g, 5.7 mmol) in THF. The reaction mixture was stirred at RT for 2 days. At the conclusion of the reaction, the reaction mixture was concentrated, diluted with chloroform (150 ml) and washed with water and brine, and then dried over Na2SO4. Evaporation of the solvent gave a crude yellow product, which crystallized in EtOAc to give 6-bromo-N-(6-bromopyridin- 2-yl)nicotinamide 3 (1.1 g, 54 %) as a white solid. Mp. 171-173 0C.1H-NMR (400 MHz, DMSO-d6): delta = 8.94 (d, J = 2.0 Hz, IH), 8.26 (dd, J = 2.4, J - 8.0 Hz, 2H), 7.80- 7.84 (m, 2H), 7.45 (d,- J = 7.6 Hz, IH). MS (ESI): m/z = (357 M+H)
To a round bottom flask containing <strong>[6311-35-9]2-bromo-5-pyridinecarboxylic acid</strong> (10.0 g, 49 mmol) in DCM (500 mL) was added oxalyl bromide (7.4 mL) and 5 drops of DMF. After some gas evolution, the reaction mixture was stirred at reflux ca 6 h, then cooled to rt and heptane 100 mL was added, followed by concentration of the mixture. The mixture was then suspended in THF 400 mL, cooled to 0 C. t-BuOK (5.8 g, 52 mmol) was then added and the r×n allowed to warm to rt and stirred for 2 h. The mixture poured into EtOAc, washed with 1 N NaOH, water, brine, dried MgSO4 filtered and concentrated. The residue was purified by silica gel chromatography Biotage 40S Heptane EtOAc 0-80% 3 L to afford the title compound 4.2 g (36%) of as a white solid. 1H NMR (400 MHz, DMSO-d6) ppm 8.78-8.86 (1 H, m), 8.14 (1 H, dd, J=8.4, 2.4 Hz), 7.81 (1 H d, J=8.4 Hz), 1.56 (9H,s).
6-Bromopyridine-3-carboxylic acid (122 mg, 0.82 mmol, 1.3 eq) was dissolved in DCM (5 mL) and oxalyl chloride (72 muL, 0.82 mmol, 1.3 eq) was added dropwise followed by a drop of DMF. The reaction was stirred for 1 h at ambient temperature, then N,N-diethylethanamine (1 mL, 1.89 mmol, 3 eq) was added followed by tert-butyl 5-amino-3-[2-(3-methoxyphenyl)ethyl]pyrazole-1-carboxylate (200 mg, 0.63 mmol, 1 eq). The reaction was stirred for 2 h, then diluted with DCM and washed with water, brine, dried (MgSO4), filtered and evaporated to give the crude Boc-protected compound as a yellow gum. The gum was dissolved in 2-propanol (5 mL) and a solution of 6M HCl in 2-propanol (4 mL) was added. The solution was stirred at ambient temperature overnight and was then evaporated to dryness and loaded onto a SCX-2 column. The column was washed with methanol and the product eluted with 2N ammonia in methanol to give an orange solid. Trituration with a small volume of methanol gave 6-chloro-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyridine-3-carboxamide (39 mg, 17%) as a white solid; 1H NMR (400.13 MHz, DMSO) delta 2.89 (4H, s), 3.74 (3H, s), 6.46 (1H, s), 6.75 (1H, m), 6.81 (2H, m), 7.20 (1H, t), 7.65 (1H, d), 8.35 (1H, m), 8.95 (1H, d), 10.99 (1H, s), 12.23 (1H, s) MS m/z 357 (MH+) Mean of n=1, FGFR Kinase assay-Caliper, IC50 4.54 muM.
With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide; In acetonitrile; at 120℃; for 0.5h;
Example No.35: Preparation of 5-(6-(lH-benzo[d][l,2,3]triazoI-l-yloxy)pyridin-3-yl)-3-(3- chIoro-4-isopropoxy phenyl)- 1 ,2,4-oxadiazole; A 25 mL microwave reaction vial was charged with (Z)-3-chloro-N'-hydroxy-4- isopropoxybenzimidamide (0.1 g, 0.437 mmol), <strong>[6311-35-9]6-bromonicotinic acid</strong> (0.097 g, 0.481 mmol), and DCC (0.099 g, 0.481 mmol) in acetonitrile (2.403 ml). HOBT (0.074 g, 0.481 mmol) was added in one portion, the resulting suspension was allowed to stir at room temperature for 10 min. DIEA (0.168 ml, 0.962 mmol) was added dropwise, the reaction mixture was heated at 1200C for 30 min under microwave irradiation (Biotage Optimizer, 300 W). The solution was cooled, the reaction mixture was partitioned between EtOAc (50 mL) and water (50 mL), the organic layer was washed by water (2x50 mL), and concentrated afforded yellow solid, which was purified via silica gel chromatography (12 g, 20% EtOAc :Heptane) to afford 5-(6- (lH-benzo[d][l,2,3]triazol-l-yloxy)pyridin-3-yl)-3-(3-chloro-4-isopropoxyphenyl)-l,2,4- oxadiazole (0.128 g, 0.285 mmol, 65.2 % yield) as a white solid. LC/MS (Table 1, Method a) R, = 3.74 min.; MS m/z: 449.18 (M+H)+. IH NMR (400 MHz, Solvent d-DMSO) ppm 8.88 (dd, J = 2.25, 0.65 Hz, IH), 8.62 (dd, J = 8.68, 2.27 Hz, IH), 8.15 (t, J = 5.28 Hz, 2H), 7.97 (dd, J = 8.62, 2.14 Hz, IH), 7.55 (d, J = 0.96 Hz, IH), 7.52-7.44 (m, 2H), 7.36 (dd, J = 8.68, 0.70 Hz, IH), 7.03 (d, J = 8.87 Hz, IH), 4.73-4.61 (m, IH), 1.46-1.40 (m, 6H).
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃;
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.508 g, 2.65 mmol) was added to a solution of <strong>[6311-35-9]6-bromonicotinic acid</strong> (0.357 g, 1.77 mmol), benzene-1,2-disulfonamide (0.418 g, 1.77 mmol) and 4-dimethylaminopyridine (0.318 g, 2.60 mmol) in N,N-dimethylformamide (20 mL) at room temperature and the mixture was stirred over night. Water was added and the aqueous phase was washed with ethyl acetate. The aqueous phase was acidified (pH2) with 2 M hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and water/brine (1:1), dried over magnesium sulfate and the solvent was evaporated to give 0.677 g (91% yield) of the title compound.1H NMR (400 MHz, DMSO-d6) delta ppm 8.80 (d, 1H) 8.29-8.37 (m, 1H) 8.08-8.16 (m, 2H) 7.81-7.92 (m, 2H) 7.78 (d, 1H) 7.46 (m, 1H); MS (ESI) m/z 420.0 [M+H]+, 421.8 [M-H]-.
91%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃;
l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.508 g, 2.65 mmol) was added to a solution of <strong>[6311-35-9]6-bromonicotinic acid</strong> (0.357 g, 1.77 mmol), benzene- 1,2- disulfonamide (0.418 g, 1.77 mmol) and 4-dimethylaminopyridine (0.318 g, 2.60 mmol) in N,N-dimethylformamide (20 mL) at room temperature and the mixture was stirred over night. Water was added and the aqueous phase was washed with ethyl acetate. The aqueous phase was acidified (pH ~ 2) with 2 M hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and water/brine (1:1), dried over magnesium sulfate and the solvent was evaporated to give 0.677 g (91% yield) of the title compound. 1H NMR (400 MHz, DMSO-J6) delta ppm 8.80 (d, 1 H) 8.29 - 8.37 (m, 1 H) 8.08 - 8.16 (m, 2 <n="101"/>H) 7.81 - 7.92 (m, 2 H) 7.78 (d, 1 H) 7.46 (m, 1 H); MS (ESI) m/z 420.0 [M+H]+, 421.8 [M-H]".
91%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃;
a) 6-Bromo-N-(2-sulfamoylphenylsulfonyl)nicotinamidel-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.508 g, 2.65 mmol) was added to a solution of <strong>[6311-35-9]6-bromonicotinic acid</strong> (0.357 g, 1.77 mmol), benzene- 1,2- disulfonamide (0.418 g, 1.77 mmol) and 4-dimethylaminopyridine (0.318 g, 2.60 mmol) in N,N-dimethylformamide (20 mL) at room temperature and the mixture was stirred over night. Water was added and the aqueous phase was washed with ethyl acetate. The aqueous phase was acidified (pH~2) with 2 M hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and water/brine (1 :1), dried over magnesium sulfate and the solvent was evaporated to give 0.677 g (91% yield) of the title compound. 1H NMR (400 MHz, DMSO-J6) delta ppm 8.80 (d, 1 H) 8.29 - 8.37 (m, 1 H) 8.08 - 8.16 (m, 2 H) 7.81 - 7.92 (m, 2 H) 7.78 (d, 1 H) 7.46 (m, 1 H); MS (ESI) m/z 420.0 [M+H]+, 421.8 [M-H]".
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 18h;
A mixture of [2-(trifluoromethyl)-1 H-indol-5-yl]methyl}amine hydrochloride (Intermediate 5, 1g, 3.99 mmol), theta-bromo-S-pyridinecarboxylic acid (Matrix Scientific; 0.887 g, 4.39 mmol), EDC (0.841 g, 4.39 mmol), HOBT (0.672 g, 4.39 mmol) and DIPEA (2.8 mL, 16.03 mmol) in DCM (50 mL) was stirred at room temperature for 18hrs. The mixture was stirred well with saturated aqueous NaHCC>3 solution, the organics separated and the aqueous further extracted (EtOAC x 3). The combined organics were dried (Phase-Sep cartridge) and evaporated under reduced pressure to a white solid. Trituration with diethyl ether overnight and filtration afforded a crude white solid (1.16 g). A portion (88 mg) was further purified via MDAP to afford the title compound as a white solid (54 mg); m/z [M+H]+ 396/398 (M+1 );1 H NMR (400MHz, d4MeOD): delta 8.79 (1 H, d), 8.10 (1 H, dd), 7.70 (1 H, dd), 7.64 (1 H, s), 7.42 (1 H, d), 7.30 (1 H, d), 6.86 (1 H, s), 4.66 (2H, s)
(6-bromopyridin-3-yl)(piperidin-1-yl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 18h;
To a solution of <strong>[6311-35-9]6-bromo-nicotinic acid</strong> (404 mg, 2.0 mmol) in 15 mL of DCM was added DIPEA (1.29 g, 10.0 mmol) and piperidine (852 mg, 10.0 mmol). HBTU (1.14 g, 3.0 mmol) was added at 0 C. The resulting mixture was stirred at r.t. for 18 h. TLC indicated that the starting material was gone. The mixture was diluted with DCM (100 mL) and washed with water (30 mL). The organic layer was separated and dried over anhydrous Na2S04. The solution was concentrated to give a crude product. This residue was purified with silica gel column (Hexane/EtOAc = 3/1) to obtain HJC-1-55 (540 mg, 100%) as a white solid. 1H NMR (600 MHz, CDC13) delta 8.41 (s, 1H), 7.60 (d, 1H, J = 8.4 Hz), 7.54 (d, 1H, J = 7.8 Hz), 3.67-3.71 (m, 2H), 3.31-3.35 (m, 2H), 1.63-1.70 (m, 4H), 1.49-1.55 (m, 2H).
60%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 2h;
To a solution of <strong>[6311-35-9]6-bromonicotinic acid</strong> (1.0 g, 4.95 mmol) in DMF (6 mL) was added piperidine (422 mg, 4.95 mmol), DIEA (1.9 g, 14.9 mmol) and HATU (2.2 g, 5.94 mmol). The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with DCM/CH3OH (20/1, v/v) to afford the title compound (800 mg, 60%) as a brown solid. LCMS (ESI, m/z): [M+H]+ = 269.2
With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; acetonitrile; at 160℃; for 0.5h;Microwave heating;
tert-Butyl 4-[4-(dimethoxyboryl)-2-(methoxymethyl)phenoxy]methyl}piperidine-l- carboxylate (100 mg, 0 245 mmol, Intermediate 2) was dissolved in a solvent mixture of acetonitrile water (2 1; 3 mL) To the homogenous mixture was added [1,1 '- bis(diphenylphosphino)-ferrocene]dichloropalladium(II)-dichloromethane complex (20.05 mg, 0.0245 mmol), potassium carbonate (84.8 mg, 0.614 mmol) and 6-bromonicotimc acid <n="50"/>(59.5 mg, 0 295 rnmol). The resulting mixture was heated at 160 0C for 30 mm using microwave heating. The mixture was allowed to reach room temperature and concentrated under reduced pressure to give the crude title compound as a dark brown solid Analytical HPLC. purity 95% (System B), LRESIMS (ESI+) m/z = 457 (M+H)+.
To a cooled (0C) mixture of DMF (25 mL) and NaH (1.00 g of a 60% suspension in oil) was added, slowly dropwise, m-toluene thiol (3.10 g). After the addition was complete, the cooling bath was removed, the resulting mixture was stirred for 1 h at room temperature (RT), <strong>[6311-35-9]6-bromo-nicotinic acid</strong> (5.00 g) was added all at once and the resulting mixture was heated at reflux for 6 h. After cooling to RT, the mixture was poured into cold water (250 mL) and the resulting solid was collected, washed with water and dried to give the desired product 1 (4.91 g) in 80% yield. To a solution of sulfide 1 (0.50 g) and THF (2 mL) was added BH3 DMS (0.61 mL), dropwise. The resulting solution was stirred for 1 h at RT, diluted with EtOAc and ice and stirred for 5 min. The pH was adjusted to 11 with 2 N NaOH and the resulting mixture was extracted with EtOAc (3 * 10 mL). The EtOAc extracts were dried with brine, then over MgSO4, filtered and evaporated to give a light colored foam 2 (0.44 g), which was used without further purification.
2,2, 6,6-Tetramethylpiperidine (9.58 mL, 56.4 mmol) was dissolved in dry THF (100 mL), and cooled to 0 , whilst n-butyllithium (1.6M in hexanes, 35.2 mL, 56. 43 mmol) was added over 15 min. The resulting solution was cooled TO-78 , and <strong>[6311-35-9]6-bromonicotinic acid</strong> (3.8 g, 18. 8 mmol. ) was added as a solid in four equal portions, with stirring over 10 min. Stirring was continued at this temperature for 1.5 h, and the resulting deep-red solution was treated with dry DMF (10 mL) and allowed to warm to room temperature overnight. The mixture was poured onto water (200 mL) and acidified with 1M HCL, and the aqueous phase was extracted with EtOAc (x4). The combined organic phases were washed (brine), dried (sodium sulfate) and concentrated to give a yellow oil, which was dissolved in THF (25 mL) and treated with hydrazine (1M in THF, 19 mL). The precipitate was filtered, and dissolved in ethanol (50 mL) and heated to reflux in the presence of potassium acetate (5 g). The mixture was concentrated under reduced pressure and the brown oily solid was triturated with diethyl ether and the ethereal solution was subjected to flash chromatography (50% ethyl acetate/ isohexane) to give a white solid (0.5 g, 12%)
With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; acetonitrile; at 160℃; for 0.333333h;Irradiation;
INTERMEDIATE A21 6- {2- [ l-(f°rt-Butoxycarbonyl)piperidin-4-yl] -4H- 1 ,3-benzodioxin-6-yl} nicotinic acid A suspension of tert-butyl 4-[6-(dimethoxyboryl)-4H-l,3-benzodioxin-2-yl]piperidine-l- carboxylate (Intermediate Al 9; 300 mg, 0.766 mmol), 2-bromopyridine-5 -carboxylic acid(201 mg, 0.996 mmol), K2CO3 (265 mg, 1.92 mmol), PdCfcdppf-DCM (63 mg, 0.077 mmol) in MeCN/eta2O (5 mL; 2:1) was heated at 160 0C for 20 min in a microwave reactor. <n="73"/>The mixture was filtered through a pad of silica and concentrated to give the title compound. Yield 338 mg (100%). Analytical HPLC: purity 80% (System A).
n-Butyllithium (2.5M in hexanes, 297 mL, 0.743 mol) was added over 1 h to a cooled (-25 C) solution of 2,2,6,6,-tetramethylpiperidine (131 mL, 0.77 mol) in tetrahydrofuran (1 L). The mixture was left to stir for 16 h at -25 C then cooled to -55 C before addition of solid <strong>[6311-35-9]6-bromonicotinic acid</strong> (50.0 g, 0.25 mmol). The mixture was allowed to warm to -20 C and stirred for 2 h. The reaction mixture was cooled to -70 C then poured onto a pre-cooled (-70 C) solution of iodine (188.5 g, 0.74 mol) in tetrahydrofuran (500 mL). The mixture was then poured into the original reaction vessel and the contents allowed to warm to ambient temperature and stirred for 1 h. The solvent was evaporated and the resultant residue dissolved in water (500 mL) and washed with dichloromethane (3 x 300 mL). The aqueous phase was separated and the pH adjusted to 2 by the addition of concentrated hydrochloric acid. Aqueous sodium metabisulfite solution (20% w/w, 30 mL) was added and the solid which deposited was collected by filtration. The resultant solid was washed with water (75 mL) and pentane (75 mL) and dried at 75 C under vacuum to furnish the title compound as a tan solid (53.1 g, 65%). 1H NMR (DMSO-D6, 300 MHz): 8.62 (s, 1H), 8.35 (s, 1H). LCMS (Method B): RT = 2.16 min, M+H+ = 328/330.
With Oxalyl bromide;N,N-dimethyl-formamide; In dichloromethane; for 6h;Reflux;
Preparation 36-(3,5-Difluorophenyl)-nicotinic acid Step A: Preparation of tert-butyl 6-bromonicotinate To a round bottom flask containing a solution of <strong>[6311-35-9]2-bromo-5-pyridinecarboxylic acid</strong> (10.0 g, 49 mmol) in DCM (500 ml.) were added oxalyl bromide (7.4 ml.) and 5 drops of DMF. After some gas evolution, the reaction mixture was stirred at reflux for approximately 6 hours, then cooled to room temperature, diluted with heptane (100 ml.) and concentrated. The mixture was then suspended in THF (400 ml.) and cooled to 0 0C. t-BuOK (5.8 g, 52 mmol) was added and the reaction was allowed to warm to room temperature and stirred for 2 hours. The mixture was poured into EtOAc, washed with 1 N NaOH, water and brine, dried overMgSO4, filtered and concentrated. The residue was purified by silica gel chromatography (Biotage 4OS, Heptane:EtOAc 0-80%, 3 L) to afford the title compound 4.2 g (36%) as a white solid. 1H NMR (400MHz, DMSO-d6) delta ppm 8.78 - 8.86 (1 H, m), 8.14 (1 H, dd, J=8.4, 2.4 Hz), 7.81 (1 H, d, J=8.4 Hz), 1.56 (9 H, s).
With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In N,N-dimethyl-formamide; at 20℃; for 18h;Inert atmosphere;
SYNTHESIS EXAMPLE 1 Preparation of Compound 2 6-Bromonicotinic acid (8.1 g, 40 mmol) was dissolved in anhydrous DMF (50 mL) under an N2 atmosphere. 4-Fluoroaniline (3.9 mL, 41 mmol) and EEDQ (9.9 g, 40 mmol) were added and stirred at room temperature for 18 hours. The product was precipitated by dilution into deionized water (1.2 L), and the precipitate was filtered and washed with additional water. The product was dried under vacuum to yield 8.1 g (69%) of 2 as a white solid. ESI-MS m/z 294.9/296.9 [M+H]+. Analysis: Calcd for C12H8BrFN2O: C, 48.84; H, 2.73; N, 9.49. Found: C, 48.75; H, 2.57; N, 9.40. 1H NMR (500 MHz, DMSO-d6) delta 10.54 (s, 1H), 8.92 (d, J=2.3 Hz, 1H), 8.25-8.23 (m, 1H), 7.86-7.85 (m, 1H), 7.79 (d, J=3.8 Hz, 2H), 7.24-7.23 (m, 2H).
43%
With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In N,N-dimethyl-formamide; at 20℃;
Synthesis Example 30; Bromonicotinamide Intermediate XVII; 6-Bromonicotinic acid (5.28 g, 26 mmol) and 4-fluoroaniline (2.90 g, 26 mmol) was dissolved in anhydrous DMF (30 mL). EEDQ was added, and the reaction was allowed to progress overnight at room temperature. The solvent was removed by rotary evaporation, and the crude material was dissolved in hot EtOAc (50 mL). Upon cooling, the product crystallized from the solution. The product was filtered, washed with cold EtOAc to yield 3.29 g (43%) as a white solid. ESI-MS m/z=294.9, 296.8 [M+H]+.
43%
With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In N,N-dimethyl-formamide; at 20℃;
6-Bromonicotinic acid (5.28 g, 26 mmol) and 4-fluoroaniline (2.90 g, 26 mmol) was dissolved in anhydrous DMF(30 mL). EEDQ was added, and the reaction was allowed to progress overnight at room temperature. The solvent wasremoved by rotary evaporation, and the crude material was dissolved in hot EtOAc (50 mL). Upon cooling, the productcrystallized from the solution. The product was filtered, washed with cold EtOAc to yield 3.29 g (43%) as a white solid.ESI-MS m/z = 294.9, 296.8 [M+H]+.
With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In N,N-dimethyl-formamide; at 20℃; for 18h;Inert atmosphere;
6-Bromonicotinic acid (1 equiv) was dissolved in anhydrous dimethylformamide (1.25 mL/mmol) under a nitrogen atmosphere. N-Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (1 equiv) was added, followed by 4-fluoroaniline (1 equiv), and the reaction was stirred at room temperature for 18 h. The product was precipitated by dilution into water (24:1 v/v), filtered, and washed to yield 10 as a white solid. ESI-MS m/z 294.9/296.9 [M+H]+. Calcd for C12H8BrFN2O: C, 48.84; H, 2.73; N, 9.49. Found: C,48.75; H, 2.57; N, 9.40. 1H NMR (500 MHz, DMSO-d6) delta 10.54 (s, 1H), 8.92 (d,1H), 8.25-8.23 (m, 1H), 7.86-7.85 (m, 1H), 7.79 (d, 2H), 7.24-7.23 (m, 2H).
3'-ethoxy-4'-methoxybiphenyl-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
5.117.2 3'-Ethoxy-4'-Methoxybiphenyl-3-Carboxylic Acid 6-Bromonicotinic acid (2.02 g, 10.0 mmol) was dissolved in DME (80 mL) under nitrogen. Pd(PPh3)4 (0.58 g, 0.5 mmol) was added, and the resulting mixture was stirred at ambient temperature for 15 minutes. 3-ethoxy-4-methoxyphenylboronic acid (2.4 g, 12.2 mmol) and 2N Na2CO3 (40 mL, 80 mmol) were added, and the resulting mixture was heated to reflux with stirring for 24 hours. The mixture was poured into 300 mL of water and extracted with ethyl acetate (3×200 mL), and the product precipitated upon standing, providing 2.05 g of the product in 76% yield: 1H NMR (CDCl3) delta 1.53 (t, J=7.0 Hz, 3H), 3.96 (s, 3H), 4.22 (q, J=7.0 Hz, 2H), 7.00 (d, J=8.6 Hz, 1H), 7.53-7.58 (m, 2H), 7.91-8.02 (m, 2H), 8.12 (dd, J=6.9 Hz, J=1.5 Hz, 1H).
Example 31 To a 50 ml_ flask containing 20 mL of DMF was added 1 mL of oxalyl chloride slowfy and stirred for 10 min at RT. 100 mg of <strong>[6311-35-9]2-bromo-5-pyridinecarboxylic acid</strong> was dissolved in 2 mL of the above solution and stirred for 5 min at RT. Then 50 mg of intermediate E was dissolved in 1 mL pyridine and added to the above solution. The reaction was completed in 5 min at RT. The solvent was then evaporated under vacuum, water added and the precipitate filtered. The precipitate was then dissolved in azetidine (1 mL) and stirred at RT for 2h. Volatiles were removed under reduced pressure and the residue dissolved in CH3CN and water and purified with prep HPLC{0% to 95% water/ Acetonitrile) to afford 31 (24.6 mg, 20%).1H-NMR (DMSO, 300 MHz): delta 10.15 (s, 1 H), 8.55 (s, 1 H), 8.09 (d, J = 9.3 Hz, 1 H)1 7.77 (d, J = 7.5 Hz1 1 H), 7.66 (s, 1 H)1 7.53 (d, J = 8.7 Hz, 1 H), 7.25 (t, J = 7.5 Hz, 1 H), 7.07 (t, J = 7.5 Hz1 1 H)1 6.97 (d, J = 7.8 Hz1 1 H), 6.82 (d, J = 9.1 Hz, 1 H)1 6.58 (d, J = 9.6 Hz, 1 H), 4.87 (me, 1 H)1 4.16-3.97 (m, 5H), 3.21-3.11 (m, 3H), 2.81-2.80 (m, 1 H), 2.39-2.36 (m, 1 H)1 0.70 (m, 2H), 0.56 (m, 2H).LCMS m/z [M+Hf C32H29N5O3S requires: 564.67. Found 564.14HPLC Tr (min), purity %: 2.58. 98%
With dmap; dicyclohexyl-carbodiimide; In tetrahydrofuran; at 60℃;
General procedure: The respective benzoic acid 1a-i (1.1 equiv) and o-iodophenol (2a) or phosphanol 2b (1 equiv) with a catalytic amount of DMAP were dissolved in dry THF and DCC (1.5-2 equiv) was added at room temperature. The mixture was allowed to stir overnight at 60 C. Afterward, the precipitate was filtered off and the filtrate was concentrated in vacuo. Purification was done via column chromatography (silica gel, petroleum ether/EtOAc).
With dmap; dicyclohexyl-carbodiimide; In tetrahydrofuran; at 60℃;
General procedure: The respective benzoic acid 1a-i (1.1 equiv) and o-iodophenol (2a) or phosphanol 2b (1 equiv) with a catalytic amount of DMAP were dissolved in dry THF and DCC (1.5-2 equiv) was added at room temperature. The mixture was allowed to stir overnight at 60 C. Afterward, the precipitate was filtered off and the filtrate was concentrated in vacuo. Purification was done via column chromatography (silica gel, petroleum ether/EtOAc).
To chloroform (150 mL) were added (4-chlorophenyl)(piperidin-4-yl)methanone hydrochloride (13 g) and 1N aqueous sodium hydroxide solution (50 mL), and the mixture was stirred at room temperature for 10 min. The chloroform layer was partitioned, methanol (50 mL), <strong>[6311-35-9]6-bromonicotinic acid</strong> (10 g) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM) (16.6 g) were added, and the mixture was stirred at room temperature overnight. After evaporation of the solvent, ethyl acetate was added, and insoluble materials were filtered off. The solvent in the filtrate was evaporated to give the title compound (16.4 g).
16.4 g
[0708] Preparation Example 190: Preparation of (6-bromopyridin-3-yl)[4-(4-chlorobenzoyl)piperidin-1-y1]methanone[0709][0710] (4-Chlorophenyl)(piperidin-4-yl)methanone hydrochloride (13 g) and 1N aqueous sodium hydroxide solution(50 mL) were added to chloroform (150 mL), and the mixture was stirred at room temperature for 10 min. The chloroformlayer was partitioned, to the obtained organic layer were added methanol (50 mL), <strong>[6311-35-9]6-bromonicotinic acid</strong> (10 g) and4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM) (16.6 g), and the mixture wasstirred at room temperature overnight. The solvent was evaporated from the reaction mixture, ethyl acetate was added,and the insoluble material was collected by filtration. The solvent was evaporated from the obtained filtrate to give thetitle compound (16.4 g).
With 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride In methanol; chloroform at 20℃;
28
To a mixture of 4-(p-tolyloxy)piperidine (765 mg), 6-bromonicotinic acid (808 mg) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM) (1.7 g) were added chloroform (5 mL) and methanol (5 mL), and the mixture was stirred at room temperature overnight. After evaporation of the solvent, the residue was purified by column chromatography (chloroform:methanol) to give the title compound (1.5 g).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; for 6h;Inert atmosphere;
General procedure: Under an argon atmosphere, compound (16, 17, 18) (1 equiv.), boronic acid (1.2 equiv.) and Pd[P(C6H5)3]4(1mol%) were dissolved in a mixed solution of dioxane/H2O (10:1). K2CO3 (2 equiv.) was added and the mixture was heated under reflux for 6h. The reaction mixture was cooled to room temperature and the dioxane was removed by rotary evaporation. H2O was added and the solution was adjusted to pH=1-3 with 2N HCl. The white solid precipitate was collected by filtration and dried to give the desired compound.
Referring to Reaction Scheme 16, Stage 1, <strong>[6311-35-9]6-bromo-nicotinic acid</strong> (leq), HOBt (1.4eq) and HATU (1.3eq) were dissolved in DMF (25vol) and the reaction mixture was stirred 1 hour at ambient temperature. Methylamine hydrochloride (1.5eq) and triethyl amine (l .leq) were added and the reaction mixture was stirred 16 hours at ambient temperature. DMF was removed in vacuo and water and EtOAc were added to the residue. The organic phase was separated and washed with a saturated aqueous solution of NaHC03, dried with MgS04, filtered and the solvent removed in vacuo. The residue was triturated with EtO Ac/heptane (1/1) to furnish the desired intermediate.
Referring to Reaction Scheme 16, Stage 1, <strong>[6311-35-9]6-bromo-nicotinic acid</strong> (1eq), HOBt (1.4eq) and HATU (1.3eq) were dissolved in DMF (25vol) and the reaction mixture was stirred 1 hour at ambient temperature. Methylamine hydrochloride (1.5eq) and triethyl amine (1.1eq) were added and the reaction mixture was stirred 16 hours at ambient temperature. DMF was removed in vacuo and water and EtOAc were added to the residue. The organic phase was separated and washed with a saturated aqueous solution of NaHCO3, dried with MgSO4, filtered and the solvent removed in vacuo. The residue was triturated with EtO Ac/heptane (1/1) to furnish the desired intermediate.
With N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide; In acetonitrile; at 20 - 120℃; for 0.666667h;microwave irradiation;
Preparation No.26: Preparation of 5-(6-(l//-benzo[i/|[l,2,3]triazol-l-yloxy)pyridin-3-yl)-3- (3-chloro-4-isopropoxy henyl)-l,2,4-oxadiazole; A 25 mL microwave reaction vial was charged with (Z)-3-chloro-A^-hydroxy-4- isopropoxybenzimidamide (0.1 g, 0.437 mmol), <strong>[6311-35-9]6-bromonicotinic acid</strong> (0.097 g, 0.481 mmol), and DCC (0.099 g, 0.481 mmol) in ACN (2.403 mL). HOBT (0.074 g, 0.481 mmol) was added in one portion, the resulting suspension was allowed to stir at RT for about 10 min. DIEA (0.168 mL, 0.962 mmol) was added dropwise, the reaction mixture was heated at about 120 C for about 30 min under microwave irradiation (Biotage Optimizer, 300 W). The solution was cooled, the reaction mixture was partitioned between EtOAc (50 mL) and water (50 mL), the organic layer was washed by water (2 x 50 mL), and concentrated afforded yellow solid, which was purified via silica gel chromatography (12 g, 20% EtOAc:Heptane) to afford 5-(6-(lH-benzo[d] [1,2,3] triazol-l-yloxy)pyridin-3-yl)-3-(3-chloro-4- isopropoxyphenyi)-l,2,4-oxadiazoie (0.128 g, 0.285 mmol, 65.2 % yield) as a white solid. LC/MS (Table 1, Method a) R, = 3.74 min.; MS m/z: 449.18 (M+H)+. 1H NMR (400 MHz, d- DMSO) ppm 8.88 (dd, J = 2.25, 0.65 Hz, 1H), 8.62 (dd, J = 8.68, 2.27 Hz, 1H), 8.15 (t, J = 5.28 Hz, 2H), 7.97 (dd, J = 8.62, 2.14 Hz, 1H), 7.55 (d, J = 0.96 Hz, 1H), 7.52-7.44 (m, 2H), 7.36 (dd, J = 8.68, 0.70 Hz, 1H), 7.03 (d, J = 8.87 Hz, 1H), 4.73-4.61 (m, 1H), 1.46-1.40 (m, 6H).
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;
15. 6-BROMO-iV-CYCLOHEXYLNICOTINAMIDE (2.2A).[00309] To a solution of DIPEA (1.27 g, 9.9 mmol), HATU (2.45 g, 6.4) mmol and 6- bromonicotinic acid (1.0 g, 5 mmol) in DMF (15 mL) was added cyclohexylamine (686 mg, 7.4 mmol) and the mixture was allowed to stir overnight at room temperature. The reaction mixture was poured into water and extracted with EtOAc (2 x 35 mL). The combined extracts were washed sequentially with water and brine, then dried (Na2S04), filtered and concentrated. The residue was purified via automated flash chromatography (silica gel) using 0-35% EtOAc in hexanes to give 1.14 g of title compound (82% yield): 1H NMR (400 MHz, CDCI3) delta 8.69 (d, J= 2.4 Hz, 1H), 7.97 (dd, Jl = 8 Hz, J2 = 2.6 Hz, 1H), 7.59 (d, J= 8 Hz, 1H), 5.93 (s, br, 1H), 3.99 (m, 1H), 2.06 (m, 2H), 1.82-1.76 (m, 2H), 1.72-1.66 (m, 1H), 1.45 (m, 2H), 1.29 (m, 3H); LC-MS (214 nm) >98%, 283.2 (M+H).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water at 120℃; for 0.333333h; Inert atmosphere; Microwave irradiation;
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In tetrahydrofuran; at 20℃; for 14h;
Step 1. Preparation of (6-Bromo-pyridin-3-yl)-morpholin-4-yl-methanone The mixture of <strong>[6311-35-9]6-bromonicotinic acid</strong> (700 mg, 3.5 mmol), morpholine (391 mg, 4.5 mmol), HATU (220 mg, 0.59 mmol) and DIPEA (0.3 mL) in 10 mL of dry THF was stirred at room temperature for 14 hours. The reaction solution was evaporated to dryness. To the residue was added 20 mL of 0.5N hydrochloride, and the mixture was extracted with ethyl acetate (50 mL*3). The organic layer was dried over sodium sulfate and concentrated to give (6-bromopyridin-3-yl)(morpholino)methanone (750 mg, 79%). LC-MS: 271, 273 [M+H]+, tR=1.290 min.
4-[(6-Bromo-pyridine-3-carbonyl)-cyclopropyl-amino]-piperidine-1-carboxylic acid tert-butyl ester 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (2.80 g) is added to a mixture of <strong>[6311-35-9]6-bromo-nicotinic acid</strong> (1.85 g) and triethylamine (1.28 mL) in N,N-dimethylformamide (25 mL) cooled in an ice bath. The mixture is stirred for 30 min prior to the addition of a solution of 4-cyclopropylamino-piperidine-1-carboxylic acid tert-butyl ester (2.00 g) in N,N-dimethylformamide (5 mL). The resulting mixture is stirred at room temperature over night. Water and ethyl acetate are added and the organic phase is separated, washed with water, 1N aqueous NaOH solution, and brine, and dried over MgSO4. The solvent is evaporated in vacuo and the residue is triturated with diisopropyl ether to yield the title compound. LC (method 5): tR=1.59 min; Mass spectrum (ESI+): m/z=424/426 (Br) [M+H]+.
4-[(6-Bromo-pyridine-3-carbonyl)-cyclopropyl-amino]-piperidine-1-carboxylic acid tert-butyl ester 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (2.80 g) is added to a mixture of <strong>[6311-35-9]6-bromo-nicotinic acid</strong> (1.85 g) and triethylamine (1.28 mL) in N,N-dimethylformamide (25 mL) cooled in an ice bath. The mixture is stirred for 30 min prior to the addition of a solution of 4-cyclopropylamino-piperidine-1-carboxylic acid tert-butyl ester (2.00 g) in N,N-dimethylformamide (5 mL). The resulting mixture is stirred at room temperature overnight. Water and ethyl acetate are added and the organic phase is separated, washed with water, 1N aqueous NaOH solution, and brine, and dried over MgSO4. The solvent is evaporated in vacuo and the residue is triturated with diisopropyl ether to yield the title compound. LC (method 1): tR=1.59 min; Mass spectrum (ESI+): m/z=424 [M+H]+.
Intermediate I 4-[(6-Bromo-yridine-3-carbonyl)-cycloroyl-amino1-rireridine-1 -carboxylic acid tertoi,butyl ester: 2-(1 H-Benzotriazol-1 -yl)-l ,1 ,3,3-tetramethyluronium tetrafluoroborate (2.80 g) is added to a mixture of <strong>[6311-35-9]6-bromo-nicotinic acid</strong> (1 .85 g) and triethylamine (1.28 mL) inN,N-dimethylformamide (25 mL) cooled in an ice bath. The mixture is stirred for 30 mm prior to the addition of a solution of 4-cyclopropylamino-piperidine-1 -carboxylic acid tert-butyl ester (2.00 g) in N,N-dimethylformamide (5 mL). The resulting mixture is stirred at room temperature overnight. Water and ethyl acetate are added and the organic phase is separated, washed with water, 1 N aqueous NaOH solution, andbrine, and dried over Mg504. The solvent is evaporated in vacuo and the residue is triturated with diisopropyl ether to yield the title compound. LC (method 1): tR = 1 .59 mm; Mass spectrum (ESI): mlz = 424 [M+H].
With benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃; for 15h;
General procedure: A mixture of compound 10 (135 mg, 0.49 mmol) and 4-(thiophen-3-yl)benzoic acid (99.4 mg, 0.49 mmol) in dichloromethane (10 mL) was stirred at 0 C (ice-water bath). Dicyclohexylcarbodiimide(DCC) (121 mg, 0.59 mmol) and hydroxybenzotriazole(HOBt) (80 mg, 0.59 mmol) were added to the above solution.The ice bath was removed, and the reaction mixture was stirred at ambient temperature for 15 h. Dichloromethane (20 mL) was added into the reaction mixture, and the solution was washed with saturated aqueous NaHCO3 solution (3*10 mL). The organic layer was dried over Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography using dichloromethane-methanol (20:1) as the mobile phase to give 11a as a white solid (194 mg, 86%). TLC Rf 0.20 (dichloromethane-methanol 20:1); mp 125.5-126.6 C. 1H NMR(300 MHz, CDCl3) delta 7.75 (d, J = 8.7 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H),7.43 (s, 1H), 7.33 (s, 2H), 7.19 (s, 1H), 6.81-6.94 (m, 4H), 3.85 (s,3H), 3.44 (q, J = 5.1 Hz, 2H), 3.25-3.20 (m, 4H), 2.83-2.76 (m,4H), 2.57 (t, J = 5.2 Hz, 2H), 1.93 (t, J = 4.2 Hz, 2H), 1.61-1.69 (m,4H). 13C NMR (CDCl3, 300 MHz): 167.4, 151.4, 142.1, 141.2,138.8, 133.4, 127.5, 126.6, 126.3, 126.1, 121.3, 121.0, 120.7,117.9, 111.6, 57.1, 56.1, 55.3, 54.3, 52.5, 51.8, 39.4, 27.7, 27.3,25.5. HRMS (ESI) Calcd for C27H33N3O2S (M+H)+: 464.2372. Found:464.2379. Anal. (C27H33N3O2S 1.5H2C2O4) C, H, N.
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 18h;
To a solution of <strong>[6311-35-9]6-bromo-nicotinic acid</strong> (404 mg, 2.0 mmol) in 15 mL of DCM was added DIPEA (1.29 g, 10.0 mmol) and pyrrolidine (711 mg, 10.0 mmol). HBTU (1.14 g, 3.0 mmol) was added at 0 C. The resulting mixture was stirred at r.t. for 18 h. TLC indicated that the starting material was gone. The mixture was diluted with DCM (100 mL) and washed with water (30 mL). The organic layer was separated and dried over anhydrous Na2S04. The solution was concentrated to give a crude product, which was purified with silica gel column (Hexane/EtOAc = 2/1) to obtain HJC-2-61 (400 mg, 78%) as a pale yellow oil. 1H NMR (600 MHz, CDCls) delta 8.54 (s, 1H), 7.73 (d, 1H, J = 7.8 Hz), 7.55 (d, 1H, J = 7.8 Hz), 3.64 (t, 2H, J = 6.6 Hz), 3.44 (t, 2H, J= 6.0 Hz), 1.96-2.00 (m, 2H), 1.92-1.96 (m, 2H).
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 0 - 25℃; for 16h;
To a mixture of 6-bromonictinic acid (2.0 g, 9.9 mmol), N,O-dimethyl hydroxyl amine hydrochloride (1.16 g, 11.9 mmol) and Et3N (1.66 mL, 11.9 mmol) in dry CH2Cl2 (20 mL), was added EDCI (2.28 g, 11.9 mmol) in portions at 0 C. The mixture was then stirred at 25 C. for 16 hours and washed with water (20 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (20 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered and concentrated to give the product (2.36 g, yield: 97%) as yellow oil which was used directly for the next step without further purification, LC/MS: m/z M++1=245, 247; 1H NMR (400 MHz, CDCl3) delta 8.74 (d, J=2.4 Hz, 1H), 7.90-7.93 (m, 1H), 7.56 (d, J=8.4 Hz, 1H), 3.56 (s, 3H), 3.39 (s, 3H).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 3h;
10447] WX035-1 (45.00 g, 222.76 mmol, 1.00 eq) was dissolved in anhydrous dichioromethane (500.00 mE), and triethylamine (45.08 g, 445.52 mmol, 61.76 mE, 2.00 eq), EDCI (46.97 g, 245.04 mmol, 1.10 eq), HOSt (33.11 g, 245.04 mmol, 1.10 eq), and N-methoxymethylamine (26.07 g, 267.31 mmol, 1.20 eq) were added to the solution at 20 C. in order. The mixture was stirred at 20 C. for 3 h. After reaction, the reaction system was added with 100 mE of dichioromethane for dilution, then added with aq. HC1 (200 mE, 0.5 N), and filtered. The filter cake was washed with dichioromethane (200 mE*2). The organic phase was separated from the filtrate, washed with saturated sodium bicarbonate (200 mE) and saturated sodium chloride solution (200 mE) in order, dried with anhydrous sodium sulfate. The filtrate was concentrated under vacuum to obtain WX035-2. ?H NMR (400 MHz, CDC13) oe ppm: 8.75-8.74 (d, J=2.4 Hz, 1H), 7.92-7.89 (m, 1H), 7.56-7.54 (m, 1H), 3.55 (s, 3H) 3.38 (s, 3H).
Step A: (6-bromopyridin-3 -yl)(phenyl methanone (4-b) <strong>[6311-35-9]6-bromopyridine-3-carboxylic acid</strong> (50g, 0.25mol) in thionyl chloride (4a, 130ml, 1.76mol) was heated at reflux for 3 hours. The mixture was then concentrated under vacuum and the residue was co-evaporated with benzene to remove the thionyl chloride. The resulting acid chloride was dissolved in benzene (120ml, 1.33mol) and treated with A1C13 (82.5g, 0.6mol) portion wise with stirring at 5 C. After heating at reflux for 6 hours, the reaction mixture was cooled to room temperature and poured into 20% HC1 (500ml), stirred for lh, and layers were separated. The aqueous layer was further extracted with ethyl acetate (3x100 mL). The combined organic layer was washed with brine, 50% KOH, and water (100 mL each), dried (Na2S04), filtered and concentrated under reduced pressure to afford the product, 4-b, (50g, 77%). NMR (CDCI3, 300MuEtazeta,):delta 8.72(d, J=24Hz, 1H), 8.04(dd, Ji=8.4Hz, J2=2.7Hz, 1H), 7.74(m, 2H), 7.61(m, 1H), 7.48(m, 3H).
(6-bromo-3-pyridyl)-[2-(indan-2-ylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 25℃; for 18h;
Preparation 39Synthesis of (6-bromo-3-pyridyl)-[2-(indan-2-ylamino)-7,8-dihydro-5H-pyrido[4,3- d]pyrimidin-6-yl]methanone.Place <strong>[6311-35-9]6-bromopyridine-3-carboxylic acid</strong> (224 mg, 1.10 mmoles), N-indan-2-yl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (266 mg, 1.00 mmoles), l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (288 mg, 1.50 mmoles), and 4-pyridinamine, N,N-dimethyl (6.1 mg, 0.05 mmoles) in a round bottom flask and dissolve in dichloromethane (4mL). Stir the reaction mixture for 18 hours at 25 C. Concentrate under reduced pressure. The residue is purified by normal phase chromatography using acetonitrile/dichloromethane to give the title compound (0.25 g, 55%). LCMS (m/z): 452.2 (M+1)
6-bromo-N-(5-phenyl-1H-pyrazol-3-yl)nicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane;Reflux;
General procedure: Compounds 5a-5w were synthesized by coupling substituted 3a-3c with nicotinic acids, using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl) and N-hydroxybenzotriazole (HOBt) as condensing agent. The mixture was refluxed in anhydrous CH2Cl2 for 1-3 h. The products were extracted with ethyl acetate. The extract was washed successively with 5% HCl, then evaporated and purified by column chromatography over silica gel to give the compound. 4.4.5 6-Bromo-N-(5-phenyl-1H-pyrazol-3-yl)nicotinamide (5e) Yellow powder, yield: 75%. Mp 156-157 C. 1H NMR (300 MHz, DMSO, delta ppm): 5.92 (s, 1H); 6.93 (s, 2H); 7.43 (d, J = 5.8 Hz, 3H); 7.76-7.78 (m, 2H); 7.89 (d, J = 6.2 Hz, 1H); 8.36-8.37 (m, 1H); 9.02 (d, J = 1.5 Hz, 1H). MS (ESI): 344.68 [M+H]+. Anal. Calcd for C15H11BrN4O: C, 52.50; H, 3.23; N, 16.33; Found: C, 52.71; H, 3.48; N, 16.42.
6-bromo-N-(5-(4-bromophenyl)-1H-pyrazol-3-yl)nicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane;Reflux;
General procedure: Compounds 5a-5w were synthesized by coupling substituted 3a-3c with nicotinic acids, using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl) and N-hydroxybenzotriazole (HOBt) as condensing agent. The mixture was refluxed in anhydrous CH2Cl2 for 1-3 h. The products were extracted with ethyl acetate. The extract was washed successively with 5% HCl, then evaporated and purified by column chromatography over silica gel to give the compound. 4.4.19 6-Bromo-N-(5-(4-bromophenyl)-1H-pyrazol-3-yl)nicotinamide (5s) Yellow powder, yield: 86%. Mp 205-206 C. 1H NMR (300 MHz, DMSO, delta ppm): 5.91 (s, 1H); 7.72-7.83 (m, 6H); 8.59 (s, 1H); 8.88 (s, 1H); 9.12 (s, 1H). MS (ESI): 422.38 [M+H]+. Anal. Calcd for C15H10Br2N4O: C, 42.68; H, 2.39; N, 13.27; Found: C, 42.51; H, 2.16; N, 13.75.
6-bromo-N-(5-(p-tolyl)-1H-pyrazol-3-yl)nicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane;Reflux;
General procedure: Compounds 5a-5w were synthesized by coupling substituted 3a-3c with nicotinic acids, using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl) and N-hydroxybenzotriazole (HOBt) as condensing agent. The mixture was refluxed in anhydrous CH2Cl2 for 1-3 h. The products were extracted with ethyl acetate. The extract was washed successively with 5% HCl, then evaporated and purified by column chromatography over silica gel to give the compound. 4.4.12 6-Bromo-N-(5-(p-tolyl)-1H-pyrazol-3-yl)nicotinamide (5l) Yellow powder, yield: 64%. Mp 178-179 C. 1H NMR (300 MHz, DMSO, delta ppm): 2.34 (s, 3H); 5.88 (s, 1H); 6.91 (s, 2H); 7.24 (d, J = 6.1 Hz, 2H); 7.66 (d, J = 6.1 Hz, 2H); 7.88 (d, J = 6.3 Hz, 1H); 8.36-8.38 (m, 1H); 9.03 (d, J = 1.8 Hz, 1H). MS (ESI): 358.61 [M+H]+. Anal. Calcd for C16H13BrN4O: C, 53.80; H, 3.67; N, 15.68; Found: C, 53.71; H, 3.58; N, 15.82.
(3S)-3-cyclopropyl-1-(2-((5-((4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)carbonyl)pyridin-2-yl)amino)pyridin-4-yl)-2-oxopyrrolidine-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Multi-step reaction with 2 steps
1: N-ethyl-N,N-diisopropylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 15 h / 20 °C
2: potassium carbonate; dicyclohexyl-(2′,4′,6′-triisopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine; chloro[2-(dicyclohexylphosphino)-3 ,6-dimethoxy-2’,4’, 6’-triisopropyl- 1,1’-biphenyl] [2-(2-aminoethyl)phenyl]palladium(II) / tert-Amyl alcohol / 22 h / 100 °C / Inert atmosphere
(6-bromopyridin-3-yl) (3-hydroxy-3-methylpiperidin-1-yl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
280 mg
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In ethyl acetate at 20℃;
301.A A) (6-bromopyridin-3-yl) (3-hydroxy-3-methylpiperidin-1-yl)methanone
To a solution of 6-bromonicotinic acid (400 mg) in ethyl acetate (8.0 mL) were added N,N-diisopropylethylamine (1.0 mL), 1.7 M propane phosphonic acid anhydride ethyl acetate solution (1.7 mL) and 3-methylpiperidin-3-ol (230 mg), and the mixture was stirred overnight at room temperature. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed successively with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (NH, hexane/ethyl acetate) to give the title compound (280 mg). MS(ESI+): [M+H]+ 298.8.
(6-bromopyridin-3-yl)(4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
650 mg
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In ethyl acetate at 20℃; for 15h;
62 (6-bromopyridin-3-yl) (4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)methanone
To a solution of 6-bromonicotinic acid (480 mg) in ethyl acetate (10 mL) were added N,N-diisopropylethylamine (1.2 mL), 1.7 M propane phosphonic acid anhydride ethyl acetate solution (2.1 mL) and 4-(trifluoromethyl)piperidin-4-ol (400 mg), and the mixture was stirred at room temperature for 15 hr. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed successively with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (NH, hexane/ethyl acetate) to give the title compound (650 mg). MS(ESI+): [M+H]+ 352.8.
6-bromo-N-(1-hydroxy-2-methylpropan-2-yl)-N-methylnicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
42 mg
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In ethyl acetate; at 20 - 50℃; for 18.0h;
To a solution of 6-bromonicotinic acid (240 mg) in ethyl acetate (10 mL) were added N,N-diisopropylethylamine (0.62 mL), 1.7 M propane phosphonic acid anhydride ethyl acetate solution (1.0 mL) and <strong>[27646-80-6]2-methyl-2-(methylamino)propan-1-ol</strong> (120 mg), and the mixture was stirred at room temperature for 16 hr, and then at 50° C. for 2 hr. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed successively with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (NH, hexane/ethyl acetate) to give the title compound (42 mg). MS(ESI+): [M+H]+ 286.8.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h;
<strong>[6311-35-9]6-bromonicotinic acid</strong> (1.00g, 4.95mmol) was dissolved in N, N-dimethylformamide (30 mL) was added methyl iodide (0.703g, 4.95mmol) and potassium carbonate (1.03g, 7.43mmol). The reaction was stirred at 20 deg.] C for 12 hours. The reaction solution was added water (100 mL) was diluted, extracted with ethyl acetate (30mLx3),The organic phase was dried over anhydrous sodium sulfate, filtered,The filtrate was concentrated under reduced pressure, purified by silica gel column chromatography separation gel (2: 1 petroleum ether / ethyl acetate, Rf = 0.5) to give <strong>[6311-35-9]6-bromo-nicotinic acid</strong> methyl ester (1.00 g of, white solid), yield: 94%.
0.909 g
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 55℃; for 4h;
Methyl iodide (1.06 g, 0.007 mole) was added at 0 - 5 C to a stirred suspension of <strong>[6311-35-9]6-bromonicotinic acid</strong> (1.0 g, 0.004 mol) and K2C03 ( 2.06 g, 0.014 mole) in DMF (15 inL) at 25 - 30 C and then reaction mass was warmed to 55 C for 4 hours. The reaction mixture was poured on to cold water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine solution (50 mL) and dried over anhydrous Na2S04 and concentrated under vacuum to obtain methyl 6-bromonicotinate. Yield: 0.909 g; - NMR (DMSO- , 400 MHz) delta ppm: 3.89 (s, 3H), 7.83 - 7.85 (d, J = 8.3 Hz, 1H), 8.18 - 8.21 (dd, J = 2.3, 8.2 Hz, 1H), 8.87 - 8.88 (d, J = 2.3 Hz, 1H); Mass (m/z): 216.1 (M+H) +.
6-bromo-N-[4-(6-methoxy-1,3-benzothiazol-2-yl)phenyl]pyridine-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
29%
<strong>[6311-35-9]6-bromo-nicotinic acid</strong> in dry THF (5ml) (0.16g, 0.78mmol) in solution in an argon atmosphere 1,1'-carbonyldiimidazole (0.13 g, 0.78 mmol) was added, the reaction the mixture was stirred at room temperature for 5 hours. To the reaction mixture over 2 minutes 2- (4-aminophenyl) -6-methoxy benzothiazole (0.2 g, 0.78 mmol) was added, stirring for 1 hour at room temperature and then heated under reflux for 18 hours . After cooling to room temperature, the reaction mixture was diluted with Et2O (30ml), the precipitate was collected by filtration, washed with Et2O (50ml), and dried under high vacuum to give the title compound (0.101 g, 29% ) was obtained as an orange solid.
(3R)-3-methyl-1,4'-bipiperidine dihydrochloride[ No CAS ]
(6-bromopyridin-3-yl)[(3R)-3-methyl-1,4'-bipiperidin-1'-yl]methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In ethyl acetate; acetonitrile; at 20℃; for 18h;
Example 10A (6-Bromopyridin-3-yl)[(3R)-3-methyl-1,4?-bipiperidin-1?-yl]methanone (0338) (0339) 8.64 ml (49.5 mmol) of N,N-diisopropylethylamine were added to a mixture of 2.00 g (9.90 mmol) of <strong>[6311-35-9]6-bromonicotinic acid</strong> and 2.53 g (9.90 mmol) of (3R)-3-methyl-1,4?-bipiperidine dihydrochloride in 20 ml of acetonitrile. 6.94 ml (11.9 mmol) of T3P (50% by weight strength solution in ethyl acetate) were then added dropwise, and the mixture was stirred at RT for 18 h. For work-up, 50 ml of saturated sodium bicarbonate solution were added and the mixture was stirred for 30 min and then extracted twice with dichloromethane. The combined organic phases were washed with saturated sodium bicarbonate solution and water, dried over magnesium sulphate, filtered, concentrated and dried under HV. This gave 3.40 g (93% of theory) of the title compound. (0340) LC-MS [Method 1]: Rt=0.48 min; MS (ESIpos): m/z=366 and 368 (M+H)+ (0341) 1H-NMR (400 MHz, DMSO-d6): delta [ppm]=0.72-0.88 (m, 4H), 1.30-1.86 (m, 9H), 2.00-2.16 (m, 1H), 2.67-2.83 (m, 3H), 2.95-3.11 (m, 1H), 3.44-3.61 (m, 1H), 4.35-4.58 (m, 1H), 7.70-7.75 (m, 1H), 7.77-7.82 (m, 1H), 8.44 (d, 1H).
(6-bromopyridin-3-yl)(3,3-difluoroazetidin-1-yl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 4h;
Synthesis of (6-bromopyridin-3 -yl)(3 , 3 -difluoroazetidin- 1 -yl)methanone (8): 6- Bromonicotinic acid (7; 2 g, 9.9 mmol) was dissolved in DCM (40 mL). 3,3- Difluoroazetidine hydrochloride (1.5 g, 12 mmol), EDCI (2.3 g, 12 mmol), HOBt hydrate(1.6 g, 12 mmol) and DIPEA (3.8 g, 30 mmol) were added. The reaction mixture was stirred at room temperature was 4 h. LCMS indicated the completion of reaction. The reaction mixture was quenched with water (30 mL), extracted with DCM (30 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated and purified by silica gel chromatography (10-50% EtOAc/petroleum ether) to give 1.8 g of(6- bromopyridin-3 -yl)(3 ,3 -difluoroazetidin- 1 -yl)methanone 8 as white solid (66% yield). LCMS: m/z 279.0 [M+H], , tR= 1.44 min
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃;Inert atmosphere;
6-bromo-N,N-dimethylnicotinamide (0260) To a solution of <strong>[6311-35-9]6-bromopyridine-3-carboxylic acid</strong> (200 mg, 0.99 mmol) in dicholormethane (5 mL) were added dimethylamine hydrochloride (97 mg, 1.19 mmol), HATU (564 mg, 1.48 mmol) and DIEA (639 mg, 4.94 mmol) at room temperature. The resulting mixture was stirred overnight at room temperature and then was quenched by the addition of water (20 mL). The reaction mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with ethyl acetate in hexane (0% to 50% gradient) to yield 6-bromo-N,N-dimethylpyridine-3-carboxamide as colorless oil (203 mg, 90%). MS: m/z=229.0 [M+H]+.
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 12h;
A mixture of <strong>[6311-35-9]6-bromonicotinic acid</strong> (11c, 1.01 g, 5.0 mmol), (S)-methyl pyrrolidine-2-carboxylate (0.71 g,5.5 mmol), TBTU (1.77 g,5.5 mmol) and DIPEA (1.65 mL, 10.0 mmol) in 15 mL of DMF werestirred at room temperature for 12 h, then DMF was removed byrotary evaporation. To the residue, 50 mL of water and 50 mL ofethyl acetate were added, extracted with ethyl acetate(50 mL 3). The extracts were dried over Na2SO4 and concentratedin vacuo to give a residue that was subjected to silica gel chromatographyto afford 12c as a white powder (1.61 g, 93% yield).tetrakis(triphenylphosphine) palladium1H NMR (300 MHz, CDCl3)d 8.97 (s, 1H), 8.35 (d, J = 8.5 Hz, 2H), 8.22 (d, J = 8.5 Hz, 2H), 8.07(d, J = 8.2 Hz, 1H), 7.88 (d, J = 8.1 Hz, 1H), 4.72 (dd, J = 7.9, 4.4 Hz,1H), 3.81 (s, 3H), 3.77-3.60 (m, 2H), 2.44-2.32 (m, 1H),2.14-1.94 (m, 3H).
Step 1: 6-Chloronicotinamide To a solution of 6-bromopyridine-3-carboxylic acid (50 g, 247 mmol) in DCM (1 L) and DMF (3 mL) at room temperature was dropwise added oxalyl dichloride (80 mL). The mixture was stirred for 30 min at room temperature. The solvent was removed under reduced pressure and ammonia (1 L, 25-28% aqueous solution) was added dropwise. The resulting mixture was stirred for a further 1 h at room temperature. The solvent was evaporated in vacuo to yield 43 g of the crude product, which was used directly in the next step without further purification. LCMS (ESI): [M+H]+=157/159.
With sulfuric acid; sodium hydrogencarbonate; In methanol;Cooling; Reflux;
Fischer esterification of <strong>[6311-35-9]6-bromo-nicotinic acid</strong> ( Scheme 2 , 3a) This synthesis is slightly modified literature procedure [45] . In the glass batch reactor with dean-stark apparatus and magnetic stirrer <strong>[6311-35-9]6-bromo-nicotinic acid</strong> (3?mmol, 0.606?g) was dissolved in 10?ml of methanol. The mixture was cooled in ice bath and added dropwise 1.5?ml of concentrated H2SO4. The suspension was then heated to refluxing conditions and under vigorous stirring let to react overnight. After cooling down, 5?ml of H2O was added and then saturated NaHCO3 solution was added to neutralize the acid, The mixture was transferred to a separation funnel and the product was extracted with dichloromethane (3?*?30?ml) as a bottom layer. Dichloromethane was evacuated in rotary evaporator at room temperature to obtain <strong>[6311-35-9]6-bromo-nicotinic acid</strong> methyl ester as a white solid (0.43?g, 66%) with m.p. 65-67?C. 1H NMR (500.20?MHz, CDCl3, 25?C): delta?=?8.97 (dd, JH2,H4?=?2.4?Hz, JH2,H5?<?1?Hz, 1H, pyH2), 8.13 (dd, JH4,H5?=?8.3?Hz, 1H, pyH4), 7.59 (dd, 1H, pyH5), 3.96 (s, 3H, -OCH3). 13C NMR (125.8?MHz, CDCl3, 25?C): delta?=?165.1 (-CO2CH3), 151.4 (pyC2), 146.9 (pyC6), 139.2 (pyC4), 128.1 (pyC5), 125.3 (pyC3), 52.6 (-OCH3) (for more details see Supplementary material).
2-bromo-N-((1-methylpiperidin-4-yl)methyl)nicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 1-propanephosphonic acid cylic anhydride; triethylamine; In ethyl acetate; N,N-dimethyl-formamide; at 0 - 20℃; for 16h;
General procedure: To a stirred solution of 6-bromopyridin-3-amine (2.0 g, 11.56 mmol) in DCM (50 mL), 2-phenylacetic acid (2.04 g, 15.02 mmol), and TEA (4.60 g, 46.24 mmol) were added, followed by the addition of T3P (9.19 g, 28.90 mmol) at 0C. The resulting mixture was stirred at rt for 16 h. The reaction mixture was washed with saturated NaHCOs aqueous solution (100 mL). The organic layer was dried over anhydrous Na2S04 and filtered. The filtered solution was concentrated under reduced pressure and the resulting crude compound was purified by flash column chromatography using 25% ethyl acetate in pet ether as eluent to afford the title compound (2,30 g, 68%) as an off-white solid.
A mixture of <strong>[6311-35-9]6-bromonicotinic acid</strong> (13.0 g, 64.3 mmol) in SOCh (150 mL) was heated at 80 C for 2 h under N2 atmosphere. After cooling, the reaction mixture was concentrated under reduced pressure. Then to the mixture was added DCM (240 mL), Me2NH (7.00 g, 85.8 mmol) and TEA (60 mL), the mixture was stirred at 25 C for 16 h under N2. TLC showed the reaction was completed. The residue was poured into water (100 mL) and extracted with DCM (100 mL x 3). The combined organic layer was washed with water (100 mL), dried over Na2S04, filtered and concentrated in vacuum. The residue was purified by Combi Flash (50% EtOAc in pentane) to afford 6-bromo-N,N-dimethylnicotinamide (12.2 g, yield: 83%) as a white solid. NMR (400 MHz, DMSO-rie) d 2.92 (3H, s), 2.99 (3H, s), 7.59 (1H, dd, J= 8.4, 0.8 Hz), 7.92 (1H, dd, J= 8.4, 2.4 Hz), 8.47 (1H, dd, J= 2.4, 0.8 Hz).
With water; sodium hydroxide; In tetrahydrofuran; at 25℃; for 16h;
To a mixture of methyl 6-bromopyridine-3-carboxylate (15.0 g, 69.4 mmol) in THF (75 mL) and H2O (15 mL) was added NaOH (11.1 g, 278 mmol) in one portion at 25 C. Then the mixture was stirred for 16 h. TLC showed the reaction was completed. The mixture was poured into water (100 mL) and washed with EtOAc (150 mL x2). The aqueous phase was acidified with HCl aq. (1N) to pH = 3 and extracted with EtOAc (150 mL x3). The combined organic phase was washed with brine (100 mL), dried over Na2S04, filtered and concentrated in vacuum to afford 6-bromonicotinic acid (13.0 g, yield: 93%) as a white solid. NMR (400 MHz, DMSO-rie) d 7.80 (1H, d, J= 8.8 Hz), 8.16 (1H, dd, J= 8.4, 2.4 Hz), 8.48 (1H, d, J= 2.4 Hz).
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine at 0 - 20℃; for 18h; Schlenk technique; Inert atmosphere;
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