* 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.
Stage #1: With tetrafluoroboric acid In water Stage #2: With sodium nitrite In water at 0 - 100℃; Stage #3: With sodium hydrogencarbonate In water
Example 1; 6-Bromo-3-pyridnoI.; 3-Amino-6-bromopyridinc (1.73 g, 10 mmol) was dissolved in HBF4 (5 mL, 50 percent aq.) and water (5 mL) was added. To the resulting brownish solution, cooled to O0C in an ice-bath, NaNO2 (759 mg, 11 mmol) in water (5 mL) was added dropwisc. The resulting yellowish heterogenous reaction mixture was stirred for 1 h at this temperature. After addition of water (5 mL), the mixture was stirred in an oil -bath for 5 h at 1000C (gas evolution). The cooled reaction mixture was then neutralized by addition OfNaHCO3 (5 percent aq.) and the product extracted with ethyl acetate (5 x 35 mL). After drying (NaiSO4) and evaporation in vacuo, the resulting brownish solid was purified by column chromatography (SiO2) using pentane/ethyl acetate (9:1) to give 1.04 g (60 percent) of the title compound, mp 137-1380C (lit. 135.5-136.5 0C; den Hertog et al\\ Rec. Tray. Chim. Pays-Bas 1959, 69, 1281).
27%
at 100℃; for 4.5 h; Cooling with ice
Step 4a. 6-Bromo-pyridin-3-ol (compound 2002) 3-Amino-6-bromopyridine (1 g, 5.8 mmol) was dissolved in HBF4 (3.6 mL, 40percent aq) and water (3 mL). To the cooled brownish solution under an ice-bath was added dropwise NaNO2 (441 mg, 6.4 mmol) solution in water (3 mL). The resulting mixture was stirred for 1 h at this temperature. After addition of water (3 mL), the mixture was stirred at 100° C. for 3.5 h. The reaction mixture was neutralized by aqueous NaHCO3 (5percent) and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4 and evaporated in vacuo. The residue was purified by column chromatography (hexanes/ethyl acetate: 9/1) to afford compound 2002 as a white solid (270 mg, 27percent yield). LCMS: m/z 174.0 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 6.65 (br, 1H), 7.13 (dd, J=8.4 Hz, 3.2 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 8.03 (d, J=3.2 Hz, 1H).
With hydrogenchloride; iron In ethanol; water for 5 h; Reflux
To a solution of 2-bromo-5-nitropyridine (2.03 g, 10 mmol) in ethanol (48 mL), iron powder (2.8 g, 50 mmol), concentrated hydrochloric acid (1.9 mL) and water (9.1 mL) were sequentially added. The mixture was reacted under reflux for 5 h, cooled and filtrated. The filtrate was concentrated, adjusted to a pH of about 7 to 8 and extracted with DCM. The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a reddish brown solid (1.58 g, 91.3percent yield).
74.4%
With hydrogenchloride In ethanol; water
1. Preparation of 6-bromopyridine-3-amine To a solution of 2-bromo-5-nitropyridine (64 g, 0.317 mol)/ethanol (1 L) was successively added Fe powder (88 g, 1.571 mmol), concentrated hydrochloric acid (61 mL) and water (287 mL). The reaction mixture was reacted under reflux for 5 h. The reaction mixture was cooled and filtered. The filtrate was concentrated and adjusted with a sodium bicarbonate solution to pH≈7-8, and re-filtered. The resulting filtrate was extracted with dichlormethane. The organic phase was dried with anhydrous sodium sulfate, and concentrated in a reduced pressure to produce 40.5 g of the title compound as a pale-yellow solid in a yield of 74.4percent.
74.4%
With hydrogenchloride; iron In ethanol; water for 5 h; Reflux
1. Preparation of 6-bromopyridine-3-amine To a solution of 2-bromo-5-nitropyridine (64g, 0.317mol)/ethanol (1L) was successively added Fe powder (88g, 1.571mmol), concentrated hydrochloric acid (61mL) and water (287mL). The reaction mixture was reacted under reflux for 5h. The reaction mixture was cooled and filtered. The filtrate was concentrated and adjusted with a sodium bicarbonate solution to pH≈7-8, and re-filtered. The resulting filtrate was extracted with dichlormethane. The organic phase was dried with anhydrous sodium sulfate, and concentrated in a reduced pressure to produce 40.5g of the title compound as a pale-yellow solid in a yield of 74.4percent.
73%
With iron; ammonium chloride In methanol; water at 50℃; for 6 h;
2-Bromo-5-nitro-pyridine (202 g, 1.0 mol) was dissolved in methanol (2.0 L), and a saturated aqueous ammonium chloride solution (2.0 L) was added thereto, followed by stirring at 50° C. Then, iron (224 g, 4.0 mol) was slowly added thereto, followed by stirring at 50° C. for 6 hours. The reaction solution was cooled to room temperature and then filtered, followed by washing with ethyl acetate. The filtrate was diluted with water, followed by extraction with ethyl acetate (1.0 L×6). The extraction liquids were combined, washed with a saturated aqueous sodium hydrogen carbonate solution (2.0 L) and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. Then, the solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1:1) to obtain the title compound (126 g, 73percent). [1152] 1H NMR (400 MHz, DMSO-d6): δ 7.69 (d, J=2.8 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 6.90 (dd, J=8.4 Hz, 2.8 Hz, 1H), 5.50 (s, 2H)
73%
With iron; ammonium chloride In methanol; water at 50℃; for 6 h;
(Step 1) 6-Bromopyridin-3-amine (0221) (0222) 2-Bromo-5-nitro-pyridine (202 g, 1.0 mol) was dissolved in methanol (2.0 L), a saturated aqueous solution of ammonium chloride (2.0 L) was added thereto, the resulting mixture was stirred at 50° C., then iron (224 g, 4.0 mol) was slowly added thereto, and the resulting mixture was stirred at 50° C. for 6 hours. The reaction solution was cooled to room temperature and then filtered and washed with ethyl acetate. The filtrate was diluted with water and then extracted with ethyl acetate (1.0 L×6). The extracts were combined, washed with a saturated aqueous solution of sodium hydrogen carbonate (2.0 L) and a saturated saline solution, dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to obtain the title compound (126 g, 73percent). (0223) 1H NMR (400 MHz, DMSO-d6): δ 7.69 (d, J=2.8 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 6.90 (dd, J=8.4 Hz, 2.8 Hz, 1H), 5.50 (s, 2H)
72%
With 5%-palladium/activated carbon; hydrogen; sodium sulfate In tetrahydrofuran at 37℃; for 20 h;
0.282 g of 5percent Pd / C and lOmmol of anhydrous sodium sulfate were added to a 100 mL round bottom flask containing 20 mmol of 5-nitro-2-bromopyridine in 40 ml of tetrahydrofuran, then hydrogen was introduced, heated to 37 ° C and stirred 20 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, suction filtered, steamed and subjected to column chromatography (eluent: dichloromethane / acetone, 10: 1 in volume ratio) and dried in vacuo to give 2.476 g of 5-amino- Bromopyridine in 72percent yield.
40.5g
With hydrogenchloride; iron In ethanol; water for 5 h; Reflux
Iron powder (88g, 1.571mmol), concentrated hydrochloric acid (61mL) and water (287mL) were sequentially added to a solution of 2-bromo-5-nitropyridine (64g, 0.317mol) in ethanol (1L). The mixture was reacted under reflux for 5 h. The reaction mixture was cooled, filtered and the filtrate was concentrated and then adjusted to approximately pH 7-8 with a saturated aqueous solution of sodium bicarbonate, filtered again, and the filtrate was extracted with 200mL of dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to give 40.5g of a pale yellow solid.
40.5 g
With hydrogenchloride; iron In ethanol; water for 5 h; Reflux
Iron powder (88 g, 1.571 mmol), concentrated hydrochloric acid (61 mL) and water (287 mL) were sequentially added to a solution of 2-bromo-5-nitropyridine (64 g, 0.317 mol) in ethanol (1 L). The mixture was reacted under reflux for 5 h. The reaction mixture was cooled, filtered and the filtrate was concentrated and then adjusted to approximately pH 7-8 with a saturated aqueous solution of sodium bicarbonate, filtered again, and the filtrate was extracted with 200 mL of dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to give 40.5 g of a pale yellow solid.
Reference：
[1] Bulletin des Societes Chimiques Belges, 1988, vol. 97, # 1, p. 51 - 54
[2] Green Chemistry, 2018, vol. 20, # 1, p. 130 - 135
[3] Journal of Organic Chemistry, 2011, vol. 76, # 23, p. 9841 - 9844
[4] Patent: EP2886540, 2015, A1, . Location in patent: Paragraph 0143; 0144
[5] Patent: US2014/93505, 2014, A1, . Location in patent: Page/Page column
[6] Patent: EP2719697, 2014, A1, . Location in patent: Paragraph 0097
[7] Patent: US2015/51395, 2015, A1, . Location in patent: Paragraph 1151-1152
[8] Patent: US2016/244451, 2016, A1, . Location in patent: Paragraph 0221; 0222; 0223
[9] Patent: CN103755744, 2016, B, . Location in patent: Paragraph 0068; 0069
[10] Chemische Berichte, 1935, vol. 68, p. 315,321
[11] Yakugaku Zasshi, 1951, vol. 71, p. 662,665[12] Chem.Abstr., 1952, p. 8109
[13] Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie, 1951, vol. 288, p. 237,241
[14] Journal of Medicinal Chemistry, 2007, vol. 50, # 25, p. 6303 - 6306
[15] Patent: EP518636, 1992, A1,
[16] Patent: EP518636, 1992, A1,
[17] Patent: EP2781520, 2014, A1, . Location in patent: Paragraph 0102; 0103; 0186 - 0188
[18] Patent: US2015/166539, 2015, A1, . Location in patent: Paragraph 0242; 0243
4
[ 4487-59-6 ]
[ 13534-97-9 ]
Yield
Reaction Conditions
Operation in experiment
86%
With sodium hydroxide In N,N-dimethyl-formamide
1.1a Synthesis of 5-amino-2-bromopyridine Tin (II) chloride hydrate (0.78 g, 3.5 mmol) was added to a stirring solution of 5-nitro-2-bromopyridine (0.24 g, 1.2 mmol) in DMF (5 mL) at RT. After 2 h, 6 N NaOH (2 mL) was added and the suspension was stirred vigorously for 10 min. The organics were extracted with diethyl ether (2*10 mL), washed with brine (2*10 mL) and dried (Na2SO4). The filtered solution was then concentrated under reduced pressure to afford the desired product as a yellow oil (0.178 g, 86percent), which was used without further purification. 1.2 Rearrangement of nicotinic acids Rearrangement of the corresponding nicotinic acids (III) (Scheme 3) using a modified Schmidt reaction, followed by deprotection of the aniline group generated the desired aminopyridines (IV) as the corresponding TFA salts.
Reference：
[1] Synthesis, 2001, # 14, p. 2175 - 2179
[2] Synthesis, 2001, # 14, p. 2175 - 2179
10
[ 462-08-8 ]
[ 13534-97-9 ]
[ 39856-58-1 ]
[ 39856-57-0 ]
Reference：
[1] Synthesis, 2001, # 14, p. 2175 - 2179
[2] Synthesis, 2001, # 14, p. 2175 - 2179
11
[ 13534-97-9 ]
[ 119830-47-6 ]
Reference：
[1] Patent: WO2009/154769, 2009, A1,
12
[ 13534-97-9 ]
[ 333-20-0 ]
[ 934266-82-7 ]
Yield
Reaction Conditions
Operation in experiment
77%
at -15 - 20℃; Inert atmosphere
Example 1; Preparation of intermediates N-(5-bromothiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide (1D) and N-(5-bromothiazolo[5,4-b]pyridin-2-yl)-4-(trifluoromethyl)benzamide (1E); Step A: Commercially available 6-bromopyridin-3-amine (1A, 20 g, 1.0 equivalent) was added in portions to a solution of potassium thiocyanate (5.0 equivalents) in acetic acid (0.4 M) at -5° C. After addition, the mixture was cooled to -15° C., and a solution of Br2 (1.3 equivalent) in acetic acic (9.4 M) was added drop wise via an additional funnel. The mixture was then warmed to room temperature and stirred for 12 h. The resulting precipitate was filtered; 100 mL EtOAc and 200 mL H2O were added to the filtrate and then 200 mL of solvent was removed in vacuo. The residue was stirred in ice bath for 10 minutes, and then the resulting precipitate was collected by filtration and washed twice with cold 10percent MeOH in Et2O. The filtrate was concentrated and the product was crystallized in ice bath to obtain a second crop of product after washing twice with cold 10percent MeOH in Et2O. The product 1B (77percent) was obtained as a brown solid after drying under vacuum, and then used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.94 (br. s., 1H) 7.44 (d, J=8.34 Hz, 1H) 7.57 (d, J=8.34 Hz, 1H) 8.04 (br. s., 1H); ESI-MS: m/z 230.0 (M+H)+.
68.93%
With bromine In acetic acid at 20℃; for 3.5 h;
Step 1: 5-bromothiazolo[5,4-b]pyridin-2-amine To a suspension of KSCN (2.2 g, 22.83 mmol) in acetic acid (10 ml) was added 6-bromopyridin-3-amine (1 g, 5.78 mmol) and the mixture was stirred at room temperature for 15 min. A solution of bromine (0.38 ml 7.51 mmol) in acetic acid (10 ml) was added dropwise to the obtained solution at room temperature for 15 min. After the completion of dropwise addition the mixture was stirred at room temperature for 3 h. Reaction was monitored by TLC. On completion to the reaction mixture was added water (25 ml); the solid so precipitated was filtered out. The filtrate was concentrated under reduced pressure; the residue was neutralised to pH=7 with aq. sol. of NaHCO3 and extracted with mixture of THF:ethyl acetate (1:1). The organic layer was dried over sodium sulphate, concentrated under reduced pressure to afford 5-bromothiazolo[5,4-b]pyridin-2-amine (0.910 g, 68.93percent) as reddish brown solid. MS: 231.86[M++1]
61%
With bromine In acetic acid at -15 - 20℃; Inert atmosphere
Example 1; Preparation of 7V-(5-Bromothiazolo[5,4-Z>]pyridin-2-yl)acetamide (1); 1A 1B Example 1[0376] To a 500 ml 3-neck under N2 was added KSCN (42.1 g, 433 mmol), followed by 225 mL of HOAc. It was cooled to -5 0C and 6-bromo-3-aminopyridine (15 g, 86.7 mmol) was added in portions. The mixture was further cooled to -15 0C, and a solution of Br2 (5.7 mL) in 12 mL of HOAc was added dropwise while keeping the bath temperature below 10 0C. It was then allowed to slowly warm up to room temperature and stirred overnight. The small amount of precipitate was filtered off. The mother liquor was cooled to 0 0C, and water was added (200 mL). It was stirred for 5 min, and the precipitate formed was collected and washed with cold MeOH/Et2O (1 :3, 50 mL, 2 times). The solid was dried under vacuum overnight to give 5-bromothiazolo[5,4-b]pyridin-2- amine the titled compound as a yellow solid (10.2 g, 51percent). The solvent was stripped from the filtrate to half the volume, and the precipitation was collected, washed with cold MeOH-Et2O, and dried to give another 2 g of product with a combined yield of 12.2 g (61percent yield).
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.583333 h; Inert atmosphere Stage #2: at 20℃; for 1 h; Inert atmosphere
To a solution of 6- bromopyridin-3 -amine (300 mg, 1.73 mmol) in tetrahydrofuran (30 ml) was added 1 M solution of lithium bis(trimethylsilyl)amide (3.46 mL, 3.46 mmol) in tetrahydrofuran over 5 min at - 78 °C under nitrogen atmosphere. After stirring for 30 min at -78 °C, iodomethane (566 mg, 3.99 mmol) was added. The resulting mixture was stirred for 1 hour at ambient temperature and then quenched by the addition of saturated aqueous solution of ammonium chloride (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers was washed with brine (2 x 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-10percent ethyl acetate in petroleum ether to afford 6-bromo- N,N-dimethylpyridin-3 -amine as a light yellow solid: MS (ESI, m/z): 201.0, 203.0 [M + 1]+.
With formaldehyd; aqueous KOH; HCO2H In dichloromethane; water; Petroleum ether
(1) Synthesis of 2-bromo-5-dimethylaminopyridine 2-bromo-5-aminopyridine (11.7 g, 67.6 mmol) was added portionwise to HCO2H (20 ml) at 0° C. Formaldehyde (37percent in water, 17 ml, 210 mmol) was then added and the mixture heated to reflux for hours. The reaction was then cooled to room temperature and an aqueous KOH solution (1N, ml) was added. The mixture was extracted with Et2O (3*100 ml) and the combined extract was dried over MgSO4, filtered and evaporated to dryness. The residual oil was purified by flash chromatography on silica (CH2Cl2). The yellowish solid was dissolved in the minimum volume of CH2Cl2, petroleum ether (150 ml) was added and the solution was stand in the fridge overnight. The white crystalline solid was filtered and washed with small portion of cold petroleum ether to afford 5.2 g (40percent) of the desired compound as white crystalline solid. 1H-NMR (CDCl3, 298K, 200 MHz, δ ppm) δ 2.96 (s, 6H), 6.87 (dd, J=2.5*9 Hz, 1H), 7.25 (d, J=9 Hz, 1H), 7.84 (d, J=2.5 Hz, 1H).
Reference：
[1] Patent: US2009/200920, 2009, A1,
17
[ 13534-97-9 ]
[ 50-00-0 ]
[ 39856-56-9 ]
Yield
Reaction Conditions
Operation in experiment
0.43 g
at 90℃; for 16 h;
Step a. To a solution of 6-bromopyridin-3 -amine (CAS Number 97-65-4) (1 g, 5.78 mmol) in formic acid (5 ml) was added para-formaldehyde (1.5 g, 1.5 eq w/w) at rt. The reaction mixture was heated at 90°C for 16 hr. The resulting reaction mixture was poured into ice cold water, basified using solid sodium carbonate and extracted using EtOAc (30ml x 3). The organic layer was combined and dried over Na2S04 concentrated under reduced pressure. The obtained residue was purified using column chromatography (20percent EtOAc in hexane) yielding 6-bromo-N, N-dimethylpyridin-3 -amine (0.43 g, 2.160 mmol). LCMS: Method C, 1.77 min, MS: ES+ 201.14. NMR (400 MHz, DMSO-d6) δ ppm 8.31-8.32 (d, 1 H), 7.84-7.85 (d, 1 H), 7.33-7.35 (d, 1 H), 2.91 (s, 6 H).
With triethylamine In dichloromethane at 20℃; for 4 h;
To a solution of 6- bromopyridin-3 -amine (5.4 g, 28.9 mmol) in dichloromethane (200 mL) were added triethylamine (4.4 g, 43.3 mmol) and di-tert-butyl dicarbonate (7.6 g, 34.7 mmol). The resulting solution was stirred for 4 hours at ambient temperature and quenched with water (300 mL). The organic layer was separated and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 2-10percent ethyl acetate in petroleum ether to afford tert-butyl (6- bromopyridin-3-yl)carbamate as a colorless solid: MS (ESI, m/z): 273.1, 275.1 [M + 1]+; 1H MR (300 MHz, OMSO-d6) δ 9.72 (s, 1H), 8.45 (d, J= 1.8 Hz, 1H), 7.83 (d, J= 5.4 Hz, 1H), 7.53 (d, J= 5.7 Hz, 1H), 1.48 (s, 9H).
25%
With triethylamine In dichloromethane at 0 - 20℃; for 16 h;
To a stirred solution of 6-bromopyridin-3-amine (5 g, 28.90 mmol) and TEA (8.75 g, 86.70 mmol) in DCM (50ml) was added Boc20 (12.6 g, 57.80 mmol) at 0°C and stirred for 16 hat RT. The reaction mixture was dilutedwith DCM washed with water. The organic layer was dried over anhydrous Na2S04 and concentrated underreduced pressure. The obtained crude compound was purified by flash column chromatography using 20percentEtOAc in petroleum ether as eluent to obtain the title compound (2.0 g, 25percent) as white solid. LC-MS (method 2): Rt = 2.65 min; m/z = 275.17 (M+H++2).
Reference：
[1] Patent: WO2015/188368, 2015, A1, . Location in patent: Page/Page column 114
[2] Journal of Medicinal Chemistry, 2010, vol. 53, # 24, p. 8709 - 8715
[3] Chemistry - A European Journal, 2010, vol. 16, # 30, p. 9056 - 9067
[4] Patent: WO2017/207813, 2017, A1, . Location in patent: Page/Page column 126
[5] Patent: WO2006/92599, 2006, A2, . Location in patent: Page/Page column 58-59
20
[ 13534-97-9 ]
[ 915006-52-9 ]
Yield
Reaction Conditions
Operation in experiment
65%
With iodine; silver sulfate In ethanol
To a stirred solution of 6-bromo-pyridin-3-ylamine (10.2 g, 0.0580 mol) and Ag2SO4 (18.1 g, 0.0580 mol) in EtOH (150 mL) was added 12 (7.59 g, 0.0580 mol) and the reaction was allowed to stir overnight. At this time hexane (200 mL) was added and the resultant mixture was filtered through Celite. The solvent was removed in vacuo, dissolved in CHCl3 (200 mL), washed with aqueous saturated Na2S2O3 (100 mL), water (1.x.100 mL), and dried (Na2SO4). The solvent was concentrated in vacuo and the residue was dissolved in hot EtOAc (100 mL), filtered and treated with hexanes (100 mL). Filtration gave 11.2 g (65percent) of the title compound as a white crystalline material. 1H-NMR (CDCl3; 400 MHz): δ 7.10 (d, 1H, J=8.2 Hz), 6.74 (d, 1H, J=8.2 Hz), 4.06 (br s, 2H).
65%
With iodine; silver sulfate In ethanol at 20℃;
To a stirred solution of 6-bromo-pyridin-3-ylamine (10.2 g, 0.0580 mol) and Ag2SO4 (18.1 g, 0.0580 mol) in EtOH (150 mL) was added I2 (7.59 g, 0.0580 mol) and the reaction was allowed to stir overnight. At this time hexane (200 mL) was added and the resultant mixture was filtered through Celite. The solvent was removed in vacuo, dissolved in CHCl3 (200 mL), washed with aqueous saturated Na2S2O3 (100 mL), water (1.x.100 mL), and dried (Na2SO4). The solvent was concentrated in vacuo and the residue was dissolved in hot EtOAc (100 mL), filtered and treated with hexanes (100 mL). Filtration gave 11.2 g (65percent) of 6-bromo-2-iodo-pyridin-3-ylamine as a white crystalline material. 1H-NMR (CDCl3; 400 MHz): δ 7.10 (d, 1H, J=8.2 Hz), 6.74 (d, 1H, J=8.2 Hz), 4.06 (br s, 2H).
65%
With iodine; silver sulfate In ethanol
Example 51; 5-Cyano- lH-imidazole-2-carboxylic acid [2-(dimethyl-cyclohex- 1 -enyl)-6-( 1 -hydroxy- 1 - methyl-ethyl)-pyridin-3-yl]-amide; a) 6-Bromo-2-iodo-pyridin-3-ylamine; <n="112"/>To a stirred solution of 6-bromo-pyridin-3-ylamine (10.2 g, 0.0580 mol) and Ag2SO4 (18.1 g, 0.0580 mol) in EtOH (150 mL) was added I2 (7.59 g, 0.0580 mol) and the reaction was allowed to stir overnight. At this time hexane (200 mL) was added and the resultant mixture was filtered through Celite. The solvent was removed in vacuo, dissolved in CHCl3 (200 mL), washed with aqueous saturated Na2S2O3 (100 mL), water (1 x 100 mL), and dried (Na2SO4). The solvent was concentrated in vacuo and the residue was dissolved in hot EtOAc (100 mL), filtered and treated with hexanes (100 mL). Filtration gave 11.2 g (65 percent) of the title compound as a white crystalline material. 1H- NMR (CDCl3; 400 MHz): δ 7.10 (d, IH, J = 8.2 Hz), 6.74 (d, IH, J = 8.2 Hz), 4.06 (br s, 2H). .
Reference：
[1] Journal of the American Chemical Society, 2013, vol. 135, # 23, p. 8436 - 8439
[2] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 15, p. 3057 - 3061
22
[ 13534-97-9 ]
[ 5720-07-0 ]
[ 52057-98-4 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 15, p. 3057 - 3061
With bromine; acetic acid; at -15 - 20℃;Inert atmosphere;
Example 1; Preparation of intermediates N-(5-bromothiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide (1D) and N-(5-bromothiazolo[5,4-b]pyridin-2-yl)-4-(trifluoromethyl)benzamide (1E); Step A: Commercially available 6-bromopyridin-3-amine (1A, 20 g, 1.0 equivalent) was added in portions to a solution of potassium thiocyanate (5.0 equivalents) in acetic acid (0.4 M) at -5 C. After addition, the mixture was cooled to -15 C., and a solution of Br2 (1.3 equivalent) in acetic acic (9.4 M) was added drop wise via an additional funnel. The mixture was then warmed to room temperature and stirred for 12 h. The resulting precipitate was filtered; 100 mL EtOAc and 200 mL H2O were added to the filtrate and then 200 mL of solvent was removed in vacuo. The residue was stirred in ice bath for 10 minutes, and then the resulting precipitate was collected by filtration and washed twice with cold 10% MeOH in Et2O. The filtrate was concentrated and the product was crystallized in ice bath to obtain a second crop of product after washing twice with cold 10% MeOH in Et2O. The product 1B (77%) was obtained as a brown solid after drying under vacuum, and then used without further purification. 1H NMR (400 MHz, DMSO-d6) delta ppm 4.94 (br. s., 1H) 7.44 (d, J=8.34 Hz, 1H) 7.57 (d, J=8.34 Hz, 1H) 8.04 (br. s., 1H); ESI-MS: m/z 230.0 (M+H)+.
68.93%
With bromine; In acetic acid; at 20℃; for 3.5h;
Step 1: 5-bromothiazolo[5,4-b]pyridin-2-amine To a suspension of KSCN (2.2 g, 22.83 mmol) in acetic acid (10 ml) was added 6-bromopyridin-3-amine (1 g, 5.78 mmol) and the mixture was stirred at room temperature for 15 min. A solution of bromine (0.38 ml 7.51 mmol) in acetic acid (10 ml) was added dropwise to the obtained solution at room temperature for 15 min. After the completion of dropwise addition the mixture was stirred at room temperature for 3 h. Reaction was monitored by TLC. On completion to the reaction mixture was added water (25 ml); the solid so precipitated was filtered out. The filtrate was concentrated under reduced pressure; the residue was neutralised to pH=7 with aq. sol. of NaHCO3 and extracted with mixture of THF:ethyl acetate (1:1). The organic layer was dried over sodium sulphate, concentrated under reduced pressure to afford 5-bromothiazolo[5,4-b]pyridin-2-amine (0.910 g, 68.93%) as reddish brown solid. MS: 231.86[M++1]
61%
With bromine; In acetic acid; at -15 - 20℃;Inert atmosphere;
Example 1; Preparation of 7V-(5-Bromothiazolo[5,4-Z>]pyridin-2-yl)acetamide (1); 1A 1B Example 1[0376] To a 500 ml 3-neck under N2 was added KSCN (42.1 g, 433 mmol), followed by 225 mL of HOAc. It was cooled to -5 0C and 6-bromo-3-aminopyridine (15 g, 86.7 mmol) was added in portions. The mixture was further cooled to -15 0C, and a solution of Br2 (5.7 mL) in 12 mL of HOAc was added dropwise while keeping the bath temperature below 10 0C. It was then allowed to slowly warm up to room temperature and stirred overnight. The small amount of precipitate was filtered off. The mother liquor was cooled to 0 0C, and water was added (200 mL). It was stirred for 5 min, and the precipitate formed was collected and washed with cold MeOH/Et2O (1 :3, 50 mL, 2 times). The solid was dried under vacuum overnight to give 5-bromothiazolo[5,4-b]pyridin-2- amine the titled compound as a yellow solid (10.2 g, 51%). The solvent was stripped from the filtrate to half the volume, and the precipitation was collected, washed with cold MeOH-Et2O, and dried to give another 2 g of product with a combined yield of 12.2 g (61% yield).
With bromine; acetic acid; at 100℃;Cooling with ice;
Step 1; To a solution of 2-bromo-5-aminopyridine (3 g, 17.3 mmol) and potassium thiocyanate (4.2 g) in acetic acid (20 mL), bromine (3.3 g) was added dropwise under icebath-cooling. The solution was then stirred for 1 hour and subsequently at 100C overnight. After the reaction mixture was cooled, water was added thereto. The precipitate was collected by filtration, then subjected to a next reaction without further purification.
With hydrogenchloride; iron; In ethanol; water; for 5h;Reflux;
To a solution of <strong>[4487-59-6]2-bromo-5-nitropyridine</strong> (2.03 g, 10 mmol) in ethanol (48 mL), iron powder (2.8 g, 50 mmol), concentrated hydrochloric acid (1.9 mL) and water (9.1 mL) were sequentially added. The mixture was reacted under reflux for 5 h, cooled and filtrated. The filtrate was concentrated, adjusted to a pH of about 7 to 8 and extracted with DCM. The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a reddish brown solid (1.58 g, 91.3% yield).
74.4%
With hydrogenchloride; In ethanol; water;
1. Preparation of 6-bromopyridine-3-amine To a solution of <strong>[4487-59-6]2-bromo-5-nitropyridine</strong> (64 g, 0.317 mol)/ethanol (1 L) was successively added Fe powder (88 g, 1.571 mmol), concentrated hydrochloric acid (61 mL) and water (287 mL). The reaction mixture was reacted under reflux for 5 h. The reaction mixture was cooled and filtered. The filtrate was concentrated and adjusted with a sodium bicarbonate solution to pH?7-8, and re-filtered. The resulting filtrate was extracted with dichlormethane. The organic phase was dried with anhydrous sodium sulfate, and concentrated in a reduced pressure to produce 40.5 g of the title compound as a pale-yellow solid in a yield of 74.4%.
74.4%
With hydrogenchloride; iron; In ethanol; water; for 5h;Reflux;
1. Preparation of 6-bromopyridine-3-amine To a solution of <strong>[4487-59-6]2-bromo-5-nitropyridine</strong> (64g, 0.317mol)/ethanol (1L) was successively added Fe powder (88g, 1.571mmol), concentrated hydrochloric acid (61mL) and water (287mL). The reaction mixture was reacted under reflux for 5h. The reaction mixture was cooled and filtered. The filtrate was concentrated and adjusted with a sodium bicarbonate solution to pH?7-8, and re-filtered. The resulting filtrate was extracted with dichlormethane. The organic phase was dried with anhydrous sodium sulfate, and concentrated in a reduced pressure to produce 40.5g of the title compound as a pale-yellow solid in a yield of 74.4%.
73%
With iron; ammonium chloride; In methanol; water; at 50℃; for 6h;
2-Bromo-5-nitro-pyridine (202 g, 1.0 mol) was dissolved in methanol (2.0 L), and a saturated aqueous ammonium chloride solution (2.0 L) was added thereto, followed by stirring at 50 C. Then, iron (224 g, 4.0 mol) was slowly added thereto, followed by stirring at 50 C. for 6 hours. The reaction solution was cooled to room temperature and then filtered, followed by washing with ethyl acetate. The filtrate was diluted with water, followed by extraction with ethyl acetate (1.0 L×6). The extraction liquids were combined, washed with a saturated aqueous sodium hydrogen carbonate solution (2.0 L) and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. Then, the solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1:1) to obtain the title compound (126 g, 73%). [1152] 1H NMR (400 MHz, DMSO-d6): delta 7.69 (d, J=2.8 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 6.90 (dd, J=8.4 Hz, 2.8 Hz, 1H), 5.50 (s, 2H)
73%
With iron; ammonium chloride; In methanol; water; at 50℃; for 6h;
(Step 1) 6-Bromopyridin-3-amine (0221) (0222) 2-Bromo-5-nitro-pyridine (202 g, 1.0 mol) was dissolved in methanol (2.0 L), a saturated aqueous solution of ammonium chloride (2.0 L) was added thereto, the resulting mixture was stirred at 50 C., then iron (224 g, 4.0 mol) was slowly added thereto, and the resulting mixture was stirred at 50 C. for 6 hours. The reaction solution was cooled to room temperature and then filtered and washed with ethyl acetate. The filtrate was diluted with water and then extracted with ethyl acetate (1.0 L×6). The extracts were combined, washed with a saturated aqueous solution of sodium hydrogen carbonate (2.0 L) and a saturated saline solution, dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to obtain the title compound (126 g, 73%). (0223) 1H NMR (400 MHz, DMSO-d6): delta 7.69 (d, J=2.8 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 6.90 (dd, J=8.4 Hz, 2.8 Hz, 1H), 5.50 (s, 2H)
72%
With 5%-palladium/activated carbon; hydrogen; sodium sulfate; In tetrahydrofuran; at 37℃; for 20h;
0.282 g of 5% Pd / C and lOmmol of anhydrous sodium sulfate were added to a 100 mL round bottom flask containing 20 mmol of <strong>[4487-59-6]5-nitro-2-bromopyridine</strong> in 40 ml of tetrahydrofuran, then hydrogen was introduced, heated to 37 C and stirred 20 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, suction filtered, steamed and subjected to column chromatography (eluent: dichloromethane / acetone, 10: 1 in volume ratio) and dried in vacuo to give 2.476 g of 5-amino- Bromopyridine in 72% yield.
platinum (IV) oxide; In ethanol;
(3) In 200 ml of ethanol, within hydrogen atmosphere, 20.0 g of <strong>[4487-59-6]2-bromo-5-nitropyridine</strong> were reduced with use of 1.0 g of platinum dioxide. After comfirming that no absorption of hydrogen was observed, the catalyst was filtered off. After removing the ethanol, the product was recrystallized with toluene to obtain 17.4 g of 5-amino-2-bromopyridine.
platinum (IV) oxide; In ethanol;
(5) In ethanol, within hydrogen atmosphere, 20.0 g of <strong>[4487-59-6]2-bromo-5-nitropyridine</strong> were reduced with use of 1.0 g of platinum dioxide. After comfirming that no absorption of hydrogen was observed, the catalyst was filtered off. After removing the ethanol, the product was recystalized with toluene to obtain 17.4 g of 5-amino-2-bromopyridine.
40.5g
With hydrogenchloride; iron; In ethanol; water; for 5h;Reflux;
Iron powder (88g, 1.571mmol), concentrated hydrochloric acid (61mL) and water (287mL) were sequentially added to a solution of <strong>[4487-59-6]2-bromo-5-nitropyridine</strong> (64g, 0.317mol) in ethanol (1L). The mixture was reacted under reflux for 5 h. The reaction mixture was cooled, filtered and the filtrate was concentrated and then adjusted to approximately pH 7-8 with a saturated aqueous solution of sodium bicarbonate, filtered again, and the filtrate was extracted with 200mL of dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to give 40.5g of a pale yellow solid.
40.5 g
With hydrogenchloride; iron; In ethanol; water; for 5h;Reflux;
Iron powder (88 g, 1.571 mmol), concentrated hydrochloric acid (61 mL) and water (287 mL) were sequentially added to a solution of <strong>[4487-59-6]2-bromo-5-nitropyridine</strong> (64 g, 0.317 mol) in ethanol (1 L). The mixture was reacted under reflux for 5 h. The reaction mixture was cooled, filtered and the filtrate was concentrated and then adjusted to approximately pH 7-8 with a saturated aqueous solution of sodium bicarbonate, filtered again, and the filtrate was extracted with 200 mL of dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to give 40.5 g of a pale yellow solid.
To a stirred solution of 6-bromo-pyridin-3-ylamine (10.2 g, 0.0580 mol) and Ag2SO4 (18.1 g, 0.0580 mol) in EtOH (150 mL) was added 12 (7.59 g, 0.0580 mol) and the reaction was allowed to stir overnight. At this time hexane (200 mL) was added and the resultant mixture was filtered through Celite. The solvent was removed in vacuo, dissolved in CHCl3 (200 mL), washed with aqueous saturated Na2S2O3 (100 mL), water (1×100 mL), and dried (Na2SO4). The solvent was concentrated in vacuo and the residue was dissolved in hot EtOAc (100 mL), filtered and treated with hexanes (100 mL). Filtration gave 11.2 g (65%) of the title compound as a white crystalline material. 1H-NMR (CDCl3; 400 MHz): delta 7.10 (d, 1H, J=8.2 Hz), 6.74 (d, 1H, J=8.2 Hz), 4.06 (br s, 2H).
65%
With iodine; silver sulfate; In ethanol; at 20℃;
To a stirred solution of 6-bromo-pyridin-3-ylamine (10.2 g, 0.0580 mol) and Ag2SO4 (18.1 g, 0.0580 mol) in EtOH (150 mL) was added I2 (7.59 g, 0.0580 mol) and the reaction was allowed to stir overnight. At this time hexane (200 mL) was added and the resultant mixture was filtered through Celite. The solvent was removed in vacuo, dissolved in CHCl3 (200 mL), washed with aqueous saturated Na2S2O3 (100 mL), water (1×100 mL), and dried (Na2SO4). The solvent was concentrated in vacuo and the residue was dissolved in hot EtOAc (100 mL), filtered and treated with hexanes (100 mL). Filtration gave 11.2 g (65%) of 6-bromo-2-iodo-pyridin-3-ylamine as a white crystalline material. 1H-NMR (CDCl3; 400 MHz): delta 7.10 (d, 1H, J=8.2 Hz), 6.74 (d, 1H, J=8.2 Hz), 4.06 (br s, 2H).
65%
With iodine; silver sulfate; In ethanol;
Example 51; 5-Cyano- lH-imidazole-2-carboxylic acid [2-(dimethyl-cyclohex- 1 -enyl)-6-( 1 -hydroxy- 1 - methyl-ethyl)-pyridin-3-yl]-amide; a) 6-Bromo-2-iodo-pyridin-3-ylamine; <n="112"/>To a stirred solution of 6-bromo-pyridin-3-ylamine (10.2 g, 0.0580 mol) and Ag2SO4 (18.1 g, 0.0580 mol) in EtOH (150 mL) was added I2 (7.59 g, 0.0580 mol) and the reaction was allowed to stir overnight. At this time hexane (200 mL) was added and the resultant mixture was filtered through Celite. The solvent was removed in vacuo, dissolved in CHCl3 (200 mL), washed with aqueous saturated Na2S2O3 (100 mL), water (1 x 100 mL), and dried (Na2SO4). The solvent was concentrated in vacuo and the residue was dissolved in hot EtOAc (100 mL), filtered and treated with hexanes (100 mL). Filtration gave 11.2 g (65 %) of the title compound as a white crystalline material. 1H- NMR (CDCl3; 400 MHz): delta 7.10 (d, IH, J = 8.2 Hz), 6.74 (d, IH, J = 8.2 Hz), 4.06 (br s, 2H). .
With iodine; silver sulfate; In ethanol; at 20℃;
5.0 g 5-Amino-2-bromopyridine were dissolved in 70 ml etha?ol. 9.0 g silver sulfate and 7.33 g iodine were added. The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue diluted with 500 ml ethyl acetate and filtered over a celite pad. The filtrate was washed with 200 ml saturated Na2S203 solution and water, dried over MgSO4 and then the solvent was removed in vacuo to obtain 7.7 g 6-Bromo-2-iodo-pyridin-3-ylamine.C5H4BrlN2 (298.91), MS(ESI+): 300.9 (M+H+), Rf(ethyl acetate : n-heptane = 1 :2) = 0.26.
With pyridine; copper diacetate; In dichloromethane;Molecular sieve;
To a solution of 6-bromo-pyridin-3-ylamine (0.20 g, 1.2 mmol, 1.0 equiv) and 2- methoxy-3-fluoropyridyl-5-boronic acid (0.39 g, 2.3 mmol, 2.0 equiv) in 10 Ml dichloromethane was added pyridine (0.24 Ml, 3.0 mmol, 2.5 equiv), copper (II) acetate (0.32 g, 1.7 mmol, 1.5 equiv) and 4A molecular sieves. The heterogeneous reaction mixture was allowed to stir vigorously open to air overnight. The reaction was then filtered through Celite, concentrated in vacuo, and purified by silica gel chromatography to afford the title compound: 1H NMR (400 MHz1 DMSO-d6) delta ppm 3.96 (s, 3 H) 7.35 (d, J=3.03 Hz, 1 H) 7.37 (d, J=3.03 Hz, 1 H) 7.42 -7.46 (m, 1 H) 7.62 (dd, J=11.87, 2.27 Hz. 1 H) 7.88 (d, J=2.53 Hz1 1 H) 8.09 (s, 1 H) 8.52 (s, 1 H); (M+H)+ 300.0.
1.1a Synthesis of 5-amino-2-bromopyridine Tin (II) chloride hydrate (0.78 g, 3.5 mmol) was added to a stirring solution of <strong>[4487-59-6]5-nitro-2-bromopyridine</strong> (0.24 g, 1.2 mmol) in DMF (5 mL) at RT. After 2 h, 6 N NaOH (2 mL) was added and the suspension was stirred vigorously for 10 min. The organics were extracted with diethyl ether (2*10 mL), washed with brine (2*10 mL) and dried (Na2SO4). The filtered solution was then concentrated under reduced pressure to afford the desired product as a yellow oil (0.178 g, 86%), which was used without further purification. 1.2 Rearrangement of nicotinic acids Rearrangement of the corresponding nicotinic acids (III) (Scheme 3) using a modified Schmidt reaction, followed by deprotection of the aniline group generated the desired aminopyridines (IV) as the corresponding TFA salts.
With sodium hydroxide; In N,N-dimethyl-formamide;
1.1a Synthesis of 5-amino-2-bromopyridine Tin (II) chloride hydrate (0.78 g, 3.5 mmol) was added to a stirring solution of <strong>[4487-59-6]5-nitro-2-bromopyridine</strong> (0.24 g, 1.2 mmol) in DMF (5 mL) at RT. After 2 h, 6N NaOH (2 mL) was added and the suspension was stirred vigorously for 10 min. The organics were extracted with diethyl ether (2*10 mL), washed with brine (2*10 mL) and dried (Na2SO4). The filtered solution was then concentrated under reduced pressure to afford the desired product as a yellow oil (0.178 g, 86%), which was used without further purification. 1.2 Rearrangement of Nicotinic Acids Aminopyridines are prepared by rearrangement of the corresponding nicotinic acids (III) (Scheme 4) using a modified Schmidt reaction, followed by deprotection of the aniline group generated the desired aminopyridines (IV) as the corresponding TFA salts.
With triethylamine; In dichloromethane; at 20℃; for 4h;
To a solution of 6- bromopyridin-3 -amine (5.4 g, 28.9 mmol) in dichloromethane (200 mL) were added triethylamine (4.4 g, 43.3 mmol) and di-tert-butyl dicarbonate (7.6 g, 34.7 mmol). The resulting solution was stirred for 4 hours at ambient temperature and quenched with water (300 mL). The organic layer was separated and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 2-10% ethyl acetate in petroleum ether to afford tert-butyl (6- bromopyridin-3-yl)carbamate as a colorless solid: MS (ESI, m/z): 273.1, 275.1 [M + 1]+; 1H MR (300 MHz, OMSO-d6) delta 9.72 (s, 1H), 8.45 (d, J= 1.8 Hz, 1H), 7.83 (d, J= 5.4 Hz, 1H), 7.53 (d, J= 5.7 Hz, 1H), 1.48 (s, 9H).
25%
With triethylamine; In dichloromethane; at 0 - 20℃; for 16h;
To a stirred solution of 6-bromopyridin-3-amine (5 g, 28.90 mmol) and TEA (8.75 g, 86.70 mmol) in DCM (50ml) was added Boc20 (12.6 g, 57.80 mmol) at 0C and stirred for 16 hat RT. The reaction mixture was dilutedwith DCM washed with water. The organic layer was dried over anhydrous Na2S04 and concentrated underreduced pressure. The obtained crude compound was purified by flash column chromatography using 20%EtOAc in petroleum ether as eluent to obtain the title compound (2.0 g, 25%) as white solid. LC-MS (method 2): Rt = 2.65 min; m/z = 275.17 (M+H++2).
In tetrahydrofuran; at 70℃; for 64h;
Di-tert-butyl dicarbonate (1.90 g, 8.67 mmol) was added to a solution of 3-amino 6- bromopyridine (1.00 g, 5.78 mmol) in THF (20 ml) and the resulting solution was stirred at 70 0C. After ca. 16 h additional di-tert-butyl dicarbonate (3.00 g, 13.74 mmol) was subsequently added in portions and the reaction was stirred an additional 48h. The reaction mixture was concentrated to a brown solution that crystallized to give 1.18 g of the desired EPO <DP n="60"/>product. M/z 273, 275; NMR: 1.48 (9H), 7.53 (d, IH)3 7.82 (dd, IH), 8.45 (d, IH), 9.74 (s, IH).
With copper(I) oxide; copper; potassium carbonate; In 1,2-dimethoxyethane; at 130℃; for 14h;Microwave irradiation;
Intermediate 65; 2-(6-Bromopyridin-3-ylamino)-5-chlorobenzoic acidA mixture of 6-bromopyridin-3-amine (27.27 mmol, 4.70 g), <strong>[50-79-3]2,5-dichlorobenzoic acid</strong> (54.34 mmol, 10.38 g), Cu (2.71 mmol, 0.2 g), Cu2O (1.36 mmol, 0.2 g) and K2CO3 (54.27 mmol, 7.5 g) in 1 ,2-dimethoxiethane (40 ml) was heated in a microwave oven at 13O0C for 14 hours, under nitrogen atmosphere. Water was added and the mixture was filtered through celite and extracted with AcOEt. The organic phase was washed with saturated K2CO3 aqueous solution and brine. The solvent was evaporated to afford 3.08 g (yield 31 %) of the expected product.ESI/MS (m/e, %): 327 [(M+1)+, 77], 329 [(M+1) 100], 331 [(M+1)+, 24].
Example 1; 6-Bromo-3-pyridnoI.; 3-Amino-6-bromopyridinc (1.73 g, 10 mmol) was dissolved in HBF4 (5 mL, 50 % aq.) and water (5 mL) was added. To the resulting brownish solution, cooled to O0C in an ice-bath, NaNO2 (759 mg, 11 mmol) in water (5 mL) was added dropwisc. The resulting yellowish heterogenous reaction mixture was stirred for 1 h at this temperature. After addition of water (5 mL), the mixture was stirred in an oil -bath for 5 h at 1000C (gas evolution). The cooled reaction mixture was then neutralized by addition OfNaHCO3 (5 % aq.) and the product extracted with ethyl acetate (5 x 35 mL). After drying (NaiSO4) and evaporation in vacuo, the resulting brownish solid was purified by column chromatography (SiO2) using pentane/ethyl acetate (9:1) to give 1.04 g (60 %) of the title compound, mp 137-1380C (lit. 135.5-136.5 0C; den Hertog et al Rec. Tray. Chim. Pays-Bas 1959, 69, 1281).
27%
With tetrafluoroboric acid; water; sodium nitrite; at 100℃; for 4.5h;Cooling with ice;
Step 4a. 6-Bromo-pyridin-3-ol (compound 2002) 3-Amino-6-bromopyridine (1 g, 5.8 mmol) was dissolved in HBF4 (3.6 mL, 40% aq) and water (3 mL). To the cooled brownish solution under an ice-bath was added dropwise NaNO2 (441 mg, 6.4 mmol) solution in water (3 mL). The resulting mixture was stirred for 1 h at this temperature. After addition of water (3 mL), the mixture was stirred at 100 C. for 3.5 h. The reaction mixture was neutralized by aqueous NaHCO3 (5%) and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4 and evaporated in vacuo. The residue was purified by column chromatography (hexanes/ethyl acetate: 9/1) to afford compound 2002 as a white solid (270 mg, 27% yield). LCMS: m/z 174.0 [M+1]+. 1H NMR (400 MHz, CDCl3): delta 6.65 (br, 1H), 7.13 (dd, J=8.4 Hz, 3.2 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 8.03 (d, J=3.2 Hz, 1H).
With formaldehyd; aqueous KOH; HCO2H; In dichloromethane; water; Petroleum ether;
(1) Synthesis of 2-bromo-5-dimethylaminopyridine 2-bromo-5-aminopyridine (11.7 g, 67.6 mmol) was added portionwise to HCO2H (20 ml) at 0 C. Formaldehyde (37% in water, 17 ml, 210 mmol) was then added and the mixture heated to reflux for hours. The reaction was then cooled to room temperature and an aqueous KOH solution (1N, ml) was added. The mixture was extracted with Et2O (3*100 ml) and the combined extract was dried over MgSO4, filtered and evaporated to dryness. The residual oil was purified by flash chromatography on silica (CH2Cl2). The yellowish solid was dissolved in the minimum volume of CH2Cl2, petroleum ether (150 ml) was added and the solution was stand in the fridge overnight. The white crystalline solid was filtered and washed with small portion of cold petroleum ether to afford 5.2 g (40%) of the desired compound as white crystalline solid. 1H-NMR (CDCl3, 298K, 200 MHz, delta ppm) delta 2.96 (s, 6H), 6.87 (dd, J=2.5*9 Hz, 1H), 7.25 (d, J=9 Hz, 1H), 7.84 (d, J=2.5 Hz, 1H).
Stage #1: 6-bromopyridine-3-amine; bis(trichloromethyl) carbonate With triethylamine In dichloromethane at 0℃; for 0.25h; Inert atmosphere;
Stage #2: 4-piperidin-1-yl-butylamine In dichloromethane at 0 - 20℃;
1-(6-Bromo-pyridin-3-yl)-3-(4-piperidin-1-yl-butyl)-urea
To a solution of 6-bromo-pyridin-3-ylamine (3.46 g, 20 mmol, 1 equiv.) in DCM (70 mL) triphosgene (1.96 g, 6.6 mmol, 0.33 equiv.) and TEA (2.2 g, 22 mmol, 1.1 equiv.) were added under N2 at 0° C. After 15 min a solution of 4-piperidin-1-yl-butylamine (3.12 g, 20 mm 1 equiv.) in DCM (10 mL) was added dropwise at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. Dichloromethane was removed in vacuo and the residue dissolved in EtOAc and washed with H2O. The aqueous layer was basified with solid Na2CO3 to pH 9-10 and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and evaporated in vacuo to give 5 g of the desired product as a solid (yield: 70%). C15H23BrN4O Mass (calculated) [355] 1H-NMR (400 MHz, CDCl3): 8.17 (d, 1H, J=2.8), 7.95 (dd, 1H, J=8.7, 2.8), 7.54 (bs, 1H), 7.35 (d, 1H, J=8.7), 6.19 (m, 1H), 3.24-3.22 (m, 2H), 2.48-2.29 (m, 8H), 1.62-1.45 (m, 8H).
70%
Stage #1: 6-bromopyridine-3-amine; bis(trichloromethyl) carbonate With triethylamine In dichloromethane at 0℃; for 0.25h; Inert atmosphere;
Stage #2: 4-piperidin-1-yl-butylamine In dichloromethane at 0 - 20℃;
To a solution of 6-bromo-pyridin-3-ylamine (3.46 g, 20 mmol, 1 equiv.) in DCM (70 mL) triphosgene (1.96 g, 6.6 mmol, 0.33 equiv.) and TEA (2.2 g, 22 mmol, 1.1 equiv.) were added under N2 at 0° C. After 15 min a solution of 4-piperidin-1-yl-butylamine (3.12 g, 20 mm 1 equiv.) in DCM (10 mL) was added dropwise at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. Dichloromethane was removed in vacuo and the residue dissolved in EtOAc and washed with H2O. The aqueous layer was basified with solid Na2CO3 to pH 9-10 and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and evaporated in vacuo to give 5 g of the desired product as a solid (yield: 70%).C15H23BrN4O Mass (calculated) [355]1H-NMR (400 MHz, CDCl3): 8.17 (d, 1H, J=2.8), 7.95 (dd, 1H, J=8.7, 2.8), 7.54 (bs, 1H), 7.35 (d, 1H, J=8.7), 6.19 (m, 1H), 3.24-3.22 (m, 2H), 2.48-2.29 (m, 8H), 1.62-1.45 (m, 8H).
70%
Stage #1: 6-bromopyridine-3-amine; bis(trichloromethyl) carbonate With triethylamine In dichloromethane at 0℃; for 0.25h; Inert atmosphere;
Stage #2: 4-piperidin-1-yl-butylamine In dichloromethane at 0 - 20℃;
To a solution of 6-bromo-pyridin-3-ylamine (3.46 g, 20 mmol, 1 equiv.) in DCM (70 mL) triphosgene (1.96 g, 6.6 mmol, 0.33 equiv.) and TEA (2.2 g, 22 mmol, 1.1 equiv.) were added under N2 at 0° C. After 15 min a solution of 4-piperidin-1-yl-butylamine (3.12 g, 20 mmol, 1 equiv.) in DCM (10 mL) was added dropwise at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. Dichloromethane was removed in vacuo and the residue dissolved in EtOAc and washed with H2O. The aqueous layer was basified with solid Na2CO3 to pH 9-10 and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and evaporated in vacuo to give 5 g of the desired product as a solid (yield: 70%).C15H23BrN4O Mass (calculated) [355]1H-NMR (400 MHz, CDCl3): 8.17 (d, 1H, J=2.8), 7.95 (dd, 1H, J=8.7, 2.8), 7.54 (bs, 1H), 7.35 (d, 1H, J=8.7), 6.19 (m, 1H), 3.24-3.22 (m, 2H), 2.48-2.29 (m, 8H), 1.62-1.45 (m, 8H).
Stage #1: 6-bromopyridine-3-amine With hydrogenchloride; sodium nitrite In water at -5 - 0℃;
Stage #2: With copper(II) choride dihydrate; sulfur dioxide; acetic acid In water at 0 - 20℃;
Preparation of 6-Bromo-pyridine-3-sulfonyl chloride; To a cooled (0° C.-5° C.) stirred solution of 5-amino-2-bromopyridine (1.5 g, 8.6 mmol) in 12 N hydrochloric acid (26.5 mL), was slowly added a solution of sodium nitrite (0.66 g, 7.76 mmol) in water (7 mL). In a separate flask, sulfur dioxide was bubbled through a stirred solution of copper(II) chloride dihydrate (0.63 g, 3.50 mmol) in glacial acetic acid at 0° C. for 30 minutes, and then the diazotized reaction mixture prepared above was added. The resulting mixture was slowly warmed to room temperature and stirred for 30 minutes, then was poured into ice water (100 mL), and extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude 6-bromo-pyridine-3-sulfonyl chloride, which was immediately used in the next step.
Stage #1: 6-bromopyridine-3-amine; 4-Nitrophenyl chloroformate In acetonitrile at 30 - 40℃; for 3h;
Stage #2: 4-piperidin-1-yl-butylamine In acetonitrile at 20 - 40℃; for 1.5h;
23.3; 23.4
A mixture of 3-Amino-6-bromopyridine (600 g, 3.47 mol) in MeCN (20 L) was prepared in a reactor. 4-Nitrophenyl chloroformate (760 g, 3.77 mol, 1.1 equiv.) in MeCN (3.8 L, 5×) was added to the reactor over 60 min while maintaining the temperature at 30-40° C. The addition vessel and reactor were rinsed with MeCN (2 L), and the reactor contents were stirred for 2 hours, monitoring reaction progress by HPLC. 1-Piperidinebutanamine (540 g, 3.46 mol, 1 equiv.) in MeCN (1.1 L, 2×) was added to the reactor over 30 min at 30-40° C., and the addition vessel and reactor rinsed with MeCN (200 mL). The reaction was stirred at room temperature for 1 h and monitored by HPLC. Upon completion, the reactor contents were filtered and washed with MeCN (2× 1L). The solids were dried at 40° C. under vacuum for 12 h to yield 1.1 kg (81.7% yield, 98.3% pure).
Stage #1: 2-amino-5-ethylthiophene-3-carboxylic acid methyl ester; bis(trichloromethyl) carbonate With triethylamine In dichloromethane at 1 - 30℃; for 2h;
Stage #2: 6-bromopyridine-3-amine In dichloromethane at 1 - 30℃; for 1h;
Stage #3: With sodium methylate In methanol at 60℃; for 1h;
53
Example 53 6-ethyl-3-(6-methoxypyridin-3-yl)-1-[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione To a solution (30 mL) of methyl 2-amino-5-ethylthiophene-3-carboxylate (0.36 g) in methylene chloride were added triphosgene (0.25 g) and triethylamine (0.4 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 6-bromopyridin-3-amine (1 g), and the mixture was further stirred at room temperature for 1 hr, and the precipitated solid was collected by filtration. The obtained solid was dissolved in methanol (20 mL), sodium methoxide (0.52 g) was added, and the mixture was stirred at 60°C for 1 hr. The reaction mixture was neutralized with hydrochloric acid (10% methanol solution), and the precipitated solid was collected by filtration. The obtained solid was dissolved in acetonitrile (40 mL), 3-[4'-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (0.83 g) and potassium carbonate (0.53 g) was added, and the mixture was stirred at 50°C for 2 hr. Insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (4 mL) and acetone (4 mL). 1N Aqueous sodium hydroxide solution (2 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was adjusted to pH 7 with water and 1N hydrochloric acid, and extracted with chloroform. The obtained chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (0.58 g, 54%). 1H NMR (300 MHz, DMSO-d6) δ1.20 (3H, t, J = 7.4), 2.76(2H, q, J = 7.4), 3.90 (3H, s), 5.22 (2H, s), 6.96 (1H, d, J = 8.7), 7.05 (1H,s), 7.33 (2H, d, J = 8.3), 7.42-7.63 (4H, m), 7.63-7.79 (3H, m), 8.17 (1H, d, J= 2.3), 12.4 (1H, s)
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 0.333333h; Inert atmosphere;
2
Preparation of N-(6-bromopyridin-3-yl)-2,6-difluorobenzamide (7).; Under an atmosphere of argon, 2,6-difluorobenzoyl chloride (1.12 g, 6.4 mmol) was added to a stirred solution of 6 (1.0 g, 5.8 mmol), Hünig's base (4.0 mL, 3.0 g, 23 mmol), and DMAP (71 mg, 0.6 mmol) in dichloromethane (26 mL) at room temperature. The reaction was stirred for 20 minutes then quenched by addition of a saturated solution of NaHCO3 (10 mL). The mixture was extracted with dichloromethane (2×30 mL) and combined extracts dried over Na2SO4 and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-50% ethyl acetate in hexane) provided 7 (1.4 g, 77%) as a crystalline solid: LRESIMS m/z 313.4 [M+H]+, calcd. for C12H8Br1F2N2O1 313.0.
With pyridine In dichloromethane at 0 - 20℃; for 0.5h;
Intermediate 52N-(6-Bromopyridin-3-yl)-2,6-difluorobenzamideTo a (0 °C) cooled and stirred solution of 2-bromo-5-aminopyridine (2.0 g, 11.56 mmol, 1.0 eq) in DCM (25 mL) was added sequentially 2,6-difluorobenzoyl chloride (1.44 mL, 11.56 mmol, 1.0 eq) and pyridine (1.19 mL, 13.87 mmol, 1.2 eq). The resulting mixture was allowed to warm to room temperature and then stirred at the same temperature for 30 min. Reaction was diluted with DCM (30 mL) and washed with water (20 mL), saturated aqueous sodium bicarbonate solution (30 mL), brine (20 mL), dried ( a2S04) and filtered. The filtrate was rotary evaporated and the residue was triturated with hexane to afford 3.4 g of the desired product as a white solid. 'HNMR (400 MHz, CDC13) δ 8.42 (d, J = 2.5 Hz, 1H), 8.18 (dd, J = 8.5, 2.5 Hz, 1H), 7.96 (brs, 1H, D20 exchangeable), 7.49 (d, J = 8.5 Hz, 1H), 7.46- 7.41 (m, 1H), 7.00 (t, J= 8.0 Hz, 2H); ESI-MS (m/z) 313, 315 [(MH)+ Br79' 81].
Stage #1: 6-bromopyridine-3-amine With hydrogenchloride; sodium nitrite In water at 0℃; for 1.5h;
Stage #2: With hydrogenchloride; tin(II) chloride dihdyrate In water at 0℃; for 1h;
74.3%
Stage #1: 6-bromopyridine-3-amine With hydrogenchloride; sodium nitrite In water at 0℃; for 0.833333h;
Stage #2: With hydrogenchloride; tin(II) chloride dihdyrate In water at 0℃; for 1.08333h;
1 Intermediate 1A: 2-bromo-5-hydrazinylpyridine
A solution of 6-bromopyridin-3-amine (10.0 g, 57.8 mmol) in 6 M aqueous HCl (111 mL) was cooled to 0° C. A solution of sodium nitrite (3.99 g, 57.8 mmol) in water (148 mL), precooled to 0° C., was added over 5 min and the reaction mixture was stirred for 45 minutes at 0° C. Tin(II) chloride dihydrate (32.6 g, 144 mmol) was suspended in 6 M aqueous HCl (111 mL), precooled to 0° C., and was added to the reaction mixture over 5 min. The reaction mixture was stirred for 60 min more at 0° C. Upon completion, the reaction was quenched via addition of 40% w/w solution of KOH in water until the solution was basic as judged by pH paper. The mixture was diluted with water and DCM. The organic layer was separated and the aqueous layer was extracted with DCM. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford 2-bromo-5-hydrazinylpyridine (8.08 g, 43.0 mmol, 74.3% yield). LCMS retention time 0.41 min [A1]. MS (E+) m/z: 190.1 [(M+2)+H+]. 1H NMR (499 MHz, CHLOROFORM-d) δ 7.98 (d, J=3.0 Hz, 1H), 7.28 (app d, J=8.5 Hz, 1H), 7.10 (dd, J=8.7, 3.0 Hz, 1H), 5.25 (br app s, 1H), 3.62 (br app s, 2H).
61%
Stage #1: 6-bromopyridine-3-amine With hydrogenchloride; sodium nitrite In water at 0℃; for 0.5h;
Stage #2: With hydrogenchloride; tin(II) chloride dihdyrate In water at 0℃; for 0.5h;
1; 6 Synthesis of Compound 1: 2-(4-((3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)methyl)-2,3,5-trimethylphenoxy)acetic acid.
A solution of NaNO2 (1.99 g, 28.90 mmol) in water (20 mL) is added dropwise to a stirred solution of 6-bromopyridin-3-amine (5 g, 28.90 mmol) in HCl (6 M aq., 100 mL) at 0° C. The reaction mixture was stirred for 0.5 hour at 0° C. Then a solution of SnCl2.2H2O (16.30 g, 72.25 mmol) in HCl (6 M, 100 mL) is added to the reaction mixture at 0° C. and stirred for 0.5 hour. The reaction mixture is basified to pH 10 with KOH (1M, aq.), the solid was removed by filtration, and the aqueous layer is extracted with EA (3*100 mL). The organic layers are combined, dried over sodium sulfate and concentrated under vacuo to afford the crude product, which was purified by silica gel chromatography, (eluent : 0 to 100% EA/PE) to afford (6-bromo-3-pyridyl)hydrazine (3.3 g, 17.55 mmol, 61% yield) as a white solid.
61%
Stage #1: 6-bromopyridine-3-amine With hydrogenchloride; sodium nitrite In water at 0℃; for 0.5h;
Stage #2: With hydrogenchloride; tin(II) chloride dihdyrate In water at 0℃; for 0.5h;
1; 6 Synthesis of Compound 1: 2-(4-((3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)methyl)-2,3,5-trimethylphenoxy)acetic acid.
A solution of NaNO2 (1.99 g, 28.90 mmol) in water (20 mL) is added dropwise to a stirred solution of 6-bromopyridin-3-amine (5 g, 28.90 mmol) in HCl (6 M aq., 100 mL) at 0° C. The reaction mixture was stirred for 0.5 hour at 0° C. Then a solution of SnCl2.2H2O (16.30 g, 72.25 mmol) in HCl (6 M, 100 mL) is added to the reaction mixture at 0° C. and stirred for 0.5 hour. The reaction mixture is basified to pH 10 with KOH (1M, aq.), the solid was removed by filtration, and the aqueous layer is extracted with EA (3*100 mL). The organic layers are combined, dried over sodium sulfate and concentrated under vacuo to afford the crude product, which was purified by silica gel chromatography, (eluent : 0 to 100% EA/PE) to afford (6-bromo-3-pyridyl)hydrazine (3.3 g, 17.55 mmol, 61% yield) as a white solid.
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; water;Inert atmosphere; Reflux;
General procedure: To 0.329 g (1.5 mmol) 4-iodoaniline, 1.8 mmol ArB(OH)2, 0.318 g (3 mmol) Na2CO3 and 75 mg (0.075 mmol) PdCl2(PPh3)2, 15 mL of a blended solution of dioxane and water (v/v = 3/1) was added under N2 atmosphere. Then the reaction was heated to reflux and monitored by TLC. Upon cooling, the reaction mixture was dilute with sat. NH4Cl solution, then extracted with EA (3×20 mL), and the organic layer was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4 and purified by flash chromatography to afford different 4-aminobiphenyl derivatives. According to the reductive amination procedure, the 4-aminobiphenyl derivative was further treated with salicylaldehyde and to afford the corresponding compound 5&6.
With potassium phosphate; copper(l) iodide; In 1,4-dioxane; at 130℃;Inert atmosphere; Schlenk technique;
In a Schlenk vessel <strong>[10010-93-2]5-methyl-3-(trifluoromethyl)-1H-pyrazole</strong> (174 mg, 1.16 mmol), 6-bromopyridin-3-amine (200 mg, 1.16 mmol), cooper (I) iodide (33 mg, 0.17 mmol) and potassium phosphate (488 mg, 2.3 mmol) were dissolved in 4 ml dioxane. The reaction was submitted to three vacuum-argon cycles and was then heated at 130C overnight. The mixture was filtered through a plug of Celite and evaporated under reduced pressure. The crude was purified by flash chromatography (0% to 100%, hexane - diethyl ether) using SP1 Purification System to obtain 226 mg (79% yield) of the title compound. LRMS (m/z): 243 (M+1)+
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; water;Inert atmosphere; Reflux;
General procedure: To 0.329 g (1.5 mmol) 4-iodoaniline, 1.8 mmol ArB(OH)2, 0.318 g (3 mmol) Na2CO3 and 75 mg (0.075 mmol) PdCl2(PPh3)2, 15 mL of a blended solution of dioxane and water (v/v = 3/1) was added under N2 atmosphere. Then the reaction was heated to reflux and monitored by TLC. Upon cooling, the reaction mixture was dilute with sat. NH4Cl solution, then extracted with EA (3×20 mL), and the organic layer was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4 and purified by flash chromatography to afford different 4-aminobiphenyl derivatives. According to the reductive amination procedure, the 4-aminobiphenyl derivative was further treated with salicylaldehyde and to afford the corresponding compound 5&6.
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; water;Inert atmosphere; Reflux;
General procedure: To 0.329 g (1.5 mmol) 4-iodoaniline, 1.8 mmol ArB(OH)2, 0.318 g (3 mmol) Na2CO3 and 75 mg (0.075 mmol) PdCl2(PPh3)2, 15 mL of a blended solution of dioxane and water (v/v = 3/1) was added under N2 atmosphere. Then the reaction was heated to reflux and monitored by TLC. Upon cooling, the reaction mixture was dilute with sat. NH4Cl solution, then extracted with EA (3×20 mL), and the organic layer was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4 and purified by flash chromatography to afford different 4-aminobiphenyl derivatives. According to the reductive amination procedure, the 4-aminobiphenyl derivative was further treated with salicylaldehyde and to afford the corresponding compound 5&6.
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; water;Inert atmosphere; Reflux;
General procedure: To 0.329 g (1.5 mmol) 4-iodoaniline, 1.8 mmol ArB(OH)2, 0.318 g (3 mmol) Na2CO3 and 75 mg (0.075 mmol) PdCl2(PPh3)2, 15 mL of a blended solution of dioxane and water (v/v = 3/1) was added under N2 atmosphere. Then the reaction was heated to reflux and monitored by TLC. Upon cooling, the reaction mixture was dilute with sat. NH4Cl solution, then extracted with EA (3×20 mL), and the organic layer was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4 and purified by flash chromatography to afford different 4-aminobiphenyl derivatives. According to the reductive amination procedure, the 4-aminobiphenyl derivative was further treated with salicylaldehyde and to afford the corresponding compound 5&6.
To a solution of 6- bromopyridin-3 -amine (300 mg, 1.73 mmol) in tetrahydrofuran (30 ml) was added 1 M solution of lithium bis(trimethylsilyl)amide (3.46 mL, 3.46 mmol) in tetrahydrofuran over 5 min at - 78 C under nitrogen atmosphere. After stirring for 30 min at -78 C, iodomethane (566 mg, 3.99 mmol) was added. The resulting mixture was stirred for 1 hour at ambient temperature and then quenched by the addition of saturated aqueous solution of ammonium chloride (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers was washed with brine (2 x 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-10% ethyl acetate in petroleum ether to afford 6-bromo- N,N-dimethylpyridin-3 -amine as a light yellow solid: MS (ESI, m/z): 201.0, 203.0 [M + 1]+.
With copper(I) oxide; <i>L</i>-proline; potassium iodide In ethanol at 110℃; for 30h; Schlenk technique; Inert atmosphere; Sealed tube;
2.2. General procedure for aryl and heteroaryl bromide-iodideexchange reaction
General procedure: A Schlenk tube was charged with Cu2O (7.2 mg, 10 mol%), l-proline (11.5 mg, 20 mol%), aryl (or heteroaryl) bromide (1 or 3,0.50 mmol), potassium iodide (KI) (249 mg, 0.75 mmol), and EtOH(1.5 mL) under nitrogen atmosphere. The Schlenk tube was sealedwith a teflon valve, and then the reaction mixture was stirred at110C for a period (the reaction progress was monitored by GCanalysis). After the reaction was completed, GC yield of high volatileproduct was determined using an appropriate internal standard(chlorobenzene or 1-chloro-4-methylbenzene) or the solvent wasremoved under reduced pressure. The residue obtained was puri-fied via silica gel chromatography (eluent: petroleum ether/ethylacetate = 10/1) to afford aryl iodides 2a-2o or heteroaryl iodides4a-4g.
Step a. To a solution of 6-bromopyridin-3 -amine (CAS Number 97-65-4) (1 g, 5.78 mmol) in formic acid (5 ml) was added para-formaldehyde (1.5 g, 1.5 eq w/w) at rt. The reaction mixture was heated at 90C for 16 hr. The resulting reaction mixture was poured into ice cold water, basified using solid sodium carbonate and extracted using EtOAc (30ml x 3). The organic layer was combined and dried over Na2S04 concentrated under reduced pressure. The obtained residue was purified using column chromatography (20% EtOAc in hexane) yielding 6-bromo-N, N-dimethylpyridin-3 -amine (0.43 g, 2.160 mmol). LCMS: Method C, 1.77 min, MS: ES+ 201.14. NMR (400 MHz, DMSO-d6) delta ppm 8.31-8.32 (d, 1 H), 7.84-7.85 (d, 1 H), 7.33-7.35 (d, 1 H), 2.91 (s, 6 H).
Step 1: 5-Bromothiazolo[5,4-b]pyridin-2-amine To a suspension of 6-bromopyridin-3-amine (20.0 g, 115 mmol) and potassium thiocyanate (56.0 g, 576 mmol) in acetic acid (250 mL) was added dropwise a solution of bromine (23.88 g, 149 mmol) in acetic acid (100 mL) at room temperature. The reaction mixture was stirred at room temperature for 15 h. The solids were filtered out, and then the resulting solution was extracted with ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (solvent gradient: 0-10% methanol in DCM) to yield 18 g (68%) of the title compound. LCMS (ESI): [M+H]+=230/232.
tert-butyl (3-((6-bromopyridin-3-yl)amino)-3-oxo-1-phenylpropyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In dichloromethane; ethyl acetate at 0 - 20℃; for 16h;
4 REFERENCE EXAMPLE 4 tert-butyl 3-((6-bromopyridin-3-yl)amino)-3-oxo-1-phenylpropylcarbamate
TEA (583g, 0058 mol) followed by T3P [50% solution in EtOAc, 11 02g 0 035 mol) were added to a stirred soluton of 6bromo3 amino pyridine (2g, 0012 mol) and 3(Boc amino)3 phenyl propionic acid (361 g, 0 011 mol) in DCM (20 mL) at 0°C, the reaction mixture was allowed to stir at RI fo 16h The progress of the reaction was monitored by LCMS, The reaction m xture was diluted with DCM (100 mL) washed with water (50 rnL) aq NaHCO3 soldtion (50 nL) The oganc laier was dned over an’ydrous Na2SO4, filtered a9d the filtratewas concentrated under reduced pressure The residue was suspended in DCM, the precipitated solid was filtered, washed with DCM and dred in vacuum to afford the title compound (2 g, 41%) as a brown gummy liquid LCMS (method 1) R = 2 26 mm, m/z = 421 85 (M+H+2),
41%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In dichloromethane; ethyl acetate at 0 - 20℃; for 16h;
4 Terf-butyl (3-((6-bromopyridin-3-yl)amino)-3-oxo-1-phenylpropyl)carbamate
TEA (5.83g, 0.0578 mol) followed by T3P [50% solution in EtOAc, 11.02g, 0.0346 mol) were added to a stirred solution of 6-bromo-3-amino pyridine (2g, 0.01156 mol) and 3-(Boc amino)-3-phenyl propionic acid (3.67 g, 0.011387 mol) in DCM (20 mL) at 0°C and the reaction mixture was allowed to stir at RT for 16h. The progress of the reaction was monitored by LCMS. The reaction mixture was diluted with DCM (100 mL), washed with water (50 mL) and aq.NaHCC solution (50 mL). The organic layer was dried over anhydrous NasSO*, filtered and the filtrate was concentrated under reduced pressure. The residue was suspended in DCM, the precipitated solid was filtered, washed with DCM and dried under vacuum to afford the title compound (2 g, 41%) as a brown gummy liquid. (0547) LC-MS (method 1): Rt = 2.26 min; m/z = 421.85 (M+H++2)
With tetrakis(triphenylphosphine) palladium(0); In toluene; at 130℃; for 48h;Inert atmosphere;
Method B: To a solution of 55 6-bromopyridin-3-amine (50 mg, 0.29 mmol) in 1.5 mL of dry 63 toluene at room temperature, was added 64 2-(tributylstannyl)pyridine (0.013 mL, 0.35 mmol) dropwise under N2 atmosphere following by the addition of 65 tetrakis(triphenylphosphine)palladium (40.2 mg, 0.03 mmol). The reaction mixture was degassed with nitrogen and was stirred at 130c for two days. The reaction was cooled to room temperature. Next, the mixture was taken up with NaOH 2M and separated with ethyl acetate (x2). The organic layer was washed with brine, was dried with Na2SO4 and the solvent was removed under vacuum. The crude was purified by CombiFlash chromatography column (DCM/DCM:MeOH 20%) to afforded the desired compound (21.6 mg, 43.5 %). 1H-NMR (400 MHz, DMSO-d6): δ = 8.54 (d, 1 H), 8.17 (d, 1 H), 8.08 (d, 1 H), 8.01 (d, 1 H), 7.80 (td, 1 H), 7.25 (m, 1 H), 7.01 (dd, 1 H), 5.65 (s, 2H). HPLC-MS: Rt 2.746; m/z 172.0 (MH+).
With N-chloro-succinimide; acetic acid; at 90℃; for 2h;
A mixture of 6-bromopyridin-3-amine (11.7 g, 67.6 mmol), 1-chloropyrrolidine-2,5-dione (9.93 g, 74.4 mmol) and acetic acid (70 mL) was stirred at 90 C for 2 h. The solvent was removed on a rotovap and the residue was washed with water and dried to provide 6-bromo-2- chloro-pyridin-3-amine (13.1 g, 93.4%). LC-MS m/z 207.1, 209.1 [M+H]+, RT: 1.12 min.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In water; N,N-dimethyl-formamide at 110℃; for 0.5h; Microwave irradiation;
3.1.8.1 N-(6-(2,5-dimethylphenyl)pyridin-2-yl)-4-(piperidin-1-ylsulfonyl)benzamide (18b)
General procedure: 2,5-dimethylphenylboronic acid (19, 50mg, 0.33mmol), tetrakis(triphenylphosphine)palladium(0) (65mg, 0.056mmol) and 2-amino-6-bromopyridine (20b, 48mg, 0.28mmol) were taken in a microwave vial. The vial was evacuated under vacuum and anhydrous DMF (1.6mL) was added. Separately sodium carbonate (89mg, 0.84mmol) was dissolved in 0.4mL of water and added to the vial. The vial was then subjected to microwave heating at 110°C for 30min. The solvent was removed under vacuum and the residue was dissolved in EtOAc, washed with water and brine, concentrated under vacuum to obtain the residue which was purified using silica gel column chromatography to obtain compound 21b. To a solution of compound 4 (15mg, 0.056mmol) in anhydrous DMF were added, 21b (12mg, 0.061mmol), HATU (23mg, 0.061mmol), and triethylamine (8.5mg, 0.084mmol) and the reaction was heated at 45°C for 12h. The solvent was then removed and the residue was suspended in aqueous sodium bicarbonate solution. The precipitate was filtered to obtain crude product which was purified using silica gel column chromatography to yield compound 18b as white solid (14mg, yield=56%).
[[5-([3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl]methyl)-3,4,6-trimethylpyridin-2-yl]oxy]acetic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With stannous chloride; sodium nitrite
6 Synthesis of Compound 6: [[5-([3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl]methyl)-3,4,6-trimethylpyridin-2-yl]oxy]acetic acid
Example 6 Synthesis of Compound 6: [[5-([3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl]methyl)-3,4,6-trimethylpyridin-2-yl]oxy]acetic acid A solution of sodium nitrite (3.99 g, 57.8 mmol) was added dropwise to a stirred solution of 6-bromopyridin-3-amine (10.0 g, 57.8 mmol) in HCl (6 M aq., 200 mL) at 0° C. The reaction mixture was stirred for 0.5 hour at 0° C. Then a solution of stannous chloride (32.6 g, 144.5 mmol) in HCl (6 M, 200 mL) was added to the reaction mixture at 0° C. and stirred for 0.5 hour. The reaction mixture is basified to pH 10 with NaOH (1M, aq.), the solid was removed by filtration, and the aqueous layer is extracted with EA (3*200 mL). The organic layers are combined, dried over sodium sulfate and concentrated under vacuo to afford the crude product, which was purified by silica gel chromatography PE/EA (1/99) to afford 2-bromo-5-hydrazinylpyridine (6 g, 55%) as a white solid. LC-MS (ESI, m/z): 188 [M+H]+.
2-(4-((3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)methyl)-2,3,5-trimethylphenoxy)acetic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With sodium nitrite
1 Synthesis of Compound 1: 2-(4-((3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)methyl)-2,3,5-trimethylphenoxy)acetic acid.
Example 1 Synthesis of Compound 1: 2-(4-((3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)methyl)-2,3,5-trimethylphenoxy)acetic acid. A solution of NaNO2 (1.99 g, 28.90 mmol) in water (20 mL) is added dropwise to a stirred solution of 6-bromopyridin-3-amine (5 g, 28.90 mmol) in HCl (6 M aq., 100 mL) at 0° C. The reaction mixture was stirred for 0.5 hour at 0° C. Then a solution of SnCl2.2H2O (16.30 g, 72.25 mmol) in HCl (6 M, 100 mL) is added to the reaction mixture at 0° C. and stirred for 0.5 hour. The reaction mixture is basified to pH 10 with KOH (1M, aq.), the solid was removed by filtration, and the aqueous layer is extracted with EA (3*100 mL). The organic layers are combined, dried over sodium sulfate and concentrated under vacuo to afford the crude product, which was purified by silica gel chromatography, (eluent : 0 to 100% EA/PE) to afford (6-bromo-3-pyridyl)hydrazine (3.3 g, 17.55 mmol, 61% yield) as a white solid.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
Life Science
For Research Only
100K+ Compounds
Competitive Price
1-2 Day Shipping
