* 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 tetrakis(triphenylphosphine) palladium(0) In tetrahydrofuran for 40 h; Heating / reflux Stage #2: With ethylenediaminetetraacetic acid; water In tetrahydrofuran Stage #3: With potassium carbonate In tetrahydrofuran; water
Methylzinc chloride in THF (2 M, 10.489 mL, 21 mmol) was added to a solution of 2-chloro-4-methoxypyridine (0.500 g, 3.48 mmol) and Pd(PPh3)4 (0.161 g, 0.14 mmol) in THF (10 mL). The mixture was refluxed for 40 h and then poured into an aqueous solution (10 mL) containing ethylenediaminetetraacetic acid (1.5 g). The resulting mixture was neutralized with K2CO3 and extracted with Et2O. The organic layer was concentrated to give a residue, which was purified on a silica gel column eluting with MeOH:EtOAc (1:10) to give 4-methoxy-2-methylpyridine (0.213 g, 50.0percent).
Reference：
[1] Patent: US2006/148801, 2006, A1, . Location in patent: Page/Page column 10
[2] Journal of Medicinal Chemistry, 2011, vol. 54, # 8, p. 3076 - 3080
2
[ 17228-69-2 ]
[ 124-41-4 ]
[ 18677-43-5 ]
Yield
Reaction Conditions
Operation in experiment
58%
Heating / reflux
EXAMPLE 33 : 1-(4-Chloro-2-fluorobenzyl)-4-inethoxy-5-(4-inethoxyphenyl) pyridin-2(1H)-one (Final Compound 9-18)Step 1 : 2,4-Dimethoxypyridine According to Scheme 23 Step 1 : To a solution of sodium methoxide (30percent in MeOH, 2eq, 35mmol) was added 2-chloro-4-methoxypyridine (leq, 17.0mmol, 2.50g). The reaction was refluxed overnight. The reaction was allowed to cool, poured onto water (10mL) and extracted with CH2Cl2 (3xl0mL). The combined organic fractions were dried (Na2SO4), filtered and concentrated under reduced pressure to afford 2,4- dimethoxypyridine (lO.lmmol, 1.40g, 58percent) as a colorless oil. The crude product was reacted on. LC (XTerra RP18, 3.5μm, 3.0x50mm Column): RT = 1.40min; MS m/z (CI) [MH]+= 140.
Reference：
[1] Patent: US6339045, 2002, B1, . Location in patent: Referential example 2
16
[ 17228-69-2 ]
[ 880870-13-3 ]
Yield
Reaction Conditions
Operation in experiment
45%
at 0 - 55℃; for 3 h;
2-Chloro-4-methoxypyridine (13.3 g, 92.6 mmol) was dissolved in concentrated sulfuric acid (65 ml), N-bromosuccinimide (16.5 g, 92.6 mmol) was added under ice-cooling, and the mixture was stirred with heating at 55° C. for 3 hr. The reaction mixture was poured into ice water, alkalified with 8N aqueous sodium hydroxide solution, and extracted with chloroform. The organic layer was washed with saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate=9:1 to 5:1) to give the object product as a white solid (9.3 g, yield 45percent). 1H NMR(CDCl3 300 MHz) (δ) ppm: 3.97 (3H, s), 6.84 (1H, s), 8.34 (1H, s)
To a solution of 2-chloro-4-methoxypyridine (0.5 g, 3.48 mmol) in sulfuric acid (2.5 mL) was added A/-iodosuccinimide (0.825 g, 3.48 mmol) portionwise at room temperature. The mixture was stirred at 55°C for 2 hours. The reaction mixture was poured into ice water (10 mL) and 8 M NaOH (20 mL) was added slowly, after which the dark brown solution turned pale yellow. The aqueous layer was extracted with CH2CI2 (2 x 20 mL). The organic layers were washed with brine (10 mL) and concentrated in vacuo onto silica gel. Dry flash chromatography, eluting with 25percent EtOAc:c-Hex, gave 2-chloro-5-iodo-4- methoxypyridine as a white crystalline solid (0.169 g, 0.760 mmol, 22percent yield). 1H NMR (500 MHz, d6-DMSO) ? 8.52 (s, 1 H), 7.19 (s, 1 H), 3.96 (s, 3H); LC-MS (LCT, 4 minutes) Rt = 2.56 minutes; m/z (ESI) 270 (M+H).
21%
at 55℃; for 2 h;
j00503j To a solution of 2-chloro-4-methoxy-pyndine (10 g, 70 mmol) in concentrated sulfuric acid (50 mL) at room temperature was added a solution of N-iodosuccinimide (15.7 g, 70 mmol) in concentrated sulfuric acid (10 mL). The mixture was stirred at 55 °C for 2 hours, then diluated with water (100 mL), adjusted to pH = 9-10 by slow addition of 8 N aqueous sodium hydroxide and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography [petroleum ether: ethyl acetate = 20:11 to give compound B-ii6(4 g, 21percent yield) as a white solid. GC-MS: tR=6.569 mi, (ES) mlz (M)=268.9.
Reference：
[1] Journal of Medicinal Chemistry, 2012, vol. 55, # 22, p. 10229 - 10240
[2] Patent: WO2013/68755, 2013, A1, . Location in patent: Page/Page column 70; 71
[3] Patent: WO2017/69980, 2017, A1, . Location in patent: Paragraph 00502; 00503
POCl3 (8.29 mL) was added to 4-methoxypyridin-2(lH)-one (311 mg) at RT. The reaction was heated at reflux overnight. The mixture was cooled to RT, ice and DCM were added. The aqueous layer was washed with DCM then the aqueous layer was basified to pH 7-8 with NaHCOs and extracted with DCM to give the desired compound
Synthesis of 1-(4-Methoxy-pyridin-2-yl)-piperazine To 756 mg (5.29 mmol) of <strong>[17228-69-2]2-Chloro-4-methoxypyridine</strong> and 2.27 g (26 mmol) of piperazine in a pressure flask was added 2.7 mL dimethylformamide, and the mixture was heated at 115 C. for 5 hours. The solution was allowed to cool before opening the flask, and the resulting slurry was partitioned between ethyl acetate and water. The phases were separated, and the aqueous phase was back-extracted once with ethyl acetate. The combined ethyl acetate phases were washed once with brine, dried over Na2SO4, filtered, and the filtrate was acidified with 2M HCl in ether. The product crystallized over night, and the solids were isolated by filtration to yield product as a white solid: 1H NMR (D2O, 400 MHz) 7.72 (d, 1H), 6.61 (d, 1H), 6.48 (s, 1H), 3.88 (s, 3H), 3.79 (m, 4H), 3.36 (m, 4H) ppm.
[0122] To 756 mg (5.29 mmol) of <strong>[17228-69-2]2-Chloro-4-methoxypyridine</strong> and 2.27g (26 mmol) of piperazine in a pressure flask was added 2. 7mL dimethylformamide, and the mixture was heated at [115C] for 5 hours. The solution was allowed to cool before opening the flask, and the resulting slurry was partitioned between ethyl acetate and water. The phases were separated, and the aqueous phase was back-extracted once with ethyl acetate. The combined ethyl acetate phases were washed once with brine, dried over [NA2S04,] filtered, and the filtrate was acidified with 2M [HC1] in ether. The product crystallized over night, and the solids were isolated by filtration to yield product as a white solid [:'H] NMR (DzO, 400MHz) 7.72 (d, [1H),] 6.61 (d, [1H),] 6.48 (s, [1H),] 3.88 (s, 3H), 3.79 (m, 4H), 3.36 (m, 4H) ppm.
10 mg
In 1-methyl-pyrrolidin-2-one; at 140 - 200℃; for 1.25h;Microwave irradiation;
6.01.03 1 -(4-methoxy-pyridin-2-yl)-piperazine 46 mg <strong>[17228-69-2]2-chloro-4-methoxy-pyridine</strong> and 277 mg piperazine in 2 mL n-methyl-2-pyrrolidinone were stirred 45 min at 140C and 30 min. at 200C under microwave conditions. The rection was diluted with water and purified by HPLC to give 10 mg desired product.
10 mg
In 1-methyl-pyrrolidin-2-one; at 140 - 200℃; for 1.25h;Microwave irradiation;
6.01.03 1-(4-methoxy-pyridin-2-yl)-piperazine 46 mg <strong>[17228-69-2]2-chloro-4-methoxy-pyridine</strong> and 277 mg piperazine in 2 mL n-methyl-2-pyrrolidinone were stirred 45 min at 140 C. and 30 min at 200 C. under microwave conditions. The reaction was diluted with water and purified by HPLC to give 10 mg desired product.
With N-Bromosuccinimide; sulfuric acid; at 0 - 55℃; for 3h;
<strong>[17228-69-2]2-Chloro-4-methoxypyridine</strong> (13.3 g, 92.6 mmol) was dissolved in concentrated sulfuric acid (65 ml), N-bromosuccinimide (16.5 g, 92.6 mmol) was added under ice-cooling, and the mixture was stirred with heating at 55 C. for 3 hr. The reaction mixture was poured into ice water, alkalified with 8N aqueous sodium hydroxide solution, and extracted with chloroform. The organic layer was washed with saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate=9:1 to 5:1) to give the object product as a white solid (9.3 g, yield 45%). 1H NMR(CDCl3 300 MHz) (delta) ppm: 3.97 (3H, s), 6.84 (1H, s), 8.34 (1H, s)
With N-Bromosuccinimide; sulfuric acid; at 0 - 60℃;
To a solution of <strong>[17228-69-2]2-chloro-4-methoxypyridine</strong> (10.0 g, 69.7 mmol) in 50 mL of sulfuric acid at 0C was added NBS. The reaction mixture was allowed to stir and warm up to room temperature for 2 hour and then heated at 60 0C for 5 h. Then it was cooled to room temperature and neutralized with 1 N NaOH (pH ~ 7), diluted with water (50 mL) and the aqueous layer was extracted with ethyl acetate (2 x 100 mL). The organic layers were washed with water (2 * 50 mL), sat. NaHCO3, brine, dried over Mg2SO4 and concentrated to provide an oil, which was chromatographed. On elution with 0-25% EtOAc / hexanes.,of the final product was obtained.1H NMR (500 MHz, DMSO-^), delta 8.4 (s, IH), 7.29 (s, IH), 3.97 (s, 3H);LC/MS (M+l)+ - 223.81; tR = 2.75 min.
With N-Bromosuccinimide; sulfuric acid; at 0 - 60℃; for 7h;
To a solution of <strong>[17228-69-2]2-chloro-4-methoxypyridine</strong> (10.0 g, 69.7 mmol) in 50 mL of sulfuric acid at 0 C was added NBS. The reaction mixture was allowed to stir and warm up to room temperature for 2 hours and then heated at 60 C for 5 hours. Then it was cooled to room temperature and neutralized with 1 N NaOH (pH ~ 7), diluted with water (50 mL) and the aqueous layer was extracted with ethyl acetate (2 chi 100 mL). The organic layers were washed with water (2 chi 50 mL), saturated NaHC03, brine, dried over Mg2S04 and concentrated to provide an oil, which was chromatographed. On elution with 0-25% EtOAc / hexanes, the final product was obtained.1H NMR (500 MHz, DMSO-i¾), delta 8.4 (s, 1H), 7.29 (s, 1H), 3.97 (s, 3H);LC/MS (M+l)+ = 223.
With N-Bromosuccinimide; sulfuric acid; at 0 - 60℃; for 7h;
To a solution of <strong>[17228-69-2]2-chloro-4-methoxypyridine</strong> (10.0 g, 69.7 mmol) in 50 mL of sulfuric acid at 0 C was added NBS. The reaction mixture was allowed to stir and warm up to room temperature for 2 hours and then heated at 60 C for 5 hours. The reaction mixture was then cooled to room temperature and neutralized with 1 N NaOH (pH ~ 7), diluted with water (50 mL) and the aqueous layer was extracted with ethyl acetate (2 chi 100 mL). The organic layers were washed with water (2 x 50 mL), saturated NaHC03 and brine, dried over Mg2S04 and concentrated to provide an oil, which was chromatographed. On elution with 0-25% EtOAc / hexanes, the final product was obtained. NM (500 MHz, DMSO-i, delta 8.4 (s, 1H), 7.29 (s, 1H), 3.97 (s, 3H); LC/MS (M+l)+ = 223.
With N-Bromosuccinimide; sulfuric acid; at 0 - 50℃; for 7h;
Step A: 5 -bromo-<strong>[17228-69-2]2-chloro-4-methoxypyridine</strong>: To a solution of <strong>[17228-69-2]2-chloro-4-methoxypyridine</strong> (10.0 g, 69.7 mmol) in 50 mL of sulfuric acid at 0 C was added NBS. The reaction mixture was allowed to stir and warm up to room temperature for 2 hour and then heated at 60 C for 5 h. Then it was cooled to room temperature and neutralized with 1 N NaOH (pH 7), diluted with water (50 mL) and the aqueous layer was extracted with ethyl acetate (2 x 100 mL). The organiclayers were washed with water (2 x 50 mL), sat. NaHCO3, brine, dried over Mg2504 and concentrated to provide an oil, which was chromatographed. On elution with 0-25% EtOAc /hexanes, the final product was obtained.
With N-Bromosuccinimide; sulfuric acid; at 0 - 60℃; for 7h;
Step A: 5-Bromo-<strong>[17228-69-2]2-chloro-4-methoxypyridine</strong>: To a solution of <strong>[17228-69-2]2-chloro-4-methoxypyridine</strong> (10.0 g, 69.7 mmol) in 50 mL of sulfuric acid at 0 C was added NBS. The reaction mixture was allowed to stir and warm up to room temperature for 2 hours and then heated at 60 C for 5 h. Then it was cooled to room temperature and neutralized with 1 N NaOH (pH ~ 7), diluted with water (50 mL) and the aqueous layer was extracted with ethyl acetate (2 x 100 mL). The organic layers were washed with water (2 x 50 mL), saturated NaHC03, and brine, dried over Mg2S04, and concentrated to provide a crude, which was chromatographed. On elution with 0-25% EtOAc / hexanes, the final product was obtained.
With N-Bromosuccinimide; sulfuric acid; at 0 - 60℃; for 7h;
Step A: 5-Bromo-<strong>[17228-69-2]2-chloro-4-methoxypyridine</strong>: To a solution of <strong>[17228-69-2]2-chloro-4-methoxypyridine</strong> (10.0 g, 69.7 mmol) in 50 mL of sulfuric acid at 0 C was added NBS. The reaction mixture was allowed to stir and warm up to room temperature for 2 hours and then heated at 60 C for 5 h. Then it was cooled to room temperature and neutralized with 1 N NaOH (pH ~ 7), diluted with water (50 mL) and the aqueous layer was extracted with ethyl acetate (2 x 100 mL). The organic layers were washed with water (2 x 50 mL), saturated NaHC03, and brine, dried over Mg2S04; and concentrated to provide a crude, which was chromatographed. On elution with 0-25% EtOAc / hexanes, the final product was obtained.
With N-Bromosuccinimide; sulfuric acid; at 0 - 60℃; for 7h;
To a solution of <strong>[17228-69-2]2-chloro-4-methoxypyridine</strong> (10.0 g, 69.7 mmol) in 50 mL of sulfuric acid at 0 was added NBS. The reaction mixture was allowed to stir and warm up to room temperature for 2 hour and then heated at 60 for 5 h. Then it was cooled to room temperature and neutralized with 1 N NaOH (pH7) , diluted with water (50 mL) and the aqueous layer was extracted with ethyl acetate (2 × 100 mL) . The organic layers were washed with water (2 × 50 mL) , sat. NaHCO3, brine, dried over Mg2SO4 and concentrated to provide an oil, which was chromatographed. On elution with 0-25 EtOAc /hexanes the final product was obtained. 1H NMR (500 MHz, DMSO-d6) , delta 8.4 (s, 1H) , 7.29 (s, 1H) , 3.97 (s, 3H) LC/MS (M+1) + 223.
With N-Bromosuccinimide; sulfuric acid; at 0 - 60℃; for 7h;
To a solution of 2-chioro-4-methoxypyridine (10.0 g, 69.7 mmol) in 50 mE of sulthric acid at 0 C. was added NI3S. The reaction mixture was allowed to stir and warm up to room temperature for 2 hours and then heated at 60 C. for 5 hours. The reaction mixture was then cooled to room temperature and neutralized with 1 N NaOH (pH.-7), diluted with water (50 mE) and the aqueous layer was extracted with ethyl acetate (2x100 mE). The organic layers were washed with water (2x50 mE), saturated NaHCO3 and brine, dried over Mg2SO4 and concentrated to provide an oil, which was chromatographed. On elution with 0-25% EtOAc/hexanes, the final product was obtained.?H NMR (500 MHz, DMSO-d5), oe 8.4 (s, 1H), 7.29 (s, 1H), 3.97 (s, 3H);EC/MS (M+1)=223.
With N-Bromosuccinimide; sulfuric acid; at 0 - 60℃; for 7h;
To a solution of <strong>[17228-69-2]2-chloro-4-methoxypyridine</strong> (10.0 g, 69.7 mmol) in 50 mL of sulfuric acid at 0C was added NBS. The reaction mixture was allowed to stir and warm up to room temperature for 2 h and then heated at 60C for 5 h. Next, the reaction mixture was cooled to room temperature, neutralized with 1 N NaOH (pH 7), diluted with water (50 ml) and the aqueous layer was extracted with ethyl acetate (2 x 100 mL).The organic layers were washed with water (2 x 50 mL), saturated NaHCO3, brine, dried over Mg2SO4 and concentrated to provide an oil, which was chromatographed to give 5-bromo-2- chloro-4-methoxypyridine eluting with 0-25% EtOAc/hexanes. ?HNMR (500 MHz, DMSO-d6) oe 8.4 (s, 1H), 7.29 (s, 1H), 3.97 (s, 3H); LC/MS: [(M+1)] = 223.
Methylzinc chloride in THF (2 M, 10.489 mL, 21 mmol) was added to a solution of <strong>[17228-69-2]2-chloro-4-methoxypyridine</strong> (0.500 g, 3.48 mmol) and Pd(PPh3)4 (0.161 g, 0.14 mmol) in THF (10 mL). The mixture was refluxed for 40 h and then poured into an aqueous solution (10 mL) containing ethylenediaminetetraacetic acid (1.5 g). The resulting mixture was neutralized with K2CO3 and extracted with Et2O. The organic layer was concentrated to give a residue, which was purified on a silica gel column eluting with MeOH:EtOAc (1:10) to give 4-methoxy-2-methylpyridine (0.213 g, 50.0%).
With potassium tert-butylate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 115℃; for 3h;
(IV.5) 1-(4-Methoxy-2-pyridinyl)- piperazine; a) 4-(4-Methoxy-2-pyridinyl)-piperazine-1-carboxylic acid tert-butyl ester; A solution of <strong>[17228-69-2]2-chloro-4-methoxypyridine</strong> (1 g; 6.97 mmol), piperazine-1-carboxylic acid tert-butyl ester (3.89 g; 20.9 mmol) and potassium tert-butylate (2.34 g; 20.9 mmol) in toluene (60 ml) is heated to 80 C under nitrogen atmosphere. Tris-(dibenzylidene acetone)-palladium (74.220 mg; 0.081 mmol) and 2,2'-bis-(diphenylphosphino)-1,1' binaphthyl (BINAP; 0.12 g; 0.189 mmol) are added and the reaction mixture is stirred for 3 h at 115C. After removal of the solvent in vacuo and aqueous work-up the crude product is purified by column chromatography (silica; dichloromethane : methanol 7:3) yielding pure 4-(4-methoxy-2-pyridinyl)-piperazine-1-carboxylic acid tert-butyl ester as yellow oil. Yield: 3.49 g (68 %) HPLC: rt = 3.056 min (Method FEC) UV (max.) = 222 nm MS: M+1 = 294 Da.
Deprotonation of this compound with n-butyllithium and reaction with <strong>[17228-69-2]2-chloro-4-methoxypyridine</strong> in dry benzene yields the title compound of m.p. 166 C. (decomposition).
4-[2-amino-4-(3-bromo-4-fluorophenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]phenyl methanesulfonate[ No CAS ]
[ 17228-69-2 ]
[ 1035268-70-2 ]
Yield
Reaction Conditions
Operation in experiment
6%
<strong>[17228-69-2]2-Chloro-4-methoxypyridine</strong> (92 uL, 0.8 mmol), hexamethyl distannane (165 uL, 0.8 mmol) and tetrakis(triphenylphospliine)palladium (28 mg, 0.024 mmol) were mixed and irradiated under an argon atmosphere in a microwave at 130 0C for 2 h. After cooling to room temperature 4-[2-amino-4-(3-bromo-4-fluorophenyl)-l-methyl-5-oxo-4,5-dihydro- lH"-imidazol-4-yl]phenyl methanesulfonate (130 mg, 0.28 mmol) and tetrakis(triphenylphosphine)palladium (28 mg, 0.024 mmol) was added. The mixture was irradiated under an argon atmosphere in a microwave at 130 C for 6 h. On cooling the mixture was filtered and the compound was purified using preparative etaPLC to afford 9 mg (6% yield) of the title compound: 1H NMR (400 MHz5 DMSO-cfe) delta ppm 8.52 (d, J = 5.77 Hz, 1 H), 8.10 - 8.14 (m, 1 H), 7.53 - 7.60 (m, 3 H)5 7.25 - 7.31 (m, 4 H), 6.99 - 7.02 (m, 1 H), 3.86 (s, 3 H), 3.35 (s, 3 H), 2.99 (s, 3 H), 1.88 (s, 2.1 H, acetate).
With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; dimethyl sulfoxide; at 80℃; for 16.25 - 16.33h;
To a solution of 1-(5-bromo-6-fluoro-benzothiazol-2-yl)-3-ethyl-urea (I) (0.15 g, 0.47 mmol) in DMSO (5 ml_) was added KOAc (0.14 g, 1.41 mmol) and bis (neopentyl glycolato) diboron (0.21 g, 0.94 mmol) at room temperature. The resulting mixture was degassed for 15-20 min. by purging nitrogen followed by the addition of PdCI2.dppf (0.013 g, 0.02 mmol). The reaction mixture was again degassed for 15- 20 min and then heated up to 8O0C for 3 h. After completion of reaction (TLC monitoring), the reaction mixture was cooled to room temperature followed by in-situ addition of <strong>[17228-69-2]2-chloro-4-methoxy-pyridine</strong> (0.035 g, 0.24 mmol) and Cs2CO3 (0.08 g, 3.70 M in H2O). The resulting reaction mixture was degassed for 10-15 min. followed by the addition of Pd(PPh3J4 (0.20 g, 0.02 mmol). The resulting reaction mixture was finally degassed for 15-20 min and heated to 8O0C for 16 h. After completion of reaction (TLC monitoring), water was added to the reaction mixture and extracted with ethyl acetate (3 x 50 mL). The combined organics was dried over Na2SO4 and evaporated. The crude residue was purified over silica-gel (230-400 M, 2-3% MeOH- DCM to obtain the desired product as beige-solid (0.07 g, 4.3%). 1H-NMR (400 MHz, DMSO-Cl6): delta 1.08 (t, J= 7.20 Hz, 3H), 3.19 (m, 2H), 3.89 (s, 3H)1 6.69 (br s, 1 H)1 7.02 (d, J= 3.60 Hz1 1H)1 7.33 (s, 1 H), 7.93 (d, J=10.80 Hz, 1 H), 8.06 (d, J= 6.00 Hz, 1 H), 8.54 (d, J=5.60 Hz, 1 H) and 10.86 (br s, 1 H). MS: 347.12 (M+H+). Qualitative HPLC Purity (Acquity BEH C-18, 2.1 x 100 mm, 247 nm): 98.52% (Rt = 5.07 min).
To a solution of 2-(3-ethylureido)-6-methylbenzo[d]thiazol-5-yl trifluoromethanesulfonate Vl (0.122 g, 0.32 mmol) in DMSO (8 mL) was added KOAc (0.09 g, 0.95 mmol) and bis (neopentyl glycolato) diboron (0.15 g, 0.64 mmol) at room temperature. The resulting mixture was degassed by nitrogen for 15-20 min. followed by the addition of PdCI2.dppf (0.03 g, 0.03 mmol). The reaction mixture was again degassed for 15- 20 min and then heated up to 8O0C for 3 h. After completion of reaction (TLC monitoring), the reaction mixture was cooled to room temperature followed by addition of 4-bromo-1-methylpyridin-2(1H)-one (0.12 g, 0.64 mmol) and Cs2CO3 (0.16 g, 3.7 M in H2O). The resulting mixture was degassed for 10-15 min. followed by the addition of Pd(PPh3J4 (0.04 g, 0.03 mmol) and again degassed for 15- 20 min and finally heated to 8O0C for 16 h. After completion of reaction (TLC monitoring), water was added to the reaction mixture and extracted with EtOAc (3 x 50 mL). The combined organics was dried over Na2SO4 and concentrated. The crude residue was purified over silica gel (100-200 M, 2-2.5% MeOH-DCM) to obtain the <n="92"/>desired product as white solid (0.025 g, 24%). 1H NMR (DMSO-d6, 400 MHz): delta 1.08 (t, J= 7.20 Hz, 3H)1 2.31 (s, 3H), 3.19 (m, 2H), 3.46 (s, 3H), 6.27 (dd, J=1.60 and 6.80 Hz, 1 H), 6.32 (s, 1 H), 6.70 (br s, 1 H), 7.41 (s, 1 H), 7.74 (d, J= 6.80 Hz1 1 H), 7.78 (s, 1 H) and 10.71 (br s, 1 H). MS: 343.18 (M+H+). Qualitative HPLC Purity (Acquity BEH C-18, 2.1 x 100 mm, 237 nm): 98.53% (Rt = 4.65 min).
2-[(4-methoxy-2-pyridinyl)amino]-ethanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Ethanolamine (4.0 ml) was added to potassium tert-butoxide (96 ml of a 1M solution in THF) and the reaction was stirred at room temperature for 30 min. 2-Chloro-4- methoxypyridine was added dropwise and the reaction mixture was heated under reflux for 16 h. The reaction mixture was cooled, filtered and evaporated to an oil. This was dissolved in xylene (100 ml) and treated with toluene-4-sulphonic acid (50 mg) and heated under reflux for 16 h. More toluene-4-sulphonic acid (50 mg) was added and the heating was continued for a further 16 h under reflux. The mixture was concentrated, the residue was passed through a pad of silica and eluted with 5% 7M ammonia in methanol/DCM to give the sub-title compound as a brown oil (5.0 g). MS APCI +VE/Z 169 ([M+H]). 1H NMR 300MHz (DMSO-d6) 7.76 (1H, d), 6.33 (1H, t), 6.13-6. 10 (1H, m), 5.99 (1H, m), 3.70 (3H, s), 3.54-3. 47 (2H, m), 3.31-3. 25 (2H, m).
With N-ethyl-N,N-diisopropylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 80℃; for 26h;Inert atmosphere;
2- (Benzylsulfanyl) -4-methoxypyridineTo a solution of <strong>[17228-69-2]2-chloro-4-methoxypyridine</strong> (786 mg) in toluene (10 mL) were added phenylmethanethiol (683 mg) , N, N- diisopropylethylamine (1.56 g) , tris (dibenzylideneacetone)dipalladium(O) (202 mg) and 4,5- bis (diphenylphosphino) -9, 9-dimethylxanthene (256 mg) , and the mixture was stirred at 80C for 26 hr under an argon atmosphere. The reaction mixture was filtered through silica gel and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane?hexane-ethyl acetate=19 : 1) to give the title compound as an orange oil (yield 454 mg, 38%) .1H-NMR(CDCl3)O: 3.79(3H,s), 4.43(2H,s), 6.57 (IH, dd, J=5.9, 2.5Hz) ,6.68 (IH, d, J=2.3Hz) , 7.19-7.34 (3H,m) , 7.36-7.44 (2H,m) , 8.27 (IH, d, J=5.7Hz) .
38%
With tris-(dibenzylideneacetone)dipalladium(0); N-ethyl-N,N-diisopropylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 80℃; for 26h;Inert atmosphere;
A mixture of <strong>[17228-69-2]2-chloro-4-methoxypyridine</strong> 3f (786 mg, 5.47 mmol), tris(dibenzylideneacetone)dipalladium(0) (202 mg, 0.22 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (256 mg, 0.44 mmol), N-ethyldiisopropylamine (1.56 g, 12.0 mmol) and benzyl mercaptane (683 mg, 5.50 mmol) in toluene (10 mL) was stirred at 80 C for 26 h under Ar atmosphere. The reaction mixture was filtered through a short pad of silica gel, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane/EtOAc = 1/0-19/1) to afford compound 4f (454 mg, 38%) as an orange oil: 1H-NMR (CDCl3) d 3.79 (3H, s), 4.43 (2H, s), 6.57 (1H, dd, J = 5.9 Hz, 2.5 Hz), 6.68 (1H, d, J = 2.3 Hz), 7.19-7.34 (3H, m), 7.36-7.44 (2H, m), 8.27 (1H, d, J = 5.7 Hz).
(1) Synthesis of <strong>[17228-69-2]2-chloro-4-methoxypyridine</strong>-3-carbaldehyde 5.61g of <strong>[17228-69-2]2-chloro-4-methoxypyridine</strong> was dissolved in 100ml of anhydrous tetrahydrofuran, 40ml of n-butyllithium (1. 6M hexane solution) was added dropwise at -70 C for 20 minutes under nitrogen atmosphere. Stirring was carried out for 20 minutes at -70 C after dropping, N, N-dimethylformamide 6.2ml was dissolved in anhydrous tetrahydrofuran 50ml afterwards and was added thereto at -70 C. This reaction liquid was stirred for another 2 hours at room temperature. Water and diethyl ether were added to reaction liquid, and the organic layer was separated. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. After removal of drying agent by filtration, the organic layer was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 2.69g of the title compound. 1H-NMR(CDCl3) delta (ppm): 4.00(s,3H), 6.91(d,1H, J=5.6Hz), 8.38(d,1H, J=5.6Hz), 10.45 (s, 1H).
To degassed dioxane (12 mL) were added <strong>[17228-69-2]2-chloro-4-methoxypyridine</strong> (0.12 mL, 1.05 mmol), vinylboronic acid MIDA ester (0.23 g, 1.26 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (0.043 g, 0.11 mmol) and palladium(II) acetate (0.012 g, 0.05 mmol) under argon and the reaction stirred for 15 min at rt then potassium phosphate (1.34 g, 6.31 mmol) dissolved in degassed water (2.5 mL) was added and the reaction heated at 90 C. overnight. 1M NaOH (aq) was added and the residue extracted with dichloromethane (3×). The combined organic phases were dried (MgSO4), filtered and evaporated carefully to avoid losing the volatile product. The crude was taken to the next step without further purification.MS (ES+) m/z 136 (M+H)+.
With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 85℃; for 4h;Inert atmosphere;
A mixture of 8 (200 mg, 0.48 mmol), 22 (0.060 mL, 0.48 mmol), diacetoxy-palladium (6 mg, 0.02 mmol), cesium carbonate (316 mg, 0.97 mmol), and Xantphos (28 mg, 0.05 mmol) in degassed dioxane (4.0 mL) was heated at 85 C in a sealed vessel under inert atmosphere for 4 h. The resulting mixture was diluted with dichloromethane and ethanol, extracted with a saturated aqueous solution of NaHCO3. The organics were dried over MgSO4 and concentrated in vacuo. TFA (5 mL) and anisole (0.32 mL, 2.9 mmol) were added to a solution of the crude product in dichloromethane (7 mL). The mixture was stirred at 25-40 C for 24 h and slowly quenched with a saturated aqueous solution of Na2CO3. Extractive workup (at pH 8-9) with ethyl acetate and then dichloromethane afforded a residue which was adsorbed on silica gel and purified by flash chromatography (2/100 to 5/100 EtOH/DCM + 0.5% NH4OH) to yield 22b (108 mg, 80%) as a pale yellow solid.1H NMR (500 MHz, DMSO) delta 8.56 (NH), 7.87 (s, 1H), 7.86 (d, J = 8.6 Hz, 2H), 7.71 (d, J = 8.6 Hz, 2H), 7.17 (SO2NH2), 2.49 (s, 3H), 2.36 (s, 3H). ESIMS (m/z): 279.3 (MH+).
With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 85℃; for 4h;Inert atmosphere;
A mixture of 8 (200 mg, 0.48 mmol), 22 (0.060 mL, 0.48 mmol), diacetoxy-palladium (6 mg, 0.02 mmol), cesium carbonate (316 mg, 0.97 mmol), and Xantphos (28 mg, 0.05 mmol) in degassed dioxane (4.0 mL) was heated at 85 C in a sealed vessel under inert atmosphere for 4 h. The resulting mixture was diluted with dichloromethane and ethanol, extracted with a saturated aqueous solution of NaHCO3. The organics were dried over MgSO4 and concentrated in vacuo. TFA (5 mL) and anisole (0.32 mL, 2.9 mmol) were added to a solution of the crude product in dichloromethane (7 mL). The mixture was stirred at 25-40 C for 24 h and slowly quenched with a saturated aqueous solution of Na2CO3. Extractive workup (at pH 8-9) with ethyl acetate and then dichloromethane afforded a residue which was adsorbed on silica gel and purified by flash chromatography (2/100 to 5/100 EtOH/DCM + 0.5% NH4OH) to yield 22b (108 mg, 80%) as a pale yellow solid.1H NMR (500 MHz, DMSO) delta 8.56 (NH), 7.87 (s, 1H), 7.86 (d, J = 8.6 Hz, 2H), 7.71 (d, J = 8.6 Hz, 2H), 7.17 (SO2NH2), 2.49 (s, 3H), 2.36 (s, 3H). ESIMS (m/z): 279.3 (MH+).
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 16h;Inert atmosphere; Sealed vial;
Example 61 2'-amino-6-(4-methoxypyridin-2-yl)-r,2,2-trimethylspiro[chroman-4,4'-imidazol]-5'( H)- one<strong>[17228-69-2]2-Chloro-4-methoxypyridine</strong> (0.019 g, 0.13 mmol), 20% aqueous sodium carbonate (0.028 g, 0.26 mmol), and tetrakis(triphenylphospine)palladium(0) (7.5 mg, 0.0065 mmol) were added to a solution of 2'-amino- 1 ',2,2-trimethyl-6-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)spiro[chroman-4,4'-imidazol]-5'( 1 'H)-one (0.050 g, 0.13 mmol) in dioxane (1 ml), and the reaction was degassed with argon. It was heated in a sealed vial to 100C for 16 hours. It was cooled to ambient temperature and loaded directly onto a silica gel column. It was purified using a 3-15% methanol with 2% ammonium hydroxide/dichloromethane linear gradient to yield 2'-amino-6-(4-methoxypyridin-2-y 1)- 1 ',2,2-trimethy lspiro[chrornan-4,4'-imidazol]- 5'(l'H)-one (0.01 1 g, 0.030 mmol, 23% yield) as a solid, m/z (APCI-pos) M + 1 = 367.2.
With palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In 1,4-dioxane; at 100℃; for 1h;Inert atmosphere;
General procedure: A suspension of dihydroisoquinolinone 8 (2.0 mmol), aryl/heteroaryl bromide (3.0 mmol), palladium acetate (0.2 mmol) and BINAP (0.2 mmol) in dioxane (10.0 mL) was degassed with argon. Then sodium tert-butoxide (3.0 mmol) was added. The reaction mixture was heated at 100 C under argon for 1 h, and then it was cooled to room temperature, quenched with ammonium chloride, and extracted with EtOAc. The organic extract was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude material obtained was purified by silica-gel flash column chromatography to give the desired dihydroisoquinolinone 9.
With N-iodo-succinimide; sulfuric acid; at 55℃; for 2.0h;
To a solution of <strong>[17228-69-2]2-chloro-4-methoxypyridine</strong> (0.5 g, 3.48 mmol) in sulfuric acid (2.5 mL) was added A/-iodosuccinimide (0.825 g, 3.48 mmol) portionwise at room temperature. The mixture was stirred at 55C for 2 hours. The reaction mixture was poured into ice water (10 mL) and 8 M NaOH (20 mL) was added slowly, after which the dark brown solution turned pale yellow. The aqueous layer was extracted with CH2CI2 (2 x 20 mL). The organic layers were washed with brine (10 mL) and concentrated in vacuo onto silica gel. Dry flash chromatography, eluting with 25% EtOAc:c-Hex, gave 2-chloro-5-iodo-4- methoxypyridine as a white crystalline solid (0.169 g, 0.760 mmol, 22% yield). 1H NMR (500 MHz, d6-DMSO) ? 8.52 (s, 1 H), 7.19 (s, 1 H), 3.96 (s, 3H); LC-MS (LCT, 4 minutes) Rt = 2.56 minutes; m/z (ESI) 270 (M+H).
21%
With N-iodo-succinimide; sulfuric acid; at 55℃; for 2.0h;
j00503j To a solution of 2-chloro-4-methoxy-pyndine (10 g, 70 mmol) in concentrated sulfuric acid (50 mL) at room temperature was added a solution of N-iodosuccinimide (15.7 g, 70 mmol) in concentrated sulfuric acid (10 mL). The mixture was stirred at 55 C for 2 hours, then diluated with water (100 mL), adjusted to pH = 9-10 by slow addition of 8 N aqueous sodium hydroxide and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography [petroleum ether: ethyl acetate = 20:11 to give compound B-ii6(4 g, 21% yield) as a white solid. GC-MS: tR=6.569 mi, (ES) mlz (M)=268.9.
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