* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With toluene-4-sulfonic acid In toluene at 25℃; for 1 h;
To a solution of ethyl glycolate (10 g, 0.0961 mol) in toluene (100 mL) was added 3,4- dihydro-2H-pyran ( 8 g, 0.096 1 mol) followed by catalytic amount of pTSA (30 mg) and stirred at 25 °C for 1 h. After completion of the reaction, the reaction mixture was washed with water and brine solution. The organic layer was dried over anhydrous Na2504, filtered and concentrated under reduced pressure to get 18 g (99 percent) ethyl 2-((tetrahydro-2H-pyran-2- yl)oxy)acetate, 2, as colorless liquid
94.7%
at 20℃; Industrial scale
Example 1.2Ethyl(tetrahydropyran-2-yloxy)-acetate (B) 100.00 kg (960.52 mol) ethyl glycolate (A) were dissolved in 180.0 L toluene and 365.22 g (1.92 mol) 4-toluenesulphonic acid monohydrate were added. At 20° C. a solution of 80.80 kg (960.52 mol) 3,4-dihydro-2H-pyran was added dropwise to the reaction mixture obtained and then the mixture was washed with 20.0 L toluene. The reaction mixture was stirred for 1 hour at 20° C. and after the reaction was complete it was combined with 100.0 L water and 6.53 kg (96.05 mol) ammonia solution (25percent). After phase separation the organic phase was washed with 100.0 L water and then the solvent was distilled off completely in vacuo.Yield: 188.4 kg (94.7percent of theory)
91.5%
at 20℃;
To a stirred solution of ethyl glycolate (35.3 g, 0.339 mol) containing a few crystals of p-toluene sulfonic acid, 3,4-dihydropyran (30.0 g, 0.357 mol) was added dropwise (15 g over one hour followed by 15 g over 30 min). After stirring overnight at room temperature, the mixture was diluted with diethyl ether (80 mL) and washed with a NaHCO3 solution (from 30 mL sat. NaHCO3 and 10 mL water). The organic layer was separated and dried (Na2504) followed by evaporation of the ether. The residue was distilled under high vacuum to give 58.4 g (91.5percent) of 28 as a clear liquid. 1H NMR (CDCl3, 400 MHz)δ: 1.29 (t, 3H, J=7.1 Hz, CH3), 1.53-1.95 (m, 6H, 3,4,5-THP-CH2's), 3.50-3.55 (m, 1H, 6-THP-CH2), 3.83-3.89 (m, 1H, 6-THP-CH2), 4.19 (s, 2H, OCH2CO2R), 4.20 (t, 2H, J=7.1 Hz, CH2Me), 4.75 (m, 1H, THP-CH). 13C NMR (CDCl3, 100 MHz) δ: 14.1, 18.7, 25.2, 30.0, 60.7, 61.9, 63.8, 170.4.
91.5%
at 20℃;
(1) Preparation of tetrahydropyran-2-yloxy-acetic acid ethyl ester (Formula 28, Scheme 4)[0378] To a stirred solution of ethyl glycolate (35.3g, 0.339mol) containing a few crystals of />toluene sulfonic acid, 3,4-dihydropyran (30.Og, 0.357mol) was added1 1 <n="113"/>dropwise (15g over one hour followed by 15g over 30min). After stirring overnight at room temperature, the mixture was diluted with diethyl ether (8OmL) and washed with a NaHCO3 solution (from 3OmL sat. NaHCO3 and 1OmL water). The organic layer was separated and dried (Na2SO4) followed by evaporation of the ether. The residue was distilled under high vacuum to give 58.4g (91.5percent) of 28 as a clear liquid. 1H NMR (CDCL3, 400MHz)δ: 1.29 (t, 3H, J = 7.1 Hz, CH3), 1.53 -1.95 (m, 6H, 3,4,5-THP-CH2's), 3.50-3.55 (m, IH, 6-THP-CH2), 3.83 - 3.89 (m, IH, 6-THP-CH2), 4.19 (s, 2H, OCH2CO2R), 4.20 (t, 2H, J = 7.1 Hz, CH2Me), 4.75 (m, IH, THP-CH). 13C NMR (CDCl3, 100MHz) δ: 14.1, 18.7, 25.2, 30.0, 60.7, 61.9, 63.8, 170.4.
81%
With pyridinium p-toluenesulfonate In dichloromethane
Step 1) ethyl 2-(tetrahydro-2H-pyran-2-yloxy)acetate To a mixture of ethyl 2-hydroxyacetate (2 g, 20 mmol, Aldrich) and 3,4-dihydro-2H-pyran (3.2 g, 40 mmol, Alfa) in 40 mL of CH2Cl2 was added PPTS (500 mg, 2 mmol) slowly at rt. The mixture was stirred at rt for 4 hours, and then the mixture was washed with brine (20 mL*2), the combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE: EtOAc=20:1) to give colorless oil (3.01 g, 81percent). 1H NMR (400 MHz, CDCl3): δ 1.22-1.38 (m, 4H), 1.55-1.63 (m, 3H), 1.69-1.88 (m, 3H), 3.50-3.53 (m, 1H), 3.82-3.88 (m, 1H), 4.18-4.23 (m, 4H), 4.73-4.74 (t, J=4 Hz, 1H).
81%
With pyridinium p-toluenesulfonate In dichloromethane at 20℃; for 4 h;
To a mixture of ethyl 2-hydroxyacetate (2 g, 20 mmol, Aldrich) and 3,4-dihydro-2H-pyran (3.2 g, 40 mmol, Alfa) in 40 mL of CH2Cl2 was added PPTS (500 mg, 2 mmol) slowly at rt. The mixture was stirred at rt for 4 hours, and then the mixture was washed with brine (20 mLx2), the combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residure was purified by a silica gel column chromatography (PE: EtOAc =20:1) to give colorless oil (3.01 g, 81 percent). 1H NMR (400MHz, CDCl3): δ 1.22 - 1.38 (m, 4H), 1.55 - 1.63 (m, 3H), 1.69 - 1.88 (m, 3H), 3.50 - 3.53 (m, 1H), 3.82 - 3.88 (m, 1H), 4.18 - 4.23 (m, 4H), 4.73 - 4.74 (t, J=4Hz, 1H).
81%
With pyridinium p-toluenesulfonate In dichloromethane at 20℃; for 4 h; Inert atmosphere
To a mixture of ethyl 2 -hydroxy acetate (2 g, 20 mmol, TCI) and 3,4- dihydro-2H-pyran (3.2 g, 40 mmol, Alfa) in 40 mL Of CH2Cl2 was added PPTS (500 mg, 2 mmol, Aldrich) in portions at rt. The mixture was stirred at rt for 4 hours. The reaction mixture was then washed with brine, and the organic layer was separated and the combined organic phases were dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel column chromatography (20: 1 (v/v) petroleum ether / EtOAc) to give the desired compound as colorless oil (3.01 g, 81 percent ).1H NMR (400MHz, CDCl3): δ 1.25 - 1.32 (m, 3H), 1.55 - 1.63 (m, 3H), 1.69 - 1.88 (m, 3H), 3.50 - 3.53 (m, IH), 3.82 - 3.88 (m, IH), 4.18 - 4.23 (m, 4H), 4.73 (t, J=3.2Hz, IH).
58%
With toluene-4-sulfonic acid In toluene at 20℃;
Step 1 Preparation of ethyl 2-(tetrahydro-2H-pyran-2-yloxy)acetate A mixture of 3,4-dihydro-2H-pyran (20.4 g, 242.3 mmol), ethyl 2-hydroxyacetate (24.0 g, 230.8 mmol) and TsOH (0.794 g, 4.6 mmol) in toluene (150 mL) was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (2percent EtOAc in petroleum ether) to afford ethyl 2-(tetrahydro-2H-pyran-2-yloxy)acetate (25.2 g, 58percent) as a colorless oil.
Reference：
[1] Patent: WO2017/83431, 2017, A2, . Location in patent: Paragraph 00216; 00217
[2] Patent: US2011/87021, 2011, A1, . Location in patent: Page/Page column 11
[3] Patent: US2005/8570, 2005, A1, . Location in patent: Page/Page column 45
[4] Patent: WO2007/121453, 2007, A2, . Location in patent: Page/Page column 111; 112
[5] Patent: US2010/239576, 2010, A1,
[6] Patent: EP2408300, 2016, B1, . Location in patent: Paragraph 0343
[7] Patent: WO2010/45095, 2010, A1, . Location in patent: Page/Page column 76
[8] Patent: US2016/168090, 2016, A1, . Location in patent: Paragraph 0348-0349
[9] Journal of the Chemical Society, 1956, p. 2124,2126
[10] Journal of the Chemical Society, 1956, p. 4665
[11] Patent: WO2008/128961, 2008, A1, . Location in patent: Page/Page column 107
5
[ 142-68-7 ]
[ 623-50-7 ]
[ 61675-94-3 ]
Yield
Reaction Conditions
Operation in experiment
32 g
at 20℃;
EXAMPLE 1422-((l-(2-(3-Fluoro-6-methoxy-l,5-naphthyridin-4-yl)ethyl)-2- oxabicyclo[2.2.2]octan-4-ylamino)methyl)-6H-pyrimido[5,4-b][l,4]oxazin-7(8H)-oneStep 1Ethyl 2-(Tetrahydro-2H-pyran-2-yloxy)acetateTo a stirred solution of ethyl hydroxyacetate (35.3 g) containing a few crystals of p-toluene sulfonic acid, dihydropyran (30.0 g) was added dropwise. After stirring overnight at room temperature, the mixture was diluted with dichloromethane (200 mL) and washed with a sodium hydrogencarbonate solution. The organic layer was separated and dried followed by evaporation of the dichloromethane. The residue was distilled under high vacuum to give the title compound (32 g) as a clear liquid.1H NMR (CDC13): δ 1.20-1.32 (m, 3H), 1.50-1.58 (m, 3H), 1.70-1.92 (m, 3H), 3.45-3.55 (m, 1H), 3.80-3.90 (m, 1H), 4.16-4.24 (m, 4H), 4.70-4.79 (m, 1H).
With hydrazine hydrate In methanol; water at 20℃; for 5 h; Cooling with ice
General procedure: To a stirred solution of esters 2a–2j (70 mmol) in MeOH (30 mL) cooled in an ice-water bath was added dropwise 80percent aqueous hydrazine hydrate (6.26 g, 100 mmol). The resulting solution was stirred at room temperature (2a–2b or 2d–2j), or reflux (2c), until the completion of reaction as indicated by TLC analysis (typically within 5 h). The reaction mixture was evaporated on a rotary evaporator to give a residue, which was purified by column chromatography through a short silica gel column to yield 3a–3k after trituration with n-hexane if possible.
81%
With hydrazine In ethanol at 85℃; for 3 h;
A. 2-Hydroxyacetohydrazide. A solution of ethyl 2-hydroxyacetate ( 1.00 g, 9.60 mmol), hydrazine (0.324 mg, 10.1 mmol), and ethanol (20 mL) were combined and heated to 85 °C for 3 h. The reaction was concentrated to afford the title compound (0.702 g, 81percent). MS (ESI) m/z 91.1 [M+ 1]+.
Reference：
[1] Molecules, 2016, vol. 21, # 11,
[2] Patent: WO2008/51493, 2008, A2, . Location in patent: Page/Page column 196
[3] Chemical Biology and Drug Design, 2016, vol. 88, # 6, p. 873 - 883
[4] Patent: WO2011/77098, 2011, A1, . Location in patent: Page/Page column 150
[5] Combinatorial Chemistry and High Throughput Screening, 2011, vol. 14, # 2, p. 132 - 137
With tetra-(n-butyl)ammonium iodide; sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 12.5 h; Inert atmosphere
Synthesis of compound 24To the solution of hydroxy-acetic acid ethyl ester 23 (99.6g, 0.96mol) in TH F (1 .5L) under nitrogen atmosphere, NaH (42g, I .Omol: 60percent in mineral oil) was added at 0°C in portions. The mixture was stirred at 0°C for 30 min and tetrabutylammonium iodide (35.3g, O.I Omol) and benzyl bromide (163.6g, 0.96mol) were added. The mixture was allowed to warm up to r.t and was stirred in this temperature for 12h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over MgSC , solvent was evaporated under high vacuum and raw product was destilled (121 °C /4mBar) to give compound 24 (135.5 g, yield: 73percent). 1H-NMR (CDC ): δ= 7.41 - 7.22 (m, 5H), 4.65 (s, 2H), 4.27 (q, 2H), 4.1 1 (s, 2H), 1.25 (t, 3H).
73%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5 h; Inert atmosphere Stage #2: With tetra-(n-butyl)ammonium iodide In tetrahydrofuran; mineral oil at 0 - 20℃; for 12 h;
To the solution of hydroxy-acetic acid ethyl ester 22 (99.6 g, 0.96 mol) in THF (1 .5L) under nitrogen atmosphere, NaH (42.0 g, 1.0 mol: 60percent in mineral oil) was added at 0°C in portions. The mixture was stirred at 0°C for 30 min and tetrabutylammonium iodide (35.3 g, 0.10 mol) and benzyl bromide (163.6 g, 0.96 mol) were added. The mix- ture was allowed to warm up to room temperature and was stirred in this temperature for 12h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over MgSC , solventwas evaporated under high vacuum and raw product was destilled (121 °C /4 mBar) to give compound 23 (135.5 g, yield: 73percent). H-NMR (CDCIs): δ= 7.41 - 7.22 (m, 5H), 4.65 (s, 2H), 4.27 (q, 2H), 4.1 1 (s, 2H), 1 .25 (t, 3H).
57%
Stage #1: With tetra-(n-butyl)ammonium iodide; sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5 h; Stage #2: at 20℃;
To a stirred and cooled (0 °C) solution of ethyl 2-hydroxyacetate (20.0 g, 19.0 mmol) in tetrahydrofuran (250 mL) was added tetrabutylammonium iodide (7.01 g, 19.0 mmol) and sodium hydride (60percent in mineral oil, 7.60 g, 19.0 mmol). The mixture was stirred at 0 °C for 30 minutes before adding benzyl bromide (32.3 g, 19.0 mmol). The reaction was stirred overnight and allowed to warm to room temperature. The mixture was then cooled (0 °C), quenched with aqueous ammonium chloride (100 mL) and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (Na2S04) and concentrated. The residue was purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford ethyl 2- (benzyloxy)acetate as a yellow oil (14.7 g, 57percent). To a stirred and cooled (0 °C) solution of this product (13.6 g, 70.0 mmol) in tetrahydrofuran (150 mL) was added dimethyl methylphosphonate (11.3 g, 91.1 mmol) followed by a 2.0 M solution of lithium diisopropylamide in tetrahydrofuran/heptane/ethylbenzene (74.0 mL, 148 mmol). The reaction was stirred at 0 °C for 3 hours before quenching with enough 5.0 M aqueous hydrochloric acid to bring the pH to ~4. The resulting mixture was then extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na2S04) and concentrated. The residue was purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford dimethyl (3-(benzyloxy)-2-oxopropyl)phosphonate as a light yellow oil (10.1 g, 54percent). To a stirred and cooled (0 °C) solution of this intermediate (9.89 g, 36.4 mmol) in tetrahydrofuran (100 mL) was added sodium hydride (60percent in mineral oil; 1.60 g, 40.0 mmol). The mixture was stirred at 0 °C for 30 minutes before adding, dropwise, a solution of tert-butyl 4-oxo-piperidine-l-carboxylate (5.79 g, 29.1 mmol) in tetrahydrofuran (50 mL). The resulting mixture was stirred at 0 °C for 2 hours, then quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na2S04), and concentrated. The residue was purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford tert-butyl 4-(3-(benzyloxy)-2- oxopropylidene)piperidine-l-carboxylate as a light yellow oil (6.50 g, 52percent). This material (6.50 g, 18.8 mmol), 10percent Pd/C (1.00 g) and ethyl acetate (50 mL) were placed in a Parr bottle and hydrogenated for 5 hours at room temperature. The mixture was filtered through Celite and concentrated to afford tert-butyl 4-(3-hydroxy-2- oxopropyl)piperidine-l-carboxylate as a yellow oil (4.80 g, 99percent). To a stirred solution of this product (4.80 g, 18.7 mmol) in methylene chloride (8 mL) was added carbon tetrabromide (12.4 g, 37.4 mmol) and triphenylphosphine (9.80 g, 37.4 mmol). After 3 hours, the reaction was concentrated and the residue purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford tert-butyl 4-(3-bromo-2- oxopropyl)piperidine-l-carboxylate as a white solid (3.30 g, 56percent). To a stirred and cooled (0 °C) solution of this product (3.30 g, 10.3 mmol) in methylene chloride (50 mL) was added trifluoroacetic acid (12.0 mL, 145 mmol). The mixture was stirred at 0 °C for 30 min before concentrating to afford crude l-bromo-3-(piperidin-4-yl)acetone trifluoroacetate, which was used without purification in the next step. To a stirred solution of diisopropylethylamine (20 mL) in acetonitrile (800 mL) at reflux was added a solution of the crude intermediate in acetonitrile (150 mL), dropwise over 4 hours (syringe pump). Reflux was continued overnight and then the mixture was concentrated. The resulting residue was partitioned between aqueous potassium carbonate solution and 9: 1 (v/v) chloroform/methanol. The organic layer was combined with a second extract using the same solvent mixture, dried (Na2S04) and concentrated. The crude material was purified flash chromatography over silica using a 95/4.5/0.5 (v/v) chloroform/methanol/ammonium hydroxide eluant to afford l-azabicyclo[3.2.2]nonan-3- one as a brown solid (770 mg, 54percent). To a stirred and cooled (0 °C) solution of this intermediate (770 mg, 5.54 mmol) in tetrahydrofuran (10 mL), was added lithium aluminum hydride (211 mg, 5.54 mmol), portion wise. After vigorous hydrogen gas evolution ceased, the reaction mixture was allowed to warm to room temperature and then heated at reflux for 1 hour. The solution was cooled to 0 °C and quenched by the successive dropwise addition of water (0.2 mL), 10percent aqueous sodium hydroxide solution (0.2 mL) and water again (0.6 mL). The colorless precipitate was removed by filtration through Celite, which was subsequently washed with tetrahydrofuran. The combined filtrate was dried (Na2S04) and concentrated to afford the title compound as yellow solid (770 mg, 99percent).
200 g
With tetra-(n-butyl)ammonium iodide; sodium hydride In tetrahydrofuran; mineral oil at 0 - 25℃; for 16 h;
Synthesis of Intermediate A-i. 10052] To a mixture of ethyl glycolate [623-50-7] (250.00 g, 2.40 mol), NaH (105.65 g, 2.64 mol), tetrabutylammonium iodide (THAI) (88.70 g, 240.14 mmol) in anhydrous THF (2 L) was added benzyl bromide (451.80 g, 2.64 mol) dropwise at 0° C. The resulting mixture was stirred at 25° C. for 16 hours. The reaction mixture was quenched with saturated, aqueous ammonium chloride (1 L), and the aqueous layer was extracted with ethyl acetate (3x1 L). The combined organic layers were washed with brine (1 L), dried over magnesium sulfate, the solids were removed via filtration, and the solvents of the filtrate were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=6: 1) to obtain intermediate A-i (200 g).10053] ‘H NMR (CDC13 400 MHz) ö ppm 7.37-7.27 (m, 5H); 4.62 (s, 2H), 4.24-4.19 (q, J=6.8 Hz, 2H); 4.07 (s, 2H);1.29-1.25 (t, J=6.8 Hz, 3H).
With sodium hydride In tetrahydrofuran at 0 - 20℃; for 1 h;
Method I: 5-bromo-2-chloro-3-nitropyridine (100 mg, 0.42 mmol) and Ethyl glycolate (0.044 mL, 0.46 mmol) were dissolved in THF (5 mL) and cooled to 0°C. Sodium hydride (0.015 mL, 0.46 mmol) was added and the mixture was stirred for 1hr at room temperature. Reaction mixture was poured in ice water and extracted with EtOAc (2 x 10ml). The organiclayer was washed with brine (10ml), dried over sodium sulphate and concentrated. The crude product was purified by flash column using 100-200 silica gel to ethyl 2-(5-bromo-3-nitropyridin-2-yloxy)acetate (105 mg, 82 percent) 9(b). 1H NMR (300 MHz, DMSO-d6) δ = 1.27 (s, 3H), 4.25 (q, 2 H), 5.12 (s, 2H) 8.40 (d, J = 2.07 Hz, 1 H), 8.47 (d, J = 2.07 Hz, 1 H); ESMS: m/z 306.8 [M+1]
49%
Stage #1: With sodium hydride In 1,4-dioxane at 70℃; for 1 h; Stage #2: at 20 - 70℃; for 17 h;
Step 1. Sodium hydride (55percent dispersion in mineral oil, 603 mg, 13.8 mmol) was added to a solution of ethyl glycolate (1.43 g, 13.8 mmol) in 1,4-dioxane, and the reaction mixture was heated at 70° C. for 1 h, then 5-bromo-2-chloro-3-nitropyridine (Eur. Pat. Appl. EP 122109 (1984); 1.64 g, 6.91 mmol) was added, and stirring was continued at 70° C. for 1 h and at room temperature for 16 h. The reaction mixture was then neutralized with sat. aq. sodium hydrogencarbonate solution and extracted three times with dichloromethane. The organic layers were pooled, dried (Na2SO4), and evaporated. Chromatography (SiO2, hexane-ethyl acetate gradient) furnished (5-bromo-3-nitro-pyridin-2-yloxy)-acetic acid ethyl ester (1.03 g, 49percent). Light yellow liquid, MS (ISP)=305.1 (M+H)+.
44%
Stage #1: With sodium hydride In 1,4-dioxane at 20 - 30℃; for 0.75 h; Stage #2: at 0 - 80℃;
To a suspension of sodium hydride (5.31 g, 133 mmol) in 1 ,4-dioxane (250 ml), ethyl glycolate (12.56 ml, 133 mmol) was added drop wise over a period of 30 minutes ensuring that the temperature was maintained below 30°C. The resulting thick suspension was stirred at room temperature for 15 minutes. In a separate 11 round- bottomed flask was added 5-bromo-2-chloro-3-nitropyridine (21 g, 88 mmol) in 1 ,4- dioxane (150 ml) to give a brown solution. The suspension of sodium hydride and ethyl glycolate was added drop wise over a period of 30 minutes at 0°C. The resulting reaction mixture was heated to 80°C overnight. The reaction mixture was concentrated under reduced pressure and the crude residue was purified by Biotage silica chromatography (gradient 0percent to 10percent ethyl acetate in n- hexanes) to give the title compound (1 .8g, 44percent). N R (500 MHz, CDCI3): 8.48 (1 H, s), 8.42 (1 H, s), 5.07 (2H, s), 4.28-4.24 (2H, q), 1.31-1.28 (3H, t).
To a stirred mixture of the pyridine 51a (2.00 g, 1.0 eq), the alcohol 51b (1.43 mL, 1.05 eq), CuI (0.05 g, 0.02 eq) is added Cs2CO3 (10.3 g, 2.2 eq) and heated at 70° C. during4 h. The reaction mixture is cooled down to RT, poured into H2O (300 mL) and allowed to stand for 1 h until precipitation. The suspension is filtered, triturated with Et2O/Hex (1:1), dried with toluene azeotrope to give 51c (2.0 g, 70percent).
50%
With caesium carbonate; 1,8-diazabicyclo[5.4.0]undec-7-ene In toluene at 80℃; for 24 h; Inert atmosphere
2- Chloro 3-pyridine carbonitrile (1, 2.0 g, 1 equiv.), Cs2C03 (14.2 g, 3 equiv.) and ethyl glycolate (1.5 mL, 1.2 equiv.) were placed in a flask under inert atmosphere. Dry toluene and DBU (4.3 mL, 2 equiv) were added and the suspension was heated at 80 °C for 24 h with vigorous stirring. The reaction mixture was cooled to RT, and then water and EtOAc were added. The organic layer was seperated and was washed with water before being dried over anhydrous Na2S04 and concentrated in vacuo. Purification was done by column chromatography on silica gel using 10-40percent EtOAC: hexane as a mobile phase to get product 2 (1.5 g, 50percent) as a white solid. *H NMR (CDC13, 400 MHz): δ 8.51 (dd, / = 5.0, 2.0 Hz, 1H), 7.96 (dd, / = 8.0, 2.0 Hz, 1H), 7.23-7.28 (m,1H), 4.44 (q, / = 7.0 Hz, 2H), 4.01 (br, s, 2H), 1.44 (t, / = 7.0 Hz, 3H); ESI-MS: nt/z 229.05 [M+Na]+
40%
With caesium carbonate In 1-methyl-pyrrolidin-2-one at 75℃; for 20 h; Inert atmosphere
2-Chloro-3-pyridinecarbonitrile, 1 , (4.0Og, 28.9mmol), Cs2CO3 (28.2g, 86.6mmol) and ethyl glycolate (3mL, 31.7mmol) were placed in a flask under Ar(g). Dry NMP was added, and the suspension was heated at 75°C for 2Oh with vigorous stirring. The reaction mixture was cooled to rt, whereupon water (200 mL) and Et2ψ (3 x 10OmL) were added. The organic layers were combined, washed with water (3 x 15mL) before being dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 15-40percent EtOAc/Hex) gave 2 (2.41 g, 1 1 Jmmol, 40percent) as a white solid.1H NMR (400MHz, CDCI3) δH: 8.51 (dd, J=5.0, 2.0Hz, 1 H), 7.96 (dd, J=8.0, 2.0Hz, 1 H), 7.23-7.28 (m, 1 H), 4.44 (q, J=7.0Hz, 2H), 4.01 (br. s., 2H), 1.44 (t, J=7.0Hz, 3H).MS (ES+) 229 (100percent, [M+Na]+).
Stage #1: With sodium hydride In diethyl ether at 20℃; for 0.75 h; Inert atmosphere; Cooling with ice Stage #2: at 20℃; Cooling with ice
Step 1-Synthesis of ethyl 4-oxotetrahydrofuran-3-carboxylate (ge). NaH (60percent, 4.6 g, 116 mmol) was suspended in ether (200 mL) and cooled in ice-bath. To this suspension was added ethyl glycolate (10 mL, 100 mmol) dropwise under N2. The resulting white slurry was stirred at rt for 45 min. Ether was removed in vacuo to give white solid. It was suspended in DMSO (130 mL), cooled in ice-bath, and ethyl arcylate (13.7 mL, 127 mmol) was added dropwise. The resulting yellow mixture was stirred at rt overnight. The reaction solution was poured into 10percent aq. HCl (500 mL) slowly. It was extracted with ether (3.x.). The combined ether extract was washed with brine, dried over MgSO4, filtered, concentrated in vacuo to give 14 g (80percent) of (ge) as clear yellow liquid. It was carried on without further purification.
46%
Stage #1: With sodium hydride In diethyl ester at 20℃; for 1.5 h; Stage #2: at 0 - 20℃; for 3 h;
Referring to the scheme immediately above, to a suspension of sodium hydride (60 percent in oil) (42.0 g, 1.05 mol) in diethyl ether (800 mL) was added ethyl glycolate (100 g, 0.96 mol) over a period of 1 hour at room temperature. The suspension was then stirred for an additional 0.5 hour and evaporated under vacuum. To the resulting solid, dimethyl sulfoxide (200 mL) was added. It was then cooled to 0 C and a solution of ethyl acrylate (115.10 g, 1.15 mol) in dimethyl sulfoxide (100 mL) was added in portions with vigorous stirring. The suspension was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was cautiously poured into ice cold aqueous solution of sulfuric acid (5 percent, 300 mL), extracted with ether (3 x 100 mL), dried over MgSO4, evaporated and chromatographed on silica gel (hexane/ethyl acetate, 10:1) to afford compound 3 (70.0 g, 46 percent). 1H NMR (400 MHz, CDCl3) δ 4.55-4.40 (m, 2H), 4.30-4.20 (m, 2H), 4.10-3.95 (m, 2H), 3.50 (t, 1H), 1.15 (t, 3H)
38%
Stage #1: With sodium hydride In tetrahydrofuran at 0 - 20℃; for 0.75 h; Inert atmosphere Stage #2: at 0 - 20℃; for 12 h; Inert atmosphere
To a 0 oC solution of ethyl 2-hydroxyacetate 1 (5 mL, 50 mmol) in THF (100 mL) was added NaH (60percent, 2.3 g, 58 mmol) under a nitrogen atmosphere. The resulting solution was stirred at the room temperature for 45 minutes. The solvents were removed under reduced pressure. The resulting residue was suspended in dimethyl sulfoxide (65 mL) and cooled to 0°C. Ethyl acrylate (6.8 mL, 63 mmol) was then added dropwisely. The resulting solution was stirred at the room temperature for 12 hours. Then the resulting solution was slowly poured into aqueous hydrochloric acid (10percent>, 250 mL). It was extracted with diethyl ether (150 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give intermediate 2 (3 g, 38percent)). which was used in the next step without further purification. LRMS (M + H+) m/z: calcd 159.15; found 159.21.
With toluene-4-sulfonic acid; In toluene; at 25℃; for 1h;
To a solution of ethyl glycolate (10 g, 0.0961 mol) in toluene (100 mL) was added 3,4- dihydro-2H-pyran ( 8 g, 0.096 1 mol) followed by catalytic amount of pTSA (30 mg) and stirred at 25 C for 1 h. After completion of the reaction, the reaction mixture was washed with water and brine solution. The organic layer was dried over anhydrous Na2504, filtered and concentrated under reduced pressure to get 18 g (99 %) ethyl 2-((tetrahydro-2H-pyran-2- yl)oxy)acetate, 2, as colorless liquid
94.7%
toluene-4-sulfonic acid; In toluene; at 20℃;Industrial scale;Product distribution / selectivity;
Example 1.2Ethyl(tetrahydropyran-2-yloxy)-acetate (B) 100.00 kg (960.52 mol) ethyl glycolate (A) were dissolved in 180.0 L toluene and 365.22 g (1.92 mol) 4-toluenesulphonic acid monohydrate were added. At 20 C. a solution of 80.80 kg (960.52 mol) 3,4-dihydro-2H-pyran was added dropwise to the reaction mixture obtained and then the mixture was washed with 20.0 L toluene. The reaction mixture was stirred for 1 hour at 20 C. and after the reaction was complete it was combined with 100.0 L water and 6.53 kg (96.05 mol) ammonia solution (25%). After phase separation the organic phase was washed with 100.0 L water and then the solvent was distilled off completely in vacuo.Yield: 188.4 kg (94.7% of theory)
91.5%
With toluene-4-sulfonic acid; at 20℃;
To a stirred solution of ethyl glycolate (35.3 g, 0.339 mol) containing a few crystals of p-toluene sulfonic acid, 3,4-dihydropyran (30.0 g, 0.357 mol) was added dropwise (15 g over one hour followed by 15 g over 30 min). After stirring overnight at room temperature, the mixture was diluted with diethyl ether (80 mL) and washed with a NaHCO3 solution (from 30 mL sat. NaHCO3 and 10 mL water). The organic layer was separated and dried (Na2504) followed by evaporation of the ether. The residue was distilled under high vacuum to give 58.4 g (91.5%) of 28 as a clear liquid. 1H NMR (CDCl3, 400 MHz)delta: 1.29 (t, 3H, J=7.1 Hz, CH3), 1.53-1.95 (m, 6H, 3,4,5-THP-CH2's), 3.50-3.55 (m, 1H, 6-THP-CH2), 3.83-3.89 (m, 1H, 6-THP-CH2), 4.19 (s, 2H, OCH2CO2R), 4.20 (t, 2H, J=7.1 Hz, CH2Me), 4.75 (m, 1H, THP-CH). 13C NMR (CDCl3, 100 MHz) delta: 14.1, 18.7, 25.2, 30.0, 60.7, 61.9, 63.8, 170.4.
91.5%
With toluene-4-sulfonic acid; at 20℃;
(1) Preparation of tetrahydropyran-2-yloxy-acetic acid ethyl ester (Formula 28, Scheme 4)[0378] To a stirred solution of ethyl glycolate (35.3g, 0.339mol) containing a few crystals of />toluene sulfonic acid, 3,4-dihydropyran (30.Og, 0.357mol) was added1 1 <n="113"/>dropwise (15g over one hour followed by 15g over 30min). After stirring overnight at room temperature, the mixture was diluted with diethyl ether (8OmL) and washed with a NaHCO3 solution (from 3OmL sat. NaHCO3 and 1OmL water). The organic layer was separated and dried (Na2SO4) followed by evaporation of the ether. The residue was distilled under high vacuum to give 58.4g (91.5%) of 28 as a clear liquid. 1H NMR (CDCL3, 400MHz)delta: 1.29 (t, 3H, J = 7.1 Hz, CH3), 1.53 -1.95 (m, 6H, 3,4,5-THP-CH2's), 3.50-3.55 (m, IH, 6-THP-CH2), 3.83 - 3.89 (m, IH, 6-THP-CH2), 4.19 (s, 2H, OCH2CO2R), 4.20 (t, 2H, J = 7.1 Hz, CH2Me), 4.75 (m, IH, THP-CH). 13C NMR (CDCl3, 100MHz) delta: 14.1, 18.7, 25.2, 30.0, 60.7, 61.9, 63.8, 170.4.
81%
With pyridinium p-toluenesulfonate; In dichloromethane;
Step 1) ethyl 2-(tetrahydro-2H-pyran-2-yloxy)acetate To a mixture of ethyl 2-hydroxyacetate (2 g, 20 mmol, Aldrich) and 3,4-dihydro-2H-pyran (3.2 g, 40 mmol, Alfa) in 40 mL of CH2Cl2 was added PPTS (500 mg, 2 mmol) slowly at rt. The mixture was stirred at rt for 4 hours, and then the mixture was washed with brine (20 mL*2), the combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE: EtOAc=20:1) to give colorless oil (3.01 g, 81%). 1H NMR (400 MHz, CDCl3): delta 1.22-1.38 (m, 4H), 1.55-1.63 (m, 3H), 1.69-1.88 (m, 3H), 3.50-3.53 (m, 1H), 3.82-3.88 (m, 1H), 4.18-4.23 (m, 4H), 4.73-4.74 (t, J=4 Hz, 1H).
81%
With pyridinium p-toluenesulfonate; In dichloromethane; at 20℃; for 4h;
To a mixture of ethyl 2-hydroxyacetate (2 g, 20 mmol, Aldrich) and 3,4-dihydro-2H-pyran (3.2 g, 40 mmol, Alfa) in 40 mL of CH2Cl2 was added PPTS (500 mg, 2 mmol) slowly at rt. The mixture was stirred at rt for 4 hours, and then the mixture was washed with brine (20 mLx2), the combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residure was purified by a silica gel column chromatography (PE: EtOAc =20:1) to give colorless oil (3.01 g, 81 %). 1H NMR (400MHz, CDCl3): delta 1.22 - 1.38 (m, 4H), 1.55 - 1.63 (m, 3H), 1.69 - 1.88 (m, 3H), 3.50 - 3.53 (m, 1H), 3.82 - 3.88 (m, 1H), 4.18 - 4.23 (m, 4H), 4.73 - 4.74 (t, J=4Hz, 1H).
81%
With pyridinium p-toluenesulfonate; In dichloromethane; at 20℃; for 4h;Inert atmosphere;
To a mixture of ethyl 2 -hydroxy acetate (2 g, 20 mmol, TCI) and 3,4- dihydro-2H-pyran (3.2 g, 40 mmol, Alfa) in 40 mL Of CH2Cl2 was added PPTS (500 mg, 2 mmol, Aldrich) in portions at rt. The mixture was stirred at rt for 4 hours. The reaction mixture was then washed with brine, and the organic layer was separated and the combined organic phases were dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel column chromatography (20: 1 (v/v) petroleum ether / EtOAc) to give the desired compound as colorless oil (3.01 g, 81 % ).1H NMR (400MHz, CDCl3): delta 1.25 - 1.32 (m, 3H), 1.55 - 1.63 (m, 3H), 1.69 - 1.88 (m, 3H), 3.50 - 3.53 (m, IH), 3.82 - 3.88 (m, IH), 4.18 - 4.23 (m, 4H), 4.73 (t, J=3.2Hz, IH).
58%
With toluene-4-sulfonic acid; In toluene; at 20℃;
Step 1 Preparation of ethyl 2-(tetrahydro-2H-pyran-2-yloxy)acetate A mixture of 3,4-dihydro-2H-pyran (20.4 g, 242.3 mmol), ethyl 2-hydroxyacetate (24.0 g, 230.8 mmol) and TsOH (0.794 g, 4.6 mmol) in toluene (150 mL) was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (2% EtOAc in petroleum ether) to afford ethyl 2-(tetrahydro-2H-pyran-2-yloxy)acetate (25.2 g, 58%) as a colorless oil.
With toluene-4-sulfonic acid;
Preparation B: 7-Oxo-6,7-dihydro-lH-pyrimi do [5,4-6] [l,4]oxazine-2-carbaldehyde; (a) 2- [(E)-2-Phenylethenyl] -5 -(tetrahydro-2H-pyran-2-yloxy)-4( 1 H)-pyrimidinone; NaH (0.38g, 9.5mmol, 60% paraffin oil) was added slowly to a THF (20 mL) solution of ethyl (tetrahydro-2H-pyran-2-yloxy)acetate (prepared by treating ethyl hydroxyacetate with 3,4-dihydro-2H-pyran and p-toluenesulphonic acid) ( 1.Og, 5.3mmol) and dry ethyl formate (3.9g, 53mmol). The reaction mixture was stirred at room temperature for 15 min. and then heated at 65 0C for 45 min. The reaction mixture was concentrated to dryness to give a pale yellow solid. The solid was added to a MeOeta/EtOeta (20mL/20mL) solution of (2E)-3-phenyl-2-propenimidamide (for a synthesis see Preparation A(b)) (0.78g, 5.3mmol), the subsequent mixture was heated at 80 0C for 4h. The resulting material was poured into DCM (1OmL) containing silica gel (3g) and evaporated. Purification by column chromatography (silica gel) using a MeOeta/DCM gradient (0-10%) provided the desired product as a pale yellow solid (Ig , 63%). LCMS: m/z 299 (MH+).
Step 3.76g of 2-glycolic acid and 46g of ethanol were added dropwise 1.38g of concentrated sulfuric acid under the protection of nitrogen at a temperature controlled below 60C, and the reaction was carried out at 60C for 3h. The raw material was less than 3% detected by GC and dropped into the reaction solution. Add 30% lye to pH value of about 7, extract the organic phase twice with DCM to obtain the organic phase, wash the organic phase with saturated brine once, then dry, concentrate under reduced pressure to distill off without distillation to obtain ethyl 2-hydroxyacetate, yield 80%, purity 98%.
104.43 g
In toluene; at 70℃;
Into a 500 mL four-necked flask, 76.82 g of 99% glycolic acid (1 mol), 67.49 g of 99% ethanol, and 38.0 g of toluene were added, and the mixture was heated to 70 C to react and dehydrate.After the reaction, the unreacted alcohol and toluene are distilled off under reduced pressure.The remaining material was ethyl hydroxyacetate and weighed 104.43 g.
With triethylamine; In tetrahydrofuran; at 0 - 10℃; for 1h;
In the reactor the magnetic stirring, 0 C lower, will 7.9g acetyl chloride (0.1mol) dissolved in 30 ml of tetrahydrofuran, add 10.6g (1.05 eq) triethylamine, then in the 0 C slowly dripping 10.4g hydroxy acetate (0.1mol), completion of the dropping, to 10 C, stirring 1h, decompression boil off some solvent, by adding a proper amount of water, tetrahydrofuran extraction three times, the organic phase dried, vacuum evaporating the organic solvent to obtain 2-acetoxy-ethyl ester (14.6g g, yield 100%).
With triethylamine; In diethyl ether; at 0℃; for 2h;
To a stirred solution of <strong>[623-50-7]ethyl glycolate</strong> (5.0 g, 48.0 mmol) and tosyl chloride (9.15 g, 48.0 mmol) in anhydrous Et2O (40 mL) was added NEt3 (96.0 mmol, 13.4 mL) dropwise at 0 C. After the reaction mixture was stirred at 0 C for 2 h, water was added and the phase separated. The aqueous phase was extracted with Et2O. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (5:1 hexanes/EtOAc) to afford 13 (9.33 g, 75%) as a white solid, mp 42-43 C. 1H NMR (CDCl3): delta 7.84 (d, J = 8.0 Hz, 2H, ArH), 7.36 (d, J = 8.0 Hz, 2H, ArH), 4.58 (s, 2H, OCH2CO), 4.19 (q, J = 7.0 Hz, 2H, OCH2CH3), 2.46 (s, 3H, ArCH3), 1.24 (t, J = 7.0 Hz, 3H, OCH2CH3).
70 - 73%
With triethylamine; In diethyl ether; at 0℃; for 2h;
A solution of <strong>[623-50-7]ethyl glycolate</strong> (500 mg, 4.8 mmol) and tosyl chloride (915 mg, 4.8 mmol) in anhydrous diethyl ether (2 ml) at 0 0C was treated dropwise with triethylamine (1.34 ml, 9.6 mmol). The temperature was maintained at 0 0C with stirring for a further 2 h. After this time, water was added and the phases separated. The aqueous phase was extracted with fresh diethyl ether. The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo. The crude product was purified by column chromatography over silica gel (Rf=0.29, 25% ethyl acetate in hexane) affording the tosylate 2 as a colorless oil which solidified on standing as a white solid (868 mg, 70%). [This procedure was repeated on 2 x scale (1.8 g, 73%)]. deltaH (400 MHz, CDCl3) 1.22-1.27 (3H, m, CH3), 2.46 (3H, s, ArCH3), 4.16-4.22 (2H, m, CH2CH3), 4.58-4.59 (2H, m, OCH2), 7.36 (2H, d, J=8.2 Hz, ArH), 7.84 (2H, d, J=8.2 Hz, ArH); deltac (100.6 MHz, CDCl3) 14.2, 21.9, 62.1, 64.9, 128.3,130.1, 132.9, 145.5, 166.2; MS (ES+) 276.0 (100%, [M+H20]+) (ion not detected in ES').
9.33 g
With triethylamine; In diethyl ether; at 0℃; for 2h;
<strong>[623-50-7]Ethyl 2-hydroxyacetate</strong> (5g, 48.0mmol) and p-toluenesulfonyl chloride (9.15g, 48 . 0mmol) were added to anhydrous diethyl ether (40 ml). At 0 C, add dropwise triethylamine (13.4 ml, 96 . 0mmol). Addition is finished. At 0 C, stir the reaction for 2h. The completion of the reaction, water is added to the system (40 ml × 2) washing, saturated salt water (40 ml) washing, separating the organic layer, drying with anhydrous sodium sulfate, filtered, concentrated, the residue by column chromatography (cyclohexane/ethyl acetate=5:1), to obtain white solid 9.33g.
A suspension of sodium hydride (11.2 g, 60% dispersion in mineral oil, 280 mmol) in1 ,2-dimethoxyethane (250 mL) was cooled to 000, treated dropwise with <strong>[623-50-7]ethyl glycolate</strong>(25.5 mL, 269 mmol) and stirred at 23 00 for 30 mi Ethyl-2-chloronicotinate (20.0 g, 108 mmol) in 1,2-dimethoxyethane (40 mL) was added dropwise over 10 mm and the mixture was stirred at 70 00 for 15 hours. The solvent was evaporated, the residue dissolved in water (500 mL) and washed with toluene. The aqueous layer was acidifiedwith acetic acid (19 mL) to pH Sand extracted five times with CH2CI2 (5 x 100 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and the solvent evaporated. Column chromatography (Si02 EtOAc/Heptane, 20:80 ->50:50) of the crude gave ethyl 3-hydroxyfuro[2,3-b]pyridine-2-carboxylate (21.1 g, 94%) as a yellow solid.1H NMR (400 MHz, Chloroform-o) 6 = 8.52 (dd, J= 4.9, 1.7 Hz, 1H, H-Ar), 8.12 (dd, J7.8, 1.7 Hz, 1H, H-Ar), 7.31 (dd, J= 7.8, 4.8 Hz, 1H, H-Ar), 4.47 (q, J= 7.1 Hz, 2H, 0-CH2CH3), 4.13 (s, 1H, OH), 1.44 (t, J= 7.1 Hz, 3H, 0-CH2CH3) ppm.MS (ESI+, H20/MeCN) mlz(%): 208.0 (100, [M + H]j.
94%
A suspension of sodium hydride (1 1.2 g, 60% dispersion in mineral oil, 280 mmol) in 1,2-dimethoxyethane (250 mL) was cooled to 0C, treated dropwise with <strong>[623-50-7]ethyl glycolate</strong> (25.5 mL, 269 mmol) and stirred at 23 C for 30 min. Ethyl-2-chloronicotinate (20.0 g, 108 mmol) in 1,2-dimethoxyethane (40 mL) was added dropwise over 10 min and the mixture was stirred at 70 C for 15 hours. The solvent was evaporated, the residue dissolved in water (500 mL) and washed with toluene. The aqueous layer was acidified with acetic acid (19 mL) to pH 5 and extracted five times with CH2CI2 (5 x 100 mL). The combined organic layers were dried over anhydrous MgS04, filtered and the solvent evaporated. Column chromatography (S1O2; EtOAc/Heptane, 20:80 -> 50:50) of the crude gave ethyl 3-hydroxyfuro[2,3-b]pyridine-2-carboxylate (21.1 g, 94%) as a yellow solid. H NMR (400 MHz, Chloroform- delta = 8.52 (dd, J= 4.9, 1.7 Hz, 1H, H-Ar), 8.12 (dd, J = 7.8, 1.7 Hz, 1H, H-Ar), 7.31 (dd, J= 7.8, 4.8 Hz, 1H, H-Ar), 4.47 (q, J= 7.1Hz, 2H, O- CH2CH3), 4.13 (s, 1H, OH), 1.44 (t, J= 7.1Hz, 3H, O-CH2CH3) ppm. MS (ESI+, hbO/MeCN) m/z {%): 208.0 (100, [M +
41%
With sodium hydroxide; In 1,2-dimethoxyethane; water;
EXAMPLE 10(i) N-(1-azabicyclo[2.2.1]hept-3-yl)-furo[2,3-b]pyridine-2-carboxamide: Ethyl glycolate (35.5 mL, 375 mmol) is slowly added (over 20 minutes) to a slurry of NaOH (15.8 g, 394 mmol) in 1,2-dimethoxyethane (400 mL) under N2 with the flask being in an ice bath. The mixture is allowed to warm to rt, is stirred for 30 min, and ethyl 2-chloronicotinate (27.84 g, 150 mmol) in 1,2-dimethoxyethane (50 mL) is added over 10 minutes. The reaction is warmed to 65 C. for 15 h in an oil bath. The mixture is concentrated to dryness, the residue is dissolved in H2O (500 mL), washed with hexane (500 mL), acidified to pH 3 with 5% HCl, and extracted with CHCl3 (4*400 mL). The combined organic layer is dried over MgSO4, filtered, and concentrated to a yellow solid. The solid is suspended in ether (200 mL) and heated on a steam bath until concentrated to a volume of 40 mL. The material is allowed to crystallize overnight, then filtered to afford ethyl 3-hydroxyfuro[2,3-b]pyridine-2-carboxylate (C40) as a pale orange solid (41% yield). Additional material is obtained by concentrating the filtrate.
41%
With sodium hydroxide; In 1,2-dimethoxyethane; water;
EXAMPLE 8 N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]furo[2,3-b]pyridine-2-carboxamide Hydrochloride Preparation of the Acid: Ethyl glycolate (35.5 mL, 375 mmol) is slowly added (over 20 min) to a slurry of NaOH (15.8 g, 394 mmol) in 1,2-dimethoxyethane (400 mL) in a dry flask under N2 with the flask being in an ice bath. The mixture is allowed to warm to rt, is stirred for 30 min, and ethyl 2-chloronicotinate (27.84 g, 150 mmol) in 1,2-dimethoxyethane (50 mL) is added over 10 min. The reaction is warmed to 65 C. for 15 h in an oil bath. The mixture is concentrated to dryness, the residue is dissolved in water (500 mL), washed with hexane (500 mL), acidified to pH 3 with 5% HCl, and extracted with CHCl3 (4*400 mL). The combined organic layer is dried over MgSO4, filtered, and concentrated to a yellow solid. The solid is suspended in ether (200 mL) and heated on a steam bath until concentrated to a volume of 40 mL. The material is allowed to crystallize overnight, then filtered to afford ethyl 3-hydroxyfuro[2,3-b]pyridine-2-carboxylate as a pale orange solid (41% yield). Additional material is obtained by concentrating the filtrate.
With 1H-imidazole; In dichloromethane; at 0℃; for 1h;
A solution of <strong>[623-50-7]ethyl 2-hydroxyacetate</strong> (16) (3.12g, 30mmol) and imidazole (2.45 g, 36mmol) in DCM (100ml) was added tert-butylchlorodimethylsilane (5.43g, 36mmol) at 0C and the reaction mixture was stirred at 0C for 1 hour. The reaction mixture was washed with saturated sodium bicarbonate (50ml) and brine (50ml). The DCM solution was dried over sodium sulfate and concentrated. The residual (17)(6.68g, 100% yield) was used in the next step without further purification.
93%
With 1H-imidazole; In dichloromethane; at 0 - 20℃; for 8h;
The <strong>[623-50-7]ethyl glycolate</strong> (100g, 961mmol) and a hydrogen - imidazole (130g, 1.9mol) was dissolved in dichloromethane (1L)Neck round bottom flask was placed, was added t-butyldimethylsilyl-chloro (158g, 1mol) at 0 , the mixture at room temperatureUnder stirring for 8 hours, washed with water (1L * 3), dried over sodium sulfate and concentrated to give the title compound as a yellow oil (195g,93%).
85.8%
With 1H-imidazole; In dichloromethane; at 0 - 20℃; for 8h;Inert atmosphere;
<strong>[623-50-7]ethyl glycolate</strong> (10g, 96.1mmol) and a imidazole (13g, 0.19mol) was dissolved in dichloromethane (100 mL)placed in three round bottom flask, was added at 0C tert-butyldimethylsilyl chloride (15.8g, 0.1mol), the mixture was stirred for 8hours at room temperature, washed with water (100mL * 3), dried over sodium sulfate and concentrated to give the titlecompound as a yellow oil (18g, 85.8%).
65%
With 1H-imidazole; at 20℃; for 60h;
[00465] Step A: Ethyl 2-(tert-butyldimethylsilyloxy)acetate: A mixture of ethyl 2- hydroxyacetate (3.00 g, 28.8 mmol), TBDMS-Cl (5.21 g, 34.6 mmol) and imidazole (2.55 g, 37.5 mmol) was stirred at ambient temperature for 60 hours. The mixture was concentrated and the residue was purified by Si02 chromatography eluting with 10% EtOAc-hexanes to provide the title compound as a colorless oil (4.12 g, 65%). 1H NMR (CDC13) delta 4.12 (s, 2H), 4.09 (q, 2H), 1.17 (t, 3H), 0.18 (s, 9H), 0.00 (s, 6H).
65%
With 1H-imidazole; at 20℃; for 60h;
1006491 Step A: Ethyl 2-(tert-butyldimethylsilyloxy)acetate: A mixture of <strong>[623-50-7]ethyl 2-hydroxyacetate</strong> (3.00 g, 28.8 mmol), TBDMS-Cl (5.21 g, 34.6 mmol) and imidazole (2.55 g,37.5 mmol) was stirred at ambient temperature for 60 hours. The mixture was concentratedand the residue was purified by Si02 chromatography eluting with 10% EtOAc-hexanes toprovide the title compound as a colorless oil (4.12 g, 65%). 1 NMR (CDC13) oe 4.12 (s, 2H),4.09 (q, 2H), 1.17 (t, 3H), 0.18 (s, 9H), 0.00 (s, 611).
65%
With 1H-imidazole; at 20℃; for 60h;
Interm iate 182 (5-amino- 1 -phenyl- 1 H-pyrazol-3-yl)methanol [00581] Step A: Ethyl 2-(tert-butyldimethylsilyloxy)acetate: A mixture of ethyl 2- hydroxyacetate (3.00 g, 28.8 mmol), TBDMS-C1 (5.21 g, 34.6 mmol) and imidazole (2.55 g, 37.5 mmol) was stirred at ambient temperature for 60 hours. The mixture was concentrated and the residue was purified by Si02 chromatography eluting with 10% EtOAc-hexanes to provide the title compound as a colorless oil (4.12 g, 65%). 1H NMR (CDC13) delta 4.12 (s, 2H), 4.09 (q, 2H), 1.17 (t, 3H), 0.18 (s, 9H), 0.00 (s, 6H).
65%
With 1H-imidazole; at 20℃; for 60h;
A mixture of ethyl 2- hydroxyacetate (3.00 g, 28.8 mmol), TBDMS-C1 (5.21 g, 34.6 mmol) and imidazole (2.55 g, 37.5 mmol) was stirred at ambient temperature for 60 hours. The mixture was concentrated and the residue was purified by Si02 chromatography eluting with 10% EtOAc-hexanes to provide the title compound as a colorless oil (4.12 g, 65%). 1H NMR (CDC13) delta 4.12 (s, 2H), 4.09 (q, 2H), 1.17 (t, 3H), 0.18 (s, 9H), 0.00 (s, 6H).
65%
With 1H-imidazole; at 20℃; for 60h;
1007781 Step A: Ethyl 2-(tert-butyldimethylsilyloxy)acetate: A mixture of <strong>[623-50-7]ethyl 2-hydroxyacetate</strong> (3.00 g, 28.8 mmol), TBDMS-Cl (5.21 g, 34.6 mmol) and imidazole (2.55 g,37.5 mmol) was stirred at ambient temperature for 60 hours. The mixture was concentratedand the residue was purified by Si02 chromatography eluting with 10% EtOAc-hexanes toprovide the title compound as a colorless oil (4.12 g, 65%). ?H NMR (CDC13) oe 4.12 (s, 2H),4.09 (q, 2H), 1.17 (t, 3H), 0.18 (s, 9H), 0.00 (s, 6H).
65%
With 1H-imidazole; at 20℃; for 60h;
A mixture of ethyl 2- hydroxyacetate (3.00 g, 28.8 mmol), TBDMS-C1 (5.21 g, 34.6 mmol) and imidazole (2.55 g, 37.5 mmol) was stirred at ambient temperature for 60 hours. The mixture was concentrated and the residue was purified by Si02 chromatography eluting with 10% EtOAc-hexanes to provide the title compound as a colorless oil (4.12 g, 65%). 1H NMR (CDC13) delta 4.12 (s, 2H), 4.09 (q, 2H), 1.17 (t, 3H), 0.18 (s, 9H), 0.00 (s, 6H).
30.5 g
With 1H-imidazole; In dichloromethane; at 0℃; for 2h;
To a stirred solution of <strong>[623-50-7]ethyl 2-hydroxyacetate</strong> (25.0 g, 240 mmol) in dichloromethane (100 mL) was added imidazole (17.98 g, 264 mmol) at 0 C. tert-Butyldimethylsilyl chloride (39.8 g, 264 mmol) was added to the mixture at 0 C and stirred for 2 h at the same temperature. The reaction mixture was diluted with water and extracted twice with ethyl acetate for 20 h. The combined organic layers were washed with aqueous sodium bicarbonate solution followed by brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 30.5 g of the titled product. 1H NMR (400 MHz, DMSO-d6) delta 0.06 (s, 6H), 0.87 (s, 9H), 1.19 (t, J = 7.2 Hz, 3H), 4.11 (q, J = 7.2 Hz, 2H), 4.23 (s, 2H).
Intermediate 50b: Ethyl 2-(prop-2-yn-1-yloxy)acetate <strong>[623-50-7]Ethyl 2-hydroxyacetate</strong> (9.3 mL, 96.1 mmol) was added to a 200-mL round-bottomed flask in THF (100 mL). To the solution was added 60% sodium hydride 60% in mineral oil (4.61 g, 115 mmol) slowly over 5 mins. The suspension was stirred at RT for 1 hour before 3-bromoprop-1-yne (10.7 mL, 96.1 mmol) was added. The reaction mixture was stirred at RT over the weekend. The mixture was concentrated under reduced pressure. To the residue was added diethyl ether (30 mL) and water (50 mL). After partition, the organic phase was washed with water (2*50 mL). The organic layer was dried (Na2SO4) and concentrated to give the crude product. The crude product was added to a silica gel column (80 g) and was eluted with EtOAc/hexane (0-25%). Collected fractions were concentrated to give the title compound (7.0 g, 51%). 1H NMR (DMSO-d6) 1.21 (3H, t), 3.49 (1H, s), 4.08-4.18 (4H, m), 4.23 (2H, d).
Example 34[0196] Preparation of allyloxy-acetic acid ethyl ester. EMI61.2[0197] A round-bottom flask was charged with NaH (1.76 g, 44 mmol, 60% dispersion in mineral oil) and flushed with argon. Hexane (10 ml x 2) was added and decanted. DMF (10 ml) was added into the flask and the resulting solution was cooled to 0 C. Ethyl glycolate (4.16 g, 40.0 mmol) was added over 10 min. The solution was allowed to gradually warm to 25 C and was maintained at that temperature for 2 h. The solution was cooled to 0 C and allyl bromide (5. 32 g, 44.0 mmol) was added over 10 min. The solution was allowed to gradually warm to 25 C and stirred at that temperature for 2h. Aqueous solutionNH4Cl(10 ml) was added to the reaction and the mixture was diluted with EtOAc (60 ml). The organic layer was separated and washed withH20 (20 ml x 2), dried overNa2S04 and concentratedin vacuo. The crude product was purified by distillation under reduced pressure. [0198] Yield = 4.29 g, 75%; colorless liquid; bp = 38-39 C, 2 mmHg. IR (neat): 1985,1756, 1724,1203, 1130 cm-l. IH NMR (CDC13, 400 MHz): 6 5.90-5. 70 (m, 1H), 5.25-5. 00 (m, 2H), 4.10-4. 20 (m, 2H), 3.92-4. 05 (m, 4H), 1.21 (t, J = 7Hz, 3H). 13C NMR (CDCl3, 100 MHz): 8 170.09 (C), 133.62 (CH), 117.78 (CH2), 72.10 (CH2), 66.99 (CH2), 60.53 (CH2), 13. 94 (CH3). MS (m/z, relative intensity): 144 (M+, 14), 115 (22), 103 (100), 83 (85); HRMS: calculated for C7HI203 (M+): 144.0786 ; found 144.0783.
With triethylamine; In ethyl acetate; at 0 - 20℃; for 1h;
112.6 g (1112.8 mmol) of triethylamine and 76.4 g (734.1 mmol) of <strong>[623-50-7]ethyl 2-hydroxyacetate</strong> (glycolic acid ethyl ester) are dissolved in 600 ml of ethyl acetate. 102.9 g (898.1 mmol) of methanesulfonyl chloride are added drop-wise with stirring to the cold solution (bath temperature: 0 C.). The reaction mixture is stirred at room temperature for 1 hour and then filtered. The solid is rinsed once with 100 ml and twice with 200 ml of ethyl acetate. The combined filtrates are washed with 200 ml of water, twice with 100 ml of 10% hydrochloric acid, 100 ml of saturated sodium hydrogencarbonate solution and 100 ml of saturated sodium chloride solution. The solvents are removed with the aid of a rotary evaporator. The residue is dissolved in 100 ml of dichloromethane and dried using MgSO4. The solution is filtered, and dichloromethane is evaporated. The crude product obtained is subjected to fractional distillation in vacuo at 0.008 mbar. 127.6 g of ethyl 2-mesylacetate are obtained (boiling point: 103 C./0.03 mbar). The yield of ethyl 2-mesylacetate is 95%, based on <strong>[623-50-7]ethyl 2-hydroxyacetate</strong>. The product, ethyl 2-mesylacetate, is characterised by means of the 1H-NMR spectrum.1H-NMR (solvent: CDCl3; reference substance: TMS), delta, ppm: 1.28 t (CH3); 3JH,H=7.2 Hz, 3.18 s (SO2CH3), 4.24 q (CH2); 3JH,H=7.2 Hz, 4.73 s (CH2).
With tetra-(n-butyl)ammonium iodide; sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 20℃; for 12.5h;Inert atmosphere;
Synthesis of compound 24To the solution of hydroxy-acetic acid ethyl ester 23 (99.6g, 0.96mol) in TH F (1 .5L) under nitrogen atmosphere, NaH (42g, I .Omol: 60% in mineral oil) was added at 0C in portions. The mixture was stirred at 0C for 30 min and tetrabutylammonium iodide (35.3g, O.I Omol) and benzyl bromide (163.6g, 0.96mol) were added. The mixture was allowed to warm up to r.t and was stirred in this temperature for 12h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over MgSC , solvent was evaporated under high vacuum and raw product was destilled (121 C /4mBar) to give compound 24 (135.5 g, yield: 73%). 1H-NMR (CDC ): delta= 7.41 - 7.22 (m, 5H), 4.65 (s, 2H), 4.27 (q, 2H), 4.1 1 (s, 2H), 1.25 (t, 3H).
73%
To the solution of hydroxy-acetic acid ethyl ester 22 (99.6 g, 0.96 mol) in THF (1 .5L) under nitrogen atmosphere, NaH (42.0 g, 1.0 mol: 60% in mineral oil) was added at 0C in portions. The mixture was stirred at 0C for 30 min and tetrabutylammonium iodide (35.3 g, 0.10 mol) and benzyl bromide (163.6 g, 0.96 mol) were added. The mix- ture was allowed to warm up to room temperature and was stirred in this temperature for 12h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over MgSC , solventwas evaporated under high vacuum and raw product was destilled (121 C /4 mBar) to give compound 23 (135.5 g, yield: 73%). H-NMR (CDCIs): delta= 7.41 - 7.22 (m, 5H), 4.65 (s, 2H), 4.27 (q, 2H), 4.1 1 (s, 2H), 1 .25 (t, 3H).
57%
To a stirred and cooled (0 C) solution of ethyl 2-hydroxyacetate (20.0 g, 19.0 mmol) in tetrahydrofuran (250 mL) was added tetrabutylammonium iodide (7.01 g, 19.0 mmol) and sodium hydride (60% in mineral oil, 7.60 g, 19.0 mmol). The mixture was stirred at 0 C for 30 minutes before adding benzyl bromide (32.3 g, 19.0 mmol). The reaction was stirred overnight and allowed to warm to room temperature. The mixture was then cooled (0 C), quenched with aqueous ammonium chloride (100 mL) and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (Na2S04) and concentrated. The residue was purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford ethyl 2- (benzyloxy)acetate as a yellow oil (14.7 g, 57%). To a stirred and cooled (0 C) solution of this product (13.6 g, 70.0 mmol) in tetrahydrofuran (150 mL) was added dimethyl methylphosphonate (11.3 g, 91.1 mmol) followed by a 2.0 M solution of lithium diisopropylamide in tetrahydrofuran/heptane/ethylbenzene (74.0 mL, 148 mmol). The reaction was stirred at 0 C for 3 hours before quenching with enough 5.0 M aqueous hydrochloric acid to bring the pH to ~4. The resulting mixture was then extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na2S04) and concentrated. The residue was purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford dimethyl (3-(benzyloxy)-2-oxopropyl)phosphonate as a light yellow oil (10.1 g, 54%). To a stirred and cooled (0 C) solution of this intermediate (9.89 g, 36.4 mmol) in tetrahydrofuran (100 mL) was added sodium hydride (60% in mineral oil; 1.60 g, 40.0 mmol). The mixture was stirred at 0 C for 30 minutes before adding, dropwise, a solution of tert-butyl 4-oxo-piperidine-l-carboxylate (5.79 g, 29.1 mmol) in tetrahydrofuran (50 mL). The resulting mixture was stirred at 0 C for 2 hours, then quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na2S04), and concentrated. The residue was purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford tert-butyl 4-(3-(benzyloxy)-2- oxopropylidene)piperidine-l-carboxylate as a light yellow oil (6.50 g, 52%). This material (6.50 g, 18.8 mmol), 10% Pd/C (1.00 g) and ethyl acetate (50 mL) were placed in a Parr bottle and hydrogenated for 5 hours at room temperature. The mixture was filtered through Celite and concentrated to afford tert-butyl 4-(3-hydroxy-2- oxopropyl)piperidine-l-carboxylate as a yellow oil (4.80 g, 99%). To a stirred solution of this product (4.80 g, 18.7 mmol) in methylene chloride (8 mL) was added carbon tetrabromide (12.4 g, 37.4 mmol) and triphenylphosphine (9.80 g, 37.4 mmol). After 3 hours, the reaction was concentrated and the residue purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford tert-butyl 4-(3-bromo-2- oxopropyl)piperidine-l-carboxylate as a white solid (3.30 g, 56%). To a stirred and cooled (0 C) solution of this product (3.30 g, 10.3 mmol) in methylene chloride (50 mL) was added trifluoroacetic acid (12.0 mL, 145 mmol). The mixture was stirred at 0 C for 30 min before concentrating to afford crude l-bromo-3-(piperidin-4-yl)acetone trifluoroacetate, which was used without purification in the next step. To a stirred solution of diisopropylethylamine (20 mL) in acetonitrile (800 mL) at reflux was added a solution of the crude intermediate in acetonitrile (150 mL), dropwise over 4 hours (syringe pump). Reflux was continued overnight and then the mixture was concentrated. The resulting residue was partitioned between aqueous potassium carbonate solution and 9: 1 (v/v) chloroform/methanol. The organic layer was combined with a second extract using the same solvent mixture, dried (Na2S04) and concentrated. The crude material was purified flash chromatography over silica using a 95/4.5/0.5 (v/v) chloroform/methanol/ammonium hydroxide eluant to afford l-azabicyclo[3.2.2]nonan-3- one as a brown solid (770 mg, 54%). To a stirred and cooled (0 C) solution of this intermediate (770 mg, 5.54 mmol) in tetrahydrofuran (10 mL), was added lithium aluminum hydride (211 mg, 5.54 mmol), portion wise. After vigorous hydrogen gas evolution ceased, the reaction mixture was allowed to warm to room temperature and then heated at reflux for 1 hour. The solution was cooled to 0 C and quenched by the successive dropwise addition of water (0.2 mL), 10% aqueous sodium hydroxide solution (0.2 mL) and water again (0.6 mL). The colorless precipitate was removed by filtration through Celite, which was subsequently washed with tetrahydrofuran. The combined filtrate was dried (Na2S04) and concentrated to afford the title compound as yellow solid (770 mg, 99%).
With tetrabutyl ammonium fluoride; sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 25℃; for 16h;
Synthesis of Intermediate A-1.A-1To a mixture of ethyl glycolate [623-50-7] (250.00 g, 2.40 mol), NaH (105.65 g, 2.64 mol), tetrabutylammonium iodide (TBAI) (88.70 g, 240.14 mmol) in anhydrous THF (2 L) was added benzyl bromide (451 .80 g, 2.64 mol) dropwise at 0C. The resulting mixture was stirred at 25C for 16 hours. The reaction mixture was quenched with saturated, aqueous ammonium chloride (1 L), and the aqueous layer was extracted with ethyl acetate (3 x 1 L). The combined organic layers were washed with brine (1 L), dried over magnesium sulfate, the solids were removed via filtration, and the solvents of the filtrate were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 6: 1 ) to obtain intermediate A-1 (200 g).1H NMR (CDCIs 400MHz) delta ppm 7.37-7.27 (m, 5H); 4.62 (s, 2H), 4.24-4.19 (q, J = 6.8 Hz, 2H); 4.07 (s, 2H); 1.29-1 .25 (t, J = 6.8 Hz, 3H).
200 g
With tetra-(n-butyl)ammonium iodide; sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 25℃; for 16h;
Synthesis of Intermediate A-i. 10052] To a mixture of ethyl glycolate [623-50-7] (250.00 g, 2.40 mol), NaH (105.65 g, 2.64 mol), tetrabutylammonium iodide (THAI) (88.70 g, 240.14 mmol) in anhydrous THF (2 L) was added benzyl bromide (451.80 g, 2.64 mol) dropwise at 0 C. The resulting mixture was stirred at 25 C. for 16 hours. The reaction mixture was quenched with saturated, aqueous ammonium chloride (1 L), and the aqueous layer was extracted with ethyl acetate (3x1 L). The combined organic layers were washed with brine (1 L), dried over magnesium sulfate, the solids were removed via filtration, and the solvents of the filtrate were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=6: 1) to obtain intermediate A-i (200 g).10053] ?H NMR (CDC13 400 MHz) oe ppm 7.37-7.27 (m, 5H); 4.62 (s, 2H), 4.24-4.19 (q, J=6.8 Hz, 2H); 4.07 (s, 2H);1.29-1.25 (t, J=6.8 Hz, 3H).
Step 1; Benzyloxy-acetic acid ethyl ether; 1 1 5 g of ethyl glycolate is dissolved in 120 ml of dry THF under an atmosphere of nitrogen and cooled to 0 4 9 g of sodium hydride is added portionwise over 40 minutes and the reaction mixture stirred at 0 for 15 minutes and then 4 3 g of tetrabutylammonium iodide is added followed by 13 3 ml of benzyl bromide The mixture allowed to warm to RT and stirred for 3 hours The reaction then quenched with 20 ml of a saturated aqueous ammonium chloride solution and the THF then removed in vacuo The residue is partitioned between EtOAc (100 ml) and H2O (150 ml) The aqueous then extracted twice with EtOAc and the combined EtOAc extracts washed with 50 ml brine then dried over magnesium sulfate, filtered and the solvent evaporated The residue is purified by flash chromatography on silica eluting with a 19 1 /so-hexane/diethyl ether to 4 1 /so-hexane/diethyl ether mixture to yield the title compound
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 1.0h;
Sodium hydride (4.8 g) was added with ice cooling to a N,N-dimethylformamide solution (150 mL) of 4-bromo-2-fluorobenzonitrile (10.0 g) and ethyl glycolate (12.49 g), stirred for 30 minutes, and then stirred for 30 minutes at room temperature. Water was added to the reaction solution, which was then extracted with diethyl ether. The extract was washed successively with water and saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography and recrystallized from the ethyl acetate-hexane to obtain ethyl 3-amino-6-bromo-1-benzofuran-2-carboxylate (3.72 g) as pale yellow crystals. 1H-NMR (300MHz, CDCl3); delta 1.44 (3H, t, J=7.2Hz), 4.44 (2H, q, J=7.2Hz), 4.95 (2H, br s), 7.37 (1H, dd, J=1.5, 8.4Hz), 7.42 (1H, dd, J=0.6, 8.4Hz), 7.63 (1H, dd, J=0.6, 1.5Hz)
With potassium fluoride; In 1,4-dioxane; at 100℃; for 2h;
1,2-dichloro-4-fluoro-5-nitrobenzene (50 g, 0.238 mol), <strong>[623-50-7]ethyl glycolate</strong> (90.1 mL, 0.952 mol), and potassium fluoride (76.1 g, 1.31 mol) were added to a 1L round-bottom flask containing 200 mL of anhydrous dioxane. The mixture was magnetically stirred and heated to 100 C. in an oil bath. After two hours, HPLC (Eclipse XDB-C18, 4.6×250 mm, 5 micron, 1-99% CH3CN/H2O with 0.1% trifluoroacetic acid) showed that all of the starting material (Rt=7.5 min) was gone and that one major peak (Rt=7.8 min) had formed. The reaction mixture was poured into 4 L of water, which resulted in precipitation of the product. The solid was filtered off and dried under vacuum to give ethyl [(4,5-dichloro-2-nitrophenyl)oxy]acetate (67.4 g, 0.229 mol, 96%) as a tan solid. MS (ES) m/e 294 [M+H]+.
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h;
To a cooled (0 0C) solution of ethyl 4-chloro-nicotinate (910 mg, 4.9 mmol) and <strong>[623-50-7]ethyl glycolate</strong> (0.48 ml, 5.1 mmol) in anhydrous DMF (17 ml), under a nitrogen atmosphere, was added sodium hydride (9.8 mmol, 60%, 392 mg). The reaction mixture was stirred for 16 hours (0 0C to room temperature), then acidified by the addition of acetic acid (1.2 ml), and subsequently concentrated to provide a residue. Water (23 ml) was added, and the mixture was stirred for 5 minutes, at which time the resulting brown precipitate was <n="67"/>collected by filtration and washed with water 3 x 30 mL to give the title compound as a light brown solid. (875 mg, 86%). IH NMR (DMSO-D6, 400MHz) 9.18 (d, J = 1.2 Hz, IH), 8.60(d, J = 6.0 Hz, IH), 7.66 (dd, J = 6.0 Hz, 0.8 Hz, IH), 4.32 (q, J = 7.2 Hz, 2H), 1.32 (t, J = 7.2Hz, 3H). LCMS (method B): Rx = 1.42 min, M+H+ = 208.
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 5 - 20℃; for 1h;
To a cold (5 0C) solution of ethyl 3-hydroxy-isonicotinate (1.67 g, 1.0 mmol), <strong>[623-50-7]ethyl glycolate</strong> (1.15 ml, 12.0 mmol) and triphenylphosphine (3.93 g, 15.0 mmol) in anhydrous THF (50 ml) was added diisopropylazodicarboxylate (2.94 ml, 15.0 mmol) dropwise. The reaction mixture was gradually warmed to ambient temperature then stirred for an additional 1 hour. The solution was concentrated and purified by flash chromatography (Si-SPE, pentane: diethyl ether, gradient 50:50 to 0: 100) to afford the title compound as a yellow oil (2.15 g, 85%). LCMS (method B): Rx = 2.69 min, M+H+ = 254.
76%
Step A: Preparation of ethyl 3-(2-ethoxy-2-oxoethoxy)isonicotinate: The reaction is carried out in a 3-neck flask (3 L) equipped with an internal thermometer, an addition funnel and a N2 inlet. Triphenylphosphine (150.6 g, 574 mmol) was dissolved in THF (1 L) and cooled to a temperature of -10 C. DIAD was added dropwise via an addition funnel over 30 minutes. The resulting white suspension was kept at -10 C. for another 30 minutes. Ethyl glycolate (50.84 mL, 526.4 mmol) was added as a solution in THF (500 mL) via the addition funnel at a rate to maintain the internal temperature below -10 C. Upon complete addition, the reaction mixture was kept at a temperature of -10 C. for an additional 30 minutes before a suspension of ethyl 3-hydroxyisonicotinate (80 g, 478.6 mmol) in THF (500 mL) was poured in. The reaction was allowed to warm up slowly to ambient temperature overnight. The reaction mixture was concentrated. The residue was taken up in ethyl acetate (1 L) and extracted with 1N HCl (1*500 mL then 5*250 mL). The aqueous layer was treated with NaHCO3 to a pH of about 8 and then extracted with ethyl acetate (1 L*3). The combined organics were dried, filtered and concentrated to give the desired product (92.0 g, 76%). MS (APCI-pos) M+1=254.3.
76%
Step A: Ethyl 3-(2-ethoxy-2-oxoethoxy)isonicotinate: Triphenylphosphine (150.6 g, 574 mmol) was dissolved in THF (1 L) and cooled to -10 C. To this was added DIAD dropwise via an addition funnel over 30 minutes. The resulting white suspension was kept at -10 C. for another 30 minutes. Ethyl glycolate (50.84 mL, 526.4 mmol) was added as a solution in THF (500 mL) via the addition funnel at a rate to maintain the internal temperature below -10 C. Upon completion of addition, the reaction mixture was kept at -10 C. for additional 30 minutes before a suspension of ethyl 3-hydroxyisonicotinate (80 g, 478.6 mmol) in THF (500 mL) was added. The reaction was allowed to warm up slowly to ambient temperature overnight. The reaction mixture was concentrated, and the residue was taken up in ethyl acetate (1 L) and extracted with 1N HCl. The aqueous layer was treated with NaHCO3 to pH 8 and then extracted with ethyl acetate. The combined organic layers were dried, filtered and concentrated to give the desired product (92.0 g, 76%). MS (APCI) m/z 254.3 (M+1).
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 0.833333h;
4-Chloro-5-fluoronicotinonitrile (4.0 g, 25.6 mmol) was dissolved in DMF (50 ml) and treated with potassium carbonate (17.8 g, 128 mmol) followed by ethyl glycolate (3.64 ml, 38.4 mmol). The resultant reaction mixture was heated at 8O0C for 50 minutes, then cooled to room temperature and diluted with ethyl acetate. The solution was washed with water (x 2), dried (Na2SO4), filtered and concentrated in vacuo. The resultant solid was triturated in diethyl ether to give the title compound as an off-white solid (3.58 g, 63%). LCMS (method B): Rx = 2.65 min, M+H+ 225.
With sodium hydride; In N,N-dimethyl-formamide; for 3.0h;
To a solution of <strong>[62022-04-2]2,4-dichloro-nicotinic acid ethyl ester</strong> (1.6 g, 7.3 mmol) and ethyl glycolate (0.72 mL, 7.6 mmol) in DMF at 00C under an inert atmosphere was added sodium hydride (60% in mineral oil, 584 mg, 14.6 mmol) portionwise. The reaction mixture was stirred at 00C for 3 hours, quenched by careful addition of acetic acid (ca. 5 mL), diluted with water and extracted into ethyl acetate. The organic layer was separated, washed with water, then brine, dried over sodium sulphate and concentrated to give the title compound as a yellow solid (1.75 g, 100%). LCMS (method B): Rx = 2.99 min, M+H+= 242.
With copper(l) iodide; caesium carbonate; at 70℃; for 4h;
To a stirred mixture of the pyridine 51a (2.00 g, 1.0 eq), the alcohol 51b (1.43 mL, 1.05 eq), CuI (0.05 g, 0.02 eq) is added Cs2CO3 (10.3 g, 2.2 eq) and heated at 70 C. during4 h. The reaction mixture is cooled down to RT, poured into H2O (300 mL) and allowed to stand for 1 h until precipitation. The suspension is filtered, triturated with Et2O/Hex (1:1), dried with toluene azeotrope to give 51c (2.0 g, 70%).
50%
With caesium carbonate; 1,8-diazabicyclo[5.4.0]undec-7-ene; In toluene; at 80℃; for 24h;Inert atmosphere;
2- Chloro 3-pyridine carbonitrile (1, 2.0 g, 1 equiv.), Cs2C03 (14.2 g, 3 equiv.) and <strong>[623-50-7]ethyl glycolate</strong> (1.5 mL, 1.2 equiv.) were placed in a flask under inert atmosphere. Dry toluene and DBU (4.3 mL, 2 equiv) were added and the suspension was heated at 80 C for 24 h with vigorous stirring. The reaction mixture was cooled to RT, and then water and EtOAc were added. The organic layer was seperated and was washed with water before being dried over anhydrous Na2S04 and concentrated in vacuo. Purification was done by column chromatography on silica gel using 10-40% EtOAC: hexane as a mobile phase to get product 2 (1.5 g, 50%) as a white solid. *H NMR (CDC13, 400 MHz): delta 8.51 (dd, / = 5.0, 2.0 Hz, 1H), 7.96 (dd, / = 8.0, 2.0 Hz, 1H), 7.23-7.28 (m,1H), 4.44 (q, / = 7.0 Hz, 2H), 4.01 (br, s, 2H), 1.44 (t, / = 7.0 Hz, 3H); ESI-MS: nt/z 229.05 [M+Na]+
40%
With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 75℃; for 20h;Inert atmosphere;
2-Chloro-3-pyridinecarbonitrile, 1 , (4.0Og, 28.9mmol), Cs2CO3 (28.2g, 86.6mmol) and <strong>[623-50-7]ethyl glycolate</strong> (3mL, 31.7mmol) were placed in a flask under Ar(g). Dry NMP was added, and the suspension was heated at 75C for 2Oh with vigorous stirring. The reaction mixture was cooled to rt, whereupon water (200 mL) and Et2theta (3 x 10OmL) were added. The organic layers were combined, washed with water (3 x 15mL) before being dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 15-40% EtOAc/Hex) gave 2 (2.41 g, 1 1 Jmmol, 40%) as a white solid.1H NMR (400MHz, CDCI3) deltaH: 8.51 (dd, J=5.0, 2.0Hz, 1 H), 7.96 (dd, J=8.0, 2.0Hz, 1 H), 7.23-7.28 (m, 1 H), 4.44 (q, J=7.0Hz, 2H), 4.01 (br. s., 2H), 1.44 (t, J=7.0Hz, 3H).MS (ES+) 229 (100%, [M+Na]+).
In diethyl ether; dimethyl sulfoxide; at 0 - 20℃; for 1.75h;
EXAMPLE 13; 4-Oxo-tetrahydro-furan-3-carboxylic acid methyl ester. To a stirred slurry of sodium hydride (1.67 g, 60% in mineral oil, 44.0 mmol) in dried ether was added with ethyl glycolate, dropwise over 15 minutes. The reaction was warmed up to room temperature for 30 min while stirring and concentrated in vacuo to provide white solid. The solid was treated with methyl acrylate (4.16 g, 49 mmol) in DMSO (20 mL) at 0 C. for 15 minutes and room temperature for 45 minutes. The mixture was poured into 5% H2SO4 and extracted with ethyl acetate. Organic layer was washed with brine, dried over Mg2SO4 and concentrated to give 4-oxo-tetrahydro-furan-3-carboxylic acid methyl ester as a colorless oil. MS (ES): [M-1]- cal'cd for C6H7O3, 143; found: 143.
With sodium hydride; In tetrahydrofuran; at 0 - 20℃;
2-Morpholino-4,6-dichloropyrimidine (2.34 g; 10 mmol) and ethyl glycolate (1.3 g; 12 mmol) were dissolved in tetrahydrofuran (100 mL), and chilled in an ice bath. To the solution was added sodium hydride (300 mg; 12 mmol), and it was stirred EPO <DP n="186"/>overnight at ambient temperature. The solvents were evaporated, and the solid was dissolved in ethyl acetate (200 mL) which was then washed with water (2x100 mL). The organic layer was dried over magnesium sulfate, and evaporated to give (6-chloro- 2-morpholin-4-yl-pyrimidin-4-yloxy)-acetic acid ethyl ester (3.16 g).
With NaH; trifluorormethanesulfonic acid; benzyl alcohol; In methanol; diethyl ether; pentane;
Synthesis of ethyl 2-(benzyloxy)acetate Benzyl alcohol (27.5 ml) was added to a suspension of NaH (1.1 g) in Et2O (250 ml) at 0 C., and after stirring at 0 C. for 10 minutes and at room temperature for 5 minutes, the reaction solution was cooled to -10 to 0 C. and trichloroacetonitrile (27 ml) was added dropwise over 15 minutes. The reaction solution was stirred for one hour while the temperature slowly increased to room temperature, and was then concentrated under reduced pressure. A solution of MeOH (1.0 ml) in n-pentane (100 ml) was added to the residue, and the mixture was vigorously stirred, filtered and concentrated. After then adding n-pentane to the residue and refiltering, the mother liquor was concentrated. Et2O (80 ml), n-pentane (80 ml) and ethyl glycolate (25 g) were added to the residue, and then TfOH (1.5 ml) was added at 0 C. and the mixture was stirred at 0 C. for 10 minutes and at room temperature for 2 hours. The reaction solution was filtered, the mother liquor was poured into a saturated NaHCO3 aqueous solution and extraction was performed with Et2O. The organic layer was rinsed with water and dried with MgSO4, and then filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=10/1?6/1) to obtain ethyl 2-(benzyloxy)acetate. Yield: 38.76 g (y. 83.2%) 1H NMR(delta ppm, CDCl3): 1.29(t, J=7.26 Hz, 3H), 4.09(s, 2H), 4.23(q, J=7.26 Hz, 2H), 4.63(s, 2H), 7.21 to 7.45(m, 5H)
Example 61 3-[5-(Benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(4-carboxymethoxy-3,5-dimethoxyphenyl)-2-propen-1-one, Sodium Salt Ex-61A: 3',5'-Dimethoxy-4'-hydroxyacetophenone (6.03 g, 31 mmol) and triphenylphosphine (8.05 g, 31 mmol) were stirred in 124 mL of tetrahydrofuran (THF). The mixture was treated with ethyl glycolate (3.2 g, 31 mmol) and diethylazodicarboxylate (4.83 mL, 31 mmol). The reaction mixture was stirred under reflux for about 3.5 h and then evaporated. The residue was crystallized from hexane/ethyl acetate. The mother liquor was concentrated to give a crude product which was purified by recrystallization from EtOH twice to give 3.14 g of 4'-ethoxycarbonyl-methoxy-3',5'-dimethoxyacetophenone. Solvent removal from the mother liquor provided additional crude product which was purified by silica gel chromatography (hexane/ethyl acetate, 1:1) to give additional product (4.2 g). The total amount of pure material isolated was 7.34 g (90% yield). mp. 81-83 C.; Anal. Calcd. for C14H18O6: C, 59.57; H, 6.43; Found: C, 59.60; H, 6.34; MS (direct probe):
ethyl 2-(5-chloro-6-ethylpyrimidin-4-yloxy)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran; water;
Synthesis of ethyl 2-(5-chloro-6-ethylpyrimidi n-4-yloxy)acetate 60% Sodium hydride (0.5 g) was washed with hexane and then suspended in tetrahydrofuran (50 ml). Ethyl glycolate (1.2 g) was added to the suspension in a dropwise manner in an ice-cooled bath, and subsequently the mixture was stirred for an hour at room temperature. Subsequently, <strong>[115617-41-9]4,5-dichloro-6-ethylpyrimidine</strong> (2.0 g) was added thereto in a dropwise manner, and the reaction mixture was stirred for 3 hours at room temperature. After completion of the reaction, water was added to the reaction liquid. The organic layer was extracted with ethyl acetate and then was dried over anhydrous magnesium sulfate. The ethyl acetate was removed under reduced pressure. The residue was purified by column chromatography on silica gel to give 2.6 g of the desired product as an oil.
PREPARATION 48 2-Hydromethyl-3H-imidazo[5,4-d]pyrimidine 8.58 g of ethyl glycolate were added to 2.27 g of <strong>[13754-19-3]4,5-diaminopyrimidine</strong>, and the resulting mixture was stirred at 140 C. for 2 hours. At the end of this time, the reaction mixture was freed from ethyl glycolate by distillation under reduced pressure. The residue thus obtained was decolorized by activated charcoal and crystallized by trituration with ethanol, to give 1.81 g of the title compound having Rf=0.27 (on silica gel thin layer chromatography using a 10:1 by volume mixture of ethyl acetate and methanol as the developing solvent).
EXAMPLE 3 Preparation of Ethyl 2-(4,6-Dimethyl-2-pyrimidinyloxy)acetate. A solution containing 4,6-dimethyl-2-methylsulfonylpyrimidine (10.0 g, 53.8 mmol), ethyl glycolate (5.60 g, 53.8 mmol), and 30 mL of N,N -dimethylformamide was prepared and to this was added with stirring potassium carbonate (8.0 g, 60 mmol). The mixture was allowed to stir at ambient temperature overnight. It was then poured into water and the resulting mixture was extracted 3 times with ethyl acetate. The combined organic extracts were extracted with water.
42
[ 67443-38-3 ]
[ 623-50-7 ]
[ 105544-30-7 ]
Yield
Reaction Conditions
Operation in experiment
82%
With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 1h;
Method I: 5-bromo-2-chloro-3-nitropyridine (100 mg, 0.42 mmol) and Ethyl glycolate (0.044 mL, 0.46 mmol) were dissolved in THF (5 mL) and cooled to 0C. Sodium hydride (0.015 mL, 0.46 mmol) was added and the mixture was stirred for 1hr at room temperature. Reaction mixture was poured in ice water and extracted with EtOAc (2 x 10ml). The organiclayer was washed with brine (10ml), dried over sodium sulphate and concentrated. The crude product was purified by flash column using 100-200 silica gel to ethyl 2-(5-bromo-3-nitropyridin-2-yloxy)acetate (105 mg, 82 %) 9(b). 1H NMR (300 MHz, DMSO-d6) delta = 1.27 (s, 3H), 4.25 (q, 2 H), 5.12 (s, 2H) 8.40 (d, J = 2.07 Hz, 1 H), 8.47 (d, J = 2.07 Hz, 1 H); ESMS: m/z 306.8 [M+1]
71%
With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 8h;
To a solution of 5-bromo-2-chloro-3-nitropyridine (6.0 g, 25.4 mmol) and <strong>[623-50-7]ethyl 2-hydroxyacetate</strong> (2.9 g, 28.0 mmol) in THF (150 mL) was added slowly 60 % NaH (1.3 g, 1.8 mmol) at 0 C. The mixture was stirred at room temperature for 8 h. After water (20 mL) was added to quench the reaction, the mixture was treated with brine (100 mL) and extracted with ethyl acetate (50 mL * 2). The combined organic layers were dried over Na2504, filtered and concentrated. Then the solid was filtered to give the title compound as a yellow solid (5.5 g 71 %). ?H NMR (400 MHz, CDC13) oe 8.46 (d, J = 2.0 Hz, 1H), 8.39 (d, J = 1.6 Hz, 1H), 5.05 (s, 2H), 4.26-4.17 (m, 2H), 1.28 (t, J= 7.2 Hz, 3H).
49%
Step 1. Sodium hydride (55% dispersion in mineral oil, 603 mg, 13.8 mmol) was added to a solution of <strong>[623-50-7]ethyl glycolate</strong> (1.43 g, 13.8 mmol) in 1,4-dioxane, and the reaction mixture was heated at 70 C. for 1 h, then 5-bromo-2-chloro-3-nitropyridine (Eur. Pat. Appl. EP 122109 (1984); 1.64 g, 6.91 mmol) was added, and stirring was continued at 70 C. for 1 h and at room temperature for 16 h. The reaction mixture was then neutralized with sat. aq. sodium hydrogencarbonate solution and extracted three times with dichloromethane. The organic layers were pooled, dried (Na2SO4), and evaporated. Chromatography (SiO2, hexane-ethyl acetate gradient) furnished (5-bromo-3-nitro-pyridin-2-yloxy)-acetic acid ethyl ester (1.03 g, 49%). Light yellow liquid, MS (ISP)=305.1 (M+H)+.
48%
Step 7: Preparation of ethyl 2-((5-bromo-3-nitropyri din-2 -yl)oxy)acetate. [0602] To a mixture of <strong>[623-50-7]ethyl 2-hydroxyacetate</strong> (14.0 g, 134 mmol) in anhydrous THF (150 mL) was added NaH (4.48 g, 112 mmol, 60% in mineral oil) at 0 C. After stirring for 30 min, 5-bromo-2-chloro-3-nitropyridine (26.6 g, 112 mmol) was added at 0 C, and the reaction mixture was stirred at 25 C for 15.5 h. TLC showed the reaction was almost completed. The colour of mixture was black. The residue was poured into water (150 mL) at 0 C and extracted with EtOAc (100 mL x3). The combined organic phase was dried over anhydrous Na2S04, filtered and concentrated in vacuum. The residue was purified by Combi Flash (6% EtOAc in pentane) to give ethyl 2-((5-bromo-3-nitropyridin-2-yl)oxy)acetate (16.5 g, yield: 48%) as a yellow solid. NMR (400 MHz, CDCb) d 1.26 (3H, t, J= 12 Hz), 4.23 (2H, q, J= 12 Hz), 5.04 (2H, s), 8.39 (1H, d, J= 2.4 Hz), 8.46 (1H, d, J= 2.4 Hz).
44%
To a suspension of sodium hydride (5.31 g, 133 mmol) in 1 ,4-dioxane (250 ml), <strong>[623-50-7]ethyl glycolate</strong> (12.56 ml, 133 mmol) was added drop wise over a period of 30 minutes ensuring that the temperature was maintained below 30C. The resulting thick suspension was stirred at room temperature for 15 minutes. In a separate 11 round- bottomed flask was added 5-bromo-2-chloro-3-nitropyridine (21 g, 88 mmol) in 1 ,4- dioxane (150 ml) to give a brown solution. The suspension of sodium hydride and <strong>[623-50-7]ethyl glycolate</strong> was added drop wise over a period of 30 minutes at 0C. The resulting reaction mixture was heated to 80C overnight. The reaction mixture was concentrated under reduced pressure and the crude residue was purified by Biotage silica chromatography (gradient 0% to 10% ethyl acetate in n- hexanes) to give the title compound (1 .8g, 44%). N R (500 MHz, CDCI3): 8.48 (1 H, s), 8.42 (1 H, s), 5.07 (2H, s), 4.28-4.24 (2H, q), 1.31-1.28 (3H, t).
With sodium hydride; In tetrahydrofuran; N,N-dimethyl-formamide; at 0 - 20℃; for 0.5h;
To a mixture of 5-bromo-2-chloro-3-nitropyridine (21.7 g) , <strong>[623-50-7]ethyl glycolate</strong> (11.4 g) , DMF (7.5 mL) and THF (90 mL) was added sodium hydride (60% in mineral oil, 6.6 g) under ice-cooling. The mixture was allowed to warm to room temperature, and stirred for 0.5 hr. The mixture was poured into ice-cooled water and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (hexane -» hexane:ethyl acetate = 4:1). Resulting crystals were collected by filtration, and washed with hexane. The title compound was obtained as crystals (15.8 g) .1H-NMR (300 MHz, DMSO-d6) delta: 1.18 (t, J = 7.0 Hz, 3H), 4.14 (q, J = 7.0 Hz, 2H), 5.11 (s, 2 H), 8.65 (d, J = 2.3 Hz, IH), 8.77 (d, J = 2.3 Hz, IH).
With hydrazine hydrate; In methanol; water; at 20℃; for 5h;Cooling with ice;
General procedure: To a stirred solution of esters 2a-2j (70 mmol) in MeOH (30 mL) cooled in an ice-water bath was added dropwise 80% aqueous hydrazine hydrate (6.26 g, 100 mmol). The resulting solution was stirred at room temperature (2a-2b or 2d-2j), or reflux (2c), until the completion of reaction as indicated by TLC analysis (typically within 5 h). The reaction mixture was evaporated on a rotary evaporator to give a residue, which was purified by column chromatography through a short silica gel column to yield 3a-3k after trituration with n-hexane if possible.
81%
With hydrazine; In ethanol; at 85℃; for 3h;
A. 2-Hydroxyacetohydrazide. A solution of <strong>[623-50-7]ethyl 2-hydroxyacetate</strong> ( 1.00 g, 9.60 mmol), hydrazine (0.324 mg, 10.1 mmol), and ethanol (20 mL) were combined and heated to 85 C for 3 h. The reaction was concentrated to afford the title compound (0.702 g, 81%). MS (ESI) m/z 91.1 [M+ 1]+.
With hydrazine hydrate; for 15h;Reflux;
Ethyl glycolate (5g, 0.047 mol) and hydrazine monohydrate (3.6g, 0.071 mol) were heated to reflux for 15 hours. The reaction mixture was concentrated under reduced pressure and the residue was treated with toluene (3 x 50ml) to azeotrope hydrazine in excess.This was repeated three times. The crude residue was used for the next step without further purification
With dmap; In pyridine; at 20℃; for 0.666667h;Inert atmosphere;
To a stirred solution of <strong>[623-50-7]ethyl glycolate</strong> (5 mL, 52.8 mmol, 1.0 equiv) in pyridine (60 mL) at room temperature were added chlorotriethylsilane (18.1 mL, 105.7 mmol, 2.0 equiv) and 4-dimethylaminopyridine (326 mg, 2.64 mmol, 0.05 equiv). After 40 min, the reaction mixture was quenched with water (20 mL). The aqueous layer was extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel to obtain the product ethyl 2-(triethylsilyloxy)acetate (11.4 g, 99% yield) as colorless oil: TLC Rf = 0.83 (silica gel, Ethyl acetate:n-Hexane = 1:3); IR(neat) upsilonmax 2956, 2878, 1762, 1241, 1206, 1145, 1017, 786 cm-1; 1H NMR (500MHz, CDCl3) delta 4.22 (s, J = 1.4 Hz, 2H), 4.20 (dd, J = 14.3, 7.2 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H), 0.97 (t, J = 7.9 Hz, 9H), 0.64 (q, J = 7.9 Hz, 6H); 13C NMR (125MHz, CDCl3) delta 171.7, 61.4, 60.8, 14.2, 6.6, 4.3; LRMS (ESI): Calcd. for C10H22NaO3Si ([M+Na]+): 241.12, found: m/z = 241.13.
With 1H-imidazole; In dichloromethane; at 20℃; for 10h;Inert atmosphere;
Hydroxy ester 5 (1.67g, 16.0 mmol) was dissolved in dichloromethane (30 mL), and triethylchlorosilane (2.89g, 19.2 mmol) and imidazole (1.31g, 19.2 mmol) were added. The solution was stirred at room temperature for 10h. The precipitate formed was removed by filtration over silica gel (elution with diethyl ether). After evaporation of the solvent, the crude silyl ether (3.50g) was used for the next reaction.
Step 1-Synthesis of ethyl 4-oxotetrahydrofuran-3-carboxylate (ge). NaH (60%, 4.6 g, 116 mmol) was suspended in ether (200 mL) and cooled in ice-bath. To this suspension was added <strong>[623-50-7]ethyl glycolate</strong> (10 mL, 100 mmol) dropwise under N2. The resulting white slurry was stirred at rt for 45 min. Ether was removed in vacuo to give white solid. It was suspended in DMSO (130 mL), cooled in ice-bath, and ethyl arcylate (13.7 mL, 127 mmol) was added dropwise. The resulting yellow mixture was stirred at rt overnight. The reaction solution was poured into 10% aq. HCl (500 mL) slowly. It was extracted with ether (3×). The combined ether extract was washed with brine, dried over MgSO4, filtered, concentrated in vacuo to give 14 g (80%) of (ge) as clear yellow liquid. It was carried on without further purification.
46%
Referring to the scheme immediately above, to a suspension of sodium hydride (60 % in oil) (42.0 g, 1.05 mol) in diethyl ether (800 mL) was added <strong>[623-50-7]ethyl glycolate</strong> (100 g, 0.96 mol) over a period of 1 hour at room temperature. The suspension was then stirred for an additional 0.5 hour and evaporated under vacuum. To the resulting solid, dimethyl sulfoxide (200 mL) was added. It was then cooled to 0 C and a solution of ethyl acrylate (115.10 g, 1.15 mol) in dimethyl sulfoxide (100 mL) was added in portions with vigorous stirring. The suspension was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was cautiously poured into ice cold aqueous solution of sulfuric acid (5 %, 300 mL), extracted with ether (3 x 100 mL), dried over MgSO4, evaporated and chromatographed on silica gel (hexane/ethyl acetate, 10:1) to afford compound 3 (70.0 g, 46 %). 1H NMR (400 MHz, CDCl3) delta 4.55-4.40 (m, 2H), 4.30-4.20 (m, 2H), 4.10-3.95 (m, 2H), 3.50 (t, 1H), 1.15 (t, 3H)
38%
To a 0 oC solution of <strong>[623-50-7]ethyl 2-hydroxyacetate</strong> 1 (5 mL, 50 mmol) in THF (100 mL) was added NaH (60%, 2.3 g, 58 mmol) under a nitrogen atmosphere. The resulting solution was stirred at the room temperature for 45 minutes. The solvents were removed under reduced pressure. The resulting residue was suspended in dimethyl sulfoxide (65 mL) and cooled to 0C. Ethyl acrylate (6.8 mL, 63 mmol) was then added dropwisely. The resulting solution was stirred at the room temperature for 12 hours. Then the resulting solution was slowly poured into aqueous hydrochloric acid (10%>, 250 mL). It was extracted with diethyl ether (150 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give intermediate 2 (3 g, 38%)). which was used in the next step without further purification. LRMS (M + H+) m/z: calcd 159.15; found 159.21.
To a solution of triphenylphosphine (29.9 g, 114 mmol) in 500 ml_ of THF, cooled to 0 0C, was slowly added a 40% solution of diethyl azodicarboxylate in toluene (52.2 ml_, 114 mmol), ethyl glycolate (10.8 ml_, 114 mmol) and 2- oxocyclohexanecarbonitrile (10 g, 81.3 mmol). The resulting solution was stirred at room temperature for 20 hours. Then 50% sodium hydride (11 g, 229 mmol) was added and the mixture was stirred at room temperature for 5 hours. The reaction mixture was cooled to 0 0C and a pH 7.8 phosphate buffer (Na2HPO4/KH2PO4) solution (375 ml_) was added. THF was evaporated and the resulting aqueous solution was extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated to dryness. The resulting crude product was chromatographed on silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, to afford 8.5 g of the desired compound (yield: 50%). <n="59"/>LC-MS (Method 2): tR = 1.97 min; m/z = 210 (MH+).
Step A: 3-Amino-4,5,6,7-tetrahydro-benzofuran-2-carboxylic acid ethyl ester A solution of resin bound PPh3 (Polymer Laboratories, 1.48 mmol/g, 150-300 muM; 3.8 g, 5.7 mmol) in THF (35 mL) at 0 C. was treated with diethyl azodicarboxylate (40% wt. in hexane; 2.60 mL, 5.7 mmol), ethyl glycolate (0.54 mL, 5.7 mmol) and a solution of <strong>[4513-77-3]2-oxo-cyclohexanecarbonitrile</strong> (0.5 g, 4.1 mmol) in THF (10 mL). The reaction mixture warmed to rt over 12 h. Filtration and concentration afforded the uncyclized intermediate, which was dissolved in THF (25 mL) and added drop-wise to a slurry of sodium hydride (95%; 0.29 g, 11.4 mmol) in THF (10 mL) at 0 C. The reaction mixture was heated to 40 C. for 12 h. The reaction was quenched with satd. aq. NH4Cl (5 mL) and the mixture was extracted with EtOAc (3*50 mL). The combined organic layers were dried (by using, for example, Na2SO4) and concentrated. Purification by FCC (50% EtOAc/hexanes) afforded the desired product as a pale yellow solid (0.36 g). MS: 210.2. 1H NMR (400 MHz, CD3OD) delta ppm 4.26 (q, J=7.1, Hz, 2H), 2.55-2.47 (m, 2H), 2.35-2.28 (m, 2H), 1.90-1.79 (m, 2H), 1.79-1.71 (m, 2H), 1.33 (t, J=7.1, 3H).
With potassium carbonate; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 96h;
To a solution of <strong>[59237-53-5]methyl 6-chloro-5-nitronicotinate</strong> (3 g, 13.85 mmol) in THF (60 mL) and DMF (30.0 mL) was added ethyl 2-hydroxyacetate (1.573 mL, 16.62 mmol) and potassium carbonate (5.74 g, 41.6 mmol). The reaction was stirred at room temperature for 24 hours. TLC analysis of the reaction mixture indicated partial consumption of starting material. Ethyl 2-hydroxyacetate (1 mL, 10.57 mmol) and potassium carbonate (2 g, 14.5 mmol) were added and the reaction was stirred at room temperature for 72 hours. TLC analysis of the reaction mixture indicated nearly complete consumption of starting material. The reaction mixture was partially concentrated under reduced pressure for removal of THF. The resulting red solution was diluted with H2O (200 mL) and 1N HCl was added to adjust the pH to 7. Theaqueous layer was extracted with EtOAc (3.x.200 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting solid was purified by flash column chromatography using a gradient elution of hexanes with 10-70percent EtOAc to provide methyl 6-(2-ethoxy-2-oxoethoxy)-5-nitronicotinate (2.43 g, 8.55 mmol, 61.7percent yield) as a white solid.1H-NMR (CDCl3) delta 8.95 (d, 1H), 8.88 (d, 1H), 5.12 (s, 2H), 4.23 (q, 2H), 3.97 (s, 3H), 1.27 (t, 3H).
7-hydroxy-6-ethoxycarbonylfuro[2,3-b]pyrazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
A solution of 17.4 ml (0.184 mmol, 2.8 eq.) of ethyl glycolate in 20 ml of DME is added drop by drop to a suspension of 6.85 g (0.171 mol, 2.6 eq.) of NaH (60% in oil) at 0 C. in 200 ml of DME. After leaving under stirring for 15 min, 11.36 g of the chlorinated derivative from step a) above in solution in 20ml of DME is then introduced. After returning to a normal temperature, the medium is heated to 80 C. for 9 hrs. After evaporation and resuspension in water, the medium is acidified with acetic acid to pH 4 and then extracted with 5 times 50 ml of ethyl acetate. After drying on Na2So4, filtration and evaporation, the residue is triturated in petroleum ether and then crystallized, filtered and vacuum dried. 9.91 g (72%) of aromatization product is obtained. FP=160 C. (dec). NMR (1H, CDCl3): 1.48 (t; J=7.2 Hz; 3H; CH3 ester), 4.53 (q; J=7.2 Hz; 2H; CH2 ester), 8.41 (m; 1H; OH), 8.50 (d, J=2.4 Hz; 1H; arom. H), 8.69 (d, J=2.4 Hz; 1H; arom. H).
Sodium hydride (116mg: 60%) was suspended in tetrahydrofuran (4mL). While the suspension was cooled on ice, ethyl glycolate (273muL) was added. The mixture was stirred at room temperature (20 to 30C) for 30 min. Subsequently, <strong>[22280-56-4]2-chloro-3-methyl-5-nitropyridine</strong> (200mg) was added to the mixture portionwise at room temperature (20 to 30C) and the mixture was stirred at room temperature (20 to 30C) for 3 hours. Water was then added to the reaction mixture and the mixture was extracted twice with chloroform. The organic layer was concentrated under reduced pressure to afford 310mg of the crude desired product of Compound 19 as a brown amorphous.
With copper(l) iodide; caesium carbonate; at 70℃; for 1h;
To a stirred mixture of the pyridine 49a (5.00 g, 1.0 eq), the alcohol 49b (2.28 mL, 1.05 eq), CuI (0.100 g, 0.02 eq) is added Cs2CO3 (16.5 g, 2.2 eq) and heated at 70 C. during 4 h. The reaction mixture is cooled down to RT, poored into H2O (500 mL) and allowed to stand for 1 h until precipitation. The suspension is filtered, triturated with Et2O/Hexanes (1:1), dried with toluene azeotrope to give 49c (4.00 g, 61%).
34%
With potassium carbonate; In N,N-dimethyl-formamide; at 115℃;Inert atmosphere;
I. Ethyl-3-amino-5-bromofuro[2, 3-b]pyridine-2-carboxylateTo a IOL flask under N2(g) was added 5-bromo-2-chloropyridine-3-carbonitrile(435g, 2.Omol, leq), DMF (2790mL) and potassium carbonate (553g, 4.Omol,2eq). This was followed by the addition of <strong>[623-50-7]ethyl glycolate</strong> (208.2mL, 2.2mol, 1.leq). The reaction mixture was heated to 115C overnight. Upon completion, the reaction mixture was cooled to rt and water (13.IL) was added, this led to the formation of a precipitate. The mixture was stirred for 20mins, then filtered.The resulting brown solid was dried at 50C, slurried in Et20:heptane (9:1, 2.8L) and filtered to give 405.6g. Further purification via soxhlet extraction using TBME (4.5L) yielded the product as a yellow solid (186g, 34%). This procedure was repeated twice.1H NMR (400MHz, CDCI3) oH: 8.53 (d, J=2.OHz, IH), 8.07 (d, J=2.OHz, IH), 5.00(br. s., 2H), 4.44 (q, J=7.OHz, 2H), 1.44 (t, J=7.OHz, 3H). MS (ESj 309 (100%, [M+Na]j, 307 (100%, [M+Na]j.
34%
With potassium carbonate; In N,N-dimethyl-formamide; at 115℃;Inert atmosphere;
To a 1OL flask under N2(g) was added 5-bromo-2-chloropyridine-3-carbonitrile (435g, 2.Omol, leq), DMF (2790mL) and potassium carbonate (553g, 4.Omol,2eq). This was followed by the addition of <strong>[623-50-7]ethyl glycolate</strong> (208.2mL, 2.2mol,1.leq). The reaction mixture was heated to 115C overnight. Upon completion, the reaction mixture was cooled to rt and water (13.1L) was added, this led to the formation of a precipitate. The mixture was stirred for 20mins, then filtered. The resulting brown solid was dried at 50C, slurried in Et20:heptane (9:1, 2.8L) and filtered to give 405.6g. Further purification via soxhlet extraction using TBME (4.5L) yielded the product as a yellow solid (186g, 34%). This procedure was repeated twice.1H NMR (400MHz, ODd3) oH. 8.53 (d, J=2.0Hz, 1H), 8.07 (d, J=2.0Hz, 1H), 5.00 (br. 5., 2H), 4.44 (q, J=7.0Hz, 2H), 1.44 (t, J=7.0Hz, 3H).MS (ESj 309 (100%, [M+Na]j, 307 (100%, [M+Na]j.
34%
With potassium carbonate; In N,N-dimethyl-formamide; at 115℃;
Intermediate 1 Ethyl-3-amino-5-bromofuro[2,3-blpyridine-2-carboxylate Ethyl glycolate Intermediate 1 To a 10L flask under N2 (g) was added 5-bromo-2-chloropyridine-3-carbonitrile (435 g, 2.0 mol, 1 eq), DMF (2790 mL) and potassium carbonate (553 g, 4.0 mol, 2 eq). This was followed by the addition of <strong>[623-50-7]ethyl glycolate</strong> (208.2 ml_, 2.2 mol, 1 .1 eq). The reaction mixture was heated to 1 15C overnight. Upon completion, the reaction mixture was cooled to rt and water (13.1 L) was added, this led to the formation of a precipitate. The mixture was stirred for 20 mins, then filtered. The resulting brown solid was dried at 50C, slurried in Et20:heptane (9: 1 , 2.8 L) and filtered to give 405.6 g. Further purification via soxhlet extraction using TBME (4.5 L) yielded Intermediate 1 as a yellow solid (186 g, 34%). 1 H NMR (400MHz, CDCI3) deltaEta: 8.53 (d, J=2.0Hz, 1 H), 8.07 (d, J=2.0Hz, 1 H), 5.00 (br. s., 2H), 4.44 (q, J=7.0Hz, 2H), 1 .44 (t, J=7.0Hz, 3H). MS (ES+) 309 (100%, [M+Na]+), 307 (100%, [M+Na]+).
34%
With potassium carbonate; In N,N-dimethyl-formamide; at 115℃;Inert atmosphere;
To a 10L flask under N2(g) was added 5-bromo-2-chloropyridine-3-carbonitrile (435g, 2.0mol, 1 eq), DMF (2790ml_) and potassium carbonate (553g, 4.0mol, 2eq). This was followed by the addition of <strong>[623-50-7]ethyl glycolate</strong> (208.2ml_, 2.2mol, 1 .1 eq). The reaction mixture was heated to 115C overnight. Upon completion, the reaction mixture was cooled to rt and water (13.1 L) was added, this led to the formation of a precipitate. The mixture was stirred for 20mins, then filtered. The resulting brown solid was dried at 50C, slurried in Et20:heptane (9: 1 , 2.8L) and filtered to give 405.6g. Further purification via soxhlet extraction using TBME (4.5L) yielded the product as a yellow solid (186g, 34%). This procedure was repeated twice. 1 H NMR (400MHz, CDCI3) deltaEta: 8.53 (d, J=2.0Hz, 1 H), 8.07 (d, J=2.0Hz, 1 H), 5.00 (br. s., 2H), 4.44 (q, J=7.0Hz, 2H), 1 .44 (t, J=7.0Hz, 3H). MS (ES+) 309 (100%, [M+Na]+), 307 (100%, [M+Na]+).
Step A: Preparation of ethyl 3-aminofuro[2,3-c]pyridine-2-carboxylate: To a cold solution (0 C.) of 3-bromoisonicotinoitrile (5.0 g, 27.3 mmol) in DMF (50 mL) was added NaH (60% dispersion in mineral oil, 1.15 g, 28.7 mmol). To this was slowly added a solution of ethyl glycolate (3.13 g, 2.84 mL, 30.1 mmol) in DMF (6.0 mL) via an addition funnel. The reaction mixture was allowed to warm up to room temperature and stirred for 1 hour, then diluted with water (50 mL) and ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were dried, filtered and concentrated. The crude product was purified by flash column chromatography, eluting with hexanes/ethyl acetate (4:1), hexanes/ethyl acetate (5:2) to give the desired product as a yellow solid (0.270 g). MS (APCI) m/z 407.1 (M+1).
2-(N-tert-butoxycarbonyl)amino-6-chloro-9H-purine[ No CAS ]
[ 1236151-75-9 ]
Yield
Reaction Conditions
Operation in experiment
83%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 0.258333h;Inert atmosphere;
To a stirred solution of purine 3 (1 equiv) in THF (0.1M) at room temperature was added <strong>[623-50-7]ethyl glycolate</strong> (1.1 equiv) followed by triphenylphosphine (1.1 equiv) under an N2 atmosphere. To the homogenous solution, DIAD (1 equiv) was added dropwise (over 30 s). TLC indicated the reaction was complete after 15 min and the solvent was removed in vacuo, then the residue was dry-loaded onto silica gel from CH2Q2, and purified by flash column chromatography (2: 1 EtOAc:hexanes) to furnish 4 as an off-white foam (83%); mp 129-136 C; JR (KBr, cm"1) 3462, 3249, 3166, 3106, 2988, 2948, 2362, 1751, 1693, 1612, 1572, 1523, 1499, 1447, 1421; deltaEta (400 MHz, DMSO-d6) 1.22 (t, J = 1.1 Hz, 3H, CH3), 1.46 (s, 9H, C(CH3)3), 4.18 (q, J = 7.1 Hz, 2H, CH2CH3), 5.11 (s, 2H, CH2C02Et), 8.46 (s, IH, H-8), 10.33 (s, IH, NHBoc); 5C (100 MHz, DMSO- 6) 13.9, 27.8, 44.2, 61.6, 79.7, 126.3, 146.4,149.0, 150.8, 152.6, 152.9, 167.3; HRMS (ESI+) calcd for Ci4H18ClN504Na [M+Na+] m/z = 378.0939, obsd 378.0945.
83%
General procedure: General Procedure A. Alkylation of N9: To a solution of purine 3 (1.0 eq) in THF (0.1 M) at room temperature, was added the appropriate alcohol (1.1 eq) followed by triphenylphosphine (PPh3; 1.1 eq) under an N2 atmosphere. To the stirring solution, diisopropylazodicarboxylate (DIAD, 1.0 eq) was added dropwise (over 30 s). According to TLC visualization the reaction was complete after 15 min and the solvent was removed in vacuo. The resulting residue was adsorbed onto silica gel from CH2Cl2, and purified by flash column chomatography (2:1 EtOAc:Hex).
With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 75℃;Inert atmosphere;
To a suspension of 2-chloro-3-cyano-6-methylpyridine, 15 (2.Og, 13.1 mmol, 1eq) and cesium carbonate (12.8g, 39.3mmol, 3eq) in anhydrous NMP (2OmL) was added at rt ethyl glycolate (1.36ml_, 14.4mmol, 1.1eq) under Ar(g). The reaction mixture was heated up at 75C overnight; once cooled down, it was partitioned with H2O (20OmL) and extracted with EtOAc (3 x 7OmL). The combined organics were thoroughly washed with H2O (3 x 75mL), then dried over MgSO4 and the solvent was removed in vacuo. The residue was further purified by silica gel column chromatography with hexane/EtOAc (4:1-1 :3) to yield 16 as a pale yellow solid (1.30 g, 45%).1H NMR (400MHz, CDCI3) deltaH: 7.84 (d, J=8.0Hz, 1 H), 7.12 (d, J=8.0Hz, 1 H), 4.41 (q, J=7.0Hz, 2H), 4.26 (br. s., 2H), 2.66 (s, 3H), 1.42 (t, J=7.0Hz, 3H).MS (ES+) 221.0 (50%, [M+H]+), 243.0 (50%, [M+Na]+).
With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 75℃;
A solution of <strong>[28900-10-9]2-chloro-6-methylnicotinonitrile</strong> (5 g, 32.77 mmol), ethyl 2- hydroxyacetate (3.36 g, 32.28 mmol), and C52CO3 (32.2 g, 98.83 mmol) in NIVIP (80 mL) was stirred overnight at 75 C. After cooling to room temperature, the mixture was poured into 100 mL of water. The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:3 ethyl acetate/pet. ether) afforded ethyl 3 -amino-6-methylfuro[2,3 -b]pyridine-2-carboxylate as a pink solid. MS: (ESI, m/z): 221 [M+H]t
To a solution of ethyl glycolate (1.90mL, 20.0mmol) in THF (25mL) was added sodium hydride (720mg, 30mmol) at 0C and stirred at room temperature for 1h. The solution of 48 (2.45g, 10.0mmol) in THF (10mL) was added at 0C. Upon complete addition, the reaction mixture was heated to reflux for 2h and quenched with water. The mixture was extracted with ethyl acetate (2×100mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate, v/v, 90:10) (750mg, Yield 36%).1H NMR (300MHz, CDCl3) delta 7.01 (s, 1H), 4.34 (q, J=7.2Hz, 4H), 3.73 (s, 2H), 2.76 (s, 2H), 1.47 (s, 9H), 1.35 (t, J=7.2Hz, 3H).
Step B: 5-tert-Butyl 2-ethyl 6,7-dihydrofuro[3,2-c]pyridine-2,5(4H)-dicarboxylateTo a solution of ethyl glycolate (2.07 mL, 19.9 mmol) in THF was added sodium hydride (1.19g, 49.9 mmol) at 0 C and stirred at room temperature for 1 hour. tert-Butyl 4-chloro-3-formyl-5,6-dihydropyridine-l(2H)-carboxylate dissolved in THF was added at 0 C, refluxed the reaction mixture for 2 hours. The reaction mixture was quenched with water and extracted with ethyl acetate (2 x 100 mL). The organic layer was separated, dried over anhydrous Na2S04 and concentrated under reduced pressure to afford crude product, which on purification by column chromatography yields the title compound (0.75 g, Yield 15 %).
phenyl[N-[N-benzyloxycarbonylglycinyl]-1-aminophenylmethyl]phosphinic acid[ No CAS ]
ethyl [[phenyl[N-[N-benzyloxycarbonylglycinyl]-1-aminophenylmethyl]phosphinyl]oxy]acetate[ No CAS ]
ethyl [[phenyl[N-[N-benzyloxycarbonylglycinyl]-1-aminophenylmethyl]phosphinyl]oxy]acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
18%
General procedure: To a solution of an N-Cbz-2-aminoalkanamide 1 (3.0 mmol) and aldehyde 2 (3.5 mmol) in dried acetonitrile (15 mL) was added aryldichlorophosphine 3 (4.0 mmol) under stirring and a nitrogen atmosphere. After the N-Cbz-2-aminoalkanamide 2 was dissolved completely, the resulting solution was stirred in refluxing acetonitrile at 80 C for 1 h. The reaction mixture was allowed to cool to room temperature under stirring. Hydroxyl ester 6 or ethanol (6.0 mmol) was added dropwise. After stirring for 15 min, triethylamine (1.67 mL, 1.22 g, 12 mmol) was added dropwise and the resulting reaction mixture was stirred for another 6 h. After removal of the solvent, the residue was dissolved in ethyl acetate. The solution was washed with saturated aqueous sodium bicarbonate (50 mL×3), saturated brine (50 mL×2), and dried over anhydrous sodium sulfate. After concentration at reduced pressure, the residue was separated on a silica gel column with a mixture of petroleum ether (30-60 C) and ethyl acetate as an eluent with gradient elution to give the desired product phosphinodepsipeptide 7. (Caution: The silica gel column was buffered by 0.5% triethylamine before the sample was loaded. The desired peptide 7 shows very weak fluorescent intensity under UV light. It is better to monitor collective fractions in the column separation after concentration). The aqueous solution was adjusted to pH 1 with 6 mol/L HCl and extracted with ethyl acetate (50 mL×3), the organic phase was dried over anhydrous sodium sulfate. After concentration at reduced pressure, the residue was crystallized from a mixture of ethyl acetate and hexanes or methanol (ethanol) and diethyl ether to afford the corresponding phosphinic acid 5.
ethyl [[(4-methylphenyl)[N-[N-benzyloxycarbonylglycinyl]-1-aminophenylmethyl]phosphinyl]oxy]acetate[ No CAS ]
ethyl [[(4-methylphenyl)[N-[N-benzyloxycarbonylglycinyl]-1-aminophenylmethyl]phosphinyl]oxy]acetate[ No CAS ]
[ 1434588-10-9 ]
Yield
Reaction Conditions
Operation in experiment
23%
General procedure: To a solution of an N-Cbz-2-aminoalkanamide 1 (3.0 mmol) and aldehyde 2 (3.5 mmol) in dried acetonitrile (15 mL) was added aryldichlorophosphine 3 (4.0 mmol) under stirring and a nitrogen atmosphere. After the N-Cbz-2-aminoalkanamide 2 was dissolved completely, the resulting solution was stirred in refluxing acetonitrile at 80 C for 1 h. The reaction mixture was allowed to cool to room temperature under stirring. Hydroxyl ester 6 or ethanol (6.0 mmol) was added dropwise. After stirring for 15 min, triethylamine (1.67 mL, 1.22 g, 12 mmol) was added dropwise and the resulting reaction mixture was stirred for another 6 h. After removal of the solvent, the residue was dissolved in ethyl acetate. The solution was washed with saturated aqueous sodium bicarbonate (50 mL×3), saturated brine (50 mL×2), and dried over anhydrous sodium sulfate. After concentration at reduced pressure, the residue was separated on a silica gel column with a mixture of petroleum ether (30-60 C) and ethyl acetate as an eluent with gradient elution to give the desired product phosphinodepsipeptide 7. (Caution: The silica gel column was buffered by 0.5% triethylamine before the sample was loaded. The desired peptide 7 shows very weak fluorescent intensity under UV light. It is better to monitor collective fractions in the column separation after concentration). The aqueous solution was adjusted to pH 1 with 6 mol/L HCl and extracted with ethyl acetate (50 mL×3), the organic phase was dried over anhydrous sodium sulfate. After concentration at reduced pressure, the residue was crystallized from a mixture of ethyl acetate and hexanes or methanol (ethanol) and diethyl ether to afford the corresponding phosphinic acid 5.
ethyl [[(4-chlorophenyl)[N-[N-benzyloxycarbonylglycinyl]-1-aminophenylmethyl]phosphinyl]oxy]acetate[ No CAS ]
ethyl [[(4-chlorophenyl)[N-[N-benzyloxycarbonylglycinyl]-1-aminophenylmethyl]phosphinyl]oxy]acetate[ No CAS ]
[ 1434588-22-3 ]
Yield
Reaction Conditions
Operation in experiment
18%
General procedure: To a solution of an N-Cbz-2-aminoalkanamide 1 (3.0 mmol) and aldehyde 2 (3.5 mmol) in dried acetonitrile (15 mL) was added aryldichlorophosphine 3 (4.0 mmol) under stirring and a nitrogen atmosphere. After the N-Cbz-2-aminoalkanamide 2 was dissolved completely, the resulting solution was stirred in refluxing acetonitrile at 80 C for 1 h. The reaction mixture was allowed to cool to room temperature under stirring. Hydroxyl ester 6 or ethanol (6.0 mmol) was added dropwise. After stirring for 15 min, triethylamine (1.67 mL, 1.22 g, 12 mmol) was added dropwise and the resulting reaction mixture was stirred for another 6 h. After removal of the solvent, the residue was dissolved in ethyl acetate. The solution was washed with saturated aqueous sodium bicarbonate (50 mL×3), saturated brine (50 mL×2), and dried over anhydrous sodium sulfate. After concentration at reduced pressure, the residue was separated on a silica gel column with a mixture of petroleum ether (30-60 C) and ethyl acetate as an eluent with gradient elution to give the desired product phosphinodepsipeptide 7. (Caution: The silica gel column was buffered by 0.5% triethylamine before the sample was loaded. The desired peptide 7 shows very weak fluorescent intensity under UV light. It is better to monitor collective fractions in the column separation after concentration). The aqueous solution was adjusted to pH 1 with 6 mol/L HCl and extracted with ethyl acetate (50 mL×3), the organic phase was dried over anhydrous sodium sulfate. After concentration at reduced pressure, the residue was crystallized from a mixture of ethyl acetate and hexanes or methanol (ethanol) and diethyl ether to afford the corresponding phosphinic acid 5.
ethyl [[phenyl[N-[N-benzyloxycarbonylglycinyl]-1-amino(4-methylphenyl)methyl]phosphinyl]oxy]acetate[ No CAS ]
ethyl [[phenyl[N-[N-benzyloxycarbonylglycinyl]-1-amino(4-methylphenyl)methyl]phosphinyl]oxy]acetate[ No CAS ]
[ 1434588-36-9 ]
Yield
Reaction Conditions
Operation in experiment
26%
General procedure: To a solution of an N-Cbz-2-aminoalkanamide 1 (3.0 mmol) and aldehyde 2 (3.5 mmol) in dried acetonitrile (15 mL) was added aryldichlorophosphine 3 (4.0 mmol) under stirring and a nitrogen atmosphere. After the N-Cbz-2-aminoalkanamide 2 was dissolved completely, the resulting solution was stirred in refluxing acetonitrile at 80 C for 1 h. The reaction mixture was allowed to cool to room temperature under stirring. Hydroxyl ester 6 or ethanol (6.0 mmol) was added dropwise. After stirring for 15 min, triethylamine (1.67 mL, 1.22 g, 12 mmol) was added dropwise and the resulting reaction mixture was stirred for another 6 h. After removal of the solvent, the residue was dissolved in ethyl acetate. The solution was washed with saturated aqueous sodium bicarbonate (50 mL×3), saturated brine (50 mL×2), and dried over anhydrous sodium sulfate. After concentration at reduced pressure, the residue was separated on a silica gel column with a mixture of petroleum ether (30-60 C) and ethyl acetate as an eluent with gradient elution to give the desired product phosphinodepsipeptide 7. (Caution: The silica gel column was buffered by 0.5% triethylamine before the sample was loaded. The desired peptide 7 shows very weak fluorescent intensity under UV light. It is better to monitor collective fractions in the column separation after concentration). The aqueous solution was adjusted to pH 1 with 6 mol/L HCl and extracted with ethyl acetate (50 mL×3), the organic phase was dried over anhydrous sodium sulfate. After concentration at reduced pressure, the residue was crystallized from a mixture of ethyl acetate and hexanes or methanol (ethanol) and diethyl ether to afford the corresponding phosphinic acid 5.
ethyl [[phenyl[N-[N-benzyloxycarbonylglycinyl]-1-amino(4-chlorophenyl)methyl]phosphinyl]oxy]acetate[ No CAS ]
ethyl [[phenyl[N-[N-benzyloxycarbonylglycinyl]-1-amino(4-chlorophenyl)methyl]phosphinyl]oxy]acetate[ No CAS ]
[ 1434588-51-8 ]
Yield
Reaction Conditions
Operation in experiment
21%
General procedure: To a solution of an N-Cbz-2-aminoalkanamide 1 (3.0 mmol) and aldehyde 2 (3.5 mmol) in dried acetonitrile (15 mL) was added aryldichlorophosphine 3 (4.0 mmol) under stirring and a nitrogen atmosphere. After the N-Cbz-2-aminoalkanamide 2 was dissolved completely, the resulting solution was stirred in refluxing acetonitrile at 80 C for 1 h. The reaction mixture was allowed to cool to room temperature under stirring. Hydroxyl ester 6 or ethanol (6.0 mmol) was added dropwise. After stirring for 15 min, triethylamine (1.67 mL, 1.22 g, 12 mmol) was added dropwise and the resulting reaction mixture was stirred for another 6 h. After removal of the solvent, the residue was dissolved in ethyl acetate. The solution was washed with saturated aqueous sodium bicarbonate (50 mL×3), saturated brine (50 mL×2), and dried over anhydrous sodium sulfate. After concentration at reduced pressure, the residue was separated on a silica gel column with a mixture of petroleum ether (30-60 C) and ethyl acetate as an eluent with gradient elution to give the desired product phosphinodepsipeptide 7. (Caution: The silica gel column was buffered by 0.5% triethylamine before the sample was loaded. The desired peptide 7 shows very weak fluorescent intensity under UV light. It is better to monitor collective fractions in the column separation after concentration). The aqueous solution was adjusted to pH 1 with 6 mol/L HCl and extracted with ethyl acetate (50 mL×3), the organic phase was dried over anhydrous sodium sulfate. After concentration at reduced pressure, the residue was crystallized from a mixture of ethyl acetate and hexanes or methanol (ethanol) and diethyl ether to afford the corresponding phosphinic acid 5.
ethyl [[phenyl[N-[N-benzyloxycarbonylglycinyl]-1-amino-2-methylpropyl]phosphinyl]oxy]acetate[ No CAS ]
ethyl [[phenyl[N-[N-benzyloxycarbonylglycinyl]-1-amino-2-methylpropyl]phosphinyl]oxy]acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
25%
General procedure: To a solution of an N-Cbz-2-aminoalkanamide 1 (3.0 mmol) and aldehyde 2 (3.5 mmol) in dried acetonitrile (15 mL) was added aryldichlorophosphine 3 (4.0 mmol) under stirring and a nitrogen atmosphere. After the N-Cbz-2-aminoalkanamide 2 was dissolved completely, the resulting solution was stirred in refluxing acetonitrile at 80 C for 1 h. The reaction mixture was allowed to cool to room temperature under stirring. Hydroxyl ester 6 or ethanol (6.0 mmol) was added dropwise. After stirring for 15 min, triethylamine (1.67 mL, 1.22 g, 12 mmol) was added dropwise and the resulting reaction mixture was stirred for another 6 h. After removal of the solvent, the residue was dissolved in ethyl acetate. The solution was washed with saturated aqueous sodium bicarbonate (50 mL×3), saturated brine (50 mL×2), and dried over anhydrous sodium sulfate. After concentration at reduced pressure, the residue was separated on a silica gel column with a mixture of petroleum ether (30-60 C) and ethyl acetate as an eluent with gradient elution to give the desired product phosphinodepsipeptide 7. (Caution: The silica gel column was buffered by 0.5% triethylamine before the sample was loaded. The desired peptide 7 shows very weak fluorescent intensity under UV light. It is better to monitor collective fractions in the column separation after concentration). The aqueous solution was adjusted to pH 1 with 6 mol/L HCl and extracted with ethyl acetate (50 mL×3), the organic phase was dried over anhydrous sodium sulfate. After concentration at reduced pressure, the residue was crystallized from a mixture of ethyl acetate and hexanes or methanol (ethanol) and diethyl ether to afford the corresponding phosphinic acid 5.
With 1H-imidazole; In dichloromethane; at 20℃; for 16h;Cooling with ice;
1 (100.0 g, 960.52 mmol) and imidazole (77.3 g, 1.15 mol)Soluble in dichloromethane (1.5L),Under an ice bath, tert-butyldiphenylchlorosilane (264.0 g, 960.52 mmol) was slowly added dropwise using a constant pressure dropping funnel.After the addition is completed,Transfer to room temperature for 16 h.filter,The filtrate was washed with a 1.0 mol/L hydrochloric acid solution (300 ml × 2).The dichloromethane layer was washed with a saturated sodium bicarbonate solution (100 ml x 2).Dry over anhydrous sodium sulfate,Concentrated to a white clear liquid 2 (297.7 g, 91%).
47.6%
With 1H-imidazole; In dichloromethane; at 20℃; for 5.33333h;
To a solution of compound 1 (200 g, 1.92 mol) in DCM (dichloromethane, 2L) was added TBDPSi-CI (tert-butyldiphenylsilyl chloride, 527 g, 1 .92 mol) and the mixture was stirred at room temperature for 20 min untill it dissolved. Then imidazole (261.9 g, 3.85 mol) was added portionwise over 20 min. The resulting mixture was stirred at room temperature for 5 h. To the mixture was added sat.NFUCI (2L), and the aqueous layer extracted with DCM. The combined organics were washed with brine, dried over anhydrous Na2SC"4 and concentrated in vacuum. The resulting crude product was purified by silica-gel column (petroleum ether:acetic acid ethyl ester (PE:AcOEt = 80:1 ) to give 300 g of compound 2 (yield 47.6%). H-NMR (CDCIs): delta= 7.68-7.70 (m, 4H), 7.26-7.43 (m, 6H), 4.23 (s, 2H), 4.14 (q, J= 6.8 Hz, 2H), 1 .22 (t, J= 6.8 Hz, 3H), 1 .09 (s, 9H).
With 1H-imidazole; dmap; In dichloromethane; at 0 - 15℃; for 2h;
[00637] To a mixture of 203-1 (2 g, 19.21 mmol, 1.9 mL, 1.06 eq), lH-imidazole (1.61 g, 23.65 mmol, 1.3 eq) and DMAP (444.5 mg, 3.64 mmol, 0.2 eq) in DCM (15 mL), was added TBDPSCI (5 g, 18.19 mmol, 4.7 mL, 1 eq) at 0 C. The resulting mixture was stirred at 15 C for 2 h. LCMS showed the reaction was completed. The mixture was diluted with water (15 mL), extracted with DCM (15 mL * 3). The organic layer was dried over anhydrous Na2S04, concentrated in vacuum. 203-2 (5.2 g, crude) was obtained, which was checked by 1HNMR. 1HNMR (400 MHz, DMSO-d6) 7.63 (dd, J= 1.4, 7.7 Hz, 4H), 7.49 - 7.41 (m, 6H), 4.27 (s, 2H), 4.06 (q, J= 7.0 Hz, 2H), 1.13 (t, J= 7.0 Hz, 3H), 1.02 (s, 9H).
General procedure: To a solution of an N-Cbz-2-aminoalkanamide 1 (3.0 mmol) and aldehyde 2 (3.5 mmol) in dried acetonitrile (15 mL) was added aryldichlorophosphine 3 (4.0 mmol) under stirring and a nitrogen atmosphere. After the N-Cbz-2-aminoalkanamide 2 was dissolved completely, the resulting solution was stirred in refluxing acetonitrile at 80 C for 1 h. The reaction mixture was allowed to cool to room temperature under stirring. Hydroxyl ester 6 or ethanol (6.0 mmol) was added dropwise. After stirring for 15 min, triethylamine (1.67 mL, 1.22 g, 12 mmol) was added dropwise and the resulting reaction mixture was stirred for another 6 h. After removal of the solvent, the residue was dissolved in ethyl acetate. The solution was washed with saturated aqueous sodium bicarbonate (50 mL×3), saturated brine (50 mL×2), and dried over anhydrous sodium sulfate. After concentration at reduced pressure, the residue was separated on a silica gel column with a mixture of petroleum ether (30-60 C) and ethyl acetate as an eluent with gradient elution to give the desired product phosphinodepsipeptide 7. (Caution: The silica gel column was buffered by 0.5% triethylamine before the sample was loaded. The desired peptide 7 shows very weak fluorescent intensity under UV light. It is better to monitor collective fractions in the column separation after concentration). The aqueous solution was adjusted to pH 1 with 6 mol/L HCl and extracted with ethyl acetate (50 mL×3), the organic phase was dried over anhydrous sodium sulfate. After concentration at reduced pressure, the residue was crystallized from a mixture of ethyl acetate and hexanes or methanol (ethanol) and diethyl ether to afford the corresponding phosphinic acid 5.
EXAMPLE 1422-((l-(2-(3-Fluoro-6-methoxy-l,5-naphthyridin-4-yl)ethyl)-2- oxabicyclo[2.2.2]octan-4-ylamino)methyl)-6H-pyrimido[5,4-b][l,4]oxazin-7(8H)-oneStep 1Ethyl 2-(Tetrahydro-2H-pyran-2-yloxy)acetateTo a stirred solution of ethyl hydroxyacetate (35.3 g) containing a few crystals of p-toluene sulfonic acid, dihydropyran (30.0 g) was added dropwise. After stirring overnight at room temperature, the mixture was diluted with dichloromethane (200 mL) and washed with a sodium hydrogencarbonate solution. The organic layer was separated and dried followed by evaporation of the dichloromethane. The residue was distilled under high vacuum to give the title compound (32 g) as a clear liquid.1H NMR (CDC13): delta 1.20-1.32 (m, 3H), 1.50-1.58 (m, 3H), 1.70-1.92 (m, 3H), 3.45-3.55 (m, 1H), 3.80-3.90 (m, 1H), 4.16-4.24 (m, 4H), 4.70-4.79 (m, 1H).
ethyl 2-((5-chloro-2-cyanopyridin-3-yl)oxy)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 20 - 80℃; for 3.3h;
To a mixture of cesium carbonate (1.63 g, 5.01 mmol) and 5-chloro-3- fluoropicolinonitrile (0.784 g, 5.01 mmol) was added NMP (5 mL) and ethyl glycolate (0.52 mL, 5.49 mmol). The reaction mixture was stirred at RT for 20 min, heated to 80 C for 1 h and additional ethyl glycolate (0.10 mL) was added. Stirring was continued at 80 C for 2 h and the reaction mixture was cooled to RT. The reaction was and diluted with EtOAc and water. The aqueous phase was extracted with EtOAc (2 x) and the combined organic extracts were washed with brine (1 x), dried over MgS04, filtered, and A-1813-WO-PCT - 191 - concentrated. Purification by flash column chromatography on silica gel eluthing with a gradient of 0% to 15% EtOAc in DCM gave ethyl 2-((5-chloro-2-cyanopyridin-3- yl)oxy)acetate (0.83 g, 3.46 mmol, 69 % yield) as a white solid. LC/MS (ESf ) m/z = 240.9 (M+H). Calculated for CioH9ClN203 240.0
3-[(1R)-1-(2,4-dioxooxazolidin-3-yl)ethyl]benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
Intermediate 4 towards Example 44: 3-[(lR)-l-(2,4-Dioxooxazolidin-3-yl)ethyl]benzonitril e [00302] A mixture of 3-[(lR)-l-aminoethyl]benzonitrile hydrochloride (1.09 g, 5.95 mmol), ethyl glycolate (619 mg, 0.563 mL, 5.95 mmol), and NaOMe (0.129 mL, 0.595 mmol) was stirred at 120C for 2 h. The mixture was cooled to rt and concentrated under reduced pressure. The residue was diluted with toluene and concentrated under reduced pressure. The residue was dissolved in DMF (30.0 mL), and CDI (1.06 g, 6.54 mmol) was added. The mixture was stirred at rt for 2 h. The mixture diluted with brine (100 mL). The aqueous phase was extracted with EtOAc (3 x 100 mL), and the combined organic phases were washed with brine (3X100 mL), dried over MgS04, filtered, and concentrated under reduced pressure. The product was purified by flash chromatography on silica gel, eluting with mixtures of hexanes and EtOAc to provide the title compound as a solid (732 mg, 53%).
3-[(1R)-1-(4-chlorophenyl)ethyl]oxazolidine-2,4-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
Intermediate 1 towards Example 40: 3-[(lR)-l-(4-Chlorophenyl)ethyl]oxazolidine-2,4- dione [00287] A mixture of (li?)-l-(4-chlorophenyl)ethanamine (797 mg, 5.12 mmol), ethyl glycolate (533 mg, 0.485 mL, 5.12 mmol), and NaOMe (0.222 mL, 1.02 mmol, 4.6M in MeOH) was stirred at 120C for 2 h. The mixture was cooled to rt and concentrated under reduced pressure. The residue was diluted with toluene and concentrated under reduced pressure. The residue was dissolved in DMF (50.0 mL), and CDI (913 mg, 5.63 mmol) was added. The mixture was stirred at rt for 2 h. The mixture diluted with brine (100 mL). The aq phase was extracted into EtOAc (3 x 100 mL). The combined organic phases were washed with brine (3X100 mL), dried over MgS04, filtered, and concentrated under reduced pressure to provide the title compound as solid (1.20 g, 98%). 1H NMR (500 MHz, CDC13) delta 7.42 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.5 Hz, 2H), 5.29 (q, J = 7.3 Hz, 1H), 4.72 - 4.52 (m, 2H), 1.85 (d, J = 7.4 Hz, 3H).
(5-bromo-pyridin-3-ylmethoxy)-acetic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.6 g
Hydroxy-acetic acid ethyl ester (3.7 g, 36 mmol) is added to a suspension of 60% NaH (1.5 g, 37 mmol) in DMF (70 ml) at 0 C. and the mixture is stirred at room temperature for 15 min. Then <strong>[120277-69-2]3-bromo-5-chloromethyl-pyridine</strong> (3.0 g, 15 mmol) is added to the mixture at 0 C. and the mixture is stirred at room temperature for 16 hrs. The reaction is quenched with saturated. NH4Cl aqueous solution, extracted with EtOAc three times. The organic layers are combined, washed with water and brine, dried over Na2SO4 and concentrated. The residue is purified by flash column chromatography to give 1.6 g of (5-bromo-pyridin-3-ylmethoxy)-acetic acid ethyl ester.
To a solution of ethyl 2-hydroxyacetate (1.6 g, 15 mmol) in tetrahydrofuran (25 mL) at 0 o C, was added sodium hydride (0.61 g, 15 mmol). The reaction was stirred for 0.5 hour, and 3-chloro- 2-fluorobenzaldehyde (2.0 g, 13 mmol) was added. The mixture was stirred at 25 C for 4.5 hours, then quenched with water (5 mL) and extracted with ethyl acetate (2 chi 40 mL). The combined organic layers were concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate =15: 1] to give compound B-291 (0.80 g, 28% yield) as a yellow solid. LCMS (J): tR=1.551 min., (ES+) m/z (M+H)+ =225.0.
With pretreated aluminium vanadium phosphate; In water; at 280℃; under 760.051 Torr;Catalytic behavior; Activation energy;
The glycerol transformation was carried out in a continuous-flow fixed-bed reactor under atmospheric pressure, as previouslydescribed [23]. The reactor was made of stainless-steel tubing(7 mm internal diameter and 190 mm long), placed in a tubularelectric furnace. The temperature was monitored by a thermocou-ple located in the catalyst bed. The analysis of the feed and reactionproducts was carried out on-line using a multicolumn gas chro-matograph (GC) equipped with both flame ionization (FID) andthermal conductivity (TCD) detectors in parallel. The compoundswere separated in a capillary column, DB-1 (100percent methylpolysilox-ane, 60 m x 0,25 mm x 0,25 m).The catalyst (100 mg) was pretreated at the reaction tempera-ture during 2 h in a N2flow (75 mL/min). A 36 wtpercent glycerol (99.5percent,Sigma-Aldrich) aqueous solution was fed at 0.6 mL/h (0.69 mol/sof glycerol). In general, each catalytic test was conducted at least for3 h at different temperatures (220C, 250C and 280C). The reac-tion products were identified by chromatographic patterns and/or agas chromatograph-mass spectrometer (GC?MS) (VARIAN CP 3800,QUADRUPOLE MS 1200) also equipped with a capillary column DB-1. A blank test showed the absence of homogeneous reactions andthe reactor inactivity in the absence of a catalyst.
General procedure: To a solution of 1,2,3,4-<strong>[4049-33-6]tetra-O-acetyl-β-D-xylopyranose</strong> 1 (1.0 equiv) and the corresponding alcohol (1.2 equiv, ethyl glycolate, methyl 6-hydroxyhexanoate or methyl 4-(hydroxymethyl)benzoate) in CH2Cl2 was added BF3.Et2O (1.5 equiv) at 0C under Ar. After stirring for 2h, at room temperature, the organic mixture was washed with a saturated solution of NaHCO3 and water, dried over Na2SO4 and concentrated to dryness under reduced pressure. To a solution of the previously xyloside obtained in MeOH was added Na (10.0mol %) under Ar. After stirring for 1h at room temperature, the mixture was neutralized with DOWEX (H+), filtered and concentrated to dryness under reduced pressure. Xyloside 2 was obtained as a white solid and was characterized without any further purification. The xyloside 3 was purified by flash chromatography over silica gel with eluting mixture CH2Cl2/MeOH: 8:2 to afford a white solid. In the case of xyloside 4, the residue was washed with CH2Cl2 (3×50mL) to afford a pure compound. (0010) Xyloside 2. Yield 72%, white solid, m.p. 95C; 1H NMR (600MHz, D2O, 25C): δ=3.29 (1H, dd, 3J5,4 10.6, 2J5,5 11.6, 5-H), 3.34 (1H, dd, 3J2,1 7.8, 3J2,3 9.3, 2-H), 3.44 (t, 3J3,2=3J3,4 9.3, 3-H), 3.60-3.62 (1H, m, 4-H), 3.78 (3H, s, OCH3), 3.95 (1H, dd, 3J5,4 5.5, 2J5,5 11.6, 5-H), 4.43 (2H, s, OCH2), 4.44 (1H, d, 3J1,2 7.8, 1-H); 13C NMR (150MHz, D2O, 25C): δ=52.5 (OCH3), 65.2 (C-5), 66.2 (OCH2), 69.1 (C-4), 72.7 (C-2), 75.5 (C-3), 102.9 (C-1), 172.3 (C=O); IR (ATR, neat): 1748cm-1(C=O); ESI-HRMS: m/z calcd for C8H14NaO7: [M+Na]+: 245.0637; found: 245.0627; elemental analysis: calcd for C8H14O7+0.25 H2O: C 42.38, H 6.44; found: C 42.12, H 6.24.
ethyl 2-((5-(trifluoromethyl)pyrazin-2-yl)oxy)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
To a solution of ethyl 2-hydroxyacetate (0.167 mL, 1.762 mmol) in tetrahydrofuran (4 mL) at room temperature was added potassium teri-butoxide (1.850 mL, 1.850 mmol). After 10 minutes, <strong>[1196152-38-1]2-bromo-5-(trifluoromethyl)pyrazine</strong> (0.2g, 0.881 mmol) in tetrahydrofuran (4 mL) was added. The mixture was stirred at room temperature overnight. The reaction mixture was quenched by addition of water (10 mL), and extracted with ethyl acetate (3 x 30 mL). The organic phase was dried with MgSO/t, filtered and concentrated under reduced pressure. The residue was used in the next step without further purification (215 mg, 0.859 mmol, 98% yield).JH NMR (400 MHz, DMSO-19F NMR (376 MHz, DMSO- 6) delta ppm -65.37 MS (ESI+) m/z 251 (M+H)+.
Example 6A: Ethyl 2-((5-(trifluoromethyl)pyrazin-2-yl)oxy)acetate To a solution of ethyl 2 -hydroxy acetate (0.167 mL, 1.762 mmol) in tetrahydrofuran (4 mL) at room temperature was added potassium /er/-butoxide (1.850 mL, 1.850 mmol). After 10 minutes, <strong>[1196152-38-1]2-bromo-5-(trifluoromethyl)pyrazine</strong> (0.2g, 0.881 mmol) in tetrahydrofuran (4 mL) was added. The mixture was stirred at room temperature overnight. The reaction mixture was quenched by addition of water (10 mL), and extracted with ethyl acetate (3 x 30 mL). The organic phase was dried with MgSC>4, filtered and concentrated under reduced pressure. The residue was used in the next step without further purification (215 mg, 0.859 mmol, 98% yield). XH NMR (400 MHz, DMSO-i) delta ppm 8.76 (dd, J = 1.4, 0.7 Hz, 1H), 8.63 (d, J = 1.2 Hz, 1H), 5.09 (s, 2H), 4.16 (q, J = 7.1Hz, 2H), 1.19 (t, J = 7.1Hz, 3H). 19F NMR (376 MHz, DMSO-c/6) delta ppm -65.37 MS (ESI+) m/z 251 (M+H)+.
ethyl 3-amino-5-chloro-4,6-dimethylfuro[2,3-b]pyridine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
15.5%
With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 75℃;
Ethyl 3-amino-5-chloro-4,6-dimethylfuro[2,3-b]pyridine-2-carboxylate (D) 2,5-chloro-4,6-dimethylnicotinolnitrile (1.0 g, 6.0 mmol, 1.0 eq.), ethyl glycolate (0.6 mL, 6.6 mmol, 1.1 eq.) and Cs2CO3 (5.9 g, 18 mmol, 3.0 eq.) were added to a 100 mL RBF with NMP (9.23 mL) and allowed to stir at 75 C. overnight. The reaction mixture was filtered through a pad of Celite which was rinsed with DCM and EtOAc. The filtrate was concentrated and purified using reverse phase HPLC to provide the title compound (250 mg, 0.930 mmol, 15.5% yield). 1H NMR (400 MHz, DMSO-d6): delta 6.09 (s, 2H), 4.34 (q, J=7.0 Hz, 2H), 2.72 (s, 3H), 2.61 (s, 3H), 1.34 (t, J=7.0 Hz, 3H); ES-MS [M+1]+: 269.2.
With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 75℃;
Ethyl 3-amino-4,6-dimethyl-furo[2,3-b]pyridine-2-carboxylate (G) <strong>[14237-71-9]2-chloro-4,6-dimethylnicotinonitrile</strong> (1.0 g, 6.0 mmol, 1.0 eq.), ethyl glycolate (0.6 mL, 6.6 mmol, 1.1 eq.), and Cs2CO3 (5.9 g, 18 mmol, 3.0 eq.) were all added to a 100 mL RBF with NMP (9.23 mL. 0.2 M) and allowed to stir at 75 C. overnight. The reaction mixture was filtered through a pad of Celite which was rinsed with DCM and EtOAc. The filtrate was concentrated and purified using reverse phase HPLC to provide the title compound (501 mg, 2.14 mmol, 35.6% yield). 1H NMR (400 MHz, DMSO-d6): delta 7.01 (s, 1H), 6.00 (s, 2H), 4.33 (q, J=7.1 Hz, 2H), 2.65 (s, 3H), 2.48 (s, 3H), 1.34 (d, J=7.1 Hz, 2H); ES-MS [M+1]+: 235.2.
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 3.0h;
To a solution of Example 61b (20.5 g, 0.10 mol), ethyl 2-hydroxyacetate (11.2 g, 0.11 mol) in 100 mL DMF was added NaH (8.0 g, 0.18 mol) by portions at ice temperature. The mixture was stirred at 0C for 1 hr and then it was turned to r.t. for another 2 hrs. The reaction was quenched by adding 80 mL water. The residue was extracted with EtOAc (200 mL * 2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and concentrated under reduced pressure to give the crude product which was further purified by silica gel chromatography to give the pure product as yellow solid (Example 61c, 10.2 g, yield 42%). LCMS [M+1]+=242.1
methyl 4-(2-ethoxy-2-oxoethoxy)-2-methyl-5-nitrobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
460 mg
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 80℃;
To a solution of <strong>[1163287-01-1]methyl 4-fluoro-2-methyl-5-nitrobenzoate</strong> (500 mg) and ethyl glycolate (0.266 mL) in DMF (5mL) was added potassium carbonate (713 mg) at 0C, and the reaction mixture was stirred overnight at 80C. Thereaction mixture was diluted with ethyl acetate/water, and extracted with ethyl acetate. The organic layer was washedwith water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (460 mg).1H NMR (300 MHz, DMSO-d6) delta 1.21 (3H, t, J = 7.1 Hz), 2.59 (3H, s), 3.83 (3H, s), 4.18 (2H, q, J = 7.1 Hz), 5.11 (2H,s), 7.33 (1H, s), 8.37 (1H, s) .
To a solution of ethyl glycolate (476 tL, 5.00 mmol) in THF (10 mL) at 0 Cwas added NaH (400 mg, 10.0 mmol, 60% in oil) in one portion. The mixture was stirred at r.t. for 15 minutes. The dichlroide (1.06 g; 5.00 mmol) was then added and the mixture stirred at r.t. for 14 hours. The mixture was concentrated and purified by silica gel chromatography (0 to 75% EtOAc in hexanes) to afford the desired product as a colorless oil (534 mg; 44%).
Sodium hydride (400 mg, 8.33 mmol) was suspended in toluene (10 mL), ethyl 2-hydroxyacetate (0.70 mL,7.40 mmol) was added and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added(M-30) (1.00 g, 4.53 mmol), and the mixture was stirred at 60C for 18 hr. The reaction mixture was allowed to cool,saturated ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The organic layerwas dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residuewas purified by silica gel column chromatography (n-hexane:ethyl acetate) to give compound (M-31) (yield 650 mg,50%) as a colorless oil
50%
Sodium hydride (400 mg, 8.33 mmol) was suspended in toluene (10 mL)Ethyl 2-hydroxyacetate (0.70 mL, 7.40 mmol) was added and the mixture was stirred at room temperature for 30 minutes.(M-30) (1.00 g, 4.53 mmol) was added to the reaction solution,And the mixture was stirred at 60 C. for 18 hours.After leaving the reaction solution to cool,Saturated ammonium chloride solution was added and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate)Compound (M-31)(Yield 650 mg, yield 50%)As a colorless oil.
ethyl 2-((4,6-dichloropyrimidin-5-yl)oxy)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
450 mg
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃;
To a mixture of <strong>[425394-89-4]4,6-dichloropyrimidin-5-ol</strong> (step 1 intermediate) (4.0 g, 24.2 mmol), ethyl glycolate (3.02 g, 29.1 mmol) and triphenylphosphine (12.7 g, 48.5 mmol) in THF (40 mL) was slowly added diethyl azodicarboxylate (DEAD) (9.8 g, 48.5 mmol) at RT. The mixture was stirred overnight at RT. The mixture was diluted with diethyl ether and filtered off theprecipitated solid. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to yield 450 mg of the desired compound. ?H NMR (400 MHz, DMSO-d6) oe 1.34 (t, J= 7.2 Hz, 3H), 4.31 (q, J= 7.2 Hz, 2H), 4.80 (s, 2H), 8.51 (s, 1H).
6-chloro-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89.9%
To a stirred solution of 3-bromo-6-chloropyrazin-2-amine (75 g, 0.3598 mol) in 1,4-dioxane (1500 mL) at room temperature under nitrogen atmosphere was added sodium tert-butoxide (110.65 g, 1.1514 mol) and stirred for 30 minutes. Then <strong>[623-50-7]ethyl glycolate</strong> (112.37 g, 1.0794 mol) was added dropwise over a period of 30 minutes at room temperature. The resulting mixture was heated to 100C and stirred for 2 hours. The progress of the reaction was monitored by TLC. After that the reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the dioxane. The residue obtained was diluted with water (750 mL) and neutralized using HC1 (1.5 N). The precipitated solid was filtered out and dried under vacuum to get the compound Va as an off white solid. Yield: 60 g, 89.9%; LC-MS Calc. for C6H4CIN3O2, 185.57, Observed 184.0 (M-IH); 1H NMR (400 MHz, DMSO-d6): delta 11.86 (s, 1H), 7.87 (s, 1H), 4.90 (s, 2H).
89.9%
To a stirred solution of 3-bromo-6-chloropyrazin-2-amine (75 g, 0.3598 mol) in l,4-dioxane (1500 mL) at room temperature under nitrogen atmosphere was added sodium tert- butoxide (110.65 g, 1.1514 mol) and stirred for 30 minutes. Then <strong>[623-50-7]ethyl glycolate</strong> (112.37 g, 1.0794 mol) was added dropwise over a period of 30 minutes at room temperature. The resulting mixture was heated to l00C and stirred for 2 hours. The progress of the reaction was monitored by TLC. After that the reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the dioxane. The residue obtained was diluted with water (750 mL) and neutralized using HC1 (1.5 N). The precipitated solid was filtered out and dried under vacuum to get the compound Va as an off white solid. Yield: 60 g, 89.9%; LC-MS Calc for C6H4CIN3O2, 185.57, Observed 184.0 (M-1H); NMR (400 MHz, DMSO-d6): d 11.86 (s, 1H), 7.87 (s, 1H), 4.90 (s, 2H)
89.9%
To a stirred solution of 3-bromo-6-chloropyrazin-2-amine (75 g, 0.3598 mol) in 1,4- dioxane (1500 mL) at room temperature under nitrogen atmosphere was added sodium tert- butoxide (110.65 g, 1.1514 mol) and stirred for 30 minutes. Then <strong>[623-50-7]ethyl glycolate</strong> (112.37 g, 1.0794 mol) was added dropwise over a period of 30 minutes at room temperature. The resulting mixture was heated to l00C and stirred for 2 hours. The progress of the reaction was monitored by TLC. After that the reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the dioxane. The residue obtained was diluted with water (750 mL) and neutralized using HC1 (1.5 N). The precipitated solid was filtered out and dried under vacuum to get the compound IV as an off white solid. Yield: 60 g, 89.9% LC_MS Calc for CefLClNsCh, 185.57, Observed 184.0 (M-1H); NMR (400 MHz, DMSO-d6): d 11.86 (s, 1H), 7.87 (s, 1H), 4.90 (s, 2H).
ethyl 3-oxo-2,3-dihydrofuro[2,3-b]pyridine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35.2%
To a stirred suspension of NaH (10.91 g, 455 mmol) in l,2-dimethoxyethane (1200 mL) was added ethyl 2-hydroxyacetate (39.4 g, 379 mmol) at 0 °C. Reaction mixture was stirred at RT for 30 min. After that methyl 2-chloronicotinate (26 g, 152 mmol) in DME (150 mL) was added to the reaction mixture and the resulting mixture was heated at 75 °C for 2 h. Reaction mixture was concentrated. The crude was basified with saturated sodium bicarbonate and washed with EtOAc (1 x 500 mL). Aqueous layer was acidify with acetic acid, extracted with DCM (2 x 500mL), washed with water (500 mL) and brine (500 mL). Organic layer was dried over anhydrous sodium sulphate filtered and concentrated. The crude residue was purified by column chromatography (100-200 mesh silica). Compound Eluted at 12percent EtOAc in hexane. The eluents were concentrated at reduced pressure and to affording ethyl 3-oxo-2,3-dihydrofuro[2,3- b]pyridine-2-carboxylate (16 g, yield 35.2percent) as off white solid. LCMS (ES) m/z 207.96 [M+l]+.
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