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To a stirred slurry of sodium hydride (2.2 g, 55 mmol) in dry ether (40 mL) at room temperature (rt) was added methyl glycolate (4.5 g, 50 mmol) dropwise. The reaction mixture was stirred for 14 h, then it was concentrated under vacuo. To the solid was added methyl acrylate (5.2 g, 55 mmol) in DMSO (20 mL) at O0C and the mixture was stirred for 15 min, and the cool bath was removed and it was stirred for 45 min. The mixture was poured into 5% H2SO4 (60 mL), and it was extracted with ether (150 mL). The organic layer was dried, concentrated and purified by column chromatography to give 1.7 g (24%) of the title compound. 1H NMR (CDCl3): 4.51-4.40 (m, 2H), 4.03 (q, J = 8.1 Hz, 2H), 3.80 (s, 3H), 3.54 (t, J = 8.1 Hz, IH).
4.5 g (31%)
With sodium; In dimethyl sulfoxide;
Synthesis of 2,5-dihydro furan 3,4-dicarboxylic acid 2.3 g (0.1 mol) sodium was pulverized under toluene and the solvent was replaced with 75 ml ether. 11 ml (0.1 mol) methylglycolate was added to the mixture under stirring until the evolution of hydrogen gas had ceased. To the dry sodium derivative remaining after destination of the ether, a solution of 10 ml (0.12 mol) distilled methylacrylate in 50 ml DMSO was added while the reaction was kept at 4 C. After 15 minutes the solution was stirred for an additional 30-40 min at room temperature and poured into aqueous H2SO4 at 4 C. and extracted with ether. Washing of the organic layer with a saturated NaCl solution, drying over NaSO4 and removal of the ether was followed by destination under reduced pressure to give 4.5 g (31%) of 4-oxo-tetrahydro furane 3-carboxylic acidmethyl ester.
To a suspension of NaH (185 g, 4.6 mol, 60% weight) in THF (4 L) was charged methyl 2-hydroxyacetate (380 g, 4.2 mol) dropwise at 0 C. After the addition, the reaction mixture was stirred for 30 mm at ambient temperature and then re-cooled to 0 C. A solution of methylacrylate (400 g, 4.64 mol) in DMSO (2 L) was added dropwise over 2 hours at 0 C. The resulting reaction mixture was stirred for 30 mm at 0 C and for 2 h at 20 C. After TLC showed that the start material was consumed completely, the mixture was quenched with 1.5 L of 5% H2S04 (slowly) and extracted with EtOAc (3 L). The combined organic layers were washed with brine (1 L), dried over Na2SO4, filtered and concentrated to afford Methyl 4-oxotetrahydrofuran-3-carboxylate (11) as a liquid. The crude oil was used in the next step without further purification. ?H NMR (CDC13, 400 MHz) : 4.3 5-4.45 (m, 2H), 3.86-3.97 (m, 2H), 3.72 (s, 3H), 3.47 (t, 1H).
To a suspension of NaH (185 g, 4.6 mol, 60 weight) in T HF (4 L) was charged methyl 2-hydroxyacetate (380 g, 4.2 mol) dropwise at 0 . After the addition, the reaction mixture was stirred for 30 min at ambient temperature and then re-cooled to 0 . A solution of methyl acrylate (400 g, 4.64 mol) in DMSO (2 L) was added dropwise over 2 hours at 0 . The resulting reaction mixture was stirred for 30 min at 0 and for 2 h at 20 . After TLC showed that the start material was consumed completely, the mixture was quenched with 1.5 L of 5 H2SO4(slowly) and extracted with EtOAc (3 L) . The combined organic layers were washed with brine (1 L) , dried over Na2SO4, filtered and concentrated to afford Methyl 4-oxotetrahydrofuran-3-carboxylate (11) as a liquid. The crude oil was used in the next step without further purification.1H NMR (CDCl3, 400 MHz) delta: 4.35-4.45 (m, 2H) , 3.86-3.97 (m, 2H) , 3.72 (s, 3H) , 3.47 (t, 1H) .
EXAMPLE 172; 4-[7-(2-Morpholin-4-yl-2-oxo-ethoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid (4-pyrrolidin-1-yl-phenyl)-amide; a. 4-[7-(2-Morpholin-4-yl-2-oxo-ethoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester; A mixture of morpholine (107.4 mg, 1.23 mmol) and methyl glycolate (77.5 mg, 860 mumol) was stirred at 150° C. for 3 hr. The resulting homogeneous clear amber oil was taken up in toluene (2.x.2 mL) with repeated rotary evaporation to remove methanol. The residue was taken up in dry THF (860 muL) and KOtBu was added (113 mg, 1.01 mmol). The mixture was stirred at 100° C. for 5-10 min until a brown slurry formed with no visible chunks. The mixture was then allowed to cool to rt, 4-(7-fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (302 mg, 912 mumol), as prepared in Example 65b, was added, and the resulting nearly homogeneous reddish-brown solution was stirred at rt for 1 hr, at which point the reaction solidified into a paste. The reaction was taken up in DCM (4 mL) and washed with 1M NaHCO3 (1.x.2 mL) and 1M NaH2PO4 (1.x.2 mL), and the organic layer was dried (Na2SO4) and concentrated. The residue was purified by silica flash chromatography (9:1 DCM/acetone-->8:2-->8:2 DCM/acetone/3percent DMEA eluent) to provide the title compound as a pale yellow oil (94.8 mg, 24percent over two steps). LC/MS (ESI): calcd mass 456.2, found 457.3 (MH)+.
With sodium hydride; In 1,4-dioxane; at 25℃; for 24h;
To a solution of methyl beta-chloro-delta-nitro-S-pyridinecarboxylate (2 g, 9.3 mmol) in dioxane (40 mL) were added NaH (0.4 g, 10.2 mmol, 60percent in mineral oil) and methyl EPO <DP n="43"/>hydroxyacetate (0.78 g, 9.3 mmol). After stirring at 25°C for 24 hr, the solution was partitioned between ethyl acetate and water. The aqueous solution was extracted several times with ethyl acetate. The organic fractions were combined, concentrated and purified with column chromatography (silica, 5 -30percent ehtyl acetate in hexane) to provide the title compound as a white solid (1.3 g, 56percent): LC/MS (ES) m/e 271 (M+H)+
Sodium hydride (4 g, 60% w/w in oil dispersion, 100 mmol) was added to a flame-dried flask along with ether (100 mL). To the reaction flask under nitrogen atmosphere, methyl glycolate (7.7 mL, 100 mmol) was added slowly with constant stirring. The reaction mixture was allowed to stir at room temperature for 2 hours under nitrogen atmosphere then solvent was removed in vacuo. To the residue, methyl acrylate (10.8 mL, 120 mmol) in DMSO (50 mL) was added in one portion while the reaction flask was kept immersed in an ice bath. The reaction mixture was allowed to stir at 0 C for 15 minutes then at room temperature for 1 hour. The reaction mixture was then filtered through Celte'3', poured into ice-cold aqueous sulfuric acid solution (150 mL, 2N), and extracted with ether (2 x 200 mL). The organic layer was washed with saturated NaCl solution (500 mL), dried over anhydrous Na2S04, filtered, and solvent was removed in vacuo. The intermediate ketoester was recovered in 26% yield (3.7 g, 25.7 mmol) afterpurificationby column chromatography on silica using 25% ethyl acetate/hexanes as the eluent (Rf= 0.3). The ketoester intermediate (3.7g, 25.7 mmol) was added slowly to a solution of sodium hydride (1.4 g, 60% w/w in oil dispersion, 34 mmol) in ether (80 mL) at 0 C with constant stirring under nitrogen atmosphere. After 30 minutes, trifluoromethanesulfonic anhydride (5.3 mL, 31.4 mmol) was added dropwise over 5 minutes. The reaction mixture was allowed to stir at 0 C for an additional 1.5 hours then the reaction was poured into water (80 mL) and the layers were separated. The aqueous phase was washed with dichloromethane (2 x 60 mL) and the organic phases were combined. The organic layer was dried over anhydrous Na2SO4, filtered, and solvent was removed in vacuo. The 2,5- dihydrofuran ester 13a was recovered in 23% yield (1.6 g, 5.8 mmol) after purification by column chromatography on silica using 25% ethyl acetate/hexanes as the eluent (Rf= 0.45). MS: calc. for C7H7F306S : 257.9 ; Found: GC-MS 7nl5 275 (MH).
b) Synthesis of (5-fluoro-3-nitro-pyridin-2-yloxy)-acetic acid methyl ester Hydroxy-acetic acid methyl ester (0.96 g, 10.7 mmol) was dissolved in 2 ml of anhydrous tetrahydrofuran under nitrogen atmosphere, and sodium hydride (0.42 g, 10.7 mmol) was added thereto at room temperature. After stirring for 30 minutes, <strong>[136888-21-6]2-chloro-5-fluoro-3-nitro-pyridine</strong> (1.57 g, 8.89 mmol) dissolved in 15 ml of anhydrous tetrahydrofuran was added dropwise at room temperature, and the reaction mixture was stirred at room temperature for 18 hours. After completion of the reaction by adding water, the mixture was extracted with dichloromethane, and the combined organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluding with a solvent of n-hexane:ethyl acetate=9:1. The fractions containing the product were collected and evaporated to obtain (5-fluoro-3-nitro-pyridin-2-yloxy)-acetic acid methyl ester as yellow liquid (1.35 g, 66%). 1H-NMR (CDCl3, 300 MHz); delta=8.25 (d, J=2.7 Hz, 1H), 8.40 (dd, J=6.9 Hz, 2.7H, 1 Hz), 5.06 (s, 2H), 3.78 (s, 3H). MS (ESI); 231.1 (M++1).
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃;
To 2- (bromomethyl)-l ,4-dichlorobenzen.e (5 g, 20.84 mmol, LOO equiv) in DMF (30 ml.) was added methyl 2-hydroxyacetate (1.89 g, 20.98 mmol, 1.01 equiv) and the solution cooled to 0 C. To this was added in portions sodium hydride (1.0 g, 41.67 mmol, 2.00 equiv). and the resulting solution was allowed to warm to T and then stirred, overnight. The reaction was quenched by the addition of 50 mL of water, the resulting solution was extracted with 3 x 50 mL of ethyl acetate and the organic layers were combined and then wshed with 1 x 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to afford 5.2 g (80%) of intermediate 179a as yellow oil.
b) Preparation of NaH (60percent) (0.022 mol) was stirred in petroleum ether and then decanted (2*). THF (40 ml) was added. A solution of methyl glycolate 98percent (0.022 mol) in THF (40 ml) was added dropwise (exothermic temperature rise to 26° C.). The reaction mixture was stirred at room temperature for 2 hours. A solution of intermediate (41) (0.02 mol) in THF (40 ml) was added dropwise at 20° C./25° C. The reaction mixture was stirred and refluxed for 20 hours, giving reaction mixture (I). NaH (60percent) was stirred twice in petroleum ether and decanted twice. THF (40 ml) was added. Methyl glycolate 98percent in THF (40 ml) was added and the reaction mixture was stirred and refluxed for one hour, giving reaction mixture (II). Reaction mixture (I) was added and the whole was stirred and refluxed for another 24 hours. The mixture was cooled and the solvent was evaporated. The residue was partitioned between water and CH2Cl2. The layers were separated. The aqueous layer was extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated, yielding 6.2 g of intermediate (42).
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