2-chloroethyl acetate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of [2-methyl-4-(5,6,7,8-tetrahydronaphthalen-2-yl)-5-oxazolyl]methanol (3.3 g) in (40 mL) was added thionyl chloride (1.5 mL) at 0° C. After stirring at room temperature for 15 min, the reaction mixture was concentrated. To the residue was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give an oil. To a mixed solution of 2-chloroethyl acetate (2.68 g) and N,N-dimethylformamide (40 mL) was added sodium hydride (60% in oil, 0.6 g) and the mixture was stirred at 0° C. for 5 min. To this the reaction mixture was added a solution of the aforementioned oil in N,N-dimethylformamide (10 mL) at room temperature and the mixture was stirred at room temperature for 2.5 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was diluted with ethanol (30 mL) and a 2N aqueous sodium hydroxide solution (16 mL) was added at 0° C. and the mixture was stirred for 20 min. Water was added to the reaction mixture and the mixture was washed with diethyl ether. The aqueous layer was acidified with 2N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The precipitated crystals were collected by filtration and recrystallized from ethanol to give 2-chloro-3-[2-methyl-4-(5,6,7,8-tetrahydronaphthalen-2-yl)-5-oxazolyl]propionic acid (3.93 g, yield 91%) as colorless prism crystals. melting point: 141–142° C. the reaction mixture was concentrated To the residue was added saturated aqueous sodium hydrogen carbonate the mixture was extracted with ethyl acetate The organic layer was washed successively with water and saturated brine dried over anhydrous magnesium sulfate concentrated to give an oil the mixture was stirred at 0° C. for 5 min the mixture was stirred at room temperature for 2.5 hrs the mixture was extracted with ethyl acetate The organic layer was washed successively with water and saturated brine dried over anhydrous magnesium sulfate concentrated The residue was diluted with ethanol (30 mL) a 2N aqueous sodium hydroxide solution (16 mL) was added at 0° C. the mixture was stirred for 20 min Water was added to the reaction mixture the mixture was washed with diethyl ether the mixture was extracted with ethyl acetate The organic layer was washed successively with water and saturated brine dried over anhydrous magnesium sulfate concentrated The precipitated crystals were collected by filtration recrystallized from ethanol

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was synthesized using a literature method (Alcaide, B.; Biurrun, C.; Martinez, A.; Plumet, J. Tetrahedron Lett. 1995, 36, 5417). To a solution of thiophene-2-carboxaldehyde (6.33 ml, 69 mmol) and chloroethylacetate (7.35 ml, 69 mmol) in 130 ml of ether was added freshly made NaOEt (4.7 g, 69 mmol) over a period of one hour. The solution was allowed to stir overnight at room temperature. The reaction mixture was then filtered and the filtrate was partitioned between water and ether. The ether layer was extracted and washed with water, brine, dried over MgSO4 and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (10% EtOAc in hexanes containing 1% NEt3, Rf=0.55). The title compound was isolated as a red oil in 64% yield. 1H NMR (CDCl3, 200 MHz) δ:7.30 (d, J=5.0 Hz, 1H), 7.17 (d, J=3.4 Hz, 1H), 6.99 (dd, J=5.0 Hz, 3.4 Hz, 1H), 4.33 (s, 1H), 4.28 (qd, J=7.0 Hz, 2.0 Hz, 2H), 3.68 (d, J=2.0 Hz, 1H), 1.33 (t, J=7.0 Hz, 3H) ppm. 13C NMR (CDCl3, 100 MHz) δ: 168.0, 138.6, 127.5, 127.4, 126.3, 69.1, 57.5, 54.9, 14.3 ppm. The title compound was synthesized The reaction mixture was then filtered the filtrate was partitioned between water and ether The ether layer was extracted washed with water, brine dried over MgSO4 concentrated under reduced pressure

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Chloroethyl acetate was slowly added to a mixture of methyl salicylate (100 g, 0.657 mol) and K2CO3 (100 g, 0.723 mol) in DMF (400 mL) at ambient temperature (20-30° C.). The reaction mixture was heated at 65-75° C. for 12-18 h. The progress of the reaction was monitored by HPLC analysis. Upon completion of reaction, the inorganics were filtered off and washed with DMF. DMF was recovered from the filtrate to obtain the product meeting the desired specifications. Yield—91-95%. Upon completion of reaction the inorganics were filtered off washed with DMF DMF was recovered from the filtrate to obtain the product

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of [2-methyl-4-(5,6,7,8-tetrahydronaphthalen-2-yl)-5-oxazolyl]methanol (3.3 g) in (40 mL) was added thionyl chloride (1.5 mL) at 0° C. After stirring at room temperature for 15 min, the reaction mixture was concentrated. To the residue was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give an oil. To a mixed solution of 2-chloroethyl acetate (2.68 g) and N,N-dimethylformamide (40 mL) was added sodium hydride (60% in oil, 0.6 g) and the mixture was stirred at 0° C. for 5 min. To this the reaction mixture was added a solution of the aforementioned oil in N,N-dimethylformamide (10 mL) at room temperature and the mixture was stirred at room temperature for 2.5 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was diluted with ethanol (30 mL) and a 2N aqueous sodium hydroxide solution (16 mL) was added at 0° C. and the mixture was stirred for 20 min. Water was added to the reaction mixture and the mixture was washed with diethyl ether. The aqueous layer was acidified with 2N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The precipitated crystals were collected by filtration and recrystallized from ethanol to give 2-chloro-3-[2-methyl-4-(5,6,7,8-tetrahydronaphthalen-2-yl)-5-oxazolyl]propionic acid (3.93 g, yield 91%) as colorless prism crystals. melting point: 141–142° C. the reaction mixture was concentrated To the residue was added saturated aqueous sodium hydrogen carbonate the mixture was extracted with ethyl acetate The organic layer was washed successively with water and saturated brine dried over anhydrous magnesium sulfate concentrated to give an oil the mixture was stirred at 0° C. for 5 min the mixture was stirred at room temperature for 2.5 hrs the mixture was extracted with ethyl acetate The organic layer was washed successively with water and saturated brine dried over anhydrous magnesium sulfate concentrated The residue was diluted with ethanol (30 mL) a 2N aqueous sodium hydroxide solution (16 mL) was added at 0° C. the mixture was stirred for 20 min Water was added to the reaction mixture the mixture was washed with diethyl ether the mixture was extracted with ethyl acetate The organic layer was washed successively with water and saturated brine dried over anhydrous magnesium sulfate concentrated The precipitated crystals were collected by filtration recrystallized from ethanol

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of sodium hydride (3.0 g, 60% in mineral oil) and dimethyl formamide (100 mL) was kept at 15-18° C. followed by the addition of a solution of 3,4-dihydroquinolin-2(1H)-one (10.0 g) in dimethyl formamide (150 mL). The resulting mixture was stirred at room temperature for 60 min followed by the addition of a solution of 2-chloroethyl acetate (10.0 g) in dimethyl formamide (50 mL) at a temperature of 20° C. The resulting mixture was heated at 80° C. for 2½ h, cooled and poured onto ice. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography on silicagel (eluent: ethyl acetate/heptane 1:1) to give crude 1-(2-acetoxyethyl)-3,4-dihydroquinolin-2(1H)-one (10.2 g). A mixture of crude 1-(2-acetoxyethyl)-3,4-dihydroquinolin-2(1H)-one, sodium methanolate (2.5 mL, 30% in methanol) and methanol (250 mL) was stirred at room temperature for 16 h and subsequently concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent: ethyl acetate/heptane 1:1) to give the corresponding alcohol as a red crystalline compound (4.9 g). This alcohol was dissolved in tetrahydrofuran (100 mL) followed by the addition of triethylamine (8.2 mL). The resulting mixture was cooled to 5-6° C. followed by the addition of a solution of methane sulfonic acid chloride (2 mL) in tetrahydrofuran (25 mL). The mixture was filtered and evaporated to dryness in vacuo. The residue was dissolved in dimethyl formamide (50 mL) followed by addition of lithium chloride (4.9 g), and the resulting mixture was heated at 70° C. for 5 min. The mixture was poured onto brine, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent:ethyl acetate/heptane 1:1) to give the product as a red oil (2.9 g). was kept at 15-18° C. The resulting mixture was heated at 80° C. for 2½ h cooled poured onto ice The aqueous phase was extracted with ethyl acetate the combined organic phases were washed with brine dried (MgSO4) concentrated in vacuo The crude product was purified by flash chromatography on silicagel (eluent: ethyl acetate/heptane 1:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Compound 161 (0.10 g, 0.34 mmol) was added with ethanol (3.0 mL) and chloroethyl acetate (43 μL, 0.41 mmol), and after heating under reflux for 7 hours, the aqueous ammonia was added to stop the reaction. The mixture was extracted with ethyl acetate, concentrated and purified by silica gel column chromatography (hexane/ethyl acetate=4/1 to 1/4), followed by triturating in ethyl acetate to obtain Compound 172 (13 mg, 12%). after heating under reflux for 7 hours the reaction The mixture was extracted with ethyl acetate concentrated purified by silica gel column chromatography (hexane/ethyl acetate=4/1 to 1/4) by triturating in ethyl acetate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 150 ml of liquid ammonia in which 7.8 g of sodium amide had been dissolved, was added 12 g of acetamide and the reaction mixture was reacted at room temperature for 5 hours in a pressure-resistant reaction tube. Then, 57 g of 2-chloroethyl acetate was added to the reaction solution, followed by a further reaction for 3 hours at room temperature. After the completion of the reaction, ammonia was distilled off and 10% aqueous hydrochloric acid solution was added to the resulting residue so as to obtain an aqueous solution of pH 5. The aqueous solution was extracted twice with 100 ml of ethylacetate. The ethylacetate layers were dried with magnesium sulfate, followed by the distillation-off of ethylacetate. The residual substance was subjected to a distillation under reduced pressure but the intended product, N-acetoxyethylacetamide(138°-140° C./ 2 mmHg) did not come out. the reaction mixture was reacted at room temperature for 5 hours in a pressure-resistant reaction tube followed by a further reaction for 3 hours at room temperature was distilled off 10% aqueous hydrochloric acid solution was added to the resulting residue so as to obtain an aqueous solution of pH 5 The aqueous solution was extracted twice with 100 ml of ethylacetate The ethylacetate layers were dried with magnesium sulfate The residual substance was subjected to a distillation under reduced pressure the intended product, N-acetoxyethylacetamide(138°-140° C./ 2 mmHg)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ten grams of sodium hydroxide was suspended in 50 ml of N,N-dimethylacetamide, followed by a further addition of 12 g of acetamide, 0.05 g of phenothiazine and 36 g of 2-chloroethyl acetate. A reaction was allowed to take place at 40° C. for 4 hours with stirring. After the completion of the reaction, the reaction solution was filtered to separate off all the undissolved materials. Under reduced pressures, N,N-dimethylacetoamide and unreacted 2-chloroethyl acetate were distilled off. After adding 100 ml of benzene and 50 ml of distilled water to the residue, the mixture was thoroughly agitated and separated into two layers. The aqueous solution layer was extracted twice with 50 ml of benzene. The benzene layers were combined and dried with magnesium sulfate. The thus-dried benzene layer was subjected to a distillation under reduced pressure. A fraction was collected at 138-140° C./ 2 mmHg, thereby obtaining 22 g of N-acetoxyethylacetamide (yield: 74%). The reaction system in the above reaction contained water of the order of 5000 ppm or so. at 40° C. for 4 hours After the completion of the reaction the reaction solution was filtered to separate off all the undissolved materials Under reduced pressures, N,N-dimethylacetoamide and unreacted 2-chloroethyl acetate were distilled off After adding 100 ml of benzene and 50 ml of distilled water to the residue the mixture was thoroughly agitated separated into two layers The aqueous solution layer was extracted twice with 50 ml of benzene dried with magnesium sulfate The thus-dried benzene layer was subjected to a distillation under reduced pressure A fraction was collected at 138-140° C./ 2 mmHg

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 0.530 g of sodium hydride is added over 20 minutes at 0° C. to a solution of 1 g of 2-hydroxymethylpyridine and DMF. 1.6 ml of chloroethyl acetate is added at 0° C. 2 ml of a solution of sodium acid phosphate is poured in, then the reaction medium is concentrated under reduced pressure. The product obtained is chromatographed on silica eluting with a methylene chloride methanol mixture 90-10. 4.5 g of product is obtained which is chromatographed on silica eluting with a methylene chloride, methanol mixture 90-10. The product is obtained is purified and 1.30 g of sought product is obtained. is concentrated under reduced pressure The product obtained is chromatographed on silica eluting with a methylene chloride methanol mixture 90-10

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of sodium hydride (3.0 g, 60% in mineral oil) and dimethyl formamide (100 mL) was kept at 15-18° C. followed by the addition of a solution of 3,4-dihydroquinolin-2(1H)-one (10.0 g) in dimethyl formamide (150 mL). The resulting mixture was stirred at room temperature for 60 min followed by the addition of a solution of 2-chloroethyl acetate (10.0 g) in dimethyl formamide (50 mL) at a temperature of 20° C. The resulting mixture was heated at 80° C. for 2½ h, cooled and poured onto ice. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography on silicagel (eluent: ethyl acetate/heptane 1:1) to give crude 1-(2-acetoxyethyl)-3,4-dihydroquinolin-2(1H)-one (10.2 g). A mixture of crude 1-(2-acetoxyethyl)-3,4-dihydroquinolin-2(1H)-one, sodium methanolate (2.5 mL, 30% in methanol) and methanol (250 mL) was stirred at room temperature for 16 h and subsequently concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent: ethyl acetate/heptane 1:1) to give the corresponding alcohol as a red crystalline compound (4.9 g). This alcohol was dissolved in tetrahydrofuran (100 mL) followed by the addition of triethylamine (8.2 mL). The resulting mixture was cooled to 5-6° C. followed by the addition of a solution of methane sulfonic acid chloride (2 mL) in tetrahydrofuran (25 mL). The mixture was filtered and evaporated to dryness in vacuo. The residue was dissolved in dimethyl formamide (50 mL) followed by addition of lithium chloride (4.9 g), and the resulting mixture was heated at 70° C. for 5 min. The mixture was poured onto brine, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent: ethyl acetate/heptane 1:1) to give the product as a red oil (2.9 g). was kept at 15-18° C. The resulting mixture was heated at 80° C. for 2½ h cooled poured onto ice The aqueous phase was extracted with ethyl acetate the combined organic phases were washed with brine dried (MgSO4) concentrated in vacuo The crude product was purified by flash chromatography on silicagel (eluent: ethyl acetate/heptane 1:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was synthesized using a literature method (Alcaide, B.; Biurrun, C.; Martinez, A.; Plumet, J. Tetrahedron Lett. 1995, 36, 5417). To a solution of thiophene-2-carboxaldehyde (6.33 ml, 69 mmol) and chloroethylacetate (7.35 ml, 69 mmol) in 130 ml of ether was added freshly made NaOEt (4.7 g, 69 mmol) over a period of one hour. The solution was allowed to stir overnight at room temperature. The reaction mixture was then filtered and the filtrate was partitioned between water and ether. The ether layer was extracted and washed with water, brine, dried over MgSO4 and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (10% EtOAc in hexanes containing 1% NEt3, Rf=0.55). The title compound was isolated as a red oil in 64% yield. 1H NMR (CDCl3, 200 MHz) δ:7.30 (d, J=5.0 Hz, 1H), 7.17 (d, J=3.4 Hz, 1H), 6.99 (dd, J=5.0 Hz, 3.4 Hz, 1H), 4.33 (s, 1H), 4.28 (qd, J=7.0 Hz, 2.0 Hz, 2H), 3.68 (d, J=2.0 Hz, 1H), 1.33 (t, J=7.0 Hz, 3H) ppm. 13C NMR (CDCl3, 100 MHz) δ: 168.0, 138.6, 127.5, 127.4, 126.3, 69.1, 57.5, 54.9, 14.3 ppm. The title compound was synthesized The reaction mixture was then filtered the filtrate was partitioned between water and ether The ether layer was extracted washed with water, brine dried over MgSO4 concentrated under reduced pressure

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Chloroethyl acetate was slowly added to a mixture of methyl salicylate (100 g, 0.657 mol) and K2CO3 (100 g, 0.723 mol) in DMF (400 mL) at ambient temperature (20-30° C.). The reaction mixture was heated at 65-75° C. for 12-18 h. The progress of the reaction was monitored by HPLC analysis. Upon completion of reaction, the inorganics were filtered off and washed with DMF. DMF was recovered from the filtrate to obtain the product meeting the desired specifications. Yield—91-95%. Upon completion of reaction the inorganics were filtered off washed with DMF DMF was recovered from the filtrate to obtain the product