Di-tert-butyl Succinate

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a precooled solution of N,N-diisopropylamine (6.2 mL, 0.044 mol) in diethyl ether (125 mL, dried over molecular seives) was added BuLi (2.5 M in hexanes) (17.8 mL, 0,044 mol) and the resulting solution was stirred at rt. for 15 minutes whereafter di-tert-butylsuccinate (5.35 g, 23 mmol) dissolved in diethyl ether (10 mL, dried over molecular seives) was slowly added. After 30 min at −78° C., 3-formyl-4-methyl-2-(pivaloylamino)-pyridine (4.65 g, 21.0 mmol) dissolved in THF (10 mL, LAB-SCAN C2520, dried over molecular seives) was slowly added, and stirring at this temperature was continued for 30 min. The solution was allowed to warm to rt. and poored into a solution of NH4Cl (sat., aqueous, 100 mL). The aqueous phase was extracted three times with diethylether (3×50 mL) and the organic extracts washed with water (50 mL) and brine (50 mL), dried over MgSO4 and evaporated in vacuo. The crude product was recrystallized from ethyl acetate/hexane to yield the diastereomeric mixture which was used as such after drying in vacuo. The diastereomeric mixture was dissolved in HCl (3M, aqueous, 50 mL) the solution was stirred under reflux for 3.5 h, cooled to rt. and washed with diethyl ether (2×50 mL), neutralised with K2CO3 and again washed with chloroform (3×50 mL). After precipitation upon cooling 1.39 g (37%) of the title compound was obtained (mp >250° C.). 1H NMR (D2O/NaOD): δ 8.25 (d, 4.9 Hz, 1H), 7.71 (s, 1H), 6.84 (d, 4.9 Hz, 1H), 2.36 (s, 2H), 1.05 (s, 3H). 13C NMR (D2O/NaOD): δ 180.30, 171.68, 155.44, 148.84, 146.04, 132.61, 127.08, 117.60, 116.21, 27.22, 16.98. FAB+ MS (m/z): 219.10 (M+H+, calc. for C11H10N2O3+H+ 219.0770). was slowly added was slowly added stirring at this temperature was continued for 30 min to warm to rt The aqueous phase was extracted three times with diethylether (3×50 mL) the organic extracts washed with water (50 mL) and brine (50 mL) dried over MgSO4 evaporated in vacuo The crude product was recrystallized from ethyl acetate/hexane to yield the diastereomeric mixture which after drying in vacuo The diastereomeric mixture was dissolved in HCl (3M, aqueous, 50 mL) the solution was stirred under reflux for 3.5 h cooled to rt and washed with diethyl ether (2×50 mL) again washed with chloroform (3×50 mL) After precipitation upon cooling 1.39 g (37%) of the title compound was obtained (mp >250° C.)

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a precooled (−78° C.) solution of N,N-diisopropylamine (4.84 g, 48.0 mmol) in diethyl ether (125 mL, dried over molecular seives) was added BuLi (2.5 M in hexanes) (19.0 mL, 48.0 mmol), the solution was stirred at this temperature for 15 min before slow addition of di-tert-butyl succinate (5.75 g, 0.0250 mol) dissolved in diethylether (10 mL). After 20 min at −78° C., 3-formyl-6-chloro-2-(pivaloylamino)pyridine (5.00 g, 23.0 mmol) dissolved in dry THF (10 mL, LAB-SCAN C2520, dried over molecular seives) was slowly added. The resulting yellow solution was stirred at −78° C. for 30 min and then allowed to warm to rt. The solution was then poured into NH4Cl (sat., aqueous) (100 mL). The aqueous layer was separated and extracted with diethyl ether (3×50 mL, dried over molecular seives). The combined organic layers were washed once with water (50 mL) and once with brine (50 mL), dried over MgSO4, and evaporated in vacuo. The crude products of diastereomeric alcohols were dissolved in HCl (3M, aqueous) (80 mL) and refluxed for 3.5 h. The aqueous phase was washed with diethyl ether (3×75 mL, dried over molecular seives), with chloroform (3×50 mL) and then adjusted to pH 7 by addition of K2CO3. The resulting yellow precipitate was filtered off, washed once with water and once with diethylether and dried in vacuo to give the desired product (1.25 g, 27%) as a yellow solid. mp. >250° C. 1H NMR (D2O/NaOH; this compound exist as two rotamers; chemical shifts for the minor rotamer is given in brackets): δ 7.53 (d, 8.1 Hz, 1H), 7.31 (s, 1H), 6.69 (d, 8.1 Hz, 1H), 3.20 (s, 2H), 2.25 (s, 3H). 13C NMR (D2O/NaOH): δ 180.4, 172.1, 159.0, 155.7, 136.5, 135.9, 126.6, 116.6, 114.8, 39.6, 23.3. FAB+ MS (m/z): 218.0768 (M+H+, calc. for C11H10N2O3+H+ 219.0770). was slowly added to warm to rt The aqueous layer was separated extracted with diethyl ether (3×50 mL, dried over molecular seives) The combined organic layers were washed once with water (50 mL) and once with brine (50 mL) dried over MgSO4 evaporated in vacuo The crude products of diastereomeric alcohols were dissolved in HCl (3M, aqueous) (80 mL) refluxed for 3.5 h The aqueous phase was washed with diethyl ether (3×75 mL, dried over molecular seives), with chloroform (3×50 mL) adjusted to pH 7 by addition of K2CO3 The resulting yellow precipitate was filtered off washed once with water and once with diethylether dried in vacuo

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of THF (15 mL) and LDA (2M in THF, 15.9 mmol, 7.95 mL), cooled to −78° C., was slowly added a solution of di-t-butyl succinate (15.9 mmol, 3.28 g) in THF (3.0 mL). After 15 minutes at −78° C. 3-Formyl-2-pivaloylaminoquinoline (1.92 g, 7.50 mmol) dissolved in THF (10 mL) was added. The clear yellow solution was stirred at −78° C. for 15 minutes and then allowed to warm to room temperature. The solution was poured into saturated aqueous ammonium chloride (200 mL) and extracted with dichloromethane (2×100 mL). The organic phase was dried (MgSO4) and evaporated in vacuo. The crude product of diastereomeric alcohols was heated to reflux for 24 hours in a mixture of THF (5 mL) and HCl (3M, aqueous) and then poured into water (100 mL) and neutralized with K2CO3. The tan precipitate was washed with water (2×25 mL) and dried in vacuo overnight. The crude product (1.60 g) was heated in acetonitrile (50 mL) and filtered while hot. The product was washed with ether (2×25 mL) and dried in vacuo to give 1.50 g (79%) of a material judged to be 61% pure according to HPLC (260 nm). was added to warm to room temperature extracted with dichloromethane (2×100 mL) The organic phase was dried (MgSO4) evaporated in vacuo The crude product of diastereomeric alcohols was heated to reflux for 24 hours in a mixture of THF (5 mL) and HCl (3M, aqueous) poured into water (100 mL) The tan precipitate was washed with water (2×25 mL) dried in vacuo overnight The crude product (1.60 g) was heated in acetonitrile (50 mL) filtered while hot The product was washed with ether (2×25 mL) dried in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 20.06 Grams (0.418 mole) of 50% sodium hydride dispersion was introduced into a 1 liter four-necked flask equipped with a thermometer, a tap funnel, a reflux cooler and a stirrer and washed with benzene. Then 500 ml of pure tetrahydrofuran and 20 ml of t-BuOH were added thereto and the mixture was refluxed for 30 mins. During the reflux, there was dropwise added 150 ml of pure tetrahydrofuran containing dissolved therein 61.87 g (0.340 mol) of cyclododecanone and 86.0 g (0.374 mol) of di-tert-butyl succinate, over 1.5 hour. After that the reflux was continued to complete the reaction. After the reaction, a mixture of 100 ml of water and 78 ml of concentrated hydrochloric acid was added to the reaction product and the obtained mixture was concentrated. The solvent was removed and the product mixture was twice extracted with 250 ml of ether. The extract liquid was washed with water and dried, followed by concentration to obtain 115.1 g of crude β-cyclododecenyl-β-tert-butoxycarbonyl propionic acid II with the purity of 86.8% and the yield of 86.9%. The crude product was found to include about 2% of cyclododecanone and about 5% of high boiling point-having by-products and the balance of the impurities was solvents. equipped with a thermometer, a tap funnel a reflux cooler and a stirrer and washed with benzene Then 500 ml of pure tetrahydrofuran and 20 ml of t-BuOH were added the mixture was refluxed for 30 mins dissolved the reaction After the reaction was added to the reaction product the obtained mixture was concentrated The solvent was removed the product mixture was twice extracted with 250 ml of ether The extract liquid was washed with water dried followed by concentration

反応条件: temp:276.53; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: An autoclave is charged with 212.5 g (1.80 mol) of succinic acid and 166.8 g (2.25 mol) of tert-butanol and then 808 g (14.40 mol) of isobutene are forced in at 263 K jacket temperature. After the addition is complete, 108.1 g (1.08 mol) of 98% sulfuric acid are pumped in over 70 minutes at a temperature of 268 to 275 K in the vessel. The reaction mixture is then stirred for 30 minutes at a temperature of 275 to 278 K in the vessel and, after increasing the temperature to 293 to 295 K, it is stirred for another 14 hours at that temperature and at a pressure from (4×105) to (5×105) Pa. The reaction mixture is then forced into an agitated mixture consisting of 1000 g of ice and 300 ml (3 mol) of 30% sodium hydroxide solution and the autoclave is then flushed with 200-300 ml of petroleum ether which is also added to the mixture of ice/sodium hydroxide solution. The mixture is warmed to room temperature and the organic phase is separated. The aqueous phase is extracted 3 times with 100-150 ml of petroleum ether each and the organic phases are then combined. The organic phases are concentrated in a rotary evaporator at a bath temperature of 323 K and (3×103) Pa (final value). To purify the crude product it is fractionally distilled, with addition of about 0.5 g of magnesium oxide, via a 30 cm packed column (Raschig rings 5×5 mm) under vacuum. The ester content of the individual fractions is determined by gas chromatography. Fractions having ester contents of <97% by weight are distilled again. After a total of 3 distillations, 329.3 g (79.4% of theory) of di-tert-butyl succinate are obtained having a 97.2% purity (percent per area), determined by gas chromatography, corresponding to 7.2% of theory a 100%. are forced in at 263 K jacket temperature After the addition are pumped in over 70 minutes at a temperature of 268 to 275 K in the vessel after increasing the temperature to 293 to 295 K it is stirred for another 14 hours at that temperature and at a pressure from (4×105) to (5×105) Pa the autoclave is then flushed with 200-300 ml of petroleum ether which is also added to the mixture of ice/sodium hydroxide solution The mixture is warmed to room temperature the organic phase is separated The aqueous phase is extracted 3 times with 100-150 ml of petroleum ether each and the organic phases The organic phases are concentrated in a rotary evaporator at a bath temperature of 323 K and (3×103) Pa (final value) To purify the crude product it is fractionally distilled, with addition of about 0.5 g of magnesium oxide, via a 30 cm are distilled again

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To absolution of THF (15 mL) and LDA (2M in THF, 15.9 mmol, 7.95 mL), cooled to −78° C., was slowly added a solution of di-t-butyl succinate (15.9 mmol, 3.28 g) in THF (3.0 mL). After 15 minutes at −78° C. 3-Formyl-2-pivaloylaminoquinoline (1.92 g, 7.50 mmol) dissolved in THF (10 mL) was added. The clear yellow solution was stirred at −78° C. for 15 minutes and then allowed to warm to room temperature. The solution was poured into saturated aqueous ammonium chloride (200 mL) and extracted with dichloromethane (2×100 mL). The organic phase was dried (MgSO4) and evaporated in vacuo. The crude product of diastereomeric alcohols was heated to reflux for 24 hours in a mixture of THF (5 mL) and HCl (3M, aqueous) and then poured into water (100 mL) and neutralized with K2CO3. The tan precipitate was washed with water (2×25 mL) and dried in vacuo overnight. The crude product (1.60 g) was heated in acetonitrile (50 mL) and filtered while hot. The product was washed with ether (2×25 mL) and dried in vacuo to give 1.50 g (79%) of a material judged to be 61% pure according to HPLC (260 nm). was added to warm to room temperature extracted with dichloromethane (2×100 mL) The organic phase was dried (MgSO4) evaporated in vacuo The crude product of diastereomeric alcohols was heated to reflux for 24 hours in a mixture of THF (5 mL) and HCl (3M, aqueous) poured into water (100 mL) The tan precipitate was washed with water (2×25 mL) dried in vacuo overnight The crude product (1.60 g) was heated in acetonitrile (50 mL) filtered while hot The product was washed with ether (2×25 mL) dried in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a precooled solution of N,N-diisopropylamine (6.2 mL, 0.044 mol) in diethyl ether (125 mL, dried over molecular seives) was added BuLi (2.5 M in hexanes) (17.8 mL, 0,044 mol) and the resulting solution was stirred at rt. for 15 minutes whereafter di-tert-butylsuccinate (5.35 g, 23 mmol) dissolved in diethyl ether (10 mL, dried over molecular seives) was slowly added. After 30 min at −78° C., 3-formyl-4-methyl-2-(pivaloylamino)-pyridine (4.65 g, 21.0 mmol) dissolved in THF (10 mL, LAB-SCAN C2520, dried over molecular seives) was slowly added, and stirring at this temperature was continued for 30 min. The solution was allowed to warm to rt. and poored into a solution of NH4Cl (sat., aqueous, 100 mL). The aqueous phase was extracted three times with diethylether (3×50 mL) and the organic extracts washed with water (50 mL) and brine (50 mL), dried over MgSO4 and evaporated in vacuo. The crude product was recrystallized from ethyl acetate/hexane to yield the diastereomeric mixture which was used as such after drying in vacuo. The diastereomeric mixture was dissolved in HCl (3M, aqueous, 50 mL) the solution was stirred under reflux for 3.5 h, cooled to rt. and washed with diethyl ether (2×50 mL), neutralised with K2CO3 and again washed with chloroform (3×50 mL). After precipitation upon cooling 1.39 g (37%) of the title compound was obtained (mp >250° C.). 1H NMR (D2O/NaOD): δ 8.25 (d, 4.9 Hz, 1H), 7.71 (s, 1H), 6.84 (d, 4.9 Hz, 1H), 2.36 (s, 2H), 1.05 (s, 3H). 13C NMR (D2O/NaOD): δ 180.30, 171.68, 155.44, 148.84, 146.04, 132.61, 127.08, 117.60, 116.21, 27.22, 16.98. FAB+ MS (m/z): 219.10 (M+H+, calc. for C11H10N2O3+H+ 219.0770). was slowly added was slowly added stirring at this temperature was continued for 30 min to warm to rt The aqueous phase was extracted three times with diethylether (3×50 mL) the organic extracts washed with water (50 mL) and brine (50 mL) dried over MgSO4 evaporated in vacuo The crude product was recrystallized from ethyl acetate/hexane to yield the diastereomeric mixture which after drying in vacuo The diastereomeric mixture was dissolved in HCl (3M, aqueous, 50 mL) the solution was stirred under reflux for 3.5 h cooled to rt and washed with diethyl ether (2×50 mL) again washed with chloroform (3×50 mL) After precipitation upon cooling 1.39 g (37%) of the title compound was obtained (mp >250° C.)

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a precooled (−78° C.) solution of N,N-diisopropylamine (4.84 g, 48.0 mmol) in diethyl ether (125 mL, dried over molecular seives) was added BuLi (2.5 M in hexanes) (19.0 mL, 48.0 mmol), the solution was stirred at this temperature for 15 min before slow addition of di-tert-butyl succinate (5.75 g, 0.0250 mol) dissolved in diethylether (10 mL). After 20 min at −78° C., 3-formyl-6-chloro-2-(pivaloylamino)pyridine (5.00 g, 23.0 mmol) dissolved in dry THF (10 mL, LAB-SCAN C2520, dried over molecular seives) was slowly added. The resulting yellow solution was stirred at −78° C. for 30 min and then allowed to warm to rt. The solution was then poured into NH4Cl (sat., aqueous) (100 mL). The aqueous layer was separated and extracted with diethyl ether (3×50 mL, dried over molecular seives). The combined organic layers were washed once with water (50 mL) and once with brine (50 mL), dried over MgSO4, and evaporated in vacuo. The crude products of diastereomeric alcohols were dissolved in HCl (3M, aqueous) (80 mL) and refluxed for 3.5 h. The aqueous phase was washed with diethyl ether (3×75 mL, dried over molecular seives), with chloroform (3×50 mL) and then adjusted to pH 7 by addition of K2CO3. The resulting yellow precipitate was filtered off, washed once with water and once with diethylether and dried in vacuo to give the desired product (1.25 g, 27%) as a yellow solid. mp. >250° C. 1H NMR (D2O/NaOH; this compound exist as two rotamers; chemical shifts for the minor rotamer is given in brackets): δ 7.53 (d, 8.1 Hz, 1H), 7.31 (s, 1H), 6.69 (d, 8.1 Hz, 1H), 3.20 (s, 2H), 2.25 (s, 3H). 13C NMR (D2O/NaOH): δ 180.4, 172.1, 159.0, 155.7, 136.5, 135.9, 126.6, 116.6, 114.8, 39.6, 23.3. FAB+ MS (m/z): 218.0768 (M+H+, calc. for C11H10N2O3+H+ 219.0770). was slowly added to warm to rt The aqueous layer was separated extracted with diethyl ether (3×50 mL, dried over molecular seives) The combined organic layers were washed once with water (50 mL) and once with brine (50 mL) dried over MgSO4 evaporated in vacuo The crude products of diastereomeric alcohols were dissolved in HCl (3M, aqueous) (80 mL) refluxed for 3.5 h The aqueous phase was washed with diethyl ether (3×75 mL, dried over molecular seives), with chloroform (3×50 mL) adjusted to pH 7 by addition of K2CO3 The resulting yellow precipitate was filtered off washed once with water and once with diethylether dried in vacuo

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of THF (15 mL) and LDA (2M in THF, 15.9 mmol, 7.95 mL), cooled to −78° C., was slowly added a solution of di-t-butyl succinate (15.9 mmol, 3.28 g) in THF (3.0 mL). After 15 minutes at −78° C. 3-Formyl-2-pivaloylaminoquinoline (1.92 g, 7.50 mmol) dissolved in THF (10 mL) was added. The clear yellow solution was stirred at −78° C. for 15 minutes and then allowed to warm to room temperature. The solution was poured into saturated aqueous ammonium chloride (200 mL) and extracted with dichloromethane (2×100 mL). The organic phase was dried (MgSO4) and evaporated in vacuo. The crude product of diastereomeric alcohols was heated to reflux for 24 hours in a mixture of THF (5 mL) and HCl (3M, aqueous) and then poured into water (100 mL) and neutralized with K2CO3. The tan precipitate was washed with water (2×25 mL) and dried in vacuo overnight. The crude product (1.60 g) was heated in acetonitrile (50 mL) and filtered while hot. The product was washed with ether (2×25 mL) and dried in vacuo to give 1.50 g (79%) of a material judged to be 61% pure according to HPLC (260 nm). was added to warm to room temperature extracted with dichloromethane (2×100 mL) The organic phase was dried (MgSO4) evaporated in vacuo The crude product of diastereomeric alcohols was heated to reflux for 24 hours in a mixture of THF (5 mL) and HCl (3M, aqueous) poured into water (100 mL) The tan precipitate was washed with water (2×25 mL) dried in vacuo overnight The crude product (1.60 g) was heated in acetonitrile (50 mL) filtered while hot The product was washed with ether (2×25 mL) dried in vacuo