| 100% |
With toluene-4-sulfonic acid In toluene at 20℃; for 20 h; |
1,4-Dioxa-spiro[4.5]decane-8-carboxylic Acid Ethyl Ester 2; 4-Oxo-cyclohexanecarboxylic acid ethyl ester 1 (52.8 g, 0.31 mol, Merck, order no. 814249), ethylene glycol (67.4 g, 1.08 mol) and p-toluenesulfonic acid (0.7 g) in toluene (160 ml) were stirred at RT for 20 hours. The reaction solution was poured into diethyl ether (300 ml), and the mixture was washed with water, sodium bicarbonate solution and sodium chloride solution. The solution was dried (Na2SO4), concentrated i. vac. and the colorless liquid which remained was processed further without purification.Yield: 66.5 g (100percent)1H-NMR (CDCl3): 1.24 (t, 3H); 1.53 (m, 2H); 1.76 (m, 4H); 1.92 (m, 2H); 2.31 (m, 1H); 3.91 (s, 4H); 4.11 (q, 2H).13C-NMR (CDCl3): 14.28 (q); 26.32 (t); 33.76 (t); 41.59 (d); 60.14 (t); 64.21 (t); 107.90 (d); 174.77 (s). |
| 100% |
With toluene-4-sulfonic acid In toluene at 20℃; for 20 h; |
4-oxocyclohexane carboxylic acid ethyl ester 9 (52.8 g, 0.31 mole, Merck, Order No. 814249), ethylene glycol (67.4 g, 1.08 mol) and p-toluenesulfonic acid (0.7 g) in toluene (160 ml) were stirred for 20 hours at RT, and the reaction solution was poured into diethyl ether (300 ml) and washed with water, sodium hydrogen carbonate solution and sodium chloride solution. The solution was dried (Na2SO4), concentrated by evaporation in vacuo, and the remaining colorless liquid was processed further without purification.Yield: 66.5 g (100percent)1H-NMR (CDCl3): 1.24 (t, 3H); 1.53 (m, 2H); 1.76 (m, 4H); 1.92 (m, 2H); 2.31 (m, 1H); 3.91 (s, 4H); 4.11 (q, 2H).13C-NMR (CDCl3): 14.28 (q); 26.32 (t); 33.76 (t); 41.59 (d); 60.14 (t); 64.21 (t); 107.90 (d); 174.77 (s). |
| 100% |
at 20℃; Inert atmosphere |
Ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate. This compound was prepared from ethyl cyclohexanone-4-carboxylate by following the procedure of Pearson et al. (J. Org. Chem., 1997, 62, 5284). A mixture of ethylene glycol (131 mL, 2350 mmol), ethyl 4-oxocyclohexanecarboxylate (100 g, 588 mmol), and p-toluene sulfonic acid monohydrate (2.012 g, 10.58 mmol) in benzene (125 mL) was stirred overnight at room temperature, under N2. The solution was poured into Et2O (1 L) and the mixture washed with water (3.x.300 mL), sat. NaHCO3 (100 mL) followed by brine (100 mL). The organic layer was then dried (MgSO4), filtered, and concentrated to yield the title compound (125.5 g, 586 mmol, 100percent yield) as a clear oil: LCMS m/z 215.13 (M+H). |
| 100% |
With toluene-4-sulfonic acid In toluene at 20℃; for 20 h; |
1,4-Dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester 1; 4-Oxo-cyclohexanecarboxylic acid ethyl ester (52.8 g, 0.31 mol, Merck, Order No. 814249), ethylene glycol (67.4 g, 1.08 mol) and p-toluenesulfonic acid (0.7 g) in toluene (160 ml) were stirred for 20 h at RT; the reaction solution was poured into diethyl ether (300 ml) and washed with water, sodium hydrogen carbonate solution and sodium chloride solution. The solution was dried (Na2SO4) and concentrated in vacuo, and the colourless liquid that remained was processed further without being purified.Yield: 66.5 g (100percent)1H-NMR (CDCl3): 1.24 (t, 3H); 1.53 (m, 2H); 1.76 (m, 4H); 1.92 (m, 2H); 2.31 (m, 1H); 3.91 (s, 4H); 4.11 (q, 2H).13C-NMR (CDCl3): 14.28 (q); 26.32 (t); 33.76 (t); 41.59 (d); 60.14 (t); 64.21 (t); 107.90 (d); 174.77 (s). |
| 100% |
With toluene-4-sulfonic acid; orthoformic acid triethyl ester In dichloromethane at 20℃; |
To a solution of ethyl 4-oxocyclohexanecarboxylate (1 equiv.) in DCM (0.6 M) were added ethane-1,2-diol (2 equiv.), triethoxymethane (2 equiv.) and pTSA (0.05 equiv.).
The reaction was stirred at room temperature overnight.
The reaction was concentrated in vacuum.
The resulting residue was diluted with petroleum/ethyl acetate, filtered through a pad of silica gel.
The filtrate was concentrated to give ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (100percent).
1H NMR (400 MHz, CDCl3) δ ppm: 4.11 (q, J=7.2 Hz, 2H), 3.93 (s, 4H), 2.37-2.26 (m, 1H), 1.98-1.87 (m, 2H), 1.85-1.71 (m, 4H), 1.59-1.48 (m, 2H), 1.22 (t, J=7.2 Hz, 3H). |
| 99.3% |
Stage #1: for 1 h; Dean-Stark trap; Heating / reflux
Stage #2: With toluene-4-sulfonic acid In toluene for 0.5 h; Heating / reflux |
[0367] A solution of 4-cyclohexanonecarboxylic acid ethyl ester (5.00 g, 29.38 mmol) and ethylene glycol (2.13 mL, 38.19 mmol) in toluene (150 mL) was heated in a Dean-Stark trap at reflux for 1 h and was then treated with p-toluenesulfonic acid monohydrate (56.74 mg, 0.294 mmol). The reaction solution was heated an additional 30 min at reflux, cooled to 25° C., and concentrated in vacuo. The resulting oil was dissolved in ethyl acetate (200 mL), washed with water (2.x.50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford pure 1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester (6.25 g, 99.3percent) as a colorless oil. [0368] A solution of 1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester (2.00 g, 9.33 mmol) in tetrahydrofuran (40 mL) at 0° C. was treated dropwise with a 1.0M solution of lithium aluminum hydride in tetrahydrofuran (10.0 mL, 10.0 mmol). The reaction mixture was stirred at 0° C. for 30 min and was then quenched by the dropwise addition of ethyl acetate. The reaction was then diluted with a saturated aqueous ammonium chloride solution (25 mL) and extracted with ethyl acetate (3.x.25 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to afford pure (1,4-dioxa-spiro[4.5]dec-8-yl)-methanol (1.60 g, 99.9percent) as a colorless oil. [0369] A solution of (1,4-dioxa-spiro[4.5]dec-8-yl)-methanol (1.60 g, 9.29 mmol) in methylene chloride (50 mL) was treated with 4-(dimethylamino)pyridine (1.26 g, 10.22 mmol) and p-toluenesulfonyl chloride (1.86 g, 9.75 mmol). The reaction mixture was stirred at 25° C. for 2 h, and was then washed with a saturated aqueous sodium bicarbonate solution (1.x.25 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was dissolved in acetone (30 mL) and treated with sodium iodide (4.73 g, 31.53 mmol). The reaction was heated under reflux for 2 h, cooled to 25° C., and then concentrated in vacuo. The resulting residue was suspended in ethyl acetate (50 mL), washed with water (2.x.15 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 19/1 hexanes/ethyl acetate) afforded 8-iodomethyl-1,4-dioxa-spiro[4.5]decane (2.32 g, 88.6percent) as a colorless oil. [0370] A solution of diisopropylamine (0.23 mL, 1.63 mmol) in dry tetrahydrofuran (5.0 mL) cooled to -78° C. under nitrogen was treated with a 2.5M solution of n-butyllithium in hexanes (0.65 mL, 1.63 mmol). The reaction mixture was stirred at -78° C. for 30 min and then treated dropwise with a solution of (3-chloro-4-methylsulfanyl-phenyl)-acetic acid methyl ester (prepared as in Example 4, 340 mg, 1.48 mmol) in dry tetrahydrofuran (3.0 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.0 mL). The reaction mixture turned dark in color and was allowed to stir at -78° C. for 1 h, at which time, a solution of 8-iodomethyl-1,4-dioxa-spiro[4.5]decane (500 mg, 1.78 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25° C., where it was stirred for 24 h. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution and then concentrated in vacuo to remove tetrahydrofuran. The aqueous residue was acidified using a 10percent aqueous hydrochloric acid solution. The resulting aqueous layer was extracted with ethyl acetate (2.x.100 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S Silica 8/2 hexanes/ethyl acetate) afforded the 2-(3-chloro-4-methylsulfanyl-phenyl)-3-(1,4-dioxa-spiro[4.5]dec-8-yl)-propionic acid methyl ester (315 mg, 55percent) as a yellow viscous oil: EI-HRMS m/e calcd for C19H25ClO4S (M+) 384.1162, found 384.1169. [0371] A solution of 2-(3-chloro-4-methylsulfanyl-phenyl)-3-(1,4-dioxa-spiro[4.5]dec-8-yl)-propio |
| 99% |
for 2.5 h; Reflux |
Example 2 - Synthesis and Characterization of MCE-I and MCE-3MCE-I and MCE-3 were synthesized as described below and summarized in Scheme2. Ethyl l,4-dioxaspiro[4,5]decane-8-carboxilate (2). A mixture of ethyl 4- oxocyclohexanecarboxylate (25 g), 10-campharsulfonic acid, ethylene glycol (40 mL), and toluene (400 mL) was heated under reflux with a Dean-Stark apparatus for 2.5 h (bath temp. 135 °C). The mixture was cooled down, and then was diluted with ether (200 mL). After the ethylene glycol layer was separated, the organic layer was washed with saturated aqueous sodium bicarbonate solution (2x) and brine (Ix), dried over MgSO4, and filtered. The filtrate was evaporated in vacuo to give 2 as an oil (31.29 g, 99percent): 1H NMR (CDCl3) δ 4.13 (2H, q, J = 7.1 Hz), 3.95 (4H, s), 2.33 (IH, m), 1.93 (2H, m), 1.79 (4H, m), 1.56 (2H, m) 1.25 (3H, t, J =7.1 Hz); 13C NMR (CDCl3) δ 175.4, 108.3, 64.5, 60.5, 41.8, 33.9, 26.5, 14.4. |
| 99% |
With toluene-4-sulfonic acid In tolueneReflux |
To ethyl 4-oxo-cyclohexanecarboxylic acid (30.0g, 176mmol), ethylene glycol (22.0g, 353mmol) and p-toluenesulfonic acid (304mg, 1.70mmol) was dissolved in toluene (315 mL), add water separator The reaction is heated to reflux overnight. The reaction was cooled to 25°C, washed with water (300mLx2), saturated sodium bicarbonate (500 mLx2), the organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure, purified by silica gel column chromatography and purified: obtained (11 petroleum ether / ethyl acetate, Rf = 0.3) the product of ethyl 1,4-dioxa-spiro [4,5] decane-8-carboxylate (37.2g, yellow liquid). yield: 99percent. |
| 99% |
With (1S)-10-camphorsulfonic acid In toluene for 8 h; Reflux; Dean-Stark; Inert atmosphere |
A mixture of ethyl 4-oxocyclohexanecarboxylate (12.7 g, 75 mmol), ethylene glycol (21 ml, 373 mmol), (1S)-(+)-1O-camphorsulfonic acid (0.175 g, 0.75 mmol) and anhydroustoluene (300 mL) was refluxed with a Dean-Stark water trap for 8 hours. The mixture wasquenched with 100 mL saturated sodium bicarbonate solution and was vigorously stirred.The separated organic phase was washed with water (100 mL), dried over Na2SO4 andconcentrated in vacuo. The cmde product was purified by silica gel column eluted with 0-15 percent ethyl acetate I hexanes to give the desired product as an oil (15.9 g, 99 percent). ‘H NMR (400MHz, CHLOROFORM-d) ö 4.13 (q, J=7.2 Hz, 2H), 3.95 (s, 4H), 2.34 (tt, J10.4, 4.0 Hz, 1H), 1.98 - 1.90 (m, 2H), 1.87-1.75 (m, 4H), 1.61 - 1.51 (m, 2H), 1.25 (t, J=7.2 Hz, 3H). |
| 99% |
With toluene-4-sulfonic acid In tolueneDean-Stark; Reflux |
The solution of ethyl 4-oxocyclohexanedicarboxy- late (30.0 g, 176 mmol), ethanediol (22.0 g, 353 mmol) and p-methylbenzenesulfonic acid (304 mg, 1.70 mmol) in methylbenzene (315 mE) was refluxed in Dean-Stark vessel overnight. The reaction solution was cooled to room temperature, and was successively washed with water (300 mLx2) and saturated sodium bicarbonate (500 mLx2). The organic phase was dried with anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel colunm chromatography (1:1, petroleum ether/ethyl acetate, Rf=0.3) to obtain the product ethyl 1, 4-dioxaspiro[4,5]decan-8- carboxylate (37.2 g, yellow liquid) with yield of 99percent. MS-ESI calculated value: [M+H]+ 215, measured value:215. |
| 98% |
With toluene-4-sulfonic acid In toluene at 150℃; for 18 h; |
(Reference Example 83) Ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate [Show Image] To a solution of ethyl 4-oxocyclohexanecarboxylate (10.0 g, 58.8 mmol) in toluene (196 mL), ethylene glycol (3.6 mL, 64.6 mmol) and p-toluenesulfonic acid monohydrate (1.12 g, 5.88 mmol) were added, and the obtained solution was heated to reflux at 150°C. The resulting solution was stirred for 18 hours. The reaction was quenched by adding a saturated sodium bicarbonate solution to the reaction solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (12.3 g, 57.4 mmol, 98percent) as a colorless oily compound. 1H-NMR (400 MHz, CDCl3) δ: 1.25 (3H, t, J= 7.2 Hz), 1.51-1.61 (2H, m), 1.75-1.86 (4H, m), 1.90-1.98 (2H, m), 2.29-2.38 (1H, s), 3.95 (4H, s), 4.13 (2H, q, J= 7.2 Hz). ESI-MS: m/z = 215 (M+H)+ |
| 98% |
With toluene-4-sulfonic acid In toluene at 150℃; for 18 h; |
Ethylene glycol (3.6 mL, 64.6 mmol) and p-toluenesulfonic acid monohydrate (1.12 g, 5.88 mmol) were added to a solution of ethyl 4-oxocyclohexanecarboxylate (10.0 g, 58.8 mmol) in toluene (196 mL), and the obtained solution was heated to reflux at 150°C. The resulting solution was stirred for 18 hours. To the reaction solution, a saturated sodium bicarbonate solution was added to stop the reaction, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain Intermediate 43 (12.3 g, 57.4 mmol, 98percent) as a colorless oily compound.1H-NMR (400 MHz, CDCl3) δ: 1.25 (3H, t, J = 7.2 Hz), 1.51-1.61 (2H, m), 1.75-1.86 (4H, m), 1.90-1.98 (2H, m), 2.29-2.38 (1H, s), 3.95 (4H, s), 4.13 (2H, q, J= 7.2 Hz).ESI-MS: m/z = 215 (M+H)+ |
| 98% |
With toluene-4-sulfonic acid In toluene at 150℃; for 18 h; Reflux |
As Intermediate 43, ethyl 1,4-dioxaspiro[4.5]decan-8-carboxylate: was synthesized by the following procedure.[0385] Ethylene glycol (3.6 mL, 64.6 mmol) and p-toluenesulfonic acid monohydrate (1.12 g, 5.88 mmol) were added to a solution of ethyl 4-oxocyclohexanecarboxylate (10.0 g, 58.8 mmol) in toluene (196 mL), and the obtained solution was heated to reflux at 150°C. The resulting solution was stirred for 18 hours. To the reaction solution, a saturated sodium bicarbonate solution was added to stop the reaction, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain Intermediate 43 (12.3 g, 57.4 mmol, 98percent) as a colorless oily compound.1H-NMR (400 MHz, CDCl3) РћТвЂ: 1.25 (3H, t, J= 7.2 Hz), 1.51-1.61 (2H, m), 1.75-1.86 (4H, m), 1.90-1.98 (2H, m), 2.29-2.38 (1H, s), 3.95 (4H, s), 4.13 (2H, q, J= 7.2 Hz).ESI-MS: m/z = 215 (M+H)+ |
| 97% |
With (1S)-10-camphorsulfonic acid In toluene for 28 h; Inert atmosphere; Dean-Stark; Reflux |
Step 1. Preparation of ethyl l,4-dioxaspiro[4.5]decane-8-carboxylate. Into a 3L, 3 neck round bottom flask was placed ethyl 4-oxocyclohexanecarboxylate (100 g, 570 mmol), ethane- 1 ,2-diol (0.159 L, 2849 mmol), ((15,4R)-7,7-dimethyl-2- oxobicyclo[2.2.1]heptan-l-yl)methanesulfonic acid (1.324 g, 5.70 mmol) and dry toluene (1.2 L). A Dean-Stark water trap and a condenser were installed and the mixture heated to reflux with stirring. Immiscible distillate was collected in the Dean-Stark trap and was periodically removed. After 28 h of total reflux time, a total of 82 mL of immiscible distillate had been removed from the Dean-Stark trap. After the mixture had cooled to approximately 40 °C, sat. NaHCC (400 mL) was added to the reaction mixture with rapid stirring. The mixture was transferred to a separatory funnel, shaken and the phases separated. The organic layer was washed with water (4 x 500 mL), then with 5percent aHC03 (200 mL) and then with brine (100 mL). The organic material was dried over anhydrous MgS04, filtered and concentrated under reduced pressure to give a slightly yellow viscous oil (1 18.50 g, 97percent yield). NMR (400MHz, CHLOROFORM-d) δ 4.15 (q, J=7.3 Hz, 2H), 3.96 (s, 4H), 2.41 - 2.27 (m, 1H), 1.96 (dt, J=8.7, 4.3 Hz, 2H), 1.89 - 1.74 (m, 4H), 1.68 - 1.49 (m, 2H), 1.27 (t, J=7.1 Hz, 3H). 13C NMR (101MHz, CHLOROFORM-d) δ 175.2, 108.1, 64.3, 60.3, 41.6, 33.8, 26.3, 14.3. |
| 97% |
With (1S)-10-camphorsulfonic acid In toluene for 28 h; Dean-Stark; Reflux |
Into a 3L, 3 neck round bottom flask was placed ethyl 4-oxo-cyclohexanecarboxylate (100 g, 570 mmol), ethane-1,2-diol (0.159 L, 2849 mmol), ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl) methanesulfonic acid (1.324 g, 5.70 mmol) and dry toluene (1.2 L). A Dean-Stark water trap and a condenser were installed and the mixture heated to reflux with stirring. Immiscible distillate was collected in the Dean-Stark trap and was periodically removed. After 28h of total reflux time, a total of 82 mL of immiscible distillate had been removed from the Dean-Stark trap. After the mixture had cooled to approximately 40 °C, sat. NaHCO3 (400mL) was added to the reaction mixture with rapid stirring. The mixture was transferred to a separatory funnel, shaken and the phases separated. The organic layer was washed with water (4 x 500 mL), then with 5percent NaHCO3 (200 mL) and then with brine (100 mL). The organic material was dried over anhydrous MgSO4, filtered and concentrated in vacuum to give a slightly yellow viscous oil (118.50 g, 97percent yield). H1 NMR (400 MHz, CHLOROFORM-d) δ 4.15(q, J=7.3 Hz, 2H), 3.96(s, 4H), 2.41 - 2.27(m, 1H), 1.96(dt, J=8.7, 4.3 Hz, 2H), 1.89-1.74(m, 4H), 1.68-1.49(m, 2H), 1.27(t, J=7.1 Hz, 3H). C13 NMR (101 MHz, CHLOROFORM-d) δ 175.2, 108.1, 64.3, 60.3, 41.6, 33.8, 26.3, 14.3. |
| 97% |
With toluene-4-sulfonic acid In benzene at 130℃; for 12 h; Dean-Stark |
A solution of ethyl 4-oxocyclohexanecarboxylate (10 g, 58.8 mmol) and ethylene glyco (16.38 ml, 294 mmol) in benzene (196 ml) in the presence of pTSA (50 mg) was heated at 130 °C wit a Dean-Stark trap for 12 h. Water was added and the aqueous layer was extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered, and the filltrate was evaporated in vacuo to give ethyl l,4-dioxaspiro[4.5]decane-8- carboxylate (12.2 g, 56.9 mmol, 97 percent yield) as a colorless oil. NMR (500MHz, (0236) CHLOROFORM-d) δ 4.15 (q, J=7.1 Hz, 1H), 3.96 (s, 2H), 2.40 - 2.31 (m, 1H), 2.01 - 1.92 (m, 2H), 1.89 - 1.76 (m, 4H), 1.63 - 1.51 (m, 3H), 1.30 - 1.24 (m, 3H). |
| 96% |
With toluene-4-sulfonic acid In toluene at 20℃; for 14 h; |
Ethyl 4-oxocyclohexanecarboxylate (15.01 g, 88.16 mmol) was combined with ethylene glycol (21 mL, 4.27 equiv.) and p-toluenesulfonic acid monohydrate (0.200 g, 0.012 equiv.) in anhydrous toluene (50 mL), and the mixture was stirred 14h at room temperature. The reaction was diluted with ether (200 mL) and was washed with H2O (2 x 200 mL), saturated sodium bicarbonate (100 mL) and brine (80 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure to yield 18.15 g ethyl 4- oxocyclohexanecarboxylate ethylene ketal (96percent yield). |
| 96% |
With toluene-4-sulfonic acid In toluene at 20℃; for 14 h; |
Step 1.
Ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate
Ethyl 4-oxocyclohexanecarboxylate (15.01 g, 88.16 mmol) was combined with ethylene glycol (21 mL, 4.27 equiv.) and p-toluenesulfonic acid monohydrate (0.2 g, 0.012 equiv.) in anhydrous toluene (50 mL), and the mixture was stirred 14 h at room temperature.
The reaction was diluted with ether (200 mL) and was washed with H2O (2*200 mL), saturated sodium bicarbonate (100 mL) and brine (80 mL).
The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure to yield 18.15 g ethyl 4-oxocyclohexanecarboxylate ethylene ketal (96percent yield). LCMS (m/z): 214.8 (MH+), 0.74 min. |
| 95% |
With toluene-4-sulfonic acid In toluene at 20℃; for 20 h; |
Stage 1: 1,4-Dioxaspiro[4.5]decane-8-carboxylic acid ethyl ester
A solution of 4-oxocyclohexane carboxylic acid ethyl ester (27.6 g, 162 mmol), ethylene glycol (35.3 g, 31.7 ml, 569 mmol) and p-toluenesulfonic acid (360 mg, 1.89 mmol) in toluene (80 ml) was stirred for 20 h at room temperature.
The reaction solution was then poured into diethyl ether (150 ml) and washed with water, 5percent sodium hydrogen carbonate solution and saturated sodium chloride solution (150 ml each).
The organic phase was dried with sodium sulfate and concentrated to small volume under vacuum.
Yield: 33 g (95percent), colourless oil
1H-NMR (DMSO-d6): 1.17 (t, 3H, J=7.3 Hz); 1.41-1.69 (m, 6H); 1.77-1.82 (m, 1H); 2.28-2.40 (m, 2H); 3.84 (s, 4H); 4.04 (dd, 2H, J=6.8, 14.6 Hz).
|
| 93% |
at 80℃; for 6 h; Inert atmosphere |
Nitrogen at room temperature conditions, to 250mL three-necked flask ethylene glycol 100mL, raw material A (10g), trimethyl orthoformate (3.0eq) and N- bromosuccinimide (0.04eq),Heating to 80 ° C reaction 6h, TLC judge the end of the reaction. The reaction was cooled to room temperature, dichloromethane and water were added. After stirring, the mixture was separated. The organic phase was collected. The aqueous phase was extracted with dichloromethane and the organic phase was combined. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated by filtration, and purified by crude column chromatography (EA / PE = 1/5 to 1/4) to obtain 11.7 g of product VI (yield 93percent). |
| 91% |
With toluene-4-sulfonic acid In tolueneReflux |
[405] To a solution of ethyl 4-oxocyclohexanecarboxylate (54.8 g, 322 mmol) in toluene (120 mL) were added ethylene glycol (21.97 g, 354 mmol) and toluene-4-sulfonic acid monohydrate (612 mg, 3.22 mmol). The reaction mixture was heated to refluxed and stirred overnight, then cooled down to rt, poured into ice water (120 mL) and adjusted to pH = 9 with 2 M NaOH aqueous solution, then extracted with EtOAc (200 mL x 3). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na2S04, concentrated in vacuo. The residue was purified by silica gel column chromatography (heptanes 100percent) to give the title compound as pale yellow oil (62.70 g, 91percent). MS (ESI, pos. ion) m/z: 215.1 [M+H]+; 1H NMR (400 MHz, CDCh): δ (ppm) 4.14 (q, J= 7.1 Hz, 2H), 3.96 (s, 4H), 2.34 (m, 1H), 1.95 (m, 2H), 1.81 (m, 4H), 1.57 (td, J= 12.9, 4.5 Hz, 2H), 1.26 (t, J= 7.1 Hz, 3H). |
| 91% |
With toluene-4-sulfonic acid In tolueneReflux |
Step 1) ethyl l ,4-dioxaspiror4.51decane-8-carboxylate [0367] To a solution of ethyl 4-oxocyclohexanecarboxylate (54.8 g, 322 mmol) in toluene (120 mL) were added ethylene glycol (21.97 g, 354 mmol) and toluene-4-sulfonic acid monohydrate (612 mg, 3.22 mmol). The reaction mixture was heated to refluxed and stirred overnight, then cooled down to rt, poured into a mixture of ice and water and adjusted to pH = 9 with 2 M NaOH aqueous solution, then extracted with EtOAc (200 mL x 3). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na2SC)4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (heptanes, 100percent) to give the title compound as pale yellow oil (62.70 g, 91percent). MS (ESI, pos. ion) m/z: 215.1 [M+H]+; NMR (400 MHz, CDCb): δ (ppm) 4.14 (q, J = 1.1 Hz, 2H), 3.96 (s, 4H), 2.34 (m, 1H), 1.95 (m, 2H), 1.81 (m, 4H), 1.57 (td, J= 12.9, 4.5 Hz, 2H), 1.26 (t, J= 7.1 Hz, 3H). |
| 91% |
With toluene-4-sulfonic acid In toluene for 24 h; Dean-Stark; Reflux |
A mixture of ethyl 4-oxocyclohexane-1 -carboxylate (62 g, 0.36 mol), ethane-1 ,2-diol (22.3 ml_, 0.4 mol) and p-TsOH (0.7 g, 3.6 mmol) in toluene was heated to reflux with a Dean-Stark water trap and a condenser for 24hr. After cooled down to r.t., the resulting mixture was diluted with EtOAc and washed with sat. NaHC03 aq. solution and brine, dried over Na2S04, filtered and concentrated under reduced pressure to give the crude product which was purified by flash chromatography (silica gel, 0-20percent EtOAc in PE) to afford the title compound as a colorless oil (70 g, 91 percent yield). LC-MS (ESI): m/z (M+1) = 215.05. 1H NMR (400 MHz, CDC ) 6 4.13 (q, J = 7.1 Hz, 2H), 3.94 (s, 4H), 2.38 - 2.28 (m, 1 H), 1 .99 - 1 .89 (m, 2H), 1 .86 - 1 .70 (m, 4H), 1 .63 - 1 .50 (m, 2H), 1 .25 (t, J = 7.1 Hz, 3H). |
| 91% |
With toluene-4-sulfonic acid In tolueneReflux |
Ethyl 4-oxocyclohexanecarboxylate (54.8 g, 322 mmol) was dissolved in toluene (120 mL), and then ethylene glycol (21.97 g, 354 mmol) and p-toluenesulfonic acid monohydrate (612 mg, 3.22 mmol) were added to the solution to obtain a mixed solution. The resulting mixture was warmed to reflux, stirred overnight, then cooled to room temperature, then poured into ice water and the mixture was adjusted to pH = 9 with 2M aqueous sodium hydroxide and then extracted with ethyl acetate (200 mL x 3) and the organic phases combined. The combined organic phases were then washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was then subjected to silica gel column chromatography (N-hexane, 100percent) to give the title compound as a pale yellow oil (62.70 g, 91percent). |
| 90% |
at 0 - 20℃; |
4-Oxocyclohexanecarboxylic acid (20 g, 117 mmol) was dissolved in toluene (60 ml, dry), and ethylene glycol (23 ml, 411 mmol) and p-toluenesulfonic acid (265 mg) were added at 0° C. The cooling bath was removed, the reaction mixture was stirred at room temperature for 16 h and hydrolysis was then carried out with ice. Extraction was carried out with ethyl acetate (300 ml) and the organic phase was washed with sodium carbonate solution and saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product was employed in the next stage without further purification. Yield: 90percent |
| 89% |
With aminosulfonic acid In cyclohexane; water at 100℃; for 2 h; |
Into a 1000 ml round-bottom flask, was placed cyclohexane (400 ml), ethyl 4- oxocyclohexane-1-carboxylate (215 g, 1.26 mol, 1.00 equiv.), ethane-1,2-diol (94.1 g, 1.52 mol, 1.20 equiv.), sulfamic acid (5.0 g, 51.50 mmol, 0.04 equiv.). The resulting solution was stirred to water segregator for 2 h at 100 °C in an oil bath. The reaction was then quenched by the addition of 800 mL of water. The resulting solution was extracted with 3x800 ml of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100-1:30). This resulted in 242 g of the title compound as light yellow oil (89percent).’H NMR (300 MHz, CDC13) & 4.09-4.02 (m, 2H), 3.87 (s, 4H), 2.30- 2.23(m, 1H), 1.90-1.85 (m, 2H), 1.80-1.67 (m, 4H), 1.53-1.48 (m, 2H), 1.20 (t, 1=7.2Hz, 3H). |
| 80% |
With sulfuric acid In toluene for 16 h; Reflux |
Step A: Preparation of ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate A mixture of ethyl 4-oxocyclohexanecarboxylate (5.4755 g, 32.17 mmol), ethylene glycol (4.13 mL, 73.99 mmol), and concentrated sulfuric acid (0.1 mL, 1.88 mmol) in toluene (55 mL) was heated under reflux for 16 hours with removal of water by a Dean Stark trap. After the standard work up, the title compound was obtained as a pale yellow oil (5.51 g, 80percent), which was used in the subsequent step without further purification. |
| 80% |
With aminosulfonic acid In cyclohexane at 100℃; |
[00331] Into a 500-mL round-bottom flask was placed ethyl 4-oxocyclohexane-1- carboxylate (150 g, 881.29 mmol, 1.00 equiv), cyclohexane (300 mL), H2NSO3H (3 g) and ethane- 1 ,2-diol (65.7 g, 1.06 mol, 1.20 equiv). The resulting solution was stirred overnight at 100°C and then diluted with 300 mL of ethyl acetate. The resulting mixture was washed with2x200 mL of brine and then concentrated under vacuum. This resulted in 152 g (80percent) of ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate as yellow oil. ‘H-NMR (300 MHz, CDC13): ö 4.05 (q, I = 7.1Hz, 2H), 3.95 (s, 4H), 2.44-2.23 (m, 1H), 2.00-1.70 (m, 6H), 1.65-1.47(m, 2H), 1.25(t, I = 7.1Hz, 3H) ppm. |
| 74% |
at 20℃; |
a)
1,4-dioxaspiro[4,5]decane-8-carboxylic acid ethyl ester
A solution of ethyl-4-oxocyclohexane carboxylate (28.9 g, 169 mmol), ethylene glycol (36.7 g, 33.0 mL, 592 mmol) and p-toluol sulphonic acid (380 mg, 2.0 mmol) in toluol (90 mL) was stirred overnight at room temperature.
The reaction solution was poured into ether (150 mL) and washed with water and 5percent sodium hydrogencarbonate solution (150 mL each).
The organic phase was dried with sodium sulphate and concentrated to low volume in a vacuum.
Since the raw product (26.8 g) was obtained in pure form, it could be directly converted further.
Yield: 26.8 g (74percent), colourless oil
|
| 68% |
With toluene-4-sulfonic acid In toluene at 20℃; Inert atmosphere |
Step 1: To a solution of ethyl 4-oxocyclohexanecarboxylate (35 g, 0.21 mol, 1.0 equiv.) in toluene, ethylene glycol (26 g, 0.42 mol, 2 equiv.) and TsOH (500 mg) were added. The mixture was stirred at room temperature under N2 overnight. The mixture was concentrated and then extracted with EtOAc, washed by water, brine and dried over anhydrous Na2S04. Concentration in vacuum provided ethyl l,4-dioxaspiro[4.5]decane-8-carboxylate. (30 g, colorless oil, yield: 68percent). Step 2: To a solution of ethyl l,4-dioxaspiro[4.5]decane-8-carboxylate (120 g, 0.56 mol, 1.0 equiv.) in THF was added LDA (336 ml, 2 M, 0.67 mol, 1.2 equiv.) dropwise at -78 °C under N2. Then it was stirred at -78 °C for lh. Dimethyl carbonate (55.5 g, 0.62 mol, 1.1 equiv.) was added dropwise at -78 °C. The mixture was stirred at room temperature for another lh. NH4Cl(aq.) was added. It was extracted with EtOAc, washed by water, brine and dried over anhydrous Na2S04. Concentration in vacuum and chromatography on silica gel (eluting conditions) provided 8-ethyl 8-methyl l,4-dioxaspiro[4.5]decane-8,8-dicarboxylate. (110 g, colorless oil, yield:70percent) Step 3: To a solution of 8-ethyl 8-methyl l,4-dioxaspiro[4.5]decane-8,8-dicarboxylate (54.4 g, 0.2 mol, 1.0 equiv.) in THF was added LAH (22.8 g, 0.6 mol, 3.0 equiv.) maintaining temperature below 50 °C. Then it was stirred at 70 °C for another lh. The reaction was quenched by the addition of Na2SO4.10H2O. After filtration, the mixture was diluted with EtOAc, washed by water, brine and dried over anhydrous Na2S04. Concentration gave 1,4- dioxaspiro[4.5]decane-8,8-diyldimethanol. (16 g, white solid, yield:40percent) Step 4: To a solution of l,4-dioxaspiro[4.5]decane-8,8-diyldimethanol (15 g, 0.074 mol, 1.0 equiv.) in THF (200 mL) was added NaH (4.46 g, 60percent, 0.11 mol, 1.5 equiv.) at 0 °C. Then it was stirred at room temperature for 1 h. TsCl (14.16 g, 0.074 mol, 1.0 equiv.) in THF was added dropwise at 0 °C under N2 and stirred for another 1 h. The mixture was extracted with EtOAc, washed by water, brine and dried over anhydrous Na2S04. Concentration and chromatography on silica gel gave (8-(hydroxymethyl)-l,4-dioxaspiro[4.5]decan-8-yl)methyl 4- methylbenzenesulfonate. (16 g, coloress oil, yield: 60percent) Step 5: To a solution of (8-(hydroxymethyl)-l,4-dioxaspiro[4.5]decan-8-yl)methyl 4- methylbenzenesulfonate (15 g, 0.042 mol, 1.0 equiv.) in THF (200 mL) was added NaH (3.4 g, 60percent, 0.084 mol, 2.0 equiv.) at bellow 20 °C . The mixture was stirred at 70 °C for 5 h. It was cooled to room temperature and extracted with EtOAC, washed by water, brine and dried over anhydrous Na2S04. Concentration and chromatography on silica gel provided ketal-protected 2- oxaspiro[3.5]nonan-7-one. (6 g, white solid, yield:77percent>) Step 6: To a solution of ketal-protected 2-oxaspiro[3.5]nonan-7-one (5 g, 0.027 mol, 1.0 equiv.) in acetone (100 mL) was added pyridinium tosylate (2.0 g, 0.08 mol, 0.3 equiv.). Then it was stirred at 60 °C overnight. The mixture was concentrated and then extracted with EtOAc, washed by water, brine and dried over anhydrous Na2S04. Concentration and chromatography on silica gel gave 2-oxaspiro[3.5]nonan-7-one (1.5 g, light yellow solid, yield = 30percent>) and 2.0 g recovered ketal starting material which can be recycled to provide additional 2- oxaspiro[3.5]nonan-7-one. |
| 65% |
With toluene-4-sulfonic acid In benzeneReflux |
Ethyl 4-oxocyclohexane carboxylate (122.56 mmol, 20.86 g) and para-toluenesulfonic acid monohydrate (12.56 mmol, 2.33 g) are charged to a 1000 rriL roundbottom flask. To this flask was added benzene (300 mL) followed by ethylene glycol (0.37 mol, 20.5 mL). The resulting bi-layer reaction mixture was refluxed overnight in a Dean-Stark trap. Upon cooling, the reaction mixture was diluted in 300 mL DCM and washed with 300 mL saturated NaHCO3(aq)- The acqueous layer was washed with DCM (3X) and the combined organics are dried over Na2SO4. The residue was disolved in DCM and purified by silica gel chromatography on 0percent to 50percent ethyl acetate in hexanes gradient. The product is tracked via PMA stain. Chromatography yields 17.05 grams (79.58 mmol, 65percent yield) ethyl 1 ,4-dioxaspiro[4.5]decane-8-carboxylate. |
| 65% |
With toluene-4-sulfonic acid In benzeneReflux |
Step A - Synthesis of Ethyl l,4-dioxaspiro[4.5]decane-8-carboxylate (Int-Sa)Ethyl 4-oxocyclohexane carboxylate (122.56 mmol, 20.86 g) and para- toluenesulfonic acid monohydrate (12.56 mmol, 2.33 g) were charged to a 1000 mL round-bottom flask. To this flask was added benzene (300 mL) followed by ethylene glycol (0.37 mol, 20.5 mL). The resulting bi-layer solution was refluxed overnight using a Dean-Stark trap. Upon cooling, the reaction mixture was diluted in 300 mL DCM and washed with 300 mL saturated NaHCψ3(aq). DCM was used to extract from the aqueous layer (x3) and the combined organics were dried over NaISO4. The residue was taken up in DCM and purified by silica gel chromatography using a 0percent to 50percent ethyl acetate in hexanes gradient. The product was monitored via PMA stain. Chromatography yielded 17.05 grams (79.58 mmol, 65percent yield) ethyl 1,4- dioxaspiro[4.5]decane-8-carboxylate (Int-5a). |
| 57% |
With toluene-4-sulfonic acid In tolueneReflux |
Example 1(5a,8 )-8-Hydroxy-2-(4-trifiuoromethoxy-phenyl)-2-aza-spiro[4.5]decan-l-one Step 1: l14-Dioxa-spiro[4.5ldecane-8-carboxylic acid ethyl esterEthyl-cyclohexanone-4-carboxylate (54.8g) was dissolved in toluene (120mL). Then, ethylene glycol (24.8mL) and toluene-4-sulfonic acid monohydrate (612mg) were added to the reaction mixture. The mixture was refiuxed over night and water was removed azeotropically with a Dean-Stark apparatus. The reaction mixture was cooled, poured into ice/water and basified with 2M aqueous NaOH to pH 9. The aqueous layer was extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2S04, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a light yellow liquid (39.5g, 57percent). MS (m/e) = 215.3 [MH+]. |
| 57% |
With toluene-4-sulfonic acid In tolueneReflux |
Step 1:
1,4-Dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester
Ethyl-cyclohexanone-4-carboxylate (54.8 g) was dissolved in toluene (120 mL).
Then, ethylene glycol (24.8 mL) and toluene-4-sulfonic acid monohydrate (612 mg) were added to the reaction mixture.
The mixture was refluxed over night and water was removed azeotropically with a Dean-Stark apparatus.
The reaction mixture was cooled, poured into ice/water and basified with 2M aqueous NaOH to pH 9.
The aqueous layer was extracted two times with ethyl acetate.
The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated.
The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a light yellow liquid (39.5 g, 57percent). MS (m/e)=215.3 [MH+]. |
| 57% |
With toluene-4-sulfonic acid In tolueneReflux |
Ethyl-cyclohexanone-4-carboxylate (54.8 g) was dissolved in toluene (120 mL). Then, ethylene glycol (24.8 mL) and toluene-4-sulfonic acid monohydrate (612 mg) were added to the reaction mixture. The mixture was refluxed over night and water was removed azeotropically with a Dean-Stark apparatus. The reaction mixture was cooled, poured into ice/water and basified with 2M aqueous NaOH to pH 9. The aqueous layer was extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of ethyl acetate in heptane) to give the title compound as a light yellow liquid (39.5 g, 57percent). MS (ESI)=215.3 (MH+). |
| 57% |
Reflux |
Ethyl-cyclohexanone-4-carboxylate (54.8 g) was dissolved in toluene (120 mL). Then, ethylene glycol (24.8 mL) and toluene-4-sulfonic acid monohydrate (612 mg) were added to the reaction mixture. The mixture was refluxed over night and water was removed azeotropically with a Dean-Stark apparatus. The reaction mixture was cooled, poured into ice/water and basified with 2M aqueous NaOH to pH 9. The aqueous layer was extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2S04, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of ethyl acetate in heptane) to give the title compound as a light yellow liquid (39.5 g, 57percent). MS (ESI) = 215.3 (MH+). |
| 52% |
With toluene-4-sulfonic acid In toluene at 20℃; |
To a reaction flask, ethyl 4-oxocyclohexane-1-carboxylate (50 g, 293.76 mmol), toluene (300 mL), ethylene glycol (20 g, 322.23 mmol) and p-methylphenyl sulfonic acid (1 g, 5.81 mmol) were added.
The reaction solution was stirred at room temperature overnight, ethyl acetate (200 mL) was added for dilution, washed sequentially with sodium hydrogen carbonate solution (200 mL*2) and water (200 mL*3), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate :petroleum ether =1:20-1:10) to obtain the title compound as yellow oil (33 g, yield 52.0percent). |
| 32.1 g |
With toluene-4-sulfonic acid In toluene at 20℃; |
Ethyl-4-oxocyclohexanecarboxylate (25.1 g) and ethylene glycol (32.3 g) were dissolved in 80 mL of toluene, p-toluenesulfonic acid monohydrate (563 mg) was added while stirring at room temperature, and the mixture was stirred at that temperature overnight. After completion of the reaction, a hexane:ethyl acetate=3:1 solution (150 mL) was added to dilute the reaction, thereafter, 100 mL of water was added, and extraction operation was performed. The resulting organic layer was sequentially washed with an aqueous saturated sodium bicarbonate solution and an aqueous saturated sodium chloride solution, dried with magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude product. This was azeotroped with toluene to obtain a ketal intermediate (32.1 g).; Lithium diisopropylamide (37.5 mL) was dissolved in 50 mL of THF, and a solution of the ketal intermediate (10.7 g) in 12 mL of THF was added dropwise over 5 minutes while stirring at an inner temperature of −30° C. After this solution was stirred at an inner temperature of −30° C. for 20 minutes, and a solution of methyl iodide (14.2 g) in 12 mL of THF was added dropwise at that temperature over 5 minutes. An inner temperature at that time was raised to −5° C. This solution was stirred for 1 hour until an inner temperature became 23° C., water was added to stop the reaction, extraction operation (THF, once) was performed, the aqueous layer was neutralized with 2N hydrochloric acid, and re-extraction operation (ethyl acetate, two times) was performed. The resulting organic layer was sequentially washed with water and an aqueous saturated sodium chloride solution, and dried with magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (12.8 g) having the following physical property values.; TLC: Rf 0.51 (hexane:ethyl acetate=4:1); 1H-NMR (CDCl3): δ 1.19 (s, 3H), 1.25 (t, J=7.2 Hz, 3H), 1.43-1.71 (m, 6H), 2.09-2.17 (m, 2H), 3.93 (s, 4H), 4.15 (q, J=7.2 Hz, 2H). |
| 25 g |
With p-toluenesulfonic acid monohydrate In toluene for 16 h; |
Ethyl 4-oxocyclohexanecarboxylate 5a (20 g, 0.12 mol),Ethylene glycol (23 mL, 0.41 mol)And p-toluenesulfonic acid monohydrate (224 mg, 1.18 mmol)Was dissolved in 70 mL of toluene,The reaction was stirred for 16 hours.The reaction solution was concentrated under reduced pressure,To the residue was added 400 mL of ethyl acetate,The reaction mixture was washed with water (100 mL X 1)Saturated sodium bicarbonate solution (100 mL X 1) and saturated sodium chloride solution (100 mL X 1)Dried over anhydrous sodium sulfate, filtered,The filtrate was concentrated under reduced pressure to give the title product, ethyl 1,4-dioxaspiro [4.5] decane-8-carboxylate5b(25g, colorless oil) which was used directly in the next step. |
| 12.77 g |
With toluene-4-sulfonic acid In toluene at 120℃; for 3 h; Dean-Stark |
A mixture of ethyl 4-oxocyclohexanecarboxylate (11.70 mL, 73.4 mmol), ethane-1,2- diol (12.29 mL, 220 mmol), and /?-toluenesulfonic acid monohydrate (1.397 g, 7.34 mmol) in toluene (200 mL) was stirred at 120 °C with a Dean-Stark trap apparatus for 180 minutes. The reaction mixture was neutralized with N-ethyl-N-isopropylpropan-2-amine and then (0775) concentrated. The residue was purified on silica gel (0-30percent ethyl acetate in heptane) to give 12.77 g of the title compound as a clear oil. XH NMR (400 MHz, DMSO-c) δ ppm 4.01 (q, J = 7.1 Hz, 2H), 3.81 (s, 4H), 2.32 (tt, J = 10.4, 3.8 Hz, 1H), 1.83 - 1.71 (m, 2H), 1.66 - 1.57 (m, 1H), 1.62 - 1.38 (m, 5H), 1.13 (t, J = 7.1 Hz, 3H). |
| 12.77 g |
With toluene-4-sulfonic acid In toluene at 120℃; for 3 h; Dean-Stark |
Example 173A: ethyl l,4-dioxaspiro[4.5]decane-8-carboxylate A mixture of ethyl 4-oxocyclohexanecarboxylate (11.70 mL, 73.4 mmol), ethane-1,2- diol (12.29 mL, 220 mmol), and /?-toluenesulfonic acid monohydrate (1.397 g, 7.34 mmol) in toluene (200) was stirred at 120 °C with Dean-Stark trap apparatus for 180 minutes. The reaction mixture was neutralized with N-ethyl-N-isopropylpropan-2-amine and concentrated. The residue was purified on silica gel (0-30percent ethyl acetate in heptane) to give 12.77 g of the title compound as a clear oil. XH NMR (400 MHz, DMSO-c) δ ppm 4.01 (q, J = 1.1 Hz, 2H), 3.81 (s, 4H), 2.32 (tt, J = 10.4, 3.8 Hz, 1H), 1.83 1.71 (m, 2H), 1.66 1.57 (m, 1H), 1.62 1.38 (m, 5H), 1.13 (t, J = 7.1 Hz, 3H). |
| 12.77 g |
With toluene-4-sulfonic acid In toluene at 120℃; for 3 h; Dean-Stark |
A mixture of ethyl 4-oxocyclohexanecarboxylate (11.70 mL, 73.4 mmol), ethane-1,2- diol (12.29 mL, 220 mmol), andp-toluenesulfonic acid monohydrate (1.397 g, 7.34 mmol) intoluene (200 mL) was stirred at 120 °C with a Dean-Stark trap apparatus for 180 minutes. The reaction mixture was neutralized with N-ethyl-N-isopropylpropan-2-amine and then concentrated. The residue was purified on silica gel (0-30percent ethyl acetate in heptane) to give 12.77 g of the title compound as a clear oil. ‘H NMR (400 MHz, DMSO-d6) 5 ppm 4.01 (q, J7.1 Hz, 2H), 3.81 (s, 4H), 2.32 (if, J 10.4, 3.8 Hz, 1H), 1.83 — 1.71 (m, 2H), 1.66— 1.57(m, 1H), 1.62— 1.38 (m, 5H), 1.13 (t, J 7.1 Hz, 3H). |
| 12.77 g |
With toluene-4-sulfonic acid In toluene at 120℃; for 3 h; Dean-Stark |
A mixture of ethyl 4-oxocyclohexanecarboxylate (11.70 mL, 73.4 mmol), ethane-1,2- diol (12.29 mL, 220 mmol), and p-toluenesulfonic acid monohydrate (1.397 g, 7.34 mmol) in toluene (200 mL) was stirred at 120 °C with a Dean-Stark trap apparatus for 180 minutes. The reaction mixture was neutralized with N-ethyl-N-isopropylpropan-2-amine and then concentrated. The residue was purified on silica gel (0-30percent ethyl acetate in heptane) to give 12.77 g of the title compound as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.01 (q, J = 7.1 Hz, 2H), 3.81 (s, 4H), 2.32 (tt, J = 10.4, 3.8 Hz, 1H), 1.83– 1.71 (m, 2H), 1.66– 1.57 (m, 1H), 1.62– 1.38 (m, 5H), 1.13 (t, J = 7.1 Hz, 3H). |
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