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Chemical Structure| 17159-79-4
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Product Details of [ 17159-79-4 ]

CAS No. :17159-79-4 MDL No. :MFCD00013285
Formula : C9H14O3 Boiling Point : -
Linear Structure Formula :- InChI Key :ZXYAWONOWHSQRU-UHFFFAOYSA-N
M.W : 170.21 Pubchem ID :317638
Synonyms :
Chemical Name :Ethyl 4-oxocyclohexanecarboxylate

Calculated chemistry of [ 17159-79-4 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 12
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.78
Num. rotatable bonds : 3
Num. H-bond acceptors : 3.0
Num. H-bond donors : 0.0
Molar Refractivity : 44.75
TPSA : 43.37 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.9 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.68
Log Po/w (XLOGP3) : 0.62
Log Po/w (WLOGP) : 1.31
Log Po/w (MLOGP) : 0.9
Log Po/w (SILICOS-IT) : 1.82
Consensus Log Po/w : 1.27

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.09
Solubility : 13.9 mg/ml ; 0.0817 mol/l
Class : Very soluble
Log S (Ali) : -1.11
Solubility : 13.4 mg/ml ; 0.0785 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.68
Solubility : 3.55 mg/ml ; 0.0208 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.89

Safety of [ 17159-79-4 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 17159-79-4 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Upstream synthesis route of [ 17159-79-4 ]
  • Downstream synthetic route of [ 17159-79-4 ]

[ 17159-79-4 ] Synthesis Path-Upstream   1~33

  • 1
  • [ 17159-79-4 ]
  • [ 17356-08-0 ]
  • [ 50850-93-6 ]
Reference: [1] Organic Letters, 2013, vol. 15, # 11, p. 2604 - 2607
  • 2
  • [ 17159-79-4 ]
  • [ 107-21-1 ]
  • [ 1489-97-0 ]
YieldReaction ConditionsOperation in experiment
100% With toluene-4-sulfonic acid In toluene at 20 - 25℃; for 20 h; 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 at RT for 20 h, 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) and concentrated i. vac. and the colourless 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).Stage AEthylene glycol (1.08 mol) and p-toluenesulfonic acid (0.7 g) were added to a solution of 4-oxo-cyclohexanecarboxylic acid ethyl ester (0.31 mol) in toluene (160 ml) and the mixture was stirred at 25° C. for 20 h. Ethyl acetate (300 ml) was then added. The organic phase separated off was washed with water, aqueous saturated NaHCO3 solution and NaCl solution. After drying of the organic phase over Na2SO4 and filtration, the solvent was removed in vacuo. The product was employed in the next stage without further purification.
100% at 20℃; for 20 h; 1,4-Dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester; 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 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 (sodium sulfate) 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 In toluene at 20℃; for 20 h; 1st Stage
Synthesis of the 1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester 4
4-oxo-cyclohexanecarboxylic acid ethyl ester (52.8 g, 0.31 mole, Merck, Order No. 814249), ethylene glycol (67.4 g, 1.08 mole) and p-toluenesulfonic acid (0.7 g) in toluene (160 ml) were stirred for 20 hours 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 tried (Na2SO4), concentrated by evaporation in vacuo, and the remaining colorless liquid was processed further without purification. 1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester 4 4-oxo-cyclohexanecarboxylic acid ethyl ester (52.8 g, 0.31 mole, Merck, Order No. 814249), ethylene glycol (67.4 g, 1.08 mole) 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)
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) РћТ‘: 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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YieldReaction ConditionsOperation in experiment
95.7%
Stage #1: With potassium <i>tert</i>-butylate In tetrahydrofuran at -20℃; for 0.5 h;
Stage #2: at 0 - 20℃; Inert atmosphere
Triphenylmethylphosphonium bromide (53.7g, 0.15mol) was dissolved in 500mL of THF, and potassium tert-butoxide (16.8g, 0.15mol) was added at -20°C. Reacted for 0.5h after the temperature was raised to 0 °C. Subsequently, ethyl 4-oxo-cyclohexylcarboxylate (Compound 8-1) (17g, 0.1mol) was dissolved in 100mL of THF and added dropwise to the flask under nitrogen, reacted at room temperature for 3 hours, then a small amount of water was added to dissolve the solid, and rotary evaporated to remove THF, extracted with anhydrous diethyl ether, dried, and concentrated, the concentrate was dissolved in n-hexane, and filtered by silica gel, then concentrated to give Compound 8-2 as a colorless liquid (16.1g, 95.7percent yield).
95.7% With potassium <i>tert</i>-butylate In tetrahydrofuran; hexane; water 1)
Ethyl 4-methylenecyclohexylcarboxylate (Compound 8-2)
Triphenylmethylphosphonium bromide (53.7 g, 0.15 mol) was dissolved in 500 mL of THF, and potassium tert-butoxide (16.8 g, 0.15 mol) was added at -20° C.
Reacted for 0.5 h after the temperature was raised to 0° C. Subsequently, ethyl 4-oxo-cyclohexylcarboxylate (Compound 8-1) (17 g, 0.1 mol) was dissolved in 100 mL of THF and added dropwise to the flask under nitrogen, reacted at room temperature for 3 hours, then a small amount of water was added to dissolve the solid, and rotary evaporated to remove THF, extracted with anhydrous diethyl ether, dried, and concentrated, the concentrate was dissolved in n-hexane, and filtered by silica gel, then concentrated to give Compound 8-2 as a colorless liquid (16.1 g, 95.7percent yield).
85%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane for 1 h;
Stage #2: at 20℃; for 3 h;
Example 6 Ethyl 4-meth lenecyclohexanecarboxylate19[0141] To a suspension of methyltriphenylphosphonium bromide (1.57 g, 4.41 mmol) in THF (9 mL) at -10 °C was added w-BuLi (2.5 M in hexanes, 1.65 mL, 4.11 mmol) dropwise and the solution was allowed to stir for lh. Ethyl 4-oxocyclohexanecarboxylate (0.47 mL, 2.94 mmol) was added and the reaction was allowed to warm to room temperature over 3 h. Acetone (3 mL) was added and the solvent was removed under reduced pressure. The residue was suspended in dichloromethane and ethyl ether (1 : 1), filtered and concentrated. The crude was purified by flash column chromatography to afford 19 as clear oil (419 mg, 85percent). H NMR: 1.25 (t, 3H), 1.50-1.70 (m, 2H), 1.90-2.16 (m, 4H), 2.30-2.50 (m, 3H), 4.12 (q, 2H), 4.65 (s, 2H).
84%
Stage #1: With n-butyllithium In tetrahydrofuran at 0℃; for 0.5 h;
Stage #2: at 0 - 20℃; for 2 h;
30A.
Ethyl 4-methylenecyclohexanecarboxylate
To a solution of (methyl)triphenylphosphonium bromide (5.18 g, 14.51 mmol) in THF (50 mL) at 0° C. was added n-butyllithium (9.07 mL, 14.51 mmol).
The reaction mixture was stirred at 0° C. for 30 min.
Ethyl 4-oxocyclohexanecarboxylate (1.9 g, 11.16 mmol) in THF (8 mL) was then added at 0° C. and the reaction was warmed to rt and stirred for 2 h.
The reaction was quenched with sat'd aq. NH4Cl and diluted with EtOAc.
The organic layer was washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo.
The residue was purified by flash chromatography on SiO2 (0 to 50percent EtOAc:hexanes) to afford the title compound (1.58 g, 84percent yield) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 4.65 (s, 2H), 4.17-4.11 (m, 2H), 2.44 (tt, J=11.1, 3.8 Hz, 1H), 2.35 (dt, J=13.7, 4.0 Hz, 2H), 2.11-1.96 (m, 4H), 1.64-1.54 (m, 2H), 1.28-1.23 (m, 3H).
81%
Stage #1: With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 20℃; for 1 h;
Stage #2: at 5 - 50℃;
Preparation of 4-Methylenecyclohexanecarboxylic acid ethyl ester; A suspension of methyl phosphonium bromide (3.15 g, 8.82 mmol) in dry THF (20 mL) was cooled to 00C, a solution of KtBuO (1.185 g, 10.58 mmol) in dry THF (15 mL) was added. The reaction mixture was allowed to rt and maintained for 1 h. The resulting mixture was cooled to 5-100C, 4-Oxo-cyclohexanecarboxylic acid ethyl ester (1.0 g, 5.88 mmol) (Chem. Abstr. Reg. No. 17159-79-4) was added over a period of 5 min, then was warmed to rt, maintained for 2h, then was heated to 50°C and maintained over night additionally. The resulted reaction mass was diluted with water (200 mL) and extracted with EtOAc (200 mL). The organic layer was washed with water (50 mL), brine solution (100 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude was purified by column chromatography over silica gel column using 3-4percent EtOAc in pet ether as eluting solvent to obtain the pure product (1) as liquid (800 mg, 81percent). 1HNMR(CDCI3): δ 4.65(s, 2H), 4.12(q, 2H), 2.3-2.5(m, 3H), 1.9-2.16(m, 4H), 1.5-1.7(m, 2H) and 1.25(t, 3H). Mass: (M+1) 169 calculated for Ci0H16O2.
76%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at 0℃; for 0.5 h;
Stage #2: at 0 - 20℃;
Stage #3: With ammonium chloride In tetrahydrofuran; water
To a suspension of MePh3PBr (37.1 g, 104 mmol) in THF (500 mL) at 0°C was added slowly LDA (1.2 eq) over 1 h. The resulting orange solution was stirred for 30 min before ethyl 4-oxocyclohexanecarboxyIate (16.1 g, 94.4 mmol) was added dropwise. The resulting suspension was warmed to rt and stirred overnight (may not necessary). A saturated NH4CI (aq) was added and THF was removed. The aqueous residue was extracted with EtOAc (100*3). The combined organic layers were washed with brine, dried over Na2S04 and concentrated. The residue was purified by passing through a short silica gel plug(hexanes/EtOAc 7:1). After being concentrated, ethyl 4-methylenecyclohexanecarboxylate was obtained as pale yellow oil (12.1 g, 76percent).
73%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at 0℃; for 0.666667 h;
Stage #2: at 0 - 20℃; for 2 h;
Lithium bis(trimethylsilyl)amide (1.0 M in THF, 15 mL, 15 mmol) was added dropwisely to a stirred solution of methyltriphenylphosphonium bromide (5.36 g, 15 mmol) in THF (50 mL) at 0 °C and stirred for 40 min at the same temperature. A solution of ethyl 4-oxocyclohexanecarboxylate (2.04 g, 12 mmol) in THF (20 mL) was added slowly at 0 °C and stirred for 2 h from 0 °C to room temperature. The reaction was quenched with saturated NH4C1 aq. and extracted with hexane. The collected organic layer was dried over MgS04 and concentrated under reduced pressure. The solvent ( 100 mL, hexane/Et20 = 5/1) was added to the residue and stirred for 30 min. The suspension was filtrated. The filtrate was concentrated under reduced pressure. The residue was purified by silicagel chromatography (5percent EtOAc/hexane as eluent) to provide compound A122-1 (1.478 g, 73percent) as a colorless oil.
68.8%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran at -78℃; for 1.16667 h; Inert atmosphere; Cooling with ice
Stage #2: for 18 h; Inert atmosphere
N-butyllithium (21 mL, 52.5 mmol) was added dropwise to a solution of diisopropylamine (7.54 mL, 52.9 mmol) in THF (40 mL) at -78° C. over a period of 10 min.
The resulted solution was stirred in an ice bath for 20 min.
The above LDA solution was canulated into a suspension of methyltriphenylphosphonium bromide (19 g, 53.2 mmol) in THF (100 mL) in ice bath and the resulted mixture was stirred in the ice bath for 40 min.
A solution of ethyl 4-oxocyclohexanecarboxylate (7.5 g, 44.1 mmol) in THF (20 mL) was added dropwise to this mixture.
The reaction mixture was stirred for 18 h and diluted with hexane.
The solid was filtered off and the filtrate was concentrated to afford a liquid.
This crude product was plugged through silica gel pad (˜2", EtOAc/hexane: 0 to 10percent) to yield the title compound as a clear liquid (5.0 g, 68.8percent yield).
1H NMR (400 MHz, CHLOROFORM-d) δ 4.76-4.60 (m, 2H), 4.20-4.08 (m, 2H), 2.45 (tt, J=11.1, 3.6 Hz, 1H), 2.35 (dt, J=13.5, 3.5 Hz, 2H), 2.14-1.96 (m, 4H), 1.67-1.52 (m, 2H), 1.30-1.22 (m, 3H)
54%
Stage #1: With potassium <i>tert</i>-butylate In 1,4-dioxane at 0℃; for 0.5 h; Inert atmosphere
Stage #2: at 20℃; for 1.5 h; Inert atmosphere
Methyltriphenylphosphonium bromide (4.20 g, 11.75 mmol) and potassium 2-methylpropan-2-olate (1.32 g, 11.75 mmol) were dissolved in 1,4-dioxane (20 mL) under nitrogen. The solution was stirred for 30 min then cooled to 0 °C. Separately, ethyl 4-methylenecyclohexane-1-carboxylate (1.06 g, 11.75 mmol) was dissolved in 1,4-dioxane (5 mL) and added dropwise over 15 min. The reaction mixture was stirred at 20 °C for 1.5 h. The volatiles were removed under reduced pressure. The crude product was dissolved in DCM (30 mL) and filtered. The filtrate was purified via silica gel chromatography eluting with 0-40percent EtOAc in heptane to afford ethyl 4-methylenecyclohexane-1-carboxylate 26 (1.06 g, 54percent) as a clear oil. 1H NMR (400 MHz, CDCl3) 1.25 (t, J = 7.1, 3H), 1.50 – 1.66 (m, 2H), 1.93 – 2.13 (m, 4H), 2.34 (dt, J = 12.9, 3.7, 2H), 2.43 (tt, J = 10.9, 3.6, 1H), 4.13 (q, J = 7.1, 2H), 4.64 (t, J = 1.4, 2H). 1H NMR consistent with reported literature data4
3.5 g
Stage #1: at 0℃; for 0.5 h; Inert atmosphere
Stage #2: at 0℃; for 16 h; Inert atmosphere
Brief procedure: KO-tBu was added to a solution of methyltriphenylphosponium bromide at 0 °C under nitrogen atmosphere and stirred for 30 min. To the above yellow colored reaction, a solution of ethyl 4-oxocyclohexane carboxylate in THF was added dropwise and the resulting mixture was stirred at the same temperature for 16 h. Work up: The reaction mixture was quenched with water and extracted with diethyl ether. The combined ethereal extract was dried and concentrated under reduced pressure. Purification: The crude residue was purified by silica gel (100-200 mesh) column chromatography by gradual elution from 5percent to 10percent EtOAc-petroleum ether. TLC system: 20percent Ethyl acetate-petroleum ether, Rf value: 0.6 Nature of the compound: Colorless liquid, Yield: 3.5 g

Reference: [1] Patent: EP2738156, 2014, A1, . Location in patent: Paragraph 0124-0125
[2] Patent: US2014/179638, 2014, A1, . Location in patent: Page/Page column
[3] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 21, p. 5719 - 5725
[4] Patent: WO2012/142237, 2012, A1, . Location in patent: Page/Page column 94
[5] Patent: US2014/275173, 2014, A1, . Location in patent: Paragraph 0421
[6] Patent: WO2008/84300, 2008, A1, . Location in patent: Page/Page column 47
[7] Patent: WO2012/27234, 2012, A1, . Location in patent: Page/Page column 64
[8] Patent: WO2015/129926, 2015, A1, . Location in patent: Page/Page column 102; 103
[9] Patent: US2014/243298, 2014, A1, . Location in patent: Paragraph 0351
[10] Journal of the American Chemical Society, 2018, vol. 140, # 22, p. 6873 - 6882
[11] Journal of Medicinal Chemistry, 2016, vol. 59, # 19, p. 8967 - 9004
[12] Tetrahedron Letters, 2018, vol. 59, # 51, p. 4479 - 4482
[13] Patent: WO2012/27239, 2012, A1, . Location in patent: Page/Page column 70
[14] Patent: WO2012/27236, 2012, A1, . Location in patent: Page/Page column 85
[15] Patent: WO2015/4455, 2015, A2, . Location in patent: Page/Page column 27
  • 14
  • [ 17159-79-4 ]
  • [ 2065-66-9 ]
  • [ 145576-28-9 ]
YieldReaction ConditionsOperation in experiment
67%
Stage #1: With potassium <i>tert</i>-butylate In tetrahydrofuran at -78℃; for 0.25 h;
Stage #2: at -78 - 20℃;
Potassium tert-butoxide (24 gm, 0.22 moles) and triphenylphosphine methyl iodide (78 gm, 28.22 moles) were dissolved in dry tetrahydrofuran (150 ml). The mixture was cooled to -780C and stirred at the same temperature for about 15 minutes. Ethyl 4- oxocyclohexane carboxylate (25 gm, 0.147 moles) in tetrahydrofuran was added drop wise and the mixture was stirred at the same temperature for about 30 minutes and then it was warmed to room temperature and stirred overnight, extraction was done with ethyl acetate and water. The organic layer was dried over sodium sulfate and concentrated. Purification was done by column chromatography using 5percent ethyl acetate in hexane. Yield: 19 gm (67percent); m/z: (M++l) 169.26NMR: (δ, CDCl3) : 4.64 (2H, s), 4.09- 4.15 (2H, q), 2.42- 2.47 (IH, m), 2.31- 2.39 (2H, m), 1.96- 2.09 (4H, m), 1.43- 1.62 (2H, m), 1.23- 1.26 (3H, t)
Reference: [1] Patent: WO2010/46791, 2010, A1, . Location in patent: Page/Page column 40
[2] Journal of Organic Chemistry, 1993, vol. 58, # 8, p. 2110 - 2114
  • 15
  • [ 17159-79-4 ]
  • [ 145576-28-9 ]
Reference: [1] Patent: WO2006/136245, 2006, A1, . Location in patent: Page/Page column 90
  • 16
  • [ 17159-79-4 ]
  • [ 24730-88-9 ]
Reference: [1] Australian Journal of Chemistry, 1994, vol. 47, # 10, p. 1833 - 1841
[2] Patent: WO2011/2887, 2011, A1,
[3] Patent: WO2012/27239, 2012, A1,
[4] Patent: WO2012/27236, 2012, A1,
[5] Patent: WO2012/27236, 2012, A1,
[6] Journal of Medicinal Chemistry, 2012, vol. 55, # 10, p. 4837 - 4846
[7] Patent: US2013/109699, 2013, A1,
[8] Patent: WO2014/26328, 2014, A1,
[9] Patent: WO2014/28597, 2014, A2,
[10] Patent: US2015/191434, 2015, A1,
[11] Patent: WO2015/129926, 2015, A1,
[12] Patent: US2016/96841, 2016, A1,
[13] Patent: CN105566324, 2016, A,
[14] Patent: WO2017/75182, 2017, A1,
[15] Organic Process Research and Development, 2017, vol. 21, # 5, p. 779 - 784
[16] Patent: US2018/305320, 2018, A1,
  • 17
  • [ 17159-79-4 ]
  • [ 1774-47-6 ]
  • [ 171361-65-2 ]
YieldReaction ConditionsOperation in experiment
65% With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 20℃; Intermediate 9; Ethyl 1 -oxaspiror2.51octane-6-carboxylate; Procedure 9a; To a mixture of trimethylsulfoxonium iodide and potassium tert-butoxide (as reported in Synthetic Communications, 33(12), 2135-2143; 3.9 g, 11.76 mmol) was added a solution of ethyl 4-oxocyclohexanecarboxylate (1 g, 5.87 mmol, Aldrich) in DMSO (20ml). The mixture was left to stir overnight at room temperature. The mixture was poured into water and extracted with diethyl ether; the organic phase was dried on Na2SO4, filtered and evaporated in vacuo to afford the title compound (704.5 mg, 65percent), which was used without purification.Another batch of the same compound prepared using an analogous method showed the following NMR spectra:1H NMR (400 MHz, CDCI3): δ 4.06 (2H, q), 2.49-2.59 (2H, m), 2.26-2.28 (1 H, m), 1.63- 2.04 (6H, m), 1.27-1.49 (2H, m), 1.20 (3H, t) cis/trans 65:35
Reference: [1] Patent: WO2008/92887, 2008, A1, . Location in patent: Page/Page column 28
[2] Patent: WO2008/129007, 2008, A1, . Location in patent: Page/Page column 32
  • 18
  • [ 17159-79-4 ]
  • [ 18107-18-1 ]
  • [ 122898-08-2 ]
  • [ 171361-65-2 ]
  • [ 171361-62-9 ]
Reference: [1] Tetrahedron, 1995, vol. 51, # 37, p. 10259 - 10280
[2] Tetrahedron, 1995, vol. 51, # 37, p. 10259 - 10280
[3] Tetrahedron, 1995, vol. 51, # 37, p. 10259 - 10280
  • 19
  • [ 17159-79-4 ]
  • [ 2181-42-2 ]
  • [ 171361-65-2 ]
Reference: [1] Patent: WO2008/92887, 2008, A1, . Location in patent: Page/Page column 28-29
  • 20
  • [ 186581-53-3 ]
  • [ 17159-79-4 ]
  • [ 122898-08-2 ]
  • [ 171361-65-2 ]
  • [ 171361-62-9 ]
Reference: [1] Tetrahedron, 1995, vol. 51, # 37, p. 10259 - 10280
[2] Tetrahedron, 1995, vol. 51, # 37, p. 10259 - 10280
  • 21
  • [ 17159-79-4 ]
  • [ 122665-97-8 ]
YieldReaction ConditionsOperation in experiment
27% With 4-(tert-butyl)-2,6-dimethylphenyl sulfur trifluoride; pyridine hydrogenfluoride In dichloromethane at 0 - 20℃; for 5 h; Inert atmosphere Ethyl 4-oxycyclohexanecarboxylate (1.13g, 6.67mmol) was dissolved in anhydrous dichloromethane (10mL) in a high density polyethylene (HDPE) container. To it, 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride (2.5g, 9.99mol) was added and stirred under N2 at 0°C. HF-pyridine (0.64mL, 2.64mmol) was added to the vessel and the reaction was allowed to reach ambient temperature. After 5h, the reaction mixture was quenched with saturated aqueous NaHCO3. The organic layer was allowed to stir at ambient temperature in 2N NaOH for 1h. The aqueous layer was washed with dichloromethane and then acidified to pH 1 and extracted with dichloromethane. A total of 0.435g title compound was obtained at 27percent yield. 1H NMR (400MHz, CDCl3) δ 2.498–2.278 (m, 1H), 1.984–1.881 (m, 4H), 1.872–1.753 (m, 4H).
Reference: [1] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 22, p. 5969 - 5987
[2] Tetrahedron Letters, 2005, vol. 46, # 30, p. 5005 - 5007
[3] Tetrahedron Letters, 2005, vol. 46, # 30, p. 5005 - 5007
[4] Patent: WO2013/13188, 2013, A1,
[5] Patent: US2014/275080, 2014, A1,
[6] Patent: US9416132, 2016, B2,
[7] Patent: CN105061188, 2017, B, . Location in patent: Paragraph 0029; 0030; 0031; 0032; 0033; 0034-0037
  • 22
  • [ 17159-79-4 ]
  • [ 122665-97-8 ]
  • [ 350-44-7 ]
Reference: [1] Patent: CN105061188, 2017, B, . Location in patent: Paragraph 0029; 0030; 0031; 0032; 0033; 0034
  • 23
  • [ 17159-79-4 ]
  • [ 178312-47-5 ]
YieldReaction ConditionsOperation in experiment
77%
Stage #1: With triethylamine tris(hydrogen fluoride); ethanaminium,N-(difluoro-λ4-sulfanylidene)-N-ethyl-,tetrafluoroborate In dichloromethane at 20℃; for 16.5 h; Inert atmosphere
Stage #2: With water; sodium hydrogencarbonate In dichloromethane at 20℃; for 0.25 h;
Example 51Deoxofluorination of 4-carboethoxycyclohexanone using diethylaminodifluorosulfinium tetrafluoroborate and triethylamine trihydrofluoride (Addition Order B) To a suspension of diethylaminodifluorosulfinium tetrafluoroborate (344 mg, 1.5 mmol) and triethylamine trihydrofluoride (163 μl_, 1.0 mmol) in dichloromethane (1.5 mL), at room temperature and under nitrogen, is added dropwise a solution of 4-carbethoxy-cyclohexanone (159 μl_, 1.0 mmol) in dichloromethane (1.5 imL) over 1.5 h. The reaction mixture was stirred 15 h, then quenched with a 5percent aqueous sodium bicarbonate solution, stirred for 15 min, and the resulting mixture was extracted using dichloromethane. The organic phases were combined, dried over magnesium sulfate and filtered through a pad of silica gel. Solvents were evaporated to provide 150 mg of a mixture comprising A- carbethoxy-1 ,1-difluorocyclohexane (77percent), 4-carbethoxy-1-fluorocyclohex-1-ene (5percent) and 4-carbethoxy-cyclohexanone (18percent) as a clear oil.
Reference: [1] Journal of the American Chemical Society, 2010, vol. 132, # 51, p. 18199 - 18205
[2] Patent: WO2010/145037, 2010, A1, . Location in patent: Page/Page column 45-46
[3] Tetrahedron Letters, 2005, vol. 46, # 30, p. 5005 - 5007
[4] Patent: US2009/325942, 2009, A1, . Location in patent: Page/Page column 52; 53
[5] Journal of Organic Chemistry, 2010, vol. 75, # 10, p. 3401 - 3411
[6] Journal of Medicinal Chemistry, 2017, vol. 60, # 7, p. 2780 - 2789
[7] Patent: CN105061188, 2017, B, . Location in patent: Paragraph 0029; 0030; 0031
  • 24
  • [ 17159-79-4 ]
  • [ 178312-47-5 ]
YieldReaction ConditionsOperation in experiment
71% With diethylamino-sulfur trifluoride In tetrachloromethane at 0 - 20℃; for 16 h; 17. N-((4.4-difluorocvclohexyl)methyl)-3-(3- trifluoromethoxy)Dhenyl)imidazo[1,2-blDyridazin-6-amine (EX. 8-17). [00312] To a solution of DAST (7.7 ml_) in 75 ml_ CCI4 was added the compound ethyl 4-oxocyclohexanecarboxylate (5 g, 29 mmol) dropwise at 0 °C, then the mixture was stirred for 16 h at r.t, water was added slowly and the organic phase washed with water, dried over Na2SO4, distilled to afford the compound ethyl 4,4-difluorocyclohexanecarboxylate (4.2 g, 71 percent) as a colorless oil.
71% With diethylamino-sulfur trifluoride In tetrachloromethane at 0 - 20℃; for 16 h; To a solution of DAST (7.7 mL) in 75 mL CCl4 was added the compound ethyl 4-oxocyclohexanecarboxylate (5 g, 29 mmol) dropwise at 0° C., then the mixture was stirred for 16 h at r.t, water was added slowly and the organic phase washed with water, dried over Na2SO4, distilled to afford the compound ethyl 4,4-difluorocyclohexanecarboxylate (4.2 g, 71percent) as a colorless oil.
69% With difluoro-4-morpholinylsulfonium tetrafluoroborate; triethylamine tris(hydrogen fluoride) In 1,2-dichloro-ethane for 2.5 h; Reflux Example 12
A solution of triethylamine trihydrofluoride (0.479 mL, 2.94 mmol) in DCE (6 mL) at RT was treated with XtalFluor-M (1.071 g, 4.41 mmol) followed by ethyl 4-oxocyclohexanecarboxylate (0.500 g, 2.94 mmol) and the mixture heated to reflux for 2.5 h.
The mixture was cooled to RT, treated with satd. NaHCO3 and stirred overnight.
The mixture was diluted with DCM, the layers separated, the aqueous layer extracted with additional DCM (1*) and the combined organics were dried over MgSO4 and filtered through a small pad of silica gel, rinsing well with DCM.
The filtrate was concentrated to dryness and purified via silica gel chromatography (DCM/Hex) to afford ethyl 4,4-difluorocyclohexanecarboxylate (390 mg, 69percent) as a colorless oil. 1H NMR (400 MHz, DMSO-d6): δ 4.05 (q, J=7.1 Hz, 2H), 2.49 (m, 1H), 2.02-1.77 (m, 6H), 1.65-1.50 (m, 2H), 1.16 (t, J=7.1 Hz, 3H).
53% With diethylamino-sulfur trifluoride In tetrachloromethane at 20℃; for 16 h; A solution of ethyl 4-oxocyclohexane-1-carboxylate (5 g, 29 mmol) in carbon tetrachloride(150 mL) was slowly added dropwise with DAST (7.7 g, 29 mmol) at rt. The reaction wasstirred for 16 h at rt. The mixture was diluted with water and was extracted with ethyl acetate.The organic layer was separated and the aqueous layer was re-extracted with ethyl acetate(3x50 mL). The combined organic layer was washed with water (lxlOO mL), brine (lxlOO mL), dried over anhydrous Na2504 and concentrated under vacuum to obtain F (3 g, 53percent) as a gummy solid: ‘H NMR (400 MHz, DMSO-d6): 5 4.07 (q, J = 7.2 Hz, 2H), 2.26-2.15 (m, 1H), 2.03-1.99 (m, 2H), 1.98-1.90 (m, 2H), 1.87-1.79 (m, 2H), 1.77-1.56 (m, 2H), 1.18 (t, J=7.6Hz,3H).

Reference: [1] Patent: WO2013/13188, 2013, A1, . Location in patent: Paragraph 00312
[2] Patent: US9416132, 2016, B2, . Location in patent: Page/Page column 134
[3] Patent: US2014/275080, 2014, A1, . Location in patent: Paragraph 0427
[4] Patent: WO2018/213150, 2018, A1, . Location in patent: Page/Page column 20; 21; 28
[5] Patent: US5968923, 1999, A,
[6] Patent: EP1985603, 2008, A1, . Location in patent: Page/Page column 7
[7] Patent: EP1985603, 2008, A1, . Location in patent: Page/Page column 7
[8] Patent: WO2005/63694, 2005, A1, . Location in patent: Page/Page column 135-136
[9] Organic Process Research and Development, 2008, vol. 12, # 6, p. 1094 - 1103
[10] Patent: WO2018/26763, 2018, A1, . Location in patent: Page/Page column 65
  • 25
  • [ 17159-79-4 ]
  • [ 178312-47-5 ]
Reference: [1] Tetrahedron Letters, 2005, vol. 46, # 30, p. 5005 - 5007
  • 26
  • [ 17159-79-4 ]
  • [ 178312-47-5 ]
Reference: [1] Journal of Medicinal Chemistry, 2017, vol. 60, # 7, p. 2780 - 2789
  • 27
  • [ 17159-79-4 ]
  • [ 178312-48-6 ]
YieldReaction ConditionsOperation in experiment
62%
Stage #1: With diethylamino-sulfur trifluoride In dichloromethane at 0 - 23℃; for 24 h;
Stage #2: With 3-chloro-benzenecarboperoxoic acid In dichloromethane; water at 23℃; for 16 h;
Stage #3: With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 4 h;
To a solution of ethyl 4-oxocyclohexanecarboxylate 13 (880 mg, 5.17 mmol) in 0H2012(15 mL)was added diethylaminosulfurtrifluoride(1.368mL, 10.35 mmol) at0°C. Theresulting mixture was stirred for 24 h at 23 0 before it was quenched with a saturated solution of NaHCO3 (20 mL). The resulting mixture was extracted with 0H2012 (4 x 10mL), the combined organic layers were dried over Na2504 and concentrated in vacuo to afford the corresponding gem-difluoro- and vinyl fluoride as an inseparable mixture. Theresidue was passed through a short silica plug (EtOAc) and concentrated in vacuo prior to use.To a CH2CI2 solution of the mixture of gem-difluoro- and vinyl fluoride at 23 00 was added3-chloroperbenzoic acid (1.158 g, 5.17 mmol, 77percent in H20). The resulting reaction mixturewas stirred for 16 h at 23 00 before it was quenched with a saturated solution of Na2SO3(10 mL). The resulting mixture was extracted with CH2CI2 (4 x 10 mL), the combinedorganic layers were dried over Na2SO4 and concentrated in vacuo to give a crude mixtureof gem-difluoride and fluoroepoxide. This mixture which was re-dissolved in THF (10 mL) and lithium aluminium hydride (392 mg, 10.33 mmol) was added at 0 c The resulting reaction mixture was stirred for 4 h at 0°C before it was diluted with Et20 (10 mL) and slowly quenched with H20 (0.5 mL) followed by NaOH (0.5 mL, 15percent aq.). The mixturewas stirred for further 30 mm at 2300 before it was filtered. The filtration cake was washed with Et20 (2 x 10 mL) and the combined filtrate concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 3:1 —* 1:1) to afford compound 14 (480 mg, 62percent for 3 steps) as a pale yellow oil.1H NMR (400 MHz, ODd3) O = 3.47 (d, J= 8.0 Hz, 2 H), 2.25—1.97 (m, 3 H), 1.86—1.47 (m, 5 H), 1.33—1.15 (m, 2 H); 19F NMR (376 MHz, 0D013) O = -91.35 (d, J= 235.3 Hz, 1 F), -102.01 (dtt, J= 235.3, 32.4, 10.0 Hz, 1 F).
Reference: [1] Patent: WO2014/184561, 2014, A1, . Location in patent: Page/Page column 71; 72
[2] Journal of Medicinal Chemistry, 2017, vol. 60, # 7, p. 2780 - 2789
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  • [ 178312-48-6 ]
Reference: [1] Patent: US6262075, 2001, B1,
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  • [ 265108-36-9 ]
Reference: [1] Patent: WO2014/184561, 2014, A1,
[2] Journal of Medicinal Chemistry, 2017, vol. 60, # 7, p. 2780 - 2789
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  • [ 1006686-08-3 ]
Reference: [1] Patent: WO2015/157483, 2015, A1,
[2] Patent: WO2016/77561, 2016, A1,
[3] Patent: WO2017/134596, 2017, A1,
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  • [ 73183-34-3 ]
  • [ 1049004-32-1 ]
Reference: [1] Patent: US2015/152065, 2015, A1, . Location in patent: Paragraph 0671
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  • [ 1049004-32-1 ]
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[2] Patent: WO2011/128265, 2011, A1,
[3] Patent: US2011/263578, 2011, A1,
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[13] Patent: EP2862856, 2015, A1,
[14] Patent: WO2017/78352, 2017, A1,
[15] Patent: WO2018/81047, 2018, A1,
[16] Patent: US2018/258076, 2018, A1,
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[18] Patent: WO2011/141396, 2011, A1,
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