56309-94-5|Bicyclohexane-4,4-dione Monoethylene Ketal| Ambeed

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Quality Control of [ 56309-94-5 ] Purity: 98% SDS Specification

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Product Details of [ 56309-94-5 ]

CAS No. :	56309-94-5
Formula :	C₁₄H₂₂O₃
M.W :	238.32
SMILES Code :	[H]C1(CCC(=O)CC1)C1CCC2(CC1)OCCO2
MDL No. :	MFCD00809704
InChI Key :	ZNWLFTSPNBLXGL-UHFFFAOYSA-N
Pubchem ID :	810913

Safety of [ 56309-94-5 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H317-H412
Precautionary Statements:	P261-P272-P273-P280-P302+P352+P333+P313+P363-P501

Computational Chemistry of [ 56309-94-5 ] Show Less

Physicochemical Properties

Num. heavy atoms	17
Num. arom. heavy atoms	0
Fraction Csp3	0.93
Num. rotatable bonds	1
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	65.48
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	35.53 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.76
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.57
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.68
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	2.01
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	3.13
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.43

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.24
Solubility	1.37 mg/ml ; 0.00575 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.93
Solubility	2.82 mg/ml ; 0.0118 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-2.67
Solubility	0.511 mg/ml ; 0.00214 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	Yes
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.64 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	3.14

Application In Synthesis of [ 56309-94-5 ]

* 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.

Downstream synthetic route of [ 56309-94-5 ]

[ 56309-94-5 ] Synthesis Path-Downstream 1~54

1
[ 56309-94-5 ]
4,4'-Difluoro-4-pentyl-4'-propyl-bicyclohexyl [ No CAS ]

References: [1]Angewandte Chemie - International Edition,1998,vol. 37,p. 484 - 489.

2
[ 56309-94-5 ]
[ 206532-90-3 ]

References: [1]Angewandte Chemie - International Edition,1998,vol. 37,p. 484 - 489.

3
[ 56309-94-5 ]
4'-Pentyl-bicyclohexyl-3'-en-4-one [ No CAS ]

References: [1]Angewandte Chemie - International Edition,1998,vol. 37,p. 484 - 489.

4
[ 56309-94-5 ]
8-(4-Pentyl-cyclohex-3-enyl)-1,4-dioxa-spiro[4.5]decane [ No CAS ]

References: [1]Angewandte Chemie - International Edition,1998,vol. 37,p. 484 - 489.

5
[ 56309-94-5 ]
[ 1073-06-9 ]
4-(1,4-dioxaspiro[4.5]dec-8-yl)-1-(3-fluorophenyl)cyclohexanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium chloride; magnesium; In tetrahydrofuran;	a) A solution of 109 g of 1-bromo-3-fluorobenzene in 270 ml of dry tetrahydrofuran was slowly added dropwise to 14.4 g (0.623 mol) of magnesium shavings and a spatula tip of iodine crystals in such a manner that the reaction mixture was held at the reflux temperature. The reaction mixture was left at 73°-75° C. until the magnesium had been consumed completely, then cooled to 5° C. and treated within 20 minutes with a solution of 117.2 g of <strong>[56309-94-5]4-(1,4-dioxaspiro[4,5]dec-8-yl)cyclohexanone</strong> in 460 ml of anhydrous tetrahydrofuran at 5°-15° C. Thereafter, the reaction solution was warmed to room temperature -and stirred for 90 minutes. Subsequently, 800 ml of 10 percent ammonium chloride solution were added dropwise in such a manner that the temperature did not exceed 35° C. The reaction mixture was thereupon extracted with ether, the organic phase was dried over sodium sulfate, filtered and the filtrate was evaporated. This gave 174.3 g of crude 4-(1,4-dioxaspiro[4,5]dec-8-yl)-1-(3-fluorophenyl)cyclohexanol as brownish crystals which were used in the next reaction without further purification. (cis/trans: 47.5:49.5).

References: [1]Patent: US5888423,1999,A .

6
[ 56309-94-5 ]
[ 348-61-8 ]
4-[4-hydroxy-4-(3,4-difluorophenyl)cyclohexyl]cyclohexanone ethyleneacetal [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium chloride; magnesium; In tetrahydrofuran;	a) A Grignard solution of 0.706 g of magnesium and 6.0 g of 1-bromo-3.4-difluorobenzene in 14 ml of tetrahydrofuran was treated dropwise at 0° C. within 30 minutes with a solution of 5.55 g of 8-(4-oxocyclohexyl)-1,4-dioxaspiro-[4.5]decane in 23 ml of tetrahydrofuran. The reaction mixture was stirred at room temperature for a further 2 hours Subsequently, the reaction mixture was treated with 39 ml of 10percent ammonium chloride solution while cooling and, then, extracted three times with diethyl ether. The organic phases where washed twice with 10percent sodium chloride solution, dried over sodium sulfate, filtered and concentrated. There were thus obtained 7.8 g of crude 1-(3,4-difluorophenyl)-4-(1,4-dioxa-8-spiro[4.5]decyl)cyclohexanol.

References: [1]Patent: US5185098,1993,A .

7
[ 106-39-8 ]
[ 56309-94-5 ]
1-(4-chlorophenyl)-4-(1,4-dioxa-8-spiro[4.5]decyl)cyclohexanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium chloride; iodine; magnesium; In tetrahydrofuran;	a) 4.53 mg of magnesium shavings and a granule of iodine were treated with 150 ml of tetrahydrofuran while stirring and gassing with nitrogen. Subsequently, the mixture was treated dropwise within 20 minutes with a solution of 38.4 g of 4-bromo-1-chlorobenzene in 150 ml of tetrahydrofuran and boiled at reflux for 1.25 hours. Thereafter, the reaction mixture was cooled to 0° C. and treated dropwise within 30 minutes at 0°-5° C. with a solution of 35.7 g of 8-(4-oxocyclohexyl)-1,4-dioxaspiro-[4.5]decane in 240 ml of tetrahydrofuran. The reaction mixture was stirred for a further 4 hours without cooling, then treated within 10 minutes with 240 ml of 10 percent ammonium chloride solution and extracted with diethyl ether. The ether phases were washed twice with water, dried over sodium sulfate, filtered and concentrated. There were thus obtained 54.7 g of 1-(4-chlorophenyl)-4-(1,4-dioxa-8-spiro[4,5]decyl)cyclohexanol as beige crystals.

References: [1]Patent: US5174921,1992,A .

8
[ 56309-94-5 ]
[ 2114-36-5 ]
4-(1,4-dioxaspiro[4.5]dec-8-yl)-1-(4-propylphenyl)cyclohexanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With magnesium; sodium sulfate; In tetrahydrofuran;	Synthesis of 4-(1,4-dioxaspiro[4.5]dec-8-yl)-1-(4-propylphenyl)cyclohexanol A solution of 160 g (0.67 mol) of 4-(1,4-dioxaspiro[4.5]dec-8-yl)cyclohexanone in 600 ml of THF is added to a solution of the Grignard reagent generated from 147 g (0.74 mol) of p-bromopropylbenzene and 18.0 g (0.74 mol) of magnesium turnings (400 ml of THF). When the addition is complete, the mixture is heated under reflux for 1 h, and sat. ammonium chloride soln. is added. The mixture is acidified using dil. hydrochloric acid and extracted a number of times with MTBE. The combined organic phases are washed with water, and the solution is dried using sodium sulfate. The crude product obtained after removal of the solvents is used without further purification.

References: [1]Patent: US2010/181533,2010,A1 .

9
[ 23391-99-3 ]
[ 107-21-1 ]
[ 56309-94-5 ]

References: [1]Patent: WO2006/118014,2006,A1 .Location in patent: Page/Page column 9-11.
[2]Patent: WO2006/118014,2006,A1 .Location in patent: Page/Page column 11-12.
[3]Patent: WO2006/118014,2006,A1 .Location in patent: Page/Page column 12.

10
[ 56309-94-5 ]
1-ethoxy-2,3-difluorobenzene [ No CAS ]
[ 954119-09-6 ]

Yield	Reaction Conditions	Operation in experiment
		99.5 g (0.63 mol) of 2,3-difluoroethoxybenzene are initially introduced in 800 ml of THF, and 384 ml (0.63 mol) of n-BuLi (15percent soln. in hexane) are added at -70° C. After 30 min at this temperature, a solution of 150 g (0.63 mol) of 4-(1,4-dioxaspiro[4.5]dec-8-yl)cyclohexanone in 700 ml of THF is metered in, and the batch is stirred for 30 min. The reaction mixture is warmed to 0° C. and hydrolyzed using 2 N HCl. The solution is extracted with MTBE, and the combined organic phases are washed with sat. sodium chloride solution and dried using sodium sulfate. The crude product remaining after removal of the solvents under reduced pressure is used directly for the next reaction.
		3-Ethoxy-l,2-difluorobenzene (s65) (10.0 g) and THF(200 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and cooled to -74° C. sec-Butyllithium (1.00 M, in n-hexane-cyclohexane; 64.0 ml)was added dropwise in the temperature range of -74° C. to -70° C, and the stirring was continued for another 2 hours. 4-(l,4-Dioxaspiro[4.5]decan-8-yl)-cyclohexanone (s66) (12.8 g) in THF (50 ml)solution was added dropwise in the temperature range of -75° C. to -70° C, andthe stirring was continued for another 8 hours while the mixture was allowed to come to 25° C. The reaction mixture was treated with an aqueous solution of ammonium chloride (3percent), and the aqueous layer was extracted withe thyl acetate. The combined organic layers were washed with water,a saturated aqueous solution of sodium hydrogencarbonate and water, and thendried over anhydrous magnesium sulfate. Distillation of the solvent underreduced pressure gave 4-(l,4-dioxaspiro[4.5]decan-8-yl)-l-(4-ethoxy-2,3-dif-luorophenyl)-cyclohexanol.The compound was mixed with 15 p-toluenesulfonic acid (0.68 g) andtoluene (200 ml), and the mixture was heated to reflux for 2 hours whiledistilled water was removed. After the reaction mixture had been cooled to 30°C, it was treated with water, and the aqueous layer was extracted with toluene.The combined organic layers were 2o washed with a saturated aqueous solution of sodium hydrogencarbonateand water, and then dried over anhydrous magnesium sulfate. The solution wasconcentrated under reduced pressure, and the residue was purified by columnchromatography with toluene as an eluent and silica gel as a stationary 25 phasepowder. Pd/C (0.3 g) was added to the purified product and the mixture wasstirred at room temperature under a hydrogen atmosphere until hydrogenabsorption had ceased. After the reaction had been completed, Pd/C was removed,and then solvent was distilled off. The residue was purified by 30 recrystallizationfrom a mixed solvent of THF and heptane (THF:heptane=l:9 by volume) to give 8-[4-(4-ethoxy-2,3-difluorophenyl)-cyclohexenyl]-l,4-dioxaspiro[4.5]decane(s67) (7.7 g). The yield based on the compound (s65) was 35.2percent.

References: [1]Patent: US2007/247585,2007,A1 .Location in patent: Page/Page column 41-42.
[2]Patent: JP5849664,2016,B2 .Location in patent: Paragraph 0240; 0241; 0242.

11
[ 56309-94-5 ]
[ 948564-42-9 ]
4-(1,4-dioxaspiro[4,5]dec-8-yl)-1-[2-fluoro-4-(pentylcyclohexyl)phenyl]cyclohexanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		1-Fluoro-3-(4-pentyl-cyclohexyl)-benzene (1) (56.2 g) and THF (500 ml) were put in a reaction vessel under a nitrogen atmosphere, and cooled to -73 °C. s-Butyllithium (1.04 M, in a n-hexane and cyclohexane solution; 250.0 ml) was added dropwise thereto in the temperature range of -74 °C to -65 °C, and the mixture was stirred for another 30 minutes. Subsequently, 4-(1,4-dioxospiro [4, 5] decan-8-yl) cyclohexane (2) (57.2 g) in a THF (160 ml) solution was added dropwise thereto in the temperature range of -76 °C to -65 °C, and the stirring was continued for another 20 hours while the mixture was allowed to return to 25 °C. Then, the reaction mixture was poured into a vessel containing ammonium chloride (27.8 g) and ice-water (1,000 ml), and mixed. Toluene (1360 ml) was added thereto and the mixture was allowed to separate into organic and aqueous phases, and then an extractive operation was carried out. The organic phase was fractionated, and washed sequentially with water and a saturated aqueous solution of sodium hydrogencarbonate and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with a fractional operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene: ethyl acetate= 7: 3 by volume) as an eluent and silica gel as a stationary phase powder and dried, giving 108.6 g of 4-(1,4-dioxa-spiro[4,5]dec-8-yl)-l-[2-fluoro-4-(pentyl-cyclohexyl)-phenyl]-cyclohexanol (3). The compound (3) was a yellow solid.

References: [1]Patent: EP2279990,2011,A1 .Location in patent: Page/Page column 44.

12
[ 56309-94-5 ]
[ 948564-44-1 ]
1-(4-(4-ethoxycyclohexyl)-2-fluorophenyl)-4-(1,4-dioxaspiro[4,5]decan-8-yl)cyclohexanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		The compound (22) (30.0 g) and THF (200 ml) were put in a reaction vessel under a nitrogen atmosphere, and cooled to -73 °C. s-Butyllithium (1. 04 M, in a n-hexane and cyclohexane solution; 155.7 ml) was added dropwise thereto in the temperature range of -74 °C to -65 °C, and the mixture was stirred for another 30 minutes. Subsequently, 4-(1,4-dioxospiro[4,5]decan-8-yl)cyclohexanone (2) (35.4 g) in a THF (100 ml) solution was added dropwise thereto in the temperature range of -76 °C to -65 °C, and the stirring was continued for another 20 hours while the mixture was allowed to return to 25 °C. Then, the reaction mixture was poured into a vessel containing ammonium chloride (18.2 g) and ice-water (500 ml), and mixed. Toluene (600 ml) was added thereto, and the mixture was allowed to separate into organic and aqueous phases, and then an extractive operation was carried out. The organic phase was fractionated, and washed sequentially with water and a saturated aqueous solution of sodium hydrogencarbonate and brine, and then dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure, giving 72.9 g of 1- (4- (4-ethoxycyclohexyl) -2-fluorophenyl) -4- (1,4-dioxaspiro[4,5]decan-8-yl)cyclohexanol (23).

References: [1]Patent: EP2279990,2011,A1 .Location in patent: Page/Page column 51-52.

13
[ 56309-94-5 ]
[ 1246299-11-5 ]
1-(2,3-difluoro-4-(4-pentylcyclohexyl)phenyl)-4-(1,4-dioxaspiro[4,5]decan-8-yl)cyclohexanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		The compound (43) (30.0 g) and THF (200 ml) were put in a reaction vessel under a nitrogen atmosphere, and cooled to -73 °C. s-Butyllithium (1. 03 M, in a n-hexane and cyclohexane solution; 131.2 ml) was added dropwise thereto in the temperature range of -74 °C to -65 °C, and the mixture was stirred for another 30 minutes. Subsequently, 4-(1,4-dioxospiro[4,5]decan-8-yl) cyclohexanone (2)(32.2 g) in a THF (100 ml) solution was added dropwise thereto in the temperature range of -76 °C to -65 °C, and the stirring was continued for another 20 hours while the mixture was allowed to return to 25 °C. Then, the reaction mixture was poured into a vessel containing ammonium chloride (14.5 g) and ice-water (500 ml), and mixed. Toluene (600 ml) was added thereto and the mixture was allowed to separate into organic and aqueous phases, and then an extractive operation was carried out. The organic phase was fractionated, and washed sequentially with water and a saturated aqueous solution of sodium hydrogencarbonate and brine, and then dried over anhydrous magnesium sulfate. Then the solvent of the solution was distilled off under reduced pressure, and the residue was purified with a fractional operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene: ethyl acetate= 5:3 by volume) as an eluent and silica gel as a stationary phase powder and dried, giving 69.3 g of 1-(2,3-difluoro-4-(4-pentylcyclohexyl)phenyl-4-(1,4-dioxaspiro[4,5]decan-8-yl)cyclohexanol (44).

References: [1]Patent: EP2279990,2011,A1 .Location in patent: Page/Page column 58.

14
[ 56309-94-5 ]
[ 1246299-08-0 ]
1-(2,3-difluoro-4-(4-propylcyclohexyl)phenyl)-4-(1,4-dioxaspiro[4,5]decan-8-yl)cyclohexanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		The compound (33) (29.1 g) and THF (200 ml) were put in a reaction vessel under a nitrogen atmosphere, and cooled to -73 °C. s-Butyllithium (1. 03 M, in a n-hexane and cyclohexane solution; 146.7 ml) was added dropwise thereto in the temperature range of -74 °C to -65 °C, and the mixture was stirred for another 30 minutes. Subsequently, 4-(1,4-dioxospiro[4,5]decan-8-yl)cyclohexanone (2) (36.1 g) in THF (100 ml) solution was added dropwise thereto in the temperature range of -76 °C to -65 °C, and the stirring was continued for another 20 hours while the mixture was allowed to return to 25 °C. Then, the reaction mixture was poured into a vessel containing ammonium chloride (16.2 g) and ice-water (500 ml), and mixed. Toluene (600 ml) was added thereto and the mixture was allowed to separate into organic and aqueous phases, and then an extractive operation was carried out. The organic phase was fractionated, and washed sequentially with water and a saturated aqueous solution of sodium hydrogencarbonate and brine, and then dried over anhydrous magnesium sulfate. Then the solvent of the solution was distilled off under reduced pressure, and the residue was purified with a fractional operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene: ethyl acetate= 5:3 by volume) as an eluent and silica gel as a stationary phase powder and dried, giving 55.3 g of 1-(2,3-difluoro-4-(4-propylcyclohexyl)phenyl-4-(1,4-dioxaspiro[4,5]decan-8-yl)cyclohexanol (34).

References: [1]Patent: EP2279990,2011,A1 .Location in patent: Page/Page column 55.

15
[ 56309-94-5 ]
[ 598-30-1 ]
2,3-difluorophenyl butyl ether [ No CAS ]
4-(1,4-dioxaspiro[4.5]decan-8-yl)-1-(4-butoxy-2,3-difluorophenyl)-cyclohexanol. p-Toluenesulfonic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium chloride; sodium hydrogencarbonate; In tetrahydrofuran; hexane; water; ethyl acetate;	Second Step3-Butoxy-1,2-difluorobenzene (s-4) (10.0 g) and THF (200 ml) were put in a reaction vessel and were cooled to -74° C. under an atmosphere of nitrogen.sec-Butyllithium (a 1.00 M solution in n-hexane and cyclohexane; 64.0 ml) was added dropwide thereto in the temperature range of -74° C. to -70° C., and the stirring was continued for another 2 hours.Then, <strong>[56309-94-5]4-(1,4-dioxaspiro[4.5]decan-8-yl)-cyclohexanone</strong> (s-5) (12.8 g) in a THF (50 ml) solution was added dropwise thereto in the temperature range of -75° C. to -70° C., and the stirring was continued for another 8 hours while the mixture was allowed to come to 25° C.The mixture was poured into a vessel containing an aqueous solution of ammonium chloride (3percent; 100 ml) and ethyl acetate (100 ml), and mixed with them.The mixture was then allowed to stand until it had separated into organic and aqueous phases, and the extraction was carried out.The combined organic phase was washed successively with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate.Then, the solvent was distilled off to give 4-(1,4-dioxaspiro[4.5]decan-8-yl)-1-(4-butoxy-2,3-difluorophenyl)-cyclohexanol. p-Toluenesulfonic acid (0.68 g) and toluene (200 ml) were mixed with this compound and the mixture was heated to reflux for 2 hours, while distilled water was removed.After the reaction mixture had been cooled to 30° C., water (200 ml) and toluene (200 ml) were added to the mixture, and mixed with it.

References: [1]Patent: US2011/240919,2011,A1 .

16
[ 123-75-1 ]
[ 56309-94-5 ]
[ 1268275-20-2 ]

Yield	Reaction Conditions	Operation in experiment
	In toluene; for 3h;Inert atmosphere; Reflux;	First StepToluene (200 ml) and pyrrolidine (90 ml) were added to <strong>[56309-94-5]4-(1,4-dioxaspiro[4.5]decan-8-yl)cyclohexanone</strong> (100 g) in a reaction vessel equipped with a Dean-Stark apparatus under an atmosphere of nitrogen.The mixture was refluxed for 3 hours while the water formed was removed by a Dean-Stark apparatus.After the reaction mixture had been cooled to a room temperature, it was washed with brine, and dried over anhydrous magnesium sulfate.The toluene was distilled off to give 1-(4-(1,4-dioxaspiro[4.5]decan-8-yl)cyclohex-1-enyl)pyrrolidine (105.8 g).

References: [1]Patent: EP2468707,2012,A1 .Location in patent: Page/Page column 42.

17
[ 56309-94-5 ]
4-(trans-6-propyl-trans-decahydronaphthalen-2-yl)cyclohexanone [ No CAS ]