147905-77-9|Ethyl 1-methyl-4-oxocyclohexanecarboxylate| Ambeed

Structure of 147905-77-9

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Quality Control of [ 147905-77-9 ] Purity: 97% SDS Specification

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Product Details of [ 147905-77-9 ]

CAS No. :	147905-77-9
Formula :	C₁₀H₁₆O₃
M.W :	184.23
SMILES Code :	CCOC(=O)C1(C)CCC(=O)CC1
MDL No. :	MFCD17018639
InChI Key :	GYDKHYAZKCAMAS-UHFFFAOYSA-N
Pubchem ID :	21911973

Safety of [ 147905-77-9 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302
Precautionary Statements:	P280-P305+P351+P338

Computational Chemistry of [ 147905-77-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	0
Fraction Csp3	0.8
Num. rotatable bonds	3
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	49.29
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	43.37 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.12
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	0.98
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.7
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.	1.2
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	2.29
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.66

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.4
Solubility	7.31 mg/ml ; 0.0397 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.48
Solubility	6.12 mg/ml ; 0.0332 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	-2.29
Solubility	0.938 mg/ml ; 0.00509 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	No
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.	-6.73 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	1.0
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)	1.99

Application In Synthesis of [ 147905-77-9 ]

* 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 [ 147905-77-9 ]

[ 147905-77-9 ] Synthesis Path-Downstream 1~35

1
[ 147905-77-9 ]
[ 161258-05-5 ]
4-[Bis-((S)-2-methyl-butoxy)-phosphoryloxy]-1-methyl-cyclohex-3-enecarboxylic acid ethyl ester [ No CAS ]

References: [1]Journal of Organic Chemistry,1994,vol. 59,p. 8197 - 8202.

2
[ 159329-33-6 ]
[ 147905-77-9 ]
ethyl 1-ethyl-3-oxocyclopentanecarboxylate [ No CAS ]

References: [1]Australian Journal of Chemistry,1994,vol. 47,p. 1833 - 1841.

3
[ 24730-88-9 ]
[ 147905-77-9 ]

Yield	Reaction Conditions	Operation in experiment
85%	With CAN; In acetonitrile; at 70℃; for 2h;	To a solution of ethyl 8-methyl-1,4-dioxaspiro[4.5]decane-8-carboxylate (7.3 g, 32.0 mmol) in MeCN (50 mL) and water (50 mL) was added CAN (2.11 g, 3.85 mmol). The mixture was heated to 70 C. and stirred for 2 h. The reaction mixture was cooled to room temperature, and partitioned between water (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (50 mL2). The combined organic layers were washed with brine (50 mL2), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (5 g, 85%) as yellow oil, which was used for next step without further purification.
85%	With ammonium cerium (IV) nitrate; In water; acetonitrile; at 70℃; for 2h;	To a solution of ethyl 8-methyl-1,4-dioxaspiro [4.5] decane-8-carboxylate (7.3 g, 32.0 mmol) in MeCN (50 mL) and water (50 mL) was added CAN (2.11 g, 3.85 mmol) was added. The mixture was heated to 70 C. and stirred for 2 hours. The reaction mixture was cooled to room temperature and partitioned between water (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (50 mL × 2), dried over Na 2 SO 4, filtered and concentrated in vacuo to afford the title compound (5 g, 85%) as a yellow oil, which was obtained without further purification It was used for the next step.
74%	With hydrogenchloride; In tetrahydrofuran; water; at 0 - 20℃; for 1h;	Ethyl-8-methyl-1,4-dioxa-spiro [4.5] decane-8-carboxylic acid tert-butyl ester (5.00g, 21.9mmol) was dissolved inIn tetrahydrofuran (50mL), was added dropwise at 0C 1N aqueous hydrochloric acid solution (20 mL) was stirred for 1 hour after 20 C. The mixture was cooled to 0 C, was added a solution of sodium bicarbonate (50 mL) to quench the reaction. Mixture of ethyl acetate(100mLx3) extraction. The organic phase was washed with saturated brine (100 ml x 3), dried over anhydrous sodium sulfate driedAfter drying concentrated under reduced pressure. Was purified by silica gel column chromatograph(1 petroleum ether / ethyl acetate, Rf = 0.4 10) y to give ethyl-1-methyl-4-oxo-cyclohexanecarboxylate (3.00g, colorless oil). Yield: 74%.

67%	With toluene-4-sulfonic acid; In water; acetone;Reflux;	Ethyl 1-methyl-4-oxocyclohexane-1-carboxylate To a solution of ethyl 8-methyl-1,4-dioxaspiro[4.5]decane-8-carboxylate (1 equiv.) in acetone/H2O (0.5 M, 1/1) was added pTSA.H2O (1 equiv.). The mixture was refluxed overnight, then concentrated to remove acetone. The resulting solution was diluted with ethyl acetate, and the layers were separated. The organic phase was washed with saturated NaHCO3, dried over Na2SO4 and filtered. The filtrate was concentrated to afford ethyl 1-methyl-4-oxocyclohexanecarboxylate (67%). 1H NMR (400 MHz, CDCl3) delta ppm: 4.23 (q, J=7.2 Hz, 2H), 2.49-2.39 (m, 4H), 2.37-2.27 (m, 2H), 1.75-1.64 (m, 2H), 1.34-1.28 (m, 6H).
	With hydrogenchloride; water; In 1,4-dioxane; ethanol; at 20℃; for 64h;Product distribution / selectivity;	Step B - Synthesis of ethyl l-methyl-4-oxocyclohexanecarboxylate (Int-6b) OC2009.701871lnt-6a lnt-6bIn a 50 mL round-bottom flask was mixed with ethyl 8-methyl-l,4- dioxaspiro[4.5]decane-8-carboxylate (Int-6a, 1.99 g, 8.72 mmol), EtOH (10 mL), H2O (5 mL), and 4N HCl in 1,4-dioxane (5 mL). The resulting solution was stirred at room temperature for 64 hours. At this time, the solvent was removed in vacuo and the residue was taken up in DCM. The suspension was washed with saturated NaHCtheta3(aq) and the organic layer was dried over Na2SO^ The resulting product was taken on without further purification. Yield = 1.00 g.
	With ammonium cerium (IV) nitrate; water; In acetonitrile; at 70℃; for 1h;	The ketal compound (2.09 g, 9.17 mmol) was dissolved in CAN (100 mL) and water (50 mL). H4)2Ce(N03)6 (503 mg, 0.92 mmol) was added in water (50 mL) was added and the mixture was heated up to 70 C and stirred for 1 hour. After cooling down to room temperature, water (100 mL) was added and extracted with Et20 (100 mL x 3) and the organics was dried over Na2S04. After concentration, the crude was purified with column (0-30% EtOAc/Hexane) to give the product (1.72 g).
	With ammonium cerium (IV) nitrate; In water; acetonitrile; at 70℃; for 1h;	The ketal compound (2.09 g, 9.17 mmol) was dissolved in CAN (100 mL) and water (50 mL). (NH )2Ce N03)6 (503 mg, 0.92 mmol) in water (50 mL) was added and the mixture was heated up to 70 C and stirred for 1 hour. After cooling down to room temperature, water (100 mL) was added and extracted with Et20 (100 mL x 3) and the organics was dried over Na2S04. After concentration, the crude was purified with column (0~30% EtOAc/Hexane) to give the product (1.72 g).
	With hydrogenchloride; In water; acetone; at 20℃; for 48h;	Intermediate 66: ethyl l-methyl-4-oxocyclohexanecarboxylateTo a solution of ethyl 8-methyl-l,4-dioxaspiro[4.5]decane-8-carboxylate (2.0 g, 8.76 mmol) in aceton (60 ml) was added HC1 (2.5 M, 60 ml, 150 mmol) at romm temperature . After stirring at room temperature over 48 hours, the reaction mixture was poured into DCM , the organic layer was then separated and the aqueous was extracted with DCM, washed with brine, dried over Na2S04 , filtered and concentrated, and purified by MPLC (5-60%> EtOAc in hexane ) to provide ethyl l-methyl-4-oxocyclohexanecarboxylate as colorlee liquid (1.12 g). LC-MS (ES, m/z) CioHi603: 184; Found: 185 [M+H]+. Intermediate 67: ethyl 4-hydroxy-l-methylcyclohexanecarboxylateTo a solution of ethyl l-methyl-4-oxocyclohexanecarboxylate (7.02 g, 38.1 mmol) in methanol (15 ml) at 0C added sodium borohydride (0.721 g, 190.5 mmol) in small portions over 30 min. The reaction mixture aged for 1 hour. Then concentrated under vacuum and applied onto a silica gel column and eluted with ethyl acetate/hexane 10-100%. This resulted in 5.58 g (79%) of ethyl 4-hydroxy-l-methylcyclohexanecarboxylate (cis&trans mixture) as colorless oil. LC-MS (ES, m/z): Ci0Hi8O3: 186; Found: 187 [M+H]+.
8.34 g	With hydrogenchloride; In water; acetone; at 20℃;	The compound (12.8 g) produced in Example 44 was dissolved in 100 mL of acetone, 50 mL of 2N hydrochloric acid was added while stirring at room temperature, and the mixture was stirred at that temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, 100 mL of tetrabutyl methyl ether 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, and dried with magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 9.7 g of the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/hexane=3%?25%) to obtain the title compound (8.34 g) having the following physical property values.; TLC: Rf 0.41 (hexane:ethyl acetate=4:1); 1H-NMR (CDCl3): delta 1.25-1.32 (m, 6H), 1.58-1.73 (m, 2H), 2.27-2.51 (m, 6H), 4.22 (q, J=7.2 Hz, 2H).
1.12 g	With hydrogenchloride; In water; acetone; at 20℃;	Intermediate 35 Ethyl 1 -methyl-4-oxocvclohexanecarboxylate To a solution of ethyl 8-methyl-l,4-dioxaspiro[4.5]decane-8-carboxylate (2.0 g, 8.76 mmol) in aceton (60 ml) was added HC1 (2.5 M, 60 ml, 150 mmol) at rt . After stirred at rt over weekend, the reaction mixture was poured into DCM , the organic layer was then separated and the aqueous was extracted with DCM, washed with brine, dried over Na2S04 , filtered and concentrated, and purified by MPLC (5-60% EtOAc in hexane ) to provide ethyl l-methyl-4- oxocyclohexanecarboxylate as colorlee liquid (1.12 g). LC-MS (ES, m/z) C10H16O3: 184; Found: 185 [M+H]+
	With sulfuric acid; In acetone; at 20℃;	Step 3. Preparation of ethyl 1-methyl-4-oxocyclohexanecarboxylate (i-ld). The mixture of ethyl 8-methyl-l,4-dioxa-spiro[4.5]decane-8-carboxylate (i-lc) (2.0 g, 8.77 mmol) in Acetone (20 mL) and IN H2S04 (20 mL) was stirred at room temperature for overnight. The mixture was diluted with H20 (50 mL). The aqueous layer was extracted with DCM (3x30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2S04 and concentrated to get the desired product as a pale yellow oil. LCMS (ESI) calc'd for Ci0Hi6O3 [M+H]+: 185, found: 185.
	With sulfuric acid; In acetone; at 20℃;	Step 3. Preparation of ethyl l-methyl-4-oxocyclohexanecarboxylate (i-ld).A mixture of ethyl 8-methyl-i ,4-dioxa-spiro [4.5] decane-8-carboxylate (i-l c) (2.0 g, 8.77 mmol) in acetone (20 mL) and iN H2504 (20 mL) was stirred at room temperature overnight. The mixture was diluted with H20 (50 mL). The aqueous layer was extracted with DCM (3x30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2504 and concentrated to obtain the desired product as a pale yellow oil. LCMS(ESI) calc?d for C10H1603 [M+H]b: 185, found: 185.
	With sulfuric acid; In water; acetone; at 20℃;	Step 3. Preparation of ethyl 1-methyl-4-oxocyclohexanecarboxylate (i-1d) [0261] A mixture of ethyl 8-methyl-1,4-dioxa-spiro[4.5]decane-8-carboxylate (i-1c) (2.0 g, 8.77 mmol) in acetone (20 mL) and 1N H2SO4 (20 mL) was stirred at room temperature overnight. The mixture was diluted with H2O (50 mL). The aqueous layer was extracted with DCM (3×30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated to obtain the desired product as a pale yellow oil. LCMS (ESI) calc'd for C10H16O3 [M+H]+: 185. found: 185.
	With hydrogenchloride; water; In acetone; at 20℃; for 18h;	To a solution of compound D2-2 (8.4 g, 36.84 mmol) in acetone (100 mL) was added HCl (3 M in water* 50 mL) dropwise at room temperature, and the whole was stirred at room temperature for 18 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to provide compound D2-3 (6.3 g) as a light yellow oil. The crude product was used in the next step without purification. 1H NMR (CDC13, 400 MHz): delta 4.22 (q, J = 7.0 Hz, 2H), 2.47-2.38 (m, 4H), 2.34-2.30 (m, 2H), 1.72-1.64 (m, 2H), 1.31- 1.29 (m. 611).
	With ammonium cerium (IV) nitrate; In water; acetonitrile; at 70℃; for 2h;	Step 3. Preparation of ethyl l-methyl-4-oxocvclohexanecarboxylate (i-23c) [00196] To a solution of ethyl 8-methyl-l,4-dioxaspiro[4.5]decane-8-carboxylate (7.3 g, 32.0 mmol) in MeCN (50 mL) and water (50 mL) was added eerie ammonium nitrate (2.11 g, 3.85 mmol). The mixture was heated to 70 C and stirred for 2 h. The reaction mixture was cooled to room temperature, and partitioned between water (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (50 mL* 2). The combined organic layers were washed with brine (50 mL*2), dried over Na2SC>4, filtered and concentrated under reduced pressure to afford the title compound (5 g, 85%) as yellow oil, which was used for next step without further purification.
	With sulfuric acid; In acetone; at 20℃; for 14h;	Into a 100-mL round-bottom flask, ethyl 8-methyl-1,4-dioxaspiro[4.5]decane-8- carboxylate (2.3 g, 10.08 mmol) was dissolved in acetone (20 mL). Then sulfuric acid (1M, 20 mL) was added. The resulting solution was stirred for 14 h at room temperature. The resulting solution was diluted with 50 ml of water and extracted with 3x50 ml of ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated under vacuum. This afforded the title compound (1.8g, crude) as a yellow oil. MS: (ES, m/z): 185 [M+H]+.

References: [1]Australian Journal of Chemistry,1994,vol. 47,p. 1833 - 1841.
[2]Patent: US2018/305320,2018,A1 .Location in patent: Paragraph 0228; 0231.
[3]Patent: JP2018/531957,2018,A .Location in patent: Paragraph 0182; 0184.
[4]Patent: CN105566324,2016,A .Location in patent: Paragraph 0337; 0341; 0342; 0343.
[5]Patent: US2016/96841,2016,A1 .Location in patent: Paragraph 0333.
[6]Patent: WO2011/2887,2011,A1 .Location in patent: Page/Page column 70-71.
[7]Patent: WO2012/27239,2012,A1 .Location in patent: Page/Page column 50.
[8]Patent: WO2012/27236,2012,A1 .Location in patent: Page/Page column 59.
[9]Patent: WO2012/164071,2012,A1 .Location in patent: Page/Page column 64.
[10]Patent: US2013/109699,2013,A1 .Location in patent: Paragraph 2011-2014.
[11]Patent: WO2013/96093,2013,A1 .Location in patent: Page/Page column 51; 52.
[12]Patent: WO2014/26328,2014,A1 .Location in patent: Page/Page column 37.
[13]Patent: WO2014/28597,2014,A2 .Location in patent: Page/Page column 43.
[14]Patent: US2015/191434,2015,A1 .Location in patent: Paragraph 0261.
[15]Patent: WO2015/129926,2015,A1 .Location in patent: Page/Page column 186.
[16]Patent: WO2017/75182,2017,A1 .Location in patent: Paragraph 00196.
[17]Patent: WO2019/55877,2019,A1 .Location in patent: Paragraph 0087.

4
[ 147905-77-9 ]
[ 24730-90-3 ]

References: [1]Tetrahedron,1969,vol. 25,p. 5287 - 5294.

5
C₂₀H₃₂N₂O₄ [ No CAS ]
[ 147905-77-9 ]

References: [1]Tetrahedron Letters,2006,vol. 47,p. 763 - 766.

6
[ 1489-97-0 ]
[ 147905-77-9 ]

References: [1]Australian Journal of Chemistry,1994,vol. 47,p. 1833 - 1841.
[2]Australian Journal of Chemistry,1994,vol. 47,p. 1833 - 1841.
[3]Patent: WO2011/2887,2011,A1 .
[4]Patent: WO2012/27239,2012,A1 .
[5]Patent: WO2012/27236,2012,A1 .
[6]Patent: WO2012/164071,2012,A1 .
[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]Patent: US2018/305320,2018,A1 .
[16]Patent: WO2019/55877,2019,A1 .

7
[ 17159-79-4 ]
[ 147905-77-9 ]

References: [1]Australian Journal of Chemistry,1994,vol. 47,p. 1833 - 1841.
[2]Australian Journal of Chemistry,1994,vol. 47,p. 1833 - 1841.
[3]Patent: WO2011/2887,2011,A1 .
[4]Patent: WO2012/27239,2012,A1 .
[5]Patent: WO2012/27236,2012,A1 .
[6]Patent: US2013/109699,2013,A1 .
[7]Patent: WO2014/26328,2014,A1 .
[8]Patent: WO2014/28597,2014,A2 .
[9]Patent: US2015/191434,2015,A1 .
[10]Patent: WO2015/129926,2015,A1 .
[11]Patent: US2016/96841,2016,A1 .
[12]Patent: CN105566324,2016,A .
[13]Patent: WO2017/75182,2017,A1 .
[14]Patent: US2018/305320,2018,A1 .
[15]Patent: WO2019/55877,2019,A1 .

8
[ 159329-32-5 ]
[ 147905-77-9 ]

References: [1]Australian Journal of Chemistry,1994,vol. 47,p. 1833 - 1841.

9
[ 147905-77-9 ]
[ 75-16-1 ]
ethyl (1,4-trans)-1,4-dimethyl-4-hydroxycyclohexanecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; at -78℃; for 0.416667h;	PRODUCTION EXAMPLE 21 ; Production of ethyl (1,4-trans)-1,4-dimethyl-4-hydroxycyclohexanecarboxylate [0674] To a solution of 4.50 g of <strong>[147905-77-9]ethyl 1-methyl-4-oxocyclohexanecarboxylate</strong> (which was prepared by the method described in WO 92/18463) in 100 ml of tetrahydrofuran, 80 ml of 0.93M methyl magnesium bromide-tetrahydrofuran solution was added at -78 C., followed by 25 minutes' stirring at the same temperature. Water was added to the reaction liquid which then was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried on anhydrous magnesium sulfate and the solvent was distilled off. Separating and purifying the residue on silica gel column chromatography (ethyl acetate/hexane=1/2) to provide 1.74 g of the title compound.

References: [1]Patent: US2003/236267,2003,A1 .Location in patent: Page 47.

10
[ 144-55-8 ]
[ 24730-88-9 ]
[ 147905-77-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In methanol;	EXAMPLE 3 Hydrolysis 5.81 g of ethyl 8-methyl-1,4-dioxaspiro[4.5]-decane-8-carboxylate (Example 2) was dissolved in 200 ml of methanol. Then, 30 ml of concentrated hydrochloric acid was added to the solution under ice-cooling, and was stirred at room temperature for one hour. After reaction, 300 ml of an aqueous sodium hydrogencarbonate solution was added to the reaction solution. The resultant solution was extracted three times with 70 ml of ethyl acetate. The resultant organic layer was washed once with each of an aqueous sodium chloride solution and an aqueous sodium hydrogen-carbonate solution, and was then dried over magnesium sulfate. Thereafter, the solvent was removed in vacuo. The oily substance obtained was refined by vacuum distillation (Kugelrohl), yielding 3.4 g of ethyl 1-methyl-4-oxo-1-cyclohexanecarboxylate as a colorless oil, which had the following physiochemical properties: Boiling point: 170 C./0.4 mmHg (Kugelrohl) Proton nuclear magnetic resonance spectrum (delta ppm in CDCl3): 0.8-2.5 (9H,m), 1.26 (3H, t, J=7Hz), 1.30 (3H, s), 4.17 (2H, q, J=7Hz) IRmax (neat, cm-1): 2964, 1724 MS (M+): 184

References: [1]Patent: US5344845,1994,A .

11
[ 860469-35-8 ]
[ 77-78-1 ]
[ 147905-77-9 ]

References: [1]European Journal of Organic Chemistry,2008,p. 895 - 913.

12
[ 147905-77-9 ]
[ 358369-80-9 ]
ethyl 3,3,9-trimethyl-1,2,5-trioxaspiro[5.5]undecane-9-carboxylate [ No CAS ]
ethyl 3,3,9-trimethyl-1,2,5-trioxaspiro[5.5]undecane-9-carboxylate [ No CAS ]

References: [1]European Journal of Organic Chemistry,2008,p. 895 - 913.

13
[ 147905-77-9 ]
[ 676-58-4 ]
[ 28886-59-1 ]
[ 845508-26-1 ]
[ 1145835-82-0 ]

References: [1]Organic Process Research and Development,2009,vol. 13,p. 621 - 624.

14
[ 147905-77-9 ]
[ 1260106-23-7 ]

References: [1]Patent: WO2011/2887,2011,A1 .
[2]Patent: WO2012/27239,2012,A1 .
[3]Patent: WO2014/26328,2014,A1 .
[4]Patent: WO2014/28597,2014,A2 .
[5]Patent: US2015/191434,2015,A1 .
[6]Patent: WO2017/75182,2017,A1 .
[7]Patent: US2018/305320,2018,A1 .
[8]Patent: JP2018/531957,2018,A .
[9]Patent: WO2019/35927,2019,A1 .

15
[ 147905-77-9 ]
[ 1260106-24-8 ]

References: [1]Patent: WO2011/2887,2011,A1 .
[2]Patent: WO2012/27236,2012,A1 .

16
[ 147905-77-9 ]
[ 1260106-25-9 ]

References: [1]Patent: WO2011/2887,2011,A1 .

17
[ 147905-77-9 ]
[ 1260106-26-0 ]

References: [1]Patent: WO2011/2887,2011,A1 .

18
[ 147905-77-9 ]
[ 1260106-27-1 ]

References: [1]Patent: WO2011/2887,2011,A1 .

19
[ 147905-77-9 ]
[ 1260105-77-8 ]

References: [1]Patent: WO2011/2887,2011,A1 .

20
[ 37595-74-7 ]
[ 147905-77-9 ]
[ 1257998-20-1 ]

Yield	Reaction Conditions	Operation in experiment
		Step C - Synthesis oflnt-18dEthyl l -methyM-oxocyclohexanecarboxylate (Int-18c, 2.65 g, 14.39 mmol) was dissolved in dry THF (10 mL) and added into LDA (17.28 mmol) in THF (20 mL) at -78 0C. The resulting mixture was stirred for 30 min and N- phenyltrifluoromethanlsulfonimide (5.66 g, 15.8 mmol) on THF (10 mL) was added at-78 0C. The resulting mixture was allowed to warm up to room temperature and stirred overnight. NH4CI (aq.) was added to quench the reaction which was extracted with ethyl acetate. The organics were dried and concentrated and purified on a column(silica gel, 0-30% EA in hexane) to give ethyl l-methyl-4-(trifluoromethylsulfonyloxyJcyclohex-S-enecarboxylate (Int-18d) (3.36 g).
		LDA (17.28 mmol) in THF (20 mL) was cooled to -78 C and the ketone (2.65 g, 14.39 mmol) in THF (10 mL) was added dropwise and stirred for 30 min. Then N- phenylbis(trifluoromethanesulfonimide) (5.66 g, 15.8 mmol) in THF (10 mL) was added. The resulting mixture was allowed to warm up to room temperature and stirred overnight. The NH4Cl(aq.) was added to quench the reaction and extracted with EtOAc. The organics was dried over Na2S04, concentrated and purified with column (0-30%) to give the product (3.36 g).
		LDA (17.28 mmol) in THF (20 mL) was cooled to -78 C and the ketone (2.65 g, 14.39 mmol) in THF (10 mL) was added dropwise and stirred for 30 min. Then N- phenylbis(1xifluoromethanesulfonimide) (5.66 g, 15.8 mmol) in THF (10 mL) was added. The resulting mixture was allowed to warm up to room temperature and stirred overnight. The- 59 - NH4Cl(aq.) was added to quench the reaction and extracted with EtOAc. The organics was dried over Na2S04, concentrated and purified with column (0~30%) to give the product (3.36 g).

	With lithium hexamethyldisilazane; In tetrahydrofuran; at -78 - 20℃; for 3.5h;Cooling with acetone-dry ice;	Step 4. Preparation of ethyl 1-methyl-4-(trifluoromethylsulfonyloxy)cyclohex-3-enecarboxylate (i-le). The mixture of ethyl l-methyl-4-oxocyclohexanecarboxylate (i-ld) (3.0 g, 16.3 mmol) in anhydrous THF (20 mL) was cooled to -78 C in a dry ice-acetone bath and LiHMDS (18 mL, 17.9 mmol) was added dropwise. The mixture was stirred at -78C for 30min. Then the solution of trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide 5 (5.37 g, 14.7 mmol) in anhydrous THF (20 mL) was added dropwise. The resulted solution was warmed to room temperature and continued to stir for 3h. Saturated NH C1 solution (50 mL) was added to quench the reaction and the aqueous layer was extracted with EA (3x50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2S04 and concentrated. The residue was chromatographed on silica gel (PE:EA 100: 1) to get the desired product as a colorless oil. LCMS (ESI) calc'd for CnHi5F305S [M+H]+: 317, found: 317;
		Step 4. Preparation of ethyl l-methyl-4-(trifluoromethylsulfonyloxy)cyclohex-3- enecarboxylate (i-le).A mixture of ethyl i-methyl-4-oxocyclohexanecarboxylate (i-ld) (3.0 g, 16.3 mmol) in anhydrous THF (20 mL) was cooled to -78C in a dry ice-acetone bath and LiHMDS (18 mL, 17.9 mmol) was added dropwise. The mixture was stirred at -78C for 30mm. Then a solution of trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide 5 (5.37 g, 14.7 mmol) in anhydrous THF (20 mL) was added dropwise. The resulting solution was warmed to room temperature and continued to stir for 3h. Saturated NH4C1 solution (50 mL) was added to quench the reaction and the aqueous layer was extracted with EA (3x50 mL). The combinedorganic layers were washed with brine (50 mL), dried over anhydrous Na2504 andconcentrated. The residue was chromatographed on silica gel (PE:EA 100:1) to obtain the+desired product as a colorless oil. LCMS (ESI) calcd for C11H15F3055 [M+H] :317, found:317;
		Step 4. Preparation of ethyl 1-methyl-4-(trifluoromethylsulfonyloxy)cyclohex-3-enecarboxylate (i-1e) [0262] A mixture of <strong>[147905-77-9]ethyl 1-methyl-4-oxocyclohexanecarboxylate</strong> (i-1d) (3.0 g, 16.3 mmol) in anhydrous THF (20 mL) was cooled to -78 C. in a dry ice-acetone bath and LiHMDS (18 mL, 17.9 mmol) was added dropwise. The mixture was stirred at -78 C. for 30 min. Then a solution of trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide 5 (5.37 g, 14.7 mmol) in anhydrous THF (20 mL) was added dropwise. The resulting solution was warmed to room temperature and continued to stir for 3 h. Saturated NH4Cl solution (50 mL) was added to quench the reaction and the aqueous layer was extracted with EA (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated. The residue was chromatographed on silica gel (PE:EA 100:1) to obtain the desired product as a colorless oil. LCMS (ESI) calc'd for C11H15F3O5S [M+H]+: 317. found: 317.
		Step 4. Preparation of ethyl l-methyl-4-(((trifluoromethyl)sulfonyl)oxy)cvclohex-3- enecarboxylate (i-23d) [00197] To a solution of LDA (20.4 mL, 2.0 M in THF, 40.8 mmol) in THF (30 mL) cooled at -78 C was added ethyl l-methyl-4-oxocyclohexanecarboxylate (5.00 g, 27.1 mmol) in THF (10 mL) dropwise. After stirring at this temperature for 30 min, N,N- bis(trifluoromethylsulfonyl)aniline (10.67 g, 29.9 mmol) in THF (20 mL) was added. The mixture was warmed to room temperature and stirred for 16 h. The mixture was quenched with NH4CI (aq.) (30 mL), extracted with EtOAc (30 mL3). The combined organic layers were washed with brine (40 mL2), dried over Na2SC>4, filtered and concentrated. The residue was purified by column chromatography on silica gel (Petro. ether: EtOAc = 100: 1-50: 1) to afford the title compound. NMR (CD3OD, 400 MHz) delta 5.71 (s, 1H), 4.04-4.21 (m, 2H), 2.62-2.75 (m, 1H), 2.27-2.48 (m, 2H), 2.01-2.19 (m, 2H), 1.68-1.75 (m, 1H), 1.14-1.25 (m, 6H).
		To a solution of LDA (20.4 mL, 2.0 M in THF, 40.8 mmol) in THF (30 mL) cooled at -78 OC was added <strong>[147905-77-9]ethyl 1-methyl-4-oxocyclohexanecarboxylate</strong> (5.00 g, 27.1 mmol) in THF (10 mL) drop wise. After stirring at this temperature for 30 min, N,N-bis(trifluoromethylsulfonyl)aniline (10.67 g, 29.9 mmol) in THF (20 mL) was added. The mixture was warmed to room temperature and stirred for 16 h. The mixture was quenched with NH4Cl (aq.) (30 mL), extracted with EtOAc (30 mL3). The combined organic layers were washed with brine (40 mL2), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (Petro. ether:EtOAc=100:150:1) to afford the title compound. 1H NMR (CD3OD, 400 MHz) delta 5.71 (s, 1H), 4.04-4.21 (m, 2H), 2.62-2.75 (m, 1H), 2.27-2.48 (m, 2H), 2.01-2.19 (m, 2H), 1.68-1.75 (m, 1H), 1.14-1.25 (m, 6H).
		To a solution of LDA (20.4 mL, 2.0 M in THF, 40.8 mmol) in THF (30 mL) cooled to -78 C. was added <strong>[147905-77-9]ethyl 1-methyl-4-oxocyclohexanecarboxylate</strong> (5 .00 g, 27.1 mmol) was added dropwise. After stirring at this temperature for 30 minutes, N, N-bis (trifluoromethylsulfonyl) aniline (10.67 g, 29.9 mmol) in THF (20 mL) was added. The mixture was warmed to room temperature and stirred for 16 h. The mixture was quenched with NH 4 Cl (aq) (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (40 mL × 2), Dried over Na 2 SO 4, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether: EtOAc = 100: 1 to 50: 1)To give the title compound.
		To a solution of ethyl l -methyl-4-oxocyclohexanecarboxylate (14 g) in tetrahydrofuran (150 mL) was added potassium hexamethyidisilazide (1 M tetrahydrofuran solution, 129 mL) at -78 C. The reaction mixture was stirred at -78 C for 1 hour and a solution of 1 ,1 ,1 -trifluoro-N-phenyl-N- ((trifluoromethyl)sulfonyl)methanesulfonamide (34.6 g) in tetrahydrofuran was slowly added at -78 C. The mixture was stirred and allowed to warm to 25 C in the period of 15 hours. The reaction was quenched with aqueous NH4CI solution (100 mL), extracted with ethyl acetate (2 x 200 mL). The combined organic layer was washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether and ethyl acetate = 100 : 1-10 : 1) to give the title compound.

References: [1]Patent: WO2011/2887,2011,A1 .Location in patent: Page/Page column 115-116.
[2]Patent: WO2012/27239,2012,A1 .Location in patent: Page/Page column 50; 51.
[3]Patent: WO2012/27236,2012,A1 .Location in patent: Page/Page column 59; 60.
[4]Patent: WO2014/26328,2014,A1 .Location in patent: Page/Page column 37.
[5]Patent: WO2014/28597,2014,A2 .Location in patent: Page/Page column 43; 44.
[6]Patent: US2015/191434,2015,A1 .Location in patent: Paragraph 0262.
[7]Patent: WO2017/75182,2017,A1 .Location in patent: Paragraph 00197.
[8]Patent: US2018/305320,2018,A1 .Location in patent: Paragraph 0228; 0232.
[9]Patent: JP2018/531957,2018,A .Location in patent: Paragraph 0182; 0185.
[10]Patent: WO2019/35927,2019,A1 .Location in patent: Paragraph 00635.

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[ 147905-77-9 ]
[ 1252900-68-7 ]

Yield	Reaction Conditions	Operation in experiment
73%	With alpha-D-glucopyranose; ketoreductase 119; NADP; sodium hydroxide; In aq. phosphate buffer; dimethyl sulfoxide; for 1h;pH 7;Enzymatic reaction;	To a solution of 0.17g of KRED, 0.17g of NADP, and 0.17g of GDH (CDX-901), and 10.8g (59.7mmol) of d-glucose in 160mL of a 0.1M pH 7 phosphate buffer was added 5.00g (27.1mmol) of ketone 14 in 10mL of DMSO. The pH of the reaction mixture was monitored and adjusted as needed with 5N NaOH to maintain a constant pH of 7. After 1h, the reaction was diluted with 150mL of MTBE and the layers were separated. The aqueous layer was back extracted with 150mL of MTBE. The combined extracts were washed with 50mL of water and then with 50mL of brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to afford 3.67g (73%) of 15 as an oil, which was sufficiently pure for use without further purification: 1H NMR (CDCl3, 400MHz) delta 1.15 (s, 3H), 1.16-1.38 (m, 7H), 1.66 (br s, 1H), 1.84 (m, 2H), 2.22 (m, 2H), 3.59 (m, 1H), 4.15 (q, 2H, J=7.0Hz)); 13C NMR (CDCl3, 100MHz) delta 14.1, 25.8, 27.0, 30.6, 32.6, 33.6, 42.6, 60.3, 69.8, 176.9. Anal. Calcd for C10H18O3: C, 64.49; H, 9.74. Found: C, 64.92; H, 9.66.
	With sodium tetrahydroborate; ethanol; at 0℃; for 2h;	Preparation Example 125 To a mixture of <strong>[147905-77-9]ethyl 1-methyl-4-oxocyclohexanecarboxylate</strong> (3 g) and ethanol (30 ml) was added sodium borohydride (616 mg) at 0 C., followed by stirring for 2 hours. To the reaction mixture were added water and ethyl acetate, followed by carrying out a separation of the layers using ethyl acetate, and the organic layer was washed sequentially with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 90:10 to 80:20) to obtain 1.27 g of ethyl cis-4-hydroxy-1-methylcyclohexanecarboxylate as a colorless oil.

References: [1]Tetrahedron,2014,vol. 70,p. 4563 - 4570.
[2]Patent: US2012/46292,2012,A1 .Location in patent: Page/Page column 15.

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[ 147905-77-9 ]
[ 1361144-68-4 ]