Structure of 17159-80-7
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| CAS No. : | 17159-80-7 |
| Formula : | C9H16O3 |
| M.W : | 172.22 |
| SMILES Code : | O=C(C1CCC(O)CC1)OCC |
| English Name : | Ethyl 4-hydroxycyclohexanecarboxylate |
| MDL No. : | MFCD00192156 |
| Num. heavy atoms | 12 |
| Num. arom. heavy atoms | 0 |
| Fraction Csp3 | 0.89 |
| Num. rotatable bonds | 3 |
| Num. H-bond acceptors | 3.0 |
| Num. H-bond donors | 1.0 |
| Molar Refractivity | 45.71 |
| TPSA ? Topological Polar Surface Area: Calculated from |
46.53 Ų |
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.2 |
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.04 |
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.1 |
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.0 |
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.23 |
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.32 |
| Log S (ESOL):? ESOL: Topological method implemented from |
-1.36 |
| Solubility | 7.43 mg/ml ; 0.0432 mol/l |
| Class? Solubility class: Log S scale |
Very soluble |
| Log S (Ali)? Ali: Topological method implemented from |
-1.61 |
| Solubility | 4.25 mg/ml ; 0.0247 mol/l |
| Class? Solubility class: Log S scale |
Very soluble |
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.99 |
| Solubility | 17.7 mg/ml ; 0.103 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| 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) |
No |
| CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
| CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
| CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
| CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
| CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
| Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.61 cm/s |
| Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
| Ghose? Ghose filter: implemented from |
None |
| Veber? Veber (GSK) filter: implemented from |
0.0 |
| Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
| Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
| Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
| PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
| Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
| Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
| Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.73 |
* 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.

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With pyridine; sodium; benzene Erwaermen des Reaktionsprodukts mit aethanol. KOH; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 100% | With hydrogen In ethanol at 20℃; for 20h; | |
| 88% | With hydrogen In ethanol at 100℃; for 48h; | |
| 61% | With hydrogen In ethanol at 145 - 150℃; for 18h; |
| With hydrogen at 160℃; | ||
| With hydrogen | ||
| With hydrogen In ethanol at 120℃; | ||
| With hydrogen for 120h; Yield given; | ||
| In methanol | 1.1 Step 1 Step 1 Ethyl 4-hydroxycyclohexanecarboxylate (32.0) STR43 To a 1-L Pyrex pressure bottle were added sequentially 50 g of ethyl 4-hydroxybenzoate, 300 mL of methanol, and 5 g of 5% Rh on Al2 O3. The sealed bottle was flashed with nitrogen and hydrogenated at 50 psi until 1 H NMR indicated complete reaction (about 8 to about 16 hrs). Filtration of the reaction mixture followed by concentration gave 50 g of the compound of Formula 32.0 as a mixture of trans and cis-isomers with a ratio of 78:22 as determined by GLC. The crude pale-yellow liquid was used directly in the oxidation step (Step 2 below) without further purification. HRMS: 173.1178 (MH+); calculated: 173.1171; 1 H NMR (CDCl3) trans: 4.12 (q, J=7.2 Hz, 2H), 3.89 (m, 1H), 2.36 (m, 1H), 2.04-1.90 (m, 3H), 1.70-1.60 (m, 5H), 1.24 (t, J=7.2 Hz, 3H). IR: 1730 cm--1. |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 100% | With jones reagent In acetone | |
| 100% | With pyridinium chlorochromate In dichloromethane at 4℃; for 6h; Heating / reflux; | 48 Example 48: preparation of Ethyl 4-ketocyclohexanecarboxylate (16). To a srirred solution of pyridinium chlorochromate (9.48 g, 44.0 mmol) in DCM (50 mL) at [4oC] was added a solution of ethyl 4-hydroxycyclohexanecarboxylate (5.00 g, 29.0 mmol). The mixture was stirred at [4oC] for 2 hours than heated at reflux and stirred for another 4 hours. The reaction was cooled at room temperature, filtered on CeliteTM and the filtrate was evaporated to a residue which was purified by column chromatography using a gradient of 25 to 45 % of EtOAc in hexane as eluant to give 4.93 g (100 %) of the ketone 16 as a clear oil: HRMS calcd for CgH1403 [(M+)] : 170.0943, found : 170.0938 [; 1H] NMR [(CDCLG)] [6] 1.26 (t, 3H, J= 7. [15),] 2.02 (m, 2H), 2.19 (m, 2H), 2.34 (m, 2H), 2.44 (m, [2H),] 2.73 (m, 1H), 4.16 (q, 2H, J= 7.13). |
| 98% | With 4-Benzoylpyridine In acetone at 20℃; for 16h; UV-irradiation; Inert atmosphere; |
| 92% | With sodium dichromate; sulfuric acid In diethyl ether; water for 3h; | |
| 90% | Stage #1: 4-hydroxycyclohexyl carboxylic acid ethyl ester With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 3.25h; Stage #2: With triethylamine In dichloromethane at -78 - 20℃; | 7.7.i Example 7: c/s-4-hydroxy-4- [2-(6-methoxy- [1,5] naphthyridin-4-yl)-ethyl] - cyclohexanecarboxylic acid (2,3-dihydro-benzo[l,4]dioxin-6-yl)-amide:7.i. 4-oxo-cyclohexanecarboxylic acid ethyl ester.To a solution of oxalyl chloride (6 mL, 68.8 mmol) in DCM (100 mL) at -78°C was added dropwise a solution of DMSO (6.4 mL, 90 mmol) in DCM (2O mL). The mixture was stirred at this temperature for 15 min before the dropwise addition of a solution of ethyl4-hydroxycyclohexane carboxylate (4.8 mL, 30 mmol) in DCM (20 mL). The mixture was stirred at -78°C for 3 h before addition of TEA (29.3 mL, 210 mmol) in DCM (20 mL).The mixture was then gradually warmed to rt, washed with a sat. aq. NH4Cl solution and brine, dried over MgSO4 and concentrated. The residue was purified by chromatography over SiO2 (Hex/EA 1 :1) to give the title ketone (4.6 g, 90% yield) as a colourless oil.1H NMR (CDCl3) δ: 4.19 (q, J = 7.1 Hz, 2H); 2.80-2.70 (m, IH); 2.55-2.45 (m, 2H);2.40-2.30 (m, 2H); 2.25-2.10 (m, 2H); 2.05-2.00 (m, 2H); 1.29 (t, J = 7.1 Hz, 3H). |
| 90% | With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -78℃; for 3.25h; | 7.i 7.i. To a solution of oxalyl chloride (6 mL, 68.8 mmol) in DCM (100 mL) at -78° C. was added dropwise a solution of DMSO (6.4 mL, 90 mmol) in DCM (20 mL). The mixture was stirred at this temperature for 15 min before the dropwise addition of a solution of ethyl 4-hydroxycyclohexane carboxylate (4.8 mL, 30 mmol) in DCM (20 mL). The mixture was stirred at -78° C. for 3 h before addition of TEA (29.3 mL, 210 mmol) in DCM (20 mL). The mixture was then gradually warmed to rt, washed with a sat. aq. NH4Cl solution and brine, dried over MgSO4 and concentrated. The residue was purified by chromatography over SiO2 (Hex/EA 1:1) to give the title ketone (4.6 g, 90% yield) as a colourless oil. 1H NMR (CDCl3) δ: 4.19 (q, J=7.1 Hz, 2H); 2.80-2.70 (m, 1H); 2.55-2.45 (m, 2H); 2.40-2.30 (m, 2H); 2.25-2.10 (m, 2H); 2.05-2.00 (m, 2H); 1.29 (t, J=7.1 Hz, 3H). |
| 88% | With pyridinium chlorochromate In dichloromethane at 0 - 23℃; for 16h; Molecular sieve; | 13 Ethyl 4-oxocyclohexanecarboxylate (13) Powdered 3 A molecular sieves (5 g) and pyridinium chlorochromate (2.23 g, 10.36mmol) were suspended in a solution of ethyl 4-hydroxycyclohexanecarboxylate (1.19 g,6.91 mmol; mixture of cis and trans isomers) in CH2CI2 (20 mL) at 0 C The resulting reaction mixture was stirred at 23 C for 16 h before it was filtered through a pad ofCelite. The filtration cake was washed with CH2CI2 (4 x 10 mL) and the filtrate wasconcentrated in vacuo. The residue was purified by flash column chromatography (silicagel, hexanes:EtOAc 5:1 -* 1:1) to afford compound 13(1.034 g, 88%) as a colourless oil.1H NMR (400 MHz, ODd3) O = 4.13 (q, J= 7.1 Hz, 2 H), 2.70 (tt, J= 9.7, 4.0 Hz, 1 H),2.43(dt, J= 14.7, 5.4 Hz, 2 H), 2.36-2.25(m, 2 H), 2.23-2.11 (m, 2 H), 2.05-1.91 (m,2 H), 1.23 (t, J= 7.1 Hz, 3 H). |
| 88% | With pyridinium chlorochromate In dichloromethane at 0 - 23℃; for 16h; Inert atmosphere; | |
| 83% | With aluminum oxide; pyridinium chlorochromate In chloroform for 3h; | |
| 40.5% | With Dess-Martin periodane In dichloromethane at 0℃; for 4h; | Synthesis of ethyl 4-oxocyclohexane-1-carboxylate (Intermediate 3) The mixture of ethyl 4-hydroxycyclohexane-1-carboxylate (2.0 g, 1 eq, 11.6 mmol) in dichloromethane (3.00 mL) was added 3-oxo-1l5-benzo[d][1,2]iodaoxole-1,1,1(3H)-triyl triacetate (493.0 mg, 0.1 eq, 1.16 mmol) and stirred at 0 °C for 4 h. LCMS indicated completion of reaction. The reaction mixture was quenched with H2O/NH4Cl (10 mL), then extracted with DCM (10 mL X2) and concentrated under vacuum. The residue was purified by silica gel column chromatography (100-200 mesh silica gel, 0-30% of ethyl acetate in petroleum ether) to afford ethyl 4-oxocyclohexane-1-carboxylate (800 mg, 4.70 mmol, 40.5%) as a yellow oily. 1H NMR (400 MHz, CDCl3) δ 4.16 (dq, J = 18.6, 7.2 Hz, 2H), 2.75 (ddd, J = 13.6, 9.6, 3.9 Hz, 1H), 2.48 (dt, J = 14.3, 5.1 Hz, 1H), 2.40 ^ 2.33 (m, 1H), 2.26 ^ 2.16 (m, 1H), 2.07 ^ 1.93 (m, 2H), 1.76 ^ 1.59 (m, 3H), 1.34 ^ 1.21 (m, 3H). |
| With sodium dichromate; sulfuric acid | ||
| With chromium(VI) oxide; sulfuric acid In water; acetone | ||
| With chromic acid Yield given; | ||
| With chromium(VI) oxide | ||
| With acetic acid | 1.2 Step 2 Step 2 Ethyl 4-oxocyclohexanecarboxylate (33.0) STR44 To a 3-L 3-neck flask equipped with a mechanical stirrer, a thermometer, and an addition funnel were added 50 g (292 mmol) of the compound of Formula 32.0 from Step 1, 33 mL (584 mmol) of acetic acid and 145 mL of commercial bleach (5.25% NaOCl). To the cooled reaction mixture, at 5° C., was added dropwise 479 mL of more bleach. The reaction was allowed to warm to room temperature for 1 hour and then was extracted with 3*400 mL ethyl acetate. The combined extract was washed with water, dried over MgSO4, and concentrated to give 49 g of crude 33.0 as an oil which was used without purification. The spectrum data are identical to that of literature (see Sanchez, I. H.; Ortega, A.; Garcia, G.; Larraza, M. I.; Flores, H. J. Synthetic comm. 1985, 15, 141). | |
| With sulfuric acid; chromic acid In diethyl ether; isopropyl alcohol; acetone | B Ethyl 4-oxocyclohexanecarboxylate EXAMPLE B Ethyl 4-oxocyclohexanecarboxylate Ethyl 4-hydroxybenzoate is reduced to ethyl 4-hydroxycyclohexanecarboxylate according to the procedure described in R. A. Finnegan and P. L. Bachman, Journal of Organic Chemistry, Volume 30, pages 4145-4150 (1965). The crude material obtained in this reduction (190 g) is dissolved in 1200 ml of reagent grade acetone. The solution is cooled to 0° C. and 152 ml of a 8 N chromic acid solution (prepared from concentrated sulfuric acid and chromium trioxide) is added dropwise to the mechanically stirred reaction mixture. Enough isopropanol is added to the mixture to discharge its red color and it is then filtered through Celite. The salts are washed with several portions of acetone. The filtrate is evaporated in vacuo. The residue is dissolved in 750 ml of diethyl ether and washed with sodium bicarbonate and brine solutions. After drying, the solvent is evaporated and the residue is distilled to yield the title compound; bp12 125 ° C. In a process analogous to Example B using appropriate starting materials the following compound is prepared: | |
| With pyridinium chlorochromate In dichloromethane at 0 - 20℃; for 1.83333h; | 1 Preparation 1 : Ethyl 4-oxocvclohexanecarboxylate; EPO In a 5 L 3-neck flask, fitted with a mechanical stirrer and gas outlet was added ethyl A- hydroxycyclohexanecarboxylate (167.3 g, 0.971 mol) and methylene chloride (2 L) followed by Celite (275 g). The resulting mixture was cooled in an ice bath and pyridium chlorochromate (272.3 g, 1.26 mol) was added in portions over 20 min. The mixture was stirred at room temperature for 1.5 hours, filtered through a plug of Celite, and rinsed with methylene chloride (2 L). The filtrate was concentrated in vacuo and the residue was chromatographed over a Biotage 75L column (eluted with 20% ethyl acetate in hexanes) to afford the title compound as a colorless liquid (165.5 g).1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.3 (t, J=7.3 Hz, 3 H) 2.0 (m, 2 H) 2.2 (m, 2 H) 2.3 (m, 2 H) 2.5 (m, 2 H) 2.7 (m, 1 H) 4.2 (q, J=7.1 Hz, 2 H) |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 100% | With 1H-imidazole In DMF (N,N-dimethyl-formamide) at 35℃; for 12h; | 5.a.A; 5.b.A A. 4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexanecarboxylic acid ethyl ester. To a solution of tert-butyldimethylsilyl chloride (10.6 g, 70 mmol) and imidazole (9.9 g, 145 mmol) in DMF (20 mL) was added 4-hydroxy-cyclohexanecarboxylic acid ethyl ester (9.4 mL, 58 mmol). The mixture was stirred at 35° C. for 12 h, diluted with EtOAc (100 mL), washed with H2O (3×), dried (Na2SO4), and concentrated. The resulting white solid was isolated in quantitative yield (16.6 g) and was used in the next step without purification. |
| 100% | With 1H-imidazole; dmap In N,N-dimethyl-formamide at 0 - 20℃; for 16h; | |
| 96% | With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 3h; | 3.1 Example 3 : 8-(3-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-lH-pyrazol-l-yl)-2- oxaspiro [4.5] decan-1-one; Step 1: ethyl 4-(tert-butyldimethyIsilyloxy)cyclohexanecarboxylate.; [124] tert-Butyldimethylsilyl chloride (3.61 g, 0.0240 mol) was added to a solution of 4- hydroxy-cyclohexanecarboxylic acid ethyl ester (3.44 g, 0.0200 mol; ), and lH-imidazole (3.40 g, 0.0499 mol; ) in N,N-Dimethylformamide (5.0 mL, 0.064 mol). The mixture was stirred at the room temperature for 3 hours. The mixture was partitioned between ethyl acetate and water. The ethyl acetate phase was washed with brine, dried over sodium sulfate, filtered, and then concentrated to give oily crude product. Column chromatography eluting with 0-20% ethyl acetate/hexanes gave 5.5 g (96%) of the title compound as colorless oil. 1H-NMR (300 MHz, CD3Cl) δ 4.12 (m, 2H), 3.72 (m, IH), 2.29 (m, IH), 1.93 (m, 2H), 1.65 (m, 2H), 1.56 (m, 2H), 1.48 (m, 2H), .125 (m, 3H), 0.88 (d, 6H), 0.03 (d, 6H). |
| 74% | With 1H-imidazole In N,N-dimethyl-formamide at 23℃; for 4h; | |
| 69.8% | With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 48h; | Intermediate 3-h: 4- ((4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) methoxy) -3-nitrobenzenesulfonamide Step 1: ethyl 4- ((tert-butyldimethylsilyl) oxy) cyclohexane-1-carboxylate To a solution of ethyl 4-hydroxycyclohexane-1-carboxylate (2 g, 11.61mmol) in DMF (50 ml) were added tert-butylchlorodimethylsilane (1.575 g, 10.4 mmol) and imidazole (1.58 g, 23.22 mmol). The mixture was stirred at r.t. for 2 days. The mixture was concentrated. The residue was dissolved with DCM (200 ml), washed with brine, dried over Na 2SO 4 and concentrated. The residue was purified by chromatography column on silica (eluent: EA/PE = 1/40) to give the product (2.32 g, 69.8%). |
| 45% | Stage #1: 4-hydroxycyclohexyl carboxylic acid ethyl ester With triethylamine In dichloromethane at 20℃; for 0.333333h; Stage #2: tert-butyldimethylsilyl chloride In dichloromethane at 20℃; for 40h; | Ethyl 4-[(tert-butyldimethylsilyl)oxy]cyclohexane-1-carboxylate To a solution of ethyl 4-hydroxycyclohexane-1-carboxylate (10 g, 58.06 mmol) in dichloromethane (25 mL) was added triethylamine (13 g, 128.47 mmol) slowly at room temperature. After stirring for additional 20 min, TBDMSC1 (24.9 g, 87.09 mmol) was slowly added. The resulting reaction mixture was then stirred at room temperature for 40 h. The reaction mixture was quenched by the addition of water (100 mL) and extracted with dichloromethane (100 mL×2). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (1% to 10% gradient) to yield ethyl 4-[(tert-butyldimethylsilyl)oxy]cyclohexane-1-carboxylate as yellow oil (7.5 g, 45%). |
| 2.25 g (79%) | With dmap; triethylamine In N,N-dimethyl-formamide at 20℃; for 18h; | 5 5-Butyl-9-[1-(4,6-dimethyl-pyrimidine-5-carbonyl)-4-methyl-piperidin-4-yl]-3-(trans-4-hydroxy-cyclohexylmethyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one (I-4) EXAMPLE 5 5-Butyl-9-[1-(4,6-dimethyl-pyrimidine-5-carbonyl)-4-methyl-piperidin-4-yl]-3-(trans-4-hydroxy-cyclohexylmethyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one (I-4) 4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexanecarboxylic acid ethyl ester (38)-To a solution of 4-oxy-cyclohexanecarboxylic acid ethyl ester (CASRN 17159-80-7, 1.7 g, 0.01 mol) in DMF (14 mL) was added DMAP (58 mg, 0.47 mmol), TEA (1.54 mL) and tert-butyl-dimethylsilyl chloride (1.65 g, 0.011 mol). The reaction mixture was stirred at RT for 18 h, poured into ice (10 g), extracted with EtOAc (3*50 mL). The organic extracts were dried (MgSO4) filtered and concentrated. The residue was purified by SiO2 chromatography eluding with EtOAc/hexane (1:20) to afford 2.25 g (79%) of 4-(tert-butyl-dimethyl-silanyloxy)-cyclohexanecarboxylic acid ethyl ester (38) as colorless oil. |
| With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 18h; | 15 tert-Butyldimethylchlorosilane (9.71 g, 64.45 mmol) was added portion wise to ethyl 4- hydroxycyclohexanecarboxylate (CAS no. 17159-80-7) (10 g, 58 mmol) and imidazole (7.9 g, 116 mmol) in DMF (58 mL) under nitrogen. The resulting solution was stirred at room temperature for 18 hours. The reaction mixture was diluted with diethyl ether (250 mL), and washed with saturated brine (500 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford the product (16.3 g). This was used without any further purification.IH NMR (300 MHz, CDCl3) δ 0.02 - 0.07 (5H, m), 0.87 - 0.90 (9H, m), 0.92 (IH, s), 1.22 - 1.29 (3H, m), 1.30 - 1.54 (3H, m), 1.59 - 1.70 (2H, m), 1.87 - 2.04 (3H, m), 2.21 - 2.32 (IH, m), 3.70 - 3.89 (IH, m), 4.07 - 4.16 (2H, m). | |
| With 1H-imidazole In N,N-dimethyl-formamide at 20 - 40℃; | 1 Chloro(1 ,1-dimethylethyl)dimethylsilane (1 15 g; 0.76 mol) was added in portions over 1 hour to a solution of commercially available ethyl 4-hydroxycyclohexanecarboxylate (118 g; 0.68 mol), imidazole (103 g; 1.52 mol) and dimethylformamide (400 ml.) stirred under an atmosphere of argon. A small exotherm was observed resulting in the reaction mixture temperature increasing to -40 0C. The mixture was stirred at room temperature overnight then poured into 10% citric acid solution (2 L) and extracted with diethyl ether (2 x 800 ml_). The ether extracts were washed with water, brine and then dried (Na2SC>4) and the solvent was removed to give the title compound as an oil (198.4 g) 1H NMR δ (CDCI3, 400 MHz): 0.01 (6H, m), 0.85 (9H, s), 1.2 (3H, m), 1.3-1.5 (2H, m), 1.6 (2H, m), 1.85-2 (3H, m), 2.15-2.3 (1 H, m) 3.5 (0.4H, m) 3.86 (1 H, m) 4.1 (1 H, m). | |
| With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 20h; | 2.a PREPARATION 2: l-(2-(Benzyloxy)ethyl)-4-(/- butyldimethylsilyloxy)cyclohexanecarbaldehyde; Step a: Ethyl 4-(tert-butyldimethylsilyloxy)cyclohexanecarboxylate; [00164] A mixture of ethyl 4-hydroxycyclohexane-carboxylate (50 mL, 0.31mol), imidazole (50.1 g, 0.74 mol), and t-butyldimethylsilyl chloride (56 g, 0.37mol) in DMF (580 mL) was stirred at room temperature for 20 hrs under atmosphere of nitrogen. Water (100 mL) was added to the mixture, and the mixture was extracted with ether (600 mL). The extract was washed with water (400 mL) and brine (500 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to give compound 2 as a colorless oil (102 g), which was used for the next step without further purification. | |
| With 1H-imidazole In DMF (N,N-dimethyl-formamide) at 20℃; for 16h; | 45A Example 45 (2S, [5R)-5-ETHYNYL-L- (N- (4-HYDROXY-L-METHYLCYCLOHEXYL)] glycyl) [PYRROLIDINE-2-CARBONITRILE] Example 45A [4- (TERT-BUTYL-DIMETHYL-SILANYLOXY)-CYCLOHEXANECARBOXYLIC] acid ethyl ester To a solution of 4-hydroxy-cyclohexanecarboxylic acid ethyl ester (10.32 g, 59.92 mmol) in dimethylformamide (50 mL) was added imidazole (8.16 g, 119.8 mmol), followed by tert-butyldimethylsilyl chloride (9.94 g, 65.9 mmol). The resulting mixture was stirred at room temperature for 16 hours. Diethyl ether was added (150 mL), and the mixture was washed with 1M [HC1] (150 mL). The aqueous layer was extracted with diethyl ether (150 mL). The combined organic layers were washed with 1M [HC1] (100 mL) and saturated sodium chloride solution (100 mL), dried over magnesium sulfate, filtered and concentrated to afford a clear oil. MS (CI) m/z 287 (M+1) [+] | |
| 34.94 g | With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 15h; Cooling with ice; | 53.3 Compound 5 (20.04 g) and imidazole (15.84 g) were dissolved in N,N-dimethylformamide (116 mL), tert-butyldimethylsilylchloride (19.47 g) was added under ice cooling, and the mixture was stirred at room temperature for 15hours. The reaction solution was added to ice water, and the mixture was extracted with diethyl ether. The extract waswashed with water and saturated brine. The solution was dried over anhydrous magnesium sulfate, and concentratedunder reduced pressure to obtain Compound 6 (34.94 g) as a colorless oil.MS (m/z): 287 [M+H]+ |
| With 1H-imidazole In N,N-dimethyl-formamide at 20℃; Inert atmosphere; | 2 4.1.2. 4-(tert-Butyldimethylsilanoxy)cyclohexane carboxylic acid (3) To a solution of ethyl 4-hydroxycyclohexanecarboxylate 2 (mixture of cis and trans) (2.5 g, 14.5 mmol) and imidazole (1.97 g, 29 mmol) in anhydrous DMF (20 mL), tert-butyldimethylsilyl chloride (2.63 g, 17.5 mmol) was added. After stirring overnight, Et2O (60 mL) and 1M aqueous HCl (60 mL) were added. After extraction with Et2O, the combined organic phases were washed with 1M aqueous HCl and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a TBS-protected alcohol as a colorless oil (4.14 g), which was used in the next step without further purification. To a solution of the former alcohol (4.14 g, 14.5 mmol) in THF (20 mL) and methanol (12 mL), lithium hydroxide (0.7 g, 29 mmol) was added. The mixture was then stirred at 60 °C for 3 h. After removal of the solvents, water and Et2O were added and the aqueous layer was extracted with diethyl ether, cooled in an ice bath then acidified to pH=1 with 1M aqueous HCl. After extraction with ethyl acetate, the organic phases were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate, 50:50) to give the title compound 3 as a mixture of cis/trans isomers (3.48 g, 100% yield) as a colorless oil; δH (400 MHz, CDCl3) 10.84 (2H, m, 2*COOH), 3.89 and 3.56 (2*1H, 2*bs, 2*H-4), 2.41-2.18 (2H, m, 2*H-1), 2.10-1.83 (6H, m), 1.74-1.59 (4H, m), 1.58-1.23 (6H, m), 0.88 and 0.87 (2*9H, 2*s, 2*(CH3)3CSi), 0.05 and 0.03 (2*6H, 2*s, 2*(CH3)2Si); δC (100 MHz; CDCl3) 181.8 (2*COOH), 70.5 and 66.7 (2*C-4), 42.0 and 41.9 (2*C-1), 34.8 (2*CH2), 32.9 (2*CH2), 27.1 (2*CH2), 23.4 (2*CH2), 26.1 and 26.0 (2*(CH3)3CSi), 18.3 and 18.2 (2*(CH3)3CSi), -4.5 and -4.7 (2*(CH3)2Si). | |
| 43.1 g | With 1H-imidazole In N,N-dimethyl-formamide at 20℃; | I56 ethyl 4-[tert-butyl(dimethyl)silyl]oxy}cyclohexanecarboxylate(mixture of cis-/trans isomers) tert-Butyldimethylsilyl chloride (26.3 g, hydroxycyclohexanecarboxylate (25.0 g, 171 59-80-7) and imidazole (24.7 g, 363174 mmol) was added to a solution of ethyl 4-145 mmol, mixture of cis-/trans-isomers, Gas Nommol) in N,N-dimethylformamide (36 ml) and the mixture was stirred over night at room temperature. For work-up, water was added and the mixture was extracted with tert-butyl methyl ether (3x). The combined organic phases were washed with brine, filtrated through a silicone filter and concentrated under reduced pressure to yield ethyl 4-[tert-butyl(dimethyl)silyl]oxy}cyclohexanecarboxylate (43.1 g, 104% yield) which was used in the next step without further purification. 1HNMR (400 MHz, DMSO-d6, mixture of isomers): 6 [ppm] = 4.10-3.99 (m, 2H), 3.93-3.86 (m, 0.7H), 3.63-3.51 (m, 0.3H), 2.39-2.28 (m, 0.8H), 2.27-2.14 (m, 0.3H), 1.91-1.21 (m, 8H), 1.20-1.13 (m, 3H), 0.89-0.79 (m, 9H), 0.08-0.00 (m, 6H). |
| With 1H-imidazole In N,N-dimethyl-formamide at 20℃; | 3 ethyl 4-[tert-butyl(dimethyl)silyl]oxy}cyclohexanecarboxylate (mixture of cis-/trans-isomers) tert-Butyldimethylsilyl chloride (26.3 g, 174 mmol) was added to a solution of ethyl 4-hydroxycyclohexanecarboxylate (25.0 g, 145 mmol, mixture of cis-/trans-isomers, Cas No 17159-80-7) and imidazole (24.7 g, 363 mmol) in N,N-dimethylformamide (36 ml) and the mixture was stirred over night at room temperature. For work-up, water was added and the mixture was extracted with tert-butyl methyl ether (3x). The combined organic phases were washed with brine, filtrated through a silicone filter and concentrated under reduced pressure to yield ethyl 4-[ferf-butyl(dimethyl)silyl]oxy}cyclohexanecarboxylate (43.1 g, 104% yield) which was used in the next step without further purification.1H-NMR (400 MHz, DMSO-cfe, mixture of isomers): δ [ppm] = 4.10-3.99 (m, 2H), 3.93-3.86 (m, 0.7H), 3.63-3.51 (m, 0.3H), 2.39-2.28 (m, 0.8H), 2.27-2.14 (m, 0.3H), 1.91-1 .21 (m, 8H), 1.20-1 .13 (m, 3H), 0.89-0.79 (m, 9H), 0.08-0.00 (m, 6H). | |
| With 1H-imidazole In N,N-dimethyl-formamide at 20℃; | Intermediate 1 ethyl 4-[tert-butyl(dimethyl)silyl]oxy}cyclohexanecarboxylate (mixture of cis-/trans-isomers) tert-Butyldimethylsilyl chloride (26.3 g, 174 mmol) was added to a solution of ethyl 4- hydroxycyclohexanecarboxylate (25.0 g, 145 mmol, mixture of cis-/trans-isomers, Gas No 17159-80-7) and imidazole (24.7 g, 363 mmol) in DMF (36 ml) and the mixture was stirred overnight at room temperature. For work-up, water was added and the mixture was extracted with tert-butyl methyl ether (3x). The combined organic phases were washed with brine, filtered through a silicone filter and concentrated under reduced pressure to yield ethyl 4-[tert- butyl(dimethyl)silyl]oxy}cyclohexanecarboxylate (43.1 g, 104% yield) which was used in the next step without further purification.1HNMR (400 MHz, DMSO-d6, mixture of isomers): 6 [ppm] = 4.10-3.99 (m, 2H), 3.93-3.86 (m,0.7H), 3.63-3.51 (m, 0.3H), 2.39-2.28 (m, 0.8H), 2.27-2.14 (m, 0.3H), 1.91-1.21 (m, 8H), 1.20-1.13 (m, 3H), 0.89-0.79 (m, 9H), 0.08-0.00 (m, 6H). | |
| With 1H-imidazole In N,N-dimethyl-formamide at 20 - 40℃; | 50 Chloro(1 ,1-dimethylethyl)dimethylsilane (115g; 0.76mol) was added in portions over 1 hour to a solution of ethyl 4-hydroxycyclohexanecarboxylate (118g; 0.68mol), imidazole(103g; 1.52mol) and dimethylformamide (400ml) stirred under an atmosphere of argon. A small exotherm was observed resulting in the reaction mixture temperature increasing to~40°C. The mixture was stirred at room temperature overnight then poured into 10% citric acid solution (2L) and extracted with diethyl ether (2 x 800ml). The ether extracts were washed with water, brine and then dried (Na2SO4) and the solvent was removed to give the title compound as a oil (198.4g) 1H NMR δ (CDCI3, 400 MHz): 0.01 (6H, m), 0.85 (9H, s), 1.2 (3H, m), 1.3-1.5 (2H, m), 1.6 (2H, m), 1.85-2 (3H, m), 2.15-2.3 (1 H, m) 3.5 (0.4H, m) 3.86 (1 H, m) 4.1 (1 H, m). | |
| With 1H-imidazole In N,N-dimethyl-formamide at 20 - 40℃; | 18 Description 18.; cis/trans-Ethy 4-[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}cyclohexanecarboxylate (D18); Chloro(1 ,1-dimethylethyl)dimethylsilane (1 15g) was added in portions over 1 hour to a solution of ethyl 4-hydroxycyclohexanecarboxylate (118g), imidazole (103g) and dimethylformamide (400ml) stirred under an atmosphere of argon. A small exotherm was observed resulting in the reaction mixture temperature increasing to -4O0C. The mixture was stirred at room temperature overnight then poured into 10% citric acid solution (2000ml) and extracted with diethyl ether (2 x 800ml). The ether extracts were washed with water, brine and then dried (Na2SO4) and the solvent was removed to give the title compound as a oil (198.4g)1H NMR δ(CDCI3, 400 MHz): 0.01 (6H, m), 0.85 (9H, s), 1.2 (3H, m), 1.3-1.5 (2H, m), 1.6 (2H, m), 1.85-2 (3H, m), 2.15-2.3 (1 H, m) 3.5 (0.4H, m) 3.86 (1 H, m) 4.1 (1 H, m). | |
| With 1H-imidazole In dichloromethane at 20℃; | 2 tert-Butyldimethylsilyl chloride (8.8 g, 58 mmol) was added to a solution of ethyl 4- hydroxycyclohexanecarboxylate (10 g, 58 mmol) and imidazole (4.3 g, 64 mmol) in DCM (300 ml), and the mixture was stirred overnight at 20 0C. After washing with water (2 X 100 ml), the organic phase was dried (MgSO4) and evaporated to dryness. The residue was dissolved in dry THF (300 ml) and cooled to -10 0C. Dibal-H (1.0 M in toluene, 174 ml, 174 mmol) was added dropwise over a period of 60 min, while the temperature was kept at - 100C. After stirring for 2 hrs the reaction was quenched by slow addition of a saturated ammonium chloride solution (30 ml). The resulting suspension was filtered, and the filtrate was concentrated in vacuo to give 13 g of the title compound as a mixture of two isomers. LC-MS {m/z) : 245 (M + l). | |
| With 1H-imidazole In N,N-dimethyl-formamide at 20 - 40℃; | 60 Description 60. c/s/frans-Ethyl 4-[(1,1 - dimethylethyl)(dimethyl)silyl]oxy}cyclohexanecarboxylate (D60); Chloro(1 ,1-dimethylethyl)dimethylsilane ( 115g ) was added in portions over 1 hour to a solution of ethyl 4-hydroxycyclohexanecarboxylate (118g), imidazole (103g) and dimethylformamide (400ml) stirred under an atmosphere of argon. A small exotherm was observed resulting in the reaction mixture temperature increasing to -4O0C. The mixture was stirred at room temperature overnight then poured into 10% citric acid solution (2000ml) and extracted with diethyl ether (2 x 800ml). The ether extracts were washed with water, brine and then dried (Na2SU4) and the solvent was removed to give the title compound as a oil (198.4g)1H NMR D(CDCI3, 400 MHz): 0.01 (6H, m), 0.85 (9H, s), 1.2 (3H, m), 1.3-1.5 (2H, m), 1.6 (2H, m), 1.85-2 (3H, m), 2.15-2.3 (1 H, m) 3.5 (0.4H, m) 3.86 (1 H, m) 4.1 (1 H1 m). | |
| With 1H-imidazole In N,N-dimethyl-formamide at 20 - 40℃; | 27; 38 Description 27. Ethyl 4-[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}cyclohexanecarboxylate (D27); Chloro(1 ,1-dimethylethyl)dimethylsilane ( 115g ) was added in portions over 1 hour to a solution of ethyl 4-hydroxycyclohexanecarboxylate (118g), imidazole (103g) and dimethylformamide (400ml) stirred under an atmosphere of argon. A small exotherm was observed resulting in the reaction mixture temperature increasing to -4O0C. The mixture was stirred at room temperature overnight then poured into 10% citric acid solution(2000ml) and extracted with diethyl ether (2 x 800ml). The ether extracts were washed with water, brine and then dried (Na2SO4) and the solvent was removed to give the title compound as a oil (198.4g)1H NMR D(CDCI3, 400 MHz): 0.01 (6H, m), 0.85 (9H, s), 1.2 (3H, m), 1.3-1.5 (2H, m), 1.6 (2H, m), 1.85-2 (3H, m), 2.15-2.3 (1 H, m) 3.5 (0.4H, m) 3.86 (1 H, m) 4.1 (1 H, m). Description 38. c/s/frans-Ethyl 4-[(1,1 - dimethylethyl)(dimethyl)silyl]oxy}cyclohexanecarboxylate (D38)Chloro(1 ,1-dimethylethyl)dimethylsilane ( 115g ) was added in portions over 1 hour to a solution of ethyl 4-hydroxycyclohexanecarboxylate (118g), imidazole (103g) and dimethylformamide (400ml) stirred under an atmosphere of argon. A small exotherm was observed resulting in the reaction mixture temperature increasing to ~40°C. The mixture was stirred at room temperature overnight then poured into 10% citric acid solution(2000ml) and extracted with diethyl ether (2 x 800ml). The ether extracts were washed with water, brine and then dried (Na2SO4) and the solvent was removed to give the title compound as a oil (198.4g).1H NMR δ (CDCI3, 400 MHz): 0.01 (6H, m), 0.85 (9H, s), 1.2 (3H, m), 1.3-1.5 (2H, m), 1.6 (2H, m), 1.85-2 (3H, m), 2.15-2.3 (1 H, m) 3.5 (0.4H, m) 3.86 (1 H, m) 4.1 (1 H, m). | |
| 88 % | With triethylamine In N,N-dimethyl-formamide at 20℃; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 99% | With methanol; sodium tetrahydroborate at 0 - 20℃; for 1h; | |
| 95% | With sodium tetrahydroborate In ethanol | |
| 88% | Stage #1: ethyl 4-oxocyclohexane-1-carboxylate With sodium tetrahydroborate In methanol at 0 - 20℃; for 3h; Stage #2: With water In methanol | 64 To a solution of ethyl 4-oxocyclohexanecarboxylate (13.5 g, 79 mmol) in MeOH (150 mL) at 0 °C was added NaBH4 (5.3 g, 140 mmol) and the mixture was stirred at rt for 3 h. Then the reaction was quenched by addition of H2O (50 mL) and extracted with AcOEt (150 mL x 1, 50 mL x 2). The combined organic layer was washed with H20 (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane-AcOEt 1.5 : 1-1 : 1) to give the titled compound (12 g, 88%, cisltrans = 3: 7) as clear oil. IH NMR (300MHz, CDC13, cisltrans mixture) 8 : 4.17-4. 08 (m, 2H), 3.90 (bs, 0.3H), 3. 68- 3.57 (m, 0.7H), 2.42-1. 28 (m, 9H), 1.27-1. 22 (m, 3H) ppm. (OH was not observed.) |
| 60% | With [InH3(P(cyclohexyl)3)] In toluene at -78 - 20℃; for 15h; | |
| In sodium borohydrid; ethanol; water | 2 Cis- and trans-8-(4-hydroxycyclohexyl)-1,3-dipropylxanthine, EXAMPLE 2 Cis- and trans-8-(4-hydroxycyclohexyl)-1,3-dipropylxanthine, To a stirred solution of ethyl 4-oxocyclohexanecarboxylate (2.0 g, 12 mmol) in 10 mL of ethanol at 5° C. was added, in portions, 0.5 g (13 mmol) of sodium borohydride. After the mixture was stirred for 30 minutes at 5° C. and 18 hours at room temperature it was diluted with 10 mL of water and acidified to pH 3 with 1N hydrochloric acid. The mixture was extracted with ethyl acetate. After being washed with water and brine the extracts were dried over anhydrous sodium sulfate and concentrated to give ethyl 4-hydroxycyclohexanecarboxylate as a colorless liquid. | |
| With sodium tetrahydroborate In methanol at 0 - 20℃; for 1h; | Prerjaration of reagent R-i0d: ethyl 4-hydroxycyclohexanecarboxylate To a solution of commercially available ethyl 4-oxocyclohexanecarboxylate(5.0 g, 0.029 mol) in MeOH (50 mL) was added NaBH4 (2.24g, 0.058 mol) at0 00 in portions, then the mixture was stirred at room temperature for 1 hr untilTLC showed the starting material was consumed completely, quenched withwater and the mixture was extracted with EtOAc, the organic layer waswashed with brine, dried over anhydrous Na2SO4, concentrated to give thecrude reagent R-i Od (4.95 g, 97.83%) as a pale yellow oil which was used for the next step directly. ESI-MS (Mi-i): 173 calc. for C9H1 603:172.1. | |
| With methanol; sodium tetrahydroborate In tetrahydrofuran at 0℃; for 1h; | Intermediate 11 a: Ethyl 4-hydroxycyclohexanecarboxylate To a solution of ethyl 4-oxocyclohexanecarboxylate (30.0 g, 176 mmol) in tetrahydrofuran (200 mL) and methanol (70 mL) was added sodium borohydride (3.40 g, 88.0 mmol) at 0 °C. Then the mixture was stirred at 0 °C for 1 hour. After that, it was quenched with water (150 mL) and extracted with ethyl acetate (250 mL) twice. The combined organic layers were washed with brine (100 mL), dried over Na2SO4() andfiltered. The filtrate was concentrated under reduced pressure to give the title compound(29.5 g, 98 % yield) as colorless oil. ‘H NIVIR (300 1VIHz, CDC13) 4.14 - 4.05 (m, 2H),3.89 -3.81 (m, 0.3H), 3.65 -3.52 (m, 0.7H), 2.39-2.31 (m, 0.3H), 2.25 -2.15 (m,0.7H), 2.02- 1.90 (m, 4H), 1.69- 1.60 (m, 1.7H), 1.54 - 1.40 (m, 1.3H), 1.31 - 1.19 (m,4H). | |
| 8.06 g | With methanol; sodium tetrahydroborate at 0 - 20℃; | Step 1: ethyl 4-hydroxycyclohexane-1-carboxylate. Sodium borohydride (4.56 g, 121 mmol) was added portionwise to a solution of ethyl 4-oxocyclohexane-1-carboxylate (10 g, 58.8 mmol) in methanol (300 mL) at 0°C, and the mixture was warmed to rt while stirring for 16h. The reaction mixture was concentrated, EtOAc (1L) added and washed with sat. aq. NaHCO3 (2x500 mL) and brine (1x500 mL), dried over Na2SO4), filtered, and concentrated to dryness to give the title compound (8.06 g). |
| 8.06 g | With methanol; sodium tetrahydroborate at 0 - 20℃; | Step 1: ethyl 4-hydroxycyclohexane-1-carboxylate. Sodium borohydride (4.56 g, 121 mmol) was added portionwise to a solution of ethyl 4-oxocyclohexane-1-carboxylate (10 g, 58.8 mmol) in methanol (300 mL) at 0°C, and the mixture was warmed to rt while stirring for 16h. The reaction mixture was concentrated, EtOAc (1L) added and washed with sat. aq. NaHCO3 (2x500 mL) and brine (1x500 mL), dried over Na2SO4), filtered, and concentrated to dryness to give the title compound (8.06 g). |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 22% | With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃; for 16h; | A 4-(4-Ethoxycarbonyl-cyclohexyloxy)-benzoic acid benzyl ester; To a solution of benzyl 4-hydroxybenzoate (50 g, 0.22 mol) and triphenylphosphine (63.2 g, 0.241 mol) dissolved in THF (800 mL) was added 4-hydroxy-cyclohexanecarboxylic acid ethyl ester (35.3 mL, 0.22 mol). The reaction mixture was cooled on an ice bath and DEAD (38 ml, 0.241 mol) was added dropwise maintaining the temperature at 0 0C. The resulting mixture was allowed slowly to reach room temperature and stirred for 16 hrs. at this temperature. The volume was reduced to app. 250 ml. by evaporation and to the resulting mixture was added water (500 ml.) followed by extraction with DCM (3x400 ml_). The combined organic phases were washed with brine (400 ml_), dried (Na2SO4), filtered and the volatiles evaporated in vacuo. Crude product ~80 g was purified on column chromatography (Flash 75) using first heptane (7.5 L) followed by a mixture of EtOAc-heptane (1 :10) (5 L) and finally a mixture of EtOAc-heptane (1 :6) (8 L). Combined fractions were evaporated in vacuo affording 18.1 g (22 %) of 4-(4-ethoxycarbonyl-cyclohexyloxy)-benzoic acid benzyl ester as an oil.1H-NMR (300 MHz, CDCI3) δ 1.26 (t, 3H), 1.42 - 1.83 (m, 4H), 1.85 - 2.26 (m, 4H), 2.27 - 2.48 (m, 1 H), 4.14 (q, 2H), 4.22 - 4.38 (m, 0.5H), 4.55 (br.s., 0.5H), 5.33 (s, 2H), 6.89 (dd, 2H), 7.27 - 7.49 (m, 5H), 8.01 (d, 2H). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 32% | With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃; for 48.5h; | E 4-[4-(Adamantan-2-ylcarbamoyl)-phenoxy]-cyclohexanecarboxylic acid ethyl ester; To a stirred solution of N-adamantan-2-yl-4-hydroxy-benzamide (6 g, 22.1 1 mmol) in dry THF (100 ml.) was added triphenyl phosphine (8.7 g, 33.17 mmol) and 4-hydroxy cyclo- hexane carboxylic acid ethyl ester (4.57 g, 26.53 mmol). The reaction mixture was cooled to 0 0C and DEAD (5.22 ml_, 33.17 mmol) was added dropwise from an addition funnel over a period of 30 min. The reaction was gradually brought to room temperature and stirring con- tinued for 48 hrs. The solvent was removed under vacuum and ether (100 ml.) was added and cooled to 0 0C. The solid formed was filtered off and the clear filtrate concentrated and purified by column chromatography (Gyan-flash). Desired fractions were collected and the solvent evaporated. The residue was crystallised from diethyl ether and filtered off affording 3 g (32 %) of 4-[4-(adamantan-2-ylcarbamoyl)-phenoxy]-cyclohexane carboxylic acid ethyl ester as a solid.1H-NMR (400 MHz, CDCI3) δ 1.27 (t, 3H), 1.41 - 2.25 (m, 22H), 2.30 - 2.47 (m, 1 H), 4.10 - 4.20 (m, 2H), 4.21 - 4.30 (m, 1 H), 4.55 (br.s., 1 H), 6.34 (d, 1 H), 6.92 (t, 2H), 7.73 (d, 2H). m/z: 427 (M+1 )+ |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 89% | With 1H-imidazole In 1,2-dichloro-ethane at 20℃; | 8.1 Intermediate (8)4-(tert-Butyl-diphenyl-silanyloxy)-1-(2-oxo-ethyl)-cyclohexanecarboxylic acid methyl ester Step 1 : 4-(tert-Butyl-diphen l-silanyloxy)-cyclohexanecarboxylic acid ethyl esterTo a solution of ethyl 4-hydroxycyclohexane carboxylate (5 g, 29.03 mmol) in dichloromethane (200 mL) was added imidazole (4.97 g, 73 mmol) and tert- butylchlorodiphenylsilane (15.96 g, 15.2 mL, 58 mmol). The reaction mixture was allowed to stir at room temperature over night. The reaction mixture was poured into water (125 mL) in a separatory funnel and the phases were separated. The aqueous phase was extracted with dichloromethane (2x200 mL). The combined organic solutions were washed with brine, dried over Na2SO4, and concentrated under vacuum. Purification by column chromatography on silica gel eluting with ethyl acetate in heptanes (0-10%) afforded 10.55 g (89%) of the title compound. |
| 89% | With 1H-imidazole In dichloromethane at 20℃; | viii.1 Step 1 : 4-(tert-Butyl-diphen l-silanyloxy)-cyclohexanecarboxylic acid ethyl esterTo a solution of ethyl 4-hydroxycyclohexane carboxylate (5.0 g, 29.03 mmol) in dichloromethane (200 mL) was added imidazole (4.97 g, 73 mmols) and tert- butylchlorodiphenylsilane (15.96 g, 15.2 mL, 58.0 mmol). The reaction mixture was allowed to stir at room temperature over night. The reaction mixture was poured into water (125 mL) in a separatory funnel and the phases were separated. The aqueous phase was extracted with dichloromethane (2x200 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. Purification by column chromatography on silica gel eluting with ethyl acetate in heptanes (0-10%) afforded 10.55 g (89%) of the title compound. |
| 89% | With 1H-imidazole In dichloromethane at 20℃; | iv.1 Step 1 : 4-(tert-Butyl-diphen l-silanyloxy)-cyclohexanecarboxylic acid ethyl esterTo a solution of ethyl 4-hydroxycyclohexane carboxylate (5 g, 29.03 mmol) in dichloromethane (200 ml_) was added imidazole (4.97 g, 73 mmol) and tert- butylchlorodiphenylsilane (15.96 g, 15.2 ml_, 58 mmol). The reaction mixture was allowed to stir at room temperature over night. The reaction mixture was poured into water (125 ml_) in a separatory funnel and the phases were separated. The aqueous phase was extracted with dichloromethane (2x200 ml_). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. Purification by column chromatography on silica gel eluted with ethyl acetate in heptanes (0-10%) afforded 10.55 g (89%) of the title compound. |
| 80% | With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 72h; | 15 Preparation 15; 4-(tert-Butyl-diphenyl-silanyloxy)-cyclohexanecarboxylic acid ethyl ester; Treat a solution of cis/trans ethyl 4-hydroxycyclohexanecarboxylate (21.3 g, 0.124 mol) and imidazole (10.10 g, 0.148 mol) in DMF (150 mL) with t-butyl-diphenylsilyl chloride (37.39 g, 0.136 mol) and stir for 72 hours at room temperature. Dilute the reaction with diethyl ether and wash with IN HCl and water. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford crude product. Purify with a 0 to 20% ethyl acetate in hexanes gradient on silica gel to afford 40.4 g (80%) of the titled product. Rf = 0.49 and 0.29 (5/1 hexanes/ethyl acetate). |
| With 1H-imidazole In N,N-dimethyl-formamide at 0 - 20℃; for 3h; | 1.1 (1) (1) Synthesis of ethyl 4-((tert-butyl(diphenyl)silyl)oxy)cyclohexanecarboxylate To a solution of 25 g of 4-hydroxycyclohexanecarboxylic acid in 125 ml of N,N-dimethylformamide were sequentially added 21.7 g of imidazole and 39.6 ml of tert-butyl (diphenyl)silyl chloride under cooling with ice, followed by stirring the reaction mixture at room temperature for 3 hours. To the reaction mixture was added water and extracted with hexane. The resulting hexane solution was washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound. | |
| With 1H-imidazole In N,N-dimethyl-formamide at 10 - 35℃; | 38.A A solution of ethyl 4-hydroxycyclohexanecarboxylate (5 g), tert-butyl(chloro)diphenylsilane (8.30 mL) and imidazole (2.17 g) in DMF (50 mL) was stirred at room temperature overnight. The reaction mixture was extracted with ethyl acetate and water. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (12.2 g).1H NMR (300 MHz, DMSO-d6) δ 0.98-1.06 (9H, m), 1.17-1.23 (5H, m), 1.23-1.63 (4H, m), 1.68-1.94 (2H, m), 2.15-2.38 (1H, m), 3.51-3.95 (1H, m), 4.03-4.09 (2H, m), 7.37-7.46 (6H, m), 7.55-7.65 (4H, m).MS (ESI+): [M+H]+ 411.1 | |
| 21 g | With 1H-imidazole; dmap In N,N-dimethyl-formamide at 20℃; for 24h; | I147 ethyl 4-[tert-butyl(diphenyl)silyl]oxy}cyclohexanecarboxylate Tert-butyl(chloro)diphenylsilane (18 ml, 68 mmol, GAS No 58479-61-1) was added drop wise to a mixture of ethyl 4-hydroxycyclohexanecarboxylate (9.4 ml, 57 mmol, GAS No 171 59-80- 7), 1H-imidazole (9.68 g, 142 mmol, GAS No 16681 -56-4) and N,N-dimethylpyridin-4-amine(348 mg, 2.85 mmol, GAS No 1122-58-3) in dimethylformamid (81 ml), and the mixture wasstirred at room temperature for 24 h. For work-up, the mixture was poured into water,extracted with ethyl acetate (3x) and the combined organic phases were washed until pH=7as reached. The organic phase was dried over sodium sulfate and was concentrated underreduced pressure. The residue was purified by flash chromatography (340 g Snap cartridge,hexane/ethyl acetate gradient, 5%-> 30% ethyl acetate) to give the title compound (21 g). |
| With 1H-imidazole; dmap In N,N-dimethyl-formamide at 20℃; for 24h; | 3 ethyl 4-[tert-butyl(diphenyl)silyl]oxy}cyclohexanecarboxylate Tert-butyl(chloro)diphenylsilane (18 ml, 68 mmol, CAS No 58479-61-1 ) was added drop wise to a mixture of ethyl 4-hydroxycyclohexanecarboxylate (9.4 ml, 57 mmol, CAS No 17159-80-7), 1H-imidazole (9.68 g, 142 mmol, CAS No 16681-56-4) and N,N-dimethylpyridin-4-amine (348 mg, 2.85 mmol, CAS No 1 122-58-3) in dimethylformamid (81 ml), and the mixture was stirred at room temperature for 24 h. For work-up, the mixture was poured into water, extracted with ethyl acetate (3x) and the combined organic phases were washed until pH=7 as reached. The organic phase was dried over sodium sulfate and was concentrated under reduced pressure. The residue was purified by flash chromatography (340 g Snap cartridge, hexane/ethyl acetate gradient, 5% -> 30% ethyl acetate) to give the title compound (21 g) | |
| 21 g | With 1H-imidazole; dmap In N,N-dimethyl-formamide at 20℃; for 24h; | Intermediate 2 ethyl 4-[tert-butyl(diphenyl)silyl]oxy}cyclohexanecarboxylate (mixture of cis-/trans-isomers) Tert-butyl(chloro)diphenylsilane (18 ml, 68 mmol, GAS No 58479-61 -1) was added drop wise to a mixture of ethyl 4-hydroxycyclohexanecarboxylate (9.4 ml, 57 mmol, GAS No 17159-80-7), 1H-imidazole (9.68 g, 142 mmol, GAS No 16681 -56-4) and N,N-dimethylpyridin-4-amine (348 mg, 2.85 mmol, GAS No 1122-58-3) in DMF (81 ml), and the mixture was stirred at roomtemperature for 24 h. For work-up, the mixture was poured into water, extracted with ethyl acetate (3x) and the combined organic phases were washed until pH=7 as reached. The organic phase was dried over sodium sulfate and was concentrated under reduced pressure. The residue was purified by flash chromatography (340 g SNAP cartridge, hexane/ethyl acetate gradient, 5% -> 30% ethyl acetate) to give the title compound (21 g). |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 91% | With hydrazine hydrate for 24h; Reflux; | 1.a a) cis/trans-4-Hydroxy-cyclohexanecarboxylic acid hydrazide (2:1)A mixture of cis/trans-4-hydroxycyclohexane carboxylic acid ethyl ester (5.0 g, 29 mmol) and hydrazine hydrate (1.4 g, 29 mmol) was heated at reflux for 24 h. Residual water was removed by azeotropic distillation with toluene. The residue was triturated from tert-butyl methyl ether. The precipitate was collected by filtration and dried in vacuo to give the title compound as white solid in 91% yield. |
| With hydrazine In methanol at 55℃; for 4h; | 1.1 Example 1; 4-{5-[1-(4-chlorophenyl)cyclopropyl]-4-methyl-4H-1,2,4-triazol-3-yl}cyclohexanol; Step 1. 4-hydroxycyclohexanecarbohydrazide; A mixture of ethyl 4-hydroxycyclohexanecarboxylate (2.0 g, 12 mmol) and hydrazine (1.5 g, 46 mmol) in methanol (20 mL) was stirred at 55° C. for 4 h and then cooled to room temperature (about 25° C.). After cooling, the solvent and excess hydrazine were removed by distillation under reduced pressure to provide a residue. The residue was co-evaporated with methanol (2×), and was then dried under high vacuum to provide the crude product 4-hydroxycyclohexanecarbohydrazide, which was used in the next synthesis step without further purification. LCMS: (M+H)+=155.2. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 11% | With sodium hydride In Isobutyramide at 4 - 20℃; for 25h; | i Intermediate 1 : c/5-4-(3-FIuoro-4-[5-(2,4,5-trifluoro-phenyIamino)-[l,3,41- oxadiazole-2-carbonyll-amino)-phenoxy)-cvclohexanecarboxylic acid ethyl ester; i) c/s-4-(3-Fluoro-4-nitro-phenoxy)-cyclohexanecarboxylic acid ethyl ester; Sodium hydride (60% dispersion in mineral oil, 5.05 g, 126 mmol) was added in one portion to a stirred solution of ethyl 4-hydroxycyclohexanecarboxylate (20.7 g, 120 mmol) and 2,4-difluoronitrobenzene (19.1g, 120.2 mmol) in DMA (100 mL) at 4°C and the mixture was stirred at 40C for 1 h and then the reaction mixture was warmed to ambient temperature and stirred for 24 h. The reaction mixture was cooled to 0°C and then water and ethyl acetate were added. The layers were separated and the organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo to leave a yellow oil. The oil was purified by column chromatography, using a gradient of 20-50% ethyl acetate in isohexane as eluent, to give the title compound as a pale yellow solid (4.1 g, 11%). 1H NMR δ 1.19 (3H3 1), 1.63-1.9 (9H, m), 4.07 (2H, q), 4.72-4.8 (IH, m), 6.99 (IH, dd), 7.22 (IH, dd), 8.13 (IH5 dd); MS m/e MH+ 312. |

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