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CAS No. : | 32529-79-6 | MDL No. : | MFCD06797561 |
Formula : | C9H14O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ZQJNPHCQABYENK-UHFFFAOYSA-N |
M.W : | 186.21 | Pubchem ID : | 296850 |
Synonyms : |
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.78 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 46.32 |
TPSA : | 63.6 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.85 cm/s |
Log Po/w (iLOGP) : | 1.58 |
Log Po/w (XLOGP3) : | 0.82 |
Log Po/w (WLOGP) : | 1.05 |
Log Po/w (MLOGP) : | 0.86 |
Log Po/w (SILICOS-IT) : | 0.79 |
Consensus Log Po/w : | 1.02 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -1.31 |
Solubility : | 9.06 mg/ml ; 0.0486 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.74 |
Solubility : | 3.41 mg/ml ; 0.0183 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.54 |
Solubility : | 54.1 mg/ml ; 0.29 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.4 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
43% | With water; barium(II) hydroxide In methanol at 25℃; for 12 h; | Step 1. Preparation of 4-(methoxycarbonyl)cyclohexanecarboxylic acid (i-12b).A mixture of dimethyl cyclohexane-1,4-dicarboxylate (i-12a) (8 g, 40 mmol) and bariumhydroxide (6.3 g, 2Ommol) in 80percent aqueous methanol (150 mL) was stirred at 25 °C for 12h.The mixture was diluted with water (200 mL) and washed with hexane (100 mLx2) to removeremaining starting material. The aqueous layer was then acidified with 2 M HC1 to pH = 3and extracted with EtOAc (100 mL x 3). The organic layer was washed with water (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The mixture was purified by column chromatography on silica gel (PE: EtOAc = 50:1 to 3:1) to afford the title compound (3.2 g, 43percent) as a white solid. LCMS (ESI): calc’d for C9H1404 [M+H]: 187,found: 187; |
43% | With water; barium(II) hydroxide In methanol at 25℃; for 12 h; | Step 1. Preparation of 4-(methoxycarbonyl)cyclohexanecarboxylic acid (i-12b) [0294] A mixture of dimethyl cyclohexane-1,4-dicarboxylate (i-12a) (8 g, 40 mmol) and barium hydroxide (6.3 g, 20 mmol) in 80percent aqueous methanol (150 mL) was stirred at 25° C. for 12 h. The mixture was diluted with water (200 mL) and washed with hexane (100 mL×2) to remove remaining starting material. The aqueous layer was then acidified with 2 M HCl to pH=3 and extracted with EtOAc (100 mL×3). The organic layer was washed with water (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The mixture was purified by column chromatography on silica gel (PE:EtOAc=50:1 to 3:1) to afford the title compound (3.2 g, 43percent) as a white solid. LCMS (ESI): calc'd for C9H14O4 [M+H]+: 187. found: 187. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With borane-dimethyl sulfide complex In tetrahydrofuran at -78℃; for 3.33333 h; | Intermediate 87Methyl 4-(hydroxymethyl)cyclohexanecarboxylate; To a solution of 4-(methoxycarbonyl)cyclohexanecarboxylic acid (5.44 g, 29.2 mmol) in dry THF at -78° C., was added borane-methyl sulfide complex (19.0 mL, 38.0 mmol) dropwise over 20 min. The mixture was stirred for 3 h and was then allowed to slowly attain r.t. The reaction was quenched with water (20 mL) and the mixture was extracted with EtOAc. The organic phase was washed once with brine, dried over MgSO4 and concentrated in vacuo to give the title compound (4.80 g, 95percent yield) as a mixture of two diastereomers: MS (EI) m/z 172 M. |
91% | With dimethylsulfide borane complex In tetrahydrofuran at 0 - 25℃; for 1.5 h; Inert atmosphere | 1,4-cyclohexanecarboxylate (1.20g, 6.45mmol) was dissolved in dry tetrahydrofuran (20 mL) in nitrogen atmosphere,borane dimethyl sulfide (10M, 1.0mL, 10.3mmol) was slowly added dropwise at 0°C ,the reaction was stirred at 0°C for 0.5 hours. Was slowly raised to 25 °C, stirring was continued for 1 hour. Was added water (40 mL) to quench the reaction, the reaction solution was extracted with ethyl acetate. The combined organic phases were washed with water, saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 4-hydroxymethyl-cyclohexanecarboxylic acid methyl ester (1.00 g of, white solid), yield : 91percent. |
90% | With borane dimethyl sulfide complex In tetrahydrofuran at 15℃; for 3 h; | Step 2. Preparation of methyl 4-(hydroxymethyl)cyclohexanecarboxylate (i-12c). To a solution of 4-(methoxycarbonyl)cyclohexanecarboxylic acid (i-12b) (1.5 g, 8.1 mmol) in 15 mL of THF was added dropwise, borane in dimethylsulfane (10 M, 1.6 mL, 16.0 mmol),while cooling to 15 °C in an ice bath. The reaction was stirred at 15 °C for 3h. The reaction mixture was slowly poured into methanol (500 mL) (cooled in an ice bath), stirred at 15 °C for 30 mm and concentrated in vacuo. The residue was partitioned with water (300 mL) and EtOAc (300 mL). The aqueous layer was extracted with EtOAc (300 mL x 2) and the combined organic layer was washed with brine (100 mL x 2), dried over anhydrous Na2SO4,filtered and concentrated in vacuo to afford the title compound (1.3 g, 90percent) as a yellow oil. LCMS (ESI): calc’d for C9H1603 [M+H]: 173, found: 173; |
90% | Stage #1: With dimethylsulfide borane complex In tetrahydrofuran at 15℃; for 3 h; Stage #2: With methanol In tetrahydrofuran at 15℃; for 0.5 h; |
Step 2. Preparation of methyl 4-(hydroxymethyl)cyclohexanecarboxylate (i-12c) [0295] To a solution of 4-(methoxycarbonyl)cyclohexanecarboxylic acid (i-12b) (1.5 g, 8.1 mmol) in 15 mL of THF was added dropwise, borane in dimethylsulfane (10 M, 1.6 mL, 16.0 mmol), while cooling to 15° C. in an ice bath. The reaction was stirred at 15° C. for 3 h. The reaction mixture was slowly poured into methanol (500 mL) (cooled in an ice bath), stirred at 15° C. for 30 min and concentrated in vacuo. The residue was partitioned with water (300 mL) and EtOAc (300 mL). The aqueous layer was extracted with EtOAc (300 mL×2) and the combined organic layer was washed with brine (100 mL×2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the title compound (1.3 g, 90percent) as a yellow oil. LCMS (ESI): calc'd for C9H16O3 [M+H]+: 173. found: 173. |
7.4 g | Stage #1: With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at 20℃; for 1 h; Inert atmosphere; Cooling with ice Stage #2: With methanol; sodium tetrahydroborate In tetrahydrofuran; water at 20℃; for 3 h; Inert atmosphere; Cooling with ice |
In a nitrogen atmosphere, 10.0 g of the compound represented by Formula (I-105-1), 6.0 g of triethylamine, and 40 mL of tetrahydrofuran were added to a reaction container. While the resulting mixture was cooled with ice, 6.4 g of ethyl chloroformate was added dropwise to the mixture. The mixture was then stirred at room temperature for one hour. The precipitate was filtered away. In a nitrogen atmosphere, 2.2 g of sodium borohydride and 10 mL of tetrahydrofuran were added to another reaction container. While the resulting mixture was cooled with ice, the filtrate prepared above was added dropwise to the mixture. A liquid mixture of 40 mL of methanol and 10 mL of water was added dropwise to the mixture. The mixture was subsequently stirred at room temperature for three hours. After 20 mL of 10percent-hydrochloric acid had been added to the mixture, extraction was performed with ethyl acetate. Then, purification was performed by column chromatography (silica gel, hexane/ethyl acetate). Hereby, 7.4 g of the compound represented by Formula (I-105-2) was prepared. (0129) In a nitrogen atmosphere, 7.4 g of the compound represented by Formula (I-105-2), 4.1 g of pyridine, and 35 mL of dichloromethane were added to a reaction container. While the resulting mixture was cooled with ice, 5.4 g of methanesulfonyl chloride was added dropwise to the mixture. The mixture was subsequently stirred at room temperature for three hours. The mixture was poured into water and then washed with 5percent-hydrochloric acid and subsequently with a saline solution. Then, purification was performed by column chromatography (silica gel, hexane/ethyl acetate) and recrystallization (acetone/hexane). Hereby, 7.5 g of the compound represented by Formula (I-105-3) was prepared. (0130) In a nitrogen atmosphere, 25.0 g of the compound represented by Formula (I-105-4), 100 mL of acetic acid, and 100 mL of 48percent-hydrobromic acid were added to a reaction container. The resulting mixture was heated to reflux for 12 hours. After the mixture had been cooled, it was poured into 1 L of water. Subsequently, extraction was performed with ethyl acetate, and washing was then performed with a saline solution. After the solvent had been distilled away, the remaining acetic acid was removed as an azeotrope with toluene. Then, purification was performed by column chromatography (alumina, ethyl acetate). Hereby, 12.0 g of the compound represented by Formula (I-105-5) was prepared. (0131) In a nitrogen atmosphere, 2.1 g of the compound represented by Formula (I-105-5), 7.5 g of the compound represented by Formula (I-105-3), 6.2 g of potassium carbonate, and 70 mL of N,N-dimethylformamide were added to a reaction container. The resulting mixture was stirred for 3 days while being heated at 90° C. The mixture was then poured into water. Subsequently, extraction with toluene and washing with a saline solution were performed. Then, purification was performed by column chromatography (silica gel, toluene) and recrystallization (toluene/hexane). Hereby, 4.8 g of the compound represented by Formula (I-105-6) was prepared. (0132) In a nitrogen atmosphere, 4.8 g of the compound represented by Formula (I-105-6), 20 mL of tetrahydrofuran, 20 mL of methanol, and 10 mL of a 25percent-aqueous sodium hydroxide solution were added to a reaction container. The resulting mixture was stirred for 2 hours while being heated at 60° C. After the solvent had been distilled away, the residue was again dissolved in a mixed solvent of tetrahydrofuran and water. To the resulting solution, 10percent-hydrochloric acid was added such that the pH of the solution became 2. After the solvent had been distilled away, water was added to the residue to precipitate a solid, which was filtered. The solid was washed with water and then dried. Hereby, 4.0 g of the compound represented by Formula (I-105-7) was prepared. (0133) To a reaction container, 15.0 g of the compound represented by Formula (I-105-8), 17.7 g of the compound represented by Formula (I-105-9), 16.0 g of potassium carbonate, and 100 mL of N,N-dimethylformamide were added. The resulting mixture was stirred for 12 hours while being heated at 80° C. After the mixture had been cooled and then diluted with dichloromethane, washing was performed with water and subsequently with a saline solution. Then, purification was performed by column chromatography (alumina, dichloromethane). Hereby, 24.2 g of the compound represented by Formula (I-105-10) was prepared. (0134) To a reaction container, 24.2 g of the compound represented by Formula (I-105-10), 60 mL of tetrahydrofuran, 60 mL of methanol, and 1 mL of concentrated hydrochloric acid were added. The resulting mixture was stirred at room temperature for eight hours. After the solvent had been distilled away, the residue was diluted with ethyl acetate. Subsequently, washing was performed with water and then with a saline solution. Then, purification was performed by column chromatography (alumina, ethyl acetate) and recrystallization (ethyl acetate/hexane). Hereby, 16.5 g of the compound represented by Formula (I-105-11) was prepared. (0135) In a nitrogen atmosphere, 3.8 g of the compound represented by Formula (I-105-11), 3.0 g of the compound represented by Formula (I-105-7), 0.9 g of N,N-dimethylaminopyridine, and 200 mL of dichloromethane were added to a reaction container. While the resulting mixture was cooled with ice, 2.3 g of diisopropylcarbodiimide was added dropwise to the mixture. The mixture was then stirred at room temperature for ten hours. After the precipitate had been filtered away, the filtrate was washed with 1percent-hydrochloric acid, with water, and then with a saline solution. After recrystallization (dichloromethane/methanol) had been performed, purification was performed by column chromatography (silica gel, dichloromethane) and recrystallization (dichloromethane/methanol). Hereby, 4.6 g of the compound represented by Formula (I-105-12) was prepared. (0136) In a nitrogen atmosphere, 7.5 g of the compound represented by Formula (I-105-13), 5.0 g of the compound represented by Formula (I-105-14), 6.3 g of potassium carbonate, and 50 mL of N,N-dimethylformamide were added to a reaction container. The resulting mixture was stirred for 12 hours while being heated at 60° C. After the mixture had been cooled and then diluted with dichloromethane, washing was performed with water and then with a saline solution. Subsequently, purification was performed by column chromatography (alumina, dichloromethane) and recrystallization (dichloromethane/hexane). Hereby, 5.8 g of the compound represented by Formula (I-105-15) was prepared. (0137) To a reaction container, 1.5 g of the compound represented by Formula (I-105-16), 4.3 g of the compound represented by Formula (I-105-12), 0.6 g of (±)-10-camphorsulfonic acid, 20 mL of tetrahydrofuran, and 20 mL of ethanol were added. The resulting mixture was stirred for 10 hours while being heated at 50° C. After the solvent had been distilled away, purification was performed by column chromatography (silica gel, dichloromethane) and recrystallization (dichloromethane/methanol). Hereby, 3.4 g of the compound represented by Formula (I-105-17) was prepared. (0138) 1H NMR (CDCl3) δ 1.24 (m, 4H), 1.48-1.93 (m, 30H), 2.08 (t, 4H), 2.23 (m, 4H), 2.54 (m, 2H), 3.86 (dd, 4H), 3.94 (t, 4H), 4.17 (t, 4H), 4.53 (t, 2H), 4.65 (t, 2H), 5.82 (dd, 3H), 6.12 (dd, 3H), 6.40 (dd, 3H), 6.88 (m, 6H), 6.97 (dd, 4H), 7.16 (t, 1H), 7.34 (t, 1H), 7.54 (d, 1H), 7.66 (d, 1H), 7.70 (d, 1H), 8.36 (s, 1H) ppm. (0139) LCMS: 1212 [M+1] |
17.6 g | With borane-THF In tetrahydrofuran for 2 h; Inert atmosphere; Cooling with ice | In a nitrogen atmosphere, 20.0 g of a compound represented by the formula (I-121-1), and 120 mL of tetrahydrofuran were put in a reactor. With cooling with ice, 143 mL of borane-tetrahydrofuran complex (0.9 mol/L) was dropwise added thereto and stirred for 2 hours. This was poured into 200 mL of 5percent hydrochloric acid, and processed with 200 mL of ethyl acetate for liquid-liquid separation. This was dried with sodium sulfate, and the solvent was evaporated away to give 17.6 g of a compound represented by the formula (I-121-2). |
7.4 g | Stage #1: With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at 20℃; for 1 h; Inert atmosphere Stage #2: With sodium tetrahydroborate In tetrahydrofuran; methanol; water at 20℃; for 3 h; Inert atmosphere |
In a nitrogen atmosphere, 10.0 g of the compound represented by the formula (I-1-1), 6.0 g of triethylamine and 40 mL of tetrahydrofuran were put into a reactor. With cooling with ice, 6.4 g of ethyl chloroformate was dropwise added thereto and stirred at room temperature for 1 hour. The precipitate was removed through filtration. In a nitrogen atmosphere, 2.2 g of sodium borohydride, and 10 mL of tetrahydrofuran were put into another reactor. With cooling with ice, the previous filtrate was dropwise added thereto. A mixed liquid of 40 mL of methanol and 10 mL of water was dropwise added and stirred at room temperature for 3 hours. After 20 mL of 10percent hydrochloric acid was added, this was extracted with ethyl acetate. Purification through column chromatography (silica gel, hexane/ethyl acetate) gave 7.4 g of the compound represented by the formula (I-1-2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7.4 g | Stage #1: With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at 20℃; for 1 h; Inert atmosphere Stage #2: at 20℃; for 3 h; Inert atmosphere |
Under a nitrogen atmosphere, 10.0 g of the compound represented by the formula (I-1-1), 6.0 g of triethylamine and 40 mL of tetrahydrofuran were added to the reaction vessel. While cooling with ice, 6.4 g of ethyl chloroformate was added dropwise and the mixture was stirred at room temperature for 1 hour. The precipitate was removed by filtration. Under a nitrogen atmosphere, In another reaction vessel, 2.2 g of sodium borohydride, Tetrahydrofuran 10 mL was added. The filtrate was added dropwise while cooling with ice. A mixed solution of 40 mL of methanol and 10 mL of water was added dropwise and the mixture was stirred at room temperature for 3 hours. After adding 20 mL of 10percent hydrochloric acid, it was extracted with ethyl acetate. Column chromatography (silica gel, hexane / ethyl acetate) To obtain 7.4 g of a compound represented by the formula (I-1-2). |
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