Stereoselective synthesis of a 4,4-disubstituted cyclohexanepropanoic acid
A representative and selected technology, applied in the preparation of organic compounds, carboxylates, thioethers, etc., can solve problems such as expensive and uneconomical preparation
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Embodiment 1
[0060] 3-(4-Oxo-cyclohexyl)propionic acid
[0061] At 70°C, 3-(4-hydroxyphenyl)acrylic acid (3.33Kg), 5%Rh / Al 2 o 3 A mixture of catalyst (248 g) and isopropyl acetate (IPAc) (30 L) was hydrogenated (200 psi) for 12 hours, then cooled and filtered.
[0062] Add RuCl to the resulting 3-(4-hydroxycyclohexyl) propionic acid solution 3 (42g) and acetic acid (5.6Kg). After cooling to 5°C, NaOCl aqueous solution (10-13%, 26Kg) was added slowly under stirring, and the temperature was maintained at 5°C. After stirring at 5 °C for an additional 3 hours, 3N HCl (20 L) and IPAc (15 L) were added, the layers were separated, and the aqueous layer was extracted with IPAc (2 x 20 L). with 2M NaHSO 3 The combined organic layers were washed with aqueous solution (10 L), dried over magnesium sulfate, treated with carbon and filtered. The resulting solution was concentrated and the solvent was changed to heptane:IPAc 2:1 (20 L). The solution was seeded and the solvent was changed to 9:1 ...
Embodiment 2
[0064] Cis and trans-3-[4-(2,5-difluorophenyl)-4-hydroxycyclohexyl]propanoic acid (Method 1)
[0065] Dilute N,N,N,N-tetramethylethylenediamine (8.8ml, 57.8mmol) with THF (70mL), and pass through N 2 (3x), then cooled to -70°C. Then n-butyllithium (25.2 mL, 57.8 mmol) was added dropwise, maintaining the temperature below -60 °C. After aging at -65°C for 10 minutes, 1,4-difluorobenzene (6 g, 5.4 mL, 52.6 mmol) was added dropwise and the temperature was kept below -60°C, and the resulting solution was aged at -60°C for 90 minutes.
[0066] In a separate container, use N 2A solution of 3-(4-oxo-cyclohexyl)propanoic acid (5.38 g, 31.6 mmol) in THF (80 mL) was purged (3x) and then cooled to -65°C. Isopropylmagnesium chloride (2M in THF) (15.5 mL, 31.0 mmol) was added dropwise over 30 minutes, maintaining the temperature below -60°C. The resulting solution was warmed up to -10°C, and then the aryllithium solution prepared above was added slowly, keeping the temperature below -...
Embodiment 3
[0072] Cis and trans-3-[4-(4-chlorophenyl)thio-4-(2,5-difluorophenyl)cyclohexyl]propanoic acid
[0073] Under nitrogen, a solution of 4-chlorothiophenol (15.67 g, 108 mmol) in dichloromethane (46 mL) was cooled to -15°C and treated with boron trifluoride diethyl etherate (14.3 g, 101 mmol). A solution of the carbinol mixture of Example 2 (22 g, 77 mmol) in dichloromethane (245 ml) was added slowly, maintaining the temperature between -9°C and -15°C. After stirring for a further 2 hours, the solvent was evaporated and replaced with acetonitrile, which was also evaporated. The residue was slurried with acetonitrile (30ml) and water (100ml) was added. The resulting solid was filtered, washed with water, dried under vacuum at 40°C and recrystallized from heptane. HPLC analysis indicated a 1:1 mixture of cis and trans isomers.
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