(αS)-α-Methyl-3,5-bis(trifluoromethyl)benzenemethanol

White solid

Working Example 23; A ruthenium complex Ru(OTf)[(S, S)-iso-BuSO3', 5'-bis(trifluoromethyl)acetophenone (3.1 ml in 17 ml) was passed through a syringe pump at 0-5°C for 2 hoursIn THF, 17 millimoles) were added to5 ml of 2M (ie 10 mmol) of different borane reagent and 0.85 ml (5 molpercent vs. 3', 5'-bis(trifluoromethyl)acetophenone)1M of a (R)-MeCBS toluene solution in a mixed solution.After stirring 3', 5'-bis(trifluoromethyl)acetophenone for 30 minutes, Then, hydrochloric acid (1M, 4.2 ml) was added dropwise to the reaction solution to quench the reaction.The organic phase of the reaction solution was extracted with 20 ml of methyl tert-butyl ether.Wash the organic layer with water and saturated saline, Dry with anhydrous Na2SO4, At last, The organic phase is evaporated andGet the product.The resulting enantiomeric excess (percent ee) of (S)-1-[3, 5-bis(trimethyl)phenyl]ethanol was determined by chiral HPLC.The results are shown in Table 5.Selective reduction of 3′, 5′-bis(trifluoromethyl)acetophenone with BTHF as reducing agentThe resulting product has a low percent ee, and, Adding sodium borohydride has a great influence on the percent ee value of the product;In the selective reduction of 3′, 5′-bis(trifluoromethyl)acetophenone with BDMS as reducing agent, The percent ee value is high, and, The presence of sodium borohydride did not reduce the percent ee value of the reactionGeotrichum candidum BPCC 1118 was grown aerobically in shake flasks containing a mineral salts medium pH 7.2, supplemented with glucose (5g/litre), yeast extract (2g/litre) and 2-propanol (15g/litre). Cultures were incubated on a shaker at 28 degrees centigrade for 24 hours and the cells recovered by centrifugation. The recovered cell pellet was dehydrated by resuspension in 10 volumes of acetone, the cells were recovered by filtration and washed twice more with acetone before drying under vacuum to provide a free-flowing powder. Reactions were analysed by GC on a DB17 column (30m x 0.32mm), using a temperature gradient (initial temperature 80 degrees C held for 2.5 minutes, rising at 20 degrees per minute to 200 degrees) the starting material eluted at 3.8 minutes and the reduction product at 5.2 minutes. Chiral analysis was carried out by GC using a Chiraldex CB column (25m x 0.32mm) on a temperature gradient (initial temperature 80 degrees held for 5 minutes, rising at 10 degrees per minute to a final temperature of 180 degrees and held for 2 minutes), the (S)-enantiomer eluted at 12.3 minutes and the (R)-enantiomer at 12.7 minutes. The reduction of 3, 5-bis- (trifluoromethyl)-acetophenone (20mg) was carried out in 2ml of sodium phosphate buffer (pH7.5) containing acetone dried Geotrichum candidum cells (100mg), EPO Accurately weighed amounts of (S5, S)-9 (0.9 mg, 1 μmol), solid KO-^-CAccurately weighed amounts of (SS, S)-9 (0.9 mg, 1 μmol), solid KO-t-CThe transition metal complex catalyst employs structure XI; the base employs potassium carbonate; and the solvent uses methylene chloride. The molar ratio of the starting material 3, 5-bistrifluoromethylacetophenone (I) to the transition metal complex was 40, 000.100L stainless steel autoclave, 3, 5-bistrifluoromethylacetophenone (I) and methylene chloride were added and the catalyst was added under N2 atmosphere[RuCl2 ((S, S) -DIOP) {(R, R) -2- (1H-benzo [d] imidazol-2-yl) cyclopentanamine}](Transition metal complex) and potassium carbonate. After replacing the hydrogen, H2 to 60atm was charged. The reaction was stirred at 25 ° C. When the hydrogen pressure was constant (about 18 hours), the stirring was stopped and the H2 in the reaction kettle was vented. The reaction solution was sampled and subjected to a conventional post-treatment to obtain a solid product. The conversion of the reaction was 99.5percent as determined by liquid chromatography. The enantiomeric excess was 98.6percent and the absolute configuration was S configuration.[RhCp*CISodium formate was added to the water to make a 3.7M solution, which was then cooled to 10Experiment 2 - Biphasic Reduction of 3, 5-(bistrifluoromethyl)phenylacetophenoneTM dimer Rh/Ru (SExperiment 2 - Biphasic Reduction of 3, 5-(bistrifluoromethyl)phenylacetophenoneTM dimer Rh/Ru (SComparative Asymmetric hydrogenation of 1-(3, 5-bis(trifluoromethyl)phenyl)-ethanone To a solution of dichloro[(S)-2, 2'-bis(diphenylphosphino)-1, 1'-binaphthyl]ruthenium(II)-N, N-dimethylformamide complex (1.7 mg, 0.00195 mmoL) synthesized in the same method as in Example 16, (2S)-(+)-1, 1-bis(4-methoxyphenyl)-3-methyl-1, 2-butanediamine (2.4 mg, 0.0078 mmoL) and potassium tert-butoxide (1.7 mg, 0.0156 mmoL) in 2-propanol (1 mL) was added a solution of 1-(3, 5-bis(trifluoromethyl)phenyl)-ethanone (0.05 g, 0.195 mmoL) in 2-propanol (1 mL). The mixture was subjected to hydrogenation under a 1.0 MPa hydrogen pressure at 25°C for 12 hr. The reaction mixture was analyzed by GC (column: CHIRASIL-DEX CB, 0.32 mmx25 m) to find a conversion ratio of 60.8percent and an optical purity of 62.9percent ee(R).A solution of the ketone in 2-propanol was added to a 50 mL Schlenk flask. After evacuating and refilling with argon, a mixture of the catalyst and base (eg. KO'Bu) was added. The resulting mixture was then injected into a 50 mL autoclave which had been previously placed under an atmosphere of hydrogen. The autoclave was pressurized with hydrogen gas and the reaction mixture was stirred at the desired temperature. The reaction progress was monitored by TLC. Upon completion of the reaction, the solvent was removed under vacuum and the mixture was filtered through a short pad of silica gel (ca. 6 cm) using hexane/ethyl acetate. The solvent was then removed from the filtrate affording the product.Biotransformation using lyophilized powder of crude ChKRED20 was performed in 5 ml potassium phosphate buffer (100 mM, pH 7.0) containing 40percent (v/v) of 2-propanol, crude enzyme (2 g/l or10 g/l), and substrate (50–200 g/l). The reaction was carried outat 30°C for 24 h and terminated by extraction with ethyl acetate.The product was purified by silica gel column chromatographyand identified by 1H NMR analysis. The absolute configuration ofthe product was determined by comparing the optical rotationwith the literature data. Spectral data for the product (R)-3, 5-bis(trifluoromethyl)-1-phenylethanol (1b) were as follows: white solid; 1H NMR (600 MHz, CDCl3): 7.85 (s, 2H), 7.79 (s, 1H), 5.04–5.03(q, 1H, J = 6.6 Hz), 1.98 (br, OH), 1.55 (d, 3H, J = 6.6 Hz); [α]General procedure: To a solution of ligand 5d (2.1 mg, 0.004 mmol) in water (1 mL) was added [Cp*RhClGeneral procedure: To a solution of ligand 5d (2.1 mg, 0.004 mmol) in water (1 mL) was added [Cp*RhClIn a Schlenk tube sealed with a rubber septum under argon atmosphere the base (potassium tert-butoxide, 0.04 mmol) was added to a solution of precatalyst 4–7 (0.8 μmol) in 4 ml of 2-propanol and the system thermostated at 40°C or 82°C; then the ketone (0.8 mmol in 1ml of 2-propanol) was added in one portion ([sub]=0.16 M). GC analysis was performed taking 0.3 ml of reaction mixture, the sample was treated with ammonium chlorideIn a Schlenk tube sealed with a rubber septum under argon atmosphere the base (potassium tert-butoxide, 0.04 mmol) was added to a solution of precatalyst 4–7 (0.8 μmol) in 4 ml of 2-propanol and the system thermostated at 40°C or 82°C; then the ketone (0.8 mmol in 1ml of 2-propanol) was added in one portion ([sub]=0.16 M). GC analysis was performed taking 0.3 ml of reaction mixture, the sample was treated with ammonium chlorideGeneral procedure: In a pressure tube, 0.5 molpercent of metal precursor [C16H24BF4Ir](2.48 mg, 0.005 mol) and 1 molpercent of chiral amine ligand (3.66 mg, 0.01 mmol) were dissolved in 2 mL of water and methanol (ratio1:1) and stirred at room temperature for 1 h under argon atmo-sphere. Then formic acid (2.5eq, 0.1 mL), sodium formate (2.5eq, 170 mg) and 1eq of ketone substrate (1 mmol) were introduced.The reaction mixture was stirred at 500 rpm and heated at 70C for22 h. After that, the tube was cooled to room temperature; and theorganic compound was extracted with either with ethyl acetate orCH2Cl2, then the solution was dried over Na2SO4, filtrated and con-centrated under reduced pressure. The crude material was purifiedby flash column chromatography on silica gel using cyclohex-ane/ethyl acetate as gradient eluent (90:10–7:3). After evaporation, alcohols were obtained as oil or solid. The products were identifiedby NMR. The conversion and the enantioselectivity were deter-mined by chiral GC or chiral HPLC analysis (Scheme 1).General procedure: First, two different cofactors NADH and NADPH were tested usingwhole cells biocatalysts to see which one could improve the activity ofKleADH. Reactions were conducted in 1 mL of triethanolamine buffer(100 mM, pH7.0) containing 10 mM substrates, 10 mM cofactors, and400 mg/mL recombinant wet cells at 30 °C with vigorous shaking for24 h. Then, a wide range of potential substrates were investigated toexplore the substrate specificity of KleADH. The substrates used in thisstudy were listed in Table. 2. Reactions were conducted in 1 mL oftriethanolamine buffer (100 mM, pH7.0) containing 10 mM substratesand 400 mg/mL recombinant wet cells at 30 °C with vigorous shakingfor 24 h. Then the aqueous phase was extracted by ethyl acetate andanalyzed by chiral HPLC or GC [30, 31].1, rac-3, 5-bis (trifluoromethyl) phenethyl alcohol:Take 3, 5-bis (trifluoromethyl) acetophenone 500g into the round bottom flask was added 30mL of ethanol, followed by stirring to dissolve, cooled to 0 deg.] C; and NaBHWorking Example 23; A ruthenium complex Ru(OTf)[(S, S)-iso-BuSO2dpen] (p-cymene) (1.4 mg, 0.002 mmol), potassium formate (1.0 g, 12 mmol), and 3', 5'-bis(trifluoromethyl)acetophenone (2.56 g, 10 mmol, substrate/catalyst ratio=5000) were set in a 20 mL glass Schlenk-type reaction tube under an argon atmosphere. Methanol (6 mL) was added thereto and stirred at 50 C. for 24 hours to give (S)-1-[3', 5'-bis(trifluoromethyl)phenyl]ethanol at 100% yield and 87.7% ee optical purity.3', 5'-bis(trifluoromethyl)acetophenone (3.1 ml in 17 ml) was passed through a syringe pump at 0-5C for 2 hoursIn THF, 17 millimoles) were added to5 ml of 2M (ie 10 mmol) of different borane reagent and 0.85 ml (5 mol% vs. 3', 5'-bis(trifluoromethyl)acetophenone)1M of a (R)-MeCBS toluene solution in a mixed solution.After stirring 3', 5'-bis(trifluoromethyl)acetophenone for 30 minutes, Then, hydrochloric acid (1M, 4.2 ml) was added dropwise to the reaction solution to quench the reaction.The organic phase of the reaction solution was extracted with 20 ml of methyl tert-butyl ether.Wash the organic layer with water and saturated saline, Dry with anhydrous Na2SO4, At last, The organic phase is evaporated andGet the product.The resulting enantiomeric excess (%ee) of (S)-1-[3, 5-bis(trimethyl)phenyl]ethanol was determined by chiral HPLC.The results are shown in Table 5.Selective reduction of 3?, 5?-bis(trifluoromethyl)acetophenone with BTHF as reducing agentThe resulting product has a low %ee, and, Adding sodium borohydride has a great influence on the % ee value of the product;In the selective reduction of 3?, 5?-bis(trifluoromethyl)acetophenone with BDMS as reducing agent, The %ee value is high, and, The presence of sodium borohydride did not reduce the %ee value of the reactionGeotrichum candidum BPCC 1118 was grown aerobically in shake flasks containing a mineral salts medium pH 7.2, supplemented with glucose (5g/litre), yeast extract (2g/litre) and 2-propanol (15g/litre). Cultures were incubated on a shaker at 28 degrees centigrade for 24 hours and the cells recovered by centrifugation. The recovered cell pellet was dehydrated by resuspension in 10 volumes of acetone, the cells were recovered by filtration and washed twice more with acetone before drying under vacuum to provide a free-flowing powder. Reactions were analysed by GC on a DB17 column (30m x 0.32mm), using a temperature gradient (initial temperature 80 degrees C held for 2.5 minutes, rising at 20 degrees per minute to 200 degrees) the starting material eluted at 3.8 minutes and the reduction product at 5.2 minutes. Chiral analysis was carried out by GC using a Chiraldex CB column (25m x 0.32mm) on a temperature gradient (initial temperature 80 degrees held for 5 minutes, rising at 10 degrees per minute to a final temperature of 180 degrees and held for 2 minutes), the (S)-enantiomer eluted at 12.3 minutes and the (R)-enantiomer at 12.7 minutes. The reduction of 3, 5-bis- (trifluoromethyl)-acetophenone (20mg) was carried out in 2ml of sodium phosphate buffer (pH7.5) containing acetone dried Geotrichum candidum cells (100mg), EPO Accurately weighed amounts of (S5, S)-9 (0.9 mg, 1 mumol), solid KO-^-C4H9 (6 mg, 0.05 mmol) and sometimes derivatives [eg. PPh3 (0.3 mg, 1 mumol)] were placed in a pre-oven-dried (120 0C) 350-mL autoclave containing a magnetic stirring bar, and placed under high vacuum for at least 20 min before purging with argon. Freshly distilled solvent (toluene, 2.7 mL; t-BuOH, 0.3 mL) and purified ketones (1 mmol, S/C = 1, 000) were placed into a pre-dried Schlenk and degassed by 3 cycles of freeze-and-thaw and then added to the autoclave under an Ar atmosphere. H2 was introduced under 20 atm pressure with several quick release-fill cycles before being set to 8 atm. The solution was vigorously stirred at 25 0C and H2 consumption monitored. The H2 was carefully released after a period of time, the solution passed through a short pad of silica gel and solvent removed under reduced pressure. The crude product mixture was analyzed by 1H NMR to determine conversion and chiral GC or HPLC to determine ee of the chiral alcohol products. The hydrogenation results are given in Table 5.Accurately weighed amounts of (SS, S)-9 (0.9 mg, 1 mumol), solid KO-t-C4H9 (6 mg, 0.05 mmol) and sometimes derivatives [e.g. PPh3 (0.3 mg, 1 mumol)] were placed in a pre-oven-dried (120 C.) 350-mL autoclave containing a magnetic stirring bar, and placed under high vacuum for at least 20 min before purging with argon. Freshly distilled solvent (toluene, 2.7 mL; t-BuOH, 0.3 mL) and purified ketones (1 mmol, S/C=1, 000) were placed into a pre-dried Schlenk and degassed by 3 cycles of freeze-and-thaw and then added to the autoclave under an Ar atmosphere. H2 was introduced under 20 atm pressure with several quick release-fill cycles before being set to 8 atm. The solution was vigorously stirred at 25 C. and H2 consumption monitored. The H2 was carefully released after a period of time, the solution passed through a short pad of silica gel and solvent removed under reduced pressure. The crude product mixture was analyzed by 1H NMR to determine conversion and chiral GC or HPLC to determine ee of the chiral alcohol products. The hydrogenation results are given in Table 5. TABLE 5 Screening of aromatic substrates using complex (SS, S)-9a Entry subPPh3b t/h Conv. % Ee % (S) 1 acetophenone 1 100 96 2 acetophenone 3eq 1 62 98 3 acetophenone 1eq 1 100 98 4 2-Me-acetophenone 13.5 87 90 5 2-Me-acetophenone 1eq 8.5 74 97 6 4-MeO-acetophenone 5 99 97 7 4-MeO-acetophenone 1eq 3 99 99.6 8 4-Br-acetophenone 15 100 93 9 4-Br-acetophenone 1eq 6 99 98 10 4-F-acetophenone 1eq 9.5 100 98 11 4-Me-acetophenone 1eq 12 99 98 12 3-Br-acetophenone 1eq 1.5 99 98 133, 5-CF3-acetophenone 1eq 3 100 92 14 1eq 5 100 99 15 1eq 2 99 99 16 1eq 10 90 98 17 1eq 3 97 91 18c 1eq 8 99 99 aConditions: Substrate/Catalyst/Base = 1000/1/50; VT = 3 mL, 25-30 C.bCompared to catalyst;cThe H2 pressure was 20 atm and the configuration of the product was R.The transition metal complex catalyst employs structure XI; the base employs potassium carbonate; and the solvent uses methylene chloride. The molar ratio of the starting material 3, 5-bistrifluoromethylacetophenone (I) to the transition metal complex was 40, 000.100L stainless steel autoclave, 3, 5-bistrifluoromethylacetophenone (I) and methylene chloride were added and the catalyst was added under N2 atmosphere[RuCl2 ((S, S) -DIOP) {(R, R) -2- (1H-benzo [d] imidazol-2-yl) cyclopentanamine}](Transition metal complex) and potassium carbonate. After replacing the hydrogen, H2 to 60atm was charged. The reaction was stirred at 25 C. When the hydrogen pressure was constant (about 18 hours), the stirring was stopped and the H2 in the reaction kettle was vented. The reaction solution was sampled and subjected to a conventional post-treatment to obtain a solid product. The conversion of the reaction was 99.5% as determined by liquid chromatography. The enantiomeric excess was 98.6% and the absolute configuration was S configuration.

Aprepitant intermediate.

Molecular Weight:258.16
XLogP3:3.2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:7
Rotatable Bond Count:1
Exact Mass:258.04793385
Monoisotopic Mass:258.04793385
Topological Polar Surface Area:20.2
Heavy Atom Count:17
Complexity:237
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes