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CAS No. : | 64920-29-2 | MDL No. : | MFCD00037533 |
Formula : | C12H14O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | STPXIOGYOLJXMZ-UHFFFAOYSA-N |
M.W : | 206.24 | Pubchem ID : | 562087 |
Synonyms : |
|
Num. heavy atoms : | 15 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.33 |
Num. rotatable bonds : | 6 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 56.93 |
TPSA : | 43.37 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.96 cm/s |
Log Po/w (iLOGP) : | 2.29 |
Log Po/w (XLOGP3) : | 2.25 |
Log Po/w (WLOGP) : | 1.75 |
Log Po/w (MLOGP) : | 1.89 |
Log Po/w (SILICOS-IT) : | 2.68 |
Consensus Log Po/w : | 2.17 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.44 |
Solubility : | 0.755 mg/ml ; 0.00366 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.8 |
Solubility : | 0.329 mg/ml ; 0.0016 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.64 |
Solubility : | 0.0469 mg/ml ; 0.000228 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.62 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P264-P270-P271-P280-P301+P312+P330-P302+P352-P304+P340+P312-P305+P351+P338-P332+P313-P337+P313-P362-P403+P233-P405-P501 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-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 |
---|---|---|
99% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; calcium methylate In acetonitrile at 0 - 20℃; | |
98% | With 4-hydroxy-TEMPO benzoate; sodium acetate In dichloromethane | |
94% | With hydrogenchloride; sodium hypobromide In dichloromethane; water at 25℃; for 5h; |
90% | With hydrogenchloride; sodium hypochlorite; sodium thiosulfate In dichloromethane | 2 Preparation of 2-Keto-4-Phenylbutyric Acid Ethyl Ester Using Soidium Hypochlorite and Hydrochloric Acid EXAMPLE 2 Preparation of 2-Keto-4-Phenylbutyric Acid Ethyl Ester Using Soidium Hypochlorite and Hydrochloric Acid A 200 ml flask was charged with a solution dissolving 20.8 g (100 mmol) of 2-hydroxy-4-phenylbutyric acid ethyl ester in methylene chloride (50 ml) and 72.6 g (purity 12.3%, 120 mmol) of sodium hypochlorite, and cooled at 6° C. To the reaction mixture was added 43 mg (0.2 mmol) of 4-acetoxy-2,2,6,6-tetramethylpiperidinyl-1-oxy and further added 10 ml (10 mmol) of 1N hydrochloric acid. The gradual exothermal reaction proceeded, and the starting material of 2-hydroxy-4-phenylbutyric acid ethyl ester was disappeared in 30 minutes. After the reaction was stopped by adding 10 ml of 5% sodium thiosulfate aqueous solution, the reaction mixture was subjected to the after treatment as described in Example 1 to obtain 18.55 g of 2-keto-4-phenylbutyric acid ethyl ester. The yield was 90%. |
81% | With 4-(benzyloxycarbonyl)-2,2,6,6-tetramethylpiperidine-1-oxyl; sodium hydrogencarbonate; pyridinium hydrobromide perbromide In dichloromethane; water at 0 - 4℃; | |
62% | With Dess-Martin periodane In dichloromethane for 1.33333h; | |
87 % Chromat. | With chromium trioxide-pyridine complex In dichloromethane for 2.5h; other reagents: K<CrO3Cl>, CrO3/Al2O3; | |
With oxygen; acetic anhydride In acetic acid at 40℃; for 8h; | 9 0.050g (0.424 mmol) of ammonium metavanadate, 20g of acetic acid, 0.43g (4.24 mmol) of acetic anhydride and 8.8g (42.4 mmol) of ethyl α-hydroxy-γ-phenylbutanoate were put in a three-necked flask having a content volume of 100ml, and the mixture was warmed to 40°C under stirring. The mixture was stirred at that temperature for 8 hours in an atmosphere of oxygen (0.1 MPa) to react. The result of analysis of the resulting reaction mixture by gas chromatography is shown in Table 3. | |
With oxygen; acetic anhydride In acetic acid; ethyl acetate at 40℃; for 10h; | 12 Reaction was carried out in the same way as in Example 9, except that 6.7g of acetic acid and further 13.3g of ethyl acetate were used in place of 20g of acetic acid. The result of analysis of the resulting reaction mixture by gas chromatography is shown in Table 3. | |
With oxygen; acetic anhydride In ethyl acetate at 40℃; for 4h; | 1 Reaction wherein a carboxylic acid was not used Reaction was carried out in the same way as in Example 9, except that 20g of ethyl acetate was used as a solvent in place of 20g of acetic acid. The result of analysis of the resulting reaction mixture by gas chromatography is shown in Table 3. | |
With oxygen; acetic anhydride In acetonitrile at 40℃; for 4h; | 2 Reaction wherein a carboxylic acid was not used Reaction was carried out in the same way as in Example 9, except that 20g of acetonitrile was used as a solvent in place of 20g of acetic acid. The result of analysis of the resulting reaction mixture by gas chromatography is shown in Table 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With water; sodium hydroxide; at 23℃; | General procedure: To compounds 5a-b, a solution of excess 2.5 N NaOH was added.The aqueous mixture was stirred at room temperature until the initiallyemulsified mixture reached uniformity, at least 12 h. The reactionmixture was quenched with 1 N HCl, and the resulting alpha-keto acidswere extracted several times with ether, and the combined organiclayers washed with brine, dried (MgSO4) and concentrated to give thecorresponding product |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With hydrogen In benzene at 75℃; for 18h; | |
83% | Stage #1: 2-oxo-4-phenylbutanoic acid ethyl ester With sodium tetrahydroborate In ethanol at -18℃; for 0.0833333h; Stage #2: With hydrogenchloride; water In ethanol | 68.a a) Ethyl 2-hydroxy-4-phenylbutanoateNaBH4 (625 mg, 16.521 mmol) was added to a -18 0C cooled solution of ethyl 2-oxo-4-phenylbutyrate in EtOH (70 ml_). The reaction mixture was stirred at low temperature for 5 min, poured into H2O (120 ml_), taken up to pH= 2 with HCI and extracted with CH2CI2 (200 ml_). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO2 (5→15% EtOAc/hexanes), to give 2.85 g of ethyl 2-hydroxy-4-phenylbutanoate (colourless oil, yield: 83%). |
76% | Stage #1: 2-oxo-4-phenylbutanoic acid ethyl ester With acetic acid In acetonitrile at 25℃; for 0.0833333h; Stage #2: In acetonitrile at 25℃; for 12h; Electrochemical reaction; |
70% | With methanol; sodium tetrahydroborate at 20℃; for 0.5h; | |
59% | With tris(triphenylphosphine)ruthenium(II) chloride; formic acid at 125℃; for 3h; | |
With 1-propyl-1,4-dihydronicotinamide In acetonitrile Heating; | ||
With sodium tetrahydroborate In methanol | ||
With hydrogen In acetic acid at 20℃; for 1 - 1.16667h; | B68 EXAMPLES B61-B71; Hydrogenation of ethyl 4-phenyl-2-oxobutyrate [0091] The procedure of Example B1 is followed using ethyl 4-phenyl-2-oxobutyrate. The results are reported in Table 6 | |
With NADPH In isopropyl alcohol at 25℃; for 10h; | ||
Stage #1: 2-oxo-4-phenylbutanoic acid ethyl ester With sodium tetrahydroborate In tetrahydrofuran at -10℃; for 0.666667h; Inert atmosphere; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 20℃; for 0.25h; Inert atmosphere; | ||
With zinc-dependent medium-chain alcohol dehydrogenase from Rhodococcus erythropolis; NADH In aq. phosphate buffer; ethanol Enzymatic reaction; regioselective reaction; | ||
With sodium tetrahydroborate In methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.7% | With Acetobacter sp. CCTCC M209061 anti-Prelog carbonyl reductase mut-G152L/Y189N mutant; isopropyl alcohol; NADH In aq. phosphate buffer at 35℃; for 4h; Enzymatic reaction; enantioselective reaction; | |
94% | With D-glucose at 30℃; for 12h; aq. phosphate buffer; optical yield given as %ee; enantioselective reaction; | |
91% | With D-glucose; sodium carbonate In dimethyl sulfoxide at 30℃; for 22h; aq. phosphate buffer; Large scale reaction; Enzymatic reaction; optical yield given as %ee; enantioselective reaction; |
89% | With SmADH31 Enzymatic reaction; stereoselective reaction; | |
88.7% | With formate dehydrogenase; recombinant diketoreductase; NAD; sodium formate In toluene at 20℃; for 9h; aq. potassium phosphate buffer; Enzymatic reaction; optical yield given as %ee; enantioselective reaction; | |
71% | With Candida parapsilosis ATCC 7330 In ethanol; water at 25℃; for 4h; | |
48% | In water at 28℃; for 24h; wet Geotrichum sp. G38 mycelium; | |
With glucose-6-phosphate dehydrogenase; α-D-glucose 6-phosphate; baker yeast YOL151w gene-pIK3 plasmid at 30℃; for 24h; | ||
With Dekera sp. cultured cells In ethanol at 30℃; for 24h; | ||
With phosphate buffer; D-glucose In water at 20℃; for 27h; | ||
With hydrogen In methanol; N,N-dimethyl-formamide at 20℃; for 20h; | ||
With [NH2Me2]+[{RuCl[(S)-(μ-Cl3)]; hydrogen optical yield given as %ee; | ||
With isopropyl alcohol; NADPH at 30℃; for 24h; Microbiological reaction; aq. buffer; optical yield given as %ee; | ||
81 % ee | With hydrogen In acetic acid at 20℃; for 1 - 1.16667h; | B61 EXAMPLES B61-B71; Hydrogenation of ethyl 4-phenyl-2-oxobutyrate [0091] The procedure of Example B1 is followed using ethyl 4-phenyl-2-oxobutyrate. The results are reported in Table 6 |
82 % ee | With hydrogen In acetic acid at 20℃; for 1 - 1.16667h; | B62 EXAMPLES B61-B71; Hydrogenation of ethyl 4-phenyl-2-oxobutyrate [0091] The procedure of Example B1 is followed using ethyl 4-phenyl-2-oxobutyrate. The results are reported in Table 6 |
81 % ee | With hydrogen In acetic acid at 20℃; for 1 - 1.16667h; | B63 EXAMPLES B61-B71; Hydrogenation of ethyl 4-phenyl-2-oxobutyrate [0091] The procedure of Example B1 is followed using ethyl 4-phenyl-2-oxobutyrate. The results are reported in Table 6 |
86 % ee | With hydrogen In acetic acid at 20℃; for 1 - 1.16667h; | B65 EXAMPLES B61-B71; Hydrogenation of ethyl 4-phenyl-2-oxobutyrate [0091] The procedure of Example B1 is followed using ethyl 4-phenyl-2-oxobutyrate. The results are reported in Table 6 |
81 % ee | With hydrogen In acetic acid for 1 - 1.16667h; | B61 Examples B61-B71: Hydrogenation of ethyl 4-phenyl-2-oxobutyrate[0056] The procedure of Example B1 is followed using ethyl 4-phenyl-2-oxobutyrate. The results are reported in Table 6. |
82 % ee | With hydrogen In acetic acid for 1 - 1.16667h; | B62 Examples B61-B71: Hydrogenation of ethyl 4-phenyl-2-oxobutyrate[0056] The procedure of Example B1 is followed using ethyl 4-phenyl-2-oxobutyrate. The results are reported in Table 6. |
81 % ee | With hydrogen In acetic acid for 1 - 1.16667h; | B63 Examples B61-B71: Hydrogenation of ethyl 4-phenyl-2-oxobutyrate[0056] The procedure of Example B1 is followed using ethyl 4-phenyl-2-oxobutyrate. The results are reported in Table 6. |
86 % ee | With hydrogen In acetic acid for 1 - 1.16667h; | B65 Examples B61-B71: Hydrogenation of ethyl 4-phenyl-2-oxobutyrate[0056] The procedure of Example B1 is followed using ethyl 4-phenyl-2-oxobutyrate. The results are reported in Table 6. |
Multi-step reaction with 4 steps 1: lithium hydroxide / ethanol / 1 h / Cooling with ice; Inert atmosphere 2: hydrogenchloride / water / 80 °C / pH 2 / Inert atmosphere 3: [RuCl(benzene){(2,2,2',2'-tetramethyl[4,4'-bibenzo[d][1,3]dioxole]-5,5'-diyl)bis(diphenylphosphine)}]Cl; hydrogen bromide; hydrogen / tetrahydrofuran; water / 20 h / 70 °C / 20686.5 Torr / Autoclave 4: sulfuric acid / 5 h / Inert atmosphere; Reflux | ||
Multi-step reaction with 4 steps 1: lithium hydroxide / ethanol / 1 h / Cooling with ice; Inert atmosphere 2: hydrogenchloride / water / 80 °C / pH 2 / Inert atmosphere 3: C52H50ClO4P2Ru(1+)*Cl(1-); hydrogen bromide; hydrogen / tetrahydrofuran; water / 12 h / Autoclave 4: sulfuric acid / 5 h / Inert atmosphere; Reflux | ||
Multi-step reaction with 3 steps 1: bromine / chloroform; tetrachloromethane 2: Candida utiliz / aq. buffer / 72 h / 30 °C / pH 4 3: sodium acetate; 5%-palladium/activated carbon / ethanol / 2 h / 20 °C / Inert atmosphere | ||
Multi-step reaction with 3 steps 1: bromine / chloroform; tetrachloromethane 2: L. mesenteroides / aq. buffer / 72 h / 30 °C / pH 4 3: sodium acetate; 5%-palladium/activated carbon / ethanol / 2 h / 20 °C / Inert atmosphere | ||
Multi-step reaction with 3 steps 1: bromine / chloroform; tetrachloromethane 2: D-(+)-glucose; ammonium hydroxide / aq. buffer / 24 h / 30 °C / pH 4 3: sodium acetate; 5%-palladium/activated carbon / ethanol / 2 h / 20 °C / Inert atmosphere | ||
Multi-step reaction with 3 steps 1: bromine / chloroform; tetrachloromethane 2: D-(+)-glucose; ammonium hydroxide / aq. buffer / 24 h / 30 °C / pH 4 3: sodium acetate; 5%-palladium/activated carbon / ethanol / 2 h / 20 °C / Inert atmosphere | ||
> 99 % ee | With D-glucose; nicotinamide adenine dinucleotide phosphate; recombinant Bacillus subtilis-derived glucose dehydrogenase; recombinant Gluconobacter oxydans carbonyl reductase 0525 In aq. phosphate buffer; ethanol at 30℃; for 12h; Enzymatic reaction; enantioselective reaction; | Activity assay and determination of kinetic parameters. General procedure: The enzyme activity toward the reduction ofketones was determined by spectrophotometricallymeasuring the oxidation of NAD(P)H at 340 nm(ε = 6.22mM-1 cm-1) in the presence of an excess amount of ketones. The change in absorbance of NAD(P)H was monitored at 340 nm using an ultraviolet-visiblespectrophotometer with a temperature-controlledcuvette holder (Shimadzu Co., Kyoto, Japan). One unit(U) activity was defined as the amount of enzymesrequired to catalyze the oxidation of 1 μmol NAD(P)Hper minute at 30 °C. The data were expressed as U/mgof protein. The standard reaction mixture contained100mM phosphate buffer (pH 7.0), 0.1mM NAD(P)H,5 mM substrate, and enzyme solvent in a total volumeof 1 mL. The reaction was initiated by adding 20 μLsolvent containing 10 μg-40 μg of enzymes. Blankswithout the enzyme were carried out for each substrate,and data were collected in triplicate. Protein concentrationswere determined with the bicinchoninic acid assayusing bovine serum albumin as a standard.NAD(P)H or NADH was assayed under standardreaction conditions for the study of coenzyme dependence.A range of substrates from 1 to 20 mM concentrationwas assayed under the standard reactionconditions for the study of kinetics. Apparent values ofMichaelis constant (Km) and kcat were calculated by fittingthe data into Michaelis-Menten equation using theSigmaPlot (Systat Software Inc., San Jose, CA, USA).All reactions followed Michaelis-Menten-type kinetics.Enantioselective reduction of ketones. The enantioselectivityof the enzymes was determined byexamining the reduction of aryl ketones, ethyl 4-chloroacetoacetate(COBE), and ethyl 2-oxo-4-phenylbutyrate(OPBE) using an NAD(P)H regeneration system consistingof BsGDH and glucose. The general procedurewas as follows: D-glucose (0.5%), recombinant BsGDH(10 U), NAD(P)+ (0.1 mM), the recombinant cell(30 g L-1, wet weight), and ketone solvated in ethanol[1 g L-1, 10%(v/v)] were mixed in a potassium phosphatebuffer (10 mL, 100 mM, pH 7.0). The mixturewas shaken at 30 °C for 12 h.22) Upon termination ofthe reaction, each sample was extracted twice withequivalent ethyl acetate. The organic layer wasremoved, dried, diluted in the mobile phase, and thensubjected to chiral high-performance liquid chromatography(HPLC) to determine the conversion and enantiomericexcess (e.e.). Chiral HPLC analysis wasperformed on an Agilent 1100 series HPLC system witha UV detector.23) Chiral CHBE was analyzed on a chiracelOB-H column (Daicel, Japan) at λ210 nm using hexane/2-propanol (90/10, v/v) as eluent at a flow rate of0.8 mL min-1 and a temperature of 25 °C. Chiral HPBEand 4-phenyl-2-butanol were analyzed on a chiracelOD-H column at λ210 nm and λ254 nm using hexane/2-propanol (98/2, v/v) as eluent at a flow rate of 1.0 mLmin-1 and a temperature of 30 °C. Authentic (relevant)standards were used for peak identification, and quantificationwas based on the peak area that was suitablycalibrated with standards of known concentration. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: 1-phenyl-2-bromoethane With magnesium In tetrahydrofuran at 20℃; for 1h; Inert atmosphere; Stage #2: oxalic acid diethyl ester In tetrahydrofuran at -78℃; for 2h; Inert atmosphere; | |
60% | Stage #1: 1-phenyl-2-bromoethane With magnesium In tetrahydrofuran for 1h; Reflux; Inert atmosphere; Stage #2: oxalic acid diethyl ester In tetrahydrofuran at -10℃; for 1.5h; Inert atmosphere; Stage #3: With hydrogenchloride In tetrahydrofuran; water Inert atmosphere; | General procedure for the preparation of 2-oxo-4-arylbutanoic acids 1: General procedure: Magnesium turnings (13.2 g, 0.55 mol) were placed in dry THF (25 mL) undernitrogen. A small amount (10 mL) of (2-bromoethyl)benzene (92.5 g, 0.50 mol) dissolvedin dry THF (300 mL), added to the magnesium slurry and stirred for a few minutes withwarming until the reaction commenced. The remainder of the (2-bromoethyl)benzenesolution was added dropwise to maintain reflux over an hour, then the reaction mixturewas aged at reflux for an additional an hour. The reaction mixture was cooled to 25 °C. In a separate flask, diethyl oxalate (88.2 g, 0.6 mol) was dissolved in dry THF (100mL) and cooled to -10 °C. The supernatant solution of (2-phenylethyl)magnesiumbromide was sucked under nitrogen through a sintered-glass filter into a dropping funnel.The reaction temperature was held at -10 °C as the solution of Grignard reagent wasadded dropwise over an hour to the diethyl oxalate. The sintered-glass funnel anddropping funnel were then rinsed with dry THF (100 mL), and the rinse was added to thebatch. The reaction mixture was allowed to stand for 30 min and then quenched byaddition of 3 M HCl (145 mL).Hexane (500 mL) was added, and the aqueous layer was discarded. The organicphase was washed with brine (100 mL) and saturated NaHCO3 (100 mL), until theaqueous layer measured to pH 5.0. The organic phase was dried with anhydrous Na2SO4.Filtered and washed with hexane, and the combined layers were concentrated to an oil invacuum. The crude keto ester (103.0 g) was vacuum distilled at 105-110 °C (0.2-0.3 mmHg) to afford a colourless oil 90.0 g with 60% yield. |
50% | Stage #1: 1-phenyl-2-bromoethane With iodine; magnesium In tetrahydrofuran for 1h; Reflux; Stage #2: oxalic acid diethyl ester In tetrahydrofuran at -78 - 0℃; for 1h; |
With magnesium THF; Yield given. Multistep reaction; | ||
With magnesium 1.) THF, reflux, 2 h, 2.) -10 deg C, 1 h; Yield given. Multistep reaction; | ||
Stage #1: 1-phenyl-2-bromoethane With magnesium In diethyl ether at 20℃; for 0.75h; Inert atmosphere; Stage #2: oxalic acid diethyl ester In tetrahydrofuran; diethyl ether at -78 - 20℃; for 2h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
the EOPB1 being transferred into (R)-EHPB22 by asymmetric reduction reaction as shown in FIG. 8 | ||
With alcohol dehydrogenase TbSADH from Thermoanaerobacter brockii I86N mutant; In aq. phosphate buffer; isopropyl alcohol; at 30℃;Enzymatic reaction; | General procedure: A test tube (10 mL)containing LB (4 mL) and kanamycin (50 mug/mL) was inoculated with mutant SZ2074 and incubated 8h (37C, 220 rpm). The pre-culture was then inoculated intoTB (400 mL) containing kanamycin (50 mug/mL) and allowed to grow at 37C until O.D.was ca. 0.6. IPTG was then added to a final concentration of 0.2 mM and theculture was grown for 16 h (30C, 180 rpm). Cells were pelleted bycentrifugation, washed once with pH=7.4 potassium phosphate buffer (100 mM) andthen resuspended in pH=7.4 potassium phosphate buffer (45 mL, 100 mM). Cellswere then transferred to a 50 mL Erlenmeyer flask and 1.4 mg/mL lysozyme (70mg), 6U DNase I (50 muL), NADP+ 100mM (200 muL) were added. Substrate 3a (30 mM) in 10% isopropanol (5 mL)was then added. Biotransformation was carried out at 30C, 220rpm. GC controlindicated a 92% conversion after 4h. The reaction was stopped after 6h when theconversion was 94%. The organic phase was extracted with ethyl acetate (3x100mL) and crude reaction product was purified using column chromatography. (EA:PE1:4, Rf=0.55) afforded (R)-4a as a colourless liquid (157 mg,yield=75%). | |
With Kluyveromyces polysporus alcohol dehydrogenase S237E mutant; isopropyl alcohol; NADPH; In aq. phosphate buffer; at 30℃;pH 7.0;Enzymatic reaction; | General procedure: Bioconversion was conducted with 20 mM 1a-10a,20 U·mL-1KpADH variants, 40 mM isopropanol in PBS buffer (pH 7.0,100 mM) in total volume of 2 mL at 30 C and 180 rpm overnight. Then,1 mL of the reaction mixture was withdrawn and extracted with ethylacetate. The organic phase was isolated by centrifugation and driedover anhydrous MgSO4. The conversion rate and enantioselectivity ofthe products were analyzed as described in supporting information. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen;(S,S)-(-)-2,2'-bis[(R)-(N,N-dimethylamino)(phenyl)methyl]-1,1'-bis[diphenylphosphine]ferrocene; | 0.01 mmol Ru (COD)2X and 0.01 mmol of the ferrocenyl ligand are dissolved in 1 ml acetone under argon in a 25 ml shaker vessel. Then, 0.022 mmol HBr (c0.3 M; produced from 48% HBr in a suitable amount of MeOH) is added to the solution and the mixture agitated 30 min at RT. The acetone is subsequently distilled off and the residue dissolved in 12 ml of the appropriate solvent. After the addition of 1 mmol of the ketoester the solution is transferred under argon into a 100 ml steel autoclave and heated after multiple rinsing with H2 for 10 min at the appropriate hydrogen pressure to reaction temperature. The mixture is then agitated 24 h, filtered and the enantiomeric excess determined by HPLC. Benzylethyl pyruvate [benzyl pyruvic-acid ethyl ester] Solvent: EtOH Reaction temperature: 50 C. Pressure: 3000 kPa The conversion was determined by 1H-NMR. The enantiomeric excess was determined by HPLC (Chiracel OD, n-heptane/isopropanol 95:5; flow 0.6 mL/min, T=20 C.; tR=14.73 (S), 23.44 (R) | |
With hydrogen;(S)-((2R)-5-ethylidene-1-azabicyclo[2.2.2]oct-2-yl)-(6-methoxy-quinoline-4-yl)-methanol; In acetic acid; at 20℃; under 45004.5 Torr; for 1 - 1.16667h;Product distribution / selectivity; | EXAMPLES B61-B71; Hydrogenation of ethyl 4-phenyl-2-oxobutyrate [0091] The procedure of Example B1 is followed using ethyl 4-phenyl-2-oxobutyrate. The results are reported in Table 6 | |
With hydrogen;10,11-dihydrocinchonine; In toluene; at 20℃; under 45004.5 Torr; for 1 - 1.16667h;Product distribution / selectivity; | EXAMPLES B61-B71; Hydrogenation of ethyl 4-phenyl-2-oxobutyrate [0091] The procedure of Example B1 is followed using ethyl 4-phenyl-2-oxobutyrate. The results are reported in Table 6 |
With hydrogen;10,11-dihydrocinchonine; In acetic acid; at 20℃; under 45004.5 Torr; for 1 - 1.16667h;Product distribution / selectivity; | EXAMPLES B61-B71; Hydrogenation of ethyl 4-phenyl-2-oxobutyrate [0091] The procedure of Example B1 is followed using ethyl 4-phenyl-2-oxobutyrate. The results are reported in Table 6 | |
With hydrogen;(+)-4-[(S)-methoxy-((2R)-5-vinyl-1-azabicyclo[2.2.2]oct-2-yl)-methyl]-quinoline; In toluene; at 20℃; under 45004.5 Torr; for 1 - 1.16667h;Product distribution / selectivity; | EXAMPLES B61-B71; Hydrogenation of ethyl 4-phenyl-2-oxobutyrate [0091] The procedure of Example B1 is followed using ethyl 4-phenyl-2-oxobutyrate. The results are reported in Table 6 | |
With hydrogen;(S)-quinoline-4-yl-((2R)-5-ethylidene-1-azabicyclo[2.2.2]oct-2-yl)-methanol; In toluene; at 20℃; under 45004.5 Torr; for 1 - 1.16667h;Product distribution / selectivity; | EXAMPLES B61-B71; Hydrogenation of ethyl 4-phenyl-2-oxobutyrate [0091] The procedure of Example B1 is followed using ethyl 4-phenyl-2-oxobutyrate. The results are reported in Table 6 | |
With hydrogen;(S)-((2R)-5-ethylidene-1-azabicyclo[2.2.2]oct-2-yl)-(6-methoxy-quinoline-4-yl)-methanol; In toluene; at 20℃; under 45004.5 Torr; for 1 - 1.16667h;Product distribution / selectivity; | EXAMPLES B61-B71; Hydrogenation of ethyl 4-phenyl-2-oxobutyrate [0091] The procedure of Example B1 is followed using ethyl 4-phenyl-2-oxobutyrate. The results are reported in Table 6 | |
With hydrogen;erythro-(1S,2R)-(+)-(1-azabicyclo[2.2.2]oct-2-yl)-naphthalene-1-yl-methanol; In toluene; at 20℃; under 45004.5 Torr; for 1 - 1.16667h;Product distribution / selectivity; | EXAMPLES B61-B71; Hydrogenation of ethyl 4-phenyl-2-oxobutyrate [0091] The procedure of Example B1 is followed using ethyl 4-phenyl-2-oxobutyrate. The results are reported in Table 6 | |
With hydrogen;erythro-(1S,2R)-(+)-(1-azabicyclo[2.2.2]oct-2-yl)-naphthalene-1-yl-methanol; In acetic acid; at 20℃; under 45004.5 Torr; for 1 - 1.16667h;Product distribution / selectivity; | EXAMPLES B61-B71; Hydrogenation of ethyl 4-phenyl-2-oxobutyrate [0091] The procedure of Example B1 is followed using ethyl 4-phenyl-2-oxobutyrate. The results are reported in Table 6 | |
With hydrogen;(2R,1'S)-2-[1-hydroxy-1-(quinolin-4-yl)]methyl-1-azabicyclo[2.2.2]octane; In toluene; at 20℃; under 45004.5 Torr; for 1 - 1.16667h;Product distribution / selectivity; | EXAMPLES B61-B71; Hydrogenation of ethyl 4-phenyl-2-oxobutyrate [0091] The procedure of Example B1 is followed using ethyl 4-phenyl-2-oxobutyrate. The results are reported in Table 6 | |
With hydrogen;[Me2NH2][{RuCl((+)-SEGPHOS-4-MeO)}2(mu-Cl)3]; In ethanol; at 50℃; under 37503.8 Torr; for 17h;Conversion of starting material; | EXAMPLE 6; Asymmetric hydrogenation of ethyl 2-oxo-4-phenylbutyrate; Under a nitrogen atmosphere, 4.3 mg (4.8 mmol) of [Me2NH2][{RuCl((+)-SEGPHOS-4-MeO)}2(mu-Cl)3] obtained in Example 3 was charged in stainless steel autoclave, and then 1.5 mL of ethanol and 500 mg (2.4 mmol) of ethyl 2-oxo-4-phenylbutyrate were added in stainless steel autoclave. The reaction was carried out with stirring under 5.0 MPa of hydrogen pressure at 50 C. for 17 hours. As the result of GLC measurement of the reaction mixture, the desired optically active ethyl 2-hydroxy-4-phenylbutyrate was obtained with a conversion of 100% and an optical purity of 79.7% ee. The conversion was measured by an ordinary method using NEUTRA BOND-1, and the optical purity was measured by an ordinary method using CP CHIRASILDEX-CB. | |
With hydrogen;5% Pt/Al2O3; (S)-((2R)-5-ethylidene-1-azabicyclo[2.2.2]oct-2-yl)-(6-methoxy-quinoline-4-yl)-methanol; In acetic acid; under 45004.5 Torr; for 1 - 1.16667h;Product distribution / selectivity; | Examples B61-B71: Hydrogenation of ethyl 4-phenyl-2-oxobutyrate[0056] The procedure of Example B1 is followed using ethyl 4-phenyl-2-oxobutyrate. The results are reported in Table 6. | |
With hydrogen;5% Pt/Al2O3; 10,11-dihydrocinchonine; In toluene; under 45004.5 Torr; for 1 - 1.16667h;Product distribution / selectivity; | Examples B61-B71: Hydrogenation of ethyl 4-phenyl-2-oxobutyrate[0056] The procedure of Example B1 is followed using ethyl 4-phenyl-2-oxobutyrate. The results are reported in Table 6. | |
With hydrogen;5% Pt/Al2O3; 10,11-dihydrocinchonine; In acetic acid; at 25℃; under 45004.5 Torr; for 1 - 1.58333h;Product distribution / selectivity; | Examples B61-B71: Hydrogenation of ethyl 4-phenyl-2-oxobutyrate[0056] The procedure of Example B1 is followed using ethyl 4-phenyl-2-oxobutyrate. The results are reported in Table 6. Examples B74-B75 and comparative example: Hydrogenation of ethyl 4-phenyl-2,4-dioxobutyrate[0059] The procedure is the same as in Example B72. The conversion is determined by gas chromatography. The results are reported in Table 9. | |
With hydrogen;5% Pt/Al2O3; (+)-4-[(S)-methoxy-((2R)-5-vinyl-1-azabicyclo[2.2.2]oct-2-yl)-methyl]-quinoline; In toluene; under 45004.5 Torr; for 1 - 1.16667h;Product distribution / selectivity; | Examples B61-B71: Hydrogenation of ethyl 4-phenyl-2-oxobutyrate[0056] The procedure of Example B1 is followed using ethyl 4-phenyl-2-oxobutyrate. The results are reported in Table 6. | |
With hydrogen;5% Pt/Al2O3; (+)-6-methoxy-4-[(S)-methoxy-((R)-5-vinyl-1-azabicyclo[2.2.2]oct-2-yl)-methyl]-quinoline; In toluene; under 45004.5 Torr; for 1 - 1.16667h;Product distribution / selectivity; | Examples B61-B71: Hydrogenation of ethyl 4-phenyl-2-oxobutyrate[0056] The procedure of Example B1 is followed using ethyl 4-phenyl-2-oxobutyrate. The results are reported in Table 6. | |
With hydrogen;5% Pt/Al2O3; (S)-quinoline-4-yl-((2R)-5-ethylidene-1-azabicyclo[2.2.2]oct-2-yl)-methanol; In toluene; under 45004.5 Torr; for 1 - 1.16667h;Product distribution / selectivity; | Examples B61-B71: Hydrogenation of ethyl 4-phenyl-2-oxobutyrate[0056] The procedure of Example B1 is followed using ethyl 4-phenyl-2-oxobutyrate. The results are reported in Table 6. | |
With hydrogen;5% Pt/Al2O3; (S)-quinoline-4-yl-((2R)-5-ethylidene-1-azabicyclo[2.2.2]oct-2-yl)-methanol; In acetic acid; at 25℃; under 45004.5 Torr; for 1 - 1.5h;Product distribution / selectivity; | Examples B74-B75 and comparative example: Hydrogenation of ethyl 4-phenyl-2,4-dioxobutyrate[0059] The procedure is the same as in Example B72. The conversion is determined by gas chromatography. The results are reported in Table 9. | |
With hydrogen;5% Pt/Al2O3; (S)-((2R)-5-ethylidene-1-azabicyclo[2.2.2]oct-2-yl)-(6-methoxy-quinoline-4-yl)-methanol; In toluene; under 45004.5 Torr; for 1 - 1.16667h;Product distribution / selectivity; | Examples B61-B71: Hydrogenation of ethyl 4-phenyl-2-oxobutyrate[0056] The procedure of Example B1 is followed using ethyl 4-phenyl-2-oxobutyrate. The results are reported in Table 6. | |
With hydrogen;5% Pt/Al2O3; erythro-(1S,2R)-(+)-(1-azabicyclo[2.2.2]oct-2-yl)-naphthalene-1-yl-methanol; In toluene; under 45004.5 Torr; for 1 - 1.16667h;Product distribution / selectivity; | Examples B61-B71: Hydrogenation of ethyl 4-phenyl-2-oxobutyrate[0056] The procedure of Example B1 is followed using ethyl 4-phenyl-2-oxobutyrate. The results are reported in Table 6. | |
With hydrogen;5% Pt/Al2O3; (2R,1'S)-2-[1-hydroxy-1-(quinolin-4-yl)]methyl-1-azabicyclo[2.2.2]octane; In toluene; under 45004.5 Torr; for 1 - 1.16667h;Product distribution / selectivity; | Examples B61-B71: Hydrogenation of ethyl 4-phenyl-2-oxobutyrate[0056] The procedure of Example B1 is followed using ethyl 4-phenyl-2-oxobutyrate. The results are reported in Table 6. | |
With hydrogen;5% Pt/Al2O3; (2R,1'S)-2-[1-hydroxy-1-(quinolin-4-yl)]methyl-1-azabicyclo[2.2.2]octane; In acetic acid; under 45004.5 Torr; for 1 - 1.16667h;Product distribution / selectivity; | Examples B61-B71: Hydrogenation of ethyl 4-phenyl-2-oxobutyrate[0056] The procedure of Example B1 is followed using ethyl 4-phenyl-2-oxobutyrate. The results are reported in Table 6. | |
With hydrogen; acetic acid; cinchonidine; at 20℃; under 37503.8 Torr; for 1h;Autoclave; | General procedure: The catalytic performance of Pt/15AM-SF-T for asymmetric hydrogenation of EOPB to (R)-(+)-ethyl 2-hydroxy-4-phenylbutyrate ((R)-(+)-EHPB) were evaluated in a 100 mL stainless-steel stirred pressure reactor at room temperature. Pt/15AM catalyst (100 mg), CD (10 mg), ethyl pyruvate (2 mL) or EOPB (1 mL), solvent (25 mL) and H2(5 MPa) were used for the reaction. The reaction was terminated after a while and then the products were analyzed by gas chromatography (Agilent 6890) equipped with capillary chiral column (CP-ChiraSil-DEX CB 25 m × 0.25 mm × 0.25 m, Agilent). The optical yield was expressed as ee value: ee (%) = ([R] - [S])/([R] + [S]) × 100. After the reaction, the catalyst was separated and washed with fresh acetic acid. Fresh reactant, CD and acetic acid were added to the reactor together with the recovered catalyst to carry out the next cycle reaction. | |
With Pt/Al2O3; hydrogen; cinchonidine; In acetic acid; at 20℃; under 37503.8 Torr; for 1h;Catalytic behavior; | The catalytic properties of Pt/xAMcatalysts for asymmetric hydrogenation of EOPB to (R)-(+)-ethyl 2-hydroxy-4-phenylbutyrate ((R)-(+)-EHPB) were evaluated in a 100-mL stainless-steel stirred pressure reactor at room temperature. Based on some precedents, about 10 wt% cinchonidine (CD, relative to the Pt supported catalyst) was the optimal concentration for the Pt/Al2O3 [21] and Pt/mesoporous carbon [22] in the asymmetric hydrogenation of EOPB. Herein, we used the same concentration of CD for the Pt/xAM catalysts. Typically, 0.1 g of catalyst, 10 mg of CD, 1 mL of EOPB, 25 mL of solvent, 5 MPa of H2 and a stirring speed of 700 rpm were used for the reaction. The reaction was terminated after 1 h and then the products were analyzed by gas chromatography (Agilent 6890) equipped with capillary chiral column (CP-ChiraSil-DEX CB 25×0.25 Agilent). The pure (R)-(+)-EHPB was used as the marker, and external standard method was used for identifying the major product. The optical yield was expressed as ee value: ee (%) = ([R] - [S]) / ([R] + [S]) × 100. After the reaction, the catalyst was separated and washed with fresh acetic acid. Fresh reactant, CD and acetic acid were added to the reactor together with the recovered catalyst to carry out the next cycle reaction. | |
With tetraethylammonium iodide; water; Cinchonidin; In acetonitrile;Electrochemical reaction; | General procedure: The synthesis of Cu (Pt) NPs was performed as follows. 5 g of CuSO4*5H2O (2.07 g H2PtCl6*6H2O) was dissolved in 100 mL deionized water. 8 mL of ethylene glycol was then added into the solution. After 10 min of stirring, 50 mL of hydrazine hydrate solution (10%) was slowly added. The mixture was then stirred at 25 C for 4 h. Cu (Pt) was precipitated immediately. The precipitate was filtered, washed with 10 mL water and 10 mL anhydrous ethanol for 4 times each, and dried for 12 h under vacuum. The electrohydrogenation procedure is as follows. Cu NP powder was pressed into a coin and used as a cathode. Typical galvanostatic electrohydrogenation was conducted in a mixture of 50mM substrate, certain concentration of alkaloid and 0.1M tetraethylammonium iodide (TEAI) in a 20mL co-solvent (MeCN/H2O=9/1) in an undivided glass cell with a Cu NP cathode and sacrificial magnesium (Mg) anode. | |
With D-glucose; nicotinamide adenine dinucleotide phosphate; recombinant Bacillus subtilis-derived glucose dehydrogenase; recombinant Gluconobacter oxydans carbonyl reductase 1462; In aq. phosphate buffer; ethanol; at 30℃; for 12h;pH 7.0;Enzymatic reaction;Kinetics; | General procedure: The enzyme activity toward the reduction ofketones was determined by spectrophotometricallymeasuring the oxidation of NAD(P)H at 340 nm(epsilon = 6.22mM-1 cm-1) in the presence of an excess amount of ketones. The change in absorbance of NAD(P)H was monitored at 340 nm using an ultraviolet-visiblespectrophotometer with a temperature-controlledcuvette holder (Shimadzu Co., Kyoto, Japan). One unit(U) activity was defined as the amount of enzymesrequired to catalyze the oxidation of 1 mumol NAD(P)Hper minute at 30 C. The data were expressed as U/mgof protein. The standard reaction mixture contained100mM phosphate buffer (pH 7.0), 0.1mM NAD(P)H,5 mM substrate, and enzyme solvent in a total volumeof 1 mL. The reaction was initiated by adding 20 muLsolvent containing 10 mug-40 mug of enzymes. Blankswithout the enzyme were carried out for each substrate,and data were collected in triplicate. Protein concentrationswere determined with the bicinchoninic acid assayusing bovine serum albumin as a standard.NAD(P)H or NADH was assayed under standardreaction conditions for the study of coenzyme dependence.A range of substrates from 1 to 20 mM concentrationwas assayed under the standard reactionconditions for the study of kinetics. Apparent values ofMichaelis constant (Km) and kcat were calculated by fittingthe data into Michaelis-Menten equation using theSigmaPlot (Systat Software Inc., San Jose, CA, USA).All reactions followed Michaelis-Menten-type kinetics.Enantioselective reduction of ketones. The enantioselectivityof the enzymes was determined byexamining the reduction of aryl ketones, ethyl 4-chloroacetoacetate(COBE), and ethyl 2-oxo-4-phenylbutyrate(OPBE) using an NAD(P)H regeneration system consistingof BsGDH and glucose. The general procedurewas as follows: D-glucose (0.5%), recombinant BsGDH(10 U), NAD(P)+ (0.1 mM), the recombinant cell(30 g L-1, wet weight), and ketone solvated in ethanol[1 g L-1, 10%(v/v)] were mixed in a potassium phosphatebuffer (10 mL, 100 mM, pH 7.0). The mixturewas shaken at 30 C for 12 h.22) Upon termination ofthe reaction, each sample was extracted twice withequivalent ethyl acetate. The organic layer wasremoved, dried, diluted in the mobile phase, and thensubjected to chiral high-performance liquid chromatography(HPLC) to determine the conversion and enantiomericexcess (e.e.). Chiral HPLC analysis wasperformed on an Agilent 1100 series HPLC system witha UV detector.23) Chiral CHBE was analyzed on a chiracelOB-H column (Daicel, Japan) at lambda210 nm using hexane/2-propanol (90/10, v/v) as eluent at a flow rate of0.8 mL min-1 and a temperature of 25 C. Chiral HPBEand 4-phenyl-2-butanol were analyzed on a chiracelOD-H column at lambda210 nm and lambda254 nm using hexane/2-propanol (98/2, v/v) as eluent at a flow rate of 1.0 mLmin-1 and a temperature of 30 C. Authentic (relevant)standards were used for peak identification, and quantificationwas based on the peak area that was suitablycalibrated with standards of known concentration. | |
With D-glucose; nicotinamide adenine dinucleotide phosphate; recombinant Bacillus subtilis-derived glucose dehydrogenase; recombinant Gluconobacter oxydans carbonyl reductase 1598; In aq. phosphate buffer; ethanol; at 30℃; for 12h;pH 7.0;Enzymatic reaction;Kinetics; | General procedure: The enzyme activity toward the reduction ofketones was determined by spectrophotometricallymeasuring the oxidation of NAD(P)H at 340 nm(epsilon = 6.22mM-1 cm-1) in the presence of an excess amount of ketones. The change in absorbance of NAD(P)H was monitored at 340 nm using an ultraviolet-visiblespectrophotometer with a temperature-controlledcuvette holder (Shimadzu Co., Kyoto, Japan). One unit(U) activity was defined as the amount of enzymesrequired to catalyze the oxidation of 1 mumol NAD(P)Hper minute at 30 C. The data were expressed as U/mgof protein. The standard reaction mixture contained100mM phosphate buffer (pH 7.0), 0.1mM NAD(P)H,5 mM substrate, and enzyme solvent in a total volumeof 1 mL. The reaction was initiated by adding 20 muLsolvent containing 10 mug-40 mug of enzymes. Blankswithout the enzyme were carried out for each substrate,and data were collected in triplicate. Protein concentrationswere determined with the bicinchoninic acid assayusing bovine serum albumin as a standard.NAD(P)H or NADH was assayed under standardreaction conditions for the study of coenzyme dependence.A range of substrates from 1 to 20 mM concentrationwas assayed under the standard reactionconditions for the study of kinetics. Apparent values ofMichaelis constant (Km) and kcat were calculated by fittingthe data into Michaelis-Menten equation using theSigmaPlot (Systat Software Inc., San Jose, CA, USA).All reactions followed Michaelis-Menten-type kinetics.Enantioselective reduction of ketones. The enantioselectivityof the enzymes was determined byexamining the reduction of aryl ketones, ethyl 4-chloroacetoacetate(COBE), and ethyl 2-oxo-4-phenylbutyrate(OPBE) using an NAD(P)H regeneration system consistingof BsGDH and glucose. The general procedurewas as follows: D-glucose (0.5%), recombinant BsGDH(10 U), NAD(P)+ (0.1 mM), the recombinant cell(30 g L-1, wet weight), and ketone solvated in ethanol[1 g L-1, 10%(v/v)] were mixed in a potassium phosphatebuffer (10 mL, 100 mM, pH 7.0). The mixturewas shaken at 30 C for 12 h.22) Upon termination ofthe reaction, each sample was extracted twice withequivalent ethyl acetate. The organic layer wasremoved, dried, diluted in the mobile phase, and thensubjected to chiral high-performance liquid chromatography(HPLC) to determine the conversion and enantiomericexcess (e.e.). Chiral HPLC analysis wasperformed on an Agilent 1100 series HPLC system witha UV detector.23) Chiral CHBE was analyzed on a chiracelOB-H column (Daicel, Japan) at lambda210 nm using hexane/2-propanol (90/10, v/v) as eluent at a flow rate of0.8 mL min-1 and a temperature of 25 C. Chiral HPBEand 4-phenyl-2-butanol were analyzed on a chiracelOD-H column at lambda210 nm and lambda254 nm using hexane/2-propanol (98/2, v/v) as eluent at a flow rate of 1.0 mLmin-1 and a temperature of 30 C. Authentic (relevant)standards were used for peak identification, and quantificationwas based on the peak area that was suitablycalibrated with standards of known concentration. | |
With alcohol dehydrogenase TbSADH from Thermoanaerobacter brockii W110E mutant; In aq. phosphate buffer; isopropyl alcohol; at 30℃;Enzymatic reaction; | General procedure: A test tube (10 mL)containing LB (4 mL) and kanamycin (50 mug/mL) was inoculated with mutant SZ2074 and incubated 8h (37C, 220 rpm). The pre-culture was then inoculated intoTB (400 mL) containing kanamycin (50 mug/mL) and allowed to grow at 37C until O.D.was ca. 0.6. IPTG was then added to a final concentration of 0.2 mM and theculture was grown for 16 h (30C, 180 rpm). Cells were pelleted bycentrifugation, washed once with pH=7.4 potassium phosphate buffer (100 mM) andthen resuspended in pH=7.4 potassium phosphate buffer (45 mL, 100 mM). Cellswere then transferred to a 50 mL Erlenmeyer flask and 1.4 mg/mL lysozyme (70mg), 6U DNase I (50 muL), NADP+ 100mM (200 muL) were added. Substrate 3a (30 mM) in 10% isopropanol (5 mL)was then added. Biotransformation was carried out at 30C, 220rpm. GC controlindicated a 92% conversion after 4h. The reaction was stopped after 6h when theconversion was 94%. The organic phase was extracted with ethyl acetate (3x100mL) and crude reaction product was purified using column chromatography. (EA:PE1:4, Rf=0.55) afforded (R)-4a as a colourless liquid (157 mg,yield=75%). | |
With alcohol dehydrogenase TbSADH from Thermoanaerobacter brockii wild type; In aq. phosphate buffer; isopropyl alcohol; at 30℃;Enzymatic reaction; | General procedure: A test tube (10 mL)containing LB (4 mL) and kanamycin (50 mug/mL) was inoculated with mutant SZ2074 and incubated 8h (37C, 220 rpm). The pre-culture was then inoculated intoTB (400 mL) containing kanamycin (50 mug/mL) and allowed to grow at 37C until O.D.was ca. 0.6. IPTG was then added to a final concentration of 0.2 mM and theculture was grown for 16 h (30C, 180 rpm). Cells were pelleted bycentrifugation, washed once with pH=7.4 potassium phosphate buffer (100 mM) andthen resuspended in pH=7.4 potassium phosphate buffer (45 mL, 100 mM). Cellswere then transferred to a 50 mL Erlenmeyer flask and 1.4 mg/mL lysozyme (70mg), 6U DNase I (50 muL), NADP+ 100mM (200 muL) were added. Substrate 3a (30 mM) in 10% isopropanol (5 mL)was then added. Biotransformation was carried out at 30C, 220rpm. GC controlindicated a 92% conversion after 4h. The reaction was stopped after 6h when theconversion was 94%. The organic phase was extracted with ethyl acetate (3x100mL) and crude reaction product was purified using column chromatography. (EA:PE1:4, Rf=0.55) afforded (R)-4a as a colourless liquid (157 mg,yield=75%). | |
With tetraethylammonium iodide; water; In acetonitrile; at 20℃;Electrochemical reaction; | General procedure: Typical electrochemical hydrogenation was conducted in a mixtureof 50 mM substrate, 0.1 M tetraethylammonium iodide (TEAI) in a20 mL co-solvent (MeCN/H2O = 9/1) in an undivided glass cell withan alkaloidCu cathode and sacrificialmagnesium(Mg) anode. The currentdensitywas 10mAcm-2 and the chargewas 300 C. The electrolytewas bubbled with high purity N2 throughout the electrolysis. All theprocedure was performed at room temperature. | |
With Kluyveromyces polysporus alcohol dehydrogenase S237Y mutant; isopropyl alcohol; NADPH; In aq. phosphate buffer; at 30℃;pH 7.0;Enzymatic reaction; | General procedure: Bioconversion was conducted with 20 mM 1a-10a,20 U·mL-1KpADH variants, 40 mM isopropanol in PBS buffer (pH 7.0,100 mM) in total volume of 2 mL at 30 C and 180 rpm overnight. Then,1 mL of the reaction mixture was withdrawn and extracted with ethylacetate. The organic phase was isolated by centrifugation and driedover anhydrous MgSO4. The conversion rate and enantioselectivity ofthe products were analyzed as described in supporting information. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With triethylamine In acetonitrile at 20℃; for 4h; Inert atmosphere; | |
With triethylamine In tetrahydrofuran for 3.5h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With 4 A molecular sieve; hydrogen In benzene at 100℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With copper(ll) bromide In chloroform; ethyl acetate for 6h; Reflux; | 1.A Example 1(5 -N-((R)-l-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-diniethylpropyl)-N- (((3S,4 f)-4-fluoropyrr -hydroxypropanaroideStep A: a-Bromination of Ethyl 2-oxo-4-phenylbutanoate[00138] To a solution of ethyl 2-oxo-4-phenylbutanoate (10 g, 48.5 mmol) in EtOAc (323 mL) and CHC13 (162 mL) was added copper(Il) bromide (32.5 g, 145 mmol). The reaction mixture was refluxed for 6 h. After cooled down, the reaction mixture was filtered through silica gel, washed with EtOAc, and concentrated. The crude product was purified by column chromatography to yield ethyl 3-bromo-2-oxo-4-phenylbutanoate (15.0 g, >99%) as light yellow oil. NMR (CDC13, 400 MHz): 6 7.42-7.28 (2H, m), 7.28-7.19 (3H, m), 5.27 (IH, m), 4.35 (2H, m), 3.54 (IH, m), 3.25 (IH, m), 1.37 (3H, m). LC/MS (uplc): MH+ 269.1 (-18), 0.79 mia |
97% | With bromine In tetrachloromethane; chloroform | |
95% | With bromine In tetrachloromethane; chloroform at 20℃; for 1h; |
89% | With copper(ll) bromide In chloroform; ethyl acetate for 18h; Heating; | |
87% | With bromine In chloroform at 20℃; for 1h; | |
84% | With copper(ll) bromide In chloroform; ethyl acetate for 13h; Reflux; | 19 5.1.19 Ethyl 3-bromo-4-[4-(methylthio)phenyl]-2-oxobutanoate (28a) General procedure: To a suspension of copper(II) bromide (212 g) in AcOEt (1600 mL) was added a solution of 27a (80 g) in 800 mL of CHCl3. The reaction mixture was refluxed for 13 h, cooled to room temperature, and filtered in vacuo. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography over silica gel with hexane/AcOEt (1:1) as an eluent to give 28a (102 g, 97%) as a yellow oil. |
With copper(ll) bromide In chloroform; ethyl acetate at 20℃; for 23h; | 3.1 Production Example 3; Synthesis of N-{4-[2-(4-[amino(imino)methyl]aminoJphenyl)ethyl]-5-[4-(aminosulfonyl)benzyl]-1,3-thiazol-2-yl}acetamidehydrochloride; Step 1; To a suspension of copper (II) bromide (9.75 g) in AcOEt(150 ml) was added a solution of ethyl 2-oxo-4-phenylbutanoate(3 g) in 75 ml of CHCla. The reaction mixture was refluxed for23 hours, cooled to r.t., and filtered through a short pad ofsilica gel eluting with AcOEt / n-hexane (1:1). The solventwas removed in 'vacua to give ethyl 3-bromo-2-oxo-4-phenylbutanoate (4.2g) as a yellow liquid. | |
With copper(ll) bromide In chloroform; ethyl acetate for 23h; Heating / reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With rac-1',2',3',4'-tetrahydro-1,1'-bisisoquinoline In tetrahydrofuran at 20℃; for 24h; | Ethyl 2-Hydroxy-2-(nitromethyl)-4-phenylbutanoate (6c)7i,8c,11a General procedure: Henry Reaction; General ProcedureMeNO2 (5, 205 μL, 4 mmol, 20 equiv) was added to a solution of1-3 (0.02 mmol, 10 mol%) in THF (1.5 mL) and the mixture wasstirred for 5 min before dropwise addition of α-keto ester/aldehyde4 (0.2 mmol). The mixture was further stirred at r.t. for the specifictime (TLC). The β-nitro alcohol product was purified by flash columnchromatography (silica gel); Purified by column chromatography (hexane-EtOAc, 5:1) to givethe product (0.053 g, 90%) as a colorless oil.1H NMR (300 MHz, CDCl3): δ = 1.36 (t, J = 7.2 Hz, 3 H), 1.98-2.06(m, 2 H), 2.52-2.56 (m, 1 H), 2.83-2.87 (m, 1 H), 3.96 (s, 1 H),4.32-4.39 (m, 2 H), 4.61 (d, J = 13.6 Hz, 1 H), 4.86 (d, J = 13.5 Hz,1 H), 7.18-7.35 (m, 5 H).13C NMR (75.6 MHz, CDCl3): δ = 14.1, 29.0, 38.2, 63.2, 75.0, 80.8,126.4, 128.3, 128.6, 140.2, 172.6. |
With copper(II) bis(trifluoromethanesulfonate); 2,2'-isopropylidenebis[(4S)-4-tert-butyl-2-oxazoline]; triethylamine at 50℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-oxo-4-phenylbutanoic acid ethyl ester With 1,3-propanedithiol copolymer; boron trifluoride diethyl etherate In chloroform at 0℃; for 10h; Stage #2: With 2,2'-azobis(isobutyronitrile); tri-n-butyl-tin hydride In toluene at 105℃; for 2.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In toluene for 18h; Heating; | |
95% | In toluene for 18h; Heating / reflux; | 1 2-ethoxycarbonyl-2-phenylethyl-1,2,3,4-tetrahydroquinazoline 2-Ethoxycarbonyl-2-phenylethyl-1,2,3,4-tetrahydroquinazoline A solution of 2-aminobenzylamine (2.4 g, 20 mmol), and ethyl 2-oxo-4-phenylbutanoate in toluene was heated at reflux using a Dean-Stark apparatus to remove water for 18 h. The solvent was removed to give Compound A as a brown oil (6 g, 95%). 1H NMR (CDCl3) δ1.20 (m, 3H), 2.10 (m, 2H), 2.33 (m, 1H), 2.40 (m, 1H), 4.00 (dd, 2H), 4.70 (m, 2H), 6.60 (d, 1H), 6.75 (t, 1H), 6.90 (m, 1H), 7.05 (t, 1H), 7.15-7.35 (m, 5H). |
In toluene at 130℃; for 18h; |
In toluene at 130℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen at 20℃; for 72h; Title compound not separated from byproducts; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With water; sodium cyanoborohydride; In ethanol; at 20℃; for 12h; | EXAMPLE 1 (0066) Changes in Vasoactive Peptide Levels Induced by Combined ACE C-domain / NEP Inhibition Ex Vivo in Human Plasma (0067) Synthesis of the ACE C-Domain-Selecthte Inhibitor Lis-Trp. (0068) Lisinopril, which is one of the commercially available ACE inhibitors, is active with a nanomolar inhibition constant, and has been shown to be relatively safe in the treatment of patients with hypertension and acute myocardial infarction. It is therefore mostly used as the first-line treatment for hypertension and heart-related diseases. The phosphinic ACE inhibitor, RXP A380, is -3,000-fold C-domain-seective and one key feature of the C-domain selectivity is the tryptophan moiety in the P2' position. (0069) The synthesis of lisinopril incorporating a tryptophan moiety at the P2" position (Lis- Trp) was carried out as follows: The starting diastereomeric material 1 was prepared by the reductive amination of ethyl 2-oxo-4-phenyl butyrate and Nu-epsilon-(/beta/- butoxycarbonyl)-L-lysine using and ethanolic solution of NaBH3CN. The ratio of the two diastereoisomers was observed as 55:45 from the NMR spectrum. Peptide coupling of the compound 1 with the L-tryptophan methyl ester 2 (prepared earlier by methylation of tryptophan in the presence of thionyl chloride and methanol according to the method described by Hvidt et a/.) was effected using EDC.HCI in the presence of HOBt and diisopropyl ethyl amine as a base to afford the diastereomeric pseudopeptide 3 in 74% yield. The characterisation of this diastereomeric mixture 3 was achieved from the EI-MS and spectroscopic data, the EI-MS data indicated a molecular ion peak at 637 corresponding to M++H. The *H NMR spectrum showed two singlets at delta 3.71 and 3.73 ppm corresponding to the two methoxy groups of the diastereomeric mixture 3. Acid hydrolysis of the resulting diastereomeric mixture 3 produces the hydrochloride salt of the diastereomeric mixture 4 in a quantitative yield. Evidence of the compound 4 was found from the disappearance of the Boc, methyl and ethyl signals on the 'H NMR spectrum. Purification and separation of the diastereomeric mixture 4 was done by HPLC. (0070) Initial attempts to remove the Boc group and concomitant hydrolysis of the ethyl and methyl esters under acid conditions at room temperature afforded a mixture of four products after HPLC separation and purification. These four products, Pi, P2, P3 and P4, were as a result of incomplete hydrolysis of compound 3, since acid hydrolysis of esters at room temperature is relatively slow. The EI-MS data indicated molecular ion peaks at 522, 522, 536 and 536 for Pt, P2, P3 and P4, respectively. However, the diastereomeric mixture 3 was stirred in AN HCI at room temperature for 24 h, after which the solvent was evaporated and then the mixture stirred with a solution of 0.5N LiOH for a further 5 h to afford the desired product 4. (0071) The characterisation of this diastereomeric mixture 4 was achieved from the EI-MS and spectroscopic data, and the EI-MS data indicated a molecular ion peak at 495 corresponding to M++H. Purification and separation of the diastereomeric mixture 4 by HPLC gave the required two diastereoisomers in a 60:40 ratio. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In dichloromethane at 0℃; | |
89% | With triethylamine In dichloromethane at 0℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: 2-oxo-4-phenylbutanoic acid ethyl ester; 4-methoxy-aniline With (S)-(+)-2,2'-diphenyl-4-biphenanthrol hydrogen phosphate; 4 A molecular sieve; diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate In toluene at 50℃; for 19h; Stage #2: With lithium aluminium tetrahydride In tetrahydrofuran for 23h; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With johnphos In tetrahydrofuran at 40℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 41 percent / xylene 2: 82 percent / 1-n-propyl-1,4-dihydronicotinamide (PNAH, 4) / Mg(ClO4)2 / acetonitrile / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.1% | With hydrogenchloride; sodium hypochlorite;tetrabutylammomium bromide; In water; at 0 - 40℃;Product distribution / selectivity; | A. putting LHPE, HCl into four-neck distilling flask and adding 4% TBAB, 5% HCl, and a certain amount of EA;_B. reducing the temperature to 0 degree Celsius;_ C. adding NaOCl slowly; _ D. increasing the temperature to room temperature;_ E. heating the bottle till 40 degrees Celsius and tracking the end point of the reaction; _ F. reducing the temperature and taking the organic layer of the result combination and removing water and evaporating out the EA; _ G. evaporating the final product under 125-135 degrees Celsius and pressure of 2 mm-Hg, and;_ H. obtaining EOPB1 with the production rate of 84.1% by the above mentioned steps. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With triethylammonium dihydrofluoride; N-(difluoro-λ4-sulfanylidene)-N-ethylethanaminium tetrafluoroborate In dichloromethane at 20℃; for 24h; Inert atmosphere; | |
94% | With (diethylamino)sulfur trifluoride | 138 2,2-Difluoro-4-phenyl-butyric acid ethyl ester EXAMPLE 138 2,2-Difluoro-4-phenyl-butyric acid ethyl ester Ethyl 2-oxo-4-phenylbutyrate (1 g, 4.7 mmol) was treated with (diethylamino)sulfur trifluoride (1.3 ml, 9.4 mmol). After 2 hours stirring at room temperature, the reaction mixture was poured on H2O-ice. The aqueous phase was extracted with CH2Cl2 (2 times). The combined organic phases were washed with H2O, dried over Na2SO4, filtered and the solvent was removed in vacuo. The residue was distilled to provide 2,2-difluoro-4-phenyl-butyric acid ethyl ester (1.0 g, 94%) as yellow oil, MS: m/e=228.1 (M+), b.p.: 90° C., 0.2 mbar. Ethyl 2-oxo-4-phenylbutyrate is a commercially available compound. |
91% | With diethylamino-sulfur trifluoride In dichloromethane at 20℃; | 1 Intermediate 1. Ethyl 2,2-difluoro-4-phenylbutanoate; To a cooled solution of ethyl 2-oxo-4-phenylbutanoate (1.0 g, 4.85 mmol) in methylene chloride (10 mL) was added DAST (1.6 ml, 12.1 mmol). The mixture was stirred at room temperature overnight. The crude reaction was diluted with methylene chloride (10 mL), washed with saturated solution of sodium bicarbonate (2 x 10 mL) and water (10 mL), dried (Na2SO4), and the solvent removed under reduced pressure. The title compound was obtained as brown oil (1.02 g, 91%). |
62% | With diethylaminosulfur trifluoride In trichlorofluoromethane | 7.A A. A. Ethyl 2,2-difluoro-4-phenyl butanoate A solution of 14.5 g (70 mmol) of ethyl 2-oxo-4-phenyl butanoate in 25 mL of trichlorofluoromethane cooled to 0° C. is treated with 11.5 mL of diethylaminosulfur trifluoride. The mixture is allowed to warm to room temperature and is stirred overnight. The mixture is cooled to 0° C. and is quenched cautiously with aqueous saturated sodium bicarbonate. The phases are separated and the organic phase is washed with saturated aqueous sodium bicarbonate and then with saturated brine. The ethereal extract is dried over magnesium sulfate, filtered and evaporated. The obtained residue is subjected to HPLC to give 10.2 g of the title compound (62%): IR (film) 1770 cm-1. Analysis for: C12 H14 F2 O2: Calculated: C, 63.15; H, 6.18; Found: C, 63.27; H, 6.27. |
59% | With diethylamino-sulfur trifluoride In dichloromethane at 0 - 25℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With hydrogenchloride; sulfuric acid; phenylhydrazine In ethanol | 103.A Ethyl 3-benzyl-1H-indole-2-carboxylate EXAMPLE 103A Ethyl 3-benzyl-1H-indole-2-carboxylate Ethyl 2-oxo-4-phenylbutyrate (5 g, 24.3 mmol) at room temperature was treated with phenylhydrazine (2.38 mL, 24.3 mmol) and concentrated H2SO4 (3 drops), heated to 120° C. for 30 minutes, cooled to toom temperature, treated with ethanol (30 mL) and HCl gas, heated to 85-90° C. for 1 hour, and extracted with ethyl acetate. The combined extracts were washed with water, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by recrystallization from ethanol/ethyl acetate to provide the desired product (4.57 g, 67%). MS (ESI) m/e 280 (M+H)+, 297 (M+NH4)+, 278 (M-H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With acetic anhydride In ethyl acetate; N,N-dimethyl-formamide | A A. A. 2-Oxo-3-phenylmethyl-but-3-enoic acid, ethyl ester A solution of ethyl-2-oxo-4-phenylbutyrate (31.8 mmol, 6.0 mL), N,N,N',N'-tetramethyldiaminomethane (6.6 mL, 54 mmol) and acetic anhydride (10 mL, 106 mmol) in DMF (100 mL) was stirred at room temperature for 16 hours and evaporated. The residue was chromatographed (flash silica, 20% EtOAc/Hexanes) to afford Compound A as a clear oil (6.46 g, 93%). MS (M+NH4)+ 236. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; In methanol; cyclohexane; | EXAMPLE 11 Nalpha-[(S)- 1-ethoxycarbonyl-3-phenylpropyl]-L-alanine 250 mmoles L-alanine benzyl ester p-toluene sulfonic acid salt (88 g) and 312.5 mmoles 2-oxo-4-phenyl butyric acid ethyl ester (65 g) were suspended in 500 ml cyclohexane. After the addition of 250 mmoles N-methylmorpholine (25.3 g), water was removed by azeotropic distillation until the end of the reaction. After the mixture had cooled, it was filtered to remove salts, evaporated to low volume and taken up in 400 ml anhydrous methanol. After the addition of 25 mmoles N-methylmorpholine (1 g) and 3 teaspoons anhydrous Raney nickel, the mixture was hydrogenated at 4 bars excess hydrogen pressure and room temperature until the adsorption of hydrogen stopped. The reaction mixture was filtered from the catalyst, post-washed with warm methanol and evaporated to low volume. The residue was partitioned at 5 C. and pH 9.6 between water and 1,1,1-trichloroethane. The aqueous phase was subsequently extracted at pH 3 and 5 C. with 1,1,1-trichloroethane and the organic phase evaporated to low volume. The residue was crystallized from ethanol or acetone while cold. Yield: 1st fraction: 35 g; 2nd fraction: 12 g Melting point: 143-145 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium cyanoborohydride; triethylamine In ethanol; water | 2 Enalapril SSR EXAMPLE 2 Enalapril SSR In a 50 ml round bottom flask, ethyl-2-oxo-4-phenylbutyrate (0.28 g) and L-alanyl-D-proline TFA salt (6.3 mg) were dissolved in 20 ml ethanol/water (1:1). With constant stirring and nitrogen protection, triethylamine (0.037 ml) was added to the solution and immediately after, a solution of sodium cyanoborohydride (26 mg) in 3 ml ethanol/water (1:1) was added dropwise through a syringe. The resulting mixture was stirred at room temperature for overnight, and absorbed on Dowex 2*50 W strong acid ion exchange resin. The resin was then washed with water followed by 100 ml 2% aqueous pyridine. First fraction was discarded and the rest were combined Finally, lyophilization of the combined fractions afforded enalapril SSR as a white powder. Mass spectrum: 377 (M+H), 234 (fragmentation ion). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
sodium cyanoborohydride; | EXAMPLE 12 1-Carboxymethyl-3S-(1S-ethoxycarbonyl-3-phenylpropylamino)2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one 3(S)-Amino-1-carboxymethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one when treated with ethyl benzylpyruvate in the presence of sodium cyanoborohydride by the procedure described in example 1 for the racemic compound gave after purification 1-carboxymethyl-3S-(1S-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one, as described below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; sodium cyanoborohydride In methanol; dichloromethane; acetic acid; butanone | 12 1-Carboxymethyl-3S-(1S-ethoxycarbonyl-3-phenylpropylamino)2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one A solution of the above sodium salt (12.9 g) and ethyl benzylpyruvate (31 g) in acetic acid (100 ml) and methanol (75 ml) was stirrred at room temperature under a dry nitrogen atmosphere for one hour. A solution of sodium cyanoborohydride (3.8 g) in methanol (30 ml) was then added dropwise over a 4 hour period. The combined solutions were stirred overnight at room temperature. Concentrated hydrochloric acid (10 ml) was added dropwise and the mixture stirred at room temperature for 1 hour followed by the evaporation of solvents. The residue was partitioned between water (400 ml) and ether (100 ml) and the pH adjusted to 9.3 with 40% sodium hydroxide. The layers were separated and the ether layer discarded. The aqueous layer was adjusted to pH 4.3 with concentrated hydrochloric acid and extracted with ethyl acetate (3*100 ml). The organic phases were combined, dried (magnesium sulfate), and evaporated. Hydrogen chloride gas was bubbled through a solution of the crude product in methylene chloride (150 ml) for 5 minutes. The solvent was evaporated and the resulting foam was dissolved in hot methyl ethyl ketone (100 ml). The solid which precipitated was collected by filtration to give a 95:5 diastereomeric mixture as determined by high pressure liquid chromatography. The product was recrystallized from 3-pentanone/methanol (10:1) to give 1-carboxymethyl-3S-(1S-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one hydrochloride, m.p. 188°-190°, [α]D =-141.0° (c=0.9 in ethanol), of formula Ic wherein Cn H2n is ethylene, R6 is ethoxy, R7 is hydroxy and R8 is phenyl. | |
With hydrogenchloride; sodium cyanoborohydride In methanol; dichloromethane; acetic acid; butanone | 12 1-Carboxymethyl-3S-(1S-ethoxycarbonyl-3-phenylpropylamino)2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one A solution of the above sodium salt (12.9 g) and ethyl benzylpyruvate (31 g) in acetic acid (100 ml) and methanol (75 ml) was stirred at room temperature under a dry nitrogen atmosphere for one hour. A solution of sodium cyanoborohydride (3.8 g) in methanol (30 ml) was then added dropwise over a 4 hour period. The combined solutions were stirred overnight at room temperature. Concentrated hydrochloric acid (10 ml) was added dropwise and the mixture stirred at room temperature for 1 hour followed by the evaporation of solvents. The residue was partitioned between water (400 ml) and ether (100 ml) and the pH adjusted to 9.3 with 40% sodium hydroxide. The layers were separated and the ether layer discarded. The aqueous layer was adjusted to pH 4.3 with concentrated hydrochloric acid and extracted with ethyl acetate (3*100 ml). The organic phases were combined, dried (magnesium sulfate), and evaporated. Hydrogen chloride gas was bubbled through a solution of the crude product in methylene chloride (150 ml) for 5 minutes. The solvent was evaporated and the resulting foam was dissolved in hot methyl ethyl ketone (100 ml). The solid which precipitated was collected by filtration to give a 95:5 diastereomeric mixture as determined by high pressure liquid chromatography. The product was recrystallized from 3-pentanone/methanol (10:1) to give 1-carboxymethyl-3S-(1S-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one hydrochloride, m.p. 188°-190°, [α]D =141.0° (c=0.9 in ethanol), of formula Ic wherein Cn H2n is ethylene, R6 is ethoxy, R7 is hydroxy and R8 is phenyl. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; hydrogen In CF3 CO2 H; ethyl acetate n-hexane; ethanol; water; sodium hydrogencarbonate | 1.d (S,S)-N-[1-(Ethoxycarbonyl)-3-phenyl-propyl]alanyl-N-phenylglycine Hydrate (I) (d) (S,S)-N-[1-(Ethoxycarbonyl)-3-phenylpropyl]alanyl-N-phenylglycine Hydrate (I). A mixture of 2-oxo-4-phenylbutyric acid ethyl ester, II, (4.8 g; 0.23 mole) and t-butyl N-S-alanyl-N-phenylglycinate (5.0 g; 0.18 mole) in hexane-ethyl acetate (2:1; 45 mL) was stirred at room temperature for 5 hr. A 10% Pd-on-C catalyst (5.0 g) was added under a nitrogen atmosphere and the resulting mixture hydrogenated at atmospheric pressure and room temperature for 48 hr. at which point one equivalent of hydrogen had been absorbed. The catalyst was removed by filtration. The filtrate was concentrated in vacuo and the resulting residue was chromatographed on a silica gel column (600 g of 250-400 mesh silica gel) eluding with hexane-ether (2:1). This chromatographic process was run under medium pressure of 20 to 40 psi and this afforded separation of the R,S- and the S,S-isomers. The isomer eluding first from the column was assigned the R,S-structure and the second product eluted, which was the major product, was assigned the S,S-structure. This isomer was dissolved in CF3 CO2 H (10 mL) and stirred for 2 hr at room temperature. The solution was then concentrated in vacuo and the residue dissolved in saturated NaHCO3 solution. Dowex 50 (40 mL of the acid form) and ethanol (10 mL) were added giving a homogenous suspension which was then poured onto a column of 25 mL of Dowex 50, washed with 100 mL of 50% ethanol, then 100 mL of water, and finally 600 mL of a 2% pyridine in water solution. The pyridine solution eluent was concentrated in vacuo giving 0.84 g of amorphous white solid, m.p. 75°-82° C. [α]D25 =+44.2° (C=1.0, CHCl3). Anal. Calcd. for C23 H28 N2 O5.0.8H2 O: C, 64.72; H, 6.99; N, 6.57. Found: C, 64.41; H, 6.77; N, 7.14. NMR (DMSO-d6): 1.00 (3, d [7.0 Hz]); 1.13 (3, t [7.4 Hz]); 1.16 (2, m); 2.60 (2, m); 3.19 (2, m); 3.99 (2, q [7.4 Hz]); 4.24 (2,s); 7.19 (5, m); 7.36 (5, m). IR (KRr): 700, 1215, 1455, 1495, 1595, 1660, 1735, 2940, 2980, 3440 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium cyanoborohydride;silica gel; In ethanol; | EXAMPLE 41 N-(1-Ethoxycarbonyl-3-Phenylpropyl)-L-Alanyl-L-Proline A solution of <strong>[13485-59-1]L-alanyl-L-proline</strong> (7.7 g) and ethyl 2-oxo-4-phenylbutyrate (42.6 g) in 140 ml of ethanol is stirred with 64 g of powdered molecular sieves at room temperature for 0.5 hr. A solution of sodium cyanoborohydride (2.6 g) in 40 ml ethanol is then added slowly over the course of 6 hours. After filtering off the sieves the reaction mixture is concentrated under vacuum to a small volume. The residue is distributed between CHCl3 and water. The pH is adjusted to 8.5 and the CHCl3 layer is separated and discarded. The aqueous layer is acidified to pH 2.7, and the product is extracted into chloroform. The chloroform extract is dried over Na2 SO4 and concentrated under vacuum to yield 10.4 g of mixed diastereomers. HPLC indicates the major product is the desired N-(1-(S)-ethoxycarbonyl-3-phenylpropyl)-<strong>[13485-59-1]L-alanyl-L-proline</strong>. The nmr spectrum showed aromatic absorption at 7.1delta and diasteromeric methyls as a multiplet centered at 1.3delta. | |
Pd on carbon; silica gel; In ethanol; water; | A. N-(1-Ethoxycarbonyl-3-phenylpropyl)-<strong>[13485-59-1]L-alanyl-L-proline</strong> A mixture of 0.814 g of <strong>[13485-59-1]L-alanyl-L-proline</strong>, 0.206 g of ethyl 2-oxo-4-phenylbutyrate, and 1.6 g of molecular sieves in 10 ml ethanol is hydrogenated at room temperature under 40 pounds pressure with 0.1 g of 10% Pd on carbon as catalyst. After uptake of hydrogen ceases the crude product obtained by filtration and concentration is absorbed on ion exchange resin, (Dowex 50, H+) and eluted with 2% pyridine in water to yield 0.224 g of N-(1-ethoxycarbonyl-3-phenylpropyl)-<strong>[13485-59-1]L-alanyl-L-proline</strong>. HPLC indicates a 55:45 isomer ratio. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium ethanolate; sodium cyanoborohydride; sodium hydrogencarbonate; In ethanol; | (c) N-[1(S)-Ethoxycarbonyl-3-phenylpropyl]-L-alanine, t-butyl ester To a solution of L-alanine, t-butyl ester, hydrochloride (4.86 g., 26.7 mmole) in 35 ml. of absolute ethanol, there is added 4.2 ml. (6.72 mmole) of 1.6 N sodium ethoxide/ethanol. To the resulting milky solution which is approximately pH 7.5, is added a solution of ethyl 2-oxo-4-phenylbutyrate [prepared by treating ethyl 2-hydroxy-4-phenylbutyrate with oxalyl chloride] (27.6 g.,0.135 mmole) in 25 ml. of ethanol followed by 22 g. of powdered 3A molecular sieves. The resulting mixture is stirred at room temperature and during the next 30 minutes a total of 4.8 ml. (7.68 mmole) of 1.6 N sodium ethoxide/ethanol is added to maintain a pH of between 6 and 7. After stirring for an additional 30 minutes, a solution of sodium cyanoborohydride (3.35 g., 53.5 mmole) in 20 ml. of ethanol is added over a period of six hours. After stirring for 40 hours, the mixture is filtered through celite and then evaporated at reduced pressure. The residue is dissolved in 350 ml. of ether and the resulting solution is washed with water (3*100 ml.) and then extracted with 1N hydrochloric acid (3*100 ml.). The hydrochloric acid extracts are combined and washed with ether and basified with 4N sodium hydroxide (70 ml.) followed by 1N sodium bicarbonate. The resulting mixture is extracted with ether (2*350 ml.). The ether fractions are combined, washed with water and brine, and dried (MgSO4). The solvent is removed at reduced pressure to give crude product as a mixture of diastereomers Rf =0.46 (undesired isomer) and 0.36 (desired isomer), silica gel, petroleum ether: ether, 1:1). The crude material is then filtered through a column of silica gel (petroleum ether:ether, 3:1). Chromatography (silica gel, hexane:ethyl acetate, 92:8) yields N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine, t-butyl ester as a colorless oil. Rf =0.36 (silica gel, petroleum ether:ether, 1:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
aluminum nickel; silica gel; In ethanol; acetic acid methyl ester; water; ethyl acetate; | EXAMPLE 2 Synthesis of Enalapril, and Obtainement of the Nitrate Salt in Ethyl Acetate A mixture of ethyl-2-oxo-4-phenylbutyrate (15 g), <strong>[13485-59-1]L-alanyl-L-proline</strong> (9 g), molecular sieves 3 A (40 g) and Raney nickel (10.8 g) in ethanol (300 ml) was hydrogenated at room temperature and at a pressure of about 3 atm. up to the hydrogen is not-consumed any more. After filtration of the undissolved substance (washing well with ethanol, the solvent was evaporated under vacuunm to obtain a mixture of diastereoisomers formed of 85% by the expected product (by HPLC). The obtained product was dissolved in a mixture made up of 200 ml of water and 70 ml of methyl acetate. By keeping the solution under stirring, the pH was adjusted to 8.6 with 50% NaOH. The organic phase was separated and the aqueous phase was thoroughly washed with ethyl acetate (3*50 ml). The aqueous phase was adjusted to pH 4.3 with hydrochloric acid, saturated with sodium chloride and then extracted with ethyl acetate (4*100 ml). After drying with sodium sulphate and evaporating the solvent off under vacuum, the residue was dissolved in ethyl acetate maintaining the reactor in an ice bath, and salified by treating with a stoichiometric amount of concentrated nitric acid. After stirring for two hours, it was cooled, filtered, washed with ethyl acetate and recrystallized from acetonitrile to obtain 12.5 g of nitric salt of the isomer (-), about 99%-pure (by HPLC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium cyanoborohydride; In water; water ethanol; | EXAMPLE 20 N-(2-maleimidoethyl)-(1(S)-Ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-prolinylamide Ethyl 2-oxo-4-phenylbutyrate 1 and <strong>[13485-59-1]L-alanyl-L-proline</strong> 2 are dissolved in a 1:1 ethanol-water solvent as indicated in the schematic below. A solution of sodium cyanoborohydride in ethanol-water is added dropwise at room temperature over the course of two hours. When reaction is complete, the product is absorbed on strong acid ion-exchange resin and eluted with 2% pyridine in water. The product-rich cuts are freeze dried to give crude N-(1-ethoxycarbonyl-3-phenylpropyl)-<strong>[13485-59-1]L-alanyl-L-proline</strong> 4 and the compound is purified by chromatography to yield the desired isomer. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran at 0℃; for 0.333333h; Stage #2: acetone In tetrahydrofuran at -78℃; for 0.5h; Stage #3: 2-oxo-4-phenylbutanoic acid ethyl ester With ammonium chloride; water more than 3 stages; | B.85 (B-85) To a solution of diisopropylamine(11.5ml, 82.1mmol)in tetrahydrofuran(100ml), was added dropwise a n-butyl lithium solution (79.5mmol) under ice-cooling and the mixture was stirred for 20 minutes.. acetone (5.85ml, 79.7mmol) was added dropwise thereto at -78°C and th mixture was stirred for 30 minutes.. A solution of 2-oxo-4-phenylbutanoic acid ethyl ester (15.0g, 72.7mmol) in tetrahydrofuran (50ml) was added dropwise thereto and the mixture was stirred for 1 hour.. An ammonium chloride aqueous solution was added to terminate the reaction, then the mixture was extracted with ethyl acetate.. The extract was washed and dried, and the solvent was evaporated under reduced pressure.. The residue was purified with silica gel column chromatography (n-hexane: ethyl acetate=5:1-2:1) to give 2-hydroxy-4-oxo-2-phenethylpentanoic acid ethyl ester (16.7g, yield: 87%). NMR(CDCl3) δ: 1.29(3H, t, J=7.2Hz), 1.96(2H, m), 2.16(3H, s), 2.49(1H, m), 2.79(1H, m), 2.88(1H, d, J=17.4Hz), 3.07(1H, d, J=17.4Hz), 3.81(1H, brs), 4.23(2H, q, J=7.2Hz), 7.13-7.31(5H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With lithium hydroxide In ethanol for 1h; Cooling with ice; Inert atmosphere; | General procedure for the preparation of 2-oxo-4-arylbutanoic acids 1: General procedure: The solution of ethyl 2-oxo-4-phenylbutyrate (6.0 g, 29 mmol) in EtOH wasdropped into a solution of 0.5 M LiOH (1.5 g, 35 mmol) which cooled in an ice bath,hydrolyzation for an hour. The solid precipitated out was filtered on a Buchner funnelunder suction and washed with chilled EtOH (20 mL) followed by diethyl ether (50 mL)to afford lithium 2-oxo-4-phenylbutyrate as a white solid (4.5 g, 87.0%). The saturatedsolution of the salt at 80 °C was poured into a rapidly stirred solution of hydrochloric acid(1 M), and justified to pH = 2.0, extracted with AcOEt (30 mL x 3), the combinedorganic phase was washed with brine (50 mL x 2), after the organic layer was separated and dried over anhydrous MgSO4. Filtered, the solvent was evaporated, the solid of2-oxo-4-phenylbutanoic acid 1a was obtained, can be used for hydrogenation reactiondirectly without more any purification. |
78% | With lithium hydroxide In methanol; water for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: 2-oxo-4-phenylbutanoic acid ethyl ester With benzoic acid; hydrazine In tetrahydrofuran at 20℃; for 16h; Stage #2: With potassium N-iodo p-toluenesulfonamide; potassium hydroxide In tetrahydrofuran; lithium hydroxide monohydrate at 20℃; | |
Multi-step reaction with 2 steps 1: hydrogenchloride / methanol; lithium hydroxide monohydrate / 20 °C 2: triethylamine / dichloromethane / 80 °C / 12929 Torr | ||
Multi-step reaction with 2 steps 1: hydrazine; benzoic acid / tetrahydrofuran / 20 °C 2: potassium N-iodo p-toluenesulfonamide / lithium hydroxide monohydrate; tetrahydrofuran / 1 h / 20 °C |
Multi-step reaction with 2 steps 1: glacial acetic acid; hydrazine hydrate monohydrate / lithium hydroxide monohydrate; methanol / 18 h / 0 - 20 °C 2: triphenylbismuthine; glacial acetic acid; sodium perborate tetrahydrate / methanol / 18 h / 20 °C | ||
Multi-step reaction with 2 steps 1: hydrazine hydrate monohydrate; glacial acetic acid / methanol; lithium hydroxide monohydrate / 0 - 20 °C 2: ammonium acetate; potassium iodide / acetonitrile / 20 °C / Electrochemical reaction; Green chemistry |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With Hexamethylphosphorous triamide In tetrahydrofuran at -78 - 20℃; for 1h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With iron(III) chloride In acetonitrile at 60℃; for 36h; | General procedures for preparation of quinoline-2,4-dicarboxylates 4 General procedure: The reaction mixture of arylamine 1 (0.5mmol), ethyl glyoxylate 2 (0.55mmol), α-ketoesters 3 (0.75mmol), FeCl3 (5mol%) and CH3CN (3mL) was stirred at room temperature or 60°C for the indicated time until complete consumption of the starting material, which was monitored by TLC analysis (30-36h). Then the solvents were removed by rotary evaporation to provide crude products. The residue was purified by flash chromatography on silica gel to give the desired product 4. Compound 4o was obtained in 33% yield according to the general procedure (60°C, 36h). TLC (n-hexane/EtOAc, 3:1 v/v): Rf=0.40; 1H NMR (600MHz, CDCl3): δ=1.17 (t, J=7.1Hz, 3H), 1.31 (t, J=7.1Hz, 3H), 3.92 (s, 3H), 4.27 (q, J=7.1Hz, 2H), 4.41-4.44 (m, 4H), 7.00 (s, 1H), 7.09 (d, J=7.4Hz, 2H), 7.15 (t, J=7.1Hz, 1H), 7.21 (t, J=7.3Hz, 2H), 7.41 (dd, J=2.2, 9.1Hz, 1H), 8.10 (d, J=9.2Hz, 1H); 13C NMR (150MHz, CDCl3): δ=13.9, 14.1, 35.5, 55.6, 62.1, 102.1, 123.1, 126.0, 126.3, 128.3, 128.8, 129.0, 131.6, 139.0, 139.7, 141.9, 148.6, 159.8, 166.3, 167.4; HRMS calcd for C23H24NO5 (M+H)+, 394.1649; found, 394.1656. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With iodine In acetonitrile at 80℃; for 48h; | 3.20 4.2.1 General procedure for the iodine-mediated cascade reaction of α-ketoesters and arylamines General procedure: A round-bottomed flask was charged with arylamine (0.3 mmol), α-ketoester (0.9 mmol), iodine (3 mol %) and MeCN (0.50 mL). The resultant mixture was stirred for a specified time at 50 °C. Upon completion of the reaction (monitored by TLC), the solvents were removed by rotary evaporation and the mixture was purified by column chromatography, eluted with petroleum ether and ethyl acetate to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With [bis(acetoxy)iodo]benzene In dichloromethane for 2h; Reflux; | Ethyl 2-oxo-4-phenylbutanoate 3n General procedure: β-Oxo-benzenepropanenitrile 1(1.0 mmol),PIDA (2.2 mmol) were dissolved in EtOH (8 mL) and stirred under refluxing for 0.5h. After the reaction was completed (monitored by TLC), thereaction mixture was concentrated under vacuum. The residue was purified by chromatographyon silica gel (20:1 petroleum ether/EtOAc) to give the product 3a-o .Thesolvent for the synthesis of 3o was MeOH. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With 10% Pd/C; hydrogen In ethanol at 20℃; for 12h; Molecular sieve; | 4.11.1 (1R, Z)-2-((2S)-2-(1-ethoxy-1-oxo-4-phenylbutan-2-ylamino)-1-fluoropropylidene)-cyclopentanecarboxylic acid (12) Fmoc-Ala-Ψ[CF=C]-Pro (Z)-10a (0.211mmol, 1equiv) in DMF (2.7mL) and morpholine (1.6equiv) were stirred for 1h at room temperature. The crude mixture was then concentrated under reduced pressure and filtered on silica gel (dichloromethane/CH3OH: 8/2+0.1% of acetic acid). The resulting Ala-Ψ[(Z)CF=C]-Pro (Z)-11 was pure enough to be engaged in the reductive amination with ethyl 2-oxo-4-phenylbutanoate (2.3equiv) in 2mL of absolute ethanol, 0.22g of molecular sieves 4, and a catalytic amount of 10% Pd/C (0.22equiv). The mixture was placed under H2 atmosphere for 12h at room temperature. Then, the reaction mixture was filtered through Celite and the filtrate concentrated under reduced pressure to give a pale yellow oil, which was purified by chromatography on silica gel (dichloromethane/CH3OH: 8/2+0.1% of acetic acid). The resulting mixture was purified by preparative HPLC (MeOH/0.005M ammonium acetate: 45/55) to afford the fluorinated analogue of Enalapril 12 (28.0mg, 0.074mmol, 35%). Rf=0.14 (CH2Cl2/CH3OH: 8/2+0.1% acetic acid). IR (neat): ν 2927, 1705, 1625, 1568, 1454, 1357, 1211, 1170, 1096, 862, 748, 699, 633, 577, 493cm-1. 1H NMR (300MHz, CDCl3): δ 7.23-7.09 (m, 5H), 5.85 (bs, 1H), 4.11 (q, 2H, 3J=9.0Hz), 3.48-3.36 (m, 2H), 3.14 (t, 1H, 3J=6.0Hz), 2.62 (m, 2H), 2.22-2.09 (m, 2H), 1.92-1.75 (m, 4H), 1.50 (m, 2H), 1.22-1.18 (m, 6H) ppm 19F NMR (282.5MHz, CDCl3): δ -124.4 (d, 3J=28.2Hz) ppm 13C NMR (75.4MHz, CDCl3): δ 175.2 (C), 152.9 (d, C, 1J=254.1Hz), 141.1 (C), 128.5 (CH), 128.3 (CH), 125.9 (CH), 119.8 (d, C, 2J=16.6Hz), 60.8 (CH2), 58.1 (CH), 51.1 (CH), 50.8 (CH), 35.0 (CH2), 31.9 (CH2), 31.5 (CH2), 28.1 (CH2), 25.8 (CH2), 18.3 (CH3), 14.3 (CH3) ppm MS (ESI+): [M+H]+=378.07. Elemental analysis for C21H28FNO4: calcd: C: 66.82; H: 7.48; N: 3.71 Found: C: 66.90; H: 7.52; N: 3.82. [α]D20=-35.7 (c 0.14, CHCl3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-{3,5-bis(trifluoromethyl)phenyl}-3-{(1R,2R)-2-(dimethylamino)cyclohexyl}thiourea In ethyl acetate at 0℃; for 96h; enantioselective reaction; | trans-4,5-Dihydrofuran-2-carboxylates; General Procedure General procedure: To a solution of nitroalkene 1 (0.1 mmol, 1.0 equiv) and α-keto ester 2 (0.2 mmol, 2.0 equiv) in EtOAc (1.0 mL) at 0 °C was added (R,R)-TUC (10 mol%). The reaction was stirred until complete conversion of the starting materials (monitored by TLC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; methanesulfonyl chloride In tetrahydrofuran at 0 - 20℃; | General procedure for the preparation of α-ketoesters General procedure: The α-ketoesters 2a-2e were synthesized starting from the corresponding commercially available α-ketoacids according to the literature (Yang, J.; List, B. Org. Lett. 2006, 8, 5653). Typically, the 1,2-ketoacid (10 mmol, 1.0 equiv), the corresponding alcohol (20 mmol, 2.0 equiv) and pyridine (25 mmol, 2.5 equiv) were dissolved in THF (10.0 mL) and the reaction mixture was cooled to 0 °C. Mesyl chloride (12 mmol, 1.2 equiv) was then added dropwise. The reaction was then warmed to room temperature and stirred for 30 hours. The reaction was quenched with water (20.0 mL) and extracted with diethyl ether (3 x 20.0 mL). The combined organic layers were then dried over Na2SO4, filtered and concentrated in vacuo. The resulting crude product was purified by flash column chromatography on silica gel (diethyl ether / petroleum ether = 1:10) to afford the desired 1,2-ketoester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-[3,5-bis(trifluoromethyl)phenylcarbamoyl]chitosan (low molecular weight chitosan) In toluene at -30℃; for 24h; Overall yield = 68 %; Optical yield = 21 %ee; enantioselective reaction; | 2.4. General procedure for the organocatalyzed cyanosilylation of α-ketoesters 1-6a in the presence of trimethylsilyl cyanide General procedure: Trimethylsilyl cyanide (99 μL, 0.75 mmol) was added to a solutionof ketones or aldehydes 1-6a (0.5 mmol) and the corresponding chitosan-based urea I-III (15 mg) in the proper solvent (0.5 mL) at thespecified temperature. The mixture was stirred for the time established(TLC monitoring). The catalyst was filtered and washed twice with thecorresponding solvent. To the crude reaction, 1.0 mL of a saturatedsolution of NH4Cl was added, and the mixture was extracted withEtOAc (2×5 mL). The organic phase was washed with 5.0 mL of asaturated solution of NaCl, dried with Na2SO4, and the solvents wereremoved under reduced pressure. The residue was purified by columnchromatography using 8:2 n-hexane/EtOAc for compounds 2-4b and9:1 n-hexane/EtOAc for products 5,6b, affording the corresponding Oprotectedcyanohydrins 2-4b and (R)-5,6b. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With phosphorous acid trimethyl ester In tetrahydrofuran at 50℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With hydrogen In ethanol at 45℃; | Procedure for hydrogenation N-alkylation of α-alanyl-α-proline with ethyl 2-oxo-4-phenylbutanoate. A weighed sample of the catalyst (100-500 mg) was loaded under a layer of solvent (50 mL) in a glass reactor equipped with a jacket for thermo stating and a magnetic stirrer for stirring in a fl ow of hydrogen. The catalyst was activated with hydrogen for 20-30 min. Then, α-alanyl-α-proline (4 g, 0.022 mol) and ethyl 2-oxo-4-phenylbutanoate (10 g, 0.043 mol) were introduced into the reactor in a fl ow of hydrogen. The reaction mixtures were stirred at a constant rate of 900-1100 rpm at a hydrogen pressure of 98-103 kPa. After the reaction completion, the mixture was fi ltered and concentrated by evaporation to give a pale yellow oily residue (6.0 g). Then, the oily residue was dispersed in a solution of sodium chloride (20 g) in water (100 mL), the pH of which was adjusted to 8.5 with K2HPO4, and extracted with ethyl acetate (2×100 mL). The aqueous solution was acidifi ed with 1 M H3PO4 to pH 4.2 and again extracted with ethyl acetate (4×100 mL). The extract was dried with anhydrous sodium sulfate and concentrated to obtain an oily substance (3.30 g). Then, the residue of the oily substance was dissolved in warm water (100 mL, 60 C) and fi ltered. Upon cooling the fi ltrate, a white amorphous substance of enalapril is formed (the highest yield on the AV-17-8-Pd catalyst was 2.63 g, 70 wt.%). The mass yields for all the studied catalysts are given in Tables 1 and 2 and ranging from 30 to 70 wt.%. The purity of the obtained enalapril, as determined by TLC, was no less than 98.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | Stage #1: 2-oxo-4-phenylbutanoic acid ethyl ester; N-butylamine With propionic acid In dichloromethane at 20℃; for 4h; Inert atmosphere; Molecular sieve; Stage #2: N-(3-iodopropyl)phthalimide With tris-(trimethylsilyl)silane; t-butyldimethylsiyl triflate In dichloromethane at 20℃; for 6h; Inert atmosphere; Molecular sieve; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | Stage #1: 4,4-difluorocyclohexan-1-amine; 2-oxo-4-phenylbutanoic acid ethyl ester With propionic acid In dichloromethane at 20℃; for 3h; Inert atmosphere; Molecular sieve; Stage #2: 2-iodo-propane With tris-(trimethylsilyl)silane In dichloromethane at 20℃; for 6h; Inert atmosphere; Molecular sieve; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | Stage #1: 2-oxo-4-phenylbutanoic acid ethyl ester; 3-(2-aminoethyl)-indole-1-carboxylic acid tert-butyl ester With propionic acid In dichloromethane at 20℃; for 3h; Inert atmosphere; Molecular sieve; Stage #2: 2-iodo-propane With tris-(trimethylsilyl)silane In dichloromethane at 20℃; for 6h; Inert atmosphere; Molecular sieve; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With bis[chlorido(η2,η2-cycloocta-1,5-diene)rhodium(I)]; methanesulfonic acid; hydrogen; (R)-N-(2-(diphenylphosphanyl)benzyl)-N-((R)-1-phenylethyl)-8,9,10,11,12,13,14,15-octahydrodinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin-4-amine; sodium tetrakis[(3,5-di-trifluoromethyl)phenyl]borate In tetrahydrofuran; acetonitrile at 70℃; for 24h; Autoclave; enantioselective reaction; |
Tags: 64920-29-2 synthesis path| 64920-29-2 SDS| 64920-29-2 COA| 64920-29-2 purity| 64920-29-2 application| 64920-29-2 NMR| 64920-29-2 COA| 64920-29-2 structure
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