* 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.
With C39H33N3O2*2ClH In methanol; water at 20℃; for 72 h;
General procedure: To a 5 mL vial equipped with a magnetic stirrer bar were added 3-cyclohexyl-2-oxopropanoic acid (1j) (0.0510 g, 0.30 mmol), 2,2-diphenylglycine (2) (0.0681 g, 0.30 mmol), chiral pyridoxamine 6g (0.0195 g, 0.030 mmol), and MeOH-H2O (8:2) (3.0 mL). The mixture was stirred at 20 °C for 3 days. The reaction mixture was transferred to a 25 mL round-bottom flask and MeOH was added until all the solid was dissolved. Then silica gel (0.50 g) was added. After removal of the solvent in vacuo at 20 °C, the resulting residue was submitted to column chromatography on silica gel (EtOH/ethyl acetate/25-28percent ammonia solution =100:58:16) to give compound 3j (0.0401 g, 78percent yield, 52percent ee) as a white solid. The enantiomeric excesses of 3b-k were deteremined by HPLC analysis after being converted to N-benzoyl methyl esters by treatment with thionyl chloride in methanol and subsequent reaction benzoyl chloride.7 The enantiomeric excess of 3a was deteremined by HPLC analysis after being converted to its methyl ester by treatment with CH2N2 in methanol.
Reference：
[1] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1987, vol. 36, # 6, p. 1254 - 1256[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1987, vol. 36, # 6, p. 1359 - 1361
30
[ 64282-12-8 ]
[ 1132-68-9 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2012, vol. 354, # 17, p. 3327 - 3332
Reference：
[1] Liebigs Annalen der Chemie, 1989, p. 1215 - 1232
40
[ 113845-29-7 ]
[ 1132-68-9 ]
Reference：
[1] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1987, vol. 36, # 6, p. 1254 - 1256[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1987, vol. 36, # 6, p. 1359 - 1361
41
[ 459-32-5 ]
[ 1132-68-9 ]
[ 151911-23-8 ]
Reference：
[1] Journal of Organic Chemistry, 2009, vol. 74, # 23, p. 9152 - 9157
42
[ 56-40-6 ]
[ 352-11-4 ]
[ 1132-68-9 ]
Reference：
[1] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1990, vol. 39, # 7.2, p. 1479 - 1485[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1990, # 7, p. 1630 - 1636
Reference：
[1] RSC Advances, 2016, vol. 6, # 61, p. 56412 - 56420
[2] Advanced Synthesis and Catalysis, 2017, vol. 359, # 9, p. 1570 - 1576
45
[ 459-57-4 ]
[ 1132-68-9 ]
[ 459-32-5 ]
[ 151911-23-8 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 9, p. 1570 - 1576
46
[ 24424-99-5 ]
[ 1132-68-9 ]
[ 41153-30-4 ]
Yield
Reaction Conditions
Operation in experiment
72.5%
With sodium hydroxide In 1,4-dioxane; water at 20℃; for 6 h; Cooling with ice
A solution of L-4F-Phe-COOH 1.97 g (10 mmol) in a mixture of dioxane (20 mL), water (20 mL) and 1 M NaOH (10 mL) was stirred and cooled in an ice-water bath. Ditert-butylpyrocarbonate 2.4 g (11 mmol) was added and stirring was continued at room temperature for 6 h. Then the solution was concentrated in vacuum to about 15—20 mL, cooled in an ice water bath, covered with a layer of ethyl acetate (about 30 mL) and a dilute solution of KHSO4 was added to acidify (pH 2—3). The aqueous phase was extracted with ethyl acetate and this operation was done three times. The ethyl acetate extracts were collected and dried over anhydrous Na2SO4 and evaporated in a vacuum. The pure material was obtained as a waxy solid.Yield: 2.115 g (7.25 mmol, 72.5percent)1H NMR (DMSO-d6, 400 MHz, ppm): 12.60 [s, 1H COOH], 7.29-7.25 & 7.11-7.07 [m, 4H, Aromatic protons], 4.10-3.00 [m, 1H, CaH 4F Phe], 3.03-2.77 [m, 2H, CI3H4F Phe], 1.33 [s, 9H, Boc].MALDI-TOF (matrix: a-cyano-4-hydroxy cinnamic acid (CHCA)) :mlz= [M+H] + 284.12 (calculated), 284.29 (observed), [M+Na]+ 306.11 (calculated), 306.25 (observed).
Reference：
[1] Chemical Communications, 2014, vol. 50, # 76, p. 11154 - 11157
[2] Patent: WO2017/42805, 2017, A1, . Location in patent: Page/Page column 24; 25
[3] Journal of Medicinal Chemistry, 1994, vol. 37, # 13, p. 2090 - 2099
[4] Bioorganic and Medicinal Chemistry, 1996, vol. 4, # 10, p. 1733 - 1745
47
[ 58632-95-4 ]
[ 1132-68-9 ]
[ 41153-30-4 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1989, vol. 37, # 3, p. 826 - 828
48
[ 1132-68-9 ]
[ 1534-90-3 ]
Yield
Reaction Conditions
Operation in experiment
98%
With hydrogenchloride In ethanol
Example 1 L-Melphalanyl-L-p-fluorophenylalanine ethyl ester hydrochloride (J1) L-p-Fluorophenylalanine (217 mg, 1.18 mmol) was dissolved in EtOH (5 ml) previously bubbled with HCl. The reaction was brought to 100° C. and was allowed to reflux for 18 hours. The solvent was evaporated off and the product was dried under high vacuum, affording L-p-fluorophenylalanine ethyl ester hydrochloride as dry white crystals (98percent). 1H NMR: (CD3OD) δ 7.30-7.26 (m, 2H, Ph-H), 7.13-7.06 (m, 2H, Ph-H), 4.29-4.22 (m, 2H, CH2-Ph), 3.31-3.10 (m, 3H, CH2CH3, α-H), 1.24 (t, 3H, CH2CH3).
With sodium hydroxide; In 1,4-dioxane; water; at 20℃; for 6h;Cooling with ice;
A solution of L-4F-Phe-COOH 1.97 g (10 mmol) in a mixture of dioxane (20 mL), water (20 mL) and 1 M NaOH (10 mL) was stirred and cooled in an ice-water bath. Ditert-butylpyrocarbonate 2.4 g (11 mmol) was added and stirring was continued at room temperature for 6 h. Then the solution was concentrated in vacuum to about 15-20 mL, cooled in an ice water bath, covered with a layer of ethyl acetate (about 30 mL) and a dilute solution of KHSO4 was added to acidify (pH 2-3). The aqueous phase was extracted with ethyl acetate and this operation was done three times. The ethyl acetate extracts were collected and dried over anhydrous Na2SO4 and evaporated in a vacuum. The pure material was obtained as a waxy solid.Yield: 2.115 g (7.25 mmol, 72.5%)1H NMR (DMSO-d6, 400 MHz, ppm): 12.60 [s, 1H COOH], 7.29-7.25 & 7.11-7.07 [m, 4H, Aromatic protons], 4.10-3.00 [m, 1H, CaH 4F Phe], 3.03-2.77 [m, 2H, CI3H4F Phe], 1.33 [s, 9H, Boc].MALDI-TOF (matrix: a-cyano-4-hydroxy cinnamic acid (CHCA)) :mlz= [M+H] + 284.12 (calculated), 284.29 (observed), [M+Na]+ 306.11 (calculated), 306.25 (observed).
L-Melphalanyl-L-p-fluorophenylalanine ethyl ester hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With hydrogenchloride; In ethanol;
Example 1 L-Melphalanyl-L-p-fluorophenylalanine ethyl ester hydrochloride (J1) L-p-Fluorophenylalanine (217 mg, 1.18 mmol) was dissolved in EtOH (5 ml) previously bubbled with HCl. The reaction was brought to 100 C. and was allowed to reflux for 18 hours. The solvent was evaporated off and the product was dried under high vacuum, affording L-p-fluorophenylalanine ethyl ester hydrochloride as dry white crystals (98%). 1H NMR: (CD3OD) delta 7.30-7.26 (m, 2H, Ph-H), 7.13-7.06 (m, 2H, Ph-H), 4.29-4.22 (m, 2H, CH2-Ph), 3.31-3.10 (m, 3H, CH2CH3, alpha-H), 1.24 (t, 3H, CH2CH3).
With chiral stationary phase including isopropyl-functionalized CF6; In methanol; acetic acid; triethylamine; acetonitrile; at 0℃;Purification / work up;
In addition to the foregoing, numerous other chromatographic separations using a column bonded with a CSP including a derivatized cyclofructan residue were carried out. Tables 5-9 list some additional examples of chromatographic separations using a column bonded with a CSP of the present invention. AU examples of chromatographic separations using columns bonded with CSPs of the present invention were carried out using the following experimental conditions and procedures.|0132| The high performance liquid chromatography (HPLC) column packing system was composed of an air driven fluid pump (HASKEL, DSTV- 122), an air compressor, a pressure regulator, a low pressure gauge, two high-pressure gauges (10,000 and 6,000 psi), a slurry chamber, check valves, and tubings. The CSPs were slurry packed into a 25 cm x 0.46 cm (inner diameter, I. D.) stainless steel column.|0133| The HPLC system was an Agilent 1 100 system (Agilent Technologies, Palo Alto,CA), which consisted of a diode array detector, an autosampler, a binary pump, a temperature- controlled column chamber, and Chemstation software. All chiral analytes were dissolved in ethanol, methanol, or other appropriate mobile phases, as indicated. For the LC analysis, the injection volume and flow rate were 5 muL and 1 mL/min, respectively. Separations were carried out at room temperature (~20 0C) if not specified otherwise. The wavelengths of UV detection were 195, 200, 210, and 254 nm. The mobile phase was degassed by ultrasonication under vacuum for 5 min. Each sample was analyzed in duplicate. Three operation modes (the normal phase mode, polar organic mode, and reversed phase mode) were tested, unless indicated otherwise. In the normal phase mode, heptane with ethanol or isopropanol was used as the mobile phase. In some cases, trifluoroacetic acid (TFA) was used as an additive, as indicated. The mobile phase of the polar organic mode was composed of acetonitrile/methanol and small amounts of acetic acid and triethylamine. Water/acetonitrile or acetonitrile/acetate buffer (20 mM, pH = 4.1 ) was used as the mobile phase in the reversed-phase mode.|0134| Two different supercritical fluid chromatographic instruments were used. One was a Berger SFC unit with an FCM 1200 flow control module, a TCM 2100 thermal column module, a dual pump control module, and a column selection valve. The flow rate was 4 mL/min. The cosolvent was composed of methanol/ethanol/isopropanol = 1 : 1 : 1 and 0.2% diethylamine (DEA). The gradient mobile phase composition was 5% cosolvent hold during 0- 0.6 min, 5-60% during 0.6-4.3 min, 60% hold during 4.3-6.3 min, 60%-5% during 6.3-6.9 min, and 5% hold during 6.9-8.0 min. The other SFC system was a Jasco (MD, USA) system comprised of an autosampler unit (AS-2059-SF Plus), a dual pump module (PU-2086 Plus), a column thermostat module (CO-2060 Plus), a UV/Vis detector (UV-2075 Plus), and a back pressure regulator module (SCH-Vch-BP). Unless otherwise specified, the mobile phase was composed of CCVmethanol (0.1 % TFA or 0.1% diethylamine). The flow rate was 3 mL/min.|0135| For the calculations of chromatographic data, the "dead time" to was determined by the peak of the refractive index change due to the sample solvent or determined by injecting l ,3,5-tri-/e/-/-butylbenzene in the normal phase mode.
With Chirosil SCA column; In methanol; water; acetic acid;Resolution of racemate;
Enantiomers were separated by chiral chromatography using a Regis Technologies (Morton Grove, Ill.) Chirosil SCA (-) 4.6×150 mm, 5-micron column using 7/3 MeOH/H2O with 10 mM AcOH at a flow rate of 1.0 mL/min and detection at 214, 230, and 254 nm. A typical injection volume was 30 muL (34.5 mug) of a 1.15 mg/mL solution of purified, racemic compound in 7/3 MeOH/H2O. Each enantiomer was collected manually in separate test tubes. The process was repeated a second time. Combined solutions of individual enantiomers were evaporated to dryness and the residues were dissolved in 200 muL of 7/3 MeOH/H2O. These solutions were then each analyzed on the chiral column (5 muL injections) to verify enantiopurity and then on an Agilent Technologies (Santa Clara, Calif.) Zorbax SB C18, 4.6×150 mm, 5-micron column (30% 1:1 MeOH:MeCN with 5 mM NH4OAc-70% H2O with 5 mM NH4OAc, 1.0 mL/min, 210, 214, 254 nm) to determine mass quantities from peak areas using the calibration equation.
With carbon dioxide; Taxus chinensis phenylalanine aminomutase; ammonia In water Enzymatic reaction; optical yield given as %ee; enantioselective reaction;
With C39H33N3O2*2ClH; In methanol; water; at 20℃; for 72h;
General procedure: To a 5 mL vial equipped with a magnetic stirrer bar were added 3-cyclohexyl-2-oxopropanoic acid (1j) (0.0510 g, 0.30 mmol), 2,2-diphenylglycine (2) (0.0681 g, 0.30 mmol), chiral pyridoxamine 6g (0.0195 g, 0.030 mmol), and MeOH-H2O (8:2) (3.0 mL). The mixture was stirred at 20 °C for 3 days. The reaction mixture was transferred to a 25 mL round-bottom flask and MeOH was added until all the solid was dissolved. Then silica gel (0.50 g) was added. After removal of the solvent in vacuo at 20 °C, the resulting residue was submitted to column chromatography on silica gel (EtOH/ethyl acetate/25-28percent ammonia solution =100:58:16) to give compound 3j (0.0401 g, 78percent yield, 52percent ee) as a white solid. The enantiomeric excesses of 3b-k were deteremined by HPLC analysis after being converted to N-benzoyl methyl esters by treatment with thionyl chloride in methanol and subsequent reaction benzoyl chloride.7 The enantiomeric excess of 3a was deteremined by HPLC analysis after being converted to its methyl ester by treatment with CH2N2 in methanol.
3-ethyl-4-(4-fluorophenyl)-5-hydroxyfuran-2(5H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
In water at 80℃; for 24h;
8 Example 8
To the round bottom flask was added 0.37 g (2 mmol) of 4-fluorophenylalanine,Butanone 2.04 g (20 mmol) was dissolved in 0.5 mL of water, reacted at 80 ° C for 24 hours,After cooling to room temperature, the organic layer was extracted with saturated brine and ethyl acetate,The product was isolated and purified to give the title product 3-ethyl-5-hydroxy-4- (4-fluorophenyl) -2 (5H) -furanone.White solid, melting point: 146.5 - 147.4oC; Yield: 74%.
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