* 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 hydrogenchloride; methanol In dichloromethane at 4.8 - 20℃; for 6 h;
Example 6; Deprotecting the bis-MOM-S-equol to S-Equol ((S)-3-(4-hydroxyphenyl)-chroman-7-ol); A solution of 42.17 g (0.128 mol) of (S)-bis-MOM-equol in 200 mL of 1:1 mixture of CH2Cl2/MeOH was placed in a 1 L 3-neck round bottom flask equipped with a magnetic stirrer, thermocouple, cooling ice bath and nitrogen line. A total of 200 mL of 10 wt percent solution of HCl in MeOH (0.438 mol, 3.4 eq.) was slowly added to pre-chilled (4.8° C.) solution of bis-MOM-equol. The reaction mixture was allowed to warm up to room temperature and monitored by TLC until all starting material is converted to S-equol (Rf=0.58 for bis-MOM-equol, 0.28 for mono-MOM-equol, and 0.10 for S-equol in ethyl acetate/hexane=2:8). After 6 hours at room temperature a complete deprotection was observed. Solvent was removed under reduced pressure and precipitated solid was treated with a 500 mL of ice-cold water, extracted with ethyl acetate (2.x.400 mL) and combined organic phases were washed with diluted sodium bicarbonate (400 mL). Organic layer was dried over sodium sulfate and solvent volume was reduced to about 100 mL. The obtained yellowish solution was carefully diluted with 400 mL of hexane and resulted clear solution was chilled on an ice bath while stirring. Precipitated white solid was filtered off, washed with hexane (3.x.200 mL) and dried in a vacuum oven overnight to yield 25.24 g of s-equol as a white solid. An additional 3.54 g of the product was obtained from mother liquor. A total 28.78 g (93percent isolated yield) of S-equol was obtained as a white solid with mp 162 C. Chemical HPLC and optical purity for synthesized S-equol were found to be 96.69percent and 100percent ee correspondingly. Reversed Phase HPLC used to determine chemical purity: Column: Waters Symmetry C18, 3.5 micron particles, 4.6.x.75 mm Mobile phase A: 0.1percent TFA in water Mobile phase B: 0.1percent TFA in acetonitrile Gradient: 5percent B to 100percent B in 16 minutes, return to initial conditions at 16 minutes. Detector wavelength=280 nm Injection volume=5 microliters Retention time: 7.87 min HPLC purity: 96.69percent Optical purity was determine by chiral HPLC: Column: Chiracel OJ, 4.6.x.250 mm Isocratic, 75percent (0.2percent phosphoric acid in water), 25percent acetonitrile Flow: 0.75 mL/min Detector wavelength: 215 nm Retention time: 54.28 min Chiral purity: 100percent ee Optical rotation: [α]=-19.1° C. A reported optical rotation for S-equol crystallized from aqueous ethanol is [α]=-21.5° C. (The Merck Index, 1996, 12th edition, p 618). LC-MS traces and spectra of the S-Equol product are shown in FIGS. 6A and 6B, respectively. 1H NMR and 13C NMR data appear below. 1H NMR (300 MHz, CDCl3, δ): 9.32 (s, 1H, OH), 9.21 (s, 1H, OH), 7.09 (d, 2H, J=8.4 Hz), 6.86 (d, 1H, J=8.1 Hz), 6.72 (d, 2H, J=8.7 Hz), 6.30 (dd, 1H, J=8.4 J=2.1), 6.21 (d, 1H, J=2.4 Hz), 4.15 (ddd, 1H, CH2O, J=10.5 Hz, J=1.80 Hz), 3.88 (t, 1H, CH2O, J=10.2 Hz), 3.00 (m, 1H, CH), 2.78 (m, 2H, CH2). 13C NMR (75 MHz, CDCl3, δ): 156.515 (C7), 156.151 (C4'), 154.557 (C9), 131.711 (C10), 130.134 (C8), 128.346 (C6), 115.321 (C3'), 112.627 (C1'), 108.048 (C5), 102.547 (C2'), 70.309 (C2), 37.197 (C3), 31.324 (C4).
Stage #1: With lithium aluminium tetrahydride In diethyl ether for 3 h; Stage #2: With water In diethyl etherCooling with ice
To a suspension Of LiAlH4 in ether, compound (4) dissolved in ether is added dropwise and stirred under backflow for about 3 hours. The reaction flask is cooled with ice water, and ice water is added carefully dropwise to the reaction mixture, until the development of hydrogen terminates. Subsequently, 10percent sulphuric acid is added until the aluminium hydroxide precipitate is dissolved. The organic phase is removed in a separatory funnel and purified by flash chromatography at a silica-gel (230-400 mesh) with the eluants ethylacetate/hexane(4: 1 v/v). The enantiomeric purity of the product is determined by HPLC at a chiral acid as 98percent ee (25 cm Chiralcel OD-H chiral column; A ethanol/hexane 10/90; B ethanol/hexane 90/10; gradient 15 min; flow rate: 1 ml/min; detection: 254 nm), yield: 95percent (S)-equol.
Reference：
[1] Bioscience, Biotechnology and Biochemistry, 2008, vol. 72, # 10, p. 2660 - 2666
[2] Chemical and Pharmaceutical Bulletin, 2009, vol. 57, # 4, p. 346 - 360
6
[ 1460202-48-5 ]
[ 531-95-3 ]
Yield
Reaction Conditions
Operation in experiment
36 g
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 15 - 20℃;
To a mixture of alcohol of formula (9) (50 g) and triphenyl phosphine (151 g) in THF (2.5 L) diisopropyl azodicarboxylate (1 16.5 g) in THF (500 mL) was added at 15-20 °C and maintained at that temperature for 1 -2 hours. About 5percent lithium hydroxide solution (1000 mL) was added into the reaction mass and extracted with MTBE (3 x 750 mL) to remove the organic impurities. The pH of the aqueous layer was adjusted to 1 -4 by dilute hydrochloric acid (250 mL). The reaction mass was maintained at RT for 5-6 hours and the product was filtered off. The crude product was taken with I PA (7.5 vol) and added water (22.5 vol). The reaction mass was then maintained at RT for 12-14 hours. The solid was filtered and dried at 50-55 for 10-12 hours to afford the title compound. Yield: 36 g Chemical purity (by HPLC): 98.9percent. Chiral purity (by HPLC): 99.7percent e.e. 1 H NMR (400 MHz, DMSO- d6) δ: 2.50-2.87 (m, 2H), 2.97-3.34 (m, 1 H), 3.86-3.92 (m, 1 H), 4.13-4.16 (m, 1 H), 6.18 (d, J=2.4 Hz, 1 H) , 6.27-6.29 (dd, J=8.0 Hz, J=2.0 Hz, 1 H), 6.71 (d, J=8.8 Hz, 2H), 6.86 (d, J=7.6 Hz, 1 H), 7.10 (d, J=8.4 Hz, 2H), 9.14 (s, 1 H), 9.26 (s, 1 H). MS: m/z = 243.10 [M+1 ].
36 g
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 15 - 20℃;
To a mixture of alcohol of formula (9) (50 g) and triphenyl phosphine (151 g) in THF (2.5 L) diisopropyl azodicarboxylate (116.5 g) in THF (500 mL) was added at 15-20° C. and maintained at that temperature for 1-2 hours. About 5percent lithium hydroxide solution (1000 mL) was added into the reaction mass and extracted with MTBE (3*750 mL) to remove the organic impurities. The pH of the aqueous layer was adjusted to 1-4 by dilute hydrochloric acid (250 mL). The reaction mass was maintained at RT for 5-6 hours and the product was filtered off. The crude product was taken with IPA (7.5 vol) and added water (22.5 vol). The reaction mass was then maintained at RT for 12-14 hours. The solid was filtered and dried at 50-55° C. for 10-12 hours to afford the title compound. Yield: 36 g Chemical purity (by HPLC): 98.9percent. Chiral purity (by HPLC): 99.7percent e.e. 1H NMR (400 MHz, DMSO-d6) δ: 2.50-2.87 (m, 2H), 2.97-3.34 (m, 1H), 3.86-3.92 (m, 1H), 4.13-4.16 (m, 1H), 6.18 (d, J=2.4 Hz, 1H), 6.27-6.29 (dd, J=8.0 Hz, J=2.0 Hz, 1H), 6.71 (d, J=8.8 Hz, 2H), 6.86 (d, J=7.6 Hz, 1H), 7.10 (d, J=8.4 Hz, 2H), 9.14 (s, 1H), 9.26 (s, 1H). MS: m/z=243.10 [M+1].
In ethanol; hexane for 0 - 0.283333h; Resolution of racemate;
c
A racemic mix of S-equol and R-equol were separated by chiral chromatography on a Chiralcel OJ Column using a flow-rate of 1.0 mL/min and with a gradient elution consisting of an initial mobile phase of 10% ethanol in hexane and increasing to 90% ethanol in hexane over a time period of 15 minutes according to the program shown in Table 1 :[00180] TABLE 1:[00181] FIG. 5 shows the mass chromatogram of the ions recording (m/z241) for a racemic mixture of S- and R-equol.[00182] The first eluting material, designated as Enantiomer- 1 , and the second eluting material, designated as Enantiomer-2, were collected separately. Each enantiomer was weighed and the weighed samples dissolved in 1 mL of spectroscopic grade ethanol. Measurement of the optical rotation of each enantiomer was carried out at 200° C. using the light of wavelength in the line D of sodium. [00183] . Enantiomer-1 material (1.6 mg exact weight) had first and second measurements of -0.023 and -0.022, resulting in an optical rotation of -14[- 0.0225x1000/1.6], which corresponds with the S-enantiomer of equol. Enanti- omer-2 material (1.7 mg exact weight) had first and second measurements of +0.023 and +0.023, resulting in an optical rotation of +13.5[+0.023xl000/1.7], which corresponds with the R-enantiomer of equol.
With CYCLOBOND I 2000 RSP In formic acid; water; acetonitrile Resolution of racemate;
With cellulose (3,5-dimethylphenylcarbamate) coated reduced graphene oxide(at)silica gel In hexane; isopropyl alcohol at 25℃; Resolution of racemate; enantioselective reaction;
The resulting S-<strong>[531-95-3]equol</strong> product was then converted into the TMS derivate and the TBDMS derivative according to the methods described in the Methods section, in order to improve volatility of the S-<strong>[531-95-3]equol</strong> compound during the mass spec analyses. The GC-MS traces and spectra of the TMS-derivative S-<strong>[531-95-3]equol</strong> products are shown in FIGS. 9A and 9B, respectively. The GC-MS traces and spectra of the TBDMS-derivative S-<strong>[531-95-3]equol</strong> products are shown in FIGS. 9C and 9D, respectively.; B. Method for TMS and TBDMS Derivitization; a. TMS: 20 mug of R-<strong>[531-95-3]Equol</strong> and S-<strong>[531-95-3]Equol</strong> were placed into separate derivitization vials and dried down under nitrogen. Six drops of Tri-Sil Reagent were added to each vial using a glass pipet, and the contents heated for 30 minutes at 65 C. The treated sample was dried under nitrogen and reconstituted in 50 muL of hexane. The sample was then run via GC/MS.
The resulting S-<strong>[531-95-3]equol</strong> product was then converted into the TMS derivate and the TBDMS derivative according to the methods described in the Methods section, in order to improve volatility of the S-<strong>[531-95-3]equol</strong> compound during the mass spec analyses. The GC-MS traces and spectra of the TMS-derivative S-<strong>[531-95-3]equol</strong> products are shown in FIGS. 9A and 9B, respectively. The GC-MS traces and spectra of the TBDMS-derivative S-<strong>[531-95-3]equol</strong> products are shown in FIGS. 9C and 9D, respectively.; b. TBDMS: 20 mug of R-<strong>[531-95-3]Equol</strong> and S-<strong>[531-95-3]Equol</strong> were placed into separate derivitization vials and dried down under nitrogen. An amount of 100 muL of Acetonitrile and 100 muL of MTBSTFA+1% t-BDMCS were added to each vial, and the contents heated for 1 hour at 100 C. The treated sample was dried under nitrogen and reconstituted in 50 muL of hexane. The sample was then run via GC/MS.
With hydrogenchloride; methanol; In dichloromethane; at 4.8 - 20℃; for 6h;
Example 6; Deprotecting the bis-MOM-S-equol to S-Equol ((S)-3-(4-hydroxyphenyl)-chroman-7-ol); A solution of 42.17 g (0.128 mol) of (S)-bis-MOM-equol in 200 mL of 1:1 mixture of CH2Cl2/MeOH was placed in a 1 L 3-neck round bottom flask equipped with a magnetic stirrer, thermocouple, cooling ice bath and nitrogen line. A total of 200 mL of 10 wt % solution of HCl in MeOH (0.438 mol, 3.4 eq.) was slowly added to pre-chilled (4.8 C.) solution of bis-MOM-equol. The reaction mixture was allowed to warm up to room temperature and monitored by TLC until all starting material is converted to S-equol (Rf=0.58 for bis-MOM-equol, 0.28 for mono-MOM-equol, and 0.10 for S-equol in ethyl acetate/hexane=2:8). After 6 hours at room temperature a complete deprotection was observed. Solvent was removed under reduced pressure and precipitated solid was treated with a 500 mL of ice-cold water, extracted with ethyl acetate (2×400 mL) and combined organic phases were washed with diluted sodium bicarbonate (400 mL). Organic layer was dried over sodium sulfate and solvent volume was reduced to about 100 mL. The obtained yellowish solution was carefully diluted with 400 mL of hexane and resulted clear solution was chilled on an ice bath while stirring. Precipitated white solid was filtered off, washed with hexane (3×200 mL) and dried in a vacuum oven overnight to yield 25.24 g of s-equol as a white solid. An additional 3.54 g of the product was obtained from mother liquor. A total 28.78 g (93% isolated yield) of S-equol was obtained as a white solid with mp 162 C. Chemical HPLC and optical purity for synthesized S-equol were found to be 96.69% and 100%ee correspondingly. Reversed Phase HPLC used to determine chemical purity: Column: Waters Symmetry C18, 3.5 micron particles, 4.6×75 mm Mobile phase A: 0.1% TFA in water Mobile phase B: 0.1% TFA in acetonitrile Gradient: 5% B to 100% B in 16 minutes, return to initial conditions at 16 minutes. Detector wavelength=280 nm Injection volume=5 microliters Retention time: 7.87 min HPLC purity: 96.69% Optical purity was determine by chiral HPLC: Column: Chiracel OJ, 4.6×250 mm Isocratic, 75% (0.2% phosphoric acid in water), 25% acetonitrile Flow: 0.75 mL/min Detector wavelength: 215 nm Retention time: 54.28 min Chiral purity: 100% ee Optical rotation: [alpha]=-19.1 C. A reported optical rotation for S-equol crystallized from aqueous ethanol is [alpha]=-21.5 C. (The Merck Index, 1996, 12th edition, p 618). LC-MS traces and spectra of the S-Equol product are shown in FIGS. 6A and 6B, respectively. 1H NMR and 13C NMR data appear below. 1H NMR (300 MHz, CDCl3, delta): 9.32 (s, 1H, OH), 9.21 (s, 1H, OH), 7.09 (d, 2H, J=8.4 Hz), 6.86 (d, 1H, J=8.1 Hz), 6.72 (d, 2H, J=8.7 Hz), 6.30 (dd, 1H, J=8.4 J=2.1), 6.21 (d, 1H, J=2.4 Hz), 4.15 (ddd, 1H, CH2O, J=10.5 Hz, J=1.80 Hz), 3.88 (t, 1H, CH2O, J=10.2 Hz), 3.00 (m, 1H, CH), 2.78 (m, 2H, CH2). 13C NMR (75 MHz, CDCl3, delta): 156.515 (C7), 156.151 (C4'), 154.557 (C9), 131.711 (C10), 130.134 (C8), 128.346 (C6), 115.321 (C3'), 112.627 (C1'), 108.048 (C5), 102.547 (C2'), 70.309 (C2), 37.197 (C3), 31.324 (C4).
To a suspension Of LiAlH4 in ether, compound (4) dissolved in ether is added dropwise and stirred under backflow for about 3 hours. The reaction flask is cooled with ice water, and ice water is added carefully dropwise to the reaction mixture, until the development of hydrogen terminates. Subsequently, 10% sulphuric acid is added until the aluminium hydroxide precipitate is dissolved. The organic phase is removed in a separatory funnel and purified by flash chromatography at a silica-gel (230-400 mesh) with the eluants ethylacetate/hexane(4: 1 v/v). The enantiomeric purity of the product is determined by HPLC at a chiral acid as 98% ee (25 cm Chiralcel OD-H chiral column; A ethanol/hexane 10/90; B ethanol/hexane 90/10; gradient 15 min; flow rate: 1 ml/min; detection: 254 nm), yield: 95% (S)-equol.
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 15 - 20℃;
To a mixture of alcohol of formula (9) (50 g) and triphenyl phosphine (151 g) in THF (2.5 L) diisopropyl azodicarboxylate (1 16.5 g) in THF (500 mL) was added at 15-20 C and maintained at that temperature for 1 -2 hours. About 5% lithium hydroxide solution (1000 mL) was added into the reaction mass and extracted with MTBE (3 x 750 mL) to remove the organic impurities. The pH of the aqueous layer was adjusted to 1 -4 by dilute hydrochloric acid (250 mL). The reaction mass was maintained at RT for 5-6 hours and the product was filtered off. The crude product was taken with I PA (7.5 vol) and added water (22.5 vol). The reaction mass was then maintained at RT for 12-14 hours. The solid was filtered and dried at 50-55 for 10-12 hours to afford the title compound. Yield: 36 g Chemical purity (by HPLC): 98.9%. Chiral purity (by HPLC): 99.7% e.e. 1 H NMR (400 MHz, DMSO- d6) delta: 2.50-2.87 (m, 2H), 2.97-3.34 (m, 1 H), 3.86-3.92 (m, 1 H), 4.13-4.16 (m, 1 H), 6.18 (d, J=2.4 Hz, 1 H) , 6.27-6.29 (dd, J=8.0 Hz, J=2.0 Hz, 1 H), 6.71 (d, J=8.8 Hz, 2H), 6.86 (d, J=7.6 Hz, 1 H), 7.10 (d, J=8.4 Hz, 2H), 9.14 (s, 1 H), 9.26 (s, 1 H). MS: m/z = 243.10 [M+1 ].
36 g
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 15 - 20℃;
To a mixture of alcohol of formula (9) (50 g) and triphenyl phosphine (151 g) in THF (2.5 L) diisopropyl azodicarboxylate (116.5 g) in THF (500 mL) was added at 15-20 C. and maintained at that temperature for 1-2 hours. About 5% lithium hydroxide solution (1000 mL) was added into the reaction mass and extracted with MTBE (3*750 mL) to remove the organic impurities. The pH of the aqueous layer was adjusted to 1-4 by dilute hydrochloric acid (250 mL). The reaction mass was maintained at RT for 5-6 hours and the product was filtered off. The crude product was taken with IPA (7.5 vol) and added water (22.5 vol). The reaction mass was then maintained at RT for 12-14 hours. The solid was filtered and dried at 50-55 C. for 10-12 hours to afford the title compound. Yield: 36 g Chemical purity (by HPLC): 98.9%. Chiral purity (by HPLC): 99.7% e.e. 1H NMR (400 MHz, DMSO-d6) delta: 2.50-2.87 (m, 2H), 2.97-3.34 (m, 1H), 3.86-3.92 (m, 1H), 4.13-4.16 (m, 1H), 6.18 (d, J=2.4 Hz, 1H), 6.27-6.29 (dd, J=8.0 Hz, J=2.0 Hz, 1H), 6.71 (d, J=8.8 Hz, 2H), 6.86 (d, J=7.6 Hz, 1H), 7.10 (d, J=8.4 Hz, 2H), 9.14 (s, 1H), 9.26 (s, 1H). MS: m/z=243.10 [M+1].
With methanol; potassium hydroxide; In methanol; at 0 - 20℃; for 1.5h;
Example 1 S-equol was prepared by treating bis-pivaloyl-S-equol with aqueous KOH in methanol at 0 C., and then allowing the solution to warm to room temperature. After about 1.5 hours, the reaction was cooled and ice was added to the solution, which was followed by the addition of acetic acid. The solution was then concentrated and the resulting suspension was washed with water to remove MeOH. After stirring for about 20 hours, the resulting solid was washed with water and hexanes and the damp solid was dried under vacuum to give an off-white solid. Next, the solid was suspended in heptane and ethyl acetate, and after about 20 hours, the solid was collected by filtration, washed with heptane/ethyl acetate, then heptane, and isolated under vacuum to provide S-equol.
With palladium 10% on activated carbon; hydrogen; acetic acid; In methanol; at 60℃; under 5250.53 Torr; for 4h;Autoclave;
50 Hydroxy equol 83.5 mg (0.36 mmol, 99.6% ee), methanol 1 mL, and acetic acid 0.3 mL were put into mL autoclave. 10 % palladium carbon 34.4 mg (0.032 mmol and 9 mol%) was added to this. Operation of decompressing the hydrogen pressure in autoclave to 0.7 MPa at application of pressure and 0.2 MPa was repeated 10 times, and hydrogen substitution was carried out. Then, maintaining hydrogen pressure to 0.7 MPa, with the oil bath, it heated to 60 degrees C and stirred for 4 hours. The obtained solution was condensed and 101.9 mg obtained the rough product (purity 68wt%, 89% of yield). When analyzed by HPLC, the selectivity of obtained (S)-equol was ee 89.4%.
With 10 wt% Pd(OH)2 on carbon; hydrogen; In tetrahydrofuran; methanol; water; at 20℃;
General procedure: To a solution of 6aa (91.6 mg, 0.208 mmol) and PPh3 (272.3 mg, 1.04 mmol) in THF (anhydrous, 4.2 mL) at 0 C was added diethyl azodicarboxylate (132.0 muL, 0.832 mmol) and the resulting solution was then stirred at rt. After completion of the reaction (monitored by TLC), purification by flash chromatography on a short silica gel column afforded 7aa (77.0 mg) as crude product, which was used in the next step without further purification.The hydrogenation was conducted following previous report.4 In brief, a mixture of 7aa (77.0 mg, 0.179 mmol) prepared above and Pd(OH)2/C (193.6 mg, 1.379 mmol) in a mixed solvent (THF/MeOH/H2O = 40/20/1, 15.3 mL) was stirred at room temperature under hydrogen atmosphere (using a balloon filled with hydrogen). After completion of the reaction (monitored by TLC), the title compound was obtained as a white solid (44.1 mg, 88% for two steps) after flash chromatography on silica gel column. [alpha]D25 = -9.8 (c 0.55, EtOH); 1H NMR (400 MHz, d6-DMSO) delta 9.24 (brs, 2H), 7.10 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.2 Hz, 1H), 6.71 (d, J = 8.4 Hz, 2H), 6.28 (d, J = 8.2, 1H), 6.18 (s, 1H), 4.14 (brd, J = 10.4 Hz, 1H), 3.89 (dd, J = 10.4, 10.4 Hz, 1H), 3.10- 2.95 (m, 1H), 2.83 (dd, J = 15.4, 10.8 Hz, 1H), 2.76 (dd, J = 15.6, 5.2 Hz, 1H). The ee was determined by chiral HPLC analysis. (Chiralpak OD-3, i-PrOH/n-Hexane = 15/85, flow rate = 1 mL/min, lambda = 220 nm): tminor = 19.818 min, tmajor = 24.924 min, ee = 85% (95% ee after one recrystallization in CH2Cl2).
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