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Structure of 5709-98-8 * Storage: {[proInfo.prStorage]}
* 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.
Stage #1: at 20℃; for 11 h; Phosphate buffer; Enzymatic reaction
Synthesis of Intermediate IV:To a stirred suspension of methylester III (5.19 g, 37.0 mmol) in pH 7.00 phosphate buffer solution (520 ml, 0.07 M), PLE (51.2 mg, 1382 units) was added. The pH was kept at 7 by adding NaOH solution (1.0 M) via syringe pump. The reaction was stirred at r.t. until one equivalent of NaOH (37 ml) was used (11 h, TLC-control: petroleum ether/Et20, 1:1). The reaction mixture was transferred into a separation funnel and washed twice with ethyl acetate (2.x.300 ml). The layers were separated and the organic layers were extracted twice with pH 7.00 phosphate buffer solution (2.x.300 ml). The combined aqueous layers were acidified to pH 2 with aqueous HCl (30 ml, 4 M) and extracted three times with ethyl acetate (3.x.400 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo (100 mbar). The crude product was filtered through a short plug of silica affording acid IV as a pale yellowish oil (3.92 g, 84percent). 96.3percent ee. (GC), 94.3percent ee. (rot.), [α]D21+89.12° (c=6.730, MeOH), (Lit. +94.5° (c=7, MeOH), [Acta Chem. Scand., 1970, 24, 2693]).
84%
Stage #1: at 20℃; Aqueous phosphate buffer; Enzymatic reaction Stage #2: With hydrogenchloride In water
To a stirred suspension of methylester III (5.19 g, 37.0 mmol) in pH 7.00 phosphate buffer solution (520 ml, 0.07 M), PLE (51.2 mg, 1382 units) was added. The pH was kept at 7 by adding NaOH solution (1.0 M) via syringe pump. The reaction was stirred at r.t. until one equivalent of NaOH (37 ml) was used (11 h, TLC-control: petroleum ether/Et2O, 1:1). The reaction mixture was transferred into a separation funnel and washed twice with ethyl acetate (2.x.300 ml). The layers were separated and the organic layers were extracted twice with pH 7.00 phosphate buffer solution (2.x.300 ml). The combined aqueous layers were acidified to pH 2 with aqueous HCl (30 ml, 4 M) and extracted three times with ethyl acetate (3.x.400 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo (100 mbar). The crude product was filtered through a short plug of silica affording acid IV as a pale yellowish oil (3.92 g, 84percent). 96.3percent ee. (GC), 94.3percent ee. (rot.), [α]D21+89.12° (c=6.730, MeOH), (Lit.+94.5° (c=7, MeOH), [Acta Chem. Scand., 1970, 24, 2693]).
Reference：
[1] Patent: US2008/161546, 2008, A1, . Location in patent: Page/Page column title page; 18
[2] Chemistry - A European Journal, 2012, vol. 18, # 5, p. 1342 - 1351
[3] Patent: US2008/200406, 2008, A1, . Location in patent: Page/Page column 25; sheet 1
[4] Patent: US2011/251148, 2011, A1, . Location in patent: Page/Page column 9
[5] Patent: WO2012/61662, 2012, A1, . Location in patent: Page/Page column 60
[6] Patent: WO2010/126888, 2010, A1, . Location in patent: Page/Page column 12; 30
2
[ 127604-94-8 ]
[ 5709-98-8 ]
Yield
Reaction Conditions
Operation in experiment
94%
Stage #1: With lithium hydroxide monohydrate In tetrahydrofuran; water at 20℃; for 26 h; Stage #2: Acidic aq. solution
A mixture of the Diels-Alder adduct (1.71 g, 7.2 mmol) and LiOH.H2O (0.81 g, 21.7 mmol) in THF/water (5:4 38 mL) was vigorously stirred at rt for 26 h. THF was removed in vacuo, the aq solution acidified to pH 2 and extracted with n-pentane/DCM (98:2). After drying the organic layer over Na2SO4, the solvent was evaporated under reduced pressure. The residue was purified through column chromatography (eluent 15percent EtOAc/hexane) to afford the acid 5 (0.86 g, 94percent) as a viscous liquid. Rf (15percent EtOAc/hexane) 0.3; [α]D25 +93.7 (c 1, MeOH); (Reported [α]D22 +95 (c 7, MeOH)); νmax (KBr) 2968, 2932, 1720, 1624, 1224, 802 cm-1; δH (300 MHz, CDCl3) 5.80-5.60 (m, 2H), 2.67-2.51 (m, 1H), 2.37-2.22 (m, 2H), 2.21-1.97 (m, 3H), 1.80-1.61 (m, 1H); δC NMR (75 MHz, CDCl3): δ 182.5, 126.6, 124.9, 39.1, 27.1, 24.7, 24.2; m/z (MS-ESI) 149 [M+Na]+.
Crude (S) -3-cyclohexane-1-carboxylic acid / (1R, 2S) -1-amino-3-cyclohexane-1-carboxylic acid (4.55 g), (1R, 2S) -1-amino-2-indanol (4.30 g) was added to water containing 2-propanol (45 mL), heated to 60 ° C. To dissolve the precipitate. The reaction solution was cooled to 50 ° C. and stirred for 2 hours after crystallization. It was gradually cooled to room temperature at 5 ° C / h and stirred for 12 hours. The precipitate was collected by filtration, washed with 2-propanol (10 mL), and dried under reduced pressure at 40 ° C. to obtain the title compound (5.05 g, 50.9percent, 26.5percent ee) as a white solid
Reference：
[1] Patent: JP2016/65024, 2016, A, . Location in patent: Paragraph 0042
A mixture of the Diels-Alder adduct (1.71 g, 7.2 mmol) and LiOH.H2O (0.81 g, 21.7 mmol) in THF/water (5:4 38 mL) was vigorously stirred at rt for 26 h. THF was removed in vacuo, the aq solution acidified to pH 2 and extracted with n-pentane/DCM (98:2). After drying the organic layer over Na2SO4, the solvent was evaporated under reduced pressure. The residue was purified through column chromatography (eluent 15% EtOAc/hexane) to afford the acid 5 (0.86 g, 94%) as a viscous liquid. Rf (15% EtOAc/hexane) 0.3; [alpha]D25 +93.7 (c 1, MeOH); (Reported [alpha]D22 +95 (c 7, MeOH)); numax (KBr) 2968, 2932, 1720, 1624, 1224, 802 cm-1; deltaH (300 MHz, CDCl3) 5.80-5.60 (m, 2H), 2.67-2.51 (m, 1H), 2.37-2.22 (m, 2H), 2.21-1.97 (m, 3H), 1.80-1.61 (m, 1H); deltaC NMR (75 MHz, CDCl3): delta 182.5, 126.6, 124.9, 39.1, 27.1, 24.7, 24.2; m/z (MS-ESI) 149 [M+Na]+.
With iodine; sodium hydrogencarbonate; potassium iodide; In water; at 0 - 20℃; for 24h;
Synthesis of Intermediate V:Acid IV (8.30 g, 65.7 mmol) was placed in a flask purged with argon and suspended in water (180 ml). The reaction mixture was cooled down to 0 C. and NaHCO3 (16.6 g, 197 mmol) was added, followed by a solution of KI (65.4 g, 394 mmol) and iodine (17.5 g, 68.9 mmol) in water (150 ml). The reaction was stirred at r.t. for 24 h and then extracted three times with CH2Cl2 (3×60 ml). The combined organic layers were washed with a solution of Na2S2O3 (50 g) in water (250 ml). The aqueous layer was extracted twice with CH2Cl2 (2×60 ml). The combined organic layers were protected from light, dried over Na2SO4, filtered and concentrated in vacuo (20 mbar) and quickly in high vacuo to afford iodolactone V as an off-white solid (15.79 g, 95%). [alpha]D21+35.960 (c=0.565, CHCl3).
95%
With iodine; sodium hydrogencarbonate; potassium iodide; In water; at 0 - 20℃; for 24h;
Acid IV (8.30 g, 65.7 mmol) was placed in a flask purged with argon and suspended in water (180 ml). The reaction mixture was cooled down to 0 C. and NaHCO3 (16.6 g, 197 mmol) was added, followed by a solution of KI (65.4 g, 394 mmol) and iodine (17.5 g, 68.9 mmol) in water (150 ml). The reaction was stirred at r.t. for 24 h and then extracted three times with CH2Cl2 (3×60 ml). The combined organic layers were washed with a solution of Na2S2O3 (50 g) in water (250 ml). The aqueous layer was extracted twice with CH2Cl2 (2×60 ml). The combined organic layers were protected from light, dried over Na2SO4, filtered and concentrated in vacuo (20 mbar) and quickly in high vacuo to afford iodolactone V as an off-white solid (15.79 g, 95%). [alpha]D21+35.96 (c=0.565, CHCl3).
93%
The acid 5 (0.86 g, 6.8 mmol) was added to a solution of NaHCO3 (1.7 g, 20.4 mmol) in water (18 mL) and the mixture stirred until it became homogenous. The flask was then protected from light and the mixture was treated in one portion with a solution of a mixture of KI (6.7 g, 40.8 mmol) and iodine (1.81 g, 7.14 mmol) in water (18 mL). The reaction mixture was stirred at rt for 20 h and then extracted with CHCl3 thrice. The combined organic extracts were washed successively with 10% aq Na2S2O3, 10% aq NaHCO3, water, and then dried over Na2SO4. The solvent was removed under reduced pressure to afford the crude compound that was purified by column chromatography (eluent 10% EtOAc/hexane) to afford the iodolactone 6 (1.6 g, 93%) as a yellow solid. Mp 135-136 C; [alpha]D25 +37.2 (c 1, CHCl3); (Reported [alpha]D24 +37.6 (c 2.03, CHCl3));6 numax (KBr) 2961, 2926, 1773, 1262, 1105, 1078, 802 cm-1; deltaH (300 MHz, CDCl3) 4.77 (t, J=5.4 Hz, 1H), 4.48 (t, J=4.3 Hz, 1H), 2.76 (d, J=12.3 Hz, 1H), 2.66-2.57 (m, 1H), 2.51-2.29 (m, 2H), 2.09 (dd, J=16.6, 4.3 Hz, 1H), 1.95-1.74 (m, 2H); deltaC (75 MHz, CDCl3) 177.4, 79.8, 38.3, 34.2, 29.4, 23.8, 22.8; m/z (MS-ESI) 275 [M+Na]+.
93%
With iodine; sodium hydrogencarbonate; potassium iodide; In water; at 20℃; for 5h;
General procedure: Sodium bicarbonate (56 g, 0.67 mol) was added to a solution of 5a (28 g, 0.22 mol) in water (450 mL). To the solution, iodine (59.8 g, 0.24 mol) and potassium iodide (220 g, 1.33 mol) were added successively, followed by stirring at room temperature for 5 h. The reaction mixture was quenched with sodium thiosulfate, and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with water (100 mL) and saturated brine (100 mL), and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The obtained pale yellow solid was added hexane (150 mL) and stirred at room temperature for 1 h, the solid was collected by filtration and dried to give 6a (50.9 g, 91%) as a white solid; [alpha]25D -20.4 (c 1.0, MeOH); 1H NMR (400 MHz, CDCl3) delta 4.97-4.74 (m, 1H), 4.51 (t, J = 4.4 Hz, 1H), 2.79 (d, J = 12.3 Hz, 1H), 2.67 (t, J = 3.9 Hz, 1H), 2.52-2.34 (m, 2H), 2.12 (dd, J = 16.5, 5.2 Hz, 1H), 1.98-1.77 (m, 2H); 13C NMR (100 MHz, CDCl3) delta 177.74, 80.21, 38.60, 34.51, 29.72, 23.81, 23.12; HRMS (ESI; m/z) [M+Na]+ calcd for C7H9O2INa 274.9545, found 274.9555. For the enantiomer 6b; a white solid; 93% yield; [alpha]25D +26.5 (c 1.0, MeOH); HRMS (ESI; m/z) [M+Na]+ calcd for C7H9O2INa 274.9545, found 274.9549.
With iodine; sodium hydrogencarbonate; potassium iodide; In water; at 0 - 20℃; for 24h;
Synthesis of compound 6:; Compound 5 (4 g) is suspended in water (90 ml) and cooled down to 0C. NaHC03 (8 g) is added followed by a solution of KI (32 g) and h (8 g) in water (75 ml). The reaction mixture is stirred at RT for 24 h and then extracted with CH2CI2 (3x30 ml). The combined organic layers are washed with a saturated solution of Na2S203 in water (125 ml). The aqueous layer is extracted with CH2CI2 (2x30 ml). The combined organic layers are protected from light, dried(Na2S04), filtered, and concentrated quickly under high vacuum to dryness to afford iodolactone 6 as an off-white solid (7.5 g).
With iodine; sodium hydrogencarbonate; potassium iodide; In water; at 0 - 20℃;
Compound 5 (4 g) is suspended in water (90 ml) and cooled down to O0C. NaHCO3 (8 g) is added followed by a solution of KI (32 g) and I2 (8 g) in water (75 ml). The reaction mixture is stirred at RT for 24 h and then extracted with CH2Cl2 (3x30 ml). The combined organic layers are washed with a saturated solution OfNa2S2O3 in water (125 ml). The aqueous layer is extracted with CH2Cl2 (2x30 ml). The combined organic layers are protected from light, dried (Na2SO4), filtered, and concentrated to dryness and quickly under high vacuum to afford iodolactone 6 as an off-white solid (7.5 g).
1) Benzyl (1R)-3-cyclohexene-1-carboxylate was obtained from (1R)-3-cyclohexene-1-carboxylic acid (J.Am. Chem. Soc., 1978, Vol. 100, p. 5199) in a similar manner to Referential Example 169.
Synthesis of Intermediate IV:To a stirred suspension of methylester III (5.19 g, 37.0 mmol) in pH 7.00 phosphate buffer solution (520 ml, 0.07 M), PLE (51.2 mg, 1382 units) was added. The pH was kept at 7 by adding NaOH solution (1.0 M) via syringe pump. The reaction was stirred at r.t. until one equivalent of NaOH (37 ml) was used (11 h, TLC-control: petroleum ether/Et20, 1:1). The reaction mixture was transferred into a separation funnel and washed twice with ethyl acetate (2×300 ml). The layers were separated and the organic layers were extracted twice with pH 7.00 phosphate buffer solution (2×300 ml). The combined aqueous layers were acidified to pH 2 with aqueous HCl (30 ml, 4 M) and extracted three times with ethyl acetate (3×400 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo (100 mbar). The crude product was filtered through a short plug of silica affording acid IV as a pale yellowish oil (3.92 g, 84%). 96.3% ee. (GC), 94.3% ee. (rot.), [alpha]D21+89.12 (c=6.730, MeOH), (Lit. +94.5 (c=7, MeOH), [Acta Chem. Scand., 1970, 24, 2693]).
84%
To a stirred suspension of methylester III (5.19 g, 37.0 mmol) in pH 7.00 phosphate buffer solution (520 ml, 0.07 M), PLE (51.2 mg, 1382 units) was added. The pH was kept at 7 by adding NaOH solution (1.0 M) via syringe pump. The reaction was stirred at r.t. until one equivalent of NaOH (37 ml) was used (11 h, TLC-control: petroleum ether/Et2O, 1:1). The reaction mixture was transferred into a separation funnel and washed twice with ethyl acetate (2×300 ml). The layers were separated and the organic layers were extracted twice with pH 7.00 phosphate buffer solution (2×300 ml). The combined aqueous layers were acidified to pH 2 with aqueous HCl (30 ml, 4 M) and extracted three times with ethyl acetate (3×400 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo (100 mbar). The crude product was filtered through a short plug of silica affording acid IV as a pale yellowish oil (3.92 g, 84%). 96.3% ee. (GC), 94.3% ee. (rot.), [alpha]D21+89.12 (c=6.730, MeOH), (Lit.+94.5 (c=7, MeOH), [Acta Chem. Scand., 1970, 24, 2693]).
With sodium hydroxide; In water; at 20℃;pH 7;Aqueous phosphate buffer;
To a suspension of compound IV (4 g) in phosphate buffer (400 ml, pH 7) is added PLE (42 mg) with stirring. The pH is kept at 7 by adding NaOH solution (1M) via syringe pump. The reaction mixture is stirred at RT until 1 equivalent of NaOH is used. The reaction mixture is transferred to a seperatory funnel and washed with EtOAc (2×250 ml). The layers are separated and the organic layers extracted with phosphate buffer (2×250 ml, pH 7). The combined aqueous layers are acidified to pH 2 with aqueous HCl solution and extracted with EtOAc (3×300 ml). The combined organic layers are dried (Na2SO4), filtered and evaporated to dryness. The crude product is filtered through a short plug of silica to afford compound V (3 g).
Synthesis of compound 5:; To a suspension of compound 4 (4 g) in phosphate buffer (400 ml, pH 7) is added PLE (42 mg) with stirring. The pH is kept at 7 by adding NaOH solution (1M) via syringe pump. The reaction mixture is stirred at RT until 1 equivalent of NaOH is used. The reaction mixture is transferred to a separatory funnel and washed with EtOAc (2x250 ml). The layers are separated and the organic layers are extracted with phosphate buffer (2x250 ml, pH 7). The combined aqueous layers are acidified to pH 2 with aqueous HC1 solution and extracted with EtOAc (3x300 ml). The combined organic layers are dried (Na2S04), filtered and evaporated to dryness. The crude product is filtered through a short plug of silica to afford compound 5 (3 g).
To a suspension of compound 4 (4 g) in phosphate buffer (400 ml, pH 7) is added PLE (42 mg) with stirring. The pH is kept at 7 by adding NaOH solution (IM) via syringe pump. The reaction mixture is stirred at RT until 1 equivalent of NaOH is used. The reaction mixture is transferred to a separatory funnel and washed with EtOAc (2x250 ml). The layers are separated and the organic layers are extracted with phosphate buffer (2x250 ml, pH 7). The combined aqueous layers are acidified to pH 2 with aqueous HCl solution and extracted with EtOAc (3x300 ml). The combined organic layers are dried (Na2SO4), filtered and evaporated to dryness. The crude product is filtered through a short plug of silica to afford compound 5 (3 g).
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20 - 120℃; for 18h;Product distribution / selectivity;
(R)-3-Cyclohexene-1-carboxylic acid (1.0 g, 97% ee) was dissolved in N,N-dimethylformamide (10 ml). To the solution, 60% sodium hydride (634 mg) was added at room temperature, and the mixture was stirred at 120C for 18 hours. The reaction solution was cooled to room temperature, and 10% aqueous citric acid solution was then added dropwise thereto, followed by extraction with cyclopentyl methyl ether. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the obtained residue was then subjected to silica gel column chromatography (chloroform-methanol=3:1) to obtain 892 mg of the title compound as a colorless oil. Its optical purity was 0% ee. The H-NMR spectroscopic data were in agreement with those of Example 3.
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