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Example 2: Production of [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-li7- pyrido [4,3-6] indole; [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-6]indole may be prepared by mixing 6-bromo-2,3,4,5-tetrahydro-lH-pyrido [4,3-6] indole hydrochloric acid salt with trifluoracetic acid (630 ml, 8.48mmol) and triethylsilane (172 ml). The mixture is stirred at room temperature under nitrogen for 19 hours. Excess trifluoroacetic acid and triethylsilane are removed in vacuo. etaexanes (550 ml) are added to the remaining oil and stirred at room temperature for 1 hour; the hexanes are decanted. An additional 250 ml of hexanes are added, stirred for 1 hour and decanted. 2N sodium hydroxide is added to the remaining oil until the peta=10 and then is extracted with dichloromethane. The organic layers are combined and washed with brine and dried (Na2SO4).[0078] Enantiomeric separation of [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b- hexahydro-lH-pyrido[4,3-6]indole may be carried out by dissolving racemate 6-bromo- 2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-]indole (8g, 31.6mmol) in methanol (16OmL) at 50C (oil bath) and adding (R)-mandelic acid (4.8g, 31.6mmol) in portions. The <n="84"/>resulting clear solution is stirred at 50C for several minutes and ether (8OmL) is added dropwise. The resulting solution is cooled to room temperature and the white precipitate (R-Mandelate sale, 3.7g) is filtered off. HPLC analysis shows >99%ee. The filtrate is concentrated, treated with IN sodium hydroxyide (10OmL) and is extracted twice with dichloromenthane (2x5 OmL). The dichloromethane layers are combined, washed with brine (2x200mL) and dried with sodium sulphate. The dichoromethane solution is concentrated to an oil (5.59g) and is redissolved in methanol (9OmL) at 5O0C. (S)-(+)-mandelic acid (3.53g, 23.2mmol) is added in portions. The resulting clear solution is stirred at 500C for several minutes and ether (45mL) is added dropwise. The resulting solution is cooled to room temperature and the white precipitate (S- Mandelate salt, 4.19g) is filtered off. HPLC analysis shows >99%ee. R-Mandelate: [alpha]D25 = -98.1, S-Mandelate: [alpha]D25 = +102, solvent: DMSO. Alternatively, the resolution may be carried out in a mixutre of methanol and t-butylmethylether (MTBE).[0079] Alternatively, [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-l//- pyrido[4,3-6]indole may be separated by dissolving racemate 6-bromo-2,3,4,4a,5,9b- hexahydro-lH-pyrido[4,3-]indole (9.61g, 38.0mmol) in methanol (19OmL) at 50C and adding (S)-(+)-Mandelic acid (5.78g, 38.0mmol) in portions. The resulting clear solution is stirred at 500C for several minutes and ether (95mL) is added dropwise. The resulting solution is cooled to room temperature. The white precipitate (S-Mandelate salt, 4.Ig) is filtered off. etaPLC analysis shows >99%ee.[0080] Enantiomeric separation of [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b- hexahydro-lH-pyrido[4,3-6]indole may also be carried out by dissolving Racemic 6- bromo-2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-&]indole (1710 gm "as is," 1570gm by theory, 6.21 mol) in methanol (24 1) by warming to 40-500C (under nitrogen). To the mixture is added (R)-(-)-Mandelic acid (944 g, 6.2 mol) in one portion. The power to the heating mantle is turned-off and MTBE (13L) is charged to the mixture. The resulting solution is allowed to cool to room temperature with stirring and aged for 30- 40hours at 15-250C with stirring. The product is isolated by filtration as a white to off- white precipitate and allowed to air dry at ambient temperature overnight. This affords 580 gm (23%) of the Int-2 R-Mandelate salt. Chiral etaPLC analysis shows the undesired slower moving enantiomer is present as a single peak (>99%ee). <n="85"/>[0081] The filtrate is concentrated, diluted with water (25 L), stirred and treated with 50% NaOH (800ml) to a pH of ~14 as measured by pH paper. The free base is extracted with dichloromethane (2 x 17L and 1 x 6L). The DCM layers are combined, dried (Na2SO4) and concentrated to afford a solid free base (~1150 g). The free base is dissolved in methanol (17 L) by warming to 40-500C under N2 and (S)-(+)-Mandelic acid (692 g, 4.55 mol) is added. The heating mantle is turned off and to the solution is added MTBE (8.5 L) in one portion. The resulting solution is allowed to cool to room temperature with stirring and aged for 30-40 hours. The product is isolated by filtration as a white to off-white precipitate and air dried at ambient temperature overnight. This afforded 828 gm (33%) of S-Mandelate salt. Chiral HPLC analysis showed the faster moving enantiomer is present (>99%ee) with two other impurities present at ~1% each (which elute just before the undesired enantiomer). R-Mandelate: [CC]D25= -98.1, S- Mandelate: [alpha]D25= +102, solvent:DMSO (about 10 mg in 3 ml DMSO). Chiral HPLC conditions: ChiralPak AD-H, 250 x 4.6 mm, 30% IPA in hexanes containing 0.1% diethylamine, flow 0.8 ml/min, UV detection at 254 ran. Samples are prepared by sonicating the salt in IP... |
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Example 2: Production of [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-li7- pyrido [4,3-6] indole; [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-6]indole may be prepared by mixing 6-bromo-2,3,4,5-tetrahydro-lH-pyrido [4,3-6] indole hydrochloric acid salt with trifluoracetic acid (630 ml, 8.48mmol) and triethylsilane (172 ml). The mixture is stirred at room temperature under nitrogen for 19 hours. Excess trifluoroacetic acid and triethylsilane are removed in vacuo. etaexanes (550 ml) are added to the remaining oil and stirred at room temperature for 1 hour; the hexanes are decanted. An additional 250 ml of hexanes are added, stirred for 1 hour and decanted. 2N sodium hydroxide is added to the remaining oil until the peta=10 and then is extracted with dichloromethane. The organic layers are combined and washed with brine and dried (Na2SO4).[0078] Enantiomeric separation of [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b- hexahydro-lH-pyrido[4,3-6]indole may be carried out by dissolving racemate 6-bromo- 2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-]indole (8g, 31.6mmol) in methanol (16OmL) at 50C (oil bath) and adding (R)-mandelic acid (4.8g, 31.6mmol) in portions. The <n="84"/>resulting clear solution is stirred at 50C for several minutes and ether (8OmL) is added dropwise. The resulting solution is cooled to room temperature and the white precipitate (R-Mandelate sale, 3.7g) is filtered off. HPLC analysis shows >99%ee. The filtrate is concentrated, treated with IN sodium hydroxyide (10OmL) and is extracted twice with dichloromenthane (2x5 OmL). The dichloromethane layers are combined, washed with brine (2x200mL) and dried with sodium sulphate. The dichoromethane solution is concentrated to an oil (5.59g) and is redissolved in methanol (9OmL) at 5O0C. (S)-(+)-mandelic acid (3.53g, 23.2mmol) is added in portions. The resulting clear solution is stirred at 500C for several minutes and ether (45mL) is added dropwise. The resulting solution is cooled to room temperature and the white precipitate (S- Mandelate salt, 4.19g) is filtered off. HPLC analysis shows >99%ee. R-Mandelate: [alpha]D25 = -98.1, S-Mandelate: [alpha]D25 = +102, solvent: DMSO. Alternatively, the resolution may be carried out in a mixutre of methanol and t-butylmethylether (MTBE).[0079] Alternatively, [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-l//- pyrido[4,3-6]indole may be separated by dissolving racemate 6-bromo-2,3,4,4a,5,9b- hexahydro-lH-pyrido[4,3-]indole (9.61g, 38.0mmol) in methanol (19OmL) at 50C and adding (S)-(+)-Mandelic acid (5.78g, 38.0mmol) in portions. The resulting clear solution is stirred at 500C for several minutes and ether (95mL) is added dropwise. The resulting solution is cooled to room temperature. The white precipitate (S-Mandelate salt, 4.Ig) is filtered off. etaPLC analysis shows >99%ee.[0080] Enantiomeric separation of [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b- hexahydro-lH-pyrido[4,3-6]indole may also be carried out by dissolving Racemic 6- bromo-2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-&]indole (1710 gm "as is," 1570gm by theory, 6.21 mol) in methanol (24 1) by warming to 40-500C (under nitrogen). To the mixture is added (R)-(-)-Mandelic acid (944 g, 6.2 mol) in one portion. The power to the heating mantle is turned-off and MTBE (13L) is charged to the mixture. The resulting solution is allowed to cool to room temperature with stirring and aged for 30- 40hours at 15-250C with stirring. The product is isolated by filtration as a white to off- white precipitate and allowed to air dry at ambient temperature overnight. This affords 580 gm (23%) of the Int-2 R-Mandelate salt. Chiral etaPLC analysis shows the undesired slower moving enantiomer is present as a single peak (>99%ee). <n="85"/>[0081] The filtrate is concentrated, diluted with water (25 L), stirred and treated with 50% NaOH (800ml) to a pH of ~14 as measured by pH paper. The free base is extracted with dichloromethane (2 x 17L and 1 x 6L). The DCM layers are combined, dried (Na2SO4) and concentrated to afford a solid free base (~1150 g). The free base is dissolved in methanol (17 L) by warming to 40-500C under N2 and (S)-(+)-Mandelic acid (692 g, 4.55 mol) is added. The heating mantle is turned off and to the solution is added MTBE (8.5 L) in one portion. The resulting solution is allowed to cool to room temperature with stirring and aged for 30-40 hours. The product is isolated by filtration as a white to off-white precipitate and air dried at ambient temperature overnight. This afforded 828 gm (33%) of S-Mandelate salt. Chiral HPLC analysis showed the faster moving enantiomer is present (>99%ee) with two other impurities present at ~1% each (which elute just before the undesired enantiomer). R-Mandelate: [CC]D25= -98.1, S- Mandelate: [alpha]D25= +102, solvent:DMSO (about 10 mg in 3 ml DMSO). Chiral HPLC conditions: ChiralPak AD-H, 250 x 4.6 mm, 30% IPA in hexanes containing 0.1% diethylamine, flow 0.8 ml/min, UV detection at 254 ran. Samples are prepared by sonicating the salt in IP... |
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In methanol; at 50℃;Resolution of racemate;Purification / work up; |
Example 2: Production of [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-li7- pyrido [4,3-6] indole; [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-6]indole may be prepared by mixing 6-bromo-2,3,4,5-tetrahydro-lH-pyrido [4,3-6] indole hydrochloric acid salt with trifluoracetic acid (630 ml, 8.48mmol) and triethylsilane (172 ml). The mixture is stirred at room temperature under nitrogen for 19 hours. Excess trifluoroacetic acid and triethylsilane are removed in vacuo. etaexanes (550 ml) are added to the remaining oil and stirred at room temperature for 1 hour; the hexanes are decanted. An additional 250 ml of hexanes are added, stirred for 1 hour and decanted. 2N sodium hydroxide is added to the remaining oil until the peta=10 and then is extracted with dichloromethane. The organic layers are combined and washed with brine and dried (Na2SO4).[0078] Enantiomeric separation of [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b- hexahydro-lH-pyrido[4,3-6]indole may be carried out by dissolving racemate 6-bromo- 2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-]indole (8g, 31.6mmol) in methanol (16OmL) at 50C (oil bath) and adding (R)-mandelic acid (4.8g, 31.6mmol) in portions. The <n="84"/>resulting clear solution is stirred at 50C for several minutes and ether (8OmL) is added dropwise. The resulting solution is cooled to room temperature and the white precipitate (R-Mandelate sale, 3.7g) is filtered off. HPLC analysis shows >99%ee. The filtrate is concentrated, treated with IN sodium hydroxyide (10OmL) and is extracted twice with dichloromenthane (2x5 OmL). The dichloromethane layers are combined, washed with brine (2x200mL) and dried with sodium sulphate. The dichoromethane solution is concentrated to an oil (5.59g) and is redissolved in methanol (9OmL) at 5O0C. (S)-(+)-mandelic acid (3.53g, 23.2mmol) is added in portions. The resulting clear solution is stirred at 500C for several minutes and ether (45mL) is added dropwise. The resulting solution is cooled to room temperature and the white precipitate (S- Mandelate salt, 4.19g) is filtered off. HPLC analysis shows >99%ee. R-Mandelate: [alpha]D25 = -98.1, S-Mandelate: [alpha]D25 = +102, solvent: DMSO. Alternatively, the resolution may be carried out in a mixutre of methanol and t-butylmethylether (MTBE).[0079] Alternatively, [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-l//- pyrido[4,3-6]indole may be separated by dissolving racemate 6-bromo-2,3,4,4a,5,9b- hexahydro-lH-pyrido[4,3-]indole (9.61g, 38.0mmol) in methanol (19OmL) at 50C and adding (S)-(+)-Mandelic acid (5.78g, 38.0mmol) in portions. The resulting clear solution is stirred at 500C for several minutes and ether (95mL) is added dropwise. The resulting solution is cooled to room temperature. The white precipitate (S-Mandelate salt, 4.Ig) is filtered off. etaPLC analysis shows >99%ee.[0080] Enantiomeric separation of [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b- hexahydro-lH-pyrido[4,3-6]indole may also be carried out by dissolving Racemic 6- bromo-2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-&]indole (1710 gm "as is," 1570gm by theory, 6.21 mol) in methanol (24 1) by warming to 40-500C (under nitrogen). To the mixture is added (R)-(-)-Mandelic acid (944 g, 6.2 mol) in one portion. The power to the heating mantle is turned-off and MTBE (13L) is charged to the mixture. The resulting solution is allowed to cool to room temperature with stirring and aged for 30- 40hours at 15-250C with stirring. The product is isolated by filtration as a white to off- white precipitate and allowed to air dry at ambient temperature overnight. This affords 580 gm (23%) of the Int-2 R-Mandelate salt. Chiral etaPLC analysis shows the undesired slower moving enantiomer is present as a single peak (>99%ee). <n="85"/>[0081] The filtrate is concentrated, diluted with water (25 L), stirred and treated with 50% NaOH (800ml) to a pH of ~14 as measured by pH paper. The free base is extracted with dichloromethane (2 x 17L and 1 x 6L). The DCM layers are combined, dried (Na2SO4) and concentrated to afford a solid free base (~1150 g). The free base is dissolved in methanol (17 L) by warming to 40-500C under N2 and (S)-(+)-Mandelic acid (692 g, 4.55 mol) is added. The heating mantle is turned off and to the solution is added MTBE (8.5 L) in one portion. The resulting solution is allowed to cool to room temperature with stirring and aged for 30-40 hours. The product is isolated by filtration as a white to off-white precipitate and air dried at ambient temperature overnight. This afforded 828 gm (33%) of S-Mandelate salt. Chiral HPLC analysis showed the faster moving enantiomer is present (>99%ee) with two other impurities present at ~1% each (which elute just before the undesired enantiomer). R-Mandelate: [CC]D25= -98.1, S- Mandelate: [alpha]D25= +102, solvent:DMSO (about 10 mg in 3 ml DMSO). Chiral HPLC conditions: ChiralPak AD-H, 250 x 4.6 mm, 30% IPA in hexanes containing 0.1% diethylamine, flow 0.8 ml/min, UV detection at 254 ran. Samples are prepared by sonicating the salt in IP... |
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