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Stage #1: With chloro-trimethyl-silane In dichloromethane at 0 - 15℃; Inert atmosphere Stage #2: With lithium aluminium tetrahydride In tetrahydrofuran; dichloromethane at -10 - 0℃; Inert atmosphere
General procedure: In typical experimental procedure for the Synthesis of (3aS,12bS)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrolemaleate(1b’): Amide (1a) (10 g, 33.43 mmol) and DCM (100 mL) were charged into a round bottomed flask and stirred under nitrogen atmosphere for 10-15 minutes and cooled to 0-5°C. Trimethylsilyl chloride (5.1 mL, 40.12 mmol) was then added to the mixture over 10-15 minutes and stirred for 10-15 minutes at same temperature.Lithium aluminum hydride (19.5 mL, 46.81 mmol) in THF solution is added dropwise at -10-0°C. After complete addition, the solution is allowed to 0-10°C and stirring is continued for 1-2 hours. After completion of reaction (TLC), thereaction was quenched by slow dropwise addition of 2M sodium hydroxide (30 mL)and stirred for 10-15 minutes. Separate aqueous and organic layer. Extract the compound from aqueous layer with DCM (50.0 mL). Combine both the organic layerand wash with 20percent sodium chloride solution. Concentrate the DCM to get the crude which was dissolved in isopropyl alcohol (50.0 mL).
7; 8
Example 7; Preparation of 2-amino-6-(alkyl)amino-4,5,6,7-tetrahydrobenzothiazole Compounds of Formulas (lOa) and(lOb) Under Normal Phase Conditions on a Chiralpak ADColumn; [0070] The resolution of a compound of formula (10) was completed asfollows. A sample solution was prepared by dissolving 100 mg of compound offormula (10) in 20 mL of EtOH by using sonication, then 80 mL of heptane wasadded. The sample solution was loaded onto the Chiralpak AD column (50 mm x500 mm) using 1:9 EtOH/Heptane with 0.1% TFA as mobile phase. The firstenantiomer was observed from 12.5-14.5 minutes while the second one elutedfrom 16-18 minutes. Both components were collected and concentrated todryness using a bench-top rotary evaporator.Example 8 Preparation of 2-amino-6-(alkyl)amino-4,5,6.)7-tetrahydrobenzothiazole Compounds of Formulas (lOa) and(lOb) Under Polar Organic Conditions on a Chiralpak ADColumn[0071] The resolution of the compound of formula (10) was completed asfollows. A sample solution was prepared by dissolving 100 mg of compound offormula (10) in 100 mL of 5:95 IPA/ACN with 0.2% DBA. The sample solutionwas loaded onto the Chiralpak AD column (50 mm x 500 mm) using the sameabove-mentioned mobile phase. The first enantiomer was observed from 18.5-22minutes while the second one eluted from 23.5-27 minutes. Both componentswere collected and processed as for the normal phase resolution processes inExample 7. This method is preferred for large-scale resolution processes.[0072] Samples of the resolved material (1 mg each) from Examples 7 and8 were dissolved at 1 mg/mL in a 15:85 EtOH/heptane solution and analyzed byHPLC. The chiral purity of both fractions was greater than 99%, while therecovery was greater than 90%. The elution order of the fractions was the same inboth methods according to the results obtained from analyzing the polar organicfractions in the normal phase method.
General procedure: In typical experimental procedure for the Synthesis of (3aS,12bS)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrolemaleate(1b?): Amide (1a) (10 g, 33.43 mmol) and DCM (100 mL) were charged into a round bottomed flask and stirred under nitrogen atmosphere for 10-15 minutes and cooled to 0-5C. Trimethylsilyl chloride (5.1 mL, 40.12 mmol) was then added to the mixture over 10-15 minutes and stirred for 10-15 minutes at same temperature.Lithium aluminum hydride (19.5 mL, 46.81 mmol) in THF solution is added dropwise at -10-0C. After complete addition, the solution is allowed to 0-10C and stirring is continued for 1-2 hours. After completion of reaction (TLC), thereaction was quenched by slow dropwise addition of 2M sodium hydroxide (30 mL)and stirred for 10-15 minutes. Separate aqueous and organic layer. Extract the compound from aqueous layer with DCM (50.0 mL). Combine both the organic layerand wash with 20% sodium chloride solution. Concentrate the DCM to get the crude which was dissolved in isopropyl alcohol (50.0 mL).