Density (g ml -1 ) Volume (cm 3 ) 2- chloroethanol

Transcription

1 Method 2: Synthesis of morpholines using copper triflate catalyst - step 1 Summary of First Pass Metrics Toolkit Yield, AE, RME, MI/PMI and OE Reactant (Limiting Reactant First) MW Mol Catalyst Reagent Reaction Volume (cm 3 ) Work up chemical Workup Volume (cm3) (R )-2-phenyl-1- tosylaziridine copper triflate chloroethanol sodium sulfate DCM chloroethanol EtOAc #DIV/0! petroleum ether #DIV/0! sat. NaHCO3 soln Total Yield Conversion x x Selectivity x x Mass MW Mol AE Product RME OE mass Unreacted limiting PMI total reactant unknown PMI Reaction Solvents (First Pass) Preferred s water, EtOH, nbuoh, AcOipr, AcOnBu, PhOMe, MeOH, tbuoh, BnOH, ethylene glycol, acetone, MEK, MIBK, AcOEt, sulfolane PMI reactants, reagents, catalyst PMI reaction s PMI Workup PMI Workup chemical PMI workup s List s below EtOAc Experimental: A solution of (R)-2-phenyl-1-tosylaziridine (100 mg, 0.37 mmol, 1.0 equiv) in 2-chloroethanol (0.25mL, 3.7 mmol, 10 equiv) was added at 0 C to anhydrous copper triflate (27mg, 20 mol %) under an argon atmosphere. The mixture was stirred for 5 min and then the reaction was quenched with saturated aqueous sodium bicarbonate solution (5mL). The aqueous layer was extracted with dichloromethane (3 x 5 ml) and dried over anhydrous sodium sulfate (1g). The crude product was purified by flash column chromatography on silica gel using 15% ethyl acetate in petroleum ether (150mL in total) to provide the pure product (S)-N-(2-chloroethoxy)-2-phenyl)-4- methylbenzenesulfonamide (112 mg, 87% yield, 78% ee). Adapted with permission from J. Org. Chem., 2009, 74, Copyright 2009 American Chemical Society. Some adaptations have been made: volumes and masses for some work-up chemicals have been estimated to allow metrics calculations. This has been done using best approximations based on the scale of the reaction where data was not provided. Problematic s: (acceptable only if substitution does not offer advantages) Hazardous s: These s have significant health and/or safety concerns. Highly hazardous s: The s which are agreed not to be used, even in screening DMSO, cyclohexanone, DMPU, AcOH, Ac2O, Acetonitrile, AcOMe, THF, heptane, Me-cyclohexane, toluene, xylene, MTBE, cyclohexane, chlorobenzene, formic acid, pyridine, Me-THF dioxane, pentane, TEA, diisopropyl ether, DME, DCM, DMF, DMA, NMP, methoxyethanol, hexane, petroleum ether Et 2 O, Benzene, CCl 4, chloroform, DCE, nitromethane, CS 2, HMPA Petroleum ether NB chloroethanol not covered Instructions for use: Enter your data into the tables above to automatically calculate yield, AE, RME, MI/PMI and OE. Use the blank boxes in the tables to enter experimental data and note the flags for each Key Parameter. Printing tips: This spreadsheet is designed to be printed with 'landscape', 'narrow margin' and 'fit all columns on one page' settings Catalyst/enzyme (First Pass) Tick Tick Catalyst or enzyme used, or reaction takes place Green without any catalyst/reagents. Facile recovery of catalyst/enzyme Green Use of stoichiometric quantities of reagents Amber catalyst/enzyme not recovered Amber Use of reagents in excess Red

2 Critical elements Supply remaining colour Note element 5-50 years Red years Amber +500 years Green Energy (First Pass) Tick Tick Reaction run between 0 to 70 o C Green Reaction run at reflux Red Reaction run between -20 to 0 or 70 to Amber Reaction run 5 o C or more below the Reaction run below -20 or above 140 o Green C Red boiling point Batch/flow Tick Work Up List Flow Batch Green Amber quenching filtration centrifugation Green crystallisation Low temperature distillation/evaporation/ exchange, quenching into aqueous Amber chromatography/ion exchange high temperature Red multiple recrystallisation Health & safety Highly explosive Explosive thermal runaway Toxic Long Term toxicity Environmental implications Red Amber Green H200, H201, H202, H203 H205, H220, H224 If no red or amber H230, H240, H250 H241 flagged H codes present then green flag H300, H310, H330 H301, H311, H331, H340, H350, H360, H370, H341, H351, H361, H371, H400, H410, H411, H420 H401, H412 List substances and H-codes List substances and H-codes List substances and H-codes chloroethanol H300, H310, H330 product This education and training material has been created with funding from the Innovative Medicines Initiative Joint Undertaking under grant agreement n , resources of which are composed of financial contribution from the European Union s Seventh Framework Programme (FP7/ ) and EFPIA companies in kind contribution The views expressed in regards to education and training materials represent the aspiration of the CHEM21 consortium, although may not always be the view of each individual organisation

3 Method 2: Synthesis of morpholines using copper triflate catalyst - step 2 Summary of First Pass Metrics Toolkit Yield, AE, RME, MI/PMI and OE Reactant (Limiting Reactant First) MW Mol Catalyst Reagent Reaction solven Volume (cm 3 ) Work up chemical Workup Volume (cm3) (S)-N-(2-chloroethoxy)-2- phenyl)-4- methylbenzenesulfonam ide KOH THF sodium sulfate water #DIV/0! EtOAc (wash) #DIV/0! brine #DIV/0! EtOAc (column) #DIV/0! petroleum ether Total Yield Conversion x x Selectivity x x Mass MW Mol AE Product RME OE mass Unreacted limiting PMI total reactant unknown PMI Reaction Solvents (First Pass) Preferred s Problematic s: (acceptable only if substitution does not offer advantages) Hazardous s: These s have significant health and/or safety concerns. Highly hazardous s: The s which are agreed not to be used, even in screening water, EtOH, nbuoh, AcOipr, AcOnBu, PhOMe, MeOH, tbuoh, BnOH, ethylene glycol, acetone, MEK, MIBK, AcOEt, sulfolane DMSO, cyclohexanone, DMPU, AcOH, Ac2O, Acetonitrile, AcOMe, THF, heptane, Me-cyclohexane, toluene, xylene, MTBE, cyclohexane, chlorobenzene, formic acid, pyridine, Me-THF dioxane, pentane, TEA, diisopropyl ether, DME, DCM, DMF, DMA, NMP, methoxyethanol, hexane, petroleum ether Et 2 O, Benzene, CCl 4, chloroform, DCE, nitromethane, CS 2, HMPA PMI reactants, reagents, catlyst 1.82 PMI reaction s PMI Workup PMI Workup chemical PMI workup s List s below Catalyst/enzyme (First Pass) Tick Tick Catalyst or enzyme used, or reaction takes place Green Facile recovery of catalyst/enzyme Green without any catalyst/reagents. Amber Use of stoichiometric quantities of reagents catalyst/enzyme not recovered Amber Use of reagents in excess Red EtOAc THF petroleum ether Experimental: To a suspension of powdered KOH (31mg, 0.56mmol, 2 equiv) in dry THF (1.0 ml) was added a solution of (S)-N-(2-chloroethoxy)-2-phenyl)-4-methylbenzenesulfonamide (100 mg, 0.28 mmol, 1.0 equiv) in dry THF (5.0 ml). The mixture was stirred at room temperature for 30min. After completion of the reaction, water was added (5mL) and the reaction mixture was extracted with ethyl acetate (3 x 5.0 ml). The combined organic layer was washed with brine (10mL) and dried over anhydrous sodium sulfate (1g) and the was removed under reduced pressure. The crude product was purified by flash column chromatography on silica gel using 15% ethyl acetate and petroleum ether (150mL in total) as the eluent to afford (S)-2-Phenyl-4-tosylmorpholine as a white solid (72 mg, 80% yield, 78% ee) Adapted with permission from J. Org. Chem., 2009, 74, Copyright 2009 American Chemical Society. Some adaptations have been made: volumes and masses for some work-up chemicals have been estimated to allow metrics calculations. This has been done using best approximations based on the scale of the reaction where data was not provided. Instructions for use: Enter your data into the tables above to automatically calculate yield, AE, RME, MI/PMI and OE. Use the blank boxes in the tables to enter experimental data and note the flags for each Key Parameter. Printing tips: This spreadsheet is designed to be printed with 'landscape', 'narrow margin' and 'fit all columns on one page' settings

4 Critical elements Supply remaining colour Note element 5-50 years Red years Amber +500 years Green Energy (First Pass) Tick Tick Reaction run between 0 to 70 o C Green Reaction run at reflux Red Reaction run between -20 to 0 or 70 Amber Reaction run 5 o C or more below the Green Reaction run below -20 or above Red boiling point Batch/flow Tick Work Up List Flow Batch Green Amber quenching filtration centrifugation Green crystallisation Low temperature distillation/evaporation/ exchange, quenching into aqueous Amber chromatography/ion exchange high temperature Red multiple recrystallisation Health & safety Highly explosive Explosive thermal runaway Toxic Long Term toxicity Environmental implications Red Amber Green H200, H201, H202, H203 H205, H220, H224 If no red or amber flagged H H230, H240, H250 H241 codes present then green flag H300, H310, H330 H301, H311, H331, H340, H350, H360, H370, H341, H351, H361, H371, H400, H410, H411, H420 H401, H412 List substances and H-codes List substances and H-codes List substances and H-codes product all starting materials This education and training material has been created with funding from the Innovative Medicines Initiative Joint Undertaking under grant agreement n , resources of which are composed of financial contribution from the European Union s Seventh Framework Programme (FP7/ ) and EFPIA companies in kind contribution The views expressed in regards to education and training materials represent the aspiration of the CHEM21 consortium, althoug h may not always be the view of each individual organisation

5 Method 1: One-pot metal-free synthesis of morpholines Summary of First Pass Metrics Toolkit Yield, AE, RME, MI/PMI and OE Reactant (Limiting Reactant First) MW Mol Catalyst Reagent Reaction Volume (cm 3 ) Work up chemical Workup Volume (cm3) (S)-2-phenyl-1- tosylaziridine (NH4)2S2O chloroethanol Na2SO sat. NaHCO3 soln choroethanol KOH THF ethyl acetate #DIV/0! brine #DIV/0! ethyl acetate (column) #DIV/0! hexane #DIV/0! #DIV/0! Total Yield Conversion x x Selectivity x x Mass MW Mol AE Product RME OE mass Unreacted limiting PMI total reactant unknown PMI Reaction PMI reactants, reagents, catalyst 5.06 PMI reaction s PMI Workup PMI Workup chemical PMI workup s Experimental: A mixture of (S)-2-phenyl-1-tosylaziridine (82mg, 0.3 mmol, 1 equiv), ammonium persulfate (137 mg, 0.6 mmol, 2 equiv) and 2-chloroethanol (240mg, 3mmol, 10 equiv) was stirred at room temperature for 30 minutes. Then THF (5.0 ml) and excess KOH (202mg, 3.6mmol, 12 equiv) were added to the reaction mixture and the mixture was stirred at room temperature for a further 1 hour. After the reaction was completed, the resulting suspension was quenched with saturated aqueous sodium bicarbonate solution (5mL) and extracted with ethyl acetate (10mL). The organic layers were combined, washed with brine (10mL) and dried over anhydrous sodium sulfate (1g). Solvents were removed under reduced pressure and the residue was purified by column chromatography on silica gel using ethyl acetate/hexane (1:4 ratio) (150mL) to afford the pure product (R)-2-Phenyl-4-tosylmorpholine (88mg, 93% yield, 70% ee). Solvents (First Pass) Preferred s water, EtOH, nbuoh, AcOipr, AcOnBu, PhOMe, MeOH, tbuoh, BnOH, ethylene glycol, acetone, MEK, MIBK, AcOEt, sulfolane List s below EtOAc Experimental detail reproduced under Creative Commons License 2.0 Generic ( from Beilstein J. Org. Chem., 2015, 11, Some adaptations have been made: volumes and masses for some work-up chemicals have been estimated to allow metrics calculations. This has been done using best approximations based on the scale of the reaction where data was not provided. Problematic s: (acceptable only if substitution does not offer advantages) Hazardous s: These s have significant health and/or safety concerns. Highly hazardous s: The s which are agreed not to be used, even in screening DMSO, cyclohexanone, DMPU, AcOH, Ac2O, Acetonitrile, AcOMe, THF, heptane, Me-cyclohexane, toluene, xylene, MTBE, cyclohexane, chlorobenzene, formic acid, pyridine, Me-THF dioxane, pentane, TEA, diisopropyl ether, DME, DCM, DMF, DMA, NMP, methoxyethanol, hexane, petroleum ether Et 2 O, Benzene, CCl 4, chloroform, DCE, nitromethane, CS 2, HMPA THF Hexane NB chloroethanol not covered Instructions for use: Enter your data into the tables above to automatically calculate yield, AE, RME, MI/PMI and OE. Use the blank boxes in the tables to enter experimental data and note the flags for each Key Parameter. Printing tips: This spreadsheet is designed to be printed with 'landscape', 'narrow margin' and 'fit all columns on one page' settings Catalyst/enzyme (First Pass) Tick Tick Catalyst or enzyme used, or reaction takes place Green Facile recovery of catalyst/enzyme Green Use of stoichiometric quantities of reagents Amber catalyst/enzyme not recovered Amber Use of reagents in excess Red

6 Critical elements Supply remaining colour 5-50 years Red Note element years Amber +500 years Green Energy (First Pass) Tick Tick Reaction run between 0 to 70 o C Reaction run between -20 to 0 or 70 to 140 o C Reaction run below -20 or above 140 o C Green Reaction run at reflux Red Amber Red Reaction run 5 o C or more below the boiling point Green Batch/flow Tick Work Up List Flow Batch Green Amber quenching filtration centrifugation crystallisation Green Low temperature distillation/evaporation/ sublimation (< 140 o C at atmospheric exchange, quenching into aqueous Amber chromatography/ion exchange high temperature Red multiple recrystallisation This education and training material has been created with funding from the Innovative Medicines Initiative Joint Undertaking under grant agreement n , resources of which are composed of financial contribution from the European Union s Seventh Framework Programme (FP7/ ) and EFPIA companies in kind contribution The views expressed in regards to education and training materials represent the aspiration of the CHEM21 consortium, although may not always be the view of each individual organisation Health & safety Highly explosive Explosive thermal runaway Toxic Long Term toxicity Environmental implications Red H200, H201, H202, H203 H230, H240, H250 Amber H205, H220, H224 H241 H300, H310, H330 H301, H311, H331, H340, H350, H360, H370, H341, H351, H361, H371, H372 H373 H400, H410, H411, H420 H401, H412 Green If no red or amber flagged H codes present then green flag List substances and H-codes Chloroethanol H300, H310, H330 List substances and H-codes Product List substances and H-codes