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 0.100 273.350 0.0004 copper triflate 0.029 2- chloroethanol 0.225 1.201 0.270 sodium sulfate 1.000 DCM 15.000 1.330 19.950 2-chloroethanol 0.030 80.510 0.0004 0.000 EtOAc 22.500 0.894 20.115 #DIV/0! 0.000 petroleum ether 127.500 0.640 81.600 #DIV/0! 0.000 sat. NaHCO3 soln 5.000 2.160 10.800 Total 0.130 353.860 0.029 0.000 0.270 1.000 132.465 Yield 86.518 86.518 Conversion x x Selectivity x x Mass MW Mol AE 100.000 Product 0.112 353.860 0.000 RME 86.154 OE 86.154 mass Unreacted limiting PMI total 1195.484 reactant unknown PMI Reaction 3.832 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 1.420 PMI reaction s 2.413 PMI Workup 1191.652 PMI Workup chemical 8.929 PMI workup s 1182.723 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, 7013-7022. 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
Critical elements Supply remaining colour Note element 5-50 years Red 50-500 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 115360, resources of which are composed of financial contribution from the European Union s Seventh Framework Programme (FP7/2007-2013) 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
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 0.100 353.860 0.0003 KOH 0.031 THF 6.000 0.889 5.334 sodium sulfate 1.000 water 5.00 1.000 5.000 #DIV/0! 0.000 EtOAc (wash) 15.00 0.894 13.410 #DIV/0! 0.000 brine 10.00 1.160 11.600 #DIV/0! 0.000 EtOAc (column) 22.50 0.894 20.115 #DIV/0! 0.000 petroleum ether 127.50 0.640 81.600 Total 0.100 353.860 0.000 0.031 5.334 1.000 131.725 Yield 80.27 80.271 Conversion x x Selectivity x x Mass MW Mol AE 89.70 Product 0.072 317.40 0.000 RME 72.00 OE 80.271 mass Unreacted limiting PMI total 1919.31 reactant unknown PMI Reaction 75.90 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 74.08 PMI Workup 1843.40 PMI Workup chemical 13.89 PMI workup s 1829.51 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, 7013-7022. 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
Critical elements Supply remaining colour Note element 5-50 years Red 50-500 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 115360, resources of which are composed of financial contribution from the European Union s Seventh Framework Programme (FP7/2007-2013) 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
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 0.0820 273.3500 0.0003 (NH4)2S2O8 0.1370 2-chloroethanol 0.1800 1.2010 0.2162 Na2SO4 1.0000 sat. NaHCO3 soln 5.00 2.1600 10.80 2-choroethanol 0.0240 80.5200 0.0003 KOH 0.2020 THF 5.0000 0.8900 4.4500 ethyl acetate 10.00 0.8940 8.94 #DIV/0! 0.0000 brine 10.00 1.1600 11.60 #DIV/0! 0.0000 ethyl acetate (column) 30.00 0.8900 26.70 #DIV/0! 0.0000 hexane 120.00 0.6590 79.08 #DIV/0! 0.0000 0.00 #DIV/0! 0.0000 0.00 Total 0.1060 353.8700 0.0000 0.3390 4.6662 1.0000 137.12 Yield 92.42 92.4232 Conversion x x Selectivity x x Mass MW Mol AE 89.69 Product 0.0880 317.40 0.0003 RME 83.02 OE 92.5579 mass Unreacted limiting PMI total 1627.63 reactant unknown PMI Reaction 58.08 PMI reactants, reagents, catalyst 5.06 PMI reaction s 53.02 PMI Workup 1569.55 PMI Workup chemical 11.36 PMI workup s 1558.18 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 (http://creativecommons.org/licenses/by/2.0/) from Beilstein J. Org. Chem., 2015, 11, 525-529. 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
Critical elements Supply remaining colour 5-50 years Red Note element 50-500 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 115360, resources of which are composed of financial contribution from the European Union s Seventh Framework Programme (FP7/2007-2013) 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