yield, ae, rme, mi/pmi and oe volume (cm ) density mass (g ...€¦ · catalyst or enzyme used, or...
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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)
Mass (g) MW Mol Catalyst Mass (g) Reagent Mass (g) Reaction
solventVolume (cm
3) Density
(g ml-1)
Mass (g) Work up
chemical
Mass (g) Workup solvent Volume
(cm3)
Density
(g ml-1)
Mass (g)
(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
#DIV/0! 0.000 0.000
#DIV/0! 0.000 0.000
#DIV/0! 0.000 0.000
Total 0.130 353.860 0.029 0.000 0.270 1.000 132.465
Flag
Yield 86.518 86.518
Conversion x x
Selectivity x x Mass MW Mol
AE 100.000 0.112 353.860 0.000
RME 86.154 OE 86.154 mass
PMI total 1195.484 unknown
PMI Reaction 3.832
PMI reactants,
reagents, catalyst 1.420
PMI reaction
solvents 2.413
PMI Workup 1191.652
PMI Workup
chemical 8.929
PMI workup
solvents 1182.723
NB chloroethanol
not covered
Catalyst/enzyme (First Pass) Tick Tick
Green
Flag Green Flag
Amber
FlagAmber Flag
Red Flag Use of reagents in excess
Use of stoichiometric quantities of reagents catalyst/enzyme not recovered
Problematic solvents: (acceptable only
if substitution does not offer
advantages)
DMSO, cyclohexanone, DMPU, AcOH, Ac2O, Acetonitrile, AcOMe,
THF, heptane, Me-cyclohexane, toluene, xylene, MTBE, cyclohexane,
chlorobenzene, formic acid, pyridine, Me-THF
Hazardous solvents: These solvents
have significant health and/or safety
concerns.
dioxane, pentane, TEA, diisopropyl ether, DME, DCM, DMF, DMA,
NMP, methoxyethanol, hexane, petroleum ether Petroleum ether
Highly hazardous solvents: The
solvents which are agreed not to be
used, even in screening
Et2O, Benzene, CCl4, chloroform, DCE, nitromethane, CS2, HMPA
Catalyst or enzyme used, or reaction takes place
without any catalyst/reagents. Facile recovery of catalyst/enzyme
Product
Unreacted limiting
reactant
Solvents (First Pass) List solvents below
Preferred solvents water, EtOH, nBuOH, AcOipr, AcOnBu, PhOMe, MeOH, tBuOH,
BnOH, ethylene glycol, acetone, MEK, MIBK, AcOEt, sulfolane 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.
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 Flag colourNote
element
5-50 years Red Flag
50-500 years Amber Flag
+500 years Green Flag
Energy (First Pass) Tick Tick
Green Flag Red Flag
Amber Flag
Red Flag
Batch/flow Tick Work Up List
Flow
Batch
Amber Flag
Health & safety
Highly explosive
Explosive thermal
runaway
Toxic
Long Term toxicity
Environmental
implications
product
H230, H240, H250 H241
H200, H201, H202, H203 H205, H220, H224 If no red or amber
flagged H codes present
then green flag
H300, H310, H330 H301, H311, H331,
H340, H350, H360, H370, H341, H351, H361, H371,
chloroethanol H300,
H310, H330
H400, H410, H411, H420 H401, H412
Red Flag Amber Flag Green Flag
List substances and H-codes List substances and H-codes List substances and H-codes
solvent exchange, quenching into aqueous
chromatography/ion exchange
Red Flag high temperature
multiple recrystallisation
Reaction run below -20 or above 140oC
Green Flag quenching
Green Flag
Amber Flag filtration
centrifugation
crystallisation
Green Flag
Low temperature distillation/evaporation/
Reaction run between 0 to 70oC Reaction run at reflux
Reaction run between -20 to 0 or 70 to Reaction run 5oC or more below the solvent
boiling point
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)
Mass (g) MW Mol Catalyst Mass (g) Reagent Mass (g) Reaction solvent Volume (cm3) Density
(g ml-1)
Mass (g) Work up
chemical
Mass (g) Workup
solvent
Volume
(cm3)
Density
(g ml-1)
Mass (g)
(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
#DIV/0! 0.000 0.000
#DIV/0! 0.000 0.000
Total 0.100 353.860 0.000 0.031 5.334 1.000 131.725
Flag
Yield 80.27 80.271
Conversion x x
Selectivity x x Mass MW Mol
AE 89.70 0.072 317.40 0.000
RME 72.00 OE 80.271 mass
PMI total 1919.31 unknown
PMI Reaction 75.90
PMI reactants,
reagents, catlyst 1.82
PMI reaction
solvents 74.08
PMI Workup 1843.40
PMI Workup
chemical 13.89
PMI workup
solvents 1829.51
Catalyst/enzyme (First Pass) Tick Tick
Green
Flag Green Flag
Amber
FlagAmber Flag
Red Flag Use of reagents in excess
Use of stoichiometric quantities of reagents catalyst/enzyme not recovered
Problematic solvents: (acceptable
only if substitution does not offer
advantages)
DMSO, cyclohexanone, DMPU, AcOH, Ac2O, Acetonitrile, AcOMe, THF,
heptane, Me-cyclohexane, toluene, xylene, MTBE, cyclohexane,
chlorobenzene, formic acid, pyridine, Me-THF THF
Hazardous solvents: These solvents
have significant health and/or safety
concerns.
dioxane, pentane, TEA, diisopropyl ether, DME, DCM, DMF, DMA,
NMP, methoxyethanol, hexane, petroleum ether petroleum ether
Highly hazardous solvents: The
solvents which are agreed not to be
used, even in screening
Et2O, Benzene, CCl4, chloroform, DCE, nitromethane, CS2, HMPA
Catalyst or enzyme used, or reaction takes place
without any catalyst/reagents. Facile recovery of catalyst/enzyme
Product
Unreacted limiting
reactant
Solvents (First Pass) List solvents below
Preferred solvents water, EtOH, nBuOH, AcOipr, AcOnBu, PhOMe, MeOH, tBuOH, BnOH,
ethylene glycol, acetone, MEK, MIBK, AcOEt, sulfolane EtOAc
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 solvent 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 Flag colourNote
element
5-50 years Red Flag
50-500 years Amber Flag
+500 years Green Flag
Energy (First Pass) Tick Tick
Green Flag Red Flag
Amber Flag
Red Flag
Batch/flow Tick Work Up List
Flow
Batch
Amber Flag
Health & safety
Highly explosive
Explosive thermal
runaway
Toxic
Long Term toxicity
Environmental
implications
product all starting materials
H230, H240, H250 H241
H200, H201, H202, H203 H205, H220, H224 If no red or amber 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
Red Flag Amber Flag Green Flag
List substances and H-codes List substances and H-codes List substances and H-codes
solvent exchange, quenching into aqueous
chromatography/ion exchange Red Flag high temperature
multiple recrystallisation
Reaction run below -20 or above
Green Flag quenching
Green Flag
Amber Flag filtration
centrifugation
crystallisation
Green Flag
Low temperature distillation/evaporation/
Reaction run between 0 to 70oC Reaction run at reflux
Reaction run between -20 to 0 or 70 Reaction run 5oC or more below the solvent
boiling point
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)
Mass (g) MW Mol Catalyst Mass (g) Reagent Mass (g) Reaction
solventVolume (cm3) Density
(g ml-1)
Mass (g) Work up
chemical
Mass (g) Workup
solvent
Volume
(cm3)
Density
(g ml-1)
Mass (g)
(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
Flag
Yield 92.42 92.4232
Conversion x x
Selectivity x x Mass MW Mol
AE 89.69 0.0880 317.40 0.0003
RME 83.02 OE 92.5579 mass
PMI total 1627.63 unknown
PMI Reaction 58.08
PMI reactants,
reagents, catalyst 5.06
PMI reaction
solvents 53.02
PMI Workup 1569.55
PMI Workup
chemical 11.36
PMI workup
solvents 1558.18
List solvents
below
EtOAc
THF
HexaneNB
chloroethanol
not covered
Catalyst/enzyme (First Pass) Tick Tick
Green Flag Green Flag
Amber Flag Amber Flag
Red Flag
Catalyst or enzyme used, or reaction takes place
Use of stoichiometric quantities of reagents
Use of reagents in excess
Facile recovery of catalyst/enzyme
catalyst/enzyme not recovered
Solvents (First Pass)
Highly hazardous solvents: The
solvents which are agreed not to be
used, even in screening
Et2O, Benzene, CCl4, chloroform, DCE, nitromethane, CS2, HMPA
Problematic solvents: (acceptable
only if substitution does not offer
advantages)
Preferred solvents
Unreacted limiting
reactant
Product
DMSO, cyclohexanone, DMPU, AcOH, Ac2O, Acetonitrile, AcOMe,
THF, heptane, Me-cyclohexane, toluene, xylene, MTBE, cyclohexane,
chlorobenzene, formic acid, pyridine, Me-THF
Hazardous solvents: These solvents
have significant health and/or safety
concerns.
dioxane, pentane, TEA, diisopropyl ether, DME, DCM, DMF, DMA,
NMP, methoxyethanol, hexane, petroleum ether
water, EtOH, nBuOH, AcOipr, AcOnBu, PhOMe, MeOH, tBuOH, BnOH,
ethylene glycol, acetone, MEK, MIBK, AcOEt, sulfolane
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). 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.
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 Flag colourNote
element
5-50 years Red Flag
50-500 years Amber Flag
+500 years Green Flag
Energy (First Pass) Tick Tick
Green Flag Red Flag
Amber Flag
Red Flag
Batch/flow Tick Work Up List
Flow
Batch
Amber Flag
Health & safety
Highly explosive
Explosive thermal
runaway
Toxic
Long Term toxicity
Environmental
implications
Chloroethanol H300, H310, H330 Product
List substances and H-codes List substances and H-codes
Red Flag
centrifugation
crystallisation
Low temperature distillation/evaporation/
sublimation (< 140 oC at atmospheric solvent exchange, quenching into aqueous
solventchromatography/ion exchange
multiple recrystallisation
List substances and H-codes
If no red or amber flagged
H codes present then
green flagH241
H205, H220, H224
H301, H311, H331,
Green Flag
Reaction run between -20 to 0 or 70
to 140oC
Reaction run at reflux
Reaction run 5oC or more below the solvent
boiling pointGreen Flag
Reaction run between 0 to 70oC
Reaction run below -20 or above
140oC
Amber Flag
Green Flag
quenching
high temperature
filtration
H400, H410, H411, H420 H401, H412
Red Flag Amber Flag
H200, H201, H202, H203
H230, H240, H250
H300, H310, H330
H340, H350, H360, H370,
H372
H341, H351, H361, H371,
H373
Green Flag
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