Yield, AE, RME, MI/PMI and OE Volume (cm ) Density Mass (g ...€¦ · Catalyst or enzyme used, or reaction takes place without any catalyst/reagents. Facile recovery of catalyst/enzyme

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


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


AE 89.70 0.072 317.40 0.000

RME 72.00 OE 80.271 mass


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


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



concerns.


NMP, methoxyethanol, hexane, petroleum ether petroleum ether






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.


Critical elements


element

5-50 years Red Flag




Green Flag Red Flag

Amber Flag

Red Flag


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


Reaction run below -20 or above

Green Flag quenching

Green Flag

Amber Flag filtration

centrifugation

crystallisation

Green Flag


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


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


AE 89.69 0.0880 317.40 0.0003

RME 83.02 OE 92.5579 mass


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


Green Flag Green Flag

Amber Flag Amber Flag

Red Flag


Use of stoichiometric quantities of reagents

Use of reagents in excess

Facile recovery of catalyst/enzyme

catalyst/enzyme not recovered

Solvents (First Pass)





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



concerns.


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.


Critical elements


element

5-50 years Red Flag




Green Flag Red Flag

Amber Flag

Red Flag


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


sublimation (< 140 oC at atmospheric solvent exchange, quenching into aqueous

solventchromatography/ion exchange


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

Documents

Yield, AE, RME, MI/PMI and OE Volume (cm ) Density Mass (g ...€¦ · Catalyst or enzyme used, or reaction takes place without any catalyst/reagents. Facile recovery of catalyst/enzyme