You need to reach base pH 12-13, not really matter concentration.
Ketamine synthesis
- Thread starter G.Patton
- Start date
8. o-Chlorophenyl cyclopentyl ketone.
To the thus obtained Grignard soln there’s added 48 g o-chlorobenzonitrile and the mixture is stirred for 3 days at RT. It is then poured into a mixture of ice/NH4Cl, with addition of some conc. aq. NH3 and left at ambient temp until all ice melts. The ketone partially floats, partially goes to the bottom. It’s extracted with benzene (Use 100 mL x2 times). The yields fluctuate, but rarely drop below 55%.
Step 2: alpha-bromo (o-chlorophenyl)-cyclopentyl ketone.
To 21.0 g of the above ketone is added 10.0 g of bromine in 80 ml of carbon tetrachloride dropwise at 0 °C. After all the Br2 has been added, an orange suspension forms. This is washed with a dilute aqueous solution of sodium bisulfite (~65 mL x2 of 10% solution) and evaporated to give 1-bromocyclopentyl-(o-chlorophenyl)-ketone, bp 111-114 °C (0.1 mm Hg). Yield is ~66%. This bromoketone is unstable and must be used immediately. Also, attempts to distill it at 0.1 mm Hg lead to some decomposition, so it should be used without further purification.
To the thus obtained Grignard soln there’s added 48 g o-chlorobenzonitrile and the mixture is stirred for 3 days at RT. It is then poured into a mixture of ice/NH4Cl, with addition of some conc. aq. NH3 and left at ambient temp until all ice melts. The ketone partially floats, partially goes to the bottom. It’s extracted with benzene (Use 100 mL x2 times). The yields fluctuate, but rarely drop below 55%.
Step 2: alpha-bromo (o-chlorophenyl)-cyclopentyl ketone.
To 21.0 g of the above ketone is added 10.0 g of bromine in 80 ml of carbon tetrachloride dropwise at 0 °C. After all the Br2 has been added, an orange suspension forms. This is washed with a dilute aqueous solution of sodium bisulfite (~65 mL x2 of 10% solution) and evaporated to give 1-bromocyclopentyl-(o-chlorophenyl)-ketone, bp 111-114 °C (0.1 mm Hg). Yield is ~66%. This bromoketone is unstable and must be used immediately. Also, attempts to distill it at 0.1 mm Hg lead to some decomposition, so it should be used without further purification.
- By kkk
Sir,how to start making o-Chlorophenyl cyclopentyl ketone.
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- By kkk
Sir,I'm trying to do this now, but I'm not sure if it's correct.,
Step 1: Add 1 mL of chlorocyclopentane, 10 mL of triethylamine, 0.1 g of iodine, 7 g of magnesium powder and 10 mL of tetrahydrofuran into a three-necked flask, stir and heat to 70 °C to initiate the reaction; Step 2: Heat to 80 °C, add 15 mL of triethylamine and 30 mL of tetrahydrofuran, slowly drop 29 mL of chlorocyclopentane, reflux for 3 h to obtain a Grignard reagent; Step 3: Drop 26 g of a mixed solution of o-chlorobenzonitrile and 80 mL of tetrahydrofuran, maintain 80 °C, and reflux for 6 h; Step 4: After cooling to room temperature, add 200 mL of water, then drop 10 mL of concentrated hydrochloric acid, maintain 50 °C, and react for 5 h; Step 5: Cool to room temperature, take the upper tetrahydrofuran solution, remove tetrahydrofuran by rotary evaporation at 80 °C, and then heat to 165 °C to remove o-chlorophenylcyclopentanone, and obtain 23.4 g of a synthetic o-chlorophenylcyclopentanone sample with a yield of about 52%.
Step 1: Add 1 mL of chlorocyclopentane, 10 mL of triethylamine, 0.1 g of iodine, 7 g of magnesium powder and 10 mL of tetrahydrofuran into a three-necked flask, stir and heat to 70 °C to initiate the reaction; Step 2: Heat to 80 °C, add 15 mL of triethylamine and 30 mL of tetrahydrofuran, slowly drop 29 mL of chlorocyclopentane, reflux for 3 h to obtain a Grignard reagent; Step 3: Drop 26 g of a mixed solution of o-chlorobenzonitrile and 80 mL of tetrahydrofuran, maintain 80 °C, and reflux for 6 h; Step 4: After cooling to room temperature, add 200 mL of water, then drop 10 mL of concentrated hydrochloric acid, maintain 50 °C, and react for 5 h; Step 5: Cool to room temperature, take the upper tetrahydrofuran solution, remove tetrahydrofuran by rotary evaporation at 80 °C, and then heat to 165 °C to remove o-chlorophenylcyclopentanone, and obtain 23.4 g of a synthetic o-chlorophenylcyclopentanone sample with a yield of about 52%.
You can substitute decalin by cyclohexane, probably
- By OrgUnikum
Cyclohexane has a boiling point of 81 °C what would mean the thermal rearrangement would need 7 to 10 days at reflux. But then one could use IPA, same bp and it is known to work from literature (7 to 10 days at reflux).
Ethylbenzoate works.
Ethylene Glycol is another solvent which works and of better availability.
The yield is never near to quantitative, actually when using the Ketimine as base yields suffer, for decent yields the HCl salt must be used. It must also be done under strictly anhydrous conditions or yields suck. (the Imine will hydrolyze back to MeNH2, unsurprisingly regarding the rigorous conditions).
The rearrangement is catalyzed by Lewis Acids, MgCl2 And AlCl3 (anhydrous) work well. 0,1 mol equivalent are needed but AlCl3 can also take care of any water still present, the amount used must be adjusted of course, say X g needed to scavenge the water plus 0,1 mol to catalyze the reaction.
The use of AlCl3 reduces the temperature needed to ~130 °C (to take the same time as 180 °C would take un-catalyzed).
Another tip: Stay away from CCl4 the stuff is not just toxic but its mean and hard to get for good reasons. Gladly it is completely unnecessary for brominating the alpha position. The foolproof way to do this is by using CuBr2 what does the job quantitativly and without side-reactions.
For reaction conditions just Google "Bromination with CuBr2" and you will quickly find the standard conditions for this described and those work perfectly well in this case.
Ethylbenzoate works.
Ethylene Glycol is another solvent which works and of better availability.
The yield is never near to quantitative, actually when using the Ketimine as base yields suffer, for decent yields the HCl salt must be used. It must also be done under strictly anhydrous conditions or yields suck. (the Imine will hydrolyze back to MeNH2, unsurprisingly regarding the rigorous conditions).
The rearrangement is catalyzed by Lewis Acids, MgCl2 And AlCl3 (anhydrous) work well. 0,1 mol equivalent are needed but AlCl3 can also take care of any water still present, the amount used must be adjusted of course, say X g needed to scavenge the water plus 0,1 mol to catalyze the reaction.
The use of AlCl3 reduces the temperature needed to ~130 °C (to take the same time as 180 °C would take un-catalyzed).
Another tip: Stay away from CCl4 the stuff is not just toxic but its mean and hard to get for good reasons. Gladly it is completely unnecessary for brominating the alpha position. The foolproof way to do this is by using CuBr2 what does the job quantitativly and without side-reactions.
For reaction conditions just Google "Bromination with CuBr2" and you will quickly find the standard conditions for this described and those work perfectly well in this case.
thank you,sir
If this Grignard reaction is not ideal, o-chlorobenzaldehyde can be used, which is easy to react to produce alcohol and then oxidize.
1-bromocyclopentyl-(o-chlorophenyl)-ketone (CAS 6740-86-9) is commercially available. It is being sold in forms of white powder or brown oil. You mentioned “This bromoketone is unstable and must be used immediately”, if that’s the case then how do they sell it. The solution has a very dark color in most of the photos, is there any point in buying them?
And how about the powder? How can we use the powder?
And how about the powder? How can we use the powder?
- By G.Patton
Hi, it can be stored in a fridge under inert atmosphere. But I'm not sure that it's commercially available.
- By OrgUnikum
Same as with all highly reactive compounds which are sold: A stabilizer (or a mix of) is added, what else? That it has to be kept below 8°C and such is just for insurance reasons to shift responsibility as this way if something goes wrong the buyer has to prove that it was always below 8°C what is quite difficult to do. It is not like: "If not kept cold and inert it will explode" but it is "might go bad quickly after opened but thats your own fault, stop bitching we told ya".
Things you made yourself go bad fast as impurities catalyze deterioration and you often do not have the right preservatives.
Things you made yourself go bad fast as impurities catalyze deterioration and you often do not have the right preservatives.
after 95 °C for 3-4 hrs,and extracted with 20% HCl. Acidic extract is basified and extracted with DCM. Solvent is removed, giving the product as an oil that DONT crystallizes. Instead, it become extremely sticky brown color oil. and cant not recrystallization from pentane/ether or hexane/ether. any tips?