Sciencemadness Discussion Board

Does anyone know a synth for Novacaine?

Douchermann - 4-11-2005 at 06:37

Hey, I was wondering if anyone knew or could think up a synthesis of Novacaine (Procaine Hydrochloride). The product has to be medical grade, or able to be turned into medical grade with basic equipment. Its formula is: C13H20N2O2*HCl And has a molar mass of 272.774 (Procaine is 263.313).

Sandmeyer - 6-11-2005 at 11:36

Chapest route would be esterification of 4-amino-benzoic acid (PABA) with 2-diethylamino-ethanol. Patent DE180291 is from 1919 and details the preparation in german. Drawback is that 2-diethylamino-ethanol, like other N,N-dialkylated aminoalcohols, is precursor to alkylphosphonothiolate family of nerve agents as well. Precursors leading to those substances are presumably heavily watched.

[Edited on 8-11-2005 by Sandmeyer]

Douchermann - 7-11-2005 at 13:46

I can't seem to find that patent, do you have a link to it? I searched the german online archives and didn't get any results. Thanks for your help.

Sandmeyer - 8-11-2005 at 03:44

http://v3.espacenet.com/origdoc?DB=EPODOC&IDX=DE180291&a...

Douchermann - 13-11-2005 at 17:58

Thanks, the only problem now is aquring these chemicals. I couldn't find a supplier for the 2-diethylamino ethanol and the only supplier for 4-aminobenzoic acid doesn't sell to residences, so I need to synthesize these chemicals. For the 4-aminobenzoic acid, all I would need to do is attach the amine group benzoic acid, but what should I use to do this? I can't think of any possible way to synthesize the DEAE though. Anyone have any ideas?

stygian - 14-11-2005 at 08:15

p-aminobenzoic acid is made from p-nitrotoluene by oxidizing the methyl group then reducing the nitro

Douchermann - 16-11-2005 at 12:29

For oxidising the nitrotoluene, which would be better, KMnO4 or a dichromate salt?. Also, how many oxygens would either of those give up?

vulture - 16-11-2005 at 14:17

Doesn't matter here as there are no sensitive functions here. Save your dichromate for something else.

Quote:

Also, how many oxygens would either of those give up?


Eh? I think you need to review oxidation/reduction theory again.

Douchermann - 17-11-2005 at 06:03

I didn't word it right, sorry. I was asking how many moles of non-diatomic oxygen 1 mole of a permanganate salt would give up, or 1 mole of a dichromate salt would give up. Because I know some oxidisers do not liberate all of them. Also, what compound would be left from the permanganate salt after it oxidises something?

sparkgap - 18-11-2005 at 04:26

Permanganate usually turns to a brown/black sludge of manganese dioxide after oxidations in neutral conditions.

IIRC Cr(VI) -> Cr(III) usually on oxidations. :)

sparky (^_^)

Douchermann - 18-11-2005 at 16:10

Ah alright

One of your forum members has told me a possible way to make the 2-diethylamino ethanol: React an anhydrous ammonia solution with ethyl iodide and distill off to yeild diethylamine, then react that with ethylene chlorohydrin. Does anyone have any details or tips for that method? If that method wont work, does anyone know one that will?

chemoleo - 18-11-2005 at 17:15

Do you know if the dimethyl rather than the diethyl variety of diethyl aminoethanol could be used?

I am asking because dimethylaminoethanol is sold OTC, as a nutritive supplement. Search for DMAE.


Also, wouldnt it be possible to use aminoethanol as a starting reagent (see recent thread on this). All it'd require is the alkylation, would ethylbromide be possible, or would the OH interfere??

Douchermann - 19-11-2005 at 06:46

I don't think the DMAE will work, I couldn't find a molecular model of it, but I'm sure its the same as the DEAE except for the two methyl groups in place of the ethyl groups. I don't know if aminoethanol would work. If you are talking ethyl bromide in place of ethyl Iodide, I think that will work, but of course the ammounts would have to be changed.
If I were to produce ethylene chlorohydrin by ethylene glycol and a 30% HCl solution, how would I extract it, would simple distilation work?

[Edited on 19-11-2005 by Douchermann]

[Edited on 19-11-2005 by Douchermann]

Chris The Great - 19-11-2005 at 12:45

I don't think ethylene chlorohydrin can be made with HCl solution, I think high yields are only had when a gas phase reaction is used. HBr and HI probably work much better at forming chlorohydrins...

Aminoethanol should work with ethylbromide/iodide.

You are correct with the structure of DMAE. I use http://chemfinder.cambridgesoft.com/ to find structures for compounds as well as some physical properties for some of them. It saves alot of time.

The_Davster - 19-11-2005 at 13:15

You can avoid the use of ethyl iodide and anhydrous ammonia by reacting commercial bug repellant(DEET) with NaOH, then distilling off the diethylamine formed.

I would have thought starting with aminoethanol and reacting with ethyl iodide(as chemoleo already mentioned), then esterifing with 4-aminobenzoic acid would be easier than the chlorohydrin route.

Douchermann - 21-11-2005 at 06:35

I read somewhere that ethylene chlorohydrin can be made with HCl solution, but the yeild is about 12%, I'm not really concerned about yeilds at this point so if that works that will be my best option. Although, for reacting in the gaseous phase, do both reactants have to be in a gaseous phase or could I just bubble dry HCl gas through dry ethylene glycol to make ethylene chlorohydrin. I would use HI or HBr, but I have no source. Do you know any fairly easy way to make HI or HBr? Mainly OTC too, i've heard of a way of reacting Iodine with formic acid, but I don't know if that will work, what are your opinions. As for the DEET, it is becoming very rare around here, people believe its a carcinogen.

stygian - 21-11-2005 at 06:40

Ethylene chlorohydrin can be made by passing ethylene into hypochlorite solution.

Edit: I think vogel has some info about this in the 'polyhydric alcohols' section. Not sure though.

[Edited on 21-11-2005 by stygian]

Douchermann - 21-11-2005 at 07:17

Whats an easy way to produce ethylene then? Keep in mind I am fairly new to organic chemistry, I used to do a lot of inorganic chemistry but I have changed pace now.

[Edited on 21-11-2005 by Douchermann]

stygian - 21-11-2005 at 07:34

Ethylene can be made from ethanol via a number of ways. Use the search feature. I think hot sand was said to even work.

Hot sand, alcohol, and hypochlorite. Doesn't get much simpler than that.

You might not want to use bleach though. The NaOH will turn your chlorohydrin into ethylene oxide.

chemoleo - 21-11-2005 at 16:59

I really don't understand why you'd want to try such a laborious route, with chlorohydrin and all..

Ethanolamine is available OTC, see the recent thread on this.
All you'd need is ethyliodide. And of course the solvents necessary for alkylation.

For that matter, is anyone aware of the conditions of such an alkylation?
I.e.

HO-CH2CH2-NH2 + 2 ICH2CH3 --> HO-CH2CH2-N(C2H5)2 + 2HI

I'd be interested to give it a shot myself.

Douchermann - 21-11-2005 at 19:48

Lol, I just like to do really long processes, I don't know why. I guess just for the experience or just because its fun. There is something that discourages me about making the diethy amine with ethyl iodide and anhydrous ammonia. One of the forum members believes the reaction would need to get up to 100C, well ethyl Iodide boils at like 70C and ammonia comes off solution freely at a fairly low temperature. You know, come to think of it I think I will try the method you suggested.


[Edited on 22-11-2005 by Douchermann]

Chris The Great - 22-11-2005 at 21:06

That was me :) I say 100 degrees because I saw a website that said that kind of reaction occurs in a sealed tube at 100 degrees. No further details except that the product is impure and so needs to be distilled to get the mono, di and tri ethylamine seperated.
I checked Vogel and there is a much easier synthesis from calcium cyanamide, which I will post later. But if you can cyanamide, you'll only need the alkyl bromide, sodium hydroxide, nothing really exotic. It also uses the crude calcium cyanamide, which is sold as fertilizer.
Basically, sodium cyanamide, Na2NCN reacts with the alkyl bromide to form the dialkyl cyanamide, which is hydrolysed to the dialkyl amine. The Na2NCN is formed by the NaOH on the CaNCN, which is really cheap.

I am also interested in the reaction conditions as well, and in amines in general. They are useful for alot of things but I haven't seen anything on making them besides methylamines from hexamine, HCl etc.

Douchermann - 23-11-2005 at 04:55

Yeah it was him, for both of the things that I said 'one of the forum members told me'. I just didn't know if you wanted me to tell people that. but now I do :p

That would be nice if you could post that synth, thank you Chris.

Chris The Great - 23-11-2005 at 20:10

The procedure is for di-n-butylamine but the n-butyl bromide could easily be replaced with ethyl bromide.

From Vogel, A Textbook of Practical Organic Chemistry, third edition.

Equip a 1500ml three necked flask with a reflux condenser and a mercury-sealed stirrer. Place 222ml of water and 44g of finely crushed ice in the flask and add slowly, with vigorous stirring, 67g of commercial calcium cyanamide (1). As soon as the solid is thoroughly suspended, fit a seperatory funnel into the third neck of the flask and introduce through it a cold solution of 34 g of sodium hydroxide in 67ml of water; replace the funnel with a cork carrying a thermometer. Continue the vigorous stirring for 1 hour to complete the decomposition of the calcium cyanamide; if the temperature rises above 25*, add a little more ice. Add to the resulting solution of sodium cyanamide a solution of 134g (105ml) of n-butyl bromide in 222ml of rectified spirit. Heat the mixture, with stirring on a water bath until it refluxes gently; continue the refluxing and the stirring for 2.5 hours. Replace the reflux condenser by one set for downward distillition and distill the mixture until 165-170ml of liquid are collected: stir during distillation. Cool the residue in the flask and filter it, with suction, through a Buchner or sintered glass funnel, and wash the residue with alcohol. Extract the filtrate, which separates into two layers, first with 90ml and then with 45ml benzene. Dry the combined benzene extracts with anhydrous magnesium or calcium sulfate, and remove the benzene in a Claisen flask. Finally, distill under reduced pressure and collect the di-n-butyl cyanamide, (C4H9)2NCN, at 147-151*/35mm. The yield is 33g.
Into a 750ml round bottomed flask furnished with a reflux condenser place a solution of 34g (18.5ml) of concentrated sulfuric acid in 100ml water: add 33g of di-n-butyl cyanamide and a few fragments of porous porcelain. Reflux gently for 6 hours. Cool the resulting homogeneous solutionand pour in a cold solution of 52g sodium hydroxide in 95ml water down the side of the flask so that most of it settles at the bottom without mixing with the solution in the flask. Connect the flask with a condenser for downward distillation and shake it to mix the two layers; the free amine seperates. Heat the flask when the amine with some water distills: continue the distillation until no amine separates from a test portion of the distillate. Estimate the weight of water in the distillate and add about half this amount of potassium hydroxide in the form of sticks, so that it dissolves slowly. Cool the solution in ice while the alkali hydroxide is dissolving: some ammonia gas is evolved. When the potassium hydroxide has dissolved, separate the amine, and dry it for 24 hours over sodium hydroxide pellets. Filter into a Claisen flask and distill. Collect the di-n-butylamine at 157-160*. The yield is 31g.

(1) Also known as "nitrolim" and "lime nitrogen". The fresh product contains approximately 55 per cent calcium cyanamide, 20 per cent of lime, 12 per cent of graphite and small amounts of other impurities. It should be protected from moisture when stored in order to prevent slow polymerization to dicyanodiamide.


Hope it helps.

Douchermann - 24-11-2005 at 07:40

I worked on the numbers and for the reaction with ethyl iodide I got 152.52 grams (in place of the 134 for butyl bromide) and using the precent yeild from before you should end up with ~20 grams of Diethyl cyanamide. Of course there is excess ethyl iodide (about 67 grams) so I think using less ethyl iodide could be done. If not it can just be distilled off and saved. I can't find the boiling point for diethyl cyanamide (only found dimethyl cyanamide) so I don't know what temp it would come off at. I didn't figure out any numbers for the second part of the synthesis, I ran out of time. Tell me what you guys think.

Douchermann - 4-1-2006 at 06:47

I can't figure out what the reaction is for turning the di-butylcyanamide into dibutylamine. Does anyone know what it is or could figure out what it is? And if I were to do this using Ethyl bromide, how would I turn the produced diethylamine into diethylamino ethanol? Sorry to keep bringing this topic up.