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All 10 posts Subject: More clarification on the 4-MAR w/out CNBr route Please login to post Down

element109
(Hive Bee)
05-23-02 23:52
No 313357
      More clarification on the 4-MAR w/out CNBr route

I've started a new threat because the old one was getting rather long and confusing. I'm still sure that it's norephedrine and not norpseudoephedrine that is required for this synthesis. Allow me to proof my point:

(taken from J.Chem.Soc. 1,(1952),p. 850 and 851) :
------------------------------------------

"We now find that, whether alkaline hydrolysis of N-cyano-(+-)-ephedrine leads to (+-)-ephedrine, hydrolysis with dilute acid gives, in high yield, 2-imino-3,4-dimethyl-5-phenyloxazolidine; the configuration of it being proved by its alkaline hydrolysis yielding exclusively pseudoephedrine."

[...]

"In order to decide between these two alternatives, N-carbamyl-(+-)-ephedrine prepared from (+-)-ephedrine.HCl, was also treated with dilute acid, 2-imino-3,4-dimethyl-5-phenyloxazolidine was again obtained. It seems therefore reasonable to assume that inversion of the configuration was induced by a nucleophilic attack by the ureido-oxygen atom, trans -placed with respect to the hydroxyl group."

[...]

"By treatment of (+-)-pseudoephedrine with KOCN the urea was obtained. However, in conditions identical with those used for the conversion of N-carbamyl-(+-)-ephedrine into 2-imino-3,4-dimethyl-5-phenyloxazolidine ; N-carbamyl-(+-)-pseudoephedrine gave (+-)-3,4-dimethyl-5-phenyloxazolid-2-one by loss of ammonia.
The oxazolidone must have been formed directly from N-carbamyl-(+-)-pseudoephedrine and not via N-carbamyl-(+-)-ephedrine, as the latter was not affected by similar treatment. The configuration of it is proved by its preparation from (+-)-pseudoephedrine and carbonyl chloride and from 2-imino-3,4-dimethyl-5-phenyloxazolidine and nitrous acid."

[...]

"In N-carbamyl-(+-)-ephedrine the hydroxyl and the ureido-group must accordingly be trans -placed."

[...]

"The reaction of pseudoephedrine with CNBr under anhydrous conditions gave 2-imino-3,4-dimethyl-5-phenyloxazolidine ; already obtained from N-cyano-(+-)-ephedrine and from (+-)-ephedrine *via* N-carbamyl-(+-)-ephedrine. "

-----------------------------

We know already that heating PPA.HCl with 25% HCl, or hydrolysis of chloro-PPA.HCl (sat'd HCl at 0œC) gives a 50/50 mixture of norephedrine and norpseudoephedrine, and I have promised you all that I have a ref on the separation of these two via their bitartrate salts, well, here it is:

taken from Helv.Chim.Acta 22,(1939),p.365
-----------------------------------------

15grs of the mixture of the bases are dissolved in 40 ml warm water with 15 grs of tartaric acid. After a short time norpseudoephedrine bitartrate precipitates (mp 202œC).

Filter this off and evaporate the water. Recrystallise the residue with alcohol: norephedrine bitartrate (mp 130-160œC)

--------------------

l-norephedrine base: mp 50œC
norephedrine.HCl : mp 171-172œC
norephedrine.HSO4 : mp 285-286œC

d-norpseudoephedrine.HSO4 : mp 290-291œC

I hope this will clarifie this issue somewhat, we are looking here on an OTC, non-toxic and high-yielding synthesis of 4-MAR; aren't there any people around here who could confirm this all by actually trying it out? SWIM has some chloro-PPA.HCl sitting in the freezer but he is really busy at the moment and there not much time for chemistry frown .
e109

SPISSHAK
(Newbee)
05-24-02 00:11
No 313362
      thanks!! Never assume the obvious to be true.

thanks!!
Never assume the obvious to be true.

SPISSHAK
(Newbee)
05-24-02 16:21
No 313658
      Epimeriztion of optically active compds.
(Rated as: excellent)

You mention racemiztion of ppa with HCl I don`t recommend this see Patent US2214034 for an alternative. This is because of aziridine formation during HCl reflux.

This patent will provide a method which according to the aurthor, The hydrogen gas liberatied during racemization serves to protect the ephedrines from decomposition.

element109
(Hive Bee)
05-26-02 14:05
No 314432
      Yes, but it required the aquisition of NaNH2

NaNH2 is maybe better but requires the construction of a downs cell and handling liquid NH3. This all sounds to me a bit Birch-like, it would be nice if LiNH2 would work but why all that extra work?
I understand that you'll try to get the most out of it, but for now I'd stay with HCl until the route has been proven to work; and after that it can be optimized.

SWIM heated the chloro-PPA.HCl in dil. HCl for 4 hours (not 24) at 50°C (not reflux), temp climbed at one unsupervised moment to 65°C for about 10 minutes.
Basified with 10% NaOH, sat'd with NaCl and extracted once with ether. Evaporated ether, gave yellowish residue which weighed 0.8 gr. The residue was added bit by bit to a hot solution of 0.8 gr tartaric acid in 2 ml dH2O. A few minutes later a white precipitate crashed out, which was filtered off (assumed to be norpseudoephedrine bitartrate).
the yellowish mother liquor was evaporated to give a gummy yellow residue; this was recrystallized from EtOH, it still looks a bit gummy but has definately hardened. Both substances are still a bit wet so SWIM hasn't weighed 'em yet. There seems to be a little more (assumed)norpseudoephedrine.
melting points have still to be taken.

I understand your worries about aziridine formation, but doesn't this require a bit harsher conditions? The authors don't seem to worry much about it. Do you have refs detailing this side reaction?

Hey, and why didn't i get at least a "good" rating on my separation procedure? I'm sure it's worth it.

e109

SPISSHAK
(Newbee)
05-26-02 17:40
No 314468
      Yes PPA is different.

PPA is diiferent than ephedrine as far as reactivity.
SWIM likes racemic crank. And tried this with ephedrine and got a good deal of aziridine.
The reason is that the methylamino group is a better nucleophile than amino.
So being the better nucleophile it has a tendency to eliminate H-X more readily than a primary amine like PPA.
This is especially true of pseudo-ephedrine, because the OH group is cis to the methylamino group.
more likely to give that by-product.
Lithium hydride can be used as opposed to the amide.
I`m wondering if the hydride could be made by exposing the Lithium in a finely divided state to hydrogen atomosphere.
I think it can. Lithium hydride is the most stable of all the alkali metal hydrides.
So it`s going to be a lot easier to handle than it`s sodium counterpart.
Caution must still be applied.
Like keeping it away from water, etc.

Here`s a good pointer, if you want to test the optical rotation of your salt, or compound, make a solution of it, then get an lcd display (any will do) and use the translucent reflector plastic screen from the back of it and cut it into two pieces.
Shine light through the solution with the two translucent plastics on each side of the beaker, test tube, whatever.
And observe how it rotates light.

Wouter
(Stranger)
02-06-03 18:35
No 405168
      tartaric acid

Which kind of tartaric acid does SWIY used for the separation of DL-norephedrine and DL-norpseudoephedrine?
L-, D- or DL- Tartaric acid?

Rhodium
(Chief Bee)
02-06-03 20:20
No 405188
User Picture       tartrate

Either D- or L-tartaric acid, as crystallization with DL-tartaric acid would have no effect. The natural isomer of tartaric acid is very much cheaper than the other, so there is one advantage of that one.

ballzofsteel
(Miss High & Mighty)
02-08-03 12:49
No 405593
User Picture       Some info on use of tartaric is found in this...

Some info on use of tartaric is found in this
Patent US5962737

Abstract:Stereospecific synthesis of the racemic threo isomers of 2-nitro-1-phenylpropanols by reacting a benzaldehyde derivative with nitroalkane in the presence of a tertiary amine and reducing 2-nitro-1-phenylpropanols with, for example, lithium aluminum hydride to 2-amino-1-phenylpropanols is described. Also described are phase transfer resolution of racemic mixtures of 2-amino-1-phenylpropanol and its derivatives into their optically pure isomers by reacting a racemic mixture with the mono alkali metal salt of a tartaric acid ester in a two phase system of a hydrocarbon and water. The specification further describes therapeutically useful optically pure isomers of threo-2-amino-1-(dialkoxy or alkoxy) phenylpropanols and acid addition salts thereof.

Wouter
(Stranger)
02-22-03 14:00
No 410749
      SWIM can't isolate his norephedrine base

Does anyone know what SWIM do wrong? First he does the akabori-momotani reaction between BzH and Ala. His yield form 100g Ala was ca. 63g with cristals. SWIM refluxed the cristals in dil. HCl for 4 h. Then he add 10% NaOH and ... nothing happend! No cristals precipated. He extract the stuff with ether (and DCM) but without any residue... What does SWIM do wrong? PLEASE HELP!

BizzyBee
(Stranger)
12-21-03 20:53
No 478239
User Picture       Heres a interesting link about ppa and ...
(Rated as: Use the [MEDLINE] tag!)

Heres a interesting link about ppa and norpseudoephedrine: h
ttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db
=PubMed&list_uids=3572747&dopt=Abstractƒ

Swim used norpseudo in the cyanate rxn, the urea formed and
precipitated out after cooling but the hcl reflux does not
effect it at all.

Not even a hint of pink

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	All 10 posts		Subject: More clarification on the 4-MAR w/out CNBr route		Please login to post		Down


		element109 (Hive Bee) 05-23-02 23:52 No 313357				More clarification on the 4-MAR w/out CNBr route
						I've started a new threat because the old one was getting rather long and confusing. I'm still sure that it's norephedrine and not norpseudoephedrine that is required for this synthesis. Allow me to proof my point: (taken from J.Chem.Soc. 1,(1952),p. 850 and 851) : ------------------------------------------ "We now find that, whether alkaline hydrolysis of N-cyano-(+-)-ephedrine leads to (+-)-ephedrine, hydrolysis with dilute acid gives, in high yield, 2-imino-3,4-dimethyl-5-phenyloxazolidine; the configuration of it being proved by its alkaline hydrolysis yielding exclusively pseudoephedrine." [...] "In order to decide between these two alternatives, N-carbamyl-(+-)-ephedrine prepared from (+-)-ephedrine.HCl, was also treated with dilute acid, 2-imino-3,4-dimethyl-5-phenyloxazolidine was again obtained. It seems therefore reasonable to assume that inversion of the configuration was induced by a nucleophilic attack by the ureido-oxygen atom, trans -placed with respect to the hydroxyl group." [...] "By treatment of (+-)-pseudoephedrine with KOCN the urea was obtained. However, in conditions identical with those used for the conversion of N-carbamyl-(+-)-ephedrine into 2-imino-3,4-dimethyl-5-phenyloxazolidine ; N-carbamyl-(+-)-pseudoephedrine gave (+-)-3,4-dimethyl-5-phenyloxazolid-2-one by loss of ammonia. The oxazolidone must have been formed directly from N-carbamyl-(+-)-pseudoephedrine and not via N-carbamyl-(+-)-ephedrine, as the latter was not affected by similar treatment. The configuration of it is proved by its preparation from (+-)-pseudoephedrine and carbonyl chloride and from 2-imino-3,4-dimethyl-5-phenyloxazolidine and nitrous acid." [...] "In N-carbamyl-(+-)-ephedrine the hydroxyl and the ureido-group must accordingly be trans -placed." [...] "The reaction of pseudoephedrine with CNBr under anhydrous conditions gave 2-imino-3,4-dimethyl-5-phenyloxazolidine ; already obtained from N-cyano-(+-)-ephedrine and from (+-)-ephedrine via* N-carbamyl-(+-)-ephedrine.* " ----------------------------- We know already that heating PPA.HCl with 25% HCl, or hydrolysis of chloro-PPA.HCl (sat'd HCl at 0œC) gives a 50/50 mixture of norephedrine and norpseudoephedrine, and I have promised you all that I have a ref on the separation of these two via their bitartrate salts, well, here it is: taken from Helv.Chim.Acta 22,(1939),p.365 ----------------------------------------- 15grs of the mixture of the bases are dissolved in 40 ml warm water with 15 grs of tartaric acid. After a short time norpseudoephedrine bitartrate precipitates (mp 202œC). Filter this off and evaporate the water. Recrystallise the residue with alcohol: norephedrine bitartrate (mp 130-160œC) -------------------- l-norephedrine base: mp 50œC norephedrine.HCl : mp 171-172œC norephedrine.HSO4 : mp 285-286œC d-norpseudoephedrine.HSO4 : mp 290-291œC I hope this will clarifie this issue somewhat, we are looking here on an OTC, non-toxic and high-yielding synthesis of 4-MAR; aren't there any people around here who could confirm this all by actually trying it out? SWIM has some chloro-PPA.HCl sitting in the freezer but he is really busy at the moment and there not much time for chemistry . e109



		SPISSHAK (Newbee) 05-24-02 00:11 No 313362				thanks!! Never assume the obvious to be true.
						thanks!! Never assume the obvious to be true.



		SPISSHAK (Newbee) 05-24-02 16:21 No 313658				Epimeriztion of optically active compds. (Rated as: excellent)
						You mention racemiztion of ppa with HCl I don`t recommend this see Patent US2214034 for an alternative. This is because of aziridine formation during HCl reflux. This patent will provide a method which according to the aurthor, The hydrogen gas liberatied during racemization serves to protect the ephedrines from decomposition.



		element109 (Hive Bee) 05-26-02 14:05 No 314432				Yes, but it required the aquisition of NaNH2
						NaNH2 is maybe better but requires the construction of a downs cell and handling liquid NH3. This all sounds to me a bit Birch-like, it would be nice if LiNH2 would work but why all that extra work? I understand that you'll try to get the most out of it, but for now I'd stay with HCl until the route has been proven to work; and after that it can be optimized. SWIM heated the chloro-PPA.HCl in dil. HCl for 4 hours (not 24) at 50°C (not reflux), temp climbed at one unsupervised moment to 65°C for about 10 minutes. Basified with 10% NaOH, sat'd with NaCl and extracted once with ether. Evaporated ether, gave yellowish residue which weighed 0.8 gr. The residue was added bit by bit to a hot solution of 0.8 gr tartaric acid in 2 ml dH2O. A few minutes later a white precipitate crashed out, which was filtered off (assumed to be norpseudoephedrine bitartrate). the yellowish mother liquor was evaporated to give a gummy yellow residue; this was recrystallized from EtOH, it still looks a bit gummy but has definately hardened. Both substances are still a bit wet so SWIM hasn't weighed 'em yet. There seems to be a little more (assumed)norpseudoephedrine. melting points have still to be taken. I understand your worries about aziridine formation, but doesn't this require a bit harsher conditions? The authors don't seem to worry much about it. Do you have refs detailing this side reaction? Hey, and why didn't i get at least a "good" rating on my separation procedure? I'm sure it's worth it. e109



		SPISSHAK (Newbee) 05-26-02 17:40 No 314468				Yes PPA is different.
						PPA is diiferent than ephedrine as far as reactivity. SWIM likes racemic crank. And tried this with ephedrine and got a good deal of aziridine. The reason is that the methylamino group is a better nucleophile than amino. So being the better nucleophile it has a tendency to eliminate H-X more readily than a primary amine like PPA. This is especially true of pseudo-ephedrine, because the OH group is cis to the methylamino group. more likely to give that by-product. Lithium hydride can be used as opposed to the amide. I`m wondering if the hydride could be made by exposing the Lithium in a finely divided state to hydrogen atomosphere. I think it can. Lithium hydride is the most stable of all the alkali metal hydrides. So it`s going to be a lot easier to handle than it`s sodium counterpart. Caution must still be applied. Like keeping it away from water, etc. Here`s a good pointer, if you want to test the optical rotation of your salt, or compound, make a solution of it, then get an lcd display (any will do) and use the translucent reflector plastic screen from the back of it and cut it into two pieces. Shine light through the solution with the two translucent plastics on each side of the beaker, test tube, whatever. And observe how it rotates light.



		Wouter (Stranger) 02-06-03 18:35 No 405168				tartaric acid
						Which kind of tartaric acid does SWIY used for the separation of DL-norephedrine and DL-norpseudoephedrine? L-, D- or DL- Tartaric acid?



		Rhodium (Chief Bee) 02-06-03 20:20 No 405188				tartrate
						Either D- or L-tartaric acid, as crystallization with DL-tartaric acid would have no effect. The natural isomer of tartaric acid is very much cheaper than the other, so there is one advantage of that one.



		ballzofsteel (Miss High & Mighty) 02-08-03 12:49 No 405593				Some info on use of tartaric is found in this...
						Some info on use of tartaric is found in this Patent US5962737 Abstract:Stereospecific synthesis of the racemic threo isomers of 2-nitro-1-phenylpropanols by reacting a benzaldehyde derivative with nitroalkane in the presence of a tertiary amine and reducing 2-nitro-1-phenylpropanols with, for example, lithium aluminum hydride to 2-amino-1-phenylpropanols is described. Also described are phase transfer resolution of racemic mixtures of 2-amino-1-phenylpropanol and its derivatives into their optically pure isomers by reacting a racemic mixture with the mono alkali metal salt of a tartaric acid ester in a two phase system of a hydrocarbon and water. The specification further describes therapeutically useful optically pure isomers of threo-2-amino-1-(dialkoxy or alkoxy) phenylpropanols and acid addition salts thereof.



		Wouter (Stranger) 02-22-03 14:00 No 410749				SWIM can't isolate his norephedrine base
						Does anyone know what SWIM do wrong? First he does the akabori-momotani reaction between BzH and Ala. His yield form 100g Ala was ca. 63g with cristals. SWIM refluxed the cristals in dil. HCl for 4 h. Then he add 10% NaOH and ... nothing happend! No cristals precipated. He extract the stuff with ether (and DCM) but without any residue... What does SWIM do wrong? PLEASE HELP!



		BizzyBee (Stranger) 12-21-03 20:53 No 478239				Heres a interesting link about ppa and ... (Rated as: Use the [MEDLINE] tag!)
						Heres a interesting link about ppa and norpseudoephedrine: h ttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db =PubMed&list_uids=3572747&dopt=Abstractƒ Swim used norpseudo in the cyanate rxn, the urea formed and precipitated out after cooling but the hcl reflux does not effect it at all. Not even a hint of pink

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