Ethyl ester of L-Proline

[myodyne]

Hello there...
Does anybody know the exact melting point of L-proline ethyl-ester ?
I am working out the preparation and testing the diphenyl-2-pyrrolidinyl-methanol compound.. I am curious to see.. But the feedback from the previous posts was not very illuminating...

Dear Rhodium would you mind helping with the m.p. ?

[Kinetic]

Hi myodyne

Are you talking about the freebase or a salt? The freebase seems to be a liquid as only the boiling points at various pressures are given in Beilstein. No mention is made of any salt derivative. The boiling points are:

82^oC at 20 torr
67-68^oC at 7 torr
55-57^oC at 5 torr
40^oC at 2 torr

I assume you're following one of the methods from

'Synthesis of diphenyl-2-pyrrolidinyl-methanol and diphenyl-2-pyrrolidinyl-methane'

(https://www.thevespiary.org/rhodium/Rhodium/chemistry/pyrrolidinyl.html)?

For the sake of others, the bioassays are in

Post 395847

(Nemo_Tenetur: "Bioassay not too pleasant ...", Chemistry Discourse) and the reports by Fastandbulbous in the thread beginning with

Post 483951 (missing)

(blunts: "(R)-(+)-alpha,alpha-Diphenyl-2-pyrrolidinemethanol", General Discourse). Nemo's not-too-pleasant bioassay appears to fit Fastandbulbous' experience with the S-isomer, whereas the more positive bioassay of the R-isomer indicates this gives the better experience. The S-isomer doesn't seem worth bothering with, at least on it's own. Nobody seems to have tried the racemic drug.

Unfortunately your end product will be the S-isomer if starting from L-proline. It may be wise to wait until you get hold of some D- (or racemic) proline for a better end result.

Have you considered the reduction of the compound to diphenyl-2-pyrrolidinyl-methane? The reduction of the tertiary alcohol with it's two attached phenyl groups is extremely easy. A standard HI/P reduction is over in minutes (according to the above link). Though the potency decreases the entire synthesis is so cheap and easy it would still be worthwhile if the product turned out to be interesting.

I haven't made either diphenyl-2-pyrrolidinyl-methanol or diphenyl-2-pyrrolidinyl-methane but I do plan on making both sometime in the future. If you start with the proline ester you only need to perform one step before you can bioassay your compound; another step, and you have the next compound to try.

[myodyne]

Thanks Kinetic...
I appreciate a lot your help and advice..

I must make the bioassay....

[myodyne]

Ok..I am waiting for the materials to come.. Yes it is the L-proline unfortunately, I was in a hurry and i didn't get the racemic.. I hope the S-form is good.. I wonder (judging from the binding studies) if it will bring the "coke"-like stimulation...
Anyway i tried some Zyban 150 mg (bupropion controlled released tablets): The effect is a mild stimulation that lasts for many hours... I will try to see if i break and smash the tablet what it will happen.. Has anybody tried to inject this stuff ?  Oooops i got out of topic...

I would like to ask Chief Bee to comment on the applicability of DAT binding studies to the in vivo effectivity of diphenyl-2-pyrrolidinyl-methanol (DP2PDM)..

[myodyne]

Started with the preparation of the ethyl-ester of L-proline..
After conducting Fischer esterification, have come up with some needles mp=190-200 C

Kinetic: Did not get a liquid instead got a solid.. Why?
Also these data:
82oC at 20 torr
67-68oC at 7 torr
55-57oC at 5 torr
40oC at 2 torr

seem to be very strange..Where do they come from ?

What happened..? Anybody

Your synthetic helping hand now...

[myodyne]

Anybody there?

Would Chief Bee mind take a look at this noble effort of mine?

[Nicodem]

Anybody there?

Yes, there is somebee out there.
If you want somebody to answer your question I suggest you to first make it possible to answer: give a write up of the procedure, details about the isolation and recrystallisation, references ...
How can anybody even know if you are talking about a freebase or the sulphate salt?
I have some doubts that you can get a proline ester with the Fisher esterification. If it is possible I would like to have a literature reference, please.

[Kinetic]

Hello again

As I mentioned in my initial post, the boiling points are taken from Beilstein, and correspond to the boiling points of the proline freebase ethyl ester. I don't see why they should be considered strange; what is it about them which makes you think this?

As Nicodem said, it is impossible to accurately answer your question without more information. It seems likely that proline ethyl ester freebase is a liquid. Are your crystals the freebase or a salt?

The melting point of plain proline is suspiciously similar to that of your product. Beilstein reports melting points ranging from 203^oC up to 220-222^oC. Recrystallising proline from ethanol will give a product with a melting point of 208-210^oC. If you are talking about the freebase having such a high melting point, then there is a possibility you have proline instead of the ester.

If you want to try a HCl catalysed esterification, you may like to take a look at the following articles which deal with this:

J. Amer. Chem. Soc., 71, 1949, 3100.
Justus Liebigs Ann. Chem., 326?, 1903, 99.
Tetrahedron, 52 (1), 1996, 225-232. [Using HCl gas to give a quantitative yield]

An alternative is to first form the acyl chloride with SOCl₂ then react this with ethanol. The highest yielding and/or most accessible references are:

J. Org. Chem, 55 (7), 1990, 2254-2256. [97% yield]
Tetrahedron Asymmetry, 11 (6), 2000, 1367-1374.
Can. J. Chem. 80, 2002, 1662-1667. [99% yield]


Edit: Here is the experimental from Tetrahedron, 52 (1), 1996, 225-232. The title refers to the N-protected amino ester. I suppose you'll have to be the judge of what is an 'enough amount' of HCl gas:

Preparation of Ethyl N-(2,2-Dimethylethoxycarbonyl)-(L)-prolinate (6a):

To a solution of (L)-proline (10 g, 87 mmol) in EtOH (150 mL) was introduced enough amount of hydrogen chloride gas and the resulting solution was heated at reflux for 1 h. Evaporation of the solvent gave ethyl (L)-prolinate hydrochloride (15.6 g, 100%) as a colorless oil.

[myodyne]

Sorry ! You are all right..I was very flippant in style..  

Nicodem & Kinetic thank you for the suggestions..

I will return with full details..

God bless.....

[myodyne]

Before attempting the esterification routes you were mentioning..
I have a question for you..

If we used L-proline methyl-ester instead of ethyl-ester would it be possible to have the same reaction product ?

Thanks for listening

[Kinetic]

As is the case for most Grignard reactions with esters, the two should behave in a similar manner. Adding phenylmagnesiumbromide to either the methyl or ethyl ester will give you the same (desired) alcohol.

With regard to the esterification problems, have you tried the method from Tetrahedron in my above post? If you're having trouble with the acid-catalysed method, you may like to try the SOCl₂/ethanol method. The following is a clever way to make the ester, taken from Tetrahedron Asymmetry, 11(6), 2000, 1367-1374:

(S)-1-Pyrrolidine-2-yl-cyclopentanol

To a solution of l-proline (43.3 mmol) in absolute ethanol was added at 0^oC 8 ml of thionyl chloride. The mixture was stirred at room temperature for 1 h and 2 h at reflux. After removal of the solvent, l-proline ethyl ester hydrochloride was obtained as oil. [Kinetic's voice: No yield was given as this was used without purification in the next step: direct addition of the Grignard reagent prepared from 1,4-dibromobutane and Mg, to give (S)-1-pyrrolidine-2-yl-cyclopentanol in 48% overall yield]

I can probably retrieve some of the other papers on the subject if you need them.

Good luck!

[myodyne]

I must say that this forum rocks.. It is unbelievable how many guys with high IQ and great skills gather together and help each other. Bravo

Thanks Kinetic..I feel more secure and less alone in this chemical exploration uncharted areas..

About the process.. I started by using the usual esterification process and failed.. Now I have to try the methods you are mentioning (Tetrahedron etc. I hope I can locate them in the medical libraries of my city..
"Adding phenylmagnesiumbromide to either the methyl or ethyl ester will give you the same (desired) alcohol."
OK this is cool because, I have found in Acros Chemicals the methyl-ester of L-proline... I would like to try..and see what gives. Kinetic have you tried this substance (bio-assayed)yet ?

Bye Kinetic and I will be back as soon as possible..

[myodyne]

Fellow Bees...

SWIM took 1-proline methyl ester HCL and dissolved in water.. Measured pH acidic (1.9).. Then SWIM adds solution of NaOH 50% till pH gets to 13, in order to neutralize the HCL and then adds abundance of NaOH for being sure…

SWIM expected to have straight, 1-proline methyl ester then.. The strange thing is, that the product continues to dissolve in water, when chem. logic says (not  the references, because I have not found any of them) that it wouldn’t dissolve in water, but to stay down as an oil (these kinds of oil usually are heavier than H2O, SWIM thinks)

Next, SWIM removed the water in vacuo and got a yellowish, viscous oil, a thing that is expected.. The Unexpected for SWIM is that this oil is not solvable in ether, in anisol (according to the original preparation oughts to dissolve in both), but it is soluble to water, methanol and ethanol………

What do you think of it ?

[moo]

Maybe your ester got hydrolyzed by the base.