Sciencemadness Discussion Board

(S)-(+)-α-Methylphenethylamine from (R)-(+)-2-Amino-3-phenylpropanoic acid

jugador69 - 21-2-2014 at 05:51

Hello everybody, this is my first post here in this forum. I am not English speaker so.. I apologize for my spelling faults. This synthesis works very well and it's OTC but it has too many steps, and specially the second is a little bit messy. Comments and improvements are welcome.

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Methyl (R)-(+)-2-amino-3-phenylpropanoate
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To a slurry of 60g (0.364 mole) of (R)-(+)-2-Amino-3-phenylpropanoic acid in 200mL CH3OH, 42 mL of concentrated H2SO4 (97%, 0.75 mole) is added slowly maintaining the solution temperature of 30°—40°C. Then the solution is heated to 84°—86°C. To the solution, 500mL of CH3OH are fed for 3 hours while 600mL of vaporized aqueous CH3OH is removed from the reactor. The prepared PM.H2SO4 solution is neutralized with 10% of methanolic-NaOH to form Na2SO4 crystals. The neutralized solution is then filtered and 1000mL of absolute ethanol are charged. The solution is distilled under vacuum to remove the residual methanol, and used in the next step.

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(R)-(+)-2-amino-3-phenylpropanol
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To the solution of previous step, ~62g (0.346 mole) [the yield in the literature is 98.7%, I calculated around 95%] of Methyl (R)-(+)-2-amino-3-phenylpropanoate in 800mL of absolute ethanol contained in a 2L round-bottomed flask, to which is attached a 40cm reflux condenser protected by a CaCl2 drying tube, is added 40g. (1.74 mole) of sodium in pieces in one lot. The vigorous reaction is kept under control by immersing the entire flask in a mixture of crushed ice and water. In a short time the reaction has subsided somewhat; the flask is then removed from the cooling mixture, and the reaction is allowed to proceed without external cooling. Reduction is completed by heating the mixture on a steam bath until all the sodium has dissolved. The partly cooled mixture is diluted with 250mL of water and vacuum distilled until no more alcohol distils. The residue is diluted with about 400mL of hot water, and the mixture is allowed to cool. The white solid that precipitated was vacuum filtered, washed with 2*25mL cold acetone and dried. 34,8g (66%) m.p. 94-95.5ºC [lit. 93-95ºC].

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(R)-(+)-2-Phthalimido-3-phenylpropanol
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In a single neck 1L round bottom flask, 34,8g (230 mmoles) of (R)-(+)-2-amino-3-phenylpropanol, 40g (270 mmoles) of phthalic anhydride and 20g CH3COONa.3H2O are dissolved in 500mL GAA. The mixture is refluxed and stirred for 80 minutes and then concentrated to 150mL in vacuo. At this point the N-sustituted phthalimide started to separate out and the mixture is poured in the fridge. A white-pale yellowish solid precipitated out of the solution. This is filtered and recrystallized twice from EtOH 96% to leave 55,6g (82%) of a white solid, supposed to be (R)-(+)-2-Phthalimido-3-phenylpropanol.

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Pyridinium Chlorochromate (PCC)
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100g (336 mmoles) of Na2Cr2O7.2H2O are dissolved in 250mL distilled H2O. To this solution 70g of H2SO4 are added in small portions with external cooling and stirring. An intense red color precipitate (CrO3) forms instantly in the solution. This is poured in the freezer and red crystals, vacuum filtered.

6M aq. HCl is added to the crystals until dissolved and then 30mL (350 mmoles) pure pyridine are added slowly while stirring; an orange precipitate (PCC) forms. This solution is cooled and filtered to recover 65g (302 mmoles) of PCC. This is used in the next step without purification.

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(R)-(+)-2-Phthalimido-3-phenylpropanal
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65g (302 mmoles) of PCC were disolved in 400mL DCM at room temperature. To this mixture 55.6g (198 mmoles) of (R)-(+)-2-Phthalimido-3-phenylpropanol in 500mL DCM were slowly added while stirring and mantaining temperature at 25-30ºC. When the addition is complete the solution was allowed to stir at room temperature for 48 hours, and most of the solvent distilled under reduced pressure.

A saturated aqueous solution of NaHSO3 was prepared by mixing ~42g (404 mmoles) in 100mL dH2O, and this was added to the previous dissolution and stirred while the solution is warmed. The dark yellow-orange precipitate was filtered and washed with 3*50mL cold DCM. The white-yellowish solid was poured in a sepparatory funnel and 1M aqueous NaOH dissolution was added until no more solids were seeing. The aqueous layer was saturated with NaCl and extracted with 5*75mL portions of Et2O. 39.65g (70%) of (R)-(+)-2-Phthalimido-3-phenylpropanal.

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Hydrazine hydrate
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37,05g (285 mmoles) of hydrazine sulfate, is powdered thoroughly and treated with ~11,5g (285 mmoles) of NaOH powder, in small portions, mantaining the temperature at 50-60ºC with a water bath. First the reaction is slow but its faster when the temperature reached, at this point small bubbles form from the powder. When all the NaOH is added the mixture is left overnight at 50ºC. The resultant white-colorless solid mixture is extracted with 5*75mL of MeOH, and all the extracts concentrated in vacuo, to aprox. 150mL. This is used in the next step without any purification.

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(S)-(+)-α-Methylphenethylamine
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39.65g (138.5 mmoles) of (R)-(+)-2-Phthalimido-3-phenylpropanal, 14,15g NH2NH2.H2O (283 mmoles) in CH3OH and 400mL of ethylene glycol are mixed and warmed to complete dissolution. The mixture, first, is heated to about 180ºC, distilling the water of the reaction mixture and hold at this temperature for 3h. The distillation setup is removed and the mixture let to cool down, then refluxed at ~200ºC with stirring about 12h. Then a saturated dissolution of NaOH in ethylene glycol is added while stirring, slowly, mantaining the temperature as low as possible. Gas formation is observed (N2) and addition is stopped when it ceased. The solution is poured in 1L ice cold saturated aqueous NaOH and stirred. Then is extracted with 5*75mL Et2O, all the extracts are treated with conc. H2SO4 in IPA, and the solvents evaporated under vacuum to give 18.5g (~81% yield) of (S)-(+)-α-Methylphenethylamine sulfate. (S)-(+)-α-Methylphenethylamine sulfate m.p. >300ºC [lit. >300ºC].

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References
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Karrer P. and Ehrhardt K. - Helv. Chim. Acta 34, 2202 (1951)
http://www.sigmaaldrich.com/catalog/product/sigma/p1751?lang...
http://www.chemspider.com/Chemical-Structure.64639.html
http://www.organic-chemistry.org/namedreactions/gabriel-synt...
http://www.organic-chemistry.org/namedreactions/wolff-kishne...
http://www.organic-chemistry.org/protectivegroups/amino.shtm
Eric Parquet and Qun Lin Vol. 74 No. 10 October 1997 • Journal of Chemical Education
David B. Repke J. Pharm. Sci. 67(8), 1167-1168 (1978)
Vogels-Practical Organic Chemistry, 5th edition (1989), 1276
http://www.drugbank.ca/drugs/DB01576
PIHKAL, 539-541.
US5334746
US6517798
Organic Syntheses, Coll. Vol. 2, p.154 (1943); Vol. 14, p.20 (1934)


turd - 21-2-2014 at 08:05

Was this actually performed by you or is this a proposed synthetic pathway?

jugador69 - 21-2-2014 at 08:38

Yes, I performed this synthesis many times, always gave 15-20g of final product; the first step can be done more simple using LAH, but it is not OTC to me; all the reagents can be bought easily in the most popular auction site of the internet. Some of the text parts are copied from the articles to make it more understandable, but the quantities and proportions are real (there may be an error).

turd - 21-2-2014 at 09:17

Congratulations. I bow before your dedication - so much work for such a simple and widely available compound.

solo - 21-2-2014 at 09:21

.......i found interesting how you used the phthalimide to remove the OH from your target compound, I have been using it to make the phenylethylamine via gabriel synthesis ........now (R)-(+)-2-Amino-3-phenylpropanoic acid (phenylalanine) is an old friend of mine......a most interesting approach to an old problem however using chromates and hydrazine is not exactly safe compounds.....solo


[Edited on 21-2-2014 by solo]

turd - 24-2-2014 at 01:15

If you find time, could you please make a salt that has a defined melting point to see if this is indeed the enantiomerically pure compound? (I suppose that most amphetamine salts crystallize as racemates).

Edit: or even make a diastereomeric salt to unambiguously prove the enantiomeric form.

[Edited on 24-2-2014 by turd]

jugador69 - 24-2-2014 at 04:36

Quote: Originally posted by solo  
.......i found interesting how you used the phthalimide to remove the OH from your target compound, I have been using it to make the phenylethylamine via gabriel synthesis ........now (R)-(+)-2-Amino-3-phenylpropanoic acid (phenylalanine) is an old friend of mine......a most interesting approach to an old problem however using chromates and hydrazine is not exactly safe compounds.....solo


[Edited on 21-2-2014 by solo]


Yes, you are right, chromates and hydrazine are not exactly safe compounds... that's why I only made this synthesis at small scale, mejor que exploten 15 gramos que 100 :D
Quote: Originally posted by turd  

If you find time, could you please make a salt that has a defined melting point to see if this is indeed the enantiomerically pure compound? (I suppose that most amphetamine salts crystallize as racemates).

Edit: or even make a diastereomeric salt to unambiguously prove the enantiomeric form.


I was interested in making the aspartate salt, but I can't find a reference of its melting point. Also the HCl salt, but I heard somewhere that it is very hygroscopic. If someone has references of different amphetamine salt melting points I will make it and test.


[Edited on 24-2-2014 by jugador69]

Methyl.Magic - 12-3-2014 at 15:16

Very nice work !!! Congratulation !! Transforming to aldehyde and reducing by wolf kichner is an odd but nicely working idea !

Cou can also directly reduce the alcohol to alcane via triethlsilane, reduction of the xanthate, superhydride or simply by SN2 via the tosylate and an complexed hydride.

Acid can be directly reduced to aldehyde via Chloro(or bromo)Thexylborane, easy and good yield but quite difficult to get it.