phenylpropanolamine from benzaldehyde

Lep.CON · Wed Mar 30, 2005 5:32 am

Origianally posted at the hive by Aurelius and write up by Driven

IndoleAmine · Dreamreader Deluxe

Concluding it doesn't work just because he fucked up a vacuum distillation of an amine freebase? No no - we'll see. Very Happy

(he made a small error in the workup, for example...)

i_a

Lep.CON · Fri Apr 01, 2005 6:37 am

I hope your right

java · Consumer

Here is the whole thread with comments on it's viability .......java

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

DRIVEN
(Stranger)
06-18-03 09:40
No 440837
PPA via Akabori of benzaldehyde and dl-alanine Bookmark

Hi everyone,

D was very excited to see Bandils' success with the synthesis of 4-MAR with the use of KOCN. D is deeply intrigued by this substance and would like to dream up its existence and was wondering if someone could possibly offer some advice about the production of the precursor, dl-PPA. Though it may seem more appropriate to derive PPA from the reaction of nitroethane and benzaldehyde, it would be nice to derive dl-PPA through the Akabori rxn of benzaldehyde and dl-alanine for practical reasons. If this direction seems futile, please by all means speak your mind and D will get off the train here as he doesn’t have any experience with this reaction.

IOC performed a run by combining 100g BnZ and 40g l-alanine, heating the mixture to 140 (until fizzing stops),extracted the post reaction with H2O, concentrated, then cleaned up the crude product (how it was cleaned wasn’t specfied). In this case there was 15 % yield - which was low but for D, 15% yield would suffice if properly purified. Given PPA is produced, D thinks the next issue is to determine the nature of side products and how to separate them from the target especially when they are likely to be in large quantities from a low yielding reaction. According to Takagi et al (1): When BzH and DL-alanine are heated directly; PhCH2NH2, PhCH(OH)CHPhNH2 (2 dl-compds.), AcH, and CO2 are formed.

D searched for the physical data on PPA and these side products. These (incomplete) data are indicated below (2).

Proposed cleanup (a work in progress): After extracting the post reaction with water, it would be expected that at least benzylamine (PhCH2NH2), being water soluble, would travel along with the PPA. Since the bp of benzylamine, 182 - 185 deg C (760mmHg), is about 80 degrees higher than PPA base then the mixture could be distilled to collect a fraction at 100-105 deg C containing PPA base and water. D is unsure about how to subsequently separate the PPA base from water given their bp’s are so close. D had difficulty finding the bp or solublity data for 2-amino-1,2-diphenylethanol (PhCH(OH)CHPhNH2) so D is still unsure about how to predict its removal.

My questions are:

1) It is assumed that the post reaction will be basic and therefore PPA in its base form, is this correct?
2) Could one separate PPA base from water by acidifying it (making PPA-HCL which has a higher bp than water) and concentrating the mixture?
3) Does anyone know where to find the solubility and bp data for the 2-amino-1,2-diphenylethanol contaminant?
4) Can benzylamine be removed from the reaction mixture as proposed above?
5) What does "AcH" abbreviate?

Any input, directions and comments would be much appreciated!

Take care

DrIvEnwink

References and Data:

(1) Reaction between aromatic aldehydes and a-amino acids. I. New facts on the Akabori reaction. Takagi, Eiichi. J. Pharm. Soc. Japan (1951), 71 648-51.

(2) Physical Data of Various Chemicals Produced by the Akabori Reaction of Benzaldehyde and dl-alanine

Phenylpropanolamine (racemic mix of d- and l-norephedrine)

Base Bp: 101-101.5°
HCl Bp : 190-194°
HCl (+)-form Bp : 171-172°

PhCH2NH2 is benzylamine:

Physical State:
Liquid Appearance: clear colorless to slightly yellow
Odor: ammonia-like
pH: Not available.
Vapor Pressure: 0.6 mbar @ 20 deg C
Viscosity: mPas 20 deg C
Boiling Point: 182 - 185 deg C @ 760.00mm Hg
Freezing/Melting Point: 10 deg C
Solubility in water: > 500 G/L (20°C) IN WATER
Specific Gravity/Density: .9810g/cm3

d,l-PhCH(OH)CHPhNH2 is 2-amino-1,2-diphenylethanol:

This compound has several racemic forms, (1R,2R)(1S,2R)(1RS,2RS),(1RS,2SR)

For example: (1R,2R)-(+)-2-Amino-1,2-diphenylethanol:

Product Number 523704 CAS Number 88082660 Formula C14H15NO Formula Weight 213.3 APPEARANCE WHITE POWDER MELTING POINT 143.8-146.8 DEGREES CELSIUS INFRARED SPECTRUM CONFORMS TO STRUCTURE. PROTON NMR SPECTRUM CONFORMS TO STRUCUTRE. TITRATION 99.1 % (WITH HCLO4) OPTICAL ROTATION +7.5 DEGREES (C=0.6198%, ETOH)
It just seems to go faster...

Aurelius
(Active Asperger Archivist)
06-18-03 11:50
No 440858
Information Bookmark

Hey DRIVEN, take a look.

Post 422067 (Aurelius: "Ephedrine Compilation", Stimulants)

Just about anything you ever wanted to know about the subject. If you've read all of this, let me know and I'll help you out with your questions.

1. Yes, the mixture begins basic, probably ends that way too. Depends on the reaction conditions mostly.

2 & 4. You should clean the reaction mixture by first acidifying the mixture with 10-30% HCl until strongly acidic to litmus. Then filter the whole mess twice to remove any nastiness that we don't want. extract the mix twice with 2x50ml of DCM (or other suitable non-polar) and Separate any layers present and keep the aqueous layer. slowly add NaOH solution (10-30%) until stongly basic to litmus. Extract the mixture with DCM 4x50ml and keep the extract. Combine the extracts and remove the solvent. Fractionally distill the remainder.
benzylamine will be removed when you fractionally distill.

3. try the merck, lang's handbook, CRC handbook, or any of the other very common handbooks with chemical data. It'll be in at least one of them, if not all.

5. AcH is just another way to write Acetic acid. It is more commonly abbreviated as AcOH.
Act quickly or not at all.

DRIVEN
(Stranger)
06-18-03 18:39
No 440932
PPA via Akabori of benzaldehyde and dl-alanine Bookmark

Thanks for being so helpful Aurelius.

Your awsome!wink
It just seems to go faster...

Rhodium
(Chief Bee)
06-19-03 10:41
No 441066
Ac signifies acetyl, CH3CO- not acetoxy, CH3COO-
(Rated as: Good Read) Bookmark

Ac is most often an abbreviation for acetyl { CH3(C=O)- } - not acetoxy { CH3(C=O)O- / AcO- } nor acetate { CH3COO- / AcO- }.

For example, Ethyl Acetate is properly abbreviated EtOAc (and not EtAc) as its structure is CH3CH2O(C=O)CH3.
EtAc is the abbreviation of CH3CH2(C=O)CH3 - methylethylketone (MEK)!

From the above follows that AcOH is a correct designation for CH3COOH, or acetic acid, and that the often incorrectly interpreted AcH really designates { CH3(C=O)H / MeCHO } - acetaldehyde, or etanal!

Aurelius
(Active Asperger Archivist)
06-19-03 11:09
No 441072
Rhodium Bookmark

I'm not going to say you're wrong, but given the large number of newbees around here, I still think that the abbreviation was probably meant to be understood as acetic acid.

Driven, could you please post the article in which you found the abbreviation and use a colored markup to point it out? (surround the word with [ r e d ] word [ / r e d ] But without ANY of the spaces and you get word.
Act quickly or not at all.

Rhodium
(Chief Bee)
06-19-03 12:18
No 441098
Ac nomenclature Bookmark

The earliest mention of [b]AcH] at the hive together with Akabori discussions is in the abstract in the first CA citation in Post 227827 (foxy2: "Re: P2P - 100% OTC !?!", Chemistry Discourse) - The reaction seem much more likely to produce acetaldehyde than acetic acid.

PhCHO + CH3CH(NH2)COOH -> PhCH2NH2 + PhCH(OH)CH(NH2)Ph + AcH + CO2

My main point wasn't to only correct this instance of possible Ac-nomenclature confusion, but also to write a post which to refer back to in the future, should confusion happen again. Regardless of what newbees may write by mistake, it is imperative that we teach them the correct nomenclature now, before we cannot find anything we can be sure of in the archive...

Astrum · Tue Apr 05, 2005 1:42 pm

Alright, well SWIM tried this reaction a few days ago. Not the traditional one, but this one:

IndoleAmine · Dreamreader Deluxe

Just wanted to remark that you can as well condense benzaldehyde with nitroethane using KOH catalyst to yield the nitro alcohol 1-phenyl-2-nitropropan-1-ol (P2NPol), which is easily reduced with Zn/HCOOH to yield phenylpropanolamine... Wink

IndoleAmine · Dreamreader Deluxe

Astrum: the BzCHO dissolves in the toluene, the l-alanine dissolves in the water - you'll need a PTC or other surfactant to accomplish any appreciable rxn rate I think, or at least vigorous stirring...

Bluechip · Wed Apr 06, 2005 2:28 pm

Bandil has had success with simular using trethylamine as catalyst.He also explains why this is favourable over NaOh catalyst, for producing the wanted isomer.

THE NEW VERSION.
.[url]
http://v3.espacenet.com/textdes?DB=EPODOC&IDX=US5750802&F=0&QPN=US5750802[/url]

Nitroethane (10.2 g., 0.132 mole) was mixed with triethylamine (17.1 g., 0.169 mole), cooled to a temperature of -8 DEG C. and benzaldehyde (5.1 g., 0.047 mole) added. After 2.7 hours at -10 DEG C., the mixture was neutralized. HPLC analysis showed a conversion of 8.25 g. (96.9%) of total 2-nitro-1-phenyl-1-propanol. 6.40 g of the 2-nitro-1-phenyl-1-propanol was the (1R*,2S*)-stereoisomer (77.6%).

EXAMPLE 2

Nitroethane (15.6 g., 0.208 mole) was mixed with triethylamine (17.1 g., 0.169 mole), cooled to a temperature of -8 DEG C. and benzaldehyde (5.02 g., 0.047 mole) added. After 2.25 hour reaction time, at -10 DEG C., the mixture was neutralized. HPLC analysis showed a conversion of 8.30 g (96.9%) of total 2-nitro-1-phenyl-1-propanol with a (1R*,2S*)-stereoisomer content of 6.11 g. (74.1%).

Hydrochloric can alkso be used for the zinc reaction
REDUCTION AND RESOLUTION.
[url]
http://v3.espacenet.com/textdes?DB=EPODOC&IDX=US5962737&F=0&QPN=US5962737[/url]

EXAMPLE 1

A racemic mixture of threo nitroalcohols was prepared by combining freshly distilled benzaldehyde (1 mole), nitroethane (2.5 moles), and triethylamine (0.05 mole) in ethanol (150 ml.) with water (75 ml.). This mixture was allowed to stand at room temperature in the dark for twenty-four hours. The mixture was then ice-cooled and acetic acid (0.05 mole) was added to the reaction mixture. Alcohol and excess nitroethane were evaporated (vacuum). Water (75 ml.) was added and the nitro alcohol extracted with ethyl acetate, dried over anhydrous sodium sulfate and the solvent evaporated (vacuum) to give the product, a viscous oil (yield 70-80% based on the benzaldehyde). GC/MS and NMR data were consistent with proposed structures. NMR indicates pure threo isomer on the basis of the coupling constant of the benzylic proton [--OCH-doublet J=9.4 Hz (formic acid)].

EXAMPLE 2

The nitro alcohols were reduced by two methods, a zinc and acid method and a lithium aluminum hydride method as described below:

(A) Zinc and Acid

Hydrochloric acid (4 moles) is added (with stirring) to a mixture of nitroalcohol (1 mole), zinc dust (4 moles), and 400 ml. of 95% ethanol. The acid is added at such a rate that the temperature remains at 45 degrees or below (several hours are usually required). Stirring is continued for 1-2 hours after completing the addition. The acid solution is extracted with ether to remove non-basic materials. Excess NaOH solution is then added and the free base extracted with ether. The ether solution is dried (MgSO4) evaporated, and the product distilled or crystallized in the usual manner (70-80% yield

The reaction mixture of reduced nitro alcohols was resolved into optically pure isomers by the following process.

A mixture of a DL-threo-2-amino-1-phenylpropanol (1 mole) in dichloromethane (600 ml.), dibenzoyltartaric acid (0.5 mole) in distilled water (30 ml.), and sodium hydroxide (0.5 mole) in distilled water (50 ml.) is stirred rapidly for two hours and allowed to stand for two hours. The dichloromethane phase is separated using a separating funnel over anhydrous magnesium sulfate. Rotary evaporation of the dichloromethane phase gives the L-threo isomer in nearly quantitative yield.

The aqueous phase is made alkaline with ammonia to pH 13 and extracted with dichloromethane. The dichloromethane extract is dried over anhydrous magnesium sulfate and evaporated to give the D-threo isomer in nearly quantitative yield. The enantiomeric purity of the products is 96-99% based on GLC analysis of the D or L-.alpha.-methoxy-.alpha.-trifluromethylphenylacetamide (MTPA) derivatives.

*****************************************

Astrum,

Thankyou for trying this out and posting your results.
Over at WD I posted a ref for a French patent in the same post.
It is in french(duh) but a quick babelfish translation shows that the reaction is conducted in ethanol with higher yield.
MAybe give this a try also please?
Im thinking that these are different mechanisms to the claimed Akabori.
Im not sure that PPA would even be produced with these.Just going by what Cherriebaby hinted at.
I did see another patent in which they did as IA suggested and used an emulsifier as apposed to PTC with O>K results.
Without PTC as like CHerriebaby posted,the french patent is the next best yield I could fine.

Cheers[/url]

Bluechip · Sat Apr 09, 2005 12:58 pm

I had to go all the way over to WetDreams to retrieve this. Laughing

Ballzofsteel
Dreamer

Posted - Mar 30 2005 : 03:26:55 AM
--------------------------------------------------------------------------------

Drug freak,
Please look at and test some of these out,like Cherriebaby suggests.
USing your alanine of course.

Abstract of GB932837

A process for the manufacture of optically active methylamino carboxylic acids comprises reacting in aqueous solution a salt formed from a strong base and an optically active amino carboxylic acid (a second amino group if present being protected if it is not to take part in the reaction) with benzaldehyde or a substituted benzaldehyde, reducing the resulting N-benzylidene or N,N1-dibenzylidene compound in a basic medium to the corresponding N-benzyl or N,N1-dibenzyl compound and then methylating the latter at the benzylated amino group or groups (i.e. unselective monomethylation or otherwise dimethylation in the case of the N,N1-dibenzyl compound) and subsequently splitting off the N-benzyl group of N,N1dibenzyl groups and any protecting group by hydrogenolysis in a neutral or acidic medium. An alkali metal salt of the amino carboxylic acid is preferably used as the starting material. The reduction of the N-benzylidene or N,N1-dibenzylidene compound may be carried out using catalytically activated hydrogen or a complex metal hydride. The methylation is preferably carried out using formaldehyde in the presence of a reducing agent, preferably formic acid. Many suitable amino carboxylic acids are specified. Suitable substituted benzaldehydes specified are salicylaldehyde, tolualdehyde, vanillin, and nitro-benzaldehydes such as p-nitrobenzaldehyde. Examples 1-5 describe the stepwise preparations of the N-methyl derivatives of L-valine, L-phenylalamine, L-alanine, L-leucine and L-serine. Example 6 describes the preparation of Ne -carbobenzoxy-Na -benzyl-L-lysine from Ne -carbobenzoxy-L-lysine and its subsequent conversion to Na -methyl-L-lysine.

http://v3.espacenet.com/textdes?DB=EPODOC&IDX=GB932837&F=0&QPN=GB932837" target="_blank"> br / br / http://v3.espacenet.com/textdes?DB=EPODOC&IDX=GB932837&F=0&QPN=GB932837

By reactionof L-alanine with benzaldehyde and reduction of the so obtained benzyli- dene compound with sodium borohydride according to the procedure of the preceding examples, N-benzyl-L-alanine was obtained in a yield of 71%; melting point 255~ C. (decomposition)[á]D22=+12.6~ (c=1.0 in 6-N hydrochloric acid).

http://v3.espacenet.com/textdes?DB=EPODOC&IDX=KR8700738&F=0&QPN=KR8700738" target="_blank"> br / http://v3.espacenet.com/textdes?DB=EPODOC&IDX=KR8700738&F=0&QPN=KR8700738

Water (400 g), 212 g of benzaldehyde and 120 g of toluene were added to 60 g of glycine. With stirring at 10 DEG to 15 DEG C., 177.8 g of 45% sodium hydroxide was added dropwise over the course of 2 hours. Then, the reaction temperature was gradually raised to 20 DEG C., and the reaction was carried out at 20 DEG to 25 DEG C. for 20 hours. After the reaction, 292.0 g of 35% hydrochloric acid was added dropwise at a temperature of not more than 40 DEG C., over 45 minutes. The mixture was further stirred at room temperature for 1 hour. After standing, the lower aqueous layer was separated and analyzed by high-performance liquid chromatography. The ratio of formation of .beta.-phenylserine was 92.6% (based on glycine). The aqueous layer was neutralized to a pH of 6 with 45% sodium hydroxide, cooled to 0 DEG to 5 DEG C., stirred at the same temperature for 1 hour, filtered, washed with cold water, and then dried under reduced pressure at 50 DEG C. to give 131.4 g of white crystals of .beta.-phenylserine. The purity of this product analyzed by high-performance liquid chromatography was 90.5%. Differential thermal analysis showed that the product had one molecule of water of crystallization. The yield of the product (based on glycine) was 82.0%. Melting point: 198 DEG-200 DEG C. (decomposition).

http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=DE3642475&F=0" target="_blank"> br / http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=DE3642475&F=0

ss-Phenylserine is prepared by condensation of glycine with benzaldehyde in the presence of an alkali metal hydroxide in a medium consisting of water and a benzaldehyde-immiscible silicone oil and subsequent treatment of the alkali metal salt of N-benzylidene-ss-phenylserine formed in this way with an acid. As a result of the additional use of silicone oil, the reaction mixture remains stirrable during the condensation reaction and the work-up is facilitated by the acid treatment.

Babelfish translation:

75 g glycine were solved in 350 g water and with 220 g Benzaldehyd and 200 ml silicone oil M 3 (manufacturer: Bavarian AG) shifts. Then 250 g 40 of a weight-per cent caustic soda solution were admitted at one time. It was ensured by occasional cooling that the reaction temperature did not rise over 50 DEG C. Subsequently, over night at ambient temperature one agitated. Then at a temperature of any more than 40 DEG C 360 g 35 of a weight-per cent hydrochloric acid were not course-dripped, still another one hour was agitated long and then the aqueous phase separated. The aqueous phase was brought with 50 to weight-per cent caustic soda solution on pH 7.5, cooled down on 0 DEG C and filtered after one hour at this temperature. The Phenylserinkristalle was washed with ice water and dried under decreased pressure with 60 DEG C up to the constant weight. The colorless Phenylserin contained then still 1 mol of crystal water. Yield: 157.8 g (79% of the theory, related to assigned glycine). Melting point: course-dripped, the cooling and was removed for 180-182 DEG C caustic soda solution still 15 hours were agitated long at ambient temperature. Then 360 g 35 of a weight-per cent hydrochloric acid course-dripped that the interior temperature did not rise to any more than 40 DEG C, it were agitated in such a way still another one hour long and then the aqueous phase separated. The aqueous phase was brought with 50 to weight-per cent caustic soda solution on pH 7.5, on 0 DEG C cooled down and 1 hour long at this temperature stands left. Then the separated crystals were filtered off, washed with ice water and dried under decreased pressure with 60 DEG C up to the constant weight. The colorless beta Phenylserin contained then still 1 mol of crystal water. Yield: 161.4 g (81% of the theory, related to assigned glycine). Melting point: 180-182 DEG C.

This is in french,Performed in alcohol.
http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=FR1017396&F=0" target="_blank"> br / http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=FR1017396&F=0

I could only get the french one in pdf format sorry.Hope you can read french.

This is ballzofsteel btw.

Bluechip · Sat Apr 09, 2005 10:11 pm

Please read this if interested in the phenylserines.
A very interesting thread indeed.

http://12.162.180.114:90/synthetika/hiveboard/methods/000448052.html

Very Happy

TY

IndoleAmine · Dreamreader Deluxe

Wow - thanks for the heaps of interesting information you provided us with!

If every bee would solely contribute in such a way, we would have the most comprehensive chemical database related to the chemistry of mind-altering compounds, within one or two years - I would bet... Laughing

(keep up the good work!)

i_a

IndoleAmine · Dreamreader Deluxe

Means that the nitroalcohol route to PPA allows for stereoselectivity through selection of certain amine catalysts.

Triethylamine is the best catalyst (followed by diethanolamine), it gives a norphedrine:isonorephedrine ratio of 79:21 and total conversion of 75 percent calculated from benzaldehyde.

This means ~60% yield of optically pure dl-norephedrine after optical resolution (if anyone would want to attempt such a thing)...

cheers

i_a

Bluechip · Wed Apr 13, 2005 3:12 pm

Sure you have permission.

Funny thing is I posted the exact same patented, "redundant'' info a couple of posts up!
Laughing

Click on the link I posted.Same as yours yeah?
Now stop that eating up of precious banwidth will you?

Off topic,
Any thought on the reduction of the isonitropropiophenone?Is catalytic hydrogenation a must do you think?

IndoleAmine · Dreamreader Deluxe

The links you posted don't contain the same things at all - they are all original text patents, and one hive thread - no link to any rhofium mirror.

Note: I searched this thread for the patent number EP960,876 with Ctrl+F, and found just my own post... Rolling Eyes

(or I'm just temporarily blinded, and you have to point me to it Wink

)

Show me where, and I will delete my post (provided its really redundant).

Next time you could say "its already here; look HERE" and give a quick link, instead of letting me search every link you posted recently, that would be nice.

And a propiophenone has a C=O instead of that C-OH we want - so yes, you have to reduce it to arrive at PPA, no way around it.

Either with cat.hydrogenation, or other reduction methods.

cheers,

i_a

Bluechip · Thu Apr 14, 2005 3:38 pm

http://v3.espacenet.com/textdes?DB=EPODOC&IDX=US5750802&F=0&QPN=US5750802

Click and compare if you want.

POST 38 by me.
It is already here.Same patent different number is all. Wink

Not meaning to be a smartarse btw.

On the reduction of the propiophenone oxime
I realise some kind of reduction is indeed needed but,I recall foxy posting a procedure at the hive describing the direct reduction of isonitrosopropiophenone leading to Cathinone,which if Im not mistaken is usually considered norpseudoephedrine.
I am wondering about the ideal conditions ie catalyst for the reduction so as to obtain norephedrine.I cant seem to find any refs for this,or any notes on the industrial methods.
Any ideas.