Sciencemadness Discussion Board - Synthesis of L-Phenylacetylcarbinol(L-PAC)

If it is an industrial process I'm sure there must be details on the web about it? Besides fermentations usually produce a nice complex soup of various biochemicals as by-products. I can envisage 25L + vessels, starter cultures, sterile equipment, mechanical stirring, temperature control. I don't think biotech is really a good method for obtaining chemicals on anything less than an industrial scale.... is it?.... I may be wrong...

this is not industrial scale.just lab scale
before i has idea for making l-pac :
http://www.sciencemadness.org/talk/viewthread.php?tid=11319&...

but i think that method wont work and i want to know what is best method for making l-pac

[Edited on 25-4-2009 by hector2000]

[Edited on 25-4-2009 by hector2000]

panziandi - 25-4-2009 at 06:42

Yes what I am saying is that biotech methods do not tend to be high yielding and require a fair scale to get a good yield of product.

Take for example making alcohol, most yeasts will only get an alcohol concentration up to 12% (some as high as 20%)...before they die from living in their excrement! So working on a 25L scale you can get perhaps 2L after work up perhaps less.

So for a fair yield of your product you are likely looking at working on a 25L fermentation (at least)! You will have to have everything sterile because if you have stray yeasts or moulds or bacteria then you'll find contaminating growth and competition vs. yeast and a much lower yield and contaminated product.

I was saying that biotech methods for chemicals work industrially because of the huge scale they can operate on. They aren't the best methods for small lab scale preps!

hector2000 - 25-4-2009 at 07:12

thanks panziandi
i found patent:
us 6,271,008
and i want try it but this patent use pyruvic acid that is expensive
if we use 25 lit container then how long may take for produce l-pac and how much l-pac we will have?
do you have better instruction with detail for making l-pac by ferment method?

panziandi - 25-4-2009 at 09:29

http://designer-drugs.com/pte/12.162.180.114/dcd/pdf/l-pac.n...

is the reference that the patent gives (Neuberg, C. and Hirsch, J. Biochem. Z., 1921 115 282-310) it is in German but perhaps you can translate it or gleen some information from the methods section?

The examples given in the patent give 20% yields and product in the milligram range! I do not know how it would scale.

hector2000 - 25-4-2009 at 10:07

UNFORTUNATELY this patent language is german and i cant use it
but really thanks
i will try pyruvic acid method soon and will write my result
also i am waitng for your advise and your another patent about this method

panziandi - 25-4-2009 at 10:22

Pyruic acid can be made from propylene glycol or from lactic acid by oxidation (both are commercially available and cheap), I expect that the acetyl chloride > acetyl cyanide > pyruvic acid method would be unavailable to you.

Well yes that reference is in German, it is the reference that the patent you found quotes.

US patent 6,271,008 describes low volumes and a low yield some 20% as i said above, I do not know how scalable that would be though. From what I can tell, it runs at a higher temperature (50*C) so the yeast is not growing, in fact you won't really get much bacterial growth either, and it really is just utilising the enzymes as a crude catalyst rather than purified enzymes.

hector2000 - 25-4-2009 at 11:09

Pyruic acid can be made from propylene glycol or from lactic acid by oxidation (both are commercially available and cheap), I expect that the acetyl chloride > acetyl cyanide > pyruvic acid method would be unavailable to you.

Well yes that reference is in German, it is the reference that the patent you found quotes.

US patent 6,271,008 describes low volumes and a low yield some 20% as i said above, I do not know how scalable that would be though. From what I can tell, it runs at a higher temperature (50*C) so the yeast is not growing, in fact you won't really get much bacterial growth either, and it really is just utilising the enzymes as a crude catalyst rather than purified enzymes.

you think us patent 6,271,008 is unreal?or not working well?
if i want to make 100gram l-pac how much i should use?and temp?baking yeast will work for this purpose?
making pyruvic acid by propylene glycol or lactic acid is simple or is hard?may descript it?
what is your idea about tartaric acid +potassium hydrogen sulfate method?
you advise that i use pyruvic acid method?

my old suggestion for making l-pac is this:

phenylacetic acid+lead acetate---heat--->benzyl methyl ketone

according to wikipedia this reaction is true and will work
but you think below reaction will work?

mandelic acid+lead acetate--heat-->l-pac
??
thanks

[Edited on 25-4-2009 by hector2000]

[Edited on 25-4-2009 by hector2000]

panziandi - 25-4-2009 at 13:46

The patent you mention states:

"EXAMPLE 1

Yeast-Mediated Acyloin Condensation of Benzaldehyde Using Pyruvic Acid

Pyruvic acid buffer was prepared by dissolving pyruvic acid (10.44 g, 119 mmol) in 100 ml of 0.05 M sodium citrate. Ammonium acetate was added to give a pH of 5.45. Benzaldehyde (106 mg, 1 mmol), petroleum ether (80 ml), ethanol (0.5 ml), baker's yeast (5 g) and the pyruvic acid buffer (5 ml) were stirred at 50° C. for 24 h. The mixture was then filtered and the yeast washed with diethyl ether.

The combined organic layers were then washed with 10% sodium carbonate. After removal of the solvent in vacuo the product was purified by flash distillation (200° C./1 mm) to give phenylacetylcarbinol (30 mg, 20% yield). Gas chromatography (GC) of the product showed pure PAC (11.88 min.). Chiral GC showed a ratio of 95:5, 90% ee."

So they made 30mg that is 0.03g of phenylacetylcarbinol, you want to make 100g that's over 3000 times the scale! If you multiply everything in their method by 3333, which you will see is starting to look a little bit silly!

And you will soon see why I told you large containers are needed!!!

Bioreactions

Paddywhacker - 25-4-2009 at 16:25

...
"EXAMPLE 1

Yeast-Mediated Acyloin Condensation of Benzaldehyde Using Pyruvic Acid

Pyruvic acid buffer was prepared by dissolving pyruvic acid (10.44 g, 119 mmol) in 100 ml of 0.05 M sodium citrate. Ammonium acetate was added to give a pH of 5.45. Benzaldehyde (106 mg, 1 mmol), petroleum ether (80 ml), ethanol (0.5 ml), baker's yeast (5 g) and the pyruvic acid buffer (5 ml) were stirred at 50° C. for 24 h. The mixture was then filtered and the yeast washed with diethyl ether.

The combined organic layers were then washed with 10% sodium carbonate. After removal of the solvent in vacuo the product was purified by flash distillation (200° C./1 mm) to give phenylacetylcarbinol (30 mg, 20% yield). Gas chromatography (GC) of the product showed pure PAC (11.88 min.). Chiral GC showed a ratio of 95:5, 90% ee."
...

I'm really tickled by the idea of this. The method deserves, IMO, to be tested and a separate thread, maybe in prepublications, created for bioconversions.

Nicodem - 25-4-2009 at 22:57

Hector2000, post one line questions without a single reference in the Beginnings section. It is pointless to be so lazy and incomprehensive in the Organic section as I will move threads where they belong anyway. Besides, what was the point of opening a new thread on the subject for which a thorough discussion with experimental results already exist in a dedicated thread?

hector2000 - 26-4-2009 at 01:49

The patent you mention states:

"EXAMPLE 1

Yeast-Mediated Acyloin Condensation of Benzaldehyde Using Pyruvic Acid

Pyruvic acid buffer was prepared by dissolving pyruvic acid (10.44 g, 119 mmol) in 100 ml of 0.05 M sodium citrate. Ammonium acetate was added to give a pH of 5.45. Benzaldehyde (106 mg, 1 mmol), petroleum ether (80 ml), ethanol (0.5 ml), baker's yeast (5 g) and the pyruvic acid buffer (5 ml) were stirred at 50° C. for 24 h. The mixture was then filtered and the yeast washed with diethyl ether.

The combined organic layers were then washed with 10% sodium carbonate. After removal of the solvent in vacuo the product was purified by flash distillation (200° C./1 mm) to give phenylacetylcarbinol (30 mg, 20% yield). Gas chromatography (GC) of the product showed pure PAC (11.88 min.). Chiral GC showed a ratio of 95:5, 90% ee."

So they made 30mg that is 0.03g of phenylacetylcarbinol, you want to make 100g that's over 3000 times the scale! If you multiply everything in their method by 3333, which you will see is starting to look a little bit silly!

And you will soon see why I told you large containers are needed!!!

ok i will use 25lit container
you think if i use this container then how much i will have?100 gram?or less?
do you have detail about making pyruvic acid by tartaric acid method or another method?

mr nicodem excuse me but my english is very bad but you want to say there is another thread about l-pac in this forum?

Sauron - 26-4-2009 at 03:02

3333 x c.100 ml is 333 liters and that is the vioreactor size needed to make 100 g L-PAC a day per this patent.

[Edited on 26-4-2009 by Sauron]

turd - 26-4-2009 at 03:44

mr nicodem excuse me but my english is very bad but you want to say there is another thread about l-pac in this forum?

Sigh... Why don't you just use the fucking search engine?
http://www.sciencemadness.org/talk/viewthread.php?tid=1936

hector2000 - 26-4-2009 at 03:49

3333 x c.100 ml is 333 liters and that is the vioreactor size needed to make 100 g L-PAC a day per this patent.

[Edited on 26-4-2009 by Sauron]

we just need 5 ml of pyruvic acid buffer solution not 100ml
and i think if we multiply 80ml(ether) to 3000 we should use240 lit and i think this is enough to use 2.5-5lit ether for separate l-pac from solution
i mistake?

Sauron - 26-4-2009 at 05:16

Read the patent

Benzaldehyde (106 mg, 1 mmol),
petroleum ether (80 ml),
ethanol (0.5 ml),
baker's yeast (5 g)
and the pyruvic acid buffer (5 ml)
were stirred at 50° C. for 24 h.

That is a little over 90 ml total so figure `100 ml and that gets you just 30 mg L-PAC

Times 3333 = 333 liters. Use a 350 L stirred bioreactor regulated to 50 C. That gets you 100 g if you do everything right.

You have a LOT to learn about biotech.

brewing L-PAC

Elena - 26-4-2009 at 05:27

Once Upon a Time the famous Uncle Fester recommended next proportion of starters for brewing L-PAC:
1 part of glucose, 1 part of yeast, 20 parts of water, 1/12 part of Benzaldehyde.
If (as Uncle Fester claimed) you could get of 85% yield of L-PAC on your Benzaldehyde,
So to get 100 gr. of L-PAC, you probably will need 120 gr. of Benzaldehyde, 1.44 kg. of sugar, 1.44 kg. yeast,
28.8 L. of water. Considering the foam, you'll probably need volume of 50-60 litre container.

Sorry, gentlemen for my broken English.

Sauron - 26-4-2009 at 05:36

No comment needed re the "famous" UF.

Elena - 26-4-2009 at 06:12

I am sorry Sauron. I am newcomer here. Why No comment about UF.
May be mentioned of him forbidden here?
Could you please explain more comprehensively?

[Edited on 26-4-2009 by Elena]

panziandi - 26-4-2009 at 07:07

I think UF methods are a little, well shall we say, unlikely to yield what they claim to yield? The %s are a little fabricated? Is the general impression I get.

Anyway my comment about requiring a large bioreactor is true, I guessed 25L before reading the patent, and before knowing what scale hector intended, Sauron indeed has a better volume at 350L for hectors scale-up.

Now then the Wattage required to maintain a 330L reaction medium at 50*C for 24hrs is going to be... quite something. Not to mention efficient stirring to keep the 16665g of yeast in suspension! And then working up the rediculous 266.64L of petroleum ether to yield your 100g of l-PAC (assuming the same % yield as in the patent which is not for sure).

Really Hector I would have thought a simple glance at the examples in the patent followed by a bit of SIMPLE maths on a calculator (in fact the rough idea of numbers comes from just a glance!) should have made you gawp at this rediculous idea...

(Using a 25L bioreactor you should in theory get approx 7g product but I shall let you do the math for that one yourself!)

[Edited on 26-4-2009 by panziandi]

hector2000 - 26-4-2009 at 11:10

Read the patent

Benzaldehyde (106 mg, 1 mmol),
petroleum ether (80 ml),
ethanol (0.5 ml),
baker's yeast (5 g)
and the pyruvic acid buffer (5 ml)
were stirred at 50° C. for 24 h.

That is a little over 90 ml total so figure `100 ml and that gets you just 30 mg L-PAC

Times 3333 = 333 liters. Use a 350 L stirred bioreactor regulated to 50 C. That gets you 100 g if you do everything right.

You have a LOT to learn about biotech.

two point is important here
first:in this scale(patent scale)this is not very important that how much ether you use because 60 ml ether is little and really i think ether will not do important work then for 100gram l-pac we can use little amount like 2.5lit because ether in this reaction is solvent no more(i think)
second:i think yeast will grow up(like ferment suger to alcohol) then we can use smaller amount but making l-pac proccess will take more time(again i think)

also i think biggest problem is making pyruvic acid anyone has complete route for making pyruvic acid?

[Edited on 26-4-2009 by hector2000]

Nicodem - 26-4-2009 at 11:26

second:i think yeast will grow up(like ferment suger to alcohol) then we can use smaller amount but making l-pac proccess will take more time(again i think)

also i think biggest problem is making pyruvic acid anyone has complete route for making pyruvic acid?

Yeast will grow up at 50°C? Yeah right, it sounds like a perfect temperature for multiplication. What is good for enzymes is not necessarily good for reproduction!

Pyruvic acid is available at any chemical supplier.

This thread is of terrible quality. hector2000, how about if you first read some literature, like all the reviews, papers and patents posted in the old thread? Just clicking to the reply button without investing any thought whatsoever will only result in another multipage thread without any relevant content.

Elena - 26-4-2009 at 12:00

Using a 25L bioreactor you should in theory get approx 7g product but I shall let you do the math for that one yourself![Edited on 26-4-2009 by panziandi]

As soon, as it not for commercial purpose, and it is only to get satisfaction on successful experiment, yielding amount of 7 g could make him happy too.
Isn't it gentlemen?

[Edited on 26-4-2009 by Elena]

Paddywhacker - 26-4-2009 at 12:09

I do believe that the solvents in the bioreactor will break the yeast cell membranes, making the reaction a crude cell-free extract reaction. The insoluble cell fragments will still be there, and that is what I suspect the workup refers to as "yeast".

Certainly, there will be no yeast growth at 50 Celcius.

I would always think that starting with actively growing yeast rather than commercial yeastcake would give better enzymatic activity, but I could easily be mistaken.

hector2000 - 26-4-2009 at 12:17

if we accept ratio of this patent then india and china should use 3000lit container for make 1kg l-pac?
i search and found that india and china make l-pac(they should use huge amount of ethanol-water..)

unfortunately pyruvic acid here is very expensive.may someone explain method of making pyruvic acid?

[Edited on 26-4-2009 by hector2000]

panziandi - 26-4-2009 at 12:59

There will be no cell growth of yeast at 50*C! This is not a microbial fermentation! This is an enzymatically catalysed reaction. The patent states that purified enzymes are terribly expensive, whereas yeast are cheap and do the job themselves!

@ Elena: I don't think hector would be satisfied with only 7g of l-PAC ...?

The quantity of yeast is just under 17kg (from the scale-up calculations). You will need more than 2.5L of Petroleum or else you will have a horrible thick paste (I'm speculating but i can picture this horrid paste!). Indeed cell lysis is going to occur releasing the enzymes that are required for the reaction.

I'm sure anyone who has been reading this thread has thought (as I have) how you could potentially better the patent method, however I am not going to divulge my ideas. I think you should be able to show some sort of problem solving skills yourself.

Pyruvic acid I think I already gave you some ideas for making:

CH3-CHOH-CH2OH + [O] => CH3-CO-COOH

or

CH3CHOH-COOH + [O] => CH3-CO-COOH

or

CH3-COCl + CN- => CH3-COCN

CH3-COCN => CH3-CO-COOH (hydrolysis of nitrile)

They are your 3 options... unless you fancy preparing pyruvic acid in a biotech fashion too...

hector2000 - 26-4-2009 at 13:13

There will be no cell growth of yeast at 50*C! This is not a microbial fermentation! This is an enzymatically catalysed reaction. The patent states that purified enzymes are terribly expensive, whereas yeast are cheap and do the job themselves!

@ Elena: I don't think hector would be satisfied with only 7g of l-PAC ...?

The quantity of yeast is just under 17kg (from the scale-up calculations). You will need more than 2.5L of Petroleum or else you will have a horrible thick paste (I'm speculating but i can picture this horrid paste!). Indeed cell lysis is going to occur releasing the enzymes that are required for the reaction.

I'm sure anyone who has been reading this thread has thought (as I have) how you could potentially better the patent method, however I am not going to divulge my ideas. I think you should be able to show some sort of problem solving skills yourself.

Pyruvic acid I think I already gave you some ideas for making:

CH3-CHOH-CH2OH + [O] => CH3-CO-COOH

or

CH3CHOH-COOH + [O] => CH3-CO-COOH

or

CH3-COCl + CN- => CH3-COCN

CH3-COCN => CH3-CO-COOH (hydrolysis of nitrile)

They are your 3 options... unless you fancy preparing pyruvic acid in a biotech fashion too...

Yes before you say these method for making pyruvic acid but problem is ratio and temp and separation , ... and it need more detail.
Really iam confuse because for making 100gram of l-pac i should buy 300lit container with stirrer and about 240lit ether and lot of ethanol.if you calculate the price it should be around 1000-2000$ just for 100gram of l-pac.
i search here and speak with company that make Pseudoephedrine with l-pac and make l-pac with Ferment method.this company sale 1kg pseudoephedrine just 70$.
Sure there is better and cheaper instruction for making l-pac

panziandi - 26-4-2009 at 13:40

There likely is! I can think of a few cost cutting routes, if you sat down and thought about it I'm sure you could too! But THIS method you found a patent for does NOT use a fermentation... It uses a crude enzyme extract! It is not ether that is used, it is petroleum ether (petrol) that is used, ether (diethyl ether) is used to wash the yeast AFTER the reaction, and the petroleum and the ether is distilled off in vacuum to leave the product.

I could have, and I think I did hint at the economics of this, that it would be EXPENSIVE. Thankfully the penny has dropped for you too!

My methods for pyruvic acid are simple and common procedures I have adopted for pyruvic acid, calulate your own stoichometry! Go look up Orgsyn method they list a method for obtaining pyruvic acid from tartaric acid. They also list a method for obtaining ethyl pyruvate from lactate which could be adopted to go form lactic acid to pyruvic acid. Do your own research it isn't too difficult (literature searches are fundamental abilities for anyone in the science community!!)

I think this biotech method really sucks to be honest and I think you'd be better off buying l_PAC or using a chemical method!

[Edited on 26-4-2009 by panziandi]

hector2000 - 26-4-2009 at 13:50

My Friend i should pay money for know your method?(how much)
before i think here every thing(teaching and learning)is free but doesnt matter i believe you spent yor time for find you method and maybe that method wasnt free for you.

DJF90 - 26-4-2009 at 13:56

Hector. Your signature is "Chemistry=Chem+ is+ Try", yet you dont seem to be trying... For lab scale production the easiest method would be a chemical one. Please dont ask how, go an research it for yourself. If you cannot do your own research then you have little hope of being able to do the procedure.

panziandi - 26-4-2009 at 14:14

Biotech is great for producing chiral compounds like l-PAC in that you have very high chiral-yield but unfortunently actual chemical yield is not always very great.

My ideas are exactly that... ideas. Ideas of how to better a scale-up of the patent. I'm not selling them since I have not got the time nor equipment to actually see if these ideas would better the reaction. Why don't you sit down, have a think about it and post some ideas of how you propose to better the reaction and then people could comment and offer advice. People are not going to spoon-feed you.

You already suggested reducing the volume of petroleum ether to 2.5L, I can assure you taht that would result in something like marmite! But you are along the right lines, you likely will not require 270L but you will require more than 2.5L... go figure some other varibales to potentially better the reaction and read some texts and get ideas down then present them for constructive criticism from people on the forum, otherwise people will feel like they are doing all the work for you and not getting anything in return, and you will end up looking lazy and having a bad reputation!

Sauron - 26-4-2009 at 16:00

This is a replay of hector's demeanor in the AA thread.

Naked wholesale demand for spoonfeeding

REeagents always too expensive

Not the slightest understanding of basics

And no attempt at self-help whatsoever.

UTFSE or Google for pyruvix acid's preps.

Organikum posted extensively on this

Solo ALREADY told you that, hector.

OBVIOUSLY you ought to go after a conventional route to racemic PAC and then resolve rge L-PAC the old way.

You have not told your purpose in making L-PAC.

Inquirinf minds want to know.

The Indians pharm industry are the main producers of L-PAC and mostly it is used in making l-psuedoephedrine ("sudafed"). However I really doubt that yoiu want to make nasal decongestant.

[Edited on 27-4-2009 by Sauron]

chemrox - 26-4-2009 at 21:01

How about kicking this one over to Detritus? Nothing worthwhile has been exchanged.

[Edited on 27-4-2009 by chemrox]

Nicodem - 27-4-2009 at 00:29

I give this thread another 24 hours. After that time, I'm going to close it since the original poster promotes nothing but extreme laziness. Asking questions that were already answered in the old thread is ridiculous! Claiming of wanting to start a large scale process and not bothering to search and read the scientific and patent literature is stupid. Continuously asking to be spoon fed is a waste of time for the helpful members. This thread is heading toward the same type of crap as seen in the acetic anhydride thread. Should I continue?

hector2000 - 27-4-2009 at 00:41

Biotech is great for producing chiral compounds like l-PAC in that you have very high chiral-yield but unfortunently actual chemical yield is not always very great.

My ideas are exactly that... ideas. Ideas of how to better a scale-up of the patent. I'm not selling them since I have not got the time nor equipment to actually see if these ideas would better the reaction. Why don't you sit down, have a think about it and post some ideas of how you propose to better the reaction and then people could comment and offer advice. People are not going to spoon-feed you.

You already suggested reducing the volume of petroleum ether to 2.5L, I can assure you taht that would result in something like marmite! But you are along the right lines, you likely will not require 270L but you will require more than 2.5L... go figure some other varibales to potentially better the reaction and read some texts and get ideas down then present them for constructive criticism from people on the forum, otherwise people will feel like they are doing all the work for you and not getting anything in return, and you will end up looking lazy and having a bad reputation!

I am Reading This Patent now:
http://rapidshare.com/files/6293040/thesis_l-_PAC.pdf

I am not lazy(never) but i am not complete human and this is very difficult to do lot of experiment for me.but i will try it
(because i am...)

I have some suggestion for this reaction and i will write it soon.
Mr sauron,
We want to check our small company can buil l-pac or cant.
We recieved order from pharmacy company and we want first research for making l-pac and make small amount(100 gram sample and test it with GC-Ms Device for purity)
and check the price and other thing.
But i think this is not easy to make l-pac because very huge container needed and lot of solution,... but i will try it
and really want to now what do the indian or chinese company that there l-pac is cheap and pure.

[Edited on 27-4-2009 by hector2000]

Sauron - 27-4-2009 at 04:16

Biotech is not simple and not cheap.

Hygiene is critical.

Anyway, S.crevicea is not the ideal yeast, just the easiest to buy (baker's yeast = brewer's yeast)

Here is some related literature

[Edited on 27-4-2009 by Sauron]

Attachment: benzaldehyde.l-pac.pdf (267kB)
This file has been downloaded 1381 times

hector2000 - 27-4-2009 at 08:28

Mr Sauron,
Making l-pac has cheaper or another method?
Before i think the cheaper and main method for making l-pac is yeast method(benz->l-pac)

Sauron - 27-4-2009 at 12:21

First of all there are many different yeast methods and many different yeasts.

There are continuous methods and batch methods.

BUT in every instance the capital costs are high and microbiology expertise is called for.

As has already been explained to you the point of using yeast is the enzymatic control of reaction to produce mainoly the L-disatereomer (typically c.90% ee (enantiomeric excess).

Getting PhCHO to condense with pyruvic acid in an acyloin reaction is not I suspect difficult, but you will get an equal mix of D and L PAC (zero ee) and then you must resolve the mixture

That is laborious.

So you choose between the scylla of biotech and the charybdis of achiral prep followed by conventional resolution.

My suggestion is: forget making L-PAC.

hector2000 - 27-4-2009 at 12:54

Mr Sauron,
You want to say there is another yeast that may make more L-pac?
If this is possible may you explain more about chemical way for make PAC(acrloin reaction)?maybe this method better than yeast method(promise to god that i search by google and yahoo and.. but i didnt find anything about this method)

DJF90 - 27-4-2009 at 13:30

My suggestion is: forget making L-PAC.

I agree with Sauron here, I'm getting fed up with your cluelessness and want of spoonfeeding displayed by this thread.

My suggestion: Use a chemical method. I believe freidel crafts acylation of benzene with oxalyl chloride, hydrolysing the resultant acid chloride and then reducing the alpha ketone to a hydroxy with sodium borohydride should work. I doubt if it'll be an entirely clean reaction (perhaps some benzil will be formed) and you will still have to resolve the stereoisomers, but it will be quicker than the biochemical method (I think), the scale of reaction should be much more manageable (no massive heating costs or need for 240/330L reactor and sterile conditions) and as a smaller volume work up should be easier also.

Disadvantages are having to work with benzene (not nice stuff) and oxalyl chloride (again not nice), with the latter being quite expensive IIRC (sodium borohydride is also quite expensive). Thats assuming you have access to these chemicals.

hector2000 - 27-4-2009 at 13:58

Thanks djf90
I am very interesting to know more about chemical method.
You dont know source or patent about chemical method?

I find out that bio method is diffrent,for example in this thread:
http://www.sciencemadness.org/talk/viewthread.php?tid=1936
an according to patent: DD51651
we use 800gram cane sugar molasses,5g potassiumdihydrogenphosphate, 2,5g MgSO4.7H2O epsom salt, 16g ammoniumsulfate, 4liters water,164g yeast,32g benzaldehyde and 48ml acetaldehyde we will get 20gram l-pac.
But i dont know this patent is valid or not
and attachment use urea!

[Edited on 27-4-2009 by hector2000]

Attachment: 433-437.pdf (214kB)
This file has been downloaded 4196 times

Acetylbenzoyl instead of L-PAC.

Elena - 27-4-2009 at 14:14

Any way, the L-PAC we mostly need to obtain ephedrine, so may be better to use other more efficient way?
Recently, I’ve got (from my friend) some theoretical recipe of obtaining racemic ephedrine
from Acetylbenzoyl aka 1-Phenyl-1,2-propanedione, via NaBH4 reduction.
As I know, no one practically tried this method yet. I am just planning to do that next month.
If someone interested to discuss about it, I will try to translate that article from Russian, and will post it here. Or may be I should open new thread?

Sauron - 27-4-2009 at 17:15

DJK, FC with benzeme and oxalyl chloride will not produce the dione you describe (1-phenyl-1,2-propanedione) because oxalyl chloride has no terminal methyl group.

You would do better with pyruvyl chloride but hector has already complained about the cost of pyruvic acod in Iran. Yje acyl chloride will noit be cheaper.

C6H6 + (COCl)2 -> Ph-C(=O)-C(=O)-Cl

which is not what is wanted it is a-phenylglycollic acid (after hydrolysis and reduction) and prior to that it is phenylglyoxalic acid.

What is wrong with acyloin comdensation of PhCHO and MeC(=O)-COOH?

Eliminaes the NaBH4 step, and no need for the acyl chloride.

Same reaction just without the enzymatic assym. control. Product DL-PAC.

[Edited on 28-4-2009 by Sauron]

hector2000 - 28-4-2009 at 00:43

In this link we can make phenylglyoxalic acid
http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv3...
phenylglyoxalic acid will convert to PAC easily?
also there is another way for making phenylglyoxalic acid:
-oxidation of acetophenone with potassium permanganate in alkaline solution
-oxidation of mandelic acid with potassium permanganate in alkaline solution

but Mr sauron you think we can convert phenylglyoxalic acid to PAC?I think this reaction will be difficult

[Edited on 28-4-2009 by hector2000]

DJF90 - 28-4-2009 at 10:55

@Mr Sauron (sorry but you gotta laugh...): Sorry I thought that L-PAC was a carboxylic acid, not a ketone, hence my (bad) suggestion. I suppose I should double check before I post but its not like its important

panziandi - 28-4-2009 at 11:28

More importantly hector2000 should have questioned it rather than asking for more details on it!

Anyway before he asks...pyruvoyl chloride can be made from pyruvic acid and a,a-dichloromethyl methyl ether in moderate yield cf Organic Syntheses, Coll. Vol. 7, p.467 (1990); Vol. 61, p.1 (1983).

Hector I do not think Sauron was ever implying that phenylglyoxalic acid could be converted to l-PAC ... though you could have fun trying that one out

Sauron - 28-4-2009 at 16:36

Quite right. I did not say that LPAC can be made from phenylglyovalic acid. Somone else posted that the Friedel Crafts acylation of benzene with oxalyl chloride, followed by hydrolysis, would give L-PAC BUT he was wrong. That gives only phenylglycolic acid.

assym-dichlorodimethyl eyjer is a powerful reagent not too easy prepared. is there no more practical way tp pyruvyl chloride?

panziandi - 28-4-2009 at 17:06

Well conventional reagents such as PCl5 would add to the ketone I'd imagine forming gym-dihalides. Orgsyn mentions that "conventional reagents are unsatisfactory" and that phosgene and oxalyl chloride both yield ether solutions with a low conversion. And that aa-dichloromethyl methyl ether was the most satisfactory method for pyruvoyl and other alpha-ketoacoyl chlorides.

I am unsure if the Ph3P/CCl4 or benzotrichloride methods would work. And I shall leave you to speculate on the use of the infamous TCT

Sauron - 28-4-2009 at 17:50

That Org.Syn. monohraph is >25 years old, a lot can happen in a quarter century of chemistry.

Remember the yield with DCMME is 45-60% which is OK but not thrilling.

An alternative prep is mentioned as useful: trimethylsilil pyruvate and oxalyl chloride

Häusler, J.; Schmidt, U. Chem. Ber. 1974, 107, 145–151.

But I have not yet obtained it, and it sounds expensive.

I may have overstated the difficulty of preparing 1,1-dichlorodimethyl ether. It is commercially available, and is prepared from methyl formate and PCl5 in POCl3. So if PCl5 and POCl3 are available to you as they certainly are to hector2000, this is rather a piece of cake.

A review of Friedel Crafts actlations should establish whether or not pyruvyl chloride works in this reaction.

Another gambit:

Is there an acyl chloride of lactic acid?

And if so will it work in the F-C acylation of bemzeme, which would give DL-PAC (racemic pehylacetylcarbinol) directly?

Lactic acid is a fermetation product and ought to be cheaper than pyruvic acid. I do not remember ever hearing about lactyl chloride but that means nothing. Nor do I recall anything about acyl chlorides of a-hydroxy carboxylic acids being impossible. Though polymerization may be problematic.

I will post the Org.Syn. prep of ptruvyl chloride bwlow.

Attachment: CV7P0467.pdf (159kB)
This file has been downloaded 1880 times

Sauron - 28-4-2009 at 18:20

And here is the prep of the reagent 1,1-dichloromethyl methyl ether

Assuming that lactyl chloride (acyl chloride of lactic acid) is a problem due to self condensattion as seems likely (cf. glycollic acid) then:

Lactic acid is 2-hydroxypropionic acid.

How about 2-chloropropionyl chloride? No oligomerization. Use this in the F-C acylation of benzene and then hydrolyze the product to racemic PAC.

Starting with cheap lactic acid, and at the end no reduction, just hydrolysis, looks better than F-C with pyruvyl chloride to me.

I would say, NCS for the a-chlorination of lactic acid then your choice of reagent for the acyl chloride:

SOCl2
TCT
benzoyl chloride

Whatever.

Attachment: CV5P0365.pdf (139kB)
This file has been downloaded 1907 times

[Edited on 29-4-2009 by Sauron]

DJF90 - 28-4-2009 at 19:07

Sauron: How selective is the F-C reaction with 2-chloropropionic chloride? I imagine that acylation will definatately dominate, but what % if any would you expect alkylation to occur? And you're right, it probably is a more attractive reaction compared with pyruvyl chloride... Lets hope our friend Hector agrees.

Sauron - 28-4-2009 at 20:01

Well, I always find acyl chloride preps interesting, esp. oddball ones. Regarding your question on F-C alkylation vs acylation as a competing reaction, I don't know. Maybe a less reactive a-halo compound such as a-bromopropionyl chloride would solve this, if it is a problem.

As for hector, I am not really concerned. He is welcome to whatever he can learn if anything, it;s a free forum.

I have not availed myself of the extensive material on L-PAC solo has posted in Recent Hournal Articles of Interest,,,simply because I am not really interested in L-PAC or any of its progeny (ephedrinem psuedoephedrine, phenylpropanolamine etc.)

hector2000 - 29-4-2009 at 00:32

I found DICHLOROMETHYL METHYL ETHER here but reaction for making PYRUVOYL CHLORIDE is very difficult.(one step need -50c temp)
Sauron,
You want to say 2-chloropropionyl chloride+benzen in the FC Reaction and hydrolyze will produce PAC?

[Edited on 29-4-2009 by hector2000]

Sauron - 29-4-2009 at 01:00

2-chloropropionyl chloride

Me-CH(-Cl)-C(=O)-Cl

Pyruvoyl chloride

Me-C(=O)-C(=O)-Cl

Ig you use former you must reduce the carbonyl adjacent to rung to hydroxyl

If you use latter you must still do that but first you must hydrolyze -Cl ro -OH then oxidize to carbonyl.

A little more work than I first rghought

[Edited on 29-4-2009 by Sauron]

solo - 29-4-2009 at 02:40

.............sometimes leading the thirsty to water isn't enough.........solo

http://www.sciencemadness.org/talk/viewthread.php?tid=1936

panziandi - 29-4-2009 at 03:58

Hector so you do not have the ability to distil under reduced pressure with ice-salt baths for condensers?

Indeed Sauron I believe lactoyl chloride would not exist. (Also yes 25years is a long time in chemistry

)

1) the alcohol OH is more prone to chlorination that the acyl OH so you would likely form the chloro-acid before the acid-chloride

2) it would react with other molecules in a polymerisation to get a polyester

Indeed I expect you could chlorinate both alcohol and acid OH's obtaining 2-chloropropanoyl chloride which would be used in a FC. I'd expect the -COCl to react most readily in an FC to give a monoacylated product.

Indeed lactic acid is cheaper than pyruvic acid. You can oxidise the lactic alcohol to a keto in order to go from lactic acid to pyruvic acid, i.e. dichromate etc. Then isolate and chlorinate, likely best route:

Lactic acid is present as 85%, and readily condenses to a lactone, at this and higher concentrations, chlorination to get chloropropanoyl chloride would be difficult since you have 15% water contamination that would react with the chlorinating agent (PCl5, SOCl2, TCT etc) then you have two chlorinations to perform, which I think would be highly wasteful of reagents... thoughts?

Sauron - 29-4-2009 at 04:31

Propionic acid is far cgeaper still.

NCS or NBS or TCCA will halogenate the 2-position of propionic acid (the a-carbon) and that acid is then readily converted to the acyl chloride.

The only part of the prep of pyruvoyl chloride that calls for low temperatures is the vacuum fractionation, in which the forerunb of methyl formate needs trapping. All that is required is a Deware comdenser with dry ice (solid CO2)-acetone slurry and a bath of same to chill the receiving flask. Thhis is a routine lab procedure. Hector, get yourself cylinders of CO2 with dip tubes and Frigimat Jr dry ice snow makers attached, make your dry ice on site same as I do. It is cheap.

panziandi - 29-4-2009 at 05:03

But I thought we were talking about 2-hydroxypropionic acid (aka lactic) and chlorinating the OH of that as opposed to chlorinating the alpha carbon of propionic acid?

If hector is going via the FC acylation I can see a few possible routes to suitable acid chlorides:

1) CH3-CH2-COOH > CH3-CHCl-COOH > CH3-CHCl-COCl

2) CH3-CHOH-COOH > CH3-CHCl-COOH > CH3-CHCl-COCl

3) CH3-CHOH-COOH > CH3-C(=O)-COOH > CH3-C(=O)-COCl

Sauron - 29-4-2009 at 08:59

Propionic acid is chaper than lactic acid which is cheaper than pyruvic acid

With propionic acid it is easy to make the a-chloro acyl chloride

Lactic acid has zero advantage amd "2-chlorolactoyl chloride" is identical to 2-chloropropionyl chloride.

Just as glycolloyl chloride cannot exist but chloroacetyl chloride does.

Pytuvoyl chloride is a lot costlier to make: cost of acid, cost of 1,1-dichlorodimethyl ether ( lots PCl5, POCl3)

With these facts it's time to try to determine from the lit. whether the F-C acylation with either the 2-chloropropionyl chloride, or pyruvyl chloride has ever been done, and what results were. If this still looks good, then examine optical resolution of DL-PAC.

hector2000 - 29-4-2009 at 09:23

Thanks Mr Sauron but,
You should accept that working with solid CO2 is difficult also working in -50c.
Here there is company that sale solid CO2 but far from my town and this is not easy to move it.
Only Chemical way for making PAC is reaction between pyruvyl chloride annd benzene?

panziandi - 29-4-2009 at 09:26

Hector: You only need the -50*C bath for preparing pyruvoyl chloride using the a,a-dichloromethyl methyl ether method.

So far Sauron has suggested using chloropropanoyl chloride in FC with benzene followed by hydrolysis of the -Cl to a -OH.

Or FC with pyruvoyl chloride with benzene followed by reduction of the C=O to a C-OH.

As yet we have no literature to support either FC acylation.

hector2000 - 29-4-2009 at 09:35

Chloropropanoyl chloride in FC with benzene really will work?
Still i believe mandelic acid is very similar to PAC.really there is no way for shoot second OH group?
I know I2/P will shoot first OH group but no hope for second OH?

panziandi - 29-4-2009 at 09:44

I have to ask if you are familiar with (organic) chemistry at all?

Mandellic acid is EXACTLY that... a carboxylic acid! The "second OH" as you describe it is actually a "COOH" it has TOTALLY different chemistry to an alcohol OH as the "first OH" is.

Besides Mandellic acid is far more expensive than a FC would cost.

Also Sauron I find that lactic acid is far cheaper an more available than propionic acid. Also if, as i expect, hector plans on a largish scale (God I hope he doesn't scale a chemical method to a 350L reactor!

) .. lactic acid is readily obtainable in high purity, high concentration (ca85%), in large quantity since it is so widely used in the food industry etc.

hector2000 - 29-4-2009 at 10:07

Mr panziandi,
I know that but why we can shoot OH group in the Phenylacetic acid by Lead acetate but we cant do this work with mandelic acid?
lactic acid,mandelic acid and tartaric acid is very cheap here.
Lactic acid is 5$ per kilogram
Tartaric acid is 3$ per kilogram
Mandelic acid is 10$ per kilogram
Maybe you dont believe but we have lot of chemical shop here (like market)

[Edited on 29-4-2009 by hector2000]

stateofhack - 29-4-2009 at 12:36

Mr panziandi,
I know that but why we can shoot OH group in the Phenylacetic acid by Lead acetate but we cant do this work with mandelic acid?
lactic acid,mandelic acid and tartaric acid is very cheap here.
Lactic acid is 5$ per kilogram
Tartaric acid is 3$ per kilogram
Mandelic acid is 10$ per kilogram
Maybe you dont believe but we have lot of chemical shop here (like market)

[Edited on 29-4-2009 by hector2000]

I think your have nearly no idea what your on about to start with. You seem to be going nowhere (just like this thread) and are waisting everyone time.

Please take your "cooking" stuff elsewhere, i mean common, am i the only one who has realized what this tool is up too?

I am surprised this stuff has stayed for so long !

panziandi - 29-4-2009 at 12:45

No Sauron guessed earlier too, and I think most contributers have twigged too!

So hector: I think you should do the biotech route, I think a full prepub write-up on a 350L biotech synthesis would be a great addition to the board to save this thread

turd - 29-4-2009 at 13:16

I know that but why we can shoot OH group in the Phenylacetic acid by Lead acetate but we cant do this work with mandelic acid?

Gosh, you don't even seem to try to understand what you're doing. The reaction you're thinking about is a variation of the Dakin-West reaction.
http://en.wikipedia.org/wiki/Dakin-West_reaction
In the first paragraph it says: "Of special note, the amino-ketone product is always racemic.", therefore - given that this is also true for this variation - you would get PAC, not L-PAC (do you even bother about which enantiomers you get?).
Then it proceeds to say that you need an alpha-amino group or an easily removable alpha-H+. I'm not good enough in organic chemistry to tell you if an alpha-OH would substitute for the alpha-amino group, but I guess the acetyl group you will get will destabilze any carboanion, and therefore the PAA mechanism will not run as smoothly. Just a guess though.

BTW, this is your chance of contributing to this board: just try it! This would actually be interesting! Also try the procedure with n-methyl-imidazole, which was posted here some time ago. You have the chemistry shops. N-methyl-imidazole, mandelic acid and small amounts of acetic anhydride are unsuspicious, so what is holding you back?

But why do I even bother, there's not going to come anything out of this...

hector2000 - 29-4-2009 at 13:27

Quote: Originally posted by stateofhack

Please dont accuse

Really i think you dont underestant my purpose
In the Tehran there is place (naser khosro)that sale lot of chemical componet(like market) this shops arent for me!
just i say we have(not me or my friend)my purpose was iranian.
I know if this reaction be possible DL-PAC will produce
In the below link you can see "making phenylacetone from phenylacetic acid by lead acetate"
http://www.erowid.org/archive/rhodium/chemistry/phenylaceton...
When i saw this i think may be this is possible for mandelic acid that convert to PAC

[Edited on 29-4-2009 by hector2000]

panziandi - 29-4-2009 at 14:57

@ Hector: as DJF90 said and as others have said: Your tagline states "Chemistry=Chem+ is+ Try" ... so you want to know if Mandelic acid will be ocnverted to PAC with lead (IV) acetate? ... Well try it!

You don't have to try it on a large scale you stated that the l-PAC would be analysed with GC-MS so you could do a small scale reaction then analyse the product as you stated you could ad find out if it worked, if it did and the yield is good you could scale it as suited.

Go try it out and post back results and this thread may have achieved something.

Sauron - 29-4-2009 at 16:47

Hector

1. You dismiss the FC with pyruboyl chloride because you say you cannot chill to -50 C. Your dry ice supplier too far away. I TOLD you buy tanks of CO2 under pressure with dip tube and a Frigimat Jr dry ice snow maker and make your own solid CO2 snow on demand on site when you need it. This is what I do, it costs very little.

2, There is NO requirement for such cooling in prep of 2-chloropropionyl chloride, so make this insteas. I do not care whether you make it from propionic acid, or from lactic acid, as panziandi suggests, use whichever is cheaper in Iran on the scale you require.

3. Dry distillation of mandelic acid with lead acetate will not produce PAC but only phenylacetone, that benzylic hydroxyl will IMO never survive the temperatures involved, and your pharm company buyer will not like product contaminated with Pb anyway.. Gorget it.

You CONSTANTLY want other people to do your thinking for you, while all you do is sit back and nitpick and dream up excuses for rehecting all suggestions.

YOU ARE WASTING EVERYONE'S TIME HERE. STOP!

For those other who are interested here is a paper from Ber. (1974) describing the prep of pyruvoyl chloride by the reaction of trimethylsilyl pyruvate and oxalyl chloride.

The TMS-pyruvate is (I think) prepared from trimethylsilyl chloride and sodium pyruvate. A proper translation by a German chemist is desired. (of the small pertinent section only - the rest of the paper is immaterial.)

[Edited on 30-4-2009 by Sauron]

Attachment: Volume 107, Issue 1 (p 145-151).pdf (389kB)
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Sauron - 29-4-2009 at 22:23

DJK

No need to be concerned about competing alkylation in the F-C acylationof benzene with a-chloropropionyl ch;oride.

The well known tear gas CN, chloroacetophenone, is manufactured by same reaction using chloroacetyl chloride. No alkylation product forms (which would be phenylacetyl chloride.)

Phenacyl bromide, military tear gas, is made in identical fashion from bromoacetyl bromide (or chloride.)

By analogy 2-chloropropionyl chloride ought to acylate benzene just fine.

The initia; product will be a chloropropiophenone, and probably lachrymatory.

Hydrolyze the chlorine. Oxidize to the same product that would have been obtained from acylation with pyruvoyl chloride.

Finally, reduce the benzilic carbonyl to hydroxyl. Same as required with product of abylation with pyruvoyl chloride.

Voila. Racemic PAC.

No expensive pyruvic acid

No oxalyl chloride

No -50 C

Nothing for hector to kvetch about.

He can start with propionic or lactic acid, whichever is cheaper in Iran. Makes no difference to me.

He will need to resolve the DL-PAC to an ee at least as good as the biotech product, c.90% L-PAC Fractional crystallization of a chiral ester, or prep scale chiral HPLC. Fat chance of the latter.

A piece of cake.

hector2000 - 30-4-2009 at 00:09

Mr Sauron,
Now i want to do lactic acid method and then test result with GC-MS
And this is interesting for me that know reaction between Lead Acetate(II) and Mandelic Acid and
Sure i will try it and test with gc-ms again.
Ok let Review:
1-I will do reaction between lactic acid and HCL or PCL5?
2-After making chloropropionyl chroride then i should react it with benzene
3-Finally Hydrolyze result
Also i find 2-chloropropionyl chloride here
Just react it with benzene in FC?
If everthing is ok i tyr it now.

[Edited on 30-4-2009 by hector2000]

Sauron - 30-4-2009 at 01:07

OK you can buy 2-propionyl chloride

Make sure that is CH3-CH(Cl)-COCl and NOT Cl-CH2-CH2-COCl

a-chloroprionyl chloro, NOT beta-chloro!

As I stated above this is a Fridel Crafts acylation so study the appropriate reaction consitions, solvent, temperature and time. The catalyst is anhydrous AlCl3.

I can tell you, add the acid chloride slowly to the benzene and AlCl3 at 25 C with stirring and then reflux at 60-70 C 2 hours.

Filter the liquids from the catalyst in a fuume hood and strip off the solvent then distill in vacuo. Purify by steam distillation.

What you have at that point is Ph-C(O)-CH(Cl)-CH3

Treat with hot aqueous sodium carbonate to hydrolyze.

Niw oxidize to the diketone

Ph-C(O)-C(O)-Me

This is same as what you would get with pyruvoyl chloride

Finally reduce the first C=O closest to ring

Ph-CH(OH)-C(O)-Me

An equal mixture of D-PAC and L-PAC

You must separate these by special means

Is all that clear?

If you do not buy the chloropropionyl chloride, my advice is make it from propionic acid not lactic acid

Lactic acid will give you trouble!

A-chlorinate with N-chlorosuccinimide in CCl4

Then make the acyl cholide with SOCl2 (thionyl chloride)

Then distill.

No solvent needed for SOCl2. Use a 5% excess.

[Edited on 30-4-2009 by Sauron]

hector2000 - 30-4-2009 at 01:26

Thanks Mr Sauron,
After react Ph-C(O)-CH(Cl)-CH3 with sodium carbonate i will have Ph-C(O)-C(O)-Me ?
How reduce the first C=O closest to ring?
I found old merck 2-propionyl chloride(820333) here.
If pac produce then i will make 2-propionyl chloride.

Sauron - 30-4-2009 at 02:20

Just read my posts above, I have spelled it out for you TWICE but you continue to skip the oxidation step\

Step 1 Friedel Crafts

Step 2 Hydrolyze -Cl to -OH classically hot aq Sod.carbonate
Step 3 Oxidize C2 -OH to C=O classically SeO2
Step 4 Reduce C1 carbonyl to OH NaBH4 suggested upthread

This is your reaction, not mine, it is up to you to select reagents and consitions and search the literature. NOT my job. You have tested the limits of my patience.

2-chloropropionyl chloride is CAS Registry # 7623-09-8

[Edited on 30-4-2009 by Sauron]

DJF90 - 30-4-2009 at 09:27

Would NaBH4 reduction predominantly reduce the C1 ketone? Also use of another oxidant (SeO2 isnt exactly nice stuff, maybe that was the point

)?

If I were to do this sythesis, I think this would be the route I would choose:
> Oxidise lactic acid with acidic dichromate (to pyruvic acid)
> For the acetal using ethylene glycol and toluene as the solvent with a dean stark trap.
> Base hydrolysis of the ester that may have formed (acetals are stable to basic conditions) with NaOH
> Form the acyl chloride of the protected sodium pyruvate with thionyl chloride.
> Do a Friedel-Crafts reaction of the acyl chloride on benzene using anhydrous AlCl3
> Reduce the C1 carbonyl with NaBH4, the C2 carbonyl is protected.
> Deprotect the C2 carbonyl by acid hydrolysis with excess water. This should yield l-PAC.

[Edited on 30-4-2009 by DJF90]

Sauron - 30-4-2009 at 09:55

DJK, what makes you think SOCl2 will succeed in making pyruvoyl chloride?

Have you read the Oth Syn prep of same?

Phosphorus chlorides failed. Phosgene and ocalyl chloride give very poor yields.

Only one reagent works well on pyruvic acid, that is 1,1-dichloromethyl methyl ether made from methyl formate and PCl5,

But workup requires dry ice-acetone temps in fractionation and hector balks.

The pyruvoyl chloride can also be made by treating trimethy;silyl chloride with pyruvic acid and TEA to obtain TMS-pyruvate, then treating that with oxalyl chloride in Et2O.

In short, the lit. does not support use of SOCl2, so it is wishdyl thinking to blithely assert it is possible without trying.

SeO2 is not so bad. It is reagent of choice for vic.dicarbonyls and tricarbonyls. It is solid and easily dispensed, removed and dispoaed of.

DJF90 - 30-4-2009 at 11:09

Sorry sauron, didnt look at the pyruvoyl chloride prep. Seeing as there is not actually a carbonyl in the alpha position (as it is protected) then perhaps SOCl2 will still work?

Sauron - 30-4-2009 at 11:50

"Perhaps" covers a multitude of errors. I can think of a dozen reagents for acyl chlorides not mentioned in the two papers I posted, that "perhaps" might work. I fasil to see the logic of assuming that protecting the C2 carbonyl with a ketal will make a difference in the efficacy of SOCl2. I do not know why SOCl2 fails and therefore do not think we have sufficient info to base any tactic to make it work.

Besides, ketals are acid labile, SOCl2 breaks down to SO2 and HCl and so will probably deprotect that carbonyl.

All in all, if you want to make a research project out of this, fine, but I's recommend taking the safer route, forget SOCl2. I do not see why pyruvoyl chloride has any advantage over 2-chloropropionyl chloride in the F-C acylation. I already answereede your cibcern re competitive alkylation. 2-chloropropionyl chloride is a one carbon homolog of chloroacetyl chloride, which works just fine in this reaction, see chloroacetophenone in Sartori's THE WAR GASES in forum library (CN tear "gas")

From a-chloropropiophenone to DL-PAC is simple. If you want to explore alt. reagents to the ones suggested feel free, but it is really Hector's headache and not mine. He is annoyingly obtuse.

hector2000 - 30-4-2009 at 12:51

Thanks everybody that guide me in this Topic(Special thanks of Mr.Sauron and panziandi)
Soon i will post GC-MS Result

[Edited on 30-4-2009 by hector2000]

Sauron - 30-4-2009 at 13:36

According to a current (April 2009) paper in JOC, a-ktoacid chlorides react with alkylstannanes such as phenyltributyltin or methyltributyltin to give 1,2-diketones

Ph-CO-CO-Cl + MeSnBu3 -> Ph-CO-CO-Me

Furthermore, the stepwise reaction of oxalyl chloride can be used to form the required a-oxoacid chloride in situ

Note that is the organostannanes are phenyl and methyl, respectively, the product will be identical to the F-C acylation product of pyruvoyl chloride and benzene (or that of 2-chloroproionyl chloride, after hydrolysis and oxidation.)

Any experience with organometallic synthesis, hector? Like a ?Grignard or lithiation?

Synthesis of 1,2-Diketones by the Transition Metal-Catalyst-Free Reaction of α-Oxo Acid Chlorides or Oxalyl Chloride with Organostannanes
Taigo Kashiwabara and Masato Tanaka*
J. Org. Chem., Articles ASAP (As Soon As Publishable)
Publication Date (Web): April 9, 2009 (Note)
DOI: 10.1021/jo802814r
The reaction of an α-oxo acid chloride with an organostannane proceeds transition metal-catalyst-free to afford a 1,2-diketone in an excellent yield. In addition, a sequence comprising pretreatment of oxalyl chloride with an organostannane and a ...

The full text is now available in References

[Edited on 30-4-2009 by Sauron]

DJF90 - 30-4-2009 at 13:40

Yes I had thought of the acid hydrolysis of the ketal by the products of acyl chlorination, but there shouldnt be any HCl formed as I suggested the use of the Na salt, and as there should be no water in the reaction medium (SOCl2 is hydrolyses, as well as the acyl chloride product) then hydrolysis should not occur? At least that was my logic anyway. But now I see that getting the anhydrous solid from the solution in the previous step may be a real pain in the ass. Looks like hector's got some kind of result...

hector2000 - 30-4-2009 at 14:48

Any experience with organometallic synthesis, hector? Like a ?Grignard or lithiation?

unfortunately No but i am ready for Learn about making it.

I have suggestion(100% wrong but better i say it)
May we use Trimethylaluminium instead of methyltributyltin?
I know trimethylaluminium is dangerous but this is just suggestion and i wont do this reaction.(I said this suggestion because i found trimethylaluminum here(in iran))

panziandi - 30-4-2009 at 16:35

Hector:

Grignards and organolithiums are on one level

Trialkylaluminiums are a whole different ball game! - Don't bother contemplating these unless you are MORE than competent with handling organolithiums, schlenk techniques and glove box manipulations etc.

And no, I doubt they will work, tin compounds would be much nicer to work with IMHO. You can make them from Grignards (or from organoaluminiums if you are competent) and the tin halides.

Sauron - 30-4-2009 at 19:02

Forget organoaluminums.

1. They burst into flame on contact with air

1. They cannot be substituted here

In marked contrast to many organometallics, tin alkyls and aryla are stable to air and water and available commercially as neat liquids of relatively low price rather than as dilute solutions in solvents.

The key compound is tri-n-butyltin chloride Sn(nBu)3Cl prepared from 3 mols of nBuMgCl and anhydrous SnCl4.

This is then reacted with phenylmagnesium chloride to afford PhSN(nBu)3, or MeMgCl to obtain MeSn(nBu)3.

These are then reacted stepwise with oxalyl chloride to form PhCOCOMe

Reduce the C1 carbonyl and you have DL-PAC.

We mine tin in Thailand and Malaysia. Good to know it is good for something other than cans.

[Edited on 1-5-2009 by Sauron]

hector2000 - 1-5-2009 at 00:10

Really interesting method
But i should prepare nBuMgCl(because i didnt find it here)
I think nBuMgCl prepare from 1-chlorobutane+Mg
May i prepare MeMgCl same?(methyl chloride+mg?)
I have another suggestion(again wrong):
A after react oxayl chloride with benzene in FC may below reaction happen?
Ph-(C=O)-(C=O)-Cl+LiCH3(Methyllithium)-->Ph-(C=O)-(C=O)-CH3+LithiumChloride

[Edited on 1-5-2009 by hector2000]

Sauron - 1-5-2009 at 01:20

Yes you could react (COCl)2 with benzene and AlCl3 catalyst, preferably in CS2 solvent below room temperature.

Yes that would give you Ph-COCOCl

And yes you can then react that with MeSn(nBu)3

You make an ether or THF soln of nBuMgCl by reacting nBuCl with Mg turnings in DRY ether and then you add SnCl4 also anhydrous, 1 eq to 3 eq of the nBuMgCl. MgCl2 will be by product

You work up the product and can isolate and distill the nBu3SnCl.

panziandi - 1-5-2009 at 03:24

To avoid any mishaps, could you not make the nBuMgCl then add SnCl4 to prepare the nBu3SnCl then add a solution of MeMgCl in order to obtain MeSn(nBu)3, then work up that. Avoids manipulating the nBu3SnCl intermediate and prepares the desired final compound in one pot?

Sauron - 1-5-2009 at 03:54

The organotin compounds are all stable to air and water, non pyrophoric, isolable as neat liquids, and commercially available as such.

So just what sort of mishaps are we avoiding?

The normal rules of organometallic prep do not appear to apply to trialkyltin halides or tetraalkylstannenes.

Here is an Org Syn prep of a tributyltin alkyl formed from tributyltin chloride and a Grignard formed in situ from the alkyl chloride and Mg turnings in THF under N2 atmosphere and with ultrasound assistance in mixing.

From this we are told that tribubtyltin compounds smell bad and are toxic. The toxicity I knew about; odor I did not Tetramethyl and tetraethyltin are described in Brauer as having pleasant ethereak aromas. Go figure. Use a hood and gloves.

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[Edited on 1-5-2009 by Sauron]

panziandi - 1-5-2009 at 05:22

Well... it's one less step, avoids having to work up and isolate an intermediate if it's possible to do it in several steps in one pot then you should avoid mechanical losses etc.

Besides it is hector to whom you propose this reaction

Sauron - 1-5-2009 at 06:02

nBu3SnX (X=halide) is the common intermediate for both the phenyl and methyl derivatives.

My surmise therefore is that it will either be purchased or prepared in relatively large amounts and stored for dispensing as needed.

While the price is not too onerous $165 US/500 g, about 1,5 mol) it can certainly be prepared for far less (nBuCl, SnCl4, Mg, Et2O or THF)

hector2000 - 1-5-2009 at 07:32

I fount Tributyltin chloride(CAS#1461-22-9)here(20$ for 100ml)
Just i should react it with MeMgCl.
I should do special work for this reaction?
I should distil final product?
Final Problem is Prepare MeMgCl(because Mecl is gas and this is difficult to controll it)
but cholorobenzene(phenyl chloride) is available and cheap
Reaction between Ph-(CO)-(CO)-Cl and PhSN(nBu)3 will Produce DL-PAC?

[Edited on 1-5-2009 by hector2000]

Sauron - 1-5-2009 at 15:05