[Eriatlov]

Hi everyone,

I set out to synthesise 7-aminoheptanoate, but since I'm a molecular biologist and not an organic chemist, I'm experiencing some difficulties.
I'm asking for help here to someone willing/able to point me out the most straightforward synthetic route to this compound one can come up with. Starting materials could be 3-Chloropropionic acid, beta-alanine, some appropriate n-alkylamine,... whatever you can think of! (better if they're cheaply available from the usual chemical distributors)

I hope there's somebody knowledgeable enough to provide an answer to my problem.

Bye.

[kiwi]

Well my answer to this depends on your level of experience with synthetic organic chemisty. If you have some background in organic synth, and/or someone who can guide through the process on a step-by-step basis then you might be able to prepare your compound relatively cheaply and easily. However, if you limited synthetic ability, then you are going to be far better buying this compound. On more than one occasion I've seen biologists charge into the synthetic lab, hoping to save a few $, yet by the time they realise organic synthesis isn't as simple as A+B -> C they have spent far more time/money than they would have if they had brought the compound. This is not intended as a slight on molecular biology, but synthesis requires a particular set of skills that takes some time to acquire. I doubt I could clone a gene wihtout a similar period of trial and error.

So in your particular case, your compound is available from Aldrich at (a rather overpriced) ~US$300/g. In terms of routes that are likely to work, I would consider the following:

cycloheptanone -> heptanolactam (by the Schmidt reaction), then lactam hydrolysis by a suitable method (refluxing with acid might do it).  not a route for the faint of heart, or the inexperienced - hydrogen azide (required for the first step) is toxic (about as toxic as hydrogen cyanide from memory), volatile and explosive. But if you get a chemist to help you (or do it for you) this route is the fastest I can think of right now.

alternatively hexanediol -> 1-bromohexan-6-ol (refluxing HBr) -> 1-cyanohexan-6-ol (NaCN/DMF) -> 7-bromoheptanoic acid (refluxing HBr in one-step? or Appel reaction then nitrile hydrolysis) -> 7-azidoheptanoic acid (NaN3/DMF) then reduction (Pd/C or Staudinger reduction). This approach is quite steppy, which might explain the high cost from Aldrich. I'm sure there are shorter routes I can't quite grasp right now.

[Eriatlov]

I've noticed that Sigma sells 6-aminohexanoate at a reasonable price (100$ for 1 kg).
Would it be feasible to do a homologization instead?

Since I specifically need the methyl ester as final product, I understand that the Kowalski ester homologation would be ideal.
Do you think it could work? Should the amine group be protected or is it unaffected by this particular reaction?

[sjb]

Once you price in all the other reagents and time taken to make the intermediates etc, I don't think it will work out that much cheaper, to be honest.

What specifically do you need the amino ester for? Could you possibly use the aminohexanoate as is or as the methyl ester?

S

[Eriatlov]

What specifically do you need the amino ester for? Could you possibly use the aminohexanoate as is or as the methyl ester?
S

I need it in a more complex pharmaceutical synthesis. I can't use the hexanoate, brain receptors aren't so easily fooled...

[kiwi]

I've noticed that Sigma sells 6-aminohexanoate at a reasonable price (100$ for 1 kg).
Would it be feasible to do a homologization instead?

Since I specifically need the methyl ester as final product, I understand that the Kowalski ester homologation would be ideal.
Do you think it could work? Should the amine group be protected or is it unaffected by this particular reaction?

I can see the amine group being a probelm for both the Kowalski and Ardnt-Eistert homologations. However in the case of the Ardnt-Eistert, mixed anhydrides can be used as substitutes for acyl chlorides. So if you are feeling particularly lucky, you might be able to mix aminohexanoate with 2 eq ClCO2Et/NEt3 (probably start the reaction quite cold to ensure you hit the nitrogen first) then lob in some diazomethane (beware: explosive, poisonous; the slightly safer trimethylsilyldiazomethane is commerically available but a little pricey given you are just buying -CH2-). Otherwise a simple Boc group would do it. Again however, you are dealing with some fairly pricey and dangerous reagents. Remember Aldrich isn't the only game in town; I see both Alfa and TCI also offer your compound, and Alfa (at least) is much cheaper than Aldrich in my experience.

[Dan]

How about this, I've been doing Wittigs on aldoses recently so this popped in first:

3,4-Dihydro-2H-pyran (CAS: 110-87-2) --Aqueous acid--> tetrahydro-2H-pyran-2-ol.
This product can then undergo Wittig chain extension to give the 7 carbon scaffold. Substitution at C-7 with azide via the corresponding triflate/tosylate/etc gives the 7-azido unsaturated ester. Catalytic hydrogenation/reduction give methyl 7-amino-heptanoate.

This is a bit long, Kiwi's Schmidt route is much better, but you do avoid HN₃ (NaN₃ is still toxic but not volatile, so provided you avoid ingestion, skin contact, and adding acid to it you should be OK). The reagents are cheap but there are several steps involved so it all adds up.

Edit: you might have to reduce out the double bond before the azide displacement otherwise you could get Michael addition competing. This additional step would also avoid the possible formation of the unwanted piperidine in the last step

[eeeaa]

alternative route

1.oxime synthesis - NH2OHxHCl, H2O/THF
2.Beckmann rearrangement - H2SO4 (conc)
3.hydrolysis