Author Topic: methyl acrylate synthesis  (Read 4263 times)

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albert_grieves

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methyl acrylate synthesis
« on: January 07, 2004, 07:56:00 PM »
is it possible to synth methyl acrylate in a home lab.  I used the search engine here and at orgsyn.org and could not find anything.  I am interested in the (micheal addition?) N-penethyl-4-piperidone synth from phenethylamine. thanks

Nicodem

  • Guest
I think you can do that in one step by ...
« Reply #1 on: January 07, 2004, 08:58:00 PM »
I think you can do that in one step by condensing the PEA with formaldehide and acetone but don't have any refs. But you might do a search before trying a three step reaction like that with the methylacrylate.


albert_grieves

  • Guest
It seemed to me like that was not really too...
« Reply #2 on: January 08, 2004, 12:07:00 AM »
It seemed to me like that was not really too well tested a method, but it sure is a more attractive set of reactants.
I understood it as 1:1 molar ratio of phenethylamine to acetone, with a slight molar excess of formaldehyde and a dash of HCl.  Followed by decarboxylation.  Pretty sparse as far as conditions go.
  I looked around for methylacrylate online, but was unable to locate a source in the hobbyist chem supply market.  I doubt its watched, but what would be a believable reason for buying it.

algebra

  • Guest
you can purchase it for its use as a plastic...
« Reply #3 on: January 08, 2004, 06:07:00 AM »
you can purchase it for its use as a plastic monomer - widely available in industry - no need to deal with a reagent specialist - search google...

Nicodem

  • Guest
I understood it as 1:1 molar ratio of ...
« Reply #4 on: January 08, 2004, 11:50:00 AM »
I understood it as 1:1 molar ratio of phenethylamine to acetone, with a slight molar excess of formaldehyde and a dash of HCl.  Followed by decarboxylation.  Pretty sparse as far as conditions go.

Consider it a normal Manich reaction and use normal Manich reaction conditions:
Reflux of 1mol PEA hydrochloride with 1mol acetone, 2.2mol formaldehide (in the trioxane or paraformaldehide form) and ethanol as a solvent for ~10h. Cool down and hope that the crystals forming are your product.
You are wrong with the decarboxylation. There no such thing. Its a one step reaction and even if the yield is less than 30% it is still more than you would get doing it in 3 steps from acrylic acid.


josef_k

  • Guest
You can use this method to use the the mannich
« Reply #5 on: January 08, 2004, 06:40:00 PM »
You can use this method to use the the mannich reaction to get N-phenethyl-4-piperidone if you change the benzylamine for phenethylamine and the 3-methyl-2-butanone for acetone.
Personally I would use methylethylketone.

From

Patent US20030232833



Preparation of N-Benzyl-3,3-dimethyl-4-piperidone. 26

In a 1 liter 3-neck flask equipped with a mechanical stirrer, an addition funnel and a calcium chloride drying tube was added a 37% weight solution of formaldehyde (168.5 mL, 2.25 mole) dissolved in 500 mL of absolute ethanol. The resulting solution was cooled in an ice-water bath to 10.degree. C., and benzylamine (109 mL, 1 mole) was added dropwise over a one hour period. In a separate 3-liter 3-neck flask equipped with a mechanical stirrer, an addition funnel and two condensers was added 3-methyl-2-butanone (113 mL, 1.06 mole) dissolved in 500 ml of absolute ethanol and concentrated hydrogen chloride (92 mL, 1.11 mole). The resulting solution was brought to reflux and the formaldehyde/benzylamine solution is added dropwise over a 2 hour period. This solution was heated at reflux overnight, and then cooled to ambient temperature. Diisopropylethylamine (142.2 g, 1.1 mole) and formaldehyde (22.46 mL, 0.3 mole) were added and the resulting solution was heated to reflux for six hours, and then cooled to ambient temperature. The solution was quenched with potassium hydroxide (61.6 g, 1.1 mole) in 200 mL of water, and then extracted 3 times with 500 ml ethyl acetate. The organic layers were concentrated under vacuum to give 225 g of a red oil. The crude oil was dissolved in 1 liter of methylene chloride. This solution was carefully poured over 1 kg of silica gel on a sintered glass filter. The silica gel was washed with 4 L of methylene chloride. The methylene chloride was concentrated under vacuum to provide 142 g of a yellow oil which was crystallized in a freezer overnight. Yield=65.4%. MS(ion spray)=218.3(M+1)

algebra

  • Guest
piperidone
« Reply #6 on: January 09, 2004, 01:18:00 AM »
Are there any specific examples either from patents or in the literature of the mannich reaction forming the piperidone ring from any type of amine without additional (eg 3,3 methyl) alkyl substitutions on the ring. sorry for the basic q  -just feel a bit skeptical about all this.

Herr_Ovalmeister

  • Guest
It can be depolymerized by slowing heating it...
« Reply #7 on: January 09, 2004, 04:39:00 AM »
It can be depolymerized by slowing heating it and distilling  the monomer.


albert_grieves

  • Guest
what would be the product
« Reply #8 on: January 11, 2004, 03:40:00 AM »
josef_k, that is very interesting, what would be the product if MEK was used?  probably some methyl groups somewhere on the piperidine ring? And why would you prefer it (less polymerzation or something)?

josef_k

  • Guest
3-metyl-4-piperidone
« Reply #9 on: January 11, 2004, 09:17:00 AM »
It would be N-phenethyl-3-methyl-4-piperidone. Possibly with higher yields than with acetone, but more importantly, the resulting fentanyl would be much more potent than the unsubstituted one.

albert_grieves

  • Guest
i am actually more interested in low potency...
« Reply #10 on: January 11, 2004, 09:23:00 AM »
i am actually more interested in low potency analogs due safety issues.  what about the acetyl version of that compound.  regular acetylfentanyl is 15x less potent than fentanyl.  also, does anyone know about fentanyls using 2,2,6,6 tetramethylpiperidone?  I know they exist and the information is out there, but i dont know where to find it.

josef_k

  • Guest
There are many things you can do to reduce the
« Reply #11 on: January 11, 2004, 09:37:00 AM »
There are many things you can do to reduce the potency of the fentanyls. For example instead of using aniline later in the synth of unsubstituted fentanyl you can use benzylamine or even phenethylamine, for two compounds that are less potent than fentanyl, but still more potent than morphine. (J Pharm. Pharmacol. 40: 605)
Also, the 2-methyl and 2,5-dimethyl compounds are less potent, but you can't make the starting piperidones using the method in this thread.

Megatherium

  • Guest
For example instead of using aniline later in...
« Reply #12 on: January 11, 2004, 01:12:00 PM »
For example instead of using aniline later in the synth of unsubstituted fentanyl you can use benzylamine or even phenethylamine, for two compounds that are less potent than fentanyl, but still more potent than morphine. (J Pharm. Pharmacol. 40: 605)

Interesting.  What is the ED50 of those compounds (& which test was used)?

Also, what is the year for the ref.?


I am actually more interested in low potency analogs due safety issues

This is very wise!  Now we 're on the topic, in literature, I never have seen a potency evalutation of 3,3-dimethyl fentanyl.  However, I estimate that the potency would be intermediate between (cis)-3-methyl-fentanyl & (trans)-3-methyl fentanyl.  In JMC (1985) vol 28 p 1947 they test 1,3,3-trimethyl-4-phenyl-4-(propionyloxy)piperidine (7-10 x demerol) on mice in a hot plate test & the ED50 of 0,61 mg/kg lies between 0,18 mg/kg (beta-prodine) and 0.92 mg/kg (alpha-prodine).

josef_k

  • Guest
Interesting. What is the ED50 of those ...
« Reply #13 on: January 11, 2004, 02:47:00 PM »
Interesting.  What is the ED50 of those compounds (& which test was used)?

Also, what is the year for the ref.?


The year is 1988. ED50 of analogue with benzylamine and N-phenethyl is 0.63mg/kg, with N-methyl 1.25mg/kg. Analogue with phenethylamine and N-phenethyl is 2.0mg/kg. In the same paper they give the ED50 of morphine as 3.15mg/kg. They used the tail-withdrawal test in rats. (When I say N-phenethyl I mean that it is substituted in the 1 position of the piperidine ring, just to clarify)

Now we 're on the topic, in literature, I never have seen a potency evalutation of 3,3-dimethyl fentanyl.  However, I estimate that the potency would be intermediate between (cis)-3-methyl-fentanyl & (trans)-3-methyl fentanyl.  In JMC (1985) vol 28 p 1947 they test 1,3,3-trimethyl-4-phenyl-4-(propionyloxy)piperidine (7-10 x demerol) on mice in a hot plate test & the ED50 of 0,61 mg/kg lies between 0,18 mg/kg (beta-prodine) and 0.92 mg/kg (alpha-prodine).

Unfortunately the SARs of the prodines and the fentanyls is not always the same, for example the 2,5-dimethylprodine is more potent than the unsubstituted, while as I said above it is not for the fentanyls. But I guess we won't find out if this is one of them cases until someone makes it =).

Megatherium

  • Guest
Thank you for this information :-) .
« Reply #14 on: January 11, 2004, 03:17:00 PM »
Thank you for this information  :) .

It seems that the 1-phenethyl 4-aminobenzyl analog (ED50: 0,63 mg/kg) of fentanyl has about the same potency as 2-methyl fentanyl ED50: 0,665 mg/kg, which is slightly more potent than 2,5-dimethylfentanyl ED50: 0,803 mg/kg (according to J Pharm Sci (1973) vol 62 n°6 p 983).

But I guess we won't find out if this is one of them cases until someone makes it =).

True  :) .

Rhodium

  • Guest
nice!
« Reply #15 on: January 11, 2004, 10:09:00 PM »
Could someone then perhaps retrieve J. Pharm. Pharmacol. 40, 605 (1988) for our curious minds?


albert_grieves

  • Guest
what is the diisopropylethylamine used for in...
« Reply #16 on: January 13, 2004, 05:09:00 PM »
what is the diisopropylethylamine used for in the mannich.  could another tertiary amine be used.  Is it possible to synthesize that one otc.

Nicodem

  • Guest
Diisopropylethylamine is the most commonly...
« Reply #17 on: January 14, 2004, 11:37:00 AM »
Diisopropylethylamine is the most commonly used non-nucleophilic organic base. It is almost non-nucleophilic because the free electron pair on the N-atom is "hiden" by the sterical bulk of the isopropyls.

To tell you the trouth I have no idea why these guys added it almost at the end of the reaction. The conditions for the Manich are slightly acidic, usualy just the hydrochloride salt of the amines are enough or 1:1 mole ration of amine:hydrochloric acid.

Maybe they added it to increase the yields forcing the Michael addition of benzylamine on the side products of the Manich, the vinylic ketones (just guesing).


Nicodem

  • Guest
There is another route to piperid-4-ones using
« Reply #18 on: January 15, 2004, 10:47:00 AM »
There is another route to piperid-4-ones using divinyl ketone. This reagent is quite useful for other stuff as well and if someone could take some time to search for an easy preparation of it, I would appreciate it very much.
I only came across two non practical preparations:

Patent GB459537


Patent GB544188


But there must be easier ways. Maybe simply a dry distillation of barium or calcium salt of acrilyc acid would yield divinyl ketone?

Check this paper for more on this way toward piperid-4-ones:
Britten-Kelly M., Willis B.J, Barton D.H.R.; Michael additions to alkyl substituted divinyl ketones. Synthesis (1980) 1, 27-29.
(and

Post 475654

(Nicodem: "Bad conscience at work!", Novel Discourse)
for a proposal of using it)


Rhodium

  • Guest
routes to divinyl ketone
« Reply #19 on: January 16, 2004, 03:02:00 AM »
Beilstein essentially provides two general routes to divinyl ketone:

Mannich alkylation of acetone followed by elimination in the presence of a polymerization inhibitor

Reactants: propan-2-one, formaldehyde
Product: penta-1,4-dien-3-one
Reagents: diethylamine, hydroquinone
Reference: J.Appl.Chem.USSR (Engl.Transl.) 40, 1710-1714 (1967) // Zh.Prikl.Khim.(Leningrad) 40, 1777-1782 (1967)


Elimination of 3-pentanones substituted in either 2,4- or 1,5-position with chlorine, bromine or methoxy groups

Reactants: 2,4-dibromo-pentan-3-one
Product: penta-1,4-dien-3-one
Reagents: KOBu-t, DMSO
Reference: Tetrahedron Lett. 40(16), 3247-3250 (1999)
(No synthetic details given, only 3-Pentanone --Br2/MeOH--> 2,4-dibromo-3-pentanone --KOtBu/DMSO--> Divinyl ketone)
A detailed prep of the dibromoketone can be found in

Organic Syntheses, CV 6, 520

(http://www.orgsyn.org/orgsyn/prep.asp?prep=cv6p0520) and in

Organic Syntheses, CV 6, 512

(http://www.orgsyn.org/orgsyn/prep.asp?prep=cv6p0512)


Reactants: 1,5-dibromo-2-pentanone
Product: penta-1,4-dien-3-one
Reagents: Na2CO3
Conditions: Heating, 65-80 Torr, 78%
Reference: J.Org.Chem.USSR (Engl.Transl.) 27; 7.1, 1251-1253 (1991) //  Zh.Org.Khim.; 27; 7; 1431-1433 (1991)

Reactants: 1,5-dichloro-pentan-3-one
Product: penta-1,4-dien-3-one
Reagents: diethylaniline
Conditions: 180°C
Reference:

Patent US2105792

Patent GB459537



Reactants: 1,5-dimethoxy-pentan-3-one
Product: penta-1,4-dien-3-one
Conditions: Distillation with p-toluenesulfonic acid
Reference: Izv.Akad.Nauk SSSR Ser.Khim.; 1947; 495, 499; Chem.Abstr.; 1948; 7735.