you know i don't have all the boiling point data on these kind of prodines.
I should compile it.
in example b the piperidinols with phenoxy-2-hydroxy notrogen substituents come over at around 230 C under hard vacumm.
it seems the alcohols are more stable than the esters because OH- is'nt as good a leaving group as it's acyl counterpart.
i'll give you a good place to start.
scribd.com
search user jonathan berry
it's a goldmine.

yes in fact i do pertinent question
to answer your question on the scheme the mannich reaction is performed on the 4-phenyl-4-piperidinol with paraformaldehyde and acetophenone.
this yeilds a propiophenone which is pretty good in it's own right.
then the esterification is carried out then, the ketone is reduced with nabh4.
the acetyl ester of the benzylic alcohol at carbon 3 is actually stronger than the alcohol.
i would just do this react some alpha-methylstyrene with formaldehyde and ammonium chloride.
distill off the 12% 4-phenylpiperidine-4-ol
take the remaning mixture and convert it to the tetrahydropyridine with h2so4 then  hydrobrominate that and boil it in water to get the remaining stuff.
of course for something this potent, who cares if you only get 12% from common industrial chemicals?
 

See

Amine Exchange Reactions of Mannich Bases
H. R. Snyder, James H. Brewster
J. Am. Chem. Soc., 1948, 70 (12), pp 4230–4232
DOI: 10.1021/ja01192a073

for an amine exchange of beta-dimethylaminopropiophenone with a cyclic secondary amine by simple heating to yeild the desired tertiary cyclic amine in 80% yield. This seems better than the 30% with the strait mannich with acetophenone and formaldehyde. Beta-dimethylaminopropiophenone can be made either from acetophenone, formaldehyde, and dimethylamine, or from styrene by aminomethylation, Eschweiler-Clarke dimethylation and oxidation.

Yes, I will upload it a little later. I can't right now b/c I am on a mobile device.

no man i just tried that it did'nt work i used a couple milliters on a gram of loperamide and got nada.it was fully dissolved in perchlorethylene.
why did it fail?
the intermediate is in equilibrium you need that gross excess to make this work trust me i know.

anyhoo, did you get that article?

I will upload that article tomorrow, for sure.

Meanwhile, what do you think about substituting 3-amino-1-phenylpropanol as the primary amine in the a-methylstyrene synthesis? I have no doubt that it would form the oxazine, which can be dehydrated to the tetrahydropyridine. What I am less sure about is whether the secondary alcohol will dehydrate to form a cinnamyl group. I suppose it doesn't matter, since the cinnamyl will get brominated in the next step and hydrolyze to the alcohol upon heating with water.

What I am concerned about is that the N-(3-phenyl-3-hydroxy)-phenyltetrahydropyridine will not undergo bromination, since according to http://127.0.0.1/talk/index.php?action=dlattach;topic=1906.0;attach=3854 the corresponding N-(2-hydroxy-3-phenoxypropyl) compound did not undergo bromination in GAA. Since according to US2784192, tetrahydropyridines with an N alkoxy ether group undergo bromination, that leaves the hydroxy as the offending group.

Furthermore, what do you think about reductively aminating phenyltetrahydropyridine with cinnamaldehyde (aluminum amalgam should not reduce the double bond), then dibrominating the resulting N-cinnamyl-phenyltetrahydropyridine and hydrating to the di-alcohol?

oooo weeee!


The phenoxy-diol [Ib ; R” = H,
R = Ph*O*CH,CH(OH)*CH,w] as also prepared in low overall yield by condensation of
3-hydroxy-3-phenoxypropylamine hydrochloride with a-methylstyrene and formaldehyde
to yield tetrahydro-3-(2-hydroxy-3-phenoxypropyl)-6-methyl-6-phenyl:- 31-o xazine [111 ;
R = Ph*O*CH,CH(OH)*CH2]f,o llowed by hot acid hydrolysis.
Acylation of the foregoing diols with propionic anhydride-concentrated sulphuric acid
furnished the dipropionates.

(b) A mixture of 2-hydroxy-3-phenoxyopylamine hydrochloride (38.0 g., 0-187 mole) and
a-methylstyrene (22 g., 0.187 mole) was heated to 60" with vigorous stirring, 37% formaldehyde
solution (63.6 g., 0.783 mole) added, and the mixture heated at 85" for 5 hr. It was then cooled,
made alkaline with excess of 50% aqueous sodium hydroxide, and the oil isolated with toluene,
and distilled at 0.2 mm. to yield a fraction (24 g.), b. p. 196-230". This was dissolved in dry
C,,H,,NBr, requires C, 41.1; H, 4.7; N, 4.4; Br, 49.8%).
C,,H,,O,N requires C, 58.5; H, 6.4%).


ether and slowly deposited 4-hydroxy- 1-( 2-hydroxy-3-phenoxypropy-l4)- phenylpiperidine
(3-2 g.), m. p. 120-121", which was removed. The fraction soluble in ether was distilled at
0.5 mm. to yield tetrahydro-3-(2-hydroxy-3-phenoxypropyl-6)- methyl-6-phenyl-1 : 3-oxazine,
b. p. 210-220". It formed a hydrochloride, m. p. 156-157O (Found: C, 65.9; H, 7-2.
C,,H,,O,NCl requires C, 66.0; H, 7.2%) strongly depressed on admixture with the hydrochloride
of the foregoing piperidinol (m. p. 138-140").
The oxazine base (5.5 g., 0.0168 mole) was dissolved in 18.5% hydrochloric acid (3-6 g.,
0.0168 mole), and the solution heated on the steam-bath for 7 hi-. It was stored at room
temperature for 3 days, reheated for 3 hr., then cooled and made alkaline with excess of 50%
aqueous sodium hydroxide. The oil which separated was isolated with ether and distilled at
0.25 mm. Unchanged oxazine (2.8 g., 51%) was obtained, b. p. 204-212", together with
4-hydroxy-l-(2-hydroxy-3-phenoxypropyl)-4-phenylpiperidi(n1e. 5 g. , 27%), b. p. 227-231",
m. p. 118-120" after crystallisation from ethanol.
1
1-(3 -Phenoxy-2-propionoxy~ropyl-)4 -phenyl-4-propionoxypiperidine.-The foregoing diol (10
g.), dissolved in propionic anhydride (100 ml.), was treated with concentrated sulphuric acid
(4 drops), and the mixture heated on the steani-bath for 3 hr. After removal of propionic
anhydride at reduced pressure, the residue was partitioned between ether and aqueous sodium
carbonate. The dried ethereal extract was treated with a slight excess of hydrogen chloride.
The resultant hydrochloride separated from acetone in shining plates, m. p. 129-131"
there you have it folks

many thanks to everlasting reign for uploading this

so according to this it is possible to run a schmidle mansfield rxn using 3-phenyl-3-propanolamine
this opens up the floodgates to  some damn potent analgesics.
fucking goldmine!!!

So the potency is judged by experimants with rats and rats are hypersensative to this class of analgesics . Isnt that pseudo science ? Judgeing the potency by observing the behaviour of rats ?That sounds like "The mescaline scale" that some "scientists" used to judge the potency of some drugs = they observed the behaviour of rats on morphine and then gave them other drugs and compaired the rats behaviour . That that shows the potency of a drug is a subjective unscientific opinion and not fact ....... and tests on rats dont show if an experience is mentaly satisfying for humans .

An example . A subjective one . I`ve had products from coffee shops in holland that were cannabis products and several times synthetic cannabinoids ( JWH-??? ) mixed up to look like cannabis products . The synthetic cannabinoid was said to be more potent than cannabis products ....... but the "high" wasnt high it was empty and shitty and after three pulls it didnt do any more . But for an observer i probably looked stoned .

Without thousands of guinea pig junkies with debts how are we going to know how potent a drug realy is ? Or if it is worth the effort to make it and take it ? And how are we going to know what the difference is between a dose that a person can feel , a dose that he likes and a dose that kills him ? I`ve read about designer drugs where the range between a dose that a person can feel and the lethal dose was in the microgram range .

A good example of the mistakes even the best and carefull scientists can make is albert hofmanns bycycle trip .

EDIT - I corrected morphine scale to mescaline scale .

it  comes over at the range of 232c under hard vacum so you need to make the piperidinol first and i can do an acylation in my sleep

What is "it"?

There is usually no need to distill the product, since the piperidinol can be purified from the oxazine by crystallization from naphtha and it is best to employ two steps anyway.

I just wanted to point out that the dehydration product of anything other than MPPP is very unlikely to be neurotoxic in practice in the same manner that MPTP is. The 4-phenyl tetrahydropyridine is sensitive to stuctural changes mediating neurotoxicity, e.g. N-substituents other than methyl are not neurotoxic, and methyl substitutions in the tetrahydropyridine ring are not neurotoxic, e.g. the dehydration product of prodine. See, e.g.: jpet.aspetjournals.org/content/249/3/820.short

The abstract doesn't exactly inspire confidence.

Nine analogs were found to be neurotoxic; all were oxidized by MAO to pyridinium compounds.

Someone needs to post the full article.

The article:

Stereochemical studies on medicinal agents. 12. Distinction of enantiotopic groups in the interaction of 1-methyl-4-phenyl-4-propionoxypiperidine with analgetic receptors

Dennis L. Larson , Philip S. Portoghese
J. Med. Chem., 1973, 16 (3), pp 195–198
DOI: 10.1021/jm00261a005
Publication Date: March 1973

is attached