Synthesis of Haldol

[flipper]

This is from Patent

GB 1596874

(http://l2.espacenet.com/espacenet/viewer?PN=GB1596874&CY=gb&LG=en&DB=EPD)

Example 2:

6kg of 4-p-chlorophenyl-4-hydroxypiperidine HCl, 2 Kg of KI and 25 Liters of water placed in a 40 gallon ss reactor and covered with Nitrogen. The reaction mixture was stirred, warmed slightly and 3.50 Kg of KOH was added. The mixture was stirred for 5 minutes, 5.95 Kg of y-chloro-4-fluorobutyrophenone enol ether was added and the mixture refluxed gently for from 3 to 5 hours. The mixture was then cooled and 63 Liters of Toluene added , the mixture was stirred for 5 minutes and then separated. 6.4 Liters of Meyhanol was added to the Toluene layer and the mixture transferred to a glass-lined vessel. 2.5 Liters of concetrated HCl acid was added while stirring vigorously, and a flocculent precipitate of Haloperidol(Haldol) HCl separated out. The mixture was stirred vigorously for 5 minutes, cooled and filtered. The residue was slurried with a mixture of acetotone: toluene: methanol and the slurry sucked dry. The residue was again washed with and acetone: toluene: methanol mixture. The residue was washed twice with an acetone: toluene: methanol and the residue sucked dry. The solid was placed in a ss vessel and dissolved in 80 Liters of Methanol , heated to reflux and filtered to a pad of "Hyflo" into a glass lined vessel. 160 Liters of water containing 800 ml of concetrated HCl was added and heated to reflux for from 15 to 20 minutes. The mixture was cooled and 15 Liters of 0.88 ammonia solution was added. The slurry was refluxed with stirring for 1.5 hours, cooled filtered, the residue washed with 2*30 liters of water: methanol mixture, and the residue dried at from 60 to 75°C to constant weight. Yield 7.1 Hg (78% ot the theoretical yield.)

Ok Let's discuss about this.

The Prep of y-chloro-4-fluorobutyrophenone enol ether is also described in

GB1596874

(http://l2.espacenet.com/espacenet/viewer?PN=GB1596874&CY=gb&LG=en&DB=EPD)

I'm still searching for the synth of 4-p-chlorophenyl-4-hydroxypiperidine. Some additional info is welcome to
 
You've gotta love me.

[flipper]

It's to make crazy people to shut up. Like Thorazine.
It's a Tranquilizer. Nobody seen ER?
You've gotta love me.

[Antoncho]

A nice piece of chemistry indeed....... But

Haloperidol is NOT a tranquilizer. It's an antipsychotic - these used to bee called 'major tranquilizers' (as distinguished from 'minor tranquilizers' like benzodiazepines) - but not any more. It doesn't get one high. In fact, it produces in many people something that physicians euphemistically call 'dysphoria' .

Even if it was a strongest euphoriant i doubt people would take it , in view of its other horrible side-effects - both immediate, like tonic muscle seizures and long-term, like tardive dyskinesia - which itself is, BTW, untreatable.

If you ever chanced to see people inside a psychiatric ward, you of course noticed how abhorrently fucked-up they were, in their speech and especially non-verbal beehaviour, often being abnormally slow, apathic or exhibiting muscle twitches of some sort, most often facial. This isn't something caused by their illness, it's a side-effect produced by neuroleptic drugs.

The only reason they are used is that nothing else would help the - poor, poor! - people with schizophrenia from the condition which is even worse than being on Haldol or some such. Although, who knows. Maybee many of them would feel better if left w/out such hideous 'medical treatment' - at least after a prolonged course of such treatment their dopaminergic system beecomes permanently dysfunctional and the road to a normal life is closed for them forever. You can't really enjoy communicating to a person whose face constantly twitches.

Happily, some new, much more perfect drugs have been developed lately. They're referred to as 'atypical antypsychotics' - these include Risperidone, Olanzapine, Seroquel and a couple of others. Markedly, they aren't dopamine antagonists, - unlike their predecessors, they act mainly on serotoninergic synapses. They possess the same antypsychotic quantities as classic neuroleptics, but lack most of those horrible side-effects. They do have quite a mouthful of undesirable effects, but still nothing as compared to Haldol or Chlorpromazine. Even more importantly, they don't only suppress the positive (positive - meaning 'something that is, but shouldn't bee there' - like auditory hallucinations) symptoms of schizophrenia, but actually help to relieve the negative ones - like absence of desire to communicate to the outer world or emotional flatness - which classical antypsychotics never do.

Often they help people who has been resistant to the classical neuroleptics; sometimes drastically help.


So, dear Flipper, if you could find a simple synth of Seroquel (on average it's the best of them, to my knowledge) or Risperdal - that would bee a really good thing . I myself often wondered if i personally could do anything about it - here in Russia the prices for atypical neuroleptics are so stellarly high that only millionairs could afford it. I think i could get some 'real' chemists interested in this project if i gave them a synth - but , AFAIK, they all are still patented


Ok, enough of that




Antoncho

[Chromic]

All drugs have nasty side effects when taken in high amounts under chronic usage... even my simple four carbon drug of choice.

If the drug itself does not directly cause the problems, then the problems are caused by the brain trying to adapt to the action of the drugs. I bet it's only a matter of time that side effects associated with the atypical antipsychotics surface. Btw, those drugs, the benzisoxazoles, the dibenzothiazepines, the thienobenzodiazepines, etc, do antagonize dopamine just as the phenothiazines like acetophenazine, chlorprothixene, fluphenazine, haloperidol, loxapine, promazine, thioridazine, etc, but I believe the idea is that they're not selective to certain types of dopamine receptors, nor selective to just dopamine itself. This logic, to me, is flawed!

For example the idea with SSRIs (such as sertraline, fluvoxamine, paroxetine, fluoxetine), is that they're apparently better than the tetra & tricyclics (such as amitripyline, clomipramine, imipramine) because they're more selective. Those words could not be further from the truth.

If you affect one thing in the brain, everything else adapts. Increase serotonin neurotransmission, and other neurotransmission drops. Increase GABA and other systems like dopamine increase to compensate. Withdraw from the GABA agonist... and live in a world of expanded perception similar to schizophrenia.    Been there, done that... and would recommend the experience to everyone else (as well as a host of other drugs I've done) to get an idea of what the words I write about really mean and to gain a respect and appreciation of how perception varies amoung people and are so dependant on things like neurochemistry, neurophysiology, situation, etc.

As I said, it's a matter of time before the new drugs manifest side effects in the patients. Long-term studies of drugs are not done before the drugs are approved. They're tested for a year in a clinical double-blind randomized study, and then released to the public. (not to say that this should be any different, HOWEVER, I think it should be STRESSED to the patients who take these drugs, that the people in white coats don't really know exactly what these drugs are going to do to the patient)

I don't think these new atypical antipsychotics released in at the turn of this century are any more miraculous than the other wonder medicines released at the turn of the last century. History should teach us that we're really not going about these problems in a substantially different fashion, and thus, the results are likely not going too much different (in the large picture). Then again, maybe you'll call me an alarmist! Keep in mind the perspective that public receptiveness to newly discovered truth often goes through three stages: At first the truth is ridiculed, then it is violently opposed and finally it is accepted as self-evident. When the phenothiazines were released, they were the "perfect" miracle drugs. In time, truth will out. But as we're living in a state of change with the knowledge of these drugs, we don't have the benefits of that perspective.

I really truly hope that these new drugs don't cause tardive dyskinesia or any other neurologically based movement disorder. If you've ever felt your skin crawling, the irrestible urge to move your legs, twirl your hair and stick out your tounge... you'd truly have an appreciation for what these people are going through.

Where's Aquagirl when you need her!  

[Antoncho]

O'kay, o'kay  let's argue.

First, i didn't say that the atypical neuroleptics (AN) weren't dopaminergic. They - on general, not always! - simply show more serotoninergic antagonism than dopaminergic. As a matter of fact, almost all drugs that show some affinity for a monoamine receptor, have some affinities also for the other monoaminergic sites - that's quite natural, since the molecules of NA, DA and 5-HT are so similar.
So it's just a matter of finding the selective ones.

Note, that there is no equal sign between binding affinities and the drug's action - in fact, the experience constantly proves these extrapolations wrong (e.g., Rhodium's 4-methyl-GHB and GHB; MDMA and Mr. Max's indamethamine).

BUT.

The very fact that a class of drugs that were thought to bee dopaminergic gets replaced by primarily 5-HTergic substances means a whole lot. Beecause dopamine systems are so crucial to our physiology, much more so than serotoninergic ones. They control voluntary movements - and, think of it, all that a person ever willingly does in his life is essentially voluntary movements.

So let me express a grossly oversimplified, yet intuitively valid, belief that you just don't fuck with dopaminergic neurotransmission in your brain if you can avoid that.

Speaking of SSRIs - it's no secret among psychiatrists that the older tricyclic antidepressants are often more efficient in alleviating depression than SSRIs. But the very idea beehind developing selective serotonin reuptake inhibitors was finding drugs with as little side effects as possible! Or at least i always thought of it this way.

Now - to the sideeffects of ANs that you predict to surface in the future. As i said, they DO have side-effects. Some of them, like Clozapine, really nasty ones.

But - whatever those side-effects are and will bee, they do not include tardive dyskinesia!!
Read this as: "they don't turn patients into maimed cripples, ruining forever their hope for a normal life".

There has been accumulated an significant body of clinical evidence about that. In fact, there seems to bee a good positive correlation between the drug's comparative affinity to DA and its ability to cause dystonia and dyskinesia - Risperidone having the narrowest safety margin (beehaves like a classical neuroleptic at higher than usual doses) and being the most dopaminergic one, and Clozapine, on the opposite end, never showing such effects and being non-DAergic at all.

However, that obviously shouldn't bee taken literally since Seroquel, which has the least side effects of all of them (to quote one research, "comparable to placebo"), is actually more dopaminergic than serotoninergic  - and chlorpromazine, on opposite, has a "5-HT2A/D-2 index" higher than one.

Anyway - however it may bee, the clinical practice shows that no matter what, ANs are much better. Re-read what i earlier wrote about their action on negative symtomatics; in fact one research i read specifically noted that the patients treated w/particularly Ziprexa (aka Olanzapine) and Seroquel (aka Quetiapine) improved not only their communicational capacities but actually the abstract thinking/cognitive functions that allowed them to communicate more effectively. This is something that a typical neuroleptic would never do - in fact, their action is way too often opposite.

Unfortunately, the vast majority of the materials i have on this subject is in Russian so i can't share them with you and the other bees. But anyway. I don't quite understand your position. What exactly do you consider to bee 'highly doubtful'?

They used HgCl₂ solution as a surgical antiseptic some hundred yrs ago, and now they use H₂O₂ - does that mean that there is no difference between using the two since the body will 'accomodate' to either?

I mean, i don't beelive in miracle drugs myself and i am deadly certain that there will never bee a perfect drug when it comes to the brain. The brain is just too complex, IMO. But i DO believe in scientific progress. Appearance of atypical neuroleptics is such an obvious (for me) step further!




Well, OK, i think we should ask some opinions from the people who have taken (been prescribed, i assume) various neuroleptics - that'd bee the only truly valid way to get the real picture. Anyone willing to share some experience? I know i'm asking for much.... Just a thought.



Thank you for your attention,


Antoncho

[flipper]

My dear Russian and European friend.
The synthesis of quetiapine (seroquel) is described in Patent

WO0155125

(http://l2.espacenet.com/espacenet/bnsviewer?CY=gb&LG=en&DB=EPD&PN=WO0155125&ID=WO+++0155125A1+I+)
It0s only alot of printing. (26 pages afortuanatly. Cartrigdes are fucking expensives.)
You've gotta love me.

[Chromic]

Reading your recent post, and rereading your original post, I believe I misinterpreted you when you said "much more perfect drugs". I thought you were referring to these new drugs as god-sends... (without the thought that it's likely these drugs cause other severe problems... eg even though GHB might be a cleaner version of EtOH, it's STILL got ridiculously bad things about it)

I guess I didn't catch the meaning of your words when you clearly stated something to the effect that these new drugs aren't perfect drugs.

I guess all I want to be taken from my posts is that hindsight of what's good & bad about these new drugs is not available and people should approach these drugs with much caution.

[Anansi]

Antoncho - I don't know about respiridone and the other atypical neuroleptics, but I do know for sure that Olanzapine (Zyprexa) definately CAN cause Tardive Dyskinesia. Whilst the risk isn't as high as it is for Chlorpromazine or haloperidol, it definately can happen. Sufferers of bi-polar affective disorder (sometimes called manic-depressive) seem to be more at risk than people who take it for other conditions such as schizophrenia or schizoaffective disorder.

...Anansi

[Antoncho]

_{(xcuse my clumsy English, i'm drunk)}


Chromic:         only a truly exceptional person, one in a ten thousand, is capable of bluntly stating that he was wrong. Really. This quality is so rare and so indicative of a really remarkable intelligence that every time i encounter it, it makes me feel shy and wanting to apologize  - please, excuse me if i was a bit over-sarcastic in my post, which i often have a tendency to do .


Flipper: WOW! Awesome!

Advanced chemistry, no doubt, but i was prepared for that - fortunately, my home city does have a organic chemistry research institute of its own, pretty distinguished in the country, BTW. I mean, i feel quite 'serious' about this project; it's gonna take some time, of course. But then again, it's gonna give some money in return, eventually. Quite a bit of them money, probably.

The only real problem would bee to overcome all the legal restrictions that are imposed on scheduled drugs in Russia.



Anansi:    thanks a lot!

I never knew that. Can you, please, elaborate?

I mean - the source of your data (in a PM, if you feel more comfortable this way) and such.

Sufferers of bi-polar affective disorder (sometimes called manic-depressive) seem to be more at risk than people who take it for other conditions such as schizophrenia or schizoaffective disorder.

Actually, although neuroleptics ARE sometimes used in treatment of diseases other than those of psychotic nature, this somehow always seemed to me ............. a bullshit.

I mean, psychiatrists, despite the veil of almost superficial awe that surrounds the medical profession and the hard intellectual labour that is required to beecome a doctor, are so FUCKEN often irresponsible, comletely non-caring people. In addition to that, they - believe me - often prescribe medicines judjing not by their clinical specifications, but by their own intuitive knowledge of 'what kind of high' this or that drug will produce, like "oh, he's agitated and Rohypnol doesn't help, ....  well, let's put him on Aminazine, that'll surely fuck him up enough to keep him quiet". You know, this kind of logic - fucking MORONS, so many of them! Not all of them, mind you - just an appreciable amount.

I mean, MDD is just something that SHOULDN't bee treated with neuroleptics. IMHO.

However, the fact that the non-psychotic patients are more susceptible to the dopaminic side-efffects of neuroleptics is immensely interesting, of course, if it's scientifically valid.





Yours,


Antoncho

[Chromic]

Neurol Sci 2001 Aug;22(4):331-2
A 21-year-old man with the diagnosis of paranoid schizophrenia was admitted to our clinic with cervical dystonia developing at the end of the first year of olanzapine therapy. The present case suggests that tardive dystonia in this patient is most likely associated with olanzapine administration as this is the main antipsychotic he received. Regarding the few case reports of olanzapine-associated tardive syndromes, patients taking olanzapine should be carefully screened for the appearance of tardive movements.

J Clin Psychiatry 2001 Apr;62(4):298-9
Olanzapine in the treatment of tardive dyskinesia: a report of 2 cases.

Eur Psychiatry 2002 May;17(3):129-38
Currently, tardive dyskinesia (TD) remains an important clinical problem. The average prevalence is estimated at 30%. The appearance of antipsychotics has opened new paths. The extrapyramidal profile of these molecules is more favorable than that of conventional neuroleptics. In order to assess their prophylactic as well as curative potential, we reviewed the literature concerning four of these atypical antipsychotics: clozapine, risperidone olanzapine and amisulpride. Clozapine seems to induce fewer cases of TD than the conventional neuroleptics, and has a specific therapeutic effect. However, the risk of agranulocytosis reduces the possibility of utilisation. Risperidone appears to be an effective therapy, but several authors report cases of TD during treatment. Furthermore, larger studies and longer follow-ups are necessary to confirm the efficiency of olanzapine and amisulpride. Further studies and observations are still necessary before drawing any conclusion for these new atypical antipsychotic actions. They are doubtlessly promising, but we cannot ignore the notion of risk-benefit; regular monitoring and listening to the subjective experience of the patients must remain uppermost in the choice of therapy.

It's clear that these drugs have a reduced risk profile for causing TD, but... we haven't used these drugs for as long as the phenothiazines, and I'm sure we're going to see the troubles that these newer drugs cause in the future.

[yellium]

>I mean, psychiatrists, despite the veil of almost
> superficial awe that surrounds the medical profession and >the hard intellectual labour that is required to beecome
>a doctor, are so FUCKEN often irresponsible, comletely
>non-caring people.

`the best psychiatrists are insane'. Most are not :-+

[Kitchenmagician]

the drug in question is not FDA approved for a particular treatment does not always mean that X drug may be able to treat another condition.  For instance, phenergan is not indicated for the treatment of cystic mastitis, however due to its anti-histamine effects it works wonders!  It would be wrong for doctors to not think outside the box as they are really just scientists, IMO! KM
Catapultam habeo. Nisi pecuniam omnem mihi dabis ad capul tuum saxum immane mittam.

[terbium]

It would be wrong for doctors to not think outside the box as they are really just scientists, IMO! KM
Why do you say this? AFAIK, doctors are not trained as scientists.

[Kitchenmagician]

is a science.  My dad practiced 50 years and understood cellular biology before they even had electron microscopes and had ever seen a golgi body.  If doctors don't hypothasize about new treatments and do scientific clinical studies then we would not have had the advancements that we have had.  What is the difference between a doctor trying out a new treatment or a scientist testing a hypothesis? KM
Catapultam habeo. Nisi pecuniam omnem mihi dabis ad capul tuum saxum immane mittam.

[OB1KNoBee]

AntochoBro,

 Ol Ben suffered the early symptoms of tardive dyskinesia from a low dose of the anti psychotic drug, loxapac. This drug allergy nearly killed me. Early symptoms are involuntary movement of the tounge and jaw and your eyes start rolling back, very uncomfortable. The doctor at the Hospital gave me an iv injection of benadryl (antihisaminic, antispasmodic) and the symptoms went away. Thank god. Ol Ben thought his number was up, all due to some quacky croker who didn't feel like writing up the usual benzo script so he wrote out one for a half benzo like loxapac (loxapine). There was no need for an antipsychotic to be administered, but the ass hole doctor gave it to me anyways,
To the Hospital I went, and I almost died, as my breathing was arresting on me just before they finally got to my number in the Emergency ward. Fuckers made me wait like a monkey while i looked like some Haldol toting freak!
  Stay away from quacky crokers and always, ALWAYS know exactly what you are taking. I found out the hard way I was allergic to antipsychotics.
Benadryl will work on Tardive Dyskinesia if treated early enough. after that, the only way to mask the symptoms is an increasingly highr dose of the antipsychotic. terrible. I'm not the only one this has happened to either.
GOOD GOOD

[dr_ruthenium]

Wrong Antocho!  Atypical anti-psychotics are dopamine blockers.  Specifically D2 receptor bockers.  There is nothing else that has proven effecacious for psychosis, not even the once hoped for D4 receptor blocker or the pure 5HT2A blockers.  Atypicals also block 5HT2A, which increases the amount of dopamine to compete with the D2 blockade in the nigro-striatal, but not in the meso-cortical or meso-limbic tracts.  This is of course the old/current theory of why atypical do not cause the nasty neurological (PD, TD, acute dystonia, etc.) side effects which the typical (neuroleptics- neuro=neuron, lepsis=spider; or to latch on to the neuron like a spider and fuck things up).  Newer theories propose that atypicality is strictly due to the pharmacokinetic properties, namely the dissociation constant (K off).  Seroquel and Clozaril having the highest K off, and interesting do not cause neurological side effects despite very high dosages (Risperdal and Zyprexa DO cause neuro SE in a dose related fashion).  The next generation atypical Geodon, and the (yet to be released) newest generation atypical Aripiprazole are more interesting.  Aripiprazole is a dopamine modulator (i.e. partial agonist).  Dosages will saturate D2 receptors, but intrisic activity is about 65% (the magic number to quell psychosis, yet not cause neuro SE).
P.S. Don't know why anyone would try to synth Haldol.  Older antipsychotics can cause quite a bit of dysphoria, save (maybe) Thorazine; which, anectdotally, may produce a tranquil, peaceful feeling.
TRISMUS!!!

[flipper]

That Haldol was also nice to take but I probably am wrong.

[dr_ruthenium]

Most folks report a rather unpleasant (dysphoric) experience with any high potency (or mid potency for that matter) D2 blocker.  Huffing xylene is a better option.  It, however, will blow holes in your white matter.
TRISMUS!!!