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Serious Chemistry  

All 60 posts   Subject: New Amph. more potent than LSD   Please login to post   Down

 
    hest
(Hive Bee)
04-19-01 01:07
No 185131
      New Amph. more potent than LSD
(Rated as: excellent)
    

In J.Med.Chem. 2001,44, 1003-1010, there is an article abouth some very potent sub. amphetamines

The TM is this one (pic 1)

[

they both make the R form and the S form

For thr most potent form, the R form, the strenght is:

When x is H the A is a bit stronger than DOB
When x is Br the A is app. 10-20 times stronger than DOB
When x is CF3 the A is app. 5-10 times stronger than DOB

The S form of the TM has app. the ½ strenght of the R form (that's still a lot:)
The synt in the article start with l alanine, and introduce the opt.act. center from the beginning. Nice but hard to do at home. But if we start with this one, it become much easyer

[

All the steps is standardt chem.
The following steps should also bee posible

[

Mabye the bromination should bee the last thing to doo.

The oxidation with DDQ is also posible with NBS or Pd/C in wacum (dehydrogenation). It is this oxidation that makes the TM so potent, the non oxidated molecule has also been made (J.Med.Chem.1996,39,2953-2961)


Some bioassayes on human would bee nice, but i'l guess we have to do the hard work :-)
 
 
 
 
    Rhodium
(Chief Bee)
04-19-01 10:43
No 185224
User Picture 
      Re: New Amph. more potent than LSD     

Great find!

The bromination cannot be done as the last step, or the furan rings will be brominated. Are all the steps in the synth of the benzo-bisdihydrofuran in the article? It seems a lot better than their original synth using bromochloroethane and BuLi...


http://rhodium.lycaeum.org
 
 
 
 
    hest
(Hive Bee)
04-19-01 11:32
No 185229
      Re: New Amph. more potent than LSD     

Yes. all the steps is in the article, if 'the beehive' wants it i'l make a nice writup after the weg.
 
 
 
 
    savestheday
(Hive Bee)
04-19-01 14:37
No 185262
User Picture 
      Re: New Amph. more potent than LSD     

Very interesting...
anymore information would be greatly appreciated. Shulgin doesn't mention anything close to this?
 
 
 
 
    Lilienthal
(Moderator)
04-19-01 17:08
No 185293
      Re: New Amph. more potent than LSD     

See also Post 122784 (dormouse: "Bromo-benzodifuranyl-isopropylamine  -Lilienthal", Serious Chemistry) for a previous discussion on this topic smile.
 
 
 
 
    yellium
(Hive Bee)
04-19-01 20:13
No 185323
      Re: New Amph. more potent than LSD     

Another question is whether it is an interesting compound. F'r instance, the 2C-G compounds are not that potent, but they are very long lasting and don't seem to be very much `fun', compared to other compounds. 
 
 
 
 
    moo
(Stranger)
04-20-01 09:56
No 185431
      Re: New Amph. more potent than LSD     

But then again, receptor binding and resistance to metabolism are two different stories. The reports on DOTFM make me scared.


understanding is everything
 
 
 
 
    Rhodium
(Chief Bee)
04-20-01 15:07
No 185476
User Picture 
      Re: New Amph. more potent than LSD     

Everybody refers to scare stories with DOTFM, but I have never heard the actual stories. Tell me? Dosage, duration, effects?


http://rhodium.lycaeum.org
 
 
 
 
    moo
(Stranger)
04-23-01 10:17
No 186117
      Re: New Amph. more potent than LSD     

It should have said "rumours". I'm referring to what drone told, but cannot be sure. I bet certain researchers we all know could provide more information on the subject.


understanding is everything
 
 
 
 
    hest
(Hive Bee)
04-24-01 20:08
No 186514
      Re: New Amph. more potent than LSD     

The fist step is posible, but i gues i'll have to tune it a bit :-)
[
The reaction was made in boiling methanol with NaOH as the base, reactiontime 2 h yeald 20% (yak)
I will try some other solvents and a longer reaktionstime
 
 
 
 
 
    Rhodium
(Chief Bee)
04-25-01 12:31
No 186707
User Picture 
      Re: New Amph. more potent than LSD     

Perhaps you should try using 2-bromoethanol instead of chloroethanol? Boiling ethylene oxide in 48% HBr should produce 2-bromoethanol. KOH is probably better than NaOH too.

Have you looked up any journal references on the synthesis of your product? It would probably help alot. 


http://rhodium.lycaeum.org
 
 
 
 
    Osmium
(Stoni's sexual toy)
04-25-01 13:53
No 186728
      Re: New Amph. more potent than LSD     

In the older ref about this class of compounds they used 1,2-bromo-chloro-ethane, or 1,2-bromo-iodo-ethane, and had higher yields.
 
 
 
 
    Rhodium
(Chief Bee)
04-26-01 02:52
No 186901
User Picture 
      Re: New Amph. more potent than LSD     

Yes, but considering the price of bromochloroethane, and the special handling of the required BuLi in the former procedure, this alternative sounds better for most of us.


http://rhodium.lycaeum.org
 
 
 
 
    hest
(Hive Bee)
04-28-01 19:51
No 187650
      Re: New Amph. more potent than LSD     

Disolve 6,16g(110mmol) KOH in 60mL wather, let the wather cool down ( 30°C), then add 5g(45mmol) hydroquinon and 8,85g(110mmol) 2-chloro-ethanol. Reflux the solution for 12 houers, cool it down (with ice) filter off the raw product.
Disolve the raw product in 100mL hot EtOAC, ekstract with 3*30mL 2M NaOH, dry the EtOAC with MgSO4, and remove the solvent in vaco.
yeald 3,5g (40%)
pure on TLC (Rf 0,44 with EtOAC as the solvent)
The same eksp. was done with 10g hydroquinon, and the yeald was again 40%

I think this is the way, the yeald is not high, but the starting materials is almost free.
I'll will now carye on withe the next step.
 
 
 
 
    yellium
(Hive Bee)
04-28-01 22:49
No 187690
      Re: New Amph. more potent than LSD     

Do you dare to ingest the final product?
 
 
 
 
    smiley_boy
(Hive Bee)
04-29-01 03:47
No 187760
      Re: New Amph. more potent than LSD     

The thing that sticks out in my mind about this is that the bromo-substituted analog is more potent in this series than its trifluoromethyl counterpart. I didn't see any discussion on this point in the paper, but it certanly warrants some sort of comment. Curious.
 
 
 
 
    hest
(Hive Bee)
04-29-01 11:30
No 187845
      Re: New Amph. more potent than LSD     

yellium- This might bee the new kitchen table 'lsd' synthesis (simple (compared to lysergacid) to manufacture, stabel product and strong enough to distribute at blotters). I think i'll firs try the phenetylamin, and a methoxy group instead of the Br would proberly make the product lighter and easyer for the metabolism to degrade.
 
 
 
 
    yellium
(Hive Bee)
04-29-01 11:47
No 187849
      Re: New Amph. more potent than LSD     

And without any substituent you also have a pretty active compound.
 
 
 
 
    weasil
(Hive Bee)
04-29-01 21:24
No 187933
User Picture 
      Re: New Amph. more potent than LSD     

NO, I strongly demand you to only produce the brominated product. To do otherwise would be undermining my authority.
 
 
 
 
    Rhodium
(Chief Bee)
05-11-01 00:26
No 193388
User Picture 
      Re: New Amph. more potent than LSD     

A VERY useful reference for the synthesis of the molecule below can be found in the journal Huaxue Shiji 15(4), 246-247 (1993). Unfortunately, I have no idea at all where to find that journal, or in what language it is written. Damn CAS Online, I don't want to be reminded of excellent reactions which are located in unreachable journals.




http://rhodium.lycaeum.org
 
 
 
 
    dildoque
(Newbee)
05-11-01 09:22
No 193458
      Re: New Amph. more potent than LSD     

I found something:

Huaxue-shiji (Chemical Reactions) : shuangyuekan / Huaxue-shiji Bianjibu bianji. - Beijing : Huaxue Huaxue Shiji Keji Qingbao Zhongxinzhan, 1979-
ISSN:  0258-3283

smile
 
 
 
 
    hest
(Hive Bee)
05-23-01 17:02
No 196477
      Re: New Amph. more potent than LSD
(Rated as: excellent)
    

Subject: Re: New Amph. more potent than LSD
Well, the chlorination of the alcohol was not that easye. Boiling it with SOCl2 for 12 h. did nothing. Guess you hawe to use pyridine as well ( they doo that in the article )
But i can't stand the smell, so this was the next idea

[

It works werrye well.
Here is the cookbok

A mixture off 11g(0,1mol) hydroquinone, 16g(0,4mol) NaOH in 80mL wather was mixet with 2,2g(0,001mol) Benzyltriethylammoniumchlorid and 0,52g NaHSO3 in 80mL 1,2dichloroethane. The mixture was refluxet for 12 houers, made acid with HCl(aq). The org layer was sep. from the wather and the 1,2-DCE was removed in wac. The solid mass was then rextalised from ethanol (250mL)
Yeald app. 80%.
Pure on TLC Rf 0,68 1:1 ether:petr.ether
The org. phase is a 'mudy' one, but thats ok.

The ammonium compound is a phase transpher catalyst. almost anny org ammonium salt works, (tetrabutylammoniumbromid and so on) It should also bee posible to doo the reaction without the PTC.
the NaHSO3 makes the hydroquinone more stabel, but is not a must.
Some refs
Synthesis 1988 p.950-952
Cannadian j.chem. 1955 p.1442-1447 (withouth PTC) 

 
 
 
 
 
 
    Rhodium
(Chief Bee)
05-23-01 17:41
No 196490
User Picture 
      Re: New Amph. more potent than LSD     

Is this procedure from an article, or from SWIM's own experience? I don't get why the hydroquinone only reacts with the dichloroethane, and not with any 2-chloroethoxyphenyl-something forming di/polymers? Is it due to the large excess of DCE? Why the NaHSO3, an antioxidant for the hydroquinone?


http://rhodium.lycaeum.org
 
 
 
 
    hest
(Hive Bee)
05-23-01 17:54
No 196496
      Re: New Amph. more potent than LSD     

From swims own experience, but the ide is from the article in synthesis. (they doo it on o-bromo-phenol)
The NaHSO3 is an antioxidant.
And yes, when the sodiumsalt off hydroquinon is transferet to the DCE with help from the ammonium thing, the large excess off DCE make polimer formation unlikley.
The ethanol, afther the xtalisation is a bit brown, so I gues that some polimers is formed.
I will go on with the bromination.
And i'v seen that the aromatisation is posible with NBS (yes). You brominate the hydrofuran and then eliminate HBr in one step due to the energi won by the aromatisation.
 
 
 
 
    otto
(Stranger)
10-04-01 21:53
No 220383
      Re: New Amph. more potent than LSD     

also you can boil aqu. HBr with ethylene glycole to get the bromoethanole thus avoiding the use of ethylene oxide. the product should be destillable right during the reaction out of the mixture as azeotropic mixture with water.
 
 
 
 
    lablozer
(Stranger)
10-19-01 22:42
No 226924
      Re: New Amph. more potent than LSD     

Hey, i was swim'in around the cpu archives, but i can't seam to find this Journal. This might help

short abstract(difuranyl-DOB) Abstract (bromo-benzodifuranyl-isopropylamine from tetrahydro compound)
J. Med. Chem. Vol 41 Page 5148 Year. 1998. First Author. M. A. Parker
 
 
 
 
    hest
(Hive Bee)
10-30-01 22:20
No 230601
      Re: New Amph. more potent than LSD
(Rated as: excellent)
    

After some other projects (hoho not that kindƒº) i'm back. I tried the bromination twice, not with the biggest success, but what the hell. It is the bromination I¡¦m fooling around with.



The story goes like this.
9,2g(67mmol) ZnCl2 was added to a solution of 6,6g(28mmol) of the 1,4-Bis(chloroethoxy)benzene. In 100mL AcOH. After enclosing the bulb in alu.foil 9,4g(58mmol) bromine dissolved in 20mL AcOH was added lower 1h. The reaction was left overnight where precipitate had formed. The reaction was then diluted whit water and sodiumthiosulfate, and then extracted twice with DCM. The DCM was washed with NaOH, dried and evaporated. The product was then rextaliced with 150mL EtOH.
Rf on TLC Ether:P 1:1 0,72 (close to the starting material, but there is a nice separation in the mixed spot)
Yield: 40% (yak yak, to times)
The yield is not great, maybe the ZnCl2 is old, ill se if I can find a new one.
 
 
 
 
    Rhodium
(Chief Bee)
10-30-01 23:31
No 230620
User Picture 
      Re: New Amph. more potent than LSD     

Great! Let us know how the process proceeds!
 
 
 
 
    malvaxman
(Newbee)
10-31-01 10:20
No 230863
      Re: New Amph. more potent than LSD     

It shouldn´t be very hard to make the meth sort of this compound. I guess it has never yet been made but it would kick ass bad!!!!
 
 
 
 
    goiterjoe
(Hive Addict)
11-03-01 17:23
No 232646
      Re: New Amph. more potent than LSD     

In most cases, the N methyl amphetamine analog is weaker than the base amphetamine.

Sed quis custodiet ipsos custodes?
 
 
 
 
    Barium
(Hive Bee)
10-05-02 12:58
No 364601
      Another way of inserting the aminopropyl
(Rated as: excellent)
    

This is from the Nichols lab again. They are still toying around with that super-potent amphetamine which I have no interest in myself. But, what´s really interesting is the way they connected the aromatic ring with the side-chain, Friedel-Craft acylation. This could be a nice way to make more interesting compounds.

JMC 2001, vol 44, No 6, 1003-1010


1,4-Bis(2-chloroethoxy)benzene[1]

Pyridine (29.4ml, 364mmol) was added to a mechanically stirred solution of 1,4-bis(hydroxyethoxy)benzene (30g, 152mmol) in DCM (300ml) at 0 deg C. Next thionyl chloride (25.4ml, 348mmol) was added dropwise  such that the internal temperature did not exceed 5 deg C. This mixture was allowed to gradually warm to room temperature and was stirred overnight. Aqueous 2N HCl (500ml) was added slowly and the layers were separated. The aqueous layer was extracted with DCM (3x75ml) and the organic extracts were combined. The pooled organic extracts were then washed with aqueous 2N HCl (2x200ml), water (200ml), 1N NaOH (100ml) and brine (100ml). The organic extracts were then dried(MgSO4) and evaporated to leave an tan solid that was recrysatallized from ethanol to afford white crystals 31.4g (88%), mp. 90-91 deg C.

1,4-Bis(2-chloroethoxy)2,5-dibromobenzene[2]

Zinc chloride (38.2g, 280mmol) was added to a solution of [1] (27.5g, 117mmol) in acetic acid (280ml). After enclosing the apparatus in aluminum foil to exclude light, bromine (39.3g, 246mmol) dissolved in acetic acid was added dropwise to the suspension over 1.5 hours. The reaction was allowed to stir overnight, during which time a precipitate had formed. The reaction was diluted with aqueous saturated sodium thiosulphate (500ml) and extracted with DCM (5x200ml). The organic layers were combined and washed with aqueous 1N NaOH (200ml), brine (100ml), dried (MgSO4), filtered and evaporated to leave an off-white solid. Recrystallization from EtOH afforded a crystalline white product 50.0g (91%), mp. 120 deg C.

2,3,6,7-Tetrahydrobenzo[1,2-b;4,5-b’]difuran[3]

To a suspension of Mg powder (50 mesh, 3.7g, 152mmol) in anhydrous THF (50ml) was slowly added EtMgBr (3.4ml, 10mmol, 3M solution in Et2O). An anhydrous solution of [2] (20g, 51mmol) in THF (125ml) was then added dropwise such that the internal reaction temperature did not exceed 35 deg C. Upon completion of the addition, the reaction was heated at reflux for 3 hours. The reaction was then cooled to room temperature and carefully poured into cold 1N HCl (200ml). Upon cessation of gas evolution, the mixture was extracted with Et2O (3x300ml). The organic layers were combined and washed with aqueous 1N NaOH (4x75ml), brine (50ml), dried (MgSO4), filtered and concentrated by rotary evaporation to afford a tan solid. This was recrystallized from EtOH to afford off-white, platelike crystals 6.5g (79%), mp. 155 deg C.

(R)-N-Trifluoroacetylalanine[4]

Triethylamine (3.1ml, 22mmol) was added to a solution of D-alanine (2g, 22mmol) in MeOH (11ml). After 5 minutes, ethyl trifluoroacetate (3.3ml, 28mmol) was added and the reaction was allowed to stir for 24 hours. The solvent was removed by rotary evaporation and the residue that remained was dissolved in water (35ml) and acidified with concentrated HCl (4ml). After stirring for 15 minutes, the mixture was extracted with EtOAc (4x30ml). The combined extracts were washed with brine (25ml), dried (MgSO4) and concentrated by rotary evaporation to leave a clear oil. After being subjected to vacuum for 24 hours, the clear oil solidified into a fluffy hydroscopic solid 2.7g (86%) mp. 69 deg C.

(R)-(+)-N-Trifluoroacetyl-2,3,6,7-tetrahydro-4-alanylbenzo[1,2-b;4,5-b’]difuran[5]

Trifluoroacetamide-protected D-alanine[4] (4.09g, 22mmol) was added to a pretared flask and placed under high-vacuum for 24 hours to remove any moisture. The flask was then reweighed to record the accurate weight of the starting material. Next, DCM (100ml) was added to the flask followed by pyridine (2 drops) and the solution was cooled to 0 deg C. Oxalyl chloride (4.3ml, 49mmol) was then added via syringe and the reaction was allowed to gradually warm to room temperature and stir for 3.5 hours. The solvent and excess oxalyl chloride was removed by rotary evaporation at 35 deg C to afford the acid chloride which was not characterized. The heterocycle [3] (1.1g, 6.6mmol) was dissolved in DCM (35ml) and this solution was slowly added via dropping funnel to a suspension of AlCl3 (2.4g, 18.3mmol) in DCM (50ml). This was followed by slow addition of the acid chloride [13] dissolved in DCM (45ml). The mixture was allowed to stir for 16 hours at which time TLC showed only one yellow spot. The reaction mixture was poured slowly onto ice to quench the reaction and the phases where then separated. The aqueous layer was extracted with DCM (4x75ml) and the organic layers were combined and washed with cold aqueous 1N HCl (75ml), water (50ml) and then saturated NaHCO3 (2x50ml). The organic solution was dried (MgSO4), filtered and concentrated to leave a yellow solid that was recrystallized from MeOH to afford fluffy yellow crystals 1.88g (86%), mp 209-210 deg C

(R)-(+)-N-Trifluoroacetyl-1-(2,3,6,7-tetrahydrobenzo-[1,2-b;4,5-b’]difuran-4-yl)-2-aminopropane[6]

The ketone [5] (0.94g, 2.9mmol) was dissolved in trifluoroacetic acid (9.4ml) and then triethylsilane (2.3ml, 14.5mmol) was added. The mixture was heated at reflux for 6 hours, at which time TLC showed no starting material. The reaction was cooled to room temperature followed by very slow addition of saturated aq. NaHCO3 until evolution of gas had ceased and the solution remained alkaline. The mixture was then extracted with Et2O (4x75ml), the organic layers combined and dried (MgSO4), filtered and evaporated to leave a tan solid. The product was titurated with hexanes and the resulting suspension was then vacuum filtered to leave a white solid 0.84g, (92%), mp. 139-140 deg C.

(R)-(-)-1-(2,3,6,7-Tetrahydrobenzo[1,2-b;4,5-b’]difuran-4-yl)-2-aminopropane Hydrochloride[7]
 
The protected amine [6] (0.1g, 0.3mmol) was dissolved in MeOH (20ml) and cooled to 0 deg C. Aqueous 5N NaOH (5ml) was added to this solution and the mixture was allowed to stir overnight and was then diluted with Et2O (50ml). The phases were separated and the aqueous layer was extracted with Et2O (3x15ml). The organic layers were combined, dried (MgSO4), filtered and the solvent evaporated to leave a tan oil. This oil was taken up in dry Et2O (15ml) and filtered through glass wool. A slight excess of  1N HCl in EtOH was added dropwise to the solution with vigorous stirring. The flask was then placed in a freezer overnight and the precipitate was collected by vacuum filtration. The resulting solid was recrystallized from IPA to afford white flyffy crystals 0.073g (86%), mp275-276 deg C.

Representative aromatization of  substituted 2,3,6,7-tetrahydrobenzo[1,2-b;4,5-b’]difurans to benzo[1,2-b;4,5-b’]difurans: (R)-(+)-N-Trifluoroacetyl-1-(benzo[1,2-b;4,5-b’]difuran-4-yl)-2-aminopropane[8]

A solution of DDQ (0.42g, 1.85mmol) in 1,4-dioxane (8ml) was slowly added to a solution of  protected amine (0.2g, 0.63mmol) in 1,4-dioxane (10ml). The solution was heated at reflux for 24 hours at which time TLC indicated reaction completion. The reaction was then cooled to room temperature and the precipitate formed was removed by vacuum filtration. The filter cake was washed thoroughly with DCM and then the solvents removed by rotary evaporation. The brown oil that remained was subjected to column chromatography (4:1 hexanes-EtOAc as eluent) to afford a white solid product 0.134g, (64%), mp. 150-151 deg C.



Catalytic hydrogenation freak
 
 
 
 
    pHarmacist
(Hive Bee)
10-05-02 13:14
No 364602
      Yes, but it's also importnant to consider that ...     

Yes, but it's also importnant to consider that Friedel-Craft reactions hava certain limitations...

Carbocation formed from an alkyl halide, alkene or alcohol can re-arrange to more stable carbocation, the major product obtained from the reaction will be from that stable carbocation...

I read about this amphetamine too couple months ago... the same article that hest read, but i don't remember when is this compound actually anounced... anyone has actuall date?

[pH]armacist - Apotekare
 
 
 
 
    otto
(Hive Bee)
10-10-02 19:34
No 366979
      hi pHarmacist, at least it shows the feasibility ...     

hi pHarmacist,

at least it shows the feasibility of that reaction with electron-rich aromatics. I assume, 1,4-DiMeOBenzene will react in a same manner.

otto
 
 
 
 
    doberman90
02-13-03 01:33
      WHAT ACTUALLY IS AN ANALOG?
(Rated as: insignificant)
    
 
 
 
    trex
(Stranger)
02-19-03 01:53
No 409596
      the first step ain't gonna work, if it does...     

the first step ain't gonna work, if it does the yield is going to be shit.  Displacing that chlorine is going to be a bitch.
 
 
 
 
    hest
(Hive Adickt)
02-19-03 21:44
No 409853
      hmmm     

Hi Trex, I'm not sure about wath you are talking abouth, but iff you look at my last drawings there is no need to sub. the OH gorup (it's not there). I'v still haven't build the furan ring, I'm a guy with manye project's going on, this is just a hoby :-)

Hest
 
 
 
 
    pHarmacist
(Hive Addict)
03-01-03 15:16
No 412785
User Picture 
      Nice Barium, Here is the full-text:     

http://pharmacist8.tripod.com/super.pdf

sonderkommando: Who is laughing now?

Accept No Imitations, There Can Only Bee One; www.the-hive.ws
 
 
 
 
    java
(Hive Bee)
03-12-03 14:37
No 416124
      Re: full text article     

Pharmacist: the  full text article you offered is not there........your host web isn't showing it....java

We're  all in this world together,
 http://www.chiapaslink.ukgateway.net/
 
 
 
 
    pHarmacist
(Hive Addict)
03-12-03 14:50
No 416130
User Picture 
      yes it is, at least I can download it...     

Anyone else have same propblem as java..................................? wink

Accept No Imitations, There Can Only Bee One; www.the-hive.ws
 
 
 
 
    Rhodium
(Chief Bee)
03-12-03 19:59
No 416229
User Picture 
      Here it is too     

J. Med. Chem. 44, 1003-1010 (2001) (https://www.rhodium.ws/pdf/nichols/nichols-dragonfly-2.pdf)
 
 
 
 
    Zimmermann
(Stranger)
03-13-03 21:02
No 416677
      New Amph. more potent than LSD"     

Would you be so kind to tell me , where in the article (JMC p.1003, 2001) had you find such potency data (CF3-benzodifuranyl-amph. is 10-20 times stronger then DOB).
Forgive me my unfamiliarity but tell me please:
--> what they mean when indicate Ki and other numbers in their Tables 1-2?
-->how this data corresponds to psychoactivity?
-->what is the activity of DOB?
 
 
 
 
    yellium
(I'm Yust a Typo)
03-13-03 22:33
No 416719
      Hest: did you ever get around to synth the...     

Hest: did you ever get around to synth the final compound?
 
 
 
 
    Rhodium
(Chief Bee)
03-13-03 23:35
No 416736
User Picture 
      Measuring the potency of receptor ligands     

Zimmermann: In Table 1 they say the Ki of racemic DOB (4b) is 2.2 nM at the 5-HT2A receptor, while both isomers of 6c (the para-CF3-substituted fully aromatic benzodifuran) has a Ki of around 0.3 nM. That makes 6c an about 7.5 times more potent ligand than DOB at the 5-HT2A receptor.

However, in Table 2, (R)-6c is shown to have an EC50 (effective concentration) of 3.8 nM, compared to 72 nM for racemic DOB (4b), a 19-fold increase in actual efficiency.

Ki is a measure of how tight a ligand binds to a receptor, while EC50 is a measure of how effective it is at activating the receptor. I have discussed things similar to this in regards to DAT ligands earlier, see Post 394040 (Rhodium: "Ki binding affinity and recreational potential", Chemistry Discourse)
 
 
 
 
    yellium
(I'm Yust a Typo)
03-14-03 23:45
No 417133
      Maybe related: in how far are Ki(binding) and...     

Maybe related: in how far are Ki(binding) and Ki(uptake) related to the compound getting on and off the receptor, at a nanosecond timescale?
 
 
 
 
    Rhodium
(Chief Bee)
03-15-03 00:37
No 417136
User Picture 
      Ki     

The Ki(binding) parameter takes that effect into consideration, as it is measured against a known standard, which also displays the same behavior.

The Ki(uptake) parameter (in the case of DAT ligands) or the EC50 value (in the case of these 5-HT2A ligands) probably has more to do with the steric/electronic effect the ligand has on the receptor, as in how well the binding of it twists and bends the receptor towards its optimum shape for full activation.
 
 
 
 
    hey_man
(LEGBA)
03-17-03 09:14
No 417986
User Picture 
      J. Med. Chem. 2001, 44, 1003-1010     

pHarmacist,
super.pdf (108KB) Enantiospecific Synthesis and Pharmacological Evaluation of a Series of Super-Potent, Conformationally Restricted 5-HT 2A/2C Receptor Agonists, downloaded just fine for me

 
 
 
 
    PEYOTE
(Sacred Cacti)
03-25-03 14:53
No 421131
User Picture 
      If you want that article...     

... I've got it in .PDF format...

"Dark star crashes, pouring its light into ashes..."
 
 
 
 
    pHarmacist
(Hive Addict)
03-25-03 15:04
No 421134
User Picture 
      Thanks, but we got it too as you can see     

It's possible to download the PDF form both my account and from rhodium's archive...

Accept No Imitations, There Can Only Bee One; www.the-hive.ws
 
 
 
 
    hellman
08-05-03 06:02
      no!
(Rated as: misinforming)
    
 
 
 
    hest
(Hive Adickt)
08-05-03 07:53
No 451762
      bet ?     

Hellman, will you have a bet on it ?
 
 
 
 
    scarmani
(Hive Bee)
06-21-04 21:42
No 514666
User Picture 
      Et3SiH / TFA Reduction - Improvements?
(Rated as: good read)
    


(R)-(+)-N-Trifluoroacetyl-1-(2,3,6,7-tetrahydrobenzo-[1,2-b;4,5-b’]difuran-4-yl)-2-aminopropane[6]

The ketone [5] (0.94g, 2.9mmol) was dissolved in trifluoroacetic acid (9.4ml) and then triethylsilane (2.3ml, 14.5mmol) was added. The mixture was heated at reflux for 6 hours, at which time TLC showed no starting material. The reaction was cooled to room temperature followed by very slow addition of saturated aq. NaHCO3 until evolution of gas had ceased and the solution remained alkaline. The mixture was then extracted with Et2O (4x75ml), the organic layers combined and dried (MgSO4), filtered and evaporated to leave a tan solid. The product was titurated with hexanes and the resulting suspension was then vacuum filtered to leave a white solid 0.84g, (92%), mp. 139-140 deg C.




Selectivities in Ionic Reductions of Alcohols and Ketones with Triethyisilane / Trifluoroacetic_Acid
Tetrahedron Lett. 1997, 38, 1013-1016.
DOI:10.1016/S0040-4039(96)02484-7



A Et3SiH / TFA reduction of of chiral ketone [5] ((R)-(+)-N-Trifluoroacetyl-2,3,6,7-tetrahydro-4-alanylbenzo[1,2-b;4,5-b’]difuran) was attempted, generally following the procedure of Nichols, but at a significantly larger scale.

Following workup, the yield of the desired aminopropane [6] was found to be ~30% [vs. lit. 92%], along with an approximately equal quantity of uncharacterized (but apparently cleaved) impurity.

The use of trifluoroacetic acid as the solvent may be an issue; it is an aggressive media and the longer the reaction is heated under reflux, the greater the number of decomposition products.

Perhaps acetic acid could be used in place of TFA (but this might not be a strong enough Bronsted acid?)

Or perhaps the reaction could be carried out with TFA, but at lower temperature under strictly anhydrous conditions?

Or possibly is there a reducing agent other than Et3SiH that could be suitable for this step?  LiAlH4 would probably cleave the protection group, but what about NaBH4?

I am not sure which methods from https://www.rhodium.ws/chemistry/reductive.alkylation.html are least like the wonderbra (unwanted cleavage) or a 4th spatial dimension (scramble chirality).

Any suggestions are appreciated, thanks!


stop, drop & roll
 
 
 
 
    descent
(Stranger)
07-11-04 12:37
No 518688
      2 questions to venerable hest     

I have 2 questions to hest on the first stage of his remarkable simplification of the Nichols procedure: hydroquinone + (CH2Cl)2 + NaOH + PTC.
1. Is mixing necessary or refluxing is enough?
2. Why you add all 4 eq. NaOH in the beginning? It will probably lead to the formation of hydroquinone dianion in the water phase and will reduce its extractability, thus slowing the reaction. May be it will be more convenient to add 1 eq. NaOH in the beginning and drop another 3 eq. during the next couple of hours.
 
 
 
 
    Lilienthal
(Moderator)
07-11-04 14:06
No 518691
User Picture 
      The reason to use a PTC is to have the anion...     

The reason to use a PTC is to have the anion in the organic phase aided by the PTC. Therefore is doesn't make sense to add the base dropwise.

Biphasic reactions have to be heavily stirred, otherwise the reaction rate will drop dramatically.
 
 
 
 
    descent
(Stranger)
07-11-04 17:47
No 518717
      I know very well what is PTC, but I am sure...     

I know very well what is PTC, but I am sure that TEBA will easily extract the MONO-anion, but not so easily the DI-anion of hydroquinone. My idea is to start with 1 eq NaOH which is enough for the reaction to begin, and then gradually add more base for the second hydroxyl.
And I know that such reaction are usually - but not always - stirred, and I still hope to know: Did hest used mixing? Because my magnetic stirrer is far from being perfect.
 
 
 
 
    hest
(Hive Adickt)
07-11-04 20:16
No 518725
      Mixing/stirring     

Yes I used a MagStirr with a big magnet. Mixin is werye important.
Why tune a 80% reaction _ the starting materials is free. Use your pover on the grignard step.
 
 
 
 
    descent
(Stranger)
07-12-04 20:06
No 518947
      thanks     

Thanks! I will use my biggest magnet. I have the intention to mix a 1.5 l mixture, to prepare a suffisant amount of you know what, and use all my power on the cyclization step. I plan to try cyclization in a planetary ball mill with Mg, Zn, Li, Na ... It sounds crazy but "crazy experiments lead to Nobel or to nothing" (Erasmus Darwin).
 
 
 
 
    hest
(Hive Adickt)
07-13-04 06:28
No 519059
      :-)     


I plan to try cyclization in a planetary ball mill with Mg, Zn, Li, Na



Sodium in a ball mill, I would love to see that. Might add some permanganatewink
Have fun

 
 
 
 
    azole
(A Truly Remarkable HyperLab Bee)
08-03-04 16:52
No 523406
      Friedel-Crafts rxn with CF3CONHCH(R)COCl
(Rated as: excellent)
    

Friedel-Crafts Acylation with N-(Trifluoroacetyl)-α-amino Acid Chlorides. Application to the Preparation of β-Arylalkylamines and 3-Substituted 1,2,3,4-Tetrahydroisoquinolines
J. E. Nordlander, M. J. Payne, F. G. Njoroge, M. A. Balk, G. D. Laikos, and V. M. Vishwanath
J. Org. Chem.
, 49(22), 4107-4111.

(Ref. #13 from https://www.rhodium.ws/pdf/nichols/nichols-dragonfly-2.pdf .)

Abstract

   Several N-(trifluoroacetyl)-α-amino acid chlorides have been reacted with PhH, MeOPh, and 1,2-(MeO)2PhH in the presence of AlCl3 or SnCl4 to produce ArCOCH(NHCOCF3)R in fair to high yields. The (trifluoroacetyl)amino group of the products can be N-methylated with MeI/K2CO3 in boiling Me2CO. Reduction of the ketones with H2 - Pd/C in EtOH under neutral conditions resulted in alcohols. Hydrogenation in the presence of HCl led to complete deoxygenation. Reductions with Et3SiH in refluxing CF3COOH or in BF3·Et2O at rt gave alcohols (Ar = Ph) or deoxygenated products (Ar = 4-MeOPh or 3,4-(MeO)2Ph). The products of reduction can be readily detrifluoroacetylated by mild basic hydrolysis and thence converted to the corresponding 3-substituted 1,2,3,4-tetrahydroisoquinolines by condensation with CH2O.


N-(Trifluoroacetyl)-α-amino Acid Chlorides as Chiral Reagents for Friedel-Crafts Synthesis
J. E. Nordlander, F. G. Njoroge, M. J. Payne, and D. Warman
J. Org. Chem.
, 50, 3481-3484 (1985).


Abstract

   Chiral N-(trifluoroacetyl)-α-amino acid chlorides undergo Friedel-Crafts reaction with PhH and 1,2-(MeO)2PhH under mild conditions commonly with complete (>99%) preservation of configurational identity. The resultant (trifluoroacetyl)amino ketones may be deoxygenated with Et3SiH or H2/Pd-C in acidic media to the corresponding N-(trifluoroacetyl)-β-arylalkylamines likewise without loss of configurational purity.


A Short Enantiospecific synthesis of 2-Amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (ADTN)
J. E. Nordlander, M. J. Payne,  F. G. Njoroge, V. M. Vishwanath, Gi Rin Han, G. D. Laikos, and M. A. Balk
J. Org. Chem.
, 50, 3619-3622 (1985).


ADTN_.gif


A Short Synthesis of (S)-(+)-Tylophorine
J. E. Nordlander and F. G. Njoroge
J. Org. Chem.
, 52, 1627-1630 (1987).


Abstract

   Friedel-Crafts acylation of 2,3,6,7-tetramethoxyphenanthrene with (S)-N-(trifluoroacetyl)prolyl chloride (1.2 eq.) followed by deoxygenation of the resultant ketone with Et3SiH in BF3·Et2O at rt, removal of the trifluoroacetyl group (NH3 - MeOH), and Pictet-Spengler cyclomethylenation with CH2O in ethanolic HCl resulted in  (S)-(+)-Tylophorine.


Facile Approach to Enantiomerically Pure α-Amino Ketones by Friedel-Crafts Aminoacylation and Their Conversion into Peptidyl Ketones
Maria Luisa Di Gioia, Antonella Leggio, Angelo Liguori, Anna Napoli, Carlo Siciliano, and Giovanni Sindona
J. Org. Chem.
, 66(21), 7002-7007 (2001).
DOI:10.1021/jo010414q


jo010414qn00001.gif


   See also Post 475692 (Rhodium: "A two-step method for chiral cathinones", Novel Discourse).
 
 
 
 
    Organikum
(Wonderful Personality)
08-25-04 21:05
No 527320
      The link in scarmanis post Post 514666 to the...     

The link in scarmanis post Post 514666 (scarmani: "Et3SiH / TFA Reduction - Improvements?", Serious Chemistry) to the uploaded article is broken. Not the DOI which leads to a download for registered users only but the link to the uploaded file here on the board.

regards
ORG

so near, so far......
 
 
 
 
    java
(Hive Addict)
08-25-04 21:29
No 527326
User Picture 
      The wrong thread......     

OrganikumI think you meant to post on the serious chemistry Phenylalanine to
amphetamine.... I have the article , do you want me to upload it ....java

Edit: I uploaded it on the Phenylalanine to a
amphetamine thread......java

It is better to die on your feet than to live on your knees.......
-Emiliano Zapata-
 
 

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