Author Topic: OK Extraction done .  (Read 3869 times)

0 Members and 1 Guest are viewing this topic.

Radiumhero

  • Guest
OK Extraction done .
« on: November 08, 2004, 10:14:00 PM »
Well i extracted the P2P and i have to say that the yield is not as bad as exspected ~ 24 ml P2P. And I used 63 ml Benzylchlorid and little more than 38 ml Acetonitril. But my P2P is really dark ! dark brown colored , with a really lets call it unpleasant smell , ( little bit like some sort of plant but this must be an ugly one ...)

Bandil

  • Guest
How did you extract it and verify that it is...
« Reply #1 on: November 08, 2004, 10:27:00 PM »
How did you extract it and verify that it is P2P?

In my experience with this method, you get something from the distillation, with a b.p. not too far for that of P2P (cant remember the exact b.p., lost the notes). It is however NOT p2p...

Regards
Bandil


Radiumhero

  • Guest
workup :
« Reply #2 on: November 08, 2004, 11:34:00 PM »
Well started with acidifation of this funny white salt  followed by 3 times extraction with 35 ml Et2O( NaCl has been added to mixture .) to remove the yellow color from the bottom (water ) Layer. Et2O extracts pooled together and washed with Water .
Water removed by Dropping funnel and heatng to 110 C. Well ill make a sample with anilin acrylation and compare Products by chromatography. by the way ( wich solvent dont know the english word for it // Fließmittel // works best ?)
And i also looked at the pics by xicori (Meerwein acrylisation...) and his crude >Keton looks exactly like mine !! the only Problem is my Vakuumpump broke . ( u can still turn it on but it makes really unpleasant sounds like sth is scraping insinde ...) Can i destill it without too much loss @ atmospheric pressure ?

moo

  • Guest
The problem isn't the reactivity of the ...
« Reply #3 on: November 09, 2004, 05:11:00 PM »
The problem isn't excactly the reactivity of the nitrile. One major problem is the fact that the nitrile is acidic enough to protonate the Grignard reagent, turning your precious benzylmagnesium chloride to plain toluene. The deprotonated acetonitrile then goes on and forms different side reaction products. I have a reference to back this up somewhere. Of course one can argue that it is about reactivity because if the reaction with the nitrile was much faster than a proton transfer, this problem would not exist. But proton transfers are known to be very fast reactions.

I think that another problem is the addition of a second molecule of the Grignard reagent to the formed salt of the imine (iminate?), the reason why Grignard reagent should be added to an excess of the nitrile and not the other way around.

However, the reaction is proven to give P2P in literature several times, yields are the problem.


Novice

  • Guest
If the problem is deprotonation of ...
« Reply #4 on: November 09, 2004, 07:30:00 PM »
If the problem is deprotonation of acetonitril, then the exact same reaction but instead of hydrolysis with acid, reduction with NaBH4 to amphetamine is consulted should not give an 80% yield1. Am I wrong in my reasoning? As the reduction step comes post-imin formation...

1

JACS 109, 3378-3387 (1987) Procedure adapted from the synthesis of #49

(https://www.thevespiary.org/rhodium/Rhodium/chemistry/amphetamine.html)

moo

  • Guest
Thanks for asking, an interesting example...
« Reply #5 on: November 12, 2004, 07:45:00 PM »
Thanks for asking, an interesting example which I had overlooked, even though I've seen it several times before. That preparation is obviously tried and true. I'm convinced that steric factors play a major role here as phenylacetonitrile is more acidic than acetonitrile, and methylmagnesium iodide more basic than benzylmagnesium chloride. Also note the inverted addition. So, I must take my word back about the reactivity of the nitrile group not being the issue. Here is another example of a Grignard addition to nitrile, propionitrile in this case:

Post 475862

(moo: "one pot 1-phenyl-2-butanamine etc", Novel Discourse)
.

Here is the reaction scheme from the original article JACS 109 3378-3387:




Rhodium

  • Guest
Nitrile + Grignard + NaBH4 -> Amphetamine
« Reply #6 on: November 13, 2004, 01:27:00 AM »
Novel diacid accelerated borane reducing agent for imines
Zhi-Hui Lu, Nandkumar Bhongle, Xiping Su, Seth Ribe and Chris H. Senanayake

Tetrahedron Letters 43, 8617–8620 (2002)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/grignardimine.amph-2002.pdf)



Abstract
A remarkable effect of diacids in modulating the reactivity of borane has been discovered. This novel process provides a rapid and excellent access for reduction of a variety of imines with different functionalities.
____ ___ __ _

New resolution approach for large-scale preparation of enantiopure didesmethylsibutramine (DDMS)
Zhengxu Han, Dhileepkumar Krishnamurthy, Q. Kevin Fang, Stephen A. Wald and Chris H. Senanayake

Tetrahedron: Asymmetry 14, 3553–3556 (2003)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/grignardimine.amph-2003.pdf)



Abstract
An improved synthesis and efficient resolution method to prepare both enantiopures of DDMS using crystallization of enantiomerically pure tartaric acid salts of racemic DDMS are disclosed.

Experimental
A 1 L three-necked round-bottomed flask was charged with 1-(4-chlorophenyl)-1-cyclobutylcarbonitrile (CCBC, 50.0 g, 261 mmol) and toluene (150 mL), followed by iso-butyl magnesium chloride (395 mL, 1.0 M in MTBE), and the resulting mixture was distilled until the internal temperature reached 105°C. After stirring at that temperature for 2 h, the mixture was cooled to 0°C and methanol was added slowly (295 mL), followed by sodium borohydride (10.4 g, 1.06 equiv.) portion-wise. The resulting mixture was stirred at rt for 15 min and was added to a 2N HCl solution (330 mL) slowly, stirred for 15 min and the phases were separated. The aqueous phase was extracted with toluene (300 mL), the combined organic phases were distilled to remove methanol, and then washed with aqueous NaOH solution (1.5 M, 100 mL) and water (100 mL) twice. The resulting organic phase was heated to 50–60°C, followed by an addition of D-tartaric acid (40.0 g) in water (80 mL) and acetone (40 mL) slowly. The reaction mixture was azeotrope distilled until the internal temperature reached 92°C and then cooled to ambient temperature in 1–2 h. The slurry was filtered, and the wet cake was washed with MTBE (100 mL) and dried at 40–45°C under reduced pressure to afford (RS)-DDMS·D-TA (100.5 g) in 95.8% yield.

____ ___ __ _

A Study and Identification of Potential By-Products of Sibutramine
G. Om Reddy, M. R. Sarma, B. Chandrasekhar, J. Moses Babu, A. S. R. Prasad, and C. M. Haricharan Raju

Organic Process Research & Development 3, 488-492 (1999)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/grignardimine.byproducts.pdf)

Abstract
In the synthesis and process development of sibutramine (9), the isolation and characterization of two potential by-products namely heptane dinitriles (4a-b) and bis-cyclobutyl alkylamine (10) have been studied. The key steps in the synthesis of sibutramine which have contributed to the formation of above by-products are cycloalkylation of 4-chlorophenyl acetonitrile (1) and tandem Grignard reduction on 1-(4-chlorophenyl)-cyclobutyl carbonitrile (3).
____ ___ __ _

Synthesis of sibutramine, a novel cyclobutylalkylamine useful in the treatment of obesity, and its major human metabolites
J.E. Jeffery, F.Kerrigan, T.K. Miller, G.J. Smith and G.B. Tometzki, J. Chem. Soc. Perkin Trans. 1, 2583-2589 (1996)
DOI:

10.1039/P19960002583



Abstract
Synthetic routes to N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N,N-dimethylamine (sibutramine) 1 and its demethylated and hydroxylated human metabolites N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N-methylamine 2, 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine 3, 4-amino-4-[1-(4-chlorophenyl)cyclobutyl]-2-methylbutan-1-ol 4 and c-3-(1-amino-3-methylbutyl)-3-(4-chlorophenyl)cyclobutan-r-1-ol 5a are described. Key steps are tandem Grignard–reduction reactions on 1-(4-chlorophenyl)cyclobutanecarbonitrile 7 and its 3-(tetrahydropyran-2-yloxy)-substituted analogue 14 and a convenient one-pot conversion of 4-chlorophenylacetonitrile 6 into the 3-hydroxycyclobutanecarbonitrile 13.