kmno4
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modafinil with bad melting point
I have some modafinil (prepared by standard procedures) but there is a problem with melting point.
Raw modafinil was crystallised twice from ethanol (95%) - it gave crystalline powder (=CP)) mp. 158-159 C.
Additional cryst. of CP from isopraponol - mp. without change.
Another sample of CP was agitated (at r.t.) for ~12h with toluene - mp. without change.
According to literature ( ex. DOI: 10.1021/cg301630d, and countless patents) pure modafinil should have mp. 164-168 C (depending on polymorph).
Melting point 158-159 C indicates not-modafinil compound, however it melts sharply and looks good (especially under the microscope: nice small
crystals).
Searching this forum I found indentical mp. 158-159 C, for home-made modafinil.
Does anybody know what is the reason of it ?
I suspect that material I have is not pure modafinil, but some kind of "strange molecular adduct" (sounds better than 'shit').
BTW: starting 2-(benzhydrylthio)acetamide had good mp. 110-111 C (after purification)
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paw_20
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http://www.google.com/patents/EP1787980B1?cl=en
This patent claims that the sulfide can overoxidize to the sulfone in one industrial process, but I don't know if they are talking about the same
process as you, and I don't know if that explains your mp results. They also don't discuss mp at all, purity is determined by HPLC
http://www.google.com/patents/EP1575915A1?cl=en&dq=water...
This patent claims a mp of 159 C for one crystalline form (they call it form 6, or VI, whatever)
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kmno4
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This link gives OCR results from WO2004014846A1 patent.
They claim there m.p. for forms III......VII(!) 158-161 C.
They also cite another patent (US4177290), where form I is obtained (mp 164-166). However, in this patent author does not mention any "forms", just
gives mp. of his product.
Paper from ACS (DOI linked earlier) gives mp. for form I 164 C and for form IV 165 C....
I will try one more crystallization, this time from methanol ( but somehow I feel that mp. will stay the same, hah).
I do not belive in patents, in most cases they are disinformative
, but thanks for links.
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kristofvagyok
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In patent WO2009/90663 A1, 2009 they give 153 - 154 °C
In patent WO2007/98273 A2, 2007 they give 146 - 147 °C
In patent DE2809625 , 1978 ; they give 164 - 166 °C
In Tetrahedron: Asymmetry, 2004 , vol. 15, # 23 p. 3811 - 3816 they give 158 - 159 °C
In Russian Chemical Bulletin, 2010 , vol. 59, p. 91 - 101 they give 164 - 165 °C
In Medicinal Chemistry letters, 2011 , vol. 2, # 1 p. 48 - 52 they give 152.5 - 154 °C
for the melting point. So I would say that your 158-159 °C is perfectly good, no need to worry.
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kmno4
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patent WO2009/90663 A1, 2009 they give 153 - 154 °C :: single enantiomer, from ethanol
patent WO2007/98273 A2, 2007 they give 146 - 147 °C :: single enantiomer, "about 146°C to about 147°C" (surely impure sample)
patent DE2809625 , 1978 ; they give 164 - 166 °C :: racemat, crystal. from CH3OH, but this value is given in a table earlier, possible that
rewritten from another paper
Tetrahedron: Asymmetry, 2004 , vol. 15, # 23 p. 3811 - 3816 they give 158 - 159 °C :: single enantiomer R(-)
Russian Chemical Bulletin, 2010 , vol. 59, p. 91 - 101 they give 164 - 165 °C :: racemat, cryst. from IPA-DMF
Medicinal Chemistry letters, 2011 , vol. 2, # 1 p. 48 - 52 they give 152.5 - 154 °C :: single enantiomer S(+)
-----------------------------------------------------------------------
Please save my time and read literature before quoting.
[Edited on 16-4-2013 by kmno4]
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Nicodem
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Kmno4, are you sure about the measurement? Is it possible that the thermometer you use needs a calibration? You can check on a pure sample of some
sharp melting compound to see if it is still OK. In my experience, it is not that unusual for some thermometers to be a few kelvins off. Some digital
thermometers show wrong values when the battery is coming to its end.
Since you got the same mp from ethanol, 2-propanol and from slurring in toluene, I do not think the discrepancy has to do with you having a specific
polymorphic form. The mp of these can easily vary for 20 kelvins or more, but it is not so common to obtain different forms from recrystallizations in
the same solvent without seeding (can happen though) and you used ethanol for which the mp is already reported. Besides, all the polymorphic forms
should already be described in the patents, because the pharmaceutical industry just loves to claim polymorphs, but I don't have the time to go trough
the immense number of modafinil patents to see if there is any that fits the 158-159 °C measurement.
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
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kmno4
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Unfortunately I am sure of my measurement, I have just checked it for sublimated benzoic acid - very sharp melting at 123 C (slight overheating,
device was set for ~170 C). I also recrystallised a sample from CH3OH, mp. without change.
What is the most amazing for me - crystallisation does not change mp. at all. It seems that I have some pure compound, but mp. fits to nothing.
Chiral modafinil has mp. ~158 C, but it is ruled out. Racemic modafinil has ~165 C. These data are from chemical publications, not suspicious patents.
I would not bother SM members with this problem, but I have found that the others also obtained the same mp.
For example on this shitty site:
http://about.mdma.ch/000429898.html
Polymorph called "I" is the most stable , thermodynamic product. The rest of polymorphs is obtained in "special" conditions. "I" has mp. ~164 C and it
is what want to see, but I am not able to force my powder to melt higher.
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sonogashira
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Perhaps you have oxidized the amide? http://en.wikipedia.org/wiki/Adrafinil
[Edited on 20-4-2013 by sonogashira]
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kmno4
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I think such oxidation is not possible (in this case)
But if even, my product gives no red coloration with Fe(III).
I tried crystallisation from aqueous methanol (according to US4177290) - to my surprise mp. increased to 162-164 C.
Now I can feed my dog to see what happens ![:D](./images/smilies/biggrin.gif)
Product is crystalline mass, with no odour. Previous samples had weak, but sensible "sulfurous" aftertaste, H2O-MeOH crystallised sample is only
bitter, without this aftertaste. I thought it is characteristic, immanent feature of this amide, but I was wrong ![:P](./images/smilies/tongue.gif)
Ups, I forgot that my dog died long time ago....
I have to buy another one
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Paddywhacker
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kmno4, did you use the Rhodium procedure for your synthesis?
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kmno4
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No.
I used procedure from Russian Chemical Bulletin, 2010 , vol. 59, p. 91 - 101, however prepared 2-(benzhydrylthio)acetamide requires purification to
obtain correct m.p. but with it there is no problem.
I made oxidation step as in the paper (80% formic acid), another run in acetic acid, with old 33% H2O2 (true peroxide content 16% by my own
simple-and-quick-methode ) and fresh 35% ( measurement gave also 35%).
Results are generally the same: output mass of raw sulfoxide ≈ mass of strating sulfide, with m.p. ~150 C
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Paddywhacker
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Thanks. I have included your reference, for the record.
Attachment: Bicherov et al., New synthetic route to modafinil, 2010.pdf (540kB) This file has been downloaded 718 times
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kmno4
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Yes, it looks good.... too good.
Do not take the paper too seriously
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