Bwiti (PVC-Analog Taste-Tester)
08-15-03 11:02
No 453691
      Thalidomide Synthesis..  Bookmark   

Here's the best I can find:

Thalidomide and its derivatives preparation method

The method for synthesizing thalidomide and its derivative includes the following steps: adding phthalic anhydride and glutamine at 120-150 deg.C, addition quantity of phthalic anhydride is 1-5 timesthat of glutamine, heating, stirring, reacting for 20-40 min., then slowly heating to 160-220 deg.C, vacuum pumping, after 2-20 hr, stopping reaction, adding 1,4-dioxane, heating and stirring to make said material into solution, decompressing and evaporating out dioxane, adding acetone, stirring, filtering, washing with water and settling, washing with acetone and vacuum drying to obtain the invented thalidomide. Said invention utilizes 2-position or 4-position CH3, CH2CH3, OCH3, F, Cl, Br or NO2 substituted phthalic anhydride and glutamine, and makes them react together, so that the correspondent thalidomide derivative can be obtained.

Preparation Of Thalidomide By Heating Intermediates In Refluxing Anhydrous Tetrahydrofuran

  I went through 7 search pages at, and couldn't find a complete fucking synthesis of thalidomide. There's plenty of info on analogues though. Can someone please help me find its synthesis? Thanks!cool

Love my country, fear my government.
(Hive Bee)
08-15-03 14:25
No 453710
      Re:"Thalidomide Synthesis.."  Bookmark   

Some help,.....


We're  all in this world together,
(Chief Bee)
08-15-03 14:43
No 453718
      Patented Syntheses of Thalidomide
(Rated as: good read)


Product: N-(2,6-dioxo-piperidin-3-yl)-phthalimide
Reaction Classification: Preparation (half reaction)

Patent GB1185273
Patent JP1734163
Patent JP1963961
Patent DE1093364
Patent US2830991
Patent GB768821
08-16-03 03:26
No 453823
      Are you pregnant, Bwiti?  Bookmark   

Are you pregnant, Bwiti?
(Active Asperger Archivist)
08-16-03 03:32
No 453826
      Rhodium  Bookmark   

That pic you posted was very telling for anybody who knows the story and (stereo)chemistry behind thalidomide.

Bwiti, what is your interest in the compound?

Act quickly or not at all.
(PVC-Analog Taste-Tester)
08-16-03 13:23
No 453901
      Production Of N-Phthalyl Glutaminic Acid, Etc..  Bookmark   

Thanks everyone! What's up Aurelius?! I have severe anxiety and thalidomide should take the edge off. It seems easier to make than benzodiazepines, so why the fuck not?
  I couldn't get a hold of those JP patents(not even an abstract), and I'll try to translate that DE sometime in the future. I read all the others, so basically, n-phthalyl glutaminic acid(or anhydride) + primary amine or urea = active product, right? My question is, how is n-phthalyl glutaminic acid(or anhydride) made? Is it made by heating phthalic anhydride and glutamine together? Why isn't urea or primary amine used in that CN1405166 patent abstract I posted? I'm confused.tongue

Love my country, fear my government.
(PVC-Analog Taste-Tester)
08-17-03 06:07
No 454032
      Anyone?  Bookmark   


Love my country, fear my government.
08-17-03 10:43
No 454072
      bendzos  Bookmark   

Bwiti, cant help with the thalidomide q, but thought
this was a reasonable route to benzo's when i researched it ages ago (detail may be slightly off) ...
the main stumbling block is 2-methylamino-5-chlorobenzophenone -
dont order it since its used in almost all benzo type manufacture

benzyl cyanide   (phenylalanine + hypohalite)
p-chloro-nitrobenzene (buy it? nitrate chlorobenzene?)
(note good yield unlike other routes)

rearragnge with Fe/Hcl (can ignore the n-methylation with DMS)

acetylate with chloro-acetyl chloride (buy it? - or from chloroacetic acid + PCl3)
theres another variation in the literature using glycine.

rearrange with hexamine
--> benzo

../rhodium /diazepam.html
(PVC-Analog Taste-Tester)
08-19-03 05:06
No 454451
      Can't find a damn thing..  Bookmark   

Benzos sound good, but it's so much more involved than thalidomide. I'm searching the net to see if I can make it with just glutamine and phthalic anhydride, without the use of a primary amine or urea. Can't find anything.

Love my country, fear my government.
(Hive and HyperLab Bee)
08-19-03 15:40
No 454523
      >the story and (stereo)chemistry behind...  Bookmark   

>the story and (stereo)chemistry behind thalidomide.

The stereochemistry issue is not quite as simple as usually portrayed - one enantiomer good, another bad. AFAIK thalidomide racemises quite rapidly in vivo, so even pure single "good" isomer would be harmful to fetus in pregnant woman. On the another hand there are no reasons why males could not use thalidomide, if necessary.
(Hive Bee)
08-20-03 12:27
No 454684
      Microwave mediated synthesis of thalidomide  Bookmark   

Fifth International Electronic Conference on Synthetic Organic Chemistry (ECSOC-5),, 1-30 September 2001 [E0008]

 Urea vs Thiourea in the formation of imides:
A Microwave and Conventional Heating Comparative Study 

Julio A. Seijas*, M. Pilar Vázquez-Tato* and Carlos Álvarez-de-Gabriel
Departamento de Química Orgánica. Facultad de Ciencias.
Universidad de Santiago de Compostela. CAMPUS DE LUGO.
Aptdo. 280. 27080-Lugo. Spain, Fax +34982224904

Received: 27 July 2001 / Uploaded 7 August 2001

Imide group is an interesting functionality, due to its wide presence in the natural products pool and in the pharmacologically active compounds. This has attracted our attention as a target to be prepared by microwave irradiation. We had published a general approach to N-substituted cyclic carboxylic imides [1], and later we extended our studies towards non substituted cyclic imides, thus we developed a new synthesis of thalidomide enhanced by microwave heating [2]. Thalidomide, an old drug with a renewed interest, has two imide groups in its structure. We carried out two microwave mediated new approaches: a stepwise synthesis by preparing first N-phthaloyl-L-glutamic acid and later using urea or thiourea (as the source of nitrogen) to close the glutarimide ring (scheme 1, right) and a one step reaction (scheme 1, left) from L-glutamic acid, phthalic anhydride and thiourea in the latter, obtaining with this procedure thalidomide in a 60% yield with the formation of the two imides simultaneously. 

A feature that attracted very much our interest was the fact that when urea was used instead, we obtained a lower yield of thalidomide and a considerable amount of pyroglutamic acid. This, compared with the previous results for the formation of imides in the only study we know on urea and thiourea [3] resulted in a reversed reactivity.


We decided to study independently the reaction of formation of phthalimide and glutarimide in the reaction conditions used for thalidomide, to check if there was any marked difference between formation of phthalimide and glutarimide rings (scheme 2) which were the responsible for the good behaviour in the preparation of thalidomide. 


Thus we studied the formation of glutarimide by heating glutaric acid with urea and with thiourea. We found that after 15 minutes irradiation in the (domestic) microwave oven (Electrolux; 1000W, 70%) we obtained, 90% yield of glutarimide with urea, and 98% yield with thiourea. We also carried out both experiments in a preheated heating mantle (160ºC) for the same time as they were irradiated, getting a 50% yield for the reaction with urea and a 33% when thiourea was used.

The phthalimide formation from phthalic anhydride was studied in a similar way. The reaction with urea was irradiated for 6 minutes with a quantitative yield of phthalimide. Meanwhile, with the heating mantle it gave just 43% yield of imide. The use of thiourea with microwaves gave a lower yield of phthalimide (91%, and required 10 minutes irradiation), but with the heating mantle it was slightly higher (46%) than the conventional using urea.
Regarding to the improvement on the synthesis by microwave of our three component reaction for thalidomide, we think thiourea is less reactive than urea towards phthalic anhydride than urea, which could help to lessen the formation of phthalimide as a secondary product, and at the same time thiourea gives better yield in the formation of glutarimide ring.

In summary, for the same reaction times, microwave irradiation is the ideal choice for preparing non substituted cyclic imides. The use of urea or thiourea led to similar yields.


DGES (PB96-0932) and XUNTA DE GALICIA (PGIDT01PXI26203PR) for financial support. 


1.- Seijas, J. A.; Vázquez-Tato, M. P.; Martínez, M. M.; Nuñez-Corredoira, G. J. Chem . Res. (S), 1999, 420-421.
2.- Seijas, J. A.; Vázquez-Tato, M. P.; González-Bande, C.; Martínez, M. M.; López-Pacios, B. Synthesis, 2001, 999-1000.
3.- Rahman, A. U. Recl. Trav. Chim. Pays-Bas, 1956, 75, 164-168. Rahman, A. U.; Medrano, M. A.; Mittal, O. P., ibid. 1960, 79, 188-192.

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