Flupirtine, D 9998

2-amino-6-(4-fluoro-benzylamino)- pyridin-3-yl)-carbamic acid ethyl ester, is unique as a non-opioid, non-NSAID, non-steroidal analgesic with a favorable tolerability. It first became available in Europe in 1984, and was sold mainly under the names Katadolon, Trancolong, Awegal, Efiret, Trancopal Dolo, and Metanor

PHASE 2

MS

• Neuronal potassium channels (7)
• Membrane resting potential (6)
• NMDA receptor channels (indirectly)(14)

• Originally developed by Asta Medica (1) (4)
• Being developed and commercialized to treat fibromyalgia by Synthetic Biologics (1)

Flupirtine

75507-68-5 maleate
56995-20-1 (free base)

LAUNCHED

1986 NEUROPATHIC PAIN

Flupirtine maleate is the INN for 2-amino-3-ethylcarbamato-6- (4-fluoro-benzylamino) maleate, CAS: 75507-68-5, molar mass 420.40 g / mol, molecular formula C1 5 H17FN4O2 • C4H4O4, and corresponds to the structure of formula I.

Flupirtine maleate is used, for example, under the trade name Katadolon® as an analgesic.

PATENT
http://www.google.com/patents/CN103086963A?cl=en
FIG. 1 is flupirtine maleate 1H NMR.
[0021] FIG. 2 is flupirtine maleate A crystal X-ray diffraction pattern

Example 3
2-Amino-3-nitro-6-chloropyridine 246g, and 254g of triethylamine were added to 800ml of ethanol-necked flask and stirred under heating to reflux, fluorine was slowly added dropwise benzylamine 80g, reaction of 6 hours, the reaction was completed After the dropwise addition of purified water 500ml, cooled slowly with stirring to room temperature, filtered, dried to give 2-amino-3-nitro-6-p-fluoro-benzylamino-pyridine.
[0033] The ferric chloride hexahydrate was dissolved in purified water 41g 200ml, adding activated charcoal 20g, heated to 50 ° C, a saturated solution of sodium hydroxide was added 45g (24g of sodium hydroxide dissolved in 21ml water), 60 ° C with stirring I hours, cooled to room temperature, filtered, and dried to give ferric hydroxide / activated carbon catalyst.
[0034] A mixture of 2-amino-3-nitro-6-p-fluorobenzyl-aminopyridine 104.Sg, ferric hydroxide / activated carbon catalyst was added to 20g 2L reaction flask was added 95% ethanol 1200ml, heated with stirring to 90 ° C. Insulation 60% hydrazine hydrate was added dropwise 250g. Drops Bi insulation response to 3h. Completion of the reaction, the reaction solution is filtered hot with concentrated hydrochloric acid to 240ml and 95% ethanol IOOOml reaction flask. (TlO ° C crystallization I h, filtered, dried to give 2,3-amino-6-fluoro-benzyl-aminopyridine on
Hydrochloride.
[0035] A mixture of 2,3-diamino-6-p-fluoro-benzylamino-pyridine hydrochloride 132g, 800ml of isopropanol was added to a 2L reaction flask, the temperature control to 28 至 30 ° C, was slowly added dropwise acetic acid ester 39g. Stirred for 0.5 hours, was slowly added dropwise triethylamine 70g, after stirring for 0.5 hours, complement ethyl chloroformate 5g, stirred for 15 minutes, additional triethylamine remaining 10g. Continue stirring for I hour. The reaction solution was concentrated under reduced pressure to about 800ml of distillate was distilled out. The remaining reaction solution was poured into an aqueous solution of maleic acid with a good (39g of maleic acid was dissolved in purified water IlOOml), stirred for 30 minutes at room temperature, (T5 ° C was stirred for 5 ~ 8 hours, filtered, dried to give the maleic acid flupirtine crude.
[0036] The crude flupirtine maleate product 100g, 2000ml of ethanol into the reaction flask and heated to 70~80 ° C, was added 5g of activated carbon and dissolved, and incubated I hour, filtered hot, O~5 ° C CRYSTALLIZATION 3 hours, filtered and dried to give crude I. The crude product I 90g, 450ml of ethanol into the reaction flask and heated 20h, and then slowly cooled to room temperature, O~5 ° C for 2 hours, filtered, and dried to give crystal form A of flupirtine maleate product.













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paper

J Pharm Biomed Anal. 2014 Mar;90:27-34. doi: 10.1016/j.jpba.2013.11.015. Epub 2013 Nov 27.

Flupirtine maleate is a centrally acting, non-opioid, nonsteroidal antiinflammatory analgesic. During the manufacturing of flupirtine maleate, two unknown impurities present in the laboratory batches in the range of 0.05-1.0% along with the known impurities in HPLC analysis. These unknown impurities were obtained from the enriched mother liquor by column chromatography. Based on the complete spectral analysis (MS, (1)H, (13)C, 2D NMR and IR) and knowledge of the synthetic scheme of flupirtine maleate, these two new impurities were designated as diethyl 5-((4-fluorobenzyl)amino)-2-oxo-1H-imidazo[4,5-b]pyridine-1,3(2H)-dicarboxylate (impurity-I) and diethyl(6-((4-fluorobenzyl)amino)pyridine-2,3-diyl)dicarbamate (impurity-II). Impurity isolation, identification, structure elucidation and the formation of impurities were also discussed. Preparation and structure elucidation of impurity-III were also first reported in this paper.

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journal of pharmaceutical and biomedical analysis, 90, 2014, 27-34

 

  1H NMR INTERPRETATIONS/PREDICTIONS

13C  NMR INTERPRETATIONS/PREDICTIONS

…….

PAPER

Helvetica Chimica Acta, , vol. 77, # 8 p. 2175 – 2190

AND GIVES PRODUCT

ALSO AN INTHelvetica Chimica Acta, , vol. 77, # 8 p. 2175 – 2190

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P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.