A nine‐step synthesis of [¹⁴C]flupirtine maleate labeled in the pyridine ring

Abstract

The disposition of the drug has been studied in animals (3) and man (4) using the drug labeled with l ' C at the benzylic carbon (5). However, because of the significant amount of metabolic cleavage at the benzylic carbon occur-* A poster presentation on this subject was given at the Second International 2 i n g i n a l l species, a d d i t i o n a l s t u d i e s on the d i s p o s i t i o n o f f l u p i r t i n e malea t e are needed w i t h t h e ' Y -l a b e l i n t h e p y r i d i n e r i n g . Yong M . Choi, N . Kucharczyk and R. Duane SofiaA nine-step procedure f o r t h e p r e p a r a t i o n o f t h e maleate s a l t o f e t h y l 2-amino-6-{ [ ( 4 -f l uorophenyl )methyl ]ami no}-3-pyri dinyl-2,6-"C carbamate [lo] nas been developed i n our qaboratories. T h i s paper describes t h e d e t a i s o f the l a b e l i n g procedure s t a r t i n g w i t h the r e a d i l y a v a i l a b l e m a t e r i a l s , 1 3-dibromopropane [l] and potassium cyanide-l'C as summarized i n Scheme I* DISCUSSIONA.Development o f Small-Scale Synthesis o f F l u p i r t i n e Maleate [lo1 w i t h Unlabeled M a t e r i a lThe p r e p a r a t i o n o f n i t r i l e s by t h e s u b s t i t u t i o n r e a c t i o n o f primary a l k y l h a l i d e s w i t h a l k a l i metal cyanide was described p r e v i o u s l y (6,7). A Nine-Step Synthesis of ['4C]Flupirtine Maleate 3o t h e r s o l v e n t s were s i g n i f i c a n t l y b e t t e r g i v i n g a 66% y i e l d o f t h e product. Moreover, the lower y i e l d (18%) under t h e same c o n d i t i o n s , was a t t r i b u t e d t o a l o s s o f t h e v o l a t i l e c a t a l y s t , t r i f l u o r o a c e t i c a c i d (bp. 72°C) d u r i n g t h eh e a t i n g o f t h e mixture.o f a c i d was u t i l i z e d l e a d i n g t o a c o n s i s t e n t y i e l d o f t h e product (see Table 1). Increased temperature a l s o gave higher y i e l d s f o r t h e same r e a c t i o n t i m e . The r e s u l t s are l i s t e d i n Table 1.To circumvent t h i s problem, an excess amount o f 1 mL The synthesis o f 2,6-dichloropyridine [4] by t h e r e a c t i o n o f 3 w i t h phosphorus pentachloride-phosphorus t r i c h l o r i d e was r e p o r t e d (10). However, under t h e c o n d i t i o n s published t h i s r e a c t i o n gave a m i x t u r e o f other c h l o r inated p y r i d i n e s w i t h t h e d e s i r e d product 4. 4, t h e c h l o r i n a t i o n r e a c t i o n s were c a r r i e d o u t on a 4-5 mmol scale o f 3 w i t h excess o f reagents where t h e r a t i o o f phosphorus t r i c h l o r i d e t o phosphorus p e n t a c h l o r i d e was varied.PClJPCl, r a t i o o f 6 a t room temperature f o r 70 h. To optimize t h e y i e l d o f t h e The optimum y i e l d o f 4 was obtained by using t h e Compound 4 was n i t r a t e d w i t h a m i x t u r e o f n i t r i c a c i d and s u l f u r i c a c i dt o g i v e 2,6-dichloro-3-nitropyridine [5] as p r e v i o u s l y described (11). The r e a c t i o n was performed on a 3-6 mmol scale o f t h...

Isolation, Structure, Synthesis and Cytotoxicity of an Unprecedented Flupirtine Dimer

“…Compound 8 was reduced by Zn/NH 4 Cl [14] to yield the diamine 9. The reduction of 8 using Zn/NH 4 Cl proceeds with better results than the well-established reduction using Raney-Nickel/H 2 at elevated temperatures and high pressures [8,9]. Under these harsh conditions impure 9 is obtained that has to be re-crystallized several times.…”

“…To shorten our synthesis [8,9] of flupirtine analogs we decided to use commercial 1 as a suitable starting material. Thus, commercial samples of 1 (as its maleate) were bought.…”

“…Thus, reaction of 2-amino-6-chloro-3-nitro-pyridine (5) with 4-fluorobenzylamine (6) [10,11] for 10 h under reflux gave the known compound 7 [8,12] in excellent yield. Compound 7 is characterized in its 19 F NMR spectrum by the presence of a signal at δ = − 115.9 ppm showing J F,H = 8.9 and 5.5 Hz, respectively.…”

Synthesis of stable isotopes of auxinic herbicides 4‐amino‐3,5,6‐trichloropicolinic acid and 4‐amino‐3,6‐dichloropicolinic acid

“…9,10 In order to minimize loss from over-reduction, the reaction was stopped after HPLC analysis showed $85% conversion to 4-amino-3,6-dichloropicolinic acid-1-15 N-2,6-13 C 2 (3). For purification purposes the crude carboxylic acid was converted to the methyl ester 13 by refluxing in methanol with a catalytic amount of sulfuric acid.…”

“…[3][4][5] An excess of commercially available potassium cyanide-13 C- 15 N was heated to reflux with 1,3-dibromopropane in a mixture of acetonitrile and water to give a high yield of isotopically labeled glutaronitrile (5). 6 A mixture of 5 in acetic acid and trifluoroacetic acid was heated to 2301C in a Hastelloy-C Parr pressure reactor for 2 days affording glutarimide-1-15 N-2,6-13 C 2 (6) in 82% yield after crystallization from ethanol.…”