AZASETRON,  NAZASETRON

N-(1-azabicyclo[2.2.2]octan-8-yl)-6-chloro-4-methyl-3-oxo-1,4-benzoxazine-8-carboxamide

6-chloro-3,4-dihydro-4-methyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide

123039-99-6 , 123040-69-7 (free base)

141922-90-9 HYD SALT

Y-25130 (hydrochloride)LAUNCHED 1994 AS HCL SALT FORM SEROTONE

a selective 5-HT3 receptor antagonist , ANTIEMETIC

• UNII-77HC7URR9Z

Mitsubishi Tanabe Pharma, JAPAN TOBACCO (Originator)

FOR..Nausea and Vomiting, Treatment of
Prokinetic Agents

Azasetron is an antiemetic which acts as a 5-HT₃ receptor antagonist.

Chemical and Pharmaceutical Bulletin, 1992 ,  vol. 40,  3  p. 624 – 630, ENTRY 15 , MP 305 OF HCL SALT

Biological and Pharmaceutical Bulletin, 2006 ,  vol. 29,  9  p. 1931 – 1935, AS MERCK 903

US 4892872…

CN 101786963…

WO 1996001630..

WO 2006006595..

WO 2007134077..

CN 102526740,  CN 102451166, US 4892872, JP 2008297277

US5773436 A1, WO2006/119295 A2, EP1336602 A1, US4892872 A1,

US2003/18008 A1, US2002/147197 A1, US4892872

AZASETRON

The nitration of 5-chloro-2-hydroxybenzoic acid methyl ester (I) with nitric acid in sulfuric acid gives 5-chloro-2-hydroxy-3-nitrobenzoic acid methyl ester (II), which is reduced with Fe and NH4Cl in water yielding 3-amino-5-chloro-2-hydroxybenzoic acid methyl ester (III). The cyclization of (III) with chloroacetyl chloride (IV) by means of NaHCO3 in CHCl3 – water affords 6-chloro-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid methyl ester (V), which is methylated with methyl iodide and K2CO3 in DMF affording the corresponding 4-methyl derivative (VI). Hydrolysis of (VI) with ethanolic NaOH gives the corresponding acid (VII), which by treatment with refluxing SOCl2 is converted into its acyl chloride (VIII). Finally, this compound is condensed with 3-aminoquinuclidine (IX) by means of N-methylmorpholine (NMM) in CHCl3.

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SYNTHESIS

CN101786963B

Azasetron hydrochloride (Azasetron hydrochloride) is a secondary cancer drugs, mainly synthetic route is as follows

[0003]

[0004] In EP 0313393; JP 1989207290; JP 1990005415; US 4892872; Eur.Pat.Appl., 313393,, Chem pharm Bull, 1992,40 (3) :624-630 reported the synthesis of intermediates III is with ammonium chloride, iron as the reducing agent, the nitro substrate was dissolved in toluene and added dropwise to a reduction of the media inside, the study found that this approach has a number of disadvantages, notably the reaction can not be completely, while post-processing is very troublesome, purity of the product obtained is poor, and difficult purification. Although the “Chinese Medicinal Chemistry” magazine, 10 (2) ,138-140; 2000, the author hydrochloride instead of ammonium chloride, but still need the nitro group was dissolved in toluene was added dropwise, in fact, the nitro compound in toluene the solubility is limited, and in the process will precipitate dropwise addition, there are also incomplete reaction, impurities, and complicated post-treatment problems.

[0005] In the “China Pharmaceutical Industry” magazine 34 (3) ,214-215; 2003 in order to restore hydrosulfite as reductant,

Azasetron preparation of intermediates, the steps are as follows:

[0015] (I) A mixture of 3 – nitro-5 – chloro-salicylate added glacial acetic acid was stirred for 30-40 minutes, add water, temperature 30 ~ 100 ° C, adding iron powder, 2.5-3 hour plus finished, the addition was completed, at a temperature of 30 ~ 100 ° C the reaction for 5 to 10 hours; give 3 – amino-5-chloro-salicylate mixture;

[0016] The mass ratio of the added material is 3 – nitro-5 – chloro-salicylate: acetic acid: water: iron = 1: 5 ~ 10: 5 ~ 10: 0.5 ~ I;

[0017] (2) obtained in the step ⑴ added to a mixture of glacial acetic acid, glacial acetic acid added in the amount of step ⑴ same amount of glacial acetic acid, 70 ° C was stirred for 30-35 minutes, filtered through celite to remove the iron sludge to obtain filter cake; this procedure to that step (I) the resulting product was dissolved in glacial acetic acid solvent sufficient, in order to facilitate post-processing; while removing impurities.

[0018] (3) The filter cake was washed with an organic solvent, the combined filtrate and stirred for 10-15 minutes, allowed to stand for 30-35 minutes, the organic layer was separated; aqueous phase was extracted once again with an organic solvent, the combined organic solution was washed three times , mention made three – amino -5 chloro methyl salicylate (intermediate III) sulphate solution.

[0019] (4) of step (3) of 3 – amino-5-chloro-salicylate was added a saturated NaHCO3 solution, saturated NaHCO3 solution and the amount of acetic acid in step ⑴ same volume, cooling to _1 ° C ~ 0 ° C, control the temperature -1 ° C_5 ° C was added dropwise acetyl chloride, drop Bi. Reaction 2-3 hours. To give 3 – (2 – chloro-acetylamino)-5-chloro-mixed solution of methyl salicylate;

[0020] The amount of chloroacetyl chloride is added in step ⑴ source material 3 – nitro-5 – chloro molar ratio of methyl salicylate

I: 0.9-0.95.

[0021] (5) obtained in the step ⑷ 3 – (2 – chloro-acetylamino) methyl salicylate _5 chloride mixture was heated to 30-40 ° C, stirred for 1-1.5 hours; organic layer was separated, water phase extracted once again with an organic solvent, the combined organic layer was washed with water three times, separated and the organic layer is directly subjected to atmospheric distillation, the organic solvent is distilled off, distillation was complete, methanol or ethanol as the crystallization solvent, 80 ° C under stirring for 2.5 hours under reflux , to give 3 – (2 – chloro-acetylamino) _5 chlorine in alcohol solution of methyl salicylate. This step is intended to 3 – (2 – chloro-acetylamino)-5-chloro methyl salicylate purification.

[0022] (6) in the step (5) cooling to room temperature, an alcoholic solution, crystallization, centrifugation, and washed with ethanol crystal; 80 ° C drying in needle-like crystals 3 – (2 – chloro-acetylamino) _5 Chlorine methyl salicylate (intermediate IV).

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USEFUL PATENTS

………..AZASETRON

AZASETRON

NMR OF HCL SALT

http://file.selleckchem.com/downloads/nmr/S210601-Azasetron-hydrochloride-NMR-Selleck.pdf

…………….

SYNTHESIS

US4892872

EXAMPLE 15

To a solution of 3.0 g of 3-aminoquinuclidine and 3.0 g of N-methylmorpholine in 60 ml of chloroform is added 6.2 g of 6-chloro-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid chloride under cooling and stirring followed by stirring for 2 hours. The resultant solution is washed with water, aqueous sodium hydrogen carbonate and then water, and dried over magnesium sulfate. After the solvent is distilled off under reduced pressure, the residue is recrystallized from ethanol-isopropyl ether and treated with ethanolic hydrochloric acid to give 6-chloro-3,4-dihydro-4-methyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide hydrochloride, melting at 281

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SYNTHESIS AND + AND – ISOMERS

US4892872

EXAMPLE  36

A solution of 6 g of 6-chloro-3,4-dihydro-4-methyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide and 2.7 g of D-(-)-tartaric acid in 100 ml of methanol and 200 ml of ethanol is allowed to stand. The precipitated crystals are collected by filtration and recrystallized from methanol repeatedly to give the R-(+) isomer, [α].sub.D.sup.25 =+36.72 (c=1, chloroform), melting at 177 with ethanolic hydrochloric acid, and then the precipitated crystals are collected by filtration and dried to give the R-(+) isomer hydrochloride, [α].sub.D.sup.25 =+1.4 (c=1, water), melting at 309

By using L-(+)-tartaric acid in a similar manner, the R-(-) optical isomer, [α].sub.D.sup.25.5 =-36.76 (c=1, chloroform), melting at 176 [α].sub.D.sup.25.5 =-1.2 (c=1, water), melts at 310

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DR ANTHONY MELVIN CRASTO Ph.D

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

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