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3 Production of a 2-amino-3-carbethoxyamino-6-(p-fluoro-benzylamino)-pyridine-maleate having a content of crystal modification A of 71% (+-5% error limit)
EXAMPLE 3 Production of a 2-amino-3-carbethoxyamino-6-(p-fluoro-benzylamino)-pyridine-maleate having a content of crystal modification A of 71% (+-5% error limit) A solution of 45 grams of 2-amino-3-carbethoxyamino-6-(p-fluoro-benzylamino)-pyridine (base as in Example 2) in 1626 ml of ethanol prepared at 65° C. is treated with a mixture of 18.9 grams of maleic acid in 146 ml of ethanol in which there were admixed undissolved inoculant crystals of a mixture enriched in modification A (content of A=80%, obtained according to Example 2). The mixture was immediately cooled to 8° C. and the compound crystallized out centrifuged off. Yield: 94.1% of theory. M.P.: 176.5°-176.7° C. *Mettler FP-1-apparatus). IR Spectrum in KBr see FIG. 4a (I,II) and 4b. Maxima at: 3430, 3300, 3218, 1920, 1710, 1645, 1630, 1571, 1520, 1390, 1362, 1280, 1229, 1170, 1127, 1076, 970, 865, 656 cm-1.
1.s.t.E.x.a Preparation of Pure Flupirtine Maleate
1st Example Preparation of Pure Flupirtine Maleate 75 g (0.286 mol) of ANFP are hydrogenated in a suspension of 12.5 g of Raney nickel in 400 ml of isopropanol at 65° C. and a hydrogen pressure of 5 bar. After hydrogenation is complete, 26.4 ml of ethyl chloroformate and then 50.6 ml of triethylamine are added to the solution. After the addition of a further 6.3 ml of ethyl chloroformate, the reaction solution is stirred for a further hour at 60° C. The hot solution is then sucked, with stirring, into a solution of 53.3 g of maleic acid in 1.5 l of H2 O, which solution has been heated to 50-60° C., and the catalyst is rinsed with a little isopropanol. The flupirtine maleate is precipitated in colourless form and the crystal suspension is cooled to 20° C. with further stirring and is left at this temperature for 20 minutes. The flupirtine maleate is filtered off with suction, rinsed with about 500 ml of water and dried in vacuo at 35° C. Yield: 107.55 g (89.6% of theory, based on ANFP used).
Yield
Reaction Conditions
Operation in experiment
In methanol at 20℃; for 2.16667h; Heating / reflux;
1
5 g flupirtine maleate of the crystal modification A is heated in argon atmosphere in 100 ml methanol under reflux for 10 min. The mixture is then cooled to room temperature under agitation. The substance is filtrated after 2 hours and dried for 2 hours in a vacuum at a temperature of 600C. 4.8 g flupirtine maleate (crystal modification A) are obtained as shown by an X-ray diffractogram (Fig. 1).
at 150℃; for 2h;
5
Example 5Preparation of Flupirtine Maleate Form B30 g of Flupirtine base were dissolved in 1080 ml of Isopropanol at 60° C. 12.8 g of Maleic acid was dissolved in 96 ml of Isopropanol. 0.2 g of flupirtine maleate B crystals made according EP 977 736 patent were added. Flupirtine maleate B was made according EP 977 736 through heating of part of maleat A for 2 h at 150° C. Maleic acid solution was added to Flupirtine solution at 60° C. in the course of stirring. The mixture was stirred for 2 minutes and cooled down to 17° C. The sediment formed was filtered. The color of the sediment was white. 40.9 g of the product was formed.
In water; isopropyl alcohol at 0 - 65℃; for 6.25h; Industry scale;
3
Crude flupirtine maleate (14.0 kg) was mixed with isopropanol (146.8 L) and deionized water (63.2 L) and the reaction mixture was stirred and heated to 65°C to dissolve the crude flupirtine maleate. The solution was cooled to 0°C over 5.25 h and maintained at 0°C for 1 h. The crystals were filtered off, washed with an aqueous isopropanol solution (25.2 L isopropanol and 2.8 L water) or acetone (20 L), and dried at about 30°C under reduced pressure. Purity of flupirtine maleate: 99.9% (mixture of polymorphs A and B).
5
[ 56995-20-1 ]
[ 110-16-7 ]
flupirtine maleate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In isopropyl alcohol at 17 - 60℃;
5
Example 5Preparation of Flupirtine Maleate Form B30 g of Flupirtine base were dissolved in 1080 ml of Isopropanol at 60° C. 12.8 g of Maleic acid was dissolved in 96 ml of Isopropanol. 0.2 g of flupirtine maleate B crystals made according EP 977 736 patent were added. Flupirtine maleate B was made according EP 977 736 through heating of part of maleat A for 2 h at 150° C. Maleic acid solution was added to Flupirtine solution at 60° C. in the course of stirring. The mixture was stirred for 2 minutes and cooled down to 17° C. The sediment formed was filtered. The color of the sediment was white. 40.9 g of the product was formed.
In isopropyl alcohol at 20 - 60℃;
5
Example 5; Preparation of Flupirtine Maleate Forms A and BFlupirtine Base was Prepared According to patent EP 0 977 736.Flupirtine Maleate Form A30 g of Flupirtine base were dissolved in 1080 ml of isopropanol at 50° C. 12.8 g of Maleic acid was dissolved in 96 ml of isopropanol at 20° C. Flupirtine solution was cooled down to 20° C. Maleic acid solution was added to Flupirtine solution in the course of stirring. The sediment was formed almost at once. The mixture was heated and stirred for 60 min at 60° C. Then the mixture was cooled down to 20° C. The sediment was filtered and washed three times with cooled (0° C.) Isopropanol. The sediment formed was white. 41.4 g of the product was formed.
In isopropyl alcohol at 20 - 60℃;
5
30 g of Flupirtine base were dissolved in 1080 ml of isopropanol at 50 C. 12.8 g of Maleic acid was dissolved in 96 ml of isopropanol at 20 C. Flupirtine solution was cooled down to 20 C. Maleic acid solution was added to Flupirtine solution in the course of stirring. The sediment was formed almost at once. The mixture was heated and stirred for 60 min at 60 C. Then the mixture was cooled down to 20 C. The sediment was filtered and washed three times with cooled (0 C) Isopropanol. The sediment formed was white. 41.4 g of the product was formed.
In isopropyl alcohol at 60℃;
5
30 g of Flupirtine base were dissolved in 1080 ml of Isopropanol at600C. 12.8 g of Maleic acid was dissolved in 96 ml of Isopropanol. 0.2 g of flupirtine maleate B crystals made according EP 977 736 Patent were added. Flupirtine maleate B was made according EP 977 736 through heating of part of maleat A for 2 h at 1500C. Maleic acid solution was added to Flupirtine solution at 600C in the course of stirring. The mixture was stirred for 2 minutes and cooled down to 170C. The sediment formed was filtered. The colour of the sediment was white. 40.9 g of the product was formed.
Stage #1: flupirtine maleate With sodium hydrogencarbonate In diethyl ether; water
Stage #2: With hydrogenchloride In diethyl ether; water
6.1; 6.2
Example 6: Preparation of 1 ; 1 Flupirtine Hydrochloride Maleic Acid Cocrystal by Milling and Its Characterization[00105] Example 6.1: Preparation of Flupirtine Free Base[00106] To a 250-mL separatory funnel containing 2.9 g (6.9 mmol) of flupirtine maleate was added 50 mL of diethyl ether. Saturated aqueous sodium bicarbonate (75 mL) was added, and the funnel was shaken vigorously. Additional diethyl ether (75 mL) and saturated aqueous sodium bicarbonate (25 mL) were added with shaking until almost all solids were dissolved. The top, ether layer, was removed and washed twice with 10-mL portions of water. The pH of the final wash water was approximately 5-6 (stick). The ether layer was dried by addition of solid magnesium sulfate. The resulting mixture was filtered through a 0,2-μm nylon filter into a clean glass round bottom flask. A precipitate formed in the filtered solution. Additional diethyl ether (30 mL) was added with stirring and the precipitate dissolved.[00107] Example 6.2: Preparation of Flupirtine Hydrochloride[00108] The solution of free base in diethyl ether from Example 6.1 was acidified by addition of 6.9 mL (6.9 mmol) of 1,0 N hydrochloric acid in diethyl ether over a few minutes. Precipitation occurred immediately on acid addition. The flask was covered with aluminum foil and the mixture was stirred overnight. Solids were recovered by vacuum filtration, washed with two 10-mL portions of diethyl ether , and allowed to dry in the filter funnel for several minutes to give 1.9 g (79% yield from flupirtine maleate) of flupirtine hydrochloride. X-ray powder diffraction analysis showed the solids to be a mixture of crystalline forms of flupirtine hydrochloride,
The processes described in Examples 2 to 4 were repeated under slightly different reaction conditions (such as varying the redox catalyst (e.g., Pt/C), the reducing system (e.g., a formate salt with redox catalyst or a dithionite salt without redox catalyst; cf. also Example 5), the ester solvent, the reaction temperatures and times, the amounts of reactants, and washing/purification reagents) and flupirtine maleate was obtained with yield and purity values similar to those presented above in Examples 2 to 4. For example, the following procedure has been used to prepare flupirtine maleate. A round bottom flask (1 L) was charged with acetonitrile (200 niL), followed by ANFP (20.0 g, 76 mmol), sodium dithionite (55.0 g, 315 mmol) and 29% aqueous ammonia (250 mL). The reaction mixture was stirred and gently heated at 36 to 37C for 60 min. The mixture was heated up to 44C over 35 min and then gradually cooled. The colour turned from yellow (starting material) to white. Acetonitrile, ammonia and water were removed by distillation at reduced pressure on a rotary evaporator. After distillation the mixture was diluted with water (100 mL) and ethyl acetate (310 mL) under a nitrogen stream. The water layer was separated and discarded. The air sensitive ethyl acetate layer was treated with ethyl chloroformate (14.5 mL, 151 mmol), while stirring and slowly flushing with nitrogen for 30 min. Triethylamine (25 mL, 179 mmol) was added and stirred for 30 min. An aqueous solution of maleic acid prepared from maleic acid (14.0 g, 120 mmol) and water (160 mL) was added to the reaction mixture. The mixture was maintained at 40C for 1 h, then cooled to 20C. The precipitate was collected by filtration, the vessel and the precipitate were washed with an additional portion of ethyl acetate (55 mL). The obtained wet product was dried in a vacuum drying oven at 50C, until the loss on drying was less than 1.0%. Yield: 29.5 g (94.3%> assay, 66.2 mmol; 87.1%> of theory); purity: 99.84%.
In an autoclave, 100 gm. 2-amino-3-nitro-6-p-fluorobenzylamino- pyridine is taken in 500 ml. 1, 4-dioxane and 20 ml aqueous ammonia solution. 10 gm of raney nickel is added under nitrogen atmosphere and hydrogenated at 75-80C for 2-3 hours under 4-5 kg pressure. After completion of the reaction, the reaction mass is cooled and filtered at 40- 45Cthen in filtrate 45 ml of ethyl chloroformate is added slowly at 5- 10C. The temperature is raised to 25-30C and 80 ml triethyl amine is added under nitrogen atmosphere. The reaction mass, is heated at 55- 60C under stirring for 3-4 hours. After completion of the reaction, the reaction mass is distilled up to 70-80% under vacuum. This concentrated reaction mass is added into aqueous solution of maleic acid (72 gm in 2000 ml DM water at 65-70C and maintained at 65-70C for 2 hours under nitrogen to get crude Flupirtine Maleate as a solid. The reaction mass is cooled to 25-30C in 5-6 hours and maintained at this temperature for next 2-3 hours then filtered. The wet cake is washed with 200 ml water and dried to get 145 gm of flupirtine maleate.
Stage #1: chloroformic acid ethyl ester; N<SUP>6</SUP>-(4-fluorobenzyl)pyridine-2,3,6-triamine With triethylamine In isopropyl alcohol at 40 - 50℃; Inert atmosphere; Large scale;
Stage #2: maleic acid for 5h; Inert atmosphere; Large scale;
15
24.7kg adding isopropanol in an autoclave, intermediate 5.86kg, Raney nickel 0.826kg, sealed autoclave, after nitrogen gas was hydrogen, the temperature controlled at ≤70 , hydrogen pressure control 3.0 ~ 4.0Mpa hydrogenation.After the hydrogenation, under nitrogen, was added dropwise temperature ≤40 ethyl 2596ml, stirred for 0.3 hours, triethylamine was added rapidly dropwise 3972ml.0.5Mpa nitrogen under 40 ~ 50 stirred overnight incubation with nitrogen filtered and the filtrate was added rapidly stirred aqueous solution of maleic acid state, the above crystallization five hours, centrifuged solid, temperature controlled at 60 ~ 70 , dried 5 to 8 hours to give flupirtine maleate crude.Refining: 0.109kg with 86.7kg of methanol and maleic acid to dissolve the crude product, obtained after recrystallization flupirtine maleate 4.24kg, 78.2% yield, 99.5% purity.
Stage #1: flupirtine hydrochloride In water at 70℃;
Stage #2: With triethylamine at 45℃; Inert atmosphere;
Stage #3: maleic acid In ethanol at 20 - 65℃; for 1h;
6 Example 6: Preparation of flupirtine maleate (Compound 6)
To a reaction flask with 300mL of water, 34.08g of compound 5 was added with stirring and the mixture was heated to 70 °C then was filtered. The filtrates were cooled to about 45°C under N2 protection and dropping triethylamine to adjust the pH to 8-9 then was filtered. The filtrates was dissolved in 100.00mL ethanol and heated to 65°C, then dropping 11.60g of maleic acid dissolved in 20mL ethanol solution then cooled to 20-25°C, continue stirring for 1hr then filtered and dried to obtain 33.21g of Compound 6 with a yield of 79.0%, purity 99.9% (HPLC), single impurity less than 0.1%.
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