CN103086963A - Synthetic method of flupirtine maleate A-type crystal compound and midbody - Google Patents
Synthetic method of flupirtine maleate A-type crystal compound and midbody Download PDFInfo
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Abstract
The invention discloses a synthetic method of flupirtine maleate A-type crystal compound and midbody. The synthetic method comprises the following steps of (1) synthetizing 2-amino-3-nitryl-6-p-fluorobenzyl aminopyridine by fluorobenzylamine and 2-amino-3-nitryl-6-chloropyridine organic alkali; (2) carrying out mixing and reduction reaction on the 2-amino-3-nitryl-6-p-fluorobenzyl aminopyridine, a catalyst and a solvent to obtain 2,3-diamido-6-p-fluorobenzyl aminopyridine; (3) reacting by the 2,3-diamido-6-p-fluorobenzyl aminopyridine, ethyl chloroformate and the organic alkali to obtain flupirtine, and continuing to add maleic acid aqueous solution to obtain flupirtine maleate-2-amino-6-(((4-fluorophenyl)methyl)amino)-3-pyridyl) ethyl carbamate maleate crude product; and (4) recrystallizing the 2-amino-6-(((4-fluorophenyl)methyl)amino)-3-pyridyl) ethyl carbamate maleate crude product by methanol or ethanol to obtain pure A-type crystal flupirtine maleate. The synthetic method has the beneficial effects that the water supply volume is reduced; the operation is safe; the reaction step is shortened; and the A-type flupirtine maleate is high in purity.
Description
Technical field
The invention belongs to the chemicals field, be specifically related to the synthetic method of flupirtine maleate A crystal formation compound and the synthetic method of intermediate.
Background technology
Flupirtine maleate (Flupirtine Maleate) chemistry 2-amino-6-(((4-fluorophenyl) methyl) amino) by name-3-pyridyl) urethanum maleate, as shown in the structural formula I:
Ⅰ
Flupirtine maleate is a kind of novel non-opium central analgesics of German AWD company development, oral easy absorption.Its mechanism of action is a kind of selectivity neuron potassium channel openers, has pain relieving, of flaccid muscles and neuroprotective three efficacy.The experimentation on animals demonstration, flupirtine all has analgesic activity in the multiple pain model experiment such as mouse, rat hot plate method, dental pulp electrostimulation.Its analgesia intensity (ED50) is weaker than methadone, buprenorphine and morphine, and is suitable with pentazocine, is better than Pethidine, morphine monomethyl ether, Phenacetin and paracetamol.As in the hot plate method experiment, the action intensity of flupirtine maleate (ED50 is 32mg/Kg, gastric infusion) is approximately half of morphine, is 2 times of morphine monomethyl ether, and is stronger 10 times than Phenacetin and Paracetamol.In conscious dogs dental pulp electricity irritation experiment, analgesia intensity (ED50 is 3.5mg/Kg, gastric infusion) is suitable with pentazocine, its analgesic activity 30min peaking after administration, and effect continues 75min at least.The analgesic activity of flupirtine maleate is to mediate by maincenter.The receptors bind of flupirtine maleate and main metabolites thereof studies show that, flupirtine maleate and opiate receptor almost without or there is no avidity, belong to nonopioid analgesic, do not have habituation.
There is the synthetic method of reported in literature flupirtine maleate to be: to use 2-amino-3-nitro-6-chloropyridine and NSC 158269 using anhydrous sodium carbonate as acid binding agent, alcohols is as preparing 2-amino-3-nitro-6-under solvent condition to the luorobenzyl aminopyridine, make 2 through Hydrogenation again, 3-diamino-6-is to the luorobenzyl aminopyridine, obtain flupirtine as solvent with the Vinyl chloroformate reaction with dioxane again, with the toxilic acid salify, make the flupirtine maleate finished product at last.This synthetic method need to use large water gaging to remove the inorganic salt of generation when preparing 2-amino-3-nitro-6-to the luorobenzyl aminopyridine, produces a large amount of waste water, and manufacturing enterprise's environmental protection is posed a big pressure; Need to use reaction under high pressure at preparation 2,3-diamino-6-to the luorobenzyl aminopyridine, have potential safety hazard; Total reactions steps is long, and three industrial wastes are many, and production cost is high, is not suitable for large-scale industrial production.
US Patent specification US4481205 has described the crystal formation of flupirtine maleate the earliest, and the polymorphous existence of flupirtine maleate has been described, and discloses the preparation method of crystal form B.
Once there was reported in literature to use the method for Virahol recrystallization to prepare the flupirtine maleate of A crystal formation.But when the Virahol recrystallization, turn brilliant process need for a long time, and can not obtain high purity A crystal formation flupirtine maleate sample, simultaneously because solubleness is too small, its refining effect to impurity is very poor, is not easy to obtain the flupirtine maleate product of low impurity.
Summary of the invention
The purpose of this invention is to provide a kind of intermediate 2-amino-3-nitro-6-to the synthetic method of luorobenzyl aminopyridine, use organic basic compound to replace mineral alkali of the prior art in reaction process, overcome the large deficiency of prior art water consumption.
Another object of the present invention is to provide a kind of intermediate 2, the synthetic method of 3-diamino-6-to the luorobenzyl aminopyridine, and overcoming prior art also needs to use the shortcoming of heavy metal catalyst and condition of high voltage in former reaction.
Another purpose of the present invention is to provide a kind of method for preparing high purity Malaysia acid flupirtine.With the Toxic dioxane that uses in ethanol replacement prior art, eliminate the pollution to environment.
A further object of the present invention is to provide a kind of method for preparing high purity Malaysia acid flupirtine A crystal form.Use ethanol to replace Virahol, overcome the deficiency that the prior art waste liquid amount is large, product purity is low.
Intermediate 2-amino of the present invention-3-nitro-6-to the synthetic method of luorobenzyl aminopyridine is: reaction under organic bases exists obtains with NSC 158269 and 2-amino-3-nitro-6-chloropyridine, and reaction formula is:
Wherein:
Ingredient proportion is NSC 158269: 2-amino-3-nitro-6-chloropyridine: organic bases mol ratio 1:0.8 ~ 2:0.8 ~ 4;
Organic bases is that triethylamine, pyridine or both mol ratios are the mixture of 1:0.02 ~ 2;
Reaction solvent be methyl alcohol, ethanol, Virahol or with the mixture of water arbitrary proportion, usage quantity should be 1 ~ 10 times of volume of NSC 158269 quality; Reaction conditions is 40 ~ 90 ℃ of temperature, 1 ~ 6 hour reaction times.
Intermediate 2 of the present invention, 3-diamino-6-to the synthetic method of luorobenzyl aminopyridine is: add catalyzer and solvent to carry out reduction reaction to the luorobenzyl aminopyridine 2-amino-3-nitro-6-, after reaction, acid adding gets in conjunction with salify, and reaction formula is:
Wherein:
2-amino-3-nitro-6-is to the routine 1:0.1 ~ 4:1 of the molar ratio of luorobenzyl aminopyridine, catalyzer, hydrazine hydrate ~ 20;
Use catalyzer be trivalent inorganic molysite and Mixture of Activated Carbon, be preferably the Mixture of Activated Carbon of iron trichloride, ironic hydroxide or both mixtures, in the mixture preparation process, the molar ratio of trivalent inorganic molysite, sodium hydroxide and activated carbon example is 1:0.5 ~ 2:2 ~ 20.In catalyzer, the mass ratio of iron trichloride or ironic hydroxide and gac is 1:1 ~ 5;
The reductive agent that uses is hydrazine hydrate, and hydrazine hydrate concentration is 10% ~ 80%, is preferably 80%;
The solvent that uses as methyl alcohol, ethanol, Virahol or with the mixture of water arbitrary proportion, solvent load is for being 1 ~ 40 times volume of input 2-amino-3-nitro-6-to luorobenzyl aminopyridine quality;
Reaction conditions is 20 ~ 90 ℃ of temperature, and the reaction times is 1 ~ 4 hour;
Gains and acid are combined into hydrochloride, acetate, the form of the salt such as vitriol.
The synthetic method of flupirtine maleate of the present invention comprises the following steps:.
1, NSC 158269 and 2-amino-3-nitro-6-chloropyridine under existing, organic bases are synthesized 2-amino-3-nitro-6-to the luorobenzyl aminopyridine, wherein:
Ingredient proportion is NSC 158269: 2-amino-3-nitro-6-chloropyridine: the mol ratio 1:0.8 of organic bases ~ 2:0.8 ~ 4;
The organic bases that uses is triethylamine, pyridine or both mol ratios mixture as 1:0.02 ~ 2;
The solvent that uses as methyl alcohol, ethanol, Virahol or with the mixture of water arbitrary proportion, the usage quantity of solvent should be 1 ~ 10 times of volume of NSC 158269 quality.
Reaction conditions is 40 ~ 90 ℃ of temperature, 1 ~ 6 hour reaction times.
2, the 2-amino of step 1 gained-3-nitro-6-being carried out reduction reaction to luorobenzyl aminopyridine and catalyzer and solvent gets 2,3-diamino-6-and is combined the form of salify to the luorobenzyl aminopyridine and with acid;
Wherein:
Ingredient proportion is 2-amino-3-nitro-6-to the mol ratio 1:0.1 of luorobenzyl aminopyridine, catalyzer, hydrazine hydrate ~ 4:1 ~ 20;
The catalyzer that uses is the Mixture of Activated Carbon of trivalent inorganic molysite, be preferably the Mixture of Activated Carbon of iron trichloride, ironic hydroxide or both mixtures, in the mixture preparation process, the molar ratio of trivalent inorganic molysite, sodium hydroxide and activated carbon example is 1:0.5 ~ 2:2 ~ 20, and in catalyzer, the mass ratio of iron trichloride or ironic hydroxide and gac is 1:1 ~ 5;
The reductive agent that uses is hydrazine hydrate, and hydrazine hydrate concentration is 10% ~ 80%, is preferably 80%;
The solvent that uses as methyl alcohol, ethanol, Virahol or with the mixture of water arbitrary proportion, the solvent ingredient proportion is that 2-amino-3-nitro-6-is to 1 ~ 40 times of volume of luorobenzyl aminopyridine quality;
Reaction conditions is 20 ~ 90 ℃ of temperature, and the reaction times is 1 ~ 4 hour;
To synthesize gains and be combined into hydrochloride, acetate, the form of the salt such as vitriol is preferably hydrochloride.
3, with 2,3-diamino-6-obtains flupirtine to luorobenzyl aminopyridine and Vinyl chloroformate and organic bases reaction, and continue to add the toxilic acid aqueous solution to get flupirtine maleate-2-amino-6-(((4-fluorophenyl) methyl) amino)-3-pyridyl) urethanum maleate crude product, reaction formula is:
Wherein:
Ingredient proportion is 2,3-diamino-6-to luorobenzyl aminopyridine, organic bases: Vinyl chloroformate: toxilic acid mol ratio 1:0.8 ~ 3.5:0.5 ~ 2:0.5 ~ 3;
The organic bases that uses is pyridine or triethylamine;
The solvent that uses as methyl alcohol, ethanol, Virahol or with the mixture of water arbitrary proportion, the solvent ingredient proportion is that 2,3-diamino-6-is to 1 ~ 10 times of volume of luorobenzyl aminopyridine quality;
Reaction conditions is 0 ~ 80 ℃ of temperature, and the reaction times is 1 ~ 4 hour;
The crystallization method of flupirtine maleate A crystal formation compound of the present invention is:
With 2-amino-6-(((4-fluorophenyl) methyl) amino)-3-pyridyl) urethanum maleate crude product obtains pure A crystal formation flupirtine maleate with methyl alcohol or ethyl alcohol recrystallization
Wherein:
The methyl alcohol that is used or alcohol solvent are 2-amino-6-(((4-fluorophenyl) methyl) amino)-3-pyridyl) 5 ~ 40 times of volumes of urethanum maleate crude product quality.
Reaction conditions is 0 ~ 90 ℃ of temperature, and the reaction times is 1 ~ 10 hour.
By the synthetic flupirtine maleate bulk drug the Nomenclature Composition and Structure of Complexes of this synthesis technique, adopted nuclear-magnetism and X-ray diffraction for conclusive evidence, with documents and materials relatively, composition and the structure of trial-product characterized, confirm its chemical structure and crystal formation.
Nucleus magnetic hydrogen spectrum is table as a result
Beneficial effect of the present invention is: ⑴ 2-amino-3-nitro-6-has reduced the consumption of aftertreatment link water to the organic basess such as synthetic method use triethylamine of luorobenzyl aminopyridine, reduced the difficulty of wastewater treatment, it is original 1/3 that wastewater flow rate is reduced to, environmental protection more.⑵ 2, use iron trichloride/gac or ironic hydroxide/activated-carbon catalyst in the synthetic method of 3-diamino-6-to the luorobenzyl aminopyridine, and reductive agent uses hydrazine hydrate, avoid using palladium carbon, the reaction of Raney's nickel high-pressure hydrogenation, and operational safety is convenient.⑶ intermediate 2,3-diamino-6-is salt to luorobenzyl aminopyridine end form attitude, has avoided 2,3-diamino-6-to the amino pyrrole of the luorobenzyl risk of Oxidative demage very easily.Use one kettle way directly by 2,3-diamino-6-to luorobenzyl aminopyridine salt, directly be prepared into flupirtine maleate, shortened reactions steps.⑸ do not re-use dioxane as solvent, greatly reduces the waste liquid amount of output, more safety and environmental protection.⑹ recrystallization in methyl alcohol or ethanol obtains pure A crystal formation flupirtine maleate, and environmental pollution is little, has reduced the residual solvent kind, has improved quality product.
Description of drawings
Fig. 1 is the flupirtine maleate nucleus magnetic hydrogen spectrum.
Fig. 2 is flupirtine maleate A crystal form X ray diffraction collection of illustrative plates
Embodiment
2-amino-3-nitro-6-chloropyridine 100g, triethylamine 87.5g, pyridine 20g and ethanol 400ml are joined in there-necked flask, be heated under stirring reflux, slowly drip NSC 158269 80g, reacted 3 ~ 4 hours, react complete rear dropping purified water 500ml, slowly cool to room temperature under stirring, filter, dry 2-amino-3-nitro-6-to the luorobenzyl aminopyridine.
Ferric chloride (FeCl36H2O) 41g is dissolved in purified water 500ml, adds gac 77.5g, be heated to 50 ℃, add sodium hydroxide saturated solution 30g(16g dissolution of sodium hydroxide in 14ml water), 60 ℃ were stirred 1 hour, and were down to room temperature, filter, dry to get ironic hydroxide/activated-carbon catalyst.
2-amino-3-nitro-6-is joined in the 2L reaction flask luorobenzyl aminopyridine 104.8g, ironic hydroxide/activated-carbon catalyst 54.4g, add 95% ethanol 1600ml, be heated to 70 ~ 90 ℃ under stirring.Insulation drips 80% hydrazine hydrate 196g.Drip Bi Jixu insulation reaction 1h-3h.Reaction finishes the reaction solution heat filtering to the reaction flask that concentrated hydrochloric acid 240ml and 95% ethanol 1000ml are housed.0 ~ 10 ℃ of crystallization 2 hours filters, dry 2,3-diamino-6-is to the luorobenzyl aminopyridine hydrochloride.
2,3-diamino-6-is joined in the 2L reaction flask luorobenzyl aminopyridine hydrochloride 132g, Virahol 1100ml, and temperature control to 20 slowly drips Vinyl chloroformate 47g to 30 ℃.Stirred 0.5 hour, and slowly dripped triethylamine 90g, stir after 0.5 hour, add Vinyl chloroformate 9.4g, stirred 15 minutes, add remaining triethylamine 20g.Continue to stir 1 hour.With the reaction solution concentrating under reduced pressure, steam approximately 800ml distillate.Remaining reaction solution is poured into (the 39g toxilic acid is dissolved in the 1100ml purified water) in the toxilic acid aqueous solution for preparing, stirring at normal temperature 30 minutes, 0 ~ 5 ℃ was stirred 5 ~ 8 hours.Filter, dry to get the flupirtine maleate crude product.
With flupirtine maleate crude product 100g, dehydrated alcohol 2000ml drops into reaction flask, is heated to 70～80 ℃, adds the 5g gac after dissolving, is incubated 1 hour, heat filtering, and 0～5 ℃ of crystallization 3 hours filters, and dries to get the crude product I.Crude product I 90g, dehydrated alcohol 3600ml are dropped into reaction flask, be heated to dissolving, slow cooling to 55～58 ℃ add crystal seed, slowly are being down to room temperature, and 0～5 ℃ of insulation 2 hours is filtered, and dries to get A crystal formation flupirtine maleate finished product.
2-amino-3-nitro-6-chloropyridine 98g, triethylamine 63.7g, pyridine 5g and ethanol 200ml are joined in there-necked flask, be heated under stirring reflux, slowly drip NSC 158269 80g, reacted 5 hours, react complete rear dropping purified water 500ml, slowly cool to room temperature under stirring, filter, dry 2-amino-3-nitro-6-to the luorobenzyl aminopyridine.
Ferric chloride (FeCl36H2O) 41g is dissolved in purified water 1000ml, adds gac 300g, be heated to 50 ℃, add sodium hydroxide saturated solution 90g(48g dissolution of sodium hydroxide in 42ml water), 60 ℃ were stirred 1 hour, and were down to room temperature, filter, dry to get ironic hydroxide/activated-carbon catalyst.
2-amino-3-nitro-6-is joined in the 2L reaction flask luorobenzyl aminopyridine 104.8g, ironic hydroxide/activated-carbon catalyst 80g, add 95% ethanol 2000ml, be heated to 70 ~ 90 ℃ under stirring.Insulation drips 80% hydrazine hydrate 120g.Drip Bi Jixu insulation reaction 3h.Reaction finishes the reaction solution heat filtering to the reaction flask that concentrated hydrochloric acid 240ml and 95% ethanol 1000ml are housed.0 ~ 10 ℃ of crystallization 2 hours filters, dry 2,3-diamino-6-is to the luorobenzyl aminopyridine hydrochloride.
2,3-diamino-6-is joined in the 2L reaction flask luorobenzyl aminopyridine hydrochloride 132g, Virahol 1300ml, and temperature control to 20 slowly drips Vinyl chloroformate 55g to 22 ℃.Stirred 0.5 hour, and slowly dripped triethylamine 120g, stir after 0.5 hour, add Vinyl chloroformate 12g, stirred 15 minutes, add remaining triethylamine 40g.Continue to stir 1 hour.With the reaction solution concentrating under reduced pressure, steam approximately 800ml distillate.Remaining reaction solution is poured into (the 50g toxilic acid is dissolved in the 1100ml purified water) in the toxilic acid aqueous solution for preparing, stirring at normal temperature 30 minutes, 0 ~ 5 ℃ was stirred 5 ~ 8 hours.Filter, dry to get the flupirtine maleate crude product.
With flupirtine maleate crude product 100g, dehydrated alcohol 2000ml drops into reaction flask, is heated to 70～80 ℃, adds the 5g gac after dissolving, is incubated 1 hour, heat filtering, and 0～5 ℃ of crystallization 3 hours filters, and dries to get the crude product I.Crude product I 90g, dehydrated alcohol 1600ml are dropped into reaction flask, heating 15h, more slowly be down to room temperature, 0～5 ℃ is incubated 2 hours, filters, and dries to get A crystal formation flupirtine maleate finished product.
2-amino-3-nitro-6-chloropyridine 246g, triethylamine 254g and ethanol 800ml are joined in there-necked flask, be heated under stirring reflux, slowly drip NSC 158269 80g, reacted 6 hours, react complete rear dropping purified water 500ml, slowly cool to room temperature under stirring, filter, dry 2-amino-3-nitro-6-to the luorobenzyl aminopyridine.
Ferric chloride (FeCl36H2O) 41g is dissolved in purified water 200ml, adds gac 20g, be heated to 50 ℃, add sodium hydroxide saturated solution 45g(24g dissolution of sodium hydroxide in 21ml water), 60 ℃ were stirred 1 hour, and were down to room temperature, filter, dry to get ironic hydroxide/activated-carbon catalyst.
2-amino-3-nitro-6-is joined in the 2L reaction flask luorobenzyl aminopyridine 104.8g, ironic hydroxide/activated-carbon catalyst 20g, add 95% ethanol 1200ml, be heated to 90 ℃ under stirring.Insulation drips 60% hydrazine hydrate 250g.Drip Bi Jixu insulation reaction 3h.Reaction finishes the reaction solution heat filtering to the reaction flask that concentrated hydrochloric acid 240ml and 95% ethanol 1000ml are housed.0 ~ 10 ℃ of crystallization 1 hour filters, dry 2,3-diamino-6-is to the luorobenzyl aminopyridine hydrochloride.
2,3-diamino-6-is joined in the 2L reaction flask luorobenzyl aminopyridine hydrochloride 132g, Virahol 800ml, and temperature control to 28 slowly drips Vinyl chloroformate 39g to 30 ℃.Stirred 0.5 hour, and slowly dripped triethylamine 70g, stir after 0.5 hour, add Vinyl chloroformate 5g, stirred 15 minutes, add remaining triethylamine 10g.Continue to stir 1 hour.With the reaction solution concentrating under reduced pressure, steam approximately 800ml distillate.Remaining reaction solution is poured into (the 39g toxilic acid is dissolved in the 1100ml purified water) in the toxilic acid aqueous solution for preparing, stirring at normal temperature 30 minutes, 0 ~ 5 ℃ was stirred 5 ~ 8 hours.Filter, dry to get the flupirtine maleate crude product.
With flupirtine maleate crude product 100g, dehydrated alcohol 2000ml drops into reaction flask, is heated to 70～80 ℃, adds the 5g gac after dissolving, is incubated 1 hour, heat filtering, and 0～5 ℃ of crystallization 3 hours filters, and dries to get the crude product I.Crude product I 90g, dehydrated alcohol 450ml are dropped into reaction flask, heating 20h, more slowly be down to room temperature, 0～5 ℃ is incubated 2 hours, filters, and dries to get A crystal formation flupirtine maleate finished product.
Claims (4)
1. the intermediate 2-amino for the synthesis of flupirtine maleate-3-nitro-6-synthetic method to the luorobenzyl aminopyridine, it is characterized in that: reaction under organic bases exists obtains with NSC 158269 and 2-amino-3-nitro-6-chloropyridine, and reaction formula is:
Wherein:
Ingredient proportion is NSC 158269: 2-amino-3-nitro-6-chloropyridine: organic bases mol ratio 1:0.8 ~ 2:0.8 ~ 4;
Organic bases is that triethylamine, pyridine or both mol ratios are the mixture of 1:0.02 ~ 2;
Reaction solvent be methyl alcohol, ethanol, Virahol or with the mixture of water arbitrary proportion, usage quantity should be 1 ~ 10 times of volume of NSC 158269 quality; Reaction conditions is 40 ~ 90 ℃ of temperature, 1 ~ 6 hour reaction times.
2. intermediate 2 for the synthesis of flupirtine maleate, the synthetic method of 3-diamino-6-to the luorobenzyl aminopyridine, it is characterized in that: add catalyzer and solvent to carry out reduction reaction to the luorobenzyl aminopyridine 2-amino-3-nitro-6-, after reaction, acid adding gets in conjunction with salify, and reaction formula is:
Wherein:
2-amino-3-nitro-6-is to the routine 1:0.1 ~ 4:1 of the molar ratio of luorobenzyl aminopyridine, catalyzer, hydrazine hydrate ~ 20;
Use catalyzer be trivalent inorganic molysite and Mixture of Activated Carbon, be preferably the Mixture of Activated Carbon of iron trichloride, ironic hydroxide or both mixtures, in the mixture preparation process, the molar ratio of trivalent inorganic molysite, sodium hydroxide and activated carbon example is 1:0.5 ~ 2:2 ~ 20, and in catalyzer, the mass ratio of iron trichloride or ironic hydroxide and gac is 1:1 ~ 5;
The reductive agent that uses is hydrazine hydrate, and hydrazine hydrate concentration is 10% ~ 80%, is preferably 80%;
The solvent that uses as methyl alcohol, ethanol, Virahol or with the mixture of water arbitrary proportion, solvent load is for being 1 ~ 40 times volume of input 2-amino-3-nitro-6-to luorobenzyl aminopyridine quality;
Reaction conditions is 20 ~ 90 ℃ of temperature, and the reaction times is 1 ~ 4 hour;
Gains and acid are combined into hydrochloride, acetate, the form of the salt such as vitriol.
3. the synthetic method of a flupirtine maleate is characterized in that comprising the following steps:
(1) under existing, organic bases synthesizes 2-amino-3-nitro-6-to the luorobenzyl aminopyridine with NSC 158269 and 2-amino-3-nitro-6-chloropyridine,
Wherein:
Ingredient proportion is NSC 158269: 2-amino-3-nitro-6-chloropyridine: the mol ratio 1:0.8 of organic bases ~ 2:0.8 ~ 4; The organic bases that uses is triethylamine, pyridine or both mol ratios mixture as 1:0.02 ~ 2;
The solvent that uses as methyl alcohol, ethanol, Virahol or with the mixture of water arbitrary proportion, the usage quantity of solvent should be 1 ~ 10 times of volume of NSC 158269 quality;
Reaction conditions is 40 ~ 90 ℃ of temperature, 1 ~ 6 hour reaction times;
(2) with the 2-amino of step (1) gained-3-nitro-6-, luorobenzyl aminopyridine and catalyzer and solvent being carried out reduction reaction gets 2,3-diamino-6-and is combined the form of salify to the luorobenzyl aminopyridine and with acid;
Wherein:
Ingredient proportion is 2-amino-3-nitro-6-to the mol ratio 1:0.1 of luorobenzyl aminopyridine, catalyzer, hydrazine hydrate ~ 4:1 ~ 20;
The catalyzer that uses is the Mixture of Activated Carbon of trivalent inorganic molysite, be preferably the Mixture of Activated Carbon of iron trichloride, ironic hydroxide or both mixtures, in the mixture preparation process, the molar ratio of trivalent inorganic molysite, sodium hydroxide and activated carbon example is 1:0.5 ~ 2:2 ~ 20, and in catalyzer, the mass ratio of iron trichloride or ironic hydroxide and gac is 1:1 ~ 5;
The reductive agent that uses is hydrazine hydrate, and hydrazine hydrate concentration is 10% ~ 80%, is preferably 80%;
The solvent that uses as methyl alcohol, ethanol, Virahol or with the mixture of water arbitrary proportion, the solvent ingredient proportion is that 2-amino-3-nitro-6-is to 1 ~ 40 times of volume of luorobenzyl aminopyridine quality;
Reaction conditions is 20 ~ 90 ℃ of temperature, and the reaction times is 1 ~ 4 hour;
To synthesize gains and be combined into hydrochloride, acetate, the form of the salt such as vitriol is preferably hydrochloride;
(3) with 2 of step (2) gained, 3-diamino-6-obtains flupirtine to luorobenzyl aminopyridine and Vinyl chloroformate and organic bases reaction, and continue to add the toxilic acid aqueous solution to get flupirtine maleate-2-amino-6-(((4-fluorophenyl) methyl) amino)-3-pyridyl) urethanum maleate crude product, reaction formula is:
Wherein:
Ingredient proportion is 2,3-diamino-6-to luorobenzyl aminopyridine, organic bases: Vinyl chloroformate: toxilic acid mol ratio 1:0.8 ~ 3.5:0.5 ~ 2:0.5 ~ 3;
The organic bases that uses is pyridine or triethylamine;
The solvent that uses as methyl alcohol, ethanol, Virahol or with the mixture of water arbitrary proportion, the solvent ingredient proportion is that 2,3-diamino-6-is to 1 ~ 10 times of volume of luorobenzyl aminopyridine quality;
Reaction conditions is 0 ~ 80 ℃ of temperature, and the reaction times is 1 ~ 4 hour.
4. the crystallization method of flupirtine maleate A crystal formation compound is characterized in that:
With 2-amino-6-(((4-fluorophenyl) methyl) amino)-3-pyridyl) urethanum maleate crude product obtains pure A crystal formation flupirtine maleate with methyl alcohol or ethyl alcohol recrystallization;
Wherein:
The methyl alcohol that is used or alcohol solvent are 2-amino-6-(((4-fluorophenyl) methyl) amino)-3-pyridyl) 5 ~ 40 times of volumes of urethanum maleate crude product quality;
Reaction conditions is 0 ~ 90 ℃ of temperature, and the reaction times is 1 ~ 10 hour.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104974087A (en) * | 2015-01-30 | 2015-10-14 | 吉林修正药业新药开发有限公司 | Synthesis method of flupirtine dimer |
| CN110317167A (en) * | 2019-08-17 | 2019-10-11 | 西安都创医药科技有限公司 | A kind of preparation method of Flupirtine derivative and its inorganic acid salt |
| WO2023098592A1 (en) * | 2021-11-30 | 2023-06-08 | 奥锐特药业股份有限公司 | Preparation method for carbon-loaded iron-based catalyst and use thereof in synthesis of intermediates of anti-cancer inhibitors |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US4481205A (en) * | 1980-09-13 | 1984-11-06 | Degussa Aktiengesellschaft | 2-Amino-3-carbethoxyamino-6-(p-fluoro-benzylamino)-pyridine-maleate |
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| WO2023098592A1 (en) * | 2021-11-30 | 2023-06-08 | 奥锐特药业股份有限公司 | Preparation method for carbon-loaded iron-based catalyst and use thereof in synthesis of intermediates of anti-cancer inhibitors |
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