CN109053563A - A method of preparing hydrochloric acid Flupirtine - Google Patents
A method of preparing hydrochloric acid Flupirtine Download PDFInfo
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
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Abstract
The invention discloses a kind of methods for preparing hydrochloric acid Flupirtine, are specially starting material using 2,6- dichloro-3-nitropyridine; through ammonolysis, 4-Fluorobenzylamine replaces, purifying; it is hydrogenated simultaneously, acylation reaction, through filtering, crystallization, is dried under reduced pressure to obtain hydrochloric acid Flupirtine.The method of the present invention is easy to operate, while carrying out hydrogenation and acylation reaction, the situation that can avoid polyamino pyridine derivate rotten as far as possible, carries out dropwise addition ethyl chloroformate without kettle cover is opened, reduces the injury to human body.
Description
Technical field
The application belongs to chemicals preparation technical field, and in particular to a kind of method of synthetic hydrochloric acid Flupirtine.
Background technique
Flupirtine maleate, chemical name: 2- amino -3- acyl group ethyoxyl amino -6- divides luorobenzyl pyridine maleate
Minor: C19H21FN4O6；Molecular weight: 420.21；Its structural formula is as follows:
Flupirtine maleate is a kind of central nonopioid analgesic developed by German AWD company, is triamido pyrrole
Pyridine class compound, mechanism of action are as follows: flupirtine maleate is a kind of selection sexual centre K ~+Channel Opener, is had simultaneously
Indirect asparatate (NMDA) receptor antagonist attribute, can activate G- G-protein linked receptor and stimulate the potassium of nerve cell from
Subchannel, cause neuron membrane hyperpolarization and neuronal excitability reduce so that tranquillization neuron membrane stabilize from
And reach analgesic purpose.Its analgesic activity is independent of any central opiate sample substance, not by naloxone antagonism, will not induce and appoint
What relies on or is not necessarily to increase dosage to maintain clinical efficacy and known opiate receptor not to have any compatibility.In addition,
Serotonin receptor antagonist will not inhibit its analgesic effect, not have relevant compatibility to α 1- or α 2- adrenocepter,
There is good tolerance in clinical use.Flupirtine adverse reaction is few and it is slight, it is accidental out of strength, drowsy, dizzy, nauseous
And appetite stimulator.
From the point of view of the comprehensive reported preparation method in relation to flupirtine maleate, currently, being widely used with the chloro- 3- of 2,6- bis-
Nitropyridine is starting material, obtains key intermediate 2- amino -3- nitro -6- chloropyridine through ammonolysis, then take through 6 4-Fluorobenzylamines
In generation, restores, acylated, and flupirtine maleate is made at processes such as salt.In the process, some prior arts prompt can pass through elder generation
Synthetic hydrochloric acid Flupirtine obtains flupirtine maleate by reacting final with maleic acid again, and hydrochloric acid Flupirtine is synthesis maleic acid fluorine
The key intermediate in pyrrole spit of fland.
Hydrochloric acid Flupirtine, C15H18FN4O2Cl；Chemical name: 2- amino -3- acyl group ethyoxyl amino -6- is to luorobenzyl pyridine
Hydrochloride, structural formula are as follows:
Chinese patent CN105541705A discloses a kind of method by preparing hydrochloric acid Flupirtine.With 2- amino -3- nitre
Base -6- chloropyridine is raw material through being condensed with 4-Fluorobenzylamine, protects amino with di-tert-butyl dicarbonate, palladium chloride makees catalyst hydrogenation
Reduction, ethyl chloroformate is acylated, prepares hydrochloric acid Flupirtine with hydrochloric acid deprotection.But 2- amino -3- nitro -6- chloropyridine price is high
Expensive, production cost is higher.And hydrogenation and acylation process are cumbersome, and hydrogenated products are again very apt to deteriorate, are unfavorable for subsequent reactions.
Reaction ethyl chloroformate also belongs to hypertoxic control class hazardous chemical, opens kettle cover and is added dropwise, big to human injury, and to environment
It is unfriendly.The yield of the patent hydrochloric acid Flupirtine is using protected 2- amino -3- nitro -6- 4-Fluorobenzylamine yl pyridines as base
What standard calculated.The yield cannot can be regarded as the yield of entire route.
Document J.Med.Chem.1994,37,3016-3022 reports the compound including a kind of Flupirtine containing hydrochloric acid
General formula preparation method, with 2,6- dichloro-3-nitropyridine be starting material, obtain key intermediate 2- amino -3- through ammonolysis
Nitro -6- chloropyridine.Substitution reaction occurs with benzyl amine derivative again, is restored using Raney's nickel as catalyst hydrogenation, acylating agent acyl
Change prepares hydrochloric acid Flupirtine.A kind of synthetic intermediate 2- amino -3- nitro -6- is merely provided in document to fluorobenzylamino pyrrole
The route of piperidine derivatives, there is no disclose specific reaction condition.And high-risk material Raney's nickel has been used in catalytic hydrogenation reaction,
Raney's nickel is inflammable, and risk is high.
Therefore, it is simple to still need to provide a kind of preparation process for this field, small to human injury, environmentally friendly to prepare salt
The technique of sour Flupirtine, and the present invention meets such demand.
Summary of the invention
In order to solve the above technical problems, the present invention provides a kind of method of synthetic hydrochloric acid Flupirtine, whole process operation
Simply, production cost is reduced, injury of the ethyl chloroformate to human body is reduced.
The present invention provides a kind of preparation methods of hydrochloric acid Flupirtine, to key intermediate 2- amino -3- nitro -6- to fluorine
Benzylamino pyridine carries out " one kettle way " and simplifies production operation directly using excessive ammonium hydroxide as acid binding agent.It is produced into reduce
This, is starting material using 2,6- dichloro-3-nitropyridine；To obtain the product of high-purity, to key intermediate 2- amino -3-
Nitro -6- purifies fluorobenzylamino pyridine.To avoid step-by-step processing from bringing intermediate 2,3- diamino -6- 4-Fluorobenzylamine
The injury of pyridine and Flupirtine easy oxidation discoloration and reduction ethyl chloroformate to human body, is carried out " one kettle way "；By ethyl chloroformate,
2- amino -3- nitro -6- is to fluorobenzylamino pyridine, and palladium carbon, fatty alcohol put into reaction kettle together while being hydrogenated, acyl
Change reaction.
The present invention is achieved by the following technical solutions:
The application uses following synthetic route:
The method of the present invention for preparing hydrochloric acid Flupirtine reacts with ammonia water generation with 2,6- dichloro-3-nitropyridine
- 6 chloropyridine of -3 nitro of 2- amino；Excessive ammonium hydroxide is as acid binding agent, then reacts with 4-Fluorobenzylamine and generate key intermediate 2- ammonia
Base -3- nitro -6- is refined to fluorobenzylamino pyridine, and with fatty alcohol；Gained wet product and ethyl chloroformate, palladium carbon, normal propyl alcohol
It puts into reaction kettle, while being hydrogenated, acylation reaction together, finally release material, filter, cooling crystallization obtains hydrochloric acid fluorine pyrrole
Spit of fland.
The method of the present invention for preparing hydrochloric acid Flupirtine specifically includes the following steps:
1. a kind of method for preparing hydrochloric acid Flupirtine, comprising the following steps:
(1) with 2,6- dichloro-3-nitropyridine for starting material, ammonium hydroxide is added in methanol, ethyl alcohol or normal propyl alcohol 30
~40 DEG C of 6~7h of reaction are added 4-Fluorobenzylamine, are warming up to 55~80 DEG C of reaction about 4~7h, are cooled to 5~10 DEG C of 1~2h of crystallization
After filter, obtain 2- amino -3- nitro -6- to fluorobenzylamino pyridine crude product；
(2) intermediate 2-amino -3- nitro -6- obtained by is heated to reflux molten fluorobenzylamino pyridine in fatty alcohol
Cooling crystallization after clear, is refined；
(3) 2- amino -3- nitro -6- obtained by step (2) is added in normal propyl alcohol or isopropanol to fluorobenzylamino pyridine
Wet product, ethyl chloroformate and mono- pot of Pd/C are added in reaction kettle, are passed through hydrogen, are heated at 60~70 DEG C while being hydrogenated
It with 5~7h of acylation reaction, filters while hot, filtrate cooling crystallization obtains hydrochloric acid Flupirtine；
Wherein, ammonium hydroxide and 2 in step (1), the molar feed ratio of 6- dichloro-3-nitropyridine are (2.2~4): 1, preferably
For (2.2~3): 1.
Wherein, fatty alcohol is methanol, ethyl alcohol, isopropanol or normal propyl alcohol, preferably normal propyl alcohol or isopropanol in step (2).
Wherein, fatty alcohol and 2 in step (2), the weight ratio of 6- dichloro-3-nitropyridine are (10~20): 1, fatty alcohol
Weight ratio with 2,6- dichloro-3-nitropyridine is preferably (12~15): 1.
Wherein, ethyl chloroformate, 2- amino -3- nitro -6- add fluorobenzylamino pyridine, Pd/C together in step (3)
Enter into reaction kettle, while carrying out hydrogenation and acylation reaction.Catalyst Pd/C is 5%Pd/C, palladium carbon and the chloro- 3- nitro of 2,6- bis-
The weight ratio of pyridine is (0.02~0.1): 1, the pressure of hydrogen is 1.0~2.0MPa.
Preparation process of the invention has the advantage that
1, the substitution reaction of ammonolysis reaction and 4-Fluorobenzylamine carries out in the same reaction vessel, and excessive in ammonolysis reaction
Ammonium hydroxide can be used as the acid binding agent of substitution reaction.It is easy to operate, reduce production cost.
2, intermediate 2-amino -3- nitro -6- refines fluorobenzylamino pyridine, is provided for next step reaction pure
Spend high raw material.Intermediate 2,3- diamino -6- are polyamino pyridine derivate to fluorobenzylamino pyridine and Flupirtine, very
It is easy to oxidize rotten.Hydrogenation and acylation reaction are carried out simultaneously, can avoid rotten situation as far as possible, in order to avoid influence subsequent reactions.
Dropwise addition ethyl chloroformate is carried out without kettle cover is opened.Reduce the injury to human body.And catalyst used herein is palladium carbon, it can
To reduce environmental pollution.
3, the yield of hydrochloric acid Flupirtine can prepare hydrochloric acid Flupirtine of the purity 99% or more 70% or so.
Specific embodiment
Below will by example, the invention will be further described, these descriptions are not to make to the content of present invention into one
The restriction of step.It should be understood by those skilled in the art that changing to equivalent replacement made by technical characteristic of the invention, or accordingly
Into still falling within protection scope of the present invention.
In the present invention, related Nuclear Magnetic Resonance (1H NMR) be Bruker AVANCE-400, nuclear magnetic resonance (1H
NMR) displacement (δ) is provided with the unit of hundred a ten thousandths (ppm), is inside designated as tetramethylsilane (TMS), chemical shift is with 10-6
(ppm) it is provided as unit.
Embodiment 1:
2,6- dichloro-3-nitropyridine (50g, 259.1mmol) is added in the reaction kettle equipped with 200ml methanol, room
Temperature is lower to be added 25% ammonium hydroxide (145.3g, 1.036mol), controls interior 30~35 DEG C, insulation reaction about 7h of temperature, it is anti-that TLC monitors raw material
It should completely be to stop reaction, be added 4-Fluorobenzylamine (38.9g, 310.8mmol), be warming up to 75~80 DEG C of reactions about 4h, TLC monitoring
Raw material fully reacting stops reaction, filters after being cooled to 5~10 DEG C of 1~2h of crystallization.Gained wet product is added to 940ml normal propyl alcohol
It is heated to reflux dissolved clarification, is cooled to room temperature crystallization 2h, is filtered, wet product retains in a kettle.750ml positive third is added to reaction kettle
Alcohol, 5% Pd/C 1.0g and ethyl chloroformate (30g, 276.5mmol) are passed through hydrogen 1.0~1.3MPa of pressure maintaining, and temperature control 60~
70 DEG C of reaction 5h.Filtering, filtrate are cooled to 0~5 DEG C of stirring and crystallizing 2h, and 60 DEG C are dried under reduced pressure 4h, obtain off-white color hydrochloric acid Flupirtine
59.2g, yield 67.0%, chromatographic purity 99.68%, largest single impurity 0.075%.
Nuclear-magnetism result is as follows:
1H NMR (400MHz, DMSO): δ=1.20 (br s, 3H, CH3), 4.05 (q, J=6.8Hz, 2H), 4.35 (s, J
=6.0Hz, 2H), 5.80 (d, J=8.0Hz, 1H), 7.02 (t, J=6.0Hz, 1H), 7.25 (m, 2H) 7.40 (m, 2H), 8.27
(br s,1H)ppm。
13C NMR (400MHz, DMSO): δ=14.5,44.5,59.4,106.5,114.6,128.9,135.7,137.2,
153.2,155.2,155.6,159.7,162.5ppm.
Embodiment 2:
2,6- dichloro-3-nitropyridine (50g, 259.1mmol) is added in the reaction kettle equipped with 250ml ethyl alcohol, room
Temperature is lower to be added 25% ammonium hydroxide (109.0g, 777.5mmol), controls interior 35~40 DEG C, insulation reaction about 6h of temperature, and TLC monitors raw material
Fully reacting stops reaction, is added 4-Fluorobenzylamine (38.9g, 310.8mmol), is warming up to 55~60 DEG C of reactions about 7h, TLC prison
It surveys raw material fully reacting and stops reaction, filtered after being cooled to 5~10 DEG C of 1~2h of crystallization.Gained wet product is added to 630ml methanol
It is heated to reflux dissolved clarification, is cooled to room temperature crystallization 2h, is filtered, wet product retains in a kettle.800ml isopropyl is added to reaction kettle
Alcohol, 5% Pd/C 2g and ethyl chloroformate (30g, 276.5mmol), is passed through hydrogen 1.2~1.5MPa of pressure maintaining, temperature control 60~70
DEG C reaction 5h.Filtering, filtrate are cooled to 0~5 DEG C of stirring and crystallizing 2h, and 60 DEG C are dried under reduced pressure 4h, obtain off-white color hydrochloric acid Flupirtine
64.3g, yield 72.8%, chromatographic purity 99.74%.Its nuclear magnetic data keeps almost the same with 1 data of embodiment.
Embodiment 3:
2,6- dichloro-3-nitropyridine (50g, 259.1mmol) is added in the reaction kettle equipped with 300ml normal propyl alcohol,
It is added at room temperature 25% ammonium hydroxide (76.3g, 544.1mmol), controls interior 30~35 DEG C of temperature, insulation reaction about 6h, TLC monitor raw material
Fully reacting stops reaction, is added 4-Fluorobenzylamine (38.9g, 310.8mmol), is warming up to 60~65 DEG C of reactions about 6h, TLC prison
It surveys raw material fully reacting and stops reaction, filtered after being cooled to 5~10 DEG C of 1~2h of crystallization.Gained wet product is added to 760ml ethyl alcohol
It is heated to reflux dissolved clarification, is cooled to room temperature crystallization 2h, is filtered, wet product retains in a kettle.800ml positive third is added to reaction kettle
Alcohol, 5% Pd/C 5g and ethyl chloroformate (30g, 276.5mmol), is passed through hydrogen 1.8~2.0MPa of pressure maintaining, temperature control 60~70
DEG C reaction 5h.Filtering, filtrate are cooled to 0~5 DEG C of stirring and crystallizing 2h, and 60 DEG C are dried under reduced pressure 4h, obtain off-white color hydrochloric acid Flupirtine
60.4g, yield 68.0%, chromatographic purity 99.71%.Its nuclear magnetic data keeps almost the same with 1 data of embodiment.
Embodiment 4:
2,6- dichloro-3-nitropyridine (5kg, 25.9mol) is added in the reaction kettle equipped with 16kg methanol, at room temperature
It is added 25% ammonium hydroxide (10.89kg, 777.7mol), controls interior 30~35 DEG C of temperature, insulation reaction about 6h, TLC monitor raw material reaction
Stop reaction completely, be added 4-Fluorobenzylamine (3.89kg, 31.1mmol), be warming up to 65~70 DEG C of reactions about 5h, TLC monitoring is former
Expect that fully reacting stops reaction, is filtered after being cooled to 5~10 DEG C of 1~2h of crystallization.Gained wet product is added to 50kg normal propyl alcohol and adds
Heat is cooled to room temperature crystallization 2h, filters, wet product retains in a kettle to reflux dissolved clarification.60kg normal propyl alcohol is added to reaction kettle,
5% Pd/C0.1kg and ethyl chloroformate (3kg, 27.6mol), is passed through hydrogen 1.3~1.6MPa of pressure maintaining, and 60~70 DEG C of temperature control
React 5h.Filtering, filtrate are cooled to 0~5 DEG C of stirring and crystallizing 2h, and 60 DEG C are dried under reduced pressure 4h, obtain off-white color hydrochloric acid Flupirtine
6.12kg, yield 69.3%, chromatographic purity 99.58%.Its nuclear magnetic data keeps almost the same with 1 data of embodiment.
Embodiment 5:
2,6- dichloro-3-nitropyridine (5kg, 25.9mol) is added in the reaction kettle equipped with 20kg ethyl alcohol, at room temperature
It is added 25% ammonium hydroxide (9.07kg, 64.8mol), controls interior 30~35 DEG C of temperature, insulation reaction about 6h, TLC monitoring raw material has reacted
It is complete to stop reaction, it is added 4-Fluorobenzylamine (3.8kg, 31.1mol), is warming up to 60~65 DEG C of reactions about 6h, it is anti-that TLC monitors raw material
It should completely be to stop reaction, be filtered after being cooled to 5~10 DEG C of 1~2h of crystallization.Gained wet product is added to 60kg isopropanol and is heated to
Flow back dissolved clarification, is cooled to room temperature crystallization 2h, filters, and wet product retains in a kettle.To reaction kettle be added 75kg isopropanol, 5%
Pd/C 0.3kg and ethyl chloroformate (3kg, 27.6mol), be passed through hydrogen 1.2~1.5MPa of pressure maintaining, 60~70 DEG C of temperature control are anti-
Answer 5h.Filtering, filtrate are cooled to 0~5 DEG C of stirring and crystallizing 2h, and 60 DEG C are dried under reduced pressure 4h, obtain off-white color hydrochloric acid Flupirtine 6.48kg,
Yield 73.4%, chromatographic purity 99.62%.Its nuclear magnetic data keeps almost the same with 1 data of embodiment.
Embodiment 6:
2,6- dichloro-3-nitropyridine (5kg, 25.9mol) is added in the reaction kettle equipped with 25kg normal propyl alcohol, room temperature
25% ammonium hydroxide of lower addition (7.98kg, 57.0mol), controls interior 35~40 DEG C of temperature, and insulation reaction about 6h, TLC monitor raw material reaction
Stop reaction completely, be added 4-Fluorobenzylamine (3.89kg, 31.1mmol), be warming up to 55~60 DEG C of reactions about 7h, TLC monitoring is former
Expect that fully reacting stops reaction, is filtered after being cooled to 5~10 DEG C of 1~2h of crystallization.Gained wet product is added to 100kg normal propyl alcohol and adds
Heat is cooled to room temperature crystallization 2h, filters, wet product retains in a kettle to reflux dissolved clarification.100kg positive third is added to reaction kettle
Alcohol, 5% Pd/C 0.5kg and ethyl chloroformate (3kg, 27.6mol) are passed through hydrogen 1.8~2.0MPa of pressure maintaining, and temperature control 60~
70 DEG C of reaction 5h.Filtering, filtrate are cooled to 0~5 DEG C of stirring and crystallizing 2h, and 60 DEG C are dried under reduced pressure 4h, obtain off-white color hydrochloric acid Flupirtine
6.28g, yield 71.1%, chromatographic purity 99.66%.Its nuclear magnetic data keeps almost the same with 1 data of embodiment.
Therefore, compared with the prior art for the preparation method of Flupirtine, the application's prepares that reaction condition is mild, operation
Simply, technique favorable reproducibility, environmentally friendly, products obtained therefrom purity is high small to human injury.To key intermediate 2- amino-
3- nitro -6- carries out " one kettle way " to fluorobenzylamino pyridine and simplifies production operation directly using excessive ammonium hydroxide as acid binding agent
To avoid step-by-step processing from bringing intermediate 2,3- diamino -6- 4-Fluorobenzylamine pyridine and Flupirtine easy oxidation discoloration and reducing chloromethane
Injury of the acetoacetic ester to human body is carried out " one kettle way "；By ethyl chloroformate, 2- amino -3- nitro -6- to fluorobenzylamino pyrrole
Pyridine, palladium carbon, fatty alcohol put into reaction kettle together while being hydrogenated, acylation reaction.
For the ordinary skill in the art it is evident that without departing from the application spirit or scope the case where
Under, can to the application compound, composition with and preparation method thereof carry out a variety of modification and transformations, therefore, the guarantor of the application
Shield range cover to the application carry out various modification and transformations, as long as it is described modification or variation in claim and its etc.
In the range of covering with embodiment.
Claims (10)
1. a kind of preparation method of hydrochloric acid Flupirtine, which comprises the following steps:
(1) with 2,6- dichloro-3-nitropyridine for starting material, ammonium hydroxide is added in methanol, ethyl alcohol or normal propyl alcohol 30~40
DEG C reaction 6~7h, be added 4-Fluorobenzylamine, be warming up to 55~80 DEG C of reaction about 4~7h, be cooled to mistake after 5~10 DEG C of 1~2h of crystallization
Filter, obtains 2- amino -3- nitro -6- to fluorobenzylamino pyridine crude product；
(2) intermediate 2-amino -3- nitro -6- is to fluorobenzylamino pyridine obtained by, after being heated to reflux dissolved clarification in fatty alcohol
Cooling crystallization is refined；
(3) 2- amino -3- nitro -6- obtained by step (2) is added in normal propyl alcohol or isopropanol to fluorobenzylamino pyridine wet product,
Ethyl chloroformate and mono- pot of Pd/C are added in reaction kettle, are passed through hydrogen, are heated at 60~70 DEG C while being carried out hydrogenation and acyl
Change 5~7h of reaction, filters while hot, filtrate cooling crystallization obtains hydrochloric acid Flupirtine.
2. preparation method according to claim 1, which is characterized in that ammonium hydroxide and 2 in step (1), the chloro- 3- nitro pyrrole of 6- bis-
The molar feed ratio of pyridine is (2.2~4): 1.
3. preparation method according to claim 1 or 2, which is characterized in that ammonium hydroxide and 2 in step (1), the chloro- 3- nitre of 6- bis-
The molar feed ratio of yl pyridines is (2.2~3): 1.
4. preparation method according to claim 1, which is characterized in that step (2) fatty alcohol is methanol, ethyl alcohol, different
Propyl alcohol or normal propyl alcohol.
5. the preparation method according to claim 4, which is characterized in that step (2) fatty alcohol is normal propyl alcohol or isopropyl
Alcohol.
6. preparation method according to claim 1, which is characterized in that step (2) fatty alcohol and 2, the chloro- 3- nitre of 6- bis-
The weight ratio of yl pyridines is (10~20): 1.
7. preparation method according to claim 6, which is characterized in that step (2) fatty alcohol and 2, the chloro- 3- nitre of 6- bis-
The weight ratio of yl pyridines is (12~15): 1.
8. preparation method according to claim 1, which is characterized in that step (3) ethyl chloroformate, 2- amino -3- nitro -
6- is added in reaction kettle fluorobenzylamino pyridine, Pd/C together, while carrying out hydrogenation and acylation reaction.
9. preparation method according to claim 1, which is characterized in that step (3) the catalyst Pd/C is 5%Pd/C,
Palladium carbon and the weight ratio of 2,6- dichloro-3-nitropyridine are (0.02~0.1): 1, the pressure of hydrogen is 1.0~2.0MPa.
10. preparation method according to claim 1, which comprises the following steps:
2,6- dichloro-3-nitropyridine (5kg, 25.9mol) is added in the reaction kettle equipped with 20kg ethyl alcohol, is added at room temperature
25% ammonium hydroxide (9.07kg, 64.8mol), controls interior 30~35 DEG C of temperature, and insulation reaction about 6h, TLC monitoring raw material fully reacting is
Stop reaction, be added 4-Fluorobenzylamine (3.8kg, 31.1mol), be warming up to 60~65 DEG C of reactions about 6h, TLC monitoring raw material has reacted
It is complete to stop reaction, it is filtered after being cooled to 5~10 DEG C of 1~2h of crystallization；Gained wet product is added to 48kg isopropanol and is heated to flowing back
Dissolved clarification is cooled to room temperature crystallization 2h, and filtering, wet product retains in a kettle；To reaction kettle be added 64kg75kg isopropanol, 5%
Pd/C 0.3kg and ethyl chloroformate (3kg, 27.6mol), be passed through hydrogen 1.2~1.5MPa of pressure maintaining, 60~70 DEG C of temperature control are anti-
Answer 5h；Filtering, filtrate are cooled to 0~5 DEG C of stirring and crystallizing 2h, and 60 DEG C are dried under reduced pressure 4h, obtain off-white color hydrochloric acid Flupirtine 6.48kg.
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