Flupirtine, D 9998
2-amino-6-(4-fluoro-benzylamino)- pyridin-3-yl)-carbamic acid ethyl ester, is unique as a non-opioid, non-NSAID, non-steroidal analgesic with a favorable tolerability. It first became available in Europe in 1984, and was sold mainly under the names Katadolon, Trancolong, Awegal, Efiret, Trancopal Dolo, and Metanor
- Neuronal potassium channels (7)
- Membrane resting potential (6)
- NMDA receptor channels (indirectly)(14)
- Originally developed by Asta Medica (1) (4)
- Being developed and commercialized to treat fibromyalgia by Synthetic Biologics (1)
56995-20-1 (free base)
|LAUNCHED||1986 NEUROPATHIC PAIN|
Flupirtine maleate is the INN for 2-amino-3-ethylcarbamato-6- (4-fluoro-benzylamino) maleate, CAS: 75507-68-5, molar mass 420.40 g / mol, molecular formula C1 5 H17FN4O2 • C4H4O4, and corresponds to the structure of formula I.
Flupirtine maleate is used, for example, under the trade name Katadolon® as an analgesic.
NMDA receptor channels (indirectly)
Katadolon (Brazil, Germany, Latvia, Estonia, Slovakia, Lithiania, Russian Federation)
Stabilizes membrane resting potential by activating neuronal Kv7 potassium channels
Indirectly antagonizes NMDA receptors
Reduces muscle spasticity in humans
Prevents apoptosis and reduced formation of reactive oxygen species by in cultured human retinal pigment epithelial cells
Regulatory and Commercial Status
Marketed for pain indications in various European countries by Meda
Flupirtine is an aminopyridine that functions as a centrally acting non-opioid analgesic. It first became available in Europe in 1984, and is sold mainly under the names Katadolon, Trancolong, Awegal, Efiret, Trancopal Dolo, and Metanor. Flupirtine is sold by Intas Pharma under the brand name Pruf in India. Like nefopam, it is unique among analgesics in that it is a non-opioid, non-NSAID, non-steroidal centrally acting analgesic. In 2010 the chemically related drug (the difference being that the pyridine group in flupirtine is replaced with a phenyl group) retigabine (INN; ezogabine [USAN]) was approved by the FDA as an anticonvulsant for the treatment of refractory partial-onset seizures in treatment-experienced patients. Retigabine also works by opening the neuronal KCNQ/Kv7 potassium channel, just like flupirtine.
It was approved for the treatment of pain in 1984 in Europe. However, it has never been introduced to the United States market for any indication. In 2008, Adeona Pharmaceuticals, Inc. (now called Synthetic Biologics, Inc.) obtained an option to license issued and patent pending applications relating to flupirtine’s use in the treatment of ophthalmic indications, particularly retinitis pigmentosa.
Mechanism of Action
Flupirtine is used as an analgesic for acute and chronic pain, in moderate-to-severe cases. Its muscle relaxant properties make it popular for back pain and other orthopedic uses, but it is also used for migraines, in oncology, postoperative care, and gynecology.
Flupirtine has been noted for its neuroprotective properties, and it is being investigated for possible use in Creutzfeldt–Jakob disease, Alzheimer’s disease, and multiple sclerosis. It has also been proposed as a possible treatment for Batten disease.
Flupirtine underwent a clinical trial as a treatment for multiple sclerosis and fibromyalgia. Flupirtine showed promise for fibromyalgia due to its different action than the three approved by U.S. FDA drugs: Lyrica (pregabalin), Savella (milnacipran), and Cymbalta (duloxetine). Additionally, there are case reports regarding flupirtine as a treatment for fibromyalgia. Adeona Pharmaceuticals (now called Synthetic Biologics) sub-licensed its patents for using flupirtine for fibromyalgia to Meda AB in May 2010.
Abuse and Dependence
Although some studies have reported flupirtine has no addictive properties, there was suggestion that it may possess some abuse potential and liability. There were at least two registered cases of flupirtine abuse. Drug tolerance does not develop in most cases; however, tolerance may develop in single cases.
Flupirtine is 2-amino-3-carbethoxyamino-6-(p-fluorobenzylamino) pyridine; CAS No: 56995-20-1 , an aminopyridine that functions as a centrally acting non-opioid analgesic. It first became available in Europe in 1984, and is sold mainly under the names atadolon, Trancolong, Awegal, Efiret, Trancopal Dolo, and Metanor. It is unique as a non- opioid, non-NSAID, non-steroidal analgesic. Flupirtine is used as an analgesic for acute and chronic pain, in moderate to severe cases. Its muscle relaxant properties make it popular for back pain and other orthopaedic uses, but it is also used for migraines, in oncology, postoperative care, and gynaecology. Flupirtine has been noted for its neuro-protective properties, as well as its possible uses for Creutzfeld- Jakob disease, Alzheimer’s disease, and multiple sclerosis are being investigated. It has also been proposed as a possible treatment for Batten disease. Flupirtine also acts as an antioxidant and prevent free radical- mediated structural damage.
US3481943 (hereinafter referred as ‘943) discloses the process for the preparation of flupirtine hydrochloride of formula (T) wherein p- fluorobenzylamine (formula R) is reacted with 2-amino-3-nitro-6- chloropyridine (Q) in n-propanol using potassium carbonate to prepare 2-amino-3-nitro-6-p-fluorobenzylamino-pyridine of formula (S) which is hydrogenated in dioxane using raney nickel at 50 C under a gauge pressure of 30 atmospheres. Solution is filtered off to remove the catalyst and then reacted with chloroformic acid ethyl ester (ethyl chloroformate) while stirring. The product is filtered off and recrystallized from water to give flupirtine hydrochloride salt of formula (T). The process disclosed therein in ‘943 is depicted as given below
Drawbacks associated with the process disclosed in ‘943 are:
1) The yield of 2-amino-3-nitro-6-p-fluorobenzylamino-pyridine of formula S obtained is around 40% only. ‘943 does not disclose the preparation of maleate salt of flupirtine.
2) During the preparation hydrochloride salt of flupirtine on an industrial scale, intensely blue colored by products are formed which are either difficult to remove or can not be removed completely.
3) Use of n-propanol as reaction solvent is expensive. reaction mass thereby hindering the progress of the reaction. Another most probable reason attributed for getting poor yield of 40% in the said process could be masking of hydrochlorides of both the reactants of formulae (Q’) and (R’) (as both reactants are amino compounds and form hydrochlorides) over potassium carbonate making it unavailable for further reaction posing problem towards the completion of reaction thereby adversely affecting the yield.
DE3133519 (US4481205) discloses the preparation of flupirtine maleate of formula (IA), wherein 2-amino-3-nitro-6-chloro-pyridine of formula (S) is prepared by taking 2,6-dichloro-3-nitropyridine of formula (P) (90%, water wet) in isopropanol at 20°-30°C and purging ammonia gas (or dropping liquid ammonia) into the said reaction mixture and then resulting 2-amino-3-nitro-6-chloro-pyridine of formula (Q) is reacted with p-fluorobenzylamine (R) in isopropanol using triethyl amine as a base ; the reaction mixture is refluxed for 6 hours. Thereupon after addition of a large volume of water the compound 2-amino-3-nitro-6-(p- fluorobenzylamino)-pyridine of formula (S) precipitates.
2-amino-3-nitro-6-(4-fluorobenzylamino) pyridine of formula (S) is then hydrogenated in the presence of raney nickel at 5 bar at 60°C to give 2,3- diamino-6-(4-fluorobenzylamino) pyridine using 2-methoxy ethanol as hydrogenating solvent. This is followed by acylation with ethyl chloroformate using triethylamine as a base under inert gas atmosphere to obtain flupirtine base of formula (I). The catalyst is filtered off and filtrate containing dissolved triethyi amine hydrochloride is directly added to solution of maleic acid in isopropanol resulting into formation of crude flupirtine maleate (IA). It also discloses the importance of the exclusion of atmospheric oxygen by an intensive supply of inert gas and closed reactor system to avoid development of troublesome coloured complexes.
The purification of crude flupirtine maleate is carried out by converting crude flupirtine maleate into crude flupirtine base by contacting with ammonia or sodium hydroxide solution. Then the crude flupirtine base is recrystallized from isopropanol and, after contacting with activated carbon/kieselguh’r, it is reacted with a solution of maleic acid in isopropanol to give flupirtine maleate of formula (IA). The reaction scheme of DE3133519 is depicted herein below.
Drawbacks associated with the process disclosed in DE3133519 (US4481205) are:
1) Use of gaseous ammonia or liquid ammonia for the preparation of 2-amino-3-nitro-6-chloro-pyridine of formula (Q) starting from 2, 6- dichloro-3-nitropyridine of formula (P) contributes towards increased level of impurities of formulae X and Y as the gaseous ammonia and liquid ammonia as sources of ammonia are in concentrated forms and it is not easy to control the purging or addition in appropriate quantities and as a consequence it results in the formation of higher amounts of impurities and poor yield of the desired compound.
Another disadvantage of using ammonia gas is that it is classified as a hazardous material and is subject to strict regulations and risk management procedures for transport, storage, and handling. These requirements result in additional costs and may generate local community concerns over transporting and storing hazardous materials. While aqueous ammonia used by the inventors requires minimal special handling, social and regulatory requirements.
2) Preparation of 2-amino-3-nitro-6-(p-fluorobenzylamino)-pyridine of formula (S comprises reaction between 2-amino-3-nitro-6-chloro- pyridine of formula (Q) and p-fluorobenzylamine of formula (R) using isopropanol as solvent and triethyl amine as base. To induce separation of 2-amino-3-nitro-6-(p-fluorobenzylamino)-pyridine of formula (S from the reaction mixture in IP A a large volume of water is required which makes reaction mass highly voluminous therefore, not preferred at industrial scale. 3) Basification of crude flupirtine maleate comprising the process of liberating free flupirtine base using ammonia or sodium hydroxide produces an ammonium or sodium salt which pollutes the water.
4) Use of activated charcoal and kieselgulir during the purification of flupirtine base (that contains three amino groups known for their light and colour sensitive nature) takes prolonged time for filtration through filtering bed thereby exposing to environment producing high coloration.
5) The crude flupirtine maleate remains trapped with triethyl amine hydrochloride.
US59591 15A (hereinafter referred as Ί 15) discloses a process for the preparation of flupirtine maleate (IA) as discussed under DE3133519 (US4481205). It also discloses crystalline form “A” of flupirtine maleate by the use of water soluble alcohols (such as ethanol or isopropanol) during synthesis and/or purification. There are three proposed variants in Ί 15 as shown below: process variant:
A: ANFP (S)→hydrogenation→acylation→crude flupirtine base.
B: crude flupirtine base→maleic acid→crude flupirtine maleate
C-E (as shown in scheme-II): not applicable F: crude maleate→pure maleate.
1 s process variant comprises synthesis of oxygen sensitive crude base in situ in process step A and it was converted by a “very rapid” suction filtration process into an aqueous maleic acid solution from which coloured crude flupirtine maleate (IA) is obtained, which is to be purified by recrystallization from isopropanol-water.
2″ process variant:
A: ANFP (S)→hydrogenation→acylation→crude flupirtine base.
B: flupirtine base→maleic acid→crude flupirtine maleate.
C-F (as shown in scheme-II): Not applicable.
G: without isolation of the crude maleate→pure maleate.
As compared to the process step F in 1st variant, process step G in 2nd variant represents substantially shorter alternative process in which the precipitation of crude flupirtine maleate from the flupirtine base formed in situ in isopropanol is effected by Alteration with suction into an aqueous maleic acid solution at 50-60°C and, after that without isolation of the crude maleate, colourless pure material is obtained.
3rd process variant:
A: ANFP (S)→hydrogenation→acylation→cmde flupirtine base (isolated)
B: pure flupirtine base→maleic acid→pure flupirtine maleate.
Herein, after acylation, the flupirtine base (I) is precipitated preferably in ethanol or water and is purified by recrystallization and than treated with maleic acid to prepare pure flupirtine maleate (IA).
Ί 15 disclose hydrogenation of ANFP (S), acylation and precipitation in water-soluble alcohols, such as ethanol or isopropanol.
1) In 1st process variant “very rapid” suction filtration process is a great limitation at plant scale.
2) 2nd process variant also does not produce colorless pure maleate.
3) In 3 process variant, after acylation, the flupirtine base is precipitated preferably in ethanol or water and is purified by recrystallization and than treated with maleic acid to prepare pure flupirtine maleate salt (IA).
It also discloses that although the treatment of final product with activated carbon and recrystallization is known as a reasonably successful procedure to remove impurities. This approach is reluctantly accepted because of the losses in overall yield as it is applied in the last production step of a drug and particularly in the case of flupirtine, it is not a preferred/desirable procedure as it may result into the formation of colored impurities.
US47851 10A discloses a process for the preparation of 2-amino-3-nitro- 6-fluorobenzylamino pyridine of formula (S) comprising reaction of 2- amino-3-nitro-6-methoxypyridine of formula (T) (1 mole) with 4-fluoro- benzylamine of formula R (2-4 mole) optionally as a mineral acid salt in water at a temperature between 70°C and 150°C; preferably between 90° and 120°C. The said condensation is also performed in autoclave as the temperature is above 100°C.It also discloses the necessity of using basic material suitably as an aqueous solution in case when acid addition salts of 4-fluoro-benzylamine of formula (R) is used to liberate the free base for the reaction. It also discloses subsequent reduction of nitro group of 2-amino-3-nitro-6-methoxypyridine by various modes with preference to catalytic hydrogenation optionally in the presence of carriers selected from barium sulphate, calcium sulphate, magnesium sulphate, sodium sulphate etc.
The drawbacks associated with the process described in US47851 10A are: 1) As per the experimental section of the said process of condensation for the preparation of 2-amino-3-nitro-6-fluorobenzylamino pyridine of formula (S) discloses heating at boiling for ten hours. The temperature would be around 100°C as water is used as solvent. However, inventors of the subject invention disclose herein the same process comprising using 6-chlorpyridine instead of 6-methoxy pyridine and water as solvent’, wherein the reaction is carried out at temperature much below boiling point of water and reaction gets completed in 3 hrs compare to 10 hrs at temperature of boiling water as in’ 1 10. Furthermore, the said reaction disclosed herein in the present invention does not require autoclave. There is no teaching or anticipation on this aspect from Ί 10.
2) Excessive use of 2-4 moles of 4-fluoro-benzylamine of formula ( ) for the preparation of 2-amino-3-nitro-6-fluorobenzylamino pyridine of the formula (S) comprising the reaction of 2-amino-3-nitro-6- methoxypyridine of formula (T)with 4-fluoro-benzylamine of formula (R).Unreacted 4-fluoro-benzylamine is then removed by steam distillation which is not only time and energy consuming but also increase in an extra unit operation.
3) In case when acid addition salts of 4-fluoro-benzylamine are used that requires another additional operation of basification to liberate free base to enable 4-fluoro-benzylamine to be available to react further with 2- amino-3-nitro-6-methoxypyridine forming 2-amino-3-nitro-6- fluorobenzylamino pyridine of the formula (S)
DE 31 33 519 describes a process for the preparation of flupirtine maleate as a mixture of polymorphic forms A and B, wherein A is present in a proportion> 60%. The key reaction steps are the hydrogenation of 2-amino-6- (4-fluorobenzylamino) -3-nitropyridine (Formula II) shown in Figure 1, hereinafter also referred to as ANFP, by means of Ra-Nickel for 2,3-diamino- 6- (4-fluoro-benzylamino) -pyridine (Formula III) and subsequent regioselective acylation with chloroformate for free flupirtine base. By precipitation as maleate to blue contaminants that are incurred in the production of HCl salt, are eliminated. Purification of flupirtine maleate is obtained as maleate by releasing the base from the maleate, treatment with activated carbon and reprecipitation. Despite this lengthy and economically expensive purification strategy traces of colored impurities can be difficult to remove.
In WO 98/47872 a process for the preparation of flupirtine maleate is described, in which, in water-soluble alcohols (IPA) is carried out. There are three proposed variants. Option 1 includes an implementation of ANFP to Ra-nickel in the IPA is directly attached to the acylation and the precipitation of a product by Rohmaleat called “very fast” extraction process in an aqueous solution of maleic acid. It falls on a colored Rohmaleat which is to be purified by recrystallization from isopropanol / water. However, the enactment of this variant in the laboratory showed a colored product. In variant 2 should already be colorless an image obtained by aspiration in 50 to 60 0 C warm maleic Rohmaleat. This also could not be confirmed. According to the third variant, the Flupirtinbase formed after acylation is not converted in situ but precipitated in ethanol or water and recrystallized before further reaction with maleic acid. Even with the procedure referred to in this document is a pure white flupirtine maleate is not readily available.
Example 3 Preparation of flupirtine maleate
50 g of 2-amino-6- (4-fluorobenzylamino) -3-nitropyridine, 2.5 g of palladium on activated carbon and 267 g of isopropanol were hydrogenated with hydrogen at 4.5 bar and 70 0 C. After completion of the reaction was additionally hydrogenated for 8 hours at 70 0 C. Then 20.2 g of ethyl chloroformate, 24.8 g of triethylamine and 4.96 g of ethyl chloroformate at 20 0 C was added. Thereafter, the reaction mixture was stirred for 1.5 h at 55 0 C. It was then filtered at room temperature. The filtrate was then added to a solution of 35.6 g of maleic acid in 1000 g of water at room temperature slowly. The resulting suspension was stirred for 1 h at room temperature. The precipitate was filtered off and washed with water and isopropanol. Dried filter cake (HPLC purity 91.5%) was dissolved in 828 g of isopropanol / water mixture (mass ratio 5.3: 1), and heated to 70 0 C. The resulting clear solution was cooled to room temperature and stirred at room temperature. The precipitate was filtered off and washed with isopropanol / water mixture. The filter cake was dried at 50 0 C. 43 g flupirtine maleate (HPLC purity 97.8%) was obtained as a white-gray solid. The yield was 55%.
The invention relates to an improved process for the preparation of flupirtine of formula (I) and its pharmaceutically acceptable salts, particularly flupirtine maleate of formula (IA) preferably pure crystal modification A of flupirtine maleate.
(c) reducing nitro group of 2-amino-3-nitro-6-p-fluorobenzylamino- pyridine of formula (S) in a solvent base combination as solvent system in the presence of a catalyst;
EXAMPLE 1 : Preparation of 2-amino-3-nitro-6-chloro-pyridine.
A solution of 100 gm. 2, 6-dichloro-3-nitro-pyridine in 800 ml isopropyl alcohol is taken in round bottom flask. 300 ml of aqueous ammonia solution (20-25%) is added at 20-25°C. The reaction mass is stirred for 20-24 hours at 20-25°C. After completion of the reaction
The solid is filtered and washed with 100 ml isopropyl alcohol then dried to obtain 70-75 gm 2-amino-3-nitro-6-chloro-pyridine.
EXAMPLE 2: Preparation of 2-amino-3-nitro-6-p-fluorobenzylamino- pyridine.
100 gm of 2-amino-3-nitro-6-chloro-pyridine is taken in 800 ml of water. 90 gm of p-fluorobenzylamine is added dropwise into the reaction mixture at 20-25°C. Then 87 gm triethylamine is also added dropwise into the reaction mixture at 20-25°C. After complete addition, the reaction mass is stirred at 40-45°C for half an hour again the reaction mass is heated to 80-85°C and stirred at this temperature for 3-4 hours. After completion of the reaction, the reaction mass is cooled to 20-25°C and stirred at this temperature for 2-3 hours and then stirred at 15-20°C for 3-4 hours. The solid mass is filtered and then washed with 200 ml of water and 100 ml isopropyl alcohol and then dried in air oven till constant weight to get 140-150 gm. of 2-amino-3-nitro-6-p- fluorobenzylamino-py ridine .
EXAMPLE 3: Preparation of flupirtine maleate.
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 75-80°C for 2-3 hours under 4-5 kg pressure. After completion of the reaction, the reaction mass is cooled and filtered at 40- 45°Cthen in filtrate 45 ml of ethyl chloroformate is added slowly at 5- 10°C. The temperature is raised to 25-30°C and 80 ml triethyl amine is added under nitrogen atmosphere. The reaction mass, is heated at 55- 60°C 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 65-70°C and maintained at 65-70°C for 2 hours under nitrogen to get crude Flupirtine Maleate as a solid. The reaction mass is cooled to 25-30°C 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.
EXAMPLE 4: Preparation of pure flupirtine maleate crystalline modification A.
1 15 gm crude Flupirtine maleate obtained in example 3 is taken in 1 150 ml methanol and 58 ml water. This mixture is heated to reflux and 58 ml water is added slowly to get a clear solution and refluxed for about half an hour. The reaction mixture is cooled slowly to 60°C and seeded with crystals of modification A. Then it is cooled slowly to 20-25°C and maintained at this temperature for 2 hours. The crystalline mass is filtered and washed with 100 ml chilled methanol and dried to give 92 gm. flupirtine maleate crystalline modification A.
Preparation of flupirtine maleate
75 g (0.286 mol) ANFP be in a suspension of 12.5 g of Raney nickel in 400 ml of isopropanol was hydrogenated at 65 ° C and 5 bar hydrogen pressure. After hydrogenation, the solution is then mixed with 26.4 ml of ethyl chloroformate and 50.6 ml of triethylamine. After adding a further 6.3 ml of ethyl chloroformate the reaction solution is stirred at 60 ° C. for 1 hour. Then sucks the hot solution with stirring in a 50 – 60 ° C heated solution of 53.3 g of maleic acid in 1, 5 IH 2 O and washed the catalyst with little isopropanol.
The flupirtine maleate is precipitated in colorless crystal suspension is cooled with further stirring at 20 ° C and maintained at this temperature for 20 minutes. It is suctioned off, washed with 500 ml of water and dried flupirtine maleate in vacuo at 35 ° C.
Yield: 107.55 g (89.6% of theory, based on ANFP.) Example 2
Preparation of flupirtine maleate
18.5 g (0.07 mol) ANFP be analogous to Example 1 in a suspension of 2.0 g of Raney nickel in 140 ml of ethanol 60 – 70 ° C and 5 bar hydrogen pressure After hydrogenation, the further reaction takes place at 40 – 50 ° C with 9.3 g of ethyl chloroformate (0.86 mol) of triethylamine and 9.2 g (0.91 mol) The separated from the catalyst reaction solution is added with stirring to 540 ml of water After 2 hours of stirring at room temperature suctioned the failed base off and washed with water and isopropanol and crystallized in the 3.7-fold amount of isopropanol to yield 18.4 g (86.0% of theory)
The precipitation and modification of pure flupirtine maleate is carried out according to the Examples 7 and 8
The invention provides a synthesis method of flupirtine maleate. Recrystallization by use of methanol is carried out in the refining step of the crude product of the flupirtine maleate so that the product is white in appearance and high in purity, and the crystal form of the product is pure A crystal and same as the crystal form of the commercial products. The optimal reaction solvent, reaction time and reaction temperature are explored and found out by use of a simplified process flow, and a method for preparing the flupirtine maleate in the pure A crystal form, which is high in yield, low in cost and simple to operate, uses easily available raw materials and is applicable to the industrial production is found.
The preparation of a comprehensive literature about the ratio of maleic acid fluoride Jie Ting to 2_-amino-3-nitro-6-chloro-Jie ratio 唳 as a starting material, by condensation, reduction, acylation, salt and other processes for The most common route, however, due to the reduction, acylation, salt formation method of a three-step operation is different, not only the yield of the synthesis varies widely, and also on the flupirtine maleate product quality. This is mainly because of the intermediate 2,3-diamino-6-fluoro-benzyl amino pyridine and flupirtine multi-aminopyridine derivative, is easy to oxidative deterioration. So the use of continuous operation, not only simple steps, and can improve product quality and yield.
Chinese patent CN102241626 reported to 2,6_ dichloro _3_ nitropyridine as raw material by selective ammonia solution to give 2-amino-3-nitro-6-chloro-approved Li, then with amine fluoride Festival to afford a yellow solid 2-amino-3-nitro-6-p-fluoro-benzylamino-pyridine. After vacuum drying, the use of hydrogenation, and then under nitrogen and ethyl chloroformate acylation catalyst is filtered off and then a salt with maleic acid to give a pale green crude product yield was about 37% (2-amino-3-nitro-6-chloro-pyridin-meter).
Patent No. CN102838534 reported 2-amino-3-nitro-6-chloro-pyridine as starting material, the use of sub-step processing method, in a first reactor, and a condensation-fluorobenzyl amine, and dried in vacuo to give the intermediate 2-amino-3-nitro-6-p-fluorobenzyl-aminopyridine, in a second reactor to Raney nickel as the catalyst, the catalytic hydrogenation of hydrazine hydrate, after filtration the solvent was evaporated to give the intermediate 2,3-solid – diamino-6-p-fluorobenzyl-aminopyridine, in a third reactor with ethyl chloroformate acylated intermediate distillation under reduced pressure to give solid form of flupirtine with an aqueous solution of a salt of maleic acid, after purification, the total Yield 25% ~ 30%.
Patent W02012004391 discloses a method for preparing a high yield of flupirtine maleate method. In 2_-amino-3-nitro-6-chloro-fluoro-section batch Li and amines as raw material for condensation to give 2-amino-3-nitro-6-fluoro-section based on the amino pyridine granted, then using high-pressure hydrogenation the reduction, acylation step in a high pressure hydrogenation reactor concentrated completed, after the catalyst was filtered off and then the salt, the crude yield of greater than 70%. The preparation method using high-pressure hydrogenation apparatus, there are security risks, and takes too long, is not suitable for industrial production.
Patent No. CN102260209 discloses a 2_ amino _3_ _6_ fluorobenzyl nitro-pyridine as starting material, the reduction, acylation and salt-forming step of the continuous operation, the synthetic yield was improved to 58% so, no mention of product purity. Since the acylation step taken ethyl chloroformate, while an organic base is added, so that an increase in a side reaction, the product yield decreases; the same time, 2-amino-3-nitro-6-p-fluoro-benzylamino-pyridine as the raw material, the production cost high.
In the present invention, we consider the key intermediate 2,3-diamino-6-p-fluorobenzyl-aminopyridine and chemical properties of flupirtine, condensation, reduction, acylation, salt formation reaction is concentrated to the same conventional the reactor is completed, each step without intermediate separation, simplifying the process route and operations, improve efficiency, reduce costs, improve the overall yield of the crude by 40 percent following the step by step operation for more than 70% crude purity of more than 99% suitable for industrial scale production.
The 4Kg2_ amino-3-nitro-6-chloropyridine, 4.5Kg triethylamine, 40L of isopropanol into the reactor, stirred and heated to reflux for turn; the 4.4Kg of benzylamine was added to the fluorine reactor, the reaction under reflux conditions for 3 hours. After heating was stopped, the reaction solution was added to 40L of purified water, a lot of yellow solid was precipitated was filtered and the resulting wet product remains in the reaction vessel. To the reaction kettle was added 1.8Kg Raney nickel, 40L of isopropanol, stirred and heated to reflux for open, 7Kg80% hydrazine hydrate was added dropwise, the reaction was refluxed for 3 hours, after completion of the reaction down to room temperature in a nitrogen atmosphere, was added rapidly 3.6Kg chloro carboxylic acid ethyl ester, the reaction at room temperature for 3 hours. 3Kg of triethylamine was added, free 2 hours, filtered and the filtrate was added to 5Kg / 100L of maleic acid in isopropanol, cooling crystallization to give an off-white solid, 50 ° C blast drying, weight 7.8Kg, the yield was 80.5 %, purity 99.6%.
A sub-step treatment process research and data  Comparative Example
The method according to Chinese patent CN102838534 disclosed flupirtine maleate was prepared, and a number of specific steps
FIG. 1 is flupirtine maleate 1H NMR.
 FIG. 2 is flupirtine maleate A crystal X-ray diffraction pattern
2-Amino-3-nitro-6-chloropyridine 246g, and 254g of triethylamine were added to 800ml of ethanol-necked flask and stirred under heating to reflux, fluorine was slowly added dropwise benzylamine 80g, reaction of 6 hours, the reaction was completed After the dropwise addition of purified water 500ml, cooled slowly with stirring to room temperature, filtered, dried to give 2-amino-3-nitro-6-p-fluoro-benzylamino-pyridine.
 The ferric chloride hexahydrate was dissolved in purified water 41g 200ml, adding activated charcoal 20g, heated to 50 ° C, a saturated solution of sodium hydroxide was added 45g (24g of sodium hydroxide dissolved in 21ml water), 60 ° C with stirring I hours, cooled to room temperature, filtered, and dried to give ferric hydroxide / activated carbon catalyst.
 A mixture of 2-amino-3-nitro-6-p-fluorobenzyl-aminopyridine 104.Sg, ferric hydroxide / activated carbon catalyst was added to 20g 2L reaction flask was added 95% ethanol 1200ml, heated with stirring to 90 ° C. Insulation 60% hydrazine hydrate was added dropwise 250g. Drops Bi insulation response to 3h. Completion of the reaction, the reaction solution is filtered hot with concentrated hydrochloric acid to 240ml and 95% ethanol IOOOml reaction flask. (TlO ° C crystallization I h, filtered, dried to give 2,3-amino-6-fluoro-benzyl-aminopyridine on
 A mixture of 2,3-diamino-6-p-fluoro-benzylamino-pyridine hydrochloride 132g, 800ml of isopropanol was added to a 2L reaction flask, the temperature control to 28 至 30 ° C, was slowly added dropwise acetic acid ester 39g. Stirred for 0.5 hours, was slowly added dropwise triethylamine 70g, after stirring for 0.5 hours, complement ethyl chloroformate 5g, stirred for 15 minutes, additional triethylamine remaining 10g. Continue stirring for I hour. The reaction solution was concentrated under reduced pressure to about 800ml of distillate was distilled out. The remaining reaction solution was poured into an aqueous solution of maleic acid with a good (39g of maleic acid was dissolved in purified water IlOOml), stirred for 30 minutes at room temperature, (T5 ° C was stirred for 5 ~ 8 hours, filtered, dried to give the maleic acid flupirtine crude.
 The crude flupirtine maleate product 100g, 2000ml of ethanol into the reaction flask and heated to 70~80 ° C, was added 5g of activated carbon and dissolved, and incubated I hour, filtered hot, O~5 ° C CRYSTALLIZATION 3 hours, filtered and dried to give crude I. The crude product I 90g, 450ml of ethanol into the reaction flask and heated 20h, and then slowly cooled to room temperature, O~5 ° C for 2 hours, filtered, and dried to give crystal form A of flupirtine maleate product.
flupirtine maleate is a non-opioid analgesic effects on the central nervous system drugs, which is a selective neuronal potassium channel opener (Selective Neuronal Potassium Channel Opener, SNEPCO), has analgesic, muscle relaxant and neuroprotective triple effect. Acute pain treatment is mainly used for various types of moderate, such as surgery, trauma-induced pain and headache / migraine and abdominal spasms.
flupirtine maleate English name: Flupirtine Maleate, chemical name: 2_ amino-6 – [((4-fluorophenyl) methyl) amino] pyridine-3-carboxylic acid ethyl ester maleic salt; Chemical Abstracts (CAS) number = 75507-68-5; formula = C15H17FN4O2 · C4H4O4; molecular weight: 420.39; its structural formula is:
From a structural perspective, flupirtine maleate molecular compounds, the derivatives of benzene and pyridine derivatives synthetically produced flupirtine, flupirtine and then forming an organic salt with maleic acid. Comprehensive literature, synthetic routes flupirtine maleate there are two major, now its main synthetic steps described below.
Route 1 (W0 98 / 47872Α1): The route to 2,6_ dichloro _3_ nitropyridine as raw material substitution, ammoniated, high-pressure hydrogenation, acylation, a process salt, refined and so on. The reaction formula is as follows:
Route 2 (US5959115A) to 2_ amino _3_ nitro _6_ methoxypyrido as the starting material, and on fluorobenzylamine substitution reaction to produce 2-amino-3-nitro–6 – fluorobenzyl amine of pyridine, the yield was 95.2%, and the high-pressure hydrogenation, the catalyst was filtered off, and then the occurrence of an acylation reaction with ethyl chloroformate to give the hydrochloride salt of flupirtine, three-step total yield of 53.3%. The reaction formula is as follows:
Route 1 starting material is different, but relatively speaking, the route I easily controlled reaction conditions, and 2-amino-3-nitro-6-chloro-pyridine is a common chemical raw materials, easy to buy on the market, This can shorten the reaction route. Route 2 two-step reaction process route is short, but the starting 2-amino-3-nitro-6-methoxy-approved Li expensive, hydrogenation, acidification two steps yield only 56.0%.
Chinese Patent Application Publication No. CN102241626A are disclosed and CN102260209A flupirtine maleate preparation method, but the application of these two methods for the preparation of a laboratory scale, for the industrial mass production were not optimized.
The method for purifying of flupirtine maleate in the final product are as follows:
650C ± 5 ° C under the flupirtine maleate crude and ethanol mass ratio of 1: 30-40 mixed, crude completely dissolved, then add 680g of activated carbon and stirred for 15–30 minutes, and hot filtration, the filtrate, stirring down to room temperature, and then cooled to 0 ° C crystallization 5–10 hours, filtered and the filter cake to take the filter cake can be dried.
BELOW AS FREE BASE
1H NMR INTERPRETATIONS/PREDICTIONS
13C NMR INTERPRETATIONS/PREDICTIONS
Helvetica Chimica Acta, , vol. 77, # 8 p. 2175 – 2190
AND GIVES PRODUCT
ALSO AN INTHelvetica Chimica Acta, , vol. 77, # 8 p. 2175 – 2190
Instrumentation An HPLC system (Agilent HPLC Model-1200) equipped with a C18 (Agilent BDS, 250 mm x 4.6 mm, 5µ) column, binary pump, rheodyne loop injector with 20 μL, and a photodiode array detector was used. The software used for HPLC data acquisition was EZChrome Elite. A flash chromatograph equipped with silica gel as the column material, and VWD-UV detection (using the software Analogix IF 280 V 5.10) was used for the isolation and purification of degradation products. 1 H-NMR was recorded on the Varian Unity Inova at 400 MHz (using TMS as internal standard and DMSO-d6 as solvent), 13C-NMR (Mercury Plus at (abundance 100 MHz), using DMSO-d6 as solvent), and mass spectral studies were performed on the API 3000 ABPCIES instrument.
Method Development and Optimization of the Chromatographic Conditions In preliminary experiments, the drug was subjected to the reversed-phase mode using a C18 column (Agilent, 250 x 4.6 mm, 5µ) and mobile phases consisting of water (pH 3.0 adjusted with orthophosphoric acid) and methanol by varying the % aqueous phase from 10% to 30%. The drug was retained on the column, but the peak shape was not good. It was noted that increasing the % aqueous phase in the mobile phase composition increases the retention time of flupiritine maleate. Based on the suitable retention time for SIAM, the 20% aqueous phase was optimized. To reduce the tailing effect, 0.2% triethylamine (TEA) was added and the pH was adjusted to 3.0 with orthophosphoric acid and the corresponding retention of FLU was 10.3 ± 0.3 min. Finally, the mobile phase of 0.2% v/v TEA (pH-adjusted to 3.0 with OPA) and methanol in the ratio of 20:80% v/v was optimized. The flow rate was 1.0 mLmin−1. The injection volume was 20 µL and the PDA detection wavelength was at 254 nm. The chromatogram obtained in the optimized condition is shown in Fig. 2. It was observed that eight degradation products were formed with retention times 3.9 ± 0.2 min (D1), 4.8 ± 0.2 min (D2), 6.4 ± 0.1 min (D3), 6.8 ± 0.2 min (D4), 8.2 ± 0.2 min(D5), 12.0 ± 0.2 min (D6), 14.1 ± 0.1 min (D7), and 15.0 ± 0.1 min (D8), respectively. The chromatographic resolution among all of the peaks was more than 2. The % degradation was about 5–30% depending on stress conditions.
J Pharm Biomed Anal. 2014 Mar;90:27-34. doi: 10.1016/j.jpba.2013.11.015. Epub 2013 Nov 27.
Flupirtine maleate is a centrally acting, non-opioid, nonsteroidal antiinflammatory analgesic. During the manufacturing of flupirtine maleate, two unknown impurities present in the laboratory batches in the range of 0.05-1.0% along with the known impurities in HPLC analysis. These unknown impurities were obtained from the enriched mother liquor by column chromatography. Based on the complete spectral analysis (MS, (1)H, (13)C, 2D NMR and IR) and knowledge of the synthetic scheme of flupirtine maleate, these two new impurities were designated as diethyl 5-((4-fluorobenzyl)amino)-2-oxo-1H-imidazo[4,5-b]pyridine-1,3(2H)-dicarboxylate (impurity-I) and diethyl(6-((4-fluorobenzyl)amino)pyridine-2,3-diyl)dicarbamate (impurity-II). Impurity isolation, identification, structure elucidation and the formation of impurities were also discussed. Preparation and structure elucidation of impurity-III were also first reported in this paper.
journal of pharmaceutical and biomedical analysis, 90, 2014, 27-34
References: Substituted pyridine with central analgesic properties. Prepn: K. Thiele, W. von Bebenburg, ZA 6902364(1970 to Degussa); W. von Bebenburg et al., Chem. Ztg. 103, 387 (1979); eidem, ibid. 105, 217 (1981).
Prepn of maleate: W. von Bebenburg, S. Pauluhn, BE 890331; eidem, US 4481205 (1980, 1984 both to Degussa).
Comparison of pharmacology with other analgesics: V. Jakovlev et al., Arzneim.-Forsch. 35, 30 (1985).
Pharmacokinetic studies: K. Obermeier et al., ibid. 60.
Effect on driving ability: B. Biehl, ibid. 77.
Clinical trials in treatment of cancer pain: W. Scheef, D. Wolf-Gruber, ibid. 75.
Efficacy in treatment of pain after hysterectomy: R. A. Moore et al., Br. J. Anaesth. 55, 429 (1983).
Symposium on pharmacology and clinical efficacy: Postgrad. Med. J. 63, Suppl. 3, 1-113 (1987).
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- http://www.freepatentsonline.com/5721258.html Primary and secondary neuroprotective effect of flupirtine in neurodegenerative diseases The synthesis of flupirtine and its pharmaceutically acceptable salts is described in EP 160 865 and 199 951. EP0199951 December, 1986 Process for the preparation of 2-amino-3-nitro-6-(4-fluorobenzylamino) pyridine and of 2-amino-3-carbethoxyamino-6-(4-fluorobenzylamino) pyridine.
- http://patent.ipexl.com/EP/EP0199951.html#reference Process for the preparation of 2-amino-3-nitro-6-(4-fluorobenzylamino) pyridine and of EPO Patent EP0199951 1986 German.
- http://www.patentfish.com/2-amino-3-carbethoxyamino-6-4-fluoro-benzylamino Process for the preparation of 2-amino-3-nitro-6-(4-fluorobenzylamino) pyridine and of 2-amino-3-carbethoxyamino-6-(4-fluorobenzylamino) pyridine EP 0199951 B1 1986. English.
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- http://www.faqs.org/patents/app/20090306150 CARBOXYLIC ACID SALTS OF 2-AMINO-3-CARBETHOXYAMINO-6-(4-FLUORO-BENZYLAMINO)-PYRIDINE patent 20090306150. 2009. Flupirtine is commonly used in the form of pharmaceutically acceptable acid addition salts. Commercially, flupirtine is available as its maleate addition salt under the trademark Katadolon®. There are two known polymorphs of flupirtine maleate, designated in the art as flupirtine maleate A and B. European patentEP 0 977 736 discloses pure flupirtine maleate crystalline form A and a process for its preparation. Flupirtine and mixtures of flupirtine maleate polymorphs A and B can be synthesised according to EP 0 199 951.
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- Flupirtine as Oral Treatment in Multiple Sclerosis (FLORIMS) Clinical Trials.gov Accessed 20 September 2011.
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Stoessel, C; Heberlein, A; Hillemacher, T; Bleich, S; Kornhuber, J (Aug 16, 2010). “Positive Reinforcing Effects of Flupirtine—Two Case Reports”. Progress in Neuro-psychopharmacology & Biological Psychiatry 34 (6): 1120–1121. doi:10.1016/j.pnpbp.2010.03.031. PMID 20362025. Retrieved 2 June 2014.
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