CN109694367A - A method of preparing bilastine - Google Patents
A method of preparing bilastine Download PDFInfo
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- CN109694367A CN109694367A CN201910167174.XA CN201910167174A CN109694367A CN 109694367 A CN109694367 A CN 109694367A CN 201910167174 A CN201910167174 A CN 201910167174A CN 109694367 A CN109694367 A CN 109694367A
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The present invention relates to a kind of methods for preparing bilastine, including chemical compounds I oxazole alcohol is added to the water, and are added to phase transfer catalyst, paratoluensulfonyl chloride and sodium hydroxide, are filtered after being stirred to react up to oxazole alcohol sulphonic acid ester.Sulphonic acid ester is added to the water, 2-(4- piperidyl is added) 1-H- benzimidazole and phase transfer catalyst, sodium carbonate or potassium carbonate is added, suspension is heated to react 3-5 hours, the intermediate II being obtained by filtration is added in highly polar non-protonic solvent, and sodium hydroxide, phase transfer catalyst is added, be added ethylene glycol monoethyl ether p-methyl benzenesulfonic acid ester, -20-60 ° be stirred to react after filtering washing after intermediate III.Intermediate III is added in aqueous solutions of organic acids, is flowed back 3-5 hours, highly basic saturation is added in water supplement, and solution flows back 3-5 hours, and the bilastine salt of generation does not dissolve in saturation aqueous slkali, extracts to obtain bilastine.This method reaction condition is mild, easy to operate, environmentally protective, and high income is convenient for industrialized production.
Description
Technical field
The invention belongs to field of medicinal chemistry, are related to the preparation of bilastine (Bilastine).
Background technique
Bilastine (Bilastine, abbreviation blst), chemistry entitled 2- 4-(2- 4- 1-(2- ethoxy-ethyl)-
1H- benzimidazolyl-2 radicals-yl } ethyl)-phenyl ] 2- rnethyl-propanoic acid, cas 202189-78-4,.Bilastine is Spain
The oral 2nd generation histamine H 1 receptor antagonist of FAES drugmaker research and development.2009 European Union carry out new drug registration, most earlier than
Ratify to list in UK & Ireland within 2011, afterwards in succession in the listing of the states such as Italy, Japan and Canada, for treating season
Allergic rhinitis and Perennial rhinitis allergic, dosage strengths are 20mg/ piece.Other approval indications further include pruitus,
Eczema and nettle rash.The advantages that this product good security, nothing commonly uses sedation existing for antihistamine drug and cardiac toxic.Than
The structural formula in Lars spit of fland is as follows:
。
The usual synthetic route of bilastine is as follows:
It is raw material with tosylate 1 in patent CN1176964A, is heated in solvent DMF with compound 0-1 benzimidazole
Reaction, obtains intermediate 2, and NaH is added in DMF in intermediate 2, and raw material chloroethyl ether 0-2 is added, and heating reaction obtains
Mesosome 3, for intermediate 3 under the conditions of inorganic acid such as hydrochloric acid sulfuric acid, first sour water solution, then basic hydrolysis obtains bilastine
。
In patent CN 103214455A, hydrolysising condition is changed to the heating of aqueous hypochlorite solution 4- butyl Ammonium hydrogen sulfate
Hydrolysis.
In patent CN103214455A, hydrolysising condition is changed to aqueous solutions of organic acids reflux and is hydrolyzed within 36 hours.
As it is known by the man skilled in the art that DMF is valuable and not environmentally, post-process cumbersome, NaH is inflammable and explosive, industrialization behaviour
Make difficult, under strongly acidic conditions, ehter bond has the tendency that fracture, simple sour water solution or basic hydrolysis be difficult to oxazole cyclizing hydrolysis is complete,
The excessively high impurity that can generate of the too long temperature of hydrolysis time is not easy to remove, and drug quality is caused to decline, and yield reduces.It will directly react
Acid or aqueous slkali be tuned into neutrality to will cause heat release serious, entire quantity of solvent increases, and reacts not easy to operate.
The method that the present invention prepares bilastine is the ingenious N using on sulfonic group and imidazoles piperidine ring in different temperatures item
Under part, under different alkaline conditions, activity in different solvents, low temperature preparation tosylat intermediate in water, weak in heat
Sulfonic group, which is left away, in buck prepares intermediate, inorganic strong alkali normal-temperature reaction is left away second in a small amount of highly polar protonic solvent
2-ethoxyethanol sulphonic acid ester sulfonic group, product IntermediateDirect crystallization is precipitated, aqueous solutions of organic acids reflux intermediate, add
Water reinforces alkali saturation, and aqueous solution back hydrolysis obtains bilastine salt, using bilastine salt in saturation lye solubility pole
Low characteristic, solvent directly extract bilastine salt, and a small amount of hydrochloric acid adjusting pH value is adjusted after recycling design and obtains bilastine.It is whole
A reaction process mild condition, easy to operate, solvent is simply common, convenient for industrialization, meets the developing direction of Green Chemistry.
Summary of the invention
Problem to be solved by this invention is: providing a kind of method for preparing bilastine, this method reaction process condition
Mildly, easy to operate, solvent is simply common, convenient for industrialization, meets the developing direction of Green Chemistry.
Technical solution provided by the invention are as follows: a method of prepare bilastine, comprising the following steps:
(1) chemical compounds I is added to the water, is acted under 0-5 degrees Celsius through alkali, Catalyzed By Phase-transfer Catalyst, with paratoluensulfonyl chloride
It is condensed to yield compound ii；
(2) compound ii is added to the water, phase transfer catalyst and weak base is added, compound 2-(4- piperidyl is added) 1-H- benzene
And imidazoles is stirred to react to obtain compound III under 60-100 degrees celsius；
(3) compound III is added in highly polar non-protonic solvent, and highly basic, phase transfer catalyst and ethylene glycol monoethyl ether is added
P-methyl benzenesulfonic acid ester, -20-60C ° are stirred to react 5-8 hours, obtain compounds Ⅳ.
(4) compounds Ⅳ is added in aqueous solutions of organic acids, is heated to reflux 1-3 hours, is obtained intermediate state hydrolysate, will be intermediate
State hydrolysate water supplement is added highly basic to being saturated, is heated to reflux 1-3 hours, generates bilastine sodium salt, solvent extraction, recycling
Solvent adds water, adjusts water pH value to neutrality and obtains bilastine；
Chemical compounds I, compound ii, the structural formula of compound III and compounds Ⅳ are as follows:
、、、。
Alkali in the step (1) includes: sodium hydroxide, potassium hydroxide, barium hydroxide, sodium methoxide, sodium ethoxide or tertiary fourth
Potassium alcoholate, phase transfer catalyst include: tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutyl iodate amine, polyethylene glycol dimethyl ether,
Polyethylene glycol diethyl ether, 18 hat, 6,15 hat 5 or cyclodextrin.The chemical compounds I, water, alkali, phase transfer catalyst, tolysulfonyl
The dosage weight ratio of chlorine is 100:500-2000:25-200:5-15:80-150.
In step (2), the weak base includes sodium carbonate, sodium bicarbonate, potassium carbonate, saleratus, calcium carbonate, magnesium carbonate,
Barium carbonate, cesium carbonate, triethylamine, diethylamine, ethylenediamine, propane diamine, butanediamine, ethanol amine, Propanolamine or butanolamine；Phase transfer
Catalyst includes: tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutyl iodate amine, benzyltriethylammoinium chloride, tetrabutyl sulfuric acid
Hydrogen ammonium, tri-n-octyl methyl ammonium chloride, dodecyl trimethyl ammonium chloride, tetradecyl trimethyl ammonium chloride, polyethylene glycol diformazan
Ether, polyethylene glycol diethyl ether, 18 hat, 6,15 hat 5 or cyclodextrin；Compound ii and compound 2-(4- piperidyl) 1-H- benzo miaow
The reaction temperature of azoles is 60-80C °.The compound ii, water, weak base, phase transfer catalyst, compound 2-(4- piperidyl) 1-
The dosage weight ratio of H- benzimidazole is 100:500-2000:80-200:5-15:80-200.
Highly polar non-protonic solvent includes n,N-Dimethylformamide in the step (3), n,N-dimethylacetamide,
Dimethyl sulfoxide, N-Methyl pyrrolidone or hexamethylphosphoramide；Highly polar non-protonic solvent dosage is raw material compound
1-2 times of III mass；Highly basic includes: sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide or potassium tert-butoxide；Phase transfer catalyst
It include: tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutyl iodate amine, benzyltriethylammoinium chloride, 4-butyl ammonium hydrogen sulfate,
Tri-n-octyl methyl ammonium chloride, dodecyl trimethyl ammonium chloride, tetradecyl trimethyl ammonium chloride, polyethylene glycol dimethyl ether are gathered
Ethylene glycol diethyl ether, 18 hat, 6,15 hat 5 or cyclodextrin；- 20-60C ° of reaction temperature.It is the compound III, highly polar non-proton
Property solvent, phase transfer catalyst, highly basic, ethylene glycol monoethyl ether p-methyl benzenesulfonic acid ester dosage weight ratio be 100:100-200:5-
15:25-80:100-200.
After the ethylene glycol monoethyl ether p-methyl benzenesulfonic acid ester is added by every batch of temperature heating less than 5 C ° condition in batches (such as
By its it is even be divided into 10 parts, every part is a batch) be added, to prevent temperature from flying up, sulphonic acid ester fracture is too late later and imidazoles piperazine
Pyridine condensation.
Aqueous solutions of organic acids is added in compounds Ⅳ in the step (4), and sour quality is the 20-50% of water quality, aqueous acid
Quality is 1-3 times of compounds Ⅳ quality；The amount by intermediate state hydrolysate water supplement is the 2-3 of IV mass of raw material compound
Times；Acid in aqueous solutions of organic acids includes: acetic acid, propionic acid, butyric acid or trifluoroacetic acid；Highly basic includes: sodium hydroxide, hydroxide
Potassium, sodium methoxide, sodium ethoxide or potassium tert-butoxide, extractant include: methylene chloride, chloroform, 1,2- dichloroethanes, acetonitrile,
Tetrahydrofuran or toluene.The dosage weight ratio of compounds Ⅳ, aqueous solutions of organic acids and highly basic is 100:120-180.
The present invention has the advantages that easy to operate, quantity of solvent is few, and important intermediate is pollution-free using water as reaction dissolvent, green
Colour circle is protected, and very high purity, high income, reaction condition is mild, not the generation of side reaction.
Detailed description of the invention
Attached drawing 1 is bilastine nucleus magnetic hydrogen spectrum figure (CD3OD) produced by the present invention；
Attached drawing 2 is bilastine nucleus magnetic hydrogen spectrum figure (DMSO) produced by the present invention；
Attached drawing 3 is bilastine mass spectrogram produced by the present invention.
Specific embodiment
A kind of method for preparing bilastine of the present invention, comprising the following steps:
By structureCompound be added to the water, cool to 0-5 degrees Celsius, alkali, phase transfer catalyst and tolysulfonyl be added
Structure is directly obtained by filtration after the completion of stirring condensation in chlorineCompound.Wherein the alkali includes sodium hydroxide, hydroxide
Sodium, potassium hydroxide, magnesium hydroxide, lithium hydroxide, barium hydroxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide or potassium tert-butoxide,
Wherein preferred sodium hydroxide or potassium hydroxide；Phase transfer catalyst includes tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutyl iodine
Change amine, benzyltriethylammoinium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, dodecyl trimethyl ammonium chloride, ten
Tetraalkyl trimethyl ammonium chloride, polyethylene glycol dimethyl ether, polyethylene glycol diethyl ether, 18 hat, 6,15 hat 5 or cyclodextrin.Wherein preferably
Tetrabutylammonium bromide.
By structureCompound be added to the water, be added phase transfer catalyst, be added weak base, be added compound 2-(4- piperazine
Piperidinyl) 1-H- benzimidazole, strong stirring, be heated to 60-70C ° react about 1 hour, be warming up to 70-80C ° of reaction 2-3 hours,
Structure is obtained by filtration while hotCompound.Wherein the phase transfer catalyst includes: tetrabutylammonium chloride, tetrabutyl phosphonium bromide
Ammonium, tetrabutyl iodate amine, benzyltriethylammoinium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, dodecyl front three
Ammonium chloride, tetradecyl trimethyl ammonium chloride, polyethylene glycol dimethyl ether, 6,15 hat 5 of polyethylene glycol diethyl ether or 18 hat, ring paste
Essence.Wherein preferred tetrabutylammonium bromide；Weak base includes sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, barium carbonate, triethylamine, and three
Propylamine or tri-n-butylamine；Wherein preferred sodium carbonate or potassium carbonate.
By structureCompound be added in a small amount of highly polar non-protonic solvent, strong basic solid is added, phase is added and turns
Shifting catalyst, -20-60C ° of ethylene glycol monoethyl ether p-methyl benzenesulfonic acid esters are even to be divided into 10 parts, is added portionwise, in when addition each temperature
It rises and is no more than 5 °, add and be stirred to react, as reaction carries out compoundGradually dissolving, compounds Ⅳ direct crystallization is precipitated,
Fully reacting in 5-8 hours is directly filtered, and washing removes excess base and impurity.Wherein the solvent includes N, N- dimethyl
Formamide (DMF), n,N-dimethylacetamide (DMAC), dimethyl sulfoxide (DMSO), N-Methyl pyrrolidone (NMP), pregnancy
Base phosphoric triamide (HMPA), acetonitrile, propionitrile, quantity of solvent are 1-2 times of raw material；Wherein preferred DMSO, quantity of solvent are 1.5 times.By force
Alkali includes: sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium hydroxide, barium hydroxide, sodium methoxide, potassium methoxide, sodium ethoxide, ethyl alcohol
Potassium or potassium tert-butoxide；Phase transfer catalyst includes: tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutyl iodate amine, three second of benzyl
Ammonium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride or dodecyl trimethyl ammonium chloride, tetradecyltrimethylammonium
Ammonium chloride, polyethylene glycol dimethyl ether, polyethylene glycol diethyl ether, 18 hat, 6,15 hat 5 or cyclodextrin.Wherein preferred sodium hydroxide, four
Butylammonium bromide, preferred 25C ° of temperature.
Compounds Ⅳ is added in aqueous solutions of organic acids, organic acid quality is the 20-50% of water quality, sour water solvent matter
Amount is 1.0-3.0 times of raw material, is heated to reflux 1-3 hours, obtains intermediate state hydrolysate, adds 2-5 times and measure aqueous solution, cool to
10 degree, highly basic saturation is added, is heated to reflux 1-3 hours, generates bilastine sodium salt, sodium salt solubility pole in saturation aqueous slkali
Low, solvent extraction, recycling design adds water, adjusts water pH value to neutrality and obtains bilastine.Wherein the organic acid includes: second
Acid, propionic acid, malonic acid, butyric acid, succinic acid, trifluoroacetic acid, malic acid or succinic acid；It is preferred that acetic acid.Wherein the highly basic includes:
Sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium hydroxide, barium hydroxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide or uncle
Butanol potassium；It is preferred that sodium hydroxide, potassium hydroxide.Wherein the extractant includes: methylene chloride, chloroform, 1,2- dichloro
Ethane, acetonitrile, tetrahydrofuran or toluene；It is preferred that methylene chloride.
Reaction process of the present invention is as follows:
OTs is p-toluenesulfonyl in formula.
The present invention is further illustrated by the following examples, but not as limitation of the present invention.
CompoundPreparation
(1) 100g compoundIt is added in 500ml water, tetrabutylammonium bromide 5g is added, cool to 5C °, sodium hydroxide is added
25g is added paratoluensulfonyl chloride 90g, is stirred to react 5-6 hours, crude product is directly obtained by filtration, and 500ml isopropyl is added after washing
Alcohol heating, 0C ° stirred crystallization 3-5 hours after dissolution, filtering can obtain white solid 140g, yield 90%., purity 98.8%.
(2) 100g compoundIt is added in 500ml water, tetrabutylammonium bromide 5g is added, cool to 5C °, potassium hydroxide is added
30g is added paratoluensulfonyl chloride 90g, is stirred to react 5-6 hours, crude product is directly obtained by filtration, and 500ml isopropyl is added after washing
Alcohol heating, 0C ° stirred crystallization 3-5 hours after dissolution, filtering can obtain white solid 135g, yield 86%., purity 98.6%.
CompoundPreparation
(1) 100g compoundIt is added in 500ml water, tetrabutylammonium bromide 10g is added, sodium carbonate 100g is added, be added
100g compound 2-(4- piperidyl) 1-H- benzimidazole, strong stirring is first warming up to 60-70C ° and is stirred to react 1 hour, it is seen that
Suspension becomes slightly limpid emulsion, and being heated to 70-80C °, the reaction was continued 3 hours, and white solid is largely precipitated, and re-forms
Suspension directly filters while hot, and the complete imidazoles piperidines of unreacted and impurity are soluble in water, obtained solid ethyl acetate 500ml
Heating and refluxing to dissolve, is cooled to 20C ° of stirring half an hour, and filtering can obtain white solid 95g, yield 90%, purity 99.2%.
(2) 100g compoundIt is added in 500ml water, tetrabutylammonium iodide 10g is added, potassium carbonate 100g is added, adds
Enter 100g compound 2-(4- piperidyl) 1-H- benzimidazole, strong stirring is first warming up to 60-70C ° and is stirred to react 1 hour, can
See that suspension becomes slightly limpid emulsion, being heated to 70-80C °, the reaction was continued 3 hours, and white solid is largely precipitated, again shape
At suspension, directly filter while hot, the complete imidazoles piperidines of unreacted and impurity are soluble in water, obtained solid ethyl acetate
500ml heating and refluxing to dissolve, is cooled to 20C ° of stirring half an hour, and filtering can obtain white solid 92g, yield 85%, purity
99.1%。
(3) 100g compoundIt is added in 500ml water, tetrabutylammonium bromide 10g is added, triethylamine 100g is added, adds
Enter 100g compound 2-(4- piperidyl) 1-H- benzimidazole, strong stirring is first warming up to 60-70C ° and is stirred to react 1 hour, can
See that suspension becomes slightly limpid emulsion, being heated to 70-80C °, the reaction was continued 3 hours, and white solid is largely precipitated, again shape
At suspension, directly filter while hot, the complete imidazoles piperidines of unreacted and impurity are soluble in water, obtained solid ethyl acetate
500ml dissolves heating and refluxing to dissolve, is cooled to 20C ° of stirring half an hour, filtering can obtain white solid 80g, yield 70%, purity
99.0%。
The preparation of compounds Ⅳ
(1) 100g compoundIt is added in 150ml dimethyl sulfoxide, tetrabutylammonium bromide 5g is added, sodium hydroxide is added
25g, 15C ° of ethylene glycol monoethyl ether p-methyl benzenesulfonic acid ester 120g are even to be divided into 10 parts, is added portionwise in reactor, after being added every time
Temperature heating adds 25C ° and is stirred to react 5-6 hour less than 5 C °, it is seen that reaction solution becomes limpid and change by muddiness in reaction process
Muddiness directly filters, and obtains white solid, and a small amount of dimethyl sulfoxide elution is drained, and solid is added to stirring in 500ml water and washes away
Sodium hydroxide, paratoluenesulfonic acid sodium salt and a small amount of dimethyl sulfoxide, filtering can obtain white solid (compounds Ⅳ) 95g, yield
90%, purity 99.1%.
(2) 100g compoundIt is added in 150ml acetonitrile, tetrabutylammonium bromide 5g is added, sodium hydroxide 25g is added,
15C ° is added portionwise ethylene glycol monoethyl ether p-methyl benzenesulfonic acid ester 120g, adds 25C ° and is stirred to react 5-6 hours, it is seen that reaction process
Middle reaction solution is become limpid by muddiness and is become cloudy, and directly filters, and obtains white solid, and a small amount of dimethyl sulfoxide elution is drained, solid
It is added to stirring in 500ml water and washes away sodium hydroxide, paratoluenesulfonic acid sodium salt and a small amount of acetonitrile, filtering can obtain white solid and (change
Close object IV) 78g, yield 75%, purity 99.1%.
(3) 100g compoundIt is added in 150ml n,N-Dimethylformamide (DMF), tetrabutylammonium bromide is added
Sodium hydroxide 25g is added in 5g, and 15C ° is added portionwise ethylene glycol monoethyl ether p-methyl benzenesulfonic acid ester 120g, adds 25C ° and is stirred to react
5-6 hours, it is seen that reaction solution is become limpid by muddiness and become cloudy in reaction process, directly filters, obtains white solid, a small amount of DMF
Elution, is drained, and solid is added to stirring in 500ml water and washes away sodium hydroxide, paratoluenesulfonic acid sodium salt and a small amount of N, N- dimethyl
Formamide, filtering can obtain white solid (compounds Ⅳ) 82g, yield 78%, purity 99.1%.
(4) 100g compoundIt is added in 150ml N-Methyl pyrrolidone (NMP), tetrabutylammonium bromide 5g is added,
Sodium hydroxide 25g is added, 15C ° is added portionwise ethylene glycol monoethyl ether p-methyl benzenesulfonic acid ester 120g, adds 25C ° and is stirred to react 5-6
Hour, it is seen that reaction solution is become limpid by muddiness and is become cloudy in reaction process, directly filters, obtains white solid, a small amount of N- methyl
Pyrrolidones elution, is drained, and solid is added to stirring in 500ml water and washes away sodium hydroxide, paratoluenesulfonic acid sodium salt and a small amount of N-
Methyl pyrrolidone, filtering can obtain white solid (compounds Ⅳ) 85g, yield 81%, purity 99.1%.
(5) 100g compoundIt is added in 150ml hexamethylphosphoramide (HMPA), tetrabutylammonium bromide 5g is added,
Sodium hydroxide 25g is added, 15C ° is added portionwise ethylene glycol monoethyl ether p-methyl benzenesulfonic acid ester 120g, adds 25C ° and is stirred to react 5-6
Hour, it is seen that reaction solution is become limpid by muddiness and is become cloudy in reaction process, directly filters, obtains white solid, a small amount of hexamethyl
Phosphoric triamide (HMPA) elution, is drained, and solid is added in 500ml water stirring and washes away sodium hydroxide, paratoluenesulfonic acid sodium salt and few
The hexamethylphosphoramide of amount, filtering can obtain white solid (compounds Ⅳ) 65g, yield 62%, purity 99.1%.
The preparation of bilastine
(1) glacial acetic acid 20g is added in 100g compounds Ⅳ, adds water 100ml, is heated to reflux 3 hours, obtains yellowish aqueous solution, water supplement
Sodium hydroxide 150g is added in 200ml, and heating stirring flows back 2-3 hours, drops to methylene chloride 100ml stirring extraction after room temperature, returns
Methylene chloride is received, obtaining white solid is bilastine sodium salt, adds water 200ml, and 5N hydrochloric acid adjusts pH value to 7-8, is precipitated a large amount of white
Color lenticular bilastine, filtering can obtain white solid 75g, yield 85%, purity 99.4% after stirring 3 hours.
(2) propionic acid 25g is added in 100g compounds Ⅳ, adds water 100ml, is heated to reflux 3 hours, obtains faint yellow aqueous solution, add
Potassium hydroxide 150g is added in water 300ml, and heating stirring flows back 2-3 hours, drops to methylene chloride 100ml stirring extraction after room temperature,
Methylene chloride is recycled, obtaining white solid is bilastine sodium salt, adds water 200ml, and 5N hydrochloric acid adjusts pH value to 7-8, is precipitated a large amount of
White crystalline bilastine, filtering can obtain white solid 72g, yield 81%, purity 99.2% after stirring 3 hours.
(3) malonic acid 20g is added in 100g compounds Ⅳ, adds water 100ml, is heated to reflux 3 hours, obtains yellowish aqueous solution, mends
Add water 200ml, sodium hydroxide 150g is added, heating stirring flows back 2-3 hours, drops to methylene chloride 100ml stirring extraction after room temperature
It takes, recycles methylene chloride, obtaining white solid is bilastine sodium salt, adds water 200ml, and 5N hydrochloric acid adjusts pH value to 7-8, is precipitated big
White crystalline bilastine is measured, filtering can obtain white solid 70g, yield 78%, purity 99.0% after stirring 3 hours.
(4) butyric acid 25g is added in 100g compounds Ⅳ, adds water 100ml, is heated to reflux 3 hours, obtains yellowish aqueous solution, mends
Add water 200ml, sodium hydroxide 150g is added, heating stirring flows back 2-3 hours, drops to methylene chloride 100ml stirring extraction after room temperature
It takes, recycles methylene chloride, obtaining white solid is bilastine sodium salt, adds water 200ml, and 5N hydrochloric acid adjusts pH value to 7-8, is precipitated big
White crystalline bilastine is measured, filtering can obtain white solid 64g, yield 70%, purity 99.1% after stirring 3 hours.
(5) succinic acid 20g is added in 100g compounds Ⅳ, adds water 100ml, is heated to reflux 3 hours, obtains yellowish aqueous solution,
Add water 200ml, sodium hydroxide 150g is added, heating stirring flows back 2-3 hours, drops to methylene chloride 100ml stirring extraction after room temperature
It takes, recycles methylene chloride, obtaining white solid is bilastine sodium salt, adds water 200ml, and 5N hydrochloric acid adjusts pH value to 7-8, is precipitated big
White crystalline bilastine is measured, filtering can obtain white solid 64g, yield 72%, purity 99.2% after stirring 3 hours.
(6) malic acid 20g is added in 100g compounds Ⅳ, adds water 100ml, is heated to reflux 3 hours, obtains yellowish aqueous solution,
Add water 200ml, sodium hydroxide 150g is added, heating stirring flows back 2-3 hours, drops to methylene chloride 100ml stirring extraction after room temperature
It takes, recycles methylene chloride, obtaining white solid is bilastine sodium salt, adds water 200ml, and 5N hydrochloric acid adjusts pH value to 7-8, is precipitated big
White crystalline bilastine is measured, filtering can obtain white solid 68g, yield 76%, purity 99.1% after stirring 3 hours.
(7) succinic acid 20g is added in 100g compounds Ⅳ, adds water 100ml, is heated to reflux 3 hours, obtains yellowish aqueous solution,
Add water 200ml, sodium hydroxide 150g is added, heating stirring flows back 2-3 hours, drops to methylene chloride 100ml stirring extraction after room temperature
It takes, recycles methylene chloride, obtaining white solid is bilastine sodium salt, adds water 200ml, and 5N hydrochloric acid adjusts pH value to 7-8, is precipitated big
White crystalline bilastine is measured, filtering can obtain white solid 66g, yield 75%, purity 99.1% after stirring 3 hours.
Bilastine nucleus magnetic hydrogen spectrum figure and mass spectrum produced by the present invention are as shown in Figure 1, Figure 2, Figure 3 shows.
Claims (6)
1. a kind of method for preparing bulk pharmaceutical chemicals bilastine, which comprises the following steps: (1) water is added in chemical compounds I
In, it is acted under 0-5 degrees Celsius through alkali, Catalyzed By Phase-transfer Catalyst, is condensed to yield compound ii with paratoluensulfonyl chloride；(2) will
Compound ii is added to the water, and phase transfer catalyst and weak base is added, and compound 2-(4- piperidyl is added) 1-H- benzimidazole exists
It is stirred to react to obtain compound III under 60-100 degrees celsius；(3) compound III is added in highly polar non-protonic solvent,
Highly basic, phase transfer catalyst and ethylene glycol monoethyl ether p-methyl benzenesulfonic acid ester is added, -20-60C ° are stirred to react 5-8 hours, obtain
Compounds Ⅳ；(4) compounds Ⅳ is added in aqueous solutions of organic acids, is heated to reflux 1-3 hours, is obtained intermediate state hydrolysate, will in
Between state hydrolysate water supplement, be added highly basic to be saturated, be heated to reflux 1-3 hour, generate bilastine sodium salt, solvent extraction, time
Solvent is received, water is added, water pH value is adjusted to neutrality and obtains bilastine；
Chemical compounds I, compound ii, the structural formula of compound III and compounds Ⅳ are as follows:
、、、。
2. the method according to claim 1, wherein the alkali in the step (1) includes: sodium hydroxide, hydrogen-oxygen
Changing potassium, barium hydroxide, sodium methoxide, sodium ethoxide or potassium tert-butoxide, phase transfer catalyst includes: tetrabutylammonium chloride, tetrabutyl bromine
Change ammonium, tetrabutyl iodate amine, polyethylene glycol dimethyl ether, polyethylene glycol diethyl ether, 18 hat, 6,15 hat 5 or cyclodextrin.
3. the method according to claim 1, wherein the weak base includes sodium carbonate, bicarbonate in step (2)
Sodium, potassium carbonate, saleratus, calcium carbonate, magnesium carbonate, barium carbonate, cesium carbonate, triethylamine, diethylamine, ethylenediamine, propane diamine, fourth
Diamines, ethanol amine, Propanolamine or butanolamine；Phase transfer catalyst includes: tetrabutylammonium chloride, tetrabutylammonium bromide, the tetrabutyl
Iodate amine, benzyltriethylammoinium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, dodecyl trimethyl ammonium chloride,
Tetradecyl trimethyl ammonium chloride, polyethylene glycol dimethyl ether, polyethylene glycol diethyl ether, 18 hat, 6,15 hat 5 or cyclodextrin；Compound
II with compound 2-(4- piperidyl) 1-H- benzimidazole reaction temperature be 60-80C °.
4. the method according to claim 1, wherein highly polar non-protonic solvent includes in the step (3)
N,N-Dimethylformamide, n,N-dimethylacetamide, dimethyl sulfoxide, N-Methyl pyrrolidone or hexamethylphosphoramide；
Highly polar non-protonic solvent dosage is 1-2 times of III mass of raw material compound；Highly basic includes: sodium hydroxide, potassium hydroxide, first
Sodium alkoxide, sodium ethoxide or potassium tert-butoxide；Phase transfer catalyst includes: tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutyl iodate
Amine, benzyltriethylammoinium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, dodecyl trimethyl ammonium chloride, 14
Alkyl trimethyl ammonium chloride, polyethylene glycol dimethyl ether, polyethylene glycol diethyl ether, 18 hat, 6,15 hat 5 or cyclodextrin；Reaction temperature-
20 -60C°。
5. according to the method described in claim 4, it is characterized in that, the ethylene glycol monoethyl ether p-methyl benzenesulfonic acid ester is added by every batch of
Enter the heating of rear temperature to be added portionwise less than 5 C ° of conditions.
6. the method according to claim 1, wherein compounds Ⅳ addition organic acid is water-soluble in the step (4)
Liquid, aqueous solutions of organic acids quality are 1-3 times of IV mass of raw material compound, and sour quality is water quality in aqueous solutions of organic acids
20-50%；The amount by intermediate state hydrolysate water supplement is 2-3 times of IV mass of raw material compound；；In aqueous solutions of organic acids
Acid include: acetic acid, propionic acid, butyric acid, trifluoroacetic acid, malic acid or succinic acid；Highly basic includes: sodium hydroxide, potassium hydroxide, first
Sodium alkoxide, sodium ethoxide or potassium tert-butoxide, extractant include: methylene chloride, chloroform, 1,2- dichloroethanes, acetonitrile, tetrahydro furan
It mutters or toluene.
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