CN102675101B - Preparation method of 2-(4-haloethyl) phenyl-2-methyl propionic ester and synthesis method of bilastine - Google Patents
Preparation method of 2-(4-haloethyl) phenyl-2-methyl propionic ester and synthesis method of bilastine Download PDFInfo
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Abstract
The invention discloses a preparation method of 2-(4-haloethyl) phenyl-2-methyl propionic ester and a synthesis method of bilastine, which comprises the following steps of: carrying out acylation reaction on 2, 2-dimethyl phenylacetate and halogen acetyl halides under the action of catalyst, to generate 2-(4-halogen acetyl) phenyl-2-methyl propionic ester; carrying out kishner-wolff-huang reduction reaction on the 2-(4-halogen acetyl) phenyl-2-methyl propionic ester, to reduce the carbonyl so as to generate the 2-(4-haloethyl) phenyl-2-methyl propionic ester; having condensation reaction with 1-ethoxy ethyl-2-pyridine-4-group benzimidazole by taking the 2-(4-haloethyl) phenyl-2-methyl propionic ester as a midbody to obtain esterified bilastine; and hydrolyzing, to generate the bilastine. The novel synthesis method of the bilastine provided by the invention can easily obtain raw materials, and is simple to operate, lower in cost, environment-friendly, and completely suitable for the industrial production.
Description
Technical field
The invention belongs to the synthetic field of medicine, be specifically related to the preparation method of a kind of 2-(4-haloethyl) phenyl-2 Methylpropionic acid ester and the method for synthetic bilastine.
Background technology
The 2nd generation histamine H of bilastine (Bilastine) ，Wei Spain FAES drugmaker exploitation
1receptor antagonist, European Union in 2010 ratifies it and is used for the treatment of rhinallergosis and chronic idiopathic urticaria.This product security is good, variable sedative effect and the cardiac toxic existing by antihistamine drug.
Chemical structural formula:
CAS：202189-78-4。
WO2009102155 has reported the synthetic method of bilastine, and its synthetic route is as follows:
In the method, key intermediate 2-(4-hydroxyethyl phenyl)-2 Methylpropionic acid ethyl ester (compound
3) synthetic be with to bromobenzene ethanol (compound
1) and 1-methoxyl group-1-(trimethylammonium silyloxy)-2-methyl-1-propylene (compound
2) be raw material, at the two (bis-Ya Benzyl benzylacetones of catalyzer) palladium, tri-tert phosphorus and zinc fluoride exist lower condensation to make.
This reaction mainly contains three shortcomings, the first, raw material 1-methoxyl group-1-(trimethylammonium silyloxy) price such as-2-methyl-1-propylene and two (the two sub-Benzyl benzylacetones) palladiums of catalyzer and tri-tert phosphorus is all extremely expensive, and be difficult for buying, and be difficult for preserving; The second, the anhydrous and oxygen-free condition that this reaction needed is very strict, complicated operation, and products therefrom is difficult to purifying; The 3rd, react rear remaining palladium and phosphorus and all can cause severe contamination to environment.
In sum, this route cost is higher, and operational difficulty pollutes greatly, is difficult to realize suitability for industrialized production.
Summary of the invention
Object one of the present invention has been to provide a kind of new intermediate of synthetic antihistamine drug bilastine, object two of the present invention is to provide the synthetic method of this new intermediate, object three of the present invention is to provide a kind of method that adopts this intermediate to prepare bilastine, the method has been avoided the reaction conditions of harshness in prior art, and raw material is easy to get, simple to operate, cost is lower, environmental friendliness, is applicable to suitability for industrialized production.
The technical scheme of object one of the present invention is: a kind of 2-(4-haloethyl) phenyl-2 Methylpropionic acid ester, and it has the structural formula shown in formula (I):
Wherein, the alkyl that R1 is C1～C5, X is Cl or Br.
Object two of the present invention is to provide the method for a kind of synthetic 2-(4-haloethyl) phenyl-2 Methylpropionic acid ester, comprises the following steps:
A, in solvent, there is acylation reaction in 2,2-dimethyl phenyl acetic acid ester and halogen acetyl halide, generate 2-(4-halogen ethanoyl) phenyl-2 Methylpropionic acid ester under catalyst action;
B, 2-(4-halogen ethanoyl) phenyl-2 Methylpropionic acid ester carries out reduction reaction, and reducing carbonyl generates 2-(4-haloethyl) phenyl-2 Methylpropionic acid ester.
Further, the solvent described in step a is any in methylene dichloride, tetrahydrofuran (THF), DMF or Nitromethane 99Min.; Described halogen acetyl halide is any in chloroacetyl chloride, chloro-acetyl bromide, bromoacetyl chloride or bromoacetyl bromide; Described catalyzer is aluminum chloride, and the acylation reaction temperature described in step a is 0～100 ℃, and the described acylation reaction time is 1～24 hour.
Further, in b step, reduction reaction adopts this Nellie-Wolf of base-Huang Min-lon reduction reaction, and reaction system solvent is polyoxyethylene glycol, and temperature of reaction is 100～200 ℃, and the reaction times is 1～8 hour.
During reduction reaction, can also protect carbonyls with contracting two mercaptan, then Raney's nickel reduces or reduces with triethyl silicane and trifluoracetic acid; But because Raney's nickel may fall halogen, and triethyl silicane cost is too high, so preferably adopt this Nellie-Wolf of base-Huang Min-lon reduction reaction.
Preferably, the solvent described in step a is methylene dichloride, and described halogen acetyl halide is chloroacetyl chloride, and described acidylate temperature is 5 ℃, and the described acylation reaction time is 3 hours; The temperature of reaction of the reduction reaction described in step b is 180 ℃; Reaction times is for being 3 hours.
Object three of the present invention is to provide a kind of method of synthetic bilastine, and it comprises the steps:
A, in solvent, there is acylation reaction in 2,2-dimethyl phenyl acetic acid ester and halogen acetyl halide, generate 2-(4-halogen ethanoyl) phenyl-2 Methylpropionic acid ester under catalyst action;
B, 2-(4-halogen ethanoyl) phenyl-2 Methylpropionic acid ester carries out reduction reaction, and reducing carbonyl generates 2-(4-haloethyl) phenyl-2 Methylpropionic acid ester.
Under c, alkali exist, 2-(4-haloethyl) phenyl-2 Methylpropionic acid ester and 1-ethoxyethyl-2-pyridin-4-yl benzoglyoxaline generation condensation reaction obtain the bilastine of esterification;
D, in solvent, there is ester hydrolysis reaction in the bilastine of esterification, generate bilastine under catalyst action.
Further, the solvent described in step a is any in methylene dichloride, tetrahydrofuran (THF), DMF or Nitromethane 99Min.; Described halogen acetyl halide is any in chloroacetyl chloride, chloro-acetyl bromide, bromoacetyl chloride or bromoacetyl bromide; Described catalyzer is aluminum chloride, and the acylation reaction temperature described in step a is 0～100 ℃, and the described acylation reaction time is 1～24 hour.
Further, in b step, reduction reaction adopts this Nellie-Wolf of base-Huang Min-lon reduction reaction, and reaction system solvent is polyoxyethylene glycol, and temperature of reaction is 100～200 ℃, and the reaction times is 1～8 hour.
Further, the alkali described in step c is any in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium hydride, triethylamine, pyridine or DIPEA, and setting-up point is 0～100 ℃, and the reaction times is 1～24 hour.
Further, the solvent described in steps d is one or more the combination in methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), water or acetone; Described catalyzer is any in sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate or salt of wormwood, and temperature of reaction is 0～100 ℃, and the reaction times is 1～24 hour.
Particularly, the solvent described in step a is methylene dichloride, and described halogen acetyl halide is chloroacetyl chloride, and described acidylate temperature is 5 ℃, and the described acylation reaction time is 3 hours; The temperature of reaction of the reduction reaction described in step b is 180 ℃; Reaction times is for being 3 hours.Alkali described in step c is sodium carbonate, and setting-up point is 80 ℃; Reaction times is 16 hours; Catalyzer described in steps d is lithium hydroxide, and temperature of reaction is 70 ℃, and the reaction times is 16 hours.
Its synthetic route is as follows:
The present invention compared with prior art tool has the following advantages:
The invention provides a kind of synthetic method of antihistamine drug bilastine, the great advantage of the method is embodied in the synthetic of key intermediate 2-(4-haloethyl) phenyl-2 Methylpropionic acid ester.
The present invention uses Fu Ke acidylate; reduction makes key intermediate 2-(4-haloethyl) phenyl-2 Methylpropionic acid ester; two-step reaction is popular response; without special reagent; desired raw material is cheaply easy to get, and has avoided the tri-tert phosphorus using in former technique, two (bis-Ya Benzyl benzylacetone) expensive reagent such as palladium.
The raw material 1-methoxyl group-1-(trimethylammonium silyloxy using in former technique)-2-methyl-1-propylene and catalyzer tri-tert phosphorus, two (bis-Ya Benzyl benzylacetone) palladium etc. is all unstable, so reaction needed is carried out under strict anhydrous and oxygen-free condition; And in method provided by the present invention, feedstock property is stable, therefore reaction is without exacting terms, simple to operate.
In former technique, react remaining palladium compound and phosphorus compound all can cause severe contamination to environment, and the present invention having avoided the use of these reagent, is therefore eco-friendly.
In sum, the new synthetic method raw material of bilastine provided by the present invention is easy to get, and simple to operate, cost is lower, and environmental friendliness is applicable to suitability for industrialized production completely.
Embodiment
The exemplary embodiment of the present invention that provides following description to be limited by claim and equivalent thereof to help complete understanding.Below describe and comprise that various specific detail are to help understanding, but that these are only considered to is exemplary.Therefore, those of ordinary skill in the art will recognize, can make various changes and modification to embodiment described here without departing from the scope and spirit of the present invention.In addition, for clarity and brevity, omitted the description of known function and structure.
(4-haloethyl) phenyl-2 Methylpropionic acid ester, it has the structural formula shown in formula (I):
Wherein, the alkyl that R1 is C1～C5, X is Cl or Br.
A method for synthetic 2-(4-haloethyl) phenyl-2 Methylpropionic acid ester, comprises the following steps:
A, in solvent, there is acylation reaction in 2,2-dimethyl phenyl acetic acid ester and halogen acetyl halide, generate 2-(4-halogen ethanoyl) phenyl-2 Methylpropionic acid ester under catalyst action;
B, 2-(4-halogen ethanoyl) phenyl-2 Methylpropionic acid ester carries out reduction reaction, and reducing carbonyl generates 2-(4-haloethyl) phenyl-2 Methylpropionic acid ester.
Further, the solvent described in step a is any in methylene dichloride, tetrahydrofuran (THF), DMF or Nitromethane 99Min.; Described halogen acetyl halide is any in chloroacetyl chloride, chloro-acetyl bromide, bromoacetyl chloride or bromoacetyl bromide; Described catalyzer is aluminum chloride, and the acylation reaction temperature described in step a is 0～100 ℃, and the described acylation reaction time is 1～24 hour.
Further, in b step, reduction reaction adopts this Nellie-Wolf of base-Huang Min-lon reduction reaction, and reaction system solvent is polyoxyethylene glycol, and temperature of reaction is 100～200 ℃, and the reaction times is 1～8 hour.
Preferably, the solvent described in step a is methylene dichloride, and described halogen acetyl halide is chloroacetyl chloride, and described acidylate temperature is 5 ℃, and the described acylation reaction time is 3 hours; The temperature of reaction of the reduction reaction described in step b is 180 ℃; Reaction times is for being 3 hours.
A method for synthetic bilastine, it comprises the steps:
A, in solvent, there is acylation reaction in 2,2-dimethyl phenyl acetic acid ester and halogen acetyl halide, generate 2-(4-halogen ethanoyl) phenyl-2 Methylpropionic acid ester under catalyst action;
B, 2-(4-halogen ethanoyl) phenyl-2 Methylpropionic acid ester carries out reduction reaction, and reducing carbonyl generates 2-(4-haloethyl) phenyl-2 Methylpropionic acid ester.
Under c, alkali exist, 2-(4-haloethyl) phenyl-2 Methylpropionic acid ester and 1-ethoxyethyl-2-pyridin-4-yl benzoglyoxaline generation condensation reaction obtain the bilastine of esterification;
D, in solvent, there is ester hydrolysis reaction in the bilastine of esterification, generate bilastine under catalyst action.
Further, the solvent described in step a is any in methylene dichloride, tetrahydrofuran (THF), DMF or Nitromethane 99Min.; Described halogen acetyl halide is any in chloroacetyl chloride, chloro-acetyl bromide, bromoacetyl chloride or bromoacetyl bromide; Described catalyzer is aluminum chloride, and the acylation reaction temperature described in step a is 0～100 ℃, and the described acylation reaction time is 1～24 hour.
Further, in b step, reduction reaction adopts this Nellie-Wolf of base-Huang Min-lon reduction reaction, and reaction system solvent is polyoxyethylene glycol, and temperature of reaction is 100～200 ℃, and the reaction times is 1～8 hour.
Further, the alkali described in step c is any in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium hydride, triethylamine, pyridine or DIPEA, and setting-up point is 0～100 ℃, and the reaction times is 1～24 hour.
Further, the solvent described in steps d is one or more the combination in methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), water or acetone; Described catalyzer is any in sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate or salt of wormwood, and temperature of reaction is 0～100 ℃, and the reaction times is 1～24 hour.
Particularly, the solvent described in step a is methylene dichloride, and described halogen acetyl halide is chloroacetyl chloride, and described acidylate temperature is 5 ℃, and the described acylation reaction time is 3 hours; The temperature of reaction of the reduction reaction described in step b is 180 ℃; Reaction times is for being 3 hours.Alkali described in step c is sodium carbonate, and setting-up point is 80 ℃; Reaction times is 16 hours; Catalyzer described in steps d is lithium hydroxide, and temperature of reaction is 70 ℃, and the reaction times is 16 hours.
synthetic 2-(4-haloethyl) phenyl-2 Methylpropionic acid ester of embodiment 1
A, in methylene dichloride, under aluminum chloride effect, there is acylation reaction in 2,2-dimethyl phenyl acetic acid ester and chloroacetyl chloride, acylation reaction condition is: temperature is 5 ℃; Time is 3 hours, generates 2-(4-halogen ethanoyl) phenyl-2 Methylpropionic acid ester,
This Nellie-Wolf of b, 2-(4-halogen ethanoyl) phenyl-2 Methylpropionic acid ester generation base-Huang Min-lon reduction reaction, reducing carbonyl generates 2-(4-haloethyl) phenyl-2 Methylpropionic acid ester; Reduction reaction conditions is: solvent is polyoxyethylene glycol, and temperature of reaction is 180 ℃; Reaction times is 3 hours.
synthetic 2-(4-haloethyl) phenyl-2 Methylpropionic acid ester of embodiment 2
A, in tetrahydrofuran (THF), under aluminum chloride effect, there is acylation reaction in 2,2-dimethyl phenyl acetic acid ester and bromoacetyl bromide, acylation reaction condition is: temperature is 0 ℃; Time is 24 hours, generates 2-(4-halogen ethanoyl) phenyl-2 Methylpropionic acid ester,
This Nellie-Wolf of b, 2-(4-halogen ethanoyl) phenyl-2 Methylpropionic acid ester generation base-Huang Min-lon reduction reaction, reducing carbonyl generates 2-(4-haloethyl) phenyl-2 Methylpropionic acid ester; Reduction reaction conditions is: solvent is polyoxyethylene glycol, and temperature of reaction is 100 ℃; Reaction times is 8 hours.
synthetic 2-(4-haloethyl) phenyl-2 Methylpropionic acid ester of embodiment 3
A, in Nitromethane 99Min., under aluminum chloride effect, there is acylation reaction in 2,2-dimethyl phenyl acetic acid ester and chloro-acetyl bromide, acylation reaction condition is: temperature is 100 ℃; Time is 1 hour, generates 2-(4-halogen ethanoyl) phenyl-2 Methylpropionic acid ester,
This Nellie-Wolf of b, 2-(4-halogen ethanoyl) phenyl-2 Methylpropionic acid ester generation base-Huang Min-lon reduction reaction, reducing carbonyl generates 2-(4-haloethyl) phenyl-2 Methylpropionic acid ester; Reduction reaction conditions is: solvent is polyoxyethylene glycol, and temperature of reaction is 200 ℃; Reaction times is 1 hour.
it is the synthetic bilastine of intermediate that embodiment 4 utilizes 2-(4-haloethyl) phenyl-2 Methylpropionic acid ester
First by preparation 2-(4-haloethyl) phenyl-2 Methylpropionic acid ester of embodiment 1,2 or 3;
Under sodium carbonate exists, 2-(4-haloethyl) phenyl-2 Methylpropionic acid ester and 1-ethoxyethyl-2-pyridin-4-yl benzoglyoxaline generation condensation reaction obtain the bilastine of esterification; The condition of condensation reaction is: temperature of reaction is 80 ℃; Reaction times is 16 hours.
In solvent methanol, there is ester hydrolysis reaction in the bilastine of esterification under lithium hydroxide effect, generates bilastine.The condition of hydrolysis reaction is: temperature of reaction is 70 ℃; Reaction times is 16 hours.
it is the synthetic bilastine of intermediate that embodiment 5 utilizes 2-(4-haloethyl) phenyl-2 Methylpropionic acid ester
First by preparation 2-(4-haloethyl) phenyl-2 Methylpropionic acid ester of embodiment 1,2 or 3;
Under sodium hydroxide exists, 2-(4-haloethyl) phenyl-2 Methylpropionic acid ester and 1-ethoxyethyl-2-pyridin-4-yl benzoglyoxaline generation condensation reaction obtain the bilastine of esterification; The condition of condensation reaction is: temperature of reaction is 0 ℃; Reaction times is 24 hours.
In solvents tetrahydrofurane, there is ester hydrolysis reaction in the bilastine of esterification under sodium hydroxide effect, generates bilastine.The condition of hydrolysis reaction is: temperature of reaction is 0 ℃; Reaction times is 24 hours.
it is the synthetic bilastine of intermediate that embodiment 6 utilizes 2-(4-haloethyl) phenyl-2 Methylpropionic acid ester
First by preparation 2-(4-haloethyl) phenyl-2 Methylpropionic acid ester of embodiment 1,2 or 3;
Under DIPEA exists, 2-(4-haloethyl) phenyl-2 Methylpropionic acid ester and 1-ethoxyethyl-2-pyridin-4-yl benzoglyoxaline generation condensation reaction obtain the bilastine of esterification; The condition of condensation reaction is: temperature of reaction is 100 ℃; Reaction times is 1 hour.
In methanol aqueous solution, there is ester hydrolysis reaction in the bilastine of esterification under sodium hydroxide effect, generates bilastine.The condition of hydrolysis reaction is: temperature of reaction is 100 ℃; Reaction times is 1 hour.
Claims (4)
1. a method for synthetic 2-(4-haloethyl) phenyl-2 Methylpropionic acid ester, is characterized in that, comprises the following steps:
A, in solvent, there is acylation reaction in 2,2-dimethyl phenyl acetic acid ester and halogen acetyl halide, generate 2-(4-halogen ethanoyl) phenyl-2 Methylpropionic acid ester under catalyst action;
B, 2-(4-halogen ethanoyl) phenyl-2 Methylpropionic acid ester carries out reduction reaction, and reducing carbonyl generates 2-(4-haloethyl) phenyl-2 Methylpropionic acid ester;
Solvent described in step a is any in methylene dichloride, tetrahydrofuran (THF), DMF or Nitromethane 99Min.; Described halogen acetyl halide is any in chloroacetyl chloride, chloro-acetyl bromide, bromoacetyl chloride or bromoacetyl bromide; Described catalyzer is aluminum chloride, and the acylation reaction temperature described in step a is 0～100 ℃, and the described acylation reaction time is 1～24 hour;
In b step, reduction reaction adopts this Nellie-Wolf of base-Huang Min-lon reduction reaction, and reaction system solvent is polyoxyethylene glycol, and temperature of reaction is 100～200 ℃, and the reaction times is 1～8 hour.
2. the method for a kind of synthetic 2-according to claim 1 (4-haloethyl) phenyl-2 Methylpropionic acid ester, it is characterized in that, solvent described in step a is methylene dichloride, described halogen acetyl halide is chloroacetyl chloride, described acidylate temperature is 5 ℃, and the described acylation reaction time is 3 hours; The temperature of reaction of the reduction reaction described in step b is 180 ℃; Reaction times is for being 3 hours.
3. a method for synthetic bilastine, is characterized in that, it comprises the steps:
A, in solvent, there is acylation reaction in 2,2-dimethyl phenyl acetic acid ester and halogen acetyl halide, generate 2-(4-halogen ethanoyl) phenyl-2 Methylpropionic acid ester under catalyst action;
B, 2-(4-halogen ethanoyl) phenyl-2 Methylpropionic acid ester carries out reduction reaction, and reducing carbonyl generates 2-(4-haloethyl) phenyl-2 Methylpropionic acid ester;
Under c, alkali exist, 2-(4-haloethyl) phenyl-2 Methylpropionic acid ester and 1-ethoxyethyl-2-pyridin-4-yl benzoglyoxaline generation condensation reaction obtain the bilastine of esterification;
D, in solvent, there is ester hydrolysis reaction in the bilastine of esterification, generate bilastine under catalyst action;
Solvent described in step a is any in methylene dichloride, tetrahydrofuran (THF), DMF or Nitromethane 99Min.; Described halogen acetyl halide is any in chloroacetyl chloride, chloro-acetyl bromide, bromoacetyl chloride or bromoacetyl bromide; Described catalyzer is aluminum chloride, and the acylation reaction temperature described in step a is 0～100 ℃, and the described acylation reaction time is 1～24 hour;
In b step, reduction reaction adopts this Nellie-Wolf of base-Huang Min-lon reduction reaction, and reaction system solvent is polyoxyethylene glycol, and temperature of reaction is 100～200 ℃, and the reaction times is 1～8 hour;
Alkali described in step c is any in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium hydride, triethylamine, pyridine or DIPEA, and setting-up point is 0～100 ℃, and the reaction times is 1～24 hour;
Solvent described in steps d is one or more the combination in methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), water or acetone; Described catalyzer is any in sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate or salt of wormwood, and temperature of reaction is 0～100 ℃, and the reaction times is 1～24 hour.
4. the method for a kind of synthetic bilastine according to claim 3, is characterized in that, the solvent described in step a is methylene dichloride, and described halogen acetyl halide is chloroacetyl chloride, and described acidylate temperature is 5 ℃, and the described acylation reaction time is 3 hours; The temperature of reaction of the reduction reaction described in step b is 180 ℃; Reaction times is for being 3 hours; Alkali described in step c is sodium carbonate, and setting-up point is 80 ℃; Reaction times is 16 hours; Catalyzer described in steps d is lithium hydroxide, and temperature of reaction is 70 ℃, and the reaction times is 16 hours.
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| CN103012185A (en) * | 2012-12-24 | 2013-04-03 | 辽宁本源制药有限公司 | Preparing method for agomelatine drug for curing depressive disorder |
| CN103772220A (en) * | 2013-12-03 | 2014-05-07 | 镇江圣安医药有限公司 | Novel derivative of 1-[2-dimethylamino-1-(4-methoxyphenyl) ethyl] cyclohexanol and application thereof |
| CN104177331B (en) * | 2014-09-10 | 2016-08-17 | 北京科莱博医药开发有限责任公司 | The preparation method of bilastine |
| CN104326909A (en) * | 2014-09-22 | 2015-02-04 | 暨南大学 | Methods for preparation of alpha, alpha-dimethyl-4-(2-haloethyl) phenyl acetate and synthesis of bilastine |
| CN106146308A (en) * | 2015-04-09 | 2016-11-23 | 南京长澳医药科技有限公司 | Alpha, alpha-dimethyl-4-(2-halogen acetyl group) purification process of phenylacetate |
| CN106699728A (en) * | 2015-07-13 | 2017-05-24 | 南京长澳医药科技有限公司 | Bilastine intermediate impurity and preparation method thereof |
| CN111039784A (en) * | 2019-12-18 | 2020-04-21 | 厦门云凡医药科技有限公司 | Preparation method of bilastine intermediate |
| CN110903278B (en) * | 2019-12-26 | 2022-08-16 | 山东罗欣药业集团恒欣药业有限公司 | Preparation method of bilastine |
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| WO2020020873A1 (en) * | 2018-07-24 | 2020-01-30 | Faes Farma, S.A. | Process and intermediates for the preparation of bilastine |
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