CN107235913B - Method for efficiently manufacturing high-quality flibanserin on industrial scale - Google Patents
Method for efficiently manufacturing high-quality flibanserin on industrial scale Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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Abstract
The invention discloses a method for efficiently manufacturing high-quality flibanserin in an industrial scale, which belongs to the technical field of drug synthesis and comprises the following steps: A. the method comprises the following steps of (1) enabling benzimidazolone of formula I and dihalogenated ethane to exist in a first solvent, and reacting under the alkaline condition to obtain a compound of formula II; B. enabling a compound shown in a formula II and a piperazine derivative shown in a formula III or a salt thereof to exist in a second solvent, and reacting under an alkaline condition to prepare a compound shown in a formula IV; C. and (3) the compound shown in the formula IV exists in a third solvent, and the amino protecting group R is removed, so that the flibanserin free base shown in the formula V or the salt thereof is prepared. The method has the advantages of lower cost, higher yield and easier control of product quality, the total yield is improved to about 72 percent, and the purity of the final product is more than 99.9 percent.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a method for efficiently manufacturing high-quality flibanserin in an industrial scale.
Background
The compound 1- [2- [4- [3- (trifluoromethyl) phenyl ] -1-piperazine ] ethyl ] -2-benzimidazolone (flibanserin) is disclosed in european patent application EP0526434a1 in its hydrochloride salt form and has the following chemical formula:
flibanserin showed its para-5-HT1AAnd 5-HT2The receptors have affinity and are therefore promising for the treatment of a variety of diseases, such as depression, schizophrenia, parkinson's disease, anxiety, sleep disorders, sexual and psychiatric disorders and age-related memory disorders. In particular, flibanserin can be used for the treatment of the following disorders: hypoactive sexual desire disorder, loss of libido, hypoactive sexual desire, inhibition of libido, loss of sexual function, sexual dysfunction, and frigidity.
Two main synthetic routes are disclosed in the prior art, one of which is as follows:
in this synthetic route, the following disadvantages exist:
1) 1-bromo-2-chloroethane (or 1-iodo-2-chloroethane) is needed to be used for preparing the chloroethyl benzimidazolone, and the raw material is expensive and has higher cost.
2) In the structure of the intermediate chloroethyl benzimidazolone, the exposed amino group has nucleophilicity and can continue to react with the halogenated hydrocarbon. Therefore, the compound is used as a key intermediate and has stability problems in synthesis, storage and next reaction. That is, when the intermediate is prepared, it reacts with another molecule of halohydrocarbon to generate impurities connecting two chloroethyls, and when the intermediate itself reacts with two molecules to generate two or more molecules to polymerize, which results in instability during storage, and when the intermediate reacts with piperazine derivative to prepare flibanserin in the last step, side reaction between two molecules to generate byproducts also occurs, which all result in that more impurities need to be removed by an additional purification method when the flibanserin is prepared, thus increasing the production cost, and simultaneously, the quality control of the flibanserin becomes very difficult.
3) This route produces a total yield of 46%, which is relatively low.
The second synthetic route is as follows:
in this synthetic route, the following disadvantages exist:
1) 1-bromo-2-chloroethane (or 1-iodo-2-chloroethane) is needed for preparing chloroethylpiperazine, and the cost is high.
2) The key intermediate chloroethylpiperazine needs to be prepared by reacting piperazine with 1-bromo-2-chloroethane (or 1-iodo-2-chloroethane), and the reaction is prone to generate a bipiperazine substituted byproduct due to poor reaction selectivity caused by high activity of piperazine, and the specific reaction formula is as follows:
3) the overall yield of the preparation by this route is 57%, which is relatively low.
Therefore, there is a need for a process for efficiently producing flibanserin of good quality on an industrial scale at a lower cost, with higher yield and good product quality and with easy control.
Disclosure of Invention
In order to solve the problems of the prior art, the invention aims to provide a method for efficiently manufacturing flibanserin on an industrial scale, which has lower cost, higher yield, high product quality and easy control.
In a first aspect, the present invention provides a method for efficiently manufacturing high quality flibanserin on an industrial scale, comprising the steps of:
A. the benzimidazolone and the dihalogenated ethane of the formula II exist in a first solvent, and react under the alkaline condition to prepare a compound of the formula II;
B. the compound of the formula II and the piperazine derivative of the formula III exist in a second solvent and react under the alkaline condition to prepare a compound of a formula IV;
C. the compound of formula IV exists in a third solvent and removes an amino protecting group R to prepare flibanserin free alkali of formula V or salt thereof;
the reaction formula is as follows:
wherein R represents an amino protecting group, and X represents Cl, Br or I.
According to one embodiment of the invention, in step A, (I) the benzimidazolone of formula I is added into a first solvent and adjusted to alkaline conditions, and then dihaloethane is slowly dropped and reacted at 0-60 ℃;
or
(ii) Adding benzimidazolone of formula I and dihalogenated ethane into a first solvent, adding alkali, and reacting at 0-60 ℃;
after completion of the reaction, the compound of formula II is obtained by purification, optionally including a recrystallization step, preferably using an alcohol reagent/water.
According to an embodiment of the invention, in the step B, the compound of formula II is added into the second solvent and adjusted to alkaline conditions, then the compound of formula III is added, and the reaction is performed at 50-100 ℃, after the reaction is completed, the temperature is reduced, optionally filtered, and the obtained filtrate is subjected to post-treatment to obtain the compound of formula IV, wherein the purification optionally comprises a recrystallization step, and the recrystallization step preferably uses ethyl acetate/alkane for recrystallization.
According to an embodiment of the present invention, in step C, when the amino protecting group R is removed, the reaction conditions are set according to the type of the amino protecting group R. When the amino protecting group R is selected from isopropenyl, 1-styryl, 1-benzhydryl, methoxymethyl, ethoxymethyl, benzyloxymethyl, methoxybenzyl, trichloroethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, tert-butoxycarbonyl, 2-pyranyl, benzyloxycarbonyl, phenoxycarbonyl and other groups, removing the amino protecting group R under acidic conditions, reacting, adjusting to acidity, heating to 10-80 ℃, stirring for 1-8 h, cooling after the reaction is finished, filtering, and performing post-treatment on the obtained filter cake to obtain flibanserin free alkali of a formula V or salt thereof, wherein the post-treatment optionally comprises the steps of adding an aqueous alkali solution to adjust the pH value to 8-9, filtering and drying to obtain the flibanserin free alkali; when the amino protecting group R is selected from groups such as phenoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, benzoyl, formyl, acetyl and trifluoroacetyl, the amino protecting group R is removed under an alkaline condition, the reaction is adjusted to be alkaline, the temperature is raised to 50-90 ℃, the stirring is carried out for 6-8 h, the temperature is reduced after the reaction is finished, the filtration is carried out, and the obtained filter cake is subjected to post-treatment to obtain the flibanserin free alkali in the formula V.
According to one embodiment of the invention, in step a, the first solvent is selected from one or more mixtures of N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, methanol, ethanol and isopropanol.
Preferably, the first solvent is selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide.
According to an embodiment of the present invention, in step a, the base used in the alkaline condition is selected from inorganic bases or organic bases, and the inorganic bases or organic bases are one or more of potassium hydroxide, sodium hydroxide, lithium hydroxide, calcium hydroxide, sodium ethoxide, sodium methoxide, potassium tert-butoxide, sodium tert-butoxide, lithium carbonate, potassium carbonate, sodium carbonate, calcium carbonate and sodium hydride.
Preferably, the alkaline condition employs an alkali selected from potassium hydroxide, sodium hydroxide, lithium hydroxide.
According to one embodiment of the invention, in step a, the dihaloethane is selected from the group consisting of 1, 2-dibromoethane, 1-iodo-2-chloroethane and 1-bromo-2-chloroethane.
According to one embodiment of the present invention, in step a, the alcohol reagent/water of the recrystallization step is selected from methanol/water, ethanol/water, propanol/water, isopropanol/water, butanol/water, isobutanol/water.
According to an embodiment of the present invention, in step B, the second solvent is selected from one or more mixtures of N, N-dimethylformamide, N-dimethylacetamide, ethanol, dimethylsulfoxide, acetonitrile, diethyl ether, methyl t-butyl ether, tetrahydrofuran, methanol and isopropanol.
Preferably, the second solvent is selected from N, N-dimethylacetamide, ethanol, acetonitrile, methanol, isopropanol.
According to an embodiment of the present invention, in step B, the base used in the alkaline condition is selected from inorganic bases or organic bases, and the inorganic bases or organic bases are one or more of potassium hydroxide, sodium hydroxide, lithium hydroxide, calcium hydroxide, sodium ethoxide, sodium methoxide, potassium tert-butoxide, sodium tert-butoxide, lithium carbonate, potassium carbonate, sodium carbonate, calcium carbonate or sodium hydride;
preferably, the alkali used in the alkaline condition is selected from lithium carbonate, potassium carbonate and sodium carbonate.
According to one embodiment of the invention, in step B, the piperazine derivative of formula III is a free base or a hydrochloride, sulfate, hydrobromide, phosphate, acetate salt.
According to an embodiment of the present invention, in step B, the ethyl acetate/alkane in the recrystallization step is selected from ethyl acetate/n-hexane, ethyl acetate/n-heptane, ethyl acetate/cyclohexane, ethyl acetate/cycloheptane.
According to an embodiment of the invention, in step C, the third solvent is selected from one or more of ethanol, isopropanol, acetone, N-dimethylformamide, N-dimethylacetamide, methyl tert-butyl ether, dimethylsulfoxide, acetonitrile, tetrahydrofuran and methanol and a mixture of one or more of the above solvents with water.
Preferably, the third solvent is selected from one or more of ethanol, methanol, isopropanol and a mixture of one or more of the above solvents with water.
According to one embodiment of the invention, in step C, the acid employed in the acidic conditions is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, oxalic acid, p-toluenesulfonic acid or benzenesulfonic acid; the alkaline water solution used for the post-treatment is triethylamine, ammonia water, a sodium hydroxide solution, a potassium hydroxide solution, a lithium hydroxide solution or a calcium hydroxide solution; the alkali adopted in the alkaline condition is selected from aqueous solutions of ammonia water, potassium hydroxide, sodium hydroxide and lithium hydroxide.
Preferably, the acid used in the acidic condition is selected from hydrochloric acid, hydrobromic acid and sulfuric acid, and the aqueous alkali solution used in the post-treatment is selected from sodium hydroxide solution, potassium hydroxide solution and lithium hydroxide solution; the alkali adopted in the alkaline condition is selected from aqueous solution of potassium hydroxide, sodium hydroxide and lithium hydroxide.
According to one embodiment of the invention, the salt of flibanserin of formula V is the hydrochloride, sulfate, hydrobromide, oxalate, acetate, methanesulfonate, p-toluenesulfonate or benzenesulfonate salt.
Preferably, the flibanserin is prepared in a purity of at least 99.9% to give flibanserin.
Further preferably, the flibanserin is obtained in a yield of at least 72%.
In a second aspect, the invention provides a composition comprising flibanserin of greater than 99.9% purity.
In a third aspect, the invention provides the use of flibanserin or a composition thereof as described above for the preparation of a medicament for the treatment of disorders associated with libido disorders.
The steps, solvents, reagents, post-treatments, recrystallization and the like in the method for efficiently producing high-quality flibanserin on an industrial scale can be combined/separated at will, and the purpose of the invention can be achieved.
Compared with the prior art, the method for efficiently manufacturing high-quality flibanserin in an industrial scale uses protected benzimidazolone as a starting material and obtains the flibanserin mainly through three-step synthesis, wherein the total yield is improved to about 72 percent, and the production cost is reduced; in addition, the intermediates in each step of the route are easy to purify, the purity of the final product is more than 99.9%, the quality is easy to control, wherein two reaction materials in the second step only have one active site, so the selectivity of the step reaction is good, and the yield can reach more than 95%; and the third step of reaction is to remove the protecting group, the reaction effect is good, and the yield can reach more than 90%.
Detailed Description
All of the features disclosed in this specification, or all of the steps in any method or process so disclosed, may be combined in any combination, except combinations of features and/or steps that are mutually exclusive.
Any feature disclosed in this specification may be replaced by alternative features serving equivalent or similar purposes, unless expressly stated otherwise. That is, unless expressly stated otherwise, each feature is only an example of a generic series of equivalent or similar features.
Unless otherwise indicated, abbreviations used in the specification have the following meanings:
NaOH (sodium hydroxide)
KOH potassium hydroxide
Na2CO3Sodium carbonate (sodium bicarbonate)
EtOH ═ ethanol
H2O is water
m L-ml
mol to mol
g is g ═ g
mg ═ mg
The method for efficiently producing high-quality flibanserin on an industrial scale according to the present invention will be described in detail.
According to the present invention, the method for efficiently manufacturing high-quality flibanserin on an industrial scale includes the following steps.
Step A:
the benzimidazolone and the dihalogenated ethane of the formula I are added into a first solvent and react under the alkaline condition to prepare the compound of the formula II.
Wherein, the chemical structural formula of formula I is as follows:
benzimidazolones of formula I are protected benzimidazolones wherein R represents an amino protecting group. According to an exemplary embodiment of the present invention, the amino protecting group R may be any protecting group used to protect an amino functional group, and may be selected from isopropenyl, 1-styryl, 1-benzhydryl, methoxymethyl, ethoxymethyl, benzyloxymethyl, trichloroethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, tert-butoxycarbonyl, benzyl, methoxybenzyl, 2-pyranyl, benzyloxycarbonyl, phenoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, benzoyl, formyl, acetyl, trifluoroacetyl, and the like. Among these, the most preferred amino-protecting group R may be an isopropenyl group, a 1-styryl group or a tert-butoxycarbonyl group.
The chemical structural formula of the dihalo-ethane is
X represents Cl, Br or I. That is, it may be selected from 1, 2-dibromoethane, 1-iodo-2-chloroethane, 1-bromo-2-chloroethane, and the like. Among them, 1, 2-dibromoethane is the most preferable dihaloethane, which can effectively reduce the cost.
In the step, the benzimidazolone and the dihaloethane of the formula I are added into a proper first solvent and react under the alkaline condition to prepare the compound of the formula II, wherein the specific reaction formula is as follows:
among them, suitable first solvents may be selected from one or more mixtures of N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran, diethyl ether, methyl t-butyl ether, methanol, ethanol and isopropanol, preferably N, N-dimethylformamide, N-dimethylacetamide. The base used in the alkaline condition may be selected from inorganic bases or organic bases, for example, the inorganic base or organic base may be one or more of potassium hydroxide, sodium hydroxide, lithium hydroxide, calcium hydroxide, sodium ethoxide, sodium methoxide, potassium tert-butoxide, sodium tert-butoxide, lithium carbonate, potassium carbonate, sodium carbonate, calcium carbonate and sodium hydride, and preferably potassium hydroxide and sodium hydroxide.
By adopting the reaction of the benzimidazolone containing the protecting group and the dihalogenated ethane, the intermediate (namely the compound shown in the formula II) with only one active site can be prepared, so that the selectivity of the subsequent reaction is better, and the yield and the purity of the product are favorably improved.
And B:
and adding the compound shown in the formula II and the piperazine derivative shown in the formula III into a second solvent, and reacting under an alkaline condition to prepare the compound shown in the formula IV.
Wherein the chemical structural formula of formula III is as follows:
in this step, the compound of formula II prepared in step a and the piperazine derivative of formula III are added into a suitable second solvent and reacted under alkaline conditions to prepare the compound of formula IV, wherein the specific reaction formula is:
wherein, the piperazine derivative of the formula III can be free base or hydrochloride, sulfate, hydrobromide, phosphate, acetate, and preferably the piperazine derivative of the formula III is used for reaction. Suitable second solvents may be selected from N, N-dimethylformamide, N-dimethylacetamide, ethanol, dimethyl sulfoxide, acetonitrile, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, methanol and isopropanol and mixtures of one or more of the above solvents, preferably N, N-dimethylacetamide, ethanol. The base used in the alkaline condition can be selected from inorganic bases or organic bases, for example, the inorganic base or organic base can be one or more of potassium hydroxide, sodium hydroxide, lithium hydroxide, calcium hydroxide, sodium ethoxide, sodium methoxide, potassium tert-butoxide, sodium tert-butoxide, lithium carbonate, potassium carbonate, sodium carbonate, calcium carbonate or sodium hydride, and preferably potassium carbonate or sodium carbonate.
And C:
adding a compound of formula IV into a third solvent, and then removing an amino protecting group R to prepare flibanserin of formula V or a free base or a salt thereof, wherein the specific reaction formula is as follows:
in the case of removing the amino-protecting group R, the reaction conditions are set depending on the type of the amino-protecting group R.
When the amino protecting group R is isopropenyl, 1-styryl, 1-benzhydryl, methoxymethyl, ethoxymethyl, benzyloxymethyl, methoxybenzyl, trichloroethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, t-butoxycarbonyl, 2-pyranyl, benzyloxycarbonyl, phenoxycarbonyl, or the like, the reaction is carried out under acidic conditions, preferably, the acid used under acidic conditions may be selected from hydrochloric acid, sulfuric acid or hydrobromic acid, phosphoric acid, hydroiodic acid, hydrofluoric acid.
When the amino protecting group R is a group such as phenoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, benzoyl, formyl, acetyl and trifluoroacetyl, the reaction is carried out under alkaline conditions, preferably, the alkaline conditions can be selected from aqueous solutions of ammonia, potassium hydroxide, sodium hydroxide and lithium hydroxide.
Suitable third solvents may be selected from ethanol, isopropanol, acetone, N-dimethylformamide, N-dimethylacetamide, methyl tert-butyl ether, dimethyl sulfoxide, acetonitrile, tetrahydrofuran and methanol and mixtures of one or more of the above solvents with water, preferably ethanol and acetone.
And the final product can be controlled to be flibanserin free alkali or salt thereof by adjusting reaction raw materials and reaction conditions and post-processing mode. Wherein, the salt of flibanserin of formula V can be hydrochloride, sulfate, bromide, oxalate, acetate, methanesulfonate, p-toluenesulfonate or benzenesulfonate, etc.
The intermediates in the steps are easy to purify, the purity of the final product is more than 99.9 percent, and the quality is easy to control.
According to the invention, the method for the industrial scale production of flibanserin may in particular comprise the following steps:
adding benzimidazolone of formula I into a first solvent, adjusting to an alkaline condition, adding dihaloethane, reacting at 0-60 ℃,
alternatively, the first and second electrodes may be,
adding benzimidazolone of formula I and dihalogenated ethane into a first solvent, then adding alkali and reacting at 0-60 ℃;
after the reaction is finished, carrying out post-treatment and purification to obtain the compound shown in the formula II, wherein the purification comprises a recrystallization step and the recrystallization step is ethanol/water recrystallization. The work-up here can comprise a number of conventional steps of extraction, washing, rinsing, drying, etc.
And then adding the compound shown in the formula II and the piperazine derivative shown in the formula III into a second solvent, reacting at 50-100 ℃, cooling after the reaction is finished, filtering, and performing post-treatment on the obtained filtrate to obtain the compound shown in the formula IV, wherein the post-treatment comprises a water stirring step and can also comprise conventional steps such as rinsing, drying and the like.
And then, when the amino protecting group R is isopropenyl, 1-styryl, 1-benzhydryl, methoxymethyl, ethoxymethyl, benzyloxymethyl, methoxybenzyl, trichloroethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, tert-butoxycarbonyl, 2-pyranyl, benzyloxycarbonyl, phenoxycarbonyl and the like, reacting, adjusting to acidity, heating to 10-80 ℃, stirring for 1-8 h, cooling after the reaction is finished, filtering, and performing post-treatment on the obtained filter cake to obtain flibanserin free alkali of a formula V or salt thereof, wherein the post-treatment optionally comprises the steps of dropwise adding an aqueous alkali solution to adjust the pH value to 8-9, filtering and drying to obtain the flibanserin free alkali. The post-treatment can also comprise conventional steps of cooling precipitation, filtration, leaching, drying and the like. The aqueous alkali solution used for adjusting the pH may be a sodium hydroxide solution, a potassium hydroxide solution, a lithium hydroxide solution, or the like.
When the amino protecting group R is a group such as phenoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, benzoyl, formyl, acetyl, trifluoroacetyl and the like, reacting, adjusting to be alkaline, heating to 50-90 ℃, stirring for 6-8 h, cooling after the reaction is finished, filtering, and carrying out aftertreatment on the obtained filter cake to obtain the flibanserin free alkali in the formula V, wherein the alkali used under the alkaline condition can be selected from aqueous solutions of ammonia water, potassium hydroxide, sodium hydroxide and lithium hydroxide.
The synthesis method completely removes impurities generated in the first step through the processing steps of ethanol/water recrystallization in the first step, water mixing and stirring in the second step, salt formation in the third step and the like, thereby effectively controlling the quality of a final product, ensuring that the purity of the final product is over 99.9 percent and improving the total yield to 72 percent.
According to the invention, the method for the industrial scale production of flibanserin may also comprise in particular the following steps:
adding benzimidazolone of formula I into a first solvent, adjusting to an alkaline condition, slowly dropwise adding dihaloethane, reacting at 0-60 ℃,
or
Adding benzimidazolone of formula I and dihalogenated ethane into a first solvent, adding alkali, and reacting at 0-60 ℃;
after the reaction is finished, the compound of the formula II is obtained through post-treatment.
And adding the compound shown in the formula II and the piperazine derivative shown in the formula III into a second solvent, reacting at 50-100 ℃, cooling and filtering after the reaction is finished, and performing after-treatment and purification after the solvent is removed from the obtained filtrate by rotary evaporation to obtain the compound shown in the formula IV, wherein the purification comprises a recrystallization step and the recrystallization step is ethyl acetate/n-heptane recrystallization.
The subsequent step of removing the amino protecting group R may be the same as in the above examples and will not be described herein.
The synthesis method of the embodiment completely removes impurities generated in the first step through the treatment steps of recrystallization in the second step, salification in the third step and the like, thereby effectively controlling the quality of the final product.
The invention also provides a pharmaceutical composition comprising flibanserin of more than 99.9% purity; flibanserin with purity of more than 99.9% in the pharmaceutical composition can be obtained by the preparation method provided by the invention; the pharmaceutical compositions of the present invention also include a pharmaceutically acceptable carrier or diluent.
The above-mentioned pharmaceutical composition of the present invention can be administered orally, by injection, by spray inhalation, topically, rectally, nasally, buccally, vaginally or via an implantable kit. Preferred modes of administration are oral, intraperitoneal or intravenous.
The above-mentioned pharmaceutical composition of the present invention may also be in the form of discrete units, which may be aqueous liquid solutions or suspensions; a solution or suspension in a non-aqueous liquid; or a water-in-oil liquid emulsion; or an oil-in-water liquid emulsion; or encapsulated in liposomes; or pill form, etc.
The above-described pharmaceutical compositions of the present invention may be prepared by sterile injection of aqueous or oleaginous suspensions which may be formulated according to the known art using suitable dispersing, wetting and suspending agents.
The pharmaceutical composition of the present invention may be in solid dosage forms including, but not limited to, capsules, tablets, troches, elixirs, pills, granules, powders or suppositories; the pharmaceutical composition of the present invention may also be in liquid dosage forms including, but not limited to, solutions, suspensions or emulsions.
Solid dosage forms are typically formulated in dosage units that provide from about 0.01mg to about 1000mg of the active ingredient per dose some examples of solid dosage units are 0.01mg, 1mg, 10mg, 100mg, 250mg, 500mg and 1000mg liquid dosage forms are typically in the unit dosage range of 1-100mg/m L some examples of liquid dosage units are 1mg/m L, 10mg/m L, 25mg/m L, 50mg/m L and 100mg/m L.
The amount and frequency of administration of flibanserin prepared by the method of the invention may be adjusted according to the judgment of the clinician in view of, for example, the age, symptoms and size of the patient and the severity of the symptoms being treated. For oral administration, a typical recommended daily dosage regimen may range from about 0.01 to 1000 mg/day, preferably 0.05 to 800 mg/day, preferably 1 to 500 mg/day in two to four divided doses.
The actual dosage employed may vary depending upon the needs of the patient and the severity of the symptoms being treated. Determination of an appropriate dosage regimen for a particular situation is within the purview of one skilled in the art.
The invention also provides application of the pharmaceutical composition in preparing a medicament for treating diseases related to sexual desire disorders.
The flibanserin or the pharmaceutical composition thereof can be used for preventing or treating hypoactive sexual desire disorder, loss of sexual desire, lack of sexual desire, hypoactive sexual desire, inhibition of sexual desire, loss of sexual function, sexual dysfunction and frigidity-related diseases.
In some embodiments, the prepared flibanserin or composition of the invention may also optionally be used for depression, schizophrenia, parkinson's disease, anxiety, sleep disorders, sexual and psychiatric disorders and age-related memory disorders.
Flibanserin prepared by the process of the invention may be used alone or in combination with one or more other drugs suitable for the prevention or treatment of disorders associated with libido disorders.
The invention also provides a method for preparing flibanserin prepared by the method for preventing or treating diseases related to sexual desire disorders by using the flibanserin alone or in combination with other medicines for preventing or treating the diseases related to the sexual desire disorders. And a method for preventing or treating diseases related to sexual dysfunction by using the flibanserin prepared by the method of the invention alone or in combination with at least one other agent with certain effect in other drugs.
The term combination includes simultaneous, sequential or alternating use, as well as pharmaceutical dosage forms or pharmaceutical products prepared for the respective combined use in one or more pharmaceutical units.
The method for efficiently producing high-quality flibanserin on an industrial scale according to the present invention will be further described with reference to specific examples.
In example 1 and example 2, the starting material is benzimidazolone with isopropenyl as the amino protecting group R, and the reaction schemes of the two are as follows:
example 1:
1) adding 1, 3-dihydro-1- (1-methylvinyl) -2H-benzimidazolone (10g, 0.06mol), N-dimethylformamide (50m L) and NaOH (4.6g, 0.11mol) into a three-necked flask, dropwise adding 1, 2-dibromoethane (21.5g, 0.11mol), stirring at 25-30 ℃ for 4 hours, after the reaction is finished, adding water and ethyl acetate, separating an organic phase, extracting an aqueous phase with ethyl acetate, washing, drying, filtering and concentrating to obtain 13.9g of oily 1, 3-dihydro-1- (2-bromomethyl) -3- (isopropenyl) -2H-benzimidazolone (purity is 90.8%, yield is 86.2%)
Wherein, N, N-dimethylformamide can be replaced by N, N-dimethylacetamide and acetonitrile. The sodium hydroxide can be replaced by potassium hydroxide, potassium carbonate, and sodium carbonate.
2) 1, 3-dihydro-1- (2-bromomethyl) -3- (isopropenyl) -2H-benzimidazolone (20g, 0.07mol) prepared in the above step, ethanol (200m L) and Na were added to a three-necked flask2CO3(15.1g,0.14mol), adding 1- (3-trifluoromethylphenyl) piperazine hydrochloride (22.8g, 0.09mol), heating to 85-90 ℃, stirring for 24h, filtering, concentrating the filtrate to remove the solvent, adding ethyl acetate and water, separating out an organic phase, and concentrating the organic phase to remove the ethyl acetate to obtain a crude product. Adding ethyl acetate and n-heptane to the crude product, recrystallizing and filtering to obtain 28g white solid 1- (isopropenyl) and 3- [2- [4- [3- (trifluoromethyl) phenyl ] phenyl]Piperazin-1-yl]Ethyl radical]-benzimidazol-2-one (97.0% purity, 91.5% yield).
Wherein the ethanol can be replaced by isopropanol, methanol, N-dimethylformamide and N, N-dimethylacetamide. The sodium carbonate can be replaced by sodium hydroxide, potassium hydroxide, and potassium carbonate. The 1- (3-trifluoromethylphenyl) piperazine hydrochloride may be replaced with other salts or free bases.
3) Adding the 1- (isopropenyl) prepared in the previous step, 3- [2- [4- [3- (trifluoromethyl) phenyl ] piperazin-1-yl ] ethyl ] -benzimidazol-2-one (50g, 0.12mol) and isopropanol (750L) into a three-necked bottle, dropwise adding hydrochloric acid (50m L, 0.60mol) with the mass concentration of 37%, heating to 50-55 ℃, stirring for 1h, slowly cooling to 20-25 ℃, stirring for 1h, filtering to obtain solid flibanserin hydrochloride, dissolving the solid in 5-fold volume of water, dropwise adding an aqueous sodium hydroxide solution to the solution until the pH is 11, filtering, and drying by blowing to obtain 41g of solid flibanserin (99.9%, yield 92%).
Wherein the isopropanol can be replaced by ethanol, acetone, and methanol. The hydrochloric acid can be replaced by sulfuric acid and hydrobromic acid. The NaOH solution can be replaced by triethylamine, ammonia water, potassium hydroxide solution and lithium hydroxide solution.
Example 2:
1) adding 1, 3-dihydro-1- (1-methylvinyl) -2H-benzimidazolone (150.0g, 0.86mol), N-dimethylacetamide (750m L) and KOH (96.6g, 1.72mol) into a three-necked flask, cooling to 0-10 ℃, slowly adding 1, 2-dibromoethane (485.3g, 2.58mol) dropwise, stirring for 6H, adding water and ethyl acetate after the reaction is finished, separating an organic phase, extracting an aqueous phase with ethyl acetate, combining the organic phases, concentrating the organic phase at 45 ℃, adding ethanol to make the volume of the solution reach 1200ml, slowly adding water dropwise while stirring, cooling to 0-10 ℃, stirring for 1H, filtering, and drying overnight at 50 ℃ by blowing to obtain 195.0g of white-like solid 1, 3-dihydro-1- (2-bromomethyl) -3- (isopropenyl) -2H-benzimidazolone (99.2% purity: 80.6%).
Wherein, N, N-dimethyl acetamide can be replaced by N, N-dimethyl formamide and acetonitrile. The potassium hydroxide can be replaced by sodium hydroxide, potassium carbonate, and sodium carbonate. The 1- (3-trifluoromethylphenyl) piperazine hydrochloride may be replaced with other salts or free bases.
2) Adding the obtained 1, 3-dihydro-1- (2-bromomethyl) -3- (isopropenyl) -2H-benzimidazolone (180.0g, 0.64mol), N-dimethylacetamide (900m L), and Na into a three-necked flask2CO3(101.8g,0.96mol) and 1- (3-trifluoromethylphenyl) piperazine hydrochloride (188.0g, 0.70 mol); heating to 85-90 ℃, and stirring for 18 h; after the reaction is finished, filtering and washing a filter cake by using N, N-dimethylacetamide; dropping the filtrate into water, stirring at 25 deg.C for 1 hr, filtering, washing the filter cake with water, adding water, stirring, filtering the mixture, and air drying at 85 deg.C to obtain 268.7g of white solid 1- (isopropenyl) 3- [2- [4- [3- (trifluoromethyl) phenyl ] ethyl acetate]Piperazin-1-yl]Ethyl radical]-benzimidazol-2-one (purity 99.7%, yield 97.3%).
Wherein the N, N-dimethylacetamide can be selected from ethanol, isopropanol, methanol, and N, N-dimethylformamide. The sodium carbonate can be replaced by sodium hydroxide, potassium hydroxide, and potassium carbonate. The 1- (3-trifluoromethylphenyl) piperazine hydrochloride may be replaced with other salts or free bases.
3) Adding the 1- (isopropenyl) and 3- [2- [4- [3- (trifluoromethyl) phenyl ] piperazin-1-yl ] ethyl ] -benzimidazol-2-one (250g, 0.58mol) prepared in the previous step and ethanol (2.5L) into a three-necked flask, then dropwise adding hydrochloric acid (150m L, 1.74mol) with the mass concentration of 37%, heating to 30-35 ℃, stirring for 6-8 h, cooling to 0-10 ℃, filtering the solid to obtain flibanserin hydrochloride, dissolving the solid in 5-fold water, dropwise adding an aqueous sodium hydroxide solution until the pH is 9, filtering the solid, and drying by air blowing to obtain 209.2g of white solid flibanserin (99.9%, yield 92.3%).
Wherein the ethanol can be replaced by isopropanol, acetone, and methanol. The hydrochloric acid can be replaced by sulfuric acid and hydrobromic acid. The NaOH solution can be replaced by triethylamine, ammonia water, potassium hydroxide solution and lithium hydroxide solution.
Example 3: benzimidazolone taking ethoxycarbonyl as amino protecting group R is taken as a starting material, and the reaction formula is as follows:
1) step A was carried out in the same manner as in example 2 using 1, 3-dihydro-1- (ethoxycarbonyl) -2H-benzimidazolone as a raw material.
2) Step B was performed in the same manner as in example 2 using 1, 3-dihydro-1- (2-bromomethyl) -3- (ethoxycarbonyl) -2H-benzimidazolone as a starting material.
3) Adding the 1- (ethoxycarbonyl) prepared in the previous step, 3- [2- [4- [3- (trifluoromethyl) phenyl ] piperazin-1-yl ] ethyl ] -benzimidazole-2-one (50g, 0.11mol) and ethanol (0.5L) into a three-neck flask, adding 5N NaOH (22m L, 0.11mol), heating to 70-80 ℃, stirring for 6-8 h, cooling to 10-20 ℃ after the reaction is finished, filtering, and drying a filter cake by air blasting to obtain 35.4g of white solid flibanserin (99.9 percent, yield is 84.0 percent), wherein the NaOH solution can be replaced by a potassium hydroxide solution, a lithium hydroxide solution and ammonia water.
In conclusion, the method for efficiently manufacturing high-quality flibanserin in an industrial scale uses protected benzimidazolone as a starting material and obtains the flibanserin mainly through three-step synthesis, wherein the total yield is improved to about 72%, and the production cost is reduced; the intermediate in each step is easy to purify, the purity of the final product is more than 99.9 percent, and the quality is easy to control. Wherein, the two reaction materials of the second step reaction only have one active site, so the selectivity of the key step reaction is good, and the yield can reach more than 95 percent; and the third step of reaction is to remove the protecting group, the reaction effect is good, and the yield can reach more than 90%.
The invention is not limited to the foregoing embodiments. The invention extends to any novel feature or any novel combination of features disclosed in this specification and any novel method or process steps or any novel combination of features disclosed.
Claims (2)
1. A method for efficiently manufacturing high-quality flibanserin on an industrial scale, comprising the steps of:
1) adding 10g of 0.06mol of 1, 3-dihydro-1- (1-methylvinyl) -2H-benzimidazolone, 50m of L N, N-dimethylformamide and 4.6g of NaOH, 0.11mol of NaOH into a three-necked bottle, dropwise adding 21.5g of 1, 11mol of 1, 2-dibromoethane, stirring at 25-30 ℃ for 4 hours, adding water and ethyl acetate after the reaction is finished, separating out an organic phase, extracting an aqueous phase by using ethyl acetate, combining the organic phases, washing, drying, filtering and concentrating to obtain an oily substance 1, 3-dihydro-1- (2-bromoethyl) -3- (isopropenyl) -2H-benzimidazolone;
2) 20g, 0.07mol of 1, 3-dihydro-1- (2-bromoethyl) -3- (isopropenyl) -2H-benzimidazolone obtained in the above step, 200m L ethanol and 15.1g,0.14mol Na were added to a three-necked flask2CO3Adding 22.8g of 1- (3-trifluoromethyl phenyl) piperazine hydrochloride of 0.09mol, heating to 85-90 ℃, stirring for 24h, filtering, concentrating the filtrate to remove the solvent, adding ethyl acetate and water, separating an organic phase, concentrating the organic phase to remove the ethyl acetate to obtain a crude product, adding ethyl acetate and n-heptane into the crude product to recrystallize and filter to obtain a white solid 1- (isopropenyl) 3- [2- [4- [3- (trifluoromethyl) phenyl ] piperazine hydrochloride]Piperazin-1-yl]Ethyl radical]-benzimidazol-2-one;
3) adding 50g of 0.12mol of the 1- (isopropenyl) prepared in the previous step, 3- [2- [4- [3- (trifluoromethyl) phenyl ] piperazin-1-yl ] ethyl ] -benzimidazol-2-one and 750L isopropanol into a three-necked bottle, then dropwise adding hydrochloric acid with the mass concentration of 50m L and 0.60mol of 37%, heating to 50-55 ℃, stirring for 1h, slowly cooling to 20-25 ℃, stirring for 1h, filtering to obtain solid flibanserin hydrochloride, dissolving the solid in 5-fold volume of water, dropwise adding an aqueous sodium hydroxide solution until the pH value is 11, filtering, and drying by air blowing to obtain the solid flibanserin.
2. A method for efficiently manufacturing high-quality flibanserin on an industrial scale, comprising the steps of:
1) adding 150.0g, 0.86mol of 1, 3-dihydro-1- (1-methylvinyl) -2H-benzimidazolone, 750m L N, N-dimethylacetamide, 96.6g and 1.72mol of KOH into a three-necked flask, cooling to 0-10 ℃, slowly dropping 485.3g, 2.58mol of 1, 2-dibromoethane, stirring for 6H, adding water and ethyl acetate after the reaction is finished, separating an organic phase, extracting an aqueous phase with ethyl acetate, combining the organic phases, concentrating the organic phase at 45 ℃, adding ethanol to make the volume of the solution reach 1200ml, slowly dropping water while stirring, cooling to 0-10 ℃, stirring for 1H, filtering, and carrying out air-blast drying at 50 ℃ overnight to obtain a white-like solid 1, 3-dihydro-1- (2-bromoethyl) -3- (isopropenyl) -2H-benzimidazolone;
2) adding 180.0g, 0.64mol of the 1, 3-dihydro-1- (2-bromoethyl) -3- (isopropenyl) -2H-benzimidazole obtained in the previous step into a three-necked flaskOxazolone, 900m L N, N-dimethylacetamide, 101.8g,0.96mol Na2CO3And 188.0g, 0.70mol1- (3-trifluoromethylphenyl) piperazine hydrochloride; heating to 85-90 ℃, and stirring for 18 h; after the reaction is finished, filtering and washing a filter cake by using N, N-dimethylacetamide; dropping the filtrate into water, stirring at 25 deg.C for 1 hr, filtering, washing the filter cake with water, adding water, stirring, filtering the mixed solution, and air-drying the filter cake at 85 deg.C to obtain white-like solid 1- (isopropenyl) 3- [2- [4- [3- (trifluoromethyl) phenyl ] phenyl]Piperazin-1-yl]Ethyl radical]-benzimidazol-2-one;
3) adding 250g and 0.58mol of the 1- (isopropenyl) prepared in the previous step, 3- [2- [4- [3- (trifluoromethyl) phenyl ] piperazin-1-yl ] ethyl ] -benzimidazole-2-one and 2.5L ethanol into a three-necked bottle, then dropwise adding 150m L of hydrochloric acid with the mass concentration of 1.74mol of 37%, heating to 30-35 ℃, stirring for 6-8 h, cooling to 0-10 ℃, filtering the solid to obtain flibanserin hydrochloride, dissolving the solid in 5 times of water, dropwise adding an aqueous solution of sodium hydroxide until the pH is 9, filtering the solid, and drying by air blowing to obtain white solid flibanserin.
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