CN114621083A - Antihistamine medicine fexofenadine hydrochloride impurity and synthesis method and application thereof - Google Patents
Antihistamine medicine fexofenadine hydrochloride impurity and synthesis method and application thereof Download PDFInfo
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- CN114621083A CN114621083A CN202210330754.8A CN202210330754A CN114621083A CN 114621083 A CN114621083 A CN 114621083A CN 202210330754 A CN202210330754 A CN 202210330754A CN 114621083 A CN114621083 A CN 114621083A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
- C07C59/56—Unsaturated compounds containing hydroxy or O-metal groups containing halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/02—Preparation of carboxylic acids or their salts, halides or anhydrides from salts of carboxylic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/62—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating the ionisation of gases, e.g. aerosols; by investigating electric discharges, e.g. emission of cathode
Abstract
The invention provides a fexofenadine hydrochloride impurity which is a compound I shown as the following. The invention also provides a synthetic method and application of the fexofenadine hydrochloride impurity.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to an antihistamine drug fexofenadine hydrochloride impurity and a synthesis method and application thereof.
Background
Fexofenadine hydrochloride is a new generation of antihistamine, is clinically used for various allergic diseases, and has good tolerance and safety. The medicine has strong direct anti-inflammatory activity, and has no lethargy, no liver injury and cardiotoxicity, and few side effects. In addition, fexofenadine hydrochloride is also a first-line medicine for chronic urticaria, and is also the first choice for children taking antihistamine medicines.
In the prior art, fexofenadine hydrochloride is usually prepared by taking alpha, alpha-dimethyl phenylacetate as a raw material, carrying out Friedel-crafts acylation with 4-chlorobutyryl chloride to obtain an intermediate 2- [4- (4-chloro-1-butyryl) phenyl ] -2-methyl propionate, carrying out condensation reaction with azacyclo alcohol, and then carrying out reduction and hydrolysis to form salt. The synthetic route produces impurities which are recorded in the European Pharmacopoeia (European Pharmacopoeia 9.0). However, the inventors of the present application have found in their studies that the fexofenadine hydrochloride intermediate methyl 2- [4- (4-chloro-1-butyryl) phenyl ] -2-methylpropionate prepared by the above method produces an impurity (compound I) which is not included in pharmacopoeia by direct reduction and hydrolysis.
With the strict control of the drug impurities and the strict requirements of the national on the evaluation of the consistency of the preparation, the structural information and the map information of all the impurities generated in the preparation process of the drug need to be established and perfected.
Disclosure of Invention
The inventors of the present application found that in addition to fexofenadine hydrochloride impurities already disclosed in the prior art, when fexofenadine hydrochloride is synthesized by a conventional preparation method in the art, a fexofenadine hydrochloride impurity is generated as shown below,
the fexofenadine hydrochloride impurity (compound I) is not reported in the prior art. Compared with the bulk drug fexofenadine hydrochloride lacking the diphenyl piperidyl methanol structure, the structure of the impurity greatly reduces lipophilic components of molecules, thereby causing the metabolism rate of the bulk drug in organisms to be slowed down and reducing the therapeutic effect of the drug; on the other hand, the impurities are easy to accumulate in the body to a certain extent, which causes side effects.
In order to better monitor fexofenadine hydrochloride impurities generated in the process of synthesizing fexofenadine hydrochloride raw material medicaments, the invention provides fexofenadine hydrochloride impurities and a synthesis method and application thereof.
Therefore, the invention aims to provide a fexofenadine hydrochloride impurity; another object of the present invention is to provide a method for synthesizing the fexofenadine hydrochloride impurity; the invention also aims to provide the application of the fexofenadine hydrochloride impurity in quality control of fexofenadine hydrochloride.
The technical scheme adopted for achieving the purpose of the invention is as follows.
In one aspect, the invention provides a fexofenadine hydrochloride impurity which is compound I as shown below:
on the other hand, the invention provides a method for synthesizing fexofenadine hydrochloride impurity shown as compound I,
the method comprises the following steps:
(a) selecting 2- [4- (4-chloro-1-butyryl) phenyl ] -2-methyl propionate as a raw material, using methanol as a reaction solvent, carrying out reduction reaction under the action of sodium borohydride, cooling, adjusting pH, concentrating, and crystallizing to obtain a compound II: 2- [4- (4-chloro-1-hydroxy) phenyl ] -2-methylpropionic acid methyl ester;
(b) taking the compound II obtained in the step (a) as a raw material, performing hydrolysis reaction by using a sodium hydroxide aqueous solution, adjusting pH, cooling and crystallizing to obtain high-purity fexofenadine hydrochloride impurities: namely compound I: 2- [4- (4-chloro-1-hydroxy) phenyl ] -2-methylpropionic acid.
In the synthesis method provided by the invention, preferably, in step (a), the molar ratio of the methyl 2- [4- (4-chloro-1-butyryl) phenyl ] -2-methylpropionate to the sodium borohydride is 1:3-5, more preferably 1: 4.
preferably, in step (a), the temperature of the reduction reaction is 20 to 50 ℃, more preferably 20 to 40 ℃, and most preferably 40 ℃;
preferably, in step (a), the time of the reduction reaction is 2 hours;
preferably, in step (a), the temperature is reduced to 0-10 ℃; preferably 4 ℃;
preferably, in step (a), the pH adjustment is performed using a 2M dilute hydrochloric acid solution, and more preferably, the pH adjustment is performed such that the pH is adjusted to be neutral using a 2M dilute hydrochloric acid solution;
preferably, in step (a), the crystallization is performed as follows: adding methanol and water into the concentrate obtained by concentration, and stirring for 5-6h at 0-10 ℃ for crystallization; further preferably, the crystallization is performed as follows: adding a mixed solvent of methanol and water with a volume ratio of 20:9 into the concentrated substance, and stirring for 5h at 4 ℃ for crystallization.
In the synthesis method provided by the invention, preferably, in the step (b), the temperature of the hydrolysis reaction is 55-65 ℃; more preferably 65 ℃;
preferably, in step (b), the time of the hydrolysis reaction is 5 hours;
preferably, in step (b), the pH adjustment is performed using a 2M dilute hydrochloric acid solution, and more preferably, the pH adjustment is performed such that the pH is adjusted to be neutral using a 2M dilute hydrochloric acid solution;
preferably, in the step (b), the cooling crystallization is crystallization at a temperature of 0-10 ℃, preferably 4 ℃;
preferably, in step (b), the time for cooling crystallization is 4 to 8 hours, more preferably 5 to 7 hours, and most preferably 6 hours.
In a preferred embodiment of the present invention, there is provided a synthetic method of compound I, wherein the synthetic method employs the following synthetic route:
wherein, the preparation method comprises the following steps:
(a) selecting 2- [4- (4-chloro-1-butyryl) phenyl ] -2-methyl propionic acid methyl ester as a raw material, using methanol as a reaction solvent, and carrying out a reduction reaction under the action of sodium borohydride, wherein the molar ratio of the raw material to the sodium borohydride is 1: 4. the temperature of the reduction reaction is 40 ℃, the time of the reduction reaction is 2 hours, then the temperature is reduced to 4 ℃, the pH value is adjusted to be neutral, the concentration is carried out, a mixed solvent of methanol and water with the volume ratio of 20:9 is added into the concentrated product, the mixture is stirred for 5 hours at the temperature of 4 ℃ to be crystallized, and a compound II is obtained: 2- [4- (4-chloro-1-hydroxy) phenyl ] -2-methylpropanoic acid methyl ester;
(b) taking the compound II obtained in the step (a) as a raw material, carrying out hydrolysis reaction for 5h at 65 ℃ by adopting a sodium hydroxide aqueous solution, adjusting the pH value to be neutral, cooling to 4 ℃ and crystallizing for 6h to obtain high-purity fexofenadine hydrochloride impurities: namely compound I: 2- [4- (4-chloro-1-hydroxy) phenyl ] -2-methylpropionic acid.
In another aspect, the present invention provides the use of the fexofenadine hydrochloride impurity or a fexofenadine hydrochloride impurity prepared according to the above synthesis method for quality control of fexofenadine hydrochloride.
In another aspect, the invention provides the application of the synthesis method of fexofenadine hydrochloride impurities in preparation of fexofenadine hydrochloride impurity reference substances.
The beneficial effects of the invention include: the synthesis method provided by the invention has the advantages that the adopted raw materials are simple and easy to obtain, the experimental operation is simple and efficient, and the synthesized product has high purity and is suitable for laboratory scale-up production. The fexofenadine hydrochloride impurity prepared by the synthesis method provided by the invention can be used for qualitative and quantitative analysis of the impurity, provides an idea for impurity spectrum analysis of fexofenadine hydrochloride raw material medicine, and improves the medication safety of the quality of the raw material medicine. In addition, the invention also provides reference for the research on impurities of a related preparation, namely the fexofenadine hydrochloride tablet, and establishes a reasonable impurity analysis principle for the evaluation work of the pharmaceutical imitation consistency.
Drawings
Embodiments of the invention are described in detail below with reference to the attached drawing figures, wherein:
FIG. 1 shows a nuclear magnetic hydrogen spectrum of fexofenadine hydrochloride impurity (Compound I).
Detailed Description
The invention is illustrated below with reference to specific examples. It will be understood by those skilled in the art that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention in any way.
The experimental procedures in the following examples are conventional unless otherwise specified. The raw materials and reagents used in the following examples are all commercially available products unless otherwise specified. Wherein, the purchase conditions of partial reagents and equipment are as follows:
1. 2- [4- (4-chloro-1-butyryl) phenyl ] -2-methylpropanoic acid methyl ester: the preparation method comprises the following steps of preparing the compound by taking 2-methyl-2-phenyl methyl propionate as a raw material and carrying out Friedel-crafts acylation reaction with 4-chlorobutyryl chloride by a Simian Wanlong pharmaceutical Co Ltd;
2. sodium borohydride: analytical purity, chemical reagents of national drug group limited;
3. hydrochloric acid: industrial grade, lake nan er kang pharmaceuticals, ltd;
4. sodium hydroxide: industrial grade, tianjinpengkun chemical ltd;
5. three-mouth bottle: 250mL, chemical reagents of national drug group, Inc.;
6. and (3) vacuum drying and baking: DZF-6090, Shanghai-Heng scientific instruments, Inc.;
7. a circulating vacuum pump: SHZ-95B, manufactured by Instrument Ltd, Henan province.
Example 1
(a) To a 250mL three-necked flask were added 120mL of methanol and 20g of methyl 2- [4- (4-chloro-1-butyryl) phenyl ] -2-methylpropionate, followed by 10.6g of sodium borohydride, and the mixture was heated to 20 ℃ to react for 2 hours. The reaction solution is cooled to 4 ℃, 2M dilute hydrochloric acid solution is dripped, and the pH is adjusted to be neutral. Concentrating under reduced pressure, adding 100mL of methanol and 45mL of purified water into the concentrated residual solution, stirring at 4 ℃ for 5h to separate out a large amount of solid in the system, performing suction filtration to obtain a wet product, and performing vacuum drying at 55 ℃ to obtain a compound II with the molar yield of 78.5%.
(b) A250 mL three-necked flask was charged with 100mL of methanol, 15g of Compound II, and 25mL of 4M aqueous sodium hydroxide solution. Heating to 55 ℃ for reaction for 5h, dropwise adding 2M dilute hydrochloric acid solution, and adjusting the pH value to be neutral. Controlling the temperature to be 4 ℃, stirring and crystallizing for 4 hours, separating out a large amount of solid in the system, carrying out suction filtration to obtain a wet product, and drying in vacuum at 55 ℃ to obtain the compound I, wherein the HPLC (high performance liquid chromatography) is 89.6%, and the molar yield is 80.9%.
The structural confirmation information of the compound I prepared is as follows: the molecular formula is as follows: c14H19ClO3Molecular weight: 270.75.
1h NMR (400MHz, DMSO-d6), Δ:12.29(s,1H), 7.31(d,2H), 7.29(d,2H), 4.78(d,1H), 3.80(d,2H), 2.54(s,1H), 2.26(d,2H), 1.94(d,2H), 1.65(s, 6H). See fig. 1.
13C NMR(400MHz,DMSO-d6)，δ:178.02，144.21，142.05，125.99，79.99，68.24，45.97，40.43，40.02，39.88，39.60，34.65，26.86，26.05.
ESI-MS(m/z):271.7[M+H]+。
Example 2
The method of this example is substantially the same as in example 1, except that: in the step (a), the reaction temperature is 40 ℃, and 16.1g of a compound II is obtained, wherein the yield is 80.5%; in the step (b), the reaction temperature was 55 ℃ and the crystallization time was 7 hours, whereby compound i11.7g was obtained in a yield of 82.1% and HPLC 99.0%.
Example 3: screening test for Process parameters involved in step (a)
The method of this example is substantially the same as in example 1, with specific modifications as seen in table 1 below.
Table 1: step (a) test of influence factors
Example 4: screening test for Process parameters involved in step (b)
The method of this example is substantially the same as that of example 1, with specific modifications as seen in table 2 below.
Table 2: step (b) test of influence factors
Example 5:
(a) to a 250mL three-necked flask were added 120mL of methanol and 20g of methyl 2- [4- (4-chloro-1-butyryl) phenyl ] -2-methylpropionate, followed by 10.6g of sodium borohydride, and the mixture was heated to 40 ℃ to react for 2 hours. Cooling the reaction liquid to 4 ℃, dropwise adding 2M dilute hydrochloric acid solution, adjusting the pH value to be neutral, concentrating under reduced pressure, adding 100mL of methanol and 45mL of purified water into concentrated residual liquid, stirring for 5 hours at 4 ℃, separating out a large amount of solids in the system, performing suction filtration to obtain a wet product, and performing vacuum drying at 55 ℃ to obtain a compound II with the molar yield of 80.6%.
(b) A250 mL three-necked flask was charged with 100mL of methanol, 15g of Compound II, and 25mL of 4M aqueous sodium hydroxide solution. Heating to 65 ℃ for reaction for 5h, dropwise adding 2M dilute hydrochloric acid solution, and adjusting the pH value to be neutral. Controlling the temperature to be 4 ℃, stirring and crystallizing for 6h, separating out a large amount of solid in the system, carrying out suction filtration to obtain a wet product, and carrying out vacuum drying at 55 ℃ to obtain the compound I, wherein the HPLC (high performance liquid chromatography) is 99.6%, and the molar yield is 85.2%.
The above embodiments are only for illustrating the technical solutions and features of the present invention, and the purpose of the embodiments is to enable researchers in the pharmaceutical industry to understand the contents of the present invention and to implement the present invention accordingly, which should not be construed as limiting the scope of the present invention.
Claims (10)
1. A fexofenadine hydrochloride impurity, said fexofenadine hydrochloride impurity being compound I as shown below:
2. a method for synthesizing fexofenadine hydrochloride impurity shown as compound I,
the method comprises the following steps:
(a) selecting 2- [4- (4-chloro-1-butyryl) phenyl ] -2-methyl propionate as a raw material, using methanol as a reaction solvent, carrying out reduction reaction under the action of sodium borohydride, cooling, adjusting pH, concentrating, and crystallizing to obtain a compound II: 2- [4- (4-chloro-1-hydroxy) phenyl ] -2-methylpropanoic acid methyl ester;
(b) taking the compound II obtained in the step (a) as a raw material, performing hydrolysis reaction by using a sodium hydroxide aqueous solution, adjusting pH, cooling and crystallizing to obtain high-purity fexofenadine hydrochloride impurities: namely compound I: 2- [4- (4-chloro-1-hydroxy) phenyl ] -2-methylpropionic acid.
3. A synthesis process according to claim 2, wherein in step (a) the molar ratio of methyl 2- [4- (4-chloro-1-butyryl) phenyl ] -2-methylpropionate to sodium borohydride is 1:3-5, preferably 1: 4.
4. a method of synthesis according to claim 2 or 3, wherein in step (a) the temperature of the reduction reaction is 20 to 50 ℃, more preferably 20 to 40 ℃, most preferably 40 ℃;
preferably, in step (a), the time of the reduction reaction is 2 hours.
5. The synthesis process according to any one of claims 2 to 4, wherein, in step (a), the temperature reduction is a temperature reduction to 0-10 ℃, preferably to 4 ℃;
preferably, in step (a), the pH adjustment is performed using a 2M dilute hydrochloric acid solution, and more preferably, the pH adjustment is performed such that the pH is adjusted to be neutral using a 2M dilute hydrochloric acid solution;
preferably, in step (a), the crystallization is performed as follows: adding methanol and water into the concentrate obtained by concentration, and stirring for 5-6h at 0-10 ℃ for crystallization; further preferably, the crystallization is performed as follows: adding a mixed solvent of methanol and water with a volume ratio of 20:9 into the concentrated substance, and stirring for 5h at 4 ℃ for crystallization.
6. The synthesis method according to any one of claims 2 to 5, wherein in step (b), the temperature of the hydrolysis reaction is 55 to 65 ℃; preferably 65 ℃;
preferably, in step (b), the time of the hydrolysis reaction is 5 hours.
7. The synthesis method according to any one of claims 2 to 6, wherein in step (b), the pH adjustment is carried out with a 2M dilute hydrochloric acid solution, more preferably, the pH adjustment is carried out to adjust the pH to neutral with a 2M dilute hydrochloric acid solution.
8. The synthesis method according to any one of claims 2 to 7, wherein in the step (b), the temperature-reduced crystallization is crystallization at a temperature controlled between 0 and 10 ℃, preferably at 4 ℃;
preferably, in step (b), the time for cooling crystallization is 4 to 8 hours, more preferably 5 to 7 hours, and most preferably 6 hours.
9. The synthetic method according to any one of claims 2-8, wherein the synthetic method employs the following synthetic route:
wherein, the preparation method comprises the following steps:
(a) selecting 2- [4- (4-chloro-1-butyryl) phenyl ] -2-methyl propionic acid methyl ester as a raw material, using methanol as a reaction solvent, and carrying out a reduction reaction under the action of sodium borohydride, wherein the molar ratio of the raw material to the sodium borohydride is 1: 4. the temperature of the reduction reaction is 40 ℃, the time of the reduction reaction is 2 hours, then the temperature is reduced to 4 ℃, the pH value is adjusted to be neutral, the concentration is carried out, a mixed solvent of methanol and water with the volume ratio of 20:9 is added into the concentrated product, the mixture is stirred for 5 hours at the temperature of 4 ℃ to be crystallized, and a compound II is obtained: 2- [4- (4-chloro-1-hydroxy) phenyl ] -2-methylpropanoic acid methyl ester;
(b) taking the compound II obtained in the step (a) as a raw material, carrying out hydrolysis reaction for 5h at 65 ℃ by adopting a sodium hydroxide aqueous solution, adjusting the pH value to be neutral, cooling to 4 ℃ and crystallizing for 6h to obtain high-purity fexofenadine hydrochloride impurities: namely compound I: 2- [4- (4-chloro-1-hydroxy) phenyl ] -2-methylpropionic acid.
10. Use of fexofenadine hydrochloride impurity according to claim 1 or produced according to the synthesis method of any one of claims 2 to 9 for quality control of fexofenadine hydrochloride.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1128987A (en) * | 1993-06-25 | 1996-08-14 | 默里尔多药物公司 | Novel intermediates for prepn. of antihisatminic 4-diphenylmethyl/diphenymethoxy piperidine derivatives |
| WO1997022344A1 (en) * | 1995-12-21 | 1997-06-26 | Albany Molecular Research, Inc. | Process for production of piperidine derivatives |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1128987A (en) * | 1993-06-25 | 1996-08-14 | 默里尔多药物公司 | Novel intermediates for prepn. of antihisatminic 4-diphenylmethyl/diphenymethoxy piperidine derivatives |
| WO1997022344A1 (en) * | 1995-12-21 | 1997-06-26 | Albany Molecular Research, Inc. | Process for production of piperidine derivatives |
Non-Patent Citations (1)
| Title |
|---|
| BARBARA DI GIACOMO等: "A new synthesis of carboxyterfenadine (fexofenadine) and its bioisosteric tetrazole analogs", FARMACO, vol. 54, no. 9, pages 600 - 610, XP002272865, DOI: 10.1016/S0014-827X(99)00070-1 * |
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