CN111004223A - Preparation and separation method of olmesartan medoxomil dimer impurities - Google Patents

Preparation and separation method of olmesartan medoxomil dimer impurities Download PDF

Info

Publication number
CN111004223A
CN111004223A CN202010165328.4A CN202010165328A CN111004223A CN 111004223 A CN111004223 A CN 111004223A CN 202010165328 A CN202010165328 A CN 202010165328A CN 111004223 A CN111004223 A CN 111004223A
Authority
CN
China
Prior art keywords
olmesartan medoxomil
dimer
impurities
olmesartan
preparation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN202010165328.4A
Other languages
Chinese (zh)
Other versions
CN111004223B (en
Inventor
张根
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Changsha Chenchen Pharmaceutical Technology Co Ltd
Original Assignee
Changsha Chenchen Pharmaceutical Technology Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Changsha Chenchen Pharmaceutical Technology Co Ltd filed Critical Changsha Chenchen Pharmaceutical Technology Co Ltd
Priority to CN202010165328.4A priority Critical patent/CN111004223B/en
Publication of CN111004223A publication Critical patent/CN111004223A/en
Application granted granted Critical
Publication of CN111004223B publication Critical patent/CN111004223B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides a preparation and separation method of olmesartan medoxomil dimer impurities, which comprises the following steps: step S1, carrying out self-polymerization reaction on olmesartan in a vacuum environment at the temperature of 40-60 ℃ to obtain a crude product containing olmesartan medoxomil dimer impurities; and step S2, eluting and separating the impurities C of olmesartan medoxomil USP in the crude product obtained in the step S1 from other components by supercritical fluid chromatography, collecting the peak fraction of the impurities of olmesartan medoxomil dimer, and evaporating the collected fractions of the impurities of the olmesartan medoxomil dimer to dryness to obtain the impurities of the olmesartan medoxomil dimer. The technical scheme of the invention generates olmesartan medoxomil dimer impurities through a one-step reaction, and has the advantages of high reaction efficiency, simple and convenient steps, high efficiency, simple post-treatment, low cost and little pollution.

Description

Preparation and separation method of olmesartan medoxomil dimer impurities
Technical Field
The invention belongs to the technical field of chemistry, and particularly relates to a preparation and separation method of olmesartan medoxomil dimer impurities.
Background
Olmesartan Medoxomil (Olmesartan Medoxomil) was developed by Sankyo (tri-co-company) in japan and forest laboratories, usa, and was marketed in the us under the trade name Benicar in 5 months 2002, approved in germany in 8 months of the same year, and marketed in the beginning of 10 months.
Olmesartan medoxomil is a prodrug, is absorbed by gastrointestinal tract after being taken orally, is hydrolyzed into a product with biological activity to be olmesartan to play a role, has excellent tolerance and can be taken for a long time. From the domestic and foreign aspects, the antihypertensive drug market in the 21 st century is dominated by selective angiotensin II receptor inhibitors (ARBs), which generally has a good prospect for sartans. Development of olmesartan medoxomil which is an efficient, long-acting and low-toxicity antihypertensive drug has very important significance.
Olmesartan medoxomil can generate degradation reaction to generate olmesartan medoxomil dimers, the degradation way is that olmesartan medoxomil is hydrolyzed under high humidity environment to generate olmesartan, and then the olmesartan medoxomil generates esterification reaction to generate olmesartan medoxomil dimers. Namely, the olmesartan medoxomil dimer impurity is a degradation product of olmesartan medoxomil, Tomonio Murakami and the like are found to be degraded and generated (the content reaches 0.72%) when the mixture is placed for 6 months under the conditions that the temperature is 40 ℃ and the relative humidity is 75%, and the impurity C is recorded in the United states pharmacopoeia, has a chemical structure shown in the following and has important influence on the safety and the effectiveness of the medicine.
Figure DEST_PATH_IMAGE002A
In recent years, the supervision departments of various countries gradually strengthen the supervision work of drug applications, particularly the imitation drug applications, especially put forward higher requirements on the quality of the imitation drugs, pharmaceutical enterprises are required to carry out intensive research on various impurities affecting the safety and the effectiveness of the drugs, and various pharmaceutical researches can be carried out on the impurities only by obtaining a certain amount of impurity reference substances in the research process, so that the preparation of the impurity reference substances is very important work.
The existing literature discloses that Jilin correction pharmaceutical drug development Limited company adopts a 4-step method to directly synthesize the impurities, the method has more synthesis steps, troublesome post-treatment and higher cost, and various toxic organic solvents (such as acyl chloride, toluene and ethyl acetate) are adopted in the synthesis process, so that the pollution to people and the environment is greater.
Because the olmesartan medoxomil dimer impurity is tertiary alcohol ester, the steric hindrance is large, the self-polymerization of two molecules of olmesartan medoxomil through the esterification reaction is difficult to carry out, the degradation speed by itself is slow under the conventional condition, and the yield is low. Literature reports that the DCC (N, N' -dicyclohexylcarbodiimide) method can be used for the tertiary alcohol ester reaction, but the yield of the dimer is still very low by attempting to dehydrate DCC directly, because DCC is very easy to cause the tertiary alcohol to be dehydrated directly instead of esterified to obtain the product.
Disclosure of Invention
Aiming at the technical problems, the invention discloses a method for preparing and separating olmesartan medoxomil dimer impurities, which is environment-friendly, efficient and low in cost, and the product obtained by separation and preparation meets the requirements of pharmacopoeia.
In contrast, the technical scheme adopted by the invention is as follows:
a preparation and separation method of olmesartan medoxomil dimer impurities comprises the following steps:
step S1, enriching crude olmesartan medoxomil dimer impurities: carrying out self-polymerization reaction on olmesartan in a vacuum environment at the temperature of 40-60 ℃ to obtain a crude product containing olmesartan medoxomil dimer impurities; wherein, the content of olmesartan medoxomil dimer impurities in the crude product is more than 10%. Wherein, the content is the content characterized by an HPLC area normalization method, and is generally close to the real mass percentage content. The reaction scheme is as follows:
Figure 16094DEST_PATH_IMAGE004
step S2, high-efficiency and low-toxicity separation: and (4) eluting and separating the olmesartan medoxomil dimer impurity and other components in the crude product obtained in the step (S1) by using supercritical fluid chromatography, collecting the olmesartan medoxomil dimer impurity peak fraction, and evaporating the collected olmesartan medoxomil dimer impurity fraction to dryness to obtain the olmesartan medoxomil dimer impurity.
The technical scheme takes olmesartan as a raw material by changing external conditions, accelerates the polymerization of the olmesartan to obtain olmesartan medoxomil dimer impurities, and has the advantages of simple and reliable method and high reaction efficiency.
As a further improvement of the invention, the reaction time in the step S1 is 68-80 h. Further, the reaction time in step S1 was about 72 hours.
As a further improvement of the invention, in step S1, the vacuum degree of the vacuum environment is less than or equal to 1 mbar. Wherein the low vacuum is used for quickly removing water generated in the reaction so as to promote the forward reaction.
As a further improvement of the present invention, in step S2, when elution is performed by supercritical fluid chromatography, supercritical carbon dioxide-ethanol solution is used as a flow-off agent, and the Torus 2-PIC packing of Waters is used as a preparation column. The use of the stripping agent has the advantages of high efficiency, low toxicity and little pollution.
As a further improvement of the invention, the volume percentage of the carbon dioxide in the supercritical carbon dioxide-ethanol solution is 60-70%.
As a further improvement of the present invention, in step S2, the olmesartan medoxomil dimer impurity (USP impurity C) having a purity of 95% or more can be obtained by evaporating the mixture to dryness under reduced pressure using a rotary evaporator.
Compared with the prior art, the invention has the beneficial effects that:
the technical scheme of the invention adopts olmesartan as a raw material at a proper temperature (40-60 ℃) and in a low vacuum environment (less than or equal to 1 mbar), olmesartan medoxomil dimer impurities are generated through a one-step reaction, the reaction rate is more than or equal to 10%, the steps are simple, convenient and efficient, crude impurities are obtained at low cost, then the crude products obtained through the reaction are separated and prepared in one step by adopting environment-friendly Supercritical Fluid Chromatography (SFC), the mobile phases adopted are carbon dioxide and ethanol instead of the traditional alkane organic solvent with high toxicity, the preparation fractions can be directly reduced and evaporated to dryness, the post-treatment is simple, the cost is low, and the pollution is small.
Drawings
FIG. 1 is a high resolution mass spectrum of the olmesartan medoxomil dimer impurity (USP impurity C) prepared in example 2 of the present invention.
FIG. 2 is a graph of the olmesartan medoxomil dimer impurity (USP impurity C) prepared in example 2 of the present invention1And (4) H spectrum atlas.
FIG. 3 is a graph of the olmesartan medoxomil dimer impurity (USP impurity C) prepared in example 2 of the present invention13And (C) spectrum atlas.
Detailed Description
Preferred embodiments of the present invention are described in further detail below.
Example 1
The instrument comprises the following steps: preparation of supercritical fluid chromatography (Waters Corp.); glass vacuum reactor (Shanghai Yangrong Biochemical instruments factory).
Preparing crude olmesartan medoxomil dimer impurities: 10g of olmesartan is placed in a glass vacuum reactor, the heating temperature is set to be 50 ℃, the vacuum degree is set to be 0.8mbar, and the solid is stirred to react for 72 hours, so that crude olmesartan medoxomil dimer impurities with the content of 13.4 percent can be obtained. The above contents are contents characterized by HPLC area normalization.
Preparing a column: waters Torus-2-PIC (OBD 30 x 250mm,5 um).
SFC separation preparative chromatography conditions: performing isocratic elution with supercritical carbon dioxide-ethanol solution (70: 30, V/V) as eluent; the flow rate is 80 mL/min; the detection wavelength is 250 nm; the column temperature was 35 ℃; preparing pressure to 100 bar; automatic sample injection, sample volume 2 ml.
Preparing a sample solution: and (3) passing the prepared crude olmesartan medoxomil dimer impurity through a 0.45um organic filter membrane.
Collecting impurity fractions of olmesartan medoxomil dimer: after 3 minutes of the chromatographic condition equilibrium system is prepared by SFC, the instrument automatically enters a sample for elution and separation, the fraction begins to be collected when the impurity C just generates a peak, the end is reached to the tail part of the peak, and the olmesartan medoxomil dimer impurity fraction is stored at normal temperature. The instrument was repeated 5 times and all olmesartan medoxomil dimer impurity fractions were pooled.
Fraction post-treatment of olmesartan medoxomil dimer impurities: all fractions obtained by separation were evaporated to dryness at 35 ℃ under reduced pressure using a rotary evaporator to obtain a total of 1205mg of olmesartan medoxomil dimer impurity (USP impurity C) having a purity of 97.20%. The purity is characterized by HPLC area normalization and is generally close to the true mass percent.
The olmesartan medoxomil dimer impurity (USP impurity C) obtained was tested, and the specific contents were as follows:
(1) LC-MS test:
the instrument comprises the following steps: agilenggt 1260 HPLC-6530Q-TOF.
The test method comprises the following steps: an ion source: the AJS double-electric spraying; ion polarity: positive; gas temperature: 350 ℃; drying gas: 12.0L/min; an atomizer: 45 psig; a fragmenter: 150V.
And (3) testing results: the observed M/z875.4101 is [ M + H ] of the prepared olmesartan medoxomil dimer impurity (USP impurity C), respectively]+Ions. Calculating the molecule to be C48H50N12O5The calculated theoretical value deviates 0.11ppm from the actual measured value.
(2) NMR measurement:
the instrument comprises the following steps: bruker AVANCE III HD 600 Switzerland 600 superconducting pulse Fourier transform nuclear magnetic resonance spectrometer.
The test method comprises the following steps: dissolving the sample in heavy water, and testing1H spectrum and13C-NMR spectrum.
By analysis, the chemical structural formula of the olmesartan medoxomil dimer impurity (USP impurity C) is shown in the following formula, and the NMR data are shown in the following table 1.
Figure DEST_PATH_IMAGE006A
TABLE 1 method for olmesartan medoxomil USP impurity C13C and1h chemical shift data attribution
Figure DEST_PATH_IMAGE008A
Example 2
The instrument comprises the following steps: preparation of supercritical fluid chromatography (Waters Corp.); glass vacuum reactor.
Preparing crude olmesartan medoxomil dimer impurities: 10g of olmesartan is placed in a glass vacuum reactor, the heating temperature is set to be 50 ℃, the vacuum degree is set to be 1.0mbar, and the solid is stirred to react for 72 hours, so that the crude olmesartan medoxomil dimer impurity with the content of 12.5 percent can be obtained. The above contents are contents characterized by HPLC area normalization.
Preparing a column: waters Torus-2-PIC (OBD 30 x 250mm,5 um).
SFC separation preparative chromatography conditions: performing isocratic elution with supercritical carbon dioxide-ethanol solution (70: 30, V/V) as eluent; the flow rate is 80 mL/min; the detection wavelength is 250 nm; the column temperature was 35 ℃; preparing pressure to 100 bar; automatic sample injection, sample volume 2 ml.
Preparing a sample solution: and (3) passing the prepared crude olmesartan medoxomil dimer impurity through a 0.45um organic filter membrane.
Collecting impurity fractions of olmesartan medoxomil dimer: after 3 minutes of the chromatographic condition equilibrium system is prepared by SFC, the instrument automatically enters a sample for elution and separation, the fraction begins to be collected when the impurity C just generates a peak, the end is reached to the tail part of the peak, and the olmesartan medoxomil dimer impurity fraction is stored at normal temperature. The instrument was repeated 5 times and all olmesartan medoxomil dimer impurity fractions were pooled.
Fraction post-treatment of olmesartan medoxomil dimer impurities: all fractions obtained by separation were evaporated to dryness at 35 ℃ under reduced pressure using a rotary evaporator to obtain a total of 1120mg of olmesartan medoxomil dimer impurity (USP impurity C) having a purity of 98.10%. The purity is characterized by HPLC area normalization and is generally close to the true mass percent. The obtained olmesartan medoxomil dimer impurity is tested, the high-resolution mass spectrum of the impurity is shown in figure 1,1the spectrum of the H spectrum is shown in figure 2,13the spectrum of C is shown in FIG. 3.
Comparative example 1
Taking solid olmesartan and placing the solid olmesartan in a drying oven at 80 ℃ for 72 hours, wherein the content of dimer impurities is only about 0.5%, and further preparation and separation cannot be carried out.
Comparative example 2
Taking solid olmesartan, adding DMF (dimethyl formamide) to dissolve the solid olmesartan, stirring the mixture at 80 ℃ to react for 72 hours, wherein the content of dimer impurities is only about 0.7 percent, and further preparation and separation cannot be carried out.
Comparative example 3
Taking solid olmesartan, adding DMSO (dimethyl sulfoxide) to dissolve the solid olmesartan, adding a dehydrating agent DCC (N, N' -dicyclohexylcarbodiimide), stirring and reacting for 24 hours at 45 ℃, wherein the content of a product is 0.8%, and the number of byproducts is large, so that further preparation and separation cannot be carried out. The reason for the analysis is that DCC mainly causes the dehydration degradation of tertiary alcohol, and does not mainly obtain a product.
It can be seen from the comparison between the above examples and comparative examples that the invention uses olmesartan as raw material by changing external conditions, so that the olmesartan itself can be accelerated to polymerize under vacuum heating environment to obtain olmesartan medoxomil dimer impurities.
The foregoing is a more detailed description of the invention in connection with specific preferred embodiments and it is not intended that the invention be limited to these specific details. For those skilled in the art to which the invention pertains, several simple deductions or substitutions can be made without departing from the spirit of the invention, and all shall be considered as belonging to the protection scope of the invention.

Claims (6)

1. A preparation and separation method of olmesartan medoxomil dimer impurities is characterized by comprising the following steps:
step S1, carrying out self-polymerization reaction on olmesartan in a vacuum environment at the temperature of 40-60 ℃ to obtain a crude product containing olmesartan medoxomil dimer impurities;
and step S2, eluting and separating the olmesartan medoxomil dimer impurity and other components in the crude product obtained in the step S1 by using supercritical fluid chromatography, collecting the olmesartan medoxomil dimer impurity peak fraction, and evaporating the collected olmesartan medoxomil dimer impurity fraction to dryness to obtain the olmesartan medoxomil dimer impurity.
2. The process for the preparation and separation of olmesartan medoxomil dimer impurities according to claim 1, characterized in that: the reaction time in the step S1 is 68-80 h.
3. The process for the preparation and separation of olmesartan medoxomil dimer impurities according to claim 1, characterized in that: in step S1, the vacuum degree of the vacuum environment is less than or equal to 1 mbar.
4. The method for producing and separating olmesartan medoxomil dimer impurities according to any one of claims 1 to 3, characterized by comprising: in step S2, when elution is performed by supercritical fluid chromatography, a supercritical carbon dioxide-ethanol solution is used as an eluent, and a Torus 2-PIC packing is used as a preparative column.
5. The process according to claim 4, for the preparation and separation of olmesartan medoxomil dimer impurities, characterized in that: the volume percentage of carbon dioxide in the supercritical carbon dioxide-ethanol solution is 60-70%.
6. The process according to claim 4, for the preparation and separation of olmesartan medoxomil dimer impurities, characterized in that: in step S2, the mixture is evaporated to dryness under reduced pressure using a rotary evaporator.
CN202010165328.4A 2020-03-11 2020-03-11 Preparation and separation method of olmesartan medoxomil dimer impurities Active CN111004223B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202010165328.4A CN111004223B (en) 2020-03-11 2020-03-11 Preparation and separation method of olmesartan medoxomil dimer impurities

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202010165328.4A CN111004223B (en) 2020-03-11 2020-03-11 Preparation and separation method of olmesartan medoxomil dimer impurities

Publications (2)

Publication Number Publication Date
CN111004223A true CN111004223A (en) 2020-04-14
CN111004223B CN111004223B (en) 2020-06-16

Family

ID=70121057

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202010165328.4A Active CN111004223B (en) 2020-03-11 2020-03-11 Preparation and separation method of olmesartan medoxomil dimer impurities

Country Status (1)

Country Link
CN (1) CN111004223B (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20120070353A (en) * 2010-12-21 2012-06-29 대봉엘에스 주식회사 Method of producing related substance of olmesartan medoxomil
CN104650046A (en) * 2015-01-27 2015-05-27 吉林修正药业新药开发有限公司 Synthesis method of olmesartan dimer
CN108484581A (en) * 2018-05-29 2018-09-04 宣城美诺华药业有限公司 A kind of new Candesartan dimer impurity and its synthetic method

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20120070353A (en) * 2010-12-21 2012-06-29 대봉엘에스 주식회사 Method of producing related substance of olmesartan medoxomil
CN104650046A (en) * 2015-01-27 2015-05-27 吉林修正药业新药开发有限公司 Synthesis method of olmesartan dimer
CN108484581A (en) * 2018-05-29 2018-09-04 宣城美诺华药业有限公司 A kind of new Candesartan dimer impurity and its synthetic method

Also Published As

Publication number Publication date
CN111004223B (en) 2020-06-16

Similar Documents

Publication Publication Date Title
Han et al. Stability and cytotoxicity of gambogic acid and its derivative, gambogoic acid
CN111518229B (en) Method for removing element impurities and pigments in refined sugammadex sodium product
JP2016183193A (en) Solid state forms of fidaxomicin and processes for preparation thereof
Roncari et al. On the chemical nature of the antibiotic edeine
CN111217773B (en) Furan ring compound in purslane and extraction and separation method and application thereof
CN111004223B (en) Preparation and separation method of olmesartan medoxomil dimer impurities
CN113429371B (en) Chemical synthesis method of delphinidin B9 gallate
CN111533772B (en) Preparation method of iridoid compound, iridoid compound and application
CN111103375B (en) Application of chlorogenic acid derivative in medicine quality control
CN113533574A (en) Composition for drug synthesis and detection method of p-toluenesulfonyl chloride in composition
Takahashi et al. Chemical Studies on Azalomycins. I. Preliminary Study on Azalomycin-B.
CN108169399B (en) Method for separating impurities in ethyl demethylaminothiazolyloximate crude product
CN112010825A (en) Pamifixib impurity reference substance and preparation method thereof
CN115141112A (en) Acetyl L-carnitine impurity, and preparation and detection methods and application thereof
Stipanovic et al. Corroboration of techniques for assigning absolute configuration: lacinilene C methyl ether as an exemplary study
CN113582951B (en) 10- (S) -17-hydrogen-7-dehydroandrographolide and industrial chromatographic preparation method and application thereof
CN113559106A (en) Application of betulonic acid derivative in preparation of medicine for treating nervous system diseases
CN108373488B (en) Catalpol 6-caffeic acid ester derivative and preparation method and application thereof
CN113105505A (en) Preparation method of degradation impurity of prophenoltenofovir
CN111253473B (en) Preparation method of bacitracin impurity L based on photocatalysis
CA3144038A1 (en) Recrystallisation of 5-methoxy-n,n-dimethyltryptamine (5-meo-dmt) in methyl tert.-butyl ether (mtbe) and less than 5 wt% of an aliphatic anti-solvent
CN110746387A (en) Clerodane diterpene derivative, preparation method thereof and anti-inflammatory drug or inflammatory reaction inhibitor thereof
CN110003308A (en) A kind of small molecule toxins isolated and purified from the thick poison of Araneus ventricosus and application
CN112526056B (en) Separation and detection method of captopril and diastereoisomer thereof
CN114195840B (en) Method for identifying structure of macrolide compound

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant