CN108586442A - A kind of compound and the preparation method and application thereof - Google Patents
A kind of compound and the preparation method and application thereof Download PDFInfo
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- CN108586442A CN108586442A CN201810722583.7A CN201810722583A CN108586442A CN 108586442 A CN108586442 A CN 108586442A CN 201810722583 A CN201810722583 A CN 201810722583A CN 108586442 A CN108586442 A CN 108586442A
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- 0 CCC(C)(C*)CCCCC(CCC1C2=CC3C(CC)(*C)C3C12C)C1C=C1 Chemical compound CCC(C)(C*)CCCCC(CCC1C2=CC3C(CC)(*C)C3C12C)C1C=C1 0.000 description 5
- NISYFKZCXUCHDN-RXUSGZCFSA-N CC(C(c1ccc(-c(cc2)ccc2F)[s]1)c1cc([C@@H](CC2=O)O[C@H](CO)[C@@H]2O)ccc1C)c1ccc(C)c(Cc2ccc(-c(cc3)ccc3F)[s]2)c1 Chemical compound CC(C(c1ccc(-c(cc2)ccc2F)[s]1)c1cc([C@@H](CC2=O)O[C@H](CO)[C@@H]2O)ccc1C)c1ccc(C)c(Cc2ccc(-c(cc3)ccc3F)[s]2)c1 NISYFKZCXUCHDN-RXUSGZCFSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N2030/042—Standards
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- Health & Medical Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the field of chemical synthesis, in particular to a kind of compound and the preparation method and application thereof.The compound is the impurity in a kind of canagliflozin production process, can be used as standard items or reference substance and is applied in canagliflozin control of product quality.
Description
Technical field
The present invention relates to the field of chemical synthesis, in particular to a kind of compound and the preparation method and application thereof.
Background technology
Canagliflozin (Canagliflozin) is currently to be clinically used for a kind of drug for the treatment of diabetes, belongs to first
The SGLT-2 inhibitor ratified by FDA.SGLT-2 is a novel treating diabetes target spot, with traditional Remedies for diabetes
The mechanism of action is different, and glucose extra in vivo can be discharged in it from urine, so as to reduce glycosylation albumen, improves liver
Insulin sensitivity, improvement β cell functions with peripheral tissues, while can further improve hepatic insulin resistance, to promote
Higher glycogen output is set to restore normal.
The Yuan Yan companies of canagliflozin are military field, and the main method of country's canagliflozin synthesis is as follows at present：
Its in the synthesis process, since the controllability of 1 mass of compound is not high, and grignard addition reaction condition is more severe
It carves, needs to carry out in the environment of low-temperature anhydrous anaerobic, so in reaction process, special related substance can be introduced.
In the prior art, although the structure for having part canagliflozin impurity is parsed, but still there is the knot of partial impurities
Structure is unknown, is unfavorable for the optimization of control and production procedure to canagliflozin medicine production process moderate purity.
In view of this, special propose the present invention.
Invention content
In order to realize that the above-mentioned purpose of the present invention, spy use following technical scheme：
According to an aspect of the present invention, the present invention relates to a kind of compounds that chemical formula is as follows：
According to an aspect of the present invention, the invention further relates to the preparation methods of compound as described above, including：
a).Acetylation through acetic anhydride is protected to obtain
b).Grignard Reagent is generated under low temperature, nonoxidizing atmosphere with isopropylmagnesium chloride,
In, X is halogeno-group；
C) by the Grignard Reagent withNucleophilic addition is carried out to obtain
d).The anti-of reducing agent is done in low temperature, lewis acid and organosilan
Reduction reaction generation is carried out under the conditions of answering
e).It is obtained through deprotection reaction
Wherein, step a) and b) without sequencing.
This method respectively walks reaction mechanism and defines, and 5 chiral centres of the product being prepared determine；Starting material is inexpensively easy
, technological operation is easy to control, and combined coefficient is high, at low cost, is conducive to largely prepare；Operation process is simple, is not directed to spy
Different consersion unit.
According to an aspect of the present invention, the invention further relates to compound as described above as standard items or reference substance in card lattice
Application in row net products quality control.
The present invention synthesizes the standard items of the related substance of canagliflozin by preparation, further applies canagliflozin raw material
Quality control and research prepared by medicine, the quality to improve bulk pharmaceutical chemicals provide new direction.
Description of the drawings
It, below will be to specific in order to illustrate more clearly of the specific embodiment of the invention or technical solution in the prior art
Embodiment or attached drawing needed to be used in the description of the prior art are briefly described, it should be apparent that, in being described below
Attached drawing is some embodiments of the present invention, for those of ordinary skill in the art, before not making the creative labor
It puts, other drawings may also be obtained based on these drawings.
Fig. 1 is the chromatogram of canagliflozin impurity Formulas I in one embodiment of the invention；
Fig. 2 is the mass spectrogram of canagliflozin impurity Formulas I in one embodiment of the invention；
Fig. 3 is the nuclear-magnetism figure of canagliflozin impurity Formulas I in one embodiment of the invention.
Specific implementation mode
According to an aspect of the present invention, the present invention relates to a kind of compounds that chemical formula is as follows：
According to an aspect of the present invention, the invention further relates to the preparation methods of the compound；
This method is protected using D-Glucose acid lactone as raw material through acetic anhydride acetylation, and among the halides that have activated
Body carries out nucleophilic addition, then through reduction, hydrolysis obtains the crude product of the higher impurity of content, then purifies to obtain through column chromatography
The sterling of the impurity detects purity up to 99% or more through HPLC.
In some embodiments, the method includes：
a).The acetylation of (D-Glucose acid lactone) through acetic anhydride is protected to obtain
b).Grignard Reagent is generated under low temperature, nonoxidizing atmosphere with isopropylmagnesium chloride,
In, X is halogeno-group；
C) by the Grignard Reagent withNucleophilic addition is carried out to obtain
d).Reducing agent is made in low temperature, lewis acid and organosilan
Reduction reaction generation is carried out under reaction condition
e).It is obtained through deprotection reaction
Wherein, step a) and b) without sequencing.
In some embodiments, in step a), the ginseng of the reaction of acetylation protection in cation exchange resin
With lower progress；
In some embodiments, when carrying out acetylation protection, the quality of the D-Glucose acid lactone and acetic anhydride
Than being 2~4: 6~8.
In some embodiments, further include chlorination in the reaction system for generating Grignard Reagent in step b)
Lithium；
In some embodiments, the isopropylmagnesium chloride is added with lithium chloride in the form of complex solutionToluene solution in reacted；The solvent of the complex solution is selected from ether solvent, described
The preferred ether of ether solvent or tetrahydrofuran；
In some embodiments, describedToluene solution in
A concentration of 0.3g/ml~0.8g/ml, 0.4g/ml, 0.5g/ml, 0.6g/ml or 0.7g/ml can also be selected；
In some embodiments, in the complex solution complex compound a concentration of 0.8~1.0mol/L；
In some embodiments, describedToluene solution and the complex solution body
Product is than being 0.8~1.2: 0.8~1.2；
In some embodiments, the halogeno-group is I or Br.
In some embodiments, the reaction temperature for generating Grignard Reagent is -10 DEG C~0 DEG C (it is also an option that -8
DEG C, -6 DEG C, -4 DEG C, -2 DEG C), the reaction time is 1h~2h.
In some embodiments, in step c), the reaction condition of the nucleophilic addition is specially：
c1).The solution of a concentration of 0.8~1.2g/mL is mixed into ether solvent, in non-oxide gas
Atmosphere, at a temperature of -35 DEG C~-45 DEG C with the Grignard Reagent insulation reaction 40min~80min；
C2) adjust reaction system pH to 6~7 after, be warming up to 20 DEG C~30 DEG C stirring 20min~40min, stratification,
It is organic to be added to anhydrous sodium sulfate drying, it filters, filtrate decompression is concentrated into no liquid outflow.
In some embodiments, in step d), the lewis acid is the ether of boron trifluoride, preferably boron trifluoride second
Ether；
The organosilan is triethylsilane；
Preferably, the low temperature is 0~10 DEG C；
Preferably, the time of the reduction reaction is 1h~2h.
In some embodiments, after step d), further include before step e)：
Step d) after reaction, adjust reaction system pH=7~8 simultaneously methanol is added, be sufficiently stirred be precipitated precipitation
After be obtained by filtration containingFiltrate be used for step e).
In some embodiments, in step e), the deprotection reaction is carried out in methanolic sodium methoxide system.
In some embodiments, the deprotection reaction is by being added vinegar acid for adjusting pH value as 6~7 to terminate reaction.
In some embodiments, after the completion of the deprotection reaction, the method further includes：
Reaction solution is concentrated under reduced pressure, solvent evaporated obtains crude product, and the crude product is purified using column chromatography；
In some embodiments, in the column chromatography procedure, eluant, eluent is dichloromethane, n-hexane, methanol；
In some embodiments, the dichloromethane, n-hexane, methanol volume ratio be 1: 1: (2~4), preferably 1: 1
∶3。
Post-reaction treatment of the present invention is simple, it is only necessary to remove common impurity by silica gel column chromatography, be not required to by preparation solution
Chromatography is detached with expensive chiral preparatory column.
According to an aspect of the present invention, the invention further relates to compound as described above as standard items or reference substance in card lattice
Application in row net products quality control.
The synthesis of the impurity is set to realize that beam system is standby using method provided by the invention, for the net series sugar of industrialized production row
The quality research of the sick medicine product of urine and impurity quantitatively control and provide reliable impurity reference substance.
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and is not construed as limiting the scope of the invention.It is not specified in embodiment specific
Condition person carries out according to conventional conditions or manufacturer's recommended conditions.Reagents or instruments used without specified manufacturer is
It can be with conventional products that are commercially available.
Embodiment 1
S1, D-Glucose acid lactone 20g are added in the three-necked flask of 100ml dryings, and 70g acetic anhydrides are added, and add at room temperature
Enter 30g cation exchange resins, 40~50 DEG C of insulation reactions 2~3 hours after addition, TLC monitors reaction solution substantially without Portugal
Grape saccharic acid lactones, after the completion of reaction, filters out cation exchange resin, and filtrate control is concentrated under reduced pressure into without evaporating for 70~80 DEG C
Point, obtain 1 about 41g of brown yellow oil thick liquid compound, yield about 105%.
In S2, the three-necked flask dried to 100ml, toluene 30ml is added,13g, in nitrogen
It is cooled to 0~10 DEG C under protection, the tetrahydrofuran solution 30ml of sec-butyl magnesium chloride lithium chloride is added with stirring, at -10~0 DEG C
Insulation reaction 1~2 hour, the Grignard Reagent prepared.
S3, the compound 1 and 20ml tetrahydrofurans that 20g is added in the three-necked flask of other 250ml, under nitrogen protection
- 35 DEG C are cooled to, the Grignard Reagent prepared is added, insulation reaction is slowly added to 10% aqueous hydrochloric acid solution adjusting after 1 hour
PH value is 6~7, then is warming up to 30~30 DEG C and stirs 30 minutes, and stratification is organic to be added to anhydrous sodium sulfate drying, filters,
Filtrate decompression is concentrated into no liquid outflow, obtains grease intermediate 2 and is directly used in next step.
S4,60ml acetonitriles and intermediate obtained in the previous step 2 are added in 250ml three-necked flasks, 5g triethyl group silicon is added
Alkane is cooled to 0~10 DEG C, and 11g boron trifluoride ether is added, and temperature control reacts 1~2 hour, and TLC monitoring reactions are completed.It has reacted
Cheng Hou, it is 7~8 that about 15ml ammonium hydroxide, which is added, and adjusts pH value, and 60ml methanol is added, has solid precipitation, stirring to be filtered after 1 hour, will
Filtrate decompression is concentrated into no liquid outflow, obtains grease intermediate 3 and is directly used in next step.
S5, methanol 20ml and intermediate obtained in the previous step 3 are added into 50ml three-necked flasks, are stirred at room temperature uniformly, add
Enter 5ml methanol solution of sodium methylate, 20~30 DEG C of temperature control reacts 1~2 hour, and the reaction was complete for TLC monitoring.After the completion of reaction, cooling
To 0~5 DEG C, it is 6~7 that vinegar acid for adjusting pH value, which is added, then reaction solution is concentrated under reduced pressure, solvent evaporated obtains crude product canagliflozin
Impurity Formulas I, column chromatography purifying, eluant, eluent ratio are (dichloromethane: n-hexane: methanol=1: 1: 3), to collect component, concentration is dry
It is dry, obtain off-white powder canagliflozin impurity 960mg.
Embodiment 2
S1, D-Glucose acid lactone 300g are added in the three-necked flask of 1000ml dryings, and 800g acetic anhydrides, room temperature is added
Lower addition 450g cation exchange resins, 40~50 DEG C of insulation reactions 6~8 hours after addition, it is basic that TLC monitors reaction solution
Without gluconic acid lactone, after the completion of reaction, cation exchange resin is filtered out, filtrate control is concentrated under reduced pressure into nothing for 70~80 DEG C
Fraction obtains 1 about 642g of brown yellow oil thick liquid compound, yield about 110%.
In S2, the three-necked flask dried to 100ml, toluene 30ml is added,15g is protected in nitrogen
It is cooled to 0~10 DEG C under shield, is added with stirring the tetrahydrofuran solution 30ml of sec-butyl magnesium chloride lithium chloride, is protected at -10~0 DEG C
Temperature reaction 1~2 hour, the Grignard Reagent prepared.
S3~S5 leads to embodiment 1.
Experimental example
It is the method that qualitative and quantitative detection is carried out using canagliflozin impurity Formulas I prepared by the embodiment of the present invention 2 below.This
Invention finds that the canagliflozin impurity Formulas I prepared can make the quality testing of canagliflozin finished product more accurate, controllable, and uses
In the canagliflozin finished product for the process route production that original is ground, which is also the maximum contaminant remained in finished product, such as without true
Determine the structure of canagliflozin impurity Formulas I, then can not effectively control the related substance in canagliflozin bulk pharmaceutical chemicals.
The method that the canagliflozin impurity Formulas I prepared below using the present invention is detected canagliflozin finished product.
Related substance：Canagliflozin about 25mg is taken, dissolved with acetonitrile-water (80: 20) and quantifies dilution and is made in every 1ml about
Test solution containing 2mg；Canagliflozin impurity Formulas I reference substance about 25mg separately is taken, is dissolved with acetonitrile-water (80: 20) and quantitative
The reference substance solution that every 1ml contains 2 μ g is made in dilution.According to high effective liquid chromatography for measuring, it is with octadecylsilane chemically bonded silica
Filler, mobile phase A are 0.05% phosphoric acid, and Mobile phase B is acetonitrile, and according to the form below carries out gradient elution.Column temperature is 30 DEG C, and wavelength is
225nm, flow velocity 1.0ml/min.10 μ l injection liquid chromatographs are respectively taken, chromatogram is recorded.
Gradient elution table：
In test solution chromatogram, if any detection canagliflozin impurity Formulas I, is calculated, be must not exceed by external standard method
0.1%.
The results are shown in Figure 1.
Canagliflozin Formulas I is detected by above-mentioned detection method, it can be quickly and accurately in qualitative and quantitative detection raw material
Related substance, be conducive to quickly determine final product quality in process of production, determine bulk pharmaceutical chemicals quality.
In addition, the mass spectrogram of canagliflozin impurity Formulas I is as shown in Figure 2；
The nuclear-magnetism figure of canagliflozin impurity Formulas I is as shown in Figure 3.
Finally it should be noted that：The above embodiments are only used to illustrate the technical solution of the present invention., rather than its limitations；To the greatest extent
Present invention has been described in detail with reference to the aforementioned embodiments for pipe, but it will be understood by those of ordinary skill in the art that：Its
It still can be with technical scheme described in the above embodiments is modified, either to which part or all technical features
Carry out equivalent replacement；And these modifications or replacements, various embodiments of the present invention skill that it does not separate the essence of the corresponding technical solution
The range of art scheme.
Claims (10)
1. a kind of compound that chemical formula is as follows：
2. the preparation method of compound described in claim 1, which is characterized in that including：
a).Acetylation through acetic anhydride is protected to obtain
b).Grignard Reagent is generated under low temperature, nonoxidizing atmosphere, wherein X with isopropylmagnesium chloride
For halogeno-group；
C) by the Grignard Reagent withNucleophilic addition is carried out to obtain
d).The reaction item of reducing agent is done in low temperature, lewis acid and organosilan
Reduction reaction generation is carried out under part
e).It is obtained through deprotection reaction
Wherein, step a) and b) without sequencing.
3. preparation method according to claim 2, which is characterized in that in step a), the reaction of the acetylation protection
It is carried out in the presence of cation exchange resin.
4. preparation method according to claim 2, which is characterized in that in step b), in the generation Grignard Reagent
It further include lithium chloride in reaction system；Preferably, the isopropylmagnesium chloride is added with lithium chloride in the form of complex solutionToluene solution in reacted；The solvent of the complex solution is selected from ether solvent, described
The preferred ether of ether solvent or tetrahydrofuran；
Preferably, describedToluene solution inA concentration of 0.3g/
Ml~0.8g/ml；
Preferably, in the complex solution complex compound a concentration of 0.8~1.0mol/L；
Preferably, describedToluene solution and the complex solution volume ratio be 0.8~
1.2：0.8~1.2；
Preferably, the halogeno-group is I or Br.
5. preparation method according to claim 4, which is characterized in that the reaction temperature for generating Grignard Reagent is -10
DEG C~0 DEG C, the reaction time is 1h~2h.
6. preparation method according to claim 2, which is characterized in that in step c), the nucleophilic addition it is anti-
The condition is answered to be specially：
c1).The solution of a concentration of 0.8~1.2g/mL is mixed into ether solvent, in nonoxidizing atmosphere, -35
DEG C~-45 DEG C at a temperature of with the Grignard Reagent insulation reaction 40min~80min；
C2 after) adjusts reaction system pH to 6~7,20 DEG C~30 DEG C stirring 20min~40min are warming up to, stratification is organic
It is added to anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated into no liquid outflow.
7. preparation method according to claim 2, which is characterized in that in step d), the lewis acid is borontrifluoride
The ether of boron, preferably boron trifluoride ether；
The organosilan is triethylsilane；
Preferably, the low temperature is 0~10 DEG C；
Preferably, the time of the reduction reaction is 1h~2h.
8. preparation method according to claim 7, which is characterized in that after step d), further include before step e)：
Step d) after reaction, adjust reaction system pH=7~8 simultaneously methanol is added, be sufficiently stirred be precipitated precipitate after mistake
Filter is containedFiltrate be used for step e).
9. the preparation method according to claim 2 or 8, which is characterized in that in step e), the deprotection reaction is in first
Alcohol sodium methoxide system carries out；
Preferably, the deprotection reaction is by being added vinegar acid for adjusting pH value as 6~7 to terminate reaction；
Preferably, after the completion of the deprotection reaction, the method further includes：
Reaction solution is concentrated under reduced pressure, solvent evaporated obtains crude product, and the crude product is purified using column chromatography；
It is furthermore preferred that in the column chromatography procedure, eluant, eluent is dichloromethane, n-hexane, methanol.
10. application of the compound described in claim 1 as standard items or reference substance in canagliflozin control of product quality.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109374783A (en) * | 2018-12-21 | 2019-02-22 | 安徽联创生物医药股份有限公司 | A method of with the related substance of HPLC separation determination canagliflozin bulk pharmaceutical chemicals |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106938998A (en) * | 2017-04-07 | 2017-07-11 | 四川智强医药科技开发有限公司 | Synthetic method of the canagliflozin about material |
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2018
- 2018-07-03 CN CN201810722583.7A patent/CN108586442A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106938998A (en) * | 2017-04-07 | 2017-07-11 | 四川智强医药科技开发有限公司 | Synthetic method of the canagliflozin about material |
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| Title |
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| AML A. EMAM⃰: "Canagliflozin Stability Study and Eco-friendly Chromatographic Determination", 《JOURNAL OF SEPARATION SCIENCE》 * |
| SHARAD S. PACHORE ET AL.: "Synthesis and Characterization of Potential Impurities of", 《CHEMISTRYSELECT》 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109374783A (en) * | 2018-12-21 | 2019-02-22 | 安徽联创生物医药股份有限公司 | A method of with the related substance of HPLC separation determination canagliflozin bulk pharmaceutical chemicals |
| CN109374783B (en) * | 2018-12-21 | 2022-02-01 | 安徽联创生物医药股份有限公司 | Method for separating and determining related substances of canagliflozin bulk drug by using HPLC (high performance liquid chromatography) |
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Application publication date: 20180928 |