CN117486926A - Dapagliflozin impurity, preparation and removal method - Google Patents

Dapagliflozin impurity, preparation and removal method Download PDF

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Publication number
CN117486926A
CN117486926A CN202311500676.2A CN202311500676A CN117486926A CN 117486926 A CN117486926 A CN 117486926A CN 202311500676 A CN202311500676 A CN 202311500676A CN 117486926 A CN117486926 A CN 117486926A
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dapagliflozin
impurity
anhydride
esterified
preparation
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陶舟
李晓晖
张志海
张和
徐金喜
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Hubei Hongyuan Pharmaceutical Technology Co ltd
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Hubei Hongyuan Pharmaceutical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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 to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
    • 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
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention discloses dapagliflozin impurities, a preparation method and a removal method. In the process of preparing the dapagliflozin esterified compound intermediate, a larger impurity compound is newly discovered, and the impurity is a dapagliflozin-triethyl silyl ether impurity newly generated in the esterification process of triethyl silanol and dapagliflozin which are byproducts of the previous reduction reaction. The discovery of the compound is beneficial to the quality control and research of dapagliflozin and an esterified compound intermediate, and the invention also optimizes the purification method of the dapagliflozin key intermediate esterified compound, thereby improving the reaction yield, improving the product quality and reducing the raw material cost.

Description

Dapagliflozin impurity, preparation and removal method
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a dapagliflozin impurity, a preparation method and a removal method.
Background
The carbon-aryl glucose compound is an SGLT-2 inhibitor, and can remove excessive glucose from urine by inhibiting reabsorption of glucose by kidneys, so that the carbon-aryl glucose compound can directly reduce blood glucose, and is a novel antidiabetic medicament. Among the SGLT-2 inhibitors currently marketed in China are enggliflozin (europe Tang Jing), dapagliflozin (anderson), canagliflozin (yicoan). The medicine can not only control blood sugar level, but also reduce the risk of serious adverse cardiovascular events. Dapagliflozin, among others, has been approved by the U.S. FDA for use in reducing cardiovascular death and heart failure hospitalization risk in adult HFrEF/HFpEF patients, whether or not the patient is accompanied by diabetes, and is useful in the treatment of diabetic nephropathy.
The current mature synthesis process of dapagliflozin is as follows: corresponding organic metal reagent (aryl lithium/magnesium reagent) is prepared by taking bromine/iodine aromatic hydrocarbon as raw material, further reacts with gluconolactone hydroxyl TMS protection derivative to construct medicine molecular skeleton, and then the target product crude product is obtained through methylation and reduction (US 20060258749A1, WO2011039107A 1). However, the crude product is oily liquid, and is not easy to purify, so that the dapagliflozin finished product has low purity, more organic impurities and the like. Zheng Yunfeng the utility model provides a synthetic method of dapagliflozin- (S) - (+) -1, 2-propylene glycol monohydrate, which takes 4-bromo-1-chloro-2- (4-ethoxybenzyl) benzene and 2,3,4, 6-tetra-O-trimethylsilyl-D-glucolactone as raw materials, and is prepared by methyl esterification, reduction reaction, acetylation protection, refining and hydrolysis, the total yield is 48.2 percent, and the reaction process is as follows:
in order to improve the quality of dapagliflozin, reduce the risk of clinical medication, clear impurity type, and remove the dapagliflozin from intermediate esterified substances before hydrolysis, thus having important significance for preparing high-purity dapagliflozin.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a dapagliflozin impurity, a preparation method and a removal method, which solve the problems of undefined impurities and low product purity in the current dapagliflozin synthesis process.
In order to achieve the above purpose, the present invention is realized by the following technical scheme:
in a first aspect, the present invention provides a dapagliflozin impurity having the general structural formula:
wherein R is at least one selected from formyl, acetyl, propionyl and pivaloyl.
In a second aspect, the present invention provides a method for preparing dapagliflozin impurity, comprising: under the condition of a catalyst, dapagliflozin reacts with triethylsilanol, acid anhydride and an acid binding agent to protect hydroxyl in the dapagliflozin, and impurities reaching the dapagliflozin are obtained through column chromatography separation and purification and reduced pressure concentration.
Preferably, the anhydride is one or more of formic anhydride, acetic anhydride, propionic anhydride and pivalic anhydride; the molar ratio of dapagliflozin to anhydride is 1 (2.0-8.0).
Preferably, the acid binding agent is one or more of triethylamine, N-methylmorpholine, N-diisopropylethylamine, potassium carbonate, sodium acetate and potassium acetate; the molar ratio of dapagliflozin to acid binding agent is 1 (2.0-8.0).
Preferably, the molar ratio of dapagliflozin to triethylsilanol is 1: (2-4).
Preferably, the catalyst is DMAP.
In a third aspect, the present invention also provides a method for removing impurities from dapagliflozin, comprising recrystallizing an intermediate dapagliflozin ester in an alcoholic solvent to remove impurities; the dapagliflozin esterified compound intermediate has the structural formula:
wherein R is at least one selected from formyl, acetyl, propionyl and pivaloyl.
Preferably, the alcohol solvent is one or more of methanol, ethanol and isopropanol.
Preferably, the weight ratio of dapagliflozin intermediate to solvent is 1 (2.0-8.0).
Preferably, the method of recrystallization comprises: adding alcohol solvent into the dapagliflozin esterified product intermediate, heating to dissolve, and cooling to crystallize; the temperature is raised to 60-100 ℃, and the temperature is lowered to 0-40 ℃.
The beneficial effects of the invention are as follows:
1. the invention discloses an impurity generated in the production process of dapagliflozin, which is not reported in the prior art; and the impurities with high purity are prepared, and a qualified impurity reference substance is provided for impurity control of dapagliflozin process, so that the reaction yield is improved, and the product quality is improved.
2. The impurity removal method provided by the invention can effectively control the impurity content in the production process, the impurity content is less than 0.1%, and the purity of the intermediate can reach more than 99.9%.
Drawings
In order to more clearly illustrate the technical solution of the embodiments of the present invention, the following description will briefly explain the drawings of the embodiments.
FIG. 1 is a liquid chromatogram of impurity compound A in example 1;
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of the impurity compound A in example 1;
fig. 3 is a carbon spectrum of the impurity compound a in example 1.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described in the following in conjunction with the embodiments of the present invention, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the present invention without making any inventive effort, are intended to fall within the scope of the present invention.
The embodiment of the invention provides dapagliflozin impurities with the following structural general formula:
wherein R is at least one selected from formyl, acetyl, propionyl and pivaloyl.
The above impurities are creatively found compounds according to the inventor's use of triethylsilane as a reducing agent in the reduction reaction in the dapagliflozin synthesis process. And the existence of the impurities is determined by nuclear magnetism, mass spectrum and other technologies, and the generation process of the impurities considered by the inventor is further confirmed: because triethylsilane is used as a reducing agent in the reduction reaction of the previous step of esterification, triethylsilanol is generated by water quenching reaction of triethylsilane in the reduction post-treatment, and the triethylsilanol participates in the esterification reaction to influence the purity of an esterification product, so that the triethylsilanol reacts with the generated dapagliflozin after the hydrolysis of the esterification product, and the purity of the product is reduced.
Thus, by the above reaction, it is known that the impurity compound is generated in the synthesis of the esterified compound intermediate in combination with the dapagliflozin synthesis route. When the anhydride used in the esterification reaction is formic anhydride, R in the impurities is formyl; when the anhydride used is acetic anhydride, R is acetyl; when the anhydride is propionic anhydride, R is propionyl; when the acid anhydride is pivalic acid anhydride, R is pivaloyl.
The invention is further described below in conjunction with the detailed description.
Example 1
Preparation of impurity Compound A
Using dapagliflozin crude product and triethylsilanol as raw materials, and adding the dapagliflozin crude product and triethylsilanol into Ac 2 O/NEt 3 The dapagliflozin intermediate impurity A is synthesized under the action of DMAP, and the reaction formula is as follows:
in a 50mL three-necked flask, 408.9mg (1 mmol) of dapagliflozin, 246.6mg (2 mmol) of triethylsilanol, 1.2mg (0.01 mmol) of DMAP and 2.4mL of DCM are sequentially added, and 607.2mg (6 mmol) of triethylamine is dropwise added at a temperature of less than 10 ℃; after stirring for 10min, 612.6mg (6 mmol) of acetic anhydride is added dropwise at the temperature of less than 10 ℃; after the dripping is finished, the mixture is warmed to room temperature and stirred naturally for 2 hours. After the stirring reaction is finished, 3ml of water is dripped under the condition that the temperature of the solution is less than 10 ℃, acetic acid is used for adjusting the pH to 5-6, layering is carried out, and a water layer is discarded; concentrating the organic layer to dryness to obtain oily sticky substance, then performing column chromatography separation and purification (developing agent is petroleum ether: ethyl acetate=1:2), concentrating to obtain intermediate impurity A reaching gliflozin, and the yield is 61-70%.
1 H NMR(400MHz,DMSO-d 6 )δ7.41(d,J＝8.0Hz,1H),7.24(d,J＝8.5Hz,2H),7.05(d,J＝8.6Hz,2H),6.82(d,J＝8.6Hz,2H),5.33(t,J＝9.5Hz,1H),5.05(t,J＝9.7Hz,1H),4.88(t,J＝9.6Hz,1H),4.63(d,J＝9.8Hz,1H),4.04-3.90(m,4H),3.87-3.83(m,5.2,2.2Hz,1H),3.71-3.62(m,3.7Hz,2H),2.01(s,3H),1.92(s,3H),1.71(s,3H),1.30(t,J＝7.0Hz,3H),0.85(t,J＝7.9Hz,9H),0.50(q,J＝7.9Hz,6H). 13 C NMR(101MHz,DMSO-d 6 ) Delta 170.12,169.61,168.96,157.44,138.87,136.95,133.36,131.35,130.45,129.98,129.68,126.96,114.76,78.00,77.85,74.09,72.97,68.96,63.36,62.44,37.98,20.90,20.79,20.50,15.11,7.01,4.39.HPLC detection purity 97.8%.
Example 2
Removal of impurity Compound A
2.0g of dapagliflozin esterified product intermediate containing impurity compound A, 10mL of methanol, heating to 60 ℃ for dissolution, cooling to 40 ℃ for crystallization, filtering and drying are added into a 50mL reaction bottle, so as to obtain the refined dapagliflozin esterified product intermediate, wherein the purity of HPLC detection is 99.95%, the impurity compound A content is 0.05% (the purity of HPLC detection before refining is 90.3%, and the impurity content is 9.7%). The dapagliflozin esterified compound intermediate has the structural formula:
example 3
Preparation of impurity Compound B
Impurity compound B was prepared in substantially the same manner as in example 1 except that acetic anhydride was replaced with propionic anhydride. The structural formula of the impurity compound B is as follows:
example 4
Removal of impurity compound B
2.0g of dapagliflozin esterified product intermediate containing impurity compound B, 16mL of ethanol, heating to 100 ℃ for dissolution, cooling to 20 ℃ for crystallization, filtering and drying to obtain refined dapagliflozin esterified product intermediate, wherein the purity of HPLC detection is 99.96%, the impurity compound B content is 0.04% (the purity of HPLC detection before refining is 91.2% and the impurity content is 8.8%). The dapagliflozin esterified compound intermediate has the structural formula:
example 5
Preparation of impurity Compound C
An impurity compound C was produced in substantially the same manner as in example 1 except that acetic anhydride was replaced with pivalic anhydride. The structural formula of the impurity compound C is as follows:
example 6
Removal of impurity compound C
2.0g of dapagliflozin esterified product intermediate containing impurity compound C, 16mL of isopropanol, heating to 90 ℃ for dissolution, cooling to 0 ℃ for crystallization, filtering and drying are added into a 50mL reaction bottle, so as to obtain the refined dapagliflozin esterified product intermediate, wherein the purity of HPLC detection is 99.92%, the impurity compound C content is 0.08% (the purity of HPLC detection before refining is 91.8% and the impurity content is 8.2%). The dapagliflozin esterified compound intermediate has the structural formula:
in conclusion, the invention discovers a type of dapagliflozin impurity in the verification process of the dapagliflozin production process, and the discovery of the impurity compound is beneficial to the quality control and research of dapagliflozin and esterified compound intermediates.
It should be noted that, the foregoing embodiments all belong to the same inventive concept, and the descriptions of the embodiments have emphasis, and where the descriptions of the individual embodiments are not exhaustive, reference may be made to the descriptions of the other embodiments.
The foregoing examples merely illustrate embodiments of the invention and are described in more detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.

Claims (10)

1. The dapagliflozin impurity is characterized by comprising the following structural general formula:
wherein R is at least one selected from formyl, acetyl, propionyl and pivaloyl.
2. The preparation method of dapagliflozin impurity according to claim 1, wherein dapagliflozin is reacted with triethylsilanol, anhydride and acid binding agent under the condition of a catalyst, hydroxyl in dapagliflozin is protected, and the dapagliflozin impurity is obtained through column chromatography separation and purification and reduced pressure concentration.
3. The preparation method of dapagliflozin impurity according to claim 2, wherein the acid anhydride is one or more of formic anhydride, acetic anhydride, propionic anhydride and pivalic anhydride; the molar ratio of dapagliflozin to the anhydride is 1 (2.0-8.0).
4. The preparation method of dapagliflozin impurity according to claim 2, wherein the acid binding agent is one or more of triethylamine, N-methylmorpholine, N-diisopropylethylamine, potassium carbonate, sodium acetate and potassium acetate; the molar ratio of dapagliflozin to the acid binding agent is 1 (2.0-8.0).
5. The method for preparing dapagliflozin impurity according to claim 2, wherein the molar ratio of dapagliflozin to triethylsilanol is 1: (2-4).
6. The method for preparing dapagliflozin impurity of claim 2, wherein the catalyst is DMAP.
7. The method for removing dapagliflozin impurities according to claim 1, comprising recrystallizing dapagliflozin esterified intermediate in an alcohol solvent to remove the impurities; the dapagliflozin esterified compound intermediate has the structural formula:
wherein R is at least one selected from formyl, acetyl, propionyl and pivaloyl.
8. The method for removing dapagliflozin impurity according to claim 7, wherein the alcohol solvent is one or more of methanol, ethanol and isopropanol.
9. The method for removing dapagliflozin impurity of claim 7, wherein the weight ratio of dapagliflozin esterified intermediate to alcohol solvent is 1 (2.0-8.0).
10. The method for removing dapagliflozin impurity of claim 7, wherein said method for recrystallizing comprises: heating up and dissolving the dapagliflozin esterified product intermediate in an alcohol solvent, and then cooling and crystallizing; the temperature rise and dissolution temperature is 60-100 ℃, and the temperature reduction and crystallization temperature is 0-40 ℃.
CN202311500676.2A 2023-11-08 2023-11-08 Dapagliflozin impurity, preparation and removal method Pending CN117486926A (en)

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