CN113735921A - Method for synthesizing impurities of C-glucoside derivatives - Google Patents
Method for synthesizing impurities of C-glucoside derivatives Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- 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)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
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Abstract
The invention relates to the technical field of medicinal chemistry, and particularly discloses a method for synthesizing impurities of C-glycoside derivatives. The impurity is a compound shown as a formula (I), and the synthesis steps comprise: (1) dissolving a compound shown as a formula (II) in ethyl acetate, and adding TEA and DMAP; dropwise adding acetic anhydride to prepare an intermediate 1 shown in a formula (III); (2) adding the intermediate 1 into acetonitrile, and dropwise adding boron trifluoride diethyl etherate; dropwise adding a dichloromethane solution of a compound shown in a formula (IV) to react to prepare an intermediate 2 shown in a formula (V); (3) dissolving the intermediate 2 in methanol and tetrahydrofuran, and adding lithium hydroxide monohydrate to react; spin-drying solvent, extracting with ethyl acetate, backwashing organic phase with water and saturated salt solution, drying with anhydrous sodium sulfate, and spin-drying; and performing column chromatography separation on the residue, and performing spin drying to obtain the compound shown in the formula (I). The method of the invention solves the problem of mass production required by reference substances, improves the reaction yield and reduces the production cost.
Description
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to a method for synthesizing impurities of C-glucoside derivatives.
Background
Hyperglycemia is considered to be a major risk factor for developing diabetic complications and may be directly associated with impaired insulin secretion in late type ii diabetes. Thus, normalization of insulin would be expected to improve blood glucose in type II diabetics. Most of the existing diabetes drugs are insulinotropic drugs or insulin sensitizers, such as sulfonylureas, glinides, thiazolidinediones, metformin and the like, and have potential side effects, such as easy weight gain, hypoglycemia, lactic acidosis and the like, so that the development of antidiabetic drugs with novel, safe and effective action mechanisms is urgently needed.
In the kidney, glucose can freely filter from the glomerulus (about 180 g/day), but is almost actively transported in the proximal convoluted tubule and reabsorbed. Two of the sodium-glucose transporters play an important role in glucose reabsorption, namely SGLT-1 and SGLT-2, and SGLT-2 plays a particularly prominent role. Evidence has shown that an important clinical advantage of SGLT-2 inhibitors is that they are less likely to cause hypoglycemia. While inhibition of SGLT-1 causes sugar-galactose malabsorption syndrome, which may lead to dehydration, there is evidence that SGLT-1 inhibitors will delay carbohydrate absorption and cause gastrointestinal symptoms that are intolerable to individuals, while selection of high SGLT-2 inhibitors will not block the glucose absorption and transport action of SGLT-1 in the intestinal tract, and thus are not likely to cause gastrointestinal symptoms. In addition, SGLT-1 is also highly expressed in human myocardial tissue, and its blockade may cause cardiac functional or organic lesions. Therefore, the development of a compound having high selectivity for SGLT-2 is of great significance for the research of drugs for treating diabetes.
The C-glycoside derivative is an SGLT-2 (sodium-glucose cotransporter 2) inhibitor, and is a novel oral hypoglycemic medicament which is recommended internationally for treating type 2 diabetes at present. It selectively inhibits SGLT-2 receptors of kidney proximal convoluted tubule, reduces glucose reabsorption to promote urine glucose excretion, and lowers blood glucose concentration.
In previous researches, the inventor of the present application found that a C-glycoside derivative having a structure shown in formula (vi) can be used as a sodium-glucose cotransporter (SGLT) inhibitor to prepare a medicament for treating and/or preventing insulin-dependent diabetes mellitus, and is described in patent ZL 201410004395.2.
Drugs are special goods, and impurities contained in drugs are important factors affecting the quality of drugs, often related to the safety of drugs, and in a few cases, to the efficacy. Therefore, research on drug impurities, detection and control is required in relevant laws and regulations and pharmacopoeias. There has been no study on impurities related to the C-glycoside derivative represented by the formula (vi) in the ZL201410004395.2 patent, but the compound represented by the formula (i) of the present invention is an impurity component discovered in the study on the C-glycoside derivative by the applicant, and the raw material represented by the formula (II) and the product represented by the formula (vi) are generated under the catalysis of a reaction reagent boron trifluoride (lewis acid) during the synthesis process of the C-glycoside derivative, as shown in fig. 1.
Therefore, the present invention aims to develop a method for synthesizing the compound shown in formula (I) in a large scale, so as to meet the requirements of the C-glycoside derivatives in impurity analysis and quality control in the above patents.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a method for synthesizing impurities of C-glycoside derivatives.
The impurity is a compound shown as a formula (I), and the synthesis method comprises the following steps:
(1) dissolving a compound shown as a formula (II) in ethyl acetate, and adding TEA and DMAP; controlling the temperature to be 0-10 ℃, dropwise adding acetic anhydride, and heating to 20-30 ℃ for reaction; cooling to 0 ℃, and dropwise adding a sodium bicarbonate aqueous solution to quench the reaction; adjusting the pH value to 5-6, and separating liquid; backwashing the organic phase by using saturated salt water, adding anhydrous sodium sulfate, drying and spin-drying; dissolving the residual oily substance with acetonitrile, distilling and displacing to obtain intermediate 1 shown in formula (III);
(2) adding the intermediate 1 shown in the formula (III) into acetonitrile, and dissolving; cooling in ice water bath, dropwise adding boron trifluoride diethyl etherate, and reacting for 0.5-1 h; dropwise adding a dichloromethane solution of a compound shown in the formula (IV), and heating to 20-30 ℃ for reaction after the addition is finished; adding dichloromethane for extraction, and backwashing the organic phase by using water; adding anhydrous sodium sulfate, drying, and spin-drying; performing column chromatography separation on the residue to obtain an intermediate 2 shown in a formula (V);
(3) dissolving the intermediate 2 shown in the formula (V) in methanol and tetrahydrofuran, cooling in an ice water bath, adding an aqueous solution of lithium hydroxide monohydrate, and reacting at 20-30 ℃; spin-drying solvent, extracting with ethyl acetate, backwashing organic phase with water and saturated salt solution, drying with anhydrous sodium sulfate, and spin-drying; performing column chromatography separation on the residue, and performing spin drying to obtain the compound shown in the formula (I)
Preferably, in step (1), the compound of formula (II), TEA and acetic anhydride are used in a molar ratio of 8-12:50-70: 45-55.
Preferably, in step (1), DMAP is used in an amount of 1% to 5% of the total molar amount of the compound of formula (II), TEA and acetic anhydride.
Preferably, in the step (1), the pH is adjusted to 5 to 6 with 1N diluted hydrochloric acid.
Preferably, in the step (2), the molar ratio of the intermediate 1 to the boron trifluoride diethyl etherate is 1: 6.
preferably, in the step (2), the molar ratio of the intermediate 1 to the compound represented by the formula (IV) is 1: 2.
preferably, in the step (2), the elution phase separated by column chromatography is dichloromethane/methanol (1/100-1/20).
Preferably, in step (3), the molar ratio of intermediate 2 to lithium hydroxide monohydrate is 1: 5.
Preferably, in step (3), the reaction is carried out at 25 ℃ for 4 hours after adding lithium hydroxide monohydrate.
Preferably, the elution phase of the column chromatography is dichloromethane/methanol 1/100-1/10.
The raw materials or reagents involved in the invention are all common commercial products, and the operations involved are all routine operations in the field unless otherwise specified.
The above-described preferred conditions may be combined with each other to obtain a specific embodiment, in accordance with common knowledge in the art.
The invention has the beneficial effects that:
in the industrial amplification research of the compound shown in the formula (I), the invention provides a large-scale synthesis method which can meet the requirement of a reference substance (10g grade) through repeated research so as to meet the requirements of C-glucoside derivatives on impurity analysis and quality control.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments consistent with the invention and together with the description, serve to explain the principles of the invention.
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious for those skilled in the art that other drawings can be obtained according to the drawings without inventive exercise.
FIG. 1 shows the production pathway of the compound represented by formula (I) in the synthesis process of C-glycoside derivatives.
FIG. 2 is a chromatogram of a test solution according to the present invention.
FIG. 3 is a scout view of the present invention.
Detailed Description
In order that the above objects, features and advantages of the present invention may be more clearly understood, a solution of the present invention will be further described below. It should be noted that the embodiments of the present invention and features of the embodiments may be combined with each other without conflict.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways than those described herein; it is to be understood that the embodiments described in this specification are only some embodiments of the invention, and not all embodiments.
Preferred embodiments of the present invention will be described in detail with reference to the following examples. It is to be understood that the following examples are given for illustrative purposes only and are not intended to limit the scope of the present invention. Various modifications and alterations of this invention will become apparent to those skilled in the art without departing from the spirit and scope of this invention.
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Example 1
This example illustrates the synthesis of a compound of formula (I) comprising the steps of:
(1) synthesis of intermediate 1
The compound represented by the formula (II) (50g, 101.8mmol) was dissolved in ethyl acetate (500mL), and TEA (61.81g, 610.8mmol) and DMAP (0.12g, 1mmol) were added. Acetic anhydride (51.96g, 509mmol) was added dropwise at a controlled temperature of 0-10 ℃. After dropping, the temperature is raised to 25 ℃ for reaction for 4 hours. The reaction was quenched by dropping aqueous sodium bicarbonate (200mL) at 0 ℃. And adjusting the pH value to 5-6 by using 1N diluted hydrochloric acid, and separating the liquid. The organic phase was backwashed with saturated brine (200mL), dried over anhydrous sodium sulfate, and spin-dried. The remaining oil was dissolved in acetonitrile (1L × 2), and the mixture was distilled and replaced twice, to obtain intermediate 1(68.43g) represented by formula (iii).
(2) Synthesis of intermediate 2
Intermediate 1(68g, 103.2mmol) represented by formula (III) was added to acetonitrile (400mL) and dissolved. The temperature was reduced in an ice-water bath, and boron trifluoride diethyl etherate (87.88g, 619.2mmol) was added dropwise. After dropping, the reaction was carried out for 0.5 hour. A solution of the compound represented by the formula (IV) (94.96g, 206.4mmol) in methylene chloride (550mL) was added dropwise thereto, and the mixture was heated to 25 ℃ to react for 3 hours. Dichloromethane (400mL) was added for extraction and the organic phase was back-washed with water (400 mL). Adding anhydrous sodium sulfate, drying, and spin-drying. Column chromatography of the residue (elution phase, dichloromethane/methanol 1/100-1/20) gave intermediate 2(54.38g) of formula (v) in yield: 48.3 percent.
(3) Synthesis of Compound of formula (I)
Intermediate 2(54.38g, 50.0mmol) of formula (V) was dissolved in methanol (163mL) and tetrahydrofuran (163mL), cooled in an ice-water bath, and a solution of lithium hydroxide monohydrate (10.49g, 250.0mmol) in water (109mL) was added to react at 25 ℃ for 4 hours. The solvent was dried by spinning, extracted twice with ethyl acetate (200 mL. times.2), the organic phase was backwashed with water (100mL) and saturated brine (100mL), dried over anhydrous sodium sulfate, and spun dry. And (3) performing column chromatography separation on the residue (an elution phase, wherein dichloromethane/methanol is 1/100-1/10), and performing spin drying to obtain an impurity (21.2g), wherein the yield is as follows: 46.1 percent. Purity by HPLC, 96.0%.
Example 2
Structure confirmation of the compound prepared in example 1
The compound prepared in example 1 was subjected to mass spectrometry, nuclear magnetic hydrogen spectrometry and nuclear magnetic carbon spectrometry, and the detection results were as follows:
LC-MS (Agilent 1200/6110Quadrupole LC/MS, methanol) (ES, M/z) [ M +2H ]2+/2: 460.0).
1H-NMR (Bruker AVANCE III 400 NMR spectrometer, 400MHz, DMSO-d6, ppm). delta.7.57 (s,1H),7.40(d, J ═ 7.84Hz,1H),7.36(s,1H),7.35-7.31(m,1H),7.31-7.15(m,1H),7.31-7.15(m,1H),7.04(d, J ═ 7.28Hz,2H),6.97(d, J ═ 7.44Hz,2H),6.77-6.72(m,4H),5.05(s,1H),4.96(s,1H),4.90(s,1H),4.79(s,1H),4.72(s,1H),4.72(s,1H), 4.72(s,1H),4.44-4.43(m,2H), 4.43(m, 44H), 4.43H), 3.81 (m, 3.8H), 3.81H, 3.3.8 (m, 3H), 3.8, 3H), 3.63-3.58(m,1H), 3.63-3.58(m,1H), 3.38-3.33(m,1H),3.30-3.26(m,2H),3.30-3.26(m,1H), 3.30-3.26(m,1H), 3.07(s,1H),2.87-2.85(m,1H),2.27-2.23(m,4H),1.74-1.72(m,4H),1.28(s,4H),0.36-0.35(m,2H),0.13(m, 2H).
The molecular ion peak [ M +2H ]2+/2 of the sample was measured by mass spectrometry, and its mass-to-charge ratio M/z was 460.0, which was presumed to have a molecular weight of 918.0, consistent with the molecular weight of the sample (918.31).
The studies of the mass spectrum, nuclear magnetic resonance spectrum and the like prove that the compound prepared by the method of example 1 has a correct structure. The correct structure of the sample can be presumed from the nuclear magnetic hydrogen spectrum.
Example 3
The experiments for analytical high performance liquid phase analysis using the compound of formula (I) were as follows:
(1) reagent solution: diammonium phosphate, phosphoric acid, methanol, acetonitrile and ultrapure water.
The instrument equipment comprises: electronic balance, high performance liquid chromatograph, pH meter, and centrifuge.
Chromatographic conditions are as follows: measuring by high performance liquid chromatography (0512 of the four Ministry of China pharmacopoeia 2020 edition), using octadecyl silane bonded silica gel as filler (Agilent Eclipse XDB-C18, 150mm × 4.6mm, 5 μm); the mobile phase A is 0.01mol/L diammonium hydrogen phosphate solution (taking 1.32g diammonium hydrogen phosphate, adding 1000ml of water for ultrasonic dissolution, adjusting the pH value to 5.00 +/-0.05) -acetonitrile (90:10) by using phosphoric acid, and the mobile phase B is water-acetonitrile (10: 90); the flow rate is 1.0 ml/min; the detection wavelength is 225 nm; the sample injection volume is 10 mul; the column temperature was 25 ℃; the elution was performed in a linear gradient as in Table 1.
TABLE 1
(2) Solution preparation:
test solution: weighing about 15mg of the compound shown in the formula (VI) in the application, placing the compound in a 25ml measuring flask, adding methanol to dissolve the compound, quantitatively diluting the compound to a scale, preparing a solution containing 0.6mg of the compound in each 1ml, and shaking up. Liquid chromatography analysis gave the result of FIG. 2.
Positioning solution: a standard compound of formula (VI) is mixed with an impurity of formula (I) to localize the solution: weighing 2mg of an impurity shown as a formula (I) and placing the impurity in a 100mL measuring flask, adding methanol to dissolve the impurity, quantitatively diluting the impurity to a scale, and shaking up to be used as an impurity stock solution; precisely weighing 6mg of a compound standard substance shown in the formula (VI) and placing the compound standard substance in a 10mL measuring flask, precisely weighing 1mL of impurity stock solution and placing the impurity stock solution in the 10mL measuring flask, adding methanol to dissolve and dilute the impurity stock solution to a scale, and shaking up the mixture. Liquid chromatography analysis gave the graph of FIG. 3. The compound shown in the formula (V) is a standard product which is almost free of impurities after multiple purifications.
Analysis of the chromatograms leads to the conclusion that the retention time of the compound represented by the formula (I) in the application is the same as that in FIG. 2, and the synthesized impurities have accurate structures.
The foregoing are merely exemplary embodiments of the present invention, which enable those skilled in the art to understand or practice the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (10)
1. A method for synthesizing impurities of C-glycoside derivatives, which is characterized in that the impurities are compounds shown as a formula (I), and the method comprises the following steps:
(1) dissolving a compound shown as a formula (II) in ethyl acetate, and adding TEA and DMAP; controlling the temperature to be 0-10 ℃, dropwise adding acetic anhydride, and heating to 20-30 ℃ for reaction; cooling to 0 ℃, and dropwise adding a sodium bicarbonate aqueous solution to quench the reaction; adjusting the pH value to 5-6, and separating liquid; backwashing the organic phase by using saturated salt water, adding anhydrous sodium sulfate, drying and spin-drying; dissolving the residual oily substance with acetonitrile, distilling and displacing to obtain intermediate 1 shown in formula (III);
(2) adding the intermediate 1 shown in the formula (III) into acetonitrile, and dissolving; cooling in ice water bath, dropwise adding boron trifluoride diethyl etherate, and reacting for 0.5-1 h; dropwise adding a dichloromethane solution of a compound shown in the formula (IV), and heating to 20-30 ℃ for reaction after the addition is finished; adding dichloromethane for extraction, and backwashing the organic phase by using water; adding anhydrous sodium sulfate, drying, and spin-drying; performing column chromatography separation on the residue to obtain an intermediate 2 shown in a formula (V);
(3) dissolving the intermediate 2 shown in the formula (V) in methanol and tetrahydrofuran, cooling in an ice water bath, adding an aqueous solution of lithium hydroxide monohydrate, and reacting at 20-30 ℃; spin-drying solvent, extracting with ethyl acetate, backwashing organic phase with water and saturated salt solution, drying with anhydrous sodium sulfate, and spin-drying; performing column chromatography separation on the residue, and performing spin drying to obtain the compound shown in the formula (I)
2. The synthesis method according to claim 1, wherein in the step (1), the compound represented by the formula (II), TEA and acetic anhydride are used in a molar ratio of 8-12:50-70: 45-55.
3. The process of claim 2, wherein in step (1), DMAP is used in an amount of 1-5% of the total molar amount of the compound of formula (II), TEA and acetic anhydride.
4. The synthesis method according to claim 3, wherein in step (1), the pH is adjusted to 5 to 6 with 1N diluted hydrochloric acid.
5. The synthesis method according to claim 1, wherein in the step (2), the molar ratio of the intermediate 1 to the boron trifluoride diethyl etherate is 1: 6.
6. the synthesis method according to claim 5, wherein in the step (2), the molar ratio of the intermediate 1 to the compound represented by the formula (IV) is 1: 2.
7. the synthesis method of claim 6, wherein in the step (2), the elution phase separated by column chromatography is dichloromethane/methanol (1/100-1/20).
8. The synthesis method according to claim 1, wherein in step (3), the molar ratio of intermediate 2 to lithium hydroxide monohydrate is 1: 5.
9. The synthesis method according to claim 8, wherein in the step (3), the reaction is carried out at 25 ℃ for 4 hours after the addition of lithium hydroxide monohydrate.
10. The synthesis method of claim 9, wherein the elution phase of column chromatography is 1/100-1/10.
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Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101384576A (en) * | 2006-02-15 | 2009-03-11 | 贝林格尔.英格海姆国际有限公司 | Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture |
| EP2891654A1 (en) * | 2014-01-03 | 2015-07-08 | Xuanzhu Pharma Co., Ltd. | Optically pure benzyl-4-chlorophenyl-C-glucoside derivatives as SGLT inhibitors (diabetes mellitus) |
| CN104761522A (en) * | 2014-01-03 | 2015-07-08 | 山东轩竹医药科技有限公司 | Optically pure benzyl-4-chlorophenyl C-glucoside derivatives |
| CN104817554A (en) * | 2014-11-10 | 2015-08-05 | 镇江新元素医药科技有限公司 | Glucoside derivatives and pharmaceutical compositions thereof |
| CN107556276A (en) * | 2017-10-12 | 2018-01-09 | 广州医科大学 | C triaryl glucoside compounds and its preparation method and application |
| CN108976182A (en) * | 2017-06-05 | 2018-12-11 | 上海奥博生物医药技术有限公司 | A method of preparing Dapagliflozin five-membered ring impurity |
| CN111592515A (en) * | 2020-06-22 | 2020-08-28 | 广州市力鑫药业有限公司 | Preparation method of SGLT2 inhibitor for reducing blood sugar |
| CN113372315A (en) * | 2021-08-12 | 2021-09-10 | 北京惠之衡生物科技有限公司 | Method for synthesizing impurities of C-glucoside derivatives |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2009203230A (en) * | 2008-01-31 | 2009-09-10 | Daiichi Sankyo Co Ltd | Pharmaceutical composition containing benzyl phenyl glucopyranoside derivative |
| AU2014201286B2 (en) * | 2008-08-22 | 2015-07-02 | Theracosbio, Llc | Processes for the preparation of SGLT2 inhibitors |
| KR101719758B1 (en) * | 2011-06-25 | 2017-03-24 | 수안주 파마 코포레이션 리미티드 | C-glucoside derivative |
| EP3621977A4 (en) * | 2017-05-09 | 2021-04-07 | Piramal Pharma Limited | A process for the preparation of sglt2 inhibitor and intermediates thereof |
-
2021
- 2021-06-25 CN CN202110708461.4A patent/CN113248554A/en active Pending
- 2021-09-30 CN CN202111162576.4A patent/CN113735921B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101384576A (en) * | 2006-02-15 | 2009-03-11 | 贝林格尔.英格海姆国际有限公司 | Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture |
| EP2891654A1 (en) * | 2014-01-03 | 2015-07-08 | Xuanzhu Pharma Co., Ltd. | Optically pure benzyl-4-chlorophenyl-C-glucoside derivatives as SGLT inhibitors (diabetes mellitus) |
| CN104761522A (en) * | 2014-01-03 | 2015-07-08 | 山东轩竹医药科技有限公司 | Optically pure benzyl-4-chlorophenyl C-glucoside derivatives |
| CN104817554A (en) * | 2014-11-10 | 2015-08-05 | 镇江新元素医药科技有限公司 | Glucoside derivatives and pharmaceutical compositions thereof |
| CN108976182A (en) * | 2017-06-05 | 2018-12-11 | 上海奥博生物医药技术有限公司 | A method of preparing Dapagliflozin five-membered ring impurity |
| CN107556276A (en) * | 2017-10-12 | 2018-01-09 | 广州医科大学 | C triaryl glucoside compounds and its preparation method and application |
| CN111592515A (en) * | 2020-06-22 | 2020-08-28 | 广州市力鑫药业有限公司 | Preparation method of SGLT2 inhibitor for reducing blood sugar |
| CN113372315A (en) * | 2021-08-12 | 2021-09-10 | 北京惠之衡生物科技有限公司 | Method for synthesizing impurities of C-glucoside derivatives |
Non-Patent Citations (1)
| Title |
|---|
| 杜铁奇等: "C-芳基糖苷类SGLT2抑制剂的合成研究进展", 《浙江化工》 * |
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