CN114380775A - Empagliflozin intermediate and preparation method thereof - Google Patents
Empagliflozin intermediate and preparation method thereof Download PDFInfo
- Publication number
- CN114380775A CN114380775A CN202111581824.9A CN202111581824A CN114380775A CN 114380775 A CN114380775 A CN 114380775A CN 202111581824 A CN202111581824 A CN 202111581824A CN 114380775 A CN114380775 A CN 114380775A
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- acid
- reagent
- 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.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-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
- C07D307/18—Heterocyclic compounds containing five-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
- C07D307/20—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to an empagliflozin intermediate. The invention also relates to a method for preparing the empagliflozin and the intermediate thereof. Belongs to the technical field of medical chemistry. The preparation method of the empagliflozin intermediate comprises the steps of reacting a compound shown in a formula VI with an organic metal reagent to obtain a compound shown in a formula V; coupling of the compound of formula V with the compound of formula IV followed by treatment with an acidic aqueous solution affords the compound of formula III. The preparation method of the engagliflozin provided by the invention has the advantages of short synthesis steps, simple and convenient operation, good intermediate purity, easy quality control and suitability for industrial production.
Description
Technical Field
The invention belongs to the technical field of medical chemistry, and particularly relates to an engagliflozin intermediate and a method for preparing the engagliflozin and the intermediate thereof.
Background
Empagliflozin (Empagliflozin) is a novel sodium-glucose cotransporter 2(SGLT2) inhibitor drug, and can specifically inhibit the reabsorption of glucose by the kidney, so that more sugar is eliminated from urine of a patient, and the blood sugar of the patient is reduced. Chemical name of englipzin: (2S,3R, 4R, 5S,6R) -2- (4-chloro-3- (4- ((((S) -tetrahydrofuran-3-yl) oxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the formula C23H27ClO7Molecular weight of 450.91, and structural formula as follows:
in addition to its hypoglycemic effect, the FDA approved a new indication for Jardiance (engeletin) for reducing the risk of cardiovascular death in adult patients with type 2 diabetes and cardiovascular disease.
In the prior art, the preparation method of the empagliflozin comprises a plurality of synthetic routes:
chinese published patent document CN102549005A reports the following synthetic route:
the compound of formula II in the route is prepared by a one-pot reaction, and the compound of formula II is difficult to crystallize and purify, has low purity, is difficult to control quality and is not suitable for industrial production.
Chinese published patent document CN103524468A reports the following synthetic route:
the method adds an acetylation protection step and performs crystallization purification on the compound shown in the formula VIII, so that the purity of the intermediate is improved, but the reaction step is prolonged, so that the operation is complex and the yield is low.
In order to meet the expanding production requirements of raw medicines and preparations of the empagliflozin, the development of a preparation method of the empagliflozin, which is more suitable for industrialization and is easier for quality control, is still needed.
Disclosure of Invention
The invention aims to provide a novel intermediate for producing the empagliflozin, which has good purity and can shorten the steps for producing the empagliflozin aiming at the defects of the prior art.
The invention also aims to provide a preparation method for producing the empagliflozin and the intermediate thereof, which has the advantages of short steps, simple and convenient operation, easy quality control and suitability for industrialization.
The object of the present invention is achieved by the following means. The invention discloses a novel Engelliflozin intermediate, namely a compound shown in a formula III:
the invention also discloses a preparation method of the Empagliflozin intermediate, which comprises the following steps:
(1) reacting the compound shown in the formula VI with an organic metal reagent to obtain a compound shown in the formula V;
(2) coupling of the compound of formula V with the compound of formula IV followed by treatment with an acidic aqueous solution affords the compound of formula III.
The preparation method route of the empagliflozin intermediate is as follows:
in the above formula:
x is halogen; preferred X is I or Br;
m is metal Li or MgCl;
r is a hydroxyl protecting group.
The preparation method of the empagliflozin intermediate comprises the following steps:
the compound of formula V is prepared by halogen-metal exchange reaction of a compound of formula IV; the organometallic reagent is preferably an organometallic lithium reagent or a grignard reagent; the molar ratio of the compound of formula VI to the organometallic reagent is preferably 1: 0.9-1.5; the organometallic reagent is selected from one or a combination of more of n-butyllithium, n-hexyllithium, methyllithium, tert-butyllithium, isopropyl magnesium chloride-lithium chloride complex and sec-butylmagnesium chloride-lithium chloride complex, and n-butyllithium and isopropyl magnesium chloride-lithium chloride complex are particularly preferred.
Preferably, the compound of formula IV is dissolved in an inert solvent or mixture thereof at a temperature between-80 ℃ and 30 ℃, more preferably between-80 ℃ and-10 ℃, added to an inert solution of the compound of formula V or a derivative thereof, and the coupled product is then freed from the hydroxy protecting group under acidic aqueous conditions to form the compound of formula III. The inert solvent is selected from tetrahydrofuran or a combination of tetrahydrofuran and toluene, preferably a combination of tetrahydrofuran and toluene; the acid is selected from one or more of hydrochloric acid, sulfuric acid, methanesulfonic acid and trifluoroacetic acid, and trifluoroacetic acid is particularly preferred.
All the above reactions are carried out under an inert gas atmosphere, preferably under an argon or nitrogen atmosphere.
The invention also provides a novel method for preparing the empagliflozin, which comprises the following steps:
(1) reacting the compound shown in the formula VI with an organic metal reagent to obtain a compound shown in the formula V, coupling the compound shown in the formula V with a compound shown in the formula IV, and treating with an acidic aqueous solution to obtain a compound shown in the formula III;
(2) reacting the compound shown in the formula III with methanol in the presence of acid to obtain a compound shown in a formula II;
(3) reduction of the compound of formula II gives engelizin:
preferably, in the step (2), the acid is selected from one or a combination of several of hydrochloric acid, sulfuric acid, methanesulfonic acid and trifluoroacetic acid, and hydrochloric acid is preferred.
Preferably, in step (3), the reducing agent is triethylsilane; the Lewis acid is aluminum trichloride or boron trifluoride diethyl etherate, and preferably the aluminum trichloride; the solvent used is selected from acetonitrile or a combination of acetonitrile and dichloromethane, preferably a combination of acetonitrile and dichloromethane, more preferably a volume ratio of acetonitrile to dichloromethane of 1: 2.
after the reduction reaction in the step (3) is finished, the following post-treatment can be carried out: dropwise adding water to quench reaction liquid separation, concentrating the organic phase, and pulping with dichloromethane to obtain a crude product of the compound of the formula I, wherein the crude product of the empagliflozin can be further recrystallized and purified.
Compared with the prior art, the invention has the following beneficial effects: short synthetic route, simple post-treatment operation, good intermediate purity, easy quality control and suitability for industrial production.
Detailed Description
The following examples further illustrate the technical solution of the present invention. It is to be understood that they are not to be considered limitations on the scope of the invention, but merely illustrative and representative of the invention, and that various changes and modifications may be made therein by one of ordinary skill in the art without departing from the spirit and scope of the invention. All falling within the scope of the present invention. The present invention will be described in detail with reference to examples, but the present invention is not limited to the examples.
Example 1: preparation of the compound of formula III (2R,3S,4R,5R) -1- (4-chloro-3- (4- ((((S) -tetrahydrofuran-3-yl) oxy) benzyl) phenyl) -2,3,4,5, 6-pentahydroxyhexyl-1-one as the intermediate for engelizin experiment one:
adding 23L of tetrahydrofuran, 230mL of toluene and 2.3kg of (S) -3- (4- (2-chloro-5-iodobenzyl) phenoxy) tetrahydrofuran into a 100L reaction kettle, stirring to dissolve the tetrahydrofuran, cooling to-80-70 ℃ under the protection of nitrogen, dropwise adding 3L of n-butyllithium solution (2.5M n-hexane solution), and finishing temperature control reaction for 1 h. Maintaining the temperature of-80 to-70 ℃, and dropwise adding 3.2kg of 2,3,4, 6-tetra-O- (trimethylsilyl) -D-glucoseAnd reacting for 1h after the completion of dripping the mixed solution of the acid lactone and 11.5L of toluene. Adding a mixture of 1.1kg of trifluoroacetic acid and 2.3L of water, heating to room temperature, stirring for 2h, stopping stirring, standing, separating the solution, separating the lower layer, and concentrating to obtain 2.19kg of the compound of the formula III with the HPLC purity of 95.31%. MS (m/z): 489.9023[ M + Na ]]。1H NMR(500MHz,(CD3)2CO)：δ＝7.70(s,lH),7.49(dt,lH),7.29(dd,1H),7.10(dd,2H),6.77(dd,2H),5.86(s,1H),4.94-4.96(m,1H),4.71-4.74(m,lH),4.30-4.31(m,lH),3.92-4.02(m,2H),3.86-3.89(m,2H),3.71-83(d,2H),3.51-3.59(m,lH),3.42(s,2H),3.26-3.27(d,lH),3.19-3.23(m,lH),2.13-2.22(m,lH),1.92-1.98(m,lH)。13C NMR(125MHz,(CD3)2CO)：δ＝197.35,155.90,143.10,137.60,132.95,131.85,130.17,129.86,128.44,126.73,114.96,97.91,77.08,75.04,73.31,72.68,70.57,66.69,61.73,38.25,32.81.
The HPLC detection conditions were as follows:
a chromatographic column: omni Bond Orca C8 (150X 4.6mm,5 μm)
Mobile phase A: 005% aqueous trifluoroacetic acid;
mobile phase B: 0.045% trifluoroacetic acid in acetonitrile
Column temperature: 40 ℃; detection wavelength: 224 nm: injection volume is 20 mu L
Elution gradient and flow rate:
| time (minutes) | Flow rate (mL/min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 1.5 | 70 | 30 |
| 10 | 1.5 | 70 | 30 |
| 12 | 1.5 | 44 | 56 |
| 22 | 1.5 | 35 | 65 |
| 25 | 2.0 | 5 | 95 |
| 28 | 1.5 | 70 | 30 |
| 30 | 1.5 | 70 | 30 |
Example 2: preparation of the compound of formula III (2R,3S,4R,5R) -1- (4-chloro-3- (4- ((((S) -tetrahydrofuran-3-yl) oxy) benzyl) phenyl) -2,3,4,5, 6-pentahydroxyhexyl-1-one as the intermediate for engelizin experiment two:
adding 23L of tetrahydrofuran, 230mL of toluene and 2.3kg of (S) -3- (4- (2-chloro-5-iodobenzyl) phenoxy) tetrahydrofuran into a 100L reaction kettle, stirring to dissolve the tetrahydrofuran, cooling to-30-20 ℃ under the protection of nitrogen, dropwise adding 4.4L of isopropyl magnesium chloride-lithium chloride (1.3M tetrahydrofuran solution), and reacting for 1h under controlled temperature. Maintaining the temperature between minus 30 ℃ and minus 20 ℃, dropwise adding 3.2kg of mixed solution of 2,3,4, 6-tetra-O- (trimethylsilyl) -D-gluconolactone and 11.5L of toluene, and reacting for 1h after the dropwise adding is finished. Adding a mixture of 1.1kg of trifluoroacetic acid and 2.3L of water, heating to room temperature, stirring for 2h, stopping stirring, standing, separating the solution, separating the lower layer, and concentrating to obtain 2.03kg of the compound of the formula III with the HPLC purity of 92.72%.
The HPLC detection conditions were as follows:
a chromatographic column: omni Bond Orca C8 (150X 4.6mm,5 μm)
Mobile phase A: 005% aqueous trifluoroacetic acid;
mobile phase B: 0.045% trifluoroacetic acid in acetonitrile
Column temperature: 40 ℃; detection wavelength: 224 nm: injection volume is 20 mu L
Elution gradient and flow rate:
| time (minutes) | Flow rate (mL/min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 1.5 | 70 | 30 |
| 10 | 1.5 | 70 | 30 |
| 12 | 1.5 | 44 | 56 |
| 22 | 1.5 | 35 | 65 |
| 25 | 2.0 | 5 | 95 |
| 28 | 1.5 | 70 | 30 |
| 30 | 1.5 | 70 | 30 |
Example 3: preparation experiment of compound of formula II (2S,3R,4S,5S,6R) -2- (4-chloro-3- (4- ((S) -tetrahydrofuran-3-yl) oxy) benzyl) phenyl) -6- (hydroxymethyl) -2-methoxytetrahydro-2H-pyran-3, 4, 5-triol
10L of methanol is added into a 100L reaction kettle, 2kg of the compound of the formula III obtained in the example 1 is added, 3.13kg of methanesulfonic acid is dropwise added under the stirring state, after the addition is finished, the stirring reaction is carried out for 3h, and 16L of 5% sodium bicarbonate aqueous solution is added for quenching. 20L of dichloromethane were added, the mixture was stirred and allowed to stand for liquid separation, the organic phase was separated, and the aqueous phase was extracted with 10L of dichloromethane. The organic phases were combined and washed with 10L of water. And transferring the organic phase to a 50L reaction kettle, concentrating under reduced pressure to dryness, adding 7L acetonitrile, and stirring to dissolve to obtain the acetonitrile solution of the compound shown as the formula I and the formula V. The relative area of the compound of formula II was 92.45% by HPLC.
Example 4: compound of formula I empagliflozin (1S) -1, 5-anhydro-1- (4-chloro-3- [4- [ (3S) -tetrahydrofuran-3 yloxy ] benzyl ] phenyl) -D-glucitol preparation experiment one:
A100L reactor was charged with 7L of acetonitrile, 7L of dichloromethane and 1.9kg of triethylsilane, the temperature was controlled not to exceed 30 ℃ and 2.2kg of aluminum trichloride was added in portions to the reactor. After the addition, the acetonitrile solution of the compound of formula II obtained in example 3 was added to the reaction system at a temperature not exceeding 30 ℃ and stirred at room temperature to react.
After the reaction is finished, water is added for quenching, liquid is separated after standing, an organic phase is separated out, and the solvent is removed by vacuum concentration and evaporation. Then dichloromethane is added for pulping, and after filtration and vacuum drying, 1.04kg of crude product of the empagliflozin is obtained, the yield is 53.9 percent, and the HPLC purity is 98.05 percent.
The crude product of the engelet is recrystallized by toluene-ethyl acetate to obtain a pure product of the engelet, and the HPLC purity is 99.79%.
Example 5: compound of formula I empagliflozin (1S) -1, 5-anhydro-1- (4-chloro-3- [4- [ (3S) -tetrahydrofuran-3 yloxy ] benzyl ] phenyl) -D-glucitol preparation experiment two:
A100L reactor was charged with 7L of acetonitrile, 7L of dichloromethane and 1.9kg of triethylsilane, the temperature was controlled not to exceed 30 ℃ and 3.88kg of boron trifluoride diethyl etherate was added in portions to the reactor. After the addition, the acetonitrile solution of the compound of formula II obtained in example 3 was added to the reaction system at a temperature not exceeding 30 ℃ and stirred at room temperature to react.
After the reaction is finished, water is added for quenching, liquid is separated after standing, an organic phase is separated out, and the solvent is removed by vacuum concentration and evaporation. Then dichloromethane is added for pulping, and after filtration and vacuum drying, 1.21kg of the crude product of the empagliflozin is obtained, the yield is 62.7 percent, and the HPLC purity is 98.34 percent.
The crude product of the engelet is recrystallized by toluene-ethyl acetate to obtain a pure product of the engelet, and the HPLC purity is 99.82%.
The foregoing is merely an example of the embodiments of the present invention, and it should be noted that modifications or suitable variations and combinations of the intermediates of engliptin and the preparation method of engliptin described in the present invention can be made by those skilled in the art to realize the technology of the present invention without departing from the content, spirit and scope of the present invention, and all similar modifications and variations will be obvious to those skilled in the art, which are deemed to be included in the content, spirit and scope of the present invention.
Claims (10)
1. An engagliflozin intermediate, characterized in that, the intermediate is a compound shown in the following formula III:
2. a process for the preparation of the engagliflozin intermediate of claim 1, characterized in that it comprises the steps of:
(1) reacting the compound shown in the formula VI with an organic metal reagent to obtain a compound shown in the formula V;
(2) coupling a compound of a formula V with a compound of a formula IV, and then treating with an acidic aqueous solution to obtain a compound of a formula III;
in the formula:
x is halogen;
m is metal Li or MgCl;
r is a hydroxyl protecting group.
3. The method of claim 2, wherein: in the formula, X is I or Br.
4. The method of claim 2, wherein: the organometallic reagent is an organometallic lithium reagent or a Grignard reagent; the molar ratio of the compound of formula VI to the organometallic reagent is 1: 1.0-1.5.
5. The production method according to claim 2 or 4, characterized in that: the organic metal reagent is selected from one or a combination of more of n-butyllithium, n-hexyllithium, methyllithium, tert-butyllithium, isopropyl magnesium chloride-lithium chloride complex and sec-butylmagnesium chloride-lithium chloride complex.
6. The method of claim 2, wherein: the reaction solvent is a combination of tetrahydrofuran and toluene.
7. The method of claim 2, wherein: the acid in the acidic aqueous solution is selected from one or a combination of more of hydrochloric acid, sulfuric acid, methanesulfonic acid and trifluoroacetic acid.
8. A process for the preparation of engleterin starting from a compound of formula III according to claim 1, wherein the compound of formula III is reacted with methanol in the presence of an acid to form a compound of formula II, wherein the compound of formula II is reduced to form the compound of formula I;
9. the method for preparing engagliflozin according to claim 8, characterized in that: the acid is selected from one or a combination of more of hydrochloric acid, sulfuric acid, methanesulfonic acid and trifluoroacetic acid.
10. The method for preparing engagliflozin according to claim 8, characterized in that: the reducing agent used for reduction is triethylsilane; the Lewis acid is selected from aluminum trichloride or boron trifluoride diethyl etherate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111581824.9A CN114380775A (en) | 2021-12-22 | 2021-12-22 | Empagliflozin intermediate and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111581824.9A CN114380775A (en) | 2021-12-22 | 2021-12-22 | Empagliflozin intermediate and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114380775A true CN114380775A (en) | 2022-04-22 |
Family
ID=81198347
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111581824.9A Pending CN114380775A (en) | 2021-12-22 | 2021-12-22 | Empagliflozin intermediate and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114380775A (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102549005A (en) * | 2009-09-30 | 2012-07-04 | 贝林格尔.英格海姆国际有限公司 | Method for the preparation of a crystalline form of 1-chloro-4- (beta-d-glucopyranos-1-yl)-2-(4-((s)-tetrahydrofuran-3-yloxy)benzyl)benzene |
| CN106632288A (en) * | 2016-11-07 | 2017-05-10 | 安徽九华华源药业有限公司 | Method for preparing empagliflozin |
| WO2017130217A1 (en) * | 2016-01-27 | 2017-08-03 | Msn Laboratories Private Limited | The present invention relates to process for the preparation of d-glucitol, 1,5- anhydro-1-c-[4-chloro-3-[[4-[[(3s)-tetrahydro-3-furanyl] oxy]phenyl] methyl]phenyl]-, (1s) and its crystalline forms thereof. |
| US20180346502A1 (en) * | 2017-05-30 | 2018-12-06 | Emmennar Pharma Private Limited | Processes for the Preparation of SGLT-2 Inhibitors, Intermediates Thereof |
| CN111560004A (en) * | 2020-04-30 | 2020-08-21 | 江苏德源药业股份有限公司 | Preparation method of high-purity canagliflozin intermediate |
| CN112812107A (en) * | 2019-11-18 | 2021-05-18 | 上海启讯医药科技有限公司 | Preparation method of SGLT-2 inhibitor and intermediate |
-
2021
- 2021-12-22 CN CN202111581824.9A patent/CN114380775A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102549005A (en) * | 2009-09-30 | 2012-07-04 | 贝林格尔.英格海姆国际有限公司 | Method for the preparation of a crystalline form of 1-chloro-4- (beta-d-glucopyranos-1-yl)-2-(4-((s)-tetrahydrofuran-3-yloxy)benzyl)benzene |
| WO2017130217A1 (en) * | 2016-01-27 | 2017-08-03 | Msn Laboratories Private Limited | The present invention relates to process for the preparation of d-glucitol, 1,5- anhydro-1-c-[4-chloro-3-[[4-[[(3s)-tetrahydro-3-furanyl] oxy]phenyl] methyl]phenyl]-, (1s) and its crystalline forms thereof. |
| CN106632288A (en) * | 2016-11-07 | 2017-05-10 | 安徽九华华源药业有限公司 | Method for preparing empagliflozin |
| US20180346502A1 (en) * | 2017-05-30 | 2018-12-06 | Emmennar Pharma Private Limited | Processes for the Preparation of SGLT-2 Inhibitors, Intermediates Thereof |
| CN112812107A (en) * | 2019-11-18 | 2021-05-18 | 上海启讯医药科技有限公司 | Preparation method of SGLT-2 inhibitor and intermediate |
| CN111560004A (en) * | 2020-04-30 | 2020-08-21 | 江苏德源药业股份有限公司 | Preparation method of high-purity canagliflozin intermediate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112661736B (en) | Synthetic method of tylosin intermediate | |
| CN113549042B (en) | Preparation method of dapagliflozin | |
| EP0193132A2 (en) | Labdan-derivatives, a process for their preparation and their use as medicaments | |
| WO2018142422A1 (en) | Process for the preparation of dapagliflozin | |
| CN105294624B (en) | A kind of preparation method of Dapagliflozin | |
| CN112812107B (en) | Preparation method of SGLT-2 inhibitor and intermediate | |
| CN111560004A (en) | Preparation method of high-purity canagliflozin intermediate | |
| EP3256482B1 (en) | Process for the preparation of sglt inhibitor compounds | |
| CN114380775A (en) | Empagliflozin intermediate and preparation method thereof | |
| CN108610316B (en) | Preparation method of dapagliflozin | |
| CN111116530A (en) | Method for synthesizing beraprost | |
| CN113620986B (en) | Method for synthesizing medicine for treating diabetes by using D-gluconic acid-delta-lactone | |
| CN116283513A (en) | Preparation method of dapagliflozin intermediate ortho-isomer impurity | |
| CN111732589B (en) | Improved entecavir intermediate synthesis process and improved entecavir synthesis process | |
| CN109553609B (en) | Preparation method of canagliflozin | |
| CN113248464B (en) | Synthesis method of C-glycoside derivatives | |
| CN114276365B (en) | Preparation method of artemether impurity dehydrated dihydroartemisinin | |
| CN115504862B (en) | Preparation method of cannabigerol | |
| Chapleur et al. | On the reaction of 4, 6-O-benzylidene-2-deoxypyranosides with sodium cyanoborohydride: formation of 1, 5-anhydroalditols | |
| CN113004349A (en) | Preparation method of SGLTs inhibitor and key intermediate thereof | |
| CN116239643A (en) | Engliflozin intermediate compound | |
| CN116239583A (en) | Synthetic method of enggliflozin | |
| CN117756610A (en) | Synthesis method of dapagliflozin intermediate | |
| EP4023644A1 (en) | Process for the preparation of a pharmaceutical agent | |
| CN116239582A (en) | Engliflozin intermediate compound and preparation method thereof |
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 |