CN114213365A - Synthetic method of empagliflozin intermediate - Google Patents
Synthetic method of empagliflozin intermediate Download PDFInfo
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- CN114213365A CN114213365A CN202111682917.0A CN202111682917A CN114213365A CN 114213365 A CN114213365 A CN 114213365A CN 202111682917 A CN202111682917 A CN 202111682917A CN 114213365 A CN114213365 A CN 114213365A
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- 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
Abstract
The invention discloses a synthetic method of an empagliflozin key intermediate. The invention adopts (S) -3-hydroxyl tetrahydrofuran and phenol to generate (S) -3-phenoxy tetrahydrofuran under the action of BINAP and MTAD, then the (S) -3-phenoxy tetrahydrofuran and 2-chloro-5-iodobenzoic acid are subjected to acylation reaction to obtain 2-3 (5-iodo-2-chlorophenyl) [4- [ [ (3S) -tetrahydro-3-furyl ] oxy ] phenyl ] methanone, and finally the (S) -3- (4- (5-iodo-2-chlorobenzyl) phenoxy) tetrahydrofuran is obtained by reduction. Compared with the prior art, the method has the advantages of short reaction steps, mild conditions, simple post-treatment and high product yield.
Description
Technical Field
The invention relates to a method for synthesizing an empagliflozin intermediate (3S) -3- [4- [ (5-iodo-2-chlorophenyl) methyl ] phenoxy ] tetrahydrofuran, belonging to the technical field of organic synthesis.
Background
Engelizin (empagliflozin) is a sodium-glucose cotransporter (SGLT2) inhibitor developed by combining brigregathan and li, is firstly approved by the european drug administration to be marketed in 5 months in 2014, is approved by the U.S. FDA to be marketed in 8 months in 2014, is approved by the japanese drug and medical device administration in 12 months in 2014, and is approved by the chinese to be marketed in 9 months in 2017, and can be used for treating type 2 diabetes. As a highly selective SGLT2 inhibitor, engagliflozin has a unique insulin-independent glucose-lowering pathway, namely, glucose is directly excreted from urine by reducing glucose reabsorption in the kidney, and besides a definite glucose-lowering effect, the engagliflozin can bring benefits of weight reduction, blood pressure reduction and uric acid reduction. Chemical name: (1S) -1, 5-anhydro-1-C- [ 4-chloro-3- [ [4- [ [ (3S) -tetrahydro-3-furanyl ] oxy ] phenyl ] methyl ] phenyl ] -D-glucitol, of the formula empagliflozin: C23H27ClO7, molecular weight 450.91. The chemical structural formula is as follows:
the original patent CN102574829A discloses a synthetic method of engagliflozin, and the synthetic route is shown as follows.
Wherein, the compound V.1 is (3S) -3- [4- [ (5-iodo-2-chlorophenyl) methyl ] phenoxy ] tetrahydrofuran, which is used as an important intermediate of the Engelliflozin, and the synthesis method mainly comprises the following steps:
1) chinese patent CN107311962A discloses a synthetic method of (S) -3- (4- (5-bromo-2-chlorobenzyl) phenoxy) tetrahydrofuran, and the synthetic route is shown as follows.
The synthesis method adopts simple and easily-obtained 4-fluorotoluene as a starting material, has a short synthesis route, but the reaction and post-treatment steps in the 1 st to 2 nd steps of the synthesis route are complicated and need to be further improved.
2) Chinese patent CN 108178751A discloses a synthetic method of an engletin intermediate, which takes 4-hydroxybenzyl chloride as a starting material, sequentially reacts with methylsulfonyl chloride and (S) -3-hydroxytetrahydrofuran to obtain a compound III, then reacts with 4-iodoaniline to obtain a compound IV, and finally reacts with cuprous chloride to obtain (S) -3- (4- (5-iodo-2-chlorobenzyl) phenoxy) tetrahydrofuran after diazotization.
The synthetic route is short, but the yield is low, thus being not beneficial to industrial production.
Disclosure of Invention
Aiming at the technical problems in the prior art, a novel synthetic method of the empagliflozin intermediate is provided.
The invention provides a technical scheme that: a synthetic method of an empagliflozin intermediate- (S) -3- (4- (5-iodo-2-chlorobenzyl) phenoxy) tetrahydrofuran comprises the following steps:
(1) generating (S) -3-phenoxytetrahydrofuran from (S) -3-hydroxytetrahydrofuran and phenol under the action of BINAP and MTAD;
(2) acylation reaction of (S) -3-phenoxytetrahydrofuran and 2-chloro-5-iodobenzoic acid to obtain 2-3 (5-iodo-2-chlorophenyl) [4- [ [ (3S) -tetrahydro-3-furyl ] oxy ] phenyl ] methanone;
(3) and the compound 2-3 (5-iodine-2-chlorphenyl) [4- [ [ (3S) -tetrahydro-3-furyl ] oxy ] phenyl ] methanone is subjected to reduction reaction to obtain (S) -3- (4- (5-iodine-2-chlorobenzyl) phenoxy) tetrahydrofuran.
Wherein the reaction solvent in the step (1) is one or more of tetrahydrofuran and acetonitrile, and is preferably tetrahydrofuran.
Wherein the reaction solvent in the step (2) is one or more mixed solvents of tetrahydrofuran, dimethyl sulfoxide and DMF, and is preferably a mixed solvent of tetrahydrofuran and dimethyl sulfoxide.
Further, the acylating agent in the step (2) is TsCl (p-toluenesulfonyl chloride), and the reaction temperature is room temperature.
Further, the reaction solvent in step (3) is one or more of dioxane, TBME (methyl tert-butyl ether), and ethylene glycol diethyl ether (DME), and is preferably dioxane.
Further, the catalyst of step (3) is triethylamine and EDTA (N, N-diisopropylethylamine), preferably EDTA.
The method specifically comprises the following steps:
1) phenol, BINAP (binaphthyldiphenylphosphine) and (S) -3-hydroxytetrahydrofuran were added to THF (tetrahydrofuran), MTAD (N-methyl-1, 2, 4-triazoline-3, 5-dione) was added dropwise, and the solution was stirred at room temperature overnight. After the reaction is finished, filtering, concentrating, extracting and purifying to obtain (S) -3-phenoxyl tetrahydrofuran;
2) sequentially adding 2-chloro-5-iodobenzoic acid, (S) -3-phenoxytetrahydrofuran and TsCl into a mixed solution of tetrahydrofuran and dimethyl sulfoxide, stirring at room temperature, slowly dropwise adding EDTA, reacting for 1h by TLC, adjusting the pH to be neutral by using dilute acid at room temperature, removing the solvent under reduced pressure, filtering, washing with water, and drying to obtain a white solid.
3) Adding the product obtained in the step 2) into dry dioxane, adding zinc chloride, adding sodium borohydride into the mixed solution, and stirring at room temperature for 2 hours. And (3) determining the conversion condition by HPLC analysis, after the reaction is completed, extracting by using ethyl acetate, distilling under reduced pressure, washing to be neutral by using water, drying by using anhydrous sodium sulfate, filtering, and recovering the solvent from the filtrate under reduced pressure to obtain the target product.
The invention has the beneficial effects that:
the synthesis method comprises the steps of taking (S) -3-hydroxytetrahydrofuran as a starting raw material, reacting with 2-chloro-5-iodobenzoic acid in sequence to obtain a compound 2-3 (5-iodo-2-chlorophenyl) [4- [ [ (3S) -tetrahydro-3-furyl ] oxy ] phenyl ] methanone, and finally carrying out carbonyl reduction reaction to obtain (S) -3- (4- (5-iodo-2-chlorobenzyl) phenoxy) tetrahydrofuran. Compared with the prior art, the method has the advantages of short reaction steps, mild conditions, simple post-treatment and high product yield by searching more appropriate reaction reagents and solvents.
Detailed Description
The following examples are further illustrative of the present invention, but the present invention is not limited thereto.
The raw materials of the application are purchased from Shanghai Yihui Biotechnology Limited, and the reagents are purchased from Bailingwei chemical technology Limited.
The NMR was measured by a Mercury-Plus300/Bruker500 NMR spectrometer from Bruker, Germany, and the mass spectrum was measured by Waters UPLC MS from Waters, USA.
Example 1:
step 1 preparation of (S) -3-phenoxytetrahydrofuran
To THF (200mL) was added phenol (4.70g, 50mmol), BINAP (32.4g, 52mmol) and (R) -3-hydroxytetrahydrofuran (4.58g, 52mmol), and MTAD (5.65g, 50mmol) was added dropwise. The solution was stirred at room temperature overnight (HPLC monitored for reaction completion). After the reaction was completed, 6.90g of (S) -3-phenoxytetrahydrofuran was obtained by filtration, concentration, extraction and purification, with a yield of 84.6% and a purity of 99.5%.
Step 2) preparation of 2-3 (5-iodo-2-chlorophenyl) [4- [ [ (3S) -tetrahydro-3-furanyl ] oxy ] phenyl ] methanone
After adding 11.30g (40 mmol) of 2-chloro-5-iodobenzoic acid and 6.57g (40 mmol) of (S) -3-phenoxytetrahydrofuran to 150ml of a mixed solution of tetrahydrofuran and dimethylsulfoxide (ratio: 2:1) in this order, TsCl (0.3g, 1.6mmol) was added, the mixture was stirred at room temperature, 8ml of EDTA was slowly added dropwise thereto, TLC showed completion of the reaction for 1 hour, the pH was adjusted to neutral with a dilute acid at room temperature, the solvent was removed under reduced pressure, the mixture was filtered by suction, washed with water and dried to obtain 15.75g of 2-3 (5-iodo-2-chlorophenyl) [4- [ [ (3S) -tetrahydro-3-furanyl ] oxy ] phenyl ] methanone as a white solid. The yield was 91.9%, and the purity was 98.3%.
Step 3) preparation of (S) -3- (4- (5-iodo-2-chlorobenzyl) phenoxy) tetrahydrofuran
The product of step 2) was added to 200ml of dried dioxane, zinc chloride (6.8g, 50mmol) was added, sodium borohydride (1.89g, 50mmol) was added to the mixture, and the mixture was stirred at room temperature for 2 h. And (3) determining the conversion condition by HPLC analysis, after the reaction is completed, extracting twice by using 150ml of ethyl acetate, distilling under reduced pressure, washing to be neutral by water, drying by anhydrous sodium sulfate, filtering, and recovering the solvent from the filtrate under reduced pressure to obtain 13.1g of a target product. The yield was 86.1% and the purity was 99.61%.1H NMR(500MHz,CDCl3)δ7.53-7.42(m,2H),7.15-7.09(m,3H),6.81(d,J＝8.6Hz,2H),4.95(dd,J＝5.6,4.2Hz,1H),4.05-3.96(m,5H),3.91(td,J＝8.2,4.5Hz,1H),2.27-2.13(m,2H).ESI-MS m/z:414.0(M+1)+。
Example 2:
step 1 preparation of (S) -3-phenoxytetrahydrofuran
To THF (300mL) were added phenol (7.05g, 75mmol), BINAP (46.73g, 75mmol) and (R) -3-hydroxytetrahydrofuran (6.61g, 75mmol), and MTAD (8.48g, 75mmol) was added dropwise. The solution was stirred at room temperature overnight (HPLC monitored for reaction completion). After the reaction was completed, 10.53g of (S) -3-phenoxytetrahydrofuran was obtained in 84.6% yield and 99.5% purity by filtration, concentration, extraction and purification.
Step 2) preparation of 2-3 (5-iodo-2-chlorophenyl) [4- [ [ (3S) -tetrahydro-3-furanyl ] oxy ] phenyl ] methanone
After adding 2-chloro-5-iodobenzoic acid (16.95g, 60mmol) and (S) -3-phenoxytetrahydrofuran (9.86g, 60mmol) in this order to 240ml of a mixed solution of tetrahydrofuran and dimethylsulfoxide (ratio 2:1), TsCl (0.4g, 2.1mmol) was added, the mixture was stirred at room temperature, 10ml of EDTA was slowly added dropwise thereto, TLC showed completion of the reaction for 1 hour, the pH was adjusted to neutral with a dilute acid at room temperature, the solvent was removed under reduced pressure, and the mixture was subjected to suction filtration, washed with water and dried to obtain 23.86g of 2-3 (5-iodo-2-chlorophenyl) [4- [ [ (3S) -tetrahydro-3-furanyl ] oxy ] phenyl ] methanone as a white solid. The yield is 92.8 percent, and the purity is 98.5 percent.
Step 3) preparation of (S) -3- (4- (5-iodo-2-chlorobenzyl) phenoxy) tetrahydrofuran
The product of step 2) was added to 250ml of dry dioxane, zinc chloride (8.2g, 60mmol) was added, sodium borohydride (2.27g, 60mmol) was added to the mixture, and the mixture was stirred at room temperature for 2 h. And (3) determining the conversion condition by HPLC analysis, after the reaction is completed, extracting twice by using 150ml of ethyl acetate, distilling under reduced pressure, washing to be neutral by water, drying by anhydrous sodium sulfate, filtering, and recovering the solvent from the filtrate under reduced pressure to obtain 16.0g of a target product. The yield was 87.3% and the purity was 99.50%.
The foregoing shows and describes the general principles and features of the present invention, together with the advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (7)
1. A preparation method of an empagliflozin intermediate has the following structural formula:
the preparation method of the empagliflozin intermediate is characterized by comprising the following steps:
(1) generating (S) -3-phenoxytetrahydrofuran from (S) -3-hydroxytetrahydrofuran and phenol under the action of BINAP and MTAD;
(2) acylation reaction of (S) -3-phenoxytetrahydrofuran and 2-chloro-5-iodobenzoic acid to obtain 2-3 (5-iodo-2-chlorophenyl) [4- [ [ (3S) -tetrahydro-3-furyl ] oxy ] phenyl ] methanone;
(3) reducing the compound 2-3 (5-iodine-2-chlorphenyl) [4- [ [ (3S) -tetrahydro-3-furyl ] oxy ] phenyl ] methanone to obtain (S) -3- (4- (5-iodine-2-chlorobenzyl) phenoxy) tetrahydrofuran;
2. the preparation method according to claim 1, wherein the reaction solvent in step (1) is a mixed solvent of one or more of tetrahydrofuran and acetonitrile, preferably tetrahydrofuran.
3. The preparation method according to claim 1, wherein the reaction solvent in step (2) is a mixed solvent of one or more of tetrahydrofuran, dimethyl sulfoxide and DMF, preferably a mixed solvent of tetrahydrofuran and dimethyl sulfoxide.
4. The method according to claim 1, wherein the acylating agent in step (2) is TsCl (p-toluenesulfonyl chloride), and the reaction temperature is room temperature.
5. The method according to claim 1, wherein the reaction solvent in step (3) is a mixed solvent of one or more selected from dioxane, TBME (methyl tert-butyl ether), and ethylene glycol diethyl ether (DME), preferably dioxane.
6. The process according to claim 1, wherein the catalyst of step (3) is triethylamine and EDTA (N, N-diisopropylethylamine), preferably EDTA.
7. The method of claim 1, wherein the method of preparing the empagliflozin intermediate further comprises the steps of:
1) adding phenol, BINAP (binaphthyl diphenyl phosphine) and (S) -3-hydroxy tetrahydrofuran into THF (tetrahydrofuran), dropwise adding MTAD (N-methyl-1, 2, 4-triazoline-3, 5-dione), stirring the solution at room temperature overnight, and after the reaction is finished, filtering, concentrating, extracting and purifying to obtain (S) -3-phenoxyl tetrahydrofuran;
2) sequentially adding 2-chloro-5-iodobenzoic acid, (S) -3-phenoxy tetrahydrofuran and TsCl into a mixed solution of tetrahydrofuran and dimethyl sulfoxide, stirring at room temperature, slowly dropwise adding EDTA, completing the reaction after TLC shows that the reaction is 1h, adjusting the pH to be neutral by using dilute acid at room temperature, removing the solvent under reduced pressure, performing suction filtration, washing with water, and drying to obtain a white solid;
3) adding the product obtained in the step 2) into dried dioxane, adding zinc chloride, adding sodium borohydride into the mixed solution, stirring for 2 hours at room temperature, analyzing and determining the conversion condition through HPLC, extracting by using ethyl acetate after the reaction is completed, distilling under reduced pressure, washing to be neutral, drying by using anhydrous sodium sulfate, filtering, and recovering the solvent from the filtrate under reduced pressure to obtain the target product.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106117192A (en) * | 2016-06-23 | 2016-11-16 | 甘肃成纪生物药业有限公司 | The synthetic method that a kind of En Gelie is clean |
| CN108178751A (en) * | 2018-01-30 | 2018-06-19 | 扬州工业职业技术学院 | A kind of synthetic method of the net intermediates of En Gelie |
| CN110683998A (en) * | 2019-11-20 | 2020-01-14 | 杭州华东医药集团浙江华义制药有限公司 | Preparation method of empagliflozin intermediate |
| CN111410639A (en) * | 2020-04-14 | 2020-07-14 | 天津法莫西医药科技有限公司 | Preparation method of empagliflozin intermediate impurity |
| CN113480497A (en) * | 2021-07-27 | 2021-10-08 | 山东铂源药业有限公司 | Synthesis method of empagliflozin key intermediate |
-
2021
- 2021-12-31 CN CN202111682917.0A patent/CN114213365A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106117192A (en) * | 2016-06-23 | 2016-11-16 | 甘肃成纪生物药业有限公司 | The synthetic method that a kind of En Gelie is clean |
| CN108178751A (en) * | 2018-01-30 | 2018-06-19 | 扬州工业职业技术学院 | A kind of synthetic method of the net intermediates of En Gelie |
| CN110683998A (en) * | 2019-11-20 | 2020-01-14 | 杭州华东医药集团浙江华义制药有限公司 | Preparation method of empagliflozin intermediate |
| CN111410639A (en) * | 2020-04-14 | 2020-07-14 | 天津法莫西医药科技有限公司 | Preparation method of empagliflozin intermediate impurity |
| CN113480497A (en) * | 2021-07-27 | 2021-10-08 | 山东铂源药业有限公司 | Synthesis method of empagliflozin key intermediate |
Non-Patent Citations (2)
| Title |
|---|
| MATT HRAPCHAK等: ""Synthesis of empagflozin, a novel and selective sodium-glucose cotransporter-2 inhibitor, labeled with carbon-14 and carbon-13", 《JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS》 * |
| SHENGQUAN HU等: "Design, synthesis and anticancer activities of halogenated Phenstatin analogs as microtubule destabilizing agent", 《MEDICINAL CHEMISTRY RESEARCH》 * |
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