CN113943329A - Preparation method of diastereoisomer of canagliflozin intermediate - Google Patents
Preparation method of diastereoisomer of canagliflozin intermediate Download PDFInfo
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- CN113943329A CN113943329A CN202010684113.3A CN202010684113A CN113943329A CN 113943329 A CN113943329 A CN 113943329A CN 202010684113 A CN202010684113 A CN 202010684113A CN 113943329 A CN113943329 A CN 113943329A
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- compound
- canagliflozin
- diastereoisomer
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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
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic 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
Abstract
The invention discloses a preparation method of a diastereoisomer (compound I) of a canagliflozin intermediate (compound II). The method of the invention is that the compound II generates the compound I under the catalysis of Lewis acid and lithium borohydride. The method has the advantages of easily obtained raw materials, mild reaction conditions and simple operation.
Description
The technical field is as follows:
the invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of a diastereoisomer (compound I) of a canagliflozin intermediate (compound II).
Background art:
canagliflozin, Kagelliflozin, trade name
The sugar-reducing drug is produced by the Yankee pharmaceutical company under the Qiangsheng flag, is approved by the American FDA for treating adult patients with type 2 diabetes in 29 months and 3 years in 2013, and is the first SGLT2 type diabetes drug approved in the United states. The drug was also approved by the european union committee at 11/15 in 2013.
(2S, 3R, 4S, 5S, 6R) -2- (3- ((5- (4-fluorophenyl) -2-thiophene) methyl) -4-tolyl) -6- (hydroxymethyl) -2-methoxy-2H-3, 4, 5-trihydroxytetrahydropyran (Compound II) is an important intermediate for the synthesis of canagliflozin, (2R, 3R, 4S, 5S, 6R) -2- (3- ((5- (4-fluorophenyl) -2-thiophene) methyl) -4-tolyl) -6- (hydroxymethyl) -2-methoxy-2H-3, 4, 5-trihydroxytetrahydropyran (Compound I) is a diastereomer of Compound II, is a necessary substance for analyzing and detecting the purity of the compound II. In addition, compound II is easily carried into the final product during the process of preparing canagliflozin, and therefore, compound II is also a relevant substance for analyzing the purity of canagliflozin. The preparation route of canagliflozin is shown in Scheme 1.
At present, no relevant literature reports the preparation of the compound I, so that research on the preparation method is necessary.
The invention content is as follows:
the invention aims to provide a novel preparation method of a diastereoisomer (compound I) of a canagliflozin intermediate (compound II) with simple operation aiming at the fact that no report about the preparation method of the diastereoisomer (compound I) of the canagliflozin intermediate (compound II) exists at present.
The technical scheme adopted by the invention is as follows:
the invention provides a method for preparing a diastereoisomer (compound I) of a canagliflozin intermediate (compound II), which specifically comprises the following steps: dissolving a compound I in an organic solvent, adding Lewis acid and lithium borohydride into a solution of the compound I under the protection of nitrogen, and stirring for reaction. After the reaction is finished, adjusting the pH of the reaction solution to be neutral by using a 10% sodium carbonate aqueous solution, concentrating, and carrying out silica gel column chromatography to obtain a compound II.
Further, the organic solvent is dichloromethane, acetonitrile, tetrahydrofuran, preferably dichloromethane.
Further, the reaction is carried out at-50 to 25 ℃, preferably-50 to-30 ℃.
Further, the equivalent ratio of the compound II to the Lewis acid and the lithium borohydride is 1: 1-3, preferably 1:3: 3.
Further, the Lewis acid is selected from the group consisting of boron trifluoride complex, aluminum trichloride, ferric trichloride, zinc chloride, and preferably boron trifluoride complex.
Further, the boron trifluoride complex is selected from boron trifluoride acetonitrile complex, boron trifluoride diethyl etherate complex, boron trifluoride acetic acid complex, boron trifluoride tetrahydrofuran complex, preferably boron trifluoride acetonitrile complex.
Further, the eluent of the silica gel column chromatography is dichloromethane: methanol 10: 1.
The preparation method has the beneficial effects that the canagliflozin intermediate II is used as the raw material for preparing the diastereoisomer of the canagliflozin intermediate II, the total yield of the route is more than 75%, the ee value of the final product can reach more than 98%, the canagliflozin intermediate II is an important raw material for synthesizing the canagliflozin and is a raw material for synthesizing the diastereoisomer of the canagliflozin, and the raw material is easy to obtain.
Drawings
FIG. 1 Process for preparing Compound I1HNMR picture
Detailed Description
The technical content of the present invention is further described below with reference to specific examples for better understanding of the content of the present invention, but the scope of the present invention is not limited thereto.
Example 1
17.5g of Compound II and 140mL of methylene chloride were added to a 500mL reaction flask. And (5) cooling to-30 ℃ under the protection of nitrogen. 24mL of a 2.0M solution of lithium borohydride in tetrahydrofuran and 40g of boron trifluoride acetonitrile complex were added to the above reaction solution. After the addition was complete, the mixture was stirred at-30 ℃ for 3 hours. After the reaction is completed, the pH value of the reaction solution is adjusted to be neutral by using a 10% sodium carbonate aqueous solution. And concentrating the organic phase under reduced pressure until the organic phase is dried to obtain a crude product, and separating and purifying the crude product through silica gel column chromatography to obtain 13.9g of a compound II with the chiral purity of 98.7%.1The HNMR map is shown in FIG. 1.
Example 2
17.5g of Compound II and 140mL of tetrahydrofuran were added to a 500mL reaction flask. And (5) cooling to-45 ℃ under the protection of nitrogen. 24mL of a 2.0M solution of lithium borohydride in tetrahydrofuran and 40g of aluminum trichloride were added to the above reaction solution. After the addition was complete, the mixture was stirred at-45 ℃ for 3 hours. After the reaction is completed, the pH value of the reaction solution is adjusted to be neutral by using a 10% sodium carbonate aqueous solution. And concentrating the organic phase under reduced pressure until the organic phase is dried to obtain a crude product, and separating and purifying the crude product through silica gel column chromatography to obtain 13g of a compound II.
Example 3
17.5g of Compound II and 140mL of acetonitrile were charged to a 500mL reaction flask. And (5) cooling to-50 ℃ under the protection of nitrogen. 24mL of a 2.0M solution of lithium borohydride in tetrahydrofuran and 40g of ferric chloride were added to the above reaction solution. After the addition was complete, the mixture was stirred at-50 ℃ for 3 hours. After the reaction is completed, the pH value of the reaction solution is adjusted to be neutral by using a 10% sodium carbonate aqueous solution. And concentrating the organic phase under reduced pressure until the organic phase is dried to obtain a crude product, and separating and purifying the crude product by silica gel column chromatography to obtain 12.4g of a compound II.
Example 4
17.5g of Compound II and 140mL of methylene chloride were added to a 500mL reaction flask. And (5) cooling to-45 ℃ under the protection of nitrogen. 24mL of a 2.0M solution of lithium borohydride in tetrahydrofuran and 40g of zinc chloride were added to the above reaction solution. After the addition was complete, the mixture was stirred at-45 ℃ for 3 hours. After the reaction is completed, the pH value of the reaction solution is adjusted to be neutral by using a 10% sodium carbonate aqueous solution. And concentrating the organic phase under reduced pressure until the organic phase is dried to obtain a crude product, and separating and purifying the crude product by silica gel column chromatography to obtain 11.1g of a compound II.
Claims (2)
1. A process for the preparation of a diastereoisomer (compound I) of a canagliflozin intermediate (compound II), characterized in that: and the compound II generates a compound I under the catalytic action of Lewis acid and lithium borohydride. The reaction formula is as follows:
2. a process according to claim 1, wherein the Lewis acid is selected from the group consisting of boron trifluoride complex, aluminum trichloride, ferric trichloride, and zinc chloride.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202010684113.3A CN113943329A (en) | 2020-07-16 | 2020-07-16 | Preparation method of diastereoisomer of canagliflozin intermediate |
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| CN202010684113.3A CN113943329A (en) | 2020-07-16 | 2020-07-16 | Preparation method of diastereoisomer of canagliflozin intermediate |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101573368A (en) * | 2006-12-04 | 2009-11-04 | 田边三菱制药株式会社 | Crystalline form of 1- (belta-D-glucopyranosyl) -4 -methyl- 3- [5- (4 -fluorophenyl) -2-thienylmethyl] benzene hemihydrate |
| CN102264714A (en) * | 2008-10-17 | 2011-11-30 | 詹森药业有限公司 | Process for the preparation of compounds useful as inhibitors of sglt |
| US20160002275A1 (en) * | 2014-07-03 | 2016-01-07 | Cadila Healthcare Limited | Process for preparation and purification of canagliflozin |
| CN105503845A (en) * | 2015-12-01 | 2016-04-20 | 北京普德康利医药科技发展有限公司 | Defluorinated canagliflozin compound, and preparation method and application thereof |
-
2020
- 2020-07-16 CN CN202010684113.3A patent/CN113943329A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101573368A (en) * | 2006-12-04 | 2009-11-04 | 田边三菱制药株式会社 | Crystalline form of 1- (belta-D-glucopyranosyl) -4 -methyl- 3- [5- (4 -fluorophenyl) -2-thienylmethyl] benzene hemihydrate |
| CN102264714A (en) * | 2008-10-17 | 2011-11-30 | 詹森药业有限公司 | Process for the preparation of compounds useful as inhibitors of sglt |
| US20160002275A1 (en) * | 2014-07-03 | 2016-01-07 | Cadila Healthcare Limited | Process for preparation and purification of canagliflozin |
| CN105503845A (en) * | 2015-12-01 | 2016-04-20 | 北京普德康利医药科技发展有限公司 | Defluorinated canagliflozin compound, and preparation method and application thereof |
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