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Novel method for synthesizing sitagliptin phosphate and derivative thereof

A technology for sitagliptin phosphate and derivatives, which is applied in the field of synthesizing sitagliptin phosphate and derivatives thereof, and can solve problems such as difficulty in improving ee value

Inactive Publication Date: 2013-04-24
NANJING TECH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] In 2007, Jin Hee Ahn and others in South Korea invented another method, but it is difficult to improve the ee value

Method used

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  • Novel method for synthesizing sitagliptin phosphate and derivative thereof
  • Novel method for synthesizing sitagliptin phosphate and derivative thereof
  • Novel method for synthesizing sitagliptin phosphate and derivative thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] 1) Amino protection

[0052] Add 20g of L-aspartic acid and 200ml of methanol into a three-necked flask equipped with a magnetic stirrer and a thermometer, add 5ml of thionyl chloride dropwise under cooling, stir at room temperature for 5h after the dropwise addition, concentrate under reduced pressure and remove the solvent to obtain solid 4-L - methyl aspartate hydrochloride 40g;

[0053] In a three-necked flask equipped with a magnetic stirrer and a thermometer, add 20 g of 4-L-aspartic acid methyl ester hydrochloride, 20 g of sodium bicarbonate, dissolve in water and 1,4-dioxane, and dissolve Add BOC anhydride, stir overnight, filter with suction, add 2 L of water to the mother liquor, and adjust the pH with hydrochloric acid. Then extracted 3 times with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent to obtain 31 g of light yellow oily liquid N-tert-butoxycarbonyl-4-L-aspartic acid methyl ester;

[005...

Embodiment 2

[0066] 1) Amino protection

[0067] Add 22g of L-aspartic acid and 250ml of ethanol to a three-necked flask equipped with a magnetic stirrer and a thermometer, add 12ml of thionyl chloride dropwise under cooling, stir at room temperature for 5 hours after the dropwise addition, concentrate under reduced pressure and remove the solvent to obtain the solid 4-L - ethyl aspartate hydrochloride 40g;

[0068] In a three-necked flask equipped with a magnetic stirrer and a thermometer, add 22 g of 4-L-ethyl aspartic acid hydrochloride, 28 g of sodium bicarbonate, dissolve in water and 1,4-dioxane, and dissolve Add BOC anhydride, stir overnight, filter with suction, add 2 L of water to the mother liquor, and adjust the pH with hydrochloric acid. Then extracted 3 times with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure and desolventized to obtain 37 g of light yellow oily liquid N-tert-butoxycarbonyl-4-L-aspartic acid ethyl ester;

[0069] 2) ...

Embodiment 3

[0081] 1) Amino protection

[0082] Add 20g of L-aspartic acid and 200ml of methanol into a three-necked flask equipped with a magnetic stirrer and a thermometer, add 5ml of thionyl chloride dropwise under cooling, stir at room temperature for 5h after the dropwise addition, concentrate under reduced pressure and remove the solvent to obtain solid 4-L - methyl aspartate hydrochloride 40g;

[0083] In a three-necked flask equipped with a magnetic stirrer and a thermometer, add 20 g of 4-L-aspartic acid methyl ester hydrochloride, 20 g of sodium bicarbonate, dissolve in water and 1,4-dioxane, and dissolve Add BOC anhydride, stir overnight, filter with suction, add 2 L of water to the mother liquor, and adjust the pH with hydrochloric acid. Then extracted 3 times with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent to obtain 31 g of light yellow oily liquid N-tert-butoxycarbonyl-4-L-aspartic acid methyl ester;

[008...

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Abstract

The invention discloses a novel method for synthesizing sitagliptin phosphate and a derivative thereof. The method has the advantages of readily-available raw materials, mild reaction condition, no need of using very expensive catalyst, easy control over optical purity and the like. In the novel method for synthesizing sitagliptin phosphate and the derivative thereof, L-aspartic acid is taken as a raw material, and the chemical reaction steps of amino protection, esterification, reduction, iodination or bromination, coupling, hydrolysis, acylation ammoniation, removal of protecting groups andsalt formation are performed to obtain a sitagliptin phosphate chiral salt and a hydrate thereof. The method comprises the following specific steps of: performing amino protection, esterification, reduction and iodination on L-aspartic acid serving as the raw material to obtain a compound A shown as a formula I; undergoing a coupling reaction on the compound A and a compound B shown as a formula II to obtain a compound C shown as a formula III; and performing hydrolysis, acylation ammoniation, removal of protecting groups and a salt-forming reaction on the compound C to obtain a sitagliptin phosphate hydrate.

Description

technical field [0001] The present invention relates to a kind of method of synthesizing medicine intermediate, more specifically relate to a kind of new method of synthesizing sitagliptin phosphate and derivative thereof. Background technique [0002] Sitagliptin phosphate (sitagliptin) is the first dipeptidyl peptidase-IV (DPP-IV) inhibitor approved by the FDA for the treatment of type 2 diabetes. Its structural formula is as follows: [0003] [0004] (3R)-N-tert-butoxycarbonyl-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid or its methyl and ethyl esters are key intermediates of sitagliptin phosphate. Kim et al. published the first generation synthetic route of sitagliptin [J.Med.Chem.2005, 48(1):141.], the method induces chiral α-amino acid through chiral raw materials, after diazo The reaction produces β-amino acids to build the chiral center. This approach has significant limitations, as it is cumbersome to react and the product is limited to the research sector o...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04
CPCY02P20/55
Inventor 徐浩师传兴
Owner NANJING TECH UNIV
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