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Amino-protected 3-hydroxy adamantane glycine benzothiazole-2-thiol active ester as well as preparation method and application thereof

An adamantane glycine and amino protection technology, which is applied in the field of intermediates for preparing saxagliptin, can solve the problems of inapplicability of amino protecting groups, inability to recycle, harsh reaction conditions, etc., and achieves improved drug purity, mild reaction, adaptable effect

Active Publication Date: 2017-01-25
艾博仕医药科技石家庄有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] EDC / HOBt has the disadvantages of high cost and non-recyclability as a dehydration condensation reagent; Vilsmeier reagent has harsh reaction conditions as a condensation reaction condition, and the strong acidic conditions in the reaction process are difficult for some acid-sensitive amino protecting groups (such as tert-butoxy methylcarbonyl) is not applicable

Method used

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  • Amino-protected 3-hydroxy adamantane glycine benzothiazole-2-thiol active ester as well as preparation method and application thereof
  • Amino-protected 3-hydroxy adamantane glycine benzothiazole-2-thiol active ester as well as preparation method and application thereof
  • Amino-protected 3-hydroxy adamantane glycine benzothiazole-2-thiol active ester as well as preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Compound Ⅰ (PG=Boc), chemical structural formula:

[0055] .

[0056] Example 1 Compound I Melting point: 139.8~142.3 °C;

[0057] The characteristics of the NMR spectrum are: 1 H NMR (500 MHz, CDCl 3 ) δ: 1.41~1.72 (m, 21H),2.27 (s, 2H),4.26~4.28 (d, J=8.5 Hz, 1H), 5.16~5.18 (d, J=8.5 Hz, 1H), 7.41~7.44 (m, 1H),7.48~7.51 (m, 1H), 7.90 (d, J=8 Hz, 1H), 8.03 (d, J=8Hz, 1H), such as figure 1 shown.

[0058] 13 C NMR (125 MHz, CDCl 3 ) Δ: 28.35, 30.16, 30.25, 35.02, 37.47, 37.73,40.26, 44.29, 46.47, 68.35, 68.55, 81.15, 121.25, 125.61, 126.38,136.06, 155.23, 158.09, 195.58, figure 2 shown.

Embodiment 2

[0059] The preparation of embodiment 2 saxagliptin intermediate

[0060] Step 1: Synthesis of amino-protected 3-hydroxyadamantaneglycine benzothiazole-2-thiol active ester intermediate (Ⅰ) through amino-protected 3-hydroxyadamantaneglycine (Ⅱ) and dibenzothiazole disulfide (Ⅲ) ) method: add compound II and compound III to a three-necked flask, stir with an aprotic solvent, control the temperature at 10 °C, add an organic base, cool down to 0 °C, add an organic phosphine reagent dropwise, remove the ice bath and continue stirring, The color of the solution changed from white turbidity to light yellow and clear. Stirring was continued at room temperature, and solids precipitated out of the solution. Stand overnight at room temperature, and filter with suction to obtain a white solid. The product was washed with sodium carbonate aqueous solution and suction filtered to obtain the amino-protected 3-hydroxyadamantylglycine benzothiazole-2-thiol active ester compound.

[0061] Ste...

Embodiment 3

[0065] Amino-protected 3-hydroxyadamantane glycine (compound Ⅱ, PG=Boc) (10 g, 30.7 mmol), dibenzothiazole disulfide (compound Ⅲ) (11.3 g, 33.7 mmol), acetonitrile (50 mL), Add it to a 100 mL reaction bottle in turn, stir at room temperature, the solution is white and turbid. Control the temperature at 10°C, add triethylamine (5.2 mL) dropwise, when the temperature continues to drop to 0°C, add triethyl phosphite (6.2 g, 36.9 mmol) dropwise, the solution is still white and turbid after the dropwise addition, remove the ice and continue stirring , the color of the solution changed from white turbidity to light yellow and clear. Stirring at room temperature gradually precipitated solids in the solution. Stand overnight at room temperature, and filter with suction to obtain a white solid. The obtained white solid was washed with 10% aqueous sodium carbonate solution, filtered with suction, and dried to obtain 12.5 g of compound (Compound I, PG=Boc), with a yield of 85.6%.

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Abstract

The invention relates to an amino-protected 3-hydroxy adamantane glycine benzothiazole-2-thiol active ester as well as a preparation method and application thereof. The thiol active ester is prepared by virtue of reaction between amino-protected 3-hydroxy adamantane glycine and dibenzothiazyl disulfide. The invention further discloses application of the compound in the preparation of a saxagliptin intermediate and saxagliptin. The invention provides a brand new chemical structure. The preparation method is simple and low in cost; the compound is applicable to the preparation of saxagliptin, so that the preparation process can be effectively simplified; and the reaction is mild, and the compound has a wide generalization prospect.

Description

technical field [0001] The invention relates to an amino-protected 3-hydroxyadamantaneglycine benzothiazole-2-thiol active ester, its preparation method and application, and is specifically used to prepare an intermediate of saxagliptin, and then to synthesize the antidiabetic drug Sager Littin. Background technique [0002] The chemical name of saxagliptin is (1 S ,3 S ,5 S )-2-[(2 S )-2-amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile (IX), the structural formula is shown below. [0003] (Ⅸ) [0004] Saxagliptin is a new type of anti-diabetic drug, a dipeptidyl peptidase-IV inhibitor developed by Bristol-Myers Squibb for the treatment of type 2 diabetes. It has the characteristics of strong potency, high selectivity, and low adverse reactions. Saxagliptin was first launched in the United States in July 2009, approved in the European Union in October of the same year, and its formulation was approved in China in May 2011. [0005]...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/74C07D209/52
CPCY02P20/55Y02P20/582C07D277/74C07D209/52
Inventor 张勇曹文婷安玉张俏艳
Owner 艾博仕医药科技石家庄有限公司
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