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Preparation of sitagliptin intermediates

A technology of intermediates and chiral centers, applied in the field of preparation of chiral compounds, can solve problems such as toxicity

Inactive Publication Date: 2014-04-09
LEK PHARMA D D
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

One of these disadvantages is the long and complicated 5-step process to obtain the intermediate of formula II
[0016] Some other important disadvantages are: certain steps are performed under extreme conditions (-78°C) where special equipment is also required; use of extremely hazardous reagents such as BuLi which is strongly required for the aza-Michael reaction under these conditions ; some steps include using CH 2 Cl 2 As a volatile, toxic and especially non-industrial and non-environmentally friendly reaction medium

Method used

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  • Preparation of sitagliptin intermediates
  • Preparation of sitagliptin intermediates
  • Preparation of sitagliptin intermediates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0263] Example 1: Synthesis of (E)-4-(2,4,5-trifluorophenyl)-but-2-ene by cobalt-catalyzed cross-coupling process Acid methyl ester (IIa):

[0264] To a dry, nitrogen-flushed 200 mL two-neck flask equipped with a magnetic stirrer and rubber septum was added anhydrous THF (20 mL) and cooled to -20 °C. 2,4,5-Trifluorobenzene (65.2mmol, 13.7g, 7.6mL) was then introduced through the septum, followed by the very slow addition of iPrMgCl (2M in THF, 1.0 eq, relative to 2,4,5-trifluorobenzene Total, 39.6mL). The reaction temperature was maintained at -10°C and the reaction mixture was stirred for 1 hour until the Br / Mg exchange reaction was complete and 2,4,5-trifluoroarylmagnesium bromide (magnesium chloride) was formed.

[0265] Into another dry three-necked flask flushed with nitrogen, add cobalt(II) bromide (3.76mmol, 6mol%, relative to 2,4,5-trifluorobenzene, 822mg, 99.99% purity), TMEDA (3.76 mmol, 6mol%, relative to 2,4,5-trifluorobenzene, 564mL) and anhydrous THF (20mL)...

Embodiment 2

[0269] Example 2: Synthesis of 3-benzylamino-4-(2,4,5- from (IIa) in pure water by aza-Michael reaction Methyl trifluorophenyl)butyrate (Ib):

[0270] β-Unsaturated ester (E)-4-(2,4,5-trifluorophenyl)-but-2-enoic acid methyl ester (IIa) (0.5mmol, 115mg) and benzylamine (0.6mmol, 68 mg, 99% purity) was placed in a glass flask and deionized water (3 mL) was added. The heterogeneous reaction mixture (aqueous dispersion) was vigorously stirred (1000 rpm) at 60°C for 16 hours. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with anhydrous MgSO 4 After drying, the organics were evaporated under reduced pressure and the crude reaction mixture (165 mg) was obtained with 1 H NMR Spectroscopy. The crude product (Ib) was purified by column chromatography (SiO 2 , hexane:ethyl acetate=2:1) ​​to obtain the light brown liquid product (Ib) (102mg, 61% yield). Compound 3-benzylamino-4-(2,4,5-trifluoroph...

Embodiment 3

[0273] Example 3: From (IIa) in Water by Aza-Michael Reaction in Phosphine Ligands and Surfactants Copper catalysis in the presence of [Cu(OAc) 2 ] Synthetic 3-benzylamino-4-(2,4,5-trifluorophenyl) methyl butyrate (Ib):

[0274] In a two-neck round bottom flask under nitrogen, add Cu(OAc) 2 (0.11mmol, 19.1mg), NatOBu (0.13mmol, 12.6mg), Ph 3 P (0.11 mmol, 28.8 mg) and anionic surfactant sodium dodecyl sulfate (SDS) (0.042 mmol, 12 mg). Deionized water (3 mL) was then added and the reaction mixture was vigorously stirred (900 rpm) at room temperature for 30 minutes. A 2 mL dispersion of β-unsaturated ester (E)-4-(2,4,5-trifluorophenyl)-but-2-enoate (IIa) (1 mmol) in deionized water was then passed through a rubber septum Slowly added to aqueous micellar solution (final volume: 5 mL of 0.0081 MSDS in water), followed by benzylamine (1 mmol, 107 mg, 110 μL). The aqueous reaction system was vigorously stirred (900 rpm) at room temperature for 6 hours. The reaction mixtu...

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Abstract

The invention relates to the preparation of chiral compounds, in particular to the preparation of chiral compounds which may be used as intermediates for the preparation of anti-diabetic agents, preferably sitagliptin.

Description

field of invention [0001] The present invention relates to the preparation of chiral compounds, in particular to the preparation of chiral compounds useful as intermediates for the preparation of antidiabetics, preferably sitagliptin. Background technique [0002] Type 2 diabetes mellitus (T2DM) is a global epidemic. Therefore, the present study is oriented towards the development of selective inhibitors of the enzyme DPP-IV as promising new therapeutic agents for type II diabetes. [0003] Sitagliptin (CAS accession number 486460-32-6. IUPAC name: (R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4 ]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine) is an antidiabetic drug and a potent DPP - IV inhibitors. It is represented by the following structure: [0004] [0005] People are constantly seeking an improved synthetic scheme for the key intermediates, particularly the β-amino acid intermediates of formula I, for the synthesis of sitagliptin ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/34C07C239/20C07C271/22C07C311/19C07F7/10C07F7/18
CPCC07C227/32C07C303/40C07C269/06C07F7/0892C07C239/20C07F7/10C07B2200/07A61P3/10C07C229/34C07C271/22C07C311/19
Inventor Z·查萨尔G·斯塔夫伯
Owner LEK PHARMA D D
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