Preparation method of sitagliptin intermediate, sitagliptin or salts thereof

A technology for sitagliptin and intermediates, which is applied in the preparation of organic compounds, the preparation of carboxylic acid amides, chemical instruments and methods, etc., can solve the problems of unstable product quality, high cost and high cost, and avoid the problem of low synthesis efficiency. Effect

Active Publication Date: 2011-06-15
ZHEJIANG HISOAR PHARMA
View PDF5 Cites 22 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This synthetic route is relatively suitable, but there is also a big problem that it needs two catalytic hydrogenation, uses a relatively expensive platinum catalyst, and needs to use a large amount of Pd(OH) when removing the protecting group in the last step. 2 /C, very expensive
[0008] WO2007050485 publicly reported the latest generation of synthetic method

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation method of sitagliptin intermediate, sitagliptin or salts thereof
  • Preparation method of sitagliptin intermediate, sitagliptin or salts thereof
  • Preparation method of sitagliptin intermediate, sitagliptin or salts thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Preparation of (3R)-3 tert-Butoxycarbonylamino-4-bromo-butyric acid methyl ester (IV)

[0046] In a 250 ml round bottom flask, add (3R)-3 tert-butoxycarbonylamino-4-hydroxy-butyric acid methyl ester (IX) (23.3 g, 0.1 mol) and 150 ml of dichloromethane, and then add triphenyl Phosphine (26.2g, 0.1mol), bromine (17.6g, 0.11mol) was added dropwise at room temperature, and the drop was finished within ten minutes. After the addition, continue to stir for 3 hours. The reaction was quenched with 10% sodium bisulfite aqueous solution, liquid separation, the organic phase was washed with saturated brine, dried, filtered, and concentrated to obtain a crude product, which was then distilled under reduced pressure to obtain the product (26g, 0.088mol) ), the yield is 88%. 1 H NMR(300MHz, CDCl 3 ) 1.48 (9H, s), 2.67 (1H, d, J = 6.4 and 16.5), 2.80 (1H, dd, J = 5.5 and 16.5), 3.22 (2H, br), 3.78 (3H, s), 5.00 ( 1H, m), and 5.40 (1H, br); ESI-MS m / z 296.2 (M+H) + .

Embodiment 2

[0048] Preparation of 2,4,5-trifluorophenylboronic acid (III)

[0049] In a 250 ml three-necked flask, add a smooth surface of magnesium bar (3.96g, 0.165mol) and a small particle of iodine, 2,4,5-trifluorobromobenzene (II) (31.5g, 0.15mol) with 60 ml After diluting with water and ether, adding a small amount of dropwise to initiate the reaction, add the remaining ether solution dropwise to the reaction flask, keeping the dropping rate at the same rate as the reflux rate, and heating to reflux after the addition. At 4 hours, the magnesium bar basically reacted. In another 500ml three-necked flask, add trimethyl borate (15.6g, 0.15mol) and 150ml anhydrous tetrahydrofuran, under the protection of nitrogen, cool to -78℃, and add the prepared grating reagent dropwise to the rapidly stirring Trimethyl borate solution. After holding at -78°C for 1 hour, it will naturally rise to room temperature, add 150 ml of water and 150 ml of 20% citric acid, and stir for 1 hour. The tetrahydrof...

Embodiment 3

[0051] Preparation of (3R)-3 tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)-butyric acid methyl ester (V)

[0052] In a 250 ml three-necked flask, add (3R)-3 tert-butoxycarbonylamino-4-bromo-butyric acid methyl ester (IV) (14.75g, 0.05mol), 2,4,5-trifluorophenylboronic acid ( III) (10.56g, 0.06mol), potassium tert-butoxide (16.8g, 0.15mol), Pd(OAc) 2 (0.224g, 0.001mol), 100ml of 1,4-dioxane. Under nitrogen protection, stir at 50°C for 10 hours. Cool to room temperature, evaporate the solvent, add 200 ml of ethyl acetate, 200 ml of water, separate the liquids, wash the organic phase with 10% dilute hydrochloric acid, then wash with saturated brine, dry, filter, concentrate to obtain a crude product, and recrystallize from toluene White solid (13g, 0.0375mol), yield 75%. Compound physical and chemical data and literature [1] Same as described in.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention discloses a preparation method of sitagliptin intermediate, sitagliptin or salts thereof. The method comprises the following steps of: (1) preparing a compound, namely 2,4,5-trifluorobromobenzene shown as a formula (II) into a Grignard reagent; (2) reacting the Grignard reagent with boric acid trimester in an organic solvent under the action of a catalyst to obtain a compound, namely 2,4,5-trifluorobenzolc acid shown as a formula (III); and (3) preparing a compound, namely (3R)-3-substituted amido-4-bromine-butyric ester shown as a formula (IV) and the 2,4,5-trifluorobenzolc acid shown as the formula (II) into a compound, namely (3R)-3-substituted amido-4-(2,4,5-trifluorophenyl)-butyric ester shown as a formula (V) under the action of a transition metal catalyst and alkali. By using the method, the synthesis efficiency is increased, and the cost is lowered.

Description

Technical field [0001] The invention relates to a preparation method of sitagliptin intermediate, sitagliptin or its phosphate. Background technique [0002] Sitagliptin phosphate is the first dipeptidyl peptidase-IV (DPP-4) inhibitor approved by the FDA in 2006. Its chemical structure is shown in the chemical formula (I): [0003] [0004] It is used for the treatment of type II diabetes. It has obvious hypoglycemic effect when used alone or in combination with metformin and pioglitazone. It is safe to take, well tolerated, and has few adverse reactions. Sitagliptin phosphate was developed by Merck and was approved by the Mexican Ministry of Health on August 8, 2006 to treat type II diabetes as a once-a-day medication. The marketed product is Januvia. In the United States, sitagliptin phosphate was approved by the FDA on October 16, 2006. Sitagliptin phosphate has been approved for use in 60 countries around the world, and its revenue in the third quarter of 2007 alone was US$18...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
IPC IPC(8): C07C233/47C07C231/12C07D487/04
Inventor 潘仙华张群辉
Owner ZHEJIANG HISOAR PHARMA
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap