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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
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  • 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 of Merck, using a chiral rhodium catalyst to construct a chiral center by asymmetric catalytic hydrogenation of enamines. The synthetic route is brief and the steps are relatively short, but the method requires expensive Catalysts and chiral auxiliaries, and this method also has an amplification effect in industrialization, resulting in unstable product quality

Method used

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  • 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.

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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

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Application Information

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IPC IPC(8): C07C233/47C07C231/12C07D487/04
Inventor 潘仙华张群辉
Owner ZHEJIANG HISOAR PHARMA
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