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Preparation method of sitagliptin intermediate, sitagliptin or salts thereof

A sitagliptin and intermediate technology, applied in the preparation of organic compounds, carboxylic acid amide preparation, chemical instruments and methods, etc., can solve the problems of unstable product quality, amplification effect, high cost, etc., and avoid low synthesis efficiency Effect

Active Publication Date: 2015-04-15
ZHEJIANG HISOAR PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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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) In a 250 ml round bottom flask, add (3R)-3 tert-butoxycarbonylamino-4-hydroxy- Methyl butyrate (IX) (23.3g, 0.1mol) and 150ml of dichloromethane, then triphenylphosphine (26.2g, 0.1mol) was added, and bromine (17.6g, 0.11mol) was added dropwise at room temperature. Drip in ten minutes. After the dropwise addition was completed, continue to stir for 3 hours, quench the reaction with 10% aqueous sodium bisulfite solution, separate the liquids, wash the organic phase with saturated brine, dry, filter, and concentrate to obtain the crude product, which is then distilled under reduced pressure to obtain the product (26g, 0.088mol ), the yield was 88%. 1 H NMR (300MHz, CDCl 3 )1.48(9H,s),2.67(1H,d,J=6.4and16.5),2.80(1H,dd,J=5.5and16.5),3.22(2H,br),3.78(3H,s), 5.00(1H,m), and 5.40(1H,br); ESI-MS m / z296.2(M+H) + .

Embodiment 2

[0047] Preparation of 2,4,5-trifluorophenylboronic acid (III) In a 250ml three-necked flask, add magnesium bars (3.96g, 0.165mol) with a smooth surface and a small grain of iodine, 2,4,5-trifluorobromide Dilute Benzene (II) (31.5g, 0.15mol) with 60ml of anhydrous ether, add a small amount dropwise to initiate the reaction, then add the remaining ether solution dropwise into the reaction bottle, keep the dropping rate at the same rate as the reflux rate, and heat reflow. After 4 hours, the magnesium bar basically reacted. In another 500 milliliter three-necked flask, add trimethyl borate (15.6 g, 0.15 mol) and 150 milliliters of anhydrous tetrahydrofuran, under nitrogen protection, cool to-78 ℃, the prepared Grignard reagent is added dropwise to rapid Stirred trimethyl borate solution. After incubating at -78°C for 1 hour, it naturally rose to room temperature, added 150 ml of water and 150 ml of 20% citric acid, and stirred for 1 hour. The tetrahydrofuran was evaporated, ex...

Embodiment 3

[0049] Preparation of (3R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)-butyric acid methyl ester (V)

[0050] 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), 1,4-dioxane 100ml. 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 layers, wash the organic phase with 10% dilute hydrochloric acid, then wash with saturated brine, dry, filter, concentrate to obtain the crude product, and recrystallize from toluene to obtain White solid (13g, 0.0375mol), yield 75%. Compound Physicochemical Data and Literature [1] consistent with that 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 chemical formula (I): [0003] [0004] For the treatment of type Ⅱ diabetes, it has obvious hypoglycemic effect when used alone or in combination with metformin and pioglitazone, and 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 for the treatment of type 2 diabetes once a day. 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 the revenue in the third quarter of 2007 alone was 185 million...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C233/47C07C231/12C07D487/04
Inventor 潘仙华张群辉
Owner ZHEJIANG HISOAR PHARMA
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