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Ezetimibe intermediate and preparation method of ezetimibe

A compound and catalyst technology, applied in the field of preparation of ezetimibe intermediates and ezetimibe, can solve the problems of potential safety hazards, low asymmetric conversion rate, etc.

Active Publication Date: 2022-04-15
ENANTIOTECH CORP +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The above-mentioned methods are all by first synthesizing the nitrogen-containing four-membered ring, and then obtaining the hydroxyl group of the required configuration by reduction reaction. The asymmetric conversion rate of this method is low, and in mass production, sodium borohydride, borane reagents There are security risks in the large-scale use of

Method used

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  • Ezetimibe intermediate and preparation method of ezetimibe
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  • Ezetimibe intermediate and preparation method of ezetimibe

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preparation example Construction

[0046] The preparation method of the compound shown in the formula (I) of one embodiment of the present invention, comprises the following steps:

[0047] S101: providing a compound represented by formula (II);

[0048]

[0049] Among them, the compound represented by formula (II) can be commercially available raw materials, or prepared by existing methods, which are not particularly limited here, and should be understood as being within the protection scope of the present invention.

[0050] Further, S101 includes the following steps:

[0051]

[0052] S1011: providing a compound represented by formula (III);

[0053] S1012: Condensing the compound represented by formula (III) and the compound represented by formula (IV) to obtain the compound represented by formula (II);

[0054] Wherein, in step S1012, existing condensation reaction reagents, such as DDC / DMAP, can be used.

[0055] In one embodiment, in step S1012, the compound represented by the formula (III) is f...

Embodiment 1

[0099] (1) Add 200g of the compound represented by formula (III) into 2.5L of dichloromethane, cool to -10°C, slowly add 220mL of oxalyl chloride dropwise, after the dropwise addition is completed, stir for 30min, rise to room temperature for reaction, and wait until the reaction is complete After concentrating to obtain the crude product, the crude product was dissolved in 500 mL of toluene to obtain the first solution; 2.5 L of toluene, 170g and 265mL of triethylamine were mixed to obtain the second solution; the first solution was slowly dripped into the second solution, and after the addition was completed, it was reacted at 75°C. The solution was washed, the organic phase was concentrated, and recrystallized with isopropanol to obtain the compound represented by formula (II).

[0100] (2) In a 5L autoclave, under an argon atmosphere, add 100g of the compound shown in formula (II) from the feeding port, then add 1L of toluene to fully dissolve the raw material, continue t...

Embodiment 2

[0102] In a 5L autoclave, under an argon atmosphere, add 100g of the compound represented by the formula (II) through the feeding port, then add 1L of toluene to fully dissolve the raw material, continue bubbling with argon for degassing, and continue bubbling for 1h , the degassing is completed. Under argon atmosphere, add the structure catalyst shown in 0.1g formula (C) ( n is 50), finally add 10g of potassium tert-butoxide, after the feeding is finished, close the feeding port quickly. Replace the argon with hydrogen, slowly introduce hydrogen to 4MPa, and close the inflation valve. The rapidly stirred reaction was carried out at 30-40°C. When the pressure drops to 1-2 MPa, the hydrogen pressure is added back to 4 atm, and the reaction is considered to be stopped when the pressure drops to a constant value. Sampling was sent for liquid phase analysis to confirm the conversion rate. The catalyst was removed, and the filtrate was washed successively with 0.3 L of water a...

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Abstract

The present invention relates to the preparation method of ezetimibe intermediate and ezetimibe, wherein, ezetimibe intermediate has the structure of the compound shown in formula (I), and its preparation method comprises the following steps: providing formula ( Compound shown in II); adopt P-BIAMH catalyst to carry out asymmetric catalytic hydrogenation reaction to the compound shown in formula (II), make the compound shown in formula (I), wherein, P-BIAMH catalyst has the structure shown in formula (A) : X, Y are each independently halogen; R 1 for H or C 1‑9 Alkyl; R 2 It is a high molecular weight polymer; it means a double phosphorus ligand. The above method has high conversion rate and high safety, and is especially suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to an ezetimibe intermediate and a preparation method of ezetimibe. Background technique [0002] Ezetimibe, also known as ezetimibe, chemical name 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-( The structure of 4S)-(4-hydroxyphenyl)-2-azetidinone is shown below. The new cholesterol absorption inhibitor jointly developed by Schering-Plough and Merck was approved by the FDA in October 2002. It is a new type of cholesterol absorption inhibitor with excellent pharmacological activity and safety. It is a traditional Chinese medicine in the field of blood lipid regulation. A relatively new category. Clinically, when used alone, it can reduce low-level lipoprotein cholesterol (LDL-C), total cholesterol can also be significantly reduced, and high-density lipoprotein (HDL-C) can be increased; combined with statins can reduce the use of high doses of statins ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D263/26B01J31/24C07D205/08
CPCC07D263/26B01J31/2409C07D205/08B01J2531/821B01J2231/643B01J2531/0258
Inventor 毛波蒙发明李彦雄胡骆祥孔彦智
Owner ENANTIOTECH CORP
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