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Method for preparing compound Lifitegrast

A compound and catalyst technology, applied in the field of preparation of the compound Lifitegrast, can solve the problems of low purity of Lifitegrast, unsuitable for industrial production, low synthesis efficiency, etc., and achieve the effects of improving the total reaction yield, being suitable for industrial production, and improving quality and safety.

Inactive Publication Date: 2020-06-16
SUZHOU VIGONVITA LIFE SCIENCES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The above synthetic routes were published by the original research company SARcode Bioscience Inc. The two routes are common reactions in terms of the reactions involved, but the above preparation methods have the following problems: 1. The key intermediates need to be protected by protecting groups (such as intermediate A , B, C, D, E, F, H), followed by deprotection, repeated protection and deprotection, resulting in lengthy reaction steps, low synthesis efficiency, high cost, not suitable for industrial production
2. The reaction yield of some reaction steps is low. For example, in the step of preparing compound B from compound A, the highest reaction yield can only reach 70%, and the reaction yield needs to be improved urgently
3. The reaction raw materials are more expensive
4. The purity of the product Lifitegrast is low. Since the structure of compound H and the final product are very close, it is difficult to separate the two. The highest purity of the product is only 97%. The existence of residual impurities will greatly affect the quality of the drug, the stability and safety of the drug sex cannot be guaranteed

Method used

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  • Method for preparing compound Lifitegrast
  • Method for preparing compound Lifitegrast
  • Method for preparing compound Lifitegrast

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Example 1: Preparation of intermediate IV (benzofuran-6-carbonyl chloride).

[0054] Weigh the raw material I (benzofuran-6-carboxylic acid) (1eq) and triphosgene (0.5eq) into the reaction flask, add toluene (10 times the volume) into the flask, and add a catalytic amount of DMF dropwise at room temperature. The temperature of the liquid is raised to 60-70°C for about 4-6 hours, the raw materials are basically reacted (less than 2%), the feed liquid is concentrated to a small volume to obtain a solid, and the toluene is entrained once, which is directly used in the next step reaction (dissolved in dry THF, to be with), crude product yield: 96%.

Embodiment 2

[0055] Example 2: Preparation of intermediate V (2-(benzofuran-6-formyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid).

[0056] Weigh the raw material II (1.1eq, relative to the raw material I in the previous step), add DIEA (2.2eq) into the reaction bottle, add anhydrous THF (5 times the volume) into the bottle, stir for 0.5-1h, and control the temperature below 20°C. Add the intermediate IV (THF solution) in the previous step dropwise. After the addition is complete, stir at room temperature for 4 to 6 hours. The intermediate control reaction is basically complete. Quench with an appropriate amount of methanol. Heat and stir for about 0.5 hours. Concentrate the material to a small volume and add isopropanol. Adjust the pH to 3-4 with 1N dilute hydrochloric acid; the solid precipitated out, and the solid was filtered and purified with ethanol to obtain intermediate V with a yield of 83% and a purity of 99%.

[0057] 1 HNMR (DMSO-d 6 ,400MHz)δ:3.33(m,2H),3....

Embodiment 3

[0058] Example 3: Lifitegrast ((S)-2-[2-(benzofuran-6-formyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-methan Amino]-3-(3-methylsulfonylphenyl)propionic acid) preparation.

[0059] Weigh the intermediate V (1eq) obtained in the previous step, add HATU (1.1eq) into the reaction flask, add THF (10 times the volume) into the flask, stir, control the temperature below 20°C, and add DIEA (3.1eq) dropwise , the feed liquid was kept warm for 1 hour, the system was dissolved first, then heated to 30°C, and the reaction was continued for 15 hours, the raw material V basically reacted completely, and H was added to the feed liquid. 2 O (10 times the volume), stir, add raw material III (1.1eq) in batches, after the addition is complete, react the feed solution below 10°C for about 15 minutes, then slowly raise the temperature to about 30°C, stir and react for 15h, the reaction solution dissolves, and the middle The basic reaction of state VI is complete. Under the ice-water bath, a...

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Abstract

The invention provides a method for preparing a compound Lifitegrast. The method comprises the following steps of under the action of an alkali, carrying out a reaction on a compound V and HATU to generate a compound VI, optionally separating out the compound VI, reacting the compound VI with a compound III, and after the reaction is finished, carrying out post-treatment to obtain the compound Lifitegrast, wherein the reaction equation is defined in the specification. According to the invention, reaction raw materials adopted by the preparation method do not need to be subjected to protectionand deprotection steps, so that the preparation method is short in reaction route, high in reaction efficiency, low in price of the reaction raw materials and suitable for industrial production; and the single-step yield of the reaction is 80% or above, the total yield of the reaction is remarkably increased, and the product purity is 99% or above.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a preparation method of the compound Lifitegrast. Background technique [0002] Dry eye disease (DED), also known as keratoconjunctival sicca, refers to abnormal tear quality or quantity or abnormal dynamics caused by any reason, resulting in decreased tear film stability, accompanied by ocular discomfort and (or ) is a general term for various diseases characterized by ocular surface tissue lesions. It is currently the most common ocular surface disease, and the main treatment is the use of artificial tear moistening, in addition to anti-inflammatory and sex hormone therapy, including the administration of drugs for the relief of DED symptoms, such as carbomer eye drops / Ophthalmic gel, compound chondroitin sulfate eye drops, sodium hyaluronate eye drops, sodium carboxymethylcellulose eye drops, artificial tear preparations, cyclosporine A and androgen preparations, etc., only ...

Claims

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Application Information

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IPC IPC(8): C07D405/06
CPCC07D405/06C07D405/00C07D405/02
Inventor 田广辉曹标吴建忠朱杭杭杨学兵
Owner SUZHOU VIGONVITA LIFE SCIENCES CO LTD
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