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Preparation method of NK-1 receptor antagonist and intermediate thereof

A technology of -8-{, compounds, applied in the field of key intermediates and their preparation, can solve problems such as cost increase, unfavorable environmental protection, and process cost increase

Active Publication Date: 2015-11-04
QILU PHARMA HAINAN +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] CN1606545A discloses a preparation method of a compound of formula I, specifically the following route 1, the preparation method uses commercially available raw material phenylglycine as a starting raw material, and the compound of formula I is obtained after 17 steps of processing steps, and many of the methods Steps need to be separated or purified before being used in the next operation step, and the last step of the process needs to be separated by chiral preparative chromatography, which seriously restricts the scale of production
In route 3, it is necessary to use highly corrosive acids (such as hydrobromic acid, hydrofluoric acid, etc.) to remove the Cbz protecting group, resulting in a large amount of acidic wastewater and waste liquid, which is not conducive to environmental protection
In addition, the compound 27 in route 3 is prepared by the method of catalytic hydrogenation to the compound of formula I. In this reaction, the side reaction of 1-(1-methyl)-3,5-bis(trifluoromethyl)benzyl will be removed. reaction, introducing impurities into the product, reducing the yield of the process and increasing the cost
Simultaneously, this route has introduced R-1-(1-methyl)-3,5-bis(trifluoromethyl)benzyl at the beginning of the route, and the process cost will increase

Method used

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  • Preparation method of NK-1 receptor antagonist and intermediate thereof
  • Preparation method of NK-1 receptor antagonist and intermediate thereof
  • Preparation method of NK-1 receptor antagonist and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0100] Example 1 Preparation of the following formula (S)-1-(tert-butyldiphenylsilyloxy)-2-phenylbut-3-en-2-amine

[0101]

[0102] Weigh 2-hydroxyacetophenone (200.0g, 1.47mol), add 2000ml of dichloromethane and tert-butyldiphenylchlorosilane (445.3g, 1.62mol) successively, and make the temperature of the mixture drop to 0-10 ℃, add triethylamine (180.0g, 1.78mol) dropwise, after the dropwise addition, react at room temperature until the conversion of 2-hydroxyacetophenone is complete, add water for extraction, separate liquids to obtain an organic phase, add anhydrous sodium sulfate to dry, dry After the completion, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure to obtain an oil.

[0103] Add 5500ml of toluene to the obtained oil, and add tetraisopropyl titanate (829.7g, 2.94mol) and (R)-(+)-tert-butylsulfinamide (213.3g, 1.76mol) successively under stirring, The mixture was heated to 70-80°C to react. After the reaction was com...

Embodiment 2

[0108] Example 2 Preparation of the following formula (S)-1-benzyloxy-2-phenyl-but-3-en-2-amine

[0109]

[0110]Weigh 2-hydroxyacetophenone (150.0g, 1.10mol), add 1500ml tetrahydrofuran, stir and cool down to 0-5°C, and benzyl bromide (226.0g, 1.32mol), and stir to lower the temperature of the mixture to 0-5°C. 10°C, add sodium tert-butoxide (126.9g, 1.32mol), dropwise addition is complete, react until the conversion of 2-hydroxyacetophenone is complete, add 200ml of water, concentrate under reduced pressure to remove tetrahydrofuran, add 1000ml of dichloromethane for extraction, and separate The obtained organic phase was dried by adding anhydrous sodium sulfate. After drying, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure to obtain an oily substance.

[0111] Add 2000ml of toluene to the obtained oil, and add tetraisopropyl titanate (622.3g, 2.21mol) and (R)-(+)-tert-butylsulfinamide (200.4g, 1.65mol) successively under stirring,...

Embodiment 3

[0116] Example 3 Preparation of the following formula (S)-1-(4-chlorobenzoyl)oxy-2-phenyl-but-3-en-2-amine

[0117]

[0118] Weigh (R)-N-[(S)-1-(tert-butyldiphenylsilyloxy)-2-phenyl-but-3-en-2-yl prepared according to the method of Example 1 ]-2-methylpropyl-2-sulfenamide (10.1g, 0.02mol), add 100ml tetrahydrofuran, add tetrabutylammonium fluoride (10.5g, 0.04mol), stir the reaction, after the reaction, add water to extract , separated the organic phase, dried over anhydrous sodium sulfate, filtered off the desiccant after drying, cooled the filtrate to 0-5°C, added triethylamine (4.0g, 0.04mol), dropped p-chlorobenzoyl chloride (4.2 g, 0.024mol), after the reaction is complete, add purified water to extract, separate liquids, after the organic phase is dried over anhydrous sodium sulfate, filter the desiccant, and concentrate the filtrate under reduced pressure to obtain (R)-N-[(S) -1-(4-Chlorobenzoyloxy)-2-phenyl-but-3-en-2-yl]-2-methylpropyl-2-sulfinamide 6.33 g, yield ...

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Abstract

The invention relates to a preparation method of an NK-1 receptor antagonist and an intermediate thereof. The invention provides a preparation method of (5S, 8s)-8-{[1-(3, 5-bis-(trifluoromethyl)phenyl)-ethoxy]methyl}-8-phenyl-1, 7-diaza-spiro[4, 5]dec-2-one (formula I compound), which is prepared from a formula II compound, and also provides the formula II compound and a preparation method thereof. The method provided by the invention has the advantages of simple operation, mild reaction condition, high safety factor, little side reaction, high yield and high purity, lowers the production cost and operation risk, and is very suitable for large-scale industrial production. (formula II as shown in the specification).

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to an NK-1 receptor antagonist (5S,8S)-8-[{(1R)-1-[3,5-bis-(trifluoromethyl)phenyl] The preparation method of ethoxy}-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one also relates to the key intermediate in the method and the preparation method thereof. Background technique [0002] CN1606545A discloses a chemical name (5S,8S)-8-[{(1R)-1-[3,5-bis-(trifluoromethyl)phenyl]ethoxy}-methyl]-8 -The compound of phenyl-1,7-diaza-spiro[4.5]decan-2-one, whose structural formula is shown in formula I below, is neurokinin-1 (NK-1) receptor antagonist, can be used for Treats a variety of ailments including vomiting, depression, anxiety and coughing. [0003] [0004] At present, the preparation method about formula I compound mainly contains following three kinds: [0005] CN1606545A discloses a preparation method of a compound of formula I, specifically the following route 1, the prepar...

Claims

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Application Information

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IPC IPC(8): C07D471/10C07F7/18C07C217/48C07C219/22C07C213/02C07D207/26
CPCC07B53/00C07C45/64C07C67/14C07C213/02C07C217/48C07C313/06C07D207/26C07D471/10C07F7/1804C07F7/188C07C49/84C07C69/78C07C69/24C07C69/157
Inventor 田振平齐宪亮胡晓燕文东升高永宏李殿庆蒋自伟龙慎杰吴兆春范传文
Owner QILU PHARMA HAINAN
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