Preparation methods of himbacine analogue and intermediate thereof

A compound and a conversion technology, which are applied in the field of preparation of himbacine analogs and their intermediates, can solve the problems of unsuitability for industrial production, low yield and high risk

Active Publication Date: 2016-07-20
BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above-mentioned methods all have the following disadvantages: the reaction route is long, the total yield is low, and the reaction conditions are harsh, especially to obtain acid through amide or ester hydrolysis, and the reaction process of preparing aldehyde by carboxylic acid involves the preparation of acid chloride and acid chloride by carboxylic acid. Then aldehydes are obtained through palladium-carbon catalytic hydrogenation, which has low yield and poor operability, especially palladium-carbon catalytic hydrogenation needs to use anhydrous palladium carbon, which is dangerous when used and is not suitable for industrial production.

Method used

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  • Preparation methods of himbacine analogue and intermediate thereof
  • Preparation methods of himbacine analogue and intermediate thereof
  • Preparation methods of himbacine analogue and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0119] Example 1 : Preparation of compound 7

[0120]

[0121] Add 60 mL of tetrahydrofuran and 10 μL of concentrated sulfuric acid to a 1L three-necked flask in sequence, and then add the compound while stirring. 8 (10 g, 0.14 mol) and hexamethyldisilazane (11.5 g, 0.07 mol) were replaced by nitrogen three times, and heated to 60° C. for 3 h under reflux. Slowly cool the reaction solution to -40°C and add 272mL of tetrahydrofuran, add dropwise n-butyllithium (2.5M in n-hexane, 68.5mL, 0.17mol) at a temperature below -30°C, and then control the temperature at -30°C Next, a solution of chloromethyl benzyl ether (26.8 g, 0.17 mol) in toluene (110 mL) was added dropwise, and stirred for 1 h after the drop was completed. Quench the reaction with water (20 mL), filter, wash the filter cake with ethyl acetate and add to the filtrate, pull the filtrate to dryness and purify by column chromatography to obtain 20.4 g of light yellow liquid, yield: 75.25%. 1 HNMR (400MHz, CDCl 3...

Embodiment 2

[0122] Example 2 : Preparation of compound 6

[0123]

[0124] Add compounds sequentially to a 500mL three-necked bottle 7 (19g, 0.1mol), Lindlar catalyst (5%Pb poisoning, 1.9g5%Pd / CaCO 3 , 0.018mol) and ethyl acetate 380mL, after nitrogen replacement three times and hydrogen replacement three times, stir at 25°C under normal pressure for 5h. The catalyst was removed by filtration, the filter cake was washed with ethyl acetate and then added to the filtrate, and the filtrate was pulled to dryness to obtain 18.4 g of light yellow liquid, yield: 95.83%. MS[M+H] + :193.

Embodiment 3

[0125] Example 3: Preparation of Compound 4

[0126]

[0127] In the 250mL three-necked bottle, add the compound in sequence 5 (10g, 0.05mol) and 50mL of toluene, the suspension was cooled to 0°C, and slowly added N-methylmorpholine (10.5g, 0.10mol) and trimethylacetyl chloride (6g, 0.05mol ) in toluene (25mL), and stirred at 0°C for 1h after the drop was completed. Slowly add compound under temperature control below 5°C 6 (9.6g, 0.05mol) in toluene (40mL) and tetrahydrofuran (22mL) solution, then add 4-dimethylaminopyridine (0.61g, 0.005mol) in tetrahydrofuran (6mL) solution, stir the mixture at about 0°C for 12h . After the reaction is complete, add 4NH 2 SO 4 (25mL) solution to quench the reaction, raise the temperature to no more than 25°C and stir for 1h, filter, wash the filter cake three times with ethyl acetate, separate the layers, extract the aqueous layer with ethyl acetate (2*25mL) and merge it into the organic layer, organic layer by layer with 5% K 2 ...

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Abstract

The invention provides preparation methods of a himbacine analogue and intermediates thereof. The invention specifically provides novel preparation methods of a compound A, a compound 4, a compound D and a compound C. According to the invention, a scheme for preparing the compound A does not require a process for reducing carboxylic acid into aldehyde, but directly oxidizing corresponding alcohol into corresponding aldehyde. The operation is safe. In prior arts, carboxylic acid is first converted into acyl chloride, and acyl chloride is catalytically hydrogenated into aldehyde with a palladium catalyst. In the above process, anhydrous palladium-carbon is needed. With the methods provided by the invention, the above harsh condition is avoided. The preparation methods are simple, and operation steps are easy. Especially, when a hydroxyl group protection group P is benzyl group, nitro group can be reduced into amino group when the protection group P is removed. Therefore, the reaction steps are greatly simplified, and raw materials and agents are saved. The entire route has the advantages of low production cost and high yield, and is suitable for industrialized production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of a himbacine analogue and an intermediate thereof. . Background technique [0002] The patent with the authorized announcement number CN1659162B (incorporated in the present invention by reference in its entirety) discloses a hibaxin analogue with thrombin receptor antagonism, the structure of which is shown in the following formula compound C: [0003] , [0004] Compound C has the ability to treat thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, heart choking, glomerulonephritis, thrombotic stroke, peripheral vascular disease, cerebral ischemia, cancer etc. (see WO03089428). On May 8, 2014, the FDA approved the listing of the sulfate salt of compound C, which is mainly used for patients with a history of heart attack and patients with lower extremity arterial embolism. [0005] Compound A of the fo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/92C07D405/06C07C205/55C07C201/12C07F7/18
CPCC07C201/12C07C205/55C07D307/92C07D405/06C07F7/18Y02P20/55
Inventor 袁建栋陈耀孙启阳杭文明
Owner BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD
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