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Method for synthesizing letemovir intermediate

A synthesis method and intermediate technology, applied in the field of organic chemical synthesis, can solve the problems of being unsuitable for industrial scale-up production, high potential safety hazards and high production costs, and achieve the effects of low material cost, better effect and easy production.

Pending Publication Date: 2022-04-08
RAFFLES PHAMRMATECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] In order to solve the above-mentioned problems such as large potential safety hazards, high production costs, and unsuitability for industrialized scale-up production in the process of preparing Letermovir, the present invention proposes a new method for preparing Letermovir intermediates

Method used

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  • Method for synthesizing letemovir intermediate
  • Method for synthesizing letemovir intermediate
  • Method for synthesizing letemovir intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] 1), add 4-bromoanisole (0.5g), 1-tert-butoxycarbonylpiperazine (1.2eq, 0.6g) in the reaction flask

[0025] and DMSO (3mL);

[0026] 2), then add potassium tert-butoxide (1.5eq, 0.45g);

[0027] 3), heated to 115°C under nitrogen protection for 20h;

[0028] 4), the purity of the reaction solution monitored by HPLC was 61.87%.

Embodiment 2

[0042] Using the organic solvent as a single variable, adopt the method in Example 1 to prepare the Letermovir intermediate, and finally measure and calculate the reaction conversion rate, and the results obtained are as follows:

[0043]

[0044] From the results, the best organic solvent is DMSO, which has a higher conversion rate than tetrahydrofuran and isopropanol.

[0045] In addition, it is found through experiments that the stirring effect of the solvent with an organic solvent dosage of 2-4 vol is poor; the effect of 6-10 vol is better.

Embodiment 3

[0047] With alkali as a single variable, the method in Example 1 is used to prepare the Letermovir intermediate, and finally the reaction conversion rate is measured and calculated, and the results obtained are as follows:

[0048]

[0049]

[0050] It can be seen that the best strong base is potassium tert-butoxide. Although n-butyllithium is more basic than potassium tert-butoxide, its nucleophilicity may be unfavorable to the reaction, but even if its nucleophilicity may be unfavorable to the reaction, Under the condition of not adding copper catalyst, the conversion rate is also higher than the upper limit value of 26% with copper catalyst.

[0051] In addition, comparing the n-butyllithium+copper catalyst method used in Comparative Example 1 with the n-butyllithium used in this example, it can be seen that the copper catalyst is not conducive to conversion.

[0052] The consumption of different alkalis, the conversion rate that obtains is as follows:

[0053]

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Abstract

The invention relates to a method for synthesizing a letemovir intermediate, belongs to the field of organic chemical synthesis, and provides a novel method for preparing the letemovir intermediate in order to mainly solve the problems of large potential safety hazard, high production cost, unsuitability for industrial large-scale production, low conversion rate and the like. Comprising the following steps: 1) adding 4-fluoroanisole or 4-bromoanisole, 1-t-butyloxycarbonyl piperazine and an organic solvent into a reaction flask; 2) adding strong base; 3) reacting for 20 hours at 95-150 DEG C under the protection of nitrogen; and 4) observing the reaction degree through HPLC. Compared with the prior art (palladium catalytic coupling), the technical scheme provided by the invention is better in safety and lower in cost; according to the scheme provided by the invention, no copper salt is used for catalysis in the preparation process, the reaction effect is better only under a strong alkali condition, and the reaction conversion rate is increased to 62% at present from 0-26% when a copper catalyst is used.

Description

technical field [0001] The invention belongs to the field of organic chemical synthesis, and in particular relates to a method for synthesizing a key intermediate of Letermovir. Background technique [0002] Letermovir (English name: Letermovir), the chemical structural formula is as follows: [0003] [0004] The drug is a novel non-nucleoside CMV inhibitor (3,4-dihydroquinazoline) that inhibits viral replication by specifically targeting the viral terminator enzyme complex. It is currently being developed for the prophylaxis of cytomegalovirus (CMV) infection for the prevention of CMV infection and related diseases in adult patients who are seropositive for cytomegalovirus (CMV) after undergoing allogeneic hematopoietic stem cell transplantation (HSCT). [0005] tert-butyl 4-(3-methoxyphenyl)piperazine-1-carboxylate is the key intermediate of Letermovir, the English name is tert-butyl 4-(3-methoxylphenyl)piperazine-1-carboxylate, its specific The structure is as follo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/205
Inventor 叶伟平费安杰周章涛肖诗华王道功冯兰兵庞斌蹇锋
Owner RAFFLES PHAMRMATECH CO LTD
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