TMC-205, one-pot synthesis method and application

A technology of TMC-205 and synthesis method, which is applied in the direction of drug combination, organic chemistry, antineoplastic drugs, etc., can solve the problems of poor atom economy, low total yield, cumbersome steps, etc., to improve atom economy and save The effect of low time and preparation cost

Pending Publication Date: 2022-07-29
DALI UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0014] There are certain limitations in the existing route, such as demanding reaction conditions (strong acid and strong base, etc.) and expensive and toxic reagents (Pd(PPh 3 ) 4 , Cs 2 CO 3 etc.), etc., the steps are cumbersome, the total yield is low, and the atom economy is not good
[0015] Through the above analysis, the problems and defects in the prior art are: the harsh reaction conditions (strong acid and strong base, etc.) and expensive and toxic reagents (Pd(PPh, etc.) 3 ) 4 , Cs 2 CO 3 etc.), etc., the steps are cumbersome, the total yield is low, and the atom economy is not good

Method used

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  • TMC-205, one-pot synthesis method and application
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  • TMC-205, one-pot synthesis method and application

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preparation example Construction

[0052] like figure 1 As shown, the one-pot synthesis method of TMC-205 provided in the embodiment of the present invention comprises:

[0053] S101, by Friedel-Crafts acylation with 6-bromoindole and trifluoroacetic anhydride, and introduce trifluoroacetyl at the 3-position of the indole ring to obtain compound A;

[0054] S102, compound A and 2-methyl-3-butene-2-ol undergo Heck reaction under the participation of a palladium catalyst to obtain an intermediate;

[0055] S103, the intermediate introduced into the isoprene group undergoes a hydrolysis reaction to hydrolyze the three trifluoroacetyl groups into carboxyl groups to obtain TMC-205.

[0056] The one-pot synthesis method of TMC-205 provided in the embodiment of the present invention comprises the following steps:

[0057] (1) Add 0.51 g of 6-bromoindole into the reaction flask under magnetic stirring and nitrogen protection, add 8.7 mL of DMF to dissolve, place the reaction flask in an ice bath and stir for half an ...

Embodiment 1

[0077]

[0078] The synthetic route of the present invention uses cheap 6-bromoindole (1) and trifluoroacetic anhydride to introduce a trifluoroacetyl group at the 3-position of the indole ring through Friedel-Crafts acylation to obtain compound (2), which is then combined with 2-methyl-3 -Buten-2-ol undergoes a Heck reaction with the participation of a palladium catalyst to obtain an intermediate. The intermediate that has been introduced isoprene group undergoes hydrolysis reaction to hydrolyze the three trifluoroacetyl groups into carboxyl groups, which can be 78% in one step. Compound (3) is obtained in good yield, saving time and labor. The route of the present invention avoids toxic reagents (Pd(PPh) 3 ) 4 , Cs 2 CO 3 etc.), dangerous strong base reagents, highly flammable reagents, etc., the synthesis process is simple, the operation is simple and the synthesis raw materials are readily available, the preparation cost is low, the yield is high, and the atom econom...

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Abstract

The invention belongs to the technical field of compound synthesis and preparation, and discloses TMC-205, a one-pot synthesis method and application, 6-bromoindole and trifluoroacetic anhydride are subjected to Friedel-Crafts acylation to introduce trifluoroacetyl at the 3-site of an indole ring to obtain a compound A; carrying out Heck reaction on the compound A and 2-methyl-3-butene-2-alcohol in the presence of a palladium catalyst to obtain an intermediate; and carrying out hydrolysis reaction on the intermediate into which the isoprene group is introduced to hydrolyze three-position trifluoroacetyl into carboxyl so as to obtain TMC-205. According to the synthesis method, toxic reagents (Pd (PPh3) 4, Cs2CO3 and the like), dangerous strong alkali reagents, highly flammable reagents and the like are avoided, the synthesis process is simple, operation is easy and convenient, synthesis raw materials are easy to obtain, the preparation cost is low, the yield is high, and atom economy is good. And time and labor can be saved through a one-pot method, and meanwhile, the total yield is also improved.

Description

technical field [0001] The invention belongs to the technical field of compound synthesis and preparation, in particular to a TMC-205, a one-pot synthesis method and application. Background technique [0002] Currently, in 2001, TMC-205 was isolated from the secondary metabolite of an unidentified fungal strain TC 1630 by Japanese scientists Masaaki Sakurai et al. antiproliferative activity of the cell line and also activates the SV40 promoter. Kazunori Koide's group first completed the total synthesis of TMC-205 in 2014. The synthetic route is shown in the figure: [0003] [0004] Synthetic route 1 [0005] [0006] In this synthetic route, Kazunori Koide's research group used 6-bromoindole as the starting material, and trifluoroacetic anhydride was acylated with trifluoroacetic anhydride to introduce a trifluoroacetyl group at the 3-position of the indole ring to obtain compound 2; Sodium is hydrolyzed, and after neutralization with hydrochloric acid, the triflu...

Claims

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Application Information

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IPC IPC(8): C07D209/42A61P35/00
CPCC07D209/42A61P35/00
Inventor江世智雷婷鹿贵东
OwnerDALI UNIV