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Method for preparing retegravir intermediate by using continuous flow reactor

A technology of remdesivir and intermediates, which is applied in the field of remdesivir synthesis, can solve problems such as difficult reaction conditions, unfavorable pilot production, and low reaction yield, and achieve precise control of reaction conditions, shortened reaction time, and reduced The effect of production costs

Pending Publication Date: 2021-02-12
SHANGHAI PUYI CHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This step reaction is one of the key steps in the process route of Remdesivir. Due to the complex mechanism and the use of multiple metal reagents at low temperature, it is difficult to accurately control the reaction conditions in the traditional kettle reaction method, resulting in a low reaction yield. , only 40%; at the same time, due to the low temperature reaction involved, it is difficult to enlarge the reaction parameters of the small test, which is not conducive to the pilot production

Method used

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  • Method for preparing retegravir intermediate by using continuous flow reactor
  • Method for preparing retegravir intermediate by using continuous flow reactor
  • Method for preparing retegravir intermediate by using continuous flow reactor

Examples

Experimental program
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Effect test

Embodiment 1

[0037]

[0038] 1. Flow path 1: Add 120g of 7-iodopyrrole[2,1-f][1,2,4]triaza-4-amine 1-1 into 2600mL tetrahydrofuran, cool down to -5~- At 10°C, add 260g of phenylmagnesium chloride dropwise, finish adding in 30 minutes, keep warm for 30 minutes, add 55g of trimethylchlorosilane dropwise, stir for 60 minutes, then add 260g of phenylmagnesium chloride to form a solution of about 0.14mol / L , as a backup channel 1.

[0039] 2. Flow path 2: Dilute 500 mL of 1.2 mol / L isopropylmagnesium chloride lithium chloride solution with 400 mL of anhydrous THF to prepare a solution of about 0.72 mol / L, which is used as flow path 2 for later use.

[0040] 3. Flow path 3: Add 240g of (3R,4R,5R)-3,4-dibenzyl-5-(benzylmethyl)dihydrofuran-2(3H)-one 1-3 to 1100mL In the tetrahydrofuran solution of neodymium trichloride (0.58mol / L), stir and dissolve and add 200mL of tetrahydrofuran to form a tetrahydrofuran solution, which is used as the flow path 3 for later use.

[0041] 4. Connect the reac...

Embodiment 2

[0050]

[0051] 1. Flow path 1: Add 75.6g of 7-bromopyrrole[2,1-f][1,2,4]triaza-4-amine 2-1 into 2000mL tetrahydrofuran, cool down to -15~ -20°C, add 200g of phenylmagnesium chloride dropwise, finish adding in 30 minutes, keep warm for 30 minutes, add 42.3g of trimethylchlorosilane dropwise, stir for 60 minutes, then add 200g of phenylmagnesium chloride, and configure it to about 0.14mol / L solution, as solution A.

[0052] Dilute 400 mL of a 1.2 mol / L ethylmagnesium bromide lithium chloride solution with 267 mL of anhydrous THF to prepare a solution of about 0.72 mol / L as solution B.

[0053] Keep at -15~-20°C, slowly drop solution B into solution A, stir for 60 minutes, and use it as flow path 1 for later use.

[0054] 2. Flow path 2: Add 184.6g of (3R,4R,5R)-3,4-dibenzyl-5-(benzylmethyl)dihydrofuran-2(3H)-one 1-3 to 846mL lanthanum trichloride tetrahydrofuran solution (0.58mol / L), stirring and dissolving and adding 154mL tetrahydrofuran to configure a tetrahydrofuran so...

Embodiment 3

[0064]

[0065] 1. Flow path 1: Add 100g of pyrrole[2,1-f][1,2,4]triaza-4-amine 1-1 into 1500mL tetrahydrofuran, cool down to -5~0℃, add 86.5 g tetramethylethylenediamine, slowly dropwise add 81 g of trimethylchlorosilane, stir for 60 minutes, and use it as flow path 1 for later use.

[0066] 2. Flow path 2: 1000 mL of 2.5 mol / L n-butyllithium tetrahydrofuran solution is used as flow path 2 for standby.

[0067] 3. Flow path 3: Add 312g of (3R,4R,5R)-3,4-dibenzyl-5-(benzylmethyl)dihydrofuran-2(3H)-one 1-3 to 1435mL In a tetrahydrofuran solution of neodymium trichloride (0.52 mol / L), stir at 20-25° C. for 60 minutes, and use it as flow path 3 for later use.

[0068] 4. Connect the reactor pipeline, such as image 3 shown. Connect flow path 1 and flow path 2 to reaction module 1, set temperature zone 1, as a negative ion module; connect the outlet of module 1 and flow path 3 to reaction module 1, set temperature zone 2, as a coupling reaction module.

[0069] 5. Set the t...

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Abstract

The invention provides a method for preparing a retegravir intermediate (3R, 4R, 5R) 2 (4aminopyrrole [2, 1f] [1, 2, 4] triaza7yl) 3, 4dibenzyl 5benzyl methyl) tetrahydrofuran diol (I) by using a continuous flow reactor. The method comprises the following steps: taking a prepared negative ion solution of an intermediate pyrrole [2,1-f] [1, 2, 4] triaza4amine (III) as a material 1, taking a mixed solution of (3R, 4R, 5R) 3, 4-dibenzyl-5-(benzyl methyl) dihydrofuran-2(3H)-ketone (II), a catalyst and a solvent as a material 2, and reacting through a continuous flow reactor to synthesize a compound (I) at -20 to 0 DEG C for 50-150 seconds. the negative ion solution of the intermediate pyrrole [2,1-f] [1, 2, 4] triaza-4amine (III) is prepared by taking 7halogenated pyrrole [2,1-f] [1, 2, 4] triaza-4-amine or pyrrole [2,1-f] [1, 2, 4] triaza-4amine (IV) as a raw material and enabling the raw material, a metal reagent and the like to pass through a kettle type or continuous flow reactor. Compared with an existing conventional tank reactor, the process is short in reaction time and small in liquid holding volume, the temperature of a low-temperature reaction is increased, energy consumption is reduced, the safety of the reaction is also improved, and continuous automatic control is facilitated.

Description

technical field [0001] The present invention relates to the technical field of remdesivir synthesis, more specifically, to the intermediate (3R,4R,5R)-2-(4-aminopyrrole[2,1-f][1,2,4]triaza -7-yl)-3,4-dibenzyl-5-benzylmethyl)tetrahydrofuran-2-ol (I) technical field. Background technique [0002] Remdesivir is an antiviral drug developed by Gilead Sciences of the United States, code-named GS5742, which was first used to prevent and treat Ebola virus infection. In the context of the global outbreak of the new crown virus in 2020, the US FDA first approved the emergency use of Remdesivir, and then officially approved the marketing of Remdesivir in October 2020. [0003] [0004] The synthesis method of Remdesivir was first developed by Gilead, and generally consists of two fragments spliced ​​together. Intermediate 1, namely GS-441524, is a specific drug for the treatment of feline infectious peritonitis (celiac disease). Remdesivir can be obtained by reacting with phosphol...

Claims

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Application Information

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IPC IPC(8): C07H7/06C07H1/00C07D487/04C07F7/10
CPCC07H7/06C07H1/00C07D487/04C07F7/10C07B2200/07
Inventor 祁彥涛李涛屠长刚王博
Owner SHANGHAI PUYI CHEM CO LTD
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