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Preparation method of dolutegravir ring-opening impurities, and impurities thereof

A dolutegravir and impurity technology, which is applied in the field of preparation of dolutegravir ring-opening impurities, can solve problems such as difficult separation and extraction, undisclosed preparation methods of impurity A and impurity B, and achieve good yield, easy research, and reaction conditions simple effect

Inactive Publication Date: 2020-01-07
ANHUI BIOCHEM BIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Because it is speculated that impurity A is generated by heating under acidic conditions, the applicant tried to use dolutegravir to reflux and degrade it in 6N hydrochloric acid aqueous solution. After 6 hours of reaction, the reaction solution was identified by LC-MS, and only a trace amount of impurity A was still generated, and Mixed with other impurities, it is difficult to separate and extract; and the prior art does not disclose the preparation method of impurity A and impurity B

Method used

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  • Preparation method of dolutegravir ring-opening impurities, and impurities thereof
  • Preparation method of dolutegravir ring-opening impurities, and impurities thereof
  • Preparation method of dolutegravir ring-opening impurities, and impurities thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0049] refer to figure 1 , taking the preferred raw materials to synthesize dolutegravir ring-opening impurity A and impurity B as an example, the synthesis principle is as follows:

[0050] The first step: compound 1 and compound 2 react to generate compound 3

[0051] Using dichloromethane as a solvent and N,N-dicarbonylimidazole (CDI) as a condensation reagent, compound 1 and compound 2 undergo a condensation reaction at room temperature. Wash with saturated brine, evaporate the organic phase to dryness under reduced pressure, and refine Compound 3. The purification uses silica gel column chromatography, and the eluent uses n-hexane:ethyl acetate=3:1; the reaction equation is as follows:

[0052]

[0053] Step 2: Compound 3 is hydrolyzed to generate Compound 4

[0054] Stir and mix ethanol and compound 3, add 2N aqueous sodium hydroxide solution for hydrolysis reaction, adjust the pH to 3-4 with 6N aqueous hydrochloric acid solution at the end of the reaction, spin dry...

Embodiment 2

[0072] Compound 1 is condensed with compound 2 to generate compound 3:

[0073]

[0074] Compound 1 (20.0 g, 63.4 mmol) and dichloromethane (150 mL) were added into the reaction flask, and stirred at room temperature to dissolve. Cool down to 15-20°C, add N,N-carbonyldiimidazole (13.9 g, 85.7 mmol), and keep the reaction for 2 hours under the protection of nitrogen. Compound 2 (10.0 g, 69.9 mmol) was added dropwise, and the reaction was carried out at room temperature for 2 hours after the drop was completed. The reaction solution was washed successively with 1N aqueous HCl (100 mL), 5% aqueous sodium carbonate (130 mL), and saturated brine (100 mL). The organic phase was concentrated to dryness, and the obtained oil was separated by column chromatography [mobile phase: n-hexane: ethyl acetate (2:1)] to obtain compound 3 (18.9 g, 68%) as a white solid powder.

[0075] The proton nuclear magnetic spectrum of the obtained compound 3 sees figure 2 , and its H NMR and mass ...

Embodiment 3

[0077] Compound 3 prepared in Example 2 of the present invention was hydrolyzed under alkaline conditions to generate compound 4, and compound 4 was condensed with compound 5 to generate compound 6:

[0078]

[0079] Add compound 3 (18.9 g, 42.9 mmol) and ethanol (190 mL) into the reaction flask, and stir to dissolve. 2N NaOH aqueous solution (95 mL) was added, and the reaction was stirred at room temperature for 1 hour, and TLC identified that the starting material disappeared. The pH was adjusted to 3-4 with 6N aqueous HCl. The reaction solution was concentrated to dryness, water (50 mL) was added to the residue, extracted with dichloromethane (100 mL×3), the combined organic phases were concentrated to dryness to obtain compound 4 as a white solid, which was directly added to dichloromethane (180 mL), and 1 -Hydroxybenzotriazole (8.7g, 64.4mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (12.3g, 64.4mmol), compound 5 (7.7g , 85.8 mmol). After stirring...

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Abstract

The invention discloses a preparation method of dolutegravir ring-opening impurities. The preparation method comprises steps of preparation of an impurity A and an impurity B, specifically comprises following steps: taking a compound 1 as an initial raw material, condensing with a compound 2 to generate a compound 3, hydrolyzing into a compound 4 under an alkaline condition, then reacting with a compound 5 to generate a compound 6, obtaining the impurity A from the compound 6 by adopting a protection-ring closing-deprotection method, and further reacting to obtain the impurity B. The inventionalso discloses the impurities. Compared with the prior art, the preparation method disclosed by the invention has the advantages that the preparation of the impurity A and the impurity B of the dolutegravir bulk drug is completed by using a new synthetic route disclosed for the first time; the designed impurity synthesis route is simple and mild in reaction condition, good in yield and safe in reaction operation, and the problems that the dolutegravir degradation impurities A and B are small in amount in an acid-base damage test and cannot be separated are solved; characterization work of theimpurity A and the impurity B is completed, and subsequent further research on the impurity A and the impurity B is facilitated.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a method for preparing ring-opened impurities of dolutegravir and impurities thereof. Background technique [0002] HIV (human immunodeficiency virus) integrase inhibitor dolutegravir sodium (dolutegravir sodium), developed by GlaxoSmithKline, was approved by the US FDA (Food and Drug Administration) in August 2013. The chemical name is (4R,12aS)-9-{[(2,4-difluorophenyl)methyl]carbamoyl}-4-methyl-6,8-dioxo-3,4, Sodium 6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazine[2,1-b][1,3]oxazine-7-enol, structural formula for: [0003] [0004] Dolutegravir is a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor (INSTI), suitable for the treatment of adults and children over 12 years old and weighing at least 40kg in combination with other antiretroviral drugs HIV-1 infection. Patent US9120817 discloses its preparation method, specifically: starti...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04Y02P20/55
Inventor 王志邦徐靖坤田磊张祖良廖洁海邹慧王尧刘洋
Owner ANHUI BIOCHEM BIO PHARMA
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