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Darunavir midbody as well as preparation method and application thereof

An intermediate and reaction technology, applied in the field of drug synthesis, can solve the problems of uneconomical industrial scale production, low reaction yield, and difficulty in realization, and achieve the effects of low cost, simple operation, and cheap and easy-to-obtain raw materials

Inactive Publication Date: 2014-07-02
SHANGHAI DESANO CHEM PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The reaction yield of this method is low, which is uneconomical in industrial scale production, and a low temperature of -78°C is required when using metal catalysts, which is also difficult to achieve in industrial large-scale production

Method used

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  • Darunavir midbody as well as preparation method and application thereof
  • Darunavir midbody as well as preparation method and application thereof
  • Darunavir midbody as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Embodiment 1: Preparation of intermediate of the present invention (compound of formula IIa)

[0027]

[0028] a) Add lithium hexamethyldisilazide (LiHMDS) (1.1L, 1mol / L) into the reaction flask under the protection of argon, cool the system to -78°C, add 1,4-butyrolactone dropwise (88.75g, 1.03mol) THF solution 250mL, after dropping, keep warm at -78°C and stir for 1 to 3 hours; add 250mL THF solution containing ethyl chloroacetate (125.05g, 1.02mol) dropwise, keep warm at -78°C after dropping Stir at ℃ for 1 to 3 hours; add 100mL of 4N hydrochloric acid aqueous solution, stand still, separate the liquids, extract the aqueous phase with ethyl acetate (100mL×3), combine the organic phases, wash with 100mL saturated brine, dry over anhydrous sodium sulfate, and filter. The filtrate was concentrated under reduced pressure and dried to obtain 156.07 g of a light yellow oil (compound of formula III), with a molar yield of 96% and an HPLC purity of 96.3%.

[0029] b) The...

Embodiment 2

[0032] Embodiment 2: application above-mentioned intermediate preparation formula I compound

[0033]

[0034]c) Dissolve the compound of formula IIa (2.49g, 0.01mol) in 25mL of absolute ethanol, slowly add sodium borohydride (1.14g, 0.03mol) under ice-water bath, then react at room temperature for 0.5-4 hours, add 10m3L4N hydrochloric acid The aqueous solution was extracted with ethyl acetate (20mL×3), the organic layers were combined, the organic phase was washed with 20mL saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and dried to obtain a light yellow oil (compound of formula V ) 1.16g, directly used in the next step reaction.

[0035] d) Dissolve the compound of formula V (4.0g, 0.027mol) in 9mL of tetrahydrofuran, add methanesulfonic acid (0.34g, 0.0027mol) under ice-cooling, after the addition is complete, heat to 30-55°C, and keep stirring for 0.5 ~2 hours, cooled to room temperature, added trie...

Embodiment 3

[0036] Embodiment 3: preparation intermediate of the present invention (compound of formula IIb)

[0037]

[0038] The compound of formula III (16.2g, 0.1mol) prepared according to the method in Example 1 was dissolved in 50mL of acetone, and acetic acid (6.6g, 0.11mol) was slowly added; triethylamine (11.1g, 0.11mol), the dropwise addition was completed, and the temperature was raised to reflux. When the reflux reaction was completed (about 2 to 5 hours), a large amount of white solids precipitated, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow solid. Add 30 mL of ethyl acetate and 20mL saturated sodium bicarbonate solution, separated, the aqueous phase was extracted with ethyl acetate (20mL×2), the organic phases were combined, washed with 20mL saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and dried to obtain Pale yellow oil (compound of formula IIb) 16.3g, mola...

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Abstract

The invention discloses a darunavir midbody as well as a preparation method and application thereof. The midbody has a chemical structure shown by a formula II which is as shown in the specification. The preparation method of the midbody comprises the step b or step a-b of the synthetic route, wherein X is selected from Cl, Br or I, R is selected from aryl or alkyl, and R1 is selected from the alkyl of C1-C4. The midbody can be used for preparing the key midbody of darunavir, namely, hexahydrofuran-[2,3-b] furan-3-alcohol and (3R,3aS,6aR) hexahydrofuran-[2,3-b] furan-3-alcohol. The midbody has the advantages of using cheap and easily-available raw materials, being simple to prepare, having low cost, and being applicable to large scale production, thus having significance and practical value to realization of industrial production of darunavir.

Description

technical field [0001] The invention relates to a darunavir intermediate and its preparation method and application, belonging to the technical field of drug synthesis. Background technique [0002] The (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-oxyl group is a pharmacologically important moiety present in the structure of protease inhibitors of retroviruses. For example, it is an important synthetic fragment of darunavir, whose chemical structural formula is as follows: Darunavir is developed by Tibotec Pharmaceuticals Co., Ltd. (Tibotec Pharmaceuticals), also known as TMC114, trade name Prezista, approved by the FDA on June 23, 2006, the drug can selectively inhibit the HIV encodes Gag-Pol polyproteins that prevent the formation of mature virions. [0003] An important precursor for the synthesis of the above-described protease inhibitors containing hexahydrofuro[2,3-b]furan-3-oxyl groups is hexahydrofuro[2,3-b]furan-3-ol (compound of formula I): Wherein the enantiomer ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/33C07D493/04
CPCC07D307/33C07D493/04
Inventor 李金亮赵楠谢益明
Owner SHANGHAI DESANO CHEM PHARMA
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