Synthesis method of baloxavir marboxil intermediate

A synthesis method and compound technology, applied in organic chemistry and other directions, can solve the problems of few synthesis routes, difficult production control, purchase and use restrictions, etc., and achieve the effect of facilitating industrial production, avoiding potential dangers, and solving toxicity problems.

Active Publication Date: 2019-08-20
BEIJING SIHUAN PHARMA +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] During the first step of operation in CN109311911A, diisopropylamine vapor is very irritating to the respiratory tract, eyes and skin; in addition, diisopropylamine is flammable, and its vapor can form an explosive mixture when mixed with air
This step involves two low-temperature sensitive reactions, and the reagents and solvents used must be strictly removed from water, so diisopropylamine needs to be re-distilled, so a large amount of steam will be exposed, which is a potential hazard
In addition, this step also involves the timing of adding methanol, otherwise it will cause by-products, etc., which are difficult to control in production
This step reaction is not suitable for industrial production
The second step uses the reagent thiophenol, which has a foul smell and is extremely toxic when inhaled. It has been included in the list of controlled chemicals-highly toxic chemicals. Its purchase and use are restricted, and higher requirements are placed on the construction of production plants. Not suitable for commercial production
In step 1, adopt 40% hydrobromic acid to carry out bromination reaction in the reaction, hydrobromic acid strong acid, strong corrosiveness, damage equipment easily, also need to pay attention to environmental protection problem in addition; And adopt phosphorus tribromide to carry out bromination in step 3 reaction, the yield is low, and the Grignard reagent has high requirements on anhydrous and oxygen-free, which is not suitable for industrial production; in addition, a large amount of CO is used in production 2 special equipment required
In addition, the total yield calculated according to the highest yield of each step of the embodiment is only 35.7%, and the production cost is greatly increased, which is not suitable for large-scale industrial production.
[0014] In summary, there are few synthetic routes for the intermediates of the lower fragment of barrosavir maple ester, and the above-mentioned problems exist, so it is urgent to develop new synthetic methods

Method used

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  • Synthesis method of baloxavir marboxil intermediate
  • Synthesis method of baloxavir marboxil intermediate
  • Synthesis method of baloxavir marboxil intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Embodiment 1: the preparation of compound I N, N-diethyl-3,4-difluorobenzamide

[0063] Put 31.62g of 3,4-difluorobenzoic acid, 500ml of dichloromethane, 5ml of N'N-dimethylformamide into the reaction bottle, stir at room temperature, drop in 48.22g of oxalyl chloride, stir at room temperature for 1 hour after dropping, evaporate under reduced pressure Dry solvent, add 200ml of dichloromethane to dissolve the residual oily matter and directly drop into diethylamine aqueous solution (dissolve 60.81g of potassium carbonate and 26.26g of diethylamine hydrochloride in 200ml of water), stir at room temperature after dropping, separate the organic layer, and use Extracted with dichloromethane, combined organic layers, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure to obtain 39.23 g of an oily substance. Yield 92.1%, 1 H NMR (400MHz, CDCl 3 )δ7.13~7.25(m,3H),3.52(br m,2H),3.27(br m,2H),1.21(br m,3H)...

Embodiment 2

[0064] Example 2: Preparation of compound II N, N-diethyl-2-formyl-3,4-difluorobenzamide

[0065] Put 26.00g of N,N-diethyl-3,4-difluorobenzamide, 250ml of tetrahydrofuran, and 18.42g of tetramethylethylenediamine into the reaction flask, cool down to -80°C, and drop in 84ml of 1.6M n-butyl Lithium, stir for 1 hour after dropping, add 22.30g of N'N-dimethylformamide dropwise, remove the refrigerant after dropping for half an hour, quench the reaction with dilute hydrochloric acid, separate the organic layer, and extract the aqueous phase with ethyl acetate , combined the organic layers, and evaporated to dryness under reduced pressure to obtain 29.50 g of oily substance, with a yield of 100%. 1 H NMR (400MHz, CDCl 3 )δ10.33(s,1H),7.41~7.46(m,1H),7.03~7.07(m,1H), 3.56(q,J=7.2Hz,2H),3.06(q,J=7.2Hz,2H ),1.30(t,J=7.2Hz,2H),1.02(t,J=7.2Hz,2H); MS(ESI)m / z(M+H) + :242.1

Embodiment 3

[0066] Example 3: Preparation of compound III 4,5-difluoro-3-hydroxyisobenzofuran-1(3H)-one

[0067] Put 29.50g of N,N-diethyl-2-formyl-3,4-difluorobenzamide and 200ml of 6M hydrochloric acid into the reaction flask, heat up to 100°C, stir for 2.5h, extract with 100ml X4 dichloromethane, The organic layer was separated, washed with purified water and saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure to obtain 20.98 g of a brown solid with a yield of 92.4%. 1 H NMR (400MHz, CDCl 3 )δ7.66~7.70(m,1H),7.40~7.50(m,1H),6.78(s,1H),4.54(br s,1H); (MS-ESI)m / z(M-H) - :185.0

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Abstract

The invention provides a synthesis method of a baloxavir marboxil intermediate. The invention provides a synthesis method of a compound (III), which is prepared through three steps. The yield is improved, and the production is easy to control. At the same time, a synthesis method of a compound (IV) is provided. According to the synthesis method, the compound (III) and disulfide diphenyl carry outone-pot self-catalytic circulation reactions to generate the compound (IV). The invention provides a method for preparing a baloxavir marboxil intermediate (VIII) through the reactions mentioned above. Through the one-pot self-catalytic circulation reactions, thiophenol, which is strongly toxic and is strictly controlled, is not used, a safe baloxavir marboxil synthesis method is provided, and thesynthesis method is suitable for industrial production.

Description

technical field [0001] The invention relates to a synthesis method of a pharmaceutical intermediate, in particular to a newly discovered "one-pot self-catalysis cycle" reaction and a method for preparing a barosavir-marbolate intermediate. Background technique [0002] Influenza is an acute respiratory infectious disease caused by influenza virus. The World Health Organization estimates that there are approximately 3 million to 5 million influenza cases each year, resulting in approximately 250,000 to 500,000 deaths. Barosavir Marbolate is a new anti-influenza drug developed by Shionogi Company. It was approved for marketing in Japan on February 23, 2018, and is used for the treatment of influenza A and B in adults and children. Barosavir marbolate is the first anti-influenza drug with a new mechanism of action in the past 20 years. It inhibits the transcription and replication of influenza virus by inhibiting the cap-dependent endonuclease of influenza virus. The mechanism...

Claims

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Application Information

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IPC IPC(8): C07D307/89C07D307/88C07D337/12
CPCC07D307/88C07D307/89C07D337/12
Inventor 王祖元夏亮甄志彬赵寅堡高院院段浩田韩保嘉袁景洋张明刚霍彩霞
Owner BEIJING SIHUAN PHARMA
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