Preparation method of key intermediate of baloxavir marboxil

An intermediate and key technology are applied in the field of preparation of key intermediates of baloxavir, can solve problems such as incapable replacement of vaccination, and achieve the effects of less production risk factors, simple and convenient post-processing, and high yield

Active Publication Date: 2019-05-07
ZHEJIANG UNIV OF TECH +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] Antiviral drugs can be used for the prevention and treatment of seasonal influen

Method used

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  • Preparation method of key intermediate of baloxavir marboxil
  • Preparation method of key intermediate of baloxavir marboxil
  • Preparation method of key intermediate of baloxavir marboxil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1: Preparation of 1-bromo-2-(bromomethyl)-3,4-difluorobenzene

[0034] Add (6-bromo-2,3-difluorophenyl)methanol (4.46g, 20mmol), 40% hydrobromic acid (8.1g, 40mmol), and 70mL of acetonitrile into a 250ml two-necked flask, and stir the reaction at room temperature 4 hour, TLC tracked to after the completion of the reaction, added water to the reaction solution (the volume of water and the reaction solution was the same), then added ethyl acetate for extraction, left to separate into organic phase and water phase, and the organic phase was washed with water and dried Afterwards, it was concentrated under reduced pressure to remove acetonitrile and ethyl acetate solvents to obtain 5.12 g of brown-yellow liquid with a yield of 89.5%.

[0035] 1 H NMR (600MHz, Chloroform-d) δ7.35 (ddd, J = 8.3, 4.1, 1.9Hz, 1H), 7.06 (q, J = 8.3Hz, 1H), 4.62 (q, J = 1.6Hz, 2H) . 13C NMR (101MHz, Chloroform-d) δ150.81(dd, J=54.0, 13.4Hz), 148.30(dd, J=59.0, 13.4Hz), 128.43(dd, J=6.1...

Embodiment 2

[0036] Example 2: Preparation of 1-bromo-2-(bromomethyl)-3,4-difluorobenzene

[0037] Add (6-bromo-2,3-difluorophenyl)methanol (4.46g, 20mmol), phosphorus tribromide (8.12g, 30mmol) and 70mL dry ether into a 250ml two-necked flask, and stir the reaction at 0°C After 4 hours, TLC tracked to the completion of the reaction, poured the reaction solution into ice water, added ethyl acetate for extraction, left to separate into an organic phase and an aqueous phase, washed the organic phase with water, dried, and concentrated under reduced pressure to remove ethyl acetate solvent to obtain 3.32 g of brown-yellow liquid with a yield of 58.1%.

[0038] 1 H NMR (600MHz, Chloroform-d) δ7.35 (ddd, J = 8.3, 4.1, 1.9Hz, 1H), 7.06 (q, J = 8.3Hz, 1H), 4.62 (q, J = 1.6Hz, 2H) . 13 C NMR (101MHz, Chloroform-d) δ150.81(dd, J=54.0, 13.4Hz), 148.30(dd, J=59.0, 13.4Hz), 128.43(dd, J=6.1, 4.5Hz), 127.74(d , J=13.2Hz), 118.98 (dd, J=3.8, 1.9Hz), 118.35 (d, J=18.1Hz), 24.64 (dd, J=4.5, 2.4Hz).

Embodiment 3

[0039] Example 3: Preparation of 1-bromo-2-(bromomethyl)-3,4-difluorobenzene

[0040] Add (6-bromo-2,3-difluorophenyl)methanol (4.46g, 20mmol), 40% hydrobromic acid (8.1g, 40mmol), and 70mL ethyl acetate into a 250ml two-necked flask, and stir at room temperature Reacted for 4 hours, after TLC tracked to the completion of the reaction, water was added to the reaction solution (the volume of water and the reaction solution was the same), then ethyl acetate was added for extraction, and the standing layering was divided into an organic phase and an aqueous phase, and the organic phase was washed with water, After drying, it was concentrated under reduced pressure to remove the ethyl acetate solvent to obtain 4.3 g of a brownish-yellow liquid with a yield of 75%.

[0041] 1 H NMR (600MHz, Chloroform-d) δ7.35 (ddd, J = 8.3, 4.1, 1.9Hz, 1H), 7.06 (q, J = 8.3Hz, 1H), 4.62 (q, J = 1.6Hz, 2H) . 13 C NMR (101MHz, Chloroform-d) δ150.81(dd, J=54.0, 13.4Hz), 148.30(dd, J=59.0, 13.4Hz),...

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Abstract

The invention discloses a preparation method of a key intermediate of baloxavir marboxil. The preparation method comprises the following steps: carrying out a nucleophilic substitution reaction on polysubstituted 2,3-difluoro-6-halogenated benzyl alcohol represented by a formula (I) to synthesize 2,3-difluoro-6-halogenated benzyl halide represented by a formula (II), carrying out a nucleophilic substitution reaction on the polysubstituted benzyl halide represented by the formula (II) to synthesize 2,3-difluoro-6-halogenated benzyl phenylsulfide represented by a formula (III), carrying out a Grignard reaction on the polysubstituted benzyl phenylsulfide represented by the formula (III) to synthesize 3,4-difluoro-2-(phenylthio)methyl)benzoic acid represented by a formula (IV), and carrying out a Friedel-Crafts acylation reaction on the polysubstituted benzoic acid to synthesize 7,8-difluorodibenzo[b,e]thiophene-11(6H)-one represented by a formula (V). In the formula (I), the formula (II)and the formula (III), X<1> and X<2> are separately and independently selected from chlorine, bromine or iodine. According to the preparation method, the polysubstituted benzyl alcohol is used as a starting raw material, and the steps of two-step nucleophilic substitution, Grignard exchange, Friedel-Crafts acylation and the like are carried out to prepare the key intermediate of the anti-influenzadrug baloxavir marboxil, so that original innovation is achieved.

Description

technical field [0001] The invention relates to a preparation method of a key intermediate of baloxavir. Background technique [0002] Influenza, the full name of influenza, is a disease caused by acute infection of the respiratory tract with highly contagious influenza virus. Its symptoms include fever, myalgia, listlessness and upper respiratory symptoms. [0003] Antiviral drugs can be used for the prevention and treatment of seasonal influenza, but they can only be strictly used as adjuvant drugs for vaccination, not as a substitute for vaccination. At present, drugs including M2 inhibitors (amantadine and rimantadine) and neuraminidase inhibitors (oseltamivir and zanamivir) are used for chemoprevention of influenza, and the effective rate is 70-90%. [0004] Baloxavir marboxil is an innovative Cap-dependent endonuclease inhibitor developed by Shionogi in Japan for the treatment of influenza A and influenza B. The advantage of this therapy is that it is taken in a shor...

Claims

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Application Information

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IPC IPC(8): C07D337/12
Inventor 俞传明郑祥云卫禾耕姜昕鹏邵鸿鸣金逸中
Owner ZHEJIANG UNIV OF TECH
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