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Preparation method of potential anti-new coronavirus drug monaprevir

A virus, a potential technology, applied in the preparation of sugar derivatives, chemical instruments and methods, sugar derivatives, etc., can solve the problems of long reaction time and low reaction yield, and achieve simple operation, high quality purity, and high yield Effect

Pending Publication Date: 2022-04-12
海化生命(厦门)科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] The biggest problem with this route is that the yield of the two steps of esterification and deprotection is relatively low, and the reaction time is long, so it is necessary to develop a route with simple operation, high yield, high product quality and purity, and suitable for scale-up production

Method used

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  • Preparation method of potential anti-new coronavirus drug monaprevir
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  • Preparation method of potential anti-new coronavirus drug monaprevir

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preparation example Construction

[0022] A preparation method of potential anti-new coronavirus drug monaprevir, which comprises the following process steps:

[0023] Step (1) Synthesis of intermediate ML-B: Dissolving material ML-A in an organic solvent, reacting with hydroxylamine salt to obtain intermediate ML-B, the structural formulas of said ML-A and intermediate ML-B are respectively:

[0024]

[0025] The synthesis of step (2) intermediate ML-C: the intermediate ML-B obtained in step (1) reacts with acid anhydride to obtain intermediate ML-C through transesterification, and the structural formula of said intermediate ML-C is:

[0026]

[0027] The synthesis of step (3) monaprevir: the intermediate ML-C deprotection reaction of step (2) gained obtains monaprevir, and the structure of described monaprevir is:

[0028]

[0029] Concrete synthetic route of the present invention is as follows:

[0030]

[0031] In step (1), the material ML-A is dissolved in an organic solvent, and reacts with h...

Embodiment 1

[0050] 1.1 Synthesis of intermediate ML-B

[0051] In a 2L three-necked flask, add ML-A (28.3g, 0.10mol), DMF (500ml), HOBt (14.8g, 0.11mol), hydroxylamine hydrochloride (8.3g, 0.13mol) and stir to dissolve, heat up to 75- 80 ° C, stirring at this temperature for 10-12h. After the reaction was completed, 500ml of water was added and stirred for 15min. Extracted 2 times with 300ml*2 acetic acid, the obtained organic layer solution was washed 2 times with 300ml*2 water, and the organic layer was dried and concentrated to obtain 28.1g of solid ML-B with a yield of 93.8%.

[0052] NMR analysis:

[0053] ML-B:1H NMR(400MHz,DMSO)δ10.05(s,1H),9.61(s,1H),7.00(d,J=8.2Hz,1H),5.80(d,J=3.1Hz,1H) ,5.60(d,J=8.1Hz,1H),5.04(t,J=5.1Hz,1H), 4.84(dd,J=6.4,3.1Hz,1H),4.74(dd,J=6.3,3.8Hz, 1H), 3.99(dd, J=8.1, 4.2Hz, 1H), 3.67–3.51(m, 2H), 1.51(s, 3H), 1.31(s, 3H).

[0054] ESI-MS: m / z 322.38[M+Na] + .

[0055] 1.2 Synthesis of intermediate ML-C

[0056] In a 2L three-neck flask, add solid ML-...

Embodiment 2

[0066] 2.1 Synthesis of intermediate ML-B

[0067] In a 2L three-necked flask, add ML-A (28.3g, 0.10mol), DMSO (500ml), BOP (53.1g, 0.12mol), hydroxylamine sulfate (24.6g, 0.15mol) and stir to dissolve, heat up to 85- 90°C, stirring at this temperature for 11-13h. After the reaction was completed, 500ml of water was added and stirred for 15min. Extracted 2 times with 300ml*2 acetic acid, the obtained organic layer solution was washed 2 times with 300ml*2 water, and the organic layer was dried and concentrated to obtain 26.8g of solid ML-B with a yield of 89.8%.

[0068] 2.2 Synthesis of intermediate ML-C

[0069] In a 2L three-necked flask, add solid ML-B (29.9g, 0.1mol), anhydrous DMF 300ml and stir to clarify, then add DCC (6.18g, 0.03mol), DMAP (3.66g, 0.03mol), and then add TEA (25.3g, 0.25mol) was stirred for 30min, then the temperature was controlled to 20-25°C, and isobutyric anhydride (20.56g, 0.13mol) was added slowly at this temperature, and the reaction was conti...

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Abstract

The invention relates to a preparation method of a potential anti-new coronavirus drug monaprevir, which comprises the following process steps: step (1) synthesis of an intermediate ML-B: dissolving a material ML-A in an organic solvent, and reacting with hydroxylamine salt to obtain the intermediate ML-B; (2) synthesizing an intermediate ML-C: reacting the intermediate ML-B obtained in the step (1) with anhydride, and carrying out ester exchange to obtain the intermediate ML-C; and (3) synthesis of monaprevir: carrying out a deprotection reaction on the intermediate ML-C obtained in the step (2) to obtain monaprevir. The preparation method is simple to operate and high in yield. According to the embodiment of the invention, the product obtained by the preparation method is quite high in quality and purity, tedious product purification operation is not needed, and the production efficiency of the product is greatly improved. Therefore, the preparation method provided by the invention is a process method particularly suitable for large-scale production, and can effectively meet the current requirements.

Description

technical field [0001] The invention relates to a preparation method of a potential anti-new coronavirus drug monaprevir. Background technique [0002] Coronavirus (Coronavirus, CoV) exists widely in nature. It is a kind of RNA virus with envelope and linear single-strand positive strand. CoV only infects vertebrates and is related to various diseases of humans and animals. It can cause human And animal respiratory tract, digestive tract and nervous system diseases. At present, there are 6 kinds of coronaviruses known to infect humans, namely human coronavirus HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, severe acute respiratory syndrome coronavirus SARS-CoV and Middle East respiratory syndrome Coronavirus MERS-CoV. SARS-CoV-2 is the seventh known coronavirus that can infect humans. The virus causes novel coronavirus pneumonia. Based on current epidemiological investigations, the incubation period is 1-14 days, mostly 3-7 days. The main manifestations are fever, dry cough...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/067C07H1/00
Inventor 陈华栋邱炳林钟宝香李金林黄志征陈书红
Owner 海化生命(厦门)科技有限公司
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