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Preparation method of daclatasvir and its intermediate

A technology of daclatasvir and intermediates, which is applied in the field of preparation of daclatasvir and its intermediates, can solve the problems of harsh reaction conditions, high production cost, low product purity, etc., and achieves short reaction route and low production cost. , the effect of high product purity

Inactive Publication Date: 2017-03-15
FUJIAN COSUNTER PHARMA
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  • Description
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  • Application Information

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Problems solved by technology

[0006] The technical problem to be solved by the present invention is to overcome the harsh reaction conditions, severe equipment corrosion, dangerous operation, low purity of the obtained product, difficult purification and high production cost in the preparation method of daclatasvir and its intermediates in the prior art. , not suitable for industrialized production and other defects and provide a preparation method of daclatasvir and its intermediates

Method used

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  • Preparation method of daclatasvir and its intermediate
  • Preparation method of daclatasvir and its intermediate
  • Preparation method of daclatasvir and its intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Embodiment 1: The preparation method of daclatasvir intermediate compound IV

[0068]

[0069] Add 5.00kg of 4,4'-bis(2-bromoacetyl)biphenyl, 5.98kg of BOC-L-proline and 32.00kg of acetonitrile into a 100L reactor equipped with mechanical stirring and a thermometer. Start stirring, control the reaction temperature to below 20°C, add 3.59kg of N,N-diisopropylethylamine dropwise, after the drop is complete, control the reaction temperature to 25°C to 30°C and stir for 3 hours. After completion of the reaction, it is 10% sodium chloride aqueous solution (described mass percent refers to the percentage of the quality of sodium chloride in the total mass of sodium chloride aqueous solution) that is pumped into the preconfigured mass percentage into 26.5kg, after stirring, leave standstill layered. The organic phase was repeatedly washed with water twice, and the layers were separated after standing. After the upper organic phase was separated, it was concentrated under ...

Embodiment 2

[0070] Embodiment 2: the preparation method of daclatasvir intermediate II

[0071]

[0072] Add 14.59 kg of ammonium acetate to a solution of 8.5 Kg of daclatasvir intermediate IV in 45.5 Kg (51 liters) of toluene, and raise the temperature to 95-100° C. After stirring for 15 hours, the temperature was lowered to 20-25°C, and 1.75Kg of glacial acetic acid, 8.14Kg of n-butanol and 20.1Kg of 13% sodium chloride aqueous solution were added by mass percentage (the mass percentage refers to that the mass percentage of sodium chloride accounted for The percentage of the total mass of sodium chloride aqueous solution) forms a mixed solution, which is stirred and left to stand for layering. Add 20.1Kg of 13% sodium chloride aqueous solution (the mass percentage refers to the percentage of the mass of sodium chloride in the total mass of sodium chloride aqueous solution) to the organic phase, stir and let stand to separate layers. The organic phase was decompressed and rotary evap...

Embodiment 3

[0073] Embodiment 3: the preparation method of daclatasvir intermediate I

[0074]

[0075] Add 5.00Kg daclatasvir intermediate II in 5 liters of methanol, 30 liters of dioxane, add dropwise 10L concentrated hydrochloric acid (mass concentration is 37%) under rapid stirring percentage of the total mass of hydrochloric acid), stirred at room temperature (25° C. to 30° C.) for 6 hours, and the reaction solution was filtered and washed. Add 20L methanol to the obtained wet product, heat up to 50-55°C and stir for 4 hours, cool to 15°C-20°C, stir for 1 hour, filter, wash, vacuum (-0.08MPa~-0.1 MPa) was dried for 6-10 hours to obtain 3.88Kg of daclatasvir intermediate I, with a yield of 85.0% and a HPLC purity of 99.68%.

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Abstract

The invention discloses a preparation method of daclatasvir and its intermediate. The invention provides a preparation method of a daclatasvir intermediate I. The method includes the step of: in an organic solvent or under a solvent-free condition, subjecting a daclatasvir intermediate II and hydrochloric acid to reduction reaction to obtain a daclatasvir intermediate I, wherein the mass concentration of the hydrochloric acid is 5%-37%, and the mass concentration refers to the percentage of the hydrogen chloride mass to the total mass of hydrochloric acid. The preparation method provided by the invention has short reaction route and high total yield, the prepared intermediate has high purity up to 99% or more, the prepared daclatasvir reaches the bulk drug standard, has purity of more than 99.80% and single impurity content of less than 0.10%. With the advantages of safe operation, low production cost and environmental friendliness, the method provided by the invention is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of daclatasvir and its intermediate. Background technique [0002] Daclatasvir III is a hepatitis C virus (HCV) NS5A inhibitor, suitable for the treatment of chronic HCV genotype 3 infection. Daclatasvir was developed by Bristol-Myers Squibb and was approved by the EU for marketing at the end of 2014. It is used in combination with other drugs for the treatment of adults with genotype 1, 2, 3, and 4 chronic hepatitis C (HCV) infection. Daclatasvir is currently on the market in the United Kingdom and Japan, and its clinical treatment effect is that the average cure rate reaches 95%, and the cure rate for adults with genotype 1 chronic hepatitis C infection is even close to 100%. [0003] [0004] Daclatasvir III is synthesized from daclatasvir intermediate I in one step, so daclatasvir intermediate I is the key intermediate of daclatasvir III. The synthetic methods that have been publicly reported under...

Claims

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Application Information

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IPC IPC(8): C07D403/14
CPCC07D403/14
Inventor 应述欢皮红军王亮陈健
Owner FUJIAN COSUNTER PHARMA
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