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Preparation method of deuterated daclatasvir intermediate

A technology of compound and carboxyl protecting group, which is applied in the field of drug synthesis and can solve problems such as large environmental pollution

Pending Publication Date: 2021-06-11
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route is more polluting to the environment and has obvious defects: first, although triphosgene is safer than phosgene, it will inevitably produce a small amount of phosgene during use, especially in hot summer; second, a large amount of phosgene is used Pyridine; third, with reference to the toxicity of methyl chloroformate, deuterated methyl chloroformate is also a highly toxic drug; the above three are all more polluting to the environment

Method used

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  • Preparation method of deuterated daclatasvir intermediate
  • Preparation method of deuterated daclatasvir intermediate
  • Preparation method of deuterated daclatasvir intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060]

[0061] Synthesis of N-tert-butoxycarbonyl-L-valine p-bromobenzyl ester (4):

[0062] Dissolve N-tert-butoxycarbonyl-L-valine (3) (21.73g, 0.1mol) in NMP (150mL), add p-bromobenzyl bromide (27.49g, 0.11mol), Cs 2 CO 3 (19.55g, 0.06mol), stirred, reacted at 25°C for 3h, TLC showed that the reaction was complete, added 0.8L ice water to the reaction solution, extracted with EtOAc (200mL×3), washed the organic phase with 500mL saturated NaCl aqueous solution, anhydrous sodium sulfate Dry, filter, and spin dry the solvent under reduced pressure to obtain 44.40 g of crude compound 4, which can be directly put into the next step reaction. It can also be separated and purified by silica gel column chromatography (PE:EtOAc 50: 1~20:1) to obtain light yellow syrup (4) with a yield of 99%.

[0063] 1 H NMR (500MHz, CDCl 3 ), δ: 0.87 (d, J=7.0Hz, 3H, CH 3 ),0.96(d,J=6.5Hz,3H,CH 3 ),1.46(s,9H, (CH 3 ) 3 C),2.15(m,1H,CH(CH 3 ) 2 ), 4.27 (dd, J = 4.5, 9.0Hz, 1H, NHCH), ...

Embodiment 2

[0088] Compound 5' and CD of different molar ratios of embodiment 2 3 OD prepared compound 6'

[0089] Taking NO.2 as an example, the experimental operation is as follows: CDI (3.73g, 0.023mol), CD 3 OD (0.83g, 0.023mol) and KOH (44.9 mg, 0.8mmol) were added to toluene (25mL), heated to 70°C, and after 3h of reaction, L-valine methyl ester (5') (1.31g , 0.01mol), the reaction was continued at 70°C for 20h. The peak area ratio of the product detected by HPLC was 90%.

[0090] The experimental operation of NO.1 and NO.3-4 is the same as that of NO.2, only compound 5' and CD 3 The molar ratio of OD is different, and the specific ratio is shown in the table below.

[0091]

Embodiment 3

[0092] Embodiment 3 prepares compound 6' under different alkaline conditions

[0093] CDI (3.73g, 0.023mol), CD 3 OD (0.83g, 0.023mol) and NaOH (32.0mg, 0.8mmol) were added to toluene (25mL), heated to 70°C, and after 3h of reaction, L-valine methyl ester (5') (1.31g , 0.01mol), the reaction was continued at 70°C for 20h. The peak area ratio of the product detected by HPLC was 85%.

[0094]

[0095] The HPLC detection condition of embodiment 2-3 is: chromatographic column is Waters Sunfire C18, 250mm * 4.6mm, 5 μm; With 0.01% trifluoroacetic acid solution as mobile phase A, acetonitrile is mobile phase B, flow rate is 1.0ml per minute, Carry out linear gradient elution according to the table below; column temperature is 35°C; detection wavelength is 200nm. Calculated by peak area normalization method.

[0096]

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Abstract

The invention provides a preparation method of a deuterated daclatasvir intermediate, and particularly relates to a preparation method of N-(trideuteromethoxycarbonyl)-L-valine. According to the preparation method, the intermediate is obtained through two-step synthesis by taking CDI as an activating reagent. Compared with a triphosgene route in the prior art, the route has the advantages that the yield and the utilization rate of deuterated methanol can be improved, and meanwhile, the pollution to the environment is greatly reduced.

Description

technical field [0001] The application belongs to the field of pharmaceutical synthesis, and relates to a preparation method of a deuterated daclatasvir intermediate, in particular to a preparation method of an intermediate-N-(trideuteromethoxycarbonyl)-L-valine and its use in the preparation of deuterium Uses of daclatasvir. Background technique [0002] Daclatasvir Dihydrochloride (Daclatasvir Dihydrochloride) is an HCV NS5A inhibitor developed by Bristol-Myers Squibb. It was approved by EMA in August 2014. It is the first NS5A inhibitor for the treatment of HCV infection. -6 types have good therapeutic effect. [0003] The deuterated daclatasvir (Deudaclatasvir) has the same mechanism of action as daclatasvir, and exerts its pharmacodynamic effect by binding to the HCV virus NS5A protein. Compared with daclatasvir, deuterated daclatasvir has higher druggability and is currently in phase I clinical trials. [0004] [0005] During the synthesis of deuterated daclatas...

Claims

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Application Information

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IPC IPC(8): C07C269/06C07C271/22
CPCC07C269/06C07C269/04C07B2200/05C07C271/22Y02P20/55
Inventor 丰巍伟任成彭岩严正磊刘飞张喜全王善春顾红梅
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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