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Preparation method of aprepitant intermediate impurity

A technology for aprepitant and intermediates, applied in the field of preparation of aprepitant intermediate impurities, can solve the problems of low repetition rate and yield, complex ethanol synthesis route, etc., and achieve the effect of simple equipment and environmental friendliness

Active Publication Date: 2020-04-07
ENANTIOTECH CORP +1
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  • Claims
  • Application Information

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Problems solved by technology

[0006] Based on this, one of the objects of the present invention is to target the impurity intermediate (1S, 2R)-2-(2-aminoethoxy)-2-[(R)-1-[3,5-bis(trifluoromethane) Base) phenyl] ethoxy] -1-(4-fluorophenyl) ethanol has the defects of complex synthetic route, low repeatability and low yield, and provides a synthetic process with high repeatability and simple and stable process

Method used

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  • Preparation method of aprepitant intermediate impurity
  • Preparation method of aprepitant intermediate impurity
  • Preparation method of aprepitant intermediate impurity

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preparation example Construction

[0031] The preparation method comprises the following reaction steps:

[0032] (A) carry out Grignard reaction with raw material 1 and Grignard reagent 4-fluorophenylmagnesium halide;

[0033] (B) reducing the reaction product obtained in step (A) with a reducing agent to obtain compound 4;

[0034] (C) debenzylation reaction of obtained compound 4 with a deprotection reagent to obtain crude product 5;

[0035] (D) reacting the obtained crude product 5 with a protecting reagent in the presence of a solvent and a base to obtain compound 6;

[0036] (E) deprotecting the obtained compound 6 with an acid or a base in the presence of a solvent, and then obtaining the refined product 5 after separation and purification;

[0037] The protecting reagent is selected from: fluorenylmethoxycarbonyl chloride, benzyloxycarbonyl chloride or Boc-anhydride.

[0038] In some of these embodiments, the base in reaction (D) is at least one of triethylamine, N,N-diisopropylethylamine, potassium...

Embodiment 1

[0070]

[0071] (A) Add 50g of APT04 (raw material 1) and 50mL of THF into a 500mL three-necked flask, stir to dissolve and cool down to about 10°C in an ice-water bath under the protection of nitrogen. Add 168mL (1mol / L) of p-fluorophenylmagnesium bromide Grignard reagent dropwise at a temperature of 10-20°C. After the addition is complete, stir and react at a constant temperature of 5-20°C for 0.5h. After the reaction is monitored by TLC, the reaction system Slowly drop into 190mL of cold methanol to quench, and control the temperature below 5°C.

[0072] (B) Cool the obtained quenched reaction system to below 0°C, then add 8.5 g of sodium borohydride in batches, stir for 10 min, remove the ice-water bath, and let the temperature naturally rise to room temperature for the reaction. After 0.5 h, the reaction was monitored by TLC until complete. Concentrate the above system under reduced pressure at 48-50°C to dryness, add 300mL of ethyl acetate and 900mL of water, wash th...

Embodiment 2

[0077] The difference between this embodiment and Example 1 is that in reaction (D), the protective reagent is selected Boc-anhydride Instead of Fmoc-Cl.

[0078] (D) After dissolving 5 g of the crude oily product of Compound 5 obtained in step (C) of Example 1 with 70 mL of dioxane, add 6.2 mL of DIPEA and lower the temperature to -5 to 0°C, and add Boc- Acid anhydride 2.5g, after the dropwise addition, sample TLC to monitor the progress of the reaction. After the reaction, add 50mL of water and then add 80mL of DCM for extraction, let stand to separate layers, wash the organic phase with 50mL of saturated saline and concentrate to dryness to obtain compound 6. Crude sticky substance 8g. Petroleum ether-petroleum ether: ethyl acetate = 4:1 was used as the eluent to separate by silica gel column chromatography to remove small polar impurities, and further obtain 6 g of the crude product of compound 5 protected by the amino group. Take 6 g of the obtained crude product, put ...

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Abstract

The invention relates to a preparation method of an aprepitant intermediate impurity. The preparation method comprises the following reaction steps: (A) carrying out a Grignard reaction on a raw material 1 and a Grignard reagent 4-fluorophenylmagnesium halide; (B) carrying out a reduction reaction on a reaction product obtained in step (A) and a reducing agent to obtain a compound 4; (C) carryingout a debenzylation reaction on the obtained compound 4 and a deprotection reagent to obtain a crude product 5; (D) reacting the obtained crude product 5 with a protective reagent in the presence of asolvent and an alkali to obtain a compound 6; and (E) carrying out a deprotection reaction on the obtained compound 6 and an acid or alkali in the presence of a solvent, and carrying out separation and purification to obtain a refined product 5. The compound 4 is obtained through the reduction reaction, and then undergoes the debenzylation reaction to synthesize the compound 5, so the compound 5can be successfully synthesized, and the yield and purity of the crude product 5 are greatly improved. Furthermore, the crude product 5 reacts with the protective reagent and is purified to obtain thecompound 6, and the compound 6 is subjected to the deprotection reaction, and then is separated through conventional column chromatography to obtain the high-purity compound 5.

Description

technical field [0001] The invention relates to the field of chemical synthesis, in particular to a method for preparing an aprepitant intermediate impurity. Background technique [0002] Aprepitant, the chemical name is 5-[2(R)-[1(R)-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4- Fluorophenyl)morpholin-4-ylmethyl]-3,4-dihydro-2H-1,2,4-triazol-3-one, its structural formula is shown in the figure below. Aprepitant is a highly selective NK1 receptor antagonist developed and produced by Merck. Clinically, it is mainly used to prevent acute and delayed nausea and vomiting during the initial and repeated treatment of highly emetogenic antitumor chemotherapy. [0003] [0004] There are 3 chiral centers in the structural formula of aprepitant, and there are 7 chiral isomer impurities in total. With my country's accession to ICH (International Conference on Harmonization of Technical Requirements for Registration of Drugs for Human Use), more and more attention has been pai...

Claims

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Application Information

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IPC IPC(8): C07C213/00C07C213/08C07C213/10C07C213/02C07C217/10C07C269/04C07C271/16
CPCC07B2200/07C07C213/00C07C213/02C07C213/08C07C213/10C07C269/04C07C2603/18C07C217/10C07C271/16
Inventor 李苏泳蒙发明温锦涛郭俊毛波李彦雄徐亮
Owner ENANTIOTECH CORP
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