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Preparation method of aliskiren intermediate

An intermediate, isopropyl technology, applied in the field of drug preparation, can solve the problems of reduced final yield of aliskiren, low reaction yield, long reaction time and the like, shortening reaction time, improving reaction yield and cost low effect

Active Publication Date: 2019-03-01
常州红太阳药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in the preparation process of Aliskiren intermediates, there are usually the defects of long reaction time and low reaction yield, which easily lead to the reduction of the final yield of Aliskiren, therefore, there is still room for improvement

Method used

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  • Preparation method of aliskiren intermediate
  • Preparation method of aliskiren intermediate
  • Preparation method of aliskiren intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] A method for preparing aliskiren intermediate includes the following steps:

[0042] S1. The synthesis of the first intermediate is as follows:

[0043] Pump 600kg of dichloromethane into the No. 1 2000L reactor, open the lid, and then add 120kg of compound ((1S, 3S)-3-(hydroxymethyl-1-(2S, 4S)-tetrahydro-4- Isopropyl-5-oxo-2-furyl)pentyl) butyl carbamate was stirred and dissolved, and the temperature in the kettle was reduced to -4°C. Open the lid, put 12kg potassium bromide and 4kg 2,2,6,6-tetramethylpiperidine oxide, and close the lid. Vacuum 250kg sodium hypochlorite solution into a 500L high-position dripping tank, and slowly drip it into the reaction kettle, control the temperature at -5°C, keep it warm and stir for 4h after dripping for 2h. Into a 500L high-position dripping tank, vacuum-pump 600kg of 10% sodium bisulfite aqueous solution in batches and add it dropwise to the reaction kettle, control the temperature at 0°C, and complete the addition in 2 hours.

[00...

Embodiment 2

[0062] A method for preparing aliskiren intermediate includes the following steps:

[0063] S1. The synthesis of the first intermediate is as follows:

[0064] Pump 500kg of dichloromethane into No. 1 2000L reactor, open the lid, and add 100kg of compound ((1S, 3S)-3-(hydroxymethyl-1-(2S, 4S)-tetrahydro-4- Isopropyl-5-oxo-2-furyl)pentyl) butyl carbamate was stirred and dissolved, and the temperature in the kettle was reduced to -5°C. Open the lid, put in 10kg potassium bromide and 3kg 2,2,6,6-tetramethylpiperidine oxide and close the lid. Vacuum 208kg sodium hypochlorite solution into the 500L high-position dripping tank, and slowly drip it into the reaction kettle, control the temperature to -4°C, keep it warm and stir for 4h after dripping for 2h. Into a 500L high-position dripping tank, vacuum-pump 600kg of 10% sodium bisulfite aqueous solution in batches and add it dropwise to the reaction kettle, control the temperature at 1°C, and complete the addition in 2.5 hours.

[0065]...

Embodiment 3

[0077] A method for preparing aliskiren intermediate includes the following steps:

[0078] S1. The synthesis of the first intermediate is as follows:

[0079] Pump 650kg of methylene chloride into the No. 1 2000L reactor, open the lid, and add 130kg of compound ((1S, 3S)-3-(hydroxymethyl-1-(2S, 4S)-tetrahydro-4- Isopropyl-5-oxo-2-furyl)pentyl) butyl carbamate was stirred and dissolved, and the temperature in the kettle was reduced to -6°C. Open the lid, put in 13kg potassium bromide and 5kg 2,2,6,6-tetramethylpiperidine oxide and close the lid. Vacuum 270kg sodium hypochlorite solution into the 500L high-position dripping tank, and slowly drip it into the reaction kettle, control the temperature at 0°C, keep it warm and stir for 4h after dripping for 2h. Into a 500L high-position dripping tank, vacuum-pump 600kg of 10% sodium bisulfite aqueous solution in batches and add it dropwise to the reactor, control the temperature at 5°C, and complete the addition in 3 hours.

[0080] Aft...

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Abstract

The invention relates to the technical field of preparation methods of medicines, and provides a preparation method of aliskiren to solve the problems of long reaction time and low yield of the existing preparation method. The preparation method includes the step S1 of preparation of a first intermediate: dissolving raw materials in a solvent, and adding sodium hypochlorite and sodium hydrogen sulfite for reaction to obtain the first intermediate; the step S2 of preparation of a second intermediate: adding a 4-bromo-1-methoxy-2-(3-methoxypropoxy)benzene and tetrahydrofuran solution dropwise tothe first intermediate and adding low deuterium water as a catalyst for reaction to obtain the second intermediate; the step S3 of preparation of an aliskiren intermediate: dissolving the second intermediate in ethyl acetate, then adding water, conducting nitrogen displacement and hydrogen displacement for three times respectively, and then adding hydrogen to have hydrogenation to obtain a product. By adding the low deuterium water as the catalyst, the reaction rate of the step S2 can be increased favorably, so that the reaction time is shortened, the reaction yield in the step S2 can be increased favorably, and the total reaction yield is increased according.

Description

Technical field [0001] The invention relates to the technical field of preparation methods of medicines, and more specifically, it relates to a preparation method of aliskiren intermediates. Background technique [0002] Aliskiren is a second-generation renin inhibitor that acts on the renin angiotensin aldosterone system (RAS). The chemical name of Aliskiren: (2S, 4S, 5S, 7S)-5-amino-N-(2-carbamoyl-2-methylpropyl)-4-hydroxy-2-isopropyl-7 -[4-Methoxy-3-(3-methoxypropoxy)benzyl]-8-methylnonanamide, the chemical structure is shown in I: [0003] [0004] At present, there are various preparation methods for Aliskiren, but the preparation of Aliskiren generally requires a multi-step reaction and the transformation of multiple intermediates to form the final product. The existing aliskiren preparation usually takes 4-methoxy-3-hydroxy-benzaldehyde as the raw material, after 2-3 steps of reaction, 4-methoxy-3-(3-methoxypropoxy )-Benzyl alcohol can be finally prepared to obtain aliski...

Claims

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Application Information

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IPC IPC(8): C07D307/33
CPCC07D307/33
Inventor 陈建林张雪皎
Owner 常州红太阳药业有限公司
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