Method for preparing key intermediate of medicament

A process control and transparent liquid technology, applied in the field of medicine, can solve the problems of difficult industrial production and low product yield, and achieve the effect of high chiral purity and good chemical purity of the product

Active Publication Date: 2015-05-20
CHANGZHOU PHARMA FACTORY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The above-mentioned method for preparing compound I and II is difficult to realize industrialized production because the final product will be separated and purified by column chromatography, and the product yield is relatively low

Method used

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  • Method for preparing key intermediate of medicament
  • Method for preparing key intermediate of medicament
  • Method for preparing key intermediate of medicament

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Synthesis of (R)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyl bromide

[0028] (R-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutanol (14.82g, 50mmol) dissolved in N,N-dimethylformaldehyde Phosphorus oxybromide (14.33g, 50mmol) was slowly added dropwise to amide (234ml), the temperature was controlled at 20°C during the dropwise addition, and reacted at 20°C for 8 hours after the dropwise addition. Cool to room temperature, and slowly pour water (702ml) , extracted three times with n-hexane, combined the n-hexane layers, washed twice with saturated sodium bicarbonate and saturated sodium chloride respectively, dried the organic layer with anhydrous sodium sulfate, filtered, and concentrated the filtrate to obtain 17g of oily matter. Add methanol 51ml, Crystallize at -10°C, filter, and vacuum-dry the filter cake at room temperature to obtain 14.3 g of white solid, yield 79.6%. mp: 51-53°C, chiral purity above 99.9%. 1 HNMR (ppm, CDCl 3 ):6.72-6.81(m,3H),...

Embodiment 2

[0030] Synthesis of (R)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyl bromide

[0031] (R)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutanol (14.82g, 50mmol), N,N-dimethylformaldehyde Amide (0.4g, 5.5mmol) was dissolved in toluene (234ml), and phosphorus oxybromide (15.05g, 52.5mmol) was slowly added dropwise. During the dropping process, the temperature was controlled below 60°C. After the dropwise addition, it was reacted at 80°C for 2 hours. Cool to room temperature, add water (234ml), stir for 20 minutes, separate layers, extract the aqueous layer three times with petroleum ether, combine the organic layers, wash twice with saturated sodium bicarbonate and saturated sodium chloride, and wash the organic layer with anhydrous sulfuric acid It was dried over sodium, filtered, and the filtrate was concentrated to obtain 17.2 g of oil. Add ethyl acetate / n-hexane mixed solvent 17.2ml / 34.4ml, crystallize at -10°C, filter, and vacuum-dry the filter cake at room te...

Embodiment 3

[0033] Synthesis of (S)-2-(benzyloxymethyl)-3-methylbutyl bromide

[0034] (R)-2-(Benzyloxymethyl)-3-methylbutanol (15.6g, 75mmol) was dissolved in N,N-dimethylformamide (246ml), slowly added dropwise phosphorus oxybromide (22.58 g, 78.75mmol), the dropwise addition process controlled the temperature below 50°C, and reacted at 50°C for 3 hours after the dropwise addition. Cool to room temperature, slowly pour into water (246ml), extract three times with n-hexane, combine the n-hexane layers, wash twice with saturated sodium bicarbonate and saturated sodium chloride respectively, dry the organic layer with anhydrous sodium sulfate, filter, The filtrate was concentrated to obtain 18.1 g of oily substance, which was distilled under reduced pressure to obtain 16.6 g of a colorless transparent liquid with a yield of 81.1% and a chiral purity of over 99.9%.

[0035] 1 HNMR (ppm, CDCl3): 7.38-7.24 (m, 5H), 4.52 (s, 2H), 3.70 (dd, J=4.4Hz, 10Hz, 1H), 3.62 (dd, J=4.4Hz, 9.6Hz, 1H ),...

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Abstract

The invention relates to the field of medicines, and in particular relates to a method for preparing a key intermediate (II) of a medicament. The method is characterized in that the key intermediate is prepared by a reaction of a compound IV and phosphorus oxybromide. According to the preparation method, the defects that a compound II is prepared by using a column chromatography in the prior art and large-scale industrial production is difficult to realize by the prior art can be overcome, the key intermediate can be directly prepared by a re-crystallization or reduced-pressure distillation method, and the key intermediate is high in purity.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a preparation method of an antihypertensive drug Aliskiren intermediate. Background technique [0002] Cardiovascular disease, including hypertension, is the number one cause of death in the world, and is known as "the number one executioner of human health". At present, the antihypertensive drugs that have been marketed are mainly divided into the following categories: diuretics (thiazides), beta-blockers (lores), calcium antagonists (dipines), angiotensin Converting enzyme inhibitors (pril drugs), angiotensin II receptor antagonists (sartan drugs). Only 25% of patients with high blood pressure can be controlled with current drugs. Aliskiren is the first non-peptide renin inhibitor approved by the US FDA in 2007. It reduces the levels of angiotensin I and angiotensin II in the body by inhibiting the activity of renin to achieve relaxation. Vascular and blood pressure lowering effects....

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C43/174C07C41/22
CPCC07C41/22C07C43/174
Inventor 殷学治王兵计莹刘明元
Owner CHANGZHOU PHARMA FACTORY
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