CN102718747B - Olprinone hydrochloride derivate and synthetic method thereof - Google Patents

Abstract

The invention relates to an Olprinone hydrochloride derivate II, namely 1, 2-dihydro-5-imidazo [1, 2-a] pyridine-6-radical-6-methyl-2-oxo-3-picolinic acid, as well as a synthetic method and application of the Olprinone hydrochloride derivate II. The Olprinone hydrochloride derivate II is one of hydrolysis products of Olprinone hydrochloride, as well as one of main impurities of an Olprinone hydrochloride medicine and a preparation thereof; and the derivate II can be used for analyzing and detecting the purity of the Olprinone hydrochloride, and controlling the quality of the Olprinone hydrochloride. The invention discloses a synthetic method of the impurities in the Olprinone hydrochloride and the preparation thereof, and application of prepared impurity reference substances in the quality control of the Olprinone hydrochloride and the preparation thereof.

Description

Olprinone HCl derivative and synthetic method thereof

Technical field

The invention belongs to and belong to chemical field of medicaments, specifically disclose a kind of Olprinone HCl derivative II, 1,2-dihydro-5-imidazo [1,2-a] pyridine-6-base-6-methyl-2-oxo-acidum nicotinicum, and synthetic method, and purposes.

Background technology

Olprinone HCl is a kind of medicine that is used for the treatment of acute heart failure disease.Olprinone HCl optionally hinders the special phosphodiesterase (PDE of cAMP

), strengthen myocardial contraction, vasodilation, thus reach therapeutic purpose.

The chemistry of Olprinone HCl derivative II is by name: 1,2-dihydro-5-imidazo [1,2-a] pyridine-6-base-6-methyl-2-oxo-acidum nicotinicum, and structure is as follows:

In the detection of Olprinone HCl drug quality, find carrying out, compound ii is present in Olprinone HCl and preparation as impurity.

Through structural confirmation and mass analysis checking, compound ii is the impurity that in Olprinone HCl building-up process, partial hydrolysis produces.

The people of this area knows: synthesize highly purified known impurities compound, by this compound product in contrast, for containing the drug testing of this impurity, be very necessary for the quality of controlling this medicine, but open source information does not also have the relevant report of compound ii and synthetic method thereof.

Therefore, our urgent problem is now, how synthetic compound II.

Summary of the invention

We find all to contain 1 impurity in Olprinone HCl raw material and preparation in the quality examination process of carrying out Olprinone HCl bulk drug and preparation, definite through scrutinizing, and find that in surprise this impurity is compound shown in formula II.

The invention discloses compound ii, and the synthetic method of compound ii is provided.

Compound ii can be hydrolyzed by olprinone or olprinone hydrochloride under alkaline condition, then obtains after acidifying, and synthetic route is as follows:

Reaction solvent is water or water and organic solvent.Alkaline matter is sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydride, sodium bicarbonate, preferably sodium hydroxide.Make alkaline hydrolysis reagent with sodium hydroxide, extent of reaction is suitable, and product yield is higher.

The organic solvent being used in conjunction with alkaline aqueous solution can be methyl alcohol, ethanol, Virahol, ether, acetone etc., particular methanol.

The synthetic method of compound ii is:

(1) in olprinone or olprinone salt, add alkali, water, stirs reacting by heating;

(2) reacted, added Glacial acetic acid and regulate reaction solution to neutral, be chilled to room temperature, separated out solid, suction filtration;

(3) dry, obtain derivative II.

Its synthetic method can be also:

(1) in olprinone or olprinone salt, add alkali, water and organic solvent, stir reacting by heating;

(2) reacted, added Glacial acetic acid and regulate reaction solution to neutral, be chilled to room temperature, separated out solid, suction filtration;

(3) dry, obtain derivative II.

Organic solvent is methyl alcohol, ethanol, Virahol, ether, acetone etc.Particular methanol.

The proportioning of water and organic solvent is 1:0.1 ~ 1.0.Best with 1:0.4.

Reaction comprises sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydride, sodium bicarbonate with alkali, preferably sodium hydroxide.

Purification process is recrystallization simply, also can use column chromatography, or adopts liquid phase separation preparation.Recrystallization solvent can be used methyl alcohol, ethanol, Virahol, water or methanol-water, ethanol water, isopropanol water etc.Also can adopt the preparation of column chromatography or liquid phase separation, its moving phase is degree or the gradient elution such as methanol-water or acetonitrile water or methyl alcohol, acetonitrile water, accepts product flow point, is concentrated into dry product.Product selective finishing method as required, generally selects and does standard substance or reference substance, and purity generally needs more than 90%, more selects more than 98%, most preferably more than 99%.We show in research, can obtain the above product of purity 99%, can be used to do quality approach completely.Can be used for impurity standard substance or impurity reference substance in Control of drug quality.

We study and show, in Olprinone HCl bulk drug and preparation, impurity HPLC peak position is consistent with our synthetic compound II liquid phase retention time, and liquid matter molecular weight is consistent, and its compound ii nuclear magnetic data ownership rationally.Therefore illustrate that synthetic compound II is the impurity in Olprinone HCl bulk drug and preparation, determine through LC-MS, both molecular weight are consistent.

Compound ii proton nmr spectra data: ¹h NMR(CDCl ₃): δ 2.39(3H), 7.26-7.29(1H), 7.61-7.64(2H), 7.95(1H) and, 8.19(1H), 8.65(1H)

Therefore explanation, the compound ii of our synthesized is the impurity existing in Olprinone HCl and preparation thereof.

Embodiment

embodiment 1 compound

synthetic method 1

In three mouthfuls of reaction flasks, add 20g Olprinone HCl, 120gNaOH, water 600mL, stir, reflux, reacts 12 hours, reaction completes, and adds Glacial acetic acid and regulates reaction solution to neutral, is naturally chilled to room temperature, separate out a large amount of solids, suction filtration, is dried to obtain crude product, carry out recrystallization with second alcohol and water again, be naturally chilled to room temperature, separate out a large amount of solids, suction filtration, is dried to obtain off-white color solid 17.2g, is compound , yield 79.9%, HPLC areas of peak normalization method content 99.1%.

Proton nmr spectra data: ¹h NMR(CDCl ₃): δ 2.39(3H), 7.26-7.29(1H), 7.61-7.64(2H), 7.95(1H) and, 8.19(1H), 8.65(1H)

Mass spectrum (m/z) ⁺: 270.8

embodiment 2 compounds

synthetic method 2

In three mouthfuls of reaction flasks, add 20g Olprinone HCl, 120gNaOH, water 1800mL, stir, reflux, reacts 12 hours, and reaction completes, add Glacial acetic acid and regulate reaction solution to neutral, be naturally chilled to room temperature, separate out a large amount of solids, suction filtration, dry, obtain crude product, carry out recrystallization with first alcohol and water again, be naturally chilled to room temperature, separate out a large amount of solids, suction filtration, is dried to obtain off-white color solid 17.1g, is compound , yield 79.5%, HPLC areas of peak normalization method content 99.1%.

embodiment 3 compounds

synthetic method 3

In three mouthfuls of reaction flasks, add 20g Olprinone HCl, 120gNaOH, water 600mL, methyl alcohol 240mL, stirs, and reflux, reacts 12 hours, reaction completes, and adds Glacial acetic acid and regulates reaction solution to neutral, is naturally chilled to room temperature, separates out a large amount of solids, suction filtration, dry, obtain crude product, carry out recrystallization with second alcohol and water again, be naturally chilled to room temperature, separate out a large amount of solids, suction filtration, is dried to obtain off-white color solid 16.2g, is compound

, yield 75.3%, HPLC areas of peak normalization method content 99.6%.

the different proportionings of embodiment 4 water-methanols are to compound

the impact of preparing yield, quality

According to compound

synthetic method 3, select the proportioning of water and methyl alcohol to be respectively 1:0.1,1:0.4,1:0.5,1:0.6,1:0.7,1:0.8, complete 8 experiments, obtain 8 samples, its yield, qualitative data sees the following form:

Conclusion: water: methyl alcohol is 1:0.4, and yield is better, best in quality.

embodiment 5 compounds

application in the HPLC of Olprinone HCl detects

HPLC testing conditions: with being that octadecane base key and silica gel are weighting agent (end group sealing, BDS post); Take phosphate buffered saline buffer (Sodium phosphate dibasic: SODIUM PHOSPHATE, MONOBASIC: quality than as 1:3.44:320.51)-methyl alcohol (70:30), mix afterwards with phosphoric acid adjusting PH to 5.5, detection wavelength is 254nm; Theoretical plate number is calculated and should be not less than 1500 by Olprinone HCl.

Get Olprinone HCl appropriate, add appropriate Olprinone HCl derivative

, with distilled water diluting, configuration, into about the biased sample solution of 0.2mg/ mL, is got 20uL and is injected sample introduction, under above HPLC condition, detects and separates.

Claims (9)

1. a derivative II for Olprinone HCl, derivative II is shown below:

（Ⅱ）。

2. Olprinone HCl derivative II according to claim 1, is characterized in that: derivative II obtains take olprinone or olprinone salt as the preparation of reaction starting raw material.

3. Olprinone HCl derivative II according to claim 2, its synthetic method is:

(1) in olprinone or olprinone salt, add alkaline matter, water, stirring heating reaction;

(2) reacted, added Glacial acetic acid and regulate reaction solution to neutral, be chilled to room temperature, separated out solid, suction filtration;

(3) dry, obtain crude product, more purified more than 99% derivative II of purity that obtains.

4. Olprinone HCl derivative II according to claim 2, its synthetic method is:

(1) in olprinone or olprinone salt, add alkaline matter, water and organic solvent, stirring heating reaction;

(2) reacted, reaction solution adds Glacial acetic acid and is adjusted to neutrality, is chilled to room temperature, separates out solid, suction filtration;

(3) dry, obtain derivative II.

5. Olprinone HCl derivative II according to claim 4, is characterized in that: organic solvent is selected methyl alcohol or ethanol.

6. Olprinone HCl derivative II according to claim 4, is characterized in that: the proportioning of water and organic solvent is 1:0.1 ~ 1.0.

7. according to Olprinone HCl derivative II described in claim 3 or 4, it is characterized in that: alkaline matter is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydride or sodium bicarbonate.

8. Olprinone HCl derivative II according to claim 1, is characterized in that: derivative II is for the quality control of olprinone and salt thereof.

9. Olprinone HCl derivative II according to claim 1, is characterized in that: compound

the HPLC that is applied to Olprinone HCl detects, and detection method is as follows:

HPLC testing conditions: be with octadecane base key and silica gel be weighting agent, end group sealing, BDS post; With phosphate buffered saline buffer-methyl alcohol of 70:30, phosphate buffered saline buffer is by Sodium phosphate dibasic: SODIUM PHOSPHATE, MONOBASIC: quality, than forming for 1:3.44:320.51, mixes rear use phosphorus acid for adjusting pH to 5.5, and detection wavelength is 254nm; Theoretical plate number is calculated and should be not less than 1500 by Olprinone HCl;

Get Olprinone HCl appropriate, add appropriate Olprinone HCl derivative

, with distilled water diluting, configuration, into about the biased sample solution of 0.2mg/ mL, is got 20uL and is injected sample introduction, under above HPLC condition, detects and separates.