AU2022100005A4

AU2022100005A4 - Method for refining omeprazole

Info

Publication number: AU2022100005A4
Application number: AU2022100005A
Authority: AU
Inventors: Shuang HUANG; Weisi LI; Qiang Xu; Yi XUE; Xiaobo Yang; Xiaoqing Zhang
Original assignee: Nanjing Costar Biotechnology Research Institute Co Ltd
Current assignee: Nanjing Costar Biotechnology Research Institute Co Ltd
Priority date: 2020-02-26
Filing date: 2022-01-14
Publication date: 2022-02-10
Anticipated expiration: 2028-06-05

Abstract

The invention discloses a method for refining omeprazole, belonging to the field of chemical synthesis. The method includes the steps of dissolution, decolorization, washing, pH adjustment, extraction and filtration, thereby obtaining the omeprazole refined product. According to the invention, the refining effect is good, the purity can reach 99.8% or above, the yield is 90% or above, and the method has the advantages of simple operation and low uncontrollabitlty and is suitable for industrial production.

Description

Method for Refining Omeprazole

TECHNICAL FIELD The invention belongs to the field of chemical synthesis, particularly relates to a

method for refining omeprazole, and more particularly relates to a method for refining

-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol

e.

BACKGROUND Omeprazole is a first-generation benzimidazole gastric acid proton pump inhibitor

developed by Astra, Sweden. It has a strong inhibitory effect on gastric acid, has

better curative effects than H 2 receptor antagonists, prostaglandin E 2 , sucralfate,

colloidal bismuth and large doses of antacids, and quickly improves symptoms of

peptic ulcer and reflux esophagitis. It is mainly used for gastric ulcer and duodenal

ulcer in clinic. The dual and triple combination regimens of omeprazole and

antibiotics can be used to treat peptic ulcers related to Helicobacter pylori (HP), reflux

esophagitis, and gastrinoma (Zollinger-Ellison syndrome). The omeprazole

intravenous injection can be used for the treatment of acute bleeding of peptic ulcers,

such as bleeding of acute gastric mucosal lesions. The drug has no serious side effects

and is well tolerated. The structural formula is as follows.

H S N

0 - N o 0

Chemical Strctural Fomula of Omeprazole

At present, there are few literature reports on purification and refinement processes of

omeprazole, and the main ones are CN1160050A, CN104592201 and CN109206406.

Among them, in the first two literatures, crude omeprazole is salified and acidified. In

CN1160050A, a solid acid salt is used for acidification in an aqueous solution. Since

the finally obtained omeprazole contains a large amount of inorganic salts, the finally

obtained omeprazole has a low content and since the omeprazole is finally

precipitated in an aqueous solvent, the omeprazole has low dispersibility and high

viscosity, is difficult to filter or centrifuge, and is not suitable for industrial production.

In CN104592201, carbon dioxide is used for acidification. Since omeprazole is more

sensitive to pH, poor flow control of carbon dioxide can easily cause omeprazole to

produce a large amount of impurities, and the use of carbon dioxide gas is not suitable

for industrial production. In the above two patents, the solvent for final refinement is

water. The omeprazole has poor stability in an aqueous solution, so it is easy to

produce impurities in the post-treatment process. In CN109206406, a supercritical

fluid chromatography system is used, and it is only suitable for small-scale research

and not suitable for industrial production.

Any references to prior art should not be taken as admissions of common general

knowledge in the field.

SUMMARY In view of the deficiencies of the prior art, the invention provides a method for

refining omeprazole, which has the advantages of good refining effects, high yield,

simple operation and low uncontrollabitlty and is suitable for industrial production.

The technical solution of the invention is:

A method for refining omeprazole is including the following steps:

1) adding crude omeprazole into an aqueous solution of an alkali, performing stirring until the crude omeprazole is dissolved and the solution is clear, washing the mixture with an organic solvent, and adding a reducing agent a chelating agent into the aqueous phase to prevent generation of impurities;

2) adjusting the pH of the aqueous phase with a weak acid or an acid salt to 7.0-8.5,

preferably 7.4-8.0, adding an organic solvent, and performing extraction with the

organic solvent; and

3) performing decolorization, desolventization, pulping and filtration on the organic

phase to obtain the omeprazole refined product.

Preferably, the alkali is one selected from sodium hydroxide, potassium hydroxide,

sodium carbonate and potassium carbonate, more preferably sodium hydroxide.

Preferably, the organic solvent for the washing is one of dichloromethane, chloroform,

ethyl acetate and toluene, more preferably dichloromethane.

Preferably, the decolorization method is decolorization with activated carbon, wherein

stirring is performed at 10-30°C for 10 min to 3 h, and the activated carbon is 1% to

% by weight of the omeprazole.

Preferably, the reducing agent added to the aqueous phase is sodium dithionite, the

chelating agent is disodium ethylenediaminetetraacetate (EDTA) and/or tetrasodium

ethylenediaminetetraacetate, and a molar ratio of the reducing agent to the chelating

agent is 1:1 to 1:4, more preferably 1:2.

Preferably, the weak acid or the acid salt for adjusting the pH is one of glacial acetic acid, sodium bicarbonate and potassium bicarbonate.

Preferably, the solvent for the pulping is one of dichloromethane, chloroform, ethyl

acetate, toluene and acetone, more preferably acetone.

Preferably, according to the method for refining omeprazole, the filtration is

performed at -10 to 20°C.

The crude omeprazole includes many impurities, the main impurity is peroxide, and

the method of the invention is aimed at removing the peroxide.

Beneficial effects

(1) According to the invention, in the step 1), the organic solvent is used for washing,

so that organic impurities that cannot be salified in the crude product can be removed,

and most of the peroxide impurities in the crude omeprazole can be removed.

(2) According to the invention, the reducing agent and the chelating agent added to the

aqueous solution of the omeprazole salt in the step 1) can effectively inhibit

generation of new impurities in the post-treatment process, which is more conducive

to improving the refining effect and reaching more stringent quality standards.

(3) According to the invention, the weak acid or the acid salt is used to adjust the pH

in the step 2), so that the conditions are milder, which is more conducive to pH

adjustment and reduces the risk of the increase in impurities caused by sensitivity of

omeprazole to acids.

(4) According to the invention, the activated carbon is used for decolorization in the

step 3), so that the decolorization effect is significant, thereby ensuring that the final

omeprazole refined product has a white appearance.

(5) According to the invention, the step 2) and the step 3) can avoid the risk of low

content caused by residual inorganic salts in omeprazole after pH adjustment.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is an HPLC chromatogram of crude omeprazole in Example 1 to Example 4

and Comparative Example 1.

FIG. 2 is an HPLC chromatogram of refined omeprazole in Example 1.

FIG. 3 is a hydrogen spectrum of refined omeprazole in Example 1.

FIG. 4 is a carbon spectrum of refined omeprazole in Example 1.

FIG. 5 is an MS (ESI-) of refined omeprazole in Example 1.

FIG. 6 is an MS (ESI+) of refined omeprazole in Example 1.

FIG. 7 is an HPLC chromatogram of refined omeprazole in Example 2.

FIG. 8 is an HPLC chromatogram of refined omeprazole in Example 3.

FIG. 9 is an HPLC chromatogram of refined omeprazole in Example 4.

FIG. 10 is an HPLC chromatogram of refined omeprazole in Comparative Example 1.

DETAILED DESCRIPTION In order to make the technical problems to be solved, technical solutions and

beneficial effects of the invention clearer, the invention will be further described in

detail below reference to the examples. However, this is not a limitation to the

invention. Any equivalent replacement in the field made according to the disclosure of

the invention belongs to the protection scope of the invention.

Example 1

Omeprazole refining process:

Step 1: 5.0 kg of purified water was pumped into a 20 L reactor, 2.0 kg of sodium

hydroxide was added into the reactor, and stirring was performed at room temperature

until the sodium hydroxide was dissolved and the solution was clear. 1.0 kg of crude

omeprazole (HPLC: 98.5%, as shown in FIG. 1) was added, and stirring was

performed at room temperature until the omeprazole crude product was dissolved and

the solution was clear. 2.5 kg of dichloromethane was pumped into the reactor, stirring

was performed at room temperature for 15±5 minutes, the mixture was allowed to

stand and subjected to liquid separation, the dichloromethane phase entered a waste

water bucket, and the upper aqueous layer was added into a clean reactor. 30 g of

EDTA and 36 g of sodium dithionite were added to the aqueous layer.

Step 2: 5 kg of dichloromethane was pumped into the aqueous phase reactor, and the

pH was adjusted with sodium bicarbonate to 8.5. After the pH adjustment was

completed, the mixture was allowed to stand and subjected to liquid separation. The

aqueous phase was subjected to extraction with 2 kg of dichloromethane. The upper

aqueous phase entered the waste water bucket, and the organic phases were mixed and

pumped into a clean reactor.

Step 3: the temperature in the reactor was controlled at 10°C, 10.0 g of medicinal

activated carbon was added, and the temperature was kept and stirring was performed

for decolorization for 3 h. Suction filtration was performed, the filter residue was

washed with 1.0 kg of dichloromethane, and the filtrates were mixed and pumped into

a clean reactor. The mixture was desolventized under reduced pressure and subjected

to distillation until a white solid was precipitated, 1.0 kg of acetone 1 was pumped in for distillation, the mixture was subjected to distillation until no liquid dripped out, and the distillation was stopped. 2.0 kg of acetone was pumped into the reactor, the mixture was subjected to pulping for 2.0 hours while keeping the temperature at 20C, the pulp was filtered, and the filter cake was dried at 35-45C under reduced pressure to obtain 0.96 kg of omeprazole refined product. Yield 96.0%, HPLC: 99.92%. 1HNMR (500 MHz, DMSO-d): 68.21(s, 1H), 67.31(d, 1H), 6.98(d, 1H), 6.56(m,1H),

4.71(d, 1H), 4.40(d, 1H), 3.69(d,6H), 2.2(d,6H); MS(m/z): 368.1[M+Na]+, 344[M-H]

The hydrogen spectrum is shown in FIG. 3, the carbon spectrum is shown in FIG. 4,

and the mass spectra are shown in FIGS. 5 and 6.

Example 2

Step 1: 6.0 kg of purified water was pumped into a 20 L reactor, 2.7 kg of sodium

carbonate was added into the reactor, and stirring was performed at room temperature

until the sodium carbonate was dissolved and the solution was clear. 1.0 kg of crude

omeprazole (HPLC: 98.5%, as shown in FIG. 1) was added, and stirring was

the solution was clear. 3 kg of ethyl acetate was pumped into the reactor, stirring was

performed at room temperature for 15+5 minutes, the mixture was allowed to stand

and subjected to liquid separation, the ethyl acetate phase entered a waste water

bucket, and the upper aqueous layer was added into a clean reactor. 30 g of EDTA and

18 g of sodium dithionite were added to the aqueous layer.

pH was adjusted with glacial acetic acid to 7.0. After the pH adjustment was

aqueous phase entered the waste water bucket, and the organic phases were mixed and pumped into a clean reactor.

Step 3: the temperature in the reactor was controlled at 30°C, 50.0 g of medicinal

for decolorization for 10 min. Suction filtration was performed, the filter residue was

to distillation until a large amount of white solid was precipitated, and the distillation

was stopped. The system was cooled to -10°C and subjected to pulping for 2.0 hours

while keeping the temperature, the pulp was filtered, and the filter cake was dried at

-45°C under reduced pressure to obtain 0.92 kg of omeprazole refined product.

Yield 92.0%, HPLC: 99.94% (the HPLC chromatogram of the refined omeprazole is

shown in FIG. 7).

Example 3

Step 1: 5.0 kg of purified water was pumped into a 20 L reactor, 2.8 kg of potassium

until the potassium hydroxide was dissolved and the solution was clear. 1.0 kg of

crude omeprazole (HPLC: 98.5%, as shown in FIG. 1) was added, and stirring was

the solution was clear. 3 kg of toluene was pumped into the reactor, stirring was

and subjected to liquid separation, the toluene phase entered a waste water bucket, and

the upper aqueous layer was added into a clean reactor. 15 g of EDTA, 17 g of

tetrasodium ethylenediaminetetraacetate and 72 g of sodium dithionite were added to

the aqueous layer.

pH was adjusted with glacial acetic acid to 7.5. After the pH adjustment was

pumped into a clean reactor.

Step 3: the temperature in the reactor was controlled at 20°C, 150.0 g of medicinal

for decolorization for 1 h. Suction filtration was performed, the filter residue was

washed with 3.0 kg of dichloromethane for 3 times, and the filtrates were mixed and

pumped into a clean reactor. The mixture was desolventized under reduced pressure

and subjected to distillation until a white solid was precipitated, 1.0 kg of ethyl acetate

was pumped in for distillation, the mixture was subjected to distillation until no liquid

dripped out, and the distillation was stopped. 3.0 kg of ethyl acetate was pumped into

the reactor, the mixture was subjected to pulping for 1.0 hour while keeping the

temperature at 10°C, the pulp was filtered, and the filter cake was dried at 35-45°C

under reduced pressure to obtain 0.94 kg of omeprazole refined product. Yield 96.0%,

HPLC: 99.92% (the HPLC chromatogram of the refined omeprazole is shown in FIG.

8).

Example 4

Step 1: 700 g of purified water was pumped into a 2 L reactor, 350 g of potassium

until the potassium carbonate was dissolved and the solution was clear. 100 g of crude

omeprazole (HPLC: 98.5%, as shown in FIG. 1) was added, and stirring was

performed at room temperature until the omeprazole crude product was dissolved and the solution was clear. 250 g of chloroform was pumped into the reactor, stirring was performed at room temperature for 15+5 minutes, the mixture was allowed to stand and subjected to liquid separation, the chloroform phase entered a waste water bucket, and the upper aqueous layer was added into a clean reactor. 3.4 g of tetrasodium ethylenediaminetetraacetate and 4 g of sodium dithionite were added to the aqueous layer.

Step 2: 500 g of dichloromethane was pumped into the aqueous phase reactor, and the

pH was adjusted with glacial acetic acid to 7.8. After the pH adjustment was

aqueous phase was subjected to extraction with 200 g of dichloromethane. The upper

pumped into a clean reactor.

Step 3: the temperature in the reactor was controlled at 20°C, 5.0 g of medicinal

washed with 100 g of dichloromethane, and the filtrates were mixed and pumped into

to distillation until a white solid was precipitated, 1.0 kg of toluene was pumped in for

distillation, the mixture was subjected to distillation until no liquid dripped out, and

the distillation was stopped. 250 g of toluene was pumped into the reactor, the mixture

was subjected to pulping for 3 hours while keeping the temperature at 5°C, the pulp

was filtered, and the filter cake was dried at 35-45°C under reduced pressure to obtain

91 g of omeprazole refined product. Yield 91.0%, HPLC: 99.87% (the HPLC

chromatogram of the refined omeprazole is shown in FIG. 9).

Comparative Example 1

At 0°C, 7.2 g of crude omeprazole (HPLC: 98.5%, as shown in FIG. 1) was added into

a 500 mL reaction flask, then a solution prepared from 1.5 g of potassium hydroxide

and 5 g of methanol was added, the mixture was stirred for 0.5 h and filtered, and

washing was performed with 8 g of methanol. After the filter cake was dissolved with

16 g of water, 0.2 g of activated carbon was added, the mixture was stirred for 1 h and

filtered, carbon dioxide was introduced into the filtrate while stirring until the pH

reached 9 finally, the mixture was filtered, washing was performed with deionized

water, and the filter cake was dried at 35-45°C under reduced pressure to obtain 3.1 g

of omeprazole refined product. Yield 43%, HPLC: 99.1% (the HPLC chromatogram

of the refined omeprazole is shown in FIG. 10).

Claims

1. A method for refining omeprazole, including the following steps:

1) adding crude omeprazole to an aqueous solution of an alkali, washing the

mixture with an organic solvent, and adding a reducing agent and a chelating agent to

the aqueous phase, wherein the reducing agent is sodium dithionite, and the chelating

agent is disodium ethylenediaminetetraacetate and/or tetrasodium

ethylenediaminetetraacetate;

2) adjusting the pH of the aqueous phase to 7.0-9.0, adding an organic solvent,

and performing extraction with the organic solvent; and

3) performing decolorization, desolventization, pulping and filtration on the

organic phase to obtain the omeprazole refined product.

2. The method for refining omeprazole as recited in claim 1, wherein the alkali in the

step 1) is one selected from sodium hydroxide, potassium hydroxide, sodium

carbonate and potassium carbonate.

3. The method for refining omeprazole as recited in claim 1, wherein a molar ratio of

the reducing agent to the chelating agent in the step 1) is 1:1 to 1:4.

4. The method for refining omeprazole as recited in claim 3, wherein the molar ratio

of the reducing agent to the chelating agent in the step 1) is 1:1 to 1:2.

5. The method for refining omeprazole as recited in any one of claims 1 to 4, wherein

the organic solvent in the step 1) and the step 2) is one of dichloromethane,

chloroform, ethyl acetate and toluene.

6. The method for refining omeprazole as recited in any one of claims 1 to 4, wherein

in the step 2), one of glacial acetic acid, sodium bicarbonate and potassium

bicarbonate is used to adjust the pH of the aqueous phase.

7. The method for refining omeprazole as recited in any one of claims 1 to 4, wherein

in the step 3), activated carbon is used for the decolorization, stirring is performed at

-30°C for 10 min to 3 h, and the activated carbon is 1% to 15% by weight of the

omeprazole.

8. The method for refining omeprazole as recited in any one of claims 1 to 4, wherein

in the step 3), a pulping solvent is used for the pulping, and the pulping solvent is one

of dichloromethane, chloroform, ethyl acetate, toluene and acetone.

9. The method for refining omeprazole as recited in any one of claims 1 to 4, wherein

in the step 3), the filtration is performed at -10 to 20°C.

10. The method for refining omeprazole as recited in claim 1, wherein

1) adding the crude omeprazole into an aqueous solution of sodium hydroxide,

performing stirring until the crude omeprazole is dissolved and the solution is clear,

washing the mixture with dichloromethane, and adding the reducing agent sodium

dithionite and the chelating agent disodium ethylenediaminetetraacetate into the

aqueous phase, wherein a molar ratio of the reducing agent to the chelating agent is

1:2;

2) adjusting the pH of the aqueous phase with a weak acid or an acid salt to

7.4-8.0, adding an organic solvent dichloromethane, and performing extraction with

the organic solvent dichloromethane; and

3) performing decolorization, desolventization, pulping and filtration on the organic phase to obtain the omeprazole refined product, wherein an acetone solvent is used for the pulping.