CN1342650A

CN1342650A - Process for refining meloxicam

Info

Publication number: CN1342650A
Application number: CN 01128086
Authority: CN
Inventors: 刘学良; 王俊德; 于亿年
Original assignee: Dalian Institute of Chemical Physics of CAS
Current assignee: Dalian Institute of Chemical Physics of CAS
Priority date: 2001-08-24
Filing date: 2001-08-24
Publication date: 2002-04-03
Anticipated expiration: 2021-08-24
Also published as: CN1098265C

Abstract

A process for refining meloxicam, a new non-steroids antipyretic analgesics, includes such steps as adding the crude meloxicam to dimethyl formamide (DMF), thermal dissolving, decolouring, filtering, cooling the filtrate to educe out crystal; dissolving in alkaline alcohol solution, stirring while dripping the diluted hydrochloric acid to regulate pH value to 2-3, filtering, and washing the collected solid until it become neutral to obtain the product. Its advantages are simple process, no poison, and low DMF content.

Description

A kind of process for refining of meloxicam

Technical field

The present invention relates to a kind of new non-steroidal analgesic-antipyretic, be specially a kind of process for refining of meloxicam.

Background technology

Meloxicam is a kind of new non-steroidal analgesic-antipyretic, has higher anti-inflammatory activity and good especially enteron aisle tolerance, and does not have renal toxicity, and internally rheumatic arthritis and osteoarthritis have significant curative effect, go on the market at home in calendar year 2001.

United States Patent (USP) (USPat.) 4,233,299 (1980), the process for purification that discloses a kind of meloxicam is to use tetrahydrofuran (THF) to carry out recrystallization, because the solubleness of meloxicam in tetrahydrofuran (THF) is little, this method need be used a large amount of recrystallization solvents, and the ratio of solvent and meloxicam reaches 50: 1 (v/w); In addition, tetrahydrofuran (THF) is a kind of inflammable and explosive organic solvent, and unstable in air, and the dangerously explosive superoxide of easy oxidized generation brings hidden danger to production safety, should avoid using.

It is recrystallization solvent (Xu Youjun that the another kind of process for purification of meloxicam is to use dimethyl formamide (DMF), Liu Feng; Yang Zhi Min, synthetic chemistry, 1999,7:118), though can the purifying meloxicam, dimethyl formamide content residual in the finished product is very high, usually above 1000ppm, the allowed band that is higher than Chinese Pharmacopoeia far away must manage to remove the dimethyl formamide in the finished product.

Summary of the invention

The object of the present invention is to provide that a kind of technology is simple, safety non-toxic, can effectively reduce the process for refining of the meloxicam of dimethyl formamide (DMF) content in the finished product.

Technical scheme of the present invention is to operate as follows:

1. with meloxicam recrystallization of dimethyl formamide (DMF), carry out preliminary purification:

With meloxicam first product and DMF (g) by weight: volume (mL) is to mix in 1: 5～1: 7, is heated to meloxicam is all dissolved, and use activated carbon decolorizing, filters, and the filtrate cooling is filtered up to separating out the meloxicam crystal fully, the collection solid;

2. with the meloxicam behind the preliminary purification, further handle, remove dimethyl formamide with alkaline alcohol solution:

The meloxicam that above-mentioned steps is obtained is (g) by weight: volume (mL) is to be dissolved in alkaline alcohol solution in 1: 1～1: 3 (wherein the concentration range of alkali is in 1～2mol/L), stir and drip dilute hydrochloric acid down, its concentration range is 5～7mol/L, being adjusted to the pH value of solution value is 2～3, filter, collect solid, use ethanol, water, water, washing with alcohol successively, obtain the meloxicam finished product to neutral;

Described alkaline alcohol solution is one of ethanol hydro-oxidation sodium, ethanol hydro-oxidation potassium, propyl alcohol hydro-oxidation sodium, propyl alcohol hydro-oxidation potassium, Virahol hydro-oxidation sodium and Virahol hydro-oxidation potassium.

Advantage of the present invention is as follows:

1. technology is simple.The present invention is directed to the bigger characteristics of meloxicam changes in solubility in DMF, adopted the DMF recrystallization, handle meloxicam in conjunction with alkaline alcohol solution simultaneously, the DMF that carries secretly in the meloxicam is dissolved in the alcohol and removes, the potential of hydrogen of re-adjustment solution is separated out meloxicam, has removed harmful DMF simply from the meloxicam first product, avoid using a large amount of inflammable and explosive tetrahydrofuran (THF)s, simplified the purifying process of meloxicam.

2. safety non-toxic.The ratio (v/w) of recrystallization solvent consumption of the present invention and meloxicam has dropped to 5: 1 from 50: 1, and the DMF security is better.

3. can effectively reduce the DMF content in the finished product.The present invention is owing to increased the alkaline alcohol solution treatment step, and the DMF content in the finished product is usually from reducing to below the 10ppm more than the 1000ppm.

Embodiment

Following example is specifically addressed the present invention, but is not limited thereto.

Embodiment 1

With the refining meloxicam of the alkaline dehydrated alcohol that contains sodium hydroxide, concrete steps are as follows:

1. the recrystallization of meloxicam:

20g meloxicam first product and 100mLDMF are placed the 250mL round-bottomed flask, be heated to meloxicam is all dissolved, use activated carbon decolorizing, filter, the filtrate cooling is filtered up to separating out the meloxicam crystal fully, collect solid, obtain 17g meloxicam crystal, the rate of recovery is not less than 80%;

2. the purifying of meloxicam:

Get the meloxicam solid 10g that the step obtains, be dissolved in the 20mL alkalescence dehydrated alcohol that contains 1.14g sodium hydroxide, stir down, drip dilute hydrochloric acid, its concentration is 6mol/L, to the pH value of solution value be 2, filter, collect solid, use ethanol, water, water, washing with alcohol successively to neutral, obtain meloxicam finished product 9.5 grams, the rate of recovery is not less than 90%.

Detect through combined gas chromatography mass spectrometry (GC-MS), the DMF residual quantity has been reduced to 8ppm from 1200ppm, has reached the requirement of Chinese Pharmacopoeia.

Embodiment 2

With the refining meloxicam of the alkaline dehydrated alcohol that contains potassium hydroxide, concrete steps are as follows:

1. adopt the method preliminary purification meloxicam of step 1 among the embodiment 1;

2. adopt the refining meloxicam of method of step 2 among the embodiment 1, its difference is: just change sodium hydroxide into potassium hydroxide, consumption is 1.59g, and the meloxicam finished product that obtains detects through GC-MS, the DMF residual quantity has been reduced to 8ppm from 1200ppm, has reached the requirement of Chinese Pharmacopoeia.

Embodiment 3

With the refining meloxicam of the alkaline propyl alcohol that contains sodium hydroxide, concrete steps are as follows:

1. get meloxicam first product 50 gram and DMF300mL, adopt the method preliminary purification meloxicam of step 1 among the embodiment 1, obtain meloxicam crystal 43 grams;

2. adopt the refining meloxicam of method of step 2 among the embodiment 1, its difference is: the meloxicam 35g that gets preliminary purification, change dehydrated alcohol into propyl alcohol, consumption is 100mL, and sodium hydrate content is 5.7g in the solution, dripping dilute hydrochloric acid to pH value of solution value is 3, dilute hydrochloric acid concentration is 5mol/L, obtains meloxicam finished product 32.8 grams, detects through GC-MS, the DMF residual quantity has been reduced to 8ppm from 1500ppm, has reached the requirement of Chinese Pharmacopoeia.

Embodiment 4

With the refining meloxicam of the alkaline Virahol that contains sodium hydroxide, concrete steps are as follows:

1. get meloxicam first product 120 gram and DMF800mL, adopt the method preliminary purification meloxicam of step 1 among the embodiment 1, obtain meloxicam crystal 104 grams;

2. adopt the refining meloxicam of method of step 2 among the embodiment 1, its difference is: the meloxicam 100g that gets preliminary purification, change dehydrated alcohol into Virahol, consumption is 100mL, and sodium hydrate content is 5.7g in the solution, dripping dilute hydrochloric acid to pH value of solution value is 3, dilute hydrochloric acid concentration is 7mol/L, obtains meloxicam finished product 92 grams, detects through GC-MS, the DMF residual quantity has been reduced to 8ppm from 2000ppm, has reached the requirement of Chinese Pharmacopoeia.

Solvent of the present invention is the commercially available prod, and it is as follows to originate:

Dimethyl formamide (DMF), the federal chemical reagent work in Shenyang City, Liaoning

Dehydrated alcohol, the federal chemical reagent work in Shenyang City, Liaoning

Propyl alcohol, the federal chemical reagent work in Shenyang City, Liaoning

Virahol, the federal chemical reagent work in Shenyang City, Liaoning

Reagent of the present invention is the commercially available prod, and it is as follows to originate:

Meloxicam, Shandong Xinhua Pharmaceutical Factory

Sodium hydroxide, the federal chemical reagent work in Shenyang City, Liaoning

Potassium hydroxide, the federal chemical reagent work in Shenyang City, Liaoning

Gac, extraordinary chemical reagent development centre, North China

Claims

1. the process for refining of a meloxicam is characterized in that operating as follows:

1) with meloxicam recrystallization of dimethyl formamide, carry out preliminary purification:

With meloxicam first product and dimethyl formamide (g) by weight: volume (mL) is to mix in 1: 5～1: 7, is heated to meloxicam is all dissolved, and use activated carbon decolorizing, filters, and filtrate is cooled to the meloxicam crystal and separates out fully, filters the collection solid;

2) with the meloxicam behind the preliminary purification, further handle with alkaline alcohol solution, remove dimethyl formamide:

The meloxicam that above-mentioned steps is obtained is (g) by weight: volume (mL) is to be dissolved in the alkaline alcohol solution in 1: 1～1: 3, the concentration of alkali is 1～2mol/L in the described alkaline alcohol solution, stir and drip dilute hydrochloric acid down, its concentration range is 5～7mol/L, being adjusted to the pH value of solution value is 2～3, filters, and collects solid, use ethanol, water, water, washing with alcohol to neutral successively, obtain the meloxicam finished product.

2. according to the process for refining of the described meloxicam of claim 1, it is characterized in that: described alkaline alcohol solution is one of ethanol hydro-oxidation sodium, ethanol hydro-oxidation potassium, propyl alcohol hydro-oxidation sodium, propyl alcohol hydro-oxidation potassium, Virahol hydro-oxidation sodium and Virahol hydro-oxidation potassium.