SK9892003A3 - An improved process for preparing pure ondansetron hydrochloride dihydrate - Google Patents

Abstract

An improved method for preparing dimethylamino-methyl-carbazolone and ondansetron base. A recrystallization process for preparing pure ondansetron hydrochloride dihydrate with a purity of at least 99.0% is also disclosed.

Description

The present invention relates to a method of preparation

The present invention relates to an improved dimethylaminomethylcarbazolone. This invention also provides an improved process for preparing ondansetron base also an improved process for recrystallizing ondansetron hydrochloride dihydrate to produce pure ondansetron hydrochloride dihydrate.

BACKGROUND OF THE INVENTION

Also known as 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one, Ondansetron is a potent and highly selective serotonin antagonist ( 5-HT 3, 5-hydroxytryptamine receptor 3) and has the following formula:

Ondansethron is commonly available as an anti-emetic, especially for cancer chemotherapy and for some other uses as an antidepressant, anti-migraine agent and antipsychotic. It is generally used to alleviate cognitive disorders such as Alzheimer's disease, in the treatment of rhinitis, psychiatric disorders, insomnia, and in the control of addiction to narcotics.

U.S. Pat. No. 4,695,578 assigned to Glaxo Group Limited describes a process for preparing ondansetron and its use. However, Ondansetron prepared according to this process contains impurities and by-products such as e.g. 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one.

Accordingly, there is still a need for an improved process for preparing ondansetron of high purity to meet standards for clinical use.

pharmaceutical zu is to enter purity (i.e.

SUMMARY OF THE INVENTION

The known processes for the preparation of ondansetron do not reach the stated purity and color. The essence of the present invention meets the requirements of the art (at least 99.0% high) and color improvement.

Another object of the present invention is to prepare pure ondansetron hydrochloride dihydrate thoroughly free of all impurities and by-products such as e.g. 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one (i.e., exomethylene by-products).

It is a further object of the present invention to provide ondansetron hydrochloride dihydrate having a purity of at least 99.0%. More preferably, the ondansetron hydrochloride dihydrate has a purity of at least 99.5%. Most preferably, the ondansetron hydrochloride dihydrate has a purity of at least 99.9%.

It is another object of the present invention to provide a process for the preparation of dimethylamino-methyl-carbazone. This method includes the following steps:

a)

b)

c)

d)

e)

a)

b)

c)

d)

e)

a)

b) preparing a methylcarbazolone solution;

heating the solution in the presence of dimethylamine hydrochloride and paraformaldehyde;

alkalizing the solution to form a precipitate;

separating the precipitate from solution to give dimethylamino-methylcarboazolone and drying dimethylamine-methylcarbazolone.

Another object of the present invention is a process for preparing ondansetron base. This method includes the following steps:

preparing a solution of methyl-imidazole and dimethylamino-methylcarbazolone; heating the solution;

removing the precipitate containing ondansetron base; washing the precipitate and drying the precipitate to form a pure ondansetron base.

Another object of the present invention is a process for the preparation of ondansetron hydrochloride dihydrate. This method includes the steps of:

preparing a solution of ondansetron base acidifying the solution with hydrogen chloride to form a precipitate, washing the precipitate and crystallizing ondansetron hydrochloride dihydrate

DETAILED DESCRIPTION OF THE INVENTION

C)

d)

As used herein, the term "exo-methylene by-product" refers to 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4one. This is one of the major impurities in the preparation of ondansetron. Another impurity in the preparation of ondansetron is the dimeric exomethylene by-product.

Unless otherwise indicated, "% refers to% wt.

As used herein, the term "pure ondansetron" refers to ondansetron thoroughly devoid of exo-methylene by-products and having a purity of at least about 99.0%.

As used herein, the term "hydrogen chloride" refers to both hydrogen chloride gas and a solution of hydrogen chloride gas in water.

As used herein, the term "equivalent" refers to the molar equivalent.

As used herein, the term "vacuum distillation" refers to the separation of solids from liquids by passing the mixture through a vacuum filter.

As used herein, the term "reflux" refers to a chemical process where part of the product flow can be returned to the process to increase the degree of conversion, such as e.g. For distillation or liquid-liquid extraction.

As used herein, the term "filter cake" refers to a concentrated solid or semi-solid material that has separated from the liquid and remains on the filter after pressure filtration.

The present invention is an improved process for preparing pure ondanstrone hydrochloride dihydrate having a purity of at least 99.0%. More preferably, ondansetron hydrochloride dihydrate has a purity of at least 99.5%.

Most preferably, ondansetron hydrochloride dihydrate has a purity of at least

99.9%.

The present invention provides an improved process for the preparation of dimethylaminomethyl-carbazolone. The present invention further provides an improved process for preparing ondansetron base. The present invention further provides an improved process for preparing pure ondansetron hydrochloride dihydrate.

Preparation of dimethylamino-methyl-carbazolone

The present invention provides a process for the preparation of diethylamino-methylcarbazolone comprising the steps of:

a) preparing a solution of methyl carbazolone of the formula

0 s X- Ν ' 1 R where R = C 1-4 alkyl) b) warming up solution of in the present c) basify solution of to form a precipitate

d) separating the precipitate from the solution to form dimethylaminomethylcarbazolone; and

e) drying the dimethylamino-methyl-carbazolone.

During the heating step, the solution is heated in the presence of dimethylamine hydrochloride and paraformaldehyde in an organic solvent. The solvent is preferably acetic acid.

Preferably, one equivalent of methyl carbazolone is refluxed with about 1.1 to 1.5 equivalents of dimethylamine hydrochloride and paraformaldehyde. Most preferably, one equivalent of methyl carbazolone is refluxed with about 1.2 equivalents of dimethylamine hydrochloride and paraformaldehyde. During the heating step, paraformaldehyde can be replaced by formaldehyde at reflux.

Preferably, one equivalent of methyl carbazolone is refluxed with about 4 to 16 parts by volume of acetic acid. Most preferably, one equivalent of methyl carbazolone is refluxed with about 4 volumes of acetic acid.

The heating step is preferably carried out at a temperature of about 70 ° C to 100 ° C. Most preferably, the heating step is performed at a temperature of about 80 to 90 ° C.

Heating step is carried out for a period of time about 6 to 2 4 hours. Most promising is the step hours. heating takes place after for about 6 to 2 Preferably, the step heating takes place without application vacuum

distillation or extraction. The heating step carried out without the use of vacuum distillation or extraction consistently produces a purer dimethylamino-methyl-carbazolone.

The present invention also provides a process for preparing pure dimethylaminomethyl-carbazolone further comprising dissolving the filter cake in acetone and treating with activated carbon and hydrogen chloride.

The water is preferably added during the update step after the addition of a basic basic solution of about 45% sodium hydroxide (NaOH) to a pH of about 13 to about 14. Preferably, the alkalization step is carried out in the presence of celite (10%). is.

The dry cake is preferably dissolved in acetone. The dissolved cake is treated with activated carbon and hydrogen chloride to precipitate dimethylamino-methyl-carbazolone.

Preparation of ondansetron base

a)

b)

c)

The present invention provides a process for synthesizing ondansetron base comprising the steps of:

preparing a solution of methyl imidazole and dimethylaminomethylcarbazolone of the formula

ABOUT

N (Me) 2. HCl (where

Removing the precipitate containing ondansetron base from the solution

d) washing the precipitate _e ) drying the precipitate to form pure ondansetron base.

The present invention further provides a process for the synthesis of consistently pure ondansetron base by the following additional steps: recrystallization in the presence of activated carbon and methanol.

During the step of preparing a solution of methyl-imidazole and dimethylaminomethyl-carbazolone, preferably about 4 to 6 equivalents of methylimidazole is added to one equivalent of dimethylamino-methyl-carbazolone, and most preferably about 5 equivalents of methylimidazole is added to one equivalent.

Preferably, this step is carried out in the presence of 10% celite.

Preferably, the present invention provides a process for preparing ondansetron base comprising (after step e) another step of recrystallizing ondansetron base in the presence of activated carbon and methanol.

Crystallization to prepare pure ondansetron hydrochloride dihydrate

The present invention provides an improved process for preparing pure ondansetron hydrochloride dihydrate. In particular, the preparation comprises crystallizing ondansetron hydrochloride dihydrate from a mixture of ondansetron base, water and activated carbon in the absence of an organic solvent.

The crystallization process of the present invention greatly increases the purity of ondansetron hydrochloride dihydrate and dramatically reduces the content of impurities represented by exomethylene by-products. Preferably, the crystallization step is performed 1-3 times. Most preferably, the crystallization step is performed twice.

The present invention provides a process for crystallizing ondansetron hydrochloride dihydrate comprising the steps of:

(a) preparing a solution of ondansetron base

b) acidifying the solution with hydrogen chloride to form a precipitate

c) washing the precipitate; and

d) crystallizing pure ondansetron hydrochloride dihydrate.

Preferably, the solution preparation step is carried out by adding about 3 to 7 parts by volume of water to the ondansetron base. Most preferably, the solution preparation step is performed by adding about 5 volumes of water to the ondansetron base.

The acidification step is preferably carried out by the addition of hydrochloric acid. Preferably, about 1.0 to 1.4 equivalents of about 32% (v: v) of hydrochloric acid is added to induce precipitation. Most preferably, about 1.1 equivalents of about 32% (v: v) of hydrochloric acid is added to induce precipitation. More preferably, the acidification step is performed at a pH of about 1 to about 4. Most preferably, the acidification step is performed at a pH of about 3.

The washing step is preferably performed using isopropanol. Preferably, about 5 to about 15 mL of isopropanol is used to wash the precipitate. Most preferably, about 10 mL of isopropanol is used to wash the precipitate.

The crystallization step is preferably performed by adding about 3 to about 5 parts by volume of water to induce crystallization. Most preferably about 4 volumes of water are used to induce crystallization.

Preferably, the crystallization step is carried out in the presence of activated carbon. The activated carbon is preferably selected from the group consisting of SX-2, CA-1, CXV and SX-1 ·.

Preferably, the crystallization step is carried out in the presence of about 5 to about 15% SX-1 activated carbon. Most preferably, the crystallization step is carried out in the presence of about 10% SX-1 activated carbon.

The present invention is further illustrated by the following examples. The present invention is by no means limited to these examples. Even a person skilled in the art will understand how to change the preparations in the examples to obtain the desired results.

Examples

Example 1: Preparation of pure dimethylamino-methyl-carbazolone salt

To 180 mL of glacial acetic acid was added 45 g (0.226 mol, 1.0 eq) of methylcarbazolone, 22.4 g (0.275 mol, 1.22 eq) of dimethylamine hydrochloride and 9 g (0.3 mol, 1.33) equiv) paraformaldehyde.

The reaction was maintained at about 80 + 2 ° C for 12 hours, then 540 ml of water and 4.5 g of hichloride were charged to the reactor, the batch was cooled to about 10 ° C and basified with about 45% NaOH to a pH of about 13 to 20 ° C. about 14 while the batch temperature did not exceed about 25 ° C.

Thereafter, the batch was stirred at about 5 to about 10 ° C for an additional 1 hour, the precipitate formed along with the "highflow" was collected and dried in a vacuum oven at about 60 ° C to constant weight to give a crude product containing the "highflow".

The crude product was treated with 3.3 g of SX-1 activated carbon (NORI) in 990 mL of acetone, filtered, cooled to about 25 ° C and bubbled with hydrogen chloride until the pH reached 3.

The batch was cooled to about 0 to about 5 ° C, held at this temperature for half an hour, filtered, washed with about 20 mL acetone and dried in an oven at about 50 ° C to constant weight to give 49.6 g of dimethylamino- methyl-carbazolone HCl.

Example 2: Preparation of pure ondansetron base

To 330 mL of water was added 33 g (0.112 mol, 1 eq.) Of dimethylaminomethyl-carbazolone-HCl, 3.3 g highflow and 46.3 g (0.563 mol, 5 eq.) Of methyl imidazole. The reaction mixture was heated at reflux (reflux) for 12 hours and then cooled to about 10 ° C, the precipitate was filtered, washed 3x with 300 ml of water and dried in a vacuum oven at about 60 ° C to constant weight to give a crude highflow containing compounds.

The crude compound was treated with 1.5 g of SX-1 activated carbon (NORIT) in 930 mL of methanol, filtered (hot filtration) from hihgflow and activated carbon and crystallized for one hour at about 0 to about 5 ° C. The hot filtration was at about 60 ° C and the methanol was near its boiling point (i.e. about 65 ° C). The precipitate was collected by filtration, washed with 2 x 20 mL cold methanol and dried in a vacuum oven at about 60 ° C to constant weight to give 21.3 g of ondansetron.

Example 3: recrystallization of ondansetron hydrochloride dihydrate

Ondansetron-HCl-2H ₂ O crystallized twice from 1: 4 w / v water and about 10% w / w. SX-1 activated carbon (NORI) at about 95 ° C for half an hour, filtered (hot filtration), washed with 1 volume water, cooled to about 5 ° C, and held at this temperature for about 1 hour. The crystals were separated, washed with about 10 mL of cold isopropanol and dried to give pure ondansetron-HCl-2H ₂ O. The obtained pure ondansetrin hydrochloride dihydrate was tested by HPLC to a purity of at least 99.0%. The obtained pure ondansetron hydrochloride dihydrate contained less than 0.01% exomethylene by-products or undetectable impurities.

Claims (1)

PATENT CLAIMS 1. dihydrate hydrochloride ondansetron ABOUT clean at least 99.0 5 Second dihydrate hydrochloride ondansetron about clean at least cc c. _>> _t a ABOUT, C Third dihydrate hydrochloride ondansetron about clean at least 99, 9 p. about A process for preparing dimethylamino-methyl-carbazolone comprising the steps of: (a) preparing a solution of methyl carbazolone of the formula: (wherein R = C 1-4, alkyl) b) heating the solution in the presence of dinethylamine hydrochloride and paraformaldehyde; c) alkalizing the solution to form a precipitate; d) separating the precipitate from the solution; e) drying the precipitate. 5th methyl 5. The method of claim 4 wherein R is The method of claim 4, wherein the heating step is carried out at a temperature of about 70 ° C to about 100 ° C. 7th The method of claim 4, wherein the heating step is carried out at a temperature of from about 80 ° C to about 90 ° C. The method of claim 4, wherein the heating step is carried out for a period of from about 6 to about 24 hours. The method of claim 4, wherein the heating step is carried out for a period of about 6 to about 12 hours. The method of claim 4, wherein the heating step is carried out in acetic acid. 11. The process of claim 4, wherein about one equivalent of methylcarbazolone is heated in the presence of about 1.1 to about 1.5 equivalents of dimethylamine hydrochloride and paraformaldehyde. The method of claim 4, wherein about one equivalent of methylcarbazolone is heated in the presence of about 1.2 equivalents of dimethylamine hydrochloride and formaldehyde. The method of claim 4, wherein about one equivalent of methylcarbazolone is heated in the presence of about 1.1 to about 1.5 equivalents of dimethylamine hydrochloride and paraformaldehyde. The method of claim 4, wherein about one equivalent of methylcarbazolone is heated in the presence of about 1.2 equivalents of dimethylamine hydrochloride and formaldehyde. The method of claim 4, wherein about one equivalent of methylcarbazolone is heated in the presence of about 4 to about 6 parts by volume of acetic acid. 16. The process of claim 4, wherein about one equivalent of methylcarbazolone is heated in the presence of about 4 volumes of acetic acid. 17. The process of claim 4, wherein the methylcarbazolone solution is basified with about 45% sodium hydroxide. The method of claim 17, wherein the methylcarbazolone solution is basified to a pH of about 13 to about 14. The method according to claim 17 or 18, wherein the alkalizing step is carried out in the presence of 10% celite. a) A process for preparing a base for preparing a solution of ondansetron comprising the steps of: methyl-imidazole and dimethylamino- (where R = c _M , alkyl) b) heating the solution; c) removing the precipitate containing ondansetron base from the solution; d) washing the precipitate; e) drying the precipitate to form pure ondansetron base. The method of claim 20, wherein the solution is prepared by adding about 4 to 6 equivalents of methylimidazole to one equivalent of diemtylamino-methylcarbazolone. The method of claim 20, wherein the solution is prepared by adding about 5 equivalents of methylimidazole to one equivalent of diemtylamino-methylcarbazolone. The method of claim 20, wherein the solution is prepared in the presence of 10% celite. 24. The method of claim 20, comprising the further step of recrystallizing the ondansetron base. is that by 25. The process of claim 24 wherein the recrystallization step is carried out in the presence of activated carbon and methanol. A process for preparing pure ondansetron hydrochloride dihydrate comprising the steps of: (a) preparing a solution of ondansetron base; b) acidifying the solution with hydrogen chloride to form a precipitate; c) washing the precipitate; d) crystallizing pure ondansetron hydrochloride dihydrate. . . 29th 30th 31st The method of claim 26 wherein about 3 to about 7 volumes of water is added to the ondansetron base to prepare ondansetron base. The method of claim 26, wherein about 5 parts by volume of water is added to the ondansetron base to prepare ondansetron base. The method of claim 26, wherein about 1.0 to about 1.4 equivalents of 32% (v: v) hydrochloric acid is added to acidify the solution to induce precipitation. The method of claim 26 wherein about 1.1 equivalents of 32% (v: v) hydrochloric acid is added to acidify the solution to induce precipitation. The method of claims 29 or 30, wherein the solution is acidified to a pH of about 1 to about 4. 32nd 33rd . 35th 36th The method of claims 29 or 30, v by acidifying the solution to a pH of about 3. y z n a č u j ú c i sa 10. The method of claim 26 the precipitate is washed with about 5 to about 15 ml of isopropanol. the T that Method according to Claim 26, characterized by the precipitate is washed with about 10 ml of isopropanol. u j ú c i the T that Method according to Claim 26, characterized by u j ú c i the T that the crystallization step is carried out by addition parts of water to induce crystallization 3 to about 5 volume Method according to Claim 26, characterized by u j ú c i the T that the crystallization step is carried out by addition water to induce crystallization. about 4 vol parts Method according to Claim 26, characterized by u j ú c i the T that the crystallization step is repeated twice. 37th . The process of claim 26 wherein the crystallization step is carried out in the presence of activated carbon. 39th The method of claim 36, wherein the activated carbon is selected from the group consisting of SX-2, CA-1, i. by SXV and SX40. The method of claim 39, wherein the activated carbon is about 5 to about 15% SX-1. because of 41st . 43rd . 45th 46th The method of claim 39, wherein the activated carbon is about 5 to about 10% SX-1. Ondansetron hydrochloride dihydrate prepared in accordance with the method of claim 26, characterized in that its purity is at least about 99.0%. Ondansetron hydrochloride dihydrate prepared in accordance with the method of claim 26, wherein its purity is at least about 99.5%. The ondansetron hydrochloride dihydrate prepared in accordance with the process of claim 26, wherein the purity is at least about 99.9%. A pharmaceutical composition comprising ondansetron hydrochloride dihydrate prepared in accordance with the method of claim 26, wherein the purity of ondansetron hydrochloride dihydrate is at least about 99.0%. A pharmaceutical composition comprising ondansetron hydrochloride dihydrate prepared in accordance with the method of claim 26, wherein the purity of ondansetron hydrochloride dihydrate is at least about 99.5%. A pharmaceutical preparation comprising ondansetron hydrochloride dihydrate prepared in accordance with the method of claim 26, wherein the purity of ondansetron hydrochloride dihydrate is at least about 99.9%. .