CN1496350A - Improved method for preparing pure ondansetron hydrochloride dihydrate - Google Patents

Abstract

An improved process for the preparation of dimethylamino-methyl-carbazolone and ondansetron base is disclosed, as well as a recrystallization process for the preparation of pure ondansetron hydrochloride dihydrate having a purity of at least 99.0%.

Description

Improved method for preparing pure ondansetron hydrochloride dihydrate

Cross References to Related Applications

This application claims the benefit of Provisional Application Serial No. 60/261,051, filed January 11, 2001, the entire disclosure of which is incorporated herein by reference.

field of invention

The present invention relates to an improved process for the preparation of dimethylaminomethylcarbazolones. The present invention relates to an improved process for the preparation of ondansetron base. The present invention also relates to an improved method of recrystallizing ondansetron hydrochloride dihydrate to obtain pure ondansetron hydrochloride dihydrate.

Background of the invention

Ondansetron is also known as 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazole-4 -ketone, which is an effective and highly selective serotonin (5-HT ₃ , serotonin receptor 3) antagonist, has the structure of the following formula:

Ondansetron is currently used as an antiemetic, especially as an antiemetic in cancer chemotherapy, and for a number of other uses such as antidepressants, antimigraines and antipsychotics. It is commonly used in the alleviation of cognitive disorders such as Alzheimer's disease, in the treatment of rhinitis, psychosis, in exacerbated alertness and in the management of dependence on narcotics.

A process for the preparation of ondansetron and its use is described in US Patent No. 4,695,578, assigned to Glaxo Group Limited. However, ondansetron prepared according to this method contains impurities and by-products such as 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one.

There is therefore a continuing need for improved processes for the preparation of ondansetron with high purity meeting the criteria for clinical use.

Purpose and summary of the invention

The known methods of preparing ondansetron do not achieve the high purity and color described pharmaceutically. It is an object of the present invention to meet the need in the art for high purity (ie, at least about 99.0%) and improved color.

Another object of the present invention is to prepare substantially free of any impurities and by-products such as 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one (such as exo-methylene by-product) pure ondansetron hydrochloride dihydrate.

Another object of the present invention is to prepare ondansetron hydrochloride dihydrate having a purity of at least about 99.0%. Preferably, said ondansetron hydrochloride dihydrate has a purity of at least about 99.5%. Most preferably said ondansetron hydrochloride dihydrate is at least about 99.9% pure.

Another object of the present invention is to provide a method for preparing dimethylamino-methyl-carbazolone, said method comprising the following steps:

a) preparing methyl-carbazolone solution;

b) heating said solution in the presence of dimethylamine hydrochloride and paraformaldehyde;

c) basifying the solution to form a precipitate;

d) separating the formed precipitate from said solution to give dimethylamino-methyl-carbazolone; and

e) drying the resulting dimethylamino-methyl-carbazolone.

Another object of the present invention is a process for the preparation of ondansetron base, said process comprising the steps of:

a) preparing methyl-imidazole and dimethylamino-methyl-carbazolone solutions;

b) heating said solution;

c) separating the precipitate containing ondansetron base;

d) washing said precipitate; and

e) drying the precipitate to obtain pure ondansetron base.

Preferably after step e), the ondansetron base is recrystallized in the presence of activated charcoal and methanol.

Another object of the present invention is a process for the preparation of ondansetron hydrochloride dihydrate, said process comprising the steps of:

a) preparing ondansetron base solution;

b) acidifying the solution with hydrochloric acid to form a precipitate;

c) washing said precipitate; and

d) Crystallization of ondansetron hydrochloride dihydrate.

Detailed description of the invention

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

Unless otherwise stated, "%" means percent by weight.

As used herein, the term "pure ondansetron" refers to ondansetron that is substantially free of exo-methylene by-products and has a high purity of at least about 99.0%.

As used herein, the term "hydrogen chloride" refers to both hydrogen chloride gas and an aqueous solution of hydrogen chloride gas.

The term "equivalent" as used herein means 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" means that in a chemical process, such as distillation or liquid-liquid extraction, a portion of a product stream can be returned to the process to help increase conversion or recovery.

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

The present invention is an improved process for the preparation of pure ondansetron hydrochloride dihydrate having a purity of at least 99.0%. More preferably said ondansetron hydrochloride dihydrate has a purity of at least 99.5%. Most preferably said ondansetron hydrochloride dihydrate has a purity of at least 99.9%.

The present invention provides an improved process for the preparation of dimethylamino-methyl-carbazolones. The present invention also provides an improved method for preparing ondansetron base. The present invention also provides an improved process for the preparation of pure ondansetron hydrochloride dihydrate.

Preparation of dimethylamino-methyl-carbazolone

The invention provides a method for preparing dimethylamino-methyl-carbazolone, said method comprising the following steps:

a) Preparation of a methyl-carbazolone solution having the formula:

(其中R＝C_1-4，烷基)

(where R=C _1-4 , alkyl)

b) heating said solution in the presence of dimethylamine hydrochloride and paraformaldehyde;

c) basifying the solution to form a precipitate;

d) separating the formed precipitate from said solution to give dimethylamino-methyl-carbazolone; and

e) drying the resulting dimethylamino-methyl-carbazolone.

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

Preferably, 1 equivalent of methyl-carbazolone is refluxed with about 1.1 to about 1.5 equivalents of dimethylamine hydrochloride and paraformaldehyde. More preferably, 1 equivalent of methyl-carbazolone is refluxed with about 1.2 equivalents of dimethylamine hydrochloride and paraformaldehyde. Formaldehyde may be used in place of paraformaldehyde in the reflux reaction of the heating step.

Preferably, 1 equivalent of methylcarbazolone is refluxed with about 4 to about 16 volumes of acetic acid. Most preferably, 1 equivalent of methyl-carbazolone is refluxed with about 4 volumes of acetic acid.

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

Preferably the heating step is performed for about 6 to about 24 hours. Most preferably the heating step is performed for about 6 to about 12 hours.

Filtration is preferably used to carry out the separation step.

The heating step is preferably performed without the use of vacuum distillation or extraction. A heating step performed without vacuum distillation or extraction consistently yields more pure dimethylamino-methyl-carbazolone.

The present invention also provides a method for preparing pure dimethylamino-methylcarbazolone comprising the steps of dissolving the obtained filter cake in acetone and treating with activated carbon and hydrochloric acid.

Water is preferably added during the basification step, and the solution is then basified to a pH of about 13 to about 14 with about 45% sodium hydroxide (NaOH). Preferably the basification step is carried out in the presence of Celite (10%), followed by filtration and drying.

Preferably the dried filter cake is dissolved in acetone. The dissolved filter cake is preferably treated with activated carbon and hydrochloric acid to precipitate dimethylamino-methyl-carbazolone.

Preparation of ondansetron base

The invention provides a method for synthesizing ondansetron base, said method comprising the following steps:

a) Preparation of methyl-imidazole and dimethylamino-methyl-carbazolone solutions of the formula

(其中R＝C_1-4，烷基)

(where R=C _1-4 , alkyl)

b) heating said solution;

c) separating the ondansetron base-containing precipitate from said solution;

d) washing said precipitate;

e) drying the precipitate to obtain pure ondansetron base.

The present invention also provides a method for synthesizing substantially pure ondansetron base, said method further comprising the steps of:

Recrystallization was carried out in the presence of activated charcoal and methanol.

In the step of preparing a solution of methyl-imidazole and dimethylamino-methyl-carbazolone, preferably about 4 to about 6 equivalents of methylimidazole are added to 1 equivalent of dimethylamino-methyl-carbazolone . Most preferably about 5 equivalents of methylimidazole are added to 1 equivalent of dimethylamino-methyl-carbazolone.

Preferably said preparation step is carried out in the presence of 10% celite.

Preferably, the method for preparing ondansetron base provided by the present invention further includes the step of recrystallizing ondansetron base in the presence of activated carbon and methanol (performed after step e).

     Crystallization to prepare pure ondansetron hydrochloride dihydrate

The present invention provides an improved process for the preparation of pure ondansetron hydrochloride dihydrate. Specifically, the preparation method includes crystallizing ondansetron base with water and activated carbon in the absence of organic solvents to obtain dihydrate ondansetron hydrochloride.

The crystallization method of the present invention greatly improves the purity of ondansetron hydrochloride dihydrate, and greatly reduces the content of exo-methylene by-product impurities. Preferably said crystallization step is carried out 1-3 times. Most preferably said crystallization step is carried out twice.

The invention provides a method for crystallizing ondansetron dihydrate hydrochloride, the method comprising the following steps:

a) preparing ondansetron base solution;

b) acidifying the solution with hydrochloric acid to form a precipitate;

c) washing said precipitate; and

d) Crystallization of pure ondansetron dihydrate hydrochloride.

Preferably said solution precipitation step is accomplished by adding from about 3 to about 7 volumes of water to the ondansetron base. Most preferably this is achieved by adding about 5 volumes of water to the ondansetron base.

Preferably said acidifying step is carried out by adding hydrochloric acid. Precipitation is preferably induced by adding about 1.0-1.4 equivalents of about 32% by volume hydrochloric acid. Most preferably, about 1.1 equivalents of about 32% by volume hydrochloric acid are added to induce the formation of a precipitate. More preferably, the acidification step results in a pH of from about 1 to about 4. Most preferably the acidification step results in a pH of about 3.

Preferably said washing step is achieved by 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.

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

Preferably said crystallization step is carried out in the presence of activated carbon. Preferably the activated carbon is selected from SX-2, CA-1, CXV and SX-1.

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

The present invention is further explained by the following examples. It is not intended that the present invention be limited by these specific examples. Those of ordinary skill in the art will understand how to modify these exemplary preparations to obtain the desired results.

Example

Embodiment 1: the preparation of pure dimethylamino-methyl-carbazolone salt

Add 45g (0.226mol, 1.0 equivalent) of methylcarbazolone, 22.4g (0.275mol, 1.22 equivalent) of dimethylamine hydrochloride and 9g (0.3mol, 1.33 equivalent) of paraformaldehyde to 180ml of glacial acetic acid.

Keep the reactants at about 80±2°C for 12 hours, then introduce 540ml of water and 4.5g of highflow into the reactor, cool the batch to about 10°C, and basify to pH with about 45% NaOH from about 13 to about 14 while maintaining the temperature of the batch not to exceed about 25°C.

The batch was then stirred for another hour at about 5°C to about 10°C, and the precipitate formed along with the highflow was collected and dried in a vacuum oven at about 60°C until constant weight to obtain a crude product containing highflow.

The crude product was treated with a solution of 3.3 g of SX-1 type activated carbon (available from NORIT) in 990 ml of acetone, filtered, cooled to about 25° C., and hydrochloric acid was bubbled through the acetone solution until the pH was about 3 , the batch was cooled to about 0 to about 5°C, kept at this temperature for half an hour, filtered, washed with about 20 ml of acetone and dried in an oven at about 50°C until constant weight, yielding 49.6 g of dimethylamino- Methyl-carbazolone-HCl.

Embodiment 2: the preparation of pure ondansetron base

To 330 ml of water were added 33 g (0.112 mol, 1 equivalent) of dimethylamino-methyl-carbazolone-HCl, 3.3 g of highflow and 46.3 g (0.563 mol, 5 equivalents) of methyl-imidazole.

The reactant was heated to reflux for 12 hours, cooled to about 5°C to about 10°C, the precipitate was filtered, washed with water (3×300ml), and dried in a vacuum oven at about 60°C until constant weight to obtain a crude product containing highflow.

The crude product was treated with a solution of 1.5 g of SX-1 type activated carbon (available from NORIT) in 930 ml of acetone, filtered (hot filtered) to remove the highflow and activated carbon, and crystallized at 0 to about 5° C. for 1 hour. Hot filtration was performed at about 60°C with methanol near its boiling point (ie, 65°C). The precipitate was collected by filtration, washed with cold methanol (2 x 20 ml), and dried in a vacuum oven at about 60°C until constant weight to yield 21.3 g of ondansetron base.

Embodiment 3: the preparation of pure dihydrate ondansetron hydrochloride

20 g of ondansetron base were introduced into 100 ml of water. To the stirred suspension was added 7.5 ml (1.1 equivalents) of about 32% hydrochloric acid (HCl). A slightly exothermic reaction occurred, the suspension became almost transparent and a precipitate began to form.

The reaction was cooled, maintained at about 3-5°C for an additional hour, filtered, washed with about 10 mL of cold isopropanol, and dried under vacuum at about 50°C.

Embodiment 4: Preparation of dihydrate ondansetron hydrochloride

Ondansetron-HCl-2H2O was crystallized from 1:4 w/v water and about 10% w/w type SX- ₁ activated carbon (available from NORIT) within half an hour at about 95°C. Once, filter (hot filter), wash with 1 volume of hot water, cool to about 5°C and keep at this temperature for about 1 hour. The crystals were collected, washed with about 10 ml of cold isopropanol, and dried to obtain pure ondansetron-HCl-2H ₂ O. The purity of the obtained pure ondansetron hydrochloride dihydrate detected by HPLC is at least over 99.0%. The resulting pure ondansetron hydrochloride dihydrate contained less than 0.01% or no detectable exo-methylene by-product.

Claims (47)

CLAIMS 1. Ondansetron hydrochloride dihydrate having a purity of at least 99.0%. 2. Ondansetron hydrochloride dihydrate having a purity of at least 99.5%. 3. Ondansetron hydrochloride dihydrate having a purity of at least 99.9%. 4. A method for preparing dimethylamino-methyl-carbazolone, said method comprising the following steps: a) Preparation of a methyl-carbazolone solution having the formula:

(where R=C _1-4 , alkyl) b) heating said solution in the presence of dimethylamine hydrochloride and paraformaldehyde; c) basifying the solution to form a precipitate; d) separating the formed precipitate from said solution; e) drying the resulting precipitate. 5. The method of claim 4, wherein said R is methyl. 6. The method of claim 4, wherein said heating step is performed at a temperature of about 70°C to about 100°C. 7. The method of claim 4, wherein said heating step is performed at about 80°C to about 90°C. 8. The method of claim 4, wherein said heating step is performed for about 6 to about 24 hours. 9. The method of claim 4, wherein said heating step is performed for about 6 to about 12 hours. 10. The method of claim 4, wherein said heating step is performed in acetic acid. 11. The method of claim 4, wherein about 1 equivalent of methylcarbazolone is heated in the presence of about 1.1 to about 1.5 equivalents of dimethylamine hydrochloride and paraformaldehyde. 12. The method of claim 4, wherein about 1 equivalent of methylcarbazolone is heated in the presence of about 1.2 equivalents of dimethylamine hydrochloride and formaldehyde. 13. The method of claim 4, wherein about 1 equivalent of methylcarbazolone is heated in the presence of about 1.1 to about 1.5 equivalents of dimethylamine hydrochloride and formaldehyde. 14. The method of claim 4, wherein about 1 equivalent of methylcarbazolone is heated in the presence of about 1.2 equivalents of dimethylamine hydrochloride and formaldehyde. 15. The method of claim 4, wherein about 1 equivalent of methylcarbazolone is heated in the presence of about 4 to about 6 volumes of acetic acid. 16. The method of claim 4, wherein about 1 equivalent of methylcarbazolone is heated in the presence of about 4 volumes of acetic acid. 17. The method of claim 4, wherein said methylcarbazolone solution is basified with about 45% sodium hydroxide. 18. The method of claim 17, wherein the solution is basified to a pH of about 13 to about 14. 19. The method of claim 17 or 18, wherein the alkalization step is performed in the presence of 10% celite. 20. A method for preparing ondansetron base, said method comprising the steps of: a) Preparation of methyl-imidazole and dimethylamino-methyl-carbazolone solutions of the formula (where R=C _1-4 , alkyl) b) heating said solution; c) separating the ondansetron base-containing precipitate from said solution; d) washing said precipitate; e) drying the precipitate to obtain pure ondansetron base. 21. The method of claim 20, wherein said solution is prepared by adding about 4 to about 6 equivalents of methyl-imidazole to 1 equivalent of dimethylamino-methyl-carbazolone. 22. The method of claim 20, wherein said solution is prepared by adding about 5 equivalents of methyl-imidazole to 1 equivalent of dimethylamino-methyl-carbazolone. 23. The method of claim 20, wherein said solution is prepared in the presence of 10% celite. 24. The method of claim 20, further comprising the step of: recrystallizing ondansetron base. 25. The method of claim 24, said recrystallization step being carried out in the presence of activated carbon and methanol. 26. A process for the preparation of pure ondansetron hydrochloride dihydrate, said process comprising the steps of: a) preparing ondansetron base solution; b) acidifying the solution with hydrochloric acid to form a precipitate; c) washing said precipitate; and d) Crystallization of pure ondansetron hydrochloride dihydrate. 27. The method of claim 26, wherein about 3 to about 7 volumes of water are added to the ondansetron base to prepare the ondansetron base solution. 28. The method of claim 26, wherein about 5 volumes of water are added to the ondansetron base to prepare the ondansetron base solution. 29. The method of claim 26, wherein the solution is acidified by adding about 1.0 to about 1.4 equivalents of about 32% by volume hydrochloric acid to induce the formation of a precipitate. 30. The method of claim 26, wherein the solution is acidified by adding about 1.1 equivalents of about 32% by volume hydrochloric acid to induce the formation of a precipitate. 31. The method of claim 29 or 30, wherein the solution is acidified to a pH of about 1 to about 4. 32. The method of claim 29 or 30, wherein the solution is acidified to a pH of about 3. 33. The method of claim 26, wherein the precipitate is washed with about 5 to about 15 ml of isopropanol. 34. The method of claim 26, wherein the precipitate is washed with about 10 ml of isopropanol. 35. The method of claim 26, wherein said crystallizing step is accomplished by adding about 3 to about 5 volumes of water to induce crystallization. 36. The method of claim 26, wherein said crystallizing step is accomplished by adding about 4 volumes of water to induce crystallization. 37. The method of claim 26, wherein said crystallizing step is repeated twice. 38. The method of claim 26, wherein said crystallization step is accomplished in the presence of activated carbon. 39. The method of claim 36, wherein the activated carbon is selected from the group consisting of SX-2, CA-1, CXV, and SX-1. 40. The method of claim 39, wherein the activated carbon is about 5 to about 15% SX-1. 41. The method of claim 39, wherein the activated carbon is about 5 to about 10% SX-1. 42. Ondansetron hydrochloride dihydrate prepared according to the method of claim 26, wherein said ondansetron hydrochloride dihydrate has a purity of at least about 99.0%. 43. Ondansetron hydrochloride dihydrate prepared according to the method of claim 26, wherein said ondansetron hydrochloride dihydrate has a purity of at least about 99.5%. 44. Ondansetron hydrochloride dihydrate prepared according to the method of claim 26, wherein said ondansetron hydrochloride dihydrate has a purity of at least about 99.9%. 45. A pharmaceutical formulation comprising ondansetron hydrochloride dihydrate prepared according to the method of claim 26, wherein said ondansetron hydrochloride dihydrate has a purity of at least about 99.0%. 46. A pharmaceutical formulation comprising ondansetron hydrochloride dihydrate prepared according to the method of claim 26, wherein said ondansetron hydrochloride dihydrate has a purity of at least about 99.5%. 47. A pharmaceutical formulation comprising ondansetron hydrochloride dihydrate prepared according to the method of claim 26, wherein said ondansetron hydrochloride dihydrate has a purity of at least about 99.9%.