Title:
Improved process for the preparation of omeprazole form-A.

Field of the invention:
The invention relates to an improved process for the preparation of omeprazole form A.

Background of the invention:
The compound 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benz imidazole, having the generic name omeprazole, as well as therapeutically acceptable salts thereof, are described in EP 5129. The single crystal X-ray data and the derived molecular structure of the so far only known crystal form of omeprazole is described by Ohishi et al., Acta Cryst. (1989), C45, 1921-1923. This published crystal form of omeprazole is hereinafter referred to as omeprazole form B.

Omeprazole, the generic name for 5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzi midazole (denoted as Formula I below) is a well-described gastric proton-pump inhibitor and is on the market as LOSEC.RTM. or PRILOSEC.RTM. for the treatment of gastric and duodenal ulcers, gastritis, duodenitis, and reflux esophagitis (see Merck Index, 14th Ed., and references cited therein). Omeprazole is commercially prepared via a multi-step sequence, the last step of which is oxidation of the sulfide intermediate, 5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]methylthio]-1H-ben zimidazole which is typically effected with a peroxy acid, such as meta-chloroperoxybenzoic acid (hereinafter referred to as MCPBA) (U.S. Pat. Nos. 4,255,431 and 5,386,032), magnesium monoperoxyphthalate (MMPP) (U.S. Pat. No. 5,391,752), or peroxyacetic acid (WO 98/09962), in a suitable non-alcoholic organic reaction solvent. The preferred oxidizing agent is usually meta-chloroperoxybenzoic acid, and suitable non-alcoholic organic reaction solvents include aromatic hydrocarbon solvents, such as benzene and toluene, and chlorinated aliphatic hydrocarbon solvents, such as chloroform and methylene chloride, in admixture with an alcoholic solvent, such as methanol, ethanol, isopropanol, or 1-butanol. The preferred non-alcoholic organic reaction solvents are usually methylene chloride and toluene, and the preferred alcoholic solvent is ethanol.

US6166213 claims the process for the preparation of omeprazole and its crystallization steps as
(a) crystallizing crude product from said aqueous phase by subsurface addition of a C1-3 alkyl formate to adjust the pH from about 13.5 to about 10.6-10.8, aging for about 10-20 minutes, allowing the temperature to reach about 20 DEG C., seeding, and adding remainder of said alkyl formate over 6-8 hours to adjust the pH to about 9.0-9.3; and (b) isolating crude product by filtration and washing with ammonia-water and methanol. Further dependent claim states as: (a) recrystallizing crude product in methanol-water containing aqueous sodium hydroxide by cooling to about 0-5 DEG C., adjusting the pH to about 10.5 by subsurface addition of 25% aqueous acetic acid, seeding, adding 25% aqueous acetic acid to a pH of about 9.0, and aging for about 0.5 hours; and (b) isolating pure product by filtration, washing with methanol-water and cold methanol, and vacuum drying.

US6384059 states the novel crystalline form of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl-1H-benzimidazole, omeprazole substance is thermodynamically stable at room temperature, essentially non-hygroscopic. Omeprazole form A is prepared by dissolving methanol containing ammonia in omeprazole stirring for approximately 2 to 45 hours in darkness and filtered. Where omeprazole form B takes less time for crystallization.

US6147103 discloses an improved process for the preparation, isolation, and purification of the omeprazole by reacting sulfide precursor pyrmetazole with exactly one molar equivalent of meta-chloroperoxybenzoic acid in methylene chloride or toluene solution, thereby crude product is obtained by reactive crystallization with an alkyl formate, and pure product is isolated by recrystallization in methanol-water mixture containing aqueous NaOH, where PH is adjusted with aqueous acetic acid to pH 9.0, then filtration, washing, and drying.
Further prior art comprises and is described hereunder

WO 9908500 described process for the preparation of omeprazole A is time-consuming e.g. 45 hours. The described synthesis is based on slow crystallization at room temperature, product is suspended in a solvent in which it is insoluble or poorly soluble and a resulting suspension is stirred for a defined time period with alkyl alcohol. This states that omeprazole form A exhibits better thermodynamic stability, photostability and hygroscopicity compared to previously-known omeprazole form B.

EP969819 Claims a process for the preparation of omeprazole form A by dissolving any form omeprazole in a solvent (methanol, ethanol, acetone, ethyl acetate, methyl tert. butyl ether, toluene, or any mixture). Omeprazole form A is optionally used for crystallization, and it is isolated. Describes a process for the preparation of omeprazole form A by adding omeprazole to methanol and ammonia. Also describes a process for the preparation of omeprazole form B by adding omeprazole to methanol and ammonia. The crystals are filtered and washed with ice-cooled methanol and then dried.

EP1221314 Claims a process for the preparation of omeprazole form A by dissolving omeprazole or mixtures of any form in a suitable solvent (methanol, ethanol, acetone, ethyl acetate, methyl tert. butyl ether, toluene, or any mixture).

The 2-(2-pyridylmethylsulfinyl) benzimidazole compounds are produced by subjecting 2-(2-pyridylmethylthio) benzimidazole compounds to oxidation with hydrogen peroxide in the presence of vanadium compounds in good yield and with low production of by-products is described in EP 0302720.

US6384059 describes the preparation of omeprazole form A, with certain conditions like prolonged crystallization time and the reaction must be carried out in darkness etc., while the present invention is overcoming these problems.

The desired product of omeprazole form A can be obtained rapidly when compared to the prior art patents.

According to the present invention, the method for production of stable omeprazole form A can be obtained in a good yield of about 75% or more, with minimum level of by product formation such as 2-(2-pyridylmethylsulfonyl) benzimidazole, and it’s derivative of N-oxide.

Summary of the invention:

The present invention is to provide a process for the preparation of stable omeprazole form A, comprising the steps of reacting 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-1H-benzimidazole in methanol with hydrogen peroxide in presence of a mixture of ammonium molybdate and ammonium dihydrogen ortho phosphate, resulting in the crude form of omeprazole. Further purification of the crude omeprazole with an admixture of water and methanol, wherein ammonium formate is used to adjust pH, further purified by a mixture of acetone and triethylamine followed by isolation of the pure product by filtration, and finally washing with mixture of acetone with catalytic amount of triethylamine and drying the compound.

Process eliminates the prolong steps for purification and thus making the process efficient with increase of productivity in commercial scale.

Brief description of drawings:
Table 1: An X-ray powder diffractogram of omeprazole form A.

Omeprazole form A
(d-values)
d-Value (Å) Relative Intensity
9.58 VS
7.94 S
7.45 W
7.19 VS
5.97 M
5.15 VS
4.9 W
4.66 M
4.6 M
4.5 M
4.33 M
4.2 W
3.95 W
3.71 S
3.59 M
3.49 M
3.46 S
3.3 M
3.22 VS
3.18 S
3.11 M
3.03 M
2.91 M
2.84 M
2.75 W
2.37 M

Description of the invention:

The present invention is to provide a process for the preparation of stable omeprazole form A, substantially free from other forms of omeprazole. The crystalline nature of omeprazole form A is characterized by X-ray powder diffraction.
An object of the present invention is to provide stable rapid production of omeprazole form A.

Another aspect of the invention is achieving a stable compound of omeprazole form A, by reducing the purification steps as well as the time of crystallization.

Improved process for the preparing a compound of formula I comprising the steps of
a) oxidation of thio compound of formula II

with an oxidizing agent in presence of at least one C1-C4 alcohols, or its mixtures;
b) first purification of the compound obtained from step a) is crude form of formula I
with a suitable solvent;
c) second purification of the compound obtained from step b); and
d) isolating the compound of formula I.

A process for the preparing omeprazole form A, by a) oxidation of thio compound of with an oxidizing agent selected from the group of hydrogen peroxide, m-chloroperoxybenzoic acid, peroxy acetic acid, Sodium per borate, Sodium per carbonate and Sodium hypochlorite, preferably hydrogen peroxide, in presence of at least one C1-C4 alcohols, or its mixtures selected from the group of methanol, ethanol, n-butanol, 2-butnaol, isopropyl alcohol, preferably methanol;
b) first purification of the crude compound obtained from step a) is done with a with an admixture of water and an alcohol, where adjusted the pH with the inorganic formate;
c) second purification of the compound obtained from step b) with an at least one solvent like acetone and at least one stabilizer such as triethylamine; and
d) isolating the pure product by filtration, washing with acetone with catalytic amount of triethylamine and dried at a temperature of 30-35 deg C.

The present invention includes the said oxidizing agent can be selected from the group of hydrogen peroxide, m-chloroperoxybenzoic acid, peroxy acetic acid, sodium per borate, sodium per carbonate and sodium hypochlorite, preferably hydrogen peroxide.

Wherein the step a) is performed at about –5 to about 5 deg C, preferably at about –2 to 2 deg C and the said organic solvent in step b) is water.

The present invention oxidation step is carried out in presence of a catalyst selected from the group ammonium dimolybdate, ammonium quarta molybdate, ammonium heptamolybdate, ammonium molybdate and sodium molybdate, preferably a mixture of ammonium molybdate and ammonium dihydrogen ortho phosphate.

Inorganic salt of formate is used to adjust pH to about 11 to 9, preferably about 9.7 to 9.5 at the temperature of about 0-5 deg C;

The above inorganic formate is selected from the group consisting of ammonium formate, tetra methyl ammonium formate, tetra methyl ammonium acetate and tetra methyl ammonium propionate, preferably ammonium formate.

Further purification of the crude compound is performed in a mixture of acetone and triethylamine, followed by isolation by filtration and finally washing with a mixture acetone and with catalytic amount of triethylamine and dried at a temperature of 30-35 deg C.

Omeprazole form A is effective as a gastric acid secretion inhibitor, and is useful as an antiulcer agent. In a more general sense, it can be used for treatment of gastric-acid related conditions in mammals and especially in man, including e.g. reflux esophagitis, gastritis, duodenitis, gastric ulcer and duodenal ulcer. Furthermore, it may be used for treatment of other gastrointestinal disorders where gastric acid inhibitory effect is desirable e.g. in patients on NSAID therapy, in patients with Non Ulcer Dyspepsia, in patients with symptomatic gastro-esophageal reflux disease, and in patients with gastrinomas. The compound of the invention may also be used in patients in intensive care situations, in patients with acute upper gastrointestinal bleeding, pre- and postoperatively to prevent aspiration of gastric acid and to treat stress ulceration.

Omeprazole form A is thermodynamically more stable and less hygroscopic, especially at room temperature.

Final product obtained in the present invention of Formula I having minimum level of level of bi products.

Omeprazole form A, according to the present invention, is characterized by X-ray powder diffraction pattern, as mentioned in Table 1,

Table 1:
Omeprazole form A
(d-values)
d-Value (Å) Relative Intensity
9.58 VS
7.94 S
7.45 W
7.19 VS
5.97 M
5.15 VS
4.9 W
4.66 M
4.6 M
4.5 M
4.33 M
4.2 W
3.95 W
3.71 S
3.59 M
3.49 M
3.46 S
3.3 M
3.22 VS
3.18 S
3.11 M
3.03 M
2.91 M
2.84 M
2.75 W
2.37 M

Legends:

% Relative Intensity Definition

25-100 (Very Strong)
10-25 S (Strong)
3-10 M (Medium)
1-3 W (Weak

XRD pattern of omeprazole form A obtained with as per present invention is comparable of XRD pattern as described in US6384059 for form A.

The comparison data is provided in Table II.

Table II:
Omeprazole form A
(d-values) Refernce patent
US6384059B1
9.58 9.5
7.94 7.9
7.45 7.4
7.19 7.2
5.97 6
5.62 5.6
5.15 5.1
4.9 4.89
4.66 4.64
4.6 4.6
4.5 4.53
4.33 4.31
4.2 4.19
3.95 3.95
3.71 3.71
3.59 3.59
3.49 3.48
3.46 3.45
3.3 3.31
3.22 3.22
3.18 3.17
3.11 3.11
3.03 3.04
2.91 2.91
2.84 2.86
2.75 2.75
2.37 2.41

Example 1:
Preparation of Omeprazole form A:
A solution of 5- Methoxy –2-[[(4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl] thio]-1H- benzimidazole of 100gm was dissolved in methanol of 200 ml in 2L, of three necked round bottom flask and the mixture was cooled to 18-20 ?C. A solution of ammonium molybdate (1.8g) and ammonium dihydrogen ortho phosphate (2.7g) solution was added at same temperature and mixture was cooled to –2 to 2?C. Hydrogen peroxide (21 g) solution was slowly added over a period of 10-12 hrs at –2 to 2?C. Stirred for 6-8 hours, after the reaction completion, De-Mineralized water (120 ml) was added at 0-5?C for about 60 minutes and agitated the reaction mixture for about 1 hour. Isolated crude omeprazole was filtered and washed with De-Mineralized water followed by washing with De-Mineralized water (12ml) and Methanol mixture (12 ml).

Purification of crude omeprazole:
A solution of crude omeprazole in aqueous sodium hydroxide was cooled to 10-15º C. treated with activated carbon along with EDTA and hydrose. The obtained clear filtrate is treated with methanol (33ml), and cooled to 0-5°C. The PH of the resultant solution was adjusted with (50%) ammonium formate solution, upto 10.7-10.8 over a period of 2 hours. The mixture was allowed to stir for 30 minutes. Omeprazole form A (0.1g) was seeded to reaction mixture; further PH was adjusted with ammonium formate solution upto 10.1-10.3 over a period of 1 hour and allowed mixture to stir for 30 min. Finally the pH was adjusted with ammonium formate solution to 9.5-9.7 over a period of 1 hour, followed by 2 hours stirring. The precipitate was filtered and slurry washed with De-Mineralized water (300 ml), obtained wet material was further purified with acetone (180 ml) at room temperature. The slurry was heated to 40-42?C, followed by the addition of triethylamine (3.3ml) and stirred for 1 hour at 0-5?C. The obtained material was filtered and washed with mixture of acetone (40 ml) and triethylamine (1.6 ml). Dried for 20-25 hours at 30-35?C under vacuum. Thus the obtained material is omeprazole form A confirmed by XRD.
Yield: 78.0 g (74.4%)
Purity: ~99.8%
Claims:
1. Omeprazole form A of formula I,

characterized by an X-ray powder diffraction pattern exhibiting substantially the following data

Omeprazole form A
(d-values)
d-Value (Å) Relative Intensity
9.58 VS
7.94 S
7.45 W
7.19 VS
5.97 M
5.15 VS
4.9 W
4.66 M
4.6 M
4.5 M
4.33 M
4.2 W
3.95 W
3.71 S
3.59 M
3.49 M
3.46 S
3.3 M
3.22 VS
3.18 S
3.11 M
3.03 M
2.91 M
2.84 M
2.75 W
2.37 M

2. A process for the preparing a compound of formula I comprising the steps of
a) oxidation of thio compound of formula II

with an oxidizing agent in presence of at least one C1-C4 alcohols, or its mixtures;
b) first purification of the compound obtained from step a) is crude form of formula I,
with a suitable solvent;
c) second purification of the compound obtained from step b); and
d) isolating the compound of formula I.

3. The process according to claim 2, wherein the said oxidizing agent is selected from the group of hydrogen peroxide, m-chloroperoxybenzoic acid, peroxy acetic acid, sodium per borate, sodium per carbonate and sodium hypochlorite, preferably hydrogen peroxide.

4. The process according to claims 2, wherein that step a) is performed at about –5 to about 5 deg C, preferably at about –2 to 2 deg C.

5. The process according to claim 3, wherein the said oxidation is carried out in presence of at least one catalyst selected from the group ammonium dimolybdate, ammonium quartmolybdate, ammonium heptamolybdate, ammonium molybdate and sodium molybdate, preferably a mixture of ammonium molybdate and ammonium dihydrogen ortho phosphate, along with an alcoholic solvent preferably methanol.

6. The process according to claims 2b, wherein the process for preparation of omeprazole form A comprising steps of
a) first purification of the crude omeprazole with an admixture of water and methanol, wherein inorganic salt of formate is used to adjust pH to about 11 to 9, preferably about 9.7 to 9.5 at the temperature of about 0-5 deg C;
c) second purification of the compound obtained from step b) in acetone and triethylamine;
d) isolating the pure product by filtration, then washing with acetone and triethylamine and dried at a temperature of 30-35 deg C.

7. The process according to claims 6, characterized in that step b) wherein the inorganic salt of formate is selected from the group consisting of ammonium formate, tetra methyl ammonium formate, tetra methyl ammonium acetate and tetra methyl ammonium propionate, preferably ammonium formate.

Abstract:

An improved method for the synthesis of omeprazole form A, comprising the steps of reacting 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-1H-benzimidazole in methanol with hydrogen peroxide in presence of a mixture of ammonium molybdate and ammonium dihydrogen ortho phosphate, resulting in crude form of omeprazole, which is purified to obtain the desired product, where the product is stable and useful for pharmaceutical compositions.