EP1467987A1

EP1467987A1 - Preparation of lansoprazole and related compounds

Info

Publication number: EP1467987A1
Application number: EP03748985A
Authority: EP
Inventors: Nina Finkelstein
Original assignee: Teva Pharmaceutical Industries Ltd
Current assignee: Teva Pharmaceutical Industries Ltd
Priority date: 2002-07-26
Filing date: 2003-07-28
Publication date: 2004-10-20
Also published as: WO2004011455A1; AU2003268034A1

Abstract

The present invention provides a process for preparing lansoprazole (LNP) (I) and related compounds having a high yield and a low level of impurities by oxidation of corresponding sulfide (compound having formula (II)) with tert-butyl hydroperoxide (TBHP), catalyzed by a catalyst vanadium oxytrichloride in an organic solvent selected from the group consisting of a C1-C5 alkanol, decane, nonane, toluene and a mixture of the organic solvent and water, preferably in the presence of a base.

Description

PREPARATION OF LANSOPRAZOLE AND RELATED COMPOUNDS

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of Provisional Application Serial No. 60/398,686 filed July 26, 2002, the disclosure of which is incorporated by reference in its entirety herein.

FIELD OF THE INVENTION

The present invention relates to a process of preparing 2-(2-pyridylmethyl) sulfinyl-lH-benzimidazole derivatives.

BACKGROUND OF THE INVENTION

Substituted 2-(2-pyridylmethyl) sulfinyl-lH-benzimidazole derivatives are well-known gastric proton pump inhibitors and these benzimidazole derivatives include lansoprazole (LNP) and LNP related compounds (for example, omeprazole, pantoprazole, and rabeprazole). Within the benzimidazole group, lansoprazole has its chemical name as (2-[[[3-methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyridinyl]methyl] s lfmyl]-iH-benzimidazole), i.e., when R is hydrogen, Ri is hydrogen, R₂ is methyl, R₃ is trifluoro-ethoxy, R₄ is hydrogen of the following chemical formula (I) and lansopraozle can inhibit gastric acid secretion (due to its proton pump inhibiting activity) and is commonly used as an antiulcer agent.

( I ) ( II) or (III)

(I)=LNP (R^R^R^Η, R²= methyl, (D)=LNPS R³=OCΗ₂CF₃) (in N-oxide LPNS

U.S. Pat. No. 4,628,098 generically describes the lansoprazole compound. Several known methods for preparing lansoprazole involve the use of a lansoprazole precursor having a thioester group. The primary route for synthesis of lansoprazole consists of the oxidation of the corresponding sulfide (LNPS) having the chemical formula (II). During the synthesis, the thioether group of lansoprazole precursor is oxidized in the last step of preparation to form the lansoprazole.

Keiji et al. Chem. Pharm. Bull., 38(10), 2853-2858 (1990), describe oxidation of the thioether group with m-chloroperbenzoic acid as the oxidizing agent. The use of m-chloroperbenzoic acid, however, often results in a non-selective oxidation of the thioether group.

U.S. Pat. No. 5,578,732 and EP302720 further describe the process of lansoprazole preparation by an oxidation method using hydrogen peroxide (H₂O₂) in the presence of vanadium pentoxide, sodium metavanadate, ammonium metavanadate or vanadium acetyl acetonate catalyst.

ES 2105953, WO 0121617, ES 2063705, U.S. Pat. No. 6,313,303, WO9947514, WO0168594, and US 2003/36554A1 all describe the use of other oxidation reagents and/or catalysts. For example, US 2003/46554A1 and ES2063705 describe the use of with tert-butylhydroperoxide (TBHP) and a vanadium catalyst, preferably, vanadium acetyl acetonate, for the oxidation of LNPS (II) and N-oxide LPNS (III). All of the disclosed methods could be improved by increasing their selectivity for the sulfinyl product.

There is a continuing need for a better oxidation method with catalysts in the preparation of lansoprazole.

SUMMARY OF THE INVENTION

The present invention provides a process for preparing lansoprazole (LNP) (I) and related compounds by oxidation of corresponding sulfide (II) with tert- butyUiydroperoxide (TBHP), catalyzed by vanadium oxytrichloride. The vanadium oxytrichloride is used in the presence of an alkanol. Preferably, the vanadium oxytrichloride in the alkanol is treated with a base. The present invention provides a process for preparing a compound having formula (I):

wherein R_1; R₂, and R₄ are each selected from the group consisting of hydrogen, substituted or unsubstituted lower alkyl and substituted or unsubstituted lower alkoxy; and R is selected from the group consisting of hydrogen and substituted or unsubstituted lower alkyl, comprising the steps of: a) reacting a compound of formula (IT)

II wherein Ri through R₄ are as in formula (I), with tert- butylhydroperoxide in the presence of a catalyst vanadium oxytrichloride, wherein the reaction is carried out in a organic solvent selected from the group consisting of C_1-; C -, C_3-, C_4- and C_5- alkanols, decane, nonane, toluene, and a mixture of the organic solvent and water; and b) isolating a compound having formula (I).

Lower alkanol such as C1-C₅ alkanol is preferred. -Cs alkanol includes methanol, ethanol, isopropanol, propanol, sec-butanol, butanol and pentanol.

Preferably, the reaction step is performed in the presence of a weak base. Preferably, the process relates to preparing a compound having formula (II) is (2-[[[3-methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyridinyl]methyl] sulfide]-'H- benzimidazole). Preferably, the compound having formula (I) is lansoprazole. Preferably, the compound having the formula (I) is omeprazole. Preferably, the compound having the formula (I) is pantoprazole. Preferably, the compound having the formula (I) is rabeprazole.

Preferably, tert-butylhydroperoxide is used in an amount of from about 1 to about 3 mol. equivalents relative to the compound having the formula (II). More preferably, tert-butylhydroperoxide is used in an amount of from about 1.3 to about 2 mol. equivalents relative to the compound having the formula (II).

Preferably, vanadium oxytrichloride is used in an amount of from about 0.01 to about 0.5 mol. equivalent relative to the compound having the formula (II). More preferably, vanadium oxytrichloride is used in an amount of from about 0.005 to about 0.3 mol. equivalent relative to the compound having the formula (II).

Preferably, the oxidation is performed in the presence of a weak base which is an inorganic base or an organic base. Preferably, the organic base is N,N-diethyl amine.

Preferably, the reacting step is performed at a temperature of 5°C to about 15°C. More preferably, the reacting step is performed at a temperature of about 10°C.

Preferably, the reacting step is performed for about 4 to about 24 hours. More preferably, the reacting step is performed for about 4 to about 15 hours. More preferably, the reacting step is performed for about 6 hours.

Preferably, the isolating step is preformed by filtration. More preferably, the step of drying is carried out at about 40°C in vacuo at 10 mmΗg overnight.

The present invention provides an oxidation which gives the lansoprazole product with a high yield and a low level of impurities. The impurities include, but not limited to sulfones, N-oxides and N-oxide sulfones. DETAILED DESCRIPTION OF THE INVENTION

Definition:

As used herein, "LNP" refers to lansorpazole having the chemical name of 2-

[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfmyl-lHbenzimidazole.

"LNPS" refers to the sulfide-containing starting compound for lansoprazole preparation having the chemical name of 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridinil]thio]-lHbenzimidazole. "TBΗP" refers to tert-butylhydroperoxide.

"NOCl₃" refers to vanadium oxytrichloride. "Alkanol" refers to an alkane with one or more hydrogen atoms substituted by the hydroxyl functional group. Exemplary alkanols are C1-C₅ which include methanol, ethanol, isopropanol, propanol, butanol, sec-butanol and pentanol. Branched alkanol may be functionally equivalent as to primary alkanol. "IP A" refers to isopropanol which is a representative primary alkanol. "Et2ΝΗ" refers to N,N-diethyl amine. "Room temperature" refers to the ambient temperature which is about 20°C to about 25°C.

Unless otherwise stated, % refers to % (wt/wt).

The present invention provides a process for preparing a compound having formula (I):

wherein R_1? R₂, and R-ι are each selected from the group consisting of hydrogen, substituted or unsubstituted lower alkyl and substituted or unsubstituted lower alkoxy; and R₃ is selected from the group consisting of hydrogen and substituted or unsubstituted lower alkyl, comprising the steps of: a) reacting a compound of formula (II)

II wherein R₁ through R₄ are as in formula (I), with tert- butylhydroperoxide in the presence of a cataylst vanadium oxytrichloride, wherein the reaction is carried out in an organic solvent selected from the group consisting of Ci., C₂_, C_3-, C - and Cs. alkanols, decane, nonane, toluene, and a mixture of the organic solvent and water; and b) isolating a compound having formula (I).

Preferably, the reaction is performed in the presence of a weak base.

Preferably, the present invention is to provide a process of preparing 2-[[[3- methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyridinyl]methyl]sulfinyl]-iH-benzimidazole (lansoprazole). (i.e., compound of formula (I), wherein Ri is methyl; R₂ is 2-trifluoroethoxy; R is hydrogen and R₄ is hydrogen). The compound is lansoprazole.

Preferably, the present invention is to provide a process of preparing 5- methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-iH-benzimidazole (omeprazole) (i.e., compound of formula (I), wherein Ri is methyl; R₂ is methoxy; R₃ is methyl and R is methoxy). The compound is omeprazole.

Preferably, the present invention is to provide a process of 5- (difluoromethoxy)-2- [ [(3 ,4-dimethoxy-2-pyridinyl)methyl] sulfinyl] -1H- benzimidazole (pantoprazole) (i.e., compound of formula (I), wherein Ri is methoxy; R₂ is methoxy; R₃ is hydrogen and R-i is difluoromethoxy). The compound is pantoprazole. Preferably, the present invention is to provide a process of 5-methoxy-2-[[(4- methoxy-3,5-dimethyl-2-pyridyl) methyl]sulfinyl]-iH-benzimidazole (rabeprazole) (i.e., compound of formula (I), wherein Ri is methyl; R₂ is MeOCΗ₂CΗ CΗ₂O, R₃ is hydrogen and R is hydrogen. The compound is rabeprazole.

The present invention provides a method to prepare 2-(2-pyridylmethyl) sulfinyl-lH- benzimidazole compounds by selective oxidation with tert- butylhydroperoxide. This oxidation method is generally applicable to benzimidazole derivatives including lansoprazole, omerparazole, pantoprazole, and rabeprazole.

According to one aspect of the invention, there is provided a process of preparing lansoprazole (LNP; 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridyl]methyl]sulfinyl-lHbenzimidazole) (i.e., compound of formula (I), wherein R is hydrogen, Ri is hydrogen, R is methyl, R₃ is trifluoro-ethoxy, R₄ is hydrogen). In accordance with the present invention, LNPS (i.e., 2-[[3-methyl-4-(2,2,2-trifluoro ethoxy)-2-pyridinil]thio]-lHbenzimidazole) is used as a starting material for preparation of LNP.

According to another aspect of the invention, there is provided a process of preparing omerparazole by using the corresponding omerprazole sulfide as a precursor and selectively oxidize the thioether group of omperprazole precursor to form omerprazole.

According to another aspect of the invention, there is provided a process of preparing pantoprazole by using the corresponding pantoprazole sulfide as a precursor and selectively oxidize the thioether group of pantoprazole precursor to form pantoprazole.

According to another aspect of the invention, there is provided a process of preparaing rabeprazole by using the corresponding raberprazole sulfide as a precursor and selectively oxidize the thioether group of pantoprazole precursor to form raberprazole. According to the present invention, selective oxidation of the thioether group in the benizimidiazole derivatives is achieved by vanadium catalyzed oxygenation. The vanadium catalyzed oxidation of thioether with vanadium oxytrichloride and tertiary butyl hydroperoxide yields a high yield and a low level of impurities.

Preferably, the vanadium oxytrichloride and tertiary butyl hydroperoxide catalyzed oxidation is performed in the presence of an alkanol. Preferably, the reaction is performed in the presence of an alkanol and a weak base.

The amount of the vanadium oxytrichloride used is generally about 0.01 to about 0.5 mole relative to one mole of the compound having the formula (II). More preferably, the vanadium oxytrichloride is used at about 0.005 to about 0.3 mole relative to one mole of the compound having the formula (II).

The method of this invention for selective oxidation is carried out with an aqueous solution of tertiary butyl hydroperoxide. A solution of tertiary butyl hydroperoxide in organic solvent such as decane, nonane, toluene and a mixture of said organic solvent and water may also be used. The concentration of teritary butyl hydroperoxide used is usually 10 to 70%, preferably 70%, but should not be limited only to these ranges.

The amount of oxidizing agent (i.e., tertiary butyl hydroperoxide) used is usually a slight excess relative to one molar equivalent of the compound having the formula (II). Preferably, the oxidizing agent used is about 1 to about 3 equivalents. More preferably, about 1.3 to about 2 equivalents.

The solvents used for the vanadium catalyzed oxidation of thioether with vanadium oxytrichloride include an alkanol. A lower alkanol is preferred. Exemplary alkanol includes C1-C₅ alkanols such as methanol, ethanol, isopropanol, propanol, sec-butanol, butanol and pentanol. Primary alkanols and secondary alkanols can be used. Preferably, isopropanol is used. These solvents may be used singly or in combination. It is convenient to conduct this reaction in the presence of a weak base. The weak base is exemplified by alkali metal carboante (e.g., potassium carbonate and sodium carbonate), and organic amines (e.g., diethyl amine and triethyl amine). Preferably, the amount of weak base used is in an amount of about from about 4 to about 5 mol. equivalent relative to the compound having the formula (II). More preferably, the weak base is from about 3 mol. equivalent relative to the compound having the formula (11).

The reaction temperature for vanadium catalyzed oxidation of thioether with vanadium oxytrichloride is usually the temperature below the room temperature. Preferably, the temperature is about 5°C to about 15°C. More preferably, the temperature is about 10°C. The reaction time is about 4 to about 24 hours. Preferably, the reaction time is about 4 to about 15 hours. More preferably, the reaction time is about 6 hours.

To neutralize the oxidation reaction, sodium sulfite is used. Other compounds (e.g., sodium bisulfite) that can neutralize the oxidizing agent may be used as well.

The compound of the formula (I) produced by the oxidation reaction described above may be separated out by conventional methods such as filtration, after the addition of sodium sulfite. The filtrate may be washed. The filtrate may then be dried to obtain the compound of formula (I). Drying may be optimized. Preferably, drying is performed by exposing filtrate at about 40°C in vacuo at 10 mm Hg for overnight.

The obtained compound of formula (I) may further be purifed by crystallization or chromatography. Crystallization in an organic solvent may be used and exemplary crystallizing organic solvents include aqueous ethanol and acetone.

According to the present method, the obtained compound of formula (I) is of good yield and high purity. For example, the obtained 2-(2-pyridylmethylsulfinyl) benzimidazole is routinely obtained in a good yield (about 85% or more) and with low production of by-products such as 2-(2-pyridylmethylsulfonyl) benzimidazole N- oxide. The invention will be better understood from the following experimental details. These examples are provided to illustrate specific embodiments of the present invention but they are not intended to be limiting in any way.

Example 1

0.1 N solution of VOCl₃ in IPA was used. To a suspension of LNPS (5.0 grams, 14.16 mmoL) in IPA (25 mL), 0.02 mol. eq. of NOCl₃ (i.e., 0.02 x 14.16 mmoL) was added. A 70% aqueous TBHP (2.9 mL, 21.24 mmoL) solution was then added and the resulting reaction mixture was maintained at 10°C.

The reaction mixture was then stirred at 10°C for 6 hours. Then an aqueous solution of sodium sulfite (5%, 25 mL) was added dropwise to the reaction mixture. The mixture was further stirred at room temperature for 1 hour. The suspension was filtered and washed with water. The filtrate was dried at 40°C in vacuo at 10 mm Hg overnight to give crude LΝP (5 grams, assay 86.28%, yield was 83%).

Example 2

0.05 Ν solution of NOCl₃ in IPA was used. To a suspension of LΝPS (5.0 grams, 14.16 mmoL) in IPA (25 mL), 0.01 mol. eq. of NOCl₃ (i.e., 0.01x14.16 mmole) was added. A 70% aqueous TBHP (2.9 mL, 21.24 mmoL) solution was then added and the resulting reaction mixture was maintained at 10°C.

The reaction mixture was then stirred at 10°C for 6 hours. Then an aqueous solution of sodium sulfite (5%, 25 mL) was added dropwise to the reaction mixture. The mixture was further stirred at room temperature for 1 hour. The suspension was filtered and washed with water. The filtrate was dried at 40°C in vacuo at 10 mm Hg overnight to give crude LΝP (5 grams, assay 86.28%, yield was 86%).

Example 3 0.1 Ν solution of NOCl₃ in IPA was used. To a suspension of LΝPS (5.0 grams, 14.16 mmoL) in IPA (25 mL), 0.01 mol. eq. of NOCl₃ (i.e., 0.01 x 14.16 mmoL) was added and treated with Et₂ΝH [1.3 mL of 0.1 N solution VOCl₃ in IPA treated with 88 microliter (0.03 eq x 14.16 mmoL) of Et₂NH]. A 70% aqueous TBHP (2.9 mL, 21.24 mmoL) was subsequently added and the resultant mixture was held at 10°C.

The reaction mixture was stirred at the same temperature for 16 hours. Then an aqueous solution of sodium sulfite (5%, 25 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The suspension was filtered. The filtrate was washed with water and dried at 40°C in vacuo 10 mm Hg overnight to give crude LNP (4.7 grams, yield was 90%).

The invention has been described with reference to its preferred embodiments.

All cited references are incorporated herein by reference in their entirety. From this description, those skilled in the art may appreciate changes that could be made in the invention that does not depart from the scope and spirit of the invention.

Claims

WHAT IS CLAIMED IS:

1. A method for preparing a compound having formula (I):

wherein R_ls R₂, and R₄ are each selected from the group consisting of hydrogen, substituted or unsubstituted lower alkyl and substituted or unsubstituted lower alkoxy; and R₃ is selected from the group consisting of hydrogen and substituted or unsubstituted lower alkyl, comprising the steps of: a) reacting a compound of formula (II)

II wherein Ri through R₄ are as in formula (I), with tert- butylhydroperoxide in the presence of a catalyst vanadium oxytrichloride, wherein the reaction is carried out in an organic solvent selected from the group consisting of Cι_, C_2-, C_3-, C - and C_5- alkanols, decane, nonane, toluene and a mixture of the organic solvent and water thereof; and b) isolating a compound having formula (I).

The method of claim 1, wherein the alkanol is methanol, ethanol, isopropanol, propanol, sec-butanol, butanol, or pentanol.

The method of claim 1, wherein the reacting step is performed for about 4 to about 24 hours.

4. The method of claim 1 , wherein the reacting step is performed for about 4 to about 15 hours.

5. The method of claim 1 , wherein the reacting step is performed for about 6 hours. 6. The method of claim 1, wherein the reaction step is performed in the presence of a weak base.

7. The method of claim 6, wherein the weak base is potassium carbonate or sodium carbonate.

8. The method of claim 6, wherien the weak base is N,N-diethyl amine or triethyl amine.

9. The method of claim 6, wherein the weak base is present in an amount of about 4 to about 5 mol. equivalents of the weak base relative to the compound having the formula (11).

10. The method of claim 6, wherein the weak base is present in an amount of about 3 mol. equivalents of the weak base relative to the compound having the formula (II).

11. The method of claim 1 , after the reacting step of a), further comprising the step of: a') neutralizing the tert-butylhydroperoxide. 12. The method of claim 11, wherein the neutralizing step is performed by an neutralizing compound selected from the group consisting of sodium sulfite and sodium bisulfite.

13. The method of claim 1 , after the isolating step of b), further comprising the step of: b') crystallizing the isolated compound of formula (I).

14. The method of claim 13, wherein the crystallizing step is performed in an organic solvent selected from the group consisting of ethanol and acetone.

15. The method of claim 1, wherein Ri is methyl; R₂ is methoxy; R₃ is methyl and R-_t is methoxy. 16. The method of claim 1, wherein R_\ is methyl; R₂ is trifluoro-ethoxy; R₃ is hydrogen and R₄ is hydrogen. 17. The method of claim 1, wherein Ri is methoxy; R₂ is methoxy; R₃ is hydrogen and R₄ is difluoromethoxy.

18. The method of claim 1, wherein Ri is methyl; R₂ is MeOCH₂CH₂CH₂O; R₃ is hydrogen and R is hydrogen.

19. A compound having formula (I):

wherein Ri is methyl; R₂ is trifluoro-ethoxy; R is hydrogen and R is hydrogen as prepared according to the process of claim 1.