WO2010068049A2

WO2010068049A2 - Process for preparing (r)-(+)-lansoprazole and intermediate used therein

Info

Publication number: WO2010068049A2
Application number: PCT/KR2009/007389
Authority: WO
Inventors: Sun Young Jang; Tai Won Kim; Sungbum Kim; Byung-Ku Kim; Chang-Ju Choi; Cheol Kyung Kim; Tae Hee Ha; Kwee Hyun Suh; Gwan Sun Lee
Original assignee: Hanmi Pharmaceutical Co Ltd; Hanmi Pharmaceutical Industries Co Ltd
Current assignee: Hanmi Pharmaceutical Co Ltd; Hanmi Pharmaceutical Industries Co Ltd
Priority date: 2008-12-12
Filing date: 2009-12-10
Publication date: 2010-06-17
Anticipated expiration: 2011-06-12
Also published as: KR101001646B1; WO2010068049A3; KR20100067886A

Abstract

A process for the preparation of (R)-(+)-lansoprazole having a high optical purity and a novel intermediates used therein are provided. The inventive process provides (R)-(+)-lansoprazole having a high optical purity through optical resolution of racemic lansoprazole.

Description

PROCESS FOR PREPARING (R)-(+)-LANSOPRAZOLE AND INTERMEDIATE USED THEREIN

FIELD OF THE INVENTION

The present invention relates to a process for the preparation of (R)-(+)-lansoprazole having a high optical purity, and a novel intermediate used therein.

BACKGROUND OF THE INVENTION

Lansoprazole, 2-[[3-methyl-4-(2,2,2,-trifluoroethoxy)-2-pyridinyl]methyl] sulfinyl- lH-benzimidazole disclosed in EP Patent No. 0 174 726 Bl, is a proton pump inhibitor, which suppresses gastric acid secretion to prevent ulcer. Lansoprazole molecule has a chiral center at the sulfur atom, and thus, two enantiomers thereof exist: dextrorotatory (R)-(+)-lansoprazole and levorotatory (S)-(-)-lansoprazole as disclosed in WO 1992/08716.

Η. Katsuki et al. (Η. Katsuki et ai, Pharm. Res. 13, 611-615 (1996)) have found that two enantiomers of lansoprazole are stereoselectively metabolized in human showing different pharmacokinetic profiles, and (R)-(+)-lansoprazole is more effective than the other due to its high bioavailability and less adverse effects it causes. Thus, there have been several approaches for preparing (R)-(+)-lansoprazole which is more useful in the preparation of pharmaceutical compositions for treating gastric acid related diseases. For instance, WO 1996/02535 and WO 1997/02261 describe enantioselective synthesis of a single enantiomer by catalytic asymmetric oxidation, and CN 1,329,003 proposes an optical resolution of racemic lansoprazole by using (R)-(+)-BINOL.

Such methods are mainly divided into following categories: 1) isolating an enantiomer by chromatography using a chiral column; 2) preparing an enantiomer by catalytic asymmetric oxidation of the corresponding prochiral sulfide to sulfoxide; and 3) optically resolving racemic lansoprazole using a suitable optical resolving agent.

However, a method using chromatography is not suitable for use in industrial production. Further, the catalytic asymmetric oxidation requires the use of a number of reaction agents as well as a complicated reaction procedure under delicate conditions, besides the problem that it requires further steps such as post-treatment and purification, in order to reach the optical purity suitable for a pharmaceutical grade.

Meanwhile, the method of optical resolution of racemic lansoprazole using a resolving agent has not yet been proven satisfactory. For instance, such method using (R)-(+)-BINOL as an optical resolving agent, (R)-(+)-BINOL as disclosed in CN 1,329,003 has disadvantages in that: 1) the optical resolving agent is expensive; 2) solvents such as benzene and toluene are used, use of which is prohibited or regulated in the preparation of pharmaceuticals due to their potential high toxicity; 3) the optical purity of the initial product obtained thereby is as low as 75~85%ee, requiring several steps of further purification; and 4) the intermediate product is often colored, requiring decolorization.

Accordingly, the present inventors have endeavored to develop an improved process for the preparation of (R)-(+)-lansoprazole from racemic lansoprazole using an inexpensive, easily available optical resolving agent and have found that (R)-(+)-lansoprazole of a high optical purity can be prepared in a high yield by a novel, simple method. [reference 1] EP 174,726, Takeda Chemical Industries Limited, 1986. 03. 19

[reference 2] H. Katsuki et al., Pharmaceutical Research, 13, 611-615, 1996 [reference 3] WO 1992/08716, Byk Gulden Lomberg Chemische Fabrik GMBH, 1992. 05. 29

[reference 4] WO 1996/02535, Astra Actiebolag, 1996. 02. 01 [reference 5] WO 1997/02261 , Astra Actiebolag, 1997. 01. 23

[reference 6] CN 1,329,003, Chengdu Organic Chemical Institute, 2000. 06. 19

SUMMARY OF THE INVENTION

Accordingly, it is an object of the present invention to provide a novel but simple process for preparing (R)-(+)-lansoprazole having a high optical purity in a high yield.

It is another object of the present invention to provide a novel intermediate used in the above process.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, there is provided a process for preparing (R)-(+)-lansoprazole of formula (II) comprising the steps of: 1) Subjecting racemic lansoprazole to a reaction with

(R)-(+)-l,l,2-triphenyl-l,2-ethanediol to produce the complex of (R)-(+)-lansoprazole and (R)-(+)-l,l,2-triphenyl-l,2-ethanediol of formula (I); and

2) treating the compound of formula (I) with an organic solvent and a basic aqueous solution to allow its partition between the organic and aqueous layers, separating the aqueous layer, and neutralizing the aqueous layer thus obtained with an acid.

(i)

The present invention also provides the complex of (R)-(+)-lansoprazole and (R)-(+)-l,l,2-triphenyl-l,2-ethanediol of formula (I), which is used as an intermediate in the preparation of the compound of formula (II).

Each step of the inventive method is explained in detail below.

Step (1)

In step (1), racemic lansoprazole is allowed to react with (R)-(+)- l,l,2-triphenyl-l,2-ethanediol to produce a complex of (R)-(+)-lansoprazole and (R)-C⁺)- 1 _> 1 ,2-triphenyl- 1 ,2-ethanediol.

Specifically, in step (1) of the present invention, racemic lansoprazole and (R)-(+)-l,l,2-triphenyl-l,2-ethanediol are completely dissolved in an organic solvent selected from the group consisting of chloroform, methanol, ethanol, isopropanol, acetone, acetonitrile, and a mixture thereof under a reflux condition, and the resulting mixture is cooled to induce the precipitation of the complex of formula (I) which is composed of (R)-(+)-lansoprazole and (R)-(+)- 1 , 1 ,2-triphenyl- 1 ,2-ethanediol in an equivalent ratio of about 1 :2.

The solvent (1^st solvent) used in the step (1) selected from the group consisting of chloroform, methanol, ethanol, isopropanol, acetone, acetonitrile, and a mixture thereof may be employed alone or it may be used as a mixed solvent with a 2^nd solvent selected from the group consisting of hexane, diisopropyl ether, and water (with the proviso that the mixed solvent is not a mixture of chloroform and water).

When used as the mixed solvent, the preferable 1^st organic solvent to 2^nd solvent mix ratio is 1 : 1 to 10: 1 by volume, the volume of 2^nd solvent is not over 50% of the volume of the mixture.

When a mixed solvent is used, a mixture of chloroform and hexane is preferred.

Also, a mixed solvent of diisopropyl ether and an organic solvent selected from the group consisting of methanol, ethanol, isopropanol, acetone, and acetonitrile is preferred. Also preferred is a mixed solvent of water and an organic solvent selected from the group consisting of methanol, ethanol, isopropanol, acetone, and, acetonitrile.

The solvent or mixed solvent may be used in an amount of 10 niL to 50 mL, preferably 15 mL to 40 mL, per 1 g of racemic lansoprazole.

Further, (R)-(+)-l,l,2-triphenyl-l,2-ethanediol may be used in an amount of 1.5 to 3 equivalents, preferably 1.8 to 2.5 equivalents based on racemic lansoprazole, and preferably has an optical purity of not less than 99.5%ee.

Crystallization of the compound of formula (I) is accomplished by dissolving racemic lansoprazole and (R)-(+)-l,l,2-triphenyl-l,2-ethanediol by maintaining the mixture at a temperature in the range of room temperature to the boiling point of the solvent, and slowly cooling the resulting homogenous solution to 0⁰C to room temperature. The complex of formula (I) obtained in accordance with above method carries (R)-(+)-lansoprazole moiety whose optical purity is not less than 90%ee.

Further, the method of the present invention may comprise a further recrystallization step prior to step (2). After such recrystallization step, the optical purity of (R)-(+)-lansoprazole may increase to not less than 99.0%ee when the solvent for this step is carefully controlled. As the solvent for the recrystallization, a 1^st organic solvent or a mixture of a 1^st organic solvent and a 2^nd solvent may be used, the volume of the 2^nd solvent being preferably 75% based on the volume of the mixture.

Step (2)

In step (2), the complex of (R)-(+)-lansoprazole and (R)-(+)-l,l,2-triphenyl-l,2-ethanediol obtained in step (1) is allowed to partition between an organic solvent and a basic aqueous solution. Then, the aqueous layer is isolated and neutralized with an acid to obtain (R)-(+)-lansoprazole of formula (II).

Specifically, in step (2) of the present invention, added to the complex of (R)-(+)-lansoprazole and (R)-(+)-l,l,2-triphenyl-l,2-ethanediol obtained in step (1), is an organic solvent and a basic aqueous solution and the resulting mixture is kept at room temperature. The aqueous layer of the reaction mixture is then isolated, and neutralized to pH in the range of 5 to 7 using an acid such as acetic acid and hydrochloric acid. Subsequently, the precipitated solid is filtered or the precipitate is extracted with ethyl acetate or dichloromethane to obtain (R)-(+)-lansoprazole.

The organic solvent used in the step (2) may be selected from the group consisting of methyl acetate, ethyl acetate, isopropyl acetate, ethyl ether, dichloromethane, chloroform, and a mixture thereof, and may be used in an amount of 10 to 30 niL, preferably 15 to 20 mL per 1 g of the complex of (R)-(+)-lansoprazole and (R)-(+)- 1 , 1 ,2-triphenyl- 1 ,2-ethanediol .

The basic aqueous solution is preferably an aqueous solution containing sodium hydroxide or potassium hydroxide, in an amount of 1 to 5 equivalents, preferably 2 to 2.5 equivalents based on the compound of formula (I).

Further, according to the present invention, solid residue obtained by concentrating the organic layer isolated from the aqueous layer in the step (2) is recrystallized by using a mixture of ethyl acetate and hexane to obtain (R)-(+)-l,l,2-triphenyl-l,2-ethanediol in a yield of more than 85%. The present invention may further comprise the step of recycling (R)-(+)-l,l,2-triphenyl-l,2-ethanediol used in the preparation of the compound of formula (I).

The present invention is explained in detail with reference to the Examples described below, which are given for the purpose of illustration only, and are not intended to limit the scope of the invention.

The optical purity of each compound described in Examples was calculated based on Equation 1 using the peak areas of R-(+)-lansoprazole and S-(-)-lansoprazole obtained by conducting liquid chromatography (Column: Chromtech AGP, 4.6 X 250 mm, 5 μm; wave length for detection: 285 nm; Mobile phase: pH 7.0 phosphate buffer/acetonitrile = 90/10; Flow rate: 0.8 mL/min) using a chiral column.

Equation 1

A(+) - A(-)

Optical purity (%ee) = x lOO

A(+) + A(-) (%ee indicates the percentage of enantiomeric excess amount; A(+) means the peak area of R-(+)-lansoprazole; and A(-) means the peak area of S-(-)-lansoprazole) Examples 1 to 11: Preparation of a complex of (R)-(+)-lansoprazole and (R)-(+)-l,l,2-triphenyl-l,2-ethanediol (compound (I))

Example 1 40.0 g (108.3 mmol) of racemic lansoprazole and 62.9 g (216.6 mmol: optical purity 99.7%ee) of (R)-(+)-l,l,2-triphenyl-l,2-ethanediol were suspended in 640 niL of chloroform, and refluxed until they were dissolved. The resulting mixture was slowly cooled to room temperature, stirred for 4 hours, and the precipitate formed was isolated by filtering, washed with cold chloroform, and dried at 40⁰C, to obtain 41.1 g (80%) of the compound of formula (I) as a white crystalline powder (step A).

Melting point: 147.8~149.9°C Optical purity: 97.2%ee

Specific optical rotation: [α]_D ²⁵ = +174.32 (c=1.0, MeOH)

15 g (optical purity: 97.2%ee) of the complex thus obtained was added to 120 mL of chloroform, and the resulting mixture was refluxed until the complex was dissolved. Then, 180 mL of hexane was added thereto, slowly cooled to room temperature, stirred for 1 hour, and the precipitate formed was filtered, dried at 40⁰C, to obtain 12 g (80%) of the compound of formula (I) as a white crystalline powder.

Melting point: 149.6~151.4°C Optical purity: >99.9%ee

Specific optical rotation: [α]_D ²⁵ = +182.76 (c=1.0, MeOH) 1H-NMR (CDCl₃, ppm): δ 8.24(d, IH), 7.68(d, 2H), 7.34~7.39(m, 4H),

7.28-7.3 l(m, 4H), 7.04-7.16(m, 22H), 6.63(d, IH), 5.63(s, 2H), 4.64~4.80(q, 2H), 4.32~4.39(q, 2H), 3.36(s, 2H), 2.20(s, 3H)

IR (KBr, cm^"1): 3541, 3390, 3228, 3087, 3058, 3027, 2965, 2886, 2817, 2699, 1950, 1815, 1584, 1492, 1474, 1448, 1379, 1345, 1320, 1174, 1113, 1042, 1003, 974, 962, 929, 896, 760, 736, 696, 387

Example 2

15 g (optical purity: 97.2%ee) of the compound of formula (I) obtained in step A of Example 1 was suspended in 90 mL of chloroform, refluxed until the compound was dissolved. Then, 210 mL of hexane was added thereto, cooled to room temperature, stirred for 1 hour, and the precipitate formed was filtered, dried, to obtain 13.O g (87%) of the compound of formula (I) as a white crystalline powder.

Melting point: 149.8~151.5°C

Optical purity: 99.9%ee Specific optical rotation: [α]_D ²⁵ = +182.16 (c=1.0, MeOH)

Example 3

5.0 g (13.5 mmol) of racemic lansoprazole and 7.9 g (27.1 mmol) of (R)-(+)-l,l,2-triphenyl-l,2-ethanediol were suspended in 90 mL of chloroform, refluxed until they were dissolved, and 60 mL of hexane was added dropwise thereto. The resulting mixture was slowly cooled to room temperature, stirred for 4 hours, and the precipitate formed was filtered, washed with a mixture of chloroform and hexane (1 :2, v/v), and dried at 40⁰C, to obtain 5.4 g (84%) of the compound of formula (I) as a white crystalline powder. Melting point: 148.9-150.1 °C

Optical purity: 95.4%ee Specific optical rotation: [α]_D ²⁵ = +176.42 (c=1.0, MeOH)

Example 4 10.0 g (27.1 mmol) of racemic lansoprazole and 15.7 g (54.1 mmol) of

(R)-(+)-l,l,2-triphenyl-l,2-ethanediol were suspended in a mixture of 200 mL of isopropanol and 100 mL of diisopropylether, refluxed until they were dissolved. The resulting mixture was slowly cooled to room temperature, stirred for 4 hours, and the precipitate formed was isolated by filtering, washed with 100 mL of a mixture of isopropanol and diisopropylether (1 :4, v/v), dried at 40⁰C, to obtain 10.2 g (80%) of the compound of formula (I) as a white crystalline powder. Melting point: 147.5~149.2°C Optical purity: 95.8%ee

Specific optical rotation: [α]_D ²⁵ = +173.88 (c=1.0, MeOH)

Examples 5 and 6

The compound of formula (I) was obtained by repeating the procedure of Example 4, except for conducting under the condition of Table 1 using 1 g of racemic lansoprazole. <Table 1>

* TPED : (R)-(+)-l,l,2-triphenyl-l,2-ethanediol

Example 7

10.0 g (27.1 mmol) of racemic lansoprazole and 15.8 g (54.4 mmol) of (R)-(+)-l,l,2-triphenyl-l,2-ethanediol were suspended in a mixture of 250 mL of ethanol and 50 mL of water, refluxed until they were dissolved. The resulting mixture was cooled to room temperature, stirred for 4 hours, and the precipitate formed was isolated by filtering, washed with 50 mL of a mixture of ethanol and water (4:1, v/v), and dried at 40⁰C, to obtain 8.9 g (70%) of the compound of formula (I) as a white crystalline powder.

Melting point: 149.6~150.8°C

Optical purity: 98.9%ee

Specific optical rotation: [α]_D ²⁵ = +180.79 (c=1.0, MeOH)

Examples 8 to 11

The compound of formula (I) was obtained by repeating the procedure of Example 7, except for conducting under the condition of Table 2 using 1 g of racemic lansoprazole. <Table 2>

* TPED : (R)-(+)-l,l,2-triphenyl-l,2-ethanediol

Examples 12 and 13: Preparation of (R)-(+)-lansoprazole

Example 12

10.0 g (10.5 mmol, optical purity: >99.9%ee) of the inclusion complex of formula (I) obtained in Example 1 was dissolved in 155 mL of methylene chloride, 105 mL (21.0 mmol) of 0.2N potassium hydroxide was added thereto, and stirred. The aqueous layer was isolated therefrom, 50 mL of methanol was added thereto, the resulting mixture was adjusted to pH 6.5 using acetic acid, and stirred at room temperature for 2 hours. The precipitate formed was isolated by filtering, washed with water. The resulting product was dissolved in 40 mL of ethyl acetate, 80 mL of hexane was added thereto, and stirred for 1 hour. The precipitate formed was isolated by filtering, and dried at 40⁰C, to obtain 3.4 g (89%) of (R)-(+)-lansoprazole as 1.5 hydrate.

Melting point: 80~90°C

Optical purity: 99.9%ee

Specific optical rotation: [α]_D ²⁵ = +154.70 (c=1.0, Chloroform) Water content: 6.8% (K.F Moisture Analyzer)

¹H-NMR (CDCl₃, ppm): δ 8.32(d, IH), 7.60~7.68(m, 2H), 7.26~7.33(m, 2H), 6.65(d, IH), 4.73~4.88(q, 2H), 4.32~4.40(q, 2H), 2.22(s, 3H)

IR (KBr, cm^"1): 3631, 3363, 3072, 2976, 1645, 1583, 1475, 1443, 1315, 1262, 1249, 1200, 1110, 1079, 1033, 973, 917, 828, 743.

In addition, the organic layer isolated from the aqueous layer was washed two times with 100 mL of water, concentrated by drying over anhydrous magnesium sulfate, and the solid residue was crystallized using a mixture of ethylacetate and hexane (1 :10, v/v), to obtain 5.5 g (90%) of (R)-(+)- 1 , 1 ,2-triphenyl- 1 ,2-ethanediol.

Melting point: 127~130°C

Optical purity: 99.8%ee

Specific optical rotation: [α]_D ²⁵ = +205.54 (c=1.0, MeOH)

¹H-NMR (CDCl₃, ppm); δ 7.66(d, 2H), 7.28-7.41(m, 2H), 7.02-7. l(m, 10H), 5.58(d, IH), 3.13(s, IH), 2.47(d, IH)

IR (KBr, cm^"1): 3563, 3536, 3448, 3323, 3056, 3025, 2878, 2851, 1951, 1885, 1813, 1597, 1581, 1490, 1445, 1387, 1180, 1165, 1101, 1060, 1031, 1007, 897, 787, 766,750,715,697,613

Example 13

10.0 g (10.5 mmol, optical purity: >99.9%ee) of the inclusion complex of formula (I) obtained in Example 2 was dissolved in 155 mL of methylene chloride,

105 mL (21.0 mmol) of 0.25 N sodium hydroxide was added thereto, and stirred.

The aqueous layer was isolated therefrom, 200 mL of ethylacetate was added thereto, and the resulting mixture was adjusted to pH 7.0 using hydrochloric acid.

The organic layer was isolated therefrom, washed with 50 mL of salt water, dried over anhydrous magnesium sulfate, and concentrated under a reduced pressure, to obtain 3.5 g (91%) of (R)-(+)-lansoprazole as an amorphous form.

Melting point: 76.8~77.2°C

Optical purity: >99.9%ee Water content: 0.24% (K.F Moisture Analyzer)

While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.

Claims

WHAT IS CLAIMED IS:

1. A process for preparing (R)-(+)-lansoprazole of formula (II) comprising the steps of:

(1) subjecting racemic lansoprazole to a reaction with (R)-(+)-l,l,2-triphenyl-l,2-ethanediol to produce the complex of (R)-(+)-lansoprazole and (R)-(+)-l,l,2-triphenyl-l,2-ethanediol of formula (I); and

(2) treating the compound of formula (I) with an organic solvent and a basic aqueous solution to allow its partition between the organic and aqueous layers, separating the aqueous layer, and neutralizing the aqueous layer thus obtained with an acid.

(I)

2. The process of claim 1, wherein step (1) is conducted in an organic solvent selected from the group consisting of chloroform, methanol, ethanol, isopropanol, acetone, acetonitrle, and a mixture thereof.

3. The process of claim 1, wherein step (1) is conducted in a mixed solvent of a 1^st organic solvent selected from the group consisting of chloroform, methanol, ethanol, isopropanol, acetone, acetonitrile, a mixture thereof, and a 2^nd solvent selected from the group consisting of hexane, diisopropyl ether, and water, with the proviso that the mixed solvent is not a mixture of chloroform and water.

4. The process of claim 3, wherein the mixed solvent is a mixture of chloroform and hexane.

5. The process of claim 3, wherein the mixed solvent is a mixture of diisopropyl ether and an organic solvent selected from the group consisting of methanol, ethanol, isopropanol, acetone, and acetonitrile.

6. The process of claim 3, wherein the mixed solvent is a mixture of water and an organic solvent selected from the group consisting of methanol, ethanol, isopropanol, acetone, and acetonitrile.

7. The process of claim 3, wherein the 1^st organic solvent to the 2^nd solvent volume ratio is 1 : 1 to 10: 1.

8. The process of claim 1, wherein the amount of (R)-(+)-l,l,2-triphenyl-l,2-ethanediol used is 1.5 to 3 equivalents based on the racemic lansoprazole.

9. The process of claim 1, further comprising the step of recrystallizing the complex of (R)-(+)-lansoprazole and (R)-(+)-l,l,2-triphenyl-l,2-ethanediol of formula (I) obtained in step (1) prior to conducting step (2).

10. The process of claim 1, wherein the organic solvent used in step (2) is selected from the group consisting of methyl acetate, ethyl acetate, isopropyl acetate, ethyl ether, dichloromethane, chloroform, and a mixture thereof.

11. The process of claim 1 , wherein the basic aqueous solution is aqueous sodium hydroxide or aqueous potassium hydroxide.

12. The process of claim 1, wherein the basic aqueous solution comprises sodium hydroxide or potassium hydroxide in an amount of 1 to 5 equivalents based on the compound of formula (I).

13. The process of claim 1, wherein the acid is acetic acid or hydrochloric acid.

14. The process of claim 1, wherein the pH of the solution neutralized with an acid is 5 to 7.

15. The process of claim 1, further comprising the step of recovering (R)-(+)-l,l,2-triphenyl-l,2-ethanediol from the organic layer isolated in step (2) for recycling.

16. The complex of (R)-(+)-lansoprazole and (R)-(+)-l,l,2-triphenyl-l,2-ethanediol of formula (I):

(I)