HK1118553B - Method of preparing esomeprazole and salts thereof - Google Patents

Description

Process for preparing esomeprazole and salts thereof

Technical Field

The present invention relates to a process for the preparation of optically pure esomeprazole and its salts from omeprazole by applying an improved optical resolution process.

Background

Esomeprazole of formula (II), the levorotatory isomer of racemic omeprazole, is an ulcer treating agent very effective in treating conditions such as gastric ulcer, duodenal ulcer and reflux esophagitis, is less affected by hepatic metabolism and exerts less side effects compared to omeprazole racemate. It is currently NexiumIs commercially available in the form of:

various methods for preparing esomeprazole are described in the literature, for example, US patent nos. 5,693,818 and 6,369,085, international published patent nos. WO1996/002535, WO1997/002261 and WO2004/002982, chinese patent No. 1,087,739, [ j.deng et al, Tetrahedron (Tetrahedron): (ii) Asymmetry (Asymmetry),11，1729-1732，2000]and [ h.cotton et al, Tetrahedron (Tetrahedron): (ii) Asymmetry (Asymmetry),11，3819-3825，2000]. Among these methods, according to commercial utility, a method involving resolution of racemic omeprazole using an optical resolution agent or asymmetric oxidation of a precursor of esomeprazole using a chiral agent is preferred.

For example, chinese patent No. 1,087,739 discloses a method for preparing esomeprazole of formula (II) via reaction of omeprazole of the exo-racemization formula with (S) - (-) -binaphthol (binol) (levo isomer of β -binaphthol) as an optical resolution agent to form an inclusion complex of esomeprazole of formula (I) and (S) - (-) -binaphthol, and removing the (S) - (-) -binaphthol moiety therefrom:

however, this approach has several problems, among others;

1) in order to obtain esomeprazole of high optical purity, a relatively expensive (S) - (-) -binaphthol must be used in a 1.5 molar equivalent excess with respect to omeprazole,

2) benzene (class I; ICH Q3C impurity: the guidelines for residual Solvents (CPMP/ICH/283/95), which are used as Solvents in the process, may cause toxicity,

3) the inclusion complex of formula (I), and solutions containing the same, are pitch-black, requiring a decolorization step in the recycle of the separation of unreacted (S) - (-) -binaphthol from the reaction mixture containing the inclusion complex,

4) removal of (S) - (-) -binaphthol from the inclusion complex of formula (I) by chromatography, which is not suitable for mass production, and

5) the optical purity of the inclusion complex of formula (I) is unsatisfactorily low, i.e., about 90% ee (enantiomeric excess), which requires further purification of the final esomeprazole product, resulting in a reduced yield ([ j.deng et al, Tetrahedron: asymmetry (Asymmetry), 11, 1729-1732, 2000).

Summary of The Invention

It is therefore a main object of the present invention to provide an improved optical resolution process for the preparation of optically pure esomeprazole and its salts.

According to one aspect of the present invention, there is provided a process for preparing esomeprazole of formula (II) or a salt thereof having an optical purity of at least 98% ee, which comprises:

(A) dissolving (S) - (-) -binaphthol, a weak base and racemic form omeprazole in a mixture of a water-compatible organic solvent and water at a temperature ranging from 30 to 70 ℃, and cooling the resulting solution to a temperature ranging from-5 ℃ to room temperature to crystallize the inclusion complex of esomeprazole and (S) - (-) -binaphthol of formula (I); and is

(B) Removing the (S) - (-) -binaphthol moiety from the inclusion complex of formula (I) obtained in step (a) by filtration or extraction:

brief Description of Drawings

The above and other objects and features of the present invention will become apparent from the following description of the invention, taken in conjunction with the following drawings, which respectively show:

FIG. 1: photographs of esomeprazole/(S) - (-) -binaphthol inclusion complex obtained in example 1 and comparative example 3, respectively; and

FIG. 2: the visible light absorption spectra of the esomeprazole/(S) - (-) -binaphthol inclusion complex obtained in example 1, comparative example 2 and comparative example 3, respectively.

Detailed Description

Step (A) according to the present invention comprises dissolving (S) - (-) -binaphthol, a weak base and racemic form omeprazole as an optical resolution agent in a mixture of a water-compatible organic solvent and water at a temperature in the range of 30 to 70 ℃, and then cooling the mixed solution to a temperature of-5 ℃ to room temperature, preferably 0 to 15 ℃, to crystallize the inclusion complex of esomeprazole and (S) - (-) -binaphthol of formula (I).

The (S) - (-) -binaphthol optical resolution reagent may be used in an amount of 0.5 to 0.7 molar equivalents based on omeprazole, which is much less than that used in the conventional optical resolution method.

The weak base used in the present invention prevents the inclusion complex of formula (I) from blackening and typical examples thereof include ammonium hydroxide, methylamine, ethylamine, dimethylamine, diethylamine, trimethylamine, triethylamine and a mixture thereof. The weak base may be used in an amount of 0.05 to 1 molar equivalent, preferably 0.1 to 0.5 molar equivalent, based on omeprazole.

The water-compatible organic solvent-water mixture for use in the present invention may comprise an organic solvent and water in a volume ratio of 98-40: 2-60. If necessary, additional water may be added to the mixed solvent just before cooling, as long as the final mixture meets the above volume ratio. The non-toxic water compatible organic solvent may be methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, acetone, acetonitrile, 1, 4-dioxane or mixtures thereof (class II or III; ICH Q3C impurity: guidance for Residual Solvents (CPMP/ICH/283/95)), which may be used in amounts of 3 to 15ml based on 1g omeprazole.

The esomeprazole/(S) - (-) -binaphthol inclusion complex of formula (I) crystallized by cooling can be obtained as a crystalline powder by conventional filtration or drying methods. The white or off-white crystalline inclusion complex thus obtained has a satisfactory optical purity of at least 95% ee, which does not require further purification, but, if necessary, can be further recrystallized from a mixture of a water-compatible organic solvent and water to further improve its purity.

Step (B) according to the invention comprises removing the (S) - (-) -binaphthol moiety from the inclusion complex of formula (I) obtained in step (A) by filtration or extraction to obtain esomeprazole of formula (II) or its salt.

Specifically, in step (B), esomeprazole of formula (II) or its salt can be obtained by suspending the inclusion complex of (I) in water or alcohol and adding a base thereto, followed by filtration or extraction with an organic solvent to separate the (S) - (-) -binaphthol moiety from the inclusion complex. This step (B) may be carried out at room temperature.

When the inclusion complex of formula (I) is suspended in water, sodium hydroxide or potassium hydroxide may be used as a base in an amount of 1 to 1.5 molar equivalents, preferably from 1 to 1.2 molar equivalents, based on the inclusion complex. In this case, (S) - (-) -binaphthol is separated in a subsequent filtration or extraction step and esomeprazole of formula (II) or its salt can be recovered from the alkaline filtrate by conventional methods. For example, esomeprazole can be recovered by acidifying the filtrate with acetic acid, followed by filtration or extraction with an organic solvent; sodium or potassium salt of esomeprazole by concentrating the filtrate and adding an organic solvent to the concentrate to induce crystallization of the desired product, or by acidifying the filtrate with acetic acid, extracting with an organic solvent and adding sodium or potassium hydroxide to the resulting organic layer to induce crystallization of the desired product; and esomeprazole magnesium salt by adding an aqueous solution of magnesium chloride to the filtrate containing the sodium or potassium salt of esomeprazole, or to a previously obtained aqueous solution of the sodium or potassium salt of esomeprazole, to induce crystallization of the desired product.

On the other hand, when the inclusion complex of formula (I) is suspended in an alcohol such as methanol, ethanol and isopropanol, strontium hydroxide is suitably used as the base, and it may be used in an amount of 0.5 to 0.75 molar equivalents, preferably 0.5 to 0.6 molar equivalents, based on the inclusion complex. In this case, the strontium salt of esomeprazole is directly isolated in a subsequent filtration or extraction step, and the (S) - (-) -binaphthol can be recovered from the alkaline filtrate by conventional methods for further recycling. For example, the (S) - (-) -binaphthol may be recovered by adding water to the filtrate followed by filtration.

The organic solvent suitably used in the extraction step may be methyl acetate, ethyl acetate, isopropyl acetate, diethyl ether, dichloromethane, chloroform or a mixture thereof.

The (S) - (-) -binaphthol thus separated can be recovered in a yield of 85% or more. Because no black color is developed, (S) - (-) -binaphthol can also be reused in the preparation of the inclusion complex of formula (I) by a simple purification step, including a recrystallization step.

Esomeprazole, or a salt thereof, obtained according to the process of the invention has a high optical purity of at least 98% ee, which complies with the minimum pharmaceutical purity required by the united states pharmacopeia.

As described above, the process of the present invention can be advantageously used for the simple and economical preparation of optically pure esomeprazole and its salt without coloring problems that hinder the recycling of the (S) - (-) -binaphthol optical resolution reagent.

The following examples are given for the purpose of illustration only and are not intended to limit the scope of the invention.

The esomeprazole/(S) - (-) -binaphthol inclusion complex, and esomeprazole and its salt, obtained in the following examples and comparative examples, were each determined in optical purity by chiral HPLC (high performance liquid chromatography) under the following conditions:

-a column: chiral (Chiral) -AGP (5 μm, 150 mm. times.4 mm)

-the detection wavelength: 280nm

-flow rate: 0.8ml/min

-an eluent: 10% acetonitrile-phosphate buffer pH 6.5

< preparation of Inclusion Complex of Esomeprazole and (S) - (-) -binaphthol (formula (I) >

Example 1

25.0g of (S) - (-) -binaphthol (87.3mmol) was dissolved in a mixture of 400ml of ethanol and 100ml of water at 60 ℃ and 5.0ml of triethylamine (35.9mmol) and 50.0g of racemic omeprazole (144.8mmol) were dissolved therein while maintaining the temperature at 50-55 ℃. The resulting solution was then slowly cooled to room temperature and stirred at this temperature for 12 hours. The precipitated solid was filtered, washed sequentially with a mixture of 85ml of ethanol and 15ml of water and with 100ml of n-hexane, and dried at 40 ℃ to obtain 38.9g of the title compound in yellow-white color (yield: 85%).

M.p.：158-160℃。

Specific linear luminosity: [ alpha ] to]_D ²⁰＝-146.2°(c＝1，THF)。

Optical purity: 98.7% ee (chiral HPLC).

¹H-NMR(CDCl₃，ppm)：δ2.24(s，6H)，3.73(s，3H)，3.87(s，3H)，4.65(d，1H)，4.78(d，2H)，5.50(br.s，2H)，6.96(br.s，2H)，7.18(d，2H)，7.40-7.28(m，8H)，7.70(br.s，1H)，7.90(d，2H)，7.98(d，2H)，8.16(s，1H)，11.60(bs，1H).

IR(KBr，cm^-1)：3057，1619，1595，1576，1471，1462，1401，1380，1271，1205，1146，1073，1028，815，570，506，422.

Example 2

99.6g of (S) - (-) -binaphthol (0.35 mol) was dissolved in a mixture of 1200ml of isopropanol and 200ml of water at 60 ℃ and 10ml of 28% aqueous ammonia (0.15 mol) and 200.0g of ecto-racemic omeprazole (0.58 mol) were added thereto while maintaining the temperature at 50-55 ℃. 600ml of water were slowly added to the resulting solution and after complete dissolution of the contents was achieved, 0.2g of an inclusion complex of esomeprazole and (S) - (-) -binaphthol was added thereto as a seed crystal. The resulting solution was slowly cooled to room temperature and stirred for 6 hours, and further cooled to 5-10 ℃ and stirred for 4 hours. The precipitated solid was filtered, washed sequentially with a mixture of 160ml of isopropyl alcohol and 40ml of water and with 200ml of n-hexane, and dried at 40 ℃ to obtain 163.1g of the title compound in the form of yellow-white (yield: 89%). Proton nuclear magnetic resonance of product: (¹H-NMR) and Infrared (IR) spectra were the same as those obtained in example 1.

M.p.：157-159℃。

Specific linear luminosity: [ alpha ] to]_D ²⁰＝-145.9°(c＝1，THF)。

Optical purity: 96.8% ee (chiral HPLC).

Examples 3 to 14

The procedure of example 1 or 2 was repeated using 50.0g of exo-racemic omeprazole (144.8mmol), 500ml of reaction solvent and other specific substances shown in Table 1 to obtain various compounds, the yields and optical purities of which are shown in Table 1.

TABLE 1

Example 15: purification of Inclusion Complex of Esomeprazole and (S) - (-) -Binaphthol (formula (I))

50.0g of an inclusion complex of the formula (I) having an optical purity of 95-98% ee was added to a mixture of 255ml of isopropyl alcohol and 45ml of water in which 1.0ml of 28% aqueous ammonia was dissolved, and stirred at 50-55 ℃ for 4 hours, slowly cooled to 5-10 ℃ and stirred for 12 hours. The precipitated solid was filtered, washed sequentially with a mixture of 85ml of isopropyl alcohol and 15ml of water and with 100ml of n-hexane, and dried at 40 ℃ for 3 hours to obtain 44g of the title compound of yellowish white optically pure (yield: 88%). Proton nuclear magnetic resonance of product: (¹H-NMR) and Infrared (IR) spectra were the same as those obtained in example 1.

M.p.：158-161℃。

Specific linear luminosity: [ alpha ] to]_D ²⁰＝-147.3°(c＝1，THF)。

Optical purity: 99.4% ee (chiral HPLC).

<Preparation of esomeprazole (formula (II)) or a salt thereof>

Example 16: preparation of esomeprazole

65.0g of an inclusion complex of esomeprazole and (S) - (-) -binaphthol (optical purity: 99.4% ee) obtained in example 15 and 300ml of isopropyl acetate were sequentially added to 300ml of an aqueous solution containing 4.95g of sodium hydroxide, which was stirred at room temperature for 30 min. The organic layer was separated and the aqueous layer was further extracted with 150ml isopropyl acetate. The organic layers were combined and concentrated to recover 25g of (S) - (-) binaphthol therefrom (recovery: 85%). On the other hand, 300ml of methylene chloride was added to the aqueous layer, the resulting mixture was adjusted to pH 8.0 with 1N acetic acid, and then the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 33.7g of the title compound as a foam (yield: 95%).

Specific linear luminosity: [ alpha ] to]_D ²⁰＝-146.9°(c＝1，THF)。

Optical purity: 99.4% ee (chiral HPLC).

¹H-NMR(CDCl₃，ppm)：δ2.14(s，3H)，2.24(s，3H)，3.72(s，3H)，3.86(s，3H)，4.76(dd，2H)，6.96(dd，1H)，7.04(br.s，1H)，7.29(s，1H)，7.56(br.s，1H)，8.23(s，1H).

IR(KBr，cm^-1)：3529，3349，1628，1590，1571，1465，1414，1398，1270，1211，1156.4，1079，1048，1029，837，625，518.

Example 17: preparation of esomeprazole

65.0g of the inclusion complex of esomeprazole and (S) - (-) -binaphthol (optical purity: 99.4% ee) obtained in example 15 and 300ml of isopropyl acetate were sequentially added to 300ml of an aqueous solution containing 4.95g of sodium hydroxide, which was stirred at room temperature for 30 min. The organic layer was separated and the aqueous layer was further extracted with 150ml isopropyl acetate. Then, 30ml of isopropyl alcohol was added to the aqueous layer, and the resulting mixture was adjusted to pH 8.0 with 1N acetic acid and stirred at 5-10 ℃ for 20 hours. The precipitated solid was filtered, washed with 100ml of water and 100ml of n-hexane in this order, and dried under reduced pressure at room temperature to obtain 30.9g of the title compound as an off-white solid (yield:87%). Proton nuclear magnetic resonance of product: (¹H-NMR) and Infrared (IR) spectra were the same as those obtained in example 16.

M.p.：70℃。

Specific linear luminosity: [ alpha ] to]_D ²⁰＝-1 50.7°(c＝0.5，CHCl₃)。

Optical purity: 99.5% ee (chiral HPLC).

Example 18: preparation of esomeprazole sodium salt

65.0g of an inclusion complex of esomeprazole and (S) - (-) -binaphthol having an optical purity of 95.2% ee and 300ml of isopropyl acetate were sequentially added to 300ml of an aqueous solution containing 4.95g of sodium hydroxide, which was stirred at room temperature for 30 min. The organic layer was separated and the aqueous layer was further extracted with 150ml isopropyl acetate. The aqueous layer was distilled under reduced pressure to remove water. To the resulting residue was added 20ml of methyl isobutyl ketone and 80ml of acetonitrile, which was stirred. The precipitated solid was filtered and dried at 40 ℃ to obtain 34.1g of the title compound as a white crystalline powder (yield: 90%).

M.p.：238-240℃。

Water content: 4.87%

Specific linear luminosity: [ alpha ] to]_D ²⁰＝+29.9°(c＝0.5，H₂O)。

Optical purity: 99.6% ee (chiral HPLC).

¹H-NMR(DMSO-d₆Ppm): δ 2.21(s, 6H), 3.69(s, 3H), 3.73(s, 3H), 4.38(d, 1H, J ═ 12.9Hz), 4.68(d, 1H, J ═ 12.9Hz), 6.54(dd, 2H, J ═ 8.5Hz and J ═ 2.3Hz), 6.98(d, 1H, J ═ 2.3Hz), 7.32(d, 1H, J ═ 8.5Hz), 8.23(s, 1H).

IR(KBr，cm^-1)：2936，2828，2615，2655，2056，1651，1644，1614，1574，1568，1557，1479，1472，1455，1372，1361，1295，1269，1199，1153，1077，1019，1000，952，867，414.

Example 19: preparation of esomeprazole potassium salt

65.0g of an inclusion complex of esomeprazole and (S) - (-) -binaphthol having an optical purity of 96.5% ee and 300ml of isopropyl acetate were sequentially added to 300ml of an aqueous solution containing 6.35g of sodium hydroxide, which was stirred at room temperature for 30 min. The organic layer was separated and the aqueous layer was further extracted with 150ml isopropyl acetate. The aqueous layer was distilled under reduced pressure to remove water. To the resulting residue, 200ml of methanol and 20ml of toluene were added, which was stirred. The precipitated solid was filtered and dried at 40 ℃ to obtain 33.54g of the title compound as a white crystalline monohydrate powder (yield: 85%).

M.p.：118-120℃。

Water content: 3.54 percent

Specific linear luminosity: [ alpha ] to]_D ²⁰＝+27.8°(c＝1，H₂O)。

Optical purity: 99.6% ee (chiral HPLC).

¹H-NMR(CDCl₃Ppm): δ 2.21(s, 6H), 3.69(s, 3H), 3.74(s, 3H), 4.43(d, 1H, J ═ 12.9Hz), 4.75(d, 1H, J ═ 12.9Hz), 6.59(dd, 2H, J ═ 8.6Hz and J ═ 1.8Hz), 7.00(d, 1H, J ═ 1.8Hz), 7.34(d, 1H, J ═ 8.6Hz), 8.22(s, 1H).

IR(KBr，cm^-1)：2830，2361，2344，1614，1592，1570，1478，1445，1397，1362，1296，1270，1200，1154，1075，1027，953，842，804，632，522，439.

Example 20: preparation of esomeprazole magnesium salt

65.0g of an inclusion complex of esomeprazole and (S) - (-) -binaphthol having an optical purity of 98.7% ee and 300ml of isopropyl acetate were sequentially added to 300ml of an aqueous solution containing 4.95g of sodium hydroxide, which was stirred at room temperature for 30 min. The organic layer was separated and the aqueous layer was further extracted with 150ml isopropyl acetate. 150ml of an aqueous solution containing 5.0g of magnesium chloride was added to the aqueous layer and the resulting suspension was stirred for 1 hour. The precipitated solid was filtered, washed with water and dissolved in 100ml of methanol. 400ml of acetone were added to the resulting solution and stirred at room temperature for 2 hours. The precipitated solid was filtered and dried at 40 ℃ to obtain 31.6g of the title compound as a white crystalline dihydrate powder (yield: 82%).

M.p.：174-177℃.

Water content: 5.12% (2H)₂O：4.81％)

Optical purity: 99.6% ee (chiral HPLC).

IR(KBr，cm^-1)：3070，2994，2939，2830，1615，1590，1570，1477，1436，1409，1303，1272，1200，1156，1078，1029，1003，956，835，806，770，632，580.

Example 21: preparation of esomeprazole strontium salt

153.0g of an inclusion complex of esomeprazole and (S) - (-) -binaphthol having an optical purity of 98.3% ee was dissolved in 1000ml of methanol, and strontium hydroxide (37.3g, in the form of octahydrate) was added thereto, followed by stirring the resulting mixture at room temperature for 3 hours. The formed precipitate was filtered, washed with 300ml of methanol and dried at 45 ℃ for 12 hours to obtain 93.0g of the title compound as a white crystalline powder (yield: 93%). Then, 3000ml of water was added to the filtrate and the mixture was stirred at room temperature for several hours. The precipitated solid was recovered by filtration, followed by washing with water, to give 63.0g of (S) - (-) binaphthol (yield: 90%).

M.p.：201-203℃.

Water content: 9.0% (4H)₂O：8.49％)

Optical purity: 99.6% ee (chiral HPLC).

¹H-NMR(DMSO-d₆)：δ8.26(s，1H)，7.38(d，1H)，7.02(bs，1H)，6.54(dd，1H)，4.58(d，2H，J＝13.3)，4.46(d，2H，J＝13.4)，3.68(s，3H)，3.66(s，3H)，2.22(s，3H)，2.10(s，3H).

IR(KBr，cm^-1)：3422，2991，2831，2364，1638，1611，1569，1561，1476，1444.4，1390，1365，1271，1204，1156，1077，1027，1000，855，844，798，637，487.

Comparative examples 1 to 3: according to the formula [ J.Deng et al, Tetrahedron: asymmetric (Asymmetry), 11, 1729-]And [ h.cotton et al, Tetrahedron (Tetrahedron): asymmetric (Asymmetry), 11, 3819-3825, 2000]The method disclosed in (a) prepares an inclusion complex of esomeprazole and (S) - (-) -binaphthol (formula (I))

(S) - (-) -binaphthol and 10.0g of ecto-racemic omeprazole were dissolved in 288ml of benzene and 72ml of n-hexane at 110 ℃. (S) - (-) -binaphthol was used in amounts of 0.6, 1.0 and 1.5 molar equivalents, respectively, based on omeprazole, as shown in Table 2. The resulting solution was then slowly cooled to 0 ℃ and stirred for 12 hours. The precipitated solid was filtered and washed with a mixture of benzene and hexane to obtain the title compound.

The optical purity and/or color of the product thus obtained, together with the optical purity and/or color of the product obtained in example 1, are shown in table 2 and fig. 1.

TABLE 2

	Process for preparation of (S) - (-) -binaphtholAmount (molar equivalent)	Optical purity (% ee)	Colour(s)
				Example 1	0.6	98.7	Yellow and white
Comparative example 1	0.6	20.0	Yellow colour
				Comparative example 2	1.0	82.6	Black colour
Comparative example 3	1.5	92.2	Black colour

As shown in table 2 and fig. 1, the compound of the present invention obtained in example 1 was less colored and its optical purity was much higher than those of the comparative compounds.

Test example: measurement of absorbance in the visible region

The visible light absorbance of the respective esomeprazole/(S) - (-) -binaphthol inclusion complexes obtained in example 1, comparative example 2 and comparative example 3 was measured after dissolving in acetonitrile at a concentration of 0.1% according to the absorbance-measuring method disclosed in the united states pharmacopoeia. The results are shown in table 3 and fig. 2.

TABLE 3

	Absorbance of the solution
			402nm	540nm
Comparative example 2	0.392	0.313
			Comparative example 3	0.510	0.368
Example 1	0.010	0.001

The absorbances shown in table 3 and fig. 2 indicate that the compound of the present invention obtained in example 1 did not develop color, whereas the compound of comparative example developed a severe black color.

As shown above, the process of the present invention can provide optically pure esomeprazole and its salts without coloration problems that hinder the recycling of the (S) - (-) -binaphthol optical resolution reagent.

While embodiments of the invention have been described and illustrated, it is evident that various changes and modifications may be made therein without departing from the spirit of the invention, which is limited only by the scope of the appended claims.

Claims (14)

1. A process for preparing esomeprazole of formula (II) or its salt having an optical purity of at least 98% ee, comprising:

(A) dissolving (S) - (-) -binaphthol, a weak base and racemic form of omeprazole in a mixture of a water-compatible organic solvent and water at a temperature in the range of 30 to 70 ℃, and cooling the resulting solution to a temperature of-5 ℃ to room temperature to crystallize the inclusion complex of esomeprazole and (S) - (-) -binaphthol of formula (I); and is

(B) Removing the (S) - (-) -binaphthol moiety from the inclusion complex of formula (I) obtained in step (a) by filtration or extraction:

2. the process of claim 1, wherein the amount of (S) - (-) -binaphthol used in step (A) is in the range of 0.5 to 0.7 molar equivalents based on omeprazole.

3. The process of claim 1, wherein the water compatible organic solvent used in step (a) is selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, acetone, acetonitrile, 1, 4-dioxane and mixtures thereof.

4. The process of claim 1, wherein the volume ratio of water-compatible organic solvent and water used in step (A) is in the range of 98-40: 2-60.

5. The process according to claim 1, wherein the water-compatible organic solvent used in step (a) is in the range of 3 to 15ml based on 1g omeprazole.

6. The process of claim 1 wherein the weak base used in step (a) is selected from the group consisting of ammonium hydroxide, methylamine, ethylamine, dimethylamine, diethylamine, trimethylamine, triethylamine and mixtures thereof.

7. The process according to claim 1, wherein the amount of the weak base used in step (a) is in the range of 0.05 to 1 molar equivalent based on omeprazole.

8. The process of claim 1, wherein the inclusion complex of esomeprazole and (S) - (-) binaphthol crystallized in step (A) has an optical purity of at least 95% ee.

9. The method of claim 1, wherein step (B) comprises: suspending the inclusion complex of formula (I) obtained in step (a) in water or alcohol and adding a base thereto, followed by isolating the (S) - (-) -binaphthol moiety from said inclusion complex by filtration or extraction with an organic solvent.

10. The method of claim 9, wherein when the inclusion complex of formula (I) is suspended in water, the base used in step (B) is sodium hydroxide or potassium hydroxide and its amount is in the range of 1 to 1.5 molar equivalents based on the inclusion complex.

11. The method of claim 9, wherein when the inclusion complex of formula (I) is suspended in an alcohol, the base used in step (B) is strontium hydroxide and its amount is in the range of 0.5 to 0.75 molar equivalents based on the inclusion complex.

12. The method of claim 11, wherein the alcohol is selected from the group consisting of methanol, ethanol, and isopropanol.

13. The process of claim 9, wherein the organic solvent used in step (B) is selected from the group consisting of methyl acetate, ethyl acetate, isopropyl acetate, diethyl ether, dichloromethane, chloroform and mixtures thereof.

14. The process of claim 1 wherein the (S) - (-) -binaphthol released in step (B) is separated for reuse in step (A).