WO2010091652A1

WO2010091652A1 - A method for the manufacture of (s) -5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyrimidinyl) methyl] sulfinyl] -ih-benz imidazole using a chiral complex with lactic acid

Info

Publication number: WO2010091652A1
Application number: PCT/CZ2010/000018
Authority: WO
Inventors: Hana Stepankova; Josef Zezula; Josef Hajicek; Vladimir Kral
Original assignee: Zentiva, K.S.
Priority date: 2009-02-16
Filing date: 2010-02-16
Publication date: 2010-08-19
Also published as: CZ200990A3

Abstract

The invention deals with a new method of manufacturing (S)-5-methoxy-2-[[(4- methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole of formula (I) and its salts of general formula (II), wherein the sulfide of general formula (III) is oxidized with hydroperoxides on a catalyst consisting of a chiral metallic complex containing ligands constituted by chiral functional derivatives of lactic acid.

Description

A METHOD FOR THE MANUFACTURE OF (S) -5-METHOXY-2- [ [ (4-METH0XY-3 , 5-DIMETHYL-2-PYRIMIDINYL) METHYL]

SULFINYL] -IH-BENZ IMIDAZOLE USING A CHIRAL COMPLEX WITH LACTIC ACID

Technical Field

The invention deals with a new method for the manufacture of (iS)-5-methoxy-2-[[(4- m.ethoxy-3,5-dimethyl-2-ρyridinyl)methyl]sulfmyl]-lH-benzimidazole of formula I and its salts of the general formula II.

Background Art

Racemic 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfmyl]-lH- benzimidazole, known under the name omeprazole is described in EP 0 005 129 as an inhibitor of gastric juice secretion, used to treat ulcerous diseases. Its (S^-enantiomer, (iS)-5- methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfmyl]-lH-benzimidazole of formula I, known under the INN name esomeprazole, or (^-omeprazole, is more efficient, and thus safer as it allows lower dosing. Therefore, looking . for new, efficient ways of its manufacture is an important challenge of pharmaceutical chemistry.

The known manufacturing methods of esomeprazole can be divided into the methods that use enantioselective oxidation of the sulfide of formula III directly to esomeprazole, and the methods that split the racemic omeprazole by means of optical resolution or chromatography.

It is Kagan's method of asymmetrical synthesis of sulfoxides (see e.g. Tetrahedron 1987, 43, 5135; Synlett 1990, 643) upon which the manufacturing process of optically active sulfoxides according to EP0773940 (AstraZeneca) rests. Said process comprises, in the case of omeprazole, oxidation of prochiral 2-[[(3,5-dimethyl-4-methoxypyridin-2-yl)methyl]thio]-5- methoxy-lΗ-benzimidazole with peroxides in the presence of a chiral complex formed of a titanium (IV) alkoxide and the diethyl ester of (-)- or (+)-tartaric acid in the presence of a base such as diisopropylethylamine, the presence of which significantly increases optical purity of the obtained omeprazole (e.g. 87 % as compared to 23 % without the base). An optimization of the procedure is described e.g. in Tetrahedron Asym. 2000, 11, 3819 and Chem. Commun. 2007, 2187. The procedure has the disadvantage that the expensive (-)-D-tartrate has to be used in the manufacture of esomeprazole. The document WO 2008/018091 (Jubilant Organosyn Ltd.) describes manufacture of esomeprazole in an alternative procedure from 2-[[(3,5-dimethyl-4-methoxypyridin-2- yl)methyl]thio]-5-methoxy-lH-benzimidazole, which comprises generation of a complex in the presence of Ti(Oz-Pr)₄ and (^^-diethyl-tartrate, followed by oxidation with cumene hydroperoxide without the presence of a base, in which high optical purity of up to 99.9% is achieved. This process has the same disadvantage as in the above-mentioned method.

It is the same asymmetrical oxidation of sulfides upon which the procedure of the document WO 2005/080374 (EP 1 718 636, AstraZeneca) rests, wherein the sulfide carrying a leaving group in the pyridine ring is oxidized and the leaving group is then replaced with a methoxyl, e.g. 2-[[(4-chloro-3,5-^;dimethylpyridin-2-yl)methyl]thio]-5-methoxy-lH- benzimidazole, which offered 2-[[(4-chloro-3,5-dimethylpyridin-2-yl)methyl]sulfmyl]-5- methoxy-lH-benzimidazole by oxidation with cumene hydroperoxide in the presence of Ti(Oz-Pr)₄, (,S,iS)-diethyl-tartrate and diisopropylethylamine.

According to the patent document CN 1 995 037 the prochiral sulfide is oxidized to esomeprazole in the presence of vanadium alkoxides and chiral derivatives of tartaric acid, such as esters and amides. The procedure is also claimed for ^-lansoprazole, (S)- pantoprazole, (>S)-rabeprazole and (»S)-tenatoprazole and their salts.

Patent CN 101012141 covers a preparation method of chiral sulfoxides, which consists in oxidation of the corresponding sulfides with peroxides in the presence of titanium or zirconium tetraalcoxides and chiral β-amino-alcohols, such as (5)-phenylglycinol, (S)-valinol, (5)-prolinol, and the like. The procedure is claimed for the synthesis of (iS)-omeprazole, (S)- lansoprazole, (<S)-pantoprazole, (<S)-rabeprazole and (5)-tenatoprazole.

Patent CN 1810803 (Shanghai Institute of Organic Chemistry) describes a manufacturing method of esomeprazole using enantioselective oxidation of 5-methoxy-2-(4-methoxy-3,5- dimethylpyridin-2-ylmethylthio)-lH-benzimidazole with a peroxide in the presence of the chiral ligand (Λ,i?)/(£,,S)-l,2-diaryl-ethylene glycol, titanium tetraalkoxide in a molar ratio of l:(0.5-3):(0.02-0.4):(0.01-0.2). This method does not require the presence of a base during the oxidation and the use of the relatively expensive cumene hydroperoxide; ee 92-99 %. (ee = enantiomeric excess, which is defined as the content of the (j?)-isomer minus the (i?)-isomer, more precisely [S]-[R] divided by ([S]+[R]).100%), i.e. 98% ee means the ratio of eriantiomers of 99:1.)

A similar procedure is described in the document WO 2007079784 (equiv. EP 1 966 188; Ratiopharm). The oxidation is preceded by formation of a complex from {R,R)- or (£,£^■)- l,2-bisarylethane-l,2-diols and titanium tetraalkoxide. The oxidation is carried out with peroxides; (^-omeprazole is obtained from 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2- pyridinyl)methyl]thio]-lH-benzimidazole by S-oxidation with tert-butylhydroperoxide in the presence of a complex generated from Ti(Oz-Pr)₄ and (JR,i?)-l,2-bis(2-bromoρhenyl)-l_s2- ethandiole in the yield of up to 94% and with >99% ee. Document WO 2004/087702 (equiv. EP 1 608 649, Sidem Pharma) describes a manufacturing method of esomeprazole (and tenatoprazole) by oxidation of sulfides with peroxides (hydrogen peroxide, cumene- or tert-butyl-hydroperoxide) in the presence of complexes, which are generated from vanadium or tungsten salts and chiral ligands, produced by coupling amino alcohols, amino ethers, amino acids or their esters with substituted salicylaldehydes. A disadvantage is represented by the impossibility of repeated use of the chiral catalyst as well as the by fact that many chiral ligands are more expensive and hard to regenerate by themselves, such as the aminoether (DHQD)₂-PYR, which has first to be manufactured from cinchona alkaloids. In this manner (S)-(-)-omeprazole is obtained in the yield of 72% with the initial 90% ee. Document WO 2006/094904 (equiv. EP 1 858 881, Esteve Quimica) describes optical resolution of omeprazole by means of generation of inclusion complexes with (S)-(-)- or (R)- (+)-[l,r-binaphthalene]-2,2'-diol in the presence of an amine, from which esomeprazole is then released by means of an alkali metal hydroxide. This way a 1 : 1 inclusion complex of (S)- omeprazole and (iS)-binaphthol is obtained in the presence of triethylamine in the 38% (76% of the theoretical quantity) yield.

A similar method is described in document WO 2007/013743 (EP 1 919 897, Hanmi). Esomeprazole and its salts with the optical purity of >98 % can be manufactured by means of generation of a crystalline inclusion complex with (S)-(-)-binol in the presence of a base and its re-crystallization; from the complex with 99.4 % ee esomeprazole with the same 99.4 ee is produced. (iS)-(-)-Binol may be regenerated.

This method of resolving the enantiomers of racemic omeprazole is also described in document WO 2008/004245 (Lupin Ltd.). It uses the formation of crystalline inclusion complexes with a molar excess of (S)- or (i?)-binol. The inclusion complex with the optical purity of >99.5 % is then directly converted into salts of esomeprazole (or (i?)-omeprazole) by the effect of hydroxides, optionally followed by trans-metallation. Said resolution processes have common disadvantages in the necessity to ensure availability of large amounts of the expensive optically pure binol, as well as uneconomical usage of the initial racemate. The process of document WO 2007/074099 (Union Quimico Farmaceutica) also rests upon formation of inclusion complexes. (^-Omeprazole, and optionally its salts, is produced from omeprazole racemate via a solid complex with (5)-l,l,2-triphenyl-l,2-ethandiol. The disadvantages are the same as those of the above-mentioned resolution procedures.

Document WO 2008/092939 (equiv. EP 2007-19823, Krka) is based on optical resolution of omeprazole by means of formation of solid salts with optically active amines. Disadvantages of the process consist in the fact that many of the claimed amines are expensive natural alkaloids, and also in the fact that more than 50% of the initial racemate is waste.

Literature (Org. Proc. Res. Dev. 2006, 10, 33) describes a different concept of the resolution process of racemic omeprazole. The sodium salt of omeprazole is solubilized by means of

(1 molar equiv.), Ti(OZ-Pr)₄ (0.5 equiv.) and an excess Of Et₃N. Addition of an excess of (+)-mandelic acid causes separation of a solid complex of esomeprazole with sodium mandelate, from which esomeprazole is released with high optical purity by the effect of a weak base. A disadvantage of this method consists in the fact that more than 50% of the initial racemate is waste. Patent WO 2003/051867 (equiv. EP 1 458 709, AstraZeneca) describes resolution of omeprazole enantiomers by means of a chromatographic method on Rromasjl-CHI-DMB (the simulated moving-bed technique). A disadvantage of this method consists in high demands for the production equipment.

Disclosure of Invention

The invention consists in a new efficient method for the manufacture of esomeprazole of formula I and its salts of general formula II,

wherein M means an atom of a metal from the 1^st or 2^nd group of the periodic table, which method comprises oxidation of the sulfide of formula III

with hydroperoxides on chiral metallic complexes, which contain ligands constituted by chiral functional derivatives of lactic acid.

In a preferred embodiment, the chiral complexes are generated in situ by reaction of metal tetraalkoxides of general formula V, Z(OR⁴)₄

V

such as titanium R-butoxide, titanium isopropoxide or zirconium π-propoxide, with chiral derivatives of (5)-lactic acid, such as esters of general formula IVa or amides of general formula IVb,

\ X:00R¹ \ Λ:0N R²R³

OH OH

IVa IVb

preferably with (5)-methyl-lactate of formula IVc, or (5}-ethyl-lactate of formula FVd.

\ _/COOMe \ _/COOEt

OH OH IVc IVd

hi a similar way, in accordance with the invention, (i?)-omeprazole of formula ent-l

or its salts can be manufactured using the respective (i?)-isomers of the functional derivatives of lactic acid.

A substantial advantage of the invention consists in the use of the inexpensive chiral ligand which has not been used for these purposes yet.

Detailed description of the invention

We have found out that optically pure or optically enriched salts of esomeprazole of general formula II,

wherein M means an atom of a metal from the 1^st and 2^nd group of the periodic table, such as an alkali metal, e.g. sodium or potassium, or an alkaline earth metal, such as magnesium or calcium, can be efficiently manufactured in such a way that the sulfide of formula III,

is oxidized on a chiral metallic complex, wherein the role of the chiral ligand is played by functional derivatives of lactic acid, by means of hydroperoxides.

The reaction can be carried out in the presence of an inert solvent, but without a solvent as well. The use of a base, especially of tertiary amines, however, may lead to a further improvement of optical purity.

In one of the aspects of the invention the chiral metallic complex of the new type is generated in situ by reaction of chiral derivatives of lactic acid having the absolute configuration (S) of general formula IV,

\ Λ:OX

OH IV wherein X means an alkoxyl group OR¹ or an amide group NR²R³, wherein • .

R¹ means an alkyl group having 1 to 8 carbon atoms, branched or unbranched, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl or hexyl, R² and R³ mean the same or different groups selected from the group including an alkyl group having 1 to 8 carbon atoms, branched or unbranched, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl or hexyl, or hydrogen, an arylalkyl group having 7 to 9 carbon atoms, such as benzyl, 4-methylbenzyl, α-methylbenzyl, or 2-phenylethyl, and an aryl group, substituted or unsubstituted with hetero-substituents, such as phenyl, 4- chlorophenyl, 2-methoxyphenyl or 1-naphthyl or 2-naphthyl, or R² and R³ together mean a cycle having 5 to 6 atoms, which optionally contains another heteroatom, and which optionally carries a chiral substituent, such as 1-pyrrolidinyl,

1 -piperidinyl, 4-morpholinyl, or l-(2-methoxymethyl)pyrrolidinyl, with metal tetraalkoxides of general formula V,

Z(OR⁴)₄

V ^'

wherein Z means a quadrivalent metal, such as titanium of zirconium and R⁴ means an alkyl group having 1 to 6 carbon atoms.

This aspect of the invention is based on the non-trivial finding that the chiral metallic complexes of the new type, which catalyze efficiently and with high enantioselectivity oxidation of sulfides to sulfoxides, can be generated in situ by reaction of tetraalkoxides of general formula V with monoalcohols of the type of chiral derivatives of lactic acid of general formula IV. Said derivatives can include esters of general formula IVa, as well as amides of general formula IVb,

IVa IVb wherein R¹ means an alkyl group having 1 to 8 carbon atoms, branched or uribranched, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl or hexyl, and R² and R³ mean the same or different groups selected from the group including an alkyl group having 1 to 8 carbon atoms, branched or unbranched, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl or hexyl, or hydrogen, an arylalkyl group having 7 to 9 carbon atoms, such as benzyl, 4-methylbenzyl, α-methylbenzyl, or 2-phenylethyl, and an aryl group, substituted or unsubstituted with hetero-substituents, such as phenyl, 4- chlorophenyl, 2-methoxyphenyl or 1-naphthyl or 2-naphthyl, or R² and R³ together mean a cycle having 5 to 6 atoms, which optionally contains another heteroatom, and which optionally carries a chiral substituent, such as 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, or l-(2-methoxymethyl)pyrrolidinyl.

From the practical point of view it is convenient to use esters of lactic acid of general formula IVa,

\ ^COOR¹

OH IVa

wherein R¹ means an alkyl group having 1 to 8 carbon atoms, branched or unbranched, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl or hexyl, wherein it is especially convenient to use the methyl ester of (<S)-lactic acid of formula IVc

V COOMe

OH IVc

and ethyl ester of (5)-lactic acid of formula IVd.

ϊOOEt

OH

IVd

In formation of the chiral metallic complex of the new type by an in situ reaction of the tetraalkoxide of the general formula V, Z(OR⁴)₄, wherein Z and R⁴ are as defined above, with the chiral derivatives of lactic acid having the absolute configuration (S) of the general formula IV, wherein X, OR¹ and NR²R³ are as defined above, the compound of the general formula IV is used in the molar ratio to the compound of formula V of 1 : 1 to 5: 1; however, preferably with an excess of 1.5 : 1 to 4 : 1, especially preferably of 2.0 — 4.0 : 1.

One can use, as the metal tetraalkoxide of general formula V, Z(OR⁴)₄, e.g., titanium isopropoxide, titanium «-butoxide or zirconium rø-propoxide, in an amount of 0.1 to 1.0 equivalents, preferably titanium n-butoxide or titanium isopropoxide in an amount of 0.1 to 1.0 equivalents, preferably 0.15 to 0.8 equivalents. In doing so, the chiral complex of the new type is generated in the presence or absence of the sulfide of formula III by means of an in situ reaction of the compound of formula V with the ligand of formula IV without the presence of an organic solvent, or is generated in an inert organic solvent, such as toluene, ethyl acetate, chloroform, or dichloromethane. The complexes are generated in a wide range of temperatures of 20 ⁰C to 100 ⁰C; preferably in the temperature range of 35 °C to 75 ⁰C.

In accordance with a convenient embodiment the chiral metallic complex of the new type is generated by reaction of 0.15 - 0.8 molar equivalents of titanium n-butoxide, or titanium isopropoxide, and 2.0 to 4.0 fold of lactic acid esters of the general formula IVa,

\ _/COOR¹

OH IVa

wherein R¹ means an alkyl group having 1 to 8 carbon atoms, branched or unbranched, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl or hexyl, the use of the methyl ester of (^-lactic acid of formula IVc,

\ Λ300Me

OH IVc

or ethyl ester of (5)-lactic acid of formula IVd,

V 0OEt

OH IVd in the temperature range of 35 to 75 °C being especially preferred.

In the present method, optically active lactic acid can also be used. However, this technique is very inconvenient as the achieved enantioselectivity is considerably worse and, in addition, the chemical yields and purity are lower due to the sensitivity of both the starting sulfide of formula III and the reaction product to acidic agents.

The oxidation is conducted by means of hydroperoxides, in practice with cumene hydroperoxide or tert-butyl hydroperoxide, in the temperature range of -20 ⁰C to +40 °C, preferably in the temperature range of 0 ⁰C to +25 ⁰C.

During processing of the experiments the compound of formula I is isolated, or it is isolated in the form of salts with metals of the 1^st and 2^nd groups of the periodic table, such as salts with alkali metals or salts with alkaline earth metals, such as sodium, potassium, magnesium, or calcium salts.

If necessary, the manufacturing method can be applied with the same efficiency to the manufacture of optically pure, or optically enriched salts of (i?)-omeprazole of the general formula ent-ll,

wherein M is as defined above, by a procedure, characterized in that the enantiomer of the chiral derivative of lactic acid having the absolute configuration (R) of the general formula ent-IVa,

\_/COOR¹

OH enf-IVa

wherein OR¹ is as defined above, is used.

Similarly, it is possible to manufacture optically pure or optically enriched (i?)-omeprazole of formula ent-ϊ

by the above mentioned-method, characterized in that the enantiomer of the chiral derivative of lactic acid having the absolute configuration (R) of the general formula ent-TVa,

-v^COOR¹

OH ent-Wa

wherein OR¹ is as defined above, is used.

The following working examples illustrate, but do not limit in any way, the general character of the manufacturing method of the present invention.

Examples

Example 1

2.7 g (9.45 mmol) of Ti(OPr)₄ and 3.93 g of ©-lactic acid methyl ester (general formula IV: X =^■ OMe, IVc ) (37.8 mmol) are placed into a 3-neck 100 ml flask purged with an inert gas (argon), equipped with a magnetic stirrer and a thermometer. The resulting solution is heated up to a temperature in the range of 55 to 60 ⁰C and 4.47 g (13.5 mmol) of the compound of formula III are added to the solution. The resulting thick slurry is stirred at a temperature in the range of 55 to 60 °C for 30 minutes. Then 60 μl of water are added to the reaction mixture. The reaction mixture is stirred at the same temperature for another 60 minutes. Subsequently, the reaction flask is put in a cooling bath and cooled to an inner temperature of +5 to +10 °C. Then, 2.25 ml of 88% cumene hydroperoxide are added to the reaction flask. The resulting slurry-like reaction mixture is stirred at a temperature in the range of +5 to +10 ⁰C for 15 hours. Then, under cooling to +5 to +10 ⁰C, the reaction mixture is diluted with 75 ml of a 12.5% solution Of NH₄OH and stirred for 30 minutes. The separated solid fraction is filtered off through a paper filter. The filter cake is washed with another 25 ml of the 12.5% solution OfNH₄OH. 75 ml of dichloromethane are added to the filtrate and, under stirring and cooling with ice, pH of the mixture is adjusted to pH 8 to 9 with acetic acid. The dichloromethane fraction is separated and the aqueous layer is extracted with another 30 ml of dichloromethane. The combined dichloromethane fractions are dried with sodium sulfate and concentrated to dryness in a rotary vacuum evaporator. The evaporation residue is taken with 120 ml of ethyl methyl ketone and 6.5 ml of a solution of KOH in methanol (3 g of KOH in 25 ml of methanol) are added to the obtained mixture under cooling with ice. The resulting solution is seeded and left at standstill at a temperature of +5 to + 10 °C for 5-10 hours. Separated crystals are aspirated through a frit. Wet crystals are dissolved in 20 ml of water in an Erlenmeyer flask. 25 ml of dichloromethane are added to the solution, pH of the mixture is adjusted to pH 8 to 9 with acetic acid under stirring and cooling with ice. The dichloromethane fraction is separated and the aqueous layer is extracted with another 10 ml of dichloromethane. The combined dichloromethane fractions are dried with anhydrous sodium sulfate and concentrated to dryness in a rotary vacuum evaporator. The evaporation residue is taken with 100 ml of ethyl methyl ketone and 2.5 ml of a solution of KOH in methanol (3 g of KOH in 25 ml of methanol) are added to the obtained mixture under cooling with ice. The resulting solution is seeded and left at standstill at a temperature of +5 to + 10 °C for 5-10 hours. The separated product is aspirated and 2.93 g . of the potassium salt of esomeprasole are obtained. After repeated re-crystallization from boiling methanol 1.5 g (28.9% yield) of the potassium salt of esomeprazole are obtained. HPLC chemical purity: 99.65 %. HPLC on the chiral phase (CHIRALPAK AD-H^®, mobile phase 50% hexane : 50% ethanol, detection 302 nm): enantiomeric excess 99.9 %. 1H-NMR (250 MHz. DMSO): 8.22 (s, IH), 7.31 (d, 8.9 Hz, IH), 6.96 (d, 2.3 Hz, IH), 6.55 (dd, 2.3 Hz, 8.6 Hz, IH), 4.78 (d, 13.1 Hz, IH), 4.38 (d, 13.1 Hz₅ IH), 3.72 (s, 3H), 3.69 (s, 3H), 2.23 (s, 3H), 3.20 (s, 3H).

Example 2

2.7 g (9.45 mmol) of Ti(OPr)₄ and 4.44 g of (_S)-lactic acid methyl ester (general formula IV: X

= OEt, rVd ) (37.8 mmol) are placed into a 3 -neck 100-ml flask purged with an inert gas (argon), equipped with a mechanical stirrer and a thermometer. The resulting solution is heated up to a temperature in the range of 55 to 60 °C and 4.47 g (13.5 mmol) of the compound of formula III are added to the solution. The resulting thick slurry is stirred at a temperature in the range of 55 to 60 ⁰C for 30 minutes. Then 60 μl of water are added to the reaction mixture. The reaction mixture is stirred at the same temperature for another 60 minutes. Subsequently, the reaction flask is put in a cooling bath and cooled to an inner temperature of +5 to +10 °C. Then, 2.25 ml of 88% cumene hydroperoxide are added to the flask. The resulting slurry- like reaction mixture is stirred at a temperature in the range of +5 to +10 °C for 15_. hours. Then, under cooling to +5 to +10 ⁰C, the reaction mixture is diluted with 75 ml of a 12.5% solution OfNH₄OH and stirred for 30 minutes. The separated solid fraction is filtered off through a paper filter. The filter cake is washed with another 25 ml of the 12.5% solution Of NH₄OH. 75 ml of dichloromethane are added to the filtrate and pH of the mixture is adjusted to 8 to 9 with acetic acid under stirring and cooling with ice. The dichloromethane fraction is separated and the aqueous layer is extracted with another 30 ml of dichloromethane. The combined dichloromethane fractions are dried with anhydrous sodium sulfate and concentrated to dryness in a rotary vacuum evaporator. The evaporation residue is taken with 120 ml of ethyl methyl ketone and 6.5 ml of a solution of KOH in methanol (3 g of KOH in 25 ml of methanol) are added to the obtained mixture under cooling with ice. The resulting solution is seeded and left at standstill at a temperature of +5 to + 10 °C for 5-10 hours. Separated crystals are aspirated through a frit. Wet crystals are dissolved in 20 ml of water in an Erlenmeyer flask. 25 ml of dichloromethane are added to the solution, pH of the mixture is adjusted to pH 8 to 9 with acetic acid under stirring and cooling with ice. The dichloromethane fraction is separated and the aqueous layer is extracted with another 10 ml of dichloromethane. The combined dichloromethane fractions are dried with sodium sulfate and concentrated to dryness in a rotary vacuum evaporator. The evaporation residue is taken with 100 ml of ethyl methyl ketone are poured and 2.5 ml of a solution of KOH in methanol (3 g of KOH in 25 ml of methanol) are added to the obtained mixture under cooling with ice. The resulting solution is seeded and left at standstill at a temperature of +5 to + 10 ⁰C for 5-10 hours. The separated product is aspirated and 2.52 g of the potassium salt of esomeprasole are obtained. After repeated re-crystallization in ethanol 1.02 g (19.7% yield) of the potassium salt of esomeprazole are obtained.

HPLC chemical purity: 99.5 %. HPLC on the chiral phase (CHIRALPAK AD-H^®, mobile phase 50% hexane : 50% ethanol, detection 302 nm): enantiomeric 99.8 %. Example 3

0.495 g (1.5 mmol) of the compound of formula III, 5 ml of dried toluene and 104.1 mg (1.0 mmol) of (<S)-lactic acid methyl ester (general formula IV: X = OMe, IVc) were placed in a 3- neck 50ml flask, which was equipped with a magnetic stirrer and a thermometer. The mixture in the flask was heated up in an oil bath to a temperature in the range of 50 to 55 ⁰C. Then, 0.15 ml OfTi(OPr)₄ were added to this mixture at a time. The resulting mixture was stirred at a temperature in the range of 50 to 55 ⁰C for 1 hour. Then, the reaction mixture was maintained at a temperature of 25 to 30 ⁰C and 85 μl of diisopropylethylamine were added to the reaction mixture. The mixture was stirred for 5 minutes and 0.25 ml of 88% cumene hydroperoxide were added to the solution. The resulting reaction mixture was stirred at the room temperature for 4 hours. The reaction was terminated by addition of 5 ml of a 5% aqueous solution of Na₂S₂O₃ and diluted with 5 ml of toluene. The resulting mixture was filtered through filtration paper. The two-phase filtrate was separated in a separating funnel and the toluene fraction was extracted with anther 5 ml of water. After drying with anhydrous magnesium sulfate the toluene solution was evaporated in a rotary vacuum evaporator until dry. The resulting evaporation residue (0.55g) was subjected to chromatography on 16.0 g of silica gel. Chloroform : methanol : 25% NH₄OH in the ratio of (10 : 1 : 0,1) were used as the eluent. The fractions containing the compound of formula Ia were combined, evaporated in a rotary vacuum evaporator and analyzed with HPLC on the chiral phase (CHIRALPAK AD-H^®, mobile phase 50% hexane : 50% ethanol, detection 302 nm): (.^-omeprazole has the enantomeric excess of 56.0 %.

Example 4 2.7 g (9.45 mmol) of Ti(OPr)₄ and 3.93 g of (_S)-lactic acid methyl ester (general formula IV: X = OMe, rVc ) (37.8 mmol) are placed in a 3-neck 100-ml flask, purged with an inert gas (argon), equipped with a mechanical stirrer and a thermometer. The resulting solution is heated up to a temperature in the range of 55 to 60 ⁰C and 4.47 g (13.5 mmol) of the compound of formula III are added to the solution. The resulting thick slurry is stirred at a temperature in the range of 55 to 60 ⁰C for 30 minutes. Then 60 μl of water are added to the reaction mixture. The reaction mixture is stirred at the same temperature for another 60 minutes. Subsequently, the reaction flask is put in a cooling bath and cooled to an inner temperature of +5 to +10 ⁰C. Then, 2.25 ml of 88% cumene hydroperoxide are added to the flask. The resulting slurry-like reaction mixture is stirred at a temperature in the range of +5 to +10 ⁰C for 15 hours. Then, the reaction mixture is diluted with 75 ml of a 12.5% solution of NH₄OH under cooling to +5 to +10 ⁰C and stirred for 30 minutes. The separated solid fraction is filtered off through a paper filter. The filter cake is washed with another 25 ml of the 12.5% solution OfNH₄OH. 75 ml of dichloromethane are added to the filtrate and pH of the mixture is adjusted to pH 8 to 9 with acetic acid under stirring and cooling with ice. The dichloromethane fraction is separated and the aqueous layer is extracted with another 30 ml of dichloromethane. The combined dichloromethane fractions are dried with anhydrous sodium sulfate and concentrated until dryness in a rotary vacuum evaporator. The evaporation residue is taken with 120 ml of ethyl methyl ketone and 6.5 ml of a solution of KOH in methanol (3 g of KOH in 25 ml of methanol) are added to the resulting mixture under cooling with ice. The resulting solution is seeded and left at standstill at a temperature of +5 to + 10 ⁰C for 5-10 hours. Separated crystals are aspirated through frit. Wet crystals are dissolved in 20 ml of water in an Erlenmeyer flask. 25 ml of dichloromethane are added to the solution, pH of the mixture is adjusted to pH 8 to 9 with acetic acid under stirring and cooling with ice. The dichloromethane fraction is separated and the aqueous layer is extracted with another 10 ml of dichloromethane. The combined dichloromethane fractions are dried with anhydrous sodium sulfate and concentrated to dryness in a rotary vacuum evaporator. 120 ml of ethyl methyl ketone are added to the evaporation residue and 6.5 ml of a solution of KOH in methanol (3 g of KOH in 25 ml of methanol) are added to the resulting mixture under cooling with ice. The resulting solution is seeded and left at standstill at a temperature of +5 to +10 °C for 5-10 hours. Separated crystals are aspirated through frit. Wet crystals are dissolved in 20 ml of water in an Erlenmeyer flask. 25 ml of dichloromethane are added to the solution, pH of the mixture is adjusted to pH 8 to 9 with acetic acid under stirring and cooling with ice. The dichloromethane fraction is separated and the aqueous layer is extracted with another 10 ml of dichloromethane. The combined dichloromethane fractions are dried with anhydrous sodium sulfate and concentrated to dryness in a rotary vacuum evaporator. 30 ml of acetonitrile are added to the evaporation residue and a 50% solution of NaOH (0.7 g) is added under cooling with ice. The solution is seeded and left at standstill at a temperature of + 5 to + 1O⁰C until the next day. The separated product is aspirated and 1.35 g of the sodium salt of esomeprasole are obtained, which, after re-purification, provide the sodium salt of esomeprazole with the following purity. HPLC chemical purity: 99.85 %. HPLC on the chiral phase (CHIRALPAK AD-H^®, mobile phase 50% hexane : 50% ethanol, detection 302 am): enantiomeric excess 99.8 %.

Claims

1. A method for the manufacture of optically pure or optically enriched esomeprazole of formula I

or its salt of the general formula II

wherein M means an atom of a metal from the 1^st and 2^nd groups of the periodic table, ch aracterized in that the sulfide of formula III

is oxidized with a hydroperoxide on a catalyst constituted by a chiral metallic complex containing ligands constituted by chiral functional derivatives of lactic acid, optionally followed by neutralization by means of bases derived from metals of the 1^st or 2^nd groups of the periodic table.

2. The method according to claim 1, characterized in that the neutralization is performed with an alkali metal hydroxide, such as sodium or potassium hydroxide, or with an alkaline earth metal hydroxide, such as magnesium or calcium hydroxide.

3. The method according to claims 1 or 2, characterized in that the metallic catalyst contains ligands constituted by functional derivatives of S-lactic acid.

4. The method according to any one of the preceding claims, characterized in that the metallic catalyst contains ligands consisting of esters or amides of chiral lactic acid.

5. The method according to any one of the preceding claims, characterized in that the chiral metallic complex is generated by an in situ reaction of a chiral derivative of lactic acid having the absolute configuration (S) of general formula IV,

\ χ;ox

OH IV

wherein X means an alkoxyl group OR¹ or an amide group NR²R³, wherein R¹ means an alkyl group having 1 to 8 carbon atoms, branched or unbranched, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl or hexyl, R and R mean the same or different groups selected from the group including an alkyl group having 1 to 8 carbon atoms, branched or unbranched, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl or hexyl, or hydrogen, an arylalkyl group having 7 to 9 carbon atoms such as benzyl, 4-methylbenzyl, α-methylbenzyl, or 2-phenylethyl, and an aryl group, substituted or unsubstituted with hetero-substituents, such as phenyl, 4- chlorophenyl, 2-methoxyphenyl or 1-naphthyl or 2-naphthyl, or R² and R³ together mean a cycle having 5 to 6 atoms, which optionally contains another hetero-atom and which optionally carries a chiral substituent, such as 1-pyrrolidinyl, 1-piperidinyl, 4- morpholinyl, or l-(2-methoxymethyl)pyrrolidinyl, with a metal tetraalkoxide of the general formula V

Z(OR⁴)₄

V

wherein Z means a quadrivalent metal, such as titanium of zirconium, and R⁴ means an alkyl group having 1 to 6 carbon atoms.

6. The method according to claim 5, characterized in that the molar ratio of the compound of formula IV to the compound of formula V is 1 : 1 to 5: 1, preferably 1.5 : 1 to 4 : 1.

7. The method according to claims 5 or 6, characterized in that titanium isopropoxide, titanium n-butoxide or zirconium n-propoxide is used as the metal tetraalkoxide of the general formula V in an amount of 0.1 to 1.0 equivalents.

8. The method according to claims 1-7, characterized in that titanium n-butoxide or titanium isopropoxide is used as the metal tetraalkoxide of the general formula V in an amount of 0.1 to 1.0 equivalents, preferably 0.15 to 0.8 equivalents.

9. The method according to claims 1-8, characterized in that the chiral derivative of lactic acid having the absolute configuration (S) of the general formula IV, wherein X, OR and NR R are as defined in claim 5, is used in an amount of 0.1 to 5.0 equivalents, preferably 1.5 to 3.5 equivalents.

10. The method according to claims 2-9, characterized in that the chiral derivative of lactic acid with the absolute configuration (S) is a compound of general formula IVa₃

-V ^COOR¹

OH IVa

wherein R¹ means an alkyl group having 1 to 8 carbon atoms, branched or unbranched, preferably an alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, isopropyl, or tert-butyl.

11. The method according to claims 2-9, characterized in that the chiral derivative of lactic acid with the absolute configuration (S) is a compound of general formula FVb,

IVb wherein R and R are as defined in formula IV.

12. The method according to claims 1-11, characterized in that the hydroperoxide is an organic hydroperoxide, such as cumene hydroperoxide or tert-butylhydroperoxide, in an amount of 0.9 to 1.8 equivalents, preferably 0.95 to 1.3 equivalents.

13. The method according to claims 1-12, characterized in that the reaction is conducted in the presence of a base.

14. The method according to claim 13, characterized in that a tertiary amine, e.g. diisopropylethylamine or triethylamine, in an amount of 0.1 to 1.0 equivalents is used as the base.

15. The method according to claims 1-14, characterized in that the reaction is carried out without the presence of a solvent or in an inert solvent.

16. The method according to claim 15, characterized in that the inert solvent is an inert organic solvent selected from the group including toluene, dichloromethane, esters such as ethyl acetate, ethers such as tetrahydrofuran and ketones such as ethyl methyl ketone.

17. The method according to claims 1-16, characterized in that the chiral metallic complex is generated in the temperature range of 20 ⁰C to 100 °C, preferably in the temperature range of 35 ⁰C to 75 °C.

18. The method according to claims 1-17, characterized in that the oxidation with the hydroperoxide is carried out in the temperature range of -20⁰C to +40 ⁰C, preferably in the temperature range of 0 ⁰C to +25 ⁰C.

19. The method according to claims 5-10 and 12-18, characterized in that the compound of formula IVc

IVc

in an amount of 0.1 to 5.0 equivalents, preferably 1.5 to 3,5 equivalents, is used as the chiral derivative of lactic acid with the absolute configuration (S).

20. The method according to claims 5-10 and 12-18, characterized in that the compound of formula IVd

\ /COOEt

OH IVd

in an amount of 0.1 to 5.0 equivalents, preferably 1.5 to 3.5 equivalents, is used as the chiral derivative of lactic acid with the absolute configuration (S).

21. The method according to claim 19, characterized in that the chiral metallic complex is generated by reaction of the chiral derivative of lactic acid with the absolute configuration (S) of formula IVc and titanium tetraisopropoxide in the molar ratio of the compound of formula IVc to titanium tetraisopropoxide of 1 : 1 to 5: 1, preferably 1.5 : 1 to 4 : 1.

22. The method according to claim 20, characterized in that the chiral metallic complex is generated _by reaction of the chiral derivative of lactic acid with the absolute configuration (S) of formula IVd and titanium tetraisopropoxide in the molar ratio of the compound of formula IVc to titanium tetraisopropoxide of 1 : 1 to 5: 1, preferably 1.5 : 1 to 4 : 1.

23. The method according to claims 2-22, characterized in that neutralization is performed with potassium hydroxide.

,

24. A method for the manufacture of optically pure or optically enriched salts of (R)- omeprazole of general formula ent-ll,

wherein M is as defined in formula II, or of optically pure or optically enriched (i?)-omeprazole of the general formula ent-I,

characterized in th at the sulfide of formula III is oxidized with a hydroperoxide on a catalyst constituted by a chiral metallic complex containing ligands constituted by chiral functional derivatives of lactic acid, optionally followed by neutralization by means of bases derived from metals of the 1^st and 2^nd groups of the periodic table, wherein the chiral metallic complex is generated from the enantiomer of the chiral derivative of lactic acid with the absolute configuration (R) of general formula ent-ΪVa,

\^COOR¹

OH enf-lVa

wherein R is as defined in formula IV.