WO2011120475A1 - A method of manufacturing (s)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2- pyrimidinyl)methyl]sulfinyl]-1h-benzimidazole using a chiral complex with mandelic acid - Google Patents
A method of manufacturing (s)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2- pyrimidinyl)methyl]sulfinyl]-1h-benzimidazole using a chiral complex with mandelic acid Download PDFInfo
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- 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 (. ⁇ -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.
- R 1 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 2 and. R 3 mean the same or different groups 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,
- aryl group substituted or unsubstituted with hetero-substituents, such as phenyl, 4- chlorophenyl, 2-methoxyphenyl or 1-naphthyl or 2-naphthyl,
- the oxidation is performed with the use of hydroperoxides, in practice with cumene hydroperoxide or tert-butylhydroperoxide, in the temperature range of -5 to +50 °C, preferably in the temperature range of + 5 to +40 °C.
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Abstract
The invention deals with a new manufacturing method of (S)-5-methoxy-2-[[(4-methoxy- 3,5-dimethyl-2-pyridinyl)methyl]sulphinyl]-1H-benzimidazole of formula (I) and its salts of general formula (II), wherein the sulfide of general formula (III) is oxidized by hydroperoxides on a catalyst consisting of a chiral metallic complex containing ligands constituted by chiral functional derivatives of mandelic acid.
Description
A METHOD FOR THE MANUFACTURE OF
(S) -5-METHOXY-2- [ [ (4-METHOXY-3 , 5-DIMETHYL-2-PYRIMIDINYL) METHYL] SULFINYL] -1H-BENZ IMIDAZOLE USING A CHIRAL COMPLEX WITH MANDELIC ACID
Technical Field
The invention deals with a new production method of (iS)-5-methoxy-2-[[(4-methoxy- 3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-l/ -benzimidazole of formula I and its salts of general formula II.
Background Art
The racemic 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfmyl]- 1H- benzimidazole, known under the name omeprazole, is described in EP 0 005 129 as an inhibitor of secretion of gastric acids used for treatment of ulcerous diseases. Its (S)- enantiomer, (5)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfmyl]-lH- benzimidazole of formula I, known under the INN name esomeprazole or (<S)-omeprazole, is more efficient and consequently safer as it enables lower dosing. Thus, looking for new, more efficient ways to its production is a significant challenge of the pharmaceutical chemistry.
Known procedures can be divided into asymmetrical procedures of production of the chiral sulfoxide, and resolution of the racemic sulfoxide by optical resolving 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-lH-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 (S^-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; for example 2-[[(4-chloro-3,5-dimethylpyridin-2-yl)methyl]thio]-5-methoxy-lH- benzimidazole offered 2-[[(4-chloro-3,5-dimethylpyridin-2-yl)methyl]sulfinyl]-5-methoxy- lH-benzimidazole by oxidation with cumene hydroperoxide in the presence of Ti(0i-Pr)4, (S^-diethyl-tartrate and diisopropylethylamine.
According to patent CN 1995037 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, (iS)-pantoprazole, (5)-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 tetraalkoxides and chiral β-amino-alcohols, such as (5)-phenylglycinol, (5)-valinol, (5)-prolinol, and the like. The procedure is claimed for the synthesis of (^-omeprazole, (5)- lansoprazole, OS)-pantoprazole, (5)-rabeprazole and (S)-tenatoprazole.
Patent CN 1 810 803 (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 (R,i?)/(5,5)-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 (S)-isomer minus the (i?)-isomer,
more precisely [S]-[R] divided by ([S]+[R]).100%), i.e. 98% ee means the ratio of enantiomers 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 (5,5)- 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(0 -Pr)4 and (i?,i?)-l,2-bis(2-bromophenyl)-l ,2- ethandiol in the yield of up to 94% and with >99% ee.
Document WO 2004/087702 (equiv. EP 1608649, 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 salem 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 difficult to recover 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 (/?)- (+)-[l,l'-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 (5)-binaphthol is obtained in the presence of triethylamine in the 38% yield (76% of the theoretical quantity).
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. (S)-(-)-Binol may be recovered.
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 (.^-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 (S)-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 (S,5)-diethyl-tartrate (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.
Document WO 2003/051867 (equiv. EP 1 458 709, AstraZeneca) describes resolution of omeprazole enantiomers by means of a chromatographic method on Kromasil-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 formula II,
which consists in oxidation of the sulfide of formula III
In a preferable embodiment of the invention the chiral metallic complexes are generated in situ by a reaction of metal tetraalkoxides of the general formula V
Z(OR5)4
(V), such as titanium n-butoxide or titanium isopropoxide, with chiral derivatives of (^-mandelic acids, such as esters of the general formula IVa and amides of the general formula IVb,
especially preferably with (5)-methyl-mandelate of formula IVe, or (5)-ethyl-mandelate of formula IVf.
In a similar manner it is possible in accordance with the invention to obtain R-omeprazole of formula ent-l
or its salts, using the respective R isomers of functional derivatives of mandelic acid.
Detailed description of the invention
We have found out that optically pure or optically enriched salts of esomeprazole of general formula II,
can be efficiently produced by oxidizing the sulfide of formula III
The manufacturing method is characterized by generating the chiral metallic complexes of the new type by an in situ reaction of chiral derivatives of mandelic acids with the absolute configuration (S) of the general formula 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 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,
or an arylalkyl group having 7 to 9 carbon atoms, such as benzyl, 4-methylbenzyl, a-methylbenzyl, or 2-phenylethyl,
or 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 may but need not contain another heteroatom, and which may but need not carry a chiral substituent, such as 1- pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, or l-(2-methoxymethyl)pyrrolidinyl,
and Y means one or more groups, identical or different, positioned on the benzene nucleus, including hydrogen, alkyl groups having 1 to 5 carbon atoms, such as methyl, ethyl, isopropyl or tert-butyl groups,
aryl groups, such as phenyl or 1- or 2-naphthyl groups,
halogen groups, such as fluoro, chloro, or bromo, or
alkoxyl groups OR4, wherein R4 means an alkyl group having 1 to 4 carbon atoms, such as methyl,
with metal tetraalkoxides of general formula V,
Z(OR5)4
V wherein Z means a tetravalent metal, such as titanium or zirconium, and
R5 means an alkyl group having 1 to 6 carbon atoms.
One of the aspects of the invention is based on the nontrivial finding that the chiral metallic complexes of the new type, which efficiently and with high enantioselectivity catalyze oxidation of sulfides to sulfoxides, can be generated in situ by a reaction of tetraalkoxides of the general formula V with monoalcohols of the type of chiral derivatives of mandelic acids of the general formula IV, wherein it is possible to use, as said derivatives, both esters of the general formula IVa and amides of the general formula IVb,
R2 and. R3 mean the same or different groups 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,
or an arylalkyl group having 7 to 9 carbon atoms, such as benzyl, 4-methylbenzyl, -methylbenzyl, or 2-phenylethyl,
or 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 ring having 5 to 6 atoms, which may but need not contain another heteroatom, and which may but need not carry a chiral substituent, such as 1- pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, or l-(2-methoxymethyl)pyrrolidinyl,
and Y means one or more groups, identical or different, positioned on the benzene nucleus, including hydrogen, alkyl groups having 1 to 5 carbon atoms, such as methyl, ethyl, isopropyl or tert-butyl groups,
aryl groups, such as phenyl or 1- or 2-naphthyl groups,
halogen groups, such as fluoro, chloro, or bromo, or
alkoxyl groups OR4, wherein R4 means an alkyl group having 1 to 4 carbon atoms, such as methyl.
From the practical point of view it is preferable to use easily available esters of mandelic acids of the general formula IVa,
wherein R 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,
and Y means one or more groups, identical or different, positioned on benzene nucleus, including hydrogen, alkyl groups having 1 to 5 carbon atoms, such as methyl, ethyl, isopropyl, or tert-butyl groups,
aryl groups, such as phenyl or 1- or 2-naphthyl groups,
halogen groups, such as fluoro, chloro, or bromo, or
alkoxyl groups OR4, wherein R4 means an alkyl group having 1 to 4 carbon atoms, such as methyl group,
wherein it is especially convenient to use methyl esters of (5)-mandelic acids of the general formula IVc
or ethyl esters of (5)-mandelic acids of the general formula IVd
During the generation of the chiral metallic complex of the new type by an in situ reaction of a tetraalkoxide of the general formula V, Z(OR4)4, wherein both Z and R5 are as defined above, with chiral derivatives of mandelic acid with the absolute configuration (S) of the general formula IV, wherein X, OR1 as well as NR2R3 are as defined above, the compound of the general formula IV is used in the molar proportion to the compound of formula V of 1 : 1 to 7 : 1, however preferably in an excess of 1.5 : 1 to 4 : 1, more preferably 2-3 : 1.
One can use, as the metal tetraalkoxide of the general formula V,
Z(OR4)4,
e.g., titanium isopropoxide, titanium «-butoxide or zirconium w-propoxide in an amount of 0.1 to 1.0 equivalents, preferably titanium w-butoxide or titanium isopropoxide in an amount of 0.1 to 0.8 equivalents, preferably 0.15 to 0.4 equivalents. The chiral metallic complex of the new type is generated in the presence or absence of the sulfide of formula III in an inert organic solvent such as toluene, chloroform, or dichloromethane. The complexes are generated in a wide range of temperatures from 20 °C to the boiling temperature of the solvent, preferably in the range from 35 °C to the boiling temperature of the solvent.
In a preferable embodiment the chiral metallic complex of the new type is generate by a reaction of 0.2-0.5 molar equivalents of titanium w-butoxide or titanium isopropoxide and 2 to 3 fold of esters of mandelic acids of the general formula IVa,
and Y means one or more groups, identical or different, positioned on the benzene nucleus, including hydrogen, alkyl groups having 1 to 5 carbon atoms, such as methyl, ethyl, isopropyl, or tert-butyl groups,
aryl groups, such as phenyl or 1- or 2-naphthyl groups,
halogen groups, such as fluoro, chloro, or bromo, or
alkoxyl groups OR4, wherein R4 means an alkyl group having 1 to 4 carbon atoms, such as methyl group
wherein it is convenient to use methyl esters of (5)-mandelic acids of the general formula IVc
In this process it is also possible to use optically active mandelic acid with the (S) configuration. However, the procedure is very inconvenient as the achieved enantioselectivity
is substantially worse and additionally the chemical yields and purity are lower due to sensitivity of both the initial sulfide of formula III and the reaction products to acidic reagents.
The oxidation is performed with the use of hydroperoxides, in practice with cumene hydroperoxide or tert-butylhydroperoxide, in the temperature range of -5 to +50 °C, preferably in the temperature range of + 5 to +40 °C.
Experiments have shown that the enantioselectivity of the process is positively influenced by an addition of an organic base, e.g. diisopropylethylamine or triethylamine.
During processing of the experiments the compound of formula I is isolated, or is isolated in the form of a salt with metals of the 1st and 2nd group, e.g. as salts with alkali metals or alkaline earth metals, such as sodium, potassium, magnesium or calcium salts.
If necessary, the production method can be applied with equal efficiency to the production of optically pure or optically enriched salts of (i?)-omeprazole of the general formula ent-U,
using a procedure characterized in using the enantiomer of the chiral derivative of mandelic acid with the absolute configuration (R) of the general formula ent-TVa,
eni-IVa wherein R and Y are as defined above.
Similarly, optically pure or optically enriched (i?)-omeprazole of formula ent-l,
enf-IVa wherein R and Y are as defined above.
The following working examples illustrate, but do not limit in any way, the general character of the manufacturing method of the present invention.
Specific working examples Example 1
0.495 g (1.5 mmol) of the compound of formula III, 5 ml of dried toluene and 1 mmol of a chiral ligand (166.1 mg of the methyl ester of (S)-mandelic acid (general formula IV: X = OMe, Y = H, rVc)) were placed in a 3 -neck 50-ml flask, which was equipped with a magnetic stirrer and a thermometer. The mixture in the flask was heated in an oil bath to a temperature in the range of 50 to 55 °C. Then, 0.15 ml of Ti(Oz-Pr)4 (general formula V: Z = Ti, R5 = i-Pr) were added to this mixture at once. The resulting mixture was stirred at a temperature in the range of 50 to 55 °C for 1 hour. Then, the temperature of the reaction mixture was maintained at 25 to 30 °C and 85 μΐ 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 Na2S203 and diluted with 5 ml of toluene. The resulting mixture was filtered through filtration paper. The two-phase filtrate was divided in a separating funnel and the toluene fraction was extracted with additional 5 ml of water. After drying with anhydrous magnesium sulfate the toluene solution was evaporated to dryness in a rotational vacuum evaporator. The resulting
evaporation residue was chromatographed on silica gel. Chloroform : methanol : 25% NH OH in the (10 : 1 : 0.1) proportion was used as the eluent. The fractions of the product were combined, evaporated in a rotational vacuum evaporator and analyzed in a HPLC system on a chiral phase (CHIRALPAK AD-H®); mobile phase 50% of hexane : 50% of ethanol, detection 302 nm).
Esomeprazole (formula I) with the enantiomeric excess of 80 % was obtained.
Example 2 (R)-omeprazole was prepared with the same procedure as described in example 1. 1 mmol (200 mg) of (jf?)-3-chloromandelic acid methyl ester (general formula ent-TV: X = OMe, Y = 3-Cl) was used as the chiral ligand.
(/?)-omeprazole (formula ent-I) with the enantiomeric excess of 67.6 % was obtained. Example 3
Esomeprazole (formula I) was prepared using the same procedure as described in example 1. 1 mmol (196.2 mg) of (25,3i?)-2,3-dihydroxy-3-phenyl propionic acid methyl ester was used as the chiral ligand.
Esomeprazole with the enantiomeric excess of 78.6 % was obtained. Example 4
Esomeprazole (formula I) was prepared using the same procedure as described in example 1. 1 mmol (255.3 mg) of (25)-N-benzyl-2-hydroxy-N-methylphenylacetamide (general formula IV: X = NBnMe, Y = H; general formula IVb R 2 - Bn, R3 = Me) was used as the chiral ligand. Esomeprazole with the enantiomeric excess of 60.8 % was obtained.
Example 5
Esomeprazole was prepared using the same procedure as described in example 1. 1 mmol (207.3 mg) of (2S N,N-diethyl-2-hydroxyphenylacetamide (general formula IV: X = NEt2, Y = H; general formula IVb R 2 = R3 = Et) was used as the chiral ligand.
Esomeprazole with the enantiomeric excess of 33.3 % was obtained. Example 6 0.495 g (1.5 mmol) of the compound of formula III, 5 ml of dried toluene and 1.5 mmol of a chiral ligand (249 mg of (5 -mandelic acid methyl ester (general formula IV: X = OMe, Y = H, rVc)) were placed in a 3-neck 50-ml flask, which was equipped with a magnetic stirrer and a thermometer. The mixture in the flask was heated in an oil bath to a temperature in the range of 50 to 55 °C. Then, 0.15 ml of Ti(Oz'-Pr)4 (general formula V: Z = Ti, R5 = z'-Pr) were added to this mixture at once. The resulting mixture was stirred at a temperature in the range of 50 to 55 °C for 1 hour. Then, the temperature of the reaction mixture was maintained at 25 to 30 °C and 0.25 ml of 88% cumene hydroperoxide were added to the solution. The resulting reaction mixture was stirred at the room temperature for 1.5 hours. The reaction was terminated by addition of 5 ml of a 5% aqueous solution of Na2S203 and diluted with 5 ml of toluene. The resulting mixture was filtered through filtration paper. The two-phase filtrate was divided in a separating funnel and the toluene fraction was extracted with additional 5 ml of water. After drying with anhydrous magnesium sulfate the toluene solution was evaporated to dryness in a rotational vacuum evaporator. The resulting evaporation residue was chromatographed on silica gel. Chloroform : methanol : 25% NH4OH in the (10 : 1 : 0.1) proportion was used as the eluent. The product fractions were combined, evaporated in a rotational vacuum evaporator and analyzed in a HPLC system on a chiral phase (CHIRALPAK AD-H®); mobile phase 50% of hexane : 50% of ethanol, detection 302 nm).
Esomeprazole (formula I) with the enantiomeric excess of 71 % was obtained. Example 7
3.28 g (10 mmol) of the compound of formula III, 35 ml of dried toluene and 1.10 g (6.67 mmol) of (5)-mandelic acid methyl ester (general formula IV: X = OMe, Y = H; IVc) were placed in a 3-neck 100-ml flask, which was equipped with a magnetic stirrer and a thermometer. The mixture in the flask was heated in an oil bath to a temperature in the range of 50 to 55 °C. Then, 0.98 ml of Ti(Oz-Pr)4 (general formula V: Z = Ti, R5 = z-Pr; 3.3 mmol) were added to this mixture at once. The resulting mixture was stirred at a temperature in the range of 50 to 55 °C for 1 hour. Then, the temperature of the reaction mixture was maintained
at 25 to 30 °C and 0.426 g of diisopropylethylamine (3.3 mmol) and then 1.67 ml of 88% cumene hydroperoxide were added to the reaction mixture. The reaction mixture was stirred at a temperature of 28 to 34 °C for 2 hours. Then, 20 ml of a 12.5% solution of ammonium hydroxide were added to the reaction mixture at the room temperature. The resulting suspension was filtered through filtration paper. The filtration cake was washed with 15 ml of a 12.5% solution of ammonium hydroxide.
The aqueous fraction was placed in an Erlenmeyer flask, 15 ml of dichloromethane were added and it was carefully acidified with acetic acid under stirring and cooling. The dichloromethane fraction was separated in a separating funnel, washed with 5 ml of water, dried with anhydrous sodium sulfate and evaporated in an evaporator. 1.85 g of crude esomeprazole was obtained and dissolved in a mixture of isopropylmethylketone and acetonitrile and 500 mg of a 50% aqueous solution of NaOH were added. After concentration in a rotational vacuum evaporator 0.86 g of the sodium salt of esomeprazole were obtained (general formula II, M = Na). The enantiomeric excess was determined to be 95% by means of the HPLC method on a chiral phase described in example 1.
Example 8
4.47 g (13.5 mmol) of the compound of formula III, 45 ml of dried toluene and 2.21 g (13.35 mmol) of (5)-mandelic acid methyl ester (general formula IV: X = OMe, Y = H; IVc) were placed in a 3-neck 100-ml flask, which was equipped with a magnetic stirrer and a thermometer. The mixture in the flask was heated in an oil bath to a temperature in the range of 50 to 55 °C. Then, 1.37 ml of Ti(Oz'-Pr)4 (general formula V: Z = Ti, R5 = z-Pr; 3.3 mmol) were added to this mixture at once. The resulting mixture was stirred at a temperature in the range of 50 to 55 °C for 1 hour. Then, the reaction mixture was maintained at a temperature of +5 to 10 °C and 2.14 ml of 88% cumene hydroperoxide were added. The reaction mixture was stirred at a temperature of +5 to 10 °C for 4 hours. Then 75 ml of a 12.5% solution of ammonium hydroxide were added to the reaction mixture. The resulting suspension was filtered through filtration paper. The filtration cake was washed with 15 ml of a 12.5% solution of ammonium hydroxide. The toluene fraction was separated and the aqueous fraction was placed in an Erlenmeyer flask, 75 ml of dichloromethane were added and it was carefully acidified with acetic acid to pH 8-9 under stirring and cooling with ice. The dichloromethane fraction was separated in a separating funnel, washed with 15 ml of water, dried with
anhydrous sodium sulfate and evaporated in an evaporator. 3.51 g of crude esomeprazole were obtained and mixed with 75 ml of ethylmethylketone. 5.2 ml of a KOH solution in methanol (3 g of KOH in 25 ml of methanol) were added to the mixture cooled with ice. After seeding the solution was left to crystallize at the temperature of +5 °C for 5 hours. The crystalline product was extracted and air dried. 2.93 g of the potassium salt of esomeprazole were obtained, which provided 1.15 g of the potassium salt of esomeprazole after repeated crystallization.
Ή-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 Hz, IH), 3.72 (s, 3H), 3.69 (s, 3H), 2.23 (s, 3H), 3.20 (s, 3H).
HPLC chemical purity: 99.85 %. HPLC on the chiral phase (CHIRALPAK AD-H®, mobile phase 50% hexane : 50% ethanol, detection 302 nm): enantiomeric excess 99.8 %.
Claims
C l a i m s
A method for the manufacture of optically pure or optically enriched S-omeprazole of
2. A method for the manufacture of optically pure or optically enriched salts of S- omeprazole of general formula 
and/or R-omeprazole of formula ent-II 
enf-ll N wherein M means an atom of a metal from the 1st or 2nd groups,
characterized in that the sulfide of formula III 
is oxidized with a hydroperoxide on a catalyst consisting of a chiral metallic complex containing ligands constituted by chiral functional derivatives of mandelic acid or ligands constituted by functional derivatives of mandelic acid substituted on the benzene nucleus,
followed by neutralization by means of a base s derived from a metal of the lsl or 2nd groups with subsequent optional recovery of the chiral derivatives of mandelic acid.
3. The method according to claims 1 or 2, characterized in that the metallic catalyst contains ligands constituted by of esters or amides of chiral mandelic acid, with optional substitution in the aromatic nucleus.
4. The method according to any one of the preceding claims, characterized in that the chiral metallic complex is generated in situ by reaction of chiral derivatives of mandelic acid with the absolute configuration (S) of general fo 
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, 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, or an arylalkyl group having 7 to 9 carbon atoms, such as benzyl, 4-methylbenzyl, a-methylbenzyl, or 2-phenylethyl,
or an aryl group, substituted or unsubstituted with heterosubstituents, such as phenyl, 4- chlorophenyl, 2-methoxyphenyl, or 1-naphthyl or 2-naphthyl,
or R2 and R3 together mean a ring 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, and Y means one or more groups, the same or different, positioned on the benzene nucleus, including hydrogen, alkyl groups having 1 to 5 carbon atoms, such as methyl, ethyl, isopropyl, or tert-butyl groups, aryl groups, such as phenyl or 1- or 2-naphthyl groups,
halogen groups, such as fluoro, chloro, or bromo, or
alkoxyl groups OR4, wherein R4 means an alkyl group having 1 to 4 carbon atoms, such as the methyl group,
with a metal tetraalkoxide of the general formula V,
Z(OR5)4
V wherein Z means a tetravalent metal such as titanium or zirconium, and
R5 means an alkyl group having 1 to 6 carbon atoms.
5. The method according to claim 4, characterized in that the chiral metallic complex is generated by reaction of a chiral derivative of mandelic acid of general formula IV or IVa, wherein X, OR1, NR2R3 and Y are as defined in formulas IV and IVa, and a metallic tetraalkoxide of the general formula V, Z(OR5)4, wherein Z and R5 are as defined in formula V, in the molar proportion of 1 : 1 to 7 : 1, preferably 1.5 : 1 to 4 : 1.
6. The method according to claims 5 or 6, characterized in that titanium isopropoxide, titanium rc-butoxide, or zirconium «-propoxide, in an amount of 0.1 to 1.0 equivalents, is used as the metal tetraalkoxide of the general formula V, Z(OR5)4.
7. The method according to claim 6, characterized in that titanium isopropoxide in an amount of 0.1 to 0.8 equivalents, preferably 0.15 to 0.4 equivalents, is used as the metal tetraalkoxide of the general formula V, Z(OR5)4.
8. The method according to any one of claims 1 to 7, characterized in that the chiral derivative of mandelic acid with the absolute configuration (S) of general formula IV as defined in claim 4 is used in an amount of 0.1 to 1.5 equivalents, preferably 0.5 to 1.5 equivalents, with regard to the compound of formula III.
9. The method according to any one of claims 1-8, characterized in that a compound of the general formula IVa (general formula IV: X = OR1),
Y means one or more groups, the same or different, positioned on the benzene nucleus, including hydrogen, alkyl groups having 1 to 5 carbon atoms, such as methyl, ethyl, isopropyl, or tert-butyl groups,
aryl groups, such as phenyl or 1- or 2-naphthyl groups,
halogen groups, such as fluoro, chloro, or bromo, or
alkoxyl groups OR4, wherein R4 means an alkyl group having 1 to 4 carbon atoms, such as the methyl group,
is used as the chiral derivative of mandelic acid with the absolute configuration (S).
10. The method according to any one of claims 1-8, characterized in that a compound of the
2 3
general formula IVb (general formula = NR R ),
or an aryl group, substituted or unsubstituted with heterosubstituents, such as phenyl, 4- chlorophenyl, 2-methoxyphenyl, or 1-naphthyl or 2-naphthyl,
or R2 and R3 together mean a ring 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,
and Y means one or more groups, the same or different, positioned on the benzene nucleus, including hydrogen, alkyl groups having 1 to 5 carbon atoms, such as methyl, ethyl, isopropyl, or tert-butyl groups,
aryl groups, such as phenyl or 1- or 2-naphthyl groups,
halogen groups, such as fluoro, chloro, or bromo, or
alkoxyl groups OR4, wherein R4 means an alkyl group having 1 to 4 carbon atoms, such as the methyl group,
is used as the chiral derivative of mandelic acid with the absolute configuration (5).
1 1. The method according to any one of claims 1-10, characterized in that cumene hydroperoxide or tert-butylhydroperoxide, in an amount of 0.9 to 1.8 equivalents, preferably 0.9 to 1.3 equivalents, with regard to the compound of formula III is used as the organic hydroperoxide.
12. The method according to any one of claims 1-1 1, characterized in that the reaction is carried out in the presence of a base.
13. The method according to claim 12, characterized in that a tertiary amine, e.g. diisopropylethylamine or triethyl amine, in an amount of 0.2 to 1.0 equivalents is used as the base.
14. The method according to any of claims 1-13, characterized in that the reaction is carried out in an inert organic solvent.
15. The method according to claim 14, characterized in that toluene, dichloromethane, esters such as ethyl acetate, ethers such as tetrahydrofuran or ketones such as ethylmethylketone are used as the inert organic solvents.
16. The method according to any one of claims 4-15, characterized in that the chiral metallic complex is generated in the temperature range from 20 °C to the boiling temperature of the solvent, preferably in the temperature range from 35 °C to the boiling temperature of the solvent.
17. The method according to any one of claims 1-16, characterized in that the oxidation with the hydroperoxide is carried out in the temperature range of -5 °C to +50 °C, preferably in the temperature range of +5 to +40 °C.
18. The method according any one of to claims 1-9, or 1 1-17, characterized in that a compound of the general formula IVc,
in an amount of 0.05 to 0.8 equivalents, preferably 0.15 to 0.6 equivalents,
is used as the chiral methyl ester of mandelic acid with the absolute configuration (S).
19. The method according to any one of claims 1-9, or 1 1-17, characterized in that a compound of the general formula IVd, 
wherein Y is as defined in formula IV,
in an amount of 0.1 to 1.5 equivalents, preferably 0.5 to 1.5 equivalents, with regard to the compound of formula III, is used as the chiral methyl ester of mandelic acid with the absolute configuration (S).
20. The method according to claims 1-9 or 1 1-17, characterized in that the compound of formula IVe 
in an amount of 0.1 to 1.5 equivalents, preferably 0.5 to 1.5 equivalents, with regard to the compound of formula III is used as the chiral methyl ester of mandelic acid with the absolute configuration (S).
21. The method according to claim 19, characterized in that the compound of formula IVf 
in an amount of 0.1 to 1.5 equivalents, preferably 0.5 to 1.5 equivalents, with regard to the compound of formula III is used as the chiral methyl ester of mandelic acid with the absolute configuration (S).
22. The method according to any one of claims 1-9, or 1 1-18, characterized in that the chiral derivative of mandelic acid with the absolute configuration (S) of formula IVe and titanium n- butoxide, or titanium isopropoxide in a molar proportion of the compound IVe and titanium n- butoxide, or titanium isopropoxide of 1 : 1 to 7: 1, preferably 1.5 : 1 to 4.0 : 1, are used for the generation of the chiral metallic complex.
23. The method according to any one of claims 1-9, or 1 1-17, or 19, characterized in that the chiral derivative of mandelic acid with the absolute configuration (S) of formula IVd and titanium w-butoxide, or titanium isopropoxide in a molar proportion of 1 : 1 to 7: 1 , preferably 1.5 : 1 to 4.0 : 1 , are used for the generation of the chiral metallic complex.
24. The method according to any one of claims 1-9, or 1 1-18, or 20, characterized in that the chiral derivative of mandelic acid with the absolute configuration (5) of formula IVe and titanium «-butoxide, or titanium tetraisopropoxide in a molar proportion of the compound of formula IVe and titanium «-butoxide, or titanium tetraisopropoxide of 1 : 1 to 7: 1 , preferably 1.5
: 1 to 4 : 1 , are used for the generation of the chiral metallic complex.
25. The method according to any one of claims 1-9, or 1 1- 17, or 19, or 21, characterized in that the chiral derivative of mandelic acid with the absolute configuration (S) of formula IVf and titanium n-butoxide, or titanium tetraisopropoxide in a molar proportion of the compound of formula IVf and titanium w-butoxide, or titanium tetraisopropoxide of 1 : 1 to 7 : 1 , preferably 1.5 : 1 to 4 : 1 , are used for the generation of the chiral metallic complex.
26. The method according to any one of claims 1 -25, characterized in that the chiral derivative of mandelic acid with the absolute configuration (S) of formula IVc and titanium isopropoxide in a molar proportion of the compound IVc and titanium tetraisopropoxide of 2 : 1 to 3 : 1 are used for the generation of the chiral metallic complex.
27. The method according to any one of claims 1-25, characterized in that the neutralization is carried out by means of bases derived from metals of the 1st and 2nd groups, such as hydroxides of alkali metals or alkaline earth metals such as sodium hydroxide, potassium hydroxide, magnesium hydroxide or calcium hydroxide.
28. The method according to any one of claims 1-27, characterized in that recovery of the chiral derivative of mandelic acid of the general formula IV is carried out.
29. The method according to any one of claims 1 -27, characterized in that recovery of the chiral derivative of mandelic acid of the general formula IVa is carried out.
30. The method according to any one of claims 1-27, characterized in that recovery of the chiral derivative of mandelic acid of the general formula IVc, wherein Y is as defined in formula IV, is carried out.
31. The method according to any one of claims 1-27, characterized in that recovery of the chiral derivative of mandelic acid of the general formula IVd, wherein Y is as defined in formula IV, is carried out.
32. The method for manufacturing optically pure or optically enriched salts of (R)- omeprazole of the general formula ent-ll as defined in claim 2, characterized in that the enantiomer of the chiral derivative of mandelic acids with the absolute configuration (R) of the general formula ent-TVa, 
enMVa wherein OR1 and Y are as defined in formula IV, is used for the generation of the chiral metallic complex.
33. The method for manufacturing optically pure or optically enriched (i?)-omeprazole of formula ent-l as defined in claim 1, characterized in that the enantiomer of the chiral derivative of mandelic acid with the absolute confi e general formula e«t-IVa,
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| CN104098546A (en) * | 2013-04-15 | 2014-10-15 | 北大方正集团有限公司 | Preparation method for esomeprazole |
| CN104098545A (en) * | 2013-04-15 | 2014-10-15 | 北大方正集团有限公司 | Preparation method for esomeprazole sodium |
| CN105418589A (en) * | 2016-01-17 | 2016-03-23 | 青岛辰达生物科技有限公司 | Preparation method of esomeprazole magnesium trihydrate for treating digestive system diseases |
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| CN105418589A (en) * | 2016-01-17 | 2016-03-23 | 青岛辰达生物科技有限公司 | Preparation method of esomeprazole magnesium trihydrate for treating digestive system diseases |
| CN105418589B (en) * | 2016-01-17 | 2017-09-26 | 青岛市中心医院 | A kind of esomeprazole magnesium trihydrate preparation method for treating disease of digestive system |
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