Technical field
[0001]
　The present invention relates to a method of manufacturing a proton pump inhibitor compound in the optically active. More particularly, the presence of a chiral ligand, a method for producing a proton pump inhibitor compound in the optically active due to asymmetric oxidation using iron salts.
Background technique
[0002]
　Proton pump inhibitors, acts on proton pump parietal cells of the stomach and suppresses drug gastric acid secretion, gastric ulcer, duodenal ulcer, anastomotic ulcer, reflux esophagitis, non-erosive gastroesophageal reflux disease, or Zollinger treatment of -Ellison syndrome, and gastric ulcer, duodenal ulcer, gastric MALT lymphoma, idiopathic thrombocytopenic purpura, the aid of eradication of Helicobacter pylori in after endoscopic resection stomach or Helicobacter pylori infection gastritis for early gastric cancer It has been used to treat such. As a proton pump inhibitor compound, for example, omeprazole shown below, esomeprazole, lansoprazole, rabeprazole, tenatoprazole, pantoprazole, leminoprazole, typified dexlansoprazole, benzimidazole type or imidazopyridine type compounds and the like known It is. As used herein, a proton pump inhibitor compound, the term benzimidazole type or imidazopyridine type of compound, either neutral or salt forms, or includes both forms.
[Formula 1]

[0003]
　Proton pump inhibitor compounds, based on the solid sulfur atom of the sulfoxide contained in the characteristic structures of the common, S bodies, R and racemic forms may be present. As for omeprazole, racemate called omeprazole, one of its S isomer is called esomeprazole, it is commercially available. Esomeprazole, small inter-individual variability of pharmacokinetic and pharmacodynamic effect as compared to omeprazole, have been developed with the aim of drug to exert clinical benefit over omeprazole. Thus, the proton pump inhibitor compound, since the optically active substance can be expected to better clinical effect compared to racemate method for producing an optically active form thereof efficiently has been desired.
　Patent Document 1, a method of manufacturing a esomeprazole by dividing the diastereomers by inducing omeprazole racemic ester with an optically active acid is described. However, multi-step process is required, to discard other optical isomers, not a preferred method.
[0004]
　Non-Patent Document 1 and Patent Document 2, a method of manufacturing a esomeprazole optically active substances by asymmetric oxidation is described. In the same way, the titanium as catalyst, in FuHitoshihai ligand (S, S) - diethyl tartrate, is used cumene hydroperoxide as an oxidizing agent, it is reported to have obtained enantioselectivity than ee 94% ing. However, although this is the asymmetric oxidation reaction using the titanium catalyst is described that is not reproducible, was able to asymmetric oxidation of ee 91% with a catalytic amount of 4 mol%, especially small scale, on a large scale that not reproduced high asymmetric oxidation in catalytic amounts, it is described as was necessary catalytic amount of for example 30 mol%. Thus, in the industrial scale, a catalyst and chiral ligand are required in large quantities, more these catalysts, a chiral ligand and oxidant expensive, in terms not easy to handle there was a problem.
　Patent Documents 3 and 4, examples of applying the non-patent document 1 a method to other proton pump inhibitor compounds such as lansoprazole is described. Patent Document 5, in Non-Patent Document 1 method, a method of manufacturing a esomeprazole using mandelic acid methyl optically active instead of tartaric acid derivatives. In the above Patent Documents 3-5 method, a large amount of titanium catalyst similar to the non-patent document 1 methods are used.
[0005]
　Patent Document 6, in Non-Patent Document 1 method, how to prepare optically active forms, such as pantoprazole with zirconium or hafnium in place of titanium catalyst. However, catalysts, chiral ligand and an oxidizing agent is expensive, there is a problem in that it is not easy to handle.
　Patent Document 7 discloses a method for producing an optically active compound of tenatoprazole hydrogen peroxide as an oxidizing agent with alkaloid derivative or imine derivatives as chiral ligand tungsten or vanadium as a catalyst. For example, in the embodiment 1, after the reaction, extracted and concentrated under reduced pressure, the desired optical isomer is written obtained in 90% ee in 70% yield. However, not only describes the content of a sulfide form of the extracted is only should coexist sulfone and unreacted not described at all further yield after recrystallization. For, above the yield appears to numerical containing impurities, no reliability, yield is high not believed. More as in Patent Document 6, the catalyst and chiral ligand are expensive, there is a problem handling is not easy.
[0006]
　Non-Patent Document 2, it hydrogen peroxide using alkaloid derivative tungsten catalyst and chiral ligand to produce optically active body lansoprazole as an oxidizing agent. However, catalyst and chiral ligand are expensive, there is a problem in that it is not easy to handle.
　Patent Document 8 describes a method of producing a esomeprazole salen derivative manganese as a catalyst hydrogen peroxide as an oxidizing agent as a chiral ligand. However, a yield from 6 to 62% is ee enantioselectivity 3 to 62% is not sufficient as a method for producing an optically active substance. Furthermore, as an example for changing the manganese iron, have been described in Example 37, the yield was ee enantioselectivity 18% 17%. Those skilled in the art upon reading the patent document 8, in the preparation of proton pump inhibitors having similar structure benzimidazole type and imidazopyridine types including esomeprazole, iron is poor as a catalyst than manganese, is not a preferred catalyst and to understand.
[0007]
　Respect Asymmetric oxidation of sulfides, a method of using an iron catalyst is described in Non-Patent Documents 3 and 4. In the same way, the specific imine compound as a chiral ligand, iron (III) acetylacetonate to iron salts, are used hydrogen peroxide as an oxidizing agent. According to Table 3 of Non-Patent Document 4, the additive was added experiment, a yield of 36-78%, the enantioselectivity is 23 ~ 96% ee. Thus, the yield and enantioselectivity significantly changes, it appears to be due to highly dependent on the structure of the material of the sulfide. The sulfide used are limited to those having predominantly aromatic hydrocarbon group and an alkyl group. Therefore, when applied to a compound having a heterocyclic ring, it can asymmetric oxidation of any yield and enantioselectivity was not at all predictable to those skilled in the art.
CITATION
Patent Literature
[0008]
Patent Document 1: Japanese Kohyo 7-509499
Patent Document 2: Kohyo 10-504290
Patent Document 3: WO01 / 83473
Patent Document 4: WO2008 / 047681
Patent Document 5: WO03 / 089408
Patent Document 6: JP 2006-516261
Patent Document 7: JP 2006-523201
Patent Document 8: WO2010 / 043601
Non-Patent Document
[0009]
Non-Patent Document 1: Tetrahedron: Asymmetry, 2000, 11, 3819-3825
Non-Patent Document 2: Tetrahedron: Asymmetry, 2003, 14, 407-410
Non-Patent Document 3: Angew Chem Int Ed, 2004 , 43,.... 4225-4228
non-Patent Document 4:.. Chem Eur J., 2005, 11, 1086-1092
Summary of the Invention
Problems that the Invention is to Solve
[0010]
　An object of the present invention, a proton pump inhibitor compound of a high purity of the optically active in high yield and enantioselectivity is to provide a method for safely and inexpensively manufactured.
Means for Solving the Problems
[0011]
　The present inventors, in order to solve the above problem, a result of intense study, was subjected to asymmetric oxidation using iron catalyst material sulfide of the proton pump inhibitor compound, a high yield and not achieved to date It has found to be able to produce a proton pump inhibitor compound in the optically active with high enantioselectivity, and completed the present invention. That is, the present invention is as follows.
　[1] A method for producing a sulfoxide or a salt thereof of one sulfide or optically active formula 2 by oxidizing a salt thereof wherein
[Formula 2]

[In the formula, A represents CH or N.
　R 1 represents a hydrogen atom, alkyl which may be substituted by halogen or alkoxy optionally substituted with halogen,.
　R 2 may be a 1-3, each independently, alkyl, represents a dialkylamino or halogen or alkoxy optionally substituted by alkoxy.
　* Represents R or S configuration. ]
[0012]
　The presence of chiral ligand of the formula 3,
[Chemical Formula 3]

[wherein, R 3 are each independently a hydrogen atom, a halogen, cyano, alkylsulfonyl, arylsulfonyl, alkanoyl, alkoxycarbonyl, nitro, halogen in represents the optionally substituted alkyl optionally or alkoxy optionally substituted with halogen,.
　R 4 represents a tertiary alkyl.
　** indicates the R or S configuration. ]
Using an iron salt, a manufacturing method which is characterized in that oxidation with hydrogen peroxide.
[0013]
　[2] substituted an oxidation reaction by adding a good benzoic acid or its salts, the production method according to [1].
　[3] a sulfoxide or sulfone corresponding to other sulfide or other sulfide after adding to the reaction system, an oxidation reaction of sulfide or a salt thereof of formula 1, the production method according to [1] or [2].
　[4] R 3 is both a chlorine atom, R 4 is t- butyl, The process according to any one of [1] to [3].
　[5] sulfoxides 2 of optically active formula, omeprazole, lansoprazole, rabeprazole, tenatoprazole, an optically active substance of pantoprazole or leminoprazole method according to any one of [1] to [4].
[0014]
　[6] Formula 4 coordination iron complexes with chiral ligands.
[Formula 4]

wherein, ** represents the R or S configuration. ]
Effect of the invention
[0015]
　By the manufacturing method of the present invention using the iron complexes, the proton pump inhibitor compound of a high purity of the optically active in high yield and enantioselectivity, can be safely manufactured at low cost. Also, unlike many conventional cumene hydroperoxide are used in techniques such as, due to the use of inexpensive and safe hydrogen peroxide as an oxidizing agent, after the reaction is only generated water, by-products processing of it is unnecessary.
DESCRIPTION OF THE INVENTION
[0016]
　The present invention provides a method for producing a sulfoxide or a salt thereof sulfide or optically active formula 2 by oxidizing the salt of formula 1, the presence of a chiral ligand of Formula 3, with iron salt a manufacturing method characterized by oxidation with hydrogen peroxide.
[0017]
1. Sulfoxides of the sulfide and Formula 2 optically active Formula 1
　R 1 "Alkyl optionally substituted by halogen" in, for example, substituted with a fluorine atom, 1 or more halogens chosen from chlorine and bromine is C good straight or branched chain optionally 1 ~ C 5 alkyl, and the like.
　R 1 as "halogen substituted alkoxy" in, for example, fluorine atom, chlorine atom and one or more of which may linear be substituted by halogen or branched chain is selected from bromine C 1 ~ C 5 alkoxy and the like, with preference given to 1 or 2 may methoxy like optionally substituted by a fluorine atom.
　R 2 As the "alkyl" in, for example, C straight or branched chain 1 ~ C 5 alkyl, and the like, preferably methyl, and the like.
　R 2 As the "dialkylamino" in, for example, two straight or branched chain C of 1 ~ C 5 alkylamino or the like which is substituted by and the like, preferably methyl isobutyl amino and the like.
　R 2 "halogen or alkoxy optionally substituted by alkoxy" in, for example, fluorine atom, C of one or more of halogen or a linear or branched chain, chosen from chlorine and bromine 1 ~ C 5 alkoxy, C of optionally substituted straight or branched chain 1 ~ C 5 include alkoxy such as preferably methoxy, 3-methoxypropoxy, 2,2,2-trifluoroethoxy, and the like.
[0018]
　In sulfoxides optically active formula 2 * represents the R or S configuration. Desired configuration of the sulfoxide optically active is determined according to their biological activity, and the like, preferably a S configuration.
　Preferred examples of the sulfoxide of the optically active formula 2, omeprazole, lansoprazole, rabeprazole, tenatoprazole, an optically active form of pantoprazole or leminoprazole. Particularly preferred is an optically active substance of S-configuration of omeprazole lizardfish Mepurazoru and the like.
　The "salt of sulfide Formula 1" and "salt of the sulfoxide of optically active Formula 2", for example, alkali metal salts, alkaline earth salts, ammonium salts and the like. Specifically, lithium salt, sodium salt, potassium salt, magnesium salt, calcium salt, ammonium salt and the like. The salts of the sulfoxide of the optically active formula 2, a pharmaceutically acceptable salt is preferable.
[0019]
2. Chiral ligand of Formula 3
　R 3 "Halogen" in, for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, preferably a fluorine atom, a chlorine atom, a bromine atom, and more preferably a chlorine atom, a bromine atom, particularly preferably a chlorine atom.
　R 3 as "alkylsulfonyl" in the example, C straight or branched chain 1 ~ C 5 alkylsulfonyl, and the like, preferably, methylsulfonyl, ethylsulfonyl, and the like.
　R 3 as "arylsulfonyl" in, for example, C 6 ~ C 10 mentioned arylsulfonyl etc., preferably include phenylsulfonyl and the like.
　R 3 as "alkanoyl" in the example, C straight or branched chain 1 ~ C 5 alkanoyl and the like, preferably, acetyl and the like.
　R 3 The "alkoxycarbonyl" of, for example, C straight or branched chain 1 ~ C 5 include such alkoxycarbonyl, preferably methoxycarbonyl, ethoxycarbonyl and the like.
[0020]
　R 3 as "alkyl substituted with halogen" in, for example, fluorine atom, chlorine atom and one or more of which may linear be substituted by halogen or branched chain is selected from bromine C 1 ~ C 5 alkyl, and the like, preferably include perfluoroalkyl such, or more preferably trifluoromethyl or the like.
　R 3 as "alkoxy substituted by halogen" in, for example, fluorine atom, chlorine atom and one or more of which may linear be substituted by halogen or branched chain is selected from bromine C 1 ~ C 5 alkoxy and the like, preferably, trifluoromethoxy, pentafluoroethoxy, and the like.
　R 3 Preferred examples of a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, cyano, methylsulfonyl, phenylsulfonyl, acetyl, methoxycarbonyl, nitro, trifluoromethyl and the like, and more preferably, hydrogen atom, a chlorine atom, a bromine atom, an iodine atom, methylsulfonyl, nitro, trifluoromethyl or the like, more preferably a chlorine atom, a bromine atom, and an iodine atom, particularly preferably a chlorine atom. Two R 3 may be the same, respectively, may be different, with preference given to those with at.
[0021]
　R 4 as a "tertiary alkyl" in, for example, t- butyl, t-pentyl, t-hexyl, and the like, preferably, a t-butyl.
　** in chiral ligand of Formula 3 represents R configuration or S configuration, in accordance with the three-dimensional sulphoxide optical activity of interest can be selectively used R or S configuration of the chiral ligand. Preferably include the S configuration. By performing asymmetric oxidation using an asymmetric ligand of the formula 3 of S configuration, it is possible to produce the sulfoxides of the optically active formula 2 of S-configuration.
　Particularly preferred chiral ligands include chiral ligand of Formula 4.
[0022]
3. Production process
　the production method of the present invention, for example, a chiral ligand of Formula 3 is reacted with iron salt to form an iron complex having chiral ligand is coordinated expression 3, then equation 1 sulfide or a salt thereof added, can be carried out by reacting with hydrogen peroxide.
　The "iron" as used in the production method of the present invention, can be used any as long as it is coordinated with chiral ligand of Formula 3 in the reaction system. Iron iron salt may be a divalent or a trivalent. Specific iron salts such as iron (III) acetylacetonate, iron (II) chloride, iron (III), ferric bromide (II), iron bromide (III), iron acetate (II), trifluoromethanesulfonic iron (II), tetrafluoroborate, iron (II), perchlorate (II), perchlorate (III), iron sulfate (II), iron (II) di [bis (trifluoromethyl methylsulfonyl) imide], and the like. Preferred iron salts, iron (III) acetylacetonate and the like.
　In the production method of the present invention, the amount of iron salt, relative to the sulfide of the formula 1, for example, an about 0.1 to about 20 mole%, preferably it includes from about 2 to about 15 mole%, more preferably it includes from about 5 to about 12 mole%. The titanium catalyst disclosed in Non-cited document 1 and the like differ, there is no need to increase the equivalent amount of iron salts with production scale is increased.
　The amount of chiral ligand of Formula 3, with respect to iron, include from about 1 to about 5 equivalents, include preferably from about 1.05 to about 3 equivalents, more preferably about 1.1 It includes about 2 equivalents, more preferably include about 1.1 to about 1.5 equivalents.
　Chiral ligand of Formula 3, iron salts and in a reaction solvent, for example, from about 0 to about 40 ° C. such as, preferably, from about 10 to about 30 ° C., for example from about 10 minutes to about 24 hours, preferably about 20 minutes to about 5 hours, more preferably from about 30 minutes to about 1 hour, by mixing, can be chiral ligand of formula 3 to form a coordinated iron complex.
[0023]
　As the "hydrogen peroxide" as used in the production method of the present invention, for example, it can be suitably used 30-50% hydrogen peroxide water or the like which are commercially available. Further, for example, urea-hydrogen peroxide hydrogen peroxide is clathrated urea (urea - hydrogen peroxide adduct, abbreviated UHP) can also be used. The amount of hydrogen peroxide, with respect to the sulfide of the formula 1, for example, include from about 1.1 to about 5 equivalents, include preferably from about 1.2 to about 3 equivalents, more preferably about 1. 5 to about 2.5 equivalents and the like, more preferably include about 1.8 to about 2.3 equivalents.
　The "reaction solvent", for example, ethyl acetate, esters such as isopropyl acetate, methylene chloride, chloroform, 1,2-dichloroethane and the like halogenated hydrocarbons, methanol, ethanol, alcohols such as ethylene glycol, nitriles such as acetonitrile, acetone, ketones such as methyl isobutyl ketone, ethers such as t- butyl methyl ether, dimethylformamide, amides such as dimethylacetamide, and mixed solvents of aromatic hydrocarbons such as these solvents with toluene, anisole, and these solvents It includes mixtures of. Furthermore, these solvents can also be a mixed solvent of water. Preferred reaction solvents, ethyl acetate, esters such as isopropyl acetate, methanol, a mixed solvent of aromatic hydrocarbon such as alcohol and toluene ethanol and the like, give higher enantioselectivity.
　The amount of the reaction solvent, with respect to the sulfide of the formula 1, for example, include an amount of from about 4 to about 15 times by weight, preferably include an amount of from about 5 to about 10 times by weight.
[0024]
　The "reaction temperature", for example, include from about -80 to about 30 ° C. and the like, preferably include from about -30 to about 15 ° C., more preferably about -15 to about 5 ° C.. At temperatures above 15 ° C., for enantioselectivity it tends to decrease, it is preferable to react at a temperature lower than 15 ° C..
　The "reaction time", for example, from about 1 to about 50 hours, etc., preferably include about 2 to about 24 hours, such as from the operation surface. The progress of the reaction, it is preferred to stop the reaction at the point of optimum was followed by HPLC or the like. While sulfide will sulfoxides of interest is oxidized, the sulfoxide is further oxidized as a side reaction sulfone is produced. When using the chiral ligand of Formula 3 S-configuration, S- sulfoxide is produced in preference to the R- sulfoxide. Also, oxidation of secondary reactions is sulfone, conversely R- sulfoxide proceeds in preference to the S- sulfoxide body. Therefore, the oxidation of the second stage, enantioselectivity also can be improved.
[0025]
　In the production method of the present invention, by performing the oxidation reaction by the addition of optionally substituted benzoic acid or a salt thereof, it is possible to further improve the enantioselectivity. The optionally substituted or optionally acid salts thereof may be added after the chiral ligand of Formula 3 to form a coordinated iron complex.
　The substituent in "which may benzoate also be substituted", for example, aryl such as phenyl, methoxy and alkoxy, nitro, fluorine atom, chlorine atom, a halogen such as bromine atom, methyl, alkyl of ethyl, and the like, dimethyl dialkylamino such amino and the like. Preferred substituents, dimethylamino, methoxy and the like. Substituent group may be 1 or more, preferred substitution positions include 4-position. Preferable examples of the "optionally acid which may be substituted" include 4-dimethylaminobenzoic acid, 4-methoxybenzoic acid and the like.
　The salt in the "optionally acid which may be substituted", for example, lithium salt, sodium salt, potassium salt, cesium salt, tetrabutylammonium salt, and the like. In terms of the stirring resistance in enantioselectivity and reaction system, a lithium salt is preferred.
　The amount of substituted optionally or which may benzoic acid its salts, relative to iron, for example, an about 30 to about 200 mole%, preferably include from about 50 to about 150 mole%, more preferably about 80 to about 120 mole%, and the like.
[0026]
　In the production method of the present invention, immediately after the start of the oxidation reaction low enantioselectivity of the sulfoxide product which is slightly enantioselectivity is enhanced with the progress of the oxidation reaction. The present inventors have generated sulfoxide body this phenomenon was thought to going to have a subsequent oxidation contribution of what like to. Therefore, prior to the oxidation reaction of the sulfide of the formula 1 where, in advance was added to the reaction system a sulfoxide or sulfone corresponding to other sulfide or other sulfide was then subjected to oxidation of the sulfide of the formula 1, enantioselectivity It found that selectivity is further improved.
[0027]
　As "other sulfide" is to be added, for example, the formula: R 5 -S-R 6 in the
Formula, R 5 and R 6 are each independently alkyl optionally substituted, may be substituted aryl represents a heteroaryl optionally substituted. ]
Sulfide and the like represented by. R 5 and R 6 , the alkyl, for example, C straight or branched chain 1 ~ C 5 alkyl, and the like, for example, methyl, ethyl, propyl, butyl, pentyl, and the like. The substituted alkyl, e.g., C 6 ~ C 10 aryl, include 5 or 6 membered heteroaryl or the like, and specific examples thereof include phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, furyl, oxazolyl, etc. . R 5 and R 6 , examples of the aryl, for example, C 6 ~ C 10 include aryl etc., specifically, phenyl, naphthyl and the like. The substituted aryl, for example, alkyl, alkoxy, halogen, nitro, alkanoyl, alkoxycarbonyl, aryl, heteroaryl and the like. R 5 and R 6 , examples of heteroaryl include, for example, monocyclic heteroaryl 5 or 6 membered, bicyclic heteroaryl, and the like, specifically pyridyl, pyrimidinyl, imidazolyl, furyl, oxazolyl, benz imidazolyl, quinoxalyl, and the like. The substituted heteroaryl, for example, alkyl, alkoxy, halogen, nitro, alkanoyl, alkoxycarbonyl, aryl, heteroaryl and the like.
[0028]
　Examples of other sulfides, dimethyl sulfide, diethyl sulfide, dipropyl sulfide, dibutyl sulfide, thioanisole, ethyl phenyl sulfide, diphenyl sulfide, benzyl phenyl sulfide, benzimidazolyl pyridyl methyl sulfide and the like, and more preferably thio anisole, ethyl phenyl sulfide, diphenyl sulfide, benzyl phenyl sulfide, benzimidazolyl pyridyl methyl sulfide and the like, particularly preferably, diphenyl sulfide, benzyl phenyl sulfide, benzimidazolyl pyridyl methyl sulfide and the like. Enantioselectivity is improved more by using a bulky sulfides. The amount of other sulfide for a sulfide of the formula 1, for example, include about 2 to about 30 mole%, preferably about 5 to about 15 mole%.
　Other sulfide is added after the chiral ligand of Formula 3 to form a coordinated iron complex, after addition of hydrogen peroxide, it is preferable to carry out the reaction by adding a sulfide of the formula 1.
　Further, instead of adding other sulfides, sulfoxides or sulfones corresponding to other sulfides may be added after the chiral ligand of Formula 3 to form a coordinated iron complex.
[0029]
4. Preparation of the proton pump inhibitor compound in the optically active
　after completion of the oxidation reaction, it is possible to stop the degradation to an oxidation reaction of hydrogen peroxide by adding an aqueous solution of a reducing agent. As the reducing agent, for example, thiosulfates such as sodium thiosulfate, and sulfites such as sodium sulfite and the like. Upon addition of an aqueous solution of a reducing agent, iron has been used to dissolve in aqueous solution. Following the above operation, the product was extracted into the organic layer may then be purified according to a conventional method. Sulfoxides of optically active Formula 2, to dissolve the basic aqueous, was dissolved in pH8 more basic water solvent, and washed with a hydrophobic organic solvent, then an acid is added to the aqueous layer, the organic it can be extracted to the layer. In this operation, the sulfide form of the sulfone and unreacted by-product can be easily removed. It can then be purified by recrystallization. Further, it sulfoxides optically active formula 2 optionally may be salified according to a conventional method.
[0030]
5. Use of a proton pump inhibitor compound in the optically active
　proton pump inhibitor compound in the optically active produced by the production method of the present invention, like the known racemate, possible to prepare pharmaceutical compositions containing the appropriate amount as an active ingredient can. Prepared pharmaceutical composition acts on proton pump parietal cells of the stomach and suppresses drug gastric acid secretion, gastric ulcer, duodenal ulcer, anastomotic ulcer, reflux esophagitis, non-erosive gastroesophageal reflux disease or Zollinger-Ellison syndrome, and gastric ulcer, duodenal ulcer, gastric MALT lymphoma, idiopathic thrombocytopenic purpura, the eradication of Helicobacter pylori in after endoscopic resection stomach or Helicobacter pylori infection gastritis for early gastric cancer used in the treatment or the like of the auxiliary.
Example
[0031]
　Hereinafter be described in further detail by the present invention examples and comparative examples, the present invention is not limited to these examples.
　Hereinafter, each component contained in the reaction solution expressed using respective abbreviations of the following.
[Sulfide form A] 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] thio] -1H- benzimidazole (raw
material) [S- sulfoxide body A] sulfide form A Bruno S- sulfoxide
(esomeprazole) R- sulfoxide [R- sulfoxide body a] sulfide form a
sulfone [sulfone a] sulfide form a
[S- dichloro chiral ligand] 2,4-dichloro-6 - [(E) - [[(1S)-1-(hydroxymethyl) -2,2-dimethylpropyl] imino] methyl] - phenol (chiral ligand of formula 4 having a S-configuration)
[0032]
　The amount of each component contained in the reaction solution was measured using HPLC analysis conditions 1 to 3 below.

　were subjected to high performance liquid chromatography using the following parameters.
Columns Daicel Chiralpak IA (4.6mm × 250mm, particle size 5 [mu] m)
Column temperature] 25 ° C.
[mobile phase] t-butyl methyl ether: ethyl acetate: ethanol: diethylamine: trifluoroacetic acid = 60: 40: 5: 0.1: 0.1
[flow rate] 1.0 mL / min
detection wavelength] 299 nm
[measurement time 30 min
[approximate retention times]
　4-dimethylaminobenzoic acid: 3.6 min
　S- dichloro asymmetric coordinating child: 4.0 minutes
　sulfone A: 5.5 minutes
　sulfide form A: 6.6 minutes
　R- sulfoxide body A: 10.3 minutes
　S- sulfoxide body A: 14.6 minutes
[0033]

　was performed by high performance liquid chromatography using the following parameters.
[Column] ZORBAX SB-C8 (4.6mm × 150mm, particle size 3.5 [mu] m)
Column temperature] 25 ° C.
[mobile phase]
　Mobile phase A: pH 7.6 aqueous sodium phosphate; mobile phase B: acetonitrile
(pH 7. 6 aqueous solution of sodium phosphate, dissolved disodium hydrogen phosphate dodecahydrate 2.83g and sodium dihydrogen phosphate dihydrate 0.21g into water 1000 mL, adjusted to pH7.6 with 1 vol% phosphoric acid aqueous solution was.)
　was gradient controlled by changing as follows the mixing ratio of mobile phase a and mobile phase B.
[Table 1]

[flow rate] 1.0 mL / min
Detection Wavelength] 280 nm
[Measurement Time 45 min
[Approximate retention
times] (1) lansoprazole
　sulfone: 20.4 minutes
　sulfoxide isomer: 22.9 minutes
　sulfide form: 30.5 min
(2) rabeprazole
　sulfone: 13.7 minutes
　sulfoxide isomer: 18.3 minutes
　sulfide form: 27.9 minutes
(3) pantoprazole
　sulfone: 8.6 minutes
　sulfoxide isomer: 17.5 minutes
　sulfide form : 28.2 minutes
[0034]

　was carried out by high performance liquid chromatography using the following parameters.
Columns Daicel Chiralpak IC (4.6mm × 250mm, particle size 5 [mu] m)
Column temperature] 40 ° C.
in the mobile phase] pH 6.5 5M aqueous solution of potassium dihydrogen phosphate: methanol: tetrahydrofuran = 37:
60: 3 (pH 6 5M aqueous solution of potassium dihydrogen phosphate of .5, dissolving potassium dihydrogen phosphate 0.7g in water 1000 mL, was adjusted to pH6.5 with triethylamine.)
[flow rate] 1.0 mL / min
detection wavelength] 300 nm
[ measurement time 30 min
[approximate retention times]
(1) omeprazole
　S- sulfoxide body a: 12.5 min
　R- sulfoxide body a: 15.7 min
(2) lansoprazole
　S- sulfoxide isomer: 8.8 min
　R- sulfoxide isomer: 10.6 minutes
(3) rabeprazole
　S- sulfoxide isomer: 16.2 min
　R- sulfo Sid body: 20.9 min
(4) pantoprazole
　S- sulfoxide isomer: 7.8 min
　R- sulfoxide isomer: 8.8 min
[0035]
Example
1 S- preparation of sulfoxide body A (esomeprazole)
　0 iron (III) acetylacetonate 79.3mg of (273μmol) S- dichloro chiral ligand and 32.2mg (91.1μmol). It was dissolved at 25 ° C. in ethyl acetate in 6 mL, and stirred over 30 minutes. Mixed solution 7.8mg of 4-dimethylamino lithium benzoate salt and ethyl acetate 0.3mL of (45.5μmol) was added, and the suspension was stirred for 30 minutes or more. 0.3g (911μmol) a sulfide form A and ethyl acetate 0.9mL added, and the suspension was stirred for 30 minutes or more. The mixture was cooled to -5 ° C., was added dropwise over a 30% hydrogen peroxide aqueous solution of 186μL (1.82mmol) over 2 minutes. After 4.5 hours, the reaction mixture was analyzed by HPLC analysis condition 1.
sulfoxide body A 88%; sulfone form A 11%; sulfide form A 0%
98% ee
[0036]
Examples 2-8
Reaction Study of the solvent
　in Example 1, and ethyl acetate was subjected to asymmetric oxidation reaction in place of the reaction solvent set forth in Table 1. The results of analysis of the reaction mixture in the reaction time of the described HPLC analysis condition 1 in Table 1 are listed in Table 1.
[Table 2]

　Since the reaction rate was different depending on the reaction solvent was changed analysis time of the reaction mixture. As seen from the above results, giving a generally good enantioselectivity in any of the reaction solvent. Among them ethyl acetate and toluene / methanol showed a very high enantioselectivity.
[0037]
Examples 9-12
examined the reaction temperature
　in Example 2, 4 instead of dimethylamino benzoic acid lithium salt with 4-dimethylaminobenzoic acid, temperature to asymmetric oxidation reaction according to the reaction temperature shown in Table 2 It was carried out. The results of analysis of the reaction mixture in the reaction time of the described HPLC analysis condition 1 in Table 2 set forth in Table 2.
[Table 3]

　Since the reaction rate was different depending on the reaction temperature was changed analysis time of the reaction mixture accordingly. As seen from the above results, it showed good enantioselectivity was greater than 90% selectivity at inter alia 5 ° C. or less.
[0038]
Example 13
urea as an oxidizing agent - with hydrogen peroxide S- sulfoxide body A preparation of (esomeprazole)
　In Example 1, a mixed solvent of ethyl acetate and water instead of ethyl acetate as reaction solvent (10: 1 (v / v)) were performed using asymmetric oxidation reaction using a solid urea-hydrogen peroxide instead of 30% hydrogen peroxide aqueous solution as oxidant (171 mg). After 6 hours, the reaction mixture was analyzed by HPLC analysis condition 1.
sulfoxide body A 77%; sulfone form A 6%; sulfide form A 17%
87% ee
[0039]
EXAMPLE
14 S- preparation of sulfoxide body A (esomeprazole)
　0 iron (III) acetylacetonate 52.9mg of (182μmol) S- dichloro chiral ligand and 32.2mg (91.1μmol). It was dissolved at 25 ° C. in ethyl acetate in 6 mL, and stirred over 30 minutes. Mixed solution 7.8mg of 4-dimethylamino lithium benzoate salt and ethyl acetate 0.3mL of (45.5μmol) was added, and the suspension was stirred for 30 minutes or more. 0.3g (911μmol) a sulfide form A and ethyl acetate 0.9mL added, and the suspension was stirred for 30 minutes or more. The mixture was cooled to -5 ° C., was added dropwise over a 30% hydrogen peroxide aqueous solution of 186μL (1.82mmol) over 2 minutes. After 4.5 hours, the reaction mixture was analyzed by HPLC analysis condition 1.
sulfoxide body A 83%; sulfone form A 15%; sulfide form A 2%
97% ee
　mixture 8% aqueous sodium bicarbonate solution 2.8 mL, 1.4 g after addition of sodium thiosulfate pentahydrate and 1.4mL of water was stirred and heated to 25 ° C.. After removal of the aqueous phase, the organic phase was washed twice with 8% aqueous sodium bicarbonate 1 mL. The organic phase was analyzed by HPLC analysis condition 1.
sulfoxide body A 86%; sulfone form A 14%; sulfide form A 0%
98% ee
　then concentrated and purified by silica gel column chromatography (developing solvent: a mixed of chloroform and methanol performing a post-treatment by solvent), the title compound 0.3 g (purity 87%; yield of 98% ee).
1 H NMR (400 MHz, CDCl 3 ): [delta] 8.21 (IH, s), 7.58 (IH, br s), 6.96 (2H, br m), 4.75 (2H, q, -SOCH 2 -), 3.84 (3H , s), 3.69 (3H, s), 2.23 (3H, s), 2.21 (3H, s)
[0040]
Example 15
Addition of dibutyl sulfide
　in Example 1, before adding the sulfide form A, added dibutyl sulfide (91.1μmol) of 16 [mu] L, after the mixture was cooled to -5 ° C., 30 of 186μL (1.82mmol) % aqueous hydrogen peroxide was added dropwise and the mixture was stirred for 30 minutes, ethyl acetate was added sulfide form a and 0.9mL of 0.3g (911μmol). After 16.5 hours, it analyzed a small amount of the reaction mixture by HPLC analysis condition 1.
sulfoxide body A 88%; sulfone form A 8%; sulfide form A 4%
96% ee
[0041]
EXAMPLE 16
Addition of diphenyl sulfide
　in Example 15, an experiment was conducted as an additive in place of dibutyl sulfide with diphenyl sulfide. After 16.5 hours, it analyzed a small amount of the reaction mixture by HPLC analysis condition 1.
sulfoxide body A 88%; sulfone form A 11%; sulfide form A 1%
99.5% ee
　8% aqueous sodium bicarbonate 3.7mL to the reaction mixture, after addition of water, sodium thiosulfate pentahydrate and 1.4mL of 1.4g, it was stirred and heated to 25 ° C.. After removal of the aqueous phase, the organic phase was washed twice with 8% aqueous sodium bicarbonate 1mL, product twice with 0.75M sodium hydroxide solution 1M aqueous sodium hydroxide and 1mL of 1mL from the organic phase Extracted. The combined aqueous phases were neutralized with acetic acid and extracted twice with 4-methyl-2-pentanone 2 mL. The combined organic phases were analyzed by HPLC analysis condition 1.
sulfoxide body A 89%; sulfone form A 11%; sulfide form A 0%
99.7% ee
[0042]
EXAMPLE
17 S- lansoprazole preparation
　234mg of (808μmol) S- dichloro chiral ligand, 4-dimethylaminobenzoic acid iron (III) acetylacetonate and 23.2mg (136μmol) of 94.9mg (269μmol) It is suspended in 25 ° C. the lithium salt of ethyl acetate 7.5 mL, and stirred over 30 minutes. Monohydrate and ethyl acetate 7.5mL of a sulfide form of lansoprazole 1.00 g (2.69 mmol) was added. After cooling at a rate of 1 ℃ the mixture to -5 ° C., was added dropwise over a 30% hydrogen peroxide aqueous solution of 550μL (5.39μmol) over 2 minutes. After 20.5 h, the reaction mixture was analyzed by HPLC analysis condition 2 and HPLC analysis condition 3.
sulfoxide body 87%; sulfone form 12%; sulfide form 1%
98% ee
　mixed solution in a mixed solvent of a saturated aqueous sodium thiosulfate solution and saturated sodium bicarbonate aqueous sulfuric acid 5mL added after, it stirred and heated to 5 ° C.. After removing the water layer, the organic layer was concentrated under reduced pressure.
sulfoxide 86%; sulfone form 13%; sulfide form 1%
98% ee
　silica column chromatography: performed workup (developing solvent a mixed solvent of ethyl acetate and methanol) Te, the title compound 0.86 g (purity 98%; 97% ee) was obtained.
1 H-NMR (400 MHz, DMSO): [delta] 13.6 (IH, s), 8.29 (IH, d), 7.65 (IH, br s), 7.31 (2H, m), 7.10 (IH, d), 4.92 ( 2H, q), 4.80 (2H, q, -SOCH 2 -), 2.18 (3H, s)
LRMS: [M + Na] + calcd 392.07, found 392.40
　Note that the lansoprazole obtained optically active sulfoxide solid was presumed S configuration from the behavior and HPLC retention time of omeprazole and pantoprazole.
[0043]
EXAMPLE
18 S- rabeprazole preparation
　253mg of (874μmol) S- dichloro chiral ligand, 4-dimethylamino benzoic acid lithium salt of an iron (III) acetylacetonate and 25.2mg (147μmol) of 103mg (291μmol) are suspended in 25 ° C. in ethyl acetate in 5 mL, and stirred over 30 minutes. Sulfide form and 5mL of ethyl acetate of rabeprazole 1.00 g (2.91 mmol) was added. After cooling at a rate of 1 ℃ the mixture to -5 ° C., it was added dropwise over a 30% hydrogen peroxide aqueous solution of 595μL (5.82mmol) over 2 minutes. After 21.5 h, the reaction mixture was analyzed by HPLC analysis condition 2 and HPLC analysis condition 3.
sulfoxide 82%; sulfone form 17%; sulfide form 1%
97% ee
　mixed solution in a mixed solvent of a saturated aqueous sodium thiosulfate solution and saturated sodium bicarbonate aqueous sulfuric acid 5mL added after, it stirred and heated to 5 ° C.. After removing the water layer, the organic layer was concentrated under reduced pressure.
sulfoxide 82%; sulfone form 18%; sulfide form 0%
97% ee
　silica column chromatography: performed workup (developing solvent a mixed solvent of ethyl acetate and methanol) Te, the title compound 0.73 g (purity 97%; 96% ee) was obtained.
1 H-NMR (400 MHz, DMSO): [delta] 13.5 (IH, s), 8.21 (IH, d), 7.65 (IH, br s), 7.31 (2H, m), 6.96 (IH, d), 4.75 ( 2H, q, -SOCH 2 -), 4, 10 (2H, d), 3.48 (2H, t), 3.25 (3H, s), 2.14 (3H, s), 1.99 (2H, m)
LRMS: [M + Na] + calcd 382.12, found 382.44
　Note that the three-dimensional sulfoxides of rabeprazole of the resulting optically active from the behavior and HPLC retention time of omeprazole and pantoprazole, was estimated S configuration.
[0044]
Example
19 S- pantoprazole preparation
　237mg of (815μmol) S- dichloro chiral ligand, 95.8Mg of (271μmol) iron (III) acetylacetonate and 23.4mg (137μmol) 4- dimethylaminobenzoate the lithium salt are suspended in 25 ° C. in ethyl acetate in 5 mL, and stirred over 30 minutes. Sulfide form and 5mL of ethyl acetate of pantoprazole 1.00 g (2.72 mmol) was added. The mixture was cooled at a rate of 1 ℃ to -8 ° C., and thereto is added dropwise a 30% aqueous hydrogen peroxide 556μL (5.44mmol) over a period of 1 minute. After 44 hours, the reaction mixture was analyzed by HPLC analysis condition 2 and HPLC analysis condition 3.
sulfoxide body 75%; sulfone form 13%; sulfide form 12%
83% ee
　mixed solution in a mixed solvent of a saturated aqueous sodium thiosulfate solution and saturated sodium bicarbonate aqueous sulfuric acid 5mL added after, it stirred and heated to 10 ° C.. After removing the water layer, the organic layer was concentrated under reduced pressure.
sulfoxide body 75%; sulfone form 13%; sulfide form 12%
83% ee
　silica column chromatography: performed workup (developing solvent a mixed solvent of ethyl acetate and methanol) Te, the title compound 0.74 g (purity 95.13%; 82% ee) was obtained.
1 H-NMR (400 MHz, DMSO): [delta] 13.8 (IH, s), 8.15 (IH, d), 7.72 (IH, d), 7.44 (IH, s), 7.26 (IH, t), 7.16 (IH , dd), 7.11 (IH, d), 4.69 (2H, q, -SOCH 2 -), 3.90 (3H, s), 3.77 (3H, s)
LRMS: [M + Na] + calcd 406.06, found 406.36
Optical rotation [alpha] D 25 : -79.4 (c 0.3, MeOH)
　optical rotation of the S-form of pantoprazole (ee 96%) [alpha] D 25 may be a -95.5 (c 0.3, MeOH), Tetrahedron: Asymmetry, 2012, 23, are described in the 457-460.
[0045]
　It summarized the results of an analysis of reactions of Examples 17-19 and Example 1 in Table 4.
[Table 4]

　As described above, by the manufacturing method of the present invention, a proton pump inhibitor compound high yield and enantioselectivity of various optically active, it is understood that it is possible to manufacture.
[0046]
Example 20
production scale changes S- sulfoxide body A (esomeprazole)
　as described in Non-Patent Document 1 or the like, when the titanium catalyst, there is a problem with a large scale it is necessary to increase the amount of catalyst It was. Therefore, in the manufacturing method of the present invention, it was subjected to sulfide form A of raw material 1g, the 20g and 100g using experiments. It describes the reaction conditions in the case of using 100g below, in the case of using 1g and 20g reaction was conducted in the same manner using the reagents of the amount corresponding thereto.
　S- dichloro chiral ligand of 7.93g (27.3mmol), 4- dimethylaminobenzoic acid iron (III) acetylacetonate and 3.9g (22.77mmol) of 8.04g (22.77mmol) the lithium salt was suspended in ethyl acetate at room temperature 300 mL, and stirred over 30 minutes. Of ethyl acetate was added sulfide form A and 500mL of 100g (303.56mmol) to the mixture. The mixture was cooled to -5 ° C., was added dropwise 30% hydrogen peroxide aqueous solution of 68.82g (607.12mmol). After 8 hours, the reaction mixture was analyzed by HPLC analysis condition 3.
　Hereinafter, the analysis of these scales different reactions are shown in Table 5.
[Table 5]

　As described above, good reproducibility was observed in the production method of the present invention, even by increasing the scale, it is possible to maintain a high yield and enantioselectivity, it is not necessary to increase the amount of catalyst It can be seen.
Industrial Applicability
[0047]
　By the production method of the present invention, the proton pump inhibitor compound of a high purity of the optically active in high yield and enantioselectivity, it can be safely manufactured at low cost.

claims
[Claim 1]
　By oxidizing a sulfide or a salt of formula 1 A process for producing a sulfoxide or a salt of the optically active formula 2,
[Formula 1]

[In the formula, A represents CH or N.
　R 1 represents a hydrogen atom, alkyl which may be substituted by halogen or alkoxy optionally substituted with halogen,.
　R 2 may be a 1-3, each independently, alkyl, represents a dialkylamino or halogen or alkoxy optionally substituted by alkoxy.
　* Represents R or S configuration. ]
　The presence of chiral ligand of Formula 3,
Formula 2]

wherein, R 3 are each independently a hydrogen atom, a halogen, cyano, alkylsulfonyl, arylsulfonyl, alkanoyl, alkoxycarbonyl, nitro, alkyl optionally substituted by halogen or substituted by halogen, it represents also alkoxy.
　R 4 represents a tertiary alkyl.
　** indicates the R or S configuration. ]
Using an iron salt, a manufacturing method which is characterized in that oxidation with hydrogen peroxide.
[Claim 2]
　Optionally substituted benzoic acid or the addition salt thereof an oxidation reaction process according to claim 1.
[Claim 3]
　After addition of the sulfoxide or sulfone corresponding to other sulfide or other sulfide to the reaction system, an oxidation reaction of sulfide or a salt thereof of the formula 1 The process according to claim 1 or 2.
[Claim 4]
　R 3 are both chlorine atoms, R 4 is t- butyl, The process according to any one of claims 1-3.
[Claim 5]
　Sulfoxides of the optically active formula 2, omeprazole, lansoprazole, rabeprazole, tenatoprazole, an optically active substance of pantoprazole or leminoprazole method according to any one of claims 1-4.
[Claim 6]
　Coordinated iron complex in the chiral ligand of Formula 4.
[Chemical Formula 3]

[wherein, ** represents the R or S configuration. ]