# US 10,307,748 B2 · Method for producing proton pump inhibitor compound having optical activity

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- Number: US 10,307,748 B2
- Document ID: US10307748B2
- Status: Granted
- Kind: B2
- Application number: 15/539,849
- Filed: 2015-12-25
- Published: 2018-01-11
- Granted: 2019-06-04
- Earliest claimed: 2014-12-26
- Assignees: The University of Tokyo
- Applicants: The University of Tokyo; Towa Pharmaceutical Co., Ltd.
- Inventors: Eiichi Nakamura; Laurean Ilies; Yoji Oderaotoshi; Takuhiro Izumi; Shigenobu Nishiguchi
- Web page: https://patentgrep.com/patent/US10307748B2

## CPC

- B01J 31/2243: {At least one oxygen and one nitrogen atom present as complexing atoms in an at least bidentate or bridging ligand}
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- B01J 23/745: Iron
- B01J 31/00: Catalysts comprising hydrides, coordination complexes or organic compounds (catalyst compositions used only in polymerisation reactions C08 {; catalytic antibodies C12N9/0002})
- C07B 53/00: Asymmetric syntheses
- C07C 251/24: having carbon atoms of imino groups bound to carbon atoms of six-membered aromatic rings
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 471/04: Ortho-condensed systems
- C07F 15/025: {without a metal-carbon linkage}
- B01J 2231/763: of -CH-XH (X= O, NH/N, S) to -C=X or -CX triple bond species
- B01J 2531/0205: Bi- or polynuclear complexes, i.e. comprising two or more metal coordination centres, without metal-metal bonds, e.g. Cp(Lx)Zr-imidazole-Zr(Lx)Cp
- B01J 2531/0216: Bi- or polynuclear complexes, i.e. comprising two or more metal coordination centres, without metal-metal bonds, e.g. Cp(Lx)Zr-imidazole-Zr(Lx)Cp
- B01J 2531/0244: Pincer-type complexes, i.e. consisting of a tridentate skeleton bound to a metal, e.g. by one to three metal-carbon sigma-bonds
- B01J 2531/0288: Sterically demanding or shielding ligands
- B01J 2531/842: Iron
- C07B 2200/07: Optical isomers
- B01J: CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

A highly pure optically active proton pump inhibitor compound can be produced safely and inexpensively in a high yield and enantioselectivity by a method of producing an optically active sulfoxide of Formula 2 or a salt thereof, comprising oxidizing a sulfide of Formula 1 or a salt thereof with hydrogen peroxide using an iron salt in the presence of a chiral ligand of Formula 3; wherein A is CH or N; R1 is hydrogen atom, an alkyl optionally substituted by halogen(s), or an alkoxy optionally substituted by halogen(s); one to three R2 may exist, and each of R2 is independently an alkyl, a dialkylamino, or an alkoxy optionally substituted by halogen(s) or alkoxy(s); each of R3 is independently hydrogen atom, a halogen, cyano or the like; R4 is a tertiary alkyl; and * and ** represent respectively R configuration or S configuration.

## Claims

### Claim 1

A method of producing an optically active sulfoxide of Formula 2 or a salt thereof, comprising oxidizing a sulfide of Formula 1 or a salt thereof:
wherein A is CH or N; R1 is hydrogen atom, an alkyl optionally substituted by halogen(s), or an alkoxy optionally substituted by halogen(s); one to three R2 may exist, and each of R2 is independently an alkyl, a dialkylamino, or an alkoxy optionally substituted by halogen(s) or alkoxy(s); and * represents R configuration or S configuration, with hydrogen peroxide using an iron salt in the presence of a chiral ligand of Formula 3:
wherein each of R3 is a halogen; R4 is a tertiary alkyl; and ** represents R configuration or S configuration;
wherein the iron salt is divalent or trivalent; and
wherein the oxidation reaction is performed after adding an optionally substituted benzoic acid or salt thereof.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the oxidation reaction of a sulfide of Formula 1 or a salt thereof is performed after adding another sulfide or a sulfoxide or sulfone corresponding to another sulfide to the reaction system wherein the another sulfide is represented by the Formula R5—S—R6, wherein R5 and R6 are each independently an optionally substituted alkyl, or an optionally substituted aryl.

### Claim 3 (depends on 1)

The method according to claim 1, wherein both R3 are chlorine atoms, and R4 is t-butyl.

### Claim 4 (depends on 1)

The method according to claim 1, wherein the optically active sulfoxide of Formula 2 is an optically active form of omeprazole, lansoprazole, rabeprazole, tenatoprazole, pantoprazole or reminoprazole.