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A kind of method for catalyzing asymmetric oxidation of sulfide to prepare chiral sulfoxide drugs

A sulfoxide-based, asymmetric technology, applied in the field of catalytic asymmetric oxidation of prochiral sulfides to prepare chiral sulfoxide drugs, can solve the problem of large usage of chiral ligands, increased reaction system complexity and operating costs, Limit the industrial production of chiral sulfoxide drugs and other problems, and achieve the effects of high conversion rate, mild reaction conditions and easy availability of raw materials

Active Publication Date: 2018-03-27
DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Although the above methods can prepare chiral sulfoxide drugs, they all have the following disadvantages: 1) the amount of chiral ligand used is large, and some are equivalent to the amount of substrate; 2) the use of cumene hydroperoxide or tert-butyl peroxide Hydrogen is an oxidizing agent; 3) A large amount of special organic base is required as an additive, which increases the complexity and operation cost of the reaction system
These disadvantages limit the industrial production of chiral sulfoxide drugs

Method used

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  • A kind of method for catalyzing asymmetric oxidation of sulfide to prepare chiral sulfoxide drugs
  • A kind of method for catalyzing asymmetric oxidation of sulfide to prepare chiral sulfoxide drugs
  • A kind of method for catalyzing asymmetric oxidation of sulfide to prepare chiral sulfoxide drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Synthesis of a chiral tetradentate nitrogen ligand

[0032]

[0033] In 50mL toluene solution, add 22.5mg (0.1mmol) palladium acetate and 72mg (0.3mmol)

[0034]Tri-tert-butylphosphine, stirred for 10min. 2.36 g (10 mmol) of o-dibromobenzene, 3.63 g (24 mmol) of methyl 2-aminobenzoate and 10.1 g (31 mmol) of cesium carbonate were successively added. After the reaction solution was heated to reflux for 24 hours, it was cooled to 25°C, and 50 mL of saturated ammonium chloride solution was added. 200 mL of dichloromethane was added, the organic phase was separated, and the aqueous phase was extracted twice with 60 mL of dichloromethane each time. The organic phases were combined, dried, concentrated, and 1.47 g of compound 1 (yield 39%) was obtained by column chromatography (ethyl acetate / petroleum ether=1:50). 1 HNMR (400MHz, CDCl 3 )δ9.21(2H,s),7.89(2H,d,J=7.4),7.42(2H,s),7.25(3H,s),7.11(2H,d,J=2.8),7.04(2H, d,J=8.1),6.70(2H,s),3.80(6H,s). 13 CNMR (101MHz, CDCl ...

Embodiment 2

[0038] Embodiment 2 (S) - the synthesis of omeprazole

[0039]

[0040] At 25°C, add Mn(OTf) to 3.0 mL of dichloromethane 2 (1.5mg, 0.0042mmol) and L2 (2.0mg, 0.0042mmol) were stirred for 3h. Then 0.42 mmol thioether and 2.1 mmol glacial acetic acid and 30% hydrogen peroxide (0.92 mmol) were added. The reaction mixture was cooled to 0 °C and stirred at 0 °C for 1 h. The organic phase was separated, dried, analyzed by high performance liquid chromatography to obtain the ee value, and the product was obtained by column chromatography, and the yield was calculated.

[0041] Using 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfanyl]-1H-benzimidazole as a model substrate versus reaction conditions optimize. The results are shown in the table below.

[0042]

[0043]

[0044] [a] Separation yield. [b] Chiral HPLC determination.

[0045] It can be seen from the table that the solvent is dichloromethane, the molar ratio of hydrogen peroxide to substrate thio...

Embodiment 3

[0047] The preparation of embodiment 3 S-lansoprazole

[0048] Experimental procedure is identical with embodiment 2. 89% yield, 98% ee value.

[0049] 1 HNMR (300MHz, DMSO-d 6 ):δ13.6(br s,1H),8.28(d,J=5.6Hz,1H),7.65(br s,2H),7.30(m,2H),7.09(d,J=5.6Hz,1H) ,4.90(q,J=8.7Hz,2H),4.83 and 4.75(AB-system,J=13.7Hz,2H),2.17(s,3H).[α] D 25 =-199.7(c1.0,acetone).Ee value is determined by chiral high performance liquid chromatography (chromatographic column: Kromasil KR100-5CHI-TBB mobile phase: n-hexane / isopropanol / acetic acid / triethylamine (volume ratio )=90:10:0.1:0.2, flow rate: 1.5mL / min, wavelength 284nm, retention time=8.3min, 10.4min)

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Abstract

The invention provides a method for preparing chiral sulfoxide drugs by catalyzing asymmetric oxidation of thioether compounds. Using a chiral complex formed by a tetradentate nitrogen organic ligand and a metal manganese compound as a catalyst, hydrogen peroxide is used as an oxidant to perform an asymmetric catalytic oxidation reaction on a prochiral sulfide compound to obtain the corresponding chiral sulfoxide Drug compound, S‑omeprazole, S‑lansoprazole, S‑pantoprazole, S‑rabeprazole, R‑modafinil, R‑sulindac. The reaction is clean, mild reaction conditions, high conversion and enantioselectivity. Has industrial prospects.

Description

technical field [0001] The invention relates to a method for preparing chiral sulfoxide drugs by catalyzing asymmetric oxidation of prochiral sulfides. Background technique [0002] The sulfoxide compound with pyridine-2-methylidene-1H-benzimidazole structure has the ability to inhibit H + / K + -ATPase (also known as proton pump) activity can effectively inhibit gastric acid secretion, and is widely used in the treatment of peptic ulcer-related diseases caused by excessive gastric acid secretion. The sulfoxide proton pump inhibitors currently on the market at home and abroad include 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl ]-1H-benzimidazole (Omeprazole, Omeprazole), 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl] Sulfinate]-1H-benzimidazole (Lansoprazole, Lansoprazole), 5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridyl)methyl] Sulfinyl]-1H-benzimidazole (Pantoprazole, Pantoprazole), 2-[[[3-methyl-4-(3-methoxy-1-propoxy)-2-pyridyl] Methyl]s...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12C07C317/44C07C315/02
CPCC07C315/02C07C2602/08C07D401/12C07C317/44
Inventor 高爽戴文李军吕迎张恒耘张毅
Owner DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI