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Preparation method of chiral sulfoxide medicament though catalysis of asymmetric oxidation of sulfides compound

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 increasing the complexity of the reaction system and operating costs, the use of large amounts of chiral ligands, 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: 2015-03-25
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

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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  • Preparation method of chiral sulfoxide medicament though catalysis of asymmetric oxidation of sulfides compound
  • Preparation method of chiral sulfoxide medicament though catalysis of asymmetric oxidation of sulfides compound
  • Preparation method of chiral sulfoxide medicament though catalysis of asymmetric oxidation of sulfides compound

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Synthesis of a chiral tetradentate nitrogen ligand

[0032]

[0033]Add 22.5 mg (0.1 mmol) of palladium acetate and 72 mg (0.3 mmol) of tri-tert-butylphosphine into 50 mL of toluene solution, and stir for 10 min. 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...

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 the substrate ...

Embodiment 3

[0047] The preparation of embodiment 3S-lansoprazole

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

[0049] 1 HNMR (300MHz, DMSO-d 6 ):δ13.6(brs,1H),8.28(d,J=5.6Hz,1H),7.65(brs,2H),7.30(m,2H),7.09(d,J=5.6Hz,1H),4.90 (q,J=8.7Hz,2H),4.83and4.75(AB-system,J=13.7Hz,2H),2.17(s,3H).[a] 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 preparation method of a chiral sulfoxide medicament though catalysis of asymmetric oxidation of sulfides compounds. A chiral complex formed by quadridentate nitrogen organic ligand and metal manganese compound as a catalyst and hydrogen peroxide as an oxidant are used for asymmetric catalytic oxidation of prochiral thioether compound, so as to obtain the corresponding chiral sulfoxide medicament compounds including S-omeprazole, S-lansoprazole, S-pantoprazole, S-rabeprazole, R-Modafinil and R-sulindac. The reaction has the advantages of cleaness, mild reaction conditions, high conversion rate and antipodal selectivity, and shows 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 Applications(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
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