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A kind of preparation method of compound a

A compound and mixed solvent technology, applied in the preparation of chiral intermediate side chain -2,8-diazabicyclo[4.3.0]nonane, in the field of preparation of pharmaceutical intermediates, can solve the problem of unstable resolving agent, Solve problems such as low yield and complicated process, achieve high industrial production value, reduce production cost, and achieve high chiral purity

Active Publication Date: 2022-03-22
TAIAN HAVAY CHEM
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Problems solved by technology

[0007] The chiral intermediate obtained by the above process route: (S, R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane exists in a single resolution Low yield (generally less than 30%) and low ee value, in order to achieve high chiral purity, it is necessary to add resolving agent to (S,R)-8-benzyl-7,9-dioxo The resolution of -2,8-diazabicyclo[4.3.0]nonane is cumbersome, with low resolution yield and high production cost
[0008] U.S. Patent No. 6,566,523 relates to a resolving agent: (-)-2,3:4,6-diisopropylidene-2-keto-L-gulonic acid. This resolving agent is more expensive and consumes a large amount (molecular weight is big), the problem that resolving agent is unstable under acidic conditions; Propose resolving agent N-acetyl-L-leucine at the above-mentioned problem in CN102408427A, but the price of this resolving agent is still on the high side relatively, causes material The cost is high. In addition, the yield of 70% to 80% in this patent is converted on the basis of the theoretical maximum yield of 50%, and the actual yield of the input material should be divided by 2; WO2009 / 125425 proposes a resolving agent D(-) tartaric acid and L(+) tartaric acid also have the problem of relatively high prices. In addition, they have to go through two splits, and the process is complicated

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  • A kind of preparation method of compound a

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preparation example Construction

[0031] A method of preparation of compound A, the compound A is (S, R) -8-benzyl-7,9-dioxidant-2,8-diazorane bicyclic ring [4.3.0] decane, its step include:

[0032] (1) Preparation of the split salt: dissolve the hydrogenate in a mixed solvent to add the splitter coolean acid, and the temperature is warmed to react, then cool the crystalline, filtrate, wash, dry the salt;

[0033] (2) Stripping the alkaloid: The splitting salt obtained by step (1) is extracted by alkali, organic solvent, and the solvent is evaporated, the EE value is greater than 98% (S, R) -8-benzyl-7, 9-dioxidine-2,8-diazorane bicyclic ring [4.3.0] decane.

[0034] The product (S, R) 8-benzyl-7,9-dioxo-2,8-diazine-7,9-dioxo-2,8-diaza-7,9-dioxo-2,8-diazine-7,9-dioxo-2,8-diazine-7,9-dioxo-2,8-bisz-7,9-dioxo-2,8-diazo-7,9-dioxane-proof Determination of Moshisha Cross of Moshisa Food and Drug Food and Drug in 2013.

Embodiment 1

[0036] (1) 50 g of a hydrogen product of 98% of the liquid phase purity was dissolved in a mixed solvent of 300 ml of ethanol, butanone and water in which the water obtained was 10%, and 20.19 g of citrison acid was added after dissolving, and heated to 50 ° C. 2 hours, then cooled to 20 degrees Celsius for 2 hours crystalline, filtered, filter cake was flush with a mixed solvent of the above ethanol, butanone and water, and the filter cake was dried to obtain a split salt 36.6 g;

[0037] (2) The split salt obtained by step (1) was added to 80 ml of purified water, 8.0 g of slicat, and then adding the pH 8-9 to add toluene 80 ml * 2 extraction, dried over anhydrous sodium sulfate and evaporated. Oil liquid is (S, R) -8-benzyl-7,9-dioxidine-2,8-diazoracy double ring [4.3.0] decane 21.5 g, yield 43%; EE value 99%.

Embodiment 2

[0039] (1) 50 g of the hydrogen 50g of the liquid phase purity was dissolved in 150 mL of methanol and water mixed solvent, wherein the water-based volume fraction was 5%, and 40.38 g of ancient dragon acid was added after dissolving, and the water was gradually warmed to 80 ° C for 1 hour. Then, then slowly cool to 30 degrees Celsius insulation for 1 hour. Filtration, the filter cake was flushed with 100 mL of the above methanol and the mixed solvent of water, and the filter cake was dried to obtain a split salt 38.1 g.

[0040] (2) The split salt obtained by step (1) was added 80 ml of purified water, 8.0 g of a piece of base, and then adding the pH 8-9 to 80 ml * 2 extraction, dried over anhydrous sodium sulfate and evaporated. Yellow oily liquid is (S, R) -8-benzyl-7,9-dioxo-2,8-diaza-bicyclic ring [4.3.0] decane 20.8 g, yield 41.6%; EE value 98.2% .

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Abstract

The invention discloses a preparation method of compound A, which is (S,R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonyl Alkane, the preparation method is obtained by salting and crystallizing the hydrogenated product and the resolving agent to obtain the resolution salt, and then extracting the resolution product (S, R)-8-benzyl-7,9-di Oxo‑2,8‑diazabicyclo[4.3.0]nonane. The process is simple to operate, and the single resolution yield is greater than 40%; the chiral purity ee value is greater than 98%, and has high industrial production value.

Description

Technical field [0001] The present invention belongs to the technical field of medical intermediate preparation, and the chiral intermediate side chain (S, S) -2, 8-diazeplastic double ring [4.3.0] decane is prepared by the chiral intermediate side chain (S, S) -2, 8-diazorane bicyclic ring [4.3.0] decanes Technical field. [0002] technical background [0003] Moxivaca, Moxivaca, is a fluoroquinoloid antibiotic drug developed by Bayer, Germany, which belongs to the fourth-generation quinolone drug broad-spectrum antibacterial drug, mechanism and in vitro antibiotics, similar to other fluoroquinolones, but to Gram-positive The antibacterial activity of the bacteria and anaerobic bacteria is similar to the curva, better than some old varieties. Compared with other fluoroquinolone drugs, it is very slow or resistant to this product. It has been made of drug resistance, and the intersection between other fluoroquinolone drugs is found in Gram-negative bacteria and enterococcus. Bacte...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04
CPCC07D471/04C07B2200/07
Inventor 孙桂彬李贺存王加旺张亦林
Owner TAIAN HAVAY CHEM
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