Resolving and racemization method for 1-amino-1,2,3,4-tetrahydronaphthalene

A technology for tetralin and tetralin crude products, which is applied in the purification/separation of amino compounds, preparation through nitrogen-oxygen/nitrogen-nitrogen bonds, organic chemistry, etc. too good and so on

Inactive Publication Date: 2012-09-19
SHANGHAI LANGTZE BIOMEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] Although the design idea of ​​the above synthetic route is very good, its actual effect is very general. When reducing chiral imines, a low temperature of -30°C is required, and because the selectivity of chiral reduction is not very good, it is necessary to use Chiral L-tartaric acid salt purification, that is, still need to use L-tartaric acid for resolution, the overall yield is relatively low, only 18%
[0012] ...

Method used

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  • Resolving and racemization method for 1-amino-1,2,3,4-tetrahydronaphthalene
  • Resolving and racemization method for 1-amino-1,2,3,4-tetrahydronaphthalene
  • Resolving and racemization method for 1-amino-1,2,3,4-tetrahydronaphthalene

Examples

Experimental program
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Effect test

Embodiment 1

[0061] 3,4-dihydro-1-(2H)-naphthalenone oxime (the raw material 3,4-dihydro-1 ( 2H)-naphthalene oxime.) Reduction to mixed 1-amino-1,2,3,4-tetralin, the reaction formula is as follows:

[0062]

[0063]Add 200ml of anhydrous methanol to a 500ml three-neck flask, then add 10.0g of 3,4-dihydro-1(2H)-naphthalenone oxime (62.1mmol) and stir for 10 minutes, and the raw materials are completely dissolved. First replace the air in the bottle with nitrogen, then under the protection of nitrogen, add 0.5g of wet palladium carbon (Pd / carbon, 10%) containing 50% water, and then replace it with hydrogen for more than three times, then at room temperature (20-30°C) , stirred for 15-20 hours under normal pressure (0.95-1.05atm). Thin-layer chromatography showed complete disappearance of the starting material spot and only new spot appeared.

[0064] Filter under the protection of nitrogen, wash the filter cake twice with 20ml and 20ml of anhydrous methanol, combine the mother liquor, c...

Embodiment 2

[0067] Add 70ml of anhydrous methanol to a 250ml three-neck flask, then add 10.0g of 3,4-dihydro-1(2H)-naphthalenone oxime (62.1mmol) and stir for 10-20 minutes, the raw materials are completely dissolved. Under the protection of nitrogen, add 0.3g of wet palladium carbon with 50% water content (Pd / carbon, 10%), and then replace it with hydrogen for more than three times, stir at room temperature (20-30°C) and normal pressure (0.95-1.05atm) for 15 -20 hours. Thin-layer chromatography showed that some raw material points remained, and the product 1-amino-1,2,3,4-tetrahydronaphthalene new point and by-products of deamination appeared. Column separation, yield 30-70%.

Embodiment 3

[0069] The vortexed 1-amino-1,2,3,4-tetralin obtained in Example 1 was first resolved with an L-type acidic resolving agent to separate (S)-1-amino-1,2,3, 4-tetrahydronaphthalene, and then use D-type acidic resolving agent to resolve (R)-1-amino-1,2,3,4-tetrahydronaphthalene. Concrete reaction process is as follows:

[0070] Add 30.6g (0.204mmol) of L-tartaric acid into 300ml of anhydrous methanol and stir for 10-15 minutes to dissolve it completely. Subsequently, 30 g (0.204 mmol) of vortexed 1-amino-1,2,3,4-tetralin was added, the temperature was raised to reflux, and the mixture was stirred for 10-15 minutes. Cool to room temperature (20-25°C) and stir at this temperature for 0.5 hours. During the cooling process, many white solids were precipitated.

[0071] Warming up to reflux again, stirring for 0.5 hour, and making all solids dissolve completely, then slowly cooling down to room temperature in 1-2 hours, followed by stirring at room temperature for 2 hours, filterin...

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Abstract

The invention provides a resolving and racemization method for 1-amino-1,2,3,4-tetrahydronaphthalene. The method comprises the following steps of: reducing 3,4-dihydro-1-(2H)-naphthalene ketoxime into DL-1-amino-1,2,3,4-tetrahydronaphthalene; and resolving DL-1-amino-1,2,3,4-tetrahydronaphthalene into optically pure (S)-1-amino-1,2,3,4-tetrahydronaphthalene and (R)-1-amino-1,2,3,4-tetrahydronaphthalene by using an acidic resolving agent, or oxidizing chiral secondary amine into corresponding imine or derivatives thereof, reducing into DL-secondary amine and continuously resolving to obtain a single optical product. The enantiomeric excess (ee) value of the obtained product is more than 99.5 percent; and the yield of one-time resolving exceeds 30 percent, and the total yield of the route reaches 46 to 54 percent. Compared with the methods reported by various documents and patents at present, the method has obvious technological and economical advantages.

Description

technical field [0001] The invention relates to a resolution and racemization method of a class of chiral secondary amines, in particular to a resolution and racemization method of 1-amino-1,2,3,4-tetralin. Background technique [0002] Chiral drugs are a hot spot in the research and development of new drugs in recent years. In the past 20 years, more than half of the new drugs launched in the world are chiral. Chemically pure mixed 1-amino-1,2,3,4-tetralin, optically pure (S)-1-amino-1,2,3,4-tetralin and (R)-1 -Amino-1,2,3,4-tetralin is an important pharmaceutical intermediate and an intermediate commonly used in the research and development of small molecule innovative drugs. E.g: [0003] Document [Bioorganic & Medicinal Chemistry 12 (2004), 4189-4196] report, the 1-amino-1 of mixed rotation, 2,3, the compound of 4-tetralin is used for synthesizing following formula I structure, and this class compound has very good Appetite-reducing and weight-loss effects. [0004]...

Claims

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Application Information

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IPC IPC(8): C07C211/42C07C209/40C07C209/88
Inventor 张明杰曾凡云黄彦昌龚熙见
Owner SHANGHAI LANGTZE BIOMEDICAL TECH
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