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A kind of preparation method of n-(9-fluorenylmethoxycarbonyl)-o-tert-butyl-l-tyrosine

A technology of tert-butyl and tyrosine, which is applied in the field of medicine and chemical industry, can solve the problems of high energy consumption per unit product, harsh synthesis conditions of tyrosine, and low product recovery rate, and achieve convenient acquisition, low toxicity, and high purity Effect

Inactive Publication Date: 2016-08-17
四川什邡市三高生化实业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

N-(9-fluorenylmethoxycarbonyl)-O-tert-butyl-L-tyrosine synthesis conditions are harsher, the energy consumption per unit product is high, and the final product recovery rate is low, therefore, it is urgent to need a kind of product cost low, does not need High-purity products containing enantiomers

Method used

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  • A kind of preparation method of n-(9-fluorenylmethoxycarbonyl)-o-tert-butyl-l-tyrosine
  • A kind of preparation method of n-(9-fluorenylmethoxycarbonyl)-o-tert-butyl-l-tyrosine

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Embodiment 1

[0045] Embodiment 1, with reference to synthetic route:

[0046] 1. Add 20g of L-Tyr (tyrosine) and 600g of methanol into the reaction flask, and add SOCl dropwise under stirring 2 (Thionyl chloride) 100g, reflux reaction. When TLC (thin layer chromatography) detects that there is no L-Tyr (tyrosine) in the reaction system, the reaction is complete and Tyr-OMe·HCl (tyrosine hydrochloride) is obtained. The reaction solution after the above reaction was concentrated to dryness with hot water in vacuum at a temperature of 60°C.

[0047] 2. Add 300 g of AcOEt (ethyl acetate) to the solid Tyr-OMe HCl (tyrosine hydrochloride) obtained above, and add Na 2 CO 3 (Sodium carbonate) 100g, add water 50g, slowly add Z-Cl (benzyl chloroformate) 230g dropwise. Control system pH = 8, when TLC (thin layer chromatography) detects that there is no Tyr-OMe HCl (tyrosine hydrochloride) in the reaction system, then add citric acid, acidify to pH = 3, and statically separate to obtain an ester l...

Embodiment 2

[0052] Embodiment 2, with reference to synthetic route:

[0053] 1. Add 20g of L-Tyr (tyrosine) and 600g of methanol into the reaction flask, and add SOCl dropwise under stirring 2 (Thionyl chloride) 100g, reflux reaction. When TLC (thin layer chromatography) detects that there is no L-Tyr (tyrosine) in the reaction system, the reaction is complete and Tyr-OMe·HCl (tyrosine hydrochloride) is obtained. The reaction solution after the above reaction was concentrated to dryness with hot water in vacuum at a temperature of 60°C.

[0054] 2. Add 300 g of AcOEt (ethyl acetate) to the solid Tyr-OMe HCl (tyrosine hydrochloride) obtained above, and add Na 2 CO 3 (Sodium carbonate) 100g, add water 50g, slowly add Z-Cl (benzyl chloroformate) 230g dropwise. Control the pH of the system to 9, and when it is detected by TLC (thin layer chromatography) that there is no Tyr-OMe HCl (tyrosine hydrochloride) in the reaction system, then add citric acid, acidify to pH = 3, and statically sep...

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Abstract

The invention relates to a method for preparing N-(9-fluorenylmethoxy carbony)-O-tertiary butyl-L-tyrosine. The problem that an enantiomer is easily generated is solved. The method comprises the following synthetic steps: (1) dissolving L-Tyr into a methanol solution, adding SOCl2 and then carrying out reflux reaction, so as to obtain Tyr-OMe.HCl; (2) dissolving the Tyr-OMe.HCl into a water solution, adding AcOEt and Na2CO3 and then reacting with Z-Cl, and controlling the pH of the system at 7-10, so as to obtain Z-L-Tyr-OMe; (3) dissolving the Z-L-Tyr-OMe into a CH2Cl2 solution, adding H2SO4 and isobutene, reacting at normal temperature for 1-10 days, so as to obtain Z-L-Tyr(tBu)-OMe; (4) adding the NaOH solution to the Z-L-Tyr(tBu)-OMe to react, so as to obtain Z-L-Tyr(tBu); (5) dissolving the Z-L-Tyr(tBu) into methanol, adding Pd / C, and leading in hydrogen to react, so as to obtain L-Tyr(tBu); (6) dissolving Z-L-Tyr(tBu) into the water solution, adding the Na2CO3 and THF and then reacting with Fmoc-osu, and controlling the pH of the system at 8-10, so as to obtain Fmoc-Tyr(tBu). By adopting the method, generation of the enantiomer is avoided, and the citric acid is taken as an acidifier, so that the product is more stable, and the reaction processes do not relate to high-temperature and high-pressure reaction, and the method is applicable to large-scale production.

Description

technical field [0001] The invention relates to a preparation method of N-(9-fluorenylmethoxycarbonyl)-O-tert-butyl-L-tyrosine, which belongs to the technical field of medicine and chemical industry. Background technique [0002] Due to the presence of one or more asymmetric carbon atoms in drug molecules, enantiomers have different physical, chemical, physiological and biochemical properties. In drugs, chirality may have an important impact on its biological response relationship, such as drug absorption, transport, tissue distribution, interaction with active sites, metabolism and elimination in the body. It is directly related to the pharmacological action of the drug, clinical effect, toxic and side effects, time to exert drug effect and time to act on drug effect. In the prior art, N-(9-fluorenylmethoxycarbonyl)-O-tert-butyl-L-tyrosine is used as a pharmaceutical intermediate, and it is easy to generate N-(9-fluorenylmethoxycarbonyl)-O - Tert-butyl-D-tyrosine, which h...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C271/22C07C269/04
Inventor 李万昌冯旭斌王俊王佰国田明成王明东
Owner 四川什邡市三高生化实业有限公司
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