Method for practical synthesizing optically active 2 - amido - 8 - butenic acid

Abstract

This invention relates to a method for preparing 2-amino-8-nonenoic acid, especially optically active 2-amino-8-nonenoic acid. The method overcomes the problems of long synthesis route, low yield and expensive chiral catalyst or resolution reagent faced by the present method. The method comprises: attacking chiral pyroglutamate containing protecting groups with Grignard reagent of crotyl bromide to obtain chiral 2-amino-5-oxy-8- nonanoate, reducing to remove carbonyl and obtain chiral or racemized 2-amino-8-nonanoate, and hydrolyzing to obtain optically active 2-amino-8-nonenoic acid. The method in this invention has such advantages as simple route, reasonable process, and high yield, and is suitable for mass production.

Description

Technical field:

[0001] The present invention relates to a practical synthesis of optically active 2-amino-8-nonenoic acid with terminal double bonds. Background technique:

[0002] HCV may cause cirrhosis and liver cancer. Currently, about 170 million people around the world are infected with the virus, but there is no relevant preventive vaccine. Treatment is usually a combination of interferon and antiviral drugs, but can cause patients to develop symptoms such as colds, muscle pain and anemia. Due to the rapid spread of hepatitis C disease and the huge unsatisfied demand for hepatitis C treatment in the medical field, the current anti-hepatitis C drugs under research in the research and development lines of major pharmaceutical companies constitute a "dazzling" landscape. Boehringer Ingelheim's research product BILN2061 is the first high-profile product in this regard, and it only needs 2 days of treatment to destroy the virus. However, because the initial experiments...

Examples

Embodiment 1

[0024] Synthesis of (S)-N-tert-butoxycarbonyl-2-amino-8-nonenoic acid

[0025] The first step: the synthesis of (S)-N-tert-butoxycarbonyl-2-amino-5-oxo-8-nonenoic acid ethyl ester

[0026]

[0027] In a 3L three-neck flask equipped with a spherical condenser and a dropping funnel, add magnesium chips (51g, 2.09mol) and a small amount of iodine particles, and heat under a nitrogen stream to drive away the humid air. After 10 minutes, the system is sealed and protected by N2. Then inject anhydrous tetrahydrofuran solution (1.5L) of 1-butyl bromide (177g, 1.31mol) into the dropping funnel, and add 100mL solution at a time, after the reaction is triggered, slowly add it again, keep the reaction temperature at 60- between 70°C. After the dropwise addition, wait for the temperature of the reaction solution to drop to room temperature, and heat it with a hot air blower for half an hour to make the reaction fully. A solution of (S)-N-tert-butoxycarbonyl-pyroglutamic acid ethyl es...

Embodiment 2

[0035] Synthesis of (R)-N-tert-butoxycarbonyl-2-amino-8-nonenoic acid

[0036] The first step: the synthesis of (R)-N-tert-butoxycarbonyl-2-amino-5-oxo-8-nonenoic acid ethyl ester

[0037]

[0038] In a 3L three-neck flask equipped with a spherical condenser and a dropping funnel, add magnesium chips (3.6g, 0.15mol) and a small amount of iodine particles, heat under a nitrogen stream to drive off the humid air, and after 10 minutes, seal the system and protect it with nitrogen. , then inject anhydrous tetrahydrofuran solution (150mL) of 1-butyl bromide (13.5g, 1.00mol) into the dropping funnel, and add 100mL solution at a time, after the reaction triggers, slowly add it again, keeping the reaction temperature at 60 Between -70°C. After the dropwise addition, wait for the temperature of the reaction solution to drop to room temperature, and heat it with a hot air blower for half an hour to make the reaction fully. A solution of (R)-N-tert-butoxycarbonyl-pyroglutamic acid eth...

Embodiment 3

[0043] Synthesis of (S)-N-tert-butoxycarbonyl-2-amino-8-nonenoic acid ethyl ester

[0044]

[0045] Add p-toluenesulfonylhydrazide (20.5g, 0.11mol) to (S)-N-tert-butoxycarbonyl-2-amino-5-oxo-8-nonenoic acid ethyl ester (31.3g, 0.10mol) in acetic acid ( 400 mL) solution, stirred at room temperature for one hour, then added sodium borohydride (19 g, 0.50 mol) in batches, and continued to stir for 12-24 hours after the addition was complete. After the reaction was detected by TLC, it was quenched by adding water and extracted with ethyl acetate. The organic phases were combined, washed successively with saturated aqueous sodium bicarbonate solution and saturated saline solution, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography to obtain (S)-N-tert-butoxycarbonyl-2-amino-8-nonene Acetate ethyl ester (16.8 g, 56% yield). MS(E / Z): 300(M+H + ).

Technical field:

[0001] The present invention relates to a practical synthesis of optically active 2-amino-8-nonenoic acid with terminal double bonds. Background technique:

[0002] HCV may cause cirrhosis and liver cancer. Currently, about 170 million people around the world are infected with the virus, but there is no relevant preventive vaccine. Treatment is usually a combination of interferon and antiviral drugs, but can cause patients to develop symptoms such as colds, muscle pain and anemia. Due to the rapid spread of hepatitis C disease and the huge unsatisfied demand for hepatitis C treatment in the medical field, the current anti-hepatitis C drugs under research in the research and development lines of major pharmaceutical companies constitute a "dazzling" landscape. Boehringer Ingelheim's research product BILN2061 is the first high-profile product in this regard, and it only needs 2 days of treatment to destroy the virus. However, because the initial experiments...

Examples

Embodiment 1

[0024] Synthesis of (S)-N-tert-butoxycarbonyl-2-amino-8-nonenoic acid

[0025] The first step: the synthesis of (S)-N-tert-butoxycarbonyl-2-amino-5-oxo-8-nonenoic acid ethyl ester

[0026]

[0027] In a 3L three-neck flask equipped with a spherical condenser and a dropping funnel, add magnesium chips (51g, 2.09mol) and a small amount of iodine particles, and heat under a nitrogen stream to drive away the humid air. After 10 minutes, the system is sealed and protected by N2. Then inject anhydrous tetrahydrofuran solution (1.5L) of 1-butyl bromide (177g, 1.31mol) into the dropping funnel, and add 100mL solution at a time, after the reaction is triggered, slowly add it again, keep the reaction temperature at 60- between 70°C. After the dropwise addition, wait for the temperature of the reaction solution to drop to room temperature, and heat it with a hot air blower for half an hour to make the reaction fully. A solution of (S)-N-tert-butoxycarbonyl-pyroglutamic acid ethyl es...

Embodiment 2

[0035] Synthesis of (R)-N-tert-butoxycarbonyl-2-amino-8-nonenoic acid

[0036] The first step: the synthesis of (R)-N-tert-butoxycarbonyl-2-amino-5-oxo-8-nonenoic acid ethyl ester

[0037]

[0038] In a 3L three-neck flask equipped with a spherical condenser and a dropping funnel, add magnesium chips (3.6g, 0.15mol) and a small amount of iodine particles, heat under a nitrogen stream to drive off the humid air, and after 10 minutes, seal the system and protect it with nitrogen. , then inject anhydrous tetrahydrofuran solution (150mL) of 1-butyl bromide (13.5g, 1.00mol) into the dropping funnel, and add 100mL solution at a time, after the reaction triggers, slowly add it again, keeping the reaction temperature at 60 Between -70°C. After the dropwise addition, wait for the temperature of the reaction solution to drop to room temperature, and heat it with a hot air blower for half an hour to make the reaction fully. A solution of (R)-N-tert-butoxycarbonyl-pyroglutamic acid eth...

Embodiment 3

[0043] Synthesis of (S)-N-tert-butoxycarbonyl-2-amino-8-nonenoic acid ethyl ester

[0044]

[0045] Add p-toluenesulfonylhydrazide (20.5g, 0.11mol) to (S)-N-tert-butoxycarbonyl-2-amino-5-oxo-8-nonenoic acid ethyl ester (31.3g, 0.10mol) in acetic acid ( 400 mL) solution, stirred at room temperature for one hour, then added sodium borohydride (19 g, 0.50 mol) in batches, and continued to stir for 12-24 hours after the addition was complete. After the reaction was detected by TLC, it was quenched by adding water and extracted with ethyl acetate. The organic phases were combined, washed successively with saturated aqueous sodium bicarbonate solution and saturated saline solution, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography to obtain (S)-N-tert-butoxycarbonyl-2-amino-8-nonene Acetate ethyl ester (16.8 g, 56% yield). MS(E / Z): 300(M+H + ).

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