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Method for synthesizing carbobenzoxyserine-beta-lactone

A technology for synthesizing benzyloxycarbonylserine and benzyloxycarbonylserine, which is applied in the field of synthesis of chiral unnatural amino acids, can solve the problems of a large number of synthesis limitations, difficult product separation, difficult scale-up production, etc., and achieve low process reaction temperature requirements, The effect of high product purity and simple post-processing

Active Publication Date: 2012-08-15
上海予利生物科技股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] However, because benzyloxycarbonyl-L-serine-β-lactone and benzyloxycarbonyl-D-serine-β-lactone are very difficult to prepare, the traditional process is that benzyloxycarbonyl-D / L-serine passes three times at -78°C. Phenylphosphine is obtained by the reaction of diethyl azodicarboxylate. Since the reaction temperature requires -78°C, the large-scale synthesis is relatively limited, and it is difficult to scale up production. In addition, there are a large amount of triphenylphosphine and by-products in the reactant Triphenylphosphine oxide makes it difficult to separate products, so benzyloxycarbonyl-D / L-serine-β-lactone is expensive, and it is difficult to use it as a starting material for the synthesis of other chiral amino acids

Method used

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  • Method for synthesizing carbobenzoxyserine-beta-lactone
  • Method for synthesizing carbobenzoxyserine-beta-lactone

Examples

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Embodiment 1

[0018] A synthetic method for benzyloxycarbonylserine-β-lactone, which uses benzyloxycarbonyl-3-amino-alanine as raw material, reacts with sodium nitrite and citric acid aqueous solution to obtain benzyloxycarbonylserine-β-lactone ester. The reaction formula is as follows:

[0019]

[0020] The synthetic method of benzyloxycarbonyl-L-serine-β-lactone comprises the following steps:

[0021] Dissolve 11.9 grams of benzyloxycarbonyl-L-3-aminoalanine and 40 grams of citric acid in 300 milliliters of water, then cool to 0-5 ° C, add dropwise 60 milliliters of aqueous solution containing 3.45 grams of NaNO2, and keep the temperature at 0-5 5°C, add dropwise for about half an hour, then continue to react at 5°C for 2 hours, add ethyl acetate to extract, wash with 5wt% sodium bicarbonate, wash with water, dry, concentrate and crystallize to obtain 4.1 g of the product.

[0022] Melting point: 133-134°C [α] 20D: -25.5° (C=1, acetonitrile)

[0023] 'H NMR (300MHz, CDC13) 7.50-7.10...

Embodiment 2

[0025] A method for synthesizing benzyloxycarbonyl-L-serine-β-lactone, the method comprising the following steps:

[0026] Dissolve 11.9 grams of benzyloxycarbonyl-L-3-aminoalanine and 50 grams of citric acid in 300 milliliters of water, then cool to 0-5 ° C, add dropwise 120 milliliters of aqueous solution containing 17.25 grams of NaNO2, and keep the temperature at 0- Add dropwise at 5°C for about 2 hours, then continue to react at 15-25°C for 10 hours, add ethyl acetate for extraction, wash with 5wt% sodium bicarbonate, wash with water, dry, concentrate and crystallize to obtain 5.8 grams of the product.

[0027] Melting point: 133-135°C [α] 20D: -25.0° (C=1, acetonitrile)

[0028] 'H NMR (300MHz, CDC13) 7.50-7.10 (m, 5H), 5.40-5.12 (m, 2H), 5.00-4.82 (m, 1H), 4.45-4.08 (m, 2H)

Embodiment 3

[0030] A method for synthesizing benzyloxycarbonyl-D-serine-β-lactone, the method comprising the following steps:

[0031] Dissolve 11.9 grams of benzyloxycarbonyl-D-3-aminoalanine and 40 grams of citric acid in 300 milliliters of water, then cool to 0-5 ° C, add dropwise 80 milliliters of aqueous solution containing 6.9 grams of NaNO2, and keep the temperature at 5- Add dropwise at 10°C for about 1 hour, then continue to react at 25°C for 6 hours, add ethyl acetate to dissolve the solid, wash with 5wt% sodium bicarbonate, wash with water, dry, concentrate and crystallize to obtain 4.7 g of the product.

[0032] Melting point: 132-134°C [α] 20D: +25.3° (C=1, acetonitrile)

[0033] 'H NMR (300MHz, CDC13) 7.50-7.10 (m, 5H), 5.40-5.12 (m, 2H), 5.00-4.82 (m, 1H), 4.45-4.08 (m, 2H)

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Abstract

The invention relates to a method for synthesizing carbobenzoxyserine-beta-lactone. Carbobenzoxy-L-3-amino-alanine or carbobenzoxy-D-3-amino-alanine, which is used as a raw material, reacts with sodium nitrate and citric acid water solution to obtain the carbobenzoxy-L-serine-beta-lactone or carbobenzoxy-D-serine-beta-lactone. Compared with the method for synthesizing carbobenzoxy-D / L-serine from triphenylphosphine and diethyl azodiformate at -78 DEG C in the prior art, the technique provided by the invention has the advantages of low reaction temperature requirement and simple after-treatment, and is suitable for industrialized large-scale production.

Description

technical field [0001] The invention relates to a method for synthesizing chiral unnatural amino acids, in particular to a method for synthesizing benzyloxycarbonylserine-β-lactone. Background technique [0002] Benzyloxycarbonyl-D / L-serine-β-lactone is a very important starting material for the synthesis of chiral unnatural amino acids and special amino acids. Serine-β-lactone can be combined with carbon, nitrogen, sulfur, oxygen, halogen Groups such as ring-opening form new Alpha-amino acids [Organic Syntheses, Coll.Vol.9, p.24 (1998); Vol.70, p.10 (1992)], and can also be catalyzed by CuBr.SMe2 with Various Grignard reagents react to form special amino acids with extended carbon chains (J. Am. Chem. Soc. 1987, 109, 4649-4659). [0003] [0004] However, because benzyloxycarbonyl-L-serine-β-lactone and benzyloxycarbonyl-D-serine-β-lactone are very difficult to prepare, the traditional process is that benzyloxycarbonyl-D / L-serine passes three times at -78°C. Phenylphos...

Claims

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Application Information

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IPC IPC(8): C07D305/12
Inventor 俞建新顾建良
Owner 上海予利生物科技股份有限公司
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