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Synthesis method of substituted aspartic acid

A technology of aspartic acid and synthesis method, applied in the direction of organic chemistry, etc., to achieve the effects of easy post-processing, simple operating conditions and high ee value

Inactive Publication Date: 2016-07-06
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The source of carbonyl used in these methods is carbon monoxide, which itself is a highly toxic gas, which has high requirements for storage, safety, and convenience; secondly, there is no report on the direct esterification of methyl
On the other hand, the more inert methylene esterification is more challenging than the methyl esterification

Method used

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  • Synthesis method of substituted aspartic acid
  • Synthesis method of substituted aspartic acid
  • Synthesis method of substituted aspartic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] In the reactor, add 0.15 mmoles of L-phenylalanine whose nitrogen end is protected with phthaloyl group and carboxy end with 8-aminoquinoline, 0.45 mmoles of ethyl chloroformate 2a, 0.015 mmoles of palladium acetate catalyst , 0.3 mmol of silver carbonate, 0.15 mmol of elemental iodine and 2 milliliters of toluene, reacted in an air atmosphere at 120° C. for 16 hours and then finished the reaction for post-treatment. The product 3a with a structure such as formula 1 was obtained by silica gel column chromatography, and the yield was 76% with an ee of 97%.

[0031] The structure of product 3a is as follows:

[0032]

[0033] The structural characterization data are as follows:

[0034] 1 HNMR (400MHz, CDCl 3 )δ8.69(dd, J=4.1,1.6Hz,1H),8.28(dd,J=7.2,1.3Hz,1H),7.96(dd,J=8.3,1.6Hz,1H),7.83(dd,J =5.5,3.0Hz,2H),7.70(dd,J=5.4,3.1Hz,2H),7.54(dd,J=8.1,1.4Hz,1H),7.52–7.46(m,1H),7.42(d, J=7.2Hz, 2H), 7.25–7.12(m, 4H), 6.58(d, J=2.7Hz, 1H), 5.45(d, J=2.7Hz, 1H). 13 CNMR (1...

Embodiment 2~16

[0045] The operation steps are the same as in Example 1, the difference is that different aspartic acid derivatives can be obtained by changing the substituent on the aromatic ring of the raw material (see Table 3).

[0046] The structural formula of the raw material is as follows:

[0047]

[0048] The experimental results of the synthetic aspartic acid derivatives of table 3 embodiment 2~16

[0049]

Embodiment 17

[0051] In the reactor, add 0.15 mmoles of substituted L-phenylalanine 1q, 0.45 mmoles of ethyl chloroformate 2a whose nitrogen end is protected with phthaloyl group and carboxyl end with 8-aminoquinoline , 0.015 millimole palladium acetate catalyst, 0.3 millimole silver carbonate, 0.15 millimole elemental iodine and 2 milliliters of toluene, after reacting in 120 ℃ of air atmospheres for 16 hours, finish reaction and carry out aftertreatment, obtain as structure formula 2 by silica gel column chromatography The yield of product 3q was 73%. 1 HNMR (400MHz, CDCl 3 ):δ10.15(s,1H),8.68(dd,J=6.7,2.2Hz,1H),8.51(d,J=3.1Hz,1H),8.05(d,J=8.2Hz,1H),7.75 (dd,J=5.4,3.1Hz,2H),7.65(dd,J=5.4,3.1Hz,2H),7.50–7.43(m,2H),7.31(dd,J=8.2,4.2Hz,1H), 6.87(d, J=2.0Hz, 1H), 6.79(dd, J=8.4, 2.1Hz, 1H), 6.64(d, J=8.3Hz, 1H), 5.94(d, J=11.5Hz, 1H), 4.92(d, J=11.5Hz, 1H), 4.28(dq, J=10.7, 7.1Hz, 1H), 4.21–4.02(m, 5H), 1.24(t, J=7.1Hz, 3H); 13 CNMR (101MHz, CDCl 3 )δ 172.1, 167.5, 166.0, 148.4, 143.5, 1...

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Abstract

The invention discloses an efficient synthesis method of substituted aspartic acid.The efficient synthesis method includes: using amino acid of nitrogen terminal all-protected and carboxyl terminal introduced 8-aminoquinoline as a raw material; adopting chloroformate as an ester group source, palladium acetate as a catalyst and silver salt and iodine element as additives; in an organic solvent, reacting for 16 h at 120 DEG C or 140 DEG C, and obtaining a substituted aspartic acid derivative through column chromatography purifying separation.The synthesis method is mild in reaction condition, simple in process and convenient and quick to operate, and ester groups can be well introduced into an amino acid substrate directly to obtain the aspartic acid derivative high in stereoselectivity.

Description

technical field [0001] The invention relates to a high-efficiency synthesis method for synthesizing substituted aspartic acid, which belongs to the field of carbon-hydrogen bond-activated carbon-carbon bond coupling catalyzed by oriented transition metals. Background technique [0002] Unnatural amino acids, as constituent fragments of biologically active natural products, have been widely used in chiral modules and drug synthesis; with the development of biochemical synthesis, separation and testing technologies, many drug molecules or drug intermediates with amino acid fragments Therefore, in the research and development of amino acid or peptide drugs, it has become a consensus to replace natural amino acids with unnatural amino acids to enhance their biological activity. . Among them, aspartic acid can be used in medicine to treat heart disease, and can also be used as a liver function enhancer, ammonia antidote, fatigue reliever, and amino acid infusion components. The...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D405/14
CPCC07D401/12C07D405/14
Inventor 史炳锋廖港阴雪松
Owner ZHEJIANG UNIV
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