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Method for synthesizing substituted phenylalanine and substituted phenyllactic acid derivatives by using palladium as catalyst

A technology of phenylalanine and phenyllactic acid, which is applied in the production of bulk chemicals and organic chemistry, can solve the problems of difficult activation, and achieve the effects of high selectivity, mild reaction conditions and strong reaction versatility

Inactive Publication Date: 2013-04-03
ZHEJIANG UNIV
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  • Abstract
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Problems solved by technology

[0005]At present, in the field of transition metal catalyzed carbon-hydrogen bond activation arylation, on the one hand, it is difficult to activate sp3 C-H, on the other hand, it is There is a problem of single and double substitution selectivity in the arylation of methyl groups. Therefore, further development of palladium-catalyzed synthesis methods for the β-position monoaryl groups of alanine and lactic acid compounds is of great significance for the synthesis of natural products and the screening of new drugs.

Method used

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  • Method for synthesizing substituted phenylalanine and substituted phenyllactic acid derivatives by using palladium as catalyst
  • Method for synthesizing substituted phenylalanine and substituted phenyllactic acid derivatives by using palladium as catalyst
  • Method for synthesizing substituted phenylalanine and substituted phenyllactic acid derivatives by using palladium as catalyst

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] In the reactor, add 1 mmol of L-alanine whose nitrogen end is protected with a phthaloyl group and whose carboxyl end is introduced into 8-aminoquinoline, 1.2 mmol of 4-methoxy-3-nitroiodobenzene 2a , 0.1 mmol palladium acetate catalyst, 1.5 mmol silver tetrafluoroborate and 10 ml tert-butanol, at 75 o After C reacted for 24 hours, the reaction was terminated for post-treatment, and the monoarylation product such as structural formula 1 was obtained by silica gel column chromatography or dichloromethane / petroleum ether mixed solvent beating 3a The yield was 79%, and the yield of the bisarylated product of structural formula 2 was 3%. 1 H NMR (400 MHz, CDCl 3 ) δ 10.28 (s, 1 H), 8.78 – 8.66 (m, 1 H), 8.60 (d, J = 2.7 Hz, 1 H), 8.13 (dd, J = 8.3, 1.4 Hz, 1 H), 7.86 (dt, J = 7.1, 3.5 Hz, 2 H), 7.75 (dd, J = 5.5, 3.1 Hz, 2 H), 7.57 – 7.47 (m, 3 H), 7.40 (dd, J = 8.2, 4.3 Hz, 1 H), 6.98 (d, J = 8.7 Hz, 1 H), 5.38 (dd, J = 10.3, 6.2 Hz, 1H), 3.89 (s, 2H), 3...

Embodiment 2～16

[0029] The operation steps are the same as in Example 1, the difference is that by changing the substituent R of the aryl iodide, different β-monoarylalanine derivatives can be obtained (see Table 1).

[0030]

[0031] Table 1: Experimental results of monoarylation of alanine derivatives

[0032] Numbering R 3 Yield b (%) 1 4-OMe-3-NO 2 ( 2a ) 3a 79 2 4-Me ( 2b ) 3b 86 3 3-Me ( 2c ) 3c 87 4 4-OMe ( 2d ) 3d 82 5 3-OMe ( 2e ) 3e 82 6 2-OMe ( 2f ) 3f 71 7 4-Et ( 2g ) 3g 88 8 4-NHAc ( 2h ) 3h 79 9 4-NO 2 ( 2i ) 3i 78 10 4-Ac ( 2j ) 3j 80 11 4-F ( 2k ) 3k 62 12 4-CN ( 2l ) 3l 69 13 3,4-Me 2 ( 2m ) 3m 83 14 2,4-OMe 2 ( 2n ) 3n 85 15 3-F-4-NO 2 ( 2o ) 3o 75 16 3-NO 2 -4-OAc-5-I ( 2p ) 3p 74

[0033] Among them, the resulting product The characterization data of 3b and 3...

Embodiment 17

[0041] In the reactor, add 0.3 mmol of L-lactic acid, 0.45 mmol of 4-acetyl iodobenzene, 0.03 mmol of palladium acetate catalyst and 0.39 mmol of silver oxide and 2 ml of N, N-dimethylformamide solvent at 75 o C. After reacting for 24 hours under a nitrogen atmosphere, the reaction was terminated for post-treatment, and the monoarylation product of structural formula 3 was obtained by silica gel powder column chromatography, with a yield of 62%. 1 H NMR (400 MHz, CDCl 3 ) δ 10.73 (s, 1 H), 8.85 – 8.74 (m, 2 H), 8.14 (dd, J = 8.3, 1.5 Hz, 1 H), 7.86 (d, J = 8.2 Hz, 2 H), 7.58 – 7.50 (m, 2 H), 7.46 – 7.38 (m, 3 H), 4.09 (dd, J = 8.2, 3.6 Hz, 1 H), 3.50 (s, 3 H), 3.34 (dd, J = 14.1, 3.6 Hz, 1 H), 3.14 (dd, J = 14.1, 8.2 Hz, 1 H), 2.53 (s, 3 H).; 13 C NMR (101 MHz, CDCl 3 ) δ 197.96, 170.35, 148.68, 143.39, 138.92, 136.26, 135.68, 133.81, 129.83, 128.49, 128.05, 127.27, 122.22, 121.75, 116.70, 84.00, 77.48, 77.16, 76.84, 59.34, 39.33, 26.65.

[0042] The product...

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Abstract

The invention discloses a method for synthesizing substituted phenylalanine and substituted phenyllactic acid derivatives by using palladium as a catalyst, which comprises the following steps: reacting raw materials nitrogen-terminal or oxygen-terminal completely-protected alanine or lactic acid, to the carboxyl terminal of which 8-aminoquinoline is introduced, and aryl iodide in an organic solvent at 75 DEG C for 3-24 hours, wherein the aryl iodide is used as an arylation reagent, palladium acetate or palladium trifluoracetate is used as a catalyst, and a silver salt is used as an additive; and purifying and separating by column chromatography to obtain the substituted phenylalanine and substituted phenyllactic acid derivatives. The invention has the advantages of mild reaction conditions and simple technique, and is convenient and simple to operate; and the product has high mono / diarylation selectivity.

Description

Technical field [0001] The present invention involves a method of catalytic synthesis replacement of phenylalanine and derivatives replaced benzenal lactic acid derivatives. It belongs to a guided transitional metal catalytic carbon bonding carbon bonding in the field of carbon bonds. Background technique [0002] Replacement of phenylalanine and replacement of phenyl lactate derivatives are some constituent fragments with biological active natural products; more importantly, with the development of biochemical synthesis, separation, and testing technology, many drugs with amino acids or lactic acid fragmentsIn molecular or drug intermediates, if only natural amino acids can not achieve higher biological activity or biomagitar, in the development of amino acids or polypeptide drugs, by replacing natural amino acids with non -natural amino acids or lactic acid fragments to enhance itBiological activity has become a consensus.Some drugs and natural product structures are shown in t...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07D215/40
CPCY02P20/55
Inventor 史炳锋陈凯蒋怀志张硕卿
Owner ZHEJIANG UNIV
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