CN115894366A - Rhodium catalyzed hydrocarbon activation for preparation of novel amino acid - Google Patents
Rhodium catalyzed hydrocarbon activation for preparation of novel amino acid Download PDFInfo
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Abstract
The invention discloses a method for preparing novel amino acid by rhodium-catalyzed hydrocarbon activation, belonging to the technical field of organic synthesis. The method comprises the following steps: to the reactor, lysine derivatives, disubstituted alkynes, pentamethylcyclopentadienylrhodium catalyst, cesium acetate and anhydrous copper acetate were added. Stirring in a solvent, removing the solvent by using a rotary evaporator after the reaction is finished to obtain a crude product, and separating the crude product by silica gel column chromatography to obtain the target compound. The synthesis method of the novel amino acid provided by the invention has the characteristics of scientificity, reasonableness, simplicity in operation, high yield of the target compound, easiness in product purification, fluorescence activity and the like. The reaction equation is as follows:
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing novel amino acid by rhodium-catalyzed hydrocarbon activation.
Background
Polypeptide drugs have the advantage of binding specifically to targets over small molecule drugs, based on which polypeptide therapy has received a great deal of attention from pharmaceutical enterprises and research institutions, and over the past decade more and more polypeptide drugs have been approved for clinical trials. Polypeptides derived from unnatural amino acids have better biological and pharmaceutical activity than polypeptides derived from natural amino acids. It is therefore of great importance to develop methods for the preparation of unnatural amino acids by selective modification of natural amino acids to fine-tune the structure in order to alter their physicochemical and biological properties. Although traditional amino acid modification methods have made great progress, they often rely on pre-functionalized substrates, requiring lengthy synthetic steps. The development of a method with high atom and step economy not only can make the selective modification of amino acid more direct and efficient, but also can increase the complexity and diversity of the amino acid, and can be used for the development of new drugs.
Disclosure of Invention
The purpose of the invention is as follows: in order to overcome the defects of the prior art, the invention provides a method for preparing novel amino acid by rhodium catalytic hydrocarbon activation as a supplement to the existing unnatural amino acid synthesis method.
The technical scheme is as follows: in order to achieve the purpose, the invention adopts the technical scheme that:
rhodium catalyzed hydrocarbon activation is used in the preparation of novel amino acids having the structure shown in formula I:
the R substituent is selected from phenyl, p-methylphenyl, p-methoxyphenyl, p-trifluoromethylphenyl and n-propyl; the method is characterized in that lysine derivatives, disubstituted alkyne, pentamethylcyclopentadienylrhodium catalyst, cesium acetate and anhydrous copper acetate are added into a reactor. Stirring in a solvent, removing the solvent by using a rotary evaporator after the reaction is finished to obtain a crude product, and separating the crude product by silica gel column chromatography to obtain the target compound. The chemical process is shown in a reaction formula II:
the mol ratio of the lysine derivative, the disubstituted alkyne, the pentamethyl cyclopentadienyl rhodium catalyst, the cesium acetate and the anhydrous copper acetate is 1: 1.1: 0.05: 2. The solvent is 2-methyl-2-butanol, the reaction temperature is 120 ℃, and the reaction time is 24 hours.
The invention has the beneficial effects that: the novel amino acid provided by the invention is scientific and reasonable in synthesis method, provides a novel way for synthesizing novel amino acid, obtains novel amino acid with various substituent groups through the method, and is characterized by simple synthesis method, high yield of target product, easy purification of product and fluorescence activity.
Drawings
FIG. 1 is a chemical reaction scheme for the preparation of novel amino acids;
FIG. 2 is an NMR spectrum of Compound 3a prepared in example 1;
FIG. 3 is an NMR spectrum of Compound 3b prepared in example 2;
FIG. 4 is an NMR spectrum of compound 3c prepared in example 3;
FIG. 5 is a graph showing the result of emission spectrum of Compound 3 c.
Detailed Description
The invention is described in further detail below with reference to the figures and specific examples.
The test methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.
Example 1
To a 10mL pressure resistant tube were added lysine derivative 1a (0.1mmol, 36.4 mg), diphenylacetylene 2a (0.11mmol, 19.6 mg), pentamethylcyclopentadienylrhodium catalyst (0.005mmol, 3.1mg), cesium acetate (0.2mmol, 38.4mg), anhydrous copper acetate (0.2mmol, 36.3mg) and 2-methyl-2-butanol (1 mL), and the mixture was stirred at 120 ℃ for 24 hours. After the reaction was completed, the solvent was removed by using a rotary evaporator to obtain a crude product, and the crude product was separated by silica gel column chromatography (200-300 mesh silica gel) (petroleum ether/ethyl acetate = 2/1), and the solvent was removed by using a rotary evaporator to obtain the objective product 3a with a yield of 71%.
1 H NMR(400MHz，CDCl 3 )δ8.57(d，J＝8.1Hz，1H)，7.58-7.48(m，2H)，7.26-7.20(m，4H)，7.19-7.13(m，5H)，7.07(t，J＝6.5Hz，2H)，5.15(d，J＝8.2Hz，1H)，4.17(q，J＝7.2，6.4Hz，1H)，3.97-3.82(m，2H)，3.71(s，3H)，1.65-1.60(m，2H)，1.45(s，9H)，1.32-1.26(m，2H)，1.24-1.15(m，2H). 13 C NMR(101MHz，CDCl 3 )δ173.2，162.3，155.4，141.0，137.2，136.5，134.6，132.1，131.5，130.3，130.2，128.3，128.0，127.9，127.9，127.9，126.8，126.7，125.4，125.1，119.3，79.8，53.4，52.2，45.5，31.8，28.4，28.3，22.6.
Example 2
The experiment results are shown in Table 1, except that 2b is used instead of 2a in example 1 and the conditions are the same as in example 1.
1 H NMR(400MHz，CDCl 3 )δ8.55(d，J＝7.7Hz，1H)，7.56-7.45(m，2H)，7.14(d，J＝7.8Hz，1H)，7.02(d，J＝16.7Hz，6H)，6.94(t，J＝6.5Hz，2H)，5.14(d，J＝8.2Hz，1H)，4.17(q，J＝7.2Hz，1H)，3.86(hept，J＝6.8Hz，2H)，3.71(d，J＝1.6Hz，3H)，2.34-2.26(m，6H)，1.60(t，J＝7.5Hz，2H)，1.48-1.42(m，9H)，1.37-1.28(m，2H)，1.20(q，J＝7.8Hz，2H). 13 C NMR(101MHz，CDCl 3 )δ173.2，162.3，155.4，141.0，137.9，137.4，136.1，133.5，131.9，131.7，131.2，130.0，130.0，128.6，128.6，128.6，127.8，126.4，125.4，125.0，119.2，79.7，53.4，52.1，45.4，31.8，28.4，28.3，22.6，21.3，21.2.
Example 3
The same conditions as in example 1 were used except that 2c was used instead of 2a in example 1, and the results of the experiment are shown in Table 1. A certain amount of compound 3c was dissolved in methylene chloride to prepare a 2X 10-4 concentration solution, and the emission spectrum was measured and shown in FIG. 5, indicating that the maximum emission wavelength of compound 3c was 443nm.
1 H NMR(400MHz，CDCl 3 )δ8.56(d，J＝7.9Hz，1H)，7.52(dt，J＝19.4，7.3Hz，2H)，7.16(d，J＝7.9Hz，1H)，7.06(d，J＝8.2Hz，2H)，6.97(dd，J＝8.1，4.7Hz，2H)，6.77(t，J＝8.7Hz，4H)，5.15(d，J＝8.2Hz，1H)，4.17(q，J＝7.1Hz，1H)，3.89(q，J＝7.9，7.4Hz，2H)，3.79(s，3H)，3.78(s，3H)，3.71(s，3H)，1.60(t，J＝7.4Hz，2H)，1.45(s，9H)，1.38-1.29(m，2H)，1.20(q，J＝7.6Hz，2H). 13 C NMR(101MHz，CDCl 3 )δ173.3，162.4，159.1，158.1，155.4，141.0，137.6，132.5，132.0，131.5，131.4，128.9，127.8，127.1，126.5，125.4，125.1，119.2，113.4，79.8，55.1，55.1，53.4，52.2，45.4，31.9，28.4，28.3，22.7.
Example 4
The same conditions as in example 1 were used except that 2d was used instead of 2a in example 1, and the results of the experiment are shown in Table 1.
Spectrogram analysis data 3d
1 H NMR(400MHz，CDCl 3 )δ7.78(d，J＝7.6Hz，1H)，7.57(q，J＝7.8，6.1Hz，2H)，7.50(d，J＝7.3Hz，1H)，7.44(q，J＝7.4，6.7Hz，2H)，7.38(d，J＝7.7Hz，1H)，7.31(s，1H)，7.24(d，J＝7.5Hz，1H)，7.16(t，J＝9.8Hz，1H)，6.95-6.73(m，1H)，[6.30(s)，5.77(s)，1H]，5.12(dd，J＝23.1，8.3Hz，1H)，4.30(s，1H)，3.75(d，J＝3.7Hz，3H)，3.47(q，J＝6.7Hz，1H)，1.67(dq，J＝14.0，7.5Hz，2H)，1.42(d，J＝11.2Hz，13H).Mixture of rotamer(1.6∶1). 13 C NMR(101MHz，CDCl 3 )δ173.3，173.1，169.9，167.7，155.6，142.9，142.9，142.7，142.3，139.3，138.2，137.7，137.0，136.5，134.7，133.2，131.4，131.2，131.0，129.1，128.5，128.3，126.9，126.0，125.0，124.2，124.0，53.2，52.9，52.4，52.3，39.6，39.4，32.7，32.5，29.7，29.1，28.3，28.3，22.6，22.6.Mixture of rotamer.
Example 5
The same conditions as in example 1 were used except that 2e was used instead of 2a in example 1, and the results of the experiment are shown in Table 1.
Spectrogram analysis data 3e
1 H NMR(400MHz，CDCl 3 )δ8.47(d，J＝8.0Hz，1H)，7.65(d，J＝4.0Hz，2H)，7.47-7.39(m，1H)，5.30(d，J＝8.2Hz，1H)，4.30(q，J＝6.9Hz，1H)，4.12(t，J＝7.6Hz，2H)，3.75(d，J＝1.8Hz，3H)，2.70(q，J＝8.8Hz，4H)，1.97-1.73(m，4H)，1.63(q，J＝8.0Hz，4H)，1.46(d，J＝1.8Hz，11H)，1.13-1.06(m，6H). 13 C NMR(101MHz，CDCl 3 )δ173.2，162.5，155.5，139.3，136.6，132.0，128.3，125.6，124.9，122.6，114.2，79.8，53.4，52.2，43.6，32.2，31.4，29.9，28.9，28.3，23.6，23.4，22.8，14.5，14.3.
TABLE 1
Claims (3)
1. Rhodium catalyzed hydrocarbon activation is used in the preparation of novel amino acids having the structure shown in formula I:
the R substituent is selected from phenyl, p-methylphenyl, p-methoxyphenyl, p-trifluoromethylphenyl and n-propyl; the method is characterized in that lysine derivatives, disubstituted alkyne, pentamethylcyclopentadienylrhodium catalyst, cesium acetate and anhydrous copper acetate are added into a reactor. Stirring in a solvent, removing the solvent by using a rotary evaporator after the reaction is finished to obtain a crude product, and separating the crude product by silica gel column chromatography to obtain the target compound. The chemical process is shown in a reaction formula II:
2. the method according to claim 1, wherein the lysine derivative, the disubstituted alkyne, the pentamethylcyclopentadienylrhodium catalyst, the cesium acetate and the anhydrous copper acetate are present in a molar ratio of 1: 1.1: 0.05: 2.
3. The production method according to claim 1, characterized in that: the solvent is 2-methyl-2-butanol, the reaction temperature is 120 ℃, and the reaction time is 24 hours.
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