CN114874227A - Catalyst for amide synthesis and preparation and application thereof - Google Patents

Catalyst for amide synthesis and preparation and application thereof Download PDF

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CN114874227A
CN114874227A CN202210800829.4A CN202210800829A CN114874227A CN 114874227 A CN114874227 A CN 114874227A CN 202210800829 A CN202210800829 A CN 202210800829A CN 114874227 A CN114874227 A CN 114874227A
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catalyst
compound
reaction
amide
mmol
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CN114874227B (en
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王锐
孙旺盛
李一平
李景月
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Institute of Materia Medica of CAMS
Lanzhou University
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Abstract

The invention discloses a catalyst for amide synthesis and preparation and application thereof, wherein the catalyst is a thio-or seleno-pyrano-bipyrimidine compound, and has the advantages of simple and novel structure, high catalytic efficiency and good atom economy; the catalyst can be used for synthesizing amide compounds, and specifically comprises the following components: adding an organic solvent into a carboxylic acid component, an amine component, a catalyst and triphenylphosphine or diphenylphosphine oxide, stirring under illumination or room temperature or heating condition until the triphenylphosphine or diphenylphosphine oxide is completely consumed, and separating and purifying to obtain the amide compound. The amide compound synthesis method is simple and easy to purify, the catalytic reaction does not need additional operations such as water removal or inert gas protection, the carboxylic acid can be directly catalyzed and converted into corresponding amide under the conditions of normal temperature, heating, illumination and the like, the reaction time under the illumination condition is short, the yield is high, the byproduct is single, the N, O selectivity is good, the amide compound can be directly used for solid-phase synthesis of amide or polypeptide, and the method has wide industrial application prospect.

Description

Catalyst for amide synthesis and preparation and application thereof
Technical Field
The invention belongs to the technical field of organic synthesis and biochemistry, and particularly relates to a catalyst for amide synthesis and a preparation method of the catalyst.
Background
Amide is a very important functional group, which is widely present in various natural products, materials and drugs, and is the core structure of polypeptides and proteins. For example, in the field of materials, polyamides and polyimides are one of the most important chemical products in modern society, and in the field of pharmaceuticals, 1/4 is marketed as a drug and 2/3 is a drug candidate containing an amide structure (org. biomol. chem., 2006, 4, 2337-. The wide existence determines its enormous demand and the synthesis of amides continues to be an important area of methodology. In the 2018 ACS Green chemistry round-table conference, the 'synthesis of amide by avoiding using an atom poor economical reagent' which is one of ten major key challenges is referred to as a 'catalytic or sustainable direct amide synthesis method', from which it can be seen that the greening research of amide synthesis has been the key direction of attention for many years, and the synthesis of amide by a catalytic method gradually becomes the key point of future research as the research in the field goes deep (Green chem., 2018, 20, 5082-containing 5103; Green chem., 2007, 9, 411-containing 420).
The direct catalysis of the amidation reaction of carboxylic acids with amines is indeed an ancient field of research, but the research in this field has progressed very slowly over a long period of time, with some breakthrough progress not being achieved until the last 20 years, with catalytic models becoming more diverse, and with catalytic conditions tending to be milder (chem. rev., 2016, 116, 12029-12122). These studies have undoubtedly widened the research and development thought in this field, but we should clearly recognize that catalytic amidation is still a relatively late research direction, the existing various catalytic modes are not ideal from reaction conditions, application range to reaction effect, and there is a great gap from industrial application (Nat cat., 2019, 2, 10-17; Nat cat., 2019, 2, 98-102), and therefore it is necessary to develop a milder and more efficient catalytic reaction mode with practical orientation.
Disclosure of Invention
Based on the above, the present invention aims to provide a catalyst for amide synthesis, which has a novel structure, mild and efficient reaction conditions, a wide application range, and an excellent reaction effect.
It is another object of the present invention to provide a method for preparing the above catalyst for amide synthesis.
It is a further object of the present invention to provide the use of the above catalyst for the preparation of amide compounds.
In order to realize the purpose, the invention adopts the following technical scheme:
the catalyst for amide synthesis provided by the invention is a thio catalyst or a seleno catalyst, and the main structure of the catalyst is 4, 6-dimercapto or diseleno-mercapto-5R 1 -5H-pyrano [2,3-d:6,5-d']The general structural formula of the bipyrimidine catalyst is as follows:
Figure 544277DEST_PATH_IMAGE001
wherein R is 1 Is hydrogen, C1-C6 alkyl, phenyl or substituted phenyl; r 2 And is SH or SeH; the preparation method specifically comprises the following steps:
step one, heating the aqueous solution mixed with aldehyde, 4, 6-dihydroxypyrimidine and benzyltriethylammonium chloride at 90-130 ℃ for 8-12h, then cooling to room temperature, filtering and collecting powdery precipitate, washing with water and drying to obtain 5, 5' - (R) 1 Methylene) bis-4, 6-dihydroxypyrimidine compounds are marked as compound 1; the molar ratio of the aldehyde to the 4, 6-dihydroxypyrimidine to the benzyltriethylammonium chloride is 5:10: 1;
secondly, adding phosphorus oxychloride into a round-bottom flask containing the compound 1, carrying out reaction reflux for 2-12 h, cooling to room temperature, carrying out rotary evaporation to remove unreacted phosphorus oxychloride, dropwise adding the reaction system into ice water under a stirring state, separating out a white solid, collecting the solid, washing with water, and drying to obtain pure 4, 6-dichloro-5-R 1 -5H-pyrano [2,3-d:6,5-d']The bipyrimidine compound is marked as a compound 2; the molar ratio of the compound 1 to the phosphorus oxychloride is 1: 12-20; the reaction equation is as follows:
Figure 694635DEST_PATH_IMAGE002
step three, synthesis of a thio catalyst: will combine withAdding the substance 2 and thiourea into 0.1-0.5mol/L ethanol, heating and refluxing at 90-130 ℃ until the compound 2 is completely consumed, then cooling the reaction system to room temperature, collecting the solid, dissolving the solid with 2M sodium hydroxide solution, adjusting the acidity with 1M dilute hydrochloric acid solution until the solid is not separated out, filtering, washing with water and drying to obtain 4, 6-dimercapto-5-R 1 -5H-pyrano [2,3-d:6,5-d']A bipyrimidine catalyst, denoted as catalyst 3; the molar ratio of the compound 2 to the thiourea is 1: 4-10;
Figure 961669DEST_PATH_IMAGE003
synthesis of a seleno catalyst: adding the compound 2 (1 eq.) and 3-10 eq of selenourea into 0.1-0.5mol/L ethanol, heating and refluxing at 90-130 ℃ until the compound 2 is completely consumed, then cooling the reaction system to room temperature, concentrating, filtering, washing with water and drying to obtain the 4, 6-diseleno mercapto-5-R 1 -5H-pyrano [2,3-d:6,5-d']A bipyrimidine catalyst, denoted as catalyst 4; the molar ratio of the compound 2 to the selenourea is 1: 2-5.
Figure 160569DEST_PATH_IMAGE004
The catalyst provided by the invention can be used for preparing amide compounds, and the specific operation is as follows:
weighing a carboxylic acid component 5, an amine component 6, the catalyst and triphenylphosphine or diphenylphosphine oxide, placing the mixture in a reaction vessel, adding an organic solvent, stirring the mixture under illumination or room temperature or heating condition until the triphenylphosphine or diphenylphosphine oxide is completely consumed, and then separating and purifying to obtain an amide compound 7, wherein the reaction formula is as follows:
Figure 563868DEST_PATH_IMAGE005
in the above reaction scheme, the carboxylic acid component 5 is R 3 Carboxylic acids or N-protected amino acids optionally selected from C1-C20 alkyl, aryl, N heteroaryl(ii) a The amine component 6 being R 4 And R 5 An amine or carboxy-protected amino acid optionally selected from hydrogen, C1-C20 alkyl, aryl, N heteroalkyl; in the reaction formula, the amine component 6 can also be a mixture of amino acid ester hydrochloride and equal amount of DIPEA; the amine component 6 may also be a deprotected amino resin.
The term "amino acid" as used herein refers to a common amino acid used in polypeptide synthesis, and not to all organic compounds having a basic amino group and an acidic carboxyl group.
Preferably, the carboxylic acid component 5 is R 3 Carboxylic acids optionally selected from C1-C6 alkyl, aryl, N heteroaryl; the amine component 6 being R 4 And R 5 An amine selected from hydrogen, C1-C6 alkyl, aryl, N heteroalkyl.
The molar ratio of the carboxylic acid component 5, the amine component 6, the triphenylphosphine/diphenylphosphine oxide and the catalyst is 1 (1-5) to (1-16) to (0.05-0.2). The reaction atoms are poor in economy and serious in raw material waste after the proportion is exceeded.
The organic solvent is one or two of acetonitrile, dichloromethane, N-dimethylformamide, tetrahydrofuran or toluene.
The reaction temperature of the carboxylic acid component 5 and the amine component 6 is 25-60 ℃.
The light source of the illumination is one of sunlight, visible light or ultraviolet light.
The amide compound 7 is an amide or a polypeptide.
The invention provides a catalyst for amide synthesis and a preparation method of the catalyst, aiming at the defects that the reaction conditions, the application range and the reaction effect of various existing catalytic modes for catalytic amidation are not ideal enough and cannot be industrially applied, and the catalyst is used for preparing amide compounds such as amide, polypeptide and the like. Specifically, the invention has the following beneficial effects:
1. the catalyst for amide synthesis has the advantages of simple and novel structure, high catalytic efficiency and wide application range, and has better atom economy compared with other types of catalysts.
2. The catalyst of the invention has simple synthesis method and easy purification, and is suitable for industrial production.
3. The amidation catalytic reaction of the invention does not need additional operations such as dehydration or inert gas protection, can directly catalyze carboxylic acid to be converted into corresponding amide under the conditions of normal temperature, heating, illumination and the like, has short reaction time under the illumination condition, high yield, single byproduct and good N, O selectivity, can be directly used for solid phase synthesis of amide or polypeptide, and has wide industrial application prospect.
4. In the amidation catalytic reaction of the invention, triphenylphosphine or diphenylphosphine oxide is an essential component, and the catalyst forms phosphonium salt with high reaction activity with the triphenylphosphine or diphenylphosphine oxide, thereby realizing the coupling of carboxylic acid and amine.
Detailed Description
The present invention is further described in detail by the following specific embodiments, but it should not be understood that the scope of the present invention is limited to the following embodiments, and various changes and modifications made to the technical solution of the present invention by those skilled in the art without departing from the spirit of the present invention should be construed as falling within the scope of the present invention defined by the claims.
Catalyst 4, 6-dimercapto-5-R in the examples of the invention 1 -5H-pyrano [2,3-d:6,5-d']The synthesis of bipyrimidine 3a-3e was performed as follows:
an aqueous solution (50 mL) containing the corresponding aldehyde (10 mmol), 4, 6-dihydroxypyrimidine (2.24 g, 20 mmol) and benzyltriethylammonium chloride (TEBAC, 456 mg) was heated at 90 ℃ for 8-12h, then cooled to room temperature, filtered to collect a powdery precipitate, washed with water and dried to give 5, 5' - (R) 5 1 Benzylidene) bis-4, 6-dihydroxypyrimidine 1a-1 e. Thereafter, an excess of phosphorus oxychloride (16 eq.) was added to the round bottom flask containing 1a-1e, the reaction was refluxed for 4 h to get full conversion of the starting material, and then cooled to room temperature. And after the reaction is finished, cooling, removing part of phosphorus oxychloride which does not participate in the reaction by rotary evaporation, then slowly dropwise adding the rest reaction solution into an ice water bath while stirring, separating out a large amount of white solid, and continuously stirring and maintaining an ice bath environment until the phosphorus oxychloride is completely quenched. Standing and filtering, washing the filter cake with water, and drying in a vacuum drying ovenDrying and drying to obtain pure intermediate 4, 6-dichloro-5-R 1 -5H-pyrano [2,3-d:6,5-d']Bipyrimidines 2a-2 e.
Figure 635861DEST_PATH_IMAGE006
An excess of thiourea (1.2 g, 16 mmol) was added to 4, 6-dichloro-5-p-nitrophenyl-5H-pyrano [2,3-d:6,5-d']Heating a mixed solution of bipyrimidine 2a (1.5 g, 4 mmol) and ethanol (20 mL) to 120 ℃, refluxing and stirring, precipitating a large amount of yellow solid in the solution after reacting for a period of time, monitoring that all raw materials in the reaction solution are converted by TLC, cooling and filtering, washing a filter cake by using ethanol and petroleum ether in sequence, and sending the filter cake into a vacuum drying oven for drying. Dissolving the dried filter cake with 2M sodium hydroxide solution to complete the decomposition process of the isothiourea, then adjusting the acidity to be acidic with 1M dilute hydrochloric acid solution until no solid is separated out, filtering and washing, and drying the obtained filter cake in vacuum to obtain the 4, 6-dimercapto-5-p-nitrophenyl-5H-pyrano [2,3-d:6,5-d']The structural formula and mass spectrum experimental data of the product of the bipyrimidine 3a (1.26 g, 3.4 mmol) are shown in the following, and the nuclear magnetic resonance experimental data are shown in Table 3.
Figure 390190DEST_PATH_IMAGE007
HRMS (ESI) found: m/z 370.0062, [M-H] - calcd. for C 15 H 8 N 5 O 3 S 2 370.0074。
An excess of thiourea (608 mg, 8 mmol) was added to 4, 6-dichloro-5-p-methylphenyl-5H-pyrano [2,3-d:6,5-d']Heating a mixed solution of bipyrimidine 2b (345 mg, 1 mmol) and ethanol (10 mL) to 120 ℃, refluxing and stirring, dissolving the raw materials after reacting for a period of time, separating out yellow solid, monitoring that all the raw materials in the reaction solution are converted by TLC, cooling and spin-drying, washing with water and dissolving with 2M sodium hydroxide solution to finish the isothioureaThe decomposition process is followed by adjusting to acidity with 1M dilute hydrochloric acid solution until no solid is precipitated, filtering and washing, and the obtained filter cake is dried in vacuum to obtain 4, 6-dimercapto-5-p-methylphenyl-5H-pyrano [2,3-d:6,5-d']Bipyrimidine 3b (285 mg, 0.84 mmol), the structural formula of the product and the experimental data of mass spectrometry are as follows, and the experimental data of nuclear magnetic resonance are shown in Table 3.
Figure 127202DEST_PATH_IMAGE008
HRMS (ESI) found: m/z 363.0345, [M+Na] + calcd. for C 16 H 12 N 4 OS 2 Na 363.0342。
An excess of thiourea (760 mg, 10 mmol) was added to 4, 6-dichloro-5-phenyl-5H-pyrano [2,3-d:6,5-d']Heating a mixed solution of bipyrimidine 2c (330 mg, 1 mmol) and ethanol (10 mL) to 120 ℃, refluxing and stirring, dissolving the raw materials to form a yellow solution after reacting for a period of time, monitoring that all the raw materials in the reaction solution are converted by TLC, cooling and spin-drying, washing with water and dissolving with 2M sodium hydroxide solution to finish the decomposition process of isothiourea, adjusting the acidity to be acidic by using 1M dilute hydrochloric acid solution until no solid is precipitated, filtering and washing with water, and drying the obtained filter cake in vacuum to obtain 4, 6-dimercapto-5-phenyl-5H-pyrano [2,3-d:6,5-d']The structural formula and mass spectrum experimental data of the product of the bipyrimidine 3c (190 mg, 0.58 mmol) are shown in the following, and the nuclear magnetic resonance experimental data are shown in Table 3.
Figure 650587DEST_PATH_IMAGE009
HRMS (ESI-API) found: m/z 327.1, [M+H] + calcd. for C 15 H 11 N 4 OS 2 327.0。
An excess of thiourea (760 mg, 10 mmol) was added to 4, 6-dichloro-5H-pyrano [2,3-d:6,5-d']Mixing of bipyrimidine 2c (508 mg, 2 mmol) and ethanol (10 mL)Heating the mixed solution to 120 ℃, refluxing and stirring, dissolving the raw materials to form a yellow solution after reacting for a period of time, monitoring that the raw materials in the reaction solution are completely converted by TLC, cooling and spin-drying the solution, washing the solution with water, dissolving the solution with 2M sodium hydroxide solution to finish the decomposition process of isothiourea, adjusting the solution to acidity by using 1M dilute hydrochloric acid solution until no solid is separated out, filtering and washing the solution, and drying the obtained filter cake in vacuum to obtain 4, 6-dimercapto-5H-pyrano [2,3-d:6,5-d']The structural formula and mass spectrum experimental data of the product of the bipyrimidine 3d (240 mg, 0.96 mmol) are shown in the following, and the nuclear magnetic resonance experimental data are shown in Table 3.
Figure 142748DEST_PATH_IMAGE010
HRMS (ESI-API) found: m/z 251.1, [M+H] + calcd. for C 9 H 7 N 4 OS 2 251.0。
An excess of thiourea (304 mg, 4 mmol) was added to 4, 6-dichloro-5-n-butyl-5H-pyrano [2,3-d:6,5-d']Heating a mixed solution of bipyrimidine 2e (310 mg, 1 mmol) and ethanol (10 mL) to 120 ℃, refluxing and stirring, reacting for a period of time to form yellow precipitates, monitoring that all raw materials in a reaction solution are converted by TLC, cooling and spin-drying, washing with water and dissolving with 2M sodium hydroxide solution to finish the decomposition process of isothiourea, adjusting the acidity to be acidic by 1M dilute hydrochloric acid solution until no solid is separated out, filtering and washing with water, and drying the obtained filter cake in vacuum to obtain 4, 6-dimercapto-5-n-butyl-5H-pyrano [2,3-d:6,5-d']Bipyrimidine 3e (50 mg, 0.16 mmol), the structural formula of the product and the experimental data of mass spectrometry are as follows, and the experimental data of nuclear magnetic resonance are shown in Table 3.
Figure 118795DEST_PATH_IMAGE011
HRMS (ESI) found: m/z 329.0496, [M+Na] + calcd. for C 13 H 14 N 4 OS 2 Na 329.0501。
In the embodiment of the invention, the catalyst 4, 6-diselenylthio-5-p-nitrophenyl-5H-pyrano [2,3-d:6,5-d']The synthesis of bipyrimidine 4a was carried out as follows:
an excess of selenourea (738 mg, 6 mmol) was added to 4, 6-dichloro-5-p-nitrophenyl-5H-pyrano [2,3-d:6,5-d']In a mixed solution of bipyrimidine 2a (0.75 g, 2 mmol) and ethanol (10 mL), heating to 120 ℃ and stirring under reflux, after a period of reaction time, the solution turns dark yellow with a large amount of yellow solid, the conversion of the raw material 2a in the reaction solution is completely detected by TLC, then cooling, concentrating and filtering, washing the filter cake with water to remove possible residual selenourea, then washing with petroleum ether and drying in a vacuum drying oven, carefully collecting the washed filtrate and pouring the whole into a waste liquid recovery bucket without sprinkling into a sewer. The dried filter cake is the target product catalyst 4, 6-diseleno mercapto-5-p-nitrophenyl-5H-pyrano [2,3-d:6,5-d']The structural formula and mass spectrum experimental data of the product of bipyrimidine 4a (0.67 g, 1.4 mmol) are shown in the following, and the nuclear magnetic resonance experimental data are shown in Table 3.
Figure 659497DEST_PATH_IMAGE012
HRMS (ESI) found: m/z 489.8904, [M+Na] + calcd. for C 15 H 9 N 5 O 3 Se 2 Na 489.8931。
The following examples illustrate the use of the catalysts 3a-3e and 4a for the construction of amide bonds and polypeptide synthesis according to the invention.
With the exception of the amino acid-based compounds, examples 1-23, 66 are alkyl carboxylic acids, examples 62-64 are aryl carboxylic acids, example 65 is N-heteroaryl carboxylic acid; examples 1 to 14 and examples 21 to 33, 62, 63, 65, 66 are primary alkylamines, examples 15, 17 are arylamines, example 16 is secondary alkylamines, example 64 is an N-heteroalkylamine.
Example 1
Phenylacetic acid (0.10 mmol), phenethylamine (0.10 mmol), catalyst 4a (0.01 mmol) and triphenylphosphine (0.10 mmol) were added to a clean 10 mL reaction tube, the solvent was 1 mL acetonitrile, the reaction was stirred at room temperature in the dark for 12h, then the pure product was obtained by concentration and column chromatography, yield 31%.
Example 8
Phenylacetic acid (0.10 mmol), phenethylamine (0.10 mmol), catalyst 4a (0.01 mmol) and diphenylphosphine oxide (0.10 mmol) were added to a clean 10 mL quartz reaction tube in 1 mL acetonitrile as a solvent, and the reaction was carried out for 30 minutes under irradiation of a 440 nm LED lamp at room temperature, followed by concentration and column chromatography to give the pure product in 85% yield as shown in Table 1.
Examples 2 to 7, examples 9 to 13
The solvent, reaction conditions and yield are shown in Table 1, and other conditions are the same as in example 1. In example 7, the amount of catalyst 4a was 0.005 mmol.
Table 1 examples 1-13 reaction conditions, solvents and yields
Figure 302968DEST_PATH_IMAGE013
The structural formulas and mass spectrum experimental data of the products of the above examples 1-13 are as follows, and the nuclear magnetic resonance experimental data are shown in Table 3.
Figure 451184DEST_PATH_IMAGE014
HRMS (ESI) found: m/z 262.1201, [M+Na] + calcd. for C 16 H 17 NONa 262.1202。
Examples 14 to 65
The reaction operates according to the following general formula: corresponding carboxylic acid component (0.10 mmol), amine component (0.10 mmol) (or 0.10 mmol of amino acid ester hydrochloride and DIPEA), catalyst 4a (0.01 mmol) and triphenylphosphine in an amount equivalent to that of catalyst 4a are added into a clean 10 mL quartz reaction tube, the solvent is 2 mL acetonitrile, the reaction is carried out under the irradiation of a 440 nm LED lamp at room temperature, and then the pure product is obtained through concentration and column chromatography. The specific reaction substrate and reaction result are shown in table 2, and the structural formula, nuclear magnetic resonance experimental data and mass spectrum experimental data of the corresponding product are shown in table 3.
TABLE 2 examples 14-65 reaction conditions and yields
Figure 180106DEST_PATH_IMAGE015
Figure 258920DEST_PATH_IMAGE016
Example 66
Naphthylacetic acid (0.10 mmol), phenethylamine (0.10 mmol), catalyst 3a (0.02 mmol) and triphenylphosphine (0.10 mmol) are added into a clean 10 mL quartz reaction tube, the solvent is 1 mL dichloromethane, the reaction is carried out for 12h under the irradiation of a 440 nm LED lamp at room temperature, and then pure products are obtained by concentration and column chromatography with the yield of 49%. The structural formula and mass spectrum experimental data of the product are shown in the following table 3.
Figure 756897DEST_PATH_IMAGE017
HRMS (ESI) found: m/z 312.1360, [M+Na] + calcd. for C 20 H 19 NONa312.1359。
Example 67
Fmoc-glycine (0.10 mmol), phenethylamine (0.10 mmol), catalyst 3b (0.01 mmol) and triphenylphosphine (0.15 mmol) were added to a clean 10 mL quartz reaction tube in 2 mL acetonitrile, the reaction was performed under irradiation of a 440 nm LED lamp at room temperature for 5h, after which the corresponding product was obtained by concentration and column chromatography in 41% yield.
Example 68
Fmoc-glycine (0.10 mmol), phenethylamine (0.10 mmol), catalyst 3c (0.01 mmol) and triphenylphosphine (0.15 mmol) were added to a clean 10 mL quartz reaction tube in 2 mL acetonitrile, the reaction was performed under irradiation of a 440 nm LED lamp at room temperature for 5h, after which the corresponding product was obtained by concentration and column chromatography in 21% yield.
Example 69
Fmoc-glycine (0.10 mmol), phenethylamine (0.10 mmol), catalyst 3d (0.01 mmol) and triphenylphosphine (0.15 mmol) were added to a clean 10 mL quartz reaction tube in 2 mL acetonitrile, the reaction was performed for 5h under irradiation of a 440 nm LED lamp at room temperature, and then the corresponding product was obtained by concentration and column chromatography with a yield of 24%.
Example 70
Fmoc-glycine (0.10 mmol), phenethylamine (0.10 mmol), catalyst 3e (0.01 mmol) and triphenylphosphine (0.15 mmol) were added to a clean 10 mL quartz reaction tube in 2 mL acetonitrile, the reaction was performed under irradiation of a 440 nm LED lamp at room temperature for 5h, after which the corresponding product was obtained by concentration and column chromatography in 16% yield. The product structures and mass spectrum experimental data of examples 67-70 are as follows, and the nuclear magnetic resonance experimental data are shown in Table 3.
Figure 325282DEST_PATH_IMAGE018
HRMS (ESI) found: m/z 423.1688, [M+Na] + calcd. for C 25 H 24 N 2 O 3 Na 423.1679。
Example 71
Fmoc-L-aspartic acid-beta-tert-butyl ester (2.0 mmol), L-tryptophan methyl ester hydrochloride (2.0 mmol), DIPEA (2.0 mmol), catalyst 4a (0.2 mmol) and triphenylphosphine (3.0 mmol) are added into a clean 100 mL glass reaction kettle, the solvent is 2 mL acetonitrile, the reaction is carried out for 80min under the irradiation of a 440 nm LED lamp at room temperature, then pure products are obtained by concentration and column chromatography, the yield is 93%,drvalue of>99 percent. The structural formula and mass spectrum experimental data of the product are shown in the following table 3.
Figure 541500DEST_PATH_IMAGE019
HRMS (ESI) found: m/z 634.2533, [M+Na] + calcd. for C 35 H 37 N 3 O 7 Na634.2524。
Example 72
0.5 mL of acetonitrile was added to weighed seven peptide fragment 72a (29.6 mg, 0.02 mmol), tripeptide fragment 72b (55.1 mg, 0.1 mmol), triphenylphosphine (21.0 mg, 0.08 mmol) and 0.002 mmol of catalyst 4a, respectively, and dissolved, and then they were mixed together and transferred to a 10 mL quartz tube, and the solvent was added to 4 mL, followed by addition of a stirrer and irradiation with blue light, and further with 3 times as much triphenylphosphine (15.7 mg) every 30min, four times, after which the total reaction time was extended to 2.5H and the reaction solution was spin-dried to obtain crude peptide 72c with side chain protection, followed by addition of 2 mL of a cleavage solution (the cleavage solution composition was TFA/TIPS/H) 2 O = 95:2.5: 2.5), stirring at low speed for 2h, spin-drying again, adding 5 mL of ethyl acetate, separating out a white solid from the solution, standing for precipitation, separating a supernatant, and extracting with an appropriate amount of deionized water. The above operation was repeated 2 times and the extracted aqueous phases were combined. The separated precipitate was dissolved with a system of water and acetonitrile and combined with the previously extracted aqueous phase before preparative lyophilization and the final product leuprolide 72d (8.1 mg, 34%, 93% purity) was obtained.
Figure 424005DEST_PATH_IMAGE020
HRMS (ESI-API) found: m/z 1210.0, [M+H] + calcd. for C 59 H 85 N 16 O 12 1209.6。
Example 73
Solid phase synthesis of triptorelin, procedure a1 for resin-to-first amino acid attachment as follows:
0.1 mmol of rink amide MBHA resin was weighed into a 20 mL conventional glass synthesizer, and the resin was then swollen with dichloromethane (5 mL) for 30min with shaking in a shaker (300 r/min) and finally drained and washed with DMF. Immediately thereafter, 5.0 mL of a deprotection solution consisting of DBU: piperidine: DMF (3:3:94, v/v) was added. After stirring for 5min, it was drained and the deprotection solution was added repeatedly and stirred again for 15min, after which it was drained and washed sequentially with DMF (2X 5.0 mL) and dichloromethane (3X 5.0 mL), after which a solution of Fmoc-Gly-OH (0.15 mmol), DIPEA (0.15 mmol) and triphenylphosphine (0.15 mmol) in dichloromethane (8 mL) dissolved with catalyst 4a (0.01 mmol) was added to the synthesizer and shaken under irradiation with blue light (light a) at 440 nm, after about 1.5 h the solution was monitored by TLC for complete consumption of triphenylphosphine, after which irradiation was stopped and drained, after which it was washed sequentially with dichloromethane (3X 5.0 mL) and DMF (2X 5.0 mL).
Deprotection step b operates as follows:
5.0 mL of a deprotection solution consisting of DBU, piperidine and DMF (3:3:94, v/v) was added to the reaction system. After stirring for 5min, it was drained and the deprotection solution was added repeatedly and stirred again for 15min, after which it was drained and washed sequentially with DMF (2X 5.0 mL) and dichloromethane (3X 5.0 mL).
Peptide chain extension step a2 was performed as follows:
a solution of Fmoc-amino acid (0.15 mmol), DIPEA (0.15 mmol) and triphenylphosphine (0.15 mmol) and catalyst 4a (0.01 mmol) in dichloromethane (8 mL) was added to the synthesizer and shaken under 440 nm blue light (light a) irradiation, after about 1.5 h the reaction was monitored by TLC that the triphenylphosphine had been completely consumed in solution, after which the irradiation was stopped, drained and washed sequentially with dichloromethane (3X 5.0 mL) and DMF (2X 5.0 mL).
The polypeptide cleavage and purification process c operates as follows:
the resin was washed with DMF (4X 5 mL), dichloromethane (2X 5 mL), methanol (1X 5 mL), dichloromethane (1X 5 mL) and methanol (2X 5 mL) in that order and thoroughly drained. Then adding cutting fluid and stirring for 3H under the condition of 150 r/min, wherein the cutting fluid has the composition of TFA/TIPS/H 2 O (4.75 mL/0.125 mL/0.125 mL). The cleavage solution was then collected and washed with TFA (3X 2 mL). The combined cutting fluid is concentrated by reduced pressure distillation, then 40 mL of ethyl ether is added, a large amount of yellow-white solid is separated out, supernatant is separated after standing and precipitation, and a proper amount of deionized water is used for extraction. Repeating the above operation for 2-3 times, and mixing the extracted water phases. The separated precipitate is dissolved by a system of water and acetonitrile and is mixed withThe water phases extracted before are combined, then freeze-drying is carried out, and the crude peptide obtained after freeze-drying can be prepared to obtain the corresponding product triptorelin 73.
Figure 776489DEST_PATH_IMAGE021
HRMS (ESI-API) found: m/z 1312.0, [M+H] + calcd. for C 64 H 83 N 18 O 13 1311.6。
TABLE 3 Nuclear magnetic and Infrared data for catalysts and amide compounds of the invention
Figure 529157DEST_PATH_IMAGE022
Figure 967091DEST_PATH_IMAGE023
Figure 387708DEST_PATH_IMAGE024
Figure 860278DEST_PATH_IMAGE025
Figure 770465DEST_PATH_IMAGE026
Figure 695696DEST_PATH_IMAGE027
Figure 920004DEST_PATH_IMAGE028
Figure 247080DEST_PATH_IMAGE029
Figure 344480DEST_PATH_IMAGE030
Figure 757007DEST_PATH_IMAGE031
Figure 519427DEST_PATH_IMAGE032
Figure 701009DEST_PATH_IMAGE033
Figure 218578DEST_PATH_IMAGE034

Claims (8)

1. The catalyst for amide synthesis is characterized in that the catalyst is a thio catalyst or a seleno catalyst, and the structural general formula of the catalyst is as follows:
Figure 604428DEST_PATH_IMAGE001
wherein R is 1 Is hydrogen, C1-C6 alkyl, phenyl or substituted phenyl; r 2 And is SH or SeH.
2. The method of claim 1, comprising the steps of:
step one, heating the aqueous solution mixed with aldehyde, 4, 6-dihydroxypyrimidine and benzyltriethylammonium chloride at 90-130 ℃ for 8-12h, then cooling to room temperature, filtering and collecting powdery precipitate, washing with water and drying to obtain 5, 5' - (R) 1 Methylene) bis-4, 6-dihydroxypyrimidine compounds are marked as compound 1; the molar ratio of the aldehyde to the 4, 6-dihydroxypyrimidine to the benzyltriethylammonium chloride is 5:10: 1;
secondly, adding phosphorus oxychloride into a round-bottom flask containing the compound 1, carrying out reaction reflux for 2-12 h, cooling to room temperature, carrying out rotary evaporation to remove unreacted phosphorus oxychloride, dropwise adding the reaction system into ice water under a stirring state, separating out a white solid, collecting the solid, washing with water, and drying to obtain pure 4, 6-dichloro-5-R 1 -5H-pyrano [2,3-d:6,5-d']The bipyrimidine compound is marked as a compound 2; the molar ratio of the compound 1 to the phosphorus oxychloride is 1: 12-20;
step three, synthesis of a thio catalyst: adding the compound 2 and thiourea into 0.1-0.5mol/L ethanol, heating and refluxing at 90-130 ℃ until the compound 2 is completely consumed, cooling a reaction system to room temperature, collecting solids, dissolving the solids by using 2M sodium hydroxide solution, adjusting the acidity by using 1M dilute hydrochloric acid solution until the solids are not separated out, filtering, washing by water and drying to obtain 4, 6-dimercapto-5-R 1 -5H-pyrano [2,3-d:6,5-d']A bipyrimidine catalyst, denoted as catalyst 3; the molar ratio of the compound 2 to the thiourea is 1: 4-10;
synthesis of a seleno catalyst: adding the compound 2 (1 eq.) and 3-10 eq of selenourea into 0.1-0.5mol/L ethanol, heating and refluxing at 90-130 ℃ until the compound 2 is completely consumed, then cooling the reaction system to room temperature, concentrating, filtering, washing with water and drying to obtain the 4, 6-diseleno mercapto-5-R 1 -5H-pyrano [2,3-d:6,5-d']A bipyrimidine catalyst, denoted as catalyst 4; the molar ratio of the compound 2 to the selenourea is 1: 2-5.
3. The application of the catalyst for amide synthesis is characterized in that a carboxylic acid component 5, an amine component 6, the catalyst in claim 1, triphenylphosphine or diphenylphosphine oxide are weighed, placed in a reaction vessel, added with an organic solvent, stirred under illumination or room temperature or heating conditions until the triphenylphosphine or diphenylphosphine oxide is completely consumed, and then separated and purified to obtain an amide compound 7, wherein the reaction formula is as follows:
Figure 708519DEST_PATH_IMAGE002
in the above reaction scheme, the carboxylic acid component 5 is R 3 A carboxylic acid or N-protected amino acid selected from the group consisting of C1-C20 alkyl, aryl, N heteroaryl; the amine component 6 being R 4 And R 5 An amine or carboxy-protected amino acid optionally selected from hydrogen, C1-C20 alkyl, aryl, N heteroalkyl; in the reaction formula, the amine component 6 can also be a mixture of amino acid ester hydrochloride and equal amount of DIPEA; the amine component 6 may also be a deprotected amino resin.
4. Use of a catalyst for amide synthesis according to claim 3, characterized in that the carboxylic acid component 5 is R 3 Carboxylic acids optionally selected from C1-C6 alkyl, aryl, N heteroaryl; the amine component 6 being R 4 And R 5 An amine selected from hydrogen, C1-C6 alkyl, aryl, N heteroalkyl.
5. The use of a catalyst for amide synthesis according to claim 3 or 4, wherein the molar ratio of the carboxylic acid component 5, the amine component 6, triphenylphosphine/diphenylphosphine oxide and catalyst is 1 (1-5): 1-16: 0.05-0.2.
6. The use of a catalyst for amide synthesis according to claim 3 or 4, wherein the organic solvent is one or two of acetonitrile, dichloromethane, N-dimethylformamide, tetrahydrofuran or toluene.
7. Use of a catalyst for amide synthesis according to claim 3 or 4, characterized in that the reaction temperature of the carboxylic acid component 5 and the amine component 6 is 25-60 ℃.
8. The use of the catalyst for amide synthesis according to claim 3 or 4, wherein the light source for the illumination in the reaction formula is one of sunlight, visible light or ultraviolet light.
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