CN112358423A - Preparation and application of novel polypeptide guanidizing agent - Google Patents
Preparation and application of novel polypeptide guanidizing agent Download PDFInfo
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- CN112358423A CN112358423A CN202011289366.7A CN202011289366A CN112358423A CN 112358423 A CN112358423 A CN 112358423A CN 202011289366 A CN202011289366 A CN 202011289366A CN 112358423 A CN112358423 A CN 112358423A
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- Prior art keywords
- guanidine
- tert
- boc
- toluenesulfonyl
- chloride
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
- C07C311/18—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/38—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reaction of ammonia or amines with sulfonic acids, or with esters, anhydrides, or halides thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C311/05—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by nitrogen atoms, not being part of nitro or nitroso groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses preparation and application of a polypeptide guanylating agent for synthesizing polypeptide drugs, and belongs to the field of polypeptide guanylating agents. Reacting 1, 3-di (tert-butoxycarbonyl) guanidine with p-toluenesulfonyl chloride in the presence of an organic base to obtain 1, 3-di-Boc-2- (p-toluenesulfonyl) guanidine; reacting the guanidino group with primary amine in the presence of organic base to obtain an N-substituted amino-bis-BOC guanidine compound; meanwhile, a one-pot reaction system is developed. The preparation of the polypeptide guanylating agent in the route avoids ultralow temperature reaction and the use of trifluoromethanesulfonyl chloride or trifluoromethanesulfonic anhydride with strong corrosivity, and effectively replaces the existing condensing agent.
Description
Technical Field
The invention belongs to the technical field of amino acid polypeptide, and particularly relates to preparation and application of a polypeptide guanylating agent for synthesizing polypeptide drugs.
Background
In a living body, a guanidyl functional group in guanine and arginine has a molecular recognition property and plays an important role in DNA base pairing and active centers of some enzymes, so that a guanidyl compound becomes one of important research points of life science. Many guanidino compounds have pharmacological activity and molecular recognition characteristics, so that the synthesis of the compounds is very important.
The two main guanylating agents have the structures as follows:
and RNH2When the reaction is carried out, the reaction equations are respectively as follows:
however, the two guanylating agents have the problems of high cost and low efficiency.
Disclosure of Invention
The invention aims to provide a preparation method of a cheap and efficient polypeptide guanylating agent, which has the following structure:
the invention also provides the synthesis of the high-efficiency polypeptide guanylating agent, and the preparation route is as follows: (taking p-toluenesulfonyl substitution as an example)
The method comprises the following operations: reacting 1, 3-di (tert-butoxycarbonyl) guanidine with p-toluenesulfonyl chloride/methanesulfonyl chloride in the presence of an organic base in an organic solvent to give 1, 3-di-Boc-2- (p-toluenesulfonyl/methanesulfonyl) guanidine.
Further, in the above technical solution, the organic solvent is selected from common organic solvents such as dichloromethane, tetrahydrofuran, ethyl acetate, 2-methyltetrahydrofuran, cyclopentyl methyl ether, and the like.
Further, in the above technical solution, the organic base is selected from triethylamine, pyridine, diisopropylethylamine, and the like.
Further, in the above technical scheme, the reaction is carried out at 0-30 ℃, preferably at room temperature.
Further, in the above technical scheme, the molar ratio of 1, 3-bis (tert-butoxycarbonyl) guanidine, organic base and p-toluenesulfonyl chloride/methylsulfonyl chloride is 1: 1-1.5: 1-1.2.
Using the intermediate and RNH2The reaction is as follows:
in the above reaction, the primary amine acts as a nucleophile, since Ts-and Ms-are good leaving groups, with sulfonyl being a strong electron withdrawing group.
The invention also improves the step method, adopts a one-step method for direct preparation, and comprises the following operations: mixing 1, 3-di (tert-butoxycarbonyl) guanidine, primary amine and an organic solvent, and dropwise adding p-toluenesulfonyl chloride to react with the organic solvent solution in the presence of alkali to obtain the N-substituted amino-bis-BOC guanidine compound.
Further, in the above technical solution, the organic solvent is selected from common organic solvents such as dichloromethane, tetrahydrofuran, ethyl acetate, 2-methyltetrahydrofuran, cyclopentyl methyl ether, and the like.
Further, in the above technical solution, the base is selected from sodium hydride, sodium methoxide, lithium methoxide, potassium tert-butoxide, sodium tert-butoxide, and lithium tert-butoxide.
Further, in the above technical scheme, the reaction is carried out at-10 ℃ to 0 ℃, preferably at 0 ℃.
Further, in the above technical scheme, the molar ratio of 1, 3-bis (tert-butoxycarbonyl) guanidine, base and p-toluenesulfonyl chloride/methylsulfonyl chloride is 1: 1-1.5: 1-1.2.
Advantageous effects of the invention
The invention adopts p-toluenesulfonyl chloride/methylsulfonyl chloride and 1, 3-di (tert-butoxycarbonyl) guanidine which are easily obtained as raw materials and have lower cost as raw materials, and synthesizes a target product more simply and conveniently at room temperature.
The specific implementation mode is as follows:
example 1
2L of tetrahydrofuran is added into a 5L reaction kettle, 680g (2.622mol,1eq) of 1, 3-di (tert-butoxycarbonyl) guanidine and 291g (2.884mol,1.2eq) of triethylamine are added under stirring, stirring is carried out to dissolve the mixture after the addition is finished, then 500g (2.623mol,1eq) of p-toluenesulfonyl chloride solution in tetrahydrofuran is added dropwise, the temperature is controlled to be 20-25 ℃, after stirring and reacting for 2 hours, sampling TLC detects that no raw material is left, solvent is concentrated under reduced pressure and then dichloromethane is used for extraction, a large amount of solid is separated out after the dichloromethane is concentrated, the filtration is carried out, a filter cake is washed by 500mL of water, and 950g of a product is obtained after drying. The yield was 87.6%, and the content of the liquid phase was 99.61%.
Example 2
3.5L of ethyl acetate was added to a 5L reactor, 680g (2.622mol,1eq) of 1, 3-di (tert-butoxycarbonyl) guanidine and 291g (2.884mol,1.2eq) of triethylamine were added with stirring, after the addition was completed, the mixture was dissolved with stirring, 300.5g (2.623mol,1eq) of methanesulfonyl chloride was added dropwise thereto, the temperature was controlled at 20 to 25 ℃ and the reaction was carried out with stirring for 2 hours, then sampling TLC was carried out to detect that no starting material remained, the solvent was concentrated under reduced pressure and then extracted with dichloromethane, after concentrating dichloromethane, a large amount of solid was precipitated, the filtrate was washed with 500mL of water, and after drying, 790.9g of the product was obtained. The yield was 89.4%, and the content of UPLC in the liquid phase was 99.3%.
Example 3
3.4L of dichloromethane is added into a 5L reaction kettle, 680g (2.622mol,1eq) of 1, 3-di (tert-butoxycarbonyl) guanidine and 372.8g (2.884mol,1.2eq) of diisopropylethylamine are added under stirring, after the addition is finished, the mixture is stirred and dissolved, then 0.5L of dichloromethane solution containing 500g (2.623mol,1eq) of p-toluenesulfonyl chloride is added dropwise, the temperature is controlled at 15-20 ℃, after stirring and reacting for 2 hours, TLC sampling is carried out to detect that no raw material is left, solvent is concentrated under reduced pressure and then extracted by dichloromethane, after the dichloromethane is concentrated, a large amount of solid is separated out, the filter cake is washed by 500mL of water, and after the drying, 1020.2g of the product is obtained. The yield is 94.1 percent, and the content of the liquid phase UPLC is 99.9 percent.
Example 4
Adding 3L of 2-methyltetrahydrofuran into a 5L reaction kettle, adding 680g (2.622mol,1eq) of 1, 3-di (tert-butoxycarbonyl) guanidine and 228.1g (2.884mol,1.2eq) of pyridine under stirring, stirring to dissolve after the addition is finished, then dropwise adding 300.5g (2.623mol,1eq) of methylsulfonyl chloride, controlling the temperature at 20-25 ℃, stirring to react for 2 hours, sampling TLC to detect that no raw material is left, concentrating the solvent under reduced pressure, extracting with dichloromethane, concentrating the dichloromethane, precipitating a large amount of solid, filtering, washing a filter cake with 500mL, and drying to obtain 745.7g of a product. The yield was 84.3%, and the content of the liquid phase was 99.5%.
Example 5
Adding 250mL of dichloromethane into a 500mL reaction kettle, adding 25g (0.0605mol,1eq) of 1, 3-di-Boc-2- (p-toluenesulfonyl) guanidine and 12.23g (0.121mol,2.0eq) of triethylamine under stirring, stirring to dissolve after the addition is finished, cooling to 15 ℃, adding 5.93g (0.0575mol,0.95eq) of aminocarboxamide, controlling the temperature to be 20-25 ℃, stirring to react for 20 hours, sampling and detecting by HPLC (high performance liquid chromatography) that the aminocarboxamide is less than 0.4%, concentrating the solvent under reduced pressure, extracting by dichloromethane, concentrating the dichloromethane, precipitating a large amount of solid, filtering, washing a filter cake by 500mL of water, and drying to obtain 16.2g of a product. The yield was 81.7% and the content of liquid phase was 99.5%.
Example 6
Adding 250mL of dichloromethane into a 500mL reaction kettle, adding 25g (0.0741mol,1eq) of 1, 3-di-Boc-2- (methylsulfonyl) guanidine and 15g (0.1482mol,2.0eq) of triethylamine under stirring, stirring to dissolve after the addition is finished, cooling to 15 ℃, adding 7.26g (0.704mol,0.95eq) of aminocarboxamide acid, controlling the temperature to be 20-25 ℃, stirring to react for 20 hours, sampling HPLC to detect that the aminocarboxamide acid is less than 0.4%, concentrating the solvent under reduced pressure, extracting with dichloromethane, concentrating the dichloromethane, precipitating a large amount of solid, filtering, washing a filter cake with 500mL of water, and drying to obtain 21.4g of a product. The yield was 87.9%, and the content of the liquid phase was 99.4%.
The foregoing embodiments have described the general principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are merely illustrative of the principles of the present invention, and that various changes and modifications may be made without departing from the scope of the principles of the present invention, and the invention is intended to be covered by the appended claims.
Claims (7)
1. A cheap and efficient polypeptide guanylating agent is characterized by having the following structure:
2. a preparation method of N-substituted amino-bis-BOC guanidine compounds is characterized by comprising the following two methods:
method A, first step: reacting 1, 3-di (tert-butoxycarbonyl) guanidine with p-toluenesulfonyl chloride/methanesulfonyl chloride in the presence of an organic base in an organic solvent to obtain 1, 3-di-Boc-2- (p-toluenesulfonyl/methanesulfonyl) guanidine; the second step is that: reacting 1, 3-di-Boc-2- (p-toluenesulfonyl/methylsulfonyl) guanidine with primary amine in an organic solvent in the presence of organic alkali to obtain an N-substituted amino-bis-BOC guanidine compound;
and the method B comprises the steps of mixing 1, 3-di (tert-butoxycarbonyl) guanidine, primary amine and an organic solvent, dropwise adding a solution formed by p-toluenesulfonyl chloride/methanesulfonyl chloride and the organic solvent in the presence of alkali, and reacting to obtain the N-substituted amino-bis-BOC guanidine compound.
3. The method for producing a guanidino condensing agent according to claim 2, characterized in that: the organic solvent is selected from dichloromethane, tetrahydrofuran, ethyl acetate, 2-methyltetrahydrofuran, and cyclopentyl methyl ether.
4. The method for producing a guanidino condensing agent according to claim 2, characterized in that: in method A, the organic base is selected from triethylamine, pyridine, diisopropylethylamine.
5. The method for producing a guanidino condensing agent according to claim 2, characterized in that: in Process B, the base is selected from the group consisting of sodium hydride, sodium methoxide, lithium methoxide, potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide.
6. The method for producing a guanidino condensing agent according to claim 2, characterized in that: the reaction of the method A is carried out at 0-30 ℃, and the reaction of the method B is carried out at-10-0 ℃.
7. The method for producing a guanidino condensing agent according to claim 2, characterized in that: the mole ratio of 1, 3-bis (tert-butoxycarbonyl) guanidine, organic base/base to p-toluenesulfonyl chloride/methylsulfonyl chloride is 1: 1-1.5: 1-1.2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011289366.7A CN112358423A (en) | 2020-11-17 | 2020-11-17 | Preparation and application of novel polypeptide guanidizing agent |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011289366.7A CN112358423A (en) | 2020-11-17 | 2020-11-17 | Preparation and application of novel polypeptide guanidizing agent |
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| Publication Number | Publication Date |
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| CN112358423A true CN112358423A (en) | 2021-02-12 |
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| CN202011289366.7A Withdrawn CN112358423A (en) | 2020-11-17 | 2020-11-17 | Preparation and application of novel polypeptide guanidizing agent |
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- 2020-11-17 CN CN202011289366.7A patent/CN112358423A/en not_active Withdrawn
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Application publication date: 20210212 |