CN112940074A - Synthesis method of N-acetyl-L-tyrosyl-L-arginine hexadecyl ester - Google Patents
Synthesis method of N-acetyl-L-tyrosyl-L-arginine hexadecyl ester Download PDFInfo
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Abstract
The invention relates to the field of medicines, and particularly provides a synthetic method of N-acetyl-L-tyrosyl-L-arginine hexadecyl ester. The synthetic route is as follows:
the invention aims to provide a method for quickly, efficiently and highly universally preparing and synthesizing tyrosine-arginine dipeptide alkanol ester in large scale. The synthesis method of the tyrosine-arginine dipeptide alkanol ester is simple, overcomes common side reactions such as racemization and the like, has cheap and easily obtained raw materials, low production cost and strong practicability, and is easy for large-scale production.
Description
Technical Field
The disclosure relates to the field of medicine, and particularly provides a synthetic method of N-acetyl-L-tyrosyl-L-arginine hexadecyl ester.
Background
The statements herein merely provide background information related to the present disclosure and may not necessarily constitute prior art.
Sensitive skin is one of the most common skin conditions. According to the results of epidemiological studies, more than 50% of adults suffer from this condition. The syndrome is characterized by sensory symptoms such as stinging, burning, tightening of the skin, itching and pain, which may be associated with objective inflammatory symptoms such as erythema. Environmental factors (heat, cold, pollution, uv radiation, exposure) as well as lifestyle (cosmetics, diet, alcohol) and pre-existing diseases play a vital role. As the skin ages naturally or prematurely, it thins, gradually loses its firmness, begins to wrinkle and/or sag. This can be explained by the fact that the elastic fibers that make up the skin support, the skin extracellular matrix that gives the skin its elasticity and strength, are destroyed and diminished with age. The condition of sensitive skin is very disturbing and can negatively impact the quality of life of a person. In areas where the skin can swell (sag) under its own weight, unsightly, incongruous marks may become apparent, such as the chin of the face; or swelling, wilting of the skin between the underarm, breast or lower abdomen; the skin takes on a creped paper appearance; or there is also sagging of the area above the eyes. The present invention aims to propose a solution to prevent and/or treat the loss or lack of firmness of the skin, in particular due to an insufficient quality or quantity of elastic fibres. Oligopeptides and polypeptides are capable of reducing what we call the "appearance" of wrinkles.
Tyrosine-arginine dipeptide alkanol esters have been found in the prior art to be useful in combating skin sagging. In addition, the tyrosine-arginine dipeptide alkanol ester has anti-inflammatory and anti-allergy effects, and is applied to skin care products as an anti-allergy and soothing component. It can significantly reduce the secretion of prostaglandin E2(PGE2) and nuclear transcription factor kappaB (NF-kB) signals, thereby relieving inflammation symptoms, and treating redness, inflammation, mild edema, lack of blood color and alopecia. Tyrosine-arginine dipeptide alkanol esters can also be used for weight loss, or for reducing, eliminating or preventing overweight subcutaneous fat.
The tyrosine-arginine dipeptide alkanol ester has various medicinal values and health care effects, so the method which is provided by the invention has high yield, simple method and low cost and has important value.
Disclosure of Invention
The invention aims to provide a method which is rapid, efficient and strong in universality and can be used for preparing and synthesizing tyrosine-arginine dipeptide alkanol ester in a large scale. The synthesis method of the tyrosine-arginine dipeptide alkanol ester is simple, overcomes common side reactions such as racemization and the like, has cheap and easily obtained raw materials, low production cost and strong practicability, and is easy for large-scale production.
The present disclosure provides a method for synthesizing N-acetyl-L-tyrosyl-L-arginine hexadecyl ester, the synthetic route is as follows:
one or some of the above technical solutions have the following advantages or beneficial effects:
1) in the synthetic route disclosed by the invention, N-fluorenylmethoxycarbonyl-2, 2,4,6, 7-pentamethyl dihydrobenzofuran-5-sulfonyl-L-arginine and hexadecanol are subjected to esterification reaction to obtain the N-fluorenylmethoxycarbonyl-2, 2,4,6, 7-pentamethyl dihydrobenzofuran-5-sulfonyl-L-arginine-hexadecanol. The arginine protected by the N-fluorenylmethoxycarbonyl has characteristic ultraviolet absorption and is convenient for real-time monitoring of the reaction; the esterification product is obtained with high yield by utilizing the regulation and control of substrate concentration, reaction solvent and activation system to avoid common side reactions such as racemization, cyclization and the like.
2) The synthesis method of the tyrosine-arginine dipeptide prepared by the method is simple, the raw materials are easy to obtain, the practicability is high, the yield is high, and the cost is low, so that the method has important significance for the industrial production of the substances.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this disclosure, illustrate embodiments of the disclosure and, together with the description, serve to explain the disclosure and not to limit the disclosure.
FIG. 1 is a nuclear magnetic spectrum of Compound 3 synthesized in example 1;
FIG. 2 is a nuclear magnetic spectrum of Compound 4 synthesized in example 2;
FIG. 3 is a nuclear magnetic spectrum of Compound 6 synthesized in example 3;
FIG. 4 is a nuclear magnetic spectrum of Compound 7 synthesized in example 4;
FIG. 5 is a nuclear magnetic spectrum of Compound 8 synthesized in example 5;
figure 6 is a nuclear magnetic spectrum of compound 9 synthesized in example 6.
Detailed Description
The technical solutions in the embodiments of the present disclosure will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present disclosure, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments of the disclosure without making any creative effort, shall fall within the protection scope of the disclosure.
The invention aims to provide a method which is rapid, efficient and strong in universality and can be used for preparing and synthesizing tyrosine-arginine dipeptide alkanol ester in a large scale. The synthesis method of the tyrosine-arginine dipeptide alkanol ester is simple, overcomes common side reactions such as racemization and the like, has cheap and easily obtained raw materials, low production cost and strong practicability, and is easy for large-scale production.
The present disclosure provides a method for synthesizing N-acetyl-L-tyrosyl-L-arginine hexadecyl ester, the synthetic route is as follows:
preferably, the method comprises the following steps:
step 1), carrying out esterification reaction on N-fluorenylmethoxycarbonyl-2, 2,4,6, 7-pentamethyl dihydrobenzofuran-5-sulfonyl-L-arginine and hexadecanol;
step 2), removing the N-fluorenylmethoxycarbonyl protecting group on the N-fluorenylmethoxycarbonyl-2, 2,4,6, 7-pentamethyl dihydrobenzofuran-5-sulfonyl-L-arginine-hexadecanol;
step 3), carrying out amidation reaction on the 2,2,4,6, 7-pentamethyl dihydrobenzofuran-5-sulfonyl-L-arginine-hexadecanol and N-fluorenylmethoxycarbonyl-O-tert-butyl-L-tyrosine;
step 4), removing the N-fluorenylmethoxycarbonyl protecting group on the N-fluorenylmethoxycarbonyl-O-tert-butyl-L-tyrosine-2, 2,4,6, 7-pentamethyl dihydrobenzofuran-5-sulfonyl-L-arginine-hexadecanol;
step 5), acetylating the amino group of O-tert-butyl-L-tyrosine-2, 2,4,6, 7-pentamethyl dihydrobenzofuran-5-sulfonyl-L-arginine-hexadecanol;
and step 6), removing the tertiary butyl and 2,2,4,6, 7-pentamethyl dihydrobenzofuran-5-sulfonyl-L-arginine-hexadecyl alcohol protecting groups on the N-acetyl-O-tertiary butyl-L-tyrosine-2, 2,4,6, 7-pentamethyl dihydrobenzofuran-5-sulfonyl to obtain the final product N-acetyl-L-tyrosyl-L-arginine hexadecyl ester.
Preferably, in the step 1), the molar ratio of the N-fluorenylmethoxycarbonyl-2, 2,4,6, 7-pentamethyl dihydrobenzofuran-5-sulfonyl-L-arginine to the cetyl alcohol is 1: 1-1: 5.
preferably, in the step 1), the N-fluorenylmethoxycarbonyl-2, 2,4,6, 7-pentamethyl dihydrobenzofuran-5-sulfonyl-L-arginine and hexadecanol are subjected to esterification reaction, dissolved in a newly distilled solvent and subjected to reaction, the reaction is carried out for a certain time at a proper concentration, the TLC (thin layer chromatography) monitoring reaction is complete, and a product is obtained through column chromatography separation;
preferably, the solvent is a conventional organic solvent including, but not limited to: dichloromethane, ethyl acetate, DMF, DMSO, and the like;
preferably, DCC/DMAP, PyBOP/DIPEA, HATU/DIPEA, PyBOP/HOBt and DIC/Oxyma are used as activation conditions, and more preferably, the molar ratio of DIC to Oxyma is 1: 1-1.5.
Preferably, in the step 2), the reaction for removing the N-fluorenylmethoxycarbonyl protecting group is carried out in a morpholine system, the TLC is used for monitoring the reaction to be complete, and the product is obtained by column chromatography separation;
preferably, the morpholine system is a mixture of an organic solvent and morpholine, including but not limited to: dichloromethane, ethyl acetate, DMF, DMSO, and the like, and further preferably, the volume ratio of the mixture is 1: 1;
preferably, after the reaction is completed, the mixture is diluted by dichloromethane, then is washed by hydrochloric acid aqueous solution and saturated sodium chloride aqueous solution, an organic phase is dried by anhydrous sodium sulfate, a drying agent is filtered out, and filtrate is concentrated and dried in a spinning mode;
preferably, the column chromatography solvent is a mixture of dichloromethane and methanol, and the volume ratio of the dichloromethane to the methanol is 15: 1;
preferably, the product is separated by column chromatography, diluted with dichloromethane, washed with aqueous hydrochloric acid and saturated aqueous sodium chloride, the organic phase is dried over anhydrous sodium sulfate, the drying agent is filtered off, and the filtrate is concentrated and dried by spinning.
Preferably, in step 3), 2,2,4,6, 7-pentamethyl dihydrobenzofuran-5-sulfonyl-L-arginine-hexadecanol is subjected to amide reaction with N-fluorenylmethoxycarbonyl-O-tert-butyl-L-tyrosine, and the molar ratio of the amide reaction with the N-fluorenylmethoxycarbonyl-O-tert-butyl-L-tyrosine is 1: 1-1: 5.
preferably, in the step 3), 2,2,4,6, 7-pentamethyl dihydrobenzofuran-5-sulfonyl-L-arginine-hexadecanol and N-fluorenylmethoxycarbonyl-O-tert-butyl-L-tyrosine are subjected to an amide reaction, a newly distilled solvent is adopted, the TLC is used for monitoring the completion of the reaction, and a product is obtained by column chromatography separation;
preferably, the solvent is a conventional organic solvent including, but not limited to: dichloromethane, ethyl acetate, DMF, DMSO, and the like;
preferably, DCC/DMAP, PyBOP/DIPEA, HATU/DIPEA, PyBOP/HOBt, DIC/Oxyma are used as activation conditions, and more preferably, the molar ratio of HATU to DIPEA is 1: 1-1: 2;
preferably, after the reaction is completed, the mixture is diluted by dichloromethane, washed by aqueous hydrochloric acid and saturated aqueous sodium chloride in turn, the organic phase is dried by anhydrous sodium sulfate, the drying agent is filtered out, the filtrate is concentrated and dried, and then column chromatography separation is carried out.
Preferably, in the step 4), the reaction for removing the N-fluorenylmethoxycarbonyl-O-tert-butyl-L-tyrosine-2, 2,4,6, 7-pentamethyl dihydrobenzofuran-5-sulfonyl-L-arginine-hexadecanol ester protecting group is carried out in a morpholine system, the TLC monitoring reaction is complete, and the product is obtained by column chromatography separation;
preferably, the morpholine system is a mixture of an organic solvent and morpholine, including but not limited to: dichloromethane, ethyl acetate, DMF, DMSO, and the like, and further preferably, the volume ratio of the mixture is 1: 1;
preferably, after the reaction is completed, dichloromethane is used for dilution, hydrochloric acid aqueous solution and saturated sodium chloride aqueous solution are used for washing, an organic phase is dried by anhydrous sodium sulfate, a drying agent is filtered out, a filtrate is concentrated and dried, and then column chromatography separation is carried out;
preferably, the column chromatography solvent is a mixture of dichloromethane and methanol, and the volume ratio of the dichloromethane to the methanol is 20: 1.
preferably, in the step 5), the acetyl protection of the amino group on the O-tert-butyl-L-tyrosine-2, 2,4,6, 7-pentamethyl dihydrobenzofuran-5-sulfonyl-L-arginine-hexadecanol is carried out by adding acetic anhydride and triethylamine into a dichloromethane solvent, stirring at room temperature until the TLC monitoring reaction is completed, adding methanol to quench the reaction, and carrying out column chromatography separation on the product to obtain the product.
Preferably, in the step 6), the removal of the tert-butyl group and the 2,2,4,6, 7-pentamethyl dihydrobenzofuran-5-sulfonyl-L-arginine-hexadecanol protecting group on the N-acetyl-O-tert-butyl-L-tyrosine-2, 2,4,6, 7-pentamethyl dihydrobenzofuran-5-sulfonyl group is carried out by stirring trifluoroacetic acid and water (9/1) at room temperature until TLC monitoring raw materials are complete, concentrating the spin-dried solvent, adding water to precipitate a solid, and obtaining the target product N-acetyl-L-tyrosyl-L-arginine hexadecanol ester with nearly quantitative yield.
The specific experimental steps are as follows:
example 1:
this example provides a method for synthesizing N-fluorenylmethoxycarbonyl-2, 2,4,6, 7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine-hexadecanol ester, the synthetic route is as follows:
the preparation of N-fluorenylmethoxycarbonyl-2, 2,4,6, 7-pentamethyl dihydrobenzofuran-5-sulfonyl-L-arginine-hexadecanol ester comprises the following steps:
in a 100mL round-bottom flask, Compound 1(7g) and Compound 2(7.9g) were added, and freshly distilled CH was added2Cl2After completion of the reaction was monitored by TLC by stirring under ultrasonic conditions and stirring until dissolved, oxyyma (4.6g) and DIC (5.0g) were slowly added, and the reaction system was diluted with 300mL of dichloromethane, saturated aqueous sodium chloride solution (100mL x3), the organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, the filtrate was concentrated and dried, washed with petroleum ether (10mL x2), and further washed with column chromatography (petroleum ether: ethyl acetate: 1) and petroleum ether to give compound 3(7.3g) as a yellow foamy solid.
Example 2:
this example provides a synthetic method of 2,2,4,6, 7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine-hexadecanol ester, the synthetic route of which is shown below:
the preparation of 2,2,4,6, 7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine-hexadecanol ester comprises the following steps:
in a 250mL round bottom flask, compound 3(7.3g) was added to a mixture of dichloromethane and morpholine (36.6mL) (v/v 1:1), stirred at room temperature until TLC monitoring reaction was complete, the reaction was diluted with 300mL dichloromethane, washed with 1N aqueous hydrochloric acid (100mL x3), saturated aqueous sodium chloride (100mL x3), the organic phase was dried over anhydrous sodium sulfate, the drying agent was filtered off, the filtrate was concentrated and dried, the product was isolated by column chromatography (dichloromethane: methanol volume ratio 15: 1) to give crude compound, which was diluted with 300mL dichloromethane, 1N aqueous hydrochloric acid (100mL x3), saturated aqueous sodium chloride (100mL x3), the organic phase was dried over anhydrous sodium sulfate, the drying agent was filtered off, the filtrate was concentrated and dried to give compound 4(5.2 g).
Example 3:
this example provides a method for synthesizing N-fluorenylmethoxycarbonyl-O-tert-butyl-L-tyrosine-2, 2,4,6, 7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine-hexadecanol ester, the synthetic route of which is shown below:
the preparation method of the N-fluorenylmethoxycarbonyl-O-tertiary butyl-L-tyrosine-2, 2,4,6, 7-pentamethyl dihydrobenzofuran-5-sulfonyl-L-arginine-hexadecanol ester comprises the following steps:
in a 100mL round-bottom flask, compound 4(5.2g) and compound 5(4.4g) were added, and freshly distilled CH was added2Cl2After completion of the reaction was monitored by TLC by adding HATU (3.6g) and DIPEA (2.1mL) slowly thereto under ultrasonic agitation and stirring at that temperature, the reaction system was diluted with 300mL of methylene chloride, washed with 1N aqueous hydrochloric acid (100 mL. times. 3) and saturated aqueous sodium chloride (100 mL. times. 3), the organic phase was dried over anhydrous sodium sulfate, the drying agent was filtered off, the filtrate was concentrated and dried by spin-drying, and the compound 6(6.9g) was isolated by column chromatography.
Example 4:
this example provides a synthetic method of O-tert-butyl-L-tyrosine-2, 2,4,6, 7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine-hexadecanol ester, the synthetic route of which is shown below:
the preparation of O-tert-butyl-L-tyrosine-2, 2,4,6, 7-pentamethyl dihydrobenzofuran-5-sulfonyl-L-arginine-hexadecanol ester comprises the following steps:
compound 6(6.9g) was added to a 250mL round bottom flask, a mixture of dichloromethane and morpholine (5.5mL) (v/v ═ 1:1) was added, the mixture was stirred at room temperature for 1 hour, and after completion of the reaction of compound 6 by TLC, the reaction system was diluted with 300mL dichloromethane, washed with 1N aqueous hydrochloric acid (100mL × 3), saturated aqueous sodium chloride (100mL × 3), the organic phase was dried over anhydrous sodium sulfate, the drying agent was filtered off, the filtrate was concentrated and dried, and compound 7(3.9g) was obtained by column chromatography (dichloromethane: methanol ═ 20: 1).
Example 5:
this example provides a synthetic method of N-acetyl-O-tert-butyl-L-tyrosine-2, 2,4,6, 7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine-hexadecanol ester, the synthetic route of which is shown below:
the preparation of N-acetyl-O-tert-butyl-L-tyrosine-2, 2,4,6, 7-pentamethyl dihydrobenzofuran-5-sulfonyl-L-arginine-hexadecanol comprises the following steps:
in a 250mL round bottom flask, compound 7(3.8g) was added, freshly distilled dichloromethane was added, acetic anhydride (2.1mL) and triethylamine (3.1mL) were added, the reaction was monitored by TLC at room temperature, the reaction was quenched by addition of methanol, the solvent was concentrated and the product was isolated by column chromatography (dichloromethane: methanol 50: 1) to give compound 8(3.4 g).
Example 6:
this example provides a method for synthesizing N-acetyl-L-tyrosyl-L-arginine hexadecanol ester, the synthetic route is as follows:
the preparation of N-acetyl-L-tyrosyl-L-arginine hexadecanol ester comprises the following steps:
compound 8(3.4g) was added to a 250mL round bottom flask, trifluoroacetic acid and water (9/1) were added, and after completion of the reaction monitored by TLC stirring at room temperature, the solvent was concentrated and the solid precipitated by addition of water to give compound 9 in near quantitative yield.
The disclosure of the present invention is not limited to the specific embodiments, but rather to the specific embodiments, the disclosure is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (10)
1. The synthesis method of the N-acetyl-L-tyrosyl-L-arginine hexadecyl ester is characterized in that the synthesis route is as follows:
2. the method of synthesizing N-acetyl-L-tyrosyl-L-arginine hexadecyl esters according to claim 1, comprising the steps of:
step 1), carrying out esterification reaction on N-fluorenylmethoxycarbonyl-2, 2,4,6, 7-pentamethyl dihydrobenzofuran-5-sulfonyl-L-arginine and hexadecanol;
step 2), removing the N-fluorenylmethoxycarbonyl protecting group on the N-fluorenylmethoxycarbonyl-2, 2,4,6, 7-pentamethyl dihydrobenzofuran-5-sulfonyl-L-arginine-hexadecanol;
step 3), carrying out amidation reaction on the 2,2,4,6, 7-pentamethyl dihydrobenzofuran-5-sulfonyl-L-arginine-hexadecanol and N-fluorenylmethoxycarbonyl-O-tert-butyl-L-tyrosine;
step 4), removing the N-fluorenylmethoxycarbonyl protecting group on the N-fluorenylmethoxycarbonyl-O-tert-butyl-L-tyrosine-2, 2,4,6, 7-pentamethyl dihydrobenzofuran-5-sulfonyl-L-arginine-hexadecanol;
step 5), acetylating the amino group of O-tert-butyl-L-tyrosine-2, 2,4,6, 7-pentamethyl dihydrobenzofuran-5-sulfonyl-L-arginine-hexadecanol;
and step 6), removing the tertiary butyl and 2,2,4,6, 7-pentamethyl dihydrobenzofuran-5-sulfonyl-L-arginine-hexadecyl alcohol protecting groups on the N-acetyl-O-tertiary butyl-L-tyrosine-2, 2,4,6, 7-pentamethyl dihydrobenzofuran-5-sulfonyl to obtain the final product N-acetyl-L-tyrosyl-L-arginine hexadecyl ester.
3. The method of synthesizing hexadecyl N-acetyl-L-tyrosyl-L-arginine according to claim 2, wherein in the step 1), the molar ratio of the N-fluorenylmethoxycarbonyl-2, 2,4,6, 7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine to the cetyl alcohol is 1: 1-1: 5.
4. the method for synthesizing hexadecyl N-acetyl-L-tyrosyl-L-arginine according to claim 2, wherein in the step 1), the N-fluorenylmethoxycarbonyl-2, 2,4,6, 7-pentamethyl dihydrobenzofuran-5-sulfonyl-L-arginine is subjected to esterification reaction with hexadecanol, dissolved and reacted in a newly distilled solvent, and the reaction is carried out for a certain time at a proper concentration, the reaction is monitored by TLC (thin layer chromatography) to be complete, and the product is obtained by column chromatography separation;
preferably, the solvent is a conventional organic solvent including, but not limited to: dichloromethane, ethyl acetate, DMF, DMSO;
preferably, DCC/DMAP, PyBOP/DIPEA, HATU/DIPEA, PyBOP/HOBt and DIC/Oxyma are used as activation conditions, and more preferably, DIC and Oxyma are used, wherein the molar ratio of DIC to Oxyma is 1: 1-1.5.
5. The method for synthesizing N-acetyl-L-tyrosyl-L-arginine hexadecyl ester according to claim 2, wherein in the step 2), the reaction for removing the N-fluorenylmethoxycarbonyl acyl protective group is carried out in a morpholine system, the TLC monitors the reaction to be complete, and the product is obtained by column chromatography separation;
preferably, the morpholine system is a mixture of an organic solvent and morpholine, including but not limited to: dichloromethane, ethyl acetate, DMF, DMSO, further preferably, the volume ratio of the mixture is 1: 1;
preferably, after the reaction is completed, the mixture is diluted by dichloromethane, then is washed by hydrochloric acid aqueous solution and saturated sodium chloride aqueous solution, an organic phase is dried by anhydrous sodium sulfate, a drying agent is filtered out, and filtrate is concentrated and dried in a spinning mode;
preferably, the column chromatography solvent is a mixture of dichloromethane and methanol, and the volume ratio of the dichloromethane to the methanol is 15: 1;
preferably, the product is separated by column chromatography, diluted with dichloromethane, washed with aqueous hydrochloric acid and saturated aqueous sodium chloride, the organic phase is dried over anhydrous sodium sulfate, the drying agent is filtered off, and the filtrate is concentrated and dried by spinning.
6. The method for synthesizing hexadecyl N-acetyl-L-tyrosyl-L-arginine according to claim 2, wherein in the step 3), 2,2,4,6, 7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine-hexadecanol is subjected to an amide reaction with N-fluorenylmethoxycarbonyl-O-tert-butyl-L-tyrosine in a molar ratio of 1: 1-1: 5.
7. the method for synthesizing hexadecyl N-acetyl-L-tyrosyl-L-arginine according to claim 2, wherein in the step 3), 2,2,4,6, 7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine-hexadecanol and N-fluorenylmethoxycarbonyl-O-tert-butyl-L-tyrosine are subjected to an amide reaction, dissolved in a newly distilled solvent and reacted, the reaction is carried out for a certain time at a proper concentration, the reaction is monitored by TLC to be complete, and the product is obtained by column chromatography separation;
preferably, the solvent is a conventional organic solvent including, but not limited to: dichloromethane, ethyl acetate, DMF, DMSO;
preferably, DCC/DMAP, PyBOP/DIPEA, HATU/DIPEA, PyBOP/HOBt, DIC/Oxyma are used as activation conditions, and further preferably, the molar ratio of HATU to DIPEA is 1: 0.8-2.
Preferably, after the reaction is completed, the mixture is diluted with dichloromethane, washed with an aqueous hydrochloric acid solution and a saturated aqueous sodium chloride solution, the organic phase is dried with anhydrous sodium sulfate, the drying agent is filtered off, the filtrate is concentrated and dried, and then column chromatography separation is performed.
8. The method for synthesizing hexadecyl N-acetyl-L-tyrosyl-L-arginine according to claim 2, wherein in the step 4), the reaction for removing the protective group of the N-fluorenylmethoxycarbonyl-O-tert-butyl-L-tyrosine-2, 2,4,6, 7-pentamethyl dihydrobenzofuran-5-sulfonyl-L-arginine-hexadecyl alcohol ester is carried out in a morpholine system, the TLC monitors the reaction to be complete, and the product is obtained by column chromatography separation;
preferably, the morpholine system is a mixture of an organic solvent and morpholine, including but not limited to: dichloromethane, ethyl acetate, DMF, DMSO, further preferably, the volume ratio of the mixture is 1: 1;
preferably, after the reaction is completed, dichloromethane is used for dilution, hydrochloric acid aqueous solution and saturated sodium chloride aqueous solution are used for washing, an organic phase is dried by anhydrous sodium sulfate, a drying agent is filtered out, a filtrate is concentrated and dried, and then column chromatography separation is carried out; preferably, the column chromatography solvent is a mixture of dichloromethane and methanol, and the volume ratio of the dichloromethane to the methanol is 20: 1.
9. the method for synthesizing N-acetyl-L-tyrosyl-L-arginine hexadecyl ester according to claim 2, wherein in the step 5), the acetyl protection of the amino group on O-tert-butyl-L-tyrosine-2, 2,4,6, 7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine-hexadecanol is performed by adding acetic anhydride and triethylamine to a dichloromethane solvent, stirring at room temperature until TLC monitors the completion of the reaction, adding methanol to quench the reaction, and performing column chromatography to separate the product.
10. The method for synthesizing N-acetyl-L-tyrosyl-L-arginine hexadecyl ester according to claim 2, characterized in that in the step 6), the removal of the tert-butyl and 2,2,4,6, 7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine-hexadecanol protecting groups on the N-acetyl-O-tert-butyl-L-tyrosine-2, 2,4,6, 7-pentamethyldihydrobenzofuran-5-sulfonyl is carried out in trifluoroacetic acid and water (9/1), stirring at room temperature until TLC monitors that the raw materials are complete, concentrating, spin-drying the solvent, adding water to precipitate a solid, the target product N-acetyl-L-tyrosyl-L-arginine hexadecanol ester is obtained with a nearly quantitative yield.
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| CN114805476A (en) * | 2022-04-14 | 2022-07-29 | 南京莱昂生物科技有限公司 | Preparation method of cetyl ester |
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