A kind of synthesis process of acetyl dipeptide-1

Abstract

The invention relates to a synthesis process of acetyl dipeptide-1, and belongs to the technical field of peptides. The process is characterized in that the process comprises the following steps: adding Ac-Tyr-OH and HOSU into a solvent, controlling the temperature at 5-10 DEG C, dripping a DCC solution, and reacting after the dripping is completed; then adding water, arginine hydrochloride and sodium bicarbonate to react; removing the solvent from the reaction product, crystallizing the reaction product, and obtaining acetyl dipeptide-1. The acetyl dipeptide-1 product with a purity of more than 99% can be prepared by a one-pot method, and the process is simple and easy to industrialize.

Description

Technical Field

[0001] The invention relates to the technical field of peptides, and in particular to a synthesis process of acetyl dipeptide-1. Background Art

[0002] The English name of acetyl dipeptide-1 is Acetyl Dipeptide-1, which is a substance containing tyrosine and arginine. Acetyl dipeptide-1 is a neuropeptide that stimulates the production of proendorphins and releases them around the skin nerve endings, reducing pain and heat sensation, making the skin comfortable and relaxed. At the same time, by inhibiting CGRP and SP mediators, it controls plasma extravasation and microvascular dilation, and inhibits the occurrence of red blood streaks and redness and swelling. Through the dual regulation of neurotransmitters that stimulate muscle activity, it relaxes muscles, prevents the appearance of the first wrinkles, improves the depth and length of fine lines, and smoothes dynamic lines, static lines and fine lines.

[0003] Currently, there is no relevant technology for the synthesis process of acetyl dipeptide-1. The present application aims to provide a novel method for synthesizing acetyl dipeptide-1 with a simple process. Summary of the invention

[0004] In view of the above problems existing in the prior art, the present invention provides a synthesis process of acetyl dipeptide-1 which has a simple process method and is easy for industrial production.

[0005] The technical solution of the present invention to solve the above technical problem is as follows: A synthesis process of acetyl dipeptide-1, characterized in that it comprises the following steps:

[0006] Add Ac-Tyr-OH and HOSU (N-hydroxysuccinimide) to the solvent, control the temperature at 5-10°C, and dropwise add DCC (dicyclohexylcarbodiimide) solution until the addition is complete to carry out the reaction;

[0007] Then water, arginine hydrochloride and sodium bicarbonate were added to react;

[0008] After removing the solvent from the reaction product, the product is crystallized to obtain acetyl dipeptide-1.

[0009] Furthermore, the solvent is THF, ethyl acetate, butyl acetate, DMF, acetonitrile, dichloromethane, chloroform or NMP; the solvent in the DCC solution is the same as the reaction solvent of the system.

[0010] Furthermore, the reaction of Ac-Tyr-OH, HOSU and DCC solution is carried out at room temperature.

[0011] Furthermore, the reaction after adding water, arginine hydrochloride and sodium bicarbonate is carried out at room temperature.

[0012] Furthermore, the reaction product is concentrated to remove the solvent, preferably by heating and concentrating to remove the solvent.

[0013] Further, the crystallization process is:

[0014] The pH of the reaction product after the solvent is removed is adjusted to 1.8-2.2, and an organic solvent is used for extraction. The water phase is cooled to 0-5°C, the pH is adjusted to 4.0-4.4, and seed crystals of acetyl dipeptide-1 are added for crystallization. Finally, acetyl dipeptide-1 is obtained after suction filtration and filter cake washing.

[0015] Furthermore, the organic solvent used for extraction is ethyl acetate, butyl acetate or tert-butyl acetate.

[0016] The beneficial effects of the present invention are as follows: the present invention uses Ac-Tyr-OH, HOSU, DCC, arginine hydrochloride and sodium bicarbonate as raw materials, can prepare acetyl dipeptide-1 by a one-pot method, has a simple production process, a product yield of about 70%, and a purity of more than 99%. DETAILED DESCRIPTION

[0017] The principles and features of the present invention are described below. The examples given are only used to explain the present invention but not to limit the scope of the present invention.

[0018] Example 1

[0019] The synthesis process of acetyl dipeptide-1 in this embodiment comprises the following steps:

[0020] 92.4 g of DCC was dissolved in 100 ml of THF and kept at room temperature for later use to prepare a DCC / THF solution.

[0021] In a 2L three-necked flask, add 500mlTHF, 100gAc-Tyr-OH, 51.6gHOSU, keep the internal temperature at 5-10 degrees, add the prepared DCC / THF solution dropwise, and after the dripping is complete, react at an internal temperature of 25 degrees for about 2 hours, then add 600ml water, 94.4gargine hydrochloride, 45.2gsodium bicarbonate. React at an internal temperature of 25 degrees, and perform post-treatment after TLC detection shows that there is no residual raw material.

[0022] The THF was concentrated at an external temperature of 45 degrees, and then the pH was adjusted to 2.0, extracted with ethyl acetate three times (200 ml each time), the internal temperature of the aqueous phase dropped to 0-5 degrees, the pH was adjusted to 4.3, and the seed crystal of acetyl dipeptide-1 was added. After about 3 hours, the filter was filtered and the filter cake was washed with ice water three times, 50 ml each time; the filter cake was dried at 55 degrees to obtain 121.7 g of white solid, with a yield of 71.6% and a purity of 99.2%.

[0023] Example 2

[0024] The synthesis process of acetyl dipeptide-1 in this embodiment comprises the following steps:

[0025] 92.4 g of DCC was dissolved in 100 ml of ethyl acetate and kept at room temperature for later use to prepare a DCC / ethyl acetate solution.

[0026] In a 2L three-necked flask, add 500ml ethyl acetate, 100g Ac-Tyr-OH, and 51.6g HOSU, keep the internal temperature at 5-10 degrees, and drop the prepared DCC / ethyl acetate solution. After the drop is complete, react at an internal temperature of 25 degrees for about 2 hours, then add 600ml water, 94.4g arginine hydrochloride, and 45.2g sodium bicarbonate. React at an internal temperature of 25 degrees, and perform post-treatment after TLC detection shows that there is no residual raw material.

[0027] The solvent was concentrated at an external temperature of 45 degrees, and then the pH was adjusted to 2.0, extracted with butyl acetate 3 times (200 ml each time), the internal temperature of the aqueous phase dropped to 0-5 degrees, the pH was adjusted to 4.3, and the seed crystal of acetyl dipeptide-1 was added. After about 3 hours, it was filtered and the filter cake was washed 3 times with ice water, 50 ml each time; the filter cake was dried at 55 degrees to obtain 119.8 g of white solid, with a yield of 70.5% and a purity of 99.1%.

[0028] Example 3

[0029] The synthesis process of acetyl dipeptide-1 in this embodiment comprises the following steps:

[0030] 92.4 g of DCC was dissolved in 100 ml of DMF and kept at room temperature for later use to prepare a DCC / DMF solution.

[0031] In a 2L three-necked flask, add 500ml DMF, 100g Ac-Tyr-OH, and 51.6g HOSU, keep the internal temperature at 5-10 degrees, and drop the prepared DCC / DMF solution. After the drop is complete, react at an internal temperature of 25 degrees for about 2 hours, then add 600ml water, 94.4g arginine hydrochloride, and 45.2g sodium bicarbonate. React at an internal temperature of 25 degrees, and perform post-treatment after TLC detection shows that there is no residual raw material.

[0032] The solvent was concentrated at an external temperature of 45 degrees, and then the pH was adjusted to 2.0, and extracted with dichloromethane for 3 times (200 ml each time), the internal temperature of the aqueous phase was reduced to 0-5 degrees, the pH was adjusted to 4.3, and the seed crystal of acetyl dipeptide-1 was added. After about 3 hours, suction filtration was performed, and the filter cake was washed with ice water for 3 times, 50 ml each time; the filter cake was dried at 55 degrees to obtain 118.1 g of white solid. The yield was 69.5%, and the purity was 98.7%.

[0033] Comparative Example 1

[0034] The synthesis process of this comparative example is basically the same as that of Example 1, except that the extraction solvent ethyl acetate is replaced by dichloromethane. The final yield is 90.4 g, the yield is 53.2%, and the purity is 97.8%.

[0035] Comparative Example 2

[0036] The synthesis process of this comparative example is basically the same as that of Example 1, except that the extraction solvent ethyl acetate is replaced by methyl tert-ether. The final yield is 76.5 g, the yield is 45%, and the purity is 95.4%.

[0037] Comparative Example 3

[0038] 184.8 g of DCC was dissolved in 200 ml of DMF and kept at room temperature for later use to prepare a DCC / DMF solution.

[0039] In a 5L three-necked flask, add 1000ml DMF, 200g Ac-Tyr-OH, and 103.2g HOSU, keep the internal temperature at 5-10 degrees, and drop the prepared DCC / DMF solution. After the drop is complete, react at an internal temperature of 25 degrees for about 2 hours, then add 1200ml water, 188.8g arginine hydrochloride, and 90.4g sodium bicarbonate. React at an internal temperature of 25 degrees, and perform post-treatment after TLC detection shows that there is no residual raw material.

[0040] The solvent was concentrated at an external temperature of 45 degrees, and then the pH was adjusted to 2.0, and extracted with ethyl acetate for 3 times (400 ml each time), the internal temperature of the aqueous phase was reduced to 0-5 degrees, the pH was adjusted to 3.8, and the seed crystal of acetyl dipeptide-1 was added. After about 3 hours, the filter was filtered, and the filter cake was washed with ice water for 3 times, 100 ml each time; the filter cake was dried at 55 degrees to obtain 222g of white solid. The yield was 65.3%, and the purity was 97.7%.

[0041] Comparative Example 4

[0042] 184.8 g of DCC was dissolved in 200 ml of DMF and kept at room temperature for later use to prepare a DCC / DMF solution.

[0043] In a 5L three-necked flask, add 1000ml DMF, 200g Ac-Tyr-OH, and 103.2g HOSU, keep the internal temperature at 5-10 degrees, and drop the prepared DCC / DMF solution. After the drop is complete, react at an internal temperature of 25 degrees for about 2 hours, then add 1200ml water, 188.8g arginine hydrochloride, and 90.4g sodium bicarbonate. React at an internal temperature of 25 degrees, and perform post-treatment after TLC detection shows that there is no residual raw material.

[0044] The solvent was concentrated at an external temperature of 45 degrees, and then the pH was adjusted to 2.0, and extracted with ethyl acetate for 3 times (400 ml each time), the internal temperature of the aqueous phase was reduced to 0-5 degrees, the pH was adjusted to 4.5, and the seed crystal of acetyl dipeptide-1 was added. After about 3 hours, suction filtration was performed, and the filter cake was washed with ice water for 3 times, 100 ml each time; the filter cake was dried at 55 degrees to obtain 214.8 g of white solid. The yield was 63.2%, and the purity was 97.3%.

Claims

1. A synthesis process of acetyl dipeptide-1, characterized in that: The one-pot method includes the following steps: Add Ac-Tyr-OH and HOSU to the solvent, control the temperature at 5-10°C, add DCC solution dropwise, and react at room temperature after the addition is complete; the solvent is THF, ethyl acetate, butyl acetate, DMF, acetonitrile, dichloromethane, chloroform or NMP; the solvent in the DCC solution is THF, ethyl acetate, butyl acetate, DMF, acetonitrile, dichloromethane, chloroform or NMP; Then add water, arginine hydrochloride and sodium bicarbonate, and react at room temperature; After the reaction product is freed from solvent, it is crystallized. The crystallization process is as follows: The pH of the reaction product after the solvent is removed is adjusted to 1.8-2.2, and an organic solvent such as ethyl acetate, butyl acetate or tert-butyl acetate is used for extraction. The aqueous phase is cooled to 0-5°C, the pH is adjusted to 4.0-4.4, and seed crystals of acetyl dipeptide-1 are added for crystallization. Finally, the product is filtered and the filter cake is washed to obtain acetyl dipeptide-1.

2. The synthesis process of acetyl dipeptide-1 according to claim 1, characterized in that: The reaction product is concentrated to remove the solvent.

3. The synthesis process of acetyl dipeptide-1 according to claim 2, characterized in that: The reaction product was concentrated by heating to remove the solvent.