CN115073352A - Synthetic method of 2,5, 7-tri-tert-butyl tryptophan - Google Patents

Synthetic method of 2,5, 7-tri-tert-butyl tryptophan Download PDF

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Publication number
CN115073352A
CN115073352A CN202210738756.0A CN202210738756A CN115073352A CN 115073352 A CN115073352 A CN 115073352A CN 202210738756 A CN202210738756 A CN 202210738756A CN 115073352 A CN115073352 A CN 115073352A
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tert
tri
tryptophan
butyl
synthesizing
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徐红岩
李响
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Jill Peptide Biopharmaceutical Dalian Co ltd
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Jill Peptide Biopharmaceutical Dalian Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/584—Recycling of catalysts

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)

Abstract

The invention relates to a synthetic method of 2,5, 7-tri-tert-butyl tryptophan. Mainly solves the technical problems of long reaction time, low yield and low purity of the existing synthetic method. The invention is realized by the following technical scheme: a synthetic method of 2,5, 7-tri-tert-butyl tryptophan is characterized in that tryptophan is dissolved in tert-butyl alcohol and trifluoroacetic acid, a catalyst is added, and after the heating reaction is finished, the 2,5, 7-tri-tert-butyl tryptophan with high purity is obtained through refining.

Description

Synthetic method of 2,5, 7-tri-tert-butyl tryptophan
Technical Field
The invention relates to a synthetic method of 2,5, 7-tri-tert-butyl tryptophan with optimized synthetic conditions.
Background
Due to the development of drug resistance, the search for new antibiotics has attracted a great deal of attention from the pharmaceutical industry and academic research groups, and in recent years, several cationic antibacterial peptides have been clinically studied as potential future antibiotics. The antibacterial peptide molecules replace tryptophan with 2,5, 7-tri-tert-butyl tryptophan, so that the antibacterial property of the medicine can be greatly enhanced. Various documents describe the synthesis method of the compound, such as WO 2012026989, WO2000012542, US20080019993, Journal of Medicinal Chemistry (51, 4306-.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a method for synthesizing 2,5, 7-tri-tert-butyl tryptophan with optimized synthesis conditions. Mainly solves the technical problems of long reaction time, low yield, low product purity and the like of the existing synthesis method.
The invention is realized by the following technical scheme:
a method for synthesizing 2,5, 7-tri-tert-butyl tryptophan is characterized by comprising the following steps: dissolving tryptophan in tert-butyl alcohol and trifluoroacetic acid, adding a catalyst, heating to react, and refining to obtain high-purity 2,5, 7-tri-tert-butyl tryptophan.
In a preferred embodiment, in the above reaction, the catalyst is one of methanesulfonic acid, ethylsulfonic acid, isopropylsulfonic acid, phenylsulfonic acid, and p-methylbenzenesulfonic acid, and methanesulfonic acid is preferred.
In the above reaction, the catalyst is used in an amount of 5 to 25% by weight, preferably 8 to 12% by weight, based on the trifluoroacetic acid.
In the above reaction, tert-butanol is used in an amount 4 to 8 times (by weight) that of tryptophan, and trifluoroacetic acid is used in an amount 8 to 12 times (by weight) that of tryptophan.
In the above reaction, the reaction temperature is 60 to 70 ℃ and the reaction time is 5 to 15 hours, preferably 8 to 10 hours.
In the above reaction, the mixed solvent used for purification is methanol, ethanol or isopropanol/water in a weight ratio of =1/1-3, preferably isopropanol/water in a weight ratio of = 1/2.
In the above reaction, in the refining process, after dissolving the crude product, it is necessary to stand at 5-10 ℃ for 15-20 hours.
The specific process route of the invention is as follows:
Figure DEST_PATH_IMAGE001
the invention has the beneficial effects that: the conversion rate of raw materials is improved by adding the catalyst and controlling the reaction temperature and the reaction time, and the research finds that the conversion rate is reduced along with the prolonging of the reaction time. The purity and yield of the product are improved by refining the preferred mixed solvent of isopropanol and water.
Detailed Description
The following provides a detailed description of the preferred embodiments of the present invention.
Example 1
Adding tryptophan (20 g), tert-butyl alcohol (100 g), trifluoroacetic acid (200 g) and methanesulfonic acid (20 g) into a three-necked flask, raising the temperature to 60 ℃, stirring and reacting for 10 hours, wherein the conversion rate of raw materials is more than 90%, removing most of solvent under reduced pressure, adjusting the pH value to 7-8 with sodium bicarbonate, filtering, heating and dissolving a filter cake by using isopropanol and water (the weight ratio of 2/1), standing for 20 hours at 5-10 ℃, filtering, and drying the filter cake under reduced pressure to obtain 28 g of a product, wherein the yield is 75%, and the purity is 97%.
1 H NMR (CDCl 3 ): δ=1.36 (9H, s), 1.48 (9H, s), 1.51 (9H, s), 7.47 (1H, s), 7.20 (1H, s), 5.31 (1H, s)。
Example 2
Tryptophan (20 g), tert-butanol (100 g), trifluoroacetic acid (200 g) and methanesulfonic acid (20 g) were added to a three-necked flask, and the mixture was heated to 60 ℃ and stirred for 20 hours to achieve a raw material conversion of 75% and a yield of 51% as in example 1.
1 H NMR (CDCl 3 ): δ=1.36 (9H, s), 1.48 (9H, s), 1.51 (9H, s), 7.47 (1H, s), 7.20 (1H, s), 5.31 (1H, s)。
Example 3
Tryptophan (20 g), tert-butanol (100 g), trifluoroacetic acid (200 g) and methanesulfonic acid (40 g) were added to a three-necked flask, and the mixture was heated to 60 ℃ and stirred for 10 hours to achieve a conversion of the starting material of 78% and a yield of 56% as in example 1.
1 H NMR (CDCl 3 ): δ=1.36 (9H, s), 1.48 (9H, s), 1.51 (9H, s), 7.47 (1H, s), 7.20 (1H, s), 5.31 (1H, s)。
Example 4
Tryptophan (20 g), tert-butanol (80 g), trifluoroacetic acid (160 g) and methanesulfonic acid (16 g) were added to a three-necked flask, and the reaction was stirred at 60 ℃ for 15 hours, in the same manner as in example 1, except that the yield was 72%.
1 H NMR (CDCl 3 ): δ=1.36 (9H, s), 1.48 (9H, s), 1.51 (9H, s), 7.47 (1H, s), 7.20 (1H, s), 5.31 (1H, s).
Example 5
Tryptophan (20 g), tert-butanol (160 g), trifluoroacetic acid (240 g) and methanesulfonic acid (22 g) were added to a three-necked flask, and the reaction was stirred at 60 ℃ for 10 hours, in the same manner as in example 1, except that the yield was 68%.
H NMR (CDCl 3 ): δ=1.36 (9H, s), 1.48 (9H, s), 1.51 (9H, s), 7.47 (1H, s), 7.20 (1H, s), 5.31 (1H, s)。
Example 6
Tryptophan (20 g), tert-butanol (100 g), trifluoroacetic acid (200 g) and methanesulfonic acid (10 g) were added to a three-necked flask, and the reaction was stirred at 60 ℃ for 15 hours, and the other operations were performed in the same manner as in example 1, with a yield of 45%.
H NMR (CDCl 3 ): δ=1.36 (9H, s), 1.48 (9H, s), 1.51 (9H, s), 7.47 (1H, s), 7.20 (1H, s), 5.31 (1H, s)。

Claims (9)

1. A method for synthesizing 2,5, 7-tri-tert-butyl tryptophan is characterized by comprising the following steps: dissolving tryptophan in tert-butyl alcohol and trifluoroacetic acid, adding a catalyst, heating to react, and refining to obtain high-purity 2,5, 7-tri-tert-butyl tryptophan.
2. The method for synthesizing 2,5, 7-tri-tert-butyl tryptophan according to claim 1, wherein the catalyst is one of methanesulfonic acid, ethanesulfonic acid, isopropylsulfonic acid, phenylsulfonic acid or p-methylbenzenesulfonic acid.
3. The method for synthesizing 2,5, 7-tri-tert-butyl tryptophan according to claim 2, wherein the catalyst is methanesulfonic acid.
4. The method for synthesizing 2,5, 7-tri-tert-butyl tryptophan according to claim 1, wherein the amount of methanesulfonic acid used as a catalyst is 5-25 wt% of trifluoroacetic acid, the amount of tert-butanol is 4-8 times of tryptophan, and the amount of trifluoroacetic acid is 8-12 times of tryptophan.
5. The method for synthesizing 2,5, 7-tri-tert-butyl tryptophan according to claim 4, wherein the amount of the catalyst methyl is 8-12% of the weight of the trifluoroacetic acid.
6. The method for synthesizing 2,5, 7-tri-tert-butyl tryptophan according to claim 1, wherein the reaction temperature is 60-70 ℃ and the reaction time is 5-15 hours.
7. The method for synthesizing 2,5, 7-tri-tert-butyl tryptophan according to claim 6, wherein the reaction time is 8-10 hours.
8. The method for synthesizing 2,5, 7-tri-tert-butyl tryptophan according to claim 1, wherein a mixed solvent is adopted for purification, and after a crude product is dissolved, the mixed solvent is kept for 15-20 hours at 5-10 ℃, and the mixed solvent is one of methanol, ethanol or isopropanol/water in a weight ratio = 1/1-3.
9. The method for synthesizing 2,5, 7-tri-tert-butyl tryptophan according to claim 1, wherein the mixed solvent is isopropanol/water with a weight ratio = 1/2.
CN202210738756.0A 2022-06-28 2022-06-28 Synthetic method of 2,5, 7-tri-tert-butyl tryptophan Pending CN115073352A (en)

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000012541A2 (en) * 1998-08-28 2000-03-09 Alpharma As Cytotoxic peptides modified by bulky or lipophilic moieties
WO2005014568A2 (en) * 2003-08-04 2005-02-17 Great Lakes Chemical (Europe) Gmbh Production of dialkylated hydroquinones
CN101613258A (en) * 2009-07-21 2009-12-30 广东省食品工业研究所 A kind of 2, the preparation method of 5-ditert-butylhydro quinone
WO2012026988A2 (en) * 2010-08-27 2012-03-01 New York University Dendrimeric peptides, pharmaceutical compositions and methods of using the same
CN104003847A (en) * 2014-05-16 2014-08-27 华南理工大学 Directional synthetic method of 2, 5-di tertiary butyl hydroquinone
CN106317382A (en) * 2015-06-30 2017-01-11 江苏圣奥化学科技有限公司 Preparation method of anti-aging agent
US20180339966A1 (en) * 2017-04-21 2018-11-29 Regents Of The University Of Minnesota Therapeutic compounds
KR20220017695A (en) * 2020-08-05 2022-02-14 주식회사 레미바이오 Ascorbic acid derivative and composition including thereof

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000012541A2 (en) * 1998-08-28 2000-03-09 Alpharma As Cytotoxic peptides modified by bulky or lipophilic moieties
WO2005014568A2 (en) * 2003-08-04 2005-02-17 Great Lakes Chemical (Europe) Gmbh Production of dialkylated hydroquinones
CN101613258A (en) * 2009-07-21 2009-12-30 广东省食品工业研究所 A kind of 2, the preparation method of 5-ditert-butylhydro quinone
WO2012026988A2 (en) * 2010-08-27 2012-03-01 New York University Dendrimeric peptides, pharmaceutical compositions and methods of using the same
CN104003847A (en) * 2014-05-16 2014-08-27 华南理工大学 Directional synthetic method of 2, 5-di tertiary butyl hydroquinone
CN106317382A (en) * 2015-06-30 2017-01-11 江苏圣奥化学科技有限公司 Preparation method of anti-aging agent
US20180339966A1 (en) * 2017-04-21 2018-11-29 Regents Of The University Of Minnesota Therapeutic compounds
KR20220017695A (en) * 2020-08-05 2022-02-14 주식회사 레미바이오 Ascorbic acid derivative and composition including thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
王建新: "《精细有机合成》", pages: 120 - 121 *

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