CN111302975A - Preparation method of N-tert-butyloxycarbonyl-O-allyl-L-tyrosine - Google Patents
Preparation method of N-tert-butyloxycarbonyl-O-allyl-L-tyrosine Download PDFInfo
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Abstract
The invention relates to the technical field of organic chemistry, in particular to a preparation method of N-tert-butyloxycarbonyl-O-allyl-L-tyrosine, which comprises the following steps: Boc-Tyr-OMe was dissolved in dry THF and CH was added rapidly to the solution2CHCH2Br; dropwise adding DIEA (diisopropylethylamine) into the solution in the step (1) for reaction, adding ethyl acetate for extraction after the reaction is finished, and using NaHCO for extraction liquid3Washing with an aqueous solution; concentrating and crystallizing the ethyl acetate layer to obtain Boc-L-Tyr (allyl) -OMe; dissolving Boc-L-Tyr (allyl) -OMe in a mixed solvent of ethanol and water, and adjusting pH = 9-10 to perform hydrolysis reaction; after the reaction was substantially complete, the impurities were extracted with ethyl acetate, the aqueous phase was collected and adjusted to pH =3-4, extracted with ethyl acetate; concentrating and crystallizing the extracted ethyl acetate phase to obtain Boc-L-Tyr (allyl) -OH. The preparation method of N-tert-butyloxycarbonyl-O-allyl-L-tyrosine provided by the invention is simple in synthesisThe method has the advantages of low cost, high yield and convenience for large-scale production.
Description
Technical Field
The invention relates to the technical field of organic chemistry, in particular to a preparation method of N-tert-butyloxycarbonyl-O-allyl-L-tyrosine.
Background
N-tert-butyloxycarbonyl-O-allyl-L-tyrosine is an important intermediate for polypeptide synthesis. The existing preparation method for preparing N-tert-butyloxycarbonyl-O-allyl-L-tyrosine generally comprises the following steps: firstly, dissolving NaH in DMF at-10 ℃; secondly, slowly adding a DMF solution of Boc-Tyr-OH to the DMF solution of NaH obtained in the step one at-10 ℃; thirdly, CH is dripped at-10 DEG C2CHCH2Br; fourthly, after 48 hours of reaction, crude Boc-Tyr (allyl) -OH is obtained through treatment; fifthly, dissolving the crude Boc-Tyr (allyl) -OH in ethyl acetate, and adding DCHA to obtain the crude Boc-Tyr (allyl) -OH DCHA; sixthly, recrystallizing the crude Boc-Tyr (allyl) -OH DCHA product to obtain a refined Boc-Tyr (allyl) -OH DCHA product; seventhly, removing DCHA salt from the Boc-Tyr (allyl) -OH DCHA fine product, and performing post-treatment to obtain the Boc-Tyr (allyl) -OH. The method has the disadvantages of harsh synthesis conditions, active, flammable and toxic raw material NaH, high synthesis risk, more product impurities, and 30 percent or so of total yield, and is not beneficial to mass production.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: the preparation method of the N-tert-butyloxycarbonyl-O-allyl-L-tyrosine overcomes the technical problems of toxic and flammable raw materials and low product purity and yield in the preparation method of the N-tert-butyloxycarbonyl-O-allyl-L-tyrosine in the prior art, and provides the preparation method of the N-tert-butyloxycarbonyl-O-allyl-L-tyrosine with low risk and high yield.
The technical scheme for solving the technical problems is as follows:
a preparation method of N-tert-butyloxycarbonyl-O-allyl-L-tyrosine comprises the following steps:
(1) Boc-Tyr-OMe was dissolved in dry THF and CH was added to the solution2CHCH2Br；
(2) Dropwise adding DIEA (diisopropylethylamine) into the solution in the step (1) for reaction, adding ethyl acetate for extraction after the reaction is finished, and using NaHCO for extraction liquid3Washing with an aqueous solution; concentrating and crystallizing the ethyl acetate layer to obtain Boc-L-Tyr (allyl) -OMe;
(3) dissolving Boc-L-Tyr (allyl) -OMe obtained in the step (2) in a mixed solvent of ethanol and water, and adjusting the pH value to 9-10 by using NaOH to perform hydrolysis reaction; after the reaction is almost complete, extracting impurities by using ethyl acetate, collecting an aqueous phase, adjusting the pH to 3-4, and extracting by using ethyl acetate; concentrating and crystallizing the extracted ethyl acetate phase to obtain Boc-L-Tyr (allyl) -OH; the specific reaction formula is as follows: Boc-Tyr-OMe + CH2CHCH2Br+DIEA→Boc-L-Tyr(allyl)-OMe+NaOH→Boc-L-Tyr(allyl)-OH。
Preferably, the mass of THF added in the step (1) is 3-10 times of that of Boc-Tyr-OMe.
Preferably, in said step (1), Boc-Tyr-OMe is reacted with CH2CHCH2The molar ratio of Br is 1: 1-2; further, in the step (1), Boc-Tyr-OMe is reacted with CH2CHCH2The molar ratio of Br is 1: 1 to 1.2.
Preferably, the mole ratio of Boc-Tyr-OMe to DIEA in step (2) is 1: 1-2; further, the mole ratio of Boc-Tyr-OMe to DIEA in the step (2) is 1: 1 to 1.2.
Preferably, the reaction temperature in the steps (1) and (2) is controlled below 0 ℃.
Preferably, the reaction time in the step (2) is 1-6 h, and the mass of the added ethyl acetate after the reaction is finished is 1-3 times of that of the reaction liquid; added NaHCO3NaHCO in aqueous solution3The mass concentration of the NaHCO is 3-10%3The adding amount of the aqueous solution is 30-150% of the mass of the reaction solution, and the aqueous solution can be added for multiple timesAnd (6) adding.
Preferably, in the mixed solvent of ethanol and water in the step (3), the volume ratio of ethanol to water is 1: 0.5 to 2; further, the volume ratio of ethanol to water is 1: 1.
preferably, the mass of the mixed solvent of ethanol and water in the step (3) is 6-15 times of that of Boc-L-Tyr (allyl) -OMe.
Preferably, the reagent used for adjusting pH 3 to 4 in step (3) is 2N HCl.
The preparation method of N-tert-butyloxycarbonyl-O-allyl-L-tyrosine provided by the invention is simple in synthesis, low in cost, high in yield and convenient for large-scale production.
Drawings
FIG. 1 shows a Boc-L-Tyr (allyl) -OH IR spectrum obtained according to an embodiment of the present invention;
FIG. 2 shows a Boc-L-Tyr (allyl) -OH nuclear magnetic spectrum obtained by the embodiment of the invention.
Detailed Description
The invention is illustrated but not limited by the following examples. The technical solutions protected by the present invention are all the simple replacements or modifications made by the skilled person in the art.
Some of the abbreviations commonly used in the present invention have the following meanings:
Boc-Tyr-OMe Boc-L-tyrosine methyl ester
CH2CHCH2Br3-bromopropene
DIEA N, N-diisopropylethylamine
Boc-L-Tyr (allyl) -OMe N-tert-butyloxycarbonyl-O-allyl-L-tyrosine methyl ester
Boc-L-Tyr (allyl) -OH N-tert-butyloxycarbonyl-O-allyl-L-tyrosine
Example 1:
(1) 100g (0.3386mol) of Boc-Tyr-OMe were dissolved in 1L of dry THF; 49g (0.4063mol) of CH2CHCH2B, quickly adding Br into the step a, and keeping the temperature of the reaction solution below 0 ℃ in the feeding process;
(2) 52.5g (0.4063mol) DIEA are added dropwise at below 0 DEGPutting the mixture into a system; the reaction was carried out for 4 hours, 2.5L of ethyl acetate were added and extracted, and the organic phase was washed with 5% NaHCO3Washing with water solution for 3 times, 0.5L each time; washing the organic phase twice with 1L of water, drying, concentrating at least a little to crystallize, filtering and drying to obtain 103g of Boc-Tyr (allyl) -OMe;
(3) 103g (0.3071mol) of Boc-Tyr (allyl) -OMe were dissolved in 500ml of ethanol and 500ml of water, and 6N NaOH was used to adjust pH to 9-10 for hydrolysis; after the reaction is almost complete, extracting impurities with ethyl acetate for 2 times, 500ml each time; adjusting the pH of the water phase to 3-4 by using 2N HCl, and adding 1L ethyl acetate to extract a product; after the ethyl acetate phase is washed by water and dried, at least a little of the ethyl acetate phase is concentrated and crystallized to obtain Boc-L-Tyr (allyl) -OH 72g (0.224mol), and the purity is 99.34 percent and the yield is 66.2 percent by HPLC detection. The structure is confirmed by infrared and nuclear magnetism.
Example 2:
(1) 100g (0.3386mol) of Boc-Tyr-OMe were dissolved in 1L of dry THF; 40.1g (0.3386mol) of CH2CHCH2B, quickly adding Br into the step a, and keeping the temperature of the reaction solution below 0 ℃ in the feeding process;
(2) 43.8g (0.3386mol) of DIEA was added dropwise to the system at a temperature below 0 ℃; the reaction was carried out for 4 hours, 2.5L of ethyl acetate were added and extracted, and the organic phase was washed with 5% NaHCO3Washing with water solution for 3 times, 0.5L each time; washing the organic phase twice with 1L of water, drying, concentrating at least a little to crystallize, filtering and drying to obtain 99g of Boc-Tyr (allyl) -OMe;
(3) 99g (0.2952mol) of Boc-Tyr (allyl) -OMe were dissolved in 500ml of ethanol and 500ml of water, and the pH was adjusted to 9-10 with 6N NaOH to carry out hydrolysis; after the reaction is almost complete, extracting impurities with ethyl acetate for 2 times, 500ml each time; adjusting the pH of the water phase to 3-4 by using 2N HCl, and adding 1L ethyl acetate to extract a product; after washing and drying the ethyl acetate phase, concentrating at least a little to crystallize to obtain Boc-L-Tyr (allyl) -OH 71g (0.221mol), and the purity is 99.45% by HPLC detection, and the yield is 65.3%. The structure is confirmed by infrared and nuclear magnetism.
Example 3:
(1) 100g (0.3386mol) of Boc-Tyr-OMe were dissolved in 1L of dry THF; 81.0g (0.6772mol) of CH2CHCH2B, quickly adding Br into the step a, and keeping the temperature of the reaction solution below 0 ℃ in the feeding process;
(2)adding dropwise 87.5g (0.6772mol) of DIEA into the system at a temperature below 0 ℃; the reaction was carried out for 4 hours, 2.5L of ethyl acetate were added and extracted, and the organic phase was washed with 5% NaHCO3Washing with water solution for 3 times, 0.5L each time; washing the organic phase twice with 1L of water, drying, concentrating at least a little to crystallize, filtering and drying to obtain 115g of Boc-Tyr (allyl) -OMe;
(3) 115g (0.3429mol) of Boc-Tyr (allyl) -OMe were dissolved in 500ml of ethanol and 500ml of water, and 6N NaOH was used to adjust pH to 9-10 for hydrolysis; after the reaction is almost complete, extracting impurities with ethyl acetate for 2 times, 500ml each time; adjusting the pH of the water phase to 3-4 by using 2N HCl, and adding 1L ethyl acetate to extract a product; after the ethyl acetate phase is washed by water and dried, at least a little of the ethyl acetate phase is concentrated and crystallized to obtain 70g (0.2178mol) of Boc-L-Tyr (allyl) -OH, the purity is 99.50 percent by HPLC detection, and the yield is 64.3 percent. The structure is confirmed by infrared and nuclear magnetism.
Example 4:
(1) 100g (0.3386mol) of Boc-Tyr-OMe were dissolved in 1L of dry THF; 49.0g (0.4063mol) of CH2CHCH2B, quickly adding Br into the step a, and keeping the temperature of the reaction solution below 0 ℃ in the feeding process;
(2) adding 52.5g (0.4063mol) of DIEA dropwise into the system below 0 ℃; the reaction was carried out for 4 hours, 2.5L of ethyl acetate were added and extracted, and the organic phase was washed with 5% NaHCO3Washing with water solution for 3 times, 0.5L each time; washing the organic phase twice with 1L of water, drying, concentrating at least a little to crystallize, filtering and drying to obtain 105g of Boc-Tyr (allyl) -OMe;
(3) 105g (0.3131mol) of Boc-Tyr (allyl) -OMe were dissolved in 500ml of ethanol and 500ml of water, and 6N NaOH was used to adjust pH to 9-10 for hydrolysis; after the reaction is almost complete, extracting impurities with ethyl acetate for 2 times, 500ml each time; adjusting the pH of the water phase to 3-4 by using 2N HCl, and adding 1L ethyl acetate to extract a product; after washing and drying the ethyl acetate phase, concentrating at least a little to crystallize to obtain 70g (0.221mol) of Boc-L-Tyr (allyl) -OH, the purity is 99.47% by HPLC detection, and the yield is 64.3%. The structure is confirmed by infrared and nuclear magnetism.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various changes and modifications can be made without departing from the inventive concept of the present invention, and these changes and modifications are all within the scope of the present invention.
Claims (9)
1. A preparation method of N-tert-butyloxycarbonyl-O-allyl-L-tyrosine is characterized by comprising the following steps:
(1) Boc-Tyr-OMe was dissolved in dry THF and CH was added to the solution2CHCH2Br；
(2) Dropwise adding DIEA (diisopropylethylamine) into the solution in the step (1) for reaction, adding ethyl acetate for extraction after the reaction is finished, and using NaHCO for extraction liquid3Washing with an aqueous solution; concentrating and crystallizing the ethyl acetate layer to obtain Boc-L-Tyr (allyl) -OMe;
(3) dissolving Boc-L-Tyr (allyl) -OMe obtained in the step (2) in a mixed solvent of ethanol and water, and adjusting the pH value to 9-10 by using NaOH to perform hydrolysis reaction; after the reaction is almost complete, extracting impurities by using ethyl acetate, collecting an aqueous phase, adjusting the pH to 3-4, and extracting by using ethyl acetate; concentrating and crystallizing the extracted ethyl acetate phase to obtain Boc-L-Tyr (allyl) -OH.
2. The method for preparing N-t-butoxycarbonyl-O-allyl-L-tyrosine as claimed in claim 1, wherein the mass of THF added in the step (1) is 3-10 times of the mass of Boc-Tyr-OMe.
3. The method for preparing N-t-butoxycarbonyl-O-allyl-L-tyrosine as claimed in claim 1, wherein the Boc-Tyr-OMe is reacted with CH in the step (1)2CHCH2The molar ratio of Br is 1: 1-2; further, in the step (1), Boc-Tyr-OMe is reacted with CH2CHCH2The molar ratio of Br is 1: 1 to 1.2.
4. The method of preparing N-t-butoxycarbonyl-O-allyl-L-tyrosine as claimed in claim 1, wherein the molar ratio of Boc-Tyr-OMe to DIEA in the step (2) is 1: 1-2; further, the mole ratio of Boc-Tyr-OMe to DIEA in the step (2) is 1: 1 to 1.2.
5. The process for producing N-t-butoxycarbonyl-O-allyl-L-tyrosine as claimed in claim 1, wherein the reaction temperature in the step (2) is controlled to 0 ℃ or lower.
6. The method for preparing N-tert-butoxycarbonyl-O-allyl-L-tyrosine as claimed in claim 1, wherein the reaction time in the step (2) is 1-6 h, and the mass of ethyl acetate added after the reaction is finished is 1-3 times of the mass of the reaction solution; added NaHCO3NaHCO in aqueous solution3The mass concentration of the NaHCO is 3-10%3The adding amount of the aqueous solution is 30-150% of the mass of the reaction solution.
7. The process for producing N-t-butoxycarbonyl-O-allyl-L-tyrosine as claimed in claim 1, wherein in the mixed solvent of ethanol and water in the step (3), the volume ratio of ethanol to water is 1: 0.5 to 2.
8. The method of producing N-t-butoxycarbonyl-O-allyl-L-tyrosine as claimed in claim 1, wherein the mass of the mixed solvent of ethanol and water in the step (3) is 6 to 15 times that of Boc-L-Tyr (allyl) -OMe.
9. The process for preparing N-t-butoxycarbonyl-O-allyl-L-tyrosine as claimed in claim 1, wherein the reagent used for adjusting pH 3-4 in the step (3) is 2N HCl.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002085923A2 (en) * | 2001-04-19 | 2002-10-31 | The Scripps Research Institute | In vivo incorporation of unnatural amino acids |
| CN102659619A (en) * | 2012-04-18 | 2012-09-12 | 上海骏捷生化科技有限公司 | Method for synthesis of tyrosine derivative |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002085923A2 (en) * | 2001-04-19 | 2002-10-31 | The Scripps Research Institute | In vivo incorporation of unnatural amino acids |
| CN102659619A (en) * | 2012-04-18 | 2012-09-12 | 上海骏捷生化科技有限公司 | Method for synthesis of tyrosine derivative |
Non-Patent Citations (4)
| Title |
|---|
| CHIEN TRAN VAN等: "Macrocyclic analogues of the diuretic insect neuropeptide helicokinin I show strong receptor-binding", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| GUILLERMO TOUS等: "0"-(Epoxyalkyl)tyrosines and (Epoxyalkyl)phenylalanine as Irreversible Inactivators of Serine Proteases: Synthesis and Inhibition Mechanism", 《J. MED. CHEM.》 * |
| SHANE L.MANGOLD和ROBERT H. GRUBBS: "Stereoselective synthesis of macrocyclic peptides via a dual olefin metathesis and ethenolysis approach", 《CHEM. SCI.》 * |
| 宋小礼等: "N-叔丁氧酰基-O-烷基-L-酪氨酸甲酯的合成工艺研究", 《西南大学学报（自然科学版）》 * |
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Application publication date: 20200619 |