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CN117658866A - Synthesis method of azido amino acid derivative - Google Patents

Synthesis method of azido amino acid derivative Download PDF

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Publication number
CN117658866A
CN117658866A CN202311670792.9A CN202311670792A CN117658866A CN 117658866 A CN117658866 A CN 117658866A CN 202311670792 A CN202311670792 A CN 202311670792A CN 117658866 A CN117658866 A CN 117658866A
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formula
amino acid
iii
acid derivative
reaction
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汪明中
朱明新
苏道
李金金
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Suzhou Amatek Biotechnology Co ltd
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Suzhou Amatek Biotechnology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups
    • C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C247/12—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes
    • 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
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting 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)

Abstract

The invention relates to a synthesis method of an azido amino acid derivative, which comprises the following steps: step S1, reacting a compound represented by the formula (II)Reacting with an amino protecting agent to produce a compound represented by the formula (III)Step S2, the compound shown in the formula (III) and an azide source are reacted in the presence of a catalyst and a solvent to generate the compound shown in the formula (I) under the action of infrared radiationI.e. the azido amino acid derivative; in the formula (I)The R is 1 is-CH 2 ‑N 3 The method comprises the steps of carrying out a first treatment on the surface of the In the formula (I) and the formula (III), R is 2 Is an amino protecting group; in the formula (II) and the formula (III), R is 3 is-CH 2 -OH. The synthesis method of the invention uses the 2-amino-hydroxymethyl-phenyl propionic acid derivative as a starting material, firstly performs amino protection on the derivative, and then converts hydroxyl into azide groups under the actions of infrared radiation and a catalyst, thus having high yield and simple operation. Furthermore, the use of a strong toxic azide source is avoided, the safety is higher, and the method is more suitable for industrial production.

Description

Synthesis method of azido amino acid derivative
Technical Field
The invention belongs to the technical field of synthesis of organic compounds, and particularly relates to a synthesis method of an azido amino acid derivative.
Background
Unnatural amino acids have found widespread use in the study of proteins, nucleosides, and nucleic acids as part of amino acids: the non-natural amino acid is doped into protein sequence to design new protein, which has important significance in researching the folding and function of natural protein. To date, more than 30 unnatural amino acids have been artificially inserted into the natural proteins synthesized by living organisms. Furthermore, the presence of unnatural amino acids can limit the flexibility of polypeptide conformation, provide deoxyribonucleic acid or ribonucleic acid molecules with stable secondary structures, enhance the stability of polypeptides to enzymes, and enhance pharmacokinetics and biological activity. Therefore, efficient synthesis of unnatural amino acids has become an important topic of research in the chemical and biochemical fields.
Attachment of azide groups to amino acid molecular structures has an important impact on the properties and function of amino acids. First, the presence of azide enables amino acids to form polypeptide chains, which link amino acid molecules together through peptide bonds, thus constituting proteins. Secondly, azide also participates in the regulation of the acid-base and hydrophilic properties of amino acids, affecting the solubility and interaction of amino acids. Whereas the commonly used azide source is NaN 3 However, naN is used 3 As an azide source, the material is easy to explode, and not only is easy to explode due to friction, collision, vibration and the like, but also has strong toxicity and poor safety.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a synthesis method of an azido amino acid derivative with high safety, and the synthesis method is simple to operate, high in yield and suitable for industrial production.
In order to achieve the purpose, the invention adopts the following technical scheme:
a synthesis method of azido amino acid derivatives is provided, wherein the structural formula of the azido amino acid derivatives is shown as formula (I),
the synthesis method comprises the following steps:
step S1, reacting a compound shown in a formula (II) with an amino protective agent to generate a compound shown in a formula (III);
s2, enabling the compound shown in the formula (III) and an azide source to generate the compound shown in the formula (I) under the action of infrared radiation in the presence of a catalyst and a solvent;
the structural formula of the compound shown in the formula (II) is as follows:
the structural formula of the compound shown in the formula (III) is as follows:
in the formula (I), the R 1 is-CH 2 -N 3 The method comprises the steps of carrying out a first treatment on the surface of the In the formula (I) and the formula (III), R is 2 Is an amino protecting group; in the formula (II) and the formula (III), R is 3 is-CH 2 -OH。
In some embodiments, in formula (I), the R 1 Is CH on benzene ring 2 Para, meta or ortho to the group; in the formula (II) and the formula (III), R is 3 Is CH on benzene ring 2 Para, meta or ortho to the group.
In some embodiments, the compound of formula (I) is as follows:
in some embodiments, in step S2, the infrared radiation has a power of 200 to 350W and a radiation temperature of 10 to 40 ℃.
Further, the infrared radiation has a power of 250-300W.
In some embodiments, in step S2, the infrared radiation is for a period of 4 to 8 hours.
In some embodiments, in step S2, the azide source is one or a combination of diphenyl phosphoryl azide (DPPA), azido trimethylsilane. NaN with strong toxicity avoidance 3 The use of the azide source avoids explosion and has higher safety.
In some embodiments, in step S2, the solvent is one or a combination of several of acetone, n-hexane, toluene, dimethyl sulfoxide (DMSO); the catalyst is one or a combination of a plurality of 1, 5-diazabicyclo [4.3.0] -5-nonene (DBN), 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) and Tetramethylguanidine (TMG).
Preferably, in step S2, the solvent is a mixture of acetone and n-hexane. Avoiding the use of toxic solvents such as toluene and the like, and being beneficial to improving the yield of the product.
Further, the volume ratio of the acetone to the n-hexane is 1:0.8-1.2.
Advantageously, the azide source adopts diphenyl phosphoryl azide, the solvent adopts a mixture of acetone and n-hexane, and the reaction is carried out under infrared radiation, so that the reaction can be greatly promoted, the reaction time is greatly shortened, the product yield is high, the experimental operation is simple, the post-treatment is simple, other auxiliary solvents are not needed, and the cost is reduced.
In some embodiments, in step S2, the reaction is performed under an inert gas atmosphere. Such as nitrogen.
In some embodiments, the molar ratio of the compound of formula (III) to the azide source is 1:1 to 1.5; the feeding mole ratio of the compound shown in the formula (III) to the catalyst is 1:0.8-1.2.
In some embodiments, the implementation of step S2 is as follows: under the condition of inert gas, the compound shown in the formula (III) is dissolved in a solvent, then an azide source and a catalyst are added into the system under the condition of ice bath, then the reaction is carried out under the condition of infrared radiation at the temperature of 10-40 ℃, and after the reaction is finished, the reaction is quenched.
In some embodiments, the synthesis method further comprises the step of post-treating the reaction solution after the quenching reaction is completed, wherein the post-treatment comprises drying, spin-drying the solvent and purifying by a chromatographic column.
In some embodiments, the R 2 Boc, fmoc; the amino protecting agent is selected from di-tert-butyl dicarbonate and fluorenylmethoxycarbonyl succinimide (Fmoc-OSu).
In some embodiments, in step S1, the reaction is performed in the presence of a solvent, the solvent being a mixture of an organic solvent and water, the organic solvent being one or a combination of several of dioxane, tetrahydrofuran, N-dimethylformamide.
In some embodiments, in step S1, the reaction is performed at 15 to 40 ℃, and the reaction is performed in the presence of a base, where the base is one or a combination of several of sodium carbonate, sodium hydroxide, sodium bicarbonate, potassium carbonate, and potassium tert-butoxide.
In some embodiments, when the amino protecting agent is di-tert-butyl dicarbonate, the implementation of step S1 is: under ice bath condition, adding the compound shown in the formula (II), a solvent and alkali into a reactor, adding an amino protective agent and alkali into the reactor, reacting for 6-10 hours at 15-40 ℃, spin-drying the solvent, diluting with ethyl acetate in ice bath, acidifying to pH of 2-3, extracting, washing with water, combining organic phases, drying and spin-drying to obtain the compound shown in the formula (III).
In some embodiments, when the amino protecting agent is fluorenylmethoxycarbonyl succinimide, the implementation of step S1 is: under ice bath condition, amino protective agent is dissolved in solvent and then added into a reactor filled with compound shown in formula (II), solvent and alkali, and the compound shown in formula (III) is obtained through reaction for 6-10 h at 15-40 ℃, extraction, pH value adjustment to 1-3, extraction, weak acid water washing, drying, concentration and recrystallization.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
the synthesis method of the invention uses the 2-amino-hydroxymethyl-phenyl propionic acid derivative as a starting material, firstly performs amino protection on the derivative, and then converts hydroxyl into azide groups under the actions of infrared radiation and a catalyst, thus having high yield and simple operation. Furthermore, the use of a strong toxic azide source is avoided, the safety is higher, and the method is more suitable for industrial production.
Drawings
FIG. 1 is a nuclear magnetic resonance spectrum of 3- (4- (azidomethyl) phenyl) -2- ((tert-butoxycarbonyl) amino) propionic acid of example 1.
Detailed Description
The following detailed description of the present invention is provided in connection with specific embodiments so that those skilled in the art may better understand and practice the present invention, but is not intended to limit the scope of the present invention.
The starting materials may be obtained commercially, or prepared by methods known in the art, or prepared according to the methods described herein.
The structure of the compound was obtained by nuclear magnetic resonance (1H-NMR). The NMR measurement was performed using an ACF-400BRUKER type nuclear magnetic resonance apparatus, and the solvent was deuterated chloroform (CDCl) 3 ) Or deuterated dimethyl sulfoxide (DMSO-D) 6 ) Or heavy water (D) 2 O), TMS is an internal standard. Column chromatography adopts 200-300 mesh silica gel (produced by Qingdao ocean chemical plant).
Example 1
This example provides the synthesis of 3- (4- (azidomethyl) phenyl) -2- ((tert-butoxycarbonyl) amino) propanoic acid
The synthesis method comprises the following steps:
step S1, 2-amino-3- (4- (hydroxymethyl) phenyl) propionic acid (1.95 g,10 mmol), dioxane/H under ice bath conditions 2 O (v/v=2:1, 30 mL), naOH (1M, 10 mmol) was added to a 150mL round bottom flask. Will (Boc) 2 O (Boc anhydride) (3.27 g,15 mmol) and NaHCO 3 (10 mmol) was added to the reaction mixture and reacted at room temperature overnight for 8h. The solvent was dried by spinning, the residue diluted with ethyl acetate (40 mL) in an ice bath and acidified with 1.0M HCl to ph=2-3. The aqueous phase was extracted with EtOAc (2X 20 mL), and the organic phases were combined after multiple water washes, anhydrous Na 2 SO 4 Dried and spun-dried to give 2- ((tert-butoxycarbonyl) amino) -3- (4- (hydroxymethyl) phenyl) propanoic acid (2.9 g, 98.1%).
Step S2, at N 2 2- ((tert-Butoxycarbonyl) amino) -3- (4- (hydroxymethyl) phenyl) propanoic acid (2.95 g,10 mmol) was dissolved in a mixed solution of acetone and n-hexane (1:1) (10 mL) under the conditions. Diphenylphosphorylazide (3.0 g,11 mmol) and DBN (1.3 g,10.5 mmol) were then added rapidly to the mixture under ice-bath conditions followed by stirring at room temperature for 6h with infrared radiation from an infrared radiation meter (220 v 275 w). After the reaction was completed, the reaction was quenched with water (10 mL) and 5% aqueous HCl (10 mL) in this order. The reaction mixture was extracted with EtOAc (2X 10 mL). With anhydrous MgSO 4 The solvent was dried and spun dry. Purification by column chromatography followed by elution with hexane/EtOAc (V/v=20/1) afforded 3- (4- (azidomethyl) phenyl) -2- ((tert-butoxycarbonyl) amino) propanoic acid (3.17 g, 99.1%).
Nuclear magnetic results:
1 H NMR(400MHz,CDCl 3 )δ8.03(s,1H),7.30(dt,2H),6.96(dt,2H),6.67(d,1H),4.24(m,3H),3.05(m,2H),1.41(s,9H)。
example 2
This example provides the synthesis of 2- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -3- (4- (azidomethyl) phenyl) propanoic acid
The synthesis method comprises the following steps:
step S1 Fmoc-OSu (1.35 g,4 mmol) was dissolved in tetrahydrofuran (10 mL) at 0deg.C and added to 2-amino-3- (4- (hydroxymethyl) phenyl) propionic acid (0.78 g,4 mmol) in 12mL10% Na 2 CO 3 In solution, the mixture was stirred at room temperature overnight for 7h. After the reaction, the mixture was extracted with PE, followed by adjusting pH to 2, extraction with ethyl acetate (20 ml. Times.3), washing with acetic acid, drying, concentration, and recrystallization gave 2- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -3- (4- (hydroxymethyl) phenyl) propanoic acid (1.6 g, 96.5%).
Step S2, at N 2 2- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -3- (4- (hydroxymethyl) phenyl) propanoic acid (4.17 g,10 mmol) was dissolved in a mixed solution of acetone and n-hexane (1:1) (10 mL) under the conditions. Diphenylphosphorylazide (3.0 g,11 mmol) and DBN (1.3 g,10.5 mmol) were then added rapidly to the mixture under ice-bath conditions followed by stirring at room temperature for 7h with infrared radiation from an infrared radiation meter (220 v 275 w). After the reaction was completed, the reaction was quenched with water (10 mL) and 5% aqueous HCl (10 mL) in this order. The reaction mixture was extracted with EtOAc (2X 10 mL). With anhydrous MgSO 4 The solvent was dried and spun dry. Purification by column chromatography followed by elution with hexane/EtOAc (V/v=20/1) afforded 2- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -3- (4- (azidomethyl) phenyl) propanoic acid (4.39 g, 99.3%).
Nuclear magnetic results:
1 H NMR(400MHz,DMSO)δ10.11(s,1H),7.65(m,8H),7.30(dt,2H),6.91(dt,2H),6.18(d,1H),5.60(m,1H),4.36(d,2H),4.25(m,3H),3.06(dq,2H)。
example 3
This example provides the synthesis of 3- (3- (azidomethyl) phenyl) -2- ((tert-butoxycarbonyl) amino) propanoic acid
This example uses 10mmol of 2-amino-3- (3- (hydroxymethyl) phenyl) propionic acid instead of 2-amino-3- (4- (hydroxymethyl) phenyl) propionic acid, and the total yield of final 3- (3- (azidomethyl) phenyl) -2- ((tert-butoxycarbonyl) amino) propionic acid was 97.1%.
1 H NMR(400MHz,CDCl 3 )δ8.24(s,1H),7.33(dp,1H),7.23(t,1H),7.13(hept,1H),7.01(dq,1H),6.67(d,1H),4.21(m,3H),3.08(ddt,1H),3.01(ddt,1H),1.41(s,9H)。
Example 4
This example provides the synthesis of 3- (2- (azidomethyl) phenyl) -2- ((tert-butoxycarbonyl) amino) propanoic acid
This example uses 10mmol of 2-amino-3- (2- (hydroxymethyl) phenyl) propionic acid instead of 2-amino-3- (4- (hydroxymethyl) phenyl) propionic acid, and the total yield of final 3- (2- (azidomethyl) phenyl) -2- ((tert-butoxycarbonyl) amino) propionic acid was 96.9%.
1 H NMR(400MHz,CDCl 3 )δ8.11(s,1H),7.30(ddt,1H),7.23(td,1H),7.16(td,1H),7.00(dq,1H),6.90(d,1H),4.33(m,2H),4.24(dt,1H),3.09(m,2H),1.45(s,9H)。
Example 5
This example provides the synthesis of 2- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -3- (3- (azidomethyl) phenyl) propanoic acid
This example uses 10mmol of 2-amino-3- (3- (hydroxymethyl) phenyl) propionic acid instead of 2-amino-3- (4- (hydroxymethyl) phenyl) propionic acid, the overall yield of final 2- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -3- (3- (azidomethyl) phenyl) propionic acid was 97.3%.
1 H NMR(400MHz,DMSO)δ9.93(s,1H),7.81(dd,2H),7.70(m,2H),7.60(td,2H),7.52(td,2H),7.33(m,1H),7.24(t,1H),7.13(hept,1H),6.99(m,1H),6.38(d,1H),5.41(m,1H),4.36(d,2H),4.23(m,1H),4.18(m,2H),3.05(m,2H)。
Example 6
This example provides the synthesis of 2- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -3- (2- (azidomethyl) phenyl) propanoic acid
This example uses 10mmol of 2-amino-3- (2- (hydroxymethyl) phenyl) propionic acid instead of 2-amino-3- (4- (hydroxymethyl) phenyl) propionic acid, the overall yield of final 2- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -3- (2- (azidomethyl) phenyl) propionic acid was 96.6%.
1 H NMR(400MHz,DMSO)δ9.82(s,1H),7.81(dd,2H),7.70(m,2H),7.60(td,2H),7.52(td,2H),7.30(ddt,1H),7.22(dtd,2H),6.95(ddt,1H),6.52(d,1H),5.61(m,1H),4.35(m,4H),4.24(dt,1H),3.07(m,2H)。
Example 7
This example provides the synthesis of 3- (4- (azidomethyl) phenyl) -2- ((tert-butoxycarbonyl) amino) propionic acid, the synthesis method being essentially the same as in example 1, except that: 10mL of toluene was used instead of the acetone and n-hexane mixed solution.
At N 2 2- ((tert-Butoxycarbonyl) amino) -3- (4- (hydroxymethyl) phenyl) propanoic acid (2.95 g,10 mmol) was dissolved in toluene solution (10 mL) under conditions. Diphenylphosphorylazide (3.0 g,11 mmol) and DBN (1.3 g,10.5 mmol) were then added rapidly to the mixture under ice-bath conditions followed by stirring at room temperature for 6h with infrared radiation from an infrared radiation meter (220 v 275 w). After the reaction was completed, the reaction was quenched with water (10 mL) and 5% aqueous HCl (10 mL) in this order. The reaction mixture was extracted with EtOAc (2X 10 mL). With anhydrous MgSO 4 The solvent was dried and spun dry. Purification by column chromatography followed by elution with hexane/EtOAc (V/v=20/1) afforded 3- (4- (azidomethyl) phenyl) -2- ((tert-butoxycarbonyl) amino) propanoic acid (2.7 g, 85%).
Example 8
This example provides the synthesis of 3- (4- (azidomethyl) phenyl) -2- ((tert-butoxycarbonyl) amino) propionic acid, the synthesis method being essentially the same as in example 1, except that: DBU is used instead of DBN.
At N 2 2- ((tert-Butoxycarbonyl) amino) -3- (4- (hydroxymethyl) phenyl) propanoic acid (2.95 g,10 mmol) was dissolved in a mixed solution of acetone and n-hexane (1:1) (10 mL) under the conditions. Diphenylphosphorylazide (3.0 g,11 mmol) and DBU (1.6 g,10.5 mmol) were then added rapidly to the mixture under ice-bath conditions followed by stirring at room temperature for 6h with infrared radiation from an infrared radiation meter (220 v 275 w). After the reaction was completed, the reaction was quenched with water (10 mL) and 5% aqueous HCl (10 mL) in this order. The reaction mixture was extracted with EtOAc (2X 10 mL). With anhydrous MgSO 4 The solvent was dried and spun dry. Purification by column chromatography followed by elution with hexane/EtOAc (V/v=20/1) afforded 3- (4- (azidomethyl) phenyl) -2- ((tert-butoxycarbonyl) amino) propanoic acid (2.85 g, 89%).
Comparative example 1
This comparative example provides the synthesis of 3- (4- (azidomethyl) phenyl) -2- ((tert-butoxycarbonyl) amino) propionic acid, the synthesis method being essentially the same as in example 1, except that: in step S2, infrared radiation is performed without using an infrared radiation meter.
At N 2 2- ((tert-Butoxycarbonyl) amino) -3- (4- (hydroxymethyl) phenyl) propanoic acid (2.95 g,10 mmol) was dissolved in a mixed solution of acetone and n-hexane (1:1) (10 mL) under the conditions. Then diphenylphosphorylazide (3.0 g,11 mmol), DBN (1.3 g,10.5 mmol) were added rapidly to the mixture under ice-bath conditions and the reaction stirred at room temperature for 6h. After the reaction was completed, the reaction was quenched with water (10 mL) and 5% aqueous HCl (10 mL) in this order. The reaction mixture was extracted with EtOAc (2X 10 mL). With anhydrous MgSO 4 The solvent was dried and spun dry. Purification by column chromatography followed by elution with hexane/EtOAc (V/v=20/1) afforded 3- (4- (azidomethyl) phenyl) -2- ((tert-butoxycarbonyl) amino) propanoic acid (1.6 g, 50%).
The above embodiments are provided to illustrate the technical concept and features of the present invention and are intended to enable those skilled in the art to understand the content of the present invention and implement the same, and are not intended to limit the scope of the present invention. All equivalent changes or modifications made in accordance with the spirit of the present invention should be construed to be included in the scope of the present invention.
The endpoints and any values of the ranges disclosed herein are not limited to the precise range or value, and are understood to encompass values approaching those ranges or values. For numerical ranges, one or more new numerical ranges may be found between the endpoints of each range, between the endpoint of each range and the individual point value, and between the individual point value, in combination with each other, and are to be considered as specifically disclosed herein.

Claims (10)

1. A synthesis method of azido amino acid derivatives is provided, wherein the structural formula of the azido amino acid derivatives is shown as formula (I),
the synthesis method is characterized by comprising the following steps of:
step S1, reacting a compound shown in a formula (II) with an amino protective agent to generate a compound shown in a formula (III);
s2, enabling the compound shown in the formula (III) and an azide source to generate the compound shown in the formula (I) under the action of infrared radiation in the presence of a catalyst and a solvent;
the structural formula of the compound shown in the formula (II) is as follows:
the structural formula of the compound shown in the formula (III) is as follows:
in the formula (I), the R 1 is-CH 2 -N 3 The method comprises the steps of carrying out a first treatment on the surface of the In the formula (I) and the formula (III), R is 2 Is an amino protecting group; in the formula (II) and the formula (III)The R is 3 is-CH 2 -OH。
2. The method for synthesizing an azido amino acid derivative according to claim 1, characterized in that: in the step S2, the power of the infrared radiation is 200-350W, and the radiation temperature is 10-40 ℃.
3. The method for synthesizing an azido amino acid derivative according to claim 2, characterized in that: in the step S2, the time of the infrared radiation is 4-8 h.
4. The method for synthesizing an azido amino acid derivative according to claim 1, characterized in that: in the step S2, the azide source is one or a combination of more of diphenyl phosphoryl azide and azido trimethylsilane.
5. The method for synthesizing an azido amino acid derivative according to claim 1, characterized in that: in the step S2, the solvent is one or a combination of more of acetone, normal hexane, dimethyl sulfoxide and toluene; and/or the catalyst is one or a combination of a plurality of 1, 5-diazabicyclo [4.3.0] -5-nonene, 1, 8-diazabicyclo [5.4.0] undec-7-ene and tetramethyl guanidine.
6. The method for synthesizing an azido amino acid derivative according to claim 5, characterized in that: in step S2, the solvent is a mixture of acetone and n-hexane.
7. The method for synthesizing an azido amino acid derivative according to claim 1, characterized in that: in step S2, the reaction is performed under an inert gas atmosphere; and/or the feeding mole ratio of the compound shown in the formula (III) to the azide source is 1:1-1.5; and/or the feeding mole ratio of the compound shown in the formula (III) to the catalyst is 1:0.8-1.2.
8. The method for synthesizing an azido amino acid derivative according to any of claims 1-7, characterized in that: the implementation of the step S2 is as follows: under the condition of inert gas, the compound shown in the formula (III) is dissolved in a solvent, then an azide source and a catalyst are added into the system under the condition of ice bath, then the reaction is carried out under the condition of infrared radiation at the temperature of 10-40 ℃, and after the reaction is finished, the reaction is quenched.
9. The method for synthesizing an azido amino acid derivative according to claim 8, characterized in that: the synthesis method further comprises the step of carrying out post-treatment on the reaction liquid after the quenching reaction is finished, wherein the post-treatment comprises drying, spin-drying the solvent and purifying by a chromatographic column.
10. The method for synthesizing an azido amino acid derivative according to claim 1, characterized in that: the R is 2 Boc, fmoc; and/or the number of the groups of groups,
the amino protective agent is selected from di-tert-butyl dicarbonate and fluorenylmethoxycarbonyl succinimide; and/or the number of the groups of groups,
in the step S1, the reaction is carried out in the presence of a solvent, wherein the solvent is a mixture of an organic solvent and water, and the organic solvent is one or a combination of a plurality of dioxane, tetrahydrofuran and N, N-dimethylformamide; and/or the number of the groups of groups,
in step S1, the reaction is carried out at 15 to 40℃and in the presence of a base.
CN202311670792.9A 2023-12-07 2023-12-07 Synthesis method of azido amino acid derivative Pending CN117658866A (en)

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