CN117658866B - Synthesis method of azido amino acid derivative - Google Patents
Synthesis method of azido amino acid derivativeInfo
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- CN117658866B CN117658866B CN202311670792.9A CN202311670792A CN117658866B CN 117658866 B CN117658866 B CN 117658866B CN 202311670792 A CN202311670792 A CN 202311670792A CN 117658866 B CN117658866 B CN 117658866B
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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
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- 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
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- 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
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
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Abstract
本发明涉及一种叠氮氨基酸衍生物的合成方法，包括以下步骤：步骤S1、使式(II)所示化合物与氨基保护剂进行反应，生成式(III)所示化合物步骤S2、使式(III)所示化合物与叠氮源在催化剂和溶剂的存在下，在红外辐射作用下生成式(I)所示化合物即所述叠氮氨基酸衍生物；式(I)中，所述R1 1为‑CH2 2‑N3 3；式(I)、式(III)中，所述R2 2为氨基保护基；式(II)、式(III)中，所述R3 3为‑CH2 2‑OH。本发明的合成方法以2‑氨基羟甲基苯基丙酸衍生物为起始原料，先对其进行氨基保护，然后在红外辐射和催化剂的作用下将羟基转化为叠氮基团，收率高，操作简便。进一步地，避免强毒性叠氮源的使用，安全性更高，更加适合工业化生产。
This invention relates to a method for synthesizing an azide amino acid derivative, comprising the following steps: Step S1, making the compound shown in formula (II) It reacts with an amino protecting agent to produce the compound shown in formula (III). Step S2: The compound shown in formula (III) is reacted with an azide source in the presence of a catalyst and a solvent under infrared radiation to generate the compound shown in formula (I). That is , the azide amino acid derivative; in formula (I), R11 is -CH22 - N33 ; in formulas (I) and (III), R22 is an amino protecting group; in formulas (II) and (III), R33 is -CH22 - OH . The synthesis method of this invention uses a 2-aminohydroxymethylphenylpropionic acid derivative as the starting material, first protecting it with an amino group, and then converting the hydroxyl group into an azide group under infrared radiation and a catalyst. This method has a high yield and is simple to operate. Furthermore, it avoids the use of highly toxic azide sources, resulting in higher safety and making it more suitable for industrial production.
Description
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 protein, nucleoside and nucleic acid studies as part of amino acids, where incorporation of unnatural amino acids into protein sequences to design novel proteins is of great importance in studying the folding and function of natural proteins. 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. The commonly used azide source is NaN 3, but NaN 3 is used as the azide source, so that the explosion is easy to occur, and the explosion is easy to occur due to friction, collision, vibration and the like, and the toxicity is strong and the safety is poor.
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), R 1 is-CH 2-N3, in the formula (I) and the formula (III), R 2 is an amino protecting group, in the formula (II) and the formula (III), R 3 is-CH 2 -OH.
In some embodiments, in formula (I), R 1 is the para, meta, or ortho position to the CH 2 group on the phenyl ring, and in formula (II), such that in formula (III), R 3 is the para, meta, or ortho position to the CH 2 group on the phenyl ring.
In some embodiments, the compound of formula (I) is as follows:
in some embodiments, in step S2, the power of the infrared radiation is 200-350 w, and the radiation temperature is 10-40 ℃.
Further, the power of the infrared radiation is 250-300W.
In some embodiments, in step S2, the time of the infrared radiation is 4-8 hours.
In some embodiments, in step S2, the azide source is one or a combination of diphenyl phosphoryl azide (DPPA), azido trimethylsilane. The use of a NaN 3 azide source with strong toxicity is avoided, explosion is avoided, and the safety is higher.
In some specific embodiments, in the step S2, the solvent is one or a combination of several of acetone, normal hexane, toluene and dimethyl sulfoxide (DMSO), and the catalyst is one or a combination of several of 1, 5-diazabicyclo [4.3.0] -5-nonene (DBN), 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) and tetramethyl guanidine (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 shown in the formula (III) to the azide source is 1:1-1.5, and the molar ratio of the compound shown in the formula (III) to the catalyst is 1:0.8-1.2.
In some specific embodiments, the step S2 is specifically implemented by dissolving a compound shown in a formula (III) in a solvent under the condition of inert gas, adding an azide source and a catalyst into the system under the condition of ice bath, then carrying out reaction under the condition of infrared radiation at 10-40 ℃, and quenching the reaction after the reaction is finished.
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 is Boc, fmoc, and the amino-protecting agent is selected from the group consisting of di-tert-butyl dicarbonate, 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 specific embodiments, in step S1, the reaction is performed at 15-40 ℃, 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 specific embodiments, when the amino protective agent is di-tert-butyl dicarbonate, the specific implementation of the step S1 is that under the ice bath condition, adding the compound shown in the formula (II), a solvent and alkali into a reactor, then adding the amino protective agent and the alkali into the reactor, reacting for 6-10 hours at 15-40 ℃, spin-drying the solvent, diluting with ethyl acetate in the ice bath, acidifying to pH of 2-3, extracting, washing with water, merging organic phases, drying and spin-drying to obtain the compound shown in the formula (III).
In some specific embodiments, when the amino protective agent is fluorenylmethoxycarbonyl succinimide, the specific implementation of the step S1 is that under the ice bath condition, the amino protective agent is dissolved in a solvent and then added into a reactor filled with a compound shown in a formula (II), the solvent and alkali, the mixture is reacted for 6 to 10 hours at 15 to 40 ℃, the mixture is extracted, the pH value is adjusted to 1 to 3, and the mixture is extracted, washed with weak acid water, dried, concentrated and recrystallized to obtain the compound shown in the formula (III).
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 nuclear magnetic resonance apparatus, the measurement solvent being deuterated chloroform (CDCl 3) or deuterated dimethyl sulfoxide (DMSO-D 6) or heavy water (D 2 O), TMS being 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 2 O (v/v=2:1, 30 mL), naOH (1 m,10 mmol) were added to a 150mL round bottom flask under ice-bath conditions. (Boc) 2 O (Boc anhydride) (3.27 g,15 mmol) and NaHCO 3 (10 mmol) were 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), the organic phases were combined after multiple water washes, dried over anhydrous Na 2SO4 and spun-dried to give 2- ((tert-butoxycarbonyl) amino) -3- (4- (hydroxymethyl) phenyl) propanoic acid (2.9 g, 98.1%).
Step S2, 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 N 2 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). Dried over anhydrous MgSO 4 and spin-dried. 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:
1H NMR(400MHz,CDCl3)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, added to 2-amino-3- (4- (hydroxymethyl) phenyl) propionic acid (0.78 g,4 mmol) in 12mL10% Na 2CO3 solution and 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, 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 N 2 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). Dried over anhydrous MgSO 4 and spin-dried. 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:
1H 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%.
1H NMR(400MHz,CDCl3)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%.
1H NMR(400MHz,CDCl3)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%.
1H 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%.
1H 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, essentially as in example 1, except that 10mL toluene was used instead of the acetone and n-hexane mixed solution.
2- ((Tert-Butoxycarbonyl) amino) -3- (4- (hydroxymethyl) phenyl) propanoic acid (2.95 g,10 mmol) was dissolved in toluene solution (10 mL) under N 2. 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). Dried over anhydrous MgSO 4 and spin-dried. 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) propanoic acid, the synthesis method being essentially the same as example 1, except that DBU was used instead of DBN.
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 N 2. 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). Dried over anhydrous MgSO 4 and spin-dried. 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 example 1, except that in step S2, infrared radiation is not carried out using an infrared radiator.
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 N 2. 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). Dried over anhydrous MgSO 4 and spin-dried. 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.
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