CN114195684B - Synthesis method of amino protecting group N-substituted chiral amino acid - Google Patents
Synthesis method of amino protecting group N-substituted chiral amino acid Download PDFInfo
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Abstract
The invention relates to a synthesis method of amino protecting group N-substituted amino acid, which comprises the following steps: (1) Make the following stepsCarrying out acetylation reaction to generate(2) Make the following stepsWith R under the action of a base and in the presence of a solvent 1 X is subjected to substitution reaction and then deacetylation to obtain(3) Make the following stepsWith an amino protecting agent in the presence of a base and a solvent to produceNamely the amino protecting group N-substituted chiral amino acid; wherein R is 1 Alkyl selected from C1-6; x is halogen; r is R 2 Is an amino protecting group, R 3 Selected from C1-6 alkyl. The invention firstly protects amino on chiral amino acid by acetyl, and then the amino is protected by alkyl halide R 1 X is subjected to substitution reaction, deacetylation is carried out, and then an amino protecting group is connected to nitrogen to prepare the amino protecting group N-substituted chiral amino acid, so that the operation is simple, the product is high in yield, no selection is carried out in the synthesis process, the product is chiral, and the purity is high.
Description
Technical Field
The invention belongs to the technical field of synthesis of organic compounds, and particularly relates to a synthesis method of an amino protecting group N-substituted chiral amino acid.
Background
Based on N-substituted chiral amino acids, the N-substituted chiral amino acids are an important medical intermediate, and are widely applied in the field of medicinal chemistry, such as adding the substance into bioactive peptides in the research of medicines.
At present, relatively few reports are made on the synthesis of N-substituted amino acids, and the presently published synthetic methods, such as the document Baxter, ellen w.; reitz, allen B. Reduction aminations of carbonyl compounds with borohydride and borane reducing agents, general Review,2002,59 published synthetic methods for this class of compounds are as follows:
the method utilizes sodium borohydride to reduce amino acid to obtain N-substituted amino acid. However, the process has low yields and sodium borohydride used in the reaction tends to result in racemization of the product.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a high-yield and high-purity synthesis method of amino protecting group N-substituted chiral amino acid.
In order to achieve the above purpose, the invention adopts the following technical scheme:
a method for synthesizing an amino protecting group N-substituted chiral amino acid, the method comprising the steps of:
(1) Carrying out an acetylation reaction on a compound shown in a formula I to generate a compound shown in a formula II;
(2) The compound shown in the formula II is reacted with R under the action of alkali and in the presence of solvent 1 X is subjected to substitution reaction, and then deacetylation is carried out to obtain a compound shown in a formula III;
(3) Reacting the compound shown in the formula III with fluorenylmethoxycarbonyl succinimide in the presence of a base and a solvent to generate a compound shown in the formula IV, namely the amino protecting group N-substituted chiral amino acid;
wherein, the structural formula of the compound shown in the formula I is as follows:
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:
the structural formula of the compound shown in the formula IV is as follows:
the R is 1 Alkyl selected from C1-6; x is halogen;
in the formulas I-IV, R is 2 Fmoc, the R 3 Selected from C1-6 alkyl.
In the present invention, the dotted line in formula I, II, III, IV indicates that the configuration of the corresponding molecular structure is variable, and may be L-type or D-type.
Further, the R 1 Selected from methyl, ethyl, propyl. Preferably, said R 1 Selected from ethyl, propyl
Further, X is Cl, br or I. Preferably, X is I. By R 1 I has better activity than other halogenated compounds, and is favorable for substitution reaction.
Further, the R 3 Selected from n-propyl, isopropyl, n-butyl, isobutyl. Preferably, said R 3 Selected from n-propyl, n-butyl, isobutyl.
In some embodiments, the amino protecting group N-substituted amino acid is a compound as shown below:
Fmoc-N-ethyl-L-norleucine:
Fmoc-N-ethyl-D-norleucine:
Fmoc-N-ethyl-D-leucine:
Fmoc-N-ethyl-L-norvaline:
Fmoc-N-ethyl-D-norvaline:
Fmoc-N-propyl-L-norleucine:
Fmoc-N-propyl-D-norleucine:
Fmoc-N-propyl-D-leucine:
further, in the step (1), the acetyl reagent used in the acetylation reaction is one or a combination of more of acetic anhydride and acetyl chloride, preferably, the acetyl reagent is acetic anhydride.
Further, the acetylation reaction is performed in the presence of a base and water.
Preferably, in the step (1), the alkali is NaOH or KOH; and/or adding hydrochloric acid into the system to adjust the pH value of the system to 2-3 after the acetylation reaction is finished.
In some preferred and specific embodiments, the specific implementation of step (1) is: adding a compound shown in a formula I into an aqueous solution of alkali, dropwise adding an acetyl reagent, reacting for 10-14 h at 15-40 ℃, then adjusting the pH value to 2-3 by using 4-8N hydrochloric acid, separating out solids, filtering, washing a filter cake with water, and drying to obtain the compound shown in the formula II.
Further, in step (2), the base is K 2 CO 3 、Cs 2 CO 3 A composition of one or more of NaH; and/or the solvent is one or a combination of more of acetone, acetonitrile, DMF and THF; and/or, the substitution reaction is carried out at 40-90 ℃; and/or, the deacetylation reaction is carried out in hydrochloric acid and under reflux conditions.
Preferably, in the step (2), the base is NaH, the solvent is THF, and the temperature of the substitution reaction is 50-70 ℃. The substitution reaction can obtain excellent conversion rate and product yield under the cooperation of proper alkali and solvent and the reaction at 50-70 ℃. More preferably, the reaction temperature is 60 ℃.
Preferably, the deacetylation reaction uses a concentration of hydrochloric acid of 1.5 to 2.5N, more preferably a concentration of 2N.
Further preferably, in the step (2), the amount of NaH is 2 to 3eq, and more preferably 2.5eq. The R is 1 The amount of X is 1 to 2eq, more preferably 1.5eq.
In some preferred and specific embodiments, the specific embodiments of step (2) are: dissolving the compound shown in the formula II in a solvent, adding alkali at the temperature of-5 ℃, heating to the temperature of 20-40 ℃, stirring for 10-40 min, cooling to the temperature of-5 ℃, and dripping R 1 And X, after titration is finished, heating to 50-70 ℃ for reaction for 6-10 h, cooling, mixing with water, extracting impurities with methyl tertiary butyl ether, adding hydrochloric acid to adjust the pH value to 3-4, extracting with ethyl acetate, drying with anhydrous magnesium sulfate, concentrating under reduced pressure, adding hydrochloric acid, and reacting for 5-8 h at 90-110 ℃ to obtain the compound shown in the formula III.
In some embodiments, the deacetylation reaction in step (2) is followed directly by the next step.
Further, in the step (3), the solvent is a mixture of an organic solvent and water; and/or the reaction with the amino protecting agent is carried out at 15-40 ℃; and/or the alkali is sodium carbonate or sodium bicarbonate.
Preferably, the organic solvent is THF.
In some preferred and specific embodiments, the specific implementation of step (3) is: and (3) adding alkali into the system to adjust the pH value of the system to be neutral after the deacetylation reaction result of the step (2), adding an organic solvent and alkali into the system to enable the system to be alkaline, adding fluorenylmethoxycarbonyl succinimide (Fmoc-OSu) under ice bath, reacting for 1-3 hours at room temperature, extracting impurities by petroleum ether, adjusting the pH value to 3-4 by 5-7N hydrochloric acid, extracting by ethyl acetate, washing an organic phase weak acid aqueous solution, drying by anhydrous magnesium sulfate, concentrating to remove the solvent, and recrystallizing by petroleum ether to obtain the amino protecting group N-substituted chiral amino acid.
The weak acid is weak acid solution with pH value of 5-6.
In some embodiments, the synthetic methods of the invention are routed as follows:
the invention adopts a second technical scheme that: a process for the preparation of a compound of formula III as hereinbefore described.
Compared with the existing published synthetic method, the synthetic method has the advantages of cheap raw materials, safe and simple operation, mild reaction conditions, safety, high efficiency, high yield, non-racemization of products and high purity.
The amino protecting group N-substituted chiral amino acid synthesized by the method is applied to the fields of synthesis or pharmaceutical chemistry.
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 firstly protects amino on chiral amino acid by acetyl, and then the amino is protected by alkyl halide R 1 X is subjected to substitution reaction and deacetylation, and then an amino protecting group is connected to nitrogen to obtain the N-substituted chiral amino acid with the amino protecting group, so that the operation is simple, the product is high in yield, no selection is performed in the synthesis process, and the product is good in chirality and pureThe degree is high.
The synthesis method of the invention protects the amino on chiral amino acid with acetyl, which not only has simple and efficient reaction, but also facilitates subsequent acetyl removal, and simultaneously has efficient N-substitution reaction.
Drawings
FIG. 1 is a nuclear magnetic resonance spectrum of Fmoc-N-ethyl-L-norleucine of example 1.
FIG. 2 is a chiral HPLC chromatogram (detection wavelength 220 nm) of Fmoc-N-ethyl-L-norleucine of example 1, wherein (b) is an enlarged view of (a).
FIG. 3 is a chiral HPLC chromatogram (detection wavelength 254 nm) of Fmoc-N-ethyl-L-norleucine of example 1, wherein (b) is an enlarged view of (a).
Detailed Description
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Accordingly, the examples provided below are merely to further illustrate the invention and are not intended to limit the scope of the invention in any way.
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 is changed into a nuclear magnetic resonance structure 1 H-NMR)、( 13 C-NMR and/or Mass Spectrometry (MS). The NMR measurement was performed using an ACF-400BRUK type nuclear magnetic resonance apparatus, and the solvent was deuterated chloroform (CDCl) 3 ) Or deuterated dimethyl sulfoxide (DMSO-D) 6 ) TMS is an internal standard.
Example 1
Synthesis of Fmoc-N-ethyl-L-norleucine
L-norleucine (20 g,0.15 mol) was dissolved in 30% aqueous NaOH (45 mL), and acetic anhydride (23.4 g,0.225 mol) was slowly added dropwise thereto, and the reaction was completed at room temperature for 12 hours. After the reaction, the pH was adjusted to 2-3 with 6N HCl hydrochloric acid, and a solid was precipitated, filtered, and the cake was washed with water and dried to give Compound 1 (25 g, 95%).
Compound 1 (10 g,0.056 mol) was dissolved in THF, naH (5.78 g,0.14 mol) was slowly added at 0deg.C, and after half an hour of reaction at room temperature, the temperature was lowered to 0deg.C, iodoethane (13.5 g,0.084 mol) was added dropwise, and the reaction was completed at 60deg.C for 8 hours. The reaction solution was cooled to room temperature, poured into water, extracted with methyl tert-butyl ether three times under alkaline conditions, pH adjusted to 3-4 with HCl solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude product (9.3 g, 80%) without further purification.
To the crude product (9.3 g,0.046 mol) was added a 2N HCl solution (30 mL), and the mixture was reacted at 100℃for 6 hours, after the completion of the reaction, the reaction solution was cooled to room temperature to obtain Compound 2.
The reaction liquid containing the compound 2 is directly subjected to the next step: the system was adjusted to neutrality with sodium carbonate solids, then THF (30 mL) and sodium carbonate (5.4 g,0.05 mol) were added thereto, fmoc-OSu (12.5 g,0.037 mol) was added in portions under ice bath, and reacted at room temperature for 2h. After the reaction, petroleum ether was used for extraction, pH was adjusted to 3-4 with 6N HCl solution, ethyl acetate was used for extraction, the obtained organic phase was washed with weak acid water (pH: 5-6), dried over anhydrous magnesium sulfate, concentrated to remove most of the solvent, and petroleum ether was recrystallized to obtain Fmoc-N-ethyl-L-norleucine (16.6 g, 81%).
The total yield of the four steps was 61.5%. The optical purity index test result of Fmoc-N-ethyl-L-norleucine product is 99.8%ee.
The nuclear magnetic pattern of Fmoc-N-ethyl-L-norleucine is shown in FIG. 1.
1 H NMR(400MHz,DMSO-d 6 )δ12.60(s,1H),7.89(d,2H),7.66(d,2H),7.44–7.23(m 4H),4.59–4.02(m,4H),3.27–2.88(m,2H),1.90–1.44(m,2H),1.37–1.02(m,4H),0.85(m,6H).
Chiral HPLC patterns of Fmoc-N-ethyl-L-norleucine at different detection wavelengths are shown in fig. 2 and 3, analyzed in fig. 2 and 3, and the results are shown in tables 1 and 2.
Table 1 shows the profile analysis of FIG. 2
| No. | t R (min) | Area | Area％ | T.Plates | Tailing | Resolution |
| 1 | 4.671 | 2676063 | 99.9295 | 6114.376 | 1.091 | -- |
| 2 | 5.693 | 1888 | 0.0705 | 9271.451 | 1.408 | 4.300 |
Table 2 shows the profile analysis of FIG. 3
| No. | t R (min) | Area | Area％ | T.Plates | Tailing | Resolution |
| 1 | 4.673 | 2266444 | 99.9478 | 6216.396 | 1.091 | -- |
| 2 | 5.706 | 1185 | 0.0522 | 7633.330 | 1.101 | 4.149 |
From the analysis of FIGS. 2 and 3 in combination with Table 1 and Table 2, it was found that the optical purity index test result of Fmoc-N-ethyl-L-norleucine product was 99.8% ee.
Example 2
Synthesis of Fmoc-N-ethyl-D-norleucine
The starting materials for this example were D-norleucine (0.15 mol) and iodoethane (0.084 mol), with a total yield of Fmoc-N-ethyl-D-norleucine of 60% in the same manner as in example 1. The optical purity index test result of Fmoc-N-ethyl-D-norleucine product is 99.1% ee.
1 H NMR(400MHz,DMSO-d 6 )δ12.61(s,1H),7.89(d,2H),7.66(d,2H),7.43–7.22(m 4H),4.58–4.02(m,4H),3.25–2.88(m,2H),1.89–1.44(m,2H),1.37–1.00(m,4H),0.87(m,6H).
Example 3
Synthesis of Fmoc-N-ethyl-D-leucine
The starting materials for this example were D-leucine (0.15 mol) and iodoethane (0.084 mol), with the exception of the Fmoc-N-ethyl-D-leucine in a total yield of 62%. The optical purity index test result of Fmoc-N-ethyl-D-leucine product is 99.1% ee.
1 H NMR(400MHz,DMSO-d 6 )δ12.59(s,1H),7.86(d,2H),7.62(d,2H),7.41–7.22(m,4H),4.55–4.08(m,4H),3.28–2.79(m,2H),1.84–1.40(m,2H),1.31–0.95(m,3H),0.93–0.57(m,7H).
Example 4
Synthesis of Fmoc-N-ethyl-L-norvaline
The starting materials for this example were L-norvaline (0.15 mol) and ethyl iodide (0.084 mol), and the overall yield of Fmoc-N-ethyl-L-norvaline was 60% in the same manner as in example 1. The optical purity index test result of Fmoc-N-ethyl-L-norvaline product is 99.7% ee.
1 H NMR(400MHz,DMSO-d 6 )δ12.59(s,1H),7.88(d,2H),7.64(d,2H),7.43–7.24(m,4H),4.54–4.09(m,4H),3.30–2.89(m,2H),1.83–1.41(m,2H),1.26–0.94(m,3H),0.92–0.55(m,5H).
Example 5
Synthesis of Fmoc-N-ethyl D-norvaline
The starting materials for this example were D-norvaline (0.15 mol) and ethyl iodide (0.084 mol) in the same manner as in example 1, fmoc-N-ethyl-D-norvaline at a total yield of 61%. The optical purity index test result of Fmoc-N-ethyl-D-norvaline product is 98.7%ee.
1 H NMR(400MHz,DMSO-d 6 )δ12.60(s,1H),7.87(d,2H),7.65(d,2H),7.43–7.22(m,4H),4.52–4.05(m,4H),3.30–2.87(m,2H),1.84–1.40(m,2H),1.26–0.95(m,3H),0.92–0.57(m,5H).
Example 6
Synthesis of Fmoc-N-propyl-L-norleucine
The starting materials for this example were L-norleucine (0.15 mol) and iodopropane (0.084 mol), with a total yield of Fmoc-N-propyl-L-norleucine of 58% in the same manner as in example 1. The optical purity index test result of Fmoc-N-propyl-L-norleucine product is 99.3%ee.
1 H NMR(400MHz,DMSO-d 6 )δ12.58(s,1H),7.85(d,2H),7.62(d,2H),7.40–7.19(m,4H),4.48–4.03(m,4H),3.27–2.83(m,2H),1.85–1.40(m,2H),1.34–0.97(m,4H),0.93–0.57(m,8H).
Example 7
Synthesis of Fmoc-N-propyl-D-norleucine
The starting materials for this example were D-norleucine (0.15 mol) and iodopropane (0.084 mol), with a total yield of Fmoc-N-propyl-D-norleucine of 62% in the same manner as in example 1. The optical purity index test result of Fmoc-N-propyl-D-norleucine product is 98.0%ee.
1 H NMR(400MHz,DMSO-d 6 )δ12.59(s,1H),7.85(d,2H),7.62(d,2H),7.40–7.19(m,4H),4.49–4.03(m,4H),3.28–2.85(m,2H),1.85–1.41(m,2H),1.35–0.98(m,4H),0.95–0.59(m,8H).
Example 8
Synthesis of Fmoc-N-propyl-D-leucine
The starting materials for this example were D-leucine (0.15 mol) and iodopropane (0.084 mol), with the exception of the Fmoc-N-propyl-D-leucine in a total yield of 61% as in example 1. The optical purity index test result of Fmoc-N-propyl-D-leucine product is 98.9% ee.
1 H NMR(400MHz,DMSO-d 6 )δ12.60(s,1H),7.88(d,2H),7.63(dd,2H),7.45–7.23(m,4H),4.59–4.11(m,4H),3.31–2.82(m,2H),1.85–1.41(m,2H),1.34–0.94(m,2H),0.90–0.58(m,10H).
Example 9
Synthesis of Fmoc-N-ethyl-L-norleucine
Compound 1 of example 1 (10 g,0.056 mol) was dissolved in THF and Cs was slowly added at 0deg.C 2 CO 3 (0.14 mol) was allowed to react at room temperature for half an hour, then cooled to 0℃again, and ethyl iodide (13.5 g,0.084 mol) was added dropwise, followed by completion of the reaction at 60℃for 8 hours. The reaction solution was cooled to room temperature, poured into water, extracted with methyl tert-butyl ether three times under alkaline conditions, then with HCl solution to adjust pH to 3-4, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to give crude product (4 g, 34.4%), the product was not further purified.
To the crude product was added a 2N HCl solution (30 mL), and the mixture was reacted at 100℃for 6 hours, after the completion of the reaction, the reaction mixture was cooled to room temperature to give Compound 2.
The reaction liquid containing the compound 2 is directly subjected to the next step: the system was adjusted to neutrality with sodium carbonate solids, then THF (30 mL) and sodium carbonate (2.3 g,0.02 mol) were added thereto, fmoc-OSu (5.4 g,0.016 mol) was added in portions under ice bath, and reacted at room temperature for 2 hours. After the reaction, petroleum ether was used for extracting impurities, the pH was adjusted to 3-4 with 6N HCl solution, ethyl acetate was used for extraction, the obtained organic phase was washed with weak acid water, dried over anhydrous magnesium sulfate, concentrated to remove most of the solvent, and petroleum ether was recrystallized to obtain Fmoc-N-ethyl-L-norleucine (7 g, 80%).
The total yield of Fmoc-N-ethyl-L-norleucine was 26.1% and the optical purity index test results were 99% ee.
Example 10
Synthesis of Fmoc-N-ethyl-L-norleucine
Compound 1 (10 g,0.056 mol) of example 1 was dissolved in DMF, naH (0.14 mol) was slowly added at 0deg.C, the reaction was allowed to proceed for half an hour at room temperature, then the temperature was lowered to 0deg.C, iodoethane (13.5 g,0.084 mol) was added dropwise, and the reaction was completed at 60deg.C for 8 hours. The reaction solution was cooled to room temperature, poured into water, extracted with methyl tert-butyl ether three times under alkaline conditions, pH adjusted to 3-4 with HCl solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude product (6 g, 52%) without further purification.
To the crude product was added a 2N HCl solution (30 mL), and the mixture was reacted at 100℃for 6 hours, after the completion of the reaction, the reaction mixture was cooled to room temperature to give Compound 2.
The reaction liquid containing the compound 2 is directly subjected to the next step: the system was adjusted to neutrality with sodium carbonate solids, then THF (30 mL) and sodium carbonate (3.4 g,0.032 mol) were added thereto, fmoc-OSu (7.8 g,0.023 mol) was added in portions under ice bath, and reacted at room temperature for 2h. After the reaction, petroleum ether was used for extracting impurities, the pH was adjusted to 3-4 with 6N HCl solution, ethyl acetate was used for extraction, the obtained organic phase was washed with weak acid water, dried over anhydrous magnesium sulfate, concentrated to remove most of the solvent, and petroleum ether was recrystallized to obtain Fmoc-N-ethyl-L-norleucine (10.5 g, 78%).
The total yield of Fmoc-N-ethyl-L-norleucine was 38.5% and the optical purity index test results were 98.8% ee.
Example 11
Synthesis of Fmoc-N-ethyl-L-norleucine
L-norleucine (20 g,0.15 mol) was dissolved in 30% aqueous NaOH (45 mL), and acetic anhydride (23.4 g,0.225 mol) was slowly added dropwise thereto, and the reaction was completed at room temperature for 12 hours. After the reaction, the pH was adjusted to 2-3 with 6N HCl hydrochloric acid, and a solid was precipitated, filtered, and the cake was washed with water and dried to give Compound 1 (25 g, 95%).
Compound 1 (10 g,0.056 mol) was dissolved in CH 3 In CN, slowly adding K at 0 DEG C 2 CO 3 (19.3 g,0.14 mol), the reaction time was half an hour after returning to room temperature, the temperature was lowered to 0℃again, and iodoethane (13.5 g,0.084 mol) was added dropwise, followed by a reaction at 60℃for 8 hours. The reaction solution was cooled to room temperature, poured into water, extracted with methyl tert-butyl ether three times under alkaline conditions, pH adjusted to 3-4 with HCl solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude product (2.3 g, 20%) without further purification.
To the above crude product (2.3 g,0.013 mol) was added a 2N HCl solution (30 mL), and after the reaction was completed at 100℃for 6 hours, the reaction mixture was cooled to room temperature to give Compound 2.
The reaction liquid containing the compound 2 is directly subjected to the next step: the system was adjusted to neutrality with sodium carbonate solids, then THF (30 mL) and sodium carbonate (1.35 g,0.0125 mol) were added thereto, fmoc-OSu (3.1 g,0.009 mol) was added in portions under ice bath, and reacted at room temperature for 2h. After the reaction, petroleum ether is used for extracting impurities, the pH value is regulated to 3-4 by using 6N HCl solution, ethyl acetate is used for extraction, the obtained organic phase is washed by weak acid water, dried by anhydrous magnesium sulfate, concentrated and removed for most of solvent, and petroleum ether is recrystallized to obtain Fmoc-N-ethyl-L-norleucine (4 g, 80%), and the total yield of four steps is 15.2%. The optical purity index test result of the product is 99.2%ee.
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 (9)
1. A method for synthesizing an amino protecting group N-substituted chiral amino acid, which is characterized by comprising the following steps:
(1) Carrying out an acetylation reaction on a compound shown in a formula I to generate a compound shown in a formula II;
(2) The compound shown in the formula II is reacted with R under the action of alkali and in the presence of solvent 1 X is subjected to substitution reaction, and then deacetylation is carried out to obtain a compound shown in a formula III;
(3) Reacting the compound shown in the formula III with an amino protective agent in the presence of alkali and a solvent to generate a compound shown in the formula IV, namely the amino protective group N-substituted chiral amino acid;
wherein, the structural formula of the compound shown in the formula I is as follows:；
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:；
the structural formula of the compound shown in the formula IV is as follows:；
the R is 1 Ethyl or propyl; x is halogen;
in the formulas I-IV, R is 2 Fmoc, the R 3 Alkyl selected from C1-C6;
in the step (2), the alkali is NaH, the solvent is THF, and the temperature of the substitution reaction is 40-90 ℃;
the deacetylation reaction is carried out in hydrochloric acid and under reflux conditions;
the amino protective agent is fluorenylmethoxycarbonyl succinimide.
2. The synthesis method according to claim 1, wherein: x is Cl, br or I; and/or, the R 3 Selected from n-propyl, isopropyl, n-butyl, isobutyl.
3. The synthesis method according to claim 1, wherein: the specific implementation mode of the step (2) is as follows: dissolving the compound shown in the formula II in a solvent, adding alkali at the temperature of-5 ℃, heating to the temperature of 20-40 ℃, stirring for 10-40 min, cooling to the temperature of-5 ℃, and dropwise adding R 1 And (3) after the titration is finished, heating to 50-70 ℃ for reaction for 6-10 hours, cooling, mixing with water, extracting impurities with methyl tertiary butyl ether, adding hydrochloric acid to adjust the pH value to 3-4, extracting with ethyl acetate, drying with anhydrous magnesium sulfate, concentrating under reduced pressure, adding into 1.5-2.5N hydrochloric acid, and reacting for 5-8 hours at 90-110 ℃ to obtain the compound shown in the formula III.
4. The synthesis method according to claim 1 or 2, characterized in that: in the step (2), the temperature of the substitution reaction is 50-70 ℃.
5. The synthesis method according to claim 1 or 2, characterized in that: in the step (1), the acetyl reagent adopted in the acetylation reaction is one or a combination of more of acetic anhydride and acetyl chloride; and/or, the acetylation reaction is carried out in the presence of a base and water.
6. The method of synthesis according to claim 5, wherein: in the step (1), the alkali is one or a combination of more than one of NaOH and KOH; and/or adding hydrochloric acid into the system to adjust the pH value of the system to 2-3 after the acetylation reaction is finished.
7. The method of synthesis according to claim 6, wherein: the specific implementation of the step (1) is as follows: adding a compound shown in a formula I into an aqueous solution of alkali, dropwise adding an acetyl reagent, reacting for 10-14 h at 15-40 ℃, then adjusting the pH value to 2-3 by using 4-8N hydrochloric acid, separating out solids, filtering, washing a filter cake with water, and drying to obtain the compound shown in the formula II.
8. The synthesis method according to claim 1, wherein: in the step (3), the solvent is a mixture of an organic solvent and water; and/or the reaction with the amino protective agent is carried out at 15-40 ℃; and/or the alkali is one or a combination of more of sodium carbonate and sodium bicarbonate.
9. A method for producing a compound represented by formula III according to any one of claims 1 to 7.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1633289A (en) * | 2002-03-22 | 2005-06-29 | 卫材株式会社 | Hemiasterlin derivatives and uses thereof |
| WO2007107008A1 (en) * | 2006-03-22 | 2007-09-27 | Innodia Inc. | Compounds and compositions for use in the prevention and treatment of disorders of fat metabolism and obesity |
| CN106674035A (en) * | 2015-11-06 | 2017-05-17 | 浙江九洲药业股份有限公司 | Preparation method of N-methylamino acid with optical configurations |
| WO2021046315A2 (en) * | 2019-09-05 | 2021-03-11 | Wisconsin Alumni Research Foundation | Inhibitors of encephalitic alphaviruses |
| CN112876502A (en) * | 2021-02-09 | 2021-06-01 | 上海嘉莱多生物技术有限责任公司 | Preparation method of N-trimethylsiloxyethoxycarbonyl-N-methyl-L/D-leucine |
-
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1633289A (en) * | 2002-03-22 | 2005-06-29 | 卫材株式会社 | Hemiasterlin derivatives and uses thereof |
| WO2007107008A1 (en) * | 2006-03-22 | 2007-09-27 | Innodia Inc. | Compounds and compositions for use in the prevention and treatment of disorders of fat metabolism and obesity |
| CN106674035A (en) * | 2015-11-06 | 2017-05-17 | 浙江九洲药业股份有限公司 | Preparation method of N-methylamino acid with optical configurations |
| WO2021046315A2 (en) * | 2019-09-05 | 2021-03-11 | Wisconsin Alumni Research Foundation | Inhibitors of encephalitic alphaviruses |
| CN112876502A (en) * | 2021-02-09 | 2021-06-01 | 上海嘉莱多生物技术有限责任公司 | Preparation method of N-trimethylsiloxyethoxycarbonyl-N-methyl-L/D-leucine |
Non-Patent Citations (1)
| Title |
|---|
| Determination of the Complete Absolute Configuration of PetriellinA;Luigi Aurelio等;《Australian Journal of Chemistry》;20061231;第59卷(第6期);407-414页 * |
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