CN114195684A - 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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- CN114195684A CN114195684A CN202111568543.XA CN202111568543A CN114195684A CN 114195684 A CN114195684 A CN 114195684A CN 202111568543 A CN202111568543 A CN 202111568543A CN 114195684 A CN114195684 A CN 114195684A
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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 it
By acetylation reaction to
(2) Make it
With R under the action of a base and in the presence of a solvent1X is subjected to a substitution reaction and then deacetylated to obtain
(3) Make it
With an amino protecting agent in the presence of a base and a solvent to form
I.e. the amino protecting group N-substituted chiral amino acid; wherein R is1Selected from C1-6 alkyl; x is halogen; r2Is an amino protecting group, R3Selected from C1-6 alkyl. The invention firstly protects the amino group on the chiral amino acid with acetyl and then reacts with alkyl halide R1And carrying out substitution reaction on the X, deacetylating, and connecting an amino protecting group on nitrogen to prepare the amino protecting group N-substituted chiral amino acid.
Description
Technical Field
The invention belongs to the technical field of organic compound synthesis, and particularly relates to a synthesis method of an amino protecting group N-substituted chiral amino acid.
Background
N-substituted chiral amino acids are important medical intermediates, and are widely applied in the field of medical chemistry, for example, the substance is often added into bioactive peptides in pharmaceutical research.
Relatively few reports are currently reported on the synthesis of N-substituted amino acids, and the synthesis methods disclosed in the literature, e.g. Baxter, Ellen w; reitz, Allen B.reduction amides with carbonyl compounds and carbonyl reduction agents, general Review,2002,59. published methods for the synthesis of such compounds, the specific routes are as follows:
the method utilizes sodium borohydride to reduce amino acid to obtain N-substituted amino acid. However, the method has low yield, and sodium borohydride used in the reaction is easy to cause racemization of the product.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a synthetic method of an amino protecting group N-substituted chiral amino acid with high yield and high purity.
In order to achieve the purpose, the invention adopts the technical scheme that:
a method for synthesizing an amino protecting group N-substituted chiral amino acid, the method comprising the steps of:
(1) carrying out acetylation reaction on the compound shown in the formula I to generate a compound shown in a formula II;
(2) reacting the compound shown as the formula II with R under the action of alkali and in the presence of a solvent1Carrying out substitution reaction on X, and then deacetylating 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 alkali and a solvent to generate a compound shown in a 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 is1Selected from C1-6 alkyl; x is halogen;
in the formulae I to IV, R is2Is Fmoc, said R3Selected from C1-6 alkyl.
In the present invention, the dotted lines in formulae I, II, III, and IV indicate that the corresponding molecular structure has an arbitrary configuration, and may be L-type or D-type.
Further, said R1Selected from methyl, ethyl, propyl. Preferably, said R is1Selected from ethyl and propylBase of
Further, X is Cl, Br and I. Preferably, said X is I. By the use of R1Compared with other halogenated compounds, the compound I has better activity and is beneficial to the substitution reaction.
Further, said R3Selected from n-propyl, isopropyl, n-butyl and isobutyl. Preferably, said R is3Selected from n-propyl, n-butyl and 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 acetylation reagent used in the acetylation reaction is one or a combination of acetic anhydride and acetyl chloride, and preferably, the acetylation reagent is acetic anhydride.
Further, the acetylation reaction is carried out in the presence of a base and water.
Preferably, in step (1), the base is NaOH or KOH; and/or after the acetylation reaction is finished, adding hydrochloric acid into the system to adjust the pH value of the system to 2-3.
In some preferred and specific embodiments, step (1) is performed by: adding a compound shown in the formula I into an alkali water solution, dropwise adding an acetyl reagent, reacting for 10-14 h at 15-40 ℃, then adjusting the pH value to 2-3 with 4-8N hydrochloric acid, separating out solids, filtering, washing a filter cake with water, and drying to obtain a compound shown in the formula II.
Further, in the step (2), the alkali is K2CO3、Cs2CO3A combination of one or more of NaH; and/or the solvent is one or 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 matching of proper alkali and solvent and at the temperature of 50-70 ℃. More preferably, the reaction temperature is 60 ℃.
Preferably, the concentration of hydrochloric acid used for the deacetylation reaction is 1.5-2.5N, and more preferably the concentration is 2N.
More preferably, in the step (2), the amount of NaH is 2 to 3eq, and more preferably 2.5 eq. The R is1The amount of X is 1 to 2eq, more preferably 1.5 eq.
In some preferred and specific embodiments, the step (2) is embodiedThe formula is as follows: dissolving the compound shown as the formula II in a solvent, adding alkali at-5 ℃, heating to 20-40 ℃, stirring for 10-40 min, cooling to-5 ℃, and dropwise adding R1And X, after titration, heating to 50-70 ℃ for reaction for 6-10 h, cooling, mixing with water, extracting impurities with methyl tert-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 hydrochloric acid, and reacting at 90-110 ℃ for 5-8 h to obtain the compound shown in the formula III.
In some embodiments, the deacetylation reaction in step (2) is completed before proceeding to 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 protective 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, step (3) is performed by: and (3) after the deacetylation reaction result in the step (2), adding alkali into the system to adjust the pH value of the system to be neutral, adding an organic solvent and alkali to make the system be alkaline, adding Fmoc-OSu (Fmoc-OSu) under ice bath, reacting at room temperature for 1-3 h, after the reaction is finished, extracting petroleum ether, adjusting the pH value to be 3-4 by using 5-7N hydrochloric acid, extracting with ethyl acetate, washing with an organic phase weak acid aqueous solution, drying with anhydrous magnesium sulfate, concentrating to remove the solvent, and recrystallizing with petroleum ether to obtain the amino protecting group N-substituted chiral amino acid.
The weak acid is a weak acid solution with the pH value of 5-6.
In some embodiments, the synthetic methods of the invention are routed as follows:
the second technical scheme adopted by the invention is as follows: a method for preparing the compound shown in the formula III.
Compared with the existing published synthesis method, the synthesis method has the advantages of cheap raw materials, safe and simple operation, mild reaction conditions, safety, high efficiency, high yield, no racemization of the product and high purity.
The amino protecting group N-substituted chiral amino acid synthesized by the method is applied to the field of synthesis or medicinal 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 the amino group on the chiral amino acid with acetyl, and then reacts with the alkyl halide R1And carrying out substitution reaction on the X, deacetylating, and connecting an amino protecting group on nitrogen to obtain the amino protecting group N-substituted chiral amino acid.
The synthesis method firstly protects the amino group on the chiral amino acid by acetyl, so that the reaction is simple and efficient, the subsequent acetyl removal is also convenient, and the N-substitution reaction is also efficient.
Drawings
FIG. 1 is a nuclear magnetic spectrum of Fmoc-N-ethyl-L-norleucine of example 1.
FIG. 2 is a chiral HPLC chromatogram (detection wavelength 220nm) 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 254nm) 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 following examples are provided only to further illustrate the present invention and are not meant to limit the scope of the present invention in any way.
The starting materials may be obtained from commercial sources or prepared by methods known in the art or according to the methods described herein.
The structure of the compound is determined by nuclear magnetic resonance1H-NMR)、(13C-NMR and/or Mass Spectrometry (MS). NMR was measured using an ACF-400BRUK type nuclear magnetic resonance spectrometer using deuterated chloroform (CDCl) as a solvent3) Or deuterated dimethyl sulfoxide (DMSO-D)6) And TMS is an internal standard.
Example 1
Synthesis of Fmoc-N-ethyl-L-norleucine
L-norleucine (20g,0.15mol) was dissolved in 30% aqueous NaOH (45mL), and acetic anhydride (23.4g,0.225mol) was slowly added dropwise thereto, followed by reaction at room temperature for 12 hours. After the reaction was completed, the pH was adjusted to 2-3 with 6N HCl, and a solid precipitated, which was filtered, and the filter cake was washed with water and dried to give Compound 1(25g, 95%).
Dissolving the compound 1(10g,0.056mol) in THF, slowly adding NaH (5.78g,0.14mol) at 0 ℃, returning to room temperature for reaction for half an hour, then cooling to 0 ℃, dropwise adding iodoethane (13.5g,0.084mol), finishing dropping, and reacting for 8 hours at 60 ℃. The reaction was cooled to room temperature, poured into water, extracted three times with methyl tert-butyl ether under basic conditions, adjusted pH to 3-4 with HCl solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to give crude product (9.3g, 80%) without further purification.
To the crude product (9.3g,0.046mol) was added 2N HCl solution (30mL) and reacted at 100 ℃ for 6h, after the reaction was completed, 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 solid, then THF (30mL) and sodium carbonate (5.4g,0.05mol) were added thereto, Fmoc-OSu (12.5g,0.037mol) was added in portions under ice bath, and reacted at room temperature for 2 h. After the reaction was completed, petroleum ether was used to extract impurities, the pH was adjusted to 3-4 with 6N HCl solution, ethyl acetate was used for extraction, the resulting 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 give Fmoc-N-ethyl-L-norleucine (16.6g, 81%).
The total yield of the four steps is 61.5 percent. The optical purity index test result of the Fmoc-N-ethyl-L-norleucine product is 99.8% ee.
The NMR spectrum of Fmoc-N-ethyl-L-norleucine is shown in FIG. 1.
1H NMR(400MHz,DMSO-d6)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 profiles of Fmoc-N-ethyl-L-norleucine at different detection wavelengths are shown in FIGS. 2 and 3, and the results of analyzing FIGS. 2 and 3 are shown in tables 1 and 2.
Table 1 is a map analysis of FIG. 2
| No. | tR(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 is a map analysis of FIG. 3
| No. | tR(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 |
As a result of the analysis of FIG. 2 and FIG. 3 in combination with Table 1 and Table 2, the optical purity index of Fmoc-N-ethyl-L-norleucine product was found to be 99.8% ee.
Example 2
Synthesis of Fmoc-N-ethyl-D-norleucine
The starting materials in this example were D-norleucine (0.15mol) and iodoethane (0.084mol), and the overall yield of Fmoc-N-ethyl-D-norleucine was 60% as in example 1. The optical purity index of Fmoc-N-ethyl-D-norleucine product was found to be 99.1% ee.
1H NMR(400MHz,DMSO-d6)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 in this example were D-leucine (0.15mol) and iodoethane (0.084mol), with an overall yield of 62% Fmoc-N-ethyl-D-leucine otherwise similar to that of example 1. The optical purity index test result of the Fmoc-N-ethyl-D-leucine product is 99.1% ee.
1H NMR(400MHz,DMSO-d6)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 used in this example were L-norvaline (0.15mol) and iodoethane (0.084mol), and the total yield of Fmoc-N-ethyl-L-norvaline was 60% as in example 1. The optical purity index test result of the Fmoc-N-ethyl-L-norvaline product is 99.7% ee.
1H NMR(400MHz,DMSO-d6)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 in this example were D-norvaline (0.15mol) and iodoethane (0.084mol), and the total yield of Fmoc-N-ethyl-D-norvaline was 61% as in example 1. The optical purity index test result of the Fmoc-N-ethyl-D-norvaline product is 98.7% ee.
1H NMR(400MHz,DMSO-d6)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 in this example were L-norleucine (0.15mol) and iodopropane (0.084mol), and the overall yield of Fmoc-N-propyl-L-norleucine was 58% as in example 1. The optical purity index test result of the Fmoc-N-propyl-L-norleucine product is 99.3% ee.
1H NMR(400MHz,DMSO-d6)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 in this example were D-norleucine (0.15mol) and iodopropane (0.084mol), and the overall yield of Fmoc-N-propyl-D-norleucine was 62% as in example 1. The optical purity index test result of the Fmoc-N-propyl-D-norleucine product is 98.0% ee.
1H NMR(400MHz,DMSO-d6)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 in this example were D-leucine (0.15mol) and iodopropane (0.084mol), with an overall yield of 61% Fmoc-N-propyl-D-leucine otherwise similar to that of example 1. The optical purity index test result of the Fmoc-N-propyl-D-leucine product is 98.9% ee.
1H NMR(400MHz,DMSO-d6)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 from example 1(10g,0.056mol) is dissolved in THF and Cs is added slowly at 0 deg.C2CO3(0.14mol), returning to room temperature, reacting for half an hour, then cooling to 0 ℃, dropwise adding iodoethane (13.5g,0.084mol), finishing dropping, and reacting for 8 hours at 60 ℃. The reaction was cooled to room temperature, poured into water, extracted three times with methyl tert-butyl ether under basic conditions, adjusted pH to 3-4 with HCl solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to give crude product (4g, 34.4%) without further purification.
2N HCl solution (30mL) was added to the crude product, and the reaction was carried out at 100 ℃ for 6 hours, and after completion of the reaction, the reaction mixture 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 solid, then THF (30mL) and sodium carbonate (2.3g,0.02mol) were added thereto, Fmoc-OSu (5.4g,0.016mol) was added in portions under ice bath, and the reaction was carried out at room temperature for 2 h. After the reaction is finished, petroleum ether is used for impurity extraction, the pH value is adjusted to 3-4 by using 6N HCl solution, ethyl acetate is used for extraction, the obtained organic phase is washed by weak acid water, anhydrous magnesium sulfate is used for drying, most of solvent is removed by concentration, and the petroleum ether is recrystallized to obtain Fmoc-N-ethyl-L-norleucine (7g, 80%).
The total yield of Fmoc-N-ethyl-L-norleucine was 26.1%, and the optical purity index found 99% ee.
Example 10
Synthesis of Fmoc-N-ethyl-L-norleucine
The compound 1(10g,0.056mol) of example 1 is dissolved in DMF, NaH (0.14mol) is slowly added at 0 ℃, the temperature is returned to room temperature for reaction for half an hour, then the temperature is reduced to 0 ℃, iodoethane (13.5g,0.084mol) is added dropwise, and the reaction is finished at 60 ℃ for 8 hours. The reaction solution was cooled to room temperature, poured into water, extracted three times with methyl tert-butyl ether under alkaline conditions, adjusted pH to 3-4 with HCl solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to give crude product (6g, 52%) without further purification.
2N HCl solution (30mL) was added to the crude product, and the reaction was carried out at 100 ℃ for 6 hours, and after completion of the reaction, the reaction mixture 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 solid, then THF (30mL) and sodium carbonate (3.4g,0.032mol) were added thereto, Fmoc-OSu (7.8g,0.023mol) was added in portions under ice bath, and reacted at room temperature for 2 h. After the reaction is finished, petroleum ether is used for impurity extraction, the pH value is adjusted to 3-4 by using 6N HCl solution, ethyl acetate is used for extraction, the obtained organic phase is washed by weak acid water, anhydrous magnesium sulfate is used for drying, most of solvent is removed by concentration, and the petroleum ether is recrystallized to obtain Fmoc-N-ethyl-L-norleucine (10.5g, 78%).
The total yield of Fmoc-N-ethyl-L-norleucine was 38.5%, and the optical purity index found 98.8% ee.
Example 11
Synthesis of Fmoc-N-ethyl-L-norleucine
L-norleucine (20g,0.15mol) was dissolved in 30% aqueous NaOH (45mL), and acetic anhydride (23.4g,0.225mol) was slowly added dropwise thereto, followed by reaction at room temperature for 12 hours. After the reaction was completed, the pH was adjusted to 2-3 with 6N HCl, and a solid precipitated, which was filtered, and the filter cake was washed with water and dried to give Compound 1(25g, 95%).
Compound 1(10g,0.056mol) is dissolved in CH3Adding K slowly into CN at 0 deg.C2CO3(19.3g,0.14mol), returning to room temperature, reacting for half an hour, then cooling to 0 ℃, dropwise adding iodoethane (13.5g,0.084mol), and reacting for 8 hours at 60 ℃. The reaction was cooled to room temperature, poured into water, extracted three times with methyl tert-butyl ether under basic conditions, adjusted pH to 3-4 with HCl solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to give crude product (2.3g, 20%) without further purification.
To the crude product (2.3g,0.013mol) was added 2N HCl solution (30mL) and reacted at 100 ℃ for 6h, after completion of the reaction, the reaction 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 solid, then THF (30mL) and sodium carbonate (1.35g,0.0125mol) were added thereto, Fmoc-OSu (3.1g,0.009mol) was added in portions under ice bath, and reacted at room temperature for 2 h. After the reaction is finished, petroleum ether is used for extracting impurities, the pH value is adjusted to 3-4 by using 6N HCl solution, ethyl acetate is used for extraction, the obtained organic phase is washed by weak acid water, anhydrous magnesium sulfate is used for drying, most of solvent is removed by concentration, and the Fmoc-N-ethyl-L-norleucine (4g, 80%) is obtained by petroleum ether recrystallization, wherein the total yield of the four steps is 15.2%. The product optical purity index test result is 99.2% ee.
The above embodiments are merely illustrative of the technical ideas and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.
Claims (10)
1. A method for synthesizing an amino protecting group N-substituted chiral amino acid, comprising the steps of:
(1) carrying out acetylation reaction on the compound shown in the formula I to generate a compound shown in a formula II;
(2) reacting the compound shown as the formula II with R under the action of alkali and in the presence of a solvent1Carrying out substitution reaction on X, and then deacetylating to obtain a compound shown in a formula III;
(3) reacting the compound shown in the formula III with an amino protecting agent in the presence of a base and a solvent to generate a compound shown in a 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 is1Selected from C1-6 alkyl; x is halogen;
in the formulae I to IV, R is2Is an amino protecting group, said R3Selected from C1-6 alkyl.
2. The method of synthesis according to claim 1, characterized in that: the R is1Selected from methyl, ethyl, propyl; and/or, X is Cl, Br, I; and/or, said R3Selected from n-propyl, isopropyl, n-butyl, isobutyl; and/or the amino protective agent is fluorenylmethoxycarbonyl succinimide; the R is2Is Fmoc.
3. The synthesis method according to claim 1 or 2, characterized in that: in the step (2), the alkali is K2CO3、Cs2CO3A combination of one or more of NaH; and/or the solvent is acetone or ethyl acetateA combination of one or more of nitrile, DMF, 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.
4. The method of synthesis according to claim 3, characterized in that: the specific implementation mode of the step (2) is as follows: dissolving the compound shown as the formula II in a solvent, adding alkali at-5 ℃, heating to 20-40 ℃, stirring for 10-40 min, cooling to-5 ℃, and dropwise adding R1And X, after titration, heating to 50-70 ℃ for reaction for 6-10 h, cooling, mixing with water, extracting impurities with methyl tert-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 at 90-110 ℃ for 5-8 h to obtain the compound shown in the formula III.
5. The synthesis method according to claim 1 or 2, characterized in that: in the step (2), the alkali is NaH, the solvent is THF, and the temperature of the substitution reaction is 50-70 ℃.
6. The synthesis method according to claim 1 or 2, characterized in that: in the step (1), the acetylation 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.
7. The method of synthesis according to claim 6, characterized in that: in the step (1), the alkali is one or a combination of more of NaOH and KOH; and/or after the acetylation reaction is finished, adding hydrochloric acid into the system to adjust the pH value of the system to 2-3.
8. The method of synthesis according to claim 7, characterized in that: the specific implementation of the step (1) is as follows: adding a compound shown in the formula I into an alkali water solution, dropwise adding an acetyl reagent, reacting for 10-14 h at 15-40 ℃, then adjusting the pH value to 2-3 with 4-8N hydrochloric acid, separating out solids, filtering, washing a filter cake with water, and drying to obtain a compound shown in the formula II.
9. The method of synthesis according to claim 1, characterized in that: 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 more of sodium carbonate and sodium bicarbonate.
10. A process for the preparation of a compound of formula III as claimed in any one of claims 1 to 8.
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| CN1633289A (en) * | 2002-03-22 | 2005-06-29 | 卫材株式会社 | Hemiasterlin derivatives and uses thereof |
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