CN108129404B - Synthesis method of chiral piperazinone derivative - Google Patents

Synthesis method of chiral piperazinone derivative Download PDF

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CN108129404B
CN108129404B CN201810088386.4A CN201810088386A CN108129404B CN 108129404 B CN108129404 B CN 108129404B CN 201810088386 A CN201810088386 A CN 201810088386A CN 108129404 B CN108129404 B CN 108129404B
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protecting group
piperazinone
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吴生文
邹丽
吴磊
李文革
刘洪峰
彭立鹏
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Jiangxi Longlife Bio Pharmaceutical Co ltd
Kairesde Biochemical Suzhou Co Ltd
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Kairesde Biochemical Suzhou Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • 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
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention relates to a synthesis method of chiral piperazinone derivatives, which comprises the following steps: the ethanolamine with the protecting group in the formula (I) is subjected to oxidation reaction to obtain aminoacetaldehyde with the protecting group in the formula (II); in an alcohol solvent, performing reductive amination reaction on aminoacetaldehyde with a protecting group in a formula (II) and amino acid ester in the presence of a reducing agent to obtain a chiral diamine derivative in a formula (III), wherein the temperature of the reductive amination reaction is-10-0 ℃, and the amino acid ester is L-type amino acid ester or D-type amino acid ester; in an alcohol solvent, carrying out deprotection reaction and cyclization on the chiral diamine derivative shown in the formula (III) to obtain a chiral piperazinone derivative shown in the formula (IV); the reaction route is as follows:

Description

Synthesis method of chiral piperazinone derivative
Technical Field
The invention relates to the technical field of chiral compound synthesis, in particular to a synthesis method of a chiral piperazinone derivative.
Background
Piperazine (formula 1) and its derivatives are very useful pharmaceutical molecule fragments, and are considered to play an important role in the pharmacodynamic and pharmacological aspects of drug molecules; for example, substituted piperazine structures exist in molecules of the anticancer drug Imatinib (Imatinib, formula 2), the antibiotic ciprofloxacin (ciprofloxacin, formula 3) and the antiparkinsonian drug Piribedil (Piribedil, formula 4), and the molecular formulas of the molecules are as follows:
Figure BDA0001563019600000011
in addition, some drug molecules contain chiral piperazine structure or piperazinone structure, such as HIV inhibitor Indinavir (Indinavir, formula 5) contains chiral piperazine structure, and (-) -Nutlin-3 (formula 6) contains piperazinone segment, and the molecular formulas of the above molecules are as follows:
Figure BDA0001563019600000012
WO2013050424 reports a series of compounds with potential treatment of central or peripheral nerves, the key synthetic raw material of which is a chiral piperazinone compound represented by formula 7:
Figure BDA0001563019600000021
the above examples show that chiral piperazinone derivatives represented by formula (iv) are a key class of chiral drug intermediates, and it is of practical significance to develop efficient synthetic methods thereof, wherein formula (iv) is as follows:
Figure BDA0001563019600000022
for the synthesis of piperazine rings and piperazine derivatives, there are some reports in the literature, but all are limited to the synthesis of achiral piperazine derivatives; chiral asymmetric synthesis is less. For the synthesis of chiral piperazinone derivative racemates of formula (iv), the earlier literature (US2700668, 1952) is prepared by reacting ethylenediamine, acetaldehyde and hydrocyanic acid, the reaction raw materials are highly toxic and the process is highly polluting, and the reaction route is as follows:
Figure BDA0001563019600000023
patent US2006/199817a1 reports the synthesis of its racemate by heating ethylenediamine and methyl 2-bromopropionate in an alcoholic solvent, the reaction scheme being as follows:
Figure BDA0001563019600000024
there are also references (Angewandte Chemie, International Edition,2015,54, 179- > 183) reporting the use of ethyl 2-chloropropionate, etc., but the yields are all low.
For the synthesis of different isomers of chiral methylpiperazinones of the formula (IV), the methods of kinetic resolution are reported in the literature chemical communications,2012,48(71),8892-8894 and in the patent WO2013/7371A 2. The chiral piperazinone racemate of formula (IV) undergoes several series of selective reactions with the compound of formula 13 in the presence of 5-10 mol% of a chiral reagent (formula 14). The R isomer reacts slowly and exists more in a free form, and the selectivity of two configurations of the product is only 90/10; the S configuration reacts faster and is more present in the amide form, and the ratio of the two configurations of the product amide is 79/21. Although the above method provides a new attempt, the results are not ideal, and the synthesis of the chiral reagent of formula 14 and the resolution reagent of formula 13 is required, which is less practical.
Figure BDA0001563019600000031
The literature Tetrahedron: Asymmetry 2008, (19) 1689-. Starting from compound 15, selective deprotection thereof affords two differently configured compounds 16 and 17 which can selectively induce the introduction of the R substituent to form two differently configured piperazinones. However, this method is lengthy, and involves a multi-step synthesis of compound 15 first, and deprotection of compounds 18, 19, etc.
Figure BDA0001563019600000032
Patent EP3144307a1 also describes the preparation of piperazinones of other chiralities by reaction of amino acids with ternary nitrogen heterocycles. However, the method uses malodorous thiophenol, and the ring-closing yield is not high, only 42 percent, and the reaction route is as follows:
Figure BDA0001563019600000041
in a word, the existing preparation method of chiral piperazinone has the defects of high raw material toxicity, large pollution or long and inefficient route, and a method for solving the problems does not exist at present.
Disclosure of Invention
In order to solve the technical problems, the invention aims to provide a method for synthesizing chiral piperazinone derivatives, which has the advantages of easily available raw materials, low cost, safe operation, less pollution, high yield and product purity and ee value of more than 99%.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a synthesis method of chiral piperazinone derivatives, which comprises the following steps:
(1) the ethanolamine with the protecting group in the formula (I) is subjected to oxidation reaction to obtain aminoacetaldehyde with the protecting group in the formula (II);
(2) in an alcohol solvent, performing reductive amination reaction on aminoacetaldehyde with a protecting group in a formula (II) and amino acid ester in the presence of a reducing agent to obtain a chiral diamine derivative in a formula (III), wherein the temperature of the reductive amination reaction is-10-0 ℃, and the amino acid ester is L-type amino acid ester or D-type amino acid ester;
(3) in an alcohol solvent, carrying out deprotection reaction and cyclization on the chiral diamine derivative shown in the formula (III) to obtain the chiral piperazinone derivative shown in the formula (IV);
the reaction route is as follows:
Figure BDA0001563019600000042
wherein the protecting group X is carbobenzoxy (Cbz group) or tert-butyloxycarbonyl (Boc group);
r is methyl, ethyl, isopropyl, isobutyl, hydroxyethyl, benzyl or p-hydroxybenzyl;
r' is methyl, ethyl or isopropyl.
Further, in the step (1), the amino acid ester is alanine methyl ester, alanine ethyl ester, valine methyl ester, valine ethyl ester, leucine methyl ester, leucine ethyl ester, isoleucine methyl ester, isoleucine ethyl ester, phenylalanine methyl ester, phenylalanine ethyl ester, tyrosine methyl ester or tyrosine ethyl ester. Preferably, the amino acid ester is alanine methyl ester in the L form or alanine methyl ester in the D form.
Further, in the step (1), a TEMPO oxidation reaction system is adopted for carrying out oxidation reaction, and the reaction temperature is-10 ℃. Preferably, the reaction temperature is from-5 ℃ to 0 ℃. TEMPO oxidation reaction system conditions are mildest and environment-friendly, and the reaction is usually carried out at a lower temperature.
Further, the reaction solvent of the TEMPO oxidation reaction system is a mixed system of one of acetonitrile, ethyl acetate, ethyl propyl acetate and THF and water. Preferably, the reaction solvent is ethyl acetate/water or ethyl propyl acetate/water.
Further, in the step (1), an oxidation reaction may be performed by using an agar oxidation reaction system, a manganese dioxide oxidation reaction system, a DCC oxidation reaction system, a Swern oxidation reaction system, or an IBX oxidation reaction system.
Further, in the step (2), the reducing agent is sodium triacetoxyborohydride (NaBH (OAc))3) Or raney nickel.
Further, in the step (2) and the step (3), the alcohol solvent is one or more of common alcohol solvents such as methanol, ethanol, ethylene glycol, glycerol, n-butanol and n-hexanol. Preferably, the alcohol is methanol and/or ethanol.
Further, in the step (3), deprotection reaction and cyclization are carried out under the action of Pd/C and hydrogen, wherein the reaction temperature is 10-30 ℃.
In step (2), the reaction needs to be controlled at a temperature between-10 ℃ and 0 ℃ to prevent aldehyde groups from being directly reduced to alcohol. The step (2) can select amino acids with different configurations to obtain chiral diamine derivatives, when the L-type amino acid ester is selected, the final target product is S configuration, and when the D-type amino acid ester is selected, the final target product is R configuration.
In the step (3), after the protective group is removed, the amino group directly attacks the ester group to close the ring to obtain the target product, the reaction is usually carried out in a low-carbon alcohol solvent such as methanol or ethanol, and the reaction is environment-friendly.
Further, after the step (2) and after the step (3), a step of purifying the product is further included. The products obtained in step (2) and step (3) can be purified by column chromatography.
Further, before the step (1), the following steps are also included:
(S1) in an organic solvent, ethanolamine is subjected to an upper protection reaction in the presence of alkali to obtain ethanolamine with a protecting group of the formula (I);
the reaction route is as follows:
Figure BDA0001563019600000061
wherein the protecting group X is carbobenzoxy or tert-butyloxycarbonyl.
Further, in the step (S1), the protecting group X is benzyloxycarbonyl, wherein the upper protection reaction temperature is 0 ℃ to 25 ℃.
Further, in the step (S1), when the protecting group X is benzyloxycarbonyl, the protecting agent used in the up-protection reaction is benzyloxycarbonyl succinimidyl (Z-OSu) or benzyl chloroformate (Cbz-Cl).
Further, in the step (S1), the base is an inorganic base, and the inorganic base is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.
Further, in the step (S1), the base is an organic base, and the organic base is one or more of triethylamine, pyridine, and dimethylaminopyridine.
Further, in the step (S1), the organic solvent is one or more of Tetrahydrofuran (THF), dichloromethane, acetonitrile, toluene, and N, N-dimethylformamide.
The reaction temperature in the step (S1) is low, and the reaction product in this step can be used as the next reaction without purification.
Further, when the protecting group is benzyloxycarbonyl (Cbz group), before step (2), the following steps are included:
(S1) in an organic solvent, ethanolamine and a protecting reagent containing benzyloxycarbonyl are subjected to an upper protection reaction in the presence of alkali to obtain benzyloxycarbonyl protected ethanolamine of the formula (Ia), wherein the reaction temperature is 0-25 ℃; the protecting reagent containing benzyloxycarbonyl is benzyloxycarbonyl succinimide (Z-OSu) or benzyl chloroformate (Cbz-Cl);
(1) oxidizing the benzyloxycarbonyl protected ethanolamine of formula (Ia) to obtain a benzyloxycarbonyl protected aminoacetaldehyde of formula (IIa);
the reaction route is as follows:
Figure BDA0001563019600000062
wherein Cbz represents benzyloxycarbonyl.
Specifically, when the protecting group is benzyloxycarbonyl and the amino acid ester is alanine methyl ester hydrochloride, the synthetic route of the chiral piperazinone derivative with the R configuration is as follows:
Figure BDA0001563019600000071
specifically, when the protecting group is benzyloxycarbonyl and the amino acid ester is alanine methyl ester hydrochloride, the synthetic route of the chiral piperazinone derivative with the S configuration is as follows:
Figure BDA0001563019600000072
by the scheme, the invention at least has the following advantages:
the invention overcomes the defects of high toxicity and pollution of raw materials or long and low route efficiency in the existing preparation method of chiral piperazinone, and provides a novel preparation method of chiral piperazinone derivatives, which has the advantages of easily available raw materials, low cost, safe operation, less pollution, high yield, high product purity and ee value higher than 99%, and is suitable for industrial production.
The foregoing is a summary of the present invention, and in order to provide a clear understanding of the technical means of the present invention and to be implemented in accordance with the present specification, the following is a preferred embodiment of the present invention and is described in detail below.
Detailed Description
The following examples are given to further illustrate the embodiments of the present invention. The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
In the following examples of the present invention, the synthetic route of the R-configuration chiral piperazinone derivative is as follows:
Figure BDA0001563019600000081
the synthetic route of the S-configuration chiral piperazinone derivative is as follows:
Figure BDA0001563019600000082
see the examples below for specific methods of preparation thereof.
Example 1
Synthesis of N-Cbz-ethanolamine (shown as formula I)
45g of ethanolamine and 91g of triethylamine were dissolved in 400mL of THF, and 206g Z-OSu was added in portions with stirring and stirred at room temperature overnight. After the reaction was complete, filtration was carried out, the filtrate was concentrated under reduced pressure, and the product solidified after a little standing to give 157g of a solid in 106% yield with an HPLC purity of 73.6%. The crude product obtained in this example was not purified and directly fed to the next reaction.
Example 2
Synthesis of N-Cbz-aminoacetaldehyde (shown in formula II)
57g of N-Cbz-ethanolamine is dissolved in 700mL of isopropyl acetate and cooled to-5 to 0 ℃. To the solution were added, with stirring, 51g of sodium bromide, 31g of sodium bicarbonate, 0.4g of TEMPO (tetramethylpiperidine nitroxide), 31g of sodium bicarbonate and 250mL of water. And slowly adding 320mL of sodium hypochlorite solution dropwise, and keeping the temperature of the reaction system to be less than 0 ℃. And monitoring by TLC, adding sodium thiosulfate to quench the reaction after the reaction is completed until the raw material is completely converted, and separating the liquid. The organic phase was collected and dried for 4h with anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure gave 40g of a colorless liquid in a yield of 70%. The crude product obtained in this example was not purified and directly fed to the next reaction.
Example 3
Synthesis of methyl (R) -2- ((2- (((benzyloxy) carbonyl) amino) ethyl) amino) propionate (shown in formula a)
33g of D-alanine methyl ester hydrochloride were dissolved in 200mL of DCM, neutralized with 25g of triethylamine and filtered to remove the salts. The filtrate was collected, 40g N-Cbz-aminoacetaldehyde in 300mL methanol was added, stirred for 15min and cooled to 0 ℃. 48g of triethylamine are added and 87g of sodium triacetoxyborohydride are added in portions. After the addition was complete, stirring was continued, slowly warmed to room temperature and stirred overnight. TLC monitored until the reaction conversion was complete. Adding saturated sodium bicarbonate solution into the reaction system to quench the reaction, separating the solution, extracting the water layer once more by using 200ml of EDCM, combining the organic phases, and concentrating to obtain transparent liquid. The product was isolated and purified by silica gel column chromatography (using n-heptane/ethyl acetate 1/2 as eluent) to give 40.7g of a colorless viscous liquid, i.e., 83% yield, and characterized by nuclear magnetism as follows:
1H NMR(400MHz,CDCl3):δ＝7.35～7.28(m,5H),5.37(s,1H),5.14(s,1H),5.11(s,1H),3.72(s,3H),3.36～3.31(m,2H),3.24～3.21(m,1H),2.81～2.75(m,1H),2.64～2.58(m,1H),1.30～1.28(d,3H)。
example 4
Synthesis of (R) -3-methylpiperazin-2-one (shown in formula c)
10g of methyl (R) -2- ((2- (((benzyloxy) carbonyl) amino) ethyl) amino) propionate was added to 100mL of methanol, 3g of palladium on carbon was added, hydrogen was added to 1.8MPa, and the reaction was stirred at room temperature overnight. HPLC monitored the reaction to completion. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (using ethyl acetate/methanol 9/1 as eluent) to give 3.71g of a white solid as the product of formula c in 91% yield, 98.2% HPLC purity and 98.3% ee. Performing nuclear magnetic characterization, mass spectrum characterization and optical rotation test on the product, wherein the results are as follows:
1H NMR(400MHz,CDCl3):δ＝6.48(s,1H),3.58～3.52(m,1H),3.49～3.42(m,1H),3.35～3.29(m,1H),3.19～3.14(m,1H),3.06～2.99(m,1H),2.12(s,1H),1.42～1.40(d,3H)。
MS(ES+)m/z:137.15[M+Na+],115.16[M+H+]。
[α]D 28＝+36(c＝0.2g/100mL,CHCl3) WO2013/7371A2 reports optical rotation data of (R) -3-methylpiperazin-2-one with an ee value of 80% [ α ]]D 28＝+/-0(c＝0.2g/100mL,CHCl3). The above results indicate that the product obtained in this example is of the R configuration.
Example 5
Synthesis of methyl (S) -2- ((2- (((benzyloxy) carbonyl) amino) ethyl) amino) propionate (shown in formula b)
33g of L-alanine methyl ester hydrochloride were dissolved in 200mL of DCM, neutralized with 25g of triethylamine and filtered to remove the salts. The filtrate was collected, 40g N-Cbz-aminoacetaldehyde in 300mL methanol was added, stirred for 15min and cooled to 0 ℃. 48g of triethylamine are added and 87g of sodium triacetoxyborohydride are added in portions. After the addition was complete, stirring was continued, slowly warmed to room temperature and stirred overnight. TLC monitored until the reaction conversion was complete. Adding saturated sodium bicarbonate solution into the reaction system to quench the reaction, separating the solution, extracting the water layer once more by using 200ml of EDCM, combining the organic phases, and concentrating to obtain transparent liquid. The product was isolated and purified by silica gel column chromatography (using n-heptane/ethyl acetate 1/2 as eluent) to give 41.5g of a colorless viscous liquid, i.e., the product of formula b in 85% yield, and characterized by nuclear magnetic resonance as follows:
1H NMR(400MHz,CDCl3):δ＝7.35～7.28(m,5H),5.37(s,1H),5.14(s,1H),5.11(s,1H),3.72(s,3H),3.36～3.31(m,2H),3.24～3.21(m,1H),2.81～2.75(m,1H),2.64～2.58(m,1H),1.30～1.28(d,3H)。
example 6
Synthesis of (S) -3-methylpiperazin-2-one (represented by formula d)
10g of methyl (S) -2- ((2- (((benzyloxy) carbonyl) amino) ethyl) amino) propionate was added to 100mL of methanol, 3g of palladium on carbon was added, hydrogen was added to 1.8MPa, and the reaction was stirred at room temperature overnight. HPLC monitored the reaction to completion. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (using ethyl acetate/methanol 9/1 as eluent) to give 3.67g of a white solid, which was the product of formula d in 90% yield, 98.1% HPLC purity and 98.0% ee. Performing nuclear magnetic characterization, mass spectrum characterization and optical rotation test on the product, wherein the results are as follows:
1H NMR(400MHz,CDCl3):δ＝6.48(s,1H),3.58～3.52(m,1H),3.49～3.42(m,1H),3.35～3.29(m,1H),3.19～3.14(m,1H),3.06～2.99(m,1H),2.12(s,1H),1.42～1.40(d,3H)。
MS(ES+)m/z:137.15[M+Na+],115.16[M+H+]。
[α]D 28＝-34(c＝0.2g/100mL,CHCl3). The above results show that the product obtained in this example is in the S configuration.
Example 7
Synthesis of N-Cbz-ethanolamine
45g ethanolamine and 32.5g sodium hydroxide were dissolved in 400mL THF and 120mL water, and 206gZ-OSu was added portionwise with stirring and stirred at room temperature overnight. After the reaction was completed, filtration was carried out, the filtrate was concentrated under reduced pressure, extracted with ethyl acetate, the organic phase was concentrated, and the product solidified after being left slightly to obtain 157g of a solid. The crude product obtained in this example was not purified and directly fed to the next reaction.
Example 8
Synthesis of N-Boc-ethanolamine
45g ethanolamine and 91g triethylamine were dissolved in 400mL THF, and 180g Boc anhydride was added portionwise with stirring and stirred at room temperature overnight. After the reaction was completed, filtration was carried out, the filtrate was concentrated under reduced pressure, and the product was solidified after being left to stand a little to obtain 120g of a solid. The crude product obtained in this example was not purified and directly fed to the next reaction.
Example 9
Synthesis of N-Boc-aminoacetaldehyde
43g of N-Boc-ethanolamine was dissolved in 700mL of isopropyl acetate and cooled to-5 to 0 ℃. To the solution were added, with stirring, 51g of sodium bromide, 31g of sodium bicarbonate, 0.4g of TEMPO (tetramethylpiperidine nitroxide), 31g of sodium bicarbonate and 250mL of water. And slowly adding 320mL of sodium hypochlorite solution dropwise, and keeping the temperature of the reaction system to be less than 0 ℃. And monitoring by TLC, adding sodium thiosulfate to quench the reaction after the reaction is completed until the raw material is completely converted, and separating the liquid. The organic phase was collected and dried for 4h with anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure to give 30g of a colorless liquid. The crude product obtained in this example was not purified and directly fed to the next reaction.
Example 10
Synthesis of methyl (R) -2- ((2- (((tert-butoxy) carbonyl) amino) ethyl) amino) propionate
33g of D-alanine methyl ester hydrochloride were dissolved in 200mL of DCM, neutralized with 25g of triethylamine and filtered to remove the salts. The filtrate was collected, added with 300mL of 30g N-Boc-aminoacetaldehyde in methanol, stirred for 15min and cooled to 0 ℃. 48g of triethylamine are added and 87g of sodium triacetoxyborohydride are added in portions. After the addition was complete, stirring was continued, slowly warmed to room temperature and stirred overnight. TLC monitored until the reaction conversion was complete. Adding saturated sodium bicarbonate solution into the reaction system to quench the reaction, separating the solution, extracting the water layer once more by using 200ml of EDCM, combining the organic phases, and concentrating to obtain transparent liquid. Purification by column chromatography on silica gel (using n-heptane/ethyl acetate 1/2 as eluent) gave 30g of a colorless viscous liquid.
Example 11
Synthesis of ethyl (R) -2- ((2- (((benzyloxy) carbonyl) amino) ethyl) amino) propionate
36g of ethyl D-alanine hydrochloride are dissolved in 200mL of DCM, neutralized with 25g of triethylamine and filtered to remove the salts. The filtrate was collected, 40g N-Cbz-aminoacetaldehyde in 300mL methanol was added, stirred for 15min and cooled to 0 ℃. 48g of triethylamine are added and 87g of sodium triacetoxyborohydride are added in portions. After the addition was complete, stirring was continued, slowly warmed to room temperature and stirred overnight. TLC monitored until the reaction conversion was complete. Adding saturated sodium bicarbonate solution into the reaction system to quench the reaction, separating the solution, extracting the water layer once more by using 200ml of EDCM, combining the organic phases, and concentrating to obtain transparent liquid. Purification by column chromatography on silica gel (using n-heptane/ethyl acetate 1/2 as eluent) gave 42g of a colorless viscous liquid.
Example 12
Synthesis of methyl (R) -2- ((2- (((benzyloxy) carbonyl) amino) ethyl) amino) 4-methylbutanoate
40g of D-valine methyl ester hydrochloride was dissolved in 200mL of DCM, neutralized with 25g of triethylamine, and the salt was removed by filtration. The filtrate was collected, 40g N-Cbz-aminoacetaldehyde in 300mL methanol was added, stirred for 15min and cooled to 0 ℃. 48g of triethylamine are added and 87g of sodium triacetoxyborohydride are added in portions. After the addition was complete, stirring was continued, slowly warmed to room temperature and stirred overnight. TLC monitored until the reaction conversion was complete. Adding saturated sodium bicarbonate solution into the reaction system to quench the reaction, separating the solution, extracting the water layer once more by using 200ml of EDCM, combining the organic phases, and concentrating to obtain transparent liquid. Purification by column chromatography on silica gel (using n-heptane/ethyl acetate 1/2 as eluent) gave 49g of a colorless viscous liquid.
Example 13
Synthesis of methyl (R) -2- ((2- (((benzyloxy) carbonyl) amino) ethyl) amino) phenylpropionate
48g of D-phenylalanine methyl ester hydrochloride was dissolved in 200mL of DCM, neutralized with 25g of triethylamine, and the salt was removed by filtration. The filtrate was collected, 40g N-Cbz-aminoacetaldehyde in 300mL methanol was added, stirred for 15min and cooled to 0 ℃. 48g of triethylamine are added and 87g of sodium triacetoxyborohydride are added in portions. After the addition was complete, stirring was continued, slowly warmed to room temperature and stirred overnight. TLC monitored until the reaction conversion was complete. Adding saturated sodium bicarbonate solution into the reaction system to quench the reaction, separating the solution, extracting the water layer with 200mL of DCM once again, combining the organic phases, and concentrating to obtain transparent liquid. Purification by column chromatography on silica gel (using n-heptane/ethyl acetate 1/2 as eluent) gave 58g of a colorless viscous liquid.
Example 14
Synthesis of (R) -3-methylpiperazin-2-one
10g of ethyl (R) -2- ((2- (((benzyloxy) carbonyl) amino) ethyl) amino) propionate was added to 100mL of methanol, 3g of palladium on carbon was added, hydrogen was added to 1.8MPa, and the reaction was stirred at room temperature overnight. HPLC monitored the reaction to completion. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (using ethyl acetate/methanol-9/1 as eluent) to give 3.6g of a white solid.
Example 15
Synthesis of (R) -3-isopropylpiperazin-2-one
11g of methyl (R) -2- ((2- (((benzyloxy) carbonyl) amino) ethyl) amino) 4-methylbutanoate was added to 100mL of methanol, 3g of palladium on carbon was added, hydrogen was added to 1.8MPa, and the reaction was stirred at room temperature overnight. HPLC monitored the reaction to completion. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (using ethyl acetate/methanol-9/1 as eluent) to give 4.6g of a white solid.
Example 16
Synthesis of (R) -3-benzylpiperazin-2-one
12g of methyl (R) -2- ((2- (((benzyloxy) carbonyl) amino) ethyl) amino) propionate was added to 100mL of methanol, 3g of palladium on carbon was added, hydrogen was added to 1.8MPa, and the reaction was stirred at room temperature overnight. HPLC monitored the reaction to completion. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (using ethyl acetate/methanol-9/1 as eluent) to give 5.7g of a white solid.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, it should be noted that, for those skilled in the art, many modifications and variations can be made without departing from the technical principle of the present invention, and these modifications and variations should also be regarded as the protection scope of the present invention.

Claims (2)

1. A method for synthesizing chiral piperazinone derivatives is characterized by comprising the following steps:
(1) the ethanolamine with the protecting group in the formula (I) is subjected to oxidation reaction to obtain aminoacetaldehyde with the protecting group in the formula (II); in the step, a TEMPO oxidation reaction system is adopted for oxidation reaction, and the reaction temperature is-10 ℃;
(2) in an alcohol solvent, performing reductive amination reaction on aminoacetaldehyde with a protecting group in a formula (II) and amino acid ester in the presence of a reducing agent to obtain a chiral diamine derivative in a formula (III), wherein the temperature of the reductive amination reaction is-10-0 ℃, and the amino acid ester is L-type or D-type alanine methyl ester; the reducing agent is sodium triacetoxyborohydride and/or raney nickel;
(3) in an alcohol solvent, carrying out deprotection reaction and cyclization on the chiral diamine derivative of the formula (III) under the action of Pd/C and hydrogen at the reaction temperature of 10-30 ℃ to obtain the chiral piperazinone derivative of the formula (IV);
the reaction route is as follows:
Figure FDA0002384352330000011
wherein the protecting group X is benzyloxycarbonyl;
r is methyl;
r' is methyl;
before the step (1), the method also comprises the following steps:
(S1) in an organic solvent, ethanolamine is subjected to an upper protection reaction in the presence of alkali to obtain ethanolamine with a protecting group of the formula (I);
the reaction route is as follows:
Figure FDA0002384352330000012
2. the method of synthesizing a chiral piperazinone derivative as recited in claim 1, wherein: in the step (2) and the step (3), the alcohol solvent is one or more of methanol, ethanol, ethylene glycol, glycerol, n-butanol and n-hexanol.
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