CN111875544B - Synthesis method of N-substituted hydantoin compound - Google Patents

Synthesis method of N-substituted hydantoin compound Download PDF

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CN111875544B
CN111875544B CN202010812527.XA CN202010812527A CN111875544B CN 111875544 B CN111875544 B CN 111875544B CN 202010812527 A CN202010812527 A CN 202010812527A CN 111875544 B CN111875544 B CN 111875544B
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CN111875544A (en
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朱忠智
梁京文
林晗泽
郭大俊
邝妙慈
陈修文
朱伟东
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Wuyi University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C07D233/74—Two oxygen atoms, e.g. hydantoin with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to other ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

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Abstract

The invention discloses a synthetic method of an N-substituted hydantoin compound, which comprises the following steps: taking acyl azide compounds shown in a formula I and glycine ethyl ester compounds shown in a formula II as raw materials, and carrying out heating reaction in the presence of an additive to obtain N-substituted hydantoin compounds shown in a formula III, wherein the reaction formula is as follows:
Figure DDA0002631549040000011
in the formula, R1And R2Independently selected from hydrocarbyl, substituted hydrocarbyl, aryl, substituted aryl or heteroaryl; r2Selected from alkyl or aryl; r3Selected from hydrogenAtoms and hydrocarbon groups. The synthesis method can efficiently synthesize the functionalized N-substituted hydantoin compound, has the advantages of few synthesis steps, mild conditions, safe operation, nontoxic and cheap and easily-obtained raw materials, good compatibility of the synthesis method for functional groups and high atom economy, obtains the N-substituted hydantoin compound with a nitrogen heterocyclic ring skeleton and a novel structure, has the yield of 92 percent and the purity of 99 percent, and is easy for industrial synthesis.

Description

Synthesis method of N-substituted hydantoin compound
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of an N-substituted hydantoin compound.
Background
Hydantoin compounds belong to a class of compounds of imidazole derivatives, and have various pharmacological effects due to various substituted groups and more substituted positions of hydantoin, and the substituted groups have biological activity and interaction between the groups. The pharmacological actions of hydantoin compounds are mainly expressed in antibacterial, anti-inflammatory, blood sugar lowering, sodium channel blocker, generation inhibition of uremic toxins and the like. In the field of medicine, hydantoin is one of important intermediates for synthesizing various amino acids, and some derivatives thereof also have extremely wide application, such as 5, 5-diphenylhydantoin and other derivatives which can be used for treating arrhythmia, anticonvulsants for treating epilepsy, Saint vitamins chorea and other diseases; certain spiro-hydantoin derivatives such as: (2R, 4S) -6-chloro-2-methyl-spiro (4-chroman-4, 4 imidazole) -2-5-dione is useful for the treatment of chronic diabetic complications; 1-aminohydantoin derivatives such as: 1- (5-nitro-2-furan) methyleneaminohydantoin may be used for the treatment of urinary system infections, and as a muscle relaxant and as a bactericide. Hydantoin compounds are widely applied to synthesis of various anti-tumor, antibiotic and pesticide and related bioactive molecules.
Because the heterocyclic small molecular skeleton has well-known potential in human bodies, the hydantoin compounds have good application prospects in the aspect of treating immune diseases such as tumors, infectious diseases, chronic obstructive pulmonary diseases, diabetes, chronic kidney diseases, renal insufficiency, uremia, rheumatoid arthritis and the like. The development of a practical and green process for the synthesis of hydantoins and their derivatives is therefore an attractive area of research.
However, the synthesis of N-substituted hydantoin compounds inevitably requires the use of catalysts and solvents, and is environmentally unfriendly due to the use of highly toxic additives. Therefore, it is very significant to develop a reaction without using a solvent and a catalyst, and a solvent-free, catalyst-free organic synthesis is a simple and widely applicable method, which can reduce the application of organic solvents and the generation of pollutants. The method has the advantages of mild reaction conditions without solvent or catalyst, capability of effectively shortening reaction time and optimizing reaction steps and operation, simple post-treatment, simple experimental instrument and equipment and the like. Therefore, from both the environmental and economic aspects, the development of such an environmentally-friendly, economical and practical method for synthesizing the N-substituted hydantoin compounds has a wide market prospect.
Disclosure of Invention
The present invention is directed to solving at least one of the problems of the prior art. Therefore, the invention provides a green and environment-friendly synthesis method of N-substituted hydantoin compounds, which utilizes acyl azide compounds and glycine ester compounds to carry out cycloaddition reaction to synthesize the N-substituted hydantoin compounds, so that the product is synthesized in a green, simple and direct manner, the yield is good, and another green synthesis idea is provided for constructing more N-substituted hydantoin drugs.
A synthesis method according to an embodiment of the present invention comprises the steps of: taking acyl azide compounds shown in a formula I and glycine ethyl ester compounds shown in a formula II as raw materials, and carrying out heating reaction in the presence of an additive to obtain N-substituted hydantoin compounds shown in a formula III, wherein the reaction formula is as follows:
Figure BDA0002631549020000021
in the formula, R1And R2Independently selected from hydrocarbyl, substituted hydrocarbyl, aryl, substituted aryl or heteroaryl; r2Selected from alkyl or aryl; r3Selected from hydrogen atoms and hydrocarbon groups.
In the present invention, "substituted" in "substituted hydrocarbyl" or "substituted aryl" each refers to a substituent conventional in the art so as not to interfere with the reaction, such as halogen, haloalkyl, haloalkoxy, cyano (-CN), alkoxy, amino protected by an N-protecting group, silyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted benzyl, optionally substituted aryloxy, or an N-protecting group when attached to N; said optional substitution is unsubstituted or substituted with groups including, but not limited to: F. cl, Br, I, CF3-, -CN, amino protected by N protecting group; the number of "substitutions" may not be limited (e.g., the number of "substitutions" may be one or more<E.g. 2,3, 4 or 5>When there are a plurality of "substitutions", the "substitutions" are the same or different).
The position of the term "substituted" may be arbitrary, if not specifically stated; for example, each independently at the "site of attachment of the aryl group to another group", or at the "site of attachment of the heteroaryl group to another group", and phenyl, for example, means that the substituent is at the ortho, meta, or para position relative to the central bond.
"aryl" means a substituent having the nature of an aromatic ring structure, e.g. "C6～30Aryl "useful aryl groups of the present invention include, but are not limited to: phenyl, naphthyl, tetrahydronaphthyl2, 3-indanyl, biphenyl, phenanthryl, anthryl or acenaphthenyl (acenaphthyl), and the like.
Similarly, "heteroaryl" denotes an aryl group containing one or more heteroatoms selected from N, O or S. In a specific embodiment, a "heteroaryl" group in the present invention contains 6 to 30 carbon atoms and has at least one 5-8 membered heterocyclic ring containing 1 to 4 heteroatoms independently selected from O, N or S. Heteroaryl groups within the scope of this definition include, but are not limited to: acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrahydroquinoline. As defined below for heterocycles, "heteroaryl" is also to be understood to include any N-oxide derivative of a nitrogen-containing heteroaryl group. In the case where the heteroaryl substituent is a bicyclic substituent and one ring is non-aromatic or contains no heteroatoms, it is understood that the attachment is via the aromatic ring or via the heteroatoms containing the ring, respectively.
According to some embodiments of the invention, R is1And R2Independently selected from C1～10Hydrocarbyl, phenyl-substituted C1～10Hydrocarbyl radical, C6～30Aryl radical, C6～30Substituted aryl or 5-to 8-membered heteroaryl containing 1 to 2O, N or S atoms; r3Is selected from C1～10A hydrocarbyl group.
Herein "C1～10The "hydrocarbon group" refers to a cyclic or linear hydrocarbon group having 1 to 10 carbon atoms; the alkyl refers to saturated or unsaturated groups containing only carbon atoms, including alkyl, alkenyl and alkynyl; for example, the term "alkyl" is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms. E.g. C1～10E.g. in "C1～10Alkyl is defined to include groups having 1, 2,3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms in a straight or branched chain structure. For example, "C1～10Alkyl "includes specifically methyl, ethyl, n-propyl, isopropyl, n-butylT-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and the like.
The term "phenyl substituted C1～10By hydrocarbyl "is meant" C1～10The hydrocarbyl group is substituted with a phenyl group at any position.
Further, in the formula, R1Selected from phenyl, substituted phenyl, phenyl substituted C1～6Alkyl radical, C1～6Alkyl or 5-membered heteroaryl containing 1O, N or S atom; r2Selected from phenyl, substituted phenyl, phenyl substituted C1～6Alkyl or C1～6An alkyl group; r3Is selected from C1～6An alkyl group.
Further, R1Selected from phenyl, substituted phenyl, benzyl, cyclohexyl, thienyl, furyl or naphthyl, wherein the substituted phenyl is selected from halophenyl, 4-methylphenyl, 4-cyano, 4-trifluoromethylphenyl, 4-tert-butylphenyl or 4-methoxy; r2Is selected from phenyl, substituted phenyl, benzyl or methyl, wherein the substituted phenyl is 4-chlorine, 3, 4-dimethyl or 2, 5-dimethoxy; r3Is ethyl, isopropyl, butyl or hexyl.
The term "halo" means substitution of the halogen atom F, Cl, Br or I.
According to some embodiments of the invention, the additive is a base comprising one or more of an inorganic base and an organic strong base of an alkali metal or alkaline earth metal.
Further, the additive is selected from one or more of potassium tert-butoxide, sodium hydroxide, cesium carbonate, lithium acetate, lithium carbonate, calcium bicarbonate, sodium acetate, sodium phosphate, potassium phosphate and potassium carbonate. Among them, sodium bicarbonate, sodium acetate, sodium phosphate, potassium phosphate and potassium carbonate have the best effect. The effect of potassium carbonate is optimal.
According to some embodiments of the invention, the molar ratio of the acyl azide compound, the glycine ethyl ester compound and the additive is 1-1.5: 1: 1 to 2.
Further, the molar ratio of the acyl azide compound, the glycine ethyl ester compound and the additive is 1.2: 1: 1.5.
according to some embodiments of the invention, the temperature of the heating reaction is 40 to 120 ℃.
Further, the temperature of the heating reaction is 60-100 ℃.
Further, the temperature of the heating reaction is 100 ℃. The reaction yield and purity are optimal at this reaction temperature.
According to some embodiments of the invention, the heating reaction time is 0.5-24 h.
Further, the heating reaction time is 4-10 h.
Further, the heating reaction time is 8 h.
According to some embodiments of the invention, the method further comprises a step of purifying the obtained alpha-ketoamide compound.
Further, the purification operation is separation and purification by column chromatography.
The synthesis method of the invention at least has the following beneficial effects: the synthesis method does not need to use a solvent and a catalyst, and compared with transition metal catalysis, the method avoids trace metals in the product during separation, and avoids complex post-treatment; meanwhile, the method has the advantages of simple synthesis steps, safe operation, good functional group compatibility of the synthesis method and high atom economy, obtains the N-substituted hydantoin compound with high added value, has the yield of 92 percent and the purity of 99 percent, and is easy for industrial synthesis; a series of N-substituted hydantoin compounds containing potential pharmaceutical activity are constructed by effectively combining the structural units of acyl azide compounds and glycine ethyl ester compounds, and a new drug choice can be provided for human defeating diseases.
Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Drawings
FIG. 1 is a hydrogen spectrum of a product 3aa obtained in example 1 of the present invention;
FIG. 2 is a carbon spectrum of the product 3aa obtained in example 1 of the present invention;
FIG. 3 is a hydrogen spectrum of a product 3ab obtained in example 2 of the present invention;
FIG. 4 is a carbon spectrum of a product 3ab obtained in example 2 of the present invention;
FIG. 5 shows a hydrogen spectrum of a product 3ac obtained in example 3 of the present invention;
FIG. 6 shows the carbon spectrum of the product 3ac obtained in example 3 of the present invention;
FIG. 7 is a hydrogen spectrum of 3ad, a product obtained in example 4 of the present invention;
FIG. 8 is a carbon spectrum of 3ad, a product obtained in example 4 of the present invention;
FIG. 9 is a hydrogen spectrum of 3ae, a product obtained in example 5 of the present invention;
FIG. 10 is a carbon spectrum of 3ae, a product obtained in example 5 of the present invention;
FIG. 11 shows the hydrogen spectrum of the product 3af obtained in example 6 according to the invention;
FIG. 12 shows the carbon spectrum of 3af, a product obtained in example 6 according to the invention;
FIG. 13 is a hydrogen spectrum of 3ag, a product obtained in example 7 of the present invention;
FIG. 14 is a carbon spectrum of 3ag, a product obtained in example 7 of the present invention;
FIG. 15 is a hydrogen spectrum of 3ah, a product obtained in example 8 of the present invention;
FIG. 16 is a carbon spectrum of 3ah, a product obtained in example 8 of the present invention;
FIG. 17 is a hydrogen spectrum of the product 3ai obtained in example 9 of the present invention;
FIG. 18 is a carbon spectrum of the product 3ai obtained in example 9 of the present invention;
FIG. 19 is a hydrogen spectrum of product 3aj obtained in example 10 of the present invention;
FIG. 20 is a carbon spectrum of a product 3aj obtained in example 10 of the present invention;
FIG. 21 is a hydrogen spectrum of 3ak, a product obtained in example 11 of the present invention;
FIG. 22 is a carbon spectrum of 3ak, a product obtained in example 11 of the present invention;
FIG. 23 is a hydrogen spectrum of product 3al obtained in example 12 of the present invention;
FIG. 24 is a carbon spectrum of 3al, a product obtained in example 12 of the present invention;
FIG. 25 is a hydrogen spectrum of product 3am obtained in example 13 of the present invention;
FIG. 26 is a carbon spectrum of 3am, a product obtained in example 13 of the present invention.
Detailed Description
In order to explain technical contents, achieved objects, and effects of the present invention in detail, the following description is made with reference to the accompanying drawings in combination with the embodiments.
The novel process for the synthesis of N-substituted hydantoins of the present invention is further illustrated below with reference to specific examples, but the scope of the invention is not limited to the scope of the examples.
Raw material synthesis: all acyl azide compounds used in the invention are obtained by preparation, and the method comprises the following steps: dissolving 5 millimole benzoyl chloride compound in 10mL of acetone solution, dissolving 10 millimole sodium azide in 10mL of water, stirring and mixing in a 100mL flask at normal temperature, reacting for 24 hours to obtain a crude product, and purifying the crude product by column chromatography to obtain the raw material acyl azide compound.
All glycine compounds used in the present invention are also obtained by the preparation method which comprises: adding 5 mmol aniline compound, 10 mmol halide, 10 mmol sodium acetate and 10mL ethanol into a 50 mL screw test tube in sequence, stirring and reacting at 90 ℃ for 8 hours, cooling to room temperature after the reaction is finished to obtain a crude product, and purifying the crude product by column chromatography to obtain the raw material glycine. Other raw materials used in the examples were all commercially available unless otherwise specified.
Example 1
Adding 0.6 mmol of benzoyl azide compound, 0.5 mmol of phenylglycine ethyl ester and 0.75 mmol of potassium carbonate into a 25 ml screw test tube in sequence, stirring and reacting at 100 ℃ for 8 hours, cooling to room temperature after the reaction is finished to obtain a crude product, and purifying the crude product by column chromatography to obtain a product 3aa, wherein the yield is 92% and the purity is 99%.
The synthetic route is as follows:
Figure BDA0002631549020000061
the obtained product 3aa is a yellow solid, a hydrogen spectrogram and a carbon spectrogram of the product are respectively shown in fig. 1 and fig. 2, and structural characterization data are as follows:
1H NMR(500MHz,CDCl3)δ7.63(d,J＝7.9Hz,2H),7.52-7.49(m,2H),7.46-7.40(m,5H)7.20(t,J＝7.4Hz,1H),7.20(t,J＝7.4Hz,1H),4.48(s,2H)；13C NMR(126MHz,CDCl3)δ187.0,161.9,158.7,156.3,146.5 132.2,131.8,130.7,129.4,125.2,120.8,49.8。
example 2
Adding 0.6 mmol of 4-tert-butylbenzoyl azide, 0.5 mmol of phenylglycine ethyl ester and 0.75 mmol of potassium carbonate into a 25 ml screw test tube in sequence, stirring and reacting at 100 ℃ for 8 hours, cooling to room temperature after the reaction is finished to obtain a crude product, and purifying the crude product by column chromatography to obtain a product 3ab, wherein the yield is 75% and the purity is 99%.
The synthetic route is as follows:
Figure BDA0002631549020000071
the obtained product 3ab is a light yellow solid, the hydrogen spectrogram and the carbon spectrogram of the product are respectively shown in fig. 3 and 4, and the structural characterization data are as follows:
1H NMR(500MHz,CDCl3)δ7.62(d,J＝7.9Hz,2H),7.52(d,J＝8.6Hz,2H),7.42(t,J＝8.0Hz,2H),7.37(d,J＝8.6Hz,2H),7.19(t,J＝7.4Hz,1H),4.45(s,2H),1.35(s,9H)；13C NMR(126MHz,CDCl3)δ167.6,153.4,151.7,137.5,129.4,128.5,126.3,125.9,124.7,118.6,49.8,34.8,31.3。
example 3
Sequentially adding 0.6 mmol of 4-methoxybenzoyl azide, 0.5 mmol of phenylglycine ethyl ester and 0.75 mmol of potassium carbonate into a 25 ml screw test tube, stirring at 100 ℃ for reaction for 8 hours, cooling to room temperature after the reaction is finished to obtain a crude product, and purifying the crude product by column chromatography to obtain a product 3ac, wherein the yield is 80% and the purity is 99%.
The synthetic route is as follows:
Figure BDA0002631549020000072
the obtained product 3ac is a light yellow solid, the hydrogen spectrum and the carbon spectrum of which are respectively shown in fig. 5 and fig. 6, and the structural characterization data are as follows:
1H NMR(500MHz,CDCl3)δ7.66-7.58(m,2H),7.41(t,J＝8.0Hz,2H),7.34(d,J＝9.6Hz,2H),7.19(t,J＝7.4Hz,1H),7.00(d,J＝2.7Hz,2H),4.43(s,2H),3.98(s,3H)；13C NMR(126MHz,CDCl3)δ167.7,159.5,153.5,137.5,129.4,127.7,124.8,123.9,118.6,114.6,55.6,49.8。
example 4
Adding 0.6 mmol of 4-fluorobenzoyl azide, 0.5 mmol of phenylglycine ethyl ester and 0.75 mmol of potassium carbonate into a 25 ml screw test tube in sequence, stirring and reacting at 100 ℃ for 8 hours, cooling to room temperature after the reaction is finished to obtain a crude product, and purifying the crude product by column chromatography to obtain a product 3ad with the yield of 76% and the purity of 99%.
The synthetic route is as follows:
Figure BDA0002631549020000081
the obtained product 3ad is a light yellow solid, the hydrogen spectrogram and the carbon spectrogram of the product are respectively shown in fig. 7 and fig. 8, and the structural characterization data are as follows:
1H NMR(500MHz,CDCl3)δ7.59(d,J＝8.1Hz,2H),7.50-7.36(m,4H),7.24-7.12(m,3H),4.42(s,2H)；13C NMR(126MHz,CDCl3)δ167.4,162.1(d,J＝247.5Hz),153.1,137.3,129.5,128.3,128.2(d,J＝8.8Hz),127.1,124.9,118.6,116.2(d,J＝23.8Hz),116.14,49.75。
example 5
Adding 0.6 mmol of 4-trifluoromethyl benzoyl azide, 0.5 mmol of phenylglycine ethyl ester and 0.75 mmol of potassium carbonate into a 25 ml screw test tube in sequence, stirring and reacting at 100 ℃ for 8 hours, cooling to room temperature after the reaction is finished to obtain a crude product, and purifying the crude product by column chromatography to obtain a product 3ae, wherein the yield is 73%, and the purity is 98%.
The synthetic route is as follows:
Figure BDA0002631549020000082
the obtained product 3ae is a light yellow solid, the hydrogen spectrum and the carbon spectrum of which are respectively shown in fig. 9 and fig. 10, and the structural characterization data are as follows:
1H NMR(500MHz,CDCl3)δ7.76-7.75(m,2H),7.66-7.65(m,2H),7.61-7.59(m,2H),7.43(t,J＝8.0Hz,2H),7.24-7.21(m,1H),4.48(s,2H)；13C NMR(126MHz,CDCl3)δ167.0,152.6,137.1,134.5,130.4,130.1,129.5,126.3,126.2,125.1,118.8,49.8。
example 6
Adding 0.6 mmol of 3-fluorobenzoyl azide, 0.5 mmol of phenylglycine ethyl ester and 0.75 mmol of potassium carbonate into a 25 ml screw test tube in sequence, stirring and reacting at 100 ℃ for 8 hours, cooling to room temperature after the reaction is finished to obtain a crude product, and purifying the crude product by column chromatography to obtain a product 3af, wherein the yield is 78%, and the purity is 98%.
The synthetic route is as follows:
Figure BDA0002631549020000091
the obtained product 3af is a gray solid, the hydrogen spectrum and the carbon spectrum of which are respectively shown in fig. 11 and fig. 12, and the structural characterization data are as follows:
1H NMR(500MHz,CDCl3)δ7.59-7.57(m,2H),7.46-7.39(m,3H),7.30-7.29(m,1H),7.25-7.24(m,1H),7.12-7.08(m,1H),4.39(s,1H)；13C NMR(126MHz,CDCl3)δ167.0,163.0(d,J＝246.3Hz),161.6,152.7,137.3,132.7,130.3,130.2,129.4,124.9,121.8,118.7,115.4(d,J＝20Hz),113.7(d,J＝25Hz),49.7。
example 7
Sequentially adding 0.6 mmol of 3, 5-dimethylbenzoyl azide, 0.5 mmol of phenylglycine ethyl ester and 0.75 mmol of potassium carbonate into a 25 ml screw test tube, stirring and reacting at 100 ℃ for 8 hours, cooling to room temperature after the reaction is finished to obtain a crude product, and purifying the crude product by column chromatography to obtain a product 3ag, wherein the yield is 78%, and the purity is 98%.
The synthetic route is as follows:
Figure BDA0002631549020000101
the obtained product 3ag is a light yellow solid, the hydrogen spectrogram and the carbon spectrogram of the product are respectively shown in fig. 13 and fig. 14, and the structural characterization data are as follows:
1H NMR(500MHz,CDCl3)δ7.62-7.61(m,2H),7.48-7.42(m,2H),7.23-7.17(m,1H),7.05-7.04(m,3H),4.23(s,2H),2.37(s,6H)；13C NMR(126MHz,CDCl3)δ167.6,153.4,139.1,137.6,131.0,130.5,129.4,124.6,124.2,118.2,49.8,21.3。
example 8
Sequentially adding 0.6 mmol of 2-thenoyl azide, 0.5 mmol of phenylglycine ethyl ester and 0.75 mmol of potassium carbonate into a 25 ml screw test tube, stirring and reacting at 100 ℃ for 8 hours, cooling to room temperature after the reaction is finished to obtain a crude product, and purifying the crude product by column chromatography to obtain a product 3ah, wherein the yield is 74%, and the purity is 98%.
The synthetic route is as follows:
Figure BDA0002631549020000102
the obtained product 3ah is a light yellow solid, the hydrogen spectrogram and the carbon spectrogram of the product are respectively shown in fig. 15 and fig. 16, and the structural characterization data are as follows:
1H NMR(500MHz,CDCl3)δ7.59-7.53(m,3H),7.40(t,J＝7.8Hz,2H),7.20-7.17(m,2H),7.02-7.00(m,1H),4.37(s,2H)；13C NMR(126MHz,CDCl3)δ165.8,152.0,137.1,131.8,129.4,125.2,125.0,122.2,120.6,118.7,49.4。
example 9
Sequentially adding 0.6 mmol of 2-furoyl azide, 0.5 mmol of phenylglycine ethyl ester and 0.75 mmol of potassium carbonate into a 25 ml screw test tube, stirring and reacting at 100 ℃ for 8 hours, cooling to room temperature after the reaction is finished to obtain a crude product, and purifying the crude product by column chromatography to obtain a product 3ai, wherein the yield is 73%, and the purity is 98%.
The synthetic route is as follows:
Figure BDA0002631549020000111
the obtained product 3ai is a light yellow solid, the hydrogen spectrum and the carbon spectrum of which are respectively shown in fig. 17 and 18, and the structural characterization data are as follows:
1H NMR(500MHz,CDCl3)δ7.97-7.94(m,2H),7.89-7.87(m,2H),7.65-7.63(m,2H),7.56-7.51(m,3H),7.45-7.41(m,2H),7.22-7.19(m,1H),4.49(s,2H)；13C NMR(126MHz,CDCl3)δ167.6,153.4,137.4,129.5,127.8,126.7,125.5,124.8,123.7,118.7,49.9。
example 10
Sequentially adding 0.6 mmol of 2-naphthoyl azide, 0.5 mmol of phenylglycine ethyl ester and 0.75 mmol of potassium carbonate into a 25 ml screw test tube, stirring and reacting at 100 ℃ for 8 hours, cooling to room temperature after the reaction is finished to obtain a crude product, and purifying the crude product by column chromatography to obtain a product 3aj, wherein the yield is 73%, and the purity is 98%.
The synthetic route is as follows:
Figure BDA0002631549020000112
the obtained product 3aj is a light yellow solid, the hydrogen spectrogram and the carbon spectrogram of the product are respectively shown in fig. 19 and fig. 20, and the structural characterization data are as follows:
1H NMR(500MHz,CDCl3)δ7.97-7.94(m,2H),7.89-7.86(m,2H),7.65-7.63(m,2H),7.54-7.51(m,3H),7.45-7.42(m,2H),7.21-7.18(m,1H),4.49(s,2H)；13C NMR(126MHz,CDCl3)δ187.0,161.9,132.2,131.8,130.7,129.4,125.2,120.8。
example 11
Adding 0.6 mmol of cyclohexyl formyl azide, 0.5 mmol of phenylglycine ethyl ester and 0.75 mmol of potassium carbonate into a 25 ml screw test tube in sequence, stirring and reacting at 100 ℃ for 8 hours, cooling to room temperature after the reaction is finished to obtain a crude product, and purifying the crude product by column chromatography to obtain a product 3ak, wherein the yield is 68%, and the purity is 98%.
The synthetic route is as follows:
Figure BDA0002631549020000121
the obtained product 3ak is a light yellow solid, the hydrogen spectrum and the carbon spectrum of which are respectively shown in fig. 21 and fig. 22, and the structural characterization data are as follows:
1H NMR(500MHz,CDCl3)δ7.53(d,J＝7.9Hz,2H),7.36(t,J＝7.9Hz,2H),7.14-7.11(m,1H),4.17(s,2H),4.02-3.97(m,1H),2.22-2.15(m,2H),1.86-1.83(m,2H),1.74-1.65(m,3H),1.41-1.29(m,2H),1.26-1.19(m,1H)；13C NMR(126MHz,CDCl3)δ168.4,154.2,137.7,129.3,124.2,118.2,52.0,49.3,29.2,25.9,25.0。
example 12
Sequentially adding 0.6 mmol of benzyl formyl azide, 0.5 mmol of phenylglycine ethyl ester and 0.75 mmol of potassium carbonate into a 25 ml screw test tube, stirring and reacting at 100 ℃ for 8 hours, cooling to room temperature after the reaction is finished to obtain a crude product, and purifying the crude product by column chromatography to obtain a product 3al, wherein the yield is 68%, and the purity is 98%.
The synthetic route is as follows:
Figure BDA0002631549020000122
the obtained product 3al is a light yellow solid, and the hydrogen spectrogram and the carbon spectrogram are respectively shown in fig. 23 and 24, and the structural characterization data are as follows:
1H NMR(500MHz,CDCl3)δ7.56-7.54(m,2H),7.48-7.47(m,2H),7.39-7.30(m,5H),7.16-7.13(m,1H),4.75(s,2H),4.28(s,2H)；13C NMR(126MHz,CDCl3)δ168.1,154.1,137.5,135.7,129.3,129.0,128.8,128.1,124.5,118.2,49.8,42.7。
example 13
0.6 mmol of benzoyl azide, 0.5 mmol of N- (4-methoxyphenyl) glycine ethyl ester and 0.75 mmol of potassium carbonate are sequentially added into a 25 ml screw test tube, stirred and reacted for 8 hours at 100 ℃, and cooled to room temperature after the reaction is finished to obtain a crude product, and the crude product is purified by column chromatography to obtain a product 3am, wherein the yield is 85 percent and the purity is 98 percent.
The synthetic route is as follows:
Figure BDA0002631549020000131
the obtained product 3am is a light yellow solid, the hydrogen spectrum and the carbon spectrum of the product are respectively shown in FIG. 25 and FIG. 26, and the structural characterization data are as follows:
1H NMR(500MHz,CDCl3)δ7.52-7.47(m,4H),7.46-7.44(t,J＝4.3Hz,2H),7.40(d,J＝10.2,4.3Hz,1H),4.43(s,2H),3.81(s,3H)；13C NMR(126MHz,CDCl3)δ167.7,156.8,153.3,131.4,130.4,129.2,128.5,126.3,120.8,114.6,55.5,50.3。
example 14
0.6 mmol of benzoyl azide, 0.5 mmol of N- (4-chlorophenyl) glycine ethyl ester and 0.75 mmol of potassium carbonate are sequentially added into a 25 ml screw test tube, stirred and reacted for 8 hours at 100 ℃, and cooled to room temperature after the reaction is finished to obtain a crude product, and the crude product is purified by column chromatography to obtain a product 3an, wherein the yield is 68% and the purity is 98%.
Figure BDA0002631549020000132
The product 3an was obtained as a pale yellow solid with the following structural characterization data:
1H NMR(500MHz,CDCl3)δ7.56-7.53(m,2H),7.51-7.48(m,2H),7.43-7.40(m,3H),7.37-7.35(m,1H),4.40(s,2H)；13C NMR(126MHz,CDCl3)δ167.1,153.2,136.1,131.1,129.9,129.4,129.3,128.7,126.3,119.7,49.7。
example 15
0.6 mmol of benzoyl azide, 0.5 mmol of N- (3, 4-dimethyl) glycine ethyl ester and 0.75 mmol of potassium carbonate are sequentially added into a 25 ml screw test tube, stirred and reacted for 8 hours at 100 ℃, and cooled to room temperature after the reaction is finished to obtain a crude product, and the crude product is purified by column chromatography to obtain a product 3ao, wherein the yield is 88 percent and the purity is 98 percent.
Figure BDA0002631549020000141
The product 3ao was obtained as a pale yellow solid with the following structural characterization data:
1H NMR(500MHz,CDCl3)δ7.51-7.48(m,2H),7.46-7.45(m,2H),7.43-7.39(m,2H),4.44(s,2H),2.29(s,3H),2.26(s,3H)；13C NMR(126MHz,CDCl3)δ167.7,153.2,137.8,135.1,133.4,131.4,130.4,129.2,128.5,126.3,120.3,116.3,50.17,20.1,19.2。
example 16
0.6 mmol of benzoyl azide, 0.5 mmol of N- (2, 5-dimethoxy) glycine ethyl ester and 0.75 mmol of potassium carbonate are sequentially added into a 25 ml screw test tube, stirred and reacted for 8 hours at 100 ℃, and cooled to room temperature after the reaction is finished to obtain a crude product, and the crude product is purified by column chromatography to obtain a product 3ap, wherein the yield is 79 percent and the purity is 98 percent.
Figure BDA0002631549020000142
The product 3ap was obtained as a pale yellow solid with the following structural characterization data:
1H NMR(500MHz,CDCl3)δ7.49-7.46(m,4H),7.40-7.36(m,1H),7.05-7.04(d,J＝3.0Hz,1H),6.92-6.91(d,J＝9.1Hz,1H),6.88-6.85(m,1H),4.48(s,2H),3.83(s,3H),3.76(s,3H)；13C NMR(126MHz,CDCl3)δ169.2,154.8,153.6,148.9,131.7,129.1,128.3,126.3,124.9,114.4,114.1,113.0,56.2,55.9,51.8。
example 17
0.6 mmol of benzoyl azide, 0.5 mmol of 2- (methylamino) ethyl acetate and 0.75 mmol of potassium carbonate are sequentially added into a 25 ml screw test tube, the mixture is stirred and reacted for 8 hours at 100 ℃, a crude product can be obtained after the reaction is finished and is cooled to room temperature, the crude product is purified by column chromatography to obtain a product 3aq, the yield is 89%, and the purity is 98%.
Figure BDA0002631549020000151
The product 3aq obtained was a white solid with the following structural characterization data:
1H NMR(500MHz,CDCl3)δ7.45(t,J＝7.7Hz,2H),7.37(d,J＝17.1,7.8Hz,3H),4.02(s,2H),3.06(s,2H)；13C NMR(126MHz,CDCl3)δ168.7,155.8,131.8,129.1,128.2,126.1,51.6,29.9。
example 18
Sequentially adding 0.6 mmol of benzoyl azide, 0.5 mmol of N-benzyl glycine ethyl ester and 0.75 mmol of potassium carbonate into a 25 ml screw test tube, stirring and reacting at 100 ℃ for 8 hours, cooling to room temperature after the reaction is finished to obtain a crude product, and purifying the crude product by column chromatography to obtain a product 3ar, wherein the yield is 92%, and the purity is 98%.
Figure BDA0002631549020000152
The resulting product, 3ar, was a light yellow solid with the following structural characterization data:
1H NMR(500MHz,CDCl3)δ7.49-7.47(m,1H),7.46-7.43(m,3H),7.41-7.38(m,3H),7.36-7.34(m,1H),7.33-7.30(m,2H),4.62(s,2H),3.88(s,2H)；13C NMR(126MHz,CDCl3)δ168.8,155.7,135.3,131.8,129.1,128.4,128.2,126.1,60.4,49.0,46.9,21.1,14.3。
example 19
0.6 mmol of benzoyl azide, 0.5 mmol of ethyl 2-phenyl-aminobutyrate and 0.75 mmol of potassium carbonate are sequentially added into a 25 ml screw test tube, stirred and reacted for 8 hours at 100 ℃, and cooled to room temperature after the reaction is finished to obtain a crude product, and the crude product is purified by column chromatography to obtain a product 3as, wherein the yield is 68%, and the purity is 98%.
Figure BDA0002631549020000153
The product 3as was obtained as a white solid with the following structural characterization data:
1H NMR(500MHz,CDCl3)δ7.51-7.38(m,9H),7.24-7.23(d,J＝4.9,2.6Hz,1H),4.80-4.78(m,1H),2.16-2.09(m,1H),2.02-1.95(m,1H),0.91(t,J＝7.4Hz,3H)；13C NMR(126MHz,CDCl3)δ171.1,153.7,135.5,131.5,129.4,129.2,128.4,126.2,125.7,122.1,60.4,21.9,7.1。
example 20
0.6 mmol of benzoyl azide, 0.5 mmol of ethyl 2-phenylamino hexanoate and 0.75 mmol of potassium carbonate are sequentially added into a 25 ml screw test tube, stirred and reacted for 8 hours at 100 ℃, and cooled to room temperature after the reaction is finished to obtain a crude product, and the crude product is purified by column chromatography to obtain a product 3at, the yield is 88%, and the purity is 98%.
Figure BDA0002631549020000161
The product 3at was obtained as a pale yellow solid with the following structural characterization data:
1H NMR(500MHz,CDCl3)δ7.51-7.38(m,9H),7.24(d,J＝7.4Hz,1H),4.78(d,J＝5.6,3.1Hz,1H),2.09-2.03(m,0H),1.97-1.90(m,0H),1.37-1.15(m,1H),1.36-1.20(m,4H),0.83(t,J＝7.0Hz,3H)；13C NMR(126MHz,CDCl3)δ171.2,153.6,135.5,131.5,129.4,129.2,128.4,126.3,125.7,122.1,59.8,28.4,24.9,22.3,13.8。
example 21
0.6 mmol of benzoyl azide, 0.5 mmol of ethyl 2-phenylamino caprylate and 0.75 mmol of potassium carbonate are sequentially added into a 25 ml screw test tube, stirred and reacted for 8 hours at 100 ℃, and cooled to room temperature after the reaction is finished to obtain a crude product, and the crude product is purified by column chromatography to obtain a product 3au, wherein the yield is 87%, and the purity is 98%.
Figure BDA0002631549020000162
The product 3au was obtained as a pale yellow solid with the following structural characterization data:
1H NMR(500MHz,CDCl3)δ7.51-7.47(m,4H),7.46(d,J＝4.1,1.7Hz,1H),7.44(d,J＝8.8,3.3Hz,2H),7.42-7.41(m,1H),7.39(t,J＝6.4,1.7Hz,1H),7.24-7.23(m,1H),4.78(t,J＝12.0,6.0Hz,1H),2.08-2.00(m,1H),1.26-1.16(m,8H),0.83(t,J＝7.0Hz,3H)；13C NMR(126MHz,CDCl3)δ171.20,153.56,135.53,131.55,129.38,129.16,128.41,126.33,125.68,122.12,59.83,31.43,28.77,28.69,22.77,22.43,14.01。
example 22
0.6 mmol of benzoyl azide, 0.5 mmol of 2-phenyl amino ethyl isovalerate and 0.75 mmol of potassium carbonate are sequentially added into a 25 ml screw test tube, stirred and reacted for 8 hours at 100 ℃, and cooled to room temperature after the reaction is finished to obtain a crude product, and the crude product is purified by column chromatography to obtain a product 3av, wherein the yield is 89%, and the purity is 98%.
Figure BDA0002631549020000171
The obtained product 3av is a white solid, and the structural characterization data of the hydrogen spectrum and the carbon spectrum are as follows:
1H NMR(500MHz,CDCl3)δ7.53-7.52(m,2H),7.49-7.42(m,4H),7.40-7.36(m,2H),7.34-7.32(m,2H),1.54(d,J＝2.4Hz,6H)；13C NMR(126MHz,CDCl3)δ175.2,154.0,134.0,131.8,129.6,129.1,129.0,128.6,128.1,126.2,63.5,24.1。
as is clear from the analysis of examples 1 to 22, the synthetic method of the present invention has good compatibility with the substrate group, R1And R2The groups have wide applicable types, have small influence on the reaction and have high reaction yield.
In conclusion, the synthesis method provided by the invention does not need to use a solvent and a catalyst, and compared with a transition metal catalytic reaction, the method avoids trace metals in the product during separation and avoids complex post-treatment; the synthesis method can efficiently synthesize the functionalized alpha-ketoamide compound, has the advantages of simple synthesis steps, safe operation, good functional group compatibility and high atom economy, obtains the alpha-ketoamide compound with high added value, has the yield of 92 percent and the purity of 99 percent, greatly saves the experiment cost or the production cost, and is easy for industrialized synthesis.
The above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all equivalent changes made by using the contents of the present specification and the drawings, or applied directly or indirectly to the related technical fields, are included in the scope of the present invention.

Claims (7)

1. A method for synthesizing an N-substituted hydantoin compound is characterized by comprising the following steps: taking acyl azide compounds shown in a formula I and glycine ethyl ester compounds shown in a formula II as raw materials, heating and reacting in the presence of an additive without using a solvent to obtain N-substituted hydantoin compounds shown in a formula III, wherein the reaction formula is as follows:
Figure FDA0003461912980000011
the additive is selected from potassium carbonate;
in the formula, R1And R2Independently selected from C1～10Hydrocarbyl, phenyl-substituted C1～10Hydrocarbyl radical, C6～30Aryl radical, C6～30Substituted aryl or 5-to 8-membered heteroaryl containing 1 to 2O, N or S atoms; r3Is selected from C1～10A hydrocarbyl group.
2. The method for synthesizing an N-substituted hydantoin compound according to claim 1, wherein R is1Selected from phenyl, substituted phenyl, phenyl substituted C1～6Alkyl radical, C1～6Alkyl or 5-membered heteroaryl containing 1O, N or S atom; r2Selected from phenyl, substituted phenyl, phenyl substituted C1～6Alkyl or C1～6An alkyl group; r3Is selected from C1～6An alkyl group.
3. The method for synthesizing N-substituted hydantoin compounds according to any one of claims 1-2, wherein the molar ratio of said acyl azide compounds, glycine ethyl ester compounds and additives is 1-1.5: 1: 1 to 2.
4. The method for synthesizing an N-substituted hydantoin compound according to any one of claims 1 to 2, wherein the temperature of the heating reaction is 40 to 120 ℃.
5. The method for synthesizing an N-substituted hydantoin compound according to claim 4, wherein the temperature of the heating reaction is 60 to 100 ℃.
6. The method for synthesizing an N-substituted hydantoin compound according to claim 1, wherein the heating reaction time is 0.5 to 24 hours.
7. The method for synthesizing an N-substituted hydantoin compound according to any one of claims 1 to 2, further comprising the step of purifying the obtained N-substituted hydantoin compound.
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