Synthesis method of 3-oxazoline-5-ketone and derivatives thereof

Abstract

The invention discloses a synthesis method of 3-oxazoline-5-ketone and derivatives thereof, and belongs to the technical field of synthesis of organic compounds. The synthesis method comprises the following steps: mixing a carbonyl ketone compound, an acetophenone compound, an inorganic ammonium salt and an organic solvent, heating and stirring for reaction, and then purifying to obtain the 3-oxazoline-5-ketone and the derivative thereof. The 3-oxazoline-5-ketone and the derivative thereof have the advantages that the acetophenone compound, the carbonyl ketone and the inorganic ammonium salt are used as raw materials to be heated and stirred to synthesize the 3-oxazoline-5-ketone and the derivative thereof, and the 3-oxazoline-5-ketone and the derivative thereof have the advantages of simple raw materials, low synthesis cost, mild reaction conditions, simple reaction system, wide material source, easiness in application expansion, high product utilization value and the like; transition metal catalysis is not needed, and a new path is provided for synthesis of the 3-oxazoline-5-ketone compound; the method has the characteristics of high regioselectivity, simple reaction conditions, less reaction equipment, easiness in expansion, high product utilization value and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of organic compound synthesis, and particularly relates to a method for synthesizing 3-oxazoline-5-one and its derivatives. Background Art

[0002] 3-Oxazolin-5-one compounds, first reported in the 1960s, are well known but poorly studied because they are not readily accessible with current synthetic methods and are not widely found in natural products or pharmaceutical compounds. Summary of the invention

[0003] The purpose of the embodiments of the present invention is to provide a method for synthesizing 3-oxazolin-5-one and its derivatives, which has the characteristics of simple raw materials, high regioselectivity, simple reaction conditions, and no need for transition metal catalysis, thereby solving at least one technical problem involved in the background technology.

[0004] In order to solve the above-mentioned technical problems, the present invention is achieved as follows:

[0005] The embodiment of the present invention provides a method for synthesizing 3-oxazolin-5-one and its derivatives, and the method comprises the following steps:

[0006] An α-keto acid compound, a carbonyl ketone compound, an inorganic ammonium salt and an organic solvent are mixed, heated and stirred to react, and then purified to obtain 3-oxazoline-5-one and its derivatives, the structural formula of which is shown in Formula I:

[0007]

[0008] Wherein, R1 is selected from phenyl, substituted phenyl, benzyl, phenethyl, styryl; R2 and R3 are selected from chain compounds or cyclic compounds formed by connecting R2 and R3.

[0009] Optionally, the organic solvent is selected from dimethyl sulfoxide, acetonitrile, methanol, acetone, ethylene dichloride, toluene, mesitylene, 1,4-dioxane, n-hexane, and cyclohexane.

[0010] Optionally, the organic solvent is acetonitrile or methanol.

[0011] Optionally, the molar ratio of the α-keto acid compound, the carbonyl ketone ring compound, and the inorganic ammonium salt is 1:(1.25-2.5):(1.25-3), the reaction temperature is 30-60° C., the reaction atmosphere is air, and the reaction time is 6-12 h.

[0012] Optionally, the α-keto acid compound is represented by the following general formula II:

[0013]

[0014] Wherein, R1 is selected from phenyl, substituted phenyl, benzyl, phenethyl, and styryl.

[0015] Optionally, the α-keto acid compound is selected from benzoylformic acid, 4-methylbenzoylformic acid, 4-ethylbenzoylformic acid, 4-tert-butylbenzoylformic acid, 4-methoxybenzoylformic acid, 4-iodobenzoylformic acid, 4-nitrobenzoylformic acid, 3-morpholinobenzoylformic acid, 2-methylbenzoylformic acid, α-oxophenylpropionic acid, and α-oxophenylbutyric acid.

[0016] Optionally, the carbonyl ketone compound is represented by the following general formula III:

[0017]

[0018] Wherein, R2 and R3 are selected from chain compounds or cyclic compounds formed by connecting R2 and R3.

[0019] Optionally, the carbonyl ketone compound is selected from cyclohexanone, cyclobutanone, cyclododecanone, adamantane ketone, benzocycloheptanone, 4,4-dimethylcyclohexanone, 2-tetralone, tetrahydrofuran-3-one, tetrahydropyran-3-one, tetrahydrothiopyran-4-one, 4-heptanone, 7-tridecanone, 1-phenyl-2-butanone, 1,3-dihydroxyacetone, tert-butyl acetoacetate, 4-nitrophenylacetone, 3-indolylacetone, and nabumetone.

[0020] Optionally, the inorganic ammonium salt is selected from ammonium acetate, ammonium formate, ammonium trifluoroacetate, ammonium bicarbonate, ammonium benzoate, ammonium thiocyanate, ammonium hexafluorophosphate, diammonium hydrogen phosphate, ammonium oxalate, and ammonium citrate.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] 1. The present invention uses a carbonyl compound, an acetophenone compound, an inorganic ammonium salt and an organic solvent to mix, heat and stir to react, and synthesize 3-oxazolin-5-one and its derivatives. The raw materials are simple and easy to obtain and do not require pretreatment, and the synthesis cost is low;

[0023] 2. The synthesis method of the present invention does not require the use of metal catalysts, any additional acids, bases or other additives, and provides a new path for the synthesis of 3-oxazolin-5-one and its derivatives;

[0024] 3. The synthesis method of the present invention has the characteristics of high regional selectivity, simple reaction conditions, less reaction equipment, easy expansion, and high product utilization value. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the following briefly introduces the drawings required for describing the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative work, among which:

[0026] Figure 1 is the H NMR spectrum of the product of Example 1;

[0027] Figure 2 is the NMR carbon spectrum of the product of Example 1;

[0028] Figure 3 is the H NMR spectrum of the product of Example 2;

[0029] Figure 4 is the NMR carbon spectrum of the product of Example 2;

[0030] Figure 5 is the H NMR spectrum of the product of Example 3;

[0031] Figure 6 is the NMR carbon spectrum of the product of Example 3;

[0032] Figure 7 is the H NMR spectrum of the product of Example 4;

[0033] Figure 8 is the NMR carbon spectrum of the product of Example 4;

[0034] Fig. 9 is the H NMR spectrum of the product of Example 5;

[0035] Fig.10 is the NMR carbon spectrum of the product of Example 5;

[0036] Fig.11 is the H NMR spectrum of the product of Example 6;

[0037] Fig.12 is the NMR carbon spectrum of the product of Example 6;

[0038] Fig.13 is the H NMR spectrum of the product of Example 7;

[0039] Fig.14 is the NMR carbon spectrum of the product of Example 7;

[0040] Fig.15 is the H NMR spectrum of the product of Example 8;

[0041] Fig.16 is the NMR carbon spectrum of the product of Example 8;

[0042] Fig.17 is the H NMR spectrum of the product of Example 9;

[0043] Fig.18 is the NMR carbon spectrum of the product of Example 9;

[0044] Fig.19 is the H NMR spectrum of the product of Example 10;

[0045] Fig. 20 This is the NMR carbon spectrum of the product of Example 10. DETAILED DESCRIPTION

[0046] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0047] The terms "first", "second", etc. in the specification and claims of the present invention are used to distinguish similar objects, and are not used to describe a specific order or sequence. It should be understood that the data used in this way can be interchanged where appropriate, so that the embodiments of the present invention can be implemented in an order other than those illustrated or described herein, and the objects distinguished by "first", "second", etc. are generally of the same type, and the number of objects is not limited. For example, the first object can be one or more. In addition, "and / or" in the specification and claims represents at least one of the connected objects, and the character " / " generally indicates that the objects associated with each other are in an "or" relationship.

[0048] The present invention provides a method for synthesizing 3-oxazolin-5-one and its derivatives, and the method comprises the following steps:

[0049] The carbonyl ketone compound, the α-keto acid compound, the inorganic ammonium salt and the organic solvent are mixed, heated and stirred to react, and then purified to obtain 3-oxazoline-5-one and its derivatives, whose structural formula is shown in Formula I:

[0050]

[0051] Wherein, R1 is selected from phenyl, substituted phenyl, benzyl, phenethyl, styryl; R2 and R3 are selected from chain compounds or cyclic compounds formed by connecting R2 and R3.

[0052] Wherein, the organic solvent is selected from dimethyl sulfoxide, acetonitrile, methanol, acetone, ethylene dichloride, toluene, mesitylene, 1,4-dioxane, n-hexane, and cyclohexane. In a preferred embodiment of the present invention, the organic solvent is acetonitrile or methanol.

[0053] The molar ratio of the α-keto acid compound, the carbonyl ketone ring compound, and the inorganic ammonium salt is 1:(1.25-2.5):(1.25-3), the reaction temperature is 30-60° C., the reaction atmosphere is air, and the reaction time is 6-12 hours.

[0054] The α-keto acid compound is represented by the following general formula II:

[0055]

[0056] Wherein, R1 is selected from phenyl, substituted phenyl, benzyl, phenethyl, styryl and the like.

[0057] The α-keto acid compound is selected from benzoylformic acid, 4-methylbenzoylformic acid, 4-ethylbenzoylformic acid, 4-tert-butylbenzoylformic acid, 4-methoxybenzoylformic acid, 4-iodobenzoylformic acid, 4-nitrobenzoylformic acid, 3-morpholinylbenzoylformic acid, 2-methylbenzoylformic acid, α-oxyphenylpropionic acid, α-oxyphenylbutyric acid, etc.

[0058] The carbonyl ketone compound is represented by the following general formula III:

[0059]

[0060] Wherein, R2 and R3 are selected from chain compounds or cyclic compounds formed by connecting R2 and R3.

[0061] It should be noted that the carbonyl ketone compounds include some cycloalkyl ketones, chain alkyl ketones, heterocyclic ketones and the like.

[0062] Preferably, the carbonyl ketone compound is selected from cyclohexanone, cyclobutanone, cyclododecanone, adamantane ketone, benzocycloheptanone, 4,4-dimethylcyclohexanone, 2-tetralone, tetrahydrofuran-3-one, tetrahydropyran-3-one, tetrahydrothiopyran-4-one, 4-heptanone, 7-tridecanone, 1-phenyl-2-butanone, 1,3-dihydroxyacetone, tert-butyl acetoacetate, 4-nitrophenylacetone, 3-indolylacetone, nabumetone, etc.

[0063] The synthetic reaction system process of the present invention for synthesizing 3-oxazoline-5-one and its derivatives is as follows:

[0064]

[0065] Wherein, solvent is the solvent, T is the reaction temperature, and t is the reaction time.

[0066] It can be concluded that the compound synthesized in the present invention is 3-oxazoline-5-one and its derivatives synthesized by heating and stirring in acetonitrile or methanol solvent using α-keto acid compounds, carbonyl ketone and ammonium salt as raw materials.

[0067] In conclusion, the compounds synthesized by the present invention have the characteristics of simple and readily available reaction raw materials, high regioselectivity, simple conditions, etc., and the synthesized series of 3-oxazolin-5-ones and their derivatives have certain biological and pharmacological activities.

[0068] The yields of the synthesis methods of 3-oxazolin-5-one and its derivatives provided by the present invention under different reaction conditions are described in detail below with reference to Table 1 for details.

[0069] Table 1 Reaction substrates, reaction conditions and yields of Examples 1-10

[0070]

[0071]

[0072]

[0073] The NMR data of the products of Examples 1-10 are:

[0074] The H NMR spectrum and C NMR spectrum of the product of Example 1 are as follows: Figure 1 and Figure 2 As shown, the NMR data of the product of Example 1 are as follows:

[0075] 1 H NMR (400MHz, Chloroform-d) δ8.45–8.38(m,2H),7.59–7.47(m,3H),2.03–1.71(m,9H),1.60–1.47(m,1H). 13 C NMR (101MHz, Chloroform-d) δ164.40,155.31,132.27,128.99,128.71,128.56,105.44,35.97,24.60,22.76.

[0076] The H NMR spectrum and C NMR spectrum of the product of Example 2 are as follows: Figure 3 and 4 , the NMR data of the product of Example 2 are as follows:

[0077] 1H NMR (400MHz, Chloroform-d) δ8.46–8.35(m,2H),7.59–7.46(m,3H),2.08–2.01(m,2H),1.73–1.59(m,6H),1.08(s,3H),1.07(s,3H). 13 C NMR (101MHz, Chloroform-d) δ164.33,155.40,132.28,128.98,128.71,128.55,105.40,35.37,32.23,30.21,29.36,25.72.

[0078] The H NMR spectrum and C NMR spectrum of the product of Example 3 are as follows: Figure 5 and 6 , the NMR data of the product of Example 3 are as follows:

[0079] 1 H NMR (400MHz, Chloroform-d) δ8.55–8.40(m,2H),7.65–7.50(m,3H),7.24(s,4H),3.13(d,J=60.2Hz,4H),2.25–1.90(m,4H). 13 C NMR (101MHz, Chloroform-d) δ164.24,155.25,141.33,132.49,129.13,128.91,128.80,128.71,126.89,107.29,37.99,30.14.

[0080] The H NMR spectrum and C NMR spectrum of the product of Example 4 are as follows: Figure 7 and 8 , the NMR data of the product of Example 4 are as follows:

[0081] 1 H NMR (400 MHz, Chloroform-d)δ 1 H NMR (400 MHz, CDCl 3 )δ8.28–8.23(m,2H),8.11(d,J=8.7Hz,2H),7.61–7.55(m,1H),7.51–7.45(m,2H),7.38(d,J=8.7Hz,2H),3.45(s,2H),1.77(s,3H). 13C NMR (101MHz, Chloroform-d) δ163.77,156.67,147.28,140.88,132.76,131.80,128.84,128.48,128.07,123.36,103.72,44.78,25.14.

[0082] The H NMR spectrum and C NMR spectrum of the product of Example 5 are as follows: Fig. 9 and 10 , the NMR data of the product of Example 5 are as follows:

[0083] 1 H NMR(400MHz,Chloroform-d)δ8.28–8.13(m,2H),7.57–7.51(m,1H),7.49–7.43(m,2H),7. 26–7.16(m,5H),3.34(s,2H),2.15–2.05(m,2H),1.42–1.25(m,2H),0.95(t,J=7.4Hz,3H). 13 C NMR (101MHz, Chloroform-d) δ164.27,156.72,133.01,132.21,131.04,128.65,128.54,128.41,128.09,127.20,106.12,44.15,39.53,16.08,13.90.

[0084] The H NMR spectrum and C NMR spectrum of the product of Example 6 are as follows: Fig.11 and 12 , the NMR data of the product of Example 6 are as follows:

[0085] 1 H NMR (400MHz, Chloroform-d) δ8.46–8.33(m,2H),7.62–7.57(m,1H),7.55–7.49(m,2H),2.07–1.94(m,4H),1.38–1.23(m,12H),0.88(t,J=6.8Hz,6H). 13 C NMR (101MHz, Chloroform-d) δ164.71,156.05,132.29,128.79,128.75,128.56,107.47,37.61,31.60,22.41,22.27,13.95.

[0086] The H NMR spectrum and C NMR spectrum of the product of Example 7 are as follows: Fig.13 and 14 , the NMR data of the product of Example 7 are as follows:

[0087] 1 H NMR (400MHz, Chloroform-d) δ8.38 (d, J = 8.9 Hz, 2H), 6.99 (d, J = 9.0 Hz, 2H), 3.90 (s, 3H), 2.02–1.70 (m, 9H), 1.57–1.47 (m, 1H). 13 C NMR (101MHz, Chloroform-d) δ164.77,162.85,154.41,130.44,121.73,114.09,105.22,55.45,36.06,24.62,22.79.

[0088] The H NMR spectrum and C NMR spectrum of the product of Example 8 are as follows: Fig.15 and 16 , the NMR data of the product of Example 8 are as follows:

[0089] 1 H NMR (400MHz, Chloroform-d) δ8.49 (d, J = 8.4Hz, 2H), 7.81–7.64 (m, 4H), 7.57–7.38 (m, 3H), 2.06–1.73 (m, 9H), 1.61–1.49 (m, 1H). 13 C NMR (101MHz, Chloroform-d) δ164.51,155.00,144.94,140.02,129.06,128.97,128.16,127.86,127.35,127.23,105.54,36.03,24.63,22.79.

[0090] The H NMR spectrum and C NMR spectrum of the product of Example 9 are as follows: Fig.17 and 18 , the NMR data of the product of Example 9 are as follows:

[0091] 1 H NMR (400MHz, Chloroform-d) δ8.13(d,J=8.5Hz,2H),7.86(d,J=8.6Hz,2H),2.01–1.70(m,9H),1.58–1.47(m,1H). 13 C NMR (101MHz, Chloroform-d) δ164.11,154.75,138.01,129.97,128.36,105.72,99.90,35.89,24.56,22.73.

[0092] The H NMR spectrum and C NMR spectrum of the product of Example 10 are as follows: Fig.19 and 20 , the NMR data of the product of Example 10 are as follows:

[0093] 1 H NMR (400MHz, Chloroform-d) δ7.33–7.20(m,5H),3.10–3.07(m,1H),2.95–2.90(m,2H),1.86–1.68(m,7H),1.59–1.43(m,3H). 13 C NMR (101MHz, Chloroform-d) δ165.18,161.60,140.02,128.51,128.50,126.40,106.76,35.72,31.56,29.64,24.51,22.70.

[0094] It should be noted that, in this article, the terms "include", "comprises" or any other variations thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device. In the absence of further restrictions, an element defined by the sentence "comprises a ..." does not exclude the existence of other identical elements in the process, method, article or device including the element.

[0095] In addition, it should be noted that the scope of the methods and systems in the embodiments of the present invention is not limited to performing functions in the order shown or discussed, and may also include performing functions in a substantially simultaneous manner or in reverse order according to the functions involved. For example, the described methods may be performed in an order different from that described, and various steps may be added, omitted, or combined. In addition, features described with reference to certain examples may be combined in other examples.

[0096] The embodiments of the present invention are described above in conjunction with the accompanying drawings, but the present invention is not limited to the above-mentioned specific implementation modes, which are merely illustrative rather than restrictive. Under the guidance of the present invention, ordinary technicians in this field can also make many forms without departing from the scope of protection of the present invention and the claims, all of which are within the protection of the present invention.

Claims

1. A method for synthesizing 3-oxazoline-5-one and its derivatives, characterized in that: The synthesis method comprises the following steps: An α-keto acid compound, a carbonyl ketone compound, an inorganic ammonium salt and an organic solvent are mixed, heated and stirred to react, and then purified to obtain 3-oxazoline-5-one and its derivatives, the structural formula of which is shown in Formula I: Wherein, R1 is selected from phenyl, substituted phenyl, benzyl, phenethyl, styryl; R2 and R3 are selected from chain compounds or cyclic compounds formed by connecting R2 and R3.

2. The method according to claim 1, characterized in that The organic solvent is selected from dimethyl sulfoxide, acetonitrile, methanol, acetone, ethylene dichloride, toluene, mesitylene, 1,4-dioxane, n-hexane, and cyclohexane.

3. The method according to claim 1, characterized in that The organic solvent is acetonitrile or methanol.

4. The method according to claim 1, characterized in that: The molar ratio of the α-keto acid compound, the carbonyl ketone ring compound, and the inorganic ammonium salt is 1:(1.25-2.5):(1.25-3), the reaction temperature is 30-60° C., the reaction atmosphere is air, and the reaction time is 6-12 hours.

5. The method according to claim 1, characterized in that The α-keto acid compound is represented by the following general formula II: Wherein, R1 is selected from phenyl, substituted phenyl, benzyl, phenethyl, and styryl.

6. The method according to claim 1 or 5, characterized in that: The α-keto acid compound is selected from benzoylformic acid, 4-methylbenzoylformic acid, 4-ethylbenzoylformic acid, 4-tert-butylbenzoylformic acid, 4-methoxybenzoylformic acid, 4-iodobenzoylformic acid, 4-nitrobenzoylformic acid, 3-morpholinylbenzoylformic acid, 2-methylbenzoylformic acid, α-oxyphenylpropionic acid, and α-oxyphenylbutyric acid.

7. The method according to claim 1, characterized in that The carbonyl ketone compound is represented by the following general formula III: Wherein, R2 and R3 are selected from chain compounds or cyclic compounds formed by connecting R2 and R3.

8. The method according to claim 1, characterized in that The carbonyl ketone compound is selected from cyclohexanone, cyclobutanone, cyclododecanone, adamantane ketone, benzocycloheptanone, 4,4-dimethylcyclohexanone, 2-tetralone, tetrahydrofuran-3-one, tetrahydropyran-3-one, tetrahydrothiopyran-4-one, 4-heptanone, 7-tridecanone, 1-phenyl-2-butanone, 1,3-dihydroxyacetone, tert-butyl acetoacetate, 4-nitrophenylacetone, 3-indolylacetone, and nabumetone.

9. The method according to claim 1, characterized in that: The inorganic ammonium salt is selected from ammonium acetate, ammonium formate, ammonium trifluoroacetate, ammonium bicarbonate, ammonium benzoate, ammonium thiocyanate, ammonium hexafluorophosphate, diammonium hydrogen phosphate, ammonium oxalate, and ammonium citrate.

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