Method for synthesizing 1, 3-benzoxazine compound
Through the heterodiels-Alder reaction catalyzed by binaphthol phosphate, the problems of high environmental burden and high cost of synthesis of 1,3-benzooxazine compounds in the prior art have been successfully solved, and an efficient, economical and environmentally friendly preparation method is achieved, which is suitable for large-scale industrial production.
Patent Information
- Application Number
- CN202311192618.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-09-15
- Publication Date
- 2025-03-18
AI Technical Summary
The existing methods for synthesizing 1,3-benzoxazine compounds have problems such as high environmental burden, high cost and poor economicality, and it is difficult to achieve large-scale application.
The 1,3-benzooxazine compound was prepared by using binaphthol phosphate as a catalyst and the heterodiels-Alder reaction of p-methylenequinone and ketoimine was carried out at room temperature by substituting o-hydroxyphenyl.
It realizes the efficient, economical and environmentally friendly preparation of 1,3-benzooxazine compounds, which reduces production costs and is suitable for large-scale industrial production.
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Abstract
Description
Technical Field
[0001] The present invention specifically relates to a method for synthesizing 1,3-benzoxazine compounds, and belongs to the technical field of organic compound process application. Background Art
[0002] 1,3-Benzoxazine is a very important skeleton structure, existing in many biologically active molecules and drug molecules, and has a wide range of application value. T638 and T615 show good antiviral properties in organisms; 6-arylbenzoxazine is reported as an effective non-steroidal progesterone receptor agonist; Efavirenz is a non-nucleoside reverse transcriptase inhibitor that can be used to treat HIV infection. In view of this, how to efficiently synthesize 1,3-benzoxazine compounds is crucial.
[0003]
[0004] Traditional methods for synthesizing 1,3-benzoxazine compounds are mainly prepared by using metal catalysis or by multi-step reactions. Metal-catalyzed reactions have a large environmental burden and are expensive, poor economic efficiency, and difficult to apply on a large scale. The hetero Diels-Alder reaction can be used to construct complex heterocyclic compounds in one step, which is an efficient and economical method for synthesizing 1,3-benzoxazine compounds. Summary of the invention
[0005] In view of the problems existing in the synthesis of 1,3-benzoxazine compounds, the present invention overcomes the above defects of the prior art and proposes a new economical and environmentally friendly method for simply and efficiently preparing 1,3-benzoxazine compounds. By using binaphthol phosphate as a catalyzer, efficient conversion such as reaction I can be achieved. In the present invention, o-hydroxyphenyl-substituted p-methylenequinone and ketimine are used as reaction raw materials, binaphthol phosphate is used as a catalyst, and 1,3-benzoxazine compounds are obtained by reaction in a solvent at room temperature.
[0006]
[0007] In the present invention, R 1 , R 2 , R 3 are independently selected from H, alkyl, aromatic, substituted aromatic ring, halogen, -CO 2 Me.
[0008] In the present invention, the ratio of the o-hydroxyphenyl-substituted p-methylenequinone to the ketimine is 1.2:1.
[0009] In the present invention, the catalyst used is binaphthol phosphate, the catalyst dosage is 5 mol%, and when B(C 6 F 5 ) 3When (5 mol%) was synergistically catalyzed with binaphthol phosphate, the product was diastereoselectively flipped to give product 4.
[0010]
[0011] In the present invention, the reaction solvent used is dichloromethane, chloroform, tetrahydrofuran, 1,2-dichloroethane, acetonitrile, toluene, 1,4-dioxane, ethyl acetate, among which dichloromethane is preferred. The reaction solvent includes but is not limited to the above, and can also be ether, trifluorotoluene, xylene compounds or anisole.
[0012] In the present invention, the synthesis reaction is carried out at a temperature of -40-25°C, preferably at 25°C.
[0013] Specifically, the present invention is to dissolve o-hydroxyphenyl substituted p-methylenequinone (X mmol) and ketimine (Y mmol) in Z mL solvent in a reaction bottle A, and add binaphthol phosphate (W mmol) at room temperature. The reaction is carried out at -40-25°C, and after the reaction is complete by thin layer chromatography, column chromatography is performed to obtain 3.
[0014] Beneficial Effects
[0015] The present invention successfully prepares 1,3-benzoxazine compounds and has the following advantages:
[0016] First, the present invention uses o-hydroxyphenyl substituted p-methylenequinone and ketimine to undergo hetero-Diels-Alder reaction under the catalysis of binaphthol phosphate to prepare 1,3-benzoxazine compounds.
[0017] Second, the preparation method disclosed in the present invention has cheap and easily available raw materials, stable performance, low cost, the catalyst can be purchased and does not require special storage, and the reaction conditions are mild and the reaction yield is high, which is suitable for large-scale industrial production.
[0018] Third, the preparation method disclosed in the present invention successfully applies the hetero-Diels-Alder reaction to the field of synthesizing 1,3-benzoxazine compounds, thus broadening the method of synthesizing such compounds.
[0019] Fourthly, the 1,3-benzoxazine compound synthesized by the present invention is the core skeleton of many natural products and pharmaceutically active molecules, and the present invention provides a generally applicable method for synthesizing such compounds.
[0020] Fifth, after adding a simple Lewis acid into the system, the product is diastereoselectively reversed under the same conditions. BRIEF DESCRIPTION OF THE DRAWINGS
[0021] Figure 1is the hydrogen spectrum of compound 3aa obtained in a specific example of the present invention;
[0022] Figure 2 is the carbon spectrum of compound 3aa obtained in a specific embodiment of the present invention;
[0023] Figure 3 is the hydrogen spectrum of compound 4aa obtained in a specific example of the present invention;
[0024] Figure 4 This is the carbon spectrum of compound 4aa obtained in a specific example of the present invention. DETAILED DESCRIPTION
[0025] In order to make the specific technology of the present invention clearer, the present invention is further explained in conjunction with the following examples. The following examples are only examples, and the protection content of the present invention is further described, but not limited. All reactions made based on the given examples are within the scope of protection, and the attached claims are specifically the scope of protection. Except for the following specific instructions, the raw materials and reagents used in the examples can be purchased or invented, and the present invention has no special restrictions. The data in the examples include experimental operations, reaction conditions, and product characterization. The product yield is obtained after separation and purification reaction, and its diastereoselectivity is determined by nuclear magnetic resonance.
[0026] Example 1: Preparation of Compound 3aa
[0027]
[0028] In a 10 mL reaction tube, o-hydroxyphenyl-substituted p-methylidequinone (0.12 mmol, 37.3 mg) and ketimine (0.1 mmol, 20.7 mg) were weighed in turn, 1 mL of dichloromethane was added, and then binaphthol phosphate (0.005 mmol, 1.74 mg) was added; the reaction system was reacted at room temperature, and after the reaction was completed by thin layer chromatography, column chromatography was performed using a silica gel column, using petroleum ether and ethyl acetate as eluents to obtain a yellow solid 3aa (43.9 mg, 85% yield, 96:4 dr).
[0029] 1 H NMR (400 MHz, Acetone-d 6 ): δ7.63-7.60 (m, 2H), 7.50 (d, J=7.0Hz, 1H), 7.33-7.22 (m, 6H), 7.13-7.09 (m, 2H), 7.0 1 (d, J=7.7Hz, 1H), 6.81-6.72 (m, 2H), 6.13 (s, 1H), 6.05 (d, J=8.5Hz, 2H), 1.35 (s, 18H); 13C NMR (101 MHz, Acetone-d 6 )δ194.2, 158.6, 153.6, 150.7, 138.2, 137.0, 135.6, 131.7, 128.8, 128.1, 127.9, 127.7, 127.0, 125.0, 124.9, 122.6, 91.9, 59.1, 34.3, 29.7; mp145-147℃; HRMS(ESI)calculated for C 35 H 35 NaNO 3 + [M+Na] + :540.2509, found:540.2513.
[0030] Example 2: Preparation of Compound 4aa
[0031]
[0032] In a 10 mL reaction tube, o-hydroxyphenyl substituted p-methylenequinone (0.12 mmol, 37.3 mg) and ketimine (0.1 mmol, 20.7 mg) were weighed in the reaction tube in sequence, 1 mL of dichloromethane was added, followed by binaphthol phosphate (0.005 mmol, 1.74 mg), B(C 6 F 5 ) 3 (0.005mmol, 2.56mg); The reaction system was reacted at room temperature. After the reaction was completed by thin layer chromatography, it was chromatographed on a silica gel column using petroleum ether and ethyl acetate as eluents to obtain a yellow solid 4aa (46.5mg, 90% yield, 4:96dr).
[0033] 1 H NMR (400 MHz, Acetone-d 6 )δ7.74-7.70 (m, 1H), 7.60 (d, J=7.6Hz, 1H), 7.55 (d, J=8.3Hz, 1H), 7.29-7.09 (m, 7H), 6. 97 (t, J=7.6Hz, 1H), 6.93-6.89 (m, J=7.3Hz, 4H), 6.09 (s, 1H), 5.99 (s, 1H), 1.27 (s, 18H); 13 C NMR (101 MHz, Acetone-d 6)δ195.9,163.5,154.7,153.4,139.9,138.3,137.3,133.2,130.2,129.7,129.5,128.6,128.4,127.2,127.0,126.3,124.8,123.0,121.4,119.5,112.2,91.4,59.1,35.6,31.1;m.p.141-142℃;HRMS(ESI)calculated for C 35 H 35 NaNO 3 + [M+Na] + :540.2509,found:540.2513.。
Claims
1. A method for synthesizing 1,3-benzoxazine compounds, characterized in that: Taking o-hydroxyphenyl substituted p-methylenequinone and ketimine as reaction raw materials and using binaphthol phosphate (PA) as catalyst, a 1,3-benzoxazine compound is obtained by reaction in a solvent at room temperature; the reaction process is shown in Formula I; Where R 1 , R 2 , R 3 Each of them is independently selected from H, alkyl, aromatic, substituted aromatic ring, halogen, -CO2Me.
2. The compound according to claim 1, characterized in that The compound of formula I is selected from the following compound 3: Where R 1 , R 2 , R 3 Each of them is independently selected from H, alkyl, aromatic, substituted aromatic ring, halogen, -CO2Me.
3. A method for synthesizing 1,3-benzoxazine compounds, characterized in that: The steps include: Where R 1 , R 2 , R 3 Each of them is independently selected from H, alkyl, aromatic, substituted aromatic ring, halogen, -CO2Me. In a 10 mL reaction tube, 0.12 mmol of o-hydroxyphenyl-substituted p-methylenonequinone, 0.1 mmol of ketimine and 0.005 mmol of binaphthol phosphate were weighed into the reaction tube in sequence, and 1 mL of dichloromethane was added; the reaction system was reacted at room temperature, and after the reaction was completed by thin layer chromatography, column chromatography was performed to obtain 3.
4. The method for synthesizing 1,3-benzoxazine compounds according to claim 3, characterized in that: The catalyst is binaphthol phosphate; the amount of the catalyst used is 5 mol%.
5. The method for synthesizing 1,3-benzoxazine compounds according to claim 3, characterized in that: The reaction solvent is dichloromethane, chloroform, tetrahydrofuran, 1,2-dichloroethane, acetonitrile, toluene, 1,4-dioxane, and ethyl acetate.
6. The method for synthesizing 1,3-benzoxazine compounds according to claim 3, characterized in that: The ratio of the compound o-hydroxyphenyl-substituted p-methylenequinone to the compound ketimine is 1.2:
1.
7. The method for synthesizing 1,3-benzoxazine compounds according to claim 3, characterized in that: When B(C6F5)3 (5 mol%) was added to coordinate the catalysis with binaphthol phosphate, the product was diastereoselectively reversed to obtain the following compound 4.