A method for synthesizing 3-trifluoromethyl-1,4-benzoxazepine compounds

Abstract

The present application relates to the technical fields of medical and pharmaceutical chemical synthesis, in particular to a synthesis method of 3-trifluoromethyl-1,4-benzoxazepine compound, the steps are as follows: in the reactor, compound 1, compound 2, additive are added, stirred for 4 hours under the condition of 100 DEG C air, after the reaction is finished, cooling to 0 DEG C, adding base and reacting overnight.Extraction, vacuum distillation to obtain the crude product, and then column chromatography and thin layer chromatography chromatography purification to obtain 3-trifluoromethyl-1,4-benzoxazepine compound.The present application uses trifluoromethyl imine ylide compound and salicylate compound as raw materials, and synthesizes 3-trifluoromethyl-1,4-benzoxazepine compound by one-pot method.The present application has the advantages of simple synthesis steps, easy-to-obtain raw materials, no need to separate intermediate, no need to use precious metal catalyst, good functional group compatibility, etc.;and high reaction conversion, low cost, which is conducive to industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical and chemical synthesis technology, specifically to a 3-trifluoromethyl-1,4-benzoxazine synthesis method. Synthetic methods for similar compounds. Background Technology

[0002] Organic compounds are important organic building blocks in chemical synthesis and commonly used basic skeletons for drug molecules, with broad application prospects in organic molecular synthesis, materials science, medicinal chemistry and natural product chemistry, and medicine. It is worth mentioning that... Drugs designed with benzodiazepine compounds as the basic skeleton have been widely used in clinical practice; for example, commonly used nervous system drugs such as diazepam, clonazepam, lorazepam, quetiapine fumarate, and calcium channel blocker diltiazem are derivatives with benzo7-membered heterocyclic compounds as the basic skeleton.

[0003] Given The wide range of applications of these compounds and the development of efficient synthetic methods have been a hot research topic for organic chemists in recent years. For example, Wei-wei Wang's team used L-cysteine ​​and 2-fluorobenzaldehyde as raw materials to condense... The compound (Wei-wei Wang.; Ting YU.; Chao Wang., Synthesis of a novel comfomational restricted ammo Acid for potential use inpeptide chemistry. Heterocyctic Communications 2009, 15(6), 397-400); Wei-Sheng Huang's team used cuprous iodide to catalyze the coupling reaction of 2-iodoaniline with methyl 2-mercaptoacetate to generate Compounds of this type (Wei-Sheng Huang.; Rongsong Xu.; Rory Dodd.; William C. Shakespeare., Facile synthesis of 1,4-benzothiazin-3-ones from Cu-catalyzed coupling of 2-iodoanilines and 2-mercaptoacetate. Tetrahedron Letters 2013, 54(2013), 5214–5216); Toshiaki Saitoh's team synthesized 2-(phenylthio)ethylamine and aldehydes under titanium(IV) catalysis. The above reaction can effectively obtain the following compounds (Toshiaki Saitoh.; Michikazu Kitabatake.; Yuuko Sugihara.; Yuuki Ono.; Yo-shie Horiguchi.; Kunihiko Mohri., Short synthesis of 5-substitude-2,3,4,5-tetrahydro-benzo[f][1,4]thiazepines by a modified pictet-spengler reaction. HETEROCYCLES 2017, 94(6), 1063-1073). These are similar compounds, but most have some drawbacks. For example, the raw materials are not readily available, the reaction process is cumbersome, toxic reagents and precious metals are used, the reaction conditions are relatively harsh, and the reaction conversion rate is low, making them difficult to apply to industrial production. Previously, a 1,4-benzothiazazepine was invented. A synthetic method for thiosalicylic acid esters. In this method, the thiol group in the thiosalicylic acid ester has extremely high nucleophilicity, enabling the synthesis of thioazines without any additives or under stepwise conditions. However, the hydroxyl groups in salicylate esters have weak nucleophilicity, making it impossible to synthesize 1,4-benzoxazine using similar methods. Summary of the Invention

[0004] The purpose of this invention is to solve the problems mentioned in the background art, and to provide a 3-trifluoromethyl-1,4-benzoxazine solution. This method for synthesizing compounds uses a one-pot synthesis process, eliminating the need to separate intermediates. It is safe, simple, and uses readily available raw materials. It also boasts high reaction conversion rates and low costs, making it suitable for industrial production.

[0005] To achieve the above objectives, the present invention provides the following technical solution:

[0006] A 3-trifluoromethyl-1,4-benzoxazine The synthetic method for this type of compound includes the following synthetic steps:

[0007] In a reactor, compounds 1, 2, additives, and a suitable solvent were added, and the temperature was raised to 100°C for 4 hours. After the reaction was completed, the mixture was cooled to 0°C, and alkali was added, followed by overnight reaction. Extraction and vacuum distillation were performed to obtain the crude product, which was purified by column chromatography and thin-layer chromatography to obtain 3-trifluoromethyl-1,4-benzoxazine. The reaction equation for this type of compound is as follows:

[0008]

[0009] Compound 1 refers to a compound having the structure of formula (1): salicylate; Compound 2 refers to a compound having the structure of formula (2): sulfoxide ylide;

[0010]

[0011] Among them, R 1 H, 5-methoxy; R 2 Methyl, ethyl; R 3 It is phenyl, 4-methylphenyl, or 4-fluorophenyl.

[0012] Wherein, compound 1 refers to either methyl salicylate or ethyl salicylate.

[0013] Preferably, the molar ratio of compound 1 to compound 2 is 1:1 to 3, and the preferred molar ratio is 1:1.1.

[0014] Preferably, the solvent is one of acetonitrile, tetrahydrofuran, and toluene; the ratio of solvent to compound 1 is 1–5 mL: 0.3 mmol. Here, the solvent is preferably acetonitrile; the ratio of solvent to compound 1 is 2 mL: 0.3 mmol.

[0015] Preferably, the additive is lithium bromide, and the molar ratio of the additive to compound 1 is 0.5 to 2:1. Here, the molar ratio is preferably 1:1.

[0016] Preferably, the base is any one of sodium tert-butoxide, cesium carbonate, and potassium tert-butoxide; the molar ratio of the base to compound 1 is 1 to 3:1. Here, the base is preferably sodium tert-butoxide; the molar ratio is preferably 2:1.

[0017] Preferably, the eluent used for column chromatography purification is any one or a mixture of petroleum ether, n-hexane, and ethyl acetate. The preferred eluent is a petroleum ether:ethyl acetate solvent ratio of 30:1 to 5:1.

[0018] Preferably, the reactor refers to a Schlenk tube.

[0019] Compared with the prior art, the beneficial effects of the present invention are:

[0020] 1. This invention uses trifluoromethylimine ylidene compounds and methyl salicylate as raw materials to synthesize 3-trifluoromethyl-1,4-benzoxazine via a one-pot method. This type of compound is a rapid method for constructing benzo[a]oxazine hybrids. The method.

[0021] 2. This invention overcomes the low nucleophilicity of the hydroxyl groups in salicylates by adding lithium bromide and a base to enhance reactivity, and by employing a one-pot stepwise strategy to improve selectivity. This method offers advantages such as high flexibility, readily available raw materials, simple operation, and a wide substrate range; it also eliminates the need for precious metal catalysis and is low-cost, thus facilitating industrial production. Attached Figure Description

[0022] Figure 1 The hydrogen spectrum of product 3a obtained in Example 1 of this invention;

[0023] Figure 2 The carbon spectrum of product 3a obtained in Example 1 of this invention;

[0024] Figure 3 The hydrogen spectrum of product 3b obtained in Example 2 of this invention;

[0025] Figure 4 The carbon spectrum of product 3b obtained in Example 2 of this invention;

[0026] Figure 5 The hydrogen spectrum of product 3c obtained in Example 3 of this invention;

[0027] Figure 6 The carbon spectrum of product 3c obtained in Example 3 of this invention;

[0028] Figure 7 The hydrogen spectrum of the product obtained in Example 4 of this invention is shown in Figure 3.

[0029] Figure 8 This is the carbon spectrum of the product obtained in Example 4 of the present invention, 3d. Detailed Implementation

[0030] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0031] Example 1

[0032] 0.3 mmol methyl salicylate, 0.33 mmol phenyl sulfoxide ylide, 0.3 mmol lithium bromide, and 2 mL acetonitrile were added to a Schlenk tube. The mixture was reacted at 100°C for 4 hours under air. After the reaction was completed, the mixture was cooled to 0°C, and 0.6 mmol sodium tert-butoxide was added, and the reaction was carried out overnight. The crude product was extracted and distilled under reduced pressure. The crude product was purified by column chromatography and thin-layer chromatography to obtain product 3a. The column chromatography eluent was petroleum ether solvent: ethyl acetate solvent = 30:1 to 5:1, with a yield of 84%.

[0033] The proton and carbon spectra of the obtained product 3a are as follows: Figure 1 and Figure 2 As shown, the structural characterization data are as follows:

[0034] 1 H NMR (400MHz, CDCl3) δ10.24 (s, 1H), 7.83 (d, J = 7.7Hz, 1H), 7.67–7.58 (m, 1H), 7.42–7.32 (m, 3H), 7.27–7.16 (m, 4H).

[0035] 13 C NMR (101MHz, CDCl3) δ183.55,163.61,139.20,135.78,134.14,129.90,129.5 5,129.26,126.14,124.41,123.86,122.27,121.63,121.17,118.85,113.11.

[0036] HRMS(ESI):Calcd.for C 16 H 10 F3NO2[M+H] + :306.0736; found:306.0734.

[0037] Based on the above experimental results, the structure of product 3a is shown in the following formula:

[0038]

[0039] Example 2

[0040] In a Schlenk tube, 0.3 mmol of methyl salicylate, 0.33 mmol of 4-methylphenyl sulfoxide ylide, 0.3 mmol of lithium bromide, and 2 mL of acetonitrile were added. The mixture was reacted at 100°C for 4 hours under air. After the reaction was completed, the mixture was cooled to 0°C, and 0.6 mmol of sodium tert-butoxide was added, and the reaction was carried out overnight. The crude product was extracted and distilled under reduced pressure. The crude product was purified by column chromatography and thin-layer chromatography to obtain product 3b. The column chromatography eluent was petroleum ether:ethyl acetate in a ratio of 30:1 to 5:1, with a yield of 87%.

[0041] The proton and carbon spectra of the obtained product 3b are as follows: Figure 3 and Figure 4 As shown, the structural characterization data are as follows:

[0042] 1H NMR (400MHz, CDCl3) δ10.34(s,1H),7.87–7.79(m,1H),7.68–7.54(m,1H),7.35(d,J=8. 4Hz,1H),7.27–7.21(m,1H),7.17(d,J=8.1Hz,2H),7.09(d,J=8.1Hz,2H),2.36(s,3H).

[0043] 13 C NMR (101MHz, CDCl3) δ183.28,163.39,136.30,135.56,130.76,130.41,129.83,1 24.17,123.77,123.06,122.35,122.35,121.57,122.57,118.80,113.08,21.02.

[0044] HRMS(ESI):Calcd.for C 17 H 12 F3NO2[M+H] + :320.0892; found:320.0890.

[0045] Based on the above experimental results, the structure of product 3b is shown in the following formula:

[0046]

[0047] Example 3

[0048] 0.3 mmol ethyl salicylate, 0.33 mmol 4-fluorophenylphenyl sulfoxide ylide, 0.3 mmol lithium bromide, and 2 mL acetonitrile were added to a Schlenk tube. The mixture was reacted at 100°C for 4 hours under air. After the reaction was completed, the mixture was cooled to 0°C, and 0.6 mmol sodium tert-butoxide was added, and the reaction was allowed to proceed overnight. The crude product was extracted and distilled under reduced pressure. The crude product was purified by column chromatography and thin-layer chromatography to obtain product 3c. The column chromatography eluent was petroleum ether:ethyl acetate in a ratio of 30:1 to 5:1, with a yield of 87%.

[0049] The proton and carbon spectra of the obtained product 3C are as follows: Figure 5 and Figure 6 As shown, the structural characterization data are as follows:

[0050] 1H NMR (400MHz, CDCl3) δ10.19(s,1H),7.85–7.79(m,1H),7.70–7.60(m,1H),7. 34(d,J=8.4Hz,1H),7.27–7.22(m,1H),7.20–7.15(m,2H),7.09–7.04(m,2H).

[0051] 13 C NMR (101MHz, CDCl3) δ183.69,163.66,162.29,159.84,135.89,134.97,133.8 3,130.22,126.27,123.86,123.20,122.17,121.54,116.24,116.01,113.12.

[0052] HRMS(ESI):Calcd.for C 16 H9F4NO2[M+H] + :324.0642; found:324.0640.

[0053] Based on the above experimental results, the structure of product 3c is shown in the following formula:

[0054]

[0055] Example 4

[0056] In a Schlenk tube, 0.3 mmol of ethyl 5-methoxysalicylate, 0.33 mmol of 2-methylphenyl sulfoxide ylide, 0.3 mmol of lithium bromide, and 2 mL of acetonitrile were added. The mixture was reacted at 100°C for 4 hours under air. After the reaction was completed, the mixture was cooled to 0°C, and 0.6 mmol of sodium tert-butoxide was added, and the reaction was allowed to proceed overnight. The crude product was extracted and distilled under reduced pressure. The crude product was purified by column chromatography and thin-layer chromatography to obtain product 3d. The column chromatography eluent was petroleum ether:ethyl acetate in a ratio of 30:1 to 5:1, with a yield of 69%.

[0057] The 3d proton and carbon spectra of the obtained product are as follows: Figure 7 and Figure 8 As shown, the structural characterization data are as follows:

[0058] 1 H NMR (400MHz, CDCl3) δ9.83 (s, 1H), 7.70 (d, J = 8.4Hz, 1H), 7.36-7.08 (m, 4H), 6.79 (d, J = 8.4Hz, 2H), 3.91 (s, 3H), 2.37 (s, 3H).

[0059] 13C NMR (101MHz, CDCl3) δ182.47,166.76,166.09,138.12,134.73(q,J C-F =1.91Hz),133.17,130.73,129.88(q,J C-F =37.37Hz),126.57,126.40,124.77,121.70(q,J C-F =280.28Hz),115.52,112.89,96.14,56.01,18.00.

[0060] HRMS(ESI):Calcd.for C 18 H 14 F3NO3[M+H] + 350.0999; found: 350.0996.

[0061] Based on the above experimental results, the 3D structure of the product is shown in the following formula:

[0062]

[0063] In summary, this invention utilizes sulfoxide ylidene compounds and salicylates as raw materials to synthesize 3-trifluoromethyl-1,4-benzoxazine compounds in a one-pot process. This invention offers advantages such as simple synthesis steps, readily available raw materials, and safe synthetic operation; furthermore, it requires no precious metal catalysts, exhibits high reaction conversion rates, and low costs, making it suitable for industrial production.

[0064] Any aspects of this invention not described in detail are well-known to those skilled in the art.

[0065] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from its spirit or essential characteristics. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, all variations falling within the meaning and scope of equivalents of the claims are intended to be included within the present invention. No reference numerals in the claims should be construed as limiting the scope of the claims.

Claims

1. A method for synthesizing a 3-trifluoromethyl-1,4-benzoxazine compound, characterized in that: The synthesis steps include the following: In a reactor, compound 1, compound 2, additives, and an appropriate amount of solvent were added, and the temperature was raised to 100°C and reacted for 4 hours. After the reaction was completed, the temperature was cooled to 0°C, alkali was added, and the reaction was carried out overnight. Extraction and vacuum distillation were performed to obtain the crude product. The crude product was purified by column chromatography and thin-layer chromatography to obtain 3-trifluoromethyl-1,4-benzoxazine compounds. The reaction equation is as follows: ； Among them, R 1 H, 5-methoxy; R 2 Methyl, ethyl; R 3 It is phenyl, 4-methylphenyl, or 4-fluorophenyl; The additive is lithium bromide, and the base is sodium tert-butoxide or potassium tert-butoxide.

2. The method for synthesizing a 3-trifluoromethyl-1,4-benzoxazine compound according to claim 1, characterized in that: The molar ratio of compound 1 to compound 2 is 1:1~3.

3. The method for synthesizing a 3-trifluoromethyl-1,4-benzoxazine compound according to claim 1, characterized in that: The solvent is one of acetonitrile, tetrahydrofuran, and toluene; the ratio of solvent to compound 1 is 1~5 mL: 0.3 mmol.

4. The method for synthesizing a 3-trifluoromethyl-1,4-benzoxazine compound according to claim 1, characterized in that: The molar ratio of the additive to compound 1 is 0.5 to 2:

1.

5. The method for synthesizing a 3-trifluoromethyl-1,4-benzoxazine compound according to claim 1, characterized in that: The molar ratio of the base to compound 1 is 1 to 3:

1.

6. The method for synthesizing a 3-trifluoromethyl-1,4-benzoxazine compound according to claim 1, characterized in that: The eluent used for column chromatography purification is any one or a mixture of petroleum ether, n-hexane, and ethyl acetate.

7. The method for synthesizing a 3-trifluoromethyl-1,4-benzoxazine compound according to claim 1, characterized in that: The reactor refers to a Schlenk tube.

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