A kind of bisphenothiazine compound and its synthesis method

Abstract

The present invention primarily relates to a method for synthesizing bisphenothiazine and its derivatives. This method utilizes a catalyst and an oxidant to react cyclohexanone compounds, elemental sulfur, and ammonium iodide in an air or oxygen atmosphere in a one-pot reaction, resulting in highly selective bisphenothiazine and its derivatives. This method produces products with stable structures and excellent chemical properties, as well as by-products. This method features a simple reaction system, mild reaction conditions, minimal reaction equipment, facile experimental operation, a wide range of material sources, excellent atom economy, and the absence of transition metal catalysts. It provides a new pathway for the synthesis of bisphenothiazine compounds. The bisphenothiazine derivatives and their synthesis methods of the present invention can be used in a variety of industrial production fields, including pharmaceuticals, pesticides, and organic functional materials. They are particularly suitable for the scientific research, development, and utilization of the efficient, selective, one-pot synthesis of bisphenothiazine compounds. #imgabs0#

Description

Technical Field

[0001] The invention relates to a bisphenothiazine compound and a synthesis method thereof, and belongs to the field of organic synthesis. Background Art

[0002] Phenothiazines are a very important class of heterocyclic compounds. With diverse biological and therapeutic activities observed, these compounds have been widely used in pharmaceutical and biological applications, including as sedatives, tranquilizers, antituberculosis agents, antipyretics, antitumor agents, bactericides, and parasiticides. Several phenothiazine derivatives, such as promazine, chlorpromazine, and triflupromazine, are marketed or in clinical trials. Phenothiazines have been described as antipsychotics and central dopamine receptor antagonists. Due to their high electron-donating capacity and non-planar butterfly conformation that inhibits molecular aggregation, phenothiazines are promising materials for light-emitting diodes, photovoltaic cells, and photosensitizers. Summary of the Invention

[0003] Therefore, the purpose of the present invention is to provide a bisphenothiazine and its derivatives. These substances have stable molecular structures and excellent chemical properties. They are both important molecular fragments and compound fragments with physiological and pharmacological activities, and have certain photoelectric properties, biological activities, and pharmaceutical activities.

[0004] Another object of the present invention is to provide a method for synthesizing bisphenothiazine and its derivatives, which has the advantages of readily available and inexpensive raw materials, simple reaction conditions, convenient operation, a small number of reaction steps, simple equipment, and readily available and inexpensive raw materials. The reaction does not require the use of metal catalysts or metal oxidants, maintains atom economy to the greatest extent possible, has low input and high output, and is amenable to industrial production and widespread adoption.

[0005] In order to achieve the above-mentioned purpose, the present invention provides a diphenothiazine and its derivatives, which have the general formula of Formula I:

[0006]

[0007] in:

[0008] R is selected from alkyl and phenyl.

[0009] The present invention also provides a method for synthesizing the bisphenothiazine and its derivatives according to claim 1, which is obtained by heating and stirring three components of cyclohexanone compounds, elemental sulfur and ammonium iodide under the reaction conditions of a catalyst, an oxidant and an organic solvent.

[0010] Preferably, in the method of the present invention, the general formula of the cyclohexanone compound is Formula II:

[0011]

[0012] in:

[0013] R is selected from alkyl and phenyl.

[0014] In the method of the present invention, the cyclohexanone compound is selected from the group consisting of: 4-methyl-cyclohexanone, 4-ethyl-cyclohexanone, 4-propyl-cyclohexanone, 4-tert-butyl-cyclohexanone, 4-pentyl-cyclohexanone, 4-tert-pentyl-cyclohexanone, and 4-phenyl-cyclohexanone.

[0015] In the method of the present invention, the catalyst is one of sodium iodide, ammonium iodide, elemental iodine, potassium iodide, N-iodosuccinimide, iodine bromide, potassium iodate, sodium periodate, iodine chloride, hydroiodic acid, [bis(trifluoroacetoxy)iodo]benzene, trimethylsilyl iodide, iodobenzene, nickel iodide, cuprous iodide, and palladium iodide.

[0016] In the method of the present invention, the oxidant is one of dimethyl sulfoxide, benzylphenyl sulfoxide, methylphenyl sulfoxide, dimethyl sulfone, diphenyl sulfoxide, diphenyl sulfone, cyclopentane, 2-iodoxybenzoic acid, di-tert-butyl peroxide, tert-butyl hydroperoxide, 2,3-dichloro-5,6-dicyano-p-benzoquinone, and p-benzoquinone.

[0017] In the method of the present invention, the organic solvent is selected from one of ethyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate, benzyl acetate, amyl acetate, hexyl acetate, petroleum ether, chlorobenzene, toluene, trifluorotoluene, o-xylene, m-xylene, nitrobenzene 1,4-dioxane, acetonitrile, anisole, 1,1,2,2-tetrachloroethane, N,N-dimethylacetamide, and o-dichlorobenzene, and the amount of the solvent used is 0.4-1.2 mL.

[0018] According to the method of the present invention, the molar ratio of the cyclohexanone compound, elemental sulfur, ammonium iodide, catalyst, and oxidant is 1.0:1.0-8.0:1.0-5.0:0.01-1.0:0.5-3.0; the reaction temperature is 100-160° C.; the reaction atmosphere is air or oxygen atmosphere; and the reaction time is 8-36 hours.

[0019] The technical solution of the present invention has the following advantages:

[0020] (I) The present invention realizes a one-pot reaction of cyclohexanone compounds, elemental sulfur and ammonium iodide in an air atmosphere under the action of a catalyst and an oxidant to obtain a technical solution of a bisphenothiazine and its derivatives with high selectivity. The target product is directly and selectively synthesized in one step, overcoming the huge waste of manpower, money and materials caused by the existing multi-step synthesis method requiring the use of a metal catalyst, saving a lot of research time and shortening the production cycle; (II) The technical solution of a bisphenothiazine and its derivatives is selectively obtained by heating and stirring the three components of cyclohexanone compounds, elemental sulfur and ammonium iodide under the reaction conditions of a catalyst, an oxidant and an organic solvent. The reaction system is simple and the reaction conditions are The invention is mild, has a wide range of material sources, significantly increases product added value and is highly available, and has foreseeable market commercialization prospects; (III) The technical solution for converting cyclohexanone compounds, elemental sulfur and ammonium iodide into bis-phenothiazine and its derivatives has a scientific and reasonable process, good group positioning and selectivity, a wide range of material sources, good atom economy, stable structure, easy experimental operation, significantly shortened reaction steps, and required fewer instruments and equipment; (IV) The bis-phenothiazine derivatives of the present invention and the synthesis method thereof can be used in multiple industrial production fields such as medicine, pesticides, and organic functional materials; and are particularly suitable for the scientific research, development and utilization of the one-pot efficient and selective synthesis of bis-phenothiazine compounds. DETAILED DESCRIPTION

[0021] The present invention will now be described in further detail with reference to the following reaction formula. The following reaction formula is a simplified schematic diagram, which only illustrates the basic structure of the present invention in a schematic manner, and therefore only shows the composition related to the present invention:

[0022]

[0023] Examples 1-7

[0024] The following steps are involved:

[0025] (1) Add cyclohexanone compounds, elemental sulfur, ammonium iodide, catalyst, oxidant and organic solvent into a reaction vessel;

[0026] (2) After the reactants are fully mixed, they are heated;

[0027] ⑶ After the reaction, purification is carried out to obtain the product.

[0028] Example 1 Synthesis of 3,7,11-trimethylbenzo[5,6][1,4]thiazin[2,3,4-kl]phenothiazine

[0029]

[0030] Take a reaction tube, add 0.6mmol (78μL) of p-methylcyclohexanone, 1.6mmol (51.2mg) of elemental sulfur, 0.5mmol (73.0mg) of ammonium iodide, 0.4mmol (28μL) of dimethyl sulfoxide, 0.06mmol (10.0mg) of sodium iodide, and 0.6mL of ethyl acetate, fill with oxygen, seal and react at 150°C with stirring for 24 hours. Conventional treatment gives 41.6mg of pure product with a yield of 60%.

[0031] Cyclohexanone compounds, elemental sulfur, ammonium iodide, reaction conditions, reaction products and yields are shown in Table 1:

[0032] Table 1: Reactants and reaction conditions in Examples 1-7

[0033]

[0034]

[0035] The product synthesized by the present invention (Example 1) can be further subjected to the following reaction to prepare a bisphenothiazine derivative having certain luminescent properties:

[0036] BRIEF DESCRIPTION OF THE DRAWINGS

[0037] In order to prove the products of the present invention, the present invention provides H-NMR spectra and C-NMR spectra of some examples.

[0038] Figure 1-1 H NMR spectrum of the product of Example 1.

[0039] Figure 1-2 NMR carbon spectrum of the product of Example 1.

[0040] Figure 2-1 H NMR spectrum of the product of Example 2.

[0041] Figure 2-2 The NMR carbon spectrum of the product of Example 2.

[0042] Figure 3-1 H NMR spectrum of the product of Example 3.

[0043] Figure 3-2 NMR carbon spectrum of the product of Example 3.

[0044] The NMR data of the product of Example 1 are as follows:

[0045] 1H NMR (400MHz, CDCl3, ppm) δ7.05 (d, J = 8.25Hz, 2H), 7.00 (d, J = 1.94Hz, 2H), 6.90 (dd, J = 8.22, 2.03Hz, 2H), 6.78 (s, 2H), 2.29 (s, 6H), 2.21 (s, 3H); 13 C NMR (100MHz, CDCl3, ppm) δ140.24,137.31,134.38,134.03,128.09,128.06,126.55,125.98,125.32,120.15,20.65,20.42.

[0046] The NMR data of the product of Example 2 are as follows:

[0047] 1 H NMR (400MHz, CDCl3, ppm) δ7.08 (d, J = 8.33Hz, 2H), 7.02 (d, J = 1.98Hz, 2H), 6.93-6.90 (m, 2H), 6.80 (s ,2H),2.57(q,J=7.56Hz,4H),2.49(d,J=7.58Hz,2H),1.21(t,J=7.67Hz,6H),1.15(t,J=7.55Hz,3H); 13 C NMR (100MHz, CDCl3, ppm) δ140.90,140.57,140.45,126.96,126.93,126.54,125.45,124.90,120.25,117.47,28.11,27.92,15.59,15.51.HRMS calcd.for C 24 H 24 NS2 + [M+H] + 390.1345,found 390.1346

[0048] The NMR data of the product of Example 3 are as follows:

[0049] 1H NMR (400MHz, CDCl3, ppm) δ7.07 (d, J = 8.22Hz, 2H), 6.99 (d, J = 1.95Hz, 2H), 6.91-6.88 (m, 2H), 6.77 (s, 2H), 2.50 (dd, J = 8.5 7,6.65Hz,4H),2.42(d,J=3.00Hz,2H),1.63-1.57(m,4H),1.54(dd,J=8.48,6.26Hz,2H),0.91(dt,J=18.25,7.35Hz,9H). 13 C NMR (100MHz, CDCl3, ppm) δ140.48,139.31,139.01,137.51,127.56,127.51,12 6.47,125.48,125.38,120.15,37.23,36.96,24.50,24.35,13.80,13.67.HRMS calcd.for C 27 H 30 NS2 + [M+H] + 432.1814,found 432.1814

[0050] The NMR data of the product of Example 4 are as follows:

[0051] 1 H NMR (400MHz, CDCl3, ppm) δ7.20-7.19 (m, 2H), 7.11 (d, J = 1.74Hz, 4H), 6.97 (s, 2H), 1.29 (s, 18H), 1.23 (s, 9H); 13 HRMS calcdfor C 30 H 36 NS2 + [M+H] + 474.2284,found 474.2284

[0052] The NMR data of the product of Example 5 are as follows:

[0053] 1 H NMR (400MHz, CDCl3, ppm) δ7.58-7.55(m,3H),7.53-7.30(m,19H),7.25(s,1H);13 C NMR (100MHz, CDCl3, ppm) δ141.53,139.74,138.47,138.04,128.89,128.79,127.6 2,127.43,127.26,126.71,126.65,126.38,126.35,126.01,124.36,120.83.HRMS calcd.forC 36 H 24 NS2 + [M+H] + 534.1345, found 533.1311

[0054] The NMR data of the product of Example 6 are as follows:

[0055] 1 H NMR(400MHz, CDCl3, ppm) δ7.08(d,J=8.26Hz,2H),7.01(d,J=1.95Hz,2H),6.92–6.90(m,2H) ,6.79(s,2H),2.55-2.43(m,6H),1.73-1.45(m,8H),1.41-1.20(m,16H),0.92-0.88(m,9H); 13 C NMR (100MHz, CDCl3, ppm) δ140.42,139.57,139.26,127.49,127.45,126.44,125.42,125 .36,120.15,35.14,34.89,31.45,31.30,31.14,30.98,22.58,22.54,14.08,14.05.HRMS calcd.for C 33 H 42 NS2 + [M+H] + 516.2753, found 516.2741

[0056] The NMR data of the product of Example 7 are as follows:

[0057] 1H NMR (400MHz, CDCl3, ppm) δ7.13 (s, 2H), 7.11 (s, 1H), 7.08-7.03 (m, 3H), 6.92 (s, 2H), 1.61 (d, J = 7.49Hz, 3H), 1 .58-1.55(m,3H),1.24(d,J=7.16Hz,14H),1.20(d,J=2.70Hz,4H),0.71(d,J=7.34Hz,3H),0.69–0.64(m,6H); 13 C NMR (100MHz, CDCl3, ppm) δ145.97,139.94,125.93,125.36,125.34,125.12,124.38 ,123.32,119.78,117.11,37.68,36.76,28.51,28.50,28.43,9.22,9.17,9.14.HRMS calcd.for C 33 H 43 NS2 + [M+H] + 516.2753, found 516.2737

[0058] The NMR data of application A are as follows:

[0059] 1H NMR (400MHz, CDCl3, ppm) δ8.12 (s, 2H), 7.94 (d, J = 2.09Hz, 2H), 7.53 (d, J = 8.50Hz, 2H), 7.39 (dd, J = 8.49, 2.09Hz, 2H), 2.56 (s, 3H), 2.47 (s, 6H); 13C NMR (100MHz, CDCl3, ppm) δ137.12,136.55,135.45,134.94,134.32,129.09,128.59,127.87,123.86,121.96,20.94,20.93.HRMS calcd.for C 21 H 18 NO4S2 + [M+H] + 412.0672,found 412.0674

[0060] With the above-described preferred embodiments of the present invention as a guide, and with reference to the above description, relevant personnel are fully capable of making various changes and modifications without departing from the technical scope of this invention. The technical scope of this invention is not limited to the contents of the specification and must be determined according to the scope of the claims.

Claims

1. A method for synthesizing bisphenothiazine and its derivatives, characterized in that: The general formula of the bisphenothiazine and its derivatives is Formula I: Wherein: R is selected from alkyl, phenyl; The method is: The three components of cyclohexanone compounds, elemental sulfur and ammonium iodide are heated and stirred under the reaction conditions of catalyst, oxidant and organic solvent to obtain the product; Reaction atmosphere: air or oxygen; The general formula of the cyclohexanone compound is Formula II: Wherein: R is selected from alkyl, phenyl; The catalyst is one of sodium iodide, ammonium iodide, elemental iodine, potassium iodide, N-iodosuccinimide, iodine bromide, potassium iodate, sodium periodate, iodine chloride, hydroiodic acid, [bis(trifluoroacetoxy)iodo]benzene, trimethylsilyl iodide, iodobenzene, nickel iodide, cuprous iodide, and palladium iodide; and the oxidant is one of dimethyl sulfoxide, benzylphenyl sulfoxide, methylphenyl sulfoxide, dimethyl sulfone, diphenyl sulfoxide, diphenyl sulfone, cyclopentane, 2-iodoacylbenzoic acid, di-tert-butyl peroxide, tert-butyl hydroperoxide, 2,3-dichloro-5,6-dicyano-p-benzoquinone, and p-benzoquinone.

2. The method according to claim 1, characterized in that The cyclohexanone compound is selected from the group consisting of: 4-methyl-cyclohexanone, 4-ethyl-cyclohexanone, 4-propyl-cyclohexanone, 4-tert-butyl-cyclohexanone, 4-pentyl-cyclohexanone, 4-tert-pentyl-cyclohexanone, and 4-phenyl-cyclohexanone.

3. The method according to claim 1, characterized in that The organic solvent is selected from one of ethyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate, benzyl acetate, amyl acetate, hexyl acetate, petroleum ether, chlorobenzene, toluene, trifluorotoluene, o-xylene, m-xylene, nitrobenzene 1,4-dioxane, acetonitrile, anisole, 1,1,2,2-tetrachloroethane, N,N-dimethylacetamide, and o-dichlorobenzene.

4. The method according to claim 1, wherein The molar ratio of the cyclohexanone compound, elemental sulfur, ammonium iodide, catalyst, and oxidant is 1.0:1.0-8.0:1.0-5.0:0.01-1.0:0.5-3.0; the reaction temperature is 100°C-160°C; and the reaction time is 8-36 hours.

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