A photocatalytic synthesis method of bromopropazine compounds

Abstract

The present invention discloses a photocatalytic synthesis method of bromopropipazine compounds. Using bromopropanol and piperazine as raw materials, in the presence of an oxygen-containing atmosphere, an organic solvent, a base, and a transition metal oxide / C3N4 composite photocatalyst, the bromopropipazine compounds are prepared through a photocatalytic reaction. The present invention uses bromopropanol as a raw material, avoiding the use of SOCl2, and preparing bromopropipazine compounds in a green and economical manner.

Description

Technical Field

[0001] The present invention relates to a photocatalytic synthesis method of bromopiprazine compounds, belonging to the technical field of organic pharmaceutical synthesis. Background Art

[0002] Bromopiprazine compounds play an important role in the field of drug research and development. The marketed drug Pipobroman, with the chemical name 1,4-bis(3-bromopropionyl)piperazine, is an anticancer drug that acts as an alkylating agent. Pipobroman has good clinical activity in polycythemia vera (PV) and essential thrombocythemia (ET). The preparation of 1,4-bis(3-bromopropionyl)piperazine uses bromopropionic acid as the raw material, which first reacts with SOCl2 to form bromopropionyl chloride, and then reacts with piperazine to form the product 1,4-bis(3-bromopropionyl)piperazine (Shandong Pharmaceutical Industry, 2003, 22). This method uses strong acid SOCl2, and the piperazine reaction needs to be carried out in an alkaline environment, and a large amount of alkali is required to neutralize during the reaction process, which is extremely unfavorable to the environment. In terms of atom economy, such methods have problems such as a large amount of waste, a complex post-treatment process, poor atom economy, and are not conducive to large-scale production. Summary of the Invention

[0003] Aiming at the above technical problems existing in the prior art, the purpose of the present invention is to provide a photocatalytic synthesis method of bromopiprazine compounds, using bromopropanol as the raw material, avoiding the use of SOCl2, and preparing bromopiprazine compounds in a green and economical way.

[0004] In order to achieve the above technical purpose, the present invention adopts the following technical scheme:

[0005] A photocatalytic synthesis method of bromopiprazine compounds, using bromopropanol and piperazine as raw materials, and under the conditions of an oxygen-containing atmosphere, an organic solvent, a base, and a transition metal oxide / C3N4 composite photocatalyst, the bromopiprazine compound is prepared through a photocatalytic reaction;

[0006]

[0007] Preferably, the molar ratio of bromopropanol to piperazine is 1-4:1.

[0008] Preferably, the oxygen-containing atmosphere is air and / or oxygen.

[0009] Preferably, the organic solvent is one or more of toluene, benzotrifluoride, xylene, benzene, cyclohexane, n-hexane, acetonitrile, mesitylene, and dichloromethane; more preferably one or more of n-hexane, cyclohexane, toluene, and benzene.

[0010] Preferably, the base is one or more of potassium tert-butoxide, sodium tert-butoxide, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, potassium hydroxide, barium hydroxide, cesium carbonate, and potassium carbonate; more preferably, it is one or more of sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, sodium hydride, and potassium hydride.

[0011] Preferably, the molar ratio of bromopropanol to the base is 1:0.1 - 3.

[0012] Preferably, the transition metal in the transition metal oxide / C3N4 composite photocatalyst is one or more of silver, ruthenium, cobalt, copper, iron, gold, platinum, palladium, praseodymium, germanium, nickel, and manganese.

[0013] Preferably, in the transition metal oxide / C3N4 composite photocatalyst, the mass ratio of the transition metal to C3N4 is 0.01 - 0.5:1.

[0014] Preferably, the amount of the transition metal oxide / C3N4 composite photocatalyst is 0.1 - 5 wt% of bromopropanol.

[0015] It should be noted that the transition metal oxide / C3N4 composite photocatalyst in the present invention can be prepared by existing conventional methods. For example, first disperse C3N4 in water, then add a soluble transition metal salt and mix well, and obtain it after drying and calcination.

[0016] Preferably, the conditions for the photocatalytic reaction are: reacting for 1 - 10 h under a 3 - 100 W LED lamp or xenon light source.

[0017] Compared with the prior art, the present invention has the following beneficial effects:

[0018] (1) The present invention uses bromopropanol as a raw material, which is more inexpensive and easily available. Avoiding the use of SOCl2 makes it greener and more economical in terms of raw materials. Moreover, the reaction conditions are mild, reducing the reaction steps and being easy to operate.

[0019] (2) The present invention reacts in an oxygen-containing atmosphere, has mild oxidation performance, avoids the use of peroxides, and is more conducive to the recycling of the catalyst; moreover, the transition metal oxide / C3N4 composite photocatalyst can be separated from the reaction system by simple filtration, effectively solving the problem that it is difficult to separate the homogeneous catalyst from the reaction solution. The loss of catalytic activity is not significant, reducing the production cost and meeting the requirements of green chemistry;

[0020] (3) The photocatalyst of the present invention forms electron-hole pairs under visible light radiation, which can effectively avoid high-temperature thermal reactions and make the selectivity of the product higher. Description of the Drawings

[0021] Figure 11H NMR spectrum of bromopropazine in Example 1. Detailed implementation mode

[0022] The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art belong to the scope of protection of the present invention. Unless otherwise defined, all professional terms used hereinafter have the same meaning as commonly understood by those skilled in the art. The professional terms used herein are only for the purpose of describing specific embodiments, and are not intended to limit the scope of protection of the present invention.

[0023] All parts and percentages in the embodiments refer to mass unless otherwise specified.

[0024] The specific preparation process of the transition metal oxide / C3N4 composite photocatalyst in the present invention is as follows:

[0025] (1) According to the mass ratio of melamine: water: concentrated phosphoric acid of 1:40 - 100:1.5 - 5, dissolve melamine in water, then add concentrated phosphoric acid, crystallize at 120 - 200 °C, filter, and dry to obtain solid I;

[0026] (2) Calcinate solid I at 400 - 550 °C in an N2 atmosphere for 2 - 8 h to obtain C3N4;

[0027] (3) Add C3N4 to water, add a soluble transition metal salt, control the mass ratio of C3N4 to the transition metal to be 1:0.01 - 0.5, and the mass ratio of water to C3N4 to be 10 - 200:1, and vacuum dry at 30 - 80 °C to obtain solid II;

[0028] (4) Calcinate solid II at 200 - 550 °C for 0.5 - 6 h to obtain the transition metal oxide / C3N4 composite photocatalyst.

[0029] Example 1

[0030] The preparation process of the Ag2O / C3N4 photocatalyst is as follows:

[0031] (1) According to the mass ratio of melamine: water: concentrated phosphoric acid of 1:80:2, dissolve melamine in water, add concentrated phosphoric acid, crystallize at 190 °C, filter, and dry to obtain solid I;

[0032] (2) Calcinate solid I at 520 °C in an N2 atmosphere for 5 h to obtain C3N4;

[0033] (3) Add C3N4 into water, then add AgNO3, control the mass ratio of C3N4 to Ag to be 1:0.05, and the mass ratio of water to C3N4 to be 20:1, and vacuum dry at 60 °C to obtain solid II;

[0034] (4) Calcinate solid II at 300 °C for 2 h to obtain the Ag2O / C3N4 photocatalyst.

[0035] Add 1.3936 g of 3-bromopropanol (with a content of 99%) into a 100 mL reaction flask, add 25 mL of toluene as a solvent, then add 0.4 g of sodium hydride (with a content of 60%), add 1.4501 g of piperazine (with a content of 60%), and then add 50 mg of Ag2O / C3N4. React under normal temperature and 30 W LED light irradiation conditions for 8 hours to obtain a mixed solution, which is filtered, rotary evaporated, and washed with water to obtain a pale yellow solid. Through analysis and detection, the content of bromopropiopiperazine is 92.51%, and the yield of bromopropiopiperazine based on 3-bromopropanol is 81.4%.

[0036] The white solid was characterized, and its 1H NMR spectrum is as Figure 1 shown: δ 2.50 is the solvent peak, δ 1.51 - 1.64 (m, 4H), δ 2.29 (t, J = 8 Hz, 4H), δ 3.34 - 3.43 (m, 8H). Its chemical shift and the number of hydrogens are consistent with those of bromopropiopiperazine.

[0037] Comparative Example 1

[0038] Add 1.3936 g of 3-bromopropanol (with a content of 99%) into a 100 mL reaction flask, add 25 mL of toluene as a solvent, then 0.4 g of sodium hydride (with a content of 60%), add 1.4501 g of piperazine (with a content of 60%), and then add 0.6100 g of MnO2 (with a content of 99%) and 9.7363 g of tert-butyl hydroperoxide (with a content of 70%). React under normal temperature and 15 W LED light irradiation conditions for 10 hours. Through analysis and detection, the target product bromopropiopiperazine was not obtained.

[0039] Example 2

[0040] The preparation process of the Ru2O3 / C3N4 photocatalyst is as follows:

[0041] (1) According to the mass ratio of melamine: water: concentrated phosphoric acid of 1:70:3, dissolve melamine in water, add concentrated phosphoric acid, crystallize at 170 °C, filter, and dry to obtain solid I;

[0042] (2) Calcinate solid I at 550 °C under N2 atmosphere for 4.5 h to obtain C3N4;

[0043] (3) Add C3N4 into water, then add RuCl3. Control the mass ratio of C3N4 to Ru to be 1:0.1, and the mass ratio of water to C3N4 to be 40:1. Vacuum dry at 50 °C to obtain Solid II;

[0044] (4) Calcine Solid II at 500 °C for 3.5 h to obtain the Ru2O3 / C3N4 photocatalyst.

[0045] Add 1.3936 g of 3-bromopropanol (content 99%) into a 100 mL reaction flask, add 25 mL of n-hexane as the solvent, then add 0.67 g of potassium hydride (content 60%), add 1.4501 g of piperazine (content 60%), and then add 50 mg of Ru2O3 / C3N4. React under normal temperature and 30 W LED light illumination for 8 hours to obtain a mixed solution. After filtration, rotary evaporation, and washing with water, a pale yellow solid is obtained. Through analysis and detection, the content of bromopropionyl piperazine is 90.79%, and the yield of bromopropionyl piperazine based on 3-bromopropanol is 80.15%.

[0046] Comparative Example 2

[0047] Add 1.3936 g of 3-bromopropanol (content 99%) into a 100 mL reaction flask, add 25 mL of n-hexane as the solvent, then add 0.67 g of potassium hydride (content 60%), add 1.4501 g of piperazine (content 60%), and then add 0.10 g of RuCl3. React under normal temperature and 30 W LED light illumination for 8 hours. Through analysis and detection, the target product bromopropionyl piperazine is not obtained.

[0048] Example 3

[0049] The preparation process of the CuO / C3N4 photocatalyst is as follows:

[0050] (1) According to the mass ratio of melamine: water: concentrated phosphoric acid being 1:70:3, dissolve melamine in water, add concentrated phosphoric acid, crystallize at 190 °C, filter, and dry to obtain Solid I;

[0051] (2) Calcine Solid I at 550 °C in an N2 atmosphere for 4.5 h to obtain C3N4;

[0052] (3) Add C3N4 into water, then add CuCl2. Control the mass ratio of C3N4 to Cu to be 1:0.15, and the mass ratio of water to C3N4 to be 40:1. Vacuum dry at 50 °C to obtain Solid II;

[0053] (4) Calcine Solid II at 500 °C for 3.5 h to obtain the CuO / C3N4 photocatalyst.

[0054] 1.3936 g of 3-bromopropanol (with a content of 99%) was added to a 100 mL reaction flask, 50 mL of cyclohexane was added as a solvent, then 0.9796 g of sodium tert-butoxide (with a content of 98%) was added, 1.4501 g of piperazine (with a content of 60%) was added, and then 50 mg of CuO / C3N4 was added. The reaction was carried out under normal temperature and xenon lamp illumination conditions for 8 hours to obtain a mixed solution, which was filtered, rotary evaporated, and washed with water to obtain a pale yellow solid. Through analysis and detection, the content of bromopropiopiperazine was 93.79%, and the yield of bromopropiopiperazine based on 3-bromopropanol was 78.53%.

[0055] Comparative Example 3

[0056] 1.3936 g of 3-bromopropanol (with a content of 99%) was added to a 100 mL reaction flask, 50 mL of cyclohexane was added as a solvent, 0.9796 g of sodium tert-butoxide (with a content of 98%) was added, 1.4501 g of piperazine (with a content of 60%) was added, and then 0.10 g of CuCl2 was added. The reaction was carried out under normal temperature and xenon lamp illumination conditions for 8 hours. Through analysis and detection, the target product bromopropiopiperazine was not obtained.

[0057] Example 4

[0058] The preparation process of the Mn3O4 / C3N4 photocatalyst is as follows:

[0059] (1) According to the mass ratio of melamine: water: concentrated phosphoric acid of 1:80:2, melamine was dissolved in water, concentrated phosphoric acid was added, and crystallization was carried out at 150 °C, followed by filtration and drying to obtain solid I;

[0060] (2) Solid I was calcined at 520 °C in a N2 atmosphere for 5 h to obtain C3N4;

[0061] (3) C3N4 was added to water, and manganese acetate was added. The mass ratio of C3N4 to manganese was controlled to be 1:0.1, and the mass ratio of water to C3N4 was 20:1. Vacuum drying was carried out at 60 °C to obtain solid II;

[0062] (4) Solid II was calcined at 300 °C for 2 h to obtain the Mn3O4 / C3N4 photocatalyst.

[0063] 1.3936 g of 3-bromopropanol (with a content of 99%) was added to a 100 mL reaction flask, 25 mL of benzene was added as a solvent, then 1.1445 g of potassium tert-butoxide (with a content of 98%) was added, 1.4501 g of piperazine (with a content of 60%) was added, and then 50 mg of Mn3O4 / C3N4 was added. The reaction was carried out under normal temperature and 15 W LED lamp illumination conditions for 9 hours to obtain a mixed solution, which was filtered, rotary evaporated, and washed with water to obtain a pale yellow solid. Through analysis and detection, the content of bromopropiopiperazine was 93.79%, and the yield of bromopropiopiperazine based on 3-bromopropanol was 78.53%.

[0064] Comparative Example 4

[0065] 1.3936 g of 3-bromopropanol (with a content of 99%) was added to a 100 mL reaction flask, 25 mL of benzene was added as a solvent, then 1.1445 g of potassium tert-butoxide (with a content of 98%) was added, 1.4501 g of piperazine (with a content of 60%) was added, and then 1.5206 g of MnO₂ (with a content of 99%) was added. The reaction was carried out for 9 hours under normal temperature and 15 W LED light irradiation. After analysis and detection, the target product bromopropazine was not obtained.

Claims

1. A photocatalytic synthesis method of bromopropazine compounds, characterized in that: Using bromopropanol and piperazine as raw materials, in the presence of an oxygen-containing atmosphere, an organic solvent, a base, and a transition metal oxide / C3N4 composite photocatalyst, the compound bromopropazine is prepared by a photocatalytic reaction; The transition metal in the transition metal oxide / C3N4 composite photocatalyst is one of silver, ruthenium, copper, and manganese; The specific preparation process of the transition metal oxide / C3N4 composite photocatalyst is as follows: (1) According to the mass ratio of melamine: water: concentrated phosphoric acid of 1:40-100:1.5-5, dissolve melamine in water, then add concentrated phosphoric acid, crystallize at 120-200 °C, filter, and dry to obtain solid I; (2) Calcinate solid I at 400-550 °C in an N2 atmosphere for 2-8 h to obtain C3N4; (3) Add C3N4 to water, add a soluble transition metal salt, control the mass ratio of C3N4 to the transition metal to be 1:0.01-0.5, and the mass ratio of water to C3N4 to be 10-200:1, and vacuum dry at 30-80 °C to obtain solid II; (4) Calcinate solid II at 200-550 °C for 0.5-6 h to obtain the transition metal oxide / C3N4 composite photocatalyst.

2. The photocatalytic synthesis method of the bropropazine compound according to claim 1, wherein: The molar ratio of the bromopropanol to piperazine is 1-4:

1.

3. The photocatalytic synthesis method of the bromopropiophenazone compound according to claim 1, characterized in that: The oxygen-containing atmosphere is air and / or oxygen.

4. The photocatalytic synthesis method of the bromopropiophenazone compound according to claim 1, characterized in that: The organic solvent is one or more of toluene, trifluorotoluene, xylene, benzene, cyclohexane, n-hexane, acetonitrile, mesitylene, and dichloromethane.

5. The photocatalytic synthesis method of the bromopropiophenazone compound according to claim 1, characterized in that: The base is one or more of potassium tert-butoxide, sodium tert-butoxide, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, potassium hydroxide, barium hydroxide, cesium carbonate, and potassium carbonate.

6. The photocatalytic synthesis method of the bromopropiophenazone compound according to claim 5, characterized in that: The molar ratio of the bromopropanol to the base is 1:0.1-3.

7. The photocatalytic synthesis method of the bromopropiophenazone compound according to claim 1, characterized in that: The amount of the transition metal oxide / C3N4 composite photocatalyst is 0.1-5 wt% of the bromopropanol.

8. The photocatalytic synthesis method of the propipazine bromide compound according to claim 1, characterized in that: The conditions of the photocatalytic reaction are: reacting under a 3-100 W LED lamp or xenon lamp light source for 1-10 h.

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