Synthesis method of pimozide intermediate

Abstract

The invention discloses a synthesis method of a pimozide intermediate, and relates to the field of organic synthesis methods and electrochemical catalysis. The technical problem that in the prior art, non-activated olefin and aryl halide are efficiently coupled to generate 4, 4-bis (4-fluorobenzene) chlorobutane is solved. The method comprises the following steps: reducing a nickel catalyst through a constant current in an inert gas atmosphere by utilizing an electrochemical catalysis means, carrying out an oxidative addition reaction on the reduced nickel catalyst and aryl halide, then adding the reduced nickel catalyst to non-activated olefin, and carrying out a nickel migration reaction to form the aryl-shifted nickel compound intermediate. According to the method, the synthesis steps are greatly reduced, the reaction efficiency and selectivity are improved, especially when the pimozide intermediate is synthesized, the production cost can be remarkably reduced, the reaction time can be remarkably shortened, and higher industrial application potential is shown. The pimozide intermediate prepared by the invention is used in the field of chronic mental disorder treatment.

Description

Technical Field

[0001] The invention relates to the fields of organic synthesis methods and electrochemical catalysis, and in particular to a synthesis method of a pimozide intermediate. Background Art

[0002] Pimozide, also known as pimozide, is a typical second-generation antipsychotic drug, mainly used to treat schizophrenia, acute bipolar disorder and mental symptoms caused by Parkinson's disease. The drug was first developed and marketed by Novartis in the 1980s. It was initially approved in the European market and subsequently entered other regional markets. Pimozide helps relieve patients' mental symptoms, such as hallucinations and delusions, by regulating the activity of dopamine receptors, especially the antagonism of D2 receptors. Due to its fewer sedative side effects, pimozide is considered more effective in treating patients with chronic mental disorders, especially for refractory schizophrenia and bipolar disorder.

[0003] In the synthesis process of pimozide, the acquisition of key intermediates is one of the core links that determine the efficiency and cost of the synthesis. At present, the synthesis methods of the pimozide intermediate 4,4,-di(4-fluorophenyl)chlorobutane mostly rely on transition metal-catalyzed coupling reactions and halogenated arylation reactions. Although the traditional methods can meet the synthesis needs to a certain extent, there are problems such as poor catalyst selectivity, harsh reaction conditions and many by-products in practical applications. Especially for the diarylation reaction of non-activated olefins, the reaction activity is low, resulting in low yield and poor selectivity, and high temperature or strong acid-base conditions are often required, which not only increases the production cost, but also may bring the risk of environmental pollution. Therefore, it is urgent to develop a more efficient, more selective and mild synthesis method to optimize the synthesis process of pimozide intermediates and meet the requirements of industrial production. Summary of the invention

[0004] The present invention solves the technical difficulties in the prior art of efficiently coupling non-activated olefins with halogenated aromatics to generate 4,4-di(4-fluorophenyl)chlorobutane, especially the complexity problem in the synthesis process of pharmaceutical intermediates such as pimozide intermediates. Traditional pharmaceutical intermediate synthesis methods usually rely on multi-step chemical reactions and expensive catalysts, and the process is cumbersome and the yield is low. In comparison, the present invention provides a method for synthesizing the pimozide intermediate 4,4-di(4-fluorophenyl)chlorobutane based on electrochemical reduction nickel catalysis, which significantly simplifies the synthesis steps of the pharmaceutical intermediate, and is particularly suitable for the synthesis of 1,1-bis-4-fluorophenylated products of pimozide intermediates and other non-activated olefins.

[0005] A method for synthesizing a pimozide intermediate is specifically carried out according to the following steps:

[0006] 1. Place the anode electrode and cathode electrode in the reaction bottle and place them in N 2 4-chloro-1-butene, 4-fluoroiodobenzene, electrolyte, nickel catalyst, ligand and base were added under atmosphere, and then ultra-dry solvent was added, and the system was sealed;

[0007] 2. Pass a constant current through the closed system of step 1 and stir to obtain a crude product;

[0008] 3. The crude product obtained in step 2 is subjected to reduced pressure distillation to remove the solvent, and then separated and purified by thin layer chromatography to obtain a product that is a pimozide intermediate.

[0009] Furthermore, the electrolyte in step 1 is tetrabutylammonium bromide, tetrabutylammonium chloride or tetrabutylammonium tetrafluoroborate.

[0010] Further, the base in step 1 is 2,6-lutidine, K 2 HPO 4 Or Na 2 HPO 4 .

[0011] Furthermore, the ultra-dry solvent in step 1 is ultra-dry N,N-diethylacetamide, ultra-dry N,N-dimethylacetamide, ultra-dry dimethyl sulfoxide or ultra-dry N-methylpyrrolidone.

[0012] Furthermore, the nickel catalyst in step 1 is ethylene glycol dimethyl ether nickel bromide, ethylene glycol dimethyl ether nickel chloride, nickel bromide or nickel chloride.

[0013] Furthermore, the ligand in step 1 is 6,6-dimethyl-2,2-bipyridine.

[0014] Furthermore, in step 1, the dosage ratio of 4-fluoroiodobenzene to the ultra-dry solvent is 0.2mmol:3mL; the dosage ratio of 4-chloro-1-butene to the ultra-dry solvent is 0.3-0.4mmol:3mL; the dosage ratio of the nickel catalyst to the ultra-dry solvent is 0.015mmol:3mL; the dosage ratio of the ligand to the ultra-dry solvent is 0.018mmol:3mL; the dosage ratio of the electrolyte to the ultra-dry solvent is 0.3mmol:3mL; and the dosage ratio of the base to the ultra-dry solvent is 0.1mmol:3mL.

[0015] Furthermore, in step 1, the anode electrode is an iron electrode, and the cathode electrode is a nickel electrode.

[0016] Furthermore, in step 2, the current of the constant current is controlled to be 1-3 mA, the reaction temperature is 30-50° C., and the continuous power-on time is 10 hours.

[0017] Furthermore, the solvent used in the thin layer chromatography separation and purification in step 3 is petroleum ether solvent.

[0018] The present invention utilizes electrochemical catalysis means to reduce a nickel catalyst to low-valent nickel (0) by a constant current under an inert gas atmosphere. The nickel (0) species first undergoes an oxidative addition reaction with a halogenated aromatic hydrocarbon to generate a nickel (II) intermediate. The nickel (II) species is then added to a non-activated olefin, and a nickel migration reaction occurs to form an aromatic-displaced nickel compound intermediate. At the cathode, the nickel (II) species is reduced to a nickel (I) species again, and then undergoes a secondary oxidative addition reaction with another halogenated aromatic hydrocarbon, and finally generates the pimozide intermediate 4,4-di(4-fluorophenyl)chlorobutane through a reduction elimination step. The valence state cycle of the nickel catalyst is maintained by electrochemical conditions, avoiding the use of an external chemical reducing agent, which not only simplifies the reaction steps, but also reduces environmental pollution and operational difficulty.

[0019] Compared with the traditional method, the present invention greatly reduces the number of synthesis steps, improves the efficiency and selectivity of the reaction, and can significantly reduce the production cost and reaction time when synthesizing the intermediate of pimozide, showing stronger potential for industrial application. The universality and efficiency of the method also enable it to be widely used in the modification and synthesis of natural products and drug molecules, with significant green chemistry advantages.

[0020] Reaction formula of the present invention:

[0021]

[0022] The traditional reaction pathway is as follows:

[0023]

[0024] The reaction mechanism of the present invention is shown in FIG. Figure 4 shown.

[0025] Initially, the nickel complex is electrochemically reduced to generate Ni 0 Species (A). This species undergoes oxidative addition with 4-fluoroiodobenzene (1) to form the aryl nickel intermediate (B). Subsequently, 4-chloro-1-butene (2) inserts into the aryl nickel bond to generate intermediate (C). Intermediate (C) then undergoes rapid β-hydrogen elimination and migration insertion steps to generate π-benzyl Ni II Species (D). The π-benzyl intermediate (D) is further reduced at the cathode to generate Ni I Species (E) undergoes oxidative addition with another molecule of 4-fluoroiodobenzene to generate intermediate (F). Finally, intermediate (F) releases the target product through reductive elimination and generates Ni I The catalytic cycle involves the addition of Ni I Species (G) is further reduced back to Ni 0 species (A).

[0026] Beneficial effects of the present invention:

[0027] Compared with the prior art, the present invention synthesizes the pimozide intermediate 4,4-di(4-fluorophenyl)chlorobutane through a simple, green and efficient method, which mainly has the following advantages:

[0028] (1) The electrochemical reaction system of the present invention utilizes electric current to control the reduction process of the catalyst, thus avoiding the use of an external chemical reducing agent, reducing the consumption and emission of harmful chemicals, and conforming to the principles of green chemistry and sustainable development. In addition, the reaction is carried out under mild conditions without the need for high temperature, high pressure or strong acid and alkali conditions, thereby reducing the requirements for equipment and energy consumption.

[0029] (2) The present invention can accurately control the valence state change of the nickel catalyst by means of electrochemical catalysis, avoiding the side reactions and by-products generated in the traditional method, thereby improving the selectivity and yield of the reaction. In particular, in the diarylation reaction of non-activated olefins, it can effectively overcome the problem of low reaction activity and ensure efficient synthesis of the target product.

[0030] (3) Traditional synthesis methods of pimozide intermediates and other drug intermediates usually require multi-step reactions and complex catalyst systems, and the reaction process is cumbersome and the yield is low. In contrast, the present invention can efficiently complete the synthesis of pimozide intermediate 4,4-di(4-fluorophenyl)chlorobutane in a simplified reaction system through electrochemical reduction of nickel catalysis, significantly reducing the steps and reaction time required for the synthesis of pimozide and its intermediates, and greatly improving the synthesis efficiency.

[0031] The pimozide intermediate prepared by the invention is used in the field of treating chronic mental disorders. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 The intermediate 4,4-di(4-fluorophenyl)chlorobutane prepared in Example 1 H NMR spectrum;

[0033] Figure 2 The intermediate 4,4-di(4-fluorophenyl)chlorobutane prepared in Example 13 C NMR spectrum;

[0034] Figure 3 The intermediate 4,4-di(4-fluorophenyl)chlorobutane prepared in Example 19 F NMR spectrum;

[0035] Figure 4 Reaction mechanism diagram of the present invention. DETAILED DESCRIPTION

[0036] Specific embodiment 1: This embodiment is a method for synthesizing a pimozide intermediate, which is specifically carried out according to the following steps:

[0037] 1. Place the anode electrode and cathode electrode in the reaction bottle and place them in N 2 4-chloro-1-butene, 4-fluoroiodobenzene, electrolyte, nickel catalyst, ligand and base were added under atmosphere, and then ultra-dry solvent was added, and the system was sealed;

[0038] 2. Pass a constant current through the closed system of step 1 and stir to obtain a crude product;

[0039] 3. The crude product obtained in step 2 is subjected to reduced pressure distillation to remove the solvent, and then separated and purified by thin layer chromatography to obtain a product that is a pimozide intermediate.

[0040] Specific embodiment 2: This embodiment differs from specific embodiment 1 in that the electrolyte in step 1 is tetrabutylammonium bromide, tetrabutylammonium chloride or tetrabutylammonium tetrafluoroborate. The rest is the same as specific embodiment 1.

[0041] Specific embodiment 3: This embodiment is different from specific embodiment 1 or 2 in that: the base in step 1 is 2,6-lutidine, K 2 HPO 4 Or Na 2 HPO 4 The rest is the same as the first or second embodiment.

[0042] Specific embodiment 4: This embodiment differs from any one of specific embodiments 1 to 3 in that the ultra-dry solvent in step 1 is ultra-dry N,N-diethylacetamide, ultra-dry N,N-dimethylacetamide, ultra-dry dimethyl sulfoxide or ultra-dry N-methylpyrrolidone. The rest is the same as any one of specific embodiments 1 to 3.

[0043] Specific embodiment 5: This embodiment differs from specific embodiments 1 to 4 in that the nickel catalyst in step 1 is ethylene glycol dimethyl ether nickel bromide, ethylene glycol dimethyl ether nickel chloride, nickel bromide or nickel chloride. The rest is the same as specific embodiments 1 to 4.

[0044] Specific embodiment 6: This embodiment is different from specific embodiments 1 to 5 in that the ligand in step 1 is 6,6-dimethyl-2,2-bipyridine. The rest is the same as specific embodiments 1 to 5.

[0045] Specific embodiment 7: This embodiment is different from specific embodiments 1 to 6 in that: in step 1, the dosage ratio of 4-fluoroiodobenzene to the ultra-dry solvent is 0.2mmol:3mL; the dosage ratio of 4-chloro-1-butene to the ultra-dry solvent is 0.3-0.4mmol:3mL; the dosage ratio of the nickel catalyst to the ultra-dry solvent is 0.015mmol:3mL; the dosage ratio of the ligand to the ultra-dry solvent is 0.018mmol:3mL; the dosage ratio of the electrolyte to the ultra-dry solvent is 0.3mmol:3mL; the dosage ratio of the base to the ultra-dry solvent is 0.1mmol:3mL. The rest is the same as specific embodiments 1 to 6.

[0046] Specific implementation eight: This implementation differs from specific implementations one to seven in that the anode electrode in step one is an iron electrode and the cathode electrode is a nickel electrode. The rest is the same as specific implementations one to seven.

[0047] Specific embodiment 9: This embodiment differs from specific embodiments 1 to 8 in that: in step 2, the current of the constant current is controlled to be 1-3 mA, the reaction temperature is 30-50° C., and the continuous power-on time is 10 hours. The rest is the same as specific embodiments 1 to 8.

[0048] Specific embodiment 10: This embodiment differs from specific embodiments 1 to 9 in that the solvent used for separation and purification by thin layer chromatography in step 3 is petroleum ether. The rest is the same as specific embodiments 1 to 9.

[0049] The content of the present invention is not limited to the content of the above-mentioned embodiments. The combination of one or several specific embodiments can also achieve the purpose of the invention.

[0050] Example:

[0051] The present embodiment provides a method for preparing a pimozide intermediate 4,4-di(4-fluorophenyl)chlorobutane, which is specifically carried out according to the following steps:

[0052] 1. In a dry 8 mL reaction vial (equipped with a magnetic stirrer, iron anode and nickel cathode), add 0.2 mmol 4-fluoroiodobenzene, 0.4 mmol 4-chloro-1-butene, 0.3 mmol nBu 4 NBr, 0.015mmol NiBr 2 DME, 0.018mmol 6,6-dimethyl-2,2-bipyridine and 0.1mmol 2,6-lutidine, and 3.0mL ultra-dry DMA as solvent, inert gas protection and seal the system;

[0053] 2. Stir the sealed system in step 1 at room temperature, continuously pass a constant current of 1 mA, and react for 10 hours to obtain a crude product;

[0054] 3. Extract the crude product obtained in step 2, dry it, distill it under reduced pressure to remove the solvent, and then separate and purify it by thin layer chromatography to obtain a product, which is identified as the intermediate of pimozide 4,4,-di(4-fluorobenzene)chlorobutane (4,4'-(4-chlorobutane-1,1-diyl)bis(fluorobenzene)) by nuclear magnetic resonance hydrogen spectrum, carbon spectrum and mass spectrum, and its structural formula is:

[0055]

[0056] Purity 99%, yield 43%; its NMR data analysis is: 1 H NMR (400 MHz, CDCl 3 )δ7.18(dd,J=8.1,5.2Hz,4H),6.98(t,J=8.5Hz,4H),3.90(t,J=7.9Hz,1H),3.54(t,J=6.5Hz,2H),2.16(q,J=7.9Hz,2H),1.73(p,J=6.6Hz,2H).

[0057] 19 F NMR(376MHz,Chloroform-d)δ-116.63(m).

[0058] 13 C NMR (101 MHz, CDCl 3 )δ161.50(J=246.0Hz), 140.10(J=3.3Hz), 129.13(J=7.9Hz), 115.47(J=21.3Hz), 49.20, 44.95, 33.13, 30.94.

Claims

1. A method for synthesizing a pimozide intermediate, characterized in that The method is specifically carried out in the following steps:

1. Place an anode electrode and a cathode electrode in a reaction bottle, add 4-chloro-1-butene, 4-fluoroiodobenzene, electrolyte, nickel catalyst, ligand and base under N2 atmosphere, and then add ultra-dry solvent to seal the system; 2. Pass a constant current through the closed system of step 1 and stir to obtain a crude product; 3. The crude product obtained in step 2 is subjected to reduced pressure distillation to remove the solvent, and then separated and purified by thin layer chromatography to obtain a product that is a pimozide intermediate.

2. A method for synthesizing a pimozide intermediate according to claim 1, characterized in that In step 1, the electrolyte is tetrabutylammonium bromide, tetrabutylammonium chloride or tetrabutylammonium tetrafluoroborate.

3. A method for synthesizing a pimozide intermediate according to claim 1, characterized in that In step 1, the base is 2,6-lutidine, K2HPO4 or Na2HPO4.

4. A method for synthesizing a pimozide intermediate according to claim 1, characterized in that The ultra-dry solvent in step 1 is ultra-dry N,N-diethylacetamide, ultra-dry N,N-dimethylacetamide, ultra-dry dimethyl sulfoxide or ultra-dry N-methylpyrrolidone.

5. A method for synthesizing a pimozide intermediate according to claim 1, characterized in that The nickel catalyst in step 1 is ethylene glycol dimethyl ether nickel bromide, ethylene glycol dimethyl ether nickel chloride, nickel bromide or nickel chloride.

6. A method for synthesizing a pimozide intermediate according to claim 1, characterized in that The ligand in step 1 is 6,6-dimethyl-2,2-bipyridine.

7. A method for synthesizing a pimozide intermediate according to claim 1, characterized in that In step 1, the dosage ratio of 4-fluoroiodobenzene to the ultra-dry solvent is 0.2mmol:3mL; the dosage ratio of 4-chloro-1-butene to the ultra-dry solvent is 0.3-0.4mmol:3mL; the dosage ratio of the nickel catalyst to the ultra-dry solvent is 0.015mmol:3mL; the dosage ratio of the ligand to the ultra-dry solvent is 0.018mmol:3mL; the dosage ratio of the electrolyte to the ultra-dry solvent is 0.3mmol:3mL; and the dosage ratio of the base to the ultra-dry solvent is 0.1mmol:3mL.

8. A method for synthesizing a pimozide intermediate according to claim 1, characterized in that In step 1, the anode electrode is an iron electrode, and the cathode electrode is a nickel electrode.

9. A method for synthesizing a pimozide intermediate according to claim 1, characterized in that Step 2: Control the constant current to be 1-3 mA, the reaction temperature to be 30-50° C., and the continuous power-on time to be 10 hours.

10. A method for synthesizing a pimozide intermediate according to claim 1, characterized in that The solvent used for the thin layer chromatography separation and purification in step 3 is petroleum ether.

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