A synthetic method for a pimozide intermediate

Abstract

A method for synthesizing a pimozide intermediate, the present invention relates to the field of organic synthesis and electrochemical catalysis. The present invention solves the technical problem of efficiently coupling non-activated olefins with halogenated aromatics to generate 4,4,-bis(4-fluorobenzene)chlorobutane in the prior art. The present invention utilizes electrochemical catalysis means, and under an inert gas atmosphere, a nickel catalyst is reduced by a constant current, an oxidative addition reaction occurs with the halogenated aromatics, and then added to the non-activated olefin, a nickel migration reaction occurs, and an aromatic-displaced nickel compound intermediate is formed. The present invention greatly reduces the synthesis steps, improves the efficiency and selectivity of the reaction, and especially when synthesizing the pimozide intermediate, can significantly reduce production costs and reaction time, showing stronger industrial application potential. The pimozide intermediate prepared by the present invention is used to treat the field of chronic mental disorders.

Description

Technical Field

[0001] The present 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 of Switzerland 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 of pimozide, obtaining key intermediates is one of the core links that determines the efficiency and cost of the synthesis. Currently, 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 traditional methods can meet the synthesis requirements to a certain extent, they have problems in practical applications such as poor catalyst selectivity, harsh reaction conditions, and many by-products. In particular, for the diarylation reaction of non-activated alkenes, the reaction activity is low, resulting in low yield and poor selectivity, and often requires high temperature or strong acid and base conditions, which not only increases production costs but also may bring the risk of environmental pollution. Therefore, it is urgent to develop a more efficient, more selective, and milder 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 produce 4,4-bis(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 synthesis method of the pimozide intermediate 4,4-bis(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 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, then add ultra-dry solvent and seal the system;

[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] Furthermore, the base in step 1 is 2,6-lutidine, K2HPO4 or Na2HPO4.

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

[0018] The present invention utilizes electrochemical catalysis to reduce a nickel catalyst to a 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 then adds to a non-activated olefin, undergoing a nickel migration reaction to form an aromatic-displaced nickel compound intermediate. At the cathode, the nickel (II) species is reduced again to a nickel (I) species, which then undergoes a secondary oxidative addition reaction with another halogenated aromatic hydrocarbon, ultimately generating the pimozide intermediate 4,4-di(4-fluorophenyl)chlorobutane through a reduction elimination step. By maintaining the valence cycle of the nickel catalyst under electrochemical conditions, the use of an external chemical reducing agent is avoided, which not only simplifies the reaction steps but also reduces environmental pollution and operational difficulty.

[0019] Compared with traditional methods, this method significantly reduces the number of synthetic steps and improves reaction efficiency and selectivity. This method, particularly for the synthesis of pimozide intermediates, significantly reduces production costs and reaction time, demonstrating greater potential for industrial application. The method's universality and efficiency also lend themselves to widespread application in the modification and synthesis of natural products and drug molecules, offering 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 an aryl nickel intermediate (B). Subsequently, 4-chloro-1-butene (2) inserts into the aryl nickel bond to produce intermediate (C). Intermediate (C) then undergoes rapid β-hydrogen elimination and migratory insertion steps to produce 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 Species (G). The catalytic cycle is carried out by Ni I Species (G) is further reduced back to Ni 0 Species (A) is completed.

[0026] Beneficial effects of the present invention:

[0027] Compared with the prior art, the present invention synthesizes the pimozide intermediate 4,4-bis(4-fluorophenyl)chlorobutane through a simple, green and efficient method, which 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, avoiding the use of external chemical reducing agents, reducing the consumption and emission of harmful chemicals, and conforming to the principles of green chemistry and sustainable development. Furthermore, the reaction proceeds under mild conditions, without the need for high temperature, high pressure, or strong acid or alkaline conditions, thereby reducing equipment and energy requirements.

[0029] (2) The present invention precisely controls the valence state of the nickel catalyst through electrochemical catalysis, avoiding the side reactions and byproduct formation seen in conventional methods, thereby improving the selectivity and yield of the reaction. In particular, in the diarylation of non-activated olefins, the present invention effectively overcomes the problem of low reactivity and ensures efficient synthesis of the target product.

[0030] (3) Traditional synthesis methods for pimozide intermediates and other drug intermediates typically require multi-step reactions and complex catalyst systems, resulting in cumbersome reaction processes and low yields. In contrast, the present invention utilizes electrochemical nickel reduction catalysis to efficiently complete the synthesis of the pimozide intermediate 4,4-bis(4-fluorophenyl)chlorobutane in a simplified reaction system, significantly reducing the steps and reaction time required for the synthesis of pimozide and its intermediates, and greatly improving 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-bis(4-fluorobenzene)chlorobutane prepared in Example 1 H NMR spectrum;

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

[0034] Figure 3 The intermediate 4,4-bis(4-fluorobenzene)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 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, then add ultra-dry solvent and seal the system;

[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. Other aspects are the same as specific embodiment 1.

[0041] Specific embodiment 3: This embodiment differs from specific embodiment 1 or 2 in that the base in step 1 is 2,6-lutidine, K2HPO4 or Na2HPO4. Other aspects are the same as specific embodiment 1 or 2.

[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. Otherwise, this embodiment 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. Other aspects are the same as specific embodiments 1 to 4.

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

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

[0046] Specific embodiment 8: This embodiment differs from specific embodiments 1 to 7 in that the anode electrode in step 1 is an iron electrode and the cathode electrode is a nickel electrode. Other aspects are the same as specific embodiments 1 to 7.

[0047] Specific embodiment 9: This embodiment differs from specific embodiments 1 to 8 in that the current in step 2 is controlled to be 1-3 mA, the reaction temperature is 30-50° C., and the continuous power-on time is 10 hours. Other aspects are 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. Other aspects are 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 more specific embodiments can also achieve the purpose of the invention.

[0050] Example:

[0051] This embodiment provides a method for preparing a pimozide intermediate 4,4-bis(4-fluorophenyl)chlorobutane, which is specifically carried out by 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 nBu4NBr, 0.015 mmol NiBr2·DME, 0.018 mmol 6,6-dimethyl-2,2-bipyridine, and 0.1 mmol 2,6-lutidine. Add 3.0 mL ultra-dry DMA as solvent, protect with inert gas, 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. The crude product obtained in step 2 was extracted, dried, and the solvent was removed by distillation under reduced pressure. The product was separated and purified by thin layer chromatography to obtain a product, which was identified as the pimozide intermediate 4,4,-di(4-fluorophenyl)chlorobutane (4,4'-(4-chlorobutane-1,1-diyl)bis(fluorobenzene)) by nuclear magnetic resonance spectroscopy, carbon spectrum, and mass spectrometry. Its structural formula is:

[0055]

[0056] The purity is 99% and the yield is 43%. The NMR data analysis is as follows: 1 H NMR (400MHz, CDCl3) 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 (101MHz, CDCl3) 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, then add ultra-dry solvent and 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. The resulting product is a pimozide intermediate, and the structural formula of the pimozide intermediate is: ; 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 ligand in step 1 is 6,6-dimethyl-2,2-bipyridine; Step 2: Control the constant current to 1-3 mA.

2. A synthetic method for 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 synthetic method for a pimozide intermediate according to claim 1, characterized in that The base in step 1 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, super dry N , N - dimethylacetamide, super dry dimethyl sulfoxide or super dry N -Methylpyrrolidone.

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

6. 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.

7. A method for synthesizing a pimozide intermediate according to claim 1, characterized in that In step 2, the reaction temperature was controlled at 30-50°C and the continuous power-on time was 10 hours.

8. 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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