Method for synthesizing blonanserin by taking ammonium iodide as nitrogen source

Abstract

The invention develops two efficient conversion methods for synthesizing the anti-schizophrenia drug blonanserin. The method I comprises the following steps: carrying out [2 + 1 + 2 + 1] cascade cyclization reaction on commercially available cyclooctanone, 4-fluorobenzaldehyde, Meldrum's acid and ammonium acetate as starting raw materials, chlorinating, and reacting with N-ethylpiperazine to obtain the blonanserin compound. And the method II comprises the following steps: carrying out cascade cyclization on commercially available cyclooctanone, 1-(4-fluorophenyl) prop-2-ene-1-ketone and NH4I in the form of three components [2 + 1 + 3], then oxidizing by m-CPBA to obtain nitrogen oxide, and finally reacting with N-ethylpiperazine to obtain the blonanserin compound. The two methods respectively obtain the functional group tolerant blonanserin compound with high yield. The two interesting methods have the characteristics of simple operation, easily available starting materials, mild reaction conditions, good functional group tolerance, high atom economy and the like. In addition, compared with a traditional method (at least five steps are needed), the strategy can provide two good synthesis routes for the anti-schizophrenia drug blonanserin with a highly functionalized structure.

Description

[Technical field]

[0001] The invention belongs to the field of catalytic organic synthesis and relates to a method for synthesizing blonanserin by using ammonium iodide as a nitrogen source. [Background technology]

[0002] Schizophrenia is a persistent mental disorder characterized by abnormalities in perception, emotion, and behavior. Confused thinking and emotional reactions are typical symptoms. Schizophrenia often develops in youth and middle age, and the prevalence of men and women is similar, but men generally develop the disease earlier. The treatment of schizophrenia is mainly through the use of antipsychotic drugs. Blonanserin is an atypical antipsychotic drug, a potent dopamine D2 (Ki: 14.8nM) and serotonin 5-HT2 (Ki: 3.98nM) receptor antagonist, and is mainly used in the treatment of schizophrenia in clinical practice. In April 2017, the drug obtained the import drug registration license from the State Food and Drug Administration (CFDA), which will bring new hope to patients with schizophrenia.

[0003] Although blonanserin has attracted much attention in medicinal chemistry due to its unique pharmaceutical properties, its synthesis method usually has problems such as cumbersome steps, troublesome post-treatment and low yield. The main case at present is to use methyl 4-fluorobenzoate as the starting material, NaH as the base, MePh as the solvent and acetonitrile to condense to obtain 4-fluorobenzoylacetonitrile. Hydrolysis in polyphthalamide to synthesize 3-(4-fluorophenyl)-3-oxopropionamide, followed by cyclization with cyclooctanone using TsOH as an additive to obtain 4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctanopyridin-2(1H)-one. Then, phenylphosphonyl dichloride is used for chlorination reaction, and finally, blonanserin is reacted with N-ethylpiperazine under the action of 1 equivalent of potassium iodide (Hardy M L.Chenosphere, 2002, 46:757-777). Despite this remarkable achievement, it takes at least five steps to finally obtain blonanserin and the process introduces many by-products. Therefore, commercially available, inexpensive aldehydes and ketones can be directly used as starting materials, thus avoiding the problems of expensive raw materials, many by-products, low functional group compatibility and multi-step synthesis. Therefore, we have developed a new method for constructing blonanserin under base promotion. The commercially available cyclooctanone is used with 4-fluorobenzaldehyde, Michler's acid and ammonium acetate as four-component starting materials to form a [2+1+2+1] cascade cyclization reaction method to obtain 4-(4-fluorophenyl)-3,4,5,6,7,8,9,10-octahydrocyclooctanone [b] pyridin-2(1H)-one, which is then chlorinated with phosphorus oxychloride and finally reacted with N-ethylpiperazine under the action of 1 equivalent of potassium iodide to obtain blonanserin compounds. This method is simple and easy to operate, has good substrate adaptability, high yield, and the starting materials can be directly purchased commercially. At present, there are no public documents or patent applications reporting the multi-component formation of [2+1+2+1] tandem cyclization to obtain blonanserin at home and abroad. [Summary of the invention]

[0004] The present invention develops an efficient conversion method for synthesizing an anti-schizophrenia drug, blonanserin. The method uses commercially available cyclooctanone and four-component starting materials, namely, 4-fluorobenzaldehyde, Michler's acid and ammonium acetate, to form a [2+1+2+1] cascade cyclization reaction, followed by chlorination and then reaction with N-ethylpiperazine to obtain a blonanserin compound. This method obtains a functional group-tolerant blonanserin compound in high yield. This interesting method has the characteristics of simple operation, easy availability of starting materials, mild reaction conditions, good functional group tolerance and high atom economy. In addition, compared with the traditional method (requiring at least 5 steps), this strategy can provide a good synthetic route for the highly functionalized anti-schizophrenia drug blonanserin.

[0005] To achieve the above object, the technical solution of the present invention is as follows:

[0006] A novel method for obtaining a blonanserin compound is provided by using commercially available cyclooctanone and four-component starting materials of 4-fluorobenzaldehyde, Michler's acid and ammonium acetate to form a [2+1+2+1] cascade cyclization, followed by chlorination, and then reacting with N-ethylpiperazine. The method comprises the following steps: in a nitrogen atmosphere, using CrCl3 as a catalyst, ammonium acetate as a nitrogen source, triethylamine as a base, and methanol as a solvent, stirring cyclooctanone, 4-F benzaldehyde and Michler's acid at 30°C-100°C for 2-48 hours to obtain a dihydropyridone compound, then treating it with phosphorus oxychloride, and finally reacting it with N-ethylpiperazine under the action of 1 equivalent of potassium iodide to obtain a blonanserin compound.

[0007] A further improvement is that the product containing the dihydropyridone compound is diluted with ethyl acetate, water is added, and then extracted three times with ethyl acetate, the organic phases are collected and combined, and then anhydrous Na2SO4 is added to dehydrate the combined organic phases, and then concentrated under reduced pressure to obtain a crude product. The crude product is separated by column chromatography on silica gel to obtain a purified dihydropyridone compound.

[0008] Further improvement, after the reaction is completed, POCl3 is removed from the reaction mixture under vacuum. Ice water is added to the residue. The resulting solution is alkalized with NaOH (1N) aqueous solution and then extracted with ethyl acetate (2x 50mL). The organic layer is dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by silica gel column chromatography using PE / EtOAc as eluent to obtain 2-chloropyridine compounds.

[0009] In a further improvement, after the reaction is completed, ice water is added to the residue. Then, it is extracted with ethyl acetate (2 x 50 mL). The organic layer is dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by silica gel column chromatography using MeOH / DCM as eluent to obtain the final product, blonanserin compound.

[0010] As a further improvement, the molar ratio of NH4OAc, CrCl3, cyclooctanone, 4-fluorobenzaldehyde, triethylamine and Michaelis acid is 0.75:0.09:0.30:0.42:0.9:0.75.

[0011] In a further improvement, the chemical formula of the dihydropyridone compound is as follows:

[0012]

[0013] In a further improvement, the chemical formula of the 2-chloropyridine compound is as follows:

[0014]

[0015] In a further improvement, the chemical formula of blonanserin is as follows:

[0016]

[0017] The advantages of the present invention are as follows:

[0018] The present invention discloses a method for obtaining bunanserin by a multi-component [2+1+2+1] cascade cyclization. This method uses cheap and readily available cyclooctanone as the initial raw material. Compared with the traditional method that can obtain bunanserin in 5 steps, this method is a new method that obtains bunanserin in only 3 steps. This method uses CrCl3 as a low-cost catalyst and avoids the use of complex and sensitive organic metal reagents. At the same time, this [2+1+2+1] multi-component reaction mode has the characteristics of low additive price, mild reaction conditions, and readily available starting materials. A multi-component cascade cyclization protocol is achieved under mild conditions using commercially available starting materials, and a new method for synthesizing bunanserin with high regioselectivity is constructed.

Brief Description of the Drawings

[0019] Figure 1 It is the reaction formula of the present invention.

[0020] Figure 2 It is the chemical formula of dihydropyridone compound.

[0021] Figure 3 It is the chemical formula of 2-chloropyridine compounds.

[0022] Figure 4 is the chemical formula of blonanserin. [Specific implementation method]

[0023] Reaction formula of the present invention is as follows:

[0024]

[0025] Embodiment 1:

[0026] NH4OAc (2.5 equivalents), CrCl3 (0.03 equivalents) and Michaelis acid (2.5 equivalents) were added to a 50 mL Schlenk tube equipped with magnetic stirring. Nitrogen was filled after vacuuming with a pump, three times. Then, cyclooctanone (10 mmol), 4-fluorobenzaldehyde (14 mmol, 1.4 equivalents), triethylamine (30 mmol, 3 equivalents) and 15 mL methanol solution (MeOH) were added under N2 atmosphere. The mixture was stirred at 50 ℃ for 24 hours (thermostatic oil bath). After the reaction was completed, it was cooled to room temperature, and after the mixture was diluted with ethyl acetate, an appropriate amount of water was added, and then extracted with ethyl acetate three times, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain purified dihydropyridone [4-(4-fluorophenyl)-3,4,5,6,7,8,9,10-octahydrocycloocta[b]pyridin-2(1H)-one].

[0027] The above dihydropyridone was then added to a 50.0 mL reaction tube equipped with a magnetic stirring bar, and then 15.0 mL POCl3 was injected at 0°C. The reaction solution was heated to 90°C and stirred in an oil bath for 6 hours. After the reaction was completed, POCl3 was removed from the reaction mixture under vacuum. Ice water (50 mL) was added to the residue. The resulting solution was alkalized with aqueous NaOH (1N) solution and then extracted with ethyl acetate (2x 50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EtOAc as eluent to obtain a 2-chloropyridine compound [2-chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctane [b] pyridine].

[0028] Then, 1.0 equivalent of potassium iodide and 1.0 equivalent of 2-chloropyridine compound were added to ethylpiperazine as solvent. The reaction solution was heated to 160°C and stirred in an oil bath for 12 hours. After the reaction was completed, water (50 mL) was added to the residue. Then it was extracted with ethyl acetate (2 x 50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using MeOH / DCM (volume ratio of 1 / 15) as eluent to obtain the final product, blonanserin, as a white solid. Total yield: 1.95 g, 53%. Rf = 0.5 (DCM: MeOH = 20: 1). 1H NMR (400MHz, CDCl3) δ7.18–7.11(m,2H),7.01(t,J=8.5Hz,2H),6.23(s,1H),3.47(t,J=5.1Hz,4H),2.82(t,J=6.2Hz,2 H), 2.50 (t, J = 5.2Hz, 6H), 2.40 (q, J = 7.2Hz, 2H), 1.72 (p, J = 5.8Hz, 2H), 1.33 (d, J = 27.1Hz, 6H), 1.06 (t, J = 7.2Hz, 3H). 13 C NMR (101MHz, CDCl3) δ162.2 (d, J = 245.9Hz), 160.0, 157.4, 150.5, 137.5 (d, J = 3.4Hz), 130.2 (d, J = 8.0Hz), 1 23.0,115.0(d,J=21.3Hz),106.1,52.9,52.6,45.6,35.7,31.6,30.7,29.8,26.6(d,J=13.2Hz),25.9,12.1. 19 FNMR (377MHz, CDCl3) δ-115.36.

[0029] The above-mentioned embodiments only express several implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A novel method for obtaining a blonanserin compound by using commercially available cyclooctanone and four-component starting materials of 4-fluorobenzaldehyde, Michler's acid and ammonium acetate to form a [2+1+2+1] cascade cyclization, followed by chlorination and then reaction with N-ethylpiperazine. The method comprises the following steps: 3 As a catalyst, ammonium acetate as a N source, triethylamine as a base, methanol as a solvent, cyclooctanone, 4-F benzaldehyde and Michaelis acid are stirred at 30°C-100°C for 2-48 hours to obtain a dihydropyridone compound, which is then treated with phosphorus oxychloride and finally reacted with N-ethylpiperazine under the action of 1 equivalent of potassium iodide to obtain a blonanserin compound.

2. Further improvement: the product containing the dihydropyridone compound was diluted with ethyl acetate, water was added, and then extracted with ethyl acetate three times, the organic phases were collected and combined, and then anhydrous Na 2 SO 4 The combined organic phases are dehydrated and concentrated under reduced pressure to obtain a crude product, which is separated by column chromatography on silica gel to obtain a purified dihydropyridone compound.

3. A further improvement is to remove POCl from the reaction mixture under vacuum after the reaction is completed. 3 Ice water was added to the residue, and the resulting solution was alkalified with aqueous NaOH (1N) and then extracted with ethyl acetate (2 x 50 mL). The organic layer was purified by Na 2 SO 4 The residue was purified by silica gel column chromatography using PE / EtOAc as eluent to obtain 2-chloropyridine compounds.

4. Further improvement: After the reaction was completed, ice water was added to the residue, and then extracted with ethyl acetate (2 x 50 mL). The organic layer was purified by Na 2 SO 4 The residue was purified by silica gel column chromatography using MeOH / DCM as eluent to obtain the final product, blonanserin compound.

5. Further improvements, NH 4 OAc、CrCl 3 The molar ratio of cyclooctanone, 4-fluorobenzaldehyde, triethylamine and Michaelis acid is 0.75:0.09:0.30:0.42:0.9:0.

75.

6. A further improvement, the chemical formula of the dihydropyridone compound is as follows:

7. Further improvement, the chemical formula of the 2-chloropyridine compound is as follows:

8. A further improvement, the chemical formula of the blonanserin is as follows:

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