Process for the synthesis of brunamorelin using ammonium acetate as a nitrogen source

Abstract

This invention develops two efficient conversion methods for synthesizing the antipsychotic drug bromelain. Method 1: A [2+1+2+1] cascade cyclization reaction is formed using commercially available cyclooctanone with 4-fluorobenzaldehyde, Mischel acid, and ammonium acetate as starting materials. Following chlorination, the mixture reacts with N-ethylpiperazine to obtain the bromelain compound. Method 2: A three-component [2+1+3] cascade cyclization reaction is formed using commercially available cyclooctanone with 1-(4-fluorophenyl)prop-2-en-1-one and NH4I. This is followed by oxidation with m-CPBA to obtain nitrogen oxides, which are then reacted with N-ethylpiperazine to obtain the bromelain compound. Both methods yield functionalized, tolerable bromelain compounds in high yield. These two interesting methods are characterized by simple operation, readily available starting materials, mild reaction conditions, good functionalized tolerance, and high atom economy. Furthermore, compared to traditional methods (which require at least 5 steps), this strategy can provide two excellent synthetic routes for the structurally highly functionalized antipsychotic drug brnanserin.

Description

[Technical Field]

[0001] This invention belongs to the field of catalytic organic synthesis and relates to a method for synthesizing Bunansserin using ammonium iodide as a nitrogen source. [Background Technology]

[0002] Schizophrenia is a persistent mental disorder characterized primarily by abnormalities in perception, emotion, and behavior; confused thinking and emotional responses are its typical symptoms. Schizophrenia typically develops in adolescence and middle age, with similar prevalence in men and women, although men generally experience onset earlier. Treatment for schizophrenia primarily involves the use of antipsychotic medications. Blonanserin is an atypical antipsychotic drug, a potent dopamine D2 (Ki: 14.8 nM) and serotonin 5-HT2 (Ki: 3.98 nM) receptor antagonist, mainly used clinically to treat schizophrenia. In April 2017, this drug received import drug registration approval from the China Food and Drug Administration (CFDA), which will bring new hope to patients with schizophrenia.

[0003] Although bunamserin has attracted much attention in medicinal chemistry due to its unique pharmacological properties, its synthesis methods are often plagued by cumbersome steps, complicated post-processing, and low yield. Currently, the main approach involves condensing methyl 4-fluorobenzoate with acetonitrile using NaH as a base and MePh as a solvent to obtain 4-fluorobenzoylacetonitrile. This is followed by hydrolysis in polyphthalamide to synthesize 3-(4-fluorophenyl)-3-oxopropionamide, which is then cyclized with cyclooctanone using TsOH as an additive to yield 4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctanopyridin-2(1H)-one. Chlorination is then carried out using phenylphosphonic dichloride, and finally, bunamserin is obtained by reacting with N-ethylpiperazine in the presence of one equivalent of potassium iodide (Hardy M L. Chenosphere, 2002, 46: 757-777). Despite this remarkable achievement, the process requires at least five steps to obtain bromelain, introducing numerous byproducts. Therefore, commercially available and inexpensive aldehydes and ketones can be used directly as starting materials, avoiding the problems of expensive starting materials, numerous byproducts, low functional group compatibility, and multi-step synthesis. Thus, we developed a new base-promoted method for constructing bromelain. This method utilizes a [2+1+2+1] cascade cyclization reaction of commercially available cyclooctanone with 4-fluorobenzaldehyde, Michaelis-Menten acid, and ammonium acetate to obtain 4-(4-fluorophenyl)-3,4,5,6,7,8,9,10-octahydrocyclooctan[b]pyridin-2(1H)-one, followed by chlorination with phosphorus oxychloride, and finally reaction with N-ethylpiperazine in the presence of one equivalent of potassium iodide to yield the bromelain compound. This method is simple to operate, has good substrate adaptability, high yield, and the starting materials are commercially available. Currently, there are no published documents or patent applications reporting on the formation of [2+1+2+1] tandem cyclization of multiple components to obtain Bunansserin, either domestically or internationally. [Summary of the Invention]

[0004] This invention develops an efficient conversion method for synthesizing the antipsychotic drug budesonide. The method utilizes a commercially available cyclooctanone with four starting materials—4-fluorobenzaldehyde, Miescherichia coli 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 the budesonide compound. This method yields functionalized budesonide compounds in high yield. This interesting method is characterized by its simplicity, readily available starting materials, mild reaction conditions, good functionalized tolerance, and high atom economy. Furthermore, compared to traditional methods (requiring at least five steps), this strategy provides a superior synthetic route for the highly functionalized antipsychotic drug budesonide.

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

[0006] A novel method for obtaining Bunanserin compounds involves the following steps: A [2+1+2+1] cascade cyclization of commercially available cyclooctanone with 4-fluorobenzaldehyde, Miescherichic acid, and ammonium acetate as starting materials, followed by chlorination and then reaction with N-ethylpiperazine. The method includes the following steps: Under a nitrogen atmosphere, using CrCl3 as a catalyst, ammonium acetate as the nitrogen source, triethylamine as the base, and methanol as the solvent, cyclooctanone, 4-F-benzaldehyde, and Miescherichic acid are stirred at 30°C-100°C for 2-48 hours to obtain a dihydropyridinone compound. This compound is then treated with phosphorus oxychloride, and finally reacted with N-ethylpiperazine in the presence of 1 equivalent of potassium iodide to obtain Bunanserin.

[0007] Further improvements involved diluting the product containing the dihydropyridone compound with ethyl acetate, adding water, and extracting it three times with ethyl acetate. The organic phases were collected and combined, and then anhydrous Na2SO4 was added to dehydrate the combined organic phases. The mixture was then concentrated under reduced pressure to obtain a crude product. The crude product was then separated by column chromatography on silica gel to obtain the purified dihydropyridone compound.

[0008] In a further improvement, after the reaction was complete, POCl3 was removed from the reaction mixture under vacuum. Ice water was added to the residue. The resulting solution was alkalized with an aqueous solution of NaOH (1N) and then 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 PE / EtOAc as the eluent to give 2-chloropyridine compounds.

[0009] In a further improvement, ice water was added to the residue after the reaction was complete. The residue was then 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 as eluent to give the final product, Brønsserin compound.

[0010] Further improvements were made, with the molar ratio of NH4OAc, CrCl3, cyclooctanone, 4-fluorobenzaldehyde, triethylamine, and Miescherichia coli being 0.75:0.09:0.30:0.42:0.9:0.75.

[0011] A further improvement is made to the chemical formula of the dihydropyridone compound as follows:

[0012]

[0013] A further improvement is made to the chemical formula of the 2-chloropyridine compound as follows:

[0014]

[0015] A further improvement is made to the chemical formula of the stated Bunansserin, as follows:

[0016]

[0017] The advantages of this invention are as follows:

[0018] This invention discloses a multi-component method for obtaining bromelain through a [2+1+2+1] cascade cyclization. This method uses readily available and inexpensive cyclooctanone as the starting material, and compared to the traditional method requiring five steps to obtain bromelain, this new method achieves the result in only three steps. This method uses CrCl3 as a low-cost catalyst, avoiding the use of complex and sensitive organometallic reagents. Furthermore, this [2+1+2+1] multi-component reaction mechanism features inexpensive additives, mild reaction conditions, and readily available starting materials. It realizes a multi-component cascade cyclization protocol using commercially available starting materials under mild conditions, constructing a new method for the synthesis of bromelain with high regioselectivity. [Attached Image Description]

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

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

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

[0022] Figure 4 This is the chemical formula for Bunansserin.

Detailed Implementation Methods

[0023] The reaction formula of this invention is as follows:

[0024]

[0025] Example 1:

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

[0027] The dihydropyridone was then added to a 50.0 mL reaction tube equipped with a magnetic stir bar, followed by the injection of 15.0 mL of POCl3 at 0 °C. The reaction solution was heated to 90 °C and stirred in an oil bath for 6 hours. After the reaction was complete, POCl3 was removed from the reaction mixture under vacuum. Ice water (50 mL) was added to the residue. The resulting solution was alkalized with an aqueous solution of NaOH (1N) and then 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 PE / EtOAc as eluent to give the 2-chloropyridine compound [2-chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctano[b]pyridine].

[0028] Then, using ethylpiperazine as a solvent, 1.0 equivalent of potassium iodide and 1.0 equivalent of 2-chloropyridine compound were added. The reaction solution was heated to 160°C and stirred in an oil bath for 12 hours. After the reaction was complete, water (50 mL) was added to the residue. The residue was then 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 (v / v) as eluent to give the final product, bromelain, as a white solid. Overall 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 embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

Claims

1. A method for obtaining bunamserin compound by forming a [2+1+2+1] cascade cyclization of cyclooctanone with 4-fluorobenzaldehyde, Miescherichia coli acid, and ammonium acetate as starting materials, followed by chlorination and then reaction with N-ethylpiperazine, characterized in that... The process includes the following steps: Under a nitrogen atmosphere, using CrCl3 as a catalyst, ammonium acetate as a nitrogen source, triethylamine as a base, and methanol as a solvent, cyclooctanone, 4-F benzaldehyde, and Michaelis-Menten acid are stirred at 30℃-100℃ for 2-48 hours to obtain a product containing dihydropyridinone compounds. Subsequently, the product is treated with phosphorus oxychloride to obtain a product containing 2-chloropyridine compounds. Finally, the product is reacted with N-ethylpiperazine in the presence of 1 equivalent of potassium iodide to obtain a product containing Bunanserin compounds. The chemical formula of the dihydropyridone compound is as follows: The chemical formulas of the 2-chloropyridine compounds are as follows: The chemical formula of the Brønsserin is as follows:

2. The method as described in claim 1, characterized in that, The purification method of the dihydropyridone compound is as follows: the product containing the dihydropyridone compound is diluted with ethyl acetate, water is added, and the product is extracted three times with ethyl acetate. The organic phases are collected and combined, and then anhydrous Na2SO4 is added to dehydrate the combined organic phase. The product is then concentrated under reduced pressure to obtain a crude product. The crude product is separated by column chromatography on silica gel to obtain the purified dihydropyridone compound.

3. The method as described in claim 1, characterized in that, The purification method of the 2-chloropyridine compounds is as follows: 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 aqueous solution, then extracted with ethyl acetate, the organic layer is dried with Na2SO4, concentrated under reduced pressure, and the residue is purified by silica gel column chromatography with PE / EtOAc as eluent to obtain 2-chloropyridine compounds.

4. The method as described in claim 1, characterized in that, The purification method of the Bunanserin compound is as follows: After the reaction is completed, ice water is added to the residue, and then it is extracted with ethyl acetate. The organic layer is dried with Na2SO4 and concentrated under reduced pressure. The residue is purified by silica gel column chromatography with MeOH / DCM as the eluent to obtain the final product Bunanserin compound.

5. The method as described in claim 1, characterized in that, The molar ratio of NH4OAc, CrCl3, cyclooctanone, 4-fluorobenzaldehyde, triethylamine and Miescherichia coli is 0.75:0.09:0.30:0.42:0.9:0.75.

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