A preparation method of 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole hydrochloride

Abstract

The invention discloses a method for preparing 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole hydrochloride, which comprises the following steps: (1) mixing 4-fluorosalicylaldehyde, an organic base, hydroxylamine and an alcohol, and then refluxing and water-dividing and ring-closing under the action of a catalyst to obtain a compound 2; (2) mixing 2,2,6,6-tetramethylpiperidine and tetrahydrofuran, adding n-butyl lithium at ultra-low temperature to prepare 2,2,6,6-tetramethylpiperidinium lithium, and then adding 2,2,6,6-tetramethylpiperidinium lithium to a mixed solution of compound 2, N-tert-butyloxycarbonyl-4-piperidone and tetrahydrofuran at low temperature, and quenching with acetic anhydride to obtain a compound 4; (3) mixing compound 3 with an alcohol, performing palladium-carbon catalytic hydrogenation, and then removing Boc protection to obtain 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole hydrochloride. The raw materials and reagents used in the method of the present invention are easily available, and the product prepared by the new process has high purity and lower impurity content than that of the traditional synthesis method.

Description

Technical Field

[0001] The invention relates to a preparation method of 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole hydrochloride, belonging to the technical field of organic synthesis. Background Art

[0002] Isoxazole compounds are a class of five-membered nitrogen-oxygen heterocyclic compounds with good biological and pharmaceutical activities. The skeleton of isoxazole compounds is widely present in many natural products and drugs with biological activity. The introduction of fluorine atoms can enhance and modify their original biological activity, making them attract much attention in new drug research and material applications.

[0003] 6-Fluoro-3-piperidin-4-yl-1,2-benzisoxazole hydrochloride is an important intermediate of risperidone, a drug used to treat mental illness, and is also a key intermediate of paliperidone (9-hydroxyrisperidone), a drug used to treat schizophrenia. Paliperidone is the main active metabolite of risperidone; paliperidone has pharmacological characteristics and potency comparable to the parent drug risperidone, but has a longer elimination half-life. Due to its relatively low degree of enzymatic metabolism, paliperidone differs from risperidone and most other antistress agents.

[0004] The synthesis of 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole hydrochloride is mainly based on 4-piperidinic acid as raw material, followed by amino protection with acetic anhydride, chlorination with thionyl chloride, acylation with m-difluorobenzaldehyde, deacylation, condensation with hydroxylamine, and intramolecular cyclization. The total yield is about 33-36%. The advantage of the traditional synthesis process is stability, but it cannot get rid of the use of corrosive equipment and environmentally unfriendly reagents such as thionyl chloride and aluminum chloride. Secondly, a small amount of raw materials will remain during the condensation of hydroxylamine, and purification needs to be done twice or more, and the purification efficiency is low. The reaction equation is as follows:

[0005]

[0006] The present invention overcomes the above disadvantages and provides a preparation method with short steps, simple operation, safety and controllability. In addition, qualified products can be obtained without special purification during the preparation process, and the method has industrialization potential. Summary of the invention

[0007] In order to overcome the above technical defects, the present invention provides a method for preparing 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole hydrochloride. The core steps include: (1) mixing 4-fluorosalicylaldehyde, an organic base, hydroxylamine and an alcohol, and then refluxing and water-dividing ring closure under the action of a catalyst to obtain compound 2; (2) mixing 2,2,6,6-tetramethylpiperidine with tetrahydrofuran, adding n-butyl lithium at ultra-low temperature to prepare 2,2,6,6-tetramethylpiperidinium lithium, and then adding 2,2,6,6-tetramethylpiperidinium lithium to a mixture of compound 2, N-tert-butyloxycarbonyl-4-piperidone and tetrahydrofuran at low temperature, quenching with acetic anhydride, and obtaining compound 4; (3) mixing compound 3 with an alcohol, catalyzing hydrogenation with palladium carbon, and then removing Boc protection to obtain 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole hydrochloride. The raw materials and reagents used in the method of the present invention are easily available, and the product prepared by the new process has high purity and lower impurity content than that of the traditional synthesis method.

[0008] The preparation method of 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole hydrochloride of the present invention comprises the following steps:

[0009] Step A: 4-fluorosalicylaldehyde, an organic base, hydroxylamine and an alcohol are mixed, and then refluxed under the action of a catalyst to separate water and close the ring to obtain compound 2;

[0010] Step B: 2,2,6,6-tetramethylpiperidine is mixed with tetrahydrofuran, and n-butyl lithium is added at ultra-low temperature to prepare 2,2,6,6-tetramethylpiperidinium lithium. Subsequently, 2,2,6,6-tetramethylpiperidinium lithium is added to a mixture of compound 2, N-tert-butyloxycarbonyl-4-piperidone and tetrahydrofuran at low temperature, and quenched with acetic anhydride to obtain compound 4;

[0011] Step C: Compound 3 is mixed with an alcohol, subjected to palladium-carbon catalytic hydrogenation, and then deprotected to obtain 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole hydrochloride.

[0012] The aforementioned process is expressed as follows using a reaction equation:

[0013]

[0014] Furthermore, in the above technical solution, the hydroxylamine in step A is selected from hydroxylamine hydrochloride or hydroxylamine sulfate.

[0015] Furthermore, in the above technical solution, the organic base in step A is selected from sodium methoxide / methanol solution or sodium ethoxide / ethanol solution, and the reaction solvent corresponds to the corresponding alcohol solution.

[0016] Furthermore, in the above technical solution, the catalyst in step A is selected from tri(pentafluorophenyl)borane.

[0017] Furthermore, in the above technical solution, the molar ratio of 4-fluorosalicylaldehyde, hydroxylamine, organic base and catalyst in step A is 1:1.5-1.6:2.0-2.2:0.03-0.05.

[0018] Furthermore, in the above technical scheme, the molar ratio of 6-fluorobenzo[D]isoxazole, N-tert-butyloxycarbonyl-4-piperidone, 2,2,6,6-tetramethylpiperidine and n-butyllithium in step B is 1:1.03-1.08:1.1-1.2:1.15-1.25.

[0019] Furthermore, in the above technical solution, the palladium carbon in step C is selected from 5% or 10% by mass of palladium carbon, and the hydrogenation pressure is 15-25 psi.

[0020] Furthermore, in the above technical solution, the Boc deprotection reagent in step C is selected from acetyl chloride or oxalyl chloride.

[0021] Furthermore, in the above technical scheme, the 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole hydrochloride product in step C has an English name: 6-Fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride, CAS number: 84163-13-3.

[0022] Advantageous Effects of the Invention

[0023] 1. Step A: First, the conversion rate of the condensation aldoxime process is high. The excess alkali and impurities are filtered out by filtering the sodium salt together with sodium chloride. Secondly, a non-traditional Lewis acid catalyst such as tri(pentafluorophenyl)borane is used. The amount is small, and the intramolecular cyclization efficiency is higher through reflux water separation, and the product purity is high.

[0024] 2. In step B, the hydroxyl group is eliminated while quenching with acetic anhydride. There is a competitive relationship between the two, and the product is easier to purify.

[0025] 3. Step C utilizes catalytic hydrogenation to reduce the double bond and uses acetyl chloride or oxalyl chloride to remove Boc protection, which is highly efficient and more convenient to operate, and avoids the use of hydrogen chloride gas to generate impurities that are difficult to remove. Specific embodiments

[0026] The present invention will be further described below by specific examples. These embodiments should be understood to be only used to illustrate the present invention and not to limit the scope of protection of the present invention. After reading the content of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent changes and modifications also fall within the scope defined by the claims of the present invention.

[0027] Preparation method of 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole hydrochloride

[0028] Example 1

[0029]

[0030] Under nitrogen protection, 145.9 g (2.1 mol) of hydroxylamine hydrochloride and 840 mL of methanol were added to a 2000 mL four-necked round-bottom flask, the temperature was lowered by 0-10°C, 450.2 g (2.5 mol) of 30% sodium methoxide / methanol solution was added dropwise, the temperature was raised to room temperature, 140.1 g (1.0 mol) of 4-fluorosalicylaldehyde was added dropwise, the temperature was raised to 40°C for reaction for 3 hours, the temperature was lowered to 0°C for filtration, the filter cake was collected, the filter cake was put back into the bottle, 800 mL of ethyl acetate and 200 mL of water were added, 2.0 M hydrochloric acid was added dropwise to adjust the pH to 4-5, the organic phase was concentrated under reduced pressure until no liquid flowed, 1800 mL of toluene and 20.5 g (0.04 mol) of tris(pentafluorophenyl)borane were added, the temperature was raised to reflux for 5 hours, petroleum ether was added for pulping to obtain 128.6 g of 6-fluorobenzo[D]isoxazole, the yield was 93.8%, and the HPLC was 99.8%. Spectral characterization: 1 HNMR(400MHz, CDCl3):8.13(s,1H),7.59-7.55(m,1H),7.25-7.21(m,1H),7.09-7.04(m,1H).

[0031] Example 2

[0032]

[0033] Under nitrogen protection, 180.6 g (1.1 mol) of hydroxylamine sulfate and 850 mL of ethanol were added to a 2000 mL four-necked round-bottom flask, the temperature was lowered by 0-10°C, 816.6 g (2.4 mol) of 20% sodium ethoxide / ethanol solution was added dropwise, the temperature was raised to room temperature, 140.1 g (1.0 mol) of 4-fluorosalicylaldehyde was added dropwise, the temperature was raised to 40-45°C, the reaction was continued for 3 hours, the temperature was lowered to 0°C, the filter cake was collected, the filter cake was put back into the bottle, and ethanol was added. 800mL of ethyl acetate and 300mL of water were added dropwise with 1.0M hydrochloric acid to adjust the pH to 4-5, and the mixture was allowed to stand for stratification. The organic phase was concentrated under reduced pressure until it was liquid-free, and 1800mL of toluene and 15.4g (0.03mol) of tri(pentafluorophenyl)borane were added. The mixture was heated to reflux for 7 hours to remove water, and concentrated under reduced pressure. Petroleum ether was added to make a pulp for 1 hour, and the mixture was filtered and washed to obtain 127.1g of 6-fluorobenzo[D]isoxazole with a yield of 92.7% and an HPLC index of 99.7%.

[0034] Example 3

[0035]

[0036] Under nitrogen protection, add 31.1 g (0.22 mol) of 2,2,6,6-tetramethylpiperidine and 240 mL of tetrahydrofuran into a 500 mL four-necked round-bottom flask, cool to -60°C, add 96 mL of 2.5 mol / L n-butyllithium solution, and keep warm for 1 hour.

[0037] Add 27.4g (0.2mol) of 6-fluorobenzo[D]isoxazole, 41.8g (0.21mol) of N-tert-butyloxycarbonyl-4-piperidone and 100mL of tetrahydrofuran to a 1000mL four-necked round-bottom flask, control the temperature at -60 to -50°C, add the above-mentioned 2,2,6,6-tetramethylpiperidinium lithium solution, keep warm for 2 hours, slowly raise the temperature to -5 to 0°C, add acetic anhydride, react at room temperature for 1 hour, add 10% potassium bicarbonate aqueous solution to adjust pH to 7-8, stand for stratification, extract the aqueous layer with ethyl acetate, combine the organic phases, wash with water, reduce the pressure and concentrate the organic phase, add petroleum ether to pulp for 1 hour, filter and rinse to obtain 53.2g of tert-butyl 4-(6-fluoro-benzo[d]isoxazole)-3,6-dihydro-2H-pyridine-1-carboxylate, with a yield of 83.6% and HPLC99.1%. Spectral characterization: 1 HNMR(400MHz, CDCl3):7.42-7.38(m,1H),7.16-7.12(m,2H),6.15-6.11(m, 1H),4.84-4.79(m,2H),4.25-4.20(m,2H),2.74-2.69(m,2H),1.42(s,9H).

[0038] Example 4

[0039]

[0040] To a 500mL pressure-resistant round-bottom flask, add 4-(6-fluoro-benzo[d]isoxazole)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 20g (0.0628mol), methanol 200mL and 5% Pd-C1.0g. Evacuate the container and purge it with hydrogen 3 times, maintaining the hydrogen pressure at 22-25psi and reacting at room temperature for 6 hours. Filter the palladium carbon, concentrate the filtrate under reduced pressure, add 200mL of methanol, add 23.9g (0.1884mol) of oxalyl chloride dropwise, and react at room temperature for 3 hours. After the reaction is completed, concentrate under reduced pressure until there is no liquid, add MTBE, and a large amount of solid precipitates at this time. Filter, rinse the filter cake with MTBE, and dry to obtain 14.8g of 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole hydrochloride, with a yield of 91.6%, HPLC99.8%. Spectral characterization: 1HNMR(400MHz,D2O):7.94-7.91(m,1H),7.45-7.42(m,1H),7.22-7.19(m,1H) ,3.56-3.49(m,2H),3.31-3.26(m,2H),2.40-2.36(m,2H),2.20-2.12(m,2H).

[0041] Example 5

[0042]

[0043] To a 500mL pressure-resistant round-bottom flask, add 4-(6-fluoro-benzo[d]isoxazole)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 20g (0.0628mol), ethanol 200mL and 5% Pd-C2.2g. The container was evacuated and purged with hydrogen 3 times. After maintaining the hydrogen pressure at 18-20psi and reacting at room temperature for 10 hours, palladium carbon was filtered, and after the filtrate was concentrated under reduced pressure, ethanol 200mL was added, and acetyl chloride 14.8g (0.1884mol) was added dropwise, and reacted at room temperature for 5 hours. After the reaction was completed, it was concentrated under reduced pressure until there was no liquid, and MTBE was added to replace it. At this time, a large amount of solid precipitated, filtered, the filter cake was rinsed with MTBE, and dried to obtain 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole hydrochloride 14.3g, with a yield of 88.7%, HPLC99.9%.

[0044] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A method for preparing 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole hydrochloride, characterized in that: The steps include: Step A: 4-fluorosalicylaldehyde, an organic base, hydroxylamine and an alcohol are mixed, and then refluxed under the action of a catalyst tri(pentafluorophenyl)borane to separate water and close the ring to obtain compound 2; the molar ratio of the 4-fluorosalicylaldehyde, hydroxylamine, organic base and catalyst is 1:1.5-1.6:2.0-2.2:0.03-0.05; Step B: 2,2,6,6-tetramethylpiperidine is mixed with tetrahydrofuran, and n-butyl lithium is added at -60°C to prepare 2,2,6,6-tetramethylpiperidinium lithium, and then 2,2,6,6-tetramethylpiperidinium lithium is added to a mixture of compound 2, N-tert-butyloxycarbonyl-4-piperidone and tetrahydrofuran at -60 to -50°C, and quenched with acetic anhydride to obtain compound 4; Step C: Compound 4 is mixed with an alcohol, subjected to palladium-carbon catalytic hydrogenation, and then deprotected to obtain 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole hydrochloride.

2. The method for preparing 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole hydrochloride according to claim 1, characterized in that: In step A, the organic base is selected from sodium methoxide / methanol solution or sodium ethoxide / ethanol solution, and the reaction solvent corresponds to the corresponding alcohol solution.

3. The method for preparing 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole hydrochloride according to claim 1, characterized in that: In step B, the molar ratio of the compound 2, N-tert-butyloxycarbonyl-4-piperidone, 2,2,6,6-tetramethylpiperidine and n-butyllithium is 1:1.03-1.08:1.1-1.2:1.15-1.

25.

4. The method for preparing 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole hydrochloride according to claim 1, characterized in that: In step C, the palladium carbon is selected from 5% or 10% palladium carbon by mass, and the hydrogenation pressure is 15-25psi.

5. The method for preparing 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole hydrochloride according to claim 1, characterized in that: In step C, the Boc deprotection reagent is selected from acetyl chloride or oxalyl chloride.

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