Preparation method of 3, 5-difluoropiperidine and derivatives thereof

Abstract

The invention relates to a preparation method of 3, 5-difluoropiperidine and derivatives thereof, which comprises the following steps: in an organic solvent, under the catalysis of an organic primary amine catalyst, enabling piperidone raw materials of different protection types as shown in a formula (I) to react with an electrophilic fluorination reagent to generate a compound as shown in a formula (II), and further reducing to generate a compound as shown in a formula (III). According to the method, a piperidone compound is taken as a raw material, and an electrophilic fluorination reagent such as N-fluorobenzenesulfonamide (NFSI) or a SelectFluor reagent is taken as a fluorine source, so that the 3, 5-difluoropiperidine and the derivative thereof are prepared. The method is simple to operate, mild in reaction condition and easy in reaction purification. In addition, by adjusting the catalyst, the method can also be used for preparing a corresponding optically pure multi-chiral center product.

Description

Technical Field

[0001] The present invention relates to the field of fluorine chemistry, and specifically relates to a preparation method of 3,5-difluoropiperidine and its derivatives. Background Art

[0002] Since fluorine is the element with the strongest electronegativity, it often provides the required hydrogen bond interaction during the interaction between a drug molecule and a biological target, thereby improving the binding degree between the drug molecule and the target and enhancing the activity of the drug. Due to the strong carbon-fluorine bond, it is difficult to break the carbon-fluorine bond. Introducing fluorine atoms into a drug molecule can often improve the metabolic stability of the drug. The strong electron-withdrawing effect of fluorine atoms changes the distribution of the internal electron density of the molecule, affects the acidity and alkalinity of the compound, and further changes the activity and bioavailability of the drug molecule. The introduction of fluorine atoms often changes the lipophilicity of the drug molecule and then affects the absorption of the drug molecule in the human body. In addition, the introduction of fluorine atoms can change the selective recognition of the drug molecule for the target, and can also change the conformation of the molecule, etc. Therefore, introducing fluorine atoms into drug molecules is a powerful means in new drug development. (Reference: "Fluorine-Containing Drugs", Xiao Jichang, Lu Shoufu, Lin Jinhong, Chemical Industry Press, Publication Date: April 1, 2022; CIP Approval Number: 2021257632; ISBN: 978-7-122-40413-8).

[0003] The piperidine structure is a very important intermediate in new drug research and development, and this structure is contained in many drugs. Considering the special role of fluorine atoms in drug molecules, introducing fluorine atoms and fluorine-containing groups into piperidine molecules for new drug research and development is a new strategy.

[0004] For example, the 3,5-difluoro-4,4-dihydroxypiperidine structure is a very important structural unit in drug design. Through it, 3,5-difluoro-4-hydroxy or 4-aminopiperidine derivatives can be easily and directly prepared by reduction or reductive amination, and can be used as fragments for new drug research and development.

[0005] Compound A shown below is one of a class of novel T790M inhibitors including EGFR mutations screened by Genentech. The overexpression or dysregulation of EGFR is related to various types of human cancers, such as rectal cancer, pancreatic cancer, glioma, and lung cancer, etc. (WO2014081718A1). Compound B is a new compound molecule screened by Acadia Pharmaceuticals for treating diseases or disorders related to the 5-hydroxytryptamine (5-HT) receptor. 5-hydroxytryptamine (5-HT) is an important neurotransmitter and is related to various behaviors such as sleep, diet, exercise, pain perception, and learning and memory (WO2019040106A2).

[0006]

[0007] Although the application of similar 3,5-difluoro-substituted piperidine structures in new drug research and development is increasing, there are few reports on the methods for synthesizing such compounds. In the patents reported by Genentech, starting from 1,3-dicarbonyl substrates and using SelectFluor reagent as the fluorine source, two fluorine atoms are introduced in two steps, and finally, the ester group needs to be removed through 4 steps to obtain the 3,5-difluoro-4-bishydroxy intermediate (Formula 2).

[0008]

[0009] The overall yield of this method is medium, it requires multiple steps of reaction, and only racemic products can be obtained. These problems also greatly restrict the preparation and application of such products. Summary of the Invention

[0010] The object of the present invention is to provide a new method for synthesizing 3,5-difluoropiperidine and its derivatives. The method of the present invention has mild reaction conditions and is easy to operate. After further chemical transformation, the construction of three chiral centers of the piperidine ring can be achieved at one time.

[0011] To achieve the object of the present invention, the technical solution of the present invention is:

[0012] A method for preparing 3,5-difluoropiperidine and its derivatives. In an organic solvent, piperidone raw materials of different protection types shown in Formula (I) react with an electrophilic fluorination reagent under the catalysis of an organic primary amine catalyst to generate a compound shown in Formula (II), and then further reduce to generate a compound shown in Formula (III);

[0013]

[0014] In the compound shown in Formula (II), where X, Y = OH, OH; H, OH;

[0015] where R is hydrogen, C 1 -C 9 alkyl, aryl, benzyl, CF 3 CO, R 1 CO or R 2 OCO;

[0016] R 1 is C 1 -C 9 alkyl, aryl or benzyl,

[0017] R 2 is C 1 -C 9 alkyl, aryl or benzyl.

[0018] In a preferred embodiment of the present invention, the organic primary amine catalyst is benzylamine, substituted benzylamine, racemic or chiral 1-phenylethylamine, racemic or chiral substituted 1-phenylethylamine, and the equivalent of the organic primary amine catalyst is 0.1-0.5 equivalent.

[0019] In a preferred embodiment of the present invention, the electrophilic fluorination reagent is N-fluorobenzenesulfonimide or 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) (SelectFluor), and the dosage of the electrophilic fluorination reagent is 2.0-4.0 equivalents.

[0020] In a preferred embodiment of the present invention, the organic solvent is any one of ethers, chlorinated alkanes, esters or alcohols.

[0021] The present invention uses piperidone or its substituted derivatives as starting materials to prepare 3,5-difluoropiperidine derivatives, and the provided technical solution has the following technical effects:

[0022] First, the present invention provides a new method for synthesizing 3,5-difluoro-4,4-dihydroxypiperidine structures by a one-step reaction, and provides the preparation of corresponding optically pure product derivatives, realizing the construction of three chiral centers of the piperidine ring;

[0023] Second, the reagents used are cheap and easily available, two fluorine atoms can be introduced simultaneously through a one-step reaction, the synthesis reaction is simple, and the technical solution is reasonable;

[0024] Third, the reaction yield is very good, the treatment and purification are simple, and it can be mass-produced to meet the production of pharmaceutical raw materials. Description of the Drawings

[0025] Figure 1 It is a diagram for confirming the absolute configuration of the product of Example 2 of the present invention by X-ray single crystal diffraction. Detailed Embodiments

[0026] The following examples are helpful for understanding the present invention, but do not limit the content of the present invention. In particular, for the synthesis of chiral compounds in the examples, it should be understood that the synthesis methods of the intermediates and products with the opposite configurations are also within the scope of protection of this patent.

[0027] Example 1

[0028]

[0029] Dissolve 301.5 g (2.49 mol, 0.5 eq) of R-phenethylamine in 3 L of THF. Add 616.2 g (3.81 mol, 0.75 eq) of trichloroacetic acid and 45.2 g (2.51 mol, 0.5 eq) of water respectively. After controlling the temperature at 5 - 10 °C and stirring for 15 min, transfer it to a 50 L reaction kettle. Then add 10 L of THF, 1.60 kg (15.1 mol, 3.0 eq) of sodium carbonate, and 4.75 kg (15.08 mmol, 3.0 eq) of NFSI respectively. Keep the temperature at 5 - 10 °C and react for 10 mins. Add 1.0 kg (5.02 mol, 1.0 eq) of 1-Boc-4-carbonylpiperidine to the reaction kettle in batches, and add it up in about 1 h. React at 40 °C overnight. TLC shows that the raw materials have basically reacted completely. Filter, wash the filter cake with 2 L x 2 of THF, concentrate the filtrate, and obtain 3 kg of crude yellow oil. The obtained crude product is quickly filtered through a short silica gel column, and further purification can obtain 1.2 kg of the target product as a light yellow oil.

[0030] Example 2

[0031]

[0032] In a 10 L reaction kettle, dissolve 600 g (~2.37 mol, 1.0 eq.) of the crude product of N-Boc-3,5-difluoro-4,4-dihydroxypiperidine prepared in the previous step in 5 L of MeOH. Control the temperature at -5 - 0 °C, and slowly add NaBH 4 (135 g, 3.55 mol, 1.5 eq.). Keep the temperature and react for 0.5 h. TLC detects that the reaction is complete. Quench the reaction solution with saturated ammonium chloride aqueous solution, extract with ethyl acetate, combine the organic phases, wash the organic phases with saturated NaCl aqueous solution, dry with anhydrous sodium sulfate, quickly filter through silica gel and concentrate. The obtained crude product is recrystallized to obtain 250 g (1.05 mmol) of the product (3S,5S)-N-Boc-3,5-difluoro-4-hydroxypiperidine as a white solid, and the two-step reaction yield is 42%.

[0033] 1 H NMR (400 MHz, CDCl 3 ) δ 1.46 (s, 9H), 2.64 (s, 1H), 3.18~3.65 (m, 2H), 3.72~4.19 (m, 3H), 4.59~4.88 (m, 2H). Its absolute configuration is confirmed by X-ray single crystal diffraction as Figure 1 shown.

Claims

1. A method for preparing 3,5-difluoropiperidine and its derivatives, characterized in that: In an organic solvent, a piperidone raw material of different protection types represented by formula (I) reacts with an electrophilic fluorination agent under the catalysis of an organic primary amine catalyst to generate a compound represented by formula (II), which is further reduced to generate a compound represented by formula (III); In the compound represented by formula (II), wherein X, Y = OH, OH; H, OH; Where R is hydrogen, C1-C9 alkyl, aryl, benzyl, CF3CO, R 1 CO or R 2 OCO; R 1 is a C1-C9 alkyl, aryl or benzyl group, R 2 It is C1-C9 alkyl, aryl or benzyl.

2. A method for preparing 3,5-difluoropiperidine and its derivatives as claimed in claim 1, characterized in that: The organic primary amine catalyst is benzylamine, substituted benzylamine, racemic or chiral 1-phenylethylamine, racemic or chiral substituted 1-phenylethylamine, and the organic primary amine catalyst equivalent is 0.1-0.5 equivalent.

3. A method for preparing 3,5-difluoropiperidine and its derivatives as claimed in claim 1, characterized in that: The electrophilic fluorination agent is N-fluorobisbenzenesulfonamide or 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (SelectFluor), and the amount of the electrophilic fluorination agent used is 2.0 to 4.0 equivalents.

4. A method for preparing 3,5-difluoropiperidine and its derivatives as claimed in claim 1, characterized in that: The organic solvent is any one of ethers, chlorinated alkanes, esters or alcohols.

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