CN115772141A

CN115772141A - Synthetic method of aryl-containing piperidine derivative Boc piperidine 4-fluorophenylethanol

Info

Publication number: CN115772141A
Application number: CN202211480666.2A
Authority: CN
Inventors: 茅仲平; 马东旭; 李景伟
Original assignee: SUZHOU HANDE CHUANGHONG BIOCHEMICAL TECHNOLOGY CO LTD
Current assignee: SUZHOU HANDE CHUANGHONG BIOCHEMICAL TECHNOLOGY CO LTD
Priority date: 2022-11-24
Filing date: 2022-11-24
Publication date: 2023-03-10

Abstract

The invention discloses a synthetic method of aryl-containing piperidine derivative Boc piperidine 4-fluorophenylethanol in the technical field of synthesis of ligand intermediates of biological receptors, aiming at solving the problem that the prior art lacks of research on the synthetic method of Boc piperidine 4-fluorophenylethanol capable of being combined with MC4R, wherein 4-fluorophenylacetic acid is taken as a raw material, methyl esterification is firstly carried out to synthesize 4-fluorophenylacetic acid methyl ester, and then bromination is carried out on a benzyl position by using a bromination reagent to synthesize 2-bromo-2- (4-fluorophenylacetic acid) methyl ester; and (3) coupling the obtained 2-bromo-2- (4-fluorobenzene) methyl acetate with Boc piperidine under alkaline conditions to synthesize Boc piperidine 4-fluorobenzene methyl acetate, and finally reducing the Boc piperidine 4-fluorobenzene ethanol by using methyl ester. The synthesis method of Boc piperidine 4-fluorophenylethanol provided by the invention has the advantages of low cost, easiness in operation, high efficiency, high yield and the like, and fills the blank of research on the synthesis method at present.

Description

Synthetic method of aryl-containing piperidine derivative Boc piperidine 4-fluorophenylethanol

Technical Field

The invention relates to a synthesis method of aryl-containing piperidine derivative Boc piperidine 4-fluorophenylethanol, belonging to the technical field of synthesis of ligand intermediates of biological receptors.

Background

Melanocortin receptors belong to the G protein-coupled receptor family and function via a 3, 5-adenosine monophosphate (cyclic 3',5' -adenosine monophosphate, cAMP) -dependent signaling pathway, which is coupled to Adenylyl Cyclase (AC), and stimulates cAMP production to stimulate Protein Kinase A (PKA), which in turn phosphorylates cyclic adenosine response element-binding proteins (CREB). Melanocortin (MC) action is mediated by 5 different receptors (MC 1R, MC2R, MC3R, MC4R, MC 5R). MCRs are expressed in a variety of tissues and are involved in regulating a variety of physiological functions, such as skin pigmentation, energy homeostasis, red blood cell differentiation, appetite, epinephrine secretion, and sexual function. Whereas MC4R is expressed in almost all central nervous system regions of mammals, including cortex, thalamus, hypothalamus, brainstem and spinal cord, MC4R is substantially absent from surrounding tissues except adipose tissue. Therefore, MC4R is mainly involved in central regulation, and its mutation can cause diseases such as obesity, inflammation and sexual dysfunction.

With the improvement of the quality of living standard, the human dietary structure and the dietary habit tend to be diversified, the fat intake is increased, and the number of obese patients is increased worldwide. Obesity can also cause a series of serious complications, such as hypertension, diabetes, coronary heart disease, dyslipidemia, malignant tumor and the like, and brings great harm to human health. The melanocortin system plays a very important role in regulating animal feeding and energy metabolism, particularly MC4R.

If a proper chemical ligand can be found and can be specifically combined with MC4R, the regulation of the physiological activity of MC4R is realized, and a good treatment effect on genetic diseases such as obesity and the like is generated. Foreign documents report that a class of aryl-containing piperidine derivatives Boc piperidine 4-fluorophenetol can be well combined with MC4R, so that the compounds are very promising prodrug molecules, but the synthesis method of Boc piperidine 4-fluorophenetol is a blank area.

Disclosure of Invention

The invention aims to overcome the defects in the prior art, provides a synthetic method of aryl-containing piperidine derivative Boc piperidine 4-fluorophenetol, has the advantages of low cost, easy operation, high efficiency, high yield and the like, and fills the gap of the research on the synthetic method at present.

In order to achieve the purpose, the invention adopts the following technical scheme: taking 4-fluorophenylacetic acid as a raw material, synthesizing 4-fluorophenylmethyl acetate through methyl esterification, and then synthesizing 2-bromo-2- (4-fluorophenylacetic acid) methyl ester through bromination of a bromination reagent at a benzyl position;

and (3) coupling the obtained 2-bromo-2- (4-fluorobenzene) methyl acetate and Boc piperidine under alkaline conditions to synthesize Boc piperidine 4-fluorobenzene methyl acetate, and finally reducing the Boc piperidine 4-fluorobenzene ethanol by using methyl ester.

Further, the method specifically comprises the following steps,

a. synthesis of methyl 4-fluorophenylacetate: dissolving 4-fluorophenylacetic acid in a reaction solvent I, slowly dripping concentrated sulfuric acid under stirring, heating, concentrating to remove the reaction solvent I, and slowly pouring into water for extraction operation to obtain 4-fluorophenylacetic acid methyl ester;

b. synthesis of methyl 2-bromo-2- (4-fluorobenzene) acetate:

adding 4-fluorophenylmethyl acetate into a reaction solvent II for dissolving, adding a brominating agent and a catalyst, and heating overnight;

after the reaction is finished, adding sodium bisulfite to quench the reaction, and finally performing extraction operation to obtain 2-bromo-2- (4-fluorobenzene) methyl acetate;

c. synthesis of Boc piperidine 4-fluorophenylacetic acid methyl ester:

adding 2-bromo-2- (4-fluorobenzene) methyl acetate into a reaction solvent II for dissolving, adding Boc piperidine and potassium carbonate, and stirring until the reaction is finished;

filtering the obtained solution, rinsing a filter cake by using ethyl acetate, washing the filtrate by using water, concentrating an organic phase, adding n-heptane to separate out a white solid, and filtering to obtain Boc piperidine 4-fluorophenylmethyl acetate;

d. synthesis of Boc piperidine 4-fluorophenethyl alcohol:

adding lithium aluminum hydride into tetrahydrofuran, and cooling to-5 ℃ to obtain a lithium aluminum hydride reaction system;

dissolving Boc piperidine 4-fluorophenylacetic acid methyl ester in a reaction solvent III, then dropwise adding lithium aluminum hydride into a reaction system, preserving heat after dropwise adding, and stirring to obtain a reaction liquid;

dropwise adding the reaction liquid into a sodium hydroxide aqueous solution to quench the reaction;

after the quenching reaction is finished, extracting and concentrating for many times by using methanol;

adding dichloromethane to obtain clear solution, adding silica gel, stirring, filtering to remove silica gel, and concentrating the filtrate to obtain colorless oily substance, i.e. Boc piperidine 4-fluorophenylethanol.

Further, the concentrated sulfuric acid in step a may be replaced with p-toluenesulfonic acid, thionyl chloride or oxalyl chloride.

Further, methanol is adopted as the reaction solvent I; the reaction solvent II is one of N, N-dimethylformamide, dichloromethane, carbon tetrachloride, N-dimethylacetamide, N-methylpyrrolidone, toluene and tetrahydrofuran.

Further, in the step b, the brominating reagent is one of bromosuccinimide, dibromohydantoin and liquid bromine; the catalyst is hydrobromic acid at a concentration of 48%.

Further, in the step d, the reaction solvent III is one of tetrahydrofuran, heptane, toluene or diethyl ether.

Further, the concentration of the sodium hydroxide aqueous solution in the step d is 5-20%, and the sodium hydroxide aqueous solution can be replaced by one of potassium hydroxide and potassium sodium tartrate.

Further, the reaction temperature range of the step a is 60 to 80 ℃, the reaction temperature range of the step b is 40 to 60 ℃, the reaction temperature range of the step c is 20 to 30 ℃, the reaction temperature range of the step d is-10 to 30 ℃, and the temperature of the dropping and heat preservation process is controlled to be-5 to 10 ℃.

Compared with the prior art, the invention has the following beneficial effects:

the synthesis method of the piperidine derivative Boc piperidine 4-fluorophenylethanol containing the aromatic group comprises four steps of reaction, namely, taking commercially available 4-fluorophenylacetic acid as a raw material, synthesizing 4-fluorophenylmethyl acetate through methyl esterification, and synthesizing 2-bromo-2- (4-fluorophenylethyl) methyl acetate through bromination at a benzyl position by using a bromination reagent; coupling the obtained 2-bromo-2- (4-fluorobenzene) methyl acetate and Boc piperidine under alkaline conditions to synthesize Boc piperidine 4-fluorobenzene methyl acetate, and finally reducing the Boc piperidine 4-fluorobenzene ethanol by using methyl ester;

the method provided by the invention has the advantages of simple and feasible process, high yield, no noble metal, no high-risk reaction, suitability for commercial production and the like, and the purity of the prepared product exceeds 99%, the single impurity content is less than 0.5%, and the correction content exceeds 97%. Lays a material foundation for the research of the domestic MC4R field and fills the blank.

Drawings

FIG. 1 is a schematic flow chart of a synthetic method of Boc piperidine 4-fluorophenetol, a piperidine derivative containing an aromatic group, according to an embodiment of the present invention.

Detailed Description

The invention is further described below with reference to the accompanying drawings. The following examples are only for illustrating the technical solutions of the present invention more clearly, and the protection scope of the present invention is not limited thereby.

The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.

For the purposes of this specification and the appended claims, unless otherwise indicated, all numbers expressing quantities, percentages, or proportions, and other numerical values used in the specification and the appended claims, are to be understood as being modified in all instances by the term "about". Moreover, all ranges disclosed herein are inclusive of the endpoints and independently combinable.

The invention provides a synthesis method of aryl-containing piperidine derivative Boc piperidine 4-fluorophenylethanol, which comprises the steps of taking 4-fluorophenylacetic acid as a raw material, synthesizing 4-fluorophenylmethyl acetate through methyl esterification, and synthesizing 2-bromo-2- (4-fluorophenylethyl) methyl acetate through bromination at a benzyl position by using a bromination reagent; and (3) coupling the obtained 2-bromo-2- (4-fluorobenzene) methyl acetate and Boc piperidine under alkaline conditions to synthesize Boc piperidine 4-fluorobenzene methyl acetate, and finally reducing the Boc piperidine 4-fluorobenzene ethanol by using methyl ester.

The method specifically comprises the following steps:

(1) Synthesis of methyl 4-fluorophenylacetate: dissolving 4-fluorophenylacetic acid in methanol with volume ratio of 3-20 times, slowly adding concentrated sulfuric acid with 0.1-5.0 equivalents under stirring, wherein the concentrated sulfuric acid can be replaced by reagents such as p-toluenesulfonic acid, thionyl chloride, oxalyl chloride and the like, and heating to 60-80 ℃.

After the reaction is finished, concentrating to remove methanol, slowly pouring 10 times of water, extracting with ethyl acetate for three times, each time with 5 times of volume, combining organic phases, washing once with 5 times of saturated sodium bicarbonate water solution, washing once with 5 times of saturated saline solution, and concentrating the filtrate at 45 ℃ to obtain colorless transparent liquid, thereby obtaining the 4-fluorophenylacetic acid methyl ester.

(2) Synthesis of methyl 2-bromo-2- (4-fluorophenyl) acetate: 1 to 10 times of volume of methyl 4-fluorophenylacetate is added into N, N-dimethylformamide to dissolve 1 to 1.5 equivalents of bromosuccinimide, the bromosuccinimide can be replaced by other bromides such as dibromohydantoin and liquid bromine, and the N, N-dimethylformamide can be replaced by other solvents such as dichloromethane, carbon tetrachloride, N, N-dimethylacetamide, N-methylpyrrolidone and toluene. Then, hydrobromic acid with the concentration of 48 percent is added dropwise in an amount of 0 to 3 equivalents, and the mixture is heated to 40 to 60 ℃ overnight.

After the reaction is finished, adding 10 times volume of sodium bisulfite aqueous solution for quenching reaction, adding 10 times volume of ethyl acetate for extraction, washing once with 10 times volume of saturated sodium bicarbonate aqueous solution, washing once with 10 times volume of saturated sodium chloride aqueous solution, and concentrating the filtrate at 45 ℃ to obtain colorless transparent liquid, namely 2-bromo-2- (4-fluorobenzene) methyl acetate.

(3) Synthesis of Boc piperidine 4-fluorophenylacetic acid methyl ester: n, N-dimethylformamide in which 1 equivalent of methyl 2-bromo-2- (4-fluorobenzene) acetate is dissolved in a volume of 1 to 10 times may be replaced with other solvents such as methylene chloride, carbon tetrachloride, N, N-dimethylacetamide, N-methylpyrrolidone, toluene, and tetrahydrofuran.

And then adding 1 to 1.5 equivalents of Boc piperidine and 2 to 3 equivalents of potassium carbonate, and stirring at the temperature of 0 to 100 ℃ until the reaction is finished. Filtering, washing a filter cake with ethyl acetate, adding 10 times of volume of water into the filtrate for washing once, concentrating an organic phase to 2 times of volume, adding 4 times of volume of n-heptane, and separating out a white solid to obtain Boc piperidine 4-fluorobenzene methyl acetate.

(4) Synthesis of Boc piperidine 4-fluorophenethyl alcohol: adding 2-3 equivalents of lithium aluminum hydride into 1-5 times of tetrahydrofuran (subjected to redistilled treatment and with the water content of 150 ppm) (with the highest temperature rise and air release phenomenon of 20 ℃) and cooling to-5 ℃ to obtain a lithium aluminum hydride lateral reaction system. The tetrahydrofuran may be replaced by other solvents such as methyltetrahydrofuran, heptane, toluene, and diethyl ether.

Dissolving Boc piperidine 4-fluorophenylacetic acid methyl ester in tetrahydrofuran with the volume 2 times of that of the solution, and then dropwise adding the solution into the lithium aluminum hydride-containing reaction system, wherein the dropwise adding temperature is controlled to be-5 to 10 ℃. After the dripping is finished, the internal temperature is maintained at 0 to 5 ℃ and stirred,

after the controlled reaction in the liquid phase is finished, cooling to-5 to 0 ℃, and dropwise adding the reaction liquid into 5-fold volume of 5 to 20 percent sodium hydroxide aqueous solution for quenching. The quenching method can be water or other methods, but direct water quenching can generate a large amount of aluminum hydroxide precipitate, which causes troubles for post-treatment, so that a 5 to 20 percent sodium hydroxide aqueous solution is selected, wherein sodium hydroxide can be replaced by other alkalis such as potassium hydroxide, potassium sodium tartrate and the like. The quenching reaction is accompanied with violent deflation and heat release, the dropping speed is controlled, and the quenching temperature is maintained between minus 5 ℃ and 10 ℃.

After quenching, the mixture was extracted twice with ethyl acetate (5 volumes each), concentrated to 2 volumes, added with 2 times of methanol and concentrated again to 2 volumes, then added with 2 times of methanol and concentrated again to 2 volumes, and added with 80 times of dichloromethane to obtain a clear solution. Adding silica gel of which the weight is 5 times that of the Boc piperidine, stirring at the temperature of 20-30 ℃, filtering to remove the silica gel, and concentrating and drying the filtrate to obtain colorless oily matter, namely the Boc piperidine 4-fluorophenethyl alcohol.

Example 1

Synthesis of methyl 4-fluorophenylacetate:

15.4 g (100 mmol,1.0 eq.) of 4-fluorophenylacetic acid is dissolved in 154 mL of methanol, 0.2 eq concentrated sulfuric acid is slowly added with stirring, and the mixture is heated to 60 to 70 ℃ for reaction. After the reaction, the mixture was concentrated to remove methanol, poured slowly into 154 mL of water, extracted three times with ethyl acetate (77 mL each), the organic phases were combined, washed once with 77 mL of saturated aqueous sodium bicarbonate solution and once with 77 mL of saturated brine, and the filtrate was concentrated at 45 ℃ to give a colorless transparent liquid. Purity 95A%, correct yield 80%.

Example 2

Synthesis of methyl 2-bromo-2- (4-fluorobenzene) acetate:

methyl 4-fluorophenylacetate (16 g, 100 mmol,1.0 eq.) was dissolved in N, N-dimethylformamide (80 mL), followed by addition of bromosuccinimide (19.6 g, 110 mmol,1.0 eq.) and dropwise addition of hydrobromic acid (48% strength) (0.1 eq.) and heating at 50 ℃ overnight.

After the reaction was completed, 160 mL of an aqueous solution of sodium bisulfite was added to quench the reaction, and 160 mL of ethyl acetate was added to extract the reaction product. 160 mL of saturated aqueous sodium bicarbonate solution was added and washed once, 160 mL of saturated aqueous sodium chloride solution was washed once, and the filtrate was concentrated at 45 ℃ to obtain a colorless transparent liquid. The purity is 97A percent, and the corrected yield is 95 percent.

Example 3

Synthesis of Boc piperidine 4-fluorophenylacetic acid methyl ester:

24 g (100 mmol,1.0 eq.) of methyl 2-bromo-2- (4-fluorobenzene) acetate was dissolved in 240 mL of N, N-dimethylformamide, and 18.6 g (100 mmol,1.0 eq.) of Boc piperidine and 27.6 g (200 mmol, 2.0 eq.) of potassium carbonate were added, followed by stirring at 20-30 ℃ for 15 hours until the reaction was complete. Filtering, rinsing a filter cake with ethyl acetate, adding 240 mL of water into a filtrate to wash the filtrate once, concentrating an organic phase to 40 to 50 mL, adding 96 mL of n-heptane to precipitate a white solid, and filtering to obtain a colored solid with the purity of 98A% and the corrected yield of 85%.

Example 4

Synthesis of Boc piperidine 4-fluorophenethyl alcohol:

9 g (100 mmol, 2.0 eq.) of lithium aluminum hydride is added into 60 mL of tetrahydrofuran (redistilled and processed, the water content is 150 ppm) (the temperature rise and the air release phenomenon are up to 20 ℃), and after the lithium aluminum hydride is added, the temperature is reduced to-5 ℃.

20 g (50 mmol,1.0 eq.) of Boc piperidine 4-fluorophenylacetic acid methyl ester was dissolved in 40 mL of tetrahydrofuran, and then added dropwise to the above lithium aluminum hydride-containing reaction system at a temperature of-5 to 10 ℃. After the dropwise addition, the internal temperature is maintained at 0-5 ℃ and stirring is carried out for 2 h.

After the controlled reaction in the liquid phase is finished, the temperature is reduced to minus 5 to 0 ℃, the reaction liquid is dripped into 100 mL of 10 percent sodium hydroxide aqueous solution for quenching along with violent gas release and heat release, the dripping speed is controlled, and the quenching temperature is maintained between minus 5 to 10 ℃.

After quenching was complete, the mixture was extracted twice with ethyl acetate (100 mL each). The mixture was concentrated to 40 to 50 mL, 40 mL of methanol was added and the mixture was concentrated again to 40 mL, and 1.6L of dichloromethane was added to obtain a clear solution. 100 g of silica gel is added, the mixture is stirred for 1 hour at 20 to 30 ℃, the silica gel is removed by filtration, and the filtrate is concentrated to dryness to obtain colorless oily matter with the purity of 99A percent and the corrected yield of 92 percent.

The synthesis method of Boc piperidine 4-fluorophenethyl alcohol has the advantages of low price of raw materials, low cost and easy obtainment. The invention has short synthetic route, high yield, high chemical purity of the obtained product, no need of special production equipment for all reactions and no cryogenic operation. Is convenient for industrial scale-up production and provides high-purity products for the market.

The above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, it is possible to make various improvements and modifications without departing from the technical principle of the present invention, and those improvements and modifications should be considered as the protection scope of the present invention.

Claims

1. A synthetic method of aryl-containing piperidine derivative Boc piperidine 4-fluorophenylethanol is characterized by comprising the following steps: taking 4-fluorophenylacetic acid as a raw material, synthesizing 4-fluorophenylmethyl acetate through methyl esterification, and then synthesizing 2-bromo-2- (4-fluorophenylacetic acid) methyl ester through bromination of a bromination reagent at a benzyl position;

and (3) coupling the obtained 2-bromo-2- (4-fluorobenzene) methyl acetate with Boc piperidine under alkaline conditions to synthesize Boc piperidine 4-fluorobenzene methyl acetate, and finally reducing the Boc piperidine 4-fluorobenzene ethanol by using methyl ester.

2. The method for synthesizing Boc piperidine 4-fluorophenetol as a piperidine derivative with an aromatic group as claimed in claim 1, wherein: the method specifically comprises the following steps of,

a. synthesis of methyl 4-fluorophenylacetate: dissolving 4-fluorophenylacetic acid in a reaction solvent I, slowly dripping concentrated sulfuric acid into the reaction solvent I under stirring, heating, concentrating the reaction solvent I, and slowly pouring the reaction solvent I into water for extraction to obtain 4-fluorophenylacetic acid methyl ester;

b. synthesis of methyl 2-bromo-2- (4-fluorobenzene) acetate:

adding 4-fluorobenzene methyl acetate into a reaction solvent II for dissolving, adding a bromination reagent and a catalyst, and heating overnight;

c. synthesis of Boc piperidine 4-fluorophenylacetic acid methyl ester:

filtering the obtained solution, rinsing a filter cake with ethyl acetate, washing the filtrate with water, concentrating an organic phase, adding n-heptane, separating out a white solid, and filtering to obtain Boc piperidine 4-fluorophenylacetic acid methyl ester;

d. synthesis of Boc piperidine 4-fluorophenethyl alcohol:

3. The method for synthesizing Boc piperidine 4-fluorophenetol as a piperidine derivative with an aromatic group as claimed in claim 2, wherein: the concentrated sulfuric acid in step a may be replaced by p-toluenesulfonic acid, thionyl chloride or oxalyl chloride.

4. The method for synthesizing Boc piperidine 4-fluorophenetol as a piperidine derivative with an aromatic group as claimed in claim 2, wherein: the reaction solvent I adopts methanol; the reaction solvent II is one of N, N-dimethylformamide, dichloromethane, carbon tetrachloride, N-dimethylacetamide, N-methylpyrrolidone, toluene and tetrahydrofuran.

5. The method for synthesizing Boc piperidine 4-fluorophenylethanol as a piperidine derivative according to claim 2, wherein the method comprises the following steps: in the step b, the brominating reagent is one of bromosuccinimide, dibromohydantoin and liquid bromine; the catalyst is hydrobromic acid at a concentration of 48%.

6. The method for synthesizing Boc piperidine 4-fluorophenylethanol as a piperidine derivative according to claim 2, wherein the method comprises the following steps: in the step d, the reaction solvent III is one of tetrahydrofuran, heptane, toluene or diethyl ether.

7. The method for synthesizing Boc piperidine 4-fluorophenetol as a piperidine derivative with an aromatic group as claimed in claim 2, wherein: and d, replacing the sodium hydroxide aqueous solution with one of potassium hydroxide and potassium sodium tartrate, wherein the concentration of the sodium hydroxide aqueous solution in the step d is 5-20%.

8. The method for synthesizing Boc piperidine 4-fluorophenetol as a piperidine derivative with an aromatic group as claimed in claim 2, wherein: the reaction temperature range of the step a is 60 to 80 ℃, the reaction temperature range of the step b is 40 to 60 ℃, the reaction temperature range of the step c is 20 to 30 ℃, the reaction temperature range of the step d is-10 to 30 ℃, and the temperature of the dropping and heat preservation process is controlled to be-5 to 10 ℃.