Synthesis method of 2-[(-4-chlorophenyl)(4-piperidinyl-oxy)methyl]pyridine having single optical isomer

A configuration, hydroxyl technology, applied in the field of synthesis of 2-[methyl]pyridine, can solve the problems of limited industrial application, many side reactions, complicated steps, etc., achieve short steps, reduce side reactions, and simplify reaction steps Effect

Inactive Publication Date: 2014-09-10
CHONGQING HUAPONT PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The method uses benzyl-protected piperidine compound as a raw material, and after condensation, it is first substituted and then deprotected, and the required steps are relatively cumbersome.
In addition, the stability of the raw material formula IV pyridine chloroalkane is poor, and it will decompose at normal temperature, with many side reactions, and the yield of the first step can only reach 74.8%
In short, many defects of this method limit its industrial application

Method used

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  • Synthesis method of 2-[(-4-chlorophenyl)(4-piperidinyl-oxy)methyl]pyridine having single optical isomer
  • Synthesis method of 2-[(-4-chlorophenyl)(4-piperidinyl-oxy)methyl]pyridine having single optical isomer
  • Synthesis method of 2-[(-4-chlorophenyl)(4-piperidinyl-oxy)methyl]pyridine having single optical isomer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Example 1 Preparation of 2-[(4-chlorophenyl)(piperidine-4-oxyl group)methyl]pyridine (racemate)

[0063]In a three-necked reaction flask, add 50.4g (0.23mol) of (4-chlorophenyl)(2-pyridyl)methanol (formula II, racemate, X is chlorine), 250g mesitylene, and 166.3g methanesulfonic acid , 27.9 g of solid 4-hydroxypiperidine (formula III) was added under stirring. After the addition is complete, open the mouth of the reaction bottle and raise the temperature to 120-125°C for reaction. After monitoring by HPLC that the raw material (4-chlorophenyl)(2-pyridyl)methanol basically disappeared, the reaction was stopped. After cooling down to room temperature, the reaction solution was extracted twice with 1N hydrochloric acid, the aqueous phases were combined, NaOH was added to adjust the pH to alkaline, and then extracted twice with ethyl acetate, the organic phases were combined, dried, filtered, and concentrated to obtain 2- [(4-Chlorophenyl)(piperidin-4-oxyl)methyl]pyridine...

Embodiment 2～5

[0064] Examples 2-5 Preparation of 2-[(4-halophenyl)(piperidine-4-oxyl)methyl]pyridine (racemate, R configuration, S configuration)

[0065] With reference to the operating process of Example 1, the raw material consumption, reaction conditions and product situation are shown in Table 2.

[0066] Table 2 embodiment 1-5 raw material consumption, reaction conditions and product situation

[0067]

[0068] Note: Chiral HPLC in Examples 2, 3, and 5 refers to the chiral HPLC method, that is, the second condition detection in the aforementioned "detection conditions"

Embodiment 6

[0069] Example 6 Preparation of Bepotastine Besilate

[0070] With the obtained (S)-2-[(4-chlorophenyl)(piperidine-4-oxyl)methyl]pyridine in embodiment 2 as raw material, then with reference to the method of CN1098262C, the specific operation is as follows:

[0071] Get (S)-2-[(4-chlorophenyl) (piperidine-4-oxyl group) methyl] pyridine 20g obtained in Example 2, dissolve in acetone, then add 15.5g ethyl 4-bromobutyrate and 11 g of anhydrous potassium carbonate, and the mixture was refluxed for 7 hours with stirring. The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to obtain 27 g of a yellow oil.

[0072] Dissolve the oily substance in ethanol, then add 20mL of 5N aqueous sodium hydroxide solution for hydrolysis, add 20mL of 5N hydrochloric acid to neutralize after hydrolysis, filter out insoluble matter, and concentrate the filtrate under reduced pressure to obtain 23g of foam.

[0073] The foam was dissolved in ethyl acetate, 1...

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Abstract

A preparation method of a compound of formula I is characterized in that the compound of formula I is obtained through one step direct condensation ether formation on a raw material of formula II and a raw material of formula III. The protection of reactive hydrogen on the nitrogen atom of the compound of the formula III is not needed in the invention, and a sulfonic acid compound is adopted as a reaction assistant, so the side reaction is reduced, reaction steps are simplified, and a satisfactory product yield can be realized. The compound of formula I having a single optical isomer can be obtained when the raw material of formula II having different isomers is selected.

Description

technical field [0001] The invention relates to a synthesis method of 2-[(4-chlorophenyl)(piperidine-4-oxyl)methyl]pyridine with a single optical isomer. Background technique [0002] 2-[(4-Chlorophenyl)(piperidin-4-oxy)methyl]pyridine (Formula I) is an ether with optical isomers containing ortho-pyridyl and para-piperidyl Bepotastine is an important intermediate in pharmacy. For example, after alkylating the amino group on the piperidine ring in its S isomer, an antihistamine drug bepotastine can be obtained. [0003] [0004] None of the methods in the prior art can directly synthesize the compound of formula I. First, the amino group on the piperidine needs to be protected, followed by a condensation reaction, and finally deprotection is required, resulting in a complicated process. For example, the preparation method provided by JP10120677 requires a three-step reaction: using formula IV pyridine chloroalkane and hydroxypiperidine compound formula V (protecting the a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 张波赵舟邹长忠毛启良
Owner CHONGQING HUAPONT PHARMA
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