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Synthesis method of pharmaceutical intermediate for treating arrhythmia

A synthetic method and arrhythmia technology, applied in the direction of organic chemistry, etc., can solve the problems of low yield of asymmetric diester and low yield of piperidone products, etc., and achieve the effect of high yield

Inactive Publication Date: 2018-05-22
JINAN SHUNJING PHARMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] But the defect of this method is that: when the raw material is an asymmetric diester, if the mixture of primary amines such as methylamine, propylamine, benzylamine, etc. For tertiary amines containing diester groups, there are many by-products, such as tertiary amines of diester groups generated by primary amines and A, tertiary amines of diester groups generated by primary amines and B, so the target asymmetric diester The yield is extremely low, thereby making the target piperidone product yield extremely low

Method used

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  • Synthesis method of pharmaceutical intermediate for treating arrhythmia
  • Synthesis method of pharmaceutical intermediate for treating arrhythmia

Examples

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preparation example Construction

[0036] The technical solution provided by the examples in this embodiment is: a method for synthesizing a drug intermediate for treating arrhythmia, wherein the drug intermediate for treating arrhythmia is 2-methyl-4-piperidone; The synthetic method comprises the steps:

[0037] Step 1: Trans-2-butenoic acid and ethanol undergo esterification reaction to obtain compound 1;

[0038] Step 2: Compound 1 is obtained through addition reaction with ammonia gas to obtain Compound 2;

[0039] Step 3: compound 2 and ethyl acrylate are added to obtain compound 3;

[0040] Step 4: react compound 3 with ethyl chloroformate to protect the amine group to obtain compound 4;

[0041] Step 5: compound 4 is ring-closed to obtain compound 5 through Dickmann condensation reaction;

[0042] Step 6: compound 5 is hydrolyzed to obtain compound 6;

[0043] in:

[0044] .

Embodiment 1

[0047] The technical scheme of the synthetic method of the pharmaceutical intermediate 2-methyl-4-piperidone provided in this example is that the specific operations of step 1 include: 25.03 g (0.29 mol) trans-2-butenoic acid, 64 mL Add absolute ethanol and 2.50 g of concentrated sulfuric acid into a 250 mL three-necked flask equipped with a thermometer, reflux condenser and drying tube, stir magnetically, heat and reflux for 5 h, pour the reaction solution into 250 ml of water, and after thorough stirring, use two Extracted three times with methyl chloride, combined the organic phases, washed with water until neutral, dried over anhydrous sodium sulfate, distilled the obtained crude product under atmospheric pressure, collected fractions at 138-140°C, and obtained compound 1 as a colorless liquid with a yield of 96.6%

[0048] The specific operation of step 2 includes: adding 60 mL of absolute absolute ethanol to a dry 100 mL single-necked bottle, and feeding 0.33 mol of ammon...

Embodiment 2-3 and comparative example 1-2

[0059] The difference between embodiment 2-3 and comparative example 1-2 and embodiment 1 is that the reaction temperature and time of step 2 and step 3 are different. Concrete temperature, time, productive rate are shown in Table 2.

[0060] Table 2 step two, three reaction conditions comparison

[0061]

[0062] It can be seen from the above table that the embodiment provided by the present invention is passed, and the reaction conditions of step 2 are controlled at: heating to reflux, reacting for 5-10 h, and at the same time controlling the reaction conditions of step 3 at 10-20°C for 18-36 h , the temperature was raised to 30-50°C for 2-5 h, which greatly improved the yield of a single step, thereby increasing the total yield.

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Abstract

The invention belongs to the technical field of synthesis of pharmaceutical intermediates, and in particular relates to a synthesis method of a pharmaceutical intermediate for treating arrhythmia. Themethod adopts ammonia gas, acrylate and 2-butenoic acid as raw materials, and the target product is obtained by six steps; in the second step, a primary amine compound 2 is obtained by enabling the ammonia gas to react with butenolide; in the third step, the acrylate and the compound 2 are enabled to react so as to obtain a compound 3; finally, the target product is synthesized by using a diestersynthesis method. The yield of a whole route reaches up to 40% or above.

Description

technical field [0001] The invention belongs to the technical field of synthesis of pharmaceutical intermediates, and in particular relates to a synthesis method of a drug intermediate for treating arrhythmia. Background technique [0002] Piperidone and its derivatives are very important members of piperidine derivatives, generally referred to as 4-piperidone. In the molecular structure of piperidone, not only nitrogen atom and carbonyl group can be used as active sites, but also the introduction of carbonyl makes the two methylene groups on the ortho position active, so piperidone can be used as the parent to trigger many Organic reactions, from which many practical medicines, pesticides and chemical intermediates are derived. [0003] The structural formula is compounds that are effective in the treatment of cardiac arrhythmias. [0004] In the structural formula of the drug for treating arrhythmia, L is hydrogen, cyclohexyl, 2-hydroxycyclohexyl, etc., R is hydrogen...

Claims

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Application Information

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IPC IPC(8): C07D211/74
CPCC07D211/74
Inventor 盛秀群
Owner JINAN SHUNJING PHARMA TECH
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