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Environment-friendly ritodrine hydrochloride production method

A technology of ritodrine hydrochloride and its production method, which is applied in chemical instruments and methods, preparation of organic compounds, organic chemistry, etc., can solve the problems of high price, increased production cost, complicated preparation process, etc., and achieves favorable product yield and Quality, reduced impurity formation, good bromination selectivity

Inactive Publication Date: 2015-11-18
GUANGDONG XIANQIANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Inadequacies, there are environmental pollution problems and production safety problems in the production of this synthetic route
[0008] The specific problems are: 1. In the bromination process, bromine is usually directly used in production at low temperature for bromination
The reaction needs to be equipped with an autoclave and a high-pressure reaction workshop, which increases the production cost, operation difficulty and safety issues.
[0009] The common main problems of B and C synthesis routes are: 1. Difficult source of raw materials and high cost
The preparation process of 1-hydroxy-1-(4-hydroxyphenyl)-2-propanone in B is complicated, the price is expensive, and the source of raw materials is few; 2-amino-1-(4-hydroxyphenyl)propanol or its salt in C Pseudoephedrine (i.e. p-hydroxypseudoephedrine or its hydrochloride) is a drug controlled by the state; 2. The synthesis steps are short, the impurities are not easy to control, and the product quality is uncontrollable
B and C are not practical for the synthesis of ritodrine hydrochloride bulk drug

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] (1) Bromination reaction: Put 43.2kg of p-benzyloxypropiophenone, 150L of methanol, and 15.7kg of p-toluenesulfonic acid into the reaction kettle. After stirring and dissolving, add 64kg of dibromohydantoin in batches, and heat up to 45°C for reaction 2h. Evaporate the solvent under reduced pressure, cool to room temperature, add 50 L of water, stir and crystallize, and centrifuge to obtain 52.8 kg of α-bromo-p-benzyloxypropiophenone (Ⅲ), with a yield of 92%.

[0037] (2) Condensation reaction: 51kg of α-bromo-p-benzyloxypropiophenone and 300L of ethanol were put into the reaction kettle, stirred and dissolved, then 36.4kg of p-methylbenzylamphetamine and 21.6kg of triethylamine were put in successively, and the temperature was raised to reflux for 3 hours. After fully reacting, cool, the precipitated solid is triethylamine hydrobromide, filter, evaporate part of the solvent from the filtrate under reduced pressure, until most of the crystals are precipitated, and centr...

Embodiment 2

[0042] (1) Bromination reaction: Put 43.2kg of p-benzyloxypropiophenone, 225L of methanol, and 15.7kg of p-toluenesulfonic acid into the reaction kettle. After stirring and dissolving, add 96kg of dibromohydantoin in batches and react at room temperature for 4h. Evaporate the solvent under reduced pressure, cool to room temperature, add 50 L of water, stir and crystallize, and centrifuge to obtain 54.5 kg of α-bromo-p-benzyloxypropiophenone (Ⅲ), with a yield of 95%.

[0043] (2) Condensation reaction: Put 51kg of α-bromo-p-benzyloxypropiophenone and 300L of ethanol into the reaction kettle, stir and dissolve, then put in 40kg of p-benzyloxyphenethylamine and 27.6kg of potassium carbonate in sequence, and heat up to 60°C for 3 hours . Cool, filter, evaporate part of the solvent from the filtrate under reduced pressure until most of the crystals are precipitated, and centrifuge to obtain 1-(4-benzyloxyphenyl)-2-[2-(4-benzyloxyphenyl)ethylamino ] Acetone (Ⅳ) 60kg, yield 80%.

...

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PUM

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Abstract

The invention discloses an environment-friendly ritodrine hydrochloride production method. The environment-friendly ritodrine hydrochloride production method comprises the following steps of: (1) carrying out bromination reaction: carrying out bromination reaction under catalysis by taking p-benzyloxybenzene acetone (II) as a raw material and taking 1,3-dibromo-5,5-dimethylhydantoin (namely dibromohydantoin) as a brominating agent, thereby generating alpha-bromo-p-benzyloxybenzene acetone (III); (2) carrying out condensation reaction: condensing the alpha-bromo-p-benzyloxybenzene acetone (III) and p-benzyloxybenzene ethylamine under an alkali condition to generate 1-p-benzyloxyphenyl-2-(2-benzyloxybenzene ethylamino) acetone (IV); (3) carrying out reduction reaction: under the action of a reducing agent, reducing carbonyl by the 1-p-benzyloxyphenyl-2-(2-benzyloxybenzene ethylamino) acetone (IV), thereby generating 1-p-benzyloxyphenyl-2-(2-benzyloxybenzene ethylamino) propyl alcohol (V); (4) carrying out debenzylation reaction: carrying out catalytic debenzylation on the 1-p-benzyloxyphenyl-2-(2-benzyloxybenzene ethylamino) propyl alcohol (V) by a palladium carbon / ammonium formate catalyst, thereby generating ritodrine (VI); and (5) carrying out salt forming reaction: carrying out salt forming on the ritodrine (VI) in a saturated hydrogen chloride organic solution, thereby generating ritodrine hydrochloride (I). The production method is green and environmentally-friendly, easy to operate, higher in yield, low in cost, and capable of greatly improving the quality of the product, so that bulk pharmaceuticals have higher market competitiveness.

Description

technical field [0001] The invention relates to the technical field of production of anti-premature drugs, in particular to an environment-friendly production method of ritodrine hydrochloride. Background technique [0002] Ritodrine hydrochloride, also known as hydroxyephedrine hydrochloride, has a chemical name of 1-(4-hydroxyphenyl)-2-[2-(4-hydroxyphenyl)ethylamino]propanol hydrochloride. Ritodrine hydrochloride is a β-sympathomimetic drug, belonging to β 2 -Adrenoceptor agonists that stimulate beta of uterine smooth muscle 2 -receptor, inhibits uterine smooth muscle contraction, reduces uterine activity and prolongs pregnancy. [0003] Ritodrine hydrochloride is the only drug approved by the U.S. Food and Drug Administration (FDA) for the prevention of premature birth. One of the birth control drugs. [0004] There are many preparation methods of ritodrine hydrochloride involved in the published literature reports at present, and the main synthesis routes can be summ...

Claims

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Application Information

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IPC IPC(8): C07C215/60C07C213/08
Inventor 刘斌张志生李雪辉周绍付培荣黄彩逢
Owner GUANGDONG XIANQIANG PHARMA