CN107935912A - A kind of preparation process of Amlodipine intermediate - Google Patents

Abstract

The present invention relates to a kind of safe and efficient method for preparing amlodipine intermediate: The specific steps are: step 1, using ethyl 4-chloroacetoacetate and sodium p-toluenesulfonate as raw materials, heating and reacting in a reaction solvent to obtain compound 2; step 2, compound 2 and N-hydroxyethylphthaloimide Amine, adding a basic compound as a catalyst, adding a phase transfer catalyst at the same time, heating to obtain compound 1. The intermediate compound 2 of the present invention adopts 4-hydroxyacetoacetate ethyl ester protected by p-toluenesulfonic acid. Due to the use of p-toluenesulfonate, the conditions of the etherification step are greatly reduced, while avoiding the use of dangerous or expensive reagents, making the production Security is greatly improved.

Description

A kind of preparation technology of amlodipine intermediate

technical field

The invention relates to the field of medicinal chemistry, in particular to a preparation process of an amlodipine intermediate.

Background technique

Amlodipine is a calcium antagonist and can be used to treat various types of hypertension (alone or in combination with other drugs) and angina, especially spontaneous angina (alone or in combination with other drugs). This product has a certain protective effect on the kidneys.

Amlodipine is characterized by a slow rate of binding and dissociation with receptors, so the drug effect occurs later and lasts longer. The selective effect on vascular smooth muscle is greater than that of nifedipine. In patients with myocardial ischemia, this product can increase cardiac output and coronary flow, increase myocardial oxygen supply and reduce oxygen consumption, and improve exercise capacity. In addition, this product may activate LDL receptors, reduce fat accumulation on the arterial wall and inhibit collagen synthesis, so it has anti-arteriosclerosis effect.

Among the synthetic routes reported in the literature, the following route is one of the main industrial methods.

The process of this route is relatively simple, multi-step does not require purification and can be directly used in the next step reaction, the overall yield is high, and no special equipment is required. But step 2 uses a large amount of sodium hydride, which is lacking in safety. So, finding an effective alternative is worthwhile work.

According to the reaction mechanism, it is first necessary to remove the hydrogen of the hydroxyl group with a strong base to form sodium alkoxide, and then react with ethyl chloroacetoacetate to remove sodium chloride to obtain the target product. Therefore, the methods reported in the literature are all based on this mechanism, using a limited number of strong base reactions.

method 1

In the method disclosed in Chinese patent CN106749187, the target compound can be obtained by reacting N-hydroxyethylphthalimide and ethyl 4-chloroacetoacetate in THF solution with sodium hydride as a strong base.

As stated above, since sodium hydride catches fire with water and releases a large amount of hydrogen gas during the reaction, there are obvious safety hazards in the production process.

Method 2

The method disclosed in US2012022251, using sodium tert-butoxide and THF system, can also complete similar conversion.

The sodium tert-butoxide used in this method is expensive, and it reacts violently with water, which also has the danger of fire.

Method 3

The method disclosed in US4120956, using sodium ethoxide/THF system, can also complete similar conversion.

But we tried repeatedly, and the results were not satisfactory. Some conditions did not even yield the target product.

In order to overcome the shortcomings of the above methods, the present invention provides a safe and efficient method for preparing amlodipine intermediates. The raw materials of this method are cheap and easy to obtain, the production operation is simple, and it is suitable for industrial production.

Contents of the invention

The purpose of the present invention is to overcome the defects in the prior art and provide a safe and efficient method for preparing the amlodipine intermediate, which is easy to prepare, high in yield and low in implementation cost.

The technical solution adopted by the present invention to solve its technical problems is:

A safe and efficient method for preparing the amlodipine intermediate:

The specific steps are:

Step 1, using ethyl 4-chloroacetoacetate and sodium p-toluenesulfonate as raw materials, heating in a reaction solvent, and reacting to obtain compound 2;

Step 2, compound 2 and N-hydroxyethylphthalimide, adding a basic compound as a catalyst, adding a phase transfer catalyst at the same time, heating to obtain compound 1.

Preferably, in step 1, the molar ratio of ethyl 4-chloroacetoacetate and sodium p-toluenesulfonate is 1:1-1:1.3. Preferably, in step 1, the molarity of ethyl 4-chloroacetoacetate and sodium p-toluenesulfonate

The ratio is 1:1.16.

Preferably, in step 1, the reaction temperature is 100-105°C.

Preferably, in step 1, the reaction solvent is any one of absolute ethanol, isopropanol, dioxane, DMF or THF.

Preferably, in step 2, the molar ratio of compound 2 to N-hydroxyethylphthalimide is 1:1-1:1.3.

Preferably, in step 2, the molar ratio of compound 2 to N-hydroxyethylphthalimide is 1:1.2.

Preferably, in step 2, the basic compound is sodium hydroxide.

Preferably, in step 2, the reaction solvent is any one of toluene, dioxane, DMF or acetonitrile.

Preferably, in step 2, the phase transfer catalyst is selected from any one of sodium dodecylbenzenesulfonate, PEG-400 or tetrabutylammonium bromide.

Beneficial effect: the present invention solves the defects existing in the background technology,

1. Amlodipine intermediate compound 2 adopts ethyl 4-hydroxyacetoacetate protected by p-toluenesulfonic acid. Due to the use of sodium p-toluenesulfonate, the conditions of the etherification step are greatly reduced, while avoiding the use of dangerous or expensive reagents, The production safety is greatly improved.

2. Through comparative experiments, the yield of adding sodium p-toluenesulfonate is much greater than that of adding p-toluenesulfonic acid/triethylamine.

3. Through comparative experiments, in step 2, the purity of the product added with the phase transfer catalyst is greatly improved.

Detailed ways

The preferred embodiments of the present invention are described in detail below, so that the advantages and features of the present invention can be more easily understood by those skilled in the art, so as to define the protection scope of the present invention more clearly.

Embodiments of the invention include:

Embodiment 1: the preparation of compound 2

350ml of DMF, 49.5g of ethyl 4-chloroacetoacetate and 67.9g of sodium p-toluenesulfonate were added to the flask, and the temperature was raised to 105°C for 5.5h. About 2/3 of the solvent was distilled off under reduced pressure to obtain a solid-liquid mixture. Cool to room temperature, add 500ml of water and stir for 1h. Suction filtration and washing with water gave light brown solid. It was directly used in the second reaction without purification. Yield: 88.5%.

Embodiment 2: the preparation of compound 2

350ml of DMF, 49.5g of ethyl 4-chloroacetoacetate and 67.9g of sodium p-toluenesulfonate were added to the flask, and the temperature was raised to 105°C for 5.5h. After cooling to room temperature, the reactant was poured into 1000ml of water, stirred for 1 hour, filtered with suction and washed with water to obtain a light brown solid. It was directly used in the second reaction without purification. Yield: 86.1%.

Example 3:

In the comparative experiment of the preparation of compound 2, the effect of replacing sodium p-toluenesulfonate with p-toluenesulfonic acid and triethylamine on the reaction was investigated.

Add 350ml of DMF, 49.5g of ethyl 4-chloroacetoacetate and 60.2g of p-toluenesulfonic acid into the flask, and cool to 5-10°C. Slowly add 35.4 g of triethylamine dropwise, keep warm for 1 h after the addition, and then raise the temperature to 105° C. for 5.5 h. About 2/3 of the solvent was distilled off under reduced pressure to obtain a solid-liquid mixture. Cool to room temperature, add 500ml of water and stir for 1h. There was oil sticking to the bottle wall, poured off the water layer, added 40ml of ethyl acetate and stirred overnight. Suction filtration and washing with water gave light brown solid. Yield: 26.7%.

It can be seen from the yield that the yield of compound 2 prepared by adding p-toluenesulfonic acid and triethylamine to ethyl 4-chloroacetoacetate is much lower than that of the reaction between ethyl 4-chloroacetoacetate and sodium p-toluenesulfonate.

Embodiment 4: the preparation of compound 1

Add 420ml of dioxane, 33.0g of compound 2, 25.6g of N-hydroxyethylphthalimide and 55.0g of sodium hydroxide into the flask, and then add 5.5g of PEG-400. Warm up to reflux for 3h, cool down to room temperature, and filter. The filtrate was concentrated to near dryness under reduced pressure, added 300ml of water and stirred for 1h, but it could not solidify. Add toluene for extraction (50ml x 3), combine toluene, wash with water, and dry. The solvent was distilled off to obtain a light brown viscous liquid. Yield: 89.1%, purity: 92.5% (according to the peak area normalization method of high performance liquid chromatography).

Embodiment 5: the preparation of compound 1

Add 420ml of dioxane, 33.0g of compound 2, 25.6g of N-hydroxyethylphthalimide and 55.0g of sodium hydroxide into the flask, and then add 5.5g of tetrabutylammonium bromide. Warm up to reflux for 3h, cool down to room temperature, and filter. The filtrate was concentrated to near dryness under reduced pressure, added 300ml of water and stirred for 1h, but it could not solidify. Add toluene for extraction (50ml x 3), combine toluene, wash with water, and dry. The solvent was distilled off to obtain a light brown viscous liquid. Yield: 82.7%, purity: 83.9% (according to the peak area normalization method of high performance liquid chromatography).

Embodiment 6:

In the comparative experiment of the preparation of compound 1, the effect of not adding a phase transfer catalyst on the reaction was investigated.

420 ml of dioxane, 33.0 g of compound 2, 25.6 g of N-hydroxyethylphthalimide and 55.0 g of sodium hydroxide were added to the flask. Warm up to reflux for 3h, cool down to room temperature, and filter. The filtrate was concentrated to near dryness under reduced pressure, added 300ml of water and stirred for 1h, but it could not solidify. Add toluene for extraction (50ml x 3), combine toluene, wash with water, repeat 3 times, and dry. The solvent was distilled off to obtain a light brown viscous liquid. Yield: 86.5%, purity: 59.6% (according to the peak area normalization method of high performance liquid chromatography).

From the purity of the reaction product, it can be seen that in the preparation of compound 1, the purity of compound 1 was lower without adding phase transfer catalyst than adding phase transfer catalyst PEG-400 and tetrabutylammonium bromide.

It should be understood that the specific embodiments described above are only used to explain the present invention, not to limit the present invention. Obvious changes or variations derived from the spirit of the present invention are still within the protection scope of the present invention.

Claims (10)

1. A kind of 1. safe and efficient method for preparing Amlodipine intermediate, it is characterised in that：Its reactions steps is：

   Concretely comprise the following steps：

   Step 1, using 4- chloroacetyl acetacetic esters and paratoluenesulfonic acid sodium salt as raw material, in reaction dissolvent, heating, reactionization Compound 2；

   Step 2, compound 2 and N- ethoxy phthalimides, addition alkali compounds is catalyst, while adds phase transfer catalysis (PTC) Agent, heating, obtains compound 1.
2. A kind of 2. safe and efficient method for preparing Amlodipine intermediate according to claim 1, it is characterised in that：Step In rapid 1, the molar ratio of 4- chloroacetyl acetacetic esters and paratoluenesulfonic acid sodium salt is 1:1-1:1.3.
3. A kind of 3. safe and efficient method for preparing Amlodipine intermediate according to claim 2, it is characterised in that：Step In rapid 1, the molar ratio of 4- chloroacetyl acetacetic esters and paratoluenesulfonic acid sodium salt is 1:1.16.
4. A kind of 4. safe and efficient method for preparing Amlodipine intermediate according to claim 1, it is characterised in that：Step In rapid 1, reaction temperature is 100-105 DEG C.
5. A kind of 5. safe and efficient method for preparing Amlodipine intermediate according to claim 1, it is characterised in that：Step In rapid 1, reaction dissolvent is selected any in absolute ethyl alcohol, isopropanol, dioxane, DMF or THF.
6. A kind of 6. safe and efficient method for preparing Amlodipine intermediate according to claim 1, it is characterised in that：Step In rapid 2, the molar ratio of compound 2 and N- ethoxy phthalimides is 1:1-1:1.3.
7. A kind of 7. safe and efficient method for preparing Amlodipine intermediate according to claim 6, it is characterised in that：Step In rapid 2, the molar ratio of compound 2 and N- ethoxy phthalimides is 1:1.2.
8. A kind of 8. safe and efficient method for preparing Amlodipine intermediate according to claim 1, it is characterised in that：Step In rapid 2, the alkali compounds is sodium hydroxide.
9. A kind of 9. safe and efficient method for preparing Amlodipine intermediate according to claim 1, it is characterised in that：Step In rapid 2, reaction dissolvent is selected any in toluene, dioxane, DMF or acetonitrile.
10. A kind of 10. safe and efficient method for preparing Amlodipine intermediate according to claim 1, it is characterised in that： In step 2, the phase transfer catalyst is selected from any of neopelex, PEG-400 or tetrabutylammonium bromide.