A kind of preparation method of levamlodipine maleate

Abstract

This invention provides a method for preparing levamlodipine maleate, belonging to the field of organic synthesis technology. The method comprises the following steps: mixing amlodipine base, D-(-)tartaric acid, and an organic solvent for a resolution reaction to obtain levamlodipine hemitartaric acid salt; and mixing the levamlodipine hemitartaric acid salt, maleic acid, and a reaction solvent for a salt substitution reaction to obtain levamlodipine maleate. This invention utilizes readily available raw materials, is simple to operate, and employs mild reaction conditions. The direct use of a salt substitution reaction to obtain levamlodipine maleate reduces the risk of racemization, improves product quality, lowers medication risks, and results in high yields at each step with minimal waste, making it suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a preparation method of levamlodipine maleate. Background Art

[0002] Amlodipine Besylate is a third-generation 1,4-dihydropyridine calcium antagonist developed by Pfizer in the United States in the 1990s. Its trade name is Norvasc, and its chemical name is: 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine benzenesulfonate. Its structural formula is shown in Formula 1:

[0003]

[0004] The structure of amlodipine contains two chiral enantiomers, of which the levorotatory enantiomer shows excellent calcium antagonism, which is about 1000 times that of the dextrorotatory enantiomer and twice that of the racemic enantiomer. In addition, levorotatory amlodipine can reduce the side effects such as acroedema, headache, and dizziness caused by racemic amlodipine. Therefore, the use of levorotatory amlodipine has a greater advantage than racemic amlodipine. The structure of levorotatory amlodipine maleate is shown in Formula 2:

[0005]

[0006] WO200860093, EP1407773, CN1278684A and CN104326970A reported that levoamlodipine maleate was obtained by salification in a solvent using levoamlodipine base and maleic acid as starting materials, with a yield of 78-91% and an ee value of about 98.4%. The yield of the product is low and the chiral purity is low. The reaction principle is shown in Formula 3:

[0007]

[0008] The preparation of levorotatory amlodipine base requires the separation and liberation of the racemic amlodipine base. The reaction principle is shown in Formula 4. During the liberation process, the racemization reaction of levorotatory amlodipine is prone to occur, which seriously affects the subsequent product quality of levorotatory amlodipine and its salts.

[0009] Summary of the invention

[0010] In view of this, the object of the present invention is to provide a method for preparing levamlodipine maleate. The present invention directly adopts a salt replacement reaction to obtain levamlodipine maleate, thereby reducing the risk of racemization and improving product quality.

[0011] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0012] The present invention provides a method for preparing levamlodipine maleate, comprising the following steps:

[0013] The amlodipine base, D-(-) tartaric acid and an organic solvent are mixed to perform a resolution reaction to obtain levorotatory amlodipine hemi-tartrate;

[0014] The levamlodipine hemi-tartrate, maleic acid and a reaction solvent are mixed to carry out a salt replacement reaction to obtain the levamlodipine maleate.

[0015] Preferably, the molar ratio of amlodipine base to D-(-) tartaric acid is 1.0:0.15-0.3.

[0016] Preferably, the organic solvent comprises methanol and acetonitrile, and the dosage ratio of the amlodipine base to the organic solvent is 1.0 g:5.0-15.0 mL.

[0017] Preferably, the volume ratio of methanol to acetonitrile in the organic solvent is 1:5.

[0018] Preferably, the resolution reaction is carried out under reflux conditions for 0.5 to 2.0 h.

[0019] Preferably, the molar ratio of the levamlodipine hemi-tartrate to maleic acid is 1.0:0.9-1.5.

[0020] Preferably, the temperature of the salt replacement reaction is 40-50° C. and the time is 2-8 hours.

[0021] Preferably, the reaction solvent includes one or more of water, methanol, ethanol, isopropanol and n-butanol.

[0022] Preferably, the maleic acid is added dropwise to the reaction system in the form of a maleic acid aqueous solution.

[0023] Preferably, the D-(-) tartaric acid is added dropwise to the reaction system in the form of a D-(-) tartaric acid solution.

[0024] The invention provides a method for preparing levamlodipine maleate, comprising the following steps: mixing amlodipine base, D-(-) tartaric acid and an organic solvent for splitting reaction to obtain levamlodipine hemi-tartrate; and mixing the levamlodipine hemi-tartrate, maleic acid and a reaction solvent for salt replacement reaction to obtain the levamlodipine maleate.

[0025] The raw materials of the invention are easily available, the operation is simple, the reaction conditions are mild, and the levamlodipine maleate is directly obtained by salt replacement reaction, thereby reducing the risk of racemization, improving the product quality, reducing the risk of medication, and having high yields in each step, less three wastes, and being suitable for industrial production.

[0026] Furthermore, the present invention adopts low boiling point organic solvent for splitting, which is easy to recover and apply after detection. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 It is the HPLC spectrogram of amlodipine hemi-tartrate in Example 1;

[0028] Figure 2 The levamlodipine maleate prepared in Example 1 1 H-NMR spectrum;

[0029] Figure 3 The HPLC spectrum of levamlodipine maleate prepared in Example 1;

[0030] Figure 4 The XRD spectrum of levamlodipine maleate prepared in Example 1;

[0031] Figure 5 The HPLC spectrum of levamlodipine maleate prepared in Example 2. DETAILED DESCRIPTION

[0032] The present invention provides a method for preparing levamlodipine maleate, comprising the following steps:

[0033] The amlodipine base, D-(-) tartaric acid and an organic solvent are mixed to perform a resolution reaction to obtain levorotatory amlodipine hemi-tartrate;

[0034] The levamlodipine hemi-tartrate, maleic acid and a reaction solvent are mixed to carry out a salt replacement reaction to obtain the levamlodipine maleate.

[0035] In the present invention, unless otherwise specified, the raw materials used are all commercially available products in the art.

[0036] The invention mixes amlodipine base, D-(-) tartaric acid and an organic solvent to carry out a splitting reaction to obtain levorotatory amlodipine hemi-tartrate.

[0037] In the present invention, the molar ratio of amlodipine base to D-(-) tartaric acid is preferably 1.0:0.15-0.3.

[0038] In the present invention, the D-(-) tartaric acid is preferably added dropwise to the reaction system in the form of a D-(-) tartaric acid solution.

[0039] In the present invention, the solvent of the D-(-) tartaric acid solution is preferably methanol, and the dosage ratio of the D-(-) tartaric acid solution to methanol in the D-(-) tartaric acid solution is preferably 4.6 g:30 mL.

[0040] In the present invention, the organic solvent includes methanol and acetonitrile, and the usage ratio of the amlodipine base to the organic solvent is preferably 1.0 g:5.0-15.0 mL.

[0041] In the present invention, the volume ratio of methanol to acetonitrile in the organic solvent is preferably 1:5.

[0042] In the present invention, the volume ratio of methanol to acetonitrile in the reaction system of the resolution reaction is preferably 3:10.

[0043] In the present invention, the resolution reaction is preferably carried out under reflux conditions, and the time is preferably 0.5 to 2.0 h, more preferably 1 h.

[0044] After the split reaction is completed, the present invention preferably subjects the obtained split reaction product to natural cooling, heat preservation, suction filtration and acetonitrile washing in sequence to obtain a wet product, and the wet product is mixed with ethanol for reflux purification, cooled again and then suction filtered, washed with ethanol, and then dried under reduced pressure to obtain the levamlodipine hemi-tartrate.

[0045] In the present invention, the final temperature of the natural cooling is preferably 10-40°C, more preferably 35°C, and the insulation time is preferably 10 minutes.

[0046] In the present invention, the reflux purification time is preferably 1 h.

[0047] In the present invention, the final temperature of the further cooling is preferably 10-40°C, more preferably 25°C.

[0048] After obtaining the levamlodipine hemi-tartrate, the present invention mixes the levamlodipine hemi-tartrate, maleic acid and a reaction solvent to carry out a salt replacement reaction to obtain the levamlodipine maleate.

[0049] In the present invention, the molar ratio of the levamlodipine hemi-tartrate to maleic acid is preferably 1.0:0.9-1.5.

[0050] In the present invention, the temperature of the salt replacement reaction is preferably 40 to 50° C., and the time is preferably 2 to 8 hours, more preferably 4 to 6 hours.

[0051] In the present invention, the reaction solvent preferably includes one or more of water, methanol, ethanol, isopropanol and n-butanol.

[0052] In the present invention, the maleic acid is preferably added dropwise to the reaction system in the form of a maleic acid aqueous solution.

[0053] In the present invention, the mass ratio of maleic acid to water in the maleic acid aqueous solution is preferably 1:10-11.

[0054] After the salt exchange reaction is completed, the present invention preferably cools the obtained salt exchange reaction product to 25° C. naturally, filters it, washes it with cold purified water, and dries it under reduced pressure to obtain the maleate levamlodipine.

[0055] The principle of preparing levamlodipine maleate of the present invention is shown in Formula 5:

[0056]

[0057] In order to further illustrate the present invention, the preparation method of levamlodipine maleate provided by the present invention is described in detail below in conjunction with examples, but they should not be construed as limiting the scope of protection of the present invention.

[0058] Example 1

[0059] Levoamlodipine hemi-tartrate

[0060] In a 1L four-necked flask, add 60mL of methanol, 300mL of acetonitrile, and 50g of amlodipine base, heat to reflux, slowly drop a mixed solution of 4.6g of D-(-)tartaric acid and 30mL of methanol, and react for 1 hour after the addition. Slowly cool to 35°C, stir for 10 minutes, filter, and wash the filter cake with an appropriate amount of acetonitrile to obtain a wet product.

[0061] The wet product was added into a 500 mL four-necked bottle, and 200 mL of ethanol was added. The mixture was heated to reflux and kept warm for 1 hour. The mixture was slowly cooled to 25° C. and kept warm for 1 hour. The mixture was filtered and washed with an appropriate amount of ethanol. The mixture was dried under reduced pressure to obtain 26.2 g of levamlodipine hemi-tartrate with a yield of 48.0%.

[0062] HPLC detection of levamlodipine hemi-tartrate Figure 1 , the peak area of ​​levamlodipine hemi-tartrate accounts for 100%, which shows that the chiral purity of levamlodipine hemi-tartrate reaches 100%.

[0063] Levaline maleate

[0064] In a 500mL four-necked bottle, add 20g of amlodipine hemi-tartrate and 200g of purified water, control the temperature at 40°C, slowly dropwise add a mixed solution of 2.4g of maleic acid and 24g of purified water, after the addition, keep warm for 6 hours, slowly cool to 25°C, filter, wash with cold purified water, and dry under reduced pressure to obtain 17.8g of amlodipine maleate with a yield of 92.2%.

[0065] NMR data of levamlodipine maleate (see Figure 2 ): 1 H-NMR(500MHz,DMSO-d6)δ:8.4(1H,s),7.9(3H,s),7.4(1H,t),7.3(1H,d),7.2(1H,t),7.1(1H,m),6.1(2H,s ),5.3(1H,s),4.7(1H,s),4.6(1H,s),4.0(2H,m),3.7(2H,t),3.5(3H,s),3.1(2H,m),2.3(3H,s),1.1(3H,t).

[0066] HPLC detection of isomers Figure 3 , it can be seen that the isomer is less than 0.1%.

[0067] Crystal form detection see Figure 4 , the data are shown in Table 1.

[0068] Table 1 XRD data

[0069]

[0070]

[0071] Example 2

[0072] The preparation of levamlodipine hemi-tartrate is the same as in Example 1

[0073] Add 20g of levamlodipine hemi-tartrate and 100mL of ethanol to a 500mL four-necked bottle, control the temperature at 50°C, slowly drop 2.4g of maleic acid and 250g of purified water, after addition, keep warm for 6 hours, slowly cool to 25°C, filter, wash with cold purified water, and dry under reduced pressure to obtain 16.5g of levamlodipine maleate, with a yield of 85.5%. HPLC detection of isomers: Figure 5 , it can be seen that the isomer is less than 0.1%.

[0074] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A method for preparing levamlodipine maleate, characterized in that: The specific steps are as follows: The amlodipine base, D-(-) tartaric acid and an organic solvent are mixed to perform a resolution reaction to obtain levorotatory amlodipine hemi-tartrate; The levamlodipine hemi-tartrate, maleic acid and a reaction solvent are mixed to perform a salt replacement reaction to obtain the levamlodipine maleate; The organic solvent is methanol and acetonitrile, the dosage ratio of the amlodipine base to the organic solvent is 1.0 g:5.0-15.0 mL, and the volume ratio of methanol to acetonitrile in the organic solvent is 1:5; The reaction solvent is water.

2. The preparation method according to claim 1, characterized in that: The molar ratio of amlodipine base to D-(-) tartaric acid is 1.0:0.15-0.

3.

3. The preparation method according to claim 1, characterized in that: The resolution reaction is carried out under reflux conditions for 0.5 to 2.0 hours.

4. The preparation method according to claim 1, characterized in that: The molar ratio of the levamlodipine hemi-tartrate to maleic acid is 1.0:0.9-1.

5.

5. The preparation method according to claim 1, characterized in that: The temperature of the salt replacement reaction is 40-50° C. and the time is 2-8 hours.

6. The preparation method according to claim 1, characterized in that: The maleic acid is added dropwise into the reaction system in the form of maleic acid aqueous solution.

7. The preparation method according to claim 1, characterized in that: The D-(-) tartaric acid is added dropwise into the reaction system in the form of a D-(-) tartaric acid solution.

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