Method for production of amlodipine enantiomer of high optic purity

FIELD: medicine.

SUBSTANCE: method for production of optically pure solvate dimethyl formamide of L-hemiartrate(S)-amlodipine includes stages of processing of (R,S)-amlodipine base with L-tartaric acid in presence of dimethyl formamide and cosolvent. Invention is also related to solvate DMFA of L-hemiartrate(S)-amlodipine, solvate of DMFA of L-hemiartrate(R)-amlodipine, solvate of dimethyl formamide L-hemiartrate(S)-amplodipine, produced according to clause 1 and characterised with the following spectrum 1H NMR: 1H NMR (CDCl3): 8.01 (s, 1H, CHO); 7.04-7.41 (m, 4H); 5.40 (s, 1H); 4.72 (kk, 2H), 4.36 (s, 1H), 4.02 (m, 2H), 3.77 (m, 2H), 3.57 (s, 3H), 3.28 (m, 2H), 3.0 (s, 3H; DMFA); 2.8 (s, 3H; DMFA); 2.31 (s, 3H), 1.15 (t, 3H), and also to methods for production of salt of hemipentahydrate bezylate(S)-amlopidine, salt of dihydrate of bezylate(S)-amlodipine.

EFFECT: production of specified compound by economic and industrially realisable method with high enantiomer purity.

20 cl, 14 ex, 1 dwg

 

The technical field to which the invention relates.

This invention relates to a method for producing optically active isomer of amlodipine of formula (1) with a high degree of optical purity and its pharmaceutically acceptable salts.

The invention also relates to a method of obtaining MES of dimethylformamide (DMF) L hemitartrate (S)-amlodipine (2A) and MES DMF L-hemitartrate (R)-amlodipine (3A) of racemic (RS)-amlodipine free base using L-tartaric acid and their effective separation and purification of salts with a high degree of optical purity. The invention also relates to a method of transforming MES DMF L-hemitartrate (S)-amlodipine (2A) and MES DMF L-hemitartrate (R)-amlodipine (3A) in their pharmaceutically acceptable salts, such as besilate, maleate, fumarate, succinate, oxalates, etc. with allocation or no allocation of free chiral amlodipine base after splitting.

X=(a) MES DMF 1/2 L-(+)-tartaric acid; (b) benzolsulfonat acid; (s) 1/2 maleic acid; (d) 1/2 fumaric acid; (e) 1/2 succinic acid; (g) nicotinic acid; (h) camphorsulfonic acid; etc

The level of technology

Amlodipine and its salts are long-term sustainable Blackthorne calcium is s channels, applicable in the treatment of cardiovascular disorders. Racemic amlodipine currently applied in the form of its salts besilate or maleate in the treatment of angina, hypertension and congestive heart failure. Amlodipine has a chiral center at position 4 dihydropyridine cycle and exists in two enantiomeric forms R and S, showing the different pharmacological profiles. S-Isomer is more severe calcium channel blocker, while the R-isomer has a low activity block calcium channels or does not have it. The use of optically pure (S)-amlodipine for the treatment of hypertension and angina disclosed in US 6057344.

R-(+)-Amlodipine has weak activity as a calcium channel blocker, but he is not pharmacologically inert, in fact, he is a strong inhibitor of migration of smooth muscle cells (U.S. patent No. 6080761). Therefore, patients with a specific medical need (S)-amlodipine need to obtain pharmaceutical compositions containing (S)-amlodipine, which essentially does not contain (R)-amlodipine. At the present time there is no amlodipinesee product, which contains (S)-amlodipine, essentially free of R-(+)-enantiomer.

Enantiomerically pure isomers amlodipine were first obtained by the separation between the exact complex diastereotopic of azidoethyl 2-methoxy-2-phenylethanol [J.E.Arrowsmith et al., J. Med. Chem., 29, 1696, 1986].

The separation of R - and S-isomers amlodipine also achieved by splitting the intermediate racemic salts azidocillin and cinchonidine, which are then turned in the desired enantiomerically pure (R)- and (S)-isomers [J.E.Arrowsmith et al., EP 0331215].

In the US 6046338 revealed that the splitting of racemic amlodipine base can be carried out using L - or D-tartaric acid in dimethyl sulfoxide and receive, respectively, L-hemitartrate R-(+)-amlodipine and D-hemitartrate 3-(-)-amlodipine [US 2003176706; EP 1348697]. In these patents also clearly indicated that DMSO is essential for such a unique way.

Spargo has described a method of obtaining monosulfate DMSO D-hemitartrate (S)-amlodipine. Also provides an example of the use of co-solvent in combination with DMSO. Senior installation FDA provide that the residual concentration of DMSO should not exceed 0.5% [Guidance for Industry impurities: residual solvents, FDA, September 1999, page 9].

However, the use of DMSO in the final stage, i.e. the stage of cleavage, though undesirable, but is included in most of the procedures described in the literature.

There are the following disadvantages associated with the method disclosed in prior art.

1) the Use of naturally occurring and cost-L-tartaric acid for cleavage of racemic amlodipine leads to madelenenorell R-(+)-isomer of amlodipine, while the desired S-(-)-isomer passes into the mother liquor, together with other impurities. The desired S-(-)-isomer have to allocate using a more expensive D-tartaric acid to the next stage, and due to this, the whole process becomes lengthy, inefficient and cumbersome.

2) Sulfoxide is a solvent with an unpleasant odor and are therefore not suitable for use on an industrial scale because of the interests of the environment.

3) High boiling point of dimethyl sulfoxide (183°C), which is present in the selected (S)-amlodipine, makes it very difficult to remove it from the final product during drying, and through this increase the content of organic volatile impurities (S)-amlodipine, and it becomes unsuitable for pharmaceutical applications.

In EP 1407773 and US 6608206 disclosed is a method of obtaining besilate (S)-amlodipine, including the interaction of (S)-amlodipine free base with benzosulfimide acid in an organic solvent.

In these patents describes a method of obtaining salt accession acid (S)-amlodipine free base and clearing of such salts by recrystallization from isopropanol, but there is no indication about the splitting of racemic amlodipine.

Further, in the US 6822099 and WO 03/035623 opisivaetsya splitting racemic the ski amlodipine base using L - or D-tartaric acid in the solvent is dimethylacetamide.

In these patents describes a method of splitting amlodipine via obtaining MES dimethylacetamide L - or D-tartrate, respectively, (R)- or (S)isomer of amlodipine.

In this case, (S)-isomer is removed from the racemic mixture by using a relatively expensive D-tartaric acid. MES dimethylacetamide D-hemitartrate (S)-amlodipine get after stirring for 3-5 hours.

Need MES of dimethylacetamide extracted and converted into the desired salt accession acid through to obtain the free base after processing inorganic base such as sodium hydroxide.

The predominant method disclosed in US 6822099, has the following disadvantages:

a) the use of expensive D-tartaric acid for cleavage of racemic amlodipine, as in the prior art (S)-isomer of amlodipine produce only D-tartaric acid instead of L-tartaric acid;

b) the use of naturally occurring relatively cheap L-tartaric acid leads to the separation of the undesired (R)-isomer of amlodipine, while the desired (S)-isomer should be distinguished from the mother liquor, already containing significant impurities unwanted (R)-isomer.

In another application WO 2004/024689 describes the splitting of racemic amlodipine base using L - or D-tartaric acid and dimethyl sulfoxide in quality is the firmness of the solvent.

This application describes a method of splitting of racemic amlodipine using DMSO and L-tartaric acid. In this way first, select the unwanted (R)-isomer of amlodipine in the form of salts of L-hemitartrate, while as desired (S)-isomer together with impurities enters the uterine fluid.

The desired (S)-isomer is recovered from the mother liquor by adding an organic solvent, such dichlormethane. Then salt Hemi-L-tartrate (S)-amlodipine boiling under reflux is dissolved in an organic solvent such as methanol and neutralized by adding a solution of an inorganic base.

This method, although for the splitting of racemic amlodipine use relatively cheap L-tartaric acid, has several disadvantages that make the method unsuitable for the organization of serial production, and one of them is that L-hemitartrate (S)-amlodipine separated from the mother liquor, which itself contains many impurities.

a) (S)-Amlodipine get not directly after adding L-tartaric acid to a mixture of racemic amlodipine and DMSO, and produce Hemi-L-tartrate (S)-amlodipine from the mother liquor, which, in addition to (S)-amlodipine, also contains other impurities. Thus, there is a possibility that some of these impurities, presence is existing in the mother liquor, go into a solid (S)-amlodipine during deposition of the organic solvent, such dichlormethane.

b) the Method of obtaining (S)-amlodipine is a long and cumbersome, as it involves three stages, namely

i) adding L-tartaric acid, filtering off the resulting precipitate,

ii) isolation of MES DMSO right Hemi-L-tartrate (S)-amlodipine together with part of the undesired isomer, as well as other impurities, which is a common drawback in obtaining the desired enantiomer from the filtrate,

iii) processing MES DMSO Hemi-L-tartrate (S)-amlodipine base to obtain (S)-amlodipine free base.

C) using a solvent such as dimethyl sulfoxide, which has an unpleasant odor and unsuitable for industrial applications.

In the US 6646131 disclosed the use hexadeuterated dimethyl sulfoxide (DMSO-d6in combination with D - or L-tartaric acid for separation of (R)- and (S)-isomers of amlodipine.

This method is not suitable for industrial application because hexadeuterated dimethyl sulfoxide very expensive. In addition, hexadeuterated dimethyl sulfoxide, being hygroscopic in nature, has a tendency to destruction to Mediterraneo dimethyl sulfoxide or during storage or use. In addition, in this case t is the train requires a relatively expensive D-tartaric acid to highlight the desired (S)-isomer of amlodipine.

The main shortcomings of the prior art consist of or use of expensive agents cleavage, such as D-tartaric acid or camphorsulfonic acid, or lack of suitability for industrial applications.

In addition, also disclosed the use of L-tartaric acid to obtain L-hemitartrate (S)-amlodipine [US 2003176706 and EP 1348697]. However, the enantiomeric purity of (S)-amlodipine obtained in this way is only 97%. In addition, this method includes the use of only the required quantity of tartaric acid (0.5 equivalent) at the beginning of the interaction, subsequent separation of precipitated precipitated L-hemitartrate (R)-amlodipine and then separated from the filtrate precipitated precipitated L-hemitartrate (S)-amlodipine subsequent filtering.

Thus, using the solvent dimethylacetamide or dimethylsulfoxide cannot be avoided initial allocation of R-isomer. First, there is a selection of (R)-isomer, and its removal at 100% is a task that requires voltage, the remaining (R)-isomer precipitates in the final crystallization, which leads to poor enantiomeric purity of (S)-isomer. Thus, the application of this method for splitting amlodipine base on his inationary on a large scale gives unsatisfactory results as output, so the enantiomeric purity. Hence, there is an urgent need to develop cost-effective industrial feasible way of splitting through which stands out mainly MES S-amlodipine high enantiomeric purity.

The purpose of the invention

The main aim of the invention is industrially feasible method of obtaining MES S-amlodipine and MES R-amlodipine high enantiomeric purity using readily available and more economical reagent.

Another aim of the invention is the preferential allocation of MES S-amlodipine after adding L-tartaric acid to racemic amlodipine, rather than allocating L-hemitartrate (S)-amlodipine from the mother liquor.

Another aim of the invention is a method of obtaining (S)-amlodipine high purity cost-effective and industrially feasible by reducing processing time and, consequently, each working cycle, labor, utilities, employment reactor, etc.

Another aim of the invention is a single enantiomer of MES DMF L-hemitartrate amlodipine.

Another purpose of this invention is a method of turning pure chiral (S)-amlodipine base or tartrate its pharmaceutically acceptable salt.

Description of the invention

One aspect of the invention relates to methods for the receiving of MES DMF L-hemitartrate (S)-amlodipine high optical purity and in good yield by treatment of (R,S)-amlodipine base wine acid, selected from among D-tartaric acid and L-tartaric acid, in the presence of dimethylformamide and co-solvent.

Also, adding to the above reaction mixture of D - or L-tartaric acid in excess gives MES DMF L-hemitartrate R-amlodipine.

Thus, the invention relates to a simple, economically feasible and effective ways to obtain MES amlodipine and pharmaceutically acceptable salts in good yield and with good enantiomeric purity (>99% CI). Accordingly, the invention relates to a superb tool for industrial preparation of solvate and salts of S-amlodipine.

To effect the splitting of racemic amlodipine L-tartaric acid with the formation of (S)-amlodipine tested several solvents belonging to different classes, such as ketones (acetone, methyl ethyl ketone and methyl isobutyl ketone), alcohols (methanol, ethanol, isopropanol, n-butanol), esters (ethyl acetate, isopropylacetate, butyl acetate), ethers (diethyl ether, diisopropyl ether, tetrahydrofuran), chlorinated hydrocarbons (dichloromethane, chloroform), hydrocarbons (toluene, cyclohexane), amides (dimethylformamide, dimethylacetamide, and acetonitrile.

For some conventional experiments, the inventors have unexpectedly discovered that the use of the solvent Dimity is of formamide gives MES (S)-amlodipine optical purity of more than 76%, while dimethylacetamide, about which there are messages on the prior art, gives (S)-amlodipine optical purity of 49.39%. This result the authors of the invention in the case of dimethylacetamide was very unexpected and completely different from these prior art.

Therefore, further work was carried out with dimethylformamide with the intention of improving the optical purity of S-amlodipine. The inventors have unexpectedly discovered that the use of co-solvent in combination with dimethylformamide gives MES S-amlodipine very high degree of purity of at least 95%. Therefore, the splitting of racemic amlodipine was carried out with DMF in combination with a co-solvent.

Accordingly, the racemic (R,S)-amlodipine free base is treated with L-tartaric acid in dimethylformamide (DMF) or in combination with a co-solvent. The co-solvent can be selected from the group consisting of water, alcohols, esters, amides, halogenated hydrocarbons, hydrocarbons, etc. Preferred alcohol is a linear saturated alcohol. The preferred alcohol is methanol. Preferred chlorinated solvent is dichloromethane, and the preferred aliphatic hydrocarbon is hexane.

In addition, the research noted that when L-sour wine is from, dissolved in a mixture of dimethylformamide and co-solvent, is added to a mixture of racemic amlodipine and mixtures of dimethylformamide and co-solvent, the product was completely unexpected. It was salt hemitartrate (S)-amlodipine, which stood out first instead hemitartrate (R)-amlodipine, which was expected and which, as a rule, it was reported on prior art. In addition, the specified salt hemitartrate (S)-amlodipine allocated in the form of MES DMF, obtained with high optical purity (over 98%).

The main advantage is that now the method according to the invention the connection MES hemitartrate S-amlodipine can be obtained in one step, cheap and without the use of complicated procedures. In addition, there is no loss of product, produced as the first product.

In addition, when dimethylformamide is used with water, the output besilate S-amlodipine is 80-95%.

The addition of 0.20-0.30 equivalent, preferably 0.25 to 0.3 equivalent of L-tartaric acid or as such or in the form of a mixture with one-dimethylformamide or a mixture of dimethylformamide/co-solvent ensures that formed mainly only MES DMF L-hemitartrate (S)-amlodipine. We found that the chiral purity of MES DMF L-hemitartrate (S)-amlodipine is pharmaceutically acceptable. In affect, the, get enriched in R-isomer mother liquor, from which emit MES DMF L-hemitartrate (R)-amlodipine using another 0.2 to 0.25 equivalent of L-tartaric acid. High diastereomeric purity L-hemitartrate S-amlodipine can be achieved by using, optionally, an appropriate co-solvent from among the above organic solvents, getting S-isomer enriched MES DMF Hemi-L-tartrate. Pharmaceutically acceptable salts of amlodipine, for example, besylate amlodipine, receive, adding benzosulfimide acid to the MES DMF L-hemitartrate (S)-amlodipine in aqueous medium or in a mixture of organic solvent and water, and get (hydrate)nbesilate (S)-amlodipine, where n=1/2, 1-3, preferably, hemipentahydrate or the dihydrate salt besilate (S)-amlodipine.

On the other hand, the addition of 0.25 to 0.3 equivalent of D-tartaric acid guarantees, which is formed, preferably, only the MES DMF D-hemitartrate (R)-amlodipine. We found that the chiral purity of MES DMF D-hemitartrate (R)-amlodipine is >99% CI. Thus, uterine liquid becomes enriched S-isomer, from which the MES DMF salt D-hemitartrate (S)-amlodipine (90% CI) was isolated by adding 0.2 to 0.25 equivalent of D-tartaric acid. High diastereomeric purity (>99% CI), for example, D-hemitartrate R-amlodipine reach the placenta is the fact that temperature-dependent crystallization of enriched MES DMF hemitartrate of alcoholic solvents, such as methanol, ethanol, n-propanol, isopropanol and mixtures thereof, etc., preferably methanol and/or ethanol.

The amount of the mixture of DMF/water splitting amlodipine can range from 9-13 amount of amlodipine. The amount of organic solvent in a mixture of DMF/co-solvent may be 14-16%. The preferred amount of co-solvent 15%.

Chiral pure salt, L-hemitartrate R - and S-amlodipine can, optionally, be converted into their corresponding free base by treatment with bases, such as hydroxides of alkali metals, for example, NaOH, KOH, at 20-35°C. Pharmaceutically applicable salts of R - and S-amlodipine get to or from their respective tartratami or of their free bases with acids, such as benzolsulfonat acid, nicotinic acid, succinic acid, maleic acid, fumaric acid, oxalic acid, camphor-10-sulfonic acid, etc.

According to the present invention, a method of obtaining pure chiral L-hemitartrate (S)-amlodipine and L-hemitartrate (R)-amlodipine includes stage

i) obtaining a mixture of L-tartaric acid or D-tartaric acid and (RS)-amlodipine in DMF with a co-solvent;

ii) filtering the received MES DMF L-hemitartrate (S)-amlodipine, or MES DMF D-hemitartrate (R)-amlodipine;

iii) optionally, adding an excess of RAS is e added enantiomer of tartaric acid to the mother liquor from stage (ii) and filtering DMF L-hemitartrate (R)-amlodipine, or MES DMF D-hemitartrate (S)-amlodipine.

The co-solvent mentioned above may be an inorganic solvent or an organic solvent. Inorganic solvent is water.

I) Splitting of racemic amlodipine L-tartaric acid in the presence of aqueous dimethylformamide

Found that the splitting of racemic amlodipine is achieved by using as the solvent of the aqueous dimethylformamide.

The influence of presence of water in dimethylformamide in the splitting of racemic amlodipine.

The authors of the present invention in the course of the study found that when dimethylformamide is used alone, it does not lead to a complete splitting of racemic amlodipine.

The splitting of racemic amlodipine occurs only when the dimethylformamide add water (one of the co-solvents) in an amount of 2-50% (vol./vol.).

The preferred amount of water added to the dimethylformamide is from 8 to 20% (vol./about.) of the total volume of a mixture of dimethylformamide/water.

To obtain high enantiomeric purity more preferred amount of water added to the dimethylformamide for splitting varies from 10% to 15%.

Also the purity of the obtained (S)-amlodipine depends on dilution of the reaction mixture. Dilution of the reaction mixture, preferably reaches 9-13 times relates the flax racemic amlodipine base.

Splitting can be performed at a temperature from 24°C to 40°C, preferably from 24°C to 28°C.

II) Splitting of racemic amlodipine in the presence of dimethylformamide and an organic solvent

This invention also relates to a method, in which the splitting of racemic amlodipine can be achieved with the use of dimethylformamide in combination with other organic solvents as co-solvents.

The co-solvent selected from the group consisting of alcohols, esters, amides, halogenated solvents, hydrocarbons, etc.

The influence of co-solvent in the mixture with dimethylformamide in the splitting of racemic salt of L-hemitartrate amlodipine for better understanding shown in the table.

The influence of co-solvent in the mixture with dimethylformamide in the splitting of racemic amlodipine
No.The co-solvent, 15% in a mixture with dimethylformamideOptical purity of (S)-amlodipineOutput %
1.Methanol99,7042,37
2.Di is Loretan 99,3852,9
3.n-Hexane99.9731,77
4.The ethyl acetate99,3721,18
5.Note: without co-solvent optical purity of MES DMF L-hemitartrate (S)-amlodipine is only 76% when the output 96,25% (wt./wt.)

It is found that the optical purity of MES DMF L-hemitartrate (S)-amlodipine also depends on the amount of organic solvent.

The amount of organic co-solvent in the mixture of DMF/co-solvent that may be required for obtaining optical purity with one or crystallization, is from 3 to 30 vol.% of the total volume of the mixture of DMF/co-solvent.

However, the preferred amount of organic cosolvent is from 12 to 18% (about./about.) of the total volume of the mixture of DMF/co-solvent.

To obtain the desired purity of the different parameters that you can modify are the temperature of the mixture, the time of crystallization, the concentration of the mixture, making seed mixture, etc.

MES DMF L-hemitartrate (S)-amlodipine allocated to the th so confirm spectra1H NMR (2 methyl signals from DMF), and then converted into its pharmaceutically acceptable salt accession acid, preferably, besylate and its hydrates, any of the methods described below. Range1H NMR MES DMF L-hemitartrate (S)-amlodipine shows values, confirming his identity as the MES DMF L-hemitartrate (S)-amlodipine.

1H NMR (CDCl3): 8,01 (s, 1H, Cho);? 7.04 baby mortality-7,41 (m, 4H); of 5.40 (s, 1H); 4.72 in (QC, 2H), 4,36 (s, 1H), was 4.02 (m, 2H), of 3.77 (m, 2H), only 3.57 (s, 3H), of 3.28 (m, 2H), 3.0 a (s, 3H; DMF); and 2.8 (s, 3H; DMF); 2,31 (s, 3H)and 1.15 (t, 3H).

Salt hemipentahydrate besilate (S)-amlodipine obtained from the MES of dimethylformamide L-hemitartrate (S)-amlodipine processing benzosulfimide acid in a mixture of organic solvent and water.

MES DMF L-hemitartrate (S)-amlodipine added to water. To this mixture an organic solvent, preferably representing the alcohol.

Alcohol is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, secondary butanol, tertiary butanol, etc. Preferred alcohol is isopropanol.

The amount added isopropanol is from 0.90 up to 1.5 volumes per gram of MES DMF L-hemitartrate (S)-amlodipine.

Benzosulfimide acid, dissolved in water, add to the MES DMF L-hemitartrate (S)-amlodipine.

The amount, in moles, is added benzosulfimide acid is from 2.0 to 2.3 molar equivalents per mole of MES of dimethylformamide L-hemitartrate (S)-amlodipine.

The amount of water used for dissolving benzosulfimide acid, is from 0.90 up to 1.5 volumes per gram of MES DMF L-hemitartrate (S)-amlodipine.

The mixture obtained after adding the aqueous solution of benzosulfimide acid, stirred at ambient temperature for 10-30 minutes. Then to the mixture, water is added to complete precipitation of the salt besilate (S)-amlodipine.

The amount of added water is five volumes per gram of MES DMF L-hemitartrate (S)-amlodipine. Then the reaction mixture is stirred for 15-60 minutes for complete precipitation of the salt besilate (S)-amlodipine.

Analysis of the thus obtained salt besilate (S)-amlodipine by the method of differential scanning calorimetry shows an endothermic peak at 71,9°C and the moisture content of 7.0% to 8.0%. X-ray analysis of single crystals shows that besilate (S)-amlodipine contains five molecules of water, socialized two molecules besilate (S)-amlodipine, which means that there are 2.5 water molecules per molecule besilate (S)-amlodipine, and it shows that the obtained hemipentahydrate of MES besilate (S)-amlodipine. That is e thing shown on the drawing.

Size 20 for monokristallicheskogo range of hemipentahydrate of MES besilate (S)-amlodipine follow.

The 2Θ values of hemipentahydrate besilate (S)-amlodipineIntensity, %
3,31573,5
6,66970,1
7,4876,8
8,22510,3
10,039100,0
10,7728,3
12,27644,1
12,95625,0
13,50139,0
13,99345,3
14,4488,6
15,00634,5
15,650the 5.7
16,58614,6
17,207to 19.9
18,871 8,9
19,80614,7
20,19945,0
20,68410,2
21,47021,3
21,73037,6
22,96427,4
23,70948,3
24,93637,2
27,03230,7
27,96811,8
34,00210,5
35,4737,9
35,9866,2
38,4127,8

Thus obtained salt hemipentahydrate of MES besilate (S)-amlodipine can also be turned into salt dihydrate besilate simple method described below.

Salt hemipentahydrate besilate (S)-amlodipine added to water. The amount of water by volume is 20-25 volumes per gram of salt hemipentahydrate of MES besilate (S)-amlodipine.

The mixture is warm when the temperature is round 55°C - 65°C for 15-30 minutes. The mixture is cooled to ambient temperature and left for complete crystallization of the product for 8-12 hours.

The mixture is then filtered, and the product is dried.

Thus obtained Sol besilate (S)-amlodipine has a moisture content of from 5.85% to 6.0%, which corresponds to the dihydrate besilate (S)-amlodipine.

Dehydrate besilate (S)-amlodipine can also be obtained from the MES of dimethylformamide (DMF) L hemitartrate (S)-amlodipine next method.

MES of dimethylformamide (DMF) L hemitartrate (S)-amlodipine added to water.

The amount of water used per gram of MES of dimethylformamide (DMF) L hemitartrate (S)-amlodipine, is from 20 up to 25 volumes per gram of MES of dimethylformamide (DMF) L hemitartrate (S)-amlodipine.

Benzosulfimide acid, dissolved in water, add to the MES DMF L-hemitartrate (S)-amlodipine.

The amount, in moles, is added benzosulfimide acid is from 2.0 to 2.3 moles per mole of MES DMF L-hemitartrate (S)-amlodipine.

The amount of water used for dissolving benzosulfimide acid, is from 1.25 to 1.50 volumes per gram of MES DMF L-hemitartrate (S)-amlodipine.

Thus obtained mixture was heat at 55°C - 65°C. the Preferred temperature is 60±2°C.

The solution is cooled to complete to the stallization salt dihydrate besilate (S)-amlodipine.

Besilate filtered off, washed with water and dried, and get salt besilate (S)-amlodipine with moisture content from 5.85% to 6.0%.

The method of the present invention below in this description are described with reference to examples, which are only explanatory and should not be construed as limiting the present invention in any way.

A brief description of the accompanying drawing - radiography hemipentahydrate besilate S-amlodipine.

- Corresponds to the chlorine atoms
- Corresponds to the oxygen atoms
- Corresponds to the nitrogen atoms
- Corresponds to the sulfur atoms
- Corresponds to the carbon atoms.

Molecular formula besilate S-amlodipine C20H25ClN2O5·C6H6SO3. The associated single crystal shows C40H50Cl2N4O10·C12H12O6·5H2O. This clearly shows that five water molecules socialized two molecules besilate S-amlodipine.

Example 1

MES of dimethylformamide L-hemitartrate (S)-amlodipine

(RS)-Amlodipine (16 g, 0.04 mol) is dissolved in 140 ml of a mixture of dimethylformamide and water (15% water in DMF).

To the mixture is added dropwise over 30 min a solution of L-tartaric acid, obtained by dissolving tartaric acid (1.47 g, 0.01 mol) in 20 ml of a mixture of DMF + water (the proportion is the same which is mentioned above). At the end of the addition the mixture is stirred for 4 hours at room temperature. The suspension is filtered and the remaining solid washed with acetone (10 ml) and dried, and get named in the title of the product.

Output = 7,8,

Output in % 82,62%.

The melting point of 137°C.

Optical purity by the method of chiral HPLC to 99.00%.

Example 2

MES of dimethylformamide L-hemitartrate (S)-amlodipine

(RS)-Amlodipine (16 g, 0.04 mol) is dissolved in 140 ml of a mixture of dimethylformamide and water (20% water in DMF).

To the mixture is added dropwise over 30 min a solution of L-tartaric acid, obtained by dissolving tartaric acid (1.47 g, 0.01 mol) in 20 ml of a mixture of DMF + water (the proportion is the same which is mentioned above). At the end of the addition the mixture is stirred for 4 hours at room temperature. The suspension is filtered and the remaining solid is washed with are the one (10 ml) and dried, and you get named in the title of the product.

Output = 9,0,

Output in % to 95.3%.

Optical purity by the method of chiral HPLC 98,86%.

Example 3

MES of dimethylformamide L-hemitartrate (S)-amlodipine

(RS)-Amlodipine (16 g, 0.04 mol) is dissolved in 220 ml of a mixture of dimethylformamide and water (10% water in DMF).

To the mixture is added dropwise over 30 min a solution of L-tartaric acid, obtained by dissolving tartaric acid (1.47 g, 0.01 mol) in 20 ml of a mixture of DMF + water (the proportion is the same which is mentioned above). At the end of the addition the mixture is stirred for 4 hours at room temperature. The suspension is filtered and the remaining solid washed with acetone (10 ml) and dried, and get named in the title of the product.

Output = 9,0,

Output in % to 95.3%.

Optical purity by the method of chiral HPLC 98,69%.

Example 4

MES of dimethylformamide L-hemitartrate (S)-amlodipine

(RS)-Amlodipine (16 g, 0.04 mol) is dissolved in 140 ml of a mixture of dimethylformamide and water (15% water in DMF).

To the mixture is added dropwise over 30 min a solution of L-tartaric acid, obtained by dissolving tartaric acid (1.47 g, 0.01 mol) in 20 ml of a mixture of DMF + water (the proportion is the same which is mentioned above). At the end of the addition the mixture is stirred for 1.5 hours at room temperature. The suspension is filtered and the remaining solid is washed with Aceto the Ohm (10 ml) and dried, and you get named in the title of the product.

Output = 8,0,

Output in % 84,74%.

The melting point of 137°C.

Optical purity by the method of chiral HPLC 99,94%.

Example 5

MES of dimethylformamide L-hemitartrate (S)-amlodipine

(RS)-Amlodipine (16 g, 0.04 mol) is dissolved in 140 ml of a mixture of dimethylformamide and methanol (15% methanol in DMF).

To the mixture is added dropwise over 30 min a solution of L-tartaric acid, obtained by dissolving tartaric acid (1.47 g, 0.01 mol) in 20 ml of a mixture of DMF + methanol (ratio is the same which is mentioned above). At the end of the addition the mixture is stirred for 4 hours at room temperature. The suspension is filtered and the remaining solid washed with acetone (10 ml) and dried, and get named in the title of the product.

Output = 4.0 g (wt./wt.).

Output in % 42,37%.

The melting point of 137°C.

Optical purity by the method of chiral HPLC 99,70%.

Example 6

MES of dimethylformamide L-hemitartrate (S)-amlodipine

(RS)-Amlodipine (16 g, 0.04 mol) is dissolved in 140 ml of a mixture of dimethylformamide and dichloromethane (15% dichloromethane in DMF).

To the mixture is added dropwise over 30 min a solution of L-tartaric acid, obtained by dissolving tartaric acid (1.47 g, 0.01 mol) in 20 ml of a mixture of DMF + dichloromethane (ratio is the same which is mentioned above). After adding a mixture of peremeci is up for 4 h at room temperature. The suspension is filtered and the remaining solid washed with acetone (10 ml) and dried, and get named in the title of the product.

Output = 5.0 g (wt./wt.).

Output in % 52,9%.

The melting point of 137°C.

Optical purity by the method of chiral HPLC 99,38%.

Example 7

MES of dimethylformamide L-hemitartrate (S)-amlodipine

(RS)-Amlodipine (16 g, 0.04 mol) is dissolved in 140 ml of a mixture of dimethylformamide and hexane (15% hexane in DMF).

To the mixture is added dropwise over 30 min a solution of L-tartaric acid, obtained by dissolving tartaric acid (1.47 g, 0.01 mol) in 20 ml of a mixture of DMF + hexane (ratio is the same which is mentioned above). At the end of the addition the mixture is stirred for 4 hours at room temperature. The suspension is filtered and the remaining solid washed with acetone (10 ml) and dried, and get named in the title of the product.

Output = 3,0,

Output in % 31,77%.

The melting point of 137°C.

Optical purity by the method of chiral HPLC of 99.97%.

Example 8

MES of dimethylformamide L-hemitartrate (S)-amlodipine

(RS)-Amlodipine (16 g, 0.04 mol) is dissolved in 140 ml of a mixture of dimethylformamide and ethyl acetate (15% ethyl acetate in DMF).

To the mixture is added dropwise over 30 min a solution of L-tartaric acid, obtained by dissolving tartaric acid (1.47 g, 0.01 mol) in 20 ml of a mixture of DMF + ethyl acetate (PDEC is the resource center is the same what is listed above). At the end of the addition the mixture is stirred for 4 hours at room temperature. The suspension is filtered and the remaining solid washed with acetone (10 ml) and dried, and get named in the title of the product.

Output = 2,0,

Output in % 21,18%.

The melting point of 137°C.

Optical purity by the method of chiral HPLC 99,37%.

Example 9

MES of dimethylformamide D-hemitartrate (R)-amlodipine

(RS)-Amlodipine (16 g, 0.04 mol) is dissolved in 140 ml of a mixture of dimethylformamide and water (15% water in DMF).

To the mixture is added dropwise over 30 min a solution of D-tartaric acid, obtained by dissolving tartaric acid (1.47 g, 0.01 mol) in 20 ml of a mixture of DMF + water (the proportion is the same which is mentioned above). At the end of the addition the mixture is stirred for 4 hours at room temperature. The suspension is filtered and the remaining solid washed with acetone (10 ml) and dried, and get named in the title of the product.

Output = 7,4,

Output in % 78,38%.

The melting point of 137°C.

Optical purity by the method of chiral HPLC 99,50%.

Example 10

Getting salt hemipentahydrate besilate (S)-amlodipine from MES DMF L-tartrate (S)-amlodipine

MES DMF L-hemitartrate (S)-amlodipine (1000 g; to 1.034 mol) is added to distilled water (5500 ml). To the mixture is added isopropyl alcohol (1000 ml) and p is remediat for 10 minutes. Benzosulfimide acid (327 g; 2,068 mol) dissolved in distilled water (1000 ml) and added dropwise to the mixture at ambient temperature. The reaction mixture is stirred for 10-15 minutes to complete education besilate. To the mixture for 15-30 minutes, add distilled water (5000 ml) and stirred for 30 min for complete deposition besilate. Besilate (S)-amlodipine is filtered off, washed with distilled water and then with cyclohexane (1000 ml). The product is dried at 35-40°C.

Output 1000

Chemical purity of 99.5%.

Optical purity >99%.

The water content of 7.0%-8,0%. This is confirmed by elemental analysis.

IR-Spectrum: 3347-3521 (tensile-NH), 2898-3057 (tensile-HE); 1684 (stretching-C=O), 1603 (-NH, primary amine), 1481 (-NH, secondary amine), 1198 (-CH2-O-CH2-; ether bond).

The analysis method DSK 71,9°C.

Example 11

Getting dihydrate besilate (S)-amlodipine from MES DMF L-hemitartrate (S)-amlodipine

MES DMF L-hemitartrate (S)-amlodipine (200 g) is mixed with water (4500 ml). To this mixture a solution of benzosulfimide acid (65,4 g) in water (300 ml), and the mixture is stirred while heating to 60°C. in a nitrogen atmosphere, the solution is cooled to room temperature and left to crystallize overnight. The solid is collected by filtration, washed with water (1000 ml), and get a b the Silat (S)-amlodipine, which is dried at room temperature to constant weight.

Exit 264,

The water content of 5.85% to 6.0%.

Optical purity >99%.

Example 12

Getting dihydrate besilate (S)-amlodipine from hemipentahydrate (S)-amlodipine

Hemipentahydrate (S)-amlodipine (200 g) is mixed with water (4800 ml). The warm mixture at 60°C. in a nitrogen atmosphere for 15 to 30 minutes. The mixture is then gradually cooled to room temperature, and then leave for full crystallization of the dihydrate (S)-amlodipine for 8-12 hours. The isolated product is filtered and dried at ambient temperature.

Exit 180,

The water content of 5.85% to 6.0%.

The optical purity of ≥99%.

Example 13

Receiving MES DMF L-hemitartrate (R)-amlodipine

To the mother liquor obtained in example 1 was added L-tartaric acid (1.47 g; 0.01 mol) and stirred at ambient temperature for 240-300 minutes until complete precipitation of the reaction product. Then named the title compound is filtered off and dried.

The output of 6.4,

Output in % 67,7%.

Example 14

Receiving MES DMF D-hemitartrate (R)-amlodipine

To the mother liquor obtained in example 1 add D-tartaric acid (1.47 g; 0.01 mol) and stirred at ambient temperature for 240-300 minutes until complete precipitation of the reaction product. Then called in the header of the giving is filtered off and dried.

The output of 6.4,

Output in % 67,7%.

Advantages of the method according to the present invention are as follows.

A) the MES DMF L-hemitartrate (S)-amlodipine precipitates first, and there is no need to besiege it from the mother liquid, and thus it is possible to avoid the presence of undesirable isomers and other impurities.

B) Splitting to obtain (S)-amlodipine is performed with the use of less expensive naturally occurring tartaric acid, i.e. L-tartaric acid, which makes the method more economical and feasible on an industrial scale.

C) processing Time, labor, utilities, etc. required otherwise to obtain (S)-enantiomer of the filtrate or mother liquor, are eliminated through the development of the way in which the desired salt is obtained when the first filter instead of receiving it from the mother liquor.

D) the Received optical purity is high with minimal contamination unwanted R-isomer.

E) Removing the desired isomer is the predominant and occurs during the first filtering.

F) cycle Time / cost / employment reactor, etc. suitable for industrial purposes.

G) cleaning Method gives high-purity enantiomeric S-isomer per crystallization.

1. A method of obtaining optically pure MES DMF L-Guitart is the (S)-amlodipine, including the stage of processing (R,S)-amlodipine base L-tartaric acid in the presence of dimethylformamide and co-solvent.

2. The method according to claim 1, further comprising a stage of adding L-tartaric acid after extraction MES DMF L-hemitartrate (S)-amlodipine for receiving MES DMF L-hemitartrate R-amlodipine.

3. The method according to claim 1, where the co-solvent selected from the group consisting of water, alcohol, complex ether, halogenated solvents and hydrocarbons.

4. The method according to claim 3, where the alcohol is a methanol.

5. The method according to claim 3, where the halogenated solvent represents dichloromethane.

6. The method according to claim 3, where the ester is an acetate.

7. The method according to claims 1 and 2, where L-tartaric acid is added in the form of a solution in dimethylformamide.

8. The method according to claim 7, where dimethylformamide solution contains dimethylformamide or dimethyl formamide in combination with a co-solvent.

9. MES DMF L-hemitartrate (S)-amlodipine.

10. MES DMF L-hemitartrate (R)-amlodipine.

11. MES of dimethylformamide L-hemitartrate (S)-amlodipine, obtained according to claim 1 and characterized by the following range of1H NMR:1H NMR (CDCl3): 8,01 (s, 1H, Cho);? 7.04 baby mortality-7,41 (m, 4H); of 5.40 (s, 1H); 4.72 in (QC, 2H), 4,36 (s, 1H), was 4.02 (m, 2H), of 3.77 (m, 2H), only 3.57 (s, 3H), of 3.28 (m, 2H), 3.0 a (s, 3H; DMF); and 2.8 (s, 3H; DMF); 2,31 (s, 3H)and 1.15 (t, 3H).

12. The method of obtaining with the Lee hemipentahydrate besilate (S)-amlodipine, comprising a stage of mixing MES DMF L-hemitartrate (S)-amlodipine with a mixture of water and an organic solvent and adding the aqueous solution of benzosulfimide acid.

13. The method according to item 12, further comprising adding water to the reaction mixture, filtering off the hydrate.

14. The method according to item 12, where the organic solvent is an alcohol.

15. The method according to 14, where the alcohol is chosen from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, secondary butanol and tertiary butanol.

16. The method according to clause 15, where the alcohol is a isopropanol.

17. The method of obtaining salt dihydrate besilate (S)-amlodipine, comprising a stage of mixing MES DMF L-hemitartrate (S)-amlodipine with water and adding an aqueous solution of benzosulfimide acid and heating the mixture.

18. The method according to 17, further comprising the stage of cooling of the mixture and extracted salt dihydrate besilate (S)-amlodipine.

19. The method according to 17, where the temperature at which heat the mixture, ranges from 55 to 65°C.

20. The method of obtaining salt dihydrate besilate (S)-amlodipine, which includes stages
a) mixing salt hemipentahydrate besilate (S)-amlodipine with water,
b) heating the mixture,
c) cooling the mixture to crystallization of salt dihydrate besilate (S)-amlodipine and
d) extracting the crystals Digi the rata besilate (S)-amlodipine.



 

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