JP3275232B2 - Preparation of dihydropyridine derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to 3-ethyl-5-
Methyl-2- (2-aminoethoxymethyl) -4- (2
-Chloro-phenyl) -6-methyl-1,4-dihydro-3,5-pyridine-dicarboxylate benzenesulfonate. This compound is a known pharmaceutically active ingredient with INN amlodipine besylate.

[0002]

BACKGROUND ART Amlodipine besylate (amlodipine)
besylate) is dihydropyridine dicarboxylate
It is a type of calcium antagonist and has useful potent long lasting hypotensive and anti-anginal properties.

[0003] According to known processing reactions, the dihydropyridine structure of amlodipine is constructed by the Hantzsch synthesis shown by the prior art for this type of reaction. A key characteristic of the processes shown in EP 89,167 and Hungary 186,868 is that the primary amino group can be obtained by removing the protecting group from the protected amino group or by converting the corresponding azide. By reduction, it is formed at the last stage of the synthesis. The protected amino or azide group can be incorporated into the acetoacetate component of the Hantzsch synthesis by
Introduced into the molecule.

According to the first method of the Hantzsch synthesis described above, 4- (2-aminoethoxy) -acetoacetate contains a protected amino group, 2-chlorobenzaldehyde and aminocrotonate. And reacting or, in the above-mentioned modification of the production method,
(2-Aminoethoxy) -acetoacetate is first
Condensed with 2-chloro-benzaldehyde to give
Reacting the "ylidene" derivative with an aminocrotonate. Amlodipine is obtained by removing the protected group from a dihydropyridine derivative containing a protected primary amino group obtained by a Hantzsch synthesis method. Manufactured.

[0005] According to another method, referred to as the Hantzsch synthesis method, the synthesis is obtained by reacting 4- (2-azidoethoxy) -acetic acid ester, 2-chlorobenzaldehyde and aminocrotonate. The primary amino group of amlodipine is formed by reducing the azide group.

In the above-mentioned European patent, pharmaceutically acceptable acid addition salts of amlodipine are disclosed. Said salts are prepared from amlodipine by salt formation. Among the salts, maleate is described as the most advantageous.

A disadvantage of the above process is that the individual reaction steps have a relatively low yield (Hantz).
sch) The yield of the synthesis is also not disclosed). In addition, it is known that azides are explosive (see references for related azide compounds, CA 105, 11321t).

[0008] German Patent No. 3,710,457 states that
Amlodipine benzenesulfonate and its preparation are disclosed. According to this patent, said salt has many advantages over other known amlodipine salts, especially when converting the salt into a pharmaceutical composition. Amlodipine besylate is obtained by reacting amlodipine base with a benzenesulfonic acid solution or its ammonium salt formed with an inert solvent,
It has been produced by isolating besylate from the reaction mixture.

In European Patent No. 599,220,
A novel process for preparing amlodipine besylate is disclosed. Amlodipine derivatives containing a trityl protecting group on the primary amino group are prepared using conventional Hantzsch synthesis methods. The protective trityl group is removed by hydrolysis performed in the presence of benzenesulfonic acid.
In this way, amlodipine besylate is obtained without isolation of amlodipine base. A major disadvantage of this process is the low yield. Furthermore, an important disadvantage is that pure end products can only be obtained with very complex solutions. The overall yield is only 7% for 2-chloro-benzaldehyde.

[0010]

It is therefore an object of the present invention to overcome the disadvantages of the known methods, and
The present invention provides a method in which amlodipine benzylate can be produced in a high yield, can be carried out by a simple method, and does not require isolation of amlodipine base. The above objective is obtained with the aid of the process of the present invention.

[0011]

According to the present invention, (a ₁ )
Formula (XI)

Embedded image With a compound of formula (XII)

Embedded image Or (a ₂ ) of the formula (IX)

Embedded image With a compound of formula (X)

Embedded image And then reacting the resulting compound of formula (XI) with benzenesulfonic acid of formula (XII); or (a ₃ ) of formula (VIII)

Embedded image In the compounds of formula (I), chlorine is exchanged for iodine; the resulting compound of formula (IX) is reacted with hexamethylenetetramine of formula (X); and the resulting compound of formula (XI) is Reacting with benzenesulfonic acid of (XII); or (a ₄ ) Formula (VI)

Embedded image With a compound of formula (VII)

Embedded image In the resulting compound of formula (VIII), wherein chlorine is exchanged with iodine; the compound of formula (IX) is converted to a hexamethylenetetramine of formula (X) And the resulting formula (X
The compound of I), reacted with benzenesulfonic acid of formula (XII); or (a ₅₎ formula (IV)

Embedded image With a compound of formula (V)

Embedded image Reacting the resulting compound of formula (VI) with a methyl-3-aminocrotonate of formula (VII); converting the resulting compound of formula (VIII) with chlorine After exchanging with iodine, the resulting formula (I
Reacting a compound of formula (X) with hexamethylenetetramine of formula (X); and reacting the resulting compound of formula (XI) with a benzenesulfonic acid of formula (XII);
Or (a ₆ ) formula (II)

Embedded image Of ethyl-4-bromo-acetoacetic acid of formula (III)

Embedded image Reacting the resulting compound of formula (IV) with 2-chlorobenzaldehyde of formula (V); converting the resulting compound of formula (VI) to a methyl compound of formula (VII) Chlorinated with iodine in the resulting compound of formula (VIII); and the resulting compound of formula (IX) is converted to a hexamethylene compound of formula (X) And reacting the resulting compound of formula (XI) with a compound of formula (XI
Reacting with benzenesulfonic acid of I); or
(a ₇ ) In the compound of the formula (IV), chlorine is exchanged with iodine to obtain a compound of the formula (XIII)

Embedded image Is reacted with 2-chloro-benzaldehyde of formula (V); the resulting compound of formula (XIV)

Embedded image Is reacted with a methyl-3-amino-crotonate of formula (VII); the resulting compound of formula (IX) is
Reacting the resulting compound of formula (XI) with hexamethylenetetramine of formula (X); and reacting the obtained compound of formula (XI) with benzenesulfonic acid of formula (XII)

Embedded image 3-ethyl-5-methyl-2- (2-aminoethoxymethyl) -4- (2-chloro-phenyl) -6-methyl-1,4-dihydro-3,5-pyridine-dicarboxylate benzenesulfone A process for preparing an acid salt is provided.

An essential feature of the present invention is the Hantz (Hantz).
sch) In a synthesis process, ethyl 4- (2-chloroethoxy) -acetoacetate of formula (IV) and 2- (2-chloroethoxy) -acetoacetate of formula (V)
The benzylidene derivative of formula (VI) prepared from chloro-benzaldehyde is reacted with an aminocrotonate of formula (VII), whereby the new compound of formula (VIII)
Is obtained, and after a chlorine → iodine exchange, a novel 2-iodoethoxy-dihydropyridine derivative of formula (IX) is obtained in good yield.

The compounds of the formulas (VIII) and (IX) are new and not prior art. In this way, amlodipine besylate is produced by a novel and very advantageous method by the so-called ammonium decomposition of halogeno derivatives by the Delepine reaction. The halogen is replaced by an amino group by using hexamethylenetetramine as a source of ammonia. The urotropin salt formed is decomposed by using benzenesulfonic acid, whereby amlodipine besylate is separated directly from the reaction mixture. The latter process is new and has not been disclosed in the prior art.

[0014]

According to the process of the invention, contrary to the prior art methods, the primary amino group is protected in a protected form by the amino group protecting group in the molecule as part of the acetoacetate component. Rather than being constructed by removal and then by a halogen-to-amine exchange reaction performed after the Hantzsch reaction performed with the corresponding halogeno compound.
According to a characteristic and essential element of the process according to the invention, the latter reaction is carried out in a manner not disclosed in the prior art, and the desired besylate salt is formed directly, rather than the amlodipine base reaction. This process is illustrated in the reaction flow sheet of FIG.

According to the first step of the process of the present invention, the compound represented by the formula (II)
The ethylene chlorohydrin (2-chloro-ethanol) of I) is O-alkylated with ethyl-4-bromo-acetoacetate of formula (II). The compounds of the formula (IV) thus obtained are novel. This manufacturing method is performed by a known method. The reaction is carried out in a suitable inert solvent,
Preferably, it is formed in an aliphatic or cycloaliphatic ether, especially tetrahydrofuran, at a temperature of about -10C or less. The hydrogen bromide formed is combined with a basic substance, preferably with sodium hydride, which can be used as an oily suspension or can be prepared without prior paraffin. The reaction mixture can be decomposed in a known manner with an acid, neutralized, and finally treated by extraction. Pure products are obtained by fractional distillation in vacuo.

According to the next step in the synthesis, the chloroethoxy-acetoacetate of formula (IV) is
Subject to aldol condensation with chlorobenzaldehyde. As reaction product, an "ylidene" derivative of formula (VI) is obtained. The reaction of the aldehyde with the acetoacetic acid derivative is preferably carried out in the presence of a catalytic amount of piperidine acetate, whereby the 2-chloro-benzylidene-4-chloroethoxy-acetoacetate of formula (VI) Obtained in high yield. Piperidine acetate catalyst
Suitably, 0.0 mole per mole of compound of formula (IV)
It is used in an amount of 1 to 0.1 mol. As reaction medium, a polar protic solvent is preferably an alkanol, in particular isopropanol. Reaction temperature is 10 ° C to 60 ° C
It is also preferable to carry out at room temperature. The reaction time is between 5 hours and 15 hours, preferably 10 hours.
The reaction mixture is purified by evaporating the solvent and washing with water. The crude product thus obtained is
Furthermore, it is suitable to be subjected to a chemical transformation.

Furthermore, the compound of the formula (VI) is further
By directly subjecting to a chemical reaction, the reaction can be performed without an isolation treatment in a solvent.

According to the next step of the synthesis, the compound of formula (VII)
The compounds of I) are prepared by the Hantzsch synthesis method. Generally, the treatment is further carried out by heating the benzylidene derivative of formula (VI) and the aminocrotonate of formula (VII) to the boiling point in a suitable organic solvent. The reaction medium is preferably a C _1-4 alkanol (particularly,
Either isopropanol, methanol or ethanol) or a polar aprotic solvent (eg acetonitrile) or mixtures thereof are used.

The 2-chloro-benzaldehyde of the formula (V), the ketoester of the formula (IV) and the aminocrotonate of the formula (VII) are completed without isolating the benzylidene derivative of the formula (VI). Process by reacting until The reaction time is 15 to 20 hours or less. The reaction mixture can be prepared by known methods (eg,
It is purified by cooling and filtering.

In the next step, the compound of formula (VIII) is converted to the compound of formula (IX). Chlorine is exchanged for iodine by the "Frankelstein reaction" known in the prior art. Preferably, the reaction is carried out with an alkali iodide, especially with sodium iodide. According to the prior art, this reaction is preferably carried out in acetone, depending on the solubility state. Although the process of the invention is carried out in acetone, the use of high boiling alkanols, especially isopropanol, has proven to be particularly advantageous. The reaction is carried out under heating, preferably at the boiling point of the reaction mixture. The reaction time is generally 20 to 25 hours or less. The reaction mixture is purified by known methods (eg,
After cooling strongly, filter). The dihydropyridine derivative of the formula (IX) is obtained in high yield.

According to another embodiment of the process of the present invention, the chlorine → iodine exchange reaction is carried out at the stage of chloroethoxy acetoacetate of the formula (IV). This reaction gives the iodoacetoacetate of formula (XIII). The reaction is suitably carried out in acetone as medium and at the boiling point of the reaction mixture. The product is purified by fractional distillation. The compound of formula (XIII) thus obtained is represented by the formula (V)
With 2-chlorobenzaldehyde of formula (X)
IV) is converted to a benzylidene derivative. This reaction is carried out as described above, in conjunction with the reaction of the compounds of formulas (IV) and (V). The compound of formula (XIV) thus obtained is reacted with a compound of formula (VII) to obtain an iodoethoxy-dihydropyridine derivative of formula (IX). The reaction is based on the Hanche
tzsch) reaction.

According to the next step of the process of the present invention, the quaternary salt is reacted with hexamethylenetetramine (urotropin) of the formula (X) to form the iodo derivative of the formula (IX)
The chloroethoxy of formula (VIII) is formed from-which is more reactive than dihydropyridine. According to the prior art, salts of this type are generally prepared in non-polar-aprotic solvents. However, it has been found that the reaction of the compounds of the formulas (IX) and (X) is carried out more advantageously by using lower alkanols (eg methanol, ethanol, isopropanol) or acetonitrile as the medium. Preferably, the reaction is carried out in acetonitrile as a medium. The reactants are used in equimolar amounts, but the urotropin of formula (X) is also preferably
Used at 5% or more. The reaction is carried out at a temperature between room temperature and the boiling point of the solvent, preferably at 40-55 ° C. The reaction is carried out by simultaneously adding the reaction components to the solvent, or by adding the iodine compound of the formula (IX), preferably in a small amount, to a solution of hexamethylenetetramine. The reaction time is 20 to 50 hours, preferably 30 to 40 hours. The dihydropyridine-urotropine quaternary salt of formula (XI) precipitates as a solid and can be easily filtered at room temperature. The crude product has a purity suitable for the production of the final product and no further purification method is required.

In the following step, amlodipine besylate of formula (I) is prepared by subjecting a quaternary salt of formula (XI) to hydrolysis with a benzenesulfonic acid of formula (XII).

The hydrolysis with benzenesulfonic acid is
It is performed in a mixture of water and an organic solvent. Water-miscible, partially water-miscible or water-immiscible organic solvents can be used for this purpose.
The water-miscible solvent is preferably a linear or branched alkanol having 1 to 3 carbon atoms (for example,
Methanol, ethanol, and isopropanol). As the organic solvent, an alkanol having 4 to 8 carbon atoms (for example, n-butanol) or ethyl acetate that is partially miscible with water or preferably not miscible is used. The reaction is carried out at room temperature and up to the boiling point of the solvent; preferably at the boiling point of the reaction mixture. Benzenesulfonic acid is preferably of the formula (X
It is used in an amount of at least 4 mol with respect to the compound of I). For practical reasons, it is preferred to use no more than 10 molar equivalents of benzenesulfonic acid. In a preferred embodiment of the process of the present invention, the reaction is carried out using about 5 molar equivalents of benzenesulfonic acid. The reaction mixture is purified by known methods.

Starting materials of formulas (III), (V), (X) and (XII) are commercially available. Bromo acetoacetate of formula (II) is a known compound and is disclosed in US Pat.
082 and EP 102,893. Aminocrotonates of the formula (VI) are also known (see Hungarian patent 202,474).

Formulas (IV), (VI), (VIII), (IX),
The intermediates of (XI), (XIII) and (XIV) are new compounds and are not known in the prior art.

In another aspect of the present invention, formulas (IV), (V
Novel compounds of I), (VIII), (IX), (XI), (XIII) and (XIV) are provided and their preparation.

The compound having a dihydropyridine dicarboxylate structure is a mixed ester and contains an asymmetric center. Such compounds formally form paired enantiomers, which can be separated by methods known in the art. The present invention includes the individual isomers (dextrorotatory and levorotatory rotamers) and mixtures thereof (including racemates).

According to the process of the present invention, the desired compound of formula (I) is obtained via a novel intermediate which is not in the prior art. Hydrolysis of the quaternary salt of formula (XI) with benzenesulfonic acid is a novel method.

An advantage of the process according to the invention is that the yield of the individual steps is high. Hanche used in the production method of the present invention
The yield of the (Hantzsch) cyclization step is higher than that of the known cyclization reaction to produce amlodipine. A further advantage of the present invention is that the precipitated salt is formed directly in one step, so that no base isolation is required. The manufacturing method is
Even on an industrial scale, it is easy to apply and does not require special equipment.

Further details of the present invention are given in the following examples, which do not limit the scope of the claims.

[0032]

Example 1 Ethyl-4- (2-chloroethoxy) -a
10.38 g (0.25 mol) of cetacetate (IV) 57.8% sodium hydride are added to 110 ml of tetrahydrofuran. The mixture is cooled to a temperature between -10C and -20C,
Then, at this temperature, 10.08 g (0.125 mol) of ethylene chlorohydrin (III) are added dropwise under a nitrogen atmosphere. The mixture is stirred for 20 minutes and, at the same temperature, a solution of 26.18 g (0.125 mol) of ethyl-4-bromoacetoacetate (II) and 35 ml of tetrahydrofuran is added. The reaction mixture was stirred for 20 minutes,
Leave to room temperature, hold at this temperature for 6 hours, pour with cooling into 270 ml of 1N hydrochloric acid and extract with dichloromethane. The organic layer is dried and evaporated. The residual oil is produced without paraffin by treating with a 1: 1 mixture of acetonitrile and benzene. Distill the product in vacuo. In this way, 17.47 g of the desired compound are obtained, with a yield of 67% and a boiling point of 110 ° C.
/ 2Hgmm.

Elemental analysis: Formula C ₈ H ₁₃ ClO ₄ (208.41) Calculated: C 46.05%, H 6.28%, Cl 16.99% Measured: C 46.45%, H 6.11%, Cl. 16.52%

[0034]

Example 2 Ethyl-4- (2-iodoethoxy) -a
Cetoacetate (XIII) To a solution of 19 g (91 mmol) of ethyl-4- (2-chloroethoxy) -acetoacetate (IV) and 380 ml of acetone is added 134.4 g (910 mmol) of sodium iodide. Bring the reaction mixture to boiling point 13
Heat for hours. Filter off the inorganic material and evaporate the filtrate in vacuo. The residual oil is dissolved in dichloromethane and the solution is washed with water, dried and evaporated. The crude product is subjected to a partial distillation in vacuo. Boiling point: 170 ° C / 0.1
Hgmm. In this way, 18.3 g of the desired product are obtained. Yield: 67%

Elemental analysis: Formula C ₈ H ₁₃ IO ₄ (300.091) Calculated: C 32.02%, H 4.37% Measured: C 31.86%, H 4.36%

[0036]

Example 3 Ethyl-4- (2-chloroethoxy) -2
-(2-chlorobenzylidene) -acetoacetate (V
I) 365 ml of 2-chloro-benzaldehyde (V) and 24.7 g (0.118 mol) of ethyl-4- (2-chloroethoxy) -acetoacetate (IV) In the presence of a piperidine acetic acid catalyst [10 g (11.8 mmol) piperidine + 0.7 g (11.8 mmol) acetic acid] in 10 g of isopropanol at room temperature. The reaction mixture is evaporated down, the residual oil is dissolved in dichloromethane, washed with water and dried. The organic phase is evaporated in a vacuum. In this way, 37.9 g of the desired product are obtained as a yellow oil. Yield: 97%

Elemental analysis: Formula C ₁₅ H ₁₆ Cl ₂ O ₄ (331.203) Calculated: C 54.39%, H 4.87%, Cl 21.41% Measured: C 53.69%, H 5.03 %, Cl 20.98%

[0038]

Example 4 Ethyl-4- (2-iodo-ethoxy)-
2- (2-chloro-benzylidene) -acetoacetate
(XIV) 10 g (33 mmol) of ethyl-4- (2-iodoethoxy) -acetoacetate (XIII) and 4.64 g (3
3 mmol) of 2-chloro-benzaldehyde (V)
Is dissolved in 100 ml of isopropanol with piperidine acetate catalyst [0.28 g (3.3 mmol) of piperidine +
0.198 g (3.3 mmol) of acetic acid]
Let react for 10 hours at room temperature. The reaction mixture is evaporated down, the residual oil is dissolved in dichloromethane, washed with water and dried. The organic phase is evaporated in a vacuum. In this way, 11.55 g of the desired product are obtained as a reddish-brown oil. Yield: 83%

Elemental analysis: Formula C ₁₅ H ₁₆ ClIO ₄ (422.643) Calculated: C 42.63%, H 3.82%, Cl 8.39% Measured: C 43.00%, H 4.12%, 8.13% of Cl

[0040]

Embodiment 53-ethyl-5-methyl-2- (2-chloro
Ro-ethoxy-methyl) -4- (2-chloro-phenyl)
) -6-methyl-1,4-dihydro-3,5-pyridi
Dicarboxylate (VIII) 36 g (0.1087 mol) of ethyl-4- (2-chloro
(Low-ethoxy) -2- (2-chloro-benzylidene)-
Acetoacetate (VI) and 12.5 g (0.1087
Mol) of methyl-3-aminocrotonate (VII)
The mixture in 35 ml of isopropanol was added to the reaction mixture.
Let react for 20 hours at the boiling point. The reaction mixture is brought to
Cool to a temperature of -5 ° C and keep in refrigerator overnight. Next
In the morning, filter the precipitate, followed by cold isopropanol.
And diisopropyl ether. The crude product is
From isopropyl ether or, if necessary, aqueous acetic acid
And recrystallize. Thus, 21.88 g of the desired
Is obtained. Yield: 47%, melting point: 152-1
54 ° C

Elemental analysis: Formula C ₂₀ H ₂₃ Cl ₂ NO ₅ (428.32) Calculated: C 56.08%, H 5.41%, N 3.27%, Cl 16.56% Measured: C56.10 %, H 5.42%, N 3.37%, Cl 16.18%

[0042]

Example 6 3-ethyl-5-methyl-2- (2-io
Doethoxy) -methyl-4- (2-chloro-phenyl)
-6-methyl-1,4-dihydro-3,5-pyridine-
Dicarboxylate (IX) Method a) 16 g (37 mmol) of 3-ethyl-5-methyl-2
-(2-chloro-ethoxy-methyl) -4- (2-chloro-phenyl) -6-methyl-1,4-dihydro-3,
5-pyridine-dicarboxylate (VIII) 55.46 g (370 mmol) of sodium iodide and 1
83 ml of isopropanol are stirred at the boiling point for 20 hours. The reaction mixture is cooled to a temperature between 0 ° C. and −5 ° C. and kept in a refrigerator overnight. The next morning, the precipitate is filtered off and washed with cold isopropanol. The crude product is recrystallized from isopropanol. In this way, 16.35 g of the desired compound are obtained. Yield: 85%, melting point: 152
~ 154 ° C

Elemental analysis: Formula C ₂₀ H ₂₃ ClINO ₅ (519.76) Calculated: C 46.22%, H 4.46%, N 2.69%, Cl 6.82% Measured: C 45.92%, H 4.45%, N 2.73%, Cl 6.77%

Method b) 11 g (26 mmol) of ethyl-4- (2-iodo-
Ethoxy) -2- (2-chlorobenzylidene) -acetoacetate (XIV), 2.99 g (26 mmol) of methyl-3-amino-crotonate (VII) and 110
Heat the mixture of ml of isopropanol to the boiling point for 8 hours. The reaction mixture is evaporated down and the residue is crystallized from cold isopropanol, filtered and washed with cold isopropanol. The crude product is recrystallized from isopropanol. 2.97 g of the desired compound are obtained. Its yield:
22%, melting point: 152-155 ° C

[0045]

Example 7 3-ethyl-5-methyl-2- (2-yl)
-Ethoxy-methyl) -4- (2-chloro-phenyl)
-6-methyl-1,4-dihydro-3,5-pyridine-
Radical Bokishireto - Hekisaminiumu iodide and (XI) 1.77 g hexamethylenetetramine (12.7 mmol) (X), is added in acetonitrile 15 ml. The mixture is stirred at room temperature for 10 minutes, warmed to 45-50 ° C. and then 6.0 g (115 mmol) of 3-ethyl-5-methyl-2- (2-iodoethoxy) -methyl-
4- (2-chloro-phenyl) -6-methyl-1,4-
Dihydro-3,5-pyridine-dicarboxylate (I
X) is added in a small amount in about 2 hours. The reaction mixture is stirred at this temperature for 40 hours, left to cool to room temperature, filtered and subsequently washed successively with acetonitrile and dichloromethane.
In this way, 6.83 g of the desired product are obtained as a white powder. Yield: 90%, melting point: 177-17
9 ℃

Result of elemental analysis: Formula C ₂₆ H ₃₅ ClIN ₅ O ₅ (65.9957) Calculated: C 47.32%, H 3.35%, N 10.61% Measured: C 46.84%, H 5.42 %, N 10.40%

[0047]

Example 8 3-ethyl-5-methyl-2- (2-amido
Noethoxy-methyl) -4- (2-chloro-phenyl)
-6-methyl-1,4-dihydro-3,5-pyridine-
Dicarboxylate benzenesulfonate (Amuro
Dipin besylate) (I) Method a) 3.3 g (5 mmol) of 3-ethyl-5-methyl-2
-(2-yl-ethoxy-methyl) -4- (2-chloro-phenyl) -6-methyl-1,4-dihydro-3,5
Pyridine-dicarboxylate hexaminium iodide (XI), 3.95 g (25 mmol) of benzenesulfonic acid (XII), 350 ml of n-butanol and 3
A mixture of 50 ml of water is heated to the boiling point under vigorous stirring for 45 minutes. The reaction mixture is allowed to cool to room temperature and the resulting layers are separated. The organic layer is washed with water, dried and evaporated.

The residual oil is crystallized by keeping it in cold ethyl acetate overnight in a refrigerator. The next morning, the crystals are filtered off, washed with ethyl acetate and dried. The dried product is washed thoroughly with water, dried and recrystallized from acetonitrile. 1.5 g of amlodipine besylate are thus obtained. Yield: 52.9%, melting point: 202
~ 203 ° C

Method b) 8.8 g (0.013 mol) of 3-ethyl-5-methyl-2- (2-yl-ethoxy-methyl) -4- (2-chloro-phenyl) -6-methyl- 1,4-dihydro-
3,5-Pyridine-dicarboxylate A mixture of hexaminium iodide (XI), 10.54 g (0.066 mol) of benzenesulfonic acid (XII), 535 ml of methanol and 535 ml of water are refluxed for 1 hour. The reaction mixture is allowed to cool to room temperature, poured into water, extracted with dichloromethane, washed with water, dried and evaporated. The residue is crystallized by keeping it in acetonitrile in a refrigerator overnight. In this way, 4.18 g of amlodipine besylate are obtained. Yield: 55.4
%, Melting point: 205-206 ° C (acetonitrile)

Result of elemental analysis: Formula C ₂₆ H ₃₁ ClN ₂ O ₈ S (567.055) Calculated values: C 55.07%, H 5.51%, N 4.94%, Cl 6.25%, S 5.65% Measured values: C 54.71%, H 5.53%, N 4.95%, Cl 6.05%, S 5.57%

As shown in the above data, in the process of the present invention, amlodipine can be obtained in a high yield with a simple processing method.
Besylate was produced.

[0052]

The technical effects of the method for producing the dihydropyridine derivative of the present invention are as follows. That is, a useful, antihypertensive anti-anginal agent, amlodipine besylate of the formula (I), which can be obtained in a simple manner and in a high yield, and does not require an amlodipine base isolation treatment. It is.

[Brief description of the drawings]

FIG. 1 is a reaction flow sheet showing the production method of the present invention.

────────────────────────────────────────────────── ─── Continuing on the front page (72) Inventor Zura Smiig Hungary H-1126 Budapest Holosui Suimon Uzza 25 (72) Inventor Zell ヂ Krasnay Hungary H-1172 Budapest Tisenharlomedik Uzza 38 (72) Inventor Garbol Brascoe Hungary H-1141 Budapest Ev Uzza 107 / Bee (72) Inventor Peter Temupe Hungary Hart-1116 Budapest Saloki Uzza 29 (72) Inventor Karlman Ná Hungary Há 1025 Budapest N ヂ banya Ut 43 / A (72) Invention Zelzy Donatou Velecsky Hungary Her 1034 Budapest Shammarzo Uzza 52 (72 ) Inventor Gerbol Nehmet Hungary H-1149 Budapest Kever Lajos Uzza 49 / A (72) Inventor Norbert Nehmetu Hungary Hah-1119 Budapest Mashodik / 3 Fehervalliut 69 (56) References JP 3-7668 () JP, B2) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 211/90 REGISTRY (STN) CA (STN) CAOLD (STN)

Claims (14)

(57) [Claims] [Claim 1] (a ₁₎ formula (XI) ## STR1 ## With a compound of formula (XII) Or (a ₂ ) of formula (IX) With a compound of formula (X) And reacting the resulting compound of formula (XI) with benzenesulfonic acid of formula (XII); or (a ₃ ) of formula (VIII) In the compounds of formula (I), chlorine is exchanged for iodine; the resulting compound of formula (IX) is reacted with hexamethylenetetramine of formula (X); and the resulting compound of formula (XI) is (XII) with benzenesulfonic acid; or (a ₄ ) of formula (VI) With a compound of formula (VII) In the resulting compound of formula (VIII), wherein chlorine is exchanged with iodine; the compound of formula (IX) is converted to a hexamethylenetetramine of formula (X) And the resulting formula (X
Reacting the compound of I) with a benzenesulfonic acid of formula (XII); or (a ₅ ) a compound of formula (IV) With a compound of formula (V) Reacting the resulting compound of formula (VI) with a methyl-3-aminocrotonate of formula (VII); converting the resulting compound of formula (VIII) with chlorine After exchanging with iodine, the resulting formula (I
Reacting a compound of formula (X) with hexamethylenetetramine of formula (X); and reacting the resulting compound of formula (XI) with a benzenesulfonic acid of formula (XII);
Or (a ₆ ) Formula (II) Of ethyl-4-bromo-acetoacetic acid of formula (III) With ethylene chlorohydrin of the formula (IV) With a compound of formula (V) With 2-chlorobenzaldehyde of the formula (VI) With a compound of formula (VII) With the resulting methyl-3-aminocrotonate; then the resulting compound of formula (VIII) In the compound of formula I, the chlorine is exchanged with iodine; the resulting compound of formula (IX) With a compound of formula (X) With hexamethylenetetramine of the formula; and the resulting formula (XI) With a compound of formula (XII) Or (a ₇ ) in the compound of formula (IV), the chlorine is exchanged with iodine to obtain the compound of formula (XIII) Is reacted with 2-chloro-benzaldehyde of the formula (V); the resulting compound of the formula (XIV) Is reacted with a methyl-3-amino-crotonate of formula (VII); the resulting compound of formula (IX) is
Reacting hexamethylenetetramine of the formula (X) with the resulting compound of the formula (XI) and benzenesulfonic acid of the formula (XII). 3-ethyl-5-methyl-2- (2-aminoethoxymethyl) -4- (2-chloro-phenyl) -6-methyl-1,4-dihydro-3,5-pyridine-dicarboxylate benzenesulfone Preparation of acid salt. 2. The process according to claim 1, wherein the compound of the formula (XI) is reacted with a benzenesulfonic acid of the formula (XII). 3. The process according to claim 1, wherein the compound of the formula (XI) is hydrolyzed in a mixture of benzenesulfonic acid, water and an organic solvent. 4. The method according to claim 3, wherein a water-miscible organic solvent is used. 5. A process according to claim 4 which comprises using an alkanol of C ₁ ~ _3. 6. The process according to claim 3, wherein an organic solvent which is partially miscible or immiscible with water is used. 7. A containing n- butanol A process according to claim 6, wherein the use of alkanols or ethyl acetate C ₄ ~ _8. 8. The process according to claim 2, wherein benzenesulfonic acid is used in an amount of at least 4 mol per 1 mol of the compound of the formula (XI). 9. The process according to claim 1, wherein the compounds of the formulas (IX) and (X) are reacted in a lower alkanol or acetonitrile. 10. The method according to claim 1, wherein chlorine is exchanged with iodine in the compound of the formula (VIII) by reacting with an alkali iodide containing sodium iodide. 11. The material comprises isopropanol,
The method according to claim 10, wherein the reaction is carried out in an alkanol having a high boiling point. 12. methanol, including isopropanol or acetonitrile, claims in an alkanol or a non-polar organic solvent of C ₁ ~ _4, and performing the reaction of the compound of formula (VI) and formula (VII) Item 1. The production method according to Item 1. 13. The process according to claim 1, wherein the reaction of the compounds of the formulas (IV) and (V) is carried out in the presence of a piperidine acetate as a catalyst. 14. The process according to claim 1, wherein in the compound of the formula (IV), chlorine is exchanged with iodine by reacting with an alkali metal iodide containing sodium iodide.