KR20070092594A - Process for preparing lercanidipine hydrochloride - Google Patents

Abstract

A method for preparing lercanidipine hydrochloride is provided to synthesize the lercanidipine hydrochloride under safe and mild conditions with improved yield through a simplified reaction process. A method comprises the steps of: (a) reacting 2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid represented by the formula(2) with a dialkylchlorophosphate derivative compound represented by the formula(4) to obtain a dialkyl phosphonoester compound represented by the formula(5); and (b) reacting the compound of the formula(5) with 2,N-dimethyl-N-(3,3-diphenylpropyl)-1-amino-2-propanol represented by the formula(3) to obtain lercanidipine hydrochloride represented by the formula(1). In the formulae, R' is O or S, and each R1 and R2 is methoxy, ethoxy, or phenoxy. The obtained lercanidipine hydrochloride is further purified by tetrahydrofuran.

Description

Production method of lercanidipine hydrochloride {PROCESS FOR PREPARING LERCANIDIPINE HYDROCHLORIDE}

1 is an XRD spectrum of lercanidipine hydrochloride crystalline form prepared according to the method of the present invention,

2 shows the DSC melting point of lercanidipine hydrochloride crystals prepared according to the method of the present invention.

The present invention relates to a novel method for preparing lercanidipine hydrochloride having a therapeutic effect on hypertension.

Lercanidipine hydrochloride is 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid [2-[(3,3-diphenylpropyl) methyl A hydrochloride salt of amino] -1,1-dimethylethyl] methyl ester having the structure of Formula 1.

L-type calcium channel antagonist is the first synthetic method of lercanidipine that is effective in treating antihypertensives and angina (inflammation of throat tonsil, etc.) and coronary artery disease, Korean Patent Registration No. 10-0046328 (Nov. 1991) 22) is disclosed as in Scheme 1 below.

The manufacturing method according to Scheme 1 has a problem that the synthesis process is long and various by-products are generated, and the yield is low and it is difficult to apply to large-scale production. Accordingly, Korean Patent Registration No. 10-0395441 (August 9, 2003) proposes an improved synthesis method as in Scheme 2 below.

Method of Scheme 2 in relation to the method of Scheme 1 is the reaction by-product is hardly formed, but the advantage that the yield is improved, the strong acid sulfide using a reaction process when thionyl chloride (SOCl ₂₎ (SO ₂₎ and hydrochloric acid ( HCl) gas is generated, and the resulting acyl chloride intermediate is very sensitive to moisture in the air, which causes a decrease in yield, which makes it difficult to apply to mass production.

In order to improve the above two manufacturing process problems, Korean Patent Publication No. 10-2005-0013348 (February 4, 2005) proposes an improved synthesis method of Scheme 3.

In the method of Scheme 3, by-products generated during the reaction using dicyclohexylcarbodiimide (DCC) as a coupling reagent can be removed by a simple filtration process, and the reaction is safely performed under mild conditions. On the other hand, the use of reaction catalysts and dicyclohexylcarbodiimide (DCC) is expensive, and the dicyclohexyl urea produced as a by-product has poor solubility in water and solvents, making it difficult to remove and remaining as impurities in the product. There is a problem in that it is an obstacle to the production of high quality products.

The present invention is to improve the above problems in the lercanidipine manufacturing process, the purpose of providing a manufacturing method is simpler than the conventional method and the yield is high by synthesizing lercanidipine hydrochloride under safe and mild conditions. It is done.

Method for producing lercanidipine hydrochloride (1) of the present invention for achieving the above object,

Reaction of 2,6-dimethyl-5-methoxycarbonyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid (2) with dialkylchlorophosphate derivative compound (4) To obtain a dialkylphosphono ester compound (5);

Reacting the resulting dialkylphosphonoester compound (5) with 2, N-dimethyl-N- (3,3-diphenylpropyl) -1-amino-2-propanol (3).

[Formula 1]

In the above formula, R 'represents an oxygen or sulfur atom, R1 and R2 may be the same or different, respectively represents a methoxy, ethoxy or phenoxy group.

In the present invention, since lercanidipine hydrochloride is synthesized by one pot reaction using dialkylchlorophosphate derivatives in the production of activated esterification as a reaction intermediate, lercanidipine hydrochloride with high yield through a simple reaction process under safe and mild conditions. Can be obtained. Furthermore, the dialkyl chlorophosphate derivative compound is not only economically low in price, but also excellent in water-soluble dialkyl phosphonic acid, which is a by-product produced after the reaction, so that it can be easily removed, thereby producing a large amount of high quality lercanidipine. There is an advantage that it can.

Hereinafter, the preparation method of lercanidipine hydrochloride according to the present invention will be described in detail for each step. The whole process of this manufacturing method consists of following Reaction Formula 4.

Wherein R 'represents an oxygen or sulfur atom, R1 and R2 may be the same or different and each represents a methoxy, ethoxy or phenoxy group.

The process for preparing lercanidipine hydrochloride (1) of the present invention consists of the following steps:

(A) 2,6-dimethyl-5-methoxycarbonyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid (2) and dialkylchlorophosphate derivatives in a suitable solvent Reacting compound (4) to obtain an intermediate dialkylphosphono ester compound (5);

(B) 2, N-dimethyl-N- (3,3-diphenylpropyl) -1-amino-2-propanol (3) was added to the resulting dialkylphosphono ester compound (5) for reaction;

(C) making the resulting lercanidipine anhydrous hydrochloride; And

(D) Purify using a suitable nonpolar solvent.

The synthesis of compounds (2) and (3) in the above scheme is known from German Patent No. 284737 and US Patent No. 4,705,797. In addition, the dialkylchlorophosphate derivative compound (4) can be easily purchased on the market as a general reagent.

In step (a), toluene may be used as a suitable reaction solvent in the preparation of the dialkylphosphono ester compound (5), which is an activated ester, which is a key intermediate of the present invention. In addition, a base such as KOH, NaOH, triethylamine, pyridine, diisopropylamine, tetramethylguanidine may be used as a base for generating anion of the dihydropyridine acid compound (2).

In the step (a), a suitable activating esterification agent may be a dialkylchlorophosphate derivative compound (4) or the like in the range of 1.0 to 2.0 equivalents, the reaction temperature is 10 to 40 ° C., and the reaction time is preferably 1 to 2 hours. .

The reaction temperature of step (b) is preferably 100 to 110 ° C., and the reaction time is about 2 hours.

In the process of making lercanidipine of step (c) to anhydrous hydrochloride, aqueous hydrochloric acid is generally used.

Tetrahydrofuran, dioxane, etc. may be used as a nonpolar solvent suitable for the purification process of (d).

In steps (c) and (d), the resulting recardipine is made into hydrochloride and recrystallized using a suitable nonpolar solvent by a conventional method.

The lercanidipine hydrochloride prepared according to the present invention is anhydrous in crystalline form. The crude product in hydrochloride form is prepared from solvents such as ethyl acetate and tetrahydrofuran, and the product recrystallized with an optional solvent such as tetrahydrofuran has a melting point of 185. To 190 ° C.

The activated dialkylphosphonoester compound (5), which is a key intermediate in the process of the invention, is in fact a one pot reaction since it does not need to be separated. In addition, the process of the present invention produces little reaction by-products compared to the processes of the prior art, so that the yield is improved and the lercanidipine separation process and purification process are simpler.

Lercanidipine hydrochloride prepared according to the present invention is of high quality and has high stability and low hygroscopicity. Therefore, the method for producing lercanidipine hydrochloride of the present invention can be said to be a very efficient method in the industry, which has the advantages of low manufacturing cost and little process waste.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, these Examples are only illustrative of the present invention, and the scope of the present invention is not limited thereto.

EXAMPLE

Example  1: 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid [2-[(3,3- Diphenylpropyl ) Methylamino ] -1,1-dimethylethyl] Methyl ester  Hydrochloride crew Of de (zolecanidipine hydrochloride)  Produce

5.0 g of 2,6-dimethyl-5-methoxycarbonyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid (2) in 50 mL of toluene, 2.31 mL of triethylamine And 2.4 mL of diethylchlorophosphate was added and stirred at room temperature for 1 hour. After TLC confirmed the dialkylphosphonoester compound (5) as an intermediate, 4.49 g of 2, N-dimethyl-N- (3,3-diphenylpropyl) -1-amino-2-propanol (3) was added thereto. It was refluxed for time. After treating with activated carbon, concentrated under reduced pressure to remove toluene, and the residue was dissolved in 30 mL of ethyl acetate. The organic solution was washed successively using 11 mL of 10% NaOH aqueous solution, 11 mL of purified water, 13.1 mL of 6N HCl, and 11 mL of purified water. The organic layer was separated, dried over activated carbon and anhydrous sodium sulfate for 30 minutes, and the organic layer was concentrated under reduced pressure. The residue was dissolved in 15.7 mL of tetrahydrofuran and then sprinkled with 50 mg of lercanidipine hydrochloride. After stirring for 24 hours at 20 to 25 ℃ filtered and dried in vacuo at 70 to 80 ℃ 8.3 g (85.1% of theory) of the crude lercanidipine hydrochloride.

1 H NMR (DMSO-d6, 400 MHz) (ppm): 10.8 to 9.4 (bb, 1H), 9.5 (bs, 1H), 8.30 to 8.05 (m, 2H), 7.85 to 7.60 (m, 2H), 7.55 to 7.20 (m, 10H), 5.05 (s, 1H), 4.15 to 3.35 (m, 6H), 3.20 to 2.15 (m, 13H), 2.6 (s, 3H), 1.50 (s, 6H).

Example  2: 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid [2-[(3,3- Diphenylpropyl ) Methylamino ] -1,1-dimethylethyl] Methyl ester  Hydrochloride Of rude (crude lercanidipine hydrochloride)  Produce

5.0 g of 2,6-dimethyl-5-methoxycarbonyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid (2) in 50 mL of toluene, 2.31 mL of triethylamine And 3.1 g of diethylchlorothiophosphate were added and stirred at room temperature for 1 hour. After TLC confirmed the dialkylphosphonoester compound (5) as an intermediate, 4.49 g of 2, N-dimethyl-N- (3,3-diphenylpropyl) -1-amino-2-propanol (3) was added thereto. It was refluxed for time. After treating with activated carbon, concentrated under reduced pressure to remove toluene, and the residue was dissolved in 30 mL of ethyl acetate. The organic solution was washed successively using 11 mL of 10% NaOH aqueous solution, 11 mL of purified water, 13.1 mL of 6N HCl, and 11 mL of purified water. The organic layer was separated, dried over activated carbon and anhydrous sodium sulfate for 30 minutes, and the organic layer was concentrated under reduced pressure. The residue was dissolved in 15.7 mL of tetrahydrofuran and then sprinkled with 50 mg of lercanidipine hydrochloride. After stirring for 24 hours at 20-25 ° C, it was filtered and dried in vacuo at 70-80 ° C to obtain 8.1 g (83.1% of theory) of crude lercanidipine hydrochloride.

1 H NMR (DMSO-d6, 400 MHz) (ppm): 10.8 to 9.4 (bb, 1H), 9.5 (bs, 1H), 8.30 to 8.05 (m, 2H), 7.85 to 7.60 (m, 2H), 7.55 to 7.20 (m, 10H), 5.05 (s, 1H), 4.15 to 3.35 (m, 6H), 3.20 to 2.15 (m, 13H), 2.6 (s, 3H), 1.50 (s, 6H).

Example  3: 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxy practice  [2-[(3,3- Diphenylpropyl ) Methylamino ] -1,1-dimethylethyl] Methyl ester  Preparation of Hydrochloride (Lercanidipine Hydrochloride) (1)

25.2 mL of tetrahydrofuran was added to 3.6 g of each crude lercanidipine hydrochloride prepared in Examples 1 and 2, and the mixture was refluxed for 30 minutes. After stirring for 24 hours at 20 to 25 ℃ filtered and dried in vacuo at 70 to 80 ℃ 3.42 g (95% of theory) of lercanidipine hydrochloride (1).

Melting Point: 187 ℃

The structure of the crystalline XRD spectrum shows the results in Table 1 when analyzed according to the following conditions, and the spectrum is illustrated in FIG. 1.

[Condition]

RIGAKU D-MAX2200

X-ray: Cu K-ALPHA1 / 40KV / 40mA

Scan mode: FT

Sampling time: 2.00 seconds

Step angle: 0.020 degrees

Scan axis: 2 Theta / Theta

Scan range: 2.000 → 50.000 degree

2 θ angle D (Δ) Relative Strength (Ι / ΙO) 5.30 16.66 44 10.66 8.29 12 10.94 8.08 14 14.12 6.26 24 16.06 5.51 22 16.34 5.42 18 18.44 4.80 22 18.96 4.67 12 21.54 4.12 22 21.76 4.08 16 21.98 4.04 14 22.66 3.92 100

DSC melting point: 197.64 ° C.

Figure 2 shows the DSC melting point of lercanidipine hydrochloride crystals, indicating that it is in the range of 190 to 201 ° C. DSC melting point is measured under the following conditions:

Temperature rise rate: up to 220 ° C. at a rate of 10 ° C./min.

50 cc / min of N ₂ Purge

Instrument model: Universal V4. 1 D TA instrument (2910 MDSC V4.4E)

As can be seen from the above results, the yields of lercanidipine hydrochloride in Examples 1 and 2 were 85.1% and 83.1%, respectively, which can be seen to be improved compared to 75 to 78% of the yield obtained when preparing lercanidipine according to the conventional method.

As described above, the method for producing lercanidipine hydrochloride according to the present invention has almost no reaction by-products compared to the conventional process, so that the yield is improved, and the lercanidipine separation process and purification process are simpler, resulting in higher product yield. You can expect quality. In addition, the method of the present invention is an environmentally friendly manufacturing method with low manufacturing cost and almost no process waste, which is advantageous in industrial mass production.

Claims (6)

Reaction of 2,6-dimethyl-5-methoxycarbonyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid (2) with dialkylchlorophosphate derivative compound (4) To obtain a dialkylphosphono ester compound (5); Lercanidipine comprising reacting the resulting dialkylphosphonoester compound (5) with 2, N-dimethyl-N- (3,3-diphenylpropyl) -1-amino-2-propanol (3) Method for producing hydrochloride (1). [Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

In the above formula, R 'represents an oxygen or sulfur atom, R1 and R2 may be the same or different, respectively represents a methoxy, ethoxy or phenoxy group. The method according to claim 1, wherein the dialkylchlorophosphate derivative compound (4) is diethylchlorophosphate or diethylchlorothiophosphate. The dialkyl phosphono ester compound (5) according to claim 1, wherein the dialkylphosphonoester compound (5) is 2,6-dimethyl-5-methoxycarbonyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxyl. Acid diethylphosphono ester or 2,6-dimethyl-5-methoxycarbonyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid diethylthiophosphono ester How to feature. The lercany according to Claim 1 obtained by reacting a dialkyl phosphono ester compound (5) with 2, N-dimethyl-N- (3,3-diphenylpropyl) -1-amino-2-propanol (3). Further comprising purifying dipine hydrochloride with tetrahydrofuran. Lercanidipine hydrochloride crystalline form having the XRD spectrum of the following Table 1. TABLE 1 2 θ angle D (Δ) Relative Strength (Ι / ΙO) 5.30 16.66 44 10.66 8.29 12 10.94 8.08 14 14.12 6.26 24 16.06 5.51 22 16.34 5.42 18 18.44 4.80 22 18.96 4.67 12 21.54 4.12 22 21.76 4.08 16 21.98 4.04 14 22.66 3.92 100 Lercanidipine hydrochloride crystalline form having a DSC melting point in the range of 190 to 201 ° C.

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