KR100844336B1 - Novel Method for Preparing Levobupicaine and its Hydrochloride - Google Patents

Abstract

The present invention relates to a method of preparing levobuivacaine and its hydrochloride having high optical purity, (S) -2 ', 6' having an optical purity of more than 85% enantiomeric excess (ee) -Pefecoloxylidide reacts with 1-bromobutane under a base to obtain levobupivacaine, and then recrystallization to obtain levobupivacaine having an optical purity of 98% ee or more, which is reacted with hydrochloric acid. To prepare a high-purity levobupivacaine hydrochloride having an optical purity of 99% ee or more.

According to the present invention, the preparation method of levobupivacaine and its hydrochloride salt is simple, the handling of reagents used is easy, and the enantiomeric excess rate of levobupivacaine can be prepared to 98% ee or more. Converting the prepared levobupivacaine to hydrochloride has the advantage of producing a high-purity levobupivacaine hydrochloride having an optical purity of 99% ee or more.

Description

New Synthetic Method of Levobupivacaine and its Hydrochloride

The present invention relates to a method for preparing levobupivacaine and its hydrochloride, and more particularly to a method for producing levobupivacaine and its hydrochloride having high optical purity.

Analogues such as levobuivacaine and ropivacaine are useful as local anesthetics. In particular, optically divided pure (S) -enantiomers are widely used as analgesics with higher therapeutic modulus than racemates. In addition, (S) -enantiomers showed less cardiac toxicity than racemates and thus maintained the same anesthetic efficacy, and thus appeared to be advantageous for clinical use.

J. Med. Chem., (9), 891-892 (1971) and U.S. Patent Publication No. 4,180,712 disclose optical resolution of bupivacaine using natural (R, R) -tin acid as a disintegrant, thereby providing a levobupivaca A method of obtaining phosphorus is described. That is, racemic bupivacaine is reacted with (R, R) -tartrate to crystallize (R) -bupivacaine (R, R) -tartrate first, and then (S) -bupivacaca present in the filtrate. Phosphorus (R, R) -tin salts are crystallized secondarily to obtain levobupivacaine, resulting in poor overall operating efficiency and impractical industrial use. In addition, it is difficult to obtain reproducible yields, and the enantiomeric excess (ee) value is also variable, making it difficult to obtain high purity levobupivacaine.

Org. Pro. Res. & Devel., 4, p530-533 (2000) and GB 1995/002513 describe a method for optically splitting racemic bupivacaine using (S, S) -tartrate as a disintegrant. In other words, racemic bupivacaine is reacted with (S, S) -tartrate to produce (S) -bupivacaine (S, S) -tartrate with 98% ee but is used as a disintegrant (S, S ) -Tinic acid is difficult to obtain naturally and has a disadvantage of high production cost. In addition, there is a disadvantage in that the total yield of the two steps of obtaining the levobupivacaine hydrochloride by optical cleavage and reacting with hydrochloric acid is 32%.

Tetrahedron Lett., Vol. 37, No 35, pp 6399-6640 (1996) describes a method for obtaining levobupivacaine in five steps in N ^α -CBZ (S) -lysine as shown in Scheme 1 below. Starting with N ^α -CBZ (S) -lysine to obtain (S) -2 ′, 6′-Pipecoloxyllided as 98% ee and then reacting with potassium carbonate and 1-bromobutane to prepare levobupivacaine That's how. This process is too long and the diazonium salt intermediates produced during the reaction are not suitable for industrial production due to the high risk of explosion.

Scheme 1

The present invention is suitable for industrial production in the preparation of levobupivacaine and its hydrochloride salts, wherein pure (S) -enantiomers have a higher therapeutic modulus than racemates and are always constant in enantiomeric excess without complex processes. The purpose is to provide a stable manufacturing method having an enantiomeric excess (ee).

That is, an object of the present invention is to provide a method for producing levobupivacaine having an optical purity of 98% ee or more through a simple and easy industrial application process, and also has an optical purity of 98% ee or more. It is another object of the present invention to provide a method for preparing levobupivacaine hydrochloride having an optical purity of 99% ee or more from levobupivacaine.

The manufacturing process suitable for industrial production should be simple, easy to handle the reagents to be used, and by-products generated in the reaction step should not generate a large amount of harmful gas or waste, and there is no risk of explosion. In order to satisfy these conditions and to produce high optical purity of levobupivacaine and its hydrochloride salt, research has been carried out to show that (S) -2 ′, 6′-pipecolyoxylide and 1-bromobutane having low optical purity. (S) -Bupivacaine having an optical purity of 98% ee or more, ie, levobupivacaine, was prepared by reaction and recrystallization under a base. It has been found that phosphoric acid hydrochloride can be prepared to complete the present invention.

The present invention relates to a method for preparing levobupivacaine having an optical purity of at least 98% ee and a method for producing levobupivacaine hydrochloride having an optical purity of at least 99% ee.

According to the present invention, a method for preparing levobupivacaine is selected from a specific organic solvent group after reacting (S) -2 ′, 6′-pifecoloxylidide with low optical purity with 1-bromobutane under a base. Through recrystallization with an organic solvent, it is characterized in that the manufacturing of high optical purity levobupivacaine.

More specifically, the method for preparing levobupivacaine according to the present invention is characterized by including the following steps.

a) Levobupivacaine of Formula (II) was prepared by reacting (S) -2 ′, 6′-Pipecocholoxylide of Formula (I) with 1-bromobutane with an optical purity of at least 85% ee under a base in an organic solvent. Doing; And

b) Recrystallization of the prepared levobupivacaine of formula II in a solvent selected from isopropanol, acetonitrile, cyclohexane, normal hexane, toluene or acetone to prepare levobupivacaine of formula II having an optical purity of at least 98% ee Steps.

[Formula I]

[Formula II]

(S) -2 ′, 6′-Pipecoloxilide in the method for preparing levobubivacaine may be used having an enantiomeric excess (ee) of 85% to 99%, and (S) -2 If the enantiomeric excess (ee) of ′, 6′-Pipecoloxylidide is less than 85% ee, the yield decreases because the recrystallization process must be performed repeatedly to make the optical purity of levobupivacaine more than 98% ee. The higher the enantiomeric excess (ee) of (S) -2 ', 6'- pipepecoloxylidide, the higher the optical purity of the product, and the higher the ee value, the higher the unit cost. Since the production cost increases, it is preferable to use an enantiomeric excess (ee) of 85% to 95% in consideration of economical aspects.

In addition, the recrystallization step may be performed more than once, and when recrystallization several times, the optical purity may be improved, but since the yield is reduced, the number of recrystallizations is preferably 3 or less.

In addition, the present invention relates to a method for preparing levobupivacaine hydrochloride, specifically, 99% by reacting with hydrochloric acid in an organic solvent after the step of preparing levobupivacaine of formula II having an optical purity of 98% ee or more It is characterized in that the preparation of levobupivacaine hydrochloride of formula III having an optical purity of ee or more.

[Formula III]

The preparation method of levobupivacaine according to the present invention is simple, the handling of reagents to be used is easy, and the enantiomeric excess of levobupivacaine is constant at 98% ee or more. In addition, there is an advantage that can be prepared with the optical purity of levobubivacaine hydrochloride more than 99%.

Hereinafter, the present invention will be described in more detail. At this time, if there is no other definition in the technical terms and scientific terms used, it has a meaning commonly understood by those of ordinary skill in the art. In addition, repeated description of the same technical configuration and operation as in the prior art will be omitted.

The present invention relates to a method for preparing levobupivacaine having an optical purity of at least 98% ee and a method for producing levobupivacaine hydrochloride having an optical purity of at least 99% ee.

Levobupivacaine and its hydrochloride method according to the present invention is shown in Scheme 2 below.

Scheme 2

Levobubivacaine hydrochloride having an optical purity of 98% ee or more through the steps a) and b) of Scheme 2, and reacting with hydrochloric acid of step c) therefrom, to produce levobupivacaine hydrochloride having an optical purity of 99% ee or more. To prepare.

Starting material (S) -2 ′, 6′-Pipecoloxylidide can be used having an optical purity of 85% to 99% ee value of 85% ee or more, but as described above, 85% in consideration of economics Preference is given to using those having a value of from 95% ee. The manufacturing method of the (S) -2 ', 6'- pipepecoloxylidide can be prepared by a method of optically dividing the racemic 2', 6'- pipepecoloxylidide, prepared (S) -2 ' The optical purity of, 6′-pipepeoxyoxylide is required to be at least 85% ee.

As a more preferred method for preparing (S) -2 ', 6'-pipecolicoxylidide having a value of 85% to 95% ee, (S) -2', 6'-pipepeoxyoxylidide is used in racemic 2 ', Processes obtained by reacting 6'-pipecolyoxylide with dibenzoyl tartrate may be used. It can be obtained with a high yield of 40% using the above method is very advantageous in terms of economics, it is possible to increase the optical purity in the subsequent recrystallization step, as a result can be produced levobupibacaine with high optical purity. .

The base used in step a) of Scheme 2 uses potassium carbonate, sodium carbonate, sodium bicarbonate, and the like, preferably potassium carbonate. Dimethylformamide, isopropanol, acetonitrile and the like are used as the reaction solvent in step a), and isopropanol is more preferable because of high yield.

In step b) of the present invention, as the recrystallized solvent, a solvent selected from isopropanol, acetonitrile, cyclohexane, normal hexane, toluene or acetone is preferably used, and the use of cyclohexane or normal hexane is more preferable in terms of yield and optical purity. Preferred, cyclohexane is most preferred.

The solvent used in the step of preparing the levobupivacaine hydrochloride is preferably used a solvent selected from acetone, isopropanol or acetonitrile, when acetone is used in terms of yield and purity of levobupivacaine hydrochloride more excellent It is more preferable.

The present invention will be described in more detail with reference to the following examples. However, the following examples are merely examples of the present invention, and the claims of the present invention are not limited thereto.

Production Example 1 Synthesis of Racemic 2 ′, 6′-Pipecoloxylate

Triphenylphosphine 87.4 g (0.33 mol) was added to a mixed solution of 900 mL acetonitrile and hexachloroethane 78.9 g (0.33 mol), followed by stirring at room temperature for 1 hour. 50 g (0.3 mol) of racemic pipecolic acid hydrochloride is added thereto, followed by stirring at 55 ° C. for 3 hours. 37 g (0.3 mol) of 2,6-dimethylaniline was added dropwise for 30 minutes, followed by stirring for 5 hours.

After slowly cooling to room temperature and stirring for 3 hours, the solid is filtered and washed with 100 mL of acetonitrile.

The obtained solid is suspended in a mixed solution of 195 mL dichloromethane and 195 mL purified water. 20 mL of 50% sodium hydroxide solution is added and stirred for 30 minutes. After layer separation, the aqueous layer is extracted once more with 65 mL of dichloromethane. The organic layers are combined, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. 263 mL of cyclohexane was added to the obtained residue, and the mixture was refluxed for 1 hour, and stirred for 1 hour after cooling to room temperature. The resulting crystals were filtered off, washed with 54 mL of cyclohexane cooled to 0 ° C., and dried at 60 ° C. for 5 hours to obtain racemic 2 ′, 6′-pipecolyloxylide as the target compound.

yield; 88%,

water; 99.85% (HPLC% aera),

¹ HNMR (CDCl ₃ ) δ 1.65 (m, 5H), 2.01 (s, 1H), 2.13 (m, 1H), 2.22 (m, 1H), 2.78 (m, 1H), 3.10 (m, 1H), 3.42 (m, 1 H) 7.08 (m, 3 H), 8.23 (br s, 1 H).

Production Example 2 Preparation of (S) -2 ′, 6′-Pipecoloxylidide

50 g (0.22 mol) of racemic 2 ′, 6′-pipecolicoxylidide are suspended in 340 mL of isopropanol and warmed to 60 ° C. 47.9 g (0.12 mol) of (-)-dibenzoyl-L-tartaric acid monohydrate is dissolved in 170 mL of isopropanol, and a solution warmed to 60 DEG C is added to the reaction solution. After refluxing for 10 minutes, the mixture is slowly cooled to room temperature for 1 to 2 hours. The resulting crystals are filtered off, washed with 50 mL of isopropanol and dried at 50 ° C. for 6 hours.

The obtained solid is suspended in 200 mL of purified water and 200 mL of ethyl acetate and adjusted to pH 11 with aqueous sodium hydroxide solution. The separated aqueous layer is extracted once more with 100 mL of ethyl acetate. Wash combined organic layers with saturated brine 100mL, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure of the solvent (S) - 2 ', 6'-piperazine to obtain the call oksilri bonded.

yield; 40% (90% ee)

[a] _D = + 41.8 ° (c 2.035, 1N HCl).

Example 1 Synthesis of Levobupivacaine

a) the (S) produced in Production Example 2 and a suspension of 2 ', 6'-yl-call oksilri bonded 10g (43mmol) in 70mL of isopropanol. 12 g (86 mmol) of potassium carbonate and 12 g (86 mmol) of 1-bromobutane are added and refluxed for 15 hours. 100 mL of purified water was added to the residue obtained by distillation under reduced pressure at 50 ° C, and stirred for 2 hours. The resulting crystals are filtered off and washed with 30 mL of purified water. The obtained crystals are dried in vacuo at 50 ° C. (yield: 97%).

b) The obtained crystals are added to 35 mL of cyclohexane and refluxed for 30 minutes. The mixture was gradually cooled to room temperature, stirred for 2 hours, and the precipitated crystals were filtered out. After washing with 10 mL of cyclohexane and dried at 50 ℃ to obtain levobupivacaine.

yield; 85%,

mp 136 ° C.,

[α] _D = -79.4 ° (c 2, 1N HCl). 98.1% ee

¹ H-NMR (DMSO-d ₆ ); δ 0.87 (3H, t), 1.26 (3H, m), 1.53 (4H, m), 1.71 (2H, m), 1.81 (1H, m), 1.99 (1H, m), 2.12 (6H, S), 2.21 (1H, m), 2.62 (1H, m), 2.84 (1H, m), 3.08 (1H, m), 7.05 (3H, S).

Example 2 Synthesis of Levobupivacaine

a) the (S) produced in Production Example 2 and a suspension of 2 ', 6'-yl-call oksilri bonded 20g (86mmol) in 50mL of dimethylformamide. 14.4 g (103.2 mmol) of potassium carbonate and 14.4 g (103.2 mmol) of 1-bromobutane are added and stirred at 70 ° C. for 3 hours. After cooling the reaction solution to 30 ℃, 225 mL of purified water was added and stirred for 2 hours. The resulting solid is filtered and washed with 50 mL of purified water. The obtained crystals are dried in vacuo at 50 ° C. (yield: 95%).

b) 70 mL of cyclohexane was added to the above crystals and refluxed for 30 minutes. The crystal obtained by cooling gradually to room temperature and stirring for 2 hours is filtered. After washing with 20 mL of cyclohexane, it is dried at 50 ° C to obtain levobupivacaine.

yield; 80%,

mp 136 ° C.,

[a] _D = -79.6 ° (c 2, 1N HCl). 98.3% ee

¹ H-NMR (DMSO-d ₆ ); Same as that of Example 1.

Example 3 Synthesis of Levobupivacaine Hydrochloride

9 g (31.2 mmol) of (S) -Bupivacaine having an optical purity of 98% ee or more obtained in Example 2 or 3 was suspended in 45 mL of acetone, and then 13.5 mL of hydrochloric acid was added and stirred at room temperature for 2 hours. The resulting crystals were cooled to 0 ° C. and stirred for 2 hours, filtered and washed with 9 mL of acetone, followed by vacuum drying at 50 ° C. for 15 hours to obtain the above-mentioned levobupivacaine hydrochloride as white crystals.

yield; 85%,

mp 250 ° C.,

[a] _D = -12.56 ° (c 2, H ₂ O). > 99% ee

¹ H-NMR (CD ₃ OD); δ 1.0 (3H, t), 1.4 (2H, m), 1.6 ~ 2.1 (7H, m), 2.2 (6H, s), 2.5 (1H, m), 3.2 (3H, m), 3.7 (1H, d ), 4.2 (1H, m), 7.1 (3H, m).

According to the present invention, the preparation method of levobupivacaine and its hydrochloride salt is simple, the handling of reagents used is easy, and the enantiomeric excess rate of levobupivacaine can be prepared to 98% ee or more. Converting the prepared levobupivacaine to hydrochloride has the advantage of producing a high-purity levobupivacaine hydrochloride having an optical purity of 99% ee or more.

Claims (6)

1) (S) -2 ', 6'- of formula (I) having an optical purity of 85% ee or more by optically dividing racemic 2', 6'-pipeecolyoxylide into (-)-dibenzoyl-L-tartaric acid Preparing pipepeoxyoxylide; 2) Levobupivacaine of Formula (II) was prepared by reacting (S) -2 ′, 6′-Pipecoloxilide of Formula (I) having an optical purity of 85% ee or more with 1-bromobutane under a base in an organic solvent. Doing; And 3) recrystallizing the prepared levobupivacaine of formula (II) with cyclohexane to prepare (S) -bubivacaine of formula (II) having an optical purity of 98% ee or more; Levobubivacaine manufacturing method comprising a. [Formula I]

[Formula II]

delete The method of claim 1, The organic solvent of step 2) is levobupivacaine production method characterized in that selected from dimethylformamide, isopropanol or acetonitrile. The method of claim 1, The base of step 2) is a method for producing levobupivacaine, characterized in that selected from potassium carbonate, sodium carbonate or sodium bicarbonate. Preparing (S) -Bupivacaine of Formula (II) having an optical purity of 98% ee or more according to the method of any one of claims 1 and 3 to 4; And Reacting (S) -Bupivacaine of Formula II having an optical purity of 98% ee or more with hydrochloric acid in an organic solvent to prepare Levobupivacaine Hydrochloride of Formula III having an optical purity of 99% ee or more; Method for producing levobupicaine hydrochloride comprising a. [Formula II]

[Formula III]

The method of claim 5, The organic solvent is a method for producing levobupivacaine hydrochloride, characterized in that selected from acetone, isopropanol or acetonitrile.