DD260927A5 - PROCESS FOR MAKING ESPECIALLY OPTICALLY PURE S - (-) - 1-PROPYL-2 ', 6'-PIPECOLOXYLIDIDE HYDROCHLORIDE - Google Patents

Abstract

The invention relates to a process for the preparation of substantially optically pure S - (-) - 1-propyl-2,6-pipecoloxylidide hydrochloride for use in human medicine and veterinary medicine in locally anesthetically active preparations. By the process of the present invention, the monohydrate of S - (-) - 1-propyl-2,6-pipecoloxylidide hydrochloride is prepared by dissolving it in water, then adding acetone heated to a temperature of 45C to its boiling point the monohydrate is isolated.

Description

Field of application of the invention

The S - (-) - 1-propyl-2 ', 6'-pipecoloxylidide hydrochloride prepared by the process of the present invention can be made into local anesthetic preparations for use in human and veterinary medicine.

Characteristic of the known technical solutions

A new local anesthetic, namely S - (-) - 1-propyl-2 ', 6'-pipecoloxylidide hydrochloride is described in WO 85/00599. The new compound has a surprisingly long duration of action compared to the racemate and the corresponding R - (+) enantiomer. However, the method of preparation described in WO85 / 00599 gives a product containing about 10% of the R (+) enantiomer. This means that from a physico-chemical point of view the product contains only about 80% of the S - (-) enantiomer, while the remainder consists of about 20% of the racemic form. In addition, the product obtained is hygroscopic and thus unstable and contains about 2% water. 1 mol of water of crystallization means a water content of 5.5%. A product with a variable water content has the disadvantage that the percentage of water must be analyzed in each case if a pharmaceutical formulation is to be produced. Since the S - (-) enantiomer is the most effective enantiomer, a product containing less R - (+) enantiomer is desired.

Object of the invention

The aim of the invention is the preparation of a more effective S - (-) - 1-propyl-2 ', 6'-pipecoloxylidid hydrochloride.

Explanation of the essence of the invention

The object of the invention is a process for the preparation of S - (-) - 1-propyl-2 ', 6'-pipecoloxylidide hydrochloride, which is stable and does not change when stored at ordinary room temperature and ordinary humidity. A second object of the invention is to obtain a product consisting essentially of the pure S - (-) enantiomer. The invention relates to the monohydrate of S-1-1-i-propyl-3'-e'-pipecoloxylidide hydrochloride. With the aid of a special process for preparing the designated hydrate, the S - <- enantiomer is obtained in optically extremely pure form, namely> 99.5%, even from a highly visually contaminated preparation. The monohydrate of S - (-) - 1-propyl-2 ', 6'-pipecoloxylidide hydrochloride has the further advantage that it is very stable and is hardly affected by drying in a desiccator over calcium chloride at room temperature and 0.5 mm Hg. Only when the compound was heated to 75 ° C for 16 hours under otherwise identical conditions, the water of crystallization was removed. No further change in the compound was observed

 The monohydrate of S - (-) - 1-propyl-2 ', 6'-pipecoloxylid hydrochloride of the structural formula

- 'NO'

HCl · H ₂ O

^3H 7

is prepared according to the invention by dissolving SiJi-Propyl ^ '. e'-pipecoloxylidid hydrochloride in water, followed by adding hot acetone. The solution is then filtered as hot as possible and allowed to crystallize. In the preparation, the starting compound is dissolved in an amount of water equal to about one to three times the weight of the added compound, and the added acetone volume is five to fifteen times the volume of water. When more water is added, ie, an amount of water equal to four times the weight of the added compound, the volume of added acetone is fifteen to twenty times the volume of water. It is particularly preferred to carry out the preparation in the following manner: The starting compound is heated with an amount of water equal to the weight of the starting compound. Hot acetone in such an amount that the compound is completely dissolved is added. Further acetone up to a volume ten times the volume of the added water is then poured into the solution, after which the solution is filtered and allowed to crystallize. The quantitative ratio between water and acetone is important. If too much acetone is added, the product obtained is less pure and more recrystallizations are required. On the other hand, if less acetone is added than ten times the volume of water, the yield is lowered. The added acetone is hot, preferably boiling (bp 56 ⁰ C). Acetone at a temperature between 45 and 56 ° C can be used according to the invention.

The invention also relates to pharmaceutical preparations containing the novel pure compound as an active ingredient for the use of the novel compound in therapy, in particular for the production of local anesthetics in mammals, including humans. Furthermore, the invention includes a method to obtain local anesthesia in mammals including humans by administering the novel compound, and the use of the novel compound in the preparation of pharmaceutical preparations having a local anesthetic effect.

For the preparation of pharmaceutical preparations, the new compound is dissolved in a liquid diluent suitable for injection. The preparations used are aqueous solutions containing between 1.25 and 15.0 mg / ml of the active ingredient, calculated as the hydrochloride salt. For some applications, a vasoconstrictor, epinephrine, is included in concentrations between 2.0 and 20.0 μg / ml calculated as the base. The solutions are rendered iso-osmotic with physiological saline by adding a suitable amount of sodium chloride. Solutions containing epinephrine also contain sodium metabisulfite to protect epinephrine against oxidation. The pH of solutions without epinephrine is adjusted to about 5.5, while the pH in solutions containing epinephrine is adjusted to about 3.6.

embodiments

Example 1 illustrates a particularly preferred way of carrying out the method according to the invention.

example 1

The preparation of the monohydrate of S - (-) - 1-propyl-2 ', 6'-pipecoloxylidide hydrochloride. 82 g of the hydrochloride of S - (-) - 1-propyl ''e'-pipecoloxylidide hydrochloride containing 10% of the R - (+) - enantiomer were dissolved in 85 ml of water, then heated to boiling point acetone up to a Final volume of 850 ml was added. The solution was filtered and allowed to crystallize. The first crystallization gave 71.7g. Further recrystallization was carried out by dissolving the resulting product in 72 ml of H ₂ O, followed by adding boiling acetone to a final volume of 750 ml. The solution was filtered and allowed to crystallize. The final yield was 62.3 g (76%) of the optically pure (> 99.5%) product containing 5.4-5.6% water of the monohydrate of S - (-) - 1-propyl-2 ', 6'-pipecoloxyldid hydrochloride with a melting interval of 266 to 267.5 ° C.

Example 2

S - (-) - 1-propyl-2 ', 6'-pipecoloxylidid-

hydrochloride monohydrate 1.64 mg

Sodium chloride 8.53 mg

Sodium hydroxide to pH 5.5

Water for injection to 1.0 ml

2.64 mg of the monohydrate of S - (-) - 1-propyl-2 ', 6'-pipecoloxylidide hydrochloride were dissolved in 1 ml of sterile water. 8.53 mg of sodium chloride were added and the solution was adjusted to pH 5.5 with sodium hydroxide.

Example 3

S - (-) - 1-propyl-2 ', 6'-pipecoloxylidid-

hydrochloride monohydrate 5.29 mg? -

Epinephrine hydrogen tartrate 10.0 mm

Sodium chloride 7.89 mg

Hydrochloric acid to pH 3.6

Water for injection to 1.0 ml

The preparation was carried out as described in Example 2.

Further attempts to purify the compound were carried out as follows:

In order to try to purify the product described in WO 85/00599, further recrystallizations were carried out from 2-propanol, the solvent used according to said patent application. Although water was added, it was not possible to obtain a more optically pure product or product better defined in terms of water contents.

Other common solvents, such as methanol and ethanol, are not suitable because of the too great solubility of the hydrochloride of S - (-) - 1-propyl-2 ', 6'-pipecoloxylidide hydrochloride in methanol and ethanol. On the other hand, in solvents such as ethyl acetate and dioxane, the compound is almost insoluble.

Claims (5)

1. A process for the preparation of substantially optically pure S - (-) - 1-propyl-2 ', 6'-pipecoloxylididhydrochlorid, characterized by reacting S - (-) - 1-propyl-2', 6'-pipecoloxylididhydrochlorid in water, then acetone heated to a temperature of 45 ^° C. to its boiling point and the monohydrate isolated from S - (-) - 1-propyl-2 ', 6'-pipecoloxylidide hydrochloride. Process according to claim 1, characterized in that the S - (-) - 1-propyl-2 ', 6'-pipecoloxylidide hydrochloride is dissolved in an amount of water equal to one to three times its weight, and acetone in a volume of Add five to fifteen times the volume of water, then filter the solution and isolate the final product. 3. The method according to claim 2, characterized in that one uses the weight of the S - (-) - 1-Propyl ^ Sö'-pipecoloxylididhydrochlorids equal weight of water and an acetone volume ten times as large as the volume of the added water. 4. The method according to any one of claims 1 to 3, characterized in that the isolated compound is substantially optically pure. 5. The method according to any one of claims 1 to 4, characterized in that the isolated compound contains less than 0.5 wt .-% of the corresponding R - (+) - entaniomer.