(S)-(-)-1-PROPYL-2',6'-PIPECOLOXYLIDIDE HYDROCHLORIDE MONOHYDRATE, PROCESS FOR ITS PREPARATION AND PHARMACEUTICAL PREPARATION CONTAINING IT

Abstract: Optically pure S-(-)-l-propyl-2′,6′-pipecoloxylidide hydrochloride monohydrate, with the structural formula a process for the preparation thereof and the use for inducing local anesthesia.

Description: Field of the invention The present invention is directed to a new optically pure compound, a process for its preparation and its use in the manufacture of pharmaceutical preparations. Background of the invention A new local anesthetic namely S-(-)-l-propyl-2′,6′-pipecoloxylidide hydrochloride is described in WO 85/OO599. The new compound has an unexpected long duration compared to the racemate and the corresponding R-(+)-enantiomer. The preparation method described in WO 85/OO599 gives however a product which contains about lO % of the R-(+)-enantiomer. This means that the product from a physical chemical point of view, contains only about 8O % of the S-(-)-enantiomer, while the residual about 2O % constitutes the racemic form. In addition the product obtained is hygroscopic and thus not stable and contains about 2 % of water. One mole of water of crystallization implies a water content of 5,5 %.A product having a varying content of water has the drawback that the percentage of water must be analyzed each time a pharmaceutical formulation shall be prepared. As the S-(-)-enantiomer is the most potent enantiomer a product containing less R-(+)-enantiomer was wanted. One object of this invention is thus to produce the compound in a form, which is stable and which does not change by storing at ordinary room temperature and humidity. A second object of this invention is to obtain a product consisting of the substantially pure S-(-)-enantiomer. Outline of the invention The present invention is related to the monohydrate of S-(-)-l-propyl-2′,6′-pipecoloxylidide hydrochloride. By means of a specific method of preparing the named hydrate, the S-(-)-enantiomer is obtained in high optical purity, namely ≧99.5 %, even from an optically highly contaminated preparation. This specific method is a further aspect of this invention. The monohydrate of S-(-)-l-propyl-2′,6′-pipecoloxylidide hydrochloride has the further advantage that it is very stable and hardly affected by drying in a desiccator over calcium chloride at room temperature and O.5 mm Hg. Only when the compound was heated at 75°C for l6 hours, other conditions being equal, the water of crystallization was removed. No further change of the compound was noticed. Preparation The monohydrate of S-(-)-l-propyl-2′,6′-pipecoloxylidide hydrochloride with the structural formula is prepared according to the invention by dissolving S-(-)-l-propyl­ -2′,6′-pipecoloxylidide hydrochloride in water, whereupon hot acetone is added. The solution is then filtered as hot as possible and left for crystallization. At the preparation the starting compound is dissolved in an amount of water, which corresponds to about l-3 times of the weight of the added compound and the volume of acetone added is 5-l5 times of the water volume. If more water is added, that is an amount of water, which corresponds to up to 4 times of the weight of the added compound, the volume of the acetone added is l5-2O times of the water volume. It is especially preferred to make the preparation in the following way: 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. Additional acetone to a volume of ten times of the volume of the added water is then poured into the solution, whereafter the solution is filtered and left for crystallization.The proportion between water and acetone is important. If too much acetone is added the product obtained is less pure and more recrystallizations are needed. When acetone less than lO times the volume of water is added on the other hand the yield diminishes. The acetone added is hot preferably boiling (b. p. 56°C). Acetone having a temperature between 45-56°C can be used according to the invention. The invention also relates to pharmaceutical preparations containing the new pure compound as active ingredient: to the use of the new compound in therapy, especially for obtaining local anesthesia in mammals including man; to a method for obtaining local anesthesia in mammals including man by administering the new compound; and to the use of the new compound in the manufacture of pharmaceutical preparations having local anesthetic effect. For the preparation of pharmaceutical preparations the new compound is dissolved in a liquid diluent, which is suitable for injection. The preparations used are aqueous solutions which contain between l.25 and l5.O mg/ml of the active compound calculated as the hydrochloride salt. In some applications a vasoconstrictor, epinephrine, is included in concentrations between 2.O and 2O.O µg/ml calculated as the base. The solutions are made isoosmotic with physiologic saline by the addition of an appropriate amount of sodium chloride. Solutions containing epinephrine will also contain sodium metabisulphite in order to protect epinephrine from oxidation. pH of solutions without epinephrine is adjusted to approximately 5.5 wheras pH in solutions containing epinephrine is adjusted to approximately 3.6. The invention is illustrated by the following examples. Example l illustrates a specially preferred way of carrying out the process according to the invention. Example l Preparation of the monohydrate of S-(-)-l-propyl-2′,6′-pipecoloxylidide hydrochloride. 82 g of the hydrochloride of S-(-)-l-propyl-2′,6′­ -pipecoloxylidide containing lO % of the R-(+)-enantiomer was dissolved in 85 ml of water, whereupon acetone heated to its boiling point was added to a final volume of 85O ml. The solution was filtered and left for crystallization. This first recrystallization yielded 7l,7 g. Another recrystallization was carried out by dissolving the obtained product in 72 ml of H₂O, whereupon boiling acetone to a final volume of 75O ml was added. The solution was filtered and left for crystallization. The final yield was 62.3 g (76 %) of an optically pure ( ≧ 99.5 %) product containing 5.4-5.6 % of water, being the monohydrate of S-(-)-l-propyl-2′,6′-pipecoloxylidide hydrochloride, melting interval 266-267.5°C. Example 2 S-(-)-l-propyl-2′,6′-pipecoloxylidide hydrochloride monohydrate 2.64 mg Sodium chloride 8.53 mg Sodium hydroxide to pH 5.5 Water for injection to l.O ml 2.64 mg of the monohydrate of S-(-)-l-propyl-2′,6′-pipecoloxylidide hydrochloride was dissolved in l ml of sterile water. 8.53 mg of sodium chloride was added and the solution was adjusted to pH 5.5 with sodium hydroxide. Example 3 S-(-)-l-propyl-2′,6′-pipecoloxylidide hydrochloride monohydrate 5.29 mg Epinephrine hydrogentartrate lO.O µg Sodium chloride 7.89 mg Hydrochloric acid to pH 3.6 Water for injection to l.O ml The preparation was prepared as described in Example 2 Further attempts to purify the compound In order to try to purify the product described in WO 85/OO599 further recrystallizations from 2-propanol, the solvent used according to that patent application, were performed. Although water was added it was not possible to obtain an optically more pure or, with respect to the water contents, more well defined product. Other common solvents such as methanol and ethanol are not suitable because of the too high solubility of the hydrochloride of S-(-)-l-propyl-2′,6′-pipecoloxylidide in methanol and ethanol. In solvents such as ethyl acetate and dioxan on the other hand the compound is almost insoluble.

Claims: 1. S-(-)-l-propyl-2′,6′-pipecoloxylidide hydrochloride characterized in that the compound is in the form of its monohydrate. 2. Compound according to claim l characterized in that it is substantially optically pure. 3. Compound according to claim l characterized in that it contains less than O.5 % by weight of the corresponding R-(+)-enantiomer. 4. A process for the preparation of substantially optically pure S-(-)-l-propyl-2′,6′-pipecoloxylidide hydrochloride characterized in that S-(-)-l-propyl-2′,6′-pipecoloxylidide hydrochloride is dissolved in water, whereupon acetone heated to a temperature of from 45°C to its boiling point is added and the monohydrate of S-(-)-l-propyl-2′,6′-pipecoloxylidide hydrochloride is isolated. 5. A process according to claim 4 characterized in that the S-(-)-l-propyl-2′,6′-pipecoloxylidide hydrochloride is dissolved in an amount of water which corresponds to l-3 times of its weight, acetone of a volume 5-l5 times of the water volume is added, whereupon the solution is filtered and the end product is isolated. 6. A process according to claim 5 characterized in that the weight of the water is equal to the weight of the S-(-)-l-propyl-2′,6′­ -pipecoloxylidide hydrochloride and the volume of the acetone is lO times of the volume of the added water. 7. Pharmaceutical preparation for local anesthesia characterized in that it contains the compound according to claim l. 8. Compound according to claim l for use in inducing local anesthesia. 9. A method for inducing local anesthesia comprising administration to mammals including man needing local anasthesia an anesthetizing amount of the compound according to claim l. lO. Use of the compound according to claim l in the manufacture of pharmaceutical preparations having local anesthetic effect. Claims for the following Contracting States : AT, ES and GR 1. A process for the preparation of substantially optically pure S-(-)-l-propyl-2′,6′-pipecoloxylidide hydrochloride characterized in that S-(-)-l-propyl-2′,6′-pipecoloxylidide hydrochloride is dis­ solved in water, whereupon acetone heated to a temperature of from 45°C to its boiling point is added and the monohydrate of S-(-)-l-­ propyl-2′,6′-pipecoloxylidide hydrochloride is isolated. 2. A process according to claim 2 characterized in that the S-(-)-l-­ propyl-2′,6′-pipecoloxylidide hydrochloride is dissolved in an amount of water which corresponds to l-3 times of its weight, acetone of a volume 5-l5 times of the water volume is added, whereupon the solu­ tion is filtered and the end product is isolated. 3. A process according to claim 2 characterized in that the weight of the water is equal to the weight of the S-(-)-l-propyl-2′,6′-­ pipecoloxylidide hydrochloride and the volume of the acetone is lO times of the volume of the added water. 4. A process according to claim l characterized in that the isolated compound is substantially optically pure. 5. A process according to claim l characterized in that the isolated compound contains less than O.5 % by weight of the corresponding R-(+)-enantiomer. 6. A process for the preparation of a pharmaceutical preparation for local anesthesia characterized in that it contains the compound isolated according to claim l. 7. Use of the compound isolated according to claim l in the manufac­ ture of pharmaceutical preparations having local anesthetic effect.

Inventors: SANDBERG, RUNE VERNER
Applicants: ASTRA LAEKEMEDEL AKTIEBOLAG
Application year: 1986
Main classification: C07D211
IPC codes: A61P25, A61K31, C07D211