SI8711067A8 - Process for obtaining monohydrate of optically pure s-(-)-1 propyl-2',6' pipecoloxylidid chlorinehydrate - Google Patents

Description

Ovaj pronalazak se odnosi na novo optički čisto jedinjenje, postupak za njegovo dobivanje i njegovu upotrebu u proizvodnji farmaceutskih preparata.The present invention relates to a new optically pure compound, a process for its preparation and its use in the manufacture of pharmaceutical preparations.

Pozadina pronalaskaBackground of the invention

Novi lokalni anastetik, odnosno S-(-)-1-propil-2’,6’-pipekoloksilidid hlorhidrat je opisan u WO 85/00599. Novo jedinjenje ima neočekivano dugo trajanje u poredjenju sa racematom i odgovarajučim R-(+)-enatiomerom. Postupak dobijanja opisan u WO 85/00599 daje medjutim proizvod koji sadrži oko 10% R-(+)enantiomera. To znači da proizvod sa fiziko-hemijske tačke gledišta sadrži samo oko 80% S-(-)-enatiomera, dok preostalih oko 20% čini racemski oblik. Osim toga, dobiveni proizvod je hidroskopan i stoga nestabilan i sadrži oko 2% vode. Jedan mol kristalizacione vode stvara sadržaj vode od 5,5%. Proizvod koji ima različiti sadržaj vode ima nedostatak da se procenat vode mora analizirati svaki put kad treba da se pripremi farmaceutski preparat. Kako je S-(-)-enatiomer najpotentniji enantiomer, tražen je proizvod koji sadrži manje R-(+)-enantiomera. Jedan cilj ovog pronalaska je stoga da se proizvede jedinjenje u obliku koji je stabilan i koji se ne menja skladištenjem na običnoj sobnoj temperaturi i vlažnosti. Drugi cilj ovog pronalaska je da se dobije proizvod koji se sastoji od čistog S-(-)-etantiomera.A new local anesthetic, namely S - (-) - 1-propyl-2 ', 6′-pipecoloxylidide chloride is described in WO 85/00599. The new compound has an unexpectedly long duration compared to the racemate and the corresponding R - (+) - enantiomer. The preparation process described in WO 85/00599 provides, however, a product containing about 10% of the R - (+) enantiomer. This means that from a physicochemical point of view, the product contains only about 80% of the S - (-) - enantiomers, while the remaining about 20% is racemic. In addition, the product obtained is hydroscopic and therefore unstable and contains about 2% water. One mole of crystallization water creates a water content of 5.5%. A product having a different water content has the disadvantage that the percentage of water must be analyzed each time a pharmaceutical preparation is to be prepared. As the S - (-) - enantiomer is the most potent enantiomer, a product containing less R - (+) - enantiomers was sought. One object of the present invention is therefore to provide a compound in a form which is stable and unalterable by storage at ordinary room temperature and humidity. Another object of the present invention is to provide a product consisting of pure S - (-) - ethantiomer.

Izvod iz pronalaskaExcerpt from the invention

Predstavljeni pronalazak se odnosi na monohidrat S-(-)-1-propil2',6’-pipecoloksilidid hlorhidrat. Putem posebnog postupka za dobivanje ovog hidrata, S-(-)-enantiomer se dobiva sa visokom optičkom čistočom, odnosno ^99.5%, čak iz optički vrlo žagadjenih preparata. Ovaj specifičan postupak čini dalji aspekt ovog pronalaska. Monohidrat S-(-)-1-propil-2'.6'-pipecoloksilidid hlorhidrata ima dalju prednost da je vrlo stabilan i teško se menja sušenjem u eksikatoru preko kalcijum hlorida na sobnoj temperaturi i 0.5 mm'Hg. Kristalizaciona voda se uklanja jedino ako se jedinjenje zagreva na 75°C tokom 16 h, pri čemu su ostali uslovi isti. Ne primečuje se nikakva druga promena jedinjenja. jThe present invention relates to the monohydrate S - (-) - 1-propyl2 ', 6′-pipecoloxylidide chloride. By a special process for the preparation of this hydrate, the S - (-) - enantiomer is obtained with high optical purity, or ^ 99.5%, even from optically very sawn preparations. This specific process constitutes a further aspect of the present invention. The monohydrate of S - (-) - 1-propyl-2'.6'-pipecoloxylidide chloride has the further advantage of being very stable and difficult to change by drying in a desiccator over calcium chloride at room temperature and 0.5 mm'Hg. The crystallization water is only removed if the compound is heated to 75 ° C for 16 h, with the other conditions being the same. No other change in the compound is observed. j

DobijanjeGetting it

Monohidrat S-(-)-1-propil-2',6’-pipekoloksilidid hlorhidrat strukturne formuleMonohydrate S - (-) - 1-Propyl-2 ', 6′-pipececoxoxide hydrochloride of structural formula

se dobiva prema pronalasku rastvaranjem S-(-)-1-propil-2’,6 pipekoloksilidid hlorhidrata u vodi, posle čega se dodaje vruč aceton. Rastvor se potom procedi što je moguče vruč i ostavi da kristališe. Pri pripremanju polazno jedinjenje se rastvara u količini vode koja odgovara oko 1-3 puta mase dodatog jedinjenja a zapremina dodatog acetona je 5-15 puta od zapremine vode. Ukoliko se doda više vode, tj. količina vode koja odgovara do 4 puta od mase dodatog jedinjenja, zapremina dodatog acetona je 15 -20 puta od zapremine vode. Naročito je povoljno da.se preparat napravi na sledeči način: Polazno jedinjenje se zagreva sa količinom vode koja je jednaka masi polaznog jedinjenja. Doda se vruč aceton u takvoj količini da se jedinjenje potpuno rastvori. Zatim se u rastvor sipa još acetona do zapremine deset puta veče od zapremine dodate vode, posle čega se rastvor procedi i ostavi da kristališe. Važan je odnos izmedju vode i acetona. Ako se doda previše acetona, dobiveni proizvod je manje čist i potrebno je više kristalizacija. S druge Strane, kada se doda manje od 10 puta od zapremine vode, prinos je smanjen. Poželjno je da je aceton koji se dodaje vruč (t.kij.56°C). Prema pronalasku se može koristiti aceton sa temperaturom odis obtained according to the invention by dissolving S - (-) - 1-propyl-2 ', 6 pipecoloxylidide chloride in water, followed by hot acetone. The solution was then heated as hot as possible and allowed to crystallize. In preparation, the starting compound is dissolved in an amount of water corresponding to about 1-3 times the weight of the added compound and the volume of the added acetone is 5-15 times the volume of the water. If more water is added, ie. amount of water corresponding to up to 4 times the mass of the added compound, the volume of acetone added is 15 -20 times the volume of water. It is particularly advantageous to make the preparation as follows: The starting compound is heated with an amount of water equal to the weight of the starting compound. Hot acetone is added in such an amount that the compound is completely dissolved. Then, more acetone is poured into the solution to a volume ten times the volume of water added, after which the solution is allowed to crystallize. The relationship between water and acetone is important. If too much acetone is added, the resulting product is less pure and more crystallization is required. On the other hand, when added less than 10 times the volume of water, the yield is reduced. Preferably, the acetone to be added is hot (m.p. 56 ° C). According to the invention, acetone with a temperature of

45-56°C.45-56 ° C.

Pronalzak se takodje.odnosi na farmaceutske preparate koji sadrže novo čisto jedinjenje kao aktivan sastojak: na upotrebu novog jedinjenja u terapiji, naročito za- ostvarivanje lokalne anastezije kod sisara uključujuči čovjeka; na metod za postizanje lokalne anastezije kod sisara uključujuči čoveka, davanjem novog jedinjenja; i na upotrebu novog jedinjenja u. proizvodnji farmaceutskih preparata sa efektom lokalne anastezije.The invention also relates to pharmaceutical preparations containing a novel pure compound as an active ingredient: the use of the new compound in therapy, in particular for the production of local anesthesia in mammals including man; the method for achieving local anesthesia in mammals, including man, by administering a new compound; and the use of the new compound in. production of pharmaceutical preparations with local anesthesia effect.

Za pripremanje farmaceutskih preparata novo jedinjenje se rastvara u tečnom razblaživaču, koji je podesan za injekcije. Koriščeni preparati su vodeni rastvori koji sadrže izmedju 1.25 i 15.0 mg/ml aktivnog jedinjenja obračunatog kao hlorhidratna so. U nekim primenama uključen je i vazokonstriktor, epinefrin, u koncetraciji od 2.0 do 20.0/ug/ml obračunato kao baza. Rastvori se podese izoosmotski sa fiziološkim rastvorom soli dodavanjem odgovarajuče količine natrijum hlorida. Rastvori koji sadrže epinefrin če takodje sadržavati natrijum metabisulfit da bi se epinefrin zaštitio od oksidacije. pH rastvora bez epinefrina se podešava na približno 5.5 dok se pH rastvora koji sadrže epinefrin podešava na približno 3.6.For the preparation of pharmaceutical preparations, the new compound is dissolved in an injectable liquid diluent. The preparations used are aqueous solutions containing between 1.25 and 15.0 mg / ml of the active compound calculated as the chlorhydrate salt. In some applications, a vasoconstrictor, epinephrine, at a concentration of 2.0 to 20.0 / µg / ml calculated as a base is also included. The solutions were iso-osmotically adjusted with brine by adding an appropriate amount of sodium chloride. Epinephrine-containing solutions will also contain sodium metabisulphite to protect epinephrine from oxidation. The pH of the epinephrine-free solution is adjusted to approximately 5.5 while the pH of epinephrine-containing solutions is adjusted to approximately 3.6.

Pronalazak je ilustrovan sledečim primerima.The invention is illustrated by the following examples.

Primer 1 ilustruje poseban poželjan način za izvodjenje postupka prema pronalasku.Example 1 illustrates a particularly preferred way of performing the process of the invention.

Primer 1Example 1

Dobivanje monohidrata S-(-)-1-propil-2',6'-pipekoloksilidid hlorhidrata.Preparation of S - (-) - 1-Propyl-2 ', 6'-pipececoxoxide hydrochloride monohydrate.

g hlorhidrata S-(-)-1-propil-26'-pipekoloksilidida koji sadrži 10% R-(+)-enantiomera rastvori se u 85 ml vode, nakon čega se doda aceton zagrejan do svoje tačke ključanja do finalne zapremine od 850 ml. Rastvor se procedi i ostavi da kristališe. Ova prva kristalizacije je dala 71.7 g. Druga prekristalizacije je izvedena rastvaranjem dobivenog proizvoda u 72 ml H2O, nakon čega je dodat ključali aceton do zapremine od 750 ml. Rastvor je procedjen i ostavljen da kristališe. Konačni prinos je bio 62.3 g (76%) optički čistog (^.99.5%) proizvoda koji sadrži 5.4-5.6% vode, koji je monohidratg of S - (-) - 1-propyl-26'-pipecoloxilide hydrochloride containing 10% R - (+) - enantiomer is dissolved in 85 ml of water, then acetone heated to its boiling point to a final volume of 850 ml is added. . The solution was purified and allowed to crystallize. This first crystallization gave 71.7 g. A second recrystallization was performed by dissolving the product obtained in 72 ml H2O, followed by the addition of boiling acetone to a volume of 750 ml. The solution was treated and allowed to crystallize. The final yield was 62.3 g (76%) of optically pure (^ .99.5%) product containing 5.4-5.6% water, which is a monohydrate

S-(-)-1-propil-2’,6'-pipekoloksilidid hlorhidrata, sa intervalom topljenja od 266-267.5°C.S - (-) - 1-propyl-2 ', 6'-pipececoxoxide hydrochloride, with a melting point of 266-267.5 ° C.

i iand i

Primer 2Example 2

S-(-)-1-propil-2',6'-pipekoloksilidid hlorhidrat monohidrat 2.64 mgS - (-) - 1-propyl-2 ', 6'-pipecoloxylidide chlorhydrate monohydrate 2.64 mg

Natrijum hlorid 8.53 mgSodium chloride 8.53 mg

Natrijum hidroksid do pH 5.5Sodium hydroxide up to pH 5.5

Voda za injekcije do 1.0 mlWater for injections up to 1.0 ml

2.64 mg monohidrata S-(-)-1-propil-2'.6'-pipekoloksilidid hlorhidrata rastvoreno je u 1 ml sterilne vode. 8.53 mg natrijum hlorida je dodato i rastvor je podešen na pH 5.5 sa natrijum hidroksidom.2.64 mg of monohydrate S - (-) - 1-propyl-2'.6'-pipececoxoxide hydrochloride was dissolved in 1 ml of sterile water. 8.53 mg of sodium chloride was added and the solution was adjusted to pH 5.5 with sodium hydroxide.

Primer 3Example 3

S-(-)-1-propil-2',6'-pipekoloksilidid hlorhidrat monohidrat 5.29 mgS - (-) - 1-propyl-2 ', 6'-pipececoxoxide hydrochloride monohydrate 5.29 mg

Epinefrin hidrogentartarat 10.0 ^ugEpinephrine Hydrogentartarate 10.0 ^ ug

Natrijum hlorid 7.89 mgSodium chloride 7.89 mg

Hlorovodonična kiselina do pH 3.6Hydrochloric acid to pH 3.6

Voda za injekcije do 1.0 mlWater for injections up to 1.0 ml

Preparat je pripremljen kao što je opisano u Primeru 2.The preparation was prepared as described in Example 2.

Dalji napori za prečiščavanje jedinjenjaFurther efforts to purify the compound

Da bi se pokušalo da se prečisti propizvod opisan u WO 85/00599 izršeno je dalje prekristalisavanje iz 2-propanola, rastvarača koji je koriščen prema toj patentnoj prijavi. Mada se dodavala voda, nije bilo moguče dobiti optički čistiji ili, u odnosu na sadržaj vode, bolje definisan proizvod.In order to attempt to purify the product described in WO 85/00599, further recrystallization from 2-propanol, a solvent used according to that patent, was carried out. Although water was added, it was not possible to obtain an optically pure or better defined product relative to the water content.

Drugi uobičajeni rastvarači kao što je metanol i etanol nisu podesni zbog suviše visoke rastvor1jivosti hlorhidrata S-(-)-1-propil-2',6’-pipekoloksilidida u metanolu i etanolu U rastvaračima kao što su etil acetat i dioksan, s druge strane, jedinjenje je skoro nerastvorno.Other common solvents such as methanol and ethanol are not suitable because of the too high solubility of S - (-) - 1-propyl-2 ', 6'-pipecoloxylidide hydrochloride in methanol and ethanol In solvents such as ethyl acetate and dioxane, on the other hand , the compound is almost insoluble.

Claims (5)

1. Postupak za dobivanfeVoptički^čistog S-(-)-1-propil-2',6'pipekoloksilidid hlorhidrata, naznačen tim e,Što se S-(-)-1-propil-2',6'-pipekoloksilidid hlorhidrat rastvara u vodi, nakon čega se dodaje aceton zagrejan do temperature od 45°C do svoje tačke ključanja i izoluje monohidrat S-(-)-1propil-2',6’-pipekoloksilidid hlorhidrata. jA process for the preparation of optically pure P - (-) - 1-propyl-2 ', 6'-pipecoloxylidide hydrochloride, characterized in that S - (-) - 1-propyl-2', 6'-pipececoxoxide hydrochloride is dissolved in water, after which acetone warmed to 45 ° C was added to its boiling point and the monohydrate of S - (-) - 1propyl-2 ', 6'-pipecoloxylidide chloride was isolated. j 2. Postupak prema zahtevu 1,naznačen time, što se S-(-)-1-propil-2',6'-pipekoloksilidid hlorhidrat rastvara u količini vode koja odgovara 1-3 puta njegove mase, dodaje se aceton zapremine od 5-15 puta od zapremine vode, nakon čega se rastvor procedi i izoluje krajnji proizvod.2. The process of claim 1, wherein S - (-) - 1-propyl-2 ', 6'-pipecoloxylidide chloride is dissolved in an amount of water corresponding to 1-3 times its mass, acetone of 5- 15 times the volume of water, after which the solution is processed and the final product is isolated. 3. Postupak prema zahtevu 2,naznačen time, što je masa vode jednaka masi S-{-)-1-propil-2',6'-pipekoloksilidid hlorhidrata a zapremina acetona je 10 puta zapremine dodate vode.3. The process of claim 2, wherein the weight of water is equal to the mass of S - {-) - 1-propyl-2 ', 6'-pipecoloxylidide chloride and the volume of acetone is 10 times the volume of water added. 4. Postupak prema zahtevu 1,naznačen time, što je izolovano jedinjenje optički Čisto.The method of claim 1, wherein the isolated compound is optically Pure. 5. Postupak prema zahtevu 1,naznačen time, što izolovano jedinjenje sadrži manje od 0.5% mas. odgovarajučeg R- (+)-enantiomera.5. The method of claim 1, wherein the isolated compound contains less than 0.5% by weight. of the corresponding R- (+) - enantiomer.