MXPA97008494A

MXPA97008494A - New process for the preparation of clorhidratode ropivacain monohidrat

Info

Publication number: MXPA97008494A
Application number: MXPA/A/1997/008494A
Authority: MX
Original assignee: Astra Ab
Priority date: 1995-05-16
Filing date: 1997-11-04
Publication date: 1998-01-01

Abstract

New process for the preparation of ropivacaine hydrochloride monohydrate adapted for production in the plant, which is a process that includes three stages

Description

NEW PROCESS FOR THE PREPARATION OF MONOPODRATED ROPIVACAIN CHLORHYDRATE FIELD OF THE INVENTION The present invention relates to a new process for the preparation of ropivacaine hydrochloride monohydrate.

BACKGROUND AND PREVIOUS ART The problem underlying the present invention was to provide a new process adapted for production in the plant, which gives a high reproducible enantiomeric yield and a high optical purity. Ropivacaine hydrochloride is the generic name for the compound of (S) - (-) - 1-propyl-2 ', 6'-pipecoloxylidene monohydrate, which is a local anesthetic compound described in EP 0 239 710. It is prepared by adding hot water and acetone to ropivacaine hydrochloride where the desired product is then crystallized. The process for the preparation of the starting material, hydrochloride and ropivacaine, was described in EP 0 151 110. US Patent no. 1,180,712 discloses a process for the preparation of levo-l-n-butyl-2 ', 6'-pipecoloxidide. Saying REF: 25937 process includes a first resolution stage of dl-2 ', 6' -pipecoloxidide, whereby dl-2 ', 6' -pipecoloxidide reacts with 0, 0-dibenzoyl-d-tartaric acid and subsequently the resulting mixture of 0, 0-dibenzoyl-d-tartrate diastereoisomeric reacts with acetone to boiling, the dextro-2 ', 6' -pipecoloxidide salt insoluble in acetone is separated and the salt levo-2 ', 6' -pipecoloxidide is isolated from acetone in solution. However, the process described is intricate and includes isolation of the hot acetone product, e.g. ex. It is a clear method for laboratories that could not be used for production in the plant. The idea of using a resolution method to obtain functions of larger single enantiomers of local anesthetics of mepivacaine and bupivacaine was published in J Med Chem 14: 891-892, 1971. A mixture of 2 ', 6' -pipecoloxidide was treated with dibenzoyl-dL-tartaric acid monohydrate in which isopropanol was added separating the insoluble enantiomer in isopropanol subsequently the desired enantiomer was isolated. Using isopropanol does not give a crystallization system that is stable for the time required for production in the plant. This is because the solution is supersaturated with the unwanted enantiomer, and thus crystallization in the wrong way could easily be initiated by means of small alterations which means that isopropanol is not suitable for use in large-scale production. scale. In Acta Chem Scand B41: 757-761, 1987 it was described using isopropanol in combination with various amounts of water for the resolution step. These combinations give variations in performance and quality. Also the combination of isopropanol and water gives a crystallization system not sufficiently stable for production in the plant.

BRIEF DESCRIPTION OF THE INVENTION The present invention is directed to a process suitable for the large-scale preparation of ropivacaine hydrochloride monohydrate, which is a compound of the formula (I) HCl x H20 (I) This new process comprises three stages, the first stage is a resolution stage. It has been found that by using a resolving agent that forms a stable crystallization system with water, preferably a combination of a ketone and water, it is possible to separate the unwanted (R) -pipecoloxidide and isolate the (S) -pipecoloxidide in the first stage. In this way, a crystallization system is reached that is stable for up to 24 hours, which is sufficient for production in the plant. It is not possible to increase the enantiomeric production in any of the two subsequent stages, which means that this first stage is the most important. In this way, a further aspect of the present invention was to obtain a high reproducible enantiomeric yield and a high optical purity in the first stage. This was accomplished by using the combination of a ketone, which together with water forms a stable crystallization system, and water. The novel process according to the present invention for the preparation of compound (I) comprises the following steps: Step 1 (i) The racemic initial material of pipecoloxylide hydrochloride of the formula. { II) it is released from its HCl salt, by extraction to an organic solvent with a diluted base; (ii) the pipecoloxidide is separated by crystallization with a resolving agent that forms a stable crystallization system with water, and the crystalline product is released from its salt by extraction in an organic solvent that dissolves a minimum of about 1% (p / p) of water with diluted base, giving the compound (S) -pipecoloxidide of the formula (III) (m) Step 2: (i) S-pipecoloxidide of the formula (III) is alkylated with a 1-halopropane, preferably l-bromopropane or 1-iodopropane, in the presence of a base and optionally in the presence of a catalyst, the reaction it is completed by heating, preferably at reflux temperature, or optionally at a lower temperature which means, however, that the reaction is completed more slowly, where after the inorganic salts are removed by extraction with water; (ii) The solution reached in step 2 (i) is optionally diluted and the product is precipitated as ropivacaine hydrochloride of the formula (IV) which is subsequently isolated; Step 3: The product (IV) reached in step 2 (ii) is dissolved in aqueous acetone, preferably at reflux temperature, the product (I) is precipitated by addition of acetone, and the product is finally isolated and dried .

The resolving agents that could be used in step 1 (i) are L- (-) -dibenzoyl tartaric acid or L- (-) -ditoluoyl tartaric acid, L- (-) -dibenzoyl tartaric acid is the agent of preferred resolution. The base diluted in step 1 (i) is preferably selected from sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate. The preferred resolving agents for crystallization in step 1 (ii) are ketones which form a stable crystallization system together with water. The preferred solvents for this crystallization are acetone 0 ethyl methyl ketone, with acetone being the most preferred. .

Preferably the water content of the organic solvent used in the crystallization step 1 (ii) is 15-25%, more preferably 20%. The organic solvent used in the extraction stage 1 (ii) should dissolve a minimum of approximately 1% (w / w) of water. If not, the reaction is carried out in a two-phase system. In addition, an additional amount of water, about 5%, should preferably be present during the reaction. The choice of the organic solvent used in the extraction step 1 (ii) will be appreciated by an expert person. However, the organic solvent is preferably selected from isobutyl methylketone, acetonitrile, ethanol, butanol or toluene, but other solvents could also be used. Particular preference is given to isobutyl methyl ketone. The alkylation reaction of step 2 (i) is carried out in the presence of a base and preferably in the presence of a catalyst. If 1-iodopropane is used as the alkylating reagent, it is not necessary to use a catalyst for the reaction to be performed. However, the reaction could take a long time if catalyst is not used. The bases that can be used in the reaction stage 2 (i) will be appreciated by a person skilled in the art. However, carbonates, in particular potassium carbonate or sodium carbonate, or amines, in particular triethylamine, are preferred. More preferably, potassium carbonate is the selected base. The catalyst used in step 2 (i) is a iodide catalyst, preferably sodium iodide. The solution reached in step 2 (i) is preferably diluted with acetone in step 2 (ii).

DETAILED DESCRIPTION OF THE INVENTION The invention will now be described in more detail by means of the following examples.

Example 1: Stage i. resolution pipecoloxidide hydrochloride (1.0 kg), acetone (3.75 L), and water (0.85 L) were loaded. NaOH (aq) was added at pH > ll. The phases, thus formed, were separated and the organic phase was diluted with water (1.4 L). L- (-) -dibenzoyltartaric acid (0.67 kg), dissolved in acetone (3.75 L), was added. The solution was planted. The crystalline suspension was cooled to 2 ° C. The crystals were collected by centrifugation and washed with acetone followed by isobutyl methyl ketone. The product did not dry.

The wet crystalline product was extracted with isobutyl methyl ketone (3.60 L) and diluted with NaOH (2.60 L).

L) at pH > ll. The phases separated. The organic phase was washed with water (0.6 L) and used directly in the next step. Yield (ca. on dry basis): approximately 0.39 kg of (S) -pipecoloxilidide (approximately 90%).

Example 2: Stage 2. Rental! and precipitation of the salt Example 2A: To the organic phase of the previous step K2C03 (0.32 kg), Nal (catalytic amount), and 1-bromopropane (0.28 kg) and about 5% water were added. The mixture was heated to reflux to complete the reaction.

The excess bromopropane was removed by distillation. The reaction mixture was extracted with water (1.70 L). Acetone (1.70 L) was added to the organic phase followed by HCl (aq) to pH about 2. The solution was seeded. The crystalline suspension was cooled to 9 ° C. The crystals were collected by centrifugation and washed with acetone. The product was used directly in the next step and was not dried. Yield (cale, on dry basis): 0.47 kg of ropivacaine hydrochloride (approximately 90%).

Example 2B: As an alternative, the following procedure was carried out. They were added to the organic phase of the previous stage K2C03 (0.32 kg), Nal (catalytic amount), 1-bromopropane (0.28 kg) and water (1.70 kg). The mixture was heated to reflux to complete the reaction. The excess bromopropane was removed by distillation. The reaction mixture was separated. Acetone (1.70 L) was added to the organic phase followed by HCl (aq) to pH about 2. The solution was seeded. The crystalline suspension was cooled to 9 ° C. The crystals were collected by centrifugation and washed with acetone. The product was used directly in the next step and was not dried.

Yield (cale, on dry basis): 0.47 kg of ropivacaine hydrochloride (approximately 90%).

Example 3: Step 3. recrystallization Ropivacaine hydrochloride, from the previous step, was suspended in acetone (1.0 L) at reflux temperature. Water (0.60 L) was added. The resulting mixture was filtered and acetone (7.6 L) was added to > 40 ° C. The solution was planted. The crystal suspension was cooled to 3 ° C. The crystals were collected by centrifugation and washed with acetone. The crystals were dried at 30-40 ° C under vacuum (< 20 kPa). Yield: approximately 0.42 kg of ropivacaine hydrochloride monohydrate (approximately 80%). The chemical analyzes of the final product were performed by NMR analysis as indicated below. The NMR spectrum was obtained from a solution of 22 mg in 0.7 ml of deuterium oxide (99.95)% at 23 ° C. T-butanol was used as internal reference (i.r). The instrument used was a Varian Gemini 300. The numbers in the assigned list refer to the structure and numbering as given in the formula below. The results are given in a spectrum of protons (Table 1) and in a C13 spectrum (Table 2).

?? Table 1 Proton spectrum operating at 300.1 MHz. D .r) 1.23 ppm Table 2 Spectrum C13 operating at 75.5 MHz. D (i r! = 30.6 ppm The station could be connected to a

Claims

1. A process for the preparation of ropivacaine hydrochloride monohydrate of the formula (I) characterized in that it comprises the reaction steps: Step 1 (i) The racemic initial material of pipecoloxylidide hydrochloride of the formula (II) it is released from its HCl salt, by extraction to an organic solvent with a diluted base; (ii) the pipecoloxidide is separated by crystallization with a resolving agent that forms a stable crystallization system with water, and the crystalline product is released from its salt by extraction in an organic solvent that dissolves a minimum of about 1% (p / p) of water with diluted base, giving the compound (S) -pipecoloxidide of the formula (III) Step 2: (i) S-pipecoloxidide of the formula (III) is alkylated with a 1-halopropane, in the presence of a base and optionally in the presence of a catalyst, the reaction is completed by heating, subsequently the inorganic salts are removed by extraction with water; (ii) the solution reached in step 2 (i) is optionally diluted and the product is precipitated as ropivacaine hydrochloride of the formula (IV) which is subsequently isolated; Stage 3: the product (IV) reached in stage 2 (ii), it is dissolved in aqueous acetone, preferably at reflux temperature, the product (I) is precipitated by the addition of acetone, and the product is finally isolated and dried.

2. A process according to claim 1, characterized in that the resolving agent forming a stable crystallization system together with water in step 1 (ii) is a ketone.

3. A process according to claim 2, characterized in that the ketone is selected from acetone and ethyl methyl ketone.

4. A process according to claim 3, characterized in that the ketone is acetone.

5. A process according to claim 1, characterized in that the water content of the organic solvent used in crystallization step 1 (ii) is 15-25%.

6. A process according to claim 5, characterized in that the water content is 20%.

7. A process according to claim 1, characterized in that the base diluted in step 1 (i) is selected from sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.

8. A process according to claim 1, characterized in that the resolution agent in the stage 1 (i) is L- acid. { -) -dibenzoyl tartaric acid or L - (-) - ditoluoyl tartaric acid.

9. A process according to claim 8, characterized in that the resolving agent is L- (-) - dibenzoyl tartaric acid.

10. A process according to claim 1, characterized in that the organic solvent used for the extraction of step 1 (ii) is selected from isobutyl methyl ethano, acetonitrile, ethanol, butanol or toluene. ,eleven. A process according to claim 10, characterized in that the organic solvent used for the extraction is isobutyl methyl ketone. 12. A process according to claim 1, characterized in that the alkylation of step 2 (i) is carried out in the presence of a catalyst and at reflux temperature. 13. A process according to claim 1, characterized in that the alkylation reagent of step 2 (i) is l-bromopropane or 1-iodopropane. 14. A process according to claim 1, characterized in that the base in step 2 (i) is a carbonate or an amine. 15. A process according to claim 14, characterized in that the base in step 2 (i) is selected from potassium carbonate, sodium carbonate and triethylamine. 16. A process according to claim 14, characterized in that the base in step 2 (i) is potassium carbonate. 17. A process according to claim 1, characterized in that the catalyst in step 2 (i) is a iodide catalyst. 18. A process according to claim 17, characterized in that the catalyst is sodium iodide. 19. A process according to claim 1, characterized in that the reaction stage 1 (ii) is carried out in a two-phase system. 20. A process according to claim 1, characterized in that a further amount of water of about 5% is present during the reaction step l (ii). 21. The monivahydrated repivacaine hydrochloride of the formula (I) HCIx H2O (I) characterized in that it is prepared according to the process of claim 1.