KR20010024790A - Process for the Preparation of Isopropyl-Methyl-[2-(3-N-Propoxyphenoxy)Ethyl]Amine - Google Patents

Abstract

The present invention relates to a novel process for the synthesis of isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine. Moreover, the present invention also relates to novel intermediates and any purification steps in the process. The present invention also provides the preparation and purification of a pharmaceutical formulation containing isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine and purified isopropyl-methyl- [2- (3-n-pro Oxyphenoxy) ethyl] amine.

Description

Process for the Preparation of Isopropyl-Methyl- [2- (3-N-Propoxyphenoxy) Ethyl] Amine} Isopropyl-methyl- [2- (3-N-propoxyphenoxy) ethyl] amine

Isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine is a compound with anesthetic properties. It is particularly useful as a local anesthetic for pain treatment, including local pain on intact skin.

WO 9715548 discloses a process for the preparation of isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine. The process starts with the reaction of 3-n-propoxyphenol and 1,2-dibromoethane to produce 1- (2-bromoethoxy) -3-n-propoxybenzene, and also 1- (2 Two reaction steps of reacting bromoethoxy) -3-n-propoxybenzene with N-methylisopropylamine in the autoclave. After this time, the product isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine is further purified by vacuum distillation.

<Summary of invention>

It is an object of the present invention to provide a novel process for preparing isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine suitable for full scale production.

Scheme 1 below describes the main reaction steps in the preparation of isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine starting from 3-propoxyphenol. 3-propoxyphenols, both starting materials and also used as reactants, are readily available through methods known in the art.

The advantages of the improved process of the invention are described in the following paragraphs.

Another object of the present invention is to provide a method of using environmentally friendly reagents and solvents. There is a general concern that the pharmaceutical industry has developed and used environmentally friendly methods from environmental groups inside and outside the pharmaceutical industry. The process of the invention does not use any mutagenic alkylating agents, such as 1,2-dibromoethane, used in the process according to the prior art. It is therefore an object of the present invention to provide a process for the preparation of isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine that avoids the use of 1,2-dibromoethane. . 1,2-dibromoethane is a known mutagenic compound and its use should be limited as much as possible. This is especially true for full scale production.

Another object of the present invention is to provide novel crude isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine and any purification method thereof. The inventors have surprisingly found that the monophosphate of isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine is a crystalline compound. Optional purification steps are shown in Scheme 2 below.

In step 1, 3-propoxyphenol is reacted with ethylene carbonate using solid-liquid phase transfer catalysis conditions. This reaction is preferably carried out for an extended time at 60 to 120 ℃. This reaction is preferably carried out in an aprotic organic solvent or in an organic solvent such as xylene. Examples of such aprotic organic solvents include, but are not limited to, DMF and 1-methyl-2-pyrrolidinone. 1-methyl-2-pyrrolidinone is the preferred aprotic organic solvent. Optionally, this reaction is carried out without additional organic solvents. The amount of ethylene carbonate used is 1 to 4 molar equivalents, preferably 2 to 3 molar equivalents. Solid-liquid phase transfer catalysis conditions are formulated using a solid insoluble base and a phase transfer catalyst. The amount of base and phase transfer catalyst is not critical and can therefore vary according to methods known in the art. Base and phase transfer catalysts can be any base and phase transfer catalyst known in the art suitable for establishing solid-liquid phase transfer catalysis conditions. Examples of suitable bases include, but are not limited to, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium hydrogen carbonate. Potassium carbonate is the preferred base. Examples of suitable phase transfer catalysts include, but are not limited to, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate and tetrabutylammonium bromide. Tetrabutylammonium bromide is the preferred phase transfer catalyst.

The phase transfer catalyst used in step 1 may be replaced with a compound having inherent properties that function as a phase transfer catalyst under the conditions used in step 1. Examples of such compounds include, but are not limited to, polyethylene glycol (PEG), such as PEG 6000.

After completion of the reaction, the reaction mixture is cooled, diluted with water and extracted with a suitable organic solvent such as xylene or methyl tert-butyl ether. The organic phase is concentrated and the crude 2- (3-propoxyphenoxy) ethanol is purified via distillation.

In step 2, 2- (3-propoxyphenoxy) ethanol formed in step 1 is further reacted with a suitable reagent to produce a compound of formula (2).

<Formula 2>

Wherein X is a bromine, chlorine, iodine or sulfonate ester group. Examples of sulfonate esters include, but are not limited to, alkane- and arylsulfonate esters such as methanesulfonate, ethanesulfonate, p-toluenesulfonate, p-bromophenylsulfonate. Preferred compounds of formula (2) are sulfonate esters. Examples of reagents capable of producing the preferred compounds of formula (2) include, but are not limited to, methanesulfonyl chloride, ethanesulfonyl chloride, p-toluenesulfonyl chloride and p-bromosulfonyl chloride.

In step 3, the compound of formula 2 in an organic solvent such as methyl tert-butyl ether or toluene is further reacted with isopropylamine in the presence of water. This reaction is carried out at elevated temperature, preferably at 60 to 110 ° C. for an extended time, under elevated pressure, preferably 1 to 10 atmospheres. Isopropylamine should be added in excess, such as 2 to 6 equivalents, preferably 3 to 4 equivalents. Optionally, additional non-nucleophilic bases such as potassium carbonate or sodium carbonate can be added to the reaction mixture. The amount of water present in the reaction mixture is not critical and can optionally be omitted. After this, the reaction mixture is cooled and the aqueous acid is added with vigorous stirring until the pH of the aqueous acid reaches a constant value of 3 to 5, preferably 3 to 3.5. The aqueous phase is separated off and washed with methyl tert-butyl ether or toluene and then used in the next step without further purification.

In step 4, the acidic aqueous solution of isopropyl- [2- (3-propoxyphenoxy) ethyl] amine prepared in step 3 is reacted with formaldehyde in the presence of palladium on charcoal. The reaction mixture is hydrogenated for several hours at atmospheric pressure, for example from 1 to 6 bar. The amount of formaldehyde is not critical but can be 1 to 10 equivalents by weight. The amount of palladium on charcoal used is from 0.01 to 0.5 molar equivalents, preferably from 0.05 to 0.2 molar equivalents. After this time, the reaction mixture is treated to pH about 12 with an aqueous base such as sodium hydroxide and extracted with methyl tert-butyl ether. The organic phase is separated and distilled to give pure isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine.

Surprisingly, we are able to crystallize isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine from the reaction mixture in step 4 by converting the reaction mixture in step 4 to the corresponding monophosphate. It became. Monophosphate of isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine is crystalline and stable of isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine It is a salt and therefore has beneficial properties. It is advantageous to introduce crystalline intermediates into the production process of isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine. This introduces any further purification steps that are simple and convenient in a series of reactions in which all intermediates are syrups. This avoids the time and energy consuming distillation used in the process according to the prior art. Crystallization of the monophosphate of isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine was carried out by a simple alkalizing step to give the corresponding isopropyl-methyl- [2- (3-n-propoxyphenoxy C) ethyl] amine to produce an intermediate of high purity which can be further converted.

In any purification step, the crude isopropyl-methyl- is first analyzed by analyzing the content of crude isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine prepared in step 4 above in ethyl acetate. Adjust to 6-10 ml of ethyl acetate per gram of [2- (3-n-propoxyphenoxy) ethyl] amine. The content of isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine in ethyl acetate is isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine 1 Preference is given to 7 to 9 ml of ethyl acetate per g. To the solution of isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine analyzed is added methanol and phosphoric acid solution in methanol. The amount of phosphoric acid should be about 0.9 to 1.0 molar equivalents, preferably 0.95 molar equivalents. The total amount of methanol added to the analyzed solution should be adjusted to the amount of phosphoric acid used. The concentration of phosphoric acid in the resulting solution of isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine in a mixture of methanol and ethyl acetate is about 5 to 15% by volume, preferably 9 to Should be 11% by volume. The precipitated salt is collected by filtration or centrifugation and then washed with ethyl acetate.

After this, the monophosphate of isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine prepared above is mixed with water and aqueous sodium hydroxide is added to a pH of about 11.5. Methyl tert-butyl ether or other suitable solvent is added and the two phases are separated. The organic phase is washed with water and concentrated to yield pure isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine.

The final distillation of the crude isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine prepared in step 4 above is an optional purification step, i.e. isopropyl-methyl- [2- (3-n -Propoxyphenoxy) ethyl] amine can be replaced by the preparation of monophosphate. Under these circumstances, the alkaline aqueous phase containing crude isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine would be preferably extracted with ethyl acetate instead of methyl tert-butyl ether. After this, the monophosphate of isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine prepared is prepared by a simple alkalization step to the corresponding isopropyl-methyl- [2- (3-n- Propoxyphenoxy) ethyl] amine. The procedure form can be easily performed by any person skilled in the art.

The invention is illustrated in more detail in the following non-limiting examples. The bold Roman numerals in parentheses refer to Schemes 1 and 2.

The present invention relates to a novel process for the synthesis of isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine. Moreover, the present invention also relates to novel intermediates and any purification steps in the process. The present invention also provides the preparation of a pharmaceutical formulation containing isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine and isopropyl-methyl- [2- (3-n-propoxyphenoxy C) ethyl] amine.

<Example 1>

<2- (3-propoxyphenoxy) ethanol (1)>

To 17.9 kg (117.4 mol) of 3-propoxyphenol, 20.7 kg (234.8 mol) of ethylene carbonate, 17.9 kg (126.7 mol) of K ₂ CO ₃ , 3.8 kg (11.5 mol) of tetrabutylammonium bromide and 1-methyl-2 56.5 L of pyrrolidinone was added. The mixture was heated to about 90 ° C. for about 10 hours and then cooled to 45 ° C., to which 132 L of water was added followed by 82 L of methyl tert-butyl ether. The phases were separated and the organic phase was washed with 0.5 M HCl (aq) followed by 0.5 M NaHCO ₃ (aq). The organic phase was concentrated under reduced pressure and crude (1) was purified via distillation (150 ° C./0.95 mbar) to yield 17.9 kg (1) as an oil with a purity greater than 97% as determined by chromatography.

<Methanesulfonic acid 3-propoxyphenoxyethyl ester (2)>

17.9 kg (91.0 mol) (1) dissolved in 83 L methyl tert-butyl ether and 15.2 L (108.1 mol) triethylamine were reacted with 7.7 L (99.12 mol) MsCl. The resulting slurry was left at ambient temperature for about 2 hours, water was added, the phases were separated and the organic phase was used in the next step.

<Isopropyl- [2- (3-propoxyphenoxy) ethyl] amine (3)>

To the solution of (2), 14.0 kg (98.1 mol) K ₂ CO ₃ , 36.2 L (455.9 mol) isopropylamine and 31 L water were added. The mixture was heated to 90 ° C. for 16 hours in a sealed reactor to a pressure of about 2 bar. The reaction mixture was cooled to ambient temperature, the aqueous phase was decanted and the organic phase washed with water. 0.5 MH ₂ SO ₄ (aq) was added to the organic phase to pH about 3.5 and the phases were separated. The aqueous phase was washed with methyl tert-butyl ether and used in the next step.

<Isopropyl-methyl- [2- (3-propoxyphenoxy) ethyl] amine (4)>

To the acidic aqueous solution of (3) was added 5.2 kg (41.1% Pd / C) of wet, charcoal 10% palladium and 20.3 L (270.2 mol) of 37% formaldehyde. The mixture was hydrogenated at 3 bar for about 4 hours. The reaction mixture was treated to pH about 12 with concentrated NaOH. The solids were filtered off and the resulting biphasic system was extracted with EtOAc. The phases were separated and the organic phase was washed after it was concentrated. The residue was distilled at 128-130 ° C./0.3 mbar to yield 18.1 kg (72.1 mol) of pure isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine.

<Optional purification of crude isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine>

4.85 L (72.5 mol) of H ₃ PO ₄ dissolved in 9.6 L of MeOH followed by 19.2 L of MeOH in a solution of 19.0 kg (75.7 mol) of crude (4) in ethyl acetate (8 ml of ethyl acetate per g of (4)) ) Was added over 3 hours at ambient temperature. The resulting slurry of monophosphate of isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine was then isolated by filtration and the solid material was washed with EtOAc. 41.8 kg (67.6 mol, 89% yield) of wet product with a purity greater than 99% as determined by chromatography were used in the next step. Melting point: 131 to 134 ° C. The content of H ₃ PO ₄ was 27.8% (w / w), corresponding to a 1: 1 molar ratio of (5) and H ₃ PO ₄ (28.0% w / w theory). 41.8 kg (67.6 mol) of wet product were mixed with an integer of 66 L, concentrated NaOH was added to pH about 11.5, and the resulting biphasic mixture was extracted with methyl tert-butyl ether. The phases were separated and the organic phase was washed with purified water and then concentrated under reduced pressure. 14.28 kg (56.67) of isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine as an oil of more than 99% purity as determined by chromatography using a thin film evaporator. mol).

Claims (19)

A process for preparing isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine comprising the reaction step of Scheme 1 below. <Scheme 1> 2. The process of claim 1 wherein the solid insoluble base and the phase transfer catalyst are used in step 1. The method of claim 2 wherein the base is sodium carbonate, potassium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate. 3. The process of claim 2 wherein the phase transfer catalyst is PEG 6000, tetrabutylammonium bromide, tetrabutylammonium sulfate or tetrabutylammonium iodide. The method of claim 1 wherein step 1 is carried out in an aprotic organic solvent. 6. The method of claim 5 wherein the aprotic organic solvent is 1-methyl-2-pyrrolidinone. The method according to claim 1, wherein X is a bromine group, chlorine group, iodine group, methanesulfonate group, p-toluenesulfonate group or p-bromophenylsulfonate group. The method of claim 1 wherein step 3 is carried out at a pressure above atmospheric pressure. The method of claim 1 wherein step 3 is carried out at a pressure of 1 to 10 bar. The method of claim 1 wherein step 3 is performed at elevated temperature. The process according to claim 1, wherein step 3 is carried out at 60 to 110 ° C. The method of claim 1, wherein step 3 is carried out using additional base present in the reaction mixture. The method of claim 1 wherein step 3 is carried out using water present as solvent. The method of claim 1 wherein the metal catalyst in step 4 is palladium. The method of claim 10 wherein palladium is supported on charcoal. The method according to claim 1, wherein the formaldehyde in step 4 is added as an aqueous solution of formaldehyde. Isopropyl- [2- (3-propoxyphenoxy) ethyl] amine. Isopropyl-methyl- [2- (3), characterized in that isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine is prepared according to any one of claims 1 to 16. -n-propoxyphenoxy) ethyl] amine and a pharmaceutically acceptable carrier or diluent. Isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine prepared by the method of any one of claims 1-16.