MXPA00006129A - 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 a novel intermediate and an optional purification step in the novel process. Additionally, the present invention also relates to the manufacture of a pharmaceutical formulation containing isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine and the use of purified isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine in medicine.

Description

PROCESS FOR THE PREPARATION OF ISOPROPIL-METHYL- [2- (3-N-PROPOXIFENOXY) ETHYL] AMINE Field of the Invention The present invention relates to a new process for the synthesis of isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine. In addition, the present invention also relates to a new intermediate and an optional purification step in the process. Additionally, the present invention also relates to the manufacture of a pharmaceutical formulation comprising i-propyl-met il - [2 - (3-n -propoxyphenoxy) ethyl] amine and the use of isopropyl-methyl- [2- ( 3-n-pro? Oxyphenoxy) ethyl] amine in medicine.

Ancestor of the invention and prior art La i sopropil-met il- [2- (3-n-propoxy phenoxy) ethyl] amine is a compound with anesthetic properties. It is useful as a local topical anesthetic for the treatment of pain, including localized pain, and especially in intact skin.

WO 9715548 describes a process for the preparation of isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine. The process comprises a couple of reaction steps that REF.120790 begin by reacting 3-n-propoxyphenol with 1,2-dibromoethane, which results in 1- (2-bromoethoxy) -3-n-propoxybenzene. In addition, 1- (2-bromoethoxy) -3-n-propoxybenzene is reacted with N-methylisopropylamine in an autoclave. The product, isopropyl-methyl- [2- (3-n-? Ropoxyphenoxy) ethyl] amine, is further purified further by means of distillation.

Brief Description of the Invention The objective of the present invention is to provide a new process for the preparation of isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine suitable for large scale production.

The post-reaction reaction 1 describes the main reaction steps in the manufacture of isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine, starting with 3-propoxyphenol. The starting material, as well as the reagents used, are readily available by processes known in the art.

Scheme of Rsat-ci 1 Step 1 Ethylene carbonate, phase transfer catalysis? Cr "solid-liquid Step 2 reactive Xf ^ OH halogenation or sulfonation XT x (2) (D X = halogen or sulfonated ester Step 3 X = halogen or sulfonated ester (3) 0 Formaldehyde, H: r metal catalyst (3) - ° X7 ° X (4) The advantages of the improved process of the present invention are described in the following paragraphs.

Another objective of the present invention is to provide a process that utilizes reagents and solvents that are environmentally friendly. This is a general interest of environmental groups, both within and outside the pharmaceutical industry, that the industry should develop and use environmentally friendly processes. The process of the present invention does not use any mutagenic alkylating agent, such as 1,2-dibromoethane, which is used in processes according to the prior art. It is therefore an object of the present invention to provide a process for the manufacture of isopropyl-methyl- [2- (-n-propoxyphenoxy) ethyl] amine where the use of 1,2-dibromoethane is avoided. 1,2-dibromoethane is a known mutagenic compound and therefore its use should be limited, if possible. This is especially true in large-scale production.

Another object of the present invention is to provide a new and optional purification of crude isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine. It has surprisingly been found that the isopropyl-methyl- [2- (3-n-propoxy-enoxy) -ethyl] amine monophosphate salt is a crystalline compound. The optional purification step is shown in Reaction Scheme 2.

Reaction Reaction 2 H3PQ4 xr .o 'XX x H3PO (4) Base and (5) In Step 1, 3-propoxy-phenol is reacted with ethylene carbonate using solid-liquid phase transfer catalysis conditions. The reaction is preferably carried out at 60-120 ° C and for a prolonged period of time. The reaction is preferably carried out in an organic solvent, such as an aprotic organic solvent or xylene. Examples of such aprotic organic solvents include, but are not limited to, DMF, and l-methyl-2-pyrrolidinone. l-Methyl-2-pyrrolidinone is the preferred aprotic organic solvent. Optionally, the reaction is carried out without any additional organic solvent. The amount of ethylene carbonate used is 1-4 molar equivalents, preferably 2-3 equivalents. Solid-liquid phase transfer catalysis conditions are created using a non-soluble solid base and a phase transfer catalyst. The amount of base and phase transfer catalyst are non-crucial and can therefore be varied according to the procedures known in the art. The base and the phase transfer catalyst can be any suitable base and phase transfer catalyst, known in the art to create solid-liquid phase transfer catalysis conditions. Examples of suitable bases include, but are not limited to, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate. Potassium carbonate is the preferred base. Examples of suitable phase transfer catalysts include, but are not limited to, tetrabutyl ammonium iodide, tetrabutyl ammonium bisulfate, and tetrabutyl ammonium bromide. Tetrabutyl ammonium bromide is the preferred phase transfer catalyst.

The phase transfer catalyst used in step 1 can be replaced by a compound having as an intrinsic property to function as a phase transfer catalyst under the conditions used in Step 1. Examples of such compounds include, but are not limited to a, polyethylene glycol (PEG), eg PEG 6000.

After completing 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-propoxy-phenoxy) -ethanol is purified by distillation.

In step 2, the 2- (3-propoxy-phenoxy) -ethanol formed in Step 1 above, is further reacted with a suitable reagent to produce a compound of formula 2, wherein X is a bromine, chlorine, iodine or a sulfonate ester group. Examples of sulfonate esters include, but are not limited to, alloy- and arylsulfonate esters, e.g. 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 is an organic solvent, such as methyl tert-butyl ether or toluene, is further reacted with isopropylamine in the presence of water. The reaction is carried out at elevated temperature, preferably 60-110 ° C, for a prolonged period of time and under increased pressure, preferably 1-10 atmospheres. The isopropylamine should be added in an excess, such as 2 to 6 equivalents, preferably 3-4 equivalents.

Optionally an additional and non-nucleophilic base, such as potassium or sodium carbonate, can be added to the reaction mixture. The amount of water present in the reaction mixture is not crucial and may optionally be omitted. Therefore the reaction mixture is cooled and aqueous acid is added under vigorous stirring until the pH of the aqueous phase reaches a constant value of 3-5, preferably 3-3.5. The aqueous phase is separated, washed with methyl tert-butyl ether or toluene and subsequently used without further purification in the subsequent step.

In Step 4, the aqueous acid solution of isopropyl- [2- (3-propoxy-phenoxy) ethyl] amine, prepared in Step 3 above, is reacted with formaldehyde in the presence of palladium or carbon. The reaction mixture is hydrogenated at atmospheric pressure or higher, such as 1-6 bar, for several hours. The amount of formaldehyde is not crucial, but it can be between 1-10 equivalents by weight. The amount of palladium or carbon used is 0.01 to 0.5 molar equivalents, preferably 0.05-0.2. The reaction mixture is subsequently treated with aqueous base, such as sodium hydroxide, at pH -12 and extracted with methyl tert-butyl ether. The organic phase is separated and the distillation gives pure isopropyl-methyl- [2- (3-n-propoxy-enoxy) ethyl] amine.

Surprisingly, it has been possible to crystallize isopropyl-methyl- [2- (3-n-propoxy-enoxy) -ethyl] -amine from the reaction mixture in step 4, converting it into the corresponding monophosphate salt. The monophosphate salt of isopropyl-methyl- [2- (3-n -propoxyphenoxy) ethyl] amine is a crystalline and stable salt of isopropyl-meth i l- [2- (3-n-propoxy-enoxy) -ethyl] -amine and therefore has advantageous properties. Advantageous is the introduction of a crystalline intermediate in the process for the preparation of isopropyl-methyl- [2- (3-n-propoxy-enoxy) -ethyl] -amine. Introduces an optional and additional purification step, simple and convenient, in a reaction sequence where all intermediates are syrups. Thus, the distillation that consumes time and energy used in processes according to the previous art is avoided. The crystallization of the isopropyl-methyl- [2- ('3-n-propoxy-enoxi) ethyl] amine monophosphate salt results in an intermediate of high purity which can be further converted to isopropyl-methyl- [2- (3 -n-propoxyphenoxy) ethyl] amine corresponding by a simple step of alkalization.

In the optional purification step, the content of crude isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine in ethyl acetate is first tested and adjusted to 6-10 ml of ethyl acetate per gram of isopropyl-me ti 1- [2 - (3-n-propoxy f enoxy) eti 1] ami na crude, prepared in Step 4 above. The content of isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine in ethyl acetate is preferably 7-9 ml of ethyl acetate per gram of isopropyl-methyl- [2- (3-n- propoxyphenoxy) ethyl] amine. To the tested solution of isopropyl-methyl- [2- (3-n-propoxy phenoxy) ethyl] amine, methanol and a solution of phosphoric acid in methanol are added. The amount of phosphoric acid should be about 0.9 to 1.0 molar equivalents, preferably 0.95 equivalents. The total amount of methanol added to the tested 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, should be about 5-15% by volume, preferably 9-11% in volume. The precipitated salt is collected, for example by filtration or centrifugation, and subsequently washed with ethyl acetate.

The isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine monophosphate salt, prepared above, is subsequently mixed with water and aqueous sodium hydroxide is added at pH -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 crude isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine, prepared by step 4 above, could be replaced by the optional purification step, i.e. the preparation of the isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine monophosphate salt. Under these circumstances the alkaline aqueous phase containing the crude isopropyl-methyl- [2- (3-n-propoxy phenoxy) et i 1] amine will preferably be extracted with ethyl acetate instead of methyl tert-butyl ether. The prepared isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine monophosphate salt can then be converted to the corresponding isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine by a single step of alkalization. The procedure can be easily done by a technician.

The present invention is described in more detail in the following non-limiting examples. The Roman numbers refer to Reaction Schemes 1 and 2.

Examples Example 1 2- (3-Propoxy-phenoxy) -ethanol (1) To 3-propoxyphenol (17.9 kg, 117.4 mole) was added ethylene carbonate (20.7 kg, 234.8 mole), K2C03 (17.9 kg, 126.7 mole) , tetrabutylammonium bromide (3.8 kg, 11.5 mol) and l-methyl-2-pyrrolidinone (56.5 L). The mixture is heated to ca 90 ° C for about 10 hours, then cooled to 45 ° C where water (132 L) is added followed by methyl tert-butyl ether (82 L). The phases are separated and the organic phase is washed with 0.5 M HCl (ac) followed by 0.5 M NaHC03 (ac). The organic phase is concentrated under reduced pressure and crude 1 is purified by distillation, 150 ° C / 0.95. mbar, yielding 1 (17.9 kg) as an oil with a chromatographic purity above 97%.

MS (El): 196 (34), 153 (13), 152 (7), 135 (4), 111 (67), 110 (100). XH NMR (200 MHz): d 7.15 (t, 1H), 6.5 (m, 3H), 4.0 (m, 2H), 3.9 (m, 4H), 2.5 (s, 1H), 1.79 (m, 2H), 1.0 (t, 3H). 13 C NMR (50 MHz): d 160.4, 159.8, 129.9, 107.2, 106.7, 101.6, 69.5, 69.2, 61.4, 22.6, 10.5. 3-Propoxy-phenoxyethyl ester of methanesulfonic acid (2) 1 (17.9 kg, 91.0 mol) is dissolved in methyl tert-butyl ether (83 L) and triethylamine (15.2 L, 108.1 mol), allowed to react with MsCl (7.7 L, 99.12 mol). The resulting suspension is allowed to stand at room temperature for about 2 hours, water is added, the phases are separated and the organic phase is used as it is in the subsequent step.

MS (El): 274 (55), 232 (7), 195 (1), 153 (6), 135 (16), 123 (100), 110 (66), 79 (64).

Isopropyl- [2- (3-propoxy-phenoxy) -ethyl] -amine (3) To the solution of 2 is added K2C03 (14.0 kg, 98.1 mol), isopropylamine (36.2 L, 455.9 mol) and water (31 L) . The mixture is heated at 90 ° C for 16 hours with the sealed reactor resulting in a pressure of about 2 bar. The reaction mixture is cooled to room temperature, the aqueous phase is discarded and the organic phase is washed with water. To the organic phase is then added H2SO4 (ac) 0.5 M at pH -3.5 and the phases are separated. The aqueous phase is washed with methyl tert-butyl ether and used as is in the subsequent step.

MS (El): 237 (7), 222 (34), 194 (1), 135 (7), 85 (80), 72 (100). 2 H NMR (200 MHz): d 7.1 (m, 1 H), 6.5 (m, 3 H), 4.1 (t, 2 H), 3.9 (t, 2 H), 3.0 (t, 2 H), 2.9 (m, 2 H), 1.9 (m, 2H), 1.6 (m, 1H), 1.0 (d + t, 9H). 13 C NMR (50 MHz): d 160.4, 160.1, 129.8, 107.0, 106.6, 101.5, 69.5, 67.6, 48.5, 46.5, 23.0, 22.6, 10.5.

Isopropyl-methyl- [2- (3-propoxy-phenoxy) -ethyl] -amine (4) To the aqueous acid solution of 3 is added 10% palladium wet in carbon (5.2 kg, 41.1% Pd / C) and 37% formaldehyde (20.3 L, 270.2 mol). The mixture is hydrogenated at 3 bar for about 4 hours. The reaction mixture is treated with conc. NaOH. at pH -12. The solids are filtered and the resulting two-phase system is extracted with EtOAc. The phases are separated and the organic phase is washed with water and then concentrated. The residue is distilled at 128-130 ° C / 0.3 mbar to yield pure isopropyl-methyl- [2- (3-n-propoxyphenoxy) -ethyl] -amine (18.1 kg, 72.1 mol).

Optional purification of crude isopropyl-methyl- [2- (3-propoxy-phenoxy) -ethyl] -amine To a solution of crude 4 (19.0 kg, 75.7 mol) in ethyl acetate (8 ml of ethyl acetate per gram of 4) MeOH (9.6 L) is added followed by H3P04 (4.85 L, 72.5 mol), dissolved in MeOH (19.2 L) for 3 hours at room temperature. The resulting suspension of the isopropyl-methyl- [2- (3-n-propoxyphenoxy) -ethyl] -amine monophosphate salt is then isolated by filtration and the solid material washed with EtOAc. The wet product (41.8 kg, 67.6 mol, 89% yield) with a chromatographic purity above 99% is used as it is in the subsequent step. Mp: 131-134 ° C.

The content of H3P04 is 27.8% (w / w) which corresponds to a molar ratio of 1: 1 between 5 and H3P04 (theoretical value of 28.0% w / w).

The wet product (41.8 kg, 67.6 mol) is mixed with purified water (66 L) and conc. NaOH is added. to pH -11.5 and the resulting mixture of two phases is extracted with methyl tert-butyl ether. The phases are separated, the organic phase is washed with purified water and then concentrated under reduced pressure. The residual solvents are finally removed using a thin film evaporator, affording isopropylmethyl- [2- (3-n-propoxyphenoxy) ethyl] amine (14.28 kg, 56.67 mol) as an oil with a chromatographic purity above 99%.

MS (El): 251 (10), 236 (9), 86 (100). a H NMR (400 MHz): d 7.1 (m, 1H), 6.5 (m, 3H), 4.0 (t, 2H), 3.9 (t, 2H), 2.9 (m, 1H), 2.8 (t, 2H), 2.3 (s, 3H), 1.8 (m, 2H), 1.0 (d + t, 9H). 13 C NMR (50 MHz): d 160.3, 160.1, 129.7, 106.9, 106.5, 101.4, 69.4, 66.8, 54.0, 51.7, 38.2, 22.5, 17.9, 10.5. % Found: C, 71.5; H, 10.3; N. 5.7; O, 12.5. % Calculated: C, 71.67; H, 10.02; N. 5.57; O, 12.73.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (17)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A process for the preparation of isopropyl-methyl- [2- (3-propoxy-phenoxy) -ethyl] -amine, characterized in that it comprises the following reaction steps: Step 1 Ethylene carbonate, solid-liquid phase transfer catalysis (D Step 2 halogenation reagent or (D X = halogen or sulfonated ester Step 3 X = halogen or sulfonated ester (3) Step 4 (4)

2. A process in accordance with the claim 1, characterized in that a solid insoluble base and a phase transfer catalyst are used in Step 1.

3. A process in accordance with the claim 2, characterized in that the base is sodium carbonate, potassium carbonate, sodium bicarbonate, or potassium bicarbonate.

4. A process in accordance with the claim 2, characterized in that the phase transfer catalyst is PEG 6000, tetrabutyl ammonium bromide, tetrabutyl ammonium bisulfate, or tetrabutyl ammonium iodide.

5. A process according to claim 1, characterized in that Step 1 is carried out in an aprotic organic solvent.

6. A process according to claim 5, characterized in that the aprotic organic solvent is l-methyl-2-pyrrolidinone.

7. A process in accordance with the claim 1, characterized in that X is a bromine, chlorine, iodine, methanesulfonate group, p-toluenesulfonate or p-bromophenylsulfonate.

8. A process according to claim 1, characterized in that Step 3 is carried out at a pressure above atmospheric pressure.

9. A process according to claim 1, characterized in that Step 3 is carried out at a pressure between 1-10 bar.

10. A process according to claim 1, characterized in that Step 3 is carried out at an elevated temperature.

11. A process according to claim 1, characterized in that Step 3 is carried out at 60-110 ° C.

12. A process according to claim 1, characterized in that Step 3 is carried out with an additional base present in the reaction mixture.

13. A process according to claim 1, characterized in that Step 3 is carried out with water present as a solvent.

14. A process according to claim 1, characterized in that the metal catalyst of Step 4 is palladium.

15. A process in accordance with the claim 10, characterized in that the palladium is supported on carbon.

16. A process according to claim 1, characterized in that the formaldehyde of Step 4 is added as an aqueous solution of formaldehyde.

17. Isopropyl- [2- (3-propoxy-phenoxy) -ethyl] -amine N-PROPOXrf? NOXI) ETHYL] AMINE SUMMARY OF THE INVENTION The present invention relates to a new process for the synthesis of isopropyl-methyl- [2- (3-n- • propoxyphenoxy) ethyl] amine. In addition, the present invention also relates to a new intermediate and an optional purification step in the new process. Additionally, the present invention also relates to the manufacture of a pharmaceutical formulation containing isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine and to the use of isopropyl-methyl- [2- (3-n- propoxyphenoxy) ethyl] amine in medicine.