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WO1999032430A1 - Process for the preparation of isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine - Google Patents

Process for the preparation of isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine Download PDF

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Publication number
WO1999032430A1
WO1999032430A1 PCT/SE1998/002315 SE9802315W WO9932430A1 WO 1999032430 A1 WO1999032430 A1 WO 1999032430A1 SE 9802315 W SE9802315 W SE 9802315W WO 9932430 A1 WO9932430 A1 WO 9932430A1
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Prior art keywords
process according
isopropyl
methyl
ethyl
amine
Prior art date
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PCT/SE1998/002315
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French (fr)
Inventor
Ulf Larsson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca AB
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Astra AB
AstraZeneca AB
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Priority to JP2000525367A priority Critical patent/JP2001526253A/en
Priority to AU19891/99A priority patent/AU1989199A/en
Priority to KR1020007006880A priority patent/KR20010024790A/en
Priority to EP98964599A priority patent/EP1045826A1/en
Priority to SK805-2000A priority patent/SK8052000A3/en
Priority to IL13682598A priority patent/IL136825A0/en
Priority to PL98341438A priority patent/PL341438A1/en
Priority to EEP200000369A priority patent/EE200000369A/en
Application filed by Astra AB, AstraZeneca AB filed Critical Astra AB
Priority to BR9814377-8A priority patent/BR9814377A/en
Priority to CA002314988A priority patent/CA2314988A1/en
Publication of WO1999032430A1 publication Critical patent/WO1999032430A1/en
Priority to IS5523A priority patent/IS5523A/en
Priority to NO20002944A priority patent/NO20002944L/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
    • C07C217/20—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by halogen atoms, by trihalomethyl, nitro or nitroso groups, or by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A61P23/02—Local anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

  • 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 said 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 isopropyl-methyl-[2- (3-n-propoxyphenoxy)ethyl]amine in medicine.
  • Isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine is a compound with anaesthetic properties. It is useful as a topical local anaesthetic for the treatment of pain, including localised pain, and especially on intact skin.
  • WO 9715548 discloses a process for the preparation of isopropyl-methyl-[2-(3-n-propoxy- phenoxy)ethyl]amine. Said process comprises a couple of reaction steps starting with reacting 3-n-propoxyphenol with 1 ,2-dibromoethane resulting in l-(2-bromoethoxy)-3-n- propoxybenzene. Further, l-(2-bromoethoxy)-3-n-propoxybenzene is reacted with N- methylisopropylamine in an autoclave. The product, isopropyl-methyl-[2-(3-n-propoxy- phenoxy)ethyl]amine, was thereafter further purified by distillation in vacuo.
  • the object of the present invention is to provide a new process for the preparation of isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine suitable for full scale production.
  • Scheme 1 describes the main reaction steps in the manufacture of isopropyl-methyl- [2-(3-n-propoxyphenoxy)ethyl]amine starting from 3-propoxyphenol.
  • the starting material as well as the reactants used, are readily available through processes known in the art.
  • X halogen or sulphonate ester
  • Another object of the present invention is to provide a process utilizing reagents and solvents that are environmentally friendly. There is a general interest from environmental groups both inside and outside the pharmaceutical industry that the industry shall develop and use environmentally friendly processes.
  • the process of the present invention does not use any mutagenic alkylating agents, such as 1 ,2-dibromoethane, which is used in processes according to prior art.
  • One object of the present invention is therefore to provide a process for the manufacture of isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine wherein the use of 1 ,2-dibromoethane is avoided.
  • 1 ,2-dibromoethane is a known mutagenic compound and its use should therefore, if possible, be limited. This is especially true in full 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.
  • the optional purifaction step is shown in Scheme 2.
  • Step 1 3-propoxy -phenol is reacted with ethylene carbonate using solid-liquid phase- transfer catalysis conditions.
  • the reaction is preferably carried out at 60-12CPC 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.
  • aprotic organic solvents include, but are not limited to, DMF, and l-methyl-2-pyrrolidinone.
  • l-Metyl-2-pyrrolidinone is the preferred aprotic organic solvent.
  • 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.
  • the solid-liquid phase-transfer catalysis conditions are created using a solid, non-soluble base and a phase-transfer catalyst.
  • the amount of base and phase-transfer catalyst are not crucial and can therefore be varied according to 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.
  • suitable bases include, but are not limited to, sodium carbonate, sodium hydrogencarbonate, potassium carbonate and potassium hydrogencarbonate. Potassium carbonate is the preferred base.
  • phase- transfer catalysts include, but are not limited to, tetrabutyl ammonium iodide, tetrabutyl ammonium hydrogensulphate, and tetrabutyl ammonium bromide.
  • Tetrabutyl ammonium bromide is the preferred phase-transfer catalyst.
  • phase-transfer catalyst used in step 1 can be replaced by a compound which has as an intrinsic property to function as a phase-transfer catalysts under the conditions used in Step 1.
  • examples of such compounds include, but are not limited to, polyethyleneglycol (PEG), e.g. PEG 6000.
  • reaction mixture is cooled, diluted with water and extracted with a suitable organic solvent, such as xylene or methyl tert-butyl ether.
  • 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 means of distillation.
  • 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,
  • X is a bromine, chlorine, iodine or a sulphonate ester group.
  • sulphonate esters include, but are not limited to, alkane- and arylsulphonate ester, e.g. methanesulphonate, ethanesulphonate, p-toluenesulphonate, p-bromophenylsulphonate.
  • Preferred compounds of formula 2 are sulphonate esters.
  • reagents capable of producing preferred compounds of formula 2 include, but are not limited to, methanesulphonyl chloride, ethanesulphonyl chloride, p-toluenesulphonyl chloride and p- bromosulphonyl chloride.
  • 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.
  • the reaction is performed at elevated temperature, preferably 60-110°C, for a prolonged period of time and under increased pressure, preferably 1-10 atmospheres.
  • Isopropylamine should be added at an excess, such as 2 to 6 equivalents, preferably 3-4 equivalents.
  • 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 can optionally be omitted.
  • reaction mixture is thereafter 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.
  • aqueous phase is separated, washed with methyl tert-butyl ether or toluene and thereafter used without any further purification in the subsequent step.
  • Step 4 the acidic aqueous solution of isopropyl-[2-(3-propoxy-phenoxy)-ethyl]-amine prepared in Step 3 above, is reacted with formaldehyde in the presence of palladium on charcoal.
  • the reaction mixture is hydrogenated at atmospheric pressure or above, such as 1-6 bars, for several hours.
  • the amount of formaldehyde is not crucial, but can be between 1-10 equivalents, by weight.
  • the amount of palladium on charcoal used is 0.01 to 0.5 molar equivalents, preferably 0.05-0.2.
  • the reaction mixture is thereafter treated with aqueous base, such as sodium hydroxide, to pH ⁇ 12 and extracted with methyl tert-butyl ether.
  • the organic phase is separated and distillation gives pure isopropyl-methyl-[2-(3-n- propoxyphenoxy)ethyl]amine.
  • the monophosphate salt of isopropyl-methyl-[2-(3-n-propoxy- phenoxy)ethyl]amine is a crystalline and stable salt of isopropyl-methyl-[2-(3-n- propoxyphenoxy)ethyl]amine and therefore has advantageous properties.
  • the introduction of a crystalline intermediate in the process for the preparation of isopropyl-methyl-[2-(3-n- propoxyphenoxy)ethyl]amine is advantageous.
  • the content of crude isopropyl-methyl-[2-(3-n-propoxy- phenoxy)ethyl]amine in ethyl acetate is first assayed and adjusted to 6-10 ml ethyl acetate per gram of crude isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine, prepared inStep 4 above.
  • the content of isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine in ethyl acetate is preferably 7-9 ml ethyl acetate per gram of isopropyl-methyl-[2-(3-n-propoxy phenoxy)ethyl]amine.
  • methanol and a solution of phosphoric acid in methanol are added to the assayed solution of isopropyl-methyl-[2-(3-n- propoxyphenoxy)ethyl]amine.
  • the amount of phosphoric acid should be around 0.9 to 1.0 molar equivalents, preferably 0.95 equivalents.
  • the total amount of methanol added to the assayed solution should be adjusted to the amount of phosphoric acid used.
  • 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 around 5-15%, by volume, preferably 9- 11%, by volume.
  • the precipitated salt is collected, for example by filtration or centrifugation, and thereafter washed with ethyl acetate.
  • the monophosphate salt of isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine, prepared above, is thereafter mixed with water and aqueous sodium hydroxide is added to 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 yielding 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, may be replaced by the optional purification step,/.e. the preparation of the monophosphate salt of isopropyl-methyl- [2-(3-n- propoxyphenoxy)ethyl] amine.
  • the alkaline aqueous phase containing the crude isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine will preferably be extracted with ethyl acetate instead of methyl tert-butyl ether.
  • the prepared monophosphate salt of isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine can thereafter be converted to the corresponding isopropyl-methyl-[2-(3-n-propoxy- phenoxy)ethyl] amine by a simple alkalization step.
  • the mode of procedure can easily be made by a technician.
  • H 3 PO The content of H 3 PO is 27.8 % (w/w) which corresponds to a 1:1 molar ratio between 5 and H 3 PO 4 (28.0 % w/w theoretical value).
  • the wet product (41.8 kg, 67.6 mol) is mixed with water purified (66 L) and cone. NaOH is added to pH ⁇ l 1.5 and the resulting two phase mixture is extracted with methyl tert-butyl ether. The phases are separated, the organic phase is washed with water purified and then concentrated under reduced pressure. The residual solvents are finally stripped off using a thin film evaporator, affording isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine (14.28 kg, 56.67 mol) as an oil with a chromatographic purity over 99 %. MS (El): 251 (10), 236 (9), 86 (100).

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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 ISOPROPYL-METHYL-[2-(3-N- PROPOXYPHENOXY)ETHYL]AMINE
Field of the invention
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 said 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 isopropyl-methyl-[2- (3-n-propoxyphenoxy)ethyl]amine in medicine.
Background of the invention and prior art
Isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amineis a compound with anaesthetic properties. It is useful as a topical local anaesthetic for the treatment of pain, including localised pain, and especially on intact skin.
WO 9715548 discloses a process for the preparation of isopropyl-methyl-[2-(3-n-propoxy- phenoxy)ethyl]amine. Said process comprises a couple of reaction steps starting with reacting 3-n-propoxyphenol with 1 ,2-dibromoethane resulting in l-(2-bromoethoxy)-3-n- propoxybenzene. Further, l-(2-bromoethoxy)-3-n-propoxybenzene is reacted with N- methylisopropylamine in an autoclave. The product, isopropyl-methyl-[2-(3-n-propoxy- phenoxy)ethyl]amine, was thereafter further purified by distillation in vacuo.
Summary of the Invention
The object of the present invention is to provide a new process for the preparation of isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine suitable for full scale production. Scheme 1 below describes the main reaction steps in the manufacture of isopropyl-methyl- [2-(3-n-propoxyphenoxy)ethyl]amine starting from 3-propoxyphenol. The starting material as well as the reactants used, are readily available through processes known in the art.
Scheme 1 Step 1
Ethylene carbonate, solid-liquid phase-transfer catalysis
Figure imgf000004_0001
Figure imgf000004_0002
(1)
Step 2
Figure imgf000004_0004
halogenating or
Figure imgf000004_0003
sulphonating reagent
(1) - (2)
X = halogen or sulphonate ester
Step 3
Isopropylamine
Figure imgf000004_0005
Figure imgf000004_0006
(2) (3)
X = halogen or sulphonate ester Step 4
Formaldehyde, H2 metal catalyst
Figure imgf000005_0001
Figure imgf000005_0002
(3) (4)
Advantages of the improved process of the present invention are disclosed in the following paragraphs.
Another object of the present invention is to provide a process utilizing reagents and solvents that are environmentally friendly. There is a general interest from environmental groups both inside and outside the pharmaceutical industry that the industry shall develop and use environmentally friendly processes. The process of the present invention does not use any mutagenic alkylating agents, such as 1 ,2-dibromoethane, which is used in processes according to prior art. One object of the present invention is therefore to provide a process for the manufacture of isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine wherein the use of 1 ,2-dibromoethane is avoided. 1 ,2-dibromoethane is a known mutagenic compound and its use should therefore, if possible, be limited. This is especially true in full 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. We have surprisingly found that the monophosphate salt of isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine is a crystalline compound. The optional purifaction step is shown in Scheme 2. Scheme 2
H3P04
Figure imgf000006_0001
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 60-12CPC 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-Metyl-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. The solid-liquid phase-transfer catalysis conditions are created using a solid, non-soluble base and a phase-transfer catalyst. The amount of base and phase-transfer catalyst are not crucial and can therefore be varied according to 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 hydrogencarbonate, potassium carbonate and potassium hydrogencarbonate. Potassium carbonate is the preferred base. Examples of suitable phase- transfer catalysts include, but are not limited to, tetrabutyl ammonium iodide, tetrabutyl ammonium hydrogensulphate, 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 which has as an intrinsic property to function as a phase-transfer catalysts under the conditions used in Step 1. . Examples of such compounds include, but are not limited to, polyethyleneglycol (PEG), e.g. PEG 6000.
After complete 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 means of 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,
Figure imgf000007_0001
(2)
wherein X is a bromine, chlorine, iodine or a sulphonate ester group. Examples of sulphonate esters include, but are not limited to, alkane- and arylsulphonate ester, e.g. methanesulphonate, ethanesulphonate, p-toluenesulphonate, p-bromophenylsulphonate. Preferred compounds of formula 2 are sulphonate esters. Examples of reagents capable of producing preferred compounds of formula 2 include, but are not limited to, methanesulphonyl chloride, ethanesulphonyl chloride, p-toluenesulphonyl chloride and p- bromosulphonyl 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. The reaction is performed at elevated temperature, preferably 60-110°C, for a prolonged period of time and under increased pressure, preferably 1-10 atmospheres. Isopropylamine should be added at 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 can optionally be omitted. The reaction mixture is thereafter 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 thereafter used without any further purification in the subsequent step.
In Step 4, the acidic aqueous solution of isopropyl-[2-(3-propoxy-phenoxy)-ethyl]-amine prepared in Step 3 above, is reacted with formaldehyde in the presence of palladium on charcoal. The reaction mixture is hydrogenated at atmospheric pressure or above, such as 1-6 bars, for several hours. The amount of formaldehyde is not crucial, but can be between 1-10 equivalents, by weight. The amount of palladium on charcoal used is 0.01 to 0.5 molar equivalents, preferably 0.05-0.2. The reaction mixture is thereafter treated with aqueous base, such as sodium hydroxide, to pH ~ 12 and extracted with methyl tert-butyl ether. The organic phase is separated and distillation gives pure isopropyl-methyl-[2-(3-n- propoxyphenoxy)ethyl]amine.
Surprisingly, we have been able to crystallize isopropyl-methyl-[2-(3-n-propoxyphenoxy> ethyljamine from the reaction mixture in step 4, by converting it to the corresponding monophosphate salt. The monophosphate salt of isopropyl-methyl-[2-(3-n-propoxy- phenoxy)ethyl]amine is a crystalline and stable salt of isopropyl-methyl-[2-(3-n- propoxyphenoxy)ethyl]amine and therefore has advantageous properties. The introduction of a crystalline intermediate in the process for the preparation of isopropyl-methyl-[2-(3-n- propoxyphenoxy)ethyl]amine is advantageous. It introduces a simple and convenient optional and additional purification step in a reaction sequence where all intermediates are syrups. Thereby, the time and energy consuming distillation used in processes according to prior art is avoided. The crystallization of the monophosphate salt of isopropyl-methyl-[2- (3-n-propoxyphenoxy)ethyl]amine results in an intermediate of a high purity that can be further converted to the corresponding isopropyl-methyl-[2-(3-n-propoxy- phenoxy)ethyl]amine by a simple alkalization step. In the optional purification step, the content of crude isopropyl-methyl-[2-(3-n-propoxy- phenoxy)ethyl]amine in ethyl acetate is first assayed and adjusted to 6-10 ml ethyl acetate per gram of crude isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine, prepared inStep 4 above. The content of isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine in ethyl acetate is preferably 7-9 ml ethyl acetate per gram of isopropyl-methyl-[2-(3-n-propoxy phenoxy)ethyl]amine. To the assayed solution of isopropyl-methyl-[2-(3-n- propoxyphenoxy)ethyl]amine, methanol and a solution of phosphoric acid in methanol are added. The amount of phosphoric acid should be around 0.9 to 1.0 molar equivalents, preferably 0.95 equivalents. The total amount of methanol added to the assayed 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 around 5-15%, by volume, preferably 9- 11%, by volume. The precipitated salt is collected, for example by filtration or centrifugation, and thereafter washed with ethyl acetate.
The monophosphate salt of isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine, prepared above, is thereafter mixed with water and aqueous sodium hydroxide is added to 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 yielding 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, may be replaced by the optional purification step,/.e. the preparation of the monophosphate salt of isopropyl-methyl- [2-(3-n- propoxyphenoxy)ethyl] amine. Under those circumstances the alkaline aqueous phase containing the crude isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine will preferably be extracted with ethyl acetate instead of methyl tert-butyl ether. The prepared monophosphate salt of isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]aminecan thereafter be converted to the corresponding isopropyl-methyl-[2-(3-n-propoxy- phenoxy)ethyl] amine by a simple alkalization step. The mode of procedure can easily be made by a technician.
The present invention is described in more detail in the following non-limiting examples. Roman numerals are referring to Scheme 1 and 2.
Examples
Example 1
2-(3-Propoxy-phenoxy)-ethanol (1)
To 3 -propoxy phenol (17.9 kg, 117.4 mol) was added ethylene carbonate (20.7 kg, 234.8 mol), K2CO3 (17.9 kg, 126.7 mol), tetrabutylammonium bromide (3.8 kg, 11.5 mol) and 1- 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) followed by methyl tert-butyl ether (82 L) are added. The phases are separated and the organic phase is washed with 0.5 M HCl (aq) followed by 0.5 M NaHCO3 (aq). The organic phase is concentrated under reduced pressure and the crude 1 is purified by means of distillation, 150°C/0.95 mbar, yielding 1 (17.9 kg) as an oil with a chromatographic purity over 97 %. MS (El): 196 (34), 153 (13), 152 (7), 135 (4), 111 (67), 110 (100). 1H NMR (200 MHz): 5 7.15 (t, 1 H), 6.5 (m, 3 H), 4.0 (m, 2 H), 3.9 (m, 4 H), 2.5 (s, 1 H), 1.79 (m, 2 H), 1.0 (t, 3 H). I3C NMR (50 MHz): 6 160.4, 159.8, 129.9, 107.2, 106.7, 101.6, 69.5, 69.2, 61.4, 22.6, 10.5.
Methanesulphonic acid 3-propoxy-phenoxyethyl ester (2)
1 (17.9 kg, 91.0 mol) dissolved in methyl tert-butyl ether (83 L) and triethylamine (15.2 L, 108.1 mol) is allowed to react with MsCl (7.7 L, 99.12 mol). The resulting slurry is allowed to stand at ambient temperature for about 2 hours, water is added, the phases are separated and the organic phase is used as is in the subsequent step.
MS (El): 274 (55), 232 (7), 195 (1), 153 (6), 135 (16), 123 (100), 110 (66), 79 (64).
IsopropyI-[2-(3-propoxy-phenoxy)-ethyl] -amine (3)
To the solution of 2 are added K2CO3 (14.0 kg, 98.1 mol), isopropylamine (36.2 L, 455.9 mol) and water (31 L). The mixture is heated to 90°C for 16 hours with the reactor sealed resulting in a pressure of about 2 bar. The reaction mixture is cooled to ambient temperature, the aqueous phase is discarded and the organic phase is washed with water. To the organic phase is then added 0.5 M H2SO (aq) to 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). _ NMR (200 MHz): δ 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, 2 H), 1.6 (m, 1 H), 1.0 (d + t, 9 H). 13C NMR (50 MHz): 5 160.4, 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-methyI-[2-(3-propoxy-phenoxy)-ethyl] -amine (4)
To the acidic aqueous solution of 3 are added wet 10 % palladium on charcoal (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 cone. NaOH to pH~12, The solids are filtered off and the resulting two phase system is extracted with EtOAc. The phases are separated and the organic phase is washed with water and thereafter 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 ethyl acetate per gram 4) is added MeOH (9.6 L) followed by H3PO4 ( 4.85 L, 72.5 mol) dissolved in MeOH (19.2 L) over 3 hours at ambient temperature. The resulting slurry of the monophosphate salt of isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine is then isolated by filtration and the solid material is washed with EtOAc. The wet product (41.8 kg, 67.6 mol, 89 % yield) with a chromatographic purity over 99 % is used as is in the subsequent step. Mp: 131-134°C.
The content of H3PO is 27.8 % (w/w) which corresponds to a 1:1 molar ratio between 5 and H3PO4 (28.0 % w/w theoretical value).
The wet product (41.8 kg, 67.6 mol) is mixed with water purified (66 L) and cone. NaOH is added to pH~l 1.5 and the resulting two phase mixture is extracted with methyl tert-butyl ether. The phases are separated, the organic phase is washed with water purified and then concentrated under reduced pressure. The residual solvents are finally stripped off using a thin film evaporator, affording isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine (14.28 kg, 56.67 mol) as an oil with a chromatographic purity over 99 %. MS (El): 251 (10), 236 (9), 86 (100). 1H NMR (400 MHz): δ 7.1 (m, 1 H), 6.5 (m, 3H), 4.0 (t, 2 H), 3.9 (t, 2 H), 2.9 (m, 1 H), 2.8 (t, 2 H), 2.3 (s, 3 H), 1.8 (m, 2 H), 1.0 (d + t, 9 H). 13C NMR (50 MHz): δ 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.

Claims

Claims
1. A process for the preparation of isopropyl-methyl-[2-(3-propoxy-phenoxy)-ethyl]-amine comprising the following reaction steps;
Step .
Figure imgf000014_0001
(1 )
Step 2
Figure imgf000014_0003
halogenating or
Figure imgf000014_0002
sulphonating reagent
(1) " <2>
X = halogen or sulphonate ester
Step 3
Isopropylamine
Figure imgf000014_0004
Figure imgf000014_0005
(2) (3)
X = halogen or sulphonate ester Step 4
Formaldehyde, H2 metal catalyst
Figure imgf000015_0001
Figure imgf000015_0002
(3) (4)
2. A process according to claim 1 characterized in that a solid insoluble base and a phase- transfer catalyst is used in Step 1.
3. A process according to claim 2, characterized in that the base is sodium carbonate, potassium carbonate, sodium hydrogen carbonate, or potassium hydrogencarbonate.
4. A process according to claim 2, characterized in that the phase-transfer catalyst is PEG 6000, tetrabutyl ammonium bromide, tetrabutyl ammonium hydrogen sulphate, or tetrabutyl ammonium iodide.
5. A process according to claim 1, characterized in that Step 1 is performed in an aprotic organic solvent.
6. A process according to claim 5, characterized in that aprotic organic solvent is 1-metyl- 2-pyrrolidinone.
7. A process according to claim 1, characterized in that X is a bromine, chlorine, iodine, methanesulphonate, p-toluenesulphonate or p-bromophenylsulphonate group.
8. A process according to claim 1, characterized in that Step 3 is performed at a pressure above atmospheric pressure.
9. A process according to claim 1, characterized in that Step 3 is performed at a pressure between 1-10 bar.
10. A process according to claim 1, characterized in that Step 3 is performed at elevated temperature.
1 LA process according to claim 1, characterized in that Step 3 is performed at 60-110°C.
12.A process according to claim 1, characterized in that Step 3 is performed with an additional base present in the reaction mixture.
13. A process according to claim 1, characterized in that Step 3 in performed with water present as a solvent.
14. A process according to claim 1, characterized in that the metal catalyst in Step 4 is palladium.
15. A process according to claim 10, characterized in that the palladium is supported on charcoal.
16. A process according to claim 1, characterized in that the formaldehyde in Step 4 is added as an aqueous solution of formaldhyde.
17.Isopropyl-[2-(3-propoxy-ρhenoxy)-ethyl]-amine.
18. A pharmaceutical formulation comprising isopropyl-methyl-[2-(3-n-propoxyphenoxy)- ethyljamine and a pharmaceutically acceptable carrier or diluent characterized in that the isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine is prepared according to any of claims 1-16.
19.Isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine prepared by a process according to any of claims 1-16.
PCT/SE1998/002315 1997-12-22 1998-12-15 Process for the preparation of isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine Ceased WO1999032430A1 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
PL98341438A PL341438A1 (en) 1997-12-22 1998-12-15 Method of obtaining isopropylmethyl-[2-(3-n-propoxyphenoxy)ethyl amine
KR1020007006880A KR20010024790A (en) 1997-12-22 1998-12-15 Process for the Preparation of Isopropyl-Methyl-[2-(3-N-Propoxyphenoxy)Ethyl]Amine
EP98964599A EP1045826A1 (en) 1997-12-22 1998-12-15 Process for the preparation of isopropyl-methyl- 2-(3-n-propoxyphenoxy)ethyl]amine
SK805-2000A SK8052000A3 (en) 1997-12-22 1998-12-15 Process for the preparation of isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine
IL13682598A IL136825A0 (en) 1997-12-22 1998-12-15 Process for the preparation of isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine
EEP200000369A EE200000369A (en) 1997-12-22 1998-12-15 Process for the preparation of isopropylmethyl [2- (3-n-propoxyphenoxy) ethyl] amine
BR9814377-8A BR9814377A (en) 1997-12-22 1998-12-15 Process for preparing isopropyl-methyl- [2- (3-propoxyphenoxy) ethyl] amine, compound, and, pharmaceutical formulation
JP2000525367A JP2001526253A (en) 1997-12-22 1998-12-15 Method for producing isopropyl-methyl- [2- (3-N-propoxyphenoxy) ethyl] amine
AU19891/99A AU1989199A (en) 1997-12-22 1998-12-15 Process for the preparation of isopropyl-methyl-{2-(3-n-propoxyphenoxy)ethyl}amine
CA002314988A CA2314988A1 (en) 1997-12-22 1998-12-15 Process for the preparation of isopropyl-methyl-¬2-(3-n-propoxyphenoxy)ethyl|amine
IS5523A IS5523A (en) 1997-12-22 2000-06-07 Process for producing isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine
NO20002944A NO20002944L (en) 1997-12-22 2000-06-08 Process for Preparation of Isopropylmethyl- (2-) 3-n-Propolysphenoxy) Ethyl) Amine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9704834A SE9704834D0 (en) 1997-12-22 1997-12-22 New process
SE9704834-2 1997-12-22

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EP2714639A1 (en) * 2011-05-26 2014-04-09 Solvay Specialty Polymers Italy S.p.A. Hydro-fluorocompounds
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JP6635999B2 (en) * 2017-10-13 2020-01-29 株式会社ダイセル Method for producing potassium salt, and potassium salt

Citations (2)

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Publication number Priority date Publication date Assignee Title
EP0403952A2 (en) * 1989-06-21 1990-12-27 Makhteshim Chemical Works Limited An environmentally safe method of preparing a certain dialkylamine
WO1997015548A1 (en) * 1995-10-27 1997-05-01 Astra Aktiebolag New [(3-alkoxy-phenoxy)-ethyl]-dialkylamine derivatives and their use as local anaesthetics

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0403952A2 (en) * 1989-06-21 1990-12-27 Makhteshim Chemical Works Limited An environmentally safe method of preparing a certain dialkylamine
WO1997015548A1 (en) * 1995-10-27 1997-05-01 Astra Aktiebolag New [(3-alkoxy-phenoxy)-ethyl]-dialkylamine derivatives and their use as local anaesthetics

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