Classifications

• • 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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• Chemical & Material Sciences (AREA)
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• Chemical Kinetics & Catalysis (AREA)
• Animal Behavior & Ethology (AREA)
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• Public Health (AREA)
• Medicinal Chemistry (AREA)
• Pain & Pain Management (AREA)
• Engineering & Computer Science (AREA)
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• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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• 1997
  • 1997-12-22 SE SE9704834A patent/SE9704834D0/xx unknown
• 1998
  • 1998-12-08 ZA ZA9811238A patent/ZA9811238B/xx unknown
  • 1998-12-09 AR ARP980106239A patent/AR017198A1/es not_active Application Discontinuation
  • 1998-12-09 TW TW087120435A patent/TW436474B/zh not_active IP Right Cessation
  • 1998-12-15 TR TR2000/01976T patent/TR200001976T2/xx unknown
  • 1998-12-15 JP JP2000525367A patent/JP2001526253A/ja active Pending
  • 1998-12-15 WO PCT/SE1998/002315 patent/WO1999032430A1/en not_active Application Discontinuation
  • 1998-12-15 AU AU19891/99A patent/AU1989199A/en not_active Abandoned
  • 1998-12-15 PL PL98341438A patent/PL341438A1/xx not_active Application Discontinuation
  • 1998-12-15 EP EP98964599A patent/EP1045826A1/de not_active Ceased
  • 1998-12-15 CN CN98812528A patent/CN1283177A/zh active Pending
  • 1998-12-15 SK SK805-2000A patent/SK8052000A3/sk unknown
  • 1998-12-15 HU HU0100616A patent/HUP0100616A2/hu unknown
  • 1998-12-15 KR KR1020007006880A patent/KR20010024790A/ko not_active Application Discontinuation
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  • 1998-12-15 CA CA002314988A patent/CA2314988A1/en not_active Abandoned
  • 1998-12-15 ID IDW20001192A patent/ID27591A/id unknown
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  • 1998-12-15 IL IL13682598A patent/IL136825A0/xx unknown
• 2000
  • 2000-06-07 IS IS5523A patent/IS5523A/is unknown
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