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WO2000050379A1 - Procede de preparation de (1r, 2s, 4r) -(-) -2 - (2 -dimethylaminoethoxy) -2 -phenyl -1,7,7 - trimethylbicyclo [2.2.1] heptane - Google Patents

Procede de preparation de (1r, 2s, 4r) -(-) -2 - (2 -dimethylaminoethoxy) -2 -phenyl -1,7,7 - trimethylbicyclo [2.2.1] heptane Download PDF

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Publication number
WO2000050379A1
WO2000050379A1 PCT/HU2000/000014 HU0000014W WO0050379A1 WO 2000050379 A1 WO2000050379 A1 WO 2000050379A1 HU 0000014 W HU0000014 W HU 0000014W WO 0050379 A1 WO0050379 A1 WO 0050379A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
process according
phenyl
compound
trimethylbicyclo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/HU2000/000014
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English (en)
Inventor
Gyula Simig
Tibor Mezei
Lívia GREGORNÉ BOROS
Endréné FLÓRIÁN
Márta PORCS-MAKKAY
Gyula LUKÁCS
Sándorné CSEH
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.)
Egyt Gyogyszervegyeszeti Gyar
Egis Pharmaceuticals PLC
Original Assignee
Egyt Gyogyszervegyeszeti Gyar
Egis Pharmaceuticals PLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Egyt Gyogyszervegyeszeti Gyar, Egis Pharmaceuticals PLC filed Critical Egyt Gyogyszervegyeszeti Gyar
Priority to AU31823/00A priority Critical patent/AU3182300A/en
Publication of WO2000050379A1 publication Critical patent/WO2000050379A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • C07C217/52—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups or amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • 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
    • C07C213/08—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 not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
    • C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms

Definitions

  • the invention relates to a process for the preparation of (1 R,2S,4R)-(-)-2-(2-dimethy!aminoethoxy)-2-phenyl-1 ,7,7- -trimethylbicyclo[2.2.1]heptane and pharmaceutically acceptable acid addition salts thereof.
  • the compound of the Formula I falls under the scope of the Formula I of HU-179,164.
  • the compound of the Formula I is prepared by reacting camphor with the corresponding organic metal compound, hydrolyzing the adduct thus obtained and introducing the basic sidechain by etherification of the hydroxy group of the compound thus obtained.
  • organic metal compound a Grignard compound or an organic alkali compound - preferably lithium or sodium compound - can be used.
  • the preparation of the compound of the Formula I is disclosed in none of the examples of HU-179,164. Following the general disclosure the compound of the Formula I cannot be prepared in a purity which meets the requirements of Pharmacopoeia or only with considerable losses.
  • the present invention is based on the recognition that the new compound of the Formula V, never described in prior art, can be readily crystallized and can be easily purified.
  • the contaminations and by-products formed in the course of the synthesis can be removed by crystallization of the compound of the Formula V to a very great extent and due to this fact a highly pure compound is used as last intermediate in the synthesis of the desired compound of the Formula I. Details of the invention
  • an alkali salt of the compound of the Formula III is reacted with a 2-halogeno-N,N-dimethyl-acetamide of the general Formula IV.
  • the compound of the Formula III is known from prior art [Deno et al. J. Amer. Chem. Soc, 77, 3044 (1955)].
  • the starting material of the Formula III is converted into an alkali salt, preferably the sodium or potassium salt, particularly advantageously the sodium salt.
  • the reaction is carried out by using an alkali hydride or alkali amide, such as sodium hydride, potassium hydride, sodium amide or potassium amide.
  • An ether e.g.
  • the alkali salt of the compound of the Formula III can be prepared at 10-50°C, preferably at room temperature.
  • the alkali salt formed is reacted with a compound of the general Formula IV. It is preferred to use 2-chloro-N,N- -dimethyl-acetamide, i.e. a compound of the general Formula IV, wherein X stands for chlorine. According to a preferred form of realization of the process of the present invention the reaction between the alkali salt of the compound of the Formula III and the 2-halo-N.N-dimethyl-acetamide of the general Formula IV is carried out without isolating the in situ formed alkali salt, i.e. in the reaction mixture obtained by the formation of said alkali salt.
  • reaction medium used by the reaction between the alkali salt of the compound of the Formula III and the compound of the general Formula IV is the same as used in the alkali salt formation.
  • the reaction between the alkali salt of the compound of the Formula III and the 2-halo-N,N-dimethyl-acetamide of the general Formula IV can be carried out at 10-50°C, preferably at room temperature. The reaction takes place within some hours, the advantageous reaction time being 1-3 hours.
  • the formed compound of the Formula V is isolated from the reaction mixture by extraction (preferably with ethyl acetate) and evaporation of the extract.
  • the compound of the Formula V is purified by crystallization. Said crystallization can be carried out from a hydrocarbon (e.g. pentane, hexane, heptane, cyclohexane etc.) or a mixture thereof formed with ethyl acetate.
  • a hydrocarbon e.g. pentane, hexane, heptane, cyclohexane etc.
  • One may work preferably by crystallizing the compound of the Formula V from a mixture of hexane and ethyl acetate.
  • the crystalline compound of the Formula V obtained is of high purity, contains only small amounts of contaminations and is suitable for the preparation of the end product of the Formula I meeting the up-to-date requirements of Pharmacopoeia.
  • the compound of the Formula V thus obtained is reduced into the desired compound of the Formula I.
  • Reduction can be carried out with any metal hydride suitable for the reduction of acid amides, or a complex of a Lewis acid formed with a metal hydride or a borohydride/dimethyl sulfide complex. It is preferred to use lithium aluminium hydride or a borohydride/dimethyl sulfide complex as reducing agent.
  • Reduction can be performed in an ether type solvent as reaction medium (e.g. tetrahydrofurane, dimethyl ether, diisopropyl ether etc.). One may work preferably in tetrahydrofurane as medium.
  • Reduction can be carried out under heating, advantageously at the boiling point of the reaction mixture. The reaction is complete within some hours, the preferred reaction time being 1-3 hours.
  • the product can be isolated from the reaction mixture by extraction with an organic solvent (preferably ethyl acetate), drying and evaporating the extract.
  • an organic solvent preferably ethyl acetate
  • the crude product of the Formula I obtained after reduction is of high purity, the contamination content determined by HPLC being below 1 %.
  • the compound of the Formula I can be converted, if desired, into a pharmaceutically acceptable salt by known methods.
  • inorganic acids e.g. hydrochloric acid, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid
  • organic acids e.g. acetic acid, tartaric acid, succinic acid, lactic acid, malic acid, maleic acid, fumaric acid etc.
  • the fumarate can be formed in a known manner by adding to the solution of the base of the Formula I and a suitable inert organic solvent a solution of fumaric acid formed with a suitable organic solvent. It is preferred to dissolve the base of the Formula I and fumaric acid in the same solvent.
  • reaction medium preferably lower alkanols, particularly ethanol can be used.
  • Example 1 Further details of the present invention are to be found in the Examples, without limiting the scope of protection to said Examples.
  • Example 1
  • the mixture is heated to boiling for an hour, whereupon it is cooled to 25°C and a solution of 14.0 g (0.12 mole) of 2-chloro-N,N-dimethyl- -acetamide and 50 ml of anhydrous tetrahydrofurane is added.
  • the reaction mixture is stirred at 25°C for half an hour, whereupon 250 ml of water are added.
  • the product is extracted with ethyl acetate, filtered over silica and evaporated. The residue is crystallized from a 4:1 mixture of hexane and ethyl acetate.
  • reaction mixture is heated to boiling for 3 hours, cooled to 25°C, at this temperature 40 ml of a saturated ammonium chloride solution are added, the mixture is stirred at 40-50°C for 5 hours and the reaction mixture is made alkaline to pH 10.
  • the product is extracted with ethyl acetate, the extract is dried and evaporated to dryness in vacuo. Salt formation

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention porte sur un procédé de préparation du (1R, 2S, 4R) -(-) -2 - (2-diméthylaminoéthoxy) -2 -phényl- 1,7,7 - triméthylbicyclo [2.2.1] heptane de formule (I) et ses sels acidifiants pharmacocompatibles à partir de (1R, 2S, 4R)-(-) -2 - phényl- 1,7,7- triméthylbicyclo [2.2.1] heptane-2-ol de formule (III), avec une conversion facultative du (1R,2S,4R)-(-)-2- (2-diméthylaminoéthoxy) -2-phényl-1,7,7- triméthylbicyclo [2.2.1] heptane en l'un de ses sels en faisant réagir un sel alcalin de (1R,2S,4R)-(-)-2- phényl-1,7,7- triméthylbicyclo [2.2.1] heptane-2-ol de formule (III) avec de la 2-halo-N,N- diméthyl-acétamide de formule générale (IV) (où X est halogène) puis en réduisant la (1R,2S,4R)-(-)-N, N-diméthyl- (2-phényl-1,7, 7-triméthylbicyclo [2.2.1] hept-2-yl) -oxy-acétamide de formule (V) ainsi obtenue. Le composé de formule (I) est un ingrédient pharmaceutique actif connu des anxiolytiques. Ledit procédé facilement réalisable également à l'échelle industrielle peut recourir à un dernier intermédiaire cristallin facile à purifier et donnant un produit final très pur avec d'excellents rendements.
PCT/HU2000/000014 1999-02-24 2000-02-23 Procede de preparation de (1r, 2s, 4r) -(-) -2 - (2 -dimethylaminoethoxy) -2 -phenyl -1,7,7 - trimethylbicyclo [2.2.1] heptane Ceased WO2000050379A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU31823/00A AU3182300A (en) 1999-02-24 2000-02-23 Process for the preparation of (1r, 2s, 4r) -(-) -2 - (2 -dimethylaminoethoxy) -2 -phenyl -1,7,7 - trimethylbicyclo (2.2.1) heptane

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HUP9900445 1999-02-24
HU9900445A HUP9900445A2 (hu) 1999-02-24 1999-02-24 Eljárás (1R,2S,4R)-(-)-N,N-(dimetilamino-etoxi)-2-fenil-1,7,7-trimetil-biciklo[2.2.1]heptán előállítására és ennek köztiterméke

Publications (1)

Publication Number Publication Date
WO2000050379A1 true WO2000050379A1 (fr) 2000-08-31

Family

ID=89997834

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/HU2000/000014 Ceased WO2000050379A1 (fr) 1999-02-24 2000-02-23 Procede de preparation de (1r, 2s, 4r) -(-) -2 - (2 -dimethylaminoethoxy) -2 -phenyl -1,7,7 - trimethylbicyclo [2.2.1] heptane

Country Status (3)

Country Link
AU (1) AU3182300A (fr)
HU (1) HUP9900445A2 (fr)
WO (1) WO2000050379A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2793489A1 (fr) * 1999-05-11 2000-11-17 Egyt Gyogyszervegyeszeti Gyar (1r,2s,4r)-(-)-2-[(2'-{n,n-dimethylamino}-ethoxy)]-2- [phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]-heptane, ses sels d'addition et procede de preparation
JP2010501589A (ja) * 2006-08-24 2010-01-21 ブリストル−マイヤーズ スクイブ カンパニー 環状１１−βヒドロキシステロイドデヒドロゲナーゼＩ型阻害剤

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4342762A (en) * 1979-12-14 1982-08-03 Egyt Gyogyszervegyeszeti Gyar Basic ethers and pharmaceutical compositions containing the same

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4342762A (en) * 1979-12-14 1982-08-03 Egyt Gyogyszervegyeszeti Gyar Basic ethers and pharmaceutical compositions containing the same

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Section Ch Week 199302, Derwent World Patents Index; Class B05, AN 1993-011166, XP002142099 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2793489A1 (fr) * 1999-05-11 2000-11-17 Egyt Gyogyszervegyeszeti Gyar (1r,2s,4r)-(-)-2-[(2'-{n,n-dimethylamino}-ethoxy)]-2- [phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]-heptane, ses sels d'addition et procede de preparation
EP1052245A3 (fr) * 1999-05-11 2001-02-28 Egis Gyogyszergyar Rt. (1R, 2S, 4R)-(-)-2-[(2'-(N,N-dimethylamino)-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane à haute pureté, ses sels d'addition d'acides pharmaceutiquement acceptables, leur procédé de préparation et médicaments les contenant
WO2000068183A3 (fr) * 1999-05-11 2001-07-26 Egyt Gyogyszervegyeszeti Gyar (1r,2s,4r)-(-)-2- [(2'-{n,n-dimethylamino} -ethoxy)] -2-[phenyle] -1,7,7-tri-[methyle]-bicyclo [2.2.1]heptane de grande purete et sels d'addition acides pharmaceutiquement acceptables de ceux-ci et processus de preparation de ces composes ainsi que de medicaments contenant un ou plusieurs de ces composes et leur utilisation
US6335469B1 (en) 1999-05-11 2002-01-01 Orion Corporation High purity (1R,2S,4R)-(-)-2-[(2′-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane and pharmaceutically acceptable acid addition salts thereof
US6624201B2 (en) 1999-05-11 2003-09-23 Orion Corporation High purity (1r,2s,4r)-(−)-2-[(2′-{n,n-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7 -tri-[methyl]-bicyclo [2.2.1]heptane and pharmaceutically acceptable acid addition salts thereof and a process for the preparation of these compounds as well as medicaments containing 1 or more of these compounds and their use
JP2010501589A (ja) * 2006-08-24 2010-01-21 ブリストル−マイヤーズ スクイブ カンパニー 環状１１−βヒドロキシステロイドデヒドロゲナーゼＩ型阻害剤
JP2013173783A (ja) * 2006-08-24 2013-09-05 Bristol Myers Squibb Co 環状１１−βヒドロキシステロイドデヒドロゲナーゼＩ型阻害剤

Also Published As

Publication number Publication date
AU3182300A (en) 2000-09-14
HUP9900445A2 (hu) 2001-06-28
HU9900445D0 (en) 1999-04-28

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