WO2011001373A1 - Procédé pour la préparation d'un dérivé trisubstitué énantiomériquement pur de la 1,2,3,4-tétrahydroisoquinoline - Google Patents

Procédé pour la préparation d'un dérivé trisubstitué énantiomériquement pur de la 1,2,3,4-tétrahydroisoquinoline Download PDF

Info

Publication number
WO2011001373A1
WO2011001373A1 PCT/IB2010/052962 IB2010052962W WO2011001373A1 WO 2011001373 A1 WO2011001373 A1 WO 2011001373A1 IB 2010052962 W IB2010052962 W IB 2010052962W WO 2011001373 A1 WO2011001373 A1 WO 2011001373A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
acid
mixture
process according
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/IB2010/052962
Other languages
English (en)
Inventor
Thomas Dax
Andreas Hendrikus Maria De Vries
Matthias Helms
Peter Kapitan
Sylvia Krich
Laurent Lefort
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.)
Actelion Pharmaceuticals Ltd
Original Assignee
Actelion Pharmaceuticals Ltd
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 Actelion Pharmaceuticals Ltd filed Critical Actelion Pharmaceuticals Ltd
Publication of WO2011001373A1 publication Critical patent/WO2011001373A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/18—Aralkyl radicals

Definitions

  • the present invention relates to a process for the preparation of the compound of formula 7 below starting from an iminium salt of formula 4 * HX below
  • the compound of formula 7 is useful in the preparation of (2R)-2- ⁇ (1 S)-6,7-dimethoxy-1- [2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1 H-isoquinolin-2-yl ⁇ - ⁇ /-methyl-2-phenyl- acetamide (almorexant), i.e. the compound of formula I drawn below, especially in form of the hydrochloride salt I * HCI,
  • almorexant which is known from WO2005/1 18548 and Nat. Med. (2007), 13, 150-155 and which is especially useful as orexin receptor antagonist. It can be obtained through a multiple-step synthesis.
  • the key intermediate in the synthesis of almorexant is the 1 -substituted 1 ,2,3,4- tetrahydroisoquinoline derivative of formula 7.
  • almorexant can be prepared by cyclisation of the respective N-phenethyl-propionamide derivative with POCI3 leading to the imine of formula 4, followed by asymmetric transfer hydrogenation in the presence of a chiral Ru(ll)-complex (Noyori catalyst, Uematsu et al. J. Am. Chem. Soc.
  • a drawback of the preparation process using the Noyori transfer hydrogenation process as described in the references cited above is that, especially when the process is performed using an appropriate substrate to catalyst ratio for industrial scale synthesis, relatively high amounts of side-product, such as the N-formylated optically active amine, may be formed.
  • side-product such as the N-formylated optically active amine
  • the above process may lead to unsatisfactory overall yields of the compound of formula 7, and in consequence, to unsatisfactory overall yields of the compound of formula I * HCI.
  • the formation of side products may require more laborious purification steps.
  • the compound of formula 7 and thus almorexant and its hydrochloride salt
  • the substrate 4 in the asymmetric transfer hydrogenation reaction is a protonated imine, i.e. compound 4 * HX.
  • the formation of side-product is reduced significantly.
  • the asymmetric transfer hydrogenation of the free imine 4 leading to full conversion may, depending on the reaction time, result in formation of > 10% N-formylated side-product (i.e. 6,7- Dimethoxy-1 -[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1 H-isoquinoline-2- carbaldehyde), whereas the asymmetric transfer hydrogenation of the protonated imine according to the invention leading to full conversion may result in formation of less than 3% of the N-formylated side-product.
  • it is an advantage of the process of the invention that when the substrate imine 4 is produced as a salt to ease purification, no separate process step is needed to remove the acid.
  • the invention relates to a process for the preparation of the compound of formula 7
  • X " represents the conjugate base of the acid HX; wherein the acid HX is selected from the group consisting of sulfuric acid, trifluoro acetic acid, methanesulfonic acid, benzene sulfonic acid, tetrafluoroboric acid and hydrochloric acid (in particular methanesulfonic acid);
  • Noyori-type transfer hydrogenation catalyst notably (R,R)-[p- ((CHa) 2 CH)-C 6 H 4 -CH 3 ]RuH(NH 2 -CHPh-CHPh-N-SO 2 -C 6 H 4 -P-CH 3 ), or a precursor thereof,
  • a reducing agent selected from the group consisting of formic acid, a mixture of formic acid and triethylamine, and sodium formate;
  • the acids HX that may be used in the process of the invention to form the protonated imine 4 * HX have the common characteristic that they have a pK a ⁇ 3. It is well understood that equivalent acids having a pK a ⁇ 3, said acids being well known to the skilled person, may also be used.
  • Suitable optically active Noyori-type transfer hydrogenation catalysts, or transfer hydrogenation catalysts that may alternatively be used in the above process, are known from AJ. Blacker, Chapter 35, in "The Handbook of Homogeneous Hydrogenation” (Ed. J. G. de Vries, C. J. Elsevier, Wiley, 2007), T. lkariya and AJ. Blacker (Accounts Chem. Res.
  • transition-metal based catalysts are commercially available, prepared beforehand, or can be prepared in situ from any commercially available transition-metal complex (also known as precursors) and an optically active ligand as known for example from S. Gladiali and E. Alberico (Chem. Soc. Rev. 2006, 35, 226) and references therein.
  • a transition metal selected from iridium, rhodium and notably ruthenium (introduced via suitable precursors such as dichloro (pentamethylcyclopentadienyl) iridium(lll) dimer, or especially dichloro (pentamethylcyclopentadienyl) rhodium(lll) dimer, or (notably) [RuCI 2 (p-cymene)] 2 );
  • an optically active mono- ⁇ /-sulfonated ethan-1 ,2-diamine derived ligand which may be cyclic (such as 1-sulfonamido-(2-amino)-cyclohexane derivatives, such as especially (R,R)-N-(2-amino-cyclohexyl)-4-methyl-benzene-sulfonamide); or which may notably be acyclic (such as 1-sulfonamido-(2-amino-1 ,2-diphenyl)-ethane derivatives; such as especially (R,R)-N-(2-amino-1 ,2-diphenyl-ethyl)-2,4,6- trimethyl-benzenesulfonamide, (R,R)-N-(2-amino-1 ,2-diphenyl-ethyl)- methanesulfonamide, (R,R)-N-(2-amino-1 ,2-diphenyl-ethyl
  • an ⁇ 5 -cyclopentadienyl-, or notably an ⁇ 6 -arene coordinating ligand such as pentamethylcyclopentadiene, benzene, trimethylbenzene, toluene, or notably p- cymene ⁇ -((CHa) 2 CH)-C 6 H 4 -CH 3 )).
  • Noyori catalyst (R,R)-[p-((CH 3 ) 2 CH)-C 6 H 4 -CH 3 ]RuH(NH 2 -CHPh-CHPh-N- SO 2 -C 6 H 4 -P-CH 3 ), or precursors thereof (such as for example (R,R)-[p-((CH 3 ) 2 CH)-C 6 H 4 - CH 3 ]RuCI(NH 2 -CHPh-CHPh-N-SO 2 -C 6 H 4 -P-CH 3 ), which is commercial or obtained e.g.
  • Suitable reducing agents are well known in the field of transfer hydrogenation of imines. Frequently, such reducing agents are based on formic acid, such as especially formic acid; mixtures of formic acid and triethylamine; or formic acid salts, such as ammonium formate or alkali metal formates (in particular sodium or potassium formate); or mixtures thereof.
  • reducing agents based on formic acid are for example isopropanol or Hantzsch ester, which reducing agents, when used for the reduction of iminium substrates, may require particular reaction conditions and the use of an appropriate catalyst such as for example a Noyori-type transfer hydrogenation catalyst comprising iridium or rhodium and a ⁇ 5 -cyclopentadienyl ligand (see), or an equivalent catalyst comprising for example an aminoethanol derived ligand.
  • an appropriate catalyst such as for example a Noyori-type transfer hydrogenation catalyst comprising iridium or rhodium and a ⁇ 5 -cyclopentadienyl ligand (see), or an equivalent catalyst comprising for example an aminoethanol derived ligand.
  • Such particular reaction conditions and alternative combinations of reducing agent and catalyst are well known to the skilled person (see AJ. Blacker, Chapter 35, in the Handbook of Homogeneous Hydrogenation (Ed. J. G. de Vries, C. J. Els
  • the reducing agent is a mixture of formic acid and triethylamine; or sodium formate.
  • the reducing agent is a mixture of formic acid and triethylamine, it is notably triethylamine/formic acid (i.e. the ratio of formic acid and triethylamine is 1 :1 eq.) or a mixture of formic acid and triethylamine/formic acid; such mixture is optionally formed in situ from formic acid and triethylamine.
  • the ratio of formic acid and triethylamine is less than 5:2 mol eq., preferably less than 2:1 mol eq., more preferably less than 1.5:1 mol eq..
  • the reducing agent is triethylamine/formic acid (i.e. the ratio of formic acid and triethylamine is 1 :1 eq.).
  • the ratio of formic acid and triethylamine is less than 1 :1 mol eq., notably about 4:5 mol eq..
  • sodium formate is applied as reducing agent.
  • the amount of reducing agent (as counted from the hydrogen donor) is less than 5.8 mol eq. compared to mol eq. of substrate, more preferably less than 4 mol eq., even more preferably less than 3 mol eq..
  • a mixture of formic acid and triethylamine is applied as reducing agent, at a concentration of about 3 mol eq. or less (such as e.g. 2 mol eq.).
  • Sodium formate is preferably applied at a concentration of about 3 mol eq. or less.
  • the substrate to catalyst ratio is more than 100:1 mol eq.. More preferably, the ratio of substrate to catalyst is more than 500:1. Even more preferably, this ratio is more than 1000:1 , notably more than 2000:1. In particular, the ratio is between about 1000 and 3000, notably between about 1500 and 2500, especially about 2000.
  • Suitable solvents are for instance water, methanol, dichloromethane, isopropanol, methanol, ethylacetate, methylisobutylketone, toluene, 1 ,4-dioxane, acetonitrile, dimethylformamide, N-methylpyrrolidinone, 1 ,3-dimethyl-2-imidazolidinone, N, N- dimethylacetamide, 2,3,4,5-tetrahydrothiophene-1 ,1-dioxide, tetrahydrofuran, dimethylsulfoxide, sulfolane or mixtures thereof.
  • the solvent is water, methanol, dichloromethane, or any mixture thereof.
  • the solvent is dichloromethane.
  • the solvent is a mixture of water and methanol.
  • the reducing agent may also be the solvent, and has as such a double role.
  • refluxing conditions are applied prior to the transfer hydrogenation reaction, or during the asymmetric transfer hydrogenation reaction, to remove undesired gases, such as oxygen, CO 2 and/or CO.
  • undesired gases such as oxygen, CO 2 and/or CO.
  • refluxing conditions are obtained by applying a small under-pressure (e.g. 200 to 800 mbar and preferably 400 to 500 mbar).
  • the undesired gases can be removed by bubbling through any inert gas, e.g. nitrogen gas, or by applying an inert gas flow.
  • the product of the process of the invention (i.e. the compound of formula 7) can be isolated in a number of ways.
  • the reaction mixture is worked up by aqueous extraction(s) and the product can be either used as is (in solution) for further reactions, or crystallized as amine or crystallized as a suitable salt.
  • the secondary amine product is crystallized as amine or as suitable salt. More preferably, the secondary amine product of the asymmetric transfer hydrogenation of the invention is treated with acetic acid, as such precipitating the product as the amine acetic acid salt.
  • Another embodiment relates to the process according to embodiment i), characterized in that the compound of formula 4 * HX is the compound of formula 4 * methanesulfonic acid (4 * CH 3 SO 3 H):
  • the compound 4 * CH 3 SO 3 H as used according to embodiment ii) in the process according to embodiment i) is isolated from toluene or a mixture of toluene and acetone.
  • the optically active Noyori-type transfer hydrogenation catalyst comprises a transition metal selected from iridium, rhodium and notably ruthenium; an optically active mono- ⁇ /-sulfonated ethan-1 ,2-diamine derived ligand; and an ⁇ 5 - cyclopentadienyl-, or notably an ⁇ 6 -arene coordinating ligand.
  • Another embodiment relates to the process according to any one of embodiments i) to iii), characterized in that the ⁇ 5 -cyclopentadienyl- or ⁇ 6 -arene coordinating ligand is selected from the group consisting of pentamethylcyclopentadiene, benzene, trimethylbenzene, toluene, and notably p-cymene (p-((CH 3 ) 2 CH)-C 6 H 4 -CH 3 ).
  • Another embodiment relates to the process according to any one of embodiments i) to iv), characterized in that the transition metal and the ⁇ 5 -cyclopentadienyl- or ⁇ 6 -arene coordinating ligand of the optically active Noyori-type transfer hydrogenation catalyst are introduced via dichloro (pentamethylcyclopentadienyl) iridium(lll) dimer, or especially dichloro (pentamethylcyclopentadienyl) rhodium(lll) dimer, or (notably) [RuCI 2 (p- cymene)] 2 .
  • optically active mono- ⁇ /-sulfonated ethan-1 ,2-diamine derived ligand is (R,R)-N-(2-amino-cyclohexyl)-4-methyl-benzene-sulfonamide, (R,R)-N-(2-Amino- 1 ,2-diphenyl-ethyl)-2,4,6-trimethyl-benzenesulfonamide, (R,R)-N-(2-Amino-1 ,2-diphenyl- ethyl)-methanesulfonamide, (R,R)-N-(2-Amino-1 ,2-diphenyl-ethyl)-camphorsulfonamide, or notably (R 1 R)-TsDPEN ((R,R)-N-(2-Amino-1 ,2-diphenyl-ethyl)-4-methyl
  • Another embodiment relates to the process according to any one of embodiments i) to vi), characterized in that the optically active Noyori-type transfer hydrogenation catalyst is (R 1 R)-[p-((CH 3 ) 2 CH)-C 6 H 4 -CH 3 ]RuH(NH 2 -CHPh-CHPh-N-SO 2 -C 6 H 4 -p-CH 3 ), or a precursor thereof.
  • the optically active Noyori-type transfer hydrogenation catalyst is (R 1 R)-[p-((CH 3 ) 2 CH)-C 6 H 4 -CH 3 ]RuH(NH 2 -CHPh-CHPh-N-SO 2 -C 6 H 4 -p-CH 3 ), or a precursor thereof.
  • Another embodiment relates to the process according to any one of embodiments i) to vii), characterized in that the solvent is dichloromethane.
  • Another embodiment relates to the process according to any one of embodiments i) to vii), characterized in that the solvent is a mixture of water and methanol.
  • Another embodiment relates to the process according to any one of embodiments i) to viii), characterized in that the reducing agent is triethylamine/formic acid, or a mixture of formic acid and triethylamine/formic acid.
  • Another embodiment relates to the process according to any one of embodiments i) to viii), characterized in that the reducing agent is a mixture of formic acid and triethylamine wherein the ratio of formic acid and triethylamine is less than 5:2 mol eq..
  • xii) Another embodiment relates to the process according to any one of embodiments i) to viii), characterized in that the reducing agent is a mixture of formic acid and triethylamine, wherein the ratio of formic acid and triethylamine is less than 2:1 mol equivalent (notably less than 1.5:1 mol equivalent). In a sub-embodiment, the ratio is less than 1 :1 mol eq., notably about 4:5 mol eq..
  • xiii) Another embodiment relates to the process according to any one of embodiments i) to viii), characterized in that the reducing agent is triethylamine/formic acid (i.e. the ratio of formic acid and triethylamine is 1 :1 mol equivalent).
  • the reducing agent is triethylamine/formic acid (i.e. the ratio of formic acid and triethylamine is 1 :1 mol equivalent).
  • Another embodiment relates to the process according to any one of embodiments i) to vii) or ix), characterized in that the reducing agent is sodium formate.
  • xv) A process according to any one of embodiments i) to xiv), characterized in that the amount of reducing agent is less than 4 mol equivalents compared to mol equivalent of substrate (in one sub-embodiment less than 3 mol equivalents, in another sub- embodiment about 3 mol equivalents).
  • xvi) Another embodiment relates to the process according to any one of embodiments i) to xv), characterized in that the ratio of substrate to catalyst is more than 500:1 (notably more than 1000:1 ; especially between about 1000 and 3000, and notably between about 1500 and 2500).
  • xvii) Another embodiment relates to the process according to any one of embodiments i) to xvi), characterized in that the compound of formula 7 is isolated as compound of formula 7 * CH 3 COOH:
  • Another embodiment relates to the process according to any one of embodiments i) to xvii), wherein the compound of formula 7 is further transformed to (2R)-2- ⁇ (1 S)-6,7- dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1 H-isoquinolin-2-yl ⁇ - ⁇ /-methyl- 2-phenyl-acetamide, or a salt thereof (especially the hydrochloride salt thereof).
  • abbreviations "aq.”, “ee”, “eq.”, “mol%”, “wt%”, and RT refer respectively to the 5 aqueous, enantiomeric excess of an enantiomeric mixture, equivalent(s), to the molar percentage of a component in a mixture, to the weight percentage of a component in a mixture, and to room temperature.
  • the abbreviation “MIBK” refers to methylisobutylketone.
  • DCM refers to dichloromethane.
  • the term "about” placed before a numerical value "X” refers in the current application to an interval extending from X minus 10% of X to X plus 10% of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of X.
  • the term “about” placed before a temperature “Y” refers in the current application to an interval extending from the temperature Y minus 1O 0 C to Y plus 1O 0 C, and preferably to an interval extending from Y minus 5 0 C to Y plus 5 0 C.
  • room temperature refers to about 25°C.
  • step a of the reaction commercially available 4-trifluoromethylcinnamic acid is hydrogenated (e.g. in methanol at 2 bar hydrogen pressure, in the presence of 2 wt% Pd/C, having 5% Pd on charcoal at 15 to 25°C), to obtain compound of formula 1.
  • step b of the reaction the compound of formula 1 is reacted with methanol (e.g. in the presence of 5 mol% H 2 SO 4 , at the boiling point of the mixture) to obtain the corresponding ester of formula 2.
  • the compound of formula 1 is not isolated after step a (only the catalyst is removed by filtration), and the reaction is continued with step b.
  • step c of the reaction compound of formula 2 is reacted with commercially available 2- (3,4-dimethoxy-phenyl)-ethylamine (e.g. 30% sodium methoxide in methanol, toluene, 100 0 C) to obtain the compound of formula 3.
  • commercially available 2- (3,4-dimethoxy-phenyl)-ethylamine e.g. 30% sodium methoxide in methanol, toluene, 100 0 C
  • step d-1 of the reaction the compound of formula 3 is reacted e.g. in the presence of phosphorus oxychloride in an amount of 0.5 to 1.5 eq. (notably 0.7 to 1.0 eq.) per eq. of compound of formula 3 to obtain the compound of formula 4 ⁇ CI (said compound is a mixture of phosphorus imine salts and/or chlorophosphorous imine salts).
  • Suitable solvents are aromatic solvents such as benzene, xylene, mesitylene, or toluene
  • step d-2 of the reaction the reaction mixture of step d-1 is reacted with a solution of an alkaline hydroxide (preferably a sodium hydroxide solution), to obtain the compound of formula 4.
  • an alkaline hydroxide preferably a sodium hydroxide solution
  • step d-3 of the reaction the reaction mixture of step d-2 is reacted with methanesulfonic acid (preferably 0.9 - 1.5 eq.; particularly 1.0 - 1.2 eq.) to obtain the compound of formula 4 * mesylate.
  • the reaction is carried out at a reaction temperature from -5 to 60 0 C, preferably between 0 to 40 °C, in another embodiment preferably 0 to 10°C.
  • Suitable solvent systems for the crystallization of compound 4 * mesylate are aromatic solvents (notably toluene) and ketones (notably acetone) as well as mixtures thereof.
  • step d-3 compared to the prior art, are the following:
  • step e of the reaction commercially available methylamine is reacted with commercially available methyl (S)-mandelate to obtain the compound of formula 5 (e.g. 3.8 eq. methylamine, 30% in aqueous solution, at 0 to 10 0 C). After the reaction has been judged complete, excess methylamine may for example be distilled off at reduced pressure.
  • step f of the reaction the compound of formula 5 is reacted with p-toluene sulfonic acid chloride in the presence of a base such as N-ethyldiisopropylamine (e.g. 1.0 eq. p-toluene sulfonic acid chloride and 1.1 eq.
  • a base such as N-ethyldiisopropylamine
  • a base like aqueous sodium hydroxide may be used.
  • the solution is concentrated, cooled to -2 0 C and the precipitate is filtered.
  • toluene may be used in the above procedure and the solution is cooled to 0 to 10 0 C.
  • step g of the reaction the compound of formula 4 * HX, especially 4 * mesylate is hydrogenated in the presence of a chiral transfer hydrogenation catalyst, especially an optically active Noyori-type transfer hydrogenation catalyst); a reducing agent, especially a formic acid based reducing agent; and a solvent, to yield the compound of formula 7.
  • a chiral transfer hydrogenation catalyst especially an optically active Noyori-type transfer hydrogenation catalyst
  • a reducing agent especially a formic acid based reducing agent
  • solvent a solvent
  • Said catalysts or their precursors are commercially available, prepared beforehand, or prepared in situ, from a commercially available Ru, Ir and Rh complex (also known as precursor complex), and a commercially available chiral ligand, especially an optically active mono- ⁇ /-sulfonated ethan-1 ,2-diamine derived ligand using methods well known in the art.
  • the preferred chiral transfer hydrogenation catalyst of the invention is the optically active Noyori catalyst (R,R)-[p-((CH 3 ) 2 CH)-C 6 H 4 -CH 3 ]RuH(NH 2 -CHPh-CHPh-N-SO 2 -C 6 H 4 -p- CH 3 ), or a precursor thereof ⁇ such as (R,R)-[p-((CH 3 ) 2 CH)-C 6 H 4 -CH 3 ]RuCI(NH 2 -CHPh- CHPh-N-SO 2 -C 6 H 4 -P-CH 3 )J.
  • the amount of catalyst compared with the amount of substrate is preferably as low as possible. In practice for industrial production, molar substrate to catalyst ratio's are preferably at least 1000.
  • the transfer hydrogenation reaction is carried out at a temperature between -10 0 C and 100 0 C, preferably between 10°C and 75°C and more preferably between 15 and 35°C.
  • Particular solvents for the transfer hydrogenation reaction are water, methanol, DCM or any mixture thereof.
  • DCM is preferably used as solvent.
  • such combination may lead to the formation of a potentially genotoxic side product: chloromethyl-triethylammonium chloride.
  • the presence of said side product may require more laborious purification steps.
  • DCM may also cause formation of side products derived from its reaction with the amine of formula 7. Formation of DCM related side products may be avoided by using a mixture of methanol and water as solvent, preferably using sodium formate as reducing agent.
  • step g compared to the prior art (e.g. Uematsu et al. J. Am. Chem. Soc. 1996, 1 18, 4916-4917 and WO2005/1 18548), are the following:
  • the substrate 4 * HX, especially 4 * mesylate is used directly in the transfer hydrogenation reaction without prior free-basing of the imine. Thus, reduction of unit steps (free-basing step) is achieved.
  • step h of the reaction the compound of formula 7 is reacted with acetic acid, to obtain the compound of formula 7 * acetate.
  • the reaction is carried out in a suitable solvent, such as any aromatic solvent (such as benzene, toluene and/or xylene) or mixture of aromatic solvents and distillation fractions containing mainly heptane.
  • a suitable solvent such as any aromatic solvent (such as benzene, toluene and/or xylene) or mixture of aromatic solvents and distillation fractions containing mainly heptane.
  • toluene and pure heptane are used. More preferred is a 4 to 1 mixture of toluene and heptane.
  • the reaction is carried out at a reaction temperature between -10 to 55°C preferably between 0 and 20 0 C.
  • the reaction is carried out with 0.9 to 1.3 eq. of acetic acid, more preferred with 1.0 eq. of acetic acid.
  • Free basing is preferably performed with an aqueous solution of sodium hydroxide.
  • Suitable solvents are acetone, ethyl methyl ketone, tert.-butyl methyl ether, DCM, or MIBK, preferably MIBK.
  • the reaction is carried out at a reaction temperature between 0- 50 0 C, preferably between 15-25°C.
  • the coupling with the compound of formula 6 is carried out with 1.1-2.0 eq. (preferably 1.2 eq.) of compound of formula 6.
  • Appropriate bases are Li 2 CO 3 , Cs 2 CO 3 , the corresponding bicarbonates, caustic soda, potassium carbonate, and mixtures thereof. In a preferred embodiment, caustic soda is used in an amount of 0-2.2 eq.
  • the reaction is carried out at a reaction temperature between 30-120 0 C, preferably between 70-90 0 C.
  • the compound of formula I ⁇ CI is formed by reaction with 0.95-1.1 eq. (preferably 1.0 eq.) of aqueous hydrochloric acid.
  • Steps d-1 to d-3 Synthesis of 6,7-dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]- 3,4-dihydro-isoquinoline methanesulfonic acid (compound 4*mesylate)
  • the compound 3 is suspended in toluene and heated to 80 - 100 0 C. After addition of 1.5 eq. phosphorus oxychloride the mixture is heated for 6 hours to 80 - 100 0 C and then cooled within 3 hours to 20 0 C. The suspension is added to water while maintaining the pH of the aqueous layer during addition and subsequent stirring between 7-8 by addition of a sodium hydroxide solution. The mixture is stirred until all precipitate is dissolved. After phase separation the water is removed by azeotropic distillation. Then 1.0 eq. of methanesulfonic acid is added and the formed suspension stirred for some time.
  • parts of the solvent may be replaced by acetone, and the mixture is slowly cooled to 0 - 10 °C and stirred at this temperature for another couple of hours. After filtration the product is washed with toluene and dried in vacuo.
  • Step g Synthesis of (7S)-6,7-dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]- 1 ,2,3,4-tetrahydro-isoquinoline (compound 7)
  • Noyori catalyst prepared from (R 1 R)-TsDPEN (64g), dichloro-bis-(p-cymene)ruthenium(lll) (53.9 g) in acetonitrile (6 L), and addition of triethylamine (98 mL), followed by reflux (8O 0 C) for 1 hour, then cooling to RT ⁇ is added, followed by a mixture of triethylamine and formic acid (45 L) ⁇ prepared from formic acid (5 eq., 28.2 L) and triethylamine (2 eq.) at a temperature below 15°C ⁇ , and the mixture is stirred at 20 0 C for ca. 60 hours.
  • Step g DCM and formic acid are charged and cooled to 0-10 0 C. Triethylamine is dosed slowly to keep the temperature below 15°C. The resulting mixture is stirred for one hour at 20-25 0 C. 6,7-dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-isoquinoline methanesulfonic acid salt (compound 4 * CH 3 SO 3 H) is charged and the reaction mixture is degassed at reflux.
  • the solution is cooled to RT and the Noyori catalyst precursor ((R 1 R)- ⁇ -((CHa) 2 CH)-C 6 H 4 -CH 3 ]RuCI(NH 2 -CHPh-CHPh-N-SO 2 -C 6 H 4 -P-CH 3 )) is charged (typical conditions are for example: 3 eq. triethylamine/formic acid (1 :1 ); substrate to catalyst ratio: 1500:1 to 2000:1 ) under inert conditions.
  • the mixture (8-9 wt% substrate) is stirred for 15- 2Oh until full conversion is obtained (max. 2% remaining substrate, typically -5% N-formyl impurity, i.e.
  • Step h Solvent is switched from DCM to toluene and the concentration is adjusted to 12 wt%. Afterwards, heptane is added to target at 4:1 mixture of toluene to heptane, 9-10 wt%.
  • the product (7S)-6,7-dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]- 1 ,2,3,4-tetrahydro-isoquinoline acetic acid salt (compound 7 * CH 3 COOH) is precipitated by addition of 1eq. of concentrated acetic acid at 20 0 C. The resulting product suspension is stirred for 2-3 hours at 20°C, filtered off and washed with heptane. The wet product is dried under reduced pressure at 40°C. Isolated Yield: about 80%.
  • N-Formyl impurity typically ⁇ 5 area% of N-formyl impurity is formed. This impurity is well depleted during work up.
  • Step g 6,7-dimethoxy-1 -[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-isoquinoline methanesulfonic acid salt (compound 4XH 3 SO 3 H) (40 g) is added at RT to DCM (120 g), followed by formic acid (8 g, 2 eq.). The solution is cooled to 0-10 0 C. Triethylamine (22 g, 2.5 eq.) is dosed slowly to keep the temperature below 15°C. The resulting mixture is warmed up to 25-30°C and stirred for 10 minutes under vacuum (500 mbar) at 25-30°C.
  • the flask is charged with nitrogen and the Noyori catalyst precursor ((R,R)-[p-((CH 3 ) 2 CH)- C 6 H 4 -CH 3 ]RuCI(NH 2 -CHPh-CHPh-N-SO 2 -C 6 H 4 -P-CH 3 )) is charged (27 mg, substrate to catalyst ratio: 2000:1 ) as a solution in degassed DCM (0.5 ml_). The mixture is stirred at 25-30 0 C under reflux (450-550 mbar) until full conversion is obtained and then cooled to RT.
  • Noyori catalyst precursor ((R,R)-[p-((CH 3 ) 2 CH)- C 6 H 4 -CH 3 ]RuCI(NH 2 -CHPh-CHPh-N-SO 2 -C 6 H 4 -P-CH 3 )
  • Step h Solvent is switched from DCM to toluene and the concentration is adjusted.
  • the product ( • /S)-6,7-dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]-1 ,2,3,4-tetrahydro- isoquinoline acetic acid salt (compound 7 * CH 3 COOH) is precipitated by addition of concentrated acetic acid (4.96 g, 0.95 eq.) at 20-30 0 C. The resulting mixture is stirred for 1 hour at RT, then cooled to 10-20°C and further stirred. The product is filtered off and washed with toluene. The wet product is dried under reduced pressure at 40 0 C.
  • Step g 6,7-dimethoxy-1 -[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-isoquinoline methanesulfonic acid salt (compound 4 * CH 3 SO 3 H) (0.8 - 1.2 kg) is mixed at RT with methanol (1.0 - 2.1 kg), followed by water (0.85 - 2.0 kg) and formic acid sodium salt (0.18 - 0.75 kg).
  • the solution is warmed to 25-45°C and the Noyori catalyst precursor ((R,R)-[p- ((CHs) 2 CH)-C 6 H 4 -CH 3 ]RuCI(NH 2 -CHPh-CHPh-N-SO 2 -C 6 H 4 -P-CH 3 )) (0.46 - 1.37 g, substrate to catalyst ratio of 1000-3000) is charged as a solution in methanol (0.5 - 3 w%). The mixture is stirred at 25-45°C, optionally under reflux, for up to 72 hours (leading to a loss of methanol/water of 0-30%).
  • the Noyori catalyst precursor ((R,R)-[p- ((CHs) 2 CH)-C 6 H 4 -CH 3 ]RuCI(NH 2 -CHPh-CHPh-N-SO 2 -C 6 H 4 -P-CH 3 )
  • Step h The product (7S)-6,7-dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]- 1 ,2,3,4-tetrahydro-isoquinoline acetic acid salt (compound 7 * CH 3 COOH) is precipitated by addition of concentrated acetic acid (0.09 - 0.17 kg per kg 4XH 3 SO 3 H) at 0-40 0 C. The resulting mixture is stirred for 0 - 48 hours at RT, then cooled to 10 0 C and further stirred for 0 to 48 hours. The product is filtered off and washed with toluene (0 - 3 kg per kg 4XH 3 SO 3 H). The wet product is dried, optionally under reduced pressure, at 20-70X.
  • Step g 6,7-dimethoxy-1 -[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-isoquinoline methanesulfonic acid salt (compound 4XH 3 SO 3 H) (210 g) is mixed at RT with methanol (367 g), followed by a solution of formic acid sodium salt (94 g, 3 eq.) in water (262 g).
  • the solution is warmed to 35°C and the Noyori catalyst precursor ((R,R)-[p-((CH 3 ) 2 CH)- C 6 H 4 -CH 3 ]RuCI(NH 2 -CHPh-CHPh-N-SO 2 -C 6 H 4 -P-CH 3 )) is charged (144 mg, substrate to catalyst ratio: 2000:1 ) as a solution in methanol (10 ml_).
  • the mixture is stirred at 35°C under reflux (reduced pressure) until full conversion is obtained and a total of approximately 150 ml. of solvent has been distilled off. Then the mixture is cooled to RT.
  • Step h The product (7S)-6,7-dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]- 1 ,2,3,4-tetrahydro-isoquinoline acetic acid salt (compound 7XH 3 COOH) is precipitated by addition of concentrated acetic acid (27.3 g, 1 eq.) at 20-30X. The resulting mixture is stirred for 2 hour at RT, then cooled to 1OX and further stirred. The product is filtered off and washed with toluene. The wet product is dried under reduced pressure at 4OX.
  • step 3 To the organic phase of step 2 is added 1 eq. aqueous hydrochloric acid and then the water removed by azeotropic distillation in vacuo.
  • the compound I * HCI is obtained by crystallization from the organic phase of step 2 (MIBK) containing an adjusted amount of residual water (0.4 - 1.5%, e.g. 0.7%) without using 2-propanol at a temperature of above 40 0 C (e.g. about 65°C) using seeding crystals.
  • the product is isolated e.g. on an inverting bag centrifuge and dried in vacuo at 50 0 C.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention a pour objet un procédé pour la préparation du composé de formule 7, lequel procédé comprend : l'hydrogénation par transfert asymétrique du composé de formule 4 * HX : HX étant tel que décrit dans la description; en présence d'un catalyseur d'hydrogénation par transfert de type Noyori optiquement actif, avec un rapport du substrat au catalyseur supérieur à 100:1 équivalents molaires; d'un agent réducteur; et d'un solvant; pour obtenir le composé de formule 7.
PCT/IB2010/052962 2009-06-30 2010-06-29 Procédé pour la préparation d'un dérivé trisubstitué énantiomériquement pur de la 1,2,3,4-tétrahydroisoquinoline Ceased WO2011001373A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IBPCT/IB2009/052835 2009-06-30
IB2009052835 2009-06-30

Publications (1)

Publication Number Publication Date
WO2011001373A1 true WO2011001373A1 (fr) 2011-01-06

Family

ID=42646506

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2010/052962 Ceased WO2011001373A1 (fr) 2009-06-30 2010-06-29 Procédé pour la préparation d'un dérivé trisubstitué énantiomériquement pur de la 1,2,3,4-tétrahydroisoquinoline

Country Status (2)

Country Link
TW (1) TW201105635A (fr)
WO (1) WO2011001373A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000018708A1 (fr) * 1998-09-29 2000-04-06 Avecia Limited Hydrogenation par transfert
WO2003095426A1 (fr) * 2002-05-07 2003-11-20 Hye-Sook Yun-Choi Nouveaux enantiomeres de derives de tetrahydroisoquinoline et leurs sels pharmaceutiquement acceptables, preparations et compositions pharmaceutiques de ces derniers
WO2004085403A1 (fr) 2003-03-26 2004-10-07 Actelion Pharmaceuticals Ltd Derives de tetrahydro-isoquinolyl-acetamide destines a servir d'antagonistes des recepteurs d'orexine
WO2005118548A1 (fr) 2004-03-01 2005-12-15 Actelion Pharmaceuticals Ltd Derives de 1,2,3,4-tétrahydroisoquinoléine substitués
WO2009083903A1 (fr) 2007-12-28 2009-07-09 Actelion Pharmaceuticals Ltd Composé 3,4-dihydro-1h-isoquinoléine trisubstituée, méthode de préparation, et son utilisation
WO2009083899A2 (fr) 2007-12-28 2009-07-09 Actelion Pharmaceuticals Ltd Procédé de préparation d'un dérivé énantiomère trisubstitué de 3,4-dihydro-isoquinoléine

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000018708A1 (fr) * 1998-09-29 2000-04-06 Avecia Limited Hydrogenation par transfert
WO2003095426A1 (fr) * 2002-05-07 2003-11-20 Hye-Sook Yun-Choi Nouveaux enantiomeres de derives de tetrahydroisoquinoline et leurs sels pharmaceutiquement acceptables, preparations et compositions pharmaceutiques de ces derniers
WO2004085403A1 (fr) 2003-03-26 2004-10-07 Actelion Pharmaceuticals Ltd Derives de tetrahydro-isoquinolyl-acetamide destines a servir d'antagonistes des recepteurs d'orexine
WO2005118548A1 (fr) 2004-03-01 2005-12-15 Actelion Pharmaceuticals Ltd Derives de 1,2,3,4-tétrahydroisoquinoléine substitués
WO2009083903A1 (fr) 2007-12-28 2009-07-09 Actelion Pharmaceuticals Ltd Composé 3,4-dihydro-1h-isoquinoléine trisubstituée, méthode de préparation, et son utilisation
WO2009083899A2 (fr) 2007-12-28 2009-07-09 Actelion Pharmaceuticals Ltd Procédé de préparation d'un dérivé énantiomère trisubstitué de 3,4-dihydro-isoquinoléine

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
NAT. MED., vol. 13, 2007, pages 150 - 155
S. GLADIALI; E. ALBERICO, CHEM. SOC. REV., vol. 35, 2006, pages 226
T. IKARIYA; A.J. BLACKER, ACCOUNTS CHEM. RES., vol. 40, 2007, pages 1300
UEMATSU ET AL., J. AM. CHEM. SOC., vol. 118, 1996, pages 4916 - 4917
W. BARATTA ET AL., CHEM. EUR. J., vol. 15, 2009, pages 726
WANG ET AL., CHEMISTRY: AN ASIAN JOURNAL, vol. 3, 2008, pages 1750

Also Published As

Publication number Publication date
TW201105635A (en) 2011-02-16

Similar Documents

Publication Publication Date Title
CN112062767B (zh) 一种卢美哌隆的制备方法及其中间体
DK3107900T3 (en) 5-BENZYLISOQUINOLINE DERIVATIVES FOR TREATING CARDIOVASCULAR DISEASES
EP3812371B1 (fr) Procédé de préparation de brivaracétam
KR101416595B1 (ko) 이바브라딘 및 이의 약제학적으로 허용되는 산과의 부가염을 합성하는 방법
EP2227454B1 (fr) Procédé de préparation d'un dérivé énantiomère trisubstitué de 3,4-dihydro-isoquinoléine
MX2011001563A (es) Procedimiento para la preparacion de compuestos de piperazina sustituidos con cloalquilo.
US20190112273A1 (en) An improved process for the preparation of butorphanol tartrate
US8247560B2 (en) Trisubstituted 3,4-dihydro-1H-isoquinolin compound, process for its preparation, and its use
CA2894826C (fr) Synthese asymetrique d'un pyrrolidine-2-carboxamide substitue
WO2011001373A1 (fr) Procédé pour la préparation d'un dérivé trisubstitué énantiomériquement pur de la 1,2,3,4-tétrahydroisoquinoline
KR20140010900A (ko) （７ｓ）－１－（３，４－디메톡시바이시클로［４．２．０］옥타－１，３，５－트리엔－７－일) ｎ－메틸 메탄아민의 효소적 합성방법, 및 이바브라딘 및 이의 염의 합성에 대한 적용
US8148527B1 (en) Resolution of 1-(4-methoxybenzyl)-octahydro-isoquinoline
CN1989097A (zh) 用于制备非对映异构体富集的化合物的方法
WO1998030540A1 (fr) Synthese efficace d'un mediateur chiral
TW202606686A (zh) Protac嵌合化合物及其合成中間體的製備方法
HK40049416B (en) A process for preparing brivaracetam
HK40049416A (en) A process for preparing brivaracetam
US20190194122A1 (en) Processes for the Preparation of Dasotraline and Intermediates Thereof
Fuchter 7.1 Betti Reaction

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10740744

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10740744

Country of ref document: EP

Kind code of ref document: A1