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WO2014140318A1 - Procédé amélioré pour réactions de transfert d'acyle - Google Patents

Procédé amélioré pour réactions de transfert d'acyle Download PDF

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Publication number
WO2014140318A1
WO2014140318A1 PCT/EP2014/055174 EP2014055174W WO2014140318A1 WO 2014140318 A1 WO2014140318 A1 WO 2014140318A1 EP 2014055174 W EP2014055174 W EP 2014055174W WO 2014140318 A1 WO2014140318 A1 WO 2014140318A1
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preparation
alkyl group
ester
methyl
thienyl
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Luisa ZANGIROLAMI
Monica Donnola
Lavinia CICIONE
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Khs Pharma Holding GmbH
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Khs Pharma Holding GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the present invention relates to a novel process for the preparation of esters like Aclidinium, Atropin, Glycopyrronium, Tiotropium, Trospium and their respective precursors and derivatives, based on direct acyl transfer reactions.
  • Tiotropium is the international non-proprietary name (INN) for the quaternary ammonium derivative of di-(2- thienyl)glycolic acid Scopine ester with the chemical name (1 a,2 ,4 ,7 )-7-[(hydroxy-di(2-thienyl)acetyl)oxy]-9,9-dimethyl-3-oxa-9- azoniatricyclo[3.3.1 .0 2,4 ]nonane and is a highly effective anticholinergic agent with a specificity for muscarinic receptors.
  • INN international non-proprietary name
  • Tiotropium bromide currently marketed under the brand name SPIRIVA® is presently approved for the treatment of respiratory disorders, such as asthma or chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.
  • COPD chronic obstructive pulmonary disease
  • Scopine base also referred to as Scopine
  • Scopine ester also referred to as Scopine Dithienylglycolate
  • Scopine Dithienylglycolate has to be isolated and purified before quaternization, leading to further reduction of the Tiotropium yield.
  • Scopolamine or its salts into Scopine Dithienylglycolate and/or Tiotropium halide salts can be performed in a single reaction step by the use of an acyl transfer agent.
  • esters including, but not limited to Aclidinium, Atropin, Glycopyrronium, Tiotropium, Trospium and their respective precursors and derivatives, in particular their salts, involving the reaction of an acyl transfer agent that is capable to promote the transfer of an acyl group, is described hereinafter.
  • R1 is pyrrolidine or a azapolycycle based compound, optionally substituted
  • R2 is a Ci-C 4 -alkyl group or 1 -phenyl 2-hydroxy ethyl
  • R3 is a Ci-C 4 -alkyl group, preferably methyl
  • R4 is selected from hydrogen, aryl or heteroaryl
  • R5 is selected from aryl or heteroaryl
  • n 0 or 1
  • the acyl transfer agent may be chosen among agents such as: - Azapolycycles, preferably cyclic and bicyclic guanidines having ring sizes of 5 to 8 atoms, optionally substituted with a C1-C10 alkyl substituent on one of the non-bridgehead nitrogen atoms such as tetramethylguanidine, pentamethylguanidine or 1 ,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD)
  • agents such as: - Azapolycycles, preferably cyclic and bicyclic guanidines having ring sizes of 5 to 8 atoms, optionally substituted with a C1-C10 alkyl substituent on one of the non-bridgehead nitrogen atoms such as tetramethylguanidine, pentamethylguanidine or 1 ,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD)
  • DMAP Dimethylaminopyridine
  • Isothiourea-based organocatalysts such as tetramisole and benzotetramisole - Azoles such as imidazole, pyrazole, 1 ,2,3-triazole, 1 ,2,4-triazole, tetrazole and the areno-fused and hetareno-fused derivatives of these heterocycles;
  • Tin derivatives such distannoxanes, dialkyltindicarboxylat.es, dialkyltin oxides, dialkyltin dihalides, hexaalkyldistannoxanes, trialkyltin halides, trialkyltin ethers and trialkyltin carboxylates;
  • Hydrolytic enzymes such as lipases and protease and phosphoesterases
  • Inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid and phosphoric acids
  • Sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid and camphorsulfonic acid
  • acyl transfer agents Any combination of the acyl transfer agents listed above Preferred acyl transfer agents are those operating in neutral or slightly basic/slightly acidic conditions.
  • acyl transfer agents are azapolycycles, preferably 1 ,5,7- Triazabicyclo[4.4.0]dec-5-ene (TBD).
  • TBD Triazabicyclo[4.4.0]dec-5-ene
  • Scopine Dithienylglycolate obtained by this process may be converted into Tiotropium salt involving but not limited to its quaternary ammonium salts, I methods known in the art, described in EP 0 418 716.
  • the improved process may also be applied for the preparation of Aclidinium ((3R)- [(2-Hydroxy-2,2-di-2-thienylacetyl)oxy]-1 -(3-phenoxypropyl)-1 - azoniabicyclo[2.2.2]octane) halide salts, preferably Aclidinium Bromide.
  • the improved process may be applied for the preparation of the Aclidinium precursor (R)-Quinuclidin-3-yl 2-hydroxy-2,2-di(thiophen-2-yl)acetate.
  • (R)-Quinuclidin-3-yl 2-hydroxy-2,2-di(thiophen-2-yl)acetate obtained by this process may be converted into an Aclidinium halide salt by processes known in the art, e.g. as described in WO 2001/0041 18.
  • the improved process may also be applied for the preparation of Glycopyrronium (3- [[(2R)-2-cyclopentyl-2-hydroxy- 2-phenylacetyl]oxy]-1 ,1 -dimethyl- pyrrolidinium (3S)) and 3-[[(2S)-2-cyclopentyl-2-hydroxy-2-phenylacetyl]oxy]-1 ,1 -dimethyl-pyrrolidinium (3R)) halide salts, preferably Glycopyrronium bromide.
  • the improved process may be applied for the preparation of the Glycopyrronium precursor 3-[[-2-cyclopentyl-2-hydroxy- 2-phenylacetyl]oxy]-1 methyl- pyrrolidinium.
  • the Ester ⁇ obtained by this process may be converted into an Glycopyrronium halide salt by processes known in the art, i.e. crystallization, as described in US 2,956,062.
  • the improved process may also be applied for the preparation of Atropin ((8-methyl- 8-azabicyclo[3.2.1 ]oct-3-yl) 3-hydroxy-2-phenylpropanoate).
  • Scopine base and Scopine methyl halide salts obtained by the process described above may be converted into Tiotropium or its derivatives by methods known in the art, e.g. as described in EP 0 418 716 or WO 2006/ 021559, respectively.
  • Scopolamine and its quaternary ammonium salts may be obtained using commercially available sources or may be synthesized by using methods well known in the art.
  • esters I and esters II may be obtained by using commercially available sources or may be synthesized by using methods well known in the art.
  • Scopolamine methyl halide salt may derive from any commonly used halide, most preferably bromine.
  • the counterion (X " ) may derive from any commonly used halide, most preferably bromine. In the case of Trospium halide salt synthesis, the counterion (X " ) may derive from any commonly used halide, most preferably chlorine.
  • the ester of Di-(2-thienyl)glycolic acid is an alkyl eater, more preferably one selected from the methyl ester, ethyl ester, n-propyl ester or the isopropyl ester.
  • the most preferred ester is Di-(2-thienyl)glycolic acid methyl ester.
  • the solvent involved in the process for the preparation of Tiotropium, Scopine Dithienylglycolate or Scopine free base or their respective derivatives is selected from the group consisting of aromatic hydrocarbons, sulfoxides, alcohols, nitriles, amides and mixtures thereof.
  • the solvent involved in the process for the preparation of Atropin, Glycopyrronium, Aclidinium, Trospium and their respective derivatives is selected from the group consisting of aromatic hydrocarbons, sulfoxides, alcohols, nitriles, amides and mixtures thereof.
  • a preferred aromatic hydrocarbon is toluene.
  • a preferred sulfoxide is dimethylsulfoxide (DMSO).
  • a preferred alcohol is n-butanol.
  • a preferred nitrile is acetonitrile.
  • a preferred amide is dimethylformamide (DMF).
  • the amount of acyl transfer agent is from 1 .2 to 2.5 equivalents, preferably from 1 .5 to 2.0 equivalents, compared to the molar quantity of Scopolamine.
  • the amount of Di-(2- thienyl)glycolic acid ester is from 0.8 to 1 .1 equivalents, preferable from 0.9 to 1 .0 equivalents, compared to the molar quantity of Scopolamine.
  • the preferred solvent is toluene.
  • the amount of acyl transfer agent is from 0.8 to 1 .5 equivalents, preferably from 1 .0 to 1 .2 equivalents, compared to the molar quantity of the Scopolamine N-methyl halide salt.
  • the amount of Di-(2-thienyl)glycolic acid ester is from 0.8 to 1 .1 equivalents, preferable from 0.9 to 1 .0 equivalents, compared to the molar quantity of the Scopolamine N-methyl halide salt.
  • the preferred solvent is DMSO.
  • the preferred Tiotropium halide salt is the bromine salt, resulting from Scopolamine N-methyl bromide as the preferred Scopolamine methyl halide.
  • the amount of acyl transfer agent is from 1 .0 to 1 .2 equivalents, compared to the molar quantity of Scopolamine.
  • the preferred solvent is toluene.
  • the preferred corresponding Scopolamine derivatives are Scopolamine base (resulting in the final product Scopine base) or Scopolamine N-methyl bromide (resulting in the final product Scopine methyl bromide), respectively.
  • the preferred amount of acyl transfer agent is from 1 .0 to 2.0 equivalents, compared to the molar quantity of (R)-Quinuclidin-3-yl acetate.
  • the preferred solvent is toluene.
  • Scopine (or corresponding quaternary ammonium derivatives) does not have to be isolated, avoiding the well known losses in its recovery described above.
  • neutral reaction conditions can be maintained during the whole process by the use of acyl transfer agents, resulting in a further reduction of the formation of byproducts such as Scopoline and its derivatives which are generated by using acid and/or basic conditions.
  • the present process requires fewer synthetic steps, milder reaction conditions (up to ambient temperature and pressure) resulting in reduced energy consumption, higher total yields, selectivity and purity of the desired reaction products and again less formation of byproducts.
  • the acyl transfer agent is only applied in stoichiometric or even sub- stoichiometric amounts, not only reagent costs and the amount of generated waste are reduced compared to prior art processes, but also the isolation procedures are simplified.
  • the acyl transfer reaction is very flexible since it can be run with both scopolamine and derivatives thereof, giving a direct access to Scopine and its derivatives, Di-(2- thienyl)glycolic acid Scopine alkyl esters as well as Tiotropium and its derivatives.
  • the acyl transfer reaction may be applied to a broad range of other esters as indicated above.
  • Scopolamine free base (1 .50 g; 4,94 mmol, 1 eq) and TBD (0.207 g; 7.42 mmol, 1 .5 eq) were dissolved in 2 mL of toluene at 30 °C. After stirring for 24 h at 30°C, Methyl Dithienylglycolate (1 .26 g; 4,94 mmol, 1 eq) was added to the reaction mixture. After stirring for an additional 2.5 h at 30°C under nitrogen atmosphere, a 10% solution of citric acid was added. After layer separation, the aqueous layer was washed with CH2CI2 and then basified with 10% Na2CO3 solution until a pH of 8.5 was reached.
  • Scopolamine methyl bromide (0.100 g; 0.25 mmol, 1 eq) and TBD (0.035 g; 0.25 mmol, 1 eq) were dissolved in 1 mL of dimethylsulfoxide at 25 °C under magnetic stirring; after 24 h Methyl Dithienylglycolate (0.063 g; 0.25 mmol, 1 eq) was added and the reaction mixture was stirred at 25 °C for additional 2h. The solvent was distilled off to yield 0.190g of a residue with a Tiotropium bromide assay of 14% (0.017g).
  • Preparative example 3 Preparation of Scopine base
  • Scopolamine (0.100 g; 0.33 mmol) and TBD (0.046 g; 0.40 mmol, 1 .2 eq) were charged into a round bottom flask (5 mL) and were dissolved in 0.7 mL of toluene at 25 °C. After 48 h under magnetic stirring, a suspension is formed and the reaction was found to be complete. After separating from the solid by centrifugation and subsequent concentrating under vacuum, 0.051 g (99.3%) of Scopine free base was obtained.
  • Preparative example 4 Preparation of (R)-Quinuclidin-3-yl 2-hvdroxy-2,2- di(thiophen-2-yl)acetate i. Preparation of (R)-Quinuclidin-3-yl acetate
  • Acetyl chloride (2.5 ml_, 4.5 eq) was added to a solution of (R) Quinuclidinol (1 .0 g, 1 eq) in CHCI3 at 0 °C. The formed suspension was stirred at 25°C for 30 minutes, then the mixture of reaction was heated at 50 °C under magnetic stirring. After 30 minutes a solution formed. After adding Na 2 CO 3 and H 2 O and subsequent separation of the phases, the aqueous phase was extracted with EtOAC (3x 15 ml_) and solvent was removed at reduced pressure to yield 0,95g of (R)-Quinuclidin-3-yl acetate. ii.
  • R1 is pyrrolidine or a azapolycycle, optionally substituted
  • R2 is a C1 -C4-alkyl group or 1 -phenyl 2-hydroxy ethyl
  • R3 is a C1 -C4-alkyl group, preferably methyl
  • R4 is selected from hydrogen, aryl or heteroaryl
  • R5 is selected from aryl or heteroaryl
  • n 0 or 1
  • the present invention also provides a process for the preparation of Scopine Dithienylglycolate wherein
  • R1 is 9-Methyl-3-oxa-9-azoniatricyclo[3.3.1 .0 2,4 ]nonan-7-yl
  • R2 is a C1 -C4-alkyl group or 1 -phenyl 2-hydroxy ethyl, preferably 1 -phenyl 2-Hydroxy ethyl
  • R3 is a C1 -C4-alkyl group, preferably methyl
  • R4 and R5 are 2-thienyl
  • n 0.
  • the present invention also provides a process for the preparation of a Tiotropium halide salt comprising the step of preparing Scopine Dithienylglycolate according to the process described above:
  • Scopine Dithienylglycolate produced according to a process of the invention for the preparation of a Tiotropium halide salt.
  • the present invention also provides a process for the preparation of a Tiotropium halide salt wherein
  • R1 is a 9,9-Dimethyl-3-oxa-9-azoniatricyclo[3.3.1 .0 2,4 ]nonan-7-yl halide salt
  • R2 is a C1 -C4-alkyl group or 1 -phenyl 2-hydroxy ethyl, preferably 1 -phenyl 2- hydroxy ethyl
  • R3 is a C1 -C4-alkyl group, preferably methyl
  • R4 and R5 are 2-thienyl
  • the present invention also provides a process for the preparation of (R)-Quinuclidin- 3-yl 2-hydroxy-2,2-di(thiophen-2-yl)acetate wherein
  • R1 is 1 -Azabicyclo[2.2.2]octan-3-yl
  • R2 is a C1 -C4-alkyl group, preferably methyl
  • R3 is a C1 -C4-alkyl group, preferably methyl
  • R4 and R5 are 2-thienyl
  • n 0.
  • the present invention also provides a process for the preparation of an Aclidinium halide salt comprising the step of preparing (R)-Quinuclidin-3-yl 2-hydroxy-2,2- di(thiophen-2-yl)acetate as described above.
  • the processes above may further be characterized in that Ester II selected from the group consisting of Di-(2-thienyl)glycolic acid methyl ester, the Di-(2-thienyl)glycolic acid ethyl ester or Di-(2-thienyl)glycolic acid propyl ester, preferably Di-(2- thienyl)glycolic acid methyl ester.
  • the present invention also provides a process for the preparation of 3-[[-2- cyclopentyl-2-hydroxy- 2-phenylacetyl]oxy]-1 methyl- pyrrolidinium wherein
  • R1 is 1 -Methylpyrrolidinium-3-yl halide salt
  • R2 is a C1 -C4-alkyl group, preferably methyl
  • R3 is a C1 -C4-alkyl group, preferably methyl
  • R4 is phenyl
  • R5 is cyclopentyl
  • n 0.
  • the present invention also provides a process for the preparation of a Glycopyrronium halide salt comprising the step of preparing 3-[[-2-cyclopentyl-2- hydroxy- 2-phenylacetyl]oxy]-1 methyl- pyrrolidinium as described above.
  • a process for the preparation of a Glycopyrronium halide salt comprising the step of preparing 3-[[-2-cyclopentyl-2- hydroxy- 2-phenylacetyl]oxy]-1 methyl- pyrrolidinium as described above.
  • Use of 3-[[- 2-cyclopentyl-2-hydroxy- 2-phenylacetyl]oxy]-1 methyl- pyrrolidinium produced according to a process of the invention for the preparation of a Glycopyrronium halide salt.
  • the present invention also provides a process for the preparation of a Glycopyrronium halide salt according wherein
  • R1 is a 1 ,1 -Dimethylpyrrolidinium-3-yl halide salt
  • R2 is a C1 -C4-alkyl group, preferably methyl
  • R3 is a C1 -C4-alkyl group, preferably methyl
  • R4 is phenyl
  • R5 is cyclopentyl
  • n 0.
  • the present invention also provides a process for the preparation of Atropin wherein R1 is 8-Methylazabicyclo[3.2.1 ]octan-3-yl
  • R2 is a C1 -C4-alkyl group, preferably methyl
  • R3 is a C1 -C4-alkyl group, preferably methyl
  • R4 is hydrogen
  • R5 is phenyl
  • n 1 .
  • the present invention also provides a process for the preparation of a Trospium halide salt wherein
  • R1 is Spiro[8-azoniabicyclo[3.2.1 ]octane-8,1 '-pyrrolidinium]-3-yl halide salt
  • R2 is a C1 -C4-alkyl group, preferably methyl
  • R3 is a C1 -C4-alkyl group, preferably methyl
  • R4 and R5 are phenyl
  • n 0
  • acyl transfer agent is a azapolycycle, preferably 1 ,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD).
  • the present invention also provides a process for the preparation of a Tiotropium salt comprising the step of reacting Scopine with an ester of Di-(2-thienyl)glycolic acid, characterized in that Scopine or one of its quaternary ammonium salts is prepared from Scopolamine in the presence of an acyl transfer agent, preferably 1 ,5,7- Triazabicyclo[4.4.0]dec-5-ene.
  • the present invention also provides a process for the preparation of Scopine Dithienylglycolate comprising the step of reacting Scopolamine with Di-(2- thienyl)glycolic acid methyl ester in the presence of an acyl transfer agent, preferably 1 ,5,7-Triazabicyclo[4.4.0]dec-5-ene.
  • the present invention provides a process for the preparation of Scopine Dithienylglycolate or a Tiotropium salt comprising the step of reacting Scopolamine or any of its methyl halide salts with an ester of Di-(2-thienyl)glycolic acid in the presence of an acyl transfer agent.
  • acyl transfer agent is 1 ,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD).
  • ester of ester of Di-(2- thienyl)glycolic acid is one of the methyl ester, the ethyl ester or the propyl ester, preferably Di-(2-thienyl)glycolic acid methyl ester.
  • the solvent is selected from a group consisting of aromatic hydrocarbons such as toluene, sulfoxides such as dimethylsulfoxide (DMSO), nitriles such as acetonitrile, amides such as dimethylformamide (DMF), alcohols such as n-butanol and mixtures thereof.
  • aromatic hydrocarbons such as toluene
  • sulfoxides such as dimethylsulfoxide (DMSO)
  • nitriles such as acetonitrile
  • amides such as dimethylformamide (DMF)
  • alcohols such as n-butanol and mixtures thereof.
  • the process may be further characterized in that the amount of acyl transfer agent is from 0.8 to 1 .5 equivalents, preferably from 1 .0 to 1 .2 equivalents, compared to the molar quantity of the corresponding Scopolamine methyl halide salt.
  • the process for the preparation of a Tiotropium halide salt above may be further characterized in that the amount of Di-(2-thienyl)glycolic acid ester is from 0.8 to 1 .1 equivalents, preferably from 0.9 to 1 .0 equivalents, compared to the molar quantity of the Scopolamine methyl halide salt.
  • the process for the preparation of a Tiotropium halide salt above may be further characterized in that the reaction is carried out in DMSO as the solvent.
  • the process for the preparation of a Tiotropium halide salt above may be further characterized in that the Tiotropium salt is the bromide salt that is prepared from Scopolamine methyl bromide.
  • the process may be further characterized in that in that the amount of acyl transfer agent is from 1 .2 to 2.5 equivalents, preferably from 1 .5 to 2.0 equivalents, compared to the molar quantity of Scopolamine.
  • the process for the preparation of Scopine Dithienylglycolate above may be further characterized in that the amount of Di-(2-thienyl)glycolic acid ester is from 0.8 to 1 .1 equivalents, preferably from 0.9 to 1 .0 equivalents, compared to the molar quantity of Scopolamine.
  • the present invention also provides a process for the preparation of Scopine Base, comprising the step of reacting of Scopolamine in the presence of an acyl transfer agent.
  • the process for the preparation of Scopine Base above may be further characterized in that the amount of acyl transfer agent is from 1 .0 to 1 .2 equivalents, compared to the molar quantity of Scopolamine.
  • the process may be further characterized in that the reaction is carried out in toluene as the solvent.
  • an acyl transfer agent preferably 1 ,5,7-Triazabicyclo[4.4.0]dec-5-ene.
  • the present invention also provides a process for the preparation of a Tiotropium salt comprising the step of reacting Scopine with an ester of Di-(2-thienyl)glycolic acid, characterized in that Scopine or one of its quaternary ammonium salts is prepared from Scopolamine in the presence of an acyl transfer agent, preferably 1 ,5,7- Triazabicyclo[4.4.0]dec-5-ene.
  • the present invention also provides a process for the preparation of a Tiotropium salt comprising the step of preparing Scopine Dithienylglycolate by reacting Scopolamine with an ester of Di-(2-thienyl)glycolic acid in the presence of an acyl transfer agent, preferably 1 ,5,7-Triazabicyclo[4.4.0]dec-5-ene.
  • an acyl transfer agent preferably 1 ,5,7-Triazabicyclo[4.4.0]dec-5-ene.

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  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne un nouveau procédé pour préparer des esters du type aclidinium, atropine, glycopyrroniunn, tiotropium, prospium et leurs précurseurs et dérivés respectifs en fonction des réactions de transfert d'acyle.
PCT/EP2014/055174 2013-03-14 2014-03-14 Procédé amélioré pour réactions de transfert d'acyle Ceased WO2014140318A1 (fr)

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EP13001306.3 2013-03-14
EP13001306 2013-03-14

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WO2014140318A1 true WO2014140318A1 (fr) 2014-09-18

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