TITLE

Improved process for acyl transfer reactions

DESCRIPTION OF THE INVENTION 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. 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.

A process for the preparation of Tiotropium and its salts was first reported in EP 0 418 716.

On a commercial scale, access to Tiotropium is generally based on a process involving three separate reaction steps: i) Reduction of commercially available Scopolamine or Scopolamine salts to

Scopine base (also referred to as Scopine);

ii) Reaction of Scopine base with Hydroxy-di-thiophen-2-yl-acetic acid methyl ester (Methyl di-(2-thienyl)glycolate) to form Di-(2- thienyl)glycolic acid

Scopine ester (also referred to as Scopine Dithienylglycolate);

iii) Quaternarization of the resulting Scopine Dithienylglycolate with alkylating agents to give the desired Tiotropium salt. Several drawbacks are related with this process: i) The reduction of Scopolamine or Scopolamine salts to Scopine base requires a huge excess up to 6 equivalents of sodium borohydride (NaBH ₄ ) resulting in the formation of high amounts of inorganic salts that have to be removed (see WO 2008/008376).

Since the recovery of Scopine base from the reaction mixture is plagued by solubility issues, the reaction proceeds with only low yields around 50% (see EP 1 626 970).

Most importantly, this process results in the formation of significant amounts of Scopoline, a rearrangement product of Scopine which originates from an intramolecular attack of the hydroxyl group on the epoxide ring, occurring under basic as well as acidic conditions, (see J. Meinwald et al., JACS 59, 665 (1957)).

The reaction of Scopine with methyl di-(2-thienyl)glycolate is usually performed under drastic conditions, i.e. strongly basic catalysts like metal alkoxides and at high temperatures (>80 °C). Besides the challenges that arise from the handling of hazardous materials like metal alkoxides that are generated in situ from sodium metal or strong sodium bases, sodium methylate forces the epoxide ring to open, leading to additional formation of Scopoline and corresponding byproducts. iii) Finally, Scopine Dithienylglycolate has to be isolated and purified before quaternization, leading to further reduction of the Tiotropium yield.

It has now been found that the conversion of 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.

In addition, it has been found that the reaction of Scopolamine or its derivatives with an acyl transfer agent under similar conditions as indicated above, but without addition of a di-(2-thienyl)glycolic acid ester, leads to Scopine or its corresponding derivatives with excellent yield and high purity. It has also been found that the acyl transfer reactions are not limited to reactions of Scopolamine or its derivatives with Methyl di-(2-thienyl)glycolate, but can be applied to a broader range of compounds, e.g. the reaction of (R)-Quinuclidin-3-yl acetate (Acetyl quinuclidinol) with Methyl di-(2-thienyl)glycolate, yielding (R)-Quinuclidin-3-yl 2-hydroxy-2,2-di(thiophen-2-yl)acetate, a key intermediate for the synthesis of Aclidinium. Other examples include the preparation of compounds like Atropin, Glycopyrronium, Trospium and their respective precursors.

Accordingly, a process for the preparation of 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.

In general terms, the process for the acyl transfer reaction of two esters in the presence of an acyl transfer agent capable to promote the transfer of an acyl group may be described as follows:

Ester I Ester II Ester I ^' Ester II ^' wherein

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 is 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)

- Amidines such as 1 ,5-Diazobicyclo-. [4.3.0]non-5-en, amarine and isoamarine;

- Pyridines such as 4-dialkylaminopyridines, 2-hydroxypyridines, pyridine N- oxides, preferably Dimethylaminopyridine (DMAP)

- Tertiary bicyclic diamines such as 1 ,4-Diazabicyclo[2.2.2]octane (DABCO)

- 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;

- Metal alkoxides, derived from alkaline and alkaline-earth metals.

- B(OR)3 (where R = H, C1-C20 linear or branched alkyls, aryl, hetaryl and any combination of them);

- Tin derivatives such distannoxanes, dialkyltindicarboxylat.es, dialkyltin oxides, dialkyltin dihalides, hexaalkyldistannoxanes, trialkyltin halides, trialkyltin ethers and trialkyltin carboxylates;

- N-heterocyclic carbenes;

- Thiourea-based organocatalysts;

- Cyanides such trial kylsilyl cyanides and diethoxyphosphoryl cyanides

- Titanium(IV)alkoxides, Zirconium(IV)alkoxides, Hafnium(IV)alkoxides

- 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

- Ion-exchange resins

- Any combination of the acyl transfer agents listed above Preferred acyl transfer agents are those operating in neutral or slightly basic/slightly acidic conditions.

The most preferred acyl transfer agents are azapolycycles, preferably 1 ,5,7- Triazabicyclo[4.4.0]dec-5-ene (TBD). As regards the preparation of Scopine Dithienylglycolate, the process for the reaction of Scopolamine with esters of Di-(2-thienyl)glycolic acid in the presence of an acyl transfer agent capable to promote the transfer of an acyl group can be described as follows:

Ester I Ester II Ester Γ Ester wherein R ₃ is a Ci-C ₄ -alkyl group, preferably methyl.

The 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.

As regards the direct preparation of Tiotropium halide salts, the process involving the reaction of a Scopolamine methyl halide salt with esters of Di-(2-thienyl)glycolic acid in the presence of an acyl transfer agent capable to promote the transfer of an acyl group can be described as follows:

Ester I Ester II Ester I ^' Ester II ^' wherein R ₃ is a Ci-C ₄ -alkyl group, preferably methyl.

As regards the preparation of Scopine and its derivatives, the process involving the reaction of a Scopolamine or any of methyl halide salts with an acyl transfer agent capable to promote the transfer of an acyl group can be described as follows:

Scopolamine base

Scopolamine N- Scopine methyl

methyl halide salt halide salt

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. In particular, 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.

As regards the preparation of (R)-Quinuclidin-3-yl 2-hydroxy-2,2-di(thiophen-2- yl)acetate, the process for the reaction of (R)-Quinuclidin-3-yl acetate with esters of Di-(2-thienyl)glycolic acid in the presence of an acyl transfer agent capable to promote the transfer of an acyl group can be described as follows:

Ester I Ester II Ester I ^' Ester II ^' wherein R ₂ and R3 are, independently from each other, a Ci-C ₄ -alkyl group, preferably methyl.

(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.

In particular, the improved process may be applied for the preparation of the Glycopyrronium precursor 3-[[-2-cyclopentyl-2-hydroxy- 2-phenylacetyl]oxy]-1 methyl- pyrrolidinium.

As regards the preparation of a Glycopyrronium halide salt or the intermediate 3-[[-2- cyclopentyl-2-hydroxy- 2-phenylacetyl]oxy]-1 methyl- pyrrolidinium, the reactions in the presence of an acyl transfer agent capable to promote the transfer of an acyl group may be described as follows: a) Preparation of the intermediate 3-[[-2-cyclopentyl-2-hydroxy- 2- phenylacetyl]oxy]-1 methyl- pyrrolidinium

Ester I Ester II Ester I ^' Ester II ^' wherein R ₂ and Rs are, independently from each other, a Ci-C ₄ -alkyl group, preferably methyl. 3-[[-2-cyclopentyl-2-hydroxy- 2-phenylacetyl]oxy]-1 methyl- pyrrolidinium obtained by this process may be converted into an Glycopyrronium halide salt processes known in the art, e.g. as described in US 2,956,062. b) Direct preparation of a Glycopyrronium halide salt

Ester I Ester II Ester I ^' Ester II ^' wherein R ₂ and R3 are, independently from each other, a Ci-C ₄ -alkyl group, preferably methyl.

The Ester Γ 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).

As regards the preparation of Atropin, the reaction in the presence of an acyl transfer agent capable to promote the transfer of an acyl group may be described as follows:

Ester I Ester II Ester I ^' Ester II ^' wherein R ₂ and R3 are, independently from each other, a Ci-C ₄ -alkyl group, preferably methyl. The improved process may also be applied for the preparation of Trospium (3-[(2- Hydroxy-2,2-diphenylacetyl)oxy]-spiro[8-azoniabicyclo[3.2.1 ]octane-8,1 '- pyrrolidinium]) halide salts, preferably Trospium chloride.

As regards the preparation of Trospium halide salts, the reaction in the presence of an acyl transfer agent capable to promote the transfer of an acyl group may be described as follows:

Ester I Ester II Ester I ^' Ester II ^' wherein R ₂ and R3 are, independently from each other, a Ci-C ₄ -alkyl group, preferably methyl.

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.

All other 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.

The counter ion of Scopolamine methyl halide salt (X ^" ) may derive from any commonly used halide, most preferably bromine.

In the case of Glycopyrronium halide salt synthesis, 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.

Preferably, 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).

As regards the preparation of Scopine Dithienylglycolate from Scopolamine, 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.

As regards the preparation of Tiotropium halide salts from Scopolamine N-methyl halide salts, 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.

As regards the preparation of Scopine or its methyl halide salts, 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. As regards the reaction of (R)-Quinuclidin-3-yl acetate with esters of Di-(2- thienyl)glycolic acid to yield (R)-Quinuclidin-3-yl 2-hydroxy-2,2-di(thiophen-2- yl)acetate, 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. The improved processes described above exhibit several advantages over the methods known in the art:

By the direct conversion from Scopolamine or its derivatives with acyl transfer agent into Scopine Dithienylglycolate or Tiotropium and its derivatives, Scopine (or corresponding quaternary ammonium derivatives) does not have to be isolated, avoiding the well known losses in its recovery described above. In addition, 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.

Furthermore, 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.

Since 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. Finally, 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. In addition, the acyl transfer reaction may be applied to a broad range of other esters as indicated above.

Preparative example 1 - Preparation of Scopine Dithienylqlvcolate

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. The aqueous layer was again extracted with CH2CI2. The collected organic layers were then washed with a 10% solution of Na2CO3 and water. Finally, the solvent was distilled off to obtain 0.765 g of Scopine Dithienylglycolate (41 .1 %) as a white solid.

Preparative example 2 - Preparation of Tiotropium Bromide

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. Preparation of (R)-Quinuclidin-3-yl 2-hydroxy-2,2-di(thiophen-2-yl)acetate (R)-Quinuclidin-3-yl acetate (105 mg, 1 eq), TBD (129 mg, 1 .5 eq), Di-(2- thienyl)glycolic acid methyl ester (160 mg, 1 eq) and toluene (3 ml_) were put in a vial at room temperature. The mixture of reaction, under magnetic stirring, was heated at 60 °C for 24 hours to yield 13% of the title compound (R)- Quinuclidin-3-yl 2-hydroxy-2,2-di(thiophen-2-yl)acetate. The present invention provides a process for the preparation of esters following the general scheme:

Ester I Ester II Ester Γ wherein

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 is 0 or 1

in the presence of an acyl transfer agent. 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 is 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:

Use of 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

n is 0. 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 is 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. Use of (R)-Quinuclidin-3-yl 2-hydroxy- 2,2-di(thiophen-2-yl)acetate produced according to a process of the invention for the preparation of an Aclidinium halide salt. 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 is 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. 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 is 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 is 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 is 0

The processes above may further be characterized in that the 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.

The process above may be further characterized in that the acyl transfer agent is 1 ,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD).

The process above may be further characterized in that the 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 process above may be further characterized in that 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.

Regarding the process for the preparation of a Tiotropium halide salt, 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.

Regarding the process for the preparation of Scopine Dithienylglycolate, 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.

As regarding the process for the preparation of Scopine Dithienylglycolate and the process for the preparation of Scopine Base, the process may be further characterized in that the reaction is carried out in toluene as the solvent. 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 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.

Use of an Ester Γ produces according to the process of the invention for the Production of a Glycopyrronium halide salt, an Aclidinium halide salt or a Tiotropium halide salt.