WO2008089852A1

WO2008089852A1 - Novel process for preparing tiotropium salts

Info

Publication number: WO2008089852A1
Application number: PCT/EP2007/050808
Authority: WO
Inventors: Joerg Brandenburg; Waldemar Pfrengle
Original assignee: Boehringer Ingelheim Pharma Gmbh & Co.Kg
Priority date: 2007-01-26
Filing date: 2007-01-26
Publication date: 2008-07-31

Abstract

The invention relates to a novel process for preparing tiotropium salts of the general formula (1), where X- can have the meanings given in the claims and in the description.

Description

NEW METHOD FOR THE PRODUCTION OF TIOTROPIUM SALTS

The invention relates to a novel process for the preparation of tiotropium salts of general formula 1

wherein X ^" may have the meanings given in the claims and in the description.

Background of the Invention Anticholinergics can be therapeutically useful in a variety of diseases. Special mention should be made, for example, of the treatment of asthma or COPD (chronic obstructive pulmonary disease). For the treatment of these diseases, for example, WO 02/03289 proposes anticholinergics which have a scopin, tropenol or tropine skeleton. In addition, the tiotropium bromide is disclosed in particular in the prior art as a highly potent anticholinergic. Tiotropium bromide is known, for example, from EP 418 716 A1.

In addition to the synthesis processes disclosed in the abovementioned prior art for the preparation of scopin esters, a process for the preparation of esters of scopine is disclosed in particular in WO03 / 057694.

It is an object of the present invention to provide an improved synthetic synthetic method which allows easier synthetic access to the compounds of general formula 1 in a manner improved over the prior art. Detailed Description of the Invention The present invention relates to a process for the preparation of tiotropium salts of

Formula 1.

wherein

X - a singly negatively charged anion, preferably an anion selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, p-toluenesulfonate and trifluoromethanesulfonate, may mean

characterized in that a compound of formula 2

wherein

Y ^"is a simply negatively charged lipophilic anion, preferably an anion selected from the group consisting of hexfluorophosphate, tetrafiuoroborate,

Tetraphenylborate and saccharinate, more preferably hexfluorophosphate or tetraphenylborate

in one step with a compound of formula 3

wherein R is a radical selected from the group consisting of methoxy, ethoxy, propoxy,

Isopropoxy, isopropenyloxy, butoxy, O-N-succinimide, O-N-phthalimide, phenyloxy, nitrophenyloxy, fluorophenyloxy, pentafluorophenyloxy, vinyloxy, 2-allyloxy, -S-methyl, -S-ethyl and -S-phenyl,

in a suitable solvent to give a compound of formula 4

wherein the group Y ^" may have the meanings given above, and the compound of formula 4 without isolation by reaction with a salt Kat ⁺ X ^" , where Kat ^{+ is} a cation selected from the group consisting of Li ⁺ , Na ⁺ , K ^+, Mg2 +, Ca2 + is, organic cations with quaternary N (eg, N, N-dialkylimidazolium, tetraalkylammonium) and X ^"may have the meanings given above, in the compound of formula 1 is überfuhrt.

Preferably, the present invention relates to a process for the preparation of

Tiotropium salts of the formula 1, in which

X ^"is a singly negatively charged anion selected from the group consisting of

Chloride, bromide, iodide, methanesulfonate, p-toluenesulfonate and trifluoromethanesulfonate, preferably chloride, bromide, iodide, methanesulfonate or

Trifluoromethanesulfonate, particularly preferably chloride, bromide or methanesulfonate, more preferably bromide, may mean.

An inventively particularly preferred method is characterized in that the reaction is carried out with a compound of formula 3, in the

R is a radical selected from the group consisting of methoxy, ethoxy, propoxy,

Isopropoxy, isopropenyloxy, butoxy, ON-succinimide, ON-phthalimide, phenyloxy, nitrophenyloxy, fluorophenyloxy, pentafluorophenyloxy, vinyloxy and 2-allyloxy. An inventively particularly preferred method is characterized in that the reaction is carried out with a compound of formula 3, in which R is a radical selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, isopropenyloxy, butoxy, ON-succinimide, ON-Phtalimid , Vinyloxy and 2-allyloxy, preferably selected from methoxy, ethoxy, propoxy, and butoxy, more preferably methoxy or ethoxy.

An inventively particularly preferred method is characterized in that the reaction is carried out with a compound of formula 2, in the

Y ^"is a singly negatively charged anion selected from the group consisting of

Hexfluorophosphat, Tetrafiuoroborat and tetraphenylborate, preferred

Hexafluorophosphate means.

A particularly preferred method according to the invention is characterized in that the final reaction of the compound of formula 4 to the compound of formula 1 is carried out with the aid of a salt KatX, in which Kat ^{+ is} selected from the group consisting of Li ⁺ , Na ⁺ , K ⁺ , Mg2 +, Ca2 +, organic cations with quaternary N (eg, N, N-dialkylimidazolium, tetraalkylammonium) and in which X ^" may have the meanings given above.

Alkyl groups and alkyl groups which are part of other groups are branched and unbranched alkyl groups having 1 to 4 carbon atoms. Examples include: methyl, ethyl, propyl, butyl. Unless otherwise stated, of the above designations, propyl, butyl includes all of the possible isomeric forms. For example, the term propyl includes the two isomeric radicals n-propyl and iso-propyl, the term butyl n-butyl, iso-butyl, sec. Butyl and tert. Butyl.

Alkoxy or alkyloxy groups are branched and unbranched alkyl groups having 1 to 4 carbon atoms which are linked via an oxygen atom. For example: methoxy, ethoxy, propoxy, butoxy. Unless otherwise specified, all of the possible isomeric forms are included in the abovementioned designations. The terms nitro-phenyl and fluorophenyl stand for phenyl rings which are mono- or polysubstituted, preferably monosubstituted by F or NO ₂ . All possible isomers (ortho, meta or para) are included, para- or meta-substitution being of particular importance.

According to the invention, lipophilic anions are understood as meaning those anions whose sodium or potassium salts have a solubility in polar organic solvents such as methanol or acetone of> 1% by weight.

The inventive method is characterized in particular by the fact that it can be performed in relatively nonpolar solvents due to the solubility of the starting compounds of formula 2 and the intermediates of formula 4. This allows a reaction under very mild conditions, which compared to reactions in highly polar apro tables solvents in the sensitive tiotropium salts have fewer side reactions and, consequently, a higher yield result. The reaction of the compounds of the formula 2 with the compounds of the formula 3 is preferably carried out in an aprotic organic solvent, preferably in a weakly polar organic solvent. Suitable solvents according to the invention are particularly preferably acetone, pyridine, acetonitrile and methyl ethyl ketone, with acetone, acetonitrile and pyridine preferably being used. Particularly preferably, the reaction is carried out in a solvent selected from the group consisting of acetone and acetonitrile, wherein the use of acetone is particularly preferred according to the invention.

Optionally, it may be useful to activate the reaction of the compound of formula 2 with 3 by addition of a catalyst. Particularly gentle activation is possible according to the invention by catalysts which are selected from the group consisting of zeolites, lipases, tert. Amines, for example N, N-dialkylaminopyridine, 1,4-diazabicyclo [2.2.2] octane (DABCO) and diisopropylethylamine and alcoholates, such as, for example, sodium or potassium tert-butoxide, sodium or potassium isopropylate or sodium or potassium ethoxide, wherein the use of zeolites and in particular zeolites and potassium tert-butoxide, according to the invention is particularly preferred. Particularly preferred zeolites are molecular sieves which are selected from the group of molecular sieves having basic character consisting of sodium or potassium-containing aluminosilicates, preferably molecular sieves with the Molar formula Nai ₂ [(A10 ₂ ) i ₂ (Si0 ₂ ) i ₂ ] x H ₂ O, wherein the use of molecular sieve type 4A (stands for pore size of 4 Angstrom) according to the invention is particularly preferred.

The reaction of 2 with 3 to the compound of formula 4 can be carried out at elevated temperature, depending on the type of catalyst. The reaction preferably takes place at a temperature of 30 ^° C., more preferably in a range from 0 to 30 ^° C.

The compounds of formula 3 can be obtained by methods known in the art. Reference is made, for example, to WO03 / 057694, to which reference is made at this point in full.

The compounds of the formula 2 are of central importance for the process according to the invention. Accordingly, another aspect of the present invention relates to compounds of formula 2

as such, in which

Y ^"is a simply negatively charged lipophilic anion, preferably an anion selected from the group consisting of hexafluorophosphate, tetrafluoroborate, tetraphenylborate and saccharinate, particularly preferably hexafluorophosphate or tetraphenylborate.

For the preparation of the compounds of formula 2, the procedure can be as follows. For this purpose, a scopine salt of the formula 5 is preferred,

wherein Z ^"is a single negatively charged anion other than Y ^" , in a suitable solvent, preferably in a polar solvent, more preferably in a solvent selected from the group consisting of water, methanol, ethanol, propanol or isopropanol. According to the invention, the preferred solvents are water and methanol, water being of outstanding importance in accordance with the invention.

Particularly preferred starting compounds for the preparation of the compound of the formula 2 are those compounds of the formula 5 in which Z ^"is a singly negatively charged anion, preferably an anion selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, Nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulfonate.

Further preferred starting compounds for the preparation of the compound of the formula 2 are those compounds of the formula 5 in which Z ^"is a singly negatively charged anion selected from the group consisting of chloride, bromide, 4-toluenesulfonate and methanesulfonate, preferably bromide.

The solution thus obtained is treated with a salt Kat'Y. Here, Y is one of the abovementioned anions, while Kat 'is a cation which is preferably selected from the group consisting of protons (H ⁺ ), alkali or

Alkaline earth metal cations, ammonium, preferably protons or alkali metal cations, more preferably Li ⁺ , Na ⁺ and K ⁺ ions.

1 mol, preferably 1-1.5 mol, if appropriate also 2-5 mol of the salt Kat'Y are used per mole of compound of formula 5 used according to the invention. It will be apparent to those skilled in the art that the use of lesser amounts of salt Kat'Y is possible, but that this may then only result in partial reaction of the compound of formula 5.

The resulting solution is stirred until complete reaction. This can be carried out at room temperature (about 23 ° C) or optionally at a slightly elevated temperature in a range of 25-50 ⁰ C. After complete addition, sometimes even during the addition, the compounds of formula 2 crystallize out of the solution. The products obtained can, if necessary, be purified by recrystallization from one of the abovementioned solvents. The resulting crystals are isolated and dried in vacuo. Another aspect of the present invention relates to the use of compounds of formula 2 as starting compounds for the preparation of compounds of formula L. Another aspect of the present invention relates to the use of compounds of formula 2 as starting compounds for the preparation of compounds of formula 4. Another aspect The present invention relates to the use of compounds of the formula 5 as starting compounds for the preparation of compounds of the formula 2. Another aspect of the present invention relates to the use of compounds of the formula 5 as starting compounds for the preparation of compounds of the formula 4.

A further aspect of the present invention relates to a process for preparing compounds of the formula I ₁ , which comprises using a compound of the formula 2 as starting compound for the preparation of compounds of the formula I. Another aspect of the present invention relates to a process for the preparation of compounds of formula 4, characterized in that a compound of formula 2 is used as starting compound for the preparation of compounds of formula 4. Another aspect of the present invention relates to a process for the preparation of compounds of formula 2, characterized in that a compound of formula 5 is used as starting compound for the preparation of compounds of formula 2. Another aspect of the present invention relates to a process for the preparation of compounds of formula 4, characterized in that a compound of formula 5 is used as starting compound for the preparation of compounds of formula 4.

The compounds of the formula 4 are of central importance for the process according to the invention. Accordingly, another aspect of the present invention relates to compounds of formula 4

as such, where the group Y ^" may have the meanings given above. A further aspect of the present invention relates to the use of compounds of the formula 4 as starting compounds for the preparation of compounds of the formula L. A further aspect of the present invention relates to a process for preparing compounds of the formula I ₁ , which comprises reacting a compound of the formula 4 is used as starting compound for the preparation of compounds of formula.

The compounds of the formula 4 are obtained as described above in the context of the process according to the invention for the preparation of compounds of the formula 1 as intermediates. In the context of the process according to the invention for the preparation of compounds of formula 1, in a preferred embodiment of the invention, the compound of formula 4 need not be isolated.

The following examples serve to illustrate examples of synthetic methods carried out. They are to be understood merely as possible, exemplarily illustrated procedures, without restricting the invention to their content.

Example 1: N-Methylscopinium hexafluorophosphate

N-Methylscopiniumbromid is dissolved in water and with an equimolar or molar excess amount of a water-soluble hexafluorophosphate (sodium or

Potassium salt). Also, aqueous hexafluorophosphoric acid leads to precipitation. The N-methylscopinium hexafluorophosphate precipitated / crystallized out as a white, water-insoluble product, is isolated, optionally washed with methanol and then dried at about 40 ^° C. in a drying oven.

Mp: 265-267 ° C (melt under discoloration);

H-NMR: in acetonitrile-d3 σ (ppm): 1.9 (dd, 2H), 2.55 (dd, 2H), 2.9 (s, 3H), 3.29 (s, 3H), 3 , 95 (dd, 4H), 3.85 (s, IH). Example 2: tiotropium bromide

1.6 g (5 mmol) of methylscopinium hexafluorophosphate (Example 1) and 2.0 g (7.8 mmol) of methyl dithienylglycolate are refluxed in 50 ml of acetone and in the presence of 10 g of molecular sieve 4A for 50-70 hours.

The reaction mixture is filtered, the filtrate is treated with a solution of 0.3 g of LiBr in 10 ml of acetone. The crystallized unreacted N-Methylscopiniumbromid is separated by filtration. After addition of a further 0.6 g of LiBr (dissolved in acetone), tiotropium bromide precipitates in an isolated yield of 30% (based on the compound used in Example 1).

Example 3: Tiotropium hexafluorophosphate

Tiotropium hexafluorophosphate is not isolated in the context of the implementation of Example 2 but further reacted directly to the tiotropium bromide. For the purpose of characterizing tiotropium hexafluorophosphate, it was specifically prepared and isolated. Hereby, the following characterizing data were obtained. Mp: 233-236 ° C (melting under discoloration)

H-NMR: in acetone-d6: σ (ppm): 2.08 (dd, 2H), 2.23 (dd, 2H), 3.32 (s, 3H), 3.50 (s, 3H), 3.62 (s, 2H), 4.28 (m, 2H), 5.39 (m, IH), 6.25 (s), 7.02 (m, 2H), 7.027.22 (m, 2H ), 7.46 (m, 2H), P-NMR: in acetone-d6: σ (ppm): -143.04, heptetane, J = 4.37.

Example 4: Tiotropium bromide

31.5 g (100 mmol) of methylscopinium hexafluorophosphate (Example 1) and 25.4 g (100 mmol) of methyl dithienylglycolate are dissolved in 400 ml of acetone and in the presence of 40 g of molecular sieve 4A, powder (Fluka) and DMAP (4,4-dimethylaminopyridine) for 24 h cooked under reflux. (Molsieb was replaced after 3 h in the same amount.) The reaction mixture is filtered, washed with 200 ml of acetone, the filtrate gradually treated with a solution of 9.6 g of LiBr (1 lOmmol) in 110 ml of acetone. The crystallized unreacted N-Methylscopiniumbromid is separated by filtration. (Fractionated precipitation). The crystal fractions were filtered off and dried. The composition of the fractions was determined by thin-layer chromatography. Tiotropium bromide in an isolated yield of 16.6 g (35%) (based on the compound used in Example 1). Purity HPLC> 99%. Purity DC: no impurities detectable. Example 5: Tiotropium bromide

1.6 g (5 mmol) of methylscopinium hexafluorophosphate (Example 1) and 1.25 g (5 mmol) of methyl dithienylglycolate are added in 50 ml of acetone and in the presence of 2 g of molecular sieve 4A, powder (Fluka) and 6 mg of potassium tert-butoxide 0 ⁰ C stirred for 4 h. The reaction mixture is filtered, washed with 20 ml of acetone, the filtrate is gradually added to a solution of 0.7 g of LiBr (13 mmol) in 11 ml of acetone. The crystallized unreacted is separated by filtration. (Fractionated precipitation). The crystal fractions were filtered off and dried. The composition of the fractions was determined by thin-layer chromatography. The Tiotropiumbromid- fractions were filtered off, washed with acetone, recrystallized from water, washed with acetone and dried. 1.2 g (48% yield based on the compound used in Example 1) tiotropium bromide were isolated in this way. Purity HPLC: 99.8%, TLC: no contamination visible;

Example 6: Tiotropium bromide

31.5 g (0.1 mol) methylscopinium hexafluorophosphate (Example 1) and 30.5 g (0.10 mol)

2,2 "-Dithienylglycolsäuremethylester are dissolved in 400 ml of acetone and in the presence of 90g type 4A zeolite (NaI ₂ AIi ₂ SiI ₂ O ₄ S xn H ₂ O) and 0.2 g (lmmol) of potassium tert-butoxide over a Period of 20-24 hours at 0 ⁰ C stirred.

The reaction mixture is filtered, the filtrate is treated with a solution of 8.7 g LiBr (8.7 g

0.10 mol in 100 ml of acetone).

The crystallized product is separated by filtration, washed with acetone and then dried. This gives 41.4 g (87.7%) yield, at 90% degree of conversion.

Example 7: N-methylscopinium tetraphenylborate

20 g (80 mmol) of methylscopinium bromide are dissolved in 500 ml of methanol. 27.38 (80 mmol) of sodium tetraphenylborate dissolved in 150 ml of methanol are added. The resulting suspension is stirred for 10 min at room temperature and filtered. The separated crystals are washed with 50 ml of methanol and dried. Yield: 39.1 g (91.73% yield); M .: 261 ° C. Example 8: Tiotropium tetraphenylborate

0.245 g (0.5 mmol) of methylscopinium tetraphenylborate (Example 7) and 0.154 g (0.6 mmol) of methyl 2,2-dithienylglycolate are dissolved in 25 ml of acetone and dissolved in the presence of 1.0 g type 4A zeolite (NaI ₂ Ali ₂ SiI ₂ O ₄ S xn H ₂ O) and 5 mg of potassium tert-butoxide over a period of 20-30 hours at 0 ⁰ C stirred.

According to HPLC, 79% of the converted methyl 2,2-dithienylglycolate is transformed into tiotropium tetraphenylborate after 26 h (unisolated yield: 43%).

The reactions listed by way of example take place virtually without formation of by-products. If the reactions take place optionally without complete reaction of the starting materials, the N-methylscopinium bromide isolated in the first step of the workup can therefore be recycled with the reaction according to Example 1 and thus the overall yield in the context of a production process be significantly increased.

Claims

claims

1) Process for the preparation of tiotropium salts of the formula 1.

wherein

X ^" can mean a simply negatively charged anion,

characterized in that a compound of formula 2

wherein

Y ^{^"X"} different single negative charge lipophilic anion, preferably an anion selected from the group consisting of Hexfluorophosphat, tetrafluoroborate, tetraphenylborate and saccharinate, particularly preferably Hexfluorophosphat or tetraphenylborate

in one step with a compound of formula 3

wherein

R is a radical selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, isopropenyloxy, butoxy, ON-succinimide, ON-phthalimide, phenyloxy, Nitrophenyloxy, fluorophenyloxy, pentafluorophenyloxy, vinyloxy, 2-allyloxy, -S-methyl, -S-ethyl and -S-phenyl,

in a suitable solvent to give a compound of formula 4

wherein the group Y ^" may have the meanings given above, and the compound of formula 4 without isolation by reaction with a salt Kat ⁺ X ^" , where Kat ^{+ is} a cation selected from the group consisting of Li ⁺ , Na ⁺ , K ⁺ , Mg2 +, Ca2 + and organic cations with quaternary N and X ^{"may have} the abovementioned meanings, is converted into the compound of formula 1.

2) The method of claim 1, wherein

X ^"is a single negatively charged anion selected from the group consisting of chloride, bromide, iodide, methanesulfonate, p-toluenesulfonate and

Trifluoromethanesulfonate, preferably chloride, bromide or methanesulfonate, particularly preferably bromide, may mean.

3) Method according to claim 1 or 2, wherein the reaction is carried out with a compound of formula 3, in which

R is a radical selected from the group consisting of methoxy, ethoxy, propoxy,

May be isopropoxy, isopropenyloxy, butoxy, O-N-succinimide, O-N-phthalimide, phenyloxy, nitrophenyloxy, fluorophenyloxy, pentafluorophenyloxy, vinyloxy and 2-allyloxy.

4) The method of claim 1, 2 or 3, wherein the reaction is carried out with a compound of formula 2, in the

Y ^"is a singly negatively charged anion selected from the group consisting of

Hexfluorophosphat, tetrafluoroborate, tetraphenylborate and saccharinate can be. 5) Method according to one of claims 1 to 4, characterized in that the final reaction of the compound of formula 4 to the compound of formula 1 is carried out using a salt KatX, in which Kat ^{+ is} selected from the group consisting of Li ⁺ , Na ⁺ , K ⁺ , Mg2 +, Ca2 +, quaternary N organic cations and in which X ^" may have the meanings given above.

6) Method according to one of claims 1 to 5, characterized in that the reaction of the compound of formula 2 with 3_ is activated by addition of a catalyst.

7) Method according to claim 6, characterized in that the catalyst is selected from the group consisting of zeolites, alcoholates, lipases, and tertiary amines.