SUCCINATE

TECHNICAL FIELD

This invention relates to a process for the preparation of solifenacin and pharmaceutically acceptable salts thereof, including solifenacin succinate.

BACKGROUND AND PRIOR ART

Solifenacin, (S)-l -phenyl- 1, 2,3, 4-tetrahydroisoquinoline-2-carboxylic acid (i?)-3-quinuclidine ester (IUPAC name : l-azabicyclo[2.2.2]oct-8-yl (lS -l-phenyl-3,4-dihydro-lH-isoquinoline-2- carboxylate is a competitive, selective antagonist of the muscarinic receptor, M3 subtype. It works by relaxing the involuntary muscle that is found in the wall of the bladder.

The muscle in the wall of the bladder is called the detrusor muscle. It can sometimes contract in uncontrollable spasms, and this is often referred to as having an overactive bladder. The overactive detrusor muscle can cause uncontrollable urges to pass urine, or involuntary leakage of urine (urinary incontinence).

Solifenacin works by relaxing the detrusor muscle in the wall of the bladder. It does this by blocking receptors called cholinergic (or muscarinic) receptors that are found on the surface of the muscle cells. This prevents a natural body chemical called acetylcholine from acting on these receptors.

The processes for the preparation of 1 -phenyl- 1, 2,3, 4-tetrahydroisoquinoline-2-carboxylic acid (i?)-3-quinuclidine ester, both as a racemic mixture and as a pharmacologically active isomer (15,3'i?), include two approaches;

The first approach employs a reaction between quinuclidinol and a carbamoyl derivative of 1- phenyl- 1,2,3,4-tetrahydroisoquinoline which contains a leaving group and the second approach uses a reaction between 1 -phenyl- 1,2,3, 4 tetrahydroisoquinoline and an active quinuclidinol derivative, such as chloroformate or carbonate.

The following leaving groups are listed in the publications of patent EP 801067 Bl and application WO 2005/105795: chlorine, lower alkoxy groups, phenoxy group, lH-imidazol-l-yl, 2,5-dioxypyrrolidin-l-yloxy and 3 -methyl- lH-imidazol-3-ium-l-yl.

Patent specification EP 801067 Bl indicates that solifenacin can be prepared by the condensation of (S)-l -phenyl- 1, 2,3, 4-tetrahydroisoquinolinecarbonyl chloride with (R)-3 -quinuclidinol; however, no example embodiment is provided. One of the variants of solifenacin synthesis are disclosed in publication WO 2005/105795 and recites the reaction between (S - 1 -phenyl- 1, 2,3, 4-tetrahydroisoquinoline carbonyl chloride and (i?)-3-quinuclidinol in the presence of a base.

In one embodiment, (S)-l -phenyl- 1,2,3, 4-tetrahydroisoquinoline is reacted with phosgene in toluene in the presence of triethylamine, where the reaction product is isolated as an oil and the steps include addition of methanol and water to the reaction solution, concentration of the organic layer under reduced pressure. This product dissolved in toluene is slowly added to the (i?)-3-quinuclidinol and sodium hydride solution in toluene at boiling point and the contents were allowed to reflux overnight. The inventors state that "the formation of solifenacin was confirmed". However, neither the yield of the resulting product (solifenacin) or its purity are provided. It was observed on repeating the experiment as disclosed above the that purity of the solifenacin base so obtained was not higher than 43% as determined by HPLC. Further, product yield may also be low as a result of the formation of impurities due to the demethylation of the aliphatic amine in the presence of phosgene is discussed in literature.

WO 2007/147374 discloses that the reaction between 1 -phenyl- 1,2,3, 4- tetrahydroisoquinolinecarbonyl chloride and 3-quinuclidinol (as mentioned in EP0801067) results in significant amounts of the unwanted symmetrical urea derivatives as side products , which considerably reduce the yield of the desired product. This method therefore cannot be employed on an industrial scale.

The formation of the derivative is considered to be the result of the acylation reaction at the 3- quinuclidinol nitrogen atom which leads to a quaternary salt. Upon contact with water used during the product isolation step, the salt hydrolyses to an acid. The acid undergoes decarboxylation and the resulting l-phenyl-l,2,3,4-tetrahydroisoquinoline reacts immediately with the residue of the acylating agent (intermediate) resulting in a in a nearly quantitative yield, a urea with another molecule of l-phenyl-l,2,3,4-tetrahydroisoquinoline forming a product as depicted below;

Due to its very low solubility in organic solvents, it is very hard to remove this impurity from final solifenacin using conventional methods applied in the purification of organic compounds, such as crystallization. Therefore, in order to obtain pharmaceutical grade solifenacin, it is necessary to significantly reduce the formation of the urea derivative or remove it before the salt formation step.

WO-2009142522 ( P-385265) discloses a method employed to overcome this problem which involves the use of (S)-l -phenyl- 1, 2,3 ,4-tetrahydroisoquinolinecarbonyl chloride with minimal impurities, since it was observed that any impurities present in l-(5 -phenyl-l ,2,3,4- tetrahydroisoquinolinecarbonyl chloride, and especially in unreacted l-(iS)-phenyl- 1 ,2,3,4- tetrahydroisoquinoline, lead to difficulties in the purification of the final product. The difficulties increase even more due to the fact that l-(S)-phenyl-l,2,3,4-tetrahydroisoquinoline has polarity similar to that of solifenacin base. Therefore, it co-crystallizes with solifenacin succinate as a succinic acid salt. Furthermore, as noted before, l-(iS)-phenyl-l,2,3,4-tetrahydroisoquinoline reacts with solifenacin formed in the next step resulting in unwanted side products.

Advantageous results were obtained when l-(S)-phenyl-l ,2,3,4-tetrahydroisoquinolinecarbonyl chloride was used with chemical purity of at least 98%, prepared by reacting l-(5 -phenyl- 1,2,3,4-tetrahydroisoquinoline with molar excess of triphosgene in the presence of a tertiary aromatic amine which prevents the formation of any other impurities. Even though l-(5)-phenyl- 1,2,3,4-tetrahydroisoquinolinecarbonyl chloride obtained by this condition was a oil, it had relatively high chemical purity, necessary to obtain the pharmaceutical grade product could be achieved only when it was converted to the crystalline form by dissolving the oil in an aprotic non-polar solvent, such as heptane at reflux and the hot solution is filtered. The filtrate is concentrated to reduce the volume of solvent and allowed to crystallize to afford the required product.

Furthermore, the optical purity of all reagents used and intermediates is vital in the preparation of solifenacin, which depends on the enantiomeric purity of the starting (S)-l -phenyl- 1 , 2,3,4- tetrahydroisoquinoline. As disclosed in WO 2009142521( P- 385264), in order to obtain (S)-l- phenyl-l,2,3,4-tetrahydroisoquinoline with enantiomeric purity close to 100%, specific conditions of optical resolution of the diastereomeric salt of 1 -phenyl- 1 ,2,3, 4- tetrahydroisoquinoline and D-(-)-tartaric acid are preferable such as the use of the solvent system of methanol and water in the volume ratio of between 3.3:1 and 1 :1. The process for the preparation of solifenacin disclosed in application WO-2009142522 ( P- 385265) consists in that from 3-(<S)-quinuclidinol the 3-(i?)-quinuclidinolate anion is generated in situ using a strong base, acylated with l -(5)-phenyl-l ,2,3,4-tetrahydroisoquinolinecarbonyl chloride and maintaining constant excess of anion in the reaction environment. The acylation reaction is carried out in an aprotic polar solvent, such as tetrahydrofuran, dioxane, dimethylsulfoxide, dimethylformamide, dimethylacetamide or N-methylpyrrolidone, optionally with a non-polar solvent added, such as pentane, heptane, hexane, cyclohexane, methylcyclohexane, used to dissolve (S)- 1 -phenyl- 1, 2,3, 4-tetrahydroisoquinolinecarbonyl chloride. In the example embodiment, the reaction is carried out in a tetrahydrofuran and heptane mixture.

The limitations of the known processes for the preparation of solifenacin known in the art by the acylation of 3-(i?)-quinuclidinol by l-(5)-phenyl-l ,2,3,4-tetrahydroisoquinolinecarbonyl chloride are the following: a) Difficulties in the preparation of (5)- 1 -phenyl- 1, 2,3, 4-tetrahydroisoquinoline with high enantiomeric purity on which depends the optical purity of the final solifenacin and its maintenance throughout further synthesis; b) The need of initial purification of l-(S)-phenyl-l,2,3,4-tetrahydroisoquino-linecarbonyl chloride to obtain more than 98% purity;

c) The need of maintaining anhydrous conditions in all operations involving l-(S)-phenyl- 1,2,3,4-tetrahydroisoquinolinecarbonyl chloride in order to avoid the formation of the urea derivative which is difficult to remove; d) Change of solvents during the various steps such as synthesis, isolation, crystallization of intermediates, etc. e) Furthermore, the various solvents used in the successive synthetic steps, must be removed from the final product so that it conforms to the requirements of active pharmaceutical ingredients (API) by health authorities as patients safety is very important. f) The last limitation involves the need of additional operations, increased energy consumption (solvent distillation) and environmental burden due to the disposal of all waste generated. The standards to be fulfilled by active pharmaceutical ingredients authorized for human use and set forth by the "International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use" (ICH) impose the requirement to seek more efficient methods than those known in the art for solifenacin preparation with high pharmaceutical purity.

Whenever the term "pharmaceutical grade solifenacin" is referred to in the following texts , it is to be understood that it refers to solifenacin or the corresponsing succinate which contain below 0.15% of single identified impurities and below 0.5% of all total impurities.

Accordingly, the objects of the current invention is to provide methods to overcome the difficulties discussed above.

In the process of preparation solifenacin according to the instant invention, the steps are carried out in one reaction vessel without the isolation of any intermediates in solid form.

SUMMARY OF THE INVENTION

This invention relates to a process for the preparation of solifenacin with high pharmaceutical purity .

One aspect of the invention relates to a process of preparation of solifenacin succinate

Wherein;

(i) (S)-l-phenyl-l,2,3,4-tetrahydroisoquinoline is released from its diastereoisomeric salt with D-(-)-tartaric acid;

(ii) (S)-l-phenyl-l,2,3,4-tetrahydroisoquinoline is converted to into l-(S)-phenyl-l,2,3,4- tetrahydroisoquinolinecarbonyl chloride in the presence of chlorocarbonylating agent, preferably triphosgene and aromatic azines, preferably pyridine.

(iii) l-(5)-phenyl-l,2,3,4-tetrahydroisoquinolinecarbonyl chloride is allowed to react with 3- (S)-quinuclidinol in the presence of a a strong base, preferably sodium hydride,

(iii) (iv) Optionally, the resulting solifenacin in the free base form is converted into a salt thereof, preferably the succinic acid salt, using methods known in the art; wherein the steps (i) to (iii) are carried out without the isolation of intermediates from the reaction medium. In an embodiment the chlorocarbonylating agent is triphosgene, the aromatic azine is pyridine and the strong base is sodium hydride.

In an embodiment the solvents used in steps (i) to (iii) comprise aprotic solvents or mixtures thereof.

In an embodiment the solvents used in steps (i) to (iii) are aprotic non-polar solvents or mixtures thereof or in the case of step (iii) an aprotic polar solvent might also be added to the reaction medium.

In an embodiment, the solvent in step (iii) is a mixture of aprotic solvents.

In an embodiment, the solvent in step (iii) is a mixture of at least one aprotic non-polar solvent and at least one aprotic polar solvent.

In an embodiment, the solvent in step (iii) is a mixture of tetrahydrofuran and toluene.

In an embodiment toluene is used as a solvent or co-solvent in any or all the steps from (i) to (iii).

In an embodiment the aprotic solvents are mixtures of tetrahydrofuran and toluene.

In an embodiment, the products of steps (i) to (iii), are purified by washing impurities with water and this followed by extraction in aprotic solvents, preferably in toluene or mixtures of toluene and tetrahydrofuran.

In another embodiment, the products of steps (i)-(iii) are freed of impurities by washing with water and drying by azeotropic distillation.

In an embodiment, the steps (i) to (iii) are carried out in a single reaction vessel.

In an embodiment, the steps (i) to (iv) are carried out without the isolation of intermediates in solid form from the reaction medium. In an embodiment, the product of step (iii) (solifenacin free base) is isolated as an oil.

A second aspect of the present invention is solifenacin free base isolated as an

The reaction medium in the processes of this invention is preferably toluene or tolune -THF mixture which ensures that the appropriate reaction environment is maintained. Tolune also serves as the solvent in extraction processes which follow the successive synthesis steps (i)-(iii) according to the first aspect mentioned above .

Further tolune also serves as a component of the azeotropic system which facilitates the drying of reaction mixture by azeotropic distillation following successive synthesis steps for the preparation of solifenacin succinate as described in steps (i)-(iii) according to the first aspect

DETAILED DESCRIPTION OF THE INVENTION

The following terms used to describe this invention in this document are to be interpreted according to the definitions below:

The term "chlorocarbonylating agent" should include phosgene, diphosgene or tri phosgene and any other equivalent agent.

The term " aromatic azines" includes pyridine, pyrazine and pyrimidines and substituted derivatives of them or any other equivalent agent.

A strong base can be defined as a base , which hydrolyses completely, raising the pH of the solution towards 14.

One preferred embodiment of the present invention can be described by the following scheme:

Step -Iii

According to the present process, the starting material is (S)- 1 -phenyl- 1,2,3, 4- tetrahydroisoquinoline D-(-)-tartrate in the crystalline form. This is disclosed for example in application P-385264 (WO 2009142521). The crystalline solid is added to toluene and treated with aqueous NaOH.

Ssubsequently, inorganic impurities are removed by washing with water and the organic (toluene) phase is dried by azeotropic distillation process to afford the product as a oil

Subsequently, pyridine is added to solution containing (S)- 1 -phenyl- 1,2, 3,4- tetrahydroisoquinoline ( solution A) in toluene and the mixture is added dropwise to a solution of triphosgene in toluene (solution B)

The reaction is carried out at a temperature of 70-80°C until (S)-l -phenyl- 1,2,3, 4- tetrahydroisoquinoline reacts completely. The progress of the reaction is monitored by thin-layer chromatography (TLC).

Any pyridine hydrochloride precipitate formed during the course of the reaction is filtered, the reaction mixture is cooled to a temperature of 0-10°C, diluted with water and the aqueous and organic phases were allowed to separate. Subsequently, the separated organic (toluene phase) containing (S)-l-phenyl-3,4-dihydro-lH-isoquinoline-2-carbonyl chloride is washed several times with water and dried azeotropically by concentrating at reduced pressure.( Solution C) Unexpectedly and contrary to all previous literature findings, it was found that the use of water to remove unreacted substrates and undesired reaction products according to the procedure described in the current invention do not lead to the degradation of (S)-l-phenyl-l,2,3,4- tetrahydroisoquinolinecarbonyl chloride. This fact is proved by the results of analyses provided in the examples section.

The acylation reaction of 3-(i?)-quinuclidinol by l-(S)-phenyl-l,2,3,4- tetrahydroisoquinolinecarbonyl chloride is carried out by gradual addition of a solution which contains (S)-l -phenyl- 1, 2,3, 4-tetrahydroisoquinolinecarbonyl chloride in toluene and tetrahydrofuran into a suspension of 3-(i?)-quinuclidinol and a strong base and preferably sodium hydride in tetrahydrofuran.

The addition is carried out at temperatures ranging from room temperature to boiling point of the reaction mixture.

Subsequently, the temperature is increased and the mixture is maintained at its boiling point until the substrate disappears. The course of the reaction is monitored by thin-layer chromatography (TLC). After the completion of the reaction, tetrahydrofuran is distilled from the reaction mixture and the reaction mixture is cooled to room temperature. Water and toluene are added into the reaction mixture and the aqueous and organic phases are allowed to separate. The organic phase is washed several times with water and concentrated until solifenacin is obtained as an oil.

Solifenacin prepared according to the process of this invention is characterized by high chemical and optical purity, sufficient for the direct conversion to the corresponding succinic acid salt, without the need of additional purification steps.

The solifenacin succinic acid salt is prepared in the processes known in the art by reacting equimolar quantities of solifenacin in the free base form and succinic acid in the presence of organic solvents or a mixtures thereof, whereby the solifenacin succinate salt is obtained.

The appropriate solvents include but are not limited to aliphatic alcohols, such as ethanol, butan- l-ol, 2-methylbutyl alcohol, isopropanol;

ketones, such as acetone, methyl-isobutyl ketone and others;

esters, such as ethyl acetate, n-butyl acetate, ethyl propionate;

aromatic hydrocarbons, such as toluene;

aliphatic hydrocarbons, such as heptane. The crystalline product may be additionally recrystallized from the same solvent from which the salt was obtained, and preferably the solvent is an alcohol and more preferably isopropanol.

The process of the invention provides a simple and efficient process for the preparation of solifenacin and its succinic acid salt which can be used in manufacture on an industrial scale. The yield of the solifenacin succinate preparation process expressed as per the starting (S)-l- phenyl-l,2,3,4-tetrahydroisoquinoline tartrate is between 75 and 81% and product purity determined by HPLC is more than 99.5%.

BEST MODE OF CARRYING OUT THE INVENTION

The present invention is further exemplified in following non-limiting examples.

Example -1

Separation of (S)-l-phenyl-l,2,3,4-tetrahydroisoquinoline from the corresponding salt with D-(-)-tartaric acid.

100 mL of toluene was added into a 250 mL reactor with a jacket, stirrer and bottom outlet and, subsequently, 27.34 g (0.076 mol) of (S)-l -phenyl- 1,2, 3 ,4-tetrahydroisoquinoline D-(-)-tartrate was suspended.

62 mL of 15% NaOH solution was added to the same flask. The resulting solution was stirred for 15 minutes. Subsequently, the stirrer was switched off and the aqueous and organic layers were allowed to separate over a period of 15 min. The aqueous layer was discarded and 40 mL of purified water was added to the organic phase. The contents were stirred for 15 min. Thereafter, the layers were separated and the bottom (aqueous) layer was discarded. Washing with purified water was additionally repeated thrice.

In order to dry the organic phase, azeotropic distillation of toluene with water was carried out in the following way:

70 mL of toluene was added to the organic phase obtained in the previous step and 70 mL of toluene was distilled from the organic phase. Subsequently, 50 mL of toluene was added to the residue, the content was stirred for 15 min and 50 mL of toluene was distilled again. The same operation was additionally repeated twice and the distillation residue was added to the dropping funnel and used for the next (solution A).

Enantiomeric purity of (S)-l -phenyl- 1, 2,3, 4-tetrahydroisoquinoline:

99.17% (HPLC). B. Synthesis of S-l-phenyl-3,4-dihvdro-lH-isoquinoline-2-carbonyl chloride

45 mL of toluene was measured into a 250 mL reactor with a jacket, stirrer and bottom outlet and 9.27 g (0.03 mol) of triphosgene was added to it. The resulting mixture was stirred at room temperature until the triphosgene dissolved (solution B).

2.59 mL (0.032 mol) of pyridine was added to solution A. Solution A with pyridine was added dropwise for 15 min to solution B at a temperature not higher than 50°C.

The reaction mixture was heated for 15 min to a temperature of 70°C and maintained at a temperature of 70-80°C for 30 min upon stirring.

The complete conversion of (S)-l -phenyl- 1, 2,3, 4-tetrahydroisoquinoline was monitored by a TLC solvent system of CH ₂ Cl ₂ -MeOH (95:5,v/v) against the reference (standard); the product formation ((S)-l-phenyl-3,4-dihydro-lH-isoquinoline-2-carbonyl chloride) was monitored using a solvent system of hexane-ethyl acetate system (95:5,v/v).

After the completion of the reaction, the reaction mixture was cooled to a temperature of 5°C and 40 mL of water was added.The temperature increased to 15°C (optionally, the resulting pyridine hydrochloride precipitate was filtered off before adding water). The aqueous-toluene phase was stirred for 0.5 hour; subsequently, it was left for 0.5 h for the layers to separate. The aqueous (bottom) phase was discarded and the organic phase was additionally washed 4 times with water (30 mL each) at a temperature of 20-25°C. The aqueous washings were discarded. After washing with water, the organic phase (toluene solution) was concentrated under a pressure of 50 mBar and temperature of 45°C (azeotropic drying) until no condensate appeared.

40 mL of THF was added to the toluene solution of (S)-l-phenyl-3,4-dihydro-lH-isoquinoline-2- carbonyl chloride (purity: 99.7%, HPLC) and the mixture was measured into a dropping funnel (solution C).

Testing the stability of (S)-l -phenyl- 1.2.3.4-tetrahydroisoquinolinecarbonyl chloride in conditions of solifenacin synthesis process

Two independent tests of chloride stability were carried out.

Test 1. Samples were taken up for HPLC analysis after 0, 1 and 3 hours of contact between the chloride toluene solution and water. Test 2. Samples were taken up for HPLC analysis after 1, 5 and 20 hours of contact between the chloride toluene solution and water.

Procedure:

150 mL of toluene was measured into a 500 mL round-bottom flask and, subsequently, 30 g of (iS -l -phenyl- 1, 2,3, 4-tetrahydroisoquinoline chloride was added. The content was stirred at room temperature until the (S)- 1 -phenyl- 1,2, 3, 4-tetrahydroisoquinoline chloride dissolved. Subsequently, 50 mL of water was added to the solution and the contents were stirred at ambient temperature to achieve phase contact. In order to sample the organic phase for HPLC analysis, the stirring was stopped for 10 min and a sample of the chloride toluene solution was taken from the upper organic layer. The chloride content was analysed by HPLC.

The result showed that no decomposition of 5)-l-phenyl-l,2,3,4-tetrahydroisoquinolinecarbonyl chloride had occurred in contact with water

C. Preparation of solifenacin

75 mL of THF was measured into a 250 mL reactor with a jacket, stirrer and bottom outlet and, subsequently, 9.61 g (0.076 mol) of R-3-quinuclidinol and 3.32 g (0.083 mol) of 60% NaH was suspended. The mixture was heated at boiling point for 45 min. White, dense suspension was formed in the reactor (mixture D).

Solution C was added dropwise for 1 h at boiling point to mixture D.

After the addition, the reaction mixture was maintained at this boiling temperature for 0.5 h with stirring. The complete conversion of (S)-l-phenyl-3,4-dihydro-lH-isoquinoline-2-carbonyl chloride was monitored by a TLC system of CH ₂ Cl ₂ -MeOH (9: 1 vol/vol). After the reaction was completed, THF was distilled from the reaction mixture at a temperature of 50-55°C under reduced pressure. The reaction mixture was cooled to a temperature of 20-25°C, 140 mL of toluene was added and, subsequently, 40 mL of water was added drop wise at a temperature of 20-25°C.

The organic phase was washed for 0.5 h at a temperature of 20-25°C and the layers were allowed to separate for 0.5 h. After separation, the aqueous phase was discarded and the organic (toluene) phase was additionally washed 4 times with water (30 mL each) at a temperature of 20-25°C. After phase separation, the organic phase was concentrated at reduced pressure at a temperature of 50-55°C until the product was obtained as an oil.

D. Preparation of solifenacin succinate

105 mL of isopropanol was added to the residue (crude solifenacin in the oil form (purity: 97.33% by HPLC)) at a temperature of 20-25°C. A solution of 8.50 g (0.072 mol) of succinic acid in 117 mL of isopropanol was prepared in a separate flask.

The mixture was heated to reflux for 5 min until the acid dissolved and, subsequently, clear hot succinic acid solution was added to the solifenacin isopropanol solution. The content was cooled with stirring. Crystallisation was observed at a temperature of 45°C. The mixture was cooled to 25°C and stirred at a temperature of 20-25°C for 2 h. The resulting precipitate was collected and washed twice with isopropanol (2 x 42 mL). The washed precipitate was dried using a dryer at a temperature of 55-60°C.

27.5 g of solifenacin succinate (purity: > 99.5% by HPLC and 99.89% by UPLC) was obtained. The yield of solifenacin succinate expressed as per (S)-l -phenyl- 1, 2,3, 4-tetrahydroisoquinoline tartrate was 75.3%. T _(onse t) (DSC): 150°C.

IR, λ (cm- ¹ ): 602, 621, 698, 752, 881, 934, 1015, 1045, 1073, 1098, 1123, 1181, 1202, 1246, 1320, 1384, 1425, 1448, 1491, 1588, 1686, 1721, 2936.

Solvents content by GC: pyridine <20 ppm, toluene 1 ppm, isopropanol 1000 ppm, THF - not found.