WO2011086003A1 - Procédé de préparation de solifénacine et de succinate de solifénacine - Google Patents

Procédé de préparation de solifénacine et de succinate de solifénacine Download PDF

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Publication number
WO2011086003A1
WO2011086003A1 PCT/EP2011/000175 EP2011000175W WO2011086003A1 WO 2011086003 A1 WO2011086003 A1 WO 2011086003A1 EP 2011000175 W EP2011000175 W EP 2011000175W WO 2011086003 A1 WO2011086003 A1 WO 2011086003A1
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Prior art keywords
iii
phenyl
solifenacin
process according
steps
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PCT/EP2011/000175
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English (en)
Inventor
Roman Szramka
Jersy Drygas
Marcin Szulc
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Zaklady Farmaceutyczne Polpharma Sa
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Publication of WO2011086003A1 publication Critical patent/WO2011086003A1/fr

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    • 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

Definitions

  • This invention relates to a process for the preparation of solifenacin and pharmaceutically acceptable salts thereof, including solifenacin succinate.
  • 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 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.
  • 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.
  • (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.
  • 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.
  • 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;
  • WO-2009142522 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.
  • 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.
  • 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.
  • the reaction is carried out in a tetrahydrofuran and heptane mixture.
  • solifenacin refers to solifenacin or the corresponsing succinate which contain below 0.15% of single identified impurities and below 0.5% of all total impurities.
  • the objects of the current invention is to provide methods to overcome the difficulties discussed above.
  • 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
  • (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.
  • chlorocarbonylating agent preferably triphosgene and aromatic azines, preferably pyridine.
  • 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.
  • the chlorocarbonylating agent is triphosgene
  • the aromatic azine is pyridine
  • the strong base is sodium hydride.
  • solvents used in steps (i) to (iii) comprise aprotic solvents or mixtures thereof.
  • 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.
  • the solvent in step (iii) is a mixture of aprotic solvents.
  • the solvent in step (iii) is a mixture of at least one aprotic non-polar solvent and at least one aprotic polar solvent.
  • the solvent in step (iii) is a mixture of tetrahydrofuran and toluene.
  • toluene is used as a solvent or co-solvent in any or all the steps from (i) to (iii).
  • the aprotic solvents are mixtures of tetrahydrofuran and toluene.
  • 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.
  • the products of steps (i)-(iii) are freed of impurities by washing with water and drying by azeotropic distillation.
  • the steps (i) to (iii) are carried out in a single reaction vessel.
  • steps (i) to (iv) are carried out without the isolation of intermediates in solid form from the reaction medium.
  • 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 .
  • chlorocarbonylating agent should include phosgene, diphosgene or tri phosgene and any other equivalent agent.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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
  • 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%.
  • the present invention is further exemplified in following non-limiting examples.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • solifenacin succinate purity: > 99.5% by HPLC and 99.89% by UPLC
  • the yield of solifenacin succinate expressed as per (S)-l -phenyl- 1, 2,3, 4-tetrahydroisoquinoline tartrate was 75.3%.
  • Solvents content by GC pyridine ⁇ 20 ppm, toluene 1 ppm, isopropanol 1000 ppm, THF - not found.

Abstract

La présente invention porte sur un procédé de préparation de solifénacine dans lequel toutes les étapes réactionnelles, depuis (i) la séparation de la (S)-1-phényl-1,2,3,4-tétrahydroisoquinoléine de son sel diastéréoisomérique avec l'acide D-(-)-tartrique, (ii) la conversion de la (S)-1-phényl-1,2,3,4-tétrahydroisoquinoléine en chlorure de 1-(5)-phényl-1,2,3,4-tétrahydroisoquinoléinecarbonyle au cours d'une réaction avec du triphosgène en présence de pyridine, jusqu'à (iii) la réaction entre le chlorure de 1-(5)-phényl-1,2,3,4-tétrahydroisoquinoléinecarbonyle et le 3-(S)-quinuclidinol en présence d'hydrure de sodium sont effectuées sans isolement des intermédiaires sous forme solide et les solvants utilisés pour les réactions sont des solvants aprotiques. La solifénacine ainsi obtenue sous forme de base libre est convertie en sel d'acide succinique correspondant à l'aide de procédés connus dans la technique.
PCT/EP2011/000175 2010-01-18 2011-01-18 Procédé de préparation de solifénacine et de succinate de solifénacine WO2011086003A1 (fr)

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PL390214A PL234208B1 (pl) 2010-01-18 2010-01-18 Sposób wytwarzania bursztynianu solifenacyny
PLP.390214 2010-01-18

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102875544A (zh) * 2012-09-19 2013-01-16 成都新恒创药业有限公司 琥珀酸索非那新的制备工艺
CN103450183A (zh) * 2013-08-16 2013-12-18 威海迪素制药有限公司 一种琥珀酸索利那新的制备方法
CN104447734A (zh) * 2014-12-11 2015-03-25 荆楚理工学院 一种琥珀酸索利那新的合成方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0801067A1 (fr) 1994-12-28 1997-10-15 Yamanouchi Pharmaceutical Co. Ltd. Nouveaux derives de quinuclidine et composition pharmaceutique les contenant
WO2005105795A1 (fr) 2004-04-28 2005-11-10 Astellas Pharma Inc. Procédé servant à produire de la solifénacine ou son sel
WO2007147374A2 (fr) 2006-06-21 2007-12-27 Zentiva A.S. Procédé de synthèse de solifénacine
WO2008062282A2 (fr) * 2006-11-22 2008-05-29 Medichem S.A. Procédé perfectionné pour la synthèse de solifénacine
WO2009142522A1 (fr) 2008-05-23 2009-11-26 Zaklady Farmaceutyczne Polpharma Sa Procede de preparation de solifenacine et/ou de ses sels pharmaceutiquement acceptables de haute purete pharmaceutique
WO2009142521A1 (fr) 2008-05-23 2009-11-26 Zaklady Farmaceutyczne Polpharma Sa Procédé de préparation de (s)-1-phényl-1,2,3,4-tetrahydroisoquinoléine enantiomériquement pure

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0801067A1 (fr) 1994-12-28 1997-10-15 Yamanouchi Pharmaceutical Co. Ltd. Nouveaux derives de quinuclidine et composition pharmaceutique les contenant
EP0801067B1 (fr) 1994-12-28 2003-03-05 Yamanouchi Pharmaceutical Co. Ltd. Nouveaux derives de quinuclidine et composition pharmaceutique les contenant
WO2005105795A1 (fr) 2004-04-28 2005-11-10 Astellas Pharma Inc. Procédé servant à produire de la solifénacine ou son sel
WO2007147374A2 (fr) 2006-06-21 2007-12-27 Zentiva A.S. Procédé de synthèse de solifénacine
WO2008062282A2 (fr) * 2006-11-22 2008-05-29 Medichem S.A. Procédé perfectionné pour la synthèse de solifénacine
WO2009142522A1 (fr) 2008-05-23 2009-11-26 Zaklady Farmaceutyczne Polpharma Sa Procede de preparation de solifenacine et/ou de ses sels pharmaceutiquement acceptables de haute purete pharmaceutique
WO2009142521A1 (fr) 2008-05-23 2009-11-26 Zaklady Farmaceutyczne Polpharma Sa Procédé de préparation de (s)-1-phényl-1,2,3,4-tetrahydroisoquinoléine enantiomériquement pure

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102875544A (zh) * 2012-09-19 2013-01-16 成都新恒创药业有限公司 琥珀酸索非那新的制备工艺
CN102875544B (zh) * 2012-09-19 2015-05-20 成都新恒创药业有限公司 琥珀酸索非那新的制备工艺
CN103450183A (zh) * 2013-08-16 2013-12-18 威海迪素制药有限公司 一种琥珀酸索利那新的制备方法
CN103450183B (zh) * 2013-08-16 2017-09-12 威海迪素制药有限公司 一种琥珀酸索利那新的制备方法
CN104447734A (zh) * 2014-12-11 2015-03-25 荆楚理工学院 一种琥珀酸索利那新的合成方法

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PL234208B1 (pl) 2020-01-31

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