WO2005103035A1 - Preparation d'eletriptan consistant en une synthese modifiee d'indole par la methode de fischer - Google Patents

Preparation d'eletriptan consistant en une synthese modifiee d'indole par la methode de fischer Download PDF

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Publication number
WO2005103035A1
WO2005103035A1 PCT/IB2005/000942 IB2005000942W WO2005103035A1 WO 2005103035 A1 WO2005103035 A1 WO 2005103035A1 IB 2005000942 W IB2005000942 W IB 2005000942W WO 2005103035 A1 WO2005103035 A1 WO 2005103035A1
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Prior art keywords
formula
compound
solution
group
acid
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PCT/IB2005/000942
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English (en)
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Christopher Paul Ashcroft
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Pfizer Limited
Pfizer Inc.
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Priority claimed from GB0409134A external-priority patent/GB0409134D0/en
Application filed by Pfizer Limited, Pfizer Inc. filed Critical Pfizer Limited
Publication of WO2005103035A1 publication Critical patent/WO2005103035A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a new process for the preparation of eletriptan, or its enantiomer, or a pharmaceutically acceptable salt of either.
  • Eletriptan is currently marketed worldwide for the treatment of migraine as Relpax® and is therefore manufactured in bulk quantity.
  • the large-scale synthesis of a drug molecule should be short, high-yielding and selective and avoid the use of toxic or dangerous materials.
  • the prior art syntheses of eletriptan exemplified in the prior art discussed above, suffer from the use of phenyl vinyl sulphone, which is a toxic chemical and hazardous to handle on a large scale and the use of palladium in a later-stage step which can necessitate extensive purification.
  • the known routes are non-convergent and rather long which leads to a relatively high cost of goods.
  • the present invention therefore provides a process for the preparation of a compound of formula (I) (I)
  • R 1 is a suitable hydrazine protecting group, with a compound of formula (III)
  • R 2 is an aldehyde group (-CHO) or the functional equivalent thereof.
  • the reaction may optionally be carried out in the presence of an inert solvent.
  • a preferred solvent is acetonitrile.
  • the reaction is usually carried out in the presence of an acid catalyst, preferably sulphuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid or tetrafluoroboric acid, most preferably sulphuric acid.
  • the product may be isolated as the free base or, depending on which acid catalyst is used, as a salt.
  • a suitable hydrazine protecting group is one that is able to stabilise the hydrazine under the reaction conditions but does not prevent its participation in the reaction with compound (III).
  • Such a protecting group will usually be acid-labile.
  • Compounds of formula (II) embodying particularly preferred protecting groups include a compound of formula:
  • R 3 is a C- ⁇ -C 6 tertiary alkyl group or a -CH 2 (aryl) group.
  • a tertiary alkyl group bears no hydrogen atoms on the carbon atom through which it is attached.
  • Example of tertiary alkyl groups are -C(CH 3 ) 3 (1 ,1-dimethylethyl) and -C(CH 3 ) 2 CH 2 CH 3 (1 ,1-dimethylpropyl).
  • Aryl means a radical formed by removing a hydrogen atom from an aromatic hydrocarbon and is preferably phenyl or naphthyl.
  • Preferred salts of a compound of formula (IIA) are the ammonium salt and salts containing a Group I or Group II metal cation. Most preferred is the calcium salt of formula:
  • a functional equivalent of an aldehyde is one that will break down under the reaction conditions to release an aldehyde or one that will take part in the reaction as an electrophile as if it were an aldehyde.
  • Particular functional equivalents worthy of mention are aldehyde hydrates, hemiacetals and acetals.
  • a preferred compound of formula (III) is an acetal of formula:
  • R 4 and R 5 are each independently Ci-Ce alkyl, or R 4 and R 5 , taken together, form a 1 ,2-ethylene or 1 ,3-propylene group optionally substituted by one or more d- C ⁇ alkyl group(s).
  • alkyl groups containing the requisite number of carbon atoms, can be unbranched or branched chain. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl.
  • Particularly preferred compounds of formula (IIIA) are compounds of formula:
  • a compound of formula (I) may exist in either of two enantiomeric forms (IA) and (IB):
  • the compound of formula (IB) being eletriptan.
  • the process of the invention is equally suitable for preparing a compound of formula (IA) or (IB) or any mixture thereof.
  • Individual enantiomers (IA) and (IB) may be prepared by using the corresponding enantiomerically pure starting material of formula (III) or by resolution of a racemic compound of formula (I), using, for example, chiral HPLC, or fractional crystallisation of diastereoisomeric salts formed by reaction of the racemate with a suitable optically active acid or base.
  • a compound of formula (IIIA) may be prepared by the hydrogenation of a compound of formula:
  • R 4 and R 5 are as defined above.
  • a solution of the compound of formula (IV) in an inert solvent such as ethanol is treated with a hydrogenation catalyst, preferably a rhodium catalyst, and hydrogen.
  • a hydrogenation catalyst preferably a rhodium catalyst, and hydrogen.
  • elevated temperature preferably about 70°C
  • pressure preferably about 690 kPa, 100 p.s.i.
  • a compound of formula (IV) may be prepared by the reaction of a compound of formula:
  • R 4 and R 5 are as defined above.
  • a solution of the compound of formula (VI) and the compound of formula (V), in an inert solvent such as dimethylformamide, is treated with a base such as sodium ethoxide.
  • the reaction is carried out at an elevated temperature, typically at about 80 °C.
  • a compound of formula (VI) may be prepared by treating a compound of formula:
  • R 4 and R 5 are as defined above, with triphenylphosphine.
  • a solution of the compound of formula (VII) in an inert solvent such as acetonitrile is treated with triphenylphosphine and heated to a temperature of about 80 °C.
  • R 4 /R 5 groups can be interchanged by treating a compound of formula (VII) with an appropriate alcohol and an acid catalyst, such as sulphuric acid, optionally in an inert solvent such as toluene.
  • R 4 and R 5 are as defined above and P 1 is a protecting group which is removable by hydrogenation, preferably benzyloxycarbonyl.
  • P 1 is a protecting group which is removable by hydrogenation, preferably benzyloxycarbonyl.
  • Other suitable protecting groups are described in 'Protective Groups in Organic Synthesis' by Theorora Greene and Peter Wuts (third edition, 1999, John Wiley and Sons).
  • a solution of a compound of formula (VIII) in an inert solvent such as methanol is treated with a hydrogenation catalyst, preferably a palladium catalyst such as palladium on carbon, " and hydrogenated, preferably at elevated temperature (most preferably at about 50°C) and elevated pressure (most preferably at about 414 Kpa, 60 psi).
  • a compound of formula (VIII) may be prepared by the reaction of a compound of formula:
  • the compound of formula (IX) is a Weinreb amide, i.e. L 1 is -N(OCH 3 )CH 3 . L 1 may also be -O(CrC 6 alkyl).
  • M 1 will be - Li, -MgX (wherein X is a halide) or an aluminium compound such as -AI(CH 3 )2-
  • a solution of a compound of formula (IX) in a suitable inert solvent, such as tetrahydrofuran is added to a solution of a compound of formula (X) in a suitable inert solvent, such as tetrahydrofuran.
  • suitable inert solvent such as tetrahydrofuran
  • Compounds of formula (X) can be prepared by conventional methods well known to the skilled person. For instance, where M 1 is -MgBr (i.e.
  • the compound of formula (X) is a Grignard reagent
  • a solution of a compound of formula (X) wherein M 1 is a bromo group in a suitable inert solvent, such as tetrahydrofuran, is treated with magnesium and a suitable catalyst such as iodine and heated, preferably to about 65 °C.
  • a compound of formula (MA) may be prepared by diazotisation of a compound of formula:
  • a solution of a compound of formula (XII) in a suitable water-miscible solvent such as acetonitriie is treated with an acid, preferably sulphuric acid and an aqueous sojution of a nitrite, preferably sqdium nitrite.
  • the diazonium salt so produced is then reduced by addition of an aqueous solution of ascorbic acid to give the compound of formula (IIA).
  • This compound is easily converted into a salt form by conventional techniques. For instance, treatment with potassium hydroxide and calcium chloride in a mixture of water and acetonitriie gives the calcium salt.
  • Characteristic chemical shifts are given in parts-per-million downfield from tetramethylsilane using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad.
  • the mass spectra were recorded using either electrospray ionisation (ESI) or atmospheric pressure chemical ionisation (APCI).
  • ESI electrospray ionisation
  • APCI atmospheric pressure chemical ionisation
  • the following abbreviations have been used for common solvents: CDCI3, deuterochloroform; D 6 DMSO, deuterodimethylsulphoxide;
  • Carbonyldiimidazole (32g, 195mmoles) was added to a solution of the acid of
  • the freshly prepared Grignard solution was added to a solution of the Weinreb amide of Example 2 (40g, 136mmoles) in THF (250ml) at 4°C under an atmosphere of nitrogen. The mixture was refluxed for 2 hours, which gave a white precipitate.
  • the reaction was poured into aqueous citric acid solution (10%w/v, 250ml) and the organic layer was separated, concentrated at reduced pressure and redissolved in (tert -butylmethyl ether (200ml). The resulting solution was washed with the original citric acid solution and water (200ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (47.5g, 95%) as a clear oil.
  • the catalyst was removed by filtration through a filter aid (Cellite TM) and evaporation of the filtrate at reduced pressure gave the free base product as a clear oil.
  • the free base was dissolved in a mixture of ethyl acetate (200ml) and methanol (20ml) and a solution of fumaric acid (10.5g, 95mmoles) in methanol (100ml) was added.
  • the methanol was removed azeotropically by distilling off 180ml of solvent and further ethyl acetate (180ml) was added.
  • the precipitated product was granulated for 16 hours, collected by filtration and dried under vacuum to constant mass to yield the title compound (20.2g, 71%) as a white crystalline solid.
  • Tributylphosphine (100ml, 717mmoles) was added to a solution of the alkyl bromide of Example 5 (96g, 458mmoles) in acetonitriie (400ml) under an atmosphere of nitrogen and the resulting mixture was heated at 80°C for 16 hours. The solvent was removed at reduced pressure and the residue was dissolved in dimethylformamide (500ml) under an atmosphere of nitrogen. To this solution was added 1-methyl-1 H- pyrrole-2-carboxaldehyde (50g, 458mmoles) and then a solution of sodium ethoxide in ethanol (21%w/w, 221 ml, 595mmoles). The resulting mixture was heated at 80°C for 3 hours.
  • the reaction mixture was diluted with water (500ml) and extracted twice with heptane (2 x 350ml). The combined organic extracts were repeatedly washed with water (7 x 250ml), dried over magnesium sulfate, filtered and concentrated to give a brown oil which crystallised on standing. Trituration with heptane (150ml) and filtration gave the title compound (35.5g, 35%) as a brown solid.
  • Example 6 A solution of the pyrrole acetal of Example 6 (4.9g, 22.1 mmoles) in ethanol (100ml) was treated with 5% rhodium on carbon (50%, wet, 1g) and hydrogenated at 70°C and 690 kPa (100 p.s.i.) for 16 hours with stirring. After this time the catalyst was removed by filtration through a filter aid (Cellite T ) and the filtrate was evaporated at reduced pressure. The residue was dissolved in ethyl acetate (25ml) and a solution of fumaric acid (2.57g, 22.1 mmoles) in methanol (25ml) was added.
  • the methanol was removed by azeotropic distillation and replaced with ethyl acetate, maintaining a volume of 50ml.
  • the precipitated product was granulated for 16 hours, collected by filtration and dried under vacuum to constant mass to yield the title compound (7.2g, 95%) as a white crystalline solid.
  • 2-(4-Nitrophenyl)ethylphenyl sulfone (Example 8, 10g, 0.034 mol) was charged to a flask and tetrahydrofuran (340 ml) was added. The reaction mixture was placed under an inert atmosphere. Under a steady flow of inert gas, palladium on carbon (10%, 1g) was added and rinsed in with tetrahydrofuran (20 ml). A slurry of ammonium formate (10.9g, 0.17 moles) in methanol (70 ml) was charged to the flask and rinsed in with tetrahydrofuran (20 ml).
  • Aqueous sulfuric acid (1.88M, 84ml, 158mmoles) was added to a slurry of the calcium salt of Example 11 (11.7g, 15.9mmoles) and the fumarate salt of Example 4 (10.0g, 31.8mmoles) in acetonitriie (84ml).
  • the reaction mixture was heated at 80°C with stirring for 16 hours, and then poured into aqueous potassium hydroxide solution (82ml, 2M, 164mmoles).
  • the resulting mixture was extracted twice with ethyl acetate (2 x 200ml).
  • the combined organic phases were washed with water (200ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (10.2g, 84%) as a brown oil.
  • Example 10 To a solution of the hydrazinooxalate of Example 10 (1.33g, 3.83mmoles) in acetonitriie (7ml) was added the pyrrolidine acetal fumarate salt of Example 4 (1.2g, 3.83mmoles) followed by aqueous sulfuric acid (1.88M, 7ml, 13.2mmoles). The resulting solution was heated at 80°C, with stirring, for 16 hours and poured into aqueous potassium hydroxide solution (10ml, 2M, 19.7mmoles). The mixture was extracted twice with ethyl acetate (2 x 10ml). The combined organic phases were washed with water (10ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (1.05g, 72%) as a brown oil.
  • the mixture was diluted with water and the pyrrolidine acetal fumarate salt of Example 4 (1.2g, 3.83mmoles) was added.
  • the reaction mixture was heated at 80°C for 16hours and subsequently neutralised with aqueous potassium hydroxide solution (15ml, 5M, 75.0mmoles) and diluted with water (50ml).
  • the product was extracted twice with ethyl acetate (2 x 20ml) and the combined organic phases were washed with water (20ml), dried with magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (1.45g, 100%) as a brown oil.
  • Example 11 To a slurry of the hyazinooxalate calcium salt of Example 11 (0.1 Og, 0.136mmoles) and the pyrrolidine acetal fumarate salt of Example 7 (0.94g ⁇ 0.272mmoles) in acetonitriie (3ml) was added aqueous sulfuric acid (1.88M, 7ml, 13.2mmoles). The solution was heated at 80°C with stirring for 16 hours and then poured into aqueous potassium hydroxide solution (10ml, 2M, 20mmoles).
  • Example 11 To a slurry of the hydrazinooxalate calcium salt of Example 11 (1.Og, 1.35mmoles) and the pyrollidine acetal dibenzoyl-L-tartrate salt of Example 16 (1.5g, 2.7mmoles in acetonitriie (8ml) was added aqueous sulfuric acid (10%v/v, 1.88M, 8ml, 15mmoles). The resulting solution was heated at 80°C with stirring for 16hours, and then poured into aqueous potassium hydroxide solution (50ml, 2M, lOOmmoles).

Abstract

L'invention concerne un nouveau procédé de préparation d'élétriptan ou de son énantiomère comprenant une synthèse modifiée d'indole par la méthode de Fischer. Ce procédé consiste à faire réagir un composé représenté par la formule (II), dans laquelle R1 représente un groupe protecteur hydrazine, avec un groupe aldéhyde (-CHO) ou son équivalent fonctionnel.
PCT/IB2005/000942 2004-04-23 2005-04-08 Preparation d'eletriptan consistant en une synthese modifiee d'indole par la methode de fischer WO2005103035A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB0409134A GB0409134D0 (en) 2004-04-23 2004-04-23 Improved process
GB0409134.4 2004-04-23
US57025604P 2004-05-11 2004-05-11
US60/570,256 2004-05-11

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WO2005103035A1 true WO2005103035A1 (fr) 2005-11-03

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102786514A (zh) * 2012-07-26 2012-11-21 武汉人福医药集团股份有限公司 依来曲普坦的新制备方法
US8633239B2 (en) 2008-10-31 2014-01-21 Biophore India Pharmaceuticals Private Limited Process for the preparation of eletriptan
CN107628973A (zh) * 2017-09-19 2018-01-26 济南大学 一种依来曲普坦中间体4‑硝基苯基‑2‑(4‑苯磺酰肼)乙烷的合成方法
WO2019224138A1 (fr) 2018-05-24 2019-11-28 Bayer Aktiengesellschaft Procédé de fabrication de n-arylpyrazoles substitués

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001034561A1 (fr) * 1999-11-06 2001-05-17 Basf Aktiengesellschaft Procedes de preparation du sumatriptan et composes associes

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001034561A1 (fr) * 1999-11-06 2001-05-17 Basf Aktiengesellschaft Procedes de preparation du sumatriptan et composes associes

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8633239B2 (en) 2008-10-31 2014-01-21 Biophore India Pharmaceuticals Private Limited Process for the preparation of eletriptan
CN102786514A (zh) * 2012-07-26 2012-11-21 武汉人福医药集团股份有限公司 依来曲普坦的新制备方法
CN107628973A (zh) * 2017-09-19 2018-01-26 济南大学 一种依来曲普坦中间体4‑硝基苯基‑2‑(4‑苯磺酰肼)乙烷的合成方法
WO2019224138A1 (fr) 2018-05-24 2019-11-28 Bayer Aktiengesellschaft Procédé de fabrication de n-arylpyrazoles substitués

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