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WO2001034561A1 - Procedes de preparation du sumatriptan et composes associes - Google Patents

Procedes de preparation du sumatriptan et composes associes Download PDF

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Publication number
WO2001034561A1
WO2001034561A1 PCT/EP2000/010581 EP0010581W WO0134561A1 WO 2001034561 A1 WO2001034561 A1 WO 2001034561A1 EP 0010581 W EP0010581 W EP 0010581W WO 0134561 A1 WO0134561 A1 WO 0134561A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
acid
salt
nhch
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2000/010581
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English (en)
Inventor
Nicholas John Holman
Christopher Lyndon Friend
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
BASF SE
Abbott GmbH and Co KG
Original Assignee
Knoll GmbH
BASF SE
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Knoll GmbH, BASF SE filed Critical Knoll GmbH
Priority to EP00972875A priority Critical patent/EP1226116A1/fr
Priority to CA002389514A priority patent/CA2389514A1/fr
Priority to AU11452/01A priority patent/AU1145201A/en
Priority to IL14864000A priority patent/IL148640A0/xx
Priority to JP2001536510A priority patent/JP2003513953A/ja
Publication of WO2001034561A1 publication Critical patent/WO2001034561A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups

Definitions

  • the present invention relates to processes for preparing phenylhydrazines which are useful intermediates in the preparation of indoles which are useful as therapeutic agents.
  • phenylhydrazines are key intermediates which may be cyclised into indoles using the well known Fischer indole synthesis.
  • the method of preparation of such compounds involves the diazotisation of an aniline followed by reduction of the diazonium salt obtained with stannous chloride dihydrate.
  • tin reagents in this reduction presents a number of problems. Firstly there are environmental issues relating to the disposal of toxic wastes containing tin residues. Secondly, low temperature vessels are required to carry out the reduction and thirdly it is often difficult to remove the last traces of tin salts from the intermediate and from later stages of the reaction sequence.
  • the present invention provides a process for preparing a compound of formula including salts thereof
  • R represents CH 2 SO 2 NHCH 3 , CH 2 CH 2 S0 2 Ph, CH 2 CH 2 S ⁇ 2 NHMe or a group of structure:
  • R is as previously defined and X- represents an anion derived from hydrochloric acid, sulphuric acid, acetic acid, phosphoric acid, tetrafluoroboric acid or hydrobromic acid, with a dithionite salt.
  • the present invention provides a process for preparing a compound of formula I or a salt thereof
  • R is as previously defined comprising the steps of a) reacting a compound of formula III or salt thereof
  • Suitable salts of the compounds of formula I and III include acid addition salts formed with organic or inorganic acids for example hydrochlorides, hydrobromides, sulphates, nitrates, phosphates, formates, mesylates, citrates, benzoates, fumarates, maleates, toluene-p-sulphonates and succinates.
  • the salt is the hydrochloride or hydro- bromide salt .
  • the present invention provides a process in which the compound of formula III or salt thereof as previously defined is prepared by reacting a compound of formula IV
  • the present invention comprises a process for preparing a compound of formula V
  • R is as previously defined and R1 is a group of formula a), b), c), d), or e)
  • a protected form of the aldehyde such as an acetal may be used this reaction.
  • an aldehyde or a protected form of the aldehyde of formula VII may be used where R2 is a group capable of being transformed into a group R1 upon cyclisation to a compound of formula V, for instance when R2 is -CH 2 CH 2 CI to give compounds of formula V with R1 is -CH2CH2NH 2 using the well known Grandberg version of the Fischer Indole synthesis.
  • R2C4CHO VII it may be preferred to synthesise one compound of formula V by reacting another compound of formula V, for instance, when R1 is CH 2 CH 2 NMe 2 by reductive alkylation of the compound V where R1 is CH 2 CH 2 NH 2
  • the diazotising agent is a metal nitrite salt or alkyl nitrite.
  • the diazotising agent is sodium nitrite or butyl nitrite.
  • the diazotising agent is sodium nitrite.
  • the diazotising agent is present in the range of 0.5-3 molar equivalents with respect to the compound of formula II.
  • the diazotising agent is present in the range of 0.8-1.5 molar equivalents with respect to the compound of formula II.
  • the diazotising agent is present in the range of 0.9-1.1 molar equivalents with respect to the compound of formula II.
  • a reagent for example sulphamic acid, to destroy excess nitrous acid at the end of this step.
  • the acid is hydrochloric acid, sulphuric acid, acetic acid, phosphoric acid, tetrafluoroboric acid or hydrobromic acid.
  • the acid is hydrochloric acid.
  • the acid is present in the range of 1 -10 molar equivalents with respect to the c KSoK m, , ipound of formula II .
  • the acid is present in the range of 2-8 molar equivalents with respect to the compound of formula II. More preferably the acid is present in the range of 3-6 molar equivalents with respect to the compound of formula II.
  • the dithionite salt is a metal dithionite salt.
  • the dithionite salt is sodium dithionite.
  • the dithionite is present in the range of 1-5 molar equivalents with respect to the compound of formula II and is used as an aqueous solution or suspension in the presence of base, preferably sodium hydroxide.
  • the dithionite is present in the range of 2-4 molar equivalents with respect to the compound of formula II and is used as an aqueous solution or suspension in the presence of base, preferably sodium hydroxide.
  • isopropanol can be used as a co-solvent to reduce foaming.
  • the diazotisation step is carried out at a temperature in the range of -20° C to +20° C.
  • the diazotisation step is carried out at a temperature in the range of -10°C to +10°C. More preferably the diazotisation step is carried out at a temperature in the range of -5°C to +5°C.
  • the reduction of the diazonium salt is carried out at a temperature in the range of -50 °C to +50° C.
  • the reduction of the diazonium salt is carried out at a temperature in the range of— 10°C to +30°C. More preferably the reduction of the diazonium salt is carried out at a temperature in the range of -5°C to +25 °C.
  • the reducing agent for the nitro compound is hydrogen in the presence of a catalyst, sodium dithionite, iron in the presence of acid or lithium aluminium hydride.
  • the reducing agent for the nitro compound is hydrogen in the presence of a catalyst, sodium dithionite, or lithium aluminium hydride.
  • the reducing agent for the nitro compound is hydrogen in the presence of a palladium catalyst.
  • the hydrogenation/diazonium reaction/reduction can be carried out as a one-pot reaction.
  • the present invention provides a process in which a compound of formula V
  • R is CH 2 SO 2 NHCH 3 and R1 is CH 2 CH 2 NMe 2
  • R is prepared by reacting a compound of formula V, in which R is CH 2 SO 2 NHCH 3 and R1 is CH 2 CH 2 NH 2 , with a reducing agent and a formaldehyde equivalent in the presence of a buffer.
  • the present invention provides a process for the preparation of sumatriptan or a pharmaceutically acceptable salt thereof comprising the following steps:
  • R is CH 2 SO 2 NHCH 3 and
  • R is CH 2 SO 2 NHCH 3 and X ⁇ represents a chloride, bromide, acetate, hydro- sulphate or phosphate anion and
  • R2 represents CICH 2 CH 2 -and the aldehyde group is protected as an acetal (preferably the dimethyl acetal) in the presence of a buffer optionally in the presence of an acid catalyst to give a compound of formula V
  • R is CH 2 SO 2 NHCH 3 and R1 is CH 2 CH 2 NH 2 and
  • the reducing agent is a hydride equivalent such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and lithium aluminium hydride.
  • the reducing agent is sodium borohydride or sodium cyanoborohydride.
  • the reducing agent is sodium borohydride.
  • the reducing agent is present in the range of 0.25 - 5 molar equivalents with respect to the compound of formula V.
  • the reducing agent is present in the range of 0.5 - 4 molar equivalents with respect to the compound of formula V. More preferably the reducing agent is present in the range of 0.75 - 3 molar equivalents with respect to the compound of formula V.
  • the formaldehyde equivalent is formaldehyde, paraformaldehyde or dimethoxymethane.
  • the formaldehyde equivalent is formaldehyde or paraformaldehyde.
  • the formaldehyde equivalent is formaldehyde as an aqueous solution.
  • the formaldehyde equivalent is present in the range of 0.5 - 18 molar equivalents with respect to the compound of formula V.
  • the formaldehyde equivalent is present in the range of 1 - 10 molar equivalents with respect to the compound of formula V. More preferably the formaldehyde equivalent is present in the range of 1.9 - 5 molar equivalents with respect to the compound of formula V.
  • the buffer used keeps the pH of the reaction solution between pH 6 and pH 14.
  • the buffer keeps the pH of the reaction solution between pH 7 and pH 11.
  • the buffer keeps the pH of the reaction solution between pH 8 and pH 10.
  • the buffer is sodium hydrogenphosphate.
  • the buffer is present in the range of 0.1 - 10 molar equivalents with respect to the compound of formula V.
  • the buffer is present in the range of 0.2 - 5 molar equivalents with respect to the compound of formula V.
  • the buffer is present in the range of 0.5 - 3 molar equivalents with respect to the compound of formula V.
  • Suitable pharmaceutically acceptable salts of the compound of formula V include acid addition salts formed with organic or inorganic acids for example hydrochlorides, hydrobromides, sulphates, nitrates, phosphates, formates, mesylates, citrates, benzoates, fumarates, maleates and succinates.
  • Other salts may be useful in the preparation of the compound of formula I e.g. creatinine sulphate adducts, and salts with e.g. toluene-p-sulphonic acid.
  • the salt is preferably the succinate salt or the hemisulphate salt .
  • the suspension was stirred for 2.75 hours. 46/48% w/w Sodium hydroxide (22 ml) was added and the mixture was stirred for 20 minutes at 20°C and then for 40 minutes at 0-5°C. The mixture was filtered and the product was washed with water (3 x 110 ml) and dried to give the free base of the product.
  • the mixture was stirred and boiled under reflux for a further 3 hours and then allowed to stand for 16 hours at ambient temperature.
  • the mixture was concentrated under reduced pressure (around 60 ml removed) and then dichioromethane (25 ml) and water (25 ml) were added, followed by potassium carbonate (0.74 g). At this point the pH was 5.
  • the mixture was filtered and the filtrate was separated.
  • the aqueous layer was washed with more dichioromethane (2 x 25 ml) and the combined organic layer and washings were evaporated to dryness under reduced pressure to give a solid by-product, yield 1.60 g.
  • the aqueous layer was mixed with dichioromethane (125 ml), absolute ethanol (60 ml) potassium carbonate (37 g) and water (12 ml). The mixture was stirred for 35 minutes and then separated. The organic layer was treated with charcoal and stirred at ambient temperature for 1 hour. The mixture was filtered and the filtrate was concentrated to a mass of 20 g under reduced pressure. The mixture was stirred for 1 hour and isopropyl acetate (62 ml) was added and the suspension was stirred for 64 hours.
  • V-Methyl-4-nitrobenzenemethanesulphonamide (46.0 g, 0.23 mol), 10% palladium on carbon (4.6 g) and 2M hydrochloric acid (180 ml) in water (200 ml) were stirred for 1.5 hours under 2.5 atmospheres of hydrogen at 20°C.
  • the reaction mixture was then filtered through a celite bed and washed with further water (100 ml). A portion of this filtrate (50 ml) was taken and then diluted with concentrated hydrochloric acid (12.7 ml).
  • the stirred suspension was cooled to below 0°C and a solution of sodium nitrite (2.2 g, 32 mmol) in water (4 ml) added dropwise over 20 minutes under an atmosphere of nitrogen.
  • the reaction mixture was then added via a cannula to a stirred suspension of sodium dithionite (135 g, 0.66 mol), water (365 ml), 46/48% w/w sodium hydroxide solution (23.5 ml) and IPA (40 ml) at -5°C. The temperature was kept around -5°C during the 40 minute addition. The suspension was then warmed to room temperature and stirred for 2.5 hours before 46/48% w/w Sodium hydroxide (53.5 ml) was added to give a pH of 7-8. Finally, the mixture was stirred for 30 minutes, product filtered and then washed with water (123 ml) to give a cream solid.
  • hydrochloric acid (20 ml) was added to the free base suspended in isopropanol (400 ml) at ambient. After stirring for 15 minutes, the product was collected by filtration, washed with isopropanol (125 ml) and dried to give 4-hydrazino- N-methylbenzenemethanesulphonamide hydrochloride (45.7 g, 73% at 97% purity by HPLC).
  • N-Methyl-4-nitrobenzenemethanesulphonamide (23.0 g, 0.1 mol), 5% palladium on carbon (9.4 g) and cone, hydrochloric acid (11 ml) in water (245 ml) were stirred for 2 hours under 5 atmospheres of hydrogen at 50°C.
  • the reaction mixture was then filtered through a celite bed and washed with further cone, hydrochloric acid (6 ml) in water (34 ml). The filtrate was then diluted with cone, hydrochloric acid (30 ml) and the solution cooled to -5°C to give a suspension.
  • 3-(2-Aminoethyl)- ⁇ /-methyl-1 H-indole-5-methanesulphonamide (5.0 g, 18.7 mmol), prepared by the method of Example 1 , and sodium hydrogenphosphate (5.0 g, 35.2 mmol) were heated to 40° C in methanol (50 ml) for 15 minutes and then recooled to room temperature. Solutions of 37% aqueous formaldehyde (5 ml) and sodium borohydride (0.72 g) in water (5 ml stabilised with one drop of 46/48% w/w sodium hydroxide) were added simultaneously over one hour at a temperature between 17 and 21 °C.
  • This material was of suitable quality for conversion into sumatriptan mono-succinate or sumatriptan hemisulphate as described in GB 2,162,522 and EP 490,689 respectively.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Indole Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention se rapporte à un procédé de préparation de phénylhydrazines de formule (I) dans laquelle R représente CH2SO2NHCH3, CH2CH2SO2Ph, CH2CH2SO2NHMe ou un groupe de structure (A), (B), (C), consistant à réduire par un sel de dithionite un sel de diazonium représenté par la formule (II), dans laquelle X représente un anion dérivé de l'acide chlorhydrique, de l'acide sulfurique, de l'acide acétique, de l'acide phosphorique, de l'acide tétrafluoroborique ou de l'acide bromhydrique. Les phénylhydrazines résultantes peuvent être transformées en dérivés indole correspondants par une synthèse d'indole de Fischer.
PCT/EP2000/010581 1999-11-06 2000-10-27 Procedes de preparation du sumatriptan et composes associes Ceased WO2001034561A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
EP00972875A EP1226116A1 (fr) 1999-11-06 2000-10-27 Procedes de preparation du sumatriptan et composes associes
CA002389514A CA2389514A1 (fr) 1999-11-06 2000-10-27 Procedes de preparation du sumatriptan et composes associes
AU11452/01A AU1145201A (en) 1999-11-06 2000-10-27 Processes for the preparation of sumatriptan and related compounds
IL14864000A IL148640A0 (en) 1999-11-06 2000-10-27 Processes for the preparation of sumatriptan and related compounds
JP2001536510A JP2003513953A (ja) 1999-11-06 2000-10-27 スマトリプタン及び関連化合物の製造方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9926250.3 1999-11-06
GBGB9926250.3A GB9926250D0 (en) 1999-11-06 1999-11-06 Chemical process

Publications (1)

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WO2001034561A1 true WO2001034561A1 (fr) 2001-05-17

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PCT/EP2000/010581 Ceased WO2001034561A1 (fr) 1999-11-06 2000-10-27 Procedes de preparation du sumatriptan et composes associes

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EP (1) EP1226116A1 (fr)
JP (1) JP2003513953A (fr)
AR (1) AR026362A1 (fr)
AU (1) AU1145201A (fr)
CA (1) CA2389514A1 (fr)
GB (1) GB9926250D0 (fr)
IL (1) IL148640A0 (fr)
WO (1) WO2001034561A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004014877A1 (fr) * 2002-08-07 2004-02-19 Vita Cientifica, S.L. Procede de preparation de rizatriptan
WO2004099141A1 (fr) * 2003-05-12 2004-11-18 Ramesh Babu Potluri Nouveau procede pour la preparation de derives d'indole
WO2005103035A1 (fr) * 2004-04-23 2005-11-03 Pfizer Limited Preparation d'eletriptan consistant en une synthese modifiee d'indole par la methode de fischer
KR100566562B1 (ko) 2004-04-23 2006-03-31 주식회사 카이로제닉스 수마트립탄의 제조방법
US7645886B2 (en) 2002-12-20 2010-01-12 Ciba Specialty Corporation Synthesis of amines and intermediates for the synthesis thereof
CN102351754A (zh) * 2011-08-03 2012-02-15 山东新华制药股份有限公司 4-氨基-n-甲基苯甲磺酰胺的制备工艺
CN102432519A (zh) * 2011-11-21 2012-05-02 山东新华制药股份有限公司 3-（2-氨乙基）-n-甲基-1h-吲哚-5-甲烷磺酰胺的制备方法
CN102964287A (zh) * 2012-11-13 2013-03-13 苏州永健生物医药有限公司 一种3-（4-氯丁基）-5-氰基吲哚新的合成方法
CN106397359A (zh) * 2016-08-31 2017-02-15 重庆华森制药股份有限公司 阿莫曲坦中间体4‑（1‑吡咯烷基磺酰甲基)‑苯肼的制备方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2170824A1 (fr) * 2007-08-02 2010-04-07 Generics Ýuk¨Limited Nouveau procédé

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L.J. STREET, ET AL.: "Synthesis and serotonergic activity of N,N-dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethylamine and analogues: potent agonists for 5-HT1D reseptors", JOURNAL OF MEDICINAL CHEMISTRY, vol. 38, no. 10, 12 May 1995 (1995-05-12), American Chemical Society, Washington, DC, US, pages 1799 - 1810, XP000608327, ISSN: 0022-2623 *
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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7279581B2 (en) 2002-08-07 2007-10-09 Inke, S.A. Process for preparing a pharmaceutically active compound
WO2004014877A1 (fr) * 2002-08-07 2004-02-19 Vita Cientifica, S.L. Procede de preparation de rizatriptan
EP2666772A1 (fr) 2002-12-20 2013-11-27 Basf Se Synthèse d'amines et intermédiaires pour leur synthèse
US7645886B2 (en) 2002-12-20 2010-01-12 Ciba Specialty Corporation Synthesis of amines and intermediates for the synthesis thereof
US7968730B2 (en) 2002-12-20 2011-06-28 Basf Se Synthesis of amines and intermediates for the synthesis thereof
US8822702B2 (en) 2002-12-20 2014-09-02 Basf Se Synthesis of amines and intermediates for the synthesis thereof
WO2004099141A1 (fr) * 2003-05-12 2004-11-18 Ramesh Babu Potluri Nouveau procede pour la preparation de derives d'indole
WO2005103035A1 (fr) * 2004-04-23 2005-11-03 Pfizer Limited Preparation d'eletriptan consistant en une synthese modifiee d'indole par la methode de fischer
KR100566562B1 (ko) 2004-04-23 2006-03-31 주식회사 카이로제닉스 수마트립탄의 제조방법
CN102351754A (zh) * 2011-08-03 2012-02-15 山东新华制药股份有限公司 4-氨基-n-甲基苯甲磺酰胺的制备工艺
CN102432519A (zh) * 2011-11-21 2012-05-02 山东新华制药股份有限公司 3-（2-氨乙基）-n-甲基-1h-吲哚-5-甲烷磺酰胺的制备方法
CN102432519B (zh) * 2011-11-21 2013-12-11 山东新华制药股份有限公司 3-(2-氨乙基)-n-甲基-1h-吲哚-5-甲烷磺酰胺的制备方法
CN102964287B (zh) * 2012-11-13 2014-04-09 苏州永健生物医药有限公司 一种3-（4-氯丁基）-5-氰基吲哚的合成方法
CN102964287A (zh) * 2012-11-13 2013-03-13 苏州永健生物医药有限公司 一种3-（4-氯丁基）-5-氰基吲哚新的合成方法
CN106397359A (zh) * 2016-08-31 2017-02-15 重庆华森制药股份有限公司 阿莫曲坦中间体4‑（1‑吡咯烷基磺酰甲基)‑苯肼的制备方法
CN106397359B (zh) * 2016-08-31 2017-12-05 重庆华森制药股份有限公司 阿莫曲坦中间体4‑(1‑吡咯烷基磺酰甲基)‑苯肼的制备方法

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AU1145201A (en) 2001-06-06
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