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EP2396308A1 - Nouveau procédé de fabrication - Google Patents

Nouveau procédé de fabrication

Info

Publication number
EP2396308A1
EP2396308A1 EP10703274A EP10703274A EP2396308A1 EP 2396308 A1 EP2396308 A1 EP 2396308A1 EP 10703274 A EP10703274 A EP 10703274A EP 10703274 A EP10703274 A EP 10703274A EP 2396308 A1 EP2396308 A1 EP 2396308A1
Authority
EP
European Patent Office
Prior art keywords
general formula
compound
sodium
alkyl
compounds
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.)
Withdrawn
Application number
EP10703274A
Other languages
German (de)
English (en)
Inventor
Adil Duran
Markus Frank
Waldemar Pfrengle
Juergen Schnaubelt
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.)
Boehringer Ingelheim International GmbH
Original Assignee
Boehringer Ingelheim International GmbH
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 Boehringer Ingelheim International GmbH filed Critical Boehringer Ingelheim International GmbH
Priority to EP10703274A priority Critical patent/EP2396308A1/fr
Publication of EP2396308A1 publication Critical patent/EP2396308A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring

Definitions

  • the present invention is a process for the preparation of compounds of general formula I.
  • m, n, R 1 and R 2 are defined as mentioned below, their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically acceptable salts with organic or inorganic acids or bases.
  • the present invention relates to a technical process for the preparation of compounds of general formula I which have B1 -antagonistic properties. Furthermore, the invention relates to the compounds of general formulas V per se, since these are particularly suitable for the preparation of the compounds of general formula I.
  • a first subject of the present invention relates to a process for the preparation of compounds of general formula I.
  • n is the number 0, 1 or 2
  • R 2 is H or C 1-3 alkyl
  • step (c) reacting a compound of the general formula obtained under step (b)
  • X is a hydrogen atom, an alkali metal such as lithium, sodium or potassium, or a Ci -4 alkyl group is, preferably, however, sodium, and Y is a halogen atom, for example chlorine or bromine, preferably chlorine;
  • step (d) optionally recrystallization of a compound of general formula V obtained in step (c)
  • R 2 is as hereinbefore defined and X is a hydrogen atom, an alkali metal such as lithium, sodium or potassium, or a C 4 alkyl group, but preferably sodium, in a solvent;
  • R 2 is as hereinbefore defined and X is a hydrogen atom, an alkali metal such as lithium, sodium or potassium, or a C 4 alkyl group, but preferably sodium, with a compound of general formula VI
  • n, R 1 and R 2 are defined as mentioned above and o is one of the numbers 0, 1, 2 or 3, preferably 3;
  • step (a) preferably 1.0 equivalents of 3,5-dimethylanisole are reacted with 1.5 to 2.5 equivalents, preferably 1.8 to 2.2 equivalents, of chlorosulfonic acid.
  • the reaction can be carried out in a solvent which is selected from the group consisting of dichloromethane, chloroform and 1, 2-dichloroethane.
  • the solvent may be used in an amount of 0.25 to 1.25 L / mol, preferably 0.60 to 0.90 L / mol of 3,5-dimethylanisole used.
  • the reaction at a low temperature, for example between -40 and 0 C 0 0 C, preferably between -30 ° C and 0 0 C, more preferably between -35 ° C and -10 ° C, more preferably between -20 ° C and -10 0 C, performed.
  • step (b) preferably 1.0 equivalents of 2,6-dimethyl-4-methoxysulfonyl chloride are reacted with from 1.5 to 2.5 equivalents, preferably from 1.8 to 2.2 equivalents, of a compound of the general formula II.
  • the reaction may be carried out in a solvent selected from the group consisting of dichloromethane, chloroform and 1, 2-dichloroethane.
  • the solvent may be used in an amount of 0.25 to 1.25 L / mol, preferably 0.5 to 1.0 L / mol of 2,6-dimethyl-4-methoxysulfonyl chloride used.
  • the reaction is carried out at a temperature below room temperature, for example between -0 ° C and 20 ° C, preferably between 5 ° C and 15 ° C.
  • the reaction mixture may further be added to a base.
  • the base may be selected from the group consisting of potassium tert-butylate, potassium carbonate, sodium carbonate, lithium carbonate, sodium hydride, sodium methoxide and
  • Sodium ethanolate preferably potassium tert-butylate. It can be added in an amount of from 1.2 to 2.0 equivalents, preferably from 1.3 to 1.6 equivalents, based on the amount of compound of general formula III used.
  • the compound of general formula V obtained in step (c) may be purified by recrystallization from a solvent selected from the group consisting of water, tetrahydrofuran, methyltetrahydrofuran, acetone or mixtures thereof prior to the reaction described in step (e).
  • 1.0 equivalents of a compound of general formula VI are reacted with 1.0 to 1.5 equivalents, preferably 1.0 to 1.2 equivalents, of a compound of general formula V.
  • the reaction can be carried out in a solvent which is selected from the group consisting of tetrahydrofuran, methyltetrahydrofuran, dichloromethane, toluene,
  • the reaction mixture may further be added to a base.
  • the base may be selected from the group consisting of potassium tert -butylate, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine and diazabicyclo [5.4.0] undec-7-ene (DBU), preferably potassium tert -butylate.
  • a coupling reagent can be added to the reaction mixture.
  • the coupling reagent may be selected from the group consisting of propane phosphonic anhydride, thionyl chloride, N, N, N ', N'-tetramethyl-O- (benzotriazol-1-yl) uronium tetrafluoroborate, carbodiimide and 1, 1'carbonyldiimidazole; Propanephosphonic anhydride is preferably used according to the invention.
  • the reaction is carried out at elevated temperature, for example between 40 0 C and 60 0 C.
  • the isolation described under (f) is preferably carried out by concentration to dryness or crystallization from water or dichloromethane, methanol, ethanol, propanol, butanol, isopropyl acetate, ethyl acetate, tetrahydrofuran, methyltetrahydrofuran, dioxane, methyl isobutyl ketone, toluene, xylene or mixtures of these solvents, water , Ethanol, tetrahydrofuran, ethyl acetate, methyl isobutyl ketone and toluene or mixtures thereof are preferably used.
  • a second object of the present invention relates to a process described above under the first article for the preparation of compounds of general formula I, characterized in that
  • n 1
  • n is the number 1
  • a third object of the present invention relates to the compounds of general formula V
  • R 2 is H or d -3 alkyl
  • X is hydrogen, lithium, sodium, potassium or a Ci -4 alkyl group, preferably sodium.
  • a preferred third article comprises the following compounds Va to Vd of general formula V: No structure
  • a further preferred third object relates to the compound of the formula Vd
  • the value given was determined by differential of a melting point determining apparatus determines (Mettler Toledo FP90 Central, 5 ° C / min in the range 50-150 0 C and / or 1 ° C / min in the range 100-180 0 C).
  • a fourth subject of the present invention relates to the use of the abovementioned compounds of general formula V as intermediates for the preparation of compounds of general formula I according to a method described above in the first embodiment.
  • the compounds of the invention including their salts, in which one or more hydrogen atoms, for example one, two, three, four or five hydrogen atoms, are replaced by deuterium.
  • C 1-3 -alkyl (including those which are part of other groups) are branched and unbranched alkyl groups having 1 to 3 carbon atoms and the term “C- M- alkyl” are branched and unbranched alkyl groups having 1 to 4 Carbon atoms understood. Examples include: methyl, ethyl, n-propyl, / so-propyl, n-butyl, / so-butyl or te / f.-butyl.
  • the abbreviations Me, Et, n-Pr, / -Pr, n-Bu, / -Bu, tert-Bu, etc. are also used for the abovementioned groups.
  • Cs- ⁇ -cycloalkyl (including those which are part of other radicals) is understood as meaning cycloalkyl groups having 3 to 6 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopenty or cyclohexyl.
  • the compounds of general formula I may have basic groups such as amino functions. They can therefore be used as internal salts, as salts with pharmaceutically usable inorganic acids such as hydrobromic acid, phosphoric acid, nitric acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or organic acids such for example, malic acid, succinic acid, acetic acid, fumaric acid, maleic acid, mandelic acid, lactic acid, tartaric acid or citric acid.
  • the compounds of general formula I may be present as salts or co-crystals with chiral organic acids.
  • chiral acids are chiral amino acids, tartaric acid, derivatives of tartaric acid, chiral sulfonic acids such as (S) - (+) - camphorsulfonic acid, camphanic acid, derivatives of camphanic acid, mandelic acid or malic acid, wherein (S) - (+) - camphorsulfonic acid outstanding importance.
  • the invention relates to the respective compounds, optionally in the form of the individual optical isomers, enantiomers or diastereomers, mixtures of the individual enantiomers or racemates, in the form of the tautomers and in the form of the free bases or the corresponding acid addition salts.
  • the aqueous phase was separated, diluted with 2.0 L of water and treated at 50 0 C with 42 L of methyl isobutyl ketone and a mixture of 4.45 kg (55.65 mol) of sodium hydroxide solution (50%, techn.) And 3.5 L of water. After about 5 minutes stirring at 50 0 C, the aqueous phase was separated and distilled off in vacuo 28.0 L of solvent. The cloudy residue was filtered at 60 ° C and the filtrate was mixed with 14.0 L of methyl isobutyl ketone. Subsequently, the solvent was completely removed in vacuo and product (G) was isolated. Yield: 4.69 kg (82% of theory)
  • Plasticizer A water / 0.1% formic acid
  • Plasticizer B acetonitrile / 0.1% formic acid

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention porte sur un procédé de fabrication de composés de la formule générale (I) dans laquelle m, n, R1 et R2 sont définis comme mentionné ci-après, sur leurs énantiomères, sur leurs diastéréoisomères, leurs mélanges et leurs sels, en particulier leurs sels physiologiquement acceptables avec les acides ou bases organiques ou inorganiques.
EP10703274A 2009-02-13 2010-02-11 Nouveau procédé de fabrication Withdrawn EP2396308A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP10703274A EP2396308A1 (fr) 2009-02-13 2010-02-11 Nouveau procédé de fabrication

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP09152777 2009-02-13
PCT/EP2010/051681 WO2010092098A1 (fr) 2009-02-13 2010-02-11 Nouveau procédé de fabrication
EP10703274A EP2396308A1 (fr) 2009-02-13 2010-02-11 Nouveau procédé de fabrication

Publications (1)

Publication Number Publication Date
EP2396308A1 true EP2396308A1 (fr) 2011-12-21

Family

ID=42123042

Family Applications (1)

Application Number Title Priority Date Filing Date
EP10703274A Withdrawn EP2396308A1 (fr) 2009-02-13 2010-02-11 Nouveau procédé de fabrication

Country Status (7)

Country Link
US (1) US8207335B2 (fr)
EP (1) EP2396308A1 (fr)
JP (1) JP2012517457A (fr)
AR (1) AR075425A1 (fr)
CA (1) CA2744949A1 (fr)
TW (1) TW201041855A (fr)
WO (1) WO2010092098A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2025675A1 (fr) 2007-08-14 2009-02-18 Boehringer Ingelheim International GmbH Arylsulfonamides ayant activité analgésique
MX2011001563A (es) * 2008-08-12 2011-03-04 Boehringer Ingelheim Int Procedimiento para la preparacion de compuestos de piperazina sustituidos con cloalquilo.
AU2011287581A1 (en) * 2010-08-05 2013-02-14 Boehringer Ingelheim International Gmbh Acid addition salts of the 2-[2-[[(4-methoxy-2,6-dimethylphenyl) sulfonyl]-(methyl)amino]ethoxy]-N-methyl-N-[3- (4-methylpiperazin-1-yl)cyclohexyl] acetamide and the use thereof as bradykinin B1 receptor antagonists
CN109810031B (zh) * 2017-11-21 2023-10-17 乳源瑶族自治县东阳光生物科技有限公司 非罗考昔中间体的制备方法

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4220761A (en) * 1978-09-12 1980-09-02 Fujisawa Pharmaceutical Co., Ltd. 7-[Substituted oximinoacetamido]-3-[hydroxy alkyltetrazolo]cephalosporin derivatives
SI1606288T1 (sl) * 2003-03-25 2009-10-31 Fournier Lab Sa Derivati benzensulfonamida, postopek za njihovo pripravo in njihova uporaba za zdravljenje bolečine
DE102006039003A1 (de) * 2006-08-19 2008-02-21 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Verbindungen
WO2008024692A1 (fr) * 2006-08-23 2008-02-28 Neurogen Corporation Sulfones de n-oxyde aryle et sulfoxydes
JP2009021944A (ja) * 2007-07-13 2009-01-29 Mitsubishi Electric Corp イメージリジェクションミクサ、直交ミクサ及び受信機
WO2009021944A1 (fr) * 2007-08-14 2009-02-19 Boehringer Ingelheim International Gmbh Nouveaux composés

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2010092098A1 *

Also Published As

Publication number Publication date
US8207335B2 (en) 2012-06-26
JP2012517457A (ja) 2012-08-02
TW201041855A (en) 2010-12-01
WO2010092098A1 (fr) 2010-08-19
AR075425A1 (es) 2011-03-30
US20100210842A1 (en) 2010-08-19
CA2744949A1 (fr) 2010-08-19

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