Classifications

• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D231/18—One oxygen or sulfur atom
  • C07D231/20—One oxygen atom attached in position 3 or 5
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
  • C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms

Definitions

• the present invention relates to processes for preparing of pyrazole-O-glycoside derivatives of the general formula (I),
• R 1 to R 5 are defined as hereinafter.
• R 1 to R 5 and Q are defined as hereinafter.
• the present invention relates to a process for preparing a pyrazole derivative of the formula (Xl)
• the aim of the present invention is to find new processes for preparing of pyrazole-O- glycoside derivatives of the formula (I); in particular processes with which the product may be obtained in high yields and/or high chemical and diastereomeric purity and which allow the manufacture of the product in a commercial scale with a low technical expenditure and a high space/time yield.
• Another aim of the present invention is to provide processes for preparing the starting materials of the beforementioned processes.
• the present invention relates to a process for preparing the compounds of general formula (I),
• R 1 denotes Ci -4 -alkyl, a Ci -4 -alkyl group substituted with one or more fluorine atoms, or C 3-6 -cycloalkyl;
• R 2 denotes d -4 -alkyl, a Ci -4 -alkyl group substituted with one or more fluorine atoms, or C 3-6 -cycloalkyl;
• R 3 denotes fluorine, chlorine, bromine, Ci -4 -alkyl, C 3-6 -cycloalkyl, Ci -4 -alkoxy, or C 3-6 - cycloalkyl-oxy;
• R 4 , R 5 independently of one another denote hydrogen, fluorine, chlorine, bromine, Ci -4 -alkyl, or Ci -4 -alkoxy;
• R 7b , R 7c independently of one another have a meaning selected from the group hydrogen, (Ci -6 -alkyl)carbonyl, phenylcarbonyl and phenyl-(Ci -3 -alkyl)-carbonyl; including the tautomers, stereoisomers, mixtures thereof and the salts thereof;
• R 1 to R 5 are defined as hereinbefore; is obtained by a catalytic hydrogenation of a compound of the formula (IV)
• R 1 to R 5 are defined as hereinbefore, and
• Q is Cl, Br, I, d -4 -alkoxy, Ci -4 -alkylthio, phenylthio, C 3-6 -CyClOaIkYl-OXy, Ci -4 -alkylcarbonyloxy, -NR a R b , wherein R a , R b independently of one another denote Ci -4 -alkyl, or -NR a R b denotes pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl or N-Ci -4 -alkyl-piperazinyl;
• the present invention relates to a process for preparing compounds of the above given general formula (I), wherein R 1 to R 5 , R 6 , R 7a , R 7b , R 7c are defined as hereinbefore, including the tautomers, stereoisomers, mixtures thereof and the salts thereof;
• R 1 to R 5 are defined as hereinbefore;
• X denotes bromine or chlorine
• R , R , R and R independently of one another have a meaning selected from the group (Ci -6 -alkyl)carbonyl, phenylcarbonyl and phenyl-(Ci -3 -alkyl)-carbonyl;
• the present invention relates to a process for preparing compounds of the formula (IH)
• R 1 to R 5 are defined as hereinbefore and hereinafter,
• R 1 to R 5 are defined as hereinbefore and R 6 , R 7a , R 7b and R 7c are defined as hereinbefore and hereinafter but one or more of them not being hydrogen, by cleaving the substituents R 6 , R 7a , R 7b and R 7c not being hydrogen in a solvent or a mixture of solvents.
• the present invention relates to a process for preparing compounds of the formula (III) wherein
• R 1 denotes Ci -4 -alkyl, a Ci -4 -alkyl group substituted with 1 to 3 fluorine atoms, or C 3-6 - cycloalkyl;
• R 2 denotes Ci -4 -alkyl, a Ci -4 -alkyl group substituted with one or more fluorine atoms, or C 3-6 -cycloalkyl;
• R 3 denotes fluorine, chlorine, bromine, Ci -4 -alkyl, C 3-6 -cycloalkyl, Ci -4 -alkoxy, or C 3-6 - cycloalkyl-oxy;
• R 4 , R 5 independently of one another denote hydrogen, fluorine, chlorine, bromine, Ci -4 -alkyl, or Ci -4 -alkoxy;
• R 1 to R 5 are defined as hereinbefore;
• Q is Cl, Br, I, Ci -4 -alkoxy, Ci -4 -alkylthio, phenylthio, C 3-6 -cycloalkyl-oxy, Ci -4 -alkylcarbonyloxy, -NR a R b , wherein R a , R b independently of one another denote Ci -4 -alkyl, or -NR a R b denotes pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl or N-Ci -4 -alkyl-piperazinyl,
• the present invention relates to a process for preparing compounds of the formula (IV)
• R 1 denotes Ci -4 -alkyl, a Ci -4 -alkyl group substituted with one or more fluorine atoms, or C 3-6 -cycloalkyl;
• R 2 denotes Ci -4 -alkyl, a Ci -4 -alkyl group substituted with one or more fluorine atoms, or C 3-6 -cycloalkyl;
• R 3 denotes fluorine, chlorine, bromine, d -4 -alkyl, C 3-6 -cycloalkyl, Ci -4 -alkoxy, or C 3-6 - cycloalkyl-oxy;
• R 4 , R 5 independently of one another denote hydrogen, fluorine, chlorine, bromine, Ci -4 -alkyl, or Ci -4 -alkoxy;
• Q is Ci -4 -alkoxy, Ci -4 -alkylthio, C 3-6 -cycloalkyl-oxy, phenylthio, -NR a R b , wherein R a , R b independently of one another denote Ci -4 -alkyl, or -NR a R b denotes pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl or N-Ci -4 -alkyl-piperazinyl;
• R 1 and R 2 are defined as hereinbefore;
• a secondary amine H-Q wherein Q denotes -NR a R b , wherein R a , R b independently of one another denote Ci -4 -alkyl, or -NR a R b denotes pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl or N-Ci -4 -alkyl-piperazinyl; or b) an alcohol or thiol H-Q, wherein Q denotes d -4 -alkoxy, Ci -4 -alkylthio, phenylthio or C 3-6 - cycloalkyl-oxy, and a secondary amine.
• the present invention relates to a process for preparing a pyrazole derivative of the formula (III)
• R 1 to R 5 are defined as hereinbefore;
• R 2 to R 5 are defined as before;
• R 1 -X 1 wherein R 1 is defined as before and X denotes chlorine, bromine, iodine or Ci -3 -alkyl-SO 2 -O-, in the presence of a base in a solvent or mixture of solvents yielding an intermediate of the formula (Xl 1 ) wherein R 1 to R 5 are defined as hereinbefore; and subsequent cleaving the R 1 -O-group at the 3-position of the pyrazole ring in the presence of an acid yielding the aglycone of the formula (III).
• the present invention relates to a process for preparing a pyrazole derivative of the formula (Xl)
• R to R are defined as hereinbefore;
• R ⁇ , R and R are defined as hereinbefore,
• R 2 is defined as hereinbefore; and R c is methyl, ethyl, n-propyl or i-propyl; in the presence of an acid and a secondary amine and subsequent or concomitant catalytic hydrogenation; and
• step (ii) reacting the product of step (i) with hydrazine in a solvent or mixture of solvents.
• the present invention relates to a process for preparing compounds of the general formula (I) as defined hereinbefore characterized in that the process comprises the process step according to the fifth aspect of the present invention.
• the present invention relates to a process for preparing compounds of the general formula (I) as defined hereinbefore characterized in that the process comprises one or both process step according to the sixth and/or seventh aspect of the present invention.
• the present invention relates to a compound of the formula (IV)
• R 1 to R 5 are defined as hereinbefore, and
• Q is Cl, Br, I, Ci -4 -alkoxy, Ci -4 -alkylthio, phenylthio, C 3-6 -cycloalkyl-oxy, Ci -4 -alkylcarbonyloxy, -NR a R b , wherein R a , R b independently of one another denote d -4 -alkyl, or -NR a R b denotes pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl or N-Ci -4 -alkyl-piperazinyl, including the tautomers, the stereoisomers, the mixtures thereof and the salts thereof.
• the present invention relates to a compound of the formula (III)
• R 1 to R 5 are defined as in hereinbefore or hereinafter, including the tautomers, the stereoisomers, the mixtures thereof and the salts thereof.
• Another aspect of the present invention relates to a compound of the formula (Vl)
• R 1 and R 2 are defined as in claim 1 , 21 or 22, including the tautomers, the mixtures thereof and the salts thereof.
• di-(Ci -4 -alkyl)amine encompasses secondary amines with two identical or different alkyl groups, such as ethyl-isopropyl-amine.
• R 1 preferably denotes a group of the formula ; wherein R 11 denotes d -3 -alkyl or Ci -3 -alkyl substituted with one or more fluorine atoms; and
• R 12 denotes H, or in case R 11 denotes methyl, R 12 may also denote a methyl- or ethyl-group or a methyl- or ethyl-group substituted with one or more fluorine atomes; or R 11 and R 12 are linked and form together with the CH-group to which they are attached a
• R 1 denotes ethyl, n-propyl, i-propyl, cyclobutyl or cyclopentyl; most preferably i-propyl or cyclobutyl.
• R 2 preferably denotes methyl, ethyl, n-propyl or i-propyl; most preferably methyl.
• R 3 preferably denotes fluorine, chlorine, methyl, methoxy, ethoxy, n-propoxy or i- propoxy; most preferably methyl, methoxy, ethoxy or i-propoxy.
• R 4 preferably denotes fluorine, chlorine, methyl, methoxy, ethoxy, n-propoxy or i- propoxy; in particular fluorine. Furthermore the substituent R 4 is preferably a substituent in 2- position of the phenyl-ring. Most preferably R 4 is a substituent in 2-position of the phenyl-ring and denotes fluorine.
• R 5 preferably denotes hydrogen, fluorine, chlorine, methyl or methoxy; most preferably hydrogen or fluorine.
• the substituents R 6 , R 7a , R 7b , R 7c preferably have independently of one another a meaning selected from the group hydrogen, (Ci -4 - alkyl)carbonyl, phenylcarbonyl and benzylcarbonyl. Even more preferably in compounds of the formula (I) the substituents R 6 , R 7a , R 7b , R 7c independently of one another have a meaning selected from the group hydrogen, methylcarbonyl and ethylcarbonyl, in particular hydrogen.
• the substituents R 6 , R 7a , R 7b , R 7c preferably have independently of one another a meaning selected from the group (Ci -4 -alkyl)carbonyl, phenylcarbonyl and benzylcarbonyl. Even more preferably in compounds of the formula (II) the substituents R 6 , R 7a , R 7b , R 7c independently of one another have a meaning selected from the group methylcarbonyl and ethylcarbonyl, in particular methylcarbonyl.
• the substituents R 6 , R 7a , R 7b , R 7c , R 7d preferably have independently of one another a meaning selected from the group (Ci -4 -alkyl)carbonyl, phenylcarbonyl and benzylcarbonyl. Even more preferably in compounds of the formula (M 1 ) the substituents R 6 , R 7a , R 7b , R 7c , R 7d independently of one another have a meaning selected from the group methylcarbonyl and ethylcarbonyl, in particular methylcarbonyl.
• the aglycone of the formula (III) is obtained via catalytic hydrogenation of a compound of the formula (IV) according to the reaction scheme I: Scheme I:
• the group Q preferably denotes methoxy, ethoxy, n-propoxy, i-propoxy, -NR a R b , wherein R a , R b independently of one another denote methyl, ethyl, n-propyl or i-propyl, or -NR a R b denotes pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl or N-d -3 -alkyl-piperazinyl.
• Q denotes methoxy, ethoxy, n-propoxy, i-propoxy, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl or N-Ci -3 -alkyl-piperazinyl; most preferably ethoxy, pyrrolidinyl, piperidinyl or morpholinyl.
• suitable solvents are aliphatic hydrocarbons, aromatic hydrocarbons, alcohols, aliphatic ethers, cyclic ethers, esters, amide type solvents, acetic acid, mixtures thereof and mixtures thereof with water.
• suitable solvents are pentane, hexane, benzene, toluene, methanol, ethanol, i-propanol, n-propanol, diethylether, tetrahydrofuran, tetrahydropyran, ethyl acetate, isopropyl acetate, butyl acetate, NMP, DMF, glacial acetic acid, mixtures thereof and mixtures thereof with water.
• Preferred solvents are methanol, ethanol, i-propanol, n-propanol, tetrahydrofuran, mixtures thereof and mixtures thereof with water.
• the catalytic hydrogenation is carried out in the presence of one or more acids, in particular hydrochloric acid, a car boxy lie acid or an alkanesulfonic acid.
• acids in particular hydrochloric acid, a car boxy lie acid or an alkanesulfonic acid.
• suitable acids are hydrochloric acid, acetic acid and trifluoroacetic acid.
• the acid is preferably taken in an amount equivalent to from about 1 to 150 mol-% relative to the educt of the formula (IV).
• H-Q is an alcohol or a thiol
• the acid is preferably taken in an amount equivalent to from about 1 to 50 mol-%, relative to the educt of the formula (IV); even more preferably from about 1 to 20 mol-%, for example about 10 mol-%.
• the amount may even be up to 100 mol-%.
• Q is selected from -NR a R b according to a preferred embodiment the catalytic hydrogenation may be carried out without the addition of an acid.
• an acid is preferably taken in an amount equivalent to from about 1 to 120 mol-%, such as for example in an about equimolar amount based on the educt of the formula (IV).
• the catalytic hydrogenation is preferably carried out in the presence of a transition metal catalyst such as Pd-based catalysts, for example as finely dispersed Pd, Pd on charcoal or Pd(OH) 2 , or Ni-based catalysts, for example as finely dispersed Ni such as Raney-nickel.
• a transition metal catalyst such as Pd-based catalysts, for example as finely dispersed Pd, Pd on charcoal or Pd(OH) 2 , or Ni-based catalysts, for example as finely dispersed Ni such as Raney-nickel.
• the suitable amount of catalyst may vary according to the reaction conditions and lies for example in the range from about 0.1 to about 50 weight-%, preferably from about 1 to about 10 weight-% relative to the educt of the formula (IV).
• the hydrogenation is advantageously carried out at temperatures in the range from -30 to 150 °C, preferably from 20 to 100 °C, more preferably from 20 to 70 °C, most preferably from 40 to 60 0 C.
• Suitable hydrogen pressures are usually about equal to or above normal atmospheric pressure, preferably in the range from about 1 to 20 bar, even more preferably from 2 to 8 bar.
• the reaction mixture is preferably agitated or stirred.
• the time period necessary to complete the hydrogenation can be optimized by experimentation. Usually the hydrogenation is performed in a time period from about 30 min to about 24 hours, preferably from about 1 to 12 hours.
• the catalyst is preferably removed from the reaction mixture, for example by filtration.
• the next reaction step i.e. synthesis of a compound of the formula (I), may be carried out with the reaction solution containing the product of the formula (III) or with the isolated product of the formula (III).
• the product of the formula (III) may be isolated from the reaction solution for example by removing the solvent in vacuum and/or at elevated temperature.
• the product of the formula (III) may also be obtained by precipitation out of a concentrated reaction solution, for example by adding an antisolvent, such as water, and isolating from the suspension, for example by filtration.
• the reaction is carried in the presence of a secondary amine.
• H-Q is selected from among pyrrolidine, piperidine, morpholine, piperazine and N-Ci -3 -alkyl-piperazine; most preferably from among pyrrolidine, piperidine and morpholine.
• the amine derivative H-Q is preferably employed in an equimolar amount or in a molar excess compared to the pyrazole derivative of the formula (IV).
• a preferred molar ratio of the amine H-Q to the pyrazole derivative is in the range from about 1 : 1 to 10 : 1 , even more preferably in the range from 1 : 1 to 5 : 1.
• the reaction is advantageously carried out in the presence of a secondary amine.
• Q is selected from among methoxy, ethoxy, n- propoxy and i-propoxy; most preferably ethoxy.
• Preferred secondary amines are selected from among di-(Ci -4 -alkyl)amine or cyclic secondary amines, such as for example pyrrolidin, piperidin, morpholin, piperazin, N-Ci -3 -alkyl-piperazin.
• the secondary amine is selected from among pyrrolidine, piperidine, morpholine, piperazine and N-Ci -3 - alkyl-piperazine; most preferably from among pyrrolidine, piperidine and morpholine.
• the secondary amine may be used in a catalytic amount, in an about equimolar amount or even in a molar excess.
• a preferred molar ratio of the secondary amine to the pyrazole derivative is in the range from about 0.05 : 1 to 2 : 1 , even more preferably from about 0.1 : 1 to 1.5 : 1 , most preferably from about 1.0 : 1.0 to 1.5 : 1.0.
• the alcohol or thiol H-Q is preferably employed in an equimolar amount or in a molar excess compared to the pyrazole derivative of the formula (Vl).
• the alcohol H-Q may also serve as a solvent so that in this case molar excesses of H-Q may be used.
• Suitable acids are for example Ci -6 -alkylcarboxylic acids, which may be unsubstituted or substituted with one or more flourine or chlorine substituents, d -6 -alkyl- sulfonic acids, which may be unsubstituted or substituted with one or more flourine or chlorine substituents, dicarboxylic acids, tricarboxylic acids, methylchlorosilanes, nonaqueous mineral acids.
• acids are glacial acetic acid, trimethylchlorosilane, hydrochloric acid (aqueous or for example as a solution in an alcohol, such as ethanol), trifluoromethanesulfonic acid.
• the acid is preferably employed in an equimolar amount or in a molar excess relative to the pyrazole derivative of the formula (IV).
• a preferred molar ratio of the acid to the pyrazole derivative is in the range from about 0.05 : 1 to 1 : 1, even more preferably from about 0.1 : 1 to 0.5 : 1.
• the acid is preferably used in at least the molar amount of the secondary amine.
• the reaction may be carried with or without the addition of an acid; whereby preferred acids and molar ratios are given above.
• suitable solvents are aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons, alcohols, aliphatic ethers, cyclic ethers, acetonitril, amide type solvents, acetic acid and mixtures thereof.
• suitable solvents are dichloromethane, 1,2-dichloroethane, methanol, ethanol, i-propanol, n-propanol, diethylether, tetrahydrofuran, tetrahydropyran, acetonitril, NMP, DMF, glacial acetic acid and mixtures thereof.
• Preferred solvents are methanol, ethanol, i-propanol, n-propanol, tetrahydrofuran, acetonitril and mixtures thereof.
• the compound H-Q is an alcohol, it may additionally serve as a solvent and thus may be used in a stoichiometric excess.
• a particularly preferred solvent is acetonitril.
• the educts of the formulae (V) and (Vl) are preferably reacted in a molar ratio of about 2 : 1 to 1 : 2, preverably in an about equimolar ratio.
• the synthesis step is advantageously carried out at temperatures in the range from -30 to 150 0 C, preferably from 10 to 100 0 C, more preferably from 20 to 80 °C, most preferably from 30 to 70°C.
• the time necessary to complete the reaction is usually in the range from about 1 h to 96 h.
• the product of the formula (IV) is only sparsely soluble in the reaction mixture, thus forming a suspension.
• the next reaction step i.e.
• synthesis of a compound of the formula (III), may be carried out using the crude or the isolated product of the formula (IV).
• the product of the formula (IV) may be isolated from a reaction solution for example by removing the solvent in vacuum and/or at elevated temperature.
• the product of the formula (IV) may also be obtained by precipitation out of a concentrated reaction solution or suspension, for example by adding an antisolvent, such as water, and/or cooling of the solution or suspension and isolating from the suspension, for example by filtration.
• the pyrazole derivative of the formula (Vl) is preferably obtained by dehydrogenation of the pyrazole derivative of the formula (VII) according to the reaction scheme III:
• the dehydrogenation is performed using an oxidizing agent, such as for example H 2 O 2 , inorganic peroxides, peroxomonosulfuric acid or salts thereof, peroxodisulfuric acid or salts thereof, carboxylic peracids, peroxoborates and the like.
• an oxidizing agent such as for example H 2 O 2 , inorganic peroxides, peroxomonosulfuric acid or salts thereof, peroxodisulfuric acid or salts thereof, carboxylic peracids, peroxoborates and the like.
• a preferred oxidizing agent is H 2 O 2 or peracetic acid.
• H 2 O 2 is preferably employed as an aqueous solution, for example with a content of 3 to 90%-weight, preferably 10 to 70%-weight of H 2 O 2 .
• the preferred amount of the oxidizing agent is about equimolar or in a molar excess, for example in a molar ratio in the range from 1 : 1 to 2 : 1 , more preferably from 1.0 : 1.0 to 1.3 : 1.0, relative to the educt of the formula (VIII).
• the educt of the formula (VII) is dissolved or suspended in a suitable solvent or mixture of solvents.
• suitables solvents are carboxylic acids such as for example acetic acid or aqueous mixtures thereof.
• the oxidizing agent is added to the solution or suspension preferably continuously or in portions over a period of time, for example in the range from 30 min to 24 h. If necessary the reaction mixture may be cooled.
• the reaction is carried out preferably at temperatures in the range from 0°C to 130°C, more preferably in the range from 10°C to 90 0 C, even more preferably in the range from 20 0 C to 80°C.
• the reaction is usually completed within 1 to 24 h.
• the final product of the formula (Vl) may be obtained in a solid form for example by adding to the reaction mixture water or pouring the reaction mixture into water, preferably in a temperature range from 0 to 20 0 C, and optionally neutralizing the reaction mixture to a pH in the range from 5 to 9, preferably to a pH of about 7, by using a suitable base, such as for example an aqueous sodium hydroxide, potassium hydroxide or ammonium hydroxide solution, and by removing the solid product from the aqueous reaction mixture, for example by filtration. If the reaction mixture is not neutralized the product may be obtained in a salt form, for example as the acetate.
• a suitable base such as for example an aqueous sodium hydroxide, potassium hydroxide or ammonium hydroxide solution
• the dehydrogenation is performed catalytically, preferably in the presence of a transition metal catalyst such as Pd-based catalysts, for example as finely dispersed Pd or Pd on charcoal.
• a transition metal catalyst such as Pd-based catalysts, for example as finely dispersed Pd or Pd on charcoal.
• the catalytic dehydrogenation is preferably carried out at elevated temperatures, for example in the range from about 80°C to 240°C, preferably from about 100 0 C to 200 0 C in an chemically inert solvent or solvent mixture, such as aliphatic or aromatic hydrocarbon, for example toluene.
• the product may be isolated from the reaction, preferably after removing the catalyst, e.g. by filtration, using methods well known in the art.
• R denotes a group of the formula ; wherein R 11 denotes Ci -3 -alkyl or d -3 -alkyl substituted with one or more fluorine atoms; and R 12 denotes H, or in case R 11 denotes methyl, R 12 may also denote a methyl- or ethyl-group or a methyl- or ethyl-group substituted with one or more fluorine atomes; or R 11 and R 12 are linked and form together with the CH-group to which they are attached a C 3-6 -cycloalkyl-group;
• the pyrazole derivative of the formula (VII) is preferably obtained by reacting the pyrazole derivative of the formula (VIII) with an aldehyde or ketone of the formula (IX) and subsequent or concomitant reduction according to the reaction scheme IV:
• the substituent R 11 preferably denotes methyl, ethyl, n-propyl or i-propyl; and the substituent R 12 denotes H; and in case R 11 denotes methyl or ethyl, R 12 may also denote methyl or ethyl.
• R 11 and R 12 may be linked and form together with the C-atom to which they are attached a cyclobutyl- or cyclopentyl-ring. Most preferably both substituents R 11 and R 12 denote methyl or they are linked to form a cyclobutyl-ring.
• the neutral form of the formula (VIII) may be obtained by adding a base such as for example sodium hydroxide, potassium hydroxide or ammonium hydroxide, preferably as a solution in an alcohol or water, or an alcoholate, in particular alkali metal alcoholate, such as for example sodium ethanolate in ethanol.
• a base such as for example sodium hydroxide, potassium hydroxide or ammonium hydroxide
• the neutralization step and the synthesis step may be performed in situ or the neutral form of the educt of the formula (VIII) may be obtained beforehand.
• the reactants of the formula (VIII) and (IX) are dissolved or suspended in a suitable solvent or mixture of solvents.
• Preferred solvents are alcohols, ethers or mixtures thereof with water, such as for example methanol, ethanol, n-propanol, i- propanol, mixtures thereof or mixtures thereof with water.
• the educt of the formula (IX), such as for example aceton, may serve as a solvent and thus may be employed in a stoichiometric excess.
• a preferred molar ratio of the educt of the formula (VIII) and the educt of the formula (IX) is in the range from 1 : 1 to 1 : 5, more preferably in the range from 1 : 1 to 1 : 3, even more preferably in the range from 1.0 : 1.5 to 1.0 : 2.5.
• the reduction is preferably performed as a catalytic hydrogenation or alternatively as a reduction using hydrides, in particular borohydrides, such as for example sodium triacetoxyborohydride or sodium cyanoborohydride.
• the reaction solution or suspension is catalytically hydrogenated preferably in the presence of a transition metal catalyst such as Pd-based catalysts, for example as finely dispersed Pd or Pd on charcoal.
• a transition metal catalyst such as Pd-based catalysts, for example as finely dispersed Pd or Pd on charcoal.
• the suitable amount of catalyst may vary according to the reaction conditions and lies for example in the range from 0.1 to 50 weight-%, preferably from 1 to 20 weight-% relative to the educt of the formula (IV).
• the hydrogenation is advantageously carried out at temperatures in the range from -30 to 150 °C, preferably from 20 to 100 °C, more preferably from 20 to 80 °C, most preferably from 40 to 70°C.
• Suitable hydrogen pressures are usually about equal to or above normal atmospheric pressure, preferably in the range from about 1 to 20 bar, even more preferably from 2 to 8 bar.
• reaction mixtures is preferably agitated or stirred.
• catalyst is preferably removed from the reaction mixture, for example by filtration.
• next reaction step i.e. synthesis of a compound of the formula (Vl) may be carried out using with the reaction solution containing the product of the formula (VII) or with the isolated product of the formula (VII).
• the product of the formula (VII) may be isolated from the reaction solution for example by removing the solvent in vacuum and/or at elevated temperature.
• the product may be purified via a salt form, for example as its chloride, by adding an acid, such as for example hydrochloric acid in ethanol, to a solution of the product, followed by crystallization, for example supported by cooling and/or inoculating with seed crystalls, and finally isolating the precipitate.
• a salt form for example as its chloride
• an acid such as for example hydrochloric acid in ethanol
• the pyrazole derivative of the formula (VIII) is preferably obtained by reacting an acrylic acid ester derivative of the formula (X) with a hydrazine in a solvent or mixture of solvents according to the reaction scheme V:
• the substituent R c denotes optionally substituted Ci -6 -alkyl, preferably methyl, ethyl, n-propyl or i-propyl; preferably methyl or ethyl.
• the acrylic acid ester derivative of the formula (X) is dissolved in a suitable solvent or mixture of solvents such as alcohols, aliphatic ethers, cyclic ethers, and mixtures thereof.
• suitable solvents are methanol, ethanol, i-propanol, n-propanol, diethylether, tert.-butylmethylether, tetrahydrofuran, tetrahydropyran, dioxane and mixtures thereof or a solution of one or more of these solvents with water.
• Preferred solvents are ethanol, i- propanol, mixtures thereof or aqueous mixtures thereof.
• the hydrazine is advantageously employed as a solution in water, for example as hydrazine monohydrate, or in an alcohol, such as methanol, ethanol, i-propanol, mixtures thereof or mixtures of one or more of such alcohols with water.
• an alcohol such as methanol, ethanol, i-propanol, mixtures thereof or mixtures of one or more of such alcohols with water.
• a preferred molar ratio of the acrylic acid ester derivative of the formula (X) and of hydrazine is in the range from 1 : 1 to 1 : 2, more preferably from 1.0 : 1.0 to 1.0 : 1.5, even more preferably in the range from 1.0 : 1.0 to 1.0 : 1.2.
• the hydrazine is added to the solution of the acrylic acid ester derivative preferably continuously or in portions over a period of time, for example in the range from 15 min to 24 h. If necessary the reaction mixture may be cooled.
• the reaction is carried out preferably at temperatures in the range from 0°C to 130°C, more preferably in the range from 20 0 C to 100 0 C, even more preferably in the range from 40°C to 90 0 C.
• the final product of the formula (VIII) may be obtained by removing the solvents, for example by evaporation in vacuum and/or at elevated temperature.
• the final product may be purified via crystallization in the form of a salt, for example in the form of its hydrohalide, such as hydrochloride.
• a salt for example in the form of its hydrohalide, such as hydrochloride.
• an acid such as for example hydrochloric acid in ethanol or i-propanol, is added to a solution of the product. Crystallization may be supported for example by cooling and/or inoculating with seed crystalls, and finally the precipitate is isolated.
• this reaction step is carried out in an alcohol, in particular in i-propanol, and an aqueous solution of hydrazine, in particular hydrazine hydrate is used.
• an aqueous solution of hydrazine in particular hydrazine hydrate is used.
• water is preferably removed from the reaction mixture by azeotropic destination.
• the product is advantageously obtained as described above, in particular by precipitating a salt form, preferably the chloride, for example by adding a solution of hydrochloric acid in ethanol.
• the compound of the formula (I) is preferably obtained by reacting the aglycone of the formula (III) as described hereinbefore with a glucose derivative of the formula (II) according to the reaction scheme Via:
• the substituents R 6 , R 7a , R 7b , R 7c are independently of one another selected from the group consisting of (Ci -4 -alkyl)carbonyl, phenylcarbonyl and benzylcarbonyl. Even more preferably the substituents R 6 , R 7a , R 7b , R 7c independently of one another have a meaning selected from the group methylcarbonyl and ethylcarbonyl, in particular methylcarbonyl.
• the substituent X preferably denotes a bromine atom.
• the substituents R 1 to R 5 are defined as hereinbefore.
• this process step may be carried out in a solvent or a mixture of solvents which exhibits sufficient solubility properties in view of the starting materials of the formulae (II) and (III) and in the presence of a suitable base.
• Preferred organic solvents with such properties are ketones, ethers, cyclic ethers, acetonitril, and mixtures thereof. Examples of preferred organic solvents are acetone, methyl ethyl ketone, diethyl ketone, cyclohexanone, cyclopentanone, acetonitril, THF, NMP, DMF, and mixtures thereof.
• Suitable bases are in particular carbonates, such as for example sodium carbonate, potassium carbonate, silver carbonate or cadmium carbonate.
• this process step is carried out in a reaction mixture comprising two liquid phases, preferably under phase-transfer conditions.
• a biphasic solvent system and one or more phase-transfer catalysts are used.
• Preferred solvents of the first phase are aprotic organic solvents, in particular aromatic hydrocarbons (for example benzene, chlorobenzene, trifluoromethylbenzene, toluene, xylenes), alkanes (for example pentane, hexane, heptane, octane), halogenated alkanes (for example CH 2 CI 2 , CHCI 3 , CICH 2 CH 2 CI), ethers (for example 2-methyl-tetrahydrofuran), esters (for example isopropylacetate), and mixtures thereof.
• a particularly preferred solvent of the first phase comprises a chlorinated Ci_ 3 -alkane which additionally may have one or more fluorine substituents, most preferably CH 2 CI 2
• the second phase is preferably water or an aqueous mixture of a protic solvent.
• the most preferred solvent of the second phase is water.
• a preferred ratio of the volume of the first solvent phase to the volume of the second phase is in the range from 1 : 10 to 10 : 1, even more preferably in the range from 1 : 5 to 5 : 1, most preferably in the range from 1 : 5 to 2 : 1.
• Preferred phase-transfer catalysts possess a quartemary ammonium cation, as for example tetraalkylammonium, N-aryl-N-trialkylammonium, N-arylalkyl-N-trialkyl-ammonium compounds, wherein the alkyl-residues may be identical or different. Examples are tetramethylammonium compounds, tetraethylammonium compounds, tetrabutylammonium or benzyl trimethyl ammonium compounds.
• phase-transfer catalyst are tetrabutylammonium compounds, in particular tetrabutylammonium salts with inorganic acids, such as tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogensulfate, etc..
• phase-transfer catalyst depends on the kind of solvents used and their quantities and can be determined by standard experimentation. Usually per 1 mole of the starting material of the formula (III) an amount from 0.01 to 1.0 mol, even more preferably from 0.02 to 0.5, such as for example about 0.05 mol of a phase-transfer catalyst is used.
• the second solvent phase is basified or buffered.
• preferred pH-values of an aqueous solvent phase are greater than or equal to about 10, in particular greater than or equal to about 11 , even more preferably greater than or equal to about 12, most preferably in the range from about 11 to about 15, most preferably in the range from about 12 to about 14.
• the pH value is advantageously kept in the desired basic pH range advantageously by the addition of at least one basifying reagent, preferably selected from the group consisting of hydroxides, carbonates, phosphates and/or borates.
• the corresponding alkali salts are preferred, as for example sodium carbonate, sodium hydroxide, potassium carbonate, potassium hydroxide and/or sodium borate.
• the basifying reagent is added in the form of an aqueous solution; for example as an aqueous sodium or potassium hydroxide solution.
• a preferred molar ratio of the educt of the formula (II) and the educt of the formula (III) is in the range from 5 : 1 to 1 : 2, more preferably in the range from 3 : 1 to 1 : 1 , even more preferably in the range from 2.0 : 1.0 to 1.0 : 1.0.
• a preferred temperature range for the reaction of the compound (II) with the compound of the formula (III) is from about 0 0 C to 50 0 C, even more preferably in the range from about 5°C to 45°C, most preferably in the range from about 15°C to 40°C. As the reaction is exothermic cooling of the reaction mixture might become necessary.
• reaction is carried out usually in a time period from 30 min to 48 hours, preferably from 2 to 24 hours.
• An end point of the reaction may be detected by the amount of remaining compound of the formula (III), for example by HPLC.
• the compound of the formula (I) may be isolated from the reaction mixture by methods well known to the one skilled in the art. For example if the reaction was carried out under phase transfer conditions involving an aqueous and an organic phase, the aqueous phase is separated and extracted with an organic solvent or mixture of organic solvents; the organic phases are combined and washed with water or an aqueous solution, preferably with an acidic aqueous solution, and finally dried and the solvents are removed by evaporation in reduced pressure and/or at elevated temperature to yield the compound of the formula (I).
• this reaction step is carried out using the crude product or the reaction mixture of the previous reaction step.
• the isolated and optionally purified product of the formula (I) is used.
• Suitable methods for deprotection are well-known to the one skilled in the art.
• acyl protecting groups may be cleaved hydrolytically in an aqueous solvent, e.g. in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid.
• acyl protecting groups are cleaved using an alcoholate, in particular Ci -4 - alcoholate, for example sodium ethanolate or potassium-t-butoxide in ethanol, whereby the absence of water is preferred.
• Suitable solvents are alcohols, such as methanol, ethanol or n-propanol.
• this deprotection is preferably carried out as a transesterefication, advantageously only catalytical amounts of the alcoholate, preferably from about 0.1 to 50 mol-%, even more preferably from about 1 to 20 mol-% relative to the educt of the formula (I) are needed.
• Suitable temperatures are between 0°C and the boiling point of the reaction mixture, preferably between 5 and 40 0 C.
• the reaction is usually completed within 1 to 48 h. After completion of the reaction the reaction mixture is preferably neutralized or slightly acidified, for example by using acetic acid, and solvents may be removed by destination under reduced pressure and/or elevated temperatures.
• the product of the formula (IH) is obtained as a resinous solid.
• the glucose derivative of the formula (II) wherein X denotes a chlorine or a bromine atom may be obtained by methods known to the one skilled in the art and described in the literature.
• the glucose derivative of the formula (II) is obtained by reacting a protected glucose derivative of the formula (M 1 ) with HBr in a solvent or mixture of solvents according to the reaction scheme VII.
• the substituents R 6 , R 7a , R 7b , R 7c and R 7d are independently of one another selected from the group consisting of (Ci -4 -alkyl)carbonyl. Even more preferably the substituents R 6 , R 7a , R 7b , R 7c and R 7d , where applicable, independently of one another have a meaning selected from the group methylcarbonyl and ethylcarbonyl, in particular methylcarbonyl.
• the substituent X preferably denotes bromine.
• This reaction step is preferably carried out in a solvent or a mixture of solvents.
• Suitable solvents are preferably aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons and mixtures thereof.
• suitable solvents are pentane, hexane, dichloromethane, 1 ,2-dichloroethane, benzene, toluene, xylenes, and mixtures thereof.
• Preferred solvents are dichloromethane, benzene, toluene, xylenes or mixtures thereof, in particular dichloromethane or toluene.
• the starting material of the formula (M 1 ) is dissolved or suspended in the solvent or mixture of solvents and HX or a solution of HX is added.
• HX is HBr
• a preferred solution is HBr in acetic acid, for example a 30% solution of HBr in acetic acid.
• a suitable amount of HX is about equimolar or in a molar excess relative to the protected glucose of the formula (M 1 ).
• the molar ratio of HX to the glucose derivative of the formula (II 1 ) is in the range from about 1 : 1 to 10 : 1 ; even more preferably in the range from about 2 : 1 to 6 : 1.
• the reaction is preferably carried out at temperatures in a range from 0 0 C to 40 0 C, most preferably from 10°C to 30°C. Usually the reaction is completed in a period of time from 10 min to 12 hours.
• the product of the formula (II) may be isolated from the reaction mixture by methods well known in the art.
• the reaction mixture may be washed with water and/or a saturated sodium chloride solution; any excess of acids may be neutralized, in particular by washing the combined organic phases with a basic aqueous solution, such as for example an aqueous saturated sodium hydrogencarbonate solution; and finally the solvents may be evaporated in vacuum.
• the product may be isolated and purified by crystallization, preferably by using a suitable solvent, for example by solving the product in tert. -butyl methylether and then adding methylcyclohexane.
• the following reaction step according to the scheme Via is carried out using the crude product of the formula (II), which is advantageously neutralized beforehand.
• the reaction mixture is washed with an aqueous basic solution and the neutralized organic phase is dried.
• the pyrazole derivative of the formula (III) may be obtained by reacting a pyrazole derivative of the formula (Xl) with an alkylating agent R 1 -X 1 wherein R 1 is defined as hereinbefore and X 1 denotes chlorine, bromine, iodine or Ci -3 -alkyl-SO 2 -O-, in the presence of a base in a solvent or mixture of solvents yielding an intermediate of the formula (Xl') and subsequent cleaving the R 1 -O-group at the 3-position of the pyrazole ring, in particular in the presence of an acid, yielding the aglycone of the formula (III) according to the reaction scheme VIII:
• R 1 to R 5 are defined as hereinbefore.
• R 1 denotes methyl, ethyl, n-propyl, i-propyl, cyclobutyl or cyclopentyl; most preferably i-propyl or cyclobutyl.
• the group X 1 is preferably bromine.
• the pyrazole derivative of the formula (Xl) is reacted with an alkylating agent R 1 -X 1 in the presence of a base, preferably a strong base.
• a base preferably a strong base.
• Suitable strong bases are selected from the group consisting of alkali hydroxides, alcoholates, hydrides. Examples of preferred strong bases are sodium hydroxide and potassium hydroxide.
• O-atom of the pyrazolon-group is also at least partially alkylated, advantageously a molar excess of the alkylating agent is employed.
• a preferred molar ratio of the alkylating agent compared with the educt of the formula (Xl) is above about 2 : 1, even more preferably in the range from 2 : 1 to 8 : 1; for example in the range from 3 : 1 to 5 : 1.
• the molar amount of the base advantageously employed is about the same as the amount of the alkylating agent. Therefore advantageously a molar excess of the base is taken.
• a preferred molar ratio of the base compared with the educt of the formula (Xl) is above about 2 : 1 , even more preferably in the range from 2 : 1 to 8 : 1 ; for example in the range from 3 : 1 to 5 : 1.
• Suitable solvents are polar solvents or mixtures thereof which exhibit sufficient solubility properties in view of the starting material (Xl), the alkylating agent R 1 -X 1 and the base.
• Suitable solvents may be selected from the group consisting of aliphatic ethers, cyclic ethers, amide type solvents, and mixtures thereof. Examples of preferred solvents are NMP, DMF, DMA, and mixtures thereof.
• the alkylating agent or a solution thereof is preferably added to the reaction mixture at once or advantageously over a period time, for example within a period from 5 min to 4 hours.
• the reaction is preferably carried out at temperatures in a range from -20°C to 50°C, even more preferably from -10 0 C to 40 0 C, most preferably from 5°C to 35°C.
• An end point of the reaction may be detected for example by thin layer chromatography or HPLC.
• the reaction is usually carried out in a time period from 30 min to 48 hours, preferably from 2 to 24 hours.
• the product of the formula (Xl 1 ) may be obtained from the reaction mixture by methods well- known to the one skilled in the art. A further purification is usually not necessary. In particular in case the reaction yields any by-products, such as for example derivatives which are alkylated in the 2-position of the pyrazole ring, such by-products do not necessarily need to be removed at the end of this reaction step. According to an example how to obtain the reaction product the reaction mixture is poured onto cold water and an organic solvent, such as an aliphatic or aromatic hydrocarbon, for example toluene, is added. The aqueous phase is neutralized or slightly acidified using an acid, such as concentrated hydrochloric acid.
• an organic solvent such as an aliphatic or aromatic hydrocarbon, for example toluene
• the organic phase is separated and optionally the aqueous phase is extracted again with organic solvents.
• the combined organic phases may be washed with water and/or saturated aqueous sodium chloride solution and dried.
• the product of the formula (Xl 1 ) may be obtained by removing the organic solvents, preferably in vacuum and/or at elevated temperatures.
• the substituent R 1 -O- has to be cleaved at the 3-position of the pyrazole ring of the compound (Xl 1 ).
• the cleavage is done in the presence of an acid, more preferably in the presence of a strong acid, such as HCI, HBr, HI, H 2 SO 4 , or alkylsulfonic acids, such as for example methanesulfonic acid, which is added for example as aqueous solution.
• a molar excess of the acid is employed.
• a preferred molar ratio of the acid compared with the educt of the formula (Xl 1 ) is above about 2 : 1, even more preferably in the range from 2 : 1 to 40 : 1 ; for example in the range from 4 : 1 to 20 : 1.
• the educt of the formula (Xl 1 ) and the acid are dissolved or suspended in a suitable solvent or mixture of solvents.
• suitable solvents are for example water, alcohols, carboxylic acids, and mixtures thereof; in particular water, ethanol, acetic acid.
• the acid is used in the form of a solution in water, an alcohol or a mixture thereof; in this case the acidic solution may serve as a solvent so that less or no additional solvent may be needed.
• the reaction is preferably carried out at temperatures in a range from 40 0 C to 180 0 C, even more preferably from 60°C to 160 0 C, most preferably from 80°C to 160°C.
• the reaction is preferably carried out in a closed reactor or autoclave.
• An end point of the reaction may be detected for example by thin layer chromatography or HPLC.
• the reaction is carried out usually in a time period from 15 min to 24 hours, preferably from 1 to 12 hours.
• the product may be obtained via crystallization from the reaction mixture.
• the type and the amount of the solvent is chosen such that the reactants are dissolved at the reaction temperatures.
• the product may precipitate whereby additional measures to start crystallization such as inoculating with seed-cr ⁇ stalls and/or adding an antisolvent may be employed.
• the crystalls may be isolated for example by filtration and washed in a suitable solvent such as an alcohol, for example iso-propanol, and optionally dried thereafter.
• the pyrazole derivative of the formula (Xl) may be obtained by
• step (ii) reacting the product of step (i) with hydrazine in a solvent or mixture of solvents:
• the group R c denotes methyl, ethyl, n-propyl or i-propyl; preferably methyl or ethyl.
• the group R 2 preferably denotes methyl, ethyl, n-propyl or i-propyl; most preferably methyl.
• a preferred compound of the formula XII is methylacetoacetate.
• This reaction step is suitably carried at conditions of Knoevenagel reactions which are known to the one skilled in the art.
• the molar ratio of the benzaldehyde of the formula (V) to the ⁇ -ketoester of the formula (XII) is preferably in the range from about 2 : 1 to 1 : 2, more preferably from about 1.3 : 1 to 1 : 1.3, in particular equimolar.
• Suitable acids are carboxylic acids, and mixtures thereof, such as for example acetic acid.
• the molar ratio of the acid to the benzaldehyde derivative of the formula (V) is preferably from about 2 : 1 to about 0.8 : 1, more preferably from about 1.5 : 1 to about 1 : 1. Most preferably about equimolar amounts of the acid and the benzaldehyde derivative are taken.
• Suitable secondary amines are di(Ci_ 4 -alkyl)amines, saturated or unsatured heterocycles with at least one secondary amine group, such as for example dimethylamine, ethylmethylamine, diethylamine, di(isopropyl)amine, pyrrolidine, piperidine, piperazine, morpholine, N-(Ci -3 - alkyl)piperazine, and mixtures thereof.
• Preferred amines are piperidine and pyrrolidine.
• the molar ratio of the secondary amine to the benzaldehyde derivative of the formula (V) is preferably from about 0.05 : 1 to about 1 : 1 , more preferably from about 0.1 : 1 to about 0.7 : 1 , most preferably from about 0.15 : 1 to about 0.5 : 1.
• the reaction may be carried without an additional solvent or in a solvent or a mixture of solvents.
• Suitable solvents are aromatic solvents, ethers, alkanes, cycloalkanes, alcohols, or mixtures thereof. According to a preferred embodiment no additional solvent is used.
• the benzaldehyde derivative of the formula (V), the ⁇ -ketoester derivative of the formula (XII) and the acid are mixed; optionally with one or more solvents.
• the secondary amine is added to the reaction mixture whereby if needed the reaction mixture may be cooled.
• the reaction is carried out at temperatures in the range from -10 0 C to 80 0 C, more preferably from 0°C to 60 0 C, even more preferably from 10°C to 40°C.
• the intermediate of the formula (XM 1 ) may be isolated and, if needed, purified using methods well known in the art.
• the intermediate of the formula (XN 1 ) is catalytically hydrogenated.
• the hydrogenation is carried out with the raw product of the previous reaction step, for example using the reaction mixture of the previous reaction step.
• the catalytic hydrogenation may be carried out after the completion of the first reaction step or concomitantly to the first reaction step, i.e. when the reaction according to the first reaction step is not completed, as during the hydrogenation a reaction according to the first reaction step still may take place.
• solvents are aliphatic hydrocarbons, aromatic hydrocarbons, alcohols, aliphatic ethers, cyclic ethers, and mixtures thereof.
• suitable solvents are pentane, hexane, benzene, toluene, methanol, ethanol, i-propanol, n-propanol, diethylether, tetrahydrofuran, tetrahyd ropy ran and mixtures thereof.
• Preferred solvents are methanol, ethanol, i-propanol, n-propanol, tetrahydrofuran and mixtures thereof. In case in the previous reaction step no additional solvent was used, preferably one or more solvents are added before the catalytic hydrogenation is performed.
• the catalytic hydrogenation is preferably carried out in the presence of a transition metal catalyst such as Pd-based catalysts, for example as finely dispersed Pd or Pd on charcoal, or Ni-based catalysts, for example as finely dispersed Ni such as Raney-nickel.
• a transition metal catalyst such as Pd-based catalysts, for example as finely dispersed Pd or Pd on charcoal, or Ni-based catalysts, for example as finely dispersed Ni such as Raney-nickel.
• the suitable amount of catalyst may vary according to the reaction conditions and lies for example in the range from about 0.1 to about 50 weight-%, preferably from about 1 to about 10 weight-% relative to the educt of the formula (V) or to the intermediate of the formula (XM 1 ).
• the appropriate amount of the catalyst and optionally additional solvent or mixture of solvents are added to the reaction mixture.
• the isolated intermediate of the formula (XM') is dissolved in the solvent or mixture of solvents and the catalyst is added thereto.
• the hydrogenation is advantageously carried out at temperatures in the range from -10 to 150 0 C, preferably from 20 to 100 0 C, more preferably from 20 to 80 0 C, most preferably from 40 to 70 0 C.
• Suitable hydrogen pressures are usually about equal to or above normal atmospheric pressure, preferably in the range from about 1 to 20 bar, even more preferably from 2 to 8 bar.
• the reaction mixtures is preferably agitated or stirred.
• the time period necessary to complete the hydrogenation can be optimized by experimentation. Usually the hydrogenation is performed in a time period from about 30 min to about 24 hours, preferably from about 1 to 12 hours.
• the catalyst is preferably removed from the reaction mixture, for example by filtration.
• the product of the hydrogenation of the formula (XN 1 ) may be isolated and, if needed, purified using methods well known in the art.
• the intermediate of the formula (XM) is reacted with hydrazine to yield the product of the formula (Xl).
• this reaction step is carried out with the raw product, for example using the reaction mixture of the previous reaction step; preferably after the catalyst has been removed from the reaction mixture.
• the isolated product of the formula (XM) is used.
• Suitable solvent or mixture of solvents of this reaction step are alcohols, aliphatic ethers, cyclic ethers, mixtures thereof and mixtures of one or more of these solvents with water.
• suitable solvents are methanol, ethanol, i-propanol, n-propanol, diethylether, tert.-butylmethylether, tetrahydrofuran, tetrahydropyran, mixtures thereof or a solution of one or more of these solvents with water.
• a preferred solvent is the solvent as used in the previous reaction, in particular isopropanol. In case the reaction mixture of the previous reaction step, i.e. not the isolated product of the formula (XM”), is taken, no additional solvent may be needed.
• the hydrazine is advantageously employed as a solution in water, for example as hydrazine monohydrate, or in an alcohol, such as methanol, ethanol, i-propanol, mixtures thereof or mixtures of one or more of such alcohols with water.
• an alcohol such as methanol, ethanol, i-propanol, mixtures thereof or mixtures of one or more of such alcohols with water.
• a preferred molar ratio of the intermediate of the formula (XM") or relative to the educt of the formula (V) and of hydrazine is in the range from 1 : 1 to 1 : 2, more preferably from 1.0 : 1.0 to 1.0 : 1.5, even more preferably in the range from 1.0 : 1.0 to 1.0 : 1.2.
• the appropriate amount of hydrazine and optionally additional solvent or mixture of solvents are added to the reaction mixture.
• the isolated intermediate of the formula (XM) is dissolved in the solvent or mixture of solvents and the hydrazine is added thereto.
• the addition of hydrazine is preferably done continuously or in portions over a period of time, for example in the range from 30 min to 24 h. If necessary the reaction mixture may be cooled.
• the reaction is carried out preferably at temperatures in the range from 0°C to 140°C, more preferably in the range from 20°C to 110°C, even more preferably in the range from 40°C to 90°C. It may be advantageous to complete the reaction at lower temperatures, for example in the range from 15°C to 40 0 C, for an additional period of time, for example from 1 to 24 hours.
• the final product of the formula (Xl) is advantageously obtained as a solid or a precipitate out of the reaction mixture or suspension by isolating it from the liquid phase, for example by filtration.
• the solid may be purified, for example by washing in a suitable solvent, such as those described at the beginning of this reaction step.
• the product may be obtained by removing the solvents, for example by evaporation in vacuum and/or at elevated temperature.
• the final product may be purified via crystallization.
• reaction steps according to this invention are carried out under an inert atmosphere, for example in nitrogen or argon.
• Preferred compounds of the formula Vl are selected from the formulae Vl.1 and Vl.2
• the present invention also relates to a compound of the formula (IV)
• R 1 to R 5 and Q are defined as hereinbefore.
• R 1 preferably denotes methyl, ethyl, n-propyl, i-propyl, cyclobutyl or cyclopentyl; most preferably i-propyl or cyclobutyl.
• R 2 preferably denotes methyl, ethyl, n-propyl or i-propyl; most preferably methyl.
• R 3 preferably denotes fluorine, chlorine, methyl, methoxy, ethoxy, n-propoxy or i-propoxy; most preferably methyl, methoxy, ethoxy or i-propoxy;
• R 4 preferably denotes fluorine, chlorine, methyl, methoxy, ethoxy, n-propoxy or i-propoxy; most preferably fluorine. Furthermore R 4 is preferably a substituent in 2-position of the phenyl-ring, i.e. in meta-position relative to R 3 .
• R 5 preferably denotes hydrogen, fluorine, chlorine, methyl or methoxy; most preferably hydrogen or fluorine.
• the group Q preferably denotes methoxy, ethoxy, n-propoxy, i-propoxy, -NR a R b , wherein R a , R b independently of one another denote methyl, ethyl, n-propyl or i-propyl, or -NR a R b denotes pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl or N-Ci -3 -alkyl-piperazinyl.
• Q denotes methoxy, ethoxy, n-propoxy, i-propoxy, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl or N-Ci -3 -alkyl-piperazinyl; most preferably ethoxy, pyrrolidinyl, piperidinyl or morpholinyl.
• Q is defined as hereinbefore and hereinafter.
• Q is selected from methoxy, ethoxy, iso-propoxy, pyrrolidinyl, piperidinyl, morpholinyl or methylcarbonyloxy.
• Q denotes ethoxy.
• the compounds of the formula (I), in particular of the formula (IH), including prodrugs thereof and pharmaceutically acceptable salts, show activity as inducers of urinary sugar excretion and thus may be used in the manufacture of medicaments in the treatment of diabetes.
• H atoms of hydroxyl groups are not explicitly shown in every case in structural formulae.
• the Examples that follow are intended to illustrate the present invention without restricting it.
• the pressure is indicated in the unit "bar”
• the pressure is indicated in the unit "psi”
• Ethyl crotonate (500 ml; 3.94 mol) is dissolved in isopropanol (1.85 L) and heated to 50°C. Hydrazine hydrate (215 ml; 4.34 mol) is added within 30 min. and the reaction mixture is heated to reflux for 2 h. The solvent is then distilled off (approx. 1 L) under reduced pressure. Isopropanol (400 ml) is then added and the reaction mixture is cooled to 22°C. Hydrochloric acid 11.7 N in ethanol (375 ml, 3.94 mol) is added and the reaction mixture is stirred at about 20 to 25°C 15 h.
• 5-Methyl-3-pyrazolidinone monohydrochloride (692 g; 5.07 mol) is suspended in isopropanol (4.9 L).
• Aqueous 50% sodium hydroxide (270 ml; 5.07 mol) and palladium (10 %-weight) on charcoal (70 g) together with acetone (744 ml, 10 mol) are added.
• the mixture is then hydrogenated under an atmosphere of hydrogen at 50 0 C 3 bar (42 psi) until uptake of hydrogen ceases.
• the reaction mixture is filtered and solvent is distilled off under reduced pressure.
• the residue is treated two times with 1L of isopropanol which is subsequently distilled off under reduced pressure.
• the remainder is dissolved in isopropanol (3.5 L) and filtered.
• 1-(1-Methylethyl) -5-methyl-3-pyrazolidinone monohydrochloride 150 g; 0.84 mol
• saturated aqueous potassium carbonate 1.2 L
• ethyl acetate 1.0 L
• the mixture is filtered and the phases are separated.
• the organic phase is dried with anhydrous sodium sulphate, filtered and evaporated in vacuo to yield 1-(1-methylethyl)-5-methyl-3- pyrazolidinone as a solid.
• Variant 1 1-(1-methylethyl)-5-methyl-3-pyrazolidinone (390 g; 2.74 mol) is dissolved in acetic acid (170 ml) with warming. 35% aqueous hydrogen peroxide (260 ml; 3.0 mol) is added within 3 h while keeping the temperature at about 65°C. The reaction mixture is then stirred at about 20 to 25°C for 15 h. Water (1.2 L) is then added and the pH of the mixture is adjusted to about 7 by means of addition of approx. 1 L 50%-weight aqueous sodium hydroxide solution. Upon cooling to 5°C the reaction mixture is filtered. The product is washed with water and dried at about 50 0 C. Colourless crystals are obtained.
• the synthesis of the intermediate VIII.1 is described in example 1.1.
• the intermediate Vll.2a may be obtained by employing the example 1.2 wherein instead of propanon the appropriate amount of cyclobutanon (IX.2) is taken.
• the compounds VII.2 and VI.2 may be obtained by using the procedure as described in the examples 1.3 and 1.4 in an analogous manner.
• Variant 3 To a mixture of 50 g (0,144 mol) 1,2-dihydro-1-(1-methylethyl)-4-[(2-fluor-4-methoxyphenyl)- (1-pyrrolidino)methyl]-5-methyl-3H-pyrazol-3-one and 500 ml ethanol is added aq. 30% hydrochloric acid. The reaction mixture is heated to 50 0 C for 2-3 h. 175 ml of water is then added and the mixture is cooled. The product is isolated by filtration and washed with ethanol. It is dried under inert gas atmosphere at 45°C.
• the intermediate of the formula IV.2 may be obtained using the procedure as described in the example 3b in an analogous manner.
• the intermediate of the formula IV.3 may be obtained using the procedure as described in the example 3b in an analogous manner.
• the intermediate of the formula IV.4 may be obtained using the procedure as described in the example 3b in an analogous manner.
• the intermediate of the formula IV.5 may be obtained using the procedure as described in the example 3b in an analogous manner.
• the intermediate of the formula IV.7 may be obtained using the procedure as described in the example 3b in an analogous manner.
• the intermediate of the formula IV. ⁇ may be obtained using the procedure as described in the example 3b in an analogous manner.
• the intermediate of the formula IV.10 may be obtained using the procedure as described in the example 3b in an analogous manner.
• the intermediate of the formula IV.11 may be obtained using the procedure as described in the example 3b in an analogous manner.
• the compound of the formula III.2 may be obtained by employing the synthetic procedure as outlined in example 14 in an analogous manner.
• the compound of the formula III.3 may be obtained by employing the synthetic procedure as outlined in example 14 in an analogous manner.
• the compound of the formula III.4 may be obtained by employing the synthetic procedure as outlined in example 14 in an analogous manner.
• the compound of the formula III.5 may be obtained by employing the synthetic procedure as outlined in example 14 in an analogous manner.
• Example 20 The compound of the formula III.6 may be obtained by employing the synthetic procedure as outlined in example 14 in an analogous manner.
• Example 20 The compound of the formula III.6 may be obtained by employing the synthetic procedure as outlined in example 14 in an analogous manner.
• Example 20
• the compound of the formula III.7 may be obtained by employing the synthetic procedure as outlined in example 14 in an analogous manner.
• the compound of the formula III.8 may be obtained by employing the synthetic procedure as outlined in example 14 in an analogous manner.
• the compound of the formula 111.10 may be obtained by employing the synthetic procedure as outlined in example 14 in an analogous manner.
• the compound of the formula 111.11 may be obtained by employing the synthetic procedure as outlined in example 14 in an analogous manner.
• Aqueous potassium hydroxide (1 M; 870 ml) is added to a mixture of (2,3,4,6-O-tetraacetyl)- ⁇ -D-glucopyranosyl bromide (485 g; 1.169 mol), 1,2-dihydro-1-(1-methylethyl)-4-[(2-fluor-4- methoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one (161 g; 0.58 mol) and tetrabutylammonium chloride (9.4 g; 0.029 mol ) in dichloromethane (780 L).
• the two phase mixture is vigorously stirred at 25 to 27°C while the pH of the aqueous layer is kept constant at approx.
• the compound of the formula 1.2 may be obtained by employing the synthetic procedure as outlined in example 26 in an analogous manner.
• the compound of the formula 1.3 may be obtained by employing the synthetic procedure as outlined in example 26 in an analogous manner.
• the compound of the formula 1.5 may be obtained by employing the synthetic procedure as outlined in example 26 in an analogous manner.
• the compound of the formula 1.6 may be obtained by employing the synthetic procedure as outlined in example 26 in an analogous manner.
• the compound of the formula 1.7 may be obtained by employing the synthetic procedure as outlined in example 26 in an analogous manner.
• Example 33 Synthesis of 1 '-(1 -methylethyl)- 4 -[(3-fluoro-4-ethoxyphenyl)methyl]-5'-methyl-1 H- pyrazol-3'-O-(2,3,4,6-O-tetraacetyl)- ⁇ -D-glucopyranoside (L8)
• the compound of the formula 1.8 may be obtained by employing the synthetic procedure as outlined in example 26 in an analogous manner.
• the compound of the formula 1.9 may be obtained by employing the synthetic procedure as outlined in example 26 in an analogous manner.
• the compound of the formula 1.10 may be obtained by employing the synthetic procedure as outlined in example 26 in an analogous manner.
• the compound of the formula 1.11 may be obtained by employing the synthetic procedure as outlined in example 26 in an analogous manner.
• the compound of the formula IH.2 may be obtained by employing the synthetic procedure as outlined in example 37 in an analogous manner.
• Example 39 Synthesis of 1 '-(1 -methylethyl)- 4 -[(2,6-difluoro-4-methoxyphenyl)methyl]-5'-methyl- 1 H-pyrazol-3'-O- ⁇ -D-glucopyranoside (IH.3)
• Example 40 The compound of the formula IH.3 may be obtained by employing the synthetic procedure as outlined in example 37 in an analogous manner.
• Example 40
• the compound of the formula IH.4 may be obtained by employing the synthetic procedure as outlined in example 37 in an analogous manner.
• the compound of the formula IH.5 may be obtained by employing the synthetic procedure as outlined in example 37 in an analogous manner.
• the compound of the formula IH.6 may be obtained by employing the synthetic procedure as outlined in example 37 in an analogous manner.
• the compound of the formula IH.7 may be obtained by employing the synthetic procedure as outlined in example 37 in an analogous manner.
• the compound of the formula IH.9 may be obtained by employing the synthetic procedure as outlined in example 37 in an analogous manner.
• Example 46 Synthesis of 1 '-(1 -methy lethyl)- 4 -[(2-fluoro-4-(1-methylethoxy)phenyl)methyl]-5 - methyl-1 H-pyrazol-3'-O- ⁇ -D-glucopyranoside (IH.10)
• the compound of the formula IH.10 may be obtained by employing the synthetic procedure as outlined in example 37 in an analogous manner.
• the compound of the formula IH.11 may be obtained by employing the synthetic procedure as outlined in example 37 in an analogous manner.
• reaction mixture is heated to reflux for 3 hrs after which it is allowed to cool to about 20 to 25°C.
• resulting suspension is then filtered, the product being washed with methyl-t-butyl ether and dried at 50 0 C to yield colourless crystals.
• the compound of the formula XI.2 may be obtained by employing the synthetic procedure as outlined in example 48 in an analogous manner.
• the compound of the formula XI.3 may be obtained by employing the synthetic procedure as outlined in example 48 in an analogous manner.
• the compound of the formula XI.6 may be obtained by employing the synthetic procedure as outlined in example 48 in an analogous manner.
• the compound of the formula XI.7 may be obtained by employing the synthetic procedure as outlined in example 48 in an analogous manner.
• the compound of the formula XI.9 may be obtained by employing the synthetic procedure as outlined in example 48 in an analogous manner.
• the compound of the formula Xl.10 may be obtained by employing the synthetic procedure as outlined in example 48 in an analogous manner.
• Example 58 The compound of the formula Xl.11 may be obtained by employing the synthetic procedure as outlined in example 48 in an analogous manner.
• Step 1
• the compound of the formula III.2 may be obtained by employing the synthetic procedure as outlined in example 58 in an analogous manner.
• the compound of the formula III .3 may be obtained by employing the synthetic procedure as outlined in example 58 in an analogous manner.
• Example 61 i ⁇ -Dihydro-i-cyclobutyM- ⁇ S-fluoro ⁇ -methylphenyOmethylJ-S-methyl-SH-pyrazol-S- one (111.4)
• Example 62 i ⁇ -Dihydro-i-cyclobutyM- ⁇ -fluoro ⁇ -methoxyphenyOmethylJ-S-methyl-SH-pyrazol-S- one (111.5)
• the compound of the formula 111.5 may be obtained by employing the synthetic procedure as outlined in example 58 in an analogous manner.
• the compound of the formula III.7 may be obtained by employing the synthetic procedure as outlined in example 58 in an analogous manner.
• the compound of the formula 111.8 may be obtained by employing the synthetic procedure as outlined in example 58 in an analogous manner.
• the compound of the formula III.9 may be obtained by employing the synthetic procedure as outlined in example 58 in an analogous manner.
• the compound of the formula 111.10 may be obtained by employing the synthetic procedure as outlined in example 58 in an analogous manner.
• the compound of the formula 111.11 may be obtained by employing the synthetic procedure as outlined in example 58 in an analogous manner.

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