JP4888840B2 - Process for the preparation of pyrazole-O-glycoside derivatives and novel intermediates of said process - Google Patents

Description

  The present invention relates to general formula (I)

(Wherein the substituents R ^{1 to} R ⁶ and R ^7a , R ^7b , R ^7c are defined below)
Relates to a process for the preparation of the pyrazole-O-glycoside derivatives.
Furthermore, the present invention provides a compound of formula (III)

(Where R ^{1 to} R ⁵ are defined below)
To a process for the preparation of
Furthermore, the present invention provides a compound of formula (IV)

(Where R ^{1 to} R ⁵ and Q are defined below)
To a process for the preparation of
Furthermore, the present invention provides a compound of formula (XI)

(Where R ^{2 to} R ⁵ are defined below)
It relates to a process for preparing pyrazole derivatives of
Furthermore, the present invention relates to novel intermediates and starting materials useful in the process of the present invention.

The object of the present invention is a novel process for the preparation of pyrazole-O-glycoside derivatives of the formula (I), in particular the product may be obtained in high yield and / or high chemical and diastereomeric purity and low technology To find a method that allows the production of commercial scale products at low cost and high space / time yield.
Another object of the present invention is to provide a process for the preparation of the starting material of the process.
A further object of the present invention relates to novel intermediates and starting materials in the process of the present invention.
Other objects of the invention will be apparent to the skilled person directly from the foregoing and following description.

  In the first aspect, the present invention relates to a general formula (I)

(Where
R ¹ represents C _1-4 -alkyl, a C _1-4 -alkyl group substituted with one or more fluorine atoms, or C _3-6 -cycloalkyl, and
R ² represents C _1-4 -alkyl, a C _1-4 -alkyl group substituted with one or more fluorine atoms, or C _3-6 -cycloalkyl, and
R ³ represents fluorine, chlorine, bromine, C _1-4 -alkyl, C _3-6 -cycloalkyl, C _1-4 -alkoxy, or C _3-6 -cycloalkyl-oxy, and
R ⁴ and R ⁵ independently of one another represent hydrogen, fluorine, chlorine, bromine, C _1-4 -alkyl, or C _1-4 -alkoxy, and
R ⁶ , R ^7a , R ^7b and R ^7c each independently represents a group selected from hydrogen, (C _1-6 -alkyl) carbonyl, phenylcarbonyl and phenyl- (C _1-3 -alkyl) -carbonyl. Have)
Comprising the tautomers, stereoisomers, mixtures thereof and salts thereof, comprising:
Formula (III)

(Wherein R ^{1 to} R ⁵ are as defined above)
An aglycone of the formula (IV) in a solvent or solvent mixture

Wherein R ^{1 to} R ⁵ are as defined above and Q is Cl, Br, I, C _1-4 -alkoxy, C _1-4 -alkylthio, phenylthio, C _3-6 -cyclo Alkyl-oxy, C _1-4 -alkylcarbonyloxy, —NR ^a R ^b (wherein R ^a and R ^b independently represent C _1-4 -alkyl, or —NR ^a R ^b is pyrrolidinyl, piperidinyl Represents morpholinyl, piperazinyl or NC _1-4 -alkyl-piperazinyl))
It is obtained by the catalytic hydrogenation of a compound of
In a second aspect, the present invention provides a compound of formula (III)

(Wherein R ^{1 to} R ⁵ are as defined above)
An aglycone of the formula (II) in a solvent or mixture of solvents

(Where
X represents chlorine or chlorine,
R ⁶ , R ^7a , R ^7b , R ^7c independently of one another have the meaning selected from the groups: (C _1-6 -alkyl) carbonyl, phenylcarbonyl and phenyl- (C _1-3 -alkyl) -carbonyl)
The product of formula (I) where necessary, wherein the substituents R ⁶ , R ^7a , R ^7b , R ^7c are not hydrogen, and particularly preferably the third aspect of the invention Wherein R ^{1 to} R ⁵ , R ⁶ , R ^7a , R ^7b and R ^7c are as defined above, characterized in that the deprotection is carried out by the method described in ) Compounds (including their tautomers, stereoisomers, mixtures thereof and salts thereof).
In a third aspect, the present invention provides a compound of formula (IH)

(Wherein R ^{1 to} R ⁵ are as defined earlier and later)
(Including their tautomers, stereoisomers, mixtures thereof and salts thereof)
A method for preparing a compound of
Formula (I)

Wherein R ^{1 to} R ⁵ are as defined above, and R ⁶ , R ^7a , R ^7b and R ^7c are as defined above and below, one of them. The above is not hydrogen)
And a step of deprotecting the compound by cleaving the non-hydrogen substituents R ⁶ , R ^7a , R ^7b and R ^7c in a solvent or a mixture of solvents.
In a fourth aspect, the present invention provides a compound of formula (III)

(Where
R ¹ represents C _1-4 -alkyl, a C _1-4 -alkyl group substituted with 1 to 3 fluorine atoms, or C _3-6 -cycloalkyl, and
R ² represents C _1-4 -alkyl, a C _1-4 -alkyl group substituted with one or more fluorine atoms, or C _3-6 -cycloalkyl, and
R ³ represents fluorine, chlorine, bromine, C _1-4 -alkyl, C _3-6 -cycloalkyl, C _1-4 -alkoxy, or C _3-6 -cycloalkyl-oxy, and
R ⁴ and R ⁵ each independently represent hydrogen, fluorine, chlorine, bromine, C _1-4 -alkyl, or C _1-4 -alkoxy)
Comprising the tautomers, stereoisomers, mixtures thereof and salts thereof, comprising:
Formula (IV)

Wherein R ^{1 to} R ⁵ are as defined above and Q is Cl, Br, I, C _1-4 -alkoxy, C _1-4 -alkylthio, phenylthio, C _3-6 -cyclo Alkyl-oxy, C _1-4 -alkylcarbonyloxy, —NR ^a R ^b (wherein R ^a and R ^b independently represent C _1-4 -alkyl, or —NR ^a R ^b is pyrrolidinyl, piperidinyl Represents morpholinyl, piperazinyl or NC _1-4 -alkyl-piperazinyl))
A process for the preparation of said compound, comprising the step of catalytic hydrogenation of said pyrazole derivative in a solvent or a mixture of solvents.
In a fifth aspect, the present invention provides a compound of formula (IV)

(Where
R ¹ represents C _1-4 -alkyl, a C _1-4 -alkyl group substituted with one or more fluorine atoms, or C _3-6 -cycloalkyl, and
R ² represents C _1-4 -alkyl, a C _1-4 -alkyl group substituted with one or more fluorine atoms, or C _3-6 -cycloalkyl, and
R ³ represents fluorine, chlorine, bromine, C _1-4 -alkyl, C _3-6 -cycloalkyl, C _1-4 -alkoxy, or C _3-6 -cycloalkyl-oxy, and
R ⁴ and R ⁵ each independently represent hydrogen, fluorine, chlorine, bromine, C _1-4 -alkyl, or C _1-4 -alkoxy, and Q is C _1-4 -alkoxy, C _1-4 -alkylthio , C _3-6 -cycloalkyl-oxy, phenylthio, —NR ^a R ^b (wherein R ^a and R ^b independently represent C _1-4 -alkyl, or —NR ^a R ^b represents pyrrolidinyl, piperidinyl Represents morpholinyl, piperazinyl or NC _1-4 -alkyl-piperazinyl))
Comprising the tautomers, stereoisomers, mixtures thereof and salts thereof, comprising:
Formula (VI)

(Wherein R ¹ and R ² are as defined above)
Pyrazole derivatives of
a) Secondary amine HQ (wherein Q is —NR ^a R ^b (wherein R ^a and R ^b independently represent C _1-4 -alkyl, or —NR ^a R ^b is pyrrolidinyl, piperidinyl, Represents morpholinyl, piperazinyl or NC _1-4 -alkyl-piperazinyl)), or
b) an alcohol or thiol HQ (wherein Q represents C _1-4 -alkoxy, C _1-4 -alkylthio, phenylthio or C _3-6 -cycloalkyl-oxy) and a secondary amine in the presence of a secondary amine (V)

(Wherein R ³ , R ⁴ and R ⁵ are as defined above)
The method of preparing the said compound characterized by including the process made to react with the benzaldehyde derivative | guide_body of this.
In a sixth aspect, the present invention provides a compound of formula (III)

(Wherein R ^{1 to} R ⁵ are as defined above)
A process for the preparation of pyrazole derivatives of (including their tautomers, stereoisomers, mixtures thereof and salts thereof),
Formula (XI)

(Wherein R ^{2 to} R ⁵ are as defined above)
An alkylating agent R ¹ -X ′ in the presence of a base in a solvent or mixture of solvents wherein R ¹ is as defined above and X ′ is chlorine, bromine, iodine or C _1-3 -alkyl-SO ₂ -O-) and the formula (XI ')

(Wherein R ^{1 to} R ⁵ are as defined above)
To an aglycone of the formula (III) by subsequently cleaving the R ¹ —O— group at the 3-position of the pyrazole ring in the presence of an acid to obtain an aglycone of formula (III) .
In a seventh aspect, the present invention provides formula (XI)

(Wherein R ^{2 to} R ⁵ are as defined above)
A process for the preparation of pyrazole derivatives of (including their tautomers, stereoisomers, mixtures thereof and salts thereof),
(i) Formula (V)

(Wherein R ³ , R ⁴ and R ⁵ are as defined above)
The benzaldehyde derivatives of formula (XII) in the presence of acids and secondary amines

(Wherein R ² is as defined above and
R ^c is methyl, ethyl, n-propyl or i-propyl)
Reacting with a β-ketoester derivative of, followed by or simultaneous catalytic hydrogenation, and
(ii) It relates to a process for the preparation of said derivative, characterized in that it comprises a step of reacting the product of step (i) with hydrazine in a solvent or a mixture of solvents.
In an eighth aspect, the present invention relates to a process for the preparation of a compound of general formula (I) identified above, characterized in that the process comprises the process steps described in the fifth aspect of the present invention.
In a ninth aspect, the invention relates to a general formula as specified above, characterized in that the method comprises one or both method steps as described in the sixth and / or seventh aspect of the invention. The present invention relates to a method for preparing the compound (I).
In a tenth aspect, the present invention provides a compound of formula (IV)

Wherein R ^{1 to} R ⁵ are as defined above and Q is Cl, Br, I, C _1-4 -alkoxy, C _1-4 -alkylthio, phenylthio, C _3-6 -cyclo Alkyl-oxy, C _1-4 -alkylcarbonyloxy, —NR ^a R ^b (wherein R ^a and R ^b independently represent C _1-4 -alkyl, or —NR ^a R ^b is pyrrolidinyl, piperidinyl Represents morpholinyl, piperazinyl or NC _1-4 -alkyl-piperazinyl))
(Including their tautomers, stereoisomers, mixtures thereof and salts thereof).
In an eleventh aspect, the present invention provides a compound of formula (III)

(Wherein R ^{1 to} R ⁵ are as defined above and below)
(Including their tautomers, stereoisomers, mixtures thereof and salts thereof).
Another aspect of the invention is a compound of formula (VI)

Wherein R ¹ and R ² are as defined in claim 1, 21 or 22.
(Including their tautomers, mixtures thereof and salts thereof).

Unless otherwise stated, groups, residues and substituents, especially R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^7a , R ^7b , R ^7c , R ^7d , R ¹¹ , R ¹² , R ^c , Q, X and X ′ are defined above and below.
If a residue, substituent or group appears several times in a compound, they may have the same or different meanings. For example, the meaning di- (C _1-4 -alkyl) amine includes secondary amines having two identical or different alkyl groups, for example ethyl-isopropyl-amine.
In the methods and compounds, intermediates and starting materials of the present invention, the following meanings of groups and substituents are preferred.
R ¹ is the formula

(Wherein, R ¹¹ is C _1-3 - When alkyl, and R ¹² represents H, or the R ¹¹ represents methyl - C _1-3 substituted by alkyl or one or more fluorine atoms R ¹² may also represent a methyl or ethyl group or a methyl or ethyl group substituted with one or more fluorine atoms, or R ¹¹ and R ¹² are joined together Together with the CH- group forms a C _3-6 -cycloalkyl group)
It is preferable to represent this group.
More preferably, R ¹ represents ethyl, n-propyl, i-propyl, cyclobutyl or cyclopentyl, most preferably i-propyl or cyclobutyl.
It is preferred that R ² represents methyl, ethyl, n-propyl or i-propyl, most preferably methyl.
It is preferred that R ³ represents fluorine, chlorine, methyl, methoxy, ethoxy, n-propoxy or i-propoxy, most preferably methyl, methoxy, ethoxy or i-propoxy.
R ⁴ preferably represents fluorine, chlorine, methyl, methoxy, ethoxy, n-propoxy or i-propoxy, especially fluorine. Further, the substituent R ⁴ is preferably a substituent at the 2-position of the phenyl ring. Most preferably, R ⁴ is a substituent at the 2-position of the phenyl ring and represents fluorine.
It is preferred that R ⁵ represents hydrogen, fluorine, chlorine, methyl or methoxy, most preferably hydrogen or fluorine.
In the compounds of the formula (I), the substituents R ⁶ , R ^7a , R ^7b , R ^7c are independently selected from the group: hydrogen, (C _1-4 -alkyl) carbonyl, phenylcarbonyl and benzylcarbonyl. It is preferable to have. In the compounds of the formula (I) it is further preferred that the substituents R ⁶ , R ^7a , R ^7b , R ^7c have a meaning independently selected from the group: hydrogen, methylcarbonyl and ethylcarbonyl, in particular hydrogen.

In the compound of formula (II), the substituents R ⁶ , R ^7a , R ^7b , R ^7c have a meaning selected independently of each other from the group: (C _1-4 -alkyl) carbonyl, phenylcarbonyl and benzylcarbonyl Is preferred. In the compound of formula (II), it is further preferred that the substituents R ⁶ , R ^7a , R ^7b , R ^7c have a meaning independently selected from the group: methylcarbonyl and ethylcarbonyl, in particular methylcarbonyl.
In the compound of formula (II ′), the substituents R ⁶ , R ^7a , R ^7b , R ^7c , R ^7d are independently selected from the group: (C _1-4 -alkyl) carbonyl, phenylcarbonyl and benzylcarbonyl It preferably has a meaning. In the compound of formula (II ′), it is further preferred that the substituents R ⁶ , R ^7a , R ^7b , R ^7c , R ^7d have the meaning independently selected from the group: methylcarbonyl and ethylcarbonyl, in particular methylcarbonyl preferable.
It is understood that the corresponding tautomers of the compounds specified above by the general formula or special formula and below are also included within the scope of every method of the invention and the definition of each method or compound. Should. In particular for pyrazole derivatives, the following tautomers may exist depending on the reaction conditions and preparation conditions.

  In the formula, the following symbols are used to indicate bonds towards chemical groups or substituents (including hydrogen)

In the following, the method of the present invention will be described in detail.
According to a first aspect of the present invention, an aglycone of formula (III) is obtained by catalytic hydrogenation of a compound of formula (IV) according to reaction scheme I.
Scheme I:

The group Q is methoxy, ethoxy, n-propoxy, i-propoxy, —NR ^a R ^b (wherein R ^a , R ^b independently of one another represents methyl, ethyl, n-propyl or i-propyl, or —NR ^a R ^b preferably represents pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl or NC _1-3 -alkyl-piperazinyl). It is further preferred that Q represents methoxy, ethoxy, n-propoxy, i-propoxy, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl or NC _1-3 -alkyl-piperazinyl, most preferably ethoxy, pyrrolidinyl, piperidinyl or morpholinyl.
In the above synthesis step, 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. Examples of suitable solvents are pentane, hexane, benzene, toluene, methanol, ethanol, i-propanol, n-propanol, diethyl ether, tetrahydrofuran, tetrahydropyran, ethyl acetate, isopropyl acetate, butyl acetate, NMP, DMF, glacial acetic acid, These mixtures and their mixtures with water. Preferred solvents are methanol, ethanol, i-propanol, n-propanol, tetrahydrofuran, mixtures thereof and mixtures thereof with water.

The catalytic hydrogenation is preferably carried out in the presence of one or more acids, in particular hydrochloric acid, carboxylic acid or alkanesulfonic acid. Examples of suitable acids are hydrochloric acid, acetic acid and trifluoroacetic acid. The acid is preferably used in an equivalent amount or from about 1 mol% to 150 mol% relative to the educt of formula (IV).
When HQ is an alcohol or thiol, the acid is equivalent or about 1 mol% to 50 mol%, more preferably about 1 mol% to 20 mol%, for example about 10 mol, relative to the educt of formula (IV). It is preferably used in an amount of%. In the case of acetic acid, the amount may be up to 100 mol%.
When Q is selected from —NR ^a R ^b according to ^a preferred embodiment, catalytic hydrogenation may be performed without the addition of acid. According to another preferred embodiment, when Q is selected from —NR ^a R ^b , the acid is equivalent or about 1 mol% to 120 mol% based on the educt of formula (IV), eg about It is preferably used in equimolar amounts.

Catalytic hydrogenation is a transition metal catalyst, e.g. Pd based catalyst, e.g. finely dispersed Pd, Pd / charcoal or Pd (OH) ₂ , or Ni based catalyst, e.g. finely dispersed Preferably, the reaction is performed in the presence of Ni, for example, Raney nickel. Suitable amounts of catalyst may vary according to the reaction conditions, for example in the range from about 0.1% to about 50%, preferably from about 1% to about 10% by weight relative to the educt of formula (IV). It is. Hydrogenation is advantageously carried out at temperatures ranging from -30 ° C to 150 ° C, preferably from 20 ° C to 100 ° C, more preferably from 20 ° C to 70 ° C, most preferably from 40 ° C to 60 ° C. Suitable hydrogen pressures are usually approximately equal to or higher than atmospheric pressure, preferably in the range from about 1 bar to 20 bar, more preferably from 2 bar to 8 bar. It is preferred that the reaction mixture is stirred during the hydrogenation. The period of time required to complete the hydrogenation can be optimized by experiment. Usually, the hydrogenation is carried out for a period of time from about 30 minutes to about 24 hours, preferably from about 1 hour to 12 hours. After hydrogenation, the catalyst is preferably removed from the reaction mixture, for example by filtration. The next reaction step, i.e. the synthesis of the compound of formula (I), may be carried out using a reaction solution containing the product of formula (III) or an isolated product of formula (III). The product of formula (III) may be isolated from the reaction solution, for example by removing the solvent in vacuo and / or at an elevated temperature. The product of formula (III) may also be obtained by precipitation from the concentrated reaction solution, for example by adding an anti-solvent such as water and isolating from the suspension, for example by filtration.

Free form of formula (IV) wherein Q is C _1-4 -alkoxy, C _1-4 -alkylthio, phenylthio, C _3-6 -cycloalkyl-oxy or -NR ^a R ^b (where R ^a , R ^b independently of one another represents C _1-4 -alkyl, or —NR ^a R ^b represents pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl or NC _1-4 -alkyl-piperazinyl)) According to the fifth aspect, i.e. the pyrazole derivative of formula (VI) according to reaction scheme II
a) Secondary amine HQ (wherein Q is —NR ^a R ^b (wherein R ^a and R ^b independently represent C _1-4 -alkyl, or —NR ^a R ^b is pyrrolidinyl, piperidinyl, Represents morpholinyl, piperazinyl or NC _1-4 -alkyl-piperazinyl)), or
b) an alcohol or thiol HQ (wherein Q represents C _1-4 -alkoxy, C _1-4 -alkylthio, phenylthio or C _3-6 -cycloalkyl-oxy) and a secondary amine in the presence of a secondary amine It is preferably obtained by reacting with the benzaldehyde derivative of (V).
Scheme II:

The reaction is carried out in the presence of a secondary amine.
If the compound HQ is used, where Q is -NR ^a R ^b as defined, no additional secondary amine is required. HQ is preferably selected from pyrrolidine, piperidine, morpholine, piperazine and NC _1-3 -alkyl-piperazine, most preferably pyrrolidine, piperidine and morpholine. The amine derivative HQ is preferably used in an equimolar amount or molar excess compared to the pyrazole derivative of formula (IV). A preferred molar ratio of amine HQ to pyrazole derivative is in the range of about 1: 1 to 10: 1, more preferably in the range of 1: 1 to 5: 1.
When an alcohol or thiol HQ is used, where Q represents C _1-4 -alkoxy, C _1-4 -alkylthio, phenylthio or C _3-6 -cycloalkyl-oxy, the reaction is a secondary amine In the presence of It is preferred that Q is selected from methoxy, ethoxy, n-propoxy and i-propoxy, most preferably ethoxy. Preferred secondary amines are selected from di- (C _1-4 -alkyl) amines or cyclic secondary amines such as pyrrolidine, piperidine, morpholine, piperazine, NC _1-3 -alkyl-piperazine. More preferably, the secondary amine is selected from pyrrolidine, piperidine, morpholine, piperazine and NC _1-3 -alkyl-piperazine, most preferably pyrrolidine, piperidine and morpholine. Secondary amines may be used in catalytic amounts, approximately equimolar amounts or even in molar excess. Preferred molar ratios of secondary amine to pyrazole derivatives range from about 0.05: 1 to 2: 1, 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 HQ is preferably used in an equimolar amount or molar excess compared to the pyrazole derivative of formula (VI). In addition to its function as a reaction partner, alcohol HQ may also be available as a solvent, so that in this case a molar excess of HQ may be used.

Furthermore, this reaction of the present invention is preferably carried out under acidic conditions. Suitable acids are, for example, C _1-6 -alkyl carboxylic acids (which may be unsubstituted or substituted with one or more fluorine or chlorine substituents), C _1-6- Alkyl sulfonic acids (which may be unsubstituted or substituted with one or more fluorine or chlorine substituents), dicarboxylic acids, tricarboxylic acids, methylchlorosilanes, non-aqueous mineral acids. Examples of preferred acids are glacial acetic acid, trimethylchlorosilane, hydrochloric acid (aqueous or as a solution in an alcohol such as ethanol), trifluoromethanesulfonic acid. The acid is preferably used in an equimolar amount or molar excess relative to the pyrazole derivative of formula (IV). A preferred molar ratio of acid to pyrazole derivative ranges from about 0.05: 1 to 1: 1, more preferably from about 0.1: 1 to 0.5: 1.
When compound HQ is an alcohol or thiol derivative as defined above, the acid is preferably used in at least a molar amount of the secondary amine. When the group Q is selected from —NR ^a R ^b , the reaction may be carried out with or without the addition of acids, whereby preferred acids and molar ratios are given above.

In the above synthesis process, suitable solvents are aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons, alcohols, aliphatic ethers, cyclic ethers, acetonitrile, amide type solvents, acetic acid, and mixtures thereof. Examples of suitable solvents are dichloromethane, 1,2-dichloroethane, methanol, ethanol, i-propanol, n-propanol, diethyl ether, tetrahydrofuran, tetrahydropyran, acetonitrile, NMP, DMF, glacial acetic acid and mixtures thereof. Preferred solvents are methanol, ethanol, i-propanol, n-propanol, tetrahydrofuran, acetonitrile and mixtures thereof. If compound HQ is an alcohol, it may be further available as a solvent and thus may be used in stoichiometric excess. A particularly preferred solvent is acetonitrile when the group Q is selected from —NR ^a R ^b .

The educts of formulas (V) and (VI) are preferably reacted in a molar ratio of about 2: 1 to 1: 2, preferably in an approximately equimolar ratio. The synthesis step is advantageously carried out at temperatures ranging from -30 ° C to 150 ° C, preferably from 10 ° C to 100 ° C, more preferably from 20 ° C to 80 ° C, most preferably from 30 ° C to 70 ° C. The time required to complete the reaction usually ranges from about 1 hour to 96 hours. Depending on the choice of solvent, the product of formula (IV) is slightly sparingly soluble in the reaction mixture, thus producing a suspension. The next reaction step, ie the synthesis of the compound of formula (III), may be carried out using the crude product of formula (IV) or the isolated product. The product of formula (IV) may be isolated from the reaction solution, for example by removing the solvent in vacuo and / or at an elevated temperature. The product of formula (IV) can also be concentrated reaction solution or by adding an anti-solvent such as water and / or cooling the solution or suspension and isolating it from the suspension, for example by filtration. It may be obtained by precipitation from suspension.
Synthetic operations of benzaldehyde derivatives of formula (V) are known in the literature or may be carried out in a manner similar to methods known in organic chemistry.
The pyrazole derivative of formula (VI) is preferably obtained by dehydrogenation of the pyrazole derivative of formula (VII) according to reaction scheme III.
Scheme III:

Dehydrogenation is preferably carried out using an oxidizing agent such as H ₂ O ₂ , inorganic peroxide, peroxomonosulfuric acid or a salt thereof, peroxodisulfuric acid or a salt thereof, percarboxylic acid, peroxoborate and the like. Preferred oxidizing agents are H ₂ O ₂ or peracetic acid. H ₂ O _2, for example, 3 to 90 wt%, preferably in a content of H ₂ O ₂ 10 to 70 wt%, is preferably used as an aqueous solution. The preferred amount of oxidizing agent is approximately equimolar or molar excess relative to the educt of formula (VIII), e.g. in the range from 1: 1 to 2: 1, more preferably from 1.0: 1.0 to 1.3: 1.0. Is the ratio.
According to the above synthesis step, the free form of formula (VII) is dissolved or suspended in a suitable solvent or mixture of solvents. An example of a suitable solvent is a carboxylic acid such as acetic acid or an aqueous mixture thereof. For the exothermic reaction, the oxidizing agent is preferably added to the solution or suspension preferably continuously or in portions over a period of time ranging for example from 30 minutes to 24 hours. If necessary, the reaction mixture may be cooled. The reaction is preferably carried out at a temperature in the range from 0 ° C to 130 ° C, more preferably in the range from 10 ° C to 90 ° C, more preferably in the range from 20 ° C to 80 ° C. The reaction is usually completed within 1 to 24 hours. The final product of formula (VI) can be obtained, for example, by adding water to the reaction mixture, preferably in the temperature range of 0-20 ° C., or pouring the reaction mixture into water, if necessary with a suitable base, such as sodium hydroxide, By using aqueous potassium hydroxide or ammonium hydroxide solution, the reaction mixture is neutralized to a pH in the range of 5 to 9, preferably about 7, and the solid product is subjected to aqueous reaction mixture, for example by filtration. May be obtained in solid form by removal from If the reaction mixture is not neutralized, the product may be obtained in salt form, for example as acetate.
The dehydrogenation is also carried out by a catalyst, preferably in the presence of a transition metal catalyst, for example a Pd-based catalyst, for example finely dispersed Pd or Pd / charcoal. Catalytic dehydrogenation is carried out in a chemically inert solvent or solvent mixture such as an aliphatic or aromatic hydrocarbon such as toluene at an elevated temperature, for example from about 80 ° C to 240 ° C, preferably from about 100 ° C to 200 ° C. It is preferable to be performed in the range up to. The product may be isolated from the reaction solution using methods known in the art, preferably after removing the catalyst, for example by filtration.
R ¹ is the formula

(Wherein, R ¹¹ is C _1-3 - When alkyl, and R ¹² represents H, or the R ¹¹ represents methyl - C _1-3 substituted by alkyl or one or more fluorine atoms R ¹² may represent a methyl group or an ethyl group or a methyl group or an ethyl group substituted with one or more fluorine atoms, or R ¹¹ and R ¹² are bonded to each other, and the CH to which they are bonded. Together with the-group to form a C _3-6 -cycloalkyl group)
Wherein the pyrazole derivative of formula (VII) is preferably obtained by reduction of the pyrazole derivative of formula (VIII) with the aldehyde or ketone of formula (IX) according to reaction scheme IV and after or simultaneously with the reduction. .
Scheme IV:

The substituent R ¹¹ preferably represents methyl, ethyl, n-propyl or i-propyl, and the substituent R ¹² represents H, and when R ¹¹ represents methyl or ethyl, R ¹² is also methyl or It may represent ethyl and R ¹¹ and R ¹² may be joined together with the C atom to which they are attached to form a cyclobutyl or cyclopentyl ring. Most preferably, both substituents R ¹¹ and R ¹² represent methyl or they are joined to form a cyclobutyl ring.
When the free salt form of formula (VIII) is used, the neutral form of formula (VIII) is a base such as sodium hydroxide, potassium hydroxide or ammonium hydroxide, preferably as a solution in alcohol or water. Or by addition as an alcoholate in ethanol, in particular as an alkali metal alcoholate, for example sodium ethanolate. The neutralization and synthesis steps may be performed in situ or the neutral form of the free form of formula (VIII) may be obtained in advance.

The above reaction according to Scheme IV is preferably carried out under reductive amination conditions known to those skilled in the art.
According to this synthetic step, the reactants of 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, for example methanol, ethanol, n-propanol, i-propanol, mixtures thereof or mixtures with water. The educt of formula (IX), such as acetone, may be available as a solvent and may thus be used in stoichiometric excess.
The preferred molar ratio of educt of formula (VIII) and educt of formula (IX) is in the range from 1: 1 to 1: 5, more preferably in the range from 1: 1 to 1: 3, more preferably 1.0: The range is from 1.5 to 1.0: 2.5.

The reduction is preferably carried out as catalytic hydrogenation or as reduction using hydrides, in particular borohydrides such as sodium triacetoxyborohydride or sodium cyanoborohydride.
The reaction solution or suspension is preferably catalytically hydrogenated in the presence of a transition metal catalyst, such as a Pd-based catalyst, such as finely dispersed Pd or Pd / charcoal. Suitable amounts of catalyst may vary according to the reaction conditions, for example in the range from 0.1% to 50% by weight, preferably from 1% to 20% by weight relative to the educt of formula (IV). Hydrogenation is advantageously carried out at temperatures ranging from -30 ° C to 150 ° C, preferably from 20 ° C to 100 ° C, more preferably from 20 ° C to 80 ° C, most preferably from 40 ° C to 70 ° C. Suitable hydrogen pressures are usually approximately equal to or greater than atmospheric pressure, preferably in the range from about 1 bar to 20 bar, more preferably from 2 bar to 8 bar. It is preferred that the reaction mixture is stirred during the hydrogenation. After hydrogenation, the catalyst is preferably removed from the reaction mixture, for example by filtration. The next reaction step, ie the synthesis of the compound of formula (VI) may be carried out using a reaction solution containing the product of formula (VII) or an isolated product of formula (VII). The product of formula (VII) may be isolated from the reaction solution, for example by removing the solvent in vacuo and / or at an elevated temperature. In addition, the product may be added to an acid in ethanol, such as hydrochloric acid, to the product solution, followed by crystallization, and finally precipitation, supported by, for example, cooling and / or seeding. By separation, it may be purified via the salt form, for example as chloride.
The pyrazole derivative of formula (VIII) is preferably obtained by reacting the acrylate derivative of formula (X) with hydrazine in a solvent or mixture of solvents according to Reaction Scheme V.
Scheme V:

The substituent R ^c represents optionally substituted C _1-6 -alkyl, preferably methyl, ethyl, n-propyl or i-propyl, preferably methyl or ethyl.
In principle, this reaction is known to the person skilled in the art. For example, the condensation of crotonic acid ethyl ester with hydrazine has been described by Holan, George et al., Bioorg. Med. Chem. Lett .; 6; 1; 1996;
The acrylic ester derivative of formula (X) is preferably dissolved in a suitable solvent or mixture of solvents such as alcohols, aliphatic ethers, cyclic ethers, and mixtures thereof. Examples of suitable solvents are methanol, ethanol, i-propanol, n-propanol, diethyl ether, tert.-butyl methyl ether, tetrahydrofuran, tetrahydropyran, dioxane and mixtures thereof or a solution of one or more of these solvents with water. is there. Preferred solvents are ethanol, i-propanol, mixtures thereof or aqueous mixtures thereof.
Hydrazine is advantageously used as a solution in water, such as hydrazine monohydrate, or in alcohols such as methanol, ethanol, i-propanol, mixtures thereof or mixtures of one or more such alcohols and water. .
A preferred molar ratio of the acrylate derivative of formula (X) to hydrazine is from 1: 1 to 1: 2, more preferably from 1.0: 1.0 to 1.0: 1.5, more preferably from 1.0: 1.0 to 1.0: 1.2. Range.
During the exothermic reaction, hydrazine is added to the solution of the acrylate derivative, preferably continuously or in portions, for example, over a period of time ranging from 15 minutes to 24 hours. If necessary, the reaction mixture may be cooled. The reaction is preferably carried out at a temperature in the range from 0 ° C to 130 ° C, more preferably in the range from 20 ° C to 100 ° C, more preferably in the range from 40 ° C to 90 ° C.

The final product of formula (VIII) may be obtained by removing the solvent, for example by evaporation at vacuum and / or elevated temperature. Additionally or alternatively, the final product may be purified by crystallization in the form of a salt, for example its hydrohalide salt, for example the hydrochloride salt. For this purpose, an acid in ethanol or i-propanol, for example hydrochloric acid, is added to the product solution. Crystallization may be supported, for example, by cooling and / or seeding with seed crystals, and finally the precipitate is isolated.
According to a preferred embodiment, this reaction step is carried out in alcohol, in particular i-propanol, and an aqueous solution of hydrazine, in particular hydrazine hydrate, is used. It is preferred that water is removed from the reaction mixture by azeotropic distillation after or during the reaction. The product is advantageously obtained as described above, in particular by precipitating a salt form, preferably chloride, for example by adding a solution of hydrochloric acid in ethanol.
The compound of formula (I) is preferably obtained by reacting an aglycone of formula (III) as described above with a glucose derivative of formula (II) according to reaction scheme VIa.
Scheme VIa:

In the compounds of formula (II) and (I), the substituents R ⁶ , R ^7a , R ^7b , R ^7c are independently selected from the group consisting of (C _1-4 -alkyl) carbonyl, phenylcarbonyl and benzylcarbonyl. It is preferable. More preferably, the substituents R ⁶ , R ^7a , R ^7b , R ^7c have a meaning independently selected from the group: methylcarbonyl and ethylcarbonyl, in particular methylcarbonyl.
The substituent X preferably represents a bromine atom. The substituents R ^{1 to} R ⁵ are as defined above.
According to a first embodiment, this process step is carried out in the presence of a suitable base in a solvent or mixture of solvents that exhibits sufficient solubility properties in view of the starting materials of formulas (II) and (III). May be. Preferred organic solvents having such properties are ketones, ethers, cyclic ethers, acetonitrile, and mixtures thereof. Examples of preferred organic solvents are acetone, methyl ethyl ketone, diethyl ketone, cyclohexanone, cyclopentanone, acetonitrile, THF, NMP, DMF, and mixtures thereof. Suitable bases are in particular carbonates such as sodium carbonate, potassium carbonate, silver carbonate or cadmium carbonate.

According to a preferred second embodiment, this process step is carried out in a reaction mixture comprising two liquid phases, preferably under phase transfer conditions. Advantageously, a two-phase solvent system and one or more phase transfer catalysts are used. Preferred solvents for the first phase are aprotic organic solvents, especially aromatic hydrocarbons (eg benzene, chlorobenzene, trifluoromethylbenzene, toluene, xylene), alkanes (eg pentane, hexane, heptane, octane), halogenated Alkanes (eg, CH ₂ Cl ₂ , CHCl ₃ , ClCH ₂ CH ₂ Cl), ethers (eg, 2-methyl-tetrahydrofuran), esters (eg, isopropyl acetate), and mixtures thereof. Particularly preferred solvents for the first phase include chlorinated C _1-3 -alkanes (which may additionally have one or more fluorine substituents), most preferably CH ₂ Cl ₂ .
The second phase is preferably water or an aqueous mixture of protic solvents. The most preferred solvent for the second phase is water.
The preferred ratio of the volume of the first solvent phase to the volume of the second phase is in the range of 1:10 to 10: 1, more preferably in the range of 1: 5 to 5: 1, most preferably 1: 5 to 2: The range is up to 1.

Preferred phase transfer catalysts have quaternary ammonium cations, such as tetraalkylammonium compounds, N-aryl-N-trialkylammonium compounds, N-arylalkyl-N-trialkyl-ammonium compounds, where alkyl residues May be the same or different. Examples are tetramethylammonium compounds, tetraethylammonium compounds, tetrabutylammonium compounds or benzyltrimethylammonium compounds. The most preferred phase transfer catalysts are tetrabutylammonium compounds, especially tetrabutylammonium salts with inorganic acids, such as tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogensulfate and the like.
The preferred amount of phase transfer catalyst depends on the type of solvent used and their amount and is determined by routine experimentation. Usually, an amount of phase transfer catalyst of from 0.01 mol to 1.0 mol, more preferably from 0.02 mol to 0.5 mol, for example about 0.05 mol, is used per mol of starting material of formula (III).

The second solvent phase is advantageously basified or buffered. During or after the reaction, the preferred pH value of the aqueous solvent phase is about 10 or more, particularly about 11 or more, more preferably about 12 or more, most preferably about 11 to about 15, most preferably about 12 to about 14 Range.
The pH value is advantageously kept in the desired basic pH range by the addition of at least one basifying reagent, preferably selected from the group consisting of hydroxides, carbonates, phosphates and / or borates. Is advantageous. Corresponding alkali salts such as sodium carbonate, sodium hydroxide, potassium carbonate, potassium hydroxide and / or sodium borate are preferred. The basing reagent is advantageously added in the form of an aqueous solution, for example as an aqueous sodium hydroxide solution or an aqueous potassium hydroxide solution.

The preferred molar ratio of educt of formula (II) and educt of formula (III) is in the range 5: 1 to 1: 2, more preferably in the range 3: 1 to 1: 1, more preferably 2.0: The range is from 1.0 to 1.0: 1.0.
A preferred temperature range for the reaction of compound (II) with a compound of formula (III) is from about 0 ° C. to 50 ° C., more preferably from about 5 ° C. to 45 ° C., most preferably from about 15 ° C. to 40 ° C. Range. Since the reaction is exothermic, it may be necessary to cool the reaction mixture.
Depending on the reaction conditions, the reaction is usually carried out over a period of time from 30 minutes to 48 hours, preferably from 2 hours to 24 hours.
The end point of the reaction can be detected by the amount of residual compound of formula (III), for example by HPLC.
The compound of formula (I) may be isolated from the reaction mixture by methods known to those skilled in the art. For example, if the reaction is carried out under phase transfer conditions involving an aqueous phase and an organic phase, the aqueous phase is separated and extracted with an organic solvent or mixture of organic solvents, the organic phases combined, water or an aqueous solution, preferably acidic Washing with an aqueous solution and finally drying, the solvent is removed by evaporation at reduced pressure and / or elevated temperature to give a compound of formula (I).
In the following reaction steps according to the third aspect of the present invention, a compound of formula (I) wherein one or more of the substituents R ⁶ , R ^7a , R ^7b , R ^7c is not hydrogen is a reaction scheme Deprotected according to VIb to give the final product of formula (IH).
Scheme VIb:

This reaction step is preferably carried out using the crude product or reaction mixture of the previous reaction step. Also used are products of the formula (I) which may be isolated and optionally purified.
Suitable methods for deprotection are known to those skilled in the art. For example, acyl protecting groups are cleaved by hydrolysis in an aqueous solvent such as water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid. May be.
The acyl protecting group is preferably cleaved using an alcoholate, in particular a C _1-4 -alcolate, such as sodium ethanolate or potassium tert-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 transesterification so that only a catalytic amount of alcoholate, preferably from about 0.1 mol% to 50 mol%, more preferably from about 1 mol% to 20 mol, relative to the educt of formula (I). Advantageously, up to mol% is required. Suitable temperatures are from 0 ° C to the boiling point of the reaction mixture, preferably from 5 ° C to 40 ° C. The reaction is usually completed within 1 to 48 hours. After completion of the reaction, the reaction mixture is preferably neutralized or made slightly acidic, for example by using acetic acid, and the solvent may be removed by distillation at reduced pressure and / or elevated temperature. The product of formula (IH) is obtained as a resinous solid.
The glucose derivative of formula (II) (wherein X represents a chlorine atom or a bromine atom) is known to those skilled in the art and may be obtained by methods described in the literature. The glucose derivative of formula (II) is preferably obtained by reacting the protected glucose derivative of formula (II ′) with HBr in a solvent or mixture of solvents according to reaction scheme VII.
Scheme VII:

In the compounds of formula (II) and (I), the substituents R ⁶ , R ^7a , R ^7b , R ^7c and R ^7d consist of (C _1-4 -alkyl) carbonyl independently of each other, where applicable. Preferably selected from the group. It is further preferred that the substituents R ⁶ , R ^7a , R ^7b , R ^7c and R ^7d have a meaning selected from the groups: methylcarbonyl and ethylcarbonyl, in particular methylcarbonyl, independently of one another, where applicable.
The substituent X preferably represents 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. Examples of suitable solvents are pentane, hexane, dichloromethane, 1,2-dichloroethane, benzene, toluene, xylene, and mixtures thereof. Preferred solvents are dichloromethane, benzene, toluene, xylene or mixtures thereof, in particular dichloromethane or toluene.
According to a preferred embodiment of this reaction step, the starting material of formula (II ′) is dissolved or suspended in a solvent or a mixture of solvents and HX or a solution of HX is added. When HX is HBr, a preferred solution is a 30% solution of HBr in acetic acid, for example HBr in acetic acid. A suitable amount of HX is approximately equimolar or molar excess over the protected glucose of formula (II ′). The molar ratio of HX to glucose derivative of formula (II ′) is preferably in the range of about 1: 1 to 10: 1, more preferably in the range of about 2: 1 to 6: 1.
In order to remove the amount of water in the reaction mixture, for example the water content of the hygroscopic solution of HX, it is advantageous to add a compound that chemically binds or removes water, such as acetic anhydride.

The reaction is preferably carried out at a temperature ranging from 0 ° C to 40 ° C, most preferably from 10 ° C to 30 ° C. Usually, the reaction is completed in a period of time from 10 minutes to 12 hours.
The product of formula (II) may be isolated from the reaction mixture by methods known in the art. For example, in the case of a solvent or mixture of solvents that is not miscible with water or only slightly miscible, the reaction mixture may be washed with water and / or saturated sodium chloride solution, with excess acid especially combined. The organic phase may be neutralized by washing with a basic aqueous solution, such as a saturated aqueous sodium bicarbonate solution, and finally the solvent may be evaporated in vacuo. The product may be isolated and purified by crystallization, preferably by using a suitable solvent, for example by dissolving the product in tert.-butyl methyl ether and then adding methylcyclohexane. .
Also, the following reaction steps according to scheme VIa are carried out using the crude product of formula (II), which is advantageously neutralized beforehand. For example, the reaction mixture is washed with a basic aqueous solution and the neutralized organic phase is dried.
In another embodiment corresponding to the sixth aspect of the present invention, the pyrazole derivative of formula (III) is alkylated in the presence of a base in a solvent or mixture of solvents according to reaction scheme VIII. Reaction with the agent R ¹ -X ′, wherein R ¹ is as defined above and X ′ represents chlorine, bromine, iodine or C _1-3 -alkyl-SO ₂ —O—. To obtain an aglycone of formula (III) by cleaving the R ¹ —O— group at the 3-position of the pyrazole ring, particularly in the presence of an acid. May be.
Scheme VIII:

In the formula of Scheme VIII, the substituents R ^{1 to} R ⁵ are as defined above. It is preferred that R ¹ represents methyl, ethyl, n-propyl, i-propyl, cyclobutyl or cyclopentyl, most preferably i-propyl or cyclobutyl.
The group X ′ is preferably bromine.
The pyrazole derivative of formula (XI) is reacted with an alkylating agent R ¹ -X ′ in the presence of a base, preferably a strong base. Suitable strong bases are selected from the group consisting of alkali hydroxides, alcoholates and hydrides. Examples of preferred strong bases are sodium hydroxide and potassium hydroxide.
Since the O atom of the pyrazole group is also at least partially alkylated, it is advantageous to use a molar excess of the alkylating agent. The preferred molar ratio of the alkylating agent compared to the educt of formula (XI) is about 2: 1 or more, more preferably in the range of 2: 1 to 8: 1, for example 3: 1 to 5: 1. It is a range.
The molar amount of base advantageously used is approximately the same as the amount of alkylating agent. It is therefore advantageous to use a molar excess of base. The preferred molar ratio of base compared to the free form of formula (XI) is about 2: 1 or more, more preferably in the range 2: 1 to 8: 1, for example in the range 3: 1 to 5: 1. is there.

According to the alkylation step, the free form of formula (XI) and the strong base are dissolved or suspended in a suitable solvent or mixture of solvents. Suitable solvents are polar solvents or mixtures thereof, which show sufficient solubility properties in view of the starting material (XI), the alkylating agent R ¹ -X ′ 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 solution thereof is then preferably added to the reaction mixture at once or advantageously over a period of time, for example within a period of from 5 minutes to 4 hours. The reaction is preferably carried out at a temperature in the range from -20 ° C to 50 ° C, more preferably from -10 ° C to 40 ° C, most preferably from 5 ° C to 35 ° C. The end point of the reaction can be detected, for example, by thin layer chromatography or HPLC. Depending on the reaction conditions, the reaction is usually carried out for a period of time from 30 minutes to 48 hours, preferably from 2 hours to 24 hours.

The product of formula (XI ′) may be obtained from the reaction mixture by methods known to those skilled in the art. Further purification is usually not necessary. In particular, if the reaction yields by-products, such as derivatives that are alkylated at the 2-position of the pyrazole ring, such by-products need not necessarily be removed at the end of the reaction step. According to an example method for obtaining a reaction product, the reaction mixture is poured into cold water and an organic solvent, such as an aliphatic or aromatic hydrocarbon, such as toluene, is added. The aqueous phase is neutralized using acid, for example concentrated hydrochloric acid, or made slightly acidic. The organic phase is separated and, if necessary, the aqueous phase is extracted again with an organic solvent. The combined organic phases may be washed with water and / or saturated aqueous sodium chloride solution and dried. The product of formula (XI ′) may be obtained by removing the organic solvent, preferably in vacuum and / or at elevated temperature.
In order to obtain the aglycone of formula (III), the substituent R ¹ —O— needs to be cleaved at the 3-position of the pyrazole ring of compound (XI ′). Cleavage is in the presence of an acid, more preferably the presence of a strong acid such as HCl, HBr, HI, H ₂ SO ₄ , or an alkyl sulfonic acid such as methane sulfonic acid (which is added, for example, as an aqueous solution) It is preferable to be carried out below.
It is advantageous to use a molar excess of acid. The preferred molar ratio of acid compared to the free form of formula (XI ′) is about 2: 1 or more, more preferably in the range of 2: 1 to 40: 1, for example in the range of 4: 1 to 20: 1. It is.
The educt of formula (XI ′) 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 preferably used in the form of a solution in water, alcohol or a mixture thereof, in which case an acidic solution may be available as a solvent, so that less additional solvent is required, or Additional solvent may not be required.

The reaction is preferably carried out at a temperature ranging from 40 ° C to 180 ° C, more preferably from 60 ° C to 160 ° C, most preferably from 80 ° C to 160 ° C. The reaction is preferably carried out in a closed reactor or autoclave.
The end point of the reaction can be detected, for example, by thin layer chromatography or HPLC. Depending on the reaction conditions, the reaction is usually carried out for a period of time from 15 minutes to 24 hours, preferably from 1 hour to 12 hours.
The product may be obtained from the reaction mixture by crystallization. The type and amount of solvent is preferably chosen so that the reactants are dissolved at the reaction temperature. Then, after cooling the reaction mixture, the product may precipitate, whereby additional means for initiating crystallization may be used, such as seeding with seed crystals and / or addition of antisolvent. The crystals may be isolated, for example, by filtration, washed in a suitable solvent, such as an alcohol, such as iso-propanol, and optionally dried thereafter.
According to a seventh aspect of the present invention, a pyrazole derivative of formula (XI) is
(i) reacting a benzaldehyde derivative of formula (V) with a β-ketoester derivative of formula (XII) in the presence of an acid and a secondary amine, followed by or simultaneous catalytic hydrogenation, and
(ii) It may be obtained by reacting the product of step (i) with hydrazine in a solvent or mixture of solvents.
Scheme IX:

The group R ^c represents methyl, ethyl, n-propyl or i-propyl, preferably methyl or ethyl.
The group R ² preferably represents methyl, ethyl, n-propyl or i-propyl, most preferably methyl.
A preferred compound of formula XII is methyl acetoacetate.
In the first reaction step according to the above scheme, a benzaldehyde derivative of formula (V) is reacted with a β-ketoester derivative of formula (XII) in the presence of an acid and a secondary amine.
This reaction step is preferably carried out under the conditions of the Knoevenager reaction known to those skilled in the art.
The molar ratio of the benzaldehyde of formula (V) to the β-ketoester of formula (XII) is preferably in the range of about 2: 1 to 1: 2, more preferably about 1.3: 1 to 1: 1.3, in particular equimolar. is there.
Suitable acids are carboxylic acids and mixtures thereof, such as acetic acid.
The molar ratio of acid to the benzaldehyde derivative of 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, approximately equimolar amounts of acid and benzaldehyde derivatives are used.
Suitable secondary amines are di- (C _1-4 -alkyl) amines, saturated or unsaturated heterocycles having at least one secondary amine group, such as dimethylamine, ethylmethylamine, diethylamine, di (isopropyl) amine Pyrrolidine, piperidine, piperazine, morpholine, N- (C _1-3 -alkyl) piperazine, and mixtures thereof. Preferred amines are piperidine and pyrrolidine.
The molar ratio of secondary amine to benzaldehyde derivative of 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. Up to about 0.5: 1.
The reaction may be carried out without the use of an additional solvent or in a solvent or 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.

According to a preferred embodiment of this reaction step, the benzaldehyde derivative of the formula (V), the β-ketoester derivative of the formula (XII) and the acid are mixed together, if necessary, with one or more solvents. Secondary amines may be added to the reaction mixture so that the reaction mixture can be cooled if required.
The reaction is preferably carried out at a temperature in the range from -10 ° C to 80 ° C, more preferably from 0 ° C to 60 ° C, more preferably from 10 ° C to 40 ° C.
In order to complete the reaction, usually a period of time from 30 minutes to 48 hours, in particular from 2 hours to 24 hours, is required.
The intermediate of formula (XII ′) may be isolated and, if required, purified using methods known in the art.

In the following reaction step, the intermediate of formula (XII ′) is catalytically hydrogenated. The hydrogenation is preferably carried out with the raw product of the previous reaction step, for example using the reaction mixture of the previous reaction step. Catalytic hydrogenation is complete after completion of the first reaction step or simultaneously with the first reaction step, i.e. the reaction of the first reaction step may still occur during the hydrogenation, so that the reaction of the first reaction step is completed. It may be done when not done.
With respect to the catalytic hydrogenation step, those solvents or mixtures thereof described as suitable or preferred according to the previous synthesis step may be used. Generally suitable solvents are aliphatic hydrocarbons, aromatic hydrocarbons, alcohols, aliphatic ethers, cyclic ethers, and mixtures thereof. Examples of suitable solvents are pentane, hexane, benzene, toluene, methanol, ethanol, i-propanol, n-propanol, diethyl ether, tetrahydrofuran, tetrahydropyran and mixtures thereof. Preferred solvents are methanol, ethanol, i-propanol, n-propanol, tetrahydrofuran and mixtures thereof. If no additional solvent is used in the previous reaction step, it is preferred to add one or more solvents before the catalytic hydrogenation takes place.

Catalytic hydrogenation is a transition metal catalyst, such as a catalyst based on Pd, such as finely dispersed Pd or Pd / charcoal, or a catalyst based on Ni, such as finely dispersed Ni, such as Raney nickel. It is preferable to be carried out in the presence of Suitable amounts of catalyst may vary according to the reaction conditions, for example from about 0.1 wt.% To about 50 wt.%, Preferably about 1 wt.% Relative to the free form of formula (V) or the intermediate of formula (XII ′). It is in the range from weight percent to about 10 weight percent.
Therefore, at the end of the previous synthesis step, or if hydrogenation is performed simultaneously with the first reaction step, an appropriate amount of catalyst and, if necessary, during or at the start of the previous synthesis step. Additional solvent or mixture of solvents is added to the reaction mixture. Alternatively, the isolated intermediate of formula (XII ′) is dissolved in a solvent or mixture of solvents and a catalyst is added thereto.
The hydrogenation is advantageously carried out at a temperature in the range from -10 ° C to 150 ° C, preferably from 20 ° C to 100 ° C, more preferably from 20 ° C to 80 ° C, most preferably from 40 ° C to 70 ° C. is there. Suitable hydrogen pressures are usually above about atmospheric pressure, preferably in the range from about 1 bar to 20 bar, more preferably from 2 bar to 8 bar. It is preferred that the reaction mixture is stirred during the hydrogenation. The period of time required to complete the hydrogenation can be optimized by experiment. Usually, the hydrogenation is carried out for a period of time from about 30 minutes to about 24 hours, preferably from about 1 hour to 12 hours. After hydrogenation, the catalyst is preferably removed from the reaction mixture, for example by filtration.
The product of hydrogenation of formula (XII ′) may be isolated and, if required, purified using methods known in the art.
In the following final reaction step, the intermediate of formula (XII ′) is reacted with hydrazine to give the product of formula (XI). This reaction step is preferably carried out with the raw product, for example, preferably after the catalyst has been removed from the reaction mixture, using the reaction mixture from the previous reaction step. Also, an isolated product of formula (XII ′) is used.

Suitable solvents or mixtures of solvents for this reaction step are alcohols, aliphatic ethers, cyclic ethers, mixtures thereof and mixtures of one or more of these solvents with water. Examples of suitable solvents are methanol, ethanol, i-propanol, n-propanol, diethyl ether, tert.-butyl methyl ether, tetrahydrofuran, tetrahydropyran, mixtures thereof or solutions of one or more of these solvents with water. . A preferred solvent is the solvent as used in the previous reaction, especially isopropanol. If the reaction mixture from the previous reaction step (ie not the isolated product of formula (XII ′)) is used, no additional solvent may be required.
Hydrazine should be used as a solution in water, such as hydrazine monohydrate, or in alcohols such as methanol, ethanol, i-propanol, mixtures thereof or mixtures of one or more such alcohols with water. Is advantageous.
The preferred molar ratio of the intermediate of formula (XII ′) (or for the educt of formula (V)) and hydrazine is in the range from 1: 1 to 1: 2, more preferably in the range from 1.0: 1.0 to 1.0: 1.5, The range is preferably 1.0: 1.0 to 1.0: 1.2.
Therefore, at the end of the previous synthesis step, an appropriate amount of hydrazine and optionally additional solvent or mixture of solvents is added to the reaction mixture. Also, the isolated intermediate of formula (XII ′) is dissolved in a solvent or mixture of solvents and hydrazine is added to it.
Due to the exothermic reaction, the addition of hydrazine is preferably carried out continuously or in portions over a period of time, for example ranging from 30 minutes to 24 hours. If necessary, the reaction mixture may be cooled. The reaction is preferably carried out at a temperature in the range from 0 ° C to 140 ° C, more preferably in the range from 20 ° C to 110 ° C, more preferably in the range from 40 ° C to 90 ° C. It may be advantageous to complete the reaction at a low temperature, for example in the range from 15 ° C. to 40 ° C., for an additional period of time, for example from 1 hour to 24 hours.

The final product of formula (XI) is advantageously obtained as a solid or a precipitate from 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 it in a suitable solvent, such as the solvent described at the beginning of the reaction step. The product may also be obtained by removing the solvent, for example by evaporation in vacuum and / or at high temperature. In addition or alternatively, the final product may be purified by crystallization.
All reactions of the present invention (not reactions involving hydrogenation) are preferably carried out at atmospheric pressure. Since these process steps are not sensitive to pressure, they can also be performed at slightly reduced pressure or elevated pressure.
Furthermore, all reaction steps of the present invention are preferably carried out under an inert atmosphere, for example in nitrogen or argon.
Preferred compounds of formula VI are formulas VI.1 and VI.2.

(Including these tautomers and mixtures).
The present invention also provides a compound of formula (IV)

(Wherein R ^{1 to} R ⁵ and Q are as defined above)
Of the compound.
R ¹ preferably represents methyl, ethyl, n-propyl, i-propyl, cyclobutyl or cyclopentyl, most preferably i-propyl or cyclobutyl.
R ² preferably represents methyl, ethyl, n-propyl or i-propyl, most preferably methyl.
R ³ preferably represents fluorine, chlorine, methyl, methoxy, ethoxy, n-propoxy or i-propoxy, most preferably methyl, methoxy, ethoxy or i-propoxy.
R ⁴ preferably represents fluorine, chlorine, methyl, methoxy, ethoxy, n-propoxy or i-propoxy, most preferably fluorine. Further, R ⁴ is preferably a substituent at the 2-position of the phenyl ring, that is, the meta-position relative to R ³ .
R ⁵ preferably represents hydrogen, fluorine, chlorine, methyl or methoxy, most preferably hydrogen or fluorine.
The group Q is methoxy, ethoxy, n-propoxy, i-propoxy, —NR ^a R ^b (wherein R ^a , R ^b independently of one another represents methyl, ethyl, n-propyl or i-propyl, or —NR ^a R ^b preferably represents pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl or NC _1-3 -alkyl-piperazinyl). It is further preferred that Q represents methoxy, ethoxy, n-propoxy, i-propoxy, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl or NC _1-3 -alkyl-piperazinyl, most preferably ethoxy, pyrrolidinyl, piperidinyl or morpholinyl.
Therefore, according to the present invention, compounds of formulas (IV.1) to (IV.11) as listed in the table below are preferred.

(In the table, Q is defined as above and as follows)
Particularly preferred are compounds of formulas (IV.1) to (IV.11), wherein Q is selected from methoxy, ethoxy, iso-propoxy, pyrrolidinyl, piperidinyl, morpholinyl or methylcarbonyloxy. In the above compounds of formulas (IV.1) to (IV.11), it is most preferred that Q represents ethoxy.
Furthermore, according to the invention, compounds of the formulas (III.1) to (III.11) as listed in the table below are preferred.

In addition, the formulas (I.1), (I.2), (I.3), (I.4), (I.5), (I.6), (I.7), (I.8) ), (I.9), (I.10), (I.11) compounds (they are shown in the experimental part) (these tautomers, stereoisomers, mixtures thereof and these Salt) are preferred.
The compounds of formula (I), in particular of formula (IH), including their prodrugs and pharmaceutically acceptable salts, exhibit activity as inducers of urinary glucose excretion and thus in the manufacture of drugs in the treatment of diabetes. Can be used.
In the description above and below, the H atom of the hydroxyl group is not clearly shown in the structural formula in each case. The following examples are intended to illustrate the invention and are not intended to limit the invention. If the pressure is indicated in the unit “bar”, the corresponding value can be converted to SI units by using 1 bar = 0.1 MPa. If the pressure is indicated in units of “psi”, the corresponding value can be converted to SI units by using 1 psi = 6894.757 Pa. The following abbreviations are used first and below.
DMA dimethylacetamide
DMF Dimethylformamide
NMP N-methyl-2-pyrrolidone
THF tetrahydrofuran

Experimental operation:
Example 1: Synthesis of the preparation of 1,2-dihydro-1- (1-methylethyl) -5-methyl-3H-pyrazol-3-one ( VI.1 )

Example 1.1:
Preparation of 5-methyl-3-pyrazolidinone monohydrochloride ( VIII.1 )

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 minutes and the reaction mixture is heated to reflux for 2 hours. The solvent is then distilled off under reduced pressure (about 1 L). Isopropanol (400 ml) is then added and the reaction mixture is cooled to 22 ° C. Hydrochloric acid 11.7N (375 ml, 3.94 mol) in ethanol is added and the reaction mixture is stirred at about 20-25 ° C. for 15 hours. The reaction mixture is then cooled to 0 ° C., filtered, the product washed with isopropanol (3 × 200 ml each) and then dried to constant weight at 45 ° C. to give colorless crystals. The mass spectrum and ¹ H-NMR spectrum are consistent with the assigned structure.
Mass spectrum (ESI ⁺ ): m / z = 101 [M + H] ⁺
Example 1.2:
Preparation of 1- (1-methylethyl) -5-methyl-3-pyrazolidinone monohydrochloride ( VII.1a )

5-Methyl-3-pyrazolidinone monohydrochloride (692 g, 5.07 mol) is suspended in isopropanol (4.9 L). 50% aqueous sodium hydroxide solution (270 ml, 5.07 mol) and palladium (10 wt%) / charcoal (70 g) are added along with acetone (744 ml, 10 mol). The mixture is then hydrogenated at 50 ° C. and 3 bar (42 psi) under an atmosphere of hydrogen until hydrogen uptake ceases. The reaction mixture is filtered and the solvent is distilled off under reduced pressure.
The residue is treated twice with 1 L of isopropanol, which is subsequently distilled off under reduced pressure. The remainder is dissolved in isopropanol (3.5 L) and filtered. To the filtrate is added hydrogen chloride 10.5N in ethanol (482 ml, 5.06 mol), which results in the precipitation of the hydrochloride salt, which is isolated by filtration. It is washed twice with isopropanol (2 × 500 ml) and dried at 45 ° C. to give the product as colorless crystals. The mass spectrum and ¹ H-NMR spectrum are consistent with the assigned structure.
Mass spectrum (ESI ⁺ ): m / z = 143 [M + H] ⁺
Example 1.3:
Preparation of 1- (1-methylethyl) -5-methyl-3-pyrazolidinone ( VII.1 )

1- (1-Methylethyl) -5-methyl-3-pyrazolidinone monohydrochloride (150 g, 0.84 mol) is treated with saturated aqueous potassium carbonate (1.2 L) and ethyl acetate (1.0 L). The mixture is filtered and the phases are separated. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give 1- (1-methylethyl) -5-methyl-3-pyrazolidinone as a solid.
The mass spectrum and ¹ H-NMR spectrum are consistent with the assigned structure.
Mass spectrum (ESI ⁺ ): m / z = 143 [M + H] ⁺
Example 1.4:
Preparation of 1,2-dihydro-1- (1-methylethyl) -5-methyl-3H-pyrazol-3-one (VI.1)

Alternative 1:
1- (1-Methylethyl) -5-methyl-3-pyrazolidinone (390 g, 2.74 mol) is dissolved in acetic acid (170 ml) with warming. A 35% aqueous hydrogen peroxide solution (260 ml, 3.0 mol) is added within 3 hours while maintaining the temperature at about 65 ° C. The reaction mixture is then stirred at about 20-25 ° C. for 15 hours. Water (1.2 L) is then added and the pH of the mixture is adjusted to about 7 by the addition of about 1 L of 50% by weight aqueous sodium hydroxide. After cooling to 5 ° C., the reaction mixture is filtered. The product is washed with water and dried at about 50 ° C. Colorless crystals are obtained.
Alternative 2:
To a solution of 77 g potassium carbonate in 150 mL water is added 50 g (279.86 mmol) 1- (1-methylethyl) -5-methyl-3-pyrrolidinone monohydrochloride ( VII.1a ) followed by 250 mL isopropyl acetate. The mixture is heated to 50 ° C. with stirring for 5 minutes, after which the aqueous phase is separated. From the organic phase, 175 mL of solvent is distilled off in vacuo. The remaining solution is filtered and the filter is washed with 50 mL of isopropyl acetate. The combined organic phases are concentrated in vacuo to give an oil. To this is added 50 mL of acetic acid and the mixture is cooled to about 3 ° C. Add 66.9 g of peracetic acid along with 12.5 mL of acetic acid. The mixture is stirred at 3 ° C. for about 1 hour. Then 325 mL of water is added and the pH of the solution is adjusted to 6.6-7.0 by addition of 50% aqueous sodium hydroxide. The resulting suspension is stirred at 10 ° C. for 30 minutes, after which it is filtered. The product is washed with water and dried at 45 ° C.
The mass spectrum and ¹ H-NMR spectrum are consistent with the assigned structure.
Mass spectrum (ESI ⁺ ): m / z = 141 [M + H] ⁺

Example 2:
Synthesis of 1,2-dihydro-1-cyclobutyl-5-methyl-3H-pyrazol-3-one ( VI.2 )

The synthesis of intermediate VIII.1 is described in Example 1.1. Intermediate VII.2a may be obtained by using Example 1.2, in which case an appropriate amount of cyclobutanone ( IX.2 ) is used instead of propanone. Starting from intermediate VII.2a, compounds VII.2 and VI.2 may be obtained by using the procedures described in Examples 1.3 and 1.4 in a similar manner.

Example 3a:
1,2-dihydro-1- (1-methylethyl) -4-[(2-fluoro-4-methoxyphenyl)-(1-pyrrolidino) methyl] -5-methyl-3H-pyrazol-3-one ( IV .1a )

To a mixture of 70 g (0.50 mol) of 1,2-dihydro-1- (1-methylethyl) -5-methyl-3H-pyrazol-3-one and 350 mL of acetonitrile, 2-fluoro-4-methoxybenzaldehyde in 280 mL of acetonitrile 77 g (0.50 mol) of solution is added. 6 g of acetic acid and 53.3 g (0.75 mol) of pyrrolidine are added successively to the reaction mixture at 70 ° C. together with 70 mL of acetonitrile. The reaction mixture is heated to 75 ° C. over 1 hour, after which it is cooled to 3 ° C. The cooled reaction mixture is stirred for an additional 30 minutes after which the product is isolated by filtration. It is washed twice with 140 mL each of cold acetonitrile and subsequently dried at 40 ° C. under an inert atmosphere.
Example 3b:
1,2-dihydro-1- (1-methylethyl) -4-[(2-fluoro-4-methoxyphenyl)-(ethoxy) methyl] -5-methyl-3H-pyrazol-3-one ( IV.1b )

Alternative 1:
Pyrrolidine (21 ml, 0.257 mol) and acetic acid (22 ml, 0.385 mol) were combined with 1,2-dihydro-1- (1-methylethyl) -5-methyl-3H-pyrazol-3-one in ethanol (2.7 L) ( 180 g, 1.28 mol) and 2-fluoro-4-methoxybenzaldehyde (198 g, 1.28 mol). The suspension is heated to about 50 ° C. for about 67 hours. The reaction mixture is then cooled to about 17 ° C. and filtered. The product is washed with diisopropyl ether (500 ml) and subsequently refluxed with THF (2.5 L). The resulting solution is filtered through a pad of celite and charcoal. The filtrate is concentrated in vacuo and water (2 L) is added to the suspension, which is cooled and filtered. The colorless crystals are dried at 50 ° C.

Alternative 2:
To a suspension of 7 g (50 mmol) of 1,2-dihydro-1- (1-methylethyl) -5-methyl-3H-pyrazol-3-one in 50 ml of ethanol was added 2-fluoro-4 in 20 ml of ethanol. 7.7 g (50 mmol) of methoxybenzaldehyde are added. 0.6 g (10 mmol) of acetic acid is added, followed by 5.33 g (75 mmol) of pyrrolidine. The reaction mixture is then heated to 70 ° C. for 1-2 hours after which it is cooled to about 20 ° C. Then 30% aqueous hydrochloric acid (65 mmol) is added and the reaction mixture is heated to 50 ° C. for 3 hours. Water is then added and the mixture is cooled. The product is filtered and washed with 50% aqueous ethanol. It is dried at 45 ° C. under an inert gas atmosphere.

Alternative 3:
1,2-dihydro-1- (1-methylethyl) -4-[(2-fluoro-4-methoxyphenyl)-(1-pyrrolidino) methyl] -5-methyl-3H-pyrazol-3-one 50 g ( 0.144 mol) and 500 ml of ethanol are added with 30% aqueous hydrochloric acid. The reaction mixture is heated to 50 ° C. over 2-3 hours. Then 175 ml of water are added and the mixture is cooled. The product is isolated by filtration and washed with ethanol. It is dried at 45 ° C. under an inert gas atmosphere.
The mass spectrum and ¹ H-NMR spectrum are consistent with the assigned structure.
Mass spectrum (ESI ⁺ ): m / z = 323 [M + H] ⁺

Example 4:
1,2-dihydro-1- (1-methylethyl) -4-[(2,3-difluoro-4-methoxyphenyl)-(ethoxy) methyl] -5-methyl-3H-pyrazol-3-one ( IV .2 ) Synthesis

The procedure described in Example 3b may be used to obtain an intermediate of formula IV.2 in a similar manner.
Example 5:
1,2-dihydro-1- (1-methylethyl) -4-[(2,6-difluoro-4-methoxyphenyl)-(ethoxy) methyl] -5-methyl-3H-pyrazol-3-one ( IV .3 ) Synthesis

実施例3bに記載された操作を使用して同様の様式で式IV.3の中間体を得てもよい。

The procedure described in Example 3b may be used to obtain an intermediate of formula IV.3 in a similar manner.

Example 6:
Synthesis of 1,2-dihydro-1-cyclobutyl-4-[(3-fluoro-4-methylphenyl)-(ethoxy) methyl] -5-methyl-3H-pyrazol-3-one ( IV.4 )

実施例3bに記載された操作を使用して同様の様式で式IV.4の中間体を得てもよい。

The procedure described in Example 3b may be used to obtain an intermediate of formula IV.4 in a similar manner.

Example 7:
Synthesis of 1,2-dihydro-1-cyclobutyl-4-[(2-fluoro-4-methoxyphenyl)-(ethoxy) methyl] -5-methyl-3H-pyrazol-3-one ( IV.5 )

実施例3bに記載された操作を使用して同様の様式で式IV.5の中間体を得てもよい。

The procedure described in Example 3b may be used to obtain an intermediate of formula IV.5 in a similar manner.

Example 8:
1,2-dihydro-1- (1-methylethyl) -4-[(2,3-difluoro-4-methylphenyl)-(ethoxy) methyl] -5-methyl-3H-pyrazol-3-one ( IV .6 )

実施例3bに記載された操作を使用して同様の様式で式IV.6の中間体を得てもよい。

The procedure described in Example 3b may be used to obtain an intermediate of formula IV.6 in a similar manner.

Example 9:
1,2-dihydro-1- (1-methylethyl) -4-[(2-fluoro-4-methylphenyl)-(ethoxy) methyl] -5-methyl-3H-pyrazol-3-one ( IV.7 )

実施例3bに記載された操作を使用して同様の様式で式IV.7の中間体を得てもよい。

The procedure described in Example 3b may be used to obtain the intermediate of formula IV.7 in a similar manner.

Example 10:
1,2-dihydro-1- (1-methylethyl) -4-[(3-fluoro-4-ethoxyphenyl)-(ethoxy) methyl] -5-methyl-3H-pyrazol-3-one ( IV.8 )

実施例3bに記載された操作を使用して同様の様式で式IV.8の中間体を得てもよい。

The procedure described in Example 3b may be used to obtain an intermediate of formula IV.8 in a similar manner.

Example 11:
1,2-dihydro-1- (1-methylethyl) -4-[(3-fluoro-4- (1-methylethoxy) phenyl)-(ethoxy) methyl] -5-methyl-3H-pyrazole-3- Synthesis of ON ( IV.9 )

実施例3bに記載された操作を使用して同様の様式で式IV.9の中間体を得てもよい。

The procedure described in Example 3b may be used to obtain an intermediate of formula IV.9 in a similar manner.

Example 12:
1,2-dihydro-1- (1-methylethyl) -4-[(2-fluoro-4- (1-methylethoxy) phenyl)-(ethoxy) methyl] -5-methyl-3H-pyrazole-3- Synthesis of on ( IV.10 )

実施例3bに記載された操作を使用して同様の様式で式IV.10の中間体を得てもよい。

The procedure described in Example 3b may be used to obtain an intermediate of formula IV.10 in a similar manner.

Example 13:
1,2-dihydro-1- (1-methylethyl) -4-[(2-fluoro-4-ethoxyphenyl)-(ethoxy) methyl] -5-methyl-3H-pyrazol-3-one ( IV.11 )

実施例3bに記載された操作を使用して同様の様式で式IV.11の中間体を得てもよい。

The procedure described in Example 3b may be used to obtain an intermediate of formula IV.11 in a similar manner.

Example 14:
Synthesis of 1,2-dihydro-1- (1-methylethyl) -4-[(2-fluoro-4-methoxyphenyl) methyl] -5-methyl-3H-pyrazol-3-one ( III.1 )

1,2-dihydro-1- (1-methylethyl) -4-[(2-fluoro-4-methoxyphenyl)-(ethoxy) methyl] -5-methyl-3H-pyrazol-3-one (294 g, 1.28 Mol), methanol (4.5 L), aqueous hydrochloric acid (30%, 11 g) and water (80 mL) at 50 ° C. with palladium / charcoal (10 wt%) (65 g) until hydrogen absorption ceases. Hydrogenate at a hydrogen pressure of 3 bar. THF (2.3 L) is added to the reaction mixture, which is then filtered. The catalyst is washed with THF (1 L) and the solvent is distilled off under reduced pressure to a residual volume of about 700-800 ml. The resulting suspension is poured into water (1 L) with stirring. The precipitate is isolated by filtration, washed with water (400 ml) and dried at 55 ° C. to give crystals (light beige).
The mass spectrum and ¹ H-NMR spectrum are consistent with the assigned structure.
Mass spectrum (ESI ⁺ ): m / z = 279 [M + H] ⁺

Example 15:
1,2-dihydro-1- (1-methylethyl) -4-[(2,3-difluoro-4-methoxyphenyl) methyl] -5-methyl-3H-pyrazol-3-one ( III.2 ) Composition

実施例14に概説された合成操作を使用することにより同様の様式で式III.2の化合物を得てもよい。

The compound of formula III.2 may be obtained in a similar manner by using the synthetic procedure outlined in Example 14.

Example 16:
1,2-dihydro-1- (1-methylethyl) -4-[(2,6-difluoro-4-methoxyphenyl) methyl] -5-methyl-3H-pyrazol-3-one ( III.3 ) Composition

実施例14に概説された合成操作を使用することにより同様の様式で式III.3の化合物を得てもよい。

By using the synthetic procedure outlined in Example 14, the compound of formula III.3 may be obtained in a similar manner.

Example 17:
Synthesis of 1,2-dihydro-1- (1-cyclobutyl) -4-[(3-fluoro-4-methylphenyl) methyl] -5-methyl-3H-pyrazol-3-one ( III.4 )

実施例14に概説された合成操作を使用することにより同様の様式で式III.4の化合物を得てもよい。

The compound of formula III.4 may be obtained in a similar manner by using the synthetic procedure outlined in Example 14.

Example 18:
Synthesis of 1,2-dihydro-1- (1-cyclobutyl) -4-[(2-fluoro-4-methoxyphenyl) methyl] -5-methyl-3H-pyrazol-3-one ( III.5 )

実施例14に概説された合成操作を使用することにより同様の様式で式III.5の化合物を得てもよい。

The compound of formula III.5 may be obtained in a similar manner by using the synthetic procedure outlined in Example 14.

Example 19:
1,2-dihydro-1- (1-methylethyl) -4-[(2,3-difluoro-4-methylphenyl) methyl] -5-methyl-3H-pyrazol-3-one ( III.6 ) Composition

実施例14に概説された合成操作を使用することにより同様の様式で式III.6の化合物を得てもよい。

The compound of formula III.6 may be obtained in a similar manner by using the synthetic procedure outlined in Example 14.

Example 20:
Synthesis of 1,2-dihydro-1- (1-methylethyl) -4-[(2-fluoro-4-methylphenyl) methyl] -5-methyl-3H-pyrazol-3-one ( III.7 )

実施例14に概説された合成操作を使用することにより同様の様式で式III.7の化合物を得てもよい。

The compound of formula III.7 may be obtained in a similar manner by using the synthetic procedure outlined in Example 14.

Example 21:
Synthesis of 1,2-dihydro-1- (1-methylethyl) -4-[(3-fluoro-4-ethoxyphenyl) methyl] -5-methyl-3H-pyrazol-3-one ( III.8 )

実施例14に概説された合成操作を使用することにより同様の様式で式III.8の化合物を得てもよい。

The compound of formula III.8 may be obtained in a similar manner by using the synthetic procedure outlined in Example 14.

Example 22:
1,2-dihydro-1- (1-methylethyl) -4-[(3-fluoro-4- (1-methylethoxy) -phenyl) methyl] -5-methyl-3H-pyrazol-3-one ( III .9 ) Synthesis

実施例14に概説された合成操作を使用することにより同様の様式で式III.9の化合物を得てもよい。

The compound of formula III.9 may be obtained in a similar manner by using the synthetic procedure outlined in Example 14.

Example 23:
1,2-dihydro-1- (1-methylethyl) -4-[(2-fluoro-4- (1-methylethoxy) -phenyl) methyl] -5-methyl-3H-pyrazol-3-one ( III .10 )

実施例14に概説された合成操作を使用することにより同様の様式で式III.10の化合物を得てもよい。

The compound of formula III.10 may be obtained in a similar manner by using the synthetic procedure outlined in Example 14.

Example 24:
Synthesis of 1,2-dihydro-1- (1-methylethyl) -4-[(2-fluoro-4-ethoxyphenyl) methyl] -5-methyl-3H-pyrazol-3-one ( III.11 )

実施例14に概説された合成操作を使用することにより同様の様式で式III.11の化合物を得てもよい。

By using the synthetic procedure outlined in Example 14, the compound of formula III.11 may be obtained in a similar manner.

Example 25:
Synthesis of 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide ( II.1 )

  1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose (100 g, 0.251 mol) is suspended in toluene (210 ml). Acetic anhydride (9.5 ml, 0.1 mol) is added, followed by 30% hydrobromic acid in acetic acid (200 ml, 1 mol). The mixture is stirred at 18 ° C. for 30 minutes. A mixture of ice / water (300 ml) and brine (100 ml) is then added with stirring. The phases are separated and the aqueous phase is extracted with toluene (100 ml). The organic phases are combined and washed with aqueous sodium bicarbonate (100 ml) and brine (100 ml). Dry and evaporate the solvent under reduced pressure to give an oil which crystallizes by the addition of methyl-t-butyl ether (150 ml) and methylcyclohexane (300 ml). The product is isolated by filtration, washed with methylcyclohexane and dried at 45 ° C. in vacuo.

Example 26:
1 '-(1-methylethyl) -4'-[(2-fluoro-4-methoxyphenyl) methyl] -5'-methyl-1H-pyrazole-3'-O- (2,3,4,6- Synthesis of O-tetraacetyl) -β-D-glucopyranoside ( I.1 )

Aqueous potassium hydroxide (1M, 870 ml) was added (2,3,4,6-O-tetraacetyl) -α-D-glucopyranosyl bromide (485 g, 1.169 mol) in dichloromethane (780 L), 1,2 -Dihydro-1- (1-methylethyl) -4-[(2-fluoro-4-methoxyphenyl) methyl] -5-methyl-3H-pyrazol-3-one (161 g, 0.58 mol) and tetrabutylammonium chloride To the mixture (9.4 g, 0.029 mol). The biphasic mixture is stirred vigorously at 25-27 ° C., during which time the pH of the aqueous layer is adjusted by adding additional aqueous potassium hydroxide (4N, about 870 ml) until base consumption ceases (about 5 hours). Keep constant at around 13. The progress of the reaction can be monitored by HPLC. The phases are then separated and the aqueous phase is extracted with dichloromethane (800 ml). The combined organic phases are dried (Na ₂ SO ₄ ), filtered and evaporated under reduced pressure to give an oil (yellow). This is used in the next reaction step without further purification.
The mass spectrum and ¹ H-NMR spectrum are consistent with the assigned structure.
Mass spectrum (ESI ⁺ ): m / z = 609 [M + H] ⁺

Example 27:
1 '-(1-methylethyl) -4'-[(2,3-difluoro-4-methoxyphenyl) methyl] -5'-methyl-1H-pyrazole-3'-O- (2,3,4, Synthesis of 6-O-tetraacetyl) -β-D-glucopyranoside ( I.2 )

実施例26に概説された合成操作を使用することにより同様の様式で式I.2の化合物を得てもよい。

The compound of formula I.2 may be obtained in a similar manner by using the synthetic procedure outlined in Example 26.

Example 28:
1 '-(1-methylethyl) -4'-[(2,6-difluoro-4-methoxyphenyl) methyl] -5'-methyl-1H-pyrazole-3'-O- (2,3,4, Synthesis of 6-O-tetraacetyl) -β-D-glucopyranoside ( I.3 )

実施例26に概説された合成操作を使用することにより同様の様式で式I.3の化合物を得てもよい。

The compound of formula I.3 may be obtained in a similar manner by using the synthetic procedure outlined in Example 26.

Example 29:
1 '-(1-cyclobutyl) -4'-[(3-fluoro-4-methylphenyl) methyl] -5'-methyl-1H-pyrazole-3'-O- (2,3,4,6-O -Tetraacetyl) -β-D-glucopyranoside ( I.4 ) synthesis

実施例26に概説された合成操作を使用することにより同様の様式で式I.4の化合物を得てもよい。

The compound of formula I.4 may be obtained in a similar manner by using the synthetic procedure outlined in Example 26.

Example 30:
1 '-(1-cyclobutyl) -4'-[(2-fluoro-4-methoxyphenyl) methyl] -5'-methyl-1H-pyrazole-3'-O- (2,3,4,6-O -Tetraacetyl ) -β-D-glucopyranoside ( I.5 )

実施例26に概説された合成操作を使用することにより同様の様式で式I.5の化合物を得てもよい。

The compound of formula I.5 may be obtained in a similar manner by using the synthetic procedure outlined in Example 26.

Example 31:
1 '-(1-methylethyl) -4'-[(2,3-difluoro-4-methylphenyl) methyl] -5'-methyl-1H-pyrazole-3'-O- (2,3,4, Synthesis of 6-O-tetraacetyl) -β-D-glucopyranoside ( I.6 )

実施例26に概説された合成操作を使用することにより同様の様式で式I.6の化合物を得てもよい。

The compound of formula I.6 may be obtained in a similar manner by using the synthetic procedure outlined in Example 26.

Example 32:
1 '-(1-methylethyl) -4'-[(2-fluoro-4-methylphenyl) methyl] -5'-methyl-1H-pyrazole-3'-O- (2,3,4,6- Synthesis of O-tetraacetyl) -β-D-glucopyranoside ( I.7 )

実施例26に概説された合成操作を使用することにより同様の様式で式I.7の化合物を得てもよい。

The compound of formula I.7 may be obtained in a similar manner by using the synthetic procedure outlined in Example 26.

Example 33:
1 '-(1-methylethyl) -4'-[(3-fluoro-4-ethoxyphenyl) methyl] -5'-methyl-1H-pyrazole-3'-O- (2,3,4,6- Synthesis of O-tetraacetyl) -β-D-glucopyranoside ( I.8 )

実施例26に概説された合成操作を使用することにより同様の様式で式I.8の化合物を得てもよい。

The compound of formula I.8 may be obtained in a similar manner by using the synthetic procedure outlined in Example 26.

Example 34:
1 '-(1-methylethyl) -4'-[(3-fluoro-4- (1-methylethoxy) phenyl) methyl] -5'-methyl-1H-pyrazole-3'-O- (2,3 , 4,6-O- Tetraacetyl ) -β-D-glucopyranoside ( I.9 )

実施例26に概説された合成操作を使用することにより同様の様式で式I.9の化合物を得てもよい。

The compound of formula I.9 may be obtained in a similar manner by using the synthetic procedure outlined in Example 26.

Example 35:
1 '-(1-methylethyl) -4'-[(2-fluoro-4- (1-methylethoxy) phenyl) methyl] -5'-methyl-1H-pyrazole-3'-O- (2,3 , 4,6-O- Tetraacetyl ) -β-D-glucopyranoside ( I.10 )

実施例26に概説された合成操作を使用することにより同様の様式で式I.10の化合物を得てもよい。

The compound of formula I.10. May be obtained in a similar manner by using the synthetic procedure outlined in Example 26.

Example 36:
1 '-(1-methylethyl) -4'-[(2-fluoro-4-ethoxyphenyl) methyl] -5'-methyl-1H-pyrazole-3'-O- (2,3,4,6- Synthesis of O-tetraacetyl) -β-D-glucopyranoside ( I.11 )

実施例26に概説された合成操作を使用することにより同様の様式で式I.11の化合物を得てもよい。

The compound of formula I.11 may be obtained in a similar manner by using the synthetic procedure outlined in Example 26.

Example 37:
1 '-(1-methylethyl) -4'-[(2-fluoro-4-methoxyphenyl) methyl] -5' -methyl-1H-pyrazole-3'-O-β-D-glucopyranoside ( IH.1 )

Crude 1 '-(1-methylethyl) -4'-[(2-fluoro-4-methoxyphenyl) methyl] -5'-methyl-1H-pyrazole-3'-O- (2 , 3,4,6-O-tetraacetyl) -β-D-glucopyranoside (413 g, approx. 0.58 mol) is dissolved in dry ethanol (1 L). Potassium-t-butoxide (6.6 g, 0.058 mol) is then added and the reaction mixture is stirred at about 20-25 ° C. for about 15 hours. Acetic acid (3.3 ml, 0.058 mol) is then added and the solvent is distilled off under reduced pressure. The resulting residue is then dissolved in ethyl acetate (2 L) and washed with brine (800 ml). The organic phase is separated, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give a resinous solid.
The mass spectrum and ¹ H-NMR spectrum are consistent with the assigned structure.
Mass spectrum (ESI ⁺ ): m / z = 441 [M + H] ⁺

Example 38:
1 '-(1-methylethyl) -4'-[(2,3-difluoro-4-methoxyphenyl) methyl] -5'-methyl-1H-pyrazole-3'-O-β-D-glucopyranoside ( IH .2 ) Synthesis

実施例37に概説された合成操作を使用することにより同様の様式で式IH.2の化合物を得てもよい。

The compound of formula IH.2 may be obtained in a similar manner by using the synthetic procedure outlined in Example 37.

Example 39:
1 '-(1-methylethyl) -4'-[(2,6-difluoro-4-methoxyphenyl) methyl] -5'-methyl-1H-pyrazole-3'-O-β-D-glucopyranoside ( IH .3 ) Synthesis

実施例37に概説された合成操作を使用することにより同様の様式で式IH.3の化合物を得てもよい。

The compound of formula IH.3 may be obtained in a similar manner by using the synthetic procedure outlined in Example 37.

Example 40:
Synthesis of 1'-cyclobutyl-4 '-[(3-fluoro-4-methylphenyl) methyl] -5' -methyl-1H-pyrazole-3'-O-β-D-glucopyranoside ( IH.4 )

実施例37に概説された合成操作を使用することにより同様の様式で式IH.4の化合物を得てもよい。

The compound of formula IH.4 may be obtained in a similar manner by using the synthetic procedure outlined in Example 37.

Example 41:
Synthesis of 1'-cyclobutyl-4 '-[(2-fluoro-4-methoxyphenyl) methyl] -5' -methyl-1H-pyrazole-3'-O-β-D-glucopyranoside ( IH.5 )

実施例37に概説された合成操作を使用することにより同様の様式で式IH.5の化合物を得てもよい。

The compound of formula IH.5 may be obtained in a similar manner by using the synthetic procedure outlined in Example 37.

Example 42:
1 '-(1-methylethyl) -4'-[(2,3-difluoro-4-methylphenyl) methyl] -5'-methyl-1H-pyrazole-3'-O-β-D-glucopyranoside ( IH .6 )

実施例37に概説された合成操作を使用することにより同様の様式で式IH.6の化合物を得てもよい。

The compound of formula IH.6 may be obtained in a similar manner by using the synthetic procedure outlined in Example 37.

Example 43:
1 '-(1-methylethyl) -4'-[(2-fluoro-4-methylphenyl) methyl] -5' -methyl-1H-pyrazole-3'-O-β-D-glucopyranoside ( IH.7 )

実施例37に概説された合成操作を使用することにより同様の様式で式IH.7の化合物を得てもよい。

The compound of formula IH.7 may be obtained in a similar manner by using the synthetic procedure outlined in Example 37.

Example 44:
1 '-(1-methylethyl) -4'-[(3-fluoro-4-ethoxyphenyl) methyl] -5' -methyl-1H-pyrazole-3'-O-β-D-glucopyranoside ( IH.8 )

実施例37に概説された合成操作を使用することにより同様の様式で式IH.8の化合物を得てもよい。

The compound of formula IH.8 may be obtained in a similar manner by using the synthetic procedure outlined in Example 37.

Example 45:
1 '-(1-methylethyl) -4'-[(3-fluoro-4- (1-methylethoxy) phenyl) methyl] -5'-methyl-1H-pyrazole-3'-O-β-D- Synthesis of glucopyranoside ( IH.9 )

実施例37に概説された合成操作を使用することにより同様の様式で式IH.9の化合物を得てもよい。

The compound of formula IH.9 may be obtained in a similar manner by using the synthetic procedure outlined in Example 37.

Example 46:
1 '-(1-methylethyl) -4'-[(2-fluoro-4- (1-methylethoxy) phenyl) methyl] -5'-methyl-1H-pyrazole-3'-O-β-D- Synthesis of glucopyranoside ( IH.10 )

実施例37に概説された合成操作を使用することにより同様の様式で式IH.10の化合物を得てもよい。

The compound of formula IH.10 may be obtained in a similar manner by using the synthetic procedure outlined in Example 37.

Example 47:
1 '-(1-methylethyl) -4'-[(2-fluoro-4-ethoxyphenyl) methyl] -5' -methyl-1H-pyrazole-3'-O-β-D-glucopyranoside ( IH.11 )

実施例37に概説された合成操作を使用することにより同様の様式で式IH.11の化合物を得てもよい。

The compound of formula IH.11 may be obtained in a similar manner by using the synthetic procedure outlined in Example 37.

Examples relating to the separate synthesis of aglycones Example 48:
Synthesis of 1,2-dihydro-4-[(2-fluoro-4-methoxyphenyl) methyl] -5-methyl-3H-pyrazol-3-one ( XI.1 )

Piperidine (19.3 ml, 0.195 mol) is added to a mixture of methyl acetoacetate (71 mL, 0.65 mol), 2-fluoro-4-methoxybenzaldehyde (100 g, 0.65 mol) and acetic acid (37 ml, 0.65 mol) and the reaction mixture Is stirred at about 20-25 ° C. for 24 hours. Then isopropanol (500 ml) is added along with palladium (10 wt%) / charcoal (5 g) and the solution is hydrogenated until hydrogen uptake ceases. After removal of the catalyst by filtration, hydrazine hydrate (43 mL, 0.7 mol) is added to the filtrate with stirring. The reaction mixture is heated to reflux for 3 hours after which it is cooled to about 20-25 ° C. The resulting suspension is then filtered and the product is washed with methyl-t-butyl ether and dried at 50 ° C. to give colorless crystals.
The mass spectrum and ¹ H-NMR spectrum are consistent with the assigned structure.
Mass spectrum (ESI ⁺ ): m / z = 237 [M + H] ⁺

Example 49:
Synthesis of 1,2-dihydro-4-[(2,3-difluoro-4-methoxyphenyl) methyl] -5-methyl-3H-pyrazol-3-one ( XI.2 )

実施例48に概説された合成操作を使用することにより同様の様式で式XI.2の化合物を得てもよい。

The compound of formula XI.2 may be obtained in a similar manner by using the synthetic procedure outlined in Example 48.

Example 50:
Synthesis of 1,2-dihydro-4-[(2,6-difluoro-4-methoxyphenyl) methyl] -5-methyl-3H-pyrazol-3-one ( XI.3 )

実施例48に概説された合成操作を使用することにより同様の様式で式XI.3の化合物を得てもよい。

The compound of formula XI.3 may be obtained in a similar manner by using the synthetic procedure outlined in Example 48.

Example 51:
Synthesis of 1,2-dihydro-4-[(3-fluoro-4-methylphenyl) methyl] -5-methyl-3H-pyrazol-3-one ( XI.4 )

実施例48に概説された合成操作を使用することにより同様の様式で式XI.4の化合物を得てもよい。

The compound of formula XI.4 may be obtained in a similar manner by using the synthetic procedure outlined in Example 48.

Example 52:
Synthesis of 1,2-dihydro-4-[(2,3-difluoro-4-methylphenyl) methyl] -5-methyl-3H-pyrazol-3-one ( XI.6 )

実施例48に概説された合成操作を使用することにより同様の様式で式XI.6の化合物を得てもよい。

The compound of formula XI.6 may be obtained in a similar manner by using the synthetic procedure outlined in Example 48.

Example 53:
Synthesis of 1,2-dihydro-4-[(2-fluoro-4-methylphenyl) methyl] -5-methyl-3H-pyrazol-3-one ( XI.7 )

実施例48に概説された合成操作を使用することにより同様の様式で式XI.7の化合物を得てもよい。

The compound of formula XI.7 may be obtained in a similar manner by using the synthetic procedure outlined in Example 48.

Example 54:
Synthesis of 1,2-dihydro-4-[(3-fluoro-4-ethoxyphenyl) methyl] -5-methyl-3H-pyrazol-3-one ( XI.8 )

実施例48に概説された合成操作を使用することにより同様の様式で式XI.8の化合物を得てもよい。

The compound of formula XI.8 may be obtained in a similar manner by using the synthetic procedure outlined in Example 48.

Example 55:
Synthesis of 1,2-dihydro-4-[(3-fluoro-4- (1-methylethoxy) phenyl) methyl] -5-methyl-3H-pyrazol-3-one ( XI.9 )

実施例48に概説された合成操作を使用することにより同様の様式で式XI.9の化合物を得てもよい。

The compound of formula XI.9 may be obtained in a similar manner by using the synthetic procedure outlined in Example 48.

Example 56:
Synthesis of 1,2-dihydro-4-[(2-fluoro-4- (1-methylethoxy) phenyl) methyl] -5-methyl-3H-pyrazol-3-one ( XI.10 )

実施例48に概説された合成操作を使用することにより同様の様式で式XI.10の化合物を得てもよい。

The compound of formula XI.10. May be obtained in a similar manner by using the synthetic procedure outlined in Example 48.

Example 57:
Synthesis of 1,2-dihydro-4-[(2-fluoro-4-ethoxyphenyl) methyl] -5-methyl-3H-pyrazol-3-one ( XI.11 )

実施例48に概説された合成操作を使用することにより同様の様式で式XI.11の化合物を得てもよい。

The compound of formula XI.11 may be obtained in a similar manner by using the synthetic procedure outlined in Example 48.

Example 58:
1,2-dihydro-1- (1-methylethyl) -4-[(2-fluoro-4-methoxyphenyl) methyl] -5-methyl-3H-pyrazol-3-one ( III.1 )

Step 1:
2-Bromopropane (144.5 ml, 1.52 mol) was added within about 10 minutes at 5 ° C. within 1,10-dihydro-4-[(2-fluoro-4-methoxyphenyl) methyl] -5-methyl-3H-pyrazole- Add to a mixture of 3-one (90 g, 0.38 mol), powdered potassium hydroxide (88 g, 1.33 mol) and N-methylpyrrolidinone (540 ml). The reaction mixture is warmed to about 20-25 ° C. and stirring is continued for 15 hours. It is then poured into a mixture of ice / water (1.5 L) and toluene (450 ml). A pH of about 3 is maintained by addition of concentrated aqueous hydrochloric acid (16.5 ml). The phases are separated and the aqueous phase is extracted twice with toluene. The combined toluene phases are washed with water and brine, dried and evaporated under reduced pressure to give an oil (orange). This is used in the next reaction without further purification.
The mass spectrum and ¹ H-NMR spectrum are consistent with the assigned structure of XI'.1.
Mass spectrum (ESI ⁺ ): m / z = 321 [M + H] ⁺

Step 2:
1- (1-Methylethyl) -3- (1-methylethoxy) -4-[(2-fluoro-4-methoxyphenyl) -methyl] -5-methyl-pyrazole (132 g, 0.33 mol) and methanesulfonic acid A mixture of aqueous solution (20%, 925 ml) is heated to about 140 ° C. in a closed reactor for about 5 hours. It is then cooled to about 20-25 ° C. The product is isolated by filtration, washed successively with water and isopropanol, and dried at 50 ° C. to give the product as pale crystals (yellow). The mass spectrum and ¹ H-NMR spectrum are consistent with the assigned structure of III.1a.
Mass spectrum (ESI ⁺ ): m / z = 279 [M + H] ⁺
Step 3:
1,2-dihydro-1- (1-methylethyl) -4-[(2-fluoro-4-methoxyphenyl) methyl] -5-methyl-3H-pyrazol-3-one methanesulfonate (85 g, 0.23 Mol) is treated with a mixture of dichloromethane (600 ml) and 4N aqueous sodium hydroxide solution (57 ml). Separate the phases. The organic phase is washed with brine, dried over sodium sulfate, filtered and evaporated. The resulting residue is treated with boiling ethanol, filtered and dried at 50 ° C. Bright beige crystals.
The mass spectrum and ¹ H-NMR spectrum are consistent with the assigned structure of product III.1.
Mass spectrum (ESI ⁺ ): m / z = 279 [M + H] ⁺
Example 59:
1,2-dihydro-1- (1-methylethyl) -4-[(2,3-difluoro-4-methoxyphenyl) methyl] -5-methyl-3H-pyrazol-3-one ( III.2 )

実施例58に概説された合成操作を使用することにより同様の様式で式III.2の化合物を得てもよい。

The compound of formula III.2 may be obtained in a similar manner by using the synthetic procedure outlined in Example 58.

Example 60:
1,2-dihydro-1- (1-methylethyl) -4-[(2,6-difluoro-4-methoxyphenyl) methyl] -5-methyl-3H-pyrazol-3-one ( III.3 )

実施例58に概説された合成操作を使用することにより同様の様式で式III.3の化合物を得てもよい。

The compound of formula III.3 may be obtained in a similar manner by using the synthetic procedure outlined in Example 58.

Example 61:
1,2-dihydro-1-cyclobutyl-4-[(3-fluoro-4-methylphenyl) methyl] -5-methyl-3H-pyrazol-3-one ( III.4 )

実施例58に概説された合成操作を使用することにより同様の様式で式III.4の化合物を得てもよい。

The compound of formula III.4 may be obtained in a similar manner by using the synthetic procedure outlined in Example 58.

Example 62:
1,2-dihydro-1-cyclobutyl-4-[(2-fluoro-4-methoxyphenyl) methyl] -5-methyl-3H-pyrazol-3-one ( III.5 )

実施例58に概説された合成操作を使用することにより同様の様式で式III.5の化合物を得てもよい。

The compound of formula III.5 may be obtained in a similar manner by using the synthetic procedure outlined in Example 58.

Example 63:
1,2-dihydro-1- (1-methylethyl) -4-[(2,3-difluoro-4-methylphenyl) methyl] -5-methyl-3H-pyrazol-3-one ( III.6 )

The compound of formula III.6 may be obtained in a similar manner by using the synthetic procedure outlined in Example 58.
Example 64:
1,2-dihydro-1- (1-methylethyl) -4-[(2-fluoro-4-methylphenyl) methyl] -5-methyl-3H-pyrazol-3-one ( III.7 )

実施例58に概説された合成操作を使用することにより同様の様式で式III.7の化合物を得てもよい。

The compound of formula III.7 may be obtained in a similar manner by using the synthetic procedure outlined in Example 58.

Example 65:
1,2-dihydro-1- (1-methylethyl) -4-[(3-fluoro-4-ethoxyphenyl) methyl] -5-methyl-3H-pyrazol-3-one ( III.8 )

実施例58に概説された合成操作を使用することにより同様の様式で式III.8の化合物を得てもよい。

The compound of formula III.8 may be obtained in a similar manner by using the synthetic procedure outlined in Example 58.

Example 66:
1,2-dihydro-1- (1-methylethyl) -4-[(3-fluoro-4- (1-methylethoxy) phenyl) methyl] -5-methyl-3H-pyrazol-3-one ( III. 9 )

実施例58に概説された合成操作を使用することにより同様の様式で式III.9の化合物を得てもよい。

The compound of formula III.9 may be obtained in a similar manner by using the synthetic procedure outlined in Example 58.

Example 67:
1,2-dihydro-1- (1-methylethyl) -4-[(2-fluoro-4- (1-methylethoxy) phenyl) methyl] -5-methyl-3H-pyrazol-3-one ( III. 10 )

実施例58に概説された合成操作を使用することにより同様の様式で式III.10の化合物を得てもよい。

The compound of formula III.10 may be obtained in a similar manner by using the synthetic procedure outlined in Example 58.

Example 68:
1,2-dihydro-1- (1-methylethyl) -4-[(2-fluoro-4-ethoxyphenyl) methyl] -5-methyl-3H-pyrazol-3-one ( III.11 )

  The compound of formula III.11 may be obtained in a similar manner by using the synthetic procedure outlined in Example 58.

Claims (15)

Formula (I)

(Where
R ¹ represents C _1-4 -alkyl, a C _1-4 -alkyl group substituted with one or more fluorine atoms, or C _3-6 -cycloalkyl, and
R ² represents C _1-4 -alkyl, a C _1-4 -alkyl group substituted with one or more fluorine atoms, or C _3-6 -cycloalkyl, and
R ³ represents fluorine, chlorine, bromine, C _1-4 -alkyl, C _3-6 -cycloalkyl, C _1-4 -alkoxy, or C _3-6 -cycloalkyl-oxy, and
R ⁴ and R ⁵ independently of one another represent hydrogen, fluorine, chlorine, bromine, C _1-4 -alkyl, or C _1-4 -alkoxy, and
R ⁶ , R ^7a , R ^7b and R ^7c each independently represents a group selected from hydrogen, (C _1-6 -alkyl) carbonyl, phenylcarbonyl and phenyl- (C _1-3 -alkyl) -carbonyl. Have)
A compound comprising the tautomers, mixtures thereof and salts thereof, comprising:
Formula (III)

(Wherein R ^{1 to} R ⁵ are as defined above)
An aglycone of the formula (IV) in a solvent or solvent mixture

Wherein R ^{1 to} R ⁵ are as defined above and Q is C _1-4 -alkoxy, C _3-6 -cycloalkyl-oxy or —NR ^a R ^b (where R ^a , R ^b independently represents C _1-4 -alkyl, or —NR ^a R ^b represents pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl or NC _1-4 -alkyl-piperazinyl))
Obtained by catalytic hydrogenation of the compound,
And the aglycone of formula (III) in formula (II) in a solvent or mixture of solvents

(Where
X represents bromine or chlorine,
R ⁶ , R ^7a , R ^7b , R ^7c are independently of each other a group: having a meaning selected from (C _1-6 -alkyl) carbonyl, phenylcarbonyl and phenyl- (C _1-3 -alkyl) -carbonyl)
Process for the preparation of is glucose derivative of the reaction, characterized in Rukoto, said compounds. A compound of formula (IV) wherein Q is C _1-4 -alkoxy, C _3-6 -cycloalkyl-oxy or —NR ^a R ^b (wherein R ^a and R ^b are independently of each other C _{1- 4} represents -alkyl, or -NR ^a R ^b represents pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl or NC _1-4 -alkyl-piperazinyl))
a) Secondary amine HQ (wherein Q is —NR ^a R ^b (wherein R ^a and R ^b independently represent C _1-4 -alkyl, or —NR ^a R ^b is pyrrolidinyl, piperidinyl, Represents morpholinyl, piperazinyl or NC _1-4 -alkyl-piperazinyl)), or
b) Alcohol HQ (wherein Q represents C _1-4 -alkoxy or C _3-6 -cycloalkyl-oxy) and in the presence of a secondary amine (VI)

(Wherein R ¹ and R ² are as defined in claim 1)
A pyrazole derivative of formula (V)

(Wherein R ³ , R ⁴ and R ⁵ are as defined in claim 1)
A process according to claim 1, characterized in that it is obtained by reacting with a benzaldehyde derivative of   3. The reaction according to claim 2, characterized in that the reaction is carried out in the presence of an alcohol HQ (wherein Q is selected from methoxy, ethoxy, n-propoxy and i-propoxy) and a cyclic secondary amine. Method. A pyrazole derivative of formula (VI) is represented by formula (VII)

(Wherein R ¹ and R ² are as defined in claim 2 or 3)
A process according to claim 2 or 3, characterized in that it is obtained by dehydrogenation of a pyrazole derivative of Formula (VII)

(Where
R ¹ is the formula

(Wherein, R ¹¹ is C _1-3 - When alkyl, and R ¹² represents H, or the R ¹¹ represents methyl - C _1-3 substituted by alkyl or one or more fluorine atoms R ¹² may also represent a methyl or ethyl group or a methyl or ethyl group substituted with one or more fluorine atoms, or R ¹¹ and R ¹² are joined together Together with the CH- group forms a C _3-6 -cycloalkyl group)
And represents the group of
R ² is as defined in claim 4)
A pyrazole derivative of formula (VIII)

(Wherein R ² is as defined above)
A pyrazole derivative of formula (IX)

(Wherein R ¹¹ and R ¹² are as defined above)
A process according to claim 4, characterized in that it is obtained by reacting with an aldehyde or ketone and subsequently or simultaneously reducing it. The pyrazole derivative of formula (VIII) is converted to formula (X) in a solvent or mixture of solvents.

Wherein R ² is as defined in claim 5 and R ^c is methyl, ethyl, n-propyl or i-propyl.
A process according to claim 5, characterized in that it is obtained by reacting an acrylate derivative of this with hydrazine. The product of any one formula obtained by the method according to claim 1 to 6 (I) of (in the formula, one or more substituents ^{R 6, R 7a, R 7b} , R 7c are not hydrogen) Deprotecting the compound by cleaving the non-hydrogen substituents R ⁶ , R ^7a , R ^7b and R ^7c in a solvent or mixture of solvents, comprising formula (IH)

(Wherein R ^{1 to} R ⁵ are as defined in claim 1)
(Including their tautomers, mixtures thereof and salts thereof). Formula (III)

(Where
R ¹ represents C _1-4 -alkyl, a C _1-4 -alkyl group substituted with one or more fluorine atoms, or C _3-6 -cycloalkyl, and
R ² represents C _1-4 -alkyl, a C _1-4 -alkyl group substituted with one or more fluorine atoms, or C _3-6 -cycloalkyl, and
R ³ represents fluorine, chlorine, bromine, C _1-4 -alkyl, C _3-6 -cycloalkyl, C _1-4 -alkoxy, or C _3-6 -cycloalkyl-oxy, and
R ⁴ and R ⁵ each independently represent hydrogen, fluorine, chlorine, bromine, C _1-4 -alkyl, or C _1-4 -alkoxy)
A compound comprising the tautomers, mixtures thereof and salts thereof, comprising:
Formula (IV)

Wherein R ^{1 to} R ⁵ are as defined above and Q is C _1-4 -alkoxy, C _3-6 -cycloalkyl-oxy or —NR ^a R ^b (where R ^a , R ^b independently represents C _1-4 -alkyl, or —NR ^a R ^b represents pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl or NC _1-4 -alkyl-piperazinyl))
A process for the preparation of said compound comprising the step of catalytic hydrogenation of a pyrazole derivative of in a solvent or a mixture of solvents. Formula (IV)

(Where
R ¹ represents C _1-4 -alkyl, a C _1-4 -alkyl group substituted with 1 to 3 fluorine atoms, or C _3-6 -cycloalkyl, and
R ² represents C _1-4 -alkyl, a C _1-4 -alkyl group substituted with one or more fluorine atoms, or C _3-6 -cycloalkyl, and
R ³ represents fluorine, chlorine, bromine, C _1-4 -alkyl, C _3-6 -cycloalkyl, C _1-4 -alkoxy, or C _3-6 -cycloalkyl-oxy, and
R ⁴ and R ⁵ each independently represent hydrogen, fluorine, chlorine, bromine, C _1-4 -alkyl, or C _1-4 -alkoxy, and Q is C _1-4 -alkoxy, C _3-6 -cyclo Alkyl-oxy or -NR ^a R ^b (wherein R ^a and R ^b independently represent C _1-4 -alkyl, or -NR ^a R ^b is pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl or NC _1-4 Represents alkyl-piperazinyl))
A compound comprising the tautomers, mixtures thereof and salts thereof, comprising:
Formula (VI)

(Wherein R ¹ and R ² are as defined above)
Pyrazole derivatives of
a) Secondary amine HQ (wherein Q is —NR ^a R ^b (wherein R ^a and R ^b independently represent C _1-4 -alkyl, or —NR ^a R ^b is pyrrolidinyl, piperidinyl, Represents morpholinyl, piperazinyl or NC _1-4 -alkyl-piperazinyl)), or
b) Alcohol HQ (wherein Q represents C _1-4 -alkoxy or C _3-6 -cycloalkyl-oxy) and in the presence of a secondary amine (V)

(Wherein R ³ , R ⁴ and R ⁵ are as defined above)
A process for preparing the compound, comprising the step of reacting with a benzaldehyde derivative of The aglycone of formula (III) is converted to formula (XI) in the presence of a base in a solvent or mixture of solvents.

(Wherein R ^{2 to} R ⁵ are as defined in claim 1 )
An alkylating agent R ¹ -X ′, wherein R ¹ is as defined in claim 1 and X ′ is chlorine, bromine, iodine or C _1-3 -alkyl-SO ₂ — (Represents O-) and reacts with the formula (XI ')

(Wherein R ^{1 to} R ⁵ are as defined above)
Characterized in that it is obtained by subsequent cleavage of the R ¹ —O— group at the 3-position of the pyrazole ring, in particular in the presence of an acid, to give an aglycone of formula (III), The method according to claim 1 or 7 . A pyrazole derivative of formula (XI)
(i) Formula (V) in the presence of acid and secondary amine

(Wherein is as R ^3, R ⁴ and R ⁵ are as defined in claim 1 0)
The benzaldehyde derivative of formula (XII)

(Is as in the formula, R ² is defined in claim 1 0, and
R ^c is methyl, ethyl, n-propyl or i-propyl)
Reaction with a β-ketoester derivative of, followed by or simultaneous catalytic hydrogenation, and
(ii) the product of step (i) and obtaining by reaction with hydrazine in a solvent or mixture of solvents, according to claim 1 0 The method according. Where applicable, substituents are defined as follows:
R ¹ represents methyl, ethyl, n-propyl, i-propyl, cyclobutyl or cyclopentyl, and
R ² represents methyl, ethyl, n-propyl or i-propyl, and
R ³ represents fluorine, chlorine, methyl, methoxy, ethoxy, n-propoxy or i-propoxy, and
R ⁴ represents fluorine, chlorine, methyl, methoxy, ethoxy, n-propoxy or i-propoxy, and
R ⁵ is hydrogen, fluorine, chlorine, methyl or wherein a represents methoxy, method according to any one of claims 1 to 11. Where applicable, substituents are defined as follows:
R ¹ represents i-propyl or cyclobutyl, and
R ² represents methyl and
R ³ represents methyl, methoxy, ethoxy or i-propoxy, and
R ⁴ represents fluorine, and
R ⁵ is characterized in that hydrogen or fluorine, The method of claim 12, wherein. Where applicable, substituents are defined as follows:
In the formula (I), the substituents R ⁶ , R ^7a , R ^7b and R ^7c represent hydrogen, and in the formula (II), the substituents R ⁶ , R ^7a , R ^7b and R ^7c are (C _{1 -4} -alkyl) carbonyl, in particular methylcarbonyl, and in the formula (II '), the substituents R ⁶ , R ^7a , R ^7b , R ^7c , R ^7d are (C _1-4 -alkyl) carbonyl, in particular 14. Process according to any one of claims 1 to 13 , characterized in that it represents methylcarbonyl. Formula (IV)

Wherein R ^{1 to} R ⁵ are as defined in claim 1, 12 or 13 and Q is C _1-4 -alkoxy, C _3-6 -cycloalkyl-oxy or —NR ^a R ^b Wherein R ^a and R ^b independently represent C _1-4 -alkyl, or —NR ^a R ^b represents pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl or NC _1-4 -alkyl-piperazinyl. )
(Including their tautomers, mixtures thereof and salts thereof).