Goal of the invention
Target of the present invention is to find the novel method of the pyrazole-O-glycoside derivatives of preparation formula (I); Be in particular can be thus with high yield and/or high chemistry and diastereomer purity obtain this product and can the low technical cost and high spatial/time productive rate with the method for this product of commercial scale production.
Another target of the present invention is to provide the method for the initial substance in the preparation aforesaid method.
Another target of the present invention relates to novel intermediates and the initial substance in the inventive method.
Other targets of the present invention are for those of ordinary skill in the art, and based on context describing will be apparent.
In first aspect, the present invention relates to a kind of method for preparing general formula (I) compound,
Wherein
R
1Expression C
1-4-alkyl, the C that is replaced by one or more fluorine atoms
1-4-alkyl or C
3-6-cycloalkyl; And
R
2Expression C
1-4-alkyl, the C that is replaced by one or more fluorine atoms
1-4-alkyl or C
3-6-cycloalkyl; And
R
3Expression fluorine, chlorine, bromine, C
1-4-alkyl, C
3-6-cycloalkyl, C
1-4-alkoxyl group or C
3-6-cycloalkyloxy; And
R
4, R
5Represent hydrogen, fluorine, chlorine, bromine, C independently of one another
1-4-alkyl, or C
1-4-alkoxyl group; And
R
6, R
7a, R
7b, R
7cBe independently from each other: hydrogen, (C
1-6-alkyl) carbonyl, phenylcarbonyl group and phenyl-(C
1-3-alkyl)-carbonyl;
It comprises tautomer, steric isomer, its mixture and salt thereof;
This method feature is the aglycon of formula (III):
R wherein
1To R
5Define as mentioned:
Be by the hydrogenation of formula (IV) compound for catalysis is obtained:
R wherein
1To R
5Define as mentioned, and
Q is Cl, Br, I, C
1-4-alkoxyl group, C
1-4-alkylthio, thiophenyl, C
3-6-cycloalkyloxy, C
1-4-alkyl-carbonyl oxygen base ,-NR
aR
b, R wherein
a, R
bRepresent C independently of one another
1-4-alkyl, or-NR
aR
bExpression pyrrolidyl, piperidyl, morpholinyl, piperazinyl or N-C
1-4-alkyl-piperazinyl.
The present invention relates to R in the above-mentioned general formula of a kind of preparation (I) in second aspect
1To R
5, R
6, R
7a, R
7b, R
7cThe method of defined compound as mentioned (comprising its tautomer, steric isomer, its mixture and salt thereof);
It is characterized in that in solvent or solvent mixture, making the aglycon of formula (III):
R wherein
1To R
5Define as mentioned;
Glucose-derivative reaction with formula (II):
Wherein
X represents bromine or chlorine;
R
6, R
7a, R
7bAnd R
7cBe independently from each other: (C
1-6-alkyl) carbonyl, phenylcarbonyl group and phenyl-(C
1-3-alkyl)-carbonyl;
And randomly make wherein substituent R
6, R
7a, R
7b, R
7cBe not formula (I) the product deprotection of hydrogen, the method by third aspect present invention especially preferably.
In the third aspect, the present invention relates to the method for a kind of preparation formula (IH) compound,
R wherein
1To R
5As above hereinafter define;
Comprise its tautomer, steric isomer, its mixture and salt thereof;
This method comprises the step that makes formula (I) compound deprotection:
R wherein
1To R
5Define as mentioned, and R
6, R
7a, R
7bAnd R
7cAs above hereinafter define, but wherein one or more are not hydrogen; Be by in solvent or solvent mixture, making the substituent R that is not hydrogen
6, R
7a, R
7bAnd R
7cCracking.
In fourth aspect, the present invention relates to the method for a kind of preparation formula (III) compound,
Wherein
R
1Expression C
1-4-alkyl, the C that is replaced by 1 to 3 fluorine atom
1-4-alkyl or C
3-6-cycloalkyl; And
R
2Expression C
1-4-alkyl, the C that is replaced by one or more fluorine atoms
1-4-alkyl or C
3-6-cycloalkyl; And
R
3Expression fluorine, chlorine, bromine, C
1-4-alkyl, C
3-6-cycloalkyl, C
1-4-alkoxyl group or C
3-6-cycloalkyloxy; And
R
4, R
5Represent hydrogen, fluorine, chlorine, bromine, C independently of one another
1-4-alkyl or C
1-4-alkoxyl group;
Comprise its tautomer, steric isomer, its mixture and salt thereof;
This method is included in the step of the pyrazole derivatives catalytic hydrogenation that makes formula (IV) in solvent or the solvent mixture,
R wherein
1To R
5Define as mentioned; And
Q is Cl, Br, I, C
1-4-alkoxyl group, C
1-4-alkylthio, thiophenyl, C
3-6-cycloalkyloxy, C
1-4-alkyl-carbonyl oxygen base ,-NR
aR
b, R wherein
a, R
bRepresent C independently of one another
1-4-alkyl, or-NR
aR
bExpression pyrrolidyl, piperidyl, morpholinyl, piperazinyl or N-C
1-4-alkyl-piperazinyl.
Aspect the 5th, the present invention relates to the method for a kind of preparation formula (IV) compound,
Wherein
R
1Expression C
1-4-alkyl, the C that is replaced by one or more fluorine atom
1-4-alkyl or C
3-6-cycloalkyl; And
R
2Expression C
1-4-alkyl, the C that is replaced by one or more fluorine atom
1-4-alkyl or C
3-6-cycloalkyl; And
R
3Expression fluorine, chlorine, bromine, C
1-4-alkyl, C
3-6-cycloalkyl, C
1-4-alkoxyl group or C
3-6-cycloalkyloxy; And
R
4, R
5Represent hydrogen, fluorine, chlorine, bromine, C independently of one another
1-4-alkyl or C
1-4-alkoxyl group; And
Q is C
1-4-alkoxyl group, C
1-4-alkylthio, C
3-6-cycloalkyloxy, thiophenyl ,-NR
aR
b, R wherein
a, R
bRepresent C independently of one another
1-4-alkyl, or-NR
aR
bExpression pyrrolidyl, piperidyl, morpholinyl, piperazinyl or N-C
1-4-alkyl-piperazinyl;
Comprise its tautomer, steric isomer, its mixture and salt thereof;
This method comprises the pyrazole derivatives that makes formula (VI),
R wherein
1And R
2Define as mentioned;
Under the situation that following material exists:
A) secondary amine H-Q, wherein Q represents-NR
aR
b, R wherein
a, R
bRepresent C independently of one another
1-4-alkyl, or-NR
aR
bExpression pyrrolidyl, piperidyl, morpholinyl, piperazinyl or N-C
1-4-alkyl-piperazinyl; Or
B) alcohol or mercaptan H-Q, wherein Q represents C
1-4-alkoxyl group, C
1-4-alkylthio, thiophenyl, C
3-6-cycloalkyloxy; And secondary amine,
With the step of the benzaldehyde derivative of formula V reaction,
R wherein
3, R
4And R
5Define as mentioned.
Aspect the 6th, the present invention relates to the method for the pyrazole derivatives of a kind of preparation formula (III),
R wherein
1To R
5Define as mentioned;
Comprise its tautomer, steric isomer, its mixture and salt thereof;
This method is included in the pyrazole derivatives that makes formula (XI) in solvent or the solvent mixture under there is situation in alkali,
R wherein
2To R
5Define as mentioned;
With alkylating agent R
1-X ' reaction, wherein R
1Define as mentioned and X ' expression hydrogen, bromine, iodine or C
1-3-alkyl-SO
2-O-, thereby the intermediate of production (XI '),
R wherein
1To R
5Define as mentioned;
And under existing situation, acid makes the R on the 3-position of this pyrazoles ring subsequently
1The cracking of-O-group, the aglycon of production (III).
Aspect the 7th, the present invention relates to the method for the pyrazole derivatives of a kind of preparation formula (XI),
R wherein
2To R
5Define as mentioned;
Comprise its tautomer, steric isomer, its mixture and salt thereof;
This method comprises the following step:
(i) in the presence of acid or secondary amine, make the benzaldehyde derivative of formula V,
R wherein
3, R
4And R
5Define as mentioned,
With the 'beta '-ketoester derivatives reaction of formula (XII),
R wherein
2Define as mentioned; And
R
CBe methyl, ethyl, n-propyl or sec.-propyl; And reach and carry out catalytic hydrogenation subsequently or simultaneously; And
(ii) product and the hydrazine with step (i) reacts in solvent or solvent mixture.
In eight aspect, the present invention relates to a kind of preparation in as mentioned the method for the general formula that defines (I) compound, it is characterized in that this method comprises the method steps according to fifth aspect present invention.
Aspect the 9th, the present invention relates to a kind of preparation in as mentioned the method for the general formula that defines (I) compound, it is characterized in that this method comprises one or two method steps of the 6th and/or the 7th aspect according to the present invention.
Aspect the tenth, the present invention relates to the compound of a kind of formula (IV),
R wherein
1To R
5Define as mentioned, and
Q is Cl, Br, I, C
1-4-alkoxyl group, C
1-4-alkylthio, thiophenyl, C
3-6-cycloalkyloxy, C
1-4-alkyl-carbonyl oxygen base ,-NR
aR
b, R wherein
a, R
bRepresent C independently of one another
1-4-alkyl, or-NR
aR
bExpression pyrrolidyl, piperidyl, morpholinyl, piperazinyl or N-C
1-4-alkyl-piperazinyl,
Comprise its tautomer, steric isomer, its mixture and salt thereof;
In the tenth one side, the present invention relates to the compound of formula (III),
R wherein
1To R
5Define as mentioned or hereinafter,
Comprise its tautomer, steric isomer, its mixture and salt thereof.
Another aspect of the present invention relates to the compound of a kind of formula (VI),
R wherein
1And R
2Such as in the claim 1,21 or 22 definition,
Comprise its tautomer, its mixture and salt thereof.
Detailed Description Of The Invention
Unless otherwise indicated, otherwise described group, residue and substituting group are in particular 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 ', define in the context all as described.
If residue, substituting group and group occur repeatedly in compound, then it can have identical or different meaning.Two-(C for example
1-4-alkyl) meaning of amine comprises the secondary amine with two identical or different alkyl groups, as ethyl-sec.-propyl-amine.
In the method according to this invention and compound, intermediate and initial substance, following group and substituent meaning are preferred:
R
1Expression preferably
Group;
R wherein
11Expression C
1-3-alkyl or the C that is replaced by one or more fluorine atom
1-3-alkyl; And R
12Expression H, or at R
11Under the situation of expression methyl, R
12Also can represent methyl or ethyl group or the methyl or the ethyl group that are replaced by one or more fluorine atom;
Or R
11With R
12Connect and form C with the CH-group that it connected
3-6-cycloalkyl-group.
Even R
1More preferably represent ethyl, n-propyl, sec.-propyl, cyclobutyl or cyclopentyl; Be most preferably sec.-propyl or cyclobutyl.
R
2Preferred expression methyl, ethyl, n-propyl or sec.-propyl; Be most preferably methyl.
R
3Preferred expression fluorine, chlorine, methyl, methoxyl group, oxyethyl group, positive propoxy or isopropoxy; Be most preferably methyl, methoxyl group, oxyethyl group or isopropoxy.
R
4Preferred expression fluorine, chlorine, methyl, methoxyl group, oxyethyl group, positive propoxy or isopropoxy; Especially be fluorine.This substituent R in addition
4Be preferably the substituting group of 2-position on the phenyl ring.R
4Be most preferably the substituting group and the expression fluorine of 2-position on the phenyl ring.
R
5Preferred expression hydrogen, fluorine, chlorine, methyl or methoxy; Be most preferably hydrogen or fluorine.
In formula (I) compound, substituent R
6, R
7a, R
7b, R
7cPreferably have independently of one another and be selected from following meaning: hydrogen, (C
1-4-alkyl) carbonyl, phenylcarbonyl group and benzyloxycarbonyl group.In formula (I) compound, substituent R
6, R
7a, R
7b, R
7cMore preferably be selected from following meaning for having independently of one another: hydrogen, methyl carbonyl and ethyl carbonyl especially are hydrogen.
In formula (II) compound, substituent R
6, R
7a, R
7b, R
7cPreferably have independently of one another and be selected from following meaning: (C
1-4-alkyl) carbonyl, phenylcarbonyl group and benzyloxycarbonyl group.In formula (II) compound, substituent R
6, R
7a, R
7b, R
7cMore preferably be selected from following meaning for having independently of one another: methyl carbonyl and ethyl carbonyl especially are the methyl carbonyl.
In formula (II ') compound, substituent R
6, R
7a, R
7b, R
7c, R
7dPreferably have independently of one another and be selected from following meaning: (C
1-4-alkyl) carbonyl, phenylcarbonyl group and benzyloxycarbonyl group.In formula (II ') compound, substituent R
6, R
7a, R
7b, R
7c, R
7dMore preferably be selected from following meaning for having independently of one another: methyl carbonyl and ethyl carbonyl especially are the methyl carbonyl.
Should be understood that in context by the corresponding tautomer of the specified compound of general formula or particular chemical formula, also be included in the category that reaches each method or definition arbitrarily of The compounds of this invention.Especially for pyrazole derivatives, can there be following tautomer according to reaction and preparation condition:
And
This mark wherein
Be used to indicate this key to point to the chemical group or the substituting group of (comprising hydrogen).
Below will describe the method according to this invention in detail.
According to a first aspect of the invention, according to reaction process I through the catalytic hydrogenation of formula (IV) compound and the aglycon of acquisition formula (III):
Flow process I:
This group Q preferably represent methoxyl group, oxyethyl group, positive propoxy, isopropoxy ,-NR
aR
b, R wherein
a, R
bRepresent methyl, ethyl, n-propyl or sec.-propyl independently of one another, or-NR
aR
bExpression pyrrolidyl, piperidyl, morpholinyl, piperazinyl or N-C
1-3-alkyl-piperazinyl.Even Q more preferably represents methoxyl group, oxyethyl group, positive propoxy, isopropoxy, pyrrolidyl, piperidyl, morpholinyl, piperazinyl or N-C
1-3-alkyl-piperazinyl; Be most preferably oxyethyl group, pyrrolidyl, piperidyl or morpholinyl.
In above-mentioned synthesis step, suitable solvent be aliphatic hydrocrbon, aromatic hydrocarbon, alcohol, aliphatic ether, cyclic ethers, ester, amide type solvent, acetate, its mixture and with the mixture of water.The example of suitable solvent be pentane, hexane, benzene, toluene, methyl alcohol, ethanol, Virahol, n-propyl alcohol, ether, tetrahydrofuran (THF), tetrahydropyrans, ethyl acetate, isopropyl acetate, butylacetate, NMP, DMF, Glacial acetic acid, its mixture and with the mixture of water.Preferred solvent be methyl alcohol, ethanol, Virahol, n-propyl alcohol, tetrahydrofuran (THF), its mixture and with the mixture of water.
Preferably in the presence of one or more acid (especially being spirit of salt, carboxylic acid or alkyl sulfonic acid), carry out catalytic hydrogenation.The example of appropriate acid is spirit of salt, acetate and trifluoroacetic acid.The preferred acid of adopting about 1 to the 150 mole of % amount of isolate that equals to be equivalent to formula (IV).
At H-Q is under the situation of alcohol or mercaptan, the preferred acid of adopting about 1 to the 50 mole of % amount of isolate that equals to be equivalent to formula (IV); More preferably about 1 to 20 mole of %, 10 moles of % according to appointment.Under the situation of acetate, its amount can be 100 moles of % at the most.
Be selected from-NR as if Q according to embodiment preferred
aR
b, then need not to add acid and can carry out catalytic hydrogenation.According to another preferred embodiment, if Q is selected from-NR
aR
b, then preferably adopt the acid that equals about 1 to 120 mole of % amount, for example based on the acid of about equimolar amount of the isolate of formula (IV).
Catalytic hydrogenation is preferably at transition-metal catalyst, as palladium catalyst (for example fine dispersive palladium, palladium-carbon or Pd (OH)
2), or nickel-base catalyst (for example fine dispersion nickel is as Raney nickel) existence is carried out down.The appropriate amount of catalyzer can change according to reaction conditions, and for example to be in isolate with respect to formula (IV) be about 0.1 to about 50 weight %, and preferred about 1 to the scope of about 10 weight %.Hydrogenation should-30 to 150 ℃, preferred 20 to 100 ℃, more preferably 20 to 70 ℃, most preferably carry out under the temperature in 40 to 60 ℃ of scopes.Suitable hydrogen pressure approximates usually or is higher than standard atmospheric pressure, preferably at about 1 to 20 crust (bar), more preferably in the scopes of 2 to 8 crust.During hydrogenation, preferably this reaction mixture is stirred or stirs.Finishing this hydrogenation time necessary can be through optimum experimental.Usually hydrogenization is carried out the time in about 30 minutes to about 24 hours, preferred about 1 to 12 hour.After the hydrogenation, preferably this catalyzer is removed from this reaction mixture by for example filtering.Next reactions steps, promptly the synthetic available of formula (I) compound contains the reaction soln of formula (III) product or contains carrying out through separated product of formula (III).The product of formula (III) can by for example in a vacuum and/or elevated temperature remove down this solvent, and by separating in this reaction soln.Also can be by from concentrated reaction solution precipitation and acquisition formula (III) product, for example by adding for example anti-solvent of water, and separate in by this suspension through for example filtering.
(wherein Q represents C to the isolate of this formula (IV)
1-4-alkoxyl group, C
1-4-alkylthio, thiophenyl, C
3-6-cycloalkyloxy or-NR
aR
b, R wherein
a, R
bRepresent C independently of one another
1-4-alkyl, or-NR
aR
bExpression pyrrolidyl, piperidyl, morpholinyl, piperazinyl or N-C
1-4-alkyl-piperazinyl) preferably obtain, promptly press reaction process II, in the presence of following arbitrary material, make the benzaldehyde derivative reaction of the pyrazole derivatives and the formula V of formula (VI) by a fifth aspect of the present invention:
A) secondary amine H-Q, wherein Q represents-NR
aR
b, R wherein
a, R
bRepresent C independently of one another
1-4-alkyl, or-NR
aR
bExpression pyrrolidyl, piperidyl, morpholinyl, piperazinyl or N-C
1-4-alkyl-piperazinyl; Or
B) alcohol or mercaptan H-Q, wherein Q represents C
1-4-alkoxyl group, C
1-4-alkylthio, thiophenyl or C
3-6-cycloalkyloxy, and secondary amine.
Flow process II:
This reaction is to carry out in the presence of secondary amine.
If (wherein Q is defined as-NR to use compound H-Q
aR
b), then need not to add secondary amine.H-Q is preferably selected from tetramethyleneimine, piperidines, morpholine, piperazine and N-C
1-3-alkyl-piperazinyl; Most preferably be selected from tetramethyleneimine, piperidines and morpholine.Sulfonamide derivatives H-Q preferably uses with equimolar amount or mole excess quantity with the pyrazole derivatives compared to formula (IV).The preferred molar ratio of amine H-Q and pyrazole derivatives is in about 1: 1 to 10: 1 scope, even more preferably in 1: 1 to 5: 1 scope.
If (wherein Q represents C to use alcohol or mercaptan H-Q
1-4-alkoxyl group, C
1-4-alkylthio, thiophenyl or C
3-6-cycloalkyloxy), then reaction should be carried out in the presence of secondary amine.Q is preferably selected from methoxyl group, oxyethyl group, positive propoxy and isopropoxy; Be most preferably oxyethyl group.Preferred secondary amine is to be selected from two-(C
1-4-alkyl) amine or cyclic secondary amine, for example tetramethyleneimine, piperidines, morpholine, piperazine, N-C
1-3-alkyl-piperazine.This secondary amine even more preferably for being selected from tetramethyleneimine, piperidines, morpholine, piperazine and N-C
1-3-alkyl-piperazine; Most preferably be selected from tetramethyleneimine, piperidines and morpholine.Secondary amine can by catalytic amount, about equimolar amount or even the amount of molar excess use.The preferred molar ratio of this secondary amine and pyrazole derivatives is about 0.05: 1 to 2: 1 even more preferably about 0.1: 1 to 1.5: 1, most preferably in about 1.0: 1.0 to 1.5: 1.0 scope.This alcohol or mercaptan H-Q preferably use with the amount of equimolar amount or molar excess with the pyrazole derivatives compared to formula (VI).Except the function as reaction partner, this alcohol H-Q also can be used as solvent, can use the H-Q of molar excess in the case.
This reaction according to the present invention is in addition preferably carried out under acidic conditions.The C of suitable acid for for example being unsubstituted or being replaced by one or more fluorine or chlorine substituting group
1-6-alkyl carboxylic acid, the C that is unsubstituted or is replaced by one or more fluorine or chlorine substituting group
1-6-alkylsulphonic acid, dicarboxylic acid, tricarboxylic acid, methyl chlorosilane, non-aqueous mineral acid.The example of preferred acid is Glacial acetic acid, trimethylchlorosilane, spirit of salt (moisture or for example as the solution in the alcoholic acid alcohol), trifluoromethanesulfonic acid.Preferably use this acid with the amount of equimolar amount or molar excess with pyrazole derivatives with respect to formula (IV).The preferred molar ratio of this acid and pyrazole derivatives is in about 0.05: 1 to 1: 1 scope, more preferably in 0.1: 1 to 0.5: 1 scope.
If compound H-Q be as hereinbefore defined alcohol or a thiol derivative, then preferably use this acid with the molar weight of this secondary amine at least.If this group Q is selected from-NR
aR
b, then can under the situation of adding or not adding acid, carry out this reaction; Preferred thus acid and mol ratio are as previously mentioned.
In the above-mentioned synthesis step, suitable solvent is aliphatic hydrocrbon, halogenated aliphatic hydrocarbon, aromatic hydrocarbon, alcohol, aliphatic ether, cyclic ether, acetonitrile, amide type solvent, acetate and composition thereof.The example of suitable solvent is a methylene dichloride, 1,2-ethylene dichloride, methyl alcohol, ethanol, Virahol, n-propyl alcohol, ether, tetrahydrofuran (THF), tetrahydropyrans, acetonitrile, NMP, DMF, Glacial acetic acid and composition thereof.Preferred solvent is methyl alcohol, ethanol, Virahol, n-propyl alcohol, tetrahydrofuran (THF), acetonitrile and composition thereof.If this compound H-Q be an alcohol, then its can be in addition as solvent and so can be by the excessive use of stoichiometry.If this group Q is selected from-NR
aR
b, then especially preferred solvent is an acetonitrile.
The isolate of formula V and formula (VI) preferably by about 2: 1 to 1: 2 mol ratio, preferably waits molar ratio reaction approximately.This synthesis step should-30 to 150 ℃, preferred 10 to 100 ℃, more preferably 20 to 80 ℃, most preferably carry out under the temperature in 30 to 70 ℃ of scopes.Finish this reaction time necessary usually at about 1 hour to about 96 hours scope.According to choice of Solvent, the product of formula (IV) is only slightly solvable in this reaction mixture, therefore forms suspension.Can use the crude product of formula (IV) or carry out next reactions steps through separated product, promptly formula (III) compound is synthetic.Can by for example in a vacuum and/or elevated temperature remove down this solvent, and with the product of this formula (IV) by separating in the reaction soln.Also can be by obtaining this formula (IV) product from concentrated reaction solution or suspension precipitation, for example by adding for example anti-solvent of water, and/or cool off this solution or suspension and separate with this suspension by for example filtering.
The synthetic method of the benzaldehyde derivative of formula V is known in the document, maybe can be similar to the method for knowing in the organic chemistry and carry out.
According to reaction process III, the dehydrogenation of the pyrazole derivatives of preferred through type (VII) and the pyrazole derivatives of acquisition formula (VI):
Flow process III:
Dehydrogenation is preferably used oxygenant (H for example
2O
2, inorganic peroxide, permonosulphuric acid or its salt, the two sulfuric acid of peroxide or its salt, percarboxylic acids, peroxide boric acid and analogue thereof) carry out.Preferred oxidant is H
2O
2Or peracetic acid.Preferably with H
2O
2Use with the aqueous solution, for example have 3 to 90 weight %, the H of 10 to 70 weight % content preferably
2O
2The preferably amount of oxygenant is for waiting mole or molar excess approximately, for example with respect to the isolate of formula (VIII) 1: 1 to 2: 1, the mol ratio in 1.0: 1.0 to 1.3: 1.0 scopes more preferably.
According to above synthesis step, with the dissolving of the isolate of formula (VII) or be suspended in suitable solvent or the solvent mixture.The example of suitable solvent is a carboxylic acid, for example acetate or its aqueous mixture.Because thermopositive reaction, this oxygenant preferably with continuously or in batches, is added in this solution or the suspension in for some time (for example 30 minutes to 24 hours scope).Can be if need with this reaction mixture cooling.Preferably at about 0 ℃ to 130 ℃, more preferably 10 ℃ to 90 ℃ even more preferably carry out this reaction under 20 ℃ to 80 ℃ the temperature range.This reaction was finished in 1 to 24 hour usually.Preferably under the temperature in 0 to 20 ℃ of scope, for example maybe this reaction mixture is poured in the water by water being added into this reaction mixture, and randomly appropriate base (for example sodium hydroxide, potassium hydroxide or ammonium hydroxide aqueous solution) is neutralized to this reaction mixture in 5 to 9 scopes, about 7 pH preferably through using, and for example after filtration this solid product is shifted out, thereby obtain the final product of formula (VI) with solid form from this aqueous reaction mixture.If this reaction mixture is without neutralization, then for example the salt form of acetate obtains this product.
Perhaps, preferably having transition-metal catalyst (as palladium catalyst, for example fine dispersion palladium or palladium-carbon) to exist down, this dehydrogenation is carried out in catalysis.This catalytic dehydrogenation is under elevated temperature (for example about 80 ℃ to 240 ℃, preferably about 100 ℃ to 200 ℃ scopes in) preferably, carry out in (for example aliphatic hydrocrbon or aromatic hydrocarbon, for example toluene) in unreactiveness solvent or solvent mixture.Preferably after removing this catalyzer, for example after filtration, use the method for knowing in the present technique, separate during product is reacted by this.
If R wherein
1Expression
Group, R wherein
11Expression C
1-3-alkyl or the C that is replaced by one or more fluorine atom
1-3-alkyl and R
12Expression H, or at R
11Under the situation of expression methyl, R
12Also can represent methyl or ethyl group or the methyl or the ethyl group that are replaced by one or more fluorine atom;
Or R
11With R
12Connect and form C with the CH-group that it connected
3-6-cycloalkyl-group;
The pyrazole derivatives of formula (VII) preferably according to reaction process IV by with the aldehydes or ketones reaction of the pyrazole derivatives of formula (VIII) with formula (IX), reach and carry out reduction reaction subsequently or simultaneously and obtain:
Flow process IV:
This substituent R
11Expression methyl, ethyl, n-propyl or sec.-propyl; And this substituent R
12Expression H; And if R
11Expression methyl or ethyl, then R
12Also can represent methyl or ethyl.R
11Can with R
12Connect and form cyclobutyl-or cyclopentyl-ring with the C-atom that it connected.Substituent R
11And R
12Most preferably all represent methyl, or they are connected to form the cyclobutyl ring.
If the salt form of use formula (VIII) isolate, then can be by adding alkali (for example sodium hydroxide, potassium hydroxide or ammonium hydroxide, preferably with the solution in alcohol or water) or alcoholate (especially be alkali metal alcoholate, the sodium ethylate in the ethanol for example), and acquisition formula (VIII) in and form.But this neutralization procedure and synthesis step original position are carried out, or obtain in advance formula (VIII) isolate in and form.
Above-mentioned reaction according to flow process IV is suitable for carrying out under one skilled in the relevant art's the known reduction amination condition.
According to this synthesis step, with the reactants dissolved of formula (VIII) and formula (IX) be suspended in suitable solvent or solvent mixture in.Preferred solvent is the mixture of alcohol, ether or itself and water, for example methyl alcohol, ethanol, n-propyl alcohol, Virahol, its mixture and with the mixture of water.The isolate of formula (IX), acetone for example can be used as solvent and therefore can be by the excessive use of stoichiometry.
The preferred molar ratio of formula (VIII) isolate and formula (IX) isolate is in 1: 1 to 1: 5 scope, more preferably in 1: 1 to 1: 3 scope, even more preferably in 1.0: 1.5 to 1.0: 2.5 scope.
This reductive action is preferably carried out with catalytic hydrogenation or is used hydride, and especially hydroborate (for example sodium triacetoxy borohydride or sodium cyanoborohydride) carries out with reduction reaction.
Preferably exist down, with this reaction soln or suspension catalytic hydrogenation at transition-metal catalyst (as palladium catalyst, for example fine dispersion palladium, palladium-carbon).The appropriate amount of catalyzer can change according to reaction conditions, and to be in be 0.1 to 50 weight % with respect to formula (IV) isolate for example, preferably in the scope of 1 to 20 weight %.This hydrogenation is-30 to 150 ℃, preferred 20 to 100 ℃, more preferably 20 to 80 ℃, favourable carrying out under the temperature in 40 to 70 ℃ of scopes most preferably.Suitable hydrogen pressure approximates usually or is higher than standard atmospheric pressure, preferably at about 1 to 20 crust even more preferably in the scopes of 2 to 8 crust.During hydrogenation, preferably this reaction mixture is stirred or stirs.After the hydrogenation, preferably this catalyzer is removed from this reaction mixture through for example filtering.That can use the reaction soln that contains formula (VII) product or formula (VII) arranged carries out next reactions steps through separated product, and promptly formula (VI) compound is synthetic.Can by for example in a vacuum and/or elevated temperature remove down this solvent, and with this formula (VII) product by separating in the reaction soln.Can be added in the solution of this product by the acid that will for example be contained in the spirit of salt in the ethanol through for example muriatic salt form in addition, subsequent crystallisation, by for example by cooling and/or with crystal seed inoculation assisting crystallisation, and final precipitation separation, thereby this product of purifying.
Preferably, in solvent or solvent mixture, react the pyrazole derivatives of acquisition formula (VIII) by acrylate derivative and hydrazine with formula (X) according to reaction process V:
Flow process V:
This substituent R
CThe C that expression randomly is substituted
1-6-alkyl is preferably methyl, ethyl, n-propyl or sec.-propyl; Be preferably methyl or ethyl.
This reacts by those of ordinary skill in the art is known and knows in theory.For example by Holan, people such as George, Bioorg.Med.Chem.Lett.6; 1; 1996; The described condensation of 77-80 by ethyl crotonate and hydrazine.
Preferably the acrylate derivative with formula (X) is dissolved in suitable solvent or the solvent mixture (for example alcohol, aliphatic ether, cyclic ethers and composition thereof).The example of suitable solvent is the solution of methyl alcohol, ethanol, Virahol, n-propyl alcohol, ether, t-butyl methyl ether, tetrahydrofuran (THF), tetrahydropyrans, two alkane and composition thereof or one or more these solvents and water.Preferred solvent is ethanol, Virahol, its mixture or its aqueous mixture.
Advantageously use hydrazine as the solution in the water, for example as single hydrazine hydrate; Or the solution in the alcohol, for example mixture of methyl alcohol, ethanol, Virahol, its mixture or one or more this alcohol and water.
The acrylate derivative of formula (X) and the preferred molar ratio of hydrazine are in 1: 1 to 1: 2 scope, more preferably in 1.0: 1.0 to 1.0: 1.5 scope, even more preferably in 1.0: 1.0 to 1.0: 1.2 scope.
Because exothermic reaction, preferably continuously or in batches, be added in the solution of this acrylate derivative in for some time (for example 15 minutes to 24 hours scope in) with hydrazine.Can be if need with this reaction mixture cooling.Preferably at 0 ℃ to 130 ℃, more preferably 20 ℃ to 100 ℃ even more preferably carry out this reaction under the temperature in 40 ℃ to 90 ℃ scopes.
Can by by for example in a vacuum and/or elevated temperature down evaporation remove this solvent, thereby obtain the final product of this formula (VIII).In addition or optionally can be through this final product of crystallization purifying of salt form (for example with its hydrohalogen form, as hydrochloride).For this reason, for example acid of the spirit of salt in ethanol or Virahol is added in the solution of this product.For example can be through cooling and/or with crystal seed inoculation assisting crystallisation, and this precipitate and separate the most at last.
According to embodiment preferred, in alcohol (being in particular Virahol), carry out this reactions steps, and use the aqueous solution (being in particular hydrazine hydrate) of hydrazine.After this reaction or between the reaction period, preferably use component distillation that water is removed from this reaction mixture.This product that advantageously obtains as indicated above especially is preferably muriatic salt form by precipitation, for example by add the hydrochloric acid solution in ethanol.
According to reaction process VIa, preferably pass through the aglycon of formula as indicated above (III) and the glucose-derivative reaction of formula (II), and the compound of acquisition formula (I):
Flow process VIa:
In the compound of formula (II) and formula (I), substituent R
6, R
7a, R
7b, R
7cBe preferably and be independently from each other following each group: (C
1-4-alkyl) carbonyl, phenylcarbonyl group and benzyloxycarbonyl group.Even substituent R
6, R
7a, R
7b, R
7cMore preferably be selected from following each basic implication for having independently of one another: methyl carbonyl and ethyl carbonyl especially are the methyl carbonyl.
This substituent X is preferably represented bromine atoms.Substituent R
1To R
5Define as mentioned.
According to first embodiment, this method steps can carry out in solvent or solvent mixture, considers that the initial substance of this formula (II) and formula (III) reaches under the situation that appropriate base exists, and these solvents have enough solubility properties.Preferred organic solvent with this character is ketone, ether, cyclic ethers, acetonitrile and composition thereof.The example of preferred organic solvent is acetone, methylethylketone, diethyl ketone, pimelinketone, cyclopentanone, acetonitrile, THF, NMP, DMF and composition thereof.Suitable alkali is carbonate particularly, for example yellow soda ash, salt of wormwood, silver carbonate or cadmium carbonate.
According to preferred second embodiment, this method steps carries out in reaction mixture, and this mixture preferably contains two liquid phases under condition of phase transition.Advantageously use two-phase solvent system and one or more phase-transfer catalyst.The preferred solvent of first phase is an aprotic organic solvent, especially is aromatic hydrocarbon (for example benzene, chlorobenzene, trifluoromethyl benzene,toluene,xylene), alkane (for example pentane, hexane, heptane, octane), halogenated alkane (CH for example
2Cl
2, CHCl
3, ClCH
2CH
2Cl), ether (for example 2-methyl-tetrahydrofuran (THF)), ester (for example isopropyl acetate) and composition thereof.The especially preferred solvent of this first phase comprises the chloro C that can have one or more fluoro substituents in addition
1-3-alkane is most preferably CH
2Cl
2
This second aqueous mixture that is preferably water or protonic solvent mutually.The most preferably solvent of this second phase is a water.
The preferred ratio of first phase volume and second phase volume is in 1: 10 to 10: 1 scope, even more preferably in 1: 5 to 5: 1 scope, most preferably in 1: 5 to 2: 1 scope.
Preferred phase-transfer catalyst has quaternary ammonium cation, for example four alkane ammoniums, N-aryl-N-three alkane ammoniums, N-aralkyl-N-three alkane ammonium compounds, and wherein this alkyl residue can be identical or different.Example is tetramethylammonium compound, tetraethyl ammonium compount, tetrabutylammonium compound or benzyl TMA (TriMethylAmine) compound.Phase-transfer catalyst most preferably is the tetrabutylammonium compound, especially for the tetrabutylammonium salt of mineral acid is arranged, as TBAC tetrabutylammonium chloride, bromination tetrabutylammonium, hydrogen sulfate tetrabutylammonium etc.
The preferable amount of phase-transfer catalyst depends on the solvent types of using and amount thereof, and can be determined by standard test.Usually per 1 mole formula (III) initial substance uses the phase-transfer catalyst of 0.01 to 1.0 mole even more preferably 0.02 to 0.5 mole (for example about 0.05 mole).
Advantageously with this alkalization of second solvent phase or bufferingization.During reaction reach after the reaction, the pH value of aqueous solvent phase is more than or equal to about 10, especially more than or equal to about 11, even more preferably more than or equal to about 12, most preferably about 11 to about 15 scope, most preferably about 12 to about 14 scope.
Advantageously, this pH value is remained in the required alkaline pH scope by adding at least a basifier (it is preferably selected from following each material: oxyhydroxide, carbonate, phosphoric acid salt and/or borate).Corresponding alkali metal salt is preferably, for example yellow soda ash, sodium hydroxide, salt of wormwood, potassium hydroxide and/or Sodium Tetraborate.Advantageously add this basifier with aqueous solution form; For example as sodium hydroxide or potassium hydroxide aqueous solution.
The preferably mol ratio of formula (II) isolate and formula (III) isolate is in 5: 1 to 1: 2 scope, more preferably in 3: 1 to 1: 1 scope, even more preferably in 2.0: 1.0 to 1.0: 1.0 scope.
Compound (II) is about 0 ℃ to 50 ℃ with the preferred range of formula (III) compound reaction, even more preferably in about 5 ℃ to 45 ℃ scopes, most preferably in about 15 ℃ to 40 ℃ scopes.Because this reaction is heat release, may be with this reaction mixture cooling.
According to reaction conditions, usually in 30 minutes to 48 hours, preferred 2 to 24 hours period, carry out this reaction.
But the residual content (as HPLC) of through type (III) compound detects the terminal point of this reaction.
By the known method of those of ordinary skill in the art, can be with formula (I) compound by separating in this reaction mixture.For example if this is reflected under the condition of phase transition that comprises water and organic phase and carries out, then with organic solvent or ORGANIC SOLVENT MIXTURES with this aqueous phase separation and extraction; Merge the organic phase water or the aqueous solution, preferably with the acidic aqueous solution washing, and finally drying is also removed this solvent through evaporating under decompression and/or intensification condition, thereby obtains this formula (I) compound.
In following reactions steps, according to reaction process VIb, with formula (I) compound (wherein one or more substituent R according to third aspect present invention
6, R
7a, R
7b, R
7cBe not hydrogen) deprotection, with the final product of production (IH).
Flow process VIb:
Preferably use the crude product or the reaction mixture of last reactions steps to carry out this reactions steps.Can use in addition formula (I) through separating or randomly purified product.
The proper method of deprotection is known by those of ordinary skill in the art.For example can be in aqueous solvent (for example water, isopropanol, acetic acid/water, tetrahydrofuran (THF)/water or two alkane/water), in the presence of for example trifluoroacetic acid, spirit of salt or vitriolic are sour, with acyl group blocking group hydrolytic rupture.
The preferred alcoholate that uses especially is C
1-4-alcoholate (for example the uncle's fourth potassium oxide in sodium ethylate or the ethanol wherein is preferably anhydrous) is with the cracking of acyl group blocking group.Suitable solvent is an alcohol, as methyl alcohol, ethanol or n-propyl alcohol.Because this deprotection preferably carries out as transesterification reaction, therefore advantageously only need the alcoholate of catalytic amount, be preferably with respect to about 0.1 to the 50 mole of % of formula (I) isolate, even more preferably about 1 to 20 mole of %.Suitable temperature be 0 ℃ between this reaction mixture boiling point, preferably between 5 to 40 ℃.This reaction was finished in 1 to 48 hour usually.After this reaction is finished,,, and can under decompression and/or intensification condition, pass through distillation with removal of solvents preferably with this reaction mixture neutralization or acidifying slightly for example by using acetate.Obtain the product of this formula (IH) with arborescens solid form.
By those of ordinary skill in the art know and document described in method, can obtain the glucose-derivative (wherein X represents chlorine atom or bromine atoms) of formula (II).According to reaction process VII, preferably by will in solvent or solvent mixture, reacting the glucose-derivative of acquisition formula (II) through formula (the II ') glucose-derivative and the HBr of protection:
Flow process VII:
In the compound of formula (II) and formula (I), this suitable substituents R
6, R
7a, R
7b, R
7cAnd R
7dBe preferably and be independently from each other (C
1-4-alkyl) carbonyl.Even this suitable substituents R
6, R
7a, R
7b, R
7cAnd R
7d, especially be the group of methyl carbonyl more preferably for having the methyl of being selected from carbonyl and ethyl carbonyl independently of one another.
This substituent X is preferably represented bromine.
This reactions steps is preferably carried out in solvent or solvent mixture.Suitable solvent is preferably aliphatic hydrocrbon, halogenated aliphatic hydrocarbon, aromatic hydrocarbon and composition thereof.The example of suitable solvent is pentane, hexane, methylene dichloride, 1,2-ethylene dichloride, benzene,toluene,xylene and composition thereof.Preferred solvent is methylene dichloride, benzene,toluene,xylene or its mixture, especially is methylene dichloride or toluene.
According to the preferred embodiment of this reactions steps, with the initial substance dissolving of this formula (II ') or be suspended in solvent or the solvent mixture, and add HX or HX solution.If HX is HBr, then preferred solution is the HBr in the acetate, for example the 30%HBr solution in the acetate.Appropriate H X amount waits mole or molar excess approximately for the glucose through protection with respect to formula (II ').The preferably mol ratio of this HX and formula (II ') glucose-derivative is in about 1: 1 to 10: 1 scope, even more preferably in 2: 1 to 6: 1 scope.
In order to remove all water in this reaction mixture, the water-content in the HX water absorbability solution for example, advantageously add can be chemically in conjunction with or remove the compound of water, as diacetyl oxide.
Preferably 0 ℃ to 40 ℃, most preferably carry out this reaction under the temperature in 10 ℃ to 30 ℃ scopes.Usually this is reflected in period of 10 minutes to 12 hours and finishes.
By the method for knowing in the present technique, can be with this formula (II) product by separating in this reaction mixture.For example if solvent or solvent mixture are not miscible or only slightly miscible with water, then used water and/or saturated nacl aqueous solution wash this reaction mixture; Especially the organic phase by using alkaline aqueous solution (as saturated sodium bicarbonate aqueous solution) washing to merge can neutralize any excess acid; And final evaporating solvent in a vacuum.Can this product be separated and purifying by crystallization, preferably by using suitable solvent, as this product being dissolved in the t-butyl methyl ether and adding methylcyclohexane subsequently.
In addition, use favourable in advance neutral formula (II) crude product, carry out following reactions steps according to flow process VIa.For example the use alkaline solution washs this reaction mixture, and should be through neutral organic phase drying.
With corresponding another embodiment of sixth aspect present invention in, according to reaction process VIII, can be by pyrazole derivatives and alkylating agent R with formula (XI)
1-X ' (R wherein
1Define as mentioned and X ' expression chlorine, bromine, iodine or C
1-3-alkyl-SO
2-O-) under being present in situation in solvent or the solvent mixture, alkali reacts, and the intermediate of production (XI ') also makes the R of 3-position on the pyrazoles ring subsequently
1The cracking of-O-group, especially under there is situation in acid, the aglycon of production (III), thereby the pyrazole derivatives of acquisition formula (III):
Flow process VIII:
In flow process VIII chemical formula, substituent R
1To R
5Define as mentioned.R
1Preferred expression methyl, ethyl, n-propyl, sec.-propyl, cyclobutyl or cyclopentyl; Be most preferably sec.-propyl or cyclobutyl.
Radicals X ' be preferably bromine.
Pyrazole derivatives and alkylating agent R with this formula (XI)
1-X ' exists under the situation at alkali (being preferably highly basic) and reacts.Suitable highly basic is selected from following each material: alkali metal hydroxide, alcoholate, hydride.Preferred alkaline example is sodium hydroxide and potassium hydroxide.
Because the O atom of this pyrazole group also by partially alkylated at least, therefore advantageously uses the alkylating agent of molar excess.Alkylating agent compared to the preferred molar ratio of formula (XI) isolate greater than about 2: 1, even more preferably in 2: 1 to 8: 1 scope, for example in 3: 1 to 5: 1 scope.
The alkali molar weight of favourable use and this alkylation dosage are roughly the same.Therefore advantageously adopt the alkali of molar excess.This alkali compared to the preferred molar ratio of formula (XI) isolate greater than about 2: 1, even more preferably in 2: 1 to 8: 1 scope, for example in 3: 1 to 5: 1 scope.
According to above alkylation step, with the isolate of formula (XI) and highly basic dissolving or be suspended in suitable solvent or the solvent mixture.Suitable solvent is polar solvent or its mixture, considers initial substance (XI), alkylating agent R
1-X ' and alkali, this solvent or solvent mixture have enough solubility properties.Suitable solvent is selected from following each material: aliphatic ether, cyclic ethers, amide type solvent and composition thereof.The example of preferred solvent is NMP, DMF, DMA and composition thereof.
Subsequently, immediately or advantageously in for some time (for example in 5 minutes to 4 hours period), preferably alkylating agent or its solution are added in this reaction mixture.Preferably-20 ℃ to 50 ℃ even more preferably-10 ℃ to 40 ℃, most preferably carry out this reaction under the temperature in 5 ℃ to 35 ℃ scopes.For example can detect the terminal point of this reaction through thin layer chromatography or HPLC.According to reaction conditions, usually in 30 minutes to 48 hours, preferred 2 to 24 hours period, carry out this reaction.
By the known method of those of ordinary skill in the art, can obtain the product of formula (XI ') by this reaction mixture.Usually needn't carry out further purifying.Especially, if reaction generates any by product, for example in the 2-position of pyrazoles ring by alkylating derivative, then needn't when this reactions steps finishes, remove this by product.According to the example that how to obtain this reaction product, reaction product is poured in the cold water, and added organic solvent, as aliphatic hydrocrbon or aromatic hydrocarbon, for example toluene.The acid of using spissated spirit of salt for example is with this aqueous phase and or acidifying slightly.This organic phase separation is also randomly extracted this water with organic solvent once more.The organic phase that used water and/or saturated sodium-chloride water solution washing merge also is dried.Preferably can be in a vacuum and/or elevated temperature remove this organic solvent down and the product of acquisition formula (XI ').
For the aglycon of acquisition formula (III), must make the substituent R on the pyrazoles ring 3-position of formula (XI ')
1-O-cracking.Preferably for example have the acid added as the aqueous solution, more preferably for strong acid (as HCl, HBr, HI, H
2SO
4Or alkylsulphonic acid, as methylsulfonic acid) exist under the situation, finish this cracking.
Advantageously use the acid of molar excess.This acid compared to the preferred molar ratio of formula (XI ') isolate greater than about 2: 1, even more preferably in 2: 1 to 40: 1 scope, for example in 4: 1 to 20: 1 scope.
With formula (XI ') isolate and acid dissolving or be suspended in suitable solvent or the solvent mixture.Suitable solvent is for example water, alcohol, carboxylic acid and composition thereof; Especially water, ethanol, acetate.Preferred acid is used with the form of the aqueous solution, alcohol or its mixture; In the case, this acidic solution can be used as solvent, adds or do not add solvent to reduce.
Preferably 40 ℃ to 180 ℃ even more preferably 60 ℃ to 160 ℃, most preferably carry out this reaction under the temperature in 80 ℃ to 160 ℃ scopes.Preferably in closed reactor or autoclave, carry out this reaction.
For example can detect the terminal point of this reaction through thin layer chromatography or HPLC.According to reaction conditions, this reaction usually 15 minutes to 24 hours, preferably carry out in period of 1 to 12 hour.
Can obtain this product from this reaction mixture through crystallization.Preferred type and the consumption of selecting this solvent is so that dissolve this reactant under this temperature of reaction.After with this reaction mixture cooling, this product can precipitate with the beginning crystallization by additive method, for example can use crystal seed and/or add anti-solvent.For example can reach after filtration for example alcohol suitable solvent (as Virahol) in the washing, with this crystal separation, and after randomly the drying.
According to seventh aspect present invention, available following method obtains the pyrazole derivatives of formula (XI)
(i) in the presence of acid or secondary amine, the benzaldehyde derivative of formula V and the 'beta '-ketoester derivatives reaction of formula (XII) are also carried out catalytic hydrogenation subsequently or simultaneously; And
(ii) product and the hydrazine with step (i) reacts in solvent or solvent mixture:
Flow process IX:
This radicals R
CExpression methyl, ethyl, n-propyl or sec.-propyl; Be preferably methyl or ethyl.
This radicals R
2Preferred expression methyl, ethyl, n-propyl or sec.-propyl; Be most preferably methyl.
The preferred compound of formula XII is a methyl acetoacetate.
In first reactions steps, exist under the situation in acid or secondary amine, the benzaldehyde derivative of formula V and the 'beta '-ketoester derivatives reaction of formula (XII) according to above flow process.
Carry out this reactions steps under the Knoevenagel reaction conditions known to one skilled in the relevant art suitably.
The mol ratio of the 'beta '-ketoester of the phenyl aldehyde of formula V and formula (XII) is preferably in about 2: 1 to 1: 2 scope, more preferably in about 1.3: 1 to 1: 1.3 scope, especially for waiting mole.
Suitable acid is carboxylic acid and composition thereof, as acetate.
The mol ratio of the benzaldehyde derivative of this acid and formula V preferably about 2: 1 to about 0.8: 1 scope, more preferably at about 1.5: 1 to about 1: 1 scope.Most preferably adopt the acid and the benzaldehyde derivative of about equimolar amount.
Suitable secondary amine is two-(C
1-4-alkyl) amine has the saturated of at least one parahelium group or unsaturation heterogeneous ring compound, for example dimethylamine, thyl methyl amine, diethylamine, Diisopropylamine, tetramethyleneimine, piperidines, piperazine, morpholine, N-(C
1-3-alkyl)-piperazine and composition thereof.Preferred amines is piperidines and tetramethyleneimine.
The mol ratio of the benzaldehyde derivative of this secondary amine and formula V preferably about 0.05: 1 to about 1: 1 scope, more preferably about 0.1: 1 to about 0.7: 1 scope, most preferably at about 0.15: 1 to about 0.5: 1 scope.
Can not have other solvent or in solvent or solvent mixture, carry out this reaction.Suitable solvent is aromatic solvent, ether, alkane, naphthenic hydrocarbon, alcohol or its mixture.According to preferred embodiment, do not use other solvent.
According to the preferred embodiment of this reactions steps, the benzaldehyde derivative of formula V, the 'beta '-ketoester derivative and the acid of formula (XII) are mixed; Randomly use one or more solvents.Secondary amine is added in this reaction mixture, thereby cools off this reaction mixture as required.
Preferably at-10 ℃ to 80 ℃, more preferably 0 ℃ to 60 ℃ even more preferably carry out this reaction under the temperature in 10 ℃ to 40 ℃ scopes.
In order to finish this reaction, need 30 minutes to 48 hours usually, especially 2 to 24 hours period.
The intermediate of formula (XII ') can be separated and uses as required the method purifying of knowing in the present technique.
In following reactions steps, with the intermediate catalytic hydrogenation of formula (XII ').The preferred primary product (for example using the reaction mixture of previous reactions steps) of previous reactions steps that uses carries out this hydrogenation.This catalytic hydrogenation can be carried out after first reactions steps is finished, or carries out simultaneously with first reactions steps, promptly when still imperfect tense according to the reaction of first reactions steps, during the hydrogenation according to the reaction of first reactions steps still when taking place.
Relate to this catalytic hydrogenation step, can adopt to be described as suitable or preferably those solvents or its mixture according to previous synthesis step.Generally speaking, suitable solvent is aliphatic hydrocrbon, aromatic hydrocarbon, alcohol, aliphatic ether, cyclic ethers and composition thereof.The example of suitable solvent is pentane, hexane, benzene, toluene, methyl alcohol, ethanol, Virahol, n-propyl alcohol, ether, tetrahydrofuran (THF), tetrahydropyrans and composition thereof.Preferred solvent is methyl alcohol, ethanol, Virahol, n-propyl alcohol, tetrahydrofuran (THF) and composition thereof.If formerly do not use other solvent in the reactions steps, then before carrying out this catalytic hydrogenation, preferably add one or more solvent.
Preferably,, or under the situation of nickel-base catalyst (for example fine dispersion nickel is as Raney nickel) existence, carry out this catalytic hydrogenation as palladium catalyst (for example fine dispersion palladium or palladium-carbon) at transition-metal catalyst.The appropriate amount of catalyzer can change according to reaction conditions, and for example is in respect to formula V isolate or formula (XII ') intermediate about 0.1 to about 50 weight %, preferably about 1 scope to about 10 weight %.
Therefore the ending of synthesis step formerly or (if this hydrogenation will be carried out together with first reactions steps) be formerly during the synthesis step or beginning, with proper catalyst and randomly other solvent or solvent mixture are added in this reaction mixture.Perhaps should separated formula (XII ') intermediate be dissolved in solvent or the solvent mixture, and catalyzer be added into wherein.
This hydrogenization-10 to 150 ℃, preferred 20 to 100 ℃, more preferably 20 to 80 ℃, most preferably under the temperature in 40 to 70 ℃ of scopes, advantageously carry out.Suitable hydrogen pressure approximates usually or is higher than standard atmospheric pressure, preferably at about 1 to 20 crust even more preferably in the scopes of 2 to 8 crust.During hydrogenation, preferably stir or stirred reaction mixture.Can optimize by experiment and finish the necessary period of this hydrogenation.Usually about 30 minutes to about 24 hours, preferably carry out this hydrogenation in about 1 to 12 hour period.After hydrogenation, preference is removed this catalyzer as filtering from this reaction mixture.
The hydrogenated products of formula (XII ') can be separated, and use the method purifying of knowing in the present technique as required.
In following end reaction step, with this formula (XII ') intermediate and hydrazine reaction product with production (XI).Preferably use primary product (for example using the reaction mixture of previous reactions steps); Preferably after from this reaction mixture, removing this catalyzer, carry out this reactions steps.Perhaps use the separated product of formula (XII ').
The suitable solvent of this reactions steps or solvent mixture are the mixture of alcohol, aliphatic ether, cyclic ethers, its mixture and one or more this solvent and water.The example of suitable solvent is the solution of methyl alcohol, ethanol, Virahol, n-propyl alcohol, ether, t-butyl methyl ether, tetrahydrofuran (THF), tetrahydropyrans, its mixture or one or more this solvent and water.Preferred solvent is an employed solvent in the previous reaction, especially is Virahol.If adopt the reaction mixture of previous reactions steps, promptly non-formula (XII ") through separated product, then can not need other solvent.
Advantageously hydrazine is used as the solution in the water, for example as single hydrazine hydrate; Or the solution in the alcohol, for example methyl alcohol, ethanol, Virahol, its mixture or one or more should alcohol and the mixture of water.
Formula (XII ") intermediate or with respect to the preferred molar ratio of formula V isolate and hydrazine in 1: 1 to 1: 2 scope, more preferably in 1.0: 1.0 to 1.0: 1.5 scope, even more preferably in 1.0: 1.0 to 1.0: 1.2 scope.
Therefore the ending of synthesis step formerly is added into this reaction mixture with an amount of hydrazine and optional additional solvent or solvent mixture.Perhaps, should separated formula (XII ") intermediate be dissolved in this solvent or the solvent mixture, and hydrazine be added into wherein.
Because exothermic reaction, preferably continuously or in batches, finish the interpolation of hydrazine in for some time (for example 30 minutes to 24 hours).Can be if need with this reaction mixture cooling.Preferably at 0 ℃ to 140 ℃, more preferably 20 ℃ to 110 ℃ even more preferably carry out this reaction under the temperature in 40 ℃ to 90 ℃ scopes.(for example in 15 ℃ to 40 ℃ scopes) finish this reaction through the other time period (for example 1 to 24 hour) advantageously at a lower temperature.
Through from liquid phase separation (as filtering), from this reaction mixture or suspension, advantageously obtain as solid or sedimentary formula (XI) final product.For example by beginning to wash in the described suitable solvent in for example this reactions steps, can be with this solid purifying.Perhaps by for example in a vacuum and/or under the elevated temperature this solvent of evaporative removal obtain this product.In addition can be through this final product of crystallization purifying.
Except that the reaction that comprises hydrogenization, institute according to the present invention responds preferably all to depress at standard atmosphere and carries out.Because these reaction pair air pressure and insensitive, so it carries out under can or boosting in slightly reduced pressure.
Preferably in the inert atmosphere of for example nitrogen or argon gas, carry out according to of the present invention responding in addition.
The compound of preferred formula VI is selected from formula VI.1 and formula VI.2
It comprises tautomer and composition thereof.
The present invention also relates to the compound of formula (IV)
R wherein
1To R
5And Q defines in as mentioned.
R
1Preferred expression methyl, ethyl, n-propyl, sec.-propyl, cyclobutyl or cyclopentyl; Be most preferably sec.-propyl or cyclobutyl.
R
2Preferred expression methyl, ethyl, n-propyl or sec.-propyl; Be most preferably methyl.
R
3Preferred expression fluorine, chlorine, methyl, methoxyl group, oxyethyl group, positive propoxy or isopropoxy; Be most preferably methyl, methoxyl group, oxyethyl group or isopropoxy.
R
4Preferred expression fluorine, chlorine, methyl, methoxyl group, oxyethyl group, positive propoxy or isopropoxy; Be most preferably fluorine.R in addition
4Be preferably 2-position on the phenyl ring, promptly with respect to R
3Between the position substituting group.
R
5Preferred expression hydrogen, fluorine, chlorine, methyl or methoxy; Be most preferably hydrogen or fluorine.
This group Q preferably represent methoxyl group, oxyethyl group, positive propoxy, isopropoxy ,-NR
aR
b, R wherein
a, R
bRepresent methyl, ethyl, n-propyl or sec.-propyl independently of one another, or-NR
aR
bExpression pyrrolidyl, piperidyl, morpholinyl, piperazinyl or N-C
1-3-alkyl-piperazinyl.Even Q more preferably represents methoxyl group, oxyethyl group, positive propoxy, isopropoxy, pyrrolidyl, piperidyl, morpholinyl, piperazinyl or N-C
1-3-alkyl-piperazinyl; Be most preferably oxyethyl group, pyrrolidyl, piperidyl or morpholinyl.
Therefore according to the present invention, as the formula (IV.1) listed in the following table to the compound of formula (IV.11) for preferred:
Wherein Q as above hereinafter defines.
Particularly, formula (IV.1) is preferred to those compounds of formula (IV.11), and wherein Q is selected from methoxyl group, oxyethyl group, isopropoxy, pyrrolidyl, piperidyl, morpholinyl or methyl ketonic oxygen base.With following formula (IV.1) to the compound of formula (IV.11), be most preferably Q and represent oxyethyl group.
According to the present invention, the formula of listing in the following table (III.1) to the compound of formula (IIII.11) is preferred in addition:
In addition such as experiment part description, the compound of formula (I.1), (I.2), (I.3), (I.4), (I.5), (I.6), (I.7), (I.8), (I.9), (I.10), (I.11) that comprises tautomer, steric isomer, its mixture and salt thereof is for preferably.
Formula (I) compound that comprises its prodrug and pharmacologically acceptable salt, especially formula (IH) compound demonstrates the activity of draining inducer as glucose in urine, and therefore is used to make the medicine of treatment diabetes.
In context, the H atom of hydroxyl is not all clearly to show in all structural formulas.The purpose of following examples is to illustrate the present invention, but not limits it.If pressure represents with unit " crust ", then can use 1 crust=0.1MPa and analog value is converted to International System of Units.If pressure then can use 1psi=6894.757Pa and analog value is converted to International System of Units with unit " psi " expression.Abbreviation below in context, using:
The DMA N,N-DIMETHYLACETAMIDE
The DMF dimethyl formamide
NMP N-N-methyl-2-2-pyrrolidone N-,
The THF tetrahydrofuran (THF)
Experimental procedure:
Embodiment 1:1,2-dihydro-1-(1-methylethyl)-5-methyl-3H-pyrazoles-3-ketone (
VI.1) preparation synthetic
Embodiment 1.1:
5-methyl-3-pyrazolidone mono-hydrochloric salts (
VIII.1) preparation
With (500 milliliters of ethyl crotonates; 3.94 mole) be dissolved in the Virahol (1.85 liters), and be heated to 50 ℃.In 30 minutes, add (215 milliliters of hydrazine hydrates; 4.34 mole), and with this reaction mixture reflux 2 hours.Under reduced pressure solvent is distilled (about 1 liter) subsequently.Add Virahol (400 milliliters) subsequently, and this reaction mixture is cooled to 22 ℃.(375 milliliters of spirit of salt 11.7N in the interpolation ethanol; 3.94 mole), and with this reaction mixture stirred 15 hours down at about 20 to 25 ℃.Subsequently this reaction mixture is cooled to 0 ℃, filters and with this product of washed with isopropyl alcohol (3 times, each 200 milliliters); Under 45 ℃, be dried to constant weight subsequently to generate clear crystal.Mass spectrum reaches
1H-NMR spectrum is consistent with specified structure.
Mass spectrum (ESI
+): m/z=101[M+H]
+
Embodiment 1.2:
1-(1-methylethyl)-5-methyl-3-pyrazolidone mono-hydrochloric salts (
VII.1a) preparation
With 5-methyl-3-pyrazolidone mono-hydrochloric salts (692 grams; 5.07 mole) be suspended in the Virahol (4.9 liters).Add (270 milliliters of 50% aqueous sodium hydroxide solutions; 5.07 mole) and palladium (10 weight %)-carbon (70 gram) and (744 milliliters in acetone; 10 moles).Subsequently at nitrogen atmosphere, 50 ℃, 3 crust (42psi) down with this mixture hydrogenation, absorb until hydrogen and to stop.This reaction mixture is filtered, and under reduced pressure distill solvent.Handle resistates twice with 1 liter of Virahol, under reduced pressure distill Virahol subsequently.Be dissolved in the Virahol (3.5 liters) this residuum and filtration.With (482 milliliters of the spirit of salt 10.5N in the ethanol; 5.06 mole) be added in this filtrate, it precipitates and separation after filtration the hydrogen chlorate.It is used twice of washed with isopropyl alcohol (2 * 500 milliliters), and dry down at 45 ℃ to generate product as clear crystal.
Mass spectrum reaches
1H-NMR spectrum is consistent with specified structure.
Mass spectrum (ESI
+): m/z=143[M+H]
+
Embodiment 1.3:
1-(1-methylethyl)-5-methyl-3-pyrazolidone (
VII.1) preparation
Handle 1-(1-methylethyl)-5-methyl-3-pyrazolidone mono-hydrochloric salts (150 grams with unsaturated carbonate aqueous solutions of potassium (1.2 liters) and ethyl acetate (1.0 liters); 0.84 mole).Filter this mixture and separate phase.With this organic phase of anhydrous sodium sulfate drying, filter and evaporation in a vacuum, to generate as solid 1-(1-methylethyl)-5-methyl-3-pyrazolidone.
Mass spectrum reaches
1H-NMR spectrum is consistent with specified structure.
Mass spectrum (ESI
+): m/z=143[M+H]
+
Embodiment 1.4:
1,2-dihydro-1-(1-methylethyl)-5-methyl-3H-pyrazoles-3-ketone (
VI.1) preparation
Variant 1:
Warm down with 1-(1-methylethyl)-5-methyl-3-pyrazolidone (390 grams; 2.74 mole) be dissolved in the acetate (170 milliliters).Add (260 milliliters of 35% aqueous hydrogen peroxide solutions in about 65 ℃ 3 hours keeping temperature; 3.0 mole).Subsequently this reaction mixture was stirred 15 hours down at 20 to 25 ℃.Add water (1.2 liters) subsequently, and the pH of this mixture is adjusted to about 7 by adding about 1 liter of 50 weight % aqueous sodium hydroxide solution.Be cooled to 5 ℃ of these reaction mixtures of after-filtration.Wash this product with water and drying under about 50 ℃.Obtain clear crystal.
Variant 2:
1-(1-the methylethyl)-5-methyl-3-pyrazolidone mono-hydrochloric salts (VII.1a) of 50 grams (279.86 mmole) is added into the solution that 77 in 150 ml waters restrain salt of wormwood, adds 250 milliliters of isopropyl acetates subsequently.With this mixture heating up to 50 ℃, stirred simultaneously 5 minutes.Thereafter water phase separated.In a vacuum 175 milliliters of solvents are distilled from this organic phase.Filter surplus solution and wash this filter with 50 milliliters of isopropyl acetates.Concentrate the organic phase of merging in a vacuum to becoming oil.50 milliliters of acetate are added into the latter, and this mixture is cooled to about 3 ℃.Add 66.9 gram peracetic acid and 12.5 milliliters of acetate.With this mixture 3 ℃ of following stir abouts 1 hour.Add 325 ml waters subsequently, and the pH of this solution is adjusted to about 6.6 to 7.0 by adding 50% aqueous sodium hydroxide solution.Gained suspension was stirred 30 minutes down at 10 ℃, filter afterwards.Wash this product and dry down with water at 45 ℃.
Mass spectrum reaches
1H-NMR spectrum is consistent with specified structure.
Mass spectrum (ESI
+): m/z=141[M+H]
+
Embodiment 2:
1,2-dihydro-1-cyclobutyl-5-methyl-3H-pyrazoles-3-ketone (
VI.2) synthetic
Among the embodiment 1.1 intermediate has been described
VIII.1Synthetic.By use embodiment 1.2 (wherein adopt an amount of cyclobutanone (
IX.2) replacement acetone), can obtain intermediate
VII.2aBy using with similar approach as the step described in embodiment 1.3 and 1.4, can be from this intermediate
VII.2aBegin to obtain compound
VII.2And
VI.2
Embodiment 3a:
1,2-dihydro-1-(1-methylethyl)-4-[(2-fluoro-4-p-methoxy-phenyl)-(1-tetramethyleneimine) methyl]-5-methyl-3H-pyrazoles-3-ketone (
IV.1a) synthetic
The solution that in 280 milliliters of acetonitriles 77 is restrained the 2-fluoro-4-methoxybenzaldehyde of (0.50 mole) is added into 70 gram (0.50 moles) 1, in the mixture of 2-dihydro-1-(1-methylethyl)-5-methyl-3H-pyrazoles-3-ketone and 350 milliliters of acetonitriles.Under 20 ℃, acetate 6 grams and tetramethyleneimine 53.3 grams (0.75 mole) are added into this reaction mixture successively with 70 milliliters of acetonitriles.This reaction mixture is heated to 75 ℃ continues 1 hour, be cooled to 3 ℃ afterwards.To separate this product afterwards after filtration through refrigerative reaction mixture restir 30 minutes.140 milliliters of cold acetonitriles of each use, with its washed twice, dry in 40 ℃ of following inert atmospheres subsequently.
Embodiment 3b:
1,2-dihydro-1-(1-methylethyl)-4-[(2-fluoro-4-p-methoxy-phenyl)-(oxyethyl group) methyl]-5-methyl-3H-pyrazoles-3-ketone (
IV.1b) synthetic
Variant 1:
With (21 milliliters of tetramethyleneimine; 0.257 mole) and (22 milliliters of acetate; 0.385 mole) be added into 1 in the ethanol (2.7 liters), 2-dihydro-1-(1-methylethyl)-5-methyl-3H-pyrazoles-3-ketone (180 grams; 1.28 mole) with 2-fluoro-4-methoxybenzaldehyde (198 grams; 1.28 in mixture mole).This suspension is heated to about 50 ℃ continues about 67 hours.Subsequently this reaction mixture is cooled to about 17 ℃ and filtration.Wash this product and use THF (2.5 liters) to reflux subsequently with diisopropyl ether (500 milliliters).Filter bed through diatomite and charcoal filters the solution that is obtained.Concentrate this filtrate in a vacuum and water (2 liters) is added into this in cooling and filtering suspension.At 50 ℃ of down dry these clear crystals.
Variant 2:
2-fluoro-4-methoxybenzaldehyde in 20 milliliters of ethanol 7.7 grams (50 mmole) are added into 1 in 50 milliliters of ethanol, in the suspension of 2-dihydro-1-(1-methylethyl)-5-methyl-3H-pyrazoles-3-ketone 7 grams (50 mmole).Add acetate 0.6 gram (10 mmole), add tetramethyleneimine 5.33 grams (75 mmole) subsequently.Subsequently this reaction mixture is heated to 70 ℃ and continues 1 to 2 hour, afterwards it is cooled to about 20 ℃.Add 30% spirit of salt (65 mmole) aqueous solution subsequently, and this reaction mixture is heated to 50 ℃ continues 3 hours.Add water subsequently also with this mixture cooling.This product is filtered and wash with 50% aqueous ethanolic solution.Under 45 ℃ of atmosphere of inert gases, be dried.
Variant 3:
The 30% spirit of salt aqueous solution is added into 50 gram (0.144 moles) 1,2-dihydro-1-(1-methylethyl)-4-[(2-fluoro-4-p-methoxy-phenyl)-(1-tetramethyleneimine) methyl]-5-methyl-3H-pyrazoles-3-ketone and 500 milliliters of alcoholic acid mixtures in.This reaction mixture is heated to 50 ℃ continues 2 to 3 hours.Add 175 ml waters subsequently and with its cooling.Separated product after filtration, and use washing with alcohol.Under 45 ℃ of atmosphere of inert gases, be dried.
Mass spectrum reaches
1H-NMR spectrum is consistent with specified structure.
Mass spectrum (ESI
+): m/z=323[M+H]
+
Embodiment 4:
1,2-dihydro-1-(1-methylethyl)-4-[(2,3-two fluoro-4-p-methoxy-phenyls)-(oxyethyl group) methyl]-5-methyl-3H-pyrazoles-3-ketone (
IV.2) synthetic
Use as the step described in the embodiment 3b with similar approach, can obtain the intermediate of this formula IV.2.
Embodiment 5:
1,2-dihydro-1-(1-methylethyl)-4-[(2,6-two fluoro-4-p-methoxy-phenyls)-(oxyethyl group) methyl]-5-methyl-3H-pyrazoles-3-ketone (
IV.3) synthetic
Use as the step described in the embodiment 3b with similar approach, can obtain the intermediate of this formula IV.3.
Embodiment 6:
1,2-dihydro-1-cyclobutyl-4-[(3-fluoro-4-p-methoxy-phenyl)-(oxyethyl group) methyl]-5-methyl-3H-pyrazoles-3-ketone (
IV.4) synthetic
Use as the step described in the embodiment 3b with similar approach, can obtain the intermediate of this formula IV.4.
Embodiment 7:
1,2-dihydro-1-cyclobutyl-4-[(2-fluoro-4-p-methoxy-phenyl)-(oxyethyl group) methyl]-5-methyl-3H-pyrazoles-3-ketone (
IV.5) synthetic
Use as the step described in the embodiment 3b with similar approach, can obtain the intermediate of this formula IV.5.
Embodiment 8:
1,2-dihydro-1-(1-methylethyl)-4-[(2,3-two fluoro-4-aminomethyl phenyls)-(oxyethyl group) methyl]-5-methyl-3H-pyrazoles-3-ketone (
IV.6) synthetic
Use as the step described in the embodiment 3b with similar approach, can obtain the intermediate of this formula IV.6.
Embodiment 9:
1,2-dihydro-1-(1-methylethyl)-4-[(2-fluoro-4-aminomethyl phenyl)-(oxyethyl group) methyl]-5-methyl-3H-pyrazoles-3-ketone (
IV.7) synthetic
Use as the step described in the embodiment 3b with similar approach, can obtain the intermediate of this formula IV.7.
Embodiment 10:
1,2-dihydro-1-(1-methylethyl)-4-[(3-fluoro-4-ethoxyl phenenyl)-(oxyethyl group) methyl]-5-methyl-3H-pyrazoles-3-ketone (
IV.8) synthetic
Use as the step described in the embodiment 3b with similar approach, can obtain the intermediate of this formula IV.8.
Embodiment 11:
1,2-dihydro-1-(1-methylethyl)-4-[(3-fluoro-4-(1-methyl ethoxy) phenyl)-(oxyethyl group) methyl]-5-methyl-3H-pyrazoles-3-ketone (
IV.9) synthetic
Use as the step described in the embodiment 3b with similar approach, can obtain the intermediate of this formula IV.9.
Embodiment 12:
1,2-dihydro-1-(1-methylethyl)-4-[(2-fluoro-4-(1-methyl ethoxy) phenyl)-(oxyethyl group) methyl]-5-methyl-3H-pyrazoles-3-ketone (
IV.10) synthetic
Use as the step described in the embodiment 3b with similar approach, can obtain the intermediate of this formula IV.10.
Embodiment 13:
1,2-dihydro-1-(1-methylethyl)-4-[(2-fluoro-4-ethoxyl phenenyl)-(oxyethyl group) methyl]-5-methyl-3H-pyrazoles-3-ketone (
IV.11) synthetic
Use as the step described in the embodiment 3b with similar approach, can obtain the intermediate of this formula IV.11.
Embodiment 14:
1,2-dihydro-1-(1-methylethyl)-4-[(2-fluoro-4-p-methoxy-phenyl) methyl]-5-methyl-3H-pyrazoles-3-ketone (
III.1) synthetic
Use palladium carbon (10 weight %) (65 gram), under the hydrogen-pressure of 50 ℃ and 3 crust, with 1,2-dihydro-1-(1-methylethyl)-4-[(2-fluoro-4-p-methoxy-phenyl)-(oxyethyl group) methyl]-5-methyl-3H-pyrazoles-3-ketone (294 grams; 1.28 mole), methyl alcohol (4.5 liters), the spirit of salt aqueous solution (30%; 11 grams) and the mixture hydrogenation of water (80 milliliters), absorb until hydrogen and stop.THF (2.3 liters) is added into this reaction mixture, subsequently with its filtration.Wash this catalyzer with THF (1 liter), and under reduced pressure distill this solvent, to about 700 to 800 milliliters residual volume.Pour in the water gained suspension into (1 liter) and stirred.Separate this precipitation after filtration, in 55 ℃ of following waters (400 milliliters) washing, and dry to generate crystal (oldlace).
Mass spectrum reaches
1H-NMR spectrum is consistent with specified structure.
Mass spectrum (ESI
+): m/z=279[M+H]
+
Embodiment 15:
1,2-dihydro-1-(1-methylethyl)-4-[(2,3-two fluoro-4-p-methoxy-phenyls) methyl]-5-methyl-3H-pyrazoles-3-ketone (
III.2) synthetic
Use as the synthesis step described in the embodiment 14 with similar approach, can obtain the compound of this formula III .2.
Embodiment 16:
1,2-dihydro-1-(1-methylethyl)-4-[(2,6-two fluoro-4-p-methoxy-phenyls) methyl]-5-methyl-3H-pyrazoles-3-ketone (
III.3) synthetic
Use as the synthesis step described in the embodiment 14 with similar approach, can obtain the compound of this formula III .3.
Embodiment 17:
1,2-dihydro-1-(1-cyclobutyl)-4-[(3-fluoro-4-aminomethyl phenyl) methyl]-5-methyl-3H-pyrazoles-3-ketone (
III.4) synthetic
Use as the synthesis step described in the embodiment 14 with similar approach, can obtain the compound of this formula III .4.
Embodiment 18:
1,2-dihydro-1-(1-cyclobutyl)-4-[(2-fluoro-4-p-methoxy-phenyl) methyl]-5-methyl-3H-pyrazoles-3-ketone (
III.5) synthetic
Use as the synthesis step described in the embodiment 14 with similar approach, can obtain the compound of this formula III .5.
Embodiment 19:
1,2-dihydro-1-(1-methylethyl)-4-[(2,3-two fluoro-4-aminomethyl phenyls) methyl]-5-methyl-3H-pyrazoles-3-ketone (
III.6) synthetic
Use as the synthesis step described in the embodiment 14 with similar approach, can obtain the compound of this formula III .6.
Embodiment 20:
1,2-dihydro-1-(1-methylethyl)-4-[(2-fluoro-4-aminomethyl phenyl) methyl]-5-methyl-3H-pyrazoles-3-ketone (
III.7) synthetic
Use as the synthesis step described in the embodiment 14 with similar approach, can obtain the compound of this formula III .7.
Embodiment 21:
1,2-dihydro-1-(1-methylethyl)-4-[(3-fluoro-4-ethoxyl phenenyl) methyl]-5-methyl-3H-pyrazoles-3-ketone (
III.8) synthetic
Use as the synthesis step described in the embodiment 14 with similar approach, can obtain the compound of this formula III .8.
Embodiment 22:
1,2-dihydro-1-(1-methylethyl)-4-[(3-fluoro-4-(1-methyl ethoxy) phenyl) methyl]-5-methyl-3H-pyrazoles-3-ketone (
III.9) synthetic
Use as the synthesis step described in the embodiment 14 with similar approach, can obtain the compound of this formula III .9.
Embodiment 23:
1,2-dihydro-1-(1-methylethyl)-4-[(2-fluoro-4-(1-methyl ethoxy) phenyl) methyl]-5-methyl-3H-pyrazoles-3-ketone (
III.10) synthetic
Use as the synthesis step described in the embodiment 14 with similar approach, can obtain the compound of this formula III .10.
Embodiment 24:
1,2-dihydro-1-(1-methylethyl)-4-[(2-fluoro-4-ethoxyl phenenyl) methyl]-5-methyl-3H-pyrazoles-3-ketone (
III.11) synthetic
Use as the synthesis step described in the embodiment 14 with similar approach, can obtain the compound of this formula III .11.
Embodiment 25:
2,3,4,6-four-O-ethanoyl-α-D-glucopyranosyl bromine (
II.1) synthetic
With 1,2,3,4,6-five-O-ethanoyl-β-D-Glucopyranose (100 grams, 0.251 mole) is suspended in the toluene (210 milliliters).Add (9.5 milliliters of diacetyl oxides; 0.1 mole), be added on the Hydrogen bromide 30% in the acetate (200 milliliters, 1 mole) subsequently.This mixture was stirred 30 minutes down at 18 ℃.Under agitation add ice/water mixture (300 milliliters) and salt solution (100 milliliters) subsequently.This is separated, and extracts this water with toluene (100 milliliters).Merge organic phase and use sodium bicarbonate aqueous solution (100 milliliters) and salt solution (100 milliliters) washing.Drying under reduced pressure also evaporates this solvent and obtains oil, makes its crystallization by adding methyl tertiary butyl ether (150 milliliters) and methylcyclohexane (300 milliliters).Separate this product after filtration, with the methylcyclohexane washing, and dry under 45 ℃ of vacuum.
Embodiment 26:
1 '-(1-methylethyl)-4 '-[(2-fluoro-4-p-methoxy-phenyl) methyl]-5 '-methyl isophthalic acid H-pyrazoles-3 '-O-(2,3,4,6-O-is tetra-acetylated)-β-D-glucopyranoside (
I.1) synthetic
With potassium hydroxide aqueous solution (1M; 870 milliliters) be added into (2,3,4,6-is tetra-acetylated)-α-D-glucopyranosyl bromine in the methylene dichloride (780 liters) (485 grams; 1.169 the mole), 1,2-dihydro-1-(1-methylethyl)-4-[(2-fluoro-4-p-methoxy-phenyl) methyl]-5-methyl-3H-pyrazoles-3-ketone (161 the gram; 0.58 mole) and TBAC tetrabutylammonium chloride (9.4 grams; 0.029 in mixture mole).This two-phase mixture 25 to 27 ℃ of following vigorous stirring, is passed through to add in addition potassium hydroxide aqueous solution (4N simultaneously; About 870 milliliters) absorb until alkali and to stop (about 5 hours), make the pH of this water layer keep constant and be about 13.This reaction process can be monitored by HPLC.Subsequently this is separated, and extracts this water with methylene dichloride (800 milliliters).Organic phase drying (Na with this merging
2SO
4), filter and vapourisation under reduced pressure, to generate oil (yellow).This oil need not to be further purified and can use in next reactions steps.
Mass spectrum reaches
1H-NMR spectrum is consistent with specified structure.
Mass spectrum (ESI
+): m/z=609[M+H]
+
Embodiment 27:
1 '-(1-methylethyl)-4 '-[(2,3-two fluoro-4-p-methoxy-phenyls) methyl]-5 '-methyl isophthalic acid H-pyrazoles-3 '-O-(2,3,4,6-O-is tetra-acetylated)-β-D-glucopyranoside (
I.2) synthetic
Use as the synthesis step described in the embodiment 26 with similar approach, can obtain this formula compound I.2.
Embodiment 28:
1 '-(1-methylethyl)-4 '-[(2,6-two fluoro-4-p-methoxy-phenyls) methyl]-5 '-methyl isophthalic acid H-pyrazoles-3 '-O-(2,3,4,6-O-is tetra-acetylated)-β-D-glucopyranoside (
I.3) synthetic
Use as the synthesis step described in the embodiment 26 with similar approach, can obtain this formula compound I.3.
Embodiment 29:
1 '-(1-cyclobutyl)-4 '-[(3-fluoro-4-aminomethyl phenyl) methyl]-5 '-methyl isophthalic acid H-pyrazoles-3 '-O-(2,3,4,6-O-is tetra-acetylated)-β-D-glucopyranoside (
I.4) synthetic
Use as the synthesis step described in the embodiment 26 with similar approach, can obtain this formula compound I.4.
Embodiment 30:
1 '-(1-cyclobutyl)-4 '-[(2-fluoro-4-p-methoxy-phenyl) methyl]-5 '-methyl isophthalic acid H-pyrazoles-3 '-O-(2,3,4,6-O-is tetra-acetylated)-β-D-glucopyranoside (
I.5) synthetic
Use as the synthesis step described in the embodiment 26 with similar approach, can obtain this formula compound I.5.
Embodiment 31:
1 '-(1-methylethyl)-4 '-[(2,3-two fluoro-4-aminomethyl phenyls) methyl]-5 '-methyl isophthalic acid H-pyrazoles-3 '-O-(2,3,4,6-O-is tetra-acetylated)-β-D-glucopyranoside (
I.6) synthetic
Use as the synthesis step described in the embodiment 26 with similar approach, can obtain this formula compound I.6.
Embodiment 32:
1 '-(1-methylethyl)-4 '-[(2-fluoro-4-aminomethyl phenyl) methyl]-5 '-methyl isophthalic acid H-pyrazoles-3 '-O-(2,3,4,6-O-is tetra-acetylated)-β-D-glucopyranoside (
I.7) synthetic
Use as the synthesis step described in the embodiment 26 with similar approach, can obtain this formula compound I.7.
Embodiment 33:
1 '-(1-methylethyl)-4 '-[(3-fluoro-4-ethoxyl phenenyl) methyl]-5 '-methyl isophthalic acid H-pyrazoles-3 '-O-(2,3,4,6-O-is tetra-acetylated)-β-D-glucopyranoside (
I.8) synthetic
Use as the synthesis step described in the embodiment 26 with similar approach, can obtain this formula compound I.8.
Embodiment 34:
1 '-(1-methylethyl)-4 '-[(3-fluoro-4-(1-methyl ethoxy) phenyl) methyl]-5 '-methyl isophthalic acid H-pyrazoles-3 '-O-(2,3,4,6-O-is tetra-acetylated)-β-D-glucopyranoside (
I.9) synthetic
Use as the synthesis step described in the embodiment 26 with similar approach, can obtain this formula compound I.9.
Embodiment 35:
1 '-(1-methylethyl)-4 '-[(2-fluoro-4-(1-methyl ethoxy) phenyl) methyl]-5 '-methyl isophthalic acid H-pyrazoles-3 '-O-(2,3,4,6-O-is tetra-acetylated)-β-D-glucopyranoside (
I.10) synthetic
Use as the synthesis step described in the embodiment 26 with similar approach, can obtain this formula compound I.10.
Embodiment 36:
1 '-(1-methylethyl)-4 '-[(2-fluoro-4-ethoxyl phenenyl) methyl]-5 '-methyl isophthalic acid H-pyrazoles-3 '-O-(2,3,4,6-O-is tetra-acetylated)-β-D-glucopyranoside (
I.11) synthetic
Use as the synthesis step described in the embodiment 26 with similar approach, can obtain this formula compound I.11.
Embodiment 37:
1 '-(1-methylethyl)-4 '-[(2-fluoro-4-p-methoxy-phenyl) methyl]-5 '-methyl isophthalic acid H-pyrazoles-3 '-O-β-D-glucopyranoside (
IH.1) synthetic
Will be according to rough 1 '-(1-methylethyl)-4 '-[(2-fluoro-4-p-methoxy-phenyl) methyl]-5 '-methyl isophthalic acid H-pyrazoles-3 '-O-(2,3,4,6-O-is tetra-acetylated)-β-D-glucopyranoside (413 grams of embodiment 26 reactions; About 0.58 mole) be dissolved in the dehydrated alcohol (1 liter).Add potassium tert.-butoxide (6.6 grams subsequently; 0.058 mole), and with this reaction mixture about 20 to 25 ℃ of following stir abouts 15 hours.Add (3.3 milliliters of acetate subsequently; 0.058 mole), and under reduced pressure this solvent is distilled.Subsequently the gained resistates is dissolved in the ethyl acetate (2 liters) and and washs with salt solution (800 milliliters).This organic phase is separated, through Na
2SO
4Drying is under reduced pressure filtered and is evaporated to generate the arborescens solid.
Mass spectrum reaches
1H-NMR spectrum is consistent with specified structure.
Mass spectrum (ESI
+): m/z=44 1[M+H]
+
Embodiment 38:
1 '-(1-methylethyl)-4 '-[(2,3-two fluoro-4-p-methoxy-phenyls) methyl]-5 '-methyl isophthalic acid H-pyrazoles-3 '-O-β-D-glucopyranoside (
IH.2) synthetic
Use as the synthesis step described in the embodiment 37 with similar approach, can obtain the compound of this formula IH.2.
Embodiment 39:
1 '-(1-methylethyl)-4 '-[(2,6-two fluoro-4-p-methoxy-phenyls) methyl]-5 '-methyl isophthalic acid H-pyrazoles-3 '-O-β-D-glucopyranoside (
IH.3) synthetic
Use as the synthesis step described in the embodiment 37 with similar approach, can obtain the compound of this formula IH.3.
Embodiment 40:
1 '-(1-cyclobutyl)-4 '-[(3-fluoro-4-aminomethyl phenyl) methyl]-5 '-methyl isophthalic acid H-pyrazoles-3 '-O-β-D-glucopyranoside (
IH.4) synthetic
Use as the synthesis step described in the embodiment 37 with similar approach, can obtain the compound of this formula IH.4.
Embodiment 41:
1 '-(1-cyclobutyl)-4 '-[(2-fluoro-4-p-methoxy-phenyl) methyl]-5 '-methyl isophthalic acid H-pyrazoles-3 '-O-β-D-glucopyranoside (
IH.5) synthetic
Use as the synthesis step described in the embodiment 37 with similar approach, can obtain the compound of this formula IH.5.
Embodiment 42:
1 '-(1-methylethyl)-4 '-[(2,3-two fluoro-4-aminomethyl phenyls) methyl]-5 '-methyl isophthalic acid H-pyrazoles-3 '-O-β-D-glucopyranoside (
IH.6) synthetic
Use as the synthesis step described in the embodiment 37 with similar approach, can obtain the compound of this formula IH.6.
Embodiment 43:
1 '-(1-methylethyl)-4 '-[(2-fluoro-4-aminomethyl phenyl) methyl]-5 '-methyl isophthalic acid H-pyrazoles-3 '-O-β-D-glucopyranoside (
IH.7) synthetic
Use as the synthesis step described in the embodiment 37 with similar approach, can obtain the compound of this formula IH.7.
Embodiment 44:
1 '-(1-methylethyl)-4 '-[(3-fluoro-4-ethoxyl phenenyl) methyl]-5 '-methyl isophthalic acid H-pyrazoles-3 '-O-β-D-glucopyranoside (
IH.8) synthetic
Use as the synthesis step described in the embodiment 37 with similar approach, can obtain the compound of this formula IH.8.
Embodiment 45:
1 '-(1-methylethyl)-4 '-[(3-fluoro-4-(1-methyl ethoxy) phenyl) methyl]-5 '-methyl isophthalic acid H-pyrazoles-3 '-O-β-D-glucopyranoside (
IH.9) synthetic
Use as the synthesis step described in the embodiment 37 with similar approach, can obtain the compound of this formula IH.9.
Embodiment 46:
1 '-(1-methylethyl)-4 '-[(2-fluoro-4-(1-methyl ethoxy) phenyl) methyl]-5 '-methyl isophthalic acid H-pyrazoles-3 '-O-β-D-glucopyranoside (
IH.10) synthetic
Use as the synthesis step described in the embodiment 37 with similar approach, can obtain the compound of this formula IH.10.
Embodiment 47:
1 '-(1-methylethyl)-4 '-[(2-fluoro-4-ethoxyl phenenyl) methyl]-5 '-methyl isophthalic acid H-pyrazoles-3 '-O-β-D-glucopyranoside (
IH.11) synthetic
Use as the synthesis step described in the embodiment 37 with similar approach, can obtain the compound of this formula IH.11.
The another kind of synthetic embodiment of aglycon
Embodiment 48:
1,2-dihydro-4-[(2-fluoro-4-p-methoxy-phenyl) methyl]-5-methyl-3H-pyrazoles-3-ketone (
XI.1) synthetic
With (19.3 milliliters of piperidines; 0.195 mole) be added into (71 milliliters of methyl acetoacetates; 0.65 mole), 2-fluoro-4-methoxybenzaldehyde is (100 milliliters; 0.65 mole) and (37 milliliters of acetate; 0.65 in mixture mole), and this reaction mixture stirred 24 hours down at about 20 to 25 ℃.Add Virahol (500 milliliters) and palladium (10 weight %)-carbon (5 gram) subsequently, and this solution hydrogenation is stopped until the hydrogen absorption.After removing this catalyzer after filtration, with (43 milliliters of hydrazine hydrates; 0.7 mole) be added in the filtrate and also stirred.This reaction mixture reflux is continued 3 hours, allow afterwards it is cooled to about 20 to 25 ℃.With the gained suspension filtered, wash this product and dry down to generate clear crystal subsequently at 50 ℃ with methyl tertiary butyl ether.
Mass spectrum reaches
1H-NMR spectrum is consistent with specified structure.
Mass spectrum (ESI
+): m/z=237[M+H]
+
Embodiment 49:
1,2-dihydro-4-[(2,3-two fluoro-4-p-methoxy-phenyls) methyl]-5-methyl-3H-pyrazoles-3-ketone (
XI.2) synthetic
Use as the synthesis step described in the embodiment 48 with similar approach, can obtain the compound of this formula XI.2.
Embodiment 50:
1,2-dihydro-4-[(2,6-two fluoro-4-p-methoxy-phenyls) methyl]-5-methyl-3H-pyrazoles-3-ketone (
XI.3) synthetic
Use as the synthesis step described in the embodiment 48 with similar approach, can obtain the compound of this formula XI.3.
Embodiment 51:
1,2-dihydro-4-[(3-fluoro-4-aminomethyl phenyl) methyl]-5-methyl-3H-pyrazoles-3-ketone (
XI.4) synthetic
Use as the synthesis step described in the embodiment 48 with similar approach, can obtain the compound of this formula XI.4.
Embodiment 52:
1,2-dihydro-4-[(2,3-two fluoro-4-aminomethyl phenyls) methyl]-5-methyl-3H-pyrazoles-3-ketone (
XI.6) synthetic
Use as the synthesis step described in the embodiment 48 with similar approach, can obtain the compound of this formula XI.6.
Embodiment 53:
1,2-dihydro-4-[(2-fluoro-4-aminomethyl phenyl) methyl]-5-methyl-3H-pyrazoles-3-ketone (
XI.7) synthetic
Use as the synthesis step described in the embodiment 48 with similar approach, can obtain the compound of this formula XI.7.
Embodiment 54:
1,2-dihydro-4-[(3-fluoro-4-ethoxyl phenenyl) methyl]-5-methyl-3H-pyrazoles-3-ketone (
XI.8) synthetic
Use as the synthesis step described in the embodiment 48 with similar approach, can obtain the compound of this formula XI.8.
Embodiment 55:
1,2-dihydro-4-[(3-fluoro-4-(1-methyl ethoxy) phenyl) methyl]-5-methyl-3H-pyrazoles-3-ketone (
XI.9) synthetic
Use as the synthesis step described in the embodiment 48 with similar approach, can obtain the compound of this formula XI.9.
Embodiment 56:
1,2-dihydro-4-[(2-fluoro-4-(1-methyl ethoxy) phenyl) methyl]-5-methyl-3H-pyrazoles-3-ketone (
XI.10) synthetic
Use as the synthesis step described in the embodiment 48 with similar approach, can obtain the compound of this formula XI.10.
Embodiment 57:
1,2-dihydro-4-[(2-fluoro-4-ethoxyl phenenyl) methyl]-5-methyl-3H-pyrazoles-3-ketone (
XI.11) synthetic
Use as the synthesis step described in the embodiment 48 with similar approach, can obtain the compound of this formula XI.11.
Embodiment 58:
1,2-dihydro-1-(1-methylethyl)-4-[(2-fluoro-4-p-methoxy-phenyl) methyl]-5-methyl-3H-pyrazoles-3-ketone (
III.1)
Step 1:
Descend in about 10 minutes, at 5 ℃ (144.5 milliliters of 2-N-PROPYLE BROMIDEs; 1.52 mole) be added into 1,2-dihydro-4-[(2-fluoro-4-p-methoxy-phenyl) methyl]-5-methyl-3H-pyrazoles-3-ketone (90 grams; 0.38 Powdered potassium hydroxide (88 grams mole); 1.33 mole) and in the mixture of N-Methyl pyrrolidone (540 milliliters).This reaction mixture can be heated to about 20 to 25 ℃ also continues to stir 15 hours.Be poured into subsequently in the mixture of ice/water (1.5 liters) and toluene (450 milliliters).By adding concentrated hydrochloric acid (16.5 milliliters), can keep about 3 pH.This is separated, and extracts this water twice with toluene.The toluene phase that water and salt water washing should merge, drying under reduced pressure and evaporation are to generate oil (orange).It need not to be further purified and can use in next reaction.
Mass spectrum reaches
1H-NMR spectrum is consistent with the specified structure of XI ' .1.
Mass spectrum (ESI
+): m/z=321[M+H]
+
Step 2:
With 1-(1-methylethyl)-3-(1-methyl ethoxy)-4-[(2-fluoro-4-p-methoxy-phenyl)-methyl]-5-methyl-pyrazoles (132 grams; 0.33 mole) with aqueous methane sulfonic acid (20%; 925 milliliters) mixture in closed reactor, be heated to about 140 ℃ and continue about 5 hours.Allow subsequently it is cooled to about 20 to 25 ℃.Separate this product after filtration, water and washed with isopropyl alcohol successively, and dry down at 50 ℃ to generate product as light crystal (yellow).
Mass spectrum reaches
1H-NMR spectrum is consistent with the specified structure of III.1a.
Mass spectrum (ESI
+): m/z=279[M+H]
+
Step 3:
With the mixture process 1 of methylene dichloride (600 milliliters) and 4N aqueous sodium hydroxide solution (57 milliliters), 2-dihydro-1-(1-methylethyl)-4-[(2-fluoro-4-p-methoxy-phenyl) methyl]-5-methyl-3H-pyrazoles-3-ketone mesylate (85 grams; 0.23 mole).This is separated.With this organic phase of salt water washing,, filter and evaporation through dried over sodium sulfate.With boiling Ethanol Treatment gained resistates, filter down and drying at 50 ℃.The oldlace crystal.
Mass spectrum reaches
1H-NMR spectrum is consistent with the specified structure of III.1 product.
Mass spectrum (ESI
+): m/z=279[M+H]
+
Embodiment 59:
1,2-dihydro-1-(1-methylethyl)-4-[(2,3-two fluoro-4-p-methoxy-phenyls) methyl]-5-methyl-3H-pyrazoles-3-ketone (
III.2)
Use as the synthesis step described in the embodiment 58 with similar approach, can obtain the compound of this formula III .2.
Embodiment 60:
1,2-dihydro-1-(1-methylethyl)-4-[(2,6-two fluoro-4-p-methoxy-phenyls) methyl]-5-methyl-3H-pyrazoles-3-ketone (
III.3)
Use as the synthesis step described in the embodiment 58 with similar approach, can obtain the compound of this formula III .3.
Embodiment 61:
1,2-dihydro-1-cyclobutyl-4-[(3-fluoro-4-aminomethyl phenyl) methyl]-5-methyl-3H-pyrazoles-3-ketone (
III.4)
Use as the synthesis step described in the embodiment 58 with similar approach, can obtain the compound of this formula III .4.
Embodiment 62:
1,2-dihydro-1-cyclobutyl-4-[(2-fluoro-4-p-methoxy-phenyl) methyl]-5-methyl-3H-pyrazoles-3-ketone (
III.5)
Use as the synthesis step described in the embodiment 58 with similar approach, can obtain the compound of this formula III .5.
Embodiment 63:
1,2-dihydro-1-(1-methylethyl)-4-[(2,3-two fluoro-4-aminomethyl phenyls) methyl]-5-methyl-3H-pyrazoles-3-ketone (
III.6)
Use as the synthesis step described in the embodiment 58 with similar approach, can obtain the compound of this formula III .6.
Embodiment 64:
1,2-dihydro-1-(1-methylethyl)-4-[(2-fluoro-4-aminomethyl phenyl) methyl]-5-methyl-3H-pyrazoles-3-ketone (
III.7)
Use as the synthesis step described in the embodiment 58 with similar approach, can obtain the compound of this formula III .7.
Embodiment 65:
1,2-dihydro-1-(1-methylethyl)-4-[(3-fluoro-4-ethoxyl phenenyl) methyl]-5-methyl-3H-pyrazoles-3-ketone (
III.8)
Use as the synthesis step described in the embodiment 58 with similar approach, can obtain the compound of this formula III .8.
Embodiment 66:
1,2-dihydro-1-(1-methylethyl)-4-[(3-fluoro-4-(1-methyl ethoxy) phenyl) methyl]-5-methyl-3H-pyrazoles-3-ketone (
III.9)
Use as the synthesis step described in the embodiment 58 with similar approach, can obtain the compound of this formula III .9.
Embodiment 67:
1,2-dihydro-1-(1-methylethyl)-4-[(2-fluoro-4-(1-methyl ethoxy) phenyl) methyl]-5-methyl-3H-pyrazoles-3-ketone (
III.10)
Use as the synthesis step described in the embodiment 58 with similar approach, can obtain the compound of this formula III .10.
Embodiment 68:
1,2-dihydro-1-(1-methylethyl)-4-[(2-fluoro-4-ethoxyl phenenyl) methyl]-5-methyl-3H-pyrazoles-3-ketone (
III.11)
Use as the synthesis step described in the embodiment 58 with similar approach, can obtain the compound of this formula III .11.