CN103649055A - Method for manufacturing pyrazole derivative - Google Patents
Method for manufacturing pyrazole derivative Download PDFInfo
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- CN103649055A CN103649055A CN201280027128.6A CN201280027128A CN103649055A CN 103649055 A CN103649055 A CN 103649055A CN 201280027128 A CN201280027128 A CN 201280027128A CN 103649055 A CN103649055 A CN 103649055A
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- C07—ORGANIC CHEMISTRY
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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Abstract
The present invention provides a prolinamide compound useful as a drug or the like and an industrially advantageous method for producing a piperazinyl pyrazole compound that is a production intermediate of the prolinamide compound. Specifically, the invention is a method for producing a compound represented by general formula (1) as represented by the following formula (where the symbols in the formula are the same as defined in the specification) or a salt thereof, wherein a compound represented by general formula (2) is produced, a pyrazole ring being formed via a reaction between a compound represented by general formula (3) and phosphorus pentasulfide; and, once the compound represented by general formula (2) is deprotected, a carboxylate of a compound represented by general formula (6) is produced, the compound obtained by forming a carboxylic acid and a salt.
Description
Technical field
The present invention relates to the new preparation process of piperazinyl pyrazole compound of the synthetic intermediate of useful as drug etc.In addition, the present invention relates to by prepare the method for the prolineamide compound of the curative drug that can be used as diabetes etc. with the new preparation process of this piperazinyl pyrazole compound.
Background technology
Reported and a kind ofly containing the prolineamide compound of the side chain of piperazinyl pyrazoles part (for example had, 3-{ (2S, 4S)-4-[4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl) piperazine-1-yl] pyrrolidin-2-yl carbonyl } thiazolidine etc.) demonstrate DPP-IV inhibition activity and can be used for (referring to patent documentations 1,2) such as treatment or prevent diabetes.
With regard to this prolineamide compound, its preparation method is disclosed and as preparation method's (referring to patent documentation 1) of the piperazinyl pyrazole compound of its synthetic intermediate.
This preparation method comprise make β-hydrazone amide compound of producing from beta-keto acyl amine compound pyridine exists with phosphorus oxychloride reaction to produce required piperazinyl pyrazole compound.Yet this preparation method only provides piperazinyl pyrazole compound with low yield, and it is required further improvement as before industrial production process.
Typically, as the method for the pyrazole compound for the preparation of replacing, following methods is known.For example, reported by making β-hydrazone amide compound and phosphorus oxychloride reaction prepare the additive method of pyrazole compound (referring to non-patent literature 1).Yet the yield of pyrazole compound is inadequate in this report.
As another kind of method, reported β-hydrazone amide compound by making to prepare from beta-keto acyl amine compound and hydrazine compound original position pyridine exists with tetrahydrofuran (THF) in Lawesson reagent (2, two (the 4-methoxyphenyls)-1 of 4-, 3,2,4-dithia two phosphorus heterocycle butane-2,4-disulphide) react and the method (referring to non-patent literature 2) of preparation 5-(amino of replacement) pyrazole compound.Yet in this report, the production example of the pyrazole compound of replacement is all in the scale of tens milligrams, and whether unknown this method can be used in technical scale.
[listed files]
[patent documentation]
Patent documentation 1:WO2002/014271
Patent documentation 2:WO2006/088129
[non-patent literature]
The people such as non-patent literature 1:H.G.Viehe; " Trifluoromethylated Heterocycles from β-Trifluoroacetyl-Lactams and-Benzolactams(is from the trifluoromethylation heterocycle of β-trifluoroacetyl group-lactan and β-trifluoroacetyl group-benzo lactan) "; Tetrahedron Letters; 1993; the 34th volume; the 32nd phase, 5075-5078 page
The people such as non-patent literature 2:D.S.Dodd, and " One-pot synthesis of5-(substituted-amino) amino that replaces of the synthetic 5-(of pyrazoles(one kettle way) pyrazoles) ", Tetrahedron Letters, 2004, the 45th volume, the 22nd phase, 4265-4267 page
Summary of the invention
The technical problem that the present invention is to be solved
Effective and the superior preparation method who the object of this invention is to provide piperazinyl pyrazole compound, its applicable industrial production.In addition, be intended to provide the efficient and superior preparation method of the prolineamide compound that is applicable to industrial production useful as drug etc.
The means that solve the technical problem
As mentioned above, when phosphorus oxychloride is during for the preparation of piperazinyl pyrazole compound, this compound may only obtain with low yield.In addition, even when using Lawesson reagent to substitute phosphorus oxychloride, this compound can not obtain with enough yields, and as industrial production process, the method is not gratifying.
The inventor has carried out sufficient research and has found, by using thiophosphoric anhydride to substitute phosphorus oxychloride, can preferably with high yield, preparing the piperazinyl pyrazole compound of being paid close attention to, and this causes of the present invention completing.
Therefore, the invention provides the method for preparing the compound being represented by formula (2):
R wherein
1alkyl or cycloalkyl, R
2be that amino protecting group and Ar are aryl or heteroaryl, described preparation method comprises that the compound by formula (3) is represented reacts and forms pyrazole ring with thiophosphoric anhydride:
Wherein each symbol is as definition above.
In addition, the invention provides the method for the carboxylate salt of preparing the compound being represented by formula (6):
Wherein each symbol is as definition above, and described method comprises the compound or its salt representing by aforementioned preparation method's preparation formula (2), removes the amino protecting group R of this compound
2the compound representing with production (6), and make this compound change into carboxylate salt.
The carboxylate salt of the compound being represented by formula (6) is a kind of new compound, and also contains this compound in the present invention.
In addition, the invention provides the method that produces the compound or its salt being represented by formula (1):
Wherein each symbol is as definition above, described method comprises the carboxylate salt of the compound representing by the compound or its salt of aforementioned preparation method's preparation formula (2) expression or formula (6), and makes consequent compound transform the compound or its salt that an accepted way of doing sth (1) represents.
[effect of the present invention]
According to the present invention, can advantageously efficiently prepare the piperazinyl pyrazole compound that represented by formula (2) or its salt and the carboxylate salt of the compound that represented by formula (6) by industrial mode.In addition, can advantageously efficiently prepare by industrial mode the prolineamide compound or its salt being represented by formula (1) of useful as drug etc.
According to the present invention, β-hydrazone amide compound that the compound or its salt being represented by formula (2) can be represented by formula (3) obtains with high yield.
Because the compound that formula (6) represents is non-crystallizable, so its large scale purification is difficult.Yet the method according to this invention, obtain at the superior high-purity crystal in the aspects such as operability, storage stability, so it is conducive to industrial production owing to changing into its carboxylate salt by the compound that formula (6) is represented.
Specific embodiments
(definition)
In the present invention, as alkyl, can mention and there is 1-6 carbon atom (C
1-6) straight or branched group.Particularly, for example, can mention methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the second month in a season-butyl, tert-butyl, n-pentyl, isopentyl and n-hexyl.
As cycloalkyl, can mention and there is 3-8 carbon atom (C
3-8) cyclic group.Particularly, for example, as cycloalkyl, can mention cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.Cycloalkyl comprises that circular part wherein has a kind of group of 1-2 alkyl substituent.
As alkoxyl group, can mention and there is 1-8 carbon atom (C
1-8) group, wherein abovementioned alkyl or above-mentioned cycloalkyl and Sauerstoffatom combination.Particularly, for example, can mention methoxyl group, oxyethyl group, positive propoxy, isopropoxy, uncle-butoxy, ring propoxy-and cyclobutoxy group.
As by R
1the alkyl or cycloalkyl representing, alkyl is preferred.More preferably, can mention methyl, ethyl, n-propyl or sec.-propyl, and methyl is particularly preferred.
As the aryl being represented by Ar, can mention have 6 carbon atoms mononuclear aromatics group, there is the double ring arene group of 9-11 carbon atom etc.Particularly, for example, can mention phenyl, naphthyl or indenyl.
As the heteroaryl being represented by Ar, can mention 5 yuan of containing 1-4 heteroatoms (oxygen, sulphur or nitrogen) or 6 yuan of monocyclic aromatic heterocyclic radicals, contain 1-4 heteroatoms (oxygen, sulphur or nitrogen) 8 yuan to 10 yuan of bicyclic aromatic heterocyclic radicals etc.Particularly, for example, can mention imidazolyl, thiazolyl, pyrazolyl, pyridyl, pyrimidyl, pyridazinyl, indyl, indolinyl, isoquinolyl or quinolyl.
As the aryl being represented by Ar or heteroaryl, aryl is preferred, and particularly, phenyl or naphthyl is preferred, and phenyl is preferred.
By R
2or R
3it is the protecting group that does not hinder reaction that the amino protecting group representing only needs; and as this amino protecting group; alkoxy carbonyl (the carbobenzoxy-(Cbz), 2 that can preferably use alkoxy carbonyl (methoxycarbonyl, ethoxycarbonyl, positive the third oxygen carbonyl, tertbutyloxycarbonyl etc.) and replace; 2,2-trichloro-ethoxycarbonyl, 9-fluorenylmethyloxycarbonyl etc.).As the R from these protecting groups
2, alkoxy carbonyl is preferred, and ethoxycarbonyl is particularly preferred.As the R from these protecting groups
3, alkoxy carbonyl is preferred, and tertbutyloxycarbonyl is particularly preferred.
Thiophosphoric anhydride is by molecular formula P
4s
10the compound representing, and implication is identical with phosphoric sulfide (V) with thiophosphoric anhydride.
As carboxylic acid, can mention 1-7 the carbon atom (C that have optionally replacing
1-7) straight or branched carboxylic acid.Particularly, for example, can mention formic acid, there is 2-7 carbon atom (C
2-7) alkyl carboxylic acid (acetic acid, propionic acid, butyric acid or isopropylformic acid etc.) and there is 2-7 carbon atom (C
2-7) the alkyl carboxylic acid (trifluoroacetic acid etc.) of replacement.In the middle of these carboxylic acids, alkyl carboxylic acid is preferred, and acetic acid is particularly preferred.
(preparation method of the present invention)
Hereinafter explain in detail preparation method of the present invention.
Starting compound is obtainable easily as commercially available prod, maybe can prepare by the preparation method or the known method itself that below show, or can be according to similarly method preparation with it.
As long as reaction is unaffected, for the compound of following every kind of reaction can form salt as inorganic acid salt (for example, hydrochloride, hydrobromate, vitriol, nitrate, phosphoric acid salt), organic acid salt (for example, acetate, tartrate, Citrate trianion, fumarate, maleate, tosylate, mesylate), metal-salt (for example, sodium salt, sylvite, calcium salt, aluminium salt) or the salt (for example, ethylamine salt, guanidinesalt, ammonium salt, hydrazonium salt, quinine salt, cinchonine salt (cinchoninium)) that forms with alkali etc.
In addition, the compound obtaining by following every kind of reaction can be used for subsequent reactions not from reaction mixture separation in the situation that or as crude product.Or this compound can be separated from reaction mixture according to conventionally known method, or by general separation means (as recrystallization, distillation, chromatogram etc.) purifying easily.In addition, this compound can be separated with the salt of alkali as inorganic acid salt, organic acid salt, metal-salt or its according to conventionally known method.
For the present invention's compound and the compound or its salt of acquisition, comprise its solvate or its hydrate.
In the present invention, the compound (β-hydrazone amide compound) being represented by formula (3) can carry out as follows with the reaction of thiophosphoric anhydride (pyrazole ring forms and reacts).That is, reacting of the compound being represented by formula (3) and thiophosphoric anhydride can be in the situation that in suitable solvent or do not follow solvent, in alkali existence or while not depositing, carries out.
The amount of the thiophosphoric anhydride using preferably (for example) is the compound 0.2-0.8mol that represented by formula (3) of every 1mol, 0.25-0.35mol preferably.
This reaction is preferably carried out under alkali exists.As the alkali using, can mention mineral alkali, as as salt of wormwood, sodium carbonate, Quilonum Retard, saleratus, sodium bicarbonate etc., and can mention organic bases, as pyridine, picoline, lutidine, triethylamine, N, N-diisopropylethylamine etc., preferably, can mention mineral alkali, as salt of wormwood, sodium carbonate, Quilonum Retard, saleratus or sodium bicarbonate etc., and more preferably, can mention sodium carbonate.The compound 0.7-10mol that alkali can be represented by formula (3) with every 1mol conventionally, preferably 0.8-2mol is used.
This reaction is preferably carried out in suitable reaction solvent.As reaction solvent, can use tetrahydrofuran (THF) (below will be abbreviated as THF), Isosorbide-5-Nitrae-dioxs, 1,2-glycol dimethyl ether, methylene dichloride, chloroform, toluene, acetonitrile, propionitrile or its mixed solvent, and can preferably use THF.
Conventionally, temperature of reaction can optionally be selected from 0-110 ℃, and normally approximately 10 minutes to 2 days reaction times.This reaction is preferably carried out under as nitrogen, argon gas etc. at inert gas atmosphere.
The compound (piperazinyl pyrazole compound) being represented by formula (2) obtaining as above mentioned or its salt can transform the carboxylate salt of the compound of an accepted way of doing sth (6) expression as follows.
Wherein each symbol is as definition above.
That is the carboxylate salt of the compound that, preparation formula (6) represents in the following manner: the compound or its salt representing from formula (2) removes amino protecting group R
2the compound representing with production (6), and form subsequently the salt of this compound with carboxylic acid.
As a kind of compound or its salt representing from formula (2), remove amino protecting group R
2method, can suitably use suitable currently known methods according to protecting group used.
Particularly, for example, when using tertbutyloxycarbonyl as protecting group, deprotection can be by the situation that in suitable solvent or do not follow solvent and acid-respons to carry out.As acid, can mention trifluoroacetic acid, hydrogenchloride, hydrogen bromide, sulfuric acid etc., and can preferably mention trifluoroacetic acid.
This reaction is preferably carried out in suitable reaction solvent.As reaction solvent, for example, methylene dichloride, chloroform, methyl alcohol, ethanol, 2-propyl alcohol, THF, Isosorbide-5-Nitrae-dioxs, acetonitrile, toluene or water or above-mentioned acid or its mixed solvent can be used as solvent, and preferably, above-mentioned acid can be used as solvent.
When using methoxycarbonyl, ethoxycarbonyl, positive the third oxygen carbonyl etc. as protecting group, deprotection can be by the situation that in suitable solvent or do not follow solvent and alkali reaction to carry out.As alkali, can mention lithium hydroxide, sodium hydroxide, potassium hydroxide etc., and preferably, can mention potassium hydroxide.With respect to reaction mixture, the concentration of alkali is 0.1-100mol/L, preferably 1-10mol/L.
This reaction is preferably carried out in suitable reaction solvent.As reaction solvent, can use methyl alcohol, ethanol, 2-propyl alcohol, THF, acetonitrile or water or its mixed solvent, and preferably, the mixed solvent of operable first alcohol and water.
Conventionally, temperature of reaction can optionally be selected from 0-100 ℃, and normally approximately 10 minutes to 2 days reaction times.
When using carbobenzoxy-(Cbz) as protecting group, deprotection can carry out in suitable solvent under nitrogen atmosphere under palladium-carbon catalyst or the existence of hydroxide palladium/carbon catalyst.
When using 2,2,2-trichloro-ethoxycarbonyl as protecting group, deprotection can be undertaken by reacting with zinc powder in suitable solvent.
When using 9-fluorenylmethyloxycarbonyl as protecting group, deprotection can be by the situation that in suitable solvent or do not follow solvent to react to carry out with tetramethyleneimine, piperidines or morpholine.
Salify for the compound being represented by formula (6) and carboxylic acid is processed, and can use known method conventionally.For example, the compound being represented by formula (6) and carboxylic acid salify processing can in suitable solvent, carry out.Particularly, for example, the carboxylate salt of the compound being represented by formula (6) can be by every 1mol by compound and the 0.7-3mol of formula (6) expression, preferably prepared by 0.9-1.1mol carboxylic acid reaction.
As reaction solvent, can use methylene dichloride, chloroform, methyl alcohol, ethanol, 2-propyl alcohol, THF, Isosorbide-5-Nitrae-dioxs, acetonitrile or toluene or its mixed solvent, and preferably, can use toluene.
Conventionally, temperature of reaction can optionally be selected from 0-100 ℃ and normally approximately 10 minutes-1 day reaction times.
The carboxylate salt of the compound or its salt being represented by formula (2) obtaining as above mentioned or the compound being represented by formula (6) can suitably transform compound (prolineamide compound) or its salt that an accepted way of doing sth (1) represents by currently known methods or its combination.Or this compound can be by preferably transforming as the method below exemplifying the compound or its salt that an accepted way of doing sth (1) represents.
R wherein
3that amino protecting group and other are as definition above.
; the compound or its salt that preparation formula (10) represents in the following manner: make the compound (4-oxa-prolineamide compound) that formula (9) represents carry out reductive amination reaction under the carboxylate salt of the compound of formula (6) expression exists, and remove subsequently the amino protecting group R of this compound
3the compound (piperazinyl prolineamide compound) representing with production (1).When needed, can make this compound change into its salt by adopting acid to carry out salify processing.
For the carboxylate salt of the compound representing in formula (6), there is the reductive amination reaction of the compound of following formula (9) expression, can use known method conventionally.Particularly, this reaction can by make the compound that formula (6) represents carboxylate salt, compound and reductive agent that formula (9) represents in suitable solvent, react and carry out.
For example, as reductive agent, can mention sodium borohydride, sodium triacetoxy borohydride, dimethylamine borane, triethylamine borine, Trimethylamine 99 borine, tert-butylamine borine, N, N-Diethyl Aniline borine or 2-picoline borine, and preferably, can mention sodium triacetoxy borohydride.
As reaction solvent, can use methylene dichloride, methyl alcohol, ethanol, 2-propyl alcohol, THF, acetonitrile, toluene or dimethyl formamide or its mixed solvent, and preferably, can use toluene.
Conventionally, temperature of reaction can optionally be selected from-20 ℃-100 ℃ and normally approximately 10 minutes-1 day reaction times.
As a kind of compound or its salt representing from formula (10), remove the method for amino protecting group R3, can suitably use suitable currently known methods according to protecting group used.
Particularly, for example, when using tertbutyloxycarbonyl as protecting group, deprotection can be by the situation that in suitable solvent or do not follow solvent and acid-respons to carry out.As acid, can mention trifluoroacetic acid, hydrogenchloride, hydrogen bromide, sulfuric acid etc., and can preferably mention hydrogen bromide.With respect to reaction mixture, the concentration of acid is 0.01-10mol/L, preferably 0.1-4mol/L.
This reaction is preferably carried out in suitable reaction solvent.As reaction solvent, can use methylene dichloride, chloroform, methyl alcohol, ethanol, 2-propyl alcohol, THF, Isosorbide-5-Nitrae-diox, acetonitrile, toluene or water or its mixed solvent, and preferably, can use the mixed solvent of 2-the third alcohol and water.
Conventionally, temperature of reaction can optionally be selected from 0-100 ℃ and normally approximately 10 minutes-2 days reaction times.
When using methoxycarbonyl, ethoxycarbonyl, positive the third oxygen carbonyl etc. as protecting group, deprotection can be by the situation that in suitable solvent or do not follow solvent and alkali reaction to carry out.As alkali, can mention lithium hydroxide, sodium hydroxide, potassium hydroxide etc., and preferably, can mention potassium hydroxide.With respect to reaction mixture, the concentration of alkali is 0.1-100mol/L, preferably 1-10mol/L.
This reaction is preferably carried out in suitable reaction solvent.As reaction solvent, can use methyl alcohol, ethanol, 2-propyl alcohol, THF, acetonitrile or water or its mixed solvent, and preferably, can use the mixed solvent of first alcohol and water.
Conventionally, temperature of reaction can optionally be selected from 0-100 ℃ and normally approximately 10 minutes-2 days reaction times.
When using carbobenzoxy-(Cbz) as protecting group, deprotection can carry out under palladium-carbon catalyst or the existence of hydroxide palladium/carbon catalyst in suitable solvent under nitrogen atmosphere.
When using 2,2,2-trichloro-ethoxycarbonyl as protecting group, deprotection can be undertaken by reacting with zinc powder in suitable solvent.
When using 9-fluorenylmethyloxycarbonyl as protecting group, deprotection can be by the situation that in suitable solvent or do not follow solvent to react to carry out with tetramethyleneimine, piperidines or morpholine.
The compound being represented by formula (1) and sour salify are processed can be conventionally by processing to carry out by known method with corresponding acid.For example, can carry out salify by the compound with acid represents formula (1) in suitable solvent and process to carry out this processing.
As acid, can mention mineral acid as hydrogenchloride, hydrogen bromide or nitric acid etc.; Or organic acid is as tosic acid, methylsulfonic acid, Phenylsulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, gallic acid or camphorsulfonic acid etc., and preferably, can mention hydrogen bromide.The salt of the compound particularly, being represented by formula (1) can be by every 1mol by compound and the 1-10mol of formula (1) expression, preferably prepared by the acid-respons of 2-5mol.
As reaction solvent, can use methylene dichloride, chloroform, methyl alcohol, ethanol, 2-propyl alcohol, THF, acetonitrile, toluene or water or its mixed solvent, and preferably, can use the mixed solvent of 2-the third alcohol and water.
Conventionally, temperature of reaction can optionally be selected from 0-100 ℃ and normally approximately 10 minutes-2 days reaction times.
When the salt of the compound representing by sour preparation formula (1), more preferably use the amino protecting group R of the compound or its salt that the protecting group that can be removed by acid (as tertbutyloxycarbonyl etc.) represents as formula (10)
3, because remove protecting group R
3reaction and follow-up salify process and can carry out simultaneously.
Although the compound being represented by formula (3) can suitably be prepared by known method or its combination as one of initial compounds in the present invention, it more preferably (for example) prepare by the following method.
Wherein each symbol is as definition above.
; the β-one carboxylic acid that the compound (diethylenediamine compound) being represented by formula (4) or its salt and reaction formula (a) represent or its reactive derivatives be with the compound (beta-keto acyl amine compound) of production (5) expression, and this compound and formula Ar-NH-NH subsequently
2the hydrazine compound or its reactant salt that represent, the compound thus can production (3) representing.
The reactive derivatives of the β-one carboxylic acid representing as formula (a), can be used alkyl ester and the dicthenone of the β-one carboxylic acid that formula (a) represents.
The β-one carboxylic acid or its reactive derivatives that as formula (a), represent, dicthenone is preferred.
The method that the β-one carboxylic acid representing with formula (a) as the compound or its salt that formula (4) is represented or its reactive derivatives react, β-one carboxylic acid or its reactive derivatives that can represent according to the formula (a) of using, suitably used suitable currently known methods.
Particularly, reacting of the β-one carboxylic acid that the compound or its salt representing as formula (4) represents with formula (a), can be used in alkali existence or not, in the situation that in suitable solvent or do not follow solvent to use the condensation reaction of condensing agent.As condensation reaction, can mention method and the mixed acid anhydride method of using carbodiimide.As concrete condensing agent, can mention N-(3-dimethylamino-propyl)-N'-ethyl carbodiimide, dicyclohexylcarbodiimide, methyl-chloroformate, Vinyl chloroformate, propyl chloroformate, isopropyl chlorocarbonate, butyl chlorocarbonate, isobutyl chlorocarbonate etc.
During the reactive derivatives of the β-one carboxylic acid that the alkyl ester of the β-one carboxylic acid representing when use formula (a) represents as formula (a), the alkyl ester of the β-one carboxylic acid that the compound or its salt that formula (4) represents can represent with formula (a) is in suitable catalyzer existence or not, when alkali exists or does not exist, in the situation that in suitable solvent or do not follow solvent to react.The concrete alkyl ester of the β-one carboxylic acid representing as formula (a), can mention the methyl ester of the β-one carboxylic acid that formula (a) represents, the ethyl ester of the β-one carboxylic acid that formula (a) represents, the tertiary butyl ester of the β-one carboxylic acid that formula (a) represents etc.
When using dicthenone as the reactive derivatives of the β-one carboxylic acid representing as formula (a), the compound or its salt that formula (4) represents can with dicthenone alkali exist or not in the presence of, in the situation that in suitable solvent or do not follow solvent to react.
As compound and formula Ar-NH-NH that formula (5) is represented
2the hydrazine compound representing or the method for its reactant salt, can be used known condensation reaction conventionally.Particularly, reacting of the compound being represented by formula (5) and hydrazine compound or its salt can be in acid or alkali existence or not, in the situation that in suitable solvent or do not follow solvent to carry out.
Although the compound being represented by formula (9) can suitably produce by known method or its combination as one of initial compounds in the present invention, this compound more preferably (for example) produces by the following method.
Wherein symbol is as definition above.
That is, this compound can more preferably be prepared by compound or its salt and thiazolidine condensation that formula (8) is represented.
The compound or its salt that formula (8) represents and the condensation reaction of thiazolidine can be in alkali existence or not, in the situation that in suitable solvent or do not follow solvent to use condensing agent to carry out.
As this condensation reaction, can mention the method for mixed acid anhydride method and use phosphonic acid anhydride derivative.As concrete condensing agent, can mention the aryl carboxylic acid acyl chlorides of alkyl chloroformate, replacement, the aryl carboxylic acid acid anhydride of replacement or phosphonic acid anhydride cyclic trimer; Preferably, can mention methyl-chloroformate, Vinyl chloroformate, propyl chloroformate, isopropyl chlorocarbonate, butyl chlorocarbonate, isobutyl chlorocarbonate, 2,4,6-trichloro-benzoyl chloride, 2-methyl-6-nitrobenzoyl acid anhydrides or n-propyl phosphonic acid anhydride (tripolymer of ring-type), and more preferably, can mention n-propyl phosphonic acid anhydride (cyclic trimer).As alkali, can mention pyridine, picoline, lutidine, triethylamine, DIPEA etc., and preferably, can mention DIPEA.
As reaction solvent, can use THF, Isosorbide-5-Nitrae-dioxs, 1,2-glycol dimethyl ether, methylene dichloride, chloroform, toluene, methyl acetate, ethyl acetate, propyl acetate, acetonitrile or propionitrile or its mixed solvent, and preferably, can use ethyl acetate.
Conventionally, temperature of reaction can optionally be selected from-20 ℃-110 ℃ and normally approximately 10 minutes-2 days reaction times.
In the present invention, preparation method of the present invention can more preferably use every kind of following compound to carry out, wherein R
1alkyl (methyl etc. in particular), R
2to replace or unsubstituted alkoxy carbonyl, R
3be to replace or unsubstituted alkoxy carbonyl, and Ar it is aryl (in particular phenyl etc.).In addition, as the compound representing with formula (6), prepare the carboxylic acid of salt, preferably use alkyl carboxylic acid (especially acetic acid etc.).In addition, as the salt of the compound representing with formula (1), preferably use and the salt of mineral acid (in particular hydrobromate etc.).The compound or its salt that formula (1) represents can form solvate or its hydrate.
As the compound of more preferably preparing by preparation method of the present invention, can mention 3-{ (2S, 4S)-4-[4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl) piperazine-1-yl] pyrrolidin-2-yl carbonyl } thiazolidine or its salt.
More specifically, as this compounds, for example can mention 3-{ (2S, 4S)-4-[4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl) piperazine-1-yl] pyrrolidin-2-yl carbonyl } thiazolidine 2.5 hydrobromates.More specifically, can mention 3-{ (2S, 4S)-4-[4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl) piperazine-1-yl] pyrrolidin-2-yl carbonyl } thiazolidine 2.5 hydrobromate 1-2 hydrates.
In this manual, abbreviation " Me " means methyl, and " Et " means ethyl, and " Ph " means phenyl, and " Ac " means ethanoyl, and " t-Bu " means the tertiary butyl.
(example)
By explaining in detail the present invention at hereinafter with reference example, described embodiment should not be construed as restrictive.In an embodiment, " w% " means % by weight.
Embodiment 1
The preparation of 5-(4-tert-butoxycarbonyl-piperazine-1-yl)-3-methyl isophthalic acid-phenylpyrazole
To 4-tertbutyloxycarbonyl-1-[3-(2-phenyl hydrazones) butyryl radicals] piperazine (compound 3b) (721mg) and sodium carbonate (254mg) at THF(10mL) in solution add thiophosphoric anhydride (267mg), and mixture is heated 30 minutes under refluxing.Vapourisation under reduced pressure solvent, is added into resistates and filtering mixt by diethyl ether (30mL).Water (20mL) is added into filtrate, and separated this mixture.By saturated brine washing dry and filtration on anhydrous magnesium sulfate for the organic layer obtaining.Filtrate is under reduced pressure concentrated to produce 5-(4-tert-butoxycarbonyl-piperazine-1-yl)-3-methyl isophthalic acid-phenylpyrazole (compound 2b) (580mg, yield 85%).
1H-NMR（500MHz,DMSO-d
6）δ1.39（9H,s）,2.15(3H,s）,2.73（4H,m）,3.37（4H,m）,5.83（1H,s）,7.28（1H,t,J=7.4Hz）,7.46（2H,t,J=7.4Hz）,7.76（2H,d,J=7.4Hz）。
Embodiment 2
The preparation of 3-methyl isophthalic acid-phenyl-5-(1-piperazinyl) pyrazolyl acetic acid salt
1-ethoxy carbonyl piperazine (compound 4a) (37.5kg) is dissolved in to THF(550L) in.Cooling this solution, dropwise adds dicthenone (19.9kg) at 0-7 ℃, and mixture is stirred 1.5 hours at 1 ℃-5 ℃.To reaction mixture, dropwise add phenylhydrazine (25.6kg) at THF(10L) in solution, and mixture is stirred 7 hours at 20 ℃-26 ℃.Reaction mixture is under reduced pressure concentrated until residual quantity becomes 100L, and by THF(260L) be added into remaining reaction mixture.To this reaction mixture, add sodium carbonate (25.1kg) and thiophosphoric anhydride (26.3kg), and mixture is stirred 1.5 hours at 36 ℃-44 ℃, and stir 3 hours at 45 ℃-52 ℃.Reaction mixture, adds thiophosphoric anhydride (5.3kg), and mixture is stirred 1 hour and cooling at 45 ℃-51 ℃.To this reaction mixture, add toluene (375L) and water (375L), and separating mixture.By organic layer water (375L) washing obtaining, and under reduced pressure concentrated.To resistates, add methyl alcohol (190L), and mixture is under reduced pressure concentrated.To resistates, add methyl alcohol (260L) and water (110L), and at cooling lower interpolation potassium hydroxide (112.6kg).By reaction mixture refluxed 2.5 hours, be cooled to 51 ℃, and distribute between toluene (260L) and water (55L).The organic layer obtaining washs 1 time with 20w% salt solution (75kg) washing 3 times water (38L).Organic layer is concentrated under normal pressure, and evaporating solvent (210L).To remaining reaction mixture, at 55 ℃, dropwise add acetic acid (10.7kg), and by mixture 51 ℃ of-56 ℃ of crystallizations 1 hour, and subsequently 17 ℃ of-25 ℃ of crystallizations 1.5 hours.The crystal of precipitation is collected and is used toluene (40L) washing by filtration.The warm air for crystal (40 ℃-46 ℃) obtaining is dried to 15 hours to produce 3-methyl isophthalic acid-phenyl-5-(1-piperazinyl) pyrazolyl acetic acid salt (compound 7a) (47.4kg, yield 66%)
1H-NMR（500MHz,DMSO-d
6）δ1.90(3H,s）,2.14(3H,s）,2.70（8H,m）,5.77（1H,s）,7.37（1H,t）,7.45（2H,t）,7.75（2H,d）。
Embodiment 3
4-tertbutyloxycarbonyl-1-[3-(2-phenyl hydrazones) butyryl radicals] piperazine synthetic
Ice-cooled lower to 1-tert-butoxycarbonyl-piperazine (compound 4b) (80g) solution in DMF (256mL) dropwise add dicthenone (34.7mL), and by this mixture stirring at room 1 hour.Under water cooling, to this reaction mixture, dropwise add the mixing solutions of phenylhydrazine (48.7g) in ethanol (192mL) and water (192mL), and by this mixture stirring at room 1 hour.To this reaction mixture, dropwise add water (320mL), and by this mixture stirring at room 1 hour.Throw out is collected by filtration; 1:1 mixture washing with first alcohol and water; and dry to produce 4-tertbutyloxycarbonyl-1-[3-(2-phenyl hydrazones) butyryl radicals under vacuum] piperazine (compound 3b) (149g, yield 97%, regional isomer ratio 1:1).
1H-NMR(300MHz,CDCl
3）δ1.46,1.48（9H,s）,1.95（1.5H,s）,2.11（1.5H,s）,2.88（0.5H,s）,2.96（0.5H,s）,3.35-3.64（10H,m）,6.80-7.32（5H,m）。
Embodiment 4
3-{ (2S, 4S)-4-[4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl) piperazine-1-yl] pyrrolidin-2-yl carbonyl } preparation of thiazolidine compound
Wherein Y is 1-2.
Toluene (425L) is added into 3-methyl isophthalic acid-phenyl-5-(1-piperazinyl) pyrazolyl acetic acid salt@ester (compound 7a) (25.2kg) and 3-[(2S)-1-tertbutyloxycarbonyl-4-oxa-pyrrolidin-2-yl carbonyl] thiazolidine (compound 9a) is (25.0kg), and at 8 ℃, add the slurries of sodium triacetoxy borohydride (23.0kg) in toluene (75L), and this mixture is stirred 3 hours at 20 ℃-28 ℃.To this reaction mixture, add water (150L), and separating mixture.The toluene layer obtaining is washed successively with 5w% sodium bicarbonate aqueous solution (158kg) and water (150L), under reduced pressure concentrate and be dried.To the resistates obtaining, add 2-propyl alcohol (125L), and mixture is again lower concentrated in decompression, and dry.To resistates, add 2-propyl alcohol (375L), rising temperature is dropwise added 48w% Hydrogen bromide (42.14kg) and refluxes 2.5 hours at 75 ℃-77 ℃.Reaction mixture is cooling, and at 58 ℃, add by the crystal seed that sampling produces to reaction mixture, and make mixture crystallization 1 hour at 58 ℃, subsequently 33 ℃ of-40 ℃ of crystallizations 1 hour, and further 17 ℃ of-25 ℃ of crystallizations 1 hour, and standing over night.The crystal of precipitation is collected and is used 2-propyl alcohol (50L) washing by filtration.Within 18 hours, using generation 3-{ (2S, 4S)-4-[4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl) piperazine-1-yl by warm air crystal for (40 ℃-47 ℃) obtaining is dry] pyrrolidin-2-yl carbonyl } thiazolidine hydrobromate (50.0kg) is as crude product.
Ethanol (144L) is added into this crude product (24.0kg), by heating (73 ℃), dissolves, filtered while hot, and wash with ethanol (24L).Filtrate and washings are merged, at 67 ℃, add water (3.4L), and make mixture 49 ℃ of-55 ℃ of crystallizations 2 hours, subsequently 19 ℃ of-25 ℃ of crystallizations 1 hour.The crystal of precipitation is collected and is used ethanol (24L) washing by filtration.The crystal obtaining is under reduced pressure dried to 19 hours at 45 ℃, by the warm air of 50 ℃, be dried 18 hours to produce 3-{ (2S, 4S)-4-[4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl) piperazine-1-yl] pyrrolidin-2-yl carbonyl } thiazolidine 2.5 hydrobromate 1-2 hydrate (compound 11a) (20.9kg, yield 79%, calculates yield value by usining dihydrate form) as purified product.
1H-NMR（400MHz,C
5D
5N）δ2.02-2.14（1H,m）,2.33(3H,m）,2.46-2.56（4H,m）,2.87（4H,m）,2.91-3.12(3H,m）,3.45-3.51（1H,m）,3.63-3.67（1H,m）,3.80-3.90（1.4H,m）,4.08（0.6H,m）,4.11-4.16（1H,m）,4.68（0.6H,d,J=10.1Hz）,4.72（0.6H,d,J=10.1Hz）,4.80（0.4H,d,J=8.8Hz）,4.96（0.4H,d,J=8.8Hz）,5.42（0.6H,dd,J=8.8,8.8Hz）,5.52（0.4H,dd,J=8.8,8.8Hz）,5.76（0.4H,s）,5.77（0.6H,s）,7.32（1H,t=7.8Hz）,7.53（2H,dd,J=8.8,7.8Hz）,8.07（2H,d=8.8Hz）。
Embodiment 5
3-[(2S)-1-tertbutyloxycarbonyl-4-oxa-pyrrolidin-2-yl carbonyl] preparation of thiazolidine compound
To (2S)-1-tertbutyloxycarbonyl-4-oxa-tetramethyleneimine-2-carboxylic acid (compound 8a) (60.0kg), thiazolidine (30.3kg) and N, the solution of N-diisopropylethylamine (118kg) in ethyl acetate (595kg) adds the solution of 28w% propyl phosphonous acid acid anhydride (cyclic trimer) in ethyl acetate (446kg) at 2 ℃-7 ℃, and reaction mixture is stirred 2 hours at 2 ℃-4 ℃.To this reaction mixture, add 15w% aqueous citric acid solution (600kg) for distributing, and ethyl acetate for water layer (271kg) is extracted.The ethyl acetate layer obtaining is mixed, and use successively 10w% ammonium dibasic phosphate aqueous solution (600kg) and water (300kg) washing.Ethyl acetate layer is concentrated into residual quantity 300L, normal heptane (739kg), 23 ℃ of-25 ℃ of interpolations, and is stirred this mixture 1 hour at 23 ℃-25 ℃, and stir 2 hours at 1 ℃-5 ℃.The crystal of precipitation is collected by filtration, is used normal heptane (164kg) washing drying under reduced pressure to produce 3-[(2S)-1-tertbutyloxycarbonyl-4-oxa-pyrrolidin-2-yl carbonyl] thiazolidine (compound 9a) (67.8kg, yield 86%).
1H-NMR（500MHz,DMSO-d
6）δ1.36,1.40（9H,s）,2.36-2.45（1H,m）,2.97-3.12(3H,m）,3.62-3.71（2H,m）,3.74-3.94（2H,m）,4.33-4.80（2H,m）,4.91-5.04（1H,m）。
Comparative example 1
Use Lawesson reagent to prepare 5-(4-tert-butoxycarbonyl-piperazine-1-yl)-3-methyl isophthalic acid-phenylpyrazole
To 4-tertbutyloxycarbonyl-1-[3-(2-phenyl hydrazones) butyryl radicals] piperazine (compound 3b) (1.00g) solution in toluene (18mL) add Lawesson reagent (674mg), and by mixture 80 ℃ of heating 1.5 hours.After confirming that raw material disappears, vapourisation under reduced pressure solvent, and pass through column chromatography purification resistates to produce 5-(4-tert-butoxycarbonyl-piperazine-1-yl)-3-methyl isophthalic acid-phenylpyrazole (compound 2b) (551mg, yield 58%).
1H-NMR（500MHz,DMSO-d
6）δ1.39（9H,s）,2.15(3H,s）,2.73（4H,m）,3.37（4H,m）,5.83（1H,s）,7.28（1H,t,J=7.4Hz）,7.46（2H,t,J=7.4Hz）,7.76（2H,d,J=7.4Hz）。
Compare with using this method of Lawesson reagent, when using method of the present invention to prepare, described in previous embodiment 1, can make with quite high yield required compound (compound 2b).
[industrial applicibility]
Preparation in accordance with the present invention, the piperazinyl pyrazole compound of the synthetic intermediate of useful as drug etc. or its salt can be by the advantageously efficiently preparations of industrial mode.In addition, the prolineamide compound or its salt of useful as drug etc. can be by the advantageously efficiently preparation of industrial mode.
Although embodiments more of the present invention are in above-detailed, yet, for those of ordinary skills can to shown in specific embodiment party make various modifications and variations, and substantially do not depart from instruction of the present invention and advantage.Therefore, these class modifications and variations are covered by the spirit and scope of the invention described in appended claims.
The number of patent application 2011-123819 of the application based on submitting in Japan, the content of described patent application is incorporated to herein in full.
Claims (15)
1. the preparation method of the compound or its salt being represented by formula (2):
R wherein
1alkyl or cycloalkyl, R
2be that amino protecting group and Ar are aryl or heteroaryl, described preparation method comprises that the compound by formula (3) is represented reacts and forms pyrazole ring with thiophosphoric anhydride:
Wherein each symbol is as definition above.
2. the preparation method of the carboxylate salt of the compound being represented by formula (6):
Wherein each symbol is as limited in claim 1, and described preparation method comprises the compound or its salt representing by preparation method's preparation formula claimed in claim 1 (2), removes the amino protecting group R of described compound
2the compound representing with production (6), and make this compound change into carboxylate salt,
Wherein each symbol is as limited in claim 1.
3. the preparation method of the compound or its salt being represented by formula (1):
Wherein each symbol is as limited in claim 1, and described preparation method comprises the compound or its salt representing by preparation method's preparation formula claimed in claim 1 (2), and makes the compound so producing transform the compound or its salt that an accepted way of doing sth (1) represents:
Wherein each symbol is as limited in claim 1.
4. the preparation method of the compound or its salt being represented by formula (1):
Wherein each symbol is as limited in claim 2, described preparation method comprises the carboxylate salt of the compound representing by preparation method's preparation formula claimed in claim 2 (6), and makes the compound so producing transform the compound or its salt that an accepted way of doing sth (1) represents:
Wherein each symbol is as above limited.
5. the preparation method of the compound or its salt being represented by formula (1):
Wherein each symbol is as limited in claim 2, and described preparation method comprises the carboxylate salt of the compound representing by preparation method's preparation formula claimed in claim 2 (6):
Wherein each symbol is as above limited; Make the compound that formula (9) represents under described carboxylate salt exists, carry out the compound or its salt that reductive amination reaction represents with production (10):
R wherein
3amino protecting group,
Wherein each symbol is as above limited, and removes subsequently the amino protecting group R of the compound or its salt that formula (10) represents
3.
6. a preparation method for the salt of the compound being represented by formula (1),
Wherein each symbol is as limited in claim 5, and described method comprises the compound representing by preparation method's preparation formula claimed in claim 5 (1), and adopts acid that described compound is carried out to salify processing.
7. the carboxylate salt of the compound being represented by following formula (6):
Wherein each symbol is as limited in claim 1.
8. preparation method according to claim 1 and 2, the compound that wherein preparation formula (3) represents in the following manner: make β-one carboxylic acid or its reactive derivatives that compound or its salt that formula (4) represents represents with formula (a) react the compound with production (5) expression:
R wherein
2as limited in claim 1,
R wherein
1as 1 restriction in claim,
Wherein each symbol is as above limited, and
The hydrazine compound or its reactant salt that make subsequently this compound and following formula represent,
Ar-NH-NH
2
Wherein Ar is as limited in claim 1.
9. preparation method according to claim 5, the compound that wherein preparation formula (9) represents in the following manner: compound or its salt and thiazolidine condensation that formula (8) is represented,
R wherein
3as limited in claim 5.
10. preparation method according to claim 1 and 2, wherein R
1methyl, R
2be to replace or unsubstituted alkoxy carbonyl, and Ar is phenyl.
11. according to the preparation method described in claim 5 or 6, wherein R
1methyl, R
3be to replace or unsubstituted alkoxy carbonyl, and Ar is phenyl.
12. according to the preparation method described in any one in claim 3-6, the compound or its salt wherein being represented by formula (1) is 3-{ (2S, 4S)-4-[4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl) piperazine-1-yl] pyrrolidin-2-yl carbonyl } salt of thiazolidine.
13. according to the preparation method described in any one in claim 3-6, the compound or its salt wherein being represented by formula (1) is 3-{ (2S, 4S)-4-[4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl) piperazine-1-yl] pyrrolidin-2-yl carbonyl } thiazolidine 2.5 hydrobromates.
14. according to the preparation method described in any one in claim 3-6, the compound or its salt wherein being represented by formula (1) is 3-{ (2S, 4S)-4-[4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl) piperazine-1-yl] pyrrolidin-2-yl carbonyl } thiazolidine 2.5 hydrobromate hydrates.
15. compounds according to claim 7, wherein R1 is methyl, Ar is phenyl, and carboxylic acid is acetic acid.
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| CN105085510A (en) * | 2015-09-11 | 2015-11-25 | 沧州那瑞化学科技有限公司 | Preparation method of (S)-4-oxo-2-(thiazolidine-3-carbonyl) pyrrolidone-1-carboxylic acid tert-butyl ester |
| CN105294673A (en) * | 2014-06-18 | 2016-02-03 | 四川科伦药物研究院有限公司 | Teneligliptin synthesis method |
| CN108727364A (en) * | 2017-04-18 | 2018-11-02 | 乳源东阳光药业有限公司 | A kind of hydrobromic acid is unformed and preparation method thereof for Ge Lieting |
| WO2019205021A1 (en) * | 2018-04-25 | 2019-10-31 | 乳源东阳光药业有限公司 | Amorphous teneligliptin hydrobromide and preparation method thereof |
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| CN104177295B (en) * | 2013-05-24 | 2016-08-17 | 南京华威医药科技开发有限公司 | Preparation method for Ge Lieting key intermediate 1-(3-methyl isophthalic acid-phenyl-5-pyrazolyl) piperazine |
| CN103275010A (en) * | 2013-05-30 | 2013-09-04 | 上海皓元生物医药科技有限公司 | Preparation method of 1-(3-methyl-1-phenyl-1H-pyrazolyl-5-yl)piperazine |
| WO2015019238A1 (en) * | 2013-08-06 | 2015-02-12 | Ranbaxy Laboratories Limited | Process for the preparation of n-protected (5s)-5-(1,3-thiazolidin-3-ylcarbonyl)pyrrolidin-3-one |
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| CN105294673B (en) * | 2014-06-18 | 2018-04-13 | 四川科伦药物研究院有限公司 | A kind of hydrobromic acid replaces the synthetic method of Ge Lieting |
| CN105085510A (en) * | 2015-09-11 | 2015-11-25 | 沧州那瑞化学科技有限公司 | Preparation method of (S)-4-oxo-2-(thiazolidine-3-carbonyl) pyrrolidone-1-carboxylic acid tert-butyl ester |
| CN105085510B (en) * | 2015-09-11 | 2018-03-02 | 沧州那瑞化学科技有限公司 | A kind of preparation method of the carboxylic acid tert-butyl ester of (S) 4 oxo 2 (carbonyl of thiazolidine 3) pyrrolidines 1 |
| CN108727364A (en) * | 2017-04-18 | 2018-11-02 | 乳源东阳光药业有限公司 | A kind of hydrobromic acid is unformed and preparation method thereof for Ge Lieting |
| WO2019205021A1 (en) * | 2018-04-25 | 2019-10-31 | 乳源东阳光药业有限公司 | Amorphous teneligliptin hydrobromide and preparation method thereof |
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| JPWO2012165547A1 (en) | 2015-02-23 |
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