CN1308328C - Novel process for the preparation of pyrazolopyrimidinones - Google Patents
Novel process for the preparation of pyrazolopyrimidinones Download PDFInfo
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- CN1308328C CN1308328C CNB018114806A CN01811480A CN1308328C CN 1308328 C CN1308328 C CN 1308328C CN B018114806 A CNB018114806 A CN B018114806A CN 01811480 A CN01811480 A CN 01811480A CN 1308328 C CN1308328 C CN 1308328C
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Abstract
There is provided a process for the production a compound of general formula I: wherein A, R<1>, R<2>, R<3 >and R<4 >have meanings given in the description, which process comprises the dehydrogenation of a compound of general formula II.
Description
The present invention relates to 4-alkylpiperazine base alkylsulfonyl phenyl-and the new method for producing of 4-alkylpiperazine base sulfonyl pyridine base dihydro-pyrazolo [4,3-d] pyrimidin-7-ones derivative and husky single that furan (sildenafil) of the Alibra thing of more specifically saying so and analogue thereof.
Husky single that furan (5-[2-oxyethyl group-5-(4-methylpiperazine-1-base alkylsulfonyl) phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones) be Viagra
TMIn active ingredient, its structural formula is as follows:
Have been found that original this compound that is disclosed in the European patent application EP 463 756 is used in particular for treating especially male erectile dysfunction (referring to International Patent Application WO 94/28902).
The rapid synthetic method of multistep that is used to prepare husky single that furan has been described among the EP 463 756.Improving one's methods of its production is described in afterwards the application (European patent application EP 812 845), and the final step of this method is included in the intramolecular cyclization under alkalescence, neutrality or the acidic conditions.
We have found that at present to prepare husky single that furan and analogue thereof by a kind of novel method as mentioned below, this method has the advantage that surpasses method described in the above-mentioned prior art document.
First aspect of the present invention provides the production method of compound of Formula I:
Wherein
A represents CH or N;
R
1Represent H, low alkyl group (this alkyl can be interrupted or do not interrupted by O by O), Het, alkyl Het, aryl or alkylaryl, back 5 kinds of groups all can be by one or more halogen, cyano group, nitro, low alkyl group, OR of being selected from
5, C (O) R
6, C (O) OR
7, C (O) NR
8R
9, NR
10aR
10bAnd SO
2NR
11aR
11bSubstituting group replace or do not replaced (with regard to low alkyl group and/or can by their end-blockings or not by they end-blockings) by their;
R
2And R
4Represent low alkyl group independently;
R
3Represent low alkyl group, this alkyl can be interrupted or do not interrupted by oxygen by oxygen;
The Het representative can replace or not substituted 4-12-unit heterocyclic radical, and this group contains one or more heteroatomss that are selected from nitrogen, oxygen and sulphur;
R
5, R
6, R
7, R
8, R
9, R
11aAnd R
11bRepresent H or low alkyl group independently;
R
10aAnd R
10bRepresent H or low alkyl group independently or represent azetidinyl, pyrrolidyl or piperidyl with the nitrogen-atoms that they connected;
This method comprises the step of the compound dehydrogenation that makes general formula I I,
Wherein A, R
1, R
2, R
3And R
4As hereinbefore defined;
This method is called " method of the present invention " hereinafter.
Second aspect of the present invention provides the production method of compound of Formula I:
Wherein
A represents CH or N;
R
1Represent H, low alkyl group (this alkyl can be interrupted or do not interrupted by O by O), Het, alkyl Het, aryl or alkylaryl, back 5 kinds of groups all can be by one or more halogen, cyano group, nitro, low alkyl group, OR of being selected from
5, C (O) R
6, C (O) OR
7, C (O) NR
8R
9, NR
10aR
10bAnd SO
2NR
11aR
11bSubstituting group replace or do not replaced (with regard to low alkyl group and/or can by their end-blockings or not by they end-blockings) by their;
R
2And R
4Represent low alkyl group independently;
R
3Represent low alkyl group, this alkyl can be interrupted or do not interrupted by oxygen by oxygen;
The Het representative can replace or not substituted 4-12-unit heterocyclic radical, and this group contains one or more heteroatomss that are selected from nitrogen, oxygen and sulphur;
R
5, R
6, R
7, R
8, R
9, R
11aAnd R
11bRepresent H or low alkyl group independently;
R
10aAnd R
10bRepresent H or low alkyl group independently or represent azetidinyl, pyrrolidyl or piperidyl with the nitrogen-atoms that they connected;
Condition is that the compound of general formula I is not husky single that furan;
This method comprises the step of the compound dehydrogenation that makes general formula I I,
Wherein A, R
1, R
2, R
3And R
4As hereinbefore defined;
This method is called " method of the present invention " hereinafter.
The 3rd aspect of the present invention provides the production method of compound of Formula I:
Wherein
A represents CH;
R
1Represent H, low alkyl group (this alkyl can be interrupted or do not interrupted by O by O), Het, alkyl Het, aryl or alkylaryl, back 5 kinds of groups all can be by one or more halogen, cyano group, nitro, low alkyl group, OR of being selected from
5, C (O) R
6, C (O) OR
7, C (O) NR
8R
9, NR
10aR
10bAnd SO
2NR
11aR
11bSubstituting group replace or do not replaced (with regard to low alkyl group and/or can by their end-blockings or not by they end-blockings) by their;
R
2And R
4Represent low alkyl group independently;
R
3Represent low alkyl group, this alkyl can be interrupted or do not interrupted by oxygen by oxygen;
The Het representative can replace or not substituted 4-12-unit heterocyclic radical, and this group contains one or more heteroatomss that are selected from nitrogen, oxygen and sulphur;
R
5, R
6, R
7, R
8, R
9, R
11aAnd R
11bRepresent H or low alkyl group independently;
R
10aAnd R
10bRepresent H or low alkyl group independently or represent azetidinyl, pyrrolidyl or piperidyl with the nitrogen-atoms that they connected;
Condition is that the compound of general formula I is not husky single that furan;
This method comprises the step of the compound dehydrogenation that makes general formula I I,
Wherein A, R
1, R
2, R
3And R
4As hereinbefore defined;
This method is called " method of the present invention " hereinafter.
The 4th aspect of the present invention provides the production method of compound of Formula I:
Wherein
A represents N;
R
1Represent H, low alkyl group (this alkyl can be interrupted or do not interrupted by O by O), Het, alkyl Het, aryl or alkylaryl, back 5 kinds of groups all can be by one or more halogen, cyano group, nitro, low alkyl group, OR of being selected from
5, C (O) R
6, C (O) OR
7, C (O) NR
8R
9, NR
10aR
10bAnd SO
2NR
11aR
11bSubstituting group replace or do not replaced (with regard to low alkyl group and/or can by their end-blockings or not by they end-blockings) by their;
R
2And R
4Represent low alkyl group independently;
R
3Represent low alkyl group, this alkyl can be interrupted or do not interrupted by oxygen by oxygen;
The Het representative can replace or not substituted 4-12-unit heterocyclic radical, and this group contains one or more heteroatomss that are selected from nitrogen, oxygen and sulphur;
R
5, R
6, R
7, R
8, R
9, R
11aAnd R
11bRepresent H or low alkyl group independently;
R
10aAnd R
10bRepresent H or low alkyl group independently or represent azetidinyl, pyrrolidyl or piperidyl with the nitrogen-atoms that they connected;
This method comprises the step of the compound dehydrogenation that makes general formula I I,
Wherein A, R
1, R
2, R
3And R
4As hereinbefore defined;
This method is called " method of the present invention " hereinafter.
The compound of general formula I and II can be by the general formula I A that hereinafter describes in detail and IB and IIA or IIB representative.Novel method of the present invention comprises the compound of general formula I A, IB, IIA and IIB.
It comprises 6-10-unit carbocyclic aromatic group when using in this article when term " aryl ", such as phenyl and naphthyl etc.
The Het group can be fully saturated, part is undersaturated, dicyclo complete aromatize, the part aromatize and/or suitable.The Het group that can mention comprises such as being substituted or not substituted azetidinyl, pyrrolidyl, imidazolyl, indyl, di azoly, thiadiazolyl group, triazolyl, tetrazyl, triazolyl, thiatriazole base, pyridazinyl, morpholinyl, pyrimidyl, pyrazinyl, pyridyl, quinolyl, isoquinolyl, piperidyl, pyrazolyl, imidazopyridyl, piperazinyl, thienyl and the such group of furyl.
Tie point in the Het group can be by the arbitrary atom in the ring system that comprises (if suitable) heteroatoms arbitrarily.The Het group can also exist with the form of N-or S-oxidation.
It comprises C when using in this article when term " low alkyl group " (it comprises the moieties in alkyl Het and the alkylaryl)
1-6Alkyl (C for example
1-4Alkyl).Except as otherwise noted, when having the carbon atom of sufficient amount in the alkyl it be straight or branched, saturated or undersaturated, cyclic, acyclic or part cyclisation/acyclic and/or replaced by one or more halogen atoms.
The term " halogen " of this paper definition comprises fluorine, chlorine, bromine and iodine.
The compound of general formula I, IA and IB can contain one or more unsymmetrical carbons and can show optically-active or diastereo-isomerism thus.Method of the present invention also relates to steric isomer that forms general formula I, IA and IB compound and composition thereof thus.For example can use chromatography or the such routine techniques of fractionation crystallization to come separation of stereoisomers.Can separate different steric isomers by racemize or other mixture that uses fractional crystallization for example or the such routine techniques of HPLC to separate described compound.On the other hand, can by under the condition that can not cause racemization or epimerization epimerization, make suitable optically active raw material for example with the homochiral acid-respons, use usual manner (for example HPLC, crystallization, silica gel column chromatography or for example by dissolving again) to separate the diastereomeric ester class subsequently or prepare required optically active isomer by deriving with the tradition of homochiral acid salt.All steric isomers that form include within the scope of the invention.
The preferred compound of general formula I, IA and IB comprises some compounds like this, wherein:
R
1Represent C
1-4Alkyl, this alkyl can be interrupted by Sauerstoffatom or do not interrupted by it and/or can be by Het group (such as pyridyl) end-blocking or not by its end-blocking;
R
2Represent C
1-4Alkyl;
R
3Represent C
1-5Alkyl, this alkyl can be interrupted or do not interrupted by it by Sauerstoffatom;
R
4Represent C
1-3Alkyl.
The preferred compound of general formula I, IA and IB comprises some compounds like this, wherein:
R
1Represent the C of straight chain
1-3Alkyl, this alkyl can be interrupted by Sauerstoffatom or do not interrupted by it or can be by 2-pyridyl end-blocking or not by its end-blocking (for example forming the 2-pyridylmethyl);
R
2Represent the C of straight chain
2-3Alkyl;
R
3Represent the C of straight or branched
2-4Alkyl, this alkyl can be interrupted or do not interrupted by it by Sauerstoffatom;
R
4Represent C
1-2Alkyl.
The particularly preferred compound that can form in the methods of the invention comprises husky single that furan and following 4 kinds of compounds:
Method of the present invention can (for example: catalyzer exists, is preferably having such as the such hydrogen acceptor of hexanaphthene or toxilic acid and/or such as trifluoroacetic acid, HCl or H such as palladium/carbon (for example 5%Pd/C or 10%Pd/C) in that suitable dehydrogenating agent is arranged
2SO
4Such acid, such as 2,3,5,6-tetrachloro-1,4-benzoquinones or 2,3-two chloro-5,6-dicyano 1, high oxidative capacity quinone, (atmosphere) oxygen, MnO that the 4-benzoquinones is such
2Or carry out according to reaction conditions known in those skilled in the art under the situation of the trifluoroacetic acid solution of triphenylcarbinol existence.Can also be used for removing dehydrogenation such as the such hydrosulfate of sodium pyrosulfate from general formula compound II (IIA and IIB).Preferred dehydrogenating agent comprises such as the such catalyzer of 5%Pd/C or 10%Pd/C, is preferably having under hydrogen acceptor such such as hexanaphthene or toxilic acid and/or such acid exists such as trifluoroacetic acid the situation.This reaction can be carried out in suitable organic solvent system, and described solvent systems should with reagent or in case significant chemical reaction not take place the product that forms or at reagent or in case obviously produce stereochemistry in the product that forms and change or obviously produce other side reaction.Preferred solvent systems comprises such as toluene and the such arene of dimethylbenzene.
Method of the present invention can be more than room temperature (for example 125 ℃-250 ℃, preferred 150 ℃-230 ℃, more preferably 175 ℃-220 ℃, this depends on used solvent systems) and/or high pressure (for example 13.8-68.9kPa (2-10psi), preferred 27.6-41.4kPa (4-6psi), such as about 34.5kPa (5psi)) and/or can be at inert gas environment or do not carry out at inert gas environment (promptly having under the situation about existing) such as nitrogen or the such rare gas element of argon gas.
Suitable reaction times and temperature of reaction depend on the used solvent systems and the compound of formation, and they can be determined by those skilled in the art usually.
We have found that can be by making general formula III aldehyde cpd and the compound reaction of general formula I V and advantageously prepare the compound of general formula I I defined above (and IIA and IIB), wherein the structural formula of general formula III is as follows:
Wherein A, R
3And R
4As hereinbefore defined;
Wherein the structural formula of general formula I V is as follows:
R wherein
1And R
2As hereinbefore defined.
This condensation/cyclization can (for example about reflux temperature) more than the room temperature at solvent for use and have suitable solvent (for example: aromatic hydrocarbon, such as toluene or dimethylbenzene; Chlorobenzene or phenyl ether) carry out under the situation about existing.
This reaction can also be in the temperature of the reflux temperature that is higher than used related solvents, carry out under pressure.
The compound of general formula I V can be by general formula I VA and IVB representative.
Advantageously we have found that the compound (and IA and IB) that can in " single jar " step, directly form general formula I defined above, wherein use suitable reaction vessel that the compound of general formula III and the compound of general formula I V are reacted under high temperature and high pressure by the compound of corresponding general formula III.This reaction after, can in reaction vessel, add dehydrogenating agent and to similar condition mentioned above under in position formation general formula I IA or the midbody compound of IIB carry out dehydrogenation reaction.
Owing to do not wish to be subjected to the restriction of particular theory, so think that the reaction between compound III and the IV undertaken by the imine intermediate of following general structure or the amino alcohol intermediate of general structure, wherein the structural formula of imine intermediate is as follows:
Wherein the structural formula of the intermediate of amino alcohol is as follows:
Thereby form the compound of general formula I I as hereinbefore defined.
The compound that can prepare general formula III by known technology.For example:
(a) can according to mode like the technology type described in the German patent application DE 24 44 720 by the R that is easy to obtain
3The feedstock production A of general formula V as hereinbefore defined represents the compound of the general formula III of CH, and the structural formula of its formula of V is as follows:
The disclosure of above-mentioned document is incorporated herein by reference.
(b) on the other hand, can there be suitable oxygenant (for example: MnO
2Four n-propyls that are mixed with 4-methylmorpholine N-oxide compound are crossed shackles acid ammonium (catalyzer); Or be mixed with the oxalyl chloride of methyl-sulphoxide and triethylamine) and suitable organic solvent is (for example: acetone; Methylene dichloride; Aromatic hydrocarbon (for example toluene or dimethylbenzene); Chlorobenzene; Or aliphatic hydrocarbon (for example pentane, hexane or sherwood oil)) under the situation of Cun Zaiing by oxidation R
3And R
4The compound of general formula VI as hereinbefore defined prepares the compound that A represents the general formula III of CH, and the structural formula of its formula of VI is as follows:
Can under condition known in those skilled in the art, (for example use: LiAIH
4Borine; NaBH
4, after with iodo activation, add; Diisobutyl aluminium hydride; Or be mixed with the NaBH of acidic activator (for example carbonyl dimidazoles, thionyl chloride or methyl chlorogenate)
4) by reduction R
3And R
4The corresponding carboxylic acid of general formula VII as hereinbefore defined and directly prepare the compound of general formula VI, the structural formula of its formula of VII is as follows:
Can according to the method described in the European patent application EP 812 845 or by with it similarly method prepare the compound of general formula VII.
Yet in order to prepare the compound of general formula VI more expediently, we preferably at first make the compound esterification of general formula VII become the compound of general formula VIIIA under standard conditions,
R wherein
aRepresent low alkyl group (C for example
1-6Alkyl is such as the C of straight or branched
1-4Alkyl (for example methyl, ethyl or n-propyl or sec.-propyl)) and R
3And R
4As hereinbefore defined; Use technology known in those skilled in the art (for example catalytic hydrogenation or more preferably chemical reduction) to reduce described ester subsequently.Suitable chemical reducing agent for example comprises Red-Al , DIBAL-H or LiAlH
4When using the such reductive agent of Red-Al for example, can there be suitable organic solvent (for example: aromatic hydrocarbon (for example toluene or dimethylbenzene); Chlorobenzene; Aliphatic hydrocarbon (for example pentane, hexane or sherwood oil); THF; Diisopropyl ether; Or methylene dichloride) under the situation of Cun Zaiing in the positive pressure of rare gas element (for example nitrogen or argon gas) with for example under the room temperature or carry out reduction reaction about room temperature.
(c) can the respective compound by reduction general formula VIIIB prepare the compound that A represents the general formula III of N under the situation that has the so suitable reductive agent of Red-Al for example or DIBAL-H to exist, the structural formula of its formula of VIIIB is as follows:
R wherein
a, R
3And R
4As hereinbefore defined.When reductive agent is DIBAL-H, can be for example at low temperature (for example under-78 ℃) with there is being suitable solvent (for example: aromatic hydrocarbon (for example toluene or dimethylbenzene); Chlorobenzene; Aliphatic hydrocarbon (for example pentane, hexane or sherwood oil); THF; Diisopropyl ether; Or methylene dichloride) situation of Cun Zaiing gets off to carry out this reduction reaction.
The preferred compound of general formula III comprises that those A represent the compound of N.
Can be according to preparation method that part describes in detail or the compound for preparing general formula VIIIB by known technology.For example, can according to the step described in the WO 99/54333 (the particularly step described in the preparation in the document 18 and 19) or by with it similarly step prepare the compound of general formula VIIIB, the disclosure of the document is incorporated herein by reference.
In the time can not being purchased or do not describe subsequently, can be by the synthesis step of routine or by obtain compound and the derivative thereof of general formula I V and V by the raw material that is easy to obtain, the suitable reagent of use and reaction conditions with the similar step of methods described herein, according to standard technique.
Can use known technology separating compound from reaction mixture.
Can use the well-known technology of those skilled in the art that aryl (for example phenyl) in the compound of this paper definition and the substituting group on (if suitable) heterocyclic radical are changed into other substituting group.For example, amino can be changed into amido, amido can be hydrolyzed into amino, hydroxyl can be changed into alkoxyl group, alkoxyl group can be hydrolyzed into hydroxyl etc.
Those skilled in the art will appreciate that in the aforesaid method that the functional group of midbody compound can protected base protection maybe may need protected base protection.
The functional group who needs protection comprises hydroxyl, amino and carboxylic acid thus.The appropriate protection base of hydroxyl comprises trialkylsilkl and alkyl diaryl silyl (for example t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), THP trtrahydropyranyl, benzyl and alkyl-carbonyl (for example methyl carbonyl and ethyl carbonyl).Amino appropriate protection base comprises benzyl, tert-butoxycarbonyl, 9-fluorenyl methoxy carbonyl or benzyloxycarbonyl.The appropriate protection base of carboxylic acid comprises C
1-6The ester class of alkyl, allyl group or benzyl.
Functional group's protection and deprotection can take place before or after any reactions steps mentioned above.
Can remove protecting group according to those skilled in the art's technology well-known and as mentioned below.
The application of protecting group intactly is described in the following document: " protecting group in the organic chemistry " (" Protective Groups in Organic Chemistry "), editor: JWFMcOmie, P1enum Press (1973), " protecting group in the organic synthesis " (" ProtectiveGroups in Organic Synthesis ") the 3rd edition, TW Greene﹠amp; PGM Wutz, Wiley-Interscience (1999).
It will be understood by those skilled in the art that for according to selectable and be that mode obtains the compound of general formula I I, IIA or IIB more easily in some cases, can carry out each reactions steps as herein described and/or can carry out each reaction (promptly can on the different intermediates relevant, add substituting group and/or carry out chemical conversion) according to different orders in the different steps in the whole approach with the specific reaction of preamble.This depends on the strategy (if any) such as the operability of the character that is present in other functional group in the specific substrates, key intermediate and the protecting group adopted especially.Related chemical reaction type obviously can influence the requirement and the type of the selection of the reagent that uses, used protecting group and finish this synthetic order in described synthesis step.
Some intermediate that uses in method as herein described is new.The present invention further provides the compound of general formula I IA, IIB, III, VI and VIIIA as hereinbefore defined.
Method of the present invention can have following advantage: can be by the raw material that is purchased, prepare husky single that furan and analogue thereof according to being less than the step in the method described in the prior art, and the loss of with regard to the productive rate of key intermediate and end product, not following.Method of the present invention can further have following advantage: can be by the intermediate as herein described that is easy to obtain (being the compound of general formula III), prepare husky single that furan and analogue thereof according to single jar of step easily.
In addition, method of the present invention can have following advantage: time that can be when being less than that method prepares described in the prior art, more advantageously the one-tenth when being lower than that method prepares described in the prior art prepared husky single that furan and analogue thereof originally.
Explain the present invention and never be used for limiting the present invention by the following example.
Use Varian Unity 300MHz instrument to write down all
1H NMR spectrum.
Embodiment A
1-(4-oxyethyl group-3-formyl radical phenyl sulfonyl)-4-methylpiperazine
(a) 2-oxyethyl group-5-(4-methyl isophthalic acid-piperazinyl alkylsulfonyl) ethyl benzoate
To 2-oxyethyl group-5-(4-methyl isophthalic acid-piperazinyl alkylsulfonyl) phenylformic acid (16.4g; 0.05mol; referring to EP 812 845) be dissolved in and add concentrated hydrochloric acid in the suspension of ethanol (160mL) gained (12.5mL, 0.15mol), this step obtains a kind of solution when stirring.This solution was heated to reflux state 25 hours and cooling then.Concentrate and obtain a kind of orange in a vacuum, generation crystallization when cooling.Obtain the crude product of 13.7g by filter collecting them, by recrystallization purifying in acetonitrile they obtain 8.1g product, be a kind of thin white crystals (45.5%).
mp182-183℃
1H?NMR(CDCl
3)δ1.39(3H，t)，1.51(3H，t)，2.80(3H，s)，3.08(2H，s)，3.17(2H，s)，3.48(2H，s)，3.86(2H，s)，4.19(2H，q)，4.38(2H，q)，7.08(1H，d)，7.78(1H，d)，8.17(1H，s)
M/z measured value 357[M+H
+] 100%, C
16H
25N
2SO
5Require 357
(b) 1-(4-oxyethyl group-3-hydroxymethyl phenyl sulfonyl)-4-methylpiperazine
Toluene (40mL) solution of preparation 2-oxyethyl group-5-(4-methyl isophthalic acid-piperazinyl alkylsulfonyl) ethyl benzoate (2.0g, 0.006mol is from above-mentioned steps (a)).(4.3mL 0.01mol) changes dropping funnel and dropping in 30 minutes over to Red-Al under the positive pressure of nitrogen.Water/THF makes this reaction system cooling, washs with NaOH subsequently.Add DCM and separate each phase.Remove DCM in a vacuum and obtain crude product, make its from toluene recrystallization and obtain the subhead compound, for a kind of yellow crystal (40.5g, 92%).
mp?120℃
1H?NMR(CDCl
3)δ1.46(3H，t)，2.23(3H，s)，2.49(4H，m)，3.02(4H，m)，4.12(H，m)，4.69(2H，s)，6.92(1H，d)，7.63(1H，d)，7.72(1H，s)
M/z measured value 315[M+H
+] 100%, C
14H
23N
2O
4S requires 315
(c) 1-(4-oxyethyl group-3-formyl radical phenyl sulfonyl)-4-methylpiperazine
With MnO
2(100g 1.15mol) adds flask, adds 1-(4-oxyethyl group-3-hydroxymethyl phenyl sulfonyl)-4-methylpiperazine (15g, 0.05mol is from above-mentioned steps (b)) subsequently.This system was stirred 3 hours with acetone (150mL) washing and with this suspension.Filter out MnO with Celite
2And concentrated filtrate and obtain a kind of faint yellow oily thing in a vacuum.Make its from toluene recrystallization and obtain title compound, for a kind of light green solid (7.4g, 47%).
mp?107-108℃
1H?NMR(CDCl
3)δ1.55(3H，t)，2.28(3H，s)，2.47(4H，m)，3.02(4H，m)，4.26(2H，q)，7.12(1H，d)，7.93(1H，d)，8.19(1H，s)，10.47(1H，s)
M/z measured value 313[M+H
+] 100%, C
14H
21N
2O
4S requires 313
Can also be according to preparing title compound with the similar method of method described in the DE 24 44 720.
Embodiment 1
5-[2-oxyethyl group-5-(4-methylpiperazine-1-base alkylsulfonyl) phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (husky single that furan)
To contain 1-(4-oxyethyl group-3-formyl radical phenyl sulfonyl)-4-methylpiperazine (4.0g; 0.013mol; according to the preparation of the similar method of method described in the DE 24 44 720) and 4-amino-1-methyl-3-propyl group-1H-pyrazoles-5-methane amide (embodiment 37 among the EP 0463756) (2.6g, dimethylbenzene 0.014mol) (60mL) was 200 ℃ and 34.5kPa (5psi) time maintenance 46 hours.With the cooling of this reaction system and add catalyzer (10%Pd/C, 3.1g, 50%w/w).Under the pressure of 200 ℃ and 34.5kPa (5psi) with the further heating 12 hours of this reaction system.Also remove the crude product that organic solvent obtains 4.2g in a vacuum by filtering recovering catalyst, it is ground and purifying in methyl ethyl ketone (MEK).This step produce 3.3g (53%) title compound, be a kind of pure white solid.
mp184-185℃
1H?NMR(CDCl
3)δ0.98(3H，t)，1.62(3H，t)，1.86(2H，m)，2.27(3H，s)，2.47(-4H，m)，2.94(2H，t)，3.09(4H，m)，4.25(3H，s)，4.27(2H，q)，7.17(1H，d)，7.80(1H，d)，8.68(1H，s)
M/z measured value 475[M+H
+] 100%, C
22H
31N
6O
4S requires 475
The present invention aspect very preferably provide the preparation method of husky single that furan as defined herein and particularly according to embodiment 1 by make 1-(4-oxyethyl group-3-formyl radical phenyl sulfonyl)-4-methylpiperazine and 4-amino-1-methyl-3-propyl group-1H-pyrazoles-5-methane amide heat up and boost and suitable solvent in or the method for husky single that furan of prepared in reaction in solvent not.In aspect preferred, described being reflected under 200 ℃ and the 34.5.kPa (5psi) reaches 46 hours approximately.In aspect another is preferred, under the intensification and the condition of boosting, further handle described reaction mixture with suitable catalyzer.In aspect another is preferred, the further treatment step of this class comprise add 10%Pd/C and under the pressure of 200 ℃ and 34.5kPa (5psi) in dimethylbenzene further heating reach 12 hours approximately.
Embodiment 2
4-{6-oxyethyl group-5-[3-ethyl-6,7-dihydro-7-oxygen-2-(2-pyridylmethyl)-2H-pyrazolo [4,3-d] pyrimidine-5-yl]-the 3-pyridyl sulfonyl }-the 1-ethyl piperazidine
(a) 1-(6-oxyethyl group-5-formyl radical-3-pyridyl sulfonyl)-4-ethyl piperazidine
Down and in the nitrogen environment DIBAL-H (14.8mL) is dropwise joined 2-oxyethyl group-5-(4-ethyl-1-piperazinyl alkylsulfonyl) Nikithan (5.0g, 13.5mmol at-78 ℃; Described in WO99/54333, prepare) be dissolved in the resulting solution of toluene (100mL).With this mixture remain on-78 ℃ following 1 hour and dropwise add entry (20mL) then.With this mixture temperature to room temperature and add entry (200mL) and ethyl acetate (200mL) then.Separate organic layer and extract water again.With the organic phase that merges with the salt water washing and concentrate in a vacuum and obtain described product, be a kind of brown oil (1.64g, 36%).
1H?NMR(CDCl
3)δ1.26(3H，t)，1.47(3H，t)，2.52(4H，m)，3.06(4H，m)，4.09(2H，m)，4.59(2H，m)，8.35(1H，d)，8.70(1H，d)，10.35(1H，s)
(b) 4-{6-oxyethyl group-5-[3-ethyl-4,5,6,7-tetrahydrochysene-7-oxygen-2-(2-pyridylmethyl)-2H-pyrazolo [4,3-d] pyrimidine-5-yl]-the 3-pyridyl sulfonyl }-the 1-ethyl piperazidine
With 1-(6-oxyethyl group-5-formyl radical-3-pyridyl sulfonyl)-4-ethyl piperazidine (1.1g; 4.9mmol; from above-mentioned steps (a)) and 4-amino-5-ethyl-1-(2-pyridylmethyl)-1H-pyrazole-3-formamide (1.2g 4.9mmol) is dissolved in the resulting solution of toluene (10mL) and is heated to and refluxed 4 hours and concentrate this solution in a vacuum.Make products therefrom recrystallization and obtain a kind of light brown solid (1.4g, 52%) from ethyl acetate.
1H?NMR(CDCl
3)δ1.02(3H，t)，1.14(3H，t)，1.45(3H，t)，2.40(2H，m)，2.52(4H，m)，2.78(2H，m)，3.09(4H，m)，4.55(2H，m)，5.40(2H，s)，7.01(1H，d)，7.23(1H，m)，7.65(2H，m)，8.56(3H，m)，9.25(1H，s).
(c) 4-{6-oxyethyl group-5-[3-ethyl-6,7-dihydro-7-oxygen-2-(2-pyridylmethyl)-2H-pyrazolo [4,3-d] pyrimidine-5-yl]-the 3-pyridyl sulfonyl }-the 1-ethyl piperazidine
To 4-{6-oxyethyl group-5-[3-ethyl-4; 5; 6; 7-tetrahydrochysene-7-oxygen-2-(2-pyridylmethyl)-2H-pyrazolo [4; 3-d] pyrimidine-5-yl]-the 3-pyridyl sulfonyl }-1-ethyl piperazidine (50mg; 0.09mmol, from above-mentioned steps (b)) be dissolved in add in the resulting solution of toluene (1mL) 10%Pd/C (25mg, 50%w/w) and trifluoroacetic acid (14 μ L).In the nitrogen environment under 34.5kPa (5psi) with this mixture heating up to 200 ℃ following 6 hours.The filtration of gained mixture is also concentrated and obtains a kind of faint yellow oily thing in a vacuum.It is dissolved in DCM (5mL) and uses NaHCO
3(2mL) wash, use MgSO
4Dry and concentrate and obtain a kind of brown oil (42mg, 84%) as product.
1H?NMR(CDCl
3)δ1.02(3H，t)，1.30(3H，t)，1.58(3H，t)，2.41(2H，q)，2.55(4H，m)，3.04(2H，q)，3.10(4H，m)，4.75，(2H，q)，5.69(2H，s)，7.10(1H，d)，7.22(1H，m)，7.63(1H，m)，8.57(1H，d)，8.63(1H，d)，9.02(1H，d).
Preparation 1
2-ethyl-2-oxyethyl group-5-(4-ethyl-1-piperazinyl alkylsulfonyl) pyridine acid esters-compound
VIIIB
(1a) 2-hydroxyl-5-sulphur is for nicotinic acid
(27Kg 194.2mol) progressively joins in 30% oleum (58.1Kg) with the 2-hydroxy niacin down and in 1 hour at 50 ℃.This step heat release to 82 ℃.This reaction mixture further is heated to 140 ℃.After 12 hours the content in the reactor is cooled to 15 ℃ and filter keeping this temperature.At room temperature filter cake and acetone (33Kg) are stirred into slurry again, filter and are dried to then obtain title compound (35.3Kg, 83%), be a kind of white solid.273 ℃ of decomposition points.δ(DMSO
d6)：7.93(1H，d)，8.42(1H，d).
M/z (measured value: 220[M+H]
+, 100%.C
6H
6NO
6S requires 220.17).
(1b) 2-hydroxyl-5-sulphur is for Nikithan
(500g 2.28mol) is dissolved in ethanol (2.5L) and be heated to 80 ℃ for nicotinic acid with 2-hydroxyl-5-sulphur when stirring.After 30 minutes, distill out the 0.5L solvent, use fresh ethanol (0.5L) to substitute then and make the temperature of this system return to 80 ℃.Through after 60 minutes, distill out the 1.0L solvent, use fresh ethanol (1.0L) to substitute then and make the temperature of this system return to 80 ℃ again, through after 60 minutes, distill out the 1.0L solvent again, this reaction system is cooled to 22 ℃ and stirred 16 hours.Sedimentary product is filtered, obtains title compound (416g, 74%) with drying in ethanol (0.5L) washing and the vacuum under 50 ℃, is a kind of white solid.237 ℃ of decomposition points.
δ(DMSO
d6)：1.25(3H，t)，4.19(2H，q)，7.66(1H，d)，8.13(1H，d).
M/z (measured value: 248[M+H]
+, 100%.C
8H
10NO
6S requires 248.22).
Preparation (1c) 2-chloro-5-chloro sulphur is for Nikithan
With 2-hydroxyl-5-sulphur for Nikithan (24.7g, 0.1mol) thionyl chloride (238g, 2.0mol) and stir into slurry in the dimethyl formamide (1.0mL), stir simultaneously.This reaction mixture was heated to reflux state following 2.5 hours then.Remove the thionyl chloride of this batch in a vacuum, and obtain thick title compound (30.7g, 108%), be a kind of yellow oil by removing remaining thionyl chloride with methylbenzene azeotropic.
δ(CDCl
3)：1.46(3H，t)，4.50(2H，q)，8.72(1H，d)，9.09(1H，d)。
It is directly used in next step.
Preparation (1d) 2-chloro-5-(4-ethyl-1-piperazinyl alkylsulfonyl) Nikithan
Thick 2-chloro-5-chloro sulphur is dissolved in ethyl acetate (150mL), stirs simultaneously for Nikithan (30.7g, 0.1mol infers), use ice-cooled then.In 30 minutes in this system careful adding N-ethyl piperazidine (11.4g, 0.1mol) and triethylamine (22.5g, 0.22mol) be dissolved in the resulting solution of ethyl acetate (50mL), internal temperature is remained on below 10 ℃.Finish in case add step, then with this reaction system temperature to 22 ℃ and stirred 1 hour.Filter out solid and concentrate remaining filtrate in a vacuum and obtain thick title compound (37.1g, 103%), be a kind of thick yellow gummy.δ(CDCl
3)：1.10(3H，t)，1.42(3H，m)，2.50(2H，m)，2.60(4H，m)，3.19(4H，m)，4.43(2H，q)，8.40(1H，d)，8.80(1H，d).
M/z (measured value: 362[M+H]
+, 100%.C
14H
21ClN
3O
4S requires 362.85).
Preparation (1e) 2-oxyethyl group-5-(4-ethyl-1-piperazinyl alkylsulfonyl) Nikithan
(36.1g 0.1mol) is dissolved in the resulting solution of ethanol (180mL) and is cooled to 10 ℃ with 2-chloro-5-(4-ethyl-1-piperazinyl alkylsulfonyl) Nikithan when stirring.Progressively add sodium ethylate (10.2g, 0.15mol), keep temperature to be lower than 20 ℃.At ambient temperature this reaction mixture was stirred 18 hours then.Filter out precipitation and in filtrate, add entry (180mL).Then filtrate is heated to 40 ℃ following 1 hour.Then under environmental stress, distill out ethanol (180mL) and make remainder water solution be cooled to envrionment temperature.Next filter out sedimentary product, wash with water and the vacuum under 50 ℃ in be dried to and obtain title compound (12.6g, 34%), be-kind of light brown solid.
M.p.66-68℃.δ(CDCl
3)：1.04(3H，t)，1.39(3H，t)，1.45(3H，t)，2.41(2H，q)，2.52(4H，m)，3.08(4H，m)，4.38(2H，q)，2.57(2H，q)，8.38(1H，d)，8.61(1H，d).
M/z (measured value: 372[M+H]
+, 100%.C
16H
26N
3O
5S requires 372.46).
(1f) 2-oxyethyl group-5-(4-ethyl-1-piperazinyl alkylsulfonyl) nicotinic acid
(10.2g 0.0275mol) is dissolved in toluene (50mL) and to wherein adding sodium hydroxide (1.1g, 0.0275mol) water-soluble (20mL) resulting solution with 2-oxyethyl group-5-(4-ethyl-1-piperazinyl alkylsulfonyl) Nikithan.At ambient temperature this two-phase mixture vigorous stirring is spent the night then.Isolate water and be adjusted to pH=5.6 by adding concentrated hydrochloric acid.By ice-cooled with sedimentary product stir into slurry 15 minutes, filter, wash with water and vacuum under 50 ℃ in dryly obtain subhead compound (4.1g, 43%), be a kind of pure white solid.
Mpt?206-207℃.δ(CDCl
3)：1.25(3H，t)，1.39(3H，t)，(2H，q)，3.03(4H，m)，3.25(4H，m)，4.50(2H，q)，8.25(1H，d)，8.56(1H，d).
M/z (measured value: 344[M+H]
+, 100%.C
14H
22N
3O
5S requires 344.38).
This step is that the productive rate of simple hydrolysis and 43% is not the best.According to carrying out identical hydrolysis among the PCT/IB99/00519 (document is incorporated herein by reference) described in the preparation 23 and having obtained 88% more excellent productive rate because of this hydrolysis.
Preparation 2
2-oxyethyl group-5-(4-ethyl-1-piperazinyl alkylsulfonyl) nicotinic acid-from 2-hydroxyl-5-sulphur generation
Laminar flow method in the toluene of Nikithan
With 2-hydroxyl-5-sulphur for Nikithan (441.5g, 1.79mol) be dissolved in toluene (1.77L) and add then thionyl chloride (1.06Kg, 8.93mol) and dimethyl formamide (71.3mL).This suspension that then will stir was heated to backflow 3 hours and obtained a kind of yellow solution.Next distill thionyl chloride (2.87L) and use toluene (2.15L) to replace continuously.Then this yellow solution is cooled to 10 ℃ and in 90 minutes, dropwise add N-ethyl piperazidine (198.9g, 1.66mol) and triethylamine (392.2g, 3.88mol) be dissolved in the resulting stirred solution of toluene (700mL), keep the temperature of this reaction mixture to be lower than 10 ℃.This reaction system was stirred 18 hours at ambient temperature, then water (2 * 700mL) and salt solution (2 * 350mL) washing.By distilling out 1750mL that the dried toluene of continuous usefulness (1750mL) replaces with toluene phase azeotropic drying.With remaining brown solution be cooled to 10 ℃ and progressively add sodium ethylate (178.0g, 2.62mol), keep temperature to be lower than 10 ℃.Then this reaction system was stirred 1 hour down at 10 ℃, then with this system temperature to envrionment temperature and stirred 18 hours.Next join the sodium hydroxide (34.9g, * mol) of water-soluble (1.5L) in the toluene mixture and under 40 ℃ with 2 phase mixture vigorous stirring 18 hours.In case be cooled to envrionment temperature, then isolate water.In this system, add concentrated hydrochloric acid to pH=3, be settled out the light brown solid, by ice-cooled its precipitation 2 hours that make.Drying in water (300mL) filtration washing precipitation and the vacuum 50 ℃ under and obtain subhead compound (338.4g, 57.4%), be a kind of pure white solid.
Mpt?206-207℃.δ(CDCl
3)：1.25(3H，t)，1.39(3H，t)，2.82(2H，q)，3.03(4H，m)，3.25(4H，m)，4.50(2H，q)，8.25(1H，d)，8.56(1H，d).
M/z (measured value: 344[M+H]
+, 100%.C
14H
22N
3O
5S requires 344.38).
Preparation 3 and 4 provides selectable approach, can prepare in other compound two kinds by them.
Preparation 3
2-(methoxy ethyl)-5-[2-oxyethyl group-5-(4-ethyl piperazidine-1-base alkylsulfonyl) pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones
Will be in the sealed vessel under 120 ℃ from the product (0.75mmol) of following stage i), two (trimethyl silyl) acid amides (298mg, 1.50mmol) and ethyl acetate (73 microlitres 0.75mmol) are dissolved in the resulting mixture heating up of ethanol (10ml) 12 hours.Make the refrigerative mixture be distributed between ethyl acetate and the sodium bicarbonate aqueous solution and separate each layer.Dry (MgSO
4) organic phase and evaporation under reduced pressure.By using methylene dichloride: methyl alcohol (98: 2) obtains title compound 164mg as the purification by silica gel column chromatography crude product of eluent; Measured value: C, 53.18; H, 6.48; N, 18.14; C
23H
33N
7O
5S; 0.20C
2H
5CO
2CH
3Require C, 53.21; H, 6.49; N, 18.25%;
δ(CDCl
3)：1.04(3H，t)，1.40(3H，t)，1.58(3H，t)，2.41(2H，q)，2.57(4H，m)，3.08(2H，q)，3.14(4H，m)，3.30(3H，s)，3.92(2H，t)，4.46(2H，t)，4.75(2H，q)，8.62(1H，d)，9.04(1H，d)，10.61(1H，s)；LRMS：m/z?520(M+1)
+；mp161-162℃.
The preparation of embodiment 1 raw material
(a) pyridine-2-amino-5-sulfonic acid
(80g 0.85mol) and with gained solution heated 4 hours down at 140 ℃ progressively to add the 2-aminopyridine in 30 minutes in oleum (320g).When cooling, this reaction system is poured on ice (200g) goes up and the gained mixture was further stirred 2 hours in ice/salt bath.With the gained suspension filter, with frozen water (200ml) and cold IMS (200ml) washing solid and under suction drying and obtain title compound, be a kind of solid 111.3g; LRMS:m/z 175 (M+1)
+
(b) pyridine-2-amino-3-bromo-5-sulfonic acid
(108g, (99g is 0.62mol) so that keep stable reflux state 0.62mol) dropwise to add bromine in water-soluble (600ml) resulting hot solution to the product from stage (a) in 1 hour.After in case interpolation is finished, then with this reaction system cooling and filtration gained mixture.Solid washed with water and dry and obtain title compound 53.4g under puffing regimens;
δ(DMSOd
6，300MHz)：8.08(1H，s)，8.14(1H，s)；LRMS：m/z?253(M)
+.
(c) pyridine-3-bromo-2-chloro-5-SULPHURYL CHLORIDE
To product (25.3g from the stage (b), 100.0mmol) be dissolved in aqueous hydrochloric acid (115ml, 20%) dropwise add in the resulting ice-cold solution Sodium Nitrite (7.6g, 110.0mmol) water-soluble (30ml) resulting solution in case with temperature maintenance below 6 ℃.Under 0 ℃, this reaction system was stirred 30 minutes and at room temperature further stirred 1 hour.In this reaction mixture of evaporation under reduced pressure and the vacuum under 70 ℃ with dry 72 hours of resistates.Under 125 ℃ with this solid, phosphorus pentachloride (30.0g, 144mmol) and phosphoryl chloride (1ml, mixture heating up 10.8mmol) 3 hours and cooling then.This reaction mixture is poured on that ice (100g) is gone up and with the gained solid filtering and wash with water.Product is dissolved in methylene dichloride, drying (MgSO
4) and evaporation under reduced pressure and obtain title compound, for a kind of yellow solid 26.58g;
δ(CDCl
3，300MHz)：8.46(1H，s)，8.92(1H，s).
(d) 3-bromo-2-chloro-5-(4-ethyl piperazidine-1-base alkylsulfonyl) pyridine
With 1-ethyl piperazidine (11.3ml, 89.0mmol) and triethylamine (12.5ml, 89.0mmol) be dissolved in the resulting solution of methylene dichloride (150ml) and dropwise join product from stage (c) (23.0g 79.0mmol) is dissolved in the resulting ice-cooled solution of methylene dichloride (150ml) and under 0 ℃ this reaction system was stirred 1 hour.Concentrate this reaction mixture also by using methylene dichloride under reduced pressure: (99: 1-97: 3) silica gel column chromatography of gradient elution comes the brown oil of purifying remnants to obtain title compound, is a kind of orange solids 14.5g methyl alcohol;
δ(CDCl
3，300MHz)：1.05(3H，t)，2.42(2H，q)，2.55(4H，m)，3.12(4H，m)，8.24(1H，s)，8.67(1H，s).
(e) 3-bromo-2-oxyethyl group-5-(4-ethyl piperazidine-1-base alkylsulfonyl) pyridine
Will from the product of stage (d) (6.60g, 17.9mmol) and sodium ethylate (6.09g 89.55mmol) is dissolved in the resulting mixture heating up of ethanol (100ml) reflux 18 hours, cooling then.Under reduced pressure, concentrate this reaction mixture, make resistates be distributed between water (100ml) and the ethyl acetate (100ml) and separate each layer.With water with ethyl acetate (2 * 100ml) extract, with the organic solution drying (MgSO that merges
4) and evaporation under reduced pressure and obtain title compound, for a kind of brown solid 6.41g; Measured value: C, 41.27; H, 5.33; N, 11.11.C
13H
20BrN
3O
3S requires: C, 41.35; H, 5.28; N, 10.99%;
δ(CDCl
3，300MHz)：1.06(3H，t)，1.48(3H，t)，2.42(2H，q)，2.56(4H，m)，3.09(4H，m)，4.54(2H，q)，8.10(1H，s)，8.46(1H，s)；LRMS：m/z?378，380(M+1)
+.
(f) pyridine 2-oxyethyl group-5-(4-ethyl piperazidine-1-base alkylsulfonyl)-3-carboxylic acid, ethyl ester
Under 100 ℃ and 200psi and will be in the CO (carbon monoxide converter) gas environment from the product (6.40g of stage e), 16.92mmol), triethylamine (12ml, 86.1mmol) and three (triphenyl phosphine) palladium (O) be dissolved in the resulting mixture heating up of ethanol (60ml) 18 hours, then the cooling.Under reduced pressure with the evaporation of this reaction mixture and by using methylene dichloride: (100: 0-97: 3) the silica gel column chromatography purifying resistates of gradient elution obtains title compound, is a kind of orange 6.2g methyl alcohol;
δ(CDCl
3，300MHz)：1.02(3H，t)，1.39(3H，t)，1.45(3H，t)，2.40(2H，q)，2.54(4H，m)，3.08(4H，m)，4.38(2H，q)，4.55(2H，q)，8.37(1H，s)，8.62(1H，s)；LRMS：m/z?372(M+1)
+.
(g) pyridine 2-oxyethyl group-5-(4-ethyl piperazidine-1-base alkylsulfonyl)-3-carboxylic acid
At room temperature will from the product of stage f) (4.96g, 13.35mmol) and aqueous sodium hydroxide solution (25ml, 2N 50.0mmol) are dissolved in the resulting mixture of ethanol (25ml) and stirred 2 hours.Under reduced pressure, this reaction mixture is concentrated into half of its volume, with the ether washing and use the 4N hcl acidifying to pH 5.With this aqueous solution methylene dichloride (3 * 30ml) extractions, dry (MgSO
4) organic extraction that merges and evaporation under reduced pressure be to obtaining title compound, being a kind of tawny solid 4.02g;
δ(DMSOd
6，300MHz)：1.18(3H，t)，1.37(3H，t)，3.08(2H，q)，3.17-3.35(8H，m)，4.52(2H，q)，8.30(1H，s)，8.70(1H，s).
(h) 4-[2-oxyethyl group-5-(4-ethyl piperazidine-1-base alkylsulfonyl) pyridin-3-yl formamido group]-1H-3-ethyl pyrazoles-5-methane amide
With 4-amino-3-ethyl-(WO 9849166 for 1H-pyrazoles-5-methane amide, preparation 8) (9.2g, 59.8mmol) be dissolved in N, the resulting solution of dinethylformamide (60ml) joins the product (21.7g from stage g), 62.9mmol), I-hydroxybenzotriazole hydrate (10.1g, 66.0mmol) and triethylamine (13.15ml 94.3mmol) is dissolved in the resulting solution of methylene dichloride (240ml).(13.26g 69.2mmol) and at room temperature stirs this reaction system 6 hours to add 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride.Under reduced pressure, remove methylene dichloride, rest solution impouring ethyl acetate (400ml) is also washed this mixture with sodium bicarbonate aqueous solution (400ml).With the gained crystalline deposit filter, with ethyl acetate washing and dry in a vacuum and obtain title compound, be a kind of white powder 22g; δ (CDCl
3+ 1 DMSOd
6) 0.96 (3H, t), 1.18 (3H, t), 1.50 (3H, t), 2.25-2.56 (6H, m), 2.84 (2H, q), 3.00 (4H, m), 4.70 (2H, q), 5.60 (1H, br s), 6.78 (1H, br s), 8.56 (1H, d), 8.76 (1H, d), 10.59 (1H, s), 12.10-12.30 (1H, s); LRMS:m/z 480 (M+1)
+.
(i) 2-methoxy ethyl-4-[2-oxyethyl group-5-(4-ethyl piperazidine-1-base alkylsulfonyl) pyridin-3-yl formamido group]-3-ethyl pyrazoles-5-methane amide
1-bromo-2-methyl ethyl ether (1.72mmol) is joined product (750mg from the stage (h), 1.56mmol) and cesium carbonate (1.12g, 3.44mmol) be dissolved in N, in the resulting solution of dinethylformamide (15ml) and under 60 ℃ this reaction system was stirred 18 hours.Make this mixture of refrigerative be distributed between water and the ethyl acetate and separate each layer.With organic layer drying (MgSO
4), under reduced pressure, concentrate and obtain a kind of solid with the toluene azeotropic.Make this product from ether recrystallization and obtain title compound, for a kind of white solid.
Claims (24)
1. the production method of compound of Formula I:
Wherein
A represents CH or N;
R
1Represent H, C
1-6Alkyl, this alkyl can be interrupted by O or not by O interrupt, Het, C
1-6Alkyl Het, aryl or C
1-6Alkylaryl, back 5 kinds of groups all can be by one or more halogen, cyano group, nitro, C of being selected from
1-6Alkyl, OR
5, COR
6, COOR
7, CONR
8R
9, NR
10aR
10bAnd SO
2NR
11aR
11bSubstituting group replace or do not replaced by them, wherein with regard to C
1-6Alkyl and/or can be by their end-blockings or not by they end-blockings;
R
2And R
4Represent C independently
1-6Alkyl;
R
3Represent C
1-6Alkyl, this alkyl can be interrupted or do not interrupted by oxygen by oxygen;
Het representative can replace or not substituted 4-12-unit is saturated fully, part is undersaturated, complete aromatize, the part aromatize and/or bicyclic heterocyclic radical, this heterocyclic group contains one or more heteroatomss that are selected from nitrogen, oxygen and sulphur;
R
5, R
6, R
7, R
8, R
9, R
11aAnd R
11bRepresent H or C independently
1-6Alkyl;
R
10aAnd R
10bRepresent H or C independently
1-6Alkyl or represent azetidinyl, pyrrolidyl or piperidyl with the nitrogen-atoms that they connected;
This method comprises the step of the compound dehydrogenation that makes general formula I I;
Wherein the structural formula of general formula I I is as follows:
Wherein A, R
1, R
2, R
3And R
4As above-mentioned definition.
2. the method described in claim 1, wherein in the compound of general formula I, R
1Represent C
1-4Alkyl, this alkyl can be interrupted by Sauerstoffatom or do not interrupted by it or can be by the Het group end capping or not by its end-blocking.
3. the method described in claim 2, wherein R
1Represent straight chain C
1-3Alkyl, this alkyl can be interrupted by Sauerstoffatom or do not interrupted by it or can be by 2-pyridyl end-blocking or not by its end-blocking.
4. the described method of claim 1, wherein in the compound of general formula I, R
2Represent C
1-4Alkyl.
5. the method described in claim 4, wherein R
2Represent straight chain C
2-3Alkyl.
6. the described method of claim 1, wherein in the compound of general formula I, R
3Represent straight chain C
1-5Alkyl, this alkyl can be interrupted or do not interrupted by it by Sauerstoffatom.
7. the method described in claim 6, wherein R
3Represent the C of straight or branched
2-4Alkyl, this alkyl can be interrupted or do not interrupted by it by Sauerstoffatom.
8. the described method of claim 1, wherein in the compound of general formula I, R
4Represent straight chain C
1-3Alkyl.
9. the method described in claim 8, wherein R
4Represent straight chain C
1-2Alkyl.
10. the described method of claim 1, wherein said compound are selected from any one in husky single that furan or the following 4 kinds of compounds:
11. any described method among the claim 1-10, wherein said being reflected under the situation that dehydrogenating agent exists carried out, and described dehydrogenating agent is selected from: palladium/carbon; Hydrogen acceptor and/or the sour palladium/carbon that exists under the situation are being arranged; The quinone of high oxidative capacity; Oxygen; MnO
2Or the trifluoroacetic acid solution of triphenylcarbinol.
12. the method described in claim 11, wherein said palladium/carbon are 5%Pd/C or 10%Pd/C.
13. method as claimed in claim 11, wherein said hydrogen acceptor are tetrahydrobenzene or toxilic acid.
14. method as claimed in claim 11, wherein said acid are trifluoroacetic acid, HCl or H
2SO
4
15. as any described method among the claim 1-10, wherein said being reflected under the situation of aromatic hydrocarbon as the solvent existence carried out.
16. the method described in claim 15, wherein said solvent are toluene or dimethylbenzene.
17. as any described method among the claim 1-10, wherein said reaction is to be that 125-250 ℃, pressure are 13.8-68.9kPa and/or can be at rare gas element or do not carry out in rare gas element in temperature.
18. as any described method among the claim 1-10, wherein compound by making general formula III and the compound of general formula I V react the compound for preparing general formula I I, wherein the structural formula of general formula III is as follows:
Wherein A, R
3And R
4As defined in claim 1;
Wherein the structural formula of general formula I V is as follows:
R wherein
1And R
2As defined in claim 1.
19. the method described in claim 18, wherein in " single jar " step, form the compound of general formula I, wherein make the compound reaction of the compound of general formula III and general formula I V, after this, directly the midbody compound to the general formula I I that forms in position carries out dehydrogenation reaction.
20. the method described in claim 18 or claim 19, wherein in the compound of general formula III, on behalf of CH and the compound by oxidation general formula VI, A prepare this compound, and the structural formula of general formula VI is as follows:
R wherein
3And R
4As defined in claim 1.
21. the method described in claim 20 wherein prepares the compound of general formula VI by the corresponding carboxylic acid of reduction general formula VII, the structural formula of its formula of VII is as follows:
R wherein
3And R
4As defined in claim 1.
22. the method described in claim 20, wherein the compound by defined general formula VII in esterification such as the claim 21 forms the compound of general formula VIIIA, reducing the ester of described general formula VIIIA prepares the compound of general formula VI subsequently, and wherein the structural formula of VIIIA is as follows:
R wherein
aRepresent C
1-6Alkyl and R
3And R
4As defined in claim 1.
23. the method described in claim 18 or claim 19, wherein in the compound of general formula III, on behalf of N and the respective compound by reduction general formula VIIIB, A prepare this compound, and wherein the structural formula of VIIIB is as follows:
R wherein
aSuch as in the claim 22 definition and R
3And R
4As defined in claim 1.
24. the compound of general formula I I as defined in claim 1.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0015462.5 | 2000-06-22 | ||
| GB0015462A GB0015462D0 (en) | 2000-06-22 | 2000-06-22 | Novel process for the preparation of pyrazolopyrimidinones |
| GB0105878.3 | 2001-03-09 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1692114A CN1692114A (en) | 2005-11-02 |
| CN1308328C true CN1308328C (en) | 2007-04-04 |
Family
ID=9894299
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB018114806A Expired - Fee Related CN1308328C (en) | 2000-06-22 | 2001-06-07 | Novel process for the preparation of pyrazolopyrimidinones |
Country Status (4)
| Country | Link |
|---|---|
| CN (1) | CN1308328C (en) |
| DO (1) | DOP2001000186A (en) |
| GB (1) | GB0015462D0 (en) |
| ZA (1) | ZA200210276B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107814797B (en) * | 2016-09-13 | 2020-03-06 | 上海医药工业研究院 | Method for recovering and preparing racemic pyroquinamine |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1057464A (en) * | 1990-06-20 | 1992-01-01 | 美国辉瑞有限公司 | Pyrazolopyrimidinoneantianginal antianginal agents |
| CN1168376A (en) * | 1996-06-14 | 1997-12-24 | 辉瑞研究开发公司 | Process for preparing sildenafil |
| WO1999064004A1 (en) * | 1998-06-08 | 1999-12-16 | Bristol-Myers Squibb Company | QUINAZOLINONE INHIBITORS OF cGMP PHOSPHODIESTERASE |
| WO2000024745A1 (en) * | 1998-10-23 | 2000-05-04 | Pfizer Limited | PYRAZOLOPYRIMIDINONE cGMP PDE5 INHIBITORS FOR THE TREATMENT OF SEXUAL DYSFUNCTION |
-
2000
- 2000-06-22 GB GB0015462A patent/GB0015462D0/en not_active Ceased
-
2001
- 2001-06-06 DO DO2001000186A patent/DOP2001000186A/en unknown
- 2001-06-07 CN CNB018114806A patent/CN1308328C/en not_active Expired - Fee Related
-
2002
- 2002-12-19 ZA ZA200210276A patent/ZA200210276B/en unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1057464A (en) * | 1990-06-20 | 1992-01-01 | 美国辉瑞有限公司 | Pyrazolopyrimidinoneantianginal antianginal agents |
| CN1168376A (en) * | 1996-06-14 | 1997-12-24 | 辉瑞研究开发公司 | Process for preparing sildenafil |
| WO1999064004A1 (en) * | 1998-06-08 | 1999-12-16 | Bristol-Myers Squibb Company | QUINAZOLINONE INHIBITORS OF cGMP PHOSPHODIESTERASE |
| WO2000024745A1 (en) * | 1998-10-23 | 2000-05-04 | Pfizer Limited | PYRAZOLOPYRIMIDINONE cGMP PDE5 INHIBITORS FOR THE TREATMENT OF SEXUAL DYSFUNCTION |
Non-Patent Citations (2)
| Title |
|---|
| N-3-substituted imidazoquinazolinones: potent andselective PDE5 inhibitors as potential agents for treatment oferectile dysfunction D.P.ROTELLA ET AL,J. Med. Chem.,Vol.43 No.7 2000 * |
| optimization of substitutedN-3-benzylimidazoquinazolinone sulfonamides as potent andselective PDE5 inhibitors D.P.ROTELLA ET AL,J. Med. Chem.,Vol.43 No.26 2000 * |
Also Published As
| Publication number | Publication date |
|---|---|
| DOP2001000186A (en) | 2002-08-30 |
| GB0015462D0 (en) | 2000-08-16 |
| ZA200210276B (en) | 2003-12-19 |
| CN1692114A (en) | 2005-11-02 |
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