CN1692114A - Novel preparation method of pyrazolopyrimidinones - Google Patents

Abstract

The invention provides a process for the production of a compound of the general formula wherein A, R¹、R²、R³And R⁴Having the meaning given in the description, comprising the step of dehydrogenating a compound of general formula (II).

Description

Novel preparation method of pyrazolopyrimidinones

The present invention relates to 4-alkylpiperazinylsulfonylphenyl- and 4-alkylpiperazinylsulfonylpyridyldihydropyrazolo[4,3-d]pyrimidin-7-one derivatives and more particularly It is said to be a new production method of the anti-impotence drug sildenafil and its analogues.

Saldanafr (5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-di Hydrogen-7H-pyrazolo[4,3-d]pyrimidin-7-one) is the active ingredient in ^ViagraTM , and its structural formula is as follows:

This compound originally disclosed in European Patent Application EP 463 756 has been found to be particularly useful in the treatment of erectile dysfunction, especially in men (see International Patent Application WO 94/28902).

EP 463 756 describes a multi-step synthetic process for the preparation of saldanafr. An improved method for its production is described in a later application (European patent application EP 812 845), the final step of which involves an internal cyclization under basic, neutral or acidic conditions.

We have now found that sartanafr and its analogues can be prepared by a novel method as described below, which has advantages over the methods described in the above-mentioned prior art documents.

The first aspect of the present invention provides the production method of general formula I compound:

in

A stands for CH or N;

R ¹ represents H, lower alkyl (the alkyl may or may not be interrupted by O), Het, alkylHet, aryl or alkylaryl, and the latter 5 groups may be replaced by one or more one selected from halogen, cyano, nitro, lower alkyl, OR ⁵ , C(O)R ⁶ , C(O)OR ⁷ , C(O)NR ⁸ R ⁹ , NR ^10a R ^10b and SO ₂ NR ^11a The substituents of R ^11b are substituted or not substituted by them (in terms of lower alkyl and/or may or may not be capped by them);

R ² and R ⁴ independently represent lower alkyl;

R ³ represents a lower alkyl group, which may or may not be interrupted by oxygen;

Het represents a 4-12-membered heterocyclic group that may be substituted or unsubstituted, and the group contains one or more heteroatoms selected from nitrogen, oxygen and sulfur;

R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ^11a and R ^11b independently represent H or lower alkyl;

R ^10a and R ^10b independently represent H or lower alkyl or together with the nitrogen atom to which they are attached represent azetidinyl, pyrrolidinyl or piperidinyl;

The method comprises the step of dehydrogenating a compound of general formula II,

wherein A, R ¹ , R ² , R ³ and R ⁴ are as defined above;

This method is hereinafter referred to as "the method of the present invention".

The second aspect of the present invention provides the production method of general formula I compound:

in

A stands for CH or N;

R ¹ represents H, lower alkyl (the alkyl may or may not be interrupted by O), Het, alkylHet, aryl or alkylaryl, and the latter 5 groups may be replaced by one or more one selected from halogen, cyano, nitro, lower alkyl, OR ⁵ , C(O)R ⁶ , C(O)OR ⁷ , C(O)NR ⁸ R ⁹ , NR ^10a R ^10b and SO ₂ NR ^11a The substituents of R ^11b are substituted or not substituted by them (in terms of lower alkyl and/or may or may not be capped by them);

R ² and R ⁴ independently represent lower alkyl;

R ³ represents a lower alkyl group, which may or may not be interrupted by oxygen;

Het represents a 4-12-membered heterocyclic group that may be substituted or unsubstituted, and the group contains one or more heteroatoms selected from nitrogen, oxygen and sulfur;

R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ^11a and R ^11b independently represent H or lower alkyl;

R ^10a and R ^10b independently represent H or lower alkyl or together with the nitrogen atom to which they are attached represent azetidinyl, pyrrolidinyl or piperidinyl;

The proviso is that the compound of general formula I is not saldanafr;

The method comprises the step of dehydrogenating a compound of general formula II,

wherein A, R ¹ , R ² , R ³ and R ⁴ are as defined above;

This method is hereinafter referred to as "the method of the present invention".

The third aspect of the present invention provides the production method of the compound of general formula I:

in

A stands for CH;

R ¹ represents H, lower alkyl (the alkyl may or may not be interrupted by O), Het, alkylHet, aryl or alkylaryl, and the latter 5 groups may be replaced by one or more one selected from halogen, cyano, nitro, lower alkyl, OR ⁵ , C(O)R ⁶ , C(O)OR ⁷ , C(O)NR ⁸ R ⁹ , NR ^10a R ^10b and SO ₂ NR ^11a The substituents of R ^11b are substituted or not substituted by them (in terms of lower alkyl and/or may or may not be capped by them);

R ² and R ⁴ independently represent lower alkyl;

R ³ represents a lower alkyl group, which may or may not be interrupted by oxygen;

Het represents a 4-12-membered heterocyclic group that may be substituted or unsubstituted, and the group contains one or more heteroatoms selected from nitrogen, oxygen and sulfur;

R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ^11a and R ^11b independently represent H or lower alkyl;

R ^10a and R ^10b independently represent H or lower alkyl or together with the nitrogen atom to which they are attached represent azetidinyl, pyrrolidinyl or piperidinyl;

The proviso is that the compound of general formula I is not saldanafr;

The method comprises the step of dehydrogenating a compound of general formula II,

wherein A, R ¹ , R ² , R ³ and R ⁴ are as defined above;

This method is hereinafter referred to as "the method of the present invention".

The 4th aspect of the present invention provides the production method of general formula I compound:

in

A stands for N;

R ¹ represents H, lower alkyl (the alkyl may or may not be interrupted by O), Het, alkylHet, aryl or alkylaryl, and the latter 5 groups may be replaced by one or more one selected from halogen, cyano, nitro, lower alkyl, OR ⁵ , C(O)R ⁶ , C(O)OR ⁷ , C(O)NR ⁸ R ⁹ , NR ^10a R ^10b and SO ₂ NR ^11a The substituents of R ^11b are substituted or not substituted by them (in terms of lower alkyl and/or may or may not be capped by them);

R ² and R ⁴ independently represent lower alkyl;

R ³ represents a lower alkyl group, which may or may not be interrupted by oxygen;

Het represents a 4-12-membered heterocyclic group that may be substituted or unsubstituted, and the group contains one or more heteroatoms selected from nitrogen, oxygen and sulfur;

R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ^11a and R ^11b independently represent H or lower alkyl;

R ^10a and R ^10b independently represent H or lower alkyl or together with the nitrogen atom to which they are attached represent azetidinyl, pyrrolidinyl or piperidinyl;

The method comprises the step of dehydrogenating a compound of general formula II,

wherein A, R ¹ , R ² , R ³ and R ⁴ are as defined above;

This method is hereinafter referred to as "the method of the present invention".

Compounds of general formulas I and II may be represented by general formulas IA and IB and IIA or IIB as detailed below. The novel methods of the present invention include compounds of the general formulas IA, IB, IIA and IIB.

When the term "aryl" is used herein it includes 6-10-membered carbocyclic aromatic groups such as phenyl and naphthyl and the like.

Het groups may be fully saturated, partially unsaturated, fully aromatic, partially aromatic and/or suitably bicyclic. Het groups that may be mentioned include, for example, azetidinyl, pyrrolidinyl, imidazolyl, indolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, which may or may not be substituted. Azolyl, oxatriazolyl, thiatriazolyl, pyridazinyl, morpholinyl, pyrimidinyl, pyrazinyl, pyridyl, quinolinyl, isoquinolinyl, piperidinyl, pyrazolyl, imidazolyl Groups such as pyridyl, piperazinyl, thienyl and furyl.

The point of attachment in any Het group may be through any atom in the ring system including, if appropriate, heteroatoms. The Het group can also exist in N- or S-oxidized form.

When the term "lower alkyl" (which includes the alkyl moiety in alkylHet and alkylaryl) as used herein it includes C _1-6 alkyl (eg C _1-4 alkyl). Unless otherwise stated, an alkyl group is linear or branched, saturated or unsaturated, cyclic, acyclic or partially cyclized/acyclic and/or surrounded by a or more halogen atoms.

The term "halogen" as defined herein includes fluorine, chlorine, bromine and iodine.

Compounds of the general formulas I, IA and IB may contain one or more asymmetric carbon atoms and may thus exhibit optical rotation or diastereoisomerism. The process of the invention thus also involves the formation of stereoisomers of compounds of general formula I, IA and IB and mixtures thereof. Stereoisomers may be separated using conventional techniques such as chromatography or fractional crystallization. The different stereoisomers can be separated by separation of racemic or other mixtures of the compounds using conventional techniques such as fractional crystallization or HPLC. On the other hand, it can be obtained by reacting a suitable optically active starting material, for example, with a pure chiral acid under conditions which do not lead to racemization or epimerization, followed by conventional methods (for example, HPLC, crystallization, The desired optical isomers are prepared by separation of the diastereoisomeric esters by silica gel chromatography or eg by conventional redissolution with a pure chiral acid salt or by derivatization. All stereoisomers formed are included within the scope of the present invention.

Preferred compounds of general formulas I, IA and IB include those in which:

^R represents a C _1-4 alkyl group which may or may not be interrupted by an oxygen atom and/or may or may not be terminated by a Het group such as pyridyl;

R ² represents C _1-4 alkyl;

R ³ represents a C _1-5 alkyl group, which may or may not be interrupted by an oxygen atom;

R ⁴ represents a C _1-3 alkyl group.

More preferred compounds of general formulas I, IA and IB include those wherein:

R ¹ represents a straight-chain C _1-3 alkyl group which may or may not be interrupted by an oxygen atom or which may or may not be terminated by a 2-pyridyl group (e.g. forming a 2-pyridyl methyl);

R ² represents straight chain C _2-3 alkyl;

R ³ represents a straight or branched C _2-4 alkyl group, which may or may not be interrupted by an oxygen atom;

R ⁴ represents a C _1-2 alkyl group.

Particularly preferred compounds that may be formed in the process of the present invention include saltanafr and the following 4 compounds:

The process of the present invention can be carried out in the presence of a suitable dehydrogenating agent (for example: a catalyst such as palladium/carbon (for example 5% Pd/C or 10% Pd/C), preferably in the presence of hydrogen such as cyclohexane or maleic acid. Acceptors and/or acids such as trifluoroacetic acid, HCl or _H2SO4 , such as 2,3,5,6 _- tetrachloro-1,4-benzoquinone or 2,3-dichloro-5,6- In the presence of a highly oxidizing quinone such as dicyano-1,4-benzoquinone, (atmospheric) oxygen, MnO ₂ or triphenylmethanol in trifluoroacetic acid, the reaction conditions are known to those skilled in the art. Bisulfate salts such as sodium bisulfate can also be used to remove hydrogen from compounds of general formula II (IIA and IIB). Preferred dehydrogenating agents include catalysts such as 5% Pd/C or 10% Pd/C, preferably In the presence of a hydrogen acceptor such as cyclohexane or maleic acid and/or an acid such as trifluoroacetic acid, the reaction can be carried out in a suitable organic solvent system which should not react with Significant chemical reactions or significant stereochemical changes or other side reactions in the reactants or once formed products.Preferable solvent systems include aromatic hydrocarbons such as toluene and xylene.

The process of the present invention can be carried out above room temperature (for example 125°C-250°C, preferably 150°C-230°C, more preferably 175°C-220°C, depending on the solvent system used) and/or high pressure (for example 13.8-68.9kPa ( 2-10psi), preferably 27.6-41.4kPa (4-6psi), such as 34.5kPa (5psi) or so) and/or may be in an inert gas environment or not in an inert gas environment (that is, in the presence of an inert gas such as nitrogen or hydrogen) case) proceed.

Appropriate reaction times and temperatures depend on the solvent system used and the compounds formed, and can generally be determined by those skilled in the art.

We have found that compounds of general formula II (as well as IIA and IIB) as defined above can be advantageously prepared by reacting an aldehyde compound of general formula III with a compound of general formula IV, wherein the structural formula of general formula III is as follows:

wherein A, ^R and ^R are as defined above;

Wherein the structural formula of general formula IV is as follows:

wherein R ¹ and R ² are as defined above.

This condensation/cyclization reaction can be carried out above room temperature (e.g. around the reflux temperature of the solvent used) and in the presence of a suitable solvent (e.g. aromatic hydrocarbons such as toluene or xylene; chlorobenzene or diphenyl ether) .

The reaction can also be carried out under pressure at temperatures above the reflux temperature of the relevant solvent used.

Compounds of general formula IV may be represented by general formulas IVA and IVB.

Advantageously we have found that compounds of general formula I (as well as IA and IB) as defined above can be formed directly from the corresponding compounds of general formula III in a "one-pot" step, wherein the compounds of general formula III The compound of is reacted with the compound of general formula IV under high temperature and high pressure. After this reaction, a dehydrogenating agent can be added to the reaction vessel and the intermediate compound of general formula IIA or IIB formed in situ under similar conditions as described above can be subjected to a dehydrogenation reaction.

Because do not wish to be limited by specific theory, so think that the reaction between compound III and IV is carried out by the imine intermediate of following general structure or the aminoalcohol intermediate of general structure, wherein the structural formula of imine intermediate is as follows:

Wherein the structural formula of the intermediate of aminoalcohol is as follows:

Thereby a compound of general formula II as defined above is formed.

Compounds of general formula III can be prepared by known techniques. For example:

(a) Compounds of the general formula III in which A represents CH can be prepared from readily available starting materials of the general formula V with ^R as defined above in a manner analogous to the technique described in German patent application DE 24 44 720, wherein the general formula V The structural formula is as follows:

The disclosures of the aforementioned documents are incorporated herein by reference.

(b) On the other hand, it can be used in the presence of a suitable oxidizing agent (for example: MnO ₂ ; tetra-n-propyl ammonium peroxoate (catalyst) mixed with 4-methylmorpholine N-oxide; or mixed with dimethyl sulfide oxalyl chloride of sulfone and triethylamine) and suitable organic solvents (for example: acetone; methylene chloride; aromatic hydrocarbons (such as toluene or xylene); chlorobenzene; or aliphatic hydrocarbons (such as pentane, hexane, or petroleum ether)) Compounds of formula III wherein A represents CH are prepared by oxidation of compounds of formula VI wherein R ^{and R} are as defined above, wherein the formula VI is as follows:

It can be used under conditions known to those skilled in the art (e.g. using: LiAIH ₄ ; borane; NaBH ₄ , added after activation with iodine; diisobutylaluminum hydride; or mixed with an acidic activator (e.g. carbonyldiimidazole, Thionyl chloride or methyl chloroorthoate) (NaBH ₄ ) directly prepares compounds of general formula VI by reducing R ^and R ⁴ as defined above for the corresponding carboxylic acid of general formula VII, wherein the structural formula of general formula VII is as follows:

Compounds of general formula VII may be prepared as described in European Patent Application EP 812 845 or by methods analogous thereto.

However, for more convenient preparation of compounds of general formula VI, we prefer to first esterify compounds of general formula VII to compounds of general formula VIIIA under standard conditions,

wherein R ^represents a lower alkyl (for example C _1-6 alkyl, such as straight or branched C _1-4 alkyl (for example methyl, ethyl or n-propyl or isopropyl)) and R ^{and R4} is as defined above; the ester is then reduced using techniques well known to those skilled in the art, such as catalytic hydrogenation or more preferably chemical reduction. Suitable chemical reducing agents include, for example, Red-Al(R), DIBAL-H or _LiAlH4 . When using a reducing agent such as Red-Al®, it can be used in the presence of a suitable organic solvent (for example: aromatic hydrocarbons (such as toluene or xylene); chlorobenzene; aliphatic hydrocarbons (such as pentane, hexane or petroleum ether); THF ; diisopropyl ether; or dichloromethane) in the presence of a positive pressure of an inert gas (eg nitrogen or argon) and eg at room temperature or around room temperature to carry out the reduction.

(c) Compounds of the general formula III in which A represents N can be prepared by reducing the corresponding compound of the general formula VIIIB in the presence of a suitable reducing agent such as Red-Al® or DIBAL-H, wherein the structural formula of the general formula VIIIB as follows:

wherein R ^a , R ³ and R ⁴ are as defined above. When the reducing agent is DIBAL-H, it can be used, for example, at low temperature (for example at -78 ° C) and in the presence of a suitable solvent (for example: aromatic hydrocarbons (such as toluene or xylene); chlorobenzene; aliphatic hydrocarbons (such as pentane, hexane, etc.) alkane or petroleum ether); THF; diisopropyl ether; or dichloromethane) to carry out the reduction reaction.

Preferred compounds of formula III include those wherein A represents N.

Compounds of general formula VIIIB may be prepared as detailed in the Preparations or by known techniques. For example, compounds of general formula VIIIB can be prepared according to the steps described in WO 99/54333 (particularly the steps described in Preparations 18 and 19 of this document) or by steps analogous thereto, the disclosure of which The contents are incorporated herein by reference.

When not commercially available or subsequently described, compounds of general formula IV and V can be obtained by conventional synthetic procedures or by procedures analogous to the methods described herein, from readily available starting materials according to standard techniques, using suitable reagents and reaction conditions. compounds and their derivatives.

Compounds can be isolated from reaction mixtures using known techniques.

Substituents on aryl (eg phenyl) and (if appropriate) heterocyclyl groups in compounds defined herein may be converted to other substituents using techniques well known to those skilled in the art. For example, an amino group can be converted to an amido group, an amido group can be hydrolyzed to an amino group, a hydroxyl group can be converted to an alkoxy group, an alkoxy group can be hydrolyzed to a hydroxyl group, and the like.

Those skilled in the art will understand that in the above methods, the functional groups of the intermediate compounds may or may need to be protected with protecting groups.

Functional groups requiring protection thus include hydroxyl, amino and carboxylic acids. Suitable protecting groups for hydroxy groups include trialkylsilyl and diarylalkylsilyl groups (such as tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), Tetrahydropyranyl, benzyl and alkylcarbonyl (eg methylcarbonyl and ethylcarbonyl). Suitable protecting groups for amino include benzyl, tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl or benzyloxycarbonyl. Suitable protecting groups for carboxylic acids include C _1-6 alkyl, allyl or benzyl esters.

Protection and deprotection of functional groups can occur before or after any of the reaction steps described above.

Protecting groups can be removed according to techniques well known to those skilled in the art and as described hereinafter.

The use of protecting groups is fully described in: "Protective Groups in Organic Chemistry" ("Protective Groups in Organic Chemistry"), ed.: JWFMcOmie, Plenum Press (1973), and "Protective Groups in Organic Synthesis" ( "Protective Groups in Organic Synthesis") 3rd Edition, TW Greene & PGM Wutz, Wiley-Interscience (1999).

Those skilled in the art will understand that in order to obtain compounds of general formula II, IIA or IIB in an optional and in some cases more convenient manner, the various reaction steps described herein can be carried out in different orders and/or Or each reaction can be performed at a different stage in the overall pathway (ie, substituents can be added and/or chemical transformations can be performed on different intermediates associated with a particular reaction above). This depends inter alia on such factors as the nature of other functional groups present in the particular substrate, the availability of key intermediates and the strategy of protecting groups employed (if any). The type of chemical reactions involved will obviously affect the choice of reagents used in the synthetic steps, the requirement and type of protecting groups employed and the order in which the synthesis is carried out.

Certain of the intermediates used in the methods described herein are novel. The present invention further provides compounds of general formulas IIA, IIB, III, VI and VIIIA as defined above.

The method of the present invention can have the following advantages: it is possible to prepare sardanafur and its analogues from commercially available raw materials according to steps less than those described in the prior art, while the production of key intermediates and final products There is no accompanying loss in terms of rate. The process of the present invention may further have the advantage that saldanafr and its analogs may be prepared in a convenient one-pot procedure from readily available intermediates described herein (ie, compounds of general formula III).

In addition, the method of the present invention may have the following advantages: it is possible to prepare sardana in less time than the preparation time of the method described in the prior art, and more conveniently at a cost lower than that of the preparation method described in the prior art. Furan and its analogues.

The present invention is illustrated by the following examples but by no means intended to limit the invention.

^All1H NMR spectra were recorded using a Varian Unity 300 MHz instrument.

Example A

1-(4-Ethoxy-3-formylphenylsulfonyl)-4-methylpiperazine

(a) Ethyl 2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)benzoate

To a suspension of 2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)benzoic acid (16.4 g, 0.05 mol, see EP 812 845) dissolved in ethanol (160 mL) was added Concentrated hydrochloric acid (12.5 mL, 0.15 mol), this step gave a solution while stirring. The solution was heated to reflux for 25 hours and then cooled. Concentration in vacuo gave an orange oil which crystallized on cooling. They were collected by filtration to give 13.7 g of crude product, which were purified by recrystallization in acetonitrile to give 8.1 g of product as a fine white crystal (45.5%).

mp182-183℃

¹ H 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 found 357 [M+H ⁺ ] 100%, C ₁₆ H ₂₅ N ₂ SO ₅ required 357

(b) 1-(4-ethoxy-3-hydroxymethylphenylsulfonyl)-4-methylpiperazine

A solution of ethyl 2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)benzoate (2.0 g, 0.006 mol, from step (a) above) in toluene (40 mL) was prepared. Red-Al(R) (4.3 mL, 0.01 mol) was transferred to the dropping funnel and added dropwise over 30 minutes under positive pressure of nitrogen. The reaction was cooled with water/THF, then washed with NaOH. DCM was added and the phases were separated. DCM was removed in vacuo to give a crude product which was recrystallized from toluene to give the subtitle compound as yellow crystals (40.5 g, 92%).

mp120℃

¹ H NMR (CDCl ₃ ) δ1.46(3H, t), 2.23(3H, s), 2.49(4H, m), 3.02(4H, m), 4.12(2H, m), 4.69(2H, s) , 6.92(1H,d), 7.63(1H,d), 7.72(1H,s)

m/z found 315 [M+H ⁺ ] 100%, C ₁₄ H ₂₃ N ₂ O ₄ S requires 315

(c) 1-(4-Ethoxy-3-formylphenylsulfonyl)-4-methylpiperazine

_MnO2 (100 g, 1.15 mol) was added to the flask, followed by 1-(4-ethoxy-3-hydroxymethylphenylsulfonyl)-4-methylpiperazine (15 g, 0.05 mol, from the above step ( b)). The system was washed with acetone (150 mL) and the suspension was stirred for 3 hours. The _MnO2 was filtered through Celite(R) and the filtrate was concentrated in vacuo to give a pale yellow oil. This was recrystallized from toluene to give the title compound as a light green solid (7.4 g, 47%).

mp107-108℃

¹ H 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 found 313 [M+H ⁺ ] 100%, C ₁₄ H ₂₁ N ₂ O ₄ S requires 313

The title compound can also be prepared analogously to the method described in DE 24 44 720.

Example 1

5-[2-Ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)phenyl]-1-methyl-3-n-propane Base-1,6-dihydro-7H-pyrazolo[4.3-d]pyrimidin-7-one (saldanafur)

A mixture containing 1-(4-ethoxy-3-formylphenylsulfonyl)-4-methylpiperazine (4.0 g, 0.013 mol, prepared in a similar manner to that described in DE 24 44 720) and 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide (Example 37 in EP 0463756) (2.6g, 0.014mol) in xylene (60mL) at 200°C and 34.5 Hold at kPa (5 psi) for 46 hours. The reaction was cooled and catalyst (10% Pd/C, 3.1 g, 50% w/w) was added. The reaction was further heated at 200° C. and a pressure of 34.5 kPa (5 psi) for 12 hours. The catalyst was recovered by filtration and the organic solvent was removed in vacuo to give 4.2 g of crude product which was purified by trituration in methyl ethyl ketone (MEK). This step yielded 3.3 g (53%) of the title compound as a pure white solid.

mp184-185℃

¹ H 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 found 475 [M+H ⁺ ] 100%, C ₂₂ H ₃₁ N ₆ O ₄ S requires 475

A very preferred aspect of the present invention provides a process for the preparation of saldanafr as defined herein and in particular according to Example 1 by making 1-(4-ethoxy-3-formylphenylsulfonyl)-4-methane The invention discloses a method for preparing saldanafr by reacting basepiperazine and 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide at elevated temperature and elevated pressure in a suitable solvent or without a solvent. In a preferred aspect, the reaction is carried out at 200° C. and 34.5. kPa (5 psi) for about 46 hours. In another preferred aspect, the reaction mixture is further treated with a suitable catalyst at elevated temperature and pressure. In another preferred aspect, such further treatment steps include the addition of 10% Pd/C and further heating in xylene at 200° C. and a pressure of 34.5 kPa (5 psi) for about 12 hours.

Example 2

4-{6-ethoxy-5-[3-ethyl-6,7-dihydro-7-oxo-2-(2-pyridylmethyl)-2H- Pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridylsulfonyl}-1-ethylpiperazine

(a) 1-(6-ethoxy-5-formyl-3-pyridylsulfonyl)-4-ethylpiperazine

DIBAL-H (14.8 mL) was added dropwise to ethyl 2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinate (5.0 g , 13.5 mmol; prepared as described in WO99/54333) was dissolved in toluene (100 mL) to obtain a solution. The mixture was kept at -78°C for 1 hour and then water (20 mL) was added dropwise. The mixture was warmed to room temperature and then water (200 mL) and ethyl acetate (200 mL) were added. The organic layer was separated and the aqueous phase re-extracted. The combined organic phases were washed with brine and concentrated in vacuo to give the product as a brown oil (1.64 g, 36%).

¹ H 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-ethoxy-5-[3-ethyl-4,5,6,7-tetrahydro-7-oxo-2-(2- pyridylmethyl )-2H-pyrazole And[4,3-d]pyrimidin-5-yl]-3-pyridylsulfonyl}-1-ethylpiperazine

1-(6-Ethoxy-5-formyl-3-pyridylsulfonyl)-4-ethylpiperazine (1.1 g, 4.9 mmol, from step (a) above) and 4-amino-5- A solution of ethyl-1-(2-pyridylmethyl)-1H-pyrazole-3-carboxamide (1.2 g, 4.9 mmol) dissolved in toluene (10 mL) was heated to reflux for 4 hours and concentrated in vacuo the solution. The resulting product was recrystallized from ethyl acetate to give a light brown solid (1.4 g, 52%).

¹ H 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-ethoxy-5-[3-ethyl-6,7-dihydro-7-oxo-2-(2- pyridylmethyl )-2H-pyrazolo[4, 3-d]pyrimidin-5-yl]-3-pyridylsulfonyl}-1-ethylpiperazine

To 4-{6-ethoxy-5-[3-ethyl-4,5,6,7-tetrahydro-7-oxo-2-(2-pyridylmethyl)-2H-pyrazolo[ A solution of 4,3-d]pyrimidin-5-yl]-3-pyridylsulfonyl}-1-ethylpiperazine (50 mg, 0.09 mmol, from step (b) above) dissolved in toluene (1 mL) 10% Pd/C (25 mg, 50% w/w) and trifluoroacetic acid (14 μL) were added to it. The mixture was heated to 200° C. for 6 hours under a nitrogen atmosphere at 34.5 kPa (5 psi). The resulting mixture was filtered and concentrated in vacuo to give a pale yellow oil. It was dissolved in DCM (5 mL) and washed with NaHCO ₃ (2 mL), dried over MgSO ₄ and concentrated to give a brown oil as the product (42 mg, 84%).

¹ HNMR (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-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)pyridinate-compound

VIIIB

(1a) 2-Hydroxy-5-sulfonicotinic acid

2-Hydroxynicotinic acid (27 Kg, 194.2 mol) was gradually added to 30% oleum (58.1 Kg) at 50° C. within 1 hour. This step was exothermic to 82°C. The reaction mixture was further heated to 140°C. After maintaining this temperature for 12 hours the contents of the reactor were cooled to 15°C and filtered. The filter cake was then reslurried with acetone (33Kg) at room temperature, filtered and dried to give the title compound (35.3Kg, 83%) as a white solid. The decomposition point is 273°C. δ(DMSO _d6 ): 7.93(1H,d), 8.42(1H,d).

m/z (found: 220 [M+H] ⁺ , 100%. C ₆ H ₆ NO ₆ S requires 220.17).

(1b) 2-Hydroxy-5-sulfonicotinic acid ethyl ester

2-Hydroxy-5-sulfonicotinic acid (500 g, 2.28 mol) was dissolved in ethanol (2.5 L) while stirring and heated to 80°C. After 30 minutes, 0.5 L of solvent was distilled off, then replaced with fresh ethanol (0.5 L) and the temperature of the system was returned to 80°C. After another 60 minutes, 1.0 L of solvent was distilled, then replaced with fresh ethanol (1.0 L) and the temperature of the system was returned to 80° C. After another 60 minutes, 1.0 L of solvent was distilled, and the reaction system was cooled to 22°C and stirred for 16 hours. The precipitated product was filtered, washed with ethanol (0.5 L) and dried in vacuo at 50 °C to give the title compound (416 g, 74%) as a white solid. The decomposition point is 237°C.

δ(DMSO _d6 ): 1.25(3H, t), 4.19(2H, q), 7.66

(1H,d), 8.13(1H,d).

m/z (found: 248 [M+H] ⁺ , 100%. C ₈ H ₁₀ NO ₆ S requires 248.22).

Preparation of (1c) ethyl 2-chloro-5-chlorosulfonicotinate

Ethyl 2-hydroxy-5-sulfonicotinate (24.7 g, 0.1 mol) was slurried in thionyl chloride (238 g, 2.0 mol) and dimethylformamide (1.0 mL) with stirring. The reaction mixture was then heated to reflux for 2.5 hours. The bulk of thionyl chloride was removed in vacuo and the residual thionyl chloride was removed by azeotroping with toluene to give the crude title compound (30.7 g, 108%) as a yellow oil.

δ(CDCl ₃ ): 1.46(3H,t), 4.50(2H,q), 8.72(1H,d), 9.09(1H,d),

Use it directly for the next step.

Preparation of (1d) ethyl 2-chloro-5-(4-ethyl-1-piperazinylsulfonyl)nicotinate

Crude ethyl 2-chloro-5-chlorosulfonicotinate (30.7 g, 0.1 mol deduced) was dissolved in ethyl acetate (150 mL) while stirring, then cooled with ice. A solution of N-ethylpiperazine (11.4 g, 0.1 mol) and triethylamine (22.5 g, 0.22 mol) dissolved in ethyl acetate (50 mL) was carefully added to the system over 30 minutes, keeping the internal temperature Below 10°C. Once the addition step was complete, the reaction was warmed to 22°C and stirred for 1 hour. The solid was filtered off and the remaining filtrate was concentrated in vacuo to give the crude title compound (37.1 g, 103%) as a crude yellow gum. 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 (found: 362 [M+H] ⁺ , 100%. C ₁₄ H ₂₁ ClN ₃ O ₄ S requires 362.85).

Preparation of (1e) ethyl 2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinate

A solution obtained by dissolving ethyl 2-chloro-5-(4-ethyl-1-piperazinylsulfonyl)nicotinate (36.1 g, 0.1 mol) in ethanol (180 mL) was cooled to 10°C while stirring . Sodium ethoxide (10.2 g, 0.15 mol) was added gradually, keeping the temperature below 20°C. The reaction mixture was then stirred at ambient temperature for 18 hours. The precipitate was filtered off and water (180 mL) was added to the filtrate. The filtrate was then heated to 40°C for 1 hour. Ethanol (180 mL) was then distilled off at ambient pressure and the remaining aqueous solution was allowed to cool to ambient temperature. The precipitated product was then filtered off, washed with water and dried in vacuo at 50°C to afford the title compound (12.6 g, 34%) as a light brown solid.

Mp66-68°C. 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 (found: 372 [M+H] ⁺ , 100%. C ₁₆ H ₂₆ N ₃ O ₅ S requires 372.46).

(1f) 2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinic acid

Dissolve ethyl 2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinate (10.2 g, 0.0275 mol) in toluene (50 mL) and add sodium hydroxide (1.1 g , 0.0275mol) was dissolved in water (20mL) to obtain a solution. The two-phase mixture was then vigorously stirred overnight at ambient temperature. The aqueous phase was separated off and adjusted to pH=5.6 by addition of concentrated hydrochloric acid. The precipitated product was slurried by ice cooling for 15 minutes, filtered, washed with water and dried in vacuo at 50°C to give the subtitle compound (4.1 g, 43%) as a pure white solid.

Mpt206-207°C. δ(CDCl ₃ ): 1.25(3H, t), 1.39(3H, t), (2H, q), 3.03(4H, m), 3.254H, m), 4.50(2H, q), 8.25(1H, d), 8.56(1H,d).

m/z (found: 344 [M+H] ⁺ , 100%. C ₁₄ H ₂₂ N ₃ O ₅ S requires 344.38).

This step is a simple hydrolysis and the yield of 43% is not optimal. The same hydrolysis was carried out as described in Preparation 23 in PCT/IB99/00519 (which document is incorporated herein by reference) and a better yield of 88% was obtained as a result of this hydrolysis.

preparation 2

2-Ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinic acid-from 2-hydroxy-5-sulfo Laminar flow method in toluene for ethyl nicotinate

Ethyl 2-hydroxy-5-sulfonicotinate (441.5 g, 1.79 mol) was dissolved in toluene (1.77 L) and then thionyl chloride (1.06 Kg, 8.93 mol) and dimethylformamide (71.3 mL) were added . The stirred suspension was then heated to reflux for 3 hours to give a yellow solution. Next thionyl chloride (2.87 L) was distilled with continuous replacement with toluene (2.15 L). The pale yellow solution was then cooled to 10°C and N-ethylpiperazine (198.9 g, 1.66 mol) and triethylamine (392.2 g, 3.88 mol) dissolved in toluene (700 mL) were added dropwise over 90 minutes. Stir the solution, keeping the temperature of the reaction mixture below 10 °C. The reaction was stirred at ambient temperature for 18 hours, then washed with water (2 x 700 mL) and brine (2 x 350 mL). The toluene phase was azeotropically dried by distilling off a continuous 1750 mL for toluene (1750 mL) replacement. The remaining brown solution was cooled to 10°C and sodium ethoxide (178.0 g, 2.62 mol) was added gradually keeping the temperature below 10°C. The reaction was then stirred at 10°C for 1 hour, then the system was warmed to ambient temperature and stirred for 18 hours. Next sodium hydroxide (34.9 g, *mol) dissolved in water (1.5 L) was added to the toluene mixture and the 2-phase mixture was stirred vigorously at 40° C. for 18 hours. Once cooled to ambient temperature, the aqueous phase was separated. Concentrated hydrochloric acid was added to the system until pH = 3, and a light brown solid was precipitated, which was allowed to precipitate by ice cooling for 2 hours. The precipitate was washed by filtration with water (300 mL) and dried in vacuo at 50 °C to give the subtitle compound (338.4 g, 57.4%) as a pure white solid.

Mpt206-207°C. 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 (found: 344 [M+H] ⁺ , 100%. C ₁₄ H ₂₂ N ₃ O ₅ S requires 344.38).

Preparations 3 and 4 provide alternative routes by which two of the other compounds can be prepared.

preparation 3

2-(methoxyethyl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridine -3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

The product from stage i) below (0.75 mmol), bis(trimethylsilyl)amide (298 mg, 1.50 mmol) and ethyl acetate (73 microliters, 0.75 mmol) were dissolved in a sealed vessel at 120 °C The resulting mixture was heated in ethanol (10ml) for 12 hours. The cooled mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate and the layers were separated. The organic phase was dried ( _MgSO4 ) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol (98:2) as eluent to afford the title compound 164 mg; found: C, 53.18; H, 6.48; N, _18.14 ; _{C23H33N 7} O ₅ S; 0.20C ₂ H ₅ CO ₂ CH ₃ requires 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) ⁺ ; mp 161-162°C.

The preparation of embodiment 1 raw material

(a) Pyridine-2-amino-5-sulfonic acid

To oleum (320 g) was added 2-aminopyridine (80 g, 0.85 mol) gradually over 30 minutes and the resulting solution was heated at 140° C. for 4 hours. While cooling, the reaction was poured onto ice (200 g) and the resulting mixture was further stirred in an ice/salt bath for 2 hours. The resulting suspension was filtered, the solid was washed with ice water (200ml) and cold IMS (200ml) and dried under suction to give the title compound as a solid 111.3g; LRMS: m/z 175 (M+1) ⁺ .

(b) Pyridine-2-amino-3-bromo-5-sulfonic acid

To a hot solution of the product from stage (a) (108g, 0.62mol) dissolved in water (600ml) was added bromine (99g, 0.62mol) dropwise over 1 hour so as to maintain a steady reflux. Once the addition was complete, the reaction was cooled and the resulting mixture was filtered. The solid was washed with water and dried under suction to give the title compound 53.4g;

δ(DMSOd ₆ , 300MHz): 8.08(1H, s), 8.14(1H, s); LRMS: m/z253(M) ⁺ .

(c) Pyridine-3-bromo-2-chloro-5-sulfonyl chloride

To an ice-cold solution of the product from stage (b) (25.3 g, 100.0 mmol) dissolved in aqueous hydrochloric acid (115 ml, 20%) was added dropwise sodium nitrite (7.6 g, 110.0 mmol) dissolved in water (30 ml) The resulting solution is such that the temperature is maintained below 6°C. The reaction was stirred at 0°C for 30 minutes and at room temperature for a further 1 hour. The reaction mixture was evaporated under reduced pressure and the residue was dried in vacuo at 70°C for 72 hours. A mixture of this solid, phosphorus pentachloride (30.0 g, 144 mmol) and phosphorus oxychloride (1 ml, 10.8 mmol) was heated at 125°C for 3 hours and then cooled. The reaction mixture was poured onto ice (100 g) and the resulting solid was filtered and washed with water. The product was dissolved in dichloromethane, dried ( _MgSO4 ) and evaporated under reduced pressure to give the title compound as a yellow solid, 26.58g;

δ (CDCl ₃ , 300 MHz): 8.46 (1H, s), 8.92 (1H, s).

(d) 3-bromo-2-chloro-5-(4-ethylpiperazin-1-ylsulfonyl)pyridine

The product from stage (c) (23.0 g, 79.0 mmol) was dissolved in the resulting ice-cooled solution in dichloromethane (150 ml) and the reaction was stirred at 0°C for 1 hour. The reaction mixture was concentrated under reduced pressure and the residual brown oil was purified by silica gel column chromatography using gradient elution of dichloromethane:methanol (99:1-97:3) to give the title compound as a Orange solid 14.5g;

δ (CDCl ₃ , 300 MHz): 1.05 (3H, t), 2.42 (2H, q), 2.55 (4H, m), 3.12 (4H, H), 8.24 (1H, s), 8.67 (1H, s).

(e) 3-Bromo-2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridine

A mixture of the product from stage (d) (6.60g, 17.9mmol) and sodium ethoxide (6.09g, 89.55mmol) dissolved in ethanol (100ml) was heated at reflux for 18 hours and then cooled. The reaction mixture was concentrated under reduced pressure, the residue was partitioned between water (100ml) and ethyl acetate (100ml) and the layers were separated. The aqueous phase was extracted with ethyl acetate (2 x 100ml), the combined organic solutions were dried ( _MgSO4 ) and evaporated under reduced pressure to give the title compound as a brown solid, 6.41g; found: C, 41.27 ; H, 5.33; N, 11.11. C ₁₃ H ₂₀ BrN ₃ O ₃ S requirements: 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-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)-3-carboxylic acid ethyl ester

The product from stage e) (6.40 g, 16.92 mmol), triethylamine (12 ml, 86.1 mmol) and tris(triphenylphosphine)palladium(0) were dissolved in ethanol ( 60 ml) the resulting mixture was heated for 18 hours and then cooled. The reaction mixture was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with a gradient of dichloromethane:methanol (100:0-97:3) to give the title compound as an orange oil 6.2g; 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, H), 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-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)-3-carboxylic acid

A mixture of the product from stage f) (4.96 g, 13.35 mmol) and aqueous sodium hydroxide solution (25 ml, 2N, 50.0 mmol) in ethanol (25 ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated to half its volume under reduced pressure, washed with ether and acidified to pH 5 using 4N hydrochloric acid. The aqueous solution was extracted with dichloromethane (3 x 30ml), the combined organic extracts were dried ( _MgSO4 ) and evaporated under reduced pressure to give the title compound as a tan solid, 4.02g; δ( _DMSOd6 , 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-ethoxy-5- ( 4-ethylpiperazin-1-ylsulfonyl ) pyridin-3- ylcarboxamido ]-1H-3-ethylpyrazole-5- Formamide

4-Amino-3-ethyl-1H-pyrazole-5-carboxamide (WO 9849166, Preparation 8) (9.2 g, 59.8 mmol) was dissolved in N,N-dimethylformamide (60 ml) to obtain The solution was added to the product from stage g) (21.7 g, 62.9 mmol), 1-hydroxybenzotriazole hydrate (10.1 g, 66.0 mmol) and triethylamine (13.15 ml, 94.3 mmol) dissolved in dichloromethane ( 240ml) in the resulting solution. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.26 g, 69.2 mmol) was added and the reaction was stirred at room temperature for 6 hours. The dichloromethane was removed under reduced pressure, the remaining solution was poured into ethyl acetate (400ml) and the mixture was washed with aqueous sodium bicarbonate (400ml). The _resulting crystalline precipitate was filtered, washed with ethyl _acetate and dried in vacuo to give the title compound as a white powder, 22 g; ), 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-methoxyethyl-4-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridine Pyridine-3-ylcarboxamido]-3-ethylpyrazole-5-carboxamide

1-Bromo-2-methoxyethane (1.72mmol) was added to the product from stage (h) (750mg, 1.56mmol) and cesium carbonate (1.12g, 3.44mmol) dissolved in N,N-dimethyl Formamide (15ml) was added to the resulting solution and the reaction was stirred at 60°C for 18 hours. The cooled mixture was partitioned between water and ethyl acetate and the layers were separated. The organic layer was dried ( _MgSO4 ), concentrated under reduced pressure and azeotroped with toluene to give a solid. The product was recrystallized from diethyl ether to give the title compound as a white solid.

Claims (30)

1. 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 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 and/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 method described in any during aforesaid right requires, 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 method described in any during aforesaid right requires, 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 method described in any during aforesaid right requires, 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. any described method during aforesaid right requires, wherein said compound is selected from any one in husky single that furan or the following 4 kinds of compounds:

Any described method during 11. aforesaid right requires, 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. the method described in claim 11 or claim 12, wherein said hydrogen acceptor are tetrahydrobenzene or toxilic acid.

14. as any described method among the claim 11-13, wherein said acid is trifluoroacetic acid, HCl or H ₂SO ₄

15. as any described method in the above-mentioned claim, 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 in the above-mentioned claim, wherein said reaction is to be that 125-250 ℃, pressure are 13.8-68.9kPa (2-10psi) and/or can be at rare gas element or do not carry out in rare gas element in temperature.

18. as any described method in the above-mentioned claim, 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 any one definition (if suitable) among claim 1 and the 6-10;

Wherein the structural formula of general formula I V is as follows:

R wherein ¹And R ²As any one definition in claim 1-5 and 10.

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 any one definition (if suitable) among claim 1 and the 6-10.

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 any one definition (if suitable) among claim 1 and the 6-10.

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 low alkyl group and R ³And R ⁴As any one definition (if suitable) among claim 1 and the 6-10.

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 any one definition (if suitable) among claim 1 and the 6-10.

24. the compound of general formula I I as defined in claim 1.

25. the compound of general formula III as defined in claim 18.

26. the compound of general formula VI as defined in claim 20.

27. compound as defined general formula VIIIA in the claim 22.

28. 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 above-mentioned definition.

29. 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.

30. 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 above-mentioned definition.