HK1053471B - Method for producing 5-(1-piperazinyl)-benzofuran-2-carboxamide by transition metal-catalyzed amination - Google Patents

Description

Method for producing 5- (1-piperazinyl) -benzofuran-2-carboxamide by transition metal-catalyzed amination

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The invention relates to a method for preparing 5- (1-piperazinyl) -benzofuran-2-carboxamide, which is characterized in that:

a) 5-bromo-salicylaldehyde or 5-chloro-salicylaldehyde is first reacted in a one-pot reaction with a compound of formula I, followed by reaction with formamide to give 5-L-benzofuran-2-carboxamide (II), wherein formula I is as follows:

L-CH₂-COOR¹ I

in the formula I

L is Cl, Br, I or a reactive esterified OH group; and is

R¹Is alkyl or benzyl having 1 to 6 carbon atoms;

and in 5-L-benzofuran-2-carboxamide (II), L is Cl or Br;

then reacting (II) with R in a transition metal-catalyzed amination reaction²-piperazine reaction, wherein R²Is H or an amino protecting group, to give a compound of formula III:

wherein R is²Is H or an amino protecting group;

and then if R is²Not equal to H, then R is caused to be²Cracking;

or

b) Reacting a compound of the general formula IV with R in a transition metal-catalyzed amination reaction²-piperazine to give a compound of formula V, wherein the formula of the compound of formula IV is as follows:

wherein

L is Cl, Br, I or a reactive esterified OH group;

R³is H or CH₂R⁶；

R⁴And R⁵Independently of one another are OR⁷、OR⁸、SR⁷Or SR⁸；

R⁴And R⁵Together optionally carbonyl, ═ S, ═ N-OH, ═ N-OR⁷、＝N-N[(R⁷)₂]、＝N-N[(R⁸)₂]or-O- (CH)₂)_n-O-；

R⁶Is CN, COOH, COOR⁷Or CONH₂；

R⁷Is an alkyl group having 1 to 6 carbon atoms;

R⁸is unsubstituted or substituted by R⁷、OR⁷、SR⁷Or Hal mono-or di-substituted phenyl;

n is 2 or 3;

at R²In piperazine, R²Is H or an amino protecting group;

in addition, the formula of formula V is as follows:

wherein

R²Is H or an amino protecting group;

R³is H or CH₂R⁶；

R⁴And R⁵Independently of one another are OR⁷、OR⁸、SR⁷Or SR⁸；

R⁴And R⁵Together optionally is carbonyl, ═ S, -N-OH, -N-OR⁷、＝N-N[(R⁷)₂]、＝N-N[(R⁸)₂]or-O- (CH)₂)_n-O-；

R⁶Is CN, COOH, COOR⁷Or CONH₂；

R⁷Is an alkyl group having 1 to 6 carbon atoms;

R⁸is unsubstituted or substituted by R⁷、OR⁷、SR⁷Or Hal mono-or di-substituted phenyl; n is 2 or 3;

the compound of the formula V is subsequently reacted in a one-pot reaction first with a compound of the formula I and subsequently with a formamide to give a compound of the formula III, wherein the formula of the formula I is as follows:

L-CH₂-COOR¹ I

in the formula I

L is Cl, Br, I or a reactive esterified OH group;

R¹is alkyl or benzyl having 1 to 6 carbon atoms;

wherein the compound of formula III has the following structural formula:

wherein R is²Is H or an amino protecting group;

and then if R²Not equal to H, then R is caused to be²Cracking;

or

c) Reacting a compound of formula V with chloroacetamide to give a compound of formula III, wherein in the compound of formula V:

R²is an amino protecting group;

R³is H or CH₂R⁶；

R⁴And R⁵Independently of one another are OR⁷、OR⁸、SR⁷Or SR⁸；

R⁴And R⁵Together optionally carbonyl, ═ S, ═ N-OH, ═ N-OR⁷、＝N-N[(R⁷)₂]、＝N-N[(R⁸)₂]or-O- (CH)₂)_n-O-；

R⁶Is CN, COOH, COOR⁷Or CONH₂；

R⁷Is an alkyl group having 1 to 6 carbon atoms;

R⁸is unsubstituted or substituted by R⁷、OR⁷、SR⁷Or Hal mono-or di-substituted phenyl;

n is 2 or 3;

in the general formula III, R²Is an amino protecting group;

and subsequently subjecting R to²Cracking;

and/or converting 5- (1-piperazinyl) -benzofuran-2-carboxamide into one of its acid addition salts by treatment with an acid.

The invention also relates to compounds of formula V and salts and solvates thereof:

wherein

R²Is H or an amino protecting group;

R³is H or CH₂R⁶；

R⁴And R⁵Independently of one another are OR⁷、OR⁸、SR⁷Or SR⁸；

R⁴And R⁵Together optionally carbonyl, ═ S, ═ N-OH, ═ N-OR⁷、＝N-N[(R⁷)₂]、＝N-N[(R⁸)₂]or-O- (CH)₂)_n-O-；

R⁶Is CN, COOH, COOR⁷Or CONH₂；

R⁷Is an alkyl group having 1 to 6 carbon atoms;

R⁸is unsubstituted or substituted by R⁷、OR⁷、SR⁷Or Hal mono-or di-substituted phenyl;

n is 2 or 3.

5- (1-piperazinyl) -benzofuran-2-carboxamide is an important intermediate for pharmaceutically active ingredients. For example, it is described in DE 19730989, WO 9857953, EP 738722, EP 736525, DE 4414113, DE 4333254 or DE 4101686.

Benzofuran derivatives are also described, for example, in DE 19514567 as precursors.

Processes for the preparation of heterocyclic aromatic or arylamines are known, for example from EP 0802173, in which transition metal catalysts are used.

A general amination reaction is described in j.f. martinez in angelw, ch.int.372046-. Other methods for preparing tertiary arylamines using a catalyst consisting of trialkylphosphine and palladium are disclosed in JP 10-310561 (published application), application No. 9-119477 or JP11-80346 (published application), application No. 9-245218.

S.l. buchwald et al have described in US patent US 5,576,460 a process for the preparation of arylamines using a transition metal catalyzed reaction. Another process for preparing aromatic amines from chlorinated aromatic compounds in the presence of palladium catalysts is described in EP 0846676, J.F.Hartwig et al, J.org.chem., 1999, pp.5575-5580 or J.A.C.S.1999 of S.L.Buchwald et al,1219550-9561.

M. Nishiyama in Tetrahedron Letters 39(1998)617-620 describes the synthesis of N-arylpiperazines from aryl halides and piperazines by transition metal catalyzed reactions.

Surprisingly, studies during the synthesis of pharmaceutical agents such as described in DE 4333254 (EP 0648767) have shown that 5- (1-piperazinyl) -benzofuran-2-carboxamides can be obtained in an overall yield comparable to or higher than that of the prior art, the key advantages which can be mentioned here being that the reaction can be carried out conveniently and that the isolation of the product is thereby also simplified.

Another result of this study is that less solvent is used and energy consumption is lower.

If L is a reactive esterified OH group in the compounds of the general formula I or IV, it is preferably an alkylsulfonyloxy group having from 1 to 6 carbon atoms, preferably a methylsulfonyloxy or trifluoromethylsulfonyloxy group, an arylsulfonyloxy group having from 6 to 10 carbon atoms, preferably a phenylsulfonyloxy or p-tolylsulfonyloxy group, furthermore preferably a 2-naphthalenesulfonyloxy group, or on the other hand a fluorosulfonyloxy group.

R¹Is alkyl or benzyl. The alkyl radicals here have 1, 2, 3, 4, 5 or 6 carbon atoms, preferably 1, 2, 3 or 4 carbon atoms, for example methyl or ethyl, and also propyl, isopropyl, and also butyl, isobutyl, sec-butyl or tert-butyl, are particularly preferred.

In the compounds of the formula I, L is preferably Cl and may furthermore be Br.

R²Is H or an amino protecting group. Particular preference is given to R²Is an amino protecting group.

The term "amino protecting group" is known in its ordinary sense and refers to a group suitable for preventing an amino group from participating in a chemical reaction (protection), but otherwise being easily removed after the desired chemical reaction taking place in the molecule. Typical of such groups are in particular unsubstituted acyl, aryl, aralkyloxymethyl or aralkyl groups. Since the amino protecting groups are removed after the desired reaction (or reaction sequence), their type and size are furthermore not critical; however, preference is given to those amino-protecting groups having from 1 to 20, in particular from 1 to 8, carbon atoms. The term "acyl" in connection with the present process and these compounds is to be understood broadly. It includes radicals derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic or sulfonic acids and in particular alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl radicals. Examples of acyl groups of this type are: alkanoyl groups such as acetyl, propionyl, butyryl; aralkanoyl such as phenylacetyl; aroyl, such as benzoyl; aryloxyalkanoyl such as phenoxyacetyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2, 2, 2-trichloroethoxycarbonyl, BOC (tert-butoxycarbonyl), 2-iodoethoxycarbonyl; aralkoxycarbonyl groups such as CBZ (benzyloxycarbonyl), also known as "Z"), 4-methoxybenzyloxycarbonyl, FMOC (9-fluorenylmethoxycarbonyl); arylsulfonyl such as Mtr (4-methoxy-2, 3, 6-trimethylphenylsulfonyl).

Particular preference is given to R²Is benzyl or BOC.

Depending on the protective group used, the amino protective group can be removed from the compounds of the formula III using, for example, strong acids, advantageously TFA (trifluoroacetic acid) or perchloric acid, also other strong inorganic acids, such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids, such as trichloroacetic acid, sulfonic acids, such as benzenesulfonic acid or p-toluenesulfonic acid. Other inert solvents may be present, but are not always necessary. Suitable inert solvents are preferably: organic solvents, for example carboxylic acids, such as acetic acid; ethers such as tetrahydrofuran or dioxane; amides such as dimethylformamide; halogenated hydrocarbons such as dichloromethane; in addition, alcohols such as methanol, ethanol or isopropanol; and water. Mixtures of the above solvents are also suitable. It is preferred to use an excess of TFA without addition of further solvents and to use perchloric acid as a 9: 1 ratio mixture of acetic acid and 70% perchloric acid. Advantageously, the reaction temperature is in the range of from about 0 to about 50, preferably from 15 to 30. The BOC groups are cleaved at 15-30 ° preferably using TFA in dichloromethane or about 3-5N hydrochloric acid in dioxane.

For example, a protecting group (e.g., CBZ or benzyl) which can be removed hydrogenolytically can be cleaved by treatment with hydrogen in the presence of a catalyst (e.g., a noble metal catalyst, such as, advantageously, palladium on a carbon support). Suitable solvents here are those mentioned above, such as, in particular: alcohols such as methanol or ethanol; or amides, such as DMF. The hydrogenolysis is generally carried out at a temperature of about 0 to 100 ℃ and a pressure of about 1 to 200 bar, preferably at 20 to 30 ℃ and 1 to 10 bar.

R³Preferably H.

R⁴And R⁵Preferably methoxy, ethoxy, propoxy or phenoxy.

In particular R⁴And R⁵Together are a carbonyl group.

In the compounds of formula IV, L is preferably Br.

The compounds of the formulae IV and V may also be dimeric and may be cleaved back to the corresponding salicylaldehydes, where L and R²Has the indicated meanings:

R⁷is an alkyl group. The alkyl radicals here have 1, 2, 3, 4, 5 or 6 carbon atoms, preferably 1, 2, 3 or 4 carbon atoms, for example methyl or ethyl, and also propyl, isopropyl, and also butyl, isobutyl, sec-butyl or tert-butyl, are particularly preferred.

In the compounds of formulae IV and V:

＝N-OR⁷is preferably ═ N-OCH₃；

＝N-N[(R⁷)₂]Preferably, is ═ N-N [ (CH)₃)₂]；

＝N-N[(R⁸)₂]Preferably, is N-N [ (phenyl)₂]。

The compounds of the formulae I and IV are known or can be prepared in addition by Methods known per se as described in the literature (for example in standard works such as Houben-Weyl, Methoden der organischen Chemistry, Methods of Organic Chemistry, Georg-Thieme Verlag, Stuttgart), under precise reaction conditions which are known and suitable for the reaction in question. Processes consisting of variants known per se and not described in more detail herein can also be used herein.

Method variants a)

The reaction of 5-bromosalicylaldehyde or 5-chlorosalicylaldehyde with the compound of formula I and subsequently with formamide is carried out as a one-pot reaction in a suitable inert solvent with the addition of a base.

Examples of suitable inert solvents are: hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1, 2-dichloroethane, tetrachloromethane, chloroform or dichloromethane; ethers such as diethyl ether, diisopropyl ether, Tetrahydrofuran (THF), or dioxane; glycol ethers such as ethylene glycol monomethyl ether or ethylene glycol monoethyl ether, ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone; nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon disulfide; nitro compounds such as nitromethane or nitrobenzene; it is also possible for the solvents to be mixtures with one another.

Depending on the conditions used, the reaction time may be between a few minutes and 14 days; and the reaction temperature is about 0 to 150, preferably 60 to 120.

Particularly preferably the reaction time is 4 to 20 hours and the reaction temperature is 90 to 115 ℃.

Suitable bases are compounds such as, for example, sodium carbonate, potassium carbonate or cesium carbonate.

The one-pot reaction is then preferably carried out using formamide in the presence of an organic base, preferably an alkali metal alkoxide such as, for example, sodium tert-butoxide, and the corresponding alcohol, to give 5-Hal-benzofuran-2-carboxamide (II). In (II), Hal is preferably Br.

The reaction is preferably carried out at 0 ℃ to 60 ℃.

Other methods of obtaining (II) are described, for example, in the briefs of the french chemical association (bull. soc. chim. fr.) 1971; 4329 and o.dann. et al Justus liebig ann.chem.1975; 160-. The above-described one-pot reaction can be carried out with better yields than the reaction.

(II) with R in the presence of a transition metal catalyst in a suitable inert solvent²-reaction of piperazine to give the compound of formula III.

Transition metals that may be used include PdCl₂Or Pd (OAc)₂Or for example using NaBH₄Or by prereduction of phosphines (in this step at the ligand R)₃Negligible in case of excess P) of other Pd²⁺Derivatives or compounds such as, for example, Pd (DBA)₂Or Pd₂(DBA)₃Pd (o) species such as (DBA ═ dibenzylideneacetone).

To this range of Pd complexes can be added the corresponding nickel or copper ligand complex.

Furthermore, ligands which may be used are N, N-diarylimidazolium salts analogous to those described in J.Huang et al, organic letters (org.Lett.)1.1999, 1307-1309.

The phosphine or aza/phosphine ligands used include:

tri-o-tolylphosphine;

tricyclohexylphosphine;

1- (2-diphenylphosphino-1-naphthyl) isoquinoline (QUINAP);

1, 8-bis (dimethylamino) naphthalene;

Phe₂P-CH₂-PPhe₂；

in particular P (tert-butyl)₃＝P(t-Bu)₃；

1, 1' -bis (diphenylphosphino) ferrocene (DPPF is the complex DPPFpFXdCl)₂)；

2, 2 '-bis (diphenylphosphino) -1, 1' -dinaphthyl (═ BINAP);

(S) -dibutphos ═ 1- (2-di-tert-butylphosphonyl (phosphinyl) phenyl) -ethyldimethylamine;

1- (N, N-dimethylamino) -1' - (dicyclohexylphosphino) -biphenyl;

1- (di-tert-butylphosphino) biphenyl;

1, 1' -bis (di-tert-butylphosphino) biphenyl;

(t-Bu)₂P-(CH₂)_n-P(t-Bu)₂n＝1、2、3；

(t-Bu)₂P-(CH₂)_m-X-(CH₂)_n-P(t-Bu)₂ m、n＝1、2、3；X＝O；

…

or on the other hand is

DB^tPF ═ 1, 1' -bis (di-tert-butylphosphino) ferrocene.

Examples of suitable solvents are: hydrocarbons such as benzene, toluene, xylene; chlorinated hydrocarbons such as, for example, dichloromethane; ketones such as acetone, butanone; ethers such as Tetrahydrofuran (THF) or dioxane; nitriles, such as acetonitrile; mixtures of these solvents with one another are also possible.

Depending on the conditions used, the reaction time may be between a few minutes and 14 days; the reaction temperature is about 0 to 180 degrees, generally 30 to 130 degrees.

Examples of suitable bases are alkali metal alkoxides, such as for example sodium tert-butoxide.

Method variation b)

Carrying out the reaction of the compound of the formula IV with R under the conditions described in variant a)²-reaction of piperazine.

Can be substituted by R⁴And R⁵To carbonyl. The one-pot reaction of the compound of the formula V with the compound of the formula I and subsequently with formamide is then likewise carried out under the conditions described above. If R is²Not equal to H, thenIt is also possible to eliminate R under the stated conditions²。

The base of formula I or formula V can be converted into the relevant acid addition salt using an acid, for example by reaction of an equivalent amount of the base with the acid in an inert solvent such as ethanol, followed by evaporation. Particularly suitable acids for this reaction are those which yield physiologically acceptable salts. Therefore, it is possible to use: inorganic acids such as sulfuric acid, nitric acid; hydrohalic acids such as hydrochloric acid or hydrobromic acid; phosphoric acids such as orthophosphoric acid; sulfamic acid; furthermore organic acids, in particular aliphatic, cycloaliphatic, araliphatic, aromatic or heterocyclic mono-or polycarboxylic acids, sulfonic acids or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemono-or naphthalenedisulfonic acid, lauryl sulfuric acid. Salts formed with physiologically unacceptable acids, such as picrates, can be used for isolating and/or purifying compounds of formula I.

All temperatures in this context are in degrees Celsius. In the following examples, "conventional work-up" means adding water if necessary, adjusting the pH to 2-10 if necessary, depending on the composition of the final product, extracting the product with ethyl acetate or dichloromethane, separating the phases, drying the organic phase with sodium sulfate and evaporating, and purifying the product by chromatography on silica gel and/or by crystallization.

Example 1

1) Synthesis of 5-bromobenzofuran-2-carboxamide

Reaction with ethyl bromoacetate:

200g of 5-bromo-2-hydroxybenzaldehyde are dissolved in 2000ml of NMP by stirring and 144g of potassium carbonate and 175g of ethyl bromoacetate are added. The mixture was stirred at 105 ℃ under a nitrogen atmosphere for 15 hours. The resulting orange solution with punctate crystals was cooled to 25 ℃, 135g of formamide were added and the mixture was stirred for a further 30 minutes. 557ml of sodium methoxide (30%/MeOH solution) were then added over the course of 15 minutes without cooling. After 3 hours, a light brown solution with punctate crystals appeared. It is poured into 6 liters of demineralized water (10 ℃) and the mixture is stirred for a further 30 minutes. The crystals were filtered off by suction, washed with 1 l of demineralized water, resuspended in 4 l of demineralized water, filtered by suction and washed again with 1 l of demineralized water. The crystals were dried at 60 ℃ under reduced pressure overnight to constant weight (product weight: 113g of light brown crystals; m.p.210-213 ℃ C.; CAS 35351-21-4).

The physical and spectral data correspond to those disclosed in the following documents: rene; royer; BSCFAS; french brief introduction to the chemical association (bull. soc. chim. fr.) 1971; 4329; and o.dann. et al JLACBF; justus liebig ann. GE; 1975; 160-194.

5-chlorobenzofuran-2-carboxamide (m.p.200-202 ℃ C.), 5-fluorobenzofuran-2-carboxamide and 5-iodobenzofuran-2-carboxamide are obtained in comparable yields using the same procedure.

2) Synthesis of 5- (4-benzyl-1-piperazinyl) benzofuran-2-carboxamide by transition metal catalyzed amination of 5-bromobenzofuran-2-carboxamide using benzylpiperazine

Using the catalyst System Pd (OAc)₂/P(t-Bu)₃The explanatory operations of (1):

0.30g of P (t-Bu)₃4.5g of 5-bromobenzofuran-2-carboxamide, 4.9g of benzylpiperazine and 5.0g of Nat-OBu are added to a suspension of 0.085g of Pd (II) acetate in 150ml of xylene which has been stirred for 15 minutes and is stirred at 125 deg.CThe mixture was warmed under a protective nitrogen atmosphere for 12-18 hours. After cooling, the mixture is added to 500ml of 2N hydrochloric acid and the aqueous phase is extracted 3 times with 200ml of ethyl acetate. The aqueous phase is adjusted to pH 10 using aqueous NaOH (20%), while monitoring pH and temperature (20-25 ℃) and 5- (4-benzyl-1-piperazinyl) benzofuran-2-carboxamide produced as a solid is filtered and crystallized, for example, from ethanol/water (product weight: 4.0 g/64%/m.p.277-279 ℃).

3) Synthesis of 5- (1-piperazinyl) benzofuran-2-carboxamide from 5- (4-benzyl-1-piperazinyl) benzofuran-2-carboxamide

And (3) hydrogenolysis:

5.0g of 5- (4-benzyl-1-piperazinyl) benzofuran-2-carboxamide are added to 300ml of ethanol and the product is completely debenzylated using hydrogen at 20-30 ℃ after addition of 9g of palladium on activated carbon (5%) and 5g of HOAc (100%). After filtration and removal of the solvent under reduced pressure and crystallization from alcohol or water and drying under reduced pressure at 60 ℃ the product can be obtained (3.1 g/85%/m.p.252-255 ° spectrum identical to that prepared by the above-described process described in particular in DE 4101686/23.7.92, DE 4333254/6.4.95, EP 0648767/19.4.95, EP 0738722/23.10.96).

Example 2

1) Synthesis of 5- (4-tert-butoxycarbonyl-1-piperazinyl) benzofuran-2-carboxamide from 5-bromobenzofuran-2-carboxamide

0.9g of 5-bromobenzofuran-2-carboxamide, 1.1g of BOC-piperazine and 1.45g of Nat-OBu were added to 0.06g of Pd (DBA)₂And 0.25g P (t-Bu)₃Obtained by dissolving in 40ml of diethylene glycol dimethyl etherAnd the mixture was warmed at 120-130 ℃ under a protective gas atmosphere for 16 hours. After cooling, the mixture is added to water and the organic phase is diluted with 100ml of MTBE and washed with 3 × 50ml of water. The solvent was evaporated and the product formed as a solid was filtered and purified by crystallization from ethanol (product weight: 0.7 g/55%/m.p.210-213 ℃).

For example, removal of the BOC protecting group and formation of 5- (1-piperazinyl) benzofuran-2-carboxamide using hydrochloric acid, as represented by the following equation alone, can then be carried out as described IN GREENE T.W. and WUTS P.G.M. IN protecting GROUPS IN organic Synthesis (PROTECTIVE GROUPS IN OGANIC SYNTHESIS).

Example 3

1) Synthesis of 5- (1-piperazinyl) benzofuran-2-carboxamide from 5-bromobenzofuran-2-carboxamide

0.9g of 5-bromobenzofuran-2-carboxamide, 0.97g of piperazine and 2.20g of Nat-OBu were added to 0.06g of Pd (DBA)₂And 0.07g of 1- (N, N-dimethylamino) -1' - (dicyclohexylphosphino) biphenyl were dissolved in 50ml of toluene and the mixture was warmed at 120 ℃ and 130 ℃ under a protective gas atmosphere for 16 hours. After cooling, the reaction mixture was added to a mixture of 50ml of water and 10ml of 37% hydrochloric acid and the mixture was stirred for 20 minutes. The virtually insoluble product is then removed and the organic phase is separated off. The aqueous phase is washed again by shaking with 50ml of ethyl acetate and freed from solvent residues under reduced pressure, the system is clarified using activated carbon and filtered. The product is precipitated from the filtrate in crystalline form at 20-22 ℃ using 20-25ml of 32% sodium hydroxide. The product was filtered off and dried (product weight: 0.65 g/70%/m.p.252-255 ℃).

Example 4

1) Synthesis of 5- (4-benzylpiperazin-1-yl) -2-hydroxy-benzaldehyde

0.6g of palladium bis (dibenzylideneacetone) and 0.16g of tri-tert-butylphosphine were added to 200ml of toluene under a nitrogen atmosphere and the resulting dark red solution was stirred at 20 ℃ for 20 minutes. Then 10g of 5-bromo-2-hydroxybenzaldehyde, 9.7g of 1-benzylpiperazine and 7.2g of sodium tert-butoxide are added. The mixture is stirred at 60 ℃ for 24 hours and cooled, 800ml of water are added and the mixture is extracted with 2X 500ml of ethyl acetate. The organic phases are combined and washed with 300ml of water and the solvent is removed at 30 ℃ under reduced pressure. The remaining dark orange oil (9.7g) was purified by chromatography (300g silica; MTB ether/heptane 5: 1; 1.5 l). 9.9g of pale yellow crystals (67%), m.p.101-103 °; MS 296(M +), 205, 119, 91 (100%).

2) Synthesis of ethyl 4- (4-benzylpiperazin-1-yl) -2-formylphenoxyacetate

0.5g of 5- (4-benzylpiperazin-1-yl) -2-hydroxybenzaldehyde is dissolved in 5ml of NMP at 20 ℃ by stirring under nitrogen and 0.25g of potassium carbonate and 0.2ml of ethyl bromoacetate are added. The mixture was stirred at 110 ° for 4 hours and cooled to 15 °. To the mixture was added 30ml of water and 30ml of ethyl acetate, the phases were separated and the aqueous phase was extracted with 30ml of ethyl acetate. The combined organic phases were washed with 2X 30ml of water and freed from solvent under reduced pressure. The remaining yellow oil (0.7g) was chromatographed over 10g of silica gel (MTB ether/heptane 5: 1) to give 0.45g of product (70%; light yellow oil), MS 382(M +), 296, 263, 199, 149, 119, 91 (100%).

Example 5

1) Synthesis of ethyl 5- (4-benzylpiperazin-1-yl) benzofuran-2-carboxylate

0.5g of 5- (4-benzylpiperazin-1-yl) -2-hydroxybenzaldehyde is dissolved in 5ml of NMP by stirring at 20 ℃ and 0.25g of potassium carbonate and 0.2ml of ethyl bromoacetate are added. The mixture was stirred at 105 ° for 15 hours and then cooled to 25 °. This was added portionwise to 30ml of water (10 °) by stirring, the aqueous phase was extracted with 3 × 50ml of ethyl acetate at 10 ° and the combined organic phases were washed with 50ml of water and then freed from solvent under reduced pressure (1.2g of orange oil). Column chromatography (MTB ether/heptane 5: 1) on 30g of silica gel gave 0.43g of pale yellow crystals (71%), m.p.105-107 °; MS 364(M +), 268, 204, 146, 119, 91 (100%).

The corresponding hydrochloride salt samples (m.p.219-222 °) can be obtained by dissolving in ethanol, adding 1N aqueous hydrochloric acid, isolating the resulting solid and drying under reduced pressure.

Example 6

1) Synthesis of 5- (4-benzylpiperazin-1-yl) benzofuran-2-carboxamide

500mg of 5- (4-benzylpiperazin-1-yl) -2-hydroxybenzaldehyde was added to 5ml of NMP by stirring under a nitrogen atmosphere and to the solution were added 0.25g of potassium carbonate and 0.2ml of ethyl bromoacetate. The mixture was stirred at 105 ° for 15 hours and cooled to 25 °. 0.2ml of formamide is then added to the mixture and stirring is continued for 30 minutes. 1ml of sodium methoxide (30% in methanol) are then added at 25 ℃ over 15 minutes and the mixture is stirred at 25-30 ℃ for a further 3 hours. The reaction mixture was poured into 30ml of water (10 °), the aqueous phase was extracted with 3 × 50ml of ethyl acetate, the combined organic phases were washed with 50ml of water and the solvent (0.7g of orange oil) was removed under reduced pressure. The oil was recrystallized from 10ml of toluene (375mg of pale yellow crystals; 66%), m.p.206-208 °; MS 335(M +), 244, 189, 146, 91 (100%).

Removing the protecting group to obtain 5- (1-piperazinyl) benzofuran-2-carboxamide.

Example 7

1) Synthesis of 5- (4-tert-butoxycarbonylpiperazin-1-yl) -2-hydroxybenzaldehyde

0.58g of palladium bis (dibenzylideneacetone) and 0.16g of tri-tert-butylphosphine were added to 200ml of toluene under a nitrogen atmosphere and the resulting solution which became dark red was stirred at 20 ℃ for 30 minutes. Then 10g of 5-bromo-2-hydroxybenzaldehyde, 10.2g of tert-butyl 1-piperazinecarboxylate and 7.2g of sodium tert-butoxide are added. The mixture is stirred at 60 ℃ for 24 hours and cooled, 800ml of water are added and the mixture is extracted with 2X 500ml of ethyl acetate. The organic phases were combined and washed with 300ml of water and the solvent was removed at 30 ℃ under reduced pressure. The remaining dark orange oil (11g) was purified by chromatography (300g silica gel; MTB ether/heptane 5: 1; 1.5 l) to yield 7.8g of light yellow crystals (51%), m.p.84-86 °; MS 306(M +), 250 (100%), 233, 176, 164.

2) Synthesis of ethyl 4- (4-tert-butoxycarbonylpiperazin-1-yl) -2-formylphenoxyacetate

0.5g of 5- (4-tert-butoxypiperazin-1-yl) -2-hydroxybenzaldehyde was dissolved in 5ml of NMP at 20 ℃ by stirring under a nitrogen atmosphere and 0.25g of potassium carbonate and 0.2ml of ethyl bromoacetate were added. The mixture was stirred at 110 ° for 30 minutes and cooled to 25 °. To the mixture was added 30ml of water and 30ml of ethyl acetate, the phases were separated and the aqueous phase was extracted with 30ml of ethyl acetate. The combined organic phases were washed with 30ml of water and freed from solvent under reduced pressure. To the remaining crystal slurry were added 30ml of toluene, 30ml of water and 5ml of 1N HCl, the toluene phase was removed under reduced pressure and the crystalline precipitate was separated and dried at 40 ℃ and reduced pressure (0.48 g; 75%), m.p.93-94 ℃; MS 392(M +), 336 (100%), 250/249, 57.

Example 8

1) Synthesis of ethyl 5- (4-tert-butoxycarbonylpiperazin-1-yl) benzofuran-2-carboxylate

520mg of 5- (4-tert-butoxycarbonylpiperazin-1-yl) -2-hydroxybenzaldehyde are added to 5ml of NMP at 20 ℃ by stirring under nitrogen and 0.25g of potassium carbonate and 0.2ml of ethyl bromoacetate are added to the solution. The mixture was stirred at 105 ° for 3 hours and then cooled to 25 °. This was added portionwise by stirring to 30ml of water (10 °), the aqueous phase was extracted with 3 × 30ml of ethyl acetate at 10 ° and the combined organic phases were washed with 30ml of saturated NaCl solution and 30ml of water and then freed from solvent under reduced pressure (0.6g of an orange oil containing crystalline constituents). After chromatography on 30g of silica gel (MTB ether/heptane 5: 1), 0.45g of pale yellow crystals (70%) m.p.116-117 ℃ are obtained; MS 374(M +), 318 (100%), 244, 232.

Example 9

1) Synthesis of 5- (4-tert-butoxycarbonylpiperazin-1-yl) benzofuran-2-carboxamide

1.04g of 5- (4-tert-butoxycarbonylpiperazin-1-yl) -2-hydroxybenzaldehyde was added to 10ml of NMP by stirring under a nitrogen atmosphere at 20 ℃ and 0.5g of potassium carbonate and 0.4ml of ethyl bromoacetate were added to the solution. The mixture was stirred at 120 ° for 5 hours and cooled to 25 °. 0.4ml of formamide is then added to the mixture and stirring is continued for 30 minutes. Then 1.9ml of sodium methoxide (30% in methanol) are added over 15 minutes without cooling and stirring is continued at 25-30 ℃ for a further 1 hour. To this batch was added 30ml of water and 30ml of ethyl acetate, the phases were separated and the aqueous phase was extracted with 30ml of ethyl acetate. The combined organic phases were washed with 30ml of water and the solvent was removed under reduced pressure (1.1g of orange crystalline slurry). 500mg of light brown crystals are obtained after crystallization using 20ml of toluene. The mother liquor was evaporated and the remaining oil was dissolved in 10ml of toluene. After 3 hours at 0 ℃ further light brown crystals (same as the first formed crystals, 70mg) were formed. Total yield (0.57g) 49%, m.p.202-204 °; MS 345(M +), 289 (100%), 272, 244, 215, 203.

The BOC group was removed as described above to give 5- (1-piperazinyl) benzofuran-2-carboxamide.

Example 10

1) Synthesis of 5- (4-tert-butoxycarbonylpiperazin-1-yl) benzofuran-2-carboxamide

5ml of 1-methyl-2-pyrrolidone, 0.16g of chloroacetamide and 0.25g of potassium carbonate are added to 0.5g of 5- (4-tert-butoxycarbonylpiperazin-1-yl) -2-hydroxybenzaldehyde at 20 ℃ under stirring/nitrogen atmosphere. The mixture was stirred at 60 ℃ for 16 hours, cooled and then filtered and the solvent was removed under reduced pressure. The residue was dissolved in MTB ether, re-filtered and concentrated and the residue crystallized from toluene. Isolated yield 0.34g (60%).

2) Synthesis of 5- (4-benzylpiperazin-1-yl) benzofuran-2-carboxamide

10ml of 1-methyl-2-pyrrolidone, 0.4g of chloroacetamide and 0.8g of potassium carbonate are added to 1.0g of 5- (4-benzylpiperazin-1-yl) -2-hydroxybenzaldehyde at 20 ℃ under stirring/nitrogen atmosphere. The mixture was stirred at 60 ℃ for 16 hours, cooled and then filtered and the solvent was removed under reduced pressure. The residue was dissolved in MTB ether, re-filtered and concentrated and the residue crystallized from toluene. Isolated yield 0.73g (65%).

Claims (5)

1. A process for the preparation of 5- (1-piperazinyl) -benzofuran-2-carboxamide or an acid addition salt thereof, characterized in that:

a) 5-bromo-salicylaldehyde or 5-chloro-salicylaldehyde is first reacted in a one-pot reaction with a compound of formula I, and subsequently with formamide to give 5-L-benzofuran-2-carboxamide (II), wherein formula I is as follows:

L-CH₂-COOR¹ I

in the formula I

L is Cl, Br or I; and is

R¹Is an alkyl group having 1 to 6 carbon atoms;

and in 5-L-benzofuran-2-carboxamide (II), L is Cl or Br;

then (II) is reacted over a transition metal catalyst Pd (OAc)₂/P (tert-butyl)₃Or Pd (DBA)₂/P (tert-butyl)₃Or Pd (DBA)₂Reaction with R in amination reaction catalyzed by/1- (N, N-dimethylamino) -1' - (dicyclohexylphosphino) biphenyl²-piperazine reaction, wherein R²Is H, benzyl or tert-butoxycarbonyl to give a compound of formula III:

wherein R is²Is H, benzyl or tert-butoxycarbonyl;

and then if R is²Not equal to H, then R is caused to be²Cracking;

or

b) Reacting a compound of the formula IV with a transition metal catalyst Pd (OAc)₂/P (tert-butyl)₃Or Pd (DBA)₂/P (tert-butyl)₃Or Pd (DBA)₂Reaction with R in amination reaction catalyzed by/1- (N, N-dimethylamino) -1' - (dicyclohexylphosphino) biphenyl²-piperazine to give a compound of formula V, wherein the formula of the compound of formula IV is as follows:

wherein

L is Cl or Br;

R³is H or CH₂R⁶；

R⁴And R⁵Together are a carbonyl group;

R⁶is COOR⁷；

R⁷Is an alkyl group having 1 to 6 carbon atoms;

at R²In piperazine, R²Is H, benzyl or tert-butoxycarbonyl;

in addition, the formula of formula V is as follows:

wherein

R²Is H, benzyl or tert-butoxycarbonyl;

R³is H or CH₂R⁶；

R⁴And R⁵Together are a carbonyl group;

R⁶is COOR⁷；

R⁷Is an alkyl group having 1 to 6 carbon atoms;

the compound of the formula V is subsequently reacted in a one-pot reaction first with a compound of the formula I and subsequently with a formamide to give a compound of the formula III, wherein the formula of the formula I is as follows:

L-CH₂-COOR¹ I

in the formula I

L is Cl, Br or I; and is

R¹Is an alkyl group having 1 to 6 carbon atoms;

wherein the compound of formula III has the following structural formula:

wherein R is²Is H, benzyl or tert-butoxycarbonyl;

and then if R²Not equal to H, then R is caused to be²Cracking;

or

c) Reacting a compound of formula V with chloroacetamide to give a compound of formula III, wherein in the compound of formula V:

R²is benzyl or tert-butoxycarbonyl;

R³is H or CH₂R⁶；

R⁴And R⁵Together are a carbonyl group;

R⁶is COOR⁷；

R⁷Is an alkyl group having 1 to 6 carbon atoms;

in the general formula III, R²Is benzyl or tert-butoxycarbonyl;

and subsequently subjecting R to²Cracking;

and/or converting 5- (1-piperazinyl) -benzofuran-2-carboxamide into one of its acid addition salts by treatment with an acid.

2. A process according to claim 1, characterized in that in the compound of formula I L is Br.

3. Process according to claim 1, characterized in that the transition metal catalyst used is Pd (OAc)₂/P (tert-butyl)₃。

4. The process according to claim 1, characterized in that N-methylpyrrolidone is used as solvent in the reaction of 5-bromosalicylaldehyde or the compound of the formula V with the compound of the formula I.

5. A compound of formula V:

wherein

R²Is H, benzyl or tert-butoxycarbonyl;

R³is H or CH₂R⁶；

R⁴And R⁵Together are a carbonyl group;

R⁶is COOR⁷；

R⁷Is an alkyl group having 1 to 6 carbon atoms.