WO2010015656A2 - New alkoxypyrazoles - Google Patents

Abstract

The present invention relates to a process for the preparation of alkoxypyrazoles and new alkoxypyrazole compounds.

Description

New alkoxypyrazoles

The present invention relates to synthesis of 3- alkoxypyrazoles which can lead to many derivatives including pyrazol-3-ones .

In the last 20 years, the Suzuki-Miyaura¹' ² aryl-aryl cross coupling reaction has probably increased by at least an order of magnitude the number of compounds that have been synthesised and tested in many medicinal chemistry research programs. Indeed, many successful research programs in the pharmaceutical industry owe their origin to the elaboration of original core scaffolds "dressed" with substituents fine-tuned to bind known enzyme or receptor pockets or to mimic series of compounds with a known biological activity.

In the same way, heterocyclic compounds particularly five membered heterocycles have attracted the attention of pharmaceutical community over the years due to their therapeutic value.

In recent years, there has been a growing interest in discovering new pyrazoles having advantageous biological properties .

Found among these compounds, in particular, are pyrazol-3-ones having applications in the field of the treatment or prevention of diseases such as diabetes, inflammatory diseases, prion diseases, and of the treatment of pain.

Nineteen pyrazolone derivatives have been shown to inhibit PrP-res (resistant prion protein) accumulation. The most effective compound was 2-phenyl-5- (4-nitrophenyl) - pyrazol-3-one³. 1, 2-dihydro-4- [ [4- (methylthio) phenyl] methyl] -5- ( trifluoromethyl) -3H-pyrazol-3-one has been shown to be a potent antihyperglycemic agent⁴.

Propyphenazone (1, 2-dihydro-l, 5-dimethyl-4- (1- methylethyl) -2-phenyl-3H-pyrazol-3-one) is a nonsteroidal anti-inflammatory drug frequently used as mild analgesic medicament⁵.

5-alkyl-4- (arylmethyl) pyrazol-3-ones have been shown to be the most promising new class of potential antidiabetic agent⁶.

The new immunosuppressant 2- (4' -chlorophenyl) benzo- thiopyrano- (4, 3-c) pyrazol-3-one has been characterized⁷.

Moreover, few pyrazole-featuring compounds^8"10 have been reported bearing an antimicrobial activity.

The pyrazole ring system cannot be considered as an original scaffold. For instance, the analgesic Nl-phenyl- pyrazol-5-one antipyrine was first prepared in 1892. However, the core pyrazol-3-one (5) structure with at least three potential nucleophilic centres (the two nitrogens and the oxygen) and two carbons is still an attractive heterocycle. Many of these reactive centres may lend themselves to chemical transformations with a potential for "quick" chemical diversity attainable in few reaction steps. This number of reactive centres, although desirable for chemical diversity, does force the chemist to design chemical transformations involving protection and deprotection steps to insure their regioselectivity . In the case of the pyrazol-3-ones this is a problem as the protection steps themselves also face this issue of regioselectivity. From the many N-aryl or N-alkyl hydrazines, the age-old Knorr reaction^31"33 provided an easy access to many Nl-subtituted pyrazol-5-ones . On the other hand, the isomeric Nl-subtituted pyrazol-3-ones are less easy to prepare. This aspect is actually illustrated by a 2007 chemical data base survey. Out of the 156278 compounds featuring a pyrazolone moiety ever reported, some 113469 are Nl-aryl-pyrazol-5-ones and "only" 9997 are the isomeric Nl-aryl-pyrazol-3-ones . This last number actually includes compounds with a substituent on the other nitrogen (4189) as well as ring-fused l-arylindazol-3-ones (138) . In any case, from a selective O-alkylation of compound (5) to give the O-protected chemical intermediates (6) one could imagine selective chemistry on one of the pyrazole nitrogens. However, only two papers describe the selective O-alkylation of (5) or further chemical transformations.³⁴' ³⁵ It is only quite recently that the problem of selective oxygen protection of pyrazolones such as (5) was breached.

Thus, there exist important needs for a new process for a simple access to 3-alkoxypyrazoles and then to Nl- substituted pyrazol-3-ones.

The patent FR 2862647 describes the generalization of processes⁸' ⁹ involving a transient N-carboxylation⁸ or N- acetylation⁹ prior to a then selective O-alkylation.

The present inventors have shown an alternative which shunts the three following steps : preparation of the pyrazol-3-one, its transient N-protection followed by its selective O-alkylation. They prepared the readily O- protected ethyl 3-ethoxy-lH-pyrazole-4-carboxylate (8) in one step from diethyl 2- (ethoxymethylene) malonate (7) . From O-protected ethyl 3-ethoxy-lH-pyrazole-4- carboxylate (8) , the present inventors also suited few chemical transformations. These chemical transformations insured the design of accesses to fully original chemical entities .

First, from the O-protected ethyl 3-ethoxy-lH- pyrazole-4-carboxylate (8) and its 5-haloderivatives, they prepared Nl-aryl 3-alkoxypyrazoles .

Second, the inventors investigated C4- and C5-carbon- carbon forming reactions.

Therefore, the first object of the present invention relates to a process for the preparation of alkoxypyrazoles of formula (I) or (I' )

in which

Ri stands for a radical selected from the group consisting of Ci-C₆ alkyl, C2-C6 alkenyl, C2-C6 alkynyl and (C₆-

C10) aryl (Ci-C₆) alkyl;

R2 stands for a radical selected from the group consisting of hydrogen, halogen, -C (O) -O- (Ci-C₆) alkyl, -C(O)-O-(C₂-

C₆) alkenyl, -C (0) -0- (C₂-C₆) alkynyl;

R3 stands for a radical selected from the group consisting of hydrogen, halogen, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ al- kynyl C₆-Ci₀ aryl, C₆-Ci₀ heteroaryl and (C₆-Ci₀) aryl (Ci- C₆) alkyl, each optionally substituted by R₅;

R₅ is a radical selected from the group consisting of halogen, oxygen, hydroxyl, Ci-C₆ alkyl and Ci-C₆ alkoxy; R₇ stands for a radical selected from the group consisting of H, Ci-C₆ alkyl, C₆-Ci₀ aryl, (C₆-Ci₀) aryl (Ci-C₆) alkyl, C₆- Ci₀ heteroaryl or (C₆-Ci₀) heteroaryl (Ci-C₆) alkyl, each optionally substituted by a halogen;

comprising the successive following steps:

(a) reacting a derivative of formula (II)

(H) in which A stands for a radical selected from the group consisting of Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl and (C₆-Ci₀) aryl (Ci-C₆) alkyl;

B stands for a radical selected from the group consisting of hydrogen, -C (O) -O- (Ci-C₆) alkyl, -C(O)-O-(C₂- C₆) alkenyl, -C (0) -0- (C₂-C₆) alkynyl;

D stands for a radical selected from the group consisting of hydrogen, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl and (C₆-Ci₀) aryl (Ci-C₆) alkyl; each optionally substituted by R₅;

R₅ is a radical selected from the group consisting of halogen, oxygen, hydroxyl, Ci-C₆ alkyl and Ci-C₆ alkoxy; E stands for a radical 0-P or NR_αRp, P stands for a radical selected from the group consisting of Ci-C₆ alkyl C2-C6 alkenyl, C2-C6 alkynyl and (C₆-Ci₀) aryl (Ci-C₆) alkyl;

R_α and Rp, identical or different, stand for a radical selected from the group consisting of H, Ci-C₆ alkyl or C₆-CiO aryl or R_α and Rp form together an C₄-C₆ al- kylene radical, an C₄-C₆ alkenylene, an C₄-C₆ heteroal- kylene radical or an C₄-C₆ heteroalkenylene radical; with 1 to 1.5 molar equivalents of R7-NH-NH2, XHX2, in which R₇ is as defined for compound of formula (I) or (I'), X2 is Cl or Br and x is 1 or 2; in an alkylalcohol RsOH as a solvent, in which R₈ is a radical selected from the group consisting of Ci-C₆ alkyl, C2~C₆ alkenyl, C2~C₆ alkynyl and (C₆-Cio) aryl (Ci- C₆) alkyl, (C₆-Ci₀) heteroaryl (Ci-C₆) alkyl; to obtain compounds of formula (III) or (III')

(b) optionally reacting said alkoxypyrazole of formula (III) or (III') wherein R₇ = H obtained in step (a) with a X-donor to prepare compounds of formula (IV) /(IV") or (IV) /(IV")

in which

X represents Br, Cl, I or F;

A, B and D are as defined above;

(c) recovering the alkoxypyrazole of formula (I) or (I') •

Advantageously, the molar ratio of said compound of formula (II) to said R₇-NH-NH₂, xHX₂, x is 1 or 2, X₂ is Cl or Br, is close to 1, preferably comprised between 0.95 and 1.1, more preferably between 1 and 1.05.

In a preferred embodiment, said compound of formula (II) is reacted with 1.05 molar equivalents of R₇-NH-NH₂, xHCl, in which R₇ and x are as defined above.

In a preferred embodiment, E is NR_αRp in the compound of formula (II) and the reaction in step (a) is run with R₇-NH-NH₂, 2HCl.

In another preferred embodiment, E is O-P and P is Ci- Ce alkyl in the compound of formula (II) and the reaction in step (a) is run with R₇-NH-NH₂, HCl.

Advantageously, R₇ is hydrogen or a phenyl, benzyl or methyl group.

Preferably, said R₇-NH-NH₂, xHCl is R₇-NH-NH₂, HCl (x is 1), more preferably is said R₇-NH-NH₂, xHCl is NH₂-NH₂, HCl.

In one embodiment, the reaction in step (a) is run at the boiling point of the solvent, preferably for 16 hours.

In another embodiment, the reaction in step (a) is run overnight at room temperature.

Preferably, the reaction in step (a) is run in ethanol (Rs is an ethyl group) or isopropanol, more preferably ethanol . In a preferred embodiment, 1.05 equivalents of hydrazine monohydrochloride are used in boiling ethanol.

In a preferred embodiment, said compound of formula (II) is diethyl 2- (ethoxymethylene) malonate .

In a preferred embodiment, A stands for a Ci-C₆ alkyl radical, preferably stands for methyl or ethyl.

In a preferred embodiment, B stands for hydrogen, a - COOH or -COOEt radical.

In a preferred embodiment, D stands for a radical selected from the group consisting of hydrogen or Ci-C₆ alkyl, preferably methyl.

In a preferred embodiment, E stands for a radical selected from the group consisting of NMeMe or O-ethyl .

Preferably, R₇ is a hydrogen atom.

Advantageously, in step (b) the compounds of formula (IV) or (IV) are prepared using N-X-succinimide in boiling cyclohexane .

Another object of the present invention relates to alkoxyppyrazoles of formula (V) or (V ) , wherein

Rn stands for a radical selected from the group consisting of Ci-C₆ alkyl, C2-C6 alkenyl, C2-C6 alkynyl and (C₆- C10) aryl (Ci-C₆) alkyl;

R12 stands for Br or I;

Ri3 stands for a radical selected from the group consisting of hydrogen, halogen, Ci-C₆ alkyl, C2~C₆ alkenyl, C₂-Cδ alkynyl, Cδ-Cio aryl , Cδ-Cio heteroaryl, and (Ce- Cio) aryl (Ci-Cδ) alkyl, each optionally substituted by R₅;

R₅ is a radical selected from the group consisting of halogen, oxygen, hydroxyl, Ci-Cε alkyl and Ci-Cε alkoxy; except compounds of formula (V) or (V ) wherein simultaneously

Rn is methyl, R_i2 is I, R₁₃ is methyl; Rn is methyl or ethyl or benzyl, R₂ is Br, R₁₃ is H; Rn is ethyl, R₂ is Br, R_i3 is methyl; Rn is benzyl, R₂ is I, R13 is H; Rn is methyl, R₂ is Br, Ri₃ is phenyl.

In a preferred embodiment, alkoxyppyrazoles according to the invention have formula (V) or (V ) , wherein

Rn stands for a radical selected from the group consisting of methyl or ethyl, Ri₂ stands for Br or I;

Ri₃ stands for a radical selected from the group consisting of hydrogen, halogen, methyl, phenyl, benzyl, morpholino,

except compounds of formula (V) or (V ) wherein simultaneously

Rn is methyl, R_i2 is I, Ri₃ is methyl; Rn is methyl or ethyl, R₂ is Br, R_i3 is H; Rn is ethyl, R₂ is Br, R_i3 is methyl; Rn is methyl, R₂ is Br, R_i3 is phenyl.

Another object of the present invention relates to alkoxypyrazoles of formula (VI) or (VI'), wherein

R stands for a radical selected from the group consisting of Ci-C₆ alkyl, C2-C6 alkenyl, C2-C6 alkynyl and (C₆- C10) aryl (Ci-C₆) alkyl;

R' stands for a radical selected from the group consisting of hydrogen, halogen, -C (O) -O- (Ci-C₆) alkyl, -C(O)- 0- (C₂-C₆) alkenyl, -C (0) -0- (C₂-C₆) alkynyl, C₆-Ci₀ aryl and C₆- Cio heteroaryl each optionally substituted by R₅;

R₅ is a radical selected from the group consisting of halogen, oxygen, hydroxyl, Ci-C₆ alkyl and Ci-C₆ alkoxy;

Xi stands for Br or I;

except compounds of formula (VI) or (VI') wherein simultaneously

R is methyl, R' is H and Xi is Br or I.

In a preferred embodiment, alkoxyppyrazoles according to the invention have formula (VI) or (VI'), wherein

R stands for a radical selected from the group consisting of methyl or ethyl,

R' stands for a radical selected from the group consisting of a hydrogen, halogen, benzyl, a phenyl optionally substituted by Cl or Br, -COOH, -COOEt ; Xi stands for Br or I; except compounds of formula (V) or (V ) wherein simultaneously R is methyl, R' is H and Xi is Br or I.

In a preferred embodiment, alkoxypyrazoles of formula

(VI) or (VI') are the following ones, in which

R is ethyl, R' is COOEt, Xi is Br, I;

R is ethyl, X_x is Br, R' is 4-BrC₆H₄ or 4 -ClC₆H₄;

R is ethyl, R' is H, Xi is I.

Definitions

The abbreviations encountered are defined as follows: H is hydrogen,

I is iodide, Br is bromide, Cl is chloride, F is fluoride Et is ethyl.

Within the meaning of this invention, "halogen" is understood to mean an atom of fluorine, bromine (Br) , chlorine or iodine (I) .

Within the meaning of this invention, "Ci-C₆ alkyl" group is understood to mean a saturated, linear or branched hydrocarbon chain comprising from 1 to 6 carbon atoms, in particular the methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl groups.

Within the meaning of this invention, "C₂~C₆ alkenyl" group is understood to mean a linear or branched hydrocarbon chain comprising at least one double bond and comprising from 2 to 6 carbon atoms, e.g., such as an ethenyl (vinyl) or propenyl group.

Within the meaning of the invention, "C₂~C₆ alkynyl" group is understood to mean a linear or branched hydrocarbon chain comprising at least one triple bond and compris- ing from 2 to 6 carbon atoms, e.g., such as an ethynyl or propynyl group.

Within the meaning of this invention, "aryl" group is understood to mean an aromatic group preferably comprising from 5 to 10 carbon atoms and including one or more fused rings, e.g., such as a phenyl or naphtyl group. This is advantageously phenyl.

Within the meaning of the invention, "heteroaryl" group is understood to mean any aryl group as defined above wherein one or more carbon atoms have been replaced by one or more heteroatoms, advantageously 1 to 4, and even more advantageously 1 to 2, e.g., such as sulphur, nitrogen or oxygen atoms. Examples of heteroaryl groups are the furyl, thiophenyl, pyrrolyl, pyridyl, pyrimidyl, pyrazolyl, imida- zolyl, tetrazolyl or else indyl groups.

Within the meaning of this invention, "aryl- (Ci-Cε) - alkyl" group is understood to mean any aryl group as defined above, which is bound to the molecule by means of a (Ci-Cε) -alkyl group as defined above. In particular, a group such as this can be a benzyl group.

Within the meaning of this invention, "C4-C6 alkylene" group is understood to mean a saturated, linear or branched hydrocarbon chain comprising from 4 to 6 carbon atoms which forms a saturated hydrocarbon ring having 5 to 7 members, with the nitrogen atom to which it is linked.

Within the meaning of this invention, "C4-C6 al- kenylene" group is understood to mean a linear or branched hydrocarbon chain comprising at least one double bond and comprising from 4 to 6 carbon atoms which forms a saturated hydrocarbon ring having 5 to 7 members, with the nitrogen atom to which it is linked.

Within the meaning of this invention, "C4-C6 heteroal- kylene" group is understood to mean any alkylene group as defined above wherein one or more carbon atoms have been replaced by one or more heteroatoms, advantageously 1 to 2, and even more advantageously 1, e.g., such as sulphur, nitrogen or oxygen atoms, advantageously nitrogen.

Within the meaning of this invention, "C4-C6 heteroal- kenylene" group is understood to mean any alkenylene group as defined above wherein one or more carbon atoms have been replaced by one or more heteroatoms, advantageously 1 to 2, and even more advantageously 1, e.g., such as sulphur, nitrogen or oxygen atoms, advantageously nitrogen.

The invention will be better understood upon reading the following examples, these examples serving solely to illustrate the invention.

Examples

Example 1 : Preparation of 3-alkoxypyrazoles The features of the devices used to conduct analyses of all of the compounds described in Example 1 are indicated hereinbelow:

A Biotage initiator 2 microwave oven was used for of the reactions requiring microwaves irradiations. The ^H NMR and 13c NMR spectra were recorded on a Bruker Avance 400 spectrometers at 400 MHz and 100 MHz, respectively. Unless otherwise noted, CDCI3 was the solvent used. Shifts (δ) are given in ppm with respect to the TMS signal and coupling constants (J) are given in Hertz. Column chromatography were performed either with Merck silica gel 60 (0.035 0.070 mm) or neutral alumina containing a suitable proportion of water, using a solvent pump operating at pressure between 2 and 7 bar (25-50 mL/mn) and an automated collect- ing system driven by a UV detector set to 254 nm unless stated otherwise (i.e. if ethylacetate was used then it would be set to 280 nm) . Sample deposition was always carried out by absorption of the mixture to be purified on a small amount of the solid phase followed by its deposition of the top of the column. The low resolution mass spectra were obtained on an Agilent 1100 serie LC/MSD system using an atmospheric electrospray ionisation system and the high resolution mass spectroscopy spectra (HRMS) were obtained using a Waters Micromass Q-Tof with an electrospray ion source .

Preparation of compounds 8 and 9

Diethylethoxymethylenemalonate (7) (37.4 g, 0.172 mol) and hydrazine hydrochloride (12.2 g, 0.178 mol) were re- fluxed in ethanol (500 mL) for 16 hours. The solvent was removed under reduced pressure, the residue was dispersed in water (500 ml) and slowly made basic by the addition of solid sodium hydrogencarbonate . The aqueous phase was extracted with dichloromethane; this organic phase was washed with a IN solution of sodium hydrogencarbonate three times, dried over sodium sulfate and concentrated to dryness to yield compound 8 as an oil that solidified very slowly (13.22 g, 41 %) . The aqueous phase was cautiously made acid with concentrated hydrochloric acid, saturated with sodium chloride and the resulting precipitate was filtered, washed with water and dried under vacuum while heating at 60 ⁰C to yield compound 9 (10 g, 37 %) as a white powder.

Alternative preparations of compound 8 : diethyl 2-

( (dimethylamino) methylene) malonate (6)¹³ (0.25 g, 1.16 mmol) and hydrazine dihydrochloride (0.12 g, 1.16 mmol) were refluxed in ethanol (30 mL) for five hours. This was concnetrated to dryness and dispersed in dichloromethane . This was washed with a 1 N sodium hydrogenocarbonate, dried over sodium sulfate and concentrated to dryness to yield compound 8 (0.09 g; 42 %) as described below.

Ethyl 3-ethoxy-lH-pyrazole-4-carboxylate (8) : ¹H (CDCl₃) : 1.35 (t, 3H, J = 7.1) ; 1.46 (t, 3H, J = 7.1) ; 4.30 (q, 2H, J = 7.1) ; 4.36 (q, 2H, J = 7.1) ; 7.89 (s, IH) ; 11.4 (s (l) , IH) . ¹³C (CDCl₃) : 14.3; 14.5; 60.1; 65.3; 99.0; 134.0; 162.3; 163.8. HRMS: Calcd. for C₈H₁₂N₂O₃ + H : 185.0926. Found: m/z, 185.0971.

Ethyl 3-OXO-2, 3-dihydro-lH-pyrazole-4-carboxylate (9) ¹¹' ⁸: ¹H (DMSO-d_&) : 1.23 (t, 3H, J = 7.1) ; 4.15 (q, 2H, J = 7.1) ; 7.90 (S (I) , IH) ; 10.20 (s (l) , IH) . ¹³C (DMSO-d_&; Dl set to 10s) : 19.6; 64.1; 102.2; 139.5 (1) ; 165.2 (1) ; 168.0.

3-Ethoxy-lH-pyrazole (10) : Diethylethoxymethylenemalonate (38.9 g, 0.179 mol) and hydrazine hydrochloride (12.69 g, 0.185 mol) were refluxed in ethanol (500 mL) for 16 hours. The solvent was removed under reduced pressure, the residue was dispersed in 6N hydrochloric acid (100 ml) and heated to reflux until the end of the carbon dioxide evolution (4 hours in the present case) . The aqueous phase and slowly made basic by the addition of sodium hydrogenocarbonate and extracted with ethyl acetate four times. The organic phase was washed with a 1 N solution of sodium hydrogencarbonate once, with brine once, dried over sodium sulfate and concentrated to dryness to yield compound 10 as an oil (7.77 g, 38 %) . ¹H (CDCl₃) : 1.43 (t, 3H, J = 7.0); 4.23 (q, 2H, J = 7.0); 5.74 (d, IH, J = 2.5); 7.37 (d, IH, J = 2.5); 9.40 (S(I), IH) . ¹³C (CDCl₃) : 14.9; 64.9; 90.3; 130.2; 167.7. HRMS: Calcd. for C₅H₈N₂O + H : 113.0715. Found: m/z, 113.0788.

3-Ethoxy-4-iodo-lH-pyrazole (11) : Compound 10 (8.37 g, 0.074 mol) , sodium iodide (11.2 g, 0.082 mol) and potassium carbonate (40 g, 0.289 mol) were dissolved in water (400 mL) and ethanol (100 mL) . To this was added iodine (28.5 g, 0.112 mol) . The resulting suspension was stirred for 90 minutes hour, decolorized (if necessary) with sodium bisulfite and diluted with brine (400 mL) . This was filtered, washed with water and dried under vacuum while heating at 70 ⁰C in a large Petri dish in order to sublimate the iodoform also occurring in this reaction to yield compound 11 as an off-white solid (16.2 g; 91 %) . ¹H (CDCl₃) : 1.44 (t, 3H, J = 7.1); 4.31 (q, 2H, J = 7.1); 7.42 (s, IH); 9.35 (S(I), IH) . ¹³C (CDCl₃) : 14.8; 44.2; 65.5; 134.3; 163.2. HRMS: Calcd. for C₅H₇N₂OI + H : 238.9681. Found: m/z, 238.9722.

Preparation of compound 12a or 12b: Compound 8 (0.74 g; 4.02 mmol) and N-bromosuccinimide (0.75 g; 4.22 mmol) or N- iodosuccinimide (0.94 g, 4.22 mmol) were refluxed in cyclo- hexane (50 mL) for 30 minutes or 24 hours. The resulting suspension was concentrated to dryness and purified by a chromatography over silica gel (dichloromethane / ethanol 98-2) to yield compound 12a (0.75 g; 60 %) or 12b (0.5 g; 47 %) .

Ethyl 3-iodo-5-ethoxy-lH-pyrazole-4-carboxylate (12a) : Obtained as an oil that slowly solidified. ¹H (CDCI3) : 1.36 (t, 3H, J = 7.0); 1.39 (t, 3H, J = 7.0); 4.31 (m, 4H) . ¹³C (CDCI3; two broad signals only visible if Dl is increased to 10) : 14.2; 14.6; 60.4; 65.5; 87.0; 103.3; 161.9; 162.0. HRMS: Calcd. for C₈H₁₁IN₂O₃ + H : 332.9712. Found: m/z, 332.9722.

Ethyl 3-bromo-5-ethoxy-lH-pyrazole-4-carboxylate (12b) : Ob^¬ tained as white crystals. ¹H (CDCl₃) : 1.40 (t, 3H, J = 7.0) ; 1.48 (t, 3H, J = 7.0) ; 4.33 (m, 4H) ; 9.5 (s (1) , IH) . ¹³C (CDCl₃; two broad signals only visible if Dl is in^¬ creased to 10) : 14.2; 14.5; 60.4; 65.7; 99.0; 119.5 (br) ; 161.6 (br) ; 162.0. HRMS: Calcd. for C₈H₁₁BrN₂O₃ + H : 263.0031. Found: m/z, 263.0049.

^N W V If ¹

-o Ethyl 3-iodo-5-ethoxy-lH-pyrazole-4-carboxylate (13) : Compound 12a (0.99 g, 3.2 mmol) was dispersed in 6N hydrochloric acid (20 mL) and heated to reflux for 4 hours. The aqueous phase was diluted in water, slowly made basic by the addition of concentrated ammonia and extracted with ethyl acetate four times. The organic phase was washed with brine once, with brine once, dried over sodium sulfate and concentrated to dryness to yield compound 13 as an oil (0.52 g, 67 %) . ¹H (CDCl₃) : 1.40 (t, 3H, J = 7.0); 4.18 (q, 2H, J = 7.0); 5.85 (s, IH); 6.90 (s(l), IH) . ¹³C (CDCl₃) : 14.7; 65.7; 83.3; 98.4; 162.4. HRMS: Calcd. for C₅H₇IN₂IO + H : 238.9681. Found: m/z, 238.9621.

A basic hydrolysis of ester 12a is also possible and leads to an in situ decarboxylation of the corresponding acid and thus to 76 % of the 5-iodopyrazole 13.

Compound 12a (1.27 g, 4.09 mmol), sodium hydroxide (0.70 g, 13.4 mmol) in ethanol (2 mL) and water (8 mL) were heated in a microwave oven at 170 ⁰C for 45 minutes. The resulting mixture was dispersed in water and extracted with ethyl acetate. The organic layer was then washed with brine, dried over magnesium sulfate and concentrated to dryness with a high vacuum pump to yield compound 13 (0.74 g, 76

Ethyl 3-ethoxy-5-methyl-lH-pyrazole-4-carboxylate (14) : This compound was obtained from diethyl 2-(l- ethoxyethylidene) malonate, ¹⁴ using the protocol described above, as a solid in a 17 % yield after a chromatography over silica gel (dichloromethane / ethanol 94/6) . ¹H (CDCl₃) : 1.35 (t, 3H, J = 7.1); 1.43 (m, 3H); 2.47 (s, 3H); 4.30 (m, 4H); 9.2 (s, IH) . ¹³C (CDCl₃) : 12.5; 14.3; 14.6; 59.7; 64.9; 97.2; 145.5; 163.0; 163.6. Calcd. for C₉H₁₄N₂O₃ + Na : 221.0902. Found: m/z, 221.0894.

O^- NH

3-Methoxy-lH-pyrazole (15) . Methyl 3-methoxyacrylate (4) (13.36 g, 0.114 mol) and hydrazine hydrochloride (8.08 g, 0.117 mol)) were refluxed in methanol (200 mL) for 48 hours. The solvent were removed under reduced pressure, the residue was dispersed in water (500 mL) and slowly made basic by the addition of solid sodium hydrogencarbonate . The aqueous phase was saturated with salt, extracted with dichloromethane; this organic phase was washed with a 1 N solution of sodium hydrogencarbonate three times, dried over sodium sulfate and concentrated to dryness. The residue was boiled in water (50 mL) in the presence of potassium hydroxide (3.8 g) for 6 hours. This was extracted with ethyl acetate; the organic phase was washed with brine dried over sodium sulfate and concentrated to dryness to yield compound 15 as an oil (0.85 g, 7.5 %) . ¹H (CDCl₃) : 3.92 (s, 3H); 5.73 (d, IH, J = 2.5); 7.37 (d, IH, J = 2.5) . ¹³C (CDCl₃) : 56.6; 89.6; 130.4; 164.4.

Preparation of compounds 16a-b, 17a-b and 18a-b

Diethylethoxymethylenemalonate (0.0172 mol) and the relevant hydrazine hydrochloride derivative (0.0178 mol) were refluxed in ethanol (50 mL) for 16 hours. The solvent were removed under reduced pressure, the residue was dispersed in water (50 ml) and slowly made basic by the addition of solid sodium hydrogencarbonate . The aqueous phase was extracted with dichloromethane; this organic phase was washed with a 1 N solution of sodium hydrogencarbonate three times, dried over sodium sulfate and concentrated to dryness before a relevant purification if necessary as described below.

Ethyl-3<-\ethoxy-l-methyl-lH-pyrazole-4-carboxylate (16a) : Obtained as an oil in a 17 % yield that crystallizes after a chromatography over neutral alumina containing 1.5 % water (cyclohexane / ethyl acetate 95/5 to 4/1) . ¹H (CDCl₃) : 1.27 (t, 3H, J = 7.1); 1.41 (t, 3H, J = 7.1); 3.72 (s, 3H); 4.24 (q, 2H, J = 7.1); 4.28 (q, 2H, J = 7.1); 7.63 (s, IH) . ¹³C (CDCl₃) : 14.4; 14.7; 39.3; 59.7; 65.1; 99.3; 134.9; 162.1; 162.5. Calcd. for C₉H₁₄N₂O₃ + H : 199.1083. Found: m/z, 199.1046.

Ethyl 5-ethoxy-l-methyl-lH-pyrazole-4-carboxylate (16b) : Obtained as an oil in a 17 % yield after a chromatography over neutral alumina containing 1.5 % water (cyclohexane / ethyl acetate 95/5 to 4/1) . ¹H (CDCl₃) : 1.35 (t, 3H, J = 7.1); 1.41 (t, 3H, J = 7.0); 3.68 (s, 3H); 4.27 (q, 2H, J = 7.1); 4.48 (q, 2H, J = 7.0); 7.76 (s, IH) . ¹³C (CDCl₃) : 14.4; 15.4; 34.1; 59.9; 71.6; 99.3; 140.7; 154.7; 162.4 Calcd. for C₉H₁₄N₂O₃ + H : 199.1083. Found: m/z, 199.1001.

Ethyl l-benzyl-3-ethoxy-lH-pyrazole-4-carboxylate (17a) : Obtained as an oil in a 5.7 % yield after a chromatography over neutral alumina containing 1.5 % water (cyclohexane / ethyl acetate 97.5/2.5 to 95/5) . ¹H (CDCl₃) : 1.31 (t, 3H, J = 7.1); 1.44 (t, 3H, J = 7.1); 4.23 (q, 2H, J = 7.1); 4.33 (q, 2H, J = 7.1); 5.11 (s, 2H); 7.23 (m, IH); 7.35 (m, 3H); 7.64 (s, IH) . ¹³C (CDCl₃) : 14.4; 14.7; 56.2; 59.8; 65.2; 99.9; 127.9; 128.3; 128.9; 134.2; 135.3; 162.1; 162.6. Calcd. for Ci₅H₁₈N₂O₃ + Na : 297.1215. Found: m/z, 297.1219.

Ethyl l-benzyl-5-ethoxy-lH-pyrazole-4-carboxylate (17b) : Obtained as an oil in a 22 % yield after a chromatography over neutral alumina containing 1.5 % water (cyclohexane / ethyl acetate 97.5/2.5 to 95/5) . ¹H (CDCl₃) : 1.24 (m, 6H); 4.18 (q, 2H, J = 7.1); 4.31 (q, 2H, J = 7.1); 5.09 (s, 2H); 7.22 (m, 5H); 7.72 (s, IH) . ¹³C (CDCl₃) : 14.4; 15.3; 51.1; 59.9; 71.7; 99.4; 127.5; 127.9; 128.7; 136.3; 141.2; 154.7; 162.4. Calcd. for Ci₅H₁₈N₂O₃ + H : 275.1396. Found: m/z, 275.1345.

Ethyl 3-ethoxy-l-phenyl-lH-pyrazole-4-carboxylate (18a) : Obtained as crystals (cyclohexane) in a 1.9 % yield after a chromatography over neutral alumina containing 1.5 % water (cyclohexane / ethyl acetate 97.5/2.5 to 95/5) . ¹H (CDCl₃) : 1.38 (t, 3H, J = 7.1); 1.51 (t, 3H, J = 7.1); 4.33 (q, 2H, J = 7.1); 4.46 (q, 2H, J = 7.1); 7.30 (m, IH); 7.46 (m, 2H); 7.65 (m, 2H); 8.25 (s, IH) . ¹³C (CDCl₃) : 14.4; 14.7; 60.1; 65.4; 102.2; 118.5; 126.6; 129.5; 131.1; 139.3; 162.5; 162.7. HRMS: Calcd. for Ci₄H₁₆N₂O₃ + H : 261.1239. Found: m/z, 261.1275.

Ethyl 5-ethoxy-l-phenyl-lH-pyrazole-4-carboxylate (18b) : Obtained as an oil in a 22 % yield after a chromatography over neutral alumina containing 1.5 % water (cyclohexane / ethyl acetate 97.5/2.5 to 95/5) . Obtained as an oil ¹H (CDCl₃) : 1.31 (t, 3H, J = 7.1); 1.37 (t, 3H, J = 7.1); 4.32 (q, 2H, J = 7.1); 4.42 (q, 2H, J = 7.1); 7.34 (m, IH); 7.46 (m, 2H); 7.67 (m, 2H); 7.94 (s, IH) . ¹³C (CDCl₃) : 15.7; 16.5; 61.4; 73.4; 102.3; 124.5; 128.8; 130.2; 139.2; 143.2; 156.1; 163.6. HRMS: Calcd. for Ci₄H₁₆N₂O₃ + H : 261.1239. Found: m/z, 261.1272.

Results As shown in scheme 1, the readily O-protected ethyl 3- ethoxy-lH-pyrazole-4-carboxylate (8) was prepared in one step from diethyl 2- (ethoxymethylene) malonate (7) . This is achieved in a 41 % yield by the use of hydrazine hydrochloride in boiling ethanol. The other reaction product is the known ethyl 3-hydroxy-lH-pyrazole-4-carboxylate 9, which is the sole reaction product between hydrazine hydrate and 7.¹¹' ⁸ Surprisingly, this synthetic pathway has no precedent. This reaction turns out to also proceed in a similar yield when starting using hydrazine dihydrochloride and diethyl 2- ( (dimethylamino) methylene) malonate (6), which is easily prepared from diethyl malonate (5) .¹³ On the other hand, lesser amount of 3-ethoxypyrazole (10) were obtained from ethyl 3- (dimethylamino) acrylate or ethylpropiolate . In any case, an acid hydrolysis of the carboxylate moiety of compound 8 also leads to its decarboxylation and thus, in a one pot process, to compound 10 in a 38 % yield from 7. From compound 8 and 10, further transformations allowed the preparation of the two iodo-bearing derivatives 11 and 12. If the synthesis of compound 11 was trouble-free, many attempts were made to prepare the 5-halogenated alkoxypyra- zole 12a. Eventually, compound 12 was prepared from 8 in a 60 % yield using N-iodosuccinimide in boiling cyclohexane. The 5-brominated homolog 12b was also obtained, from N- bromosuccinimide, in a 47 % yield. Moreover, under acid condition, compound 12a led to 67 % of the 5-iodo-3- ethoxypyrazole (13) . Other salts of hydrazine were tried (hydrobromide) giving the same yields. )

Scheme 1: i: NH₂NH₂, 2HCl, EtOH, reflux, ii: NH₂NH₂, HCl, EtOH, reflux, iii: HCl 6 N reflux, iv: I₂, NaI, K₂CO₃, EtOH, H₂O. v: N-iodosuccinimide or N-bromosuccinimide, cyclohex- ane reflux.

As shown in scheme 2, from the methyl homolog of compound 7,¹⁴ the same reaction gave 17 % of the 5-methyl 3-alkoxy pyrazole 14. Moreover, the condensation of hydrazine hydrochloride with methyl 3-methoxyacrylate led to the 3- methoxypyrazole 15 although in a lesser 7.5 % yield.

Scheme 2: i: EtOH, reflux.

Further work led to the study of the condensation reaction between diethyl 2- (ethoxymethylene) malonate (7) and methyl, benzyl or phenyl hydrazine hydrochloride. As shown in scheme 3, these reactions led, aside from the expected iso- meric pyrazolones, to substantial amount of the isomeric 3- ethoxy pyrazoles which could be separated. Their structure assignement was achieved either by long distance ¹H, ¹³C NMR correlation experiments or, for compounds 18a and 18b by further chemical transformations as described below.

%)

Scheme 3: i: EtOH, reflux.

Example 2: N-arylation study from compounds 8, 10-13

The pyrazole derivative (5.43 mmol) , benzeneboronic acid (0.73 g, 5.97 mmol), pyridine (0.88 ml, 10.9 mmol, dried over 4A molecular sieves) , 4A molecular sieves (2 g) and copper (II) acetate hydrate (1.62 g, 8.15 mmol) were dispersed in dichloromethane (100 mL) . The suspension was stirred in open air for 48 hours. After concentration to dryness, the residue was absorbed on a small amount of silica gel and purified as described below for each pair of isomers .

From compound 8, a chromatography as over neutral alumina containing 1.5 % water (cyclohexane - dichloromethane 8/1) led in this order to compound 18b and then compound 18a (92 %) . The fraction containing 18b had to be further purified by a second chromatography over neutral alumina containing 1.5 % water (cyclohexane - ethylacetate 9/1) to yield pure 18b (7 %) .

Ethyl 3-ethoxy-l-phenyl-lH-pyrazole-4-carboxylate (18a) : as described above

Ethyl 5-ethoxy-l-phenyl-lH-pyrazole-4-carboxylate (18b) : as described above.

From compound 11, a chromatography over silica gel (cyclohexane - dichloromethane 8/2) led, in that order, to compound 19a (71 %) and its isomer 19b (1.5 %) .

3-Ethoxy-4-iodo-l-phenyl-lH-pyrazole (19a) : Obtained as an oil. 1.48 (t, 3H, J = 7.0) ; 4.42 (q, 2H, J = 7.0) ; 7.24 (m, IH) ; 7.43 (m, 2H) ; 7.58 (m, 2H) ; 7.79 (s, IH) . ¹³C (CDCl₃) : 14.7; 47.0; 65.6; 117.7; 125.7; 129.4; 131.8; 139.8; 163.7. HRMS: Calcd. for CnH₁₁N₂OI + H : 314.9995. Found: m/z, 315.0037.

5-ethoxy-4-iodo-l-phenyl-lH-pyrazole (19b) : Obtained as an oil. 1.32 (t, 3H, J = 7.0) ; 4.21 (q, 2H, J = 7.0) ; 7.34 (m, IH) ; 7.47 (m, 2H) ; 7.54 (s, IH) ; 7.68 (m, 2H) . ¹³C (CDCl₃) : 15.3; 45.3; 71.2; 122.4; 127.2; 129.0; 138.4; 144.2; 153.2. HRMS: Calcd. for C₁₁H₁₁N₂OI + H : 314.9995. Found: m/z, 315.0053. From compound 12a, a chromatography over neutral alumina containing 1.5 % water (cyclohexane - ethyl acetate 96/4) led in this order to compound 20b (26 %) and then compound 20a (60 %) .

Ethyl 5-iodo-3-ethoxy-l-phenyl-lH-pyrazole-4-carboxylate

(20a) : Obtained as a solid. 1.40 (t, 3H, J = 7.0) ; 1.45 (t, 3H, J = 7.0) ; 4.37 (m, 4H) ; 7.48 (m, 5H) . ¹³C (CDCl₃) : 14.2; 14.6; 60.3; 65.1; 90.2; 105.4; 127.1; 128.9; 129.1; 140.1; 161.9; 163.8. HRMS: Calcd. for Ci₄H₁₅N₂O₃I + Na : 409.0025. Found: m/z, 409.0036.

Ethyl 3-iodo-5-ethoxy-l-phenyl-lH-pyrazole-4-carboxylate (20b) : Obtained as an oil. 1.28 (t, 3H, J = 7.1); 1.43 (t, 3H, J = 7.1); 4.27 (q, 2H, J = 7.1); 4.38 (q, 2H, J = 7.1); 7.39 (m, IH); 7.46 (m, 2H); 7.65 (m, 2H) . ¹³C (CDCl₃) : 14.3; 15.2; 60.5; 72.7; 99.9; 104.7; 123.2; 128.3; 128.8; 137.1; 154.7; 161.2. HRMS: Calcd. for Ci₄H₁₅N₂O₃I + Na : 409.0025. Found: m/z, 315.0026.

From compound 12b, a chromatography over neutral alumina containing 1.5 % water (cyclohexane - ethyl acetate 97/3) led, in that order, to compound 21b (13 %) and then its isomer 21a (54 %) .

Ethyl 5-bromo-3-ethoxy-l-phenyl-lH-pyrazole-4-carboxylate (21a) : Obtained as an oil. 1.37 (t, 3H, J = 7.0) ; 1.46 (t, 3H, J = 7.0) ; 4.37 (m, 4H) ; 7.46 (m, 5H) . ¹³C (CDCl₃) : 14.3;

14.6; 60.4; 65.0; 101.3; 118.4; 126.2; 128.9; 129.0; 138.5; 116611..88;; 116622..77.. HHRRMMSS:: CCaallccdd.. for Ci₄H₁₅N₂O₃ ⁷⁹Br + Na 361.0164. Found: m/z, 361.0184.

Ethyl 3-bromo-5-ethoxy-l-phenyl-lH-pyrazole-4-carboxylate (21b) : Obtained as an oil. ¹H (CDCl₃) : 1.29 (t, 3H, J = 7.0) ; 1.44 (t, 3H, J = 7.0) ; 4.28 (q, 2H, J = 7.0) ; 4.38 (q, 2H, J = 7.0) ; 7.37 (m, IH) ; 7.46 (m, 2H) ; 7.66 (m, 2H) . ¹³C (CDCl₃) : 14.3; 15.2; 60.6; 72.8; 101.4; 123.2; 128.1; 128.8; 129.1; 137.1; 155.1; 161.2. HRMS: Calcd. for Ci₄H₁₅N₂O₃ ⁷⁹Br + Na : 361.0164. Found: m/z, 361.0172.

From compound 10, a chromatography over neutral alumina containing 1.5 % water (cyclohexane - dichloromethane 9/1 and then 2/1) led, in that order, to compound 22a (56 %) and its isomer 22b (20 %) .

Ethyl 3-ethoxy-l-phenyl-lH-pyrazole (22a) : Obtained as an oil. ¹H (CDCl₃) : 1.46 (t, 3H, J = 7.0); 4.33 (q, 2H, J = 7.0); 5.90 (d, IH, J = 2.5); 7.23 (m, IH); 7.42 (m, 2H); 7.63 (m, 2H); 7.74 (d, IH, J = 2.5) . ¹³C (CDCl₃) : 14.8; 64.9; 93.7; 117.8; 125.2; 125.5; 129.3; 140.2; 164.5. HRMS : Calcd. for CnH₁₂N₂O + H : 189.1028. Found: m/z, 189.1061.

Ethyl 5-ethoxy-l-phenyl-lH-pyrazole (22b) : Obtained as an oil. ¹H (CDCl₃) : 1.47 (t, 3H, J = 7.1); 4.19 (q, 2H, J = 7.1); 5.67 (d, IH, J = 1.7); 7.28 (m, IH); 7.42 (m, 2H); 7.51 (d, IH, J = 1.7); 7.77 (m, 2H) . ¹³C (CDCl₃) : 14.6; 67.9; 86.2; 122.0; 126.2; 128.8; 138.8; 139.6; 154.6. HRMS: Calcd. for CnH₁₂N₂O + H : 189.1028. Found: m/z, 189.0971.

Acid hydrolysis of compounds 18a and 18b: In a 60 mL round- bottomed thick glass tube fitted with a PTFE-faced screw- cap, a mixture of the considered pyrazole (1 mmol) and 33 % hydrogen bromide in acetic acid (1.5 mL) was heated at 140 °C for 4 hours. The resulting solution was cooled, diluted in water extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to dryness. The resulting residues were purified in both cases by a chromatography over silica gel (di- chloromethane-ethanol 99/1) to yield compound 23a or 23b as described below.

l-phenyl-lH-pyrazol-3 (2H) -one (23a) : Obtained as a white powder in an 81 % yield. ¹H (DMSO-d_&) : 5.80 (d, IH, J = 2.5) ; 7.18 (m, IH) ; 7.47 (m, 2H) ; 7.67 (m, 2H) ; 8.20 (d, IH, J = 2.5) ; 10.18 (s (br) , IH) . ¹³C (DMSO-d_&) : 94.3; 116.7; 124.5; 128.3; 129.3; 139.8; 162.6. HRMS: Calcd. for C₉H₈N₂O + H : 161.0715. Found: m/z, 161.0793.

l-phenyl-lH-pyrazol-5 (4H) -one (23b) : Obtained as an oil which solidified in a 71 % yield. ¹H (CDCl₃) : 3.51 (d, 2H, J = 1.2) ; 7.21 (m, IH) ; 7.43 (m, 2H) ; 7.49 (t, IH, J = 1.2) ; 7.88 (m, 2H) . ¹³C (CDCl₃) : 40.9; 119.0; 125.4; 128.9; 137.9; 146.8; 169.9. HRMS: Calcd. for C₉H₈N₂O + H : 161.0715. Found: m/z, 161.0799.

3-Ethoxy-l-phenyl-lH-pyrazole-4-carboxylic acid (24) : ester 18a (0.52 g, 2 mmol) was refluxed in a 1/1 water - ethanol solution (20 mL) containing sodium hydroxide (0.3 g, 3.8 mmol) for one hour. The resulting solution was diluted in water, made acid with 2N hydrochloric acid and the precipitate was filtered, washed with water and dried under vacuum to yield compound 24 as a white powder (0.39 g, 85 %) . ¹H

(DMSO-d_&) : 1.37 (t, 3H, J = 7.1); 4.33 (q, 2H, J = 7.1); 7.32 (m, IH); 7.48 (m, 2H); 7.85 (m, 2H); 8.20 (s, IH) . ¹³C

(DMSO-d_&) : 15.0; 65.1; 102.6; 118.4; 126.8; 129.9; 133.2; 139.3; 162.4; 163.3. HRMS: Calcd. for Ci₂H₁₂N₂O₃ + H : 233.0926. Found: m/z, 233.0973. Results :

Scheme 4 depicts the copper-based N-phenylation of these compounds using phenylboronic acid.^15'18 From compound 8, a 92 % yield of the N-I phenylation product 18a along with 7 % of its isomer 18b were isolated. The latter isomer is actually the only one which had been partially reported previously.¹⁹' ²⁰ The N-phenylation of the 4-iodo bearing compound 11 gave 71 % of the Nl-phenylation product 19a and only traces of 19b. On the other hand, this reaction proceeded with a lesser selectivity from compound 12a as compound 20a was obtained in a 60 % yield along with 26 % of 20b. A similar result was observed from 12b which led to compound 21a and 21b in 54 and 13 % yield respectively. And, from compound 10, the isomers 22a and 22b are obtained in 56 and 20 % yield respectively. Arylation of compound 13 also proceeded well; however, despite many trials, we could not separate the 1/3 mixture of the corresponding isomeric products .

18a-22a 18b-22b

Scheme 4: i: PhB(OH)₂, Cu(OAc)₂, pyridine, 4A molecular sieves, CH₂Cl₂, air 25 ⁰C

As long distance correlation or NOE-based NMR experiments are of little use to determine the regioselectivity of these N-phenylation reactions, this was ascertained beyond any doubt by the following transformations of the separated isomers. As depicted in scheme 5, an exhaustive acid hydrolysis of 18a and 18b led to compounds 23a and 23b. The ¹H and ¹³C NMR spectra of 23b in deuterated chloroform pointed out the occurrence of a methylene component only compatible with the mesomer 23b drawn in scheme 2. The saponification of the ester function of compound 18a gave the acid 24 which upon heating in the presence of an equivalent amount of methanesulfonic gave 56 % of decarboxylation product corresponding to the isomer 22a. A partial (as the evolving hydrogen iodide poisons the catalyst) palladium-catalysed reduction of compound 19a also gave small amount of the isomer 22a. Under these reduction conditions, the bromine-bearing compound 21a led to the isomer 18a. Moreover, as it is shown below, further chemistry using compound 20a and 21a gave the same reaction product thus completing the structure assignment of all the N- phenyl derivatives.

Scheme 5: i: HBr/AcOH 140 ⁰C. ii: NaOH, EtOH, H₂O, reflux, iii: MeSO₃H, toluene reflux, iv: NH₃, HCOOH, ethanol Pd/C reflux . Example 3: C4 and C5-phenylation of the N-arylated compounds of Example 2 or of the 5-haloderivatives compounds of Example 1

3-Ethoxy-lH-pyrazole-4-carboxylic acid (25) : compound 8 (1 g, 5.43 mmol) was heated to reflux in IN sodium hydroxide solution (11 mL) for one hour (a shorter time is likely to be better) and upon acidification the precipitate was filtered, washed with water and dried under vacuum to yield 25 as a white powder (0.49 g, 58 %) . ¹H (DMSO-d_&) : 1.30 (t, 3H, J = 7.0); 4.20 (q, 2H, J = 7.0); 7.98 (s, IH); 11.8 (s (1), IH); 12.5 (s (1), IH) . ¹³C (DMSO-d_&) : 14.6; 64.0; 98.5; 134.3; 161.4; 163.4. HRMS: Calcd. for C₆H₈N₂O₃ + H : 157.0613. Found: m/z, 157.0600.

3-Ethoxy-l , 4-diphenyl-lH-pyrazole (26) : In a 10 mL biotage- adapted tube, compound 24 (0.11 g; 0.47 mmol), bromobenzene

(0.068 mL; 0.64 mmol), potassium carbonate (0.078 g; 0.57 mmol) copper iodide (0.009 g; 0.047 mmol), phenanthroline

(0.013 mg; 0.071 mmol) and 4A molecular sieves (0.02 g) were dispersed in N-methylpyrolidinone (4 mL) . The oxygen was removed by a slow stream of argon and palladium acetate

(5 mg, 0.023 mmol) was then added before sealing the tube. This was heated in the microwave oven for 40 minutes at 210 ⁰C. The resulting suspension was concentrated to dryness under high vacuum. The residue was dispersed in water and extracted with ethyl acetate. The organic phase was washed with water, dried over sodium sulfate and concentrated to dryness. The residue was purified by a chromatography over silica gel (cyclohexane /dichloromethane 95-5) to yield compound 26 as a solid (0.010 g; 8 %) . ¹H (CDCl₃) : 1.58 (t, 3H, J = 7.0); 4.55 (q, 2H, J = 7.0); 7.27 (m, 2H); 7.48 (m, 4H); 7.70 (m, 2H); 7.81 (m, 2H); 8.04 (s, IH) . ¹³C (CDCl₃) : 15.0; 65.0; 109.9; 117.7; 124.4; 125.2; 126.1 (two signals); 128.6; 129.4; 131.8; 140.1; 161.4. HRMS: Calcd. for Ci₇H₁₆N₂O + H : 265.1341. Found: m/z, 265.1365. Under these reaction conditions, the N-phenylated derivative 22a described above was obtained in a 41 % yield from acid 25.

Representative aryl-aryl coupling procedure, preparation of compound 27. In a 10 mL biotage-adapted tube, compound 12b (0.09 g; 0.34 mmol) , phenyl boronic acid (0.054 g; 4.42 mmol) , cesium carbonate (0.28 g; 8.47 mmol) were dispersed in a mixture of propanol (3 mL) and water (2 mL) . The oxygen was removed by a slow stream of argon and [1,1'- bis (diphenylphosphino) ferrocene] dichloropalladium com- plexed with dichloromethane (0.057 mmol) was then added before sealing the tube. This was heated in the microwave oven for 30 minutes at 120 ⁰C. The resulting suspension was diluted in water, extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and concentrated to dryness. The residue was purified by a chromatography over silica gel (dichloromethane / ethanol 99-1) to yield compound 27 as an oil (0.065 g; 73 %) .

Ethyl 5-ethoxy-3-phenyl-lH-pyrazole-4-carboxylate (27) : ¹H (CDCl₃) : 1.17 (t, 3H, J = 7.0) ; 1.36 (t, 3H, J = 7.0) ; 4.16 (q, 2H, J = 7.0) ; 4.21 (q, 2H, J = 7.0) ; 7.38 (m, 3H) ; 7.51 (m, 2H) ; 10.74 (s (l) , IH) . ¹³C (CDCl₃) : 14.0; 14.6; 59.8;

65.0; 96.8; 128.1; 129.0; 129.3; 129.5; 147.3; 163.2;

163.3. HRMS: Calcd. for Ci₄H₁₆N₂O₃ + H : 261.1239. Found: m/z, 261.1228.

Ethyl 3-ethoxy-l, 5-diphenyl-lH-pyrazole-4-carboxylate (28) : This compound was obtained from compound 20a (or 21a) using the procedure described for the preparation of compound 27 as an oil that slowly solidifed in 75 % yield. ¹H (CDCl₃) : 1.22 (t, 3H, J = 7.0); 1.31 (t, 3H, J = 7.0); 4.15 (q, 2H, J = 7.0); 4.48 (q, 2H, J = 7.0); 7.28 (m, 10H) . ¹³C (CDCl₃) : 13.9; 14.8; 59.7; 65.1; 100.1; 125.1; 127.2; 127.9; 128.7; 128.9; 129.8; 130.4; 139.2; 144.4; 162.7; 162.8. HRMS: Calcd. for C₂₀H₂₀N₂O₃ + H : 337.1552. Found: m/z, 337.1545.

3-ethoxy-5-phenyl-lH-pyrazole (29) ²¹: Compound 27 (0.08 g, 0.30 mmol) and sodium hydroxide (1 g, 25 mmol) were heated to reflux in a mixture of water (4 mL) and ethanol (2 mL) for 12 hours. The solution was extracted with ethyl acetate, dried over sodium sulfate and concentrated to dryness to yield compound 29 (0.05 g, 86 %) featuring analytical data similar to the reported one. 21

3-Ethoxy-l , 5-diphenyl-lH-pyrazole-4-carboxylic acid (30) : The protocol used for the preparation of compound 24 was used from 28 to yield compound 30 as a white powder (94 % yield) . ¹H (DMSO-d_&) : 1.38 (t, 3H, J = 7.1); 4.32 (q, 2H, J = 7.1); 7.15 (m, 2H); 7.30 (m, 8H) . ¹³C (DMSO-d_&) : 14.7; 64.3; 99.8; 125.4; 127.5; 127.8; 128.7; 128.8; 129.4; 130.3; 138.8; 146.3; 161.7; 163.0. HRMS: Calcd. for Ci₈H₁₆N₂O₃ + H : 309.1239. Found: m/z, 309.1239.

3-ethoxy-l, 5-diphenyl-lH-pyrazole (31) ²¹: Acid 30 (0.08g, 0.25 mmol) and methanesulfonic acid (0.016 mL, 0.25 mmol) were refluxed in toluene (20 mL) for two hours. The solution was washed with a saturated sodium hydrogencarbonate solution dried over sodium sulfate and concentrated to dryness to yield compound 31 as an oil (0.05 g; 73 %) . ¹H

(CDCl₃) : 1.46 (t, 3H, J = 7.1); 4.34 (q, 2H, J = 7.1); 5.97 (s, IH); 7.27 (m, 10H) . ¹³C (CDCl₃) : 14.9; 64.7; 93.7; 124.9; 126.7; 128.3; 128.4; 128.7; 128.8; 130.7; 140.1; 144 . 1 ; 1 63 . 5 . HRMS : Cal cd . for Ci₇H_{1 6}N₂O + H : 2 65 . 134 1 . Found : m/ z , 2 65 . 12 8 6 .

Results :

From acid 25, readily obtained by the saponification of compound 8, the N-phenylated compound 22a, resulting from an Ullmann/Buchwald-Hartwig reaction,²² was the only product isolated (in a 41 % yield) . From acid 24, the expected C-4 arylation product 26, resulting form a decar- boxylative coupling reaction, was obtained; although in only an 8 % yield. A far better 72 % yield of 26 was obtained from the 4-iodinated isomer 19a using the more conventional Suzuki-Miyaura aryl-aryl cross coupling reaction. The duration of this coupling reaction was greatly shorten by the use of the [ 1, 1' -bis (diphenylphosphino) ferrocene] dichloropalladium as a precatalyst²³' ²⁴ as well as the recourse to a microwave oven. The use of these aryl-aryl coupling conditions successfully led to the C-5 phenyl derivatives 27 or 28, from compound 12a or 20a in 75 and 74 % yield respectively. Very similar results were obtained from the 5-bromo homologues 12b or 21a (giving 73 or 62 % yield of compound 27 or 28 respectively) . However, attempts to achieve a direct C-4 arylation of compound 11 only led to extensive decomposition. Even the addition of lithium chloride as described in previously reported palladium-based aryl coupling reaction of heterocycles featuring an NH component did not help.^25"28 To complete this synthetic exploration, the removal of the carboxyl moiety of compounds 27 and 28 was also undertook. In the case of compound 27, this was achieved using strongly basic condition leading to the known²¹ compound 29 in 86 % yield. From ester 28, a two- step sequence was devised leading first to the acid 30 which undertook an acid-catalysed decarboxylation leading to the known²¹' ⁹ compound 31 in a 68 % overall yield.

29 30(94%) 31 (73%)

Scheme 6: i: KOH, EtOH, H₂O, reflux, ii: C₆H₅Br, Pd(OAc)₂, CuI, phenanthroline, K₂Cθ3, 3A molecular sieves, NMP, 210 ⁰C μv. iii: PhB(OH)₂, PdCl₂dppf, Cs₂CO₃, PrOH / H₂O 120⁰C μv . iv: MeSO₃H, toluene reflux.

Example 4: C4- arylation, benzylation and phenethylation and C5-benzylation of derivatives of and of compounds of Example 1

Preparation of the mixture of mesyl-protected pyrazoles

5-ethoxy-4-iodo-l- (methylsulfonyl) -lH-pyrazole and 3- ethoxy-4-iodo-l- (methylsulfonyl) -lH-pyrazole (32a-b) : com- pound 11 (2.06 g, 8.65 mmol) was dissolved in ethyl acetate (150 mL) , triethylamine (1.9 mL, 13.8 mmol; dried over 4A molecular sieves) was added followed by mesylchloride (1.0 mL, 13.0 mmol) . The solution was protected from moisture by a calcium chloride guard and stirred for two hours at room temperature. This was washed with 2 N potassium carbonate, 0.5 N hydrochloric acid and brine, dried over sodium sulfate and concentrated to dryness to yield the 2/5 mixture of the two isomers as an oil that slowly crystallized (2.68 g, 98 %) . ¹H (CDCl₃) : 1.45 (d, 5/7 of 3H, J = 7.1); 1.49 (d, 2/7 of 3H, J = 7.1); 3.25 (s, 5/7 of 3H); 3.31 (s, 2/7 of 3H); 4.41 (m, 2H); 7.61 (s, 2/7 of IH); 7.90 (s, 5/7 of IH) . m/z (LC/MS) = 253.

ethyl 3-ethoxy-5-iodo-l- (methylsulfonyl) -lH-pyrazole-4- carboxylate and ethyl 5-ethoxy-3-iodo-l- (methylsulfonyl) - lH-pyrazole-4-carboxylate (33a-b) : From compound 12a, the protocol described above led to a 1/1 mixture of the possible isomers as a solid (0.46 g, 89 %) . ¹H (CDCl₃) : 1.45 (m, 6H); 3.37 (s, 1/2 of 3H); 3.40 (s, 1/2 of 3H); 4.39 (m, 3/4 of 4H); 4.49 (q, 1/4 of 4H, J = 7.1) .

General procedure for the C-4 arylation of the mesyl- protected pyrazoles 32a-b.

In a 10 mL biotage-adapted tube, the mixture of the mesyl- protected pyrazoles (1.38 g, 4.37 mmol), the relevant bo- ronic acid (5.68 mmol), cesium carbonate (3.56 g; 10.9 mmol) were dispersed in a mixture of propanol (3 mL) and water (2 mL) . The oxygen was removed by a slow stream of argon and [ 1, 1' -bis (diphenylphosphino) ferrocene] dichloro- palladium complexed with dichloromethane (0.178 g, 0.218 mmol) was then added before sealing the tube. This was heated in the microwave oven for 40 minutes at 120 ⁰C. This was diluted in water, extracted with ethyl acetate; the organic layer was washed with brine and dried over sodium sulfate and concentrated to dryness. The residue was dissolved in ethanol (150 mL) and potassium hydroxide (0.8 g) this was heated at 90 ⁰C for two hours. This was diluted in water, made slightly acid with ammonium chloride, extracted with ethyl acetate, the organic layer was washed with brine and dried over sodium sulfate and concentrated to dryness. The residue was further purified as described below.

4-phenyl-3-ethoxy-lH-pyrazole (34) : This compound was purified by a chromatography over neutral alumina containing 1.5 % of water (dichloromethane / ethanol 99/1) and the fraction was further purified by a recrystallization in cyclohexane to yield compound 34 (57 %) as a white powder. ¹H (CDCl₃) : 1.49 (t, 3H, J = 7.0); 4.39 (q, 2H, J = 7.0); 7.23 (m, IH); 7.38 (m, 2H); 7.66 (s, IH); 7.68 (m, 2H); 9.16 (s (1), IH) . ¹³C (CDCl₃) : 14.9; 64.7; 107.2; 125.8; 125.9; 127.0; 128.5; 131.9; 160.7. HRMS: Calcd. for CnH₁₅N₂O + H : 189.1028. Found: m/z, 189.0984.

4- (4-chlorophenyl) -3-ethoxy-lH-pyrazole (35) : This compound was purified by a chromatography over neutral alumina containing 1.5 % of water (dichloromethane / ethanol 99/1) to give compound 35 (23 %) as a white powder. ¹H (CDCI3) : 1.47 (t, 3H, J = 7.0); 4.38 (q, 2H, J = 7.0); 7.33 (m, 2H); 7.61 (s, 2H); 7.63 (s, IH) . ¹³C (CDCl₃) : 14.9; 64.8; 106.1; 127.0; 127.1; 128.9; 130.5; 131.3; 160.6. HRMS: Calcd. for CnH₁₄N₂O³⁵Cl + H : 223.0638. Found: m/z, 223.0676.

4- (2-chlorophenyl) -3-ethoxy-lH-pyrazole (36) : This compound was purified by a chromatography over neutral alumina containing 1.5 % of water (dichloromethane / ethanol 99/1) to give compound 36 (33 %) as a white powder. ¹H (CDCl₃) : 1.44 (t, 3H, J = 7.0); 4.37 (q, 2H, J = 7.0); 7.20 (m, IH); 7.29 (m, IH); 7.45 (s, IH); 7.70 (m, IH); 7.83 (s, IH) . ¹³C (CDCl₃) : 14.9; 65.0; 103.7; 126.6; 127.5; 130.0; 130.3; 130.4; 131.0; 132.3; 160.8. m/z (LC/MS) = 223.

General procedure for the C-4 benzylation and phenethyla- tion of 11 or C-5 benzylation of 13 and 33a-b. In a biotage 20 mL tube, benzylzinc bromide or phenethyl zinc bromide (0.5 M in THF; 2.52 mmol) and THF (1 mL) were degassed with a slow stream of argon for ten minutes. The pyrazole halide (either 11, 13 or the mixture of 33a-b) (0.84 mol) and [ 1, 1' -bis (diphenylphosphino) ferrocene] di- chloropalladium complexed with dichloromethane (0.042 mmol) were then added, and the tube was degassed again with a slow stream of argon for 5 min prior to capping. The reaction vessel was then heated at 85 ⁰C for 4 hours in an oil bath. After cooling to room temperature, water and a IN so- lution of potassium sodium tartrate (3 mL) were added. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate, filtered and concentrated to dryness. The residue was purified by chromatography over silica gel (dichloromethane - etha- nol 99/1) .

4-benzyl-3-ethoxy-lH-pyrazole (37) : Obtained as an oil. H (CDCl₃) : 1.40 (t, 3H, J = 7.1); 3.74 (s, 2H); 4.28 (q, 2H, J = 7.1); 7.06 (s, IH); 7.26 (m, 5H) . ¹³C (CDCl₃) : 14.9; 28.4; 64.7; 105.3; 125.9; 128.3; 128.5; 128.7; 141.0; 161.4. Calcd. for Ci₂H₁₄N₂O + H : 203.1184. Found: m/z, 203.1122.

3-ethoxy-4-phenethyl-lH-pyrazole (38) : Obtained as an oil. ¹H (CDCl₃) : 1.42 (t, 3H, J = 7.1); 2.71 (m, 2H); 2.88 (m, 2H); 4.28 (q, 2H, J = 7.1); 7.04 (s, IH); 7.20 (m, 3H); 7.30 (m, 2H) . ¹³C (CDCl₃) : 14.9; 24.0; 35.9; 64.5; 105.3; 125.8; 128.1; 128.2; 128.5; 141.9; 161.7. m/z (LC/MS) = 217.

ethyl 5-benzyl-3-ethoxy-lH-pyrazole-4-carboxylate (39a) Obtained as an oil. ¹H (CDCl₃) : 1.31 (t, 3H, J = 7.1); 1.34 (t, 3H, J = 7.1) ; 4.28 (m, 6H) ; 7.28 (m, 5H) . ¹³C (CDCl₃) : 14.3; 14.6; 32.7; 29.8; 64.9; 97.0; 127.1; 128.8; 128.9; 136.1; 147.5; 163.2; 163.5. m/z (LC/MS) 275.

5-benzyl-3-ethoxy-lH-pyrazole (39b) Obtained as colorless crystals. ¹H (CDCl₃) : 1.38 (t, 3H, J = 7.1); 3.96 (s, 2H); 4.17 (q, 2H, J = 7.1); 5.54 (s, IH); 7.28 (m, 5H) . ¹³C (CDCl₃) : 14.8; 32.8; 65.0; 89.6; 126.9; 128.7; 128.8; 137.2; 144.5; 163.2. m/z (LC/MS) = 203.

Ethyl 3-ethoxy-5-morpholino-lH-pyrazole-4-carboxylate (40) : In a biotage 5 mL tube, ethyl 3-ethoxy-5-iodo-lH-pyrazole- 4-carboxylate (0.2 g; 0.64 mmol) and morpholine (1.2 mL; 13.8 mmol) dissolved in toluene (5 mL) . The reaction vessel was then heated at 170 ⁰C for 4 hours using a microwave oven. This was concentrated to dryness and the residue was purified by chromatography on silica gel (dichloromethane - ethanol 98/2) to yield compound 40 as an oil (0.04 g; 23 %) . ¹H (CDCl₃) : 1.33 (t, 3H, J = 7.1); 1.40 (t, 3H, J = 7.1); 3.28 (m, 4H); 3.83 (m, 4H); 4.25 (m, 4H); 7.90 (s(l), IH) . ¹³C (CDCl₃) : 14.3; 14.7; 49.4; 59.7; 64.8; 66.3; 87.1; 154.2; 162.4; 163.00. Calcd. for Ci₂H₁₉N₃O₄ + Na : 292.1273. Found: m/z, 292.1220.

Results Despite some trials, the Suzuki-based aryl-aryl coupling reactions with the NH-bearing compound 11 were never very satisfactory. Depending on the catalyst used, some of these trials led to a mixture containing the expected compound as well as unreacted and reduced material. For this reason, we set to protect compound 11 using a mesyl group. The reaction of 11 with mesylchloride under basic conditions led to an isomeric mixture 32a-b which was used whithout further purification in the aryl-aryl coupling step. This allowed us to prepare an array of 4-aryl compounds such as 34-36. Interstingly the Negishi-beased carbon-carbon bond formation reaction turned out to be possible from the NH-bearing compound 11. The use of benzyl or phenethyl zinc bromide allowed the preparation of compound 37 and 38. On the other hand, preparation of the 5-benzyl derivative 39a required the use of the N-protected mixture of compounds 33a-b as little reaction was observed from the NH-bearing compound 12a. On the other hand, from the unprotected compound 13, the Negishi reaction with benzylzinc bromide gave 63 % of the 5-benzylderivative 39b.

13 39b

Scheme 7: i: MeSO₂Cl, NEt₃, AcOEt. ii: PhB(OH)₂, PdCl₂dppf, Cs₂CO₃, PrOH / H₂O 120°C μv. iii: KOH, 90 ⁰C. iv: BrZnPhe, PdCl₂dppf, THF, 85 ⁰C.

The difference of reactivity between compounds 11 and 12a toward the Suzuki aryl-aryl coupling reaction may have its origin in the difference of lability of the iodine atom. Indeed, it was possible to prepare compound 40 by a nucleo- philic substitution without the recourse to copper or palladium-based methods:²⁹' ³⁰ On the other hand, under these conditions, no reaction took place from compound 13 either.

Scheme 8: i: morpholine, 170⁰C μv. Example 5: Halogenation of 4-arylpyrazoles 34 and 35 aryl- aryl coupling with the reaction products

4- (4-bromophenyl) -3-ethoxy-lH-pyrazole (41) : Compound 34 (0.1 g, 0.53 mmol) and bromine (0.031 mL, 0.63 mmol) were heated to reflux in cyclohexane (5 mL) for 2 hours. This was diluted in ethyl acetate washed with water, dried over sodium sulfate and concentrated to dryness. The residu was purified by chromatography over neutral alumina containing 1.5 % of water (dichloromethane / ethanol 99/1) to yield compound 41 as a white solid (0.07 g, 49 %) . ¹H (CDCl₃) : 1.49 (t, 3H, J = 7.0); 4.40 (q, 2H, J = 7.0); 7.48 (m, 2H); 7.56 (m, 2H); 7.68 (s, IH) . ¹³C (CDCl₃) : 14.9; 65.2; 106.2; 119.5; 127.3; 127.5; 130.7; 131.6; 160.2. m/z (LC/MS) = 189.

5-bromo-4- (4-bromophenyl) -3-ethoxy-lH-pyrazole (42) : Compound 34 (0.36 g, 1.92 mmol) and bromine (0.3 mL, 5.77 mmol) were heated to reflux in ethanol (50 mL) for 5 minutes. This was concentrated to dryness, diluted in ethyl acetate washed with sodium sulfite, brine, dried over sodium sulfate and concentrated to dryness. The residu was purified by chromatography over neutral alumina containing 1.5 % of water (dichloromethane and then dichloromethane / ethanol 99/1) to yield compound 42 as a white solid (0.07 g, 49 %) . ¹H (CDCl₃) : 1.49 (t, 3H, J = 7.0); 4.40 (q, 2H, J = 7.0) ; 7.48 (m, 2H) ; 7.56 (m, 2H) ; 7. Is, IH) . 13

C

(CDCl₃) : 14.9; 65.2; 106.2; 119.5; 127.3; 127.5; 130.7; 113311..66;; 116600..22.. HHRRMMSS:: CCalcd. for CnH₁₀N₂O⁷⁹Br₂ + H : 344.9238. Found: m/z, 344.9243.

5-bromo-4- (4-chlorophenyl) -3-ethoxy-lH-pyrazole (43) : 4- (4- chlorophenyl) -3-ethoxy-lH-pyrazole (35) (0.18 g, 0.81 mmol) and potassium carbonate (0.12 g, 0.89 mmol) were dissolved in ethanol (10 mL) and water (3 mL) . To this was added bromine (0.046 mL, 0.89 mmol) and the solution was stirred at 25 ⁰C overnight. This was diluted in water, extracted with ethyl acetate, dried over sodium sulfate and concentrated to dryness. The residu was then purified by a chromatography over silica gel (dichloromethane) the fraction containing 43 was then recrystallized in cyclohexane to yield pure 43 as white crystals (0.03 g, 13 %) . ¹H (CDCl₃) : 1.47 (t, 3H, J = 7.0); 4.32 (q, 2H, J = 7.0); 7.39 (m, 2H); 7.59 (s, 2H) . ¹³C (CDCl₃) : 14.7; 65.0; 105.9; 112.6; 120.1; 128.7; 129.6; 132.8; 160.0. HRMS: Calcd. for CnH₁₃N₂O³⁵Cl⁷⁹Br + H : 302.9721. Found: m/z, 302.9715.

4- (4-chlorophenyl) -3-ethoxy-S-phenyl-lH-pyrazole (44) : In a 5 mL biotage-adapted tube, 5-bromo-4- (4-chlorophenyl) -3- ethoxy-lH-pyrazole (0.03 g; 0.1 mmol), phenyl boronic acid (0.018 g; 0.15 mmol), cesium carbonate (0.081 g; 0.25 mmol) were dispersed in a mixture of propanol (1 mL) and water (1 mL) . The oxygen was removed by a slow stream of argon and

[1, 1' -bis (diphenylphosphino) ferrocene] dichloropalladium complexed with dichloromethane (0.004g, 0.005 mmol) was then added before sealing the tube. This was heated in the microwave oven for 40 minutes at 120 ⁰C. The mixture was concentrated to dryness. The residue was purified by a chromatography over silica gel (dichloromethane / ethanol

99-1) to yield compound 44 as a solid (0.010 g; 73 %) . ¹H

(CDCl₃) : 1.42 (t, 3H, J = 7.0); 4.34 (q, 2H, J = 7.0); 7.28

(m, 2H); 7.31 (s, 2H); 7.39 (m, 5H) . ¹³C (CDCl₃) : 14.9;

64.8; 103.6; 120.0; 127.8; 128.4; 129.0; 129.9; 130.1;

130.3; 131.9; 141.4; 161.3.

Results

Unexpectedly, bromination of compound 34, turned out to lead to the 4-brominated derivative 41. Further work led to the bisbrominated compound 42. However, little selectivity was observed in our 5-arylation attempts under Suzuki reaction conditions. On the other hand, bromination of the 4- chloroderivative 35 gave the 5-bromo-bearing compound 43. This NH-bearing 5-bromopyrazole, upon coupling with phenyl- boronate led the expected 4.5-bisaryl derivative 44.

Scheme 9: i: Br₂, cyclohexane, reflux, ii: Br₂, EtOH, reflux, iii: Br₂, K₂CO₃, Ethanol / water 25 ⁰C. iv: PhB(OH)₂, PdCl₂dppf, Cs₂CO₃, PrOH / H₂O 120°C μv.

Example 6: Acidic cleavage of the ethoxy group of 3- ethoxypyrazoles

1, 4-diphenyl-lH-pyrazol-3 (2H) -one (45) : In a 60 mL round- bottomed thick glass tube fitted with a PTFE-faced screw- cap, a mixture of the considered ethoxypyrazole (1 mmol) was degassed with argon. Following this, 33 % hydrogen bromide in acetic acid (1.0 mL) was added; the tube was tightly closed and was heated at 140 ⁰C for 2 hours. The resulting reaction mixture then precipitated in water to give compound 45 in an 83 % yield as a white powder. ¹H (DMSO-d_&) : 7.17 (m, 2H); 7.43 (m, 2H); 7.39 (m, 2H); 7.47 (m, 2H); 7.77 (m, 4H); 8.76 (s, IH); 10.93 (s(l), IH) . ¹³C (DMSO-d_&) : 109.0; 117.2; 125.3; 125.9; 126.0; 126.1; 128.9; 129.9; 140.0; 160.4. HRMS: Calcd. for Ci₅H₁₂N₂O + H : 237.1028. Found: m/z, 237.1043.

4-phenyl-lH-pyrazol-3 (2H) -one (46) : In a 60 mL round- bottomed thick glass tube fitted with a PTFE-faced screw- cap, a mixture of the considered alkoxypyrazole (1 mmol) was degassed with argon. Following this, 33 % hydrogen bromide in acetic acid (1.0 mL) was added; the tube was tightly closed and was heated at 140 ⁰C for 3 hours. The resulting solution was concentrated to dryness, made basic with methanolic ammonia, cocnntrated again and the residue was purified by a chromatography over silica gel (dichloro- methane / ethanol from 99/1 to 94/6) . ¹H (DMSO-d_&) : 7.10 (m, IH); 7.29 (m, 2H); 7.68 (m, 2H); 7.90 (s, IH) .

4- (4-chlorophenyl) -lH-pyrazol-3 (2H) -one (47) : By using the protocol described above, compound 47 was obtained as a white powder. ¹H (DMSO-d_&) : 7.36 (d, 2H, J = 8.6); 7.70 (d, 2H, J = 8.6); 7.94 (s, IH) . ¹³C (DMSO-d_&) : 104.5; 126.9; 128.1; 128.7; 129.3; 132.7; 158.8. HRMS: Calcd. for C₈H₇N₂O³⁵Cl + H : 195.0325. Found: m/z, 195.0264.

4- (2-chlorophenyl) -lH-pyrazol-3 (2H) -one (48) : By using the protocol described above, compound 48 was obtained as a white powder. ¹H (DMSO-d_&) : 7.19 (m, IH); 7.33 (m, IH); 7.45 (m, IH); 7.65 (m, IH); 7.80 (s, IH) . ¹³C (DMSO-d_&) : 101.4; 126.8; 127.1; 129.6; 129.7; 130.8; 131.1; 131.4; 158.4.

Results

The ethoxy groups protecting the oxygen moiety of these alkoxypyrazoles were cleaved by the use of hydrogenbromide in acetic acid. It was found that oxygen was detrimental to these reactions which led us to conduct these hydrolyses in a sealed reactor under an argon atmosphere. As an illustration of this process, compounds 45-48 were thus obtained from the corresponding 3-ethoxypyrazoles .

Scheme 10. i: HBr/AcOH, 140⁰C.

REFERENCES

1. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-

2483.

2. Miyaura, N. Top. Curr. Chem. 2002, 219, 12-59.

3. Kimata, A.; Nakagawa, H.; Ohyama, R.; Fukuuchi, T . ; Ohta, S.; Doh-ura, K.; Suzuki, T.; Miyata, N. J. Med. Chem. 2007, 50, 5053-5056.

4. Kees, K. L.; Fitzgerald, J. J.; Steiner, K. E.; Mattes, J. F.; Mihan, B.; Tosi, T.; Mondoro, D.; McCaleb, M. L. J. Med. Chem. 1996, 39, 3920-3928.

5. Himly, M.; Jahn-Schmid, B.; Pittertschatscher, K.; Bohle, B.; Grubmayr, K.; Ferreira, F.; Ebner, H.; Eb- ner, C. J. Allergy Clin. Immunol. 2003, 111, 882-888.

6. Kees, K. L.; Caggiano, T. J.; Steiner, K. E.; Fitzgerald, J. J.; Kates, M. J.; Christos, T. E.; Kulishoff, J.M.; Moore, R. D.; McCaleb, M. L. J. Med. Chem. 1995, 38, 617-628.

7. Otterness, I. G. Clin. Exp. Immunol. 1981, 46, 332-339.

8. Ishimaru, T. Yakugaku Zasshi 1957, 77, 800-802. See Chem. Abstr. 1957: 17893.

9. Braibante, M. E. F.; Braibante, H. T. S.; de Carvalho Ta- vares, L.; Rohte, S. F.; Costa, CC; Morel, A.F.; Stuker, CZ.; Burrow, R. A. Synthesis 2007, 2485-2490.

10. Li, L.; Chen, X.; Cutler, S. T. Patent WO 2001 082930 see Chem. Abstr. 2001 135: 344479

11. Willson, T. S.; Henke, B. R.; Momtahen, T. M.; Garrison, D. T.; Moore, L. B.; Geddie, N. G.; Baer, P. G. Bioorg. Med. Chem. Lett. 1996, 6, 1047-1050.

12. Cottineau, B.; Toto, P.; Marot, C; Pipaud, A.; Che- nault, J. Bioorg. Med. Chem. Lett. 2002, 12, 2105- 2108.

13. Wasserman, H. H.; Han, W. T. Tetrahedron Lett. 1984, 25, 3743-3746.

14. McElvain, S. M.; Burkett, H. J. Am. Chem. Soc. 1942, 64, 1831-1836.

15. Chan, D. M. T.; Monaco, K. L.; Wang, R. -P.; Winters, M. P. Tetrahedron Lett. 1998, 39, 2933-2936.

16. Lam, P. Y. S.; Clark, CG.; Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941-2944.

17. Lam, P. Y. S.; Vincent, G.; Clark, CG.; Deudon, S.; Jadhav, P. K. Tetrahedron Lett. 2001, 42, 3415-3418.

18. Chan, D. M. T.; Lam, P. Y. S. Recent advances in copper- promoted C-heteroatom bond cross-coupling reactions with boronic acids and derivatives. In Boronic acids; Wiley-VCH Ed., 2005; pp. 205-240. 19. Subasinghe, N. L.; AIi, F.; llig, C. R.; Rudolph, M.J.; Klein, S.; Khalil, E.; Soil, R. M.; Bone, R.F.; Spurlino, J. C; DesJarlais, R. L.; Crysler, CS. ; Cum- mings, M. D.; Morris, P. E.; Kilpatrick, J. M.; Babu,

Y. S. Bioorg. Med. Chem. Lett. 2004, 14, 3043-3047.

20. Dyckman, A.; Das, J.; Leftheris, K.; Liu, C; Moquin, R. V.; Wrobleski, S. T. Patent WO 2004098518 see Chem. Abstr. 2004 141:424181

21. Ohta, T.; Fujisawa, H.; Nakai, Y.; Furukawa, I. Bull. Soc. ChIm. Jpn. 2000, 73, 1861-1864.

22. Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400-5449.

23. Jurcak, J. G.; Barrague, M.; Gillespy, T. A.; Edwards, M. L.; Musick, K. Y.; Weintraub, P.M.; Du, Y.; Dha- ranipragada, R. M.; Parkar, A. A. Patent WO 2005 026175 see Chem. Abstr. 2005 142: 316835

24. Guillou, S.; Janin, Y. L. J. Heterocyclic. Chem. 2008, in print.

25. Chu, L.; Fisher, M. H.; Goulet, M. T.; Wyvratt, M.J. Tetrahedron Lett. 1997, 38, 3871-3874.

26. Drysdale, M. J.; Dymock, B. W.; Barril-Alonso, X.; Workman, P.; Pearl, L. H.; Prodromou, C; MacDonald, E. Patent WO 03 55,860 see Chem. Abstr. 2003 139: 101122k

27. Beaulieu, P . L . ; Gillard, J; Bykowski, D.; Brochu, C . ; Dansereau, N.; Duceppe, J. S.; Hache, B.; Jakalian, A. ; Lagace, L.; LaPlante, S.; McKercher, G.; Moreau, E . ; Perreault, S.; Stammers, T.; Thauvette, L.; Warring- ton, J.; Kukolj, G. Bioorg. Med. Chem. Lett. 2006, 16, 4987-4993.

28. Bernal, P.; Tamariz, J. HeIv. ChIm. Acta 2007, 90, 1449-1454.

29. Kwong, F. Y; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4, 581-584.

30. Conesa, L . I . ; Cawley, M. J.; Cloke, F. G. N.; Arentsen, K.; Scott, J. S.; Pearson, S. E.; Hayler, J.; Caddick, S. J. Organomet. Chem. 2005, 690, 5841-5848.

31. Knorr, L. Ber. Dtsch. Chem. Ges. 1895, 28, 706-714.

32. Stanovik, E.; Svete, J. Product class 1: pyrazoles. In Science of Synthesis; Neier, R. Ed.; Thleme, 2002; Vol. 12; pp. 15-225.

33. Varvounis, G.; Fiamegos, Y.; Pilidis, G. Pyrazol-3- ones, Part 1: synthesis and applications. In Adv. Heterocyclic Chem.; Katritzky, A. R. Ed.; Academic Press, 2001; Vol. 80; pp. 74-144.

34. Bau, B.; Hofmann, T.; Kloss, J.; Neunhoeffer, H. ScI. Pharm. 1998, 66, 119-136.

35. Sustmann, R.; Sicking, W.; Felderhoff, M.; Tabarsi, P. Tetrahedron 1990, 46, 783-792.

Claims

Claims

1. A process for the preparation of alkoxypyrazoles of formula (I) or (I')

in which

Ri stands for a radical selected from the group consisting of Ci-C₆ alkyl, C2-C6 alkenyl, C2-C6 alkynyl and

(C₆-Ci₀) aryl (Ci-C₆) alkyl;

R2 stands for a radical selected from the group consisting of hydrogen, halogen, -C (0) -0- (Ci-C₆) alkyl, C (0) -0- (C₂-C₆) alkenyl, -C (0) -0- (C₂-C₆) alkynyl; R3 stands for a radical selected from the group consisting of hydrogen, halogen, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl C₆-CiO aryl, C₆-CiO heteroaryl and

(C₆-Cio) aryl (Ci-C₆) alkyl, each optionally substituted by R₅;

R₅ is a radical selected from the group consisting of halogen, oxygen, hydroxyl, Ci-C₆ alkyl and Ci-C₆ alkoxy;

R₇ stands for a radical selected from the group consisting of H, Ci-C₆ alkyl, C₆-Ci₀ aryl, (C₆-Ci₀) aryl (Ci- C₆) alkyl, C₆-Ci₀ heteroaryl or (C₆-Ci₀) heteroaryl (Ci- C₆) alkyl, each optionally substituted by a halogen; comprising the successive following steps: (a) reacting a derivative of formula (II)

(H) in which A stands for a radical selected from the group consisting of Ci-C₆ alkyl, C2-C6 alkenyl, C2-C6 alkynyl and (C₆-Ci₀) aryl (Ci-C₆) alkyl;

B stands for a radical selected from the group consisting of hydrogen, -C (0) -0- (Ci-C₆) alkyl, -C(O)-O-(C₂- C₆) alkenyl, -C (0) -0- (C₂-C₆) alkynyl;

D stands for a radical selected from the group consisting of hydrogen, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl and (C₆-Cio) aryl (Ci-C₆) alkyl, each optionally substituted by R₅;

R₅ is a radical selected from the group consisting of halogen, oxygen, hydroxyl, Ci-C₆ alkyl and Ci-C₆ alkoxy;

E stands for a radical 0-P or NR_αRp,

P stands for a radical selected from the group consisting of Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl and

(C₆-Ci₀) aryl (Ci-C₆) alkyl;

R_α and Rp, identical or different, stand for a radical selected from the group consisting of H, Ci-C₆ alkyl or C₆-Ci₀ aryl or R_α and Rp form together an C₄-C₆ al- kylene radical, an C₄-C₆ alkenylene, an C₄-C₆ heteroal- kylene radical or an C₄-C₆ heteroalkenylene radical; with 1 to 1.5 molar equivalents of R₇-NH-NH₂, xHX₂, in which R₇ as defined for compound of formula (I) or

(I'), X2 is Cl or Br and x is 1 or 2; in an alkylalcohol RsOH as a solvent, in which R₈ is a radical selected from the group consisting of Ci-C₆ alkyl, C2-C6 alkenyl, C2-C6 alkynyl and (C₆-Cio) aryl (Ci- C₆) alkyl, (C₆-Ci₀) heteroaryl (Ci-C₆) alkyl; to obtain compounds of formula (III) or (III')

(b) optionally reacting said alkoxypyrazole of formula (III') or (III') wherein R₇ = H obtained in step (a) with a X-donor to prepare compounds of formula (IV) / (IV") or (IV) / (IV")

(IV) (IV") (IV) (IV")

in which

X represents Br, Cl, I or F;

A, B and D are as defined above;

(c) recovering the alkoxypyrazole of formula (I) or (I') •

2. The process according to claim 1, wherein in step (a) the compound of formula (II) is reacted with 1.05 molar equivalents of R₇-NH-NH2, xHX₂, in which R₇, X₂ and x are as defined in claim 1.

3. The process according to claims 1 or 2, wherein in step (a) the reaction is run in boiling ethanol.

4. The process according to any one of the preceding claims, wherein E is NR_aR_p, X₂ is Cl and x is 2.

5. The process according to any one of claims 1 to 3, wherein E is 0-P, P is Ci-Cε alkyl, X₂ is Cl and x is 1.

6. The process according to any one of the preceding claims , wherein R₇ is a hydrogen or a methyl, benzyl or phenyl group .

7. The process according to any one of the preceding claims, wherein the reaction in step (a) is run at the boiling point of the solvent.

8. The process according to claim 5, wherein the reaction in step (a) is run for 16 hours.

9. The process according to any one of the preceding claims, wherein R₈ is an ethyl group.

10. The process according to any one of the preceding claims, wherein A stands for a radical selected from the group consisting of Ci-Cε alkyl.

11. The process according to any one of the preceding claims, wherein B stands for a radical selected from the group consisting of hydrogen, -COOH or -COOEt.

12. The process according to any one of the preceding claims, wherein D stands for a radical selected from the group consisting of hydrogen or methyl.

13. The process according to any one of the preceding claims, wherein E stands for a radical selected from the group consisting of NMeMe or O-ethyl .

14. Alkoxypyrazoles of formula (V) or (V), wherein

Rn stands for a radical selected from the group consisting of Ci-C₆ alkyl, C2-C6 alkenyl, C2-C6 alkynyl and (C₆- C10) aryl (Ci-C₆) alkyl;

R12 stands for Br or I;

Ri3 stands for a radical selected from the group consisting of hydrogen, halogen, Ci-C₆ alkyl, C₂-C₆ alkenyl, C2~C₆ alkynyl, C₆-CiO aryl, C₆-CiO heteroaryl, and (C₆- C10) aryl (Ci-C₆) alkyl, each optionally substituted by R₅;

R₅ is a radical selected from the group consisting of halogen, oxygen, hydroxyl, Ci-C₆ alkyl and Ci-C₆ alkoxy;

except compounds of formula (V) or (V ) wherein simultaneously

Rn is methyl, Ri₂ is I, R₁₃ is methyl;

R.₁n₁ is methyl or ethyl or benzyl, R₂ is Br, R₁₃ is H; R.₁₁ is ethyl, R₂ is Br, Ri₃ is methyl; Rn is benzyl, R₂ is I, R₁3 is H;

R is methyl, R₂ is Br, R₁₃ is phenyl; .

15. Alkoxyppyrazoles of formula (V) or (V) according to claim 14, wherein

Rn stands for a radical selected from the group consisting of methyl or ethyl, Ri₂ stands for Br or I;

Ri3 stands for a radical selected from the group consisting of hydrogen, halogen, methyl, phenyl, benzyl, morpholino,

except compounds of formula (V) or (V ) wherein simultaneously

Rn is methyl, R_i2 is I, R₁₃ is methyl; Rn is methyl or ethyl, R₂ is Br, Ri₃ is H; Rn is ethyl, R₂ is Br, Ri₃ is methyl; Rn is methyl, R₂ is Br, R_i3 is phenyl.

16. Alkoxypyrazoles of formula (VI) or (VI'), wherein

R stands for a radical selected from the group consisting of Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl and (C₆- C10) aryl (Ci-C₆) alkyl;

R' stands for a radical selected from the group consisting of hydrogen, halogen, -C (0) -0- (Ci-C₆) alkyl, -C(O)- O- (C₂-C₆) alkenyl, -C (O) -O- (C₂-C₆) alkynyl, C₆-Ci₀ aryl and C₆- Cio heteroaryl each optionally substituted by R₅;

R₅ is a radical selected from the group consisting of halogen, oxygen, hydroxyl, Ci-C₆ alkyl and Ci-C₆ alkoxy;

Xi stands for Br or I;

except compounds of formula (VI) or (VI') wherein simultaneously

R is methyl, R' is H and Xi is Br or I.

17. Alkoxyppyrazoles of formula (VI) or (VI') according to claim 16, wherein

R stands for a radical selected from the group consisting of methyl or ethyl,

R' stands for a radical selected from the group consisting of a hydrogen, halogen, benzyl, a phenyl optionally substituted by Cl or Br, -COOH, -COOEt ; Xi stands for Br or I;

except compounds of formula (V) or (V ) wherein simultaneously R is methyl, R' is H and Xi is Br or I.

18. Alkoxyppyrazoles of formula (VI) or (VI') according to claim 17, wherein

R is ethyl, R' is COOEt, Xi is Br, I;

R is ethyl, X_x is Br, R' is 4-BrC₆H₄ or 4 -ClC₆H₄;

R is ethyl, R' is H, Xi is I.