WO1998017666A2

WO1998017666A2 - Process for the preparation of tetrahydro-5-oxo-pyrrolizine derivatives

Info

Publication number: WO1998017666A2
Application number: PCT/EP1997/005812
Authority: WO
Inventors: Damien Belotti; Janine Cossy
Original assignee: Merckle Gmbh
Priority date: 1996-10-21
Filing date: 1997-10-21
Publication date: 1998-04-30
Also published as: AU5188198A; FR2754819A1; WO1998017666A3

Abstract

The present invention relates to a process for the preparation of a compound of general formula (I) in which R1, R2, R and Ar are as defined in claim 1.

Description

Process for the preparation of tetrahydro-5-oxo- pyrrolizine derivatives

The present invention relates to a process for the preparation of 1H-2 , 3, 5, 6-tetrahydro-5-oxopyrrolizine derivatives which are useful as synthetic intermediates, for example in the preparation of 2- [6- (4-chlorophenyl) - 2,2-dimethyl-7-phenyl-2, 3 -dihydro-lH-pyrrolizin-5-yl] - acetic acid.

Cyclooxygenase (or prostaglandin-endoperoxide synthase) inhibitors form an important family of anti-inflammatory agents. However, the administration of these compounds is currently limited since they are accompanied by many side effects such as gastrointestinal complaints, considerable nephrotoxicity and allergic reactions, especially in asthma patients. Since these phenomena are mainly associated with the specific mechanism of action of cyclooxygenase inhibitors, it has been proposed to use double inhibitors which act not only on cyclooxygenase but also on 5-lipoxygenase, in order to do away with all of these undesirable side effects.

2- [6- (4-Chlorophenyl) -2,2-dimethyl-7-phenyl-2 , 3-dihydro- lH-pyrrolizin-5-yl] acetic acid is one of these double- action inhibitors. Its pharmacological properties are reported in particular in Drugs of the Future, 1995, 20 (10), 1007-1009.

The preparation of this compound involves a step of cyclization of 5-benzyl-3, 3-dimethyl-3, 4-dihydro-2H- pyrrole with 4-chlorophenacyl bromide in a mixture of ethyl ether and ethanol, leading to an intermediate dihydropyrrolizine, according to the following reaction scheme:

More generally, the synthesis of dihydropyrrolizines is carried out by condensation of a halocarbonyl derivative onto a Δl-pyrroline:

Such a process is described in detail in particular in EP-0,397,175 or in J. Med. Chem. 1994, 37, 1894-1897.

The invention is directed toward providing a novel synthetic route to 2- [6- (4-chlorophenyl) -2, 2 -dimethyl- 7-phenyl-2, 3-dihydro-lH-pyrrolizin-5-yl] acetic acid and to its derivatives via novel synthetic intermediates derived from 1H-2, 3, 5, 6- tetrahydro-5-oxopyrrolizines .

Thus, according to a first of its aspects, the invention proposes a process for the synthesis of derivatives of general formula I

in which:

Ar represents a (C₆-C₁₄)aryl or (C₅-C₁₃)heteroaryl group optionally substituted with one or more radicals chosen independently from a halogen atom, a (C_j-C,_;) alkyl, (C^C,;) alkoxy, (Ci-C_j) alkoxy(C₁-C₅) alkyl, (Ci-C_j) alkylthio, (C^C.) alkylthio (C^C,;) alkyl, (C^-C₃) alkoxycarbonyl, (C^-C^) alkoxycarbonyl (C^C^ alkyl, (C^C_j) alkylamino, di (C^-C^ alkylamino, -N0₂ and (C₃-C₈) cycloalkyl group;

R represents a hydrogen atom, a (C^-C_j) alkyl group; (C^C,_;) alkoxy (C^C,;) alkyl group; (C^C,_;) alkoxycarbonyl group; (C₁-C₅) alkoxycarbonyl (C_j-C_j) alkyl group; (C₆-C₁₄)aryl group optionally substituted with one or more radicals chosen independently from a halogen atom, a (C₁-C₅)alkyl, (C^C^alkoxy, (C^C_j) alky1 thio, (C^C^) alkylamino and di (C^-C,;) alkylamino group; (C₆-C₁₄) - aryl (C_x-C₅) alkyl group in which the aryl ring is optionally substituted with one or more radicals chosen independently from a halogen atom, a (C^-C^) alkyl, (C₁-C₅) alkoxy, (C_J^-C_J) alkylthio, (C^-C._;) alkylamino and di (Ci-C_j) alkylamino group; (C₃-C₈) cycloalkyl group; or (C₃-C₈) cycloalkyl

alkyl group;

R_x and R₂ represent, independently of each other, a hydrogen atom, a halogen atom, a (C₁-C₅) alkyl, (Ci-C_j) alkoxy, (C^-C,;) alkylthio or phenoxy group.

The process of the invention more specifically comprises the thermal cyclization of a compound of formula II

in which

P represents a (C_j-C,;) alkyl or (C₁-C₃) alkoxycarbonyl group;

Ar, R_x, R₂ and R are as defined for formula I, at a temperature of between 100 and 220 °C, in the absence of solvent.

As used herein, the term "alkyl" denotes linear or branched hydrocarbon radicals having 1 to 5 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

The term "alkoxy" denotes the group A-O- in which A is an alkyl group as defined above and O is an oxygen atom. Examples comprise methoxy, ethoxy, propoxy, isopropoxy, isobutoxy and tert-butoxy.

The term "aryl" denotes a mono- or polycyclic monovalent aromatic hydrocarbon ring having from 6 to 14 carbon atoms. Examples of aryl radicals which may be mentioned are phenyl, naphthyl, phenanthryl and anthryl .

The term "heteraryl" denotes a mono- or polycyclic, heterocyclic aromatic ring comprising from 5 to 13 carbon atoms and one or more hetero atoms chosen from 0, S and N. The furyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazyl, pyrimidyl, pyrazyl, triazinyl, indolyl, isoindolyl, guinolyl, isoquinolyl, benzofuryl, benzothienyl, benzimidazolyl, benzothiazolyl, benzopyridazyl, acridinyl and benzopyrimidyl radicals are especially preferred.

The term "alkylthio" denotes the group A-S- in which A is an alkyl group as defined above and S is a sulfur atom. Examples include methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, isobutylthio and tert- butylthio.

The term "cycloalkyl" denotes a mono- or polycyclic hydrocarbon radical having from 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

As used herein, the term "halogen" denotes fluoro, bromo, chloro or iodo.

Except where otherwise mentioned, the reactions described here take place at atmospheric pressure.

It will moreover be noted that the isolation and purifi- cation of the compounds and intermediates can be carried out according to any appropriate mode, such as by filtration, extraction, crystallization, column chroma- tography, thin (or thick) layer preparative chromato- graphy or a combination of any of these operations.

The compounds of formula II can have up to two chiral centers: the carbon bearing the groups R_x and R₂ is asymmetric when R_x and R₂ are different; similarly, the carbon bearing R is asymmetric when R does not represent a hydrogen atom.

Under certain well-selected operating conditions, and especially of temperature, the thermal cyclization carried out in the process of the invention allows conservation of the chirality in the starting molecule of formula II. These conditions are readily determined by a person skilled in the art on the basis of his or her general knowledge of the field. The thermal cyclization of the compound of formula II can be represented schematically as follows:

According to a preferred embodiment of the invention, the compound of formula I is synthesized from a compound of formula II in which P is a {C₁-C₃) alkyl group.

In this case, an alcohol of formula P-OH is released during the thermal cyclization.

In order to facilitate the thermal cyclization reaction, it is desirable to remove the alcohol P-OH from the reaction medium progressively as it is formed.

This can be achieved according to any one of the known methods in the literature. Condensation with separation of the alcohol P-OH during the reaction is recommended.

The temperature at which the reaction medium is maintained during the thermal cyclization is within the range from 100 to 220°C.

When the reaction medium consists exclusively of the compound of formula II, a temperature of between 180 and

220°C, and better still between 190 and 200°C, is preferred.

According to a preferred embodiment of the invention, an organic acid is added to the reaction medium consisting of the compound of formula II. It has been observed that, under these conditions, the yield for the cyclization is improved. In the presence of an organic acid, the thermal cyclization can be carried out at a temperature of between 110 and 170°C, preferably between 120 and 160°C.

The amount of organic acid to be added to the compound of formula II is preferably between 0.5 and 2 equivalents. However, the addition of a large excess of organic acid is not desirable since it must be removed from the reaction medium during the isolation and purification of the cyclized compound of formula I.

When the amount of organic acid is less than 0.5 equivalents, the improvement in the yield is not satisfactory.

As organic acid, a person skilled in the art will advantageously select acetic acid or pivalic acid. The thermal cyclization reaction is generally continued for 2 to 10 h, preferably 3 to 6 h.

The yields obtained are at least 50% and can be up to 80%.

The compounds of formula II can be prepared according to the reaction scheme I represented below:

Reac tion scheme I

III

R

1 ) H,N— I— COOP Steps a)

IV and b)

2 ) Reduction

The compound of formula II is prepared by reductive amination of a compound of formula III according to a two- step process .

In a first step, step a) , the compound of formula III above, in which Ar, ^ and R₂ are as defined for II, is reacted with a compound of formula IV which is an alpha- amino acid derivative in which the carboxylic function is protected with a labile group -OP such as a (C^C^ alkoxy or (C₁-C₅) alkoxycarbonyloxy group.

The hydrochloride or the hydrobromide of the compound of formula IV is preferably used for this reaction, in which case it is essential to work in the presence of a base in order to partially release the a ino function from the salt of the compound of formula IV. As a guide, mention will be made of potassium hydroxide or triethylamine as particularly suitable bases.

It will be noted that the molar ratio of the compound of formula IV to the compound of formula III advantageously ranges between 1 and 2, preferably between 1 and 1.5.

The imination reaction carried out in this step takes place in particular at a temperature of between 15 and 35°C, preferably between 18 and 25°C, that is to say at room temperature. Depending on the nature of the reactants present, it may be necessary to work below the abovementioned preferred temperature range. In a preferred manner, the imination is carried out in a polar solvent, and better still in a polar protic solvent such as a C₁-C₄ alkanol of the methanol, ethanol or isopropanol type. However, methanol is recommended. A chlorinated solvent such as 1, 2-dichloroethane or dichloro ethane can also be used. In the case in which P is methyl, it is not useful to isolate the intermediate imine obtained (not represented in the above reaction scheme) .

In step b) , the intermediate imine is reduced by the action of a reducing agent, preferably a hydride such as sodium cyanoborohydride or sodium triacetoxyborohydride. An amount of between 0.3 and 1 equivalent of sodium cyanoborohydride, preferably from 0.5 to 0.8 equivalents, will be used for example.

The nature of the solvent used in this step depends on the nature of the reducing agent, and vice versa.

Since isolation of the intermediate imine can be avoided, it is desirable for the reaction medium of step a) to act as the solvent in step b) .

Thus, when step a) is carried out in methanol, the preferred reducing agent may be selected, namely sodium cyanoborohydride.

The temperature conditions depend on the nature of the reactants present. When the reducing agent is sodium cyanoborohydride, a temperature of between 18 and 25°C is generally sufficient.

The process can also be performed with sodium triacetoxy- borohydride in 1, 2-dichloroethane at a temperature of 18 to 25°C.

The compounds of formula III are either commercially available or can readily be prepared by a person skilled in the art, for example by alkylation of an aldehyde of formula V. The alkylation step is represented in reaction scheme I and consists in condensing a compound of formula VI, in which Ar is as defined for formula III and X is a labile leaving group such as a halogen atom, a

( C₆- C₁₄ ) arylsul fonyl or alkyl (C₆-C₁₄) arylsulfonyl group, with an aldehyde of formula V in which R_x and R₂ are as defined for formula III, in the presence of an inorganic or organic base and optionally a catalyst.

The presence of a base is essential for the reaction to proceed. As base, mention may be made of potassium hydride, sodium hydroxide or KCPh₃.

The determination of the exact operating conditions is within the capacity of a person skilled in the art. When KH is used as base, the expert can refer to Tetrahedron Letters, 491 (1978) or Tetrahedron Letters, 21, 4005 (1980) . In the case of KCPh₃, a person skilled in the art may be inspired by the Journal of Organic Chemistry, 50, 2668, 2676 (1985) . Lastly, in the case of NaOH, mention may be made of Tetrahedron Letters, 1273 (1973) or Angewandte Che ie 1585 (1979) .

In the context of the invention, it is preferred to use an aqueous sodium hydroxide solution.

In this case, it is desirable to add a catalytic amount of a tetra (C^C₅) alkylammonium iodide. As particularly preferred catalyst, mention will be made of a mixture of an alkali metal iodide and a tetra (C₁-C₅) alkylammonium iodide such as a mixture of sodium iodide and tetra- n-butylammonium iodide.

Under these conditions, NaOH/NaI/nBU₄NI, it may be advantageous to maintain the reaction medium at a temperature of between 30 and 80°C, preferably between 40 and 60 °C.

As a guide, the molar ratio of the aldehyde of formula V to the compound of formula VI is between 1 and 2 equivalents, preferably between 1.4 and 1.6 equivalents. When sodium hydroxide is used as base, the molar ratio of the base to the compound of formula VI is preferably between 1.5 and 3 equivalents, more preferably between 1.8 and 2.2 equivalents.

It is advantageous to work under phase transfer conditions, in the presence of an organic solvent such as toluene.

The compounds of formula VI are either commercially available or are obtained by conversion of the corresponding alcohols of formula XIV according to any one of the methods described in the literature:

VI

XIV

In particular, when X is a chlorine atom, a person skilled in the art can adapt the process described in Angewandte Chemie, Int. Ed. in English, 14, 801 (1975); this process consists in heating to reflux allyl alcohol or propargyl alcohol of formula XIV dissolved in carbon tetrachloride, in the presence of 1 to 2 equivalents, preferably from 1 to 1.5 equivalents, of triphenyl- phosphine .

As a variant, a person skilled in the art can carry out this conversion by the action of a mixture of mesyl chloride and triethylamine at 0°C, the alcohol of formula XIV being dissolved in dichloromethane . The molar ratio of the mesyl chloride to the alcohol XIV is preferably chosen between 1.5 and 3 equivalents. Advantageously, the molar ratio of the triethylamine to the mesyl chloride is 1. In order for the reaction to be complete, the reaction medium is allowed to rise to room temperature .

Many other methods have been described in the literature, which allow the conversion of the alcohol XIV into the compound of formula VI. Mention may be made, as a guide, of the PPh₃/Cl₃CCOCCl₃ system (Journal of Organic Chemistry, 44, 359 (1979)); the TiCl₄/PhNHMe system (Bulletin of the Chemical Soc . of Japan, 54, 1456 (1981)); the ZnBr-/PPh₃/Et0₂CN=NC0₂Et system (Journal of Organic Chemistry, 49, 3027 (1984)); the PBr₃/pyridine system (Journal of the Am. Chem. Soc, 71, 1292 (1949)); or the nBU₃P* I₂/HMPA system (Australian Journal of Chemistry, 35, 517 (1982)).

The alcohol of formula XIV which is commercially available is, itself also, readily obtained from the arylacetylene, for example according to the two-step process illustrated in the following reaction scheme:

2) (CH₂0)_n

In a first step, the acidic proton of the compound XIV is stripped out by the action of a strong base such as n-BuLi or sodium amide. According to the invention, from 1 to 1.5 equivalents of n-BuLi in hexane will advantageously be used, the reaction for the formation of the acetylide ion being carried out at about 0°C in a polar aprotic solvent such as ethyl ether or tetrahydro- furan.

The process of the invention is more particularly suitable for the preparation of the preferred sub-groups A and B below of the compounds of formula I:

The sub-group A consists of compounds of formula I in which:

Ar represents a phenyl group optionally substituted with one or more radicals chosen independently from a halogen atom and a (^-€₅) alkoxy and (C_j-C_j) alkyl group;

R represents a hydrogen atom or a (C^C,_;) alkyl or (C^C_s) alkoxycarbonyl (Ci-Cs) alkyl group;

R_x and R₂ represent, independently of each other, a hydrogen atom or a (C^C_s) alkyl group.

The sub-group B consists of compounds of formula I in which: Ar represents a phenyl group, R represents a hydrogen atom and R₁ and R₂ represent, independently of each other, a (C₁-C₅) alkyl group.

According to another of its aspects, the invention relates to the intermediate compounds of formula I obtained by carrying out the process of the invention, these compounds being novel.

According to yet another of its aspects, the invention relates to the intermediate compounds of formula II which are used as starting reagents in the process of the invention.

Lastly, according a final one of its aspects, the invention relates to a process for the preparation of compounds of formula XIII

in which Ar, R_x and R- are as defined above for formula I, and R_s is chosen from a hydrogen atom, a halogen atom and a (C_x-C₄) alkyl and (C₁-C₄) alkoxy group.

This process comprises steps (i) to (v) below, which are illustrated in reaction scheme II:

Reaction scheme II

XI IX

Step ivl

2 ) N*BH,CW

S tep ( i )

This step includes the reaction of a compound of formula I, in which R represents H (which has been prepared from the corresponding compound of formula II according to the process of the invention) with a dialkyl oxalate of formula VII

R₄0-CO-CO-OR₄ (VII) in which R₄ represents a (C_x-C₄) alkyl group, in the presence of an alkali metal alkoxide, followed by an acidification of the reaction medium in order to form a compound of formula VIII

The reaction of the dialkyl oxalate with the compound of formula I is preferably carried out in a polar protic solvent, such as a C₁-C₄ alkanol, at a temperature of between 18 and 30°C, preferably at room temperature.

Step (ii)

This step consists in treating the resulting compound of formula VIII with a strong base such as an alkali metal hydride and then in reacting the resulting compound with N-phenyltrifluoromethanesulfonimide in order to obtain a compound of formula IX

IX

The reaction of the alkali metal hydride, which is preferably sodium hydride, is carried out at a temperature of between 18 and 30°C, preferably at room temperature, in a polar aprotic solvent such as tetra- hydrofuran, in particular when the hydride used is NaH. The reaction intermediate obtained is not isolated and the N-phenyltrifluoromethanesulfonimide is added to the crude reaction medium at a temperature which is maintained between 18 and 30°C, preferably at room temperature.

Step (iii)

Step (iii) includes the reaction of the compound resulting from step (ii) with a phenylboronic acid of formula X:

in which R₅ is a hydrogen atom, a halogen atom or a (C_x-C₄) alkyl or (C₁-C₄) alkoxy group, in the presence of tetrakis (triphenylphosphine)palladium(O) and an alkali metal carbonate, in order to form a compound of formula XI

X I

In this reaction, the tetrakis (triphenylphosphine) - palladium(O) acts as a catalyst. The solvent is preferably polar and aprotic, of the tetrahydrofuran type.

Sodium carbonate dissolved in a minimum amount of water will advantageously be used as alkali metal carbonate.

The reaction is preferably carried out at a temperature of between 50 and 100°C, preferably at the reflux temperature of tetrahydrofuran.

Step (iv)

Step (iv) includes the reaction of the resulting compound obtained in step (iii) above with a (C₁-C₄) alkylphenyl- sulfonylhydrazide, such as tosylhydrazine, followed by treatment of the reaction medium with NaBH₃CN in order to form a compound of formula XII

XII

in which Ar, R_x, R₂, R₄ and R₅ are as defined above.

The reaction of tosylhydrazine with the compound of formula XI is preferably carried out under the following conditions :

- molar ratio of the hydrazine to the compound XI of between 1 and 1.5 equivalents;

- addition of a catalytic amount of para- toluene- sulfonic acid;

- polar protic solvent of the C_x-C₄ alkanol type, such as ethanol; temperature of between 50 and 100°C, for example the reflux temperature of ethanol.

As regards the addition of cyanoborohydride, this preferably takes place in situ, the NaBH₃CN being pre- dissolved in a polar protic solvent in a proportion of 2 to 6 equivalents per 1 equivalent of the compound of formula XI .

The polar protic solvent is preferably the same as that above in the reaction of the hydrazine with the compound of formula XI.

The temperature may advantageously be adjusted to between 50 and 100°C, and, for example, may be adjusted to the reflux temperature of ethanol.

Step (v)

Step (v) includes the saponification of the compound resulting from the above step by the action of a base, in order to obtain a compound of formula XIII

in which R_x, R₂, R₅ and Ar are as defined above.

As appropriate base, mention may be made of sodium hydroxide, in which case the reaction medium will be brought to a temperature outside the range from 50 to 100°C.

This reaction is described in J. Med. Chem. 1994, 37, 1894-1897.

The invention is now described in greater detail in the exemplary embodiments below, which illustrate the synthesis of the compounds represented.

All the reactions were carried out under an inert atmosphere (argon or nitrogen) .

Example 1

Compound 3

To a stirred solution of phenylacetylene (compound 1) (20 g; 21.5 ml; 0.196 mol) in dry ether (200 ml) or tetrahydrofuran (100 ml) at 0°C is added slowly (over 30 min) a 2.5 M solution of n-butyllithium in hexane (86.2 ml; 0.215 mol; 1.1 eq.). The resulting suspension is stirred at 0°C for a further 30 min. Parafoπnaldehyde powder (7.05 g; 0.235 mol of formaldehyde; 1.2 eq.) is then added rapidly. The temperature is maintained at 0°C for 15 min and then at room temperature for 6 h. The suspension is poured into a water/ice mixture (400 ml) and the mixture is stirred vigorously until the precipitate has completely dissolved. The aqueous phase is separated out and the ether phase is washed with water (100 ml) . The combined aqueous phases are extracted with dichloromethane (3 x 200 ml) . The combined organic phases (ether + dichloromethane) are dried over magnesium sulfate, filtered and evaporated.

The crude oil obtained (virtually pure compound 2) (26 g; 0.196 mol; 1 eq.) is dissolved in dry carbon tetra- chloride (200 ml) and triphenylphosphine (56.55 g; 0.216 mol; 1.1 eq.) is added. The solution is maintained at reflux for 5 h. After cooling, the precipitate formed is filtered off through a sinter funnel and washed with ether (50 ml) . The filtrate is evaporated and the residue is taken up in pentane (100 ml) . The precipitate which forms again is triturated, filtered off through a sinter funnel and washed with pentane (50 ml) . The filtrate is concentrated to 50 ml and refiltered through silica (contained in a sinter funnel) (washing with 50 ml of a 90/10 pentane/ethyl acetate mixture) . The solution obtained is evaporated in order to give 25.5 g of clean compound 3 (oil); i.e. an overall yield of 86% for the two steps.

- IR (CC1₄) : 2260, 2220, 1485, 1440, 1270, 910, 685 cm"¹

- ^XH NMR 90 MHz (CDC1₃) : δ 4.35 (s, 2H) ; 7.20-7.60 (multiplet, 5H)

- MS C₉H,C1: m/z 152 (7%); 150 (M*^*, 24%); 115 (100%); 63 (17%) .

Example 2

Ph ≡≡ _χc„

Compound 4

A mixture of a 30% solution of sodium hydroxide in water (17.7 g of solution, i.e.: 5.31 g; 132.8 mmol, 2 eq. of sodium hydroxide); sodium iodide (1 g; 6.64 mmol; 0.1 eq.); tetra-n-butylammonium iodide (0.49 g; 1.328 mmol; 0.02 eq.) and toluene (10 ml) is heated to 50°C. A solution of compound 3 (10 g; 66.4 mmol) and isobutyraldehyde (7.18 g; 9 ml; 99.6 mmol; 1.5 eq.) in toluene (5 ml) is added dropwise (over 1 h) to this vigorously stirred mixture. The resulting mixture is stirred vigorously at 50°C for 24 h. After cooling, the mixture is diluted with water (100 ml) and extracted with ether (3 x 50 ml) . The combined organic phases are dried over magnesium sulfate, filtered and evaporated. The crude product obtained is purified by flash chromatography on a column of silica (95/5 petroleum ether/ethyl acetate) in order to give 9.9 g of pure compound 4 (oil); i.e. a yield of 80%.

- IR (CC1₄) : 2700, 2240, 2220, 1730, 1460, 1440, 885, 690 cm^"1

- ^XH MR 90 MHz (CDCl₃) : δ 1.20 (s, 6H) ; 2.55 (s, 2H) ; 7.15-7.50 (multiplet, 5H) ; 9.60 (s, 1H)

- MS C₁₃H₁₄0: m/z 186 (M⁺\ 4%); 171 (100%); 143 (44%); 128 (40%); 115 (93%); 102 (48%); 63 (20%).

Example 3

Compound 5

To a well-stirred suspension of methyl glycinate hydro- chloride (3.94 g; 31.41 mmol; 1.3 eq.) in dry methanol (10 ml) at room temperature are added potassium hydroxide pellets (0.48 g) . When all of the potassium hydroxide has dissolved, a solution of compound 4 (4.5 g; 24.16 mmol) in dry methanol (10 ml) is added rapidly. After 30 min, a solution of sodium cyanoborohydride (0.759 g; 12.08 mmol; 0.5 eq.) in dry methanol (5 ml) is added dropwise (heating control) . The suspension is again stirred at room temperature for 1 h and potassium hydroxide pellets (1.8 g) are added. When all of the potassium hydroxide has dissolved, the precipitate is filtered off through a sinter funnel and washed with methanol. Most of the methanol is evaporated off and the residue is diluted with water (10 ml) and saturated sodium chloride solution in water (25 ml) . The mixture is extracted with ether (3 x 50 ml) and the combined organic phases are dried over magnesium sulfate, filtered and evaporated. The crude product obtained is purified by flash chromatography on a column of silica (95/5 dichloromethane/ethyl acetate) in order to give 4.4 g of pure compound 5 (oil); i.e. a yield of 70%.

- IR (CC1₄) : 2220, 1740, 1715, 1470, 1435, 1360, 1200, 1175, 690 cm^"1

- ¹K NMR 300 MHz (CDCl₃) : δ 1.04 (s, 6H) ; 1.60 (broad s, 1H) ; 2.38 (s, 2H) ; 2.53 (s, 2H) ; 3.44 (s, 2H) ; 3.71 (s, 3H) ; 7.25-7.45 (multiplet, 5H)

- ¹³C NMR 75 MHz (CDC1₃) : δ 25.3 (q, 2C) ; 30.5 (t) ; 35.1 (s); 51.6 (q) ; 51.9 (t) ; 59.3 (t) ; 82.4 (s) ; 88.1 (s); 124.1 (s) ; 127.5 (d) ; 128.2 (d, 2C) ; 131.5 (d, 2C); 173.2 (s) - MS C₁₆H₂₁N0₂: m/z 259 (M^+φ, 28%); 200 (76%); 115 (56%), 102 (100%) ; 74 (55%) .

Example 3a

As a variant of Example 3, the process may be carried out as follows.

To a stirred solution of compound 4 (6 g; 32.21 mmol) in dry 1, 2-dichloroethane (or dry dichloromethane) (100 ml) at room temperature, are added methyl glycinate hydro- chloride reduced to powder (4.25 g; 33.82 mmol; 1.05 eq.), followed by dry triethylamine (6.52 g; 9 ml; 64.43 mmol; 2 eq.). The resulting suspension is stirred well for 15 min and sodium triacetoxyborohydride powder

(10.24 g; 48.32 mmol; 1.5 eq.) is added portionwise

(slight release of gas and slight heating) . The suspension is stirred thoroughly at room temperature for 12 h and is then diluted with saturated sodium hydrogen carbonate solution in water (100 ml) . The mixture is stirred vigorously for 15 min and is then extracted with dichloromethane (3 x 100 ml) . The combined organic phases are dried over magnesium sulfate, filtered and evaporated. The crude product obtained is purified by flash chromatography on a column of silica (95/5 dichloromethane/ethyl acetate) in order to give 6.7 g of pure compound 5 (oil), i.e. a yield of 80%.

Example 4

Compound 6

A mixture of compound 5 (2 g; 7.71 mmol) and dry acetic acid ⁽0.463 g; 0.441 ml; 7.71 mmol; 1 eq.) is stirred and heated at 120-130°C (bath temperature) for 5 h. The methanol released is condensed in a tube containing beads during the reaction. At the end of the reaction, the residual volatile materials are evaporated off under the vacuum of a water pump at 120°C. After cooling, the crude product is purified by flash chromatography on a column of silica ⁽50/50 dichloromethane/ethyl acetate) in order to give 1.14 g of pure compound 6 (solid); i.e. a yield of 65%.

- IR (CC1₄) : 1665, 1600, 1465, 1365, 1310, 1170, 1130, 935, 695 cm"¹

- ^XH NMR 300 MHz (CDC1₃) : δ 1.25 (s, 6H) ; 2.85 (t, 2H, J = 2.5 Hz); 3.20 (s, 2H) ; 3.80 (t, 2H, J = 2.5 Hz)_; 7.10 ⁽t, 1H, J = 7 Hz); 7.30 (t, 2H, J = 7 Hz); 7.63 (d, 2H, J = 7 Hz)

- ¹³C NMR 75 MHz (CDCl₃ ) : δ 27 . 9 (q, 2C) ; 40 . 1 ( s ) ; 43 . 9 ( t ) ; 56 . 7 ( t ) ; 61 . 3 ( t) ; 106 . 5 ( s ) ; 124 . 5 (d) ; 124 . 9 ( d , 2C ) ; 12 8 . 3 (d, 2C) ; 133 . 1 ( s ) ; 181 . 0 ( s ) ;

197 . 2 ( s )

- MS C₁₅H₁₇NO: m/z 227 (M⁺\ 100%); 198 (54%); 115 (30%).

Example 4a As a variant of Example 4, the process is performed as follows.

A mixture of compound 5 (2 g; 7.71 mmol) and dry pivalic acid (0.787 g; 7.71 mmol; 1 eq.) is stirred and heated at 150°C (bath temperature) for 5 h. The methanol released is condensed in a tube containing beads during the reaction. At the end of the reaction, the residual volatile materials are evaporated off under the vacuum of a water pump at 150 °C. After cooling, the crude product is purified by flash chromatography on a column of silica (50/50 dichloromethane/ethyl acetate) in order to give 1.2 g of pure compound 6 (solid); i.e. a yield of 68%.

Example 5

Compound 6

Compound 5 (3 g; 11.56 mmol) is stirred and heated at 190-200°C under an argon atmosphere for 3.5 h. The methanol released is condensed in a tube containing beads. After cooling, the crude product is purified by flash chromatography on a column of silica (50/50 dichloromethane/ethyl acetate) in order to give 1.31 g of pure compound 6 (solid); i.e. a yield of 50%. Example 6

Compound 7

Sodium (0.394 g; 17.16 mmol; 3 eq.) is added portionwise to dry ethanol (10 ml) stirred at 0°C. When all of the sodium has reacted, a solution of compound 6 (1.3 g; 5.72 mmol) and diethyl oxalate (0.919 g; 0.854 ml; 6.29 mmol; 1.1 eq.) in dry ethanol (10 ml) is added dropwise (over 15 min) . The resulting solution is stirred at room temperature for 15 h. Acetic acid (2.5 ml) is then added, followed by water (2.5 ml). The solvents are evaporated off and the residue is taken up in water (50 ml) and extracted with ethyl acetate (50 ml, and then 2 x 25 ml) . The combined organic phases are washed with a saturated solution of salt in water (10 ml) , dried over MgS0₄, filtered and evaporated. The crude product is purified by flash chromatography on a column of silica (80/20 petroleum ether/ethyl acetate) in order to give 1.436 g of pure compound 7 (green-yellow solid); i.e. a yield of 77%.

- IR (CC1₄) : 3100 (broad), 1730, 1690, 1600, 1570 (broad), 1270, 1040, 695 cm^"1

- *H NMR 300 MHz (CDC1₃) : δ 1.27 (s, 6H) ; 1.46 (t, 3H, J = 7 Hz); 2.87 (s, 2H) ; 4.13 (s, 2H) ; 4.48 (q, 2H, J = 7 Hz); 7.20 (t, 1H, J = 7 Hz); 7.38 (t, 2H, J = 7 Hz); 7.62 (d, 2H, J = 7 Hz); 11.33 (s, 1H) ppm

- ¹³C NMR 75 MHz (CDCl₃) : δ 13.9 (q) ; 27.9 (q, 2C) ; 41.2 (s); 41.9 (t) ; 62.6 (t) ; 63.8 (t) ; 106.2 (s) ; 116.7 (s); 125.7 (d) ; 126.8 (d, 2C) ; 128.4 (d, 2C) ; 133.0 (s); 148.5 (s) ; 154.7 (s) ; 165.8 (s) ; 166.7 (s) ppm - MS C₁₉H₂₁N0₄: m/z 327 (M⁺\ 43%); 254 (100%); 115 (14%).

Example 7

Compound 8

To a well-stirred suspension of NaH (60% in mineral oil) ⁽0.183 g; ie. 0.109 g NaH; 4.582 mmol; 1.5 eq.) in dry tetrahydrofuran (10 ml) at room temperature is added dropwise a solution of compound 7 (1 g; 3.054 mmol; 1 eq.⁾ in dry tetrahydrofuran (10 ml) (control of the release of hydrogen) (formation of the deep orange sodium enolate which precipitates) . The resulting suspension is stirred at room temperature for 1 h. Solid N-phenyltri- fluoromethanesulfonimide (1.31 g; 3.665 mmol; 1.2 eq.) is then added in a single portion. The precipitate gradually dissolves and the resulting solution is stirred at room temperature for 12 h. The solution is diluted with a saturated solution of salt in water (20 ml) and with water ⁽20 ml) and is then extracted with ethyl acetate ⁽50 ml and then 2 x 25 ml) . The combined organic phases are washed with a saturated solution of salt in water ⁽10 ml), dried over MgS0₄, filtered and evaporated.

The crude product is purified by flash chromatography on a column of silica (85/15 petroleum ether/ethyl acetate) in order to give 1.12 g of clean compound 8 (oil)_; i.e. a yield of 80%.

- IR ⁽CC1₄) : 1740, 1650, 1460, 1430, 1385, 1210, 1140, 1035, 940, 695 cm^"1 - ^XH NMR 300 MHz (CDCl₃) : δ 1.29 (s, 6H) ; 1.42 (t, 3H, J = 7 Hz); 2.87 (s, 2H) ; 4.16 (s, 2H) ; 4.42 (q, 2H, J = 7 Hz); 7.25-7.45 ( ultiplet, 5H) ppm

- "C NMR 75 MHz (CDClj) : δ 13.8 (q) ; 27.8 (q, 2C) ; 40.9 (t); 41.7 (s) ; 62.9 (t) ; 63.0 (t) ; 113.1 (s) ; 117.5 (s); 118.3 (q, J « 320 Hz, OSO-CF,) ; 127.5 (d) ; 128.1 (d, 2C) ; 128.8 (d, 2C) ; 130.4 (s) ; 136.9 (s) ; 142.1 (s); 162.6 (s) ; 173.4 (s) ppm

- MS C₂₀H₂₀F₃NO_€S: m/z 327 (M^-SO_jCF_j+H, 40%); 254 (100%); 115 (20%) .

Example 8

Compound 9

A solution of compound 8 (0.6 g; 1.3 mmol) and 4-chloro- phenylboronic acid (0.224 g; 1.43 mmol; 1.1 eq.) in dry tetrahydrofuran (10 ml) is degassed with argon for 15 min. Tetrakis (triphenylphosphine)palladium (0) (0.075 g; 0.065 mmol; 0.05 eq.) and sodium carbonate (0.35 g) dissolved in water (1 ml) are added to this stirred solution at room temperature.

The two-phase mixture is stirred vigorously at room temperature until a fully dispersed suspension is obtained (release of C0₂ is observed) (for 1-2 h) , which is then refluxed for 1 h. After cooling, the suspension is diluted with ether (25 ml) and filtered through Celite contained in a sinter funnel (washing with ether) . The filtrate is washed with a saturated solution of salt in water (10 ml) and the organic phase is dried over MgS0₄, filtered and evaporated. The residue is purified by flash chromatography on a column of silica ( 90/10 petroleum ether/ethyl acetate) in order to give 0 . 51 g of c lean compound 9 (pale yellow solid) ; i . e . a yield of 92% .

- IR ⁽CC1₄ ⁾ : 1740, 1625, 1425, 1380, 1185, 1065, 700 cm"¹

- ^XK NMR 300 MHz (CDC1₃) : δ 1.05 (t, 3H, J = 7 Hz_); 1.32 ⁽s, 6H); 2.85 (s, 2H) ; 3.60 (q, 2H, J = 7 Hz_); 4.23 ⁽s, 2H) ; 6.95-7.40 ( ultiplet, 9H) ppm

- ¹³C NMR 75 MHz (CDC1₃) : δ 13.5 (q) ; 28.0 (q, 2C_{) ;} 40.2 ⁽t⁾; 42.9 (s) ; 61.8 (t) ; 62.1 (t) ; 119.4 ₍s_{) ;} 121.8 ⁽s⁾; 126.2 (d) ; 128.1 (d, 2C) ; 128.3 (d, 2_{C) ;} 128.5 ⁽d, 2C⁾; 132.2 (d, 2C) ; 132.3 (s) ; 133.4 ₍s_{) ;} 133.8 ⁽s⁾; 136.0 (s) ; 145.6 (s) ; 164.8 (s) ; 176.5 (s₎ ppm

- MS ^C ₂₅H₂₄C1N0₃: m/z 423 (7%); 421 (M*\ 20%); 350 ₍35%_{) ;} 348 (100%) .

Example 9

Compound 10

A well-stirred suspension of compound 9 (0.97 g_; 2.3 mmol⁾, tosylhydrazine (0.471 g; 2.53 mmol_; 1.1 eq.₎ and para-toluenesulfonic acid hydrate (0.115 g_; i.e. 50 mg/ mol⁾ in dry ethanol (9 ml) is refluxed for 6-7 h ⁽dissolution while hot, followed by gradual precipitation of the yellow tosylhydrazone) . The yellow suspension obtained is cooled and a solution of sodium cyanoboro_¬ hydride ⁽0.578 g; 9.2 mmol; 4 eq.) in dry ethanol ₍6 ml₎ is added dropwise. The well-stirred suspension is refluxed for 3-4 h (a homogeneous medium is obtained₎ . The resulting solution is cooled and most of the ethanol is evaporated off. The residue is taken up in water (30 ml) and extracted with ethyl acetate (3 x 20 ml) . The combined organic phases are washed with a saturated solution of salt in water (10 ml) , dried over MgS0₄, filtered and evaporated. The residue is purified by flash chromatography on a column of silica (95/5 petroleum ether/ethyl acetate) in order to give 0.84 g of clean product 10; i.e. a yield of 90%.

- IR (CC1₄) : 1735, 1485, 1450, 1370, 1175, 1100, 1030, 700 cm^"1 - ^XH NMR 300 MHz (CDC1₃) : δ 1.28 (6, 3H, J = 7 Hz); 1.30 (s, 6H) ; 2.85 (s, 2H) ; 3.51 (s, 2H) ; 3.75 (s, 2H) ; 4.18 (q, 2H, J = 7 Hz); 7.00-7.27 (multiplet, 9H) ppm

- ¹³C NMR 75 MHz (CDC1₃) : δ 14.2 (q) ; 28.0 (q, 2C) ; 31.6 (t); 40.6 (t) ; 43.3 (s) ; 58.4 (t) ; 61.0 (t) ; 114.8 (s); 117.7 (s) ; 123.6 (s) ; 124.7 (d) ; 128.0 (d, 2C) ; 128.2 (d, 2C) ; 128.3 (d, 2C) ; 131.6 (s) ; 131.7 (d, 2C) ; 134.1 (s) ; 134.7 (s) ; 136.0 (s) ; 170.8 (s) ppm

- MS C₂₅H₂₆C1N0₂: m/z 409 (12%); 407 (M⁺\ 36%); 336 (33%); 334 (100%); 299 (14%); 242 (14%) .

Claims

1. A process for the preparation of a compound of general formula I

in which: Ar represents a (C₆-C₁₄)aryl or (C₃-C₁₃) hetero- aryl group optionally substituted with one or more radicals chosen independently from a halogen atom, a (C^C_s) alkyl, (C^C.;) alkoxy, (C^C^ -alkoxy (C^C^ - alkyl, (C^C,;) alkylthio, (C^C_j) -alkylthio (C^C_j) - alkyl, (C^C,;) alkoxycarbonyl, (C^C alkoxycarbonyl- (Ci-Cj) alkyl, (C^C,;) alkylamino, di (C^C,_;) alkylamino, -NO_j and (C₃-C₈) cycloalkyl group;

R represents a hydrogen atom, a (C^C,_;) alkyl group; (C^C.;) alkoxy (C^C,;) alkyl group; (C^C^ - alkoxycarbonyl group; (C^-C^) alkoxycarbonyl (C₁-C₅) - alkyl group; (C₆-C₁₄) aryl group optionally substituted with one or more radicals chosen independently from a halogen atom, a (C₁-C₅) alkyl, (Ci-C₃) alkoxy, (C^C.;) alkylthio, (C^C,_;) alkylamino and dKC^C_j) alkylamino group; (C₆-C₁₄) aryl- (C.,-C₅) alkyl group in which the aryl ring is optionally substituted with one or more radicals chosen independently from a halogen atom, a (C^C,_;) alkyl, (Ci-Cj) alkoxy, (C^C,;) alkylthio, (C^C^ alkylamino and dKCj-C₃) alkylamino group; (C₃-C„) cycloalkyl group; or (C₃-C₈) cycloalkyl (Ci-C₃) alkyl group;

R_x and R₂ represent, independently of each other, a hydrogen atom, a halogen atom, a (C_x-C₅) alkyl, (C^C_s) alkoxy, (C^C.;) alkylthio or phenoxy group, comprising the thermal cyclization of a compound of formula II

in which

P represents a (C^C,;) alkyl or (C^C,_;) alkoxycarbonyl group;

Ar, R_x, R₂ and R are as defined above for formula I, at a temperature of between 100 and 220 °C, in the absence of solvent.

The process as claimed in claim 1, wherein P represents (C-_L-C_J) alkyl and the alcohol P-OH is removed from the reaction medium progressively as it is formed.

The process as claimed in either of claims 1 and 2, in which the thermal cyclization of the compound of formula II is carried out at a temperature of between 180 and 220°C, preferably 190 and 200°C.

The process as claimed in any one of claims 1 to 3, wherein the thermal cyclization is carried out in the presence of 0.5 to 2 equivalents of an organic acid, preferably 0.5 to 1.5 equivalents, at a temperature of between 110 and 170°C, preferably between 120 and 160 °C.

The process as claimed in claim 4, wherein the organic acid is chosen from acetic acid and pivalic acid.

The process as claimed in any one of claims 1 to 5, wherein the compound of formula II is prepared by carrying out steps a) and b) below: a) a compound of formula III

in which

Ar, R_j and R₂ are as defined for formula II, is reacted with a compound of formula IV

in which P and R are as defined for formula II; and b) the intermediate imine obtained is reduced.

The process as claimed in claim 6, wherein the compound of formula III is prepared by condensation of an aldehyde of formula V:

in which R and R₂ are as defined for formula III, with a compound of formula VI:

Ar- λ (VI)

in which Ar is as defined for formula III and X is a leaving group, in the presence of an inorganic or organic base optionally a catalyst.

8. The process as claimed in claim 7, wherein the base is NaOH and the catalyst is a mixture of sodium iodide and tetra (C₁-C₄) alkylammonium iodide.

9. The process as claimed in any one of claims 1 to 8, wherein a compound of formula I is prepared in which

Ar represents a phenyl group optionally substituted with one or more radicals chosen independently from a halogen atom and a (C^C._;) alkoxy and (C₁-C₅) alkyl group; R represents a hydrogen atom or a (C_j-C_j) alkyl or (C₁-C₅) alkoxycarbonyl (C_j-C,;) alkyl group;

R_x and R₂ represent, independently of each other, a hydrogen atom or a (C_j-C_j) alkyl group.

10. The process as claimed in any one of claims 1 to 8, wherein a compound of formula I is prepared in which

Ar represents a phenyl group, R represents a hydrogen atom, and R_x and R₂ represent, independently of each other, a (C^Cs) alkyl group.

11. A compound of formula I as defined in claim 1.

12. A compound of formula I as defined in claim 9.

13. A compound of formula I as defined in claim 10.

14. A compound of formula II

in which Ar represents a (C₆-C₁₄)aryl or (C₅-C₁₃)hetero- aryl group optionally substituted with one or more radicals chosen independently from a halogen atom, a (C^C,_;) alkyl , (C^C.;) alkoxy, (C^C,,) alkoxy- (C._.-C₃) alkyl, (C^C.;) alkylthio, (C_x-C₅) alkylthio- (Ci-C_j) alkyl, (C^C._;) alkoxycarbonyl, (C^C alkoxy- carbonyKCi-C_j) alkyl,

- alkylamino, -N0₂ and (C₃-C₈) cycloalkyl group; R represents a hydrogen atom, a (C^C,;) alkyl group; (C^C_s) alkoxy (Ci-C_j) alkyl group; (Ci-C_j) alkoxycarbonyl group;

alkyl group; (C₆-C₁₄) aryl group optionally substituted with one or more radicals chosen independently from a halogen atom, a (C_j,-C₅) alkyl, (C_j-C₃) alkoxy,

alkylamino group; (C₆-C₁₄) aryl (C^C,;) alkyl group in which the aryl ring is optionally substituted with one or more radicals chosen independently from a halogen atom, a (C₁-C₅) alkyl, (C₁-C₅) alkoxy, (C^C,_;) alkylthio, (C__,-C₅) alkylamino and di (C^C,;) alkylamino group; (C₃-C₈) cycloalkyl group; or (C₃-C₈) cycloalkyl- (C_x-C₅) alkyl group;

R_x and R₂ represent, independently of each other, a hydrogen atom, a halogen atom, a (C^C^ alkyl, (Ci-C_j) alkoxy, (C^C,;) alkylthio or phenoxy group; and P represents a (C₁-C₅) alkyl or (C₁-C₅) alkoxycarbonyl group .

15. A process for the preparation of compounds of formula XIII

in which Ar, _x and R₂ are as defined for formula I, and R₅ is chosen from a hydrogen atom, a halogen atom and a (C₁-C₄) alkyl and (C₁-C₄) alkoxy group, which comprises the following steps:

(i) reacting a compound of formula I as defined in claim 1, in which R represents a hydrogen atom, with a dialkyl oxalate of formula VII

R₄0-C0-C0-0R₄ (VII)

in which R₄ represents (C₁-C₄) alkyl, in the presence of an alkali metal alkoxide, followed by an acidification of the reaction medium in order to form a compound of formula VIII

(ii) treating the compound of formula VIII obtained with a strong base and then reacting the resulting compound with N-phenyltrifluoromethane- sulfonimide in order to obtain a compound of formula IX

(iii) reacting the compound of formula IX obtained with a phenylboronic acid of formula X

in which R₅ is a hydrogen atom, a halogen atom or a (C_j-C^ alkyl or (C₁-C) alkoxy group, in the presence of tetrakis (triphenylphosphine) palladium(O) and an alkali metal carbonate, in order to form a compound of formula XI

in which R_x, R₂, Ar, R₄ and R₅ are as defined above; (iv) reacting a (C₁-C₄) alkylphenylhydrazine with the compound of formula XI obtained and then treating the resulting compound with sodium cyanoborohydride in order to form a compound of formula XII

in which Ar, R_1# R₂, R₄ and R₅ are as defined above; (v) saponifying the compound of formula XII obtained by the action of a base, in order to obtain a compound of formula XIII

in which R_lt R₂, R₅ and Ar are as defined above.