FR2760748A1 - PROCESS FOR THE PREPARATION OF 2H-1-BENZOPYRANES - Google Patents

Abstract

The invention concerns a method for preparing a compound of formula (I) in which R1 to R5, n and Ar are as defined in claim 1, comprising thermal cyclization of a compound of formula (IV).

Description

The invention relates to a process for the preparation of 2H-1- derivatives.

  benzopyran (or 3-chromene) which are synthetic intermediates in the preparation of thiozalidinones

pharmacologically active.

  For ten years, the lipid-lowering and anti-diabetic activity of thiazolidinones of formula A:

R. R R_

  R4. 0 I I 'o R4 R i (CH2) n-O-Ar-CHR A

-.--A

R30W O R6

  R2 is studied. US Patents 4,572,912, US 4,873,255 and US 5,104,888 reveal the usefulness of these compounds in the treatment of diabetes mellitus and its complications such as cataracts, retinopathies, neuropathies, nephropatias and certain vascular diseases , But

  also in the treatment of hyperlipidemia.

  Their preparation notably involves the formation of the nitrated reaction intermediate of formula:

R 0 R1

  R30 i W R2 in which W represents a CH2 group, CO, CH-OR or C = N-OR, U represents CH2 or else U and W together form a double bond, and Ar represents a divalent aromatic radical of aryl or heteroaryl type . When, for these compounds, W and U both represent

  CH2, essentially three different synthesis routes have been proposed.

  The first is particularly suitable for obtaining the nitro derivatives B in which n represents 2 and involves the following reaction:

R R R

R I OH 1R

4 - 4 -CH -CH -OH

HO O R0

R R

  for the formation of the chromanyl nucleus.

  In the second, the construction of the chromanyl nucleus proceeds by the following step: t R Rs R5

R- OH R4 X OH R O COOR

HO- H - "CH COO CH3 HO

3 RR

R, 2 RI O

  The 4-oxochroman derivative obtained must however undergo several other transformations so that the desired substituent is introduced in position 2 and the 4-oxochromanyl nucleus is converted into a chromanyl nucleus:

R R

15 R

R -, O 0 COOR R O 1

- (CH -O-Ar-NH

HO | R0

R2 O R

  The third synthetic route enables rapid preparation of the derivative B of type 4-oxo-chroman suitably substituted in position 2, but requires its conversion to 3-chromenyl then chromanyl: R

R OH

+ R1 (CH) -O-Ar-NO2

3 COCH3

  R R R R i O 1 4 - (CH2) -O-Ar-NO R3 R0 Ri R l O 1 4 (CH2) n-O-Ar-NO2 R3 R l R OH R

R O R

(CH2) n-O-Ar-NO2 R R R

R 5 0R

  4 (CH2 nOArNH2 R The invention alternatively provides a preparation process allowing rapid access to the intermediate derivative B by direct construction of a 3-chromenyl ring suitably substituted in position 2. More generally, the process of the invention allows the preparation of compounds of formula 1: R2 R1-CO-O x [R5 R3 '- (CH2) nO_0-Ar l R4 in which Ri represents a radical chosen from (C3-C7) cycloalkyl, (C -C22) alkyl, (C2-C22) alkenyl, (C2-C22) alkynyl and (C -C6) alkoxy, said radical being optionally substituted by one or more Y groups; or R. represents a radical chosen from (C6-Cl2) aryl; heteroaryl of 5 to 10 links comprising from 1 to 5 heteroatoms

  endocyclics chosen from O, S and N, (C6-C12) aryl- (C1-C6) alkyl, (C6-

  C12) aryl- (C2-C6) alkenyl, (C6-C12) aryl- (C2-C6) alkynyl, (C6-C12) aryl- (C1-

  C6) alkoxy, (C6-C12) aryl- (C2-C6) alkenyloxy and (C6-C12) aryl- (C2C6) alkynyloxy, said radical being optionally substituted on the aryl or heteroaryl ring by one or more substituents Z; or Ri represents the group -S03L in which L represents a

  hydrogen atom, (C6-C1o) aryl- (C1-C3) alkyl, (C1-C5) alkyl or (Ci-

  C5) alkyl substituted by one or more hydroxy or (C1-Cs) alkoxy groups; R2, R3 and R4 independently of one another represent a radical chosen from a hydrogen atom; a halogen atom; (C1-Cs) alkoxy; (Cl-C2s) alkyl; (Cl-C2s) alkyl substituted by one or more YY groups; (C6-C12) aryl- (C1-C6) alkyl; (C3-C1o) cycloalkyle optionally substituted by one or more (C1-C6) alkyl groups; (C6-Cl2) aryl;

  hydroxy; hydroxy protected by a W group; (Cl-C7) alkanoyl; (C2-

  C7) alkanoyl substituted with one or more ZZ groups; (C7-

  C13) arylcarbonyl; (C3-Clo) cycloalkyl-carbonyl optionally substituted

  on the cycloalkyl part by one or more (C1-C6) alkyl; carboxy; (C2-

  C7) alkoxycarbonyl; (C6-C12) aryloxy-carbonyl; (C6-C12) aryl- (C1-C6) alkoxycarbonyl; nitro; a group of formula Il / R6 -Ns Il R7 (in which R6 and R7 independently represent a radical chosen from a hydrogen atom, (Cl-C6) alkyl, (C6-C12) aryl- (C1-C6) alkylb,

  (C3-Clo) cycloalkyl, (C6-C12) aryl, (Cl-C7) alkanoyl, (C6-C12) aryl- (ClC6) -

  alkanoyl, (C6-C12) aryl-carbonyl and (C2-C7) alkoxycarbonyl or else R6 and R7 form together with the nitrogen atom which carry them a 5 to 10-membered heterocycle optionally comprising 1 to 3 additional endocyclic heteroatoms chosen among N, O and S, said heterocycle being

  optionally substituted by one or more groups chosen from (Ci-

  C6) alkyl, (C1-C7) alkanoyl, (C3-C7) alkenylcarbonyl, (C3-C7) -

  alkynylcarbonyl and (C6-C12) aryl-carbonyl); and a group of formula III: / R'6

N {II

  R '?, (in which R'6 and R'7 are independently selected from a hydrogen atom, (C1-C6) alkyl, (C6-C12) aryl- (CO-C6) alkyl, (C3Clo) cycloalkyl and (C6-C12) aryl; or else R'6 and R'7 form, together with the nitrogen atom which carries them, a 5 to 10-membered heterocycle optionally comprising 1 to 3 additional endocyclic heteroatoms chosen from N, O and S , said heterocycle being optionally substituted by one or more groups chosen from (C, - C6) alkyl, (C, -C7) alkanoyl, (C3-C7) alkenylcarbonyl, (C3-C7) alkynylcarbonyl and (C6-C12) aryl- carbonyl); or R4 and R5 together form a (C1-C4) alkylenedioxy group; or Rs represents a hydrogen atom, a group (Cl-

  C25) alkyl, (C6-Cl2) aryl- (C1-C6) alkyl, (C3-C1o) cycloalkyl or (C3-

  C1) cycloalkyl substituted with one or more (C1-C6) alkyl; n is an integer between 1 and 10; Ar is a radical chosen from (C6C12) aryl or heteroaryl of 5 to 10 members comprising 1 to 5 endocyclic heteroatoms chosen from O, N and S, said radical being substituted by one or more nitro groups or -NHRa, Ra representing (Cl- C4) optionally substituted alkyl

  by nitro; (C2-Cs) alkylcarbonyl optionally substituted by nitro; (C1-

  C4) alkylsulfonyl optionally substituted by nitro; allyl or benzyl; Y represents (C6-C12) aryl, carboxy, (C2-C6) alkoxycarbonyl or (C6-Cl2) aryl- (C1-C5) alkoxy-carbonyl; Z represents (C1-C5) alkyl optionally substituted by one or more halogen atoms, (C1-Cs) alkoxy, a halogen atom, an amino group, (C1-C5) alkylamino, di- (C1-Cs) alkylamino, nitro, cyano,

  hydroxy or -CONR2 o R is (Cl-C5) alkyl or (C6-C12) aryl.

  YY represents hydroxy; hydroxy protected by a W group; (C1-C7) alkanoyl optionally substituted by one or more ZZ groups; (C3C7) alkenylcarbonyl optionally substituted by one or more ZZ groups; (C3-C7) alkynylcarbonyl optionally substituted by one or more ZZ groups; (C6-Cl2) aryl-carbonyl; (C3-C10) cycloalkylcarbonyl

  optionally substituted by one or more (C1-C6) alkyl; carboxy; (C2-

  C7) alkoxycarbonyl; (C6-Cl2) aryloxy-carbonyl; (C6-C12) aryl- (C1-C6) -

  alkoxy-carbonyl; hydroxyimino; hydroxyimino in which the hydroxy group is protected by a W group; a group of formula 11; or a group of formula III; groups II and III being as defined above;

  ZZ represents carboxy, (C2-C7) alkoxycarbonyl or (C6-

  C12) aryl; W represents (Cl-C6) alkyl; (C1-C6) alkyl substituted by one or more ZZ groups; (Cl-C7) alkanoyl optionally substituted by one or more ZZ groups; (C3-C7) alkenylcarbonyl optionally substituted by one or more ZZ groups; (C3-C7) alkynylcarbonyl optionally substituted by one or more ZZ groups; (C6-C12) arylcarbonyl; (C2-C7) alkoxycarbonyl; (C6-C12) aryloxy-carbonyl; sulfo; or one

  group of formula III as defined above.

  In the context of the invention, the term “alkyl” means a linear or branched saturated hydrocarbon radical; this definition is also valid for the alkyl groups of the arylalkyl, alkoxy, arylalkoxy, alkanoyl, alkoxycarbonyl, arylalkoxycarbonyl, arylalkanoyl, arylalkoxycarbonyl, alkylamino and dialkylamino radicals. Examples of alkyl groups are methyl, ethyl, propyl,

  isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, 2-

  methylbutyl, 1-ethylpropyl, hexyl, isohexyl, neohexyl, 1-

  methylpentyle, 3-methylpentyle, 1,1-dimethylbutyl, 1,3-dimethylbutyl, 2-

  ethylbutyl, 1-methyl-1 -ethylpropyl, heptyl, 1 -methylhexyl, 1-

  propylbutyl, 4,4-dimethylpentyl, octyl, 1-methylheptyl, 2ethylhexyl,, 5-dimethylhexyl, nonyl, decyl, 1-methylnonyl, 3,7dimethyloctyl and

7,7-dimethyloctyl.

  Alkenyl is understood to mean a linear or branched unsaturated hydrocarbon radical having one or more double bonds. Similarly, an alkynyl group is a linear or branched unsaturated radical having one or more triple bonds. These definitions naturally apply to the alkenyl and alkynyl moieties of the groups

arylalkenyl and arylalkynyl.

  Cycloalkyl groups correspond to cyclic saturated hydrocarbon radicals such as cyclopentyl, cyclohexyl,

cycloheptyle and cyclooctyle.

  C6-C12 aryl groups are carbocyclic aromatic groups of 6 to 12 mono- or polycyclic carbon atoms such as

  as phenyl or naphthyl (preferably 1- or 2-naphthyl).

  The 5 to 10-membered heteroaryl groups comprising from 1 to 5 endocyclic heteroatoms are mono- or polycyclic. Examples are pyridine, furan, thiophene, pyrrole, pyrrazole, imidazole, thiazole, isoxazole, isothiazole, pyridazine, pyrimidine, pyrazine and triazines. It should be understood that the nuclei

  pyridine, furan, thiophene and pyrrole are particularly preferred.

  When -NR6R7 or -NR'6R'7 form a 5 to 10-membered heterocycle optionally comprising, in addition to the nitrogen atom, 1 to 3 additional endocyclic heteroatoms chosen from O, S and N, the latter

  can be aromatic or not. The particular hetaroaryles mentioned above

  above comprising at least one nitrogen atom and their derivatives

  partially or completely saturated are examples of heterocycles.

  Mention may also be made of morpholine. Preferred examples

  of heterocycles -NR6R7 and -NR'6R'7 optionally substituted are 1-

  pyrrolyle, 1-imidazolyle, 3-thiazolidinyle, 1-pyrrolidinyle, 1pyrrolinyle, 1-

  imidazolinyl, 1-imidazolidinyl, 3-methyl-1-imidazolidinyl, 3-ethyl-1-

  imidazolidinyl, 3-acetyl-1-imidazolidinyl, 3-valeryl-1-imidazolidinyl,

  piperidino, 1-piperazinyl, 4-propyl-1 -piperazinyl, 4-pentyl-1 -

  piperazinyl, 4-formyl-1 -piperazinyl, 4-benzoyl- 1 -piperazinyl, 4-

  acryloyl-1-piperazinyl, 4-butyryl-1-piperazinyl and morpholino.

  The alkanoyl group denotes the alkyl-carbonyl radical. By way of example, mention may be made of formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl groups,

hexanoyl and heptanoyl.

  By halogen atom is meant a chlorine atom,

bromine, iodine or fluorine.

  The size of each of the substituents R1 to R7, R'6, R'7, Ar, Y, Z, W, YY and ZZ is as specified above. It should be understood that the expression (Cx-Cy) preceding the name of a radical indicates that this radical

  contains x to y carbon atoms. For example (C3-

  C7) alkenylcarbonyl is an alkenylcarbonyl radical comprising in total (including the carbonyl radical) from 3 to 7 carbon atoms. In the context of the invention, when the chemical name of the radical comprises a dash, the expression (Cx-Cy) relates exclusively to the fragment of the radical appended to the parenthesis. Thus, (C6-Cl2) aryl-carbonyl means that the aryl fragment of the arylcarbonyl radical contains from 6 to 12 carbon atoms, which implies that the arylcarbonyl radical in question

  contains from 7 to 11 carbon atoms.

  The preferred compounds of formula I are those for which: Ri represents (C1-Clo) alkyl; R5 represents (Ci-Cl0) alkyl; n represents 1, 2 or 3; and Ar represents phenyl or naphthyl, substituted in para and / or meta positions by one or more nitro groups or -NHRa, FPa

  representative (Cl-C4) alkyl optionally substituted by nitro; (C2-

  Cs) alkylcarbonyl optionally substituted with nitro; (C1C4) alkylsulfonyl optionally substituted by nitro; allyl or benzyl; R2, R3 and R4 being as defined above for formula I. Among these compounds those in which: Ri represents (Cl-C4) alkyl;

  R2, R3 and R4 represent a hydrogen atom or (Ci-

  C4) alkyl; R5 represents (Cl-C4) alkyl; n represents 1; and Ar represents phenyl substituted by a nitro group,

are particularly advantageous.

  The preferred reaction intermediate has the formula R2 AcO ".-- o

R3 0 2 \ N N02

  R4 Io in which R2, R3, R4 and Rs are as defined above for formula I. More specifically, the process of the invention comprises (i) thermal cyclization of a compound of formula IV

R2

R2

R1-CO-O IV

R's R3 O (CH2) n- O - Ar

R4

  in which Ri, R2, R3, R4, R5, Ar and n are as defined above

  above for I it being understood that the functions, present in these substituents, which are liable to be degraded by heat are protected beforehand; and (ii) where applicable, deprotection of the protected functions

  for the implementation of step (i).

  In step (i), the reaction temperature is adjusted so as to cause the cyclization of the compound of formula IV. It goes without saying that before performing this step all the thermally unstable functions present in the substituents R., R2, R3, R4, R5 and Ar must

be protected.

  The preferred protection methods for this are those known in the art and more particularly those described in Protective groups in Organic Chemistry, McOMIE, Plenum Press,

1973.

  Generally, a temperature between 130 and C is sufficient. Preferably, the thermal cyclization is carried out between 150 and 190 C. According to a preferred embodiment of the invention, the cyclization reaction is carried out in a solvent, preferably a polar solvent with high boiling point, so that that the cyclization can take place at reflux of the solvent. As solvent, ll dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone and hexamethylphosphorotriamide are particularly suitable. Note that in the context of the invention, hexamethylphosphorotriamide has for

formula [(CH3) 2N] 3PO.

  When the cyclization reaction takes place in a solvent, it is preferable to add a tertiary amine, preferably aromatic, to the reaction medium. This amine will advantageously have the following formula: T

/ 1

I - T2

X-2 T3

  in which Tl, T2 and T3, identical or different, are chosen from (Ci-

  C4) alkyl and (C6-Cl2) aryl optionally substituted by one or more halogen, (Cl-C4) alkyl or (Cl-C4) alkoxy, provided that at least one substituent among T1, T2 and T3 represents (C6- C12) optionally substituted aryl, for example phenyl. Note that the aniline derivatives such

  that diethylaniline are perfectly suitable.

  The concentration of compound of formula IV will advantageously be from 0.4 to 1.5 mol / l. Preferably, the reaction medium also comprises from 1 to 20% by weight of the tertiary amine,

preferably 10% by weight.

  In more detail, the cyclization reaction can be

  implementation as follows.

  The compound of formula IV and the tertiary amine are introduced at ambient temperature into the solvent, in any order. The reaction medium can be brought under pressure, but the cyclization will have

  more generally at atmospheric pressure.

  The reaction medium is then brought to reflux for 4 to 12

  hours so as to lead to the expected compound of formula I.

  One method of isolating the product consists in: diluting the reaction medium with a solvent such as diethyl ether or ethyl acetate in a volume ratio of the reaction medium to the dilution solvent of between 1: 2 and 1: 3; - Add a dilute hydrochloric acid solution (for example 1N) to the resulting mixture, whereby the tertiary amine is entrained in the aqueous phase, then separate the two phases; - wash the organic phase with a dilute sodium hydroxide solution (for example 1 N), then separate the two phases; - washing the organic phase repeatedly with water with intermediate separation of the aqueous and organic phases until an aqueous phase of pH 7 is obtained; - concentrating the organic phase by evaporation of the solvent, and - optionally purifying the compound of formula 1, by

  example by column chromatography.

  The compound of formula IV is obtained according to the invention by addition of a propargyl derivative of formula V

R5 V

  X (CH2) n-O-Ar in which R5 and Ar are as defined for I above and X is a leaving group, on a phenol of formula VI: R2

R1 - CO - O R4

VI

R3 OH

R3 0R

  R4 In this reaction, the leaving group X is preferably chosen from a halogen atom (preferably Cl, Br or 1), a group of formula -O-SO2-A1 and a group of formula -O-CO-A1 in which A1 represents trifluoromethyl; (Cl-C4) alkyl; (Ce-C12) aryloxy optionally substituted by (C1-C4) alkyl; (C1-C4) alkoxy; (C1-

  C4) alkylamino; or (C6-C12) arylamino optionally substituted by (Ci-

  C4) alkyl. According to a preferred embodiment, the addition reaction is carried out in a polar solvent of the dimethylformamide or acetonitrile type in the presence of a base such as a non-quaternizable tertiary amine and a copper-based catalyst. for example chosen from trifluoroacetates, halides and cuprous as cupric acetates. The preferred catalysts are cuprous halides or cupric halides, especially cuprous chloride or cupric chloride. The non-quaternizable tertiary amines have a sterically hindered nitrogen atom. This nitrogen atom carries at least two bulky groups. Examples of a non-quaternizable tertiary amine are 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) and 1,5-diazabicyclo [4.3.0] non-5-ene (DBN). Other examples of non-quaternizable tertiary amines are tertiary amines in which at least one of the radicals carried by nitrogen is a branched aliphatic radical, and preferably in which at least two of the radicals are a radical

branched aliphatic.

  As examples of amines suitable for the invention, mention may be made of those which correspond to the following formula: R ′

R "- N

  R "'in which R', R" and R "'identical or different represent: a linear or branched, saturated or unsaturated aliphatic radical having from 1 to 12 carbon atoms, - a saturated or unsaturated cycloaliphatic radical having from 5 to 7 carbon atoms, or - a phenyl radical, it being understood that at least one of the radicals R ', R "and R"' represents a branched aliphatic radical and that at most one of the radicals

  R ', R "and R"' is a phenyl radical.

  As branched radical, it is preferable to choose a branched aliphatic radical having a branching on the carbon in

  position ct with respect to the nitrogen atom.

  to Among these amines, preference is given to those for which at least two of the radicals R ', R "and R"' are branched aliphatic radicals the branches of which are located on carbon n

  cc position with respect to the nitrogen atom.

  As examples of radicals R ', R "and R"', mention may be made of methyl, ethyl, propyl, isopropyl, butyl,

  isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-

  pentyle, hexyle, isohexyle, octyle, isooctyle, décyle, dodécyle,

cyclohexyl, phenyl.

  As examples of tertiary amines which are very suitable for the invention, mention may be made of: - triethylamine, - N, N-diisopropylmethylamine, - N, N-diisopropylethylamine, - N, N-diisopropylpropylamine, - N, N -di sec-butylethylamine, - N, N- diisopropylisopropylamine, - N, N-diisopropylallylamine, - N, N-di-sec-butylallylamine, - N, N-dicyclohexylethylamine,

- N, N-diisopropylaminoethanol.

  We preferentially choose from all the bases

  cited, N, N-diisopropylethylamine, triethylamine or DBU.

  Advantageously, the reaction is carried out between -50 ° C. and room temperature, the molar ratio of compound V to compound VI being between 1 and 3 and the molar ratio of the amine

  tertiary not quaternizable to compound VI being between 1 and 1.3.

  The amount of copper-based catalyst to be used is normally very low: 0.1 to 3 moles of catalyst per 100

  moles of the compound of formula V are generally sufficient.

  More precisely, the compound of formula VI is dissolved in the polar solvent added with the non-quaternizable tertiary amine and the copper-based catalyst. The solution is then cooled to the appropriate temperature. To this solution, the compound of formula V is added in solution in a polar solvent. The same polar solvent as above can be used for this purpose, for example dimethylformamide or acetonitrile. The reaction is continued for the time necessary and results in the formation of the compound of formula IV in solution in the reaction medium. The isolation and purification of this compound is carried out in a conventional manner. The following operating protocol is provided by way of illustration. At the end of the reaction, the reaction medium is diluted with ethyl acetate or diethyl ether. A dilute hydrochloric acid solution, for example 1N, is then added to the mixture, so as to wash the organic phase. Washing with said 1N hydrochloric acid solution is continued until the entire base is entrained in the aqueous phase. Then the organic phase is washed with a sodium chloride solution until the washings are neutral. The organic phase is then concentrated by evaporation of the solvent. The product, recovered in the form of an oil, is then purified by

  example by column chromatography.

  The compounds of formula VI are described in the literature, as are their methods of preparation. The compounds of formula V are easily prepared from the corresponding propargyl alcohols according to any of the activation methods known to those skilled in the art. For example, the compound of formula V can be obtained by reaction of propargyl alcohol VIII Rs HO (CH2) nO-Ar VIII i with a reagent which can be hydrochloric, hydrobromic or hydroiodic acid, trifluoroacetic anhydride , an alkyl chloroformate, preferably methyl chloroformate, dialkyl sulfate, preferably dimethyl sulfate, or chloride

sulfonyl.

  In general, a stoichiometric quantity of said reagent is reacted with compound VIII in a solvent inert with respect to the reagent such as acetonitrile (and more generally a nitrile), anisole, an ether, in the presence an excess of a strong organic base such as a non-quaternizable tertiary amine of the type described above. The molar ratio of the base to the compound of formula VIII is for example between 1 and 1.5. The reaction is preferably

  performed between -50 C and room temperature.

  The operating protocol generally consists in adding the reagent to a cooled solution of the alcohol of formula VIII and of the base.

in the solvent.

  The compound of formula VIII can be prepared by carrying out steps 1 and 2 below: HR5 (CH2) -G Rs (CH2) - O -Ar HO-Ar il step 1 Y o O

IX X X

lx x xi step 2

M-C-CH

  XII% Rs HO (CH2) n -O-Ar VIII In step 1, a compound of formula IX which is a phenolic derivative, preferably in the form of its alkali metal salt, is reacted with a ketone of formula X wherein G represents a leaving group such as group X of the propargyl derivative of formula V; preferably G represents a mesylate group, a triflate or a halogen atom. The reaction is preferably carried out in an organic solvent promoting nucleophilic substitutions such as a ketone, preferably acetone or methyl ethyl ketone, in the presence

of an alkali metal iodide.

  More particularly, the use of potassium iodide, or even sodium iodide, is recommended. The concentration of reactants IX and X is advantageously between 0.01 and 2 mol / l, preferably between 0.2 and 1 mol / l, the amount of alkali metal iodide preferably varying between 0.01 mole and 0.4 moles per 1 mole of the compound of formula X, better still between 0.05 and 0.2 moles. As for the molar ratio of the compound of formula IX to the compound of formula X, it is

  preferably between 0.8 and 1.2.

  The reaction of step 1 is facilitated at a temperature above 50 C. This reaction is therefore preferably carried out between 50 and 100 C, for example at the boiling temperature of a

judiciously chosen solvent.

  The reaction can simply be carried out at the

atmospheric pressure.

  The operating protocol is for example briefly the following lo: the reagents are introduced into the solvent, in any order and reflux is initiated. At the end of the reaction, the salt formed precipitates, the precipitate is filtered and the mixture is extracted using an adequate solvent, preferably diethyl ether; after washing the organic phase with water and drying, the solvent is evaporated. As a variant, at the end of the reaction, diethyl ether is introduced into the reaction medium in an amount sufficient to precipitate the salts formed. After filtration, the organic phase is washed with water, dried and concentrated by evaporation

solvent.

  The product obtained of formula XI can be used as it is,

  without further purification, in step 2.

  In step 2, the compound obtained of formula Xl is reacted

with an acetylide of formula XII.

  As suitable acetylide, one can use a magnesian (BrMgC- = CH or CIMgC- = CH), a lithian (LiC-CH), acetylide

  potassium or sodium acetylide.

  Bromo- and chloromagnesians are commercial compounds. The lithiated derivative can be obtained conventionally by

  action of butyllithium on acetylene.

  The reaction can be carried out in a solvent such as tetrahydrofuran, N-methylpyrrolidone, anisole or a mixture of an ether with an amide, at a temperature between -50 ° C. and 0 ° C. Preferred method, concentration of the reagents is between 0.01 and 2 mol / l, better still between 0.2 and 1 mol / l, while the molar ratio of compound XII to compound Xl is between 1

and 1.5.

  The operating protocol followed is the conventional protocol used for this type of addition. Ketone X1 is gradually added at low temperature to acetylide XII in solution. Product VIII is obtained in the form of alcoholate then extracted and purified in a conventional manner. Water is for example added to the reaction medium, then propargyl alcohol VIII is extracted from the mixture by extraction using a suitable solvent such as diethyl ether or ethyl acetate. Purification can be carried out by chromatography

on column.

  As for the compounds of formula X, they are either commercial or prepared by conventional methods from

of commercial products.

  The compounds of formula IV are new and form a

another object of the invention.

  The compounds of formula I are intermediates in the synthesis of the following compounds of formula VII: R2 Rl-CO-O O R5 R3 \ (CH2) n-O-U-CH2 N-Ro10 Vil

R4 S

  wherein R1, R2, R3, R4, R5 and n are as defined for I in claim 1;

  U is a divalent radical chosen from a group (C6-

  C12) arylene and a 5-10 membered heteroarylene comprising 1 to 5 endocyclic heteroatoms selected from O, S and N; R9 and Rlo, identical or different, are independently chosen from a hydrogen atom, a (C1-C10) alkyl group and a (C1-Clo) alkyl group substituted by one or more radicals chosen

  among hydroxy, (C1-C5) alkoxy, (C6-C12) aryl, (C1-C23) alkanoyloxy, (C3-

  C23) alkenylcarbonyloxy, (C3-C23) alkynylcarbonyloxy, (Cl-C23) alkanoyloxy substituted by one or more substituents Y, (C3-C23) alkenylcarbonyloxy substituted by one or more substituents Y, (C3-C23) alkynylcarbonyloxy substituted by one or more substituents Y, (C6-Cl2) aryl-carbonyloxy, heteroarylcarbonyloxy in which the heteroaryl ring contains from 5 to 10 members and from 1 to 5 endocyclic heteroatoms chosen from O, S and N, a group of formula -COOR11 and a group of formula

-CONR12R13;

  Y is as defined for I above;

  R11l represents a hydrogen atom, (C6-C12) aryl- (C, -

  C3) alkyl, or (C1-C5) alkyl optionally substituted one or more times by hydroxy or (C1-C5) alkoxy; R12 and R13, identical or different, are independently chosen from a hydrogen and (C 1 -C 5) alkyl atom, or else R12 and R13, together with the nitrogen atom which carries them, represent a heterocycle of 5 to 7 links, said heterocycle possibly comprising 1 or 2 additional endocyclic heteroatoms chosen from O, S and N and

  can be substituted on the additional nitrogen atom by (C1-

  C5) alkyl, (C1-C5) alkanoyl, (C3-C5) alkenylcarbonyl or (C3-

  C5) alkynylcarbonyl. The synthesis of these compounds implies in particular the implementation of the stages schematized below: R2 Ri -CO - OR 3T (CH22) nO - U - NH2 R4 (i) NaNOe / HX (ii) H2C- CH-A i ( iii) Cu20 R2

R1 - CO -O / /

R3 O OL <2 (CH2) -O-U-CH2.CH-A

R, 10

R4 X

(i) NH2-CS-NH2 (ii) H "R2

Ri-Co- 0.

  NR R3 O CO- <H (C 2) nOU-CH2NH R4 s [R2 Rt-CO0- 0 / o RsR R. O (CH2) nOU-CH2 RO R4 SA These steps are detailed in US 4 873 255 and US 5 104 888. The transformation of the 3-chromene derivative of formula I into the chromanyl derivative of formula XIII can be carried out in a simple manner according to the methods known to those skilled in the art. One of these methods involves the catalytic hydrogenation of a compound of formula

  I in which Ar is aryl or heteroaryl substituted by a nitro group.

  As catalyst, platinum, palladium on carbon, rhodium, ruthenium, Raney nickel, Wilkinson catalyst

to (RhCI (Ph3P) 3) can be used.

  The hydrogenation will, for example, be carried out at ambient temperature at a pressure slightly higher than atmospheric pressure (from 1.5 to 10 bars, preferably 2 to 5 bars) in a

  solvent or a mixture of suitable solvents.

  The solvents generally used are C1-C5 aliphatic alcohols such as methanol or propanol, or alternatively dimethylformamide, optionally in admixture with benzene. The

  concentration of compound of formula I is for example from 0.01 to 1 mol / I.

  Hydrogenation is generally continued for 3 to 4

* hours.

  At the end of hydrogenation, the catalyst is filtered. This is washed with benzene or ethyl acetate. Then the reaction medium is concentrated and the hydrogenated compound is isolated and purified in a conventional manner. Advantageously, the compound of formula XIII is extracted by addition of a dilute hydrochloric acid solution, preferably 1 N. The aqueous phase obtained is separated, made basic and then extracted, for example with diethyl ether. The resulting organic phase is concentrated and the resulting product of formula XIII is optionally

purified.

  The following examples illustrating embodiments

preferred of the invention.

EXAMPLE 1

  2-methyl-2- (p-nitrophenoxymethyl) -5,7,8-trimethyl-6-

  acetoxy-2H-1-benzopyran (formula 1: R1 = R2 = R3 = R4 = RS = CH3; Ar = p-nitrophenyl; n = 1). a) p-nitrophenoxyacetone (formula Xl: R5 = CH3; n = 1; Ar = p-nitrophenyl) In a 250 mL flask fitted with a condenser and under argon, a mixture of anhydrous acetone (150 mL), d sodium iodide (0.75 g, 5 mmol, 0.1 eq), potassium salt of p-nitrophenol (8.85 g, 0 mmol, 1 eq) and chloro-2-acetone (4, 4 mL, 55 mmol, 1.1 eq) is brought to reflux overnight, then cooled and concentrated in vacuo. After dilution with diethyl ether (100 mL) and water (50 mL), the aqueous phase is extracted with ether three times (75 mL x 3). The organic phase is washed with

  water twice then dried over MgSO4 and concentrated in vacuo.

  The crude product (9.7 g) is dissolved in the minimum amount of boiling diethyl ether and petroleum ether is added until a persistent cloudy reflux appears. The solution thus obtained is stirred magnetically. After cooling to room temperature, this

  solution is cooled to 0 C for a few minutes and then filtered through B chner.

  The mother liquors are concentrated under vacuum and the solid recovered is recrystallized. The crystals are combined and dried under vacuum overnight. The

  pure expected product (9.3 g) is obtained with a yield of 95%.

  1H NMR (CDCI3, 300 MHz) d: 2.35 (s, 3H); 4.2 (s, 2H); 6.95 (d, 2H)

8.2 (d, 2H).

  13C NMR (CDCI3, 75 MHz) d: 202.9 (s), 162.3 (s), 142.0 (s), 125.8 (d),

114.5 (d), 72.8 (t), 26.3 (q).

  MS m / z: 196 (M +, 10); 195 (75); 153 (100); 152 (25); 136 (17); 123

  (33); 122 (22); 108 (10); 107 (10); 106 (26); 92 (19); 78 (25); 77 (20);

  76 (94); 75 (59); 74 (25); 65 (13); 64 (44); 63 (59); 62 (22).

  b) 4- (p-nitrophenoxy) -3-methyl-3-hydroxy-1-butyne (formula VIII: Ar = p-nitrophenyl; n = 1; R5 = CH3) In a 250 ml flask under argon, bromide of ethynylmagnesium in solution in 0.5 M THF (44 mL) is introduced o and cooled to -30 C. The ketone obtained in step a) above (3.9 g, 20 mmol, 1 eq ) dissolved in anhydrous THF (40 mL) is added dropwise. The solution is stirred overnight at room temperature, then hydrolyzed with a saturated NH4Cl solution until a homogeneous aqueous phase is obtained. The aqueous phase is extracted with diethyl ether (100 mL x 3), and the organic phase thus obtained is washed with brine (20 mL x 3), then dried over MgSO4. After concentration under vacuum, the crude product is isolated in the form of a viscous oil. It is purified by flash chromatography on silica gel (eluent: AcOEt / petroleum ether: 3/7, Rf: 0.5). The pure product

  crystallized (3.57 g) is then obtained (Yield: 80%).

IR (film): 3500, 2120 cm-1.

  1H NMR (CDCI3, 300 MHz) d: 1.7 (s, 3H); 2.6 (s, 1H); 3 to 3.7 (s wide,

  1H); 4.1 (d, 1H); 4.15 (d, 1H); 7.05 (d, 2H); 8.2 (d, 2H).

  13C NMR (CDCI3, 75 MHz) d: 171.8 (s); 141.6 (s); 125.7 (d); 114.6 (d);

  84.6 (s); 75.2 (t); 72.8 (d); 66.7 (s); 25.8 (q).

  MS m / z 221 (M +, 16); 153 (96) 152 (11); 136 (15); 124 (11); 123

  (48); 122 (10); 106 (12); 77 (11); 76 (26); 75 (15); 69 (100); 65 (19);

64 (16); 63 (21).

  c) 1,4-diacetoxy-3,5,6-trimethylbenzene This compound is prepared as described in Org. Synth.

Coll. III, 452, (1963).

  Trimethylhydroquinone (21.76 g, 160 mmol, 1 eq) and freshly distilled acetic anhydride (34.5 mL, 325 mmol, 2.02 eq) are introduced into a 100 ml flask. At this suspension! 1 drop of concentrated sulfuric acid is then added and the mixture is stirred slowly by hand until the trimethylhydroquinone is completely dissolved. After five minutes, the mixture is poured onto crushed ice (130 mL). The solid is filtered on B chner and washed with distilled water (160 mL), then dried under vacuum. The crude product (37 g, Yield: 98%) is pure enough to be used as it is in

the next step.

IR (CCI4): 1770 cm-1.

  1H NMR (CDCI3, 300 MHz) d: 2 (s, 3H); 2.02 (s, 3H); 2.1 (s, 3H); 2.25

  (s, 3H); 2.28 (s, 3H); 6.72 (s, 1 H).

  13C NMR (CDCI3, 75 MHz) d: 169.8 (; 168.6 (s); 146.4 (s); 145.6 (s), 0 (s); 128.1 (s); 127, 3 (s); 121.1 (d); 20.51 (q); 20.1 (q); 16.0 (q)

12.9 (q); 12.4 (q).

  MS m / z: 236 (M +, 5); 194 (7); 152 (100); 151 (11); 137 (6).

  d) 3,5,6-trimethyl-4-acetoxyphenol (formula VI: RI = R2 =

R3 = R4 = CH3)

  This compound is prepared as described in CS 239 442.

  The diacetate obtained in the previous step (2.36 g, 10 mmol, 1 eq) is dissolved in methanol (7.5 mL) and the mixture is cooled to C. Na2S203 (0.125 g, 0.79 mmol, 0.079 eq), then a solution of potassium carbonate (0.345 g, 0.79 mmol, 0.25 eq) in 1.25 ml of water are added. The suspension thus obtained is stirred for one hour at -40 ° C. and then cooled to 20 ° C. After addition of water (12.5 ml) at 5 ° C., the expected compound Vl is extracted abundantly with diethyl ether (50 ml

  x 3). The ethereal phase is dried over MgSO4 and concentrated in vacuo.

  The crude product (1.85 g) is isolated in the form of crystals (crude yield:%) then dissolved in the minimum amount of diethyl ether at reflux. Hexane is then added until persistent turbidity at reflux. After cooling and filtration, the crystals are washed with a cooled mixture of hexane and diethyl ether 95/5, then dried under vacuum. Of

  transparent crystals (1.66 g) are isolated (Yield: 86%).

  1H NMR (CDCI3, 300 MHz) d: 2 (s, 6H); 2.05 (s, 3H); 2.32 (s, 3H); 5.15

(s, 1H); 6.77 (s, 1H).

  13C NMR (CDCI3, 75 MHz) d: 170.4 (s); 151.2 (s); 141.2 (s); 129.3 (s);

  127.0 (s); 121.5 (s); 114.5 (d); 20.4 (q); 16.0 (q); 12.8 (q); 11.6 (q).

  MS mlz: 195 (M +, 13); 153 (10); 152 (100); 151 (19); 137 (31); 107

(7); 79 (7); 53 (8).

  e) 4- (p-nitrophenoxy) -3-methyl-3-trifluoroacetoxy-1-

  butyne (formula V: Ar = p-nitrophenyl; n = 1; R5 = CH3; X = -O-CO-

CF3)

  1,8-diazabicyclo [5.4.0] undec-7-ene or DBU (6.44 mL, 43.2 mmol, 2.89 eq) is added slowly to a solution of the alcohol obtained in step b ) (7.34 g, 33.2 mmol, 2.22 eq) in acetonitrile (16 mL) at -30 C in a 100 mL three-necked flask under argon, then trifluoroacetic anhydride (4.7 mL, 33.3 mmol, 2.23 eq) is added slowly so as to keep the temperature below -20 C. The reaction is strongly exothermic. The mixture is stirred one hour at -20 C before

to be used.

  f) 3- (p-nitrophenoxymethyl) -3- (2,3,5-trimethyl-4-acetoxy-

  phenoxy) -1-butyne (formula IV: Ri = R2 = R3 = R4 = R5 = CH3; Ar = p-

nitrophenyl; n = 1).

  The mixture obtained in step e) is added to a solution of the phenol obtained in step d) (2.9 g, 15 mmol, 1 eq) in acetonitrile (8 mL) in the presence of DBU (2, 85 mL, 19.1 mmol, 1.3 eq) and CuCI2 (0.003 g, 0.018 mmol, 0.12% eq) placed in a 100 mL three-necked flask under argon at -20 C. After addition, the mixture is maintained at this temperature (-20 C) for 2 hours before being stirred overnight

ambient temperature.

  The mixture is taken up in diethyl ether and hydrolyzed. The aqueous phase is extracted with diethyl ether (50 mL x 3). The organic phase is acidified with 1N HCl, then brought back to neutral pH by washing with a saturated NaCl solution. After drying over MgSO4, the solvents are evaporated under vacuum and the crude product recovered (0.78 g). The latter is purified by flash chromatography on silica gel (eluent: AcOEt / petroleum ether: 1/9) and the expected product is isolated as a mixture.

  with the starting monoacetate of formula VI (4.75 g).

  1H NMR (CDCI3, 300 MHz) d: 1.7 (s, 3H); 2.02 (s, 3H); 2.05 (s, 3H) 2.10 (s, 3H); 2.34 (s, 3H) 2.35 (s, 1H) 4.35 (d, 1H); 4.23 (d, 1H) 7.02

  (s, 2H); 7.20 (s, 1H); 8.18 (s, 2H).

  13C NMR (CDCI3, 75 MHz) d: 169.3 (s); 163.3 (s); 150.2 (s); 143.8 (s); 141.7 (s); 129.7 (s); 128.7 (s); 127.0 (s); 125.8 (d); 120.3 (s); 114.4 (d); 82.7 (s); 76.2 (d); 74.6 (s); 73.8 (t); 23.7 (q); 20.4 (q); 16.4 (q)

13.4 (q).

  MS m / z: 221 (12); 153 (70); 152 (10); 136 (11); 123 (38); 108 (10); 76

  (30); 75 (19); 69 (100); 65 (16); 64 (16); 63 (24).

  g) 2-methyl-2- (p-nitrophenoxymethyl) -5,7,8-trimethyl-6-

  acetoxy-2H-1-benzopyran (formula 1: Ri = R2 = R3 = R4 = R = CH3; Ar

= p-nitrophenyl; n = 1).

  The acetate of formula IV (4.75 g) obtained in step f) in a 1/1 mixture with the monoacetate of formula VI [ie 3.9 g of acetate of formula IV (9.8 mmol) and 0 , 85 g of monoacetate of formula VI (4.4 mmol)]

  are dissolved in anhydrous DMF (20 mL) to which is added N, N-

  diethylaniline (0.51 mL, 3.2 mmol, 0.3 eq). The mixture is heated under

  argon at 150 C overnight (bath temperature 160 C).

  The cooled reaction mixture is taken up in water (40 mL) and the aqueous phase is extracted with diethyl ether (150 mL x 3). The organic phase is acidified with a 1N HCl solution, then with a saturated NaCl solution until neutral pH, and dried over MgSO4. The mixture is purified by flash chromatography on silica gel (eluent: AcOEt / petroleum ether: 1/9). The expected product (3.03 g) is obtained in a 1/1 mixture with the monoacetate of formula VI. The overall performance of

these two steps is 60%.

  1H NMR (CDCI3, 300 MHz) d: 1.55 (s, 3H); 2.00 (s, 3H); 2.02 (s, 3H); 2.07 (s, 3H); 2.31 (s, 3H); 4.02 (d, 1H); 4.10 (d, 1H); 5.69 (d, 1H); 6.65

  (d, 1H); 6.95 (d, 2H); 8.18 (d, 2H).

  13C NMR (CDCI3, 75 MHz) d: 169.3 (s); 163.7 (s); 147.6 (s); 141.7 (s); 141.5 (s); 129.7 (s); 125.7 (d); 125.2 (d); 122.8 (s); 122.2 (d); 117.3 (s); 114.6 (d); 75.9 (s); 72.5 (t); 23.2 (q); 20.6 (q); 13.1 (q); 11.4 (q)

11.4 (q).

  MS m / z: 246 (1630); 245 (100); 204 (12); 203 (87); 202 (16); 173 (9);

159 (10).

EXAMPLE 2

  2-methyl-2- (p-nitrophenoxymethyl) -5,7,8-trimethyl-6-

  acetoxy-2H-1 -benzopyrane (formula I: Ri = R2 = R3 R = R4 = = CH3; Ar

= p-nitrophenyl; n = 1).

  In this example, 3,5,6-trimethyl-4-acetoxyphenol (formula VI) and 4 (p-nitrophenoxy) -3-methyl-3-hydroxy-1-butyne (formula

  VIII) are prepared as in Example 1.

  a) 4- (p-nitrophenoxy) -3-methyl-3-trifluoroacetoxy-1 -

  butyne (formula V: Ar = p-nitrophenyl; n = 1; R5 = CH3; X = -O-CO-

  CF3) Triethylamine (0.35 mL, 2.5 mmol, 1.25 eq) is added to a solution of the alcohol of formula VIII (0.47 g, 2 mmol, 1 eq) in acetonitrile ( 2 mL) at -20 C. The trifluoroacetic anhydride (0.3 mL, 2.12 mmol, 1.05 eq) is then added slowly so that the temperature is kept below -20 C. The mixture is restless

  one hour at -20 C before being used.

  b) 3- (p-nitrophenoxymethyl) -3- (2,3,5-trimethyl-4-acetoxy-

  phenoxy) -1-butyne (formula IV: R1 = R2 = R3 = R4 = Rs = CH3; Ar = p-

nitrophenyl; n = 1).

  To a solution of the phenol of formula VI (0.388 g, 2 mmol, 1 eq) in acetonitrile (2 mL) cooled to -20 C, triethylamine (0.35 mL, 2.5 mmol, 1.25 eq ) is added. After a few minutes CuCI2 (0.0065 g, 0.005 mmol, 0.003 eq) in solution in acetonitrile (0.1 mL) is introduced into the mixture. The trifluoroacetate prepared in step a) above is then added to this solution at -20 ° C. in one hour. The mixture is kept overnight in the refrigerator. After usual treatment, the expected product (25%) is isolated in mixture with the monoacetate of

start of formula VI.

  c) 2-methyl-2- (p-nitrophenoxymethyl) -5,7,8-trimethyl-6-

  acetoxy-2H-1-benzopyran (formula 1: Ri = R2 = R3 = = R4 = R5 = CH3; Ar

= p-nitrophenyl; n = 1).

  The expected 2H-1-benzopyran is prepared from the compound obtained in the previous step in the same way as in the example

1.g).

EXAMPLE 3

  3- (p-nitrophenoxymethyl) -3- (2,3,5-trimethyl-4-acetoxy-

  phenoxy) -1-butyne (formula IV: R1 = R2 = R3 = R4 = R5 = CH3; Ar = p-

nitrophenyl; n = 1).

  a) 3-methyl-3-methoxycarbonyloxy-4- (p-nitrophenoxy) -1 -

  butyne (formula V: Ar = p-nitrophenyl; n = 1; R6 = methyl; X = methoxycarbonyloxy) To a solution of ethynylmagnesium bromide (26.6 ml, 11.3 mmol) in THF at 0.5 M , a solution of the ketone obtained in Example 1.b) (2g, 10.25 mmol, 1 eq.) in anhydrous THF (10 mL) is added at 0 C dropwise. The mixture is then stirred for one hour at room temperature. Methyl chloroformate (0.95 mL) is added at 0 ° C. and the temperature is raised to ambient. The mixture is then stirred for one hour and then hydrolyzed with a saturated solution of sodium carbonate (50 mL). The aqueous phase is extracted with diethyl ether (50 mL x 3). The organic phase is dried over MgSO4 and concentrated in vacuo. The expected pure product (1.95 g) is isolated after purification by flash chromatography (SiO2, eluent AcOEt / petroleum ether: 5/95 then 1/9) in the form of a yellowish oil (Yield

: 68%).

  1H NMR (CDCI3, 300 MHz) d: 1.88 (s, 3H); 2.7 (s, 1H); 3.3 (s, 3H)

  4.25 (d, 1H); 4.5 (d, 1H); 7.0 (d, 2H); 8.2 (d, 2H).

  13C NMR (CDCI3, 75 MHz) d: 162.9 (s); 153.1 (s); 141.9 (s); 125.7 (d)

  114.7 (d); 80.2 (s); 75.5 (s); 74.4 (d); 72.2 (t); 54.6 (q); 23.6 (q).

  b) 3- (p-nitrophenoxymethyl) -3- (2,3,5-trimethyl-4-acetoxy-

  phenoxy) -1-butyne (formula IV: R. = R2 = R3 = R4 = R5 = CH3; Ar = p-

nitrophenyl; n = 1).

  The coupling of the carbonate obtained in the previous step with 3,5,6 trimethyl-4-acetoxyphenol is carried out according to the mode

  procedure of Example 1.f) and replacing 4- (p-nitrophenoxy) -3-

  methyl-3-hydroxy-1-butyne with the carbonate obtained in step a) above.

  19% of the expected product are isolated after purification.

  This compound can be cyclized under the same conditions as in Example 1.g) to yield the compound of formula I of Example 1.

EXAMPLE 4

  This example illustrates the transformation of the derivative 2H-1-

  benzopyran obtained in Example 1 as a chromanyl derivative of formula XlII.

  In a hydrogenating bomb, the mixture obtained in Example 1 (3.03 g) is dissolved in anhydrous methanol (20 mL) and benzene (2 mL). 10% Palladium on carbon (700 mg) is added. The hydrogen pressure is adjusted to 3.8 bars, and the mixture is stirred at room temperature until all absorption has ceased. The mixture is filtered through Celite, then the catalyst is washed with ethyl acetate (20 ml x 3). The solvents are evaporated under vacuum and the product is purified by flash chromatography on silica gel using an elution gradient (eluent Et2O / petroleum ether: 1/1, then Et2O / petroleum ether: 8 / 2 as soon as the trimethylhydroquinone monoacetate is recovered). The

  expected product (1.5 g) is then isolated (Yield: 90%).

  Melting point: 135 C 1H NMR (CDCl3, 300 MHz) d: 1.35 (s, 3H); 1.78 (m, 1H); 1.90 (s, 3H); 1.95 (s, 3H); 2.05 (m, 4H including 2.00 s 3H); 2.25 (s, 3H); 2.55 (t, 2H); 3 to 3.5 (broad s, 2H); 3.72 (d, 1H); 3.82 (d, 1H); 6.55 (d, 2H); 6.68 (d,

2H).

  13C NMR (CDCI3, 75 MHz) d: 169.6 (s); 152.2 (s); 145.0 (s); 140.7 (s); , 0 (s); 126.8 (s); 124.9 (s); 123.0 (s); 117.4 (s); 116.2 (d); 115.7 (d); 74.6 (s); 73.2 (t); 28.1 (t); 20.4 (q)); 20.1 (t); 12.8 (q)); 12.0 (q); 11.8 (q). MSiz: 369 (M +, 92); 327 (61); 247 (41); 219 (36); 218 (71); 206

  (14); 205 (92); 204 (10); 203 (26); 191 (35); 189 (13); 177 (11); 175

  (13); 165 (13); 163 (12); 109 (100); 108 (57); 91 (14); 80 (20).

Claims (17)

  1. Process for the preparation of a compound of formula 1: R2 R1-CO-O   R5 R3 (CH2) - O- Ar Re in which R1 represents a radical chosen from (C3-C7) cycloalkyl, (Cl -C22) alkyl, (C2-C22) alkenyl, (C2-C22) alkynyl and (C -C6) alkoxy, said radical being optionally substituted by one or more Y groups; or4 R, represents a radical chosen from (C6-C12) aryl; 5 to 10 membered heteroaryl comprising from 1 to 5 heteroatoms   endocyclics chosen from O, S and N, (C6-C12) aryl- (Cl-C6) alkyl, (C6-   C, 2) aryl- (C2-C6) alkenyl, (C6-C12) aryl- (C2-C6) alkynyl, (C6-C12) aryl- (Cl-   Ce) alkoxy, (C8-C12) aryl- (C2-C6) alkenyloxy and (C6-Cl2) aryl- (C2C6) alkynyloxy, said radical being optionally substituted on the aryl or heteroaryl ring by one or more substituents Z; or Ri represents the group -SO3L in which L represents a   hydrogen atom, (C6-Ci0) aryl- (C1-C3) alkyl, (Cl-C5) alkyl or (C, -   Cs) alkyl substituted by one or more hydroxy or (C1-Cs) alkoxy groups; R2, R3 and R4 independently of one another represent a radical chosen from a hydrogen atom; a halogen atom; (C- Cs) alkoxy; (C1-C25) alkyl; (C1-C25) alkyl substituted by one or more YY groups; (C6-C, 2) aryl- (C1-C6) alkyl; (C3-C10) cycloalkyl optionally substituted by one or more (C1-C6) alkyl groups; (C6-C12) aryl;   hydroxy; hydroxy protected by a W group; (Cl-C7) alkanoyl; (C2-   C7) alkanoyl substituted with one or more ZZ groups; (C7-   C13) arylcarbonyl; (C3-C10) optionally substituted cycloalkyl-carbonyl   on the cycloalkyl part by one or more (C1-C6) alkyl; carboxy; (C2-   C7) alkoxycarbonyl; (C6-C12) aryloxy-carbonyl; (C6-C12) aryl- (Cl-C6) -   alkoxycarbonyl; nitro; a group of formula Il R6 Ns, 1 -N \ II R7   (in which R6 and R7 independently represent a radical chosen from a hydrogen atom, (C, -C6) alkyl, (C6-C12) aryl- (C1-C6) alkyl,   (C3-Clo) cycloalkyl, (C6-C12) aryl, (Cl-C7) alkanoyl, (C6-C, 2) aryl- (C1C6) -   alkanoyl, (C6-C12) aryl-carbonyl and (C2-C7) alkoxycarbonyl or else R6 and R7 form together with the nitrogen atom which carry them a 5 to 10-membered heterocycle optionally comprising 1 to 3 additional endocyclic heteroatoms chosen among N, O and S, said heterocycle being   optionally substituted by one or more groups chosen from (C, -   C6) alkyl, (C1-C7) alkanoyl, (C3-C7) alkenylcarbonyl, (C3-C7) -   alkynylcarbonyl and (C6-C12) aryl-carbonyl); and a group of formula III: R'6 -X 6 III -NR 6 \   R '7 (in which R'6 and R'7 are independently selected from a hydrogen atom, (C1-C6) alkyl, (C6-C12) aryl- (C1-C6) alkyl, (C3Clo) cycloalkyl and ( C6-C12) aryl; or else R'6 and R'7 together with the nitrogen atom which carry them form a 5 to 10-membered heterocycle optionally comprising 1 to 3 additional endocyclic heteroatoms chosen from N, O and S, said heterocycle being optionally substituted by one or more groups chosen from (C, - C6) alkyl, (C, -C7) alkanoyl, (C3-C7) alkenylcarbonyl, (C3-C7) alkynylcarbonyl and (C6-C12) aryl-carbonyl ); or R4 and R5 together form a (C1-C4) alkylenedioxy group; or   R5 represents a hydrogen atom, a group (C1-   C2s) alkyl, (C6-C12) aryl- (C1-C6) alkyl, (C3-Co10) cycloalkyl or (C3-   C1) cycloalkyl substituted with one or more (C1-C6) alkyl; n is an integer between 1 and 10; Ar is a radical chosen from (C6-C12) 10-membered aryl or heteroaryl comprising from 1 to 5 endocyclic heteroatoms chosen from O, N and S, said radical being substituted by one or more nitro or -NHRa groups, Ra representing (C1 -C4) optionally substituted alkyl   by nitro; (C2-C5) alkylcarbonyl optionally substituted by nitro; (Cl-   (C4) alkylsulfonyl optionally substituted by nitro; allyl or benzyl; Y represents (C6-Cl2) aryl, carboxy, (C2-C6) alkoxycarbonyl or (C6-C12) aryl- (C1-Cs) alkoxy-carbonyl; Z represents (C1-C5) alkyl optionally substituted by one or more halogen atoms, (C1C5) alkoxy, a halogen atom, an amino group, (C, - C5) alkylamino, di- (C1-C5) alkylamino , nitro, cyano,   hydroxy or -CONR2 o R is (C1-C5) alkyl or (C6-C12) aryl.   YY represents hydroxy; hydroxy protected by a W group; (C1-C7) alkanoyl optionally substituted by one or more ZZ groups; (C3C7) alkenylcarbonyl optionally substituted by one or more ZZ groups; (C3-C7) alkynylcarbonyl optionally substituted by one or more ZZ groups; (C6-C12) aryl-carbonyl; (C3-CI0) cycloalkylcarbonyl   optionally substituted by one or more (Cl-C6) alkyl; carboxy; (C2-   C7) alkoxycarbonyl; (C6-C12) aryloxy-carbonyl; (C6-C12) aryl- (C1-C6) -   alkoxy-carbonyl; hydroxyimino; hydroxyimino in which the hydroxy group is protected by a W group; a group of formula II; or a group of formula III; groups II and III being as defined above;   ZZ represents carboxy, (C2-C7) alkoxycarbonyl or (C6-   C12) aryl; W represents (Cl-C6) alkyl; (Cl-C6) alkyl substituted by one or more ZZ groups; (Cl-C7) alkanoyl optionally substituted by one or more ZZ groups; (C3-C7) alkenylcarbonyl optionally substituted with one or more ZZ77 groups; (C3-C7) alkynylcarbonyl   optionally substituted by one or more groups 77ZZ; (C6-C, 2) aryl-   carbonyl; (C2-C7) alkoxycarbonyl; (C6-C12) aryloxy-carbonyl; sulfo; or a group of formula III as defined above, said process comprising (i) thermal cyclization of a compound of formula IV R2 R1-CO-0 IV R I R3 "0 (CH2) n-- Ar R4   in which Ri, R2, R3, R4, R5, Ar and n are as defined qi-   above for I, it being understood that the functions, present in these substituents, which are liable to be degraded by heat are protected beforehand; and (ii) where applicable, deprotection of the protected functions   for the implementation of step (i).   2. Method according to claim 1, characterized in that the compound of formula I prepared is such that: Ri represents (C1-Clo) alkyl; R5 represents (Cl-Co) alkyl; n represents 1, 2 or 3; and Ar represents phenyl or naphthyl, substituted in para and / or meta positions by one or more nitro groups or -NHRa, Ra   representative (Cl-C4) alkyl optionally substituted by nitro; (C2-   Cs) alkylcarbonyl optionally substituted with nitro; (ClC4) alkylsulfonyl   optionally substituted with nitro; allyl or benzyl.   3. Method according to any one of the claims   above, characterized in that the compound of formula I prepared is such that: R. represents (Cl-C4) alkyl;   R2, R3 and R4 represent a hydrogen atom or (C, -   C4) alkyl; R5 represents (C1-C4) alkyl; n represents 1; and Ar represents phenyl substituted with a nitro group.   4. Method according to any one of the claims   above, characterized in that the following compound of formula I is prepared: AcO (R R 0 2 oN O02 R4. in which R2, R3, R4 and R5 are as defined above to claim 1.   5. Method according to any one of the claims   above, characterized in that the thermal cyclization is carried out at a temperature between 130 and 200 C, preferably between 150 and 190 C.   6. Method according to any one of the claims   above, characterized in that the thermal cyclization is carried out in a polar solvent in the presence of an aromatic tertiary amine. 7. Method according to claim 6, characterized in that the   solvent is chosen from dimethylformamide, dimethylsulfoxide, N-   methylpyrrolidone and hexamethylphosphorotriamide of formula [(CH3) 2N] 3PO.   8. Method according to one of claims 6 or 7,   characterized in that the tertiary amine has the formula: / Ti NT T3 in which T, T2 and T3, identical or different, are chosen from (C1C4) alkyl and (C6-Cl2) aryl optionally substituted by one or more halogen, (C1-C4) alkyl or (Cl-C4) alkoxy, it being understood that at least one substituent among Tl, T2 and T3 represents (C6-Cl2) aryl possibly substituted.   9. Method according to claim 8, characterized in that the aromatic tertiary amine is a derivative of aniline such as diethylaniline.   10. Method according to any one of claims 6 to   9, characterized in that the concentration of the compound of formula IV is between 0.5 and 1.5 mol / i.   11. Method according to any one of claims 6 to   10, characterized in that the reaction medium comprises from 5 to 15% in   weight of the aromatic tertiary amine, preferably 10% by weight.   12. Method according to any one of claims   above, characterized in that the compound of formula IV is obtained by addition of a propargyl derivative of formula V: \ Xh VX (CH2) nO-Ar in which Rs and Ar are as defined for I in claim 1 and X is a leaving group, on a phenol of formula VI: R2 R1 -CO- VI R3 OH   R4 13. Method according to claim 12, characterized in that X is chosen from a halogen atom, a group of formula -O-SO2-A1 and a group of formula -O-CO-A1 in which A1 represents trifluoromethyl; (Cl-C4) alkyl; (C6-C12) aryloxy optionally substituted by (C, C4) alkyl. (C1-C4) alkoxy; (Cl-C4) alkylamino or (C6-Cl2) arylamino   optionally substituted by (Cl-C4) alkyl.   14. Method according to any one of claims 12   and 13, characterized in that the addition of compound V to compound VI is carried out in a polar solvent, at a temperature between -50 C and room temperature, in the presence of a strong base and a copper catalyst.   15. The method of claim 14, characterized in that the solvent is dimethylformamide or acetonitrile, the base is a non-quaternizable tertiary amine such as diisopropylethylamine, and the copper-based catalyst is CuCl or CuCl2, the molar ratio of compound V to compound Vl being between 1 and 3 and the molar ratio of the non-quaternizable tertiary amine to compound VI being between 1 and 1.3. 16. Compound of formula IV R 1R2 R IV R3 -OC (CH2) n- O- Ar R4   in which Rj, R2, R3, R4, R5, n and Ar are as defined to claim 1.   17. Use of a compound of formula I prepared according to the   method of any one of the preceding claims in the   synthesis of a compound of formula VII R2 R1-CO-O x Rs R R3 0 X \ (CH2) nOU-CH2 N-Rio VII R4 o in which R1, R2, R3, R4, R5 and n are as defined for I in claim 1;   U is a divalent radical chosen from a group (d6-   C12) aryl and a 5-10 membered heteroaryl comprising 1 to 5 endocyclic heteroatoms selected from O, S and N; R9 and Rio, identical or different, are independently chosen from a hydrogen atom, a (Ci-Cio) alkyl group and a (Ci-Clo) alkyl group   substituted by one or more radicals chosen from hydroxy, (Ci-   C5) alkoxy, (C6-C12) aryl, (C1-C23) alkanoyloxy, (C3C23) alkenylcarbonyloxy, (C3-C23) alkynylcarbonyloxy, (Cl-C23) alkanoyloxy substituted by one or more substituents Y, (C3-C23) alkenylcarbonyloxy substituted by one or more substituents Y, (C3-C23) alkynylcarbonyloxy substituted by one or more substituents Y, (C6-Cl2) aryl-carbonyloxy, heteroarylcarbonyloxy in which the heteroaryl nucleus contains from 5 to 10 members and from 1 to 5 endocyclic heteroatoms chosen from O, S and N, a group of formula - COOR11 and a group of formula -CONR12R13; Y is as defined in claim 1;   R1 represents a hydrogen atom, (C6-C12) aryl- (C1-   C3) alkyl, or (C1-C5) alkyl optionally substituted one or more times by hydroxy or (C1-C5) alkoxy; R12 and R13, identical or different, are independently chosen from a hydrogen atom and (Cî-Cs) alkyl, or else R12 and R13, together with the nitrogen atom which carries them, represent a heterocycle of 5 to 7 links, said heterocycle possibly comprising 1 or 2 additional endocyclic heteroatoms chosen from O, S and N and   which can be substituted on the additional nitrogen atom by (Cl-   Cs) alkyl, (C1-Cs) alkanoyl, (C3-Cs) alkenylcarbonyl or (C3- Cs) alkynylcarbonyl. i