FR2536396A2 - 8-Haloalkyl-4H-1-benzopyran-4-ones and methods of preparation - Google Patents

8-Haloalkyl-4H-1-benzopyran-4-ones and methods of preparation Download PDF

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FR2536396A2
FR2536396A2 FR8219641A FR8219641A FR2536396A2 FR 2536396 A2 FR2536396 A2 FR 2536396A2 FR 8219641 A FR8219641 A FR 8219641A FR 8219641 A FR8219641 A FR 8219641A FR 2536396 A2 FR2536396 A2 FR 2536396A2
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phenyl
hydrogen
halogen
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Philippe Briet
Jean-Jacques Berthelon
Francois Collonges
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Merck Sante SAS
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LIPHA SAS
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
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    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
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    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
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    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/34—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only
    • C07D311/36—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only not hydrogenated in the hetero ring, e.g. isoflavones
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    • C07—ORGANIC CHEMISTRY
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    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

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Abstract

The improvement relates to 8-haloalkyl-4H-1-benzopyran-4-ones. The compounds are represented by the formula: in which AR is hydrogen, a phenyl radical, a phenyl radical which is substituted by a lower alkyl radical, a lower alkoxy radical or a halogen; a thienyl, pyridyl, furyl, naphthyl, alkyl, cycloalkyl or aralkyl radical, X is a halogen and Y hydrogen, a lower alkyl radical, an alkoxy radical or a halogen, R1 is hydrogen, a phenyl or alkoxy radical. They can be used as intermediate industrial products in the synthesis of pharmaceutical products and pesticides.

Description

Le présent perfectionnement concerne des haloalkyl-8-4H-[1]-benzo- pyranones-4, leur préparation, et les nouveaux intermédiaires utilisables dans celle-ci.The present improvement relates to haloalkyl-8-4H- [1] -benzo-pyranones-4, their preparation, and the new intermediates which can be used therein.

Les haloalkyl-8-4H-[1]- benzopyranones-4 sont représentées par la formule

Figure img00010001

dans laquelle AR est l'hydrogène, un radical phényle, phényle substitue par un radioal alkyle inférieur, alkoxy inférieur ou un ahogène, un radical thényle, pyridyle, furyle, naphtyle, alkyle, cycloalkyle ou aralkyle, X est un balogène et Y l'hydrogène, un radical alkyle inférieur, alkoxy ou un halogènes R1 est lhydrogène ou un radical phényle ou alkoxy.The haloalkyl-8-4H- [1] - benzopyranones-4 are represented by the formula
Figure img00010001

in which AR is hydrogen, a phenyl radical, phenyl substituted by a radioalk lower alkyl, lower alkoxy or an ahogen, a thényl, pyridyl, furyl, naphthyl, alkyl, cycloalkyl or aralkyl radical, X is a balogen and Y l ' hydrogen, a lower alkyl radical, alkoxy or a halogen R1 is hydrogen or a phenyl or alkoxy radical.

Ces composés comme ceux du brevet principalssont utilisables en tant que produits industriels intermédiaires de synthèse, en particulier dans le domaine des pesticides et des produits pharmaceutiques, tels les acides [oxo-4-4H-[1]-benzopyran-8-yl] alcanoïques et leurs dérivés. Les bromoalkyl-8-4H-[1]-benzopyranones-4 constituent une classe particulièrement intéressante de formule

Figure img00010002

dans laquelle R1, AR et Y ont les mêmes significations que précédemment.These compounds, like those of the main patent, can be used as industrial intermediate synthesis products, in particular in the field of pesticides and pharmaceutical products, such as [oxo-4-4H- [1] -benzopyran-8-yl] alkanoic acids. and their derivatives. The bromoalkyl-8-4H- [1] -benzopyranones-4 constitute a particularly interesting class of formula
Figure img00010002

in which R1, AR and Y have the same meanings as before.

Les haloalkylbenzopyranones répondant aux formules I et II peu- vent être préparées suivant l'une des deux méthodes décrites dans le brevet principal avec de boni rendements.The haloalkylbenzopyranones corresponding to formulas I and II can be prepared according to one of the two methods described in the main patent with improved yields.

Le schéma réactionnel de la méthode A a été donné pour la bromométhyl-8-cyclohexyl-2-4H-[1]-benzopyranone-4
Méthode A

Figure img00020001
The reaction scheme of method A was given for bromomethyl-8-cyclohexyl-2-4H- [1] -benzopyranone-4
Method A
Figure img00020001

Selon la séquence préparative de la méthode Â, on traite dans un premier stade, un produit de départ de formule

Figure img00020002

dans laquelle Y est l'hydrogène, un radical alkyle inférieur, alkoxy, un halogène, R1 est l'hydrogène ou phényle et R2 l'hydrogène ou un radical aikyle inférieur, par le polyoxyméthylène en présence d'acide chlorhydrique concentré, en vue d'obtenir une chlorométhylphénylcétone de formule
Figure img00020003

dans laquelle R1, R2 et Y ont les mêmes significations que précédemment. According to the preparative sequence of the method Â, a starting material is treated in a first stage
Figure img00020002

in which Y is hydrogen, a lower alkyl radical, alkoxy, a halogen, R1 is hydrogen or phenyl and R2 hydrogen or a lower alkyl radical, by polyoxymethylene in the presence of concentrated hydrochloric acid, with a view to d '' get a chloromethylphenyl ketone of formula
Figure img00020003

in which R1, R2 and Y have the same meanings as before.

Dans le deuxième stade, l'intermédiaire ohîcrométhylé (IV) est condensé avec le méthanol et ainsi transformé en intermédiaire méthoxyméthyléde formule

Figure img00030001
In the second stage, the ohimcromethylated intermediate (IV) is condensed with methanol and thus transformed into a methoxymethylated intermediate of formula
Figure img00030001

Dans un troisième stade, l'intermédiaire obtenu est conden- sé avec un ester de formule AR-COOEt dans laquelle AR est un radical phényle, phényle substitué - par un radical alkyle inférieur, alkoxy inférieur ou un halogène - un radical thényle ou pyridyle, furyle, naphtyle, alkyle, cycloalkyle, arallyle, et transformé en propanedio- nes -1,3 de formule

Figure img00030002

dans laquelle AR, R1, R2 et Y ont les mêmes significations que précedemment.In a third stage, the intermediate obtained is condensed with an ester of formula AR-COOEt in which AR is a phenyl radical, phenyl substituted - by a lower alkyl, lower alkoxy or halogen radical - a thenyl or pyridyl radical, furyl, naphthyl, alkyl, cycloalkyl, arallyl, and transformed into propane-1,3 formula
Figure img00030002

in which AR, R1, R2 and Y have the same meanings as before.

Dans le dermier stade, les baloalkyl-8-4H-[1]-benzopyranones-4 I, dans la formule desquels X désigne le brome, sont obtenus par cyclisation des propanediones-1,3, de formule VI on présence d'acide bromhydrique. In the last stage, the baloalkyl-8-4H- [1] -benzopyranones-4 I, in the formula of which X denotes bromine, are obtained by cyclization of propanediones-1,3, of formula VI in the presence of hydrobromic acid .

Dans le cas où dans la formule de l'intermédiaire chloromé- thylé de formule IV, Y est un substituant, et plus particulièrement en position 5, le produit intermédiaire chlorométhylé est obtenu dans de bonnes conditions. Cependant pour Y = H et R2 = H, Roberto TRAVE (Gazz. Chim. Ital. 80 ; 502-9 (1950) indique une chlorométhylation en position 5 ou une dichlorométhylation en 3-5.Au contraire, la demen- deresse a montré qu'il est possible d'isoler le produit répondant à la formule IV avec Y = R2 = H qui après transformation en produit V et
VI donne accès au composé de formule i Toutefois, le manque de sélectivité au niveau de la chlorométhylation ainsi que certaines difficul- tés d'isolement ont conduit la demanderesse à rechercher un procédé sélectif, pouvant être mis en oeuvre sur des quantités importantes. In the case where in the formula of the chloromethylated intermediate of formula IV, Y is a substituent, and more particularly in position 5, the chloromethylated intermediate product is obtained under good conditions. However for Y = H and R2 = H, Roberto TRAVE (Gazz. Chim. Ital. 80; 502-9 (1950) indicates chloromethylation in position 5 or dichloromethylation in 3-5. On the contrary, the applicant has shown that it is possible to isolate the product corresponding to formula IV with Y = R2 = H which after transformation into product V and
VI gives access to the compound of formula i However, the lack of selectivity in terms of chloromethylation as well as certain isolation difficulties have led the applicant to seek a selective process, which can be implemented on large quantities.

Méthode B

Figure img00040001
Method B
Figure img00040001

La préparation du produit de formule VII a été décrite dans le bre- vet principal. La condensation de cet intermédiaire de synthèse avec une cétone de formule AR - C - CH2 dans laquelle AR et ont la o même signification que précédemment, conduit à une propanedione-1,3 de formule IV, qui par cyclisation en présence d'acide bromhydrique conduit à une bromoalkyl-8-4H-[1]-benzopyranone-4 de formule II. The preparation of the product of formula VII has been described in the main patent. The condensation of this synthetic intermediate with a ketone of formula AR - C - CH2 in which AR and have the same meaning as above, leads to a 1,3-propanedione of formula IV, which by cyclization in the presence of hydrobromic acid leads to a bromoalkyl-8-4H- [1] -benzopyranone-4 of formula II.

Dans une troisième séquence préparative et en particulier dans le cas où AR = R1 = phényle ou AR = H et R1 = phényle, la demanderesse a montré qu'il est possible d'accéder au produit répondant à

Figure img00040002
In a third preparatory sequence and in particular in the case where AR = R1 = phenyl or AR = H and R1 = phenyl, the applicant has shown that it is possible to access the product corresponding to
Figure img00040002

Les produits intermédiaires nouveaux dans la préparation des haloalkyl-8-4H-[1]-benzopyranone-4 font partie de l'invention. The intermediate products which are new in the preparation of haloalkyl-8-4H- [1] -benzopyranone-4 form part of the invention.

Il est donné ci-après des exemples qui illustrent l'inven- tion à titre non limitatif. Examples are given below which illustrate the invention without implied limitation.

Exemple 1 : (Bromométhyl)-8-(méthoxy-3-phényl)-2-4H-[1]-benzopyranone-4 (formule 1) C17H13BrO3. PM = 345,20.Example 1: (Bromomethyl) -8- (methoxy-3-phenyl) -2-4H- [1] -benzopyranone-4 (formula 1) C17H13BrO3. MW = 345.20.

Préparé selon l'exemple 8 du brevet principal à partir de 57,1 g (0,38 mole) de (méthoxy-3-phényl)-1-éthanone, et de 120 g (0,571 mole) de méthoxy-2-méthoxyméthyl-3-benzoate de méthyle. Poide obtenu : 49,8 g (Rdt : 38%). PFk = 160 C (toluène-hexene), IR : @c = O = 1655 cm-1. Prepared according to Example 8 of the main patent from 57.1 g (0.38 mole) of (methoxy-3-phenyl) -1-ethanone, and 120 g (0.571 mole) of methoxy-2-methoxymethyl- Methyl 3-benzoate. Weight obtained: 49.8 g (Yield: 38%). PFk = 160 C (toluene-hexene), IR: @c = O = 1655 cm-1.

3MN (COCl3), 3 H à 3,95 (singulet), 2 H à 4,8 (singulet) i H à 6,8 (singulet) 6 H de 7,0 à 7,9 (multiplet), 1 H à 8,2 (doublet de doublet, J1 = 8 Hz; J2 = 2 Hz). 3MN (COCl3), 3 H to 3.95 (singlet), 2 H to 4.8 (singlet) i H to 6.8 (singlet) 6 H from 7.0 to 7.9 (multiplet), 1 H to 8.2 (doublet of doublet, J1 = 8 Hz; J2 = 2 Hz).

Exemple 2 :
Hydroxy-3-méthyl-8-phényl-2-4H-[1]-benzopyranone-4 (formule 2)
C16H12O3. PM = 252,27.Example 2:
Hydroxy-3-methyl-8-phenyl-2-4H- [1] -benzopyranone-4 (formula 2)
C16H12O3. MW = 252.27.

A une solution de 90,1 g (0,6 mole) d'(hydroxy-2-méthyl-3-phényl)-1éthanone et de 63,7 g (0,6 mole) de benzaldéhyde dans 1,2 litre d'éthanol, on ajoute à température inférieure à 30 C une solution de 81,6 g (2,04 moles) de pastilles de soude dans 163 ml d'eau. On agite une nuit à température ambiantes puis on ajoute 204 ml d'une solution de soude aqueuse à 20 , dilués avec 4 1 d'éthanol. On refroidit au bain de glace et on ajoute rapidement 825 ml d'une solution d'eau oxygénée à 15 %. On agite 4 heures à 25 C puis on aoidifie aveo H2SO4 30 % et.To a solution of 90.1 g (0.6 mole) of (hydroxy-2-methyl-3-phenyl) -1ethanone and 63.7 g (0.6 mole) of benzaldehyde in 1.2 liters of ethanol, a solution of 81.6 g (2.04 moles) of sodium hydroxide tablets in 163 ml of water is added at a temperature below 30 ° C. The mixture is stirred overnight at ambient temperature and then 204 ml of a 20% aqueous sodium hydroxide solution, diluted with 4 l of ethanol, are added. Cool in an ice bath and quickly add 825 ml of a 15% hydrogen peroxide solution. Agitation is carried out for 4 hours at 25 ° C. and then aoidified with H2SO4 30% and.

on verse sur un mélange eau-giaco (15 1). On laisse reposer une nuit, on filtre le préoipitéobtenn que l'on reoristallise dans le toluène.poured onto a water-giaco mixture (15 l). It is left to stand overnight, the pre-oipite is obtained which is re-distributed in toluene.

Poids obtenu 18,3 g (Rdt : 12 %), PFK = 180 C. IR : @ OH = 3300 cm-1, # c = O (pyrone) = 1625 cm-1 (épaulement à 1640 cm-1). RMN (CDCl3) 3 H à 2,66 (singulet), 1 H à 6,7 (échangeable avec D2O), 5 H dé 7,2 à 7,7 (multiplet), 3 H de 8,0 à 8,5 (multiplet).Weight obtained 18.3 g (Yield: 12%), PFK = 180 C. IR: @ OH = 3300 cm-1, # c = O (pyrone) = 1625 cm-1 (shoulder at 1640 cm-1). NMR (CDCl3) 3 H at 2.66 (singlet), 1 H at 6.7 (exchangeable with D2O), 5 H from 7.2 to 7.7 (multiplet), 3 H from 8.0 to 8.5 (byte).

Exemple 3 :
Méthoxy-3-méthyl-8-phényl-2-4H-[1]-benzopyranone-4 (formule 3)
C17H1403. PM = 266,30
On chauffe à reflux pendant 16 heures un mélange de 18 g (0,071 mole) d'hydroxy-3-méthyl-8-phényl-2-4H-[1]-benzopyranone-4, 9,86 g (0,071 mole) de carbonate de potassium, 100 ml d'acétone et 9,9 g (0,078 mole) de diméthylsulfate. Puis on filtre à chaud, on refroidit le filtrat, on filtre le précipité obtenu que l'on recristallise dans l'acétone. Example 3:
Methoxy-3-methyl-8-phenyl-2-4H- [1] -benzopyranone-4 (formula 3)
C17H1403. PM = 266.30
A mixture of 18 g (0.071 mole) of hydroxy-3-methyl-8-phenyl-2-4H- [1] -benzopyranone-4, 9.86 g (0.071 mole) of carbonate is heated at reflux for 16 hours. potassium, 100 ml acetone and 9.9 g (0.078 mole) dimethyl sulfate. Then filtered hot, the filtrate is cooled, the precipitate obtained is filtered and recrystallized from acetone.

Poids obtenu : 14,5 g (Rdt : 76 %). PFK = 143 C. IR : @ c = O (pyrone) = 1645 cm-1. RMN (CDCl3), 3 H à 2,6 (singulet) 3 H à 3,97 (singulet) 5 H de 7,1 à 7,7 (multiplet), 3 H de 7,9 à 8,4 (multiplet).Weight obtained: 14.5 g (YId: 76%). PFK = 143 C. IR: @ c = O (pyrone) = 1645 cm-1. NMR (CDCl3), 3 H to 2.6 (singlet) 3 H to 3.97 (singlet) 5 H from 7.1 to 7.7 (multiplet), 3 H from 7.9 to 8.4 (multiplet) .

Exemple 4 : (Bromométhyl)-8-méthoxy-3-phényl-2-4H-[1]-benzopyranone-4 (formule 4)
C17H13BrO3 PM = 345,20.Example 4: (Bromomethyl) -8-methoxy-3-phenyl-2-4H- [1] -benzopyranone-4 (formula 4)
C17H13BrO3 PM = 345.20.

On chauffe à reflux pendant 8 heures sous irradiation ultra-violette un mélange de 11 g (0,041 mole) de méthoxy-3-méthyl-8-phényl-2-4H-[1] benzopyranone-4, 8,03 g (0,045 mole) de N-bromosuceinimide, 350 ml de tétrachlorure de carbone et 0,2 g d'azobisisobutyronitrile. On filtre à chaud, et on laisse le filtrat une nuit au réfrigérateur. On filtre, lave à l'eau et recristallise dans l'acétate d'éthyle. Poids obtenu m 6,2 g (Rdt : 43 %). PFK = 157 C. IR : @ c = O = 1630 cm-1. RMN (CDCl3) 3 H à 3,95 (singulet) 2 H à 4S83 (singulet) 5 H de 7,2 à 7,9 (mul- tiplet), 3 H de 8,1 à 8,5 (multiplet).A mixture of 11 g (0.041 mole) of methoxy-3-methyl-8-phenyl-2-4H- [1] benzopyranone-4, 8.03 g (0.045 mole) is heated at reflux for 8 hours under ultraviolet irradiation. ) of N-bromosuceinimide, 350 ml of carbon tetrachloride and 0.2 g of azobisisobutyronitrile. Filtered hot, and the filtrate is left overnight in the refrigerator. Filtered, washed with water and recrystallized from ethyl acetate. Weight obtained m 6.2 g (Yield: 43%). PFK = 157 C. IR: @ c = O = 1630 cm-1. NMR (CDCl3) 3 H at 3.95 (singlet) 2 H at 4S83 (singlet) 5 H from 7.2 to 7.9 (multiplet), 3 H from 8.1 to 8.5 (multiplet).

Exemple 5 : (Chlorométhyl-3-hydroxy-2-méthoxy-5-phényl)-1-éthanone (formule 5)
C10H11ClO3. PM = 214,65.Example 5: (Chloromethyl-3-hydroxy-2-methoxy-5-phenyl) -1-ethanone (formula 5)
C10H11ClO3. MW = 214.65.

On chauffe .7 heures à 50 C un mélange de 47 g (0,283 mole) d'(hydroxy- 2-méthoxy-5-phéyl)-1-éthanone, 8,5 g (0,283 mole) de polyoxyméthylène et 215 ml d'acide chlorhydrique concentré. Après refroidissement, on reprend au benzène, filtre un insoluble, lave a neutralité, évapore le benzène sous vide, et recristallise le solide obtenu dans l'hexane.A mixture of 47 g (0.283 mole) of (hydroxy-2-methoxy-5-pheyl) -1-ethanone, 8.5 g (0.283 mole) of polyoxymethylene and 215 ml of concentrated hydrochloric acid. After cooling, the residue is taken up in benzene, filtering an insoluble material, washing to neutrality, evaporating the benzene under vacuum, and recrystallizing the solid obtained from hexane.


Poids obtenu : 37,1 g (Rdt , 61%). PFK = 71 C. IR : @ c = O = 1650cm-1
RMN (CDCl3), 3 @ à 2,63 (singulet) 3 H à 3,85 (singulet) 2 H à 4,7 (singulet), 2 H de 7,2 à 7,4 (multiplet), 1 H à 12,6 (singulet).
Weight obtained: 37.1 g (yield, 61%). PFK = 71 C. IR: @ c = O = 1650cm-1
NMR (CDCl3), 3 @ at 2.63 (singlet) 3 H at 3.85 (singlet) 2 H at 4.7 (singlet), 2 H from 7.2 to 7.4 (multiplet), 1 H at 12.6 (singlet).

Exemple 6 : (Hydroxy-2-méthoxy-5-méthoxyméthyl-3-phéyl)-1-éthanone (formule 6)
C11H14O4. PM = 210,23.Example 6: (Hydroxy-2-methoxy-5-methoxymethyl-3-pheyl) -1-ethanone (formula 6)
C11H14O4. MW = 210.23.

Préparé selon l'exemple 2 du brevet principal à partir de 36,8 g (0,171 mole) de (chlorométhyl-3-hydroxy-2-méthoxy-5-phényl)-1-éthanone
Poids obtenu : 24,7 g (Rdt : 69%). PR0,3 mmHg = 110-114 C. IR : @ c =
O = 1650 cm-1. @ OH = 3000 à 3600 cm-1. RMN (CDCl3), 3 H à 2,57 (singulet), 3 H à 3,42 (singulet), 3 H à 3,77 (singulet) 2 H à 4,5 (singulet), 1 H à 7,1 (douhlet, J = 3 Hz), 1 H à 7,25 (doublet, J = 3 Hz) 1 H à 12,0 (singulet).Prepared according to Example 2 of the main patent from 36.8 g (0.171 mole) of (chloromethyl-3-hydroxy-2-methoxy-5-phenyl) -1-ethanone
Weight obtained: 24.7 g (Yield: 69%). PR0.3 mmHg = 110-114 C. IR: @ c =
O = 1650 cm-1. @ OH = 3000 to 3600 cm-1. NMR (CDCl3), 3 H at 2.57 (singlet), 3 H at 3.42 (singlet), 3 H at 3.77 (singlet) 2 H at 4.5 (singlet), 1 H at 7.1 (douhlet, J = 3 Hz), 1 H at 7.25 (doublet, J = 3 Hz) 1 H at 12.0 (singlet).

Exemple 7 : (Hydroxy-2-méthoxy-5-méthoxyméthyl-3-phényl)-1-phényl-3-propanadione1,3 (formule 7) C18H1805. PM = 314,34. Example 7: (Hydroxy-2-methoxy-5-methoxymethyl-3-phenyl) -1-phenyl-3-propanadione1,3 (formula 7) C18H1805. MW = 314.34.

On lave 3 fois à l'hexane 81,6 g (1,7 mole) d'une suspension à 50% d'hydrure de sodium dans l'huile. On place l'hydrure en Suspension dans 600 ml de dioxane anhydre, on chauffe à 800C et on ajoute goutte à goutte en 1h30 une solution de 114 g (0,542 mole) d'(hydroxy-2- méthoxy-5-méthoxyméthyl-3-phényl)-1-éthanone et de 122 g (0,813 mole) de benzoate d'éthyle dans 150 ml de dioxane anhydre. On chauffe ensuite 3 h à 80 C refroidit, dilue avec 3,5 l d'hexane, filtre, lave le solide à lthexane. Puis on ajoute ce solide par portions dans un më- lange agité énergiquement de 1 1 d'eau.., 1 1 d'acide acétique et 1,51 de chloroforme. On décante, extrait au chloroforme, lave à neutralité, sèche et évapore sous vide.On obtient 200 g d'une huile qui est utilisée sans purification supplémentaire dans l'étape suivante.81.6 g (1.7 mole) of a 50% suspension of sodium hydride in oil are washed 3 times with hexane. The hydride is placed in suspension in 600 ml of anhydrous dioxane, the mixture is heated to 800C and a solution of 114 g (0.542 mole) of (hydroxy-2-methoxy-5-methoxymethyl-3-) is added dropwise over 1 hour 30 minutes. phenyl) -1-ethanone and 122 g (0.813 mole) of ethyl benzoate in 150 ml of anhydrous dioxane. Then heated 3 h at 80 C cooled, diluted with 3.5 l of hexane, filter, wash the solid with lthexane. Then add this solid in portions in a vigorously stirred mixture of 1 L of water, 1 L of acetic acid and 1.5 L of chloroform. Decanted, extracted with chloroform, washed to neutrality, dried and evaporated in vacuo. 200 g of an oil are obtained which is used without further purification in the next step.

Exemple 8 :
Bromométhyl-8-méthoxy-6-phényl-2-4H-[1]-benzopyranone-4 (formule 8)
C17H13BrO3. PM = 345,20.Example 8:
Bromomethyl-8-methoxy-6-phenyl-2-4H- [1] -benzopyranone-4 (formula 8)
C17H13BrO3. MW = 345.20.

Préparé selon l'exemple 4 du brevet principal à partir de l'(hydroxy- 2-méthoxy-5-méthoxyméthyl-3-phényl)-1-phényl-3-propanedione-1,3 obtenue ci-dessus. Poids obtenu : 112,8 g (Rdt global : 60 %). PFK = 1940C IR : @ c = O (pyrone) = 1650 cm-1. RMN (IMSO), 3 H à 3,9 (singulet), 2 H à 5,1 (singulet) 8 H de 7,0 à 8,3 (multiplet).Prepared according to Example 4 of the main patent from (hydroxy-2-methoxy-5-methoxymethyl-3-phenyl) -1-phenyl-3-propanedione-1,3 obtained above. Weight obtained: 112.8 g (overall yield: 60%). PFK = 1940C IR: @ c = O (pyrone) = 1650 cm-1. NMR (IMSO), 3 H to 3.9 (singlet), 2 H to 5.1 (singlet) 8 H from 7.0 to 8.3 (multiplet).

Exemple 9 : (Bromométhyl)-8-(diméthoxy-3,4-phényl)-2-4H-[1]-benzopyranone-4 (formule 9). C18H15BrO4. PM= 375,23.Example 9: (Bromomethyl) -8- (dimethoxy-3,4-phenyl) -2-4H- [1] -benzopyranone-4 (formula 9). C18H15BrO4. MW = 375.23.

Préparé selon l'exemple 8 du brevet principal à partir de 68,6 g (0,38 mole) de (diméthoxy-3,4-phényl)-1-éthanone et de 120 g (0,571 mole) de méthoxy-2-méthoxyméthyl-3-benzoate de méthyle. Poids obtenu t 82 g (Rdt : 57 %). PFK = 185 C(toluène-herane). IR : @ c = O (pyrone) = 1630 cm-1. RMN (CDCl3) 3 h à 3,97 (singulet), 3 h à 4,0 (singulet), 2 H à 4,8 (singulet), 1 H à 6,8 (singulet) 5 H de 6,9 à 7,9 (multiplet), 1 H à 8,22 (doublet de doublet, J1 = 8 Hz ; J2 = 2 Hz).Prepared according to Example 8 of the main patent from 68.6 g (0.38 mole) of (dimethoxy-3,4-phenyl) -1-ethanone and 120 g (0.571 mole) of methoxy-2-methoxymethyl -Methyl benzoate. Weight obtained t 82 g (Yield: 57%). PFK = 185 C (toluene-herane). IR: @ c = O (pyrone) = 1630 cm-1. NMR (CDCl3) 3 h at 3.97 (singlet), 3 h at 4.0 (singlet), 2 h at 4.8 (singlet), 1 h at 6.8 (singlet) 5 h from 6.9 to 7.9 (multiplet), 1 H at 8.22 (doublet of doublet, J1 = 8 Hz; J2 = 2 Hz).

Exemple 10 :
Diphényl-2,3-méthyl-8-4H-[1]-benzopyranone-4 (formule 10) C22H16O2
PM = 312,37.Example 10:
Diphenyl-2,3-methyl-8-4H- [1] -benzopyranone-4 (formula 10) C22H16O2
MW = 312.37.

On chauffe 7 h entre 170 et 180 C un mélange de 98 g (0,433 mole) d'(hydroxy-2-méthyl-3-phényl)-1-phényl-2-éthanone,98 g (0,433 mole) d'anhydride benzoïque et 62,4 g (0,433 mole) de benzoate de sodium.Heated for 7 h between 170 and 180 C a mixture of 98 g (0.433 mole) of (hydroxy-2-methyl-3-phenyl) -1-phenyl-2-ethanone, 98 g (0.433 mole) of benzoic anhydride and 62.4 g (0.433 mole) of sodium benzoate.

On refroidit, reprend au benzène, lave à l'eau, puis avec une solution aqueuse de bicarbonate de sodium, puis à l'eau On évapore le benzène sous vide et on recristallise le produit obtenu dans le toluène. Poids obtenu : 36,4 g (Rdt : 27%). PFK = 209-210 C. IR : @ c = O = 1630 cm-1
RMN (CDCl3), 3 H à 2,55 (singulet), 12 H de 7,1 à 7,7 (multiplet), 1H à 8,15 (doublet de doublet, J1= 8 Hz ; J2 = 2 Hz).It is cooled, taken up in benzene, washed with water, then with an aqueous solution of sodium bicarbonate, then with water. The benzene is evaporated in vacuo and the product obtained is recrystallized from toluene. Weight obtained: 36.4 g (Yield: 27%). PFK = 209-210 C. IR: @ c = O = 1630 cm-1
NMR (CDCl3), 3 H at 2.55 (singlet), 12 H from 7.1 to 7.7 (multiplet), 1 H to 8.15 (doublet of doublet, J1 = 8 Hz; J2 = 2 Hz).

Exemple 11 :
Bromométhyl-8-diphényl-2,3-4H-[1]-benzopyranone-4 (formule 11)
C22H15BrO2. PI = 391,27. Example 11:
Bromomethyl-8-diphenyl-2,3-4H- [1] -benzopyranone-4 (formula 11)
C22H15BrO2. PI = 391.27.

Préparé selon l'exemple 4 à partir de 36 g (0,115 mole) de diphényl2,3-méthyl-8-4H-[1]-benzopyranone-4. Après filtration de la sucoinimide, le filtrat est évaporé sous vide, le solide obtenu est repris à l'eau et filtré. Poids obtenu : 45 g (Rdt quantitatif). PFK = 143-147 C. IR : @ c = O (pyrone) = 1635 cm-1. RMN (CDCl3), 2 H à 4,8 (singu- let), 12 H de 7 à 7,9 (multiplet), 1 H à 8,25 (doublet de doublet,
J1 = 8 Hz, J2 = 2 Hz).Prepared according to Example 4 from 36 g (0.115 mole) of diphenyl2,3-methyl-8-4H- [1] -benzopyranone-4. After filtration of the sucoinimide, the filtrate is evaporated under vacuum, the solid obtained is taken up in water and filtered. Weight obtained: 45 g (quantitative yield). PFK = 143-147 C. IR: @ c = O (pyrone) = 1635 cm-1. NMR (CDCl3), 2 H to 4.8 (singlet), 12 H from 7 to 7.9 (multiplet), 1 H to 8.25 (doublet of doublet,
J1 = 8 Hz, J2 = 2 Hz).

Exemple 12 :
Bromométhyl-8-(naphtyl-2)-2-4H-[1]-benzopyranone-4 (formule 12) C20s13BrO3 . PM = 362,22.Example 12:
Bromomethyl-8- (naphthyl-2) -2-4H- [1] -benzopyranone-4 (formula 12) C20s13BrO3. MW = 362.22.

Préparé selon l'exemple 8 du brevet principal à partir de 105,lg(0,5 mole) de méthoxy-2-méthoxyméthyl-3-benzoate de méthyle et 85,1 g (0,5 mole) de (naphtyl-2)-1-éthanone. Après isolement l'huile brute obtenue est reprise par 600 mi d'acide acétique et 426 ml d'acide bromhydrique à 62 %. Par traitement selon la méthode habituelle on obtient 61 g (Rdt : 30 %). PFG = 190-192 C (toluène). IR t c o O (pyrone) = 1650 cm-1.Prepared according to Example 8 of the main patent from 105.1 g (0.5 mole) of methyl methoxy-2-methoxymethyl-3-benzoate and 85.1 g (0.5 mole) of (naphthyl-2) -1-ethanone. After isolation, the crude oil obtained is taken up in 600 ml of acetic acid and 426 ml of 62% hydrobromic acid. By treatment according to the usual method we obtain 61 g (Yield: 30%). PFG = 190-192 C (toluene). IR t c o O (pyrone) = 1650 cm-1.

Exemple 13 :
Bromométhyl-8(furyl-2)-2-4H-[1]-benzopyranone-4 (formule 13)
C14H9BrO3. PX = 305,13. Example 13:
Bromomethyl-8 (furyl-2) -2-4H- [1] -benzopyranone-4 (formula 13)
C14H9BrO3. PX = 305.13.

Préparé selon l'exemple 8 du brevet principal à partir de 105,1 g (0,5 mole) de méthoxy-2-méthoxyméthyl-3-benzotate de méthyle et 55 g (0,5 mole) de (furyl-2)-1-éthanone. Après isolement de l'huile brute, celle-ci est reprise par 600 ml d'acide acétique et 426 ml d'acide bromhydrique à 62 %. Par traitement selon la méthode habituelle on obtient 23,4 g (Rdt : 15%). PFK = 210 C. IR : @c = O (pyrone) = 1660cm-1.Prepared according to Example 8 of the main patent from 105.1 g (0.5 mole) of methyl methoxy-2-methoxymethyl-3-benzotate and 55 g (0.5 mole) of (furyl-2) - 1-ethanone. After isolation of the crude oil, this is taken up in 600 ml of acetic acid and 426 ml of 62% hydrobromic acid. By treatment according to the usual method, 23.4 g (yield: 15%) are obtained. PFK = 210 C. IR: @c = O (pyrone) = 1660cm-1.

Exemple 14 :
Cyclohexyl-1-(bydroxy-2-méthoxyméthyl-3-phényl)-3-propanedione-1,3 (formule 14). C17H22O4. PM = 290,36.Example 14:
Cyclohexyl-1- (bydroxy-2-methoxymethyl-3-phenyl) -3-propanedione-1,3 (formula 14). C17H22O4. MW = 290.36.

Préparé selon l'exemple 7 à partir de 53,3 g (0,296 mole) d'(hydroxy2-méthoxyméthyl-3-phényl)-1-éthanone et de 92,4 g (0,59 mole) de cyclohexylcarboxylate d'éthyle, mais en chauffant 3 H à reflux (au lieu de 3 H à 800) et en distillant l'huile obtenue après l'évaporation finale. Poids obtenu : 18 g (Rdt : 21 %). PE0,5 mmHg = 140-180 C.Prepared according to Example 7 from 53.3 g (0.296 mole) of (hydroxy2-methoxymethyl-3-phenyl) -1-ethanone and 92.4 g (0.59 mole) of ethyl cyclohexylcarboxylate, but by heating for 3 hours at reflux (instead of 3 hours at 800) and distilling the oil obtained after the final evaporation. Weight obtained: 18 g (Yield: 21%). PE0.5 mmHg = 140-180 C.

Exemple 15 :
Bromométhyl-8-oyolohexyl-2-4H-[1]-benzopyranone-4 (formule 15)
C16H17BrO. PM =321,22.Example 15:
Bromomethyl-8-oyolohexyl-2-4H- [1] -benzopyranone-4 (formula 15)
C16H17BrO. PM = 321.22.

Préparé selon l'exemple 4 du brevet principal à partir de 18 g (0,062 mole) de cyclohexyl-1-(hydroxy-2-méthoxy-méthyl-3-phényl)-3-propanedione-1,3. Poids obtenu : 15,2 g (Rdt : 76%). PFK = 130 C (ac6tone).Prepared according to Example 4 of the main patent from 18 g (0.062 mole) of cyclohexyl-1- (hydroxy-2-methoxy-methyl-3-phenyl) -3-propanedione-1,3. Weight obtained: 15.2 g (YId: 76%). PFK = 130 C (ac6tone).

IR : @ c = O (pyrone) - 1645 cm-1.  IR: @ c = O (pyrone) - 1645 cm-1.

RMN (CDCl3), Il H de 1,1 à 3,0 (multiplet), 2 H à 4,7 (singulet), 1 H à 6,2 (singulet) 1 H à 7,3 (triplet, J = 8 Hz), 1 H à 7,65 (dou- blet de doublet, J1 = 8 Hz, J2 =2Hz, 1 H à 8,15 (doublet de doublet,
J1 = 8 Hz, J2 = 2 Hz).NMR (CDCl3), Il H from 1.1 to 3.0 (multiplet), 2 H to 4.7 (singlet), 1 H to 6.2 (singlet) 1 H to 7.3 (triplet, J = 8 Hz), 1 H at 7.65 (doublet doublet, J1 = 8 Hz, J2 = 2Hz, 1 H at 8.15 (doublet doublet,
J1 = 8 Hz, J2 = 2 Hz).

Exemple 16 : (Hydroxy-2-méthyl-3-phényl)-1-phényl-2-méthamome (formule 16)
C15h14O2. PM = 226,28.Example 16: (Hydroxy-2-methyl-3-phenyl) -1-phenyl-2-methamome (formula 16)
C15h14O2. MW = 226.28.

On chauffe 16 heures à reflux une solution de 126 g ( 0,5 mole) d'hy- droxy-4-méthyl-8-phényl-3-2H-[1]-benzopyranone-2 (C.MENTZER et Coll
Bull. Soc. Chim. Franoe 1949 749) et 100 g (2,5 moles) de soude dans 1 litre d'eau. On terse ensutie sur un mélange HCl 6 N-glace et on filtre le précipité obtenu. Poids obtenu : 91 g. PFK = 44 C. IR : @ c =
O = 1630 cm-1. @ OH = 2700 à 3500 cm-1. RMN (CDCl3) 3 H à 2,24 (sin- gulet), 2 H 7 4,24 (singulet), 1 H à 6,8 (triplet, = 8 Hz), 6H de 7,2 à 7,6 (multiplet), 1 H à 7,76 (doublet, J = 8 Jz), 1 H à 15,6 (échangeable avec Exemple 17 i
Méthyl-8-phényl-3-4H-[1]-benzopyranone-4 (formule 17)
C16H12O2. PM = 236,27.A solution of 126 g (0.5 mole) of hydroxy-4-methyl-8-phenyl-3-2H- [1] -benzopyranone-2 (C.MENTZER et al.
Bull. Soc. Chim. Franoe 1949 749) and 100 g (2.5 moles) of soda in 1 liter of water. Afterwards, the mixture is poured onto a 6N HCl-ice mixture and the precipitate obtained is filtered. Weight obtained: 91 g. PFK = 44 C. IR: @ c =
O = 1630 cm-1. @ OH = 2700 to 3500 cm-1. NMR (CDCl3) 3 H at 2.24 (single), 2 H 7 4.24 (singlet), 1 H at 6.8 (triplet, = 8 Hz), 6 H from 7.2 to 7.6 ( multiplet), 1 H at 7.76 (doublet, J = 8 Jz), 1 H at 15.6 (exchangeable with Example 17 i
Methyl-8-phenyl-3-4H- [1] -benzopyranone-4 (formula 17)
C16H12O2. MW = 236.27.

On chauffe 8 H à reflux un mélange de 85 g (0,375 mole) d'(hydroxy-2- méthyl-3-phényl)-1-phényl-2-éthanone, 500 ml de pyridine, 50 ml de pipéridine et 810 mi d'orthoformiate de triéthyle. Puis on verse dans un mélange d'acide chlorhydrique 6 N et de glace (3 1). On filtre le précipitéobtenu et on recristallise dans l'isopropanol. Poids obtenus 80,9 g (Rdt ; 91%), PFK = 110-111 C. IR : @ c = O = 1650 cm-1. RMN (CDCl3), 3 H à 2,5 (singulet), 7 H de 7,1 à 7,8 (multiplet), 1 H à 8,02 (singulet), 1 H à 2,2 (doublet de doublet, J1 = 8 Hz, J2 = 2 Hz).A mixture of 85 g (0.375 mol) of (hydroxy-2-methyl-3-phenyl) -1-phenyl-2-ethanone, 500 ml of pyridine, 50 ml of piperidine and 810 ml is heated to reflux for 8 hours. 'triethyl orthoformate. Then pour into a mixture of 6N hydrochloric acid and ice (3 1). The precipitate obtained is filtered and recrystallized from isopropanol. Weight obtained 80.9 g (yield; 91%), PFK = 110-111 C. IR: @ c = O = 1650 cm-1. NMR (CDCl3), 3 H to 2.5 (singlet), 7 H from 7.1 to 7.8 (multiplet), 1 H to 8.02 (singlet), 1 H to 2.2 (doublet of doublet, J1 = 8 Hz, J2 = 2 Hz).

Exemple 18 ,
Bromométhyl-8-phényl-3-4H-[1]-benzopyranone-4 (formule 18) C16H11BrO2
PM = 315,17.Example 18,
Bromomethyl-8-phenyl-3-4H- [1] -benzopyranone-4 (formula 18) C16H11BrO2
MW = 315.17.

Préparé selon l'exemple 4 à partir de 80,9 g (0,34 mole) de méthyl-8 phényl-3-4H-[1]-benzopyranone-4 et de 73a4 g (0,41 mole) de N-bromosucoinimide. Poids obtenu : 88,2 g (Rdt ; 82 %). PFK = 142 C (acétate d'éthyle). IR : @ c = O (pyrone) = 1640 cm-1. RMN (CDCl3), 2 H à 4,8 (singulet) 7 H de 7,2 à 8,0 (multiplet) 1 H à 8,18 (singulet), 1 H à 8,4 (doublet de doublet, J1 = 8 Hz, J2 = 2 Hz).Prepared according to Example 4 from 80.9 g (0.34 mole) of 8-methylphenyl-3-4H- [1] -benzopyranone-4 and from 73a4 g (0.41 mole) of N-bromosucoinimide . Weight obtained: 88.2 g (yield; 82%). PFK = 142 C (ethyl acetate). IR: @ c = O (pyrone) = 1640 cm-1. NMR (CDCl3), 2 H to 4.8 (singlet) 7 H from 7.2 to 8.0 (multiplet) 1 H to 8.18 (singlet), 1 H to 8.4 (doublet of doublet, J1 = 8 Hz, J2 = 2 Hz).

EXemple 19 : acide méthoxy-2-méthoxyméthyl-3-benzoïque (formule 19) C10H1204
PM = 196,20.EXAMPLE 19: methoxy-2-methoxymethyl-3-benzoic acid (formula 19) C10H1204
MW = 196.20.

A une solution de 315,3 g (1,5 mole) de méthoxy-2-méthoxyméthyl-3-ben zoate de méthyle dans 1,2 b de méthanol, on ajoute une solution de 118,8 g (1,8 mole) de potasse en pastilles dans 300 ml d'eau, et on chauffe à reflux pendant 3 h. Puis on évapore le méthanol sous vide on dilue à l'eau et lave à l'éther. La phase aqueuse est refroidie, acidifiée avec HCl 6N, extraite à l'éther. La phase éthérée est lavée à l'eau, céchée, évaporée sous vide et le solide obtenu est recristal- lisédane le cyclohexane. Poids obtenu : 278,3 g (Rdt : 94%), PFK = 68-69 C. IR : @ c = O (acide) = 1700 cm-1.RMN (CDCl3), 3 H à 3,47 (singu let), 3 H à 3,97 9singulet), 2 H 7 4,6 (singulet), 1 H à 7,23 (triplet
J , 8 Hz), 1 H à 7,7 (doublet de doublet, J1 = 8 Hz, J2 = 2 Hz), 1 H à 8,05 (doublet de doublet, J1 = 8 hz, J2 = 2 Hz).To a solution of 315.3 g (1.5 mole) of methyl methoxy-2-methoxymethyl-3-ben zoate in 1.2 b of methanol, a solution of 118.8 g (1.8 mole) is added of potassium hydroxide pellets in 300 ml of water, and the mixture is heated at reflux for 3 h. Then the methanol is evaporated in vacuo, diluted with water and washed with ether. The aqueous phase is cooled, acidified with 6N HCl, extracted with ether. The ethereal phase is washed with water, dried, evaporated in vacuo and the solid obtained is recrystallized from cyclohexane. Weight obtained: 278.3 g (Yield: 94%), PFK = 68-69 C. IR: @ c = O (acid) = 1700 cm-1.RMN (CDCl3), 3 H at 3.47 (singu let ), 3 Hrs at 3.97 9singulet), 2 Hrs 7 4.6 (singlet), 1 Hrs at 7.23 (triplet
J, 8 Hz), 1 H at 7.7 (doublet doublet, J1 = 8 Hz, J2 = 2 Hz), 1 H at 8.05 (doublet doublet, J1 = 8 Hz, J2 = 2 Hz).

Exemple 20 : (Méthoxy-2-méthoxyméthyl-3-phényl)-1-éthanone (formule 20) C11H14O3
PM = 194,23.Example 20: (Methoxy-2-methoxymethyl-3-phenyl) -1-ethanone (formula 20) C11H14O3
MW = 194.23.

A une solution de 264,9 g (1,35 mole) d'acide méthoxy-2-méthoxy-méthyl -3-benzoïque dans 1,35 1 de chloroforme et 2,7 ml. de DNF, on ajoute en filet 148,5 mi (2,02 mole) de chlorure de thionyle puis on chauffe progressivement juaqu'à la température du reflux en réglant le ohauffage sur le dégagement gazeux, et on maintient le reflux 2 H. Puis on refroidit,évapore sous vide le chloroforme et l'excès de chlorure de thionyle et reprand le chlorure d'acide méthoxy-2-méthoxyméthyl-3benzoïque obtenu avec 270 ml d'éther anhydre. On ajoute cette solu- tion goutte à goutte à une solution à reflux de 1,62 mole d'éthoxy- magnésium malonate d'éthyle (préparée selon Org. Syn. Coll Vol.IV p.708) et on chauffe 3 H à reflux. Puis on refroidit au bain de glace, hydrolyse avec H2S04 5 % jusqu'à obtention de deux phases limpides, décante, extrait à l'éthex, lave à l'eau et évapore sous vide. Le ré- sidu est repris avec 460 ml d'acide acétique, 300 ml d'eau et 58 ml d'acide sulfurique comcentré, et chauffe à reflux pendant 4 H. Âpres refroidissement, on extrait à l'éther. La phase aqueuse est refroidie au bain de glace et alcalinisée avec NaOH 10 % puis extraite à l'éther.To a solution of 264.9 g (1.35 mol) of methoxy-2-methoxy-methyl-3-benzoic acid in 1.35 l of chloroform and 2.7 ml. of DNF, 148.5 mi (2.02 mole) of thionyl chloride are added in a net, then the mixture is gradually heated up to the reflux temperature by adjusting the heating to the gassing, and the reflux is maintained for 2 hours. Then the mixture is cooled, the chloroform and the excess thionyl chloride are evaporated in vacuo and the methoxy-2-methoxymethyl-3benzoic acid chloride obtained is taken up again with 270 ml of anhydrous ether. This solution is added dropwise to a reflux solution of 1.62 mol of ethyl ethoxymagnesium malonate (prepared according to Org. Syn. Coll Vol.IV p.708) and the mixture is heated for 3 hours at reflux. . Then cooled in an ice bath, hydrolyzed with H2SO4 5% until two clear phases, decanted, extracted with ethex, washed with water and evaporated in vacuo. The residue is taken up with 460 ml of acetic acid, 300 ml of water and 58 ml of concentrated sulfuric acid, and heated to reflux for 4 hours. After cooling, extraction is carried out with ether. The aqueous phase is cooled in an ice bath and made basic with 10% NaOH and then extracted with ether.

Les phases éthérées réunies sont lavées avec une solution aqueuse de bicarbonate de sodium puis à l'eau, séchées et évaporées souz vide.The combined ethereal phases are washed with an aqueous sodium bicarbonate solution and then with water, dried and evaporated under vacuum.

Le résidu est distillé. Poids obtenu : 173,3 g (RDT = 66 %). PEO, 4mmHg 100-105 C. IR : @c = O = 1690 cm-1, RMN (CDCCl3), 3 H à 2,63 (singule) 3 H à 3,5 (singulet), 3 H à 3,8 (singulet), 2 H à 4,55 (singulet), 4 H de 7,0 à 7,8 (multiplet).The residue is distilled. Weight obtained: 173.3 g (RDT = 66%). PEO, 4mmHg 100-105 C. IR: @c = O = 1690 cm-1, NMR (CDCCl3), 3 H to 2.63 (singule) 3 H to 3.5 (singlet), 3 H to 3.8 (singlet), 2 H to 4.55 (singlet), 4 H from 7.0 to 7.8 (multiplet).

Exemple 21 i (Méthoxy-2-méthoxyméthyl-3-phényl)-1-butanedione-1,3 (formule 21)
C13H16O4. PM = 236,27.Example 21 i (Methoxy-2-methoxymethyl-3-phenyl) -1-butanedione-1,3 (formula 21)
C13H16O4. MW = 236.27.

Prépare selon l'exemple 7 à partir de 0,8 mole d'hydrure de sodium, 77,77 g (0,4 mole) de (méthoxy-2-méthoxyméthyl-3-phényl)-1-éthanone et 59 ml (0,6 mole) d'acétate d'éthyle. L'huile obtenue à la fin du traitement est distillée sous vide. Poids' obtenu : 53,7g (Rdt: 56%). PE0,3mmllg 110-140 C. IR : @ c=O=1620cm-1. RMN (CDCl4), 3Hà 2,12 (singulet), 3H à 3,4 (singulet) 3H à 3,73 (singulet) 2H à 4s47 (singulet) 1H à 6,3 (singulet), 3H de 7,0 à 7,8 (multiplet),îH à 16 (échangeable avec (forme énolique de la ss dicétone).Prepare according to Example 7 from 0.8 mole of sodium hydride, 77.77 g (0.4 mole) of (methoxy-2-methoxymethyl-3-phenyl) -1-ethanone and 59 ml (0 , 6 mol) of ethyl acetate. The oil obtained at the end of the treatment is distilled under vacuum. Weight 'obtained: 53.7 g (Yield: 56%). PE0,3mmllg 110-140 C. IR: @ c = O = 1620cm-1. NMR (CDCl4), 3H to 2.12 (singlet), 3H to 3.4 (singlet) 3H to 3.73 (singlet) 2H to 4s47 (singlet) 1H to 6.3 (singlet), 3H from 7.0 to 7.8 (multiplet), 1H to 16 (exchangeable with (enolic form of the ss diketone).

Exemple 22 :
Bromométhyl-8-méthyl-2-4H-[1]-benzopyraone-4 (formule 22) C11H9BrO2
PM = 253,10.Example 22:
Bromomethyl-8-methyl-2-4H- [1] -benzopyraone-4 (formula 22) C11H9BrO2
MW = 253.10.

Préparé selon l'exemple 4 du brevet principal à partir de 27,4 g (0,116 mole) de (méthoxy-2-méthoxyméthyl-3-phényl)-1-butanedione-1,3. Poids obtenu : 18 g (Rdt : 61 %). PFK = 126-128 C (cycloherane-acétate d'éthyle). IR : @ c = O = 1670 cm-1. RMN (CDCl3), 3 H à 2,45 (singulet), 2 H à 4,73 (singulet) à H à 6,27 (singulet) 1 H de 7,1 à 7,5 (multiplet), 1 H à 7,77 (doublet de doublet, J1 -= 8 Hz, J2 = 2 Hz), 1 H à 8,2 (dou- blet de doublet, J1 - 8 HZ, J2 = 2 Hz).  Prepared according to Example 4 of the main patent from 27.4 g (0.116 mole) of (methoxy-2-methoxymethyl-3-phenyl) -1-butanedione-1,3. Weight obtained: 18 g (yield: 61%). PFK = 126-128 C (cycloherane-ethyl acetate). IR: @ c = O = 1670 cm-1. NMR (CDCl3), 3 H at 2.45 (singlet), 2 H at 4.73 (singlet) at H at 6.27 (singlet) 1 H from 7.1 to 7.5 (multiplet), 1 H at 7.77 (doublet doublet, J1 - = 8 Hz, J2 = 2 Hz), 1 H to 8.2 (doublet doublet, J1 - 8 HZ, J2 = 2 Hz).

Exemple 23 : (HYdroxy-2-méthoxyméthyl-3-phényl)-1-phényl-4-butanedione-1,3 (formule 23), C18H18O4. PM = 298,34. Example 23: (HYdroxy-2-methoxymethyl-3-phenyl) -1-phenyl-4-butanedione-1,3 (formula 23), C18H18O4. MW = 298.34.

Préparée selon l'exemple 3 du brevet principal à partir de 37 g (0,2 mole) d'(hydroxy-2-méthoxyméthyl-3-phéyl)-1-éthanone et de 49,2 g (0,3 mole) de phénylacétate d'éthyl en remplaçant l'acide chlorhydrique 3 N par l'acide acétique 50 %. Après évaporation du solvant, on obtient 68 g d'une huile qui est utilisée sans purification ultérieure dans l'étape suivante.Prepared according to Example 3 of the main patent from 37 g (0.2 mole) of (hydroxy-2-methoxymethyl-3-pheyl) -1-ethanone and from 49.2 g (0.3 mole) of ethyl phenylacetate, replacing 3N hydrochloric acid with 50% acetic acid. After evaporation of the solvent, 68 g of an oil are obtained which is used without further purification in the next step.

Exemple 24
Bromométhyl-8-(phénylméthyl)-2-4H-[1]-benzopyranone-4 (formule 24)
C17H13BrO2. PI = 329,20.Example 24
Bromomethyl-8- (phenylmethyl) -2-4H- [1] -benzopyranone-4 (formula 24)
C17H13BrO2. PI = 329.20.

Préparé selon l'exemple 4 du brevet principal à partir de l'(hydroxy-2 -méthoxyméthyl-3-phényl)-1-phényl-4-butansdione-1,3 préparée dans l'exemple précédant poids obtenu : 47,5 g (Rdt : 72%), PFK = 128 C (toluène-hexane), IR : @ c = O (pyrone) = 1670 cm-1. RMN (CDCl3), 2 H à 4,0 (singulet), 2 H à 4,63 (singulet),1 H à 6,23 (singulet), 6 H de 7,1 à 7,55 (multiplet), 1 H à 7,7 (doublet de doublet, J1 = 8 Hz, J2 = 2 Hz), 1 H à 8,2 (deublet de doublet, J1 = 8 Hz, J2 = 2 Hz).Prepared according to example 4 of the main patent from (hydroxy-2-methoxymethyl-3-phenyl) -1-phenyl-4-butansdione-1,3 prepared in the previous example weight obtained: 47.5 g (Yield: 72%), PFK = 128 C (toluene-hexane), IR: @ c = O (pyrone) = 1670 cm-1. NMR (CDCl3), 2 H at 4.0 (singlet), 2 H at 4.63 (singlet), 1 H at 6.23 (singlet), 6 H from 7.1 to 7.55 (multiplet), 1 H at 7.7 (doublet doublet, J1 = 8 Hz, J2 = 2 Hz), 1 H at 8.2 (deublet doublet, J1 = 8 Hz, J2 = 2 Hz).

Exemple 25 : (Hydroxy-2-méthoxyméthyl-3-phényl)-1-phényl-5-pentène-4-dione-1,3 (formule 25), C19H18O4, PM = 310,35.Example 25: (Hydroxy-2-methoxymethyl-3-phenyl) -1-phenyl-5-pentene-4-dione-1,3 (formula 25), C19H18O4, PM = 310.35.

Préparé selon l'exemple 7 à partir de 60 g (0,333 mole) d'(hydroxy-2- méthoxyméthyl-3-phényl)-1-éthanone et de 88 g (0,499 mole) de phényl-3propànoate d'éthyle. PFK = 92 C (hexane-éther). IR : @ c = O = 1640 cm-1
RMN (CDCl3), 3 H à 3,46 (singulet) 2 H à 4,6 (singulet), 1 H à 6,33 (singulet) 10 H de 6,4 à 7,9 (multiplet), 1 H à 12,6 (échangeable avec 1 H à 14,7 (échangeable aveo D2O)@forme énolique de la ss-dicétone).Prepared according to Example 7 from 60 g (0.333 mole) of (hydroxy-2-methoxymethyl-3-phenyl) -1-ethanone and 88 g (0.499 mole) of ethyl phenyl-3propanoate. PFK = 92 C (hexane-ether). IR: @ c = O = 1640 cm-1
NMR (CDCl3), 3 H to 3.46 (singlet) 2 H to 4.6 (singlet), 1 H to 6.33 (singlet) 10 H from 6.4 to 7.9 (multiplet), 1 H to 12.6 (exchangeable with 1 H to 14.7 (exchangeable with D2O) @ enolic form of ss-diketone).

Exemple 26 :
Bromométhyl-8-(phényl-2-éthényl)-2-4H-[1]-benzopyranone-4 (formule 26)
C18H13BrO2. PM = 341,21.Example 26:
Bromomethyl-8- (phenyl-2-ethenyl) -2-4H- [1] -benzopyranone-4 (formula 26)
C18H13BrO2. PM = 341.21.

Préparé selon l'exemple 4 du brevet principal à partir de 10,2 g (0,033 mole) d'(hydroxy-2-méthyoxyméthyl-3-phényl)-1-phényl-5-pentène-4-dione1,3. Poids obtenu : 8,4 g (Rdt = 75%). PFK = 21200 (toluène). IR : 1 c = O (pyrone) =1660 cm-1. @ c = C = 1640 cm-1.Prepared according to Example 4 of the main patent from 10.2 g (0.033 mole) of (hydroxy-2-methyoxymethyl-3-phenyl) -1-phenyl-5-pentene-4-dione1,3. Weight obtained: 8.4 g (Yield = 75%). PFK = 21200 (toluene). IR: 1 c = O (pyrone) = 1660 cm-1. @ c = C = 1640 cm-1.

RMN (CDCl3), 2 H à 4,83 (singulet) 1 H à 6,4 (singulet) 1 H à 6,8 (doublet, J - 16 Hz), 8 H de 7,1 à 7,9 (multiplet), 1 H à 8,2 (doublet de doublet, J1 = 8 Hz, J2 = 2 Hz). NMR (CDCl3), 2 H at 4.83 (singlet) 1 H at 6.4 (singlet) 1 H at 6.8 (doublet, D - 16 Hz), 8 H from 7.1 to 7.9 (multiplet ), 1 H at 8.2 (doublet of doublet, J1 = 8 Hz, J2 = 2 Hz).

Claims (6)

REVENDICATIONS dans laquelle AR est l'hydrogène, un radical phényle, phényle substitué - par un radical alkyle inférieur,alkoxy inférieur ou un balogène - un radical thényle, pyridyle, furyle, naphtyle, alkyle, eycloalkyle ou aralkyle, X est un halogène et Y est l'hydrogène, un radical allyle inférieur, alkoxy ou un halogène, R1 est l'hydrogène ou un radical phényle, alkoxy.  in which AR is hydrogen, a phenyl radical, phenyl substituted - by a lower alkyl, lower alkoxy or a balogen radical - a thenyl, pyridyl, furyl, naphthyl, alkyl, eycloalkyl or aralkyl radical, X is a halogen and Y is hydrogen, a lower allyl radical, alkoxy or a halogen, R1 is hydrogen or a phenyl, alkoxy radical.
Figure img00130001
Figure img00130001
 i. Haloalkyl-8-4H-[1]-benzopyranones-4, selon le brevet principal, caractérisées par la formule i. Haloalkyl-8-4H- [1] -benzopyranones-4, according to the main patent, characterized by the formula dans laquelle AR, Y et R1, ont les mêmes significations que préoédemment. in which AR, Y and R1, have the same meanings as before.
Figure img00130002
Figure img00130002
 2. Bromoalkyl-8-4H-[1]-benzopyranones-4, selon la revendica- tion 1, caractérisées par la formule 2. Bromoalkyl-8-4H- [1] -benzopyranones-4, according to claim 1, characterized by the formula 3. Procédé de préparation les composés selon la revendica- tion 1, caractérisé par la séquence préparative suivante, consistant en le traitement d'un produit de départ de formule 3. Method for preparing the compounds according to claim 1, characterized by the following preparative sequence, consisting in the treatment of a starting product of formula
Figure img00130003
Figure img00130003
 dans laquelle R1 et Y ont les memes significations que précédemment,  in which R1 and Y have the same meanings as before, H2 est l'hydrogène ou un radical alkyle inférieur, par le polyoxyméthylène en présence d'acide chlorhydrique concentré 9 puis la con- densation de l'intermédiaire chlorométhylé obtenu, de formuleH2 is hydrogen or a lower alkyl radical, with polyoxymethylene in the presence of concentrated hydrochloric acid 9 and then the condensation of the chloromethylated intermediate obtained, of formula
Figure img00130004
Figure img00130004
 avec le méthanol en intermédiaire méthoxyméthylé, de formule  with methanol as a methoxymethylated intermediate, of formula
Figure img00140001
Figure img00140001
 condensé avec un ester AR-COOEt, dans lequel AR a les mêmes significations que précédemment, en vue de l'obtention des propanediones-1,3 de formule condensed with an AR-COOEt ester, in which AR has the same meanings as previously, with a view to obtaining the 1,3-propanediones of formula
Figure img00140002
Figure img00140002
 dans laquelle AR, E1, R2 et Y ont les mêmes significations que précédemment ; et en la cyclisation des propanediones intermédiaires en présence d'acide bromhydrique. wherein AR, E1, R2 and Y have the same meanings as before; and in the cyclization of the intermediate propanediones in the presence of hydrobromic acid. 4. Procédé de préparation des composés selon la revendica- tion 1, caractérisé par la séquence préparative suivante, consistant en le traitement d'un méthoxy-2 méthoxyméthyl-3 benzoate de méthyle de formule 4. Process for the preparation of the compounds according to claim 1, characterized by the following preparative sequence, consisting in the treatment of a methyl-2-methoxy-3-methoxymethyl benzoate of formula
Figure img00140003
Figure img00140003
 paP une cétone not a ketone
Figure img00140004
Figure img00140004
 dans laquelle AR désigne un radical phényle, phényle substitué par un radical allyle inférieur, alkoxy inférieur ou un halogène, un radical thényle ou pyridyle, furole, naphtyle, alkyle, cycloakyle, aralkyle en présence l'hydrure le sodium 3 et enfin en la cyclisation de la propanedione-1,3 de formule VI en présence d'acide bromhydrique. in which AR denotes a phenyl radical, phenyl substituted by a lower allyl, lower alkoxy or a halogen radical, a thényl or pyridyl, furole, naphthyl, alkyl, cycloakyl, aralkyl radical in the presence of sodium hydride 3 and finally in cyclization 1,3-propanedione of formula VI in the presence of hydrobromic acid. Y est l'hydrogène, un radical alkyle inférieur, alkoxy ou un halogène.Y is hydrogen, lower alkyl, alkoxy or halogen. dans laquelle AR est un radical phényle, phényle substitué - par un radical alkyle inférieur, alkoxy inférieur ou un halogène - un radical thényleou pyridyle, furyle, naphtyle, aikyle, cycloalkyle, aralkyle, in which AR is a phenyl radical, phenyl substituted - by a lower alkyl, lower alkoxy or halogen radical - a thenyl or pyridyl, furyl, naphthyl, aikyl, cycloalkyl, aralkyl radical,
Figure img00140005
Figure img00140005
 5, Propanediones-1,3, intermédiaires dans la préparation selon la revendication 3, caractérisées par la formule 5, Propanediones-1,3, intermediates in the preparation according to claim 3, characterized by the formula 6. Phényl cétones méthoxyméthylées, intermédiaires dans la préparation selon la revendication 3, caractérisées par la formule 6. Methoxymethylated phenyl ketones, intermediates in the preparation according to claim 3, characterized by the formula
Figure img00150001
Figure img00150001
 dans laquelle Y est l'hydrogène, un radical aikyle inférieur alkoxy ou un halogène, $1 est l'hydrogène ou un radical ;lkoxy ou phényle, R2 est l'hydrogène ou un radical alkyle inférieur.  in which Y is hydrogen, a lower alkoxy alkyl radical or a halogen, $ 1 is hydrogen or a radical; lkoxy or phenyl, R2 is hydrogen or a lower alkyl radical.
FR8219641A 1981-11-25 1982-11-24 8-Haloalkyl-4H-1-benzopyran-4-ones and methods of preparation Granted FR2536396A2 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1182669B (en) * 1958-09-12 1964-12-03 Recordati Lab Farmacologico S Process for the production of hydrochlorides of basic substituted chromones
DE1270567B (en) * 1961-05-19 1968-06-20 Klinge Co Chem Pharm Fab Process for the production of basic substituted flavones

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1182669B (en) * 1958-09-12 1964-12-03 Recordati Lab Farmacologico S Process for the production of hydrochlorides of basic substituted chromones
DE1270567B (en) * 1961-05-19 1968-06-20 Klinge Co Chem Pharm Fab Process for the production of basic substituted flavones

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 97, 1982, pages 565, no. 198071t, Columbus Ohio (USA); *

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