Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
  • C07D319/12—1,4-Dioxanes; Hydrogenated 1,4-dioxanes not condensed with other rings

Definitions

• the present invention relates to a novel method for synthesizing 2,5-dioxane-1,4-diones.
• PLGAs are generally obtained by ring-opening (co) polymerization of lactide and glycolide. These monomers derived from lactic acid and glycolic acid are the prototypes of 2,5-dioxane-1,4-diones.
• the modification of PLGA properties is an important issue, particularly in their application as a biodegradable and bioassimilable matrix for entrapment and controlled release of active ingredients.
• the approach of modifying the 2,5-dioxane-1,4-dione backbone substituents has been poorly developed so far, which can be explained in practice by low-potency. accessibility of these patterns.
• Symmetrical monomers such as lactide or glycolide are generally prepared from the corresponding ⁇ -hydroxy acids. This approach is difficult because it requires the elimination of the water formed and the vacuum distillation of the monomer.
• two different precursors must be used, typically an ⁇ -hydroxy acid and a mono- or dihalogenated derivative (CM Dong et al., Polym. ScI Part A: Polym. Chern. 4179-4184, M. Leemhuis et al, EUT J. Org Chem 2003, 3344-3349).
• the subject of the present invention is therefore a process for the preparation of 2,5-dioxane-1,4-diones of formula (I)
• R 1 , R 2 , R 3 and R 4 represent, independently, the hydrogen atom; halo; (C 2 -C 6 ) alkenyl; (C 3 -C 7 ) cycloalkyl; cyclohexenyl; a radical of formula - (CH 2 VV-W
• V represents a covalent bond, the oxygen atom or the radical -C (O) -O-;
• W represents the hydrogen atom, a (C 1 -C 18) alkyl radical optionally substituted with one or more identical or different halo radicals; the aryl or aralkyl radical, the aryl and aralkyl radicals being optionally substituted with one or more identical or different substituents chosen from: - (CH 2 ) n -YZ, halo, nitro and cyano;
• Y represents -O-, -S- or a covalent bond
• Z represents the hydrogen atom or a radical optionally substituted with one or more identical or different halo radicals; or aralkyl;
• n and n independently represent an integer of 0 to 4.
• halo represents the fluoro, chloro, bromo or iodo radical, preferably chloro, fluoro or bromo.
• the term (CrC 6 ) alkyl represents an alkyl radical having 1 to 6 carbon atoms, linear or branched, such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl radicals. or amyl, isopentyl, neopentyl, 2,2-dimethylpropyl, hexyl, isohexyl or 1,2,2-trimethylpropyl.
• (CrC 18 ) alkyl denotes an alkyl radical having from 1 to 18 carbon atoms, linear or branched, such radicals containing from 1 to 6 carbon atoms as defined above but also heptyl, octyl, 1,1 , 2,2-tetramethyl-propyl, 1,1,3,3-tetramethyl-butyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl.
• alkyl substituted with at least one halo radical it is necessary to understand any linear or branched alkyl chain containing at least one halo radical positioned along the chain such as for example -CHCl-CH 3 but also -CF 3 .
• the radical (CH 2 ) I (integer may represent m and n as defined above), represents a hydrocarbon chain, linear or branched, of i carbon atoms.
• the radical - (CH 2 ) 3 - can represent -CH 2 -CH 2 -CH 2 - but also -CH (CH 3 ) -CH 2 -, -CH 2 -CH (CH 3 ) - or -C (CH 3 ) 2 -.
• (C 2 -C 6 ) alkenyl is meant a linear or branched alkyl radical having from 2 to 6 carbon atoms and having at least one unsaturation (double bond), for example vinyl, allyl, propenyl, butenyl or pentenyl.
• cycloalkyl denotes a saturated carbon monocyclic system comprising from 3 to 7 carbon atoms, and preferably the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl rings.
• aryl represents an aromatic radical, consisting of a ring or condensed rings, such as, for example, the phenyl, naphthyl, fluorenyl or anthryl radical.
• aralkyl preferably refers to radicals in which the radicals aryl and alkyl are as defined above such as benzyl or phenethyl.
• oxidation For the conversion of the ketone function of the compound (II) to ester function, several types of oxidation can be used; the oxidation can thus be carried out for example in the presence of an oxidizing agent such as a peracid or a peroxide (according to the oxidation reaction of Baeyer Villiger), in the presence of a metal catalyst (SI Murahashi et al, Tetrahedron Lett, 1992, 33, 7557-7760 and C. BoIm et al., Tetrahedron Lett., 1993, 34, 3405-3408) or enzymatically (MD Mihovilovic et al, EW J. Org Chem 2002, 3711 -3730).
• an oxidizing agent such as a peracid or a peroxide (according to the oxidation reaction of Baeyer Villiger)
• a metal catalyst SI Murahashi et al, Tetrahedron Lett, 1992, 33, 7557-7760 and C.
• a process according to the invention is carried out in the presence of an oxidizing agent according to the oxidation reaction of Baeyer Villiger.
• the oxidation reaction is very preferably carried out on the most congested side of the ketone so that 2,5-dioxane-1,4-diones can be obtained very selectively.
• the oxidizing agent is used in the presence of a catalyst.
• the oxidizing agent (or oxidation agent) used for carrying out the process according to the invention may be a peracid or a peroxide.
• a peracid mention may be made of trifluoroperacetic acid (TFPAA), peracetic acid (PAA) and metachloroperbenzoic acid (m-CPBA), preferably in combination with
• peroxide As an example of peroxide, mention may be made of hydrogen peroxide (H 2 O 2 ); the hydrogen peroxide will be used alone or in the presence of a catalyst which may be a Lewis acid (such as BF 3 ) or a metal complex whether in a homogeneous phase (Mo,
• the present invention more particularly relates to a process as defined above, characterized in that the oxidizing agent is a peracid or a peroxide.
• the oxidizing agent is a peracid.
• the peracid is preferably used in the presence of a Lewis acid or a strong acid, and more particularly in the presence of a strong acid chosen from sulphonic acids.
• the peracid is metachloroperbenzoic acid (m-CPBA).
• Metachloroperbenzoic acid is preferably used in the presence of trifluoromethanesulfonic acid.
• the oxidizing agent is a peroxide.
• oxidation agents mentioned above are in general commercial. Non-commercial agents may be synthesized according to methods known to those skilled in the art. Thus, trifluoroperacetic acid which is not commercially available can easily be obtained by the action of hydrogen peroxide H 2 O 2 on trifluoroacetic acid or trifluoroacetic anhydride CF 3 CO 2 H and (CF 3 CO) 2 O, respectively (Liotta, R., et al., J. Org Chem 1980, 45, 2887-2890, M. Anastasia et al., J. Org Chem 1985, 50, 321-325, PA Krasutsky et al., J. Org. Chem 2001, 66, 1701-1707).
• bis (trimethylsilyl) peroxide is not commercially available but is easily accessible from the complex H 2 O 2 - 1,4-diazabicyclo [2,2,2] octane [DABCO, N (CH 2 CH 2 3 N] and Me 3 SiCl (PG Cookson et al., J Orga.nomet.Chem, 1975, 99, C31-C32, M. Taddei et al., Synth.Comm., 1986, 633-635).
• Cyclic keto esters of formula (II), used as precursors for the synthesis of 2,5-dioxane-1,4-diones (I) as defined above, are easily accessible by conventional methods known to the art. those skilled in the art (EB Reid et al, J. Org Chem 1950, 15, 572-582).
• the present invention more particularly relates to a process as defined above, characterized in that the aryl radical is the phenyl radical and the aralkyl radical is the benzyl radical.
• the present invention more particularly relates to a process as defined above, characterized in that R 1, R 2 , R 3 and R 4 represent, independently, the hydrogen atom; or a radical of formula - (CH 2 ) m -VW with V which represents a covalent bond and W a (C 1 -C 6 ) alkyl radical, and more preferably m is equal to zero.
• R 1 , R 2 , R 3 and R 4 represent, independently, the hydrogen atom, the methyl radical or the ethyl radical.
• the present invention more particularly relates to a process as defined above, characterized in that R 1 and R 2 represent, independently, a radical of formula - (CH 2 ) m -VW with V which represents a covalent bond, m is zero and W is (C 1 -C 6 ) alkyl, and R 3 and R 4 are, independently, hydrogen or a radical of formula - (CH 2 ) H iVW with V which represents a covalent bond, m is zero and W a (C 1 -C 6 ) alkyl radical.
• the present invention more particularly relates to a process as defined above, characterized in that R 1 and R 2 represent, independently, the methyl or ethyl radical, and R 3 and R 4 represent, independently, the atom hydrogen or a methyl or ethyl radical.
• the subject of the present invention is also compounds of formula (I) as obtained according to the process defined above.
• Step 1 synthesis of the precursor (II)
• the formation of the compound (2) from the compound (1) can be carried out according to H. C. Brown et al., J. Am. Chern. Soc. 1988, 110, 1539-1546.
• the synthesis steps of the compounds (3) and (4) can be carried out according to M. Conrad et al., Ber.
• the final step of forming the compound (II) from the compound (4) can be carried out according to E.B. Reid et al., J. Org. Chem. 1950, 75, 572-582.
• Step 2 synthesis of 3,3-dimethyl-2,5-dioxane-1,4-dione
• Step 1 synthesis of the precursor (II)
• the exponent of the anisotropic displacement factor takes the form: -2 ⁇ 2 [h 2 a * 2 U n + ... + 2 hka * b * U 12 ]

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

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• 2004
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• 2005
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