EP1773803A1 - Method for the synthesis of 2,5-dioxane-1,4-diones - Google Patents
Method for the synthesis of 2,5-dioxane-1,4-dionesInfo
- Publication number
- EP1773803A1 EP1773803A1 EP05793596A EP05793596A EP1773803A1 EP 1773803 A1 EP1773803 A1 EP 1773803A1 EP 05793596 A EP05793596 A EP 05793596A EP 05793596 A EP05793596 A EP 05793596A EP 1773803 A1 EP1773803 A1 EP 1773803A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- radical
- process according
- preparation process
- oxidizing agent
- represent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 17
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical class O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 230000015572 biosynthetic process Effects 0.000 title abstract description 17
- 238000003786 synthesis reaction Methods 0.000 title abstract description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 14
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 10
- 230000003647 oxidation Effects 0.000 claims abstract description 7
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims abstract description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims abstract description 4
- 125000000468 ketone group Chemical group 0.000 claims abstract description 4
- 150000001923 cyclic compounds Chemical class 0.000 claims abstract description 3
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims abstract description 3
- 125000001475 halogen functional group Chemical group 0.000 claims abstract 3
- -1 halo radicals Chemical class 0.000 claims description 29
- 150000003254 radicals Chemical class 0.000 claims description 18
- 239000007800 oxidant agent Substances 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 15
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 claims description 12
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical group OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 10
- 150000004965 peroxy acids Chemical group 0.000 claims description 9
- 150000002978 peroxides Chemical class 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical compound C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000002841 Lewis acid Substances 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 150000007517 lewis acids Chemical class 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 3
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 claims description 2
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 2
- 150000005840 aryl radicals Chemical class 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 150000003460 sulfonic acids Chemical class 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 5
- LLZIQIHXYWEQCA-UHFFFAOYSA-N 3,3-dimethyl-1,4-dioxane-2,5-dione Chemical compound CC1(C)OC(=O)COC1=O LLZIQIHXYWEQCA-UHFFFAOYSA-N 0.000 description 4
- 229930194542 Keto Natural products 0.000 description 4
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 4
- 238000006073 displacement reaction Methods 0.000 description 4
- 239000000178 monomer Substances 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- XYPISWUKQGWYGX-UHFFFAOYSA-N 2,2,2-trifluoroethaneperoxoic acid Chemical compound OOC(=O)C(F)(F)F XYPISWUKQGWYGX-UHFFFAOYSA-N 0.000 description 3
- OHODJAIYQYVURL-UHFFFAOYSA-N 3-ethyl-3-methyl-1,4-dioxane-2,5-dione Chemical compound CCC1(C)OC(=O)COC1=O OHODJAIYQYVURL-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 description 3
- 238000006220 Baeyer-Villiger oxidation reaction Methods 0.000 description 2
- 241001432959 Chernes Species 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 229940061720 alpha hydroxy acid Drugs 0.000 description 2
- 150000001280 alpha hydroxy acids Chemical class 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 230000002860 competitive effect Effects 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- XPEMYYBBHOILIJ-UHFFFAOYSA-N trimethyl(trimethylsilylperoxy)silane Chemical compound C[Si](C)(C)OO[Si](C)(C)C XPEMYYBBHOILIJ-UHFFFAOYSA-N 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 125000005919 1,2,2-trimethylpropyl group Chemical group 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 241001122767 Theaceae Species 0.000 description 1
- 229910021536 Zeolite Inorganic materials 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002447 crystallographic data Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- GDVKFRBCXAPAQJ-UHFFFAOYSA-A dialuminum;hexamagnesium;carbonate;hexadecahydroxide Chemical compound [OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Al+3].[Al+3].[O-]C([O-])=O GDVKFRBCXAPAQJ-UHFFFAOYSA-A 0.000 description 1
- 239000012973 diazabicyclooctane Substances 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 229960001545 hydrotalcite Drugs 0.000 description 1
- 229910001701 hydrotalcite Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 125000002960 margaryl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000006384 oligomerization reaction Methods 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229910052702 rhenium Inorganic materials 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000010457 zeolite Substances 0.000 description 1
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 ]
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
METHODE DE SYNTHESE DE 2,5-DIOXANE-I,4-DIONES METHOD OF SYNTHESIZING 2,5-DIOXANE-I, 4-DIONES
La présente invention concerne une nouvelle méthode de synthèse de 2,5-dioxane- 1,4-diones.The present invention relates to a novel method for synthesizing 2,5-dioxane-1,4-diones.
Les PLGA sont généralement obtenus par (co)polymérisation par ouverture de cycle du lactide et du glycolide. Ces monomères dérivés de l'acide lactique et de l'acide glycolique sont les prototypes des 2,5-dioxane-l,4-diones. La modification des propriétés des PLGA constitue un enjeu important, en particulier dans leur application en tant que matrice biodégradable et bioassimilable pour le piégeage et la libération contrôlée de principes actifs. De façon assez surprenante, l'approche qui consiste à modifier les substituants du squelette 2,5-dioxane-l,4-dione n'a été que peu développée jusqu'à présent, ce qui peut s'expliquer en pratique par Tassez faible accessibilité de ces motifs.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. Surprisingly enough, 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.
a Les monomères symétriques tels que le lactide ou le glycolide sont généralement préparés à partir des α-hydroxy acides correspondants. Cette approche est délicate car elle nécessite l'élimination de l'eau formée et la distillation sous vide du monomère. Pour accéder aux monomères dissymétriques, deux précurseurs différents doivent être utilisés, typiquement un α-hydroxy acide et un dérivé mono- ou di-halogéné (C-M. Dong et al, J Polym. ScI Part A : Polym. Chern. 2000, 38, 4179-4184 ; M. Leemhuis et al, EUT. J. Org. Chem. 2003, 3344-3349).at Symmetrical monomers such as lactide or glycolide are generally prepared from the corresponding α-hydroxy acids. This approach is difficult because it requires the elimination of the water formed and the vacuum distillation of the monomer. To access the asymmetric monomers, two different precursors must be used, typically an α-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).
- o _ - o _
Dans la pratique, la limitation majeure de toutes ces stratégies de synthèse est probablement l'étape finale de fermeture du cycle à 6 chaînons qui est de façon inhérente en compétition avec la formation de dimères et d'oligomères, par voie intermoléculaire plutôt qu'intramoléculaire. La déposante a donc envisagé une nouvelle voie de synthèse de 2,5-dioxane-l,4-diones.In practice, the major limitation of all these synthetic strategies is probably the final step of closing the 6-membered ring which is inherently competitive with the formation of dimers and oligomers, intermolecularly rather than intramolecularly. . The Applicant has therefore considered a new route of synthesis of 2,5-dioxane-1,4-diones.
La présente invention a donc pour objet un procédé de préparation de 2,5-dioxane- 1,4-diones de formule (I)The subject of the present invention is therefore a process for the preparation of 2,5-dioxane-1,4-diones of formula (I)
dans laquelle R1, R2, R3 et R4 représentent, indépendamment, l'atome d'hydrogène ; halo ; (C2-C6)alkényle ; (C3-C7)cycloalkyle ; cyclohexényle ; un radical de formule -(CH2VV-Win which 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 représente une liaison covalente, l'atome d'oxygène ou le radical -C(O)-O- ;V represents a covalent bond, the oxygen atom or the radical -C (O) -O-;
W représente l'atome d'hydrogène, un radical (Ci-Cis)alkyle éventuellement substitué par un ou plusieurs radicaux halo identiques ou différents ; le radical aryle ou aralkyle, les radicaux aryle et aralkyle étant éventuellement substitués par un ou plusieurs substituants identiques ou différents choisis parmi : -(CH2)n-Y-Z, i halo, nitro et cyano ;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 représente -O-, -S- ou une liaison covalente ;Y represents -O-, -S- or a covalent bond;
Z représente l'atome d'hydrogène ou un radical éventuellement substitué par un ou plusieurs radicaux halo identiques ou différents ; ou aralkyle ;Z represents the hydrogen atom or a radical optionally substituted with one or more identical or different halo radicals; or aralkyl;
m et n représentent indépendamment un entier de 0 à 4 ;m and n independently represent an integer of 0 to 4;
par oxydation de la fonction cétone d'un composé cyclique de formule (II) by oxidation of the ketone function of a cyclic compound of formula (II)
Dans les définitions indiquées ci-dessus, l'expression halo représente le radical fluoro, chloro, bromo ou iodo, de préférence chloro, fluoro ou bromo. L'expression (CrC6)alkyle représente un radical alkyle ayant de 1 à 6 atomes de carbone, linéaire ou ramifié, tels que les radicaux méthyle, éthyle, propyle, isopropyle, butyle, isobutyle, sec-butyle et tert-butyle, pentyle ou amyle, isopentyle, néopentyle, 2,2-diméthyl- propyle, hexyle, isohexyle ou 1,2,2-triméthyl-propyle. Le terme (CrC18)alkyle désigne un radical alkyle ayant de 1 à 18 atomes de carbone, linéaire ou ramifié, tels les radicaux contenant de 1 à 6 atomes de carbone tels que définis ci-dessus mais également heptyle, octyle, 1,1,2,2-tétraméthyl-propyle, 1,1,3,3-tétraméthyl-butyle, nonyle, décyle, undécyle, dodécyle, tridécyle, tétradécyle, pentadécyle, hexadécyle, heptadécyle, octadécyle. Par l'expression alkyle substitué par au moins un radical halo, il faut comprendre toute chaîne alkyle linéaire ou ramifiée, contenant au moins un radical halo positionnée le long de la chaîne tel que par exemple -CHCl-CH3 mais également -CF3.In the definitions given above, the expression 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. The term (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. By the expression 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 .
Dans la présente demande également, le radical (CH2)I (i entier pouvant représenter m et n tels que définis ci-dessus), représente une chaîne hydrocarbonée, linéaire ou ramifiée, de i atomes de carbone. Ainsi le radical -(CH2)3- peut représenter -CH2-CH2-CH2- mais également -CH(CH3)-CH2-, -CH2-CH(CH3)- ou -C(CH3)2-.In the present application also, 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. Thus 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 -.
Par (C2-C6)alkényle, on entend un radical alkyle linéaire ou ramifié comptant de 2 à 6 atomes de carbone et présentant au moins une insaturation (double liaison), comme par exemple vinyle, allyle, propényle, butényle ou pentényle.By (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.
Le terme (C3-C7)cycloalkyle désigne un système monocyclique carboné saturé comprenant de 3 à 7 atomes de carbone, et de préférence les cycles cyclopropyle, cyclobutyle, cyclopentyle, cyclohexyle ou cycloheptyle.The term (C 3 -C 7) cycloalkyl denotes a saturated carbon monocyclic system comprising from 3 to 7 carbon atoms, and preferably the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl rings.
L'expression aryle représente un radical aromatique, constitué d'un cycle ou de cycles condensés, comme par exemple le radical phényle, naphtyle, fluorényle ou anthryle. Le terme aralkyle (arylalkyle) désigne de préférence les radicaux dans lesquels les radicaux aryle et alkyle sont tels que définis ci-dessus comme par exemple benzyle ou phénéthyle.The term "aryl" represents an aromatic radical, consisting of a ring or condensed rings, such as, for example, the phenyl, naphthyl, fluorenyl or anthryl radical. The term aralkyl (arylalkyl) preferably refers to radicals in which the radicals aryl and alkyl are as defined above such as benzyl or phenethyl.
Ainsi, lors du procédé de transformation du composé (II) en composé (I)Thus, during the process for converting compound (II) to compound (I)
les réactions compétitives de dimérisation et d'oligomérisation qui sont observées lors de la synthèse de lactide ou glycolide par condensation, sont complètement évitées.the competitive dimerization and oligomerization reactions which are observed during the synthesis of lactide or glycolide by condensation are completely avoided.
Pour la transformation de la fonction cétone du composé (II) en fonction ester, plusieurs types d'oxydation peuvent être mis en oeuvre ; l'oxydation peut ainsi s'effectuer par exemple en présence d'un agent oxydant tels qu'un peracide ou un peroxyde (selon la réaction d'oxydation de Baeyer Villiger), en présence d'un catalyseur métallique (S. I. Murahashi et al, Tetrahedron Lett. 1992, 33, 7557-7760 et C. BoIm et al, Tetrahedron Lett. 1993, 34, 3405-3408) ou bien par voie enzymatique (M. D. Mihovilovic et al, Ew. J. Org. Chem. 2002, 3711-3730).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).
De préférence, un procédé selon l'invention s'effectue en présence d'un agent oxydant selon la réaction d'oxydation de Baeyer Villiger. Dans ce cas, la réaction d'oxydation s'effectue de façon très préférentielle du côté le plus encombré de la cétone de sorte que les 2,5-dioxane-l,4-diones peuvent être obtenues très sélectivement. De manière préférentielle, l'agent oxydant est utilisé en présence d'un catalyseur.Preferably, a process according to the invention is carried out in the presence of an oxidizing agent according to the oxidation reaction of Baeyer Villiger. In this case, 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. Preferably, the oxidizing agent is used in the presence of a catalyst.
L'agent oxydant (ou agent d'oxydation) utilisé pour la mise en œuvre du procédé selon l'invention, peut être un peracide ou un peroxyde. Comme exemple de peracide, on peut citer l'acide trifluoroperacétique (TFPAA), l'acide peracétique (PAA), l'acide métachloroperbenzoïque (m-CPBA), de préférence en association avec des acides deThe oxidizing agent (or oxidation agent) used for carrying out the process according to the invention may be a peracid or a peroxide. As an example of a peracid, mention may be made of trifluoroperacetic acid (TFPAA), peracetic acid (PAA) and metachloroperbenzoic acid (m-CPBA), preferably in combination with
Lewis (SnCl4, Sn(OTf)3, Re(OTf)3) ou des acides forts (acides sulfoniques, Nafion-H,Lewis (SnCl 4 , Sn (OTf) 3 , Re (OTf) 3 ) or strong acids (sulfonic acids, Nafion-H,
CF3COOH...). Comme exemple de peroxyde, on peut citer l'eau oxygénée (H2O2) ; l'eau oxygénée sera utilisée seule ou en présence d'un catalyseur qui peut être un acide de Lewis (comme BF3) ou un complexe métallique que ce soit en phase homogène (Mo,CF 3 COOH ...). 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,
Re, Pt) ou en phase hétérogène (zéolithe d'étain, hydrotalcite d'étain) ; on peut également citer le bis(triméthylsilyl)peroxide Me3SiOOSiMe3 qui sera utilisé en présence d'un acide de Lewis (Me3SiOTf, SnCl4 ou BF3OEt2).Re, Pt) or heterogeneous phase (tin zeolite, tin hydrotalcite); we can also mention bis (trimethylsilyl) peroxide Me 3 SiOOSiMe 3 which will be used in the presence of a Lewis acid (Me 3 SiOTf, SnCl 4 or BF 3 OEt 2 ).
La présente invention a plus particulièrement pour objet un procédé tel que défini ci-dessus, caractérisé en ce que l'agent d'oxydation est un peracide ou un peroxyde.The present invention more particularly relates to a process as defined above, characterized in that the oxidizing agent is a peracid or a peroxide.
De préférence, l'agent oxydant est un peracide. Le peracide est utilisé préférentiellement en présence d'un acide de Lewis ou d'un acide fort, et plus particulièrement en présence d'un acide fort choisi parmi les acides sulfoniques.Preferably, 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.
De manière très préférentielle, le peracide est l'acide métachloroperbenzoïque (m-CPBA). L'acide métachloroperbenzoïque est préférentiellement utilisé en présence d'acide trifluorométhanesulfonique .Most preferably, the peracid is metachloroperbenzoic acid (m-CPBA). Metachloroperbenzoic acid is preferably used in the presence of trifluoromethanesulfonic acid.
De préférence également, l'agent oxydant est un peroxyde.Also preferably, the oxidizing agent is a peroxide.
Les agents d'oxydation mentionnés ci-dessus sont en général commerciaux. Les agents non commerciaux peuvent être synthétisés selon des méthodes connues de l'homme de l'art. Ainsi, l'acide trifluoroperacétique qui n'est pas commercial peut être facilement obtenu par action d'eau oxygénée H2O2 sur l'acide ou l'anhydride trifluoroacétique CF3CO2H et (CF3CO)2O, respectivement (R. Liotta et al, J. Org. Chem. 1980, 45, 2887-2890 ; M. Anastasia et al, J Org. Chem. 1985, 50, 321-325 ; P. A. Krasutsky et al., J. Org. Chem. 2001, 66, 1701-1707). De même, le bis(triméthylsilyl)peroxide n'est pas commercial mais il est facilement accessible à partir du complexe H2O2- l,4-diazabicyclo[2,2,2]octane [DABCO, N(CH2CH2)3N] et de Me3SiCl (P. G. Cookson et al, J Orga.nomet.Chem. 1975, 99, C31-C32 ; M. Taddei et al., Synth. Comm. 1986, 633-635).The 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). Similarly, 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).
Les céto-esters cycliques de formule (II), utilisés comme précurseurs pour la synthèse de 2,5-dioxane-l,4-diones (I) telles que définies ci-dessus, sont facilement accessibles par des méthodes classiques connues de l'homme de l'art (E. B. Reid et al, J. Org. Chem. 1950, 15, 572-582).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).
La présente invention a plus particulièrement pour objet également un procédé tel que défini ci-dessus, caractérisé en ce que le radical aryle est le radical phényle et le radical aralkyle est le radical benzyle. La présente invention a plus particulièrement pour objet également un procédé tel que défini ci-dessus, caractérisé en ce que Ri, R2, R3 et R4 représentent, indépendamment, l'atome d'hydrogène ; ou un radical de formule -(CH2)m-V-W avec V qui représente une liaison covalente et W un radical (Ci-C6)alkyle, et plus préférentiellement m est égal à zéro. De préférence Ri, R2, R3 et R4 représentent, indépendamment, l'atome d'hydrogène, le radical méthyle ou le radical éthyle.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. Preferably, R 1 , R 2 , R 3 and R 4 represent, independently, the hydrogen atom, the methyl radical or the ethyl radical.
La présente invention a plus particulièrement pour objet également un procédé tel que défini ci-dessus, caractérisé en ce que Ri et R2 représentent, indépendamment, un radical de formule -(CH2)m-V-W avec V qui représente une liaison covalente, m est égal à zéro et W un radical (Ci-C6)alkyle, et R3 et R4 représentent, indépendamment, l'atome d'hydrogène ou un radical de formule -(CH2)Hi-V-W avec V qui représente une liaison covalente, m est égal à zéro et W un radical (Ci-C6)alkyle.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.
La présente invention a plus particulièrement pour objet également un procédé tel que défini ci-dessus, caractérisé en ce que Ri et R2, représentent, indépendamment, le radical méthyle ou éthyle, et R3 et R4 représentent, indépendamment, l'atome d'hydrogène ou un radical méthyle ou éthyle.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.
La présente invention a également pour objet des composés de formule (I) tels qu'obtenus selon le procédé défini ci-dessus.The subject of the present invention is also compounds of formula (I) as obtained according to the process defined above.
Partie expérimentaleExperimental part
Exemple 1 : 3,3-diméthyl-2,5-dioxane-l,4-dioneExample 1 3,3-dimethyl-2,5-dioxane-1,4-dione
Etape 1 : synthèse du précurseur (II)Step 1: synthesis of the precursor (II)
La synthèse du composé (II) s'effectue selon le schéma réactionnel suivant : The synthesis of the compound (II) is carried out according to the following reaction scheme:
La formation du composé (2) à partir du composé (1) peut s'effectuer selon H. C. Brown et al, J. Am. Chern. Soc. 1988, 110, 1539-1546. Les étapes de synthèse des composés (3) et (4) peuvent s'effectuer selon M. Conrad et al, Ber. 1898, 31, 2726- 2731. Enfin l'étape finale de formation du composé (II) à partir du composé (4) peut s'effectuer selon E. B. Reid et al., J. Org. Chem. 1950, 75, 572-582.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. Finally, 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.
Etape 2 : synthèse de la 3,3-diméthyl-2,5-dioxane-l,4-dioneStep 2: synthesis of 3,3-dimethyl-2,5-dioxane-1,4-dione
mCPBA mCPBA
Conditions 1 :Conditions 1:
Une solution de 5 g de céto-ester cyclique (39 mmol) et 13,5 g d'acide métachloroperbenzoïque (2 éq.) dans 100 ml de dichlorométhane est chauffée au reflux pendant 48 heures. Le contrôle par RMN 1H d'un aliquot du milieu réactionnel révèle la conversion complète du cycle à 5 chaînons et la formation très majoritaire de 3,3-diméthyl-2,5-dioxane-l,4-dione (rendement spectroscopique : 85 %).A solution of 5 g of cyclic keto ester (39 mmol) and 13.5 g of metachloroperbenzoic acid (2 eq) in 100 ml of dichloromethane is refluxed for 48 hours. Control by 1 H NMR of an aliquot of the reaction mixture revealed complete conversion of the 5-membered ring and the very predominant formation of 3,3-dimethyl-2,5-dioxane-l, 4-dione (spectroscopic yield: 85 %).
Conditions 2 :Conditions 2:
Une solution de 5 g de céto-ester cyclique (39 mmol) et 8,1 g d'acide métachloroperbenzoïque (1,2 éq.) dans 40 ml de dichlorométhane est chauffée au reflux pendant 24 heures. La conversion complète du cycle à 5 chaînons est contrôlée par RMN 1H sur un prélèvement. Le milieu réactionnel est ensuite refroidi à -18° C pendant une nuit puis filtré sur fritte pour éliminer l'acide métachlorobenzoïque formé. Le filtrat est concentré sous vide. Le résidu est recristallisé dans l'acétate d'éthyle à -18° C. 3,9 g de 3,3-diméthyl-2,5-dioxane-l,4-dione analytiquement pure sont ainsi obtenus (70 % de rendement en produit isolé). Le produit est caractérisé par RMN 1H [4,97 (s, 2H), 1,70 (s, 6H)] et 13C [167,7 et 163,9 (C=O), 79,8 (Cq), 65,8 (CH2), 25,8 (CH3)], RX (cf. figure 1), mp (84-85° C) et analyse élémentaire Calculé C : 50,00, H : 5,56 ; Trouvé C : 49,98, H : 5,33.A solution of 5 g of cyclic keto ester (39 mmol) and 8.1 g of metachloroperbenzoic acid (1.2 eq) in 40 ml of dichloromethane is refluxed for 24 hours. Complete conversion of the 5-membered ring is monitored by 1 H NMR on a sample. The reaction medium is then cooled to -18 ° C. for overnight and then filtered on frit to remove metachlorobenzoic acid formed. The filtrate is concentrated under vacuum. The residue is recrystallized from ethyl acetate at -18 ° C. 3.9 g of analytically pure 3,3-dimethyl-2,5-dioxane-1,4-dione are thus obtained (70% yield). isolated product). The product was characterized by 1 H NMR [4.97 (s, 2H), 1.70 (s, 6H)] and 13 C [167.7 and 163.9 (C = O), 79.8 (C q ), 65.8 (CH 2 ), 25.8 (CH 3 )], RX (see Figure 1), mp (84-85 ° C) and elemental analysis C: 50.00, H: 5.56 ; Found C: 49.98, H: 5.33.
Conditions 3 :Conditions 3:
Une solution de I g de céto-ester cyclique (7,8 mmol), 2,7 g d'acide métachloroperbenzoïque (2 éq.) et 70 μl d'acide trifluorométhanesulfonique (0,1 éq.) dans 20 ml de dichlorométhane est laissée sous agitation à température ambiante pendant 3 heures. Le solvant est éliminé sous vide, puis le milieu est analysé. La RMN 1H révèle la conversion complète du cycle à 5 chaînons et la formation majoritaire de 3,3-diméthyl-2,5-dioxane-l,4-dione (rendement spectroscopique : 60 %).A solution of 1 g of cyclic keto ester (7.8 mmol), 2.7 g of metachloroperbenzoic acid (2 eq.) And 70 μl of trifluoromethanesulfonic acid (0.1 eq.) In 20 ml of dichloromethane is left stirring at room temperature for 3 hours. The solvent is removed in vacuo and then the medium is analyzed. 1 H NMR reveals the complete conversion of the 5-membered ring and the major formation of 3,3-dimethyl-2,5-dioxane-1,4-dione (spectroscopic yield: 60%).
Exemple 2 : 3-éthyl-3-méthyl-2,5-dioxane-l,4-dioneExample 2: 3-ethyl-3-methyl-2,5-dioxane-1,4-dione
Etape 1 : synthèse du précurseur (II)Step 1: synthesis of the precursor (II)
La synthèse du composé (II) s'effectue selon le même schéma réactionnel que dans l'exemple 1 :The synthesis of the compound (II) is carried out according to the same reaction scheme as in Example 1:
Etape 2 : synthèse de la 3-éthyl-3-méthyl-2,5-dioxane-l,4-dione Step 2: Synthesis of 3-ethyl-3-methyl-2,5-dioxane-1,4-dione
mCPBA mCPBA
Une solution de 0,5 g de céto-ester cyclique (3,5 mmol) et 1,21 g d'acide métachloroperbenzoïque (2 éq.) dans 10 ml de dichlorométhane est chauffée au reflux pendant 48 heures. Après retour à température ambiante, le solvant est éliminé sous vide. L'analyse par RMN 1H révèle la conversion complète du cycle à 5 chaînons et la formation majoritaire de la 3-éthyl-3-méthyl-2,5-dioxane-l,4-dione (rendement spectroscopique : 75 %). Caractéristiques RMN 1H [4,97 (s, 2H), 1,95 (q, 2H, 3JHH = 7,5 Hz), 1,67 (s, 3H), 1,03 (t, 3H, 3JHH = 7,5 Hz)]. A solution of 0.5 g of cyclic keto ester (3.5 mmol) and 1.21 g of metachloroperbenzoic acid (2 eq) in 10 ml of dichloromethane is refluxed for 48 hours. After returning to ambient temperature, the solvent is removed in vacuo. 1 H NMR analysis reveals the complete conversion of the 5-membered ring and the major formation of 3-ethyl-3-methyl-2,5-dioxane-1,4-dione (spectroscopic yield: 75%). Characteristic 1 H NMR [4.97 (s, 2H), 1.95 (q, 2H, 3 J HH = 7.5 Hz), 1.67 (s, 3H), 1.03 (t, 3H, 3 J HH = 7.5 Hz)].
Tableau 1. Données cristallographiques pour le composé de l'exemple 1.Table 1. Crystallographic data for the compound of Example 1.
Formule empirique C6 H S 04Empirical formula C6 H S 04
Masse molaire 144, 12Molar mass 144, 12
Température 193(2) KTemperature 193 (2) K
Longueur d'onde 0,71073 ÀWavelength 0.71073 to
Système cristallin OrthorhombiqueOrthorhombic crystalline system
Groupe spatial P2( l )2( 1 )2(1)Space group P2 (l) 2 (1) 2 (1)
Paramètres de maille a = 5,8935(10) A α = 90°. b = 9,6410(16) A β = 90°. c = 1 1 , 6372(19) A γ = 90°.Mesh parameters a = 5.8935 (10) A α = 90 °. b = 9.6410 (16) β = 90 °. c = 1 1, 6372 (19) A γ = 90 °.
Volume 66 1 ,22( 19) A3 Volume 66 1, 22 (19) to 3
Z 4Z 4
Densité (calculée) 1 ,448 Mg/m3 Density (calculated) 1, 448 Mg / m 3
Coefficient d'absorption 0, 123 mm"1 Coefficient of absorption 0, 123 mm " 1
F(OOO) 304F (OOO) 304
Taille du cristal 0,2 x 0,2 x 0,6 mm3 Crystal size 0.2 x 0.2 x 0.6 mm 3
Valeurs de thêta pour l'acquisition des données de 2,74 à 26,38°.Theta values for data acquisition from 2.74 to 26.38 °.
Valeurs des indices h, k, 1 -7<=h<=4, -12<=k<=12, -14<=1<=14Values of the indices h, k, 1 -7 <= h <= 4, -12 <= k <= 12, -14 <= 1 <= 14
Réflexions collectées 4337Thoughts collected 4337
Réflexions indépendantes 1346 [R(int) = 0,0559]Independent Reflections 1346 [R (int) = 0.0559]
Rapport données coll. / thé. jusqu'à thêta 26,38 ° 100,0 %Report data coll. / tea. until theta 26.38 ° 100.0%
Correction d'absorption AucuneAbsorption correction None
Méthode d'affmement Moindres carrés sur la matrice complète en F2 Lightening method Least squares on the complete matrix in F 2
Données / contraintes / paramètres 1346 / 0 / 93Data / constraints / parameters 1346/0/93
Coefficient de corrélation sur F2 .1 ,070Correlation coefficient on F 2 .1, 070
Indices R finaux [I>2sigma(I)] Rl = 0,0308, wR2 = 0,0742Final R-indices [I> 2sigma (I)] R1 = 0.0308, wR2 = 0.0742
Indices R (toutes données) Rl = 0,0364, wR2 = 0,0774Indices R (all data) R1 = 0.0364, wR2 = 0.0774
Paramètre structural absolu 0,2( 12)Absolute structural parameter 0.2 (12)
Max et min de densité élec. résiduelle 0, 182 et -0,144 e.Â"3 Tableau 2. Coordonnées atomiques (x 104) et paramètres équivalents de déplacement isotropique (Â2 x 103) du composé de l'exemple 1. U(eq) est défini comme un tiers de la trace du tenseur U'i orthogonalisé.Max and min of electrical density residual 0, 182 and -0,144 e. "3 Table 2. Atomic coordinates (x 10 4 ) and equivalent isotropic displacement parameters (λ 2 x 10 3 ) of the compound of Example 1. U (eq) is defined as one-third of the trace of the orthogonalized tensor U'i.
U(eq)U (eq)
C(I) 1812(2) 3446(2} 10097(1) 25(1) 0(1) 2005(2) 3362( 1 ) 11125(1) 32(1) C(2) 1817(3) 2391(2) 8227(1) 30(1) 0(2) 1915(2) 2288(1) 9464(1) 28(1) C(3) 320(3) 3535(2) 7795(1) 28(1) 0(3) -557(2) 3507( 1) 6861(1) 39(1) C(4) 1500(2) 4820(2) 9471(1) 26(1) 0(4) -18(2) 4628( 1 ) 8487(1) 29(1) C(5) 3794(3) 5354(2) 9049(1) 35(1) C(6) 310(3) 5865(2) 10226(1) 37(1) C (I) 1812 (2) 3446 (2) 10097 (1) 25 (1) 0 (1) 2005 (2) 3362 (1) 11125 (1) 32 (1) C (2) 1817 (3) 2391 (1) 2) 8227 (1) 30 (1) 0 (2) 1915 (2) 2288 (1) 9464 (1) 28 (1) C (3) 320 (3) 3535 (2) 7795 (1) 28 (1) 0 (3) -557 (2) 3507 (1) 6861 (1) 39 (1) C (4) 1500 (2) 4820 (2) 9471 (1) 26 (1) 0 (4) -18 (2) 4628 (1) 8487 (1) 29 (1) C (5) 3794 (3) 5354 (2) 9049 (1) 35 (1) C (6) 310 (3) 5865 (2) 10226 (1) 37 (1) 1)
Tableau 3. Longueurs de liaison [Â] et angles de liaison [°] du composé de l'exemple 1.Table 3. Binding lengths [Å] and bond angles [°] of the compound of Example 1.
C(I)-O(I) 1,2047(17)C (I) -O (I) 1.2047 (17)
C(l)-O(2) 1,3391 (19)C (1) -O (2) 1.3391 (19)
C(l)-C(4) 1,523(2)C (1) -C (4) 1.523 (2)
C(2)-O(2) 1,4435(16)C (2) -O (2) 1.4435 (16)
C(2)-C(3) 1,499(2)C (2) -C (3) 1.499 (2)
C(3)-O(3) 1,2033(18)C (3) -O (3) 1.2033 (18)
C(3)-O(4) 1,3412(19)C (3) -O (4) 1.3412 (19)
C(4)-O(4) 1,4643(18)C (4) -O (4) 1.4643 (18)
C(4)-C(6) 1,510(2)C (4) -C (6) 1.510 (2)
C(4)-C(5) 1,528(2)C (4) -C (5) 1.528 (2)
O(l)-C(l)-O(2) 119,12(14)O (1) -C (1) -O (2) 119.12 (14)
O(l)-C(l)-C(4) 123,02(14)O (1) -C (1) -C (4) 123.02 (14)
O(2)-C(l)-C(4) 117,85(12)O (2) -C (1) -C (4) 117.85 (12)
O(2)-C(2)-C(3) 114,11(12)O (2) -C (2) -C (3) 114.11 (12)
C(l)-O(2)-C(2) 119,30(12)C (1) -O (2) -C (2) 119.30 (12)
O(3)-C(3)-O(4) 119,77(15)O (3) -C (3) -O (4) 119.77 (15)
O(3)-C(3)-C(2) 122,60(14)O (3) -C (3) -C (2) 122.60 (14)
O(4)-C(3)-C(2) 117,63(12)O (4) -C (3) -C (2) 117.63 (12)
O(4)-C(4)-C(6) 104,80(12)O (4) -C (4) -C (6) 104.80 (12)
O(4)-C(4)-C(l) 109,75(12)O (4) -C (4) -C (1) 109.75 (12)
C(6)-C(4)-C(l) 1 10,98(13)C (6) -C (4) -C (1) 1 10.98 (13)
O(4)-C(4)-C(5) 109,40(12)O (4) -C (4) -C (5) 109.40 (12)
C(6)-C(4)-C(5) 111,91(14)C (6) -C (4) -C (5) 111.91 (14)
C(l)-C(4)-C(5) 109,88(12)C (1) -C (4) -C (5) 109.88 (12)
C(3)-O(4)~C(4) 118,55(12) C (3) -O (4) ~ C (4) 118.55 (12)
Tableau 4. Paramètres de déplacement anisotropique (Â2 x 103) du composé de l'exemple 1.Table 4. Anisotropic displacement parameters (λ 2 × 10 3 ) of the compound of Example 1.
L'exposant du facteur de déplacement anisotropique prend la forme : -2π2[h2 a*2Un + ... + 2 h k a* b* U12 ]The exponent of the anisotropic displacement factor takes the form: -2π 2 [h 2 a * 2 U n + ... + 2 hka * b * U 12 ]
U11 U22 U33 U23 U13 TJ12U 11 U 22 U 33 U 23 U 13 TJ12
C(I) 16(1) 33(1) 26(1) 2(1) -1(1) 0(1)C (I) 16 (1) 33 (1) 26 (1) 2 (1) -1 (1) O (1)
0(1) 29(1) 45(1) 23(1) 5(1) -2(1) 2(1)0 (1) 29 (1) 45 (1) 23 (1) 5 (1) -2 (1) 2 (1)
C(2) 33(1) 33(1) 24(1) -3(1) 0(1) 1(1)C (2) 33 (1) 33 (1) 24 (1) -3 (1) 0 (1) 1 (1)
0(2) 30(1) 29(1) 25(1) 2(1) -2(1) 2(1)0 (2) 30 (1) 29 (1) 25 (1) 2 (1) -2 (1) 2 (1)
C(3) 25(1) 36(1) 23(1) 3(1) 0(1) -5(1)C (3) 25 (1) 36 (1) 23 (1) 3 (1) O (1) -5 (1)
0(3) 44(1) 48(1) 25(1) 0(1) -8(1) -2(1)0 (3) 44 (1) 48 (1) 25 (1) 0 (1) -8 (1) -2 (1)
C(4) 25(1) 30(1) 23(1) 1(1) -4(1) 0(1)C (4) 25 (1) (1) 23 (1) 1 (1) -4 (1) O (1)
0(4) 30(1) 30(1) 27(1) 2(1) -7(1) 3(1)0 (4) 30 (1) 30 (1) 27 (1) 2 (1) -7 (1) 3 (1)
C(5) 33(1) 36(1) 34(1) 3(1) -2(1) -10(1)C (5) 33 (1) 36 (1) 34 (1) 3 (1) -2 (1) -10 (1)
C(6) 41(1) 36(1) 35(1) -4(1) -3(1) 9(1)C (6) 41 (1) 36 (1) 35 (1) -4 (1) -3 (1) 9 (1)
Tableau 5. Coordonnées des atomes d'hydrogène (x 104) et paramètres de déplacement isotropique (A2X 103) du composé de l'exemple 1.Table 5. Hydrogen atom coordinates (x 10 4 ) and isotropic displacement parameters (A 2 X 10 3 ) of the compound of Example 1.
U(eq)U (eq)
H(2A) 1262 1499 7913 36 H(2B) 3372 2540 7930 36 H(5A) 4514 4648 8565 52 H(5B) 4770 5554 9710 52 H(5C) 3570 6203 8600 52 H(6A) 58 6723 9792 56 H(6B) 1252 6064 10900 56 H(6C) 1153 5487 10476 56 H (2A) 1262 1499 7913 36H (2B) 3372 2540 7930 36H (5A) 4514 4648 8565 52H (5B) 4770 5554 9710 52H (5C) 3570 6203 8600 52H (6A) 58 6723 9792 56H ( 6B) 1252 6064 10900 56 H (6C) 1153 5487 10476 56
Claims
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0408211A FR2873371B1 (en) | 2004-07-26 | 2004-07-26 | NEW METHOD OF SYNTHESIS OF 2,5 DIOXANE 1,4 DIONES |
| PCT/FR2005/001909 WO2006018524A1 (en) | 2004-07-26 | 2005-07-25 | Method for the synthesis of 2,5-dioxane-1,4-diones |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1773803A1 true EP1773803A1 (en) | 2007-04-18 |
Family
ID=34947240
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP05793596A Withdrawn EP1773803A1 (en) | 2004-07-26 | 2005-07-25 | Method for the synthesis of 2,5-dioxane-1,4-diones |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US7504524B2 (en) |
| EP (1) | EP1773803A1 (en) |
| AR (1) | AR049740A1 (en) |
| FR (1) | FR2873371B1 (en) |
| RU (1) | RU2382774C2 (en) |
| WO (1) | WO2006018524A1 (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2873371B1 (en) | 2004-07-26 | 2008-07-04 | Sod Conseils Rech Applic | NEW METHOD OF SYNTHESIS OF 2,5 DIOXANE 1,4 DIONES |
| US20130266706A1 (en) * | 2010-07-13 | 2013-10-10 | Nederlandse Organisatie Voor Toegepast- Natuurwetenschappelijk Onderzoek Tno | Methods and compositions for deacidifying fruit juice |
| ITMI20131300A1 (en) * | 2013-08-01 | 2015-02-02 | Nobil Bio Ricerche Srl | COMPOSITION FOR THE FILLING OF BONE AND PERIODONTAL DEFECTS |
| DK3829601T3 (en) | 2018-08-01 | 2024-09-02 | Edix O Sarl | DEPOT-RELEASED INJECTABLE COMPOSITIONS FOR USE IN THE TREATMENT OF NAIL DISEASES |
| EP3603650A1 (en) | 2018-08-01 | 2020-02-05 | Edix O Sarl | Injectable and prolonged action compositions for use in the treatment of diseases of the nail and/or to accelerate nail growth |
| IT202000014575A1 (en) | 2020-06-18 | 2021-12-18 | Pnd Costr Elettromeccaniche S R L | AVOCADO PROCESSING MACHINE. |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1052046A (en) * | 1974-01-21 | 1979-04-03 | American Cyanamid Company | Unsymmetrically substituted 1,4-dioxane-2,5-diones |
| US5326887A (en) * | 1991-02-27 | 1994-07-05 | E. I. Du Pont De Nemours And Company | Process for the preparation of 1,4-dioxane-2,5-diones |
| WO2001042333A2 (en) * | 1999-12-13 | 2001-06-14 | Michigan State University | Process for the preparation of polymers of dimeric cyclic esters |
| DE10000333A1 (en) * | 2000-01-07 | 2001-07-19 | Lohmann Therapie Syst Lts | Pharmaceutical composition for the transdermal administration of hormones with a permeation-improving additive |
| FR2873371B1 (en) | 2004-07-26 | 2008-07-04 | Sod Conseils Rech Applic | NEW METHOD OF SYNTHESIS OF 2,5 DIOXANE 1,4 DIONES |
-
2004
- 2004-07-26 FR FR0408211A patent/FR2873371B1/en not_active Expired - Fee Related
-
2005
- 2005-07-25 US US11/572,809 patent/US7504524B2/en not_active Expired - Fee Related
- 2005-07-25 EP EP05793596A patent/EP1773803A1/en not_active Withdrawn
- 2005-07-25 RU RU2007106842/04A patent/RU2382774C2/en not_active IP Right Cessation
- 2005-07-25 WO PCT/FR2005/001909 patent/WO2006018524A1/en active Application Filing
- 2005-07-26 AR ARP050103109A patent/AR049740A1/en not_active Application Discontinuation
Non-Patent Citations (1)
| Title |
|---|
| See references of WO2006018524A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2873371A1 (en) | 2006-01-27 |
| US20080004453A1 (en) | 2008-01-03 |
| WO2006018524A1 (en) | 2006-02-23 |
| FR2873371B1 (en) | 2008-07-04 |
| RU2007106842A (en) | 2008-09-10 |
| RU2382774C2 (en) | 2010-02-27 |
| AR049740A1 (en) | 2006-08-30 |
| US7504524B2 (en) | 2009-03-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2295874C (en) | Metal complexes with a tridentate ligand as polymerisation catalysts | |
| EP1196422B1 (en) | Polymerisation catalysts | |
| WO2006018524A1 (en) | Method for the synthesis of 2,5-dioxane-1,4-diones | |
| CA2342990A1 (en) | Artemisinin derivatives, method for the preparation thereof and pharmaceutical compositions containing the same | |
| EP1392752B1 (en) | Use of zinc derivatives as cyclic ester polymerisation catalysts | |
| WO2007085729A2 (en) | Novel method for synthesis of 1,4-morpholine-2,5-diones | |
| FR3093108A1 (en) | Process for perhydrolysis of aliphatic epoxides | |
| EP1218366B8 (en) | Method for producing cox-2 inhibitors | |
| EP1196421B1 (en) | Polymerisation catalysts | |
| EP0270468B1 (en) | Process for preparing a mixture containing cyclohexanol and cyclohexanone from cyclohexane | |
| FR2525224A1 (en) | Carbene type transition metal complex coordinated with Lewis acid - used as catalyst for metathesis of simple or functionalised olefin(s) | |
| EP1290062B1 (en) | Use of stannylenes and germylenes as polymerisation catalysts for heterocycles | |
| WO2020193650A1 (en) | Process for preparing 1,2-endoperoxide compounds | |
| EP4479391A1 (en) | Process for the preparation of compounds comprising a 2,5-dihydrobenzoxepine structure by photochemical rearrangement | |
| WO2024052250A1 (en) | Method for preparing alkenylaminoboranes with or without catalyst, and derivatives thereof, and uses thereof | |
| FR2826595A1 (en) | New molybdenum (VI) organometallic complexes useful as catalysts for the oxidation of sulfides to sulfoxides and for the epoxidation of olefins | |
| CH616138A5 (en) | Process for the preparation of ketones containing a secondary or tertiary aliphatic carbon atom in at least one of the positions alpha to the carbonyl group | |
| WO2009150318A1 (en) | Novel 2-substituted quinoline derivatives, and method for preparing same | |
| WO2013041807A1 (en) | New tricyclic compounds, preparation method and use thereof | |
| WO2005116007A1 (en) | Novel 7,7-disubstituted derivatives of (5h,9h)-6,8-dioxabenzocycloheptene, preparation method thereof and use of same in the synthesis of non-steroidal vitamin d analogues |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
| 17P | Request for examination filed |
Effective date: 20070226 |
|
| AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR |
|
| RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: CHERIF-CHEIKH, ROLAND Inventor name: BEN, FREDERIC,MAISON HARDOY Inventor name: MONTES, MARTIN Inventor name: GRAULLIER, MAGALIE Inventor name: MARTIN-VACA, BLANCA Inventor name: BOURISSOU, DIDIER |
|
| DAX | Request for extension of the european patent (deleted) | ||
| 17Q | First examination report despatched |
Effective date: 20080306 |
|
| RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: IPSEN PHARMA |
|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
| 18D | Application deemed to be withdrawn |
Effective date: 20110907 |