EP1773803A1

EP1773803A1 - Method for the synthesis of 2,5-dioxane-1,4-diones

Info

Publication number: EP1773803A1
Application number: EP05793596A
Authority: EP
Inventors: Didier Bourissou; Blanca Martin-Vaca; Frédéric Résidence du Parc de Lespinet BEN; Magalie Graullier; Roland Cherif-Cheikh; Martin Montes
Original assignee: Societe de Conseils de Recherches et dApplications Scientifiques SCRAS SAS
Current assignee: Ipsen Pharma SAS
Priority date: 2004-07-26
Filing date: 2005-07-25
Publication date: 2007-04-18
Also published as: FR2873371A1; RU2382774C2; RU2007106842A; AR049740A1; FR2873371B1; US7504524B2; US20080004453A1; WO2006018524A1

Abstract

The invention relates to a novel method for the synthesis of 2,5-dioxane-1,4-diones having formula (I), comprising the oxidation of the ketone function of a cyclic compound having formula (II), wherein R<sub

Description

METHOD OF SYNTHESIZING 2,5-DIOXANE-I, 4-DIONES

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. 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.

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 _

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.

The subject of the present invention is therefore a process for the preparation of 2,5-dioxane-1,4-diones of formula (I)

in 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 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;

m and n independently represent an integer of 0 to 4;

by oxidation of the ketone function of a cyclic compound of formula (II)

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 .

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 -.

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.

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.

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.

Thus, during the process for converting compound (II) to compound (I)

the competitive dimerization and oligomerization reactions which are observed during the synthesis of lactide or glycolide by condensation are completely avoided.

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).

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.

The 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 (SnCl ₄ , Sn (OTf) ₃ , Re (OTf) ₃ ) or strong acids (sulfonic acids, Nafion-H,

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) 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 ).

The present invention more particularly relates to a process as defined above, characterized in that the oxidizing agent is a peracid or a peroxide.

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.

Most preferably, the peracid is metachloroperbenzoic acid (m-CPBA). Metachloroperbenzoic acid is preferably used in the presence of trifluoromethanesulfonic acid.

Also preferably, the oxidizing agent is a peroxide.

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).

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. Preferably, 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.

Experimental part

Example 1 3,3-dimethyl-2,5-dioxane-1,4-dione

Step 1: synthesis of the precursor (II)

The synthesis of the compound (II) is carried out according to the following reaction scheme:

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.

Step 2: synthesis of 3,3-dimethyl-2,5-dioxane-1,4-dione

mCPBA

Conditions 1:

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:

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:

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%).

Example 2: 3-ethyl-3-methyl-2,5-dioxane-1,4-dione

Step 1: synthesis of the precursor (II)

The synthesis of the compound (II) is carried out according to the same reaction scheme as in Example 1:

Step 2: Synthesis of 3-ethyl-3-methyl-2,5-dioxane-1,4-dione

mCPBA

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)].

Table 1. Crystallographic data for the compound of Example 1.

Empirical formula C6 H S 04

Molar mass 144, 12

Temperature 193 (2) K

Wavelength 0.71073 to

Orthorhombic crystalline system

Space group P2 (l) 2 (1) 2 (1)

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) to ³

Z 4

Density (calculated) 1, 448 Mg / m ³

Coefficient of absorption 0, 123 mm " ¹

F (OOO) 304

Crystal size 0.2 x 0.2 x 0.6 mm ³

Theta values for data acquisition from 2.74 to 26.38 °.

Values of the indices h, k, 1 -7 <= h <= 4, -12 <= k <= 12, -14 <= 1 <= 14

Thoughts collected 4337

Independent Reflections 1346 [R (int) = 0.0559]

Report data coll. / tea. until theta 26.38 ° 100.0%

Absorption correction None

Lightening method Least squares on the complete matrix in F ²

Data / constraints / parameters 1346/0/93

Correlation coefficient on F ² .1, 070

Final R-indices [I> 2sigma (I)] R1 = 0.0308, wR2 = 0.0742

Indices R (all data) R1 = 0.0364, wR2 = 0.0774

Absolute structural parameter 0.2 (12)

Max and min of electrical density residual 0, 182 and -0,144 e.Â ^"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)

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)

Table 3. Binding lengths [Å] and bond angles [°] of the compound of Example 1.

C (I) -O (I) 1.2047 (17)

C (1) -O (2) 1.3391 (19)

C (1) -C (4) 1.523 (2)

C (2) -O (2) 1.4435 (16)

C (2) -C (3) 1.499 (2)

C (3) -O (3) 1.2033 (18)

C (3) -O (4) 1.3412 (19)

C (4) -O (4) 1.4643 (18)

C (4) -C (6) 1.510 (2)

C (4) -C (5) 1.528 (2)

O (1) -C (1) -O (2) 119.12 (14)

O (1) -C (1) -C (4) 123.02 (14)

O (2) -C (1) -C (4) 117.85 (12)

O (2) -C (2) -C (3) 114.11 (12)

C (1) -O (2) -C (2) 119.30 (12)

O (3) -C (3) -O (4) 119.77 (15)

O (3) -C (3) -C (2) 122.60 (14)

O (4) -C (3) -C (2) 117.63 (12)

O (4) -C (4) -C (6) 104.80 (12)

O (4) -C (4) -C (1) 109.75 (12)

C (6) -C (4) -C (1) 1 10.98 (13)

O (4) -C (4) -C (5) 109.40 (12)

C (6) -C (4) -C (5) 111.91 (14)

C (1) -C (4) -C (5) 109.88 (12)

C (3) -O (4) ~ C (4) 118.55 (12)

Table 4. Anisotropic displacement parameters (λ ² × 10 ³ ) of the compound of Example 1.

The exponent of the anisotropic displacement factor takes the form: -2π ² [h ² a * ² U ⁿ + ... + 2 hka * b * U ¹² ]

U ¹¹ U ²² U ³³ U ²³ U ¹³ TJ12

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)

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)

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)

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)

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)

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)

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

1. Process for preparing 2,5-dioxane-1,4-diones of formula (I)

in 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 ) _m -VW;

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 ) _H -YZ, halo, nitro and cyano;

Y represents -O-, -S- or a covalent bond;

m and n independently represent an integer of 0 to 4;

by oxidation of the ketone function of a cyclic compound of formula (II)

(ID wherein R ₁ , R ₂ , R ₃ and R ₄ are as defined above.

2. Preparation process according to claim 1, characterized in that the process is carried out in the presence of an oxidizing agent.

3. Preparation process according to claim 2, characterized in that the oxidizing agent is used in the presence of a catalyst.

4. Preparation process according to one of claims 2 to 3, characterized in that the oxidizing agent is a peracid or a peroxide.

5. Preparation process according to one of claims 2 to 4, characterized in that the oxidizing agent is a peracid.

6. Preparation process according to claim 5, characterized in that the oxidizing agent is used in the presence of a Lewis acid or a strong acid.

7. Preparation process according to claim 6, characterized in that the oxidizing agent is used in the presence of a strong acid selected from sulfonic acids.

8. Preparation process according to one of claims 5 to 7, characterized in that the oxidizing agent is metachloroperbenzoic acid.

9. Preparation process according to claim 8, characterized in that the oxidizing agent is used in the presence of trifluoromethanesulfonic acid.

10. Preparation process according to one of claims 1 to 3, characterized in that the oxidizing agent is a peroxide.

11. Preparation process according to one of the preceding claims, characterized in that the aryl radical is the phenyl radical and the aralkyl radical is the benzyl radical.

12. Preparation process according to one of the preceding claims, 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 radical (C ₁ -C (OaIlCyIe.

13. Preparation process according to one of the preceding claims, characterized in that R 1, R ₂ , R ₃ and R ₄ represent, independently, the hydrogen atom, the methyl radical or the ethyl radical.

14. Preparation process according to one of claims 1 to 12, 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 equal at zero and W a (C ₁ -C ₆ ) alkyl radical, and 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 m is zero and W is a (C ₁ -C ₆ ) alkyl radical.

15. Preparation process according to one of the preceding claims, characterized in that R 1 and R ₂ represent, independently, the methyl radical or the ethyl radical, and R ₃ and R ₄ represent, independently, the hydrogen atom or a methyl or ethyl radical.