NOVEL METHOD FOR PRODUCING (E,Z)-7,9-DODECADIENYL-1-ACETATE

Abstract

The present invention concerns a method to access (E,Z)-7,9-dodecadienyl-1-acetate in two synthesis steps with excellent yields and selectivity greater than 70% by transformation of 2-hexenal into a novel intermediate, which is itself then transformed into (E,Z)-7,9-dodecandienyl-1-acetate.

Claims

1. A compound of general formula 1 ##STR00011## where R1 and R1, identical or different, designate an alkyl or aryl group.

2. The compound according to claim 1 wherein the alkyl group is chosen from linear or branched C1-C6 alkyls and the aryl group is chosen from among phenyl, benzyl, mesityl or tolyl.

3. Use of a compound 1 according to one of claims 1 to 2, for the synthesis of a diene compound of the general formula: ##STR00012## where R represents the radical of the compound onto which the conjugated diene unit is grafted.

4. Use of a compound 1 according to one of claims 1 to 2, for the synthesis of pheromones comprising at least one conjugated radical of the formula:
CH.sub.3CH.sub.2CHCHCH

5. Use of a compound 1 according to one of claims 1 to 2 as an intermediate for the synthesis of (E,Z)-7,9-dodecadienyl-1-acetate.

6. A method for preparation of compound 1 comprising the following steps: provision of 2-hexenal in an appropriate solvent S1, addition of a weakly nucleophilic strong base at a temperature T1 comprised between 78 C. and 25 C. in order to form enolate, addition, at a temperature T2, identical to or different from T1, comprised between 78 C. and 25 C., of a halophosphate of formula:
XP(O)(OR1)(OR1) where X is a halogen and R1 and R1 designate identical or different groups chosen from among a linear or branched C1-C6 alkyl, an aryl such as phenyl, benzyl, mesityl or tolyl, recovery of compound 1 after washing and drying of the organic phase.

7. The method according to claim 6 characterized in that solvent S1 is chosen from the group consisting of tetrahydrofuran (THF), methyl tetrahydrofuran (MeTHF), tetramethylethylenediamine (TMEDA), tetrahydropyran, dimethoxyethane (DME), diethyl ether, methyl tert-butyl ether, highly polar solvents such as dimethylformamide (DMF), N-methylpyrrolidinone (NMP), N,N-dimethyl propylene urea (DMPU), methylcyclohexane (MeCy), alkanes of fewer than 8 carbon atoms, aromatic solvents such as toluene and mixtures thereof.

8. The method according to one of claim 6 or 7, characterized in that temperatures T1 and T2, identical or different, are comprised between 40 C. and 15 C.

9. The method according to one of claims 6 to 8, characterized in that temperatures T1 and T2, identical or different, are comprised between 20 C. and 0 C.

10. The method according to claims 6 to 9, characterized in that the weakly nucleophilic strong base is chosen from the group consisting of sodium or potassium terbutanolate, sodium or potassium diisopropylamide, sodium or potassium hexamethyldisilyl azane, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

11. A method for preparation of (E,Z)-7,9-dodecadienyl-1-acetate comprising the following steps: provision of product 1 in a solvent S2, addition of a catalytic system containing at least one iron atom at oxidation degree III, addition, at a temperature T3 comprised between 20 and 60 C., of the compound of general formula XMg(CH.sub.2).sub.6OMgX where X and X, identical or different, designate a halogen, addition of an acetylation agent, recovery of (E,Z)-7,9-dodecadienyl-1-acetate after washing and evaporation of organic solvents.

12. The method according to claim 11, characterized in that solvent S2 is chosen from among the group consisting of THF, MeTHF, methylcyclohexane (MeCy), diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane and mixtures thereof.

13. The method according to claims 11 and 12, characterized in that temperature T3 is comprised between 0 C. and 60 C.

14. The method according to claims 11 to 13, characterized in that the catalytic system Cat is chosen from the group consisting of iron trihalides, iron triacetate, iron tris-acetylacetonate, iron (III) nitrate, iron (III) phosphate optionally in the presence of ligands chosen from phosphorus or nitrogen ligands.

Description

EXAMPLES

[0075] The raw materials and solvents are raw materials available commercially from Sigma Aldrich.

[0076] The analytical method consists of gas chromatography (GC) analysis on a HP 5890 Series II device equipped with a FID detector. The chromatographic column is an Innowax 30 m, 0.25 mm, 0.25 m column with helium as the vector gas.

[0077] The furnace follows the following temperature profile: T0=150 C., Initial time 10 min. Gradient 20/min; Final temperature: 200 C. Duration 7 min.

[0078] The injector is at 250 C., the detector at 300 C.

[0079] The volume injected is 1 L. The concentration of the sample is 4 g/L in ethyl acetate (EtOAc).

[0080] The reactions are performed in a 2 L double-walled glass reactor provided with a low-temperature cooling system and the distillations are performed by means of a 10 theoretical-plate glass column.

Example 1: Preparation of the Key Intermediate with R1 and R1=Ethyl

[0081] In a reactor provided with stirring, 50 g (0.51 moles) of 2-hexenal diluted in 10 volumes of a 3-2 mixture of THF and NMP (S1) are prepared, the reaction medium temperature is lowered to a temperature T1 of 15 C., and then 69 g (0.61 moles) of potassium tert-butoxide are added. At the end of one hour, at temperature T2, still 15 C., 97 g (0.56 moles) of diethyl chlorophosphate are added. The reaction is stirred for one hour and then the product formed is isolated by washing with a sodium hydroxide solution that permits obtaining 500 g of a solution of enol phosphate in THF. The solution is dried on MgSO.sub.4 until the residual water content is less than 0.1%, the content in enol phosphate is assayed by gas chromatography. This solution may be used as such in the following examples.

[0082] Compound 1 is isolated by evaporation of the solvents under partial vacuum. 105 g of diethyl-hexa-1,3-dien-1-yl phosphate are recovered in the form of a mixture of two isomers in the following ratio:

[0083] Z,Z-diethyl-hexa-1,3-dien-1-yl phosphate: <1%

[0084] Z,E-diethyl-hexa-1,3-dien-1-yl phosphate: <1%

[0085] E,Z-diethyl-hexa-1,3-dien-1-yl phosphate: 72%

[0086] E,E-diethyl-hexa-1,3-dien-1-yl phosphate: 27%

[0087] Characterization:

[0088] Retention time by gas chromatography: Z,Z-diethyl-hexa-1,3-dien-1-yl phosphate: 13.96 min; Z,E-diethyl-hexa-1,3-dien-1-yl phosphate: 14.27 min; E,Z-diethyl-hexa-1,3-dien-1-yl phosphate: 14.43 min; E,E-diethyl-hexa-1,3-dien-1-yl phosphate: 15.27 min.

[0089] RMN .sup.1H ( ppm, CDCl.sub.3): 6.65 (1H, doublet of doublet, CH); 6.26 (1H, triplet, CH); 5.79 (1H, triplet, CH); 5.4 (1H, doublet of triplets), 4.15 (4H, triplet, OCH.sub.2), 2.11 (2H, multiplet, CH.sub.3CH.sub.2), 1.33 (6H, triplet, CH.sub.3CH.sub.2O), 0.97 (3H, triplet, CH.sub.3CH.sub.2CH).

Example 2: Synthesis of (E,Z) 7,9-Dodecadienyl-1-Acetate

[0090] 1.8 g (5.1) mmol of iron tri(acetylacetonate) are added to the intermediate solution of Example 1 and then 0.61 moles of BrMg(CH.sub.2).sub.6OMgBr in solution at 1.6 mol/L in MeTHF are poured gently into the reactor. During this addition, the reaction medium is kept at temperature T3 of 25 C. After two hours, 260 g of acetic anhydride are added to the reaction medium, which is now kept stirred at room temperature, until total conversion of the alkoxide formed during iron coupling.

[0091] The reaction medium is then washed with a 0.01 molar hydrochloric acid solution, and then with a sodium carbonate solution at a pH of 8. The organic phase is recovered and then concentrated under vacuum to recover crude 7,9-dodecadienyl-1-acetate (88 g assayed at 90% chemical purity and in an E,Z/Z,Z isomer ratio of 76%). I.e., a crude yield of 69% relative to hexenal.

[0092] The crude is distilled under high vacuum to give 75 g of 7,9-dodecadienyl-1-acetate with 98% chemical purity and an E,Z isomer content of 76%. I.e., a yield of 66% relative to hexenal.

[0093] Enrichment in E,Z Isomer:

[0094] The 75 g obtained are mixed with 130 g of urea in 800 ml of methanol.

[0095] The mixture is left to rest for 3 hours. The suspension is filtered and the residue is washed twice with 100 ml of diethyl ether. The washing fractions are collected with the filtrate and then evaporated under low pressure until complete evaporation of the solvents. 61 g of 7,9-dodecadienyl-1-acetate are obtained, of a chemical purity of 98% and with a content of 90% E,Z isomer.

Examples 3 to 20

[0096] In all of the following examples, the experimental protocol of Examples 1 and 2 is used, varying the following parameters: [0097] S1: hexenal dilution solvent. [0098] S2: diethyl-hexa-1,3-dien-1-yl-phosphate dilution solvent. [0099] S3: magnesium compound dilution solvent [0100] X: halide of compound XMg(CH.sub.2).sub.6OMgX [0101] T1: hexenal deprotonation temperature [0102] T2: diethyl-hexa-1,3-dien-1-yl-phosphate synthesis temperature [0103] T3: organomagnesium coupling temperature [0104] N1=number of moles of potassium terbutanolate/number of moles hexenal [0105] N2=number of moles of diethyl chlorophosphate/number of moles of hexenal [0106] N3=number of moles of magnesium/number of moles of hexenal

[0107] The parameters varying in the examples are summarized in Table 1

TABLE-US-00002 N2 N4 N4 Example S1* S2 S3 X T1 T2 T3 (mol) (mol) (mol) 3 THF/NMP THF THF Br 78 78 0 1.2 1.1 1.2 (17/12) 4 THF/NMP THF MeTHF Br 70 78 0 1.2 1.2 1.2 (36/12) 5 THF/NMP THF MeTHF Br 55 78 0 1.1 1.1 1.2 (36/17) 6 THF/DMPU THF MeTHF Br 35 78 0 1.2 1.1 1.2 (36/17) 7 THF/NMP THF MeTHF Br 25 0 25 1.2 1.1 1.2 (36/17) 8 THF/NMP THF MeTHF Br 15 0 0 1.2 1.1 1.2 (36/17) 9 THF/NMP THF MeTHF Br 15 15 0 1.2 1.1 1.2 (36/17) 10 THF/DMPU THF MeTHF Br 15 15 0 1.2 1.1 1.2 (36/17) 11 THF/TMEDA THF MeTHF Br 15 15 0 1.2 1.1 1.2 (36/17) 12 THF/NMP THF MeTHF Br 15 10 0 1.2 1.1 1.2 (36/17) 13 THF/NMP THF MeTHF Br 15 0 0 1.2 1.1 1.2 (36/17) 14 MTBE/NMP MTBE MeTHF Br 15 15 25 1.2 1.1 1.2 (36/17) 15 MeCy/NMP MeCy MeTHF Br 15 15 0 1.2 1.1 1.2 (36/17) 16 MeCy/NMP MeCy MeTHF Br 15 15 25 1.2 1.1 1.2 (10/2) 17 THF/DMF THF MeTHF Br 15 15 25 1.2 1.1 1.2 (36/12) 18 DMF/NMP THF MeTHF Br 15 15 30 1.2 1.1 1.2 (14/2) 19 DMF/NMP THF THF Br 15 15 25 1.2 1.1 1.2 (14/2) 20 DMPU/NMP THF THF Br 10 10 20 1.2 1.1 1.2 (14/2) 21 DMPU/NMP THF THF Br 10 10 25 1.2 1.1 1.2 (2/2) 22 NMP 5V THF THF 5 5 25 1.2 1.1 1.2 23 NMP 5V THF THF 5 0 25 1.2 1.1 1.2 *the solvent mixture is indicated: the figures in parentheses designate the respective volumes of solvent components relative to hexenal.

[0108] The crude yield (C.sub.Y) of each example reflects the crude molar yield before distillation.

[0109] The C.sub.Y(E,Z) ratio designates the proportion of E,Z isomer relative to E,E isomer.

[0110] The C.sub.Y and C.sub.Y(E,Z) data respectively designate the molar yield and the proportion of E,Z isomer relative to E,E isomer after the purification step.

[0111] These results for each example are summarized in Table 2:

TABLE-US-00003 Example Yc (%) Yc.sub.(E,Z) (%) Yield (%) Yield.sub.(E,Z) (%) 3 63 80 61 85 4 62 80 60 85 5 59 79 50 86 6 61 74 51 86 7 59 77 51 82 8 61 74 52 81 9 59 74 49 81 10 49 57 ** ** 11 42 66 ** ** 12 59 74 24 91 13 44 63 ** ** 14 51 74 ** ** 15 62 74 49 81 16 44 65 ** ** 17 65 74 52 80 18 14 72 ** ** 19 14 72 ** ** 20 38 66 ** ** 21 38 66 ** ** 22 25 57 ** ** 23 25 57 ** ** ** the experiments have not been purified