Improved process for producing specific α,β-unsaturated carboxylic acid esters

Abstract

The present invention relates to a method for producing specific α,β-unsaturated carboxylic acid esters.

Description

[0001] The present invention relates to a method for producing specific α,β-unsaturated carboxylic acid esters.

[0002] The specific α,β-unsaturated carboxylic acid ester to be produced is represented by the following formula (I):

[0003]

[0004] in

[0005] R1 is a C1-C4 alkyl fragment, preferably -CH3 or -CH2CH3, and

[0006] R2 is

[0007]

[0008] (*shows where the keys are located).

[0009] These specific α,β-unsaturated carboxylic acid esters are useful compounds. They can be used as such, or they are useful intermediates for producing other compounds, such as vitamins, especially vitamin A acetate (via reduction followed by acetylation).

[0010] Therefore, due to the importance of such important intermediates, there is a continuing need for superior methods of producing such compounds.

[0011] The new method for producing these compounds involves a ruthenium catalyst and mild reaction conditions.

[0012] The methods used to produce these compounds are as follows:

[0013] In the presence of at least one catalyst of formula (IV), a compound of formula (II) is reacted

[0014]

[0015] Reaction with a compound of formula (III)

[0016]

[0017] wherein R1 and R2 have the same meanings as defined above for compounds of formula (I),

[0018]

[0019] in

[0020] R3, R4, R5 and R6 independently represent -CH3, -OCH3, -NO2 or halogen, and

[0021] W, X, Y and Z independently represent neutral or ionic ligands, wherein W, X, Y and Z may be monodentate or bidentate, provided that Ru is always six-fold coordinated, and

[0022] m, n, o, and p represent integers 0, 1, 2, or 3

[0023] q represents an integer of 1, 2, 3 or 4.

[0024] The catalyst is always electrically neutral. Furthermore, it is apparent that when one or both of the ligands W, X, Y or Z are bidentate, then only three or two ligands are present.

[0025] After the reaction (first cycle) is terminated, the catalyst of formula (IV) has been converted into the form of the following formula (IV'), (IV") and / or (IV'")

[0026]

[0027]

[0028] wherein all substituents have the same meanings as defined above, and wherein R7 is H or a C1-C4 alkyl moiety.

[0029] The compounds of the formulae (IV'), (IV") and (IV'") are novel.

[0030] Therefore, the present invention relates to a process (P) for producing a compound of formula (I)

[0031]

[0032] in

[0033] R1 is a C1-C4 alkyl fragment, preferably -CH3 or -CH2CH3, and

[0034] R2 is

[0035]

[0036] (*shows where the keys are located), and where

[0037] In the presence of at least one catalyst of formula (IV), a compound of formula (II) is reacted

[0038]

[0039] Reaction with a compound of formula (III)

[0040]

[0041] wherein R1 and R2 have the same meanings as defined above for the compounds of formula (I),

[0042]

[0043] in

[0044] R3, R4, R5 and R6 independently represent -CH3, -OCH3, -NO2 or halogen, and

[0045] W, X, Y and Z independently represent neutral or ionic ligands, wherein W, X, Y and Z may be monodentate or bidentate, provided that Ru is always six-fold coordinated, and

[0046] m, n, o, and p represent integers 0, 1, 2, or 3

[0047] q represents an integer of 1, 2, 3 or 4.

[0048] Compounds of formula (I) are preferred, wherein

[0049] R1 is -CH3 or -CH2CH3.

[0050] Therefore, the present invention relates to a process (P1), wherein R1 is

[0051] -CH3 or -CH2CH3.

[0052] Compounds of formula (I) are preferred, wherein

[0053] R2 is

[0054]

[0055] Therefore, the present invention relates to a process (P2) which is process (P) or (P1), wherein

[0056] R2 is

[0057]

[0058] The compounds of formula (Ia) and formula (Ib) are most preferred,

[0059]

[0060] Very preferred catalysts are those of formula (IVa), (IVb) or (IVc)

[0061]

[0062] wherein R7 is H or CH3.

[0063] The present invention therefore relates to a process (P3) which is process (P), (P1) or (P2) wherein a catalyst of the formula (IVa) is used.

[0064]

[0065] The present invention therefore relates to a process (P3') which is process (P), (P1) or (P2) wherein a catalyst of the formula (IVb) is used.

[0066]

[0067] The present invention therefore relates to a process (P3") which is process (P), (P1) or (P2) wherein a catalyst of the formula (IVc) is used.

[0068]

[0069] wherein R7 is H or CH3.

[0070] The ratio of substrate (starting material) to catalyst (on a mole basis) is generally from 5000:1 to 10:1, preferably from 1000:1 to 20:1.

[0071] Therefore, the present invention relates to a process (P4) which is process (P), (P1), (P2), (P3), (P3') or (P3"), wherein the ratio of substrate (starting material) to catalyst (on a molar basis) is from 5000:1 to 10:1.

[0072] Therefore, the present invention relates to a process (P4') which is process (P), (P1), (P2), (P3), (P3') or (P3"), wherein the ratio of substrate (starting material) to catalyst (on a molar basis) is from 1000:1 to 20:1.

[0073] The process according to the invention is carried out in the absence of any solvent or in at least one nonpolar aprotic organic solvent.

[0074] As solvents, it is within the scope of the present invention to be able to use general nonpolar aprotic organic solvents, in particular aliphatic, cyclic and aromatic hydrocarbons, for example C7-C 10 Alkanes, C5-C7 cycloalkanes, benzene, toluene and naphthalene, and mixtures of such solvents with each other, such as paraffin oil (a mixture of saturated aliphatic hydrocarbons). And carboxylic acid esters, such as ethyl acetate.

[0075] Therefore, the present invention relates to a process (P5) which is process (P), (P1), (P2), (P3), (P3'), (P3"), (P4) or (P4'), wherein the process is carried out in the absence of any solvent.

[0076] Therefore, the present invention relates to a process (P6) which is process (P), (P1), (P2), (P3), (P3'), (P3"), (P4) or (P4'), wherein the process is carried out in at least one non-polar aprotic organic solvent.

[0077] Therefore, the present invention relates to a process (P6') which is process (P), (P1), (P2), (P3), (P3'), (P3"), (P4) or (P4'), wherein the non-polar aprotic organic solvent is selected from the group consisting of aliphatic hydrocarbons, cyclic hydrocarbons, aromatic hydrocarbons and carboxylic acid esters.

[0078] Therefore, the present invention relates to a process (P6"), wherein the non-polar aprotic organic solvent is selected from the group consisting of: C7-C 10 Alkanes, C5-C7 cycloalkanes, benzene, toluene, naphthalene, paraffin oil and ethyl acetate.

[0079] The method according to the present invention is usually carried out under very mild reaction conditions. The reaction temperature is usually between -5°C and 60°C, preferably between 0°C and 50°C, more preferably between 5°C and 45°C, most preferably between 5°C and 40°C.

[0080] Therefore, the present invention relates to a method (P7), which is method (P), (P1), (P2), (P3), (P3'), (P3"), (P4), (P4'), (P5), (P6), (P6') or (P6"), wherein the method is carried out at a temperature between -5°C and 60°C.

[0081] Therefore, the present invention relates to a method (P7'), which is methods (P), (P1), (P2), (P3), (P3'), (P3"), (P4), (P4'), (P5), (P6), (P6') and (P6"), wherein the method is carried out at a temperature between 0°C and 50°C.

[0082] Therefore, the present invention relates to a method (P7"), which is method (P), (P1), (P2), (P3), (P3'), (P3"), (P4), (P4'), (P5), (P6), (P6') or (P6"), wherein the method is carried out at a temperature between 5°C and 45°C.

[0083] Therefore, the present invention relates to a method (P7'"), which is method (P), (P1), (P2), (P3), (P3'), (P3"), (P4), or (P4'), (P5), (P6), (P6') or (P6"), wherein the method is carried out at a temperature between 5°C and 40°C.

[0084] All reactants are added together and mixed. The reaction mixture is heated to a temperature at which a transition metal-based catalyzed rearrangement reaction occurs to provide a resulting mixture.

[0085] In addition, pivalic anhydride, a compound of formula (V)

[0086]

[0087] may be added to the reaction mixture.

[0088] Pivalic anhydride may be added in an amount of 0.01-0.75 mol equivalent (relative to the compound of formula (II)), preferably 0.05-0.4 mol equivalent (relative to the compound of formula (II)), 0.1-0.25 mol equivalent (relative to the compound of formula (II)).

[0089] Therefore, the present invention relates to a process (P8) which is process (P), (P1), (P2), (P3), (P3'), (P3"), (P4), (P4'), (P5), (P6), (P6'), (P6"), (P7), (P7'), (P7") or (P7'"), wherein a compound of formula (V)

[0090]

[0091] Add to the reaction mixture.

[0092] Therefore, the present invention relates to a process (P8') which is process (P8), wherein the compound of formula (V) is added in an amount of 0.01 to 0.75 mol equivalents (relative to the compound of formula (II)).

[0093] Therefore, the present invention relates to a process (P8"), which is process (P8), wherein the compound of formula (V) is added in an amount of 0.05-0.4 mol equivalent (relative to the compound of formula (II)).

[0094] Therefore, the present invention relates to a process (P8'"), which is process (P8), wherein the compound of formula (V) is added in an amount of 0.1 to 0.25 mol equivalents (relative to the compound of formula (II)).

[0095] After the reaction, the catalyst (compounds of formula (IV'), (IV") and (IV'") can be separated by a generally known method.

[0096]

[0097]

[0098] wherein all substituents have the same meanings as defined above.

[0099] Furthermore, the catalysts of the formula (compounds of formula (IV'), (IV") and (IV'")) are all novel

[0100]

[0101]

[0102] in

[0103] R3, R4, R5 and R6 independently represent -CH3, -OCH3, -NO2 or halogen, and

[0104] W, X, Y and Z independently represent neutral or ionic ligands, wherein W, X, Y and Z may be monodentate or bidentate, provided that Ru is always six-fold coordinated, and

[0105] m, n, o, and p represent integers 0, 1, 2, or 3

[0106] q represents an integer of 1, 2, 3 or 4.

[0107] Therefore, another embodiment of the present invention is the compounds of formula (IV'), (IV") and (IV'")

[0108]

[0109]

[0110] in

[0111] R3, R4, R5 and R6 independently represent -CH3, -OCH3, -NO2 or halogen, and

[0112] W, X, Y and Z independently represent neutral or ionic ligands, wherein W, X, Y and Z may be monodentate or bidentate, provided that Ru is always six-fold coordinated, and

[0113] m, n, o, and p represent integers 0, 1, 2, or 3

[0114] q represents an integer of 1, 2, 3 or 4.

[0115] Preferred compounds of formula (IV'), (IV") and (IV'") are compounds of formula (IVa), (IVb), (IVc') and (IVc")

[0116]

[0117]

[0118] The following examples further illustrate the present invention without limiting it. Unless otherwise stated, all percentages and parts given are by weight and temperatures are given in °C. Example

[0119] Embodiment 1:

[0120] 3-Methyl-1-(2,6,6-trimethylcyclohex-1-en-1-yl)pent-1-ene-4-yn-3-ol (2.33 g, 10 mmol) and 2,2-dimethylpropionic acid (1.53 g, 15 mmol, 1.5 equivalents) were dissolved in anhydrous ethyl acetate (10 mL) under an argon atmosphere. In a countercurrent of argon, 61 mg (0.1 mmol, 1.0 mol%) of [(dppe)Ru(2-methylallyl)2] was added to form a catalyst of formula (IVa). After stirring at 20°C for 24 h, the light yellow-brown reaction mixture was concentrated under reduced pressure (rotary evaporator, 20°C water bath temperature). The crude product was dried at 20 mbar for another 2 h to give a light brown oil. The product of formula (Ia) was obtained in a yield of 99%.

[0121]

[0122] In the following table, more compounds of formula (Ia) have been produced by the same way as in Example 1. Other reaction times and / or reaction temperatures and / or the amount of ethyl acetate (solvent) have been varied.

[0123]

[0124] Embodiment 2:

[0125] Under argon atmosphere, 3-methyl-1-(2,6,6-trimethylcyclohex-1-en-1-yl)pent-1-ene-4-yn-3-ol (2.18 g, 10 mmol), 2,2-dimethylpropionic acid (1.32 g, 11 mmol) and 2,2-dimethylpropionic anhydride (0.4 mL, 2 mmol) were dissolved in anhydrous ethyl acetate (10 mL). In a countercurrent of argon, a solution of 61 mg (0.1 mmol, 1.0 mol%) of [(dppe)Ru(2-methylallyl)2] in anhydrous acetone (5 mL) was added, which formed the catalyst of formula (IVa). After stirring at 20°C for 18 h, 89% conversion of 3-methyl-1-(2,6,6-trimethylcyclohex-1-en-1-yl)pent-1-ene-4-yn-3-ol was observed.

[0126] In the following table, more compounds of formula (Ia) have been produced by the same way as in Example 3. Other additives and / or solvents have been varied.

[0127]

[0128] Embodiment 3:

[0129] Under an argon atmosphere, 2,2-dimethylpropionic acid (1.0 g, 9.8 mmol) and 60 mg (0.1 mmol) of the ruthenium catalyst of formula (IV) were dissolved in anhydrous ethyl acetate (15 mL). After 0.5 h, the solvent was evaporated for 2 hours (40 ° C). The remaining solid was dissolved in anhydrous n-hexane under reflux and gradually cooled from 60 ° C to -20 ° C to form yellow sharp crystals, thereby obtaining the ruthenium catalyst of formula (IVb).

[0130] Embodiment 4:

[0131] Under argon atmosphere, 2,2-dimethylpropionic acid (5.0 g, 49 mmol) and 60 mg (0.1 mmol) of ruthenium catalyst of formula (IV) were dissolved in anhydrous ethyl acetate (10 mL). After 0.5 h, the solvent was evaporated for 2 hours (40 ° C). The remaining solid was dissolved in acetone, and a slow diffusion of n-hexane was established to form yellow sharp crystals, thereby obtaining a ruthenium catalyst of formula (IVc').

Claims

1. A method for producing a compound of formula (I) in R1 is a C1-C4 alkyl fragment, and R2 is or in In the presence of at least one catalyst of formula (IVa), formula (IVb) or formula (IVc), a compound of formula (II) is reacted with Reaction with a compound of formula (III) wherein R1 and R2 have the same meanings as defined above for compounds of formula (I), wherein R7 is H or CH3; And wherein the compound of formula (V) Add to the reaction mixture.

2. The method according to claim 1, wherein R1 is -CH3 or -CH2CH3.

3. The method according to claim 1 or 2, wherein Produces a compound of formula (Ia) 。 4. The method according to claim 1 or 2, wherein The catalyst of formula (IVa) is used 。 5. The method according to claim 1 or 2, wherein The catalyst of formula (IVb) is used 。 6. The method according to claim 1 or 2, wherein The catalyst of formula (IVc) is used wherein R7 is H or CH3.

7. The method according to claim 1 or 2, wherein the method is carried out in the absence of any solvent.

8. The method according to claim 1 or 2, wherein the method is carried out in at least one non-polar aprotic organic solvent.

9. The method according to claim 8, wherein the non-polar aprotic organic solvent is selected from the group consisting of aliphatic hydrocarbons, cyclic hydrocarbons, aromatic hydrocarbons and carboxylic acid esters.

10. The method according to claim 1 or 2, wherein the method is carried out at a temperature between -5°C and 60°C.

11. The method according to claim 1 or 2, wherein: The compound of formula (V) is added in an amount of 0.01-0.75 mol equivalent relative to the compound of formula (II).

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