ESTERS

TECHNOLOGICAL FIELD

The invention provides a process for the preparation of alkyl 4-methyl-6-(2,6,6- trimethylcyciohex-l-enyl)hex-3-enoate which are useful precursors for the synthesis of the amber family products such as 3a,6,6;9a-tetramethyldodecahydronaphtho[2;l- b]furan.

PRIOR ART AND BACKGROUND OF THE INVENTION

References considered to be relevant as background to the presently disclosed subject matter are listed below:

WO2012085056 teaches that alkyl 4-methyl-6-(2,6,6-trimethylcyclohex-l- enyl)hex-3-enoate (3) having high E isomer content are synthesized in two steps. In the first step cited from WO2011073387, Knoevenagel condensation of 2-methyl-4-(2,6,6- trimethylcyclohex-l-en-l-yl)butanal (1) with dialkyl malonate (2) in presence of titanium tetrachloride, pyridine and a mixture of carbon tetrachloride-THF gives intermediate conjugated malonate 3.

The disadvantage of this method is due to the corrosive and fuming nature of titanium tetrachloride and the use of environmentally unfriendly solvent carbon tetrachloride. In addition, pyridine and THF are water soluble and are not easily recycled. In the following step, WO2012085056 teaches that the conjugated ester 3 is decarbalkoxylated in presence of lithium chloride and NMP (N-Methyl-2-pyrrolidone) to afford monoester 4 having high E content:

E/Z ratio 82:18

Lithium chloride can be replaced by magnesium chloride with similar results.

In a new embodiment of WO2012085056, aldehyde 1 is condensed with malonic acid (2, R = H) in presence of catalytically effective amount of an ammonium acetate or an amino acid such as proline, or a dipeptide such as glycyl-glycine in a mixture of tert-butanol-hexane to give intermediate conjugated malonate 3 (R = H). The solvent is then replaced by NMP, Lithium chloride or magnesium chloride is added and the mixture is heated to effect decarbalkoxylation to 4 (R = H).

1. L-proline, cyclohexane, t-BuOH

80 - 85°C, azeotropic distln, 3hr

2. cyclohexane, t-BuOH-H ₂ 0 distln.

3. MgCI ₂ , NMP, 3 h at 80-85°C

H 63 g, purity 79.5%

83% yield

malonic acid 4 (R = H)

2 (R = H) E/Z ratio: 90:10

The disadvantage of this step is the need to recover three different organic solvents.

According to US7932418 conjugated ester 3 can be decarbalkoxylated to 4 (R = alkyl) in high yield, high beta-gamma selectivity and high E selectivity in presence of catalytic amount of calcium 2-ethylhexanoate. Lower E-selectivity was obtained using magnesium 2-ethylhexanoate or Mg(¾ as trans esterification catalysts.

3 (R = CH ₃ ) 4 (R = CH ₃ )

E/Z ratio = 86/14 β-γ/α-β = 93.7/6.3

The disadvantage of this method is the use of the relatively expensive catalyst calcium 2-ethylhexanoate.

Acknowledgement of the above references herein is not to be inferred as meaning that these are in any way relevant to the patentability of the presently disclosed subject matter.

GENERAL DESCRIPTION

The present invention provides a process for the preparation of alkyl 4-methyl-6- (2,6,6-trimethylcyclohex-l-enyl)hex-3-enoate (4) comprising a single step wherein 2- methyl-4-(2,6,6-trimethylcyclohex-l-en-l-yl)butanal (1) is reacted with monoalkyl malonate (5); wherein R is selected from H, C ₁ -C4 alkyl.

1 5 4

In some embodiments said process of the invention is being catalyzed by at least one anhydrous metallic Lewis acid in at least one dipolar aprotic solvent.

In some embodiments said at least one dipolar aprotic solvent is selected from dimethylacetamide (DM AC), dimethylsulfoxide (DMSO), NMP (N-methyl-2- pyrrolidone) and any combination thereof.

In other embodiments said at least one anhydrous metallic Lewis acid is selected from MgCl ₂ , MgBr ₂ , LiCl, T1CI4, ZnCl ₂ , CaCl ₂ , A1C1 ₃ and SnCl ₄ and lanthanides halides. In some embodiments a process of the invention is being catalyzed by MgC . in the presence of dimethylacetamide as a single solvent.

In some embodiments said product of a process of the invention alkyl 4-methyl- 6-(2,6,6-trimethylcyclohex-l-enyl)hex-3-enoate (4) is produced in an E:Z ratio of between about 82: 18 to about 90: 10.

In some other embodiments a process of the invention is being performed at a temperature of between 60°C to 120°C.

DETAILED DESCRIPTION OF EMBODIMENTS

It has now been discovered that alkyl 4-methyl-6-(2,6,6-trimethylcyclohex-l- enyl)hex-3-enoate (4) having high E/Z ratio and high β-γ/α-β ratio can be synthesized in a single step by modified Knoevenagel condensation between 2-methyl-4-(2,6,6- trimethylcyclohex-l-en-l-yl)butanal (1) and monoalkyl malonate (5) in the presence of a single solvent.

1 5 4

The reaction is catalyzed by anhydrous magnesium chloride (MgCh) in dipolar aprotic solvents such as dimethylacetamide (DMAC), dimethylsulfoxide (DMSO) or NMP (N-Methyl-2-pyrrolidone). Other Lewis acids such as MgBr ₂ , LiCl, TiCl _4, ZnCl ₂ , CaC ., AICL and SnCL and lanthanides halides were also used for the preparation of 4.

Dimethylacetamide being of high polarity, high stability, relatively low boiling point and low cost is preferred.

When amine catalyst such as beta-alanine or L-proline was used to catalyze the condensation the undesired conjugated ester 6 was obtained in high yield.

According to the reaction conditions (solvent concentration, the nature of the R group in 2 and the catalyst concentration) the E:Z ratio could vary from 82: 18 to 90: 10. R is an alkyl group selected from CI to C4. The preferred monoalkyl malonate esters are monomethyl malonate and monoethyl malonate.

Anhydrous magnesium chloride is readily available and is environmentally friendly. Furthermore, it was unexpectedly discovered that magnesium chloride forms a liquid complex with either NMP or DMAC which easily separates from the organic product upon cooling the reaction mixture below 60°C.

The liquid complex can be recycled, thus greatly improving the overall economics of the process. DMAC is the preferred solvent due to its relatively lower cost and lower boiling point. When DMSO is used as solvent slightly lower yields are obtained and no liquid complex is obtained.

Example 1.

2-Methyl-4-(2,6,6-trimethylcyclohex-l-en-l-yl)butanal (1) (166g , 98% purity), dimethylacetamide (240g) and anhydrous magnesium chloride (55g) were charged to a reactor. The reactor was flushed with nitrogen and the mixture was stirred and heated to 105°C.

Then monoethyl malonate (160g, 99.5% purity) was added and the reaction mixture was stirred at 110°C for 2hr.

The reaction mixture was cooled down to 50°C, the lower dimethylacetamide- MgCi ₂ liquid phase was separated, and the organic phase was washed with water (120g) to afford 227g pale yellow oil. The product consisted (GC area percentages) of 10.8% Z-4 and 79.4% E-4 (E : Z = 88 : 12). The sum of isomers yield according to internal standard was 91%. Example 2.

Preparation of high-E ethyl 4-methyl-6-(2,6,6-trimethylcyclohex-l-en-l- yl)hex-3-enoate (4, R = Ethyl).

2-Methyl-4-(2,6,6-trimethylcyclohex-l-en-l-yl)butanal (1) (10 g, 79% purity) , Dimethylacetamide (12 g), monoethyl malonate (8 g, Alfa Aesar 96% purity) and MgCi ₂ (2.75 g Sigma, anhydrous, >98%) were heated to 120°C while stirring and then stirred at this temperature for 2 hours. The yield by purity of the E-4 isomer according to GC was 81%, and the Z-4 isomer was 11% (the ratio E/Z = 88:12). The content of sum of isomers according to internal standard was 75%.

The reaction mixture was cooled to 60°C, the lower MgCl ₂ -DMAC phase was separated, the organic phase was washed with water and distilled at 120-130°C/0.1 mm.

After distillation the content of the E isomer was 71% and the Z isomer content was 9.5%.

Example 3.

Preparation of high-E ethyl 4-methyl-6-(2,6,6-trimethylcyclohex-l-en-l- yl)hex-3-enoate (4, R = Ethyl).

2-Methyl-4-(2,6,6-trimethylcyclohex-l-en-l-yl)butanal (1) (10 g, 79% purity), dimethylacetamide (10 g), monoethyl malonate (5.5 g) and LiCl (2 g) were heated to 130°C for 1 hour. Then monoethyl malonate (9 g) was added at 130°C for 3 hours. The reaction mixture was cooled, and stirred with water (50 g) and hexane (15 ml). The organic phase was separated and washed with 20 ml water 3 times, then the solvent was evaporated under reduced pressure to afford 12 g of the crude product containing according to GC 52% of E-4 isomer, 9.5% of the Z-4 isomer and 10% conjugated isomer 6. The yield by purity of the E isomer was 59%.

Example 4.

Preparation of high-E 4-methyl-6-(2,6,6-trimethylcyclohex-l-en-l-yl)hex-3- enoic acid (4, R = H)

2-Methyl-4-(2,6,6-trimethylcyclohex-l-en-l-yl)butanal (1) (10 g, 79% purity), Dimethylacetamide (12 g), malonic acid (8 g) and MgCh (3 g) were heated to 130°C for 2 hours. According to GC the reaction mixture contained 39.6% E- monocyclohomofarnesic acid (4, R = H) and 14.5% of the corresponding Z-4 isomer.

Example 5.

Preparation of Ethyl (E)-4-methyl-6-(2,6,6-trimethylcyclohex-l-en-l-yl)hex- 2-enoate (6, R = Ethyl).

2-Methyl-4-(2,6,6-trimethylcyclohex-l-en-l-yl)butanal (1) (18 g, purity 74%), dimethylacetamide (48 g) and monoethyl malonate (12 g) were placed in the 100 ml round bottom flask and -alanine (0.75 g) was added. The reaction mixture was heated to 100°C and stirred at this temperature for 3 hours. Dimethylacetamide was evaporated under reduced pressure and the residue was distilled at 135-140°C/0.1 mm to give 14.7 g of a yellowish oil containing 91% of the conjugated E-6 isomer. The yield by purity of the E-6 isomer was 75%.

Example 6.

2-Methyl-4-(2,6,6-trimethylcyclohex-l-en-l-yl)butanal (1) (2 g, 79% purity), Dimethylacetamide (3 g), monoethyl malonate (2 g) and TiCL _t (0.8 g) were heated to 120°C for 0.5 hour.

According to GC there was obtained 32.2% E-monocyclohomofarnesic ethyl ester (4, R = Ethyl), 8.3% Z-4-isomer and 7.5% conjugated isomer 6.

Upon cooling of the reaction mixture no TiCL _t -DMAC complex was formed. In addition, some polymerization took place.

Example 7.

Repeating Example 5 with tin tetrachloride (SnCL _t ) gave 12% E-4 isomer and 6% Z-4 isomer.

Example 8.

Repeating example 5 using AICI ₃ gave the conjugated isomer 6 in -43% yield. The yield of E-4 isomer was only 3.7%.