Processes for the preparation of unsaturated malonates

Abstract

Disclosed is a process for preparing unsaturated malonates and/or their isomers. The process includes the step of reacting an aldehyde and a dialkyl malonate in the presence of a Lewis acid and a carboxylic acid thereby forming an unsaturated malonate.

Claims

1. A process for the preparation of an unsaturated malonate, or an isomer thereof, comprising the steps of: performing a reaction between an aldehyde of formula A and a dialkyl malonate of formula B ##STR00015## in which each of R.sub.1, R.sub.2, R.sub.3 and R.sub.4, independently, is selected from the group consisting of a straight or branched C.sub.1-C.sub.20 alkyl, straight or branched C.sub.2-C.sub.20 alkenyl, and straight or branched C.sub.2-C.sub.20 alkynyl; wherein the reaction is performed in the presence of a Lewis acid; thereby forming a product containing an unsaturated malonate of formula C ##STR00016## and the Lewis acid is magnesium chloride.

2. The process of claim 1, wherein the reaction is performed in the presence of an aprotic dipolar solvent.

3. The process of claim 1, wherein the reaction is performed in the presence of a carboxylic acid that is selected from the group consisting of formic acid, acetic acid, propionic acid, citric acid, and any combinations thereof.

4. The process of claim 2, wherein the aprotic dipolar solvent is selected from the group consisting of N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-Methyl-2-pyrrolidone (NMP), dimethylsulfoxide (DMSO), and any combinations thereof.

5. The process of claim 1, wherein the reaction is performed at a temperature of 100 to 160 C. for at least 5 hours.

6. The process of claim 1, wherein the product further contains a compound of formula D, a compound of formula E, a compound of formula F, or any isomer thereof: ##STR00017##

7. The process of claim 6, further comprising the step of converting the compound of formula C or the compound of formula D under an alkoxydecarbonylating condition thereby forming a compound of formula E, a compound of formula F, or any isomer thereof.

8. The process of claim 1, wherein the aldehyde of formula A is Compound III of the following formula: ##STR00018##

9. The process of claim 1, wherein the dialkyl malonate of formula B is dimethyl malonate or diethyl malonate.

10. The process of claim 1, wherein the product contains Compound I of the following formula: ##STR00019## in which each of R.sub.3 and R.sub.4, independently, is methyl or ethyl.

11. The process of claim 1, wherein the product contains Compound IV of the following formula: ##STR00020## Compound V of the following formula: ##STR00021## or a combination thereof, in which each of R.sub.3 and R.sub.4, independently, is methyl or ethyl.

12. The process of claim 11, further comprising the step of converting Compound I or V to Compound IV.

13. The process of claim 11, further comprising the step of converting Compound I, IV, or V to Compound II of the following formula: ##STR00022##

14. The process of claim 1, wherein the reaction is performed in a batch reactor or a continuous reactor, in which the continuous reactor is a single Continuous Stirred Tank Reactor (CSTR), multiple CSTRs in series, or a microreactor.

15. A process for the preparation of an unsaturated malonate, or an isomer thereof, comprising the steps of: performing a reaction between an aldehyde of formula A and a dialkyl malonate of formula B ##STR00023## in which each of R.sub.1, R.sub.2, R.sub.3 and R.sub.4, independently, is selected from the group consisting of a straight or branched C.sub.1-C.sub.20 alkyl, straight or branched C.sub.2-C.sub.20 alkenyl, and straight or branched C.sub.2-C.sub.20 alkynyl; wherein the reaction is performed in the presence of a Lewis acid and a carboxylic acid; thereby forming a product containing an unsaturated malonate of formula C ##STR00024## and the carboxylic acid is selected from the group consisting of formic acid, acetic acid, propionic acid, citric acid, and any combinations thereof.

16. The process of claim 15, wherein the reaction is performed in the presence of an aprotic dipolar solvent selected from the group consisting of N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-Methyl-2-pyrrolidone (NMP), dimethylsulfoxide (DMSO), and any combinations thereof.

17. The process of claim 15, wherein the product contains Compound IV of the following formula: ##STR00025## Compound V of the following formula: ##STR00026## or a combination thereof, in which each of R.sub.3 and R.sub.4, independently, is methyl or ethyl; and Compound I, IV, or V is further converted to Compound II of the following formula: ##STR00027##

18. The process of claim 15, wherein the reaction is performed in a batch reactor or a continuous reactor, in which the continuous reactor is a single Continuous Stirred Tank Reactor (CSTR), multiple CSTRs in series, or a microreactor.

19. A process for the preparation of an unsaturated malonate, or an isomer thereof, comprising the steps of: performing a reaction between an aldehyde of formula A and a dialkyl malonate of formula B ##STR00028## in which each of R.sub.1, R.sub.2, R.sub.3 and R.sub.4, independently, is selected from the group consisting of a straight or branched C.sub.1-C.sub.20 alkyl, straight or branched C.sub.2-C.sub.20 alkenyl, and straight or branched C.sub.2-C.sub.20 alkynyl; wherein the reaction is performed in the presence of a Lewis acid and an aprotic dipolar solvent; thereby forming a product containing an unsaturated malonate of formula C ##STR00029## and the aprotic dipolar solvent is selected from the group consisting of N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-Methyl-2-pyrrolidone (NMP), dimethylsulfoxide (DMSO), and any combinations thereof.

20. The process of claim 19, wherein the product contains Compound IV of the following formula: ##STR00030## Compound V of the following formula. ##STR00031## or a combination thereof, in which each of R.sub.3 and R.sub.4, independently, is methyl or ethyl; and Compound I, IV, or V is further converted to Compound II of the following formula: ##STR00032##

Description

DETAILED DESCRIPTION

(1) Dialkyl malonates (e.g., dialkyl 2-(2-methyl-4-(2,6,6-trimethylcyclohex-1-enyl)butylidene)malonates, Compound I as shown below) are intermediates for preparing commercially important compounds such as fragrance ingredient 3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan (Compound II shown below), which has a strong ambergris odor. Compound II is commercially available as Cetalox (Firmenich S.A.), Cetalor (Aromor Flavors & Fragrances), Ambroxan (Kao) and Ambermor (Aromor).

(2) ##STR00005##

(3) To prepare Compound II, the unsaturated malonate Compound I is first transformed via alkoxydecarbonylation (Synthesis, 805-822, 1982) to alkyl 4-methyl-6-(2,6,6-trimethylcyclohex-1-enyl)hex-3-enoate (Compound IV shown below), which is then converted to Compound II. See WO 2006/010287, and U.S. Pat. Nos. 8,765,980 and 7,932,418.

(4) ##STR00006##

(5) It has been found that that ,-unsaturated alkyl malonates, such as dialkyl 2-(2-methyl-4-(2,6,6-trimethylcyclohex-1-enyl) butylidene) malonates (Compound I) can be prepared by condensing the corresponding aldehydes, such as 2-Methyl-4-(2,6,6-trimethylcyclohex-1-en-1-yl)butanal (Compound III) with dialkyl malonates of the formula CO.sub.2R.sub.3CH.sub.2CO.sub.2R.sub.4 where each of R.sub.3 and R.sub.4, independently, is a straight or branched C.sub.1-C.sub.8 alkyl. The condensation reaction is typically carried out in the presence of a catalytic amount of a Lewis acid and a carboxylic acid, optionally in an aprotic dipolar solvent.

(6) In some embodiments, the Lewis acid is MX.sub.n , wherein M is an alkali or alkaline metal selected from Groups IA (i.e., Li, Na, K, Rb, Cs, and Fr) and IIA (Be, Mg, Ca, Sr, Ba, and Ra) in the periodic table, and X is a halogen (i.e., F, Cl, Br, and I). In certain embodiments, the Lewis acid is selected from the group consisting of lithium iodide, lithium bromide, lithium chloride, magnesium iodide, magnesium bromide and magnesium chloride. In other embodiments, the Lewis acid is magnesium chloride. In specific embodiments, magnesium chloride is used at a level of 0.1 to 3 (e.g., 0.2 to 2, 0.4 to 1, 0.5 to 1, 0.5 to 0.8, and 0.75) equivalents based on the aldehyde of formula A.

(7) Surprisingly, it was found that the reaction is accelerated by addition of a catalytically effective amount of a carboxylic acid of formula RCO.sub.2H where R is selected from the group consisting of H, straight or branched C.sub.1-C.sub.8 alkyl, and C.sub.5-C.sub.8 aryl.

(8) Preferably, the carboxylic acid is formic acid, acetic acid, propionic acid, citric acid, or a combination thereof. More preferably, the carboxylic acid is formic acid. In some embodiments, the carboxylic acid is used at a level of 0.1 to 1 equivalents (e.g., 0.2 to 0.3 equivalents) based on the aldehyde of formula A. It is to be noted that without adding the carboxylic acid, the reaction requires a significantly longer reaction time.

(9) In some embodiments, the reaction between the compound of formula A and the compound of formula B is carried out at a temperature of 50 to 200 C. (e.g., 100 to 160 C., 110 to 150 C., 125 to 135 C., and 130 C.).

(10) In addition to the product of an ,-unsaturated malonate, such as Compound I, the process of the invention may also produce one or more additional products, such as an (E or Z)-,-unsaturated malonate (e.g., (E or Z)-dialkyl 2-(2-methyl-4-(2,6,6-trimethyl-cyclohex-1-en-1-yl)butylidene)malonate as Compound V), a ,-unsaturated alkyl ester (e.g., Compound IV), and/or an ,-unsaturated monoester (e.g., Compound VI). Compound VI is a byproduct not suitable for preparing the final fragrance ingredient, Compound II. Although, in theory, an elevated temperature (such as 100 to 200 C.) favors the formation of the undesired compound VI, the inventors have found that the addition of the carboxylic acid (e.g., anhydrous formic acid) substantially suppresses the formation of the undesired by product Compound VI.

(11) ##STR00007##

(12) The (E or Z)-,-unsaturated isomer such as Compound V is also a useful intermediate for preparing ,-unsaturated alkyl esters, such as alkyl (E or Z)-4-methyl-6-(2,6,6-trimethylcyclohex-1-en-1-yl)hex-3-enoate (Compound IV) since the mixture of ,-unsaturated alkyl malonates, such as Compound I, and (E or Z)-,-unsaturated alkyl diesters, such as Compound V is converted to ,-unsaturated alkyl esters at elevated temperatures (in some embodiments in the range of 160 to 180 C.) via an alkoxydecarbonylating condition. Alternatively, such reactions can be performed by trans-esterification techniques as well.

(13) The process of this invention can occur either in a batch reactor, a semicontinuous reactor, or a continuous reactor.

(14) A batch reactor refers to a conventional static reactor, in which the aldehyde of formula A, the dialkyl malonate of formula B, the Lewis acid, the carboxylic acid, and the aprotic dipolar solvent are secured in the reactor to allow the Knoevenagel condensation reaction to occur.

(15) A semicontinuous or continuous reactor refers to a flow reactor including a single Continuous Stirred Tank Reactor (CSTR), multiple CSTRs in series, or a microreactor. See U.S. Pat. No. 9,216,935.

(16) In some embodiments, a solution of the starting materials (e.g., the aldehyde, malonate, Lewis acid, and carboxylic acid) is pumped into a flow reactor. In other embodiments, the starting materials are separately dissolved in a solvent. Their solutions are mixed in-line using a static mixer before entering the reactor. In still other embodiments, the reactor may be packed with materials such as a Lewis acid and glass beads (10 to 100 m particle size).

(17) As used herein, the terms packed and packing mean to fill with an amount of materials that allow effective production of the product and the amount of the packing materials often requires taking into consideration, e.g., the size of the reactor vessel, the material type, the reaction temperature, the ratio among the products (if multiple products exist), and the yields of the products.

(18) In some embodiments, the reactor system is heated using a heating circulating oil bath or electrical heater. From the reactor system, the reaction mixture is collected in a product receiver. The reaction mixture is analyzed for reaction completion using an instrument such as Gas Chromatography (GC).

(19) All parts, percentages and proportions referred to herein and in the claims are by weight unless otherwise indicated.

(20) As used herein L is understood to be liter, mL is understood to be milliliter, M is understood to be mole/liter, m is understood to be micrometer, nm is understood to be nanometer, mol is understood to be moles, mmol is understood to be millimole, g is understood to be gram, kg is understood to be kilogram, and min is understood to be minutes.

(21) The invention is described in greater detail by the following non-limiting examples. Without further elaboration, it is believed that one skilled in the art can, based on the description herein, utilize the present invention to its fullest extent without undue experimentation.

(22) All publications cited herein are incorporated by reference in their entirety.

EXAMPLE 1

(23) ##STR00008##

(24) In a flask, 2-methyl-4-(2,6,6-trimethylcyclohex-1-en-1-yl)butanal (Compound III, 2 g, 9 mmol, 96% purity), diethyl malonate (2.2 g, 13.7 mmol), N,N-dimethyl-acetamide (DMAC, 2.4 g) and MgCl.sub.2 (0.59 g, 6.2 mmol) were stirred at 130 C. for 9 hours. According to gas chromatographic (GC) analysis, the reaction mixture contained 39% ,-diester Compound I, 39% (E)---diester Compound V, 10% (E)---ester Compound IV, and 1.5% unreacted Compound III.

EXAMPLE 2

(25) ##STR00009##

(26) Formic acid (85%, 0.65 g, 12 mmol) was added to a mixture of 2-methyl-4-(2,6,6-trimethylcyclohex-1-en-1-yl)butanal (Compound III, 2 g, 9 mmol, 96% purity), N,N-dimethyl-acetamide (2.5 g), diethyl malonate (2.2 g, 13.6 mmol) and MgCl.sub.2 (0.7 g, 7.4 mmol). The reaction mixture was stirred for 3 hours at 130 C. Compound III was completely consumed. According to GC analysis, the reaction mixture contained 35% ,-diester Compound I, 28% (E)---isomer Compound V, 12.9% (E)---ester Compound IV, and 2.1% ,-ester Compound VI.

EXAMPLE 3

(27) ##STR00010##

(28) 2-Methyl-4-(2,6,6-trimethylcyclohex-1-en-1-yl)butanal (Compound III, 2 g, 9 mmol, 96% purity), dimethyl malonate (2 g, 15.1 mmol), N,N-dimethylacetamide (2.4 g) and MgCl.sub.2 (0.59 g, 6.2 mmol) were stirred at 130 C. for 7 hours. According to GC analysis, the reaction mixture contained 14% ,-diester Compound I, 34% (E)-,-diester Compound V, 10% (Z)-,-diester Compound V, 22% (E)-,-ester Compound IV and 1.1% unreacted Compound III.

EXAMPLE 4

(29) ##STR00011##

(30) Following the same procedure described in Example 3 except that 0.2 g of anhydrous formic acid (4.3 mmol) was added to the reaction mixture. After 1 hour at 130 C., the starting material 2-methyl-4-(2,6,6-trimethylcyclohex-1-en-1-yl)butanal (Compound III) was completely consumed. According to GC analysis the reaction mixture contained 14% ,-diester Compound I, 28% (E)-,-diester Compound V, 7% (Z)-,-diester Compound V, 30% (E)-,-ester Compound IV and 5% (Z)-,-ester Compound IV. The reaction was continued for additional 7 hours at 130 C. According to GC, the reaction mixture contained 12% (Z)-,-ester Compound IV, 54% (E)-,-ester Compound IV, 4% ,-diester Compound I, 5% (Z)-,-diester Compound V and 8% (E)-,-diester Compound V.

EXAMPLE 5

(31) ##STR00012##

(32) Acetic acid (AcOH, 0.2 g, 3 mmol) was added to a mixture 2-Methyl-4-(2,6,6-trimethylcyclohex-1-en-1-yl)butanal (Compound III, 2 g, 9 mmol, 96% purity), N,N-dimethyl-acetamide (2.4 g), diethyl malonate (2.2 g, 13.7 mmol) and MgCl.sub.2 (0.58 g, 6.1 mmol). The reaction mixture was stirred for 4 hours at 130 C. No Compound III was detected. According to GC analysis the mixture contained 27% ,-diester Compound I, 34% trans-,-diester Compound V, 17% (E)-,-ester Compound IV and 2.4% conjugated ,-ester Compound VI. The combined yield (based on % area in the GC spectrum) was 80.5%.

EXAMPLE 6

(33) ##STR00013##

(34) The reaction of 2-methyl-4-(2,6,6-trimethylcyclohex-1-en-1-yl)butanal (Compound III) with diisopropyl malonate and an equal mole amount of acetic acid following the procedure described in Example 5 required about 4 hours for complete conversion of Compound III. The reaction mixture contained according to GC analysis 63% ,-diester Compound I, 20% (E)-,-isomer Compound V, and 2.5% (E)-,-ester Compound IV.

EXAMPLE 7

(35) ##STR00014##

(36) Acetic acid (0.6 g, 10 mmol) was added to a mixture of 2-methyl-4-(2,6,6-trimethylcyclohex-1-en-1-yl)butanal (Compound III, 2 g, 9 mmol, 96% purity), N,N-dimethylacetamide (2.4 g), diethyl malonate (2.2 g, 13.6 mmol) and MgCl.sub.2 (0.58 g, 6.1 mmol). The reaction mixture was stirred for 6 hours at 180 C. According to GC analysis, the reaction mixture contained 62.2% (E)-,-ester Compound IV and 19.9% ,-ester Compound VI.

Other Embodiments

(37) All of the features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a generic series of equivalent or similar features.

(38) Indeed, to achieve the purpose of preparing an unsaturated malonate, one skilled in the art can choose different aldehydes, dialkyl malonate, Lewis acid, carboxylic acid, solvent, reaction temperature, and/or reaction time. Further, the ratios among the reaction reagents can also be determined by a skilled artisan without undue experimentation.

(39) From the above description, a skilled artisan can easily ascertain the essential characteristics of the present invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Thus, other embodiments are also within the claims.