Method for preparing 2-(cyclohexenylidene) malonic acid derivatives and uses thereof

Abstract

Disclosed are a method for preparing 2-(cyclohexenylidene) malonic acid derivatives and uses thereof. In this method, an olefin and a 2-substituted malonic acid derivative are used as starting materials to prepare the 2-(cyclohexenylidene) malonic acid derivative in the presence of a catalyst through cyclization reaction. This method has the following advantages: (1) the method can be very efficiently used for the synthesis of highly sterically-hindered 2-(2,6-disubstituted cyclohexenylidene) malonic acid derivatives; (2) the reaction yield is high, the reaction conditions are mild, and the wastes are less, favorable for industrial production. More importantly, the present invention extends the further use of 2-(cyclohexenylidene)malonic acid derivatives in organic synthesis, especially in the synthesis of 2-aryl malonic acid derivatives and their corresponding drugs such as Pinoxaden.

Claims

1. A method for preparing 2-(cyclohexenylidene) malonic acid derivatives, comprising: cyclizing compound (1) with compound (2) in the presence of a catalyst A to produce compound (4) via intermediate (3); or cyclizing compound (1) with compound (2) in the presence of a catalyst A to produce compound (4) directly, as shown in the following reaction scheme: ##STR00004## wherein: R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 each are independently hydrogen, a C.sub.1-C.sub.10 alkyl group, a C.sub.6-C.sub.12 aryl group or a heteroaryl group containing one or two atoms selected from nitrogen, oxygen and sulfur; and X.sup.1 and X.sup.2 each are independently a cyano group or COR.sup.6 where R.sup.6 is selected from hydrogen, a C.sub.1-C.sub.10 alkyl group, a C.sub.1-C.sub.10 alkoxy group, a C.sub.6-C.sub.12 aryloxy group, a C.sub.1-C.sub.10 alkylamino group, a C.sub.6-C.sub.12 arylamino group, a di(C.sub.1-C.sub.10 alkyl) amino group, a (C.sub.1-C.sub.10 alkyl)(C.sub.6-C.sub.12 aryl) amino group, a di(C.sub.6-C.sub.12 aryl) amino group, a C.sub.6-C.sub.12 aryl group or a heteroaryl group containing one or two atoms selected from nitrogen, oxygen and sulfur; wherein the catalyst A is selected from the group consisting of an organic acid, an organic base, an inorganic base and a mixture thereof.

2. The method of claim 1, wherein a molar ratio of compound (1) to compound (2) is 0.8-2.0:1; a molar ratio of catalyst A to compound (2) is 0.005-2.4:1; a cyclization reaction temperature is 0-150 C.; and the cyclization reaction is carried out in the absence of a solvent or in the presence of a solvent selected from water, an organic solvent or a mixture thereof.

3. The method of claim 2, wherein the molar ratio of compound (1) to compound (2) is 1.0-1.5:1; the catalyst A used for the cyclization reaction is Et.sub.3N and DABCO; the molar ratio of catalyst A to compound (2) is 0.1-1.0:1; the cyclization reaction temperature is 80-130 C.; and the solvent for the cyclization reaction is toluene.

4. A compound of formula (3) or (4) or a mixture thereof, ##STR00005## wherein: R.sup.4 is selected from a C.sub.1-C.sub.10 alkyl group, a C.sub.6-C.sub.12 aryl group or a heteroaryl group containing one or two atoms selected from nitrogen, oxygen and sulfur; R.sup.1, R.sup.2, R.sup.3 and R.sup.5 each are independently hydrogen, a C.sub.1-C.sub.10 alkyl group, a C.sub.6-C.sub.12 aryl group or a heteroaryl group containing one or two atoms selected from nitrogen, oxygen and sulfur; and X.sup.1 and X.sup.2 each are independently a cyano group or COR.sup.6 where R.sup.6 is selected from hydrogen, a C.sub.1-C.sub.10 alkyl group, a C.sub.1-C.sub.10 alkoxy group, a C.sub.6-C.sub.12 aryloxy group, a C.sub.1-C.sub.10 alkylamino group, a C.sub.6-C.sub.12 arylamino group, a di(C.sub.1-C.sub.10 alkyl) amino group, a (C.sub.1-C.sub.10 alkyl)(C.sub.6-C.sub.12 aryl) amino group, a di(C.sub.6-C.sub.12 aryl) amino group, a C.sub.6-C.sub.12 aryl group or a heteroaryl group containing one or two atoms selected from nitrogen, oxygen and sulfur.

5. The compound of claim 4, wherein R.sup.4 is a C.sub.1-C.sub.4 alkyl group or a C.sub.6-C.sub.12 aryl group; R.sup.1, R.sup.2, R.sup.3 and R.sup.5 each are independently hydrogen, a C.sub.1-C.sub.4 alkyl group or a C.sub.6-C.sub.12 aryl group; X.sup.1 and X.sup.2 each are independently a cyano group, COOMe or COOEt.

6. A method for preparing a 2-aryl malonic acid derivative, comprising: 1) cyclizing compound (1) with compound (2) in the presence of a catalyst A to produce compound (4) via intermediate (3); or cyclizing compound (1) with compound (2) in the presence of a catalyst A to produce compound (4) directly, as shown in the following reaction scheme: ##STR00006## and 2) aromatizing compound (4) in the presence of a catalyst B to give the 2-aryl malonic acid derivative (5), as shown in the following reaction scheme: ##STR00007## wherein: R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 each are independently hydrogen, a C.sub.1-C.sub.10 alkyl group, a C.sub.6-C.sub.12 aryl group or a heteroaryl group containing one or two atoms selected from nitrogen, oxygen or sulfur; and X.sup.1 and X.sup.2 each are independently a cyano group or COR.sup.6 where R.sup.6 is selected from hydrogen, a C.sub.1-C.sub.10 alkyl group, a C.sub.1-C.sub.10 alkoxy group, a C.sub.6-C.sub.12 aryloxy group, a C.sub.1-C.sub.10 alkylamino group, a C.sub.6-C.sub.12 arylamino group, a di(C.sub.1-C.sub.10 alkyl) amino group, a (C.sub.1-C.sub.10 alkyl)(C.sub.6-C.sub.12 aryl) amino group, a di(C.sub.6-C.sub.12 aryl) amino group, a C.sub.6-C.sub.12 arylgroup or a heteroaryl group containing one or two atoms selected from nitrogen, oxygen and sulfur; wherein the catalyst A is selected from the group consisting of an organic acid, an organic base, an inorganic base and a mixture thereof; and the catalyst B is a metal catalyst.

7. The method of claim 6, wherein an aromatization reaction temperature is 100-400 C.; and the aromatization reaction is carried out in the absence of a solvent or in the presence of a solvent selected from an alcohol, an ether, an ester, an amide or an aromatic hydrocarbon having a boiling point higher than 150 C.

8. The method of claim 7, wherein the catalyst B is Pd/C; and the aromatization temperature is 180-220 C.

9. A method for synthesizing Pinoxaden, comprising: 1) cyclizing methacrylaldehyde (1) with 2-(heptan-4-ylidene)malonate (2) to produce 2-(2,6-diethyl-4-methylcyclohex-2-en-1-ylidene)malonate (4) via 2-(2,6-diethyl-3-hydroxy-4-methyl-cyclohexylidene)malonate (3) in the presence of a catalyst A; or cyclizing methacrylaldehyde (1) with 2-(heptan-4-ylidene)malonate (2) in the presence of a catalyst A to produce 2-(2,6-diethyl-4-methylcyclohex-2-en-1-ylidene)malonate (4) directly; 2) aromatizing 2-(2,6-diethyl-4-methylcyclohex-2-en-1-ylidene)malonate (4) in the presence of a catalyst B to give a 2-(2,6-diethyl-4-methylphenyl)malonate (5); and 3) reacting 2-(2,6-diethyl-4-methylphenyl)malonate (5) with hexahydro-1,4,5-oxadiazapine (6) to produce compound (7); and then adding pivaloyl chloride to the reaction to obtain Pinoxaden, as shown in the following reaction scheme: ##STR00008## ##STR00009## wherein the catalyst A is selected from the group consisting of an organic acid, an organic base, an inorganic base and a mixture thereof; and the catalyst B is a metal catalyst; wherein R.sup.6 is selected from the group consisting of hydrogen, a C.sub.1-C.sub.10 alkyl group, a C.sub.1-C.sub.10 alkoxy group, a C.sub.6-C.sub.12 aryloxy group, a C.sub.1-C.sub.10 alkylamino group, a C.sub.6-C.sub.12 arylamino group, a di(C.sub.1-C.sub.10 alkyl) amino group, a (C.sub.1-C.sub.10 alkyl)(C.sub.6-C.sub.12 aryl) amino group, a di(C.sub.6-C.sub.12 aryl) amino group, a C.sub.6-C.sub.12 arylgroup and a heteroaryl group containing one or two atoms selected from nitrogen, oxygen and sulfur.

Description

DETAILED DESCRIPTION OF EMBODIMENTS

(1) Some features of the invention will be further illustrated with reference to the following embodiments, but the embodiments are not intended to limit the scope of the invention.

(2) Starting material olefin 1 can be readily purchased commercially or prepared from aldehydes and ketones by methods well known in the prior art (for example, J. Am. Chem. Soc. 136 (28), 2014, 9918-9921; Tetrahedron, 70 (13), 2014, 2257-2263). The raw material 2 can be easily prepared from ketones and malonic acid derivatives by methods well known in the prior art (for example, Eur. Med. Chem. 85, 2014, 450-457; WO 2011098398).

Preparation of 2-(4-heptylidene) malononitrile

(3) To a reaction flask were sequentially added 65.0 g of 4-heptanone (0.569 mol), 39.4 g of malononitrile (0.569 mol), 6.6 g of ammonium acetate (0.086 mol), 10.3 g of acetic acid (0.171 mol) and toluene. The reaction mixture was refluxed, and the resulted water was removed. After the reaction was complete, the reaction mixture was cooled, washed with water, concentrated and purified to give 84.9 g of 2-(4-heptylidene) malononitrile, and the yield was 92%.

(4) .sup.1H NMR (CDCl.sub.3, 500 MHz, TMS): 2.57-2.53 (m, 4H), 1.64-1.60 (m, 4H), 1.02 (t, J=7.5 Hz, 6H).

(5) .sup.13C NMR (CDCl.sub.3, 125 MHz): 186.08, 111.88, 85.91, 37.47, 21.44, 12.81.

Preparation of 2-(1-(4-methoxyphenyl)-2-propylidene) malononitrile

(6) To a reaction flask were sequentially added 82.1 g of 1-(4-methoxyphenyl)-2-propanone (0.50 mol), 33.0 g of malononitrile (0.50 mol), 5.8 g of ammonium acetate (0.075 mol), 9.0 g of acetic acid (0.15 mol) and toluene. The reaction mixture was refluxed, and the resulted water was removed. After the reaction was complete, the reaction mixture was cooled, washed with water, concentrated and purified to give 100.8 g of 2-(1-(4-methoxyphenyl)-2-propylidene) malononitrile, and the yield was 95%.

(7) .sup.1H NMR (CDCl.sub.3, 500 MHz, TMS): 7.12 (d, J=11 Hz, 2H), 6.88 (d, J=11 Hz, 2H), 3.80 (s, 5H), 2.17 (s, 3H).

(8) .sup.13C NMR (CDCl.sub.3, 125 MHz): 180.2, 159.2, 129.9, 126.1, 114.5, 112.0, 111.7, 85.6, 55.2, 42.6, 22.0.

Example 1 Preparation of 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene) malononitrile

(9) 24.3 g of 2-(4-Heptylidene) malononitrile (0.15 mol), 10.5 g of 2-methylpropenal (0.15 mol) and 15.2 g of triethylamine (0.15 mol) were sequentially added to toluene.

(10) The reaction mixture was refluxed until the reaction was complete. Then, the reaction mixture was cooled, washed with 1 N diluted hydrochloric acid, dried, concentrated and purified to give 25.7 g of 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene) malononitrile, and the yield was 80%.

(11) .sup.1H NMR (CDCl.sub.3, 500 MHz, TMS): 6.14-6.14 (m, 1H), 3.08-3.04 (m, 1H), 2.82-2.75 (m, 1H), 2.57-2.46 (m, 2H), 2.04-2.01 (m, 1H), 1.56-1.51 (m, 2H), 1.48-1.41 (m, 1H), 1.12-1.01 (m, 6H), 1.00-0.98 (m, 3H).

(12) .sup.13C NMR (CDCl.sub.3, 125 MHz): 175.12, 148.74, 134.78, 113.99, 113.74, 43.75, 34.75, 28.13, 16.55, 15.52, 20.91, 13.59, 11.98.

Example 2 Preparation of Mixture of 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene) malononitrile and 2-(2,6-diethyl-4-methyl-3-ene-1-cyclohexylidene) malononitrile

(13) 25.0 g of 2-(4-Heptylidene) malononitrile (0.154 mol), 14.0 g of 2-methylpropenal (0.200 mol) and 15.6 g of triethylamine (0.154 mol) were sequentially added to toluene. The reaction mixture was refluxed until the reaction was complete. Then, the reaction mixture was cooled, washed with 1 N diluted hydrochloric acid, dried and concentrated to give 30.4 g of the mixture of 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene) malononitrile and 2-(2,6-diethyl-4-methyl-3-ene-1-cyclohexylidene) malononitrile in a ratio of 91:9 by GC-MS analysis.

Example 3 Preparation of 2-(2,6-diethyl-3-hydroxy-4-methyl-1-cyclohexyliene) malononitrile

(14) 3.2 g of 2-(4-Heptylidene) malononitrile (0.02 mol), 1.4 g of 2-methylpropenal (0.02 mol) and 2.0 g of triethylamine (0.02 mol) were sequentially added to toluene to react at 50 C. for 5 h. Then the reaction mixture was cooled, washed with 1 N diluted hydrochloric acid, dried, concentrated and purified to give 4.4 g of 2-(2,6-diethyl-3-hydroxy-4-methyl-1-cyclohexyliene) malononitrile, and the yield was 95% yield.

(15) .sup.1H NMR (CDCl.sub.3, 500 MHz, TMS): 3.82 (s, 1H), 3.11-3.08 (m, 1H), 3.03-2.99 (m, 1H), 2.06-2.05 (m, 1H), 1.87-1.81 (m, 2H), 1.73-1.65 (m, 2H), 1.62-1.52 (m, 3H), 1.08-1.02 (m, 9H).

(16) .sup.13C NMR (CDCl.sub.3, 125 MHz): 188.8, 112.2, 112.0, 87.1, 75.1, 53.1, 44.0, 30.9, 28.4, 26.4, 26.0, 17.4, 12.9.

Example 4 Preparation of 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene) malononitrile

(17) 2.3 g of 2-(2,6-Diethyl-3-hydroxy-4-methyl-1-cyclohexyliene) malononitrile (0.01 mol) prepared in Example 3 and a solution of 1.0 g of triethylamine (0.01 mol) in toluene were reacted under reflux. After the reaction was complete, the reaction mixture was cooled, washed with 1 N diluted hydrochloric acid, dried, concentrated and purified to give 1.8 g of 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene) malononitrile, and the yield was 84%.

Example 5 Preparation of 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene) malononitrile

(18) 32.4 g of 2-(4-Heptylidene) malononitrile (0.20 mol), 14.0 g of 2-methylpropenal (0.20 mol) and 2.2 g of triethylenediamine (0.02 mol) were sequentially added to toluene to react at 130 C. After the reaction was complete, the reaction mixture was cooled, washed with 1 N diluted hydrochloric acid, extracted with ethyl acetate, dried, concentrated and purified to give 39.4 g of 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene) malononitrile, and the yield was 92%.

Example 6 Preparation of 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene) malononitrile

(19) A solution of 48.7 g of 2-(4-heptylidene) malononitrile (0.30 mol) in THF was dropwise added to a solution of 12.4 g of NaH (0.31 mol) in THF at 0-5 C. After addition, the mixture was warmed to room temperature and then reacted for 20 min. Then a solution of 27.3 g of 2-methylpropenal (0.39 mol) in THF was dropwise added. The reaction mixture was heated and then refluxed until the reaction was complete. The reaction mixture was cooled, quenched with 1 N diluted hydrochloric acid, extracted with ethyl acetate, dried, concentrated and purified to give 13.5 g of 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene) malononitrile.

Example 7 Preparation of 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene) malononitrile

(20) To a reaction flask were sequentially added 25.0 g of 2-(4-heptylidene) malononitrile (0.154 mol), 14.0 of 2-methylpropenal (0.20 mol) and 3.4 g of triethylenediamine (0.031 mol). The reaction mixture was reacted at 80 C. After the reaction was complete, the reaction mixture was cooled, dissolved in ethyl acetate, washed with 1 N diluted hydrochloric acid, dried and concentrated by distillation to give 21.4 g of the target product.

Example 8 Preparation of Mixture of 2-(2,6-diethyl-5-phenyl-2-ene-1-cyclohexylidene) malononitrile and 2-(2,6-diethyl-5-phenyl-3-ene-1-cyclohexylidene) malononitrile

(21) 64.9 g of 2-(4-Heptylidene) malononitrile (0.40 mol), 68.7 g of cinnamaldehyde (0.52 mol) and 40.5 g of triethylamine (0.40 mol) were sequentially added to toluene. The reaction mixture was refluxed until the reaction was complete. Then, the reaction mixture was cooled, washed with 1 N diluted hydrochloric acid, dried and concentrated to give 83.4 g of the mixture of 2-(2,6-diethyl-5-phenyl-2-ene-1-cyclohexylidene) malononitrile and 2-(2,6-diethyl-5-phenyl-3-ene-1-cyclohexylidene) malononitrile in a ratio of 94:6 by GC-MS analysis. The resulting mixture was further purified to give 77.4 g of 2-(2,6-diethyl-5-phenyl-2-ene-1-cyclohexylidene) malononitrile, and the yield was 70%.

(22) .sup.1H NMR (CDCl.sub.3, 500 MHz, TMS): 7.31-7.28 (m, 2H), 7.26-7.23 (m, 1H), 7.08-7.06 (m, 2H), 6.36-6.25 (m, 1H), 3.31 (d, 1H, J=5.0 Hz), 3.21-3.18 (m, 1H), 2.86-2.77 (m, 2H), 2.67 (dd, 1H, J.sub.1=20.5 Hz, J.sub.2=4.0 Hz), 2.59-2.51 (m, 1H), 1.77-1.70 (m, 1H), 1.65-1.59 (m, 1H), 1.12 (t, 3H, J=7.5 Hz), 1.05 (t, 3H, J=7.5 Hz).

(23) .sup.13C NMR (CDCl.sub.3, 125 MHz): 173.0, 142.4, 139.7, 136.7, 128.7, 127.0, 126.5, 113.3, 81.0, 51.5, 41.7, 28.0, 27.6, 26.7, 13.5, 12.1.

Example 9 Preparation of 2-(6-(4-methoxyphenyl)-4-methyl-2-ene-1-cyclohexylidene) malononitrile

(24) 31.8 g of 2-(1-(4-Methoxyphenyl)-2-propylidene) malononitrile (0.15 mol), 14.0 g of 2-methylpropenal (0.20 mol) and 15.2 g of triethylamine (0.15 mol) were sequentially added to toluene. The reaction mixture was refluxed until the reaction was complete. Then, the reaction mixture was cooled, washed with 1 N diluted hydrochloric acid, dried, concentrated and purified to give 34.9 g of 2-(6-(4-methoxyphenyl)-4-methyl-2-ene-1-cyclohexylidene) malononitrile, and the yield was 93%.

(25) .sup.1H NMR (CDCl.sub.3, 500 MHz, TMS): 9.02-7.00 (m, 2H), 6.94 (dd, J.sub.1=10.0 Hz, J.sub.2=2.5 Hz, 1H), 6.85-6.84 (m, 2H), 6.67 (d, J=10.0 Hz, 1H), 4.27-4.25 (m, 1H), 3.78 (s, 3H), 2.39-2.31 (m, 1H), 2.08-2.04 (m, 1H), 1.76-1.71 (m, 1H), 1.10 (d, J=7.5 Hz, 3H).

(26) .sup.13C NMR (CDCl.sub.3, 125 MHz): 170.7, 158.8, 155.3, 130.4, 130.3, 128.1, 124.5, 114.3, 114.1, 112.2, 111.9, 82.1, 55.2, 43.4, 37.7, 27.5, 19.9.

Example 10 Preparation of 2-(2,6-diphenyl-4-methyl-2-ene-1-cyclohexylidene) malononitrile

(27) 77.5 g of 2-(2,6-Diphenylpropylidene) malononitrile (0.30 mol), 23.1 g of 2-methylpropenal (0.33 mol) and 30.3 g of triethylamine (0.30 mol) were sequentially added to toluene. The reaction mixture was refluxed until the reaction was complete. Then, the reaction mixture was cooled, washed with 1 N diluted hydrochloric acid, dried, concentrated and purified to give 91.2 g of 2-(2,6-diphenyl-4-methyl-2-ene-1-cyclohexylidene) malononitrile, and the yield was 98%.

(28) .sup.1H NMR (CDCl.sub.3, 500 MHz, TMS): 7.46-7.24 (m, 1H), 6.38-6.37 (m, 1H), 4.54-4.52 (m, 1H), 2.57-2.51 (m, 1H), 2.36-2.30 (m, 1H), 1.95-1.88 (m, 1H), 1.17 (d, J=9.0 Hz, 3H).

(29) .sup.13C NMR (CDCl.sub.3, 125 MHz): 169.9, 153.1, 138.4, 137.8, 137.4, 129.1, 129.0, 128.8, 127.6, 127.0, 113.6, 110.9, 83.9, 45.9, 37.2, 28.5, 20.4.

Example 11 Preparation of 2-(3-methyl-2-ene-1-cyclohexylidene) malononitrile

(30) 26.5 g of 2-(2-Propylidene) malononitrile (0.25 mol), 22.8 g of vinyl methyl ketone (0.32 mol) and 25.2 g of triethylamine (0.25 mol) were sequentially added to toluene. The reaction mixture was refluxed until the reaction was complete. Then, the reaction mixture was cooled, washed with 1 N diluted hydrochloric acid, dried, concentrated and purified to give 26.1 g of 2-(3-methyl-2-ene-1-cyclohexylidene) malononitrile.

(31) .sup.1H NMR (CDCl.sub.3, 500 MHz, TMS): 6.61-6.61 (m, 1H), 2.72 (t, J=6.5 Hz, 2H), 2.34 (t, J=7.5 Hz, 2H), 2.07-2.07 (m, 3H), 1.91-1.85 (m, 2H).

(32) .sup.13C NMR (CDCl.sub.3, 125 MHz): 170.7, 162.1, 121.5, 113.0, 112.3, 31.1, 28.9, 25.2, 21.2.

Example 12 Preparation of methyl 2-cyano-2-(2,6-diethyl-4-methyl-1-cyclohexenylidene) acetate

(33) 58.6 g of Methyl 2-cyano-3-propyl-2-hexenoate (0.300 mol), 27.3 g of 2-methylpropenal (0.390 mol) and 30.3 g of triethylamine (0.300 mol) were sequentially added to toluene. The reaction mixture was refluxed until the reaction was complete. Then, the reaction mixture was cooled, washed with 1 N diluted hydrochloric acid, dried and concentrated to give 62.8 g of methyl 2-cyano-2-(2,6-diethyl-4-methyl-1-cyclohexenylidene) acetate, and the yield was 84%.

(34) .sup.1H NMR (CDCl.sub.3, 500 MHz, TMS): 6.02-5.90 (m, 1H), 3.83-3.82 (m, 3H), 3.63-3.07 (m, 1H), 2.91-2.44 (m, 2H), 2.22-1.95 (m, 2H), 1.58-1.42 (m, 3H), 1.08-1.04 (m, 4H), 1.00-0.90 (m, 5H).

Example 13 Preparation of diethyl 2-(3-methyl-2-ene-1-cyclohexylidene) malonate

(35) 120.1 g of Diethyl 2-(2-propylidene) malonate (0.60 mol), 54.7 g of vinyl methyl ketone (0.78 mol) and 60.6 g of triethylamine (0.60 mol) were sequentially added to toluene. The reaction mixture was refluxed until the reaction was complete. Then, the reaction mixture was cooled, washed with 1N diluted hydrochloric acid, dried and concentrated by distillation to give 60.5 g of diethyl 2-(3-methyl-2-ene-1-cyclohexylidene) malonate.

(36) .sup.1H NMR (CDCl.sub.3, 500 MHz, TMS): 6.61-6.60 (m, 1H), 4.28-4.18 (m, 4H), 2.65 (t, J=8.0 Hz, 2H), 2.15 (t, J=8.0 Hz, 2H), 1.898 (d, J=1.5 Hz, 1H), 1.80-1.73 (m, 2H), 1.32-1.26 (m, 6H).

(37) .sup.13C NMR (CDCl.sub.3, 125 MHz): 165.8, 165.8, 151.9, 151.6, 121.4, 118.7, 60.6, 60.4, 30.6, 27.1, 24.8, 21.8, 13.9.

Example 14 Preparation of 2-(2,6-diethyl-4-methylphenyl) malononitrile

(38) 214.1 g of 2-(2,6-Diethyl-4-methyl-2-ene-1-cyclohexylidene) malononitrile (1 mol) and 2.2 g of Pd/C were heated to 180 C. under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was cooled, and ethyl acetate was added. The mixture was filtered to remove the catalyst (Pd/C). A small amount of solvent was used to wash the catalyst. The organic phase was dried and crystallized by concentration to give 188.9 g of 2-(2,6-diethyl-4-methylphenyl) malononitrile, and the yield was 89%.

Example 15 Preparation of 2-(2,6-diphenyl-4-methylphenyl) malononitrile

(39) 15.5 g of 2-(2,6-Diphenyl-4-methyl-2-ene-1-cyclohexylidene) malononitrile (0.05 mol) and 0.8 g of Pd/C was heated to 220 C. After the reaction was complete, the reaction mixture was cooled and filtered to remove the catalyst (Pd/C). A small amount of solvent was used to wash the catalyst. The organic phase was concentrated to give 10.9 g of 2-(2,6-diphenyl-4-methylphenyl) malononitrile, and the yield was 71%.

(40) .sup.1H NMR (CDCl.sub.3, 500 MHz, TMS): 7.54-7.46 (m, 10H), 7.21 (s, 2H), 5.11 (s, 1H), 2.44 (s, 3H).

(41) .sup.13C NMR (CDCl.sub.3, 125 MHz): 143.4, 140.2, 138.8, 131.6, 129.4, 129.0, 128.7, 119.7, 112.2, 24.4, 21.0.

Example 16 Preparation of diethyl 2-(3-methylphenyl)malonate

(42) 20.0 g of Diethyl 2-(3-methyl-2-ene-1-cyclohexylidene) malonate (0.08 mol) and 0.04 g of Pt/C were heated to 160 C. in N,N-dimethylacetamide. After the reaction was complete, the reaction mixture was cooled and filtered to remove the catalyst (Pt/C). A small amount of solvent was used to wash the catalyst. The organic phase was concentrated to give 16.6 g of diethyl 2-(3-methylphenyl) malonate, and the yield was 84%.

(43) .sup.1H NMR (CDCl.sub.3, 500 MHz, TMS): 7.27-7.13 (m, 4H), 4.57 (s, 1H), 4.20 (q, J=7.0 Hz, 4H), 2.35 (s, 3H), 1.26 (t, J=7.0 Hz, 6H).

(44) .sup.13C NMR (CDCl.sub.3, 125 MHz): 168.2, 138.2, 132.6, 129.8, 128.9, 128.4, 126.2, 61.7, 57.8, 14.0, 13.9.

Example 17 Preparation of dimethyl 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene) malonate

(45) To a reaction flask were sequentially added with 22.8 g of dimethyl 2-(4-heptylidene) malonate (0.10 mol), 7.0 g of 2-methylpropenal (0.10 mol) and 2.2 g of triethylenediamine (0.02 mol) to react by heating. After the reaction was complete, the reaction mixture was cooled, dissolved with ethyl acetate, washed with 1N diluted hydrochloric acid, dried and concentrated to give dimethyl 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene) malonate.

Example 18 Preparation of dimethyl 2-(2,6-diethyl-4-methylphenyl) malonate

(46) Dimethyl 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene) malonate prepared in Example 17 and 1.1 g of Pd/C were heated to 180 C. under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was cooled, and ethyl acetate was added. The mixture was filtered to remove the solid. The organic phase was dried and concentrated to give 22.2 g of dimethyl 2-(2,6-diethyl-4-methylphenyl) malonate, and the yield was 80%.

(47) .sup.1H NMR (CDCl.sub.3, 500 MHz, TMS): 6.93 (s, 2H), 5.06 (s, 1H), 3.73 (s, 6H), 2.64 (q, J=7.0 Hz, 4H), 2.30 (s, 3H), 1.18 (t, J=7.0 Hz, 6H).

(48) .sup.13C NMR (CDCl.sub.3, 125 MHz): 15.2, 21.1, 26.6, 51.5, 52.6, 126.4, 127.9, 137.9, 143.6, 169.3.

Example 19 Preparation of Pinoxaden

(49) 15.3 g of Dimethyl 2-(2,6-diethyl-4-methylphenyl) malonate prepared in Example 18 (0.05 mol), 10.5 g of hexahydro-1,4,5-oxadiazepine dihydrochloride (0.06 mol) and 20.2 g of triethylamine (0.20 mol) were stirred to react in xylene under refluxing temperature. After the reaction was complete, the reaction mixture was cooled. 10.8 g of Pivaloyl chloride (0.09 mol) was added. The mixture was reacted at room temperature. After the reaction was complete, the reaction mixture was adjusted to be acidic with dilute hydrochloric acid and then extracted with ethyl acetate. The organic phases were combined, dried and crystallized by concentration to give 14.4 g of Pinoxaden, and the yield was 72%.

(50) .sup.1H NMR (CDCl.sub.3, 500 MHz, TMS): 8.88 (s, 2H), 4.28-4.26 (m, 2H), 3.94-3.93 (m, 2H), 3.89-3.83 (m, 4H), 2.56-2.47 (m, 2H), 2.45-2.40 (m, 2H), 2.39 (s, 3H), 1.12 (t, J=9.0 Hz, 3H), 1.23 (s, 9H).