PROCESS FOR PRODUCING HERBICIDAL PYRIDAZINONE COMPOUNDS

Abstract

The present invention provides, inter alia, a process for producing a compound of Formula (I): wherein A.sup.1, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are as defined herein. The present invention further provides intermediate compounds utilised in said process, and methods for producing said intermediate compounds.

##STR00001##

Claims

1. A process for producing a compound of Formula (I): ##STR00035## wherein R.sup.1 is selected from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.3alkoxyC.sub.1-C.sub.3alkyl-, C.sub.1-C.sub.3alkoxyC.sub.2-C.sub.3alkoxyC.sub.1-C.sub.3alkyl-, aryl and a 5 or 6-membered heteroaryl, wherein the heteroaryl contains one to three heteroatoms each independently selected from the group consisting of oxygen, nitrogen and sulphur, and wherein the aryl and heteroaryl component may be optionally substituted; R.sup.2 is C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.6 cycloalkyl; A.sup.1 is selected from the group consisting of O, C(O) and (CR.sup.7R.sup.8); R.sup.4, R.sup.6, R.sup.7 and R.sup.8 are each independently selected from the group consisting of hydrogen and C.sub.1-C.sub.4alkyl; and R.sup.3 and R.sup.5 are each independently selected from the group consisting of hydrogen and C.sub.1-C.sub.4alkyl or together may form a C.sub.1-C.sub.3alkylene chain; the process comprising reacting a compound of Formula (XII) ##STR00036## wherein R.sup.1 and R.sup.2 are as defined with regard to Formula (I); with a compound of Formula (XIII) ##STR00037## wherein A.sup.1 and R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are as defined with regard to Formula (I); to give a compound of Formula (XIV) ##STR00038## (ii) converting the compound of Formula (XIV) to a compound of Formula (XV) ##STR00039## and (iii) converting the compound of Formula (XV) to a compound of Formula (I) wherein the process is carried out in the presence of a base and in the absence of cyanide ions.

2. A process according to claim 1, wherein R.sup.1 is an optionally substituted heteroaryl.

3. A process according to claim 1, wherein R.sup.1 is an optionally substituted phenyl.

4. A process according to claim 1, wherein R.sup.1 is phenyl optionally substituted by one or two substituents independently selected from the group consisting of halo, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.3 alkoxy, cyano and nitro.

5. A process according to claim 1, wherein A.sup.1 is CR.sup.7R.sup.8 and R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are hydrogen.

6. A process according to claim 1, wherein steps (i), (ii) and (iii) are performed in a single operation.

7. A process according to claim 1, wherein the compound of Formula (XII) wherein R.sup.1 is aryl or a 5 or 6-membered heteroaryl as defined in claim 1 is produced by: (i) reacting together a compound of Formula (V) ##STR00040## wherein R.sup.1 is aryl or a 5 or 6-membered heteroaryl and R.sup.2 is as defined in claim 1 with a compound of Formula (XVI) ##STR00041## wherein each R.sup.9 is independently a C.sub.1-C.sub.6alkyl, to give compound of Formula (VI) ##STR00042## (ii) hydrolysing the compound of Formula VI to a compound of Formula (IX) ##STR00043## and (iii) converting the compound of Formula (IX) to the corresponding acid chloride of Formula (XII) ##STR00044##

8. A process according to claim 1, wherein the compound of Formula (XII) wherein R.sup.1 is aryl or a 5 or 6-membered heteroaryl and R.sup.2 is as defined in claim 1 is produced by: (i) reacting together a Compound of Formula (III) ##STR00045## wherein R.sup.1 is aryl or a 5 or 6-membered heteroaryl as defined in claim 1 and X is selected from the group consisting of Cl, Br and HSO.sub.4 with a compound of Formula (X) ##STR00046## wherein R.sup.2 is as defined in claim 1, R.sup.10 is NMe.sub.2, NEt.sub.2, OH or C.sub.1-C.sub.3alkoxy and each R.sup.9 is independently a C.sub.1-C.sub.6alkyl, to give a compound of Formula (XI) ##STR00047## (ii) cyclising the compound of Formula (XI) to a compound of Formula (VI) ##STR00048## (iii) hydrolysing the compound of Formula (VI) to a compound of Formula (IX) ##STR00049## and (iv) converting the compound of Formula (IX) to the corresponding acid chloride of Formula (XII) ##STR00050##

9. A process according to claim 1, wherein R.sup.1 is 3,4-dimethoxyphenyl.

10. A process according to claim 1, wherein R.sup.2 is methyl.

11. A compound of Formula (XV) ##STR00051## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and A.sup.1 are as defined in claim 1.

12. A compound of Formula (XVa) ##STR00052##

13. A compound of Formula (Va) ##STR00053##

14. A compound of Formula (XIa) ##STR00054## wherein R.sup.9 are both methyl or ethyl, R.sup.2 is methyl and R.sup.1 is 3,4-dimethoxyphenyl-.

Description

EXAMPLES

[0076] The following non-limiting Examples outline the subject matter of the invention in more detail. The substituent definitions are the same as defined above.

[0077] The following abbreviations were used in this section: s=singlet; br s=broad singlet; d =doublet; dd=double doublet; dt=double triplet; t=triplet, tt=triple triplet, q=quartet, quin =quintuplet, sept=septet; m=multiplet; RT=retention time, MH.sup.+=molecular mass of the molecular cation.

[0078] .sup.1H NMR spectra were recorded at 400 MHz and chemical shifts are given in ppm.

Example 1

(2Z)-2-[(3,4-Dimethoxyphenyl)hydrazono]propanal

[0079] ##STR00026##

[0080] A 5 l double jacketed reactor was charged with water (1.2 l) and cooled to 5 C. Concentrated sulfuric acid (104 ml, 1.90 mol) was added slowly while keeping the temperature below 25 C. When the internal temperature has again reached 5 C. 3,4-dimethoxyaniline (198.0 g, 1.27 mol) was added portion wise. A solution of sodium nitrite (88.3 g, 1.27 mol) in water (0.25 l) was added to the dark violet suspension over 40 min while keeping the internal temperature below 5 C. The reaction mixture was stirred at 0 C. for 90 min followed by addition of the solution of 3-dimethylamino-2-methyl-2-propanal (137.2 g, 1.15 mol) and NaOAc (105.0 g, 1.27 mol) in water (0.75 l) over 1 h while keeping the internal temperature below 5 C. After the addition was finished the temperature of the reactor jacket was raised to 0 C. and afterwards every 30 min again 5 C. After 2.5 h (internal temperature 20 C.) full conversion has been achieved. The now black suspension was transferred into 5 l Erlenmeyer flask and the reactor was washed with water (2 l) to remove most of the remaining precipitate. The solid product was filtered off, washed on filter with water (1.5 l) and dried to constant weight at 50 C. and high vacuum for 40 h to yield (2Z)-2-[(3,4-dimethoxyphenyl)hydrazono]propanal (199 g, 92% purity, 71% yield) as a brick red solid. This material was sufficiently pure to be used in the next step. Upon standing for 16 h another portion of the product precipitated out of the aqueous phase and was also filtered, washed and dried in vacuum to provide the second batch of (2Z)-2-[(3,4-dimethoxyphenyl)hydrazono]propanal (43.7 g, 70% purity, 12% yield; 83% yield for combined both batches).

[0081] .sup.1H NMR (400 MHz, CDCl.sub.3): 9.49 (s, 1H), 8.10 (br s, 1H), 7.00 (d, J=2.6 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 6.70 (dd, J=8.6, 2.4 Hz, 1H), 3.94 (s, 3H), 3.88 (s, 3H), 1.98 (s, 3H).

Example 2

Ethyl 2-(3,4-dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4-carboxylate

[0082] ##STR00027##

[0083] To a solution of piperidine (0.062 ml, 0.628 mmol) in toluene (3.0 ml) was added acetic acid (0.036 ml, 0.628 mmol). After stirring for 10 min (2Z)-2-[(3,4-dimethoxyphenyl) hydrazono]propanal (0.300 g, 93% purity, 1.26 mmol) was added followed by diethyl malonate (0.23 ml, 1.51 mmol). The resulting dark red reaction mixture was heated at 90 C. for 3 h, cooled to rt and evaporated to dryness under reduced pressure to afford ethyl 2-(3,4-dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4-carboxylate (0.564 g) as a red oil. Quantitative NMR analysis using trimethoxybenzene as an internal standard indicates purity of 67% (94% yield).

[0084] .sup.1H NMR (400 MHz, CDCl.sub.3): 7.67 (s, 1H), 7.15-7.10 (m, 2H), 6.96-6.92 (m, 1H), 4.42 (q, J=7.3 Hz, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 2.44 (s, 3H), 1.40 (t, J=7.2 Hz, 3H).

Example 3

2-(3,4-Dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4-carboxylic acid

[0085] ##STR00028##

[0086] A 5 l double jacketed reactor was charged with toluene (1.25 l). Piperidine (31.0 ml, 0.31 mol) was added followed by acetic acid (18.0 ml, 0.31 mol) resulting in a formation of white precipitate. (2Z)-2-[(3,4-dimethoxyphenyl)hydrazono]propanal (150 g, 92% purity, 0.621 mol) was added affording a dark red suspension. Diethyl malonate (114 ml, 0.745 mol) was added and the reaction mixture was heated to 96 C. (reflux). After stirring for 8 h the reaction mixture was cooled to 20 C. and stirred for further 16 h. 2M NaOH (0.621 l, 1.24 mol) was slowly added while keeping the internal temperature below 30 C. After stirring for 2 h extra water (0.5 l) was added. After stirring for further 1 h water (1.75 l) and toluene (0.20 l) was added to dissolve all precipitates. Stirring was then stopped and layers separated. Organic layer was washed with water (20.7 l) and combined aqueous layers were washed with EtOAc (20.4 l). The aqueous layer was then slowly poured into 2M HCl (1.00 l, 2.00 mol). A yellow solid precipitates from the mixture immediately. After the addition was finished (15 min) the mixture was stirred for additional 20min. The precipitate was filtered off, washed on filter with water and dried at high vacuum and 65 C. till constant weight affording ethyl 2-(3,4-dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4-carboxylate (153.8 g) as a yellow powder. Quantitative NMR analysis using trimethoxybenzene as an internal standard indicates purity of 95% (81% isolated yield).

[0087] .sup.1H NMR (400 MHz, CDCl.sub.3): 13.98 (br s, 1H), 8.18 (s, 1H), 7.16 (dd, J=8.6, 2.5 Hz, 1H), 7.09 (d, J=2.4 Hz, 1H), 6.99 (d=8.6 Hz, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 2.55 (s, 3H).

Example 4

Dimethyl 2-[(2Z)-2-[(3,4-dimethoxyphenyl)hydrazono]propylidene] propanedioate

[0088] ##STR00029##

[0089] To a suspension of 3,4-dimethoxyaniline (63 mg, 0.42 mmol) in H.sub.2O (1.51 ml) was added sulfuric acid (35 l, 0.62 mmol) at 23 C. NaNO.sub.2 (aq. sol, 1.0 M, 0.42 ml, 0.42 mmol) was added within 30 s. To this mixture a solution of dimethyl 2-[(E)-3-(dimethylamino)-2-methyl-prop-2-enylidene]propanedioate (100 mg, 86% purity, 0.38 mmol) and NaOAc (35 mg, 0.42 mmol) in H.sub.2O/MeOH (6 ml, 1:1, v:v) was added in one portion. The mixture was stirred for 5 min at 23 C. H.sub.2O (20 ml) was added to the reaction mixture and it was extracted with EtOAc (320 ml). The combined organic phases were dried over Na.sub.2SO.sub.4 and the solvent was evaporated to afford dimethyl 2-[(2Z)-2-[(3,4-dimethoxyphenyl)hydrazono]-propylidene]-propanedioate (166 mg) as a red solid. Quantitative NMR analysis using mesitylene as an internal standard indicates purity of 63% (82% yield).

[0090] .sup.1H NMR (400 MHz, CDCl.sub.3): =2.01 (s, 3H), 3.82 (s, 3H), 3.85 (s, 3H), 3.88 (s, 3H), 4.01 (s, 3H), 6.52-6.55 (m, 1H), 6.98-6.99 (m, 1H), 7.27 (s, 1H), 7.37 (s, 1H), 7.73 (bs, 1H).

Example 5

Methyl 2-(3,4-dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4-carboxylate

[0091] ##STR00030##

[0092] A solution of dimethyl 2-[(2Z)-2-[(3,4-dimethoxyphenyl)hydrazono]propylidene] propanedioate (121 mg, 63% purity, 0.23 mmol) in toluene (0.91 ml) was heated to 90 C. for 3.5 h. The solvent was evaporated to afford methyl 2-(3,4-dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4-carboxylate (85.8 mg) as a white solid. Quantitative NMR analysis using mesitylene as an internal standard indicates purity of 63% (78% yield).

[0093] .sup.1H-NMR (400 MHz, CDCl.sub.3): =2.46 (s, 3H), 3.92 (s, 3H), 3.94 (s, 3H), 3.97 (s, 3H), 6.94-6.96 (m, 1H), 7.13-7.16 (m, 2H), 7.72 (s, 1H).

Example 6

2-(3,4-Dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4-carbonyl chloride

[0094] ##STR00031##

[0095] To a suspension of 2-(3,4-dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4-carboxylic acid (10.0 g, 97% purity, 33.4 mmol) in dichloromethane (50 ml) was added DMF (0.052 ml, 0.67 mmol). Oxalyl chloride (3.87 ml, 43.4 mmol) was then added slowly (strong gas evolution). After stirring for 2 h at ambient temperature the reaction mixture was evaporated to dryness under reduced pressure to afford 2-(3,4-dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4-carbonyl chloride (10.77 g) as a dark brown solid. Quantitative NMR analysis using trimethoxybenzene as an internal standard indicates purity of 95% (99% yield).

[0096] .sup.1H NMR (400 MHz, CDCl.sub.3): 7.88 (s, 1H), 7.16-7.11 (m, 2H), 6.94 (d, J=8.1 Hz, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 2.51 (s, 3H).

Example 7

(3-Oxocyclohexen-1-yl) 2-(3,4-dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4-carboxylate

[0097] ##STR00032##

[0098] To a solution of 1,3-cyclohexadione (0.647 g, 5.77 mmol) in 1,2-dichloroethane (40 ml) was added triethylamine (0.93 ml, 6.63 mmol) at 15 C. resulting in a clear colourless solution. A solution of 2-(3,4-dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4-carbonyl chloride (1.963 g, 85% purity, 5.42 mmol) in 1,2-dichloroethane (20 ml) was added dropwise while keeping the internal temperature below 12 C. After stirring for 2 h the reaction was quenched by addition of 1M HCl (40 ml) and allowed to warm to ambient temperature. Layers were separated, organic phase washed with 1M HCl (40 ml), water (40 ml) and brine (40 ml) and dried over anhydrous Na.sub.2SO.sub.4. Concentration under reduced pressure afforded (3-oxocyclohexen-1-yl) 2-(3,4-dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4-carboxylate (2.50 g) as an amber coloured oil. Quantitative NMR analysis using trimethoxybenzene as an internal standard indicates purity of 83% (99% yield).

[0099] .sup.1H NMR (400 MHz, CDCl.sub.3): 7.79 (s, 1H), 7.13 (dd, J=8.4, 2.4 Hz, 1H), 7.10 (d, J=2.5 Hz, 1H), 6.95 (d, J=8.7 Hz, 1H), 6.04 (t, J=1.3 Hz, 1H), 3.93 (s, 3H), 3.91 (s, 3H), 2.69 (td, J=6.1, 1.3 Hz, 2H), 2.49 (s, 3H), 2.48-2.43 (m, 2H), 2.12 (quin, J=6.5 Hz, 2H).

[0100] Alternatively (3-oxocyclohexen-l-yl) 2-(3,4-dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4-carboxylate could be prepared by the following procedure:

[0101] To a solution of 2-(3,4-dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4-carbonyl chloride (3.28 g, 94% purity, 9.99 mmol) in 1,2-dichloroethane (35 ml) was added 1,3-cyclohexadione (1.50 g, 97% purity, 13.0 mmol) followed by N,N-dimethylaniline (3.2 ml, 25.0 mmol). The deep red solution was stirred at ambient temperature for 1 h. The reaction mixture was then diluted with 1,2-dichloroethane (40 ml) and washed with 1M HCl, sat. aq. NaHCO.sub.3 and brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to produce a black gummy residue. Diethyl ether (10 ml) was added and the resulting suspension was stirred vigorously for 4 h. The resulting precipitate was filtered off and washed on filter with a minimum amount of diethyl ether. Drying of precipitate in high vacuum afforded (3-oxocyclohexen-1-yl) 2-(3,4-dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4-carboxylate (2.81 g, 97% purity, 71% isolated yield) as a beige solid.

Example 8

3-(3,4-Dimethoxyphenyl)-1-methyl-7,8,9,10b-tetrahydro-4aH-chromeno[3,4-d]pyridazine-4,5,10-trione

[0102] ##STR00033##

[0103] To a solution of (3-oxocyclohexen-1-yl) 2-(3,4-dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4-carboxylate (0.444 g, 96% purity, 1.00 mmol) and 1,3-cyclohexadione (0.0376 g, 0.335 mmol) in acetonitrile (5.0 ml) was added Et.sub.3N (0.070 ml, 0.47 mmol). After stirring for 30 min the reaction mixture was quenched by pouring into 1M HCl (10 ml). The resulting mixture was extracted with CH.sub.2Cl.sub.2 (215 ml), the combined organic layers were washed with aq saturated NaHCO.sub.3, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford 3-(3,4-dimethoxyphenyl)-1-methyl-7,8,9,10b-tetrahydro-4aH-chromeno [3,4-d]pyridazine-4,5,10-trione (0.419 g) as a yellow powder. Quantitative NMR analysis using trimethoxybenzene as an internal standard indicates purity of 92% (73% yield).

[0104] Alternatively 3-(3 ,4-dimethoxyphenyl)-1-methyl-7,8,9,10b-tetrahydro-4aH-chromeno [3,4-d]pyridazine-4,5,10-trione could be prepared by the following procedure: (3 -oxocyclohexen-1-yl) 2-(3,4-dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4-carboxylate (0.222 g, 61% purity, 0.35 mmol) and DMAP (0.013 g, 0.11 mmol) were dissolved in MeCN (1.5 mL). After stirring for 30 minutes the reaction mixture was quenched by addition of 1M HCl (1.5 mL). The reaction mixture was extracted with CH.sub.2Cl.sub.2 (33.0 mL), the combined organic layers were dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford 3-(3,4-dimethoxyphenyl)-1-methyl-7,8,9,10b-tetrahydro-4aH-chromeno [3,4-d]pyridazine-4,5,10-trione (0.270 g) as an amber oil. Quantitative NMR analysis using trimethoxybenzene as an internal standard indicates purity of 43.2% (86% yield).

[0105] Alternatively 3-(3,4-dimethoxyphenyl)-1-methyl-7,8,9,10b-tetrahydro-4aH-chromeno [3,4-d]pyridazine-4,5,10-trione could be prepared by the following procedure:

[0106] To a solution of 1,3-cyclohexadione (1.825 g, 16.28 mmol) in acetonitrile (8.0 ml) was added triethylamine (2.40 ml, 17.2 mmol) and the reaction mixture was cooled to 18 C. A solution of 2-(3,4-dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4-carbonyl chloride (5.01 g, 16.23 mmol) in acetonitrile (5.0 ml) was added dropwise while keeping the internal temperature below 15 C. After stirring for 90 min a solution of 1,3-cyclohexadione (0.543 g, 4.85 mmol) and triethylamine (1.10 ml, 8.10 mmol) in acetonitrile (2.0 ml) was added and the reaction mixture was warmed up to 0 C. After stirring at this temperature for 4 h the reaction was quenched by addition of 1M HCl (40 ml). The resulting mixture was extracted with DCM (450 ml). The combined organic layers were washed with water (50 ml) and brine (50 ml). Drying over anhydrous Na.sub.2SO.sub.4 and evaporation under reduced pressure afforded 3-(3,4-dimethoxyphenyl)-1-methyl-7,8,9,10b-tetrahydro-4aH-chromeno[3,4-d]pyridazine-4,5,10-trione (6.680 g) as a beige powder. Quantitative NMR analysis using trimethoxybenzene as an internal standard indicates purity of 85% (91% yield).

[0107] .sup.1H NMR (400 MHz, CDCl.sub.3): 7.03-6.97 (m, 2H), 6.90 (d, J=8.4 Hz, 1H), 4.28 (d, J=7.7 Hz, 1H), 3.90 (s, 3H), 3.90 (s, 3H), 3.70 (d, J=7.7 Hz, 1H), 2.70 (t, J=6.2 Hz, 2H), 2.62-2.55 (m, 2H), 2.27-2.09 (m, 2H), 1.99 (s, 3H).

Example 9

2-[2-(3,4-Dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4-carbonyl] cyclohexane-1,3-dione

[0108] ##STR00034##

[0109] To a solution of 3-(3,4-dimethoxyphenyl)-1-methyl-7,8,9,10b-tetrahydro-4aH-chromeno[3,4-d]pyridazine-4,5,10-trione (0.250 g, 85% purity, 0.550 mmol) in 1,2-dichloroethane (2.0 ml) was added 1,3-cyclohexadione (0.0187 g, 0.167 mmol) followed by triethylamine (0.11 ml, 0.80 mmol). The reaction was heated at 60 C. for 4 h, then cooled to ambient temperature and quenched by addition of 1M HCl (2 ml). The resulting mixture was diluted with 1,2-dichloroethane and water. Phases were separated and the aqueous phase was extracted with dichloromethane (3). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford 2-[2-(3,4-dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4-carbonyl]cyclohexane-1,3-dione (0.268 g) as a yellow oil. Quantitative NMR analysis using trimethoxybenzene as an internal standard indicates purity of 57% (72% yield).

[0110] .sup.1H NMR (400 MHz, CDCl.sub.3): 16.15 (s, 1H), 7.15-7.11 (m, 1H), 7.10-7.08 (m, 2H), 6.91 (d, J=8.4 Hz, 1H), 3.90 (s, 3H), 3.89 (s, 3H), 2.72 (t, J=6.2 Hz, 2H), 2.48-2.43 (m, 2H), 2.41 (s, 3H), 2.04 (quin, J=6.4 Hz, 2H).