Intermediate compound for manufacturing bixin ethyl ester and method of manufacturing the same

Abstract

The present invention relates to a method of manufacturing norbixin or bixin ethyl ester, which is a carotenoid-based compound, from a novel intermediate compound. When the novel intermediate compound is used, it is possible to manufacture norbixin or bixin ethyl ester in high yield through a simple process.

Claims

1. A sulfone compound represented by Chemical Formula 11 below: ##STR00022## wherein the BT is ##STR00023##

2. A method of manufacturing a sulfone compound represented by Chemical Formula 11 below, the method comprising: mixing and reacting an ester compound represented by Chemical Formula 15 below and a solution containing acetonitrile: ##STR00024## wherein the BT is ##STR00025##

3. The method of claim 2, wherein the solution containing the acetonitrile is manufactured by mixing a mixture of urea-H.sub.2O.sub.2 and phthalic anhydride with the acetonitrile.

4. The method of claim 2, wherein the ester compound represented by Chemical Formula 15 is manufactured by adding a compound represented by Chemical Formula 13 below to a mixture containing tetrahydrofuran, (2-ethoxy-2-oxoethyl)triphenylphosphonium bromide, and sodium hydride and performing a reaction: ##STR00026##

5. A method of manufacturing bixin ethyl ester represented by Chemical Formula 2 below, the method comprising: mixing a sulfone compound represented by Chemical Formula 11 below with a compound represented by Chemical Formula 12 below or a compound represented by Chemical Formula 16 below: ##STR00027## wherein the BT is ##STR00028##

6. The method of claim 5, further comprising: adding DBU (1,8-diazabicycloundec-7-ene) to a mixture of the sulfone compound represented by Chemical Formula 11 and the compound represented by Chemical Formula 12 or the compound represented by Chemical Formula 16, and performing a reaction.

7. The method of claim 5, wherein the compound represented by Chemical Formula 16 is manufactured by adding DBU (1,8-diazabicycloundec-7-ene) to the sulfone compound represented by Chemical Formula 11 and an aldehyde compound represented by Chemical Formula 12 and performing a reaction.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The above and other objects, features and advantages of the present invention will be more clearly understood from the following detailed description taken in conjunction with the accompanying drawings, in which:

(2) FIG. 1 shows the synthesis scheme of a novel intermediate compound represented by Chemical Formula 7 according to an embodiment of the present invention;

(3) FIG. 2 shows the synthesis scheme of the novel intermediate compound represented by Chemical Formula 7 according to an embodiment of the present invention;

(4) FIG. 3 shows the synthesis scheme of norbixin using the novel intermediate compound represented by Chemical Formula 7 of the present invention;

(5) FIG. 4 shows the synthesis scheme of bixin ethyl ester according to an embodiment of the present invention; and

(6) FIG. 5 shows the synthesis scheme of bixin ethyl ester according to an embodiment of the present invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

(7) Hereinafter, the present invention will be described in more detail with reference to Examples. These Examples are only for illustrating the present invention, and thus the scope of the present invention is not to be construed as being limited by these Examples.

(8) .sup.1H- and .sup.13C-NMR spectra were respectively recorded on a 400 MHz and 100 MHz NMR spectrometer in CDCl.sub.3 with tetramethylsilane as an internal reference unless noted otherwise. High resolution mass spectroscopy was performed using magnetic sector analyzer. The column chromatography was performed by the method of Still with silica gel 60, 70-230 mesh ASTM using a gradient mixture of EtOAc/hexanes. Reactions were performed in a well-dried flask under argon atmosphere unless noted otherwise.

Example 1-1: Preparation of (4E,8E,12E,16E)-Diethyl 2,19-dibromo-3,18-dihydroxy-4,8,13,17-tetramethyl-10-(phenylsulfonyl)icosa-4,8,12,16-tetraenedioate (7), diethyl 3,3-((2E,6E,10E,14E)-6,11-dimethyl-8-(phenylsulfonyl)hexadeca-2,6,10,14-tetraene-2,15-diyl)bis(oxirane-2-carboxylate) (9)

(9) To a stirred 1.0 M solution of Lithium diisopropylamide in THF/hexanes (7.0 mL, 6.84 mmol, 5.2 equiv.) in THF (20 mL) at C. was slowly added ethyl bromoacetate 5 (0.73 mL, 6.57 mmol, 5 equiv.). The mixture was stirred for 20 min, and a solution of dialdehyde 6 (582 mg, 1.32 mmol) in THF (10 mL) was added. The mixture was stirred at 78 C. for 4 hours and quenched with 1M HCl solution. The mixture was warmed to room temperature, extracted with EtOAc, washed with 1M HCl solution, dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give bromohydrin 7 (470 mg, 0.61 mmol, 46% yield, R.sub.f=0.40 in 40% EtOAc/hexane), mono-epoxide 8 (117 mg. 0.17 mmol, 13% yield, R.sub.f=0.50), and di-epoxide 9 (60 mg, 0.098 mmol, 7% yield, R.sub.f=0.58) as yellow oils.

Example 1-2: Preparation of (4E,8E,12E,16E)-Diethyl 2,19-dibromo-3,18-dihydroxy-4,8,13,17-tetramethyl-10-(phenylsulfonyl)icosa-4,8,12,16-tetraenedioate (7)

(10) To a stirred 1.0 M solution of Lithium diisopropylamide in THF/hexanes (4.8 mL, 4.79 mmol, 5.2 equiv.) in THF (20 mL) at 78 C. was slowly added ethyl bromoacetate 5(0.51 mL, 4.61 mmol, 5 equiv.). The mixture was stirred for 20 min, and magnesium bromide (882 mg, 4.79 mmol, 5.2 equiv.) was added. Stirring was continued for 20 min at 78 C. and a solution of dialdehyde 6(408 mg, 0.92 mmol) in THF (10 mL) was added. The mixture was stirred at 78 C. for 1 hour, warmed to and stirred at room temperature for 5 hours. The mixture was quenched with 1M HCl solution, extracted with EtOAc, dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude product was purified by SiO.sub.2 flash column chromatography to give bromohydrin 7(554 mg, 0.71 mmol) in 77% yield as yellow oil.

(11) NMR and IR Analysis Result for compound 7 prepared according to EXAMPLE 1-1 and EXAMPLE 1-2 is as follows. The compound structure is represented by the following Chemical Formula 7.

(12) ##STR00015##

(13) Data for Compound 7: R.sub.f=0.40 (2:3 EtOAc/hexane); .sup.1H-NMR =1.18-1.36 (m, 6H), 1.54-1.66 (m, 12H), 1.94-2.20 (m, 8H), 2.30-2.44 (m, 1H), 2.70-2.86 (m, 1H), 3.70-3.86 (m, 1H), 4.15-4.46 (m, 8H), 4.92-5.10 (m, 2H), 5.43-5.66 (m, 2H), 7.48-7.59 (m, 2H), 7.59-7.68 (m, 1H), 7.78-7.90 (m, 2H) ppm; IR (neat) =3474, 2982, 2930, 1737, 1446, 1372, 1297, 1178, 1141, 1081, 1021, 865, 753, 693, 663, 604 cm.sup.1; HRMS (FAB) calcd for C.sub.34H.sub.45Br.sub.2O.sub.6S [C.sub.34H.sub.49Br.sub.2O.sub.8S-2H.sub.2O] 739.1304, found 739.1310.

(14) NMR and IR Analysis Result for compound 9 prepared according to EXAMPLE 1-1 is as follows. The compound structure is represented by the following Chemical Formula 9.

(15) ##STR00016##

(16) Data for Compound 9: R.sub.f=0.58 (2:3 EtOAc/hexane); .sup.1H-NMR =1.20-1.26 (m, 3H), 1.30 (t, J=7.2 Hz, 6H), 1.45 (s, 3H), 1.47 (s, 3H), 1.56-1.62 (s, 3H), 1.92-2.20 (m, 8H), 2.28-2.44 (m, 1H), 2.82-2.92 (m, 1H), 3.42 (d, J=2.0 Hz, 1H), 3.43 (br s, 1H), 3.50 (d, J=1.6 Hz, 1H), 3.53 (d, J=2.0 Hz, 1H), 3.75 (dt, J.sub.d=3.6, J.sub.t=10.4 Hz, 1H), 4.16-4.32 (m, 4H), 4.94-5.08 (m, 2H), 5.58-5.67 (m, 2H), 7.50-7.56 (m, 2H), 7.60-7.66 (m, 1H), 7.82-7.87 (m, 2H) ppm; IR (neat) =2982, 2937, 1737, 1610, 1446, 1372, 1297, 1252, 1185, 1148, 1081, 1029, 865, 745, 693, 604 cm.sup.1; HRMS (FAB) calcd for C.sub.28H.sub.39O.sub.5 [C.sub.34H.sub.46O.sub.8S PhSO.sub.2H.sub.2O] 455.2797, found 455.2803.

Example 2: Preparation of (2E,4E,6E,8E,10E,12E,14E,16E,18E)-4,8,13,17-Tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioic acidNorbixin (1)

(17) To a stirred solution of bromohydrin 7 (437 mg, 0.56 mmol) in CH.sub.2Cl.sub.2 (25 mL) at 0 C. were added pyridinium p-toluenesulfonate (28 mg, 0.11 mmol) and ethyl vinyl ether (1.60 mL, 16.80 mmol). The mixture was slowly warmed to and stirred at room temperature for 12 h. The reaction mixture was diluted with CH.sub.2Cl.sub.2, washed with aqueous NaHCO.sub.3 solution, dried over anhydrous K.sub.2CO.sub.3, filtered, and concentrated under reduced pressure to give 1-ethoxyethyl ether 10 (516 mg, 0.56 mmol) as orange yellow oil.

(18) To a stirred solution of 1-ethoxyethyl ether 10 in cyclohexane (20 mL) and benzene (20 mL) was added KOMe (1.18 g, 16.80 mmol, 30 equiv.). The mixture was heated at 80 C. for 18 hours and cooled to room temperature. The mixture was quenched with 1M HCl solution (pH 1) and extracted thoroughly with Et.sub.2O (60 mL3) to remove byproducts. The aqueous layer was then extracted with CH.sub.2Cl.sub.2 (60 mL3). Undissolved solid in the aqueous phase was filtered and dissolved in acetone. The organic phases (acetone and CH.sub.2Cl.sub.2 solutions) were mixed together, dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give norbixin 1 (175 mg, 0.46 mmol) in 82% yield in two steps from bromohydrin 7, which was further purified by recrystallization from acetone as dark red solid.

(19) NMR and IR Analysis Result for compound 1 prepared according to EXAMPLE 2 is as follows. The structure of the compound 1 is represented by the following Chemical Formula 1.

(20) ##STR00017##
[Chemical Formula 1]

(21) Data for Compound 1: m.p.>300 C.; .sup.1H-NMR (DMSO-d.sub.6) =1.93 (s, 6H), 1.98 (s, 6H), 5.84 (d, J=15.6 Hz, 2H), 6.41-6.51 (m, 2H), 6.60 (d, J=14.8 Hz, 2H), 6.64 (d, J=11.2 Hz, 2H), 6.72 (dd, J=14.8, 11.2 Hz, 2H), 6.76-6.86 (m, 2H), 7.27 (d, J=15.6 Hz, 2H) ppm; .sup.13C-NMR (DMSO-d.sub.6) 11.9, 12.0, 116.7, 124.3, 130.9, 132.9, 134.2, 136.3, 138.5, 140.9, 147.6, 167.2 ppm; IR (neat) =2915, 1670, 1610, 1558, 1424, 1312, 1282, 1260, 1193, 1141, 1006, 954, 857, 827, 775, 708, 619, 559, 477, 425 cm.sup.1; HRMS (FAB) calcd for C.sub.24H.sub.28O.sub.4 380.1988, found 380.1993.

Example 3: Preparation of (2E,4E)-Ethyl 6-(benzo[d]thiazol-2-ylthio)-4-methylhexa-2,4-dienoate (15)

(22) To a stirred suspension of (2-ethoxy-2-oxoethyl)triphenylphosphonium bromide 14(14.60 g, 34.01 mmol) in THF (100 mL) was added 60% NaH (1.95 g, 48.75 mmol) under argon atmosphere. The mixture was stirred vigorously at room temperature for 1 hour and a solution of aldehyde 13(8.00 g, 32.08 mmol) in THF (20 mL) was added. The mixture was stirred for 24 h, diluted with EtOAc, and quenched by 10% NH.sub.4Cl. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO.sub.2, eluting with 10-25% EtOAc in hexanes) to give ester 15(9.32 g, 29.18 mmol) in 91% yield as light-yellow viscose liquid.

(23) NMR and IR Analysis Result for compound 15 prepared according to EXAMPLE 3 is as follows. The structure of the compound 15 is represented by the following Chemical Formula 15.

(24) ##STR00018##

(25) Data for Compound 15: R.sub.f=0.68 (1:4 EtOAc/hexane); .sup.1H-NMR =1.27 (t, J=7.2 Hz, 3H), 1.90 (d, J=0.8 Hz, 3H), 4.14 (d, J=8.4 Hz, 2H), 4.19 (q, J=7.2 Hz, 2H), 5.89 (d, J=15.6 Hz, 1H), 6.09 (dt, J.sub.d=0.8 Hz, J.sub.t=8.4 Hz, 1H), 7.29 (d, J=15.6 Hz, 1H), 7.25-7.30 (m, 1H), 7.37-7.42 (m, 1H), 7.70-7.74 (m, 1H), 7.84-7.88 (m, 1H) ppm; .sup.13C-NMR =12.2, 14.1, 31.2, 60.1, 118.0, 120.8, 121.4, 124.2, 125.9, 133.2, 135.3, 136.4, 147.7, 152.9, 165.3, 166.7 ppm; IR (neat) =3060, 2992, 1706, 1623, 1458, 1394, 1302, 1235, 1170, 990, 848, 755 cm.sup.1; HRMS (FAB) calcd for C.sub.16H.sub.18NO.sub.2S.sub.2 320.0079, found 320.0075.

Example 4: Preparation of (2E,4E)-Ethyl 6-(benzo [d] thiazol-2-ylsulfonyl)-4-methylhexa-2,4-dienoate (11)

(26) The mixture of Urea-H.sub.2O.sub.2 (6.80 g, 72.29 mmol) and phthalic anhydride (5.35 g, 36.12 mmol) was stirred in MeCN (70 mL) for 2 hours. A solution of sulfide 15 (3.30 g, 10.33 mmol) in MeCN (15 mL) was added to the above mixture under a cold-water bath. The mixture was stirred at room temperature for 20 h, and most of solvent was removed under reduced pressure. The crude product was dissolved in CHCl.sub.3, washed with water, dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude product was purified by SiO.sub.2 flash column chromatography (10-50% EtOAc in hexane) to give sulfone 11 (2.95 g, 8.39 mmol) in 81% yields as off white form.

(27) NMR and IR Analysis Result for compound 11 prepared according to EXAMPLE 4 is as follows. The structure of the compound 11 is represented by the following Chemical Formula 11.

(28) ##STR00019##

(29) Data for Compound 11: R.sub.f=0.46 (2:1 EtOAc/hexane); m.p.: 120-122 C.; .sup.1H-NMR =1.29 (t, J=7.2 Hz, 3H), 1.76 (d, J=1.2 Hz, 3H), 4.20 (q, J=7.2 Hz, 2H), 4.44 (d, J=8.4 Hz, 2H), 5.87 (dt, J.sub.d=0.8 Hz, J.sub.t=8.4 Hz, 1H), 5.89 (d, J=15.6 Hz, 1H), 7.26 (d, J=15.6 Hz, 1H), 7.58-7.68 (m, 2H), 8.00-8.04 (m, 1H), 8.21-8.25 (m, 1H) ppm; .sup.13C-NMR =12.7, 14.2, 54.8, 60.6, 120.1, 122.0, 122.4, 125.4, 127.8, 128.2, 136.9, 142.0, 146.5, 152.6, 165.3, 166.6 ppm; IR (neat) =2982, 1710, 1623, 1466, 1414, 1394, 1300, 1234, 1146, 1023, 903, 854, 756 cm.sup.1; HRMS (ESI) calcd for C.sub.16H.sub.12NO.sub.4S.sub.2Na 374.0491, found 374.0494.

Example 5: Preparation of Ethyl (2E,4E,6E,8E,10E,12E)-4,8,13-trimethyl-14-oxotetradeca-2,4,6,8,10,12-hexaenoate (16)

(30) To a stirred solution of sulfone 11 (2.55 g, 7.26 mmol, 2.0 equiv.) and C.sub.10 dialdehyde 12 (0.60 g, 3.65 mmol) in CH.sub.2Cl.sub.2 (50 mL) was slowly added DBU (1.38 g, 9.10 mmol) under argon atmosphere. The mixture was stirred at room temperature for 12 hours and quenched with 10% NH.sub.4Cl solution. The mixture was extracted with CH.sub.2Cl.sub.2, dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude product was purified by SiO.sub.2 flash column chromatography (5%-15% EtOAc in hexanes) to give mono-coupled product 16 (0.77 g, 2.56 mmol) in 70% yield as deep red powder.

(31) NMR and IR Analysis Result for compound 16 prepared according to EXAMPLE 5 is as follows. The structure of the compound 16 is represented by the following Chemical Formula 16.

(32) ##STR00020##

(33) Data for Compound 16: R.sub.f=0.38 (1:4 EtOAc/hexane); m.p.: 148-150 C.; .sup.1H-NMR =1.31 (t, J=7.2 Hz, 3H), 1.90 (s, 3H), 1.97 (s, 3H), 2.05 (s, 3H), 4.23 (q, J=7.2 Hz, 2H), 5.93 (d, J=16.0 Hz, 1H), 6.39 (d, J=11.6 Hz, 1H), 6.51 (d, J=11.6 Hz, 1H), 6.52 (d, J=14.8 Hz, 1H), 6.75 (dd, J=14.8, 11.6 Hz, 2H), 6.97 (d, J=11.6 Hz, 1H), 7.03 (dd, J=14.8, 11.6 Hz, 1H), 7.38 (d, J=16.0 Hz, 1H), 9.47 (s, 1H) ppm; .sup.13C-NMR =9.6, 12.7, 13.0, 14.3, 60.3, 117.3, 126.3, 128.7, 133.1, 134.9, 137.1, 137.6, 138.6, 140.7, 140.8, 148.4, 148.5, 167.3, 194.5 ppm; IR (neat) =2977, 2915, 2803, 2708, 1740, 1660, 1587, 1442, 1376, 1303, 1170, 975, 835 cm.sup.1; HRMS (ESI) calcd for C.sub.19H.sub.24O.sub.3Na 323.1618, found 323.1621.

Example 6-1: Preparation of Diethyl (2E,4E,6E,8E,10E,12E,14E,16E,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate 2 from Compound 16

(34) To a stirred solution of BT-sulfone 11 (1.07 g, 3.04 mmol, 2 equiv.) and mono-coupled product 16 (0.46 g, 1.53 mmol) in CH.sub.2Cl.sub.2 (40 mL) was slowly added DBU (0.60 g, 3.97 mmol) under argon atmosphere. The mixture was stirred at room temperature for 24 hours and quenched with 10% NH.sub.4Cl solution. The mixture was extracted with CH.sub.2Cl.sub.2, dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude product was purified by SiO.sub.2 flash column chromatography (5% EtOAc in hexanes) to give bixin ethyl ester 2 (0.47 g, 1.07 mmol) in 70% yield as deep red powder.

Example 6-2: Preparation of Diethyl (2E,4E,6E,8E,10E,12E,14E,16E,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate 2 from Compound 11 and Compound 12

(35) To a stirred solution of BT-sulfone 11 (2.14 g, 6.09 mmol, 4.0 equiv.) and C.sub.10 dialdehyde 12 (0.25 g, 1.52 mmol) in CH.sub.2Cl.sub.2 (50 mL) was slowly added DBU (1.01 g, 6.68 mmol) under argon atmosphere. The mixture was stirred at room temperature for 12 hours and quenched with 10% NH.sub.4Cl solution. The mixture was extracted with CH.sub.2Cl.sub.2, dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude product was purified by SiO.sub.2 flash column chromatography (5%-15% EtOAc in hexanes) to give mono-coupled product 16 (0.24 g, 0.80 mmol) and bixin ethyl ester 2 (80 mg, 0.18 mmol) in 53% and 12% yields, respectively as deep red powder.

(36) NMR and IR Analysis Result for compound 2 prepared according to EXAMPLE 6-1 and EXAMPLE 6-2 is as follows. The structure of the compound 2 is represented by the following Chemical Formula 2.

(37) ##STR00021##

(38) Data for Compound 2: R.sub.f=0.41 (1:4 EtOAc/hexane); m.p.: 170-172 C.; .sup.1H-NMR =1.31 (t, J=7.2 Hz, 6H), 1.95 (s, 6H), 1.99 (s, 6H), 4.22 (q, J=7.2 Hz, 4H), 5.88 (d, J=15.6 Hz, 2H), 6.25-6.40 (m, 2H), 6.50 (d, J=12.0 Hz, 2H), 6.51 (d, J=14.4 Hz, 2H), 6.63 (dd, J=14.4, 12.0 Hz, 2H), 6.64-6.74 (m, 2H), 7.38 (d, J=15.6 Hz, 2H) ppm; .sup.13C-NMR 12.7, 12.8, 14.4, 60.2, 116.4, 124.5, 131.1, 133.6, 134.7, 136.9, 139.3, 141.6, 148.8, 167.5 ppm; IR (neat) =2920, 2852, 1703, 1614, 1563, 1457, 1366, 1304, 1259, 1165, 1027, 976, 841, 753 cm.sup.1; HRMS (ESI) calcd for C.sub.28H.sub.36O.sub.4Na 459.2506, found 459.2509.

Experimental Example 1: Confirmation of Yield of Bromohydrin Compound

(39) The yield of the bromohydrin compound represented by Chemical Formula 7, which was manufactured according to Examples 1-1 and 1-2, was confirmed, and the results are shown in Table 1 below.

(40) TABLE-US-00001 TABLE 1 Yield Chem- Chem- Chem- ical ical ical Metal Reaction For- For- For- No base Additive condition mula 7 mula 8 mula 9 1 LDA 78C., 4 h 46 13 7 2 LiHMDS 78C., 4 h 43 15 8 3 KHMDS 78C., 4 h 4 LDA BF.sub.3 OEt.sub.2 78C., 4 h 5 LDA Mg(N-i- 78C., 2 h 76 Pr.sub.2).sub.2 then rt, 4 h 6 LDA MgBr.sub.2 78C., 2 h 77 then rt, 4 h

(41) As a result, as shown in Table 1 above, the enolate generated from the compound of Chemical Formula 5 by LDA was reacted with the compound of Chemical Formula 6 at 78 C., thus obtaining mono- and di-epoxide products 8 and 9 at yields of 13% and 7% and the bromohydrin compound represented by Chemical Formula 7 to be manufactured by the present invention at a yield of 43%. Further, even when LiHMDS was used as a metal-amide base, the result that was obtained was similar to that of the reaction using LDA, but no compound was generated when KHMDS was used as the metal-amide base.

(42) Next, in the reaction using BF.sub.3.OEt.sub.2 as an additive while using LDA as the metal-amide base, none of the bromohydrin compound represented by Chemical Formula 7 or the mono- and di-epoxide products 8 and 9 were generated. On the contrary, in the reaction using Mg(N-i-Pr.sub.2).sub.2 or MgBr.sub.2 as an additive, the epoxide product was not generated, but only the bromohydrin compound represented by Chemical Formula 7 was generated.

(43) Although the preferred embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions are possible, without departing from the scope and spirit of the invention as disclosed in the accompanying claims.