Title of Invention

A PROCESS FOR THE SELECTIVE OXIDATION OF A LIMONOID

Abstract

A process for the selective oxidation of a limonoid comprising the preparation of a solution of 2% to 20*A of the said limonoid in methanol and subjecting the said solution to microwave or ultrasonic irradiation of 2000MHz / 30 KHz to 50 KHz in the presence of i% to 10% N-bromosuccinimide, also in the said solution, until the reaction is complete, as indicated by the disappearance of the limonoid. The said solvent is removed and the reagent separated to obtain the oxidised product.

Full Text

This invention relates to a process for the selective oxidation of a limonoid. One of the most interesting groups of anti-insect phytochemicals and the most promising as new natural pesticides are the triterpenoids isolated from the plants belonging to Meliaceae family. A representative of the Meliaceae family is the Indian neem tree. Neem oil, leaf and seeds contain major triterpenoids, such as, salannin, nimbin, desacetyl salannin and nimonol apart from highly active antifeedant azadirachtin. Oxidised products of salannin and nimbin from neem seeds, where the furan ring had been converted into an a,p-unsaturated lactone showed better antifeedant activity compared to their parent molecule. This invention proposes a quicker and more effective process of selectively oxidizing tbe-furan ring triterpenoids such as those cited above by exposure to microwave and ultrasonic irradiation. The present invention has explored the possibility of applying microwave and ultrasound irradiation for canrying out selective oxidation of the furan ring in The process for the selective oxidation of a limonoid._jaccording to this invention, comprises the preparation of a solution of 2% to 20% of the said limonoid in methanol and subjecting the said solution to microwave or ultrasonic radiation of 2000 MHz to 3000MHz / 30KHz to 50KHz in the presence of 1% to 10% N-bromosuccinimide, also in the said solution, until the reaction is complete, as indicated by the disappearance of the limonoid ; removing the said solvent and separating the reagent to obtain the oxidized product. The accompanying drawings illustrate, by way of example, and not by way of limitation, in Fig. 1 an ultrasonicator apparatus and Fig . 2 a microwave apparatus. Refen-ing to Fig .1, the reaction mixture comprising the limonoid and an oxidizing agent, (N-bromosuccinimide) in solution in methanol is taken in a round bottomed According to this invention, tlie oxidation of limonoids isolated from natural products of synthesized is out using either a domestic microwave oven or a simple ultrasonicator (used as a cleaning bath). A variety of limonoids with varied structural features in the A, B, C and D rings of the terpenoidal skeleton have been shown to undergo the above mentioned oxidation reaction in a very short span ( Results Tetranortriterpenoids such as salannin 1, nimbin 2, desacetyl nimbin 3, nimonol 4 and methylangolansate 5 were subjected to oxidation reactions using N-bromo succinimide under (a) stirring at 0°C (b) ultrasound and (c) microwave irradiations. In all these cases, the furan moiety present in these limonoids undenrwent a partial oxidation leading to butyrolactone in 48 h, 15 min and less than a minute respectively (Table-1). The proposed structure of the products were authenticated with 1H ,13C and 2D NMR studies. Table 1. Oxidation of Limonoids A perusal of the 13C NMR of the products revealed the presence of an additional lactonic carbonyl resonating at 170 -173 ppm in addition to the carbonyl group/s present in the starting materials. DEPT-135 confirmed an additional methylene carbon at 70.2 ppm, indicating it to be an oxymethylene whose1H was observed as doublet at 4.7 ppm (1H-13C COSY). This proton in turn showed connectivity with proton at 7.28 ppm (1H-1H COSY) whose carbon resonated at 144.8 ppm thereby confirming it to be an olefinic methine. The additional quaternary carbon resonating at 132.5 ppm was assigned to be the counter part of the olefinic methine. The above results confirmed the presence of butyrolactone. General experimental procedure (example) To a solution of the tetranortriterenoid (0.1 mmoi) in MeOH (2ml) freshly crystallized N-bromosuccinimide (0.1 mmol) was added and placed either in an ice bath with a magnetic stirrer for 48 h, or an ultrasonicator (40 kHz) at 300K for 15 minutes or under microwave irradiation (2450 MHz) for a minute. The reaction was monitored by TLC. The solvent was removed under reduced pressure. Crude product was chromatographed on silica gel column using 1:1 Ethyl acetate: Hexane as eluant to obtain the pure products. The oxidized products: Salanolactone 1 m.p.156°C; UV-AmaxCCHCb) 240nm(E 9638), 245nm(£ 8852), 254nm(e 7405); IR-Umax / cm-1 3376, 2976, 2880, 1760, 1708, 1696, 1651, 1596, 1488, 1465, 1379, 1315, 1273, 1068, 1001, 969, 880, 838, 646, 611; ■"" NMR (CDCI3) (6, ppm)7.28(d, 1H,J=5.6 Hz), 6.95 (m, 1H), 5.33 {t, 1H,J=6.1Hz), 4.96 (cf, 1H, J=2.6 Hz), 4.76{d, 1H,J=5.3Hz), 4.71 (d, 2H, J=5.Hz), 4.21(d, 1H, J=3.2Hz),3.96 {dd, 1H, J=12.7,3.2 Hz), 3.71 (m, 1H), 3.66 (cf, 1H, J= 7.3), 3.58 (m, 1H), 3.52 (s, 3H), 2.77(d, 1H J=13 Hz), 2.68 (m, 1H), 2.35 (m,2H) 2.21-2.31 (m, 4H), 1.93 (s, 3H), 1.87 (s, 3H), 1.81(s, 3H), 1.73 (s, 3H),1.28 (s, 3H), 1.23 (s, 3H), 1.03 (s, 3H);^^CNMR(CDCl3) (5, ppm) 174.2, 173.3, 170.3, 166.7, 149.0, 144.8, 137.3, 135.4, 132.4, 129.0, 87.4 ,85.7, 77.6, 72.4, 71.5, 71.3, 70.2, 51.6, 49.3, 48.8 , 42.7, 40.6, 40.0, 39.9, 30.7, 29.7, 27.4, 20.8, 19.6, 16.9,15.0, 14.4, 13.1, 11.9. ; Mass-m/z: 612 (M*) Nimbinlactone 2 m.p. 145-148°C; UV- UV: X max (CHCI3) / nm 240 (e 9448), at 254 e =8109 ;IR-umaxCHCI'a cnfT^3343, 2960, 2853, 1751, 1720, 1654, 1570, 1435, 1309, 1089, 976, 889, 886, 645, 607; ^H NMR(CDCl3) (5, ppm) 7.23(cf,1H, J=5.1Hz) ,6.35 (d, 1H, J=10.1 Hz), 5.87( d, 1H J=10.1 Hz), 5.40 (f ,1H), 5.21(dd, 1H, J=2.9, 12.3 Hz), 4.78(d , 1H, J=5.1Hz) ,4.08(d, 1H, J=3.1 Hz), 3.73 (s, 3H), 3.71 (s,3H), 3.68(m ,1H), 3.57 (f, 1H, J=6 Hz), 2.88 (m ,1H),2.72(m, 1H), 2.22 {dd, 1H, J=12.7, 3.9Hz ), 2.13 (m,1H), 2.04 {s,3H), 1.99 (m,1H), 1.73 (s, 3H), 1.36 (s ,3H), 1.35 (s, 3H) 1.29 (s,3H); 13CNMRCCDCb) (6, ppm) 201.8, 174.5, 174.4, 174.4, 170.5, 148.6, 147.8, 145.1, 134.9, 132.9, 125.8, 86.5, 84.6, 70.3, 68.4, 53.1, 51.7, 48.6, 48.1, 48.0, 47.1, 41.4, 40.1, 38.8, 34.3, 20.9, 17.1, 16.7, 16.5, 13.1 m/z: 556 (M^); Desacetylnimbinolactone 3 m.p 130-132°C; UV: k max (CHCI3) / nm 240 (s 9448), at 254 e =8109; IR:umax^"^'3 cm"^ 3343, 2975, 2848, 1748, 1709, 1645, 1575, 1445, 1310, 1024, 970, 880, 842, 647, 611; ( M^ );^H NMRCCDCIa) (6, ppm) 7.23 (d,1H,J=5.1Hz), 6.35 (d, 1H, J= 10Hz), 5.78 {d, 1H, J=10 Hz), 5.40 {t, 1H), 4.83(dd, 1H, J=12.3 ,2.9 Hz), 4.71 (d, 1H,J=5.1Hz), 4.08(cf, 1H, J=3.1 Hz), 3.63 (s ,3H), 3.6 (s ,3H), 3.57 (f, 1H, J=6 Hz), 3.54(m,1H), 2.88 { m, 1H) 2.72 {m ,1H), 2.22 {dd, 1H, J=12.1,3.9), 2.13 (m ,1H), 1.99 (m, 1H), 1.67 (s ,3H), 1.52 ( s,3H), 1.20 (s, 3H), 1.19 (3H, s) ; 13CNMR (CDCI3) (5, ppm) 202.4, 175.4, 174.3, 149.2, 148.2 ,145.2, 134.8, 132.6, 126.2, 87.5, 86.3, 70.4, 65.9, 53.0, 51.7, 48.7, 47.9, 47.9, 47.4, 43.4, 39.9, 39.2, 34.3, 17.4, 17.1, 16.2, 13.0; m/z498(M*) Nimonolactone 4 m.p. 130-132°C; UV: X max (CHCI3) / nm 240 (e 9448), at 254 e =8109; IR-Umax^^^'a cm-^ 3343, 2975, 2848, 1748, 1709, 1645, 1575, 1445, 1310, 1024, 970, 880, 842, 647, 611;^H NMRCCDCU) (5. ppm) 7.26 (d.lH, J=4.8Hz), 7.11(d,1H,J=10Hz), 5.88 (cl,1H,J=10Hz), 5.54 (d,1H,J=2.8 Hz), 5.46(dd,1H,J=12.3,2.3Hz), 4.89(d, 2H,J=4.8Hz), 4.06(dd,1H,J=11.5, 3Hz), 2.87(1H,d,J=7.1Hz), 2.71(m,1H), 2.66(m,1H), 2.38(m,1H), 2.31(m,1H), 2.18(s,3H), 2.03(m,1H), 1.89(m,1H), 1.78(m,1H), 1.65(m,1H), 1.32(s,3H) ,1.29(s,3H), 1.19(s,3H), 1.17(s,3H), 0.89(s,3H), 1.78 (bs, 1H, D2O exchangeable); 13CNMR (CDCI3) (6, ppm) 204.8, 174.1. 170.3, 159.8 ,157.2. 146.6, 133.8, 126.0, 119.8, 73.7, 71.6, 70.3 ,50.8, 47.3, 46.4, 44.9, 44.9, 41.0, 34.0, 32.4, 31.8, 26.8, 21.7 ,20.9, 20.6, 20.6, 16.2. ;m/z468(M*) Mmethylangolansatelactone 5 m.p 114 - 116°C;UV- X max (CHCI3) / nm 298 (log e 3.782), 227 (log e 4.395);IR-UMax/ cm1 3376, 2976, 2880, 1760, 1708, 1696, 1651, 1596, 1488, 1465, 1379, 1315, 1273, 1068, 1001, 969, 880, 838, 646, 611; 1H NMRCCDCb) (6, ppm) 7.55(d,1H,J=5.1Hz), 5.63(s,1H), 5.15(s,2H), 4.88(d,2H,J=5.1Hz), 3.70 (s,3H) 3.46(dd,1H,J=11.6,3.8 Hz), 2.94(m,1H), 2.89(m,1H), 2.85(m,1H), 2.63(m,1H), 2.56(m,1H), 2.25(m,2H) 2.18(m,1H), 2.16(m,1H), 1.28(m,1H), 1.21(m,1H), 1.17(s,3H), 1.14(m,1H), 1.08(s,3H), 0.90(s,3H), 0.86(s,3H); 13CNMRCCDCb) (5, ppm) 212.7, 173.5, 171.4, 169.5, 150.7, 145.3, 130.5, 111.7 , 79.5, 78.1, 70.4, 51.9, 49.3, 47.8, 43.9, 42.8, 39.5, 39.5, 33.6, 32.8, 28.8, 26.5, 23.3, 21.4, 21.2, 13.5. m/z: 486(M*) The salient advantages of this invention are: Reactions times are short. The reaction is easy to carry out. The reactions conditions are mild. Work up is simple. The yields are good. The reactions are highly selective. Highly useful for the generation of compounds for Quantitative Structure Activity Relationship studies from natural or synthetic molecules containing an intact furan moiety. There is virtually no effluent and therefore the problems associated with effluent disposal do not arise. The terms and expressions in this specification are of description and not of limitation having regard to the scope and ambit of this invention. We claim: 1. A process for the selective oxidation of a limonoid, comprising the preparation of a solution of 2% to 20% of the said limonoid in methanol and subjecting the said solution to microwave or ultrasonic irradiation of 2000 MHz to 3000MHz / 30KHz to 50KHz in the presence of 1% to 10% N-bromosuccinimide, also in the said solution, until the reaction is complete, as indicated by the disappearance of the limonoid ; removing jhe said solvent and~ separating the reagent to obtain the oxidized product. 2. A process as claimed in claim 1 wherein thin layer chromatography is employed to indicate the disappearance of the limonoid. 3. A process as claimed in claim 1 or claim 2,wherein, after separation of nifithanoMhe oxidant is separated by coloumn chromatography. 4. A process as claimed in any one of the preceding claims, wherein the microwave irradiation is carried out in a microwave apparatus (2000 MHz to 3000MHz), such as a domestic microwave oven in less than a minute. 5. A process as claimed in any one of the proceeding claims 1 to 3 wherein the ultrasound irradiation is carried out in an ultrasonicator apparatus, such as, an ultrasonic water bath. 6. A process for the selective oxidation of a limonoid substantially as herein described and illustrated by reference to the examples.

Documents:

453-mas-2001 abstract duplicate.pdf

453-mas-2001 abstract.pdf

453-mas-2001 claims duplicate.pdf

453-mas-2001 claims.pdf

453-mas-2001 correspondence others.pdf

453-mas-2001 correspondence po.pdf

453-mas-2001 description (complete) duplicate.pdf

453-mas-2001 description (complete).pdf

453-mas-2001 drawings.pdf

453-mas-2001 form-1.pdf

453-mas-2001 form-26.pdf