Patent Application
20220153669
The present invention relates to polysaccharide supported tetra-n-butyl ammonium fluoride complexes. More particularly, the present invention provides stable, non-hygroscopic cellulosic complexes with tetra-n-butyl ammonium fluoride as a fluorinating agent. The synthesized complexes exhibit broad substrate scope and excellent yields in fluorination reactions.
Fluorination reactions are of critical importance because fluorine (F) is one of the key elements present in most of pharmaceutical, agrochemical, and material industry products. Almost 30% of new drugs being discovered contain F as one of their crucial elements.
Introducing fluorine atom in the organic backbone is very challenging because of the small size and low solubility of the fluoride salts in most of the organic solvents. Also, fluorine atom interacts with other functional groups like esters, alcohols, amides etc. present in the organic molecules through hydrogen bonding and prevent its facile insertion. Fluoride salts are highly basic in nature and solvation effects further reduce their nucleophilic characteristics. Further, due to hygroscopic nature and lack of hydrogen-bond contributor, fluoride basicity can override its nucleophilicity and can lead to unwanted side reactions. Hence, hydrogen bonding may act as an amplifier to increase the nucleophilicity of the fluorine atoms.
Tetra alkyl ammonium fluoride salts are commonly used in fluorination reactions, but these salts are extremely hygroscopic, possess low thermal stability and are mostly available in their hydrated form which has very poor nucleophilic characteristics. The poor stability profile of tetra alkyl ammonium fluoride salts has created a need to provide more stable fluoride salts to conduct fluorination reactions.
Very few reports are present in literature for synthesizing the bench stable fluorinating complexes or reagent. Recently scientists have synthesized more stable, less hygroscopic fluorine complexes from fluoride-tert-butyl alcohol complex, fluoride-alcohol complex and fluoride-diaryluria complex. These complexes are stable through their NH—F and OH—F hydrogen bonding. However, while being used as a fluorinating agent, they lack specificity and result in formation of undesired side products.
Hence there is a long-pending need in the art for non-hygroscopic, stable flourinating agents that can provide desired flourinated compounds with high level of selectivity and specificity.
The main object of the present invention is to provide a simple, non-hygroscopic and thermally stable polysaccharide supported fluorinating agent complex.
Another object of the present invention is to provide a simple, non-hygroscopic and thermally stable polysaccharide supported tetra-n-butyl ammonium fluoride (TBAF) complex that can effectuate fluorination reactions with high selectivity towards desired fluorinated products.
Accordingly, the present invention provides a non-hygroscopic and thermally stable polysaccharide supported complex with fluorine compounds as a new fluorinating agent. More particularly, the present invention provides a new, non-hygroscopic and thermally stable bacterial cellulosic complex with TBAF fluorinating agent for the fluorination reactions.
In an embodiment, the polysaccharides are selected from plant cellulose, bacterial cellulose, starch and pectin. In a preferred embodiment, the cellulose is bacterial celluloses.
In an embodiment, the bacterial cellulose used as a polysaccharide support which is obtained from Komagataeibacter rharticus PG2 strain isolated from pomegranate host, having a crystallinity index of 80.80 measured using XRD and a nano-fibrillar width in the range of 30-80 nm measured using scanning electron microscopy.
In an embodiment, the non-hygroscopic, thermally stable polysaccharide supported TBAF complexes are useful as fluorinating agents and they facilitate the formation of the desired fluorinated products with a high degree of selectivity with minimal formation of undesired products.
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
Accordingly, the present invention relates to non-hygroscopic, thermally stable polysaccharide supported TBAF complexes and their applications in aliphatic SN2 fluorination reaction.
In an embodiment, the present invention provides non-hygroscopic, thermally stable polysaccharide supported TBAF complexes wherein the w/w ratio of polysaccharide to TBAF is in the range of 1:0.3 to 1:6.
In another embodiment, the polysaccharide support is selected from the group comprising of pectin, bacterial cellulose, plant cellulose and starch.
In an embodiment, the bacterial cellulose used as a polysaccharide support which is obtained from Komagataeibacter rharticus PG2 strain isolated from pomegranate host, having a bacterial cellulose has a crystallinity index of 80.80 measured using XRD and a nano-fibrillar width in the range of 30-80 nm measured using scanning electron microscopy.
In an embodiment the non-hygroscopic, thermally stable polysaccharide supported TBAF complex is synthesized by a process comprising the steps of:
In an embodiment, the polysaccharide supports used in the non-hygroscopic, thermally stable polysaccharide supported TBAF complexes are stable, non-hygroscopic and recyclable.
In another embodiment, the non-hygroscopic, thermally stable polysaccharide supported TBAF complexes are characterized using EDAX, SEM and TEM (
In another embodiment, hygroscopicity of the polysaccharide supported TBAF complexes were evaluated by exposing the samples to air at room temperature. After a time duration in the range of 15 minutes to 2 hours, the polysaccharide supported TBAF complexes were examined visually and the results are shown in
In another embodiment, the non-hygroscopic, thermally stable polysaccharide supported TBAF complex were used as a fluorinating agent for the fluorination of representative antibiotics, cancer drugs, sugars, steroids, pesticides, herbicides, and fungicide. The disclosed complexes provided 40-99% selectivity. We have preferred to keep the range broad because the agent is versatile and stable towards desired products with minimal side product formation.
In an embodiment, the fluorination reactions using the non-hygroscopic, thermally stable polysaccharide supported TBAF complex give selectivity towards desired products on recycling the polysaccharide support up to 4 times.
In an embodiment, the process for fluorination reaction using the non-hygroscopic, thermally stable polysaccharide supported TBAF complex comprises the steps of:
In one embodiment, the solvent used in step (i) of the fluorination reaction is selected from acetonitrile or toluene The representative process for the fluorination of compound 5 is depicted below in scheme-1; wherein X is a good leaving group to be replaced with fluorine.
Table-1 below summarizes the results obtained by using different mole ratios of NBu4. (Bact-Cell-OH)F complex for different time intervals. 3-(3,4-dimethoxyphenoxy) propyl methane sulphonate (5a) is used as a substrate and compounds 1-(3-fluoropropoxy)-3,5-dimethoxybenzene (6a) and 1-(allyloxy)-3,5-dimethoxy benzene (6b) are the fluorination products.
aAll reactions were carried out on a 1.0 mmol scale of substrate in solvent (8.0 mL) at 70° C.
bFluorine complex used equivalent ratio of TBAF (Use 2 eq. of TBAF loaded in 1 eq. bacterial cellulose ie 100% of TBAF).
cIsolated yields.
dReaction carried at 90° C.
eReaction carried in an open atmosphere.
Referring to the scheme-1 and table 1, the fluorination reaction was conducted with bacterial cellulose-TBAF complex using acetonitrile or benzene toluene (entry 6) as a solvent at a temperature in the range of 50-100° C. for a substrate: complex ratio of 1:1 to 1:2 to obtain more that 70% selectivity of desired fluorinated product. The complex used is in the range of 1:1 to 1:2 of TBAF: cellulose. In a preferred embodiment, the cellulose is bacterial cellulose.
It was found that the polysaccharide can be recycled up to 5 times. After completion of reaction as disclosed in scheme 1, the reaction mass is cooled to 25-35° C. and bacterial cellulose is filtered. It is further washed with ethyl acetate and dried under high-vacuum (2 mbar) to re-use for further loading of TBAF to form complex for further reactions. Only polysaccharide is recyclable So what is recyclable is not the polysaccharide supported TBAF complex but the support as such).
Table 2 summarizes the results obtained by using recycled complex
The invention will now be described with the help of examples.
Following examples are given by way of illustration and therefore should not be construed to limit the scope of the invention.
For the reaction pectin, starch and plant cellulose were procured from Sigma Chemicals Co., USA. Bacterial cellulose was synthesized in lab using indigenous bacteria which inventors have isolated as described in RSC Advances, 2018, 8, 29797-29805, DOI: 10.1039/c8ra05295f.
To a flame-dried round bottom flask equipped with cooling condenser, tetra-n-butyl ammonium fluoride hydrate and polysaccharide support (pectin/starch/plant cellulose/bacterial cellulose) was added in their respective equivalent amount (w/w) in 100 ml of hexane. This mixture was refluxed in nitrogen atmosphere at 80° C. for 1.5 h with vigorous stirring. During the reaction, complex shows the water droplets on sidewall of the condenser, which indicates the completion of the reaction and complex formed. The solution was allowed to cool to 25-30° C., filtered, washed with hexane and dried under high vacuum at 25-35° C. to give the desired non-hygroscopic and thermally stable polysaccharide supported TBAF complex which was used for the aliphatic nucleophilic fluorination reaction.
In this manner other fluorinating complexes were prepared with polysaccharides including pectin, starch, bacterial cellulose and plant cellulose in the ratios 1:0.1 to 1:6 w/w of polysaccharide:TBAF.
In a flame dried round bottom flask, substrate compound (maybe a range should be given 0.290 mg, 1 mmol) and NBu4(Bac-cell-OH)F.1 (0.3915 mg, 1.5 eq) in dry acetonitrile were taken and the reaction vial was flushed with N2 and stirred at a temperature in the range of 50-100° C. for a time period in the range of 1-3 h. The reaction mixture was cooled to a temperature in the range of 25-35° C. and the reaction mixture was filtered using sintered funnel. The reaction mixture was washed with ethyl acetate and evaporated under reduced pressure. The crude product was purified by flash column chromatography using (20% EtOAc/hexane) to give corresponding fluorinated compound.
4-(3-fluoropropoxy)-1,2-dimethoxybenzene: 1H NMR (400 MHz, CDCl3) δ 6.10 (s, 3H), 4.71 (t, J=5.8 Hz, 1H), 4.59 (t, J=5.8 Hz, 1H), 4.07 (t, J=6.1 Hz, 2H), 3.78 (s, 6H), 2.25-2.08 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 161.5, 160.6, 93.3, 93.1, 80.4 (d, J=164.15 Hz), 63.5, (d, J=4.62 Hz), 55.3, 30.4 (d, J=20.04 Hz). 19F NMR (400 MHz, CDCl3) δ 222.14
A similar procedure was followed for different substrates to obtain following fluorinated products.
2-fluoro-1-(3-methoxyphenyl)ethan-1-one: 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J=2.3 Hz, 1H), 7.43-7.38 (m, 2H), 7.19-7.15 (m, 1H), 5.52 (d, J=46.71 Hz, 2H), 3.87 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 193.1, (d, J=15.33 Hz), 160.0, 134.9, 129.9, 120.6, 120.6, (d, J=2.8 Hz), 112.1, (d, J=1.93 Hz), 84.5, (d, J=182.11 Hz), 55.5; 19F NMR (400 MHz, CDCl3) δ 232.60.
1-(4-chlorophenyl)-2-fluoroethan-1-one; 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J=8.2 Hz, 2H), 7.49 (d, J=8.7 Hz, 2H), 5.49 (d, J=46.71 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 192.5 (d, J=15.33 Hz), 140.7, 132.1, 129.4 (d, J=2.88 Hz), 129.3, 84.6 (d, J=184.03 Hz); 19F NMR (400 MHz, CDCl3) δ 232.60.
1-fluorododecane: 1H NMR (400 MHz, CDCl3) δ 4.50 (t, J=6.1 Hz, 1H), 4.39 (t, J=6.1 Hz, 1H), 1.75-1.63 (m, 2H), 1.28 (m, 18H), 0.89 (t, J=6.1 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 84.2 (d, J 163.68 Hz), 31.9, 30.4 (d, J=19.27 Hz) 29.6, 29.6, 29.5, 29.4, 29.3, 25.2, 25.1, 22.7, 14.1; 19F NMR (400 MHz, CDCl3) δ 232.60.
1-fluoropentadecane: 1H NMR (400 MHz, CDCl3) δ 4.50 (t, J=6.1 Hz, 1H), 4.39 (t, J=6.1 Hz, 1H), 1.80-1.61 (m, 2H), 1.44-1.26 (m, 24H), 0.90 (t, J=6.1 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 84.2 (d, J=164.15 Hz), 31.9, 30.4 (d, J=19.25 Hz), 29.7, 29.6, 29.5, 29.4, 29.3, 25.2, 25.1, 22.7, 14.1; 19F NMR (400 MHz, CDCl3) δ 232.60.
9-(2-fluoroethyl)-9H-carbazole: 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J=7.9 Hz, 2H), 7.55-7.48 (m, 2H), 7.47-7.42 (m, 2H), 7.35-7.28 (m, 2H), 4.87 (t, J=5.4 Hz, 1H), 4.75 (t, J=4.88 Hz, 1H), 4.64 (t, J=5.4 Hz, 1H), 4.63 (t, J=4.8 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 140.4, 125.8, 123.0, 120.4, 119.3, 108.5, 81.9 (d, J=172.6 Hz), 43.2, (d, J=22.3 Hz); 19F NMR (400 MHz, CDCl3) δ 232.60.
2-benzyl-4-chloro-1-(3-fluoropropoxy)benzene: 1H NMR (400 MHz, CDCl3) δ 7.33-7.26 (m, 2H), 7.26-7.13 (m, 4H), 7.09 (d, J=2.7 Hz, 1H), 6.79 (d, J=8.7 Hz, 1H), 4.58 (t, J=5.7 Hz, 1H), 4.46 (t, J=6.0 Hz, 1H), 4.06 (t, J=6.0 Hz, 2H), 3.95 (s, 2H), 2.19-2.06 (m, 2H)13C NMR (101 MHz, CDCl3) δ 155.1, 140.1, 131.5, 130.3, 128.7, 128.4, 127.1, 126.1, 125.4, 112.3, 80.4, (d, J=164.86 Hz), 63.8 (d, J=4.79 Hz), 30.4, (d, J 20.13 Hz); 19F NMR (400 MHz, CDCl3) δ 232.60.
1-(3-fluoropropoxy)-1H-benzo[d][1,2,3]triazole: 1H NMR, 2N (400 MHz, CDCl3) δ 7.51 (d, J=2.3 Hz, 1H), 7.33 (dd, J=2.3, 8.7 Hz, 1H), 6.82 (d, J=8.7 Hz, 1H), 4.76 (t, J=5.7 Hz, 1H), 4.64 (t, J=5.7 Hz, 1H), 4.14 (t, J=6.0 Hz, 2H), 2.27-2.17 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 153.6, 132.7, 130.5, 124.1, 114.6, 112.8, 80.4 (d, J=164.85 Hz), 64.9, (d, J=4.79 Hz), 30.2 (d, J=20.13 Hz); 19F NMR (400 MHz, CDCl3) δ=232.60.
1-([1,1′-biphenyl]-4-yl)-2-fluoroethan-1-one: 13C NMR (101 MHz, CDCl3) δ 193.0, (d, J=15.34 Hz 146.8, 139.5, 132.3, 129.0, 128.5, 128.4, 127.5, 127.2, 127.1, 19F NMR (400 MHz, CHLOROFORM-d) δ=232.60.
(6S)-4-(2,2-dimethyl-1,3-dioxolan-4-yl)-6-fluoro-2,2-F dimethyltetrahydrofuro[3,4-d][1,3]dioxole: 1H NMR (400 MHz CDCl3) δ 5.59 (d, J=59.51 Hz 1H), 4.86 (dd, J=3.5, 5.3 Hz, 1H), 4.78 (t, J=6.1 Hz, 1H), 4.44-4.38 (m, 1H), 4.17 (dd, J=3.1, 7.6 Hz, 1H), 4.12 (dd, J=6.10, 8.39 Hz, 1H), 4.09-4.05 (dd, J=4.4, 8.39 Hz, 1H), 1.46 (d, J=2.3 Hz, 6H), 1.39 (s, 3H), 1.35 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 114.7, 113.7 (d, J=69.09 Hz) 109.4, 84.7 (d, J=42.17 Hz) 82.6, 78.6, 72.7, 66.6, 26.9, 25.8, 25.1, 24.5: 19F NMR (400 MHz, CDCl3) δ 232.60.
3-Fluorostigmasterol:
1H NMR (500 MHz, CDCl3) δ 5.34 (d, J=5.0 Hz, 1H), 5.19-5.14 (m, 1H), 5.02 (dd, J=8.6, 15.1 Hz, 1H), 3.34-3.23 (m, 1H), 2.30 (dd, J=2.9, 13.2 Hz, 1H), 2.27-2.20 (m, 1H), 2.10-1.95 (m, 5H), 1.88-1.82 (m, 2H), 1.74-1.69 (m, 1H), 1.58 (s, 3H), 1.55-1.45 (m, 8H), 1.27 (d, J=7.2 Hz, 2H), 1.20-1.15 (m, 3H), 1.01 (s, 4H), 0.85 (d, J=6.1 Hz, 3H), 0.81 (d, J=7.6 Hz, 7H), 0.70 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 141.3, 138.3, 129.2, 121.3, 56.5 (d, J=116.34 Hz), 51.2, 50.3, 42.2, 40.5, 40.0, 39.7, 37.4, 36.9, 31.9, 31.9, 29.4, 28.9, 25.4, 24.4, 21.2, 21.1, 19.4, 19.0, 12.2, 12.0; 19F NMR (400 MHz, CDCl3) δ 232.60.
After completion of the reaction as disclosed in scheme 1, the reaction mixture was cooled to 25-35° C. Bacterial cellulose was filtered, washed with ethyl acetate and dried under high-vacuum (2 mbar) to re-use for further loading with TBAF.
| Number | Date | Country | Kind |
|---|---|---|---|
| 201911012428 | Mar 2019 | IN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/IN2020/050274 | 3/24/2020 | WO | 00 |
