Both the 1,2- and 1,3-dinitrates of glycerol have potential application in the synthesis of new energetic materials and as pharmaceuticals, for the alleviation of heart complaints.

Synthesis of dinitroglycerine (either 1,2-or 1,3-dinitrato-2-hydroxypropane) has heretofore been achieved generally by mixed acid nitration of glycerol but this inevitably leads to a mixture of the isomers which are extremely difficult to then separate. Moreover the yield of the dinitrated product by this route is not very good as the reaction mixture further includes both mono-and tri-nitrated species, and these also have to be separated off in order to obtain the desired nitro-compounds.

Hakimelahi et al (Helv. Chim. Acta 67,906 (1984)) have described the use of either thionyl chloride nitrate or thionyl nitrate as the nitrating agent in the preparation specifically of the 1,3-dinitrate in 70% yield. The use of silver nitrate to produce the nitrating agent makes the process relatively expensive and the non-quantitative yield means that extensive separation efforts are required in order to arrive at the desired product in pure form.

The applicant has now found that by use of the unconventional nitrating agent dinitrogen pentoxide in conjunction with other relatively straightforward process steps it is not only possible to achieve synthesis of specifically either the 1,2- or the 1,3- dinitrate under mild conditions but also in high (virtually quantitative) yield. In the case of the 1,3-dinitrate preparation route this result is particularly surprising as on the basis of all previous knowledge the expected product would be the 1,2-dinitrate.

However, by the present method none of the latter isomer is produced. Instead that material may be obtained in high yield by use of a variation on the preparative method for the 1,3-dinitrate.

Accordingly the present invention provides a process for the preparation of glycerol 1,2- or glycerol 1,3-dinitrate from glycidol which comprises the steps of : a) preparing either the acetate derivative of glycidol where the desired product is the 1,3-dinitrate or a trialkylsilyl ether derivative (as hereinafter defined) where the desired product is the 1,2-dinitrate; b) reacting the glycidol derivative from step (a) with dinitrogen pentoxide under anhydrous conditions in order to form the corresponding dinitrato compound; and c) removing the protective group from the product of step (b) to obtain the glycerol 1,2-dinitrate or glycerol 1,3-dinitrate product as the case may be.

For the preparation of the 1,3-dinitrate, step (a) is conveniently accomplished using acetyl chloride or acetyl bromide in the presence of triethylamine at a temperature of below 5°C, preferably around 0°C, in dichloromethane. The product is purified by aqueous workup followed by distillation. Other methods for accomplishing step (a) would include use of acetic anhydride in the presence of a catalyst such as trimethylsilyl trifluoromethanesulphonate.

Step (c) of this process is conveniently carried out by the use of potassium carbonate in methanol. Alternatively, other deprotection procedures such as treatment with iodine/methanol, p-toluenesulphonic acid/methanol and hydrochloric acid/methanol could be used.

In the nitration step (b) for either process, the protected derivative of glycidol is added to an eqimolar amount of N205 in dry dichloromethane at sub-ambient temperature (preferably below 10°C, most preferably at about-5 to 5°C) and left to stir at this temperature for about 2 hours before being allowed to warm up to ambient temperature and left for a further hour. A simple aqueous workup followed by removal of the organic solvent gives the pure glycerol dinitrate product.

For the preparation of the 1,2-dinitrate, step (a) is conveniently carried out by reaction of the glycidol with t-butyldimethylsilyl chloride in dry dichloromethane followed by slow addition to the reaction mixture of triethylamine. A temperature of below 5°C is again suitable for this step, as with the preparation of the 1,3 isomer.

After stirring for 8 to 10 hours, pentane is added to the mixture and the mixture filtered to provide, after concentration, a residue from which the product may be distilled. As an alternative to the use of the t-butyldimethylsilyl chloride, other analagous reagents with at least one higher alkyl substituent may be used. The corresponding trimethylsilyl compound is not suitable as it is subject to reaction with the N, O, nitrating agent and likewise silyl species which contain aromatic substituents such as benzyl or phenyl groups are unsuitable for use because of the competing reaction of N205 to nitrate the aromatic ring of the substituent.

Accordingly the term"trialkylsilyl ether derivative"is used herein in relation to the process of the present invention to mean a trialkylsilyl ether derivative in which at least one of the alkyl groups is a propyl group or preferably a butyl or higher alkyl group.

In the case of the 1,2-dinitrate preparation, step (c) involves the use of well- known reagents for removing the silyl ether protecting group such as 2,3-dichloro-5,6- dicyano-1,4-benzoquinone (DDQ), lithium chloride in dimethylformamide, ceric ammonium nitrate, iodine or tetrabutylammonium fluoride/boron trifluoride complex for example.

Other variations of the reaction conditions detailed above for the protection and deprotection steps, as may be readily apparent to the skilled reader, shall be encompassed within the scope of the invention.

In the case of the process for the 1,3-dinitrate, it is hypothesised that the nitration reaction involves addition of a nitronium ion at the epoxide oxygen, followed by an intramolecular rearrangement producing a stable intermediate dioxalenium salt.

This is then attacked by the nitrate anion to give (unexpectedly) the 1,3-dinitrato compound.

The invention is now further described with reference to the accompanying examples.

Preparation of Glycerol-1,2-Dinitrate Example 1-Preparation of Glycidol t-Butyldimethylsilyl Ether A three-necked round-bottom flask (100 cm3) was equipped with a stirrer bar, alcohol thermometer and a pressure equalised dropping funnel. The flask was charged with glycidol (0.74 g, 10 mmol) in dry dichloromethane (DCM) (30 cm3) followed by the addition of t-butyldimethylsilyl chloride (1.65 g, 11 mmol) in dichloromethane (30 cm3) at 0°C via the pressure equalised dropping funnel. The reaction was allowed to stir for 30 minutes before slow addition of triethylamine (1.11 g, 11 mmol in 10 cm3 of DCM). The reaction was then allowed to stir at ambient temperature overnight, after which pentane (30 cm3) was added and the mixture filtered. The filtrate was concentrated and the residue distilled on a kugelrohr to give the product in almost quantitative yield (98%).

Example 2-Nitration of Glycidol t-Butyldimethylsilyl Ether A three-necked round-bottom flask (100 cm3) was equipped with a stirrer bar, alcohol thermometer and a pressure equalised dropping funnel. The flask was charged with glycidol t-butyldimethylsilyl ether (0.36 g, 2 mmol) in dry dichloromethane (20 cm3) followed by N205 (0.33 g, 3 mmol) in dichloromethane (20 cm3) at 0°C. The reaction was allowed to stir for 2 h at 0°C and then at ambient for a further 1 h. The reaction was quenched with saturated sodium bicarbonate solution (30 cm3) and stirred for a further 15 minutes, separated, dried and the solvent removed to give the glycerol-1,2-dinitrate-3-t-butyldimethylsilyl ether derivative in 89% yield as a yellow oil.

'H nmr (CDCl3): 8 4.83 (1H, dd, 2J = 12.79, 3J = 4.20 Hz, CH2ONO2), 4.64 (1H, dd, 2J = 12.83 and 3J = 6.82 Hz, CH2ONO2), 8 3.89 (1H, dd, 2J = 5 09, 3J = 1.72 Hz, CH2OSi), 3.88 (1H, dd, 2J = 5.09 and 3J = 2.09 Hz, CH2OSi), 3.32 (1H, m, CHONO2), 0.89 (9H, CMe3) and 0.09 (6H, SiMe2)."C nmr 69.08 (C1), 78.71 (C2), 59.65 (C3), 25.42 (CMe3) and 17.94 (SiMe2).

Example 3-Deprotection of Glycerol-1, 2-Dinitrate-3-t-Butyldimethylsilyl Ether A single-neck round-bottom flask (10 cm3) was charged with glycerol-1,2- dinitrate-3-t-butyldimethylsilyl ether [2 cm3 of 1M solution in acetonitrile (0.59 g, 2 mmol)]. DDQ [2 cm3 of 1M solution in acetonitrile: water (9: 1), 2 mmol)] was added and the mixture stirred overnight. The mixture was then passed through a silica column (1 g) and the remaining residue washed with fresh ethyl acetate (5 cm3) and also passed through the column. The mixture was concentrated under vacuum to give glycerol-1,2-dinitrate in 92% yield.

'H nmr (CDCl3) 8 4.86 (1H., dd, 2J = 12.0, 3J = 4.30 Hz, CH2ONO2), 4.43 (1H, dd,'J = 12.0 and 3J = 5.80 Hz, CH2ONO2), 8 3.96, (2H, m, CH2OH), 5.38 (1H, m, CHONO2).

'3C nmr 69.12 (C1), 79.39 (C2), 59.91 (C3).

Preparation of Glycerol-1,3-Dinitrate Example 4-Preparation of Glycidyl Acetate A three-necked round-bottom flask (100 cm3) was equipped with a stirrer bar, alcohol thermometer and a pressure equalised dropping funnel. The flask was charged with glycidol (1.16 g, 10 mmol) in dry dichloromethane (30 cm3) followed by acetyl chloride (0.86 g, 11 mmol) in dichloromethane (30 cm3) at 0°C via the pressure equalised dropping funnel. The reaction was allowed to stir for 30 minutes before slow addition of triethylamine (1. 11 g, 11 mmol in 10 cm3 of DCM). The reaction was then allowed to stir at ambient temperature overnight, after which pentane (30 cm3) was added and the mixture filtered. The filtrate was concentrated and the residue distilled on a kugelrohr to give the product in almost quantitative yield (98%).

Example 5-Nitration of Glycidyl Acetate A three-necked round-bottom flask (100 cm3) was equipped with a stirrer bar, alcohol thermometer and a pressure equalised dropping funnel. The flask was charged with glycidyl acetate (0.23 g, 2 mmol) in dry dichloromethane (20 cm3) followed by N205 (0.33 g, 3 mmol) in dichloromethane (20 cm3) at 0°C. The reaction was allowed to stir for 2 h at 0°C and then at ambient for a further 1 h.

The reaction was quenched with saturated sodium bicarbonate solution (30 cm3) and stirred for a further 15 minutes, separated, dried and the solvent removed to give the product in almost quantitative yield (95%) as a yellow oil.

'H nmr (CDCl3) 6 4.71, (2H, dd 2J = 12.50, 3J = 4.01 Hz, CH2ONO2), 4.59 (2H, dd, 2J = 12.48 and 3J = 5.83 Hz, CH, ONO2), 5. 37 (1H, m, CHOCOCH3) and 2.12, (3H, s, OCOCH3). 13C nmr 69.65 (Cl and 3), 66.24 (C2), 20.44 (Me) and 169.81 (CO). Mass spectrum (CI-NH3), 242 (10, M + NH4+), 225 (15, M + H+), 162 (75, H-ONO2), 116 (38, M+-ONO2-NO2) and 46 (100, NO2+).

Example 6-Deprotection of Glycerol-2-Acetoxy-1,3-Dinitrate A single-necked round-bottom flask (10 cm3) was charged with glycerol-2- acetoxy-1,3-dinitrate (0.42 g, 2 mmol)] and methanol (10 cm3). Potassium carbonate (0.055 g, 0.4 mmol in 1 cm3 of water was added and the mixture stirred for 4 h.

The mixture was then extracted with DCM (2 x 10 cm3), separated and the organic layers combined, dried and the solvent removed in vacuo to give a 93% yield of the glycerol-1,3-dinitrate.

'H nmr (CDCl3) 8 4.62, (2H, dd 2J = 11.70, 3J = 4.26 Hz, CH2ONO2), 4.55 (2H, dd, 2J = 11.70 and 3J = 6.25 Hz, CH2ONO2), 4.41 (1H, m, CHOH) and 3.22, (OH, br). 13C nmr 72.42 (C1 and 3), 65.40 (C2).