Method of producing (+) 2-azabicyclo{2.2.1}hept-5-en-3-one

The present invention relates to a simplified method of producing .+-.2-azabicyclo2.2.1!hept-5-en-3-one from cyclopentadiene and sulfocyanides by reacting cyclopentadiene with sulfonylcyanides without the use of organic solvents.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The present invention offers a simplified method of producing 
.+-.2-azabicyclo2.2.1!hept-5-en-3-one from cyclopentadiene and 
sulfocyanides as initial materials in which the target product is obtained 
in high purity and high yield. .+-.2-azabicyclo2.2.1!hept-5-en-3-one is 
initial material for producing carbocyclic nucleoside analogues which are 
of interest in medicine on account of their antiviral and chemotherapeutic 
properties. 
2. Prior Art 
According to a method described in the literature solid, isolated p-toluene 
sulfonylcyanide is reacted in a large excess with cyclopentadiene, which 
functions at the same time as solvent. Vince et al., J. Org. Chem. 43 
(1978), 2311; J. C. Jagt et al., J. Org. Chem. 39 (1974), 564. The very 
unstable intermediate compound 3-tosyl-2-azabicyclo2.2.1!hepta-2,5-diene, 
the Diels-Alder product from cyclopentadiene and p-toluene sulfocyanide, 
is then isolated by concentrating the solution obtained. The solid is 
subsequently reacted with glacial acetic acid and then hydrolyzed by the 
addition of water, during which the tosyl group is split off. 
In the second method cyclopentadiene and chlorosulfonylisocyanate are added 
to one another under ring closure and the chlorosulfonyl group split off 
using sodium sulfite (J. R. Malpass et al., J. Chem. Soc., Perkin I, 
(1977), 874. 
EP-A 0,508,352 teaches a method in which 1,3-cyclopentadiene is reacted 
with methane sulfonylcyanide in an organic solvent. 
EP-A 0,533,048 is relative to a recycling procedure for producing lactams 
in which the same reaction takes place in the presence of organic solvents 
and water. The pH of the reaction mixture must be maintained constant 
during the reaction by the addition of lye. However, as can be read in G. 
H. Griffiths and F. E. Previdoli (J. Org. Chem. 58 (1993) 6129-6131), the 
desired product is obtained in aqueous solution with p-toluene sulfinate 
only in a low yield and in insufficient purity. 
A method is described in two Japanese published, unexamined applications 
(Hei 5-331139 and Hei 5-331140, Dec. 14, 1993) in which the 
sulfonylcyanides, which are always used as solid substance, are suspended 
in an organic solvent or water and cyclopentadiene is added to this 
suspension. A disadvantage of this method is the intermediate isolation of 
the sulfonylcyanides, which are recognized as not very stable and which 
can decompose under significant development of heat. 
SUMMARY OF THE INVENTION 
The invention provides an improved method of producing 
.+-.2-azabicyclo2.2.1!hept-5-en-3-one (RAN). The invention has as subject 
matter a method of producing 2-azabicyclo2.2.1!hept-5-en-3-one by 
reacting 1,3-cyclopentadiene with a substituted sulfonylcyanide in the 
presence of water and the absence of an organic solvent wherein 
a) a sulfinate of the general formula 
EQU RSO.sub.2 X (I) 
in which 
R signifies ethyl, propyl, benzyl, 4-methylbenzyl, 4-nitrobenzyl, 
2-nitrobenzyl, preferably ethyl, propyl, especially preferably 
4-methylbenzyl, benzyl, 
X signifies an alkali cation Na or K, H 
is reacted in water as the single solvent with chlorine cyanide to a 
sulfonylcyanide of the general formula 
EQU RSO.sub.2 CN (II), 
b) the latter is allowed to react without intermediary isolation 
subsequently with 1,3-cyclopentadiene, 
c) the precipitate of the byproduct produced in the reaction (sulfinate) is 
filtered off, 
d) the pH of the filtrate is adjusted with an aqueous solution of alkali 
hydroxide to a value between 7 and 8.5, and 
e) the desired product is extracted therefrom and obtained by separating 
off the solvent. 
Sulfinates soluble in water are especially suitable. Compounds of this type 
can be produced in situ, e.g., from the appropriate sulfonyl chlorides 
and, e.g., sodium sulfite. 
The subsequent reaction with chlorine cyanide, which is initiated either in 
liquid or gas form into the aqueous solution, generally takes place at 
temperatures of -10.degree. C. to +15.degree. C. The resulting formation 
of HCl results in a pH of the solution which is in the acidic range. 
However, the carrying out of the method requires, in contrast to the state 
of the art, no regulating of this value by the constant addition of, e.g., 
sodium hydroxide solution. The chlorine cyanide is added in such an amount 
that it has generally reacted by the addition of the cyclopentadiene. 
The developing sulfonylcyanide of the general formula 
EQU RSO.sub.2 CN (II), 
in which R has the significance cited above, generally accumulates in the 
form of a solid, so that a suspension forms. 
The amount of water is generally approximately 10 to 150 times the molar 
amount relative to the sulfonylcyanide, especially 20 to 80 times the 
molar amount. Cyclopentadiene, preferably freshly distilled, is added in a 
molar ratio of 1 to 2.0 to 1 mole sulfonylcyanide, especially 1 to 1.5, to 
this suspension, in which the sulfonylcyanide is optionally present in 
partially dissolved form. The reaction then takes place at a temperature 
of -10.degree. to +40.degree. C., especially -10.degree. to 30.degree. C. 
During this reaction the pH of the reaction mixture is especially between 
2.5 and 7. The mixture is agitated until complete reaction, generally 2 to 
5 h. 
A constant after-regulating of the pH is not necessary. 
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION 
The accumulating reaction mixture can be worked up in various ways. 
In a preferred embodiment the sulfinic acid accumulating as solid byproduct 
is separated by suitable filtering steps, the filtrate subsequently 
brought to a pH of 7 to 8.5, especially approximately 8, and the desired 
product is obtained after the expelling of an optionally present excess of 
cyclopentadiene by extraction with an organic, inert solvent. 
Organic solvents non-miscible with water such as chlorinated hydrocarbons, 
ketones, ethers and the like can be considered as extraction agents. 
Preferred solvents are methylene chloride, methyl tert. butylether, 
chloroform, methyl isobutylketone., methyl isopropylketone, nitromethane, 
nitroethane, 1- and 2-nitropropane. The final product is obtained in pure 
form by concentrating the organic solution by evaporation. The filtration 
of the p-toluene sulfinic acid accumulation e.g. as byproduct preferably 
takes place under an atmosphere of nitrogen on account of the 
decomposition properties. The byproduct is converted by dissolving in C1 
to C5 alcohols, preferably methanol, ethanol, n-propanol, isopropanol, 
into a reliable transport form. Although the byproduct tends to decompose 
after 30.degree. C. the solutions are stable up to 80.degree. C. 
The byproduct can also be suspended in water and dissolved in alkali. The 
use of sodium hydroxide solution yields, e.g., an aqueous solution of 
sodium-p-toluene sulfinate. This operational procedure has the advantage 
that the sulfinate solution can be returned and reacted again to 
sulfonylcyanide with chlorine cyanide. 
Another possibility of not isolating the byproduct precipitate, which is 
unstable in isolated form, as a solid consists in the neutralizing of the 
reaction mixture to a pH between 5 and 10, preferably 6.5 and 8.5. This 
causes the precipitate to go completely into solution. The target product 
accumulates after the extraction and concentration in pure, crystalline 
form, in contrast to the state of the art. 
The quality of the target product should be further increased by purifying 
the filtrate separated from the byproduct with activated carbon. The 
aqueous solution of the target product is generally stabilized beforehand 
already by pH adjustment to 6.5 to 8.5 and is subsequently optionally 
purified, extracted and concentrated. 
In a preferred variant the sulfonylcyanide is obtained in situ by reacting 
the corresponding sulfonylchloride with sodium sulfite (JP-OS 5,600,753) 
and subsequently reacting it with chlorine cyanide.

EXAMPLE 1 
60.2 g (0.338 mole) sodium-p-toluene sulfinate were placed in 300 ml water 
in a receiver, cooled down to -3.degree. C. and 20 ml ClCN added in 10 
min. The mixture was agitated 1 h at -3.degree. C. and 37 ml (0.47 mole) 
freshly produced cyclopentadiene added. The mixture was heated to 
18.degree. C. and agitated 3 h at this temperature. The precipitate was 
then filtered off and dissolved still in the pressure filter with 
methanol. 
The filtrate was brought to pH 8, treated 1 h with activated carbon and 
extracted with CH.sub.2 Cl.sub.2. After concentration 29.5 g (0.27 mole) 
of bright beige RAN were obtained corresponding to 80% yield. 
EXAMPLE 2 
49 g (0.39 mole) sodium sulfite were dissolved in 350 ml water and the 
solution heated to 105.degree. C. 68 g (0.357 mole) p-toluene 
sulfonylchloride were added in several portions in 75 min and the batch 
agitated 3 h at 100.degree. C. to 105.degree. C. The pH was maintained 
between 5 and 7 by adding a total of 67 ml 30% NaOH. The reaction mixture 
was cooled down to -3.degree. C. and then 20 ml chlorine cyanide were 
added. The mixture was agitated 1 h at this temperature and then 24 g 
(0.36 mole) cyclopentadiene were added. The reaction mixture was heated to 
15.degree. C. and agitated 3 h at this temperature. The precipitated 
byproduct was filtered off and dissolved in methanol. The filtrate was 
adjusted to pH 8.6 and the excess cyclopentadiene expelled. The aqueous 
RAN solution was extracted with methylene chloride and 23.3 g (0.21 mole) 
bright beige, 97% RAN was obtained after concentration, corresponding to 
58% yield. 
EXAMPLE 3 
60.2 (0.338 mole) sodium-p-toluene sulfinate were placed in 300 ml water in 
a receiver, cooled down to -3.degree. C. and 20 ml chlorine cyanide added 
in 10 minutes. The mixture was agitated 1 h at -3.degree. C. and 37 ml 
(0.47 mole) freshly produced cyclopentadiene added. The mixture was heated 
to 18.degree. C. and agitated 3 h at this temperature. The mixture was 
then neutralized with 40 ml 30% NaOH under cooling at 20.degree. to 
30.degree. C. The slightly turbid solution was filtered and excess 
cyclopentadiene expelled and the solution extracted with methylene 
chloride. After concentration 29.4 g (0.25 mole) 94% yellowish brown RAN 
were obtained, corresponding to 75% yield. 
EXAMPLE 4 
49 g (0.39 mole) Na.sub.2 SO.sub.3 were dissolved in 350 ml water and the 
solution heated to 100.degree. C. 79.8 g (0.36 mole) nitrobenzosulfonyl 
chloride were added in several portions and the batch agitated 3 h at 
100.degree. C. The pH was maintained between 5 and 7 during the addition 
of the sulfonylchloride and the post-reaction by adding a total of 60 ml 
30% NAOH. After the reaction mixture had been cooled down to -3.degree. C. 
20 ml chlorine cyanide were added. The mixture was agitated 1 h at this 
temperature and then 38 ml (0.5 mole) cyclopentadiene were added. The 
reaction mixture was heated to 15.degree. C. and agitated 3 h at 
15.degree. to 20.degree. C. The precipitated byproduct was filtered off 
and dissolved in methanol. The filtrate was neutralized and the excess 
cyclopentadiene expelled. The aqueous solution was extracted with 
methylene chloride and 21.7 g (0.2 mole) 94% RAN were obtained after 
concentration, corresponding to 60% yield relative to the sulfinate. 
EXAMPLE 5 
49 g (0.39 mole) Na.sub.2 SO.sub.3 and 65.5 g (0.78 mole) NaHCO.sub.3 were 
dissolved in 350 ml water and 46.3 g (0.36 mole) ethane sulfonylchloride 
slowly added dropwise. The solution was agitated overnight and cooled down 
to -3.degree. C. before the addition of 19.5 ml (0.39 mole) liquid 
chlorine cyanide. The mixture was agitated 1 h at 0.degree. C. to 
-3.degree. C. and the solution subsequently compounded with 38 ml (0.48 
mole) cyclopentadiene. After being heated to 15.degree. C. the mixture was 
agitated 3 h. The slightly turbid solution was filtered with 20 ml 30% 
NaOH and excess cyclopentadiene was expelled. After extraction and 
concentration 19.5 g 95% (0.17 mole) RAN was obtained, corresponding to 
59% yield relative to the sulfinate. 
EXAMPLE 6 
1,600 g (8.664 moles) sodium-p-toluene sulfinate were placed in 7 l water 
in a receiver, cooled down to -3.degree. C. and 475 ml (9.44) sic-moles?! 
chlorine cyanide added in 10 minutes. The mixture was agitated 1 h at 
-3.degree. C. and 750 g (11.35 moles) cyclopentadiene added. The mixture 
was heated to 18.degree. C. and agitated 3 h at this temperature. The 
precipitate (1,327 g) was then filtered off and the filtrate brought to pH 
8.5. 
The workup was performed in analogy with example 1. 715.7 g RAN were 
obtained, corresponding to 75.5% yield. 
144 g of the filtered-off precipitate were suspended in 500 ml water. The 
pH was brought to 12.7 by adding 64 g 50% sodium hydroxide solution and 
the suspension agitated 1 h. After filtration 629 g of a 19% 
sodium-p-toluene sulfinate solution (0.671 mole) were obtained. The 
solution was cooled down to -3.degree. C. and 40 ml chlorine cyanide 
(0.795 mole) added. After 1 h agitation at -3.degree. C. 63 g (0.953 mole) 
cyclopentadiene were added. The mixture was then agitated 3 h at 
20.degree. C. The solution was filtered, brought to pH 8.6 and worked up 
analogously to example 1. 29 g 93.7% RAN were obtained, corresponding to 
37.1% yield.