1. Field of the Invention
The present invention relates to a process for producing 2-azabicyclo[2.2.1]hept-5-en-3-one and a method of crystallizing 2-azabicyclo[2.2.1]hept-5-en-3-one into finely divided particulate crystals.
2. Discussion of the Background
Carbocyclic nucleosides have a structure in which an oxygen atom of the furanose ring of the nucleoside is substituted with a methylene group; the structure is similar to a nucleoside having a furanose ring, and it can act as a substrate or an inhibitor for various enzymes in living bodies. Since the carbocyclic nucleosides do not have a glycoside bonding, they are not subject to cleaving or splitting by enzymes such as nucleoside phospholylase or nucleoside hydrase, they have a different metabolic pathway from nucleosides having the furanose ring, and they exhibit various physiological activities.
For example, carbocyclic adenosine, also known as Aristeromycin, is a type of carbocyclic nucleoside that is a metabolite of Streptomyces citricolor and has been noted for its strong cytotoxicity, in contrast to nucleosides having the furanose ring.
Carbocyclic-2,3-dideoxy-2,3-didehydroguanosine, a type of carbocyclic nucleoside, has now been developed as an anti-HIV agent [R. Vince, et al., Biochem. Biophys. Res. Commun. 156, 1046 (1988)].
The carbocyclic part of the carbocyclic nucleoside is often formed by using, for example, 2.alpha.,3.alpha.-dihydroxy-4.beta.-aminocyclopentanone-1.beta.-methanol or cis-4-aminocyclopent-2-en-1.beta.-methanol. Such 1.beta.-methanols are often chemically synthesized from 2-azabicyclo[2.2.1]hept-5-en-3-one [R. Vince, et al., J. Org. Chem., 43, 2311 (1978); B. L. Kamm, et al., J. Org. Chem., 46, 3268 (1981); W. C. Faith, et al., J. Org. Chem., 50, 1983 (1985)]. Accordingly, 2-azabicyclo[2.2.1]hept-5-en-3-one is useful as an intermediate for synthesizing 1.beta.-methanols and, thus, carbocyclic nucleosides.
As a method for synthesizing 2-azabicyclo[2.2.]hept-5-en-3-one, a process of subjecting cyclopentadiene and p-toluenesulfonyl cyanide to a cyclizing addition reaction to form 3-p-toluenesulfonyl-2-azabicyclo[2.2.1]hepta-2,5-diene as an intermediate product and removing the toluenesulfonyl group on the 3-position in the intermediate product by using acetic acid is known [J. C. Jagt. et al., J. Org. Chem., 39, 564 (1974); R. Vince, et al., J. Org. Chem., 43, 2311 (1978)].
However, the synthesizing process described above involves various problems, for example, in that (1) cyclopentadiene, which may be used theoretically in an equimolar amount to p-toluenesulfonyl cyanide, must actually be used in a great excess of 15 to 35 molar times inclusive; (2) it is laborious and time consuming since the process is a multi-step reaction; (3) 3-p-toluenesulfonyl-2-azabicyclo[2.2.1]hepta-2,5-diene obtained by the reaction of p-toluenesulfonyl cyanide and cyclopentadiene has to be condensed and taken out as lumps, which are pulverized into powder and then reacted with acetic acid; (4) acetic acid has to be added in a great excess of 5 to 23 molar times inclusive all at once upon removing the toluenesulfonyl group at the 3-position by treating 3-p-toluenesulfonyl-2-azabicyclo[2.2.1]hepta-2,5-diene with acetic acid, so that abrupt exothermic reaction must be controlled; (5) if the exothermic reaction in (4) cannot be satisfactorily controlled and the reaction temperature rises excessively, the product, 2-azabicyclo[2.2.1]hept-5-en-3-one, cannot be obtained at all or is obtainable only at an extremely low yield; (6) solid by-products are formed upon reaction in (4) which hinder smooth stirring and the reaction cannot proceed smoothly; and (7) a great amount of waste water is formed, which increases the burden for treating the same. Therefore, by the synthesis process described above, 2-azabicyclo[2.2.1]hept-5-en-3-one cannot be produced industrially in a high purity and a high yield with a reduced amount of reagent and solvent, safely and with good productivity.
Under the circumstances as described above, the present inventors have continued studies for developing a process capable of producing 2-azabicyclo[2.2.1]hept-5-en-3-one in a high purity and a high yield with a reduced amount of reagent and solvent, safely and with good productivity. Then, we have found the following processes and filed them already: (i) a process for producing 2-azabicyclo[2.2.1]hept-5-en-3-one by way of a first step of condensing sulfonyl cyanide and cyclopentadiene in a hydrocarbon solvent and then a second step of treating with water (Japanese Published Unexamined Patent Application Hei 5-331139); (ii) a process for producing 2-azabicyclo[2.2.1]hept-5-en-3-one by reacting sulfonyl cyanide and cyclopentadiene in water or a mixed solvent of water and a hydrocarbon (Japanese Published Unexamined Patent Application Hei 5-331140); (iii) a process for producing 2-azabicyclo[2.2.1]hept-5-en-3-one by reacting benzenesulfonyl cyanide and cyclopentadiene in a mixed solvent of water and a water soluble solvent under a pH condition of from 3 to 4 inclusive (Japanese Published Unexamined Patent Application Hei 8-27110); and (iv) a process for producing 2-azabicyclo[2.2.1]hept-5-en-3-one by reacting sulfonyl cyanide and cyclopentadiene in a hydrocarbon solvent to form 3-sulfonyl-2-azabicyclo[2.2.1]hepta-2,5-diene as an intermediate product and hydrolyzing the intermediate product by adding a solution of the intermediate product into a mixed solvent of water and a water soluble solvent under a pH condition of from 3 to 7 inclusive (Japanese Published Unexamined Patent Application Hei 9-165372).
When compared with the existing process by J. C. Jagt, et al., i.e., a process for producing 2-azabicyclo[2.2.1]hept-5-en-3-one by reacting acetic acid with 3-p-toluenesulfonyl-2-azabicyclo[2.2.1]hepta-2,4-diene prepared by the reaction of cyclopentadiene and p-toluenesulfonyl cyanide, the production processes (i)-(iv) described above have various advantages such that:
(1) it is not necessary to use cyclopentadiene in a great excess relative to sulfonyl cyanide; PA0 (2) no troublesome procedures are required for taking out 3-p-toluenesulfonyl-2-azabicyclo[2.2.1]hepta-2,5-diene as the intermediate product in a condensed form, pulverizing the same into powder, then subjecting to the succeeding step; PA0 (3) since no abrupt exothermic reaction takes place, reaction control is easy and the reaction is safe; PA0 (4) the yield of the 2-azabicyclo[2.2.1]hept-5-en-3-one is high; PA0 (5) solid by-products which hinder the stirring during the reaction are reduced; and PA0 (6) the amount of waste water to be treated is small, which moderates the processing burden.
Each of the processes (i) and (iv) above is conducted by way of two steps: reacting sulfonyl cyanide and cyclopentadiene in a hydrocarbon solvent in the first step to form 3-sulfonyl-2-azabicyclo[2.2.1]hepta-2,5-diene as an intermediate product; and then processing the solution of the intermediate product in water or a mixed solvent of water and a water soluble solvent in the second step to produce 2-azabicyclo[2.2.1]hept-5-en-3-one.
On the other hand, each of the processes (ii) and (iii) above is a process for directly producing 2-azabicyclo[2.2.1]hept-5-en-3-one by reacting sulfonyl cyanide and cyclopentadiene in water or a mixed solvent of water and a hydrocarbon solvent or in a mixed solvent of water and a water soluble solvent in one step. This process is more simple than the two step processes (i) or (iv) above and is industrially advantageous.
However, in method (ii), the pH is not controlled during the reaction of sulfonyl cyanide and cyclopentadiene, and it has been found that the pH in the reaction mixture is 3 or lower (generally pH 2 to 3 inclusive) due to sulfonyl cyanide present in the mixture or sulfinic acid (for example, benzenesulfinic acid) formed by reaction. In this case, it is difficult to completely prevent deposition, in the reaction mixture, of solid products such as dimerization products (for example, benzenesulfinyl sulfone) of sulfinic acid resulted from the reaction of sulfonyl cyanide and cyclopentadiene (for example, benzenesulfinic acid), and this requires a filtration step for the deposited solid products. Then, if deposition of the solid products is to be completely prevented, a great amount of water or hydrocarbon solvent has to be used; which increases the burden on the waste water treatment and leaves room for improvement.
In method (iii) above, sulfonyl cyanide and cyclopentadiene are reacted under a pH condition of from 3 to 4 inclusive and it is difficult to completely prevent deposition of dimerization products (for example, benzenesulfinyl sulfone) of sulfinic acid (for example, benzenesulfinic acid) perhaps because a mixed solvent of water and a water soluble solvent is used as a solvent. Further, method (iii) gives a lower yield for 2-azabicyclo[2.2.1]hept-5-en-3-one, compared with the process (ii) described above.
USPTO Backgrounds
USPTO Backgrounds