Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1991-04-17
1994-02-01
Brown, Johnnie R.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 277, 514 46, C07H 19167
Patent
active
052833275
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a synthetic intermediate suitable for preparing a 2-alkynyladenosine, a process for preparing the synthetic intermediate, a process for preparing a 2-alkynyladenosine utilizing the synthetic intermediate and a stable 2-alkynyladenosine derivative.
BACKGROUND OF THE INVENTION
2-alkynyladenosines are compounds which have an antihypertensive effect and are expected to be developed as medical agents (see Japanese Patent Laid-Open Publication Nos. 99330/1987 and 99395/1987, EP 0219876 A2 and the like).
However, when 2-alkynyladenosines are intended to be developed as medical agents, they have problems in production and storage described in detail below:
I. Problems in production
As a process for preparing a 2-alkynyladenosine, there has hitherto been reported only the method by Matsuda et al. which comprises reacting 6-chloro-2-iodo-9-(2,3,5-tri-O-acetyl-.beta.-D-ribofuranosyl)purine with methanolic ammonia in a sealed tube at 60.degree. C. for 17 hours to form 2-iodoadenosine (this step being referred to hereinafter as "amination step", in which the deprotection of the acetyl group is simultaneously conducted), and reacting the 2-iodoadenosine thus obtained with an alkyne in the presence of bis(triphenylphosphine)palladium dichloride and cuprous iodide at 80.degree. C. for 1 hour or more to obtain a 2-alkynyladenosine (this step being referred to hereinafter as "cross-coupling step") [see Nucleic Acids Research, Symposium Series No. 12, pp. 5-8 (1983); Chem. Pharm. Bull., 33 (4), pp. 1766-1769 (1985); Nucleic Acids Research, Symposium Series No. 16, pp. 97-100 (1985); NUCLOSIDES & NUCLEOTIDES, 6 (1 & 2), pp. 85-94 (1987); etc]
The reaction scheme of the method by Matsuda et al. is represented by the following structural formulas: ##STR2## wherein Ac represents an acetyl group, and n denotes an integer of 1 to 15.
Although the method by Matsuda et al. is a very excellent method as a process for preparing a 2-alkynyladenosine, it has had the following problems to be solved and thus has not been necessarily a completely satisfactory method.
(1) Problems in the amination step
(i) The reaction in the amination step described above does not proceed smoothly at room temperature and thus is required to be conducted at an elevated temperature while the evaporation of methanolic ammonia is prevented, so that it is essential therefor to use a pressure vessel such as a sealed tube or the like. However, such a pressure vessel has been economically problematic because it is expensive and further always has the risk of explosion.
(ii) In the aforementioned amination step, a large amount of by-products such as acetamide and ammonium chloride are produced in addition to 2-iodoadenosine as the object compound, and it has been very difficult to separate the 2-iodoadenosine from these by-products.
(2) Problems in the cross-coupling step
(i) In the aforementioned cross-coupling step, cuprous iodide is added to the reaction solution in order to promote and complete the reaction in the proportion of about 0.06 mole to 1 mole of 2-iodoadenosine. Therefore, a large amount of copper compounds are introduced as contaminants into the crude reaction product, and treatment with hydrogen sulfide is essential for removing the copper compounds. Hydrogen sulfide is, however, a dangerous substance which has toxicity and an ill smell and is difficult to handle. Moreover it has been extremely difficult to remove completely the copper compounds from the reaction product by the treatment with hydrogen sulfide.
(ii) The reaction solution obtained after the aforementioned cross-coupling step exhibits a dark brown color, and it has been extremely difficult to remove completely colored materials from the reaction product.
(iii) The waste or waste fluid after the reaction contains a large amount of the copper compounds, and it is necessary to remove the copper compounds from the waste in order to avoid environmental pollution.
II. Problems in storage
A 2-alkynyladenosine is a compound which is
REFERENCES:
patent: 4956345 (1990-09-01), Miyasaka et al.
Matsuda et al.(I), Nucleic Acids Research Symposium Series, No. 16, IRL Press Ltd., Oxford, England, 1985, see pp. 97-100.
Matsuda et al.(II), Nucleic Acids Research Symposium Series, No. 12, IRL Press Ltd., Oxford, England, 1983, see pp. 5-8.
Matsuda et al.(III), Chem. Pharm. Bull., 33(4), 1766-1769 (1985).
Kochetkov et al., Organic Chemistry of Nucleic Acids, Part B, Plenum Press, New York, 1972, see p. 333.
Nair, V. et al., "Tetrahedron Letters", 31(6) 807-810 (1990).
Abiru Toichi
Kogi Kentaro
Matsuda Akira
Ueda Tohru
Yamaguchi Toyofumi
Brown Johnnie R.
Crane L. Eric
Toa Eiyo Ltd.
Yamasa Shoyu Kabushiki Kaisha
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