Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1999-10-12
2000-11-14
Huang, Evelyn Mei
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D21158
Patent
active
061472158
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a novel process for producing 1-chlorocarbonyl-4-piperidinopiperidine or hydrochloride thereof, which is an important intermediate as an amide group and is used in the fields of pharmaceuticals and the like.
BACKGROUND OF THE INVENTION
1 -Chlorocarbonyl-4-piperidinopiperidine and hydrochloride thereof are important intermediates as the members of amide group and are used widely in the fields of pharmaceuticals and the like.
As an example of processes for producing 1-chlorocarbonyl-4-piperidinopiperidine or hydrochloride thereof, there is a report by S. Sawada (S. Sawada, Chem. Pharm. Bull., 39, 1446(1991)), whose process is characterized by reacting 4-piperidinopiperidine with a phosgene dimer (TCF), removing an unreacted portion of the phosgene dimer to obtain 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride and, if necessary, treating this hydrochloride with an aqueous solution of a weak base such as sodium bicarbonate or potassium carbonate.
However, this process is not suitable for a large scale production of 1-chlorocarbonyl-4-piperidinopiperidine and hydrochloride thereof, as the phosgene dimer is extremely highly toxic and must be treated using special devices in a special operation area and moreover, its transportation is strictly regulated. In addition, this product is precipitated as a hydrochloride in an agar-like form and the unreacted phosgene dimer takes long time to be filtrated out, leading to a high risk in that operators could be exposed to the toxicity of the phosgene dimer. Furthermore, the yield obtained by this process is poor. Because the precipitated hydrochloride is directly dissolved into the aqueous solution and is hydrolyzed under the condition of a weak base of the aqueous solution, every part of the hydrochlorides cannot be converted to 1-chlorocarbonyl-4-piperidinopiperidine.
An object of the present invention is therefore to provide a highly safe and easily operable process for producing 1-chlorocarbonyl-4-piperidinopiperidine or hydrochloride thereof in a high yield.
DISCLOSURE OF THE INVENTION
In view of the forgoing circumstances, the present inventors have conducted an extensive investigation with a view toward attaining the above object. As a result, it has been found that 1-chlorocarbonyl-4-piperidinopiperidine or hydrochloride thereof can be obtained easily and safely in a high yield by trialkylsilylating 4-piperidinopiperidine, reacting the resulting compound with a carbon dioxide gas and then with thionyl chloride or the like and optionally treating with a strong base, leading to the completion of the present invention.
The present invention can be represented by the following reaction scheme: ##STR1## wherein R.sup.1, R.sup.2 and R.sup.3 are the same or different and each represents a linear or branched C.sub.1-6 alkyl group.
Described specifically, in the present invention, there is thus provided a process for producing 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride represented by the formula (4) or 1-chlorocarbonyl-4-piperidinopiperidine represented by the formula (5), which comprises reacting (step 1) 4-piperidinopiperidine represented by the formula (1) with a trialkylsilyl halide to obtain a 4-piperidinopiperidinyl trialkylsilyl represented by the formula (2), reacting (step 3) the resulting compound with a carbon dioxide gas to form a 4-piperidinopiperidinyl trialkylsilylcarbamate derivative represented by the formula (3), reacting the resulting derivative with one or more substances selected from the group consisting of thionyl chloride, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride and phosphoryl trichloride to obtain 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride represented by the formula (4) and then optionally treating the resulting hydrochloride with a strong base.
The process of the present invention will hereinafter be described in the order of steps.
The trialkylsilyl halide to be reacted with 4-piperidinopiperidine has a structure in which a silicon atom
REFERENCES:
patent: 4604463 (1986-08-01), Miyasaka
B. Hermans, et al., J.Med. Chem., vol. 9, pp. 49-52, "4-Substituted Piperidines. III. Reduction of 1-Benzyl-4-Cyano-4-t-Aminopiperidines with Lithium Aluminium Hydride," Jan. 1966.
S. Sawada, et al., Chemi. Pharm. Bull., vol. 39, No. 6, pp. 1446-1454, "Synthesis and Antitumor Activity of 20(S)-Camptothecin Derivatives: carbamate-Linked, Water-Soluble Derivatives of 7-Ethyl-10-Hydroxycomptothecin," 1991.
Huang Evelyn Mei
Kabushiki Kaisha Yakul't Honsha
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