Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
2001-08-10
2003-10-14
Coleman, Brenda (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
active
06632943
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a method for preparing optically active pyrroloazepine derivatives useful as drugs or raw materials as well as intermediates for the synthesis of these drugs. More particularly, it relates to a method for preparing optically active pyrroloazepine derivatives by asymmetric reduction methods.
BACKGROUND ART
Pyrrolo[3,2-c]azepine derivatives are important compounds useful as drugs for treatment of cardiovascular disease or raw materials as well as intermediates for the synthesis of these drugs. For example, International Patent Publication Number WO97/20845 disclosed pyrroloazepine derivatives having strong serotonin-2 receptor antagonistic action of excellent selectivity. The compounds are useful, for example, for the prevention or treatment of ischemic heart diseases such as angina pectoris, arrhythmia, myocardial infarction, cardiac insufficiency and post-PTCA (Percutaneous Transluminal Coronary Angioplasty) restenosis; cerebrovascular disturbances such as cerebral infarction and cerebral sequelae after subarachnoid hemorrhage; peripheral circulatory disturbances such as arteriosclerosis obliterans, Raynaud's disease and Buerger's disease; and hypertension.
Further, Japanese Laid-open Patent Publication Number Hei 10-251258disclosed compounds having pyrrolo[3,2-c]azepine skeleton for treatment of cardiovascular diseases.
Among these pyrrolo[3,2-c]azepine derivatives useful for drugs, there are some compounds having asymmetric carbon atoms in their molecule. For example, several pyrrolo[3,2-c]azepine derivatives disclosed in International Patent Publication Number WO97/20845 have a hydroxyl substituent at the 8-position carbon atom and therefore, these compounds have one pair of enantiomers due to the presence of asymmetric carbon atom at the 8-position.
It is well known that in the case of the compound having one pair of enantiomers, pharmacological activities and toxicities of both enantiomers sometimes greatly differs from each other (C. C. Pfeiffer,
Science,
Vol. 124, 29 (1956); F. P. A. Lehmann,
Quant. Struct. Act. Relat.,
Vol. 6, 57 (1987)). Therefore, when pharmacological activities and toxicities of optically active compounds are different from each other, it is demanded to select one optically active compound having more effectiveness and safety margin in comparison to their pharmacological activities, pharmacokinetics, side effects and toxicities, totally.
For the methods to obtain the optically active compound, it is divided broadly into two methods. That is, by mean of optical resolution method and asymmetric synthesis method for the desired optically active compound. As the former method, it is generally known a method for separating racemic compounds by using optically active column chromatography, by recrystallization of diastereoisomers which is derived by introducing the group having other asymmetric center or by reacting with other optically active acids or bases, by using enzyme reaction, and so on. However, these methods have a disadvantage that the chemical yield of the desired optically active compound is 50% at maximum.
As the later method, asymmetric synthesis is a typical method to obtain the desired optically active compound selectively. Examples of this asymmetric synthesis method are a method for synthesis of the desired optically active compound by using optically active sugars or amino acids as the starting materials and utilizing their stereo arrangement, a method for deriving to optically active compound from its precursor which is non optically active compound by introducing the group stereoselectively or by reducing stereoselectively, and so on. The chemical yield of the desired optically active compound by asymmetric synthesis is 100% theoretically and that makes this method advantageous; however, the optical yield is greatly changed by the substrate to be used and the optical and chemical yields are also greatly changed by the reaction conditions such as reagents, solvents, concentrations of substrate, and reaction temperature to be used. Therefore, there are extremely difficult to determine the reaction systems or the reaction conditions to be used for the asymmetric synthesis.
Furthermore, it is necessary to conduct the reaction at super-low temperature to obtain high optical yield of the asymmetric synthesis. The operation such as preparing a reagent is very complicated and the starting materials or reagents necessary for the production are expensive. These points are recognized to be disadvantages at the presence. That is, it is important to select the best reaction conditions for every substrate to be used in the asymmetric synthesis. Further, in the case of the asymmetric synthesis using the asymmetric catalyst, it is important to select the best asymmetric catalyst and reaction conditions suitable for the individual substrate.
For example, in the above-mentioned International Patent Publication Number WO97/20845, several synthetic methods for preparing the optically active pyrrolo[3,2-c]azepine compounds having a hydroxyl substituent at the 8-position are disclosed. Nevertheless, these methods are not sufficient for the industrial methods in operational and economical standpoints, and further improvements are required. In the Patent Publication, the methods for preparing the optically active pyrroloazepine derivatives from racemic pyrroloazepine derivatives by using optically active column chromatography, by recrystallization of salts with optically active acids, or by enzyme reaction are disclosed, and the desired optically active pyrroloazepine derivatives can be prepared by using one of these methods or the combination thereof. Although, these methods are simple methods for preparing the optically active pyrroloazepine derivatives, the chemical yield is low and it is not economically sufficient.
Further, other methods for preparing the optically active pyrroloazepine derivatives, for example, an asymmetric reduction method of ketone compounds, i.e., precursors of pyrroloazepine derivatives, using boran as reducing reagent with optically active oxazaborollidine catalyst, or using ruthenium complex catalyst for hydrogen transfer reduction, is disclosed.
However, these methods have several disadvantages, such as complication in reagents' preparing, requirement on selecting the strict reaction conditions, high cost of reagents and low chemical yield, and are not economically sufficient.
Under these circumstances, the purpose of the present invention is to provide the methods for preparing the optically active pyrroloazepine derivatives useful for drugs in simple, economical as well as industrial applicable scale. More specifically, the present invention is to provide the simple and economical methods for preparing the optically active pyrrolo[3,2-c]azepine compounds having a hydroxyl substituent at the 8-position from their precursors, i.e., ketone compounds having carbonyl group at the 8-position, by the asymmetric reduction.
The present inventors have proceeded with extensive investigation to develop the industrial applicable methods for preparing the optically active pyrroloazepine derivatives, and it is found that the desired optically active pyrroloazepine compounds can be synthesized easily in good chemical and optical yields by combining the asymmetric reduction process of ketone compounds using metal hydride compound and alcohol compound in the presence of optically active cobalt complex catalyst, and a purification process of the resulting pyrroloazepine compound. The present invention has been completed based on the findings mentioned above.
DISCLOSURE OF INVENTION
Accordingly, as one aspect of the present invention, it is provided a method for preparing the optically active pyrroloazepine derivatives represented by the following formula (I):
wherein Z represents optionally substituted phenyl group, which comprises;
a process for the asymmetric reduction of the ketone compound represented by the fol
Mizuno Akira
Muraishi Teruo
Nagata Takushi
Sekiuchi Kazuto
Coleman Brenda
Crowell & Moring LLP
Daiichi Suntory Pharma Co., Ltd.
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