Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
1999-09-08
2001-08-21
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C548S306700
Reexamination Certificate
active
06278027
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel key intermediates, 3-hydoxy-2-halocycloheptenones and 3-alkoxy-2-halocycloheptenones, which are useful for the synthesis of drug medicine. In detail, this invention relates to preparation of the key intermediates of novel cycloheptimidazole derivatives that have angiotensin II receptor antagonistic activities and are therefore useful for the treatment of hypertension, congestive heart failure and so on.
2. Description of the Prior Art
Many compounds containing cyclohept rings possess potent physiological activities. For example, we proposed cycloheptimidazoles of general formula (6) that have angiotensin II receptor antagonistic activities and are therefore useful for the treatment of hypertension or congestive heart failure. (Japanese Patent laid-open Publication 5-320139, 7-149761 and 8-73454.)
(wherein: R
5
is hydrogen atom or lower alkyl group, R
6
is carboxyl group, tetrazolyl group) However, the synthetic method of the cycloheptaimidazoles, shown in general formula (6), is unfavorable on an industrial scale because of the following reasons.
1) The starting material, tropolone is expensive.
2) A large number of process steps are needed.
3) This procedure is not applicable to a wide range of cycloheptanoid compounds.
Judging from the application of known method, it is a common concept that 1,3-cycloheptadione (8), prepared from the compound (2), is halogenated at the 2 position of compound (8) to obtain the general formula (1) containing compound (3) and (4).
(wherein: R
2
and R
3
is lower alkyl group, X is bromine atom or chlorine atom.)
In other words Cyclohepta-1,3-dione (8) can be obtained by known method. First, cyclopropanation of compound (2) in the presence of Et
2
Zn and CH
2
I
2
(Simmons-Smith reaction) gives the bicyclic compound (7) (L. Hadjiarapoglou, Synthesis, 525, 1996). Second, ring enlargement of (7) using FeCl
3
or periodic acid gives the compound (8) (T. Saegusa, Organic Synthesis 59, 113; M. C. Pirrung, J. Org. Chem. 52, 3606, 1987). Then the halo analogue (3) seems to be prepared in a similar manner as described by R. G. Shepherd (J. Chem. Soc. Perkin Trans. I, 2153,1987), and its etherification affords 2-halo-3-alkoxycyclohept-2-enone(4).
However, Simmons-Smith reaction is not useful industrially because of following reasons.
1) The reaction condition is anhydrous. 2) Et
2
Zn is subject to autoignition.
Moreover, the objective compound (3) is not obtained under several conditions for halogenation of the compound (8), and dihalogenation reaction occurs and 2,2-dihalo-1,3-cycloheptandione (9) is obtained as a main product.
Similarly, well-known procedure was not applicable to the synthesis of the compounds (3) and (4). Furthermore, although the compounds (10) (Chem. Abstr. 77, 48038k, 1972 (U.S. Pat. No. 3,658,841)), (11) and (12) (Chem. Abstr. 89, 179583e, 1978 (J. Org. Chem. 43, 4241, 1978)) have already been known, 3-hydroxy-2-halocycloheptenone and 3-alkoxy-2-halocycloheptenone, which are shown as general formula (1), below, are not yet reported and are new compounds.
PROBLEMS TO BE SOLVED BY THE INVENTION
This invention relates to novel key intermediates, useful for the preparation of the cycloheptanoides such as cycloheptimidazole derivatives which are useful for the synthesis of medicine and presents its use for the preparation of the cycloheptimidazoles.
SUMMARY OF THE INVENTION
We have explored to find a practical procedure, of wide range usefulness, for cycloheptanoide compounds. Consequently, we found that 3-hydroxy-2-halocycloheptenone and 3-alkoxy-2-halocycloheptenone were the most suitable intermediates and, at the same time, we found the practical synthetic procedure of these intermediates which is scalable for the industrial scale, and this invention was completed.
Namely, the compounds of the present invention are compounds of general formula (1):
wherein: R
1
is hydrogen atom or lower alkyl group, X is bromine atom or chlorine atom. In this invention, “lower” means straight or branched chain from C
1
or C
5
.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of general (1) such as 3-hydroxy-2-halocycloheptenone and 3-alkoxy-2-halocycloheptenone can be obtained from 1,2-bis(trialkylsilyloxy)cyclohexene (2) which is easily available in a few steps. The synthetic method for preparation of these compounds is shown as follows.
wherein: R
2
and R
3
are lower alkyl group, X is bromine atom or chlorine atom.
Namely, the compound (13) is obtained by the reaction of 1,2-bis(trialkylsilyloxy)cyclohexene (2) with dihalocarbene which is prepared from chloroform or bromoform in the presence of base such as potassium tert-butoxide. Thus, two reactions, namely a ring chlorination and expansion, proceed in one pot and the compound (13) is subjected to ring expansion to obtain the compound (3) without isolation. This reaction is carried out in an inert organic solvent, such as, heptane, hexane and pentane, at from −40° C. to room temperature.
Above mentioned compound (3) is reacted with alcohol such as methyl alcohol or ethyl alcohol in the presence of acid catalyst to give 3-alkoxy-2-chlorocycloheptenone (compound (4)) or 3-alkoxy-2-bromocycloheptenone. Hydrochloric acid, sulfonic acid, methanesulfonic acid, p-methylbenzene sulfonic acid and ion exchange resin can be used as an acid catalyst. This alkylation is also carried out in the presence of orthoester such as trimethyl orthoformate. In general, this reaction is carried out at a temperature of from 0° C. to room temperature. 1,2-Bis(trialkylsilyloxy) cyclohexene (2) can be prepared according to the reported methods (K. Rublmann., Synthesis, 236, 1971).
Compounds of general formula (4) are as follows: 3-Methoxy-2-chlorocycloheptenone, 3-Methoxy-2-bromocycloheptenone, 3-Ethoxy-2-chlorocyclo-heptenone, 3-Ethoxy-2-bromocycloheptenone and so on.
A compound of general formula (1) can be converted to various cycloheptanoide derivatives. For example, the compounds of general formula (5) are obtained by the reaction of compound (1) with alkylamidine hydrochloride in the presence of base. The compounds of general formula (5) are useful for the synthesis of cycloheptimidazole derivatives which have angiotensin II receptor antagonistic activities.
wherein: R
1
is hydrogen atom or lower alkyl group, X is bromine atom or chlorine atom, R
4
is lower alkyl group.
For example, the compound (1) wherein R
1
is lower alkyl group is reacted with butylamidine hydrochloride in the presence of K
2
CO
3
to give cycloheptimidazole derivatives (5) in which R
4
is n-propyl group. In this reaction, 1,4-dioxane or chloroform-H
2
O are preferred as solvent. In general, this reaction is carried out at room temperature or under heating conditions.
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patent: 4749681 (1988-06-01), Buers et al.
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Ohno Akira
Tomiyama Akira
Tomiyama Tsuyoshi
Ueyama Naoto
Higel Floyd D.
Kotobuki Pharmaceutical CO LTD
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