Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-02-14
2001-11-27
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06323348
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel process for producing 3a, 8b-cis-dihydro-3H-cyclopenta[b]benzofuran to be used for a starting material for producing 5,6,7-trinor-4,8-inter-m-phenylene PGI2 derivatives that are useful for, for example, medicines, especially for anti-thrombotic agents, and especially to optically active compounds thereof.
BACKGROUND ART
Optically active compounds of 3a, 8b-cis-dihydro-3H-cyclopenta[b]benzofuran derivatives as one of cycloalkyl-[b]benzofuran have been obtained by optical resolution of [7-bromo-3a, 8b-cis-dihydoro-3H-cyclopenta[b]benzofuran-5-il] formate using an optically active amine (Japanese Unexamined Patent Publication No. 59-161371), or by optical resolution of an intermediate compound with an enzyme (J. Chem. Soc., Chem. Commun. 811, 1995). However, the procedure becomes complicated since recrystallization is repeated by forming a complex in the optical resolution method using an optically active amine. In the optical resolution method using an enzyme, on the other hand, a dilute substrate concentration is used besides requiring a long reaction time. In addition, repeatability may be sometimes poor depending on the lot of the enzyme used.
The object of the present invention, based on the drawbacks of the conventional art, is to provide a useful process for producing desired optically active cycloalkyl[b]benzofuran by a cyclization reaction using a readily available optically active starting material.
DISCLOSURE OF INVENTION
The present invention provides a process for producing cycloalkyl[b]benzofuran represented by a general formula (II):
(in the formula, n is an integer in the range of 0 to 4, and Y and Z independently denote hydrogen, halogen, an alkyl group with a carbon number of 1 to 5, a cycloalkyl group with a carbon number of 3 to 8, a cycloalkylalkyl group with a carbon number of 4 to 9, a cycloalkenylalkyl group with a carbon number of 5 to 10, an aralkyl group with a carbon number of 7 to 12, an alkenyl group with a carbon number of 2 to 7, or an aryl group with a carbon number of 6 to 11) using a compound represented by a general formula (I) as a starting material:
(in the formula, R
1
denotes an acyl group with a carbon number of 1 to 12, an aroyl group with a carbon number of 7 to 15 or CO
2
R
2
group (wherein R
2
represents a linear or branched alkyl group with a carbon number of 1 to 12, a cycloalkyl group with a carbon number of 3 to 8, or an aryl group with a carbon number of 6 to 11), and n is the same as defined above).
In more detail, the present invention provides a process for producing an optically active compound of cycloalkyl[b]benzofuran represented by a general formula (IV):
(in the formula, n, Y and Z are the same as defined above) or a general formula (VI):
(in the formula, n, Y and Z are the same as defined above) wherein the compound represented by the general formula (IV) or (VI) is synthesized by converting the optically active compound represented by the general formula (III)
(in the formula, R
1
and n are the same as defined above) as a starting material into a compound represented by a general formula (V)
(in the formula, n, Y and Z are the same as defined above, and R
3
denotes a linear or branched alkyl group with a carbon number of 1 to 12, an aralkyl group with a carbon number of 7 to 12, a linear or branched alkylsulfonyl group with a carbon number of 1 to 12, an arylsulfonyl group with a carbon number of 6 to 12, or R
5
(wherein R
5
denotes an aryl group with a carbon number of 6 to 11), X denotes halogen), or a general formula (VII):
(in the formula, R
3
, n, X, Y and Z are the same as defined above) by a reaction using a transition metal, the Mitsunobu reaction, or a combination thereof, and cyclizing the compound represented by the general formula (V) or the general formula (VII) using a metallic reagent or an organometallic reagent.
The present invention also provide a compound that is useful in the process for producing cycloalkyl[b]benzofuran represented by a general formula (VIII):
(in the formula, R
4
denotes hydrogen, an acyl group with a carbon number of 1 to 12, an aroyl group with a carbon number of 7 to 15, a linear or branched alkyl group with a carbon number of 1 to 12, an aryl group with a carbon number of 6 to 11, an aralkyl group with a carbon number of 7 to 12, a linear or branched alkylsulfonyl group with a carbon number of 1 to 12, an arylsulfonyl group with a carbon number of 6 to 12, or CO
2
R
2
(wherein R
2
denotes a liner or branched alkyl group with a carbon number of 1 to 12, a cycloalkyl group with a carbon number of 3 to 8, or an aryl group with a carbon number of 6 to 11), n denotes an integer in the range of 0 to 4. X denotes halogen, and Y and Z independently denote hydrogen, halogen, an alkyl group with a carbon number of 1 to 5, a cycloalkyl group with a carbon number of 3 to 8, a cycloalkylalkyl group with a carbon number of 4 to 9, a cycloalkenylalkyl group with a carbon number of 5 to 10, an aralkyl group with a carbon number of 7 to 12, an alkenyl group with a carbon number of 2 to 7, and an aryl group with a carbon number of 6 to 11 (excluding the compound in which both of Y and Z denote hydrogen, or one of them denotes hydrogen and the other denotes an alkenyl group with a carbon number of 3, when R
4
denotes hydrogen and X denotes iodine.))
BEST MODE FOR CARRYING OUT THE INVENTION
A production process of the optically active compound (IV) is illustrated in Scheme 1:
(in the formula, R
1
, R
3
, n, X, Y and Z are the same as defined above.)
It is preferable that R
1
is an acyl group with a carbon number of 1 to 5, an aroyl group with a carbon number of 7 to 10 or CO
2
R
2
(wherein R
2
denotes a linear or branched alkyl group with a carbon number of 1 to 5). R
3
preferably denotes a linear or branched alkyl group with a carbon number of 1 to 5, an aralkyl group with a carbon number of 7 to 10, a linear or branched alkylsulfonyl group with a carbon number of 1 to 5, an arylsulfonyl group with a carbon number of 6 to 10, or R
5
(wherein R
5
denotes an aryl group with a carbon number of 6 to 9). The integer n is preferably 1 or 2. X preferably represents chlorine, bromine or iodine, but bromine or iodine is most preferable among them. It is preferable that Y and Z independently represent hydrogen, chlorine, bromine or an alkyl group with a carbon number of 1 to 5.
The optically active compound (III) to be used as a starting material can be synthesized by a method known in the art (Carl R. Johnson and Scott J. Bis, Tetrahedron Letters, 1992, 33, 728). In more detail, it is preferable to use (1S, 4R)-cis-4-acetoxy-2-cyclopenten-1-ol, (1S, 4R)-cis-4-benzoyloxy-2-cyclopenten-1-ol or (1S, 4R)-cis-4-ethoxycarbonyloxy-2-cyclopenten-1-ol as a starting material, (1S, 4R)-cis-4-acetoxy-2-cyclopenten-1-ol being most preferable among them. The commercially available (1S, 4R)-cis-4-acetoxy-2-cyclopentene-1-ol may be used.
The formula (1) in Scheme 1 represents a synthetic route by which, after a stereochemical inversion reaction by substituting the 4-hydroxy group in the compound (III) with an o-halogenated phenol compound in the step A1, the compound (V) is obtained by converting R
1
into a functional group by the steps B1 to B3 to obtain the compound (IV) by a cyclization reaction.
The formula (2) in Scheme 2 represents a synthetic route by which, after converting the 4-hydroxy group in the compound (III) into a functional group in the steps A2 to A4, the 1-R
1
O group is substituted with an o-halogenated phenol derivative to form the compound (V) while maintaining its stereochemical configuration in the step B4, followed by a cyclization reaction to obtain the compound (IV).
The formula (3) in Scheme 1 represents a synthetic route by which, after substituting the 1-R
1
O group in the compound (III) with an o-halogenated phenol derivative while maintaining its stereochemical configuration in the step A5, the compound (V) is obtaine
Nagase Hiroshi
Nishiyama Hisao
Wakita Hisanori
Birch & Stewart Kolasch & Birch, LLP
Covington Raymond
Rotman Alan L.
Toray Industries Inc.
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