Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-10-04
2004-03-02
Dentz, Bernard (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S389000, C546S089000
Reexamination Certificate
active
06700001
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a process for the stereoselective preparation of 2-hydroxymethyl-chromans.
BACKGROUND OF THE INVENTION
Various 2-yl chroman derivatives have been used as intermediates in the synthesis of various agents such as medicinal agents. For example, U.S. Pat. No. 5,371,094 discloses the use of 2-yl methyl chroman derivatives in the preparation of a series of azaheterocyclylmethyl-chromans that are useful for controlling diseases of the central nervous system. Also, for example, U.S. Pat. No. 5,318,988 discloses the use of 2-yl chroman derivatives of the formulae:
for preparing compounds having the formula
where M represents a typical leaving group such as chloride, bromide, iodide, tosylate, mesylate or triflate, E represents a direct bond or an alkylene or alkenylene having in each case up to 10 carbon atoms, which are optionally substituted by phenyl, G represents an optionally substituted cyclic or heterocyclic moiety containing one or more rings. These compounds are disclosed as being useful for combating disease of the central nervous system.
The processes disclosed in these patents for making chroman derivatives are nonstereoselective necessitating separation of the diastereomers into their single stereoisomeric constituents through conventional methods. It would be desirable to provide processes for the efficient production of 2-yl chroman derivatives that are stereoselective.
Processes for making 2-yl chroman derivatives in a nonstereoselective manner are known. For example, Ellis, G. P., in Heterocyclic Compounds, Vol. 31, chapter entitled “Chromenes, Chromenones, and Chromones”, John Wiley & Sons, NY (1977), discloses examples of such nonstereoselective processes.
It would be desirable to provide a stereoselective process for producing 2-yl chroman derivatives.
SUMMARY OF THE INVENTION
The present invention provides a process for the stereoselective synthesis of 2-hydroxymethyl-chroman that includes:
(a) providing an optically active benzene compound of formula (I),
where
R
0
is hydrogen or an oxygen protecting group,
R is an oxygen protecting group or hydrogen, or the moiety OR is a leaving group, and
R
1
, R
2
and R
3
are independently selected from hydrogen, a halogen atom, a cyano, azido, nitro, hydroxyl, carboxyl, acyl or carboxamido group, a C
1
to C
6
alkyl group, a 5- to 7-membered aromatic group optionally having as ring members up to 2 heteroatoms independently selected from O, N or S, a C
5
to C
7
membered aryloxy group, a C
1
to C
6
alkoxy group, a C
2
to C
7
alkenyl group, a carboalkoxy group having 1 to 6 carbon atoms in the alkyl chain, alkanamido group having 1 to 6 carbon atoms in the alkyl chain, alkanesulfonamido group having 1 to 6 carbon atoms in the alkyl chain, an alkanoyloxy group having 1 to 6 carbon atoms in the alkyl chain, a perhalogenated C
1
to C
6
alkyl or alkoxy group, an amino group or a mono- or di-alkylamino having 1 to 6 carbon atoms per alkyl chain, or two of R
1
, R
2
or R
3
, taken together, form a 5- to 7-membered saturated, partly saturated, unsaturated, or aromatic carbocyclic or bridged carbocyclic ring, wherein the ring may i) optionally have up to two ring atoms selected from S, N, or O, ii) optionally have as a ring member up to 2 carbonyl groups or iii) optionally be substituted by 1 to 2 R
5
substituents, where each R
5
substituent is independently selected from a halogen atom, a cyano, nitro or hydroxyl group, a C
1
-C
6
alkyl group, a C
1
-C
6
alkoxy group, a C
3
-C
6
cycloalkyl group, a 5- to 7-membered aromatic group optionally having 1-2 ring atoms selected from N, O or S, or in spiro form a carbocyclic ring having 5 to 7 carbon atoms or any combination of i), ii) or ii);
(b) if R
0
is not H, deprotecting the OR
0
moiety of formula (I) to produce a phenol compound of formula (IA)
(c) reacting the phenol of formula (IA) in one or more reactions to form a 2-hydroxymethyl-chroman of formula (II)
where at least one of the reactions is a stereospecific cyclization reaction.
In one embodiment, when R of formula (I) and (IA) is hydrogen, the 2-hydroxymethyl chroman is formed by one or more reactions that includes treating the phenol of formula (IA) with hydrogen bromide and acetic acid to produce a bromine compound of formula (2b)
where Ac is an acyl group; and treating the bromine compound of formula (2b) with a base in a stereospecific cyclization reaction.
In another embodiment, when the R of formula (I) and (IA) is an oxygen protecting group or the moiety OR of formula (I) and (IA) is a leaving group, the 2-hydroxymethyl chroman is formed by a stereospecific cyclization reaction that includes treating the phenol of formula (IA) with triphenylphosphine and diethyl azodicarboxylate.
In yet another embodiment of the present invention, the compound of formula (I) is formed by a reaction that includes an osmium-catalyzed asymmetric dihydroxylation of a butene compound of formula (1e)
to produce a compound of formula (IB)
where R
0
, R
1
, R
2
and R
3
are defined as above.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to a stereoselective process for preparing 2-hydroxymethyl chromans of the following formula (II):
where:
R is an oxygen protecting group or hydrogen, or the moiety OR is a leaving group; and
R
1
, R
2
and R
3
are independently selected from hydrogen, a halogen atom, a cyano, azido, nitro, hydroxyl, carboxyl, acyl or carboxamido group, a C
1
to C
6
alkyl group, a 5- to 7-membered aromatic group optionally having as ring members up to 2 heteroatoms independently selected from O, N or S, a C
5
to C
7
membered aryloxy group, a C
1
to C
6
alkoxy group, a C
2
to C
7
alkenyl group, a carboalkoxy group having 1 to 6 carbon atoms in the alkyl chain, alkanamido group having 1 to 6 carbon atoms in the alkyl chain, alkanesulfonamido group having 1 to 6 carbon atoms in the alkyl chain, an alkanoyloxy group having 1 to 6 carbon atoms in the alkyl chain, a perhalogenated C
1
to C
6
alkyl or alkoxy group such as trifluoromethyl or trifluoromethoxy, an amino group or a mono- or di-alkylamino having 1 to 6 carbon atoms per alkyl chain, or
two of R
1
, R
2
or R
3
, taken together, form a 5- to 7-membered saturated, partly saturated, unsaturated, or aromatic carbocyclic or bridged carbocyclic ring, wherein the ring may i) optionally have up to two ring atoms selected from S, N, or O, ii) optionally have as a ring member up to 2 carbonyl groups or iii) optionally be substituted by 1 to 2 R
5
substituents where each R
5
substituent is independently selected from a halogen atom, a cyano, nitro or hydroxyl group, a C
1
-C
6
alkyl group, a C
1
-C
6
alkoxy group, a C
3
-C
6
cycloalkyl group, a 5- to 7-membered aromatic group optionally having 1-2 ring atoms selected from N, O or S, or in spiro form a carbocyclic ring having 5 to 7 carbon atoms, or any combination of i), ii) or iii).
The process of the present invention requires an optically active benzene compound of formula I as a starting material:
where R
0
is hydrogen or an oxygen protecting group, and R, R
1
, R
2
and R
3
are defined as before. The benzene compound of formula I, or a derivative of this compound, as described in further detail hereinafter, is reacted in a stereospecific cyclization reaction to form the 2-hydroxymethyl chroman of formula (I).
By “stereoselective” as used herein, it is meant a reaction where one stereoisomer is preferentially formed over another. Preferably, the process of the present invention will produce a 2-hydroxymethyl-chroman having an enantiomer excess of at least about 30%, more preferably at least about 40%, and most preferably at least about 50%, where enantiomer excess is the mole percent excess of a single enantiomer over the racemate.
By “stereospecific” as used herein, it is meant a reaction where starting materials differing only in their spacial configuration are converted to stereoisomerically distinct products. For example, in a stereospecific reaction, if the starting material is enantiopure (100% enanti
Gross Jonathan L.
Stack Gary P.
Dentz Bernard
Hild Kimberly R.
Wyeth
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