Process for synthesis of 2-yl chroman derivatives

Details Process for synthesis of 2-yl chroman derivatives Process for synthesis of 2-yl chroman derivatives

2002-10-04

2004-04-06

Rotman, Alan L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S399000, C549S405000

Reexamination Certificate

active

06716998

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a stereospecific process for the preparation of 2-yl-chroman and -chromene derivatives.
BACKGROUND OF THE INVENTION
Various 2-yl-chroman and -chromene 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-ylmethyl 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-ylmethyl 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 and chromene derivatives that are stereoselective and more preferably stereospecific.
Processes for making 2-yl chroman and chromene derivatives in a nonstereoselective manner are known. S. Chang and R. H. Grubbs,
J. Org. Chem.
, Vol. 63, pp. 864-866 (1998), describe the synthesis of certain chromene derivatives from styrenyl allyl ether dienes using catalytic ring-closing olefin metathesis.
It would be desirable to provide a stereospecific process for producing 2-yl chroman and chromene derivatives.
SUMMARY OF THE INVENTION
The present invention provides a stereospecific process for preparing 2-yl chromene derivatives that includes:
(a) reacting a 2-hydroxy substituted styrene of formula (I)
and an optically active 3-hydroxy-1-butene of formula (II)
to form an optically active diene of formula (III)
wherein R is a leaving group or a protected oxygen group,
wherein 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, 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 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),
wherein R
4
is H or a C
1
to C
6
alkyl group, and
wherein R
6
is a hydroxyl group, a protected oxygen group, or a leaving group; and
(b) subjecting the diene of formula (III) to a ring closing metathesis polymerization reaction in the presence of a catalyst to stereospecifically produce an optically active 2-yl chromene derivative of formula (IV)
where R
1
, R
2
, R
3
and R
6
are defined as in formula (III).
The invention further includes a process for producing a 2-yl chroman by hydrogenating the 2-yl chromene, as well as a process for making the hydroxy substituted styrene of formula (I).
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to a stereospecific process for preparing 2-yl chroman and chromene derivatives of the formula:
where:
R
1
, R
2
and R
3
are independently selected from hydrogen, a halogen atom, or 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 a trifluoromethyl or trifluoromethoxy group, an amino group, or a mono- or di-alkylamino group 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, where 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) be optionally 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); and
R
6
is a hydroxyl group, a protected oxygen group or a leaving group.
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% enantiomer excess “ee”), the final product will also be enantiopure. Similarly if the starting material has an enantiomer excess of about 50%, the final product will also have about a 50% enantiomer excess. “Enantiomer excess” as used herein refers to the mole percent excess of a single enantiomer over the racemate.
By “optically active” as used herein, it is meant a nonracemic mixture of chiral molecules. The “*” in the formulas indicates the chiral carbon providing the optical activity.
The process of the present invention preferably produces 2-yl chromene and chroman derivatives having an enantiomer excess of at least about 30%, more more preferably at least about 50%, and most preferably at least about 95%. In the most preferred embodiment of the present invention, enantiopure 2-yl chromene and chroman derivatives are produced.
As used herein, unless otherwise indicated, any moiety containing an alkyl or alkenyl group such as for example, an alkyl, alkane, alkenyl, alkoxy, carboalkoxy, or alkanamido group, may be branched or straight chained and contain up to 7 carbon atoms in the alkyl/alkenyl chain. Alkenyl groups, unless otherwise, indicated may be monounsaturated, polyunsaturated or fully unsaturated. Cycloalkyl means a carbocyclic ring having 3-8 carbon atoms. Aromatic and aryl mean an aromatic 5- to 7-membered carbocyclic ring such as phenyl. Heteroaromatic and heteroaryl mean an aromatic 5- to 7-membered ring having one or two heteroatoms which independently may be N, O, or S. Acyl means an alkanoyl group having 2 to 7 carbon atoms. Any moiety containing

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