Processes for preparing substituted chromanol derivatives

Details Processes for preparing substituted chromanol derivatives Processes for preparing substituted chromanol derivatives

1999-03-05

2000-08-01

Dentz, Bernard

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C07D31124

Patent

active

060969067

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

This invention relates to the preparation of substituted chromanol derivatives and to intermediates useful in said preparation. The substituted chromanol derivatives that are prepared in accord with the present invention are disclosed in United States patent application Ser. No. 08/295,827, filed Jan. 9, 1995, now U.S. Pat. No. 5,552,435, entitled "Benzopyran And Related LTB.sub.4 Antagonists," PCT international application publication number WO 96/11925 (published Apr. 25, 1996), PCT international application publication number WO 96/11920 (published Apr. 25, 1996), PCT international application publication number WO 93/15066 (published Aug. 5, 1993). Each of the foregoing United States and PCT internation patent applications are incorporated herein by reference in their entirety.
The substituted chromanol derivatives that are prepared in accord with the present invention inhibit the action of LTB.sub.4, as disclosed in United States patent application Ser. No. 08/295,827, referred to above, As LTB.sub.4 antagonists, the substituted chromanol derivatives that are prepared according to the present invention are useful in the treatment of LTB.sub.4 -induced illnesses such as inflammatory disorders including rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, psoriasis, eczema, erythma, pruritis, acne, stroke, graft rejection, autoimmune diseases, and asthma.


SUMMARY OF THE INVENTION

The present invention relates to a process of preparing a compound of the formula ##STR2## or the enantiomer of said compound, wherein in said compound of formula X the R.sup.3 -substituted benzoic acid moiety is attached at carbon 6 or 7 of the chroman ring; consisting of H, fluoro, chloro, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, phenylsulfinyl, phenylsulfonyl, and --S(O).sub.n (C.sub.1 -C.sub.6 alkyl) wherein n is 0 to 2, and wherein said alkyl group, the alkyl moiety of said alkoxy and --S(O).sub.n (C.sub.1 -C.sub.6 alkyl) groups, and the phenyl moiety of said phenylsulfinyl and phenylsulfonyl groups are optionally substituted by 1 to 3 fluoro groups; -C.sub.10 aryl, or 5-10 membered heteroaryl, wherein said aryl and heteroaryl groups are optionally substituted by 1 or 2 substituents independently selected from phenyl, R.sup.2, and phenyl substituted by 1 or 2 R.sup.2 ; ##STR3## or the enantiomer of said compound of formula IX in the preparation of the enantiomer of said compound of formula X, wherein R.sup.1, R.sup.2, and R.sup.3 are as defined above, R.sup.4 is C.sub.1 -C.sub.6 alkyl, and the benzoate moiety is attached to position 6 or 7 of the chroman ring, with a base.
In said process of preparing the compound of formula X, the compound of formula IX is preferably treated with an aqueous hydroxide base, R.sup.1 is preferably benzyl, 4-fluorobenzyl, 4-phenylbenzyl, 4-(4-fluorophenyl)benzyl, or phenethyl, R.sup.2 is preferably hydrogen or fluoro, R.sup.3 is preferably fluoro, chloro, or methyl optionally substituted by 1 to 3 fluorines, and R.sup.4 is preferably ethyl or 2,2-dimethylpropyl. Most preferably, said compound of formula IX is treated with a base comprising aqueous sodium hydroxide, said compound of formula IX is (3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoic acid ethyl ester, and said compound of formula X is (3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoic acid.
In a further aspect of the present invention, said compound of formula IX, or the enantiomer of said compound, wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are as defined above, is prepared by treating a compound of the formula ##STR4## or the enantiomer of said compound of formula VII in the preparation of the enantiomer of the compound of formula IX, wherein R.sup.1 and R.sup.2 are as defined above and the boronic acid moiety is attached at position 6 or 7 of the chroman ring, with a compound of the formula ##STR5## wherein R.sup.3 and R.sup.4 are as defined above and Z is halo or C.sub.1 -C.sub.4 perfluoroalkylsulfonate, in the presence of a base or

REFERENCES:
patent: 5552435 (1996-09-01), Koch

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