Processes and intermediates for preparing substituted...

Details Processes and intermediates for preparing substituted... Processes and intermediates for preparing substituted...

2001-03-21

2002-03-12

Dentz, Bernard (Department: 1625)

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

Organic compounds

Borate esters

C558S298000

Reexamination Certificate

active

06355825

ABSTRACT:

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 U.S. patent application Ser. No. 08/295,827, filed Jan. 9, 1995, entitled “Benzopyran And Related LTB
4
Antagonists,” now U.S. Pat. No. 5,552,435, 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
4
, as disclosed in U.S. patent application Ser. No. 08/295,827, referred to above. As LTB
4
antagonists, the substituted chromanol derivatives that are prepared according to the present invention are useful in the treatment of LTB
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
or the enantiomer of said compound, wherein in said compound of formula X the R
3
-substituted benzoic acid moiety is attached at carbon 6 or 7 of the chroman ring;
R
1
is —(CH
2
)
q
CHR
5
R
6
wherein q is 0 to 4;
each R
2
and R
3
is independently selected from the group consisting of H, fluoro, chloro, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, phenylsulfinyl, phenylsulfonyl, and —S(O)
n
(C
1
-C
6
alkyl) wherein n is 0 to 2, and wherein said alkyl group, the alkyl moiety of said alkoxy and —S(O)
n
(C
1
-C
6
alkyl) groups, and the phenyl moiety of said phenylsulfinyl and phenylsulfonyl groups are optionally substituted by 1 to 3 fluoro groups;
R
5
is H, C
1
-C
6
alkyl, or phenyl substituted by R
2
;
R
6
is H, C
1
-C
6
alkyl, C
3
-C
8
cycloalkyl, C
6
-C
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
2
, and phenyl substituted by 1 or 2 R
2
;
which comprises treating a compound of the formula
or the enantiomer of said compound of formula IX in the preparation of the enantiomer of said compound of formula X, wherein R
1
, R
2
, and R
3
are as defined above, R
4
is C
1
-C
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
1
is preferably benzyl, 4-fluorobenzyl, 4-phenylbenzyl, 4-(4-fluorophenyl)benzyl, or phenethyl, R
2
is preferably hydrogen or fluoro, R
3
is preferably fluoro, chloro, or methyl optionally substituted by 1 to 3 fluorines, and R
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 (3
S
,4
R
)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoic acid ethyl ester, and said compound of formula X is (3
S
,4
R
)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoicacid.
In a further aspect of the present invention, said compound of formula IX, or the enantiomer of said compound, wherein R
1
, R
2
, R
3
, and R
4
are as defined above, is prepared by treating a compound of the formula
or the enantiomer of said compound of formula VII in the preparation of the enantiomer of the compound of formula IX, wherein R
1
and R
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
wherein R
3
and R
4
are as defined above and Z is halo or C
1
-C
4
perfluoroalkylsulfonate, in the presence of a base or fluoride salt and a palladium catalyst.
In said process of making the compound of formula IX, or the enantiomer of said compound, preferred substituents for R
1
, R
2
, R
3
and R
4
are as stated above for said process of making the compound of formula X. In another preferred embodiment, Z is halo, the base or fluoride salt is selected from sodium carbonate, triethylamine, sodium bicarbonate, cesium carbonate, tripotassium phosphate, potassium fluoride, cesium fluoride, sodium hydroxide, barium hydroxide, and tetrabutylammonium fluoride, the palladium catalyst is selected from tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium(II) acetate, allylpalladium chloride dimer, tris(dibenzylideneacetone)dipalladium(0), and 10% palladium on carbon. Most preferably, the base or fluoride salt is potassium fluoride, the palladium catalyst is 10% palladium on carbon, the compound of formula VII is (3
S
,4
R
)-(3-benzyl-4-hydroxy-chroman-7-yl)-boronic acid, and the compound of formula VIII is ethyl 2-iodo-4-trifluoromethyl-benzoate.
In a further aspect of the invention, the compound of formula VII, or the enantiomer of said compound, wherein R
1
and R
2
are as defined above, is prepared by treating a compound of the formula
or the enantiomer of said compound of formula VI in the preparation of the enantiomer of the compound of formula VII, wherein R
1
and R
2
are as defined above and X is a halide and is attached at position 6 or 7 of the chroman ring, with (1) C
1
-C
4
alkyl lithium, and (2) a borating agent.
In said process of making the compound of formula VII, or the enantiomer of said compound, preferred substituents for R
1
and R
2
are as stated above for said process of making the compound of formula X. In another preferred embodiment, X is bromo or iodo, and said compound of formula VI is treated with (1) methyl lithium, (2) butyl lithium, and (3) said borating agent which is selected from borane-tetrahydrofuran complex, triisopropyl borate, and trimethyl borate. Most preferably, the compound of formula VI is (3
S
,4
R
)-3-benzyl-7-bromo-chroman-4-ol and said borating agent is borane-tetrahydrofuran complex.
In a further aspect of the invention, the compound of formula VI, or the enantiomer of said compound, wherein R
1
, R
2
and X are as defined above, is prepared by treating a compound of the formula
or the enantiomer of said compound of formula V in the preparation of the enantiomer of the compound of formula VI, wherein R
1
, R
2
and X are as defined above and X is attached at position 4 or 5 of the phenyl ring, and Y is halo or nitro, with a base, optionally in the presence of added copper salts.
In said process of making the compound of formula VI, or the enantiomer of said compound, preferred substituents for R
1
, R
2
and X are as stated above for said process of making the compound of formula VII. In another preferred embodiment, Y is halo, and said base is potassium tert-butoxide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, cesium carbonate, or sodium hydride. Most preferably, said base is potassium tert-butoxide and the compound of formula V is (1
S
,2
R
)-2-benzyl-1-(4-bromo-2-fluoro-phenyl)-propane-1,3-diol.
In a further aspect of the invention, the compound of formula V, or the enantiomer of said compound, wherein R
1
, R
2
, X and Y are as defined above, is prepared by treating a compound of the formula
or the enantiomer of said compound of formula IV in the preparation of the enantiomer of the compound of formula V, wherein R
1
, R
2
, X and Y are as defined above and X is attached at position 4 or 5 of the phenyl ring, and X
c
is a chiral auxiliary, with a hydride reducing agent.
In said process of making the compound of formula V, or the enantiomer of said compound, preferred substituents for R
1
, R
2
, X and Y are as stated above for said process of making the compound of formu

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