Process for the preparation of farnesyltransferase inhibitors

Details Process for the preparation of farnesyltransferase inhibitors Process for the preparation of farnesyltransferase inhibitors

1999-10-05

2001-06-19

Killos, Paul J. (Department: 1623)

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

Organic compounds

Carboxylic acid esters

C560S102000, C562S450000, C562S492000, C562S856000

Reexamination Certificate

active

06248919

ABSTRACT:

TECHNICAL FIELD
The instant invention relates to a process for the preparation of farnesyltransferase inhibitors.
BACKGROUND OF THE INVENTION
Ras oncogenes are the most frequently identified activated oncogenes in human tumors. Transformed protein Ras is involved in the proliferation of cancer cells. Ras must be farnesylated before this proliferation can occur. Farnesylation of Ras by farnesyl pyrophosphate is effected by farnesyltransferase. Inhibition of farnesyltransferase and, thereby, of farnesylation of the Ras protein, blocks the ability of transformed cells to proliferate. Therefore, there is a need for compounds which are inhibitors of farnesyltransferase.
The large scale production of farnesyltransferase inhibitors requires chemical syntheses which avoid complicating factors such as use of high cost reagents, chemicals which require special handling, lengthy multi-step synthetic sequences, chromatography of intermediates, and low-yielding steps. An effective strategy to lower the cost associated with multi-step processes is the reduction in the number of steps required to complete the synthesis by combining several steps into a “single pot,” thereby forming a continuous process. However, running multiple steps in a single reaction vessel or without purification of intermediates poses a challenge due to competing side reactions, solvent incompatibilities, and purification difficulties.
The instant invention discloses a novel synthesis of farnesyltransferase inhibitors which allows multiple reaction steps in a single reaction vessel without isolation of intermediates. In addition, this invention provides a process that avoids costly chromatography of the intermediates and products.
SUMMARY OF THE INVENTION
In its principle embodiment, the instant invention discloses a process for preparing a compound of structural formula (I)
or a pharmaceutically acceptable salt or prodrug thereof, wherein
R
1
is methyl, ethyl, propyl, iso-propyl, halo, or haloalkyl;
one of R
4
or R
5
is hydrogen or alkyl, and the other is alkenyl, alkoxyalkyl, alkoxyarylalkyl, alkoxycarbonylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkyl, alkynyl, aminoalkyl, aminocarbonylalkyl, aminothiocarbonylalkyl, aryl, arylalkyl, carboxyalkyl, cyanoalkyl, cycloalkylalkoxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylsulfinylalkyl, cycloalkylsulfonylalkyl, (heterocycle)alkyl, hydroxyalkyl, hydroxyarylalkyl, sulfhydrylalkyl, thioalkoxyalkyl optionally substituted with one, two, or three halo substituents, or thiocycloalkoxyalkyl;
R
6
is hydrogen or a carboxy protecting group; and
R
7
and R
8
are independently hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, or (heterocycle)alkyl;
wherein, at each occurence, the aryl and the heterocycle can be optionally substituted with one, two, three, four, or five substituents independently selected from alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, (heterocycle)alkyl, carboxaldehyde, azido, nitro, amino, cyano, hydroxy, sulfhydryl, and —L
1
—R
6
,
wherein L
1
is —C(X)—, —S(O)
t
—, —NR
12
—, —O—, —X′C(X)—, —C(X)X′—, —N(R
12
)C(O)N(R
12
)—, —N(R
12
)C(X)—, —C(X)N(R
12
)—, —NR
12
S(O)
t
—, or —S(O)
t
NR
12
—; and
wherein R
6
and R
12
are independently hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, or (heterocycle)alkyl; and
wherein X and X′ are independently O or S, and
wherein t is zero, one, or two,
the process comprising,
(a) reacting a compound of structural formula
wherein B
1
is diazonium tetrafluoroborate, chloride, bromide, iodide, methylsulfonate, or trifluoromethylsulfonate; and R
2
and R
3
are independently alkyl, arylalkyl, cycloalkyl, or haloalkyl with a compound of structural formula
wherein R
1
is defined above, and B
2
is —Sn(alkyl)
3
, or —B(OR
9
)(OR
10
), wherein R
9
and R
10
are hydrogen or alkyl, or R
10
and R
11
, together with the oxygen atoms to which they are attached, are alkylene, wherein the alkylene can be optionally substituted with one, two, three, or four alkyl substituents, in the presence of a catalyst and a first base, to provide a first intermediate of structural formula
(b) reacting the first intermediate with a second base in a second solvent system, the second solvent system comprising water and an organic component, to provide a second intermediate of structural formula
(c) reacting the second intermediate with a reducing agent to provide a third intermediate of structural formula
(d) reacting the third intermediate with a hydrolyzing agent to provide a fourth intermediate of structural formula
(e) reacting the fourth intermediate compound with first halogenating agent to provide a fifth intermediate of structural formula
wherein X
1
is halo;
(f) reacting the fifth intermediate compound with a second halogenating agent to provide a sixth intermediate of structural formula
wherein X
2
is halo;
(g) reacting the sixth intermediate with a compound of structural formula
in the presence of a third base to provide a seventh intermediate of structural formula
(h) reacting the seventh intermediate with HN(R
7
)(R
8
) in the presence of the third base to provide the compound of structural formula (I), wherein R
6
is a carboxy-protecting group; and
(i) reacting the compound of formula (I) with the second base to provide the compound of structural formula (I), wherein R
6
is hydrogen.
In another embodiment of the instant invention is disclosed a process for preparing (2S)-2-(((5-((butyl(2-cyclohexylethyl)amino)methyl)-2′-methyl(1,1′-biphenyl)-2-yl)carbonyl)amino)-4-(methylsulfanyl)butanoic acid, or a pharmaceutically acceptable salt or prodrug thereof.
In yet another embodiment of the instant invention is disclosed a process for preparing a compound of structural formula (II)
wherein
R
1
is methyl, ethyl, propyl, iso-propyl, halo, or haloalkyl;
R
11
is carboxy, halocarbonyl, or alkoxycarbonyl, wherein the alkoxycarbonyl can be optionally substituted with cycloalkyl, aryl, or halo; and
R
12
is alkoxycarbonyl, wherein the alkoxycarbonyl can be optionally substituted with cycloalkyl, aryl, or halo, carboxy, hydroxymethyl, halomethyl, or —CH
2
OSO
2
R
4
, wherein R
4
is alkyl, haloalkyl, or phenyl, wherein the phenyl can be optionally substituted with one, two, or three substituents independently selected from halo, nitro, alkyl, or haloalkyl,
the process comprising:
(a) reacting a compound of structural formula
wherein B
1
is diazonium tetrafluoroborate, chloride, bromide, iodide, methylsulfonate, or trifluoromethylsulfonate; and R
2
and R
3
are independently alkyl, arylalkyl, cycloalkyl, or haloalkyl with a compound of structural formula
wherein R
1
is defined above, and B
2
is —Sn(alkyl)
3
, or —B(OR
9
)(OR
10
), wherein R
9
and R
10
are hydrogen or alkyl, or R
10
and R
11
, together with the oxygen atoms to which they are attached, are alkylene, wherein the alkylene can be optionally substituted with one, two, three, or four alkyl substituents, in the presence of a catalyst and a first base, to provide a first intermediate of structural formula
(b) optionally reacting the first intermediate with a second base in a second solvent system, the second solvent system comprising water and an organic component, to provide a second intermediate of structural formula
(c) optionally reacting the second intermediate with a reducing agent to provide a third intermediate of structural formula
(d) optionally reacting the third intermediate with a hydrolyzing agent to provide a fourth intermediate of structural formula
(e) optionally reacting the fourth intermediate compound with an activating agent optionally in the presence of a third base to provide a fifth intermediate of structural formula
wherein X
3
is halo or —OSO
2
R
4
;
(f) optionally reacting the fifth intermediate compound with a second halogenating agent to provide a sixth intermediate of structural formula
wherein X
2
is halo.
In still yet another embodiment of the instant invention ar

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