Processes and intermediates for preparing anti-cancer compounds

Details Processes and intermediates for preparing anti-cancer compounds Processes and intermediates for preparing anti-cancer compounds

2000-03-30

2002-11-05

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C544S283000, C544S293000

Reexamination Certificate

active

06476040

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to processes and intermediates for preparing compounds that are useful in the treatment of hyperproliferative disorders, such as cancers, in mammals.
U.S. Pat. No. 5,747,498, which issued on May 5, 1998 and is incorporated herein by reference in its entirety, refers to a novel series of quinazoline derivatives, including [6,7-bis(2-methoxyethoxy)-quinazolin-4-yl]-(3-ethynylphenyl)amine hydrochloride, which are inhibitors of the erbB family of oncogenic and protooncogenic protein tyrosine kinases, such as epidermal growth factor receptor (EGFR), and are therefore useful for the treatment of proliferative disorders, such as cancers, in humans. United States provisional patent application 60/083,441 entitled “N-(3-ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine Mesylate Anhydrate And Monohydrate,” filed Apr. 29, 1998, with named inventors T. Norris, D. Santafianos, D. J. M. Allen, R. M. Shanker, and J. W. Raggon, which is incorporated herein by reference in its entirety, refers to N-(3-ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate anhydrate and hydrate forms which possess the same anti-cancer utility as the corresponding hydrochloride salt referred to above. The present invention relates to methods and intermediates for preparing anti-cancer compounds referred to in the United States patent and patent application referred to above.
SUMMARY OF THE INVENTION
The present invention relates to a process for preparing compounds of the formula
and pharmaceutically acceptable salts and solvates of said compounds, wherein:
R
1
and R
2
are each independently selected from C
1
-C
10
alkyl and C
1
-C
10
alkoxy wherein said alkyl and alkoxy are optionally substituted by up to 2 substituents independently selected from hydroxy and C
1
-C
6
alkoxy;
R
15
is H, C
1
-C
10
alkyl, or —(CH
2
)
q
(C
6
-C
10
aryl), wherein q is an integer from 0 to 4;
which comprises treating a compound of the formula 2
wherein R
15
, R
1
and R
2
are as defined above, and G is a blocking group from —C(OH)R
3
R
4
and —SiR
3
R
4
R
5
;
with either (a) an alkali-metal or alkaline-metal hydroxide in a solvent comprising a hydroxy-substituted C
1
-C
10
alkyl where G is —C(OH)R
3
R
4
, or (b) a tetra-(C
1
-C
6
alkyl)-ammonium fluoride compound in an aprotic solvent where G is —SiR
3
R
4
R
5
.
In a preferred embodiment, where G is —C(OH)R
3
R
4
, said solvent is a secondary alcohol, such as butan-2-ol or isopropanol, and said alkali-metal or alkaline-metal hydroxide is selected from sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide and potassium hydroxide, most preferably sodium hydroxide.
In another preferred embodiment, where G is —SiR
3
R
4
R
5
, said tetra-(C
1
-C
6
alkyl)-ammonium fluoride compound is tetra-(n-butyl)-ammonium fluoride and said aprotic solvent solvent is selected from tetrahydrofuran (THF), diethyl ether, dimethoxyethane (DME), toluene, dichloromethane, chloroform, and mixtures of two or more of the foregoing solvents, most prefereably THF.
The present invention also relates to the preparation of a compound of formula 2, as described above, which comprises treating a compound of the formula 3
wherein R
1
and R
2
are as defined above, with a compound of the formula 4
wherein G and R
15
are as defined for said compound of formula 2.
In a preferred embodiment of the above method, the compound of formula 3 is treated with the compound of formula 4 in an organic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), THF, acetonitrile (MeCN), or a mixture of two or more of the foregoing solvents, more preferably acetonitrile.
The present invention also relates to the preparation of the compound of formula 3, as defined above, which comprises treating a compound of formula 5
with thionyl chloride in anhydrous dichloromethane.
In a preferred embodiment of each of the reactions described above, R
1
and R
2
are both 2-methoxyethoxy and R
15
is H.
The present invention also relates to the preparation of compounds of the formula 6 and 7
and the pharmaceutically acceptable salts and solvates thereof, wherein R
15
is as defined above, R
6
is C
1
-C
10
alkyl or —(CH
2
)
m
O(CH
2
)
n
CH
3
;
R
7
is C
1
-C
10
alkyl or —(C
1
-C
6
alkyl)(C
6
-C
10
aryl) wherein the foregoing R
7
groups are optionally substituted by 1 to 3 substituents independently selected from halo, nitro, trifluoromethyl, trifluoromethoxy, (C
1
-C
6
alkyl)sulfonyl, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
6
-C
10
aryloxy and C
6
-C
10
arylsulfonyl;
each m is independently an integer from 1 to 6, and n is an integer from 0 to 3;
which comprises treating a compound of the formula 8
wherein G
1
is —C(OH)R
3
R
4
, and R
15
, R
6
, R
3
and R
4
are as defined above, with a primary or secondary alcohol of the formula R
7
—OH wherein R
7
is as defined above, in the presence of an alkali-metal or alkaline-metal hydroxide, such as sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide or potassium hydroxide, most preferably sodium hydroxide.
In a preferred embodiment of the above reaction, R
6
is 2-methoxyethoxy and said alcohol of formula R
7
—OH is preferably a secondary alcohol.
The present invention also relates to a method of preparing compounds of the formula
and the pharmaceutically acceptable salts and solvates thereof, wherein R
15
, R
6
and R
7
are as defined above;
R
8
, R
9
and R
10
are each independently selected from H, C
1
-C
10
alkyl, halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —OR
11
, —C(O)R
11
, —C(O)OR
11
, —NR
12
C(O)OR
14
, —OC(O)R
11
, —NR
12
SO
2
R
14
, —SO
2
NR
11
R
12
, —NR
12
C(O)R
11
, —C(O)NR
11
R
12
, —NR
11
R
12
, —S(O)
j
(CH
2
)
q
(C
6
-C
10
aryl), —S(O)
j
(C
1
-C
6
alkyl), wherein j is an integer from 0 to 2, —(CH
2
)
q
(C
6
-C
10
aryl), —O(CH
2
)
q
(C
6
-C
10
aryl), —NR
12
(CH
2
)
q
(C
6
-C
10
aryl), and —(CH
2
)
q
(4-10 membered heterocyclic), wherein q is an integer from 0 to 4; said alkyl group optionally contains 1 or 2 hetero moieties selected from O, —S(O)
j
— wherein j is an integer from 0 to 2, and —N(R
12
)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other; said aryl and heterocyclic groups are optionally fused to a C
6
-C
10
aryl group, a C
5
-C
8
saturated cyclic group, or a 4-10 membered heterocyclic group; and said alkyl, aryl and heterocyclic groups are optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR
12
SO
2
R
14
, —SO
2
NR
11
R
12
, —C(O)R
11
, —C(O)OR
11
, —OC(O)R
11
, —NR
12
C(O)OR
14
, —NR
12
C(O)R
11
, —C(O)NR
11
R
12
, —NR
11
R
12
, —OR
11
, C
1
-C
10
alkyl, —(CH
2
)
q
(C
6
-C
10
aryl), and —(CH
2
)
q
(4-10 membered heterocyclic), wherein q is an integer ranging from 0 to 4;
each R
11
is independently selected from H, C
1
-C
10
alkyl, —(CH
2
)
q
(C
6
-C
10
aryl), and —(CH
2
)
q
(4-10 membered heterocyclic), wherein q is an integer ranging from 0 to 4; said alkyl group optionally includes 1 or 2 hetero moieties selected from O, —S(O)
j
— wherein j is an integer from 0 to 2, and —N(R
12
)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other; said aryl and heterocyclic R
11
groups are optionally fused to a C
6
-C
10
aryl group, a C
5
-C
8
saturated cyclic group, or a 4-10 membered heterocyclic group; and the foregoing R
11
substituents, except H, are optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —C(O)R
12
, —C(O)OR
12
, —OC(O)R
12
, —NR
12
C(O)R
13
, —C(O)NR
12
R
13
, —NR
12
R
13
, hydroxy, C
1
-C
6
alkyl, and C
1
-C
6
alkoxy;
each R
12
and R
13
is independently H or C
1
-C
6
alkyl; and,
R
14
is selected from the substituents provided in the definition of R
11
except R
14
is not H;
which c

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