Process to prepare (5R)-(methylamino)-5,...

Details Process to prepare (5R)-(methylamino)-5,... Process to prepare (5R)-(methylamino)-5,...

2001-08-22

2003-07-01

Huang, Evelyn Mei (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S084000

Reexamination Certificate

active

06586595

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is a process and intermediates to produce a pharmaceutically useful compound, (5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (VII).
2. Description of the Related Art
U.S. Pat. No. 5,273,975 discloses a genus which includes (5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one. (5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (VII) can be made by the process disclosed in U.S. Pat. No. 5,273,975.
U.S. Pat. No. 5,652,245 discloses a process to to produce heterocyclic amines similar to those of U.S. Pat. No. 5,273,975. In addition, it discloses a process which can be used to make (5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (VII).
SUMMARY OF INVENTION
Disclosed is a tricyclic compound of formula (II) where R
N
is selected from the group consisting of:
(A) &phgr;-CH
2
— where phenyl is optionally substituted with 1 or 2: (1) C
1
-C
4
alkoxy, (2) F—, (3) Cl—, (4) Br—, (5) I—, (6) C
1
-C
4
alkyl,
(B) R
N1
—CH
2
—O—CH
2
— where R
N1
is selected from the group consisting of:
(1) &phgr;-optionally substituted with: (a) C
1
-C
4
alkyl, (b) F—, (c) Cl—, (d) Br—, (e) I—, (f) C
1
-C
4
alkoxy,
(2) (CH
3
)
3
Si—CH
2
—,
(3) R
N2
—O—CH
2
— where R
N2
is C
1
-C
4
alkyl,
(4) CH
2
═CH—,
(5) —H,
(6) C
1
-C
4
alkyl;
(C) an unsaturated compound selected from the group consisting of: (1) CH
2
═CH—CH
2
—, (2) CH
3
—CH═CH—CH
2
— and (3) &phgr;-CH═CH—CH
2
—.
Also disclosed is a hydroxy compound of formula (III) where R
N
is as defined above and where R
X
is selected from the group consisting of —Br, —Cl and —I.
Further, disclosed is an ester of formula (IV) where R
N
is as defined above.
Additionally disclosed is the hydroxy-amino compound of formula (V) where R
N
is as defined above.
Disclosed is the tetracyclic compound of formula (VI) where R
N
is as defined above.
DETAILED DESCRIPTION OF THE INVENTION
(5R)-(Methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (VII) is known to be useful a a pharmaceuical agent, see U.S. Pat. No. 5,273,975. Because the compound has an enantiomeric center it is difficult to prepare this compound optically pure. One can produce the compound in racemic form and then resolve it by known means.
The invention here is a stereoselective synthetic process to preapre (5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (VII) which produces the desired enantiomer utilizing resolution of diastereomers. The material which is lost, is recycled back to the starting material (1).
The process of the present invention is the same regardless of which of the variable substituents R
N
and R
X
are utilized with the exception of how the R
N
protective group is removed. This is well known to those skilled in the art.
The starting material, 1,2-dihydro-4H-imidazo[5,4-1-ij]quinolin-2-one (I) is known, see
J. Heterocyclic Chem.,
19, 837-49 (1982). The unsubstituted tricyclic amide (I) is transformed to the corresponding tricyclic amide (II) by means well known to those skilled in the art for transformation of an amide to a substituted amide. The tricylic amide (II) requires the amide nitrogen atom be protected by R
N
. Operable R
N
groups include:
(A) &phgr;-CH
2
— where phenyl is optionally substituted with 1 or 2:
(1) C
1
-C
4
alkoxy, (2) F—, (3) Cl—, (4) Br—, (5) I—, (6) C
1
-C
4
alkyl,
(B) R
N1
—CH
2
—O—CH
2
— where R
N1
is selected from the group consisting of:
(1) &phgr; optionally substituted with:
(a) C
1
-C
4
alkyl, (b) F—, (c) Cl—, (d) Br—, (e) I—, (f) C
1
-C
4
alkoxy,
(2) (CH
3
)
3
Si—CH
2
—,
(3) R
N2
—O—CH
2
— where R
N2
is C
1
-C
4
alkyl,
(4) CH
2
═CH—
(5) —H,
(6) C
1
-C
4
alkyl;
(C) an unsaturated compound selected from the group consisting of:
(1) CH
2
═CH—CH
2
—, (2) CH
3
—CH═CH—CH
2
— and (3) &phgr;-CH═CH—CH
2
—.
It is preferred that R
N
be &phgr;-CH
2
—.
When the R
N
protecting group is &phgr;-CH
2
— optionally substituted with (A) &phgr;-CH
2
— where phenyl is optionally substituted with 1 or 2 C
1
-C
4
alkoxy, F—, Cl—, Br—, I— and C
1
-C
4
alkyl, this protecting group is removed by use of metal/ammonia at the same time the aziridine (VI) is opened. When the R
N
protecting group is non-benzyl, such as (CH
3
)
3
Si—CH
2
— this group is removed with fluoride ion or strong acid. When the R
N
protecting group is non-benzyl, non-silyl, such as R
N2
—O—CH
2
— where R
N2
is C
1
-C
4
alkyl this group is removed by Lewis acid such as zinc chloride or Bronsted acid. When the R
N
protecting group is an unsaturated non-benzyl, such as CH
2
═CH— this group is removed by palladium catalysis in the presence of a nucleophile. All of these removal methods are well known to those skilled in the art, see for example, Protective Groups In Organic Synthesis, Wiley & Sons, 1991.
The tricyclic amide (II) is transformed to the corresponding hydroxy compound (III) by reaction with an agent which can produce a halohydrin (III). Suitable agents include dibromantin (or its equivalent with other than bromine when R
X
is other than —Br). Operable R
X
include —Cl, —Br and —I; it is preferred that R
X
be —Br. It is preferred to use an aprotic solvent such as acetonitrile, a catalytic amount of fluoboric acid at a low temperature of about 0°; see EXAMPLE 2.
The optically impure hydroxy compound (III) is reacted with the acid chloride, naproxen chloride (PREPARATION I), to form diastereoisomeric esters (IVA) and (IVB); see EXAMPLE 3. The isomer that will produce the desired product (VII), is ester (IVA), The ester (IVB) is useful because it can be readily transformed back to the tricyclic compound (II), by known means, and be recycled.
The ester (IVA) is then converted to the corresponding hydroxy-amino compound (V) by the process of EXAMPLE 4.
The hydroxy-amino compound (V) is transformed to the corresponding tetracyclic compound (VI) by a multi-step reaction. First the hydroxy-amino compound (V) is contacted with a strong base. Preferred strong bases are alkyl lithium reagents (such as butyllithium, methyllithium), potassium hexamethyldisilazide and lithium diisopropylamide. Following the contacting with a strong base, the reaction mixture of step (1) is contacted with a compound of the formula R
S
—SO
2
—X where R
S
is phenyl and substituted phenyl and where X is —Cl or —Br. It is preferred that R
S
is phenyl or tolyl. The final step is quenching with a weak base. Suitable weak bases include bicarbonate, carbonate, (phosphate) buffers and hydroxide; preferred is bicarbonate. The preferred process is exemplified in EXAMPLE 5.
The tetracyclic compound (VI) is transformed to the corresponding methylamine (VII) by the process of EXAMPLE 6. The nature of this cleavage reaction depends on the particular R
N
attached to the tetracyclic compound (VI). This reaction is either a metal ammonia reduction or a metal catalyzed hydrogenolysis. This process opens the aziridine ring.
The methylamine (VII) is transformed to the desired (maleic) salt by the process of EXAMPLE 7.
The methylamine (VII), and its pharmaceutically acceptable salts, are known to be useful as a pharmaceutical agent in treating those individuals who have Parkinson's Disease, see U.S. Pat. No. 5,273,975.
It is preferred that the maleic salt (VII) be administered in the pharmaceutical dosage form describe in U.S. patent application Ser. No. 09/146,090.
The exact dosage and frequency of administration depends on the severity of the condition being treated, the age, weight, general physical condition of the particular patient, other medication the individual may be taking as is well known to those skilled in the art and can be more accurately determined by measuring the blood level or concentration of the methylamine (VI) and its metabolites in the patient's blood and/or the patient's response.
DEFINITIONS AND CONVENTIONS
The definitions and explanations below are for the terms as used throughout

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