Process for preparing certain substituted caprolactams

Details Process for preparing certain substituted caprolactams Process for preparing certain substituted caprolactams

2002-03-11

2003-04-08

Kifle, Bruck (Department: 1624)

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

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

C540S526000

Reexamination Certificate

active

06545148

ABSTRACT:

The present invention relates to a process for preparing certain substituted caprolactams.
FIELD OF INVENTION
The present invention relates to the area of synthetic methodology and, more particularly, to a process for preparing certain substituted caprolactams.
BACKGROUND OF THE INVENTION
Marine organisms provide a potential source of biologically active compounds, including compounds which are potentially useful as anti-tumor agents. For example, U.S. Pat. No. 4,831,135 discloses certain bengamide compounds which were isolated by extraction from the Jaspidae marine sponge family native to the waters surrounding the Fiji islands and which exhibit anti-tumor, antibiotic and anthelmintic properties. In fact, the chemistry of Jaspidae sponges has been the subject of numerous publications over the last 10 years.
More recently, WO 00/29382 discloses certain analogs of the bengamides disclosed in the above-mentioned U.S. patent, which analogs are useful in treating various types of tumors. Although WO 00/29382 discloses a suitable process for preparing all of the analogs disclosed therein, their ever-growing importance has resulted in a need for a more practical and commercially acceptable synthesis.
SUMMARY OF THE INVENTION
The present invention relates to an improved process for preparing certain substituted caprolactams. The process of the present invention is believed to be more practical and commercially acceptable than the process disclosed in WO 00/29382 since it is carried out under more mild reaction conditions and results in an easier work-up of the desired compounds. More particularly, the process of the instant invention involves the acylation of an aminocaprolactam compound with a lactone compound in the presence of a weak base and a polar, organic solvent, and the hydrolysis of the 1,3-dioxane group of the resulting diamide compound to obtain the desired substituted caprolactam compound.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for preparing certain substituted caprolactams of formula I:
where
R
1
is (C
1-6
)alkyl or (C
3-6
)cycloalkyl;
R
2
is hydrogen or (C
1-6
)alkyl;
X is (C
1-12
) alkylene; (C
2-12
) alkenylene; or (C
2-12
) alkynylene;
m is 0 or 1; and
R
3
is (C
3-8
)cycloalkyl; or an aromatic ring system selected from II, III, IV and V:
 where
R
4
is hydrogen, chloro, or methoxy;
R
5
is hydrogen, chloro, (C
1-18
)alkyl or (C
1-18
)alkoxy; and Z is oxygen, sulfur, N—H, or N—CH
3
;
or a pharmaceutically acceptable acid addition salt thereof, where possible. More particularly, the substituted caprolactam compounds of formula I are prepared by a two-step process as depicted below:
where each R
1
, R
2
, X, m and R
3
is as defined above.
As to the individual steps, Step A involves the acylation of an aminocaprolactam compound of formula VI, or an acid addition salt thereof, with a lactone compound of formula VII to obtain a diamide compound of formula VIII. The acylation is conducted in the presence of: 1) a weak base, preferably a carboxylate salt such as sodium 2-ethylhexanoate, and 2) a polar, organic solvent, preferably a cyclic ether such as tetrahydrofuran, at a temperature of between 0° C. and 50° C., preferably at 25° C., for a period of between 1 hour and 7 days, preferably for 20 hours.
Step B concerns the hydrolysis of the 1,3-dioxane group common to a diamide compound of formula VIII, to obtain the desired substituted caprolactam compound of formula I. The hydrolysis is typically carried out by dissolving the diamide in a mixture of solvents consisting of 1) a protic acid, preferably an organic acid such as trifluoroacetic acid, or an inorganic acid such as hydrochloric acid; 2) a protic solvent, preferably water, and 3) an inert organic solvent, preferably a cyclic ether such as tetrahydrofuran, at a temperature of between 0° C. and 50° C. for a period of between 1 hour and 5 hours.
The aminocaprolactam compounds of formula VI and the lactone compounds of formula VII may be prepared as described in WO 00/29382. As indicated above, an acid addition salt of a compound of formula VI may be utilized in Step A. For example, the compound of Example 1g) of WO 00/29382 can be reacted with HCl to form the corresponding hydrochloride salt form of the compound of Example 1h) of WO 00/29382.
Although the diamide compound that is obtained in Step A described above may, if desired, be purified by conventional techniques such as recrystallization, the crude diamide compound is advantageously employed in Step B described above without purification.
The free base of the compound of formula I may, if desired, be converted into the acid addition salt form, where possible. The acid addition salts of the compounds of formula I may be those of pharmaceutically acceptable organic or inorganic acids. Although the preferred acid addition salts are those of hydrochloric and methanesulfonic acid, salts of sulfuric, phosphoric, citric, fumaric, maleic, benzoic, benzenesulfonic, succinic, tartaric, lactic and acetic acid are also contemplated. Such salts may be obtained by reacting the free base of a compound of formula I with the corresponding acid to obtain the desired acid addition salt form.
As is evident to those skilled in the art, the substituted caprolactam compounds of formula I contain asymmetric carbon atoms. It should be understood, therefore, that the individual stereoisomers are contemplated as being included within the scope of the invention.
Preferred substituted caprolactams which may be prepared by the process of this invention are those of formula I where
R
1
is (C
1-6
)alkyl;
R
2
is hydrogen or (C
1-4
)alkyl;
X is (C
1-6
)alkylene or (C
2-6
)alkynylene;
m is 0 or 1; and
R
3
is (C
3-8
)cycloalkyl; or an aromatic ring system selected from II, III, IV and V where
R
4
is hydrogen, chloro, or methoxy; and
R
5
is hydrogen, chloro, (C
1-18
)alkyl or (C
1-18
)alkoxy; and Z is oxygen, sulfur, N—H, or N—CH
3
;
or a pharmaceutically acceptable acid addition salt thereof, where possible.
More preferred substituted caprolactams which may be prepared by the process of this invention are those of formula I where
R
1
is i-propyl or t-butyl;
R
2
is hydrogen or methyl;
m is 0 or 1;
X is (C
1-6
) alkylene; and
R
3
is (C
5-7
)cycloalkyl; or an aromatic ring system selected from IIa and V:
where
R
4
′ is in the meta position and is hydrogen or chloro; and
R
5′
is in the para position and is hydrogen, chloro, (C
1-18
)alkyl or (C
1-18
)alkoxy;
or a pharmaceutically acceptable acid addition salt thereof, where possible.
Even more preferred substituted caprolactam compounds which may be prepared by the process of this invention are those of formula I where
R
1
is i-propyl or t-butyl;
R
2
is hydrogen or methyl;
m is 0 or 1;
X is methylene or ethylene; and
R
3
is (C
5-7
)cycloalkyl, phenyl, 3,4-dichlorophenyl, 4-methoxyphenyl, 4-n-decylphenyl, 4-n-decyloxyphenyl or 3-pyridyl;
with the proviso that when m is 0, R
3
is (C
5-7
)cycloalkyl, 4-n-decylphenyl or 4-n-decyloxyphenyl;
or a pharmaceutically acceptable acid addition salt thereof, where possible.
The following examples are for purposes of illustration only and are not intended to limit in any way the scope of the instant invention.


REFERENCES:
patent: 4831135 (1989-05-01), Crews et al.
patent: 6239127 (2001-05-01), Kinder, Jr. et al.
patent: WO 00/29382 (2000-05-01), None

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