Process for forming an N-acylated, N,N-containing bicyclic...

Details Process for forming an N-acylated, N,N-containing bicyclic... Process for forming an N-acylated, N,N-containing bicyclic...

1998-08-19

2001-03-13

Gerstl, Robert (Department: 1626)

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

Organic compounds

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

Reexamination Certificate

active

06201118

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
The invention relates to a process for simultaneously N(2)-acylating piperazic acid or an ester thereof and forming a bicyclic ring structure. The invention also relates to the use of that process step in a method of synthesizing a bicyclic compound useful as an intermediate for the production of an inhibitor of a caspase, particularly an inhibitor of interleukin-1&bgr; converting enzyme (“ICE”).
BACKGROUND OF THE INVENTION
Compounds containing a bicyclic aza-containing ring systems have been prepared as conformationally restricted dipeptide surrogates for a variety of medically important compounds. In particular, such ring systems are present in angiotensin converting enzyme (ACE) inhibitors, such as Cilazapril®, and in caspase inhibitors, such as inhibitors of interleukin-1 converting enzyme (ICE).
Current methods for synthesizing compounds containing these byciclic aza-containing ring systems have many disadvantages. The typical methods of forming this ring system have been described [EP 94,095, WO 95/35308, WO 97/22619, U.S. Pat. Nos. 5,656,627, 5,716,929 and 5,756,486 and J. P. Kim, et al.,
Tetrahedron Letters,
38, pp. 4935-4938 (1997)].
These methods involve coupling an appropriately protected amino acid with the appropriately N(1)-protected piperazic acid or ester. After deprotection, the bicyclic system is then formed via an acid chloride coupling at the N(1) position.
The main disadvantages to such methods are the use of expensive reagents and the number of steps required for protection and deprotection making the overall process extremely time consuming. Moreover, these methods are often useful for research purposes but are not amenable to large scale production.
In order to be more commercially feasible, it would be desirable to produce compounds containing a byciclic aza-containing ring system in an easier, less expensive manner than has been previously described.
SUMMARY OF THE INVENTION
Applicant has solved this problem by providing a new method of simultaneously N(2)-acylating an N(1)-protected piperazic acid or an ester thereof and creating a bicyclic ring structure comprising that acylated piperazic acid or ester.
This method involves the formation of the desired bicyclic system in two, simple steps. This method also utilizes inexpensive reagents, in that no selective protection/deprotection is necessary and is quite amenable to large scale production. Moreover, this method produces very little contaminating by-products. And this method preserves chirality between the N(1)-protected piperazic acid or an ester thereof and the resulting byciclic aza-containing ring system.
This method is particularly useful for producing an intermediate that may be subsequently converted into a caspase inhibitor, particularly an inhibitor of ICE, through additional steps known in the art.
DETAILED DESCRIPTION OF THE INVENTION
The following abbreviations are used throughout this application:
According to one embodiment, the invention provides a process for converting compound G to compound H:
wherein:
R
1
is a C2-C4 straight chain alkly optionally substituted at any carbon with one or more substituents selected from C1-C6 straight or branched alkyl, C2-C6 straight or branched alkenyl or alkynyl, O—C1-C6 straight or branched alkyl, O—C2-C6 straight or branched alkenyl or alkynyl, oxo, halo, NO
2
, N(R
4
)(R
4
), CN, Ar or O—Ar;
R
2
is selected from hydrogen, C1-C
6
straight or branched alkyl, C2-C6 straight or branched alkenyl or alkynyl or Ar, wherein said alkyl, alkenyl or alkynyl is optionally substituted with Ar;
n is 0 or 1;
Ar is a saturated, partially saturated or unsaturated monocyclic or bicyclic ring structure, wherein each ring contains 5 to 7 ring atoms and each ring optionally contains from 1 to 3 heteroatoms selected from O, N and S;
wherein Ar is optionally substituted at one or more ring atoms with one or more substituents independently selected from C1-C6 straight or branched alkyl, C2-C6 straight or branched alkenyl or alkynyl, O—C1-C6 straight or branched alkyl, O—C2-C6 straight or branched alkenyl or alkynyl, oxo, halo, NO
2
, N(R
4
)(R
4
), CN, Ar
1
, O—Ar
1
; wherein
Ar
1
is a saturated, partially saturated or unsaturated monocyclic or bicyclic ring structure, wherein each ring contains 5 to 7 ring atoms and each ring optionally contains from 1 to 3 heteroatoms selected from O, N and S; and
each R
4
is independently selected from H or an amino protecting group, with the proviso that both R
4
are not simultaneously hydrogen.
The term “amino protecting group”, as used herein, means a moiety that prevents chemical reactions from occurring on the nitrogen atom to which that protecting group is attached. An amino protecting group must also be removable by a chemical reaction.
In one preferred embodiment, R
1
is substituted at the terminal carbon bound to the —COOH moiety with a protected amine. The term “protected amine” as used herein, means a nitrogen-containing moiety which can be chemically modified to an amine.
In another preferred embodiment, R
1
is substituted at the other terminal carbon (i.e., the one bound to the ring nitrogen) with oxo, making R
1
an acyl-containing moiety. More preferred is when R
1
contains both the protected amine substituent and the oxo substituent. One of the most preferred R
1
groups is:
In another preferred embodiment, n is 1.
In yet another preferred embodiment, R
2
is t-butyl.
The method of this invention comprises the steps of:
(a) dissolving compound G in an organic solvent selected from dichloroethane, dichloromethane, toluene, chlorobenzene, chloroform or CCl
4
;
(b) adjusting the temperature of the resulting solution to between 20° C. and 100° C.; and
(c) adding more than about 2 equivalents of SOCl
2
and less than about 0.2 equivalents of N,N-Dimethylformamide to said solution over a period of between 2 and 18 hours.
Not all organic solvents may be used to dissolve compound G in step (a). The list of solvents set forth above are known to work. Other similar organic solvents may also work in the reaction and are to be considered part of the present invention. Preferably, the organic solvent is toluene.
Step (b) is preferably carried out at about 70° C. In step (c), it is preferred to use about 2 equivalents of SOCl
2
and about 0.1 equivalent of N,N-Dimethylformamide (“DMF”). It is also preferred that those two reagents be added slowly over a period of about 2 hours. Addition of the SOCl
2
and DMF over less than 2 hours tends to drastically reduce the efficiency of the reaction.
According to a preferred embodiment, excess equivalents of a base are added prior to step (b). In one preferred embodiment, about 5 equivalents of base are added to the reaction. Preferably, the base is selected from pyridine, collidine, lutidine, NaHCO
3
, imidazole, triethylamine, N-methylmorpholine, diisopropylethylamine or K
2
CO
3
. Most preferably, the base is 2,6-lutidine.
Once the SOCl
2
and DMF have been added, the reaction is complete. At that point we prefer to purify compound H by diluting the reaction with the organic solvent used to dissolve compound G and then washing the solution first with NaHCO
3
and then with brine. The solution is then dried over Na
2
SO
4
and concentrated.
Starting compound G may be obtained through standard synthetic routes well-known in the art. One such route is depicted below. Scheme 1 depicts the creation of intermediate E.
In Scheme 1, “Hal” is any halogen; each R′ is an independently selected carboxyl protecting group; and n and R
2
are as defined above. Each of these steps is well-known in the art. Specifics concerning the conditions and reagents used at each step are set forth in the Examples.
The conversion of intermediate E to compound G is set forth in Scheme 2, below. That conversion may be achieved in one of two ways in the Scheme 2, depending upon the nature of R
1
.
In Scheme 2, m is 0, 1 or 2; and R′, R
1
and R
2
are as defined above. Also, in compound F any of the unsubstituted ring carbon atoms may be optionally

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