Method of preparing bicyclic intermediates from piperazic...

Details Method of preparing bicyclic intermediates from piperazic... Method of preparing bicyclic intermediates from piperazic...

2001-02-20

2004-03-09

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

06703500

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
The invention relates to a process for synthesizing piperazic acid and similar, ring-containing acids. The invention also 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 either or both processes 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”).
BACKGOUND OF THE INVENTION
Piperazic acid derivatives are important intermediates in natural product synthesis and in the synthesis of biologically useful non-natural amino acids and peptidomimetics (e.g., inhibitors described in PCT publications WO 97/22619 and WO 95/35308). Several syntheses of piperazic acid and derivatives thereof have been described [Decicco et al.,
Syn. Lett.,
p. 615 (1995); Schmidt et al.,
Synthesis,
p. 223 (1996); Rutjes et al.,
Tetrahedron,
p. 8605 (1993); PCT publications WO 97/22619 and WO 95/35308). In each case however, the synthesis requires multiple steps, utilizes expensive reagents and produces less than desirable yields.
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 the problems indicated above by providing: 1) a new method for synthesizing piperazic acid; and 2) 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.
The first method involves treating a 1,4-dihaloalkyl ester with an N,N′-bis-protected hydrazine dissolved in DMF in the presence of a water scavenger, a metal hydroxide and a phase transfer catalyst. This method produces surprisingly increased yield of the desired protected piperazic acid.
The second method involves the formation of the desired bicyclic system in two, simple steps. This method also utilizes inexpensive reagents, does not require selective protection/deprotection, and is quite amenable to large scale production. Moreover, this method produces very little contaminating by-products. This method also preserves chirality between the N(1)-protected piperazic or similar 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
Some of the abbreviations used throughout the specifications (including in chemical formulae) are:
Bu = butyl Et = ethyl Cbz = carboxybenzyl DMF = N,N-dimethylformamide THF = tetrahydrofuran MTBE = methyl tert-butyl ether DCC = dicyclohexyl carbodiimide EDC = 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride Ac = acetyl.
According to one embodiment, the invention provides a process for producing compound E by reacting compounds C and D:
comprising the steps of:
a) dissolving compounds C and D together in DMF;
b) adding to said solution of C and D:
i) a water scavenger;
ii) a metal hydroxide selected from LiOH, NaOH or KOH; and
iii) a phase transfer catalyst
c) allowing the mixture produced in step b) to react at room temperature for 2 to 48 hours;
d) adding an organic solvent and water to said mixture to create an aqueous phase and an organic phase; and
e) purifying compound E from said organic phase;
wherein:
R
2
is selected from hydrogen, C1-C6 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;
“Hal” is any halogen; and
each R′ is an independently selected carboxyl protecting group
The water scavenger referred to above may be selected from any water scavengers known in the art. These include, but are not limited to, Na
2
SO
4
, MgSO
4
, and molecular sieves. Preferably, the water scavenger is sodium sulfate.
According to another preferred embodiment, the metal hydroxide used in the above method is LiOH.
The phase transfer catalyst referred to in the above method may also be selected from any such catalysts known in the art. These include, but are not limited to, Bu
4
NI, Aliquat 336 (Aldrich Chemicals) and other quartenary ammonium salts. Preferably, the catalyst is Bu
4
NI.
According to another preferred embodiment, n is 1 .
According to yet another preferred embodiment, each Hal is Br.
In yet another preferred embodiment of the method set forth above, R
2
is t-butyl.
In another preferred embodiment, R′ is benzyl.
According to another embodiment, the invention provides a process for converting compound G to compound H:
wherein:
R
1
is a C2-C4 straight chain alkyl 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-C6 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

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