Processes and intermediates for preparing...

Details Processes and intermediates for preparing... Processes and intermediates for preparing...

2000-05-05

2002-06-25

Stockton, Laura L. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06410750

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel processes for preparing 3(S)-[(5-chloro-1H-indole-2-carbonyl)-amino]-2(R)-hydroxy-4-phenyl-butyric acid, which can be further reacted to form compounds which possess glycogen phosphorylase inhibitory activity. Also provided are novel intermediates used in those processes. These glycogen phosphorylase inhibitors are useful in the treatment of mammals, especially human beings, having glycogen phosphorylase dependent diseases or conditions including hypercholesterolemia, hyperglycemia, hyperinsulinemias, hyperlipidemia, hypertension, atherosclerosis, diabetes and myocardial ischemia.
BACKGROUND OF THE INVENTION
International PCT Application Numbers PCT/IB95/00443 published as WO 96/39385 and PCT/IB95/00442 published as WO 96/39384, counterpart U.S. Pat. No. 6,107,329, disclose novel substituted N-(indole-2-carbonyl)-amides, derivatives and intermediates including 3(S)-[(5-chloro- I H-indole-2-carbonyl)-amino]-2(R)-hydroxy-4-phenyl-butyric acid, processes for preparing such compounds, pharmaceutical compositions comprising such compounds or derivatives, and methods of treating glycogen phosphorylase dependent diseases or conditions by administering such compounds or derivatives.
As disclosed thereby, 3(S)-[(5-chloro-1H-indole-2-carbonyl)-amino]-2(R)-hydroxy-4-phenyl-butyric acid can be prepared by coupling an acid chloride with an amino acid to yield an ester of 3(S)-[(5-chloro-1H-indole-2-carbonyl)-amino]-2(R)-hydroxy-4-phenyl-butyric acid, which can then be deprotected by aqueous alkaline hydrolysis to yield the corresponding acid.
The present invention provides novel processes for preparing 3(S)-[(5-chloro-1H-indole-2-carbonyl)-amino]-2(R)-hydroxy-4-phenyl-butyric acid which utilize two fewer steps than the prior art processes referred to above which, in turn, provides for a quicker, easier and less costly method of production. The presently disclosed processes generate as few as two intermediates which need not be isolated, and a single isolation provides 3(S)-[(5-chloro-1H-indole-2-carbonyl)-amino]-2(R)-hydroxy-4-phenyl-butyric acid. Further, this product need not be isolated either, i.e., it may be carried on, as disclosed, for example, in the aforementioned WO 96/39385 and/or WO 96/39384, to form glycogen phosphorylase inhibitors disclosed therein.
All of the documents cited herein, including the foregoing, are incorporated by reference herein in their entireties.
SUMMARY OF THE INVENTION
The present invention relates to novel processes for preparing 3(S)-[(5-chloro-1H-indole-2-carbonyl)-amino]-2(R)-hydroxy-4-phenyl-butyric acid.
The present invention also relates to novel intermediates generated during the processes of this invention.
In a first aspect, this invention provides processes for preparing 3(S)-[(5-chloro-1H-indole-2-carbonyl)-amino]-2(R)-hydroxy-4-phenyl-butyric acid, the compound of Formula 6
which comprise the steps of:
preparing a solution comprising the compound of Formula 2
comprising, in sequence, adding the compound of Formula 1
to an aprotic solvent A, adding an amount of a catalytic aprotic solvent with agitation under an inert gas, and adding an activating agent;
preparing the compound of Formula 4
where M
+
is any monovalent cation from the compound of Formula 3
comprising, in sequence, adding the compound of Formula 3 and a base to a mixture of an aprotic solvent B and a protic solvent, at a temperature of from about −20° C. to about the reflux temperature of said mixture, and maintaining the pH of said mixture at from about pH 8 to about pH 13;
preparing the compound of Formula 5 by coupling said compounds of Formulae 2 and 4
comprising, in sequence, adding said solution to said mixture, under an inert gas, while maintaining said temperature and, after said addition is complete, allowing said mixture to reach room temperature;
adding an amount of an organic solvent to said mixture; and
extracting said compound of Formula 6 into said organic solvent comprising, in sequence, separating the aqueous layer A and the organic layer A, treating said organic layer A with an aqueous acid solution, or with an aqueous acid solution and H
2
O, separating the aqueous layer B from the organic layer B, and retaining said organic layer B;
provided that, when M
+
is N(C
1
-C
6
alkyl)
4
+
, tetra-C
1
-C
6
alkylammonium halide is added to said mixture after said base.
In a preferred embodiment of said first aspect, said aprotic solvent A and said aprotic solvent B are each independently THF, toluene, or CH
2
Cl
2
. Aprotic solvent A and aprotic solvent B are each preferably toluene.
In another preferred embodiment of said first aspect, said catalytic aprotic solvent is DMF.
In another preferred embodiment of said first aspect, said inert gas is N
2
.
In another preferred embodiment of said first aspect, said activating agent is oxalyl chloride or thionyl chloride. Thionyl chloride is a particularly preferred activating agent. In a preferred embodiment wherein said activating agent is thionyl chloride, said addition is completed after about 16 h.
In another preferred embodiment of said first aspect, said M
+
is Li
+
, Na
+
, K
+
, Cs
+
or tetra-C
1
-C
6
alkylammonium. A particularly preferred M
+
is Na
+
, K
+
, or NBu
4
+
. An especially preferred M
+
is K
+
. A particularly preferred tetra-C
1
-C
6
alkylammonium halide is TBAB.
In another preferred embodiment of said first aspect, said base is sodium bicarbonate, sodium hydroxide, sodium phosphate, potassium carbonate, dibasic potassium phosphate or tribasic potassium phosphate. Particularly preferred bases include sodium bicarbonate, potassium bicarbonate and tribasic potassium phosphate. Tribasic potassium phosphate is an especially preferred base. In a preferred embodiment wherein said base is potassium carbonate, said M
+
is NBu
4
+
and said tetra-C
1
-C
6
alkylammonium halide is TBAB. In a preferred embodiment wherein said base is sodium bicarbonate, said M
+
is Na
+
. In a preferred embodiment wherein said base is sodium bicarbonate and said M
+
is Na
+
, said aprotic solvent B is THF, said protic solvent is H
2
O, and said temperature is about 65° C. In a preferred embodiment wherein said base is tribasic potassium phosphate, said M
+
is K
+
. In a preferred embodiment wherein said base is tribasic potassium phosphate and said M
+
is K
+
, said aprotic solvent B is THF, said protic solvent is H
2
O, and said temperature is about −5° C.
In another preferred embodiment of said first aspect, said protic solvent is H
2
O or ROH where R is C
1
-C
4
alkyl. Particularly preferred protic solvents include H
2
O and MeOH. An especially preferred protic solvent is H
2
O.
In another preferred embodiment of said first aspect, said pH is maintained by said base.
In another preferred embodiment of said first aspect, said pH is from about pH 11 to about pH 13.
In another preferred embodiment of said first aspect, said organic solvent is EtOAc or CH
2
Cl
2
. A particularly preferred organic solvent is CH
2
Cl
2
.
In another preferred embodiment of said first aspect, said aqueous acid solution is aqueous HCl or aqueous H
2
SO
4
. A particularly preferred aqueous acid solution is aqueous HCl.
In another preferred embodiment of said first aspect, said retained organic layer B is concentrated, displaced into hexanes or heptanes, granulated in said hexanes or said heptanes for a period of time under an inert gas, and the resultant slurry is filtered and the retenate (comprising the compound of Formula 6) is dried. A preferred period of time is overnight. A preferred inert gas is N
2
.
In another preferred embodiment of said first aspect, said compound of Formula 2 is isolated before its addition to said mixture, dissolved in an aprotic solvent C, and added to said mixture by adding said aprotic solvent C comprising said compound of Formula 2 to

Affiliated with

Also associated with

Rating

Processes and intermediates for preparing... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Processes and intermediates for preparing..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Processes and intermediates for preparing... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2900933