Process for preparing toluenesulfinates

Details Process for preparing toluenesulfinates Process for preparing toluenesulfinates

2003-01-24

2003-09-09

McKane, Joseph K. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S143000, C548S203000, C548S214000, C548S314700

Reexamination Certificate

active

06617460

ABSTRACT:

This invention relates to a process for preparing certain 1H-indole-3-glyoxamides useful for inhibiting sPLA
2
mediated release of fatty acids for conditions such as septic shock and intermediates useful in the preparation of such compounds.
Certain 1H-indole-3-glyoxamides are known to be potent and selective inhibitors of mammalian sPLA
2
useful for treating diseases, such as septic shock, adult respiratory distress syndrome, pancreatitis, trauma, bronchial asthma, allergic rhinitis, rheumatoid arthritis and related sPLA
2
induced diseases. EPO publication No. 0675110, for example, discloses such compounds.
Various patents and publications describe processes for making these compounds using 4-hydroxy indole intermediates.
The article, “Recherches en serie indolique. VI sur tryptamines substituees”, by Marc Julia, Jean Igolen and Hanne Igolen,
Bull. Soc. Chim. France
, 1962, pp. 1060-1068, describes certain indole-3-glyoxylamides and their conversion to tryptamine derivatives.
The article, “2-Aryl-3-Indoleglyoxylamides (FGIN-1): A New Class of Potent and Specific Ligands for the Mitochondrial DBI Receptor (MDR)” by E. Romeo, et al.,
The Journal of Pharmacology and Experimental Therapeutics
, Vol. 262, No. 3, (pp. 971-978) describes certain 2-aryl-3-indolglyoxylamides having research applications in mammalian central nervous systems.
The abstract, “Fragmentation of N-benzylindoles in Mass Spectrometry”; Chemical Abstracts, Vol. 67, 1967, 73028h, reports various benzyl substituted phenols including those having glyoxylamide groups at the 3 position of the indole nucleus.
U.S. Pat. No. 3,449,363 describes trifluoromethylindoles having glyoxylamide groups at the 3 position of the indole nucleus.
U.S. Pat. No. 3,351,630 describes alpha-substituted 3-indolyl acetic acid compounds and their preparation inclusive of glyoxylamide intermediates.
U.S. Pat. No. 2,825,734 describes the preparation of 3-(2-amino-1-hydroxyethyl)indoles using 3-indoleglyoxylamide intermediates such as 1-phenethyl-2-ethyl-6-carboxy-N-propyl-3-indoleglyoxylamide (see, Example 30).
U.S. Pat. No. 4,397,850 prepares isoxazolyl indolamines using glyoxylamide indoles as intermediates. U.S. Pat. No. 3,801,594 describes analgesics prepared using 3-indoleglyoxylamide intermediates.
The article, “No. 565.—Inhibiteurs d'enzymes. XII.—Preparation de (propargylamino-2 ethyl)-3 indoles” by A. Alemanhy, E. Fernandez Alvarez, O. Nieto Lopey and M. E. Rubio Herraez;
Bulletin De La Societe Chimigue De France
, 1974, No. 12, pp. 2883-2888, describes various indolyl-3 glyoxamides which are hydrogen substituted on the 6-membered ring of the indole nucleus.
The article “Indol-Umlagerung von 1-Diphenylamino-2,3-dihydro-2,3-pyrrolidonen” by Gert Kollenz and Christa Labes;
Liebigs Ann. Chem
., 1975, pp. 1979-1983, describes phenyl substituted 3-glyoxylamides.
Many of these processes employ a 4-hydroxy indole intermediate. For example U.S. Pat. No. 5,654,326 U.S., herein incorporated by reference in its entirety, discloses a process for preparing 4-substituted-1H-indole-3-glyoxamide derivatives comprising reacting an appropriately substituted 4-methoxyindole (prepared as described by Clark, R. D. et al.,
Synthesis
, 1991, pp 871-878, the disclosures of which are herein incorporated by reference) with sodium hydride in dimethylformamide at room temperature (20-25° C.) then treating with arylmethyl halide at ambient temperatures to give the 1-arylmethylindole which is O-demethylated using boron tribromide in methylene chloride (Tsung-Ying Shem and Charles A. Winter,
Adv. Drug Res
., 1977, 12, 176, the disclosure of which is incorporated by reference) to give the 4-hydroxyindole. Alkylation of the hydroxy indole is achieved with an alpha bromoalkanoic acid ester in dimethylformamide using sodium hydride as a base. Conversion to the glyoxamide is achieved by reacting the ∝-[(indol-4-yl)oxy]alkanoic acid ester first with oxalyl chloride, then with ammonia, followed by hydrolysis with sodium hydroxide in methanol.
The process for preparing 4-substituted-1H-indole-3-glyoxamide derivatives, as set forth above, has utility. However, this process uses expensive reagents and environmentally hazardous organic solvents, produces furan containing by-products and results in a relatively low yield of desired product.
In an alternate preparation, an appropriately substituted propronylacetate is halogenated with sulfuryl chloride. The halogenated intermediate is hydrolyzed and decarboxylated by treatment with hydrochloric acid then reacted with an appropriately substituted cyclohexane dione. Treatment of the alkylated dione with an appropriate amine affords a 4-keto-indole which is oxidized by refluxing in a high-boiling polar hydrocarbon solvent such as carbitol in the presence of a catalyst, such as palladium on carbon, to prepare the 4-hydroxyindole which may then be alkylated and converted to the desired glyoxamide as described above.
This process however is limited by the required high temperature oxidation and requires recovery of a precious metal catalyst.
While the methods described above for preparing the 4-hydroxy indole intermediate are satisfactory, a more efficient transformation is desirable.
The process of the present invention employs a sulfinylation step.
In general, sulfinylation reactions employ the use of hydride bases which cause a delayed onset exotherm and the evolution of gas. Such process conditions are undesirable in a commercial setting.
Applicants have discovered a process for preparing sulfinylated intermediates which is not associated with a delayed onset exotherm and avoids the foaming associated with the liberation of gas.
Patai,
The Chemistry of Sulfinic Acids, Esters and Their Derivatives
, John Wiley and Sons, 1990, p. 11, teaches a synthesis of sulfinic esters and their salts using a variety of activating agents.
In yet another aspect of the invention, applicants have discovered a commercially viable process for preparing sulfinic esters which result in higher yields, avoids the production of sulfur containing byproducts, particularly sulfones and employs inexpensive reagents.
The present invention provides an improved process for preparing 1H-indole-3-glyoxamides. The process of the present invention can be performed with inexpensive, readily available, reagents under milder conditions and resulting in better overall yield while avoiding the production of furan byproducts. In addition, the present process allows for transformation with a wider variety of substituents on the indole platform. Other objects, features and advantages of the present invention will become apparent from the subsequent description and the appended claims.
The present invention provides a process for preparing a compound of the formula I or a pharmaceutically acceptable salt or prodrug derivative thereof;
wherein:
R
1
is selected from the group consisting of C
7
-C
20
alkyl;
 wherein;
R
10
is selected from the group consisting of halo, —C
1
-C
10
alkyl, —C
1
-C
10
(alkoxy), —S—(C
1
-C
10
) alkyl and halo(C
1
-C
10
)alkyl, and t is an integer from 0 to 5 both inclusive;
R
2
is selected from the group consisting of hydrogen, halo, —C
1
-C
3
(alkyl), —C
3
-C
4
(cycloalkyl), —C
3
-C
4
(cyclo-alkenyl), —O(C
1
-C
2
) alkyl, —S(C
1
-C
2
) alkyl, aryl, aryloxy, and HET;
R4 is selected from the group consisting of —CO
2
H, —SO
3
H, and —P(O)(OH)
2
or salt or prodrug derivatives thereof; and
R
5
is selected from the group consisting of hydrogen, —(C
1
-C
6
)alkyl, —(C
1
-C
6
)alkoxy, halo(C
1
-C
6
)alkoxy, halo(C
2
-C
6
)alkyl, bromo, chloro, fluoro, iodo and aryl;
which process comprises the steps of:
a) halogenating a compound of formula X
where R
8
is (C
1
-C
6
)alkyl, aryl or HET;
with SO
2
Cl
2
to form a compound of formula IX
b) hydrolyzing and decarboxylating a compound of formula IX
to form a compound of formula VIII
c) alkylating a compound of formula VII
with a compound of formula VIII
to form a compound of formula VI
d) aminating and dehydrating a compound of formula VI
with an amine of t

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