WO2000006557A1 - Novel process for making il-8 receptor antagonists - Google Patents

Novel process for making il-8 receptor antagonists Download PDF

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Publication number
WO2000006557A1
WO2000006557A1 PCT/US1999/017010 US9917010W WO0006557A1 WO 2000006557 A1 WO2000006557 A1 WO 2000006557A1 US 9917010 W US9917010 W US 9917010W WO 0006557 A1 WO0006557 A1 WO 0006557A1
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optionally substituted
alkyl
aryl
heteroaryl
heterocyclic
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PCT/US1999/017010
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French (fr)
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Hong Hie
Katherine L. Widdowson
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Smithkline Beecham Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom

Definitions

  • the present invention is to a novel process for producing novel benzoisothiazole substituted compounds for use as IL-8 receptor antagonists.
  • the present invention is directed to a novel process for producing compounds of Formula (B) as described below, which process comprises a) reacting a compound of the formula:
  • R and m are as described in Formula (B), and L is a suitable leaving group under basic conditions in an organic solvent at elevated temperatures; and then acidifying the final product.
  • the process of this invention is a novel multi-step synthetic route to produce a compound of Formula (B)
  • Rl is independently selected from hydrogen, halogen, nitro, cyano, halosubstituted Ci-io alkyl, Ci-io alkyl, C2-10 alkenyl, C ⁇ _ ⁇ o alkoxy, halosubstituted Ci-io alkoxy, azide, (CRgRg)q S(O) t R_ ⁇ , hydroxy, hydroxy Ci-K)alkyl, aryl, aryl Ci-4 alkyl, aryloxy, aryl Ci-4 alkyloxy, heteroaryl, heteroaryl C ⁇ _4 alkyl, heterocyclic, heterocyclic Ci-4- ⁇ lkyl, heteroaryl Ci-4 alkyloxy, aryl C2-10 alkenyl, heteroaryl C-2- 10 alkenyl, heterocyclic C2-10 alkenyl, (CR 8 R 8 )qNR4R5, C2-10 alkenyl C(O)NR4R5, (CR 8 R8)q C(O)NR4R5, (CR
  • n is an integer having a value of 1 to 3
  • m is an integer having a value of 1 to 3
  • q is 0, or an integer having a value of 1 to 10
  • s is an integer having a value of 1 to 3
  • t is 0, or an integer having a value of 1 or 2
  • R4 and R5 are independently hydrogen, optionally substituted Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl C ⁇ _4alkyl, optionally substituted
  • R 8 is independently hydrogen or Ci-4 alkyl
  • RlO is Ci-10 alkyl C(O) 2 R8;
  • Rl l is hydrogen, Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl
  • Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl, or optionally substituted arylalkyl;
  • Rl7 is Ci-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylCi-4alkyl, heterocyclic, or heterocyclicCi-4alkyl, and wherein the aryl, heteroaryl and heterocyclic rings may all be optionally substituted.
  • R is -NH -C(X 2 )-NH- (CR ⁇ 3 R ⁇ 4 ) v - Z;
  • Z is W, HET, ' ⁇ )n , optionally substituted C _ ⁇ o alkyl, optionally substituted C2-10 alkenyl, or optionally substituted C2-10 alkynyl;
  • X is S(O) m '
  • A is CH2;
  • Rl is independently selected from hydrogen, halogen, nitro, cyano, halosubstituted Ci-io alkyl, Ci-io alkyl, C2-10 alkenyl, Ci-io alkoxy, halosubstituted Ci-io alkoxy, azide, (CR 8 R 8 )q S(O) t R4, hydroxy, hydroxy Ci-ioalkyl, aryl, aryl Ci-4 alkyl, aryloxy, aryl Ci-4 alkyloxy, heteroaryl, heteroaryl Ci-4 alkyl, heterocyclic, heterocyclic Ci-4alkyl, heteroaryl C ⁇ _4 alkyloxy, aryl C2-10 alkenyl, heteroaryl C2- 10 alkenyl, heterocyclic C2-10 alkenyl, (CR 8 R 8 )qNR4R5, C2-10 alkenyl C(O)NR4R5, (CR 8 R 8 )q C(O)NR4R5, (CRgR 8
  • HET is an optionally substituted heteroaryl
  • R4 and R5 are independently hydrogen, optionally substituted Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic, or heterocyclic
  • Ci-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S;
  • Y is independently selected from hydrogen, halogen, nitro, cyano, halosubstituted Ci-io alkyl, Ci-io alkyl, C2-10 alkenyl, C ⁇ io alkoxy, halosubstituted Cj-io alkoxy, azide, (CR R 8 )q S(O) t R4, hydroxy, hydroxyCi-ioalkyl, aryl, aryl Ci-4 alkyl, aryloxy, arylCi-4 alkyloxy, heteroaryl, heteroaryl C ⁇ _4 alkyl, heteroaryl Ci-4 alkyloxy, heterocyclic, heterocyclic Ci-4alkyl, aryl C2-10 alkenyl, heteroaryl C2-10 alkenyl, heterocyclic C2-10 alkenyl, (CR 8 R 8 )q NR4R5, C2-10 alkenyl C(O)NR4R5, (CR 8 R 8 )q C(O)NR4R5, (CR
  • Rl ⁇ is C ⁇ _ ⁇ o alkyl C(O)2R8;
  • Rl l is hydrogen, C ⁇ _4 alkyl, optionally substituted aryl, optionally substituted aryl C ⁇ _4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCi-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocy devisC 1 _4alky 1 ;
  • Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl, or optionally substituted arylalkyl;
  • R ⁇ 3 and R14 are independently hydrogen, optionally substituted Ci-4 alkyl, or one of
  • Rl 3 and R14 may be an optionally substituted aryl;
  • Rl5 and Ri6 are independently hydrogen, or an optionally substituted Ci-4 alkyl;
  • Rl7 is Ci-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylCi-4alkyl, heterocyclic, or heterocyclicCi-4alkyl, and wherein the aryl, heteroaryl and heterocyclic rings may all be optionally substituted;
  • R a is NR5R7, alkyl, aryl C1.4 alkyl, arylC2-4 alkenyl, heteroaryl, heteroaryl-C 1.4 alkyl, heteroarylC2_4 alkenyl, heterocyclic, heterocyclicC ⁇ .4 alkyl, and wherein the aryl, heteroaryl and heterocyclic rings may all be optionally substituted;
  • the E containing ring is optionally selected from asterix * denoting point of attachment of the ring; or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (B) can be prepared from the cyclization under basic conditions, such as potassium carbonate using copper as catalyst in N,N'dimethylaniline at 170°C, followed by acidification. These particular reaction conditions result in a product having approximately a 56% yield.
  • the commercially available 2,6-dichlorobenzylbromide can be treated with potassium thioacetate to form the thioacetate 2-scheme 5, followed by oxidation using chlorine gas in ACOH/H2O to form the sulfonyl chloride 3-scheme 5.
  • the sulfonyl chloride can be converted to the corresponding sulfonamide 4-scheme 5 by using NH4OH followed by acidification.
  • the cyclic sulfonamide 5-scheme 5 can be cyclized under basic condition such as potassium carbonate using copper as catalyst followed by acidification.
  • the corresponding nitro compound can be prepared from 1 -scheme 6, under standard nitration conditions (using HNO 3 or NaNO 3 ) at 0-100°C, preferably about 23°C, under acid conditions such as acetic acid, acetic anhydride, or under biphasic condition such as aqueous sulphuric acid and a chlorinated solvent such as methylene chloride.
  • acid conditions such as acetic acid, acetic anhydride
  • biphasic condition such as aqueous sulphuric acid and a chlorinated solvent such as methylene chloride.
  • the nitration of the cyclic sulfonamide under optimized nitration conditions using NaNO3 at 23°C produced 2- shcme-6 in a 25% yield, 14% from the two steps.
  • nitro compound is then reduced to the corresponding aniline using suitable reducing agents, such as F ⁇ /Pd in an organic solvent, such as MeOH, DMF or ethylacetate (alternately SnCl2 in EtOH, or LiA HLj. or zinc metal in acetic acid ) at 0- 100°C.
  • suitable reducing agents such as F ⁇ /Pd in an organic solvent, such as MeOH, DMF or ethylacetate (alternately SnCl2 in EtOH, or LiA HLj. or zinc metal in acetic acid ) at 0- 100°C.
  • Rl is independently selected from hydrogen, halogen, nitro, cyano, halosubstituted
  • R4 and R5 are independently hydrogen, optionally substituted Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl C ⁇ _4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic, or heterocyclic Ci-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S;
  • R 8 is independently hydrogen or C ⁇ _4 alkyl
  • RlO is Ci-10 alkyl C(O)2R8;
  • Rl l is hydrogen, C ⁇ _4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCi-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC 1 _4alkyl;
  • Rl2 is hydrogen, Ci-10 alkyl, optionally substituted aryl, or optionally substituted arylalkyl;
  • Rl7 is Ci-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylCi-4alkyl, heterocyclic, or heterocyclicCi-4alkyl, and wherein the aryl, heteroaryl and heterocyclic rings may all be optionally substituted.
  • the 2,6-dihalobenzylbromide can then be treated with potassium thioacetate (or other thio acetate salts) in a polar aprotic solvent such as DMF, DMSO, THF, dioxane or NMP to form the thioacetate 3-scheme 1
  • a polar aprotic solvent such as DMF, DMSO, THF, dioxane or NMP
  • other thiols can be used like disodium sulfide, followed by oxidation, such as by using chlorine gas in ACOH/H2O to form the sulfonyl chloride 4-scheme 1 this oxidation can also be accomplished using NCS in aqueous acetic acid.
  • the sulfonyl chloride 4-scheme 1 can be converted to the corresponding sulfonamide 5-scheme 1 by using NH4OH or ammonia gas followed by acidification.
  • the new reaction route shown in scheme 2 involves the nitration of sulfonamide ]-_ scheme 2 under nitration conditions (using HNO 3 /H 2 SO 4 ) at 0°C (in 56% yield), followed by cyclization of 2-scheme 2 under basic conditions, such as potassium carbonate in DMF or other polar aprotic solvent such as propionitrile or DMSO at 60°C to about 130°C and then acidification (in 90% yield).
  • the use of copper in the reaction is no longer desired since it results in products with the wrong regio chemistry.
  • the combined yield for the two step under the new protocol described herein is 50%.
  • the yield under the previous protocol of PCT/US98/01292 for the combined the two steps is 14%.
  • Ortho substituted heterocyclic phenyl ureas in 3 ⁇ scheme 3 may be prepared by standard conditions involving the condensation of the commercially available optionally substituted aryl isocyanates with the corresponding aniline 2-scheme 3 in an aprotic solvent such as (DMF).
  • the present invention provides for an improved process of making compounds of Formula (B) which process comprises a) reacting a compound of the formula:
  • Ri and m are as described in Formula (B); and L is a suitable leaving group; preferably a halogen, such as Br, Cl, or F, more preferably bromine or chlorine; under basic conditions in an organic solvent at elevated temperatures; and then acidifying the final product.
  • a suitable leaving group preferably a halogen, such as Br, Cl, or F, more preferably bromine or chlorine
  • Suitable basic conditions for use herein include, but are not limited to potassium carbonate,sodium hydride, cesium carbonate, sodium carbonate, and lithium carbonate.
  • Suitable organic solvents for use herein include, but are not limited to DMF, THF, DMSO, NHP, and proprionitrile.
  • Suitable temperature ranges for this process are from about 50°C to about 200C. Preferred ranges are from about 60 to about 130°C. Most preferred are about 100°C.
  • All temperatures are given in degrees centigrade, all solvents are highest available purity and all reactions run under anhydrous conditions in an argon atmosphere unless otherwise indicated. In the Examples, all temperatures are in degrees Centigrade (°C). Mass spectra were performed upon a VG Zab mass spectrometer using fast atom bombardment, unless otherwise indicated.
  • NMR ⁇ H-NMR

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Abstract

The present invention is to a novel process for producing a compound of formula (B), wherein m is 1 to 3 and R1 is interalia, hydrogen, halogen, cyano, and nitro; having improved yields and purity wherein a compound of formula (C), wherein interalia, L is a leaving group; is first nitrated and then cyclized.

Description

NOVEL PROCESS FOR MAKING IL-8 RECEPTOR ANTAGONISTS FIELD OF THE INVENTION
The present invention is to a novel process for producing novel benzoisothiazole substituted compounds for use as IL-8 receptor antagonists.
SUMMARY OF THE INVENTION
The present invention is directed to a novel process for producing compounds of Formula (B) as described below, which process comprises a) reacting a compound of the formula:
Figure imgf000003_0001
wherein R and m are as described in Formula (B), and L is a suitable leaving group under basic conditions in an organic solvent at elevated temperatures; and then acidifying the final product.
DETAILED DESCRIPTION OF THE INVENTION
The process of this invention is a novel multi-step synthetic route to produce a compound of Formula (B)
Figure imgf000003_0002
wherein
Rl is independently selected from hydrogen, halogen, nitro, cyano, halosubstituted Ci-io alkyl, Ci-io alkyl, C2-10 alkenyl, Cι_ιo alkoxy, halosubstituted Ci-io alkoxy, azide, (CRgRg)q S(O)tR_ι, hydroxy, hydroxy Ci-K)alkyl, aryl, aryl Ci-4 alkyl, aryloxy, aryl Ci-4 alkyloxy, heteroaryl, heteroaryl Cι_4 alkyl, heterocyclic, heterocyclic Ci-4-ιlkyl, heteroaryl Ci-4 alkyloxy, aryl C2-10 alkenyl, heteroaryl C-2- 10 alkenyl, heterocyclic C2-10 alkenyl, (CR8R8)qNR4R5, C2-10 alkenyl C(O)NR4R5, (CR8R8)q C(O)NR4R5, (CR8R8)q C(O)NR4Rl0, S(O)3R8, (CR8R8)q C(O)Rn, C2-10 alkenyl C(O)Rn, C2-10 alkenyl C(O)ORn, C(O)Rn, (CR8Rg)q C(O)ORi2, (CR8R8)q OC(O)Rι 1, (CR8R8)q NR4C(O)Ri 1,
(CR8R8)qC(NR4)NR4R5; (CR8R8)q NR4C(NR5)Rl ι ; (CR8R8)q NHS(O)2Rl7, or (CR8R8)q S(O)2NR4R5, or two Rj moieties together may form O-(CH2)sO- or a 5 to 6 membered saturated or unsaturated ring; and wherein the aryl, heteroaryl and heterocyclic containing rings may all be optionally substituted; n is an integer having a value of 1 to 3; m is an integer having a value of 1 to 3; q is 0, or an integer having a value of 1 to 10; s is an integer having a value of 1 to 3; t is 0, or an integer having a value of 1 or 2; R4 and R5 are independently hydrogen, optionally substituted Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl Cι_4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Cι_4alkyl, heterocyclic, or heterocyclic Ci-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S;
R8 is independently hydrogen or Ci-4 alkyl;
RlO is Ci-10 alkyl C(O)2R8;
Rl l is hydrogen, Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl
Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCi_4alkyl, optionally substituted heterocyclic, or optionally substituted heterocy clicC 1 -4alkyl ; Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl, or optionally substituted arylalkyl; Rl7 is Ci-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylCi-4alkyl, heterocyclic, or heterocyclicCi-4alkyl, and wherein the aryl, heteroaryl and heterocyclic rings may all be optionally substituted.
Compounds of Formula (B) are chemical intermediates used in a process to produce the desired final product, a compound of Formula (I), as represented by the structure
Figure imgf000005_0001
wherein
R is -NH -C(X2)-NH- (CRι3Rι4)v - Z;
Figure imgf000005_0002
Z is W, HET, 'γ)n , optionally substituted C _ ιo alkyl, optionally substituted C2-10 alkenyl, or optionally substituted C2-10 alkynyl;
X is S(O)m';
X2 is =O, or =S;
A is CH2;
Rl is independently selected from hydrogen, halogen, nitro, cyano, halosubstituted Ci-io alkyl, Ci-io alkyl, C2-10 alkenyl, Ci-io alkoxy, halosubstituted Ci-io alkoxy, azide, (CR8R8)q S(O)tR4, hydroxy, hydroxy Ci-ioalkyl, aryl, aryl Ci-4 alkyl, aryloxy, aryl Ci-4 alkyloxy, heteroaryl, heteroaryl Ci-4 alkyl, heterocyclic, heterocyclic Ci-4alkyl, heteroaryl Cι_4 alkyloxy, aryl C2-10 alkenyl, heteroaryl C2- 10 alkenyl, heterocyclic C2-10 alkenyl, (CR8R8)qNR4R5, C2-10 alkenyl C(O)NR4R5, (CR8R8)q C(O)NR4R5, (CRgR8)q C(O)NR4Rl0, S(O)3R8, (CR8R8)q C(O)Ri 1, C2-10 alkenyl C(O)Rι 1, C -10 alkenyl C(O)ORι 1, C(O)Rι 1, (CR8R8)q C(O)ORi2, (CR8R8)q OC(O)Rι 1, (CR8R8)q NR4C(O)Ri 1, (CR8R8)qC(NR4)NR4R5; (CR8R8)q NR4C(NR5)Rι ι; (CR8R8)q NHS(O)2Rl7, or (CR R8)q S(O)2NR4R5, or two Ri moieties together may form O-(CH2)sO- or a 5 to 6 membered saturated or unsaturated ring; and wherein the aryl, heteroaryl and heterocyclic containing rings may all be optionally substituted; n is an integer having a value of 1 to 3; m is an integer having a value of 1 to 3; m' is an integer having a value of 2; q is 0, or an integer having a value of 1 to 10; s is an integer having a value of 1 to 3; t is 0, or an integer having a value of 1 or 2; v is 0, or an integer having a value of 1 to 4; p is an integer having a value of 1 to 3;
HET is an optionally substituted heteroaryl;
R4 and R5 are independently hydrogen, optionally substituted Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic, or heterocyclic
Ci-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S;
Y is independently selected from hydrogen, halogen, nitro, cyano, halosubstituted Ci-io alkyl, Ci-io alkyl, C2-10 alkenyl, Cμio alkoxy, halosubstituted Cj-io alkoxy, azide, (CR R8)q S(O)tR4, hydroxy, hydroxyCi-ioalkyl, aryl, aryl Ci-4 alkyl, aryloxy, arylCi-4 alkyloxy, heteroaryl, heteroaryl Cι_4 alkyl, heteroaryl Ci-4 alkyloxy, heterocyclic, heterocyclic Ci-4alkyl, aryl C2-10 alkenyl, heteroaryl C2-10 alkenyl, heterocyclic C2-10 alkenyl, (CR8R8)q NR4R5, C2-10 alkenyl C(O)NR4R5, (CR8R8)q C(O)NR4R5, (CR8R8)q C(O)NR4RlO, S(O)3R8,
(CR8R8)q C(O)Rπ, C2-10 alkenyl C(O)Rn, C2-10 alkenyl C(O)ORn, (CR8R8)q C(O)ORi2, (CR8R8)q OC(O)Rι 1, (CR8R8)q NR4C(O)Ri 1, (CR8R8)qC(NR4)NR4R5, (CR8Rg)q NR4C(NR5)Rn, (CR8R8)q NHS(O)2Ra, or (CR8R )q S(O)2NR4R5, or two Y moieties together may form O-(CH2)s -O or a 5 to 6 membered saturated or unsaturated ring; and wherein the aryl, heteroaryl and heterocyclic containing rings may all be optionally substituted; R6 and R7 are independently hydrogen or a Ci-4 alkyl group, or R6 and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur; R8 is independently hydrogen or C 1.4 alkyl;
Rlθ is Cι_ιo alkyl C(O)2R8;
Rl l is hydrogen, Cι_4 alkyl, optionally substituted aryl, optionally substituted aryl Cι_4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCi-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocy clicC 1 _4alky 1 ; Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl, or optionally substituted arylalkyl; Rι3 and R14 are independently hydrogen, optionally substituted Ci-4 alkyl, or one of
Rl3 and R14 may be an optionally substituted aryl; Rl5 and Ri6 are independently hydrogen, or an optionally substituted Ci-4 alkyl; Rl7 is Ci-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylCi-4alkyl, heterocyclic, or heterocyclicCi-4alkyl, and wherein the aryl, heteroaryl and heterocyclic rings may all be optionally substituted;
Ra is NR5R7, alkyl, aryl C1.4 alkyl, arylC2-4 alkenyl, heteroaryl, heteroaryl-C 1.4 alkyl, heteroarylC2_4 alkenyl, heterocyclic, heterocyclicCι.4 alkyl, and wherein the aryl, heteroaryl and heterocyclic rings may all be optionally substituted;
Figure imgf000007_0001
the E containing ring is optionally selected from
Figure imgf000008_0001
asterix * denoting point of attachment of the ring; or a pharmaceutically acceptable salt thereof.
Compounds of Formula (I) and Formula (B), and a process of making these compounds are described in PCT/US98/01292, Widdowson et al., filed 23 January 1998 whose disclosure is incorporated herein by reference in its entirety.
In PCT US98/01292 application compounds of Formula (I) are produced by reacting an intermediate compound of the formula
Figure imgf000008_0002
with a compound of the formula:
C(X2)-N-(CRι3Ri4)v - Z; wherein Rj , m, X2, Rl3, R-14> v and Z are as defined in Formula (I) to yield a compound of Formula (I). Compounds of Formula (A) are produced as shown by reducing a compound of Formula (B) as described herein or in PCT/US98/01292.
The relevant processes as disclosed in PCT US98/01292 application and in USSN 60/057,998, whose disclosure is also incorporated by reference in its entirey is Scheme 5 from USSN 60/057,998 and Scheme 6 from PCT/U98/01292 (both shown below). In these schemes the ring is already cyclized, and the nitro added under standard nitrating conditions to yield a compound described herein as Formula (B), which is then reduced to yield a compound of Formula (A). Using the routes described in this PCT application and USSN 60/057,998, such as shown below in "Scheme 5", and "Scheme 6", a compound of Formula (B) can be prepared from the cyclization under basic conditions, such as potassium carbonate using copper as catalyst in N,N'dimethylaniline at 170°C, followed by acidification. These particular reaction conditions result in a product having approximately a 56% yield.
Scheme 5
Figure imgf000009_0001
Figure imgf000009_0003
Figure imgf000009_0002
a) KSC(=0)CH3 b) Cl2, AcOH/H20 c) NH4OH d) K2C03> Cu
If the desired heterocyclic compound 5-scheme 5 is not commercially available, the commercially available 2,6-dichlorobenzylbromide can be treated with potassium thioacetate to form the thioacetate 2-scheme 5, followed by oxidation using chlorine gas in ACOH/H2O to form the sulfonyl chloride 3-scheme 5. The sulfonyl chloride can be converted to the corresponding sulfonamide 4-scheme 5 by using NH4OH followed by acidification. The cyclic sulfonamide 5-scheme 5 can be cyclized under basic condition such as potassium carbonate using copper as catalyst followed by acidification. Sche me 6
Figure imgf000010_0001
a) NaN03, 3M H2S04, CH2CI2, 23°C b) Pd/C, MeOH
If the desired aniline 3-scheme 6 is not commercially available the corresponding nitro compound can be prepared from 1 -scheme 6, under standard nitration conditions (using HNO3 or NaNO3) at 0-100°C, preferably about 23°C, under acid conditions such as acetic acid, acetic anhydride, or under biphasic condition such as aqueous sulphuric acid and a chlorinated solvent such as methylene chloride. The nitration of the cyclic sulfonamide under optimized nitration conditions (using NaNO3) at 23°C produced 2- shcme-6 in a 25% yield, 14% from the two steps.
The nitro compound is then reduced to the corresponding aniline using suitable reducing agents, such as F^/Pd in an organic solvent, such as MeOH, DMF or ethylacetate (alternately SnCl2 in EtOH, or LiA HLj. or zinc metal in acetic acid ) at 0- 100°C.
For purposes herein, a compound of the formula (B) is represented by the structure:
Figure imgf000010_0002
wherein
Rl is independently selected from hydrogen, halogen, nitro, cyano, halosubstituted
Ci-io alkyl, Ci-io alkyl, C2-10 alkenyl, Ci-io alkoxy, halosubstituted Cι_ιo alkoxy, azide, (CR8R )q S(O)tR4, hydroxy, hydroxy Ci-ioalkyl, aryl, aryl Ci-4 alkyl, aryloxy, aryl Cι_4 alkyloxy, heteroaryl, heteroaryl Ci-4 alkyl, heterocyclic, heterocyclic C -4alkyl, heteroaryl Ci-4 alkyloxy, aryl C2-10 alkenyl, heteroaryl C >- 10 alkenyl, heterocyclic C2-10 alkenyl, (CR8R8)qNR4R5, C2-10 alkenyl C(O)NR4R5, (CR8Rs)q C(O)NR4R5, (CR8Rs)q C(O)NR4RlO, S(O)3R8, (CR8R8)q C(O)Rn, C2-10 alkenyl C(O)Rn, C -10 alkenyl C(O)ORn, C(O)Rn,
(CR8R8)q C(O)ORi2, (CR8R8)q OC(O)Rι 1, (CR8R8)q NR4C(O)Ri 1, (CR8R8)qC(NR4)NR4R5; (CR8R8)q NR4C(NR5)Rι j ; (CR8R8)q NHS(O)2Rι7, or (CR8R8)q S(O)2NR4R5, or two Rl moieties together may form O-(CH2)sO- or a 5 to 6 membered saturated or unsaturated ring; and wherein the aryl, heteroaryl and heterocyclic containing rings may all be optionally substituted; n is an integer having a value of 1 to 3; m is an integer having a value of 1 to 3; q is 0, or an integer having a value of 1 to 10; s is an integer having a value of 1 to 3; t is 0, or an integer having a value of 1 or 2;
R4 and R5 are independently hydrogen, optionally substituted Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl Cι_4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic, or heterocyclic Ci-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S;
R8 is independently hydrogen or Cι_4 alkyl;
RlO is Ci-10 alkyl C(O)2R8;
Rl l is hydrogen, Cι_4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCi-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC 1 _4alkyl; Rl2 is hydrogen, Ci-10 alkyl, optionally substituted aryl, or optionally substituted arylalkyl; Rl7 is Ci-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylCi-4alkyl, heterocyclic, or heterocyclicCi-4alkyl, and wherein the aryl, heteroaryl and heterocyclic rings may all be optionally substituted.
It has now been found that using the processes described herein it is possible to significantly improve both the resultant purity and yields of the desired intermediate compounds of Formula (B). These improvements are achieved by first nitrating a precursor of the compound of l-Scheme-6 above. Therefore, an object of the present application is the process by which this is done.
The following illustrations will describe a synthesis for making a compound of Formula (B) using this improved process. While the schemes are shown with various compounds of Formula (B), this is merely for illustration purposes only and not a limitation on the extent of synthesis available using these methods.
Scheme 1
Figure imgf000013_0001
Figure imgf000013_0002
a)NBS, (PhCO)20 b) KSC(=0)CH3 c)CI2, AcOH/H20 d) NH4OH
If the desired heterocyclic compound 5-scheme 1 is not commercially available, bromination of the commercially available 2,6-dihalotoluene make occur with N- bromosuccinimide in benzene or other nonreactive aromatic solvents such as chlorobenzene. The 2,6-dihalobenzylbromide can then be treated with potassium thioacetate (or other thio acetate salts) in a polar aprotic solvent such as DMF, DMSO, THF, dioxane or NMP to form the thioacetate 3-scheme 1 alternatively other thiols can be used like disodium sulfide, followed by oxidation, such as by using chlorine gas in ACOH/H2O to form the sulfonyl chloride 4-scheme 1 this oxidation can also be accomplished using NCS in aqueous acetic acid. The sulfonyl chloride 4-scheme 1 can be converted to the corresponding sulfonamide 5-scheme 1 by using NH4OH or ammonia gas followed by acidification. Scheme 2
Figure imgf000014_0001
a) HN03> H2S04 0°C b) K2C03, DMF, 100°C
The new reaction route shown in scheme 2 involves the nitration of sulfonamide ]-_ scheme 2 under nitration conditions (using HNO3/H2SO4) at 0°C (in 56% yield), followed by cyclization of 2-scheme 2 under basic conditions, such as potassium carbonate in DMF or other polar aprotic solvent such as propionitrile or DMSO at 60°C to about 130°C and then acidification (in 90% yield). The use of copper in the reaction is no longer desired since it results in products with the wrong regio chemistry. The combined yield for the two step under the new protocol described herein is 50%. The yield under the previous protocol of PCT/US98/01292 for the combined the two steps is 14%.
Scheme 3
Figure imgf000015_0001
a) SnCI2, EtOH b) 2-BrPhNCO, DMF
As shown above, the desired nitro compound is subsequently reduced to the corresponding aniline using SnCl2 in EtOH. Ortho substituted heterocyclic phenyl ureas in 3^ scheme 3 may be prepared by standard conditions involving the condensation of the commercially available optionally substituted aryl isocyanates with the corresponding aniline 2-scheme 3 in an aprotic solvent such as (DMF).
The present invention provides for an improved process of making compounds of Formula (B) which process comprises a) reacting a compound of the formula:
Figure imgf000015_0002
wherein Ri and m are as described in Formula (B); and L is a suitable leaving group; preferably a halogen, such as Br, Cl, or F, more preferably bromine or chlorine; under basic conditions in an organic solvent at elevated temperatures; and then acidifying the final product.
Suitable basic conditions for use herein include, but are not limited to potassium carbonate,sodium hydride, cesium carbonate, sodium carbonate, and lithium carbonate. Suitable organic solvents for use herein include, but are not limited to DMF, THF, DMSO, NHP, and proprionitrile.
Suitable temperature ranges for this process are from about 50°C to about 200C. Preferred ranges are from about 60 to about 130°C. Most preferred are about 100°C. The invention will now be described by reference to the following examples which are merely illustrative and are not to be construed as a limitation of the scope of the present invention. All temperatures are given in degrees centigrade, all solvents are highest available purity and all reactions run under anhydrous conditions in an argon atmosphere unless otherwise indicated. In the Examples, all temperatures are in degrees Centigrade (°C). Mass spectra were performed upon a VG Zab mass spectrometer using fast atom bombardment, unless otherwise indicated. ^H-NMR (hereinafter "NMR") spectra were recorded at 250 MHz using a Bruker AM 250 or Am 400 spectrometer. Multiplicities indicated are: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet and br indicates a broad signal. Sat. indicates a saturated solution, eq indicates the proportion of a molar equivalent of reagent relative to the principal reactant.
Example 1 Preparation of N-K 1 ,3)-Dihydro-2,2-dioxo-3-methyl-4-bromo-2, 1 -benzisothiazo)-7-yn-N'-[2- bromophenyll urea
a) Preparation of 2,6-Dibromobenzylbromide
To a solution of 2,6-dibromotoluene (40 g, 160 mmol) in benzene (100 mL), N- bromosuccinimide (28.5 g, 176 mmol) and benzoyl peroxide (4 g ) were added. The reaction mixture was stirred at reflux temperature for 16 hours. Then was cooled down to room temperature and partitioned between ethyl acetate and water. The combined organic phase was dried and concentrated to give the desired product (50 g, 95%). EI- MS m/z 330 (M+).
b) Preparation of 2,6-Dibromobenzylthioacetate To a solution of 2,6-dibromobenzylbromide (62.5 g, 189.7 mmol) in DMF (100 ml), potassium thioacetate (23.8 g, 208.6 mmol) was added. The reaction mixture was stirred at room temperature for one hour. Then it was partitioned between ethyl acetate and water. The combined organic phase was dried and concentrated to give the desired product (60 g, 99%). EI-MS m z 325 (M+).
c) Preparation of 2,6-dibromobenzylsulfonylchloride
The 2,6-dbromobenzylthioacetate (10 g, 30.86 mmol) and sodium acetate (16.97 g) were dissolved in a mixture of glacial acetic acid (162 ml) and water (34 ml). Chlorine gas was passed into the solution for 10 min. The mixture was evaporated and the residue was extracted with ethyl acetate. The combined organic phase was dried and concentrated to give the desired product (9 g, 84%). EI-MS m z 349.5 (M+).
d) Preparation of 2,6-dibromobenzylsulfonamide The 2,6-dibromobenzylsulfonylchloride (10 g, 28.7 mmol) in ammonium hydroxide (100 ml) was stirred at room temperature for 16 hours. On acidification with cooled concentrated hydrochloric acid a precipitate separated and was filtered to give desired product (6.52 g, 69 %) EI-MS m/z 330 (M").
e) Preparation of 3-nitro-2,6-dibromobenzylsulfonamide
To the solution of 2,6-dibromobenzylsulfonamide (1 g, 3.04 mmol) in H2SO4 (2 mL) at 0°C, nitric acid (0.21 g, 3.2 mmol) was added dropwise. After addition, the reaction mixture was stirred at 0°C for one hour. Then it was partitioned between ethyl acetate and water. The combined organic phase was dried and concentrated. Chromatography of the residue on silica gel (30%Ethyl acetate/Hexane) gave desired product (0.65 g, 56%). EI-MS m z 376 (M+).
f) Preparation of l,3-dihydro-2,2-dioxo-4-bromo-7-nitro-2,l-benzisothiazole
To a solution of 3-nitro-2,6-dibromobenzylsulfonamide (280 mg, 0.75 mmol) in DMF (10 mL), K2CO3 (124 mg, 0.9 mmol) was added. The reaction mixture was stirred at 100 °C for 16 hours. Then it was partitioned between ethyl acetate and 10 % aqueous HC1. The combined organic phase was dried and concentrated. Chromatography of the residue on silica gel (50%Ethyl acetate/Hexane) gave desired product (198 mg, 90%). EI-MS m/z 292 (M").
g) Preparation of l,3-dihydro-2,2-dioxo-4-chloro-3-methyl-7-amino-2,l- benzisothiazole
To the solution of l,3-dihydro-2,2-dioxo-4-bromo-3-methyl-7-nitro-2,l-benzisothiazole
(50 mg, 0.17 mmol) in ethanol (5 ml), Tin (II) chloride (192 mg, 0.85 mmol) was added. The reaction mixture was stirred at reflux for 4 hours. Then was cooled to room temperature. NaHCO (aq) was added to the reaction mixture until pH= 7. Then the solution was extracted with ethyl acetate (3x). The combined organic layer was dried over MgSO , filtered and concentrated under reduced pressure to give desired product (38 mg, 85%). EI-MS m/z 262 (M").
h) Preparation of N-[(l,3)-Dihydro-2,2-dioxo-3-methyl-4-bromo-2,l-benzisothiazo)-7- yl]-N'-[2-bromophenyl] urea
To a solution of 2-bromo phenyl isocyanate (28 mg, 0.14 mmol) in DMF (1.0 ml), 1,3- dihydro-2,2-dioxo-4-chloro-7-amino-2,l-benzisothiazole (38 mg, 0.14 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours.
Chromatography of the resulting liquid on silica gel (50%Ethyl acetate Hexane) gave desired product (33 mg, 50%). EI-MS m/z 460 (M").
Example 2 Preparation of N-r( 3)-Dihvdro-2.2-dioxo-3-methyl-4-fluoro-2.1-benzisothiazo)-7-vn-N,-r2- bromophenyll urea
a) Preparation of 2,6-difluorobenzylthioacetate
To a solution of 2,6-difluorobenzylbromide (15.34 g, 74.1 mmol) in DMF (50 ml), potassium thioacetate (9.29 g, 81.5 mmol) was added. The reaction mixture was stirred at room temperature for one hour. Then it was partitioned between ethyl acetate and water. The combined organic phase was dried and concentrated to give the desired product (14.05 g, 94%). EI-MS m/z 203 (M+).
b) Preparation of 2,6-difluorobenzylsulfonylchloride
The 2,6-dfluorobenzylthioacetate (14.05 g, 69.5 mmol) and sodium acetate (38.2 g) were dissolved in a mixture of glacial acetic acid (365 ml) and water (76ml). Chlorine gas was passed into the solution for 15 min. The mixture was evaporated and the residue was extracted with ethyl acetate. The combined organic phase was dried and concentrated to give the desired product (12 g, 76%). EI-MS m/z 227.5 (M+).
c) Preparation of 2,6-difluorobenzylsulfonamide
The 2,6-difluorobenzylsulfonylchloride (6 g, 26.5 mmol) in ammonium hydroxide (60 ml) was stirred at room temperature for 16 hours. On acidification with cooled concentrated hydrochloric acid a precipitate separated and was filtered to give desired product (3.00 g, 55 %) EI-MS m/z 206 (M ).
d) Preparation of 3-nitro-2,6-difluorobenzylsulfonamide
To the solution of 2,6-difluorobenzylsulfonamide (3 g, 14.5 mmol) in H2SO (20 mL) at 0°C, nitric acid (1.0 g, 15.95 mmol) was added dropwise. After addition, the reaction mixture was stirred at 0°C for one hour. Then it was partitioned between ethyl acetate and water. The combined organic phase was dried and concentrated. Chromatography of the residue on silica gel (30%Ethyl acetate/Hexane) gave desired product (1.84 g, 50%). EI-MS m/z 254 (M+).
e) Preparation of l,3-dihydro-2,2-dioxo-4-fluoro-7-nitro-2,l-benzisothiazole
To a solution of 3-nitro-2,6-difluorobenzylsulfonamide (1.84 g, 7.3 mmol) in DMF (40 mL), K CO3 (1.21 g, 0.9 mmol) was added. The reaction mixture was stirred at 100 °C for 16 hours. Then it was partitioned between ethyl acetate and 10 % aqueous HC1. The combined organic phase was dried and concentrated. Chromatography of the residue on silica gel (50%Ethyl acetate/Hexane) gave desired product (1.18 g, 70%). EI-MS m/z 231 (M").
f) Preparation of l,3-dihydro-2,2-dioxo-4-fluoro-3-methyl-7-amino-2,l-benzisothiazole To the solution of l,3-dihydro-2,2-dioxo-4-fluoro-3-methyl-7-nitro-2,l-benzisothiazole
(150 mg, 0.65 mmol) in ethanol (15 ml), Tin (II) chloride (730 mg, 3.25 mmol) was added. The reaction mixture was stirred at reflux for 4 hours. Then was cooled to room temperature. NaHCO3 (aq) was added to the reaction mixture until pH= 7. Then the solution was extracted with ethyl acetate (3x). The combined organic layer was dried over MgSO , filtered and concentrated under reduced pressure to give desired product (100 mg, 76%). EI-MS m/z 201 (M").
g) Preparation of N-[( 1 ,3)-Dihydro-2,2-dioxo-3-methyl-4-fluoro-2, l-benzisothiazo)-7- yl]-N'-[2-bromophenyl] urea To a solution of 2-bromo phenyl isocyanate (49 mg, 0.25 mmol) in DMF (1.0 ml), 1,3- dihydro-2,2-dioxo-4-fluoro-7-amino-2,l-benzisothiazole (50 mg, 0.25 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. Chromatography of the resulting liquid on silica gel (50%Ethyl acetate/Hexane) gave desired product (33 mg, 50%). EI-MS m/z 399 (M ).
Example 3 Preparation of N- (l,3)-Dihvdro-2,2-dioxo-3-methyl-4-chloro-2 -benzisothiazo)-7-yl1-N,-[2- bromophenyll urea a) Preparation of 2,6-dichlorobenzylthioacetate To a solution of 2,6-difluorobenzylbromide (30 g, 74.1 mmol) in DMF (100 ml), potassium thioacetate (15.6 g, 136.4 mmol) was added. The reaction mixture was stirred at room temperature for one hour. Then it was partitioned between ethyl acetate and water. The combined organic phase was dried and concentrated to give the desired product (23.6 g, 76%). EI-MS m z 236 (M+).
- lϊ b) Preparation of 2,6-dichlorobenzylsulfonylchloride
The 2,6-dichlorobenzylthioacetate (23.6 g, 94 mmol) and sodium acetate (55.5 g) were dissolved in a mixture of glacial acetic acid (646 ml) and water (141ml). Chlorine gas was passed into the solution for 15 min. The mixture was evaporated and the residue was extracted with ethyl acetate. The combined organic phase was dried and concentrated to give the desired product (19 g, 73%). EI-MS m/z 260.5 (M+).
c) Preparation of 2,6-dichlorobenzylsulfonamide
The 2,6-dichlorobenzylsulfonylchloride (19 g, 73.2 mmol) in ammonium hydroxide (190 ml) was stirred at room temperature for 16 hours. On acidification with cooled concentrated hydrochloric acid a precipitate separated and was filtered to give desired product (15.2 g, 86 %) EI-MS m/z 239(M").
d) Preparation of l,3-dihydro-2,2-dioxo-4-chloro-2,l-benzisothiazole To the solution of 2,6-dichlorobenzylsulfonamide (5.2 g, 21.8 mmol) in 2,3- dimethylaniline (5 mL), K2CO3 (3 g, 21.8 mmol) and copper (391 mg) were added. The reaction mixture was stirred at 170 °C for 3 hours. Then it was cooled to room temperature and 10 % of HC1 was added until PH = 1. The reaction mixture was extracted with ethyl acetate (3x). The combined organic phase was dried and concentrated. Chromatography of the residue on silica gel (25%Ethyl acetate/Hexane) gave desired product (1.65 g, 37%). EI-MS m/z 202.5 (M~).
e) Preparation of l,3-dihydro-2,2-dioxo-4-chloro-7-nitro-2,l-benzisothiazole
To the solution of l,3-dihydro-2,2-dioxo-4-chloro-2,l-benzisothiazole (1 g, 4.91 mmol) in CH2C12 (15 mL), H2SO4 /H2O (0.97 mL/ 6.83 mL) and NaNO2 as cat. amount were added . The reaction mixture was stirred at room temperature for 16 hours. Then it was partitioned between CH2C12 and water. The combined organic phase was dried and concentrated. Chromatography of the residue on silica gel (30%Ethyl acetate/Hexane) gave desired product (330 mg, 27%). EI-MS m/z 249.5 (M+). f) Preparation of l,3-dihydro-2,2-dioxo-4-chloro-3-methyl-7-amino-2,l- benzisothiazole
To the solution of l,3-dihydro-2,2-dioxo-4-chloro-3-methyl-7-nitro-2,l-benzisothiazole (330 mg, 1.33 mmol) in ethanol (20 ml), Tin (II) chloride (1.5 g, 6.65 mmol) was added. The reaction mixture was stirred at reflux for 4 hours. Then was cooled to room temperature. NaHCO3 (aq) was added to the reaction mixture until pH= 7. Then the solution was extracted with ethyl acetate (3x). The combined organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give desired product (230 mg, 79%). EI-MS m/z 217.5 (NT).
g) Preparation of N-[(l,3)-Dihydro-2,2-dioxo-3-methyl-4-chloro-2,l-benzisothiazo)-7- yl]-N'-[2-bromophenyl] urea
To a solution of 2-bromo phenyl isocyanate (45.4 mg, 0.23 mmol) in DMF (1.0 ml), l,3-dihydro-2,2-dioxo-4-chloro-7-amino-2,l-benzisothiazole (50 mg, 0.23 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours.
Chromatography of the resulting liquid on silica gel (50%Ethyl acetate/Hexane) gave desired product (63 mg, 66%). EI-MS m/z 415.7 (M~).
All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.
The above description fully discloses the invention including preferred embodiments thereof. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration, it is believed that one skilled in the are can, using the preceding description, utilize the present invention to its fullest extent. Therefore the Examples herein are to be construed as merely illustrative and not a limitation of the scope of the present invention in any way. The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows. PAGE INTENTIONALLY LEFT BLANK

Claims

What is Claimed Is:
1. A process for producing a compound of Formula (B)
Figure imgf000024_0001
wherein
Rj is independently selected from hydrogen, halogen, nitro, cyano, halosubstituted Ci-io alkyl, Ci-io alkyl, C2-10 alkenyl, Ci-io alkoxy, halosubstituted Ci-io alkoxy, azide, (CR8Rs)q S(O)tR4, hydroxy, hydroxy Ci-ioalkyl, aryl, aryl Ci-4 alkyl, aryloxy, aryl Ci-4 alkyloxy, heteroaryl, heteroaryl Cι_4 alkyl, heterocyclic, heterocyclic Cι_4alkyl, heteroaryl Cι_4 alkyloxy, aryl C2-10 alkenyl, heteroaryl C2- 10 alkenyl, heterocyclic C2-10 alkenyl, (CR8R )qNR4R5, C2-10 alkenyl C(O)NR4R5, (CR8R8)q C(O)NR4R5, (CR8R8)q C(O)NR4RlO, S(O)3R8, (CR8R8)q C(O)Rn, C2-10 alkenyl C(O)Rn, C2-10 alkenyl C(O)ORπ, C(O)Rn, (CR8R8)q C(O)ORl2, (CR8R8)q OC(O)Rn, (CR8R8)q NR4C(O)Rn,
(CR8R8)qC(NR4)NR4R5; (CR8R8)q NR4C(NR5)Rl i ; (CR8R8)q NHS(O)2Rπ, or (CR8R8)q S(O)2NR4R5, or two Rl moieties together may form O-(CH2)sO- or a 5 to 6 membered saturated or unsaturated ring; and wherein the aryl, heteroaryl and heterocyclic containing rings may all be optionally substituted; n is an integer having a value of 1 to 3; m is an integer having a value of 1 to 3; q is 0, or an integer having a value of 1 to 10; s is an integer having a value of 1 to 3; t is 0, or an integer having a value of 1 or 2; R4 and R5 are independently hydrogen, optionally substituted Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Cι_4alkyl, heterocyclic, or heterocyclic Ci-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S; R is independently hydrogen or Ci-4 alkyl;
RlO is Ci-10 alkyl C(O)2R8ϊ
Rl 1 is hydrogen, Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC╬╣_4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC╬╣_4alkyl;
Rl2 is hydrogen, C╬╣_io alkyl, optionally substituted aryl, or optionally substituted arylalkyl; Rl7 is C╬╣_4alkyl, aryl, arylalkyl, heteroaryl, heteroarylCi-4alkyl, heterocyclic, or heterocyclicC╬╣_4alkyl, and wherein the aryl, heteroaryl and heterocyclic rings may all be optionally substituted;
which process comprises a) reacting a compound of the formula:
Figure imgf000025_0001
wherein Ri and m are as described in Formula (B); and L is a suitable leaving group; under basic conditions in an organic solvent at elevated temperatures; and then acidifying the final product.
2. The process according to Claim 1 wherein the basic conditions are potassium carbonate, sodium hydride, cesium carbonate, sodium carbonate, and lithium carbonate.
3. The process according to Claim 1 wherein the organic solvent is DMF, THF, DMSO, NHP, or proprionitrile.
4. The process according to Claim 1 wherein the elevated temperatures are from 60 to about 130┬░C.
5. The process according to Claim 1 wherein L is a halogen.
PCT/US1999/017010 1998-07-27 1999-07-27 Novel process for making il-8 receptor antagonists WO2000006557A1 (en)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10038709A1 (en) * 2000-08-09 2002-02-28 Aventis Pharma Gmbh Substituted and unsubstituted benzooxathiazoles and compounds derived from them
US7709485B2 (en) 2002-10-29 2010-05-04 Glaxosmithkline Llc IL-8 receptor antagonists
US7893089B2 (en) 2006-04-21 2011-02-22 GlaxoSmithKline, LLC IL-8 receptor antagonists
US8097626B2 (en) 2006-04-21 2012-01-17 Glaxosmithkline Llc IL-8 receptor antagonists
CN108017522A (en) * 2017-11-16 2018-05-11 贵州大学 A kind of preparation process of 2,6- dibromos tosylate chloride

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5210196A (en) * 1989-10-12 1993-05-11 Bp Chemicals Limited Chiral sultams

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5210196A (en) * 1989-10-12 1993-05-11 Bp Chemicals Limited Chiral sultams

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10038709A1 (en) * 2000-08-09 2002-02-28 Aventis Pharma Gmbh Substituted and unsubstituted benzooxathiazoles and compounds derived from them
US7211592B2 (en) * 2000-08-09 2007-05-01 Sanofi-Aventis Deutschland Gmbh Substituted an unsubstituted benzooxathiazoles and compounds derived therefrom
US7709485B2 (en) 2002-10-29 2010-05-04 Glaxosmithkline Llc IL-8 receptor antagonists
US7893089B2 (en) 2006-04-21 2011-02-22 GlaxoSmithKline, LLC IL-8 receptor antagonists
US8097626B2 (en) 2006-04-21 2012-01-17 Glaxosmithkline Llc IL-8 receptor antagonists
CN108017522A (en) * 2017-11-16 2018-05-11 贵州大学 A kind of preparation process of 2,6- dibromos tosylate chloride
CN108017522B (en) * 2017-11-16 2021-01-05 贵州大学 Preparation process of 2, 6-dibromobenzene methane sulfonyl chloride

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