WO2004031134A1

WO2004031134A1 - Process for making substituted aryl sulfonamides using an indium based catalyst system

Info

Publication number: WO2004031134A1
Application number: PCT/GB2003/004234
Authority: WO
Inventors: David Alan Griffin; Christopher Gregory Frost; Joseph Patrick Hartley
Original assignee: Syngenta Ltd
Current assignee: Syngenta Ltd
Priority date: 2002-10-02
Filing date: 2003-09-30
Publication date: 2004-04-15
Anticipated expiration: 2005-04-02
Also published as: GB0222833D0; AU2003267664A1

Abstract

A process for making substituted aryl sulfonamides by sulfamoylation of an activated aromatic compound using an indium compound as a catalyst.

Description

PROCESS FOR MAKING SUBSTITUTED ARY SULFONAMIDES USING AN INDIUM BASED

CATALYST SYSTEM

The present invention relates to a process for the preparation of aryl sulfonamides and to catalysts useful in such a process. Aromatic sulfonamides are of significant interest because of their bioactive nature, most notably as pharmaceuticals. Over thirty products containing this functionality are in clinical use, including antibacterials, diuretics, anticonvulsants, hypoglycemics and HTV protease inhibitors. Examples of such aromatic sulfonamides used in commercial products are sildenafil, acetazolamide, dichlorophenamide, sulphanilamide and sulfamethoxazole. The most popular route to aromatic sulfonamides involves the chlorosulfonation of an arene, to give the sulfonyl chloride, and subsequent reaction with an amine. However this approach is marred either by the need to employ a large excess of chlorosulfonic acid that leads to acidic waste or the undesirable formation of the diaryl sulfone. The reaction of trialkylarylstannanes and sulfonyl isocyanates has also been employed. Electrophilic substitution reactions introducing the sulfonamide moiety directly are less well known but an aluminium chloride promoted thia-Fries rearrangement has been reported in Tetrahedron Lett. 2001, 42, 8729 and a sulfamoylation reaction has been disclosed in Synthesis, 1977, 39. However the use of stoichiometric Lewis acids or tin reagents is undesirable, particularly on an industrial scale, due to serious waste problems. Thus a cleaner alternative to existing methodologies for making aryl sulfonamides is required. The applicants have now successfully synthesised aryl sulfonamides using a catalysed sulfamoylation process.

According to the invention there is therefore provided a process for making substituted aryl sulfonamides by sulfamoylation of an activated aromatic compound using an indium compound as a catalyst. The reaction is suitable for the production a wide range of substituted aryl sulfonamides. An activated aromatic compound is an aromatic compound substituted by one or more activating groups. Suitable activating groups are halogen or any electron-donating group. The skilled person would readily be familiar with groups that are known to be electron-donating but typical examples are optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkylthio and optionally substituted alkylcarbonyloxy.

The term aryl encompasses carbocyclic aromatic rings (such as phenyl, naphthyl, anthracyl, fluorenyl and indenyl) and heteroaromatic rings (also referred to as heteroaryl groups) which are aromatic ring systems containing at least one heteroatom and consisting either of a single ring or of two or more fused rings. Preferably, single rings will contain up to three and bicyclic systems up to four heteroatoms which will preferably be chosen from nitrogen, oxygen and sulphur. Examples of such groups include furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrimidinyl, 1,2,3-triazinyl, benzofuryl, benzisofuryl, benzothienyl, benzisothienyl, indolyl, isoindolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, benzotriazinyl, purinyl, pteridinyl and indolizinyl. Preferred examples of heteroaromatic rings include thienyl, furyl, oxazolyl, isoxazolyl, thiazolyl and 1 ,3 ,4-thiadiazolyl.

Halogen is fluorine, chlorine, bromine or iodine.

The substituents on the amino group maybe independently Cι-ιo alkyl groups which may themselves be optionally substituted.

Preferred catalysts are indium (DI) chloride, indium (HI) acetate, indium (ID) acetylacetonate, indium (HI) nitrate, indium (HI) perchlorate, indium (El) sulfate, indium (ITJ) trifluoroacetate, indium (El) trifluoroacetylacetonate, indium tris(trifluoromethanesulfonate) [also known as indium (ID) Inflate] and indium (in) triflamide. One particularly suitable catalyst is indium (111) triflate.

In one aspect of the invention the sulfamoylation is an intramolecular sulfamoylation reaction in which an aromatic compound carrying an electron-donating substituent and a sulphonamide is converted to a compound in which a 5-7 membered ring containing N and S (the S atom carrying two oxygen atoms) is fused onto the aromatic ring. In one particular aspect of the invention the aromatic compound may be substituted by a group that is both electron donating and sulphonamide-containing.

In another aspect of the invention there is provided a process for preparing a compound of formula (I)

Ar-SOz-NP^R² (1) where Ar is an optionally substituted aryl group and R¹ and R² are, independently H, optionally substituted C_1-10 alkyl, preferably optionally substituted C_1-6 alkyl, or optionally

1 substituted aryl; or R and R together with the N atom to which they are attached form an optionally substituted five-, six- or seven-membered heterocyclic ring, by reacting a compound of formula (IT)

Ar-H (H) where Ar is as defined in relation to formula (I) with a compound of formula (IH) Z-SOz-NR^² (HI) where R¹ and R² are as defined in relation to formula (I) and Z is a leaving group, in the presence of an indium compound.

Suitable optional substituents for Ar in formula (I) are halogen or an electron- donating group. Examples of a compound of formula (I) are sildenafil, acetazolamide, dichlorophenamide, sulphanilamide and sulfamethoxazole. Preferably Z is halo, more preferably chloro.

Each alkyl moiety is a straight or branched chain and unless otherwise stated is C^o alkyl, preferably C_1-6 alkyl, more preferably C_1-4 alkyl. Typical examples of alkyl are methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isσ-propyl, n-butyl, sec-butyl, ώo-butyl, tert-butyl or nβo-pentyl. Terms where alkyl is part of a larger grouping such as haloalkyl, alkylthio and alkoxy are to be construed accordingly.

Similarly alkenyl groups are straight or branched chains and unless otherwise stated are C_2-1o alkenyl, preferably C_2-6 alkenyl, more preferably C_2-4 alkenyl and alkynyl groups are straight or branched chains and unless otherwise stated are C_2-10 alkynyl, preferably C_2-6 alkynyl, more preferably C_2-4 alkynyl.

Cycloalkyl groups are preferably C _-7 cycloalkyl, more preferably Cs-β cycloalkyl. The terms heterocycle or heterocyclic ring refer, unless otherwise stated, to a non- aromatic ring system of one or two rings containing up to 10 atoms including one or more (preferably one, two, three or four) heteroatoms selected from O, S and N. Examples of such rings include 1,3-dioxolane, tetrahydroftrran, morpholine and pipieridine; a further example is piperazine.

When present, the optional substituents on an alkyl moiety include one or more of halogen, nitro, cyano, NCS-, C _-7 cycloalkyl (itself optionally substituted with C_1-6 alkyl or halogen), C_5-7 cycloalkenyl (itself optionally substituted with C--6 alkyl or halogen), C_MO alkoxy, CM_O alkoxy(C_1-10)alkoxy, C_1-6 alkoxy-carbonyl(C₁.₁o)alkoxy, Cι.₁₀ haloalkoxy, aryl- (d-^alkoxy (where the aryl group is optionally substituted by halo, C_1-4 alkyl or C_1- alkoxy), C₃-₇ cycloalkyloxy (where the cycloalkyl group is optionally substituted with C_1-6 alkyl or halogen), C _O alkenyloxy, CMO alkynyloxy, CM_O alkylthio, CM_O haloalkylthio, aryl(C_1-4)-alkylthio (where the aryl group is optionally substituted by halo, CM alkyl or C_1-4 alkoxy), C_3-7 cycloalkylthio (where the cycloalkyl group is optionally substituted with C-.₆ alkyl or halogen), arylthio (where the aryl group is optionally substituted by halo, C_1-4 alkyl or C_1- alkoxy), C_1-6 alkylsulfonyl, d-₆ haloalkylsulfonyl, C_1-6 alkylsulflnyl, d-₆ haloalkylsulfinyl, arylsulfonyl (where the aryl group is optionally substituted by halo, d- ₄ alkyl or C_1- alkoxy), C_MO alkylcarbonyl, CM_O alkoxycarbonyl, aminocarbonyl, C_1-6 alkylaminocarbonyl, di(Cι_6 alkyl)-aminocarbonyl, N-(Cι-3 alkyl)-N-(C_1-3 alkoxy)aminocarbonyl, C_1-6 alkylcarbonyloxy, arylcarbonyloxy (where the aryl group is optionally substituted by halo, C_1-4 alkyl or C_1- alkoxy), di(C_1-6)alkylaminocarbonyloxy, aryl (itself optionally substituted by halo, C_1-4 alkyl or C_1-4 alkoxy), heterocyclyl (itself optionally substituted by oxo, C_1- alkyl, C_1-4 alkoxy or halogen), aryloxy (where the aryl group is optionally substituted by halo, C_1-4 alkyl or C_1- alkoxy), heterocyclyloxy (where the heterocyclyl group is optionally substituted with oxo, C_1-4 alkyl, Ci^ alkoxy or halogen), d-₆ alkylamino, di(Cμ₆)alkylamino, d-₆ alkylcarbonylamino and

(C ₁.₆)alkylamino .

Preferably the optional substituents on an alkyl moiety include one or more of halogen, nitro, cyano, CM_O alkoxy (itself optionally substituted by C_MO alkoxy), aryl(Cι- ₄)alkoxy, C _O alkylthio, CM_O alkylcarbonyl, C_MO alkoxycarbonyl, d-₆ al lan inocarbonyl, di(C_!-₆ alkylaminocarbonyl, (C_1-6)alkylcarbonyloxy, d-₆ alkylcarbonylamino, phenyl (optionally substituted by halo, C_1-4 alkyl or C_1- alkoxy), heteroaryl (optionally substituted by halo, C_1-4 alkyl or C_1- alkoxy), phenoxy (optionally substituted by halo,

alkyl or C_1-4 alkoxy), heteroaryloxy (optionally substituted by halo, d-₄ alkyl or C1-4 alkoxy), heterocyclyl (optionally substituted by oxo, halo, Cι-₄ alkyl or C_1-4 alkoxy), heterocyclyloxy (optionally substituted by oxo, halo, C_1-4 alkyl or C_1-4 alkoxy), C_3-7 cycloalkyl (itself optionally substituted with (C_1-6)alkyl or halogen), C_3-7 cycloalkyloxy, Cs_₇ cycloalkenyl, Cι_-6 alkylsulfonyl or C_1-6 alkylsulfinyl.

More preferably the optional substituents on an alkyl moiety include one or more of halogen, nitro, cyano, C_MO alkoxy (itself optionally substituted by C _O alkoxy), aryl(d. ₄)alkoxy, Cι-₁₀ alkylthio, CMO alkylcarbonyl, C_1-10 alkoxycarbonyl, C-.₆ alkylaminocarbonyl, di(Cι-₆ alkylaminocarbonyl, (C₁-₆)alkylcarbonyloxy, d-₆

phenyl (optionally substituted by halo, C_1- alkyl or C_1-4 alkoxy), phenoxy (optionally substituted by halo, Cι_-4 alkyl or C_1-4 alkoxy), heteroaryl (optionally substituted by halo, C_1- alkyl or C_1-4 alkoxy), phenoxy (optionally substituted by halo, C_1-4 alkyl or C_1-4 alkoxy), heteroaryloxy (optionally substituted by halo, CM alkyl or C_M alkoxy), heterocyclyl (optionally substituted by oxo, halo, Cl-4 alkyl or Cl-4 alkoxy), heterocyclyloxy (optionally substituted by oxo, halo, Cl-4 alkyl or Cl-4 alkoxy).

Optional substituents for alkenyl, alkynyl and cycloalkyl are as those listed above for , alkyl.

Preferred Ar groups are phenyl. When present, the optional substituents on aryl (including heteroaryl) and heterocyclic groups are as those for alkyl; in addition the optional substituent maybe C_1-10 alkyl. In addition heterocyclic groups may be substituted by one or more oxo groups.

The reaction is preferably carried out at a temperature of 50-200° C, preferably at a temperature of 100-200°C. Even more preferably the reaction is carried out at a temperature of lOO-120°C.

The reaction may be carried out at elevated pressure.

The reaction may be carried out in the presence of a solvent, such as an aromatic solvent (for example toluene), mtromethane, acetonitrile, an ether (such as tetrahydrofuran or dioxane) or a chlorinated alkane such as dichloroethane. Preferred solvents are chlorinated alkanes and a more preferred solvent is dichloroethane.

Preferably the molar ratio of the compound of formula (H) to the compound of formula (ID) is from 1:1 to 100:1 and more preferably from 1:1 to 10:1; a ratio of 5:1 gives the highest yields in the shortest time. The invention is illustrated by the following Examples.

EXAMPLE 1 This Example illustrates the preparation of dimethyl-p-toluenesulfonamide by reacting toluene with N,N-dimethylsulfamoyl chloride in the presence of various catalysts.

A stirring mixture of toluene (0.46g; 5mmol) dimethylsulfamoyl chloride (0.14g; lmmol) and indium triflate (0.112g; 20mol%) in dichloroethane [DCE] (5ml) was heated to

100°C for 24hours. The reaction mixture was then partitioned between dichloromethane and

1 M HCl. The aqueous layer was washed with dichloromethane three times and the combined organics were washed with brine, dried over MgSO (anhydrous) and concentrated to afford crude sulfonamide product which was purified by flash chromatography using petroleum ether

: ethyl acetate (4 : 1) as eluent to afford dimethyl-p-toluenesulfonamide as a white crystalline solid, mp 79-81°C.

1HNMR (CDC1₃) δ: 2.45(s,3H,Ar-Me), 2.68(s,6H,N-Me), 7.23-7.26(m,2H), 7.64-7.69(m,2H)ppm.

Expected: C 54.3; H 6.60; N 7.0%. Found: C 54.3; H 6.55; N 7.0%.

Results obtained with the same mol% of different catalysts are presented in Table 1

Table 1.

EXAMPLE 2

In this Example an aromatic compound was reacted with a sulfamoyl chloride using indium triflate as catalyst.

A stirring mixture of anisole (0.89ml; 8.25mmol), N,N-dimethyl sulfamoyl chloride (0.237g; 1.65mmol) and In(OTf)₃ (0.184g; 20mol%) in dichloroethane (5ml) was heated to 100°C for 24hours. The reaction mixture was then partitioned between dichloromethane and 1 M HCl. The aqueous layer was washed with dichloromethane three times and the combined organics were washed with brine, dried over MgSO₄ (anhydrous) and concentrated to afford crude sulfonamide product which was purified by flash chromatography using petroleum ether: ethyl acetate (4 : 1) as eluent.

The procedure was repeated for various other aromatic compounds and other sulfamoyl chlorides; the results are set out in Table 2.

Table 2

Table 2 (continued)

Aromatic Sulfamoyl Product Yield

(%) Compound Chloride

Toluene Diethyl /=\J r^~Me 64 ' O — Me

(o.m.p; 0:0: 100)

Anisole Piperidyl 80

(o:m:p; 36:0:64)

Toluene Piperidyl 51

(p:m:p; 0:0:100)

Naphthalene Piperidyl 56

(a : β ; 24 : 76)

EXAM PLE3

This Example illustrates an indium catalysed intramolecular sulfamoylation reaction.

56% Yield

A stirring mixture of ethyl(phenethyl)sulfamoyl chloride (0.300g; 1.212mmol) and indium triflate (0.136g; 20mol%) in dichloroethane [DCE] (5ml) was heated to 100°C for 24 hours. The reaction mixture was then partitioned between dichloromethane and 1 M HCl. The aqueous layer was washed with dichloromethane three times and the combined organics were washed with brine, dried over MgSO₄ (anhydrous) and concentrated to afford crude sulfonamide product which was purified by flash chromatography using petroleum ether : ethyl acetate (4 : 1) as eluent to isolate 2-ethyl-3,4-d y(fro-2H-benzo[e][l,2]thiazine 1,1- dioxide as a white crystalline solid, mp 59-60°C.

1H NMR (CDC1₃) δ: 1.25-1.32(t,3H, J=7.2 Hz), 3.00(t,2H, J=6.4Hz), 3.26(q,2H, J=7.2Hz), 3.89(t,2H, J-6.4 Hz), 7.21-7.86(m, aromatic protons, 4H)ppm.

Expected: C 56.8; N 6.6; H 6.20%. Found: C 56.5; N 6.5; H 6.15%.

Claims

CLATMS

1. A process for making substituted aryl sulfonamides by sulfamoylation of an activated aromatic compound using an indium compound as a catalyst.

2. A process according to claim 1 wherein the activated aromatic compound is an aromatic compound substituted by one or more activating groups selected from halogen or an electron-donating group.

3. A process according to claim 2 wherein the activated aromatic compound is an aromatic compound substituted by one or more activating groups selected from halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkylthio and optionally substituted alkylcarbonyloxy.

4. A process for preparing a compound of formula (I)

Ar-SO₂-NR¹R² (I) where Ar is an optionally substituted aryl group and R¹ and R² are, independently H, optionally substituted C_MO alkyl or optionally substituted aryl; or R¹ and R² together with the N atom to which they are attached form an optionally substituted five-, six- or seven-membered heterocyclic ring, by reacting a compound of formula (II)

Ar-H (D) where Ar is as defined in relation to formula (I) with a compound of formula (ID)

Z-SOa-NR^² (ID) where R¹ and R² are as defined in relation to formula (I) and Z is a leaving group, in the presence of an indium compound.

5. A process according to claim 1 wherein the substituted aryl sulfonamide is sildenafil, acetazolamide, dichlorophenamide, sulphanilamide or sulfamethoxazole.

A process according to any preceding claim wherein the indium compound is indium (ID) chloride, indium (ID) acetate, indium (ID) acetylacetonate, indium (DJ) nitrate, indium (DI) perchlorate, indium (Dl) sulfate, indium (HI) trifluoroacetate, indium (DI) trifluoroacetylacetonate, indium (ID) triflate or indium (DI) triflamide.

A process according to claim 6 wherein the indium compound is indium triflate.