GB2228005A - Nitromethyl thioethers and sulphones - Google Patents

Abstract

Thioethers of the formula Q.S.CH2.NO2 (III), in which Q is an optionally substituted aromatic moiety, are obtained by heating alkylthio compounds of the formula Q.S.R (IV), in which R is (1-4C) alkyl, with halogenonitromethanes. The thioethers are intermediates for the production of a range of aldose reductase inhibitory nitromethane derivatives of the formula Q.SO2.CH2.NO2 (I) which are useful in the treatment of certain complications of diabetes.

Description

THIOETRER MANUFACTURE This invention concerns a novel process for the manufacture of thioether intermediates useful for the production of nitromethane derivatives which are inhibitors of the enzyme aldose reductase and which are of value, for example, in the treatment of certain peripheral effects of diabetes or galactosemia. The invention also includes a novel, two stage process for the manufacture of the nitromethane derivatives starting with aromatic thiols.

Aldose reductase inhibitors are useful in the reduction or prevention of the development of those peripheral effects of diabetes or galactosemia which may be due in part to the accumulation of the alditols sorbitol or galactitol. The latter are produced under the catalytic influence of the enzyme aldose reductase from elevated levels of glucose or galactose, respectively and the peripheral effects include, for example, macular oedema, cataract, retinopathy, neuropathy and impaired neural conduction. Although a number of aldose reductase inhibitors have been discovered and clinically evaluated, there is a continuing need for alternative inhibitors and for effective synthetic procedures for their production, such as those provided by the present invention.

The nitromethane aldose reductase inhibitors obtainable by the present invention are described in our European patent application no. 88307148.2 (publication number 304190) and have the formula Q.S02.CH2.N02 (I) in which Q is an aromatic moiety of 6, 10 or 14 atoms optionally bearing 1, 2 or 3 substituents, independently selected from: hydrogen, halogeno, cyano, nitro, hydroxy, carboxy, amino, alkylamino or dialkylamino of up to 6 carbon atoms, (1-6C)alkanoylamino, (l-6C)alkanoyl, (l-6C)alkyl, (2-6C)alkenyl, (3-6C)alkenyloxy, fluoro(1-4C)alkyl, (1-6C)alkoxy, fluoro(1-4C)alkoxy, hydroxy(1-6C)alkyl, (1-40)alkoxy(1-4C)alkyl, carbamoyl, alkyl or dialkylcarbamoyl of up to 7 carbon atoms, sulphamoyl, alkyl or dialkylsulphamoyl of up to 6 carbon atoms, (1-6C)alkoxyearbonyl, (1-4C)alkylenedioxy, (l-6C)alkanesulphonamido, (1-6C)alkyl.S(O)n- [in which n is zero, 1 or 2], phenyl, phenoxy, benzyloxy, benzyloxycarbonyl, benzamido and benzenesulphonamido, the benzene moiety of the last six groups optionally bearing a halogeno, (1-4C)alkyl or (1-4C)alkoxy substituent; or Q bears 4 or 5 substituents independently selected from halogeno, cyano, (1-6C)alkyl or (1-6C)alkoxy; but excluding the compounds in which Q is 2-carboxy-phenyl; together with the non-toxic salts of said nitromethane of formula I.

Specific values for Q include phenyl, naphthyl, phenanthryl and anthryl, of which phenyl is particularly preferred. Examples of the various substituents on Q are set out in the said European application.

Examples of values for an optional substituent which may be present on Q, as set out in the said European application, include the following: for halogeno: fluoro, chloro, bromo and iodo; for alkylamino or dialkylamino of up to 6 carbon atoms; methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino and (methyl)(propyl)amino; for (1-6C)alkanoylamino: (l-4C)alkanoylamino, such as formamido, acetamido and propionamido; for benzamido optionally bearing a substituent: benzamido optionally bearing a fluoro, chloro, bromo, methyl, ethyl, methoxy or ethoxy substituent; for (1-6C)alkanoyl: formyl and (2-4C)alkanoyl, such as acetyl, propionyl and butyryl; for (1-6C)alkyl: (1-4C)alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and t-butyl; for (2-6C)alkenyl: (2-4C)alkenyl, such as vinyl, allyl, 1-propenyl and 2-methyl-2-propenyl; for (3-6C)alkenyloxy: allyloxy, 2-methyl-2-propenyloxy and 3methyl-3-butenyloxy; for fluoro-(1-4C)alkyl: trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl and 3,3,3-trifluoropropyl; for (1-6C)alkoxy: (1-4C)alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy and t-butoxy; for fluoro-(1-4C)alkoxy: trifluoromethoxy, 2,2,2-trifluoroethoxy and pentafluoroethoxy; for phenyl, phenoxy, benzyloxy or benzyloxycarbonyl optionally bearing a substituent: phenyl, phenoxy, benzyloxy or benzyloxycarbonyl optionally bearing a fluoro, chloro, bromo, methyl, ethyl, methoxy or ethoxy substituent; for hydroxy-(1-6C)alkyl: hydroxy-(1-4C)alkyl, such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 3-hydroxypropyl; for (1-4C)alkoxy(1-4C)alkyl: methoxymethyl, ethoxymethyl, 1methoxyethyl, 2-methoxyethyl and 3-methoxypropyl; for (1-6C)alkoxyearbonyl: (1-4C)alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and tbutoxycarbonyl; for (1-4C)alkylenedioxy: methylenedioxy, ethylenedioxy and isopropylidenedioxy, attached to adjacent atoms on the aromatic moiety Q; for (1-6C)alkanesulphonamido: (1-4C)alkanesulphonamido, such as methanesulphonamido, ethanesulphonamido and butanesulphonamido; for benzenesulphonamido optionally bearing a substituent: benzenesulphonamido optionally bearing a fluoro, chloro, bromo, methyl, ethyl, methoxy or ethoxy substituent; for alkyl or dialkylcarbamoyl of up to 6 carbon atoms:Nmethylcarbamoyl, N, N-dimethylcarbamoyl, N-ethylcarbamoyl, N,Ndiethylcarbamoyl and N ,N-dipropylcarbamoyl; for alkyl or dialkylsulphamoyl of up to 6 carbon atoms. N-methylsulphamoyl, N-ethylsulphamoyl, N-propylsulphamoyl, N-butylsulphamoyl, N,N-dimethylsulphamoyl and N,N-dipropylsulphamoyl; and for (1-6C)alkyl.S(O)n- : (1-4C)alkyl.S(O) n such as methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, methylsulphonyl and ethylsulphonyl.

The majority of the above nitromethane derivatives of formula I are novel, that is those compounds of the formula I, and the non-toxic salts thereof, as defined hereinbefore, but excluding those compounds wherein Q is unsubstituted phenyl and phenyl bearing a 4-fluoro, 4-chloro, 4-bromo, 4-methyl, 4-vinyl, 4-acetamido or 2-carboxy substituent, and the alkali metal salts thereof. However, certain of the nitromethane derivatives of formula I are already known but have never been described as possessing aldose reductase inhibitory properties. These compounds include, for example, those compounds wherein Q is phenyl, 4-methylphenyl and 4-bromophenyl which are good inhibitors of the enzyme aldose reductase.

One group of novel compounds described in said European application and which is of particular interest comprises compounds of the formula Qa.S02.CH2.N02 (II), in which Qa is a phenyl moiety bearing one or two substituents independently selected from halogeno (such as fluoro, chloro or bromo) and (1-4C)alkyl (such as methyl or ethyl) substituents, or up to three (1-4C)alkyl substituents (such as methyl or ethyl); but excluding those compounds wherein Qa is 4-fluoro-, 4-chloro-, 4-bromo- or 4-methyl-phenyl; together with the non-toxic salts thereof.

Specific compounds of formula I which are described in said European application as of particular interest as aldose reductase inhibitors are those described in Examples 1, 2, 6, 7, 9, 19, 20, 30, 46 and 50 of the application, that is those compounds in which Q is 1-naphthyl, 2,4, 6-trimethylphenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 2-methylphenyl, 2,6-dimethylphenyl, 4-chloro-2 , 5-dimethylphenyl, 2-chloro-3-methylphenyl, 3-chloro-2-methylphenyl or 3-chloro-4-fluorophenyl, together with their non-toxic salts.

The nitromethanes of formula I are described in said European application as obtainable by a variety of standard procedures of organic chemistry already known for the production of structurally analogous compounds, for example by one or more of the procedures reviewed in the paper by Zeilstra et alia in Rec. Trav. Chim. Pays Bas 1974, 93, 11-14.

One such procedure involves oxidising a thioether Q.S.CH2.N02 (III). The starting thioethers of formula III are themselves obtained from the corresponding thiols Q.SE which are converted first to their thioacetic acids of structure O.S.CH2.CO2H (by reaction with alkali and chloro- or bromo-acetic acid) and thence to the salt of the corresponding nitroacetic acid of structure Q.S.CE(N02).C02E (by reaction with propyl nitrate and butyllithium), which is then decarboxylated by acidification. We have now discovered a simple and useful alternative procedure for the production of the thioethers of formula III.

According to the invention there is provided a process for the manufacture of a thioether of the formula Q.S. Cl'2. NO2 (III) which comprises reacting an alkylthio compound of the formula Q.SR (IV) in which R is (1-4C)alkyl (such as methyl or ethyl) with a halogenonitromethane of the formula X.CH2.NO2 (V) in which X is bromo or chloro, at an elevated temperature.

In general, the process is carried out at a temperature above 800C and below 200 C, for example conveniently in the range, for example, 90 to 1800C. However, it will be appreciated that the precise temperature chosen is a compromise between increased rate of reaction and minimising thermal decomposition of the reagents and end-product. It will also be appreciated that it is frequently desirable to remove the volatile product (alkyl bromide or chloride, respectively), for example, by entrainment with an inert gas such as nitrogen.

The halogeno group X is preferably bromo and R is preferably methyl.

The process may be conveniently performed in the absence of any solvent or diluent, but a high boiling diluent such as diphenyl ether or paraffin oil may be used if desired.

The process is particularly suitable for the production of those thioethers of formula III in which Q is a mono-substituted phenyl or a di-substituted phenyl in which only one substituent is ortho relative to the -S.CH2.N02 group.

It will be seen that the process of the invention is significantly shorter than that described in our co-pending application and avoids the use of butyllithium, both of which factors render it more suitable for use on a large-scale. Further, coupling the new method together with an oxidation step provided an improved synthesis for the nitromethane aldose reductase inhibitors of formula I.

The invention further provides such a process for the production of a compound of the formula I, or a non-toxic salt thereof, wherein Q has any of the meanings defined above, which comprises the steps of: (a) reacting a thioether of the formula Q.S.R (IV) wherein R is (1-4C)alkyl with a halogenonitromethane of the formula X.CH2.N02 (V) wherein X is bromo or chloro, at an elevated temperature; followed by (b) oxidising said thioether of formula III to said compound of formula I; whereafter, when a non-toxic salt is required, said compound of formula I is reacted with an appropriate base forming a non-toxic cation or, when Q contains a suitable basic group, with an appropriate acid, forming a non-toxic anion.

The oxidation step (b) may be performed using any suitable oxidising agent well known in the art for the conversion of thio to sulphonyl groups and which is compatible with the presence of other sensitive functional groups which may be present as substituents on Q.

Thus, for example, hydrogen peroxide, an organic peracid (such as perbenzoic acid) or lead tetraacetate may be used. Alternatively, an alkali metal periodate (such as sodium metaperiodate), persulphate (such as potassium monopersulphate) or permanganate (such as potassium permanganate), or gaseous oxygen in the presence of a suitable catalyst such as platinum, may be employed. The oxidation is preferably carried out in a suitable conventional solvent or diluent for such oxidations, for example in acetic or propionic acid, and at a temperature in the general range, for example 0 to 800C. In certain cases, the corresponding sulphoxide derivative of the thioether of formula III may be formed as an isolable intermediate which is then subsequently further oxidised to the required compound of formula I.

Particularly preferred conditions for the oxidation step (b) include, for example, the use of an alkali metal permanganate (such as potassium permanganate) in a suitable solvent such as acetic acid and at a temperature in the range, for example, 20 to 800C.

The process of the invention is suitable for the production of intermediate thioethers of formula III for both the nitromethanes of formula I which were first described in said European application and those which were previously known prior to said European application, but which were not then known to possess aldose reductase inhibitory properties. Examples of such nitromethanes include those compounds wherein Q is phenyl, 4-methylphenyl and 4-bromophenyl which are now known to be good inhibitors of the enzyme aldose reductase.

Aldose reductase inhibitory properties may be demonstrated in a variety of ways in experimental animals, for example as described in the said European application, the experimental protocols of which are incorporated herein by way of reference. In general, the compounds of formula I possess significant inhibitory properties on the enzyme aldose reductase: (a) at a concentration of 10 5 M (or much less) in a bovine lens enzyme preparation, using a spectrophotometric assay; and (b) following an oral dose of 100 mg/kg in rats rendered glucosuric by streptozotocin treatment, by measuring the effect on sorbitol levels.

The processes of the invention are illustrated in the following non-limiting Examples, of which Examples 1, 3, 5 and 6 demonstrate the production of the intermediates of formula III and Examples 2, 4 and 7 demonstrate the subsequent conversion of the formula III compound to the corresponding aldose reductase inhibitor of formula I, and in which, unless otherwise stated: (1) evaporations were performed by rotary evaporation in vacuo; (2) operations were carried out at ambient temperature, that is in the range 18-260C; (3) the purity of chemical products was assessed by nuclear magnetic resonance spectroscopy, thin layer chromatography and/or microanalysis; (4) proton nuclear magnetic resonance spectroscopy was carried out at 200 MHz and the usual abbreviations are used for the spectral signals in parts per million relative to tetramethylsilane as a standard; and (5) yields are given for illustration only and are not to be construed as the maximum attainable by diligent process development.

Example 1 Thioanisole (5ml, 0.043mol) and bromonitromethane (5.9ml, 0.085mol) were heated at 1250C for 7 hours with stirring during which time bromomethane was evolved. The reaction mixture was allowed to cool to ambient temperature, and excess bromonitromethane and thioanisole were removed by distillation under reduced pressure. The residue was purified using short path vacuum distillation (oven temperature 900C/ 0.01 millibar) to give (phenylthio)nitromethane as a yellow oil (2.2g, 30X yield) having a satisfactory NMR spectrum (200MHz, CDC13): 5.45(s,2H), 7.45(m,3H), 7.5(m,1H).

Example 2 A solution of potassium permanganate (124mg, 0.78mmol) in water (4ml) was added in one portion to a solution of (phenylthio)nitromethane (100mg, 0.59mmol) in acetic acid (lOml). The mixture was stirred at 650C for 30 minutes and then allowed to cool to ambient temperature. The reaction mixture was diluted with water (50ml), dichloromethane (20ml) was added, and the mixture filtered through diatomaceous earth. The solid was washed with dichloromethane (20ml), and the filtrate was washed with a solution of hydrazine dihydrochloride (100mg) in water (10ml), followed by extraction with a saturated solution of sodium hydrogen carbonate. The basic aqueous extract was acidified with 2M hydrochloric acid and extracted with dichloromethane (20ml). The organic extract was washed with sodium chloride solution (2x5ml) and dried (Na2S04). The solvent was removed by evaporation to give a pale yellow solid which was purified by flash column chromatography (Merck kieselgel Art. 7736, available from E Merck, Darmstadt, Federal Republic of Germany), eluting with dichloromethane, to give (phenylsulphonyl)nitromethane as a white crystalline solid (50mg, 42% yield); m.p. 78-790C; microanalysis, found: C, 41.5; H, 3.4; N, 6.7%; C7H7N04S requires: C, 41.8; H, 3.5; N, 7.0%.

Example 3 Using a similar procedure to that described in Example 1, but starting with 1,3-dimethyl-5-methylthiobenzene (4.93g; 32.4 millimole) (obtained as an oil by reaction of 3,5-dimethylbenzenethiol with iodomethane in the presence of potassium carbonate and in acetone as a solvent) and bromonitromethane heated at about 1100C, there was obtained (3,5-dimethylphenylthio)nitromethane as an oil; NMR: 2.30(s,6H), 5.45(s,2H), 7.0-7.3(m,3H).

Example 4 Using a similar oxidation procedure to that described in Example 2, but starting from (3,5-dimethylphenylthio)nitromethane, there was obtained (3,5-dimethylphenylsulphonyl)nitromethane as a solid, m.p. 64-660C (after trituration with ether).

Examples 5-6 Using a similar procedure to that described in Example 1, but starting from 5-methoxy-2-(methylthio)toluene and 5-acetoxy-2-(methylthio)toluene, there were obtained from bromonitromethane, respectively: (Example 5): (4-methoxy-2-methylphenylthio)nitromethane; and (Example 6): (4-acetoxy-2-methylphenylthio)nitromethane; both obtained as oils with satisfactory NMR spectra.

Example 7 Using a similar oxidation procedure to that described in Example 2, there was obtained (4-methoxy-2-methylphenylsulphonyl)- nitromethane, as a solid, m.p. 73-740C, starting from (4-methoxy-2 methylphenylthio)ni tromethane.

Claims (13)

1. CLAIHS

   What is claimed is: 1. A process for the manufacture of a thioether of the formula Q.S.CH2.N02 (III) wherein Q is an aromatic moiety of 6, 10 or 14 atoms optionally bearing 1, 2 or 3 substituents, independently selected from: hydrogen, halogeno, cyano, nitro, hydroxy, carboxy, amino, alkylamino or dialkylamino of up to 6 carbon atoms, (1-6C)alkanoylamino, (1-6C)alkanoyl, (1-6C)alkyl, (2-6C)alkenyl, (3-6C)alkenyloxy, fluoro(1-4C)alkyl, (i-6C)alkoxy, fluoro(1-4C)alkoxy, hydroxy(1-6C)alkyl, (1-4C)alkoxy(1-4C)alkyl, carbamoyl, alkyl or dialkylcarbamoyl of up to 7 carbon atoms, sulphamoyl, alkyl or dialkylsulphamoyl of up to 6 carbon atoms, (1-6C)alkoxycarbonyl, (1-4C)alkylenedioxy, (1-6C)alkanesulphonamido, (l-6C)alkyl.S(O)n- in which n is zero, 1 or 2], phenyl, phenoxy, benzyloxy, benzyloxycarbonyl, benzamido and benzenesulphonamido, the benzene moiety of the last six groups optionally bearing a halogeno, (1-4C)alkyl or (1-4C)alkoxy substituent; or Q bears 4 or 5 substituents independently selected from halogeno, cyano, (1-6C)alkyl or (1-6C)alkoxy; but Q is other than 2-carboxy-phenyl; which process comprises heating an alkylthio compound of the formula Q.S.R (IV), wherein R is (1-4C)alkyl and Q has any of the meanings defined above, with a halogenonitromethane of the formula X.CH2.N02 wherein X is bromo or chloro, at an elevated temperature.
2. 2. A process as claimed in claim 1 wherein Q is selected from phenyl, naphthyl, phenanthryl and anthryl, optionally bearing 1, 2 or 3 substituents, independently selected from: hydrogen, cyano, nitro, hydroxy, carboxy, amino, carbamoyl, sulphamoyl, fluoro, chloro, bromo, iodo, methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino, (methyl)(propyl)amino, formamido, acetamido, propionamido, formyl, acetyl, propionyl, butyryl, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, vinyl, allyl, 1-propenyl, 2-methyl-2-propenyl, allyloxy, 2-methyl-2-propenyloxy, 3-methyl-3-butenyloxy, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, hydroxymethyl, l-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, methoxymethyl, ethoxymethyl, l-methoxycthyll 2-methoxyethyl, 3-methoxypropyl, methoxycarbonyl, ethoxycsrbonyl, isopropoxycarbonyl, t-butoxycarbonyl, methanesulphonamldo, ethanesulphonamido, butanesulphonamido, N-methylcarbamoyl, N,N-dlmethylcarbamoyl, N-ethylcarbmoyl, N,N-diethylcarbamoyl or N,N-dipropylcarbamoyl, N-methylsulphamoyl, N-ethylsulphamoyl, N-propylsulphamoyl, N-butylsulphamoyl, N1N-dimethylsulphamoyl, N,N-dipropylsulphamoyl, methylthio, ethylthlo, methylsuiphinyl, ethyleulphinyl, methyleulphonyl and ethylsuiphonyl; and methylenedloxy, ethylenedioxy or isopropylidenedioxy attached to adjacent atoms on the ring Of and from phenyl, phenoxy, benzyloxy, benzyloxycarbonyl, beneamido or benzenesulphonemido, the ben2ene moiety of any of which may itself optionally bear a fluoro, chloro, bromo, methyl, ethyl, methoxy or ethoxy substituent; or Q bears 4 or 5 substituents independently selected from fluoro, chloro, promo, lodo, cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy and t-butoxy.
3. 3. A process as claimed in claim 1 wherein 0 is phenyl bearing 1, 2 or 3 substituents independently selected from any of those defined in claim 1 or 2.
4. 4. A process as claimed in claim 1, 2 or 3 wherein R is methyl or ethyl.
5. 5. A process as claimed in any one preceding claim wherein the compound of formula V is bromonitromethane.
6. 6. A process as claimed in any one preceding claim which is performed in the presence of a high boiling diluent such as diphenyl ether or paraffin oil.
7. 7. A process as claimed in any one preceding claim in which the reaction is carried out at a temperature above 800C and below 200'C,
8. 8. A process as claimed in any one of claims 1-6 in which the reaction is carried out at a temperature in the range 90 to 1800C.
9. 9. A process for the manufacture of a compound of the formula Q.S02.CH2.N02 (I) wherein Q has any of the meanings defined in claim 1, 2 or 3, or a non-toxic salt thereof, which comprises the steps of: (a) reacting a thioether of the formula Q.S.R (IV) wherein R is (1-4C)alkyl with a halogenonitromethane of the formula X.CH2.NO2 (V), wherein X is bromo or chloro, at an elevated temperature; followed by (b) oxidising said thioether of formula III to said compound of formula I; whereafter, when a non-toxic salt is required, said compound of formula I is reacted with an appropriate base forming a non-toxic cation or, when Q contains a suitable basic group, with an appropriate acid, forming a non-toxic anion.
10. 10. A process as claimed in claim 9 wherein, in the first reaction step (a), R is methyl or ethyl, X is bromo and the reactio is carried out at a temeperature in the range 90 to 1800C.
11. 11. A process as claimed in claim 9 or 10 wherein the oxidising agent for step (b) is selected from hydrogen peroxide, organic peracids, lead tetraacetate, alkali metal periodates, alkali metal metaperiodates, alkali metal persulphates, alkali metal permanganates and gaseous oxygen in the presence of a suitable catalyst.
12. 12. A process as defined in claim 1 for the production of a thioether of the formula III, claim 1, substantially as described herein with reference to any of the Examples 1, 3, 5 or 6.
13. 13. A process as defined in claim 9 for the manufacture of a nitromethane derivative of the formula I, substantially as described herein with reference to any of the accompanying Examples.