CA1263119A

CA1263119A - Production of 2-(2- pyridylmethylsulfinyl)benzimidazole compounds

Info

Publication number: CA1263119A
Application number: CA000573673A
Authority: CA
Inventors: Masayasu Kato; Yoshio Toyoshima; Norio Iwano
Original assignee: Takeda Chemical Industries Ltd
Current assignee: Takeda Pharmaceutical Co Ltd
Priority date: 1987-08-04
Filing date: 1988-08-03
Publication date: 1989-11-21
Also published as: EP0302720A1; DK428188D0; IE882376L; US5578732A; HU199828B; DE3875848D1; ES2052728T3; KR890003738A; GR3006974T3; EP0302720B1; ATE82283T1; DK428188A; KR960000047B1; DE3875848T2; DK171989B1; HUT49346A; IE61717B1

Abstract

Abstract of the disclosure 2-(2-pyridylmethylsulfinyl)benzimidazole compounds are produced by subjecting 2-(2-pyridylmethylthio)benz-imidazole compounds to oxidation with hydrogen peroxide in the presence of vanadium compounds in good yield and with low production of by-products.

Description

3LZ6~

1 Produc-tion of 2-(2-pyridylmethylsulElnyl)benzimidazole .
Compounds -This invention relates to ~he production of 2-(2-pyridylmethylsulEinyl)benzimidazole compounds (refer to, for example, U.S. Patent No.4255~31, European Patent Laid-Open No.45200, No.74341, No.80602, Mo.5129, No.174726, No.175464, sritish Patent Laid-Open No.2134523A), which are useful as antiulcer agents.

~s a method for production of 2-(2-pyridyl-methylsulfinyl)benzimidazole compounds, an oxida-tion o~ the corresponding 2-(2-pyridylmethyl-thio)benz-imidazole compounds with m-chloroperbenzoic acid is mentioned (r~ r to, for example, U.S. Patent No.4255431, European Patent Laid-Open No~0602).
Generally known methods for production of sulfoxides from sulfides include oxidation with peracid, hydrogen peroxide, iodosobenzene, N-halosuccinimide, tertiary butyl hypochloride, sodium metaperiodate, selenium dioxide, bromine, chlorine, or ozone [Refer -to: Saul Patai, The chemistry of ethers, crown ethers, hydroxyl groups and their sulphur analogues, Supplement E, Part 1, p.539-608, John Wllley & Sons, An In-terseience Publication (1980), Miehel Madeselaire, Tetrahedron ~eport Number 210, "Syn-thesis of Sulfoxides by Oxidation of Thioethers", Tetra-hedron, 42, 5459-5~95 (1986)].
~ lowever, the speeifications or referenees do not inelude eoncrete examples of prac-tieal production of 2-(2-pyridylmethylsulfinyl)benzimida-zole eompounds by o~idation with hydrogen peroxide as theoxidizin~ a~ent.

Oxidat:lon of 2-(2-pyridylmethylthio)benzimidazole eompounds with m-ehloroperbenzole aeid gives 2-(2-pyridyl-me~h-ylsulfinyl)benzimldazole eompounds only in low yields, producing much side products such as 2-(2~pyridylmethyl-1 sul~onyl)benzimidazole N-oxide. Such side products are very difficult to remove from 2-(2-pyridylmethylsul-finyl)benzimidazole compounds with usual methods of puri-fication, such as recrystallization. Expensiveness of m chloroperbenzoic acid is an additional problem.
There are some problems in oxidation of 2-(2-pyridyl-methylthio)benzimidazole compounds with one of the oxi-, dizing agents described above other than hydrogen per-oxide; the reaction will not proceed in many cases, and the yield is very low (less than about 75~) because of degradation or production of a great ammount of hy-products.

As the resul-ts of the inventors' researches to find a method for production of 2-(2-pyridylmethylsulfinyl)benz-imidazole compounds from 2-(2-pyridylmethyl-thio)benzimida-zole compounds in good yield and with low production of by-products such as 2-(2-pyridylmethylsulfonyl)benz-imidazole N-oxides, -the inventors have found -that oxidation wi-th hydrogen peroxide in the presence of vanadium com-pounds, for example,vanadium oxides or vanadium salts. asthe catalyst accomplishes the purpose, and have comPleted the in~ention after further researches.
This invention relates to a method for producing ~ compound having the formula (II):
~ R~

wherein the ring A may be substituted; R1 is a hydrogen atom or an N-protective group; R2, R3 an~ R~ are independently hydrogen atom, an alkyl group which may be Eluorinated or an alkoxy group which may ~e fluorinated, which comprise~ subjecting a compound having the Eormula (I):

i3.

l~vrN~--S_Cll~

wher~in ~, R1, R2, R3 and R4 are the same as described above, to oxidation with hydrogen peroxide in -the presence of vanadium compounds.
In compounds (I) and (II~, -the substituents in the ring A include alkyl, halogen, cyano, carboxy, carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, alkoxy, hydroxyalkyl, trifluoromethyl, acyl, carbamoyloxy, nitro, acyloxy, aryl, aryloxy, alkylthio and alkylsulfi-nyl etc. The alkyl groups are desirably those having to 7 carbon atoms, including methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, pentyl, hexyl and heptyl e-tc.
The halogen atoms include fluorine, chlorine and bromine atoms, among which the fluorine atom is the most desirable.
The carboalkoxy groups are desirably those in which the alkoxy group has l to 4 carbon atoms, including carbo-methoxy (CH300C-) and carboethoxy (C2H500C-) etc. The carboalkoxyalkyl groups are desirably those in which the alkoxy and alkyl groups have 1 to 4 carbon atoms each, including carbomethoxymethyl (CH300CCH2-), carbomethoxy-ethyl (CH300CC2H4-), carboethoxyllle-thyl (C2ll500CCH2-) and carboethoxyethyl (C2H500CC2H4 ~ etc. The carbamoyla~kyl groups are desirably thosè in which the alkyl group has 1 to 4 carbon atoms, including carbamoylmethyl (~l2NCOCH2-) and carbamoylethyl (H2NCOC2H~-) e-tc. The alkoxy groups are desirably those haviny 1 to 5 carbon atoms, including methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy anc1 pentoxy etc. The hydroxyalkyl groups are desirably those.in which ~le alk~l ~roup has 1 to 7 carbon atoms, inclu-diny hydroxymethyl and 1-hydroxy-propyl-2,1-hydroxy-ethyl-2,1-hydroxy-2-metl1yl-propyl-2 e-tc. The acyl 1 groups are desirably those having 1 to ~ carbon atoms, including formyl, acetyl, propionyl, butylyl an~ isobuty-lyl etc. T~le acyloxy groups are desirably those in which the acyl group has 1 to 4 carbon atoms, including ~or-myloxy, acetyloxy, propionyloxy, butylyloxy, and iso-butylyloxy etc. The aryl groups include phenyl, tolyl and naphthyl etc. The aryloxy groups include phenyloxy, tolyloxy and naphthyloxy etc. The alkylthio groups are desirably those in which the aLkyl group has 1 to 4 carbon atoms, including methylthio, ethylt}lio and propylthio etc The alkylsulfinyl groups are desirably those having l to 6 carbon atoms, including methylsulfinyl, ethylsulfi-nyl and propylsulfinyl e-tc.
The ring A is not substituted or is substituted at the 4- or 5-position particularly desirably with alkyl, halogen, trifluoromethyl or alkoxy among the substituents described above.
The N-protective groups represen-ted by R1 include alkyl, acyl, carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl, alkoxycarbonyl-me-thyl and alkylsulfonyl etc. The alkyl groups are desirably those having 1 to 5 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl and pentyl etc. The acyl groups include the same ~roups as those described ~or the substituents o~ the ring ~. The carboalko~y groups include the same groups as those described for the substituents of the ring A. The alkylcarbamoyl groups are represented by the Eormula:
}~

alkyl wherein the alkyl group has desirably 1 to ~ carbon atoms, includlng me-thylcarbamoyl, ethylcarbamoyl, propylcarba-moyl and isopropylcarbamoyl e~c. The dialykylcarbamoyl 5 groups are r~presented by the formula:
allcyl\

alkyi/

.. . .. .

~L~

1 wherein the ~lkyl groups have desirably 1 to 4 carbon ~toms each, includin~ dimethylcarbamoyl, dietllylcarbamoyl and N-methyl-N-ethylcarbamoyl e-tc. The alkylcarbonyl-methyl groups are represented by the Eormula: alkyl-CO-C1~2- wherein the alkyl group has desirably 1 to 4 carbon atoms, including acetylmethyl and propionylmethl etc.The alkoxycarbonylmethyl groups are represen-ted by the formula: alkyl-OCO-CH2- wherein the alkyl group h~s desir-ably 1 to 4 carbon atoms, including methoxycarbonylmethyl, ethoxycarbonylmethyl and propoxycarbonylmethyl etc. The alkylsulfonyl groups are represented by -the formula:
alkyl-SO2- wherein the alkyl group has desirably 1 to 4 carbon atoms, including methylsulfonyl, ethylsulfonyl, propylsulfonyl and isopropylsulfonyl etc.
The alkyl groups which may be fluorinate~ repre-sented by R2, R3 and R4, have desirably 1 to 4 carbon atoms each. Such unsubsti.tuted alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and isobutyl etc.
Such Eluorinated alkyl groups include trifluoromethyl,

2,2,2-trifluoroethyl, 2,2,3,3,3,-pentafluoropropyl, 1-(trifluoromethyl)-2,2,2-tri~luoroethyl, 2,2,3,3-tetra-fluoropropyl and 2,2,3,3,4,4,4-heptafluorobutyl etc.
The alkoxy groups which may be fluorinated, repre-s~nted hy R2, R3 and R4, have ~esirably 1 to 8 carbon atoms each. Such unsubstituted alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, hexyloxy, heptyloxy and octyloxy. Such fluori-nated alkoxy groups include 2,2,2-tri-~luoroethoxy, 2,2,3 t 3,3,-pentafluoropropoxy, 1-(tri1uoromethyl)-2,2,2-tri~luoroethoxy, 2,2,3,3-tetra~luoropropoxy, 2,2,3,3,4,4,4~hepta~1uorobutoxy and 2,2,3,3,4,4,5,5-octa-fluoropentoxy.
In more detail about the compounds ~I) and (II), it is pa~ticul~rl~ desirable that the ring ~ is unsubstituted or substituted at the 4- or 5-position wlth methoxy or trifluoromethyl, R1 ts a hydro~en atom, R2 and R~ are . . : -~ . .
, .

~,6~

1 independen-tly hydrogen atom or methyl and ~3 is a fluorinated alkoxy h~ving 2 to 5 carbol~ atoms.
The vanadium compounds used in this invention include vanadium pentaoxide (V2O5), sodium metavanadate (NaVO3), ammonium metavanadate (NH4V03~ and vanadium (IV) acetyl-acetonate [(CH3COC1l2COCH2)2VO], desirably vanadium penta-oxide, sodium metavanadate and vanadium acetylacetonate.
The amount of -tha vanadium compounds used is generally about 0.01 to 10 mole%, desirably about 0.05 to 2 mole~, particularly desirably about 0.1 to 0.5 mole%
relative to one mole of the compound (I).
Hydrogen peroxide is usually used in an aqueous solution of hydrogen peroxide, but a solution in an orga- `
nic solvent such as n-butylalcohol and a solution in the mi~ture o~ said organic solvent and water may also be used.
The concentration of hydrogen peroxide used in usually lO to 70%, desirably 20 to 40~, but should not be limited only to these ranges.
The amount oE hydrogen peroxide used is usually a slight excess relatlve to olle equivalent of the compound (I), ~0 desirably about 1 to 3 equivalents, more desirably about 1 to 1.5 equivalents.
The solvents used ~or the reaction include haloge-nated hydrocarbons such as chloroform and dichloromethane, ethers such as tetrahydrofuran and dioxane, alcohols such as ethanol, methanol and isopropanol, ketones such as acetone and methyleth~lketone, ~itriles such as aceto-nitrile and water, among which ethanol, methanol, acetone and acetonl-trile are desirable and ethanol is more desir-able. These solven-ts may be used singly or in combi-nation. The amount of the solvent used ~or the reactionis abou-t 0.5 to lO l, desirably about l to 5 l, relative to one mole of the compound (I~, but should no-t be limi-ted only to these ranges.
The re~ction temperature is usually the temperature 35 und~r ice~coollrlg to a~out the boiling point o~ the sol-vent~" usually the temperature under ice~cooling to about 7 ~ 3 3~

1 40C, more desirably about 15 to 30C.
The reaction time is usually about 0.5 to 24 hours, desirably about 1 to 8 hours.
The desired compound (II) produced by tlle reaction described above is usually separated out as crystals from -the reaction mixture, so that the crystals can be collect-ed by filtration after decomposi-tion of the excess of hydrogen peroxide remaining after the reaction by addition of an aqueous solution of sodium thiosulfate, but the crystals may also be collected by extraction with a sol-vent such as chloroform if necessary, followed by concentration~
The crystals thus collec-ted can be purified if neces-sary by a routine method such as recrystallization and chromatography.
The starting compounds (I) can be produced by the methods described in, for example, U.S. Patent No.4255431, European Patent Laid-Open No.45200, No.74341, No.80602, No.5129, No.174726, No.175464 and Great sri-tain Patent Laid-Open No.2l34523A, etc.
According to the method for production of ~s invention, 2-(2-pyridylmethylsulfinyl)benzLmldazole can be cbtained in a good yield (about 85% or more) and with low production of by-products such as 2-(~-pyridylmethylsulfonyl)benzLmidazole N-oxlde~
This invention is illustrated in more detail; in the 2S following Working ~xamples and Refere~ce Example.
Example l 2-[[3-Methyl-4-(2,2,2-tri~luoroethoxy)pyrid-2-yl]-methylthio]benzimidazole (monohydrate) (1.77 g) was dis-solved in dichloromethane (30 ml), to which was added dropwise a-t 15-20C a solut1On of hydrogen peroxide in t-butanol (2.75 ml corresponding to 0.2 g of hydrogen per-oxide~ containing vanadium pentaoxide (5 mg), and then allowed to react at 20-25C ~or about one hour. After completion of the reac-tion,an aqueous solution of sodium thiosulEate (0.5 g/30 ml) was added to the reaction mix-ture, which was stirred vigorously Eor about 10 minutes, allowed to stand still, and separated into layers. 'rhe dichlorolllethane layer was washed with wa~er (30 ml), and concentrated under reduced pressure; to the residue was I

~3~

1 added a mixture of ethanol-water (9:1, 10 ml) Eor crystal~
lization. This solution was ice-cooled, and the crystals were collected by filtration and washed with an ice-cooled mixture o ethanol-water (8 2). The crystals thus ob-tained were treated with a mixture of ethanol-water (9:1, ml), heated (65-70C) and s-tirred for dissolu-tion of the crystals, then the insoluble matters were removed by hot filtration. The filtrate was ice-cooled for crystalliza-tion, and the crystals were collected by filtration, washed with ice-cooled ethanol-water mixture (8:2) and dried in vaccuo to give white crystals of 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyrid-2-yl]me-thylsulfinyl]benz-imidazole ~1.64 g). (yield: 93.2~).
m.p. 177-178C (decomposed) Example 2 2-[[3-Methyl-~-(2,2,2-trifluoroethoxy)pyrid-2-yl]-metllylthio]benzimidazole (monohydrate) (10.0 g) was dis-solved in ethanol (75 ml)l to which was added a solution of sodium metavanadate (15 mg) in 3~% aqueous solution of hydro~en peroxide(3.07 c3), and allowed to react by stirring at 20-25 for about 8 hours. After completion of the reaction an aqueous solution of sodium thiosulfate (1 g/5 ml) was added to the reaction mixture, which was stirred vigorous-ly for about 10 minutes The crystals were collected by filtration and washed with an ice-cooled mixture of etha-nol-water (1:1). The crystals thus ~btained were -treated with a mixture of ethanol-water (9 1, 50 ml), heated (65-70C) and stirred so -that the crystals were di~solved, then the insoluble ma-tters were removed by ho-t filtra-tlon. The fLltrate was ice cooled Eor crystalliza-tion, and the crystals were collected by Eiltration, washed with ice-cooled ethanol~water mixture (8:2) and dried~ in vaccuo, to cJiVe white needles Gf 2-[[3-methyl-4-(2,2,2-tri~luoroethoxy)pyrld 2-yl]methylsulfinyl]benzimidazole (9.0 CJ). (yield: 90.5'~).
m.p. 177-17a~C (decomposed) c~

_ 9 _ 1 Example 3 2-[[3-Methyl-4-(2,2,2-trifluoroethoxy)pyrid-2-yl]-methylthiojbenzimi~azole (monohydrate) (20.0 g) was dis-solved in ethanol (150 ml), to which was added dropwise at about 20C a solution of vanadium pentaoxide (30 mg) in a mixture of 35~; a~lueous solution of hydrogen peroxide (6 .14 g) and ethanol (6 ml), and allowed to react at 18-22 for about 2.5 hours. After completion of the reaction an aqueous solution of sodium thiosulfate (2 g/60 ml) was added to -the reaction mixture, which was stirred by ice-cooling for about 1 hour. The crystals were collected by filtration .
and washed with an ice-cooled mixture of ethanol-water ~1:1). The crystals thus obtained were treated with a mixture of ethanol-water (9:1, 100 ml), heated (7o-8ooc)and stirred so that the crystals were dissolved, then the insoluble ma-tters were removed by hot fil-tration. The filtrate was lce-cooled for crystallization, and the crystals were collected by filtra-tion, washed with ice-cooled ethanol-water mixture (8:2) and dried in vaccuo, to give white needles of 2-[[3-methyl-4-(2,2,2 trifluoro-ethoxy)pyrid-2-yl]methylsulfinyl]benzimidazole (17.% g).
(yield: 89.5%).
m.p. 177-178C (decomposed) Example 4 Vanadium(IV) acetylacetonate (40 mg) was dissolved in ethanol (150 ml), to which 2-[[3-methyl-4-(2,2,2-tri-fluoroethoxy)pyr.td-2-ylimethylthio]benzimidazole (monohydrate) (20.0 g) was added and then 35~ aqueous solution of hydrogen peroxide (5.14 g) was added dropwise at Z0-25C, and the mixture was allowed to react at 20-25C ~or about 5 hours. After completion of the reaction, a solution o sodium thlosulfate (2.7 g/16 ml) was added to the reaction rnixture and sti.rred vigorously for about 10 minutes- The crystals were collected by filtration and washed wlth an ice-coo:led m:lxture o eth~nol-w~ter (8:2). The crystals thus obt~irled we.re treated w:lth a mixture of ethanol-water

3~

-- 10 ~
.
l (9-1, 90 ml), heated (60-70C) and stirred so th~t the crys-tals were disso]ved, then the insoluble matters were removed by hot filtr~tion. The filtrate was ice-cooled for crystallization and the crystals were collected by filtxation, washed with ice-cooled ethanol-water mixture (8:2) and dried in vaccuo, to give white needles of 2-~[3-methyl-4-(2~2r2-trifluoroethoxy)pyridr2-yl]methylsul-finyl]benzimidazole (18.1 g). (yield: 91.0%).
m.p. 177-178C (decomposed) Example 5 Each 2-[[3-methyl-4-(2t2~2-trifluoroethoxy)pyrid-2 yl]methylsulfinyl~benzimidazole obtained in Exam-ples 1-4 and in Reference Example described below was analyzed by high performance liquid chromatography (HPLC) and the following results were obtained.
Conditions of I~PLC
Equipment used:Shimadzu*~igh Performance Liquid Chromato-graph Type LC-6A
Detector: Shimadzu Ultraviolet Absorption Photometer Type SPD-6A, measurement wave length: 254 nm Data processor: ShimadzuType CR-3A
Column: Nucleosil 5C18 (150 x 40 mm i.d.) Column temperature: a fixed tempera-ture of about 25C
Mobile phase: A mixture of methanol-water-triethylamine (60~40:1) of which pH has been adjusted to 7.0 by addition of phosphoric acid.
Flow rate: 0.7 ml /Inin .
Time required for analysis: 30 minutes Compound Area percentage (%) in high performance liquid chromatography Exam- Exam- Exam- Exam- ReEerence _ _ ple 1 ple 2 ple 3 ple 4 Example sulfoxide derivative 1) 99 3 99.6 ~9.699.7 sa. 9 ~5 N-oxide derivative 2) 0.1 <0 1 <0.l~0,1 O.fi **rrrR(lemark --; ~
.....
::

*1 ) C OC112c~3 ~ J ~ CII.

*2) OCII 2 Cl~ 3 ~N~ Cll~Y~3 1, ~ .
Example 6 According -to the same method as in Example 4, the following compounds were produced and analyzed by HPLC
under the same conditions as in Example 5; the results are summarized as follows.

I~N,~L 11 Cll 2 ~ R ~
o R' , q~

-- 12 ~

-r~ V V V V V

~^
~ u~
~ X ~
~ ~ .

O ~ V~
:~ V V V ~ V V C~ n . ~t~ n ~ ~ _ _ _ t-- ~n co In ~co ~q_ _ .

n n n 1 n ~
r~ ~~ n n n ~ ~
cc ~ ~ cO~ o O

N n n n n _ n n ~ 0 ~0 ~ ~ n n ~a ' " '' , . ' ' . ' .~. ~ ' ~. ; -~2~

~, ~N~ C112~ N~LII ;
I I O 11' U

10 3i~ )dccompos i ~ ion Re~erenGe Example 2-[[3-Methyl-4-t2,2,2-trifluoroethoxy)pyrid-2-yl]methylth.to]benzimida.zole (monohydrate) (20 g) was dissolved in chloroform (200 ml), to which was added slowly dropwise below S C a solution of m-chloroper-benzoic acid (13.5 g) in chloroform (200 ml), and stirred at the same temperature for about 10 minutes. A~ter completion of -the reaction,the reaction mixture was washed wi-th a solution o~ sodium hydrogencarbonate, and dried : over magnesium sulfate, and chloroform was evaporated oE
under reduced pressure. To tha residue was added ethanol (100 ml) ~or crystallization; which was ice-cooled: the resulting crystals were collect~d by filtration and washed with ice-cooled ethanol. The crystals thus obtained were treated with a mixture of ethanol-water (9:1, 90 ml), ~0 heated (65-70C).and stirred SQ that the crys-taIs were dissolved, then the insoluble ma-tters were removed by hot Eiltration. The filtrate was ice-cooled ~or crystal-lization and the crystals we.re collected by filtration, washed wlth ice-cooled ethanol-water mixture (~:2), and dried in vaccuo, to glve white needles o~ 2-[~3-methyl-4-~2,2,2-trl~luoroethoxy)pyrld-2-yl]methylsulEinyl3benz-1 imidazole (14.9 g, yield: 74.9%).
m.p. 177-178C (decomposed) ' .

-~;

'' . ' ' ~ ~ .

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A method for producing a compound having the formula:
(II) (wherein the ring A may be substituted; R1 is a hydrogen atom or an N-protective group; R2, R3 and R4 are independently hydrogen atom, an alkyl group which may be fluorinated or an alkoxy group which may be fluorinated), which comprises subjecting a compound having the formula (I) (wherein A, R1, R2, R3 and R4 are the same as described above), to oxidation with hydrogen peroxide in the presence of a vanadium compound.

2. A method according to claim 1, wherein the sub-stituent of the ring A is C1-7 alkyl, halogen, cyano, carboxy, carbo-C1-4 alkoxy, carbo-C1-4 alkoxy-C1-4 alkyl, carbamoyl, carbamoyl-C1-4 alkyl, hydroxy, C1-5 alkoxy, hydroxy-C1-7 alkyl, trifluoromethyl, C1-4 acyl, carbamoyl-oxy, nitro, C1-4 acyl-oxy, aryl, aryloxy, C1-4 alkyl-thio or C1-6 alkyl-sulfinyl.

3. A method according to claim 1, whe.rein the N-protective group is C1-5 alkyl, C1-4 acyl, carbo-C1-4 alkoxy, carbomoyl, C1-4 al]cyl-carbamoyl, di(C-4 alkyl)-carbamoyl, C1-4 alkyl-carbonylmethyl, C1-4 alkoxy-carbonylmethyl or C1-4 alkyl-sulfonyl.

4. A method according to claim 1, wherein R2, R3 and R4 are independently C1-4 alkyl which may be fluorinated or C1-8 alkoxy which may be fluorinated.

5. A method according to claim 1, wherein the ring A is unsubstituted or substituted at the 4- or 5-position with methoxy or trifluoromethyl, R1 is hydrogen, R2 and R4 are independently hydrogen or methyl and R3 is a fluorinated C2-5 alkoxy.

6. A method according to claim 1, wherein the vanadium compound is vanadium pentaoxide, sodium metavanadate, ammonium metavanadate or vanadium (IV) acetylacetonate.

7. A method according to claim 1, wherein the vanadium compound is used in an amount of about 0.01 to 10 mole %
relative to the compound having the formula:

(I)

8. A method according to claim 1, wherein hydrogen peroxide is used in an amount of about 1 to 3 equivalents relative to the compound having the formula:

(I)

9. A method according to claim 2 or 3, wherein R2, R3 and R4 are independently C1-4 alkyl which may be fluorinated or C1-8 alkoxy which may be fluorinated.

10. A method according to claim 2, 3 or 4, wherein the ring A is unsubstituted or substituted at the 4- or 5-position with methoxy or trifluoromethyl, R1 is hydrogen, R2 and R4 are in-dependently hydrogen or methyl and R3 is a fluorinated C2-5 alkoxy.

11. A method according to claim 5, 7 or 8, wherein the vanadium compound is vanadium pentaoxide, sodium metavanadate, ammonium metavanadate or vanadium (IV) acetylacetonate.

12. A method according to claim 2, 3 or 5, wherein the vanadium compound is vanadium pentaoxide, sodium metavanadate, ammonium metavanadate or vanadium (IV) acetylacetonate; the vanadium compound is used in an amount of about 0.01 to 10 mole %
relative to the compound of the formula (I); and hydrogen peroxide is used in an amount of about 1 to 3 equivalents relative to the compound of the formula (I).

13. A method according to claim 2, 3 or 5, wherein the vanadium compound is vanadium pentaoxide, sodium metavanadate, ammonium metavanadate or vanadium (IV) acetylacetonate; the vanadium compound is used in an amount of about 0.05 to 2 mole %
relative to the compound of the formula (I); hydrogen peroxide is used in an amount of about 1 to 3 equivalents relative to the com-pound of the formula (I) using a solvent selected from the class consisting of halogenated hydrocarbon solvents, ether solvents, alcohol solvents, ketone solvents, nitrile solvents, water and mixtures thereof; and the oxidation reaction is carried out at an ice-cooling temperature to about 40°C.