CA1044240A - Process for the preparation of 2-arylamino-2-imidazoline derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
The preparation of 2-(substituted aryl)amino-2-imidazoline derivatives, being substituted by an aroly group on one of the nitrogens of the imidazoline nucleus by aroylation the free 2-arylamino-2-imidazolines with active amides of the appropriate aromatic carboxylic acids. These compounds are of the general formula (Ia)

Description

p`~

I This invention relates to a process for the preparation of imidazolin~ derivatives, more particularly 2-arylamino-2-imidazoline derivatives and also to certain 2-dihaloarylamino-2-imidaæoline derivatives.
It is known from Austrian Patent Specifications No.
248,428, No~ 250,344 and No. 250,345 that 2-arylamino-2-lmidazoline derivatives, especially the compound 2-(2',6'-dichlorophenylamino)-

2-imidazoline, possess a pronounced hypot~nsive action coupled with a sedative action.
1~ Belgian Patent Speicification NoO 741,947 has furthermore disclosed N-aroyl derivatives of these 2-arylamino-2~imidazoline derivatives, for example 2-[N-benzoyl-(2',6'-dichlorophenyl)-amino]~2-imidazoline, which also exhibit this hypotensive and at the same time sedative action.
These N-aroyl derivatives are obtained by aroylation of the free 2-arylamino-2-imidazolines with the appropriate acid chlorides of aromatic carboxylic acids, the acid radical being exchan~ed for the hydrogen atom bonded to the aniline nitrogen.
In the copending ~anadian application Ser. No. 223,440 of ~pril 1, 1975, novel N-aroyl derivatives of 2-arylamino-2-imidazolines were disclosed, carrying the acid radical not on the aniline nitrogen but on the imidazoline nitrogen. The different ctructure of these compounds, from that of the compounds described in Belgian Patent Specification No. 741,947 can be demonstrated :
b~ various physical experiments, inter alia by the mixed melting - poin~ and NMR. This novel compounds exhibit also this hypotensive action butthe sedative component of the activity is considerably less ~

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strongly pronounced.
It has now been found, that these N-aroyl derivatives of 2~arylamino-2-imidazolines are formed in very good yield and in outstanding purity, when the free 2~arylamino -2-imidazolines are aroylated with the aid o~ active amicles of the aromatic carboxylic acids.
In accordance with the present invention there i~ provided ;~
a process Por the preparation of 2-arylamino-2-imidazollrle :~
derivatives of the general formula R~ ~ ~ N

, r~4 : or . R1 1 ,.

- N = < ~ ( b) ~ 3 CO
;~ : 4 in which each of ~1~ R2 and R3, which may be the same ~ :
: ~ :or di~ferent is a hydrogen atom or a halogen atom, pre-ferably chlorine or bromine, a lower alkyl group, a lower :15 ~alkoxy group or the nitro group, with the proviso that at leas~t one o~ R1, R2 and R3 is not a hydrogen atom, :
: and R~ represents a phenyl group, which is optionally ~ substituted by a methyl or ethyl group,-which comprises ~ :

::: 3 :, ~ L~
reac-ting an 2-~rylamino-2-imidazoline deriva~ive having the general formula R2 \ ~

at normal or elevated tempera~ure, with ~n active amide of the general formula R4 - C - X (III) '' ' , in whlch X represents the radical o~ a five-membered, optionally ~used, nitrogen-containin~ hetero-aromatic compound or the radical o~ the formula R

2 ~ </ N ~ (IV) wherein R1~ R2- R3 and R~ are defined as in formula I.
"~ctlve amides" are to be understood, above all, as those ~; compounds which are designated "azolides" according to the publication by H.A.Staab and W.Rohr, "Synthesen mit heterocyclischen Amiden" (Syntheses ~vith Heterocyclic Amides), published in W.Foerst, Neuere Methoden der ~ 4 ~ -.~:

.

~, .. ... . ..

pr~parativen oryanischen Chemie (Recent Methods of Preparative Organic Chemistry) V, page 53 et seq. In the sense of the present invention, the azolides are to be understood, above all, as those azolides of the acids oE the formula R4.COOH which are analogous to the acetic acid azolides in Table I on page 55 of this publi-cation. Examples which may be mentioned are the 1,2,3-triazolides, 1,2,4-triazolides and the azolides derived from benztriazole and benzimidazol~. The use of the imidazolides o~ the acids of the formula R4COOH is particulaxly appropriate. In addition, however, the active amide, of the ~ompound of the formula II, which contains the acid radical bonded to the aniline nitrogen can also be used for the acylation according to the present invention.
It is very surprising that the course of the acylation using azolides is different to the course using acid chlorides since, according to the publication by H. A. Staab and WO Rohr, cited above, the reactivity of these azolides is equated to that of the acid halides and acid anhydrides.
The reaction of the compounds of the formula II with the active amides of the formula III can be carried out under all the conditions customary for the azolide methodO Preferablyt the procedure is that a solution of the 2-arylamino-2-imidaæoline, of the formula II, to be acylated is added to a solution of the active amide of the formula III. The reaction can be effected by standing at room temperature, but heating, preferably to not above the boiling point of the solvent used, can also be employed.
Examples of solvents which may be mentioned are toluene, benzene, xylene, chloroform, dimethylformamide, dioxane and tetrahydrofurane. The active amide of the formula III is employed in at least an equimolar amount, relative to the compound of the formula II, and an excess of 10 ~ 20~ is preferably used.

~,,Jf(3 D~ L~
1 The reaction time is selected in accordance with the reactivity of the active amide and the reaction temperature. ~s a rule, it is several hours.
If the active amide of the formula III which is used is that in which R4 denotes the group of the formula IV, and if, in this group of the formula IV and in the compound of the formula II, the substituents of the ~enzene nucleus Rl, R2 and R3 are identical, it is not necessary to employ the compound o~ the *ormula II in equimolar amounts or in only a little less than the equivalent amount. In this case an amount substantially less than the equivalent amount, preferably less than one hal~ and ~ore preferably even only one tenth, of the equivalent amount, relative to the active amide of the formula III, is found to be suf~icient since in the course of the acylation the compound o~ the formula II is continuously liberated from the active amide of the ~ormu~a III. This variant of the process according to th~ invention is effected, for example, simply by boiling the starting materials in an aprotic, inert solvent, such as, for example, toluene or xylene.

In all the variants of the process according to the invention it is appropriate, for working up, to remove the solven~
after the reaction is complete, it ~hen being possible to purify the dry residue by recrystallisation. ~ ;
In some cases it is advisable initially to digest the dry residue with water, if appropriate with the addition of a ;~
little alkali, such as sodium carbonate solution or Na-bicarbon~
ate solution, after which ffither crystallisation starts or the aqueous phase is taken up with an organic salvent. The evapora-tion residue or the crystals can then also be recrystallised if

3 o necessary, ~ i ,. . ~: . ; - . ::

1 For the reaCtlOn~ it is not necessary in all cases to prepare the active amide of the formula III in a separa-te operation. Azolides of the formula III can also be produced in situ from the corresponding azole and an acid chloride o~ the formula R4.CoCl, and used directly. Thus, for example, it is possible to react acid chlorides of the formula R4COCl in tetra-hydrofurane with imidazole and, after completion of the reaction, to introduce a solution of the compound of the formula II into the xeaction solution. An imidazolide of the formula III can also be prepared in situ by reacting the acid of the formula R~COOH
with N,N'-carbonyldiimidazole.
Active amides in which X denotes the group of the formula IV are obtained according to the process of Belgian Patent Specification No. 7~1,947.
The compounds of the ~ormula Ia and Ib are homogeneous, well crystallised compounds. The structure of these-compounds - cannot be determined unequivocally insofar as the the question of whether the double bond is located in the imidazoline ring tIa~
or is exocyclic (Ib) must be left open. The compounds exhibit 2~ very interesting pharmaceutical pxoperties. Compounds to be singled out in particular are compounds of the formula Ia or Ib, in which the phenyl ring is substituted in the 2-position and 6-position by halogen. Although such compounds, in which R4CO
denotes the benzoyl radical or the m- or p-toluoyl radical, also have a hypotensive action, like the compounds of the formula II, for example 2-(?',6'-dichlorophenylamino)-2-imidazoline and like those aroyl derivatives which are described in Belgian Patent Specification No. 741,947, the sedative component of the activ-ity is considerably less strongly pronounced. A parti~ularly favourable relationship between the hypotensive action and the ... . .

~3~
1 sedative action is to be found in that compound in w~ich R4CO
denotes benzoyl, so that when this compound is used as a hypo-tensive agent, the fatigue, which, inter alia, manifests i~self as an unpleasant side-effect, does not occur. All these compounds show excellent oral resorption, particularly those compounds in ~hich R4CO is benzoyl.
The same type of action can also be observed in the case of the other compounds of the formula IV a and IV b, although to varying aegrees~
The absence of the sedative or central-depressan~ action can èasily be established by ascertaining the presence o~ the ~-carotid sinus reflex on narcotised rabbits after administration of the above mentioned compounds o~ the formula Ia or Ib in doses of 100 micrograms/kg. This reflex is almost completely suppressed on administration of the same dose of 2-(2',6'-dichlorophenyl-amino)-2-imidazoline.
Furthermore the suppression of the sedative action also manifests itself in the unchanged behaviour of wake mice after administration of 5 or 10 mg/kg of these benzoyl or p-toluyl compounds of the formula Ia or Ib.
The said compounds of the formula Ia or Ib, in which R4CO denotes benzoyl or m- or p-toluyl can therefore be used in medicine as hypotensive agents, in all forms of preparation customary for pharmaceutical purposes, such as tablets, dragees, capsules, suppositories, emulsions, solutions or injection solutio~s.
Depending on the form used for administration, either the free bases or the salts can be employed. Salts used are, for example, those with inorganic or organic acids, such as hydrohalides, phosphates, oxalates, 8-chlorotheophyllinates or ~`~
2~
1 or salts with acid synthetic resins.

The examples which follow are intended to explain the process according to the invention in more detail.

The NMR absorptions indicated in these examples are quoted in ~ -values.

Example 1.

1.47 g of benzoic acid ~12 ~nols) are dissolved in 50 ml of absolute tetrahydrofurane and 1.95 g of N,N'-carbonyl-diimidazole are added to ~he solutionl while stirring. The m.ix-ture is left at room temperature for 45 minutes. A solu~ion of 2.30 g of 2-(2',6'-dichlorophenylamino)-2-imidazoline in 2S ml -~
of absolute tetrahydrofurane is ~0 ~' ~ ' "
.
;' ' ' ' - ~

.

~ 4~
added, whlle stirrin~, ~nd the mixture is then le~t to stand for 20 hours at room temperature. The solvent is distilled o~f a-t normal pressure and the residue is digested with abou-t 50 ml o.P 0.5 % stre}lg~h sodiwn bicarbonate solution, whereupon crystallisation o~curs.
The mixture is ~iltered and the cryst~ls are w~hed well with H20 and dried in vacuo over P205. 3,31 g of crude 1-benæoyl-2-(2',6'-dichlorophenylamino)-2-imidazoline are thus obtained and are recrystallised ~rom isopropanol.

Yield of pure product: 2.65 g (that is 77.2 % of theory) of melting point = 160 - 162C.
Analysi5: C1 6H1 3Cl2N3 Calculated: C ~7.19 H 3.98 N 12.55 o 5.23 Cl 21.10 ~ound: 57.4 ~.1 12.4 5.2 20.8 pKa: 4.01 ~in 70% strength methylcellosolve at room tem-perature) ~`~
UV:. ~ = 237 nm (sh; = 22,100) in ethanol IR: (KBr) 3,310 cm 1, 1,686 cm 1, 1,656 cm 1, 1,612 cm 1 t 1,579 cm~1 NMR: (100 MHz, CDCl3): 3.42 (2H, approximate triplet),

4,01.(2H, approximate triple-t), approx. 4.10 (m~ broad, NH, exchanges with D20).
2-CN-Benzo~l-(2',6~-di.chlorophenyl)-amino~-2-imidazoline according to Belgien Patent Specification No. 741,947 also has a me~ting point of 160 - 161C but the two compounds have a mixed melting point o~ 134 - 143C

. The other characteristic data of the compound according : to the Belgian Patent Speci~ication are:
pKa value = 6~10 (in 70 % strength methylcellosolve at room temperatu~e~

. - 10 -, ... . ... .

246~
NMR: (100 M~lz, CDCl3); 3.66 (S, ~H), 6.43 (m, brocld, NH, exchanges ~rith D20); ~hus ~hese data are also markedly dif~erent.
.~
t,.,.~
~x~mple 2:
4~60 g o~ 2-(2',6'-dichlorophenyIamino)-2-imidazoline (20 n~iols) and 4.23 g of p-toluylimidazolide (23 mmols) are boiled under reflux in 60 ml o~ absolu~e toluene ~or 2~5 hours. The mixture is ~hèn evaporated and the re~idue is digested with 40 ml o~ isopropanol and filtered and the product is dried; 6.27 g o~ crude 1-p-toluyl-2-(2',6'-dichlorophenylamino)-2-imidaæoline (that is 90.2 % of theory) of melting point = 156 - 176C are thus obtained and puri~ied by recrystallisation ~rom isopropanol~ ,-

5.74 g o~ the pure product (that is 82,7 % o~ theory) oP
melting point 172 - 175C are thus obtained.
Y : Cl 7H1 5(,12N30 ~;' calculated: C 58.63 H 4.34 Cl 20.36 N 12.06 0 4.59 found: 58.8 4.6 20.2 11.9 4.9 pKa: ~.18 (in 70 % strength methylcellosolve at room tem-perature) UV: ~ = 236 nm (sh,~ - 20,200) in ethanol IR: (KBr): 3,310 cm 1, 1,689 cm 1, 1,650 cm 1, 1,620 cm 1 NMR (100 MHz, CDCl3): 3.48 (2H, approximat~ triplet~p 4.07 (2H, approximate triplet), approximately 4.20 (m, broad, NH, exchanges with D20). ;~

- Example 3:
1.63 g o imidazole ~2~ mmols) are dissolved in 10 ml .

. .

o~ ~bsolute tetrahydrofurane. A solution o~ 1.85 g oP
~; p-toluyl chloride (12 mmols) in 10 ml o~ absolute ~etra-~i h~clrofurane is added dropwise to this solution and when '`Fl!! , ~, the dropwise addition is complete the mixture is stirred for ~ further 2 hours at room temperatureO The imidazole hydrochloride which ha~ precipitated out is then ~iltered of~, the crystals are covered with 5 ml of absolute tetr~-hydro~urane and the mixture is filtered using strong suction, The resulting filtrate is added, in the courSe of 5 minutes 7 while stirring to a solution of 2.30 g o~ 2-(2',6~-di- '' chlorophenylamino)-2-imidazoline (10 ~nols) and the mi~ture is then left or 20 hours at room temperature. It is then evaporated and the residue is treated hot with 25 ml of '-isopropanol and then left ~o stand for 4 hours at room temperature~ The mixture is Piltered and the product is washed with isopropanol and dried. 2.99 g of pure 1-p- -toluyl-2-(2',6'-dichlorophenylamino)-2-imidazoline~ that is 85.9 % of theory, of melting point = 172 - 175C, which is identical to the product described according to Example 2, are thu~s obtained.

Example 4:
3 g o~ o-toluic acid (22 mmols) are dissolved in 70 ml of ahsolute tetrahydrofurane, 3.57 g of N,N'-carbonyl-diimidazole are added and the mixture is stirrecl for 1 hour at room temperature. A solution of 4.60 ~ of 2-(2',6'-dichlorophenylamino)-2-imidazoline in 30 ml of tetrahydro-furane is then added. The mixture is left to stand overnight at room temperature. It is then evaporated to d~yness in vacuo7 the residue is trit~rat'ed vJe'll'with 150 ml of H20~ the mix-'12 -- -l~L~L240 ture is filtered and the product is washed with water ~nd drieds 6.05 g o~ crude 1-o-toluyl-2-(2~6l-dichloro-~; phenylamino)~2-imidazoline o~ meltlng poin~ - 160 - 175C
(that is 87.1 % o~ theory) are thus obtainedO
The product i~ puri~ied by recrystalli~ation ~rom isopropanol and 5.61 g ( that is 80.9 % of theory) of analytically pure product ~re thu~ obtained, meltin~ poin~ ~ 179 - 180C.
pKa: 3.85 (70 % strength methylcellosolve7 room tempera-ture) Uv: ~= 242 nm (sh, ~ _ 13,150) in ethanol IR: (KBr~ 3,355 cm 1, 1,706 cm 1 t 1,643 cm 1 NMR: (100 MHz, CDCl3), 3.94 (2H, approximate triplet), 4.05 and approximately 4l20 (together 3 H o~ which 1 H
can be exchanged ~or D20, in which case m at 4.05, 2H
remain).

i5 Example 5:
3 g o~ m-toluic acid (22 mols) are dissolved in 70 ml o~ tetrahydrofurane, 3.57 g of N,N'-c~rbonyldiimida%ole are added and the mixture is stirred for 1 hour at room temperature. A solution o~ 4.60 g of 2-(2',6'-dichloro-phenylamino)~2-imidazoline in 30 ml of absolute tetrahydro-Purane is then added. The mixture is le~t to stand overnight ; at room temperature. It is then evaporated to dryness in vacuo, the residue is triturated well with 150 ml o~ H20, the mixture is filtered and the product is washed with water and dried. 6.92 g o~ crude 1-m-toluyl-(2',6'-di-chlorophenylamino)-2-imidazoline are thus ob~ained and purified by recrystallisation from benzene : cyclohexane 1) and isopropanol, 6.21 g (that is 89.4 ~ of theory) ' ~

... . ~. , - ` .

~3~
of analytically pure material of meltiny point - 157 - 15~ C
being obtained.
pKa _ 4.02 (70 % strength me~hylcellosolve at room ~emperature) UV; ~ 236 nm (sh, ~ = 18,700) in etharlol IR: (KBr) 3,430 cm 1, 1,680 cm 1, 1,654 cm 1 NMR~ t100 MHz, CDCl3); 3.48 (2H, approximate triplet), 4.07 (2H, approximate triplet), approxim~tely 4.2 (m, broad, N~H, partially superposed).
Example 6:
0.65 g oP benzoic acid are dissolved in 20 ml o~ absolute tetrahydrofurane and 0.86 g of N,N'-carbonyldiimidazole are added. The mixture is le~t to stand at room temperature Por 30 to 40 minutes so that the reaction can take place.
A solution o~ 0.93 g o~ 2-(2'-chloro-6'-me~hylphenyl~mino)--2-imidazoline in 10 ml of absolute tetrahydrofurane is added to the clear solution and the mixture is heated to the re~lux temperature ~or 3.5 hours. It is then evaporated.
The residue is digested with 20 ml of 0.5 % strength sodium bicarbonate solution, the mixture is filtered and the product is washed with H20 and dried. 1.29 g o~ crude 1-benzoyl~2-(2'-chloro-6~-methylphenylamino)-2 imidazoline (that is 92.8 %
o~ theory) are thus obt~ined.
After recrystallisation from cyclohexane, 1.11 g of the pure product (that is 79.8 % of theory~ o~ melting point -124 - 127C are obtained.
UV: ~ - 234 nm (sh; ~- 16,600) in ethanol IR: (KBr) 3,415 cm 1 (sharp), 1,673 cm 1, 1,643 cm NMR:(100 MHz, CDCl3): 3.37 (2H, approximate triple-t), 3.97 (2H, approximate triplet), 4070 (m, broad, N-H, exchangeable wi~h D20).
.

... .
:; :

~. ~ .. ...... .. . .

Example 7~
1.47 g o~ benzoic acid are dissolved in 50 ml of absolute ` , tetr~hydro~urane. 1.95 g of N,N!-carbonyldiimidazole are added, whilst stirring, the mi~ture is le~-t at room te]]l-perature ~or 40 minutes, a solution o~ 3.19 g o~ 2-(2',

6~-dibromophenylamino)-2-imidazOline in 50 ml of tetra-hydrofurane is added and the mixture is left to s~and ~or 42 hours at room temperature. The solvent is then distilled off under normal pressure and the residue is digested with ~0 ml o~ 1 % stren~th sodium bicarbonate solution, whereupon crystallisation occurs. The crystals are filtered o~f, washed well with water and dried~
4.02 g of crude 1-benzoyl-2-(2',6'-dibromophenylamino)--2-imidazoline are thus obtained and are puri~ied by recrystallisation from isopropanol. 3.31 g (that is 78.6% of theory) o~ the pure product of melting point =
193 - 197C are obtained.
pKa: 3.67 (in 70% strength methylcellosolve at room tem-perature) UV: ~ = 240 nm (sh,~ = 17,400),~ = 290 nm (sh; ~ = 3,660) in ethanol IR: -(KBr) 3~375 cm 1, 1,697 cm , 1,638 cm ~
NMR: (10~ MHz, CD~13): 3.49 (2H, approximate triplet~, 4.11 (2H, approximate triplet), approximately 4.05 ;~ 25 ~ (m, broad, N-H, partially masked)~
Example 8:
200 mg o~ 2-~N-benzoyl-N-~2',6'-dichlorophenyl)-amino~--2-imidazoline are boiled under re1ux wi~h 15 mg of ., ., ., ,:

'5 , 2-(21 r6'-di.chlorophenylamino)-2-imidazoline in 10 ml of , ~
ly absolute toluene for 32 hours. The mixture is then eva--~ porated to dryness and the residue is recrystallised from l 8 ml o~ isopropanol. 160 mg o~ pur~ 1~benzoyl-2-(2',6'~
dichlorophenylamino)~2-imidazoline o~ melting point =
160 - 162C9 which is identical to the product accordin(J
to Example 1, are thus obtained.

Example 9:
500 mg of 2-CN-m-toluyl~(2',6'-dichlorophenyl)-ami no3--2-imidazoline (1.43 millimols) are heated to the re~lux temperature with 33 mg of 2-(2~t6'-dichlorophenylamino)-- -2-imidazoline (0.143 mmol) in 20 ml o~ absolute xylene for 18 hours. The solvent is stripped ofP in vacuo, the residue is dissolved hot in 3.5 ml of isopropanol and the solution is left to crystallise out slowly.
342 mg (that is 6804 % o~ theory) o~ pure 1-m-toluyl--2-(2',6'-dichlorophenylamino)-2-imidazoline o~ melting point = 157 - 158C, which is identical to the product according to Example 5, are thus obtained.
2 I N-m-Toluyl-(2',6'-dichlorophenyl)-amino~-2-imidazoline, ~-whlch serves as the starting material, is prepared by reacting 2--(2',6'-dichlorophenylamino)-2-imidazoline with m-toluic acid chloride. Melting point = 159 - 164C.
pKa - 6~68 (in 70% strength methylcellosolve at room tem~
perature.

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..... - - . -''' ' ' ' ~ ' ' ~

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Claims (8)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. Process for the preparation of 2-arylamino-2-imadazoline derivatives of the general formula (Ia) or (Ib) in which R1, R2 and R3, which may be the same or different, is a hydrogen atom or a halogen atom,a lower alkyl group, a lower alkoxy group or the nitro group, with the proviso that at least one of R1, R2 and R3 is not a hydrogen atom, and R4 represents a phenyl group, a methyl substituted phenyl group or an ethyl substituted phenyl group , which comprises reacting a 2-arylamino-2-imidazoline derivative having the general formula (II) at normal or elevated temperature, with an active amide of the general formula (III) in which X represents the radical of a 5-membered nitrogen-containing heteroaromatic compound, a 5-membered fused nitrogen-containing heteroaromatic compound or the radical of the formula (IV) wherein R1, R2, R3 and R4 are defined as in formula I.

2. Process as claimed in Claim 1 wherein the halogen atom is chlorine or bromine.

3. Process according to Claims 1 or 2, in which the active amide of the formula III is prepared in the reaction mixture by reacting the acid of the formula R4?COOH

or the acid halides thereof, with free imino compounds of the formula X-H and immediately thereafter the compound of the formula II is added to the reaction solution.

4. Process according to Claim 2, in which the active amide of the formula III is an imidazolide.

5. Process according to Claim 4, in which the imidazole is prepared in situ by reacting the acid chloride of the formula R4COCl with imidazo1e.

6. Process according to Claim 4, in which the imidazole is prepared in situ by reacting the acid of the formula with carbonyldiimidazole.

7. Process according to Claim 1, in which the active amide of the foxmula III which is employed is an active amide of the formula III in which X has the meaning (IV) R1, R2 and R3 in the radical X having the same meaning as R1, R2 and R3 in the compound of the formula II which is employed for the reaction, and the compound of the formula II is employed in a less than equivalent amount relative to the amount to the compound of the formula III which is present.

8. Process according to Claim 7, in which 1/10 of the equivalent amount of the compound of the formula II, relative to the compound of the formula III, is employed.