DD159285A5 - MEANS TO INCREASE THE PROFIT OF PLANTS - Google Patents

Abstract

There is provided a means for increasing crop yield of field and garden crops comprising an effective amount of a 2- (2-imidazilin-2-yl) -pyridine or 2- (2-imidazolin-2-yl) -quinoline derivative contains. One possible compound is methyl 2- (5-isopropyl-4-oxo-2-imidazolin-2-yl) nicotinate.

Description

23 0 46 6

14 554 55

Means for increasing crop yield in cereals or legumes -

Field of application of the invention

The invention relates to a means for increasing crop yield in cereals or legumes.

Characteristic of the known technical solutions

Although many remedies are already known for the above purpose, there is a need for improved drugs due to undesirable side effects.

Explanation of the essence of the invention

To increase the axillary branching and the yield, a sufficient amount of a compound of the formula I is applied to the leaves or the soil.

R ₁ (I)

B W

Stand in this formula

R _{1 is} C 1-4 alkyl;

R _{2 is} Cj ^ -alkyl or C - ^ -cycloalkyl; wherein R ₁ and R _{2 may} together form an optionally methyl-substituted C, g-cycloalkyl group;

A is COOR ₃ , CONHR ₆ , CHO, CH ₂ OH, COCH ,, COC ₆ CN, CH ₃ , CH = NOH, CH ₂ COOH, CONHOH, CHRqOH, CH ₂ CH ₂ COOH,

N-

COOCH

or COCH - *, where 0 »

Il J C.

R _{3 is} hydrogen;

Di-lower alkylimino; Di-niederalkylketimino;

C _1-12 alkyl optionally substituted with one of the following groups: C _1-3 alkoxy, halogen, hydroxy, C _3-6 cycloalkyl, benzyloxy, furyl, phenyl, halophenyl, lower alkylphenyl, lower alkoxyphenyl, nitrophenyl, carboxyl, lower alkoxycarbonyl , Cyano or tri-lower alkylammonium;

C _3-12 alkenyl, optionally substituted by one of the following groups: C _1-3 alkoxy, phenyl, halogen or lower alkoxycarbonyl or by two C _1-3 alkoxy groups or by two halogen atoms;

C 1-8 cycloalkyl optionally substituted by one or two C _1-3 alkyl groups;

C _3-1 Q-alkynyl optionally substituted by one or two C _1-3 alkyl groups; or

a cation selected from the group consisting of alkali metal, alkaline earth metal, manganese, copper, iron, zinc, cobalt, lead, silver, nickel, ammonium and organic ammonium;

-3- 230466

R ₆ is hydrogen, hydroxyl, C ^ -alkenyl, C ₃ -alkynyl or C ₁ _ ^ - alkyl, optionally substituted by a hydroxyl group or a chlorine atom;

B is H, COR ^ or SO ₂ R ₅ , with the proviso that when B is COR ^ or SO ₂ R ₅ , the radical A is a group of the formula COOR, (in the R, not for H and does not stand for a salt-forming cation) or for CEU or CN; the radical W is 0; and Y and Z are not alkylamino, hydroxy or hydroxy-lower alkyl;

R ^ is C ₁ ^ ₁₁ alkyl, chloromethyl or phenyl (optionally substituted by a chlorine atom, a nitro group or a methoxy group);

R _{5 is} C 1-4 alkyl or phenyl (optionally substituted by a methyl group);

W for 0 or S;

R _{8 is} C ₁ ^ -alkyl or phenyl;

X is hydrogen, halogen, hydroxyl or methyl, with the proviso that when Y and Z together form a ring and the group -YZ- has the structure - (CHp) -, where η is 3 or 4, then X is hydrogen ; and

Y and Z are each a radical from the following group: hydrogen, halogen, C 1-6 -alkyl,

Hydroxy-lower alkyl, C ₁ _ £ alkoxy, _C1 ^ alkylthio, phenoxy, Cj ^ haloalkyl, nitro, cyano, _C1 ^ alkylamino, di-lower alkylamino, Cj ^ alkylsulfonyl, or (optionally substituted by a C ^^ -Alkyl group, a C _{1 -Zf} -alkoxy group or a halogen atom-substituted) phenyl; or wherein <Y and Z may together form a ring, wherein the group -YZ- has the following structure: - (CH ₂ ) -, where η stands for 3 or 4 and wherein the condition X = H applies; or where

the group -Y-Z- has the following structure:

LMQR ₇

till '

-C = CC = C-, in which L, M, Q and Ry, each represent a member of the group of the following radicals? Hydrogen, halogen, C ^ alkyl, C _1-Zj alkoxy, _C1 ^ alkylthio, C _1-Zj alkylsulfonyl, C ₁ _ ^ - haloalkyl, NO _2, CN, phenyl, phenoxy, amino, C ^^ -Alkylaraino, di-lower alkylaraino, chlorophenyl, methylphenyl or phenoxy (optionally substituted by one of the groups Cl, CF ,, NO ₂ or CH,), under the condition that only one of the radicals L, M, Q or Ry is a group , which is different from hydrogen, halogen, C, ^ - alkyl or C ₁ λ-alkoxy;

and the N-oxides thereof when W is 0 and when A is CN, CH * or COOR, provided that R can be unsaturated alkyl and Y and Z are neither alkylamino nor dialkylamino nor alkylthio stand

can;

and the optical isomers thereof, if R ₁ and R ₂

are not equal;

and the acid addition salts thereof, if R, no

salt-forming cation means.

The invention also relates to a process for the effective initiation and / or acceleration of the ripening process of cereal plants by application of an amount of 2- (2-imidazolin-2-yl) -pyridine or 2- (2-imidazoline-2) sufficient to accelerate the ripening -yl) -quinoline compound of the formula (I) on the leaves of cereal plants and / or the soil containing seeds of these plants. A further advantage of the application of 2- (2-imidazolin-2-yl) -pyridines or -quinolines of the formula (Ϊ) in amounts between about 0.0001 and 0.01 kg / ha to the leaves of a variety of legumes or herbaceous Ornamental plants or to the soil in which these plant species are reared, is that such a treatment often a mild effect in the sense

23 0 46 6 0

of a dwarf's vixen. This dwarfism effect is particularly advantageous in the treatment of ornamental plants, since in this way the aesthetic value of the plant can be measurably improved by reducing its height and increasing its canopy effect.

A preferred group of 2- (2-imidazolin-2-yl) pyridine compounds of the above formula (I) is for use in the methods of the invention. R _{1 is} methyl; R 2 is methyl, ethyl, isopropyl or cyclopropyl; W for oxygen; B represents hydrogen, CO-alkyl-C 1-6 or CO-phenyl optionally substituted by chlorine, nitro or O-methoxy; A is COOR ₃ , CH ₂ OH or CHO, v / o where R _{5 has} the meaning given in formula (i); X is hydrogen and Y and Z are selected from the group of hydrogen, C ₁ _g-alkyl, C, _g-alkoxy, halogen, phenyl, nitro, cyano, trifluoromethyl or methylsulfonyl or Y and Z may together represent the group - (CH ₂ ) ^. A particularly preferred group of 2- (2-imidazolin-2-yl) -pyridines have the following formula (Ia)

J Ä

wherein B is hydrogen, CO-alkyl-Cj_g or CO-phenyl and wherein A is COOR ^, wherein R, has the meaning given in formula (I); and wherein X is hydrogen and Y and Z each represent hydrogen, C _1- ^ - alkyl, C ₁ _4 -alkoxy, halogen, C _1-if haloalkyl or phenyl or where Y and Z together, the "- (CH ₂ ) can form λ-.

Most preferred are compounds of formula (Ia), i. 2- (2-imidazolin-2-yl) -pyridine compounds in which B, X, Y and Z are each hydrogen and A is COOR and R is as defined for formula (I).

A preferred group of 2- (2-imidazolin-2-yl) quinoline compounds useful in the processes of the present invention has the following formula (II):

, ϊ; _M (id Y ν ν \ / ^l

⁷ ίΉ "" * ²

Here, R ₁ , R ₂ , ¥, B, A, X, L, M, Q and Ry have the meanings given in formula (I). However, particularly preferred compounds are present when Rj is methyl; and R _{2 is} methyl, ethyl, isopropyl or cyclopropyl; and when V / is oxygen; and B is hydrogen, CO-alkyl-Cj ^ g or CO-phenyl, optionally substituted by a chlorine atom, a nitro group or a methoxy group; and when A is COOR ,, CH ₂ OH or CHO and R has the meaning given in formula (I); and when X is hydrogen and L, M, Q and Ry are each selected from the following group: hydrogen, halogen, methoxy, nitro, alkylCj 1, CF ,, CN, N (CH ₂ ) ₂ , NH ₂ , SCH, or SO ₂ CH, provided that only one of L, M, Q or Ry is nitro, CF ,, CN, N (CH ₂ ) ₂ , NH ₂ , SCH ₃ or SO ₂ CH ₃ .

Particularly preferred are 2- (2-imidazolin-2-yl) -quinoline compounds of the formula (II) in which X, L and Ry are each hydrogen; and R ^ is methyl; R _{2 is} methyl, ethyl, isopropyl or cyclopropyl, and B is a hydrogen atom or a COCH 2 - group and A is one of the groups COOR ₃ , CH ₂ OH or CHO, wherein R _{3 has} the meaning given in formula (I); and wherein W is oxygen and M and Q are each selected from the following group: hydrogen, halogen, methyl, methoxy, nitro, CF ₃ , CN, N (CH ₃ ) ₂ , NH ₂ , SCH ₃ or SO ₂ CH ₃ provided that only one of the residues © M or Q is one of

230466 0

Is hydrogen, halogen, methyl or methoxy deviating radical.

Even more preferred are 2- (2-imidazolin-2-yl) quinoline compounds of formula (II) wherein R 1 is methyl; Rp for isopropyl; ¥ for oxygen; B, X, L, M, Q and R ^ are hydrogen; A is COOR ^ where R, C _1-8 -alkyl, hydrogen, C, _ ~ ₈ alkenyl, C, _Q alkynyl, C * g-cycloalkyl or a cation selected from alkali metal, alkaline earth metal, manganese, copper , Iron, zinc, cobalt, lead, silver, nickel, ammonium or aliphatic ammonium.

In the above formulas I ₁ Ia and II, the term "alkali metal" preferably includes sodium, potassium and lithium, with sodium being particularly preferred. The term "organic ammonium" defines a group having a positively charged nitrogen atom joined to from 1 to 4 aliphatic groups, each of which may contain from 1 to 20 carbon atoms. Among the organic Aramoniumgriippen for the preparation of the aliphatic ammonium salts of imidazolinyl-nicotinic acid compounds of formula (I) are the following are particularly mentioned: monoalkylamraonium, dialkylammonium, trialkylammonium, Tetraalkylammoniura, monoalkenylammonium, dialkenylammonium, Trialkenylammonium, monoalkinylammonium, dialkynylammonium, Trialkinylammonium, monoalkanolamraonium, Dialkanolammonium, Trialkanolammonium, C, - g-Cycloalkylammonium, piperidinium, morpholinium, pyrrolidinium, Benzylaramonium and equivalents thereof. The term "halogen" includes chlorine, fluorine, bromine and iodine, with chlorine and bromine being particularly preferred.

According to the process of the invention, 2- (2-imidazolin-2-yl) pyridine esters of the formula (i) wherein A is COOR, and wherein R, one of the substituents specified except hydrogen or a salt-forming cation and wherein R ₁ ZR ₂ , X, Y and Z are as defined above, are prepared by reacting an imidazopyrrolopyridine dione of the following formula (III) with an appropriate alcohol and a corresponding alkali metal alkoxide at a temperature in the range of about 20 to about 50 ^° C.

In these reactions, the alcohol can serve as both a reactant and a solvent. Thus, a secondary solvent is not required. However, if an expensive alcohol is used in the reaction, one can use a less expensive secondary solvent, e.g. Dioxane, tetrahydrofuran or another non-protic solvent. The amount of non-protic solvent added to the reaction mixture can vary widely.

The overall reaction can be represented as follows:

_ ₉ _ 230466

I fi fi

♦ RO Μ! >

\ A / ^C00R 3

T ii • ·

(Ib) HÄ

i ²

κ J M ₁ is an alkali metal and X, Y, Z, R ₁ , R ₂ and R ₃ have the meaning given above.

The 2 - (2-imidazolin-2-yl) pyridine esters of the formula (Ib) can advantageously also be prepared from a dioxopyrrolopyridine-acetamide of the formula (IV) where R ₁ , R ₂ , X, Y and Z are those indicated above Meaning, by cyclization with a strong base, such as 1,5-diazabicyclo [5.4.0] undec-5-ene (DBU), in the presence of an inert organic solvent such as xylene or toluene. This gives the crude imidazopyrrolopyridine of the formula (III). The reaction mixture is heated to a temperature of between 100 and 150 ^° C., and water is removed from the reaction mixture during the reaction using a dedicated device, eg, a Dean-Stark trap. At least 1 equiv of an alcohol is then added to the reaction mixture. The alcohol has the formula R, OH (V), where R is one of the radicals indicated except hydrogen or a salt-forming cation. R ₁ , R ₂ , X, Y and Z have the meaning given above. The resulting mixture is heated at a temperature between 100 and 150 ⁰ C at reflux. This gives the 2- (2-imidazolin-2-yl) -pyridinoster of the formula (Ib). The overall reaction can be graphically represented as follows:

(IV)

(Ib)

- 10 -

2 +

Y _n ^ _v / COOR ₃

3 046 6 ο

J I

Vy *

Ii

V '

i! ψ

(III)

R ₃ OH

(V)

Here, X, Y, Z, have meaning.

R ₂ and R _{3 are} the abovementioned Be

In a further preparation of the 2- (2-imidazolin-2-yl) pyridine esters of the formula (Ib), the cyclization of a carbamoyl-nicotinic acid of the formula (VI) takes place, namely with phosphorus pentachloride at an elevated temperature, which is generally between about 60 and 100 ⁰ C .. The reaction is preferably carried out in the presence of an inert organic solvent such as toluene or benzene. Good yields of the hydrochloride salt of the desired ester of formula (Ib) are obtained. The hydrochloride salt is then readily converted to the ester of formula (Ib) by dissolving the acid addition salt in water and neutralizing the resulting solution with a base such as sodium carbonate or potassium carbonate. The overall reaction can be represented as follows:

23 0 46 6 0

.1. 5

CONH-O-CONH ₂

(VI)

PCI.

Toluene HCl

base

_v I .COOR.

5

(Ib)

Here, A is COOR, and R. * represents one of the substituents mentioned with the exception of hydrogen or a salt-forming cation. The radicals R ₁ , R ₂ , X, Y and Z have the abovementioned meaning.

In a further process for preparing the 2- (2-imidazolin-2-yl) pyridine esters of the formula (Ib), a cyclization of a carbamoyl-nicotinic acid ester of the formula (VI) is carried out using a mixture of phosphorus pentachloride and phosphorus oxychloride , The reaction mixture is stirred at room temperature for about 4 to 8 hours and then POCl is removed in vacuo. The remaining residue is dispersed in an organic solvent such as toluene. The solvent is removed and the residue is dispersed in water and heated to a temperature between 50 and 100 ^° C. After cooling, the pH of the aqueous mixture is adjusted to 5 to 6 with sodium bicarbonate. The product is extracted with methylene chloride. The 2- (2-imidazolin-2-yl) pyridine ester of the formula (Ib) is obtained. The reaction can be represented as follows:

2 3 0 4 6 6

I «

J ^ V \ fl

rnwH - / -

C0NH - <? - C0NH ₂

(VI)

1.PCl ₅ ZPOCl ₃

ψ ² -V

V.-S V1-www LV₁*

V / ³

• ·

(Ib)

In this formula, A is a group of the formula COOR, where R - may denote one of the substituents mentioned, with the exception of hydrogen or a salt-forming cation. R ₁ , R ₂ , X, Y and Z have the meaning given above.

The 2- (2-imidazolin-2-yl) -pyridinester of formula (Ib), wherein A is COOR _5, and where R ₃ is -alkyl-C ₁ ^ _12, alkenyl-C, _ _12, alkynyl-C, j is _Q , cycloalkyl-C, g or substituted derivatives of these groups and wherein X, Y, Z, R ₁ and R ₂ are as defined above can be converted to the corresponding amide wherein A is CONH ₂ , and although by reaction with ammonia under a pressure above atmospheric pressure and at a temperature in the range of about 25 to 125 ⁰ C. This reaction can be carried out in a protic solvent such as a lower alkanol, or an aprotic solvent,

, 23 0Λ6 6

such as tetrahydrofuran, dioxane or the like., Are performed. Under similar conditions, instead of the ammonia, hydroxylamine can be used to obtain the hydroximic acid. These reactions can be graphically represented as follows:

\ Λ / ⁰ ™ »

^y'A / ³

Il ι it

112 II ² HN _JNX HN I

^v o ^N o

(Ib)

_{γ 4} .CONHOH ♦ NH ₂ OH - »YY

The treatment of the resulting primary amide with titanium tetrachloride and triethyl, preferably in the presence of an inert, aprotic solvent, such as tetrahydrofuran, provides the corresponding nitrile. The reaction generally takes place under inert gas protection, eg under nitrogen, at a temperature between about 0 and 10 ^° C. The reaction can be represented as follows:

HN iv · HN iv

-i ₅ - 23 0Λ6 6 O

In this case, X, Y, Z, R ₁ and R _{2 have} the meaning given above.

The preparation of the N-substituted imidazolinone derivatives of formula (VIII) wherein B is COR 1 or SO ₂ R ₅ and wherein A is CH 1, CN or COOR ₃ and wherein W is 0 and R ₁ , R ₂ , R ₅ , X, Y and Z have the abovementioned meaning, with the exception that Y and Z can not be alkylamino, hydroxy or hydroxy-lower alkyl, is possible by reacting the appropriately substituted 2- (2-imidazolin-2-yl) pyridines of formula (I) with an excess amount of an acyl halide, acyl anhydride or SuIfonylhalogenids, namely alone or in a solvent such as Pyridln or toluene at a temperature between about 50 and 125 ⁰ C. the reaction takes place according to the following formula

R coci or J

V ^N

: - (R ₄ CO) 0 J

(VIII)

Where A is CH, CN or COOR, and R ₁ , R ₂ , R ₃ , R ^, Rc, X, Y and Z have the meaning given above, but Y and / or Z is not alkylamino, hydroxyl or Hydroxy-lower alkyl can stand.

It is also possible to prepare N-oxides from the pyridine derivatives. In this case, the pyridine starting material used is a 2- (2-imidazolin-2-yl) -pyridine of the formula (I) or an N-substituted imidazolinone derivative of the formula (VIII) which has been described above. Where A is CH ^, CN or COOR ^, provided that R, the meaning given above

-16-230466 0

has, with the exception that it can not be an unsaturated alkyl group. B is R ^ CO-R _5, or SOp, and Y and Z can not be alkylamino, alkylthio or dialkylamino. The reaction is carried out with an excess of m-chloroperbenzoic acid in the presence of an inert solvent, such as methylene chloride , at reflux temperature. The conversion can be reproduced as follows ί

m-chloro-perbenzo.O-

 j Π _ m-chloro-per

* V \ j \ zi ¹ _ ^acid

-ν

A is CH, CN or COOR ^, but R ^ can not be an unsaturated alkyl group. B is COR or SO ₂ ^R c * ^R ₁ »& ^R 2» ^R 4 » ^R 5» ^X » ^{Y 1} → ¹ * ^{1 Z have} the abovementioned meaning, but Y and Z are not alkylamino, alkylthio or dialkylamino can. Hydrolysis of the resulting N-oxide with a strong base, such as sodium hydroxide, in a lower alcohol yields the corresponding N-oxide, where B is H.

The esters of formula (I), wherein B is hydrogen and W represents oxygen and A is COOR, is and wherein R ₃ is a saturated C ₁ ^ ₁ 2 "A ¹ ^ ¹ Sr ¹¹¹ PPe * a C C 1 -C 6 -cycloalkyl group or a benzyl group, and wherein R ₁ , Rp, X, Y and Z are as defined above, can be prepared by reacting the corresponding acid, ie a compound in which A is COOH, with an appropriate alcohol in the presence of a catalytic amount of a strong mineral acid such as hydrochloric acid, sulfuric acid or the like, at a temperature in the range of about 50 to 100 ^° C. The reaction can be represented as follows:

30466 0

v / ^cooa

Hi Hi-J

R 1 is C _1-12 alkyl, O 1-6 cycloalkyl or benzyl; and R ₁ , R ₂ , X, Y and Z are as defined above.

The acid of the formula (I) which has been described immediately above (") tert and wherein A is COOH and wherein B is hydrogen and W is o and R ₁ , R ₂ , X, γ and Z are the above can also be readily converted to the corresponding methyl ester by reaction with diazomethane at a temperature between about 0 and 25 ^° C. The methyl ester thus prepared can then be reacted with an alkali metal alkoxide, such as sodium or potassium alkoxide, which is described in U.S. Pat for convenience with R 1 ONa and an appropriate alcohol of the formula R 1 OH, wherein R 1 is a C _1-12 alkyl group which may optionally be substituted with one of the groups C ₁ , alkoxy, C , / - cycloalkyl, benzyloxy, furyl, phenyl, halo - ^/! Phenyl, lower alkylphenyl, lower alkoxyphenyl, nitrophenyl or cyano; or wherein R, is a C, ₁₂ alkenyl group which may optionally be substituted with one or z white radicals from the group C _1- ^ -alkoxy, phenyl or halogen; or wherein R, is a C, g -cycloalkyl group which may be optionally substituted by one or two C ₁ , -alkyl group ^ or wherein R, represents a Cz ^^ - alkynyl group, which may optionally be substituted by one or two C ₁ , -alkyl groups. These reactions can be represented as follows:

3 046 6 0

^Y3 / ^C00H γ ϊ .COOCH,

λ ϋ

I? R, OH / R ONa

W?

R ₁ , R ₂ , Rz, X, Y and Z are as defined above,

The conversion of the above-defined esters of formula (I) into their corresponding acid addition salts is readily accomplished by treating the ester with a strong acid, especially a strong mineral acid such as hydrochloric, sulfuric or hydrobromic acid.

If the hydrogen halide slime addition salts are desired, the ester of formula (I) wherein A is COOR ^ and R- * is a radical other than hydrogen or a salt-forming cation and R ₁ , R ₂ , X, Y and Z are the have the abovementioned meaning, in an organic solvent such as methylene chloride, chloroform, ether or the like., Dissolved. The addition of at least 1 equiv. the acid to the resulting solution then provides the acid addition salt. The reaction can be represented as follows:

23 0 46 6 O

\ Ä. / ^COOR3 ΛΛ λ α

II ²

HX

L !

Ether / CH ₂ Cl ₂

* ^R

.HX

When the sulfuric acid salt of the ester is desired, the ester of formula (I) is dissolved in a lower aliphatic alcohol such as methanol, ethanol, isopropanol or the like, or in a mixture thereof with water. The treatment of the mixture with at least 1 equiv of sulfuric acid then leads to the sulfuric acid addition salt of the ester of formula (I).

In a further embodiment of the invention, the compounds of formula (I) wherein A is COOFU and wherein FU is hydrogen and wherein R ^, Rg, X, Y and Z have the abovementioned meaning, with the exception that X , Y and Z can not denote NO ₂ or halogen, are prepared by hydrogenolysis of the benzyl ester of imidazolinylpyridine of the formula (XV), wherein

X, Y and Z are as defined above,

using a palladium or a platinum

(H

catalyst. In this reaction, the benzyl ester of the formula (XV) is dissolved or dispersed in an organic solvent such as a lower alcohol, an ether such as dioxane, tetrahydrofuran or the like, toluene or xylene. The catalyst, preferably palladium on a carbon support is then added to the mixture and the mixture is heated to a temperature between 20 and 50 ⁰ C. The heated mixture is then treated with hydrogen gas to yield the desired acid. The reaction can be represented as follows:

f K ·

^R 2 (XV)

+ H ₂ ZPd

Alternatively, the acids of formula (I) wherein A is COOH can be prepared by treating an aqueous solution of the ester of formula (I) with a strong base. In practice, the ester of formula (I) will generally be 1 equiv. the base is treated in an aqueous solution and the mixture is heated to 20 to 50 ° C. The mixture is then cooled and the pH is adjusted to 6.5 to 7.5 with a strong mineral acid, and preferably to

- ²¹ - 23 0 4 6

pH 7 set. Such treatment provides the desired acid. The reaction can be represented as follows:

\ A. / ^C00R3

1st base / H O

2. acid

/ ^C00B

ΛΛ.Λ. /? ¹

R ₅ may have the meaning given above, with the exception of hydrogen or a salt-forming cation. R ₁ , R ₂ , X "Y and Z have the meaning given in formula (I).

The acids of formula (I) wherein A is COOH and B is hydrogen; W for oxygen and X, Y, Z, R ₁ and R _{2 have} the abovementioned meaning can be prepared by reacting the appropriate, substituted imidazolinone of the formula (XVIII) with alkyllithium, preferably in the presence of an inert solvent such as tetrahydrofuran a nitrogen atmosphere at a temperature between about -70 and -80 ⁰ C. The thus formed mixture is then treated with hexamethylphosphoramide and carbon dioxide preferably in

- ²² -23 (Hδ 6 O

an inert solvent such as tetrahydrofuran to give the desired product. If it is desired to obtain a pyridine derivative of the formula (I) in which A is CH, and X, Y, Z, R ₁ and R _{2 have} the abovementioned meaning, the imidazolinone of the formula (XVIII) is obtained treated as described for the preparation of the acid, but instead of the carbon dioxide methylidyne is used. If dimethylformamide is used instead of the methyl iodide, the corresponding formyl derivatives are obtained. These reactions can be represented as follows:

A = COOH

I. Il

JU

1. Alkyl Li

(XVIII)

Second co ₂ HII -4 · Or Second CH ₅ y A = CH ₃ or Second DMF A - CHO

Advantageously, the acids of formula (I) can be converted to 5H-imidazo [i '2': 1.2] pyrrolo [3,4-b] pyridine-3 (2H), 5-diones of formula (VII) by Reaction with dicyclohexylcarbodiimide (DCC). The reaction is preferably carried out using an approximately equimolar amount of the carbodiimide in the presence of a chlorinated hydrocarbon solvent at a temperature of about 20 to 32 ^° C. The reaction can be represented as follows:

23046

\ A / ^CO0H \ ΛΛ

I Il · · \

i. ii ν> _nrr I II N

(I) (VII)

The 5H-imidazo [1 ".2 ^f : 1.2] pyrrolo [3,4-b] pyridine-3 (2H), 5-diones of the formula (VII) are isomers of imidazopyrrolo

pyridinediones of formula (III) and are particularly useful for preparing one type of 2- (2-imidazolin-2-yl) pyridine derivatives of formula (I). This will be explained in more detail below.

The 3 (2H), 5-diones of formula (VII) can be reacted with at least 1 equiv. a suitable alcohol of the formula R ^ OH (V) in the presence of triethylamine as a catalyst. This gives the pyridine ester of the formula (i) of the corresponding alcohol. The reaction is preferably conducted at a temperature between about 20 and 50 ⁰ C in the presence of an inert aprotic solvent such as tetrahydrofuran, dioxane or the like., Transit _J. The reaction can be represented as follows:

ν Ϊ? , .. Ϊ

i-p ²

(VII) (Ib)

R 1 represents one of the abovementioned substituents with the exception of hydrogen and a salt-forming cation.

- 24 - J 1 η A ß B Π

R ₁ , R ₂ , X, Y and Z have the meaning given above.

Further, the 3 (2H), 5-diones of the formula (VII) can be readily converted to 2- (2-imidazolin-2-yl) pyridine derivatives of the formula (Ib) wherein R ₁ , R ₂ , X, Y and Z is as defined above and wherein W is oxygen and B is hydrogen and A is acetyl, benzoyl, trimethylphosphonoacetate or hydroxymethyl, by reaction with methylmagnesium bromide, phenyllithium, sodium trimethylphosphonoacetate and sodium borohydride, respectively. The reactions of methyl magnesium bromide, phenyl lithium and Natriumtrimethylphosphonoacetat are preferably carried out at a temperature between about -50 and -80 ⁰ C in the presence of an inert solvent such as tetrahydrofuran or dioxane, under an inert gas such as nitrogen. The reaction of these diones of the formula (VII) with sodium borohydride is carried out under relatively mild conditions. The reaction does not require inert gas and can be carried out at temperatures between about -10 and +15 ⁰ C.

The reaction of the diones of formula (VII) with at least 1 equiv. Acetone oxime leads to the acetone oxime ester of 2- (2-imidazolin-2-yl) -pyridine of formula (I) wherein A is COON = C (CH ₃ ) ₂ and wherein B is hydrogen and wherein R ₁ , R ₂ , X, Y and Z are as defined above. The above reaction is generally conducted in the presence of an inert organic solvent such as toluene, benzene, xylene or the like at a temperature of about 40 to 80 ^° C. These reactions can be represented as follows:

* ff

I Il 1 I _R

V * Vj ^x

reactants

230466

1. CH ₃ MgBr

2. phenyllithium

3. sodium trimethylphosphonoacetate

4. NaBH ₄

5. HON = C (CH,)

Α in For mel (I)

¹ · ^C0CH 5 JI _R 2. COC ₆ H ₅

VNA / ^ ¹ 3. COCH COOCH ₃

² ()

4. CH ₂ OH

5. COON = C (CH ₃ ) ₂

wherein R ₁ , R ₂ »X, Y and Z have the meaning given above O.

Compounds of formula (I), wherein A is COOR ₃ and wherein R _{3 is} a salt-forming cation, for example alkali metal, alkaline earth metal, ammonium or aliphatic ammonium, and wherein R ₁ , R ₂ , X, Y and Z have the meaning given above , can be prepared by dissolving the 2- (2-imidazolin-2-yl) -pyridic acid of formula (I) in a suitable solvent, followed by treating the solution of the acid with 1 equiv. of the salt-forming cation. For the preparation of compounds in which the salt-forming cation is an inorganic cation,

-2 3 (U 6 6 O

such as sodium, potassium, calcium, barium or the like, the acid of formula (I) may be dissolved or dispersed in water or in a lower alcohol or in mixtures thereof. 1 equiv. of the salt-forming cation, usually in the form of the hydroxide, carbonate, bicarbonate or the like, but preferably in the form of the hydroxide, is mixed with the solution of the acid of formula (1). After several minutes, the compound d of formula (i) wherein PU is an inorganic salt-forming cation is generally precipitated and may be separated from the mixture either by filtration or by azeotropic distillation with an organic solvent such as dioxane.

To prepare the compound of formula (I) wherein A is COOR and wherein FU is ammonium or organic ammonium, the acid of formula (I) is dissolved or dispersed in an organic solvent such as dioxane, tetrahydrofuran or the like and the mixture is mixed with 1 equiv. Treated ammonia or the amine or tetraalkylammonium hydroxide. Among the amines that can be used, the following are to be mentioned: methylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine, isobutylamine, sec-butylamine, n-amylamine, isoamylamine, hexylamine, heptylamine, octylamine, nonylamine, Decylamine, undecylamine, dodecylamine, tridecylamine, tetradecylamine, pentadecylamine, hexadecylamine, heptadecylamine, octadecylamine, methylethylamine, methylisopropylamine, methylhexylamine, methylnonylamine, methylpentadecylamine, methyloctadecylamine, ethylbutylamine, ethylheptylamine, ethyloctylamine, hexylheptylamine, hexyloctylamine, dimethylamine, diethylamine, di-n-propylamine, diisopropylamine, Di-n-amylamine, diisoamylamine, dihexylamine, diheptylamine, dioctylamine, trimethylamine, triethylamine, tri-n-propylamine, triisopropylamine,

3 0 4 6 6 0

Tri-n-butylamine, triisobutylamine, tri-sec-butylarain, tri-n-amylamine, ethanolamine, n-propanolamine, isopropanolamine, diethanolamine, Ν, Ν-diethylethanolamine, N-ethyl-propanolamine, N-butylethanolamine, allylamine, n-butenyl -2-amine, n-pentenyl-2-amine, 2,3-dimethylbutenyl-2-amine, dibutenyl-2-amine, n-hexenyl-2-amine, propylenediamine, TaIgamine, cyclopentylamine, cyclohexylamine, dicyclohexylamine, piperidine, morpholine xind pyrrolidine. Among the tetraalkylammonium hydroxides may be mentioned methyl, tetraethyl, trimethylbenzylammonium hydroxides. In practice, after a few minutes, the ammonium salt or the organic ammonium salt precipitates and can be separated from the solution by conventional methods, e.g. by filtration or centrifugation. In addition, the reaction mixture can be concentrated and the remaining solvent removed with hexane. The residue is then dried to obtain the ammonium salt or the organic ammonium salt of the formula (I). These reactions can be represented as follows:

_v ? .COOH

• 5

 LA

base

.COO

] Il

VNA

 LJ

, 230466 0

R ₁ , R ₂ , X, Y and Z have the meaning given above and b is the salt-forming cation.

When R ₁ and R _{2 are} different substituents, the carbon atom connected to R ₁ and R _{2 forms} an asymmetric center, and the products and their intermediates exist in the d-form, the 1-form, and the dl-form , It should be noted that the 2- (2-imidazolin-2-yl) -pyridines and quinolines of formula (I), where B = H, may be tautomeric. However, they are presented for simplicity only with a single structure, namely with the structural formula (i). However, they can occur in any of the following isomeric forms:

γ ϊ Α

or

A, W, X, Y, Z, R ₁ and R _{2 have} the abovementioned meaning and B is H. The definitions of the formula (I) include both isomeric forms of 2- (2-imidazolin-2-yl) - pyridines and 2- (2-imidazolin-2-yl) -quinolines.

-29-230466 0

A general method for the preparation of the compounds of formula (I) comprises the reaction of a quinoline anhydride of formula (XVI) with a suitably substituted cc-aminocarbonitrile of formula (XVII). This gives a mixture of the monoamides of quinolinic acid of the formula (IX) and the formula (X). This reaction is carried out at a temperature between about 20 and 70 ⁰ C and preferably between about 35 and 40 ° C in an inert solvent such as tetrahydrofuran, methylene chloride, ether, chloroform, toluene ·, or the like .. The so-() formed Acids are then cycled to give the corresponding pyrrolopyridine acetonitrile of formula (XI) by heating the reaction mixture with an excess of acetic anhydride in the presence of a catalytic amount of sodium acetate or potassium acetate.

In general, the above reaction is carried out by treating the reaction mixture with acetic anhydride, acetyl chloride, thionyl chloride or the like and heating the mixture to a temperature of about 20 to 100 ° C. The hydration of the pyrrolopyridine acetonitrile of formula (XI) thus formed is carried out by treating the acetonitrile with a strong acid such as sulfuric acid. The reaction leads to the Pyrrolopyridinacetamid of formula (XII). Although the addition of a non-miscible solvent such as methylene chloride, chloroform or the like is not essential to carrying out the described reaction, it is preferred to add a solvent to the reaction mixture. The reaction is usually carried out at a temperature between about 10 and 70 ^° C.

The ring closure of the following Pyrrolopyridinacetamide of formula (XII) leads to the tricyclic

- ³⁰ - 2 3 O 4 6 6

Imidazopyrrolopyridinediones of the formula (III) which are intermediates of the imidazolinyl-nicotinic acids and esters of the present invention mentioned above and having the formula (Ib).

The product of this reaction is predominantly the desired imidazopyrrolopyridinedione (85%) together with the isomer of formula (IIIa). The mixtures of this ratio of the two isomers generally result in substantially pure isomeric nicotinate products.

The ring closure reaction is preferably carried out at a temperature of 80 to 150 ° C in the presence of a base such as sodium or potassium hydride, or an acid such as an aromatic sulfonic acid, and in a solvent which forms an azeotropic mixture with water. This essentially results in an immediate removal of the water formed in the reaction from the reaction mixture. Suitable solvents are toluene, benzene, xylenes and cyclohexane. Bases which can be used are alkali metal hydroxides, alkali metal hydrides, alkali metal oxides, tertiary amines such as diisopropylethylamine, 1,5-diazabicyclo [3,4] nonene-5-yl-5-diazabicyclo [5.4-.0] undecene-5; 1,4-diazabicyclo [2.2.2] octane, tetramethylguanidine, potassium fluoride and quaternary ammonium hydroxide such as trimethylbenzylammonium hydroxide, and strong base ion exchange resins.

Finally, as acidic reagents aromatic sulfonic acids can be used, such as p-toluenesulfonic acid, ß-naphthalenesulfonic acid, naphthalenedisulfonic acid and the like.

The mixture of the compounds of the formula (III) and the formula (IIIa) is then converted into a compound

of the formula (Ib), in the manner described above, with an alkali metal alkoxide and alcohol.

The above reactions can be illustrated in the following diagram wherein X, Y., Z, R ₁ , R ₂ and R- are as defined above.

230466 0

V. I

(XVI)

, COOH

Slide I

(XVII)

if V \ onh4-cn

COOH

(IX)

(X)

(CH ₃ CO) ₂ O

\ AJ _fl

.J

I ^ N

C-CN (XI)

H ₂ SO ₄

3 0 466 0

Chart I (continued)

c;

II ^ NO-CONH ₂

base

τ I

I'J I

ν ν ν

(XII)

(III)

(Ilia)

.3- 23 0 46 6 0

Chart I (continued)

R ₃ OH

o-alkali metal

XOOR,

Jut

(Ib)

In another general process for the preparation of the pyridine derivatives of formula (I), a quinoline anhydride of formula (XVI) is reacted with a suitably substituted a-aminocarboxylic acid, such as <x-methylvaline, of formula (XIX), preferably in a ketonis chen solvent, such as acetone, under nitrogen gas, whereby a mixture of isomers of the acids of formulas (XX) and (XXI) is obtained; the mixture is then treated with acetic anhydride and a catalytic amount of sodium acetate at elevated temperature to give dihydrodioxopyrrolopyridine acid of formula (XXII). The reaction of the acid so formed with a thionyl halide, such as thionyl chloride or thionyl

-23,046

bromide, in the presence of an organic solvent such as toluene, xylene, benzene or the like. Free elevated temperature, for example 80 to 150 ⁰ C, to obtain the acid halide of formula (XXIII), which corresponds to the acid of formula (XXII). The treatment of this acid halide with an excess amount of ammonia then leads to the Dihydrodioxopyrrolopyridin-acetamide of the formula (IV). The reaction is preferably carried out in the presence of an aprotic solvent.

("') Upon reaction of the acetamide of formula (IV) with 1,8-diazabicyclo [5.4-.0] undec-7-ene in an inert organic solvent such as toluene or xylene at an elevated temperature between about 80 and imidazopyrrolopyridinedione of the formula (III) is obtained at 125 ° C. This can be reacted with morpholine or a suitable amine of the formula NHpRg to give the 2- (2-imidazolin-2-yl) -nicotinamides the following diagram will be presented.

0

Diagram II

(XVI)

COOH (XIX)

CONH-i-COOH

• C

1 !

-CONH-C-COOH

* v e -COOH ^R 2 it

(XX)

J L>

O (XXII) (XXI)

(CH ₃ CO) ₂ O

_ ₃₇ _ 23 046

Chart II (continued)

SOCl.

ff

i-coci

(XXIII)

NH,

(IV)

23 046 6

Chart II (continued)

DBU

JN / V

] Il

+ Isomer it

v ^! \ / ^00NHRe

In another general method, the 2- (2-imidazolin-2-yl) -pyridic acids and esters of formula (I) can be prepared by reacting the 2-carboalkoxynicotinoyl chloride of formula (XIV), preferably as methyl ester and preferably in the form of Hydrochloride salt, with the appropriate Aminocarboxamid of formula (XIII). The reaction gives the carbamoyl picolinate of the formula (XV) and is preferably under an inert gas, such as

30466

Nitrogen, performed. During the reaction, the reaction mixture is generally kept at a temperature below 30 ⁰ C.

"The Carbamoylpicolinat of formula (XV) thus obtained can then be dispersed in an inert, non-protisehen solvent such as xylene or toluene and heated to about 50 to 130 ⁰ C, together with 1,5-diazabicyclo [5.4.0] undec This reaction gives a mixture of imidazopyrrolopyridinedione isomers of formulas (III) and (IIIa) which can be used without separation in the following reaction in which the reaction mixture is treated with an alkali metal alkoxide in the presence of an alcohol The desired nicotinate of formula (Ib) can be readily separated from the picolinate by neutralization of the reaction mixture, preferably with glacial acetic acid, concentrating the neutralized solution and chromatographing the resulting residue on silica gel in ether.

Conversion of the imidazolinyl nicotinate esters to the corresponding acids or acid addition salts can be readily accomplished by any of the methods previously described. Similarly, the imidazolinyl nicotinic acids can be converted to the corresponding alkali metal, ammonium or organic ammonium salts by the methods previously described.

The preparation of the acids and esters of the formula (I) in the manner described above can be illustrated by the following diagram III.

30466

.COCl

COOR

Chart III

.HCl

(XIV)

.if

S-C

CONH-C-CONH _n

I Il - »

^ ^V '\ oo _R

(XIII)

(XV)

DBU

Xylene Δ

V v

(III)

046

Chart III (continued)

\ Λ

R ₃ OH

R ₃ ONa

\ Ä. / ^COOE3 / V \ A Λ

• · -

(Nicotinate). (Ib)

1 I ^H

COOR,

3 0 466

Advantageously, a variety of the 2- (2-imidazolin-2-yl) quinoline derivatives of formula (II) according to the present invention can be prepared by the same procedures used to prepare the 2- (2-imidazolin-2-yl ) ~ pyridine compounds have been explained. For example, the 2- (2-imidazolin-2-yl) -quinolinecarboxylic acid esters of formula (XXXVI) wherein R represents one of the substituents other than hydrogen or a salt-forming cation and wherein R 1, R 2, X, L, M, Q be and R ^ have the meaning given above, prepared by reacting a dione of formula (XXXVII) with a z \\ swaged corresponding alcohol and an alkali metal alkoxide at a temperature between about 20 and 50 ⁰ C in these reactions, as well as with similar reactions in which the pyridines of the formula (I) are prepared, the alcohol can serve both as a reactant and as a solvent. Therefore, a secondary solvent is not required. However, it may be used if desired. When a secondary solvent is used, it is preferable to use a non-protic solvent such as tetrahydrofuran or dioxane. The reaction can be represented as follows:

_ Μ ,, -. m- D λ. D ΛΜ:> I Il

111

r Y ·, Ί? · -R ₂ + R ₃ OM '>

JU

^ o

(XXXVII) (XXXVI)

M is an alkali metal; X.ein hydrogen atom, a halogen atom, a hydroxyl group or a methyl group, with the proviso that when one of L, M, Q or a ^ Ry of hydrogen, halogen, C ₁ g alkyl or

C ₁ ^ -AlkOXy different substituent, X is hydrogen, and wherein L, M, Q and Ry are each selected from the group of the following radicals: hydrogen, halogen, C ₁ ^ -alkyl, C _1- ^ -AlkOXy, C ₁ __ ^ ~ alkylthio, C _1- ^ - alkylsulfonyl, C ₁ ^ -haloalkyl, NO ₂ , CN, phenyl, phenoxy, amino, C ₁ _ ^ - alkylamino, di-lower alkylamino, chlorophenyl, methylphenyl or phenoxy, which with is a Cl, CF ^, NO ₂ or CH-substituted, with the proviso that only one of L, M, Q or R ₇ may be a substituent which is different from hydrogen, halogen, C ₁ ^ alkyl or C 1-4 alkoxy, and wherein R ₁ , R ₂ and R are as defined above.

The 2- (2-imidazolin-2-yl) -quinolinecarboxylate esters of the formula (XXXVI) can be further prepared from a dioxopyrroloquinoline acetaraid of the formula (XXXVIII) wherein R ₁ , R ₂ , X, L, M, Q and R _{7 have} the abovementioned meaning, by ring closure with a strong base such as 1,5-diazabicyclo [5.4.O] undec-5-ene (DBU), in the presence of an inert organic solvent such as xylene or toluene. This gives the crude imidazopyrroloquinoline dione of the formula (XXXVII). The reaction mixture is heated to a temperature between 100 and 150 ° C and water is separated from the reaction mixture using a Dean-Stark trap. At least 1 equiv. Alcohol of the formula R 1 OH (formula V) is used where R is as defined above except for hydrogen and a salt-forming cation. The reaction mixture is then heated at a temperature between 100 and 150 ° C at reflux to obtain the ester of formula (XXXVI). The reaction can be graphically represented as follows:

vVA τι .... vvv \ -K

, YyVV

PBU

xylene

(XXXVIII) (XXXVII)

R ₃ OH

R ₃ O Hi ₁ (IV)

I II

• χβ, ·

• -COOR ₀

γ \ Λ /! '

(XXXVI)

R., _R2, R ,, X, L, M, Q, and R ^ have the meaning indicated above.

The 2- (2-imidazolin-2-yl) -quinolinecarboxylate esters of formula (XXXVI) can be further prepared by ring-closing a carbamoylquinolinecarboxylate ester of formula (XXXIX) with phosphorus pentachloride at elevated temperature between about 60 and 100 ^° C. The reaction generally in the presence of an inert organic solvent such as toluene or benzene, leading to the hydrochloride salt of the 2- (2-imidazolin-2-yl) -quinolinecarboxylate ester of formula (XXXVI). The treatment of the resulting hydrohalide salt with base, such as sodium or potassium carbonate, then provides the

3046

2- (2-Imidazolin-2-yl) -quinolinecarboxylate ester of the formula (XXXVI). The carbamoylquinolinecarboxylate ester of the formula (XXXIX) used in this reaction has the following formula

(XXXIX)

"A / -W '1

Here R, has the meaning given above except for hydrogen or a salt-forming cation, and R ₁ Rp, X, L, M, Q and Ry have the meaning given above.

The 2- (2-imidazolin-2-yl) -quinolinecarboxylate esters of the formula (XXXVI) can be further prepared by ring closure of the carbamoylquinolinecarboxylate esters of the formula (XXXIX)

S ₁ (XXXIX)

wherein R, has the meaning given above except hydrogen or a salt-forming cation and wherein R ^, Rp »X» L, M, Q and Ry have the meaning given above. The ring closure of the Carbamoylchinolincarboxylatesters succeeds by reacting it with a mixture of phosphorus pentachloride and phosphorus oxychloride. The reaction mixture is stirred for several hours at a temperature between about 15 and 35 C and

3 0 466 0

POCl, is removed in vacuo. The residue is taken up in an organic solvent such as toluene. The solvent is then removed from the resulting mixture, and the remaining residue is dispersed in water of 80 to 100 ⁰ C. After cooling, the pH of the aqueous mixture is adjusted to 5-6 with sodium bicarbonate or potassium bicarbonate and the product is extracted with methylene chloride to give the 2- (2-imidazolin-2-yl) -quinolinecarboxylate ester of formula (XXXVI).

The Chinolinester of formula (XXXVl) in which R, which has the abovementioned meaning, with the exception of hydrogen or a salt-forming cation, and in which Ra, Rp, X 'L, M, Q and R y have the abovementioned meaning, can be easily converted to the corresponding acid addition salts by reacting the ester with at least 1 equiv. a strong acid. Strong mineral acids such as hydrochloric acid, sulfuric acid and hydrobromic acid may be used, but organic acids may also be used In practice, the reaction is best carried out in the presence of an inert organic solvent such as ether, chloroform, methylene chloride or mixtures thereof Sulfuric acid salts are best formed by substituting a lower aliphatic alcohol for the above-mentioned solvents.

The preparation of the 2- (2-imidazolin-2-yl) quinolinyl derivatives of the formula (II) in which A is COOH and in which B is hydrogen and in which W is oxygen and R ₁ , R ₂ , X, L, M, Q and Ry have the abovementioned meaning, but with the proviso that X, L, M, Q and R _{7 are} not halogen or nitro succeed

by hydrogenolysis of the bsnzyl ester of 2- (2-imidazolin-2-yl) quinolinecarboxylate of the formula (XXXVI). To carry out this reaction, the benzyl ester is dispersed in an organic solvent as mentioned above for the hydrogenolysis of the benzyl ester of 2- (2-imidazolin-2-yl) -pyridine of the formula (XV). The reaction mixture thus obtained is treated with hydrogen gas in the presence of a catalyst such as palladium or platinum on carbon. The hydrogenolysis is generally carried out at a temperature between about 20 and 50 ⁰ C.

The acids of the 2- (2-imidazolin-2-yl) quinoline derivatives of the formula (II) wherein A is COOH and B is hydrogen and W is oxygen and wherein R ₁ , R ₂ , X, L, M, Q and Ry have the abovementioned meaning, are obtained by reacting an ester of the formula (XXXVI), wherein Rx is one of the abovementioned substituents with the exception of hydrogen and a salt-forming cation and wherein R ₁ , R ₂ , X, L, M , Q and Ry are as defined above, with at least 1 equiv. a strong, aqueous base, for example an aqueous solution of an alkali metal hydroxide, at a temperature between 20 and 50 ⁰ C. The mixture is cooled and then the pH is adjusted to 6.5 to 7.5 with a strong mineral acid. This treatment results in the desired acid.

In the following, the preparation of the 2- (2-imidazolin-2-yl) -quinoline derivatives of the formula (II) will be explained, wherein A is COOR, and wherein R ·, is a salt-forming cation and wherein B is hydrogen and W is oxygen and wherein R ₁ , R ₂ , L, M, Q and Ry have the abovementioned meaning. In this case, an acid of the formula (II), wherein A is COOH and B is hydrogen and W is oxygen and wherein R ₁ , R ₂ , L, M, Q and

"230466

have the abovementioned meaning, dissolved in a suitable solvent ^- and the resulting mixture is with at least 1 equiv. a salt-forming cation. The reaction is essentially the same as in the preparation of the corresponding pyridine compounds of formula (I) wherein A is COOR and R is a salt-forming cation.

It should be noted that the imidazolinyl quinoline carboxylic acids and esters of formula (II), where B = H, are tautomeric.

It should be noted that when R 1 and R p are different substituents of the 2- (2-imidazolin-2-yl) quinoline derivative of formula (II) and imidazopyrroloquinoline dione of formula (XXXVII), the carbon atom denoted by R * and Rp is linked as an asymmetric center. Therefore, both the products and their intermediates exist in the d-form and in the 1-form and in the dl-form.

Ring closure of the imidazopyrroloquinoline acetamides of formula (XXXVIII) results in the tetracyclic imidazopyrroloquinoline dione of formula (XXXVII) and formula (XXXVIIa). These are intermediates for the 2- (2-imidazolin-2-yl) -quinolinecarboxylic acids and esters of the formula (II).

The product obtained in this reaction predominantly the desired Imidazopyrrolochinolindion together with a small amount of an isomer of the formula (XXXVIIa). Treatment of the isomeric mixture with an alkali metal alkoxide essentially yields the isomerically pure quinolinecarboxylate product.

3 0 46

The ring closure is preferably carried out at a temperature of 80 to 15O ⁰ C in the presence of a base, such as sodium or potassium hydride, or an acid, eg an aromatic sulphonic acid, and in a solvent which forms "with the water an azeotropic mixture. Therefore, the water Toluene, benzene, xylenes and cyclohexane can be used as solvents, for example, alkali metal hydroxides, alkali metal hydrides, alkali metal oxides, tertiary amines, such as diisopropylethylamine, 1, 5-diazabicyclo [3 "4] nonene-5, 1,5-diazabicyclo [5.4.0] undecene-5, 1,4-diazabicyclo [2.2.2] octane, tetramethylguanidine, potassium fluoride and quaternary ammonium hydroxide, such as trimethylbenzylammonium hydroxide, and strongly basic ion exchange resins.

Finally, the acidic reagents used include aromatic sulfonic acids such as p-toluenesulfonic acid, β-naphthalenesulfonic acid, naphthalenedisulfonic acid or the like.

The reactions can be graphically represented as follows:

.230466

Diagram IV

ί?

γ ν

R-

(XXXVIII)

Base or acid

γ ν ν \

(XXXVII)

ti

(XXXVIIa)

Chart IV (continued)

R 0 · --alkali metal

/ V

(XXXVI)

Several different routes lead to the pyrroloquinoline acetamides of the formula (XXXVIII). Preferably, the pyrroloquinoline-acetonitrile of formula (XXXX) is hydrated by treatment with a strong acid, such as sulfuric acid. This reaction leads to pyrroloquinoline acetamide of the formula (XXXVIII). The addition of an immiscible solvent such as methylene chloride, chloroform or the like is not essential to the performance of this reaction. However, the addition of such a solvent to the reaction mixture is preferred. The reaction is usually carried out at a temperature of 10 to 70 ⁰ C.

The pyrroloquinoline-acetamides of the formula (XXXVIII) can alternatively also be prepared by a Diels-Alder cycloaddition reaction, namely from the substituted anthranils of the formula (XXXXI) and the dioxopyrroline acetamides of the formula (XXXXIl). These reactions will be

3 046 6 0

performed in a wide temperature range. Below 13O ⁰ C significant amounts of the intermediate aldehyde of the formula (XXXXIII) are obtained. In the range of 130 to 200 ⁰ C, the Pyrrolochinolinacetamid of formula (XXXVIII) is formed. Alternatively, the aldehyde of the formula (XXXXIII) serving as an intermediate can also be isolated and subjected to ring closure under reflux in xylene in the presence of an acid as catalyst, for example in the presence of p-toluenesulfonic acid. This reaction results in the desired pyrroloquinoline acetamide of formula (XXXVIII). These reactions can be illustrated in the following diagram V.

3 0

Diagram V ,

M? ' Y

Ο- · \ · ·

V v

- »/

(XXXX)

't

-CO-NH,

(XXXVIII)

3 0 46

Diagram V (continued)

-I

Λ> +

(XLI)

1.

(XXXXII)

(XXXXIII)

A.

V ι

(XXXVIII)

It is also possible to obtain the pyrroloquinoline-acetonitriles of the formula (XXXX) on a wide variety of Y-terms, depending on the nature of the radicals L, M, Q and R-. The pyrroloquinolineacetonitriles of formula (XXXX) can be prepared by reacting the appropriately substituted anhydride of formula (XXXXIV) with a suitably substituted oc-aminocarbonitrile of formula (XVII). This gives a mixture of the monoamides of the formula (XXXXVa) and the acids of the formula (XXXXVb). This reaction is carried out at a temperature between 20 and 70 ^° C., and preferably between about 35 and 40 ^° C. in an inert solvent such as tetrahydrofuran, methylene chloride, ether, chloroform, toluene and the like. The acids formed are then subjected to ring closure to give the corresponding pyrroloquinoline acetonitrile of the formula (XXXX). This is achieved by heating the Reaktionsgeraisches to a temperature between about 75 and 150 ⁰ C with an excess of acetic anhydride in the presence of a catalytic amount of sodium acetate or potassium acetate.

In general, the above reaction is carried out. by treating the reaction mixture with acetic anhydride, acetyl chloride, thionyl chloride or the like, and heating the mixture to a temperature between about 20 and 100 ^° C. The above reactions can be illustrated in the diagram below wherein R 1, R ² , X, L, M, Q and Ry are as defined above.,

2 3 0 4 6

¹ T ϊ

(XXXXIV)

Chart VI + NH ₂ -C-CN

(XVII)

XJOOH

Vn J ¹

CONH-C-CN (XXXXVa) AA /

CONH-C-CN

COOH

(XXXXVb)

(CH ₃ CO) ₂ O

M-Y

(XXXX)

_ ₅₇ _ 2

A preferred way to prepare the Pyrrolochinolinacetonitrils of formula (XXXX) is the thermal cycloaddition Diels-Alder reaction. In this case, a suitably substituted maleimide of the formula (XXXXVI) is reacted with a suitably substituted anthranil. Here X must stand for hydrogen.

The result of this reaction depends on the reaction temperature. Intermediates of formula (XLVII) can be obtained at -55 ⁰ C. When the reaction mixture is heated to temperatures between 55 and 130 C, the intermediate obtained is the aldehyde of the formula (XXXXIIl). When the reaction is carried out in the presence of an aprotic solvent, such as o-dichlorobenzene, and when the reaction mixture is heated to 140 to 200 ^° C., the pyrroloquinoline-acetonitrile of the formula (XXXX) is obtained. The reaction can be represented by the following diagram.

-sä- 23 0 46 6

^Ν · ¹ J- * ί (XXXXI)

Chart VII

ϊ H

^ N-C-CN

ii

(XLVI)

(XLVII)

Chart VII (continued)

(XXXX)

This reaction pathway is particularly effective when L, M, Q and Rj are electronegative groups, eg, halogen, nitro, CF ,, SO ₂ CEL or CN.

In a modified process of this type, an o-aminoacetal of formula (XXXXVIII) is reacted with a suitably substituted maleimide of formula (XXXXX) or a dioxopyrroline acetamide of formula (XXXXX) in the presence of an aprotic solvent such as xylene or toluene , at a temperature between about 50 and 130 ° C. This reaction can be represented as follows.

23 0 46 6

¹ T

(XLVIII)

OR '

br

Ϊ Tl

-O

1 *

(XXXXX)

ι L> r

(XXXXXI)

^0R

(XLVIII)

1. Δ ^

^cho

τι

-nh ₂

R ₇ H

(XXXXIII)

The following is a further modification which is useful for the synthesis of anilines carrying electron donor substituents, in the positions L, M, Q and Ry, or a halogen atom or a CF-z group. An o-alkyl or arylthiomethylaniline of the formula (XXXXIX) is reacted with a bromomaleimide of the formula (XXXXX) to give the maleimide of the formula (XXXXXI). This is oxidized to the maleimide of formula (XXXXXII). The maleimide of formula (XXXXXII) is then cycled in an acid catalyzed reaction to yield the pyrroloquinoline acetonitrile of formula (XXXX). These reactions can be represented as follows, wherein R 1, R p, L, M, Q and R- are as defined above.

Aryl or

CH ₂ S alkyl or aryl

(XXXXIX)

(XXXXX)

(XXXXXI)

oxidation

alkyl or aryl

M-T · ·

Q-K · ·

VV ö k

R ₇ H

(XXXXXII)

Compounds of the formula (XXXX) having electron donating substituents in the positions L, M, Q and R 1, for example with the substituents alkyl, alkoxy, alkylthio, dialkylamino, hydroxy and a single halogen, can be prepared by reacting a suitably substituted o- Aminobenzyl alcohol of the formula (XXXXXIII) or an anthranilic acid of the formula (XXXXXIV) with a bromine (or chlorine) maleimide of the formula (XXXXX).

This reaction is carried out in the presence of a protic solvent, e.g. in the presence of isopropyl alcohol or t-butyl alcohol, at 0 to 30 ° C. The hydroxymethylanilino-maleimide of the formula (XXXXXV) or the dioxopyrrolinyl-anthranilic acid of the formula (III) is obtained

23 0 46 5

Formula (XXXXXVI). Various base acceptors can be used in the above reactions, eg, alkaline earth metal hydroxides such as Ba (OH) ₂ . BaO or sodium acetate. In many cases, however, the reactions proceed satisfactorily without the aid of such a base as the acceptor.

The oxidation of an alcohol of the formula (XXXXXV) to give an aldehyde of the formula (XXXXIII) is possible with a large number of different oxidizing agents, for example with pyridinium chlorochromate in methylene chloride or with activated manganese dioxide in t-butanol. The ring closure of the aldehyde of the formula (XXXXIII) to pyrroloquinoline acetonitrile of the formula (XXXX) succeeds by one of the methods described above, for example by heating the aldehyde to a temperature between 140 and 200 ⁰ C in the presence of an aprotic solvent.

The cyclization of o-anilinocarboxylic acid of formula (XXXXXVI) to Acetoxychinolin of formula (XXXXXVII) succeeds with acetic anhydride, triethylamine and 4-dimethylaminopyridine at ambient temperature. A mild, reductive elimination provides the pyrroloquinoline acetonitrile of formula (XXXX). Hydrolysis in warm, aqueous acetic acid provides the compound of formula (XXXX) wherein X is OH. Further reaction with phosphorus oxychloride and pyridine gives compounds in which X is chlorine.

These reactions are summarized below

Diagram VIII

I!

COOH

(XXXXXIII)

Br

3-CN ö ^L 2

(XXXXX)

(XXXXXIV)

Br "

(XXXXX)

- «4- 23 0 46 6

Chart VIII (continued)

· CH ₂ OH

ff

V /

^ N-C-CN

(XXXXXV)

oxidation

^CH0

? _fl ί-C-CN R-

(XXXXIII)

reduction

ί ..

• I? H

1

CN

(X = H) (XXXX)

* / V

COOH

Q ^

(XXXXXVI)

^, OAc

A / UJ ₁

j ^ N-C-CN

(XXXXXVII)

(XXXX)

- 23046

Another approach to the 2- (2-imidazolin-2-yl) quinoline compounds of formula (II), which is particularly useful for the synthesis of analogues in which the group A is varied, starts from 2- (2 ~ Imidazolin-2-yl) quinoline of the formula (XXXXXIX). This intermediate is prepared from the quinoline carboxylic acid of formula (XXXXXVIII). This is converted to the acid chloride or acid anhydride and then reacted either with a suitably substituted a-aminocarbonitrile of formula (XVII) to give the nitrile of formula (XXXXXX) or with the amino-amide of formula (XXXXXXI) to form the Carboxamidoamids of the formula (XXXXXXII). Ring closure of the carboxamidoamide is accomplished by the methods discussed above, although ring closure with sodium hydride in the presence of xylene is preferred. The introduction of a large number of different groups A succeeds by treating the 2- (2-imidazolin-2-yl) -quinoline of the formula (XXXXXIX) with metallating reagents. Most organometallic reagents are effective when 2 moles are used and the dianion is formed. However, the yield and the composition of the reaction product depend on the nature of the organometallic compound, the solvent of the reaction and the reaction temperature and the electrophilic agent which serves to stop the reaction. In practice, organometallic reagents, such as lithium alkyls, are preferred, and anion formation is obtained with methyl, n-butyl, sec-butyl and tert-butyl-lithium. Phenyllithium and lithium diisopropylamide can also be used. The solvents must be aprotic. Diethyl ether is preferred. The reaction temperatures for the formation of the dianion are in the range of -78 to ⁰ ° C, with the range of -30 to -10 ° C being preferred. The stopping with an electrophilic agent at -78 to +20 ⁰ C transit

3 0 4660

guided. If necessary, followed by an acid treatment. All reactions are carried out under an inert gas atmosphere. Examples of reactive electrophilic agents are: CO ₂ , ClCO ₂ CH ₃ , (CH ₂ ) ₂ NCHO, CH ₃ HCO, CgH ₅ CHO, CH, J. The corresponding groups A in the formula (Ha) are COOH, COOCH ₃ , CHO, CH (OH) CH ₃ , CH (OH) CgH ₅ , CH ₃ . After stopping the reaction with the electrophilic agent, the products can be modified. The aldehyde (A = CHO), which was obtained by reaction with DMF, reacts with hydroxylamine to give an oxime. The above route is also useful for synthesizing the compounds with A = COOH by treating the dianion with carbon dioxide.

Not all substituents X, L, M, Q and R 1 are compatible with this organometallic process. If e.g. When the above-mentioned substituents are Br, I or, in some cases, fluorine, a competition reaction leads to a loss of these groups as well as a replacement of the 3-proton of quinoline. However, the presence of chlorine is compatible with this method. If L, M, Q or Ry are methoxy, then in a competing reaction anion formation may occur at the ortho position to the methoxy group.

These reactions can be represented as follows.

Chart IX

i ι

NH ₂ -C-CN

R.

(XXXXXVIII)

If- '' W ^ · \ Il I

(XXXXXiX)

(XVII)

, Close

• "* ^: -R

(XXXXXX)

, S ^ i-CONH-O-CONH ₀

γ ^s / ^T

(XXXXXXII)

R-metal / electrophilic

b / w

^ W \ A .._ _R

4th

HN

(Ha)

.230466 0

Several functional groups A can be prepared by alternative methods. For example, the reaction of the imidazopyrroloquinoline dione of formula (XXXVII) with R 1 OM provides the 2- (2-imidazolin-2-yl) quinoline ester of formula (XXXVI). In the case of the compounds of formula (II) wherein A is a group of the formula CONHCH ₂ CH ₂ OH, ring closure to the oxazoline group may be carried out by reaction of this compound with triethyl phosphite in refluxing xylene. The derivatives of formula (II) wherein A is -CONH ₂ may be converted to the corresponding cyano derivatives (A = CN) by dehydration of the group of formula -CONH ₂ .

The majority of the compounds having the substituents L, M, Q and Ry can be prepared by the methods described above. However, compounds having amino, alkylamino and dialkylamino groups can conveniently be obtained by reducing alkylation of the appropriate nitro substituent in the L, M, Q or Ry position. Alkylsulfonyl compounds are most easily prepared by mild oxidation of the alkylsulfonyl group in L, M, Q or Ry position at 0 to 20 ^° C. using m-chloroperbenzoic acid. Under these conditions, the N-oxidation of quinoline nitrogen occurs only to a small extent.

Oxidation of the quinoline to the N-oxide proceeds with prior N-protection of the Iraidazolone ring, e.g. with a COCH ^ group. Now N-oxidation can be carried out with peracetic acid or trifluoroperacetic acid, if necessary at elevated temperature.

The 2- (2-imidazolin-2-yl) pyridine and quinoline compounds of formula (I) defined above are surprisingly effective for inducing and / or accelerating the ripening process of cereal plants such as wheat, barley, rye, oats , Rice and maize, without adversely affecting the quality of the crops and their yields. The effect occurs when the plants and / or soil containing the seeds of the plants are applied in amounts of about 0.0001 to 0.01 kg / ha and preferably 0.0002 to 0.005 kg / ha.

The process of using the compounds of formula (I) to accelerate and / or induce ripening, thus allowing a harvest earlier than normal, is extremely useful to users, or at least could be. It is thus e.g. it is possible to harvest the cereals treated in this way at any given place long before their usual harvest time. The so cleared land is immediately available again for planting a second crop, which would otherwise not have enough time to grow up and reach a suitable stage or size for harvesting. Such a method would also make it possible to harvest a cereal crop on time, even if its sowing has been delayed by unfavorable weather conditions.

In addition, the use of compounds of formula (I) to accelerate the ripening process of the cereal plant enables the sowing and harvesting of such crops in certain regions of the earth where the growing season is normally shorter than the period of time required to ripen the crops enable.

-230466

Interestingly, when the 2- (2-imidazolin-2-yl) pyridines and quinolines of formula (I) contain legumes, such as soybeans, beans, peas and lentils, and / or the soil, the seeds of these plants, in amounts of from about 0.0001 to about 0.01 kg / ha, and preferably 0.002 to 0.005 kg / ha, causes an increase in axillary branching and shoot formation of these plants. The legumes thus treated also show an increased flowering, an increased Bestokkung and increased yields. The compounds of formula (I) above are also extremely effective in inducing branching and enhancing the flowering of herbaceous ornamental plants such as turnips, dahlias, georgines, daffodils, crocuses, chrysanthemums and roses, if the compounds are such plants and / or or the soil containing the seeds or other reproductive organs of these plants, in amounts of about 0.0001 to 0.01 kg / ha and preferably 0.0002 to 0.005 kg / ha.

The compounds of formulas (I), (Ia) and (II) are claimed and disclosed as herbicides in copending U.S. Patent Application No. 252,704, filed April 27, 1981 (CIP of U.S. Patent Application No. 155,909, filed on February 2, 1981) June 1980).

The compounds of the invention may advantageously be formulated as solid or liquid agents which may be dispersed in a liquid or solid diluent for application to the plants. Since the derivatives of formula (I) wherein R is a salt-forming cation are water-soluble, these compounds can be readily dispersed in water and as diluted aqueous sprays on the leaves of agricultural and horticultural crops or soil, seeds or other reproductive organs the same, be applied. These salts are also suitable for formulations such as flowable concentrates.

2 3 0 4 6 6 0

The 2- (2-imidazolin-2-yl) pyridines and quinols of formula (I) can be formulated as wettable powders, flowable concentrates, emulsifiable concentrates and as granular formulations. A typical flowable liquid can be prepared by mixing about 40 Ge \ i.% Of the active ingredient is blended with about 2.% Of a gelling agent such as bentonite, 3% by weight of a dispersing agent such as sodium lignosulfonate., 1 wt.% Of a polyethylene glycol and 54 Ge % V / asser mixed. A typical emulsifiable concentrate can be prepared by adding about 25 wt. of the active ingredient in about 65% by weight of N-methylpyrrolidone isophorone, butylcellosolve, methyl acetate or the like dissolves and disperses therein about 10% by weight of a nonionic surfactant such as alkylphenoxypolyethoxy alcohol. This concentrate is dispersed in water for use as a liquid spray. If the above compounds are to be used for purposes including a soil treatment, the compounds may be prepared and applied as granular products. The preparation of granular products can be achieved by dissolving the active compound in a solvent such as methylene chloride, N-methylpyrrolidone or the like, and dissolving the solution thus prepared on a granular carrier such as corncob escalope, sand, attapulgite, kaolin or the like, sprayed. Wettable powders can be prepared by mixing about 20 to 45% by weight of a finely divided carrier material, such as kaolin, bentonite, diatomaceous earth, attapulgite or the like, 45 to 80% by weight of the active ingredient, 2 to 5% by weight of a dispersing agent, such as Sodium lignosulfonate, and 2 to 5 wt.% Of a nonionic surfactant, such as octylphenoxypolyethoxyethanol, nonylphenoxypolyethoxyethanol or the like, milled together.

A typical flowable liquid can be prepared by adding about 40 % by weight of the active ingredient to about 2 % by weight of a gelling agent such as bentonite, 3% by weight of a dispersing agent such as sodium lignosulfonate, 1% by weight.

.230466 0

Polyethylene glycol and 54 wt.% V / asser mixed. A typical emulsifiable concentrate can be prepared by dissolving about 5 to 25% by weight of the active ingredient in about 65 to 90% by weight of N-methylpyrrolidone, isophorone, butylcellosolve, methyl acetate or the like, and containing about 5 to 10% by weight thereof .% Of a nonionic surfactant, such as alkyl phenoxypoIyäthoxyalkohol dispersed. This concentrate is dispersed for use as a liquid spray.

If the compounds according to the invention are to be used for purposes which comprise a soil treatment, the compounds can be prepared and applied as granular products. The preparation of the granular product can be achieved by dissolving the active compound in a solvent such as methylene chloride, N-methylpyrrolidone or the like and dissolving the solution thus prepared on a granular carrier such as corncob escalope, sand, attapulgite, kaolin or the like, sprayed. The granular product thus prepared comprises about 3 percent to 20 in general.% Of the active ingredient and about 97 to 80 wt.% Of the granular carrier.

An agent for treating an area of 1 ha for the purpose of increasing the yield of the crop or legume growing thereon comprises from 100 to 500 liters of water, from 0.01 to 0.001 kg of a compound of the formula

V · CH (Ia)

wherein B is hydrogen, CO-alkyl-C ^ g or CO-phenyl; the radical A is COOR, where R, in the

2304

Formula (I) has the meaning given; X is hydrogen and Y and Z are each hydrogen, G ₁ c-alkyl, C ₁ r alkoxy, halogen, Cj ^ -haloalkyl or phenyl, and wherein in the case that Y and Z are combined, YZ for - (CH ₂ ) ^ - stands; and from 0.01 to 3 wt.% Of a dispersant and / or a nonionic surfactant.

In the following the invention will be explained in more detail by means of examples and comparative examples. Unless otherwise indicated, the parts are by weight.

embodiments

example 1

Preparation of 5,7-dihydro-cc-isopropyl-α-methyl-5,7-dioxo-6H-pyrrolo [3,4-b] pyridine-6-acetonitrile

To a stirred solution containing 212 g of quinolinic anhydride in 950 ml of methylene chloride is added gradually 167 g of 2-amino-2,3-dimethylbutyronitrile. The mixture reaches the boiling point of the solution after about one quarter of the aminonitrile has been added and the rate of addition is adjusted to maintain this temperature. After the addition, the solution is heated and refluxed for a further 4 hours. The solution is cooled, filtered and concentrated until a thick oil is obtained. This oil is dissolved in 950 ml of acetic anhydride and 6 g of anhydrous sodium acetate are added. The mixture is distilled until the steam temperature reaches 118 ° C.

.230466 0

Reflux for 3 h. The mixture is concentrated in vacuo, the residue is dissolved in 500 ml of toluene and concentrated again. This process is repeated. The residue is slurried with a mixture of ether and hexane and the crude product which crystallizes is collected (3.9 g). This is dissolved in 700 ml of methylene chloride and filtered through a column containing 700 g of silica gel. The product is eluted with methylene chloride. Concentration of the eluate gives 258 g of the desired product. An analytically pure sample with a melting point of 95 to 96 ⁰ C can be obtained by recrystallizing the product from ether-methylene chloride.

Using the appropriate aminonitrile and quinolic anhydride, the following pyrrolopyridines are prepared by the above procedure:

gp ° c

CH ₃ CH ₃ I ₅ - C ₂ H ₅ H H , H 119-123 CH ₃ C ₂ H ₅ CH (CH ₃ ) ₂ H H H 95 - 97 CH ₃ -Λ CH (CH ₃ ) ₂ H H H 69 - 73 CH ₃ CH ₂ CH (CH ₃ ) ₂ CH (CH ₃ ) ₂ H H H oil - (CH ₂ : H H H 85 - 87 C ₂ H ₅ H H H 71 - 72.5 CH ₃ CH ₃ , H H 129.5 - 131.3 CH ₃ H H OCH ₃ 108 - 110 CH ₃ H H Cl 94 - 96

Example 2

Preparation of 5,7-dihydro-cc-isopropyl-a: methyl-5,7-dioxo-6H-pyrrolo [3,4-b] pyridine-6-acetamide

-To 330 ml of concentrated sulfuric acid are added in portions with vigorous stirring 298 g finely divided nitrile, and in such a manner that the "temperature not exceeding 72 ⁰ C is increasing. After the addition, the temperature at 60 to 65 ⁰ C is set, and in this area for 1 1/2 h held. the mixture is cooled, quenched with ice and finally diluted to approximately 4 1. After 'of 3 454 g of sodium acetate were added and the mixture for 2 hours was cooled at 0 ⁰ C, the mixture is filtered' The solids are collected and washed twice with 500 ml of water containing sodium acetate and then with water to remove the sulfuric acid completely The solid is dried to give 289 g of product, mp 176-178 ° C. in a similar ^ leg material prepared from analytical grade has a melting point of 188-190 ⁰ C.

Using the appropriate pyrrolopyridine-acetonitrile in the above process, the following pyrrolopyridine-acetamides are prepared.

3 0 4 6 6 0

^R 2 X Y Z CH ₃ CH ₃ H H H CH ₃ C ₂ H ₅ H H H CH ₃ H H H at s ρ i el 3

Fp ⁰ C 5 61 203 - 1 98 158 - 1 195 -

Preparation of 3-isopropyl-3-methyl-5H-imidazo [i ".2 ': 1.2] -pyrrolo [3.4.6] pyridine-2 (3H) -5-dione

A mixture of 50 g amide and 450 ml toluene is heated under a Dean-Stark type water separator to remove traces of water. To the cooled mixture is added 10.1 g of a 50% suspension of sodium hydride in mineral oil and the mixture is heated at reflux for 23 h. The hot solution is filtered and concentrated in vacuo, whereupon the residue crystallizes. The mineral oil is removed by decantation and the solid is washed with hexanes and dried in vacuo. This gives 45.5 g of product which, according to NMR analysis, consists of about 90% of the desired isomer II and 10% of the undesired isomer Ha.

A pure sample of the isomer II can be obtained by recrystallization of the crude product from hexane-methylene chloride (mp. 107 to 115 ° C).

The cyclization can be achieved either by means of the basic reagents sodium and potassium hydroxide or by means of the acidic reagents p-toluenesulfonic acid in a toluene solvent. It should be noted that a mixture of products corresponding to structures II and Ha above is obtained. In general, these are not purified, but used directly for the preparation of the derived nicotinic acid ester.

Using the appropriate pyrrolopyridinecarboxaraid, the following imidazopyrrolopyridines are prepared.

T ϊ

^ _n -1- ^

V-T-S

JLl £ 2 2 ' 1 ί Ep ⁰ C

CH ₃ CH ₃ CH (CK ₃ ) ₂ H H H 125 - 130 CH ₃ C ₂ H ₅ H H H CH ₃ -A H H H OCH ₃ 147 - 147 -CH-CH ₂ CH ₂ CH ₂ CH ₂ - H H H CH ₃ CH ₃ H H

Example 4

Preparation of 3-isopropyl-5H-imidazo [1'.2 ': 1.2] pyrrolo [3.4-6] pyridine-2 (3H) -dione

A mixture containing 52 g of 3- (1-carbamoyl-1,2- r- dimethylpropyl) picolinate, 1.77 ml of 1,5-diazabicyclo [5.4.0] undec-5-ene (DBU) in 400 ml of xylene is heated under reflux, under a Dean-Stark type water separator for 2 h. The mixture is concentrated in vacuo and the residue is chromatographed on 400 g of basic alumina. The mixture of the desired products is eluted with methylene chloride and used without further purification.

-78-230466 0

Example 5

Preparation of methyl 2- (5-isopropyl-5-methyl-4-oxo-2-imide

quinazolin-2 ~ yl) nicotinate

20 ml of dry methanol, in which 10 mg of sodium hydride had been reacted, are added 2.0 g of a mixture of imidazopyrrolopyridines. After stirring for 16 hours, 0.03 g of glacial acetic acid are added (to neutralize the base). The solution is concentrated in vacuo and the residue is chromatographed on silica gel in ether. The faster migrating material, which is the targeted ester, is recovered in multiple fractions. The fractions are combined, concentrated and crystallized from acetonitrile. This gives Imidazolinylnicotinat, mp. 121 to 123.5 ° C. An analytically pure sample, which crystallized from methylene chloride-hexane, shows a melting point of 121 to 122 ⁰ C.

Example 6

Preparation of methyl 2- (5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl) nicotinate

This process involves the formation of the tricyclic compounds of Examples 3 and 4 which react further without isolation to give the nicotinic acid ester:

1 Ii> |

CONH

DBI

JjOOCH ₃

"~ 1

tricycl.

MeOH

A mixture of 25 g of amide and 1 ml of 1,5-diaza-bicyclo [5.4.0] undec-5-ene (DBU) in 500 ml of xylene is heated under reflux for 1 hour under a Dean-Stark type water separator. The mixture is cooled a little, the water separator is removed and 100 ml of anhydrous methanol are added. The mixture is then heated under reflux for 1 h. The solvents are then removed in vacuo and the product is isolated by chromatography as described in Example 5 above. This gives 13.65 g of the product, mp 120 to 122 ° C, which is identical to that described in Example 5 above.

Example 7

Preparation of methyl 2- (5-isopropyl-5-methyl-4-oxo-2-iradiazolin-2-yl) nicotinate; Method A (diagram page

A mixture of 13.65 g of nicotinate and 9.6 g of phosphorus pentachloride in 110 ml of dry toluene is added under

230466 0

heated to 80 ° C. After 1 1/2 h, the thick mixture is cooled, filtered and the solid washed with ether and dried. This is the hydrochloride salt of the desired product. This salt is dissolved in 60 ml of water, neutralized with sodium bicarbonate, the resulting precipitate is removed by filtration, washed with water and dried in air to give the desired product, which is prepared by the method of Example 5 is identical.

Method B .. COOCH

IY k ^{u pc} V ^pocl 3, / v ^C00CH 3

A mixture of 5.0 g of nicotinate and 7.1 g of phosphorus pentachloride in 40 ml of phosphorus oxychloride is stirred overnight at room temperature. The phosphorus oxychloride is removed in vacuo, the residue suspended in 40 ml of toluene and concentrated again. This process is repeated. Water (40 ml) is added to the residue and the mixture is heated to reflux and kept at this temperature for 1 h. After cooling, the mixture is extracted with methylene chloride, the extract is dried and concentrated to give 1.05 g of the desired product. The pH of the aqueous phase from the methylene chloride extraction is adjusted to 5 to 6 with sodium bicarbonate solution, and the mixture is again extracted with methylene chloride. The dried extract is concentrated and the residue is crystallized. An additional amount of 2.65 g of the desired product is obtained

identical to the product described in Example 5.

The nicotinic acid esters listed below are prepared by one or more of the methods described above. ;

- Ί

f C

COOR ₃

S = O

.- ^e2 - 2 3 O 4 6 6 O

in ro ro

co CM VO O in in σ CM τ-tr » ro O in ti til σ OJ O rr T I T I T I I I . 26.5 104 151 117 48.5 C- co • = r CM • sr CO CO ro

XXXXX

X X XXXXX

X | XXX X XXXXXX

in m I I I OO ro ro in in X X • a- sr sr X X X X X (M O O U CJ CM CM O CM <M (M CJ CM I X X X X cc j Ü Ü

ι ro t ro ι oo

! 3C rc "* h * r? Y * r? ™ C

ro oo cj-o cj-CJ o-CJ ro ro oo ro ro

XXI I XXXXX CJ O CJ U CJ O

ro X ro X CJ X CJ hl U CM ro I X K CJ

X in X ro in in X S X VO O 8th X X VO υ X from CJ C = C CM CM CM CJ CM CM CM X X X X X X CJ O O CJ CJ CJ

in

in in • OJ • I in Η O ro .sr ι I O C- OJ r- OJ vO co :O O O ι O ^ »- · O in I ¹ I I 6 in OJ I in I O ¹ C- O • OJ vO CO OO cr> O OJ CTi OJ τ-

O "\ CO

X X X XXXXXX

X [XXXXXXXXX

I OJ OJ OJ OJ I ro X O ro X O ro X O ro X OJ cc XO XO XO XO cc ro X O ro X O ro X O ro X O

OJOJOJOJOJOJ

on ro ro on cn ro

XXXXXX

OOÜOOU

XXX

XX

OJ

OJ

ro

ro ro ro ro ro ro

XXXXXX O O O O O

ro ro ro X X X O O O

ro cc

in X vO O OJ

C X

I O

in o

OJ OJ

χ in χ oj χ υ

ι- (V (M O O X I I O

OJ X O

in

X *

OJ I

^ in cj

ro χ Γίί

X vO O

O O I

ro OJ

X OJ X

oxo

O O

OJ Il

Il

OJ X O ro

Ii x

XXO O-O

oj oj O O ι ro ι

XXX OJOJXX OJ

O O O XX CJ - O X

I I O O I O

O I

X O X O

ro oj

X X

CJ O O

, - 84 -

ο ο ο.

VO CvJ

CM

CO 79.2 119 78.5 I in OO r * r- ro 155 X I I I I CM I I ι I I 95.5 77.3 116.5 VO t- X in 128.5 128 111 in X X X X X X X X co X O O

XXXXXX

X X

XX XXXXXX

X X

• CM CM CM CM CM CVI CM CM Y Y CM CM XO m ro i "* «-> ro X O ro X O X ac X ro ro U X a: O O O O X X r ^ X : H (ci ro ro O υ ro ro ro 1 > CH (( U X X X ro ro CM I X X X X X X m O O O X X cc I O O O O O O X ro O O ro ro U X C I r- I X X O in O O O • ro I X C in O ro in X Il X X C m VO X O m vO in X X O O X O X CT> O O CM I O T T co CM vO X Ö X m CM I • · X O sy CM O X X O" O CM O X O O X m I O ro ι O X th I O

in

in in

r-Hr-H 00 ** " OJ I τ- OO I OJ in in vO OJ vO in t- ¹ : OO  = 3 " I τ- 3 I ro c- OO O vO r- OO O % I O OO I in I -> in I I I I I I i α • • OJ vO OO in in OJ in in τ- OJ vO O T-. • "- t τ- τ- OJ τ- .sr ^ in ro vO OO

C)

xxxxx

> * | xxxxxxxxxxx xxxxx

XXXXXXXXXXX XXX

OO

O X

OJ OJ OJ I OJ I OJ in OJ OJ X M in OJ OO I OJ in OO ro ro in ro in ro X ro ro O ro X ro X * - *. OO X X X X X X OJ X X Πι ζ OJ X U OJ X OJ O CJ QJ OJ CJ OJ U CJ CJ U O ro CJ U X U CJ v_ ^ X X ^ "" X CJ OJ I X X X CJ X O X X X ro CJ X X cc I O CJ CJ CJ \ _ * O CJ CJ X cj I CJ I I in α in in X ^^ X X OJ ο OJ OJ OJ U X CJ CJ ro OO ro ro OO OO OO CJ OO OO X X X X X X. X OJ X X X cc I CJ CJ CJ CJ O CJ ^u X O O O ro O III X CJ O OJ OJ I X X X X OJ in U O υ CJ X X ill Il Il ro VO X in CJ CJ X X X CJ O X III OJ B i-H CJ U OJ OJ VO O X OJ O C OO X X CJ OJ CJ X ro X Il U O OJ ro * -> CJ CJ OO X O X X X OO I r- CJ | (| O U X OJ X OJ OJ CJ ro ool X VO X X X X cc CJ CJ O U CJ CJ CJ

ro co ro 133 CO O t 135 1? 6 I i I I I I I τ-vO τ-ro r τ- in r O in ro ro IT • CM CM

I: O

:O

co ο

33 X

X X

X X CQ X X

χ ι

X X

XXXXX

CM CM

CM CM CM CM CM

CM

ro ro ro ro ro ro ro ro ro ro ro I X X X X X X X X X X X X O CJ O U CJ CJ O CJ CJ CJ U CM I X X SC ac X X ir X X X X cc I ^u CJ ^υ O O α CJ O CJ CJ CJ ro ro ro ro ro ro ro ro ro ro ro τ- I X X X X X X X X X X X O = I CJ O CJ CJ CJ O CJ CJ CJ O CJ ro ro in in X X CM ro ro X X CJ O f-l O X X CM CM O O Z CJ CJ CJ ro α U I I V COO HDO COO ro X O I // \ τ 5 ro X U A I I CMX O CJ CH- COO C O X X CM ro ro Il ar • Y Y f O CJ-O X X X X CM CM CM I O O CJ CJ CM X X X CM CM CM CM X ro I O O CJ X X X X X CJ cc O CJ CJ υ CJ

he" co O ro O O I I I α Ι "I t- O O ro

ITS

ro

sd --Q

in

ro

: O: O: O

I X

XXX

XXX _x

X I 3 =

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X I

X XX

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ro ro ro ro ro ro ro r- I X X X X X X X cc O O O CJ υ CJ O

office ro * _x XXX _x

υ ο υ υ υ

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230466

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Example 8

Preparation of the hydrochloride salt of methyl 2- (5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl) nicotinate

To a stirred suspension of 3.0 g of the ester obtained in Example 5 in 40 ml of ether is added a sufficient amount of methylene chloride to obtain a solution. Subsequently, dry hydrogen chloride gas is passed through the solution for about 20 minutes. After 1 h, the mixture is filtered to remove the product. The product is washed with ether and dried to give 1.90 g of the analytically pure hydrochloride salt with a melting point of 195 to 196 ° C.

Example 9

Preparation of 2- (5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl) nicotinic acid

To 22.63 g of the ester obtained in Example 5 in 100 ml of water is added a solution containing 3.29 g of sodium hydroxide in 25 ml of water. The mixture is refluxed for 1.5 hours with simultaneous stirring. After standing overnight at room temperature, 6.8 ml of concentrated hydrochloric acid are added, causing the formation of a heavy precipitate. This is removed by filtration, washed with 20 ml of water and then with 30 ml of ether and dried. This gives 19.27 g of acid, mp. 168 to 170 ° C. This material is dissolved in 350 mL of methylene chloride, filtered (to remove a small amount of isomeric 2-acid) and concentrated. 17.91 g of the pure acid, Fp.170 obtained in this manner to 172 ⁰ C. Recrystallization of the material from acetone-hexane gave the analytical sample, mp. 170 to 172.5 ° C is prepared.

2 3 0 4 6 6 0

Example 10

Preparation of 2- (5-isopropyl-5-methyl-4-oxo-2-imide

quinazolin-2-yl) nicotinic acid

"To 1.0 g of the benzyl ester in 20 ml of ethanol is added 50 mg of a 5% palladium on carbon catalyst and the agar is shaken in a hydrogen gas atmosphere until 1 equiv. Hydrogen was absorbed. The catalyst is removed by filtration, the solvent is removed in vacuo and the residue is crystallized from acetone-hexane to give the acid as described in Example 9.

The following acids are prepared according to the above procedures.

A .COOH

f Y

about £ 2 1 £

CH ₃ C ₂ H ₅ 1214-1260

-CH- (CH ₂ ) H- 180-183 °

-CH-CH

CH ₃ CH ₃ 204 - 205.5 °

CH ₃ Δ 198 - 200 °

.230466

Example 11

Preparation of calcium 2- (5-isopropyl-5-methyl-4-oxo

2-imidazolin-2 ~ yl) nicotinate

To 0.98 g of the acid of Example 9, partially dissolved in 10 ml of water, is added with stirring 0.18 g of calcium carbonate. After 10 minutes the solution is filtered, the filtrate concentrated and the residue treated with ether. There is obtained a crystalline product which is dried at 4O ⁰ C and a pressure of 25 mm. This gives 0.88 g of the calcium salt, mp. 265 ⁰ C.

The sodium, diisopropylammonium and triethylammonium salts are prepared in a similar manner.

The following salts can be prepared using the appropriate acid and the oxide, carbonate, bicarbonates or hydroxide of the selected metal, alkali metal, alkaline earth metal, ammonia or aliphatic amine according to the methods described above.

3 0 4 6 6 0

H Fp ⁰ C NH ₃ CH (CH ₃ ) C ₆ H ₅ , Rubber NHi ₄ sublimated> .:> 168 Ba / 2 > 225 Cu / 2 > 225 K > 225 Li > 225 Mg / 2 · \. > 225

Wax 150 - 153

(CH ₃ ) ₃ CCH ₂ C (CH ₃ ) ₂ NH _?

HIGH ₂ CH ₂ NH ₂ CH ₃

Ti-CgH ₁₇ NH ₃

--94 -

23046

* - "

(CH ₃ J ₂ CHNH ₃ CH ₂ = C (CH ₃ ) CH ₂ NH ₃ (CH ₃ J ₂ CHCH ₂ NH ₃ CH ₃ OCH ₂ CH (CH ₃ ) NH ₃ (CH ₃ J ₃ CNH ₃

(CH ₃ O) ₂ CHCH ₂ NH ₃ - • > 225 (C ₂ H ₅ OCH ₂ CH ₂ ) NH ₃ 155-158 CH ₃ O (CH ₂ J ₃ NH ₃ - (H ₂ CH ₂ CH ₂ ) ₂ NH ₂ Fe / 2 Fe / 3 HIGH ₂ CH ₂ NH ₃

30466

At s pie 1

12

Preparation of methyl 2 - [(1-carbamoyl-1,2-dimethylpropyl) carbamoyl] nicotinate

^AJ vP

AAr =

I M *

CH ₃ OH

COOCH

CH, ONa

VL ^

-NH-C-CONH ₂ CH (CH ₃ ) ₂

Sodium hydride (0.47 g of a 50% suspension in mineral oil) is reacted with 500 ml of dry methanol under nitrogen. To this is added 51.4 g of the amide of Example 2 and the mixture is stirred overnight at room temperature. The mixture is concentrated, the residue dissolved in methylene chloride and the solution washed first with 150 ml of water and then with 150 ml of brine. After drying Cffe ^ SO ^), the organic phase is concentrated and the residue is crystallized from ether to give 47.85 g of product which is analytically pure, mp 108-145 ° C (dec.).

For s ρ i e 1 13

Preparation of methyl 3 - [(i-carbamoyl-1,2-dimethyl-

propyl) carbamoyl] picolinate

COCI

.ΑΪ

I Il

Μ,

OOCH

(XIV)

j " ³

(XIII)

CONH-C-CONH.

COOCH ₃ (XV)

23 0 46 6 0

To a stirred mixture containing 25.5 g of acid chloride [Helv. Chem. Acta, H * 488 (1951)] and

29.7 ml of triethylamine in 200 ml of methylene chloride are added dropwise under nitrogen to a solution containing 13.93 g of aminoamide (as described in US Patent 4,017,510), in such a rate that the temperature of the reaction mixture below 30 ° C remains. After 1 h, the mixture is filtered. The solids are washed with methylene chloride and dried. You get

19.8 g of product, mp 176 Ms 177 ⁰ C (dec.). A recrystallized from nitromethane sample has a melting point of 196 to 196.5 ° C (dec.) And is analytically pure.

Example 14

Preparation of 5,7-dihydro-α-isopropyl-α-methyl-5,7-dioxo-6H-pyrrolo [3,4-b] pyridine-6-acetic acid (isomer)

/ \ J

^C00h

^ \ / CH ₃

^{κ 2 'i} i-CONH-C-COOH

ö CH (CH ₃ )

³² " ^N CH (CH,),

^ J-CONH-C-COOH

VS »m ^iHCCH 3

COOH

AJ

\ - <- cooh

I Il /

VI bi

T ³

S-C-i

VT

a * » ^ J w

To a stirred suspension of 18.4 g of the anhydride in 760 ml of dry acetone is added under nitrogen 16.2 g of (+) - methylvaline. After stirring at room temperature for 48 hours, the mixture is filtered and the filtrate concentrated to give the crude intermediate. This material is dissolved in 500 ml of acetic anhydride. A catalytic amount of sodium acetate is added and the mixture is stirred for 5 h at room temperature. After refluxing the mixture for 1.5 hours, it is concentrated. The residue is dissolved in ethyl acetate and washed with water. The dried extract is concentrated to give a dark syrup. A sample is dissolved in ethyl acetate, treated with charcoal, filtered and concentrated. The residue is crystallized in methylene chloride, and the product is obtained, mp. 122 to 125 ⁰ C, [cc] ^ ⁵ = -7.73 ° (c = 0.100, THF).

Following essentially the same procedure, the following acids are prepared using the appropriate starting materials, quinolinic anhydride and amino acid.

ül R ₂ I CH ₂ CH (CH ₃ J ₂ 126 Il 127 , THF) -CH ₃ -CH (CH ₃ ) ₂ CH (CH ₃ J ₂ : <= Ud ⁵ = - .93 -CHCH ₂ CH ₂ CH ₂ CH ₂ - (c = +6 , 100 .5 CH ₃ M ^ O 176 CH ₃ 196.5 - 198 CH ₃ 183 - 186 -

_ ₉₈ _ 230466

Example 15

Preparation of 5,7-dihydro-a-isopropyl-a-methyl-5,7 ~ di-

oxo-6H ~ pyrrolo [3.4-b] pyridine-6-acetamide

\ J

I Il> 4

V'1 ⁱ

3! -CONH

CH (CHJ,

To a mixture containing 32 g of the (-) acid in 375 ml of toluene are added 2 ml of dimethylformamide and then 13 ml of thionyl chloride. After refluxing for 1.25 h, it is concentrated in vacuo. The residue is dissolved in 350 ml of tetrahydrofuran, cooled to ⁰ ° C. and a slight excess of gaseous ammonia is bubbled through the mixture. The solvent is removed in vacuo to leave a gum which is washed with water and dried in air. One portion of this solid is recrystallized twice from ethyl acetate (with charcoal treatment). The desired product is obtained as a white, crystalline solid, mp 188-189 ⁰ C, [cc] ^ ⁵ = + 3.59 (c = 0.0791, DMSO).

Following essentially the same procedure, the following amides are prepared using the appropriate acid.

j> 4

-CONH ₂

-99- 23 0 ^ 66

CH ₃ CH (CH ₃ J ₂

CH ₃ CH ₂ CH (CH ₃ ) 2

-CHCH ₂ CH ₂ CH ₂ CH ₂ -

Example 16

Preparation of 5-butyl-N- (1-carbamoyl-1,2-dimethyl-

propyl) -picolinamid

S \ f " ³ - CH

9 · Fp ⁰ C 18 • J D > - 192 U = \ s -3.02 (c 76 0.074 * 4, DMSO) 1 86 - 178 1 - "188

⁹ V \ 00H ^{+ ΝΗ} 'WV ₂ ^η "° ^4Η9 " Ι _ν ^ ΟΝΗ- | 4θ _Ν Η ₂

10.7 ml of ethyl chloroformate are added with stirring to a suspension of 20 g of the acid in 200 ml of dry tetrahydrofuran. The mixture is cooled to -10 ⁰ C and 17 »1 ml of triethylamine are added dropwise so that the temperature does not rise above ^{0 0} C. Wild After 10 min, a solution containing 14.3 g of Arainoamids in 150 ml of dry tetrahydrofuran was added dropwise at 0 ⁰ C with stirring. The mixture is allowed to come to room temperature and after 2 hours, sufficient water is added to bring the solids into solution. The tetrahydrofuran is removed in vacuo. The aqueous residue is extracted with ethyl acetate and extracted again after saturation with salt. The organic phases are combined, washed with brine, dried and concentrated. The remaining oil crystallizes. One portion is first recrystallized from methylene chloride-hexane and then from ether-hexane, wherein

0 466 0

- analytically pure product, mp. 83 to 86 ⁰ C, receives.

Using the substantially same procedures as described above, the following picolinic acid derivatives are prepared.

CH (CH ₃ ) ₂ Z Y H CH ₃ CH ₃ H H C ₆ H ₅ H NO ₂

H CH ^ H 126-127.5 °

Example 17 Preparation of 2- (5-butyl-2-pyridyl) -β-1-methyl-2-imidazolin-4-one

^{CH (C} V2 HfJ i = 0

A suspension of 2.4 g of sodium hydride in 250 ml of dry toluene is heated with stirring and refluxed under a Dean-Stark trap. To this mixture is added slowly 26.52 g of the diamide. After the addition, the heating is continued for another 1.5 hours. After the batch has been left overnight, it is mixed with water

quenched, the pH is adjusted with hydrochloric acid and the phases are separated. The aqueous phase is further extracted twice with ethyl acetate. The organic extracts are combined, washed with brine, dried and concentrated. The residue is uracrystallized from hexane to give the pure product, mp 60-62 ° C.

Using the substantially same procedure, the following imidazolinones are prepared.

I = O

X Y Z H C ₆ H ₅ H H H CH ₃ H CH ₃ H H NO ₂ H

Fp ⁰ C

Example 18

Preparation of 5-butyl-2- (5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl) nicotinic acid

3 0 466 0

To a stirred solution containing 10.0 g of imidazolinone in 100 ml of dry tetrahydrofuran is added dropwise at -76 ⁰ C under nitrogen 47.3 ml of a 1.7 M solution of methyl lithium in ether. The mixture becomes very thick and 2 ml of hexamethylphosphoramide and about 150 ml of tetrahydrofuran are added. Then allowed to warm up the mixture to -10 ⁰ C and keeps it for 0.75 hours at this temperature. Subsequently, the mixture is cooled to -70 ⁰ C and a slurry of carbon dioxide (dry ice) was added in tetrahydrofuran. After stirring for 0.5 h, water is added to the mixture, the pH is adjusted to 2 with dilute sulfuric acid, and the product is extracted into methylene chloride. The extract is washed with brine, dried and concentrated to give the product as a yellow solid. Uracrystallization from methylene chloride-hexane gives an analytically pure sample, mp. 152 to 154 ° C.

Using the substantially same procedure as described above, the following imidazolinones are prepared. However, instead of 2- (5-butyl-2-pyridyl) -S-isopropyl-S-methyl-imidazolinone, the appropriate imidazolinones are used and dimethylformamide and methyl iodide and carbon dioxide are used as electrophilic agents.

-23,046

ΗΝ - 4

ii

COOH Cl COOH H COOH H ^CH 3 H CHO H COOH H

H H CH ₃ H ^C 6 ^H 5 H H H H H H ^C 6 ^H 5

Fp "C

184 - 186

203.5 - 204.5

150 - 151.5

93 -. 96

223 - 225

252 - 254

CH-

COOH H CH-O-Si-CH 2 H 82-85

2 I 3

C (CH ₃ )

COOH HC ₂ H ₅ H

Example 19

Preparation of 2- (5-isopropyl-5-methyl-4-oxo-2-imide-C.) Azolin-2-yl) -3-pyridineacetic acid

Essentially the same procedure is used as in Example 18. However, 5-isopropyl-5-methyl-2- (3-methyl-2-pyridyl) -2-imidazolin-4-one instead of

30466

5-Isopropyl-5-methyl-2- (5-n-butyl-2-pyridyl) -2-imidazolin-4-one used. The desired pyridineacetic acid, mp. This gives 173 ⁰ C (dec.).

Example 20

Preparation of methyl 2- (5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl) -6-phenoxynicotinate

λ COOH T ⁷ η CH

ft ** vv y \. Jy χ ι 9 9> y \ y ^

HN J = O ^{3 2} CF "" ^CH '

HN * = 0

A solution of the acid in ether is treated with excess diazomethane. After a few minutes, excess diazomethane is removed by heating. The solvent is removed and the residue is crystallized from ethane-hexane. The desired methyl ester, mp. 128 to 131 ⁰ C is obtained.

Under substantially the same reaction conditions as described above, using the appropriate acid as a starting material, the following methyl esters are prepared.

f COOCH

/ \ I ³

X Y Z 128-131 H H -OC ₆ H ₅ 69 - 71.5 H -C | Hq-n H 110-113 Cl H H T87 - 188 H H OCH ₂ C ₆ H ₅ 126-129 H H OC ₂ H ₅ 175 - 177 OC ₆ H ₅ H H 129 - 130.5 H CH ₃ H ^ - H C ₆ H ₅ H f H H C ₆ H ₅ ' 164-171 OCH ₂ C ₆ H ₅ H H : ·';"'" H C ₂ H ₅ η ' ^:: "l: J [ 146-147 H CH ₂ OH H B e i s ρ i e " L 21 Preparation of 4- [2- (5-isopropyl-5-methyl-4-oxo-2-iraid- quinazolin ~ 2-yl) -nicotinoyl] morpholine

f ^N «-> f

* y * ^ OH (CH ₃ )

CONH,

Γ Γχϊ ^ν

V

isomer

CON ^

HN - 4 = 0

³ CH (CH) * "

A τ τ

The cyclization of the amide is achieved by adding 7.83 g of the amide in 150 ml of toluene and 0.45 ml of 1,8-diazabicyclo [5.4.0] undec-7-ene for 2 h under a Dean-Stark water separator heated. This procedure is similar to that of Example 4. The water separator is removed, 4 ml of morpholine are added and heating is continued for an additional 3 hours. The mixture is concentrated and the residue is chromatographed on silica gel in ethyl acetate. The product is eluted first and this material is recrystallized from ether-hexane to give pure amide, mp 143-145.5 ° C.

Using the appropriate amine instead of morpholine, the following amides are prepared.

.CONHR ₁₅

V'iJ- "i-o

& FP ° C

-CH ₀ C ^ CH 171 - 173.5

227.5 - 228.5

-CH ₂ CH ₂ OH 174.5-175.5

Be i S ₁ ρ 1 e 1 22

Preparation of N- (2-chloroethyl) -2- (5-isopropyl-5-methyl)

4-oxo-2-imidazolin-2-yl) nicotinamide. CONH-CH CH OH

' _β ' 2nd J.

V'nAGchCch.)

Ην - * - ο χ '·. β- * · -

/ VI

i HR * = 0

V J

A mixture with a content of 4.04 g of hydroxyethylamide and 8.2 ml of thionyl chloride in 250 ml of methylene chloride is refluxed for 3.5 h. The mixture is cooled, poured into water and the aqueous phase is made alkaline with sodium carbonate. The mixture is shaken, the organic phase separated, washed with water, dried and concentrated leaving a white solid which is recrystallised from toluene. This gives the desired Chloräthylamid as a white, crystalline solid, melting partially at 128.5 ⁰ C and completely at 157 ⁰ C.

B ice ρ ie 1 _i 23

Preparation of 2- (5-isopropyl-5-methyl-4-oxo-2-imide

azolin-2-yl) -nicotinamide COOCH

% / 7 ^ ^CH 3 \ \} - { 1- ^ ^Η ( ^CH 3 W HN e = 0 ^{3 2} ;. V m J = O ³

230466

A solution containing 10.0 g of the ester in 50 ml of tetrahydrofuran is added to 100 ml of liquid ammonia in a glass bomb. The bomb is sealed and the contents heated to 100 ⁰ C for 16 h. After cooling, the ammonia is evaporated and the residue is concentrated. This residue is combined with material derived from similar reactions using 5 g and 7 g of the ester. The combined amounts are crystallized from ethyl acetate to give 5 g of the product. The filtrate is concentrated after treatment with charcoal to give an additional 15.7 g of the product. By two recrystallizations of a sample from ethyl acetate gives the pure nicotinamide as a white crystalline solid, Fp.178 to 182 ⁰ C.

Example 24

Preparation of 2- (5-isopropyl-5-niethyl-4-oxo-2-imide

quinazolin ~ 2-yl) -nicotinonitrile

_CH (ch ₃ ) ₂ λΑλΓ ³ l ₀ ^{3 2} vy n-ch (ch)

Hfl i = 0 ³

To 75 ml of ice-cold tetrahydrofuran is added under nitrogen and stirring 12 ml of titanium tetrachloride in 20 ml of carbon tetrachloride in such a rate that the temperature does not rise above 5 ° C. Subsequently, 5.2 g of the amide are added in 75 ml of tetrahydrofuran, again maintaining a temperature of below 5 ° C. Finally, 17 ml of triethylamine in 5 ml of tetrahydrofuran are added to the mixture under the same conditions. After 1.5 h at 5 ⁰ C, the mixture is stirred overnight at room temperature. 100 ml of water are carefully added at 0 ° C, the upper organic phase is

separated and the aqueous phase is extracted with 4 χ 100 ml of methylene chloride. The combined extracts are washed with brine, dried and concentrated. The solid residue is recrystallized from hexane-methylene chloride to give, receives the nicotinonitrile as a tan solid, mp. 144 to 148 ⁰ C. The analytically pure compound has a mp of 148 to 150 ⁰ C.

B _e_ i _s ρ i e 1 25 ·

Preparation of 2- [5- (hydroxymethyl) -2-pyridyl] -5-isopropyl-5-methyl-2-imidazolin-4-one

CH OC - * ^ ^X · N? ^Η 3

I ³ ' ² V h {,

0 0

To a stirred slurry of 23 g Lithiumaluminiuinhydrid in 250 ml of tetrahydrofuran under nitrogen is added dropwise at -70 ⁰ C 46.8 g of the ester in 350 ml of tetrahydrofuran. The mixture is warmed to room temperature, 73 ml of a saturated ammonium chloride solution is added cautiously with vigorous stirring, the mixture is filtered and the solids are washed with tetrahydrofuran. The filtrate is concentrated leaving a gummy mass. This is chromatographed on silica gel and the product is eluted with ethyl acetate; Mp. 101 to 104 ⁰ C.

B e i s ρ i e 1 26

Preparation of 2- [5- (tert -butyldimethylsiloxy) -methyl-2-pyridyl] -5-isopropyl-5-methyl-2-imidazolin-4-one

-. 110

- 23,046

HIGH

HN

V ₂ ⁺ (CH ₃ ) ₃ C-Si-Ci

, -CHCCH ₃ )

To a stirred solution containing 2.03 g of alcohol in 3 »5 ml of dimethylformamide is added under nitrogen 0.68 g of imidazole and then 3.1 g of t-butyldimethylsilyl chloride. The mixture is kept for 10 h at 35 ° C and a further 10 h at room temperature. Saturated sodium sulfate solution is added and the aqueous mixture is extracted with ether. The extract is washed with brine, dried and evaporated. The pure product is isolated in the form of a gummy mass by chromatography of the crude product on silica gel and elution with methylene chloride, followed by ether,

Example 27

Preparation of 5α (hydroxymethyl) -2- (5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl) nicotinic acid

COOH

COOH

Al ^H0H 2 ^C -T f |

· CH (CH,),

I 3 2

A solution containing 0.29 g of silyl ether in 10 ml of 80% aqueous acetic acid is added to the steam bath

Heated for 0.5 h. The mixture is concentrated and the residue is azeotroped with toluene. The residue, a gummy mass, is crystallized from methylene chloride-hexane. The pure product has a mp of 170 to 171.5 ⁰ C.

Example 28 ι .-: .- *:, '·, ·; -; . ·>

Preparation of methyl 2- (1-acetyl-4-isopropyl-4-methyl-

5-oxo-2-imidazolin-2-yl) nicotinate

A solution containing 10 g of methyl 2- (5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl) nicotinate in 100 ml of acetic anhydride is refluxed for 16 hours concentrated and the residue from ether-hexane brought to crystallization. To yield the N-acetyl derivative, mp. 88 to 90 ⁰ C. I point of analytically pure material.

the N-acetyl derivative, mp. 88 to 90 ⁰ C. This is the solid

Using the substantially same reaction conditions as described above, the following N-substituted imidazolinones are prepared by reacting the appropriate imidazolinyl nicotinate with the appropriate acyl anhydride, acyl halide, sulfonyl halide, alkyl halide or sulfate either neat or in a solvent such as pyridine or toluene , implements. coor

\ / ³

23 0 46 6 0

B CH ₃ 85 Fp ⁰ C CH ₃ COC (CH ₃ ) ₃ -Oil CH ₃ COC _n H ₂₃ -H 104 - 87 CH ₃ COC ₆ H ₅ 90 oil CH ₃ COC ₂ H ₅ 98 - 107 CH ₃ COCH ₂ Cl - 92.5 CH ₃ COC ₂ H ₅ - 100 CH ₂ C ₆ H ₅ COC (CH ₃ ) ₃ oil CH ₂ C ₆ H ₅ COCH ₂ Cl 115 oil CH ₂ C ₆ H ₅ SO ₂ CH ₃ 125 Oil. CH ₃ COCH ₃ 118 - 118 CH ₂ aCH COCH ₂ Cl 118 - 127 CH ₂ C = CH COC ₆ H ₅ 101 - 122 CH ₂ CsCH COC (CH ₃ J ₃ oil - 120 CH ₂ CsCH COOC ₂ H ₅ 114 - 104 CH ₃ 117 CH ₃ COC ₆ H ₅ 85 - 118 CH ₂ C ₆ H ₅ COC ₂ H ₅ - 125 CH ₂ CsCH - 88

-1 ! o _r ,: .n

3046

^R 3

CH ₃ CO- (\ -Cl 122-125

CH ₃ CO- ()) - OCH ₃ 119.5 - 121.5

.W-W.

CH, C0 - «( y ~ - NO ₂ 148 - 151

Example 29

Preparation of methyl 2- (1-acetyl-4-isopropyl-4-methyl-5-oxo-2-iraidazolin-2-yl) nicotinate 1-oxide

- ^C00CH 3 co HnrH

J T 3 .COOCH-

2 g of a solution containing 40 g (126 mmol) of nicotinate in 500 ml of methylene chloride are added 30 g of 80 to 90% pure (139 mmol, based on 80% purity) of m-chloroperbenzoic acid. After refluxing overnight, excess peracid is decomposed by the addition of excess 1-hexene. The solution is washed with saturated sodium bicarbonate solution, dried and concentrated. The residue is brought from methylene chloride-hexane-ether for crystallization to give to 100 ⁰ C, obtained 18.3 g of the desired N-oxide, Fp.92. The analytically pure N-oxide has a mp of 95 to 99 ⁰ C.

.2304660

Example 50

Preparation of methyl 2- (5-isopropyl-5-methyl-4-oxo-2-one

imidazolin-2-yl) nicotinate-1-oxide

I Il

• ν ·

To a solution of 30 g of the N-acetyl compound in 200 ml of methanol is added about 0.5 g Natriuromethoxid. After 2 hours of stirring, the product is separated by filtration and dried in air; Mp 197 to 201 ^° C. The analytically pure sample obtained by recrystallization from acetone-hexane has a melting point of 200 to 201 ^° C.

Example 51

Preparation of methyl 6-chloro-2- (5-isopropyl-5-methyl)

4-oxo-2-imidazolin-2-yl) nicotinate

COOCH _{3 A}

IY ^P0C1 3 1 Y

A solution containing 22.0 g of N-oxide in 135 ml of phosphorus oxychloride is refluxed for 4 hours. After the reaction has stood overnight at room temperature, excess phosphorus oxychloride is removed in vacuo, the residue treated with xylene and

in turn concentrated. The residue is dissolved in methylene chloride and treated with water, the pH is adjusted to 5 with sodium carbonate solution and ether is added to ensure that the organic layer forms the top layer, the layers are separated and the aqueous phase becomes twice more extracted with ether. the combined organic extracts are washed with brine, dried and concentrated. the residue is chromatographed on 250 g of silica gel in a mixture of ether and hexane. This gives 10.6 g> ^ ~ \ of the desired product. This is prepared from ether-hexane

V J

recrystallized to obtain 8.95 g of the 6-chloro derivative, mp. 104-106 ⁰ C, receives. The analytically pure sample melts at 102.5 to 104.5 ° C.

Example 32

Preparation of 6-chloro-2- (5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl) nicotinic acid

\ J

A suspension of 3.0 g of the ester in 5.8 ml of 2N sodium hydroxide, 5 ml of water and 3 ml of methanol is heated to 35 C to obtain a clear solution. After 3 hours of stirring the solution is cooled, extracted with ether and the organic phase is discarded. The pH of the aqueous phase is adjusted to 2 with 6N hydrochloric acid and then sodium bicarbonate solution is added to bring the pH to 4. The aqueous phase is extracted twice with methylene chloride, the pH

30466 0

the aqueous phase is adjusted to 2 and it is again extracted twice with methylene chloride. The organic phases are combined, dried and concentrated, and the residue is crystallized from methylene chloride-Tiexan. To give the analytically pure acid, mp. 154 to, / 15 [7: ⁰ C .. ₍ '

5-Bromo-2- (5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl) -nicotinic acid, mp., Is obtained by the above procedure using the 5-bromoester in place of the 6-chloro ester. 211 to 213 ⁰ C.

B eis ρ ie 1 33

Preparation of 6- (benzyloxy) -2- (5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl) nicotinic acid

_β COOH

³² / Vw

To sodium hydride (from 0.34 g of 50% sodium hydride in oil) in 2 ml of N-methylpyrrolidone is added under stirring and under nitrogen 2 ml of benzyl alcohol. After the formation of the alkoxide is complete, add 0.6 g of the chloric acid and heat the mixture to 165-175 ° C for 5 hours. After cooling, the mixture is diluted with water, adjusted to pH 1 with 1N hydrochloric acid and then brought back to pH 8 with saturated sodium bicarbonate solution. The mixture is extracted twice with ether and the ether is discarded. The pH of the aqueous phase is adjusted to 5 and it is repeated several times

extracted with methylene chloride. The extracts are combined, dried and concentrated. By crystallization from ether-hexane gives the 6-Benzyloxyderivat, mp. 205 to 207 ⁰ C.

Using the same reaction conditions as described above, the following Iraidazolinyl nicotinic acids are prepared. The appropriate 4- or 6-chloro-2- (5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl) nicotinic acids and the appropriate sodium alkoxide, phenoxide or thioalkoxide are used.

X H OCH ₃ 190 EP ° C 5 OC ₆ H ₅ H 196 - 191. H ^{OC 6H} 5 182nd - 198 5 H OC ₂ H ₅ 190 5 - 185. 5 H SCH ₃ 188th - 191. OCH ₂ C ₆ H ₅ H 172 5 - 190 H OCH ₂ C ₆ H ₅ 205 - T74 - 207

.230466 0

B ei 3 ρ ie 1 34

Preparation of 4-hydroxy-2- (5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl) nicotinic acid

¹ yr-COOH

COOH

To 15 ml of concentrated sulfuric acid is added slowly while stirring 1.55 g of Benzyloxyderivats. To this mixture is added 7 ml of ethylene dichloride. After 16 h at room temperature, the mixture is poured over ice, the pH is adjusted to 4 with dilute sodium hydroxide and extracted with ethyl acetate. The extract is dried and concentrated to leave a brownish solid which turns over from methylene chloride ether! he will become; Mp 210-211 ° C.

e 1

Preparation of 2-isopropyl-2-methyl-5H-imidazo [i * .2 *: 1.2] pyrrolo [3,4-b] pyridine-3 (2H) -5-dione

• f \ -cooh

DCC

r · CH (CH)

Hft - J = O ³ *

ff

ΠΓ ³

To a solution containing 50.9 g of dicyclohexylcarbodiimide in 600 ml of dry methylene chloride is added

- 119 - 7Ä

rsy-ir: ^y

With stirring, 60 g of the acid at such a rate that the temperature does not rise above 32 ⁰ C. After stirring at room temperature for 2.5 hours, the mixture is filtered and the filtrate concentrated. A white solid is obtained. This solid is recrystallized from methylene chloride to give 125 to 128.5 ⁰ C, obtained 57.4 g of the dione, mp.. The analytically pure Dion melts at 132 to 134 ⁰ C. yy-rrnB? π

B e i s ρ i e, 1,, 36

('") Preparation of the acetone oxime ester of 2 ~ (5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl) nicotinic acid

II ..... x? * ^bo k! ³ - »· / Ϋ

Ü δ "" ^CH 3

H. - * ft-i-0 "" ^ ³ ' ²

To a solution containing 2.0 g of the 3 »5-dione in 15 ml of toluene is added 0.6 g of acetone oxime. The mixture is heated and stirred at 50 to 60 ° C for 2.75 h. After stirring at room temperature overnight, the LI solvent is removed and the residue is chromatographed on silica gel using 1% acetonitrile in methylene chloride followed by 30% acetonitrile in methylene chloride as the eluent. The toluene is removed from the fractions containing the product and the product is collected. The product is recrystallized from methylene chloride-hexane to give analytically pure oxime ester, mp 117-119.5 ⁰ C, receives. The ester of 2,2,2-trichloroethanol, mp 114 to 116 ° C, is prepared in substantially the same manner.

- ¹² ° - 2 3 O 4 6 6 O

Example 37

Preparation of 2- (3-acetyl-2-pyridyl) -5-isopropyl-5-methyl-2-imidazolin-4-one

^ i ³

I y I CH + CH MgBr i /. / N? ^H 3

V S * 1 ^ ~ ^ CH (CH) V Υ "J-CH (CH)

^{3 2} HN i = 0 ³

To a stirred solution containing 10.0 g of the dione in 100 ml of dry tetrahydrofuran is added dropwise at -78 ° C under nitrogen 15.1 ml of a 3M solution of methylmagnesium bromide in ether. During the addition, a temperature of below -60 ° C is maintained. After the addition, the stirring at -78 ⁰ C is continued and then the mixture is slowly erwämt to room temperature. The mixture is diluted with an equal volume of water, the pH is adjusted to 4 with glacial acetic acid and extracted three times with methylene chloride. The combined extracts are dried and concentrated. The residue is chromatographed on silica gel with ether. By concentration of the appropriate fractions gives 6.1 g of the product as a crystalline solid, mp. 104 to 1'08 ⁰ C. An analytically pure sample has a mp. From 103 to 105 ⁰ C.

Using the same procedure as described above, the following imidazolinones are prepared. However, phenyllithium or sodium trimethylphosphonoacetate is used instead of methylmagnesium bromide.

ΐ Υ ^Α Λ / \

A gpOC

COC6H5 138 - no.5

JCOOCH ₃

co CfCT 131.5 - 1

Be i S ₁₁ ρ

Preparation of Z- [3- (hydroxymethyl) -2-pyridyl] -. 5 * -isopropyl-5-methyl-2-imidazolin-4-one

y * S / * \ _M NaBH ^ * \

V i

ij A V IiJ

^{3 2}

To a stirred solution of 0.32 g of sodium borohydride in 25 liters of absolute ethanol, a solution containing 2.0 g of the dione in 25 ml of dry tetrahydrofuran is added at ⁰ ° C. over 10 minutes with stirring. The mixture is stirred for a further 3 hours at room temperature, then poured into 200 ml of ice-water, extracted with methylene chloride; The extract is dried and concentrated. The residue is crystallized from methylene chloride-hexane to yield the desired product. The analytically pure sample has a mp of 145 to 149 ° C.

- ¹²² -23 O 46 6 O

example

Preparation of 1,3-dihydro-α-isopropyl-α-ethyl-1,3-dioxo-2H-pyrrolo [3,4-b] quinoline-2-acetone3.tril

Method A

γ L (CH ₁ ), vvγ c

Anthranil (59-6 g, 0.5 mol) is added dropwise under nitrogen and with stirring for 45 min to a re-fluxing solution of a-isopropyl-a-methyl-2,5-dioxo-3-pyrroline-1-acetonitrile in 450 ml of o-dichlorobenzene. After 18 h, the reaction mixture is cooled and treated with methylene chloride. This solution is passed through a 3 inch silica gel column eluting with methylene chloride. The eluate is concentrated to 500 ml and hexane is added. It forms a precipitate, which is filtered off and dried in air. This gives 110.6 g (75 O product as a light brown solid

Crystallization from ethyl acetate-hexane gives pale yellow crystals, mp. 195-196 ⁰ C.

Analysis: Calculated for C ₁₇ H ₁₅ N ₂ O ₂ : C 69.61% H 5.15 & N 14.33 # found: 69.37 5.15 14.43.

Under similar conditions, the compounds listed in Table I are prepared.

Method B Cyclization of o-formylanilino-maleimides

: _cn - »: h (ch ₃ )

₃ ) ₂

- 123 - £

A solution of N- (1-cyano-1,2-dimethylpropyl) -2- (oformylanilino) maleimide (7.19 g, 0.023 mol) in 300 mL of xylene containing 0.3 g (0.0016 mol ) p-Toluenesulfonic acid is refluxed for 4 hours using a Dean-Stark trap to collect eliminated water. The reaction mixture is cooled, evaporated at reduced pressure and dissolved in hot ethyl acetate, which is passed through a 3 inch silica gel column. The eluted ethyl acetate fractions are combined to give 5.51 g (81%) of solid 1,3-dihydro-a-isopropyl-α-methyl-1,3-dioxo-2H-pyrrolo [3,4-b] quinoline. 2-acetonitrile, mp. 195 to 195.5 ⁰ C,

Other compounds prepared by this procedure are listed in Table I.

Beis piel 40 * - * '''*'.'''*·;

Preparation of 1,3-dihydro-a-isopropyl-α-methyl-1,3-dioxo-2H-pyrrolo [3,4-b] -4-acetoxyquinoline-2-acetonitrile

Method, C ₁

OAc η

_{A 0} / vVV f

cnth °> II«> - {- -

_H (cH,), VVyO

3 2 U

3 2

3 0 4 6 6 0

A solution of N- [1- (1-cyano-1,2-dimethylpropyl) -2,5-dioxo-3-pyrrolin-3-yl! -Anthranilic acid (3.27 g, 0.01 mol) in 20 ml Acetic anhydride is treated simultaneously with 10 ml of triethylamine and 0.122 g (0.001 mol) of dimethylaminopyridine. After 1 hour of stirring at 25 ° C under nitrogen, the reaction mixture is poured into ice-water. It forms a solid, which is filtered off. Purification is by resuspension in ether, filtration and drying. This gives 2.54 g (72%) of product, mp. 145 to 151 ⁰ C, m + 1 / e = 352.

VCO Y ^VN 8

Table I

CH.CH.CH.CH.CH.CH-CH.CH.

R ₂ X L M Q ^R 7 method F) ° C P CH (CH ^ J- H H NO ₂ H H A 230-232 CH (CH ₃ J ₂ H H H NO ₂ H A 260-261 CH (CH ₃ J ₂ H NO ₂ H H H i i CH (CH,), H H H H NO ₂ A I / CH (CH ₃ J ₂ H br H H H A / I / CH (CH ₃ J ₂ H Cl H H H A, B 139.5-142 CH (CH ₃ J ₂ H H CF ₃ H H B j CH (CH ₃ J ₂ H H H Cl H B 188

Ul I

Table I (continued)

R ₂ X L M Q ^R 7. Method F, _p ° c CH (CHg) ₂ H H Chg H H B CH (CHg) ₂ H H H Chg H B 186-190 CH (CHg) ₂ H H H H Chg B CH (CHg) ₂ H H OCHg H H B CH (CHg) ₂ H H H Chg ^CH 3 B CH (CHg) ₂ H H Chg H Chg B CH (CHg) ₂ H Chg H H Chg B CH (CHg) ₂ H H H Cl Chg B CH (CHg) ₂ H Cl H H CH ₃ B CH (CHg) ₂ H H Cl H CH ₃ B CH (CHg) ₂ H Cl H H OCHg B CgH ₇ H H H H H A ^C 2 ^H 5 H H H H H A

-λ

σ »ι

cn

Γ '\

CH ₃ nC ₄ H ₉

- "

-

i ^ -4 "9 CH ₃ cyclopropyl H

CH ₃ CH ₃ CH = CH ₂ H CH ₃ cyclohexyl H

(CH ₂ J ₅ H

CH ₃ CH (CH ₃ J ₂ Cl

CH ₃ CH (CH ₃ J ₂ CH ₃

CH ₃ CH (CH ₃ J ₃ F

CH ₃ CH (CH ₃ J ₂ OCH ₃

CH ₃ CH (CH ₃ J ₂ OH

) o H

L HHHHHHHHHHHHH

Table- I. »(Continued) R-,

M HHHHHHHHHHHH Cl

_Q_ H H H H H H H H H H H H

H H H H H H H H H H H H

Method FpC

A ^/

I.Jk

ro

202.5 to 203.5

.230466 0

Be i s ρ i e 1 41

Preparation of 1,3-dihydro-α-isopropyl-α-methyl-1,3-dioxo-2H-pyrrolo [3,4-b] quinoline-2-acetamide

H (CH)

ff

·. CH

· * TTH ·. β. ·

VV \

0.44 g (0.0015 mol) of 1,3-dlhydro-a-isopropyl-a-methyl-1,3-dioxo-2H-pyrrolo [3,4-b] quinoline-2-acetonitrile is added in 5 ml of concentrated sulfuric acid Room temperature dissolved and stirred overnight. The reaction mixture is poured onto 50 ml of crushed ice. E3 forms a white precipitate which is filtered off, washed with water, aqueous sodium bicarbonate solution and water and then dried in vacuo. This gives 0.34 g (74%) of product, mp. 237-239 ° C (dec.).

Analysis: for C ^ yH ^ yN., 0,

calculated? C 65.58% H 5.50% N 13.50% Found: 65.03 5.63 13.19.

The following compounds are prepared in the manner described above.

R2 M- Q- V Λ Y \ / 5 ... Table Q II R? Fp ⁰ C CH (CH ₃ ^l ,: -conh ₂ H H 225-227 (2 @ rs.) rl CH (CH _{3 2} M NO ₂ H 221-224 CH ₃ CH (CH ₃ > 2 NO ₂ H H CH ₃ CH (CH ₃ > ₂ H H H CH ₃ CH (CH _{3 2} H H H CH ₃ CH (CH ₃ »2 H H H CH ₃ CH (CH ₃ > 2 Cl CF ₃ H CH ₃ CH (CH _{3 2} CF ₃ Cl H 232-234 CH ₃ CH (CH ₃ > 2 H H Cl CHj CH (CH ₃ > 2 H H H CHj CH (CH ₃ H H CH ₃ H 223-227 (ZersO CH ₃ CH (CH _{3 2} CH ₃ H CH ₃ CHj CH (CH ₃ > 2 H H H CH ₃ CH (CH ₃ > 2 H CH ₃ CH ₃ CH ₃ CH (CH ₃ > 2 OCH ₃ H CH ₃ CH _{3 2} H CH ₃ CH ₃ A. Il V H X L H H H H H NO ₂ H br H H H H H H H H H H H H H H H H H H H H H H

CH.

.230466 0

Table II (continued)

rl R2 X L M Q Ry FP ° C CH ₃ CH (CHj) ₂ H CH ₃ H H CH ₃ CBj CH (CHj) ₂ H H H Cl CH ₃ CH ₃ CH (CHj) ₂ H Cl H H CH ₃ CHj CH (CHj) ₂ H H Cl H CH ₃ CH ₃ CH (CHj) ₂ H Cl H H OCHj CH ₃ CjH ₇ H H H H H CH ₃ C ₂ H ₅ H H H H H CH ₃ C ₄ H ₉ H H H H H CH ₃ £ " ^C 4 ^H 9 H H H H H CH ₃ AC ₄ H ₉ H H H H H CH ₃ 1-C ₄ H ₉ H H H H H CH, H H H H H CH. CH-.CH = CH " H H H H H

(CH ₂ J ₅ H H H H H CHj CH (CH ₃ ) ₂ Cl H H H H CH ₃ CH (CH ₃ ) ₂ CH ₃ - H H H H CH ₃ CH (CH ₃ J ₂ F H H H H CH ₃ CH (CH ₃ J ₂ OCH ₃ H H H H

- 23046

- 131 Table II (continued)

R ι R2 XLMQR ₇ Fp ⁰ C

CH ₃ CH (CH ₃ J ₂ OH HHHH

CH ₃ CH (CH ₃ J ₂ OAc HH HH

CH ₃ CH (CH ₃ J ₂ H Cl H HH 198-199 ((Zers.)

Example 42

Preparation of 2 ~ (5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl) -3-quinolinecarboxylic acid

Method A

¹ '"""""j

* - \ ₍ A / V ^C ™

^ T 11 1

To a slurry of 1,3-dihydro-a-isopropyl-amethyl-1,3-dioxo-2H-pyrrolo [3,4-b] quinoline-2-acetamide (5f76 g, 0.0185 mol) in 600 ml of dry xylene a 50% oil dispersion of sodium hydride (1.33 g, 0.0278 mol) and the mixture is heated under reflux, whereupon the reaction mixture becomes homogeneous. After refluxing for 3 hours, the reaction mixture is allowed to stand overnight at room temperature, then slowly treated with 15 ml of methanol containing 0.1 g of sodium methoxide and heated under reflux for 1 h. The mixture is filtered while still hot and the organic solvents are stripped to form an oil and a solid. A mixture of methylene chloride

- 2 3 O 4 6 6

and V / asser is shaken together with the above residues until dissolved. The aqueous layer (200 ml) is separated and acidified slowly with 5 ml of acetic acid. A precipitate of the product forms, which is collected by filtration. This gives 3.91 g (72%) of product, mp 219-224 ⁰ C. Recrystallization from hexane-ethyl acetate gives a product having a mp. 219- 222 ⁰ C (dec.).

Analysis: For ^C 1 7 ^H 17 ^N 3 °: 5 5 , 50% N 13 , 50% calculated : C 65 , 58% H 5 50 13 , 59th found * * 65 , 09

The procedure of this example is used to prepare the following compounds. However, to avoid ester formation, one simply adds methanol and then water (caution: hydrogen could form) to the xylene layer instead of filtering off the insoluble materials and stripping the xylene.

- .433 -

30466

Φ HH Φ & c

CN I

in

"sr

CN

"τ

CN

I 00

CN

CN

ΧΧΧΟΧΧΧ

HOOO '

οχχχχχή χ

CN

CN

CN

CN

CN

CN

CN CN O 2 X 03 U X X Z X X X X

XXXX

CN

ro m η η η rn η η η X X X X X X X X X CJ CJ U U CJ U CJ U U X X X X X X X X X U U CJ CJ U U U U U

η co ro co cn cn ci c ro XXXXXXXX X UUUUCJUUU CJ

R1 R2 X L M Q JR CH ₃ CH (CH ₃ J ₂ H Cl H H H CH ₃ CH (CH ₃ J ₂ H H CF ₃ H H CH ₃ CH (CH ₃ J ₂ H H H CF ₃ H CH ₃ CH (CH ₃ J ₂ H H F H H CH ₃ CH (CH ₃ J ₂ H H CH ₃ H H CH ₃ CH (CH ₃ J ₂ H H H CH ₃ H CH ₃ CH (CH ₃ J ₂ H H H H CH CH ₃ CH (CH ₃ J ₂ CH ₃ H H H H CH ₃ CH (CH ₃ J ₂ H H OCH ₃ H H CH ₃ CH (CH ₃ J ₂ H H SCH ₃ H H CH ₃ CH (CH ₃ J ₂ H H SO ₂ CH 3 « H CH ₃ CH (CH ₃ J ₂ F H H H H CH ₃ CH (CH ₃ J ₂ H H H CH ₃ CH

Table III (Continued) Procedure Fp ⁰ C A 255-256 (Zers.)

AH feehandl. the preceding verb, with peracid)

/>

R 2 X L _ M Q _R Table III (continued) CH (CH ₃ ) ₂ H H CH ₃ H CH ₃ Method Fp ° C CH ₃ CH (CH ₃ ) ₂ H CH ₃ H H CH ₃ A CH ₃ CH (CH ₃ J ₂ H H H Cl CH ₃ A CH ₃ CH (CH ₃ ) ₂ H Cl. H H CH ₃ A CH ₃ CH (CHj) ₂ OCH ₃ H H H H A CH ₃ CH (CHj) ₂ OH H H H H A CH ₃ CH (CHj) ₂ OAc H H H H CH ₃ CH (CHj) ₂ H H Cl H \ ^CH 3 CH ₃ CH (CHj) ₂ H· Cl H H OCH ₃ A CH ₃ C ₃ H ₇ -O H H H H H A CH ₃ C ₂ H ₅ H H H H H A CH ₃ C ₄ H ₉ -H H H H H H A CH ₃ C, H _Q -sec H H H H /H A CH, A

Table III (continued)

R ₁ R2 X L M Q R Procedure F.p ° c CHj H H H H r H A CHj C ₄ H ₉ -tert H H H H H A CHj H H H H H A CHj CHCH = CH ₂ H H H H H A CHj ^β \ "" ζ * H H H H H A (CH ₂ ) ₅ * H H H H H A CHj CH (CHj) ₂ H H H F H A CHj CH (CHj) ₂ H H H CN H CH ₃ CH (CHj) ₂ H H H N (CHj) ₂ H A CH ₃ CH (CHj) ₂ H H H NH ₂ H (ffedu & tion Q NO ₂ ) CHj CH (CHj) ₂ H H H I H A

VVV

I Il I 1 i \ _ "

% -

- 137 -

B e. ! game 43 ^:

Preparation of ethyl 2- (5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl) -3-quinolinecarboxylic acid

Veriahrpn_A

ff ff

h } ^N CH (CH)

HO ^{3 2} .

O To 2 g (0.0068 mol) of 2-isopropyl-2-methyl-5H-imidazo [i ".2 ': 1.2] pyrazolo [3,4-b] quinoline-3H (2H), 5-dione in 40 ml Absolute ethanol is added under nitrogen 0.34 g (0.00716 mol) of 50 # sodium hydride under cooling with ice. One observes a gas evolution. After 10 minutes, the reaction is neutralized with aqueous ammonium chloride, stripped and partitioned between water and ethyl acetate. The organic layer is separated, dried over anhydrous magnesium sulfate, filtered, stripped and the residue is crystallized from ethyl acetate-hexane. One receives 1.38 g (60 #) 'one

white solid, mp. 146-147.5 ° C.

In a similar manner, the following esters listed in Table IV can be prepared by Method A.

Be IsPjeI ₁ 44.

Preparation of methyl 2- (5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl) -3-quinolinecarboxylic acid

Method B

Close . / VV

.230466 0

1.4 g (0.0292 mol) of a 50% sodium hydride oil dispersion under nitrogen to 6 g (0.0193 mol) of azeotropically dried 1,3-dihydro-a-isopropyl-a-methyl-i, 3-dioxo -2H-pyrrolo [3,4-b] quinoline-2-acetamide. The mixture is heated and stirred at reflux for 6 hours, cooled, and quenched slowly with a solution of sodium methoxide (0.1 g) in 20 ml of methanol. After 3 hours heating at 6O ⁰ C, the mixture is filtered and the filtrate stripped. A white solid is obtained which is dissolved in a mixture of methylene chloride and water. Separation of the organic layer and stripping give a solid (0.48 g) which is purified by passing it through a silica gel layer using ethyl acetate as the solvent. After removal of the solvent, the solid residue from ethyl acetate-hexane is brought to crystallization, and obtained 0.4 g of the desired ester as white needles, mp. 145 bis.154 ⁰ C.

Analysis: for C ₁ QH ₁ 9N ₃ O ₅

Calculated: C 66.44% H 5, & 9% N 12.92% \

Found: 66.35 5.93 12.83.

X i.VXGi't · - \ r :, y ·, ίΓ

Table IV

CH ₃ CH ₃ C ₂ H ₅ CH ₃ CH (CH ₃ ) ₂ CH ₃ CH ₂ CH ₂ CH ₂ CH ₃ PSl - <9 · Kn ₂ κ j; CH _{3 [} ph ρ u 2 6 5 CH ₃ ^C 6 ^H 5 CH ₃ ^C 8 ^H 17 CH ₃

CH (CH ₃ ) ₂ CH (CH ₃ ) ₂ CH (CH ₃ J ₂ CH (CH ₃ ) ₂

CH (CH ₃ ) ₂

JL.

H H H H

H H H H

H H H

H H H H

H H H H

H H H H

Q_ H FP ⁰ C Example procedure - • H H 145-154 44 B H H 146-147, 5 43 A H H H H H H H H H H H

Table IV (continued)

CH ₃ ^R l ^R 2 C ₂ H ₅ X L M Q R ₇ example ^R 3 A CH + β CH ₃ ^C 2 ^H 5 H H H H H p, p ° C -Yerfahrei CH ₃ CH ₃ CH (CH ₃ J ₂ H H H H H CH ₃ CH ₃ CH (CH ₃ J ₂ H H CH ₃ H H 43A CH ₃ CH ₃ CH (CH ₃ J ₂ H H H Cl H C ₄ H ₉ CH ₃ CH (CH ₃ J ₂ H H N (CH ₃ J ₂ H H CH ₃ CH ₃ ^C 2 ^H 5: H H H H H CH ₃ CH ₃ CH ₃ H H H H H 133.5-134.5 43A CH ₃ CH ₃ CH ₃ sec-C ^ Hg H H H H H - <CH ₂ J ₅ H H H H H H H H H H

Example 45

Acid salts of quinoline carboxylic acid esters:

Preparation of the hydrochloride salt of methyl 2- (5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl) -3-quinolinecarboxylic acid

A solution of the ester is dissolved in an ether-methylene chloride solution and dry hydrogen chloride gas is passed through the solution until the solid hydrochloride salt is formed. This is filtered, washed with ether and dried in vacuo getrock- U net; Mp 226 to 270 ° C.

The following salts can be prepared in a similar manner by using the appropriate acid HX, although some of the products are hygroscopic oils. In this case, ethyl acetate is used as the preferred solvent for the acid salts.

- 230466 0

266-270

> φ I w H H co B φ X 'S EH CTJ O

· - "

Η- ·

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co ro co ro ro X O X B X X X CN X U CJ U CJ CJ O U CN CN CN CN CN U O O O O O U U U U U

H H

ro o

»-) (- <HO COr- ^ iHrHr-I .. -v

CJ O CQ Z CN CJ CJ U -CJ RS »

BBX EXX X EX * ¹ * ' ¹ «

χχχχχχχχχΚ

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8 p

BBXXXBBBXfflU

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™ ~ CM ^

tJ ^υ ο υ

O O

CN

CN CN

CN

CN

X U

X CJ

χ U

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ro PO ro PO PO ro ro ro r X X X X X X X X X O U CJ U CJ CJ U U U

χ υ

CM CJ

ro ro ο o

W W W

U O

ro ro

X X CJ U

ro P ¹ "

X X CJ U

ro

ro C B X U U

office ro <"

cj u d ο

Example .46

Preparation of sodium 2- (5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl) -3-quinolinecarboxylic acid

HO ° * HO

('') A solution of 2- (5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl) -3-quinolinecarboxylic acid (2.33 g, 0.0075 mol) in 22 ml of water 0.3 g (0.0075 mol) of sodium hydroxide is stirred overnight at room temperature and then washed with methylene chloride The aqueous layer is separated and evaporated to an orange solid which is washed with ether and air dried Product (as dihydrate) is obtained in the form of an off-white solid, mp 235-250 ° C (dec.).

Analysis: for CL, -, H ,,, ^ 1,0, .Na + 2H _o 0

Calculated: C 55.27% H 5.45% N 11.37% Na 6.22% C) found: 55.56 5.31 11.35 6.30.

Substituting sodium hydroxide, the following salts are prepared in a similar manner. The compounds thus prepared are summarized in Table VI.

.230466 0

<· C

ο r- in ro rs rh ι I in 00 ro rs rs iH

Cs ro

ro rs

»0

SB CJ Z.

rs

ro X CJ

ro ro U

CS

I Γ-

ro CJ

ro * - '-' - '

rs s rs X X

rs

X U

Il

X U

rs X CJ

ro X Z

X CJ in

CJ rs

X U

ro X Z

EC EC EC EC EC

· CM

it ta

EC

EC

Cu

EC S

X EC

EC. EC

rs

X X X X X X X X X CJ U U U U U CJ U CJ rs , CS rs rs rs rs (N rs rs

ro ro ro ro ro ro ro ro ro X X X X X X X X X CJ U CJ CJ CJ CJ CJ CJ CJ

ro ro ro ro ro ro ro PO t X X X X X X X X X U CJ CJ U U CJ U CJ CJ

R ₂ X L M Q R table NF VI (continued) ^R l (CH ₂ ) ₂ CH H H H H H 7 M ¹ FP ⁰ C Chg (CH ₂ ) ₂ CH H H H H H NH ₃ C ₆ H ₅ Chg (CH ₂ ) ₂ CH H H H H H NH ₃ C ₈ H ₁₇ Chg (CH ₃ J ₂ CH H H H H H NH ₃ C ₁₈ H ₃₇ Chg (CH ₂ ) ₂ CH H H H H H NH ₃ C ₃ H ₇ -I Chg (CH ₂ ) ₂ CH H H H H H '3 ™ 2ΐΛί Chg (CH ₃ J ₂ CH H H H .cl H About 270-290 Chg (CH ₂ ) ₂ CH H H H Chg H Ca Chg C ₂ H ₅ H H H H H NH ₃ (C ₃ H ₇ I) ₂ Chg - (CH ₂ J ₅ H H H H H ^NH 3 ^C 8 ^H 17, NH ₃ C ₁₈ H

- «6-23 04 6

B ic ρ ie I ₁ 47 ι

Preparation of 2-isopropyl-2-methyl-5H-imidazo [i ^! 2 ': 1.2] pyrazolo] 3,4-b] quinoline-3 (2H), 5-dione; 2-isopropyl-2-methyl

Method A

'fl fl

3 2

λ,

vv w »vv

3.67 g (0.0168 mol) of dicyclohexylcarbodiimide in methylene chloride are added overnight under nitrogen to a stirred suspension of 2- (5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl) -quinolinecarboxylic acid (5 , 24 g, 0.0168 mol) in methylene chloride at room temperature. Since the reaction was incomplete, add another 0.3 g of dicyclohexylcarbodiimide and stir the mixture for a further 48 h. The reaction mixture is evaporated to a yellow solid and purified by chromatography on a silica gel column. The eluted with acetonitrile-methylene chloride product is a white solid which is brought from toluene for crystallization Fp.225 to 227 ⁰ C.

Analysis: Calculated for C ₁ H ₁ ^ NjO ₂ : C 69.61 # H 5.15% N 14.33% Found: 69.76 5.31 14.13.

For s ρ i e 1 48

Preparation of cis- and trans-1, Hb-dihydro-11b-hydroxy-3-isopropyl-3-methyl-5H-imidazo [1. 2 ': 1.2 jpyrrolo [3,4-b] quinoline-2 (3H), 5-dione

Method B

H (ZA i ^X CH (CH,)

Ao ³

3 0 466

A solution of 1,3-dihydro-α-isopropyl-α-methyl-1,3-dioxo-2H-pyrrolo [3,4-b] quinoline-2-acetamide (0.5 g, 0.0016 mol) is added 23 h heated under reflux in xylene. On cooling, a white solid precipitates (0.17 g), mp. 191-192 ⁰ C, and another batch (0.1 g), mp. 187-189 ° C, forms upon dilution of the filtrate with hexane ,

Analysis: for C ₁₇ H ₁ ^ N ₅ O ₃

Calculated: C 65.58% H 5,5O # N 13,5056 found: 66,08 5,65 13 »00

Other triethylene compounds are obtained by methods similar to methods A and B above.

Examples of tricyclic compounds: \ ? R -ff _B

U Q = CH ₃ X, L, M, R ₇ = HR ₁ = CH ₃ R ₃ = CH (CH ₃ J ₂

Q = Cl X, L, M, R ₇ = HR ₁ = CH ₃ R ₂ = CH (CH ₃ ) ₂

M = CH ₃ X, L, Q ₁ R ₇ = HR ₁ = CH ₃ R ₃ = CH (CH ₃ J ₂

M = Cl X, L, Q ₁ R ₇ = HR ₁ = CH ₃ R ₂ CH (CH ₃ J ₂

Q = CF ₃ X, L, M, R ₇ = HR ₁ = CH ₃ R ₃ = CH (CH ₃ J ₂

M = N (CH ₃ J ₂ X, L, Q, R ₇ = HR ₁ = CH ₃ R ₂ = CH (CH ₃ J ₂

M = OCH ₃ X, L, Q, R ₇ = HR ₁ = CH ₃ R ₂ = CH (CH ₃ J ₂

X = OH L, M, Q, R ₇ = HR ₁ = CH ₃ R ₃ = CH (CH ₃ J ₃

H ^R l

CH ₃ C ₂ H ₅

CH ₃ C ₃ H ₇

CH ₃ C ₄ H ₉ -n

CH ₃ C ₄ H ₉ -SeC

CH ₃ C ₄ Hg

CH ₃

- (CH ₂ )

Be i spie 1 49.

Preparation of N- (1-cyano-1,2-dimethylpropy3) -2- (o ~ for ·

mylanilino) -malelmid "

Method A

\ L ·

A solution of 3.55 g (0.0298 mol) of anthranil and 5.73 g (0.0298 mol) of a-isopropyl-a-methyl - ^^ - dioxo ^ -pyrroline-1-acetonitrile in 20 ml of xylene is added Nitrogen heated for 39 h under reflux. On cooling, a yellow precipitate forms, which is filtered off to give 2.78 g of product, mp 191 to 192 ^° C.

Analysis: for C ^ yH ^ N ^ O,

Calculated: C 65.5895 H 5.50% N 13.50% Found: 65.33 5.44 13.36.

Preparation of N- (1-cyano-1,2-dimethylpropyl) -2- (2-formyl-5-chloroanilino) maleimide

Method B

4 »g (0.0204 mol) of pyridinium chlorochromate in 20 ml of methylene dichloride are rapidly added to a solution of 4.75 g (0.0136 mol) of N- (i-cyano-1,2-dimethylpropyl) -2- ( 5-chloro-2-hydroxymethylanilino) maleimide in 20 ml of methylene chloride. After 2 h, the dark reaction mixture is diluted with 20 ml of ether. This forms a yellow precipitate, which is filtered off. This solid is redissolved in ethyl acetate-methylene chloride (1: 1) and passed through a silica gel column. 4.31 g of a yellow solid, mp. This gives 80 ⁰ C (dec.).

The following aldehydes listed in Table VII are prepared according to Method A or B.

- • 150 -

Table VII

230466 0

CH-

CH.

CH-

CH.

CH-

CH.

CH-CH.

CH.

CH.

CH.

CH.

CH.

CH.

CH.

CH (CH ₃ ) ₂ CH (CH ₃ J ₂ CH (CH ₃ ) ₂ CH (CH ₃ ) ₂ CH (CH ₃ J ₂ CH (CH ₃ ) ₂ CH (CH ₃ ) ₂ CH (CH ₃ ) ₂

-CH (CH ₃ ) ₂ CH (CH ₃ ) ₂ CH (CH ₃ ) ₂ CH (CH ₃ ) ₂

CH (CH ₃ ) ₂

CH (CH ₃ J ₂ CH (CH ₃ ) ₂

Cl H H H

CH ₃ HHHHH

Cl CH ₃ H

ö M

Cl H H H

CH ₃ HHHHH Cl

CH-,

SC-CN R ₂

Q HH

Cl H H H

CH ₃ HH Cl HH

H H H

Cl

CH ₃ OCH. CH ₃ CH ₃ CH ₃

0CH _:

CH ₃

CH,

Example procedure. FP C

5C.B 49A

80

5OB 5OB

205-212

τ.151 -

23 046 6 0

R ₂ L table M - _Q VII (Continuation) CH (CH ₃ ) ₂ H ν H CH ₃ ^R l CH (CH ₃ ) ₂ H CF ₃ H Example Vkrffiren CH ₃ CH (CH ₃ ) ₂ H H CF ₃ CH ₃ CH ₃ H H H , H CH ₃ H

Example 51

Preparation of N- (1-cyano-1,2-dimethylpropyl) -2- (2-hydroxymethylanilino) -raaleimide

ΛΛ ⁰⁸ I 2 +

To 2 g (0.0125 mol) of o-aminobenzyl alcohol and 2.7 g (0.01 mol) of 3-bromo-a-isopropyl-a-methyl-2,5-dioxo-3-pyrroline-1-acetonitrile 100 ml of absolute ethanol containing 3 g of 5A molecular sieves (pulverized) are added. The mixture is stirred for 20 h at room temperature. The solvent is removed and the residue is purified on a dry silica gel column [eluent: ether-hexane (2: 1)]. First, the starting material bromomaleimide and then a light yellow solid (189 g, 60%), mp. 39 to 45 ⁰ C, isolated.

Analysis: for C ₁ 7H ₁₉ N 3 °; 5 6 , 11% N 13 41% calculated: C 65 , 16% H 6 , 21 12 , 87th found : 65 , 94

3 0 4 6 6

Other compounds are prepared by the above method using differently substituted o-aminobenzyl alcohols. The use of isopropanol or t-butanol instead of ethanol generally improves the product yield. One can also use bases as acid acceptors.

Table VIII

\ A / ^CH 2 ^0H ft

R,

CH. CH. CH. CH-CH. CH. CH. CH-CH. CH. CH. CH. CH.

CH. CH.

CH (CH ₃ ) ₂ CH (CH ₃ J ₂ CH (CH ₃ J ₂ CH (CH ₃ J ₂ CH (CH ₃ J ₂ CH (CH ₃ J ₂ CH (CH ₃ J ₂ CH (CH ₃ J ₂ CH ( CH ₃ J ₂ CH (CH ₃ J ₂ CH (CH ₃ J ₂ CH (CH ₃ J ₂ CH (CH ₃ J ₂

CH (CH ₃ J ₂ CH (CH ₃ J ₂

CH H H

Fp ⁰ C

rubber

98-100

CH.

CH

CH

CH

- 153 Table VIII (cont'd)

^R l R ₂ 2 L M Q ^R f CH ₃ CH (CH ₃ ) 2 H H CF ₃ H CH ₃ CH (CH ₃ ) H CF ₃ H H 1 U H H U at JLJLJL-J.

Preparation of 3-bromo-a-isopropyl-a-methyl-2,5-dioxo-3-pyrroline-1-acetonitrile

! CH

s \ Γ ³

Il J ^ -C-CN

Y ¹

To a heated to 75 ⁰ C solution of 50 g (0.25 mol) of a ~ isopropyl-oc-methyl-2,5-dioxo-3-pyrroline ~ 1-acetonitrile in 500 ml of acetic acid is added dropwise with stirring 40.76 g (0.255 mol) of bromine in 80 ml of acetic acid. The reaction mixture is kept at 85 ^° C. overnight and evaporated to a syrup. This is dissolved in 300 ml of methylene chloride, cooled to 5 ° C and treated with 34.78 ml of triethylamine. After stirring for 2 hours, the brown methylene chloride solution is diluted with ether to form a white precipitate, which is extracted with 400 ml of water. The organic layer is dried over anhydrous magnesium sulfate and then passed through a 2 inch bed of silica gel eluting with methylene chloride. The eluate is obtained in the form of a dark brown oil

Analysis: for C ₁₀ H ₁₀ N ₂ O ₂ Br

Calculated: C 44.29% H 4.09% N 10.33% Found: 43.37 4.05 10.07.

- ^ - 230466 0

In a similar manner, other bromine imides are made.

R ₂

CH ₃ C ₂ H ₅

CH ₃ C ₄ H ₉

CH ₃ C ₄ Hg-JSQ

CH ₃ C ₄ H ₉ -. fc. ert

· -β

) c

CH ₃

Be I ₁₁ S ₁ P _1- I ₁₁ e 1 _{in the} preparation of α-1-acetonitrile

η ₃ > j \ -j-cx

'CONH-C-CN V OH (CH ..).

H (CH.

K 3 'CF

3

A solution of 595 g (2.83 mol) of N- (1-cyano-1,2-dimethylpropyl) maleamic acid in 3.96 g of acetic anhydride containing 13.7 g (0.167 mol) of sodium acetate is refluxed for 1 h heated, cooled and the solvent removed in vacuo. The product is at 120 to

130 ° C / 0.1 mm distilled (the pot temperature should not exceed 200 ⁰ C), and 337 g (63%) of product.

Analysis: for C ₁₀ H ₁₂ N ₂ O ₂

calculated? C 62.49% H 6.29% N 14.57% Found: .62.32 6.36 14.59.

In a similar manner, the following compounds are prepared.

R ₁ R ₂

CH ₃ CH (CH ₃ J ₂

CH ₃ C ₂ H ₅

CH ₃ C ₃ H ₇

CH ₃ C ₄ H ₉

CH ₃ C ^ Hn iso

CH, C, H "3 4 9

J CH ₃ C ₄ Hg- tert

^CH 3 <'"'>

^CH 3

CH ₃ CH ₂ CH = CH.

¹ W, '/''' ·

, 23 0 46 6

Preparation of N- [1- (1-cyano-1,2-dimethylpropyl) -2,5-dioxo-3-pyrroline-3-yl] -anthranilic acid

·, CO HQ 3 <y N / 2 Π _ "

H + 11 V-C-CN> * Il / \ T 3

V "^ β / · CH (CH) ₀ ^Χ · ΙίΗ- · ν-χΤ

² · Ä ³ J ^ (CH ₃ ),

A mixture of 13.7 g (0.1 mol) of anthranilic acid, 27 g (0.1 mol of 3-bromo-x-isopropyl-a-methyl-2,5-dodecox-3-pyrroline-1-acetonitrile, 200 ml of isopropanol and 8.2 g of sodium acetate are stirred at room temperature for 3 days and then refluxed for 1 hour The mixture is cooled and treated with ether to give 31.6 g (97.7%) of a yellow solid, m.p. 262 to 266 ° C, after uncrystallization from acetic acid.

Analysis: for C ₁ yH ₁ ^ N ^ O ^ calculated: C 62.37% H 5.24% N 12.84% found: 62.24 5.19 12.70,

Similarly, other maleimides can be prepared.

\ A / ^C0 2 ^H ff

^R l ^R 2

CH ₃ CH (CH _{3) 2} H

CH ₃ CH (CH ₃ ) j H

CH ₃ CH (CH ₃ J ₂ H

CH ₃ CH (CH _{3) 2} H

30466 C

Example 55

Preparation of N- (1-carbamoyl-1,2-dimethylpropyl) -

chinaldamid

To a cooled to -9 ° C solution of 20 g (0.116 mol) of quinaldic acid in 500 ml of tetrahydrofuran are added 8.92 g (0.116 mol) of methyl chloroformate and then 18.4 ml (0.139 mol) of triethylamine. After 20 min, add 15 »1 g (0.116 mol) of a-isopropyl-a-methyl-3-pyrroline-i-acetamide and stir the mixture overnight at room temperature. Water is added and the solution is reduced to 200 ml on a rotary evaporator. It separates a white solid, which is filtered off, washed with water and dried. Recrystallization from absolute ethanol gives 26.86 g (87 $) of the product, mp. 179-180 ⁰ C.

Analysis: Calculated for C ₁₆ H ₁₉ NyD ₂ : C 67.34% H 6.73% N 14.72% Found: 67.14 6.17 14.72.

Other quinolinecarboxamides are prepared in a similar manner.

ν y \ /> R

• · ♦ Ti

ι ίι Τ ^Μ

230466 0

-CONH-C-CONH

^R l ^R 2 X L M Q R ₇ - Il ^ N-C-COIi ^ CH (Ct CH ₃ CH (CH ₃ J ₂ OCH ₃ H H H CH ₃ CH (CH ₃ J ₂ CH ₃ i in. H H H H CH ₃ CH (CH ₃ J ₂ Cl H H H H CH ₃ CH (CH ₃ ) 2 H H H H Cl CH ₃ CH (CH ₃ ) 2 H H H H NO ₂ CH ₃ C ₂ H ₅ H H H H H CH ₃ C ₄ H ₉ -SeC H H , H H H f PH \ H H H H H H H H H br CH ₃ CH (CH ₃ ) 2 B e i s p j L e 1 56 Preparation of α-isopropyl-α-methyl-2,5-dioxo-3-pyrroline ~ 1-acetamide jj ^ NC CN I CH (CH _{3) 2}

A solution of 2.0 g (0.104 mol) of α-isopropyl-α-methyl-2,5-dioxo-3-pyrroline-1-acetonitrile in 30 ml of methylene chloride is added at a gentle temperature to concentrated sulfuric acid at room temperature. After I6stündigem stirring overnight at room temperature, the mixture

i } (3

- 159 -.

poured on ice containing sodium chloride and ethyl acetate. The organic layer is washed with aqueous sodium bicarbonate solution and brine and dried. Evaporation after the V / ash with ether-pentane gives a solid (72%), mp. 138.5 1AO to ⁰ C.

Analysis: for C ₁₀ H ₁ ^ N ₂ O ₅

Calculated: C 57.13% H 6.71% N 13.33% Found: 56.89 6.64 13.16.

Similarly, other imidamides are produced.

^R 2

CH ₃ ^C 2 ^H 5 CH ₃ C ₃ H ₇ CH ₃ , C ₄ H ₉ -n CH ₃ C ₄ Hg-JSQ CH ₃ C ₄ Hg-sec CH ₃ ' C ₄ H ₉ -ter_t CH ₃ CH ₃ CH ₂ CH = CH ₂ CH _3. , _,; / Ρ «

-160-23 0 46 6 0

B ^ e _n is 2 1 e, 1 _mu pj

Preparation of 5-isopropyl-5-niethyl-2- (2-quinolyl) -2-iradiazolin-4-one

N. CH (CH ₃ , ₂

To a slurry of 16.04 g (0.0562 mol) of N- (1-carbamoyl-1,2-dimethylpropy3) -2-quinolinecarboxamide in 610 ml of xylene are added at 20 ⁰ C under nitrogen 2.7 g (0.056 mol ) of a 50% oil dispersion of sodium hydride. The reaction mixture is heated under reflux for 2 h, cooled and precooled with 50 ml of water. The aqueous layer is extracted with methylene chloride. The organic layers are combined and evaporated; 17 g of a yellow oil are obtained. The purification is carried out by passing through a silica gel column using hexane-ethyl acetate as a solvent. The resulting pale yellow solid is recrystallized from ethyl acetate to give 11.77 g (78 ^) of a white product, mp. 112-117 ° C.

Analysis: for C ₁ gH ₁ yN ^ O ^ ^% v '· - calculated: C 71.88% H 6.41 $ N 15.72% found: 71.91 6.47 15.70.

Other compounds prepared in similar fashion are listed in Table IX.

- 230466 0

R ₂ \ M - / \ table L IX Q ^R 7 CH (CH ₃ ) ₂ * 7 H H H CH (CH ₃ ) j X H H K H H ^R l CH (CH ₃ ) j OCH ₃ H M H H CH ₃ CH (CH ₃ ) j CH (CH ₃ ) j CH ₃ H H H H H Cl NOj CH ₃ C ₂ H ₅ Cl H H H H CH ₃ C ₃ H ₇ H H H H H H CH ₃ CH ₃ C ₄ H ₉ -H H H H H H H CH ₃ C ₄ H ₉ -I H H H H H CH ₃ C _Ä H _Q -sec H H H H H CH ₃ A Q "* ι · H H H H H CH ₃ C "yclopropyl H H H H H CH ₃ CHjCH-CHj H H H H H CH ₃ cyclohexyl H H H H H CH ₃ t Ott ^ H H H H H CH ₃ (CHj) ₅ H H CK ₃ H H H

B e is ρ i el, 58

Preparation of 2- (5-isopropyl-5-methyl-4-oxo-2-imide

azolin-2-yl) -3-quinoline-carboxaldehyde VV \ f | \ "(c" ₃ , ₂ Ky ^! "

To a mixture of 3 g (0.0112 mol) of 5-isopropyl-5-methyl-2- (2-quinolyl) -2-imidazolin-4-one in 150 ml of ether are added 3.4 g (0.00225 Mol) tetramethylethylenediamine. 17 ml (0-027 mol) of n-butyllithium in hexane are added dropwise to the reaction mixture cooled to -63 ° C. It forms an intense red color, and after the addition © the mixture is held for 2 1/2 h at -10 to -20 ° C. 5 ml of dry DMF are added at -10 ⁰ C and the mixture can come to room temperature with stirring overnight. The mixture is diluted with 75 ml of water and neutralized with acetic acid. After crystallization from 95% ethanol to obtain a pale yellow solid (2.57 g; 78%)., M.p. 226-227 ⁰ C. Dilution of the 95% ethanol with 5 to 10 ml of water gives a new solid which is filtered becomes. (Purified by washing the solid with 95% ethanol, the yellow ink is removed, and a material is obtained with a mp. 168-169 ⁰ C. By m + 1 / e is confirmed either tricyclic structure A or B.]

Analysis: For 69 7 ^H 17 ^N 3 ° 2 > 5 80% N 14 , 23% calculated : C 68 , 13% H 5 , 88 , 14 , 15th found • • , 98

! ' ¹ I

/ VVV

2 3 0 4

? ^(c v _a

ί \ Η ₃

In similar ways other groups A are produced.

/ yV

I Il

ννγγ

g CH (CH ₃ ) H

, _ .. _v "" ₃ , ₂

COOH 2 CH ₂ OH COH CH 3 H 3 CH 2 co ₂ CH ₃ CH 3 CHOH CH H ₅ CH0H ^C 6 (CH 3> 2 .CO CH ^H

181-184

135-199 a diastereomeric mixture

Example $$

Preparation of 2- [3 ~ (hydroxymethyl) -2-quinolinyl-5-iso-O-

propyl-5 ~ niethyl-2-imidazolin-4-one

y \ > · ν .CH "OH

23 0 46 6

0.5 g (0.013 mol) of powdered sodium borohydride are added to 0.78 g (0.00264 mol) of 2- (5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl) suspended in 150 ml of ethanol. 3-quinoline-carboxaldehyde added under nitrogen to give a clear, yellow solution. After 20 minutes, concentrate the reaction mixture to 40 ml and dilute with 75 ml of water. Extraction with methylene chloride and evaporation. One obtains a solid which is brought to crystallization from hexane-ethyl acetate and pale yellow crystals, mp. 138 to 149 ⁰ C, provides; M / e 298.

Other compounds can be prepared by the above procedure using the appropriately substituted quinolinecarboxaldehyde. Such compounds are listed in Table X.

Table X

S VV CH

l Il - T _M / 3

Yi

X = Cl, Me L, M, Q, R ₇ = H L = Me, Cl X, M, Q, R _? = H M = Me, Cl X, L, Q, R ₇ = H Q = Me, Cl X, L, M, R ₇ = H R ₇ = Me, Cl X, L, M, Q = H

B ic ρ i el .60

Evaluation of the compounds of the invention

cause ripening of barley

In the following tests, the appropriate compounds are dissolved or dispersed in acetone-water (1: 1) mixtures to final concentrations corresponding to the kg / ha rates given in the following tables. The solutions also contain 0.1 to 0.25 # (v / v) colloidal biofilm (a product of Colloidal Products Corp.), which is a mixture of alkylaryl-polyethoxyethanol, free and bound fatty acids, glycol ethers, Dialkylbenzene carboxylate and 2-propanol.

The plant species used in these tests is barley (Hordeum vulgare, var. Mexico).

The solution or dispersion of the tested compound is sprayed at a rate of 40 ml / pot and applied to the leaves.

In the post-emergence tests, the plants are seedlings in the two-leaf stage (19 plants / pot, pot size 8.9 cm χ 6.3 cm χ 6.3 cm).

The pots are watered immediately before treatment and randomly placed on shelves in a greenhouse. Normal irrigation and fertilization practices are used (if necessary, pesticides are given to the plants). Minimum day and night temperatures of 18.3 ° C are maintained throughout the cooler seasons. During the summer time, the normal daily temperature fluctuations occur. The plants are sprayed in such a way that the kg / ha rates indicated in the following tables are guaranteed.

.23 0 46 6

are performing. Each treatment is performed six times as a replica.

Recording the measured values

After treatment, periodic observations are made and morphological changes recorded. From these observations, the ripening effect of the compounds according to the invention on barley can be determined by comparison with untreated control plants. The values obtained in this way are averaged. The results are summarized in Tables Ia to Ic.

Table Ia

Evaluation of the ripening effect of the compounds according to the invention on barley

Connection Rate Results (kg / ha) ____ "

Triethylammonium 2- (5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl) nicotinate

Methyl-2- (5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl) nicotinate

0.01 0.002

0.01 0.002

0,004

0.01 0.002

Calcium-2- (5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl) nicotinate

2- (5-ethyl-5-methyl-4-oxo-0.01 2-imidazolin-2-yl) nicotinate

low increase in tillering

big increase in tillering

earlier spike formation;

increased tillering

H Il Il

phytotoxic increased tillering

delayed ear formation; increased

tillering

Table Ib

Evaluation of the ripening effect of the compounds according to the invention on barley

Connection rate results

(Kg / ha)

Methyl 2- (5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl; nicotinate 0.005

low increase in tillering

23046

Table Ic

Evaluation of the ripening effect of the compounds according to the invention on barley

Connection rate results (kg / ha)

Methyl 2- (5-1SOPrOPyIS methyl ^ -oxo ^ -imidazolin-2-yl) nicotinate

0.1

0.05

0.01

phytotoxic

ti Il

large increase in tillering with earlier ear maturation

B ice ρ ie 1

Evaluation of the effect of the compounds according to the invention on increased branching and flowering

Following the procedure of Example 60, the effect of the compounds of the invention on soybeans (Glycine max, var. Adelphi) is evaluated. Each test is repeated six times as a replica. In each pot is a plant, and the plants are treated in 2nd to 3rd three-leaf stage. The results obtained are averaged and summarized in Tables Ha through Hc.

Table Ha

Evaluation of the compounds according to the invention with regard to the effect of increasing branching in soybeans

connection

Rate (kg / ha)

Results

Methyl 2- (5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl) nicotinate

0,002

Calcium 2- (5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl) nicotinate

2- (5-ethyl-5-methyl-4-oxo-0.01 2-imidazolin-2-yl) -nicotinic acid 0.0004

greatly increased branching; delayed flowering, greener leaves increased branching

greatly increased branching, delayed flowering, greener leaves

moderately increased branching

.23 0 46

Table lib

Evaluation of the Compounds of the Invention for the Effect of Increasing Branching and Flowering Mixture on Soybeans .

connection

Rate (kg / ha) '

Results

Methyl 2- (5-isoprolyl-5-methyl-4-oxo-2-imidazolin-2-yl) nicotinate

O »01. .. ,, .-, ™ ·; greatly increased dissemination; increased; vvri flower count, slightly delayed flowering

0.005 greatly increased branching; Moderately increased flowering

0.0025 moderately increased branching; increased

flowering Table lic

Evaluation of the compounds according to the invention with regard to the effect of increasing shoot formation in soybeans

connection

Rate (kg / ha)

Results

Methyl 2- (5-isopropyl-5-methyl-1-oxo-4-imidazo-0.05-lin-2-yl) -nicotinate 0.01

phytotoxic

It Il

strongly increased branching, dark green leaves

example

Evaluation of the yield enhancement effect of the invention compounds

The effect of the compounds according to the invention on soybeans (Glycine max var. Adelphi) is evaluated by the method of Example 60. Each test is performed six times as a replica. In each pot is a plant, the plants are treated in the 6th trefoil stage. The results obtained are averaged and are listed in the following Table III.

Table III

Evaluation of the yield-increasing effect of the compounds according to the invention on soybeans (average of six replicates)

connection

Rate number d. % (kg / ha) pods increase

decrease

Fresh weight of the pods (g) decrease

Dry weight of

Increase (+)

(-) pods (g)

Increase decrease

comparison

Methyl 2- (5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl) nicotine

99.7

126.2

32.4

0.01 27 3 - 73 28.5 - 77 7.7 - 76 0,002 115 , 0 + 15 126.3 0 29.5. - 9 0.0004 122 ,8th + 23 149.6 + 19 38.2 + 18

.170. 2 30 46 6

Example 63

Evaluation of the effects of the compounds of the invention caused by ripening in wheat in post-emergence treatment; '

By the method of Example 60, wheat (Triticum aestivum, var. Era) is treated at the early stage of early tillering stage with the kg / ha rates given in Table IV below. Each treatment is performed six times as a replica.

evaluation of results

The plants are harvested 5 weeks after the treatment. The number of ears, the fresh weight and the dry weight of the ears and the straw weight are determined and the percentage changes (+) are given. The results obtained are averaged. The mean values are listed in the following Table IV.

Table IV Evaluation of the ripening effect on wheat caused by the compounds of the invention

in post-emergence treatment

connection rate ears: % Modification in r; % Change Straw weight (^) (Kg / ha) ; Number; mass 64.3 Dry weight (g) ^ change Number of fresh weight (g) ears - % Modification comparison % Change 30.1 100.1 30.2 - - -

Methyl-2- (5-isopropyl-4-oxo-2-imidazolin-2-yl) nicotinate

0.01

JZ.0

22, s 38,2

0,004

31

77.3

20.2

56.8 62 ^, 2

30 ^ 8

2.3 38.4

27.6 28.2

^ b, f

73.3 160.7

60.5 110.8

1077

-172-230466 0

Example 64

Evaluation of the Ripening Effect on Wheat in Pre-emergence Caused by the Compounds of the Invention

treatment

The seeds of wheat (Triticum aestivum, var. Era) are mixed with potting soil and planted on top of an approximately 2.5 cm thick soil layer in fiber pots with a diameter of 12.5 cm. After planting, the pots are sprayed using an aqueous acetone solution containing the test compounds having V kg / ha rates in the following table. The treated pots are then placed on greenhouse shelves. They are watered and cared for in accordance with conventional greenhouse practices. Each treatment is performed six times as a replica.

evaluation of results

The plants are harvested 11 weeks after the treatment. The number of ears, the fresh and dry weights of the ears and the straw weight are determined and the percentage changes (+) are noted. The values obtained are averaged. The mean values are listed in Table V.

Table V Evaluation of the ripening effect on wheat caused by the compounds of the invention

at pre-emergence treatment

connection rate ears; Number; mass % Change in κ; % Change Straw ^ desired weight (e ^ (Kg / ha) Number of fresh weight (g) ears 47.2 Dry weight ( g) % Change % Modification - % Change comparison - 25.7 15.7 145.3 - _ -

Methyl-2- (5-iso- 0.1 propyl-5-methyl-4-oxo-2-imid _{n ηΛ} quinazolin-2-yl) - ^UfVi nicotinate

0.001

- - - 101, 6 29.3 50.9 17.0 -30.1 139.8 14.0 28.8 7.8 53.0 8,3 18,0 -3.8 135.3

12.1

12.3

14.6

-b, 9

23 045 6 0

Example 63

Evaluation of the test compounds with regard to increasing the yield of soybeans and wheat

In the following tests, either Era wheat seed or Adelphi soybean seed is planted in 13 cm fiber pots. The test compounds are then dispersed in acetone-water (1: 1) mixtures. which contain 0.1 to 0.25% (v / v) colloidal biofilm, which is a mixture of alkylaryl polyethoxyethanol, free and bound fatty acids, glycol ethers, dialkylbenzene carboxylate and 2-propanol. The planted seed is sprayed with a sufficient amount of the mixture to ensure at each pot a rate of 0.1, 0.01 and 0.001 kg / ha of the test compound, respectively. The treated pots are then placed on greenhouse shelves and stored according to conventional greenhouse practices. 3 months after the treatment, the soybeans are harvested, dried and weighed. Pr @ treatment, six replicates are performed and the mean determined. The results obtained are summarized below.

Table VI Assessment of yield increase in soybean compound rate dry weight % increase versus

(kg / ha) of pods (g) over control

plants

untreated - 13 control plants

Methyl-2- (5-iso- 0.1 4.8 +15 propy1-5-methyl 0.01 14.9 +18 4-oxo-2-imidazo- 0.001 15.3 lin-2-yl) -nicoti- nat

Table VI (continued)

Evaluation of yield increase in wheat

connection

Troll plant dry weight rate% increase Ge- (kg / ha) of the ears (g) genüber con- ..

untreated control plants methyl 2- (5-iso-0.1

15.7

propyl 5-methyl-4-oxo-2-imidazolin-2-yl) nicotinate 0.01 0.001 17.0 18.0 + 8,2 +14,6 untreated control plants Methyl 2- (5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl) -nicotinate.HCl 0.016 0.008 0.004 19.3 11.3 21.5 23.2 +11.4 +14.5 Example 66 Assessment of yield increase in wheat in penz application of test compound Post-Emerging

The following tests are performed according to the procedure of Example 60. However, Era wheat is used as the plant species and the plants are harvested 9 weeks after the treatment. The following results are obtained

 Evaluation of yield increase in wheat

Connection rate (kg / ha)

Dry weight % increase over ears of corn (g) control plants

untreated control plants methyl 2- (5-isopropyl-5-methyl-

4-oxo-2 ~ imidazolin-2-yl) -nico-

tinat

30.1

0.01 30.8 + 2,3 0,002 .18,4 +28.1 0.0004 28.2 - 6 3

Claims (1)

23 0 46 6 0 invention claim Agent for the treatment of a 1 ha surface for the purpose of increasing the crop yield of cereals or legumes produced thereon, characterized by from 100 "to 500 l water {from 0.01 to 0.001 kg of a compound of the formula wherein B is hydrogen, CO-alkyl-C ,, ₆ or CO-phenyl; A is COOR ₃ , where R ^ is hydrogen; Di-lower alkyliminof C ,,, .p-alkyl, optionally substituted by one of the following groups: C, n-alkoxy, halogen, hydroxyl, C, C-cycloalkyl, benzyloxy, furyl, phenyl, halopkenyl, lower alkylphenyl, lower alkoxyphenyl, nitrophenyl, Carboxyl, lower alkoxy carbonyl, cyano or tri-lower alkylammonium j ^σ 3_ΐ2 "" alkenyl, optionally substituted by one of the following groups C,., Alkoxy, phenyl, halogen or lower alkoxycarbonyl or with two C ^ __ ^ - Alkoxygruppeη or with two Halogen atoms ι Cj ^ -cycloalkyl, optionally substituted by one or two C, | o-alkyl group (s) \ C ^^ Q-alkynyl, optionally substituted by one or two C ^^^ alkyl group Cn); or a cation selected from the group consisting of alkali metal, alkaline earth metal, manganese, copper, iron, zinc, cobalt, lead, silver, nickel, ammonium and organic ammonium compounds; X is hydrogen and Y and Z are each hydrogen, C ,, g-alkyl, - 177 - C ^ ^ alkoxy, halo} C ^^ - haloalkyl or phenyl, and if Y and Z are taken together, YZ is - (CHp) -; and from 0.01 to 3% by weight of a dispersant and / or a nonionic surfactant.