HU206678B - Process for producing halogeno-pyridine derivatives - Google Patents

Abstract

(A) Prepn. of pyridine derivs. of formula (I) comprises: (a) reacting a cpd. of formula (RO)2CHCH2CH(OR)2 (II) with a cyanide of formula R1CH2CN (III) in presence of acetic anhydride and a ZnX2 catalyst at 110-150 deg.C to give a cpd. of formula (IV); and (b) reacting (IV) with HX in presence of acetic acid at 0-60 deg.C; and opt. (c) using excess HX to form the crystalline salt of (I) and sepg. this from the mixt. In the formulae, R = Me or Et; R1 = COR2 or SO2Et; R2 = di(1-2C alkyl)amino, X = F, Cl or Br. (B) (I) are new provided that when R1 = COR2 then X = F or Br. (C) (IV) are new. - Step (a): Typically 1-3 (pref. 1.2-1.5) moles (II) are reacted with 1 mole (III) in presence of 1-5 (pref. 1.5-2.5) moles acetic anhydride and 0.5-2 wt.% ZnX2 (on (II)) pref. at 120-130 deg.C. Step (b): Typically (IV) is reacted with 0.5-8 (pref. 2-4) moles HX using 0.2-1 (pref. 0.4-0.6)l acetic acid/mole reactant pref. at 10-30 deg.C.

Description

The present invention relates to a process for the preparation of halopyridine intermediates.

More particularly, the present invention is a process for the preparation of the halopyridine derivatives of the formula (I) from cyano-diene derivatives and protected 1,3-dialdehyde derivatives.

The sulfonylurea herbicides are a group of highly potent herbicides discovered in the last few years, usually consisting of sulfonylurea bridges of the formula -SO ₂ NHCONH- linking two aromatic or heteroaromatic rings. As a result of research into the production of sulfonylurea herbicides, new processes are constantly being reported. Research is still underway to produce these compounds and their intermediates more efficiently.

South African Patent Application No. 870436, published September 30, 1987, discloses the use of compounds of formula I in the preparation of pyridinesulfonylureas.

European Patent Application A-237292, published September 16, 1987, also describes the use of the compounds of formula (I) above for the preparation of pyridinesulfonylureas.

J. Org. Chem., 41, 2066 (1976), the 2-bromo-nicotinic acid esters are prepared according to Scheme 1.

J. Org. Chem., 39, 3436 (1974)], nicotinic acid amide is prepared from 2-bromo-nicotinic acid esters according to Scheme 2.

Japanese Patent Publication No. 80-86,836, published January 22, 1982, describes the preparation of 2-chloronicotinic acid according to the procedure of Scheme 3,

The present invention provides a process for the preparation of novel compounds useful for the preparation of sulfonylureas having herbicidal activity.

According to the process of the present invention, compounds of formula I wherein R 1 is -COR ₂ or -SO ₂ CH ₂ CH ₃

R ₂ is di (C 1 -C 2) alkylamino, and

X is a fluorine, chlorine or bromine atom and their acid addition salts are prepared by reacting a compound of formula (II) with a compound of formula (III)

R is methyl or ethyl;

R 1 is as defined above, acetic anhydride, a catalyst of the formula ZnX ₂ wherein X is as defined above and optionally in the presence of acetic acid at a temperature in the range of from 110 to 150 ° C to give the compound of formula IV wherein R 1 and R 2 are in the presence of acetic acid as defined above, at a temperature in the range from 0 to 60 ° C, with a compound of formula HX

X is as defined above.

The intermediates of formula (IV) wherein R and R) are novel, and are useful as intermediates of formula (I) for the sulfonylurea-type herbicidal compounds.

Compounds of formula (I) wherein

R) and X are as defined above with the proviso that if

R ₂ is di (C 1 -C 2) alkylamino, then

X is a fluorine or bromine atom and their corresponding salts are new and can be used for the preparation of sulfonylurea herbicides.

It is advantageous in terms of simplicity and efficiency of the procedure

1. The process of the invention wherein R 1 is

-C (O) R ₂ ;

2. The preferred process of claim 1, wherein R ₂ is di (C 1 -C 2) alkylamino;

3. The process of the invention wherein R 1 is

-SO ₂ CH ₂ CH ₃ ;

4. the process of the invention wherein X is bromine;

5. The process of the invention wherein the corresponding salt of the compound of formula I is the hydrobromic acid salt.

The following compounds are preferred for simplicity and efficiency of the preparation process:

6. A compound of formula IV wherein R 1 is -C (O) R ₂ ;

7. Preferred compounds according to claim 6, wherein R ₂ is C 1 -C 2 dialkylamino;

8. A compound of formula IV wherein R 1 is -SO ₂ CH ₂ CH ₃ ;

9. Compounds of formula (I) wherein R 1 is -CON (CH ₃ ) ₂ and X is fluoro or bromo;

10. A compound of formula I wherein R 1 is -SO ₂ CH ₂ CH ₃ ;

11. hydrobromide salts of the preferred compounds of item 9;

12. Hydrogen bromide salts of the preferred compounds of (10).

The process of the present invention is generally carried out by reacting 1.0 to 3 moles, preferably 1.2 to 1.5 moles, of compound (II) with 1 mole of compound (III), 1 to 5 moles, preferably 1, In the presence of 5 to 2.5 moles of acetic anhydride. Acetic acid is preferably used, but its presence is optional. We work at lower temperatures in the presence of acetic acid. The ZnX ₂ catalyst is used in an amount of 0.5 to 2% by weight based on the compound of formula II. The reaction temperature is generally 110-150 ° C, preferably 120-130 ° C; the yield of the compound of formula (IV) varies depending on the reaction conditions, but 8590% yields are obtained.

HU 206,678 Β

The second step of the process, wherein the compound of formula (IV) is reacted with a compound of formula HX, is generally carried out using 0.5 to 8 mol, preferably 2 to 4 mol of HX. The amount of acetic acid required is generally 0.2 to 1 liter, preferably 0.4 to 0.6 liter, per mole of reactant. The reaction temperature is from 0 to 60 'C, preferably from 10 to 30' C.

By di (C 1 -C 2) alkylamino is meant dimethylamino and diethylamino.

The process according to the invention is described in more detail below.

In the process of the present invention, 1.2-1.5 moles of malonodialdehyde bis (acetate) can be reacted with 1 mole of substituted acetonitrile and 1-5 moles of acetic anhydride, containing a catalytic amount of 0.5-2% zinc chloride or zinc bromide. acetic acid. The reaction may be carried out without acetic acid.

The reaction mixture is heated to 110-150 ° C and then distilled until the remaining analytical results show that the starting materials are consumed and that a mixture of geometric isomers is obtained.

The compound of formula (IV) may be isolated by distillation or crystallization.

In the next step, the compound of formula (IV) is treated with 0.5-8 equivalents of hydrogen fluoride, hydrogen chloride or hydrobromic acid in 200-1000 ml / mol acetic acid at 0-60 ° C. The product of the cyclization reaction is a compound of formula (I).

Alternatively, the compound of formula (IV) can be cyclized directly to the compound of formula (I) without isolation.

To aid in the isolation of the compound of formula (I), an excess of an acid such as hydrobromic acid may be added to the reaction mixture. The compound of formula (I) is thus obtained in the form of a crystalline salt which can be isolated from the reaction mixture, for example by filtration. The salt of the compound of formula (I) may also be used directly for the preparation of sulfonylurea herbicides. The salt of the compound of formula (I) can be neutralized with a base to liberate the compound of formula (I).

The invention is further illustrated by the following examples.

Example 1

Preparation of 2-Cyano-5-methoxy-N, N-dimethyl-2,4-pentadiene amide (IV)

In a 250 ml 3-necked round bottom flask, 50 g of malonodialdehyde bis (dimethylacetal), 22.5 g of N, N-dimethyl-2-cyanoacetamide, 60 g of acetic anhydride and 0.5 g of zinc chloride in 100 ml of acetic acid are added. . The reaction mixture is heated to reflux, distilling the low-boiling components until the reaction temperature reaches 125 ° C and the head temperature reaches 110 ° C, and a total of 60 ml of distillate is collected. Gas chromatography analysis of the reaction mixture indicated that N, N-dimethyl-2-cyanoacetamide was consumed. The reaction mixture was filtered to remove the zinc catalyst and evaporated in a rotary evaporator. The residue was crystallized from methanol in a dry ice / acetone bath.

g (44.3%) of the title compound are obtained. NMR _(DMSO-d6) δ:

2.95 (6H, s), 3.80 (3H, s), 6.85 (1H, t), 7.65 (1H, dd);

Mass Spectrum (m / e): 180 (Calculated: 180).

Example 2

Preparation of 2-chloro-Ν, Ν-dimethyl-3-pyridine carboxamide

In a 250 mL 3 neck round bottom flask was added 16 g of the compound of formula IV prepared in Example 1 and 150 mL of acetic acid. To the reaction mixture was added 15 g of hydrogen chloride gas at room temperature for 20 minutes. The resulting solution was allowed to stand overnight and evaporated on a rotary evaporator.

The residue was diluted with 500 ml of water and extracted three times with 500 ml of chloroform. The combined chloroform extracts were dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo and then distilled.

5.5 g (30%) of the title compound are obtained which is identical to the authentic sample by gas chromatography, NMR and mass spectral analysis.

Example 3

Preparation of 2-Chloro-N, N-dimethyl-3-pyridine carboxamide without isolation of the intermediate in a 250 ml 3-necked round bottom flask with 40 g of malonodialdehyde bis (dimethylacetal), 22.5 g of N, N-dimethylacetate. 2 cyanoacetamide, 60 g acetic anhydride and 0.5 g zinc chloride in 100 ml acetic acid. The reaction mixture was heated to reflux and 60 mL of by-product was distilled off and cooled to room temperature.

The mixture was diluted with 100 ml of acetic acid, 60 g of hydrogen chloride gas were added and the mixture was left standing overnight. The solvents were removed by rotary evaporation and the residue was diluted with water and extracted three times with 500 ml of chloroform. The chloroform extract was dried over anhydrous magnesium sulfate, filtered and concentrated by rotary evaporation.

14.5 g (39%) of the title compound are obtained which is identical to the authentic sample by gas chromatography, NMR and mass spectral analysis.

Example 4

Preparation of 2-Bromo-3- (ethylsulfonyl) pyridine

A mixture of 12.3 g (0.075 mol) of malonodialdehyde bis (dimethylacetal), 25 ml (0.25 mol) of acetic anhydride and 0.08 g of zinc chloride is heated at 91 ° C for 25 minutes. (Cyanomethyl) ethylsulfone (6.7 g, 0.050 mol) was added and the mixture was heated at reflux (95-109 ° C) for 16 hours.

The reaction mixture was cooled to 16 'C and 10 mL of 30% hydrobromic acid in acetic acid was added. Further

HU 206,678 Β

6.5 g of hydrogen bromide gas are introduced at 1520 'C. After 1 hour, the reaction was quenched by the addition of 100 mL of ice water. The mixture was neutralized with sodium hydroxide, extracted twice with methylene chloride, washed with water, dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated.

7.2 g of an oil are obtained.

1 H NMR (CDCl ₃ ) δ:

8.58 (m, 1H), 8.45 (m, 1H), 7.53 (m, 1H), 3.55 (q, 1H), 1.30 (t, 2H, J = 0.04). ).

A sample prepared in a similar manner was recrystallized from ethyl acetate, m.p. 78-79 ° C.

Elemental analysis results for C ₇ H _g BrNO ₂ S:

date: C = 33.61%; N = 5.60% H = 3.22%, Br = 31.95%, S = 12.82%, found: C = 33.87%; H = 3.27%, Br = 32.60%, N, 5.64% S, 12.83%.

Example 5

Preparation of 2- (ethylsulfonyl) -5-methoxy-2,4-pentadiene nitrile g (0.342 mol) of malonodialdehyde bis (dimethylacetal), 95 ml (1.0 mol) of acetic anhydride and 0.5 g of zinc the mixture was heated to 95 ° C. The mixture was heated to 90-95'C for 20 minutes and then distilled off with methyl acetate and 33.2 g (0.25 mol) of cyanomethyl ethyl sulfone was added.

The reaction mixture was heated to 120 ° C while methyl acetate was further distilled off. The reaction mixture was heated at 120 'C for 4 hours and then cooled to 25' C. Water (200 mL) was added and the mixture was extracted with methylene chloride (2 x 200 mL). The combined methylene chloride extracts were washed with 10% sodium carbonate solution, water, dried over anhydrous magnesium sulfate and filtered, and the filtrate was evaporated.

63.6 g of the title compound are obtained. The crude product was recrystallized from chlorobutane to give a yellow crystalline solid, m.p. 72-74 ° C.

Elemental analysis results for C _g H _n NO ₃ S

let by: date: C, 47.74% H = 5.51% N = 6.91%; S, 15.94; found: C = 47.83% H = 5.39%, N = 7.18%; S, 16.14%.

1 H NMR (CDCl ₃ ) δ:

7.70 (d, 1H), 7.38 (d, 1H), 6.04-5.98 (dd, 1H), 3.91 (s, 3H), 3.21 (q, 2H), 1 , 38 (t, 3H).

The compounds described in Tables 1 and 2 can also be prepared according to the fatty acid.

Table 1 Compounds of formula IV

R Ri Physical characteristics -CH ₃ -CON (CH ₃ ) ₂ NMR 2.95 (6H, s) -ch ₃ -CON (CH ₂ CH ₃ ) CH ₃

R rl Physical characteristics -ch ₃ -CON (CH ₂ CH ₃ ) ₂ -ch ₃ -so ₂ ch ₂ ch ₃ op. 72-74 ° C -ch ₂ ch ₃ -CON (CH ₃ ) ₂ -ch ₂ ch ₃ -CON (CH ₃ ) CH ₂ CH ₃ -ch ₂ ch ₃ -CON (CH ₂ CH ₃ ) ₂ -ch ₂ ch ₃ -so ₂ ch ₂ ch ₃

Table 2 Compounds of formula (I)

Ltd. X Physical characteristics -SO ₂ CH ₂ CH ₃ F -so ₂ ch ₂ ch ₃ cl -so ₂ ch ₂ ch ₃ Br op. 78-79 ° C -CON (CH ₃ ) ₂ F -CON (CH ₃ ) ₂ Br -CON (CH ₂ CH ₃ ) ₂ F -CON (CH ₂ CH ₃ ) ₂ cl -CON (CH ₂ CH ₃ ) ₂ Br -so ₂ ch ₂ ch ₃ F (HBr salt) -so ₂ ch ₂ ch ₃ cl (HCl salt) -SO ₂ CH ₂ CH ₃ Br (HBr salt), m.p. 196-198 'C -CON (CH ₃ ) ₂ Br (HBr salt)

PATENT CLAIMS

Claims (8)

PATENT CLAIMS A process for the preparation of a halopyridine derivative represented by the general formula (I) R 1 is -C (O) R ₂ or -SO ₂ CH ₂ CH ₃ , R ₂ is di (C 1 -C 2) alkylamino, and X is for the preparation of a fluorine, chlorine or bromine atom and their acid addition salts, characterized in that a compound of the formula II is a compound of the formula III in which R is a methyl or ethyl group and R 1 is acyl anhydride, a catalyst of the formula ZnX ₂ , wherein X is as defined above and in the presence of acetic acid at a temperature of 100 to 150 ° C, and the resulting compound of formula IV is represented by R and R is as defined above with an optional excess of HX - wherein X is as defined above in the presence of acetic acid at a temperature of 0 to 60 ° C and optionally in a ton of the acid addition salt (I). ) is converted into the free base form. A process for the preparation of a compound of formula (I) according to claim 1, wherein R 1 is -C (O) R ₂ , wherein HU 206,678 Β R ₂ is a d x (C 1 -C 2) alkylamino group, wherein the appropriate starting compounds are used. 3. A method according to claim 1 for preparing a compound (I) of formula wherein R] is -SO ₂ CH ₂ CH ₃ group, characterized in that corresponding starting compounds are used. A process according to claim 1 for the preparation of a compound of formula (I) wherein: X is bromine, wherein the appropriate starting compounds are used. 5. A process for the preparation of a crystalline salt of a compound of formula I as claimed in claim 1, wherein the compound of formula I is used in excess and the salt is separated from the reaction mixture. 6. A process for the preparation of a compound of formula (I): wherein R 1 is -C (O) R ₂ or -SO ₂ CH ₂ CH ₃ , R ₂ is di (C 1 -C 2) alkylamino, and X is fluorine, chlorine or bromine, with the proviso that if R 1 is -C (O) R ₂ , then X is for the preparation of a fluorine or bromine atom and their acid addition salts, characterized in that a compound of the formula II in which R is methyl or ethyl with a compound of formula (III) wherein R 1 is as defined above and the resulting compound of formula (IV) is R and R 1 are as defined above with one of the optional compounds of the formula HX, wherein X is as defined above in the presence of acetic acid at a temperature of 0 to 60 ° C and optionally in the form of an acid addition salt thereof. is converted into the free base form. A process for the preparation of a compound of formula (I) according to claim 6 wherein R f is -C (O) R ₂ , R ₂ is dimethylamino, and X is fluorine or bromine, characterized in that the appropriate starting compounds are used. A process for the preparation of a compound of formula (I) according to claim 6 wherein R 1 is -SO ₂ CH ₂ CH ₃ , wherein the corresponding starting compounds are used.