JPS6377849A - Manufacture of substituted amide derivative - Google Patents

Abstract

(57) [Abstract] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a process for producing 3g5 substituted amide useful as a herbicide and fungicide.

PRIOR ART Formula (1) provided for use as a herbicide and fungicide, where R1 is an aryl group, xl is an oxygen or sulfur atom, and R2 is optionally substituted or XlR2 is pyrazole or 1,2 .
Substituted amide derivatives of N-linked 5@nitrogen-containing heterocycles such as 4-1-lyazole are described in European Patent Application No. 59536, filed by the present applicant, along with methods for their preparation.

One such manufacturing method involves a series of chemical reactions in the following reaction scheme.

Reaction Scheme % Formula % In step (i) of the reaction scheme, acid chloride R'COI is reacted with aminoacetonitrile by a conventional method to obtain compound (n). This is then treated in step (11) with a solution of bromine in glacial acetic acid to obtain the brominated derivative (II[). Bromination simultaneously hydrates the cyano group to a carbamoyl group -CON)lz which requires subsequent treatment with a dehydrating agent. In step (iii), a bromine compound (I[[
) with a suitable alcohol, thiol or 5-membered nitrogen-containing heterocycle to obtain a carbamoyl compound (rV), which is then treated with a dehydrating agent in step (iv) to form the corresponding cyano compound (I). Change to

This series of reactions not only requires a final dehydration step to convert back to the cyano group, but also the bromination of said compound (n) in glacial acetic acid consists of a mixture of acetic acid, acetyl bromide and hydrogen bromide. It has the disadvantage of producing a corrosive reaction medium.

Furthermore, the yield of the bromoamide (II[) tends to be somewhat unstable. European Patent No. 144 filed by the applicant
Although a considerable improvement in yield can be achieved by reversing step (ii) of adding the compound (TI) dissolved in glacial acetic acid to bromine as described in No. 177 Specification 1,
However, other drawbacks remain.

Therefore, attempts have been made to carry out the bromination step in such a way as to protect the cyano group intact and avoid the formation of undesirable by-products. British Patent No. 2146 filed by the applicant
No. 983 describes another reaction scheme in which the bromination step (ii) is carried out in an inert solvent, in particular in ethyl acetate.

However, this can avoid hydration of the cyano groups only as long as the bromination is carried out in dilute solution, but only in step (i)
It is also necessary to quickly add the bromine in i) and the reactant R2X1H (eg alcohol) in step (iii). It has also been found that these structural requirements make the operation inconvenient for large-scale production, and that under these conditions the yield of the final product (I) is unpredictable.

(Means for solving the problem, effect) The inventors now have the advantage of avoiding hydration of the cyano groups of the starting materials and avoid the hindrances inherent in the last mentioned operation, i.e. Amide derivatives (1) suitable for large-scale production
) was discovered.

According to the invention, formula (II) R′ in (al inert solvent)
-CONH-CH2CN (n) (wherein,
a step of treating the N-cyanomethylamide (R1 has the same meaning as below) with a halogenating agent, (during or after the bl halogenation to the halogenated mixture,
A heterocyclic tertiary amine is added at a ratio of about 1.0 to 2.5 moles of heterocyclic tertiary amine per mole of the reacted halogenating agent to obtain the formula (wherein R1 is the same as below). have meaning,
Hal represents a halogen atom and Het represents a heterocyclic residue), and
C) The above salt (V) is represented by the formula (wherein R2 and Xl have the same meanings as below)
of the formula (+)N\X・R・ (wherein R1 is an optionally substituted aryl group, Xl is an oxygen atom or a sulfur atom, and R2 is an optionally substituted alkyl, alkenyl or alkynyl group, or xJ2 is an N-bonded 5@nitrogen-containing heterocycle such as pyrazole or C2,4-triazole). Provide the manufacturing method.

In said compounds of formulas (1), (II) and (III), the optionally substituted aryl group R1 can be a phenyl group or a naphthyl group. Specific examples of the substituents are fluorine atom, chlorine atom, bromine atom, iodine atom%C1
-C4 alkoxy group, methylenedioxy group, ethylenedioxy group, Cl-C4 alkyl group, Cl-C4 alkylthio group, CI-C4 haloalkyl group (e.g. CF3)
, a nitro group and a cyano group. There may be from 1 to 3 or more substituents and they may be the same or different. When R1 is a substituted phenyl group, the substituent is preferably in the 3-, 4- or 5-membered position. If methylenedioxy or engineered dioxy substituents are present, they are preferably attached to the 3- and 4-positions of the phenyl ring.

Halogen substituents (eg chlorine or bromine atoms) may also be present at the 4- and/or 5-positions of such compounds.

When the substituent R2 is an alkyl group, the substituent R2 preferably contains 1 to 4 carbon atoms, and is linear or branched, i.e., a methyl group, an ethyl group, n-propyl group, iso-propyl group, n-butyl group, 5ec-butyl group, iso-butyl group or ter
It can be a t-butyl group.

If R2 is an alkenyl group, it may contain 3 to 5 carbon atoms. Preferred substituents for these argyl or alkynyl groups are halogen atoms, such as fluorine atoms, chlorine atoms, bromine atoms and iodine atoms, 01-C
4 alkoxy groups, such as methoxy groups, or R
When 2 is an alkenyl group, another suitable substituent may be an 01-C4 alkyl group, such as a methyl group.

When R2 is an alkynyl group, it may contain 3 to 5 carbon atoms, for example it may be a propargyl group. Suitable substituents include chlorine, bromine or iodine atoms, or O1-C4 alkyl groups, such as methyl groups.

When XIRZ is an N-bonded 5-membered nitrogen-containing heterocycle,
It can be, for example, a pyrazole or a 1,2,4-1-lyazole, but is preferably a pyrazole.

In step (a) of the above production method, the halogenating agent used may be a chlorine atom or a bromine atom, but a bromine atom is preferred. Other halogenating agents used in the method of the invention may be, for example, sulfuryl chloride, phosphorus trichloride, and the like.

The halogenating agent is used in a ratio of 1 mol to 1 mol of compound (II), but an excess amount is not necessary. By inert solvent is meant a solvent capable of dissolving both the cyanomethylamide starting material (II) and the halogenating agent, but which is not attacked by the halogenation.

Although suitable solvents include, for example, esters such as ethyl acetate and acetonitrile, we have found that a particularly suitable solvent is diethylene glycol dimethyl ether (diglyme). It is preferable that the solvent is as free from water as possible. In the case of bromination with bromine, we have found that the reaction proceeds more smoothly in the presence of small amounts of phosphorous tribromide. Preferably, the halogenation is carried out at a temperature between -10°C and 50°C, typically in the range of 20°C to 25°C.

Regarding the heterocyclic tertiary amine added to the halogenation mixture as step (b) during or after the halogenation step (a), we found pyridine to be particularly effective, but eg picoline and ethyl We have found that substituted pyridines such as pyridine or quinoline and substituted derivatives thereof can also be used. As mentioned above, the amount of the heterocyclic tertiary amine is about 1.0% per mole of the reacted halogenating agent.
0 to 2.5 mol, preferably 1.3 to 2.1 mol (preferably 2 mol), where 1 mol of said amine is used to form the quaternary salt (V), while The remaining moles of amine neutralize the hydrogen halide produced in the halogenation reaction. The heterocyclic amine is of formula (VI) N R1-C)l (VI)aia during or following completion of the halogenation reaction.
The intermediate halogenated compound of i (in which R1 and l1ajl! have the same meanings as above) is added to the mixture obtained in step (a) without the need for isolation.

In fact, it is preferred to proceed directly to step (b) rather than attempting to dissolve compound (Vl) alone. Although the preferred procedure is to substantially combine steps (a) and (b), it is preferable to allow the halogenation (e.g. bromination) reaction to be established prior to the addition of the heterocyclic amine (e.g. pyridine). preferable. That is, for example, about 5 to 25%, e.g. 10%, of the total halogenating agent to be added may be pre-added prior to adding the heterocyclic amine substantially simultaneously with the remaining halogen, so that the total halogenating agent is The molar feed ratio of amine is preferably between 1.3 and 2.1, preferably 2. Preferred addition rates for bromine and heterocyclic amine are 0.01 moles per minute and 0.02 moles per minute, respectively.
It is a mole. The total addition time for bromine and heterocyclic amine is the same, for example 100 minutes. That is, when establishing halogenation first, for the first few minutes, for example, 10 minutes,
Add bromine alone. A heterocyclic amine (e.g. pyridine) is then added simultaneously with bromine, e.g. over the next 90 minutes. The heterocyclic amine is then added for the last few minutes, e.g.
Added for a minute alone. The quaternary salt (V) is typically a stable material, and the tertiary amino acid formed along with it prior to its treatment with an alcohol, thiol or five-membered nitrogen-containing heterocycle, as the case may be. It can be advantageously isolated and separated from the 10-hydrogenide salt. Separation can often be carried out by simple means of washing with water which dissolves the tertiary amine hydrohalide salt but does not dissolve the salt (V).

In the final step (C), the quaternary salt (V) is reacted with an alcohol, thiol or 5-membered nitrogen-containing heterocycle, optionally in a suitable medium, optionally at elevated temperature; In the case of ethanol, an excess amount thereof can be used as the solvent. Once the reaction is complete, the solvent and liberated tertiary amine can be removed by dissolving in excess water, leaving a water-insoluble substantially pure product (1). Alternatively, the reaction mixture can be placed in a mixture of brine and a suitable solvent such as ethyl acetate, the solvent phase separated, and the product recovered from the solvent phase by removing the solvent, for example by distillation.

The process of the invention is of particular interest for the preparation of 4-chloro-N-(traano-1-ethoxy)methylbenzamide (■)r and its 4-bromine congeners, which are useful for their herbicidal and fungicidal activity. It is.

(Effects of the invention) The advantages of the method of the present invention over the methods of the prior art are (i)
(ii) the rate of addition of the halogenating agent is not limited and there is no need to operate in dilute solution to avoid hydration of the cyano groups of the starting material (II); (ii) the progress of the halogenation reaction or the combination or (a) reaction substantially combined and (b) progress of the reaction controlling the temperature of the reaction mixture? (iii) at the end of step (b), the reaction medium is halogenated; (iv) the yield of the final product (I) is consistently high. All these advantages are particularly favorable for large-scale operation of systematic production processes.

(Example) The invention will be illustrated by the following examples.

On the plate 4-chloro-N-1-cyano-1 = stirrer,
2 with dripping funnel, thermometer and air cooling tube installed! 4th grade
Diethylene glycol dimethyl ether (100 hours + 1. water content: 0.2%) was placed in a double flask.

4-chloro-N-cyanmethylbenzamide (250g
, 1.285 mol) was added at room temperature with stirring and the mixture was stirred for 5 minutes to achieve complete dissolution. The resulting solution was cooled to 0-5°C in a salt-ice bath and phosphorus tribromide (2 ml) was added followed by bromine (205.7 g, 1.285 mol) to bring the temperature of the reaction mixture to 3-5°C. The mixture was added dropwise over a period of 40 minutes while maintaining the temperature within the range of C.

The resulting mixture was stirred for an additional 5 minutes. Meanwhile the temperature dropped to 2'C.

Step (b): Neutralization and base hydrogenation The bromination mixture from step (a) before neutralization is stirred in an aqueous salt bath and the temperature of the mixture is brought to a range of 9°C ± 3°C. While keeping pyridine (
204 g, 2.58 mol) was added. The resulting mixture of liquid and yellow solid was stirred for a further 2 hours at 5-10°C and then filtered to remove as much diethylene glycol dimethyl ether as possible. The separated solid was transferred to the original reaction flask and stirred with cold water (80M) at room temperature for 10 minutes. The mixture was then filtered again, washed with cold water (2 x 75 ml), the washings were discarded and the solid product was dried as much as possible. The remaining water was replaced by washing the solid with acetone and finally the product was dried in vacuo at 45°C.

The yield of pyridinium salt was 288 g.

Step C: Absolute ethanol (300 ml) was placed in an 11-volume four-bottle flask fitted with an ethoxyl stirrer, thermometer and reflux condenser, and the dry pyridinium salt (228 g) from Step et al. was added at room temperature with stirring. . The mixture was then heated to reflux temperature and stirred under reflux until the pyridinium salt was completely dissolved and then stirred for a further 5 minutes. Cold water (150d)
and a dispersant, such as the trade name rDl5PERSOL (
A mixture of a 10% aqueous solution of polyglyceryl lysyllate (10d, such as that commercially available under the trade name Dispurple) OGJ was rapidly stirred, while the aforementioned ethanol solution was added to it in a thin stream over a period of 10 minutes. .

After stirring for a further 30 minutes, the precipitated title compound was separated by filtration, washed with excess water and dried as much as possible.
It was then dried in vacuo at 50°C until quantitative. Product yield was 159g.

1 blood±1 This example describes the preparation of the same compound as described in Example 1, except illustrating an alternative method of isolating the product.

The method of step (a) and step (I)) of Example 1 was repeated using the following raw materials.

Diethylene glycol dimethyl ether 000 mN 4-chloro-N-cyanomethylbenzamide 167 g Phosphorus tribromide Number of drops Bromine 306 d Pyridine 972 d The mustard-colored pyridinium salt obtained in step (b) was treated with anhydrous ethanol (2000 mf), and then treated with anhydrous ethanol (2000 mf) under a nitrogen stream. A yellow suspension was obtained which turned into a red solution upon stirring and heating to reflux temperature. Once complete dissolution was achieved, the mixture was allowed to cool for 30 minutes.

Saturated brine (4400ml) and ethyl acetate (6600ml)
ffi) was added and the mixture was stirred and then allowed to separate into two dark phases. The organic phase was separated and diluted with brine (2300 d
x2) to remove ethanol, then dried over anhydrous magnesium sulfate, filtered, and concentrated to give a brown solid (963 g, 67% crude yield).

This product was dissolved in carbon tetrachloride (2.5 ydl per Ig)
A beige solid (618 g, yield 43%) with a melting point of 102-106°C was obtained. It was further recrystallized to obtain a substance with a melting point of 112-114°C. It was shown to be homogeneous by thin layer chromatography and identified as the title compound by IR analysis. Additional amounts of the target compound were obtained as a second crop from the second recrystallization operation.

This example describes the preparation of a pyridine quaternary salt by an alternative method involving the joint addition of bromine and pyridine.

The reaction order is as follows.

(I) Molecular weight 194.5 160 79 (II) 352.5 160 The following materials were used in the reaction as shown below.

N-cyanomethyl-4-chlorobenzamide 194.5
g 1.0 mol bromine 160 g 1.0 mol pyridine 158 g 2.0 mol phosphorus tribromide 2 g diglyme 700 g 2 mols of N-cyanomethyl-4-chlorobenzamide (I)
Dissolved in diglyme at 0-25°C and added phosphorus tribromide.

Bromine was added at a rate of 0.01 mol/min. Total bromine addition time was 100 minutes. Pyridine was added at a rate of 0.02 mol/min. The total addition time of pyridine was 100 minutes. During the joint addition of the reactants, the temperature of the reaction mixture was maintained between 20-25°C using an external ice-water bath and 10% of the bromine was added before starting the pyridine addition. The precipitated solid was filtered, washed with acetone, and dried to obtain 467.7 g of product.

-Wash out the pyridinium bromide produced at the same time with water,
And the remaining pyridine quaternary salt (II) was filtered, washed with acetone and dried, Pyridine quaternary salt 303
I got g.

This example describes the preparation of pyridine quaternary salts using pyridinium hydrobromide perbromide as the brominating agent.

The reaction order is as follows.

lBr5 (I) Molecule Δ1 194.5 320 79r~ (I[) 352.5 160 Operation method (a) Bromination step N-cyanomethyl-4-chlorobenzamide (I)
(9.7 g, 0.05 mol) in diglyme (35 g)
Dissolved at 0"C. Viridinium hydropromide barbromide (16.0g, 0.05mol) was added over about 5 minutes using an ice water bath to maintain the reaction temperature at about 20°C.

(b) Quaternary Chemical Process Pyridine (7.9 g, 0.10 mol) was added to the product of the bromination step over about 5 minutes using an ice-water bath to maintain the reaction temperature between 20 and 25°C. Ta.

The precipitated solid was filtered, washed with water to remove the co-produced pyridinium bromide, washed with acetone, and then dried to obtain 13.3 g of pyridine quaternary salt of formula (n).

EXAMPLE 1 This example describes the preparation of a pyridine quaternary salt using a mixture of bromine and pyridine verbromide as the brominating agent.

The reaction order is as follows.

R2 Molecular weight 194.5 160/239 79N (IT) 352.5 160 Operation method (a) Bromination step N-cyanomethyl-4-chlorobenzamide (1)
(9.7 g, 0°05 mol) in diglyme (35 g)
It was dissolved at 0'C. Phosphorus tribromide (0.1 g) and bromine (1
,0 g, 0.006 mol) at approximately 20° using an ice water bath.
C for about 5 minutes while maintaining the reaction temperature to start the bromination reaction, and then add pyridine verbromide (10
, 5g, 0.004 mol) were added.

(b) Add the product of the bromination step using an ice-water bath for about 5 minutes while keeping the reaction temperature between 20 and 25 °C. added.

The precipitated solid was filtered and washed with water to wash out the generated pyridinium bromide, washed with acetone, and then dried to obtain 14.3 g of pyridine quaternary salt of formula (n).

Claims (1)

[Claims] 1. (a) In an inert solvent, N- of the following formula (II) R^1-CONH-CH_2CN (II) (wherein R^1 has the same meaning as below) a step of treating cyanomethylamide with a halogenating agent, (b
) The halogenated mixture so formed, or the mixture as it is being formed, contains about 1.0 g of tertiary heterocyclic amine per mole of halogenated agent reacted.
By adding a heterocyclic tertiary amine in a proportion of 0 to 2.5 moles, the formula (V) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) (wherein, R^1 has the same meaning as below and (c) converting said salt (V) to the following formula R^2X^1H (wherein , R^2 and X^1 have the same meanings as below).
) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1 is an optionally substituted aryl group, X^1 is an oxygen atom or a sulfur atom, and R^ 2 is an optionally substituted alkyl group,
is an alkenyl group or an alkynyl group, or
^1R^2 is an N-bonded 5-membered nitrogen-containing heterocycle). 2, R^1 is a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a C_1 to C_4 alkoxy group, a methylenedioxy group, an ethylenedioxy group, a C_1 to C_4 alkyl group, C
_1-C_4 alkylthio group, C_1-C_4 haloalkyl group (e.g. CF_3), nitro group and cyano group
a phenyl or naphthyl group optionally substituted with one or more carbon atoms; an alkyl group in which R^2 contains 1 to 4 carbon atoms; or an alkyl group containing 3 to 5 carbon atoms or optionally substituted with one or more halogen atoms or C_1 to C_4 alkoxy groups, an alkyl group, an alkenyl group or an alkynyl group as defined above; or when R^2 is an alkenyl group or an alkynyl group, it may be optionally substituted with a C_1 to C_4 alkyl group, and X^1 is an oxygen atom or a sulfur atom, or X^1R^ 2 together represent an optionally substituted pyrazole group or 1
, 2,4-triazole group, representing an N-bonded 5-membered nitrogen-containing heterocycle. 3. The method according to claim 1 or 2, wherein the halogen used in step (a) is chlorine or bromine. 4. The method according to claim 3, wherein the halogen is used in a ratio of 1 mole to 1 mole of compound (II), and the heterocyclic amine is used in a ratio of 2 moles to 1 mole of the halogen. 5. A method according to any of the preceding claims, wherein the inert solvent is ethyl acetate, acetonitrile or diethylene glycol dimethyl ether. 6. A process according to any of the preceding claims, wherein the halogen used in step (a) is bromine and a small amount of phosphorus tribromide is present. 7. A process according to any of the preceding claims, wherein the heterocyclic tertiary amine used in step (b) is pyridine, a substituted pyridine such as 3-methylpyridine, quinoline or substituted quinoline. 8. The method according to claim 7, wherein the heterocyclic tertiary amine is pyridine. 9. The halogenation step (a) is first started over a period of several minutes, then the heterocyclic amine addition step (b) is started such that the addition of the heterocyclic amine is co-current with the halogen addition, and then the halogen A method according to any of the preceding claims, wherein the addition of the amine is continued alone for the same number of minutes after the end of the addition of the amine. 10. Using the isolated and separated salt (V) and carrying out the reaction with the reactant R^2X^1H in a solvent to form step (c)
).