ZA200608604B

ZA200608604B - Method for producing semicarbazones

Info

Publication number: ZA200608604B
Application number: ZA200608604A
Authority: ZA
Inventors: Zierke Thomas; Engel; Stefan; Otto Peter
Original assignee: Basf Ag
Priority date: 2004-03-17
Filing date: 2006-10-16
Publication date: 2008-05-28
Also published as: CN1934076B; CN1934076A

Description

PF 0000055449 1 I ey ~ ® Method for producing semicarbazones cen oo 0220 &)

Description

The present invention relates to a process for preparing semicarbazone compounds of the formula

HoH -N N

NT 3

I Toe iS 0

Fe where R' and R? are each independently hydrogen, halogen, CN, C4-C4-alkyl, C4-C.- alkoxy, C4-C4-haloalkyl or C,-C4-haloalkoxy, and R? is C;-Cs-alkoxy, C4-C4-haloalkyl or

C;-C,4-haloalkoxy.

EP-A 462 456 discloses compounds of the formula | as insecticides. They are prepared starting from benzyl phenyl ketones of the formula IV by the processes illustrated in

Schemes 1 and 2:

Scheme 1

O

O 3

R —_— : Zr > + Ay cn (IV) (VI)

Scheme 2:

R®

NH, 0) N OCN

H,N-NH, cy) — = —— 2

Ci <5 (IV) (Vil) (Vii)

In Schemes 1 and 2, R', R? and R® are each as defined above.

However, the reaction, illustrated in Scheme 1, of a phenyl benzyl ketone IV with an

N-pheny! semicarbazide VI only provides the compound | in poor yields. In addition, the

One disadvantage of the process illustrated in Scheme 2 is the use of hydrazine in the first reaction step, which has to be used in high excess to prevent by-product formation.

As is well known, hydrazine is a potential carcinogen which additionally tends to spontaneous decomposition with gas formation on contact with metallic materials. It is therefore only possible to handle hydrazine on the production scale with a very high level of technical complexity for safety reasons. In addition, the disposal of the hydrazine wastes obtained in this reaction on the industrial scale is associated with a high level of complexity, since the chemical destruction of highly concentrated hydrazine solutions proceeds highly exothermically and releases considerable amounts of gas. The use of hydrazine thus constitutes a considerable cost factor for this process. A further disadvantage of the process shown in Scheme 2 is the use of phenyl isocyanates VIII which firstly, as a consequence of their toxicity, require special safety measures in their handling and, additionally, have to be prepared from the corresponding anilines in a separate reaction. itis-therefore-an-object-of the presentinvention A need exists to provide a process for preparing semicarbazone compounds of the general formula | which affords the compound | in high yields and good purities, and which initially overcomes the disadvantages of the prior art outlined here.

It has been found that, surprisingly, semicarbazone compounds of the general formula are obtained in good yields and with high purity when a hydrazone compound of the general formula I!

H

-N R

N

Tr ;

R £) (In)

CL where R is C-Cs-alkoxy, amino, C,-C,-alkylamino or di(C,-C4-alkyl)amino, and R', R? are each as defined above is reacted with an aniline compound of the general formula i

NH,

Q, ow

RS

PF 0000055449 3 Co C04 ® where R® is as defined above.

The present invention therefore provides a process for preparing semicarbazone com- : pounds of the general formula |, comprising the reaction of a hydrazone compound of the general formula If with a substituted aniline of the formula Ill.

The hydrazone compounds of the general formula It may in turn be prepared in a simi- lar manner to the known prior art processes from the benzy! phenyl ketones of the for- mula IV 0 ;

R > (IV) (Fe where R', R? are each as defined above by reacting IV with a hydrazide of the formula \Y

H

N__R

HN" (Vv)

O where Ris as defined above. Accordingly, the process according to the invention pref- erably also comprises the preparation of the hydrazone compounds II by this route.

The hydrazone compounds of the formula Il are novel where R?= CN and likewise form part of the subject matter of the present invention as starting materials or intermediates in the process according to the invention.

In the definitions of the variables R, R", R? and R® specified in the above formulae, col- lective terms are used which are generally representative of particular substituents.

The term C,-C,, specifies the number of carbon atoms in the particular substituents or substituent moiety which is possible in each case. Other definitions are as follows:

Halogen: fluorine, chlorine, bromine and iodine;

Alkyl and all alkyl moieties in alkoxy, alkylamino and dialkylamino: saturated, straight-chain or branched hydrocarbon radicals having from 1 to 4 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl and 1,1- dimethylethyl (tert-butyl);

Haloalkyl and the haloalkyl moieties in haloalkoxy: straight-chain or branched alkyl groups having from 1 to 4 and in particular 1 or 2 carbon atoms (as specified above),

PF 0000055449 oo ; . and some or all of the hydrogen atoms in these groups may be replaced by halogen ; ® atoms as specified above and in particular by fluorine (fluoroalkyt), for example chloro- methyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, ‘ trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chiorodifluoromethyl, 1- chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2- trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2- fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, hepta- fluoropropyl and 1,1,1-trifluoroprop-2-yl. Preferred haloalkyl is C,-C,-fluoroalkyl such as 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, trifluoromethyl and difluoromethyl.

For the process according to the invention, it has been found to be particularly advan- tageous when R in formula Il and accordingly also in formula V is C,-C,-alkoxy, in par- ticular methoxy.

In another embodiment of the invention, R is NH,, C4-Cy4-alkylamino or di(C4-Cs- alkyl)amino. R is then preferably amino (NH,), methylamino, ethylamino or dimethyl- amino and is in particular NH..

The advantages of the process according to the invention become particularly apparent inthe preparation of compounds of the formula | where the variables R', R?and R® are each independently defined as follows, more preferably in combination:

R' is C4-Cs-haloalkyl, in particular trifluoromethyl and especially trifluoromethyl which is disposed in the meta-position (3-position) of the phenyl ring;

R? is cyano, in particular cyano which is disposed in the para-position (4-position);

R® is C,-C4-haloalkoxy, in particular trifluoromethoxy and especially trifluoromethoxy which is disposed in the para-position.

To react the aniline compound Ill with the hydrazone derivative Il, the compounds will be used preferably in a molar lll: ratio in the range from 1:1.5 to 1.5:1, in particular from 1:1 to 1.3:1 and more preferably from 1.02:1 to 1.2:1.

The aniline compound Ill is advantageously reacted with the hydrazone compound Ii at temperatures above room temperature, for example in the range from 30 to 200°C, in particular from 50 to 180°C and more preferably in the range from 70 to 150°C. The reaction pressure is of minor importance for the success of the process according to the invention and may be, for example, in the range from 500 mbar to 10 bar. Prefer- 40 ence is given to carrying out the reaction in the region of atmospheric pressure, i.e. in the range from 0.9 to 1.2 bar. The reaction time required for the reaction is generally in the range from 1 h to 24 h and in particular in the range from 3 hto 12 h.

PF 0000055449

Coe S204

The reaction may in principle be carried out in substance. However, preference is given ) ® to reacting the aniline compound Ill with the hydrazone compound Il in an organic sol- vent. Suitable solvents are in principle any which are capable of at least partly and ’ preferably fully dissolving the compounds Il and Ill under reaction conditions. Preferred 5 solvents are aprotic. They are in particular those solvents that have a boiling point at atmospheric pressure in the range from 60 to 200°C and in particular in the range from 80 to 150°C. Particularly preferred solvents are aromatic solvents, in particular alkyl- benzenes such as toluene, xylenes, ethylbenzene, cumene (2-propylbenzene), cyme- nes (isopropyltoluenes) and mesitylene, and also chlorobenzenes, e.g. chlorobenzene, 1,2, 1,3- and 1,4-dichlorobenzene, and also aliphatic nitriles such as acetonitrile and propionitrile and mixtures of these solvents.

The reaction of the aniline compound Ili with the hydrazone compound ll may be car- ried out in the presence of an acid, although the use of an acid is not required. Exam- ples of acids which are suitable in principle are sulfuric acid, organic sulfonic acids, in particular aromatic sulfonic acids such as p-toluenesulfonic acid and benzenesulfonic acid, aliphatic sulfonic acids such as methanesulfonic acid and trifluoromethanesuifonic acid, aromatic carboxylic acids such as benzoic acid and 4-trifluoromethylbenzoic acid, and aliphatic carboxylic acids having preferably from 1 to 3 carbon atoms, for example acetic acid and propionic acid. In general, the acid will be used in catalytic amounts, i.e. in amounts of less than 1 mol per mole of compound Il or lll, in particular less than 0.5 mol/mol and especially not more than 0.2 mol/mol. In a preferred variant of the process according to the invention, Il is reacted with lil in the absence of an acid.

Atleast some, preferably at least 50% and in particular at least 80%, of the compound

R-H formed in the reaction of the aniline Il with the hydrazone Ill will preferably be re- moved from the reaction mixture during the reaction, especially when the compound R-

H is a C;-Cs-alkanol such as methanol or ethanol. To this end, in the reaction will be carried out at a temperature and a pressure at which the compound R-H is distilled off, if appropriate as an azeotrope with the solvent from the reaction mixture. If appropriate, fresh solvent will be introduced into the reaction for compensation or the solvent which has been distilled off with the compound R-H is recycled into the reaction after, if ap- propriate, distillative depletion of the compound R-H. For these reasons, it is advanta- geous when the solvent used has a boiling point of at least 10 K and in particular at least 30 K above the boiling point of the compound R-H formed in the reaction (in each case at atmospheric pressure). Appropriately, the reaction of the compound Il with the compound lll is carried out in an apparatus which is equipped with at least one distilla- tion and rectification apparatus, for example a distillation column, which firstly allows the compound R-H to be distilled off, if appropriate together with solvent, and simulta- 40 neously enables removal and recovery of any solvent distilled off with the compound R-

H.

PF 0000055449

For the reaction, the compounds Il and Ill may be contacted together in any manner. : @ For example, the compounds Il and lll may be initially charged in a reaction vessel, if appropriate together with the desired solvent, and then the desired reaction conditions : can be established. However, the majority or entirety of compounds Il and ll, if appro- priate in a solvent, can be introduced into the reaction vessel under reaction conditions.

In a preferred embodiment of the invention, the majority, especially at least 80% and more preferably the entirety or virtually the entirety (> 95%) of the hydrazone com- pound ll, if appropriate in the desired solvent, is initially charged and the majority, in particular at least 80% and more preferably the entirety or virtually the entirety (> 95%) of the aniline compound is added thereto under reaction conditions in the course of the reaction, for example over a period of from 0.5 to 20 h and in particular from 1 to 10 h.

To this end, the aniline compound Ill will preferably be dissolved in a solvent. If appro- priate, the addition of the aniline compound Ill will be followed by a certain time, for example from 10 min to 10 h, in particular from 20 min to 5 h, of continued reaction.

The compound | can be isolated from the reaction mixture in a manner known per se. If the reaction has been carried out in a solvent, the reaction mixture will generally be concentrated and/or cooled, and/or a precipitant will be added. Suitable precipitants are solvents in which the compound | dissolves only to a slight extent, if at all, at least at temperatures below 25°C. These include in particular aliphatic and cycloaliphatic hy- drocarbons such as pentane, hexane, cyclohexane, heptane, petroleum ether and the like. The precipitation/crystaliization may be followed by further purification measures.

The process according to the invention affords the compounds | in high yield of gener- ally at least 80% and frequently at least 90%, based on the compound Il, and good purities even in the crude product of generally at least 90% without complicated crystal- lization or other purification measures being necessary. It will be appreciated that fur- ther purification measures, for example crystallizations, may be carried out in a manner known per se. Surprisingly, the process according to the invention affords the com- pound | with a high E/Z isomer ratio of E:Z > 4, which is advantageous with regard to the use of the compounds | as insecticide. A further increase in the E/Z ratio can be achieved in a known manner by isomerizing with iodine. The isomerization of the Z isomer of | to the E isomer in the presence of iodine is described in

PCT/EP2004/012872 of 11.12.2004, whose disclosure content is incorporated herein by way of reference.

The hydrazone compounds of the general formula Il used in the process according to the invention can be prepared in a similar manner to the prior art processes for preparing semicarbazones by reacting a phenyl benzyl ketone of the formula IV with a 40 hydrazide of the formula V, for example in a similar manner to the methods described in J. Am. Chem. Soc. 75, 1953, p. 2259-2261, J. Org. Chem. 55, 1990, p. 1070-1076 and Synthesis, 1985, p. 1048-1051.

PF 0000055449

To this end, it has been found to be advantageous when the reaction of the benzyl ’ [ phenyl ketone IV with the hydrazide V is undertaken in the presence of an acid. Exam- ples of acids which are suitable in principle are sulfuric acid, organic sulfonic acids, in : particular aromatic sulfonic acids such as p-toluenesulfonic acid and benzenesulfonic acid, aliphatic sulfonic acids such as methanesulfonic acid and trifluoromethanesulfonic acid, aromatic carboxylic acids such as benzoic acid and substituted benzoic acids such as 4-trifluoromethylbenzoic acid, and also aliphatic carboxylic acids having pref- erably from 1 to 4 carbon atoms, for example acetic acid and propionic acid. Preferred acids are carboxylic acids, in particular aliphatic carboxylic acids having preferably from 1 to 4 carbon atoms and especially acetic acid. In general, the acid will be used in an amount of from 0.01 to 2 mol per mole of compound IV and in particular in an amount of from 0.05 to 1.5 mol/mol of compound IV. In the case of sulfonic acids, preference is given to catalytic amounts, i.e. in amounts of less than 1 mol per mole of compound IV, in particular in the range from 0.01 to 0.5 mol/mol and especially in the range from 0.05 to 0.2 mol/mol. In the case of carboxylic acids, larger amounts of acids may also be used, for example from 0.1 mol to 2 mol and especially from 0.5 to 1.5 mol, per mole of compound IV.

To react the ketone IV with the hydrazide V, the compounds will preferably be used in a molar IV:V ratio in the range from 1:2 to 1.1:1, in particular from 1:1.5 to 1:1 and more preferably from 1:1.3 to 1:1.05.

In a preferred embodiment of the invention, a hydrazide of the formula V is used where

R is C;-Cs-alkoxy and in particular methoxy. Such hydrazides V are also referred to hereinbelow as carbazate V.

Ketone IV is advantageously reacted with the hydrazide V at temperatures in the range from 10 to 100°C, in particular from 20 to 80°C. The reaction pressure is of minor im- portance for the success of the reaction and may be, for example, in the range from 500 mbar to 10 bar. The reaction is preferably carried out in the region of atmospheric pressure, for example in the range from 0.9 to 1.2 bar. The reaction time required for the reaction is generally in the range from 4 h to 72 h and in particular in the range from 8 hto 60 h.

The reaction may in principle be carried out in substance. However, preference is given to reacting the hydrazide of the formula V with the ketone IV in an organic solvent. Pre- ferred organic solvents are C,-Cy-alkanols, in particular methanol and ethanol, and also aromatic solvents, in particular alkylbenzenes such as toluene, xylenes, ethylbenzene, cumene (2-propylbenzenes), cymenes (isopropyltoluenes) and mesitylene, and also 40 chlorobenzene, 1,2-, 1,3- and 1,4-dichlorobenzene and mixtures of these solvents.

The water formed in the reaction of the ketone IV with the hydrazide V may be re- moved from the reaction mixture during the reaction in a manner known per se, for ex-

PF 0000055449 Z b ~T 1 4 ample by separation as an azeotrope with the solvent used in the reaction. However, : o the water of reaction may also remain in the reaction mixture. ’ For the reaction, ketone IV and hydrazide V may be contacted together in a manner which is per arbitrary se. in general, the ketone IV and the hydrazide V will be initially charged in a reaction vessel, if appropriate together with the solvent desired, and then the desired reaction conditions will be established. However, the majority or entirety of ketone IV and hydrazide V, if appropriate in a solvent, may also be introduced into the reaction vessel under reaction conditions, or one of the components IV or V may be initially charged and the majority of the other components added in the course of the reaction.

The compound Il can be isolated from the reaction mixture in a manner known per se.

If the reaction has been carried out in a solvent, the reaction mixture will generally be concentrated and/or cooled, and/or a precipitant will be added. Suitable precipitants are solvents in which the compound Il dissolves only to a limited extent, if at all, at least at temperatures below 25°C. These include in particular aliphatic and cycloaliphatic hy- drocarbons such as pentane, hexane, cyclohexane, heptane, petroleum ether, metha- nol, ethanol, alkylbenzenes and the like. The precipitation/crystallization may be fol- lowed by further purification measures. When the reaction is carried out as preferred in an alcohol, in particular in methanol or ethanol or in an alkylbenzene, it is generally unnecessary to add a precipitant.

The reaction described here, of the ketone IV with the hydrazide V, affords the com- pounds Il in high yield of generally at least 80% and frequently at least 95%, based on the compound II, and very high purities of frequently at least 90% and in particular at least 95%, without complicated crystallization or other purification measures being re- quired. It is therefore possible to dispense with isolation of the compound II from the reaction mixture.

A preferred embodiment of the invention therefore relates to a process in which, in a first step, the hydrazone derivative of the formula Il is prepared by reacting ketone IV with the hydrazide V and the compound Il is subsequently reacted with the aniline compound lI without isolation. To this end, it may be advantageous when a portion or the entirety of the solvent used to prepare the hydrazone Il is removed and substituted by another solvent. However, the reaction of the hydrazone Il with the aniline Ill in particular will be carried out in the solvent used to prepare the hydrazone Il.

The ketones IV used to prepare the hydrazone Il and processes for their preparation 40 are disclosed by the prior art, for example by WO 00/18714, JP 4168826 and WO

PF 0000055449 ~

A J4

The examples which follow serve merely to illustrate the invention and are not to be ) ® interpreted in a restrictive manner. ’ The purities and isomer ratios reported were determined by means of high-pressure liquid chromatography (HPLC) via the area ratios of the particular peaks.

In connection with the NMR spectra, s is a singlet, d is a doublet and t is a triplet. MS stands for mass spectrum and IR for IR spectrum.

Example 1: Preparation of the hydrazone of the formula ll where R is methoxy, R'is 3-

CF; and R? is 4-CN

Variant A: 18.8 g (0.21 mol) of methyl carbazate (HN-NH-C(O)-OCHjs) and 57.8 g (0.20 mol) of 3- trifluoromethylphenyl 4-cyanobenzyl ketone (compound IV where R'=3-CF;and R?= 4-CN) were dissolved in 700 mi of methanol at 20°C. Subsequently, 2 ml of concen- trated sulfuric acid were added, the mixture was stirred at 20°C for 2 days and the pre- cipitated solid was isolated. This was washed with 100 ml of methanol and dried in a drying cabinet at 50°C/10 mbar. In this way, 62.6 g (corresponding to a yield of 86.7% of theory) of the hydrazone II {R' = 3-CF;, R? = 4-CN} were obtained with a purity (HPLC) of 99.6%.

Melting point: 171°C

MS (El): m/e = 361 (M" ion)

IR: 2245 cm™ (CN); 1704 cm™ (C=0) 'H NMR (DMSO): 8/ppm = 3.8 (s, 3H); 4.5 (s, 2H), 7.4 (d, 2H); 7.64 (t, 1H); 7.7 (d, 1H), 7.8 (d, 2H); 8.0 (d, 1H); 8.15 (s, 1H); 10.95 (s, 1H) 3C NMR (DMSO): 8/ppm = 31.77 (t); 52.19 (q); 109.30 (s); 118.64 (s); 122.51 (d), 124.01(s; C/F coupling const. 272.3 Hz); 125.30 (d); 129.16 (d, 2C); 129.24 (s); 129.61 (d); 130.25 (d); 132.51 (d, 2C); 138.07 (s); 142.11 (s); 146.45 (s); 154.58 (s)

Variant B: 7.3 g (0.025 mol) of 3-trifluoromethylphenyl 4-cyanobenzyl ketone and 2.4 g (0.025 mol) of methyl carbazate (97%) were reacted in the presence of 2.0 g of acetic acid in 50 g of xylene at 50°C for 24 h. After cooling to 20°C, the precipitated solid was removed, washed with 10 g of xylene and dried in a drying cabinet at 50°C/10 mbar. In this way, 8.0 g (corresponding to a yield of 88.1% of theory) of the hydrazone li {R'=3-

CF3, R? = 4-CN} were obtained with a purity (HPLC) of 99.9%. 40

Example 2: Preparation of the compound | where R' is 3-CF; and R? is 4-CN and R® is 4-OCF;

Claims

1. A process for preparing phenylsemicarbazone compounds of the formula Ho N N N hd R® o tO) ad Ie where R' and R? are each independently hydrogen, halogen, CN, C;-C4-alkyl, C,-Cs-alkoxy, C4-C4-haloalkyl or C,-C4-haloalkoxy, and R3 is C;-C4-alkoxy, Cy-Cs- haloalkyl or C;-C,-haloalkoxy, comprising the reaction of a hydrazone compound of the general formula 1l where R is C4-Cq4-alkoxy, amino, C-C,-alkylamino or di(C,-C,-alkyl)amino, and R’, R? are each as defined above H N R N™ NH, 7 R! > (ny; (i) 3 CL with an aniline compound of the general formula lil where R® is as defined above.

2. The process according to claim 1, wherein R is C;-C,-alkoxy.

3. The process according to claim 2, wherein R is methoxy.

4. The process according to claim 1, wherein R is amino, methylamino, ethylamino or dimethylamino.

5. The process according to any one of the preceding claims, wherein the aniline compound lll and hydrazone compound of the general formula Il are used in a molar 11:1ll ratio in from 1:1.5 to 1.5:1.

6. The process according to any one of the preceding claims, wherein the hydrazone compound of the formula Il is provided by reacting a benzyl phenyl ketone of the formula IV

. 0000055449 0] 1 R > (Iv) CF where R', R? are each as defined above, with a hydrazide of the formula V Hi

N.__R HN" Vv) oO where R is as defined above.

7. The process according to claim 6, wherein R in formula V is C4-C4-alkoxy.

8. The process according to claim 7, wherein the reaction of the benzyl phenyl ketone IV with the hydrazide V is undertaken in the presence of an acid.

9. The process according to any one of claims 6 to 8, wherein the hydrazone compound of the general formula Il is reacted with the aniline compound Ili without isolation.

10. The process according to any one of the preceding claims, wherein R' in the formulae |, Il and IV is meta-trifiuoromethyl, R? in the formulae |, Il and IV is para- CN and R? in the formulae | and Ill is para-trifluoromethoxy.

11. A hydrazone compound of the general formula Hi -N R N 7 ; R c (In (Fe where R' is hydrogen, halogen, CN, C,-C;-alkyl, C,-C4-alkoxy, C1-C4-haloalkyl or C,-C,-haloalkoxy, R? is CN and R is C,-C,-alkoxy, amino or C,-C,-alkylamino or di(C,-C-alkyl)amino.

1 I : 0000055449

12. The hydrazone compound of the general formula il according to claim 10, wherein R is C4-C,-alkoxy.

13. The hydrazone compound of the general formula | according to claim 12, wherein R is methoxy.

14. The hydrazone compound of the general formula I! according to any one of claims 11 to 13, wherein R is meta-trifluioromethy! and R? is para-CN.

15. The process according to the invention for preparing the compounds of the formula |, substantially as hereinbefore described or exemplified.

16. The process for preparing the compounds of the formula | including any new and inventive integer or combination of integers, substantially as herein described.

17. The compound of the formula Il as claimed in any one of claims 11 to 14, substantially as herein described.

18. The compound of the formula Il including any new and inventive integer or combination of integers, substantially as hereinbefore described or exemplified.