Synthesis of Novel Pyridine Fungicides - American Chemical Society

Chapter 40

Synthesis of Novel Pyridine Fungicides 1

1

2

F. Dorn , A. Pfiffner , and M. Schlageter l

SOCAR AG, Ueberlandstrasse 138, CH-8600 Dübendorf, Switzerland Central Research Department, F. Hoffmann-La Roche AG, Grenzacherstrasse 124, CH-4002 Basel, Switzerland

Downloaded by COLUMBIA UNIV on June 26, 2013 | http://pubs.acs.org Publication Date: December 7, 1991 | doi: 10.1021/bk-1991-0443.ch040

2

Research on pyridine compounds has led to the discovery of the fungicide pyrifenox. Structure activity relationships are presented and the efforts to establish an efficient technical synthesis for pyrifenox are described.

In 1976 the novel oxazoline 1 was found to exhibit interesting fungicidal activity in random screening. Especially noteworthy was its effect against powdery mildew disease on barley and wheat, which could be confirmed under field conditions with application rates as low as 125 g/ha.

1

A photochemical synthesis as well as a more conventional preparation of 3-oxazolines, described in detail by Pfoertner et al. (l),is outlined in Figure 1 for the 2,4-dichloro compound 2.

0097-6156/91/0443-0506$06.00/0 © 1991 American Chemical Society

In Synthesis and Chemistry of Agrochemicals II; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1991.

40. DORNET AL.

Novel Pyridine Fungicides


Figure 1. Synthesis of 3-Oxazolines

Variation of substituents of the oxazoline ring system soon revealed that the partial structure highlighted in Figure 2 for oxazoline 2 was essential for good fungicidal activity. A 2,4-dichlorosubstitution of the phenyl group would guarantee for optimal or nearly optimal effects. A very similar structural pattern was recognised in triadimefon (Figure 2) which appeared at about the same time as a developmental compound. Figure 2. Essential Structural Elements


507

508

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS Π

Analog Synthesis


The decision was taken to explore and optimize this random lead by the synthesis of analogs. The only published work on similar 6-membered-aromatic-N-heterocyclic compounds as fungicides was the triarimol project of Eli Lilly. But although most of the Eli Lilly patents include compounds with a two-carbon bridge between a halo gen substituted phenyl ring and the N-heterocyclic system, compounds with an onecarbon bridge seem always preferred (2). It appeared that the ketones 5 and 7 would be versatile intermediates to prepare a series of structural analogs of the 3-oxazolines, all retaining part of the functionality of the former ring system. Figure 3 shows the preparation of ketone 5. Coupling of 3 with 3-chloromethylpyridine under phase transfer conditions leads under quantitative hydrogen cyanide elimination directly to the enamine 4. Acid hydrolysis of 4 provides the desired ketone 5. Ketone 7 (Figure 4) is best preparedfrom2,4-dichlorobenzyl cyanide and nicotinic acid ethylester. The condensation product 6 is then hydrolysed and decarboxylated under acid conditions. Figure 3. Synthesis of Ketone 5

5

Ο

Figure 4. Synthesis of Ketone 7 Cl

XI

CN

.Ν

Ο

6

7

CN OH

Ο


40. DORNETAL.


509

Figure 5 gives an overview of structures synthesized from the respective ketones 5 and 7. For each reaction type a)-f) the specific example with the best fungicidal activity of a series is shown. Figure 5. Overview of Analogs Products from ketone

Example

5

7

o

ο


1

ν»

ο

Ph

OR

Ph OR R

CH,

V^Py

Y

Py R

1

2

R

1

R

Ph

Ph OH

Ph

'Py OH

Py R

OR

Py

10 R*=H QJOH

2

Ph

Ph Py 12

N 'OR

" H OCH,

Py

o

OR

Ν

O Py

N OR

O

OCH,

I I

0

ο

0

0

Py Ph = 2,4-dichlorophenyl,

il

N

Ph

ο

11 Ri=CH

N

N.

v.

1

Py = 3-pyridyl


ΛΑ

3

510

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS II

a) Alkylation confers moderate fungicidal activity to the ketones especially in the series of ketone 7 as exemplified by compound 8. b) Under standard conditions of alkylation or acylation these ketones give rise to varying amounts of enolethers or enolesters respectively. The isopropylenolether 9 is a fungicidally interesting example. c) The reduction products of the ketones with hydride or alkyl-Grignard reagents are at best slightly active. The products from reaction with simple arylGrignard reagents prove to be biologically much more interesting. The best ones however are covered by Eli Lilly patents, e.g. (2). If the ketones are first alkylated and then reduced, excellent fungicidal activity can be found for derivatives of ketone 7 for R =H as well as alkyl as shown by examples 10 and 11. d) Oximation leads to active derivatives especially for ketone 5. Activity is best for oxime ethers with a small ether function like e.g. for compounds with R=methyl, ethyl, allyl, propargyl. For derivatives with larger R groups like e.g. benzyl but also for acyl derivatives and for the free oxime only slight to moderate activity is observed. Compound 12 proved to be the most interesting example of this series. e) Oximation with inorganic nitrite or alkylnitrites leads to α-oximation of the ketones. The corresponding oxime ethers show activity as illustrated by example 13. Sodiumborohydride reduction of 13 leads to the corresponding hydroxy-oxime methylether which was later shown to be an active metabolite of pyrifenox. f) Reaction of the ketones with glycols under strongly acid conditions leads to cyclic ketals. Compound 14 was the outstanding example in this series. Inactive derivatives of the ketones and for that reason not listed here were e.g. hydrazones and nitrones. Along these lines about 200-250 compounds were prepared. Included in this number are examples which contain a 2-pyrazinyl or a 5-pyrimidyl group instead of the 3-pyridyl group. The two biologically most interesting compounds at that stage of work were definitely the oxime ether 12 and the ketal 14. Both were chosen for extended field evaluation.


l

Biological Performance Ketal 14 attracted attention because of its unusual activity spectrum (Figure 6). It showed the expected activity under field conditions against diseases on apples, against powdery mildew on grapes and against Monilia species, although somewhat elevated dosage rates were needed for good control. Its strong activity against Botrvtis cinerea was rather unusual. It performed very well against Botrvtis on vegetables at rates of 125-250 g/ha. On grapes around 750 g/ha of compound 14 were needed. However, after an extended field testing program the decision was taken not to proceed further with the development of compound 14. Economical reasons and a certain unreliability in its performance against Botrvtis on grapes were the basis for that decision. Oxime ether 12, to which the common name pyrifenox has been assigned, is a mixture of E- and Z-isomers in about a 1:1 ratio. Its performance under field conditions against various diseases on dicot crops is excellent. Some examples and the necessary dosage rates are given in Figure 7. The absence of any significant growth regulatory side effects on plants is a special advantage for a fungicide, that has been shown to inhibit C-14-demethylation in fungal sterol biosynthesis (3). Pyrifenox was presented as a new fungicide in 1986 (4,5).


40. DORN ET


511

Figure 6. Biological Performance of Ketal 14

O C X j| 0 0 1 1 14 (Ro 15-2405)

pathogen Venturia inaequalis Downloaded by COLUMBIA UNIV on June 26, 2013 | http://pubs.acs.org Publication Date: December 7, 1991 | doi: 10.1021/bk-1991-0443.ch040

dosage (g a.i./ha)

crop

Podosphaera leucotricha Uncinula necator

apples

150

grapes

100

apricots

Monilia spp.

500

almonds Botrytis cinerea

vegetables grapes

125 - 250 750

Figure 7. Biological Performance of Pyrifenox

Ν

i OCH 12 (Ro 15-1297) 3

crop

dosage (g a.i./ha)

Venturia inaequalis Podosphaera leucotricha

apples

50 - 100

Uncinula necator

grapes

30 - 50

pathogen

Monilia spp.

apricots almonds

Cercospora arachidicola Cercosporidium personatum

groundnuts

100 70 - 100


512

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS Π

Synthesis of Pyrifenox The decision to develop pyrifenox meant a challenge to establish an economical synthesis suited for large scale production. The crystalline ketone 5 was considered a key intermediate in a synthesis of the oily end product Its lab synthesis described earlier in Scheme 2 was unsatisfactory because a very variable yield of only 30-50% could not be surpassed in the phase transfer coupling of 3 with 3-chloromethylpyridine. Attention was therefore given to alternative procedures to produce 5 as illustrated in Figure 8.


Figure 8. Alternative Building Blocks for Ketone 5

Variant a) represents the reaction of metallated β-picoline with a 2,4-dichlorobenzoic acid ester. This pathway appears attractive because of its shortness and the cheapness of the starting pyridine building block. Formation of the lithium salt of β-picoline requires e.g. lithiumdiisopropylamide and 1-2 equivalents of hexamethylphosphoric triamide. This anion reacts e.g. with benzoic acid methylester to give the unsubstituted ketone in 90% yield as reported by Kaiser and Petty (6). When the anion is reacted with 4-chlorobenzoic acid methylester only a 10% yield is observed. With 2,4-dichlorobenzoic acid methylester none of the expected ketone is obtained. The reason for this failure to obtain satisfactory yields of chlorinated ketones by this procedure has not been investigated. Variant b) shows the Friedel-Crafts reaction between 3-pyridylacetic acid chloride and 1,3-dichlorobenzene. With excess aluminium chloride at a temperature of 100-120°C a good selectivity for the desired ketone is observed. The chemical yield in preliminary trials however was only about 30%. This poor yield and the high price of the 3-pyridylacetic acid building block did not motivate to study this pathway in more detail. Similar arguments as for b) hold true for the ester condensation shown as variant c).


40. DORNETAL.

513


A very original proposition illustrated in Figure 9 seemed to provide the breakthrough. œ,2,4-Trichloroacetophenone is condensed with 3-pyridine-carboxaldehyde to the epoxyketone 15. The subsequent benzylic acid type rearrangement shortens the carbon chain of 15 to the proper length giving the a-hydroxy-acid 16. Oxidative decarboxylation is achieved by treatment with eerie ammonium nitrate. The desired ketone crystallizes out of the reaction mixture as the nitrate salt in excellent yield. The kilo amounts of pyrifenox needed at that stage of development were conveniently prepared by this pathway. However, it proved to be exceedingly difficult to replace the eerie ammonium nitrate reagent by a cheaper and environmentally more tolerable oxidant.


Figure 9. Kilolab Synthesis of Ketone 5

NaOCH3/CH OH 3

+

TO^CH CI CJL 2

CHO

7

3

%

1) NaOH/CH CH OH 3

53%

c

Vv

c l

rA

Ce(NH ) (N0 ) 4

2

3

2

2) CH3COOH

6

95% Ο

HO

COOH 16

Eventually the critical parameters of the phase transfer coupling between 3 and 3-chloromethyl-pyridine could be controlled. Various further improvements helped to establish the technical synthesis of pyrifenox outlined in Figure 10. 2,4-Dichlorobenzaldehyde is activated for the phase transfer step as the cyano-diethylamino-adduct. 3-Chloromethylpyridine is prepared from 3-hydroxymethyl pyridine by treatment with thionylchloride. The hydrochloride salt of the product is taken up in water and the solution is used directly in the phase transfer step. Strict temperature control, proper speed of addition of the 3-chlormethyl pyridine solution and the use of a cosolvent like e.g. hexane ensure a reliable yield of enamine greater than 95%. The enamine reacts at room temperature quantitatively with the hydrochloride salt of O-methylhydroxylamine to give the corresponding oxime ether as an ETZ-mixture of 3:7. Addition of sulfuric acid to this oximation reaction and an increase of reaction temperature to about 50°C yields pyrifenox rapidly in the desiredtyZ-equilibriumratio of about 1:1. No special purification processes are required in the whole synthesis.


514

S Y N T H E S I S A N D C H E M I S T R Y O F A G R O C H E M I C A L S II

Conclusion Starting from information provided by a random compound a modest synthesis program provided two analogs that were evaluated in extended field trials. The implementation of a reliable technical synthesis was a crucial contribution to the successful development of one of these two products to which the common name pyrifenox was assigned. Pyrifenox has been commercialised by Dr. R. Maag AG and is an active ingredient in fungicides like e.g. Rondo, Dorado, Furado or Podigrol.


Acknowledgments The competent lab and field evaluation of the compounds of this project by P. Zobrist, K. Bohnen and H. Siegle of Dr. R. Maag AG, CH-8157 Dielsdorf, Switzerland, is gratefully acknowledged.

Literature Cited 1. 2. 3. 4. 5. 6.

Pfoertner, K.H.; Montavon, F.; Bernauer, K. Helv.Chim.Acta 1985, 68, 600-605 Von Heyningen, E.M. U.S. Patent 3 396 224, 1968 Masner, P.; Kerkenaar, A. Pestic.Sci. 1988, 22, 61-69 Zobrist, P.; Bohnen, K.; Siegle, H.; Dorn, F. Proc.Brit.Crop Prot.Conf.Pests Dis. 1986, Vol.1, pp 47-53 Myers, D.F. Phytopathology 1986, 76, 1117 Kaiser, E.M.; Petty, J.D. Synthesis 1975, 705-706

RECEIVED December 15, 1989


Synthesis of Novel Pyridine Fungicides - American Chemical Society

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