Method of obtaining novel triazol/ or imidazol/-/phenyl/tetrachlorofurane derivatives of methane

<td rowspan="2">POLAND RZECZPOSPBLIU ICE</td><td>PATENT DESCRIPTION ρκ</td><td colspan="2" rowspan="2">1 141908 The patent specification was assigned due to errors noted</td>

<td>Additional patent to patent no</td>

<td>ut</td><td rowspan="2">Reported: 85 01 25 (P. 255849) Priority: 84 26 01 France The application was announced: 86 11 04</td><td colspan="2">Int. Cl⁴ C07D 405/06</td>

<td rowspan="2">URZAO PATERTOWT PRL</td><td>1CZ '»bLNlA 1 Μ ... Χ »* ···«</td><td></td>

<td>Patent description published: 89 02 28</td><td></td><td></td>

Creators of the Invention: Jean-Claude Debourge, Alfred Greiner Patent Holder: Rhone-Poulenc Agrochimie, Lyon (France)

Method for the production of new triazolo / or imidazolo / phenyl / tetrahydrofurano methane derivatives

2

The subject of the invention is a process for the production of new triazole / or imidazole / - phenyl / tetrahydrofuran derivatives of methane of general formula 1 in which X is a halogen atom, a cyano group, a nitro group or an optionally halogenated alkyl or alkoxy group, n is 0 - 6. W is a trivalent group = CH— or = N—, R¹ represents a hydrogen atom or an alkyl group and R^Lis hydrogen or an optionally substituted hydrocarbon radical such as an alkyl, cycloalkyl, aryl or aralkyl group and the substituents may be halogen, preferably chlorine or bromine, and alkoxy or aryloxy groups.

These compounds have fungicidal activity and can be used to combat fungal parasites on plants and industrial products, e.g. on wood, paints, etc. as well as as agents for: plant growth regnlagi.

The term halogen preferably means fluorine, bromine or chlorine. The term alkyl or alkoxy means a group with 1-12 carbon atoms, preferably 1-4 carbon atoms. These groups can be mono- or polyhalogenated.

The preferred group is the —CF · group. In the compound of formula 1, n is 0 - 6, preferably 2, except that when n is greater than 1, the substituents X may be the same or different. OR group¹ preferably it is attached to the carbon atom adjacent the oxygen atom of the heterocyclic ring of the compound of formula 1 such that the compound has an acetyl functional group.

These compounds may exist in one or more forms of optical isomers, depending on the number of asymmetric centers in the molecule. The scope of the invention includes both individual optical isomers and their ceramic mixtures and corresponding diastereomers.

Said compounds may also exist and in the form of salts, especially as hydrochlorides, sulfates, oxalates and nitrates.

Compounds of general formula 1 in which X, n, W, R are the process according to the invention^l and R * have the meanings given above are obtained by reacting a compound of formula 2 in which Z is a chlorine or bromine atom and X, n, R¹ and R * are as defined for formula 1, with an alkali metal derivative, for example with a sodium or potassium salt, or with a quaternary ammonium or phosphonium derivative of imidazole or triazole.

The reaction is usually carried out in an aprotic polar solvent and can also be catalyzed, for example, by the addition of an alkali metal iodide, generally at * ^M at 50 - 250 ° C, for economic reasons, preferably 70 - 230 ° C, at a reagent concentration of 1 - 50 · / ·.

Compounds of formula 2a magna prepared by re³⁰ an alcohol action of the formula R * OH in which R^L It has

141 908

Ml 908 above meaning, in the presence of an acid catalyst, with a compound of formula 3, wherein R¹, X, Z and n have the above meanings and R³ is an organic radical, preferably a lower alkyl radical with 1-4 carbon atoms and two R radicals³ they may together form a divalent organic radical, preferably a lower alkylene radical.

The acid used in this reaction as a catalyst can be both protic and aprotic. As protic acids, mention may be made of acids such as hydrogen chloride, sulfuric acid, trifluoroacetic acid, perchloric acid, benzenesulfonic acid, toluene sulfones and methanesulfonic acid. As aprotic acids, Lewis acids such as BF may be mentioned_t, AlClj and SnCl₄. When hydrogen chloride is used as a catalyst, it can be formed in situ from, for example, acyl chloride, especially acetyl chloride, which reacts with the alcohol present there to release HCl.

The reaction is normally carried out by simply heating said reagents at a temperature usually in the range of 30 ° to the boiling point of the reaction medium. R'OH alcohol usually acts as a solvent in the reaction medium. An inert cosolvent such as an aliphatic, alicyclic or aromatic hydrocarbon, which may be optionally halogenated, or an ether can also be added.

Compounds of formula 3 are usually prepared by reacting a carbonyl compound of formula 4 with a magnesium organic derivative prepared from a compound of formula 5 in which Z * is a halogen atom, preferably a broimium and X, Z, R¹, R³ in are as defined above. The organomagnesium derivative can be obtained by known methods, for example, the action of halogenaldehyde acetal on magnesium in a solvent medium. Acetal-halaldehyde alone can be prepared by a known method, for example G. Buchi and H. Wuest, J. Org. Chem. 34, 1122 &lt;1969) and H. Meerwein, Houben-Weryl, Methoden der Org. Chem. Volume VI / 3 p. 204, 4th edition (1965).

The reaction of the compound of formula 4 with the organomagnesium derivative of the compound of formula 5 is most often carried out at a temperature between -70 ° C and + 100 ° C, preferably -50 ° C and + 50 ° C. As the solvent, ethers, especially ethyl ether, and tetrahydrofuran or aliphatic, alicyclic or aromatic hydrocarbons or mixtures thereof can be mentioned. The following are examples of the preparation of compounds of Formula 1 without limiting the scope of the invention.

Example 1 An organomagnesium derivative was prepared by activating 9.7 g (0.4 mol) magnesium with dibromoethane (0.5 ml) in 10 ml anhydrous tetrahydrofuran (abbreviated THF). While the temperature was kept below 15 ° C, a solution of 47 ml (0.4 mol) 2-Z-bromoethyl / 1,3-dioxolene in 200 ml THF was added dropwise. One quarter after the addition, the mixture was cooled to -45 ° C and a solution of 56.7 g (0.3 mol) chloromethyl para-chlorophenyl was added | in 150 ml THF keeping the temperature at -45 ° C. After half an hour, the mixture was neutralized with pure acetic acid (120 ml) and then poured into 1 liter of water. Extraction with ethyl acetate was performed. The ethyl acetate solution was dried and the solvent was evaporated. 100 g of chlorohydrin of formula 6 are obtained, melting at 99 ° C. (after recrystallization from cyclohexane).

A mixture of 0.1 ml of acetyl chloride and a solution of 6 g (0.02 mol) of the product of formula 6 in 30 ml of methanol is refluxed for 2 hours, and then poured into a 5 * aqueous sodium carbonate solution. The mixture was extracted with ethyl ether, the ether solution was dried and the ether was evaporated. Oils were obtained which were distilled at 140 ° C under absolute pressure of 5.3 Pa. 4.7 g of an oily product of formula 7 are obtained.

A mixture obtained by adding 4.2 g (0.016 mol) of the product of formula 7 to &lt;40 ml dimethyl sulfoxide containing triazole sodium prepared from 1.6 g &lt;0.024 mol) triazole and 0.7 g (0.024 mol) sodium hydride in 80 · / Oily suspension, heated for 3 hours at 170 ° C in an inert atmosphere.

The solution was poured into 200 ml of water. The mixture was extracted with diethyl ether, the solution was dried and the ether was evaporated. The residue was purified by silica gel chromatography. In this way, 3.1 g of oil was obtained, which was a mixture of substantially equal parts of diastereomers of structural formula 8.

Example II By proceeding as in Example 1, various compounds of formula 9 were obtained. The nature of the substituents in formula 9 and some of the physical data of compounds Nos. 1-50 are shown in the table.

Regarding compounds Nos. 49 and 50, it should be noted that instead of the X-substituted para-chlorophenyl group¹ in the orth position they contain a para-fluorophenyl group substituted with X¹ in ortho position. In addition, compound 50 has an imidazole group in place of the triazole group, the method for producing this compound was the same, but the reactants were selected appropriately.

In the case where R¹ is a hydrogen atom, the compounds have 2 asymmetric carbon atoms and two thin diastereomers can be distinguished on silica thin film using a methanol - ethyl acetate - hexane mixture in the proportion 2:20:75 respectively. The less polar diastereomer migrates faster in chromatography and has been designated A. more polar migrates more slowly in chromatography and has been designated B.

Where R¹ is other than hydrogen, the compounds contain 3 asymmetric atoms and have diasteroisomers. These diastereomers are arbitrarily designated A, B, C and D. Sometimes it is difficult to separate them by chromatography, but when possible A is the least polar, D is the most polar and B and C have intermediate polarities.

HlSfffi ·

Board

<td>Relationship ΗΓ</td><td>X¹</td><td>R^l</td><td>R¹</td><td>diastereomeric reoizo- mers</td><td>The temperature rature m.p. ° C</td><td>delta (NMR)</td>

<td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 5</td><td> 6</td><td> 7</td>

<td>1 the disc</td><td>H</td><td>H</td><td>CH -</td><td>A + B</td><td>Oil</td><td> 535</td>

<td> 2</td><td>H</td><td>H</td><td>C H.-</td><td>AND</td><td> 88</td><td> 5,27</td>

<td> 3</td><td>H</td><td>H</td><td>CH -</td><td>B</td><td>Oil</td><td> 5,14</td>

<td> 4</td><td>ii</td><td>H</td><td>_n QH₇—</td><td>AND</td><td>Oil</td><td> 5,26</td>

<td> 5</td><td>H</td><td>H</td><td>In-CA-</td><td>B</td><td>Oil</td><td> 5,12</td>

<td> 6</td><td>H</td><td>H</td><td>nc₄H -</td><td>A + B</td><td>Oil</td><td> 5,25 5,11</td>

<td> 7</td><td>H</td><td>H</td><td>iso-C, H₇—</td><td>AND</td><td>Oil</td><td> 5,39</td>

<td> 8</td><td>H</td><td>H</td><td>iso-C, H₇—</td><td>B</td><td> 70</td><td> 5,24</td>

<td> 9</td><td>and</td><td>H</td><td>CH -</td><td>A + B</td><td>Oil</td><td> 5,20 5,04</td>

<td> 10</td><td>and</td><td>H</td><td>CH</td><td>AND</td><td> 61</td><td> 5,30</td>

<td> 11</td><td>and</td><td>H</td><td>CA-</td><td>B</td><td> 164</td><td> 5,14</td>

<td> 12</td><td>cl</td><td>H</td><td>nC, H₇-</td><td>A + B</td><td>Oil</td><td> 5,14 5,31</td>

<td> 13</td><td>cl</td><td>H</td><td>nC, H₇—</td><td>AND</td><td>Oil</td><td> 5,31</td>

<td> 14</td><td>cl</td><td>H</td><td>nC, H₇</td><td>B</td><td> 116</td><td> 5,14</td>

<td> 15</td><td>cl</td><td>H</td><td>iso-C, H₇—</td><td>AND</td><td> 100</td><td> 5,42</td>

<td> 16</td><td>and</td><td>H</td><td>iso-C, H, -</td><td>B</td><td> 149</td><td> 5,26</td>

<td> 17</td><td>and</td><td>H</td><td>nC₄H -</td><td>A (85%)</td><td>Oil</td><td> 5,30</td>

<td> 18</td><td>and</td><td>H</td><td>n-C H -</td><td>B (90%)</td><td>Oil</td><td> 5,14</td>

<td> 19</td><td>cl</td><td>H</td><td>nC₅Hu</td><td>A (60%)</td><td>Oil</td><td> 5,30</td>

<td> 20</td><td>cl</td><td>H</td><td>nC₅HN-</td><td>B (90%)</td><td>Oil</td><td> 5,13</td>

<td> 21</td><td>cl</td><td>H</td><td>Cl-CH, -CH, -</td><td>AND</td><td> 103</td><td> 5,35</td>

<td> 22</td><td>cl</td><td>H</td><td>a-CH, -CH, -</td><td>B</td><td> 135</td><td> 5,19</td>

<td> 23</td><td>cl</td><td>H</td><td>cyclohexyl</td><td>A + B</td><td>Oil</td><td> 5,47 5,31</td>

<td> 24</td><td>cl</td><td>H</td><td>cyclohexyl</td><td>B</td><td> 118</td><td> 5,31</td>

<td> 25</td><td>cl</td><td>H</td><td>p-Cl-C_eH₄—O — CH, - —CH, -</td><td>AND</td><td>Oil</td><td> 5,39</td>

<td> 26</td><td>cl</td><td>H</td><td>p_Cl -C_eH₄—O — CH, - —CH, -</td><td>B</td><td> 128</td><td> 5,22</td>

<td> 27</td><td>cl</td><td>ch.</td><td>nC₄H -</td><td>A + B + + C + D</td><td>Oil</td><td></td>

<td> 28</td><td>cl</td><td>ch,</td><td>CH -</td><td>A + B + + C + D</td><td>Oil</td><td> 4,90( 4,74) 4,74 (4,55)</td>

<td> 29</td><td>cl</td><td>CH,</td><td>c_;H₅</td><td>A + B + + C + D</td><td>Oil</td><td> 5,01 (4,84) 4,82 (4,62)</td>

<td> 30</td><td>cl</td><td>CH,</td><td>C, H_L—</td><td>A + B + + C + D</td><td>Oil</td><td> 5,01 (4,83) 4,81 (4,60)</td>

<td> 31</td><td>and</td><td>nC_sHT</td><td>CH -</td><td>A + B- + C + D</td><td>Oil</td><td></td>

<td> 32</td><td>and</td><td>η-ίΖ, Ητ-</td><td>ca</td><td>A + B + + C + D</td><td>Oil</td><td></td>

<td> 33</td><td>and</td><td>H</td><td>1ZO-C4H -</td><td>AND</td><td> 71°</td><td> 5,29</td>

<td> 34</td><td>cl</td><td>H</td><td>iso-C₄H_e—</td><td>B</td><td> 80°</td><td> 5,12</td>

<td> 35</td><td>and</td><td>CH,</td><td>n - &lt;^ H</td><td>A + B</td><td>Oil</td><td> 5,00 (4,81)</td>

<td> 36</td><td>and</td><td>nC, HR-</td><td>CA-</td><td>C + D</td><td>Oil</td><td> 4,83 /(4,61</td>

<td> 37</td><td>and</td><td>H</td><td>allii</td><td>AND</td><td>75 ° C</td><td></td>

<td> 38</td><td>and</td><td>H</td><td>allii</td><td>B</td><td>181 ° C</td><td></td>

<td> 39</td><td>and</td><td>CH,</td><td>F ^ CH, CH, -</td><td>A + B</td><td>Oil</td><td> 5,05 (4,90)</td>

<td> 40</td><td>and</td><td>CH,</td><td>F-CA-CH, -</td><td>C + D</td><td>Oil</td><td> 4,91 (4,66)</td>

<td> 41</td><td>cl</td><td>CH,</td><td>F-CH &lt;-CH, -</td><td>A + B + + C + D</td><td>Oil</td><td> 5,05 (4,91) 4,90 (4,66)</td>

<td> 42</td><td>and</td><td>CH,</td><td>CF ^ -CHR-</td><td>A + B</td><td>Oil</td><td> 5,09 (4,95)</td>

<td> 43</td><td>and</td><td>H</td><td>F-CH »CH, -</td><td>AND</td><td> 107°</td><td> 5,29</td>

<td> 44</td><td>and</td><td>H</td><td>F-CH, -CH, -</td><td>B</td><td> 158°</td><td> 5,14</td>

<td> 45</td><td>and</td><td>H</td><td>CA-</td><td>A + B</td><td> 57°</td><td> 5,30 (5,14)</td>

<td> 47</td><td>and</td><td>H</td><td>H</td><td>A + B</td><td> 171°</td><td></td>

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<td> 1</td><td>2 AND</td><td> 1 3</td><td> 4</td><td> 5 1</td><td> 1 6 .</td><td> 7</td>

<td> 48</td><td>cl</td><td>nC₃H₇</td><td>H</td><td>A + B + + C + D</td><td> 152°</td><td></td>

<td> 49</td><td>F</td><td>H</td><td>CH</td><td>A + B</td><td>Oil</td><td> 5,24 5,08</td>

<td> 50</td><td>F</td><td>H</td><td>CJH_s—</td><td>A + B</td><td>Oil</td><td> 5,24 5,12</td>