Patent Publication Number: US-3879477-A

Title: Monohydroxyphenyl carbinols

Description:
United States Patent 11 1 Schellenbaum et al.  
 1 MONOHYDROXYPHENYL CARBINOLS [75] Inventors: Max Schellenbaum, Muttenz; Max  
 Duennenberger, Frenkendorf; Fulvio Casagrande, Binningen, all of Switzerland [73] Assignee: Ciba-Geigy AG, Basel, Switzerland [22] Filed: July 20, 1971 1 Appl. No.: 164,446  
 [30] Foreign Application Priority Data July 23, 1970 Switzerland 11172/70 [56] References Cited UNITED STATES PATENTS 2,709,704 5/1955 Brown 260/618 B X [451 Apr. 22, 1975 2.798.088 7/1957 Ritter et al 260/618 H X 2,895,871 7/1959 Entemann.... 260/618 B X 2,945,886 7/1960 Brown 260/618 H X 3,479,294 11/1969 Weck 260/619 R OTHER PUBLICATIONS Faith et al., Jour. Amer. Chem. Soc., Vol. 77, (1955), pp. 543-547.  
 Arnett et a1., Jour. Amer. Chem. Soc., Vol. 87, (1965). p 1023-1031.  
 Primary Examinen-Bernard Helfin Attorney, Agent, or Firm-Frederick H. Rabin; Nestor W. Shust [57] ABSTRACT Monohydroxyphenyl carbinols with at least two halogen atoms in the molecule have been found as microbicides which are effective against various types of bacteria and fungi.  
 8 Claims, No Drawings MONOHYDROXYPHENYL CARBINOLS This invention relates to monohydroxyphenyl carbinols, their manufacture and use.  
  According to the present invention there are provided monohydroxyphenyl carbinols of the general formula OH X OH C R X l 1 12 where X is halogen,  
 X X and X are each halogen or hydrogen, and  
  R is a straight or branched chain alkyl group of 1-8 carbon atoms, or cycloalkyl group of 3-8 carbon atoms or phenyl, unsubstituted or substituted by halogen and- /or alkyl of l2 carbon atoms, there being at least 2 halogen atoms in the molecule.  
 These compounds possess microbicidal activity.  
  The hydroxyl group in formula I is preferably in 2- or 4- position. The most important cycloalkyl groups are cyclopentyl and, especially, cyclohexyl.  
  The alkyl groups can be, for example, methyl, ethyl and all isomers of propyl, butyl, amyl, hexyl, heptyl and octyl. Halogen includes bromine and chlorine.  
  Formula I includes hydroxyphenyl carbinols of the formula wherein X, X X and X have the meanings given above, and Y and Y, are each methyl, halogen or hydrogen. Y Y and Y, are each halogen or hydrogen, there being at least 2 halogen atoms in the formula, and the phenolic hydroxy group being in the 2- or 4- position to the carbinol bridge,  
 as well as hydroxyphenyl alkyl carbinols of the formula Preferred alkyl groups have 3-7 carton atoms, these groups being preferably unbranched.  
  Particularly interesting microbicidal are those 2- hydroxyphenyl alkyl carbinols of formula 3 wherein X and X are the same and are chlorine or bromine, while X and X are hydrogen and Alk is n-butyl or n-amyl. Furthermore, of great particular interest are monohydroxybenzhydrols of the formula I I c &amp;  
  X.% H 2 Y (4) I ry Ill/T wherein n is 2, 3 or 4, and m is l, 2 or 3, and n+m is 3, 4 or 5.  
  The most important 4-hydroxybenzhydrols are given by the formula wherein p and q are each 1, 2 or 3 and p q is 3 or 4. In order to manufacture the monohydroxyphenyl carbinols of the invention, a ketone of the formula wherein X, X X X and R have the meanings given above is reduced. The compounds of formulae 2 to 6 can be made from ketones of the formula and wherein the various symbols have the meanings given above, and the numbers of substituents and position of the hydroxy group are as given above also.  
  As reducing agent, for example a hydride can be used, the reaction being carried out in a solvent medium inert to the hydride.  
  For this, sodium borohydride is used with advantage, generally 0.25 1 mol per mol of the hydroxyphenyl ketone to be reduced, corresponding to l to 4 equivalents. Particularly good yields are obtained if a polar solvent is used such as water, methanol, ethanol, isopropanol or dioxane, or mixtures of these solvents such as a water/methanol mix. The hydroxyphenyl ketone to be reduced is generally subjected to reaction in the form of a phenolate, i.e. in salt form, preferably an alkali salt such as the ammonium, potassium or, particularly the sodium salt.  
  The reaction temperature may vary for example between C and the boiling temperature of the solvent used. The reaction time is correspondingly generally 20 to 1 hours.  
  Further reduction methods which can be used are reduction with zinc dust in alcoholic alkali hydroxide solution, for example potassium hydroxide or sodium hydroxide, and reduction by means of sodium amalgam in alcoholic solution or by means of aluminum isopropylate in isopropanolic solution (the method of Meerwein-Ponndorf-Verlay).  
  Note should also be taken of the catalytic hydrogenation of hydroxyphenyl ketones. to give the hydroxyphenyl carbinols of the present invention.  
  The hydroxyphenyl ketones used as starting products are known (see Belgian Patent Specifications Nos. 753,533 and 753,534) or are manufactured by methods known per se, for example from the corresponding benzoic acid or alkane carboxylic acid phenyl esters by the Fries reaction (compare Baltzly et al. Journal of the American Chemical Society 77, 2522 (1955), L. F. and M. Fieser, Lehrbuch der organischen Chemie 1954, page 728 or G. A. Olah, Friedel-Crafts and Related Reactions 1964, page 499). The reaction can take place in the molten state or in the presence of an organic solvent medium, e.g. nitrobenzene. On heating the corresponding phenyl ester together with aluminium chloride there results the monohydroxybenzophenone or monohydroxyphenylalkyl ketone.  
  Particularly surprising for the compounds according to the invention is the broad spectrum of anti-bacterial activity, which for most of the compounds extends both over the area of gram-positive and gram-negative bac teria. From an application point of view, the lack of smell and the colourlessness of the compounds of the invention is of particular value.  
  The present invention includes quite generally the use of the compounds according to the invention in pest combating. The use of the antimicrobial compounds is possible on a very wide basis, particularly for the protection of organic substrates against attack by destructive and pathogenic micro organisms (including phytopathogenic ones). The anti-microbial agents noted are also suitable both as a preserving agent and as a disinfectant for technical products of all types, for plant protection, in farming, in veterinary medicines and in cosmetic technology.  
  The monohydroxybenzhydrols according to the invention are thus used for treating or protecting organic materials, particularly textiles, by impregnating at least one of these compounds into the material to be treated or protected or by applying such to the surface of the materials.  
  Among non-textile technical products which can be preserved with the aid of compounds according to the invention, the following examples should be noted:  
  Glues, binding agents, coating agents, textile dressings and treating agents, printing and colouring pastes and similar preparations on the basis of organic and inorganic dyes or pigments, also those which contain in admixture casein or other organic compounds. Also wall and ceiling coatings, e.g. such as have an albumen containing colour binding agent, are protected by addition of a compound according to the invention from attack by pests. Use for wood protection is likewise possible.  
  In the cellulose and paper industry also, the compounds according to the invention can be used as conservation agents, inter alia for preventing the known slime formation generated by micro organism infestation in the apparatus and machinery used for papermaking.  
  Furthermore by combination of the monohydroxybenzyhydrols of the invention with surface active agents, particularly washing active agents it is possible to produce washing and cleaning agents with exceptional anti-bacterial or anti-mycotic action. The compounds according to the invention can, for example, be  
 blended into soaps or combined with soap-free washing agents or other surface active materials, particularly non-ionic and cationic washing agents, or they can be combined together with mixtures of soaps and soapfree washing materials, wherein in these combinations their anti-microbial effectiveness is retained to the fullest degree. By the use of aqueous preparations of such washing and cleaning agents containing monohydroxybenzhydrols according to the invention, textile materials, for example, can be treated anti-microbially during washing, since the active agent is substantive to the textile material.  
  Cleaning agents which contain the compounds of the above noted formulae can be used both in industrial and domestic use, also in foodstuff industries e.g. dairies, breweries and slaughter houses. The present compounds can also be used as a component of preparations which are used for cleaning or disinfection.  
  The action of the monohydroxybenzhydrols accord ing to the invention can also be used in conserving and disinfecting preparations for plastics materials. In the use of plasticisers it is advantageous to add the antimicrobial addition to the plastics material dissolved or dispersed in the plasticiser. It is advisable to take pains to obtain as even as possible a distribution in the plastics material. The plastics materials with anti-microbial properties can be used for useful articles of all types in which an effectiveness against varied germs, e.g. bacteria and fungi, is desired, thus for example in foot mats, bath curtainings, seats, steps in swimming baths, wall coverings, etc. By incorporation into suitable waxing and polishing compositions, suitable floor cleaning and furniture care materials with disinfectant action can be produced.  
  Furthermore the compounds according to the invention can be used for the conserving and disinfecting treatment of fibres and textiles, wherein they can be applied to both natural and synthetic fibers and there effect a permanent action against harmful (and pathogenic) micro organisms, for example fungi and bacteria. The addition of these compounds can take place therein before simultaneously with or after the treatment of these textiles with other materials e.g. printing or dyeing pastes, dressings, etc.  
  Textiles treated in this way also are protected against the generation of a sweaty smell as is generated by micro organisms.  
  Treatment can take place for example by impregnating or spraying with solutions or suspensions containing the above noted compounds as active agent. The active agent can vary according to the purpose of use between 0.1 and 50 grams active substance per litre, preferably 1 grams.  
  Generally textile materials of both synthetic or natural origin can be satisfactorily protected against attack by mould fungi or bacteria by a contnt of from 0.1 to 3% of active agent. The active agent noted can be added together with other textile treatment agents as dressing agents, permanent creasing treatments etc.  
 The ways of using the active agents of the present invention can correspond to the usual formulations for 5 pest control agents, for example, agents which contain the said active agent can optionally also contain additives such as solvents, dispersing agents, wetting agents, adhesives, light protection agents, optical brighteners etc., together with other pest control agents, such as fungicides and bactericides. Particularly, however, as well as the active agent according to the invention, the agent can contain a further solid or liquid thinning agent or a solid or liquid carrier. The invention extends to microbicidal agents which contain compounds of the general formula I.  
  The following examples will serve to illustrate the invention.  
 EXAMPLE 1 the compounds of formula 30 OH OH which was an oil which crystallised on standing; melting point l20128C.  
  The purified compound from recrystallisation from chloroform melted at 130-l3lc. The pure yield amounted to 7.3 g.  
  B. To 31 g aluminiumisopropylate in 150 ml isopropanol there was added a solution of 9.0 g Z-hydroxy- 5,3&#39;,4,trichlorobenzophenone in 25 ml isopropanol. The reaction mixture was then boiled under reflux for 20 hours. After the addition of 150 ml Z-n-hydrochloric acid at 25C, the product was extracted with ethyl acetate and the extract washed first with saturated potassium bicarbonate solution and then with water. From the extract which was dried over sodium sulphate there remained after the removal of the solvent 8.5 g of the compound 100 as an oil which crystallised on standing.  
  After recrystallisation from chloroform the compound was present in pure form and melted at 130l 31C.  
  In the same way as example 1 or according to one of the other methods given above the following compounds can be prepared which are shown in the follow ing table A:  
 TABLE A Com- R R, R R R R R, R R Melting point in poun No. C  
  OH H H Cl H H Cl Cl H 131 132 101 OH H H Cl H H Cl H H 102 104 102 OH H C1 H H H Cl H Cl 30 103 OH Cl H Cl H H C1 C1 H 155 157 104 OH H H Cl H H Cl H Cl 110-112 105 OH C1 H Cl H H Cl H H 93 94 106 OH Cl H Cl H H Cl H Cl 106 107 107 OH C1 H Cl Cl H Cl H C1 133 134 108 OH Cl H C1 Cl H Cl H H 176 178 109 OH H Cl H Cl H C1 Cl H 145 146 110 OH H Cl H H H C1 C1 H 106 107 111 OH C1 H Cl Cl H Cl Cl H 189 190 1 12 OH H H C1 Cl H Cl Cl H Oil 113 OH H H Br H H Cl C] H 134 135 114 OH Br H Br H H Cl Cl H 124 125 115 OH H C] H C1 Cl Cl H H 135 136 116 OH H C1 Cl H C1 C1 H H 119- 117 OH H H Br H C1 Cl H H 103 104 1 18 OH Br H Br H Cl Cl H H 278 279 119 OH H Cl H C1 C1 H Cl H 146 147 120 OH H Cl H H C1 H C1 H 135 136 121 OH Cl H Cl Cl Cl H Cl H 156 157 122 OH H Cl Cl H Cl H Cl H 182 183 123 OH H C1 H C1 C1 H H Cl 175 176 124 OH Cl H Cl C1 C1 H H C1 189 190 125 OH H Cl Cl H C1 H H Cl 156 157 126 OH H Cl Cl H H Cl H H 98- 99 127 OH H C1 H Cl CH H H H 115- 116 I28 OH H C1 H H CH H H H 131 132 129 OH Cl H Cl Cl CH H H H 153 154 130 OH H Cl H C1 C1 H H H 99 100 131 OH H Cl H H Cl H H H 1l4-115 132 OH H H Cl H Cl H H H 97- 98 133 OH Cl H Cl H C1 H H H 78 79 134 OH Cl H Cl C1 C1 H H H 123 124 135 OH H Cl Cl H Cl H H H 109 110 136 OH Cl H Cl H H H H H 94- 95 137 OH Cl H Cl C1 H H H H 168 169 138 OH Br H Br H H H H H 121-122 139 OH Cl H Cl Cl H CH H H 175 176 140 OH Cl H Cl Cl H Br H H 178 179 141 OH Br H Br H &#39;H Br H H 135 136 142 OH H H Br H H C1 H H 105 106 143 OH Br H Br H H C1 H H 116-117 144 H H OH C] H C1 C1 H H 144 145 145 H C1 OH Cl H H C1 H H 165 167 146 H Cl OH C1 H H C1 C1 H 175 176 147 H Cl OH Cl H H Br H H 159 160 148 H C1 OH H Cl H C1 C1 H 147 148 149 C1 H OH H H C1 C1 H H 159 160 150 H Cl OH H H H C1 C1 H 121 122 151 H Cl OH C1 H H H H H 144 -145 152 H C1 OH Cl H C1 C1 H H 162 163 153 H C1 OH CI H CH H H H 158 159 154 H Cl 0H CI H Cl H H H 139 140 H C1 OH H C1 C1 H H H 176 177 156 C1 H OH H Cl H C1 C1 H 197 198 EXAMPLE 2 OH 01 9 (209) CH -CH -CH -CH- fully. This was filtered off, washed with water, dried and recrystallised once from methylene chloridehexane for purification; melting point 130131C. The Pure yield amounts to 5.2 g.  
  In similar fashion the compounds given in the following table B can be prepared. The general formula for compounds of table B is:  
 EXAMPLE 3 TABLE C-Continued Determination of the Minimum Inhibiting C d Concentration (MIC) Against Bacteria and Moulds by Dmpou&#34; Mic ppm the Gradient Plates Test Nos. (1) (2)-ll- 152 25 154 30 Gradient test 1 is given by W. Szybalsk1 et al., Sc1- 155 30 ence 116, 26 (1952). $3? Gradient plate test 2 is that given by Nuesch and 203 20 Knuesel, Sideromycins, in the book by Gottlieb and 204 60 Shaw, Antibiotics, Mechanism of Action, volume l 1 (1967), Springer Verlag. 207 30 The compounds of formulae 1 and 2 were mixed as 583 3 suitable formulations (eg as solutions in dimethylsulf- 210 oxide) of given concentration with warm brain heart g3 infusion-agar (bacteria) or mycophil-agar (moulds). 215 The liquid mixtures were poured onto a solid wedge- 216 10 shaped base agar layer and likewise allowed to solidify. g The test organism was then applied in a line perpen- 219 1 dicular to the gradient with a pasteur pipette. After incubation for 24 hours at 37C (bacteria) or 72 hours at 20 222 i 30C (moulds) the length of the bacteria which had grown on the inoculation line was measured and ex- 225 pressed in parts per million of active agent. The results 226 0,2 are given in the following tables C to F.  
  TABLE C Minimu h&#39;b t D t t&#39; t Minimum inhibiting concentration against E gag 2 g Staphylococcus aureus (Bacteriostasis) Sc la col ac enos 3515 Compound MIC in ppm Com ound MIC in ppm 8 101 20 101 30 102 20 I02 3 I03 10 I03 2 I04 50 104 20 35 105 35 I05 3 106 40 I06 3 I 108 30 I07 05 109 I5 108 0.5 110 20 109 0,25 111 20 H0 3 H2 25 111 1 40 113 30 112 2 114 30 113 0,3 115 10 114 0,5 116 20 115 0,4 117 40 H6 2 H9 20 117 10 120 40 118 0,2 45 122 15 H9 0,4 126 I0 I20 4 I27 40 121 0,1 128 50 I22 3 I30 20 123 0,3 I31 70 124 0,3 133 60 125 4 50 I35 30 126 4 136 66 127 3 137 40 128 20 I38 50 I29 3 I40 30 130 3 141 20 I3] 30 I42 40 132 50 55 143 30 133 I0 149 50 134 3 I50 45 135 9 154 50 I36 30 I56 50 137 3 201 50 138 I0 203 40 139 3,5 60 205 40 140 2 206 35 141 2 207 40 142 30 208 30 I43 2 209 30 144 20 213 30 I45 50 215 40 I46 20 65 216 20 147 25 217 20 14s 6 21s 10 149 20 222 10 Minimum inhibiting concentration against TABLE E Aspergillus niger (Fungistasis) Compound MlC in ppm TABLE F Minimum inhibiting concentration agamst 45 Trichophyton mentagrophytes (Fungistasis) Compound MlC in ppm TABLE F-Continued Compound MIC in ppm EXAMPLE 4 A specimen of 140 g cotton-poplin was impregnated at 20C for 7 minutes in a bath of the following composition:  
 1000 ml water 2.7 ml cloth softening rinsing dye (containing 7% of a mixture of di-octadecyl and di-hexadecyldimethyl-ammonium chloride) 15 mg of the compound of formula (109) (added as a solution in 0.5 ml dimethylsulfoxide) The so treated cloth specimen was squeezed out after 100% dyebath take up and then dried at 45C.  
  For testing the action against bacteria, roundels of 20 mm diameter were cut from the impregnated cloth and laid on brain-heart infusion agar plates, which had been pre-infected with Staphylococcus aureus. The plates were then incubated for 24 hours at 37C.  
  Two observations were made, that of the zone of inhibition arising around the roundels (inhibition zone in mm) and the determinable growth above or below the cloth. The inhibition zone was only a trace quantity while the determinable growth was 0%.  
  Similar effects were obtained with further compounds of formula 1 or 2.  
  EXAMPLE 5 For the manufacture of an anti-microbial tablet of soap, 2.4 g of one of the compounds of Formula 1 or 2 were added to the following mixture:  
 120 g natural soap in flake form 0.12 g disodium salt of ethylenediaminetetracetic acid (dihydrate) 0.24 g titanium dioxide.  
  The soap shavings obtained by rolling were powdered with a high speed mixture and then pressed to soap tablet form.  
  Concentrated aqueous solutions of the anti-microbial soaps were mixed into warm brain heart infusion agar so that iii-corporation dilution rose with 2, 10, 20, 100 etc. parts per million active agent were produced. The warm mixtures were poured into petri dishes, allowed to solidify and then infected with Staphylococcus aureus.  
  After 24 hour incubation at 37C the minimum inhibiting concentration was determined. The results are shown in the following table. Similar results were obtained by the use of other compounds of formulae 1 and 2.  
 EXAMPLE 6 Specimens of 100 g cotton-cretonne were impregnated on the foulard with 1% solutions of compounds of formula 1 in isopropanol at C and then squeezed out with 100% bath take-up.  
  In the same way, samples of 100 g wool cheviot were treated.  
  The textiles which were dried at 30 to 40C contained 1% by weight of active agent taken on their own weight.  
  For testing the action against bacteria, roundels of 10 mm diameter cut from the impregnated cloth, dewatered and watered, were laid for 24 hours at 29C on brain heart infusion agar plates which had been previously infected with Staphylococcus aureus. The plates were then incubated for 18 hours at 37C.  
  Two factors were observed: first, the inhibition zone (in mm) arising round the roundels and second, the microscopically determinable growth (in under or on the cloth.  
  Results are expressed in the following table; similar results were obtained also with further compounds of formulae 1 and 2 Substantivity Tests With Calf-Hide Roudels Calf-hide roudels of 10 mm diameter were dipped for termined in Results are as follows:  
 Soap with Compound No. Inhibition zone in- Growth in Similar values were obtained using other compounds of formulae 1 and 2.  
 EXAMPLE 8 The following mixture was milled on the twin-roll mill at C for 20 minutes:  
 100.00 g polyvinylchloride 19.20 g di-( Z-ethyl-hexyLphthalate) 27.00 g di-(2-ethyl-hexyl-sebacate) 1.50 g Ba/Cd-laurate 0.25 g Stearic acid 7.80 g of a solution of 3.10 g of a compound of formula 1 in 4.70 g di-(2-ethyl-hexyl-phthalate) The roll separation was adjusted so that 1 mm thick sheets were formed which were then pressed for 20 minutes at l70C under a pressure of 1,400 kglcm For testing the action against bacteria, discs of 10 mm diameter were stamped from the rolled soft polyvinylchloride sheet and laid on brain-heart infusion agar plates which had previously been infected with Staphyloccocus aureus. The plates were then incubated for 24 hours at 37C.  
  The zone of inhibition arising round the discs was measured in mm and the microscopically determinable growth above and below the soft polyvinylchloride was measured in The results are given in the following table: Similar action is observed with other compounds of formulae 1 and 2.  
 wherein X is halogen; X X and X are each hydrogen or halogen; Y is hydrogen, halogen or methyl; and Y and Y are each hydrogen or halogen; and wherein at according to claim 1. least two of X X X Y, Y; and Y are not hydrogen. 6. The compound 2. A compound according to claim 1 of formula wherein n is 2, 3, or 4, m is 1, 2 or 3 and n +m is 3,  
  The Compound according to claim 2.  
  01-3 01 7. The compound CI;  
 &#39; c1 CH- on C1 OH I Cl 01 c1 Cl CH according to claim 2. 4. The compound OH C1 C1 on I I I acc ordlng to claim 2. Cl 0 CH 7 Cl 8. The compound D I C1 C1 OH Cl according to claim 2. 0H  
 5. The compound I ,u Cl CH Ol-l Cl C1 I cl C H Cd 40 according to claim 2. C1 C1 =1: