JPH046190B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to compounds that are effective as anti-caking agents. The invention also encompasses the manufacture thereof. Such compounds include those that are particularly effective as rodenticides, and the present invention also encompasses rodenticide compositions (baits) in which the anticaking compounds of the present invention provide the rodenticide component or major rodenticide component. There is. Anticoagulants interfere with blood clotting, and their ability to do so depends on their chemical properties.
Certain 4-hydroxycoumarin compounds, represented by the general formula below, are known to have anti-caking properties and have been successfully used as the main ingredient in rodenticides. Its activity as a rodenticide is dependent on its anticaking properties. In the above formula, R is -
The compound CHPh- _CH2 -CO- _CH3 is the well-known rodenticide warfarin. With the aim of providing additional 4-hydroxycoumarin compounds as a "second generation" alternative to warfarin,
U.S. Pat. No. 3,957,824 discloses certain rodenticide 4-hydroxycoumarin compounds in which R in the above formula means: In this formula R ¹ and R ² are the same or different and are hydrogen or a halogen atom, preferably chlorine or bromine, or an alkyl or alkoxy group, preferably having up to 6 carbon atoms, and R ³ are the same or different and contain a halogen atom, preferably at least 2, more preferably 5 to 12 carbon atoms, a straight-chain or branched alkyl or alkoxy group, cycloalkyl group, aralkyl group , preferably α-aralkyl, phenyl or phenoxy, or halogeno, preferably parahalogeno, a substituted derivative thereof, and m is 1 or 2. US Pat. No. 4,035,505 discloses a rodenticide composition (bait) comprising a carrier in combination with the compound just defined above as an active ingredient. Such 4-hydroxycoumarins, especially 4-hydroxycoumarins containing diphenyl and p-bromo-diphenyl structures, known as Difenacoum and Brodifacoum, respectively, It has been of commercial importance for some time as an active ingredient in rodenticide compositions effective against rodenticides, ie, rodenticides. The most effective anticaking agent rodenticide in the prior art is brodifuracium, which has a molecular structure in the general formula above in which R ₃ includes a para-bromo-phenyl group. Its structure draws attention to the fact that a halogen atom is originally present at the free end of the tetralin ring, and the halogen atom itself is linked to the benzene ring, which is naturally attached to the tetralin ring, via a phenylene group. . In other words, a biphenyl structure with a halogen at the end is observed. Brodifacum is the most important commercial product for rodent control because of its effectiveness against warfarin-resistant rodents (MR. Hadler and R.S. Shadbolt, Nature,
253 (No. 5489), p. 275, 1975). The development of 4-hydroxycoumarin compounds as anticoagulants has led to the realization that in the above general formula R represents a limited phenyl structure as in the first warfarin or a limited biphenyl structure as in the later diphenacauum and brodiphacoum type compounds. Among the permissible properties of the R group of 4-hydroxycoumarin compounds hitherto found to have anticoagulant properties, the above limitations It is clear from the prior art that 4-hydroxycoumarin compounds are accepted in the art as limiting two areas - and only two areas - in which anti-caking agent 4-hydroxycoumarin compounds can be found.
It is therefore clear that those skilled in the art had no reason to think that research outside those areas would be worthwhile, and the applicant has no interest in engaging in such research or I am not aware of any prior publications that suggest it is challenging. The basic research of the applicant's researchers regarding the relationship between structure and anticoagulant activity, which is the basis of the present invention, surprisingly revealed other active compounds not disclosed in the prior art. and
A presently preferred example thereof is that, instead of the biphenyl structure of R ³ , two phenylene groups are linked to each other in a para-paradash fashion by a linear group as fully defined below. The structure exists, and it imparts polarizable properties to the R ³ substituent, but
The presence of an electron-withdrawing terminal atom or group that causes the compound to act in the capacity of an anti-caking agent due to volume limitations, not only with respect to that atom or group, but also with respect to the entire tetralin ring substituent. It is a compound that Similar molecular properties that Applicant's researchers have discovered to be important in achieving anticoagulant activity can be achieved in a different way than by providing two linked phenylene groups. I can,
It has therefore also been found that the following broad definition of compounds of the invention encompasses compounds in which the tetralin ring substituent does not necessarily contain two linked phenylene groups. The unexpected discovery of this additional 4-hydroxycoumarin compound is surprising and constitutes a valuable addition to the range of 4-hydroxycoumarin compounds universally available in rodenticide technology. Although, with the hindsight of this invention, it is believed that some of these compounds may have some structural similarity to the compounds of U.S. Pat. No. 3,957,824, there is There is nothing to guide the expert to the compounds of the invention. According to the present invention, there is provided a compound having anti-caking properties in relation to mice and having the following general molecular formula: In this formula, Z represents a halogen atom, preferably a chlorine atom, n is 0, 1 or 2,
And R ⁴ is (Here, X is a halogen atom, preferably fluorine,
represents a chlorine or bromine atom or a group CN or _CF3 , n' is 0 or 1, Y is a chlorine atom or a fluorine atom, and D is oxygen or a group -
(CH ₂ )m-, -0-CH ₂ - or -CH=CH-, where m is in the range 2 to 4, and n'' is 0 or 1, provided that when n'' is 0, X is not a halogen atom, n' is 0, and D is -CH=CH
- and n'' is 1 and n' is 0, X may further be a hydrogen atom, and when D is oxygen and n'' is 1, X is not a halogen atom and n ’ is 0) and (where X is as defined above) and (wherein X is as defined above but is not a halogen atom). It is noted that when D in (a) of the above formula is -( _CH2 )m-, such a group represents a special option of a chain of 2 to 4, preferably 3, methylene groups. . Preferably, the compounds of the invention are such that the substituent R comprises a 3-substituted tetralin ring, the R ⁴ moiety (see general formula) containing vitamin K and vitamin K2,3-
All 4 of the general formula () that are part of a compound that inhibits epoxide reductase
-Hydroxycoumarin compounds. Recently, it has been reported that brodiphacaum, diphenacaum and warfarin have this suppressive ability.
(Fasco et al., J. Biol. Chem. Vol. 257, (No. 19), No.
11210 pages, 1982; Park et al., Biol.Pharmac.
31, (No. 22), p. 3635, 1982 ⁾ , and without wishing to be unduly limited by theoretical considerations, the applicant has We believe that the measured stretch of the R molecule is advantageously such that it does not substantially exceed the stretch of the phytyl chain of vitamin K, which naturally inhibits the blood coagulation process. As mentioned above, the compound of the present invention has an inhibitory effect, that is, a structure that has aromaticity, that is, a structure that contains a phenylene ring structure or a heterocyclic structure corresponding thereto, and that can impart polarity to the substituent R ⁴ . ^Certain molecular properties are required to effectively provide the substituent R on the tetralin ring, including a terminal atom or group that acts as a mild electron-withdrawing group to provide the Limiting the size of R ⁴ (ie, a rotational capacity that does not substantially exceed that of the phenyl group) is also important in ensuring that the compound does not interfere with the blood clotting process. The necessary binding ability is preferably due to the provision of a polarizable structure in the group R ⁴ (rather than an already polarized one) containing an electron-withdrawing atom or group in the para position of the terminal phenylene group. The necessary molecular elongation of R is thus achieved by attaching its polarizable structure to the 3-position of the tetralin ring via a linear group and a phenylene group, the latter directly attached to the tetralin ring. and the necessary dimensional constraints are met by meta and ortho substituents in the R ⁴ group, except that a small halogen atom (fluorine or chlorine) is allowed in the meta position of the terminal phenylene group. This is achieved by avoiding the existence of Preferred compounds according to the invention are therefore preferred in the general formula in which D is _-OCH2- or -( _CH2 )m-
and m is 2 to 4. In the general formula, n is 0 and R ⁴ is or or Compounds that are cis-type, trans-type, or cis/trans mixed type are also preferred. All these structures have in common the ability to provide lipophilic groups within the molecule of the 4-hydroxycoumarin compound that can exert a restraining effect on the blood coagulation process. In addition to the discovery that although the elongation of the R ⁴ group can vary, the elongation of R measured through the 3-position of the tetralin ring naturally results in an elongation that exerts the necessary restraining force. The discovery of two important factors by the authors, namely that there is a "mild" terminal electron-withdrawing group and that it limits the size of the ^R4 substituent present, cannot be predicted from a review of the prior art. An unexpected area of anti-caking agent 4-hydroxycoumarin compounds has been developed. Although the prior patent specifications previously acknowledged herein disclose prior art relating to 4-hydroxycoumarin compound anticaking agents having the property of embodying a tetralin ring within its molecular structure. It is clear from the applicant's literature search that the delay in discovering additional and, in some cases, more attractive (as rodenticides) anticaking agents of the invention is due to Brodiphacaum. This is surprising in view of the extent to which the prior art compounds exemplified above have become known and utilized in the art. The general definition of an anticaking agent in U.S. Pat. It is noted that although the possibility exists, no examples are given (the closest examples are compounds in which a non-halogenated terminal benzyl group is present). Previous researchers did not produce such compounds, but instead used halo-terminated structures, where the extension of the R substituent measured through the 3-position of the tetralin ring gives the compound a length that inhibits the blood clotting process. It seems that they did not clearly recognize that it was necessary to select an alkyl group in the terminal α-aralkyl group of the substituted compound. According to the research conducted by the present inventors, it was pointed out that among the types of compounds of the present invention, there are some differences between the activities of individual compounds. Some appear to be less active than the most active compound of the prior art, namely brodiphacum. Of course, such compounds with low activity are also useful, but the applicant is of course particularly interested in compounds that have an activity similar to or higher than that of Dirodifacium, and the present invention has such properties. A large number of compounds have been prepared and tested. in general,
It is believed that there is a correlation between specific structure and activity, and among the important factors in this regard is the R ⁴ substituent at the 3-position of the tetralin ring, which includes (a) tetralin There is an aromatic ring connected to the ring and a terminal phenylene ring having an electron-withdrawing group at the para position, and (b) the aromatic ring is connected to the tetralin ring at the para-position. Electron-withdrawing in which there are linear groups attached in a para/para-dash relationship, (c) there are no side chains and ortho or meta ring substituents, and (d) chlorine, bromine, CN or _CF3 . atoms or groups are present, and (e) the entire basic structure of tetralin measured through the 3-position (including the 2- and 3-position carbon atoms) of the tetralin ring and including its R ⁴ substituent. There is a stretch, and that stretch exists within a maximum range beyond which activity declines. (As pointed out above, the maximum level of the distance that the phytyl side chain of the vitamin K molecule extends provides a practical criterion in this regard, and from the point of view of activity:
Although it is obvious that it is desirable to synthesize compounds of the invention with a total elongation up to, preferably as close to, as possible as possible, greater elongations are not excluded and it is possible to produce such compounds. Useful ranges can be readily determined by conventional toxicity tests on rodent species. ) The present invention also encompasses rodenticide compositions (bait) comprising as an active ingredient a carrier in combination with a rodenticide-effective amount of a compound of the present invention; It also encompasses a method of eliminating rodents in an area or preventing or reducing losses or deterioration due to rodent attacks in an area by supplying bait containing a substance to an area. . Such compositions can be formulated according to procedures well known per se in the art and by using a suitable bait base which constitutes an edible carrier. A convenient base is medium grade stabilized oatmeal, with which the proportions of the active ingredients are mixed depending on the specific activity of the compound chosen, and which proportions can be easily determined experimentally. It will be done. The compounds of the invention can be prepared by various synthetic routes using reaction steps known per se and by using reagents that are commercially available or that can themselves be easily synthesized. can. The detailed examples presented below provide an illustration of suitable synthetic chemistry. Compounds of particular interest as anticoagulant rodenticides are those represented by the following general formula. All compounds are cis/trans unless otherwise indicated. In this formula, R ⁴ is as shown in the table below.

【table】

【table】

TABLE The following description is a detailed example of the synthetic chemistry used in preparing the compounds of the present invention. One route, shown below as Route A, starts with a suitable aldehyde. The resulting tetralone can then be reduced with NaBH ₄ to the corresponding alcohol, which can be accomplished in ethanol solution at room temperature. The compounds of the present invention contain alcohols with 4-
It can be produced from alcohol by combining with hydroxycoumarin, which
This can be achieved by heating at temperatures as high as 170°C (references on this can be found in RS
Shadbolt, D. Woodward, PJ Birchwood, J.
CS (Perkins), 1190 pages, 1976; JSGillespie,
Written by SPAcharga, DA Shamblee, REDavis,
Tetrahedron, Volume 31, Page 3, 1975; R.
Sarges, J.Org.Chem., Volume 40 (No. 9), No.
1216 pages, 1975). Although benzaldehyde, which is not commercially available, has to be synthesized when using Route A, this does not pose any special problems. For example, the Sommelet reaction, using hexamethylenetetramine if appropriate, can be utilized and to prepare aldehyde precursors of compounds of the invention containing a furanyl ring, e.g. 1-bromo-4 obtained by treating aniline with NaNO ₂ /HCl and then reacting with furan
- Vilsmeir formylation of furanylbenzene (phosphonyl chloride/dimethylformamide) can be used. Another route (route B below) that takes into account the sensitivity of the -CN group is cited below. The starting compounds can be prepared by the Brodiphacaum synthetic chemistry of US Pat. No. 3,957,824. The product compound is prepared by combining a cyano-olefin with 4-hydroxycoumarin, which is conveniently carried out by the method described in GB 1,518,858. The starting alcohol can be prepared by route A. Alternatively, in a modified route B, the starting material is the corresponding Kent, which is reacted with cuprous cyanide in dimethylformamide (DMF), e.g. is produced, which is then reduced to alcohol,
This alcohol is combined with 4-hydroxycoumarin to form the desired product compound (as in Route C). The above synthesis is exemplified by the preparation of the following compounds. Compounds 1 and 2 Preparation was accomplished by Route B and chromatographic resolution to cis and trans isomers; the modified Route B described above was also utilized for the preparation of Compound 1. Compound 3 Prepared by Route A. Compound 7 This compound was prepared from p-bromobenzaldehyde by combining routes A and B. Compound 8 Compound 8 was prepared by route A, starting first with p-bromoaniline, from which the following aldehydes required for synthetic route A were prepared. Compound 10 This compound is prepared by preparing the following tetralone from anisaldehyde using Route A, This is then demethylated to hydroxytetralone by heating under reflux with HBr, followed by

It was prepared by reaction with [Formula] to produce the following derivative. The preparation was then followed by reduction and condensation steps (with 4-hydroxycoumarin) of Route A as exemplified in Route C. Compound 11 This compound is also prepared from anisaldehyde like compound 10, and its hydroxytetralone is

The following derivatives were produced by reacting with [Formula]. Thereafter, the reduction and condensation steps of Route A were continued to carry out the preparation. Compounds 12 to 16 are prepared by generating the tetralol intermediate by Route A and then alkylating it with the appropriate benzyl halide by stirring the potassium salt with the benzyl halide in dimethylformamide at room temperature. Obtained through the modification method of A. The desired alkylated product was easily liberated by crystallizing the crude product. compound 12
In this case, 4-
The para-cyano group was introduced by using bromobenzyl bromide and then heating the resulting intermediate with cuprous cyanide in dimethylformamide. The last ketone was converted to the required 4-hydroxycoumarin compound by reduction as in Route A and condensation with 4-hydroxycoumarin (as illustrated in Route C). Compounds 17-19 The key intermediate ketones required for these compounds were obtained using a chemistry similar to that used for the preparation of brodiphacum as described in US Pat. No. 3,957,824. Compound 20 This was prepared by Route A utilizing the Sommelet route for the starting aldehyde. Compounds 21 and 22 These were obtained by Route A using Witzig and Sommelet reactions to prepare the starting aldehydes. In compound 22

It is noteworthy that the [Formula] moiety is thought to supply an electron-withdrawing group at the para position. Compounds 23 to 25 The starting hydrocarbons for the preparation of compound 23 by the Brodiphacaum method were obtained by reaction of acid chlorides with appropriate cadmium compounds as described below (KMPatel et al., Tett. Letters, Vol. 45 volumes,
No. 4015, 1976). Compounds 24 and 25 were prepared by Route A, and the starting aldehyde was prepared by heating the lithium salt of p-bromo-p'-trifluoromethylbiphenyl in dimethylformamide. Biological Testing Compounds of the present invention and other substituted 4-hydroxycoumarin compounds not falling within the scope of the present invention, including brodifuracium, diphenacoum and warfarin, were tested as set forth in the following examples. The prothrombin time ED ₅₀ value is the most reliable method to measure anticoagulant activity. The LD ₅₀ value is important for the effectiveness of a compound as a rodenticide. The results obtained indicate that the new field of compounds discovered by the applicant's invention represents an important class of anticoagulants, the existence of which was not previously predicted, and which is more active than brodiphacum. It includes compounds with a high level of activity and compounds that are much more active than difenacaum. The comparative data provided by the tested compounds outside the scope of the present invention demonstrate that it characterizes the previously mentioned features that define the scope of the 4-hydroxycoumarin compounds of the present invention. Suitable as a basis for providing selection. Particular mention may be made of the following compounds.

【table】

Table: Compound 14 gave unexpected results in the test, as it produced much lower activity than the similarly structured diphenacaum, which also lacks the para electron-withdrawing group. This is likely a biological effect, but as Compound 14 is not a compound within the scope of the present invention, further investigation in that regard would only be of academic interest. (1) a terminal para substituent in the R ⁴ substituent in the 3-position of the tetralin ring which is a "mild" electron-withdrawing atom or group, e.g. -CF ₃ , (2) linked in the para-paradash position; and (3) an R ⁴ substituent containing two phenylene groups, which are advantageously linked via a linear aliphatic chain, and (3) the capacity of the R ⁴ substituent being an ortho or meta substituent and/or an aliphatic The advantage is clearly pointed out that there is no "bulk" in the R ⁴ substituent which occurs when increased by non-linear arrangement of chains. (It is currently believed that only relatively small volume increases caused by, for example, small side chain substituents, such as methyl groups or small terminal meta substituents as in compound 16, can be considered permissible. ). EXAMPLES The table below contains test data on compounds of the invention obtained by the following method and comparative data similarly obtained. Preliminary testing was carried out to ensure that potential rodenticides were on the order of anticoagulant efficacy. The method used was published in the American Journal of
Medical Science, Volume 190, Pages 501-511,
“Study of
Coagulation Defect in Haemophilia and in
It involves the measurement of prothrombin time (a measure of blood coagulability) based on the method described in the paper entitled ``Jaundice''. The compounds were dissolved in a 1:9 volume/volume mixture of triethanolamine and 200 molecular weight polyethylene glycol and serially diluted to give the appropriate dosage in 1 ml per 1 kg of animal weight. This dosage was injected into the test animals via the intraperitoneal route. Three days after injection, test animals (200-250 g Wistar male rats) were kept under "Halothane" anesthesia while blood was removed by cardiac puncture. . Three mice were used in each test for a given compound, and three prothrombin time measurements were made for each blood sample. Prothrombin time was measured using a modified one-step method of Quick. The percentage extension time of each prothrombin time was determined by assigning the 0% extension time to an arbitrary prothrombin resting time of 12 seconds and the 100% extension time to an arbitrary elevated prothrombin time of 212 seconds. . Logarithm of the result −
The plot was plotted on established graph paper, the line of best fit was drawn, and the prothrombin time ED ₅₀ was read from the graph. Half-lethal dose LD ₅₀ data were also obtained for at least some of the compounds and are included in the table. of male Wistar rats by the conventional method of giving rats various levels of oral dosage and applying regression analysis to the results to obtain a dosage level that is 50% lethal.
LD ₅₀ values were obtained.

It will be seen that among the compounds of the prior art, only brodiphacaum appears to have particularly significant activity, with diphenacaum having only about 36% of its activity. In the hindsight of the inventor's discovery, the basic

It is concluded that this group is of particular value when it is present as the R ⁴ substituent in the 3-position of the tetralin ring. This is true, of course, as previously pointed out, the art regarding anti-caking agents of the Brodiphacaum type (US Pat. No. 3,957,824) does not indicate this, and the compounds of the present invention have anti-caking properties as well. There is no hint of the possibility that this is supposed to be the case, so it is nothing more than hindsight speculation. In fact, the poor results obtained with compounds with apparent similarity to those of U.S. Pat. According to U.S. Pat. No. 3,957,824, the previously published limited area provides some insight into why the active compound was generated. Even if we assume that the average reader of the issue would think that other active compounds could exist despite the apparently specific nature of the previously patented areas, the prior art does not tell us which compounds are active and which ones. It is impossible to predict whether or not it will become active. However, the present invention provides not only a more novel range of active 4-hydroxycoumarin compounds, but also compounds with higher activity than brodiphacum in that range, such as the compounds 11, 18, 20 mentioned above.
and 23, each of which includes
Not only are there two phenylene groups in the R ⁴ substituent, but they are connected to each other by oxygen atoms or methylene groups or chains thereof and are kept at a constant spacing. EXAMPLE Appropriate amounts of compounds 1 and 3 were dissolved in acetone, serially diluted and slurried over rolled oats to give 5.0, 2.0, 0.5 and 0.2 ppm for compound 1 and 20.0 for compound 3; 10.0,
Final baits were prepared at concentrations of 5.0 and 2.0 ppm. Each food is used as non-selective food for 5 days.
It was given to five male Wistar rats in separate cages. The mice were observed for an additional 21 days and the number of deaths recorded.

【table】

Table: Example Appropriate amounts of compounds 1, 2 and 3 were dissolved in acetone and slurried over rolled oats, 20 ppm for compounds 1 and 2, and 20 ppm for compound 3.
The final bait was prepared with a concentration of 50 ppm. Each food is used as non-choice food for 24 hours.
A group of five homozygous-resistant Welsh female mice in separate cages was fed, and a male and female mouse (Cambridge Cream), also in separate cages, was fed a
Cream) was given to a group of resistant species). The mice were observed for an additional 21 days and the number of deaths recorded.

[Table] The following description provides a more detailed explanation of the preparation of the compounds mentioned herein, and includes compounds 1-3,
Analysis and melting points for 7, 8, 10-13 and 15-25 are shown in the table at the end of this description. Route A Compound 20 1 A mixture of 4-(p-trifluoromethylphenoxy)benzaldehyde (30 g) and sec-butyloxycarbonylmethylenetriphenylphosphorane (50 g) dissolved in dichloromethane was allowed to stand at room temperature for 1 hour. After evaporation of the solvent, the white solid was triturated with petroleum ether to form a solution which was evaporated to give sec-butyl 4
-(p-trifluoromethylphenoxy)cinnamate (40g), boiling point 15°C/. I got 007mm. Calculated value of C ₂₀ H ₁₉ O ₃ F ₃ : C65.9; H5.2; F15.6 Measured value: C66.1; H5.5 2 Secondary butyl 4-(p-trifluoromethylphenoxy) A solution of cinnamate (35 g) in diethyl ether (200 ml) is added to a stirred solution of benzylmagnesium chloride (prepared from 30 g of benzyl chloride in 500 ml of diethyl ether) containing 100 mg of cuprous chloride.
It was added in small portions over a period of 0.5 to 9 hours. A saturated solution of ammonium chloride was added, the ethereal extract was washed with water, dried ( _MgSO4 ) and evaporated to yield sec-butyl 3-(4(p-trifluoromethylphenoxy)phenyl)- 4-phenylbutyrate (25g), boiling point 180℃/. I got 007mm. Calculated value for C ₂₇ H ₂₇ O ₃ F ₃ : C71.0; H5.9; F12.5 Measured value: C70.9; H6.0 3 Secondary butyl 3-(4-(p-
trifluoromethylphenoxy)phenyl)-
A mixture of 4-phenylbutyrate (25g) and aqueous potassium hydroxide (21g) was refluxed for 6 hours. After evaporating the solution to low volume, water was added and the solution was extracted with ether.
The ether extract was discarded and the aqueous solution was acidified.
Then, by extraction with ether, 3-(4
(p-trifluoromethylphenoxy)phenyl)-4-phenylbutyric acid (23g), mp 74-75°
was formed in the form of a white solid. Calculated value of C ₂₃ H ₁₉ O ₃ F ₃ : C69.0; H4.7; F14.2 Measured value: C68.6; H4.7 4 3-(4-(p-trifluoromethylphenoxy) phenyl )-4-Phenylbutyric acid (23 g) was dissolved with thionyl chloride (46 ml) in benzene.
Refluxed for an hour. The solution was then evaporated to dryness and the residue was dissolved in benzene (23ml).
A solution of stannic chloride (23g) in benzene (46ml) was added at 0°C with stirring. The solution was stirred at 0°C for 30 minutes. Then ice, water,
Diethyl ether and dilute hydrochloric acid were added sequentially.
The ether extract was further washed with aqueous potassium hydroxide and evaporated to yield 3-(4-(p-trifluoromethylphenoxy)phenyl)tetralone, mp 136-137°C (ethanol). Calculated value of C ₂₃ H ₁₇ O ₂ F ₃ : C72.2; H4.4; F14.9 Measured value: C71.6; H4.5 Root B 1 3-(4'-bromo-4-biphenyl)tetralin- 1-ol (20g) was refluxed with cuprous cyanide (5.45g) in dimethylformamide (7ml) for 4 hours. After cooling, concentrate hydrochloric acid (5 ml)
Add a ferric chloride aqueous solution (21 g of ferric chloride in 30 ml of water) containing
heated to. The cooled mixture was extracted with dichloromethane to yield a solid (18 g), which was purified by chromatography on silica gel in dichloromethane. Part of it (7.1g) is 3
-(4'-cyano-4-(biphenyl)-3,4-
Identified as dihydronaphthalene, melting point 137-138°C. Calculated value of C ₂₃ H ₁₇ N: C89.9; H5.6; N4.6 Measured value: C90.4; H5.6; N4.6 2 3-(4'-bromo-4-biphenyl)tetralin-1 -one (13 g was similarly heated with cuprous cyanide to give 3-(4'-cyano-4-biphenyl)-tetralin-1-one (9.3 g), melting point
Obtained 197°C. Calculated value of C ₂₃ H ₁₇ ON: C85.4; H5.3; N4.3 Measured value: C84.4; H5.1; N4.5 Then this is
It was converted to a mixture of compounds (1) and (2) through reduction with NaBH ₄ and condensation with 4-hydroxycoumarin. Root C 1 3-(4'-trifluoromethyl-4-biphenyl)tetralin-1-one, melting point 132°C (methanol), calculated for C ₂₃ H ₁₇ OF ₃ : C75.4; H4.7; F15. 6 Measured value: C75.4; H4.8 (17g) was dissolved in ethanol (350ml).
To this solution was added sodium tetrahydroborate (2.1 g) little by little, and the mixture was stirred for 30 min.
Stirred at ℃ for 1.5 hours. The volume of the solution was then reduced by evaporation under reduced pressure, water was added and the mixture was extracted with diethyl ether. Evaporation of the extract produced a white solid, which was crystallized from acetonitrile to give 3
-(4'-trifluoromethyl-4-biphenyl)
Tetralin-1-ol (10g), melting point 171~
Obtained 172°C. Calculated value for C ₂₃ H ₁₉ OF ₃ : C75.0; H5.2; F15.5 Measured value: C74.3; H5.2 2 Phosphorous tribromide (3.69
g) at 0 to 5°C to 3-(4'-trifluoromethyl-4-biphenyl)tetralin-1-
It was added portionwise to a solution of ol (9 g) in dichloromethane (200 ml) and the mixture was stirred at room temperature for 2 hours. The dichloromethane solution separated by adding water was washed with water and dried over anhydrous magnesium sulfate. Evaporation produced an oil which was refluxed with 4-hydroxycoumarin (8.1 g) in glacial acetic acid (30 ml) for 3 hours. Water was added to the cooled mixture, which was then extracted with dichloromethane. Evaporation of the dichloromethane extract produced a solid, which was separated by chromatography on a silica gel column. Elution with dichloromethane yielded 3[3-(4'-trifluoromethyl-4-biphenyl)-1,2,
A fraction containing an isomer of 3,4-tetrahydro-1-naphthyl]-4-hydroxycoumarin was obtained. The first eluting isomer (compound 24 trans) was approximately at the 1,3 position of tetrahydronaphthyl (0.89) and had a melting point of 207.5°C. Calculated _{for C23H23O3F3} : C75.0; H4.5; F11.1 Measured: _C74.6 ; H4.6 Compound ₂₅ . The next elution of the isomer mixture (4.7 g) resulted in the elution of the second isomer (cis), 0.69 g, cis mp 212°C. Calculated value: C75.0; H4.5; F11.1 Measured value: C73.8; H4.8 A mixture of isomers is also obtained when tetralin-1-ol is heated with an equimolar amount of 4-hydroxycoumarin. It will be done. These methods are based on RShadbolt
J. by DR Woodward and PJ Birchwood.
It is described in detail in CSPerkin, page 1190, 1976. Compound 8 1 Parabromoaniline (500g) diluted hydrochloric acid (water)
A sodium nitrite solution (200 g of sodium nitrite dissolved in 290 ml of water) was added to the solution (727 ml of concentrated hydrochloric acid diluted with 3150 ml of water) at 5°C.
The rate of addition was controlled such that the reaction temperature was kept below 10°C. After the addition was complete the mixture was stirred at 3° C. for 1 hour. A solution of zinc chloride (396 g of zinc chloride dissolved in 1000 ml of water) was then added at room temperature with stirring. After stirring for an additional 10 minutes, the solid precipitate was separated and dried in a vacuum oven. Diazonium zinc chloride salt (688 g) was used without further characterization. 2 Stirred furan (600ml) of the salt from 1 above
Add powdered sodium hydroxide (49 g) to the suspension.
and sodium acetate (40 g) at 25°C.
Added over 0.3 hours. Stir the mixture for 24 hours, then dilute it with water (200 ml) and
The organic layer was separated. The aqueous solution was also extracted with diethyl ether and mixed with the furan solution. The extract was washed with water and dried over anhydrous magnesium sulfate.
Evaporation of the extract produced a dark oil, which was separated by chromatography on silica gel with dichloromethane. The fraction (32 g) was identified as 2(4-bromphenyl)furan by nuclear magnetic resonance. 3 (Vilsmeyer method) Chlorobenzene (100
Phosphorus oxychloride POCl ₃ (12.5 g) and dimethylformamide (7 ml) were added to 2(4-bromphenyl)furan (20.4 g) mixed with 2(4-bromphenyl)furan (20.4 g) and the mixture was stirred at 10° C. for 1 hour. Further POCl ₃ (1.5 g) and DMF (0.7 g) were then added and the mixture was stirred for a further 1 hour at room temperature. The mixture was poured onto ice, neutralized with sodium carbonate and the precipitated solid was crystallized from chloroform (119ml). When this solid was separated by chromatography on silica gel with chloroform, 2
(4-bromphenyl)furfural (11g),
A melting point of 153.5°C was obtained. Calculated value for C ₂₃ H ₇ O ₂ Br: C52.6; H2.3; Br31.8 Measured value: C52.9; H2.5; Br31.3 Compound 10 3(4) dissolved in glacial acetic acid (200 ml) -methoxyphenyl)tetralin-1-one, melting point 194-195
C. (35 g) was refluxed for 4 hours with 48% HBr ( ₁₅₀ ml) _{for C17H16O2} calculated: C80.9; H6.3 found: C80.9; H6.4.
After cooling, water was added, and the precipitate was separated and washed with ethanol to obtain 3(4-hydroxyphenyl)tetralin-1-one (28 g), melting point 194-195°C. Calculated for C ₁₆ H ₁₄ O ₂ : C80.6; H5.8 Measured: C80.6; H6.1 Compounds 12-16 3(4-hydroxyphenyl)tetralin-1-one ( 7g) and potassium tert-butoxide (3.3g) were mixed and the solution was evaporated to dryness under reduced pressure at 70°C. The solid was dissolved in dimethylformamide and 4-fluorobenzyl chloride (4g) was added. The mixture was stirred at room temperature overnight, then diluted with water,
Extracted with dichloromethane. Evaporation of the extract produced a solid which was crystallized from ethanol to give 3(p-fluorobenzyloxyphenyl)tetralin-1-one (2.3 g), mp 155-156°C. Calculated _{for C23H19O2F} : C79.8; H5.5; F5.5 Measured: C79.4 _; H5.7 Compounds 17 and 18 The starting compounds are known compounds and the conversion to tetralone (as described in the above-cited US patent) is carried out by Brodifa Kaum Chemistry, and further detailed description of its laboratory preparation by the inventors is not considered necessary. Compound 23 1 Phenylpropionyl chloride (33.7 g) was added to a mixture of 4-chlorophenylmagnesium bromide (derived from 38 g of 4-chlorobromobenzene) and cadmium chloride (37 g) in stirred benzene at 0°C. I added it little by little. After the mixture was stirred at room temperature for 6 hours, aqueous ammonium chloride solution was added. Extraction with ether gave p-chlorophenyl phenylethyl ketone (25 g), mp 78-79°C. Calculated value of C ₁₅ H ₁₃ OCl: C73.6; H5.3; Cl14.5 Measured value: C73.2; H5.1: Cl15.5 2 Digol (diethylene glycol)
p-chlorophenyl phenylethyl ketone (25 g) was refluxed with hydrazine hydrate (13 g) and potassium hydroxide (18 g) for 1 hour in a flask. The mixture was then distilled until the solution temperature in the still reached 175°C. The mixture was then refluxed for 3 hours, cooled, poured into water and extracted with petroleum ether (boiling point 40-60°C). 1-(4-Chlorphenyl) by evaporation of the extract.
-3-phenylpropane, boiling point 110℃/10 ^-3 mm
was gotten. Calculated for C ₁₅ H ₁₅ Cl: C78.1; H6.5 Measured: C78.3; H6.7 Compounds 24 and 25 4-bromo-4'-trifluoromethylbiphenyl (40
g), a hexane solution of N-butyllithium (95
ml, 1.55 mol) was added in portions at -70°C under nitrogen. The mixture was stirred for an additional 10 minutes after the addition and then dissolved in dry dimethylformamide (19.4
A solution of g) in dry tetrahydrofuran (100 ml) was added little by little. The mixture was then warmed to room temperature in the absence of coolant.
After stirring for 1.5 hours, water was added and the mixture was extracted with ether. After washing with water and evaporating the dried extract, p-(4-trifluoromethylphenyl) is produced.
Benzaldehyde (34.5 g), melting point 70°C, was obtained. Calculated value of C ₁₁ H ₉ OF ₃ : C65.5; H3.8; F23.92 Measured value: C66.4: H3.7

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Claims (1)

[Claims] 1. General formula [In this formula, Z represents a halogen atom,
n is 0, 1 or 2 and R ⁴ is (Here, X represents a halogen atom or a group CN or _CF3 , n' is 0 or 1, Y is a chlorine atom or a fluorine atom, D is oxygen or a group -( _CH2 )m-, -O-CH ₂ - or -CH=
in CH-, m is in the range 2 to 4, and
n'' is 0 or 1, provided that when n'' is 0, X is not a halogen atom and n' is 0, D is -CH=CH-, and n'' is 1, and n ' is 0
, X may further be a hydrogen atom, and D
is oxygen and n″ is 1, then X is not a halogen atom and n′ is 0) and (where X is as defined above) and (wherein X represents a group selected from as defined above but is not a halogen atom). 2 R ⁴ is the base (Here, D is -OCH ₂ - or -(CH ₂ )m-
4-hydroxycoumarin compound according to claim 1, wherein m is 2 to 4. 3 n is 0 and R ⁴ is or or The 4-hydroxycoumarin compound according to claim 1, wherein the compound is cis type, trans type, or cis/trans mixed type. 4 General formula [In this formula, Z represents a halogen atom,
n is 0, 1 or 2 and R ⁴ is (Here, X represents a halogen atom or a group CN or _CF3 , n' is 0 or 1, Y is a chlorine atom or a fluorine atom, D is oxygen or a group -( _CH2 )m-, -O-CH ₂ - or -CH=
in CH-, m is in the range 2 to 4, and
n'' is 0 or 1, provided that when n'' is 0, X is not a halogen atom and n' is 0, D is -CH=CH-, and n'' is 1, and n ' is 0
, X may further be a hydrogen atom, and D
is oxygen and n″ is 1, then X is not a halogen atom and n′ is 0) and (where X is as defined above) and (wherein X represents a group selected from as defined above but not a halogen atom)] A method as described above, characterized in that a compound of the formula [in which R ⁴ , Z and n have the meanings given above] is thermally condensed with 4-hydroxycoumarin. 5 General formula [In this formula, Z represents a halogen atom,
n is 0, 1 or 2 and R ⁴ is ] In the method for producing a 4-hydroxycoumarin compound, the formula () is 1-hydroxy-3-(para-halodiphenyl)
- A process as described above, characterized in that tetralin is reacted with CuCN to form the corresponding cyano-olefin, and () the olefin obtained is combined with 4-hydroxycoumarin. 6 General formula [In this formula, Z represents a halogen atom,
n is 0, 1 or 2 and R ⁴ is ] In the method for producing a 4-hydroxycoumarin compound, () reacting the corresponding 1-keto-3-(para-halodiphenyl)-tetralin with CuCN,
() The obtained cyano-tetralone corresponding to 1
- to a hydroxy compound, and () condensing the hydroxy compound with 4-hydroxycoumarin. 7 General formula as active ingredient [In this formula, Z represents a halogen atom,
n is 0, 1 or 2 and R ⁴ is (Here, X represents a halogen atom or group CN or _CF3 , n' is 0 or 1, Y is a chlorine atom or fluorine atom, D is oxygen or a group -( _CH2 )m- -O-CH ₂ - or -CH=
in CH-, m is in the range 2 to 4, and
n'' is 0 or 1, provided that when n'' is 0, X is not a halogen atom and n' is 0, D is -CH=CH-, and n'' is 1, and n ' is 0
, X may further be a hydrogen atom, and D
is oxygen and n″ is 1, then X is not a halogen atom and n′ is 0) and (where X is as defined above) and A rodenticide composition comprising a carrier together with a rodenticide-effective amount of a 4-hydroxycoumarin compound, wherein X represents a group selected from: