HU201290B - Process for producing 3-phenoxybenzyl-brackets open-2-(4-alkoxyphenyl)-2-methyl brackets closed-propyl ethers - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a raw material for compounds having particularly improved insecticidal action, by reacting a 4-alkoxyneophyl halide with a 3-phenoxybenzyl alcohol in a specific solvent. CONSTITUTION:A 4-alkoxyneophyl halide of formula I (X and Y are H, Cl or Br, and at least one thereof is Cl or Br; R is lower alkyl; X is halogen) is reacted with a 3-phenoxybenzyl alcohol of formula II (X1 and X2 are H or F) in an aprotic polar solvent, e.g. 1,3-dimethyl-2-imidazolidione, containing no sulfur, in the presence of a base, e.g. KOH, under heating at 50 deg.C- the boiling point of the solvent for 0.5-50hr to give the aimed compound of formula III, which is then subjected to the catalytic hydrogenation process and dehalogenated to afford a compound of formula IV having improved insecticidal action in high yield.

Description

The present invention relates to a process for the preparation of 3-phenoxybenzyl [2- (4-alkoxyphenyl) -2-methyl] propyl ethers.

The compounds of the present invention represented by formula (III) wherein Y1 is chloro or bromo, Y2 is hydrogen or chloro, R is C1-C5 alkyl, and X1 and X2 are each independently hydrogen or fluorine mean - can be characterized.

It has now been found that compounds of formula (ΠΙ) can be prepared by reacting 2- (3-halo-4-alkoxyphenyl) -2-methylpropyl halide of formula (I) wherein Y 1 and Y 2 and R is as defined above, and X is halogen, with a 3-phenoxybenzyl alcohol of formula (Π), wherein X1 and X2 are as defined above, per mole of compound of formula (II) 0.2-. 5 molar compound of formula I in the presence of an inorganic base in a sulfur-free aprotic polar solvent at 80-200 ° C.

Compounds of formula (ΙΠ) are starting materials of compounds of formula (IV) having excellent insecticidal and acaricidal activity. In the latter formula, R, X1 and X2 are as previously defined

Recently, certain 3-phenoxybenzyl ether derivatives, including compounds of formula IV, have been found to have excellent insecticidal and acaricidal activity, very rapid action, low activity and toxicity not only in humans and animals, but also in humans. negligible against fish. Thus, these compounds can be converted into excellent insecticidal and fungicidal compositions.

No. A154427 / 81 Japanese Patent Publication No. 35 discloses 3-phenoxybenzyl ether derivatives of formula (VI) wherein R is methyl or ethyl, R 'is hydrogen or halo or lower alkyl and R' is halo or lower alkyl 40. .

Nos. 72928/82 and 64632/82. Japanese Patent Publication No. 6,198,198 discloses compounds of formula VI wherein R 'and R' are halogen, lower alkyl or lower alkoxy, or the corresponding benzene nucleus of the 3-phenoxybenzyl group may be replaced, for example, by a halogen atom.

It has now been found that 50 of the compounds disclosed in the abovementioned publications are compounds of the formula VI in which R 'and R' are lower alkoxy and R is methyl, i.e., 3-phenoxybenzyl. ether derivatives containing only 2-phenyl-2-methylpropyl substituted at the 4-position with a lower alkoxy group. It has also been found that when the benzene ring of the 2-phenyl-2-methylpropyl group is substituted, such as a halogen or alkyl group, the excellent activity of these compounds is slightly reduced.

After very intensive research into the various methods of preparation, the final compounds of formula (IV) were obtained, whereby 65 were prepared in which the benzene ring of the 2-phenyl-2-methylpropyl group was not replaced by a halogen atom or an alkyl group.

It has an alkoxy group at the 4-position.

The aforementioned 154427/81. Japanese Patent Laid-Open Publication discloses processes for the preparation of, inter alia, compounds of formula IV. According to these methods, these compounds are prepared by reacting a compound of formula VII, wherein R, R 'and R' are as defined above, or a salt thereof with a 3-phenoxybenzyl halide or an alcohol, or alternatively, a compound of Formula VIII wherein X is halogen and R, R 'and R' are as defined above with a 3-phenoxybenzyl alcohol. The abovementioned publications also describe processes for the preparation of compounds of formula (VII) and (VHI). However, the process for the synthesis of compounds of formula VII consists of a very large number of steps and is thus considered to be highly unfavorable from an industrial point of view if the compounds of formula VII are to be used as starting material for the preparation of compounds of formula IV.

Processes for the preparation of compounds of formula (VHI) are described, for example, in Schemes (1) and (2). However, when R 'and R' are lower alkoxy at the 4-position, the process shown in Scheme (1) will preferentially carry out a cyclic chlorination, which will make the desired 2- (4-alkoxyphenyl) -2-methylpropyl substantially more difficult. chloride production. In the process depicted in Scheme (2), alkylation occurs at ortho position to the alkoxy group, so that the desired product is contaminated with a large amount of ortho-isomer and effective separation of the isomers is too difficult. Thus, high purity 2- (4-alkoxyphenyl) -2-methylpropiol chloride is formed in a very ca. A further disadvantage is that the resulting 2- (4-alkoxyphenyl) -2-methylpropyl chloride is an unstable compound and is therefore extremely difficult to store and handle on an industrial scale.

Thus, it can be stated that the compounds of formula (IV) cannot be prepared on an industrial scale by reacting preferably 2- (4-alkoxyphenyl) -2-methylpropyl chloride and 3-phenoxybenzyl alcohol.

Thus, the above-described process of the present invention has succeeded in developing an industrial process for the preparation of 3-phenoxybenzyl- [2- (4-alkoxyphenyl) -2-methyl] propyl ethers, which can be carried out very economically, i.e. at low cost. Thus, a compound of formula (I) is reacted with a compound of formula (II) in the presence of an inorganic base to give the desired compound of formula (III). The halogen atom is removed from the benzene ring of the 2-phenyl-2-methylpropyl group of the compound of formula (III) thus obtained by dehydrogenation to give the product of formula IV.

The [2- (3-halo-4-alkoxy-2H-phenyl) -2-methyl-propyl-halides of formula (I) can be obtained in high yields if a 2-halo-1-alkoxy of formula (V) benzene, in which Y1 is chlorine, Y2 is hydrogen or chloro, and R is C1-C5-alkyl, is reacted with a metal halide in the presence of an acidic catalyst.

It has been found that even though Y1 and Y2 in the compound of formula V are chlorine or hydrogen, i.e. even if the compound of formula V is an alkoxyminochlorobenzene, the resulting compound of formula I is predominantly It consists of a para-isomer formed by substitution at the 4-position of the metal halide with respect to the alkoxy group, and barely formed by substitution at the 6-position with respect to the alkoxy group.

The starting compounds of formula (V) are commercially available compounds at low cost. For example, if the compound of formula (I) is o-chlorophenethole, this compound may be prepared from a starting material obtained by a conventional method, for example, by ethylation of 2-chlorophenol with a conventional alkylating agent or by alcoholization of o-dichlorobenzene.

Examples of compounds of formula V include 2-chloro-1-methoxybenzene, 2,6-dichloro-1-methoxybenzene, 2-bromo-1-methoxybenzene, 2,6-dibromo-1-methoxy benzene, 2-chloro-1-ethoxybenzene, 2,6-dichloro-1-ethoxybenzene or 2-bromo-1-propoxybenzene. These compounds are reacted with metallyl chloride or metallyl bromide, as will be described in more detail below, to provide a suitable compound of formula (I), which is then isolated and purified for use in the process according to the invention. Use as starting material for compounds of formula (IV). For completeness, they may also be used as intermediates in the preparation of other organic compounds.

In the preparation of the 2- (3-halo-4-alkoxyphenyl) -2-methylpropyl halides of the formula I, 0.5 to 10 mol, preferably 1 to 5 mol, are used per mole of 2-halo-1-alkoxybenzene. utilizing a metal halide. If the molar ratio of the two reactants is not within the stated range, the reaction rate is reduced and the formation of by-products is accelerated, thereby reducing the yield of the desired product.

Said reaction may be carried out in the absence of a solvent or in the presence of one of the solvents commonly used in the Friedel-Crafts reaction, such as nitromethane, acetonitrile or carbon disulfide.

Further, said reaction is carried out, as mentioned, in the presence of an acidic catalyst. Acid catalysts include concentrated sulfuric acid, methanesulfonic acid, a strongly acidic ion exchange resin (e.g., Amberlyst or Nafion), trifluoromethanesulfonic acid or hydrogen fluoride. Most preferred is the use of trifluoroemanesulfonic acid. However, from an industrial point of view, the use of concentrated sulfuric acid is also advantageous.

The acid catalyst is used in an amount of 0.1 to 2.0 moles, preferably 0.5 to 1.2 moles, per mole of the metal halide. Failure to observe this range will result in a reduction in reaction rate or in the formation of large amounts of by-products, reducing yield.

The reaction is carried out at a temperature of -20 'C to + 50' C, preferably 0 'C to 30' C. It is advantageous to add the catalyst and the metal halide simultaneously to the compound of formula (V) dropwise during the reaction. If the metal halide is in contact with the acid catalyst for a prolonged period, it tends to deteriorate to form a polymer or the like. If the reaction temperature or the mode of administration of the reactants is different from those described above, the reaction rate is reduced or by-products are formed. Generally, the catalyst and the metal halide are added dropwise over a period of 0.52 hours and then the reaction mixture is kept at the specified temperature for a further 2-6 hours to complete the reaction.

The compound of formula (I) thus obtained is substantially free of the corresponding ortho-isomer or other by-product, and is therefore generally not required to be purified. Even if purification is required, this operation is easy since the compounds of formula I are stable unlike the 2- (4-alkoxyphenyl) -2-methylpropyl halides. In the subsequent etherification reaction, the ethers of formula (III) can be obtained in high yield.

Compounds of formula (III) may be prepared, for example, by the process described in the aforementioned Japanese Patent Application, wherein a compound of formula (VIII) is

Reaction with 3-phenoxybenzyl alcohol in the presence of a base such as aqueous sodium hydroxide in a solvent inert to the reactants such as dimethyl sulfoxide to give a compound of formula VI.

However, when the benzene ring of the 2-phenyl-2-methylpropyl group is substituted by an alkoxy group and a chlorine or bromine atom of the formula I

2- (3-halo-4-alkodo-phenyl) -2-methyl-propyl-halide is reacted with a compound of formula (Π)

With a 3-phenoxybenzyl alcohol derivative in dimethylsulfoxide as the preferred solvent for the process of the invention, the reaction yield is relatively low. It is further noted that the use of a sulfur-containing polar solvent, such as dimethylsulfoxide, in the etherification reaction results in very small amounts of sulfur-containing by-products formed during the reaction, even after purification by recrystallization. These sulfur-containing by-products act as catalyst poison during dehydrohalogenation of the compounds of formula (III) in the presence of a hydrogenation catalyst, thereby significantly reducing the yield of the compounds of formula (IV).

Therefore, in the preparation of the compounds of formula (I) from the compounds of formula (I) and (II), it is advantageous to carry out the reaction in the presence of an aprotic polar solvent which does not contain a sulfur atom. As such solvent3

Examples include 1,3-dimethyl-2-imidazole-idinone, N-methyl-2-pyrrolidone, tetramethylurea, diglyme (diethylene glycol monomethyl ether) or hexamethylphosphoric triamide. Of these, 1,3-dimethyl-2-imidazolidinone is preferred because of its high yield.

The amount of solvent is 0.550 volumes, preferably 2-20 volumes, per volume of 3-phenoxybenzyl alcohol derivative. If the amount of solvent is less, the reaction rate is significantly reduced. If the amount of solvent is higher, the reaction rate and productivity will decrease.

With regard to the base used, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide may be mentioned; alkaline earth metal hydroxides such as calcium hydroxide or magnesium hydroxide, alkali metal hydrides such as sodium hydride; alkali metal alcoholates such as sodium methylate, potassium ethylate or potassium tert-butylate; alkali metal oxides such as disodium oxide; alkali metal carbonates such as potassium carbonate or sodium carbonate; sodium amide; triethylamine or pyridine. 0.5-3 mol, preferably 1-2 mol, of base is used per mole of 3-phenoxybezyl alcohol derivative. If the amount of base is lower, the conversion becomes poor. If the amount of the base is higher, by-products are formed in large quantities and thus the yield is reduced.

The base is preferably sodium hydroxide or potassium hydroxide. It is preferable to use the base in solid form because the reaction rate increases and the yield is improved by using a base of the usual form, granular or flaky or, in some cases, finely powdered. The water content of the reaction system is up to 10% by weight, preferably up to 31%, based on the solvent used in the initial step of the process. In some cases, it is effective to azeotropically dehydrate toluene or xylol during the process.

Thus, the etherification step is generally carried out as follows: As regards the ratio of the compounds of formula (I) to the compounds of formula (II), one mole of 3-phenoxybenzyl alcohol of formula (II) is 0.2- 2- (3-halo-4-alkoxyphenyl) -2-methylpropyl halide of formula I is used in an amount of 5 moles, preferably 0.4 to 2 moles. If the proportion of reactants is not within the stated range, the reaction rate is reduced and the formation of by-products is accelerated, thereby reducing the yield.

The compounds of formula (I) and (H), a base and a solvent are weighed into a reaction vessel and heated to a temperature between 80 ° C and the boiling point of the reaction mixture (if the reaction mixture boils above 200 ° C then 80 ° C). 200 ° C). The reaction mixture is then heated at this temperature for 0.550 hours, preferably for 3 to 30 hours. After cooling to room temperature, the insoluble inorganic salts are filtered off. The solvent was removed from the filtrate by vacuum distillation. The residue is washed with water and dried to give 3-phenoxybenzyl- [2- (4-alkoxy-3-halophenyl) 2-methyl] propyl ether or 3-phenoxybenzyl- (III). [2- (4-Alkoxy-3,5-dihalophenyl) -2-methyl] propyl ether is obtained. The product is purified by vacuum distillation or column chromatography and, if desired, recrystallized.

As the compound of formula (ΠΙ), the 2-phenyl-2-methylpropyl group may be substituted singly on the benzene ring of the benzene, e.g., 3-phenoxybenzyl [2- (3-chloro-4-alkoxyphenyl) -2-methyl] propyl ethers. , 3-phenoxybenzyl- [2- (3-bromo-4-alkoxyphenyl) -2-methyl] propyl ethers or 3-phenoxy-4-fluorobenzyl [2- (3-chloro-4-alkoxy) -phenyl) -2-methyl] -propyl ethers, or they are substituted on the benzene ring of the 2-phenyl-2-methylpropyl group with a halogen atom, for example 3-phenoxybenzyl- [2- (3,5-dichloro) - 4-alkoxyphenyl) -2-methyl] propyl ethers can be used. The desired compound of formula (ΠΙ) may be prepared by appropriate selection of compounds of formula (I) and (II). The monochloro-substituted compounds of formula (III) are particularly preferred because they are readily dehydrohalogenated to the compounds of formula (IV). Therefore, 2- (3-chloro-4-alkoxyphenyl) -2-methylpropyl chlorides are particularly preferred among the compounds of formula (I).

The compounds of formula (III) are converted to the corresponding compounds of formula (IV) by dehydrohalogenation, preferably by catalytic hydrogenation.

Compounds of formula (IV) from compounds of formula (III), for example, by catalytic hydrogenation; hydrogenation with a reducing agent such as lithium aluminum hydride or dehalogenation with a metal in an aprotic polar solvent. Of these, hydrogenation methods, in particular catalytic hydrogenation methods, are the most advantageous from an industrial point of view. According to the catalytic hydrogenation method, a compound of formula IV can be prepared, for example, as follows:

A compound of formula (III) is reacted with hydrogen, optionally in the presence of a base and a solvent, or optionally in the presence of a catalyst, at a certain temperature under atmospheric or elevated pressure. Subsequently, a compound of formula (IV) is isolated from the reaction mixture by a suitable method.

Examples of the target compounds of formula (IV) obtained by the removal of the chlorine or bromine atom of the compounds of formula (III) include: 3-phenoxybenzyl- [2- (4-methoxyphenyl) -2-methyl] propyl ether; Phenoxy-4-fluorobenzyl- [2- (4-methoxyphenyl) -2-methyl] propyl ether, 3- (4-fluorophenoxy) benzyl [2- (4-methoxyphenyl) -2 methane

1] propyl ether, 3- (4-fluorophenoxy) -4-fluorobenzyl [2- (4-methoxyphenyl) -2-methyl] propyl ether, 3-phenoxybenzyl [2- ( 4-methoxyphenyl)] - 2-methylpropyl ether, 3-phenoxy-4-fluorobenzyl- [2- (4-ethoxyphenyl) -2-methyl] propyl ether, 3- (4- fluorophenyl) benzyl [2- (4-ethoxyphenyl) -2-methyl] propyl ether, 3- (4-fluorophenoxy) -4-fluorobenzyl {2- (4- ethoxyphenyl) -2-methyl] propyl ether, 3-phenoxy-6-fluorobenzyl [2- (4-ethoxyphenyl) -3-methyl] propyl ether, 3- (2-fluoro- phenoxy) benzyl [2- (4-ethoxyphenyl) -2-methyl] propyl ether, 3-phenoxybenzyl- [2- / 4-4HY 201290 Β (Isopropoxy) phenyl / -2-methyl ] -propyl ether, 3-phenoxy-4-fluorobenzyl- [2- / 4- (isopropoxy) phenyl] -2-methyl] propyl ether, 3-phenoxybenzyl-2- / 4- (1 -methylpropoxy) phenyl / -2-methyl] propyl ether, 3-phenoxybenzyl [2- [4- (n-butoxy) phenyl] -2-methyl] propyl ether, 3-phenoxybenzyl [2- / 4- (tert-Butoxy) methyl] -2-methyl] propyl ether or 3-phenoxybenzyl [2- / 4- (n-pentoxy) phenyl] -2-methyl] propyl; ether.

The following examples illustrate the invention.

Reference Example 1 Preparation of [2- (3-chloro-4-ethoxyphenyl) -2-methyl] propyl chloride

Weigh into a 500 ml four-necked flask

208.6 g (1.33 moles) of o-chlorophenethol are added dropwise via two dropping funnels to 39.2 g (0.40 moles) of 98% sulfuric acid and 90.6 g (1.00 moles) of chloride at 10 ° C for 2 hours. The reaction mixture was then stirred at the same temperature for a further 2 hours.

The reaction mixture was then poured into about 0.5 L of water and the resulting aqueous mixture was shaken well in a separatory funnel to separate into a lower oily and aqueous layer. The oily layer was washed three times with 200 g of 3% aqueous sodium hydroxide solution and then with 200-200 g of water and finally dried under reduced pressure to give 287.8 g of crude 2- (3-chloro-4-ethoxyphenyl). -2-methylpropyl chloride is obtained.

GC analysis of the crude product showed 96.5% by weight of 2- (3-chloro-4-ethoxyphenyl) -2-methylpropyl chloride and 3.5% by weight of 2- (3-chloro-2-ethoxy). -phenyl) -2-methylpropyl chloride.

The crude product was then purified by vacuum distillation to give 167.4 g of the pure desired product, 02.10 ² mmHg as a 127-135 ° C boiling fraction.

Purity (GC;% v / v): 96.3%

Yield: 67.7% (based on methyl chloride)

Analysis results for C12H16Cl2O: The% designation used in the analysis results is% w / w.

Found: C, 58.31; H, 6.53; CL, 28.69; Found: C, 58.11; H, 6.41; Cl, 28.72.

Nuclear Magnetic Resonance Spectrum (CDCl3, delta):

_Z CH ₃

1.3-1.6 (9H, - CCH 2 Cl and -CH 2 CH ₃ ), 3.6 (2H, s) CH ₃ qh ₃

-C-CH 2 Cl), 4.0-4.2 (2H, q, -CH 2 CH ₃ ) and 6.8-74 CH ₃ (3H, m, aromatic protons) ppm.

Reference Example 2

The reaction and the subsequent reaction were carried out as described in Reference Example 1, but instead of 39.2 g of 98% sulfuric acid,

11.6 g of trifluoromethanesulfonic acid are used. so

293.8 g of crude 2- (3-chloro-4-ethoxyphenyl) -2-methylpropyl chloride are obtained.

The crude product was analyzed by gas chromatography to give 96% by weight of the desired 2- (3-chloro-4-ethoxyphenyl) -2-methylpropyl chloride and 4% by weight of the isomeric 2- (3- chloro-2-ethoxyphenyl) -2-methylpropyl chloride.

The crude product is then distilled under reduced pressure to give 67.7 g of unreacted o-chlorophenethole and 175.1 g of the desired pure product (131-135 ° C / 665 Pa).

Purity (GC;% v / v): 93.6%

Yield: 70.9% (based on methyl chloride).

The following describes the preparation of 2- (4-ethoxyphenyl) -2-methylpropyl chloride as a comparative reference by a process such as disclosed in U.S. Pat. is based on the method described in Japanese Patent Application Laid-Open.

120 g 98% sulfuric acid were weighed into a 500 ml four neck flask and 200 g of phenethol was added dropwise keeping the temperature at 45 ° C. Thereafter, 200 g of phenethol is added over a period of 10 hours, maintaining the temperature of the mixture at 0 to 10 ° C. The reaction mixture was allowed to stand at 25 ° C for 15 hours and then poured into ice / water. The separated organic layer was separated, washed well with dilute aqueous sodium hydroxide solution and then with water, and dried over anhydrous sodium sulfate. 451.2 g of crude 2- (2-ethoxyphenyl) -2-methylpropyl chloride are obtained. The crude product was subjected to gas chromatography to determine that 22% by weight of 2- (4-ethoxyphenyl) -2-methylpropyl chloride and 78% by weight of isomer

Contains 2- (2-ethoxyphenyl) -2-methylpropyl chloride.

Example 1

Preparation of 3-Phenoxybenzyl- [2- (3-chloro-4-ethoxyphenyl) -2-methyl] propyl ether (Compound 1).

Weigh 3 liters (3156 g) of 1,3-dimethyl-2-imidazolidinone (hereinafter referred to as DMI), 618.0 g (2.5 moles)

2- (3-Chloro-4-ethoxyphenyl) -2-methylpropyl chloride (prepared as in Example 1), 1251.0 g (6.25 mol)

3-phenoxybenzyl alcohol (product of Ethyl Corp.) and 280.0 g (5.00 moles) of potassium hydroxide in scaled form and the resulting mixture was stirred under nitrogen at 120 ° C for 15 hours to complete the reaction.

The reaction mixture was then cooled to room temperature and the insoluble material was filtered off under reduced pressure. The filtrate was washed with DMI (300 mL, 320 g) to give a washed solution (5215 g). 3274 g of DMI were isolated by vacuum distillation. This gives 1845 g of a residue which also contains inorganic material.

It was found that the residual by-product was a desethylated material, i.e., Formula IX

Contains 3-phenoxybenzyl- [2- (3-chloro-4-hydroxyphenyl) -2-methyl] propyl ether having the following physical characteristics:

Melting point: 68-69 ° C

-5HU 201290 Β

Nuclear Magnetic Resonance Spectrum (CDCl3, delta):

CH ₃ : 1.4 (6H, s, -CCH 2 -), 3.3 (2H, s)

CH3

CH ₃ PH ₃

-CCH2 -) 4.4 (2H, s CCH2OCH2,5,4 (1H, s (X))

CH ₃ ch ₃ ) and 6.7 7.4 (12H, m, aromatic protons).

To isolate the desethylated product in its ethylated form, the residue was weighed with 3000 mL of water into a 5 L four neck flask and 38.5 g (0.25 mol) of diethyl sulfate was added dropwise over 1 hour at 50 ° C. The reaction mixture was then stirred at the same temperature for 1 hour, then the temperature was raised to 90 ° C and stirring was continued at this temperature for 2 hours to decompose unreacted diethyl sulfate. The reaction mixture was cooled to 50 ° C and adjusted to pH 3 to 4 by the addition of 30 g of concentrated hydrochloric acid. The reaction mixture is then allowed to stand. The lower oily phase was separated and washed with 50 L of water at 50 ° C. The wash is repeated twice more. The resulting oily product (containing water) was dried in a reduced pressure evaporator to give 1774 g of a residue.

This residue is then distilled under reduced pressure in a Smith film evaporator under reduced pressure to remove the low-boiling unreacted starting material (210 ° C / 13.3 Pa). The residue is thus divided into a low boiling fraction (990 g) and a high boiling fraction (770 g).

The weight of 770 g of high boiling fractions and 1540 ml of methanol was cooled to -10 C, ^E, and then stirred at this temperature for 2 hours to promote crystallization. The crystals are filtered off and dried.

Gas chromatographic analysis using an internal standard determines the product

96.3% by weight of 3-phenoxybenzyl- [2- (3-chloro-4-ethoxyphenyl) -2-methyl] propyl ether and 0.6% by weight of isomer

It consists of 3-phenoxybenzyl- [2- (3-chloro-4-ethoxyphenyl) -1 ₎ 1-dimethyl ethyl] ether.

The yield of crystals was 869.5 g (81.5%).

The solidification point, analytical results, and NMR spectrum of the crystals are as follows:

Melting point: 42.2 ° C

Analysis results for C25H27CIO3:

Calculated: C, 72.07; H, 6.62; Cl, 8.63. Found: C, 73.25; H, 6.55; Cl, 8.33.

Nuclear Magnetic Resonance Spectrum (CDCl 3, delta), 1.25 (6H, s), 1.2 (3H, t), 3.36 (2H, s), 3.92 (2H, q), 4.2 (2H) , s), and

6.6-7.4 (12H, m) ppm.

Example 2

3-Phenoxy-4-fluorobenzyl- [2- (3-chloro-4-ethoxyphenyl) -2-methyl] propyl ether. (Compound 2)

Weigh 30 ml of DMI into a 100 ml flask,

6.2 g (0.025 mol) of purified [2- (3-chloro-4-ethoxyphenyl) -2-methyl] propyl chloride, prepared as described in Reference Example 1, 8.5 g (0.039 mol) of 3- [ phenoxy-4-fluorobenzyl alcohol and 2.2 g (0.039 mol) of potassium hydroxide in scaled form and the resulting mixture was stirred at 120 ° C under a stream of nitrogen for 15 hours to complete the reaction.

The reaction mixture was then cooled to room temperature and poured into 200 ml of 5% aqueous hydrochloric acid. The resulting oily product was isolated by extraction with 100 mL of benzene, and the extract was washed three times with 100 mL of water and dried over anhydrous Glauber's salt. The benzene was then distilled off under reduced pressure to give 13.8 g of an oily product. GC analysis using an internal standard showed 62.4% by weight of 3-phenoxy-4-fluorobenzyl- [2- (3-chloro-4-ethoxyphenyl) -2-methyl] propyl ether. Yield: 80.5%. The oily product is then purified by column chromatography on silica gel to give 7.3 g of pure oil.

The refractive index, analytical results and NMR spectrum of the oily product are as follows:

refractive index: ηθ′θο = 1.1576

Analysis results for C25H26CIFO3:

Calc'd: C, 70.01; H, 6.11; Cl, 8.26; F, 4 43 Found: C, 70.12; H, 6.00; Cl, 8 , 58, F% = 4.21.

Nuclear Magnetic Resonance Spectrum (CDCl 3, δ): 1.27 (6H, s),

1.42 (3H, t), 3.30 (2H, s), 4.05 (2H, q), 4.34 (2H, s) and 6.6-7.4 (11H, m) ppm.

Example 3

Preparation of 3-Phenoxybenzyl- [2- (3-bromo-4-ethoxyphenyl) -2-methyl] propyl ether (Compound 3)

Weigh 30 ml of DMI into a 100 ml flask,

7.3 g (0.025 mol) as described in Reference Example 1 (except that

2- (3-Bromo-4-ethoxyphenyl) -2-methylpropyl chloride, 8.5 g (0.039 mol) of 3-phenoxybenzyl alcohol and 2-chlorophenol are used instead of 2-chlorophenol. Potassium hydroxide (2 g, 0.039 mol) was added and the resulting mixture was stirred at 120 ° C under a stream of nitrogen for 15 hours to complete the reaction.

The reaction mixture was cooled to room temperature and poured into 200 mL of 5% aqueous hydrochloric acid. The oily product formed is isolated by extraction with 100 ml of benzene. The extract was washed with water (3 x 100 mL), dried over anhydrous Glauber salt, and the benzene was distilled off under reduced pressure. 14.2 g of an oily product are obtained.

GC analysis using an internal standard showed the product to contain 58.3% by weight of 3-phenoxybenzyl [2- (3-bromo-4-ethoxyphenyl) -2-methyl] propyl. Yield: 72.7%. The product was purified by silica gel column chromatography to obtain 8.8 g of pure product as an oil.

The analytical results and the NMR spectrum of the oily product are as follows.

Analytical results based on the formula C ₂ H ₂ 7 BrO ₃ :

H, 5.99; Br, 17.55; Found: C, 65.65; H, 5.82; Br, 17.65.

NMR (CDC1 _3, delta): 1.26 (6H, s), 1.2 (3H, t), 3.35 (2H, s), 3.92 (2H, q), 4.4 ( 2H, s), 6.6-7.4 (12H, m) ppm.

Reference Example 1

Preparation of 3-Phenoxybenzyl- [2- (4-ethoxyphenyl) -2-methyl] propyl ether.

3-Phenoxybenzyl- [2- (3-chloro-4-ethoxy) -2-methyl] propyl ether (60.0 g, 0.146 mol) was added to a 500 ml autoclave, 7.5 g (0.188 mol) wasp. sodium hydroxide, 7.2 g of a 5% palladium-on-carbon catalyst (50% moisture), 108 ml of methanol and 36 ml of water, and the autoclave was sealed and purged with nitrogen. After introducing hydrogen gas at 7.8 to 10 ⁵ Pa is reached. The reaction mixture was then stirred at an internal temperature of 110 ° C for 12 hours, from 7.8 to 9.8. Hydrogen gas at a pressure of 10 ⁵ Pa, as required.

The reaction mixture is then cooled to room temperature and the gas is vented. To the autoclave was added 120 ml of benzene to dissolve the oily phase. The insoluble material is filtered off. After washing with 30 ml of benzene, the mixture of filtrate and washings as mother liquor is shaken well and allowed to stand to obtain a benzene phase. The benzene phase was washed with water (3 x 120 mL), dried and the benzene was distilled off under reduced pressure to give an oily residue. Analysis by gas chromatography using an internal standard showed that 98.5% by weight of 3-phenoxybenzyl- [2- (4-ethoxyphenyl) -2-methyl] propyl ether and 0.5% by weight of unreacted 3-phenoxy- containing benzyl [2- (3-chloro-4-ethoxyphenyl) -2-methyl] propyl ether. The amount of 3-phenoxy-toluene and 4-ethoxy-neophyl alcohol formed by the use of an ether linkage is less than 0.2% by weight. Yield 53.6 g (96.0%).

The solidification point, analytical results, and NMR spectrum of the oily product are as follows:

Solidification point: 31.2 'C

Analysis results for C25H28O3:

Found: C, 79.75; H, 7.50;

Found: C, 79.86; H, 7.69.

Nuclear Magnetic Resonance Spectrum (CDCl 3, δ): 1.25 (6H, s),

1.3 (3H, t), 3.35 (2H, s), 3.92 (2H, q), 4.2 (2H, s) and

6.6-7.4 (13H, m) ppm.

Reference Example 2

50.0 g (0.220 mole) of purified 3-phenoxybenzyl [2- (3-bromo-4-ethoxyphenyl) -2-methyl] propyl, exactly as prepared in Example 3, 4, 8 g (0.121 mol) of scaled sodium hydroxide, 2.0 g of 5% palladium on carbon (50% moisture), 90 ml of methanol and 30 ml of water were weighed in a 500 ml autoclave, then sealed and purged with nitrogen. autoclave. Subsequently, while introducing hydrogen gas into the autoclave until the pressure therein becomes 9,8.10 ⁵ Pa. The reaction mixture was stirred at an inner temperature of 80C for 12 hours while introducing 7,8-9,8.10 ⁵ psi hydrogen gas into the autoclave.

After completion of the reaction, the reaction mixture was cooled to room temperature and the gas was drained. Then, 100 ml of benzene was added to the autoclave to dissolve the precipitated oil. The insoluble material is filtered off and washed with 20 ml of benzene. The washing liquid and the filtrate are combined as mother liquors, shaken well and then allowed to stand. After separation of the benzene phase, the mixture is washed three times with 100 ml of water each time, and the benzene is distilled off under reduced pressure to give an oily product. Gas chromatography analysis using an internal standard showed that this oily product contained 98.5% of the desired 3-phenoxybenzyl-2- (4-ethoxyphenyl) -2-methylpropyl ether and 0.3% by weight. containing 3-phenoxybenzyl-2- (3-bromo-4-ethoxyphenyl) -2-methylpropyl ether as the starting material. The amount of 3-phenoxytoluene and 2- (4-methoxyphenyl) -2-methylpropanol formed by the ether bond cleavage is less than 0.2% by weight.

Yield: 41.2 g (98.0%)

The solidification point, analytical results, and NMR spectrum of the oily product are as follows:

Solidification point: 33.1 'C

Analysis results for C25H28O3:

Found: C, 79.75; H, 7.50;

Found: C, 79.50; H, 7.22;

Nuclear Magnetic Resonance Spectrum (CDCl3, delta): 1.25 (6H, s), 1.3 (3H, t), 3.35 (2H, s), 3.92 (2H, q), 4.2 (2H) , s), 6.6-7.4 (13H, m) ppm.

The target compounds listed in the following Table 1 are the following. in Reference Examples and in Examples 1-3. can be prepared by the methods described in Examples.

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Table 1

Old man anrazame s2 = sa2saBS = ssss35 = 6assBBaB! ÍaBasBS = saaiicssse = s = ssssa

Starting materials

Compounds of formula (I) li Υ _χ Y ₂ X

General pictorial. chemical (II) molar ratio (11) / (1 saasssss

CH ₃ - Cl H Cl

CH ^ - Br H Cl

CH j - Cl H Cl

CH j - Cl H Cl

CH j - Cl H Cl

2:50

4-F H

H, 4-F

4-F 4'-F

CH ₃ (CH ₂ ) ₂ Cl H Cl 4 -FH

CH ₃₂ CH-Cl HC

2:50

2.00

2.00

1.50

2.50

2.50

3.00

Molecular ratio of alkali metal hydroxide to chemical formula of general formula

KOH (2.0)

KOH (2.0)

KOH (2.0)

KOH (2,0)

KOH (1,5)

KOH (2,0)

KOH (2,0)

KOH (3.0) (I) reaction parameters temp. hour ( ⁶ C) (h)

120 15

120 15

120 15

120 15

140 15

140 10

140 15

130 15

Yield /% /

75.7

70.3

83.2

77.8

66.7

62.3

66.6

74.2% results found /% / Calculator Found ^C 24 ^H 25 ^Cl 3 Base Price C: 72.63 72.58

Η: 6.35 6.12

Cl 8.93 8.77 ^C 24 ^H 25 O 3 ^Br ^ sq base C 65.31 65.11

H: 5.71; 15r: 18.10

5.82

17.87 ° 24 ^H 24

CIFOj pictorial. from

C: 69.48 69-22 H: 5.83 5.79 Cl: 8.54 8.68 F: 4.58 4.46 ^ü 24 h ₂₄ cifo ₃ kepi. fund C: 69.48 69.71 H: 5.83 5.92 Cl: 8.54 8.27 F: 4.58 4.41

Basics of 7 _Oi jH ₂₃ ClF ₂ 0 ₃

C: 66.59 66.28 H: 5.36 5.21 Cl: 8.19 7.99 F: 8.78 9.01 ^C 26 h ₂₉ cio ₃ kepi. ala] C: 73.49 73.56 H: 6.88 6.92 Cl: 8.34 8.16

CggHjgClFOjképl. Based on

C: 70.50 70.22 H: 6.32 6.12 Cl: : 8.02 8.27 F: 4.79 4.50

^C 26 ^H 29 ^C1O based visual · C 3: 73.49 73.62

H: 6.88 7.01

Cl: 8.34 8.51

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Table 1

Buy aor number

Starting materials

Alt. compounds of formula (I> R Y. Y- λ

Alt. Compounds of Formula II (II) Xj x ₂ Mole Ratio (11) / (1)

Alkali metal hydroxide (compound of formula (I) mole ratio pa) Ramam. óx'a (° C) (h)

Yield /% / (CH 2 CHCl 1 H C

4-F

3.00

KOH (3.0)

140 15

77.6

ÍCH ₃ CH ₂₂ CH ₂ - Cl H Cl

3.00

KOH (3.0)

140 15

72.2

3.00

KOH (3.0)

130 15

65.5

COH ^ CHCHjC1 H Cl H

2.50

KOH (3.0)

140 15

67.2

Analysis results counts there found C ₂ H H ₂₈ ClF . kepi. Based on C: 70.50 70.27 H, 6.32 6.50 Cl, 8.02 7.97 F: 4.29 4.09 formula C: 73.88 73.67 H, 7.06 6.92 Cl, 8.09 7.77 formula C: 73.88 73.67 H, 7.06 7.82 Cl, 8.09 8.28 j ... ^C 27 ^H 3i ^G ^ ^U 3 formula ala pj an C: 73.88 73.59 H, 7.06 7.21 Cl, 8.09 8.02

juice

C.Hj (CHjCHj- Cl H Cl

2.50

KOH (2,0)

140 15

72.1 ^C 28 ^H 33 ^C1O 3 Image ¹ ® ¹ basis

C: 74.24 73.94 H: 7.34 7.52 Cl: : 7.83 7.56

CH ₃ (CH ₂ ^ CH ₂ - Cl H Cl

4-F

2.50

KOH (2.5)

130 15

70.8

Cj, oHt ^ CIFO ^ '28 32

C: 71.41 H: 6.80 Cl: 7.54 F: 4.03

71.11

6.59

7:28

4:29

2.5

KOH (2,0)

140 15

61.5

4-F

2.5

KOH (2.5)

140 15

60.3

C: 67.42 67.51 H, 5.88 5.22 Cl, 15.92 15.87 ^C 25 ^H 25 ^C1 2 ^F0 3 C: 64.80 64.15 H, 5.44 5.38 Cl, 15.30 15.35 F: 4.10 4.05

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Claims (4)

PATENT CLAIMS 1. A process for preparing 3-phenoxybenzyl of formula (ΙΠ) [ 2- (4-alkoxyphenyl) -2-methyl] propyl ethers of the formula Y1 is chlorine or bromine, R is C1-C5 alkyl, while X1 and X2 are independently hydrogen or fluorine characterized in that 2- (3-halo-4-alkoxy-phenyl) -2-methyl-propyl-halide of formula (I): wherein Y1, Y2 and R are as previously defined and X is halogen; Reacting a 3-phenoxybenzyl alcohol of formula (II) wherein X1 and X2 are as previously described, using 0.2-5 moles of compound of formula (I) per mole of compound (II) in the presence of an inorganic base, in polar solvent 80-200 'Con. 2. A process according to claim 1 wherein the compound of formula I is 2- (3-chloro-4-alkoxyphenyl) -2-methylpropyl chloride. 3. A process according to claim 1, wherein the compound of formula (I) is 2- (3-bromo-4-alkoxyphenyl) -2-methylpropyl chloride. 4. The process of claim 1 wherein the sulfur-free aprotic polar solvent is sulfur 1,3-dimethyl-2-imidazolidone.