HU220961B1 - Process for producing benzyl-ethers with phase transformation - Google Patents

Abstract

The subject of the invention is the process for the preparation of mixed ethers of general formula (I), wherein Ar represents an alicyclic, aromatic or one or more heteroatom-containing heterocyclic moiety, optionally substituted by one or more C1-4 alkoxy, methylenedioxy, C1-4alkyl, halogen, C1-4haloalkyl or nitro-group, and/or condensed with a benzene ring; R<1> means hydrogen, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, phenyl, substituted phenyl, C3-6cycloalkyl group; R<2> means C1-6alkyl, C3-6alkenyl, or C3-6alkinyl group, optionally mono- or poly-substituted by C1-6alkyl, C1-6alkoxy, C3-6alkenyl, C3-6alkinyl, C1-6haloalkyl group or by halogen atom; or a C1-4 alkyloxy-C1-4alkyl-oxy-C1-4alkyl group. n = 1,2 by the reaction of compounds of general formula (II), wherein R<1> and n have the same meaning as above; X means hydroxy, halogen or sulfonester leaving group, with the compounds of the general formula (III): R2-Y, wherein R<2> has the same meaning as above; Y means hydroxy, halogen or sulfonester leaving group, with the proviso that one of the reaction partners of general formulae (II) and (III) is an alcohol, characterized by, that the reaction is performed under heterogenous conditions in presence of an aqueous base and a phase transfer catalyst, and the resulting product is optionally stabilized by the addition of a base and/or anti-oxidant.

Description

The scope of the description is 8 pages (including 1 page figure)

EN 220 961 BI

SUMMARY OF THE INVENTION The present invention relates to a process for the treatment of mixed ethers of formula I wherein

Ar is optionally substituted by one or more C, _ ₄ alkoxy, methylenedioxy, Cj_ ₄ alkyl, halogen, Cj_ ₄ haloalkyl, or nitro, and / or benzo-fused alicyclic, aromatic or one or more heterocyclic group containing heteroatoms,

^R1 is hydrogen, Cj_ ₄ alkyl, C, _ ₄ haloalkyl, C ₂ _ ₄ alkenyl, phenyl, substituted phenyl, C ₃ _ ₆ cycloalkyl.

R ² optionally C, _ ₆ alkyl, Cj_ ₆ alkoxy, C ₃ _ ₆ alkenyl, C ₃ _ ₆ alkynyl, Cj_ ₆ haloalkyl or halogen-monosubstituted or polysubstituted by C, _ ₆ alkyl, C ₃ _ ₆ alkenyl or C ₃ _ ₆ alkynyl; or -C ₁₄ alkyloxy C _{(_ 4} alkoxy Cj_ ₄ alkyl.

for the preparation of n = 1.2 under phase transfer conditions, the compounds of formula II wherein

^Rl and n are as defined above

X is a hydroxy, halogen or sulfoester leaving group, and compounds of formula III wherein

R ² is as defined above,

Y is a leaving group for hydroxy, halogen or sulfoester, with the proviso that one of the reaction partners is an alcohol.

The ethers of Formula I are potential starting materials and active ingredients for many chemical products. Several of these compounds are highly potent arthropodicide synergists (Hungarian Patent Application No. 3318/95). Methyldioxide (MDP) containing the known saturated side chain is synergistic (e.g., PBO, i.e. 5- [2- (2-butoxyethoxy) ethoxymethyl] -6-propyl-1,3-benzodioxole), despite their simple structure new. Due to their outstanding importance, their production and economic synthesis are extremely important.

The above ethers can be prepared by general methods known for etherification [Gy. Matolcsy, M. Nádasdy, V. Andriska; Pesticide Chemistry, Academy (1988): 3318/95]. The essence of these is that according to the rules of nucleophilic substitution, the alcohol component of the alcohol component is reacted with the partner. This partner contains a leaving group that is usually a halogen, preferably a bromine atom. The reaction can be accomplished in two ways, depending on which part of the molecule is the nucleophile partner. Due to the higher reactivity of benzyl halides, in practice, the side chain alcoholate is usually reacted with benzyl bromide. It is only the usual barrier to do this if the alcohol is difficult to produce for some reason. At this point, the reverse solution can result, but in most cases a worse reaction can be expected. This type of ether formation is known as classic Williamson synthesis in organic chemistry [Β. P. Mundy, M.G. Ellerd, Name Reactions and Reagents in Organic Synthesis,

Wiley (1988)]. However, the reaction has several disadvantages. The formation of alcohol requires industrially expensive reagents and sophisticated, water-free or dehydrating technology (U.S. Patent No. 80,500,190,842).

Additional methods for generating ethers are generally known. Among them, the oldest and best known is the dimerization of alcohols by acid catalysis. (Houben Weyl 6/3 11-19). As described herein, the reaction is generally carried out at high temperatures and the product must be continuously removed from the reaction mixture to avoid degradation. The acid-induced oxonium cation can easily participate in a rearrangement reaction or stabilize by the so-called β-elution of the adjacent carbon atom by adding the corresponding olefin. This causes the appearance of a significant amount of decomposition products, which is further aggravated by the slowing down of water in the reaction. As a result, the performance (yield, purity) of the reaction is low. The problem is exacerbated by the fact that the ethers of formula I are, unlike usual, surprisingly sensitive to acid [J. Am. Chem. Soc., 107,1340, (79S5)].

Dimethyl sulfoxide-induced dimerization procedures have been developed for dibenzyl ethers to overcome the disadvantages [J. Org. Chem., 42, 2012, (1977)]. However, the method cannot be industrialized due to the reagent used and the high temperature (175 ° C).

The production of ethers is particularly difficult from an industrial point of view. Not only due to expensive reagents and possible side reactions, but also because the starting alcohols and the resulting ethers are easily peroxidated and potentially explosive. This is further enhanced by the sensitivity of the alkynyl compounds due to the triple bond. Large-scale production of 1000 t / year can be safely imagined only if the reaction can be conducted under mild conditions and the final product, which is liquid in most cases, does not need to be further cleaned or distilled.

In view of the above, the possibilities of preparing asymmetric ethers of formula I have been studied in detail. Based on our experimental results, our method is to produce mixed ethers of the formula I, wherein the substituents are as defined above, in which compounds of formula II wherein X is hydroxy, halogen, or sulphoester leaving, and compounds of formula III wherein Y is hydroxy, can be prepared particularly advantageously. , a halogen or sulfoester leaving group, reacting in the presence of a phase transfer catalyst under aqueous conditions, with the proviso that one of the reaction partners is an alcohol. The ether I thus obtained is isolated and optionally stabilized by addition of a base and / or antioxidant.

In formula I, II or III wherein Ar, R ¹ and R ² are as defined above.

Preferably, the compounds of formulas II and III are present in a molar ratio of 0.4 to 2.5 molar, 1.0 to 10.0 molar equivalents of the base, and 0.01 to 1.0 molar equivalents, preferably 0 to 10 molar equivalents of the phase transfer catalyst. 1 molar equivalent.

EN 220 961 B1

The base may be an alkali or alkaline earth metal hydroxide, preferably a 10 to 40 wt.% Aqueous solution of potassium hydroxide or sodium hydroxide equivalent to 2.0 molar equivalents, various ammonium salts or hydroxides, preferably tetrabutylammonium bromide or iodide as the phase transfer catalyst.

The reaction can be carried out in the absence of a solvent or in an apolar aprotic solvent at a temperature of (-10) to (+ 100) ° C, preferably at room temperature.

The reaction can then be carried out by reacting an activated benzyl derivative with an alcohol of formula III or, alternatively, an activated derivative of formula III and a benzyl alcohol of formula II. In principle, it is advisable to choose the solution where the leaving group (X or Y) is mobile, for example, with benzyl or sub-position, or when base-based elimination side reactions cannot be considered. This is the case, for example, when an activated benzyl derivative is reacted wherein Rj is a hydrogen or a hydrogen atom that is not hydrogen but can be eliminated at the beta position. However, in a particular case, the method of production and price of the starting materials is often determined. In the case of phase transfer under ether conditions, it is also advantageous from the prior art that, due to the lower polarity of the medium, said elimination side reaction is substantially less preferred, thus the product obtained with the cheapest reagents is also of good quality.

R ₂ can be highly versatile, depending on how stable R ₂ Y is under the reaction conditions. Starting from a simple alkyl group, alkenyl or alkynyl groups may also be substituted by a differently substituted, e.g., halogenated, alkoxylated, simple and branched chain. Preferably, the reaction can be carried out by reaction of halogenated alkyl, for example, 3,3-dichlorobutanyl compounds, with hydrogen halide elimination being carried out in parallel with ether formation, and in one step swallowing the corresponding unsaturated ether, e.g. further eliminated to form alkynyl ether.

The reaction is preferably carried out in an emulsion of an aqueous alkali and a water-immiscible organic solvent, or in the emulsion of the starting materials and the product formed without a solvent. The latter solution, although the reaction is faster, means a particularly favorable industrial implementation. The base is a small excess of strong alkali or alkali metal hydroxides.

As an organic solvent, non-polar aprotic, for example, halogenated solvents, are introduced, most preferably dichloroethane.

Preferably, various tetrasubstituted ammonium salts or hydroxides can be used as phase transfer catalysts. The catalyst should be sufficiently catalytic.

The reaction is preferably carried out with vigorous stirring at room temperature. Ether formation is already rapid at low temperatures, thereby reducing unwanted side reactions. By using a cheaper partner with a small excess, the reaction time can be reduced. The product can be separated from the reaction mixture by simple settling. The resulting crude product is of good quality. Purity 93-95%. Of course, it can be further purified by distillation or, if possible, by crystallization, but can also be used directly. In order to increase its stability and to prevent acid hydrolysis, it is advisable to wash it in neutral and buffer in a basic range. It is recommended to add various antioxidants to ensure safe handling.

Preferred antioxidants are, for example, TMQ; BHT; hydroquinone; hydroquinone monomethyl ether; 2,2,6,6-tetramethyl-4-piperidinol-N-oxide.

To illustrate our procedure, the following examples are given without being exhaustive.

Examples

First

With vigorous stirring of 5 (2-butynyloxymethyl) -6-propyl-1,3-benzodioxole in 40 ml of potassium hydroxide, 1.6 g (0.0225 mol) dissolved in 5 ml of dichloromethane was added. 2-Butin-1-ol and 3.2 g (0.015 mL) of chloromethyl dihydroszafrol and 0.5 g of tetrabutylammonium iodide dissolved in 10 mL of dichloromethane. The mixture was stirred at room temperature for 4 hours. The reaction was monitored by TLC (eluent hexane-EtAc 15: 1). After separation of the phases, the aqueous phase was washed with dichloromethane (2 x 5 mL), and the combined organic phases were washed with neutral ammonium chloride (2 x 5 mL). The oil obtained after drying and evaporation was purified by column chromatography (eluent hexane-EtOAc 15: 1). The yield was 3.0 g (0.01219 mol, 81.3%).

TLC (eluent hexane-EtAc 15: 1) R _f = 0.43.

GC (CP 9000, CP-SIL-5CB, 60 mx 0.53 mm, 5 mL / min N ₂ , FID, 220 ° C) t _R = 9.7 min. about 94.5%.

IR (CHCl ₃ , cm ¹ ) υ:

2950, 2867, 1602, 1502, 1485, 1355, 1260, 1068, 937, 866.

1 H-NMR (200 MHz, CDCl ₃ ) δ:

0.96 (3H, t, J = 7.3 Hz, CH ₃ ), 1.69 (2H, sextet,

J = 7.3 Hz, C H ₂ -CH ₃ ), 1.87 (3H, t, J = 2.3 Hz,

C = C-CH 3, 2.56 (2H, t, J = 7.6 Hz, aryl-Ct ₂ ), 4.10 (2H, q, J = 2.3 Hz, OCH ₂ CsC-), 4, 48 (2H, s,

CH ₂ O), 5.89 (2H, s, OCH ₂ O), 6.66 and 6.83 (2H total, s, aromatic).

¹³ C-NMR (40 MHz, CDCl ₃ ) δ:

3.56 (C = C-CH ₃ ), 14.02 (CH ₃ ), 24.66 (CH ₂ -CH ₃ ),

34.37 (aryl-CH ₂ ), 57.49 (OCH ₂ C = C-), 68.86 (CH ₂ O), 75.21 (C = C-CH ₃ ), 82.51 (CsC-CH ₃ ),

100.77 (OCH ₂ O), 109.49, 109.80 (C-4 and C-7),

128.26 (C-6), 135.53 (C-5), 145.44 (C-7a),

147.18 (C-3a).

Second

(2-Butynyloxymethyl) -3,4-dimethoxy-6-propylbenzene in dichloromethane (1 ml) was dissolved in 1.5 g (0.021 mol) of 2-butin-1-ol and 3.0 g (0, 0131 mol) 1,2-dimethoxy-4-chloromethyl-5-propylbenzene followed by vigorous stirring was added 10 ml of 40% potassium hydroxide and 0.4 g of tetrabutylammonium iodide. The mixture was stirred at room temperature for 2 hours. The reaction is monitored by TLC. After separation of the phases, the aqueous portion was washed with dichloromethane (2 x 5 mL) and the combined mixture (3).

Wash wells with 220 µl of saturated ammonium chloride (2 χ 5 ml) to near neutral. After drying and evaporation, the resulting oil was purified by column chromatography (eluent hexane-EtOAc 4: 1). The yield was 3.1 g (0.0188 mol, 90.3%).

TLC (hexane-EtAc 4: 1): R _f = 0.44 (PMA, UV)

GC (CP 9000, CP-SIL-5CB, 60 mx.53 mm, 5 mL / min N ₂ , FED, 250 ° C) t _R = 7.9 min. about 93.8%. IR (CHCl ₃ , cm ¹ ) υ:

2957, 2932, 2866, 2290, 2220, 1610, 1589, 1511,

1465, 1354, 1272, 1136, 1111, 1065, 997, 864. ¹-NMR (200 MHz, CDCl ₃ ) δ:

0.98 (3H, t, J = 7.3 Hz, CH ₃ ), 1.60 (2H, sextet,

J = 7.3 Hz, Cf ₂ -CH ₃ ), 1.88 (3H, t, J = 2.3 Hz,

C = C-Cf ₃ ), 2.59 (2H, t, J = 7.6 Hz, aryl-C H ₂ ), 3.86 (6H, s, OCH ₃ ), 4.12 (2H, q , J = 2.3 Hz,

OCH ₂ C = C-, 4.52 (2H, s, CH ₂ O), 6.69 and 6.88 (2H total, s, aromatic).

¹³ C-NMR (50 MHz, CDCl ₃ ) δ:

3.52 (C = C-CH ₃ ), 14.06 (CH ₃ ), 24.75 (CH ₂ -CH ₃ ),

34.21 (aryl-CH ₂ ), 55.84 (OCH ₃ ), 57.54 (OCH ₂ CC-), 68.81 (CH ₂ O), 75.22 (C = C-CH ₃ ),

82.41 (C = C-CH ₃ ), 112.64, 112.85 (C-3, C-6),

127.15 (C-4), 134.09 (C-5), 146.76 (C-2), 148.41 (C-1).

Third

5- (2-butynyl-oxy-methyl) -l, 3-benzodioxole

The two steps are carried out without purification of the piperonyl bromide.

Piperonyl alcohol (45 g, 0.295 mol) was dissolved in benzene (550 mL), cooled to 5 ° C, and 48% aqueous hydrogen bromide (150 mL) was added. The mixture was stirred vigorously for 30 minutes under cold and TLC (hexane-EtAc 2: 1) to show the reaction. The two phases are separated, the acidic portion is washed with 50 ml of benzene, and the combined benzene phases are washed with ice-cold 2.5% sodium bicarbonate and saturated sodium chloride solution. Thereafter, about 350 ml of benzene was distilled off from the solution by rotation. The crude product shows traces of starting material by TLC analysis.

To the benzene solution was added 31.5 g (0.45 mole) of 2-butynol, 9 g of tetrabutylammonium iodide and 90 ml of 40% aqueous potassium hydroxide solution and the mixture was intensively stirred for 1.5 hours. stirring at room temperature. TLC control (hexane-EtAc 9: 1) shows the reaction of piperonyl bromide and the appearance of one thing. The two phases are separated, the alkaline portion is extracted with 2 x 30 ml of benzene, and the combined benzene phases are then washed twice with distilled water to a neutral volume with 2 x 40 ml of 20% ammonium chloride solution. After drying and evaporation, the excess oil was removed from the oil in vacuo (80 ° C / 60 torr) under vacuum. The crude product was purified by distillation under motor vacuum.

The collected fractions of 110-120 ° C (0.2 torr) (48.0 g) showed 71.2% purity by GC analysis. Further fractionation was carried out on a Vigreux column about 10 cm long. Evaporations fp. 90-108 ° C / 0.1 torr, 19.8 g, GC% about 68%.

Main Spirits fp. 108-110 ° C / 0.1 t, 25.9 g, GC about 98%.

Further 13.4 g of a uniform product is obtained by repeatedly refolding the pre-evaporates.

The yield was 39.3 g (0.192 mol, 65.3%). n $ = 1.5408

GC (CP 9000, CP-SIL-5CB, 60 mx 0.53 mm, 5 mL / min N ₂ , FID, 250 ° C):

t _R = 4.63 min, about 97.7%. The contaminating piperonyl alcohol t _R = 3.0 min, 1.5%.

TLC (hexane-EtAc 9: 1): R _f = 0.39. The contaminating piperonyl alcohol R _f = 0.05.

IR (CHCl ₃ , cm ^-1 ) υ:

2997, 2946, 2921, 2888, 2376, 1609, 1503, 1491,

1445,1251,1099,1070,1042,937, 865, 810 Ή NMR (400 MHz, CDC1 ₃₎ δ:

1.87 (3H, t, J = 2.3 Hz, Me), 4.10 (2H, q, J = 2.3 Hz,

O-CH ₂ -C =), 4.47 (2H, s, O-CH ₂ -Ar), 5.94 (2H, s,

O-C77 ₂ -O), 6.76 (1H, d, J = 8 Hz, H-7), 6.81 (1H, dd, J = 8.15 Hz, H-6), 6.86 ( 1H, J = 1.5 Hz, H-4) ¹³ C-NMR (100 MHz, CDCl ₃ ) δ:

3.52 (Me), 57.29 (O-CTF ₂ -C =), 71.15 (O-C _7/2 -Ar), 82.54 (C / f = ₃ -C), 100.9 ( C-2),

107.95, 108.71 (C-4.7), 121.66 (C-6), 131.39 (C-5), 147.15, 147.66 (C3a, C-7a)

4th

l, 2-Dimethoxy-4- [l- (Z-oxy-3-chloro-but-2-enyl) ethyl] benzene

Dissolve 1.0 g (5.5 mmol) of alpha-methyl veratril alcohol and 1.44 g (11 mmol) of 1,3-dichlorobut-2-one (mainly Z-isomer) in 10 ml of benzene. 1.23 g (22 mmol) of potassium hydroxide and 1.95 g (5.5 mmol) of benzyl tributylammonium bromide are dissolved in 5 ml of water and the mixture is stirred for 2 days at room temperature. The phases are then separated and the aqueous portion is thoroughly extracted with benzene. The combined organic phases are washed neutral with dilute hydrochloric acid and distilled water, dried and evaporated. The crude product was purified by column chromatography.

Yield 0.47 g (1.7 mmol, 31.5%). Uniform according to GC analysis.

IR (CHCl ₃ , cm -1)

2973, 2931, 2862, 2839, 1659, 1606, 1595, 1511,

1465,1443,1261,1164,1141,1093,1028. 1 H-NMR (200 MHz, CDCl ₃ ) δ:

1.43 (3H, d, J = 6.5 Hz, CH-C / f ₃ ), 1.97 (3H, t,

J = 0.5 Hz, = _CCl-CH3), 3.80 (2H, m, _OCH2),

3.87 and 3.89 (6H total, each, OCH ₃ ),

4.38 (2H, q, J = 6.5 Hz, Ar-Ctf), 5.78 (1H, m,

CH = CCl), 6.83 (2H, d, Ar), 6.87 (1H, d, Ar).

¹³ C-NMR (50 MHz, CDCl ₃ ):

21.23 (= _CC1-CH3), 24.08 _(CH-CH3), 55.84 _(OCH3), 64.10 _(OCH2), 77.05 (Ar-CHO), 108.92 ( C-2), 110.91 (C-5), 118.74 (C-6),

124.43 (CH = CCl), 134.0 (CH = CC1), 135.89 (C-1), 148.49 and 149.23 (C-3 and C-4).

5th

l- [2- (2-butoxyethoxy) ethoxymethyl] -3,4-dimethoxybenzene

In a 100 ml round-bottomed flask, 3.0 g (17.83 mmol) of veratril alcohol was dissolved in 20.0 ml of benzene and le

HU 220 961 B1 was cooled to 10 ° C, then 48% hydrogen bromide (15.0 mL) was added and stirred for 30 minutes. The reaction mixture was separated in a separatory funnel, the organic layer was acidified with NaHCO ₃ and then reduced to two-thirds. To this solution was added diethylene glycol monobutyl ether (4.33 g, 26.7 mmol), 50 mL KOH solution (50 mL), tetrabutylammonium iodide (0.65 g, 1.75 mmol) and overnight. stirring vigorously at room temperature. The mixture was separated in a separatory funnel, the aqueous phase was back-extracted with benzene, the combined organic phases were washed to neutral with water, dried over magnesium sulfate and evaporated. The crude oil was purified by chromatography (eluent: n-hexane-ethyl acetate, 2: 1) _Rf = 0.35.

Yield: 3.62 g (11.59 mmol, 65.1%). IR (CHCl ₃ , cm ^-1 ) υ:

2999, 2958, 2935, 2913, 2870, 2448, 2371, 1722,

1608, 1595, 1513, 1466, 1443, 1420, 1353, 1328,

1265, 1239, 1157, 1140, 1094, 1029, 982, 951, 918,

889, 862, 809.725, 640, 592, 477 H-NMR (200 MHz, CDCl ₃ ) δ:

0.91 (3H, t, J = 7.2 Hz, -O-CH ₂ -CH ₂ -CH ₂ -C 77 ₃ ),

1.36 (2H, m, _{-O-CH2 -CH2 -CH3 2} -C77), 1.55 (2H, m, _-O-CH2 -C _7/2 -CH ₂ -CH ₃₎ 3 , 46 (2H, t,

-O-C7 / ₂ -CH ₂ -CH ₂ -CH _3), 3.63 (8H, m,

-O-C t ₂ -C ₂ -C ₂ O), 3.86 and 3.88 (6H, s, C77 ₃ O),

4.50 (2H, s, C77 ₂ -Ar), 6.79-6.91 (3H, m, Ar) ¹³ C NMR (50 MHz, CDC1 ₃₎ δ:

13.81 (-O-CH ₂ -CH ₂ -CH ₂ -CH ₃ ), 19.4 (-O-CH ₂ -CH ₂ -CH ₂ -CH ₃ ), 31.62 (-O-CH ₂ - CH ₂ -CH ₂ -CH ₃ ), 55.71 and 55.81 (OCH ₃ ), 69.06, 70.0, 70.58, 71.10, (-O-CH ₂ ),

73.02 (Ar-CH ₂ -O), 110.81 (Ar-C-2), 111.04 (Ar-C-4), 120.21 (Ar-C-6), 130.79 (Ar C-7);

148.49 and 148.94 (Ar-C-3 and Ai-C-4)

6th

l- [2- (2-butoxyethoxy) ethoxymethyl] -3,4-dimethoxy-benzene 6propil

Dissolve 5.02 g (21.6 mmol) of 1,2-dimethoxy-4-chloromethyl-5-propylbenzene in 25 mL of dichloromethane, add 5.96 g (36.74 mmol) of diethylene glycol monobutyl ether, , 4 g of n-tributylammonium iodide and 17 ml of 40% NaOH solution. The mixture was stirred overnight at room temperature and the two phases were separated in a separatory funnel. The aqueous layer was extracted with dichloromethane, the combined organic layer was washed with water, dried over MgSO ₄ , and evaporated. The crude product was purified by chromatography (eluent: benzene-ethyl acetate 9: 1) R _f = 0.32

Yield: 5.63 g (15.88 mmol, 74.47%). IR (CHCl ₃ , cm ^-1 ) υ:

3315, 2998, 2959, 2933, 2871, 2418, 2374, 2035,

1617,1350,1272,1224,1112,1035, 997, 893, 867,

839, 641, 556.

1 H-NMR (200 MHz, CDCl ₃ ) δ:

0.91 and 0.96 (3H, t, J = 7.2 Hz, -O- _{(CH2) 3} -C77 _3, and

Ar- (CH ₂ ) ₂ -C 77 ₃ ), 1.33-1.61 (6H, m,

_-O-CH2-C / 7 // ₂ C ₂ CH _3, -CH ₂ CH _{3 2} -C77),

2.57 (2H, m, Ar-C / 7 ₂ -CH ₂ -CH _3), 3.45 (2H, m,

-O-CH ₂ ), 3.57-3.67 (8H, m, 4x77 ₂ CO) 3.68 and

3.86 (6H, s, OCH1), 4.52 (2H, m, Ar-C / ή, -Ο)

6.69 and 6.89 (2H, m, aromatic) ¹³ C-NMR (50 MHz, CDC1 ₃₎ δ

13.82 (-CH ₂ -CH ₂ -CH ₃ ), 14.03 (-O-CH ₂ -CH ₂ -CH ₂ -CH ₃ ), 19.18 (-O-CH ₂ -CH ₂ -CH ₂₎ -CH ₃ ),

24.57 _(-CH2 -C77 ₂ -CH _3), 31.63 _{(-O-CH2 -CH2 -CH2 -CH3),} 34.15 (-CH ₂ -CH ₂ -CH _3); 55.83 (OCH?), 69.27, 70.02, 70.60 and 70.67 _(O-CH2);

71.12 _(Ar-CH2 -O), 112.51 (Ar C-2), 112.64 (Ar C-4), 127.74 (Ar C-7), 133.69 (Ar C-6);

146.75 and 148.22 (Ar-C-3 and Ar-C-4)

7th

7 / 7- (But-2-ynyloxy) ethyl] -3,4-dimethoxybenzene

Dissolve 1.0 g (5.5 mmol) of alpha-methyl veratryl alcohol in 10 mL of dichloromethane, add 1.09 g (8.2 mmol) of 1-bromo-2-butine, 0.2 g of n-tributylammonium. iodide and 10 ml of 40% NaOH solution. The mixture was stirred overnight at room temperature and the two phases were separated in a separatory funnel. The aqueous layer was extracted with dichloromethane, the combined organic layer was washed with water, dried over MgSO ₄ , and evaporated. The crude product (1.15 g) was purified by chromatography. Yield: 0.8 g (3.42 mmol, 62.1%).

n ² D ° 1.5282.

IR (CHCl ₃ cm Ov:

2976, 2855, 2837, 1605, 1595, 1514, 1465, 1419,

1371, 1353, 1311, 1260, 1164, 1141, 1086, 1027,

864

1 H-NMR (200 MHz, CDCl ₃ ) δ:

1.46 (3H, d, J = 6.5 Hz, CH-C77 ₃ ), 1.85 (3h, t,

J = 2.3 Hz, = C-C77 ₃ ), 3.83 and 4.01 (2H, ABX ₃ ,

J _AB = 15.0 Hz, J _ax = Jbx = 2.3 Hz, = C-CT / ₂ -O),

3.87 and 3.89 (6H total, each, O-C77 ₃ ),

4.55 (2H, q, J = 6.5 Hz, Ar-CZ7-O), 6.80-6.89 (3H, m, aromatic).

¹³ C-NMR (50 MHz, CDCl ₃ ) δ:

3.61 (sC-CH ₃ ), 23.76 (CH-CH ₃ ), 55.87 (O-CH ₃ ), 55.96 (= C-CH ₂ -O), 75.36 (= C- CH ₂ )

76.40 (Ar-CH-O), 81.91 (= _C-CH3);

109.06 (C-2), 110.86 (C-5), 118.94 (C-6),

135.30 / C-1, 148.52 (C-3), 149.19 (C-4).

8th

7- [7- (Prop-2-enyloxy) ethyl] -3,4-dimethoxybenzene, (1 (3 ', 4'-Dimethoxyphenyl) ethyl-allyl ether)

The same procedure as in Example 7 was followed by the addition of 3.0 g (0.0164 mol) of alpha-methyl veratryl alcohol and 1.38 g (0.018 mol) of allyl chloride.

The yield was 2.5 g (68.6%).

GC (CP 9000, CP-SIL-5CB, 60 mxO, 53 mm, 5 mL / min N ₂ , FID, 250 ° C) t _R = 3.4 min. about 95%.

IR (CHCl ₃ , cm ¹ ) υ:

3079, 2996, 2973, 2933, 2860, 2838, 1607, 1595,

1510, 1465, 1443, 1419, 1311, 1260, 1164, 1141,

1089,1027,996, 928, 860.

1 H-NMR (200 MHz, CDCl ₃ ) δ:

1.45 (3H, d, J = 6.4 Hz, CH ₃ ), 3.83 AB middle (2H, ABdt, J _AB = 12.7 Hz, J = 1.3, 6.0 Hz,

OC77 = CH _2), 3.89 and 3.87 (altogether 6H, each s, _CH3 O), 4.41 (2H, q, J = 6.4 Hz, CH-O);

EN 220 961 Β1

5.11-5.29 (2H, m), 5.81-6.0 (1H, m), 6.83 (2H, s), 6.89 (1H, s).

* ³ C-NMR (50 MHz, CDCl ₃ ) δ:

24.0 (CH-CH ₃ ), 55.77 (OCH ₃ ), 69.17 (OCH ₂ =),

108.94 (C-2), 110.82 (C-5), 116.58 (CH = CH ₂ ),

118.58 (C-6), 135.0 (Cl), 136.26 (CH = CH ₂ ),

148.29 and 149.11 (C-3 and C-4).

9th

l- [l- (2-butynyloxy) -propyl] -3,4-dimethoxybenzene

The same procedure as in Example 7 was followed by the addition of 1.07 g (5.5 mmol) of 1- [1-hydroxypropyl] -3,4-dimethoxybenzene.

Yield:

77%

Purity (GC):

CP 9000, CP-SIL-5CB, 60 mx 0.53 µm, 5 mL / min.

N ₂ , FID, 220 ° C _R = 13.0 min,> 95%.

IR (CHC1 _3, cm-l) o:

2999, 2959, 2935, 2875, 2856, 2839, 2240, 1608,

1595, 1513, 1465, 1261, 1234, 1162, 1142, 1061,

1028th

1 H-NMR (200 MHz, CDCl ₃ ) δ:

0.84 (3H, t, J = 7.4 Hz, CH ₂ Cl ₃ ), 1.65 and 1.83 (2H total, m each, CH ₂ CH ₃ ), 1.82 (3H, t , J = 2.3 Hz, C = C-CT / ₃ ), 3.84 and 3.86 (6H total, s, CH ₃ O), 3.78 and 3.99 (2H total, ABX ₃ ,

J _ab = 15.0 Hz, J _ax = J _bx = 2.3 Hz, OCH ₂ ), 4.22 (1H, t, J = 6.8 Hz, CH-O), 6.80-6.83 (3H, m, aromatic) (signs of ethyl acetate are displayed at 1.22 (t), 2.01 (s) and 4.08 (q) ppm).

* ³ C-NMR (50 MHz, CDCl ₃ ) δ:

3.55 (C = C-CH ₃ ), 10.23 (CH ₂ CH ₃ ),

30.58 <CH ₂ CH ₃ ), 55.77 (OCH ₃ ), 56.03 (OCH ₂ ),

75.41 (C = C-CH ₃ ), 81.71 (C = C-CH ₃ ), 82.24 (CH-O), 109.34.110.64 (C-2, C-5), 119, 63 (C-6)

133.95 (C-1), 148.44 and 149.09 (C-3, C-4).

10th

l- [l- (2-butynyl-oxy) -2-methylpropyl] -3,4-dimethoxybenzene

The same procedure as in Example 7 was followed except that 1- [1-hydroxy-2-methylpropyl] -3,4-dimethoxybenzene (1.15 g, 5.5 mmol) was weighed. Yield:

65%

Purity (GC):

CP 9000, CP-SIL-5CB, 60 mx 0.53 µm, 5 mL / min.

N ₂ , FID, 220 ° C, t _R = 14.0 min,> 91%.

IR (CHCl ₃ , cm -1) υ:

3029, 2995, 2958, 2937, 2871, 2857, 2839, 2238,

1606, 1595, 1510, 1466, 1443, 1420, 1263, 1238,

1157,1142,1062,1028.

1 H-NMR (400 MHz, CDCl ₃ ) δ:

0.65 and 0.97 (6H total, d each, 7 = 6.8 Hz,

CH (C7 / ₃ ) ₂ ), 1.77 (3H, t, 7 = 2.3 Hz, C = C-Ctf ₃ ),

1.87 (1H, m, C77 (CH ₃ ) ₂ ), 3.80 and 3.81 (6H total, s, OCH ₃ ), 3.71 and 3.95 (2H total, ABX ₃ , 7 _ab = 15.0 Hz, 7ax = 7 _bx = 2.3 Hz, OCH ₂ ), 3.90 (1H, d, J = 8.1 Hz, CH-O), 6.68-6.78 (3H, m , aromatic).

* ³ C-NMR (100 MHz, CDCl ₃ ) δ:

3.39 (C = C-CH ₃ ), 18.87 and 19.16 ((CH / CH ₃ ) ₂ ),

34.32 (CH (CH ₃ ) ₂ ), 55.61 (OCH ₃ ), 56.11 (OCH ₂ ), 75.44 (C = C-CH ₃ ), 81.37 (OC-CH ₃ ), 86.25 (CH-O), 109.76 (C-5), 110.32 (C-2), 120.19 (C-6), 132.91 (Cl), 148.24 (C-4) ) and 148,80 (C-3).

11th

l- (but-2-ynyloxy-methyl) naphthalene

Dissolve 1.50 g (21.4 mmol) of 2-butin-1-ol in 10 mL of dichloromethane, add 1.71 g (21.0 mmol) of 1-chloromethylnaphthalene, 0.4 g of n-tributylammonium. iodide and 10 ml 40% KOH solution. The mixture was stirred overnight at room temperature and the two phases were separated in a separatory funnel. The aqueous layer was extracted with dichloromethane, the combined organic layer was washed with water, dried over MgSO ₄ , and evaporated. The crude product was uniform at 3.61 g (17.2 mmol, 81.8%) according to GC analysis.

IR _(CHCl3, cm - ') u:

3044, 3001, 2945, 2920, 2854, 1598, 1509, 1356,

1166,1086,1067 1 H-NMR (400 MHz, CDCl ₃ ) δ:

1.93 (3H, t, J = 2.3 Hz, C = C-Cf ₃ ), 4.22 (2H, q,

J = 2.1 Hz, O-C7 / ₂ -C = C), 5.06 (2H, s,

C ₁₀ H ₇ -CH ₂ -O), 7.45 (1H, t, J = 8 Hz), 7.53 (3H, m), 7.84 (1H, d, J = 8, 1 Hz), 7.88 (3H, m), 7.88 (1H, d, J = 7.7 Hz), 8.19 (1H, d, J = 8.2 Hz) &lt; ³ &gt; C-NMR (100 MHz, CDCl3) ₃ ) δ:

3.6 (C = C-CH ₃ ), 57.71 (O-CH ₂ -C = C), 69.72 (C ₁₀ H ₇ -CH ₂ -O), 75.10 (O-CH ₂ - C = C), 82.76 _(O-CH2 -CsC), 124.03, 125.10, 125.72, 126.19,

126.85, 128.43, 128.72, 131.79 (C-8a), 133.06,

133.70

12th

5- [2- (2-Butoxyethoxy) ethoxymethyl] -6-propyl-1,3-benzodioxole, PBO

2.98 g of 5-chloromethyl-dihydro-safrole (14.02 mmol), 2.72 g of diethylene glycol monobutyl ether (16.82 mmol), 15 ml of dichloromethane are charged into a magnetic stirrer, 15 ml of dichloromethane, 10 ml of 40% potassium hydroxide solution and 0.51 g (1.38 mmol) of tetrabutylammonium iodide. The emulsion is reacted with vigorous stirring for 4 hours. The reaction was monitored by TLC. After the disappearance of the starting benzyl chloride, the mixture was settled, the phases were separated, the organic layer was washed with water, dried and evaporated. The product was distilled under vacuum. Fp: 180 ° C / 1 mm Hg. The substance is identical to commercial PBO. Yield 4.0 g (90%). Purity (GC) 98%.

Claims (7)

PATENT CLAIMS A process for the preparation of mixed ethers of formula I wherein: Ar is optionally substituted by one or more _{C) 4} alkoxy, methylenedioxy, C, _ ₄ alkyl, halogen, C _1-4 haloalkyl, or nitro, and benzo-fused alicyclic, aromatic or one or more heteroatom-containing heterocyclic / or group, HU 220 961 Bl R ¹ is hydrogen, C _l4 alkyl, Cj_ ₄ haloalkyl, C ₂ _ ₄ alkenyl, phenyl, substituted phenyl, C ₃ _ ₆ cycloalkyl, R ² optionally C, _ ₆ alkyl, Cj_ ₆ alkoxy, C ₃ _ ₆ alkenyl, C ₃ _ ₆ alkynyl, Cj_ ₆ haloalkyl or halogen singly or multiply substituted C \ _ ₆ alkyl, C ₃ _ ₆ alkenyl or C ₃ _ ₆ alkynyl; or C ₄ alkyloxy Cj_ ₄ alkoxy Cj_ ₄ alkyl. n = 1, 2 compounds of formula (II) wherein R ¹ and n are as defined above X is a hydroxy, halogen or sulfoester leaving group, and compounds of formula III wherein: R ² is as defined above, Y is a hydroxy, halogen or sulfoester leaving group, with the proviso that one of the reaction partners of formula (II) and (III) is an alcohol, characterized in that the reaction is carried out under heterogeneous conditions at 1.0 to 20.0 molar equivalents of base. It is carried out in the presence of -50% by weight aqueous solution and phase transfer catalyst, and the resulting product is optionally stabilized by addition of a base and / or antioxidant. 2. A process according to claim 1, wherein the compounds of formula (II) and (III) are used in a molar ratio of 0.4 to 2.5. Process according to Claim 1 or 2, characterized in that 1.0 to 10.0 molar equivalents of base, preferably alkaline or alkaline earth metal hydroxide, preferably 2.0 molar equivalents of potassium hydroxide or sodium hydroxide, are 10 to 40% by weight. aqueous solution. 4. Process according to any one of claims 1 to 3, characterized in that various ammonium salts or hydroxides, preferably tetrabutylammonium bromide or iodide, are used as the phase transfer catalyst. 5. The process according to any one of claims 1 to 4, characterized in that the phase transfer catalyst is used in an amount of 0.01 to 1.0 molar equivalent, preferably 0.1 molar equivalent. 6. Process according to any one of claims 1 to 3, characterized in that the reaction is carried out in the absence of a solvent or in an apolar aprotic solvent, preferably dichloroethane. 7. Process according to any one of claims 1 to 3, characterized in that the reaction is carried out at (-10) to (+ 100) ° C, preferably at room temperature.