LV11864B - Method for preparation of methoxy-alpha-methylbenzyl alcohol - Google Patents

Abstract

The invention refers to the method of obtaining methoxy-α-methyl-benzyl-spirit from methoxy-alpha-methyl-benzyl-bromide. It is found that silica gel can be successfully used for hydrolysis, which surface water and possibly hydroxyl group easily react with methoxy- replaced α-methyl-benzyl-bromide, practically quantitatively changing them in the end-product. The process is being realized in chromatography division mode on the colon.

Description

Process for the preparation of methoxy-c-methylbenzyl alcohol

The present invention relates to a process for the preparation of methoxy-α-methylbenzyl alcohol which is used as intermediates for the synthesis of physiologically active substances, pharmaceutical preparations and polymeric materials [1-4].

Methods for the preparation of methoxy-α-methylbenzyl alcohols described in the literature are based on: 1) reduction of methoxyacetophenones [1,5-8] and 2) reaction of methoxybenzaldehydes with organometallic compounds (Mg, cuprates) [9-10]. Methoxyacetophenones are reduced with sodium or potassium borohydride in water methanol

0 or aqueous ethanol solution yields 70-85% of the product [1] in 5 hours or anhydrous methanol, the process proceeds at a higher rate (45 min) and the product yields 90% [5j. Another variant of selective reduction using sodium borohydride and glacial acetic acid as a solvent or sodium borohydride in tetrahydrofuran in the presence of stoichiometric amount of acetic acid is also proposed [6]. In this case, the reaction is slower compared to the alcoholic solution. The reduction of methoxy-substituted acetophenones with sodium borohydride is also carried out under phase transfer catalytic reaction conditions. The reaction is carried out in a water-toluene mixture in the presence of benzyltriethylammonium chloride. The yield of 4-MeOC ₆ H ₄ CH (Me) OH is 98.7% [7,8]. In all but the last case, the product is preceded by labor-intensive treatment, that is, by acidification or alkalization, as appropriate, by repeated extraction with ether and by vacuum distillation.

From the corresponding benzaldehyde derivatives, the target product is synthesized by the Grignard reagent, which is usually obtained in ether from methyl iodide. 2-MeOC ₆ H ₄ CH (Me) OH yields 56%, 4-MeOC ₆ H ₄ CH (Me) OH 62% [9] and 3-MeOC ₆ H ₄ CH (Me) OH 85.4% [3]. The low yield, especially for the o- and p-isomers, is due to the fact that the dealkylation process takes place in parallel with the basic reaction [9]. There is also described a process according to which LiCu (CH ₃ ) ₂ reacts readily with aldehyde to form a secondary alcohol in a 1,2-addition reaction [10], so that 4-methoxybenzaldehyde in the presence of LiCu (CH ₃ ) ₂ in ether at -10 ° C is practically is quantitatively converted to 4-methoxy-a-methylbenzyl alcohol [10]. The disadvantage of the above techniques is that they require the precautions required for handling organometallic compounds.

One of the simplest and most convenient methods for obtaining methoxy-a-methylbenzyl alcohol may be by hydrolysis of the corresponding halogen derivatives.

Although this technique has not been described for the claimed compounds, it is known that the presence of an aromatic radical at the carbon atom bound to halogen has a positive effect on its motility. The primary and secondary halogen derivatives are usually hydrolysed with aqueous sodium hydroxide (or potassium hydroxide) solution, or with suspensions of calcium or barium carbonate, or freshly precipitated lead oxide, and usually by heating. Sometimes freshly deposited is used

- 2 silver oxides which react with halogen derivatives already in the cold [11-13]. But it is also known that in parallel with alcohols, small amounts of unsaturated side-chain compounds are formed, resulting in a target product yield of up to 75-80% [12],

It is an object of the present invention to provide a novel process for the exchange of halogen atoms with a hydroxyl group using methoxy-α-methylbenzylbromides as starting materials which allows the final product to be obtained in a sufficiently high yield without further purification.

The objective is achieved by the use of silica gel for hydrolysis, the surface water and possibly hydroxyl groups of which are readily reacted with the above compounds, practically quantitatively converted into the corresponding alcohols. The process is carried out by column chromatography on a column. The proposed process is only selective for α-monobromo derivatives with a methoxy group in the aromatic ring and can therefore be successfully used to obtain the claimed compounds and to simultaneously release them from the mixtures.

1. Example. 0.95 g (90% purity, ~ 4 mmol) of o-methoxy-α-methylbenzylbromide was passed through a column (40 x 2 cm) of silica gel (Silica Gel Woelm, Eschvege, Germany) using hexane-ethyl acetate (v / v) as eluent. : 15. Collect the fraction with R _t = 0.24 and evaporate the solvent in vacuo. The yield of 2-methoxyα-methylbenzyl alcohol is 0.57 g or ~ 94%. The purity by HPLC (Silasorb 600 4.6 x 250, UV = 254 nm, eluent: 4% ethyl acetate + hexane) is 98%.

Elemental _Analysis (C 8 H ₁₂ O 2): calculated,%: C 71.03; H, 7.95;

Found:% C, 70.58; H, 7.95.

NMR (0, ppm, CDC1 _3): 1.44 (d, 3H, CH _3, J 6 Hz); 3.40 (s, 1H, OH); 3.80 (s, 3H, OCH 3); 5.06 (kv, 1H, CH); 6.72-7.35 (m, 4H, arom).

2. Example. 1.65 g of a mixture of 0.52 g of 2-methoxyethylbenzene, 0.69 g of 2-methoxy-α-methylbenzyl bromide, 0.20 g of 2-methoxy-α, β-dibromo-styrene and 0.24 g of 2-methoxy -a, a-dibromomethylbenzene is passed through a column as described in Example 1. Collect the fraction with R _t = 0.24 and evaporate the solvent in vacuo. The yield of 2-methoxy-α-methylbenzyl alcohol is 0.45 g or about 92%. Purity by AESH - 97.6%.

All other fractions have a total mass of 0.89 g and correspond to the original composition.

Example 3. 1.5 g of a mixture of 0.63 g of 2-methoxy-α-methylbenzyl bromide, 0.53 g of 2-oxy-α-methylbenzyl bromide and 0.34 g of 2-acetoxy-α-methylbenzyl bromide are passed through a column as described. In Example 1. Collect the fraction with

- 3 Rf = 0.24, the eluent is evaporated off under vacuum. The yield of 2-methoxy-α-methylbenzyl alcohol is 0.41 g or about 92%. Purity by AESH - 97.8%.

All other fractions have a combined weight of 0.83 g and correspond to the original composition.

Claims (2)

Formula of the Invention 1. Process for the preparation of methoxy-a-methylbenzyl alcohol from methoxy-a-methylbenzyl bromide, characterized in that silica gel is used for the hydrolysis, 5 whose surface water and possibly hydroxyl groups are readily reacted with methoxy-substituted α-methylbenzyl bromides to substantially quantify it into the target products. 2. A process according to claim 1, wherein the process is carried out by column chromatography on a column. Method according to claim 1, characterized in that methoxy-α-methylbenzyl alcohol is obtained and simultaneously isolated from various mixtures.