4-methoxyethyl-2-tert.butylphenol as intermediates in the synthesis of metoprolol and its analogues


(57) Abstract:

The invention relates to 4-methoxyethyl-2-tert.-butylphenol (1) (alkyl = ethyl-, propyl-), which is obtained by processing 4-chloroalkyl-2,6-di-tert.-butylphenols the sodium methylate or sodium hydroxide solution in methanol) under heating, followed by thermolysis of the resulting 4-methoxyethyl-2,6-di-tert. -butylphenol at 280 - 290oC. Advantages of compounds 1: more technological way of getting 1, a greater purity of the subsequent intermediates and metoprolol, the possibility of obtaining analogues of metoprolol.

The invention relates to new derivatives of tert.-butylphenol, specifically to 4-(-methoxyethyl)-2-tert.-butylphenol formula:

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as intermediates in the synthesis of metoprolol and its analogues, which are known drugs for the prevention of arrhythmias and myocardial infarction.

Compounds 1A,b are not described in literature.

Object of the invention is improved method of producing metoprolol and its analogues, which will produce the desired products with high degree of purity and a more simple technological scheme.

The described connection 1 use the camping metoprolol and its analogues according to scheme I:

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according to which compound 1 is subjected to thermolysis at 290 300oC and obtained with the yield of 70 77% 4-( -methoxyethyl)phenols (II) alkylate with epichlorohydrin under 100oC. After evaporation of epichlorohydrin, taken in excess, get the mixture in the amount of 90 94%) 3-[4-( w-methoxyethyl)phenoxy]-1-chloropropanol-2 (III) and 1,2-epoxy-3-[4-(w-methoxyethyl)phenoxy]propane (IV), which, without separating, heated with Isopropylamine and get metoprolol (VA) with yields of 80% or its analogs. Then in complex with tartaric acid is prepared tartrate metoprolol, which is the current top of the dosage form.

Previously metoprolol (VA) was obtained according to scheme 2, according to which the phenol (II) was synthesized from nitro-derivatives (VI) [1]

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Recovery VI with hydrogen leads to the amine (VII). This amine diasterous and received diazoketone (VIII) hydrolyzing, which leads to 4-(2-methoxyethyl)phenol IIA with the release of 40% [1] Subsequent stages leading to metoprolol, chemistry similar to the previously proposed scheme I [2,3]

The main disadvantage of the circuit 2 is a low yield of 4-(2-methoxyethyl)phenol.

Known intermediate nitrosoaniline (VI) produced by two different schemes. Implemented a method of obtaining it from 2-femilet is Ali, getting microproduct VI with the release of 55% of the disadvantages of this scheme include low yield of the target product VI, as well as the difficulties associated with separation of p-isomer formed from a mixture of o-, m - and p-isomers.

Known another approach to the synthesis of microproduct VI interaction 4-bromonitromethane and methylvinylether ether, followed by reduction with hydrogen condensation products of [2,4,5] the Process is carried out according to the scheme:

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The main disadvantage of the scheme is the absence in Russia production of both components, and the synthesis metilfenidato ether technologically harmful [6] in Addition, the presence of stage synthesized requires regeneration of bromine and stage nitration thorough cleaning from isomers.

In these examples, the synthesis of metoprolol loss products associated with the introduction of the hydroxyl group in the aromatic fragment intermediates reach 75%

New intermediate compounds 1, obviously containing in its structure a hydroxyl group, get on the scheme:

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according to which 4-( -chloroalkyl)-2,6-di-tert.-butylphenol (IX) derived from 2,6-di-tert. -butylphenol [7] is heated with sodium methylate or sodium hydroxide in methanol, the oC leads to compounds 1 (example 2), further heating which at 290 300oC gives 4-methoxyaniline (example 3) with the output 70 of 77% Technologically transformation of compounds X in methoxyacetophenone II is carried out in the same vessel (example 4).

Thus obtained, the compound (II) possess a high degree of purity. So, technical 4-(2-methoxyethyl)phenol (II-a) with a basic substance content (OWLS) 97% melts in the range of 35 of the 37oC, and purified by crystallization from toluene has so pl. 41 43oC. In the literature, this connection is known as oil [8] or as a solid with so pl. 27 29 oC [9] This difference in the purity of the products is a natural consequence of the chosen scheme of synthesis, in which there are no processes leading to the formation of isomers.

The use of more pure compounds II in the synthesis of metoprolol resulted in cleaner metoprolol with so pl. 47.0 48.5oC (described as oil [3,8]) and tartrate obtained on its basis, so pl. 117 118oC (cf. with so pl. 114 -116oC) [10]

New intermediate compound I in the synthesis of metoprolol and its analogues in comparison with the known intermediate product VI have the following advantages:

in a more technical way poluchaiutsea product II,and, and the metoprolol obtained with lower cost;

more ease and simplicity of obtaining 4-methoxyacetophenone, which is of independent interest [II]

the ability to obtain analogues of metoprolol and dosage forms based on them.

Example 1. Getting 4-(2-methoxyethyl)-2,6-di-tert.-butylphenol (X,a).

In the autoclave Vishnevsky with a capacity of 1.5 liters of load 322 g of 4-(2-chloroethyl)-2,6-di-tert. -butylphenol (IX, a) with OWLS 94% and 70 g of sodium methylate in 1 l of methanol. The reaction mass is heated with stirring for 6 h at 100oC, cooled to room temperature and the contents are neutralized with hydrochloric acid. The precipitated sodium chloride is filtered off and the filtrate evaporated. The remainder of 310 g distilled in vacuum, collecting the fraction wikipaedia in the range of 140 to 150oC/2 3 mm RT.article Receive 250 g of compound X,and so pl. 52 54oC (OWLS 97%).

Example 2. Getting 4-(2-methoxyethyl)-2-tert.-butylphenol (I,a).

In the flask is heated under reflux 264 g (1 mol) of 4-(2-methoxyethyl)-2,6-di-tert. butylphenol (X, a) for 8 hours at a temperature of 285 295oC. Receive 214 g of colorless oil, containing according to GC 95% of product I, and which is dissolved in toluene, washed with 2% alkaline solution.article Get the product I,and in the form of oil. Found: M/z 208.1460. C13H20O3. Calculated: M/z 208,1463. Range PMR (CCL, d M. D. from TMS): 1.33 (C. 9H, C4H9); 2.74 (t, J=7 Hz, 2H, -CH2Ar); 3.33 (C. 3H, CH3O-); 3.54 (t, J=7 Hz, 2H, -CH2O-); 5.95 (S. IH, -OH); 6.31 (doctor of Jortho=8 Hz), 6.72 (m, Jortho8 Hz, Jmeta=2 Hz), 6.94 (doctor of Jmeta=2 Hz) band signals of the protons of the aromatic ring, 3H).

Example 3. Getting 4-(2-methoxyethyl)phenol (II-a) from compound I,and.

In a distillation flask with a reflux condenser are placed 191 g of compound 1,and (OWLS 95% ) and heated in a stream of nitrogen at the temperature of the reaction mass 295 - 300oC for 36 hours and Then the extract continue for another 12 h with the selection of products, wikipaedia not higher than 270oC. Obtain 120 g of oil containing 75% of compound (11), and. It is dissolved in toluene and shaken with 1 l of 4% aqueous solution of alkali. In toluene solution is separated and evaporated, receiving compound 1,a (COS 90%).

The aqueous layer was acidified with hydrochloric acid, extracted with toluene and the extract evaporated. The remainder (95 g of oil) is distilled under vacuum, collecting the fraction with so Kip. 130 135oC/2 3 mm RT.article Get 75 g of compound (11) and (OWLS 97%). Yield 60%

Example 4. Getting 4-(2-methoxyethyl)phenol (11) of the compounds X and I,and.

remaut in a weak stream of nitrogen at 290 300oC for 30 hours and Then the shirt distillation column is heated to 280oC and begin to pick a faction, wikipaedia at 271 273oC. Reflux number 6. The distillation continued for 18 hours Obtain 110 g of compound (II), and (OWLS 92%). Vakuumnaya by distillation VAT residue receive an additional 12 g of product II,and (OWLS 80%). The remote sites are combined and distilled under vacuum, collecting the fraction with so Kip. 131 135oC/2 3 mm RT.article Get 110 g II, and (OWLS 97% ), so pl. 33 35oC. After crystallization from toluene so pl. 41 43oC.

From VAT residue by vacuum distillation allocate 12.5 g I,and faction with so Kip. 140 160oC/2 3 mm RT.cent.).

Exit II,and, considering the new reaction products, is 77%

Example 5. Receiving metoprolol (V,a).

A mixture of 141 g (0.9 mol) of 4-(2-methoxyethyl)phenol (II,a), 570 ml epichlorohydrin and 1.5 ml of piperidine is heated with stirring 4 h at 100oC. Then the reaction mass is distilled off, the epichlorohydrin to the content in the reaction mass is not more than 5% Receive 223 g of oil containing 12% of 1,2-epoxy-3-[4-(2-methoxyethyl)phenoxy] -propane and 79% 3-[4-(2-methoxyethyl)phenoxy]-1-chloropropanol-2. This mixture is placed in a rotating autoclave along with 300 ml of Isopropylamine and 350 ml of isopropanol and vydareny the solution washed with 10% alkali solution, then water and dried with magnesium sulfate. After evaporation of the solvent receive 176,7 g hard metoprolol (V,a) with so pl. 39 -46oC, after crystallization from hexane with the addition of methylene chloride so pl. 47,0 - 48,5oC.

In isopropanol mix 154 g of metoprolol (V,a) with so pl. 39 46 oC and to 38.8 g of tartaric acid and heated while stirring at 50oC for 0.5 h, cooled to room temperature and incubated for 12 hours the precipitation is filtered off and dried in air to constant weight. Get 143,6 g tartrate metoprolol with so pl. 116 118oC (according to [10] T. pl. 114 - 116oC).

Example 6. Getting 4-(3-methoxypropyl)-2,6-di-tert.-butylphenol (X,b).

In steel rotating autoclave with a capacity of 0.2 l placed 60 g (0,264 mol) of 4-(3-chlorpropyl)-2,6-di-tert.-butylphenol (IX,b) and 13.5 g (0.25 mol) of sodium methylate in 70 ml of methanol, maintained at a rotating autoclave for 8 hours at 135oC. After cooling to room temperature the reaction mass is neutralized with hydrochloric acid, the precipitated sodium chloride is filtered off and the solvent evaporated. Obtain 57 g of 4-(3-methoxypropyl)-2,6-di-tert.-butylphenol (OWLS 86% ), which is clear, turning in a vacuum. Collect the fraction with so Kip. 155 160oC/4 mm RT.article and receive 4-(3-methoxypropyl)phenol (II,b).

In the cube distillation column load 211 g (0.75 mol) of 4-(3-methoxypropyl)-2,6-di-tert.-butylphenol and stand in a stream of nitrogen at 295 -300oC (the temperature of the reaction mass). After aging the reaction mass is then cooled, dissolved in 150 ml of toluene and vigorously shaken with a solution of 30 g of alkali in 0,5 l of water. From the toluene layer emit connection I,b, and water-II,b.

The balance of 30 g, obtained after evaporation of toluene layer is distilled in vacuum, collecting the fraction with so Kip. 165 170 oC/5 mm RT.article Obtain 18 g of 4-(3-methoxypropyl)-2-tert. -butyl-phenol (I, b) (COS 98% ). Found: M/z 222,1622. C14H22O2. Calculated: M/z 222,1619. Range PMR (CCl4d M. D. from TMS): 1,34 (C. N, C4H9-tert.); is 1.81 (m, 2H, -CH2-); 2,53 (so J=7 Hz, 2H, -CH2Ar); 3,31 (C. 3H, CH3O); to 3.38 (t, J=7 Hz, 2H, -CH2O-); 6,05 (S. IH, OH); 6,40 (doctor of Jortho8 Hz), of 6.68 (m, Jortho=8 Hz, Jmeta=2 Hz), 6.90 to (doctor of Jmeta=2 Hz) band signals of the protons of the aromatic ring, 3H. UV spectrum (C2H5OH, lmax(lg nm): 279,5 (3,2).

To obtain a compound (II), b the aqueous layer was acidified with hydrochloric acid to pH 5.0 and the product II,b is extracted with toluene. After evaporation of the solvent to obtain 95 g of 4-(3-methoxypropyl) phenol (OWLS 95%), oil yield was 73% PMR Spectrum (CCl4d M. D. from TMS): 1,82 (m, 2H, -CH2-); of 2.58 (t, J=7 Hz, 2H, ArCH2-); 3,34 (C. 3H, CCH3); 3,39 (so J=7 Hz, 2H, -CH2-); 4,93 (S. IH, -OH); 6,70 6,90 and system AA'BB', 4H, Ar-H).

Example 8. The intermediate formation of compound I,b in the synthesis of 4-(3-methoxypropyl) phenol (II,b).

Thermolysis of a sample of 4-(3-methoxypropyl)-2,6-di-tert.-butylphenol (X,b) at a temperature of 295 300oC under the conditions of example 7 through 14 hours gave a product containing data GC 2% of the parent compound X,b, 19% of compound (II), b and 74% of 4-(3-methoxypropyl)-2-tert.-butylphenol (I,b).

Example 9. Getting 1 isopropylamino-3-[4-(3-methoxypropyl)-phenoxy]propanol-2 (V,b).

A mixture of 15.2 g (0.1 mol) of 4-(2-methoxypropyl)phenol, 65 ml of epichlorohydrin and 0.17 ml of piperidine is heated with stirring 4 h at 100oC. Then the reaction mass is distilled off, the epichlorohydrin to the content in the reaction mass is not more than 5% Gain of 29.3 g of oil containing 24% of 1,2-epoxy-3-[4-(2-methoxypropyl)phenoxy] -propane and 59% 3-[4-(2-methoxypropyl)phenoxy]-1-chloropropanol-2. This mixture is placed in a rotating autoclave along with 35 ml of Isopropylamine and 45 ml of isopropanol and incubated for 12 h at 100oC. and Then distilled off the mixture of Isopropylamine and solvent, the residue is dissolved in ether. The ether solution is washed bukta V,b so pl. 40 50oC, after crystallization from hexane with the addition of dichloroethane so pl. 53 54oC. Found? C 67,54; H 9,26; N 5,04. Calculated C 67,39; H 9,42; N 5,23. Range PMR (CCl4d M. D. from TMS); 1,05 (D. 6N); to 1.75 (m, 2H); 2,55-2,77 (m, 2H); 3,23 (C. 3H); of 3.77-3,88 (m, 3H); 6.73 x-6,97 (system AA'BB', 4H).

Example 10. Getting tartrate V,b.

A mixture of 2.0 g of product V,b and 0.5 g of tartaric acid in 15 ml of isopropanol is heated, stirring, for 15 minutes at 50 to 60oC. the resulting solution was cooled to room temperature and was incubated for 6 hours the precipitation is filtered off, washed with isopropanol and air-dried to constant weight. Get 1.9 grams (80,5%) tartrate product V,b so pl. 106 - 107 oC. Found; C 61,18; H 8,62; N 3,86. Calculated C 60,88; H By 8.22; N 3,93.


1. Synthesis and analytical study of 4-(2-methoxyethyl)phenol Tyrazol// Rutkowska-Olma E. Sazala W. Kulawinek J. M.// Barwniki Srodki Pomocnicze 1988 at M.V.Lomonosov 32 (3) p. 55-61 // Chem. Abstr. 1989 111 - 57149v.

2. Preparation of salts of ()-1-isopropylamino-3-[4-(2-methoxyethyl)phenoxy] -2-propanol, especially the tartrate of ()-1-isopropylamino-3-[4-(2-methoxyethyl)phenoxy] -2-propanol// Zjawiony J. Kaczur-Kaczynski E. at al.//Pol. PL 158.497 (Cl. C 07 C 217/32)// Chem. Abstr. 1993 119 203128w.

3. Phenoxy-hydroxypropylamines, metod and pharmaceutiical preparations for treating cardiovascular diseases // A. E. Brandstrom, P. A. E. Carlsson at al. // Pat. US 3928601 (US Cl. 424/300, 424/330. Int Cl2A 61 K 31/27) - 1975.

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7. The method of obtaining 4-haloalkyl-2,6-di-tert.-butylphenol// Patent of the Russian Federation (the class C 07 C 39/24, 37/62), N 1376511, 1985.

8. Synthesis of cabon-14-labelled metoprolol //N. Chaudhuri K. Ball, T. J. // J. Labelled Comp. Radiopharm, 1981, 18 (9) p. 1273-1281.

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4-Methoxyethyl-2-tert.butylphenol formula I

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as intermediates in the synthesis of metoprolol and its analogues.


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