FI67690B - PROCEDURE FOR FRAMSTAELLNING AV 3,4-DI-ISOBUTYRYLOXY-N-METHYL-PHENETHYLAMINE - Google Patents

Description

67690

Process for the preparation of 3,4-diisobutyryloxy-N-methylphenethylamine - Preparation of 3,4-diisobutyryloxy-N-methylphenethylamine.

5

The invention relates to a new process for the preparation of 3,4-diisobutyryloxy-N-methylphenethylamine (i) or ibopamine (ch3) 2ch-coo- / QV-ch2ch2nhch3 10 ^ '(I) (CH3) 2Ch-COO // and pharmaceutically acceptable acid addition salts thereof.

15 Ibopamine is a known cardiac drug used especially for heart and kidney failure.

Only two methods are known for the preparation of ibopamine, which are described, for example, in GB Patent 1551661. The methods can be schematically represented as follows.

HCr / (J) VcH2CH2-NH-CH3 (CH2 ^ -CH-CO-Hal ^ HO "^ 'strong mineral acid epinine (ch3) 2ch-coo- ^ ch2ch2-nh-ch3 (ch3) 2ch-coo - ^ - Ibopamine (i) 67690

Epinine CICOOCH2 / 7Λ f1 * 3 / 7Λ - ^ H0 \ O Wh2-NC ° och2- <O / (CH3) 2CHCO3Hal (CH3) 2CH-C00— / Q \ -CH2cH2-n-COOCH? - / q \ ^ ( ch3) 2ch-cooX- '' - '10 catalytic hydrogenation ^ (i)

Hai = halogen

The process is thus either 1- or 3-step, but in both cases the starting point is epinine, which is an expensive and difficult to obtain substance. The yield does not mention any yields. Since no protecting group is used in the 1-step process, the yield would be poor, as by-products are likely to be formed in the reaction. In addition, the esterification is performed with acid chloride alone without a base. In general, esterification of phenol groups without a base is a slow and incomplete reaction. In the 3-step process, the corresponding hydrogenamide is probably formed as a by-product in the last hydrogenation step, so this method cannot give very good yields either.

25

The present invention starts from another starting material, namely 3,4-dimethoxyphenethylamine, which is a cheap Suur production raw material. The process according to the invention is a 3-step process, but since the starting material is so much cheaper than epinine and all steps are successful in excellent yields and are easy to carry out on a production scale, the process is considerably more advantageous than the known methods described above.

Il 3 67690

The invention can be described by the following synthetic scheme 11a: / _y t_v H2, catalyst ^ CH3O- / OVcH2CH2nH2 + / q \ -CH0 + c = o ^

5 CH 3 O 3 - '' - 'H

r> οη3ο7 Q Vc ^ chjNchj ^ O / ch3o - ^ - 7 (II) 10 HBr, H2O HOTOVCH2CH2-LCH2- ^ 0> (CH3) 2CH-COC1 ^ HO "^ 7 '* base (III) 15 (CH3) 2Ch-COO— / q \ -H?> Catalyst ^ (I) (C ^ ^ CH-COO - ^ "" · 7 (IV) 20 In this process, essentially the first step is inventive. First, as is said, it starts from a cheap starting material. monomethylation of the primary amine in good yield is often difficult, as can be seen, for example, in S 25 Krishnamurthy, Tetrahedron Letters 23 (1982) 3315. in the same way as in the method according to the invention.

67690

K Fujimori et al., Tetrahedron Letters 21 (1980) 3385-8) describes the reductive alkylation of amines with, for example, benzaldehyde and formalin in excess of selenophenol. D B Repke et al., Tetrahedron Letters 20 (1979) 5 4183-4 again describes the reaction of N-methylbenzylamine with a carbonyl compound followed by catalytic hydrogenation.

In the present invention, it is this simultaneous monomethylation and benzyl protection that is inventive. The benzyl group is a very good protecting group for the whole series of syntheses because it can withstand both acidic and basic conditions. The benzyloxycarbonyl protecting group of the known method could not have been used because it cleaves off under acidic conditions (McOmie: Protective Groups in Organic Chemistry, Plenum Press, London and 15 New York 1973, 56).

In the next step, the methoxy groups are converted into hydroxyl groups by a method known per se. The yield is quantitative. When the obtained intermediate (lii), which does not need to be isolated, is esterified with isobutyryl chloride in the presence of a base in the next 20 steps, this step is also successful in good yield. In the last step, the benzyl protecting group is removed by hydrogenation in the presence of a catalyst, which is also an almost quantitatively successful reaction.

25

Since it is not necessary to isolate intermediate (III), the process according to the invention is in practice a 3-step process.

Intermediate IV is a new compound.

30

In the first step, 3,4-dimethoxyphenethylamine, benzaldehyde and formaldehyde are hydrogenated in the presence of a catalyst, for example palladium carbon, at either normal pressure or low overpressure, preferably 2-3 atm, and the temperature is either room temperature or slightly higher, preferably 20- 30 ° C.

li 67690 5

As the solvent, an organic solvent is used, for example, ethanol or a mixture of ethanol and methylene chloride (1: 1). The desired product, N-benzyl-N-methyl-3,4-dimethoxyphenethylamine (II), is obtained in very pure form when compounded as an acid addition salt, for example hydrobromide. As a free base, the product is oily and difficult to handle.

In the second step, the methoxy groups are converted to hydroxyl groups, for example, by boiling in concentrated hydrobromic acid under nitrogen. After neutralization, the product III is extracted into an organic solvent, for example methylene chloride, to which isobutyryl chloride is added either as such or dissolved in an organic solvent. The esterification is carried out in the presence of a base at a low temperature, preferably below 30 ° C. As the base, for example, an organic base such as an organic amine, preferably triethylamine, is used. Compound (IV) is isolated as an acid addition salt, for example by introducing hydrogen chloride gas into the solution to give IV hydrochloride. It is preferred to isolate the product as a salt and use it as such in the next hydrogenation step. If compound (IV) is used in base form in the hydrogenation, a side product of the corresponding acetamide is formed.

In the last step, the benzyl protecting group is removed by hydrogenation in the presence of a catalyst, for example palladium on carbon. The pressure 25 is a normal pressure or a slightly elevated pressure, preferably 2-3 atm. The temperature is room temperature or elevated temperature such as 20-50 ° C. An organic solvent, preferably glacial acetic acid, is used as the solvent. If the starting material is IV x HCl, the final product is obtained as the hydrochloride. If desired, the base can be liberated and converted into other salts by conventional methods.

The invention is described in more detail in the following example.

NMR spectra were run on a Bruker WP 80 DS instrument. Displacements are reported in 35 ppm from TMS. Mass spectra were run on a Kratos MS80RF with either electron bombardment (EI) or chemical ionization (Cl) using direct input.

6 67690

Example 1 a) N-Benzyl-N-methyl-3,4-dimethoxyphenethylamine hydrobromide (II x HBr) 45.3 g (0.25 mol) of 3,4-dimethoxyphenethylamine, 26.5 g (0.25 mol) of benzaldehyde and 32.5 ml of a 35% formalin solution are hydrogenated in the presence of 1.2 g of 10% Pd / C catalyst at a pressure of 2-3 atm at 20-30 ° C in 35 ml of ethanol. The catalyst is filtered off and compound II is precipitated as hydrobromide by adding 29 ml of 48% hydrobromic acid. The yield is 83.3 g (91.0%) and m.p. 213-215 * 0 (from ethanol).

Compound II: 15 1 H-NMR (CDCl 3): 2.26 ppm (3H, s), 2.37-2.95 ppm (4H, m), 3.53 (2H, s), 3.81 (6H, s), 6.70 (3H, s), 7.26 (5H, s) 13 C-NMR (CDCl 3): 33.6 (t), 42.2 (q), 55.9 (q), 56.0 (q), 59.3 (t), 62.2 (t), 111.6 (d), 112.4 (d), 120.6 (d), 126.8 (d), 128.1 (d), 128.9 (d), 133.3 (s), 139.1 (s), 147.5 (s), 148.9 (s) MS [CI (NH3)] : m / z 286 (M + 1) 25 b) N-Benzyl-N-methyl-3,4-diisobutyryloxyphenethylamine hydrochloride (IV x HCl) 73.3 g (0.20 mol) of compound II prepared according to a) 30 HBr and 150 ml of 48% hydrobromic acid are boiled under nitrogen for 2 hours. The pH of the cooled reaction mixture is adjusted to 8-9 and the formed N-benzyl-N-methyl-3,4-dihydroxyphenethylamine (III) is extracted into methylene chloride. [If it is desired to isolate intermediate III, the methylene chloride solution is evaporated to dryness and the product 35 is crystallized from ethyl acetate, m.p. 113-115 ° C].

Il 7 67690

To the dried methylene chloride solution is added 57.0 ml (0.41 mol) of triethylamine, and 42.9 ml (0.41 mol) of isobutyryl chloride dissolved in methylene chloride are gradually added dropwise to the mixture, keeping the temperature of the reaction mixture <30 ° C. When the reaction is complete, water is added to the mixture and the layers are separated. 4.5 l of dry HCl gas are introduced into the dried methylene chloride layer, after which the solvent is evaporated off and the product (IV x HCl) is crystallized from ethyl acetate. Yield 78.1 g (90.0%). Sp.

154,5-157,5eC.

10

Compound III: 1 H-NMR (CD 3 Od): 2.26 (3H, s), 2.42-2.80 (4H, m), 3.56 (2H, s), 6.37-6.75 (3H, m), 7.30 (5H, s). 13 C-NMR (CDCl 3 + CD 3 OD): 32.8 (t), 41.8 (q), 59.1 (t), 61.9 (t), 115.0 (d), 115.5 (d), 120.2 (d), 127.2 (d), 128.2 (d), 129.4 (d), 132.1 (s), 137.6 (s), 142.7 (s), 144.3 (s) MS [CI (nH3)]: m / z 258 (M + 1)

Compound IV: 1 H-NMR (CDCl 3): 1.29 (12H, d), 2.25 (3H, s), 2.42-3.10 (6H, m), 3.54 (2H, s), 6.87 (1H, br. S ), 7.02 (2H, br. S), 7.35 (5H, s) 13 C-NMR (CDCl 3): 18.9 (q), 33.3 (t), 34.0 (d), 42.1 (q), 58.7 (t), 62.2 (t), 122.9 (d), 123.5 (d), 126.5 (d), 126.9 (d), 128.2 (d), 128.9 (d), 138.9 (s), 139.1 (s), 140.3 (s), 142.1 (s), 30 174.3 (s) MS (EI, 70 eV): m / z 397 (5), 134 (100), 91 (95) 8 67690 c) 3,4-diisobutyryloxy-N-methylphenethylamine hydrochloride (I x HCl), ibopamine hydrochloride 60.0 g of the product according to b) (IV x HCl) are hydrogenated in acetic acid in the presence of 1.25 g of 10% Pd / C catalyst for 2-3 atm. at a pressure of 20-50 ° C. When the reaction is complete, the solvent is evaporated off and the resulting ibopamine hydrochloride (1 x HCl) is crystallized from ethyl acetate. Yield 45.4 g (95.5%). Sp. 131-6eC.

10

Compound I x HCl: 13 C-NMR (CDCl 3): 18.9 (q), 31.6 (t), 33.1 (q), 34.0 (d), 50.3 (t), 123.8 (d), 126.7 (d), 134.9 (s ), 141.4 (s), 142.5 (s), 15 174.2 (s) MS [CI (NH 3)]: m / z 308 (M + 1)

II

Claims (5)

67690 Claim A process for the treatment of therapeutically active 3,4-diisobutyryloxy-N-methylphenethylamine (i) (CH3) 2CH-COO- / (2) y-CH2CH2-NH-CH3 (ch3) 2ch-coo-^ - '( I) and its acid addition salts, characterized in that a) 3,4-dimethoxyphenethylamine is reacted with benzaldehyde and formaldehyde in the presence of hydrogen and a catalyst, preferably palladium on carbon, to form a compound of formula 15. ii CH3 ° - <5V CH2Cl2h2 -VO) ch3o - ^ - '' - '(II) 20 which b) is reacted with an aqueous solution of hydrobromic acid to form a compound of formula III 25 / -V pH3 / -V HO - (Q / OT2Ch2_n-ch2 \ 0 / (C) is reacted with isobutyryl chloride in the presence of a base, preferably an organic base such as triethylamine, to give a compound of formula IV 67690 (CH3> 2CH-CO2-CH2CH2-N-CH2 ^ ^ (3 ^ (CH3) 2CH-COO— ^ '' - '(IV) 5 which d) is catalytically hydrogenated using, for example, palladium on carbon k to a compound of formula (i). Process according to Claim 1, characterized in that in step d) the starting material IV is in the form of an acid addition salt. 3. A novel compound characterized in that it is N-benzyl-N-methyl-3,4-diisobutyryloxyphenethylamine (IV). 11 67690 A process for the preparation of 3,4-diisobutyryloxy-N-methylphenethylatin (i) with therapeutic activity (ch3) 2ch-coo— ((j Y-ch2ch2-nh-ch3 (CH3) 2CH-COO-- --- (I) and, in the case of a cyclic addition salt, 10 parts of which: (a) 3,4-dimethoxyphenethylamine with benzaldehyde and formaldehyde in the form of a catalyst and a catalyst, a preferred form of palladium on color, a mixture of compounds of formula 15) ° - (OV CH2Ch2 "N-CH2_ / q \ ch3o- ^ '\ - / (II) 20 som b) in the case of brominated hydrolyses in the form of images in the form of (III) 25 HO - / Q \ -CH2CH2- N-CH2_ / q \ HO-J '> - / (III) 30 som) c) isomers of isobutyryl chloride in the form of triethylamine, colors and organic compounds of formula (IV)