RU1781210C - Process for producing 2-hydroxy-5-@@@ 1-hydroxy-2-[n-(1-methyl-3-phenylpropyl)] aminoethyl @@@ benzamide hydrochloride - Google Patents

Description

1

(21) 4785927/04

(22) 23 01.90

(46) 12/15/92, Bull. Mg 45

(71) Institute of Fine Organic Chemistry named after And l Mnjo on

(72) A.S. Avetis n, E.A. Merkar n, O.S. Medvedev and O.S. Norav n

(56) Negwer M. Organic-chemical drugs and their synonyms Berlin, Akademie-verlag, 1987, v. 2, p. 936

The patent of Germany N "2032642," p. C 07 C 103/29, 1971.

Chftion I.F et al. Med Chero. 1982. 25 (6), 670.

Patent FRG№3501582, class С07С 103/29, 1986.

Gold EH. and etc, . Med Chem, 1982, 25 (11), 1363.

(54) METHOD FOR PRODUCING 2-HYDROXY-5- {1-HYDROXY-2- M- (1-METHYL-3-PHENIPROPYL) AMINOETHYL} - 5ENZAMIDE

(57) SUMMARY OF THE INVENTION: the product is Xi-5- {1-p / droxy-2- M- (1-methyl-3-phenylpropyl) zminoethyl} benzamide hydrochloride, mp. 191-193 ° C Rf 0.63, outlet 30.2%, Reagent 1: 5-bromoacetyl-2-benzyloxybenzimide. Reagent. 2: NaH, Reaction conditions: in the case of CH3OI, the obtained 2-benzoyuksi-B-epok sibenzamide was reacted with g-benzyl-N- (1-methyl-3-phenyl) propylase. In the presence of a catalytic amount of water, followed by debenzylation in the presence of 10% palladium on charcoal and transfer of the resulting product to its hydrochloride. 1 tab.

The invention relates to the field of organic chemistry, and in particular to an improved method for the preparation of 2-hydroxy-5- {1-hydroxy-2- M- (1-methyl 3-phenylpr-opyl) aminoethyl} benzamide hydrochloride of the formula

ABOUT

H2N BUT

-with

 /

HCL

sn-sn2-sh-sn

ONSH3

-CH2-CH2-C & ris

used under the name labetalol in medical practice for the treatment of hypertensive disease

Known in the literature methods for the synthesis of 2-hydroxy-5- {1-hydroxy- (1-methyl-3-phenylpropyl) aminoep1l} benzamide hydrochloride, derivatives of 2-hydroxybisisamide, in particular 5-bromo-cetype, are proposed as intermediates for its preparation -2-hydroxybenzamide, 2-hydroxy 5- (S, M-dibenzylaminoacetyl) benzamide, or 2-hydroxy-5- (2-amino-1-hydroxyztyl) benzamide

However, the known methods of synthesis have one or another disadvantage: the use of expensive platinum oxide and (or) palladium on coal, multi-stage intermediate stages, low yield of the target product, specific methods for the isolation of intermediate substances, use

a large number of organic solvents and high pressure,

Closest to the proposed is a method of producing 2-hydroxy-5- {1-hydroxy-2- M- (1-methyl-3-phenyl propyl) aminoethyl} benzamide hydrochloride, which consists in the condensation of 5-bromoacetyl-2-benzyloxybenzamide with N-benzyl- (1-methyl-3-phenyl) propylamine in dimethylformamide in the presence of carbon dioxide

Oh and n2m-s

С6Н5 СН2 СНг

about

II H2N-C

C6H5

sn

2s-o-b-s-sn2-vg 1 n2s-ob-s-sn-ssngshg-s6n5- S6n5 okgssupmFAi5H5 o sn,

I.NaBH

About H2N-C

СБН5 СН,

twenty

n2s-o-o-sn-sng-s-sn-sngsn2-s6n5

C6H5 OH HCL CH3

The disadvantages of this method are the use of a specific catalyst - palladium on carbon, activated by lithium hydroxide, high pressure, a large number of organic solvents (acetic acid, benzene, ether, ethyl alcohol, dimethylformamide), as well as the complexity of the process.

The aim of the invention is to simplify the process for the preparation of 2-hydroxy-5- {1-hydroxy-2-G - (1-methyl-3-phenyl-propyl) aminoethyl} benzamide hydrochloride,

The goal is achieved by the proposed method for the preparation of 2-hydroxy-5- {1-hydroxy-2- / L- (1-methyl-3-phenylpropyl) / aminoethyl} benzamide hydrochloride, which consists in the action on 5-bromine O

H, 4 map

ngs-o-o-s-cng-vg

about

NaBH

Hs

and

potassium, reduction of the obtained amino ketone with sodium borohydride in ethanol and debenzylation of the isolated 2-benzyloxy-5- {1-hydroxy2- / g 1-benzyl-g - (1 methyl-3-phenylprop |, 1l | - -aminoethyl} hydrochloride beisamide in ethyl alcohol at room temperature at a pressure of 3 atm in the presence of 20% palladium on coal, obtained in a special way (5) according to

 scheme:

about

II H2N-C

C6H5

sn

2c-bb-c-cni5H5 o cn

about

||

H2N-C

BUT

HCL CH-CHG-SH-CHQH

Sn

- SNGSNGS6N5

30 35

40

ABOUT

II

C

-

5

sodium borohydride tyl-2-benzyloxybenzamide in methyl alcohol, interaction of the obtained 2-benzyloxy-5-epoxybenzylamide with Y-benzyl-M- (1-methyl-3-phenyl) propylamine in methyl alcohol in the presence of a catalytic amount of water, debenzylation without isolation of the resulting 2-benzyloxy- 5- {1-hydroxy-2- / Y-benzyl-M- (1-methyl-3-phenylpropyl) aminosyl} benzamide in methyl alcohol at room temperature and normal atmospheric pressure in the presence of standard 10% palladium on charcoal followed by transfer of the obtained 2-hydrox - 5- {1-hydroxy-2- GCH- (1-methyl-3-Phenylpro saws) aminoethyl} benzamide hydrochloride according to the scheme:

c & n5 si g CHe -CH-CH, NH CH-CHrCHf C6H5

V:

II

A distinctive feature of the proposed method is the conversion of 5-bromoacetyl-2-benzyloxybenzamide by the action of sodium borohydride to the previously undescribed 2-benzyloxy-5-epoxybenzamide, the process of interaction of the latter with M-benzyl-M- (1-methyl-3-phenyl) with propylamine in the presence of methyl alcohol in the presence of a catalytic amount of RODA, as well as debenzylozymerization at normal atmospheric pressure using standard 10% palladium-carbon as a catalyst.

Example 1.2-Benzyloxy-5-epoxybenzamide (II). To a suspension of 6.96 g (0.02 mol) of 5-bromoacetyl-2-benzyloxybenzamide (I) in 150 ml of methyl alcohol, 4.56 g (0.12 mol) of sodium borohydride are added in small portions with stirring for 70 minutes. while maintaining the temperature of the reaction medium within 3-5 ° C. Stirring is continued at room temperature for 4 hours and left overnight. 150 ml of water are added, stirred at room temperature for 40 minutes and left in the refrigerator for 2-3 hours. The precipitated crystals are filtered off, washed with cold water and dried on in the air. Yield 4.1 g (76.2%), mp. 118-119 ° C. Rf 0.51.

Found,%: C 71.42. H 580; N, 5.44.

CieHisNOa.

Calculated,%: C 71.36; H 5.61; N, 5.20.

IR (P vaseline oil), V, CM 1i 1510, 1580, 1610 (C arom); 1630, 1670 (CO); 3180, 3430 (MH2).

PMR spectrum (SOS z-TMS), b, ppm: 8.29 - 6.23 (UN, m, arom, protons and MND); 5.01 (2H, s, CHjzPh); 3.76 (1 N, m, CH); 3.18 and 2.73 (1 N each, d x d, CHa-O).

 269 (mass spectrometric).

Example 2. 2-Hydroxy-5- {1-hydroxy-2- M- (1-methyl-3-phenyl propyl} aminoethyl} benzamide hydrochloride. Mixture 1.35 g (0.005 mol) 2-benzyloxy-5-zpoxybenzamides (ill), 1.18 g (0.005 mol) M-benzyl-M- (1-methyl-3-phenyl) propylamine, 1-2 drops of water are refluxed in 40 ml methyl alcohol for 24-30 hours. The solvent is distilled off, the residue is boiled for 5-6 minutes with 30 ml of hexane, cooled and the solvent is decanted, 100 ml of methyl alcohol, 2 g of 10% palladium-carbon are added and hydrogenated with hydrogen at room temperature temperature and normal atmospheric pressure until saturated. comfort, the solvent was distilled off, the residue was dissolved with gentle heating in 100 mL of ethyl acetate and ether was added 1.

hydrogen chloride solution. It is filtered, washed with ethyl acetate, the crystals are boiled for 5-10 minutes in acetone. It is cooled, filtered and washed on the filter with acetone. Yield 0.55 g (30.2%), ill. 191-193 ° C, Rf 0.63 (Silufo UV-254, mobile phase - butyl alcohol: uccussia acid-.a: water, 4: 1: 1).

Found,%; C, 62.71; H 6.98; N, 7.95; SG 10.20.

C19H25M203CI.

Calculated,%; C, 62.54; H 6.85; N, 7.68; SG9.72.

 IR spectrum (in liquid paraffin), V, CM 1510, 1580, 1610 (С С aroma,); 1650, 1680 (CO); 3190.3350 (NH2. OH).

M + 328 (mass spectrometric).

The previously described 2-benzyloxy-5- {1-hydroxy-2-M-benzyl-M- (1-methyl-3-phenylpropyl) aminoethyl} benzamide (1U) is an oily substance of light brown color, obtained with yield not less than 95%. Rf 0.68 (Silufo UV-254, mobile phase - benzene: acetone, 4; 1 with ammonia vapors).

 M 508 (mass spectrometric).

The results of comparative studies on the testing / testing of the biological activity of the compound of formula I synthesized by the proposed method, i.e. the labetalol agent, are presented in the table. Comparative studies were carried out with labetalol manufactured by Allen and Haudburys (England).

The effect on a-adrenergic receptors was judged by the blocking effect of the pressor effect compounds of the selective agonist of s-adrenoreceptors - pheniphephrine (Sigma USA), the D-adrenergic blocking effect was determined by the test compounds reducing the positive chronotropic and depressant effects of the isadrine agonist / depressor receptor ( Sigma USA),

As can be seen from the table, by pharmacological efficiency, the compound synthesized by the claimed method is identical to the known one.

Thus, the proposed method allows to limit the use of organic solvents to a minimum, to exclude the use of a specific catalyst - 20% palladium on carbon, activated by lithium hydroxide, to avoid increased pressure, which achieves the goal, namely, simplification of the process. Moreover, the biological properties of the synthesized by the proposed method

2-hydroxy-5- {1-hydroxy-2-Y- (1-methyl-3-phenylpropyl) aminoethyl} benzamide hydrochloride is identical to the properties of the drug labetalol.

Claims (1)

 The claims Method for the preparation of 2-hydroxy-5- {1-hydroxy-2- M- (1-methyl-3-phenyl. L-propyl) aminoethyl benzzimide hydrochloride from 5-bromo-cetyl-2-benzene-suksibenzamide using M-benzyl -M- (1-methyl-3-phenyl) propylamine and sodium borohydride, including debenzylation of the obtained product in a s-alcohol medium at room temperature in the presence of palladium The blocking effect of compound I and lebetalol effects of ahedrinia and phenylephria Note. The number of animals in each group is 5. catalyst and conversion to hydrochloride, characterized in that, in order to simplify the process, 5-bromoacetyl-2-benzyloxybenzamide is reacted with sodium borohydride in methyl alcohol, the resulting 2-benzyloxy-5-epoxybenzamide is then reacted with M-benzyl-1M- (1-methyl-3-phenyl) propylamine in methyl environment alcohol in the presence of a catalytic amount of water, with & as a palladium catalyst for debenzylation.: and 10% palladium on carbon is used, and the resulting product is converted to hydrochloride.