DE1543847A1 - d, I-, l- and d-carnitine amide chlorides and a process for their preparation - Google Patents

Description

PATENTANWÄLTE DR. W. SCHALK · DIPL.-INCP. WIRTH VDIPU-INCCDaNNENBERG

.?. Weinhold

6 FRANKFURT AM MAIN O *. ISCHINHEJMCJI (TII. »9

- Wd / Bi

P 15 43 847.8 Br.39

Societe Beige de 1 «Azote et des Produits GhiTDiques du Marly, Societe Anonyme

4, Boulevard Piercot, Li ^ ge / Belgium

d | l- _T 1 and d-garnitinamide chlorides and a process for their preparation. .

The present invention relates to the manufacture of d, 1-, 1- and d-Garnitinamidehlorice of the following formula

Ν-0Η ₂ -0Η0Η-0Η ₂ -σ0Μ ₂ _7 ⁺ Cl "

in the racemic, left-handed and right-handed forms as well as 1- and d-OarnitinaTnidchloride.

As already known, the chloride of d, l-carnitine amide can pass through Conversion of hydrogen peroxide into ammonium hydroxide with the Chloride of d, l-camitin nitrile can be produced.

Bas erfindungsgemäSe method comprising the simple hydrolysis of the chlorides of d, l, 1- or d-carnitinenitrile by the action of sound on the corresponding hydrochloric acid at a temperature ITitril

009827/1949

from about 15 to about 55 ° depending on the reaction time, which can be between 60 hours at the lower temperature limit and up to about 10 hours at the upper temperature limit. However, it has been found that the most favorable reaction time is between 44 and 48 hours and the temperature is preferably between 20 and 25 ^° C. After the hydrolysis has ended, the amide is separated from the solution in crystal form by known methods, such as, for example, by cooling the solution to a temperature of ⁰ ° O or lower, adding an alcohol such as isopropanol, filtering and drying the crystals obtained. In addition to the alcohol, a ketone, such as acetone, can be added to the solution cooled in this way in order to prevent the alcohol from exerting an excessively strong dissolving effect.

The process according to the invention differs from the process mentioned for the preparation of d, l-carhitinamide not only in the type of reactant used but also in that, when using racemic nitrile as the starting material, it is possible to prepare a chloride of d, l-ornitinamide which has a higher degree of purity than the hergeste by the known method ¹ lte product. In fact, according to the process according to the invention, it is possible to ^{produce a chloride of d, l-carnitine amide with a melting point of 212 °} C., while the melting point of the product produced by the known process is only 206 ^° C. ·

The method according to the invention also has a surprising one Characteristic when you consider that the optical isomerite

the chlorides of the dextrorotatory and levorotatory orenitine nitrile are susceptible to strong acids, which can convert these chlorides into the chemical derivatives *

BATH ORIGINAL 009827/194 9

Both of the V produced by the process according to the invention new products were found to be 1-carnitine amide chloride has a stimulating effect on breathing. Also, there are both left-handed and right-handed ones Amide starting materials from which other therapeutically useful derivatives, such as d,! - carnitine and t-carnitine chlorides, can be produced.

The three amides described here can be converted into their corresponding Hydroxides are converted, such as by the action of silver hydroxide or by other known processes, for example by passing them through an ion exchange resin. However, this process is not part of the invention claimed here.

The following examples illustrate the present invention.

B is ρ ie 1 1

., 5 g (0.042 mol) of d, l-carnitine nitrile chloride (3-hydroxy-4-trimethyl-aminobutyronitrile chloride) were dissolved in 15 ecm hydrochloric acid (density 1.19); The solution was left to stand at a temperature of 20-25 ° C. for 46 hours. It was then cooled to ι 0 ° C. and, while maintaining this temperature, 60 ecm iaopropanol and then 60 ecm acetone were added. The solution was then placed in a cooling device for several hours and the crystals of d, l-carninamide chloride formed in this way were filtered off. The melting point was 212 ^° C.

For β ρ ie I 2

A solution of 1.79 g of l-carnitine nitrile chloride (0.01 mol) in

Com 3.6 hydrochloric acid (density 1.19) was 46 hours at a Temperatui of 2O ⁰ C - 25 ⁰ C allowed to stand. It was then ^{cooled to 0} ° C. and, while maintaining this temperature, 18 ecm of isopropanol and 25 com of acetone were added. The solution was

0 0 98 27/1949

then placed in the refrigerator for several hours and the crystals of l-carnitlnamide chloride thus formed are then filtered off. The melting point was 244 ^° C.

= -17.4 ° (tolerance limit: 0.3 °) (concentration: 10 #, Water).

The 1-carnitine amide chloride thus obtained can optionally converted into the corresponding Hy & roxyd. Therefor the following procedure is suitable:

A solution of 4 g of 1-cirnitinamide chloride in 20 ecm of methanol was stirred for 15 minutes with silver oxide freshly prepared from 6.9 g of AgNO. After that formed Silver chloride was filtered off and the solution was purified with activated charcoal, ether was added in an amount which caused the oil to precipitate, which was then dissolved in isopropanol. By gradually adding 1-carnitine amide hydroxide was obtained in solid form from ether, which decomposed under the action of heat and had a rotation of -21.2 °.

(Tolerance limit: 0.2 °) (concentration: $ 12, methanol). Example 3

3.9 g of d-carnitine nitrile chloride (0.022 mol) were dissolved in 8 ecm hydrochloric acid (density 1.19). The solution was left to stand at a temperature of from 20 to 25 ^{° C. for 46 hours.} It was then cooled to 0 ° C. and 40 ecm of isopropanol was added while maintaining this temperature. The. The solution was then placed in the refrigerator for several hours and the d-ornitinamide crystals formed were filtered off. The melting point was 24 <- 0.

= + 17 »5 ° (tolerance limit: 0.5 °) (concentration. ·

009827 / "1 9 /, 9

, -. BATH ORIGINAL

10 #, water). '

The d-carnitine amide chloride thus obtained can optionally be converted into the corresponding hydroxide by the same process as used for the preparation of the Hydroxyds of 1-carnitine amide was applied.

A solution of 4g of d-carnitine amide chloride in 20 ecm of methanol stirred with silver hydroxide for 15 minutes, the freshly made from 6.9 g AgNQ *. After the stooped After the silver chloride had been filtered off and the solution clarified, ether was added in an amount sufficient to cause precipitation of the Oil which was then dissolved in isopropanol. By Further addition of ether resulted in solid form of d-carnitine amide hydroxide, which decomposed under the action of heat and had a rotation of + 21.2 °. (Tolerance limit i 0.2) (Concentration; $ 12, methanol).

BATH ORIGINAL

009827/1949

Claims (6)

Claims 1. Process for the preparation of d, l-, 1- and d-carnitine amide chlorides according to the following formula , / "" (CH ₃ ) ^ - CH ₂ -CHOh-CH ₂ -CONH ₂ _7 ⁺ Cl " in the racemic, levorotatory and dextrorotatory form, characterized in that the chloride of d, l-, 1- or d- ^ carnitine nitrile by hydrochloric acid at a reaction time and temperature of about 60 hours at about 15 ° C up to about 10 hydrolyzed hours at about 55 ⁰ C, and the Amidkristalle thus formed is separated off in known manner from the hydrolysis solution, 2. The method according to claim 1, characterized in that the amide is separated from the hydrolysis solution by ^{cooling it to O 0} C or below, adding an alcohol, and the crystals obtained are filtered off and dried. 3. The method according to claim 2, characterized in that as Alcohol isopropanol is used » 4. The method according to claim 2 and 3 _f, characterized in that a ketone is added to the solution after cooling » 5. The method according to claim 4, characterized in that acetone is used as the ketone. 6. 1 -Carnitinamide chloride. 7 d-carnitine amide chloride ORiG'NAL <The attorney at law 009827/1948