NL8202677A - PROCESS FOR PREPARING CARNITINE CHLORIDE. - Google Patents

Description

* ^ 'ΐ - 1- H.O. 31 208

Process for the preparation of carnitine chloride.

The present invention relates to a method of preparing D, L-carnitine chloride,

(CH ^^ - GEg-CH-CHg-OOCl. B, L-carnitine chloride is a many-time OH

Intermediate for the preparation of various carnitine derivatives, for example esters and amides, of which therapeutic properties are known.

Carnitine, (CH,), 1I-CHo-CH-CH-C00H, contains in addition a 5 5 2 | 2

OH

Carboxyl group is a hydroxyl group, which is known to be sensitive to acidic reaction environments.

It is actually known, for example, as described in Bull. Soc. Chim. Pr. (1960), 1196, that β-hydroxy acids and their esters easily release a water molecule in an acidic environment, thus forming unsaturated compounds. In. Biochim. Biophys. Aota 131, (1967) 98-106 and 1 ^ 2 (1968) 559, discloses that dehydration of carnitine takes place under heating in an acidic environment. In J. Biol. Chem. 257/12, (1962) 3268, the formation of orotonoyl betaine as a by-product is described as occurring by heating carnitine in an acidic environment.

Since a carboxylic acid is converted to acid chloride in an acidic environment, chloritination of carnitine cannot be expected to occur without prior protection of the hydroxyl group in order to avoid degradation of the starting product and the formation of undesired by-products.

The foregoing is fully confirmed from what can be deduced from the prior art. The preparation of acid chlorides of hydroxy-substituted acids after the hydroxyl-30 group has been previously protected is described in J. Org. Chem. 45/20, (1978) 3972. More specifically, the chlorination of β-hydroxybutyric acid (which is a β-hydroxy acid as carnitine) is described after prior protection of the hydroxyl group with an acetyl group in J.Am. Chem. Soc. ££, (1975) 4106.

Surprisingly, it has now been found that it is possible to convert 8202677 - 2 - κ Ζ * '* B, L-earnitin into the acid chloride of B, L-carnitine *, yielding excellent yields without producing unacceptable amounts of by-products from induetrigel viewpoint (especially crotonoylbetaine). Bit is carried out by chlorinating B, L-carnitine without prior protection of the hydroxyl group (for example, by conversion of the hydroxyl group to an acetyl group as taught by the prior art), provided that some critical operational conditions are observed be taken.

In fact, it has been found that the molar ratio of oarnitine / chlorinating agent, the reaction temperature and the reaction time are critical parameters affecting the conversion of B, 1-carnitine to the corresponding acid chloride and that the values of the foregoing parameters are within good defined trajeots must fall 15.

In accordance with the invention, the process for the conversion of carnitine to the acid chloride of carnitine comprises the following steps: chlorination of carnitine with a chlorinating agent (preferably 20 selected from, inter alia, thionyl chloride, dichloromethyl ether and oxalyl chloride) at room temperature for reaction times between about 1, 5 and 12 iiren.

Poafer pentachloride can also be used as a chlorinating agent. However, this chlorinating agent is not preferred because of the noticeably higher reaction times (1 to 3 days) compared to the chlorinating agent indicated above.

Preferably, the molar ratio of carnitine / chlorinating agent is between 1: 1 and 1: 3. In order to obtain high yields in the conversion of carnitine to the acid chloride, it is essential that the foregoing temperature and reaction times be strictly in be taken into account since even minor variations trigger the formation of by-products. For example, when oxalyl chloride is used as the chlorinating agent, a reaction time of 15 hours produces the almost complete breakdown of carnitine to crotonoyl betaine.

The following non-limiting Examples 1 and 2 illustrate the method of the present invention.

Example 1 (chlorinating agent: thionyl chloride) 2.25 cm 2 (0.03 mol) SOClg was added to 1.98 grams (0.01 mol) 40 B, L-carnitine hydrochloride. Mon 1 hour their solubility was complete and after 1.5 hours it was considered complete ·

The excess SOClg was distilled off and the residue, consisting of carnitic acid chloride, was washed with anhydrous diethyl ether. For identification purposes, the acid chloride was converted to the methyl esters, the reaction mixture was cooled to 0 ° C and 10 cur anhydrous methanol was added dropwise; then the resulting mixture was concentrated under reduced pressure at 35-40 ° C to yield a gelatinous crude product which solidified under vacutim solid but was very hygroseopic.

D.L.C. chloroform 55 / methanol 55 / HgO 5 / M / OH 5 MR Spectrum D20 solvent 15 4.82 (1H, m, -CH-); 3.83 (3H, s, --OCH2); 3.55 (2H, d,> 1-CH 2 -);

OH

* / ° Ξ3 3.30 (9Ξ, s, 2.75 (2H, d, -CH2C0-) ΌΗ, 3 20 Basic analysis

Calculated Found 045.39 43.99 K.E. ~ 4% 8,5 '8.57 8.54: N 6.62 6.09 25 c 16.75 16.92

Example 2 (chlorinating agent; dichloromethyl ether).

The methods of the previous example were followed except that instead of thionyl chloride, 1.78 cm 2 (0.02 mol) of dichloromethyl ether were used. The reaction mixture was kept at room temperature overnight. The excess dichloromethyl ether was distilled off and the residue was washed with anhydrous diethyl ether. The residue was found to consist of carnitic acid chloride.

oh5 MR CD-HCS 3.33 (9H, s, CH5 ^ r & -), * 35 CH3 3.36-3.60 (4H, m, t-0H2, -CH2COCl); 4.40-4.90 (lH, m, -gg-) 8202677 * - 4 -

After exchange with DgO, the chemical shifts regained the same values as those of the HMR spectrum of carnitine. The crude acid chloride was then converted to the methyl ester as described above. The methyl ester of carnitine 5 exhibited the chemical-physical properties corresponding to the previously isolated product.

The following Examples A and B are intended to illustrate that the above operating conditions must absolutely be met in order to obtain the acid chloride of carnitine. 10 Example A (the appropriate reaction temperature is not met).

A mixture of carnitine and thionyl chloride (mole ratio 1s1) was stirred at 50 ° C. Samples of the reaction mixture were taken from 0.5, 1 and 1.5 hours from the start of the reaction. The samples were checked by thin layer chromatography (chloroform 55 / CH 2 OH 35 / H 2/5 / and HH 2 OH 5) after dilution with methanol to convert any acid chloride to methyl ester.

After 0.5 hours, a presence of carnitine and the methyl ester of carnitine (R ^ 0.4 nesp, 0.8) was determined.

20 Ha 1 hour, crotonoyl betaine, carnitine and earnitin methyl ester (Rf 0.2, 0.4 and 0.8, respectively) were determined.

After 1.5 hours, the presence of crotonoyl betaine along with other degradation products was not identified. could be determined.

25 Example (The appropriate reaction time is not satisfied).

2.3 cm 3 (0.03 mole) of thionyl chloride was added to 1.98 grams (0.01 mole) of camitine hydrochloride and the resulting mixture was stirred at ambient temperature for 24 hours. The excess thionyl chloride was distilled off and the crude residue was washed with anhydrous diethyl ether to give a solid product with a mp. of 217-218 ° C.

TLC chloroform 55 / methanol 35 / H ^ O 5 / HH ^ OH 5 / R ^. 0.2 HMR D 4 O 7 7.2-6.2 (2H, m, -CH = CH-); 4.2 (2H, d, 1-CHp-); 3.2 (9H, s, cA S-) CEi '3

As DLC and the HMR spectrum show, under these reaction conditions, the acid chloride of carnitine is not formed. On the other hand, a dehydration takes place to give crotonoyl betaine 8202677, 5-CH * ΟηΓ ^ t-CH2-CH = CH-G00H.

οκζ Ο 8202677

Claims (2)

1. Process for preparing the acid chloride of carnitine, characterized in that carnitine is chlorinated with a chlorinating agent selected from thionyl chloride, dichloromethyl ether and oxalyl chloride, reaction times at ambient temperature between about 1.5 hours and 12 hours. 2. Process according to claim 1, characterized in that a molar ratio of carnitine: chlorinating agent is used, which lies between 1: 1 and 1: 3 · 10 8202677