KR860001886B1 - Process for the preparation of carnitine chloride - Google Patents

Abstract

Prodn. of carnitine chloride(I), i.e. the acid chloride of DL- carnitine(II), is carried out by reacting(II) with a chlorinating agent(II) at ambient temp. for 1.5-12 hr., where (III) is SOCl2, dichloromethylether or oxalyl chloride. The (II); (III) molar ratio is pref. 1 : 1-3. (I) is an intermediate for therapeutically active carnitine derivs., e.g. esters and amides. The process gives high yields of (I) without excessive formation of by-products (esp- crotonylbetaine) and without the need to protect the OH gp.

Description

Method of preparing carnitine chloride

을 제조하는 방법에 관한 것이다.D, L-carnitine chloride

It relates to a method of manufacturing.

D, L-carnitine chloride is an overall intermediate for the preparation of several carnitine derivatives such as, for example, esters and amides whose therapeutic properties are known.

는 카르복실기 외에 알려진 바와 같이 산성반응환경에 민감한 히드록실기가 포함된다.Carnitine

In addition to the carboxyl group, hydroxyl groups which are sensitive to an acidic reaction environment, as known, are included.

See, eg, 1970. Bull. Soc. Chim. Fr. As disclosed on page 1196, it is known in practice that β-hydroxy acids and their esters readily release water molecules in an acidic environment to produce unsaturated compounds.

Biochim. Biophys. Acta 1967, pp. 137, 98-106, and 1968, pp. 152, 559 disclose that carnitine dehydration occurs in an acidic environment under heating. 1962 J. BioI. Chem. Page 3268, Vol. 237, 12, discloses that the production of crotonoylbetaine as a byproduct occurs when carnitine is heated in an acidic environment. Since carboxylic acids are converted to acid chlorides under acidic conditions, carnitine chlorination cannot be expected without protecting the hydroxyl groups in advance in order to avoid the sensitivity of the starting materials and the formation of undesirable by-products.

The foregoing disclosure is fully confirmed by what can be inferred by the prior art. The preparation of acid chlorides of hydroxy substituted acids after the hydroxyl groups have been preprotected is described in J. Org. Chem. 43, 20, published on page 3972. In more detail, chlorination of β-hydroxybutyric acid (carnitine β-hydroxy acid) after protecting the hydroxyl group in advance with an acetyl group was published in 1973, J. Am. Chem. Soc. 95, published on page 4106.

Surprisingly, it is possible that D, L-carnitine can be converted to D, L-carnitine acid, which can be obtained in excellent yields without producing an unacceptable amount of by-products (especially crotonoylbentine). Currently known. This is accomplished by chlorination of D, L-carnitine without prior protection of the hydroxyl groups (eg by converting hydroxyl groups to acetyl groups by conventional techniques). However, some critical working conditions are involved.

In practice, it is known that the molar ratio, reaction temperature and reaction time of carnitine / chlorinating agent are the critical parameters affecting the conversion of D, L-carnitine to the corresponding acid chlorides and that the values of the above mentioned parameters should fall within a certain range. .

According to the present invention, the conversion of carnitine to an acid chloride of carnitine includes the following steps.

Chlorination of carnitine to room temperature with a chlorinating agent (preferably selected from thionyl chloride, dichloromethylether and oxalyl chloride) for a reaction time between about 1.5 and 12 hours. Phosphorus pentachloride can also be used as a chlorinating agent. However, these chlorides are undesirable in that they require significantly longer reaction times (1 to 3 days) compared to those pointed out above.

Preferably the molar ratio of carnitine / chlorinating agent is between 1: 1 and 1: 3. In terms of obtaining high yields in the conversion of carnitine to acid chlorides, it is essential to strictly implement the above-mentioned temperatures and reaction times, as even small changes cause by-product generation. For example, when oxalyl chloride is used as a chlorinating agent, a reaction time of 15 hours generally causes carnitine to be completely sensitized to crotonoyl betaine.

Examples 1 and 2 which follow illustrate the method of the invention without limitation.

Example 1

(Chlorinating agent: thionyl chloride)

2.25 cc (0.03 mol) of SOCl ₂ was added to 1.98 g (0.01 mol) of D, L-carnitine hydrochloride. Solubilization was complete after 1 hour and terminated after 1.5 hours. Excess SOCl ₂ was distilled off and the residue containing carnitine acid chloride was washed with anhydrous ethyl ether. The acid chloride was converted to ethyl ether for identification purposes. The reaction mixture was cooled to 0 ° C. and 10 cc of anhydrous methanol was added dropwise. The resulting mixture was then concentrated in vacuo at 35-40 ° C. This gave a solidified product which dried under vacuum and solidified but remained extremely absorbent.

T, L, C, Chloroform 55 / Methanol 5 / NH ₄ OH 5 NMR Spectrum D ₂ O Solvent

Elemental analysis

Theory actual

C 45.39 43.99 K.F. ~ 4%

H 8.57 8.54

N 6.62 6.09

C1 16.75 16.92

Example 2 (chlorinating agent: dichloromethyl ether)

The method of the above described example was used. Dichloromethyl ether (1.78 cc; 0.02 mol) was used instead of thionyl chloride. The reaction mixture was left at room temperature overnight. Excess dichloromethyl ether was distilled off and the residue was washed with anhydrous ethyl ether. It was found that the residue contained carnitine acid chloride.

After exchange with D ₂ O, the chemical shift restored the same value as the NMR spectrum of carnitine. As a result, the crude acid salt was converted into methyl ester as described above. Carnitine methylester showed chemical-physical properties corresponding to the above-mentioned isolated product.

The following Examples A and B are intended to illustrate that the above operating conditions must be fulfilled in order to obtain carnitine acid chloride.

Example A

(Temperature does not apply)

A mixture of carnitine and thionyl chloride (molar ratio 1: 1) was stirred at 50 ° C. Samples of the reaction mixture were finished 0.5 hours, 1 hour and 1.5 hours after the start of the reaction. Samples were diluted with methanol to convert the acid chloride to methyl ester even slightly and then examined by TLC (chloroform 55 / CH ₃ OH 35 / H ₂ O 5 / NH ₄ OH 5). After 0.5 hours, the presence of carnitine and carnitine methyl ester (R _f 0.4 and 0.8, respectively) was confirmed. After 1 hour crotonoylbetaine, carnitine and carnitine methylester (R _f 0.2-0, 4-0.8, respectively) began to form. After 1.5 hours the presence of crotonoylbetaine and other unidentifiable emotional products was confirmed.

Example B

(Appropriate response time does not apply)

The reaction mixture obtained by adding thionyl chloride (2.3 cc; 0.03 mol) to carnitine hydrochloride (1.98 cc; 0.01 mol) was stirred at room temperature for 24 hours. Excess thionyl chloride was distilled off and the crude residue was washed with anhydrous ethyl ether. This gave a solid product having a melting point of 217-218 ° C.

TLC chloroform 55 / methanol 35 / H ₂ O 5 / NH ₄ OH 5 / R _f 0.2

As indicated by the TLC and NMR spectra, no acid chloride of carnitine is produced under these reaction conditions. Conversely produce crotonoylbetaine

Dehydration takes place.

Claims (2)

A process for producing carnitine chloride, characterized in that chlorination of carnitine selected from thionyl chloride, dichloromethyl ether and oxalyl chloride for a reaction time between about 1.5 hours and 12 hours at room temperature. The molar ratio of carnitine / chlorinating agent according to claim 1 is between 1: 1 and 1: 3.