DD294709A5 - PROCESS FOR PREPARING (R) -CARNITINE - Google Patents

Abstract

The invention relates to a process for the preparation of carnitine racemates using binaphthylphosphoric acid. binaphthylphosphoric}

Description

Field of application of the invention

(R) carnitine, also called vitamin Bt, is a physiological substance that plays an important role in lipometabolism as an acyl group transporter.

(R) -camitine and some of its compounds have prophylactic and therapeutic effects of various indications and are used as pharmaceuticals.

Characteristic of the known state of the art

The racemate resolution of carnitine using optically active acids, such as dibenzoyltartaric acid or camphorsulfonic acid, is known and described several times (DD-PS 23217, DD-PS 93347, DE-OS 3576098, EP-OS 0141408, IT-PS 2356383). This work identifies the obvious difficulties of racemate cleavage of carnitine, which is feasible only in complex, multi-step process and with unfavorable chemical and optical yields. Binaphthylphosphoric acid (2,2 '- / 1,1'-binaphthyl-phosphoric acid, BPA) is described in the form of its optically active (R) and (S) -isomers (Tetrahedron Letters 1971, 46, 17, 20'g. Synth. 67.1 -12 [1989]).

Object of the invention

It is the object of the invention, while avoiding deficiencies of known processes, to develop a technically advantageous preparation process of (R) -carnitine from carnitine racemates.

Explanation of the essence of the invention

The object of the invention is to obtain (R) -carnitine from carnitine racemates using inexpensive chiral auxilaria in high chemical and optical yields.

This object is achieved by a process for the preparation of (R) -carnitine by converting according to the invention racemic carnitine with an optically active form of Binaphthylphosphorsäure (BPA) in the presence of an organic solvent in the diastereomeric salts, these separated by crystallization and from the corresponding Diastereomer (R) carnitine over its acid addition salt wins. In this case, (S) -BPA is preferably used as the active form of the BPA. Salt formation takes place in organic solvents, such as ethanol, methanol, isopropanol, acetone, ethyl acetate, diethyl ether, dichloromethane (if appropriate in a mixture with water), from which salts which generally crystallize well are obtained.

Surprisingly, when using (S) -BPA, the diastereomer preferentially crystallizes with (R) -carnitine as the base component, while using (R) -BPA, preferably (S) -carnitine-binaphthyl phosphate crystallizes. In the first case, the desired (R) carnitine binaphthyl phosphate can be filtered off directly and further processed accordingly. From the mother liquor of the reaction of carnitine with (S) -BPA can after concentration, decomposition by means of acid, release of the camitin and re-reaction with (S) -BPA further (R) -Carnitin binaphthylphosphate be obtained. When (R) -BPA is used, decomposition of the (R) -carnitine-binaphthylphosphate obtained from the mother liquor after separation of (S) -casanitin-binaphthylphosphate followed by liberation; The enriched (R) carnitine required. This product will be subject to a second implementation with BPA. The diastereomers containing the (R) isomer of carnitine are recrystallized to constant rotation and subsequently decomposed with acid, preferably hydrochloric acid. Failed BPA can be recovered almost quantitatively. After concentration, the corresponding acid addition salt of (R) -carnitin can be isolated from the aqueous solution, which is converted into the betaine by subsequent treatment with a basic ion exchanger in a manner known per se. After the treatment according to the invention, (R) -carnitin is obtained in high chemical and optical yield. The method used is very effective.

embodiments example 1

2 g (0.012 mol) of carnitine and 4.3 g (0.012 mol) of (S) -BPA are brought into solution with stirring and heating in 25 ml of ethanol.

After 24 hours, the resulting crystals are filtered off, washed with ice-cold ethanol and recrystallized twice from ethanol. 1.1 g (RI-carnitine Binaphthylphoophat. This is admixed with 15 ml of half-concentrated hydrochloric acid, and vigorously stirred at 25-3O ⁰ C for 6 hours. The mixture is filtered, the filtrate is concentrated in vacuo and the residue treated with acetone.

After vacuuming and drying in vacuo, 0.42 g (34% of theory) of (R) -carnitine.HCl, [alpha] δ ⁶ = -20.7 ° (c = 2, H ₂ O), corresponding to % ee.

After treatment with a basic ion exchanger (SPW 200), 0.33 g of (R) -carnitine, [alphajg ⁶ = -26.8 ° (c = 5,

Example 2

2 g of carnitine and 4.3 g of (S) -BPA are brought into solution with stirring and heating in 40 ml of n-propanol. After 24 hours, the resulting crystals are filtered off with suction and recrystallized once from propanol.

This gives 1.7 g of salt which, after separation with HCl, gives 0.63 g (51% of theory) of (R) -carnitin.HCl, [alphalg ⁵ = -15.7 ° (c = 2, H ₂ O), results.

After recrystallization from methanol / isopropanol is obtained from the concentrated mother liquor 0.38 g (31% of theory) of (R) -Carnitin · HCl, [alphajg ⁶ = -22.2 ° (96% ee).

From this, 0.3 g of (R) -carnitine, [alphass ⁶ = -28.9 ° is liberated.

Example 3

2 g of carnitine and 4.3 g (S) -BPA are brought into solution with stirring and heating in 25 ml of ethanol. After adding 50 ml of acetone, it is allowed to stand for 24 hours. The crystals are filtered off with suction, washed with acetone and, after drying, 2.7 g of salt are obtained.

After a single recrystallization from ethanol, disassembly of the salt and release of the carnitine from the Hydrochloric! 0.585 g of (R) -carnitine is obtained with a rotation of [alphalS ⁶ = -15.7 ° (c = 5, H ₂ O), corresponding to 52% ee.

From this product, after renewed cleavage with (S) -BPA in ethanol, 0.45 g (37% of theory) of (R) -carnitine HCl, [α! "= -21.0 ° (c = 5, H ₂ O), 90% ee, from which 0.36 g of (R) -carnitine, [alpha] "= -27.1 ° (c = 5, H ₂ O), can be obtained.

Example 4

2 g of carnitine and 4.3 g of (R) -BPA are brought into solution with stirring and heating. After 24 hours, the precipitated (S) carnitine binaphthyl phosphate is filtered off with suction, the mother liquor is concentrated and the residue is decomposed with half-concentrated hydrochloric acid. 1.45 g of (R) -carnitine.HCl are obtained, [alpha ⁶ = 7.7 ° (33% ee). After release of carnitine and cleavage with (S) -BPA in ethanol, 1.1 g of (R) -carnitine · HCl, [aipha] are obtained. ⁵ = -15.0 ° (65% ee).

It is recrystallized from methanol / isopropanol and obtained from the mother liquor 0.6 g of (R) -Carnitin · HCl, [alphaß ⁶ = -22.0 ° (95% ee), resulting in a final yield of 49% of theory equivalent. After treatment with basic ion exchanger, 0.43 g of (R) -carnitine, [alpha] "= -28.6 °, are obtained.

Claims (3)

1. A process for the preparation of (R) -carnitine, characterized in that one converts racemic carnitine with an optically active form of Binaohthylphosphorsäure (BPA) in the presence of an organic solvent in the diastereomeric salts, these separated by crystallization and from the corresponding diastereomer ( R) carnitine gains over its acid addition salt. 2. The method according to claim 1, characterized in that (S) -BPA is used as the optically active form of BPA. 3. The method according to claim 1 and 2, characterized in that (R) -Carnitin is obtained via its hydrochloride.