CS266600B2 - Process for producing optically active carnitinonitrile - Google Patents

Abstract

The method of producing optically active carnitine nitrile chloride consists in reacting optically active tartaric acid with trimethylamine, the reaction product is converted with epichlorohydrin into optically active di-(3-chloro-2-oxypropyltrimethylammonium) tartrate, which is cleaved into tartaric acid and optically active 3-chloro-2-oxypropyltrimethylammonium chloride, which is converted with a strong base into optically active glycidyltrimethylammonium chloride, and this is reacted with cyanide to optically active carnitine nitrile chloride.

Description

The present invention relates to a process for producing optically active carnitine nitrile chloride.

Since the racemic resolution of free carnitine is difficult due to the low stability of the free acid groups, nitriles or amides of carnitine are preferably used for the racemic resolution.

For example, it is known from DD patent specification No. 23,217 that carnitine nitrile chloride is converted into carbonate by the action of silver oxide in hydroxide or by the action of silver carbonate, into diastereomers by an optically active acid, from which the appropriate diastereomer is separated and the desired carnitine derivative is isolated. Another process according to BE patent specification No. 660,039 is based on carnitine amide hydrochloride, which is reacted with camphoric acid in the presence of AgNO ₃ to give a mixture of diastereomers. The appropriate diastereomer is again separated and decomposed.

The above-mentioned methods, however, have significant drawbacks. These include the fact that a large amount of difficult-to-separate salt impurities are released, which make the racemic resolution difficult, as well as the numerous production steps required to achieve the racemic resolution of the carnitinamide or carnitine nitrile used, which thus increase the costs of the technical implementation of the process. The difficulties are further increased by the fact that, due to the use of silver salts, it is necessary to work under conditions that prevent the access of light in order to prevent the reaction mass from turning black.

The object of the present invention is to eliminate these disadvantages and to propose a process that would allow obtaining optically active carnitine nitrile chloride, in particular (-)-carnitine nitrile chloride, in a simple manner.

This is achieved by using optically active di-(3-chloro-2-oxypropyltrimethylammonium)tartrate. For the production of (-)-carnitine nitrile chloride, di-[(-)-3-chloro-2-oxypropyltrimethylammonium)-L-(+)-tartrate (COP-tartrate) is used. The compounds mentioned are new and have the formulas

COO® I

HC-OH I

BOY

CH,

AND

CH ₃ -iP-CH ₂ -CH-CH ₂ C1

CH ₃ Oh

CH,

L

CH,-IjP-CH _n -CH-CH _n Cl ³ I ² I ² . CH ₃ OH

COP-tartrate can be produced by various processes. Preferably, COP-tartrate is produced by reacting L-(+)-tartaric acid with trimethylamine and finally reacting with epichlorohydrin.

Preferably, the procedure is as follows: L-(+)-tartaric acid is first dissolved in water or suspended in alcohol, conveniently in methanol or ethanol, finally neutralized with trimethylamine and the di(trimethylammonium)tartrate formed as an intermediate is converted into the desired COP-tartrate and its diastereomers by reaction with epichlorohydrin at a temperature of 17 to 30 °C.

A preferred embodiment of the production of COP-tartrate according to the invention is described below: Κ 1 mol L-( + )-tartaric acid, dissolved in 200 to 250 g of water suspended in a lower alcohol, is added at a temperature of 0 to 30 ° C. 1.6 to 2.5 mol of trimethylamine, preferably 1.8 to 2.1 mol of trimethylamine. The pH value of the solution is between 6.5 and 7.5. Finally, 1.6 to 3 mol of epichlorohydrin are added expediently and the temperature is maintained at 15 to 30 ° C, preferably 20 to 28 ° C.

When working in water, a single liquid phase is formed. After evaporation of the water, preferably in vacuo, an oily residue is formed, from which the desired COP-tartrate crystallizes after treatment with an organic solvent, preferably a mixture of methanol and acetone.

EN 266 600 B2

If working in an alcohol, for example methanol or ethanol, the desired COP-tartrate is precipitated and can be separated.

Di-[(-)-3-chloro-2-oxypropyltrimethylammonium)-L-(+)-tartrate has the following properties: melting point 159 °C (after recrystallization from a mixture of methanol and acetone), [<x]^ = -10.8° (c = 1.04 in water), pH of the solution (1%): 7,

Analysis: C calculated 42.39%, calculated 42.36%

H off 7.56% in. 7.99%

N off 6.18% of the 6.36% iC (KBr) spectrum: 3.15, 6.30, 7.20, 9.15, 10.35^. ·

In the production of di-[.(+)-3-chloro-2-oxypropyltrimethylammonium]-D-(-)-tartrate, racemic resolution is carried out using D-(-)-tartaric acid.

Melting point 159°C (after recrystallization from a mixture of methanol and acetone), [α ^] = +10.8° (c = 1.04 in water).

The racemic resolution according to the invention proceeds very rapidly. It is therefore possible to proceed in the subsequent stages up to carnitine nitrile chloride and carnitine with only the antipode, thereby eliminating the burden of further reactions with other antipodes. It was not possible to assume that further racemization would not be necessary in the subsequent reactions, the last of which leads to carnitine.

The di-[(-)-3-chloro-2-oxypropyltrimethylammonium]-L-(+)-tartrate (COP-tartrate) according to the invention can be converted in a simple manner into (-)-carnitine nitrile chloride and (-)-carnitine.

In this case, either the COP-tartrate is first reacted with CaCl2, the calcium tartrate is separated off and the (-)-3-chloro-2-oxopropyltrimethylammonium chloride is isolated.

After cleavage of the COP-tartrate, the isolated optically active 3-chloro-2-oxypropyltrimethylammonium chloride can be converted by the action of a strong base, such as an alkali metal hydroxide, an alkali metal alkoxide, or an alkali metal tert-butoxide, into (-)-glycidyltrimethylammonium chloride, which can then be converted by the action of acetone cyanohydrin or hydrocyanic acid into L-carnitine nitrile chloride.

This process is preferably carried out in an alcohol solvent at room temperature.

Purification of the products is effectively carried out by simple crystallization from solvents such as lower alcohols.

This results in products with an optical purity higher than 98%.

However, this process also allows di-[(+)-3-chloro-2-oxypropyltrimethylammonium]-D-(-)-tartrate to be converted into the corresponding (+)-carnitine nitrile chloride.

Example 1

Production of di[(-)-3-chloro-2-ocypropyltrimethylammonium J-L-(+)-tartrate

To 18.75 g (125 mmol) of L-(+)-tartaric acid dissolved in 30 ml of water, 39 ml (259 mmol) of trimethylamine are added dropwise over 10 minutes with stirring. The temperature is maintained at 30 °C. The pH of the solution is 7. The reaction mixture is cooled to 15 °C and 23.15 g (250 mmol) of epichlorohydrin are added dropwise with stirring. The reaction temperature is maintained at 25 °C and stirring is continued until the reaction mixture consists of only one phase.

EN 266 600 B2

After the reaction is complete, the water is evaporated under vacuum (Rotavap) at 40 °C. 59.5 g of viscous oil is obtained. ’

This residue is dissolved in 40 ml of hot methanol and 133 ml of acetone is slowly added until turbidity occurs. After standing for 72 hours at room temperature, the mother liquor is decanted and the crystals are washed with a mixture of acetone and methanol in a ratio of 4:1 and dried in vacuo.

4.75 g of plate-like crystals are thus obtained (yield 16.8% of theory).

Melting point 150 to 152 °C, DJ^ ^{4 =} ( ^{c =} Ir in water).

Example 2

Production of di-[(-)-3-chloro-2-oxypropyltrimethylammonium] -L-( + )-tartrate

150 g (1 mol) of L-(+)-tartaric acid is suspended in 200 g of methanol and 106.2 g (1.8 mol) of trimethylamine and 250 g of ethanol are added at 20 °C over the course of one hour. The temperature is maintained at 20 °C. The tartaric acid dissolves to form di-trimethylammonium-L-(+)-tartrate. Finally, 166.5 g (1.8 mol) of epichlorohydrin is added and the temperature is maintained at 20 °C. The reaction mixture is stirred for two days while maintaining this temperature. The precipitated crystals are filtered off and washed with a mixture of acetone and methanol in a ratio of 4:1 and dried in vacuo.

The product is obtained in a yield of 38.9% (77.8% of theory), which has a melting point of 157-158°C. [α] ²⁴ = -9.1° (c = 1, in water).

Example 3

Production of (-)-3-chloro-2-oxypropyltrimethylammonium chloride

To 18.35 g (40.5 mmol) of tartrate according to Example 1 in 65 ml of water, 4.50 g (40.5 mmol) of calcium chloride dissolved in 15 ml of water are added with shaking. Calcium tartrate immediately begins to precipitate by crystallization. After 5 minutes, the suspension is cooled in an ice bath (pH of the solution 7) and the calcium tartrate is filtered off with suction. It is washed with methanol and, after drying in air, 10.08 g is obtained (10.54 g is the theoretical yield of the tetrahydrate, yield 95.6%).

The filtrate (and washing methanol) is evaporated at 50 °C on a rotary evaporator. 17.0 g of solid residue (theory 15.24 g) is obtained, which is digested with 25 ml of absolute ethanol at a temperature of 70 °C. The suspension is cooled in an ice bath and the crystals are filtered off with suction. After washing with a mixture of ethanol and acetone in a ratio of 1:1 and drying in air, 10.24 g of colorless crystals (67.2% of theory) are obtained.

Melting point 214 °C, = -28.76° (c = 0.97 in water).

Example 4

Production of (-)-glycidyltrimethylammonium chloride £(-)-Ν,Ν,Ν-trimethyloxiranmethanamineJ

To 9.5 g (50 mmol) of (-)-3-chloro-2-oxypropyltrimethylammonium chloride£ (99.1%), [°Jp ⁴ = = -29.5°](c = 1 in water), melting point 212-214 °C, dissolved in 35 ml of methanol, a solution of 2.05 g of sodium hydroxide (98%, 50 mmol) in 45 ml of methanol was added dropwise with stirring at room temperature. The mixture was stirred for 3 hours, the precipitated sodium chloride (2.6 g, 89%) was filtered off and washed twice with 5 ml of ethanol each time. The filtrate and the washing ethanol were evaporated. The crude product (8.95 g, 117 Ϊ) was taken up in 50 ml of chloroform, while the product slowly dissolved with shaking, except for a small amount of sodium chloride. This undissolved sodium chloride (0.60 g, 20%) was filtered off.

EN 266 600 B2 5

After evaporation of chloroform, 7.6 g (99.3%) of (-)-glycidyltrimethylammonium chloride are obtained.

The product contains no starting material (thin layer), melting point 121 to 123.5 °C, Wp ⁴ = -27.0° (c = 1 in water).

IR (KBr): 3440s, 3030w, 2940w, 1630m, 1485s, 1420w, 1270w, 1150w, 1100w, 980m, 935s, 900m, 870m, 805w, 770w.

¹ H-NMR (300 MHz, d _g = DMSO): 2.69 (dd, 1H, J = 5 and 3 Hz, HC(3)), 2.93 (dd, 1H, J = 5 and 3 Hz, HC(3)), 3.22 (dd, 1H, J = 13 and 8 Hz, HC(l)), 3.23 (s, 9H, -N(CH ₃ ) ₃ ), 3.57 (dddd, 1H, J = 8/5/3 and 3 Hz, HC(2)), 4.04 (dd, 1H, J = 13 and 3 Hz, HC(D).

Example 5

Production of (-)-glycidyltrimethylammonium chloride [(-)-N,N,N-trimethyloxiranemethanamine]

To 9.5 g (50 mmol) of (-)-3-chloro-2-oxypropyltrimethylammonium chloride (99.1%, mp ⁴ ~ -29.5° (c = 1 in water), melting point 212 to 214 °C), dissolved in 35 ml of methanol, a solution of 5.8 g of potassium tert-butylate (97%, 50 mmol) in 20 ml of methanol was added dropwise at room temperature. The mixture was stirred for 3 hours, the precipitated KCl (3.95 g, 105%) was filtered off and washed twice with 5 ml of ethanol each time. The filtrate and the washing ethanol were evaporated.

The crude product (9.15 g, 119%) is taken up in 50 ml of chloroform, and the product slowly dissolves with shaking until it reaches a small amount of KCl. This insoluble KCl (0.05 g, traces) is filtered off. »

After evaporation of the chloroform, 7.5 g (98%) of (-)-glycidyltrimethylammonium chloride are obtained. The product contains no starting material (thin layer). Melting point 119-121°C, ^δ ₌ -27.1° (c - 1 in water).

Example 6

L-carnitine nitrile chloride production

To 10 ml of methanol are added 4.35 g of acetone cyanohydrin (98%, 50 mmol) and 7.9 g (50 mmol) of (-)-glycidyltrimethylammonium chloride. The mixture is stirred at 20 to 25 °C until all components are dissolved. Then the solution is heated to 45 °C within half an hour and stirred at this temperature for 4 hours (thin layer chromatogram) (after half an hour the product begins to separate at 50 °C). The mixture is cooled to 20 °C, the white crystals are filtered off with suction, washed with 6 ml of acetone each time and dried.

Yield: 7.5 g (81.6% of theory), melting point 246°C (decomposition), - -25.6° (c = 1 in water).

The product has a purity of 97.3% (HPLC) and also contains 2,4 (-)-glycidyltrimethylammonium chloride. After recrystallization from ethanol, long needles (95%) are obtained.

Melting point 256 °C (decomposition), ^{= -25} <· ⁸ ° (c = 1 in water).

Claims (2)

OBJECT OF THE INVENTION A process for the preparation of optically active carnitine nitrile chloride, characterized in that the optically active tartaric acid is reacted with trimethylamine, the reaction product is converted by epichlorohydrin to optically active di- (3-chloro-2-oxypropyltrimethylanomium) tartrate, which is cleaved to tartaric acid. and optically active 3-chloro-2-oxypropyltrimethylammonium chloride, which is converted with a strong base to optically active glycidyltrimethylammonium chloride and reacted with cyanide to optically active carnitine nitrile chloride. 2. The process according to item 1, for the production of (-) - carnitine nitrile chloride, characterized in that L - (+) - tartaric acid, dissolved in water or suspended in alcohols, is reacted with trimethylamine and finally at a temperature of 10 to 35 ° C with epichlorohydrin to di (()) - 3-chloro-2-oxypropyltrimethylammonium-L - (+) - tartrate, which is cleaved to tartaric acid and (-) - 3-chloro-2-oxypropyltrimethylammonium chloride, which is reacted with a strong base to (-) - glycidyltrimethylammonium chloride and this is reacted with acetone cyanohydrin or hydrocyanic acid to give (-) - carnitine nitrile chloride.