JPH0322866B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to the production of L(-)carnitine hydrochloride and L(-)carnitine inner salt from D,L-carnitine using dibenzoyl-D(-)tartaric acid. The present invention relates to a method for industrially easily manufacturing.

[Prior Art] A method of resolving D,L-carnitine using an optically active organic acid is already known. Specifically, East German Patent No. 93347 describes a method for producing the optical isomer from D,L-carnitine using dibenzoyl-D(-)tartaric acid.

However, this method has several fatal flaws and cannot be applied industrially. Moreover, even at the laboratory scale, L
The yield of (-)carnitine is very low and contains unacceptable amounts of impurities. (Detected because the specific optical rotation is clearly smaller than that of the pure isomer).

Example 3 of the East German patent specification (dibenzoyl of L(-)carnitine and D-carnitine)
(Relating to a method for accurately separating D-tartrate)
consists of the following steps.

(a) The first dibenzoyl-D-tartrate of L-carnitine is obtained by crystallizing the mixture of diastereoisomeric salts of carnitine at +4° C. from methanol.

(b) Dibenzoyl-D-tartrate of L-carnitine ([α] _D = -95.2°, yield 62%) by recrystallizing the salt obtained in step (a) from methanol.
get it.

(c) Evaporate the mother liquors of steps (a) and (b) to dryness.

(d) Dibenzoyl-D-tartrate of D-carnitine is obtained by recrystallizing the residue of step (c) from ethanol/methanol.

(e) The residue of step (d) is subjected to unspecialized fractional crystallization to obtain the dibenzoyl-D-tartrate of L-carnitine (its specific rotation is not reported). As a result, the yield of dibenzoyl-D(-)tartrate of L-carnitine increases to 78%.

The recovery of L-carnitine from the dibenzoyl-D-tartrate salt of L-carnitine is described in Example 10 of the above-mentioned East German patent specification. (f) Suspending dibenzoyl-D-tartrate of L-carnitine in water and extracting most of the dibenzoyl-D-tartrate (91%) with ether.

(g) Remove the remaining 9% of dibenzoyl-D-tartaric acid by passing the aqueous solution through an anion exchange resin.

(h) The aqueous solution is evaporated to dryness, yielding "pure" L-carnitine (no data regarding its properties specified) in a yield of 82.5% based on the starting tartrate. The total yield is 64.3%.

[Problem to be Solved by the Invention] As can be easily seen, this method is clearly complex. This is due to (1) the use of two different solvents for the crystallization of carnitine dibenzoyl tartrate, (2) extraction with ether (a known harmful solvent), and (3) ion exchange. (4) To evaporate a highly diluted aqueous L-carnitine solution, which is eluted using a resin column.

However, all these drawbacks are due to the overall yield reported in Example 3 of the East German patent specification (the yield of L-carnitine is 64.3%, but the specific optical rotation is not reported as mentioned above). do not have)
It was thought that it could be tolerated if one took this into consideration.

However, if Examples 3 and 10 described in East Doyle Patent No. 93347 are performed exactly as described, the facts are completely different.
That is, according to the inventor's additional tests,
As a result of the operations in step (a) and step (b), the first fraction of dibenzoyl-D-tartrate of L-carnitine can only be obtained in a yield of 47% ([α] _D = -93°). . In order to bring the value of [α] _D to the allowable limit of −95°, two more recrystallizations are required, which further reduces the yield. Attempts to obtain a second fraction of salt of reasonable purity are stoichiometrically impossible. Finally, steps (f), (g), (h)
Even if all the above procedures are carried out successfully, the yield of L-carnitine never exceeds 29% of the theoretical value. Not only that, the [α] _D value of the final product obtained in this way is -18°, which is not a problem from a market point of view, and there is no need to carry out any operations that would further reduce the overall yield. Only then can the [α] _D value be raised to a good level.

Therefore, it is clear that the method taught in East German Patent No. 93347 provides poor yield and purity of L(-)carnitine, and is not an industrially applicable method.

Furthermore, the East German patent specification does not disclose any conditions for producing the starting material D,L-carnitine (presumed to be anhydrous) from D,L-carnitine hydrochloride (commonly available). It is also noteworthy that this is not the case. Considering the strong hygroscopicity of carnitine and the difficulty of obtaining carnitine in an anhydrous state starting from carnitine salts, this condition cannot be ignored.

As a result of the research conducted by the present inventor, when a diastereoisomer mixture of dibenzoyl-D(-)tartrate of D,L-carnitine is crystallized from methanol at -10°C or lower, dibenzoyl-D of L(-)carnitine is It has been found that (-)tartrate can be easily separated from its diastereoisomeric salts in high yield and purity.

Even at slightly higher temperatures, i.e. -5 to -4 °C, the separation of diastereomeric salts can be achieved with a yield (40
~50%) and optical purity ([α] ²⁰ _D = −93.2°)
In both cases, satisfactory results cannot be obtained.

[Means for solving the problem] That is, the present invention provides
- D by crystallizing the dibenzoyl-D(-)tartrate of carnitine from methanol.
(+)Carnitine dibenzoyl-D(-)tartrate to L(-)carnitine dibenzoyl-D
(-) The gist is to separate tartrate.

[Operation and Examples] This crystallization is carried out in the substantial absence of water. For example, starting from commercially available D,L-carnitine hydrochloride, it is first treated with a substantially stoichiometric amount of alkaline hydroxide in an alcoholic solvent, which is not necessarily anhydrous, and then treated with a substantially equivalent amount of alkaline hydroxide. Treat with a molar amount of dibenzoyl-D(-)tartrate (optionally humid). The precipitate obtained, consisting of a mixture of diastereoisomeric salts, is dried and crystallized.

According to a preferred embodiment of the invention, D,L-carnitine hydrochloride (commercially available raw material) is reacted with sodium alkoxide (preferably sodium methoxide) in methanol and the sodium chloride produced as a by-product is filtered off. Thereafter, it is reacted with a substantially equimolar amount of dibenzoyl-D(-)tartrate under heating. When the resulting solution is cooled to a temperature below -10°C, the dibenzoyl-D of L(-)carnitine, which is already quite pure, is produced.
(−) Tartrate precipitate is obtained directly. By recrystallizing from methanol, [α] _D was obtained with a yield of 70-80%.
Dibenzoyl-D(-)tartrate of L(-)carnitine having a angle of -95° to 96° can be obtained.

The salt thus obtained is suspended in an inert solvent such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, and then suspended in anhydrous HCl.
By adding the stoichiometric amount or a slight excess of L(-)carnitine hydrochloride, L(-)carnitine hydrochloride is obtained rapidly and in almost quantitative yield.

As described above, according to the method of the present invention, L(-)carnitine hydrochloride can be obtained from commercially available D,L-carnitine hydrochloride through very simple steps, such as changing the solvent for crystallization each time, ether extraction, and resin extraction. It can be obtained without elution or evaporation of an aqueous solution to dryness.

The operating steps of the preferred embodiment of the present invention are summarized as follows, but are not limited thereto.

(a) preparing an anhydrous methanolic solution of D,L-carnitine inner salt from D,L-carnitine hydrochloride and sodium methoxide in methanol; (b) adding dibenzoyl- D
Addition of (-)tartaric acid immediately results in the precipitation of dibenzoyl-D(-)tartrate of L(-)carnitine, which is already of fairly high purity (carried out at temperatures of -10°C or lower), (c ) The precipitate obtained in step (b) was mixed with methanol at -10
(d) the dibenzoyl-D(-)tartrate of L(-)carnitine obtained in step (c), always in the absence of water; anhydrous HCl in an aprotic solvent suspension of
By adding L(-)carnitine hydrochloride is obtained.

In addition, dibenzoyl-D(-)tartrate of L(-)carnitine can be replaced with hydrochloride of L(-)carnitine and can be changed to L(-)carnitine inner salt. For this purpose, dibenzoyl-D(-)tartrate of L(-)carnitine is suspended in a two-phase solvent system of a water-immiscible or water-resistant solvent (preferably ethyl acetate) and water, and sulfuric acid is added to the dibenzoyl-D(-)tartrate salt. Process. Dibenzoyl-D(-)tartrate is transferred to the organic phase. A stoichiometric amount of calcium or barium oxide or carbonate is added to the aqueous phase containing L(-)carnitine sulfate.

After filtering off the generated CaSO ₄ or BaSO ₄ ,
L(-)carnitine inner salt is obtained by evaporating the aqueous solution and treating with a non-solvent.

Of course, the dibenzoyl-D(-)tartaric acid can be recovered from the other solution, especially in the case of a methanolic solution, by first acidifying it with an inorganic acid and then evaporating the solvent. The overall recovery rate is over 90%.

Next, the manufacturing method of the present invention will be explained based on Examples, but the present invention is not limited to these Examples.

Example 1 [L(-)carnitine dibenzoyl-D(-)
Production of tartrate] 125 g of NaOH was added to 1500 ml of methanol with stirring, and then 600 g of D,L-carnitine hydrochloride was added. After filtering the sodium chloride using a pump and washing with a small amount of methanol, dibenzoyl-D
1146 g of (-)tartaric acid hydrate were added to the methanolic solution.

The resulting mixture was heated to about 40°C and heated under reduced pressure to about
60% of methanol was distilled off. 1200 ml of water was added and distillation was continued until methanol was completely removed. The recovery rate of methanol was 80-85%.

The obtained crystal precipitate consisting of dibenzoyl D(-)tartrate of L(-)carnitine and D(+)carnitine was filtered using a pump, washed with water, and dried under vacuum. The obtained 1480 g of dry salt was dissolved in 1630 ml of methanol while heating. This solution was cooled to a temperature of -12 to -10°C while stirring,
The resulting precipitate was filtered using a pump, washed with about 100 ml of methanol, and cooled to -12°C. Recrystallization was performed by the same procedure (first time with 600 ml of methanol, second time with 500 ml of methanol). The final precipitate was dried.

As a result, 576 g (yield 74%) of dibenzoyl-D(-)tartrate of L(-)carnitine was obtained.

Melting point 147-150℃, [α] _D = -95.4゜ (c = 10%:
_CH3OH .

Example 2 [L(-)carnitine dibenzoyl-D(-)
Production of tartrate] 164g of sodium methoxide was dissolved in methanol.
D, the solution dissolved in 400ml is added to 1000ml of methanol.
It was added dropwise to a suspension containing 600 g of L-carnitine hydrochloride. The suspension was stirred for 45 minutes, the sodium chloride formed was filtered off, and anhydrous dibenzoyl-D was added.
1120 g of (-)tartaric acid was added to a methanol solution of D,L-carnitine inner salt.

The resulting mixture was heated until completely melted and then cooled to a temperature between -10°C and -12°C.
After stirring at this temperature for 5 hours, it was filtered and washed with a small amount of cold methanol.

The obtained salt was recrystallized under the same temperature conditions without drying (600 ml of methanol was used for the first time, and 500 ml of methanol was used for the second time). When dry, L(-)
Carnitine dibenzoyl-D(-)tartrate is
588g (yield 73.3%) was obtained. Melting point 146-150℃,
[α] ²⁰ _D = -95.50° (C = 10%; CH ₃ OH) Comparative example -4 by changing the crystallization temperature from -12 to -10°C
The same treatment as in Example 1 was carried out except that the temperature was ~-5°C, except that 343g of dibenzoyl-D(-)tartrate of L(-)carnitine with [α] ²⁰ _D = -93.2° was used. I couldn't help it.

In addition, L from this salt can be obtained by the method of Example 4 below.
When (-)carnitine hydrochloride was produced, [α]
²⁰ I could only obtain one with _{a D} value of -18.8°.

Example 3 [Production of L(-)carnitine hydrochloride] 41 g of gaseous HCl was passed through a suspension of 550 g of dibenzoyl-D(-) tartrate of L(-)carnitine in 1400 ml of acetone at room temperature. did. This suspension was then stirred for 1 hour and then filtered.
1200g of L(-)carnitine hydrochloride (yield 95.5%)
I got it. Its [α] ²⁰ _D value is -21° (c = 3%;
_H2O ), the melting point was 138-139°C. When acetone was evaporated, dibenzoyl-D(-)tartaric acid could be quantitatively recovered.

Example 4 [Production of L(-)carnitine inner salt] 550g of dibenzoyl-D(-)tartrate of L(-)carnitine was mixed with 1000ml of ethyl acetate, 300ml of water and
It was added to a mixture of 55 g of 98% sulfuric acid and stirred until completely dissolved. After separating the two layers, 40 g of calcium oxide and 9 g of calcium carbonate were added to the aqueous phase, the mixture was stirred until the pH was 6.5-7.0, the resulting calcium sulfate was filtered off using a pump, and the aqueous solution was Evaporated under vacuum. The residue was treated with ethanol and evaporated to dryness again. The resulting residue was treated with ethanol and acetone to obtain L(-)carnitine inner salt as a white crystalline solid.

After filtration and drying, 165 g (yield 94%) of L(-)carnitine inner salt was obtained. Its [α] ²⁰ _D value was −28.5° (c=1%; H ₂ O), and the water content was less than 3%. Dibenzoyl-D(-)tartaric acid could be recovered in virtually quantitative yield by evaporating the ethyl acetate.

Claims (1)

[Claims] 1. A method for producing L(-)carnitine in the form of hydrochloride or inner salt by fractional crystallization of dibenzoyl-D(-)tartrate of D,L-carnitine in a methanolic solution. A method for producing a salt of L(-)carnitine, characterized in that the crystallization is carried out at -10°C or lower. 2. A method for producing L(-)carnitine in the form of hydrochloride or inner salt by fractional crystallization of dibenzoyl-D(-)tartrate of D,L-carnitine in a methanolic solution, the method comprising: ,L-
Dibenzoyl-D(-)tartrate of carnitine is obtained in an aqueous medium and dried before fractional crystallization, and the crystallization is carried out at -10°C or lower. A method for producing L(-)carnitine salt. 3. A method for producing L(-)carnitine in the form of hydrochloride or inner salt by fractional crystallization of dibenzoyl-D(-)tartrate of D,L-carnitine in a methanolic solution, the method comprising: ,L-
A methanolic solution of dibenzoyl-D(-)tartrate of carnitine was prepared by combining D,L-carnitine hydrochloride, sodium alkoxide, and dibenzoyl-D(-)tartrate.
A method for producing a salt of L(-)carnitine, which is obtained by using (-)tartaric acid in a substantially equimolar ratio and is crystallized at -10°C or lower. 4. The manufacturing method according to claim 3, wherein the sodium alkoxide is sodium methoxide. 5 A method for producing L(-)carnitine hydrochloride by fractional crystallization of dibenzoyl-D(-)tartrate of D,L-carnitine in a methanolic solution, the crystallization being carried out at -10°C or lower. conduct,
Hydrochloric acid of L(-)carnitine, characterized in that the obtained dibenzoyl-D(-)tartrate of L(-)carnitine is suspended in an aprotic solvent and a substantially equimolar amount of anhydrous HCl is added. Salt manufacturing method. 6. The method according to claim 5, wherein the aprotic solvent is selected from the group consisting of acetone, methyl ethyl ketone, methyl isopropyl ketone and ethyl acetate. 7. A method for producing an inner salt of L(-)carnitine by fractionally crystallizing dibenzoyl-D(-)tartrate of D,L-carnitine in a methanolic solution, the crystallization being carried out at -10°C. The dibenzoyl-D(-)tartrate of L(-)carnitine obtained above is suspended in a two-phase system consisting of a water-immiscible or poorly miscible solvent and water;
Treat with substantially equimolar amounts of H ₂ SO ₄ , separate the phases, and treat the aqueous phase containing L(-)carnitine sulfate with a substantially equimolar amount of calcium or barium oxide or carbonate. and generated _CaSO4 or
A method for producing an inner salt of L(-)carnitine, which comprises filtering off BaSO ₄ and evaporating the obtained aqueous solution. 8. The manufacturing method according to claim 7, wherein the solvent that is hardly miscible with water is ethyl acetate. 9 (a) treating a methanolic solution of -D,L-carnitine hydrochloride with a substantially equimolar amount of sodium methoxide; (b) filtering off the formed sodium chloride; (c) the resulting diastereoisomeric salt mixture solution was cooled to a temperature below -10°C; (d) the resulting fairly pure crystallizing the dibenzoyl-D(-)tartrate of L(-)carnitine from methanol at a temperature below -10°C; (e) suspending the resulting tartrate in an aprotic solvent and substantially Either L(-)carnitine is isolated as L(-)carnitine hydrochloride by adding an equimolar amount of anhydrous HCl, or (f) the tartrate obtained in (d) is mixed with a water-immiscible solvent and water. and treatment with substantially equimolar amounts of H ₂ SO ₄ , separating the aqueous phase from which the sulfate groups are precipitated in the form of CaSO ₄ or BaSO ₄ . A method for producing a salt of L(-)carnitine, which comprises filtering it off and evaporating the resulting aqueous phase to dryness to obtain an inner salt of L(-)carnitine.