JPS60126254A - Manufacture of l(-)carnitine salt - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention uses dibenzoyl-tartaric acid to produce 0.
Sea-carnitine to macro-)carnitine [It salt and L(-
) Carnitine inner salt is easily produced industrially.

BACKGROUND ART A method for resolving L-carnitine using an optically active organic acid is already known. Specifically, East German Patent No. 93347 describes a method for producing its optical isomer from L-carnitine using dibenzoyl-D(-1 tartaric acid).

However, this method has several fatal flaws and cannot be applied industrially. Furthermore, even on a laboratory scale, the yield of [(-)carnitine is extremely low and contains an unacceptable amount of impurities (detected by the cheerfully low specific rotation compared to the pure isomer). ).

Example 3 of the East German Patent No. IM (relating to a method for accurately separating dibenzoyl-〇-tartrate of L(-)carnitine and D-carnitine) consists of the following steps.

The first [-dibenzoyl-〇-tartrate I!i salt of carnitine is obtained by crystallizing the mixture of diastereoisomeric salts of carnitine at +4°C from ω methanol.

Yama) process (dibenzoyl-rho-tartrate of L-carnitine ([α].=-95.2°, yield 62%) is obtained by recrystallizing the salt obtained in the field from methanol.

+C> Evaporate the mother liquor of step (ω and peak) to dryness.

(D-carnitine dibenzoyl-
Obtain rho-tartrate.

(e) The residue of step td+ is subjected to unspecialized fractional crystallization to yield the dibenzoyl-rho-tartrate of [-carnitine, the specific rotation of which is not reported. As a result, shi=
The yield of dibenzoyl-〇(-)tartrate of carnitine increases to 78%.

[-Dibenzoyl-D-Tartarite F! From 1-
The recovery of phthalonidine is described in Example 10 of the above-mentioned East German patent specification. (f) The dibenzoyl-D-tartrate of [-carnitine is suspended in water and the bulk of the dibenzoyl-tartrate (91%) is extracted with ether.

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

The aqueous solution is evaporated to dryness to produce "pure" lurnithine (
(no data on its properties specified) was obtained in a yield of 82.5% based on the starting material tartrate.

The total number rate is 64.3%.

Problems to be Solved by the Invention] As can be easily seen, this method is clearly complex. The reasons for this are: (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. Elute using a resin column (4
)^ It consists in evaporating a diluted [-carnitine aqueous solution.

However, all these drawbacks are limited to the total yield reported in Example 3 of the East German patent specification (the yield of lunitine is 64.3%, but the specific optical rotation is It was thought that it could be tolerated, considering that

However, if Examples 3 and 10 described in East German Patent No. 93,347 are performed exactly as described, the IC results are completely different. That is, according to additional tests conducted by the present inventor, as a result of the operations in steps (J and step output), the first fraction of dibenzoylute tartrate of shi-carnitine was obtained with a yield of 47% ([α]
, = -93'). In order to bring the value of [α]0 up to the permissible limit of -95°, recrystallization is required two more times, which further reduces the yield.

Attempts to obtain a second fraction of salt of reasonable purity are chemically impossible. Finally, the steps ([), (9
), even if all the above procedures are carried out successfully, the yield of lunitine does not exceed 29% of the theoretical value. Not only that, the [α] value of the final product obtained in this way is -18°, which is not a problem from a market point of view, and it is not necessary to carry out any operations that would further reduce the overall yield. Only then can the value of ``α'' be raised to a good level.

Therefore, it is clear that the method taught in East German Patent No. 93,347 produces cy(-)carnitine in poor yield and purity, and is not an industrially applicable method.

Furthermore, in the East German patent specification, the starting material D3
L-carnitine (estimated to be anhydrous), L-
It should also be noted that no details are disclosed regarding the production conditions from carnitine hydrochloride (commonly available). Considering the strong hygroscopicity of carnitine and the difficulty of producing carnitine in an anhydrous state starting from carnitine salts, we cannot ignore this condition.

As a result of the research conducted by the present inventors, it was found that when a diastereoisomeric mixture of dibenzoyl-〇(-)tartrate of D,L-carnitine is crystallized from methanol at a temperature of -10° or less, -
) It has been found that dibenzoyl-〇(-)tartrate of carnitine 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 the diastereoisomeric salts improves both the yield (reduced to 400-50%) and the optical purity ([α], = -93.2
°) also did not yield satisfactory results.

Means for Solving the L Problem] That is, the present invention provides dibenzoyl of DC+1 carnitine by crystallizing 1 M of dibenzoyl-〇(-) tartar of L-carnitine from methanol at a temperature of -10° or less. The gist is to separate dibenzoyl-〇(-1 tartrate from -1 tartrate) of carnitine.

Operation and Example 1 The crystallization is carried out in the substantial absence of water. For example, starting from a commercially available paste, L-carnitine hydrochloride, which is first treated with a substantially stoichiometric amount of alkaline hydroxide in an alcoholic solvent, which is not necessarily anhydrous, and then treated with substantially equimolar amounts of alkaline hydroxide. Treat with the acid dibenzoyl-〇(-)tartaric acid (may be moist).

The precipitate obtained, consisting of a mixture of diastereoisomeric salts, is dried and crystallized.

According to a preferred embodiment of the invention, [1,L-carnitine hydrochloride (commercially available raw material) was reacted with sodium methoxide (preferably sodium methoxide) in methanol and the sodium chloride formed as a by-product was filtered off. Thereafter, substantially equimolar m of dibenzoyl-DC-
) React with tartaric acid under heat. The obtained solution -1
When cooled to a temperature below 0°C, the dibenzoyl-D (-
) The tartrate precipitate is obtained directly. By recrystallizing from methanol, [α]D is 195° with a yield of 7o to 80%.
~96° no Shiku-) carnitine dibenzoyl-D(-
) can contain tartrate.

The salt thus obtained is suspended in an inert solvent such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, and anhydrous H (J) is added in a stoichiometric or slightly excess amount. In addition, L
(-)Carnitine hydrochloride can be obtained quickly and in an almost quantitative yield.

As described above, according to the method of the present invention, [(-)carnitine hydrochloride can be obtained from commercially available L-carnitine hydrochloride in a very simple process, the solvent for crystallization can be changed each time,
It can be purified without ether extraction, resin elution, or evaporation of an aqueous solution to dryness.

Operation 2 of the preferred embodiment of the present invention [Culms are summarized as follows, but are not limited thereto.

〈Prepare an anhydrous methanolic solution of L-carnitine inner salt from glue, L-carnitine hydrochloride and 1 helium methoxade in methanol. Addition of -D(-)tartaric acid immediately results in precipitation of the dibenzoyl-D(-1 tartrate of carnitine, which is already quite pure -) (carried out at a temperature of -10° or below), ( C) Step + The precipitate obtained in b) is diluted with methanol.
Recrystallizing (once or twice) at a temperature of 0° or below, +d+dibenzoyl-D(-)tartrate of carnitine obtained in step (C) in the absence of water; L(=)carnitine hydrochloride is prepared by adding anhydrous II CI to a suspension in an aprotic solvent.

In addition, [(-)carnidine dibenzoyl-D(-
[(
-) It can also be converted into carnitine inner salt. For that purpose, 1. (-1 carnitine dibenzoyl-D(-
) The tartrate is suspended in a two-phase solvent system of water and a water-immiscible or water-immiscible solvent (preferably ethyl acetate) and treated with sulfuric acid.

Dibenzoyl-D(-)tartaric acid is transferred to the organic phase.

L(-)Carnidine lIi! Chemical M in the aqueous phase containing the salt
Add a stoichiometric amount of calcium or barium oxide or carbonate.

After removing the generated CaSo4 or BaSO4 by filtration, the aqueous solution was evaporated and treated with a non-solvent.
(-) Carnitine inner salt can be changed.

Of course, the dibenzoyl-〇(-)tartaric acid can also be recovered from the other solution, especially in the case of a methanolic solution, which has first been acidified with an inorganic acid, by 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 [Dibenzoyl-〇(-) of L(-)carnitine? Ti
? :Production of In-acid] After adding 8125 g of NaO to 1500 mQ of methanol with stirring, 0.0 g of NaO was added to 1500 mQ of methanol with stirring. L-carnitine hydrochloride 600! ? Add this.

The sodium chloride was filtered using a pump, washed with fresh methanol, and the dibenzo-tartaric acid hydrate 11469 was added to the methanolic solution.

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

The resulting precipitate of crystals consisting of dibenzoyl(-)tartrate of 1(-)carnitine and D(+)carnitine was filtered through -C using a pump, washed with water, and dried under vacuum.

While heating the obtained 1480!7 dry salt, methanol 1630I+11! dissolved in. The solution was cooled with stirring to a temperature of -12 to -10'C, and the resulting precipitate was filtered using a pump, washed with about 100 methanol, and cooled to -12C.

Recrystallization was performed in the same manner (first time with 600 d of methanol, second time with 500 m of methanol). The precipitate finally obtained was dried.

As a result, the dibenzoyl-0(-)carnitine
) tartrate salt was obtained (576y<74% yield).

Melting point 147-150℃, [α], --95,4"
(c=10%; C1bOll).

Example 2 [Dibenzoyl-D(-) liquor of L(-)carnitine? 5
Production of acid salt] 164 g of sodium methoxide was mixed with 400 g of methanol.
d solution in methanol 10100O! Garlic,
It was added dropwise to a suspension containing 600 g of L-carnitine hydrochloride. The suspension was stirred for 45 minutes, the resulting sodium chloride was filtered off, and anhydrous dibenzoyl-D(-) tartar was added.
21,120 g was added to a methanol solution of L-carnitine inner salt.

After heating the resulting mixture until completely melted, -1
It was cooled to a temperature between 0°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 mQ of methanol was used for the first time, and 500 mQ of methanol was used for the second time). When dried, 588 g (yield 7) of dibenzoyl-D(-)tartrate of L(-)carnitine was obtained.
3.3%) was obtained. Melting point 146-150℃, [Q'
] D --95,50'(C=10%;C)b O
ll) Comparative example crystallization temperature changed to -12 to -10℃ and -4 to -
The same treatment as in Example 1 was carried out except that the temperature was 5°C, but 343gL of dibenyl-〇(-)tartrate of L(-)carnitine at [α]D = -93,2° was not changed. .

In addition, when carnitine hydrochloride was produced from this salt by the method of Example 4 below, only one with 0 [α]olFi of -18.8° was obtained.

Example 3 [Production of L(-)carnitine hydrochloride] 41g of gaseous 11cI was converted into 14001nIl of [550g of dibenzoyl-〇(-)tartrate of (-)carnitine]
in acetone at room temperature. This suspension was then stirred for 1 hour, filtered after IC, and [
(-)Carnitine hydrochloride is 12009 (yield 95.5
0%) obtained. Its “α” 0 value is -21° (C=3%
:H2O), the melting point was 138-139°C. A L
Upon evaporation of -1-one, dibenzoyl-D(-)tartaric acid could be routinely recovered.

Example 4 [Production of L(-)carnitine inner salt] [Dibenzoyl-D(-)tartaric acid of (-)carnitine.

550 ml of salt, 1000 d of ethyl acetate, 300 mQ of water
and 55 g of 98% sulfuric acid, and the mixture was 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 and the mixture was stirred for 11 hours until the pll was 6.5-7.0. After stirring and removing the resulting calcium sulfate by -C filtration using a pump, 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 give [(-) carnitine intramolecular jp as a white crystalline solid.

After filtration and drying, L(-)carnitine inner salt 1655i+ (yield 94%) was obtained. Its [α].

The value is -28,5° (C=1%:H2O), the water content is 3
%. Dibenzoyl-〇(-)tartaric acid could be recovered in virtually routine yield by evaporating the ethyl acetate.

Claims (1)

[Claims] 1.0.0 in a methanolic solution. [-by fractional crystallization of dibenzoyl-tartrate of carnitine [
1. A method for producing (-)carnitine in the form of a hydrochloride or an inner salt, characterized in that the crystallization is carried out at -10°C or lower. 2. Claim 1, wherein the dibenzoyl-D(-)tartrate of L-carnitine to be subjected to fractional crystallization is obtained in an aqueous medium and dried before fractional crystallization. Manufacturing method described. 3D, a methanolic solution of dibenzoyl-D(-)tartrate of [-carnitine is 0. The method according to claim 1, which is obtained by using L-carnitine hydrochloride, sodium alkoxide, and dibenzoyl-D(-)tartaric acid in substantially equimolar ratios. 4. The manufacturing method according to claim 3, wherein the sodium alkoxide is sodium methoxide. 5 L(-)carnitine hydrochloride is obtained by suspending dibenzoyl-〇(-)tartrate of shii-)carnitine in an aprotic solvent and adding substantially equimolar m of anhydrous H(J). The manufacturing method according to claim 1, 2, 3, or 4. 6. A patent in which the aprotic solvent is selected from the group consisting of acetone, methyl ethyl ketone, methyl isopropyl ketone, and ethyl acetate. The manufacturing method according to claim 5. 7 L(-)carnitine inner salt consists of water and a solvent in which dibenzoyl-〇(-)tartrate of cy(-)carnitine is immiscible or difficult to mix with water. suspended in a phase system;
treating the aqueous phase containing carnitine sulfate with a substantially equimolar amount of calcium or barium oxide or carbonate to produce The method according to claim 1, 2, 3 or 4, which is obtained by filtering off the Ca So 4 or Ba 5 O and evaporating the resulting aqueous solution. 8. The manufacturing method according to claim 7, wherein the solvent that is hardly miscible with water is ethyl acetate. 9 (commercially available product, [-] Treating a methanolic solution of carnitine hydrochloride with a substantially equimolar amount of sodium methoxide, removing the formed sodium chloride by filtration, and adding substantially to the methanolic solution. Equimolar amounts of dibenzoyl-
Tartaric acid was added, and (C) the solution of the obtained diastereoisomer-free mixture was cooled to a temperature below -10° C. (a small amount of very pure traces of [(-)dibenzoyl-0(-) of carnitine) was obtained. The tartrate salt is crystallized from methanol at a temperature below -10°C; (e) the resulting tartrate salt is suspended in an aprotic solvent and a substantially equimolar amount of anhydrous II CJ is added to L(
-) Carnitine is isolated -) Carnitine hydrochloride, or (f) The tartrate obtained in (d) is suspended in a two-phase system of a water-immiscible solvent and water, and then the aqueous phase is separated, the sulfate groups are precipitated in the form of CaSO4 or BaSO4 and filtered off, and the aqueous phase obtained is evaporated to dryness. A method for producing a salt of L(-)carnitine, which is characterized in that it is an inner salt of L(-)carnitine.