WO2006056098A1

WO2006056098A1 - The process for resolving dl-epherine, pseudoephedrine or the derivatives thereof and the resolving agents

Info

Publication number: WO2006056098A1
Application number: PCT/CN2004/001338
Authority: WO
Inventors: Song Li; Aihua Nie
Original assignee: Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China
Priority date: 2004-11-23
Filing date: 2004-11-23
Publication date: 2006-06-01

Abstract

The invention relates to the process for resolving DL-ephedrine, DL-pseudoephedrine or the derivatives thereof and to the corresponding resolving agents. The D-(+)- or L-(-)-tartaric acid derivatives of formula (I) are the resolving agents for DL-ephedrine of formula (II), DL-pseudoephedrine of formula (III), in which the groups in formulas (I) to (III) are defined as claims.

Description

Resolution method of DL-ephedrine, DL-pseudoephedrine or its derivative and corresponding resolving agent

Technical field

The present invention relates to a D-(+)- or L-(-)-tartaric acid or a derivative thereof as a resolving agent for DL-ephedrine or a derivative thereof and a method for its resolution. The invention also relates to a recovery method for a resolving agent. Background technique

The chemical name of ephedrine is 1-phenyl-2-methylamino-1-propanol. Since the 1- and 2-positions are chiral carbon atoms, there are four isomers of this kind of compound, namely D-(-)- Ephedrine (natural) and L- ( + ) - ephedrine (non-natural) and L- ( + ) - pseudoephedrine (natural) and D- ( - ) - pseudoephedrine (non-natural), the structure is as follows:

1R, 2R-D- (-) - pseudoephedrine lS, 2S-L<+)> pseudoephedrine li^S- D ) - ephedrine 1 S, 2R-L>(+)- strontium China is the only one in the world Natural ephedra is reduced in the producing country, and the ephedrine produced is all whole grass of natural plant ephedra. The origin of ephedra is mainly concentrated in Xinjiang, Inner Mongolia, Gansu, Ningxia and other places in western China. The annual consumption of ephedra is only about 80,000 to 100,000 tons in Xinjiang alone. Because the main producing area of growing ephedra is the most serious desertification in China, and ephedra is the main sand fixing plant in these areas; therefore, the excessive excavation of ephedra has caused serious impact on the ecological environment of these areas in recent years. . Therefore, the production of ephedrine that meets market requirements by chemical synthesis will be an effective way to reduce the extraction of ephedra, protect the ecological environment, and meet market demand. At present, the main problem faced by chemical synthesis in the production of ephedrine is how to obtain optically pure products at low cost; although the method of asymmetric synthesis has been greatly developed, there are not many methods of industrial value. It is reported in the literature that there is practical value in the crystallization method: adding a chiral acid (resolving agent) to a solution of DL-ephedrine in water, an organic solvent, or a mixed solvent of water and an organic solvent to form a non-pair The isomers are preferentially precipitated by utilizing the solubility of the diastereomers in a solvent. At present, there are mainly the following methods for the resolution of DL-ephedrine or its derivatives disclosed in the literature:

1) L-(+)-mandelic acid and D-(-)-mandelic acid are resolving agents (a), US Patent: 1867274; b), J, Am. Chem. Soc., 1929, 51: 1906. ): The advantage of this method is that the resolution is high (more than 75%); the optical purity of the product is high (more than 99%). Disadvantages are: L-(+)-mandelic acid and D-(-)-mandelic acid are not easily available, and the price is high, which cannot meet the requirements of large industrial production.

2) L-(+)-tartaric acid is a resolving agent: Natural L-(+)-tartaric acid is a great repellent because its price is cheap so that people can ignore it. If L-(+)-tartaric acid can be used to separate DL-ephedrine, it will be an industrially valuable method. There are many articles (a), UK Patent: 354975, 356931; b), Ger. Patent: DE549970; c), J. Pharm. Soc. Japan, 1927, 47: 109. ) Trying to use L-(+) - a method for the resolution of DL-ephedrine or a derivative thereof by tartaric acid, but there is also literature (J, Am, Chem. Soc, 1929, 51: 1906.) which proves that this method cannot successfully resolve DL-ephedrine or its derivative .

3) Using D-arabonic acid as a resolving agent (US Patent 3478101): The advantages of this method are: the product resolution (80% or more) and optical purity are high, and the resolving agent can be recycled. However, D-arabonic acid is expensive and not readily available.

In addition, it has been reported in the literature to resolve DL-ephedrine or its derivatives by N-benzyloxycarbonyl-DL-amino acid exchange (/· Chin. Chem. Soc. (Taipei), 1978, 25(4): 209-14.) and the method of dissolving DL-ephedrine or a derivative thereof by using D-2,4-dichlorophenoxypropionic acid, US Patent: 6015903, but the prices of the two resolving agents are also relatively high. expensive.

Further literature has shown that dibenzoyltartaric acid derivatives can be used as resolving agents for the preparation of optically active N-benzyl-3-aminopyrrolidines ( JP 09176115 A2 ).

SUMMARY OF THE INVENTION Biological methods.

The present inventors have found through research that the following formula (I) D-(+)- or L-(-)-tartaric acid or a derivative thereof exhibits an excellent effect in the resolution of ephedrine or a derivative thereof, thereby The industrial production of optically active ephedrine or its derivatives and environmental protection provides a strong guarantee.

Accordingly, one aspect of the present invention relates to D-(+)- or L-(-)-tartaric acid or a derivative thereof represented by the formula (I) as a resolving agent for the resolution of DL-ephedrine or a derivative thereof:

(I) wherein the substituents R are each independently H, CH ₃ , Cl, F and N0 ₂ .

The term "DL-ephedrine or a derivative thereof" as used in the present invention means DL-ephedrine or a derivative thereof of the formula (II), or DL-pseudoephedrine or a derivative thereof of the formula (III):

among them,

In the formula (II), R _{2 is} each independently H, Ci Cs linear or branched alkyl, and R ₃ and R ₄ are each independently Η, ΟΗ, ι3⁄4, N0 ₂ or a linear or branched alkyl group, <^~< ₃ linear or branched alkoxy groups,

In the formula (III), R and R ₂ are each independently H, d to C ₅ linear or branched alkyl, R ₃ , and R ₄ are each independently H, OH, halogen, N0 ₂ or d~C. ₃ straight or branched alkyl, straight or branched alkoxy.

According to one embodiment of the present invention, the D- or L-configuration tartaric acid derivative of the above formula (I) is used as a resolving agent for DL-ephedrine or a derivative thereof.

According to a preferred embodiment of the present invention, the D- or L-configuration tartaric acid derivative of the above formula (I) is used as the DL-ephedrine of the formula (II) or a derivative thereof or the DL-pseudoephedrine of the formula (III) or Resolving agent for derivatives.

According to another preferred embodiment of the present invention, tartaric acid of the D- or L-configuration as shown in formula (IV) is used as a resolving agent for DL-ephedrine or a derivative thereof:

According to another preferred embodiment of the present invention, tartaric acid of the D- or L-configuration as shown in the above formula (IV) is used as the DL-ephedrine of the formula (II) or a derivative thereof or the DL-pseudoephedrine of the formula (III) Resolving agent for its or its derivatives:

According to a particularly preferred embodiment of the present invention, tartaric acid represented by the above formula (IV) is used as a resolving agent for the formula (V) DL-ephedrine:

Another aspect of the invention relates to a method for the resolution of DL-ephedrine or a derivative thereof, which comprises the D-(+)- or L-(-)-tartaric acid derivative represented by formula (I) and DL-ephedra The alkali or a derivative thereof is contacted at a certain molar ratio, and is subjected to a conventional treatment to obtain a crystal in which DL-ephedrine or a derivative thereof is combined with a resolving agent, and the obtained crystal is acidified to obtain an optically active ephedrine or a derivative thereof. Structure.

The term "conventional treatment" as used in the present invention refers to the addition of QrC ₄ lower aliphatic alcohol to a mixture of DL-ephedrine or a derivative thereof and a resolving agent, to completely dissolve it, at 50 to 70 ° C, and An equal volume of alcohol, water of the same temperature, stirred for 20-60 minutes, allowed to stand at room temperature overnight, the solid was filtered off and the mother liquid was recovered, and the solid was washed with acetone or diethyl ether and dried.

The term "acidification treatment" as used in the present invention refers to the addition of 0.5 N to 2.5 N of an appropriate amount of a mineral acid such as dilute hydrochloric acid to the crystal of the conjugate of the obtained DL-ephedrine or a derivative thereof and the resolving agent, at 20 - The mixture was completely dissolved by stirring at 40 ° C, extracted twice with an organic solvent, and the aqueous layer was evaporated under reduced pressure to give a solid, which was recrystallized from C ₄ lower fatty alcohol, and the solid was filtered off and the solid was washed with acetone or diethyl ether and dried.

According to the present invention, the DL-ephedrine used in the present invention may be natural DL-ephedrine or artificially synthesized DL-ephedrine or a derivative thereof.

Another aspect of the invention also relates to a method for recovering a resolving agent D-(+)- or L-(-)-tartaric acid or a derivative thereof, which comprises subjecting an organic layer separated in an acidifying treatment step to distillation, recovering a solvent The residue obtained is the recovered resolving agent D-(+)- or L-(-) tartaric acid or a derivative thereof.

According to the present invention, by using L-(-)-dibenzoyltartaric acid of the formula (IV) as a resolving agent, the DL-ephedrine of the formula (V) can be resolved by the following route: DL-Mahoximin benzophenone fe^ tartaric acid (mol ratio = 1:0.25)

Methanol: 1: 1 heated to dissolve, ^Hp

L-(+)-methicin L-i-)-diphenyl tartar mother liquor

(crystal, filtered out) L- (-) -benzil tartaric acid

Crystal, filtered out

Acidification ( 1N HCI), ' f 1

L-W-Mahoximin L-A-Two stupid tartar mother liquor

L +)-Mexoxime Acidification (1NHC1) ^ , Toluene reflux Ephedra play D-f-)-Maspoxib L-i-)-Diphenyl tartar

Acidification ( 1NHC1) ephedra

Specifically, in the split route above:

DL-ephedrine and D-(+) or L-(-)-dibenzoyltartaric acid are in a certain molar ratio (10.1 - 1:1.2, preferably in a ratio of 1:0.25 - 1:0.75, particularly preferred The ratio is 1:0.25), and then d-lower aliphatic alcohol is added thereto, such as methanol, ethanol or isopropanol, particularly preferably methanol, to completely dissolve it. At 50 to 70 ° C, the volume is the same as that of the alcohol. The temperature of the water was stirred for 20 to 60 minutes, left at room temperature (20 ° C) overnight, and the crystals were filtered out, and the mother liquor was recovered for the next experiment. The filtered crystals are washed with acetone or diethyl ether and dried to give D-(-) ephedrine D-(+)-dibenzoyl tartrate or L-(+) ephedrine L-(-)-dibenzoyl. Tartrate.

A certain amount of D-(+) or L-(-)-dibenzoyltartaric acid is added to the mother liquor recovered in the above step, and the amount of the resolving agent added is determined by the yield of the previous step. At 60 ~ 70 ° C, stir it to dissolve completely, place it at room temperature (20 ° C) overnight, filter out the crystal, the mother liquid is reserved for the next experiment; the crystal is washed with acetone or ether, and the part is D+ after drying. Ephedrine D-(+)-dibenzoyl tartrate or L-(+) ephedrine L-(-)-dibenzoyl tartrate. The mother liquid obtained above was evaporated under reduced pressure to remove water and alcohol, and toluene was added thereto, toluene was added thereto, and the mixture was heated under reflux for 4 hours. After cooling, the solid was filtered, and the mother liquid was recovered for the next step; the solid was washed with acetone or diethyl ether and dried. L-(+) ephedrine D-(+)-dibenzoyl tartrate or D-(-) ephedrine L-(-)-dibenzoyl tartrate.

The obtained D-(-) ephedrine D-(+)-dibenzoyl tartrate or L-(+) ephedrine L+)-dibenzoyl tartrate is added at a concentration of 0.5N to 2.5N, preferably 1N. The right amount of dilute hydrochloric acid, in the 20 ~ 40. C is stirred to completely dissolve, and extracted in two organic solvents, such as diethyl ether, ethyl acetate or toluene, particularly preferably diethyl ether, and the organic layer is separated to recover the resolving agent; the solid to d - C ₄ lower aliphatic alcohols such as methanol, ethanol or isopropanol, particularly preferably ethanol or 95% ethanol and recrystallized, crystals were filtered off, mother liquor was retained for recovery of DL- ephedrine. The filtered crystals are washed with acetone or diethyl ether and dried to give D-(-) ephedrine or L-(+) ephedrine hydrochloride. The resolution obtained by this method is above 75%.

The organic layer separated in the above step is evaporated to recover a solvent, and the obtained residue is a recovered resolving agent D-(+)- or L+)-dibenzoyltartaric acid.

In the same manner as above, D-(+)-dibenzoyltartaric acid can be used as a resolving agent; likewise, D-(+) and L-(-) as shown in formula (I) are applied. Derivatives of tartaric acid can be used to resolve DL-ephedrine or a derivative thereof, and DL as shown in formula (II) can be resolved by using D-(+) or L-(-)-dibenzoyltartaric acid. - ephedrine or a derivative thereof or DL-pseudoephedrine or a derivative thereof as shown in formula (III).

Compared with the prior art, the outstanding feature of the method of the invention is that L-(+)-ephedrine or its derivative and D-(-)-ephedrine or both are obtained simultaneously in a good yield in one resolution. Its derivative, and the resolving agent D-(+) or L-(-)-dibenzoyltartaric acid derivative can be recovered. detailed description The following examples will further illustrate the invention but are not intended to limit the invention.

Example 1: Preparation of DL-ephedrine

201.5 g of DL-ephedrine beneficial acid salt was dissolved in 1500 ml of IN NaOH, and heated to dissolve completely. After standing at room temperature, a large amount of solid precipitated, and the solid was filtered out. The mother liquid was extracted with diethyl ether, dried over anhydrous Na ₂ SO ₄ , filtered. The desiccant was removed, and diethyl ether was evaporated to give a solid. The solid obtained twice was combined and dried to give 156.0 g of DL- ephedrine, mp: 76-78 ° C. Example 2: Application of L-(-)-dibenzoyl Tartaric acid split DL-ephedrine

1) 16.5 g (0.1 mol) of DL-ephedrine and 9.4 g (0.025 mol) of L-(-)-dibenzoyltartaric acid monohydrate were dissolved in 30.0 ml of anhydrous methanol at 60- Under 70 Torr, add 30 ml of water of the same temperature, stir to dissolve completely, place at room temperature (20 ° C) overnight, filter out the crystals, and recover the mother liquor for the next step. The filtered crystals were washed with acetone and dried to give 14.2 g of L-(+) ephedrine L-(-)-dibenzoyl tartrate, mp: 178-179. C.

2) Add 7.7g (0.02mol) of L-(-)-dibenzoyltartaric acid to the mother liquor recovered in step 1, and dissolve it at 60-70 ° C with heating and stirring. Place at room temperature (20 ° C). Over the night, the crystals were filtered off and the mother liquor was recovered for the next experiment. The filtered crystals were washed with acetone and dried to give 2.6 g of L-(+) ephedrine L-(-)-dibenzoyl tartrate, mp: 173-175 °C.

3) Combine L-(+) ephedrine L-(-)-dibenzoyl tartrate obtained in 1 and 2 to a total of 16.8 g, add 60.0 ml of IN hydrochloric acid, stir at room temperature to completely dissolve, to 100.0 ml of ether. The extract was extracted twice, and the ether layer was separated to recover the resolving agent; the aqueous layer was evaporated under reduced pressure to give a solid, which was recrystallized from anhydrous ethanol, and crystals were filtered, and the mother liquid was retained for recovery of DL-ephedrine. The crystals which were filtered were washed with acetone and dried to give 8.84 g of L-(+) ephedrine hydrochloride, yield: 88.4%, mp: 218-220 ° C, [a] _D ²⁰ = +33.4. (5·1%, water); ¹ H-NMR (400MHz, CDC1 ₃ ): 59.00910 (brs, 2H), 7.41133-7.35411 (m, 4H), 7.30091-7.25811 (m, 1H), 6.13991 (d, 1H, /=4.416Hz), 5.18129 (dd, 1H, !=4.196Hz, 2=2.672 Hz), 3.33266 (q, 1H, /=4.808Hz), 2.61408 (s, 3H), 0.92060 (d, 3H, /=6.736Hz).

4) The mother liquid of the step 2 was evaporated under reduced pressure to remove water and methanol to obtain a thick material. 100.0 ml of toluene was added thereto, and the mixture was heated under reflux for 4 hours. After cooling, the solid was filtered, and the mother liquid was recovered for the next experiment; the solid was washed with acetone. Drying gave 15.0 g of D-(-) ephedrine L-(+ dibenzoyl tartrate, mp: 170-172 °C.

5) The solid D-(-) ephedrine L-(+ dibenzoyl tartrate salt 15.0g obtained in step 4 was added to 50 ml of IN hydrochloric acid, stirred at room temperature to completely dissolve, and divided into 100.0 ml of diethyl ether. After the second extraction, the ether layer is separated to recover the resolving agent; the aqueous layer is evaporated under reduced pressure to obtain a solid, which is recrystallized from anhydrous ethanol, and crystals are filtered out, and the mother liquid is retained for recovery of DL-ephedrine. Wash and dry to obtain 7.57g D-(-) ephedrine hydrochloride, mp: 219-221 °C

6) Add 30 ml of I hydrochloric acid to the mother liquor (toluene layer) recovered in step 4. After thoroughly stirring, the aqueous layer is separated, and the toluene layer is retained to recover the resolving agent; the aqueous layer is evaporated under reduced pressure to obtain a solid, which is recrystallized from absolute ethanol. The crystals are filtered out and the mother liquor is retained for recovery of DL-ephedrine. The filtered crystals were washed with acetone and dried to give D-(-) ephedrine hydrochloride 0.68 g, mp: 219-221. C. The D-(-) ephedrine hydrochloride salt obtained in the step 5) and the step 6) was combined to give 8.25 g of product, yield: 82.5%, [a] _D ²⁰ = - 34.0. (5.2%, water); ¹ H-NMR (400MHz, CDC1 ₃ ): 58.99578 (brs, 2H), 7.40512-7.35511 (m, 4H), 7.30183-7.26520 (m, 1H), 6.14056 (d, 1H

3.33387 (q, 1H, /=4.480Hz), 2.61443 (s, 3H), 0.92002 (d, 3H, /=6.708Hz).

7) The diethyl ether layers obtained in the steps 3 and 5 are combined, and the diethyl ether is distilled, and then the toluene layer obtained in the step 6) is added to the residue, and most of the toluene is distilled off to obtain 15.7 g of a solid, which is a recovered split. L-(-)-dibenzoyl tartar Acid, recovery: 96.3%, mp: 148-150 °C, [a] _D ² . = -118.8° (5.1%, methanol).

8) The mother liquors recrystallized from ethanol in steps 3, 5 and 6 were combined and the ethanol was distilled to obtain 1.72 g of solid, which was DL-ephedrine hydrochloride which was not separated. Example 3: Application D-(+)-dibenzoyltartaric acid resolution DL-ephedrine

1) 8.25 g (0.05 mol) of DL-ephedrine and 4.7 g (0.0125 mol) of D-(+)-dibenzoyltartaric acid monohydrate were dissolved in 15.0 ml of anhydrous methanol at 50-60 At ° C, 15.0 ml of water of the same temperature was added, stirred to completely dissolve, and left at room temperature (20 ° C) overnight, and the crystals were filtered off, and the mother liquor was recovered for the next experiment. The filtered crystals were washed with acetone and dried to give 7.5 g of D-(+ ephedrine D-(+)-dibenzoyl tartrate, mp: 172-173 °C.

2) Add ^4. lg (O.Ollmol) D-(+)-dibenzoyltartaric acid to the mother liquor recovered in step 1. Stir at 50-60 ° C with heating and stir at room temperature (20 ° C) Place overnight, filter out the crystals, and recover the mother liquor for the next experiment. The crystals which were filtered were washed with acetone and dried to give 0.82 g of D-(+ ephedrine D-(+)-dibenzoyl tartrate, mp: 171-172 °C.

3) Combine D-(+ ephedrine D-(+)-dibenzoyl tartrate obtained in 1 and 2 to a total of 8.32g, add 30.0ml of IN hydrochloric acid, stir at room temperature to completely dissolve, and divide with 50.0ml of ether. The mixture was extracted twice, and the ether layer was separated to recover the resolving agent; the aqueous layer was evaporated under reduced pressure to give a solid, which was recrystallized from anhydrous ethanol, and crystals were filtered, and the mother liquid was retained for recovery of DL-ephedrine. Wash with acetone and dry to give 4.11 g of D-(+ ephedrine hydrochloride, yield: 81.5%, mp: 218-220 °C, [a] _D ²⁰ = -33.0 (5.1%, water); ¹ H -NMR (400MHz, CDC1 ₃ ): 69.04570 (brs, 2H), 7.41331-7.35334 (m, 4H), 7.29949-7.25677 (m, 1H), 6.14163 (d, 1H, J=4.424Hz), 5.19179 (dd, 1H, /!=4.220Hz, ₂ = 2.672 Hz), 3.33115 (q, 1H, /=4.884 Hz), 2.61525 (s, 3H), 0.92368 (d, 3H, J = 6.724 Hz).

4) The mother liquid of the step 2 was evaporated under reduced pressure to remove water and methanol to obtain a thick material. 50.0 ml of toluene was added thereto, and the mixture was heated under reflux for 4 hours. After cooling, the solid was filtered, and the mother liquid was recovered for the next step; the solid was washed with acetone. Drying gave 7.02 g of L-(+) ephedrine D-(+)-dibenzoyl tartrate, mp: 168-170. C.

5) Add 7.02g of solid L-(+) ephedrine D-(+)-dibenzoyl tartrate obtained in step 4 to 30ml of IN hydrochloric acid, stir at room temperature to completely dissolve, to 50.0ml of ether. The extract was extracted twice, and the ether layer was separated to recover the resolving agent; the aqueous layer was evaporated under reduced pressure to give a solid, which was recrystallized from anhydrous ethanol, and crystals were filtered, and the mother liquid was retained for recovery of DL-ephedrine. The crystals which were filtered were washed with acetone and dried to give 3.66 g of L-(+)-ephedrine hydrochloride, mp: 218-220 °C.

6) Add the 15 ml of IN hydrochloric acid to the mother liquor (toluene layer) recovered in step 4. After thoroughly stirring, the aqueous layer is separated, and the toluene layer is retained to recover the resolving agent. The aqueous layer is evaporated under reduced pressure to obtain a solid, which is recrystallized from absolute ethanol. The crystals are filtered out and the mother liquor is retained for recovery of DL-ephedrine. The crystals which were filtered were washed with acetone and dried to give 0.21 g of L-(+)-ephedrine hydrochloride, mp: 219-221 °C:. The L-(+)-ephedrine hydrochloride salt obtained in the step 5) and the step 6) was combined to obtain 3.87 g, yield: 76.8%, [a] _D ²⁰ = +33.4 ° (5.1%, water); ¹ H -NMR (400MHz, CDC1 ₃ ): 68.9835 (brs, 2H), 7.4041-7.3543 (m, 4H), 7.3016-7.2649 (m, 1H), 6.1372 (d, 1H,

3.3400 (q, 1H, =4.66Hz), 2.6137(s, 3H), 0.9192 (d, 3H, /=6.72Hz).

7) The diethyl ether layers obtained in the steps 3 and 5 are combined, and the diethyl ether is distilled off. Then, the toluene layer obtained in the step 6) is added to the residue, and most of the toluene is distilled off to obtain 7.9 g of a solid, which is a recovered split. D-(+)-dibenzoyltartaric acid, recovery: 83.8%, mp: 141-142. C, [a] _D ²⁰ = -114·4. (5.0%, methanol). The mother liquors which were recrystallized from ethanol in steps ³ , 5 and 6 were combined and distilled to recover ethanol and obtained ^0.7 solids, which was DL-ephedrine hydrochloride which was not separated.

Claims

Rights request

1. A D-(+)- or L-(-)-tartaric acid derivative represented by the formula (I) as a resolving agent for DL-ephedrine or a derivative thereof:

Wherein the substituents R are each independently H, CH ₃ , Cl F and NO:

The resolving agent according to claim 1, wherein the DL-ephedrine or a derivative thereof is the DL-ephedrine of the formula (II) or a derivative thereof:

Wherein, R ₂ are each independently a linear or branched alkyl group of H, d~C ₅ , and R ₃ and R ₄ are H, OH, halogen, N0 ₂ or ~C ₃ straight or branched alkyl, ~C ₃ straight or branched alkoxy.

3. The resolving agent according to claim 1, wherein the DL-ephedrine or a derivative thereof is the DL-pseudoephedrine of the formula (III) or a derivative thereof:

(III)

Wherein I, R ₂ are each independently a linear or branched alkyl group of H, d~C ₅ , and R ₃ , R ₄ are H, OH, halogen, ]\0 ₂ or ~C ₃ straight chain Or a branched alkyl group, a C^C^ linear or branched alkoxy group.

The resolving agent according to claim 1, wherein the D-(+)- or L-(-)-tartaric acid derivative is D-(+)- or L-(-) having the formula (IV). -Dibenzoyltartaric acid:

The resolving agent according to claim 4, wherein the DL-ephedrine or a derivative thereof is a compound of the formula (II) DL-ephedrine or a compound thereof:

(II) wherein, R _{2 is} independently a linear or branched alkane of H, d to C ₅ The group, R ₃ and R ₄ are H, OH, halogen, N0 ₂ or C^Cs straight or branched alkyl, ~C ₃ straight or branched alkoxy.

The resolving agent according to claim 4, wherein the DL-ephedrine or a derivative thereof is the DL-pseudoephedrine of the formula (III) or a derivative thereof:

Wherein, R ₂ are each independently a linear or branched alkyl group of H, d~C ₅ , and R ₃ , R ₄ are H, OH, halogen, N0 ₂ or d~C ₃ straight chain or Branched radical, linear or branched alkoxy.

7. A method of using the formula (I) D-(+)- or L-(+ tartaric acid derivative to resolve DL- or a derivative thereof,

(I) wherein the substituents R are each independently H, CH ₃ , Cl, F and Ν0 ₂ , the method comprising deriving D-(+)- or L-(-)-tartaric acid represented by formula (I) And the DL-ephedrine or a derivative thereof or the formula (III) DL-pseudoephedrine or a derivative thereof is contacted at a certain molar ratio,

(II) (III) wherein, in the formula (II), R _{2 is} each independently H, Ci~C ₅ linear or branched alkyl, and R ₃ and R ₄ are H, OH, halogen, N0 ₂ Or a d-C ₃ linear or branched alkyl group, a d-C ₃ straight or branched alkoxy group,

In formula (III), R _{2 is} independently H, d~C ₅ straight or branched alkyl, R ₃ , R ₄ is H, OH, halogen, N0 ₂ or d~C ₃ a linear or branched alkyl group, a d~C ₃ straight or branched alkoxy group,

The optically active ephedrine or derivative isomer thereof is obtained by conventional treatment and subsequent acidification.

8. The method of claim 7 comprising the steps of:

1) The compound of the formula (II) or the formula (ΠΙ) of claim 7 and the D-(+)- or L-(-)-tartaric acid or a derivative thereof of the formula (I) are from 1:0.1 to 1:1.2. The molar ratio is mixed, and conventionally obtained, correspondingly obtained D-(-) ephedrine or its derivative dibenzoyl tartaric acid derivative salt or L-(+) ephedrine or its derivative L-(-)-diphenyl Acyl tartaric acid derivative salt crystal;

2) Step 1) The obtained crystal is acidified to obtain D-(-) ephedrine or its derivative hydrochloride or L-(+) ephedrine or its derivative hydrochloride;

In order to obtain another optically active isomer,

3) The mother liquid of step 1) is evaporated under reduced pressure to remove water and alcohol to obtain a thick substance, toluene is added thereto, and the mixture is heated under reflux to obtain L-(+) ephedrine or its derivative D-(+)- after conventional treatment. a dibenzoyl tartaric acid derivative salt crystal or D-(-) ephedrine or a derivative thereof L-(+ dibenzoyl tartaric acid derivative salt crystal; 4) Step 3) The obtained crystal is acidified to obtain L-(+) ephedrine or its derivative hydrochloride or D+) ephedrine or its derivative hydrochloride.

9. The method according to claim 8, wherein a resolving agent of the formula (I) D-(+)- or L-(-)-tartaric acid derivative can be further added to the mother liquor of the step 1), which is further obtained after conventional treatment. D-(-) ephedrine or a derivative thereof D-(+)-dibenzoyltartaric acid derivative salt or L-(+) ephedrine or a derivative thereof L-(-)-dibenzoyltartaric acid derivative salt.

10. A method for recovering a D-(+)- or L-(-)-tartaric acid derivative resolving agent, which comprises distilling the organic layer separated in the acidification treatment of step 8 of claim 8 and 4) The solvent D-(+)- or L-(-)-tartaric acid derivative is obtained after the solvent.