CN112125816A

CN112125816A - Racemization method of ketamine, its derivative or its salt

Info

Publication number: CN112125816A
Application number: CN202010185065.3A
Authority: CN
Inventors: 张福利; 高升华; 杨哲洲; 胡延雷; 苗庆柱; 陈一波
Original assignee: Shanghai Institute of Pharmaceutical Industry; China National Pharmaceutical Industry Corp Ltd
Current assignee: Shanghai Institute of Pharmaceutical Industry; China National Pharmaceutical Industry Corp Ltd
Priority date: 2020-03-17
Filing date: 2020-03-17
Publication date: 2020-12-25

Abstract

The invention discloses a racemization method of ketamine, its derivative or its salt. The racemization method comprises the following steps: in a solvent, under the action of a catalyst and a reaction temperature of 110-200 ℃, a substrate A shown as below is subjected to a reaction shown as below to obtain a compound B; the catalyst is Lewis acid; the substrate A is enantiomerically enriched ketamine, its derivative or its salt; the carbon marked by is S configuration or R configuration chiral carbon; according to the racemization method, the (R) -ketamine or its salt with an unnecessary configuration is efficiently and conveniently operated and is fully recycled to obtain the racemate compound 1, and the esketamine is prepared by a resolution method, so that waste can be changed into valuable, and the production cost of the esketamine is greatly saved.

Description

Racemization method of ketamine, its derivative or its salt

Technical Field

The invention relates to a racemization method of ketamine, its derivative or its salt.

Background

Ketamine hydrochloride (a racemic mixture of corresponding (S) -enantiomer and (R) -enantiomer, the structure of which is shown as compound 1 below) is an NMDA receptor antagonist, and is clinically applied to the present since 1962, as a unique venous anesthetic with analgesic and sedative effects, the ketamine hydrochloride can be used for anesthesia induction and anesthesia maintenance, is widely applied to operations of pediatric operations, pericardium stuffing patients, shock patients and the like, and is also a medicine stock variety prepared by the general logistics department of the Chinese people liberation force. Sedation, analgesia and treatment of bronchospasm in intensive care.

The clinical application of the ketamine is limited to a certain extent due to long recovery time and side effects of a mental system and a circulatory system after the ketamine is taken, but the ketamine has obvious clinical advantages for vulnerable groups such as pediatric patients (anesthesia induction of pediatric trauma and heart disease and preferred anesthesia methods of malignant high-fever and high-risk children), patients with unstable blood flow, patients with shock (strong adrenal-simulated action and can be safely used for induction of shock patients) and the like.

(S) -ketamine (or esketamine) has higher potency and affinity for the NMDA receptor and therefore requires less dose, and studies have shown that (S) -ketamine is more active than (R) -ketamine, and that (S) -ketamine produces analgesia and hypnotic effects 3-fold and 1.5-fold stronger than (R) -ketamine, respectively, and anesthesia 3.4-fold stronger than (R) -ketamine and 1.9-fold stronger than racemic mixture, while the side effects that produce hallucinations are mainly due to (R) -ketamine. On 5/3 in 2019, the FDA in the united states approved the (S) -ketamine nasal spray formulation Spravato of grand-bang, a poplar, in combination with other oral antidepressant drugs, for the treatment of major depression in adults resistant to standard therapy. Unlike traditional antidepressants, the action mechanism of (S) -ketamine is to achieve the effect of enhancing brain synaptic connections by regulating glutamate receptors, which can help repair the nerve connections of brain cells of depression patients.

At present, the scientific community deeply researches the synthesis of esketamine, and the main problems are high cost and difficult industrial production. Therefore, there are important economic and social benefits to developing esketamine.

According to literature reports, the synthesis of esketamine is mainly divided into two types of methods:

(1) the method uses expensive chiral catalyst or chiral auxiliary agent, has low total yield and higher cost, and cannot realize industrial production.

For example, the documents Tetrahedron,2009,65(27), p 5181-5191; the reported method for synthesizing esketamine mainly uses Noyori chiral catalyst (S) -BINAL-H to construct a chiral center, specifically, nucleophilic substitution and ring closing reaction are carried out to construct a cyclohexyl ring, methyl ketone is introduced through Grignard reaction, and then ketone is asymmetrically catalytically reduced by Noyori chiral catalyst (S) -BINAL-H to establish the chiral center. The key is to use an expensive chiral catalyst, the reaction is carried out at the ultralow temperature of-100 ℃, and NaH and LiAlH are used in the route₄、CH₃I and other dangerous reagents, the reaction steps are long, 9 steps are needed to prepare the esketamine, the total yield is only 21%, and the large-scale production is difficult, and a specific synthesis reference route I is provided.

The Journal of the American Chemical Society,2015,137(9), p 3205-3208; the reported method is as follows: taking o-chlorophenyl cyclohexyl ketone as an initial raw material, carrying out asymmetric amination reaction with di-tert-butyl azodicarboxylate to construct a chiral center, then carrying out de-Boc and reduction to prepare (S) -norketamine, and then carrying out reductive amination reaction to prepare esketamine. The key steps of the route use a chiral catalyst which is not commercialized yet, and the price is high; the final reductive amination reaction yields only 52% and it is difficult to control the amount of hypermethylated impurities. Therefore, the total yield of the route is 30%, the cost of reaction reagents is high, the product has many impurities, and the industrial large-scale production is difficult to realize.

(2) Chiral resolution, i.e. resolution of esketamine with L- (+) -tartaric acid, to obtain esketamine, as reported in document WO 2001098265 a2, see scheme three below.

The synthesis of dehydroketamine 1 has been reported in the prior literature, for example:

document J Label company radiopharm.2018; route reported for 61: p 864-868: taking o-chlorobenzonitrile as a starting material, carrying out Grignard reaction with cyclopentyl magnesium bromide to prepare a cyclopentylketone intermediate, carrying out copper bromide bromination and methylaminoylation reaction in sequence to obtain a key intermediate, namely, hydroxyimine, and carrying out high-temperature rearrangement to prepare racemic ketamine; see scheme four below. The method has advantages of mature process, easily available raw materials, and low cost. The method is a preparation method of ketamine widely used at home and abroad.

In order to reduce the production cost, the racemization mode of the other half of the waste which is not needed after the racemate resolution is generally researched, and the waste is converted into the racemate as much as possible to further resolve the target configuration, so that the aim of saving the cost is fulfilled. At present, the conventional resolution method generally has racemization modes such as high-temperature induced racemization, base-catalyzed racemization, acid-catalyzed racemization and the like. The racemization mode induced by high temperature is more common, for example, the racemization of ambrisentan reported in org. process res. dev.2018,22, p1200-1207 of the subject group, as shown in the fifth route, acetonitrile is used as a solvent, and enol interconversion is carried out on the ambrisentan and hydrogen at alpha position under high temperature, so that racemization is carried out.

Base-catalyzed racemization has also been successful in many cases, and the racemization mechanism is generally achieved by two ways, one is that a base pulls off a hydrogen from a chiral center to form a carbanion, which is stabilized by an electron-withdrawing group at the ortho position (e.g., nitro, cyano, carbonyl, etc.). Compounds as shown in scheme six, the document j. chem. soc.1927, p1276 reports that racemisation occurs only at the chiral carbon alpha to the carbonyl group under the influence of methanol and sodium methoxide.

The other is reversible elimination reaction under base catalysis, such as racemization of chlorthalidone in the scheme hepta, and the hydroxyl on a chiral center is eliminated under alkaline conditions, so that the generated olefin has a planar structure and is subjected to addition reaction with the olefin to obtain a racemate as reported in the literature of Chirality, 1992, 4, p 22.

Acid-catalyzed racemization is somewhat limited compared to base-catalyzed racemization, and our most common acid-catalyzed induced racemization has a reaction mechanism that is protonation of C ═ N or C ═ O, increasing the acidity of the hydrogen at its ortho-chiral center making it susceptible to abstraction, i.e., undergoing interconversion of enols or enamines, which is somewhat similar to the base-catalyzed process. The following compounds, as reported in JP 59021679, were racemized almost quantitatively over a period of 12h at 140 ℃ and 4N hydrochloric acid.

Tilivalline is racemized at 55 ℃ for 24h under the acid catalysis of zinc chloride. Is achieved by an open ring of seven-membered rings, but the chiral center of the compound contains a hydrogen atom and is not a quaternary carbon center, and racemization of (R) -ketamine cannot be achieved at temperatures under these conditions.

However, the conventional high temperature, base, acid catalyzed racemization above mostly requires the presence of hydrogen on the carbon of the chiral center to allow elimination or isomerization, whereas the chiral center of (R) -ketamine is a quaternary carbon and does not have hydrogen. Document J.org.chem.1992,57, p1568 reports that compounds with quaternary carbon chiral centers as shown below can be racemized by ring opening and ring closing processes in 10% hydrochloric acid catalysis at 90 ℃ for 24h, but no indication of racemization is detected when the conditions are applied to racemization of (R) -ketamine.

This is also the reason why (R) -ketamine is difficult to be racemized for recycling, and there is no report on racemization of (R) -ketamine or its salts at present, but in order to reduce the production cost of esketamine, detailed research and exploration on racemization of (R) -ketamine or its salts are urgently needed.

Disclosure of Invention

The invention provides a racemization method of (R) -ketamine, its derivative or its salt, which aims at the defects of the prior art that (R) -ketamine is difficult to racemize and recycle. According to the racemization method, the (R) -ketamine or its salt with an unnecessary configuration can be efficiently, conveniently and fully recycled to obtain the racemate compound 1, and the esketamine is prepared by a resolution method, so that waste can be changed into valuable, and the production cost of the esketamine is greatly saved.

The present invention solves the above-described problems by the following means.

The invention provides a racemization method of ketamine, its derivative or its salt, which comprises the following steps: in a solvent, under the action of a catalyst and a reaction temperature of 110-200 ℃, a substrate A shown as below is subjected to a reaction shown as below to obtain a compound B; the catalyst is Lewis acid; the substrate A is enantiomerically enriched ketamine, its derivative or its salt; the carbon marked by is S configuration and/or R configuration chiral carbon;

wherein R is¹And R²Each independently selected from H, CH₃And CH₂CH₃。

Said R¹And R²Preferably each independently selected from H and CH₃。

The solvent may be a conventional solvent in the art for performing such a reaction, and is preferably one or more of an alkane solvent, a cycloalkane solvent, an aromatic solvent, an alcohol solvent, and a polar aprotic solvent. The alkane solvent can be one or more of n-pentane, n-hexane, n-heptane, n-octane, isooctane, n-nonane, n-decanone, n-dodecane and n-tetradecane. The naphthenic solvent can be cyclopentane and/or cyclohexane. The aromatic hydrocarbon solvent can be one or more of toluene, ethylbenzene, n-propylbenzene, isopropylbenzene, n-butylbenzene, sec-butylbenzene, isobutylbenzene, tert-butylbenzene, o-xylene, p-xylene, m-xylene, 1,2, 4-trimethylbenzene, 1,3, 5-trimethylbenzene, indene, biphenyl, naphthalene, tetrahydronaphthalene, decahydronaphthalene, isopropyltoluene, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, o-chlorotoluene, nitrobenzene, nitrotoluene, quinoline and isoquinoline. The alcohol solvent can be one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, n-pentanol, isoamyl alcohol, n-hexanol, cyclohexanol, n-octanol, n-nonanol, benzyl alcohol and ethylene glycol. The polar aprotic solvent can be one or more of an ester solvent, a sulfone solvent, an amide solvent and a pyrrolidone solvent. The ester solvent can be one or more of ethyl benzoate, methyl benzoate, isopropyl benzoate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, amyl acetate, isoamyl acetate, methyl amyl acetate, benzyl acetate, propyl propionate, n-butyl propionate, amyl propionate, ethyl butyrate, n-butyl butyrate, diethyl oxalate, methyl lactate, ethyl lactate and ethyl salicylate. The sulfone solvent is preferably dimethyl sulfoxide. The amide solvent is preferably N, N-dimethylformamide and/or N, N-dimethylacetamide. The pyrrolidone solvent is preferably N-methyl pyrrolidone.

The solvent can be used in the conventional amount for carrying out the reaction in the field, and the volume mass ratio of the solvent to the substrate A is preferably 1-100 mL/g, more preferably 5-20 mL/g, for example 10 mL/g.

The Lewis acid is preferably one or more of aluminum chloride, aluminum bromide, magnesium chloride, magnesium bromide, zinc chloride, zinc bromide, calcium chloride, boron trifluoride, boron trichloride, boron tribromide, ferric trichloride, antimony pentafluoride, titanium tetrachloride, stannic chloride, stannous chloride, selenium tetrachloride, niobium pentachloride and trifluoromethanesulfonate, more preferably one or more of aluminum chloride, magnesium chloride, boron trifluoride and zinc chloride, and most preferably aluminum chloride. The boron trifluoride is preferably reacted in the form of boron trifluoride diethyl etherate, for example, 46% by mass of boron trifluoride diethyl etherate. The trifluoromethanesulfonate can be one or more of sodium trifluoromethanesulfonate, zinc trifluoromethanesulfonate, copper trifluoromethanesulfonate and silver trifluoromethanesulfonate. The Lewis acid is preferably anhydrous Lewis acid. The lewis acid may be used in an amount conventionally used in the art for carrying out such a reaction, and preferably it is used in a molar ratio of 0.05 to 2.0, more preferably 0.2 to 0.6, for example, 0.1, 0.2, 0.3 or 0.4, to the substrate a.

The enantiomerically enriched ketamine salt can be an acid salt of enantiomerically enriched ketamine, which can be an organic or inorganic acid. Such organic acids include, but are not limited to: methanesulfonic acid, ethanesulfonic acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, lactic acid, malic acid, citric acid, L-tartaric acid, D-tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, ethylenediaminetetraacetic acid, camphorsulfonic acid, picric acid, maleic acid, or glutamic acid. Such inorganic acids include, but are not limited to: hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, tetraboric acid, perboric acid, pyrophosphoric acid, phosphorous acid, hypophosphorous acid, hydrobromic acid, hypobromous acid, carbonic acid, sulfurous acid, hydrocyanic acid, pyrosulfuric acid, peroxymonosulfuric acid, peroxydisulfuric acid, thiosulfuric acid, hypochlorous acid, chloric acid, perchloric acid, chromic acid, dichromic acid, hydrofluoric acid, or hydroiodic acid. The inorganic acid is preferably hydrochloric acid, sulfuric acid or phosphoric acid.

The temperature of the reaction is preferably 140 ℃ to 160 ℃, e.g., 145 ℃, 150 ℃ or 160 ℃.

The reaction is preferably carried out under an atmosphere of protective gas. The protective gas is preferably nitrogen and/or an inert gas.

In a preferred embodiment, the substrate a is (R) -ketamine or a salt thereof, the solvent is ethyl benzoate, the lewis acid is aluminum chloride, the reaction temperature is 140 to 160 ℃, and the reaction is performed under a nitrogen atmosphere.

The progress of the reaction can be monitored by monitoring methods conventional in the art (e.g., HPLC). The reaction time is preferably 4 to 80 hours, for example, 4 to 24 hours.

The reaction may also include a post-treatment, which may be conventional for such reactions, and the present invention preferably comprises the steps of: after the reaction is completed, cooling, filtering and washing the solid to obtain the compound 1. The washing is preferably carried out by using n-hexane.

A preparation method of esketamine, which comprises the following steps: a) racemizing the ketamine or the salt thereof with enriched R configuration to obtain a compound 1; b) resolving the compound 1 to obtain esketamine; wherein the racemization in the step a) comprises the following steps: in a solvent, under the action of a catalyst and a reaction temperature of 110-200 ℃, R-1 shown below is subjected to the reaction shown below to obtain a compound 1; the catalyst is Lewis acid; said R-1 is enantiomerically enriched (R) -ketamine, a derivative thereof, or a salt thereof;

the resolution process of step b) can be referred to WO 2001098265 a 2.

On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.

In the present invention, R-1 represents (R) -ketamine, and S-1 represents (S) -ketamine.

In the present invention, the S-configuration hydrochloride salt is prepared according to the method disclosed in WO 2001098265A 2, and other reagents and starting materials are commercially available.

The positive progress effects of the invention are as follows:

by adopting the racemization method, the (R) -ketamine or its salt with an unnecessary configuration is efficiently, conveniently and fully recycled to obtain the racemate compound 1, and the esketamine is prepared by a resolution method, so that waste can be changed into valuable, and the production cost of the esketamine is greatly saved.

Drawings

Figure 1 is a chiral HPLC plot of racemic ketamine hydrochloride prepared using background art route four.

FIG. 2 is a chiral HPLC chart of a solid obtained by alkalifying a mother liquor obtained by a chiral resolution method of a third route in the background art.

FIG. 3 is a chiral HPLC plot of racemic ketamine 1 hydrochloride prepared in example 1.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The technical scheme of the invention is a technical scheme for achieving the purpose of the invention. The temperatures and reagents used in the following examples can be replaced by the corresponding temperatures and reagents described above to achieve the objects of the invention.

The experimental methods in the examples, in which specific conditions are not specified, were selected according to the conventional methods and conditions, or according to the commercial instructions.

For racemic ketamine 1, S configuration ketamine (S-1), the configuration content of R configuration ketamine (R-1) was determined by the following chiral HPLC method, where in the HPLC profile, the abscissa is time (in min) and the ordinate is mAU peak height.

Analytical methods by chiral HPLC:

a chromatographic column: 250mm × 4.6mm × 3.0 μm, CHIRALPAK OD-3;

wavelength of ultraviolet detector: 210 nm;

flow rate: 0.8 mL/min;

column temperature: 30 ℃;

mobile phase: n-hexane-isopropanol-95: 5.

Chiral HPLC of racemic ketamine hydrochloride prepared using the background art route four is shown in fig. 1. As shown in figure 1, the retention time of the S-1 hydrochloride is 8.090min, and the content is 50.15%; the retention time of the R-1 hydrochloride is 7.098min, and the content is 49.85%.

In the embodiment of the invention, after S ketamine is prepared by a chiral resolution method of route three in the background art, the mother liquor contains the components of R configuration ketamine and a small amount of S ketamine as the starting raw materials of the invention, and chiral HPLC of the mother liquor is shown in fig. 2. As shown in FIG. 2, the retention time of S-1 is 9.875min, and the content is 8.59%; r-1 retention time 8.880min, content 91.41%.

The starting materials for examples 1-21 were derived from the starting materials shown in figure 2.

The racemic ketamine product-1 prepared in examples 1-21 was tested for chemical HPLC purity of the racemate. The test method is as follows:

the chemical HPLC purity of the racemate was tested by a conventional C18 column, and the analytical method was as follows:

a chromatographic column: 150mm by 4.6mm by 3.5 μm, X-Bridge C18;

wavelength of ultraviolet detector: 210 nm;

flow rate: 1.0 mL/min;

column temperature: 35 ℃;

mobile phase: phase A is 10mmol/L potassium dihydrogen phosphate water solution (pH 7.0)/acetonitrile 9: 1; and the phase B is acetonitrile.

The gradient elution mode used, detailed in the following table:

time (min)	10mmol/L potassium dihydrogen phosphate in water/acetonitrile 9:1 (%)	Acetonitrile (%)
			0	85.0	15.0
15.0	60.0	40.0
			20.0	25.0	75.0
35.0	25.0	75.0
			35.1	85.0	15.0
40.0	85.0	15.0

Example 1

1g of (R) -ketamine hydrochloride, 0.07g of anhydrous magnesium chloride (0.1eq) and 10mL of ethyl benzoate are mixed, heated and reacted for 10h at 150 ℃ under the protection of nitrogen, cooled, filtered and washed by n-hexane to obtain the target product, which is 0.98g of off-white solid with the yield of 98 percent and the chemical HPLC purity of 99.2 percent, and the chiral HPLC is shown in figure 3. As can be seen from FIG. 3, the retention time of S-1 hydrochloride is 9.795min, the content is 50.1%; the retention time of the R-1 hydrochloride is 9.008min, and the content is 49.9%. mp 262.9-263.8 ℃.¹H NMR(400MHz,DMSO)10.29(s,1H),9.23(s,1H),7.96(dd,J＝7.0,2.4Hz,1H),7.66–7.56(m,3H),3.34(d,J＝2.4Hz,1H),2.48(dd,J＝8.6,4.3Hz,1H),2.46–2.38(m,1H),2.21(s,3H),2.06–1.91(m,2H),1.78(d,J＝13.9Hz,1H),1.71–1.57(m,1H),1.47(dt,J＝16.4,8.5Hz,1H).¹³C NMR(101MHz,DMSO)206.78,134.07,132.36,131.67,128.38,128.33,71.64,40.15,36.52,29.42,27.51,21.12.HRMS：C₁₃H₁₇ClNO，238.0996[M+H]⁺。

The racemic ketamine 1 products prepared in examples 2-21 were tested by the above chiral HPLC profile and showed that the degree of racemization of the products was the same as that of the products prepared in example 1; therefore, chiral HPLC test patterns are not listed individually herein.

Example 2

1g of (R) -ketamine hydrochloride, 0.14g of anhydrous magnesium chloride (0.2eq) and 10mL of ethyl benzoate are mixed, heated and reacted for 4h at 150 ℃ under the protection of nitrogen, cooled, filtered and washed by n-hexane to obtain the target product, which is 1g of off-white solid with the yield of 99% and the purity of 99.1% by chemical HPLC. The content of S-1 hydrochloride is 49.6 percent; the content of the R-1 hydrochloride is 50.4 percent.

Example 3

1g of (R) -ketamine hydrochloride, 0.097g (0.2eq) of anhydrous aluminum chloride and 10mL of ethyl benzoate are mixed, heated and reacted at 150 ℃ for 10h under the protection of nitrogen, cooled, filtered, and washed by n-hexane to obtain the target product, which is 0.97g of off-white solid, the yield is 97%, and the purity of chemical HPLC is 97.5%. The content of S-1 is 50.3 percent; the R-1 content is 49.7%.

Example 4

1g of (R) -ketamine hydrochloride, 0.01g (0.2eq) of anhydrous zinc chloride and 10mL of ethyl benzoate are mixed, heated and reacted for 24h at 150 ℃ under the protection of nitrogen, cooled, filtered and washed by n-hexane to obtain the target product, which is 0.9g of off-white solid, the yield is 90 percent and the purity of chemical HPLC is 93.6 percent. The content of S-1 is 48.5 percent; the content of R-1 is 51.5 percent.

Example 5

1g of (R) -ketamine hydrochloride, 0.14g of anhydrous magnesium chloride (0.2eq) and 10mL of decalin are mixed, heated and reacted for 5h at 150 ℃ under the protection of nitrogen, cooled, filtered and washed by n-hexane to obtain the target product, which is 0.98g of off-white solid, the yield is 98 percent and the purity of chemical HPLC is 98.3 percent. The content of S-1 is 50.0 percent; the content of R-1 is 50.0 percent.

Example 6

1g of (R) -ketamine hydrochloride, 0.14g (0.2eq) of anhydrous magnesium chloride and 10mL of xylene are mixed, heated and reacted at 145 ℃ for 10h under the protection of nitrogen, cooled, filtered and washed by n-hexane to obtain the target product, which is 1g of off-white solid, the yield is 99%, and the purity of chemical HPLC is 95.2%. The content of S-1 is 48.9 percent; the content of R-1 is 51.1 percent.

Example 7

1g of (R) -ketamine hydrochloride, 0.14g of anhydrous magnesium chloride (0.2eq) and 10mL of ethyl benzoate are mixed, heated and reacted for 10h at 145 ℃ under the protection of nitrogen, cooled, filtered and washed by n-hexane to obtain the target product, which is 1g of off-white solid with the yield of 99% and the purity of 99.6% by chemical HPLC. The content of S-1 is 50.1 percent; the content of R-1 is 49.9 percent.

Example 8

1g of (R) -ketamine hydrochloride, 0.14g of anhydrous magnesium chloride (0.2eq) and 10mL of ethyl benzoate are mixed, heated and reacted for 4h at 160 ℃ under the protection of nitrogen, cooled, filtered and washed by n-hexane to obtain the target product, which is 1g of off-white solid with the yield of 99% and the purity of 97.1% by chemical HPLC. The content of S-1 is 49.4 percent; the content of R-1 is 50.6 percent.

Example 9

1g of (R) -ketamine hydrochloride, 0.097g (0.2eq) of anhydrous aluminum chloride and 10mL of decahydronaphthalene are mixed, heated and reacted for 10h at 150 ℃ under the protection of nitrogen, cooled, filtered and washed by n-hexane to obtain the target product, which is 1g of off-white solid, the yield is 99%, and the purity of chemical HPLC is 97.8%. The content of S-1 is 49.6 percent; the content of R-1 is 50.4 percent.

Example 10

1g of (R) -ketamine hydrochloride, 0.097g (0.2eq) of anhydrous aluminum chloride and 10mL of ethyl benzoate are mixed, heated and reacted for 8h at 160 ℃ under the protection of nitrogen, cooled, filtered and washed by n-hexane to obtain the target product, which is 1g of off-white solid with the yield of 99% and the purity of 95.8% by chemical HPLC. The content of S-1 is 50.5 percent; the R-1 content is 49.5 percent.

Example 11

1g of (R) -ketamine hydrochloride, 0.048g of anhydrous aluminum chloride (0.1eq) and 10mL of ethyl benzoate are mixed, heated and reacted for 24h at 150 ℃ under the protection of nitrogen, cooled, filtered and washed by n-hexane to obtain the target product, which is 0.96g of off-white solid, the yield is 96 percent and the purity of chemical HPLC is 97.2 percent. The content of S-1 is 47.9 percent; the content of R-1 is 52.1 percent.

Example 12

1g of (R) -ketamine hydrochloride, 0.07g of anhydrous magnesium chloride (0.1eq) and 10mL of ethyl benzoate are mixed, heated and reacted for 10h at 160 ℃ under the protection of nitrogen, cooled, filtered and washed by n-hexane to obtain the target product, which is 1g of off-white solid with the yield of 99% and the purity of 95.8% by chemical HPLC. The content of S-1 is 48.3 percent; the content of R-1 is 51.7 percent.

Example 13

1g of (R) -ketamine sulfate (R-1), 0.083g of anhydrous aluminum chloride and 10mL of ethyl benzoate are mixed, heated and reacted for 10 hours at 150 ℃ under the protection of nitrogen, cooled, filtered, and washed by n-hexane to obtain the target product, which is 0.91g of off-white solid, the yield is 91%, and the purity of chemical HPLC is 95.2%. The content of S-1 is 47.1 percent; the content of R-1 is 52.9 percent.

Example 14

1g of (R) -ketamine phosphate (R-1), 0.083g of anhydrous aluminum chloride and 10mL of ethyl benzoate are mixed, heated and reacted for 15h at 150 ℃ under the protection of nitrogen, cooled, filtered, and washed by n-hexane to obtain the target product, which is 0.92g of off-white solid, the yield is 92%, and the purity of chemical HPLC is 96.9%. The content of S-1 is 46.6 percent; the content of R-1 is 53.4 percent.

Example 15

1g of (R) -ketamine phosphate, 0.062g of anhydrous magnesium chloride and 10mL of ethyl benzoate are mixed, heated and reacted for 8h at 150 ℃ under the protection of nitrogen, cooled, filtered, and washed by n-hexane to obtain the target product, which is 0.88g of off-white solid, the yield is 88%, and the purity of chemical HPLC is 95.2%. The content of S-1 phosphate is 49.6 percent; the content of the phosphate R-1 is 50.4 percent.

Example 16

1g of (R) -ketamine sulfate, 0.063g of anhydrous magnesium chloride and 10mL of ethyl benzoate are mixed, heated and reacted for 9h at 150 ℃ under the protection of nitrogen, cooled, filtered and washed by n-hexane to obtain the target product, which is 0.93g of off-white solid, the yield is 93%, and the purity of chemical HPLC is 91.4%. The content of S-1 sulfate is 48.9 percent; the content of R-1 sulfate is 51.1 percent.

Example 17

1g of (R) -ketamine, 0.112g of anhydrous aluminum chloride (0.2eq) and 10mL of ethyl benzoate are mixed, heated and reacted for 24h at 150 ℃ under the protection of nitrogen, cooled, filtered, and washed by n-hexane to obtain the target product, which is 0.98g of off-white solid, the yield is 98%, and the purity of chemical HPLC is 99.3%. The content of S-1 is 48.5 percent; the content of R-1 is 51.5 percent.

Example 18

1g of (R) -ketamine tartrate (L), 0.063g (0.2eq) of anhydrous aluminum chloride and 10mL of ethyl benzoate are mixed, heated and reacted for 10h at 150 ℃ under the protection of nitrogen, cooled, filtered and washed by n-hexane to obtain the target product, wherein the target product is 0.68g of off-white solid, the yield is 68%, and the purity of chemical HPLC is 94.5%. The content of S-1 tartaric acid (L) salt is 48.9%; the content of R-1 tartaric acid (L) salt is 51.1%.

Example 19

1g of (S) -ketamine hydrochloride (99.3% ee), 0.097g of anhydrous magnesium chloride (0.2eq) and 10mL of ethyl benzoate are mixed, heated and reacted at 150 ℃ for 4h under the protection of nitrogen, cooled, filtered, and washed by n-hexane to obtain the target product which is 1g of off-white solid with the yield of 99% and the purity of chemical HPLC of 99.5%. The content of S-1 hydrochloride is 51.5 percent; the content of R-1 hydrochloride is 48.5 percent.

Example 20

1g of (R) -ketamine hydrochloride, 0.45g (0.4eq) of 46% boron trifluoride diethyl etherate in mass and 10mL of ethyl benzoate are mixed, heated and reacted for 20h at 130 ℃ under the protection of nitrogen, cooled, filtered, and washed by n-hexane to obtain a target product, wherein the target product is 0.89g of off-white solid, the yield is 89%, and the chemical HPLC purity is 99.1%. The content of S-1 hydrochloride is 50.5 percent; the content of R-1 hydrochloride is 49.5 percent.

Example 21

1g of (R) -ketamine hydrochloride, 0.08g of anhydrous calcium chloride (0.2eq) and 10mL of ethyl benzoate are mixed, heated and reacted for 80h at 150 ℃ under the protection of nitrogen, cooled, filtered and washed by n-hexane to obtain the target product, which is 0.92g of off-white solid, the yield is 92% and the purity of chemical HPLC is 99.8%. The content of S-1 hydrochloride is 47.4 percent; the content of R-1 hydrochloride is 52.6 percent.

Examples 21-25 are comparative examples in which (R) -ketamine hydrochloride in 99% ee was prepared by replacing L-tartaric acid with D-tartaric acid using the method of scheme three in the background.

Racemization treatment of (R) -ketamine is attempted by racemization methods which are conventional in organic chemistry theory and experiments, such as racemization under the action of inorganic acid, alkali or high temperature; however, after several attempts, no racemization product can be obtained, and the violent conditions lead to the decomposition and destruction of (R) -ketamine to generate other impurities. Numerous experiments prove that the conventional racemization method cannot be applied to the racemization process of (R) -ketamine.

Example 21

A25 mL reaction flask was charged with 1.0g of (R) -ketamine hydrochloride (99% ee), 1mL of concentrated hydrochloric acid, 10mL of water, followed by heating at 100 ℃ under nitrogen for 24h, cooling, sampling, and manual HPLC analysis showed that the optical purity of (R) -ketamine hydrochloride was still 99% ee, and thus, no racemization effect was observed in this method.

Example 22

A25 mL reaction flask was charged with 1.0g of (R) -ketamine (99% ee), 10mL of 50% dilute sulfuric acid, heated at 120 ℃ under nitrogen for 24h, cooled, sampled, and analyzed by manual HPLC to show that the optical purity of (R) -ketamine was still 99% ee and that the product was essentially carbonized to black, thus, the method had no racemization effect. Since carbonization already occurs at the present temperature, the degree of carbonization will be higher with continued increase in temperature.

Example 23

A50 mL reaction flask was sequentially charged with 1.0g of (R) -ketamine (R-1, 99% ee), 0.47g of KOH,20mL of DMSO, and heated at 150 ℃ under nitrogen for 24h, cooled, sampled, and analyzed by manual HPLC to show that the optical purity of (R) -ketamine was still 99% ee, and thus, the method had no racemization effect.

Example 24

A50 mL reaction flask was sequentially charged with 1.0g of (R) -ketamine (R-1, 99% ee), 0.94g of potassium tert-butoxide, and 20mL of tert-butanol, and the reaction was heated at 100 ℃ under nitrogen for 24h, cooled, sampled, and analyzed by manual HPLC to show that the optical purity of (R) -ketamine was still 99% ee, and that some of (R) -ketamine was degraded to form other impurities, so this method had no racemization effect. There were no further attempts to continue using potassium tert-butoxide as a catalyst to perform other racemization conditions as the degradation impurities would be more increased by continuing to raise the temperature.

Example 25

A25 mL reaction flask was charged with 1.0g of (R) -ketamine hydrochloride (99% ee), 10mL of ethyl benzoate sequentially, heated at 160 ℃ under nitrogen for 24h, cooled, sampled, and analyzed by manual HPLC to show that the optical purity of (R) -ketamine hydrochloride was still 99% ee, and thus, no racemization effect was observed at high temperature without addition of Lewis acid.

Claims

1. A method for racemization of ketamine, its derivatives or its salts, comprising the steps of: in a solvent, under the action of a catalyst and a reaction temperature of 110-200 ℃, a substrate A shown as below is subjected to a reaction shown as below to obtain a compound B; the catalyst is Lewis acid; the substrate A is enantiomerically enriched ketamine, its derivative or its salt; the carbon marked by is S configuration and/or R configuration chiral carbon;

wherein R is¹And R²Each independently selected from H, CH₃And CH₂CH₃。

2. The racemization process according to claim 1,

said R¹And R²Each independently selected from H and CH₃。

3. The racemization process according to claim 1,

the solvent is one or more of alkane solvents, naphthenic solvents, aromatic solvents, alcohol solvents and polar aprotic solvents;

and/or the volume mass ratio of the solvent to the substrate A is 1-100 mL/g;

and/or the Lewis acid is one or more of aluminum chloride, aluminum bromide, magnesium chloride, magnesium bromide, zinc chloride, zinc bromide, calcium chloride, boron trifluoride, boron trichloride, boron tribromide, ferric trichloride, antimony pentafluoride, titanium tetrachloride, tin tetrachloride, stannous chloride, selenium tetrachloride, niobium pentachloride and trifluoromethanesulfonate;

and/or the Lewis acid is anhydrous Lewis acid;

and/or the molar ratio of the Lewis acid to the substrate A is 0.05-2.0;

and/or, the enantiomerically enriched ketamine salt is an acid salt of enantiomerically enriched ketamine;

and/or the temperature of the reaction is 140-160 ℃;

and/or the reaction is carried out under the atmosphere of protective gas.

4. The racemization process according to claim 3,

the alkane solvent is one or more of n-pentane, n-hexane, n-heptane, n-octane, isooctane, n-nonane, n-decanone, n-dodecane and n-tetradecane;

and/or the naphthenic solvent is cyclopentane and/or cyclohexane;

and/or the aromatic hydrocarbon solvent is one or more of toluene, ethylbenzene, n-propylbenzene, isopropylbenzene, n-butylbenzene, sec-butylbenzene, isobutylbenzene, tert-butylbenzene, o-xylene, p-xylene, m-xylene, 1,2, 4-trimethylbenzene, 1,3, 5-trimethylbenzene, indene, biphenyl, naphthalene, tetrahydronaphthalene, decahydronaphthalene, isopropyltoluene, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, o-chlorotoluene, nitrobenzene, nitrotoluene, quinoline and isoquinoline;

and/or the alcohol solvent is one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, n-pentanol, isoamyl alcohol, n-hexanol, cyclohexanol, n-octanol, n-nonanol, benzyl alcohol and glycol;

and/or the polar aprotic solvent is one or more of an ester solvent, a sulfone solvent, an amide solvent and a pyrrolidone solvent;

and/or the volume-mass ratio of the solvent to the substrate A is 5-20 mL/g;

and/or the Lewis acid is one or more of aluminum chloride, magnesium chloride, boron trifluoride and zinc chloride;

and/or the boron trifluoride participates in the reaction in the form of boron trifluoride ethyl ether;

and/or the trifluoromethanesulfonate is one or more of sodium trifluoromethanesulfonate, zinc trifluoromethanesulfonate, copper trifluoromethanesulfonate and silver trifluoromethanesulfonate;

and/or the molar ratio of the Lewis acid to the substrate A is 0.2-0.6;

and/or, the acid is an organic acid or an inorganic acid;

and/or the protective gas is nitrogen and/or inert gas.

5. The racemization process according to claim 4,

the ester solvent is one or more of ethyl benzoate, methyl benzoate, isopropyl benzoate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, amyl acetate, isoamyl acetate, methyl amyl acetate, benzyl acetate, propyl propionate, n-butyl propionate, amyl propionate, ethyl butyrate, n-butyl butyrate, diethyl oxalate, methyl lactate, ethyl lactate and ethyl salicylate;

and/or the sulfone solvent is dimethyl sulfoxide;

and/or the amide solvent is N, N-dimethylformamide and/or N, N-dimethylacetamide;

and/or the pyrrolidone solvent is N-methyl pyrrolidone;

and/or the Lewis acid is aluminum chloride;

and/or the organic acid is methanesulfonic acid, ethanesulfonic acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, lactic acid, malic acid, citric acid, L-tartaric acid, D-tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, ethylenediaminetetraacetic acid, camphorsulfonic acid, picric acid, maleic acid or glutamic acid.

6. The racemization process according to claim 4,

and/or the sulfone solvent is dimethyl sulfoxide;

and/or the pyrrolidone solvent is N-methyl pyrrolidone;

and/or the Lewis acid is aluminum chloride;

and/or the inorganic acid is hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, tetraboric acid, perboric acid, pyrophosphoric acid, phosphorous acid, hypophosphorous acid, hydrobromic acid, hypobromous acid, carbonic acid, sulfurous acid, hydrocyanic acid, pyrosulfuric acid, peroxymonosulfuric acid, peroxydisulfuric acid, thiosulfuric acid, hypochlorous acid, chloric acid, perchloric acid, chromic acid, dichromic acid, hydrofluoric acid, or hydroiodic acid.

7. The racemization method according to claim 1, wherein the substrate A is (R) -ketamine or a salt thereof, the solvent is ethyl benzoate, the Lewis acid is aluminum chloride, the reaction temperature is 140-160 ℃, and the reaction is carried out in a nitrogen atmosphere.