CN112409195A - Preparation method of (S) -ketamine hydrochloride, intermediate and crystal form thereof - Google Patents
Preparation method of (S) -ketamine hydrochloride, intermediate and crystal form thereof Download PDFInfo
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- CN112409195A CN112409195A CN202010185073.8A CN202010185073A CN112409195A CN 112409195 A CN112409195 A CN 112409195A CN 202010185073 A CN202010185073 A CN 202010185073A CN 112409195 A CN112409195 A CN 112409195A
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- ketamine
- solvent
- dihydrate
- degrees
- tartrate
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- VCMGMSHEPQENPE-ZOWNYOTGSA-N esketamine hydrochloride Chemical group [Cl-].C=1C=CC=C(Cl)C=1[C@@]1([NH2+]C)CCCCC1=O VCMGMSHEPQENPE-ZOWNYOTGSA-N 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 239000013078 crystal Chemical group 0.000 title description 10
- YQEZLKZALYSWHR-ZDUSSCGKSA-N (S)-ketamine Chemical compound C=1C=CC=C(Cl)C=1[C@@]1(NC)CCCCC1=O YQEZLKZALYSWHR-ZDUSSCGKSA-N 0.000 claims abstract description 60
- 150000004683 dihydrates Chemical class 0.000 claims abstract description 40
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims abstract description 37
- 239000002904 solvent Substances 0.000 claims description 40
- 238000006243 chemical reaction Methods 0.000 claims description 29
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical class CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 claims description 22
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 claims description 21
- 239000007787 solid Substances 0.000 claims description 21
- 229960003299 ketamine Drugs 0.000 claims description 19
- 238000003756 stirring Methods 0.000 claims description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- 239000003513 alkali Substances 0.000 claims description 11
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 10
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 229910052783 alkali metal Inorganic materials 0.000 claims description 8
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 150000001340 alkali metals Chemical class 0.000 claims description 6
- 238000006297 dehydration reaction Methods 0.000 claims description 6
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 238000002411 thermogravimetry Methods 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 230000004580 weight loss Effects 0.000 claims description 4
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims description 3
- 150000002576 ketones Chemical group 0.000 claims description 3
- 238000001757 thermogravimetry curve Methods 0.000 claims description 3
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 2
- -1 alkali metal bicarbonate Chemical class 0.000 claims description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 2
- 238000002144 chemical decomposition reaction Methods 0.000 claims description 2
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 230000005855 radiation Effects 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- 238000010992 reflux Methods 0.000 claims 1
- 229940095064 tartrate Drugs 0.000 abstract description 6
- 238000001035 drying Methods 0.000 description 10
- 238000005406 washing Methods 0.000 description 8
- 238000005303 weighing Methods 0.000 description 8
- 238000000967 suction filtration Methods 0.000 description 7
- 206010002091 Anaesthesia Diseases 0.000 description 6
- 230000037005 anaesthesia Effects 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 229960004184 ketamine hydrochloride Drugs 0.000 description 5
- UPXRTVAIJMUAQR-UHFFFAOYSA-N 4-(9h-fluoren-9-ylmethoxycarbonylamino)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound C1C(C(O)=O)N(C(=O)OC(C)(C)C)CC1NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 UPXRTVAIJMUAQR-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 238000004296 chiral HPLC Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- YQEZLKZALYSWHR-CYBMUJFWSA-N (R)-(+)-ketamine Chemical compound C=1C=CC=C(Cl)C=1[C@]1(NC)CCCCC1=O YQEZLKZALYSWHR-CYBMUJFWSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000006698 induction Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 230000035939 shock Effects 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000036592 analgesia Effects 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- 208000009079 Bronchial Spasm Diseases 0.000 description 1
- 208000014181 Bronchial disease Diseases 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 208000006017 Cardiac Tamponade Diseases 0.000 description 1
- 102000018899 Glutamate Receptors Human genes 0.000 description 1
- 108010027915 Glutamate Receptors Proteins 0.000 description 1
- 208000004547 Hallucinations Diseases 0.000 description 1
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 description 1
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 description 1
- 229940099433 NMDA receptor antagonist Drugs 0.000 description 1
- 241000219000 Populus Species 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000004958 brain cell Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 229960000450 esketamine Drugs 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- QKGYJVXSKCDGOK-UHFFFAOYSA-N hexane;propan-2-ol Chemical compound CC(C)O.CCCCCC QKGYJVXSKCDGOK-UHFFFAOYSA-N 0.000 description 1
- 208000021760 high fever Diseases 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000005453 ketone based solvent Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 208000024714 major depressive disease Diseases 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 238000004305 normal phase HPLC Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000001144 powder X-ray diffraction data Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 238000011301 standard therapy Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Images
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a preparation method of (S) -ketamine hydrochloride and a dihydrate of (S) -ketamine tartrate serving as an intermediate thereof. The dihydrate of the intermediate (S) -ketamine tartrate can obtain the (S) -ketamine hydrochloride with high yield.
Description
Technical Field
The invention relates to a preparation method of (S) -ketamine hydrochloride, an intermediate thereof and a crystal form thereof.
Background
Ketamine hydrochloride (a racemic mixture of corresponding (S) -enantiomer and (R) -enantiomer) is an NMDA receptor antagonist, is clinically applied to the present since 1962, can be used for anesthesia induction and anesthesia maintenance as the ketamine hydrochloride is used as the only intravenous anesthetic with pain relieving and tranquilizing effects, is widely applied to operations of pediatric operations, pericardial tamponade patients, shock patients and the like, and is also a stock variety of Chinese people' S liberation military total logistics department war preparations. 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 for high-risk children with malignant high fever), patients with unstable blood flow, patients with shock (strong adrenal-like effect and can be safely used for induction of shock patients) and the like. When the ketamine hydrochloride is clinically applied, special anesthesia monitoring equipment is not needed, and the ketamine hydrochloride is convenient to popularize and use in primary medical institutions.
(S) -ketamine (or esketamine) has higher potency and affinity for NMDA receptors 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 hypnosis at 3-fold and 1.5-fold greater strengths than (R) -ketamine, respectively, and anesthesia at 3.4-fold and 1.9-fold greater strengths than racemic mixtures, while side effects that produce hallucinations are primarily 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.
The patent DE 19619665C 2(US equivalent patent No.6040479) issued by Steiner K. et al on 8.3.2001 describes the resolution of chloroaminones with L-tartaric acid in water or a mixed solvent of water and alcohol. Russo, T. et al, 2002 reported a chiral resolution of ketamine in acetone water using L-tartaric acid in 44.4% yield (WO 01098265, US equivalent patent No. 20030212143A 1). However, the (S) -ketamine L-tartrate reported in the two patents does not mention whether the (S) -ketamine L-tartrate contains crystal water or not, and does not give out whether the crystal form of the (S) -ketamine L-tartrate obtained through verification is correct in structure or not. The method for preparing (S) -ketamine from S-camphorsulfonic acid was reported by Yansen corporation in 2016 and was identified as a monohydrate (WO 2016/180984).
Disclosure of Invention
The invention aims to overcome the defects of low yield and the like of the existing preparation method of (S) -ketamine hydrochloride, and provides a preparation method of (S) -ketamine hydrochloride, and a dihydrate and a crystal form of the intermediate (S) -ketamine tartrate thereof. The dihydrate of the intermediate (S) -ketamine tartrate can obtain the (S) -ketamine hydrochloride with high yield.
The present invention provides a dihydrate of the L-tartrate salt of (S) -ketamine:
the invention provides a crystalline form of the dihydrate of the L-tartrate salt of (S) -ketamine, having characteristic peaks in the following positions in an X-ray powder diffraction pattern expressed in 2 Θ angles using CuK α radiation: 7.576 + -0.2 deg., 14.188 + -0.2 deg., 15.194 + -0.2 deg., 16.915 + -0.2 deg., 19.752 + -0.2 deg. and 33.251 + -0.2 deg..
Preferably, the X-ray powder diffraction pattern expressed in terms of 2 θ angle further has characteristic peaks at the following positions: 7.576 + -0.2 deg., 12.704 + -0.2 deg., 14.188 + -0.2 deg., 15.194 + -0.2 deg., 16.915 + -0.2 deg., 19.752 + -0.2 deg., 21.452 + -0.2 deg., 22.616 + -0.2 deg., 23.919 + -0.2 deg., 27.506 + -0.2 deg., 30.682 + -0.2 deg., 32.441 + -0.2 deg., and 33.251 + -0.2 deg.
More preferably, the PXRD pattern for the dihydrate of the L-tartrate salt of (S) -ketamine according to the present invention is shown in figure 1.
The crystal form of dihydrate of L-tartrate of (S) -ketamine has thermogravimetric analysis (TGA) pattern between 50 deg.C and 85 deg.C, weight loss between 85 deg.C and 120 deg.C, and chemical decomposition at 180 deg.C or above.
The thermogravimetric analysis spectrum of the crystalline form of the dihydrate of the L-tartrate of (S) -ketamine according to the present invention is shown in fig. 3.
The differential scanning thermogram (DSC) of the dihydrate crystal form of the L-tartrate of the (S) -ketamine has two endothermic peaks at 97.93 +/-2 ℃ and 210.46 +/-2 ℃.
A differential scanning thermal spectrum of the crystalline form of the dihydrate of the L-tartrate salt of (S) -ketamine according to the present invention is shown in fig. 4.
The present invention also provides a method for preparing the dihydrate of the L-tartrate salt of (S) -ketamine, which comprises the following steps: reacting ketamine with L-tartaric acid in a solvent in the presence of water as follows to obtain dihydrate of L-tartrate of (S) -ketamine;
the solvent may be a conventional solvent in the art for carrying out such a reaction, and is preferably a ketone-based solvent or an ether-based solvent. The ketone solvent is preferably one or more of acetone, methyl ethyl ketone and methyl isobutyl ketone. The ether solvent is preferably tetrahydrofuran and/or 2-methyltetrahydrofuran. 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 ketamine is preferably 5.0-20.0 mL/g, for example, 9.4 mL/g.
The amount of water may be that conventionally used in the art for such reactions, and preferably is 6% to 15% by weight of the solvent.
Said ketamine is preferably racemic ketamine.
The L-tartaric acid can be used in an amount conventionally used in the art for carrying out such reactions, and preferably has a molar ratio to the ketamine of 0.5-1.0, e.g., 0.55.
The reaction temperature of the reaction may be a temperature conventional in the art for carrying out such a reaction, and is preferably 60 ℃ to the temperature at which the solvent is refluxed, for example, 55 ℃ to 65 ℃.
The method for preparing the dihydrate of the L-tartrate salt of (S) -ketamine preferably comprises the following steps: and adding an L-tartaric acid aqueous solution into the solution formed by the ketamine and the solvent, stirring, and cooling to obtain the dihydrate of the L-tartrate of the (S) -ketamine. The solution of ketamine and solvent is preferably formed by heating with stirring. The heating temperature is preferably 60 ℃ to 70 ℃, for example, 65 ℃. The concentration of the L-tartaric acid aqueous solution is preferably 1.5mL/g to 2.0mL/g, for example, 1.80 mL/g.
The progress of the reaction can be monitored by monitoring methods conventional in the art (e.g., HPLC).
The reaction may also include a post-treatment, which may be conventional for such reactions, and the present invention preferably comprises the steps of: and (4) carrying out suction filtration to obtain a solid, washing a filter cake with acetone to obtain the solid, and drying to obtain a product. The drying is preferably vacuum drying. The drying temperature is preferably from 30 ℃ to 50 ℃, for example, 40 ℃. The drying time is preferably 2 to 5 hours, for example, 2 to 3 hours.
The invention also provides a preparation method of the (S) -ketamine hydrochloride, which comprises the following steps: in a solvent, A) carrying out dehydration reaction on a dihydrate of L-tartrate of (S) -ketamine and alkali in the solvent to obtain (S) -ketamine; B. reacting the (S) -ketamine obtained in the step A with hydrogen chloride as shown in the specification to obtain (S) -ketamine hydrochloride;
in step A, the solvent is preferably water. The volume-mass ratio of the solvent to the dihydrate of the L-tartrate of (S) -ketamine is preferably 50.0-5.0 mL/g, for example, 10.0 mL/g.
In step a, the base is preferably an inorganic base, and more preferably one or more of an alkali metal hydroxide, an alkali metal carbonate and an alkali metal bicarbonate. The hydroxide of the alkali metal is preferably one or more of sodium hydroxide, potassium hydroxide and cesium hydroxide. The carbonate of the alkali metal is preferably sodium carbonate and/or potassium carbonate. The bicarbonate of an alkali metal is preferably sodium bicarbonate and/or potassium bicarbonate. The base preferably participates in the reaction in the form of an aqueous solution of the base. The concentration of the aqueous alkali solution is preferably 0.1 to 5.0mol/L, for example, 1 mol/L. The molar ratio of the base to the dihydrate of the L-tartrate salt of (S) -ketamine is preferably 0.8 to 5.0, e.g., 1.20. The alkali is preferably used in an amount such that a solid precipitates, and the pH value is 10 to 11.
In step a, the reaction temperature of the dehydration reaction may be a temperature conventional in the art for carrying out such a reaction, and is preferably room temperature.
In the step a, the progress of the dehydration reaction can be detected by using pH, and the reaction is preferably completed when the pH is 10 to 11.
In step A, the dehydration reaction may further comprise a post-treatment, the post-treatment method may be a conventional post-treatment method of such reaction, and the present invention preferably comprises the following steps: adjusting the pH value to 10-11, stirring, carrying out suction filtration, washing the solid with water, and drying to obtain the product.
In the step B, the solvent is preferably one or more of an ester solvent, a chlorinated hydrocarbon solvent, an aromatic hydrocarbon solvent and a straight-chain hydrocarbon solvent. The ester solvent is preferably ethyl acetate. The volume-mass ratio of the solvent to the (S) -ketamine is preferably 4.0-50 mL/g, for example, 10.0 mL/g.
In step B, the hydrogen chloride preferably takes part in the reaction in the form of an ethyl acetate solution of hydrogen chloride. The molar ratio of the hydrogen chloride to the (S) -ketamine is preferably 0.9-2.0, for example, 1.1.
In step B, the reaction temperature of the reaction may be a temperature conventional in the art for carrying out such a reaction, and is preferably room temperature.
In step B, the progress of the reaction can be monitored by monitoring methods conventional in the art (e.g., TLC). The reaction time is preferably 0.5 to 2 hours, for example, 1 hour.
In step B, the reaction may further comprise a post-treatment, the post-treatment may be a conventional post-treatment for such a reaction, and the present invention preferably comprises the following steps: and (5) carrying out suction filtration, washing a filter cake with ethyl acetate, and drying to obtain a product. The drying is preferably carried out under vacuum at 30-60 ℃.
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.
The reagents and starting materials used in the present invention are commercially available. Racemic ketamine was prepared according to the literature J Label compd radiopharm.2018; 61: p864-868, respectively.
The positive progress effects of the invention are as follows: it was determined that the L-tartrate salt of (S) -ketamine contained two water of crystallization and that the yield of (S) -ketamine hydrochloride was greatly improved from this intermediate.
Drawings
Fig. 1 is a PXRD spectrum of a representative sample of a crystalline dihydrate form of (S) -ketamine L-tartrate.
Figure 2 is a TGA plot of a representative sample of the crystalline dihydrate form of (S) -ketamine L-tartrate.
Figure 3 is a DSC diagram of a representative sample of the crystalline dihydrate form of (S) -ketamine L-tartrate.
Fig. 4 is a single crystal diffraction pattern of a representative sample of a crystalline dihydrate form of (S) -ketamine L-tartrate.
Figure 5 is a chiral HPLC plot of a representative sample of a crystalline dihydrate form of (S) -ketamine L-tartrate.
Figure 6 is a chiral HPLC profile of ketamine racemate.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods in the following examples, in which specific conditions are not specified, were selected according to conventional methods and conditions, or according to the commercial instructions.
EXAMPLE 12- (2-chlorophenyl) -2-methylaminocyclohexanone-L- (+) -tartrate dihydrate
Accurately weighing 1.0g of ketamine racemate into a 25mL three-necked flask, adding 9.4mL of acetone, dissolving the solid clearly, heating and stirring at 65 ℃ in an oil bath, adding a prepared L-tartaric acid aqueous solution (0.347 g of L-tartaric acid and 0.625mL of water) when the internal temperature is 55 ℃, keeping the temperature and stirring for 1h after the solution is turbid after about 10-30min, then carrying out gradient cooling, continuously stirring for 5-6h after the temperature is reduced to room temperature, carrying out suction filtration on the obtained solid, washing a filter cake for three times by using 10mL of acetone, carrying out vacuum drying on the obtained white solid at 40 ℃ for 2-3h, weighing to obtain 0.74g, obtaining the yield of 41.5%, carrying out chiral purity of 99.72% and carrying out an ee value of 99.5%.
The product has a PXRD diffraction pattern, and a representative example is shown in FIG. 1.
TGA measurements of a representative sample of the dihydrate form of the L-tartrate salt of the resulting (S) -ketamine are presented below: a weight loss of 4.248%, i.e. the weight of the first water of crystallization, occurred between 50 ℃ and 85 ℃ due to water evaporation; 4.236% weight loss, i.e. the weight of the second water of crystallization, occurred between 85 ℃ and 120 ℃ due to water evaporation; (corresponding to a theoretical 8.5% stoichiometric water content of the dihydrate) and chemically decomposes above 180 ℃. A representative example is shown in fig. 2.
DSC measured on a representative sample of the dihydrate form of the L-tartrate salt of (S) -ketamine exhibited two absorption peaks, an absorption peak at about 97.93 ℃ and an enthalpy of fusion of 134.7J/g and a melting point of 210.46 and an enthalpy of fusion of 130.9J/g, respectively. A representative example is shown in fig. 3.
Absolute optical rotations were determined for multiple samples of the dihydrate form of the L-tartrate salt of (S) -ketamine (prepared as described herein) in the range of +65.7 ° and +66.8 °, with an average absolute optical rotation of [ α [ ]]20 D＝+65.8°(c＝1.0,H2O), the test results are shown in table 2.
TABLE 2
The measured single crystal diffraction of a representative sample of the dihydrate form of the L-tartrate salt of (S) -ketamine exhibited two waters of crystallization. A representative example is shown in fig. 4.
The HPLC profile of the compound prepared in this example was determined by normal phase high performance liquid chromatography, and the results are shown in fig. 5; chiral HPLC of ketamine racemate is shown in fig. 6; the conditions of chiral HPLC chromatography are shown in table 3.
TABLE 3
| Chromatographic column | CHIRALCEL OD-3(250mm*4.6mm，5um) |
| Mobile phase | n-Hexane Isopropanol 95:5 |
| Gradient of gradient | Equal degree |
| Detection wavelength | 210nm |
| Flow rate of flow | 0.8mL/min |
| Column temperature | 30℃ |
| Time | 20min |
EXAMPLE 22 Synthesis of- (2-chlorophenyl) -2-methylaminocyclohexanone hydrochloride
Accurately weighing 0.7g of S-ketamine-L-tartrate in a 25mL single-neck flask, adding 7mL of water for dissolving, slowly dropwise adding 5mL of 1mol/L sodium hydroxide aqueous solution, gradually precipitating a solid, adjusting the pH value to 10-11, stirring for 30min, performing suction filtration, washing the solid with water, drying at 60 ℃ in vacuum for 6-10h, adding the obtained dried solid (0.4g) into the single-neck flask, dissolving the solid with 3mL of ethyl acetate, slowly dropwise adding EA-HCl (3mL) under stirring, gradually precipitating a white solid, stirring at room temperature for 2h, performing suction filtration, washing a filter cake with ethyl acetate (10mL) for three times, and performing vacuum drying at 40 ℃ on the obtained white solid for 6-8h, weighing to obtain 0.44g, the yield is 97.8%, the chiral purity is 99.9%, and the ee value is 99.9%. The test conditions for ee value are shown in Table 3.
Comparative example Synthesis of 12- (2-chlorophenyl) -2-methylaminocyclohexanone hydrochloride
Accurately weighing 0.7g of S-ketamine-L-tartrate in a 25mL single-neck bottle, adding 4mL of isopropanol into the water, slowly dropwise adding 3mL of EA-HCl while stirring, then stirring at room temperature for 5h, carrying out suction filtration, washing a filter cake with ethyl acetate for three times, carrying out vacuum drying on the obtained white solid at 40 ℃ for 6-8h, and weighing to obtain 0.38g of S-ketamine-L-tartrate with the yield of 85.1%, the chiral purity of 99.9% and the ee value of 99.8%. This direct conversion of tartrate to hydrochloride results in lower conversion yields at this step due to the two water of crystallization in the tartrate molecule, which leads to higher route costs.
Comparative example 22 Synthesis of- (2-chlorophenyl) -2-methylaminocyclohexanone hydrochloride
Weighing 3.4g of S-ketamine-L-tartrate, respectively adding 290mL of water and ether, slowly dropwise adding 30% sodium hydroxide aqueous solution under stirring, adjusting the pH to 12, stirring, layering, drying an organic phase by using anhydrous sodium sulfate, and removing a solvent by rotary evaporation until the weight is constant to obtain a white solid, wherein the weight is 1.82g, the yield is 95.2%, and the ee value is 99.6%.
Adding 1.65g of the obtained dry solid into a single-mouth bottle, dissolving the solid in 50mL of ethanol, introducing HCl gas while stirring, simultaneously cooling to 15 ℃, then slowly adding 60mL of ethyl acetate, gradually separating out white solid, stirring for 1h, filtering and washing the obtained solid, introducing 30mL of ethyl acetate filter cake for three times, cooling mother liquor again, introducing HCl gas, stirring for 1h, combining the two obtained solids, drying in vacuum at 40 ℃ for 6-8h, weighing to obtain 1.72g, wherein the yield is 90.2%, and the ee value is 99.5%. The two steps were combined to produce S-ketamine hydrochloride from L-tartrate in an overall yield of 85.6% as reported in WO 2001098265 a 2.
Claims (10)
1. A dihydrate of the L-tartrate salt of (S) -ketamine:
2. a crystalline form of the dihydrate of the L-tartrate salt of (S) -ketamine having characteristic peaks in the following positions in an X-ray powder diffraction pattern expressed in 2 Θ angles using CuK α radiation: 7.576 + -0.2 deg., 14.188 + -0.2 deg., 15.194 + -0.2 deg., 16.915 + -0.2 deg., 19.752 + -0.2 deg. and 33.251 + -0.2 deg..
3. The crystalline form of the dihydrate of the L-tartrate salt of (S) -ketamine according to claim 2, which further has characteristic peaks in the following positions in the X-ray powder diffraction pattern expressed in terms of 2 Θ angles: 7.576 +/-0.2 degrees, 12.704 +/-0.2 degrees, 14.188 +/-0.2 degrees, 15.194 +/-0.2 degrees, 16.915 +/-0.2 degrees, 19.752 +/-0.2 degrees, 21.452 +/-0.2 degrees, 22.616 +/-0.2 degrees, 23.919 +/-0.2 degrees, 27.506 +/-0.2 degrees, 30.682 +/-0.2 degrees, 32.441 +/-0.2 degrees and 33.251 +/-0.2 degrees.
4. The crystalline form of the dihydrate of the L-tartrate salt of (S) -ketamine according to claim 2, which has a thermogravimetric analysis pattern between 50 ℃ and 85 ℃, a weight loss between 85 ℃ and 120 ℃, and a chemical decomposition above 180 ℃.
5. The crystalline form of the dihydrate of the L-tartrate salt of (S) -ketamine according to claim 2, characterized by a differential scanning thermogram (DSC) with two endothermic peaks at 97.93 ± 2 ℃ and 210.46 ± 2 ℃.
6. A method for preparing the dihydrate of the L-tartrate salt of (S) -ketamine, comprising the steps of: reacting ketamine with L-tartaric acid in a solvent in the presence of water as follows to obtain dihydrate of L-tartrate of (S) -ketamine;
7. the method according to claim 6,
the solvent is a ketone solvent or an ether solvent; the ketone solvent is preferably one or more of acetone, methyl ethyl ketone and methyl isobutyl ketone; the ether solvent is preferably tetrahydrofuran and/or 2-methyltetrahydrofuran;
and/or the volume-mass ratio of the solvent to the ketamine is 5.0-20.0 mL/g;
and/or the percentage of the water to the solvent is 6-15 percent;
and/or, the ketamine is racemic ketamine;
and/or the molar ratio of the L-tartaric acid to the ketamine is 0.5-1.0;
and/or the reaction temperature of the reaction is 20 ℃ to the reflux temperature of the solvent.
8. The method of claim 6 or 7, wherein the dihydrate of the L-tartrate salt of (S) -ketamine is prepared by the steps of: adding an L-tartaric acid aqueous solution into the solution formed by the ketamine and the solvent, stirring and cooling to obtain a dihydrate of the L-tartrate of the (S) -ketamine; the solution formed by ketamine and solvent is preferably formed by heating and stirring; the heating temperature is preferably 60-70 ℃; the concentration of the L-tartaric acid aqueous solution is preferably 1.5mL/g to 2.0 mL/g.
9. A preparation method of (S) -ketamine hydrochloride is characterized by comprising the following steps: A. in a solvent, under the action of alkali, carrying out dehydration reaction on dihydrate of L-tartrate of (S) -ketamine as shown in the specification to obtain (S) -ketamine; B. reacting the (S) -ketamine obtained in the step A with hydrogen chloride as shown in the specification to obtain (S) -ketamine hydrochloride;
10. the method according to claim 9,
in the step A, the solvent is water;
and/or in the step A, the volume-to-mass ratio of the solvent to the dihydrate of the L-tartrate of the (S) -ketamine is 50.0-5.0 mL/g;
and/or, in the step A, the alkali is inorganic alkali; preferably one or more of alkali metal hydroxide, alkali metal carbonate and alkali metal bicarbonate; the hydroxide of the alkali metal is preferably one or more of sodium hydroxide, potassium hydroxide and cesium hydroxide; the carbonate of the alkali metal is preferably sodium carbonate and/or potassium carbonate; the bicarbonate of the alkali metal is preferably sodium bicarbonate and/or potassium bicarbonate;
and/or, in the step A, the alkali takes part in the reaction in the form of an aqueous alkali solution; the concentration of the alkali aqueous solution is preferably 0.1-5.0 mol/L; the dosage of the alkali is preferably based on the condition that a solid is precipitated and the pH value is 10-11;
and/or in the step A, the molar ratio of the alkali to the dihydrate of the L-tartrate of the (S) -ketamine is 0.8-5.0;
and/or in the step A, the reaction temperature of the dehydration reaction is room temperature;
and/or in the step B, the solvent is one or more of an ester solvent, a chlorinated hydrocarbon solvent, an aromatic hydrocarbon solvent and a straight-chain alkane solvent;
and/or in the step B, the volume-mass ratio of the solvent to the (S) -ketamine is 4.0-50 mL/g;
and/or, in the step B, the hydrogen chloride participates in the reaction in the form of an ethyl acetate solution of the hydrogen chloride;
and/or in the step B, the molar ratio of the hydrogen chloride to the (S) -ketamine is 0.9-2.0.
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| CN114907220A (en) * | 2022-05-30 | 2022-08-16 | 广西大学 | Synthesis method of hydrofluoaminone |
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| US6040479A (en) * | 1996-05-15 | 2000-03-21 | Goedecke Aktiengesellschaft | Racemic separation of ketamine |
| CN110218157A (en) * | 2018-03-01 | 2019-09-10 | 江苏恒瑞医药股份有限公司 | A kind of preparation method of R- ketamine and its officinal salt |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US6040479A (en) * | 1996-05-15 | 2000-03-21 | Goedecke Aktiengesellschaft | Racemic separation of ketamine |
| CN110218157A (en) * | 2018-03-01 | 2019-09-10 | 江苏恒瑞医药股份有限公司 | A kind of preparation method of R- ketamine and its officinal salt |
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Cited By (1)
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| CN114907220A (en) * | 2022-05-30 | 2022-08-16 | 广西大学 | Synthesis method of hydrofluoaminone |
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