CN117304053A - Purification method and application of agomelatine and/or intermediate thereof - Google Patents
Purification method and application of agomelatine and/or intermediate thereof Download PDFInfo
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- CN117304053A CN117304053A CN202210701773.7A CN202210701773A CN117304053A CN 117304053 A CN117304053 A CN 117304053A CN 202210701773 A CN202210701773 A CN 202210701773A CN 117304053 A CN117304053 A CN 117304053A
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- agomelatine
- solvent
- purification method
- purification
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- 229960002629 agomelatine Drugs 0.000 title claims abstract description 50
- YJYPHIXNFHFHND-UHFFFAOYSA-N agomelatine Chemical compound C1=CC=C(CCNC(C)=O)C2=CC(OC)=CC=C21 YJYPHIXNFHFHND-UHFFFAOYSA-N 0.000 title claims abstract description 50
- 238000000034 method Methods 0.000 title claims abstract description 28
- 238000000746 purification Methods 0.000 title claims abstract description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 39
- 238000001953 recrystallisation Methods 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 27
- 239000000543 intermediate Substances 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- 238000010992 reflux Methods 0.000 claims description 19
- 238000010438 heat treatment Methods 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 14
- 238000001816 cooling Methods 0.000 claims description 13
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 11
- 229940011051 isopropyl acetate Drugs 0.000 claims description 11
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- DMEGYFMYUHOHGS-UHFFFAOYSA-N cycloheptane Chemical compound C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims description 10
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 6
- 238000000926 separation method Methods 0.000 claims description 5
- YXDUMIVUPSVYLB-UHFFFAOYSA-N 2-(7-methoxynaphthalen-1-yl)ethanamine Chemical group C1=CC=C(CCN)C2=CC(OC)=CC=C21 YXDUMIVUPSVYLB-UHFFFAOYSA-N 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
- 229910002651 NO3 Inorganic materials 0.000 claims description 3
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 3
- 229940114081 cinnamate Drugs 0.000 claims description 3
- 229940049920 malate Drugs 0.000 claims description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 3
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 3
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 3
- 229940095064 tartrate Drugs 0.000 claims description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 3
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 claims description 3
- 229910021653 sulphate ion Inorganic materials 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 20
- 239000003814 drug Substances 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 4
- 239000012535 impurity Substances 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 14
- 239000012043 crude product Substances 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- HPYGZUDDGWEYDQ-UHFFFAOYSA-N 2-(7-methoxynaphthalen-1-yl)ethanamine;hydrochloride Chemical compound Cl.C1=CC=C(CCN)C2=CC(OC)=CC=C21 HPYGZUDDGWEYDQ-UHFFFAOYSA-N 0.000 description 11
- 238000001035 drying Methods 0.000 description 11
- 239000007787 solid Substances 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- -1 7-methoxy naphthalene ethylamine hydrochloride Chemical compound 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 238000010907 mechanical stirring Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 5
- 239000007868 Raney catalyst Substances 0.000 description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 4
- 229910000564 Raney nickel Inorganic materials 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- 239000013067 intermediate product Substances 0.000 description 3
- PYJMGUQHJINLLD-UHFFFAOYSA-N 2-(7-methoxynaphthalen-1-yl)acetonitrile Chemical compound C1=CC=C(CC#N)C2=CC(OC)=CC=C21 PYJMGUQHJINLLD-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 208000028017 Psychotic disease Diseases 0.000 description 2
- 238000005054 agglomeration Methods 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 208000020925 Bipolar disease Diseases 0.000 description 1
- 102000001419 Melatonin receptor Human genes 0.000 description 1
- 108050009605 Melatonin receptor Proteins 0.000 description 1
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000024714 major depressive disease Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 208000022610 schizoaffective disease Diseases 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 208000020685 sleep-wake disease Diseases 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/60—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Neurology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Anesthesiology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the field of drug synthesis, in particular to a purification method and application of agomelatine and/or an intermediate thereof. The purification method of agomelatine and/or the intermediate thereof provided by the invention is to add a water diversion step in the recrystallization process. The purification method provided by the invention has the advantages of high product yield, good purity, extremely low impurity content, good properties and simplicity and convenience in operation. And the preparation of the subsequent medicinal preparation is facilitated, the quality of the medicine is improved, and the safety and the effectiveness of the medicine are ensured.
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to a purification method and application of agomelatine and/or an intermediate thereof.
Background
Agomelatine is the first global melatonin receptor MT1 and MT2 agonist antidepressant, developed by the company Shi Weiya, france, and is approved for the treatment of major depressive episodes in adult patients.
(agomelatine)
In the prior art, agomelatine is prepared by preparing an intermediate 7-methoxy naphthalene ethylamine hydrochloride, and then performing acetylation to obtain a crude product, and refining the crude product to obtain agomelatine. The 7-methoxy naphthalene ethylamine hydrochloride has the advantages of high equipment damage in the drying process and certain risk to operators because of the hydrochloric acid. The inventor discovers that when the purity and the water content of the 7-methoxynaphthalene ethylamine hydrochloride and the water content of the agomelatine crude product are high, the product has high viscosity and poor properties, and the properties and the yield of the follow-up agomelatine or an intermediate refined product thereof are also greatly influenced.
Therefore, there is a need to develop a purification method of agomelatine and its intermediates that can be industrialized, to improve the yield and properties of agomelatine and its intermediates, to reduce the cost, and to improve the quality of the pharmaceutical products.
Disclosure of Invention
The invention aims to provide a purification method of agomelatine and/or an intermediate thereof, wherein the purification method is to add a water diversion step in the recrystallization process.
In a preferred embodiment of the present invention, the agomelatine is selected from agomelatine or a pharmaceutically acceptable salt thereof.
In a preferred embodiment of the present invention, the intermediate is selected from 7-methoxynaphthylethylamine or a pharmaceutically acceptable salt thereof.
In a preferred embodiment of the present invention, the pharmaceutically acceptable salt is selected from any one of sulfate, hydrochloride, hydrobromide, tosylate, mesylate, sulfonate, benzoate, phosphate, nitrate, tartrate, fumarate, maleate, citrate, formate, acetate, succinate, malonate, malate, cinnamate, or a combination thereof.
In a preferred embodiment of the present invention, the purification method comprises the steps of:
s1, adding a solvent A into a substance to be purified, and heating, refluxing and separating water;
s2, adding a solvent B into the mixed solution in the step S1, and heating and refluxing;
and S3, cooling and crystallizing the mixed solution prepared in the step S2 to obtain the product.
In a preferred embodiment of the present invention, the solvent a is selected from any one of ethyl acetate, isopropyl acetate, n-heptane, n-hexane, cycloheptane, cyclohexane, or a combination thereof.
In a preferred embodiment of the present invention, the solvent B is selected from any one of ethyl acetate, isopropyl acetate, methanol, ethanol, isopropanol, n-heptane, n-hexane, cycloheptane, cyclohexane, and combinations thereof.
In a preferred embodiment of the present invention, the weight ratio of the to-be-purified substance to the solvent A is 1:1 to 1:15, preferably 1:1 to 1:10, more preferably 1:1 to 1:6.
In a preferred embodiment of the present invention, the weight ratio of the to-be-purified substance to the solvent B is 5:1 to 1:10, preferably 3:1 to 1:5.
In a preferred embodiment of the present invention, the reflux water splitting temperature is 40-120 ℃, preferably 60-100 ℃.
In the preferred technical scheme of the invention, the reflux water diversion temperature is 60-80 ℃.
In a preferred embodiment of the present invention, the reflux water splitting time is 0-12h, preferably 0.5-5h.
In a preferred embodiment of the present invention, agomelatine or an intermediate thereof obtained is washed with a solvent.
In a preferred embodiment of the present invention, the washing solvent is selected from ethyl acetate, isopropyl acetate, methanol, ethanol, isopropanol, n-heptane, n-hexane, cycloheptane, cyclohexane, one or a combination thereof.
In a preferred embodiment of the present invention, agomelatine and/or intermediate thus obtained is dried.
In a preferred embodiment of the present invention, the drying is selected from any one of vacuum drying, reduced pressure drying, normal pressure drying, spray drying, and boiling drying, or a combination thereof.
In a preferred embodiment of the present invention, the drying temperature is 20 to 80 ℃, preferably 30 to 70 ℃, more preferably 40 to 60 ℃.
In a preferred embodiment of the present invention, the total impurities in the purified agomelatine are not more than 1%, preferably not more than 0.5%, more preferably not more than 0.3%.
In a preferred embodiment of the present invention, agomelatine and/or its intermediate is prepared with a water content of not more than 1%.
In a preferred embodiment of the present invention, agomelatine and/or its intermediate is prepared with a water content of not more than 0.5%, preferably not more than 0.3%.
Another object of the present invention is to provide agomelatine of high purity and/or its intermediate, obtainable by the process of the present invention.
In a preferred embodiment of the present invention, the agomelatine is selected from agomelatine or a pharmaceutically acceptable salt thereof.
In a preferred embodiment of the present invention, the intermediate is selected from 7-methoxynaphthylethylamine or a pharmaceutically acceptable salt thereof.
In a preferred embodiment of the present invention, the pharmaceutically acceptable salt is selected from any one of sulfate, hydrochloride, hydrobromide, tosylate, mesylate, sulfonate, benzoate, phosphate, nitrate, tartrate, fumarate, maleate, citrate, formate, acetate, succinate, malonate, malate, cinnamate, or a combination thereof.
In a preferred technical scheme of the invention, the purity of the prepared high-purity agomelatine and/or the intermediate thereof is not lower than 99%.
In a preferred embodiment of the present invention, agomelatine and/or intermediate products thereof are prepared with a purity of not less than 99.5%.
In a preferred embodiment of the present invention, agomelatine and/or intermediate products thereof are prepared with a purity of not less than 99.8%.
In a preferred embodiment of the present invention, agomelatine and/or intermediate products thereof are prepared with a purity of not less than 99.9%.
Another object of the present invention is to provide the use of said agomelatine of high purity and/or its intermediate for the preparation of a medicament for the prevention or treatment of psychotic disorders.
In a preferred embodiment of the present invention, the mental disorder is selected from any one of depression, anxiety, bipolar disorder, sleep disorder, schizophrenia, obsessive-compulsive disorder, schizoaffective disorder or a complication thereof.
Unless otherwise indicated, when the invention relates to a percentage between liquids, the percentages are volume/volume percentages; the invention relates to the percentage between liquid and solid, said percentage being volume/weight percentage; the invention relates to the percentage between solids and liquids, the percentage being weight/volume percentage; the balance being weight/weight percent.
Compared with the prior art, the invention has the following beneficial technical effects:
1. the purification method of agomelatine and the intermediate thereof provided by the invention has the advantages that the prepared product is high in yield and purity, and meanwhile, the cost is saved.
2. The agomelatine prepared by the invention has high purity, extremely low impurity content and good properties, is beneficial to the preparation of subsequent pharmaceutical preparations, improves the quality of medicines, and ensures the safety and effectiveness of the medicines.
3. The purification method has the advantages of simple operation, stable and controllable process, suitability for large-scale industrial production and the like.
Drawings
FIG. 1 high performance liquid chromatogram of example 1;
FIG. 2 high performance liquid chromatography, example 2;
FIG. 3 high performance liquid chromatography, example 3;
FIG. 4 high performance liquid chromatography, example 4;
FIG. 5 example 5 high performance liquid chromatogram;
FIG. 6 high performance liquid chromatography of example 6;
FIG. 7 high performance liquid chromatography of example 7;
FIG. 8 high performance liquid chromatography of example 8.
Detailed Description
The invention is illustrated by the following examples, which are given solely for the purpose of further illustration and are not intended to limit the scope of the invention. Some insubstantial modifications and adaptations of the invention by others are within the scope of the invention.
In specific embodiments, agomelatine or a salt thereof, 7-methoxynaphthylethylamine or a salt thereof may be prepared by methods disclosed in the art, such as by methods disclosed in CN101041629B, CN102206170A, CN101643431A, CN103298779a, et al. The purity of the product is detected by adopting an HPLC method according to the four-part rule 0512 of the 2020 edition of Chinese pharmacopoeia, and can also be detected by referring to the prior art such as CN 104458938A. The water content was measured according to the rule 0832 of the fourth edition of the chinese pharmacopoeia 2020.
Example 1Preparation of intermediate 7-methoxy naphthalene ethylamine hydrochloride of the invention
(1) Preparation of 7-methoxynaphthylethylamine hydrochloride crude product
Respectively adding (7-methoxy-1-naphthyl) acetonitrile (100.0 kg), raney nickel (35.0 kg), ammonia water (600 kg) and 95% ethanol (520 kg) into a hydrogenation kettle, after the materials are added, replacing nitrogen for three times, replacing hydrogen for three times, controlling the pressure of the hydrogen to be 2.1+/-0.3 MPa, controlling the temperature to be 65+/-5 ℃ for reacting for 4-5 hours, reducing the temperature and releasing the pressure of the hydrogen, replacing the hydrogen for three times, filtering the reaction liquid by using nitrogen to filter the titanium rod to remove Raney nickel, decompressing and concentrating the filtrate until the system becomes sticky, adding ethyl acetate (180 kg) into the system, stirring and dissolving, then adding normal hexane (390 kg) into the system, slowly adding concentrated hydrochloric acid (66 kg) into the system at the temperature of-5+/-5 ℃, keeping the temperature and stirring for 2-3 hours, centrifuging to obtain a crude product of the intermediate 7-methoxy naphthylethylamine hydrochloride, and the water content of 20.4%;
(2) Water separation purification
Adding the wet 7-methoxynaphthylethylamine hydrochloride and ethyl acetate (540 kg) into a reaction kettle, starting mechanical stirring, heating steam until the system flows back and separates water (the internal temperature is 65-78 ℃) until no obvious water is separated out, adding methanol (50 kg) into the system, continuously refluxing for 2-3 hours, closing heating, cooling and crystallizing, centrifuging, drying at normal pressure at 40-50 ℃ to obtain 108.5kg of white solid, wherein the yield is 90.0%, the water content is 0.14%, the purity is 99.62%, and the dispersity is good.
Example 2Preparation of intermediate 7-methoxy naphthalene ethylamine hydrochloride of the invention
(1) Preparation of crude 7-methoxynaphthylethylamine hydrochloride salt the same as in example 1
(2) Water separation purification
Adding the wet 7-methoxynaphthylethylamine hydrochloride and isopropyl acetate (540 kg) into a reaction kettle, starting mechanical stirring, heating steam until the system flows back and separates water (the internal temperature is 72-90 ℃) until no obvious water is separated out, adding ethanol (50 kg) into the system, continuously refluxing for 2-3 hours, closing heating, cooling and crystallizing, centrifuging, and drying at normal pressure at 40-50 ℃ to obtain 110kg of white solid with 91.2% yield, 0.17% water, 99.67% purity and good dispersity.
Example 3Preparation of agomelatine according to the invention
(1) Preparation of agomelatine crude product
Adding 7-methoxynaphthylethylamine hydrochloride (108.0 kg), 95% ethanol (200 kg) and acetic anhydride (58.0 kg) into a reaction kettle, starting mechanical stirring, slowly dropwise adding triethylamine (57.6 kg) into a system at a temperature of 20-30 ℃, after the addition of the triethylamine is completed, carrying out heat preservation and stirring reaction for 1-2h, adding normal hexane (150 kg) and purified water (1200 kg) into the system after the reaction is completed, cooling to 0+/-5 ℃ and stirring and crystallizing for 2-2.5h, and centrifuging to obtain an agomelatine white sticky solid crude product wet product with a water content of 23.2%;
(2) Water separation purification
Adding the agomelatine crude product wet product and ethyl acetate (200 kg) into a reaction kettle, starting stirring, heating to a system solution clear (internal temperature is 65-72 ℃), adding 500kg of n-heptane into the system, keeping the system to reflux and separate water, keeping the system to reflux until no water is separated out, cooling and crystallizing, centrifuging, eluting a filter cake by using ethyl acetate, wherein n-heptane=1:3 (V/V), and vacuum drying the wet product at 40-50 ℃ to obtain 107.8kg of white crystalline powder, wherein the yield is 97.6%, the water content is 0.08%, the purity is 99.99%, and the dispersity is good.
Example 4Preparation of agomelatine according to the invention
(1) Preparation of crude Agomelatine product the same as in example 3
(2) Water separation purification
Adding the agomelatine crude product wet product and isopropyl acetate (200 kg) into a reaction kettle, starting stirring, heating to a system solution (internal temperature is 72-90 ℃), adding 500kg of cyclohexane into the system, keeping the system to reflux and separate water in the adding process, keeping the reflux until no water is separated out after the adding process is finished, cooling and crystallizing, centrifuging, eluting a filter cake by using isopropyl acetate: cyclohexane=1:4 (V/V), and vacuum drying the wet product at 40-50 ℃ to obtain 108.1kg of white crystalline powder with a yield of 97.8%, a water content of 0.12%, a purity of 99.98% and a dispersity.
Example 5Preparation of intermediate 7-methoxynaphthalene ethylamine hydrochloride
(1) Preparation of 7-methoxynaphthylethylamine hydrochloride crude product
Respectively adding (7-methoxy-1-naphthyl) acetonitrile (100.0 g), raney nickel (35.0 g), ammonia water (600.0 g) and 95% ethanol (520.0 g) into a hydrogenation kettle, after the addition, replacing nitrogen for three times, replacing hydrogen for three times, controlling the pressure of the hydrogen to be 2.1+/-0.3 MPa, controlling the temperature to be 65+/-5 ℃ for 4-5 hours, cooling, releasing the pressure of the hydrogen, replacing the hydrogen for three times, extruding the reaction liquid by using nitrogen, filtering to remove Raney nickel, decompressing and concentrating the filtrate until the system becomes sticky, adding ethyl acetate (180 g) into the system, stirring and dissolving, then adding normal hexane (390 g) into the system, slowly adding concentrated hydrochloric acid (66 g) into the system at the temperature of-5+/-5 ℃, after the addition, keeping the temperature and stirring for 2-3 hours, filtering to obtain a white intermediate M16-1 crude wet product with the water content of 17.3%;
(2) Purification
Adding the wet 7-methoxynaphthylethylamine hydrochloride crude product and ethyl acetate (540 g) into a reaction bottle, starting mechanical stirring, heating to dissolve the system (internal temperature is 65-78 ℃), adding methanol (50 g) into the system, continuously refluxing for 2-3h, closing heating, cooling, crystallizing, filtering, and drying at normal pressure at 40-50 ℃ to obtain 96.3g of white solid with yield of 79.9%, water content of 0.22%, purity of 99.6% and easy agglomeration.
Example 6Preparation of intermediate 7-methoxynaphthalene ethylamine hydrochloride
(1) Preparation of crude 7-methoxynaphthylethylamine hydrochloride salt same as in example 5
(2) Purification
Adding the wet 7-methoxynaphthylethylamine hydrochloride and isopropyl acetate (540 g) into a reaction bottle, starting mechanical stirring, heating to dissolve the system (internal temperature is 72-90 ℃), adding ethanol (50 g) into the system, continuously refluxing for 2-3h, closing heating, cooling, crystallizing, filtering, and drying at normal pressure at 40-50 ℃ to obtain 95.4g of white solid with yield of 79.1%, water content of 0.18%, purity of 99.61% and easy agglomeration.
Example 7Preparation of agomelatine
(1) Preparation of agomelatine crude product
Adding 7-methoxynaphthylethylamine hydrochloride (100.0 g), 95% ethanol (185.0 g) and acetic anhydride (53.7 g) into a reaction bottle, starting mechanical stirring, slowly dropwise adding triethylamine (53.3 g) into the system at a temperature of 20-30 ℃, after the addition of the triethylamine is finished, carrying out heat preservation and stirring reaction for 1-2h, adding n-hexane (150 g) and purified water (1200 g) into the system after the reaction is finished, cooling to 0+/-5 ℃ and stirring and crystallizing for 2-2.5h, and filtering to obtain agomelatine white solid crude wet product with a water content of 19.6%;
(2) Purification
Adding the agomelatine crude product wet product and ethyl acetate (200 g) into a reaction bottle, starting stirring, heating to a system solution clear (internal temperature is 65-72 ℃), adding 500g of n-heptane into the system, keeping the system to reflux during the adding process, keeping the system to reflux for 2-3h, cooling and crystallizing, filtering, leaching a filter cake by using ethyl acetate: n-heptane=1:3 (V/V), and vacuum drying the wet product at 40-50 ℃ to obtain 91.7g of white solid, wherein the yield is 89.6%, the water content is 0.13%, the purity is 99.93%, and the product is easy to agglomerate into blocks.
Example 8Preparation of agomelatine
(1) Preparation of crude Agomelatine product as in example 7
(2) Purification
Adding the agomelatine crude product wet product and isopropyl acetate (200 g) into a reaction bottle, starting stirring, heating to a system solution (internal temperature is 72-90 ℃), adding 500g of cyclohexane into the system, keeping the system to reflux during the adding process, keeping the system to reflux for 2-3 hours, cooling and crystallizing, filtering, leaching a filter cake by using isopropyl acetate, wherein cyclohexane=1:4 (V/V), and drying the wet product in vacuum at 40-50 ℃ to obtain 89.2g of white solid, wherein the yield is 87.2%, the water content is 0.09%, the purity is 99.95%, and the wet product is easy to agglomerate.
Claims (10)
1. A process for purifying agomelatine and/or intermediates thereof by adding a water separation step during the recrystallization.
2. The purification process according to claim 1, wherein the agomelatine is selected from agomelatine or a pharmaceutically acceptable salt thereof.
3. The purification process according to claim 1, wherein the intermediate is selected from 7-methoxynaphthylethylamine or a pharmaceutically acceptable salt thereof.
4. A purification process according to claim 2 or 3, the pharmaceutically acceptable salt being selected from any one of or a combination of sulphate, hydrochloride, hydrobromide, tosylate, mesylate, sulfonate, benzoate, phosphate, nitrate, tartrate, fumarate, maleate, citrate, formate, acetate, succinate, malonate, malate, cinnamate.
5. The purification method according to claim 1, comprising the steps of:
s1, adding a solvent A into a substance to be purified, and heating, refluxing and separating water;
s2, adding a solvent B into the mixed solution in the step S1, and heating and refluxing;
and S3, cooling and crystallizing the mixed solution prepared in the step S2 to obtain the product.
6. The purification method according to claim 5, wherein the solvent A is selected from any one of ethyl acetate, isopropyl acetate, n-heptane, n-hexane, cycloheptane, cyclohexane or a combination thereof.
7. The purification method according to claim 6, wherein the solvent B is selected from any one of ethyl acetate, isopropyl acetate, methanol, ethanol, isopropyl alcohol, n-heptane, n-hexane, cycloheptane, cyclohexane, or a combination thereof.
8. The purification process according to claim 5, wherein the weight ratio of the substance to be purified to the solvent A is 1:1-1:15, preferably 1:1-1:10, more preferably 1:1-1:6.
9. The purification process according to claim 5, wherein the weight ratio of the substance to be purified to the solvent B is from 5:1 to 1:10, preferably from 3:1 to 1:5.
10. High purity agomelatine and/or intermediates thereof obtainable by the process of any one of claims 1 to 9.
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