CN116496259A - Preparation method of rupatadine fumarate - Google Patents
Preparation method of rupatadine fumarate Download PDFInfo
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- CN116496259A CN116496259A CN202310451955.8A CN202310451955A CN116496259A CN 116496259 A CN116496259 A CN 116496259A CN 202310451955 A CN202310451955 A CN 202310451955A CN 116496259 A CN116496259 A CN 116496259A
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- rupatadine fumarate
- rupatadine
- desloratadine
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- JYBLCDXVHQWMSU-WLHGVMLRSA-N (e)-but-2-enedioic acid;8-chloro-11-[1-[(5-methylpyridin-3-yl)methyl]piperidin-4-ylidene]-5,6-dihydrobenzo[1,2]cyclohepta[2,4-b]pyridine Chemical compound OC(=O)\C=C\C(O)=O.CC1=CN=CC(CN2CCC(CC2)=C2C3=NC=CC=C3CCC3=CC(Cl)=CC=C32)=C1 JYBLCDXVHQWMSU-WLHGVMLRSA-N 0.000 title claims abstract description 69
- 238000002360 preparation method Methods 0.000 title abstract description 29
- 238000006243 chemical reaction Methods 0.000 claims abstract description 60
- JAUOIFJMECXRGI-UHFFFAOYSA-N Neoclaritin Chemical compound C=1C(Cl)=CC=C2C=1CCC1=CC=CN=C1C2=C1CCNCC1 JAUOIFJMECXRGI-UHFFFAOYSA-N 0.000 claims abstract description 41
- 229960001271 desloratadine Drugs 0.000 claims abstract description 41
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- 239000003960 organic solvent Substances 0.000 claims abstract description 33
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims abstract description 29
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 28
- 150000001412 amines Chemical class 0.000 claims abstract description 21
- 229960005328 rupatadine Drugs 0.000 claims abstract description 20
- WUZYKBABMWJHDL-UHFFFAOYSA-N rupatadine Chemical compound CC1=CN=CC(CN2CCC(CC2)=C2C3=NC=CC=C3CCC3=CC(Cl)=CC=C32)=C1 WUZYKBABMWJHDL-UHFFFAOYSA-N 0.000 claims abstract description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 17
- 239000001530 fumaric acid Substances 0.000 claims abstract description 15
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229960003088 loratadine Drugs 0.000 claims abstract description 15
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 14
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 claims abstract description 14
- NCAHREJYXFDWGE-UHFFFAOYSA-N 3-(chloromethyl)-5-methylpyridine;hydrochloride Chemical compound Cl.CC1=CN=CC(CCl)=C1 NCAHREJYXFDWGE-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000002904 solvent Substances 0.000 claims abstract description 10
- 239000003513 alkali Substances 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 30
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 26
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- 239000012074 organic phase Substances 0.000 claims description 16
- 238000001953 recrystallisation Methods 0.000 claims description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 11
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 10
- 238000010992 reflux Methods 0.000 claims description 10
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 8
- 238000000605 extraction Methods 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 4
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 4
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 claims description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 239000007787 solid Substances 0.000 description 22
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- -1 5-methyl-3-pyridinyl Chemical group 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 230000002194 synthesizing effect Effects 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 4
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000000739 antihistaminic agent Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- HVAUUPRFYPCOCA-AREMUKBSSA-N 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 108010003541 Platelet Activating Factor Proteins 0.000 description 2
- 239000000043 antiallergic agent Substances 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- DMEGYFMYUHOHGS-UHFFFAOYSA-N cycloheptane Chemical compound C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- QLSJOGIENLKPTF-WLHGVMLRSA-N (e)-but-2-enedioic acid;pyridine Chemical compound C1=CC=NC=C1.OC(=O)\C=C\C(O)=O QLSJOGIENLKPTF-WLHGVMLRSA-N 0.000 description 1
- DJDHHXDFKSLEQY-UHFFFAOYSA-N 5-methylpyridine-3-carboxylic acid Chemical compound CC1=CN=CC(C(O)=O)=C1 DJDHHXDFKSLEQY-UHFFFAOYSA-N 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 201000009961 allergic asthma Diseases 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940124623 antihistamine drug Drugs 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000000586 desensitisation Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- 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)
Abstract
The invention relates to the technical field of medicine synthesis, in particular to a preparation method of rupatadine fumarate. The preparation method of rupatadine fumarate provided by the invention comprises the following steps: s1, reacting nitrogen methyl loratadine, phenyl chloroformate and organic amine in an organic solvent to obtain a compound I; the structural formula of the compound I is as follows:s2, reacting the compound I with alkali in an organic solvent to obtain desloratadine; s3, reacting the desloratadine, 3-chloromethyl-5-methylpyridine hydrochloride and organic amine in an organic solvent to obtain rupatadine; s4, reacting the rupatadine with fumaric acid in a salifying solvent to obtain rupatadine fumarate. Rupatadine fumarate of the inventionThe preparation method has the advantages of mild reaction conditions, short reaction time, short route, simple operation, high yield and high product purity, and is suitable for large-scale industrial production.
Description
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to a preparation method of rupatadine fumarate.
Background
Rupatadine fumarate, having the chemical name 8-chloro-6, 11-dihydro-11- [1- [ (5-methyl-3-pyridinyl) methyl ] -4-piperidino ] -5H-benzo [5,6] cyclohepta [1,2-b ] pyridine fumarate, having the structural formula:
rupatadine fumarate is an antihistamine drug, is an antiallergic drug widely used clinically, and is mainly used for desensitization of various allergic diseases. It also plays an important role in the treatment of urticaria, allergic rhinitis and allergic asthma in dermatology. Rupatadine fumarate belongs to the third generation of tricyclic antihistamines. The pharmacological action is mainly from rupatadine, and the rupatadine has dual actions of antihistamine and antagonism of Platelet Activating Factor (PAF); the fumaric acid has inhibiting effect on Escherichia coli and Staphylococcus aureus, and also has antitumor effect, and has effects of resisting shock, relieving pain, and relieving cough.
Rupatadine fumarate is a powerful antiallergic agent developed by spanish uri ach pharmaceutical company, which applied for a patent on rupatadine fumarate in 1993, with publication number ES2087818; in this patent, a route for synthesizing rupatadine fumarate is disclosed, which uses nitrogen methyl loratadine as raw material, and makes it react with ethyl chloroformate to produce loratadine, then under alkaline condition, it is produced into desloratadine, then the desloratadine is condensed with 5-methylnicotinic acid to obtain rupatadine amide, then the produced amide is reduced to prepare rupatadine, and finally the rupatadine fumarate is obtained by salifying with fumaric acid. Although the method solves the problem of synthesizing rupatadine fumarate, the method has the advantages of longer reaction route, complex operation, high requirement on production equipment because reagents for producing hydrogen such as sodium borohydride are needed, and environment friendliness because ethyl chloroformate is a highly toxic compound.
At present, the preparation process of rupatadine fumarate has more synthetic routes, but has the defects of long routes, lower yield, harsh reaction conditions, lower product purity and the like.
In view of this, the present invention has been made.
Disclosure of Invention
The invention aims to provide a preparation method of rupatadine fumarate, which has the advantages of mild reaction conditions, short reaction time, short route, simple operation, high yield and high product purity, and is suitable for large-scale industrial production.
In order to achieve the above object of the present invention, the following technical solutions are specifically adopted:
the invention provides a preparation method of rupatadine fumarate, which comprises the following steps:
s1, reacting nitrogen methyl loratadine, phenyl chloroformate and organic amine in an organic solvent to obtain a compound I;
the structural formula of the compound I is as follows:
s2, reacting the compound I with alkali in an organic solvent to obtain desloratadine;
s3, reacting the desloratadine, 3-chloromethyl-5-methylpyridine hydrochloride and organic amine in an organic solvent to obtain rupatadine;
s4, reacting the rupatadine with fumaric acid in a salifying solvent to obtain rupatadine fumarate. Further, in step S1, at least one of the following features (1) to (6) is included;
(1) The organic amine comprises triethylamine;
(2) The organic solvent comprises toluene;
(3) The molar ratio of the nitrogen methyl loratadine to the phenyl chloroformate is 1: (1.15-1.25);
(4) The molar ratio of the nitrogen methyl loratadine to the organic amine is 1: (0.095-0.15);
(5) The dosage ratio of the nitrogen methyl loratadine to the organic solvent is 1g: 8-12 mL;
(6) The reaction conditions are as follows: and reflux reaction is carried out for 6-8 h.
Further, in step S1, after the reaction, the method further includes: concentrating and recrystallizing sequentially.
Preferably, after the concentration, the compound I is obtained by recrystallization from isopropanol and/or acetonitrile.
Further, in step S2, at least one of the following features (1) to (5) is included;
(1) The base comprises sodium hydroxide and/or potassium hydroxide;
(2) The organic solvent comprises toluene and/or N, N-dimethylformamide;
(3) The molar ratio of the compound I to the base is 1: (4-8);
(4) The dosage ratio of the compound I to the organic solvent is 1g: 14-16 mL;
(5) The reaction conditions are as follows: and carrying out reflux reaction for 7-9 h.
Further, in step S2, after the reaction, the method further includes: sequentially extracting, concentrating and recrystallizing.
Preferably, after the reaction, water is added for extraction, an organic phase is collected, and after the organic phase is concentrated, ethyl acetate and/or 4-methyl-2-pentanone are adopted for recrystallization, so that the desloratadine is obtained.
Further, in step S3, at least one of the following features (1) to (5) is included;
(1) The organic amine comprises triethylamine;
(2) The organic solvent comprises N, N-dimethylformamide;
(3) The molar ratio of the desloratadine to the 3-chloromethyl-5-methylpyridine hydrochloride is 1: (1.05-1.2);
(4) The molar ratio of desloratadine to the organic amine is 1: (4-5);
(5) The dosage ratio of the desloratadine to the organic solvent is 1g: 9-12 mL.
Further, in the step S3, the temperature of the reaction is 60-80 ℃, and the time of the reaction is 55-65 min.
Further, in step S3, after the reaction, the method further includes: sequentially extracting and concentrating.
Preferably, after the reaction, an extractant is added for extraction, an organic phase is collected, and the organic phase is concentrated to obtain the rupatadine.
Further, in step S3, the extractant includes an aqueous solution of ethyl acetate and potassium dihydrogen phosphate.
Preferably, the volume ratio of the ethyl acetate to the aqueous solution of potassium dihydrogen phosphate is 1: (1-2);
preferably, the concentration of the aqueous solution of the monopotassium phosphate is 0.05-0.067 g/mL.
Further, in step S4, at least one of the following features (1) to (4) is included;
(1) The molar ratio of desloratadine to fumaric acid is 1: (1-1.1);
(2) The salifying solvent comprises ethanol and/or ethyl acetate;
(3) The dosage ratio of the fumaric acid to the salifying solvent is 1g: 90-110 mL;
(4) The temperature of the reaction is 60-80 ℃.
Compared with the prior art, the invention has the beneficial effects that:
according to the preparation method of rupatadine fumarate, nitrogen methyl loratadine is used as a starting material, phenyl chloroformate is used for replacing virulent ethyl chloroformate, and the compound I is generated by reaction under alkaline conditions; then the compound I reacts under alkaline conditions to generate desloratadine; reacting desloratadine with 3-chloromethyl-5-methylpyridine hydrochloride to obtain rupatadine, and directly salifying rupatadine to obtain rupatadine fumarate; the method has the advantages of mild reaction conditions, short reaction time, short reaction route, simple operation, low requirements on equipment, environmental friendliness, good safety and high yield and purity, and the rupatadine fumarate can be obtained.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are needed in the description of the embodiments or the prior art will be briefly described, and it is obvious that the drawings in the description below are some embodiments of the present invention, and other drawings can be obtained according to the drawings without inventive effort for a person skilled in the art.
FIG. 1 is a liquid chromatogram of rupatadine fumarate prepared in example 1 of the present invention.
Detailed Description
The technical solution of the present invention will be clearly and completely described below with reference to the accompanying drawings and detailed description, but it will be understood by those skilled in the art that the examples described below are some, but not all, examples of the present invention, and are intended to be illustrative of the present invention only and should not be construed as limiting the scope of the present invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The following specifically describes a preparation method of rupatadine fumarate in the embodiment of the invention.
In some embodiments of the present invention, there is provided a method for preparing rupatadine fumarate, comprising the steps of:
s1, reacting nitrogen methyl loratadine, phenyl chloroformate and organic amine in an organic solvent to obtain a compound I;
the structural formula of the compound I is as follows:
s2, reacting the compound I with alkali in an organic solvent to obtain desloratadine;
s3, reacting desloratadine, 3-chloromethyl-5-methylpyridine hydrochloride and organic amine in an organic solvent to obtain rupatadine;
s4, reacting rupatadine with fumaric acid in a salifying solvent to obtain rupatadine fumarate.
According to the preparation method of rupatadine fumarate, nitrogen methyl loratadine is used as a starting material, phenyl chloroformate is used for replacing virulent ethyl chloroformate, and the compound I is generated by reaction under alkaline conditions; reacting the compound I under alkaline conditions to generate desloratadine; reacting desloratadine with 3-chloromethyl-5-methylpyridine hydrochloride to obtain rupatadine, and directly salifying rupatadine without further purification to generate rupatadine fumarate; the method has the advantages of mild reaction conditions, short reaction route, short reaction time, simple operation, low requirements on equipment, environmental friendliness, good safety and high yield and purity, and the rupatadine fumarate can be obtained.
In some embodiments of the invention, the chemical name of azamethylloratadine is 8-chloro-6, 11-dihydro-11- (1-methyl-4-piperidylidene) -5H-benzo [5,6]Cycloheptane [1,2-b ]]Pyridine has the structural formula:the structural formula of the phenyl chloroformate is as follows: />Desloratadine, chemical name 8-chloro-6, 11-dihydro-11- (4-piperidylidene) -5H-benzo [5,6]]Heptane [1,2-b ]]Pyridine; the structural formula is->The structure of 3-chloromethyl-5-methylpyridine hydrochloride is->Rupatadine, chemical name 8-chloro-6, 11-dihydro-11- [1- [ (5-methyl-3-pyridinyl) methyl]-4-piperidylene]-5H-benzo [5,6]]Cyclohepta [1,2-b ]]Pyridine of the structural formulaFumaric acid has the structural formula->Rupatadine fumarate with chemical name 8-chloro-6, 11-dihydro-11- [1- [ (5-methyl-3-pyridinyl) methyl]-4-piperidylene]-5H-benzo [5,6]]Cyclohepta [1,2-b ]]Pyridine fumarate with structural formula ++>
In some embodiments of the invention, in step S1, the organic amine comprises triethylamine.
In some embodiments of the invention, in step S1, the organic solvent comprises toluene.
In some embodiments of the invention, in step S1, the molar ratio of azamethylloratadine to phenyl chloroformate is 1: (1.15-1.25); preferably, the molar ratio of azamethylloratadine to phenyl chloroformate is 1:1.2.
in some embodiments of the invention, in step S1, the molar ratio of azamethylloratadine to organic amine is 1: (0.095-0.15); preferably, the molar ratio of the azamethylloratadine to the organic amine is 1:0.1.
in some embodiments of the invention, in step S1, the ratio of the amounts of azamethylloratadine and organic solvent used is 1g: 8-12 mL; preferably, the dosage ratio of the azamethylloratadine to the organic solvent is 1g:10mL.
In some embodiments of the invention, in step S1, the reaction conditions are: and reflux reaction is carried out for 6-8 h.
In some embodiments of the present invention, in step S1, after the reaction, the method further comprises: concentrating and recrystallizing in sequence; preferably, after concentration, recrystallizing with isopropanol and/or acetonitrile to obtain compound I; preferably, the recrystallization is performed with isopropanol.
In some specific embodiments of the present invention, in step S1, after the reaction, concentrating under reduced pressure at 55 to 65 ℃ to obtain a solid, and then adding isopropanol and/or acetonitrile to perform recrystallization to obtain a compound I; preferably, isopropanol is added for recrystallization.
In some specific embodiments of the invention, in step S1, the ratio of the volumes of azamethylloratadine to isopropyl alcohol and/or acetonitrile is 1g: 5-10 mL.
In some embodiments of the invention, in step S1, the yield of the reaction is > 80% and the purity of compound I obtained after recrystallization is > 99.5%.
In some embodiments of the invention, in step S2, the base comprises sodium hydroxide and/or potassium hydroxide; preferably, the base comprises potassium hydroxide.
In some embodiments of the invention, in step S2, the organic solvent comprises toluene and/or N, N-dimethylformamide; preferably, the organic solvent comprises toluene.
In some embodiments of the invention, in step S2, the molar ratio of compound I to base is 1:4 to 8; typically, but not by way of limitation, the molar ratio of compound I to base may be 1: 4. 1: 4. 1: 5. 1: 6. 1: 7. 1:8 or any two thereof.
In some embodiments of the invention, in step S2, the ratio of compound I to organic solvent is 1g: 14-16 mL; preferably, the ratio of compound I to organic solvent is 1g:15mL.
In some embodiments of the invention, in step S2, the reaction conditions are: reflux reaction is carried out for 7-9 h; preferably, the reaction time is 8 hours.
In some embodiments of the present invention, in step S2, after the reaction, the method further includes: sequentially extracting, concentrating and recrystallizing; preferably, after the reaction, adding water for extraction, collecting an organic phase, concentrating the organic phase, and recrystallizing with ethyl acetate and/or 4-methyl-2-pentanone to obtain desloratadine; preferably, the recrystallization is performed with ethyl acetate.
In some specific embodiments of the present invention, in step S2, a reaction solution is obtained after the reaction, and water is added to the reaction solution for extraction; preferably, the volume ratio of the reaction liquid to water is 1:0.8 to 1.2.
In some embodiments of the invention, in step S2, the ratio of solid obtained after concentration to ethyl acetate is 1g: 5-15 mL.
In some embodiments of the invention, in step S2, the yield of the reaction is > 75% and the purity of the recrystallised desloratadine is greater than or equal to 99.5%.
In some embodiments of the invention, in step S3, the organic amine comprises triethylamine.
In some embodiments of the invention, in step S3, the organic solvent comprises N, N-dimethylformamide.
In some embodiments of the invention, in step S3, the molar ratio of desloratadine to 3-chloromethyl-5-methylpyridine hydrochloride is 1: (1.05-1.2); typical, but not limiting, for example, the molar ratio of desloratadine to 3-chloromethyl-5-methylpyridine hydrochloride may be 1:1.05, 1:1.1, 1:1.15, 1:1.25 or any two of them.
In some embodiments of the invention, in step S3, the molar ratio of desloratadine to organic amine is 1:4 to 5.
In some embodiments of the invention, in step S3, the ratio of desloratadine to organic solvent is 1g: 9-12 mL.
In some embodiments of the invention, in step S3, the reaction temperature is 60-80 ℃ and the reaction time is 55-65 min; typical, but not limiting, for example, the temperature of the reaction is 60 ℃, 65 ℃, 70 ℃, 75 ℃, 80 ℃ or a range of values consisting of any two of these; preferably, the temperature of the reaction is 60℃and the time of the reaction is 1h.
In some embodiments of the present invention, in step S3, after the reaction, the method further comprises: sequentially extracting and concentrating; preferably, after the reaction, an extractant is added for extraction, an organic phase is collected, and the organic phase is concentrated to obtain rupatadine.
In some embodiments of the invention, in step S3, the extractant comprises an aqueous solution of ethyl acetate and potassium dihydrogen phosphate; preferably, the volume ratio of the ethyl acetate to the potassium dihydrogen phosphate aqueous solution is 1: (1-2); preferably 3:4, a step of; preferably, the concentration of the aqueous solution of potassium dihydrogen phosphate is 0.05 to 0.067g/mL.
In some embodiments of the present invention, in step S3, a reaction solution is obtained after the reaction, and an extractant is added into the reaction solution for extraction; preferably, the volume ratio of the reaction liquid to the extractant is 1: (6-8).
In some embodiments of the invention, in step S4, the molar ratio of desloratadine to fumaric acid is 1: (1-1.1).
In some embodiments of the invention, in step S4, the salifying solvent comprises ethanol and/or ethyl acetate.
In some embodiments of the invention, in step S4, the ratio of fumaric acid to salt-forming solvent is 1g: 90-110 mL; preferably 1g: 100-105 mL.
In some embodiments of the invention, in step S4, the temperature of the reaction is 60 to 80 ℃; preferably, the reaction time is 55 to 65 minutes.
Example 1
The preparation method of rupatadine fumarate provided by the embodiment comprises the following steps:
s1, synthesizing a compound I from the nitrogen methyl loratadine, wherein the steps are as follows:
the method comprises the following specific steps:
to a 250mL four-necked flask at room temperature were added 10.0g (30.78 mmol) of azamethylloratadine, 100mL of toluene and 0.31g (3.08 mmol) of triethylamine, the mixture was warmed to reflux, 5.76g (36.94 mmol) of phenyl chloroformate was slowly added dropwise, the mixture was reacted under reflux for 6 hours after the dropwise addition, TLC was checked (developer: dichloromethane: methanol=10:1, rf=0.32), after the completion of the reaction, the mixture was concentrated to dryness under reduced pressure at 60℃and 50mL of isopropyl alcohol was added to conduct recrystallization to obtain 10.94g of a pale pink solid (Compound I) in a yield of 82.45% and a purity of 99.82%.
S2, synthesizing desloratadine from the compound I, wherein the steps are as follows:
the method comprises the following specific steps:
to a 250mL four-necked flask, 10.0g (23.21 mmol) of Compound I, 150mL of toluene and 5.21g (92.84 mmol) of potassium hydroxide were added at room temperature, the mixture was warmed to reflux for 8h, TLC was performed (developing reagent: n-heptane: ethyl acetate=1:1, rf=0.35), 150mL of water was added after completion of the reaction to extract, and the organic phase was collected, concentrated to dryness, and 50mL of ethyl acetate was added to perform recrystallization to obtain 5.59g of an off-white crystalline solid (desloratadine) in a yield of 77.53% and a purity of 99.5%.
S3, synthesizing rupatadine fumarate from desloratadine as follows:
the method comprises the following specific steps:
to a 250mL four-necked flask, 5.0g (16.09 mmol) of desloratadine, 50mL of DMF, 6.50g (64.36 mmol) of triethylamine and 3.01g (16.89 mmol) of 3-chloromethyl-5-methylpyridine hydrochloride were added at room temperature, the mixture was reacted at 60℃for 1 hour, 150mL of ethyl acetate was added, the organic phase was extracted with aqueous solution of potassium dihydrogen phosphate (10 g of potassium dihydrogen phosphate was dissolved in 200mL of water) and concentrated to dryness, 100mL of ethanol was added to dissolve the organic phase, the temperature was raised to 60℃and 2.05g (17.70 mmol) of fumaric acid was dissolved in 100mL of ethanol to obtain a mixed solution, the mixed solution was dropped into the reaction system, stirred at 60℃for 1 hour and cooled to 20 to 30℃and filtered to obtain 6.64g of pale pink solid (rupatadine fumarate) with a yield of 77.53% and a purity of 99.86%.
The liquid chromatogram of rupatadine fumarate prepared in this example is shown in FIG. 1.
Example 2
The preparation method of rupatadine fumarate provided in this example is referred to in example 1, except that 6.75g (43.09 mmol) of phenyl chloroformate is slowly added dropwise in step S1; 7.02g of a pink solid (compound I) was obtained in a yield of 52.9% and a purity of 99.58%.
Example 3
The preparation method of rupatadine fumarate provided by the embodiment is referred to in embodiment 1, and is only different in that in the step S1, the temperature is raised to 90 ℃, 5.76g (36.94 mmol) of phenyl chloroformate is slowly added dropwise, and reflux reaction is carried out for 6h after the dropwise addition is completed; 10.47g of pale pink solid (compound I) was obtained in a yield of 78.9% and a purity of 99.75%.
Example 4
The preparation method of rupatadine fumarate provided in this example is described with reference to example 1, except that in step S1, 50mL of isopropanol is replaced with 100mL of isopropanol; 9.96g of a pale pink solid (compound I) was obtained in a yield of 75.06% and a purity of 99.96%.
Example 5
The preparation method of rupatadine fumarate provided in this example is described with reference to example 1, except that in step S1, 50mL of isopropanol is replaced with 50mL of acetonitrile; 8.26g of a pale pink solid (compound I) was obtained in a yield of 62.25% and a purity of 99.06%.
Example 6
The preparation method of rupatadine fumarate provided in this example is referred to in example 1, except that in step S1, 50mL of isopropanol is replaced with 50mL of isopropanol and 50mL of n-heptane; 11.21g of a pale pink solid (compound I) was obtained in a yield of 84.48% and a purity of 98.03%.
Example 7
The preparation method of rupatadine fumarate provided in this example is referred to in example 1, except that in step S2, 5.21g (92.84 mmol) of potassium hydroxide is replaced with 3.71g (92.84 mmol) of sodium hydroxide; 5.73g of an off-white crystalline solid (desloratadine) was obtained in a yield of 79.47% and a purity of 99.80%. However, the reaction time is 18 to 20 hours, which is longer.
Example 8
The preparation method of rupatadine fumarate provided in this example is referred to in example 1, except that in step S2, 5.21g (92.84 mmol) of potassium hydroxide is replaced with 3.90g (69.63 mmol) of potassium hydroxide; 4.84g of an off-white crystalline solid (desloratadine) was obtained in a yield of 66.71% and a purity of 98.8%.
Example 9
The preparation method of rupatadine fumarate provided in this example is referred to in example 1, except that 100mL of toluene is added in step S2 to obtain 5.22g of an off-white crystalline solid (desloratadine) with a yield of 71.90% and a purity of 98.90%.
Example 10
The preparation method of rupatadine fumarate provided in this example is described with reference to example 1, except that 50mL of 4-methyl-2-pentanone is added for recrystallization in step S2; 5.65g of an off-white crystalline solid (desloratadine) was obtained in a yield of 78.36% and a purity of 99.03%.
Example 11
The preparation method of rupatadine fumarate provided in this example is described in reference to example 1, except that in step S2, 5mL of methanol and 50mL of methyl tert-butyl ether are added for recrystallization; 2.05g of an off-white crystalline solid (desloratadine) was obtained in a yield of 28.43% and a purity of 99.66%.
Example 12
The preparation method of rupatadine fumarate provided in this example is similar to example 1, except that in step S3, the temperature is raised to 80 ℃ to react for 1h, and 6.42g of light pink solid (rupatadine fumarate) is obtained, the yield is 75.03%, and the purity is 99.28%.
Example 13
The present example provides a method for preparing rupatadine fumarate with reference to example 1, except that in step S3, the mass of 3-chloromethyl-5-methylpyridine hydrochloride is 3.44g (19.308 mmol); 7g of a pale pink solid (rupatadine fumarate) was obtained in a yield of 81.80% and a purity of 99.43%.
Example 14
The preparation method of rupatadine fumarate provided in this example is as described in reference example 1, except that in step S3, the mass of triethylamine is 8.125g (80.45 mmol); 6.7g of pale pink solid (rupatadine fumarate) was obtained in a yield of 80.61% and a purity of 99.58%.
Example 15
The preparation method of rupatadine fumarate provided in this example is in reference to example 1, except that in step S3, the mass of fumaric acid is 1.86g (16.09 mmol); 6.1g of pale pink solid (rupatadine fumarate) was obtained in a yield of 72.33% and a purity of 99.57%.
Example 16
The preparation method of rupatadine fumarate provided in this example is described in reference to example 1, except that in step S3, the organic phase is concentrated to dryness and dissolved in 100mL of ethyl acetate; 6.78g of pale pink solid (rupatadine fumarate) was obtained in a yield of 79.22% and a purity of 99.49%.
Example 17
The preparation method of rupatadine fumarate provided by the embodiment is in reference to embodiment 1, and is only different in that in step S3, after dissolution, the temperature is raised to 80 ℃; 6.78g of pale pink solid (rupatadine fumarate) was obtained in a yield of 79.2% and a purity of 99.55%.
Comparative example 1
The comparative example provides a method for preparing rupatadine fumarate with reference to example 1, except that in step S1, triethylamine is not added; 10.16g of a pink solid (compound I) was obtained in a yield of 76.6% and a purity of 99.64%.
Comparative example 2
The preparation method of rupatadine fumarate provided in this comparative example was referred to in example 1, except that in step S2, the reaction was not performed after heating to 90 ℃ for 8 hours.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.
Claims (10)
1. A method for preparing rupatadine fumarate, which is characterized by comprising the following steps:
s1, reacting nitrogen methyl loratadine, phenyl chloroformate and organic amine in an organic solvent to obtain a compound I;
the structural formula of the compound I is as follows:
s2, reacting the compound I with alkali in an organic solvent to obtain desloratadine;
s3, reacting the desloratadine, 3-chloromethyl-5-methylpyridine hydrochloride and organic amine in an organic solvent to obtain rupatadine;
s4, reacting the rupatadine with fumaric acid in a salifying solvent to obtain rupatadine fumarate.
2. The method for preparing rupatadine fumarate according to claim 1, wherein in step S1, at least one of the following features (1) to (6) is included;
(1) The organic amine comprises triethylamine;
(2) The organic solvent comprises toluene;
(3) The molar ratio of the nitrogen methyl loratadine to the phenyl chloroformate is 1: (1.15-1.25);
(4) The molar ratio of the nitrogen methyl loratadine to the organic amine is 1: (0.095-0.15);
(5) The dosage ratio of the nitrogen methyl loratadine to the organic solvent is 1g: 8-12 mL;
(6) The reaction conditions are as follows: and reflux reaction is carried out for 6-8 h.
3. The method for preparing rupatadine fumarate according to claim 1, wherein in step S1, after the reaction, further comprising: concentrating and recrystallizing in sequence;
preferably, after the concentration, the compound I is obtained by recrystallization from isopropanol and/or acetonitrile.
4. The method for preparing rupatadine fumarate according to claim 1, wherein in step S2, at least one of the following features (1) to (5) is included;
(1) The base comprises sodium hydroxide and/or potassium hydroxide;
(2) The organic solvent comprises toluene and/or N, N-dimethylformamide;
(3) The molar ratio of the compound I to the base is 1: (4-8);
(4) The dosage ratio of the compound I to the organic solvent is 1g: 14-16 mL;
(5) The reaction conditions are as follows: and carrying out reflux reaction for 7-9 h.
5. The method for preparing rupatadine fumarate according to claim 1, wherein in step S2, after said reacting, further comprising: sequentially extracting, concentrating and recrystallizing;
preferably, after the reaction, water is added for extraction, an organic phase is collected, and after the organic phase is concentrated, ethyl acetate and/or 4-methyl-2-pentanone are adopted for recrystallization, so that the desloratadine is obtained.
6. The method for preparing rupatadine fumarate according to claim 1, wherein in step S3, at least one of the following features (1) to (5) is included;
(1) The organic amine comprises triethylamine;
(2) The organic solvent comprises N, N-dimethylformamide;
(3) The molar ratio of the desloratadine to the 3-chloromethyl-5-methylpyridine hydrochloride is 1: (1.05-1.2);
(4) The molar ratio of desloratadine to the organic amine is 1: (4-5);
(5) The dosage ratio of the desloratadine to the organic solvent is 1g: 9-12 mL.
7. The method for preparing rupatadine fumarate according to claim 1, wherein in step S3, the temperature of the reaction is 60-80 ℃, and the time of the reaction is 55-65 min.
8. The method for preparing rupatadine fumarate according to claim 1, wherein in step S3, after said reacting, further comprising: sequentially extracting and concentrating;
preferably, after the reaction, an extractant is added for extraction, an organic phase is collected, and the organic phase is concentrated to obtain the rupatadine.
9. The method for preparing rupatadine fumarate according to claim 8, wherein in step S3, the extractant comprises an aqueous solution of ethyl acetate and potassium dihydrogen phosphate;
preferably, the volume ratio of the ethyl acetate to the aqueous solution of potassium dihydrogen phosphate is 1: (1-2);
preferably, the concentration of the aqueous solution of the monopotassium phosphate is 0.05-0.067 g/mL.
10. The method for preparing rupatadine fumarate according to claim 1, wherein in step S4, at least one of the following features (1) to (4) is included;
(1) The molar ratio of desloratadine to fumaric acid is 1: (1-1.1);
(2) The salifying solvent comprises ethanol and/or ethyl acetate;
(3) The dosage ratio of the fumaric acid to the salifying solvent is 1g: 90-110 mL;
(4) The temperature of the reaction is 60-80 ℃.
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