CN116496254A - Preparation method of rupatadine fumarate - Google Patents
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- CN116496254A CN116496254A CN202211359359.9A CN202211359359A CN116496254A CN 116496254 A CN116496254 A CN 116496254A CN 202211359359 A CN202211359359 A CN 202211359359A CN 116496254 A CN116496254 A CN 116496254A
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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 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 53
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 35
- 229960005328 rupatadine Drugs 0.000 claims abstract description 22
- JAUOIFJMECXRGI-UHFFFAOYSA-N Neoclaritin Chemical compound C=1C(Cl)=CC=C2C=1CCC1=CC=CN=C1C2=C1CCNCC1 JAUOIFJMECXRGI-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229960001271 desloratadine Drugs 0.000 claims abstract description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 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 20
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims abstract description 12
- DJDHHXDFKSLEQY-UHFFFAOYSA-N 5-methylpyridine-3-carboxylic acid Chemical compound CC1=CN=CC(C(O)=O)=C1 DJDHHXDFKSLEQY-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 11
- 229960003088 loratadine Drugs 0.000 claims abstract description 11
- 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 11
- 239000002253 acid Substances 0.000 claims abstract description 8
- 239000011230 binding agent Substances 0.000 claims abstract description 8
- 238000004519 manufacturing process Methods 0.000 claims abstract description 8
- 239000001530 fumaric acid Substances 0.000 claims abstract description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims abstract 3
- 239000003960 organic solvent Substances 0.000 claims abstract 3
- 238000006482 condensation reaction Methods 0.000 claims abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 46
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 23
- 239000000243 solution Substances 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 239000007864 aqueous solution Substances 0.000 claims description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- 239000012044 organic layer Substances 0.000 claims description 8
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 7
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 7
- 239000012279 sodium borohydride Substances 0.000 claims description 7
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 5
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 239000002841 Lewis acid Substances 0.000 claims description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 150000007517 lewis acids Chemical class 0.000 claims description 4
- 230000001105 regulatory effect Effects 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 239000013078 crystal Substances 0.000 claims description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 150000001875 compounds Chemical class 0.000 description 12
- 238000003756 stirring Methods 0.000 description 9
- 238000001914 filtration Methods 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- -1 5-methyl-3-pyridinyl Chemical group 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- 238000004537 pulping Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 238000012795 verification Methods 0.000 description 2
- PXGPLTODNUVGFL-BRIYLRKRSA-N (E,Z)-(1R,2R,3R,5S)-7-(3,5-Dihydroxy-2-((3S)-(3-hydroxy-1-octenyl))cyclopentyl)-5-heptenoic acid Chemical compound CCCCC[C@H](O)C=C[C@H]1[C@H](O)C[C@H](O)[C@@H]1CC=CCCCC(O)=O PXGPLTODNUVGFL-BRIYLRKRSA-N 0.000 description 1
- 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
- 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 1
- DZZYVVUYEDSKBU-UHFFFAOYSA-N 3-(chloromethyl)-5-methylpyridine Chemical compound CC1=CN=CC(CCl)=C1 DZZYVVUYEDSKBU-UHFFFAOYSA-N 0.000 description 1
- 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 description 1
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 description 1
- OSFVFNVXUQRYIX-UHFFFAOYSA-N 5-methylpyridine-3-carbonyl chloride Chemical compound CC1=CN=CC(C(Cl)=O)=C1 OSFVFNVXUQRYIX-UHFFFAOYSA-N 0.000 description 1
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- 108010003541 Platelet Activating Factor Proteins 0.000 description 1
- 108700023400 Platelet-activating factor receptors Proteins 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- YEESKJGWJFYOOK-IJHYULJSSA-N leukotriene D4 Chemical compound CCCCC\C=C/C\C=C/C=C/C=C/[C@H]([C@@H](O)CCCC(O)=O)SC[C@H](N)C(=O)NCC(O)=O YEESKJGWJFYOOK-IJHYULJSSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 231100001088 no cardiovascular toxicity Toxicity 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- 102000030769 platelet activating factor receptor Human genes 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000011287 therapeutic dose Methods 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
-
- 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
- C07D401/02—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 two hetero rings
- C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of rupatadine fumarate with a structure shown as a formula (6), which comprises the following steps: the loratadine with the structure shown in the formula (1) is subjected to alkaline hydrolysis to obtain desloratadine with the structure shown in the formula (2); the 5-methylnicotinic acid with the structure shown as the formula (3) is subjected to condensation reaction in the presence of an acid binding agent to obtain rupatamide with the structure shown as the formula (4); the rupatadine with the structure shown as the formula (5) is obtained by reducing the formula (4) under the action of a reducing agent; salifying the rupatadine fumarate with fumaric acid in an organic solvent to obtain rupatadine fumarate; the organic solvent is absolute ethyl alcohol or absolute methyl alcohol. The book is provided withThe preparation method of rupatadine fumarate has the advantages of short synthetic route, mild reaction, good yield, and the purity of the finished product reaching more than 99.0 percent, and is suitable for industrial mass production.
Description
Technical Field
The invention relates to a preparation method of rupatadine fumarate.
Background
Rupatadine fumarate (Rupatadine fumarate) having the 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 is an antiallergic agent with dual blocking effects of histamine and platelet-activating factor. The medicine is prepared from Spanish Uricach&Cia SA company, developed, first on Spanish in 3/2003 under the tradename Rupafin. The oral therapeutic dose of the product can selectively block H 1 Receptor, 5-hydroxytryptamine, acetylcholine, prostaglandin F 2a Leukotriene D 4 Has weak blocking effect, can be combined with platelet activating factor receptor in a non-competitive way, and can inhibit degranulation of sensitized cells. The product has no cardiovascular toxicity and potential arrhythmia, and no central sedation.
At present, rupatadine fumarate can be prepared synthetically from 3 synthetic routes by taking loratadine as a starting material:
the first synthetic route:
the second synthetic route:
the third synthetic route:
from the above 3 routes, although the synthetic steps of the route 1 are short, the reaction is difficult to control, and a purer product is difficult to obtain, carbon tetrachloride is needed in the route, so that the method is not scientific and environment-friendly; the synthetic steps of the route 2 are long, the intermediate product is difficult to purify and obtain, and the reaction is difficult to control.
The synthetic step of the route 3 is short, the obtained intermediate is easy to purify, the reaction is mild and controllable, and the method is suitable for industrial production.
The key synthetic steps in scheme 3 are the synthesis of rupatamide and the reduction of rupatamide.
In published literature reports, the method for synthesizing rupatamide comprises the following steps: in patent CN 101531654, it is reported that 5-methylnicotinate is first reacted with thionyl chloride to give 5-methylnicotinyl chloride, which is then condensed with desloratadine to give rupatamide. However, the following disadvantages are found by experimental verification according to the method: 1. after 5-methylnicotinic acid is chlorinated, residual thionyl chloride can influence the subsequent reaction with desloratadine, so that more byproducts are generated; 2. because 5-methyl nicotinoyl chloride is unstable, an effective method cannot be adopted to monitor the reaction process, the reaction is difficult to control, and the industrial mass production is not facilitated.
Among the published literature reports, there are three methods for synthesizing rupatadine by reduction of rupatadine:
in U.S. Pat. No.5407941, a reduction process using lithium aluminum hydride as a reducing agent in tetrahydrofuran solution is described, but experimental verification was carried out according to this process, and the following disadvantages were found: 1. the reaction yield is low, and the product purity is not high; 2. because lithium aluminum hydride has high activity, severe storage and use conditions and high price, the lithium aluminum hydride is unfavorable for industrialized mass production.
In chinese laid-open patent CN1865259, a method of using sodium dihydroaluminate (red aluminum) as a reducing agent in tetrahydrofuran solution is described, but experiments are verified according to the method, and it is found that the yield is low, the product purity is not high, and the sodium dihydroaluminate (red aluminum) reagent is expensive, which is not favorable for industrial mass production.
In patent ES2087818, a method for reducing amides using POCl3/NaBH4 as the reduction system is reported. In the method, phosphorus oxychloride is used for treating rupatamide first, and then sodium borohydride is used as a reducing agent for reducing the amide. However, the method has harsh operating conditions, and the phosphorus oxychloride has strong corrosiveness and high equipment requirements, so that the method is not beneficial to industrialized mass production.
In view of the medicinal value of rupatadine fumarate, it is necessary to find a synthetic route which is simple to operate, mild in reaction conditions, good in yield and satisfactory in product purity.
Disclosure of Invention
The invention aims to provide a preparation method with mild reaction conditions, simple operation, low equipment requirements, high product purity and good yield.
The preparation method provided by the invention comprises the following steps:
the first step, a preparation method of desloratadine with a structure shown in formula (2) is characterized by comprising the following steps: and (3) adding 95 ethanol into the loratadine and alkaline water solution for heating reaction, concentrating under reduced pressure to remove the ethanol after the reaction is completed, adding toluene for extraction, adding water for washing an organic layer, concentrating the organic layer under reduced pressure, and adding ethyl acetate for recrystallization to obtain the desloratadine.
The alkali recommended by the invention is sodium hydroxide or potassium hydroxide, preferably sodium hydroxide.
The invention recommends that the mass ratio of the loratadine to the alkali feed material is 1.0:10.0-30.0, preferably 1.0:20.0-30.0.
The mass ratio of 95 ethanol to loratadine is 2.0-10.0:1.0, preferably 4.0-8.0:1.0.
The reaction temperature of the desloratadine with the preparation structure shown in the formula (2) is preferably 55-85 ℃.
The ratio of the mass of ethyl acetate to the mass of loratadine in the recrystallization is 5.0-30.0:1.0, preferably 8.0-20.0:1.0.
The second step, a preparation method of rupatamide with a structure shown as a formula (4) is characterized by comprising the following steps: reacting desloratadine, 5-methylnicotinic acid, 1-Hydroxybenzotriazole (HOBT), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and an acid binding agent with dichloromethane at a temperature rise, concentrating under reduced pressure after the reaction is completed to remove dichloromethane, adding ethyl acetate and an alkaline water solution to separate out solid, and finally adding water into the obtained solid to pulp to obtain rupatamide.
The acid binding agent is triethylamine or N, N-diisopropylethylamine, preferably N, N-diisopropylethylamine.
The invention recommends that the mass ratio of the acid binding agent to the desloratadine is 1.0-5.0:1.0, preferably 3.0-5.0:1.0.
The invention recommends that the ratio of the amount of 5-methylnicotinic acid to the amount of desloratadine dosing substance is 1.0-2.0:1, preferably 1.2-1.6:1.0.
The reaction temperature of rupatamide with the structure shown in the formula (4) is preferably 15-35 ℃.
The alkali aqueous solution is sodium hydroxide aqueous solution, sodium carbonate aqueous solution or potassium carbonate aqueous solution, preferably sodium carbonate aqueous solution.
The third step, a preparation method of rupatadine with a structure shown as a formula (5) is characterized by comprising the following steps: reducing rupatadine by adding Lewis acid activated reducer, regulating pH value to 1-3 by adding hydrochloric acid solution after reaction, concentrating under reduced pressure to remove solvent, refluxing by adding water, cooling reaction liquid, regulating pH value to 9-10 by adding sodium hydroxide aqueous solution, extracting by adding ethyl acetate, and separating the crude product by column chromatography to obtain rupatadine.
The Lewis acid is acetic acid, trifluoroacetic acid or magnesium chloride, preferably trifluoroacetic acid.
The reducing agent recommended by the invention is sodium borohydride or potassium borohydride, preferably sodium borohydride.
The invention recommends that the ratio of the reducing agent to rupatamide dosing substance is 5.0-15.0:1.0, preferably 6.0-12.0:1.0.
The reaction temperature of rupatadine with the structure shown in the formula (5) is preferably 15-55 ℃.
A fourth step, a preparation method of rupatadine fumarate with a structure shown as a formula (6) is characterized in that the preparation method is as follows: and heating and dissolving the rupatadine and the fumaric acid alcohol solvent, and cooling the reaction solution to separate out crystals to obtain rupatadine fumarate.
The alcohol solvent recommended by the invention is ethanol, isopropanol or methanol, preferably ethanol.
The reaction temperature of rupatadine fumarate with the structure shown in the formula (6) is preferably 55-85 ℃.
The temperature reduction crystallization temperature of rupatadine fumarate with the structure shown in formula (6) is preferably-15 ℃.
Drawings
FIG. 1 shows a high performance liquid chromatography of rupatadine
FIG. 2 is a high performance liquid chromatography of rupatadine fumarate
Detailed Description
The present invention will be described with reference to the following specific examples, but the present invention is not limited thereto.
Example 1
10.0g of loratadine (a compound of formula (1), 100ml of 95 ethanol and a prepared aqueous sodium hydroxide solution (15.0g+50 ml) are added into a reaction kettle, stirred and heated to reflux for reaction, and TLC (developing condition DCM: meOH=30:1) is monitored to stop the reaction after the reaction is complete. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove ethanol, 100ml of toluene and 100ml of water were added thereto, the mixture was stirred to dissolve the mixture, and the organic layer was collected by separation and washed once with 100ml of water. The organic layer was collected and concentrated to dryness, and then 150.0g of ethyl acetate was added thereto to dissolve the above concentrate at a temperature elevation, cooled to crystallize, suction-filtered and dried to obtain 6.1g of desloratadine as the compound of formula (2). Yield: 75.1%.
Example 2
100.0g of loratadine (a compound of formula (1), 800ml of 95 ethanol and prepared aqueous sodium hydroxide solution (250.0g+750 ml) are added into a reaction kettle, stirred and heated to reflux for reaction, and TLC (developing condition DCM: meOH=30:1) is monitored to stop the reaction after the reaction is complete. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove ethanol, 100ml of toluene and 100ml of water were added thereto, the mixture was stirred to dissolve the mixture, and the organic layer was collected by separation and washed once with 100ml of water. The organic layer was collected and concentrated to dryness, and 1000.0g of ethyl acetate was added thereto to dissolve the above concentrate at elevated temperature, cooled to crystallize, suction-filtered and dried to obtain 69.6g of desloratadine as the compound of formula (2). Yield: 85.7%.
Example 3
7.5g of desloratadine as a compound of formula (2) and 150.0g of methylene chloride are added into a 500mL three-port bottle, 6.0g of 5-methylnicotinic acid, 6.0g of HOBT, 7.5g of EDCI and 22.0g of DIPEA are added, the temperature is raised to 35 ℃ for reaction, TLC detection reaction is carried out, and stirring is stopped after the reaction is completed. Concentrating the reaction solution to remove dichloromethane, heating, adding 75.0g of ethyl acetate, stirring to dissolve, adding saturated sodium carbonate aqueous solution to adjust the pH of the system to 8-9, stirring, suction filtering, pulping the filter cake with water, suction filtering, and drying to obtain 8.4g of rupatamide compound shown in formula (3). Yield: 81.0%.
Example 4
7.5g of desloratadine as a compound of formula (2) and 125.0g of methylene chloride are added into a 500mL three-necked flask, 7.5g of 5-methylnicotinic acid, 7.5g of HOBT, 12.5g of EDCI and 32.0g of DIPEA are added, the temperature is raised to 35 ℃ for reaction, TLC detection reaction is carried out, and stirring is stopped after the reaction is completed. Concentrating the reaction solution to remove dichloromethane, heating, adding 60.0g of ethyl acetate, stirring to dissolve, adding saturated sodium carbonate aqueous solution to adjust the pH of the system to 8-9, stirring, suction filtering, pulping the filter cake with water, suction filtering, and drying to obtain 9.2g of rupatamide compound shown in formula (3). Yield: 88.7%.
Example 5
68.0g of desloratadine as a compound of formula (2) and 1000.0g of methylene chloride are added into a 2000mL three-port bottle, 70.0g of 5-methylnicotinic acid, 70.0g of HOBT, 122.5g of EDCI and 350.0g of DIPEA are added, the temperature is increased to 35 ℃ for reaction, TLC detection reaction is carried out, and stirring is stopped after the reaction is completed. Concentrating the reaction solution to remove dichloromethane, heating, adding 800.0g of ethyl acetate, stirring to dissolve, adding saturated sodium carbonate aqueous solution to adjust the pH of the system to 8-9, stirring, suction filtering, pulping the filter cake with water, suction filtering, and drying to obtain 86.8g of rupatamide compound shown in formula (4). Yield: 92.3%.
Example 6
Adding 8.0g of rupatamide, 60.0g of tetrahydrofuran and 7.0g of sodium borohydride of a compound shown in a formula (4) into a 250ml three-mouth bottle, cooling and dropwise adding the prepared tetrahydrofuran solution of trifluoroacetic acid, keeping the temperature not exceeding 20 ℃, stopping dropwise adding after TLC detection reaction is finished, cooling and dropwise adding a 3M hydrochloric acid aqueous solution, adjusting the PH to 1-2, concentrating to remove tetrahydrofuran in the system, adding water, heating and refluxing for 1 hour, cooling and dropwise adding a 20% NaOH aqueous solution, adjusting the PH to 8-9, adding ethyl acetate for extraction, concentrating an ethyl acetate layer to obtain a crude product, adding dichloromethane, separating by column chromatography, and separating with dichloromethane: methanol: ammonia = 30:1:0.02, and the eluate was concentrated to give 3.5g rupatadine. Yield: 45.2%.
Example 6
Adding 65.0g of rupatamide, 360.0g of tetrahydrofuran and 30.0g of sodium borohydride in a 2000ml three-mouth bottle, cooling, dropwise adding the prepared tetrahydrofuran solution of trifluoroacetic acid, keeping the temperature not to exceed 20 ℃, cooling, dropwise adding a 3M hydrochloric acid aqueous solution after TLC detection reaction is finished, adjusting the pH to 1-2, concentrating to remove tetrahydrofuran in the system, adding water, heating, refluxing for 1 hour, cooling, dropwise adding a 20% NaOH aqueous solution to adjust the pH to 8-9, adding ethyl acetate for extraction, concentrating an ethyl acetate layer, obtaining a crude product, adding dichloromethane, separating by column chromatography, and separating with dichloromethane: methanol: ammonia = 30:1:0.02, and the eluate was concentrated to give 39.0g rupatadine. Yield: 62.0%. HPLC purity: 99.819%, as shown in figure 1.
Example 7
3.0g of rupatadine compound shown in formula (5), 0.8g of fumaric acid and 30.0g of methanol are added into a 100ml three-port bottle, the temperature is raised, the reaction solution is dissolved and cleared, the solution is filtered while the solution is hot, the filtrate is placed in an ice bath at 0 ℃ for crystallization for 8 hours, the filtration and the drying are carried out, and 2.2g of rupatadine fumarate is obtained. Yield: 57.3%.
Example 8
39.0g of rupatadine of the compound shown in the formula (5), 10.9g of fumaric acid and 200.0g of ethanol are added into a 500ml three-port bottle, the temperature is raised, the reaction solution is dissolved and cleared, the solution is filtered while the solution is hot, the filtrate is placed in an ice bath at the temperature of 0 ℃ for crystallization for 4 hours, the filtration and the drying are carried out, and 42.9g of rupatadine fumarate is obtained. Yield: 86.0%. HPLC purity: 99.960%, as shown in fig. 2.
Claims (13)
1. The preparation method of rupatadine fumarate with the structure shown in the formula (6) is characterized by comprising the following steps: the loratadine with the structure shown in the formula (1) is subjected to alkaline hydrolysis reaction to obtain desloratadine with the structure shown in the formula (2); the 5-methylnicotinic acid with the structure shown as the formula (3) is subjected to condensation reaction in the presence of an acid binding agent to obtain rupatamide with the structure shown as the formula (4); the rupatadine with the structure shown as the formula (5) is obtained by reducing the formula (4) under the action of a reducing agent; salifying the formula (5) with fumaric acid in an organic solvent to obtain rupatadine fumarate.
2. The method for preparing rupatadine fumarate according to claim 1, wherein the method comprises the following steps: the alkali in the alkaline hydrolysis reaction is sodium hydroxide or potassium hydroxide.
3. The process for preparing rupatadine fumarate according to claim 1 or 2, characterized in that: the mass ratio of the loratadine to the alkali is 1.0:10.0-30.0.
4. A process for the preparation of rupatadine fumarate according to claim 1,2 or 3, characterized in that: the reaction for hydrolyzing the loratadine with the structure shown in the formula (1) to obtain the desloratadine with the structure shown in the formula (2) is as follows: reacting desloratadine and alkali aqueous solution with 95 ethanol at a temperature rise, concentrating under reduced pressure to remove ethanol after the reaction is completed, adding toluene for extraction, then adding water for washing an organic layer, concentrating the organic layer under reduced pressure, and then adding ethyl acetate for recrystallization to obtain the desloratadine.
5. The method for preparing rupatadine fumarate according to claim 1, wherein the method comprises the following steps: the acid binding agent is triethylamine or N, N-diisopropylethylamine.
6. The method for preparing rupatadine fumarate according to claim 1 or 5, wherein: the mass ratio of the acid binding agent to the desloratadine is 1.0-5.0:1.0.
7. The preparation method of rupatadine fumarate according to claim 1, 5 or 6, wherein the reaction of desloratadine with a structure shown in formula (2) and 5-methylnicotinic acid with a structure shown in formula (3) to obtain rupatadine with a structure shown in formula (4) is as follows: reacting desloratadine, 5-methylnicotinic acid, 1-Hydroxybenzotriazole (HOBT), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and an acid binding agent with dichloromethane at a temperature rise, concentrating under reduced pressure after the reaction is completed to remove dichloromethane, adding ethyl acetate and an alkaline water solution to separate out solid, and finally adding water into the obtained solid to pulp to obtain rupatamide.
8. The method for preparing rupatadine fumarate according to claim 1, wherein the method comprises the following steps: the reducing agent is sodium borohydride or potassium borohydride.
9. The process for preparing rupatadine fumarate according to claim 1 or 8, characterized in that: the Lewis acid is acetic acid, trifluoroacetic acid or magnesium chloride.
10. The process for preparing rupatadine fumarate according to claim 1, 8 or 9, characterized in that: the ratio of the reducing agent to the rupatamide is 5.0-15.0:1.0.
11. The preparation method of rupatadine fumarate according to claim 1, 8, 9 or 10, wherein the reaction of the rupatadine having the structure shown in formula (4) to the rupatadine having the structure shown in formula (5) by reduction is as follows: reducing rupatadine by adding Lewis acid activated reducer, regulating pH value to 1-3 by adding hydrochloric acid solution after reaction, concentrating under reduced pressure to remove solvent, refluxing by adding water, cooling reaction liquid, regulating pH value to 9-10 by adding sodium hydroxide aqueous solution, extracting by adding ethyl acetate, and separating the crude product by column chromatography to obtain rupatadine.
12. The method for preparing rupatadine fumarate according to claim 1, wherein the method comprises the following steps: the alcohol solvent is ethanol, isopropanol or methanol.
13. The preparation method of rupatadine fumarate according to claim 1 or 12, wherein the reaction of rupatadine having the structure shown in formula (5) and rupatadine fumarate to obtain rupatadine fumarate having the structure shown in formula (6) is as follows: and heating and dissolving the rupatadine and the fumaric acid alcohol solvent, and cooling the reaction solution to separate out crystals to obtain rupatadine fumarate.
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