CN111423442A - Epinastine hydrochloride intermediate and synthesis method thereof - Google Patents
Epinastine hydrochloride intermediate and synthesis method thereof Download PDFInfo
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- CN111423442A CN111423442A CN202010257217.6A CN202010257217A CN111423442A CN 111423442 A CN111423442 A CN 111423442A CN 202010257217 A CN202010257217 A CN 202010257217A CN 111423442 A CN111423442 A CN 111423442A
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- WHWZLSFABNNENI-UHFFFAOYSA-N epinastine Chemical compound C1C2=CC=CC=C2C2CN=C(N)N2C2=CC=CC=C21 WHWZLSFABNNENI-UHFFFAOYSA-N 0.000 title claims abstract description 41
- 238000001308 synthesis method Methods 0.000 title claims abstract description 8
- 229960002548 epinastine hydrochloride Drugs 0.000 title abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 34
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 18
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 18
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 14
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims abstract description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 40
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 24
- 150000001875 compounds Chemical class 0.000 claims description 22
- 229960003449 epinastine Drugs 0.000 claims description 21
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 14
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 10
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 7
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 7
- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 claims description 7
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 6
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 4
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 6
- -1 etc.) Chemical compound 0.000 claims 6
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 abstract description 11
- 230000008569 process Effects 0.000 abstract description 10
- 230000007613 environmental effect Effects 0.000 abstract description 7
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 abstract description 6
- 229910000037 hydrogen sulfide Inorganic materials 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 8
- FPKDBVUHIXYLNP-UHFFFAOYSA-N 6,11-dihydro-5h-benzo[c][1]benzazepin-6-ylmethanamine Chemical compound NCC1NC2=CC=CC=C2CC2=CC=CC=C12 FPKDBVUHIXYLNP-UHFFFAOYSA-N 0.000 description 7
- 239000000126 substance Substances 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229960001340 histamine Drugs 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- VAQMQKVBZQBWNV-UHFFFAOYSA-N 1-(3-amino-2,4-diazatetracyclo[12.4.0.02,6.07,12]octadeca-1(18),7,9,11,14,16-hexaen-4-yl)ethanone Chemical compound CC(=O)N1CC2C3=CC=CC=C3CC4=CC=CC=C4N2C1N VAQMQKVBZQBWNV-UHFFFAOYSA-N 0.000 description 2
- QAFLMZOQOSXBNJ-UHFFFAOYSA-N NC(N(CC1C2=C(C3)C=CC=C2)C(C2=CC=CC=C2)=O)N1C1=C3C=CC=C1 Chemical compound NC(N(CC1C2=C(C3)C=CC=C2)C(C2=CC=CC=C2)=O)N1C1=C3C=CC=C1 QAFLMZOQOSXBNJ-UHFFFAOYSA-N 0.000 description 2
- 208000003251 Pruritus Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 239000002341 toxic gas Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- AJUMGSLQADLWKL-UHFFFAOYSA-N 1h-azepine;hydrochloride Chemical compound Cl.N1C=CC=CC=C1 AJUMGSLQADLWKL-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 206010052613 Allergic bronchitis Diseases 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010048610 Cardiotoxicity Diseases 0.000 description 1
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 1
- 206010012434 Dermatitis allergic Diseases 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- GWNVDXQDILPJIG-SHSCPDMUSA-N Leukotriene C4 Natural products CCCCCC=C/CC=C/C=C/C=C/C(SCC(NC(=O)CCC(N)C(=O)O)C(=O)NCC(=O)O)C(O)CCCC(=O)O GWNVDXQDILPJIG-SHSCPDMUSA-N 0.000 description 1
- HVAUUPRFYPCOCA-AREMUKBSSA-O PAF Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP(O)(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-O 0.000 description 1
- 206010037083 Prurigo Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- WHWZLSFABNNENI-OAHLLOKOSA-N S-epinastine Chemical compound C1C2=CC=CC=C2[C@H]2CN=C(N)N2C2=CC=CC=C21 WHWZLSFABNNENI-OAHLLOKOSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- ILEXARKWTOTKSO-UHFFFAOYSA-N benzyl 2-cyanobenzoate Chemical compound O=C(OCc1ccccc1)c1ccccc1C#N ILEXARKWTOTKSO-UHFFFAOYSA-N 0.000 description 1
- NCCFXVPTAWOYBF-UHFFFAOYSA-N benzyl 3-amino-2,4-diazatetracyclo[12.4.0.02,6.07,12]octadeca-1(18),7,9,11,14,16-hexaene-4-carboxylate Chemical compound C1C2C3=CC=CC=C3CC4=CC=CC=C4N2C(N1C(=O)OCC5=CC=CC=C5)N NCCFXVPTAWOYBF-UHFFFAOYSA-N 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 231100000259 cardiotoxicity Toxicity 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- GWNVDXQDILPJIG-NXOLIXFESA-N leukotriene C4 Chemical compound CCCCC\C=C/C\C=C/C=C/C=C/[C@H]([C@@H](O)CCCC(O)=O)SC[C@@H](C(=O)NCC(O)=O)NC(=O)CC[C@H](N)C(O)=O GWNVDXQDILPJIG-NXOLIXFESA-N 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- XMTGCMRTDDLVIM-UHFFFAOYSA-N methyl 3-amino-2,4-diazatetracyclo[12.4.0.02,6.07,12]octadeca-1(18),7,9,11,14,16-hexaene-4-carboxylate Chemical compound COC(=O)N1CC2C3=CC=CC=C3CC4=CC=CC=C4N2C1N XMTGCMRTDDLVIM-UHFFFAOYSA-N 0.000 description 1
- ZSYJMXLJNPEAGP-UHFFFAOYSA-N methyl n-cyanocarbamate Chemical compound COC(=O)NC#N ZSYJMXLJNPEAGP-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- BNZBMEIFAOYZEA-UHFFFAOYSA-N n-cyanoacetamide Chemical compound CC(=O)NC#N BNZBMEIFAOYZEA-UHFFFAOYSA-N 0.000 description 1
- DBFAKALHTSOYSG-UHFFFAOYSA-N n-cyanobenzamide Chemical compound N#CNC(=O)C1=CC=CC=C1 DBFAKALHTSOYSG-UHFFFAOYSA-N 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- RZNPCVSMGBGRDA-UHFFFAOYSA-N tert-butyl 3-amino-2,4-diazatetracyclo[12.4.0.02,6.07,12]octadeca-1(18),7,9,11,14,16-hexaene-4-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC2C3=CC=CC=C3CC4=CC=CC=C4N2C1N RZNPCVSMGBGRDA-UHFFFAOYSA-N 0.000 description 1
- LRHQXZMFPRDUBF-UHFFFAOYSA-N tert-butyl N-cyanocarbamate Chemical compound CC(C)(C)OC(=O)NC#N LRHQXZMFPRDUBF-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The compound of formula II provided by the invention is used as a raw material or an intermediate for synthesizing epinastine hydrochloride, cyanogen bromide is not needed in the synthesis process, hydrogen sulfide or/and methyl mercaptan are not generated in the synthesis process, the operation safety is improved, the environmental protection pressure is reduced, and the requirements of safe production and environmental protection are met. The synthesis method has short time, complete reaction in 10 hours, obvious advantages in industrial production, high yield and suitability for industrial production.
Description
Technical Field
The invention relates to epinastine hydrochloride, in particular to an epinastine hydrochloride intermediate and a synthetic method thereof.
Background
Epinastine hydrochloride, also known as epinastine hydrochloride, was developed by the company Brigg Vargahi and the three Japanese co-preparations, histamine H, marketed in 1994 in Japan1A receptor antagonist. The chemical name of epinastine hydrochloride is 3-amino-9, 13 b-dihydro-1H-diphenyl [ c, f]Imidazo [1,5-a ]]Azepine hydrochloride having the following structural formula:
epinastine has inhibitory effect on histamine, leukotriene C4, PAF, 5-hydroxytryptamine, and can inhibit release of histamine, and slow-reacting substance A (SRS-A) chemical mediator, and is mainly used for treating allergic rhinitis, urticariA, allergic dermatitis, skin pruritus, prurigo, psoriasis vulgaris with pruritus and allergic bronchitis of adult. Epinastine is the most potent non-sedating histamine H acting on peripheral nerves1One of the receptor antagonists has good effect, high safety, wide application range, less drug interaction and low cardiotoxicity, and is widely accepted by doctors and patients, and D-epinastine, L-epinastine and racemic epinastine have no obvious difference in pharmacological activity.
At present, there are three main methods for synthesizing epinastine hydrochloride:
the first, 6-aminomethyl-6, 11-dihydro-5H-dibenzo [ b, e ] azepine (I) is cyclized with cyanogen bromide to form epinastine (e.g. EP0035749a1/CN101130544A, etc.), which is synthesized as follows:
the process adopts virulent cyanogen bromide in the reaction, and the concentration of the virulent cyanogen bromide reaches 120mg/m3The epinastine hydrochloride can die after contacting for 30 minutes under the condition, so that the epinastine hydrochloride synthesized by the method needs to prevent cyanogen bromide leakage in the synthesis process, threatens the safety of operators, and cannot ensure that cyanogen bromide cannot remain in the prepared epinastine hydrochloride to influence the medication safety.
The second, 6-aminomethyl-6, 11-dihydro-5H-dibenzo [ b, e ] azepine, under the action of sulfide and p-toluenesulfonic acid, synthesizes epinastine (CN103172638A, CN105172658A, etc.), which is as follows:
although cyanogen bromide is avoided, a large amount of stink and extremely toxic gas hydrogen sulfide is generated during synthesis, the method has great pollution to the environment, does not meet the requirement of environmental protection, and does not meet the requirement of safe production.
A third, 6-aminomethyl-6, 11-dihydro-5H-dibenzo [ b, e ] azepine synthesized epinastine (CN105153169A, et al) by the following route:
the method can also generate highly toxic and malodorous hydrogen sulfide gas during cyclization, threatens the safety of operators and does not meet the requirements of environmental protection and safe production.
Therefore, the current synthesis method of epinastine hydrochloride is yet to be further improved.
Disclosure of Invention
In the first aspect, the compound of formula II provided by the invention is used as a raw material or an intermediate for synthesizing epinastine hydrochloride, cyanogen bromide is not required in the synthesis process, hydrogen sulfide gas is not generated in the synthesis process, and the safety of operators and the safety of medication are effectively guaranteed.
The compound of formula (II) of the present invention has the following structure:
wherein,
R＝COOMe，COOEt，COO(n-Pr)，COO(i-Pr)，COO(n-Bu)，COO(i-Bu)，COO(Tr)，COO(t-Bu)，COOPh，COOBn，Fmoc，COCH3，COEt，COPh，COTs。
in a second aspect, the present invention provides a process for the synthesis of epinastine starting from a compound of formula II.
The invention relates to a synthesis method of epinastine, a compound in a formula II is subjected to base R removal to obtain epinastine; the synthetic route is as follows:
wherein,
R＝COOMe，COOEt，COO(n-Pr)，COO(i-Pr)，COO(n-Bu)，COO(i-Bu)，COO(Tr)，COO(t-Bu)，COOPh，COOBn，Fmoc，COCH3，COEt，COPh，COTs。
in the above method, the solvent is one or more of water, C1-4 lower alcohol (methanol, ethanol, N-propanol, isopropanol, N-butanol, etc.), N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran, methyltetrahydrofuran, acetone, acetonitrile, formic acid, acetic acid, propionic acid, hydrochloric acid, and trifluoroacetic acid.
The epinastine obtained by the method is salified with hydrochloric acid to obtain epinastine hydrochloride.
In a third aspect, the present invention provides a method for synthesizing a compound of formula II.
A method for synthesizing a compound of a formula II comprises the step of cyclizing a compound of a formula I and a compound of a formula A to obtain the compound of the formula II. Specifically, the synthetic route of the compound of formula II is as follows:
wherein,
R＝COOMe，COOEt，COO(n-Pr)，COO(i-Pr)，COO(n-Bu)，COO(i-Bu)，COO(Tr)，COO(t-Bu)，COOPh，COOBn，Fmoc，COCH3，COEt，COPh，COTs。
in the above method, the solvent is one or more of water, C1-4 lower alcohol (methanol, ethanol, N-propanol, isopropanol, N-butanol, etc.), N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran, methyltetrahydrofuran, acetone, and acetonitrile.
In a fourth aspect, the present invention provides a method for synthesizing epinastine.
In the above method, the solvent is one or more of water, C1-4 lower alcohol (methanol, ethanol, N-propanol, isopropanol, N-butanol, etc.), N-dimethylformamide, N-dimethylacetamide, acetone, and acetonitrile.
Has the advantages that:
the compound of formula II provided by the invention is used as a raw material or an intermediate for synthesizing epinastine hydrochloride, cyanogen bromide is not needed in the synthesis process, hydrogen sulfide gas is not generated in the synthesis process, and the safety of operators and the medication safety are effectively guaranteed. The invention provides a synthesis method of epinastine hydrochloride, which does not use virulent cyanogen bromide in the whole synthesis process, reduces the toxicity, is beneficial to safe production and environmental protection, and improves the safety of the medicine because the synthesized epinastine hydrochloride does not have cyanogen bromide residue, thereby being easy for large-scale production. The invention does not adopt sulfur-containing compounds, does not generate hydrogen sulfide or/and methyl mercaptan which are stink and highly toxic gases, improves the operation safety, reduces the environmental protection pressure, and meets the requirements of safe production and environmental protection. The method has short reaction time, complete reaction can be realized in 10 hours in total in two steps of reaction, and the method has obvious advantages in industrial production. The method is used for synthesizing epinastine, the yield can reach more than 90 percent at most, and the method is suitable for industrial production.
Detailed Description
In order to make the objects and technical solutions of the present invention clearer, preferred embodiments of the present invention are described in detail below. It is to be noted that: the following examples are intended to illustrate the invention further and are not to be construed as limiting the scope of the invention. The invention is not limited to the embodiments described above, but rather, many modifications and variations may be made by one skilled in the art without departing from the scope of the invention.
EXAMPLE 1 Synthesis of N-methoxycarbonyl-3-amino-9, 13 b-dihydro-1H-dibenzo [ c, f ] imidazo [1,5-a ] azepine (Compound of formula II-1)
The reaction route is as follows:
in the above method, the solvent is one or more of water, C1-4 lower alcohol (methanol, ethanol, N-propanol, isopropanol, N-butanol, etc.), N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran, methyltetrahydrofuran, acetone, and acetonitrile.
It has been found that in the above method, the reaction is significantly affected by the pH and reaction temperature of the reaction solution, and if the control is not good, the reaction hardly occurs or the by-products are significantly increased. Preferably, the reaction solution of the present invention has a pH of 2 to 5 (more preferably a pH of 2.5 to 4) and a reaction temperature of 40 ℃ to 100 ℃ (more preferably 60 ℃ to 90 ℃).
The specific operation is as follows:
6-aminomethyl-6, 11-dihydro-5H-dibenzo [ b, e ]]Diluting azepine (30.5g) with methyl cyanocarbamate aqueous solution (300ml, 11.5%), adjusting pH to 3.0-3.5, heating to 90 ℃, reacting for two hours, detecting that the reaction is finished by HP L C, cooling, adding ethyl acetate 600ml for extraction, washing an organic layer with purified water 600ml and saturated saline water 300ml, drying with anhydrous sodium sulfate, filtering, distilling to dryness to obtain 34.3g of light brown oily substance, namely N-methoxycarbonyl-3-amino-9, 13 b-dihydro-1H-dibenzo [ C, f-methyl-3, 13 b-dihydro-1H-dibenzo [ C, f-methyl-1 ] ethyl-l, N-methoxy-carbonyl-3-amino-9, 13b]Imidazo [1,5-a ]]Azepin, HP L C purity 98.5%, yield 92%. M/z 308[ M +1 ]]+。
EXAMPLE 2 Synthesis of N-tert-Butoxycarbonyl-3-amino-9, 13 b-dihydro-1H-dibenzo [ c, f ] imidazo [1,5-a ] azepine (compound of formula II-2)
The reaction route is as follows:
reference example 1, 6-aminomethyl-6, 11-dihydro-5H-dibenzo [ b, e]Using 400ml of tert-butyl alcohol as a solvent, adding tert-butyl cyanocarbamate (31.5g) into azepine (26.5g), heating and refluxing for 3H, cooling, distilling to dryness to obtain a light brown oily substance, namely N-tert-butoxycarbonyl-3-amino-9, 13 b-dihydro-1H-dibenzo [ c, f ] s]Imidazo [1,5-a ]]25.8g of azepine, 96.7% of purity and 87% of yield. M/z 350[ M +1 ]]+。
EXAMPLE 3 Synthesis of N-benzyloxycarbonyl-3-amino-9, 13 b-dihydro-1H-dibenzo [ c, f ] imidazo [1,5-a ] azepine (compound of formula II-3)
The reaction route is as follows:
reference example 1, 6-aminomethyl-6, 11-dihydro-5H-dibenzo [ b, e]Azepine (20.8g) is prepared by adding cyanobenzoic acid benzyl ester (22.5g) into tetrahydrofuran 400ml as solvent, heating and refluxing for 10H, cooling, distilling to dryness to obtain light brown oily substance, i.e. N-benzyloxycarbonyl-3-amino-9, 13 b-dihydro-1H-dibenzo [ c, f ] s]Imidazo [1,5-a ]]29.2g of azepine, the purity is 97.7 percent, and the yield is 82 percent; m/z 384[ M +1 ]]+。
Example 4 Synthesis of N-acetyl-3-amino-9, 13 b-dihydro-1H-dibenzo [ c, f ] imidazo [1,5-a ] azepine (Compound of formula II-4)
The reaction route is as follows:
referring to example 1, 20.4g of 6-aminomethyl-6, 11-dihydro-5H-dibenzo [ b, e ] azepine was diluted with 200ml of N-acetyl cyanamide aqueous ammonia solution (20%), the pH was adjusted to 3.0 to 3.5, the mixture was heated to 90 ℃, reacted for 2 hours, cooled, extracted with ethyl acetate, the organic layer was washed with purified water and saturated brine, dried over anhydrous sodium sulfate, filtered, and distilled to dryness to obtain 23.5g of a yellow solid, i.e., N-acetyl-3-amino-9, 13 b-dihydro-1H-dibenzo [ c, f ] imidazo [1,5-a ] azepine, 96% pure, 78% yield.
EXAMPLE 5 Synthesis of N-benzoyl-3-amino-9, 13 b-dihydro-1H-dibenzo [ c, f ] imidazo [1,5-a ] azepine (Compound of formula II-5)
The reaction route is as follows:
referring to example 1, 6-aminomethyl-6, 11-dihydro-5H-dibenzo [ b, e ] azepine 21.3g and N-benzoyl cyanamide (28.6g), diluted with 400ml of a 70% ethanol solution, adjusted to pH 3.0-3.5, heated under reflux, reacted for 4 hours, cooled, evaporated under reduced pressure to remove ethanol, extracted with ethyl acetate, the organic layer washed with purified water, saturated brine, dried over anhydrous sodium sulfate, filtered, distilled to dryness, and purified to obtain 147g of a yellow solid, i.e., N-benzoyl-3-amino-9, 13 b-dihydro-1H-dibenzo [ c, f ] imidazo [1,5-a ] azepine, 99% pure, 41.6% yield.
With reference to the above examples, compounds of formula (II) were prepared wherein R ═ COOEt, COO (n-Pr), COO (i-Pr), COO (n-Bu), COO (i-Bu), COO (Tr), COOPh, Fmoc, COEt, COTs.
EXAMPLE 6 Synthesis of 3-amino-9, 13 b-dihydro-1H-dibenzo [ c, f ] imidazo [1,5-a ] azepine (epinastine)
The reaction route is as follows:
n-methoxycarbonyl-3-amino-9, 13 b-dihydro-1H-dibenzo [ c, f]Imidazo [1,5-a ]]Adding 5% NaOH solution (400ml) into azepine (20.0g), stirring at room temperature for 2 hours, detecting that the reaction is complete by HP L C, adding toluene (400ml) for extraction, washing with 200ml of purified water and 100ml of saturated saline solution, drying with anhydrous sodium sulfate, filtering, distilling to obtain 16.1g of light yellow solid, namely epinastine, the yield is 98%, the melting point is 204-]+；1H-NMR (solvent CD)3OD)：ppm3.43～3.57(m,2H,H-4)、4.21～4.25(t,J＝10.0Hz,1H,H-4)、4.39～4.44(t,J＝14.4Hz,2H,CH-12)、5.29～5.33(t,J＝10.0Hz,1H,H-5)、6.90～7.50(m,8H,H-7、H-8、H-9、H-10、H-14、H-15、H-16、H-17)。13C-NMR (solvent CD)3OD)：ppm 37.9、50.4、64.4、127.7、128.3、128.8、129.4、129.9、130.2、133.4、133.9、135.1、135.7、140.4、158.5。
Referring to example 6, epinastine was prepared by removing the R group from the compound of formula (II) prepared in the above example.
EXAMPLE 7 Synthesis of 3-amino-9, 13 b-dihydro-1H-dibenzo [ c, f ] imidazo [1,5-a ] azepine (epinastine)
The reaction route is as follows:
referring to example 1, 10.4g of 6-aminomethyl-6, 11-dihydro-5H-dibenzo [ b, e ] azepine was diluted with 200ml of cyanamide aqueous solution (50%), the pH was adjusted to 3.0 to 3.5, the mixture was heated to 90 ℃, reacted for 2 hours, cooled, extracted with ethyl acetate, and the organic layer was washed with purified water and saturated brine, dried over anhydrous sodium sulfate, filtered, and distilled to dryness to obtain 3.5g of a yellow solid, i.e., 3-amino-9, 13 b-dihydro-1H-dibenzo [ c, f ] imidazo [1,5-a ] azepine (epinastine) with a purity of 89% and a yield of 30%.
Claims (10)
1. A compound of formula (II) having the structure:
wherein,
R＝COOMe，COOEt，COO(n-Pr)，COO(i-Pr)，COO(n-Bu)，COO(i-Bu)，COO(Tr)，COO(t-Bu)，COOPh，COOBn，Fmoc，COCH3，COEt，COPh，COTs。
2. a synthesis method of epinastine is characterized in that: the compound of formula II is synthesized by removing R group to obtain epinastine:
wherein,
R＝COOMe，COOEt，COO(n-Pr)，COO(i-Pr)，COO(n-Bu)，COO(i-Bu)，COO(Tr)，COO(t-Bu)，COOPh，COOBn，Fmoc，COCH3，COEt，COPh，COTs。
3. a method for synthesizing a compound of formula II, comprising: the compound of formula I and the compound of formula A are subjected to cyclization to obtain the compound of formula II, and the synthetic route is as follows:
wherein,
R＝COOMe，COOEt，COO(n-Pr)，COO(i-Pr)，COO(n-Bu)，COO(i-Bu)，COO(Tr)，COO(t-Bu)，COOPh，COOBn，Fmoc，COCH3，COEt，COPh，COTs。
4. a method for synthesizing a compound of formula II-1, characterized in that the reaction scheme is as follows:
the solvent used in the reaction is one or more of water, lower alcohol with 1-4 carbon atoms (methanol, ethanol, N-propanol, isopropanol, N-butanol, etc.), N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran, methyltetrahydrofuran, acetone and acetonitrile.
5. The method of claim 4, wherein: the pH of the reaction solution is 2 to 5, preferably 2.5 to 4; the reaction temperature is 40 ℃ to 100 ℃, preferably 60 ℃ to 90 ℃.
6. A method for synthesizing a compound of formula II-2, characterized in that the reaction scheme is as follows:
the solvent used in the reaction is one or more of water, lower alcohol with 1-4 carbon atoms (methanol, ethanol, N-propanol, isopropanol, N-butanol, etc.), N-dimethylformamide, N-dimethylacetamide, acetone and acetonitrile.
7. A method for synthesizing a compound of formula II-3, characterized in that the reaction scheme is as follows:
the solvent used in the reaction is one or more of water, lower alcohol with 1-4 carbon atoms (methanol, ethanol, N-propanol, isopropanol, N-butanol, etc.), N-dimethylformamide, N-dimethylacetamide, acetone and acetonitrile.
8. A method for synthesizing a compound of formula II-4, characterized in that the reaction scheme is as follows:
the solvent used in the reaction is one or more of water, lower alcohol with 1-4 carbon atoms (methanol, ethanol, N-propanol, isopropanol, N-butanol, etc.), N-dimethylformamide, N-dimethylacetamide, acetone and acetonitrile.
9. A method for synthesizing a compound of formula II-5, characterized in that the reaction scheme is as follows:
the solvent used in the reaction is one or more of water, lower alcohol with 1-4 carbon atoms (methanol, ethanol, N-propanol, isopropanol, N-butanol, etc.), N-dimethylformamide, N-dimethylacetamide, acetone and acetonitrile.
10. The synthesis method of epinastine is characterized in that the synthesis route is as follows:
the solvent used in the reaction is one or more of water, lower alcohol with 1-4 carbon atoms (methanol, ethanol, N-propanol, isopropanol, N-butanol, etc.), N-dimethylformamide, N-dimethylacetamide, acetone and acetonitrile.
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