CN109232434A - A kind of new method synthesizing flibanserin - Google Patents
A kind of new method synthesizing flibanserin Download PDFInfo
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- CN109232434A CN109232434A CN201811267749.7A CN201811267749A CN109232434A CN 109232434 A CN109232434 A CN 109232434A CN 201811267749 A CN201811267749 A CN 201811267749A CN 109232434 A CN109232434 A CN 109232434A
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- flibanserin
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- chloroethyl
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- PPRRDFIXUUSXRA-UHFFFAOYSA-N flibanserin Chemical compound FC(F)(F)C1=CC=CC(N2CCN(CCN3C(NC4=CC=CC=C43)=O)CC2)=C1 PPRRDFIXUUSXRA-UHFFFAOYSA-N 0.000 title claims abstract description 56
- 229960002053 flibanserin Drugs 0.000 title claims abstract description 56
- 238000000034 method Methods 0.000 title claims abstract description 33
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 6
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 40
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 38
- 239000000047 product Substances 0.000 claims abstract description 30
- XWXQEBMBBDIGOQ-UHFFFAOYSA-N 2-ethoxy-1h-benzimidazole Chemical compound C1=CC=C2NC(OCC)=NC2=C1 XWXQEBMBBDIGOQ-UHFFFAOYSA-N 0.000 claims abstract description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 19
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims abstract description 11
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 claims abstract description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 57
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- 238000003756 stirring Methods 0.000 claims description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 35
- 238000006243 chemical reaction Methods 0.000 claims description 32
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 28
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 27
- VKPPFDPXZWFDFA-UHFFFAOYSA-N 2-chloroethanamine Chemical compound NCCCl VKPPFDPXZWFDFA-UHFFFAOYSA-N 0.000 claims description 22
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 22
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 22
- 238000001035 drying Methods 0.000 claims description 20
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 18
- 238000001914 filtration Methods 0.000 claims description 18
- 238000002156 mixing Methods 0.000 claims description 18
- 239000007787 solid Substances 0.000 claims description 17
- 239000012074 organic phase Substances 0.000 claims description 16
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 14
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 11
- 239000012043 crude product Substances 0.000 claims description 11
- 239000004519 grease Substances 0.000 claims description 11
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 11
- 239000000243 solution Substances 0.000 claims description 10
- -1 o-phenylenediamine, tetraethyl orthocarbonate Chemical compound 0.000 claims description 8
- 238000001953 recrystallisation Methods 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- XGAGFLQFMFCIHZ-UHFFFAOYSA-N 3-[2-[4-[3-(trifluoromethyl)phenyl]piperazin-1-yl]ethyl]-1h-benzimidazol-2-one;hydrochloride Chemical compound Cl.FC(F)(F)C1=CC=CC(N2CCN(CCN3C(NC4=CC=CC=C43)=O)CC2)=C1 XGAGFLQFMFCIHZ-UHFFFAOYSA-N 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 239000002585 base Substances 0.000 claims description 7
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 claims description 7
- 238000004440 column chromatography Methods 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 7
- 239000013078 crystal Substances 0.000 claims description 7
- 235000019441 ethanol Nutrition 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 7
- 238000010792 warming Methods 0.000 claims description 7
- 125000004494 ethyl ester group Chemical group 0.000 claims description 6
- RXCVUXLCNLVYIA-UHFFFAOYSA-N orthocarbonic acid Chemical compound OC(O)(O)O RXCVUXLCNLVYIA-UHFFFAOYSA-N 0.000 claims description 6
- 238000000926 separation method Methods 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 5
- 239000012044 organic layer Substances 0.000 claims description 4
- MAIPOMCACBNHEI-UHFFFAOYSA-N 1-(2-chloroethyl)piperazine Chemical compound ClCCN1CCNCC1 MAIPOMCACBNHEI-UHFFFAOYSA-N 0.000 claims description 2
- BZHJMEDXRYGGRV-UHFFFAOYSA-N Vinyl chloride Chemical compound ClC=C BZHJMEDXRYGGRV-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 2
- UWNWYIUODRPXKH-UHFFFAOYSA-N toluene;hydrofluoride Chemical compound F.CC1=CC=CC=C1 UWNWYIUODRPXKH-UHFFFAOYSA-N 0.000 claims 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- 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 claims 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 1
- 239000005864 Sulphur Substances 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 150000003462 sulfoxides Chemical class 0.000 claims 1
- XPDWGBQVDMORPB-UHFFFAOYSA-N trifluoromethane acid Natural products FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 claims 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 35
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 abstract description 22
- 239000013067 intermediate product Substances 0.000 abstract description 6
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 5
- 239000006227 byproduct Substances 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 3
- 238000006467 substitution reaction Methods 0.000 abstract description 3
- CWLNAJYDRSIKJS-UHFFFAOYSA-N triethoxymethoxyethane Chemical compound CCOC(OCC)(OCC)OCC CWLNAJYDRSIKJS-UHFFFAOYSA-N 0.000 abstract description 3
- 230000007547 defect Effects 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- VIUDTWATMPPKEL-UHFFFAOYSA-N 3-(trifluoromethyl)aniline Chemical compound NC1=CC=CC(C(F)(F)F)=C1 VIUDTWATMPPKEL-UHFFFAOYSA-N 0.000 abstract 1
- 206010001497 Agitation Diseases 0.000 description 21
- 238000013019 agitation Methods 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 238000010189 synthetic method Methods 0.000 description 8
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical group C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 235000019628 coolness Nutrition 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- 239000012266 salt solution Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 230000035946 sexual desire Effects 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 238000010183 spectrum analysis Methods 0.000 description 3
- 206010057671 Female sexual dysfunction Diseases 0.000 description 2
- 206010024419 Libido decreased Diseases 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 150000008641 benzimidazolones Chemical class 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 description 2
- 230000001568 sexual effect Effects 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 description 1
- 229940116892 5 Hydroxytryptamine 2B receptor antagonist Drugs 0.000 description 1
- 102000006969 5-HT2B Serotonin Receptor Human genes 0.000 description 1
- 108010072584 5-HT2B Serotonin Receptor Proteins 0.000 description 1
- 102000006902 5-HT2C Serotonin Receptor Human genes 0.000 description 1
- 108010072553 5-HT2C Serotonin Receptor Proteins 0.000 description 1
- 102000003962 Dopamine D4 receptors Human genes 0.000 description 1
- 108090000357 Dopamine D4 receptors Proteins 0.000 description 1
- 208000004483 Dyspareunia Diseases 0.000 description 1
- 208000006262 Psychological Sexual Dysfunctions Diseases 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000037007 arousal Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- MYONAGGJKCJOBT-UHFFFAOYSA-N benzimidazol-2-one Chemical compound C1=CC=CC2=NC(=O)N=C21 MYONAGGJKCJOBT-UHFFFAOYSA-N 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 230000009137 competitive binding Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043237 diethanolamine Drugs 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000001794 hormone therapy Methods 0.000 description 1
- 208000017020 hypoactive sexual desire disease Diseases 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 208000024714 major depressive disease Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 208000024309 orgasm disease Diseases 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 238000009522 phase III clinical trial Methods 0.000 description 1
- DLRJIFUOBPOJNS-UHFFFAOYSA-N phenetole Chemical compound CCOC1=CC=CC=C1 DLRJIFUOBPOJNS-UHFFFAOYSA-N 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 230000001242 postsynaptic effect Effects 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 238000001671 psychotherapy Methods 0.000 description 1
- 239000004089 psychotropic agent Substances 0.000 description 1
- 230000000506 psychotropic effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000003723 serotonin 1A agonist Substances 0.000 description 1
- 239000002400 serotonin 2A antagonist Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 210000002229 urogenital system Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/26—Oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种合成氟班色林的新方法，属于有机合成技术领域。本发明分别以三乙醇胺和间氨基三氟甲苯为起始原料，制备了哌嗪中间体；然后以邻苯二胺和原碳酸四乙酯为原料，制备了乙氧基苯并咪唑类中间体；再将制得的哌嗪中间体和苯并咪唑类中间体发生取代反应，以及盐酸脱保护得到目标产物氟班色林。本发明合成步骤少，副产物少，中间产物和目标产物收率均较高，中间产物2‑乙氧基苯并咪唑的收率可达94.2％，目标产物收率可达56.2％，由此可见，本发明克服了现有技术中该物质合成步骤繁琐、且副产物多，目标产物收率较低的缺陷。另外，本发明后处理工艺简单、产物纯度高，经济环保的工业化路线，具有十分广泛的用途和潜在的经济效益。
The invention relates to a new method for synthesizing flibanserin, and belongs to the technical field of organic synthesis. In the invention, triethanolamine and m-aminotrifluorotoluene are used as starting materials to prepare piperazine intermediates; then o-phenylenediamine and tetraethyl orthocarbonate are used as raw materials to prepare ethoxybenzimidazole intermediates Then, the prepared piperazine intermediate and benzimidazole intermediate are subjected to substitution reaction, and hydrochloric acid is deprotected to obtain the target product flibanserin. The invention has few synthesis steps, few by-products, and high yields of intermediate products and target products. The yield of the intermediate product 2-ethoxybenzimidazole can reach 94.2%, and the target product yield can reach 56.2%. It can be seen that the present invention overcomes the defects in the prior art that the synthesis steps of the substance are cumbersome, the by-products are many, and the yield of the target product is low. In addition, the post-treatment process of the invention is simple, the product purity is high, and the industrialization route is economical and environmentally friendly, and has a very wide range of uses and potential economic benefits.
Description
Technical field
The invention belongs to technical field of organic synthesis, and in particular to a kind of new method for synthesizing flibanserin.
Background technique
Flibanserin (Flibanserin) is a kind of novel non-hormone drug, earliest by German Boehringer
Ingelheim company develops, wherein science of culture title are as follows: 3- [2- [4- (4- trifluoromethyl) piperazine -1- base] ethyl] -
1H- 2-ketone benzimidaozole, structure is as shown in following formula one.
Flibanserin is a kind of drug for solving women's sex dysfunction, is mainly used for treatment and obtains dysaphrodisia (sexual desire
Decline disease, HSDD) pre-menopausal women.In the world, 5.4% is accounted for by the women that hyposexuality perplexs for a long time~
13.6%, wherein Pre-menopausal Women (18~55 years old) disease incidence is about the 10% of HSDD.Flibanserin is completed in November, 2009
Phase iii clinical trial simultaneously proposes New Drug Application, in August, 2015, which is ratified to list by FDA, and withFor trade name.
Female sexual dysfunction (female sexual dysfunction, abbreviation FSD) refers to that women is low due to sexual desire
Under, sexual arousal is difficult, orgasm disorder or dyspareunia make its obviously by a kind of disease that this perplexs.Sexual desire is low in FSD illness
Under (hypoactive sexual desire disorder, HSDD) refer to non-holding caused by substance or general curative situation
Continuously or repeatedly to the desire of sexual life and sex fantasy deficiency or complete missing, and significant worries thus are brought to patient
Or human communication is difficult.HSDD is a kind of common and refractory mental disease of the genitourinary system, it can betide each age
The women of section.Though Kennedy etc. is about flibanserin treatment major depressive disorder the study found that flibanserin is made without antidepression
With, but it shows good curative effect in terms of improving patient's sexual desire, and this promotes numerous researchers using flibanserin treatment
HSDD.Currently, the treatment to HSDD includes three kinds of therapies, such as psychotherapy, hormone therapy and psychotropic therapy.Psychotropic agent
Treatment mainly releases its pathogenic factor from physiology level.In physiologic factor, research at present is more clear that maincenter mind
The excited and inhibition that property is reacted is adjusted through system and exception occurs.In central nervous system, excitation has been reacted to property
Neurotransmitter is dopamine and removes hormone on first kidney, and the neurotransmitter for having reacted inhibiting effect to property is serotonine (5-
hyroxytryptamine,5-HT).Flibanserin is cerebral cortex cynapse 5-HT1A agonist and 5-HT2A antagonist, it
Moderate affinity is all had with dopamine d 4,5-HT2B and 5-HT2C receptor.In physiology level, flibanserin by with 5-HT
Its receptor on postsynaptic membrane of competitive binding, prevent 5-HT is from playing its anaphrodisiac effect, so that maincenter
The inhibition of property reaction is weakened, excitability increases, to achieve the purpose that treat HSDD.
At present both at home and abroad about there are mainly three types of the preparation methods of flibanserin:
A, world patent WO199303016 first reported the synthetic method of flibanserin, by benzimidazolone
The substitution reaction of mesosome and piperazine intermediate obtains, and synthetic route is as shown in formula one.
B, world patent WO2010128516 discloses a kind of flibanserin improvement preparation method, mainly considers piperazine
Derivative is difficult to the case where obtaining, and is carried out using two (2- chloroethyl) amine or diethanol amine and the benzimidazolone derivatives of protection
Substituted condensed to obtain, synthetic route is as shown in formula two.
C, Chinese patent CN201510391692 also discloses a kind of flibanserin improvement preparation method, uses and first prepares
Piperazine intermediate, then the method for being condensed into benzimidazolone ring obtain, and synthetic route is as shown in formula three.
Above-mentioned three synthetic routes prepare flibanserin and all there is the acquisition of raw material difficulty, reaction step is more, active reaction point compared with
More, so that side reaction is difficult to control, yield is reduced, and industry amplification has difficulties, and leads to the drawbacks such as higher cost.Therefore, to the medicine
Object preparation finds that a raw material is easy to get, simple process, yield are higher and economic and environment-friendly industrialized route is necessary.
Summary of the invention
Of the existing technology in order to overcome the problems, such as, the purpose of the present invention is to provide a kind of new sides for synthesizing flibanserin
Method.The method of the present invention using triethanolamine and mamino-trifluoromethyl benzene as starting material, is prepared for piperazine intermediate respectively；With adjacent benzene
Diamines and tetraethyl orthocarbonate are raw material, have prepared ethoxybenzoimidazole class intermediate；It then will be among piperazine obtained
Body and benzimidazole intermediate occur substitution reaction and hydrochloric acid deprotection and etc. obtain target product flibanserin.
The new method of synthesis flibanserin provided by the invention, the synthetic route of the method is as shown in following formula four:
The new method of above-mentioned synthesis flibanserin, described method includes following steps:
(1) equipped with magnetic stir bar single-necked flask in sequentially add in proportion o-phenylenediamine, tetraethyl orthocarbonate and
Acetic acid is stirred at room temperature and continues to stir 3h after mixing under the conditions of 70 DEG C, appropriate inorganic alkali solution is then added, continues to stir
1h is reacted, then is filtered while hot, drying after organic phase is washed with water, obtains 2- ethoxybenzoimidazole；
Wherein: the 2- ethoxybenzoimidazole structural formula is as shown in following formula five:
(2) chloroform and triethanolamine are put into respectively in the three-necked flask equipped with magnetic stir bar, after mixing, in room
Appropriate thionyl chloride is added dropwise under warm stirring condition, then heats to 70 DEG C of back flow reaction 3h, is cooled to vacuum after room temperature
Concentration, washing, obtains white product, i.e., three (2- chloroethyl) amine hydrochlorates；
Wherein: described three (2- chloroethyl) amine hydrochlorate structural formula is as shown in following formula six:
(3) three (2- chloroethenes made from step (2) are sequentially added in proportion in the single-necked flask equipped with magnetic stir bar
Base) amine hydrochlorate, mamino-trifluoromethyl benzene, potassium carbonate and appropriate n-butanol, 115~120 DEG C are warming up to, reaction 21 is stirred at reflux
~25h, is concentrated in vacuo after reaction, and raffinate is dissolved with methylene chloride, then twice with isometric water washing organic phase, anhydrous
Solvent is removed under reduced pressure after sodium sulphate is dry, obtains yellow green grease, recycles column chromatography for separation purification, obtains N- (3- trifluoro
Aminomethyl phenyl)-N '-(2- chloroethyl)-piperazine；
Wherein: the structural formula of N- (3- trifluoromethyl)-N '-(2- the chloroethyl)-piperazine is as shown in following formula seven:
(4) it is proportionally added into N- (3- trifluoromethylbenzene made from step (3) respectively in the flask equipped with magnetic stir bar
Base)-N '-(2- chloroethyl)-piperazine, 2- ethoxybenzoimidazole and appropriate NaOH solution, isopropanol, water made from step (1),
2h is reacted under the conditions of 75 DEG C after being uniformly mixed, is extracted with ethyl acetate after being cooled to room temperature, then use water respectively and is satisfied
With brine It organic phase, it is concentrated under reduced pressure after dry, obtains yellowish brown oil；Appropriate isopropanol, concentrated hydrochloric acid are added,
Continue to be stirred to react 2h under the conditions of 70 DEG C, it is cooling, white crystal is precipitated, filtration drying obtains flibanserin hydrochloride, crude；It will be thick
Product are dissolved in the mixed liquor of ethyl acetate and water, and sodium hydrate aqueous solution is added, and adjust pH value to alkalinity, stirring is isolated
Organic layer, then it is dry with anhydrous sodium sulfate, solvent is removed under reduced pressure, obtains white solid, finally uses ethyl alcohol recrystallization, crosses and is filtered dry
It is dry to get arrive target product flibanserin of the present invention.
Further, the molar ratio of above-mentioned technical proposal, step (1) tetraethyl orthocarbonate and o-phenylenediamine is
1.05:1.
Further, the molar ratio of above-mentioned technical proposal, step (1) acetic acid and o-phenylenediamine is (1~1.02): 1.
Further, above-mentioned technical proposal, step (1) inorganic base are any one of potassium hydroxide or potassium carbonate.
Further, the amount ratio of above-mentioned technical proposal, step (2) triethanolamine and chloroform is 1g:16mL.
Further, the volume ratio of above-mentioned technical proposal, step (2) chloroform and thionyl chloride is 10:1.
Further, above-mentioned technical proposal, (2- chloroethyl) amine hydrochlorate of step (3) described three and mamino-trifluoromethyl benzene
Molar ratio be (1.2~1.3): 1.
Further, the molar ratio of above-mentioned technical proposal, step (3) mamino-trifluoromethyl benzene and potassium carbonate is 1:1.
Further, the amount ratio of above-mentioned technical proposal, step (3) mamino-trifluoromethyl benzene and n-butanol is
1mmol:(3~5) mL.
Further, above-mentioned technical proposal, N- described in step (4) (3- trifluoromethyl)-N '-(2- chloroethyl)-
The mass ratio of piperazine and 2- ethoxybenzoimidazole is 1:0.22.
Compared with prior art, the new method of synthesis flibanserin of the present invention has the following beneficial effects:
(1) the method for the present invention reaction step is few, and by-product is few, and intermediate product and target product yield are higher, the present invention
For the yield of intermediate product 2- ethoxybenzoimidazole up to 94.2%, target product yield overcomes existing skill up to 56.2%
The synthesis step of the substance is cumbersome in art, technique is tediously long, active reaction point is more, so that side reaction is difficult to control, target product is received
The lower defect of rate；
(2) the method for the present invention aftertreatment technology is simple, easy to operate, it is only necessary to which the method by sub-cooled and recrystallization is
Separable to obtain target product, and isolated target product purity is high, purity is up to 99.6%；
(3) synthetic method craft of the present invention is simple, and the reaction time is short, without carrying out long-time reaction in an inert atmosphere,
Low energy consumption, and the present invention is low to consersion unit requirement, and raw material is cheap to be easy to get, and economic and environment-friendly, therefore, synthetic method of the present invention is very
It is suitble to industrialized production.
Detailed description of the invention
Fig. 1 is high performance liquid chromatography (HPLC) figure for the target product flibanserin that the embodiment of the present invention 1 is prepared；
Fig. 2 is the ESI-MS mass spectral analysis figure for the target product flibanserin that the embodiment of the present invention 1 is prepared；
Fig. 3 is nuclear magnetic resonance (HNMR) spectrogram for the target product flibanserin that the embodiment of the present invention 1 is prepared；
Fig. 4 (a), (b) are respectively intermediate N (3- trifluoromethyl)-N '-that the embodiment of the present invention 1 is prepared
The ESI-MS mass spectral analysis spectrum of (2- chloroethyl)-piperazine, high performance liquid chromatography (HPLC) figure；
Fig. 5 is the high performance liquid chromatography for the intermediate 2- ethoxybenzoimidazole that the embodiment of the present invention 1 is prepared
(HPLC) figure；
Fig. 6 is the ESI-MS mass spectral analysis figure for the intermediate 2- ethoxybenzoimidazole that the embodiment of the present invention 1 is prepared；
Fig. 7 is nuclear magnetic resonance (HNMR) spectrum for the intermediate 2- ethoxybenzoimidazole that the embodiment of the present invention 1 is prepared
Figure.
Specific embodiment
It elaborates below to case study on implementation of the invention.The implementation case under the premise of technical solution of the present invention into
Row is implemented, and the detailed implementation method and specific operation process are given, but protection scope of the present invention is not limited to following realities
Apply case.
The information for including according to the application, to those skilled in the art can be easily to essence of the invention
Really description carries out various changes, without departing from spirit and scope of the appended claims.It should be understood that the scope of the present invention is not
Process, property defined by being confined to or component, because these embodiments and other descriptions are just for the sake of schematic
Illustrate certain aspects of the present disclosure.In fact, this field or those skilled in the relevant art obviously can be to embodiment party of the present invention
The various changes that formula is made all cover within the scope of the appended claims.
It is not intended to limit the scope of the invention for a better understanding of the present invention, expression dosage used in this application,
All numbers of percentage and other numerical value, are understood to be modified with word " about " in all cases.Therefore,
Unless stated otherwise, otherwise digital parameters listed in specification and appended book are all approximations, may
It can be changed according to the difference for the desirable properties for attempting to obtain.Each digital parameters at least should be considered as according to being reported
Effective digital and obtained by the conventional method of rounding up.
In following each embodiments, the test condition of intermediate product and target product purity is equal are as follows: Detection wavelength: 254nm, stream
Dynamic is mutually 25% water and 75% acetonitrile, flow velocity 1mL/min).
Embodiment 1
A kind of new synthetic method of flibanserin of the present embodiment, includes the following steps:
(1) synthesis of intermediate 2- ethoxybenzoimidazole
O-phenylenediamine (16.13g, 0.149mol) is added in the 100mL single-necked flask equipped with magnetic agitation, orthocarbonic acid four
Ethyl ester (30.02g, 0.156mol), acetic acid (9.14g, 0.152mol).After mixing in 70 DEG C of stirring 3h.It is cooled to room temperature,
It is added potassium hydroxide solution (5%, w/w, 125mL), continues to stir 1h.Filtering, it is dry after being washed with water, obtain intermediate 2- second
Oxygroup benzimidazole 21.99g, yield 91.0%, purity 98.8%.
The HPLC testing result of the intermediate 2- ethoxybenzoimidazole is as shown in figure 5, as seen from Figure 5, retain
Time 3.3min, purity 98.8%.
It can be seen from Fig. 6 and Fig. 7 the MS of the target product of the above-mentioned synthesis of the present embodiment and1H NMR test result is such as
Under: 7.38-7.41 (m, Ar-H, 2H), 7.14-7.16 (m, Ar-H, 2H), 4.59-4.64 (q ,-CH2,2H),1.44-1.57
(m,-CH3,3H)。ESI-MS(m/z):163[M+H]+。
(2) synthesis of intermediate three (2- chloroethyl) amine hydrochlorate
Be added in the 250mL three-necked flask equipped with magnetic agitation chloroform (200mL) and triethanolamine (12.5g,
83.8mmol), thionyl chloride (20mL) is added dropwise under stirring at room temperature.It is warming up to 70 DEG C of back flow reactions 3 hours.It is cooled to room
It is concentrated in vacuo after temperature, obtains white solid, washed three times with methylene chloride, obtain white solid i.e. intermediate three (2- chloroethyl)
Amine hydrochlorate 19.87g, yield 98.4%.
(3) synthesis of intermediate N (3- trifluoromethyl)-N '-(2- chloroethyl)-piperazine
Equipped with magnetic agitation 50mL single-necked flask in be added three (2- chloroethyl) amine hydrochlorates (0.3108g,
1.3mmol), mamino-trifluoromethyl benzene (0.1685g, 1.0mmol), potassium carbonate (0.139g, 1.0mmol), n-butanol (5mL).
115~120 DEG C are heated to, reaction is stirred at reflux for 24 hours, is concentrated in vacuo after reaction, raffinate is dissolved with methylene chloride.With equal bodies
Ponding washs organic phase twice, and solvent is removed under reduced pressure after anhydrous sodium sulfate is dry, obtains yellow green grease.Recycle column chromatography
Separating-purifying (petrol ether/ethyl acetate, 8:1) obtains N- (3- trifluoromethyl)-N '-(2- chloroethyl)-piperazine
0.157g, yield 51.3%, purity 98.2%, ESI-MS (m/z): 293 [M+H]+, as shown in Figure 4.
(4) synthesis of target product flibanserin
N- (3- trifluoromethyl)-N '-(2- made from step (3) is added in the 50mL flask equipped with magnetic agitation
Chloroethyl)-piperazine (0.1g, 0.34mmol), 2- ethoxybenzoimidazole (0.022g, 0.14mmol) made from step (1),
45% (w/w) NaOH solution (0.125g), isopropanol 0.5mL, water 4.4mL, after mixing 75 DEG C of reaction 2h.It is cooled to room
Temperature is extracted with ethyl acetate, and washs organic phase with water 0.4mL and saturated salt solution 0.3mL.It is concentrated under reduced pressure after drying, obtains Huang
Brown oil.
Isopropanol 3mL, concentrated hydrochloric acid 0.68mL are added into yellowish brown oil obtained above, is mixed at 70 DEG C
2h has white crystal precipitation in 4 DEG C of coolings, and filtration drying obtains crude product flibanserin hydrochloride.By crude product be dissolved in ethyl acetate with
It in the mixed liquor of water, is added sodium hydrate aqueous solution (5%, w/w), adjusts pH value to alkalinity, stirring 30 minutes is isolated to have
Machine layer, then it is dry with anhydrous sodium sulfate, solvent is removed under reduced pressure, obtains white solid.Ethyl alcohol recrystallization is finally used, filtration drying obtains
To object flibanserin 29.6mg, yield 55.8%, purity 99.4%.
High performance liquid chromatography (HPLC), ESI-MS mass spectrum is respectively adopted in the target product that above-described embodiment 1 is prepared
Analysis, nuclear magnetic resonance (400MHz,1H NMR) etc. means characterized, test result is respectively referring to attached drawing 1, Fig. 2, Fig. 3.
The HPLC testing result of the product of the above-mentioned synthesis of the present embodiment is as shown in Figure 1, as seen from Figure 1, target product
Purity is 99.2%.
The target product of the above-mentioned synthesis of the present embodiment it can be seen from Fig. 2 and Fig. 31H NMR and MS test result are such as
Under:
1H NMR(400MHz,CDCl3),11.02(s,NH,1H),7.31-7.49(t,Ar-H,1H),7.29-7.31(d,
Ar-H,3H),7.15-7.16(d,Ar-H,1H),7.03-7.06(m,Ar-H,3H),4.28(s,N-CH2,2H),4.00-4.03
(d,N-CH2,2H),3.78(s,N-CH2,2H),3.52(s,-CH2,2H),3.24(m,N-CH2,2H),3.14(m,N-CH2,
2H).ESI-MS(m/z):391[M+1]。
In summary liquid chromatogram, nuclear magnetic resonance, mass spectrometric measurement result, it may be determined that targeted made from the present embodiment
Conjunction object is flibanserin, i.e. 3- [2- [4- (4- trifluoromethyl) piperazine -1- base] ethyl] -1H- 2-ketone benzimidaozole.
Embodiment 2
A kind of new synthetic method of flibanserin of this example, includes the following steps:
(1) synthesis of intermediate 2- ethoxybenzoimidazole
O-phenylenediamine (0.8kg, 7.40mol) is added in the 5000mL single-necked flask equipped with magnetic agitation, orthocarbonic acid four
Ethyl ester (1.49kg, 7.76mol), acetic acid (444g, 7.40mol).After mixing in 70 DEG C of stirring 3h.It is cooled to room temperature, adds
Enter potassium hydroxide solution (5%, 6.4L), continues to stir 1h.Filtering, it is dry after being washed with water, obtain 2- ethoxybenzoimidazole
1.13kg, yield 94.2%, purity 96.3%.
(2) synthesis of intermediate three (2- chloroethyl) amine hydrochlorate
Be added in the 250mL three-necked flask equipped with magnetic agitation chloroform (200mL) and triethanolamine (12.5g,
83.8mmol), thionyl chloride (20mL) is added dropwise under stirring at room temperature.It is warming up to 70 DEG C of back flow reactions 3 hours.It is cooled to room
It is concentrated in vacuo after temperature, obtains white solid, washed three times with methylene chloride, obtain white solid i.e. intermediate three (2- chloroethyl)
Amine hydrochlorate 19.87g, yield 98.4%.
(3) synthesis of intermediate N (3- trifluoromethyl)-N '-(2- chloroethyl)-piperazine
Equipped with magnetic agitation 50mL single-necked flask in be added three (2- chloroethyl) amine hydrochlorates (2.89g,
12.0mmol), mamino-trifluoromethyl benzene (1.61g, 10.0mmol), potassium carbonate (1.38g, 10.0mmol), n-butanol (30mL).
115~120 DEG C are heated to, reaction 25h is stirred at reflux, is concentrated in vacuo after reaction, raffinate is dissolved with methylene chloride.With equal bodies
Ponding washs organic phase twice, and solvent is removed under reduced pressure after anhydrous sodium sulfate is dry, obtains yellow green grease.Column chromatography for separation mentions
Pure (petrol ether/ethyl acetate, 8:1) obtains N- (3- trifluoromethyl)-N '-(2- chloroethyl)-piperazine 0.158g, yield
51.7%.Purity 98.6%.
(4) synthesis of target product flibanserin
N- (3- trifluoromethyl)-N '-(2- made from step (3) is added in the 50mL flask equipped with magnetic agitation
Chloroethyl)-piperazine (0.1g, 0.34mmol), 2- ethoxybenzoimidazole (0.022g, 0.14mmol) made from step (1),
45% (w/w) NaOH solution (0.125g), isopropanol 0.5mL, water 4mL, after mixing 75 DEG C of reaction 2h.It is cooled to room temperature,
It is extracted with ethyl acetate, washs organic phase with water 0.4mL and saturated salt solution 0.3mL.It is concentrated under reduced pressure after drying, obtains yellowish-brown
Grease.
Isopropanol 3mL, concentrated hydrochloric acid 0.70mL are added into yellowish brown oil obtained above, is mixed at 70 DEG C
2h has white crystal precipitation in 4 DEG C of coolings, and filtration drying obtains crude product flibanserin hydrochloride.By crude product be dissolved in ethyl acetate with
It in the mixed liquor of water, is added sodium hydrate aqueous solution (5%, w/w), adjusts pH value to alkalinity, stirring 30 minutes is isolated to have
Machine layer, then it is dry with anhydrous sodium sulfate, solvent is removed under reduced pressure, obtains white solid.Ethyl alcohol recrystallization is finally used, filtration drying obtains
To object flibanserin 29.8mg, yield 56.2%, purity 99.4%.
Embodiment 3
A kind of new synthetic method of flibanserin of the present embodiment, includes the following steps:
(1) synthesis of intermediate 2- ethoxybenzoimidazole
O-phenylenediamine (1.60g, 14.8mmol) is added in the 5000mL single-necked flask equipped with magnetic agitation, orthocarbonic acid four
Ethyl ester (3.00g, 15.6mmol), acetic acid (0.90g, 15.0mmol).After mixing in 70 DEG C of stirring 3h.It is cooled to room temperature,
It is added potassium hydroxide solution (5%, w/w, 12.5mL), continues to stir 1h.Filtering, it is dry after being washed with water, obtain 2- ethyoxyl
Benzimidazole 2.22kg, yield 92.5%, purity 97.5%.
(2) synthesis of intermediate three (2- chloroethyl) amine hydrochlorate
Be added in the 250mL three-necked flask equipped with magnetic agitation chloroform (200mL) and triethanolamine (12.5g,
83.8mmol), thionyl chloride (20mL) is added dropwise under stirring at room temperature.It is warming up to 70 DEG C of back flow reactions 3 hours.It is cooled to room
It is concentrated in vacuo after temperature, obtains white solid, washed three times with methylene chloride, obtain white solid i.e. intermediate three (2- chloroethyl)
Amine hydrochlorate 19.87g, yield 98.4%.
(3) synthesis of intermediate N (3- trifluoromethyl)-N '-(2- chloroethyl)-piperazine
Equipped with magnetic agitation 50mL single-necked flask in be added three (2- chloroethyl) amine hydrochlorates (2.89g,
12.0mmol), mamino-trifluoromethyl benzene (1.61g, 10.0mmol), potassium carbonate (1.38g, 10.0mmol), n-butanol 30mL.Add
Heat is stirred at reflux reaction 23h, is concentrated in vacuo after reaction, raffinate is dissolved with methylene chloride to 115~120 DEG C.With isometric
Water washing organic phase twice, is removed under reduced pressure solvent after anhydrous sodium sulfate is dry, obtains yellow green grease.Column chromatography for separation purification
(petrol ether/ethyl acetate, 8:1) obtains N- (3- trifluoromethyl)-N '-(2- chloroethyl)-piperazine 0.156g, yield
51.1%.Purity 98.1%.
(4) synthesis of target product flibanserin
N- (3- trifluoromethyl)-N '-(2- made from step (3) is added in the 50mL flask equipped with magnetic agitation
Chloroethyl)-piperazine (0.1g, 0.34mmol), 2- ethoxybenzoimidazole (0.022g, 0.14mmol) made from step (1),
45% (w/w) NaOH solution (0.125g), isopropanol 0.5mL, water 4mL, after mixing 75 DEG C of reaction 2h.It is cooled to room temperature,
It is extracted with ethyl acetate, washs organic phase with water 0.4mL and saturated salt solution 0.3mL.It is concentrated under reduced pressure after drying, obtains yellowish-brown
Grease.
Isopropanol 3mL, concentrated hydrochloric acid 0.8mL are added into yellowish brown oil obtained above, in 70 DEG C of mixing 2h,
In 4 DEG C of coolings, there is white crystal precipitation, filtration drying obtains crude product flibanserin hydrochloride.Crude product is dissolved in ethyl acetate and water
Mixed liquor in, be added sodium hydrate aqueous solution (5%, w/w), adjust pH value to alkalinity, stir 30 minutes, it is isolated organic
Layer, then it is dry with anhydrous sodium sulfate, solvent is removed under reduced pressure, obtains white solid.Ethyl alcohol recrystallization is finally used, filtration drying obtains
Object flibanserin 29.4mg, yield 55.5%, purity 99.5%.
Embodiment 4
A kind of new synthetic method of flibanserin of this example, includes the following steps:
(1) synthesis of intermediate 2- ethoxybenzoimidazole
O-phenylenediamine (16.13g, 0.149mol) is added in the 100mL single-necked flask equipped with magnetic agitation, orthocarbonic acid four
Ethyl ester (30.02g, 0.156mol), acetic acid (9.14g, 0.152mol).After mixing in 70 DEG C of stirring 3h.It is cooled to room temperature,
It is added potassium hydroxide solution (5%, w/w, 125mL), continues to stir 1h.Filtering, it is dry after being washed with water, obtain 2- ethoxybenzene
And imidazoles 21.99g, yield 91.0%, purity 98.8%.
(2) synthesis of intermediate three (2- chloroethyl) amine hydrochlorate
Be added in the 250mL three-necked flask equipped with magnetic agitation chloroform (200mL) and triethanolamine (12.5g,
83.8mmol), thionyl chloride (20mL) is added dropwise under stirring at room temperature.It is warming up to 70 DEG C of back flow reactions 3 hours.It is cooled to room
It is concentrated in vacuo after temperature, obtains white solid, washed three times with methylene chloride, obtain white solid i.e. intermediate three (2- chloroethyl)
Amine hydrochlorate 19.87g, yield 98.4%.
(3) synthesis of intermediate N (3- trifluoromethyl)-N '-(2- chloroethyl)-piperazine
Equipped with magnetic agitation 50mL single-necked flask in be added three (2- chloroethyl) amine hydrochlorates (2.89g,
12.0mmol), mamino-trifluoromethyl benzene (1.61g, 10.0mmol), potassium carbonate (1.38g, 10.0mmol), n-butanol 30mL.Add
Heat is stirred at reflux reaction 22h, is concentrated in vacuo after reaction, raffinate is dissolved with methylene chloride to 115~120 DEG C.With isometric
Water washing organic phase twice, is removed under reduced pressure solvent after anhydrous sodium sulfate is dry, obtains yellow green grease.Column chromatography for separation purification
(petrol ether/ethyl acetate, 8:1) obtains N- (3- trifluoromethyl)-N '-(2- chloroethyl)-piperazine 0.162g, yield
52.8%.Purity 98.4%.
(4) synthesis of target product flibanserin
N- (3- trifluoromethyl)-N '-(2- made from step (3) is added in the 50mL flask equipped with magnetic agitation
Chloroethyl)-piperazine (0.1g, 0.34mmol), 2- ethoxybenzoimidazole (0.022g, 0.14mmol) made from step (1),
45% (w/w) NaOH solution (0.125g), isopropanol 0.5mL, water 4mL, after mixing 75 DEG C of reaction 2h.It is cooled to room temperature,
It is extracted with ethyl acetate, washs organic phase with water 0.4mL and saturated salt solution 0.3mL.It is concentrated under reduced pressure after drying, obtains yellowish-brown
Grease.
Isopropanol 3mL, concentrated hydrochloric acid 0.68mL are added into yellowish brown oil obtained above, is mixed at 70 DEG C
2h has white crystal precipitation in 4 DEG C of coolings, and filtration drying obtains crude product flibanserin hydrochloride.By crude product be dissolved in ethyl acetate with
It in the mixed liquor of water, is added sodium hydrate aqueous solution (5%, w/w), adjusts pH value to alkalinity, stirring 30 minutes is isolated to have
Machine layer, then it is dry with anhydrous sodium sulfate, solvent is removed under reduced pressure, obtains white solid.Ethyl alcohol recrystallization is finally used, filtration drying obtains
To object flibanserin 29.8mg, yield 56.2%, purity 99.6%.
Embodiment 5
A kind of new synthetic method of flibanserin of this example of the present embodiment, includes the following steps:
(1) synthesis of intermediate 2- ethoxybenzoimidazole
O-phenylenediamine (0.8kg, 7.40mol) is added in the 5000mL single-necked flask equipped with magnetic agitation, orthocarbonic acid four
Ethyl ester (1.49kg, 7.76mol), acetic acid (444g, 7.40mol).After mixing in 70 DEG C of stirring 3h.It is cooled to room temperature, adds
Enter potassium hydroxide solution (5%, w/w, 6.4L), continues to stir 1h.Filtering, it is dry after being washed with water, obtain 2- ethyoxyl benzo
Imidazoles 1.13kg, yield 94.2%, purity 96.3%.
(2) synthesis of intermediate three (2- chloroethyl) amine hydrochlorate
Be added in the 250mL three-necked flask equipped with magnetic agitation chloroform (200mL) and triethanolamine (12.5g,
83.8mmol), thionyl chloride (20mL) is added dropwise under stirring at room temperature.It is warming up to 70 DEG C of back flow reactions 3 hours.It is cooled to room
It is concentrated in vacuo after temperature, obtains white solid, washed three times with methylene chloride, obtain white solid i.e. intermediate three (2- chloroethyl)
Amine hydrochlorate 19.87g, yield 98.4%.
(3) synthesis of intermediate N (3- trifluoromethyl)-N '-(2- chloroethyl)-piperazine
Equipped with magnetic agitation 50mL single-necked flask in be added three (2- chloroethyl) amine hydrochlorates (2.89g,
12.0mmol), mamino-trifluoromethyl benzene (1.61g, 10.0mmol), potassium carbonate (1.38g, 10.0mmol), n-butanol 30mL.Add
Heat is stirred at reflux reaction 21h, is concentrated in vacuo after reaction, raffinate is dissolved with methylene chloride to 115~120 DEG C.With isometric
Water washing organic phase twice, is removed under reduced pressure solvent after anhydrous sodium sulfate is dry, obtains yellow green grease.Column chromatography for separation purification
(petrol ether/ethyl acetate, 8:1) obtains N- (3- trifluoromethyl)-N '-(2- chloroethyl)-piperazine 0.154g, yield
50.2%, purity 98.2%.
(4) synthesis of object flibanserin
N- (3- trifluoromethyl)-N '-(2- made from step (3) is added in the 50mL flask equipped with magnetic agitation
Chloroethyl)-piperazine (0.1g, 0.34mmol), 2- ethoxybenzoimidazole (0.022g, 0.14mmol) made from step (1),
45% (w/w) NaOH solution (0.125g), isopropanol 0.5mL, water 4mL, after mixing 75 DEG C of reaction 2h.It is cooled to room temperature,
It is extracted with ethyl acetate, washs organic phase with water 0.4mL and saturated salt solution 0.3mL.It is concentrated under reduced pressure after drying, obtains yellowish-brown
Grease.
Isopropanol 3mL, concentrated hydrochloric acid 0.7mL are added into yellowish brown oil obtained above, in 70 DEG C of mixing 2h,
In 4 DEG C of coolings, there is white crystal precipitation, filtration drying obtains crude product flibanserin hydrochloride.Crude product is dissolved in ethyl acetate and water
Mixed liquor in, be added sodium hydrate aqueous solution (5%, w/w), adjust pH value to alkalinity, stir 30 minutes, it is isolated organic
Layer, then it is dry with anhydrous sodium sulfate, solvent is removed under reduced pressure, obtains white solid.Ethyl alcohol recrystallization is finally used, filtration drying obtains
Object flibanserin 29.2mg, yield 55.1%, purity 99.2%.
The intermediate product of above-described embodiment 2~5 and the test method of target product and test result and embodiment 1 basic one
It causes, it may be determined that target compound made from embodiment 2~5 is flibanserin, i.e. 3- [2- [4- (4- trifluoromethyl) piperazine
Piperazine -1- base] ethyl] -1H- 2-ketone benzimidaozole.
Claims (10)
1. a kind of new method for synthesizing flibanserin, it is characterised in that: described method includes following steps:
(1) o-phenylenediamine, tetraethyl orthocarbonate and acetic acid are sequentially added in proportion in the single-necked flask equipped with magnetic stir bar,
It is stirred at room temperature and continues to stir 3h after mixing under the conditions of 70 DEG C, appropriate inorganic alkali solution is then added, continues to be stirred to react
1h, then filter while hot, drying after organic phase is washed with water, obtains 2- ethoxybenzoimidazole；
Wherein: the 2- ethoxybenzoimidazole structural formula is as shown in following formula five:
(2) chloroform and triethanolamine are put into respectively in the three-necked flask equipped with magnetic stir bar, after mixing, stir in room temperature
Appropriate thionyl chloride is added dropwise under the conditions of mixing, then heats to 70 DEG C of back flow reaction 3h, is concentrated in vacuo after being cooled to room temperature,
Washing, obtains white product, i.e., three (2- chloroethyl) amine hydrochlorates；
Wherein: described three (2- chloroethyl) amine hydrochlorate structural formula is as shown in following formula six:
(3) (2- chloroethyl) amine three made from step (2) is sequentially added in proportion in the single-necked flask equipped with magnetic stir bar
Hydrochloride, mamino-trifluoromethyl benzene, potassium carbonate and appropriate n-butanol, are warming up to 115~120 DEG C, be stirred at reflux reaction 21~
25h is concentrated in vacuo after reaction, and raffinate is dissolved with methylene chloride, then twice with isometric water washing organic phase, anhydrous sulphur
Solvent is removed under reduced pressure after sour sodium is dry, obtains yellow green grease, recycles column chromatography for separation purification, obtains N- (3- fluoroform
Base phenyl)-N '-(2- chloroethyl)-piperazine；
Wherein: the structural formula of N- (3- trifluoromethyl)-N '-(2- the chloroethyl)-piperazine is as shown in following formula seven:
(4) it is proportionally added into N- made from step (3) (3- trifluoromethyl)-respectively in the flask equipped with magnetic stir bar
2- ethoxybenzoimidazole and appropriate NaOH solution, isopropanol, water made from N '-(2- chloroethyl)-piperazine, step (1), stirring
2h is reacted under the conditions of 75 DEG C after mixing, is extracted with ethyl acetate after being cooled to room temperature, then respectively with water and saturation food
Salt water washing organic phase is concentrated under reduced pressure after dry, obtains yellowish brown oil；Appropriate isopropanol, concentrated hydrochloric acid are added, at 70 DEG C
Under the conditions of continue to be stirred to react 2h, it is cooling, white crystal is precipitated, filtration drying obtains flibanserin hydrochloride, crude；Crude product is molten
In the mixed liquor of ethyl acetate and water, sodium hydrate aqueous solution is added, adjusts pH value to alkalinity, stirring is isolated organic
Layer, then dry with anhydrous sodium sulfate, is removed under reduced pressure solvent, obtains white solid, finally uses ethyl alcohol recrystallization, filtration drying, i.e.,
Obtain target product flibanserin of the present invention.
2. the new method of synthesis flibanserin according to claim 1, it is characterised in that: step (1) orthocarbonic acid four
The molar ratio of ethyl ester and o-phenylenediamine is 1.05:1.
3. the new method of synthesis flibanserin according to claim 1, it is characterised in that: step (1) acetic acid and neighbour
The molar ratio of phenylenediamine is 1~1.02:1.
4. the new method of synthesis flibanserin according to claim 1, it is characterised in that: step (1) described inorganic base is
Any one of potassium hydroxide or potassium carbonate.
5. the new method of synthesis flibanserin according to claim 1, it is characterised in that: step (2) described triethanolamine
Amount ratio with chloroform is 1g:16mL.
6. the new method of synthesis flibanserin according to claim 1, it is characterised in that: step (2) chloroform and chlorine
The volume ratio for changing sulfoxide is 10:1.
7. the new method of synthesis flibanserin according to claim 1, it is characterised in that: described three (2- chloroethene of step (3)
Base) molar ratio of amine hydrochlorate and mamino-trifluoromethyl benzene is 1.2~1.3:1.
8. the new method of synthesis flibanserin according to claim 1, it is characterised in that: amino three between step (3) is described
The molar ratio of toluene fluoride and potassium carbonate is 1:1.
9. the new method of synthesis flibanserin according to claim 1, it is characterised in that: amino three between step (3) is described
The amount ratio of toluene fluoride and n-butanol is 1mmol:3~5mL.
10. the new method of synthesis flibanserin according to claim 1, it is characterised in that: N- (3- described in step (4)
Trifluoromethyl) mass ratio of-N '-(2- chloroethyl)-piperazine and 2- ethoxybenzoimidazole is 1:0.22.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113402467A (en) * | 2021-06-18 | 2021-09-17 | 山东汇海医药化工有限公司 | Synthetic method of flibanserin |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070032655A1 (en) * | 2001-08-02 | 2007-02-08 | Bidachem Spa | Stable polymorph of flibanserin |
| WO2010128516A2 (en) * | 2009-05-04 | 2010-11-11 | Symed Labs Limited | Process for the preparation of flibanserin involving novel intermediates |
| CN104926734A (en) * | 2015-07-07 | 2015-09-23 | 苏州立新制药有限公司 | Preparation method of flibanserin |
| CN106632066A (en) * | 2015-11-02 | 2017-05-10 | 苏州旺山旺水生物医药有限公司 | Benzimidazole compound and preparation method and application thereof |
| CN107235913A (en) * | 2016-03-29 | 2017-10-10 | 苏州科伦药物研究有限公司 | The method of commercial scale high efficiency manufacture high-quality flibanserin |
-
2018
- 2018-10-29 CN CN201811267749.7A patent/CN109232434A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070032655A1 (en) * | 2001-08-02 | 2007-02-08 | Bidachem Spa | Stable polymorph of flibanserin |
| WO2010128516A2 (en) * | 2009-05-04 | 2010-11-11 | Symed Labs Limited | Process for the preparation of flibanserin involving novel intermediates |
| CN104926734A (en) * | 2015-07-07 | 2015-09-23 | 苏州立新制药有限公司 | Preparation method of flibanserin |
| CN106632066A (en) * | 2015-11-02 | 2017-05-10 | 苏州旺山旺水生物医药有限公司 | Benzimidazole compound and preparation method and application thereof |
| CN107235913A (en) * | 2016-03-29 | 2017-10-10 | 苏州科伦药物研究有限公司 | The method of commercial scale high efficiency manufacture high-quality flibanserin |
Non-Patent Citations (2)
| Title |
|---|
| FEIPU YANG ET AL.: "A Facile Route of Synthesis for Making Flibanserin", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 * |
| JIANBING LIU ET AL.: "Branch-PCR Constructed Stable shRNA Transcription Nanoparticles Have Long-Lasting RNAi Effect", 《CHEMBIOCHEM》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113402467A (en) * | 2021-06-18 | 2021-09-17 | 山东汇海医药化工有限公司 | Synthetic method of flibanserin |
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