CN104140417B - The synthetic method of the compound in advance of the intermediate of synthesis GS5885 - Google Patents
The synthetic method of the compound in advance of the intermediate of synthesis GS5885 Download PDFInfo
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 26
- 238000010189 synthetic method Methods 0.000 title claims abstract description 16
- 230000015572 biosynthetic process Effects 0.000 title abstract description 6
- 238000003786 synthesis reaction Methods 0.000 title abstract description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims abstract description 12
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 claims abstract description 8
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 8
- 125000000879 imine group Chemical group 0.000 claims abstract description 6
- 238000007171 acid catalysis Methods 0.000 claims abstract description 3
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 claims abstract description 3
- 150000001556 benzimidazoles Chemical class 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical group [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 claims description 3
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 2
- 229910015900 BF3 Inorganic materials 0.000 claims description 2
- 239000002841 Lewis acid Substances 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 150000007517 lewis acids Chemical class 0.000 claims description 2
- 239000002808 molecular sieve Substances 0.000 claims description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 2
- 235000011152 sodium sulphate Nutrition 0.000 claims description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 239000003814 drug Substances 0.000 description 7
- 101800001014 Non-structural protein 5A Proteins 0.000 description 6
- 108010047761 Interferon-alpha Proteins 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 238000000034 method Methods 0.000 description 3
- PIAIRSYMCIVYSX-KMWAZVGDSA-N methyl n-[(2s)-1-[(5s)-5-[5-[9,9-difluoro-7-[2-[(1s,2s,4r)-3-[(2s)-2-(methoxycarbonylamino)-3-methylbutanoyl]-3-azabicyclo[2.2.1]heptan-2-yl]-3h-benzimidazol-5-yl]fluoren-2-yl]-1h-imidazol-2-yl]-4-azaspiro[2.4]heptan-4-yl]-3-methyl-1-oxobutan-2-yl]carbama Chemical compound C([C@H](N1C(=O)[C@@H](NC(=O)OC)C(C)C)C2=NC=C(N2)C2=CC=C3C4=CC=C(C=C4C(F)(F)C3=C2)C2=CC=C3N=C(NC3=C2)[C@@H]2[C@H]3CC[C@H](C3)N2C(=O)[C@H](C(C)C)NC(=O)OC)CC21CC2 PIAIRSYMCIVYSX-KMWAZVGDSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical group C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 208000005176 Hepatitis C Diseases 0.000 description 2
- 102000004890 Interleukin-8 Human genes 0.000 description 2
- 108090001007 Interleukin-8 Proteins 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000002155 anti-virotic effect Effects 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 229940079322 interferon Drugs 0.000 description 2
- 229940096397 interleukin-8 Drugs 0.000 description 2
- XKTZWUACRZHVAN-VADRZIEHSA-N interleukin-8 Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](NC(C)=O)CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCSC)C(=O)N1[C@H](CCC1)C(=O)N1[C@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC=1C=CC(O)=CC=1)C(=O)N[C@H](CO)C(=O)N1[C@H](CCC1)C(N)=O)C1=CC=CC=C1 XKTZWUACRZHVAN-VADRZIEHSA-N 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- -1 polyoxyethylene Polymers 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 229960000329 ribavirin Drugs 0.000 description 2
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 1
- 201000010000 Agranulocytosis Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 206010018687 Granulocytopenia Diseases 0.000 description 1
- 241000711549 Hepacivirus C Species 0.000 description 1
- 206010022004 Influenza like illness Diseases 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 101710188663 Non-structural protein 5a Proteins 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- FKRSSPOQAMALKA-CUPIEXAXSA-N daclatasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C1=NC(C=2C=CC(=CC=2)C=2C=CC(=CC=2)C=2N=C(NC=2)[C@H]2N(CCC2)C(=O)[C@@H](NC(=O)OC)C(C)C)=CN1 FKRSSPOQAMALKA-CUPIEXAXSA-N 0.000 description 1
- 229960005449 daclatasvir Drugs 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 208000024732 dysthymic disease Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000010710 hepatitis C virus infection Diseases 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000003448 neutrophilic effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 108010092853 peginterferon alfa-2a Proteins 0.000 description 1
- 108010092851 peginterferon alfa-2b Proteins 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- JTZZSQYMACOLNN-VDWJNHBNSA-N simeprevir Chemical compound O=C([C@@]12C[C@H]1\C=C/CCCCN(C)C(=O)[C@H]1[C@H](C(N2)=O)C[C@H](C1)OC=1C2=CC=C(C(=C2N=C(C=1)C=1SC=C(N=1)C(C)C)C)OC)NS(=O)(=O)C1CC1 JTZZSQYMACOLNN-VDWJNHBNSA-N 0.000 description 1
- 229960002091 simeprevir Drugs 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of synthetic method of synthesizing the compound in advance of the intermediate of GS5885, comprising step is: benzimidazoles formaldehyde and aminated compounds are generated the compound containing imine group through dewatering; By compound and the cyclopentadiene containing imine group under Louis acid catalysis, react the compound in advance generating the intermediate synthesizing GS5885 through azepine DA.By the way, the synthetic method of the compound in advance of the intermediate of synthesis GS5885 of the present invention, this synthetic route is short, easy to operate, starting raw material commercially all has sale, and raw material price is cheap, be applicable to suitability for industrialized production, have very important significance.
Description
Technical field
The present invention relates to medicinal chemistry art, particularly relate to a kind of synthetic method of synthesizing the compound in advance of the intermediate of GS5885.
Background technology
At present, whole world hepatitis C infection rate is 3%, estimates accordingly, and the whole world about has 200,000,000 people to infect hepatitis C virus (HVC), and annual new infections person is about 3,500,000 people.Treat the current main employing polyoxyethylene glycol alpha-interferon of this disease and ribavirin combination medication.2010, the sales volume of the peg-interferon α-2b of Merck just reached 6.57 hundred million dollars.And the PEG-IFN alpha-2a of Roche Holding Ag (Peg-IFN alpha-2b α-2a) has climbed 15.82 hundred million dollars especially at global marketing volume in 2011.But the therapy tolerance of polyoxyethylene glycol alpha-interferon and ribavirin combination medication is poor, in the patient infecting gene 1 C-type virus C, continued viral response rate is less than 50%, multiple side effect can be brought simultaneously, comprise influenza-like symptom, dysthymia disorders, neutrophilic granulocytopenia, thrombocytopenia and anaemia etc.Thus, clinically in the urgent need to more effective and can be well tolerable medicine.
Because the third liver is to the serious harm of human health and the huge market requirement, make the research and development of the third liver medicine be one of field of enlivening the most in the drug development for the treatment of communicable disease always.At present, target new role mechanism, s-generation molecule, combined treatment and the new vaccine of route of administration and the design of new anti-virus medicine, and the attention of some new drug candidates more and more attract investment person.
NS5A(nonstructuralprotein5A) be possible cause one of reason that current alpha-interferon therapy success ratio is low.Because NS5A can induce the expression of interleukin 8 (IL-8), thus HCV is made to produce suppression to the antivirus action of alpha-interferon.Meanwhile, the interferon-sensitive on NS5A albumen determines that site (interferonsensitivitydeterminingregion, ISDR) can by the protein kinase (PKR) with dependenc RNA in conjunction with the response of T suppression cell to alpha-interferon.Now confirmed that a lot of kinases take part in the Phosphorylation events of NS5A, and the phosphorylation level of NS5A HCV genomic copy with translation process in also play a part adjustment.At present, the research being antiviral target spot with NS5A has become the focus in HCV-Ab IgG field.
Daclatasvir is the NS5a inhibitor under Bristol-Myers Squibb Co., and I type third hepatopath be proved to be at present 2/3rds has good curative ratio.The compound medicine that the proteinase inhibitor simeprevir now just accepting to develop cooperatively with Bristol Myers Squibb/Johnson & Johnson/Medivir company forms is the research contrasted; The chief scientist Bischofberger of Gilid Science Co. represent lucky moral by with time of 2 years by the NS5a inhibitor GS5885 himself produced with grinding medicine GS7977 and carrying out the clinical experiment of Synergistic treatment.
According to the report that independent analysis company DatamonitorHealthcare issues, at following 9 years, hepatitis C market scale is estimated to increase by 230%, and reaches 15,500,000,000 dollars in 2022.Therefore, the synthesis exploitation carried out in advance for compound GS5885 has very important significance.The structure of compound GS5885 is:
.
Intermediate
ledipasvir(GS5885) important component part, and its in advance intermediate just can directly obtain this intermediate through hydrogenation.
Ledipasvir(GS5885) structure of intermediate is in advance:
, molecular formula is C
21h
21n
3, molecular weight is 315.41.
At present to Ledipasvir(GS5885) synthesis of this intermediate only has a following synthetic route report:
.
This synthetic route is longer, also needs by price more expensive coupling reagent when closing into benzoglyoxaline ring, from industrial angle, explores and more has the synthetic route of industrial value significant.
Summary of the invention
The technical problem that the present invention mainly solves is to provide a kind of synthetic method of synthesizing the compound in advance of the intermediate of GS5885, and the method cost is low, has industrial value.
For solving the problems of the technologies described above, the technical scheme that the present invention adopts is: provide a kind of synthetic method of synthesizing the compound in advance of the intermediate of GS5885, comprising step is: benzimidazoles formaldehyde and aminated compounds are generated the compound containing imine group by (1) through dewatering; (2) by the described compound containing imine group with cyclopentadiene under Louis acid catalysis, react the compound in advance generating the intermediate synthesizing GS5885 through azepine DA; Reaction equation is:
。
In a preferred embodiment of the present invention, in step (1), reaction solvent for use is one or more in methylene dichloride, tetrahydrofuran (THF), methyl alcohol, ethanol, toluene.
In a preferred embodiment of the present invention, in step (1), reaction solvent for use is methyl alcohol or ethanol.
In a preferred embodiment of the present invention, dewatering described in step (1) is for adding dehydrated reagent or with oily-water seperating equipment, described dehydrated reagent is anhydrous magnesium sulfate, anhydrous sodium sulphate or molecular sieve.
In a preferred embodiment of the present invention, in step (2), solvent for use is one or more in methylene dichloride, tetrahydrofuran (THF), methyl alcohol, ethanol, toluene.
In a preferred embodiment of the present invention, in step (2), solvent for use is methylene dichloride.
In a preferred embodiment of the present invention, Lewis acid described in step (2) is one or more in aluminum chloride, zinc chloride, titanium tetrachloride, boron trifluoride and title complex thereof, trimethylsilyl trifluoromethanesulfonate, camphorsulfonic acid, trifluoroacetic acid, methylsulfonic acid, trifluoromethanesulfonic acid.
The invention has the beneficial effects as follows: the synthetic method of the compound in advance of the intermediate of synthesis GS5885 of the present invention, this synthetic route is short, easy to operate, starting raw material commercially all has sale, raw material price is cheap, is applicable to suitability for industrialized production, has very important significance.
Embodiment
Be clearly and completely described to the technical scheme in the embodiment of the present invention below, obviously, described embodiment is only a part of embodiment of the present invention, instead of whole embodiments.Based on the embodiment in the present invention, those of ordinary skill in the art, not making other embodiments all obtained under creative work prerequisite, belong to the scope of protection of the invention.
There is provided a kind of synthetic method of synthesizing the compound in advance of the intermediate of GS5885, comprising step is:
(1) 2g anhydrous magnesium sulfate is joined in the 40mL methanol solution of 4.38g, 30mmoL benzoglyoxaline formaldehyde and 3.63g, 3.82mL, 30mmoL Alpha-Methyl benzylamine, be heated backflow after 3 hours, TLC point plate is monitored two reaction raw materials and is substantially disappeared, and filters and obtains white solid imines.
Reaction equation is:
.
1H-NMR(d-DMSO,400MHz)δ:8.55(s,1H),7.63-7.25(m,10H),4.77(q,J=6.4Hz,1H),1.56(d,J=6.4Hz,1H)。
(2) imines obtained is dissolved in 40mL anhydrous methylene chloride again, and be cooled to less than-50 DEG C, add 10.8mL, 60mmoL Trimethylsilyl trifluoromethanesulfonate of two equivalents, stir after 10 minutes, be slowly added dropwise to 3.7mL, 45mmoL cyclopentadiene of new distillation.After dropping terminates, continue to stir two hours at such a temperature, be then naturally warmed up to room temperature.After sodium bicarbonate aqueous solution washing, with anhydrous magnesium sulfate drying, steam the crude product obtained after desolventizing and detect through HPLC, its four isomer proportions are 1:7:1:1, wherein main component is desired structure, obtains 3.3g sterling compound through ordinary silicon is gel column chromatography eluting.
Reaction equation is:
.
MS:(ESI)m/z=316[M+H]
+；
1H-NMR(d-DMSO,400MHz)δ:11.79(brs,1H),7.33-7.26(m,4H),7.02-6.86(m,5H),6.63-6.61(m,1H),6.44-6.42(m,1H),4.37(s,1H),3.16(d,J=6.4Hz,1H),2.94(s,1H),2.86(s,1H),1.41(d,J=6.4Hz,1H)。
The foregoing is only embodiments of the invention; not thereby the scope of the claims of the present invention is limited; every utilize description of the present invention to do equivalent structure or equivalent flow process conversion; or be directly or indirectly used in other relevant technical field, be all in like manner included in scope of patent protection of the present invention.
Claims (7)
1. synthesize a synthetic method for the compound in advance of the intermediate of GS5885, it is characterized in that, comprising step is: benzimidazoles formaldehyde and aminated compounds are generated the compound containing imine group by (1) through dewatering; (2) by the described compound containing imine group with cyclopentadiene under Louis acid catalysis, react the compound in advance generating the intermediate synthesizing GS5885 through azepine DA; Reaction equation is:
。
2. synthetic method according to claim 1, is characterized in that, in step (1), reaction solvent for use is one or more in methylene dichloride, tetrahydrofuran (THF), methyl alcohol, ethanol, toluene.
3. synthetic method according to claim 2, is characterized in that, in step (1), reaction solvent for use is methyl alcohol or ethanol.
4. synthetic method according to claim 1, is characterized in that, dewatering described in step (1) is for adding dehydrated reagent or with oily-water seperating equipment, described dehydrated reagent is anhydrous magnesium sulfate, anhydrous sodium sulphate or molecular sieve.
5. synthetic method according to claim 1, is characterized in that, in step (2), solvent for use is one or more in methylene dichloride, tetrahydrofuran (THF), methyl alcohol, ethanol, toluene.
6. synthetic method according to claim 5, is characterized in that, in step (2), solvent for use is methylene dichloride.
7. synthetic method according to claim 1, it is characterized in that, Lewis acid described in step (2) is one or more in aluminum chloride, zinc chloride, titanium tetrachloride, boron trifluoride and title complex thereof, trimethylsilyl trifluoromethanesulfonate, camphorsulfonic acid, trifluoroacetic acid, methylsulfonic acid, trifluoromethanesulfonic acid.
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| CN201410255985.2A CN104140417B (en) | 2014-06-11 | 2014-06-11 | The synthetic method of the compound in advance of the intermediate of synthesis GS5885 |
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