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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- CN104140417B CN104140417B CN201410255985.2A CN201410255985A CN104140417B CN 104140417 B CN104140417 B CN 104140417B CN 201410255985 A CN201410255985 A CN 201410255985A CN 104140417 B CN104140417 B CN 104140417B
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- 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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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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